JP2002293764A - Aminoethanol derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicine having an inhibitory activity against a cholesteryl ester-transferring protein and useful as a blood lipid-reducing agent, etc. SOLUTION: This aminoethanol derivative is a compound expressed by the formula (I) (wherein, Ar<1> is an aromatic ring which may have substituent(s) Ar<2> is an aromatic ring having substituent(s); OR'' is hydroxy which may be blocked; R is an acyl; R' is H or a hydrocarbon group which may have substituent(s)) or its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel aminoethanol derivative showing cholesteryl ester transfer protein inhibition and the like.

[0002]

2. Description of the Related Art Hypercholesterolemia, in particular, high serum low density lipoprotein (LDL) -cholesterol is caused by arteriosclerotic diseases (eg, myocardial infarction, angina pectoris, cerebral infarction, etc.).
Have been identified in numerous epidemiological studies. As a drug that lowers serum LDL-cholesterol, a drug that inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase has been used in the clinic, and has been used to reduce the incidence of coronary artery disease. It has been shown in large-scale clinical trials that it has a certain effect (N. Eng
l. J. Med. , 34, 498-511 (199).
9)), but the effect is not sufficiently satisfactory.
On the other hand, it is epidemiologically known that the concentration of high-density lipoprotein (HDL) -cholesterol in serum shows an inverse correlation with the incidence of coronary artery disease (N. Engl. J. Med., 3).
21, 1311-1316 (1989), Am. Hea
rt J.R. , 110, 1100-1107 (198
5)), Drugs that increase serum HDL-cholesterol are receiving attention as drugs for preventing and treating arteriosclerotic diseases. Cholesteryl ester transfer protein (CET
P) from HDL to LDL and very low density lipoprotein (VL)
DL) is a protein that catalyzes the transfer of cholesteryl ester to (DL) (J. Lipid Res., 34, 1255-).
1274 (1993)), a reverse transfer system of cholesterol,
That is, it is greatly involved in the transfer of cholesterol from peripheral tissues to the liver. The following three pathways are mainly known as reverse cholesterol transfer systems. (1) Free cholesterol accumulated in peripheral tissues is HDL
And converted to cholesteryl ester on HDL under the action of lecithin-cholesterol acyltransferase (LCAT). Cholesteryl ester on HDL is transferred by CETP to LDL or VLDL in exchange for triglyceride, and cholesterol is transferred to the liver via LDL receptor. (2) After HDL becomes HDL containing apoprotein E, LD
It is taken up by the liver via the L receptor. (3) Cholesteryl ester on HDL is directly taken into liver via HDL receptor. Since CETP is greatly involved in the reverse cholesterol transfer system, its activity in blood is considered to be related to the control of blood HDL-cholesterol concentration. For example, the following findings have been obtained regarding the relationship between CETP and blood HDL-cholesterol levels. CE in rabbits and hamsters
Inhibition of CETP activity by TP monoclonal antibody increases serum HDL-cholesterol concentration (J. Cli).
n. Invest. , 84, 129-137 (198
9), Atherosclerosis, 110, 10
1-109 (1994)). LDL-cholesterol levels are elevated in CETP-expressing transgenic mice and transgenic rats (JB
iol. Chem. , 266, 10796-10801
(1991), Nat. Med. , 5,1383-13
89 (1999)). In addition, epidemiological studies show that those who have reduced or lost CETP activity due to gene mutation
DL-cholesterol levels are increasing (Natur
e, 342, 448-451 (1989), Ather
osclerosis, 58, 175-186 (198
5)).

[0003] From the above findings, it is considered that the intensity of CETP activity is inversely correlated with HDL-cholesterol, which is an arteriosclerosis-inhibiting agent, and it is expected that inhibiting CETP activity will reduce the risk of developing coronary artery disease. Is done. In fact, CETP activity varies between animal species,
It is known that cholesterol-loaded animals induce arteriosclerosis in animals having high TP activity (such as rabbits), whereas arteriosclerosis is unlikely to occur in animals without CETP (such as rats). In addition, when CETP activity was continuously inhibited by administering antisense RNA to rabbits, blood HDL-cholesterol levels increased, and the progression of arteriosclerotic lesions was suppressed (J. Biol.
Chem. , 273, 5033-5036 (199
8)). Therefore, drugs that suppress CETP activity
It inhibits the transfer of cholesterol from HDL to LDL and VLDL, increases HDL-cholesterol, which is an arteriosclerosis inhibitor, and at the same time, promotes VLDL-, which is an arteriosclerosis inhibitor.
By reducing cholesterol and LDL-cholesterol, it is expected to work in suppressing arteriosclerotic diseases. That is, drugs that suppress CETP activity include acute coronary syndrome, acute myocardial infarction, unstable angina,
It is expected to be a drug to prevent or treat diseases such as arterial restenosis, peripheral arterial occlusion, hyperlipidemia, cerebral infarction, and stroke after PTCA or stent placement, or as an inhibitor of the progression of atherosclerotic lesions. Drugs having CETP inhibitory activity include, for example, International Patent WO99 / 41237, lip
ids, 29, 811-818 (1994), International Patent WO98 / 35937, Atheroscleros.
is, 128, 59-66 (1997), Bioor
g. Med. Chem. Lett. , 6,919-92
2 (1996), US Pat. No. 5,925,645, US Pat. No. 5,932,587, European Patent 825185.
No., EP 818448, Angew. Che
m. , Int. Ed. , 38, 3373-3375 (1
999), International Patent WO99 / 14174, International Patent WO00 / 18724, International Patent WO00 / 1716
No. 4, etc.

On the other hand, aminoethanol derivatives include:
For example, in Japanese Patent Application Laid-Open No. 11-286478, benzyl- [2 (S) -hydroxy-2-thiazol-2-yl-1 (S)-(4-trifluoromethyl-benzyl) ) -Ethyl] -carbamic acid ter
t-butyl esters have been disclosed and have been described in International Patent
No. 9/45928 discloses a compound as a raw material of a compound having an action of improving an autoimmune disease, which is disclosed in JP-A-11-2464.
No. 37 discloses a compound which is a raw material of a compound having a protective effect on gastrointestinal mucosa, and WO 98/18794 discloses a compound which is a raw material of a compound having a chymase inhibitory effect.
ett. Pept. Sci. , 2,229-232 (1
995) has an inhibitory effect on HIV-1 protease and D
A compound serving as a raw material of a compound having a PP-IV inhibitory action is disclosed in International Patent WO93 / 25574, and a compound serving as a raw material of a compound having an angiotensin I chymase inhibitory action is described in International Patent WO89 / 10752. EP 231919 discloses a compound having a renin-inhibiting action, and French Patent No. 1578851 discloses a compound having an adrenergic action. Does not disclose that it has a preventive / therapeutic action for arteriosclerotic diseases, and there is no description suggesting this.

[0005]

[0006] Fibrate drugs and nicotinic acid have been used as drugs for increasing plasma HDL-cholesterol (HDL-C), and all of them are HDL-C.
The increasing effect is indirect and side effects are of concern. The development of new drugs that directly increase HDL-cholesterol and have a sufficiently satisfactory effect in the prevention or treatment of atherosclerotic diseases such as ischemic heart and brain diseases and peripheral arterial occlusion is awaited. It is the current situation. Disclosure of the invention

[0006]

Means for Solving the Problems The present inventors have found that an aminoethanol derivative having the following specific substituents increases plasma HDL-C by inhibiting cholesterol ester transfer protein (CETP), and has an excellent arterial potential. Finding the effect of preventing and treating sclerotic disease,
We have completed this study.

That is, the present invention provides the following equation (1)

[0008]

Embedded image

[In the formula, Ar ¹ represents an aromatic ring group which may have a substituent, Ar ² represents an aromatic ring group having a substituent,
R ″ represents a hydroxyl group which may be protected, R represents an acyl group, and R ′ represents a hydrogen atom or a hydrocarbon group which may have a substituent. Or a salt thereof (provided that benzyl- [2 (S) -hydroxy-2-thiazole is
-2-yl-1 (S)-(4-trifluoromethyl-benzyl) -ethyl] -carbamic acid tert-butyl ester); (2) Ar ¹ may have a substituent 5 or The compound according to the above (1), which is a 6-membered aromatic ring group; (3) the compound according to the above (1), wherein Ar ¹ is a phenyl group which may have a substituent; (4) Ar ² is substituted A compound according to the above (1), which is a 5- or 6-membered aromatic ring group having a group; (5) a compound according to the above (1), wherein Ar ² is a phenyl group having a substituent; The compound according to the above (1), which is a group represented by ^1N CO— (R ^1N represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent); (7) R ^1N annular optionally substituted hydrocarbon group or optionally substituted heterocyclic group That the (6) The compound according; a 'has the formula R ^1O CO- (R ^1O substituent; (8) R''(9) R wherein is a hydrogen atom or an acyl group (1) compound described' A hydrocarbon group which may have or a heterocyclic group which may have a substituent). (10) R ^1O has a substituent (11) The compound according to (1), wherein R ″ is a hydrogen atom; (12) the compound according to (1), wherein R ′ is a hydrogen atom (13) R is represented by the formula R ^1N CO— (R ^1N represents a cyclic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent) that a group, 'are hydrogen atoms, R' R 'wherein is a hydrogen atom (1) the compound according; (14) Ar ¹ is a halogen atom, halogenoalkyl A 5- or 6-membered optionally substituted lower alkyl group, an optionally halogenated lower alkoxy group and an optionally substituted aryloxy group An aromatic ring group, wherein Ar ² is a 5- or 6-membered aromatic ring group having a substituent selected from a halogen atom, an optionally halogenated lower alkyl group and an optionally halogenated lower alkoxy group; , R is a halogen atom, optionally halogenated and C _1-6 alkoxy and halogenated substituents selected from C _1-6 alkyl optionally optionally having respective C _1-6 alkoxy -Carbonyl, C _1-6 alkyl-carbonyl,
The above (1), wherein C _6-10 aryl-carbonyl, dihydronaphthalenecarbonyl, tetrahydronaphthalenecarbonyl, benzocycloheptenecarbonyl or benzocyclooctenecarbonyl, R ″ is a hydrogen atom and R ′ is a hydrogen atom. (15) The compound according to the above (14), wherein the 5- or 6-membered aromatic ring group is a phenyl group, a pyridyl group, a thienyl group, a furyl group or a thiazolyl group; (16) a 5- or 6-membered aromatic ring group Is a phenyl group, a pyridyl group or a thienyl group, and R is a substituent selected from a halogen atom, an optionally halogenated C _1-6 alkoxy and an optionally halogenated C _1-6 alkyl, Naphthalenecarbonyl, which may have
The compound according to the above (14), which is dihydronaphthalenecarbonyl, tetrahydronaphthalenecarbonyl, benzocycloheptenecarbonyl or benzocyclooctenecarbonyl;

(17) N-[(1RS, 2SR) -2-
(4-Fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, 4-fluoro-N- ((1R, 2S) -2- (4-fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -1-naphthalenecarboxamide, N-[(1R, 2S ) -2- (4-Fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2
2-tetrafluoroethoxy) benzyl] ethyl] -6
7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,
2,2-tetrafluoroethoxy) benzyl] ethyl]-
5,6-dihydronaphthalene-1-carboxamide, N-
[(1RS, 2SR) -2- (4-fluorophenyl) -2
-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene-1-carboxamide, 4- Fluoro-N-[(1R, 2S) -2- (4-
Fluorophenyl) -2-hydroxy-1- [3- (1,
1,2,2-tetrafluoroethoxy) benzyl] ethyl] naphthalene-1-carboxamide, N-[(1RS,
2SR) -2- (4-Fluorophenyl) -2-hydroxy-
1- [3- (1,1,2,2-tetrafluoroethoxy)
[Benzyl] ethyl] -5,6,7,8-tetrahydrobenzo [a] cyclooctene-1-carboxamide, N-
[(1RS, 2SR) -2- (4-fluorophenyl) -2
-Hydroxy-1- (4-isopropylbenzyl) ethyl]
-6,7-dihydro-5H-benzo [a] cycloheptene-
1-carboxamide, N-((1RS, 2SR) -2- (3
-Fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -6,7-
Dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-((1RS, 2SR) -2-hydroxy-2
-(4-phenoxyphenyl) -1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-[(1RS, 2SR) -2- (4-Chlorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] Cycloheptene-1-carboxamide, N-((1RS, 2SR) -2-hydroxy-2- (4-
(Phenyloxy) phenyl) -1-((3-((1,
1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-((1
RS, 2SR) -2- (4-((4-chloro-3-ethylphenyl) oxy) phenyl) -2-hydroxy-1-((3-
((1,1,2,2-tetrafluoroethyl) oxy)
Phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-
((1RS, 2SR) -2- (2-fluoropyridine-4-
Yl) -2-hydroxy-1-((3- (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) ethyl)-
6,7-dihydro-5H-benzo [a] cycloheptene-1
-Carboxamide, N-((1RS, 2RS) -2- (6-
Fluoropyridin-2-yl) -2-hydroxy-1-((3
-(1,1,2,2-tetrafluoroethoxy) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-[(1
RS, 2SR) -1- (4-tert-butylbenzyl) -2- (3-chlorophenyl) -2-hydroxyethyl] -5-chloro-1-naphthamide, 4-fluoro-N-{(1RS, 2SR) -2- (4-Fluorophenyl) -2-hydroxy-1-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] ethyl} (18) the compound according to the above (1), which is -1-naphthamide or a salt thereof;

[0011]

Embedded image

[Wherein, Ar ¹ represents an aromatic ring group which may have a substituent, Ar ² represents an aromatic ring group having a substituent,
R ″ represents a hydroxyl group which may be protected, R represents an acyl group, and R ′ represents a hydrogen atom or a hydrocarbon group which may have a substituent. ] Or a prodrug thereof (provided that benzyl- [2 (S) -hydroxy
-2-thiazol-2-yl-1 (S)-(4-trifluoromethyl-benzyl) -ethyl] -carbamic acid tert-
(Excluding butyl ester);

[0013]

Embedded image

[Wherein, Ar ¹ represents an aromatic ring group which may have a substituent, Ar ² represents an aromatic ring group having a substituent,
R ″ represents a hydroxyl group which may be protected, R represents an acyl group, and R ′ represents a hydrogen atom or a hydrocarbon group which may have a substituent. (20) a composition according to (19), which is a cholesteryl ester transfer protein inhibitor; (21) a high-density lipoprotein. -The composition according to (19), which is a cholesterol-elevating agent; (22) the composition according to (19), which is a low-density lipoprotein-cholesterol-lowering agent; (24) The composition according to (19), which is a triglyceride-lowering agent; (25) The composition according to (1), which is a preventive or therapeutic agent for acute coronary syndrome.
(26) The composition according to (19), which is an agent for preventing or treating acute myocardial infarction.
(27) The composition according to (19), which is a preventive or therapeutic agent for unstable angina pectoris.
(28) The composition according to the above (19), which is a prophylactic / therapeutic agent for arterial restenosis after placement of PTCA or a stent;
(30) The composition according to (19), which is a prophylactic / therapeutic agent for hyperlipidemia; (31) the composition according to (19), which is a prophylactic / therapeutic agent for cerebral infarction; 32) The composition according to the above (19), which is an agent for preventing or treating stroke; (33) the composition according to the above (19), which is an agent for inhibiting the progression of arteriosclerotic lesions;

[0015]

Embedded image

[In the formula, Ar ¹ represents an optionally substituted aromatic ring group, Ar ^{2 ′} represents an optionally substituted aromatic ring group, and OR ″ represents a protected aromatic ring group. A good hydroxyl group is represented by R
Represents an acyl group, and R ′ represents a hydrogen atom or a hydrocarbon group which may have a substituent. (35) a cholesteryl ester transfer protein inhibitor comprising a compound represented by the formula: or a salt thereof, or a prodrug thereof; (35) the agent according to (34), which is a preventive or therapeutic agent for hyperlipidemia; (3) which is a prophylactic / therapeutic agent for acute coronary syndrome.
(37) The agent according to (34), which is an agent for preventing or treating acute myocardial infarction.
(38) The agent according to (34), which is a preventive or therapeutic agent for unstable angina pectoris.
(39) The agent according to (34), which is a prophylactic / therapeutic agent for PTCA or arterial restenosis after stent placement; (40) the agent (3), which is a prophylactic / therapeutic agent for peripheral arterial occlusion.
(41) the agent according to the above (34), which is a preventive / therapeutic agent for cerebral infarction; (42) the agent according to the above (34), which is a preventive / therapeutic agent for stroke; (43) an atherosclerotic lesion (44) a method of inhibiting a cholesteryl ester transfer protein in a mammal, which comprises administering to the mammal an effective amount of the compound or a salt thereof according to (1), which is an progress inhibitor; (45) a method for preventing or treating hyperlipidemia in a mammal, which comprises administering to the mammal an effective amount of the compound according to (1) or a salt thereof; (46) inhibiting cholesteryl ester transfer protein; (47) Use of the compound or a salt thereof according to (1) for the manufacture of a medicament for the prevention or treatment of hyperlipidemia. Use of salt; ( 8) a method for preventing or treating acute coronary syndrome in a mammal, which comprises administering to the mammal an effective amount of the compound according to (1) or a salt thereof; (49) the compound according to (1) or a salt thereof. A method for preventing or treating acute myocardial infarction in a mammal, which comprises administering an effective amount of a salt to the mammal; (50) administering an effective amount of the compound or a salt thereof according to the above (1) to the mammal. (51) a method for preventing or treating unstable angina in a mammal, comprising: (51) administering to the mammal an effective amount of the compound or a salt thereof according to the above (1); (52) a method for preventing or treating coronary restenosis after stent placement; (52) administering a compound or a salt thereof according to (1) to a mammal in an effective amount. (53) a method for preventing or treating cerebral infarction in a mammal, which comprises administering an effective amount of the compound or a salt thereof according to (1) to a mammal; 54) a method for preventing or treating stroke in a mammal, which comprises administering an effective amount of the compound or a salt thereof according to (1) to a mammal; (55) a method for preventing or treating stroke in a mammal; (56) a method for inhibiting the progression of atherosclerotic lesions in a mammal, which comprises administering an effective amount to a mammal; Use; (57) Use of the compound or the salt thereof according to (1) for the manufacture of a prophylactic / therapeutic agent for acute myocardial infarction; (58) Prior to the manufacture of a prophylactic / therapeutic agent for unstable angina pectoris. (59) Use of the compound or a salt thereof according to the above (1) for the manufacture of a prophylactic or therapeutic agent for peripheral arterial occlusion; (60) Prevention of hyperlipidemia (61) Use of the compound or a salt thereof according to (1) for the manufacture of a therapeutic agent;
(62) Use of the compound or a salt thereof according to the above (62) for the manufacture of an agent for preventing or treating stroke.
(63) Use of the compound or a salt thereof according to the above (1) for the manufacture of an agent for inhibiting progression of atherosclerotic lesions; (64) Formula (I ′) according to the above (34). A method for inhibiting a cholesteryl ester transfer protein in a mammal, which comprises administering to the mammal an effective amount of the compound represented by the formula (I) or a salt thereof, or a prodrug thereof; Use of the compound represented by the formula (I ′) described in the above (34) or a salt thereof, or a prodrug thereof for the manufacture of a medicament;

[0017]

Embedded image

A compound represented by the formula (1) is as defined in the above (1) or a salt thereof is subjected to an acylation reaction,

[0019]

Embedded image

Wherein the symbols in the formula are as defined in the above (1), or a salt thereof.
The present invention relates to the above-mentioned (1) or a method for producing a salt thereof, which is subjected to a hydroxyl group protection reaction.

The term "acyl group" as used herein
As a carboxylic acid such as R ¹ COOH and R ¹ OCOOH; a sulfonic acid such as R ¹ SO ₃ H; and a sulfinic acid such as R ¹ SO ₂ H such as R ¹ OPO (O
R ² ) Phosphoric acid such as OH, for example R ¹ N (R ² ) COOH
Carbamic acid (R ¹ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and R ² represents a hydrogen atom or a substituent which may have a substituent. An acyl group obtained by removing the OH group from, for example, a good hydrocarbon group) is used. Specifically, R ¹ CO, R ¹ OCO, R
¹ SO ₂ , R ¹ SO, R ¹ OPO (OR ² ), R ¹ N (R ² ) C
O (R ¹ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and R ² represents a hydrogen atom or a hydrocarbon which may have a substituent And the like) are used.

As used herein, the term "hydrocarbon group" in the term "optionally substituted hydrocarbon group" means, for example, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an aralkyl group. And an aryl group. As the substituent that the “hydrocarbon group” may have, the same substituents as the substituents that the “alkyl group” and the “cycloalkyl group” may have, which will be described later, are used. Examples of the "alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, tridecyl, tetradecyl, pentadecyl and the like. "A linear or branched _C1-15 alkyl group" and the like are used. As the “cycloalkyl group”, for example, a “C _3-10 cycloalkyl group” such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl and the like are used.

The "alkyl group" and "cycloalkyl"
Examples of the substituent which the group may have include, for example, (i)
Toro group, (ii) hydroxy group, oxo group, (iii) cyano
Group, (iv) carbamoyl group, (v) mono- or di-C_1-4A
Alkyl-carbamoyl group (for example, N-methylcarbamo
Yl, N-ethylcarbamoyl, N, N-dimethylcar
Bamoyl, N, N-diethylcarbamoyl, etc.), mono
-Or di-phenyl-carbamoyl group, mono- or
Di-benzyl-carbamoyl group, carboxyl-carba
Moyl group, C_1-4Alkoxy-carbonyl-carbamoy
Group, (vi) carboxyl group, (vii) C_1-4Alkoxy-ka
Rubonyl group (for example, methoxycarbonyl, ethoxyca
Rubonyl, propoxycarbonyl, isopropoxycal
Bonyl etc.), (viii) sulfo group (-SO_TwoOH), (ix)
Halogen atoms (for example, fluorine, chlorine, bromine, iodine
And (x) optionally halogenated C_1-4Alkoxy
Groups (eg, methoxy, ethoxy, propoxy, isop
Loxy, etc.), may be substituted with a hydroxy group
C_1-4Substituted with an alkoxy group or a carboxyl group
Good C_1-4Alkoxy group, C_1-4Alkoxy-carboni
C which may be substituted with_1-4Alkoxy group, C_1-4
Alkoxy-C_1-4Alkoxy group, (xi) phenoxy group,
Phenoxy-C_1-4Alkyl group, phenoxy-C_1-4Al
Coxy group, (xii) phenyl which may be halogenated
Group, optionally halogenated phenyl-C_1-4Al
Alkyl group, phenyl-C which may be halogenated_2-4
Alkenyl group, optionally halogenated phenoxy
Groups such as o-, m- or p-chlorophenoxy,
o-, m- or p-bromophenoxy), pyridi
Roxy group, C_3-10Cycloalkyl group, C_3-10Cycloa
Lequil-C_1-4Alkoxy group, C_{Three -Ten}Cycloalkyl-
C_1-4Alkyl group, (xiii) optionally halogenated
C_{1- Four}Alkyl group, optionally halogenated C_2-4A
Lucenyl group, optionally halogenated C_1-4Archi
Ruthio group (for example, methylthio, ethylthio, n-pro
Pyrthio, isopropylthio, n-butylthio, etc.),
C which may be substituted by a hydroxy group_1-4Alkyl
Group optionally substituted by a hydroxy group or a hydroxy group_1-4Archi
Luthio, (xiv) mercapto, thioxo, (xv) halo
Gen atom, carboxyl group and C_1-4Alkoxy-ka
Each substituted with a substituent selected from a rubonyl group.
A benzyloxy group or a benzylthio group, (xv
i) an optionally halogenated phenylthio group, pyridi
Luthio group, phenylthio-C_1-4Alkyl group, pyridyl
Thio-C_1-4Alkyl group, (xvii) halogenated
Good C_1-4Alkylsulfinyl group (for example, methyl
Sulfinyl, ethylsulfinyl, etc.), phenyls
Rufinyl group, phenylsulfinyl-C_1-4Alkyl
Group, (xviii) optionally halogenated C_1-4Archi
Rusulfonyl group (for example, methylsulfonyl, ethyls
Phenylsulfonyl group, phenylsulfonyl group
Honyl-C_1-4Alkyl group, (xix) amino group, aminosul
Honyl group, (xx) C _1-3Acylamino group (for example, acetyl
Amino, propionylamino, etc.), benzyloxy
Carbonylamino, (xxi) mono- or di-C_1-4Archi
Amino group (eg, methylamino, ethylamino, diamino
(Xxii) 4 to
6-membered cyclic amino group (for example, 1-azetidinyl, 1-pi
Loridinyl, piperidino, morpholino, thiomorpholin
, 1-piperazinyl, etc.) 4- to 6-membered cyclic amino
-Carbonyl group (for example, 1-azetidinylcarboni
, 1-pyrrolidinylcarbonyl, piperidinocarboni
, Morpholinocarbonyl, thiomorpholinocarboni
, 1-piperazinylcarbonyl, etc.), 4 to 6 members
Cyclic amino-C_1-4Alkyl group, (xxiii) C_1-6Acyl group
(For example, halogenated formyl, acetyl, etc.
May be C_2-6Alkanoyl), (xxiv) halogen
A benzoyl group optionally substituted with an atom, such as (xxv) 5
10-membered heterocyclic group (for example, 2- or 3-thienyl
2-, 3- or 3-furyl, 3-, 4- or 5-pyr
Zolyl, 2-, 4- or 5-thiazolyl, 3-, 4-
Or 5-isothiazolyl, 2-, 4- or 5-oxo
Sazolyl, 1,2,3- or 1,2,4-triazolyl
1H- or 2H-tetrazolyl, 2-, 3- or
Is 4-pyridyl, 2-, 4- or 5-pyrimidinyl,
3- or 4-pyridazinyl, quinolyl, isoquinolyl
(Xxvi) 5- to 10-membered heterocyclic-cal
Bonyl group (for example, 2- or 3-thienylcarboni
2-, 3- or 3-furylcarbonyl, 3-, 4- or
Is 5-pyrazolylcarbonyl, 2-, 4- or 5-thio
Azolylcarbonyl, 3-, 4- or 5-isothiazo
Rylcarbonyl, 2-, 4- or 5-oxazolylca
Rubonyl, 1,2,3- or 1,2,4-triazoly
Carbonyl, 1H- or 2H-tetrazolylcarbo
Nil, 2-, 3- or 4-pyridylcarbonyl, 2
-, 4- or 5-pyrimidinylcarbonyl, 3- or
Is 4-pyridazinylcarbonyl, quinolylcarbonyl,
Isoquinolylcarbonyl, indolylcarbonyl
Etc.), (xxvii) linear or optionally halogenated
Is a branched C_2-5Alkyleneoxy group (for example, ethylene
Oxy, propylene oxy, isobutylene oxy
And (xxviii) optionally halogenated straight chain
Or branched C_1-4Alkylenedioxy group (eg,
For example, methylenedioxy, ethylenedioxy, propylene
Dioxy, tetrafluoroethylenedioxy, etc.)
Is used. The “alkyl group” and “cycloalkyl”
"Group" is a group in which 1 to 1
You may have five.

Preferred examples of the "alkyl group"
Is, for example, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl,
Linear or branched C such as ethylene, hexyl, etc._1-6A
And the "C"_1-6Alkyl group "has
Examples of the optional substituent include a halogen atom, C
_1-4Alkoxy group, hydroxy group, C_1-4Alkoxy-ka
Rubonyl group, carboxyl group, carbamoyl group, mono-
Or di-C_1-4Alkylcarbamoyl group, pyridylti
One to three groups such as O groups are used. The alkenyl
Examples of the "group" include vinyl, allyl, and isopropenyl.
, 3-butenyl, 3-octenyl, 9-octadecenyl
"C_2-18An "alkenyl group" and the like are used. The
As the “cycloalkenyl group”, for example, cycloprope
Nil, cyclobutenyl, cyclopentenyl, cyclohexyl
Cenyl, cycloheptenyl, cyclooctenyl, etc.
"C_3-8And a "cycloalkenyl group". The
"Alkenyl group" and "cycloalkenyl group" have
The substituent that may be present has the aforementioned “alkyl group”.
The same substituents as those described above may be used. The "A
Preferred examples of the `` lucenyl group '' include, for example, vinyl,
C such as allyl, 2-butenyl and 3-butenyl_2-6Al
And a kenyl group. The "C_2-6Alkenyl group "
Examples of the substituent which may have
"C_1-6Same as the substituent which the "alkyl group" may have
Is used. Examples of the “alkynyl group” include, for example,
For example, ethynyl, propynyl, 1-butynyl, 2-butyn
Nil, 1-pentynyl, 2-pentynyl, 3-pentini
"C _2-18An "alkynyl group" is used. The
Examples of the substituent which the “alkynyl group” may have include:
The same as the substituent which the "alkyl group" may have
Things are used. Preferred examples of the “alkynyl group”
For example, ethynyl, propynyl, 1-butini
And C such as 2-butynyl_2-6Alkynyl groups and the like
Can be The "C_2-6Alkynyl group "may have
Examples of the substituent include the aforementioned “C_1-6Alkyl group "
The same substituents as those which may be used are used.

As the "aralkyl group", a C _7-16 aralkyl group and the like are used, and specifically, for example, phenyl-C _1-6 alkyl such as benzyl, phenethyl, 3-phenylpropyl and 4-phenylbutyl Groups and naphthyl-C ₁ -such as, for example, (1-naphthyl) methyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) ethyl
₆ alkyl groups and the like. Examples of the substituent which the “aralkyl group” may have include the aforementioned “alkyl group”.
May have, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-4
Alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.), C _2-6 alkenyl group (eg, vinyl, allyl, 2-butenyl, 3-butenyl etc.), C _1-3 acyl group (eg, formyl , Acetyl, etc.), C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), nitro group, cyano group, hydroxy group, C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) , Propoxycarbonyl, isopropoxycarbonyl, etc.), carbamoyl group, mono- or di-C _1-4 alkyl-carbamoyl group (for example, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N- Monocarbamoyl), mono-
Or a di-C _1-4 alkenyl-carbamoyl group (eg, N-vinylcarbamoyl) and the like, and the “aralkyl group” may have 1 to 4 such substituents at substitutable positions. Good. Examples of the “aryl group” include phenyl, 1-naphthyl, 2-naphthyl,
An aromatic monocyclic, bicyclic or tricyclic C _6-14 aryl group such as phenanthryl and anthryl, a biphenyl group, a tolyl group and the like are used. The "aryl group"
As the substituent which may be possessed, in addition to the substituent which the aforementioned “aralkyl group” may have, an oxo group and the like are also used, and the “aryl group” is substituted at a substitutable position. It may have 1 to 4, preferably 1 or 2, groups. Examples of the aryl group having an oxo group include benzoquinonyl, naphthoquinonyl, anthraquinonyl and the like. When the `` hydrocarbon group '' is a cycloalkyl group, an aryl group or an aralkyl group,
For example, a C <sub>1-10</sub> alkyl group (eg, methyl, ethyl,
Propyl, isopropyl, decyl and the like), C <sub>2-10</sub> alkenyl group (for example, vinyl, allyl, 2-butenyl, 3-
Butenyl), a phenyl-C <sub>2-4</sub> alkenyl group (such as phenylethenyl), a mono- or di-C <sub>1-6</sub> alkenyl-carbamoyl group (such as N-vinylcarbamoyl), a C <sub>6-14</sub> aryl group ( For example, phenyl, 1
-Naphthyl, 2-naphthyl), a <sub>C7-20</sub> aralkyl group (e.g., benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6
-Phenylhexyl, 2- (1-naphthyl) ethyl, 2
-(2-naphthyl) ethyl), a styryl group, an oxo group and the like. The “substituent” of the “hydrocarbon group” may have 1 to 4 substituents at substitutable positions. Further, when the `` hydrocarbon group '' is a cyclic group such as a cycloalkyl group, a cycloalkenyl group, an aralkyl group, an aryl group, an optionally halogenated C _1-4 alkylenedioxy group, May be C
_It may have a substituent such as a _2-5 alkyleneoxy group, or these cyclic groups may be condensed to form a bicyclic or tricyclic fused hydrocarbon group,
Such a condensed hydrocarbon group may have the same group as the substituent which the aforementioned “alkyl group” and “cycloalkyl group” may have.

As used herein, the term "heterocyclic group" of the term "heterocyclic group optionally having substituent (s)" includes, for example, 2- or 3-thienyl, 2- or 3-furyl,
2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4-
Or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-,
4- or 5-isothiazolyl, 3- or 5- (1,
2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5- (1,2,4-thiadiazolyl),
1,3,4-thiadiazolyl, 4- or 5- (1,2,3
-Thiadiazolyl), 1,2,5-thiadiazolyl, 1,
2,3-triazolyl, 1,2,4-triazolyl, 1H
-Or a hetero atom selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like in addition to a carbon atom such as 2H-tetrazolyl.
A 5-membered ring group containing from 4 to 4, for example, 2-, 3- or 4-
Pyridyl, N-oxide-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxide-2-, 4- or 5-pyrimidinyl, thiomorpholinyl, morpholinyl, oxoimidazolyl, dioxotri Azinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl, N-oxide 6-membered ring group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like in addition to carbon atom such as -3- or 4-pyridazinyl, for example, benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl,
Triazolo [4,5-b] pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl,
Bicyclic containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen, etc. in addition to carbon such as acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like Or a 5- to 8-membered ring containing 1 to 4 hetero atoms such as an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom such as a tricyclic fused ring group or a condensed ring thereof (including condensed with a benzene ring) Are used. Examples of the `` substituent '' of the `` heterocyclic group which may have a substituent '' include the groups described in the `` substituent '' of the `` hydrocarbon group which may have a substituent '', In particular, a substituent when the "hydrocarbon group" is a cycloalkyl group, an aryl group, or an aralkyl group is used. Substituents may be substituted at 1 to 5, preferably 1 or 2, at substitutable positions on the heterocyclic ring.

As used herein, the term "lower alkyl" refers to a straight or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. And an alkyl group having 1 to 6 carbon atoms.

In the above formula, Ar ¹ represents an aromatic ring group which may have a substituent, and Ar ² represents an aromatic ring group having a substituent. "Aromatic ring group having a substituent" in the "aromatic ring group" which may have "substituents" and Ar ² in the "aromatic ring group optionally having a substituent" as Ar ¹
As the “substituent” of the “aromatic ring group” in the above, the groups described in “the substituent” of the “hydrocarbon group which may have a substituent” and the like are used. The substituent may be substituted at 1 to 5, preferably 1 or 2, at a substitutable position of the aromatic ring group. As the “substituent” that the “aromatic ring group” in the “aromatic ring group optionally having” as Ar ¹ may have, a halogen atom, a lower alkyl optionally halogenated group, halogenated which may be a lower alkoxy group, an optionally substituted aryl group (e.g., phenoxy group and the like) is preferable, and may have a "substituent as Ar ¹ `` Aromatic ring group '' in `` aromatic ring group '' is phenyl,
When the phenyl has one substituent, the substitution position is preferably the meta position or the para position. As the "substituent" that the "aromatic ring group" in the "aromatic ring group having a substituent" as Ar ² may have, a halogen atom, a lower alkyl group which may be halogenated, And a lower alkoxy group which may be
The “aromatic ring group” in the “aromatic ring group having a substituent” as r ² is phenyl, and when the phenyl has one substituent, the substitution position is preferably the meta position or the para position. As the `` aromatic ring group '' in the `` aromatic ring group which may have a substituent '' as Ar ¹ and the `` aromatic ring group '' in the `` aromatic ring group having a substituent '' as Ar ² , an aryl group, And a heteroaryl group. Examples of the “aryl group” include phenyl, 1-
Naphthyl, 2-naphthyl, phenanthryl, anthryl
An aromatic monocyclic, bicyclic or tricyclic C _6-14 aryl group such as (anthryl), a biphenyl group, a tolyl group and the like are used, and among them, phenyl is preferable.
As the “heteroaryl group”, for example, 2- or 3
-Thienyl, 2- or 3-furyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl,
3-, 4- or 5-pyrazolyl, 2-, 4- or 5
-Imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5 -(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5-
(1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, etc. Atom, a 5-membered aromatic ring group containing 1 to 4 heteroatoms selected from nitrogen atoms and the like, for example, 2-,
6-membered containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen and the like in addition to carbon atoms such as 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, pyridazinyl and pyrazinyl An aromatic ring group, or a 5- or 6-membered aromatic ring group thereof, or a 5- or 6-membered aromatic ring group thereof;
A condensed ring group formed by bonding a member aromatic ring group to a benzene ring (preferably a bicyclic condensed ring group) or the like is used. A
As the “aromatic ring group” in the “aromatic ring group optionally having substituent (s)” as r ¹ and the “aromatic ring group” in the “aromatic ring group having a substituent” as Ar ² , 5 or A 6-membered aromatic ring group is preferably used, and among them, a phenyl group, a pyridyl group, a thienyl group, a furyl group,
Thiazolyl groups and the like are preferably used. In the above formula, A
r ^{2 ′} represents an aromatic ring group which may have a substituent. Ar
As the "aromatic ring group optionally having a substituent" as ^{2 ',} having a "substituent as" aromatic ring group "and Ar ² in the" aromatic ring group having a substituent "as Ar ² And the same as "aromatic ring group".

In the above formula, R represents an acyl group. The "Ashi
The group may be any of those described above, for example, R
^1NCOOH, R^1NCarboxylic acids such as OCOOH, for example
R^1NSO_ThreeSulfonic acids such as H, for example R^1NSO_TwoH etc.
A sulfinic acid such as R^1NOPO (OR^2N) OH etc.
Phosphoric acid such as R^1NN (R^2N) Carba such as COOH
Minic acid (R^1NIs a hydrocarbon group which may have a substituent.
Or a heterocyclic group which may have a substituent;^2NIs
A hydrogen atom or a hydrocarbon group which may have a substituent
Acyl group obtained by removing the OH group from
And specifically, R^1NCO, R^1NOCO, R^1NSO_Two,
R^1NSO, R^1NOPO (OR^2N), R^1NN (R^2N) CO
(R^1NIs a hydrocarbon group which may have a substituent or
A heterocyclic group which may have a substituent;^2NIs hydrogen field
Represents a hydrocarbon group which may have a substituent or a substituent)
Are used. Where R^1NRepresented by the "substituent
A hydrocarbon group which may be present ", R^1NReplace with
A heterocyclic group which may have a group "and R^2NIndicated by
As the “optionally substituted hydrocarbon group”,
Each of the above R¹Represented by the `` may have a substituent
A hydrocarbon group ";<sup>1</sup>Having a substituent
A heterocyclic group which may be<sup>Two</sup>"Substituent represented by
And the like may be used.
It is. As R, the formula R<sup>1N</sup>CO- (R<sup>1N</sup>Has a substituent
May have a hydrocarbon group or a substituent
Which represents a good heterocyclic group) is preferably used
You. Also, R<sup>1N</sup>Represents a ring which may have a substituent
Hydrocarbon group (eg, cycloalkyl optionally having substituent (s))
Alkyl group, cycloalkenyl optionally having substituent (s)
Group, aryl group which may have a substituent, etc.),
A cyclic group such as an optionally substituted heterocyclic group is preferred.
And especially an aryl group which may have a substituent,
Substitution of an optionally substituted heteroaryl group, etc.
An aromatic ring group (Ar<sup>1</sup>Replace as
And the like aromatic groups which may have a group).
It is used well. Among them, R is a halogen atom
, Optionally halogenated C<sub>1-6</sub>Alkoxy, ha
C which may be formed into a log<sub>1-6</sub>Choose from alkyl, etc.
C which may have 1 to 3 substituents<sub>1-6</sub>
Alkoxy-carbonyl, C<sub>1-6</sub>Alkyl-carboni
Le, C<sub>6-10</sub>Aryl-carbonyl (eg, benzoyl, na
Etc.), dihydronaphthalenecarbonyl, tet
Lahydronaphthalene carbonyl, benzocycloheptene
Carbonyl (preferably benzo [a] cycloheptene-
Carbonyl), benzocyclooctenecarbonyl
preferable. In the above formula, OR ″ may be protected
Shows a hydroxyl group. Here, R ″ is a hydrogen atom or a hydroxyl group.
(Preferably, R ″ is a hydrogen atom or an acyl
And the protecting group for the hydroxyl group includes, for example, acyl
C which may have a group or a substituent<sub>1-6</sub>Alkyl, substituent
Optionally substituted phenyl, optionally substituted
C<sub>7-10</sub>Aralkyl, optionally substituted pirani
, A furanyl optionally having a substituent,
And optionally silyl. R ''
The acyl group as the “protecting group for hydroxyl group” may be any of the aforementioned groups.
May be, for example, R<sup>1O</sup>COOH, R<sup>1O</sup>OC
Carboxylic acids such as OOH, for example R<sup>1O</sup>SO<sub>Three</sub>H and others
Sulfonic acid, for example R<sup>1O</sup>SO<sub>Two</sub>H and other sulfinic acids, eg
For example, R<sup>1O</sup>OPO (OR<sup>2O</sup>) Phosphoric acid such as OH, for example R
<sup>1O</sup>N (R<sup>2O</sup>) Carbamic acids such as COOH (R<sup>1O</sup>Is replaced
Having a hydrocarbon group or a substituent which may have a group
An optionally substituted heterocyclic group;<sup>2O</sup>Is a hydrogen atom or substitution
Represents a hydrocarbon group which may have a group)
An acyl group obtained by removing the group is used.
<sup>1O</sup>CO, R<sup>1O</sup>OCO, R<sup>1O</sup>SO<sub>Two</sub>, R<sup>1O</sup>SO, R<sup>1O</sup>OP
O (OR<sup>2O</sup>), R<sup>1O</sup>N (R<sup>2O</sup>) CO (R<sup>1O</sup>Has a substituent
May have a hydrocarbon group or a substituent
A heterocyclic group;<sup>2O</sup>Has a hydrogen atom or a substituent
Or a hydrocarbon group which may be substituted). This
Where R<sup>1O</sup>Represented by the "optionally substituted carbonized
Hydrogen group ", R<sup>1O</sup>Represented by the `` may have a substituent
Heterocyclic group "and R^2OHaving a substituent
Or a good hydrocarbon group ”.¹Indicated by
The "optionally substituted hydrocarbon group" described above,
¹Represented by an "optionally substituted heterocyclic group" and
And the R^TwoRepresented by the "optionally substituted charcoal"
The same as the “hydrogen group” are used. R ''
Examples of the “acyl group” as the “hydroxyl protecting group” include:
Formula R^{1 O}CO- (R^1OIs a carbon atom which may have a substituent
Represents a hydrogen group or a heterocyclic group which may have a substituent.
Are preferably used. Also, R^1OWhen
A chain hydrocarbon group which may have a substituent
(E.g., an alkyl group which may have a substituent,
Optionally having an alkenyl group, having a substituent
Such as a good alkynyl group) are preferred.
An alkyl group which may have a substituent is preferable, and
In other words, an alkyl group having a substituent (for example, halogen
Atom, C_1-4Alkoxy group, hydroxy group, C_1-4Arco
Xy-carbonyl group, carboxyl group, carbamoyl
Group, mono- or di-C_1-4Alkylcarbamoyl group,
Amino group, mono- or di-C_1-4Alkylamino group,
1 to 3 substituents selected from a pyridylthio group and the like
Having C_1-6And the like are preferably used.
You. R "as a" protecting group for a hydroxyl group "
C optionally having a substituent _1-6Alkyl group "
"C_1-6Examples of the "alkyl group" include, for example, methyl and ethyl.
Propyl, isopropyl, butyl, tert-butyl
And the "C_{1- 6}An “alkyl group” is a halogen atom
Children (eg, fluoro, chloro, bromo, iodo
Etc.), phenyl, C_7-10Aralkyl and nitro groups
It may have about 1 to 4 substituents. Indicated by R ''
Having a substituent as the "protecting group for hydroxyl group"
Phenyl group "may have" phenyl group "
Examples of the optional substituent include a halogen atom (eg,
For example, fluoro, chloro, bromo, iodo, etc.), C
_1-6Alkyl, phenyl, C_7-10Aralkyl, nitro group
And the like, and the number of substituents is about 1 to 4
You. R "as a" protecting group for a hydroxyl group "
C optionally having a substituent _7-10In aralkyl
"C_7-10As "aralkyl", for example, benzyl
And the "C_7-10Aralkyl "
Substituents include, for example, halogen atoms (eg,
Luoro, chloro, bromo, iodo, etc.), C_{1- 6}Archi
Phenyl, C_7-10Aralkyl and nitro groups are used
And the number of substituents is about 1 to 4. R ''
Having a substituent as the shown "protecting group for hydroxyl group"
"Pyranyl group" in "optionally pyranyl group"
Examples of the optionally substituted substituent include, for example, a halogen atom
(Eg, fluoro, chloro, bromo, iodo, etc.),
C_1-6Alkyl, phenyl, C_7-10Aralkyl, nitro
And the like, and the number of substituents is about 1 to 4
You. R "as a" protecting group for a hydroxyl group "
Furanyl group which may have a substituent
Substituents which the `` aryl group '' may have, for example,
Logen atom (eg, fluoro, chloro, bromo, iodo
C)_1-6Alkyl, phenyl, C_7-10Aralki
And nitro groups are used, and the number of substituents is 1 to 4
About one. A “protecting group for a hydroxyl group” represented by R ″;
In "optionally substituted silyl group"
Examples of the substituent which the “silyl group” may have include, for example,
If C _1-6Alkyl, phenyl, C_7-10Aralkyl etc.
And the number of substituents is about 1 to 4.
As R ″, a hydrogen atom or the like is preferably used.

In the above formula, R 'represents a hydrogen atom or a hydrocarbon group which may have a substituent. As R ′,
A hydrogen atom, a lower alkyl group which may have a substituent (preferably, a halogen atom, a C _1-4 alkoxy group, a hydroxy group, a C _1-4 alkoxy-carbonyl group, a carboxyl group, a carbamoyl group, a mono- or A C _1-6 alkyl group which may have 1 to 3 substituent (s) selected from a di-C _1-4 alkylcarbamoyl group and a pyridylthio group, etc.), and a hydrogen atom, a C _1-6 alkyl group And the like are more preferable, and among them, a hydrogen atom is preferably used. As the compound represented by the formula (I) or a salt thereof, R is a compound represented by the formula R ^1N CO— (R ^1N may have a cyclic hydrocarbon group or a substituent which may have a substituent. A compound wherein R ″ is a hydrogen atom and R ′ is a hydrogen atom; or a salt thereof, wherein Ar ¹ is a halogen atom, lower alkyl which may be halogenated. A 5- or 6-membered aromatic ring group which may have a substituent selected from a group, an optionally halogenated lower alkoxy group and an optionally substituted aryloxy group (for example, a phenyl group , A pyridyl group,
Thienyl group, furyl group, thiazolyl group and the like; preferably phenyl group and the like), and Ar ² is a halogen atom,
5- or 6-membered aromatic ring group having a substituent selected from a lower alkyl group which may be halogenated and a lower alkoxy group which may be halogenated (for example, a phenyl group, a pyridyl group, a thienyl group, a furyl group) And a thiazolyl group; preferably a phenyl group), wherein R is a substituent selected from a halogen atom, an optionally halogenated C _1-6 alkoxy and an optionally halogenated C _1-6 alkyl. C optionally having a group
_1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, C _6-10 aryl-carbonyl or benzo [a] cycloheptene-carbonyl, wherein R ″ is a hydrogen atom and R ′ is a hydrogen atom Or a salt thereof; and the like. Formula (I) or formula (I ′)

[0031]

Embedded image

The compound represented by the formula: wherein each symbol is as defined above, has at least two asymmetric carbons.
There are at least four optically active isomers based on these asymmetric carbons, and each of them and any mixtures thereof also exist.
It is included in the compound represented by the formula (I). Compounds represented by the formula (I) and the formula (I ′) include a compound represented by the formula:

[0033]

Embedded image

A compound represented by the formula: wherein each symbol is as defined above, is preferably used.

As the salt of the compound represented by the formula (I) or (I ') of the present invention, a pharmaceutically acceptable salt or a physiologically acceptable acid addition salt is preferable. Such salts include, for example, inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.) or organic acids (eg,
Acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, and the like are used. Furthermore, when the compound represented by the formula (I) of the present invention has an acidic group such as a carboxylic acid, the compound represented by the formula (I) is, for example, an inorganic base (for example,
A salt may be formed with an alkali metal or alkaline earth metal such as sodium, potassium, calcium, and magnesium, or ammonia, or an organic base (eg, tri-C _1-3 alkylamine such as triethylamine). As the starting compound of the compound represented by the formula (I) of the present invention, the same salt as described above is used, but is not particularly limited as long as the reaction is not hindered. The prodrug of the compound represented by the formula (I) of the present invention or a salt thereof (hereinafter may be referred to as compound (I)) can be prepared by reacting the compound (I) with an enzyme or gastric acid under physiological conditions in a living body. )
A compound which is converted into a compound (I) by enzymatic oxidation, reduction, hydrolysis or the like, or a compound which is converted into a compound (I) by hydrolysis or the like by gastric acid or the like. As a prodrug of compound (I), the amino group of compound (I) is acylated, alkylated,
A phosphorylated compound (for example, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, Tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compound, etc.),
Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, and borated (for example, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated,
Pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbonylated compound, etc.) or a compound in which the carboxyl group of compound (I) is esterified or amidated (for example, compound (I)
The carboxyl group of ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification,
Ethoxycarbonyloxyethylesterification, phthalidylesterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methylesterification, cyclohexyloxycarbonylethylesterification, methylamidated compound, etc.) Is mentioned. These compounds can be produced from compound (I) by a method known per se. The prodrug of compound (I) is described in “Development of Pharmaceuticals”, Hirokawa Shoten, 1990, Vol.
Compounds that change to compound (I) under physiological conditions as described on pages 3 to 198 may be used. Also,
Examples of the prodrug of the compound represented by the formula (I ′) or a salt thereof (hereinafter, sometimes referred to as compound (I ′)) include the same prodrugs as compound (I).

Compound (I) or compound (I ')
May be a hydrate. If an optically active form of compound (I) or compound (I ') is required, for example, using an optically active starting material or a racemic form of said compound using conventional methods Can be obtained by dividing

Preferred specific examples of the compound (I) of the present invention are shown below. N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene -1-Carboxamide, 4-fluoro-N-((1R, 2S) -2- (4-fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -1 -Naphthalenecarboxamide, N-[(1R, 2S) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6 , 7-Dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2 , 2-Tetrafluoroethoxy) benzyl] ethyl] -5,6-dihydrido Naphthalene-1-carboxamide, N - [(1RS,
2SR) -2- (4-Fluorophenyl) -2-hydroxy-
1- [3- (1,1,2,2-tetrafluoroethoxy)
[Benzyl] ethyl] -6,7,8,9-tetrahydro-5
H-benzo [a] cycloheptene-1-carboxamide,
4-fluoro-N-[(1R, 2S) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] naphthalene
-1-carboxamide, N-[(1RS, 2SR) -2-
(4-Fluorophenyl) -2-hydroxy-1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -5,6,7,8-tetrahydrobenzo [a] cyclooctene-1-carboxamide, N-[(1
RS, 2SR) -2- (4-Fluorophenyl) -2-hydroxy-1- (4-isopropylbenzyl) ethyl] -6
7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-((1RS, 2SR) -2- (3-fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl ) Methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-((1RS, 2SR) -2-hydroxy-2-
(4-phenoxyphenyl) -1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -6,7-dihydro
-5H-benzo [a] cycloheptene-1-carboxamide, N-[(1RS, 2SR) -2- (4-chlorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoro) Ethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-((1RS, 2SR) -2-hydroxy-2- (4-
(Phenyloxy) phenyl) -1-((3-((1,
1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-((1
RS, 2SR) -2- (4-((4-chloro-3-ethylphenyl) oxy) phenyl) -2-hydroxy-1-((3-
((1,1,2,2-tetrafluoroethyl) oxy)
Phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-
((1RS, 2SR) -2- (2-fluoropyridine-4-
Yl) -2-hydroxy-1-((3- (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) ethyl)-
6,7-dihydro-5H-benzo [a] cycloheptene-1
-Carboxamide, N-((1RS, 2RS) -2- (6-
Fluoropyridin-2-yl) -2-hydroxy-1-((3
-(1,1,2,2-tetrafluoroethoxy) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-[(1
RS, 2SR) -1- (4-tert-butylbenzyl) -2- (3-chlorophenyl) -2-hydroxyethyl] -5-chloro-1-naphthamide, 4-fluoro-N-{(1RS, 2SR) -2- (4-Fluorophenyl) -2-hydroxy-1-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] ethyl} -1-naphthamide and salts thereof.

The method for synthesizing the compound (I) of the present invention is described below. In the following description of each synthesis method, the starting compound capable of forming a salt may be used in the form of a salt. Is not particularly limited, for example, the compound (I)
Salts such as those described above are used. Compound (I) of the present invention
In the compound (Ia) wherein R ″ is a hydrogen atom,
For example, it can be synthesized by the following method. (I)

[0039]

Embedded image

[The symbols in the formula are as defined above.] This method is a method of acylating compound (II) to obtain compound (I). The reaction for converting the compound (II) into the compound (I) is as follows:
It is a reaction known per se, for example, the fourth edition of Experimental Chemistry Course (Maruzen), Vol. 22, Organic Synthesis IV, pp. 138-151, 259-27.
Page 1, Vol. 24, Organic Synthesis VI, 391-392, 396-3
It can be carried out according to or referring to the conditions described or cited on page 97 or the like. In the compound (I), the compound (I) wherein R ″ is a hydrogen atom
By subjecting a) to a hydroxyl-protecting reaction, it is possible to convert the compound (Ib) in which R ″ is a hydroxyl-protecting group. For example, when R ″ is an acyl group, Can be performed according to the present method. The reaction for introducing a protecting group to a hydroxyl group may be carried out by a method known per se or a method analogous thereto.
GROUPS IN ORGANIC SYNTHE
SIS "Second Edition (JOHN W
ILEY & SONS, INC. ) It can be performed according to or referring to the conditions described or cited on pages 10-142.

(Ii)

[0042]

Embedded image

[The symbols in the formula are as defined above] In the reduction reaction of compound (III), a method using a reducing agent for compound (III), catalytic hydrogenation in the presence of a catalyst, lead or platinum Electrolytic reduction or the like serving as a cathode can be used. Examples of the reducing agent include metal hydride complex compounds such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride and zinc borohydride, and diborane. The reducing agent is used in an amount of 1 equivalent to a large excess (preferably -10 equivalents). Examples of the catalyst used in the hydrogenation include metals such as palladium, platinum, nickel, and rhodium, and oxides, salts, and complexes thereof. These catalysts can also be used by being supported on various supports such as carbon. The hydrogenation can be performed under normal pressure or under pressure. The solvent used at this time can be appropriately selected depending on the type of the reducing agent, and examples thereof include alcohols (eg, methanol and ethanol), ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), and halogenated hydrocarbons (eg, , Methylene chloride, chloroform, etc.), aprotic polar solvents (eg, N, N-dimethylformamide, dimethyl sulfoxide, etc.). In the reduction using a reducing agent, a metal halide such as zinc chloride, manganese chloride, aluminum chloride or magnesium chloride is added in a catalytic amount or a large excess (preferably 0.1 to 2 equivalents) to control the reaction. You can do it too.
The reaction time is 0.5 to 72 hours, preferably 1 to 24 hours. The reaction can be carried out at a temperature of -100 to 100C (preferably -80 to 50C).

Compound (II) can be synthesized, for example, by the following method. (I) When R 'is a hydrogen atom

[0045]

Embedded image

[In the formula, R ³ , R ⁴ and R ⁵ each represent a C _1-6 alkyl which may have a substituent, a C _7-10 aralkyl which may have a substituent, good C _{7- 16} aralkyl optionally having, M is sodium, (if the divalent metal, the remaining monovalent may be occupied by a halogen atom) a metal atom such as magnesium indicates, M '
Represents a hydrogen atom or a metal atom such as sodium or magnesium (in the case of a divalent metal, the remaining monovalent may be occupied by a halogen atom or the like), and other symbols are as defined above. The compound (IV) is reacted with Ar ² CH ₂ -M to reduce the resulting imine or iminium ion (V), and the silyl ether is deprotected with an acid to give the compound (I
I '). In the reaction, Ar ² CH ₂ -M is used in an amount of 1 equivalent to a large excess (preferably 1 to 10 equivalents) relative to compound (IV). For the subsequent reduction reaction, a method using a reducing agent, catalytic hydrogenation in the presence of a catalyst, electrolytic reduction using lead or platinum as a cathode can be used. Examples of the reducing agent include metal hydride complex compounds such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride and zinc borohydride, and diborane. The reducing agent is used in an amount of 1 equivalent to a large excess (preferably -10 equivalents). Examples of the catalyst used in the hydrogenation include metals such as palladium, platinum, nickel, and rhodium, and oxides, salts, and complexes thereof. These catalysts can also be used by being supported on various supports such as carbon. The hydrogenation can be performed under normal pressure or under pressure. The solvent used at this time is, for example, ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), hydrocarbons (eg, toluene, hexane, etc.), halogenated hydrocarbons (eg,
Methylene chloride, chloroform, etc.).
The reaction time is 0.5 to 72 hours, preferably 1 to 24 hours. The reaction can be carried out at a temperature of -100 to 100C (preferably -80 to 50C). After the reduction reaction, an aqueous solution of an acid such as hydrochloric acid, sulfuric acid, or acetic acid is added to the reaction mixture to deprotect the silyl ether, whereby the compound (II ′) can be obtained.

(Ii)

[0048]

Embedded image

[Wherein D represents an amino-protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, trifluoroacetyl, benzyl, etc., and other symbols are as defined above]. Compound (VI) In which the protecting group of the amino group is deprotected to obtain a compound (II). The reaction for removing the protecting group for the amino group is a reaction known per se, and can be performed under these conditions.

(Iii)

Embedded image

[The symbols in the formula are as defined above.] The conversion reaction of the compound (VII) into the compound (II) is performed by using an aqueous solution of a metal hydroxide such as sodium hydroxide or potassium hydride, or an aqueous solution of hydrochloric acid or sulfuric acid. The reaction is carried out in the presence of one equivalent to a large excess of an acid aqueous solution, trimethylsilyl iodide or the like. As the solvent used at this time, for example, water, alcohols (for example,
Methanol and ethanol), ethers (for example,
Tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), and aprotic polar solvents (eg, N, N-dimethylformamide, Dimethyl sulfoxide) and the like. The reaction can be performed for 10 minutes to 24 hours and at a reaction temperature of -20 to 200 ° C (preferably 0 to 100 ° C).

Compound (III) can be synthesized, for example, by the following method.

[0053]

Embedded image

[The symbols in the formula are as defined above.] The conversion reaction of the compound (VIII) into the compound (III) is carried out, for example, under the same conditions as in the method (i) in the synthesis of the compound (I). Done.

Compound (IV) can be synthesized, for example, by the following method.

[0056]

Embedded image

[The symbols in the formula are as defined above] The reaction for converting the compound (IX) to the compound (IV) is a reaction known per se, for example, Tetrahedron Le
tt. , 26, 4275-4278 (1985);
Org. Chem. , 51, 413-415 (198
6), Tetrahedron Lett. , 28,5
513-5516 (1987), Chem. Let
t. , 537-540 (1991); Chem. S
oc. Chem. Comm. 1752-1753 (19
91); Org. Chem. , 55,1479-1
483 (1990); Fluorine Che
m. , 35, 287-294 (1987), Tetra.
hedron Lett. , 33, 2159-2162
(1992), Tetrahedron Lett. ,
34, 4001-4004 (1992), etc., or according to or referring to the conditions described or cited.

Compound (VI) can be synthesized, for example, by the following method. (I)

[0059]

Embedded image

[The symbols in the formula are as defined above.] The conversion reaction of the compound (X) into the compound (VI) is performed, for example, under the same conditions as in the method (ii) in the synthesis of the compound (I). Done.

(Ii) When R 'is a hydrogen atom

[0062]

Embedded image

[The symbols in the formula are as defined above.] The conversion reaction of the compound (XI) into the compound (VI ') is performed, for example, under the same conditions as in the method (iii) in the synthesis of the compound (II). Done in

When R ′ is not a hydrogen atom, compound (VII) can be synthesized, for example, by the following method.

[0065]

Embedded image

[The symbols in the formula are as defined above.] This method is a method of reacting compound (VII ') with an alkylating agent to obtain compound (VII). In the reaction, an alkylating agent is used in an amount of 1 equivalent to a large excess (preferably 1 to 10 equivalents) relative to compound (VII '). At this time, for example, sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 4-N, N-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [5.4.
0] -7-undecene, 1,4-diazabicyclo [2.
2.2] A basic compound such as octane (DABCO) may be used in an amount of 1 to 10 equivalents. Examples of the alkylating agent to be used include halogenated hydrocarbons and sulfonates such as alkyl methanesulfonate and alkyl p-toluenesulfonate. In the reaction, 1 equivalent to a large excess (preferably 1 to 10 equivalents) of an alkali metal iodide such as sodium iodide may be added as a reaction accelerator. Examples of the solvent used at this time include water, alcohols (eg, methanol and ethanol), ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (Eg, acetone, methyl ethyl ketone, etc.), and aprotic polar solvents (eg, N, N-dimethylformamide, dimethyl sulfoxide, etc.). The reaction time is 10 minutes to 24 hours, preferably 0.5 to 6 hours.
Time. The reaction can be carried out at a temperature of -20 to 200 ° C (preferably 0 to 150 ° C).

Compound (VII ′) (when R ′ is a hydrogen atom in compound (VII)) can be synthesized, for example, by the following method.

[0068]

Embedded image

[The symbols in the formula are as defined above] This method converts the carboxyl group of compound (XII) into an acyl azide, and converts this to a so-called Curtius.
The isocyanate is induced using a rearrangement reaction, and the resulting isocyanate undergoes a cyclization reaction with a hydroxyl group in the molecule to form a compound (VI
I '). In the reaction, the acyl azide is
For example, it can be synthesized by the following three methods.

Method A: First, compound (XII) is treated with one equivalent to a large excess of a halogenating agent (eg, thionyl chloride, oxalyl chloride, phosphorus pentachloride, etc.) to convert to an acyl halide. In this reaction, 1 to 10 equivalents of a basic compound such as pyridine, 4-N, N-dimethylaminopyridine, or triethylamine may be used. In the reaction, a catalytic amount of N, N-dimethylformamide may be added as a reaction accelerator. Examples of the solvent used at this time include ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), esters (eg, For example, ethyl acetate and the like, and aprotic polar solvents (for example, N, N-dimethylformamide, dimethyl sulfoxide and the like) and the like. The reaction can be carried out at a temperature of -100 to 200C (preferably -20 to 100C). The resulting acyl halide is reacted with one equivalent to a large excess of an alkali metal azide (eg, sodium azide) to form an acyl azide. In this reaction, pyridine, 4-N, N-dimethylaminopyridine,
A basic compound such as triethylamine may be used in 1 to 10 equivalents. Examples of the solvent used at this time include ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), esters (eg, For example, ethyl acetate and the like, and aprotic polar solvents (for example, N, N-dimethylformamide, dimethyl sulfoxide and the like) and the like. The reaction can be carried out at a temperature of -100 to 200C (preferably -20 to 100C).

Method B: After converting the compound (XII) into an acyl halide by the method described in Method A, the compound is treated with 1 equivalent or a large excess of hydrazine to give hydrazide. In this reaction, pyridine, 4-N, N-dimethylaminopyridine,
A basic compound such as triethylamine may be used in 1 to 10 equivalents. Examples of the solvent used at this time include ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), esters (eg, For example, ethyl acetate and the like, and aprotic polar solvents (for example, N, N-dimethylformamide, dimethyl sulfoxide and the like) and the like. The reaction can be carried out at a temperature of -100 to 200C (preferably -20 to 100C). The resulting hydrazide is treated with one equivalent to a large excess of nitrous acid (which can also be generated from a metal nitrite such as sodium nitrite in the presence of an acid) to produce an acyl azide. As the solvent used at this time,
For example, water, alcohols (eg, methanol, ethanol, etc.), ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.),
Examples include ketones (eg, acetone, methyl ethyl ketone, etc.), esters (eg, ethyl acetate, etc.), and aprotic polar solvents (eg, N, N-dimethylformamide, dimethyl sulfoxide, etc.). The reaction temperature is from -100 to 200 ° C (preferably -2
(0 to 50 ° C).

Method C: Compound (XII) is reacted with 1 equivalent to a large excess of diphenylphosphoryl azide to produce an acyl azide. At this time, for example, sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 4-N, N-dimethylaminopyridine (DMAP),
8-diazabicyclo [5.4.0] -7-undecene,
1,4-diazabicyclo [2.2.2] octane (DA
A basic compound such as BCO) may be used in an amount of 1 to 10 equivalents. Examples of the solvent used at this time include water, alcohols (eg, methanol and ethanol), ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (Eg, acetone, methyl ethyl ketone, etc.), esters (eg, ethyl acetate, etc.), and aprotic polar solvents (eg, N, N-dimethylformamide, dimethyl sulfoxide, etc.). The reaction time is 10 minutes to 24 hours, preferably 0.5 to 6 hours. The reaction temperature can be from -20 to 200C.

By subjecting the obtained acyl azide to a Curtius rearrangement reaction, an isocyanate is derived. The reaction is carried out by heating the obtained acyl azide to 30 to 200 ° C. At this time, for example, triethylamine, diisopropylethylamine, pyridine, 4-
Basic compounds such as N, N-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [5.4.0] -7-undecene and 1,4-diazabicyclo [2.2.2] octane (DABCO) You may use 1-10 equivalent. At this time, for example, water, alcohols (eg, methanol or ethanol), ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (eg, The reaction can also be performed in a solvent such as acetone, methyl ethyl ketone, etc., esters (eg, ethyl acetate, etc.), and aprotic polar solvents (eg, N, N-dimethylformamide, dimethyl sulfoxide, etc.). The reaction time is 10 minutes to 24 hours, preferably 0.5 to 6 hours. Under the reaction conditions, the intramolecular cyclization reaction following the Curtius reaction can be allowed to proceed in the same system to induce the compound (VII '). Derivation of the isocyanate obtained by the Curtius reaction into compound (VII ') is carried out by heating the isocyanate to 30 to 200 ° C. At this time, for example, triethylamine, diisopropylethylamine,
Pyridine, 4-N, N-dimethylaminopyridine (DMA
P), 1-10 equivalents of a basic compound such as 1,8-diazabicyclo [5.4.0] -7-undecene or 1,4-diazabicyclo [2.2.2] octane (DABCO) may be used. . At this time, for example, water, alcohols (for example,
Methanol and ethanol), ethers (for example,
Tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), esters (eg, ethyl acetate, etc.), and aprotic polar solvents (eg, ethyl acetate). For example, N, N-
(Dimethylformamide, dimethylsulfoxide, etc.). The reaction time is 10 minutes to 24 hours, preferably 0.5 to 6 hours.
A series of reactions from compound (XII) to compound (VII ') can be performed in the same system without isolating each intermediate.

Compound (VIII) can be synthesized, for example, by the following method.

[0075]

Embedded image

[The symbols in the formula are as defined above.] The conversion reaction of the compound (X) into the compound (VIII) is carried out, for example, under the same conditions as in the method (ii) in the synthesis of the compound (II). Done.

When R ′ is not a hydrogen atom, compound (X) can be synthesized, for example, by the following method.

[0078]

Embedded image

[The symbols in the formula are as defined above.] The conversion reaction of compound (X ') into compound (X) is carried out, for example, under the same conditions as in the method shown in the synthesis of compound (VII).

Compound (X ′) (when R ′ is a hydrogen atom in compound (X)) can be synthesized, for example, by the following method.

[0081]

Embedded image

[Wherein, E represents a halogen atom such as chloro, bromo, iodo or the like, or a leaving group such as methanesulfonyloxy, p-toluenesulfonyloxy, etc., and other symbols are as defined above]. Compound (XIII) is reacted with Ar ^{2 in the} presence of a basic compound.
In this method, compound (X ′) is obtained by reacting with CH ₂ -E.
In the reaction, 1 equivalent to a large excess of the basic compound and 1 equivalent to a large excess of Ar ² C with respect to compound (XIII)
Use H ₂ -E. Examples of the basic compound used at this time include sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 4-N, N-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [5.4.0] -7-undecene, 1,4-diazabicyclo [2.2.2] octane (DABCO) and the like. Examples of the solvent used at this time include water, alcohols (eg, methanol and ethanol), ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (Eg, acetone, methyl ethyl ketone, etc.), esters (eg, ethyl acetate, etc.), and aprotic polar solvents (eg, N, N-dimethylformamide, dimethyl sulfoxide, etc.). The reaction time is 10 minutes to 24 hours, preferably 0.5 to 6 hours.
The reaction temperature is -20 to 200 ° C (preferably 0 to 80 ° C).
C).

Compound (XI) can be synthesized, for example, by the following method.

[0084]

Embedded image

[The symbols in the formula are as defined above.] In this reaction, compound (XI) is reacted with a reagent for introducing an amino-protecting group in the presence of a basic compound to give compound (XI). How to get. In this reaction, 1 equivalent to a large excess of a basic compound and 1 equivalent to a large excess of a reagent for introducing an amino-group-protecting group to compound (VII ′) are used. Examples of the basic compound used at this time include sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 4-N, N-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [5.4.
0] -7-undecene, 1,4-diazabicyclo [2.
2.2] octane (DABCO). As a reagent for introducing a protecting group for an amino group used at this time, for example, acetic anhydride, trifluoroacetic anhydride, acetate chloride, benzyl chlorocarbonate, di-tert-butyl dicarbonate and the like can be mentioned. Examples of the solvent used at this time include water, alcohols (eg, methanol and ethanol), ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (Eg, acetone, methyl ethyl ketone, etc.), esters (eg, ethyl acetate, etc.), and aprotic polar solvents (eg, N, N-dimethylformamide,
Dimethyl sulfoxide) and the like. The reaction time is 10 minutes to 24 hours, preferably 0.5 to 6 hours. The reaction can be carried out at a temperature of -20 to 200C (preferably 0 to 80C).

Compound (XII) can be synthesized, for example, by the following method.

[0087]

Embedded image

[Wherein, R ″ ′ represents C _1-6 alkyl which may have a substituent, C _7-10 aralkyl which may have a substituent, A good C _7-16 aralkyl, and the other symbols are as defined above.] The compound (XI) is obtained by hydrolyzing the ester group of the compound (XIV).
I) is the way to get. The hydrolysis reaction of the ester group is
All are per se known reactions, and can be carried out under these conditions.

Compound (XIII) can be synthesized, for example, by the following method.

[0090]

Embedded image

[The symbols in the formula are as defined above.] A compound (XI
II) is a method to obtain. The reactions for protecting the amino group with a protecting group are all known reactions per se, and can be performed according to those conditions.

Compound (XIV) can be synthesized, for example, by the following method.

[0093]

Embedded image

[The symbols in the formula are as defined above.] The conversion reaction of the compound (XVI) into the compound (XIV) is carried out, for example, under the same conditions as in the method (ii) in the synthesis of the compound (I). Done.

Compound (XV) can be synthesized, for example, by the following method.

[0096]

Embedded image

[The symbols in the formula are as defined above] In the reduction reaction of compound (XVII), catalytic hydrogenation in the presence of a catalyst or the like can be used. Examples of the catalyst used in the hydrogenation include metals such as palladium, platinum, nickel, and rhodium, and oxides, salts, and complexes thereof. These catalysts can also be used by being supported on various supports such as carbon. The hydrogenation can be performed under normal pressure or under pressure. The solvent used at this time can be appropriately selected and includes, for example, alcohols (eg, methanol and ethanol), ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform) And the like, esters (eg, ethyl acetate, etc.), aprotic polar solvents (eg, N, N-dimethylformamide, dimethylsulfoxide, etc.). The reaction time is 0.5 to 72 hours, preferably 1 to 24 hours. Reaction temperature is -100 to 1
It can be carried out at 00 ° C (preferably -70 to 50 ° C).

Compound (XVI) can be synthesized, for example, by the following method.

[0099]

Embedded image

[The symbols in the formula are as defined above.] The conversion reaction of compound (XVIII) into compound (XVI) is carried out, for example, under the same conditions as in the method shown in the synthesis of compound (X '). In addition, the compound (XVIII) which is a raw material compound is described in, for example, Heterocycles, 23, 2277-22.
87 (1985); Org. Chem. , 53,8
69-873 (1988); Org. Chem. ,
53, 873-875 (1986); Chem. Pha
rm. Bull. , 38, 103-109 (1990).
From Ar ¹ COOH according to the conditions described or cited in J. Am. Chem.
Soc. , 109, 7488-7494 (1987),
J. Org. Chem. , 53, 2968-2971
(1988), Tetrahedron Lett. ,
32, 7731-7734 (1991), etc., according to or referring to the conditions described in
^{From 1} C (= O) Cl, J.I. Heterocyclic
Chem. , 22, 1033-1034 (1985),
J. Heterocyclic Chem. , 25,1
737-1740 (1988); Med. Che
m. , 34, 798-806 (1991), Tetra.
hedron, 46, 4473-4486 (199)
0); Org. Chem. , 64, 1512-15
19 (1999) or the like, or can be synthesized from Ar ¹ C (＝ O) CH ₃ according to or referring to the conditions described or cited.

Compound (XVII) can be synthesized, for example, by the following method.

[0102]

Embedded image

[Wherein X represents a halogen atom and the other symbols have the same meanings as described above.] In this reaction, compound (XIX) is reacted with 1 equivalent to a large excess of an alkali metal azide (eg, sodium azide). This is a method of obtaining a compound (XVII) by reacting. Examples of the solvent used at this time include water, alcohols (eg, methanol and ethanol), ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (Eg, acetone, methyl ethyl ketone, etc.), esters (eg, ethyl acetate, etc.), and aprotic polar solvents (eg, N, N-
Dimethylformamide, dimethylsulfoxide, etc.). The reaction time ranges from 10 minutes to 24 hours. The reaction can be carried out at a temperature of -20 to 200 ° C (preferably 0 to 50 ° C).

Further, the target compound and the starting compound are
In each reaction to be synthesized, the starting compound used is
Amino, carboxyl, and hydroxy groups as substituents
If present, these groups are generally used in peptide chemistry, etc.
It may have introduced a protecting group such as used.
By removing protecting groups as necessary after the reaction.
The desired compound can be obtained. Amino group protection
As the group, for example, each may have a substituent
C_1-6Alkylcarbonyl (eg, formyl, methyl
Carbonyl, ethylcarbonyl, etc.), phenylcarbo
Nil, C_1-6Alkyl-oxycarbonyl (e.g.,
Ethoxycarbonyl, ethoxycarbonyl, etc.), C_6-10
Aryl-oxycarbonyl (e.g., phenyloxy
Carbonyl, etc.), C_7-10Aralkyl-carbonyl (eg
For example, benzyloxycarbonyl), trityl,
Taroyl or the like is used. As these substituents,
Halogen atom (eg, fluoro, chloro, bromo,
Mode), C_1-6Alkyl-carbonyl (e.g.,
Tylcarbonyl, ethylcarbonyl, butylcarbonyl
), Nitro group, etc., and the number of substituents is not 1
There are about three. As a carboxyl protecting group,
For example, C which may have a substituent_1-6Archi
(Eg, methyl, ethyl, propyl, isopropyl
Butyl, tert-butyl, etc.), phenyl, triti
And silyl are used. As these substituents
Is a halogen atom (eg, fluoro, chloro, bromine)
Mo, iodine, etc.), C_1-6Alkylcarbonyl (eg,
For example, formyl, methylcarbonyl, ethylcarbonyl,
Butyl carbonyl), nitro group, etc.
The number of substituents is about 1 to 3. Preservation of hydroxy group
As the protective group, for example, each may have a substituent.
C _1-6Alkyl (eg, methyl, ethyl, propyl
Isopropyl, butyl, tert-butyl, etc.)
Nil, C_7-10Aralkyl (eg, benzyl, etc.), C
_{1 -6}Alkylcarbonyl (eg, formyl, methyl
Rubonyl, ethylcarbonyl, etc.), C_6-10Aryl-
Oxycarbonyl (eg, phenyloxycarbonyl
Etc.), C_7-10Aralkyl-carbonyl (e.g., ben
Diyloxycarbonyl), pyranyl, furanyl,
Rill and the like are used. These substituents include halo
Gen atoms (eg, fluoro, chloro, bromo, iodo)
Etc.), C_{1- 6}Alkyl, phenyl, C_7-10Aralki
And nitro groups are used, and the number of substituents is 1 to 4
About one. As a method for removing the protecting group,
A method known per se or a method similar thereto is used.
Acid, base, reduction, ultraviolet light, hydrazine, phenyl hydride
Azine, sodium N-methyldithiocarbamate,
Trabutylammonium fluoride, such as palladium acetate
A method of processing is used.

The fractional purification of the compound (I) and its raw material from the reaction mixture is carried out according to ordinary fractional purification means (eg, extraction, concentration, filtration, recrystallization, column chromatography, thin-layer chromatography). When the compound (I) thus obtained is obtained in a free form, it can be converted into a salt by a method known per se or a method analogous thereto (eg, neutralization and the like), and conversely, By a method known per se or a method analogous thereto,
It can be converted to a free form or other salts. further,
When the compound (I) is an optically active compound, it can be separated into d-form and l-form by ordinary optical resolution means.

The compounds (I) and (I ') of the present invention have low toxicity, are useful as pharmaceuticals, have a cholesteryl ester transfer protein inhibitory effect, and have excellent HDL
-Has cholesterol-elevating, LDL-cholesterol-lowering, VLDL-cholesterol-lowering and triglyceride-lowering effects. Therefore, the agent of the present invention
It is useful as a preventive or therapeutic drug for diseases based on this pharmacological action. That is, hyperlipidemia in mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, horses, sheep, monkeys, humans, etc.), particularly high LDL-cholesterolemia, hyperlipoproteinemia and Hypertriglyceridemia,
Low HDL-cholesterolemia and atherosclerotic vascular lesions resulting therefrom and their sequelae,
For example, acute myocardial infarction, acute coronary syndrome such as unstable angina, peripheral artery occlusion, percutaneous coronary angioplasty (PTC
A) or restenosis of the artery after stent placement, myocardial infarction,
Ischemic heart disease such as angina, arteriosclerosis, intermittent claudication, stroke (cerebral infarction, cerebral embolism, cerebral hemorrhage, etc.), lacne infarction, cerebrovascular dementia, gangrene, glomerulosclerosis, nephropathy, Tangie
It is particularly suitable for treatment and prevention of R disease and the like, or suppression of the progression of atherosclerotic lesions. The compounds (I) and (I ′) of the present invention have an LDL-cholesterol-lowering effect but do not show a HDL-cholesterol-elevating effect when compared with a drug having no LDL-cholesterol-lowering effect. It is useful for prevention and treatment of HDL blood and the like. The ultimate purpose of hyperlipidemia drugs is to prevent the onset of fatal diseases such as myocardial infarction. Although an effect of preventing onset is observed, an HDL-cholesterol-elevating agent can more strongly prevent the onset of myocardial infarction and the like. Furthermore, L
A drug that has a DL-lowering effect but does not show an HDL-elevating effect is also effective for patients or diseases / symptoms (eg, intractable hyperlipidemia) where no therapeutic effect is observed, and serum lipids are at normal levels. Even in a certain human, it is possible to suppress the incidence of fatal diseases such as myocardial infarction and improve the therapeutic effect.

The compound (I) and the compound (I ′) may be in the raw form, but are usually used as carriers for preparations such as excipients (eg, calcium carbonate, kaolin, sodium hydrogen carbonate, lactose, starches, crystals) Cellulose, talc, granulated sugar, porous substances, etc.), binders (eg, dextrin, gums, alcoholized starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, etc.), disintegrants (eg, carboxymethylcellulose calcium, Croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, partially pregelatinized starch, etc.), lubricants (for example,
Magnesium stearate, calcium stearate,
Talc, starch, sodium benzoate, etc.), coloring agents (eg, tar dye, caramel, iron sesquioxide, titanium oxide,
Riboflavins, etc.), flavoring agents (eg, sweeteners, flavors, etc.), stabilizers (eg, sodium sulfite, etc.), and preservatives (eg, parabens, sorbic acid, etc.). It is administered in a form prepared according to the method. The prophylactic / therapeutic agent of the present invention containing the above-mentioned preparation suitably contains Compound (I) or Compound (I ′) in an amount effective for treating and preventing a disease. The content of compound (I) and compound (I ') in the preparation of the present invention is usually 0.1 to 100% by weight of the whole preparation. Further, the preparation used in the present invention may contain other pharmaceutical ingredients other than the compound (I) or the compound (I ′) as an active ingredient. It is not limited, and can be used at an appropriate mixing ratio. Specific examples of dosage forms include tablets (including sugar-coated tablets and film-coated tablets), pills, capsules, granules, fine granules, powders, syrups, emulsions, suspensions, injections, inhalants, Ointments and the like are used. These preparations are prepared according to a conventional method (for example, a method described in the Japanese Pharmacopoeia).

Specifically, in the method for producing tablets, compound (I) or compound (I ′) was mixed as it was with an excipient, a binder, a disintegrant or other appropriate additives. The product is made into granules by an appropriate method, and then a lubricant or the like is added and compression-molded, or the compound (I) or the compound (I ′) is used as it is, or as an excipient, a binder, a disintegrant or other materials. What is added and uniformly mixed with the appropriate additive is directly compression-molded, or is directly mixed with granules prepared in advance, or after adding the appropriate additive and uniformly mixed, then compression-molded. Can also be manufactured. In addition, the present agent can contain a coloring agent, a flavoring agent, and the like as needed. Further, the agent can be coated with an appropriate coating agent. The production method for injections is
A certain amount of compound (I) or compound (I ') is dissolved, suspended or emulsified in water for injection, physiological saline, Ringer's solution or the like in the case of an aqueous solvent, and usually in vegetable oil or the like in the case of a non-aqueous solvent. Alternatively, a predetermined amount of the compound (I) or the compound (I ′) is taken and sealed in a container for injection. As the pharmaceutical carrier for oral use, substances commonly used in the field of pharmaceuticals such as starch, mannitol, crystalline cellulose and sodium carboxymethylcellulose are used. As the carrier for injection, for example, distilled water, physiological saline, glucose solution, infusion agent and the like are used. In addition, additives generally used in preparations can be appropriately added. Further, the preparation of the present invention can be used as a sustained release preparation. The sustained-release preparation of the present invention can be prepared, for example, by microcapsules (for example, microspheres) produced by an in-water drying method (o / w method, w / o / w method, etc.), a phase separation method, a spray drying method or a method analogous thereto.・
Microcapsules, microparticles, etc.) as they are, or these microcapsules or spherical, needle-like, pellet-like, film-like, or cream-like pharmaceutical compositions can be formulated into various dosage forms as a raw material and administered. Examples of the dosage form include parenteral preparations (for example, injections or implants for intramuscular, subcutaneous, organ, etc .; transmucosal preparations for nasal cavity, rectum, uterus, etc.), oral preparations (for example, hard capsules, Soft capsules, granules, powders, suspensions and the like). When the sustained-release preparation of the present invention is an injection, a microcapsule is used as a dispersant (for example, Tween
Surfactants such as 80, HCO-60; polysaccharides such as carboxymethylcellulose, sodium alginate and sodium hyaluronate; protamine sulfate, polyethylene glycol, etc.), preservatives (eg, methylparaben, propylparaben, etc.), isotonicity agents ( For example, sodium chloride,
Mannitol, sorbitol, glucose, etc.), local anesthetics (eg, xylocaine hydrochloride, chlorobutanol, etc.)
Or a vegetable oil (eg, sesame oil, corn oil, etc.) or a mixture thereof with a phospholipid (eg, lecithin) or a medium-chain fatty acid triglyceride (eg, Miglyol 812, etc.) To give a sustained-release injection as an oily suspension. When the sustained-release preparation of the present invention is a microcapsule, the average particle size is about 0.1 to about 300 μm, preferably,
It is about 1 to about 150 μm, more preferably about 2 to about 100 μm. Examples of methods for making the microcapsules into a sterile preparation include a method of sterilizing the whole production process, a method of sterilizing with gamma rays, and a method of adding a preservative, but are not particularly limited.

In the treatment of these diseases, Compound (I) and Compound (I ′) may be used alone for prophylaxis and / or treatment, and may also be used for other lipid-lowering drugs, cholesterol-lowering drugs, myocardial protection. Drugs, coronary artery disease drugs, diabetes drugs, hypothyroid drugs, nephrotic syndrome drugs, osteoporosis drugs or other pharmaceutical ingredients including chronic renal failure drugs, in which case these compounds may be used. Is preferably administered as an oral preparation, and if necessary, may be administered in the form of suppositories as a rectal preparation. In this case, the components that can be combined include, for example, (1) PPARα agonists such as fibrates (eg, clofibrate, bezafibrate, gemfibrozil, fenofibrate, etc.);
Nicotinic acid, its derivatives and analogs (eg, acipimox, probucol, etc.), (2) bile acid-binding resins (eg, cholestyramine, colestipol, etc.), compounds inhibiting cholesterol absorption (eg, sitosterol, neomycin, etc.), 3) Compounds that inhibit cholesterol biosynthesis (eg, HMG-CoA reductase inhibitors such as lovastatin, simvastatin, pravastatin, cerivastatin, atorvastatin, fluvastatin, itavastatin, rosuvastatin), squalene epoxidase inhibitors (eg, NB) -598 and analogs thereof), squalene synthase inhibitors (eg, benzoxazepine derivatives and the like) and the like. Still other possible combination components include oxidosqualene-lanosterol cyclase (eg, decalin derivatives, azadecalin derivatives, indane derivatives, etc.), microsomal triglyceride transfer protein inhibitors (implaptide)
Etc.). Also, a therapeutic agent for diabetes [Actos, rosiglidason, kinedac, benfil, humulin, oigurcon, glimicron, daoneil, novolin, monotard, insulins, glucoby, dimerin, rustinone, basilcon, deamelin S, isgilin]; hypothyroidism Therapeutic agent [dry thyroid (thyreoid), levothyroxine sodium (thyrazine S), liothyronidine sodium (thyronine, thyromin); Nephrotic syndrome therapeutic agent: prednisolone (prednin), prednisolone sodium succinate (prednin), methylprednisolone sodium succinate (Sol Medrol), Betamethasone (Rinderone)]; Anticoagulant [Dipyridamole (Versanthin), Dilazep hydrochloride (Comerian), Tylopidine, Clovide Grell, X
a inhibitor]; a drug for treating chronic renal failure [diuretic [eg, furosemide (Lasix), bumetanide (Lunetron), azosemide (Diart)]], antihypertensive (eg, ACE inhibitor,
When used in combination with (enalapril maleate (Lenibase)) and a Ca antagonist (manidipine), an α receptor blocker, an AII antagonist (candesartan), etc., it can be preferably used orally.

Further, compound (I) and compound (I ')
Is suitable for treating diseases associated with cell hyperproliferation. A major example of a disease associated with cell overgrowth is a tumor. It has been reported that lowering serum total cholesterol or lowering LDL-cholesterol or VLDL-cholesterol reduces tumor growth (Lancet 33).
9: 1154-1156, 1992). Therefore, compound (I) and compound (I ′) are prepared from LDL-cholesterol or VLD
It has an L-cholesterol lowering effect and is capable of treating tumors and can be used alone or in combination with known treatments to treat tumors. Other applicable diseases include hyperproliferative skin diseases such as psoriasis, basal cell carcinoma, squamous cell carcinoma, keratosis and keratinization disease. Hyperproliferative vascular disease, for example, vascular stenosis and occlusion caused by surgical means such as PTCA (percutaneous angioplasty) or bypass surgery is based on smooth muscle cell proliferation and The compounds are also suitable for treating and preventing these diseases in view of their LDL-cholesterol and VLDL-cholesterol lowering effects. They can be used here alone or in combination with known active compounds, such as, for example, intravenously administered heparin, preferably for oral administration.

Further possible uses of the compounds of the present invention include:
Gallstone prevention and treatment. When cholesterol in bile exceeds its maximum solubility, cholesterol precipitates and forms gallstones. Fibrate lipid-lowering drugs increase the secretion of neutral steroids into the bile and increase the sensitivity of gallstone formation. In contrast,
Cholesterol biosynthesis inhibitors, such as lovastatin or pravastatin, do not promote gallstone formation, but can reduce the gallstone formation index because they cause a reduction in bile cholesterol levels (Gut 31: 348-350, 1990). Furthermore, lovastatin has been reported to be effective in dissolving gallstones in combination with ursodeoxy bile acids (Gastroenterology
102, No. 4, Pt. 2, A319, 1992). Thus, given the mode of action, the compounds of the invention are suitable for the prevention and treatment of gallstones. They may be used alone or in combination with known therapeutic agents (such as ursodeoxy bile acid) or known therapeutics (such as shockwave lithotripsy), preferably for oral administration.

The compounds (I) and (I ') of the present invention have a blood HDL-cholesterol increasing effect. Increase in blood HDL-cholesterol promotes export of cholesterol from cells having excess cholesterol (Current Opinion in Lipidology 4: 3
92-400), so that it is suitable for treating and preventing atherosclerosis. Given their biological properties, they are particularly suitable for the treatment and prevention of atherosclerotic vascular lesions and their net onset, such as coronary artery disease (CHD), cerebral ischemia, intermittent claudication, gangrene, and the like. Another application of the present invention is based on the antioxidant action of HDL. Lipid peroxide in blood is much higher in HDL than in LDL, and HDL has a role in protecting against lipid peroxidation that occurs in the body, such as oxidation of LDL (Curr).
ent Opinion in Lipidology 4: 392-400, Curr
ent Opinion in Lipidology 5: 354-364).

Still another use of the present invention is hypertension and its sequelae. Hyperlipidemia exacerbates arteriosclerosis and causes hypertension. On the other hand, HDL is an oxidized LD
L is known to prevent the inhibition of EDRF (endothelium-derived relaxing factor) biosynthesis and release, and to increase the vascular relaxing factor prostacyclin in macrophages (Current Opinion in Lipidology 5: 354-3).
64). Lipid-lowering effect of substance of the present invention and blood HDL-
Considering the cholesterol-elevating effect, it is suitable for treating and preventing hypertension and its sequelae, such as coronary artery disease (CHD) and cerebral ischemia. At that time, the compound of the formula (I) or (I ′) or a salt thereof can be administered alone or in combination with the agents exemplified below.
Possible combinations in this case include, for example, angiotensin-II antagonists [eg, losartan potassium (neurotan), candesartan rexetil (probres), etc.],
ACE inhibitors (eg, enalapril maleate (Lenibase), lisinopril (Zestril, Ronges), delapril hydrochloride (Adecat), captopril, etc.), calcium antagonists (eg, amlodipine tosylate (amlodin, norvasc), manidipine hydrochloride (calslot) ) Etc.], antihypertensive diuretics, α receptor blockers, β receptor blockers and the like.

Possible uses of the compounds (I) and (I ′) of the present invention include those based on cytoprotective action from cytotoxic secretions such as gastric juice / pancreatic juice and bile.
Fluid-tissue cells mainly express apoJ and serve as a natural barrier to cytotoxic secretions such as gastric juice, pancreatic juice and bile, and HDL is a carrier of apoJ (clusterin) (Current Opinion in Lipidology 4: 3
92-400). Considering the blood HDL-cholesterol elevating effect of the compounds (I) and (I ') of the present invention, the compounds (I) and (I') of the present invention are useful for treating and preventing gastric ulcer, pancreatitis and hepatitis. Are suitable.

Further possible uses of the compounds (I) and (I ') of the present invention include those based on cell proliferation activity. HDL alone or together with growth factors promotes proliferation of cells such as vascular endothelial cells (EC) and corneal endothelium, and HDL promotes proliferation of human lymphocytes (Cu
rrent Opinion in Lipidology 3: 222-226).
Compound (I) and compound (I ′) of the present invention have a high blood HD
It has an L-cholesterol increasing effect. Considering these cell proliferating activities, they are suitable for treating and preventing atherosclerotic vascular lesions and their sequelae, such as coronary artery disease and corneal injury. In addition, it is also suitable for treatment and prevention of diseases based on decreased immunocompetence, such as infectious diseases and malignant tumors.

As an additional use of the compounds (I) and (I ') of the present invention, HDL specifically acts on human placenta transplant tissues to secrete lactogen and promotes apoE secretion from macrophages. (Curr
ent Opinion in Lipidology 3: 222-226). Considering its secretion promoting activity, it is also suitable for treatment and prevention of fetal growth failure and the like.

A further noteworthy application of compound (I) and compound (I ') is secondary hyperlipidemia. These include diabetes, insulin resistance (syndrome X), hypothyroidism, nephrotic syndrome or chronic renal failure, etc. These diseases cause hyperlipidemia, but often hyperlipidemia. Is said to exacerbate these diseases and form a so-called vicious circle. In view of the lipid-lowering effect, compound (I) and compound (I ′) are also suitable for treating and preventing the progress of these diseases, wherein compound (I) and compound (I ′) are used alone or In combination with a known active compound, ie, a therapeutic agent for diabetes, for example, (1) a diuretic (eg, furosemide, spironolactone, etc.), (2) a sympathomimetic (eg, atenolol, etc.), (3) angiotensin II antagonist Drugs (eg, losartan, candesartan, etc.),
(4) Angiotensin I converting enzyme inhibitors (eg, enalapril maleate, delapril hydrochloride, etc.), (5) Calcium antagonists (eg, nifedipine, manidipine hydrochloride, etc.) and the like, and therapeutic agents for hypothyroidism In combination with dry thyroid, levothyroxine sodium, liothyronine sodium, etc., and in combination with renal disease drug, prednisolone, methylprednisolone sodium succinate, furosemide, bumetanide, azosemide, etc., preferably oral Can be used for administration.

Compound (I) and compound (I ') are also useful for preventing and treating Alzheimer's disease. Elevated blood cholesterol is known to be a risk factor for Alzheimer's disease. A CETP inhibitor such as a compound represented by the formula (I) or (I ′) or a salt thereof, or a prodrug thereof is used for prevention and treatment of Alzheimer's disease due to its excellent HDL-cholesterol increasing and lipid lowering effects. In this case, the CETP inhibitor can be administered alone or in combination with the agents exemplified below. Possible combinations in this case are:
For example, acetylcholinesterase inhibitors (e.g.,
Aricept, exelon, etc.), amyloid β production / secretion inhibitor (e.g., γ or β secretase inhibitor such as JT-52 or LY-374973, or SIB-1848, etc.), amyloid β aggregation inhibitor (e.g., PTI-00703 And BETABLOC (AN-
1792)). A further notable indication of compound (I) and compound (I ′) is osteoporosis associated with elevated blood cholesterol. Due to the excellent lipid-lowering effect of compound (I) and compound (I ′), it can be used for treatment and prevention of osteoporosis associated with an increase in blood cholesterol, in which case compound (I) and compound (I ′) It can be administered alone or in combination with the drugs exemplified below. Possible combinations in this case include, for example, sex hormones and related drugs (eg, estrogen preparations, ipriflavone (osten), raloxifene, osaterone, tibolone, etc.), calcitonins, vitamin D preparations (eg, alfacalcidol, calcitriol) Etc.), bisphosphonic acids (eg, etidronate,
Bone resorption inhibitors such as clodronate), fluorine compounds, and bone formation promoters such as PTH.

In addition, compound (I) and compound (I ') are suitable for treating diseases associated with hyperchylomicronemia, for example, acute pancreatitis. Regarding the mechanism of pancreatitis onset, micro-emboli occur in pancreatic capillaries due to chylomicron, or triglyceride is degraded by pancreatic lipase due to hyperchylomicronemia, increasing the free fatty acids produced and strongly stimulating the local area It is said to happen. Therefore, the compounds (I) and (I ′) of the present invention have a triglyceride lowering effect, and thus can treat pancreatitis, and can be used alone or in combination with known therapeutic methods for treating pancreatitis. For the treatment of this disease, the compounds (I) and (I ′) of the present invention can be administered orally or topically, or they can be used alone or in combination with known active compounds. Possible combination components in this case include, for example, aprotinin (tradirol), gabexate mesilate (EFOY FOY), nafamostat mesilate (fusan), citicoline (nicoline), ulinastatin (miracride) for antienzyme therapy. . Anticholinergics, non-narcotic analgesics, and narcotics are also used for pain relief.

A further possible use of the compounds (I) and (I ') of the present invention is in the inhibition of thrombus formation.
Blood triglyceride levels are positively correlated with factor VII involved in blood coagulation. Ingestion of ω-3 fatty acids lowers triglycerides and suppresses coagulation, so hypertriglyceridemia promotes thrombus formation I do. In addition, since VLDL of hyperlipidemic patients increased plasminogen activator inhibitor secretion from vascular endothelial cells more strongly than normolipidemic patients, it is also considered that triglycerides decrease fibrinolytic ability. Therefore, in view of the triglyceride lowering action, compound (I) and compound (I ′)
Is suitable for the prevention and treatment of thrombus formation. In that case they can be used alone or in combination with the following known therapeutic agents,
Preferably it can be used for oral administration. Antithrombotic drug: Anticoagulant (eg, heparin sodium, heparin calcium, warfarin calcium (warfarin), Xa inhibitor), thrombolytic drug (eg,
tPA, urokinase], antiplatelet drugs [eg, aspirin, sulfinpyrazolo (anturane), dipyridamole (persantin), ticlopidine (panaldine),
Cilostazol (pletal), GPIIb / IIIa antagonist (Leopro)] Coronary vasodilators: nifedipine, diltiazem, nicorazil, nitrite; cardioprotective agents: cardiac ATP-K openers, endothelin antagonists, urotensin antagonists and the like. Furthermore, when the compound of the present invention is applied to each of the above diseases, it can be used in combination with a biological agent (eg, antibody, vaccine preparation, etc.),
It can be applied as a combination therapy in combination with a gene therapy or the like. Antibodies and vaccine preparations include, for example, a vaccine preparation against angiotensin II, a vaccine preparation against CETP, a CETP antibody, an antibody against TNFα antibody and other cytokines, an amyloid β vaccine preparation, a type 1 diabetes vaccine (such as DIAPEP-277 of Peptor) Antibodies or vaccines against cytokines, renin-angiotensin enzymes and their products, antibodies or vaccines against enzymes and proteins involved in blood lipid metabolism, enzymes and proteins involved in blood coagulation / fibrinolysis system Examples include an antibody or a vaccine, an antibody against a protein involved in glucose metabolism or insulin resistance, or a vaccine preparation. Examples of the gene therapy include, for example, a therapy using a gene related to a cytokine, a renin-angiotensin enzyme and its product, a therapy using a DNA decoy such as NFκB decoy, a therapy using an antisense, Therapy using genes related to enzymes and proteins involved in lipid metabolism (eg, genes related to metabolism, excretion and absorption of cholesterol or triglyceride or HDL-cholesterol or blood phospholipids), peripheral vascular obstruction, etc. Enzymes and proteins (eg, HGF, VEGF)
And the like, such as growth factors, etc.), therapies using genes related to proteins involved in glucose metabolism and insulin resistance, and antisense to cytokines such as TNF. Also, heart regeneration,
It can be used in combination with various organ regeneration methods such as kidney regeneration, pancreatic regeneration, and blood vessel regeneration, and angiogenesis therapy utilizing transplantation of bone marrow cells (bone marrow mononuclear cells, bone marrow stem cells, etc.).

The dose of the preparation of the present invention may vary depending on the administration route, symptoms, age of the patient, body weight and the like.
For example, when orally administered to an adult patient as a therapeutic agent for arteriosclerosis, the compound (I) or compound (I ′) is 0.2 to 50 mg / day, preferably 1.
It is preferable to administer 5 to 30 mg / day in 1 to several divided doses. The administration route may be oral or parenteral.
The dose of the sustained-release preparation of the present invention may vary depending on the route of administration, symptoms, age, weight, etc. of the patient, as well as the duration of release. There is no particular limitation as long as the effective concentration of compound (I ') is maintained in the body. .

[0122]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, experimental results showing the pharmacological effects of compound (I) and compound (I ') of the present invention will be described. Test Example 1 Measurement of cholesteryl ester transfer protein inhibitory activity 1) Preparation of very low density lipoprotein (VLDL) -low density lipoprotein (LDL) After adjusting the specific gravity of fresh rabbit serum to 1.063 g / ml with KBr, ultracentrifugation Operation (SW41-Ti, 40,000
rpm, 18 hrs, 4 ° C., Beckmanmodel
L8-55) (VLDL-LD)
L, specific gravity <1.063 g / ml)
NaCl-10 mM Tris-HCl, pH 7.4
(TBS) was dialyzed, sterile filtered with a filter, and stored at 4 ° C.

2) Preparation of BODIPY-CE microemulsion (BOBIPY-CE-ME) EggPC (phosphatidylcholine) (5 ng) and triolein (2 mg) were added to BODIPY-CE (0.6 m).
After adding and dissolving the chloroform solution of g), the lipid was air-dried under nitrogen gas reflux and the solvent was removed under high vacuum. This lipid was defatted from human HDL (1.063 <d <1.21) with chloroform-methanol (2: 1, v / v), dissolved in 6M urea-containing TBS, and dialyzed against TBS. Apo HDL solution (7.5 ml) was added, and Sonic (Branson Sonifer Cell) was added.
DISRUPTOR 200, dial 6, 5 min
× 4) to prepare BOBIPY-CE-ME. After centrifugation (CENTRIPREP 10), the solution was sterile-filtered with a filter and stored at 4 ° C.

3) Standard measurement system Test compound (20% DMSO solution) 5 μl, TBS75
μl, acceptor lipoprotein (VLDL-LD
L) 20 μl and 25 μl of partially purified human CETP were mixed and incubated at 37 ° C. for 30 minutes, followed by BODIPY-CE
-Transfer reaction was started by adding 25 μl of ME (150 μl in total). After reaction at 37 ° C. for 30 minutes, Ex. 490
nm / Em. The fluorescence intensity was measured at 530 nm. CET
The P inhibitory activity (inhibition rate%) was calculated by the following formula.

[0125]

(Equation 1)

4) Measurement system containing 50% human plasma 5 μl of test compound (20% DMSO solution), 75 μl of human plasma, acceptor lipoprotein (VLDL-L)
DL) 20 μl and partially purified human CETP 25 μl
, And kept at 37 ° C for 30 minutes, then BODIPY-C
Transfer reaction was started by adding 25 μl of E-ME (150 μl in total). After reaction at 37 ° C. for 60 minutes, Ex. 49
0 nm / Em. The fluorescence intensity was measured at 530 nm. CE
The TP inhibitory activity (inhibition rate%) was calculated by the following formula.

[0127]

(Equation 2)

The IC ₅₀ value was determined as a concentration showing 50% inhibition by plotting the logarithm of the test compound concentration and the inhibition rate. Table 1 shows the results.

[0129]

[Table 1]

As is apparent from the above results, the present compound has excellent cholesteryl ester transfer protein inhibitory activity.

[0131]

The present invention will be further described in the following examples and reference examples, which are merely illustrative and do not limit the present invention, and do not depart from the scope of the present invention. May be changed. ^{The 1} H-NMR spectrum was measured with a Varian Gemini 200 (200 MHz) using tetramethylsilane as an internal standard, and all δ values were shown in ppm. The numerical values shown for the mixed solvents are volume mixing ratios of the respective solvents unless otherwise specified. % Means% by weight unless otherwise specified. The elution solvent in silica gel chromatography indicates a volume ratio unless otherwise specified.
Room temperature (normal temperature) in this specification refers to about 20 ° C. to about 3 ° C.
Represents a temperature of 0 ° C.

The symbols in the examples and reference examples have the following meanings. s: singlet, d: doublet, t: triplet, q: Kuarutetto, br: broad, J: coupling constant, dd: double doublet, m: multiplet, Hz: Hertz, CDCl _3: deuterated chloroform, DMSO-d ₆ : Heavy dimethyl sulfoxide, CD ₃ OD: heavy methanol,%:% by weight.

Example 1 N- [2- (4-fluorophenyl) -2-hydroxy-1-
[[4- (trifluoromethyl) phenyl] methyl] d
Tyl] -1-naphthalenecarboxamide 1) N- [2- (4-fluorophenyl) -2-oxoe
[Tyl] formamide α-bromo-4-fluoroacetophenone 30.0 g
(0.138 mol) of N, N-dimethylformamide 2
8.99 g of sodium azide in a 00 ml solution under ice-cooling
(0.136 mol) was added and the mixture was stirred under ice cooling for 30 minutes. Anti
After diluting the reaction solution with water, the mixture is extracted with ethyl acetate.
After washing with water and saturated saline solution in that order,
It was dried and concentrated under reduced pressure. 300 ml of methanol in the residue
And concentrated to 3.0 g of 10% Pd / C (containing 50% water).
After adding 12.7 ml (0.152 mol) of hydrochloric acid, hydrogen was added.
The mixture was stirred under a stream of air for 21 hours. After filtering off the catalyst, the reaction mixture
Was concentrated under reduced pressure. 10.3 g of sodium formate in the residue
(0.152 mol), 140 ml of acetic anhydride, 70 m of formic acid
l of the mixed solution was added, and the mixture was stirred at room temperature for 1 hour. Reduce reaction volume
After concentration under reduced pressure, the mixture was diluted with water and extracted with ethyl acetate. Lottery
The eluate was washed with saturated saline and dried over magnesium sulfate.
It was dried and concentrated under reduced pressure. Is the residue ethyl acetate-hexane
And recrystallized to give 20.21 g (81%) of the desired product as crystals.
I got it.¹ H-NMR (CDCl_Three, 200MHz) δ 4.79 (2H, dd, J = 0.6 H
z, 4.4 Hz), 6.73 (1H, br s), 7.14-7.30 (2H, m), 7.
97-8.10 (2H, m), 8.35 (1H, s). 2) 2- (4-Fluorophenyl) -2-oxo-1-
[[4- (trifluoromethyl) phenyl] methyl] d
Tilformamide 60% sodium hydride liquid paraffin suspension 0.5
5 g (0.0138 mol) of N, N-dimethylforma
N- [2- (4-fluorophenyl)-
2-oxoethyl] formamide 1.66 g (9.17
(Mmol) was added under ice cooling and stirred for 30 minutes. To the reaction solution
4- (trifluoromethyl) benzyl bromide 1.70
ml (0.011 mol) was added and the mixture was stirred at room temperature for 2 hours.
The reaction solution was extracted with ethyl acetate, and the extract was washed with water and saturated saline.
And then dried over magnesium sulfate and concentrated under reduced pressure
did. Silica gel column chromatography of the residue
(Ethyl acetate / hexane = 1 / 2-1 / 1),
1.65 g (53%) of the desired product was obtained as crystals. mp 78-81 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 3.13 (1H, d
d, J = 5.4 Hz, 13.8 Hz), 3.38 (1H, dd, J = 6.6 Hz,
 14.0 Hz), 5.87-5.96 (1H, m), 6.52 (1H, br d, J =
7.8 Hz), 7.07-7.25 (4H, m), 7.48 (2H, d, J = 8.0 H
z), 7.93-8.04 (2H, m), 8.25 (1H, s); IR (KBr) 329
5, 1680, 1661 cm^-1; Anal. Calcd for C₁₇H ₁₃F_FourNO_Two:
C, 60.18; H, 3.86; N, 4.13. Found: C, 59.99; H, 3.
87; N, 4.05 3) 2- (4-Fluorophenyl) -2-oxo-1-
[[4- (trifluoromethyl) phenyl] methyl] d
Tylamine hydrochloride 2- (4-fluorophenyl) -2-oxo-1-[[4-
(Trifluoromethyl) phenyl] methyl] ethylphor
13.87 g (40.9 mmol) of methanol
3.8 ml of concentrated hydrochloric acid (45.0 mM
And heated to reflux for 2 hours. Concentrate the reaction mixture under reduced pressure
The residue was washed with ethyl acetate to give the desired product (13.6).
3 g (96%) were obtained as crystals.¹ H-NMR (DMSO-d₆, 200MHz) δ 3.17-3.29 (2H, m), 5.4
8 (1H, t, J = 6.6 Hz), 7.27-7.44 (4H, m), 7.59 (2H,
 d, J = 8.0 Hz), 8.04-8.15 (2H, m), 8.38 (2H, br
s). 4) N- [2- (4-Fluorophenyl) -2-oxo-1
-[[4- (Trifluoromethyl) phenyl] methyl] d
Tyl] -1-naphthalenecarboxamide 0.49 g (2.84 mmol) of 1-naphthoic acid in N,
1-Ethyl-3-
(3-dimethylaminopropyl) carbodiimide / hydrochloric acid
0.74 g (3.87 mmol) of salt and 1-hydroxy
0.59 g of nzotriazole hydrate (3.87 mmol
After stirring for 5 minutes, 2- (4-fluorophenyl) was added.
L) -2-oxo-1-[[4- (trifluoromethyl) phenyl
[Enyl] methyl] ethylamine hydrochloride 0.9 g (2.
58 mmol) and 1,8-diazabicyclo [5.4.
0] -7-undecene 0.42 ml (2.84 mmol)
Was added and stirred for 3 hours. The reaction was extracted with ethyl acetate,
The extract was washed successively with water and saturated saline, and then washed with magnesium sulfate.
It was dried over sodium and concentrated under reduced pressure. Silica gel residue
Column chromatography (ethyl acetate / hexane = 1
/ 4) to give 0.92 g (77%) of the desired product
Obtained as crystals. mp 163-164 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 3.19 (1H,
dd, J = 6.2 Hz, 13.8 Hz), 3.55 (1H, dd, J = 6.2 H
z, 14.0 Hz), 6.16 (1H, dd, J = 6.2 Hz, 13.8 Hz),
6.88 (1H, d, J = 8.0 Hz), 7.15-7.30 (4H, m), 7.39-
7.59 (6H, m), 7.83-7.97 (2H, m), 8.04-8.16 (3H,
m); IR (KBr) 3289, 1686, 1640 cm^-1; Anal.Calcd for
 C₂₇H₁₉F_FourNO_Two・ 0.2H_TwoO: C, 69.14; H, 4.17; N, 2.99. F
ound: C, 69.27; H, 4.07; N, 2.85.5) N- [2- (4-fluorophenyl) -2-hydroxy
C-1-[[4- (trifluoromethyl) phenyl] methyl
[Ethyl] -1-naphthalenecarboxamide N- [2- (4-fluorophenyl) -2-oxo-1-
[[4- (trifluoromethyl) phenyl] methyl] d
Tyl] -1-naphthalenecarboxamide 500 mg (1.
08 mmol) in 5 ml of methanol
20 mg (0.538 mmol) of sodium was added and ice-cooled
Stirred for under 30 minutes. The reaction solution was extracted with ethyl acetate and extracted.
The eluate was washed successively with a 1N aqueous hydrochloric acid solution and a saturated saline solution,
It was dried over magnesium sulfate and concentrated under reduced pressure. Residue
Silica gel column chromatography (ethyl acetate / f
Purified by hexane = 1/2) to give 480 mg of the desired product (9
6%, (1RS, 2RS) body / (1RS, 2RS) body =
1/3) was obtained as crystals. mp 159-181 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 2.86 (1H ×
1/4, dd, J = 11.0 Hz, 14.6 Hz), 3.07 (1H × 3/4, dd,
J = 4.8 Hz, 15.0 Hz), 3.19 (1H, d, J = 7.8Hz), 3.2
7 (1H × 3/4, d, J = 4.6 Hz), 3.37 (1H × 1/4, d, J =
3.6 Hz), 4.61 (1H × 3/4, ddd, J = 3.4 Hz, 7.6 Hz, 1
6.8 Hz), 4.73-4.86 (1H × 1/4, m), 4.89 (1H × 3/4, t,
 J = 7.8 Hz), 5.08 (1H × 1/4, t, J = 3.6 Hz), 5.98
(1H × 1/4, d, J = 8.4 Hz), 6.20 (1H × / 4, d, J = 9.2
 Hz), 6.99-7.14 (2H, m), 7.16-7.55 (9H, m), 7.60
(2H, d, J = 8.4 Hz), 7.83 (2H, t, J = 8.8 Hz); IR
 (KBr) 3384, 3304, 1645 cm^-1; Anal. Calcd for C₂₇H
_{twenty one}F_FourNO_Two: C, 69.37; H, 4.53; N, 3.00. Found: C, 69.
21; H, 4.58; N, 3.03.

Example 2 N- (2- (4-fluorophenyl) -2-hydroxy-1-
((4- (trifluoromethyl) phenyl) methyl) ethyl) -4-methyl-1-naphthalenecarboxamide 1) 1- (4-fluorophenyl) -1-oxo-3- (4
N, N-dimethylformamide (10 ml) of-(trifluoromethyl) phenyl) -2-propylamine hydrochloride (600 mg, 1.73 mmol) and 4-methyl-1-naphthalenecarboxylic acid (354 mg, 1.90 mmol) )
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (496 mg, 2.59 mmol) and 1-hydroxy-1H-benzotriazole (39
6 mg, 2.59 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (0.28 ml, 1.9)
0 mmol) and stirred overnight. A 1N aqueous hydrochloric acid solution (10 ml) and water (100 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 2). The extract was washed with a 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give N- (2- (4-fluorophenyl) -2-oxo-1- ( (4- (Trifluoromethyl) phenyl) methyl) ethyl) -4-methyl-1-naphthalenecarboxamide (665 mg, 80%) was obtained. mp 149-150 ° C IRν max ^KBr cm ^-1 : 1693, 1634, 1539, 1510. Anal.Calcd for C ₂₈ H ₂₁ F ₄ NO ₂ : C, 70.14; H, 4.41; N,
2.92 Found: C, 70.09; H, 4.42; N, 2.91. ¹ H-NMR (CDCl ₃ ) δ: 2.71 (3H, s), 3.19 (1H, dd, J =
14.0, 6.2 Hz), 3.55 (1H, d, J = 14.0, 6.2 Hz), 6.1
6 (1H, q, J = 7.0 Hz), 6.83 (1H, d, J = 7.4 Hz), 7.
14-7.32 (5H, m), 7.36-7.64 (5H, m), 7.98-8.18 (4H,
m). 2) N- (2- (4-fluorophenyl) -2-oxo-1
-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4-methyl-1-naphthalenecarboxamide (40
0 mg, 0.83 mmol) methanol (30 ml)
Manganese (II) chloride (210 mg, 1.67 mmol) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. Sodium borohydride (63 mg, 1.67 mmol) was added to the reaction mixture under ice cooling, and the mixture was stirred for 1 hour. The reaction solution was poured into 1N hydrochloric acid (30 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), and the obtained crude crystals were washed with a mixed solvent of hexane: ethyl acetate = 10: 1 to give the title compound ((1RS, 2SR) ) Body: (1RS, 2RS) body = 1:
2,329 mg, 82%). ^{. IRν max KBr cm -1: 1634} , 1510, 1125. Anal Calcd for C 28 H 23 F 4 NO 2: C, 69.85; H, 4.81; N,
2.91 Found:. C, 69.56; H, 4.75; N, 2.80 1 H-NMR (CDCl 3) δ: 2.66 (3H, s), 2.70-3.10 (1H, m),
3.44 (2 / 3H, d, J = 4.8 Hz), 3.53 (1 / 3H, d, J = 3.
6 Hz), 4.50-4.68 (2 / 3H, m), 4.70-4.90 (1H, m), 5.0
4-5.10 (1 / 3H, m), 5.95 (1 / 3H, d, J = 8.8 Hz), 6.19
(2 / 3H, d, J = 8.8 Hz), 6.96-7.70 (13H, m), 7.96
(1H, d, J = 8.4 Hz).

Example 3 N- [2- (4-fluorophenyl) -2-hydroxy-1-
[[4- (trifluoromethyl) phenyl] methyl] ethyl] -4-phenylbutylamidonaphthalenecarboxamide 1) N- [2- (4-fluorophenyl) -2-oxo-1
-[[4- (Trifluoromethyl) phenyl] methyl] ethyl] -4-phenylbutylamidonaphthalenecarboxamide In the same manner as in 4 of Example 1, 1.01 g of the desired product (77
%) As crystals. mp 133-135 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 1.87-2.02
(2H, m), 2.18-2.26 (2H, m), 2.62 (2H, t, J = 7.4 H
z), 3.08 (1H, dd, J = 5.2 Hz, 14.0 Hz), 3.33 (1H, d
d, J = 6.6 Hz, 13.8 Hz), 5.78-5.88 (1H, m), 6.26
(1H, d, J = 7.6Hz), 7.05-7.33 (9H, m), 7.45 (2H,
d, J = 8.2 Hz), 7.92-8.03 (2H, m); IR (KBr) 3281, 1
645 cm ^-1 ; Anal.Calcd for C ₂₆ H ₂₃ F ₄ NO ₂ : C, 68.26;
H, 5.07; N, 3.06. Found: C, 68.07; H, 4.79; N, 3.1
0.2) N- [2- (4-Fluorophenyl) -2-hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] -4-phenylbutylamidonaphthalenecarboxamide Example 1-5 In the same manner as in (1), 144 mg (29
%, (1RS, 2RS) / (1RS, 2RS) = 4
/ 1) were obtained as crystals. mp 145-151 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 1.70-1.90
(2H, m), 2.00-2.14 (2H, m), 2.51 (2H, t, J = 7.4 H
z), 2.70-2.94 (2H, m), 3.44 (1H, d, J = 3.6Hz), 4.
30-4.56 (1H, m), 4.92-5.00 (1H, m), 5.38 (1H, d, J
= 7.0 Hz), 7.00-7.60 (13H, m); IR (KBr) 1645 c
m ^-1 ; Anal.Calcd for C ₂₆ H ₂₅ F ₄ NO ₂ : C, 67.96; H, 5.4
8; N, 3.05. Found: C, 67.85; H, 5.61; N, 3.04.

Example 4 N- (2- (4-fluorophenyl) -2-hydroxy-1-
((4- (trifluoromethyl) phenyl) methyl) ethyl) -4- (2-thiophenyl) butyric acid amide 1) 1- (4-fluorophenyl) -1-oxo-3- (4
-(Trifluoromethyl) phenyl) -2-propylamine hydrochloride (600 mg, 1.73 mmol) and 4- (2-
Tyrophenyl) butyric acid (323 mg, 1.90 mmol)
To a solution of N, N-dimethylformamide (10 ml)
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (496 mg, 2.59 mmol) and 1-
Hydroxy-1H-benzotriazole (396 mg,
2.59 mmol) and 1,8-diazabicyclo [5.
4.0] -7-undecene (0.28 ml, 1.90 mmol) was added and stirred overnight. A 1N aqueous hydrochloric acid solution (10 ml) and water (100 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 2). The extract was washed with a 1N aqueous solution of sodium hydroxide and saturated saline, dried over anhydrous magnesium sulfate, distilled off under reduced pressure, recrystallized from ethyl acetate-hexane, and N- (2- (4-fluorophenyl)-
2-oxo-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4- (2-thiophenyl) butyric acid amide (445 mg, 56%) was obtained. mp 123-124 ° C IRν max ^KBr cm ^-1 : 3275, 1651, 1597, 1508, 1325, 123
2, 1159, 1124. Anal.Calcd for C ₂₄ H ₂₁ F ₄ NO ₂ S: C, 62.19; H, 4.57;
N, 3.02 Found:. C, 62.02; H, 4.69; N, 3.28 1 H-NMR (CDCl 3) δ: 1.94-2.10 (2H, m), 2.26 (2H, t,
J = 7.4 Hz), 2.84 (2H, t, J = 7.4 Hz), 3.08 (1H, d
d, J = 14.0, 5.2 Hz), 3.33 (1H, d, J = 14.0,5.2 H
z), 5.84 (1H, q, J = 6.4 Hz), 6.28 (1H, d, J = 7.4
Hz), 6.74-6.80 (1H, m), 6.86-6.96 (1H, m), 7.04-7.
24 (5H, m), 7.46 (2H, d, J = 8.0 Hz), 7.92-8.06 (2
H, m). 2) N- (2- (4-fluorophenyl) -2-oxo-1
-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4- (2-thiophenyl) butyric acid amide (300 m
g, 0.65 mmol) in methanol (30 ml) was added with manganese (II) chloride (163 mg, 1.30 mmol) and stirred at room temperature for 30 minutes. The reaction solution was cooled with ice,
Sodium borohydride (49 mg, 1.30 mmol) was added and stirred for 1 hour. The reaction solution was diluted with 1 N hydrochloric acid (3
0 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
2: 1), and the obtained crude crystals were washed with a mixed solvent of hexane: ethyl acetate = 10: 1 to give the title compound ((1RS, 2SR) form: (1RS, 2RS) form = 1: 1).
1,204 mg, 68%). IRν max ^KBr cm ^-1 : 1645, 1510, 1225, 1165, 1125. Anal.Calcd for C ₂₄ H ₂₃ F ₄ NO ₂ S: C, 61.92; H, 4.98;
N, 3.01 Found:. C, 61.94; H, 4.98; N, 2.94 1 H-NMR (CDCl 3) δ: 1.70-1.96 (2H, m), 2.00-2.16 (2
H, m), 2.60-3.00 (3H, m), 3.43 (1 / 2H, d, J = 5.2 H
z), 3.51 (1 / 2H, d, J = 3.6 Hz), 4.14-4.32 (1 / 2H,
m), 4.36-4.52 (1 / 2H, m), 4.68-4.80 (1 / 2H, m), 4.90
-4.98 (1 / 2H, m), 5.44 (1 / 2H, d, J = 8.4 Hz), 5.66
(1 / 2H, d, J = 8.4 Hz), 6.62-6.72 (1H, m), 6.88-7.6
0 (10H, m).

Example 5 N- [2- (4-fluorophenyl) -2-hydroxy-1-
[[4- (trifluoromethyl) phenyl] methyl] d
Tyl] cyclopentanecarboxamide 1) N- [2- (4-fluorophenyl) -2-oxo-1
-[[4- (Trifluoromethyl) phenyl] methyl] d
[Tyl] cyclopentanecarboxamide 0.84 g of the desired product (71
%) As crystals. mp 158-159 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 1.64-1.93
(8H, m), 2.47-2.64 (1H, m), 3.08 (1H, dd, J = 5.6
Hz, 13.6 Hz), 3.35 (1H, dd, J = 6.6 Hz, 13.8Hz),
5.78-5.88 (1H, m), 6.30 (1H, br d, J = 7.2 Hz), 7.
09 (2H, d, J = 8.0 Hz), 7.12-7.23 (2H, m), 7.47 (2
H, d, J = 8.0 Hz), 7.94-8.02 (2H, m); IR (KBr) 327
4, 1684, 1644 cm^-1; Anal. Calcd for C_{twenty two}H_{twenty one}F_FourNO_Two:
C, 64.86; H, 5.20; N, 3.44. Found: C, 64.77; H, 5.
13; N, 3.36. 2) N- [2- (4-fluorophenyl) -2-hydroxy
C-1-[[4- (trifluoromethyl) phenyl] methyl
[Ethyl] cyclopentanecarboxamide In the same manner as in Example 1, 5), 433 mg (86
%, (1RS, 2RS) / (1RS, 2RS) = 3
/ 4) was obtained as crystals. mp 139-155 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 1.40-1.80
(8H, m), 2.36 (1H, brs), 2.71-3.07 (2H, m), 3.73-
3.78 (1H, m), 4.12 (1H × 4/7, ddd, J = 3.6 Hz, 8.0
Hz, 15.4 Hz), 4.33-4.47 (1H × 3/7, m), 4.75 (1H × 4 /
7, t, J = 7.2 Hz), 4.95 (1H × 3/7, t, J = 6.6 Hz),
5.40 (1H × 3/7, br d, J = 8.4 Hz), 5.62 (1H, br d, J
 = 8.0 Hz), 6.94-7.14 (2H, m), 7.17-7.30 (2H, m),
7.32-7.42 (2H, m), 7.47-7.60 (2H, m); IR (KBr) 331
2, 1651 cm^-1; Anal. Calcd for C _{twenty two}H_{twenty three}F_FourNO_Two: C, 64.5
4; H, 5.66; N, 3.42. Found: C, 64.58; H, 5.89; N,
3.67.

Example 6 4-Fluoro-N- [2- (4-fluorophenyl) -2-hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] benzamide 1) 4-fluoro- N- [2- (4-fluorophenyl)-
2-oxo-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] benzamide 1.16 g of the desired product (93) in the same manner as 4) of Example 1.
%) As crystals. mp 171-172 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 3.22 (1H,
dd, J = 5.0 Hz, 13.8 Hz), 3.49 (1H, dd, J = 6.6 H
z, 14.0 Hz), 6.00 (1H, m), 6.97-7.28 (7H, m), 7.46
(2H, d, J = 8.0 Hz), 7.74-7.85 (2H, m), 7.97-8.09
(2H, m); IR (KBr) 3316, 1698, 1638 cm ^-1 ; Anal. Cal
cd for C ₂₃ H ₁₆ F ₅ NO ₂ : C, 63.74; H, 3.72; N, 3.23. Fou
nd: C, 63.57; H, 3.87; N, 3.23.2) 4-Fluoro-N- [2- (4-fluorophenyl)-
2-Hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] benzamide 423 mg of the desired product (94
%, (1RS, 2RS) / (1RS, 2RS) = 3
/ 7) as crystals. mp 155-179 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 2.90-2.97
(2H × 1/3, m), 3.14 (2H × 2/3, d, J = 7.6 Hz), 3.22
(1H × 2/3, d, J = 4.2 Hz), 3.48 (1H × 1/3, d, J = 3.8
Hz), 4.42 (1H × 2/3, ddd, J = 3.4 Hz, 7.2 Hz, 15.8
Hz), 4.51-4.68 (1H × 1/3, m), 4.83 (1H × 2/3, t, J =
3.9 Hz), 5.08 (1H × 1/3, t, J = 3.1Hz), 6.09 (1H ×
1/3, br d, J = 8.4 Hz), 6.34 (1H × 2/3, br d, J =
8.4 Hz), 6.93-7.13 (4H, m), 7.20-7.32 (2H, m), 7.37
-7.62 (6H, m); IR (KBr) 3301,1636 cm ^-1 ; Anal.Calc
d for C ₂₃ H ₁₈ F ₅ NO ₂ : C, 63.45; H, 4.17; N, 3.22. Fou
nd: C, 63.34; H, 4.36; N, 3.24.

Example 7 N- [2- (4-fluorophenyl) -2-hydroxy-1-
[[4- (trifluoromethyl) phenyl] methyl] ethyl] -4-methoxybenzamide 1) N- [2- (4-fluorophenyl) -2-oxo-1
-[[4- (Trifluoromethyl) phenyl] methyl] ethyl] -4-methoxybenzamide 1.11 g of the desired product (87
%) As crystals. mp 144 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 3.21 (1H, dd,
J = 4.8 Hz, 14.0 Hz), 3.48 (1H, dd, J = 6.6 Hz, 13.
6 Hz), 3.86 (3H, s), 6.01 (1H, ddd, J = 4.6Hz, 4.8
Hz, 6.6 Hz), 6.90-7.02 (3H, m), 7.08 (2H, d, J =
8.2 Hz), 7.12-7.25 (2H, m), 7.45 (2H, d, J = 8.0 H
z), 7.71-7.79 (2H, m), 7.97-8.08 (2H, m); IR (KBr)
3279,1694, 1651 cm ^-1 ; Anal.Calcd for C ₂₄ H ₁₉ F ₄ N
O ₃ : C, 64.72; H, 4.30; N, 3.14. Found: C, 64.53;
H, 4.27; N, 3.25.2) N- [2- (4-Fluorophenyl) -2-hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] -4-methoxybenzamide In the same manner as in 1-5), 0.48 g (96
%, (1RS, 2RS) / (1RS, 2RS) = 3
/ 2) were obtained as crystals. mp 174-176 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 2.90-2.98
(2H × 3/5, m), 3.12 (2H × 2/5, d, J = 7.4 Hz), 3.76
(1H × 2/5, d, J = 4.8 Hz), 3.82 (3H, s), 3.99 (1H × 3
/ 5, d, J = 3.6 Hz), 4.28-4.46 (1H × 2/5, m), 4.49-
4.66 (1H × 3/5, m), 4.81 (1H × 2/5, t, J = 8.2 Hz),
5.06 (1H × 3/5, t, J = 3.0 Hz), 6.08 (1H × 3/5, d, J
= 8.2 Hz), 6.32 (1H × 2/5, d, J = 8.6 Hz), 6.82-7.
13 (4H, m), 7.20-7.32 (2H, m), 7.34-7.59 (6H, m);
IR (KBr) 3341, 1609 cm ^-1 ; Anal.Calcd for C ₂₄ H ₂₁ F ₄ N
O ₃ : C, 64.43; H, 4.73; N, 3.13. Found: C, 64.49;
H, 4.74; N, 3.02.

Example 8 N- [2- (4-fluorophenyl) -2-hydroxy-1-
[[4- (Trifluoromethyl) phenyl] methyl] ethyl] cyclohexanecarboxamide 1) N- [2- (4-Fluorophenyl) -2-oxo-1
-[[4- (Trifluoromethyl) phenyl] methyl] ethyl] cyclohexanecarboxamide 0.90 g of the desired product (83
%) As crystals. mp 169-170 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 1.51-1.52
(5H, m), 1.62-1.88 (5H, m), 2.04-2.20 (1H, m), 3.0
8 (1H, dd, J = 4.8 Hz, 14.0 Hz), 3.35 (1H, dd, J =
6.2 Hz, 13.8 Hz), 5.76-5.88 (1H, m), 6.30 (1H, d,
J = 7.6 Hz), 7.07 (2H, d, J = 8.2 Hz), 7.17 (2H,
t, J = 17.2 Hz), 7.47 (2H, d, J = 8.0Hz), 7.93-8.0
4 (2H, m); IR (KBr) 3274, 1686, 1640 cm ^-1 ; Anal.C
alcd forC ₂₃ H ₂₃ F ₄ NO ₂ : C, 65.55; H, 5.50; N, 3.32. F
ound: C, 65.52; H, 5.48; N, 3.44.2) N- [2- (4-fluorophenyl) -2-hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] cyclohexane Carboxamide In the same manner as in 5) of Example 1, 480 mg of the desired product (96 mg) was obtained.
%, (1RS, 2SR) / (1RS, 2RS) = 1
/ 1) were obtained as crystals. mp 161-178 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 1.08-1.34
(5H, m), 1.48-1.80 (5H, m), 1.92 (1H, br s), 2.77
(0.5H, dd, J = 9.8 Hz, 14.6 Hz), 2.90 (0.5H, dd, J
= 5.4 Hz, 14.6 Hz), 3.06 (1H, d, J = 7.8 Hz), 3.76
(0.5H, d, J = 2.0 Hz), 3.79 (0.5H, s), 4.11 (0.5H,
ddd, 3.8 Hz, 7.8 Hz, 15.8 Hz), 4.33-4.50 (0.5H,
m), 4.76 (0.5H, t, J = 9.0 Hz), 4.94 (0.5H, t, J =
7.0 Hz), 5.38 (0.5H, d, J = 8.2 Hz), 5.61 (0.5H,
d, J = 8.4 Hz), 6.95-7.12 (2H, m), 7.18-7.29 (2H,
m), 7.32-7.41 (2H, m), 7.54 (2H, t, J = 18.0 Hz);
IR (KBr) 3384, 3304, 1645 cm ^-1 ; Anal.Calcd for C ₂₃
H ₂₅ F ₄ NO ₂ : C, 65.24; H, 5.95; N, 3.31. Found: C, 6
4.99; H, 5.97; N, 3.25.

Example 9 4-Chloro-N- [2- (4-fluorophenyl) -2-hydroxy-1-[[4- (trifluoromethyl) phenyl]
Methyl] ethyl] benzamide 1) 4-Chloro-N- [2- (4-fluorophenyl) -2
-Oxo-1-[[4- (trifluoromethyl) phenyl]
Methyl] ethyl] benzamide 1.20 g (92%) of the target compound in the same manner as in 4) of Example 1.
%) As crystals. mp 150-153 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 3.22 (1H,
dd, J = 4.8 Hz, 14.0 Hz), 3.49 (1H, dd, J = 6.2 H
z, 14.0 Hz), 6.00 (1H, ddd, J = 4.8 Hz, 6.6 Hz, 6.
6 Hz), 7.02 (1H, br s), 7.07 (2H, d, J = 7.6 Hz),
7.20 (2H, t, J = 8.6 Hz), 7.44 (2H, d, J = 8.4 Hz),
7.46 (2H, d, J = 8.0 Hz), 7.72 (2H, d, J = 8.8 H
z), 7.97-8.08 (2H, m); IR (KBr) 3281, 1686, 1644 c
_{^{m -1; Anal.Calcd for C 23 H}} 16 ClF 4 NO 2: C, 61.41; H, 3.
59; N, 3.11. Found: C, 61.41; H, 3.80; N, 3.09.2) 4-Chloro-N- [2- (4-fluorophenyl) -2
-Hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] benzamide 467 mg of the desired product (93
%, (1RS, 2SR) / (1RS, 2RS) = 1
/ 1) were obtained as crystals. mp 170-180 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 2.92 (0.5
H, br s), 2.96 (0.5H, s), 3.04 (0.5H, d, J = 4.8 H
z), 3.15 (1H, d, J = 7.8 Hz), 3.32 (0.5H, d, J = 3.
8 Hz), 4.35-4.50 (0.5H, m), 4.53-4.68 (0.5H, m),
4.84 (0.5H, T, J = 3.7 Hz), 5.08 (0.5H, t, J = 3.8
Hz), 6.08 (0.5H, br d, J = 7.4 Hz), 6.34 (0.5H, br
d, J = 9.2 Hz), 6.94-7.14 (2H, m), 7.21-7.61 (10
H, m); IR (KBr) 3310, 1645 cm ^-1 ; Anal.Calcd for C
₂₃ H ₁₈ ClF ₄ NO ₂ : C, 61.14; H, 4.02; N, 3.10. Found: C,
61.10; H, 4.22; N, 3.15.

Example 10 N- [2- (4-fluorophenyl) -2-hydroxy-1-
[[4- (Trifluoromethyl) phenyl] methyl] ethyl] -2-phenylbenzamide 1) N- [2- (4-Fluorophenyl) -2-oxo-1
-[[4- (Trifluoromethyl) phenyl] methyl] ethyl] -2-phenylbenzamide 0.81 g of the desired product (57
%) As crystals. mp 148-149 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.93 (1H,
dd, J = 5.2 Hz, 13.6 Hz), 3.06 (1H, dd, J = 6.6 H
z, 14.0 Hz), 5.80 (1H, ddd, J = 5.6 Hz, 6.6 Hz, 9.
2 Hz), 6.19 (1H, d, J = 7.6 Hz), 6.89 (2H, d, J =
8.4 Hz), 7.11 (2H, t, J = 8.4 Hz), 7.27-7.62 (1H,
m), 7.87 (2H, dd, J = 5.0 Hz, 8.6 Hz); IR (KBr) 328
1, 1684 cm ^-1 ; Anal.Calcd for C ₂₉ H ₂₁ F ₄ NO ₂ : C, 70.8
7; H, 4.31; N, 2.85. Found: C, 70.87; H, 4.30; N,
2.83. 2) N- [2- (4-Fluorophenyl) -2-hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] -2-phenylbenzamide Same as 5) of Example 1 0.48 g (95
%, (1RS, 2SR) body / (1RS, 2RS) body = 2
/ 3) were obtained as crystals. mp 133-134 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 2.25-2.88
(3H, m), 4.22-4.52 (1H, m), 4.54 (1H × 3/5, t, J =
4.4 Hz), 4.64 (1H × 2/5, t, J = 3.8 Hz), 5.39 (1H × 2
/ 5, d, J = 8.8 Hz), 5.65 (1H × 3/5, d, J = 8.2 Hz),
6.92-7.15 (4H, m), 7.20-7.56 (13H, m); IR (KBr) 33
^{. 35, 1645 cm -1; Anal} Calcd for C 29 H 2 3 F 4 NO 2: C, 70.
58; H, 4.70; N, 2.84. Found: C, 70.46; H, 4.62; N,
2.93.

Example 11 N- [2- (4-fluorophenyl) -2-hydroxy-1-
[[4- (trifluoromethyl) phenyl] methyl] d
Tyl] -2-thiophenecarboxamide 1) N- [2- (4-fluorophenyl) -2-oxo-1
-[[4- (Trifluoromethyl) phenyl] methyl] d
[Tyl] -2-thiophenecarboxamide In the same manner as in Example 1, 4), 0.94 g of the desired product (78
%) As crystals. mp 130-131 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 3.21 (1H,
dd, J = 4.8 Hz, 13.8 Hz), 3.46 (1H, dd, J = 6.4 H
z, 13.6 Hz), 5.93-6.04 (1H, m), 6.91 (1H, d, J = 7.
0 Hz), 7.05-7.24 (5H, m), 7.45 (2H, d, J = 8.2 H
z), 7.50-7.54 (2H, m), 7.96-8.06 (2H, m); IR (KBr)
3308, 1694, 1682 cm^-1; Anal. Calcd forC_{twenty one}H₁₅F_FourNO
_TwoS: C, 59.85; H, 3.59; N, 3.32. Found: C, 59.83;
H, 3.34; N, 3.24.2) N- [2- (4-fluorophenyl) -2-hydroxy
C-1-[[4- (trifluoromethyl) phenyl] methyl
[Ethyl] -2-thiophenecarboxamide 0.45 g of the desired product (89
%, (1RS, 2SR) body / (1RS, 2RS) body = 2
/ 1) were obtained as crystals. mp 135-164 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 2.92 (2H ×
2/3, d, J = 7.8 Hz), 3.10-3.15 (1H, m), 3.40 (1H ×
2/3, d, J = 3.8 Hz), 4.30-4.64 (1H, m), 4.82 (1H × 1
/ 3, t, J = 4.0 Hz), 5.08 (1H × 2/3, t, J = 3.3 Hz),
 6.00 (1H × 2/3, br d, J = 8.4 Hz), 6.25 (1H × 1/3, b
r d, J = 8.4 Hz), 6.94-7.14 (3H, m), 7.21-7.61 (8H,
 m); IR (KBr) 3301, 1636 cm^-1; Anal. Calcd for C_{twenty one}
H₁₇F_FourNO _TwoS: C, 59.57; H, 4.05; N, 3.31. Found: C, 5
9.59; H, 4.15; N, 3.24.

Example 12 N- [2- (4-fluorophenyl) -2-hydroxy-1-
[[4- (Trifluoromethyl) phenyl] methyl] ethyl] -4- (trifluoromethyl) benzamide 1) N- [2- (4-Fluorophenyl) -2-oxo-1
-[[4- (Trifluoromethyl) phenyl] methyl] ethyl] -4- (trifluoromethyl) benzamide 1.32 g of the desired product (95
%) As crystals. mp 172-174 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 3.23 (1H,
dd, J = 4.8 Hz, 13.8 Hz), 3.51 (1H, dd, J = 6.2 H
z, 14.0 Hz), 6.01 (1H, ddd, J = 5.2 Hz, 6.4 Hz, 7.
0 Hz), 7.08 (2H, d, J = 8.0 Hz), 7.14 (1H, br s),
7.21 (2H, t, J = 8.6 Hz), 7.47 (2H, d, J = 8.0 Hz),
7.73 (2H, d, J = 8.4 Hz), 7.88 (2H, d, J = 8.4 H
z), 7.98-8.10 (2H, m); IR (KBr) 3303, 1688, 1645 c
m ^-1 ; Anal.Calcd for C ₂₄ H ₁₆ F ₇ NO ₂ : C, 59.63; H, 3.3
4; N, 2.90. Found: C, 59.55; H, 3.58; N, 2.89.2) N- [2- (4-fluorophenyl) -2-hydroxy-1-[[4- (trifluoromethyl) phenyl ] Methyl] ethyl] -4- (trifluoromethyl) benzamide In the same manner as in Example 1, 5), 444 mg (88
%, (1RS, 2SR) / (1RS, 2RS) = 1
/ 6) as crystals. mp 167-169 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 2.87 (1H,
d, J = 4.4 Hz), 3.17 (2H, d, J = 7.6 Hz), 4.40-4.5
6 (1H, m), 4.86 (1H × 6/7, t, J = 3.4 Hz), 5.10 (1H
× 1/7, s), 6.43 (1H, d, J = 8.8 Hz), 6.95-7.14 (2
H, m), 7.22-7.32 (2H, m), 7.43 (2H, d, J = 8.2 Hz),
7.59 (2H, d, J = 8.4 Hz), 7.67 (4H, s); IR (KBr)
3426, 3335, 1645 cm ^-1 ; Anal.Calcd for C ₂₄ H ₁₈ F ₇ N
O ₂ : C, 59.39; H, 3.74; N, 2.89. Found: C, 59.34;
H, 3.961; N, 2.89.

Example 13 4-butyl-N- [2- (4-fluorophenyl) -2-hydroxy-1-[[4- (trifluoromethyl) phenyl]
Methyl] ethyl] benzamide 1) 4-butyl-N- [2- (4-fluorophenyl) -2
-Oxo-1-[[4- (trifluoromethyl) phenyl]
Methyl] ethyl] benzamide 1.16 g (86) of the target compound in the same manner as in 4) of Example 1.
%) As crystals. mp 120-121 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.93 (3H,
t, J = 7.1 Hz), 1.26-1.46 (2H, m), 1.53-1.70 (2H,
m), 2.67 (2H, t, J = 7.6 Hz), 3.21 (1H, dd, J = 4.6
Hz, 13.8 Hz), 3.49 (1H, dd, J = 6.4 Hz, 13.6 Hz),
6.02 (1H, ddd, J = 4.8 Hz, 6.4 Hz, 7.4 Hz), 7.00-
7.28 (7H, m), 7.45 (2H, d, J = 8.2 Hz), 7.69 (2H,
d, J = 8.2 Hz), 7.97-8.08 (2H, m); IR (KBr) 3281,
1688, 1636 cm ^-1 ; Anal.Calcd for C ₂₇ H ₂₅ F ₄ NO ₂ : C, 6
8.78; H, 5.34; N, 2.97. Found: C, 68.95; H, 5.43;
N, 2.96.2) 4-Butyl-N- [2- (4-fluorophenyl) -2
-Hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] benzamide 946 mg (95%) of the target compound in the same manner as in Example 1, 5).
%, (1RS, 2RS) / (1RS, 2RS) = 4
/ 3) were obtained as crystals. mp 138-158 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 0.92 (3H,
t, J = 7.1 Hz), 1.24-1.43 (2H, m), 1.50-1.67 (2H,
m), 2.63 (2H, t, J = 7.7 Hz), 2.90 (1H × 4/7, d, J =
3.4 Hz), 2.94 (1H × 4/7, s), 3.13 (2H × 3/7, d, J =
4.4 Hz), 3.88 (1H × 4/7, d, J = 3.8 Hz), 4.37 (1H ×
3/7, ddd, J = 2.8 Hz, 7.0 Hz, 15.4 Hz), 4.52-4.67
(1H × 4/7, m), 4.82 (1H × 3/7, t, J = 4.2 Hz), 5.06
(1H × 4/7, t, J = 3.5 Hz), 6.14 (1H × 4/7, d, J = 8.
2 Hz), 6.37 (1H × 3/7, d, J = 8.6 Hz), 6.91-7.32 (6
H, m), 7.35-7.59 (6H, m); IR (KBr) 3274, 1615 c
^{. m -1; Anal Calcd for C} 27 H 27 F 4 NO 2: C, 68.49; H, 5.7
5; N, 2.96. Found: C, 68.35; H, 5.89; N, 3.04.

Example 14 N- [2- (4-fluorophenyl) -2-hydroxy-1-
[[4- (trifluoromethyl) phenyl] methyl] ethyl] -2-naphthalenecarboxamide 1) N- [2- (4-fluorophenyl) -2-oxo-1
-[[4- (Trifluoromethyl) phenyl] methyl] ethyl] -2-naphthalenecarboxamide In the same manner as in Example 1, 4), 1.03 g of the desired product (77
%) As crystals. mp 139-141 ° C; ¹ H-NMR (CDCl ₃ ,
200MHz) δ 3.26 (1H, dd, J = 4.8 Hz, 14.0Hz), 3.5
4 (1H, dd, J = 6.6 Hz, 13.4 Hz), 6.04-6.14 (1H,
m), 7.11 (2H, d, J = 8.2 Hz), 7.17-7.28 (3H, m),
7.46 (2H, d, J = 8.0 Hz), 7.51-7.64 (2H, m), 7.80-
7.97 (4H, m), 8.01-8.11 (2H, m), 8.29 (1H, s); IR
(KBr) 3293, 1694, 1645 cm ^-1 ; Anal.Calcd for C ₂₇ H
₁₉ F ₄ NO ₂ : C, 69.67; H, 4.11; N, 3.01. Found: C, 69.
67; H, 4.11; N, 3.01.2) N- [2- (4-fluorophenyl) -2-hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] -2-naphthalenecarboxamide In the same manner as in 5) of Example 1, 0.50 g (10
0%, (1RS, 2RS) / (1RS, 2RS) =
1/1) as crystals. mp 148-150 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 3.00 (1H,
d, J = 7.8 Hz), 3.20 (1H, d, J = 7.8 Hz), 3.38-3.5
3 (0.5H, m), 3.67-3.77 (0.5H, m), 4.39-4.55 (0.5H,
m), 4.59-4.75 (0.5H, m), 4.85-4.93 (0.5H, m), 5.14
(0.5H, t, J = 3.0 Hz), 6.28 (0.5H, br s), 6.53 (0.
5H, br s), 6.94-7.13 (2H, m), 7.26-7.36 (2H, m),
7.41-7.65 (7H, m), 7.82-7.89 (3H, m), 8.04 (1H, d,
J = 4.4Hz); IR (KBr) 3351, 1640 cm ^-1 ; Anal.Calcd
for C ₂₇ H ₂₁ F ₄ NO ₂ : C, 69.37; H, 4.53; N, 3.00. Foun
d: C, 68.51; H, 5.02; N, 2.67.

Example 15 N- [2- (4-Fluorophenyl) -2-hydroxy-1-
[[4- (Trifluoromethyl) phenyl] methyl] ethyl] adamantane-1-carboxamide 1) N- [2- (4-Fluorophenyl) -2-oxo-1
-[[4- (Trifluoromethyl) phenyl] methyl] ethyl] adamantan-1-carboxamide 0.89 g of the desired product (78)
%) As crystals. mp 169-170 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 1.71 (6H,
d, J = 2.6 Hz), 1.81 (6H, d, J = 3.0 Hz), 2.04 (3
H, br s), 3.08 (1H, dd, J = 5.2 Hz, 13.6 Hz), 3.34
(1H, dd, J = 6.6 Hz, 14.0 Hz), 5.75-5.85 (1H, m),
6.49 (1H, br d, J = 7.6 Hz), 7.07 (1H, d, J = 7.8 H
z), 7.11-7.23 (2H, m), 7.47 (2H, d, J = 8.0 Hz), 7.
93-8.03 (2H, m); IR (KBr) 3347, 1682, 1632 cm ^-1 ; A
nal.Calcd for C ₂₇ H ₂₇ F ₄ NO ₂ : C, 68.49; H, 5.75; N,
2.96. Found: C, 68.41; H, 5.70; N, 2.93.2.2) N- [2- (4-fluorophenyl) -2-hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl Adamantane-1-carboxamide In the same manner as in 5 of Example 1, 488 mg of the desired product (97 mg
%, (1RS, 2RS) / (1RS, 2RS) = 3
/ 2) was obtained as amorphous. ¹ H-NMR (CDCl ₃ , 200MHz) δ 1.55-1.74 (12H, m), 1.97
(3H, br s), 2.63-3.06 (2H, m), 4.01 (1H, br t, J =
3.4 Hz), 4.09 (1H × 2/5, ddd, J = 4.0 Hz, 7.6 Hz,
15.6 Hz), 4.33-4.47 (1H × 3/5, m), 4.75 (1H × 2/5,
t, J = 8.8 Hz), 4.91 (1H × 3/5, t, J = 6.6 Hz), 5.48
(1H × 3/5, d, J = 7.6 Hz), 5.76 (1H × 2/5, d, J =
8.0 Hz), 6.94-7.13 (2H, m), 7.17-7.28 (2H, m), 7.3
0-7.40 (2H, m), 7.48-7.59 (2H, m); IR (KBr) 3441,
^{. 3353, 1634 cm -1; Anal} Calcd forC 27 H 29 F 4 NO 2: C, 6
8.20; H, 6.15; N, 2.95. Found: C, 67.72; H, 6.31;
N, 2.86.

Example 16 N- [2- (4-fluorophenyl) -2-hydroxy-1-
[[4- (trifluoromethyl) phenyl] methyl] ethyl] -2,2-dimethylpropionamide 1) N- [2- (4-fluorophenyl) -2-oxo-1
-[[4- (Trifluoromethyl) phenyl] methyl] ethyl] -2,2-dimethylpropionamide 0.89 g of the desired product (78)
%) As crystals. mp 147-150 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 1.17 (9H,
s), 3.08 (1H, dd, J = 5.2 Hz, 13.6 Hz), 3.35 (1H, d
d, J = 6.2 Hz, 14.0 Hz), 5.74-5.84 (1H, m), 6.52 (1
H, br d, J = 6.6 Hz), 7.08 (2H, d, J = 7.6 Hz), 7.
12-7.24 (2H, m), 7.47 (2H, d, J = 8.0 Hz), 7.94-8.
04 (2H, m); IR (KBr) 3391, 1682, 1634 cm ^-1 ; Anal.
Calcd for C ₂₁ H ₂₁ F ₄ NO ₂ : C, 63.79; H, 5.35; N, 3.54.
Found: C, 63.72; H, 5.21; N, 3.48. 2) N- [2- (4-fluorophenyl) -2-hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl]- 2,2-Dimethylpropionamide In the same manner as in Example 1, 5), 498 mg (99%) of the desired product was obtained.
%, (1RS, 2RS) / (1RS, 2RS) = 3
/ 2) were obtained as crystals. mp 97-99 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.00 (9H,
s), 2.69-3.08 (2H, m), 3.83 (1H, br s), 4.13 (1H ×
2/5, ddd, J = 3.6 Hz, 8.0 Hz, 15.8 Hz), 4.34-4.47
(1H × 3/5, m), 4.76 (1H × 2/5, t, J = 4.0 Hz), 4.92
(1H × 3/5, t, J = 3.2 Hz), 5.54 (1H × 3/5, t, J = 7.
0 Hz), 5.83 (1H × 2/5, m), 6.95-7.12 (2H, m), 7.17-
7.25 (2H, m), 7.31-7.40 (2H, m), 7.47-7.59 (2H,
m); IR (KBr) 3333, 1645 cm ^-1 ; Anal.Calcd for C ₂₁ H
₂₃ F ₄ NO ₂ : C, 63.47; H, 5.83; N, 3.52.Found: C, 63.3
3; H, 5.74; N, 3.50.

Example 17 N- [2- (4-fluorophenyl) -2-hydroxy-1-
[[4- (Trifluoromethyl) phenyl] methyl] ethyl] -2,3,4-trimethylbenzamide 1) N- [2- (4-Fluorophenyl) -2-oxo-1
-[[4- (Trifluoromethyl) phenyl] methyl] ethyl] -2,3,4-trimethylbenzamide In the same manner as in Example 1, 4), 0.48 g of the desired product (36
%) As crystals. mp 141-143 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 2.08 (6H,
s), 2.25 (3H, s), 3.14 (1H, dd, J = 7.2 Hz, 14.0 H
z), 3.36 (1H, dd, J = 6.2 Hz, 14.0 Hz), 6.07-6.18
(1H, m), 6.37 (1H, br d, J = 8.4 Hz), 6.80 (2H,
s), 7.18 (2H, t, J = 8.4 Hz), 7.24-7.31 (2H, m), 7.
50 (2H, d, J = 8.0 Hz), 8.01-8.11 (2H, m); IR (KBr)
3237, 1694, 1634 cm ^-1 ; Anal.Calcd for C ₂₆ H ₂₃ F ₄ NO
₂ : C, 68.26; H, 5.07; N, 3.06. Found: C, 68.23; H,
5.25; N, 2.92.1.2) N- [2- (4-fluorophenyl) -2-hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] -2,3,4-trimethylbenzamide 325 mg of the desired product (92%) was obtained in the same manner as in 5) of Example 1.
%, (1RS, 2SR) / (1RS, 2RS) = 1
/ 10) was obtained as amorphous. ¹ H-NMR (CDCl ₃ , 200MHz) δ 1.86 (6H, s), 2.22 (3H,
s), 3.03 (1H, dd, J = 7.3 Hz, 13.9 Hz), 3.12 (1H, d
d, J = 7.6 Hz, 13.4 Hz), 3.15-3.28 (1H, m), 4.58 (1
H, ddd, J = 3.5 Hz, 7.8 Hz, 15.8 Hz), 4.70 (1H, br
s), 6.01 (1H, br d, J = 9.2 Hz), 6.73 (2H, s), 6.9
4-7.13 (2H, m), 7.22-7.31 (2H, m), 7.45 (2H, d, J =
8.4 Hz), 7.58 (2H, d, J = 8.0 Hz); IR (KBr) 3268,
1620cm ^-1 ; Anal.Calcd for C ₂₆ H ₂₅ F ₄ NO ₂ : C, 67.96;
H, 5.48; N, 3.05. Found: C, 67.80; H, 5.74; N, 3.0
Four.

Example 18 2-Fluoro-N- [2- (4-fluorophenyl) -2-h
Droxy-1-[[4- (trifluoromethyl) phenyi
[Methyl] ethyl] benzamide 1) 2-Fluoro-N- [2- (4-fluorophenyl)-
2-oxo-1-[[4- (trifluoromethyl) phenyl
[Methyl] ethyl] benzamide 136 mg (90%) of the target compound in the same manner as 4) of Example 1.
%) As crystals. mp 109-111 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 3.22 (1H,
dd, J = 5.2 Hz, 13.6 Hz), 3.46 (1H, dd, J = 6.2 H
z, 13.4 Hz), 5.98-6.11 (1H, m), 7.09-7.33 (6H, m),
 7.43-7.69 (4H, m), 7.97-8.11 (3H, m); IR (KBr) 34
39, 1686, 1655 cm ^-1; Anal. Calcd for C_{twenty three}H₁₆F_FiveNO_Two:
C, 63.74; H, 3.72; N, 3.23. Found: C, 63.56; H, 3.
66; N, 3.40. 2) 2-Fluoro-N- [2- (4-fluorophenyl)-
2-hydroxy-1-[[4- (trifluoromethyl) fe
Nyl] methyl] ethyl] benzamide 367 mg (68%) of the target compound in the same manner as in 5) of Example 1.
%, (1RS, 2SR) / (1RS, 2RS) = 1
/ 2) were obtained as crystals. mp 115-117 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 3.00-3.22
(3H, m), 4.42-4.58 (1H, m), 4.82 (1H, m), 6.92-7.6
0 (12H, m); IR (KBr) 3447, 3333, 1644 cm^-1; Anal. C
alcd for C_{twenty three}H₁₈F_FiveNO_Two: 63.45; H, 4.17; N, 3.22. Fou
nd: C, 63.45; H, 4.22; N, 3.15.

Example 19 4-tert-butyl-N- [2- (4-fluorophenyl)
-2-Hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] benzamide 1) 4-tert-butyl-N- [2- (4-fluorophenyl) -2-oxo-1- [ [4- (trifluoromethyl)
Phenyl] methyl] ethyl] benzamide 1.06 g of the desired product (78) in the same manner as in 4) of Example 1.
%) As crystals. mp 58 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 1.34 (9H, s),
3.21 (1H, dd, J = 5.6 Hz, 14.0 Hz), 3.48 (1H, dd,
J = 6.6 Hz, 14.0 Hz), 6.03 (1H, ddd, J = 4.8Hz, 5.
6 Hz, 6.6 Hz), 7.04-7.26 (5H, m), 7.41-7.50 (4H,
m), 7.68-7.75 (2H, m), 7.97-8.08 (2H, m); IR (KBr)
^{3299, 1694 cm -1;. Anal} Calcd for C 27 H 2 5 F 4 NO 2 · 0.1H
2O: C, 68.52; H, 5.37; N, 2.96.Found: C, 68.33; H, 5.2
2; N, 2.92.2.2) 4-tert-butyl-N- [2- (4-fluorophenyl) -2-hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] benzamide In the same manner as in 1-5), 0.50 g (97
%, (1RS, 2RS) / (1RS, 2RS) = 3
/ 2) was obtained as amorphous. ¹ H-NMR (CDCl ₃ , 200MHz) δ 1.31 (9H, s), 2.90-2.95
(2H × 3/5, m), 3.14 (2H × 2/5, d, J = 7.4 Hz), 3.64
(1H × 2/5, d, J = 3.4 Hz), 3.83 (1H × 3/5, d, J = 3.4
Hz), 4.37 (2H × 2/5, ddd, J = 3.2 Hz, 7.2 Hz, 15.6
Hz), 4.53-4.68 (1H × 3/5, m), 4.83 (1H × 2/5, t, J =
4.0 Hz), 5.06 (1H × 3/5, t, J = 6.6Hz), 6.13 (1H ×
3/5, d, J = 8.2 Hz), 6.37 (1H × 2/5, d, J = 8.4 H
z), 6.92-7.13 (2H, m), 7.21-7.32 (2H, m), 7.36-7.5
9 (8H, m); IR (KBr) 3301, 1620cm ^-1 ; Anal.Calcd fo
r C ₂₇ H ₂₇ F ₄ NO ₂・ 0.2H ₂ O: C, 67.97; H, 5.79; N, 2.94.
Found: C, 67.97; H, 5.80; N, 2.89.

Example 20 N- [2- (4-fluorophenyl) -2-hydroxy-1-
[[4- (trifluoromethyl) phenyl] methyl] ethyl] -4-phenylbenzamide 1) N- [2- (4-fluorophenyl) -2-oxo-1
-[[4- (Trifluoromethyl) phenyl] methyl] ethyl] -4-phenylbenzamide 1.24 g of the desired product (88
%) As crystals. mp 169 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 3.24 (1H, dd,
J = 4.6 Hz, 14.0 Hz), 3.52 (1H, dd, J = 6.4 Hz, 14.
0 Hz), 6.04 (1H, ddd, J = 4.6 Hz, 5.2 Hz, 6.4 Hz),
7.07-7.25 (5H, m), 7.38-7.52 (5H, m), 7.58-7.72
(4H, m), 7.86 (2H, d, J = 8.8 Hz), 7.99-8.10 (2H,
m); IR (KBr) 3291, 1688, 1645 cm ^-1 ; Anal.Calcd fo
r C ₂₉ H ₂₁ F ₄ NO ₂ : C, 70.87; H, 4.31; N, 2.85. Found:
C, 70.89; H, 4.23; N, 2.86. 2) N- [2- (4-Fluorophenyl) -2-hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] -4- Phenylbenzamide In the same manner as in Example 1, 5), 0.49 g (96
%, (1RS, 2RS) / (1RS, 2RS) = 3
/ 2) were obtained as crystals. mp 178-185 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 2.93-3.00
(2H × 3/5, m), 3.17 (2H × 2/5, d, J = 7.6 Hz), 3.36
(1H × 2/5, d, J = 4.4 Hz), 3.63 (1H × 3/5, d, J = 3.2
Hz), 4.35-4.52 (1H × 2/5, m), 4.55-4.71 (1H × 3/5,
m), 4.87 (1H × 2/5, t, J = 3.9 Hz), 5.11 (1H × 3/5,
t, J = 3.6 Hz), 6.17 (1H × 3/5, d, J = 8.6 Hz), 6.42
(1H × 2/5, d, J = 8.0 Hz), 6.95-7.13 (2H, m), 7.24
-7.68 (15H, m); IR (KBr) 3304, 1634 cm ^-1 ; Anal.Ca
lcd for C ₂₉ H ₂₃ F ₄ NO ₂ : C, 70.58; H, 4.70; N, 2.84. Fo
und: C, 70.53; H, 4.72; N, 2.72.

Example 21 N- [2- (4-fluorophenyl) -2-hydroxy-1-
[[4- (Trifluoromethyl) phenyl] methyl] ethyl] -3-pyridinecarboxamide 1) N- [2- (4-Fluorophenyl) -2-oxo-1
-[[4- (Trifluoromethyl) phenyl] methyl] ethyl] -3-pyridinecarboxamide In the same manner as in Example 1, 4), 0.74 g of the desired product (62
%) As crystals. mp 137-138 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 3.23 (1H,
dd, J = 5.0 Hz, 13.8 Hz), 3.49 (1H, dd, J = 6.6 H
z, 14.0 Hz), 5.98-6.07 (1H, m), 7.06-7.26 (5H, m),
7.37-7.43 (1H, m), 7.47 (2H, d, J = 8.4 Hz), 7.98
-8.11 (3H, m), 8.76 (1H, dd, J = 1.8 Hz, 4.8 Hz),
9.00 (1H, dd, J = 0.8 Hz, 2.2 Hz); IR (KBr) 3287,
1694, 1661 cm ^-1 ; Anal.Calcd for C ₂₂ H ₁₆ F ₄ N ₂ O ₂ : C,
63.46; H, 3.87; N, 6.73. Found: C, 63.19; H, 4.03;
N, 6.68.2) N- [2- (4-fluorophenyl) -2-hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] -3-pyridinecarboxamide Example 1-5) 0.43 g (86
%, (1RS, 2RS) / (1RS, 2RS) = 5
/ 2) were obtained as crystals. mp 160-165 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.95 (2H ×
5/7, br s), 3.10 (1H × 2/7, br s), 3.16 (2H × 2/7,
d, J = 7.0 Hz), 3.35 (1H × 5/7, br s), 4.43-4.75 (1
H, m), 4.86 (1H × 2/7, br s), 5.10 (1H × 5/7, br s),
6.25 (1H × 5/7, br d, J = 8.6 Hz), 6.48 (1H × 2/7,
br d, J = 8.8 Hz), 6.95-7.16 (2H, m), 7.21-7.62 (7
H, m), 7.87-7.95 (1H, m), 8.66-8.80 (2H, m); IR (K
Br) 3324, 3142, 1644 cm ^-1 ; Anal.Calcd for C ₂₂ H ₁₈ F
₄ N ₂ O ₂ : C, 63.16; H, 4.34; N, 6.70. Found: C, 62.9
7; H, 4.24; N, 6.51.

Example 22 N- (2- (4-Fluorophenyl) -2-hydroxy-1-
((4- (trifluoromethyl) phenyl) methyl) ethyl) -4-oxo-4H-pyran-2-carboxamide and N- (2- (4-fluorophenyl) -2-hydroxy-1-
((4- (trifluoromethyl) phenyl) methyl) ethyl) -4-hydroxytetrahydro-2H-pyran-2-carboxamide 1) 1- (4-fluorophenyl) -1-oxo-3- (4
-(Trifluoromethyl) phenyl) -2-propylamine hydrochloride (600 mg, 1.73 mmol) and 4-oxo-4H-pyran-2-carboxylic acid (266 mg, 1.90)
Mmol) N, N-dimethylformamide (10 m
1) 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (496 mg, 2.59 mmol), 1-hydroxy-1H-benzotriazole (396 mg, 2.59 mmol) and 1,8 -Diazabicyclo [5.4.0] -7-undecene (0.28 ml,
(1.90 mmol) and stirred overnight. 1 in the reaction solution
A normal hydrochloric acid aqueous solution (10 ml) and water (100 ml) were added, and the mixture was extracted with ethyl acetate (50 ml × 2). The extract was washed with a 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give N- (2- (4-fluorophenyl) -2-oxo-1-oxo.
((4- (trifluoromethyl) phenyl) methyl) ethyl) -4-oxo-4H-pyran-2-carboxamide (5
70 mg, 76%). mp 115-116 ℃ IRν max ^KBr cm ^-1 : 1661, 1620, 1597, 1510, 1412. Anal.Calcd for C ₂₂ H ₁₅ F ₄ NO ₄・ 0.1H ₂ O: C, 60.72; H,
3.52; N, 3.22 Found:. C, 60.60; H, 3.55; N, 3.24 1 H-NMR (CDCl 3) δ: 3.23 (1H, dd, J = 14.0, 5.2 Hz),
3.43 (1H, dd, J = 14.0, 5.2 Hz), 5.93 (1H, q, J =
6.4 Hz), 6.44 (1H, dd, J = 5.8, 2.6 Hz), 7.07 (2
H, d, J = 8.0 Hz), 7.10-7.26 (2H, m), 7.48 (2H, d,
J = 8.0 Hz), 7.59 (1H, d, J = 7.4 Hz), 7.77 (1H,
d, J = 6.0 Hz), 7.92-8.06 (2H, m). 2) N- (2- (4-fluorophenyl) -2-oxo-1
-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4-oxo-4H-pyran-2-carboxamide (4
00 mg, 0.92 mmol) of methanol (30 m
l) Manganese (II) chloride (232 mg, 1.8) was added to the solution.
5 mmol) and stirred at room temperature for 30 minutes. Sodium borohydride (70 mg, 1.85
Mmol) and stirred for 1 hour. The reaction solution was poured into 1N hydrochloric acid (30 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), the highly polar fraction was collected and concentrated, and the obtained crude crystals were washed with hexane to give N- (2- (4-fluorophenyl) -2 -Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4-oxo-4H-pyran-2-carboxamide ((1RS, 2SR) form: (1
(RS, 2RS) form = 3: 2, 139 mg, 35%). IRν max ^KBr cm ^-1 : 1659, 1607, 1512, 1416. Anal.Calcd for C ₂₂ H ₁₇ F ₄ NO ₄・ 0.1H ₂ O: C, 60.44; H,
3.97; N, 3.20 Found:. C, 61.24; H, 3.93; N, 3.03 1 H-NMR (CDCl 3) δ: 2.60-2.82 (1H, m), 2.90-2.96 (1
H, m), 3.04-3.20 (1H, m), 4.40-4.70 (1H, m), 4.78-
4.84 (2 / 5H, m), 5.02-5.10 (3 / 5H, m), 6.36-6.42 (1
H, m), 6.70-7.80 (11H, m). At the same time, low-polarity fractions were collected and concentrated, and N-
(2- (4-fluorophenyl) -2-hydroxy-1-
((4- (trifluoromethyl) phenyl) methyl) ethyl) -4-hydroxytetrahydro-2H-pyran-2-carboxamide ((1RS, 2SR) form: (1RS, 2R
S) form = 7: 3, 139 mg, 35%) was obtained as amorphous. IRν max ^KBr cm ^-1 : 1645, 1510.Anal.Calcd for C ₂₂ H ₂₃ F ₄ NO ₄ : C, 59.86; H, 5.25; N,
3.17 Found:. C, 60.02; H, 5.01; N, 3.04 1 H-NMR (CDCl 3) δ: 1.70-2.00 (3H, m), 2.70-3.40 (3
H, m), 3.70-4.60 (4H, m), 4.68-4.78 (0.3H, m), 4.9
2-5.04 (0.7H, m), 6.00 (0.3H, d, J = 4.8 Hz), 6.05
(0.7H, d, J = 4.6 Hz), 4.58-6.70 (0.7H, m), 6.76-
6.90 (0.3H, m), 6.95-7.60 (8H, m).

Example 23 4-Fluoro-N- [2- (4-fluorophenyl) -2-hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] benzenesulfonamide 1) 4- Fluoro-N- [2- (4-fluorophenyl)-
2-oxo-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] benzenesulfonamide 2- (4-fluorophenyl) -2-oxo-1-[[4-
0.84 g (4.32 mmol) of 4-fluorobenzenesulfonyl chloride in a solution of 1.0 g (2.88 mmol) of (trifluoromethyl) phenyl] methyl] ethylamine hydrochloride in 10 ml of N, N-dimethylformamide
And 1.3 ml (8.64 mmol) of 1,8-diazabicyclo [5.4.0] -7-undecene were added and stirred for 4 hours. The reaction solution was extracted with ethyl acetate, and the extract was washed with water and saturated brine in that order, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 1.02 g (76%) of the desired product as crystals. mp 209-210 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 2.96 (1H,
dd, J = 6.6 Hz, 14.0 Hz), 3.20 (1H, dd, J = 5.6 Hz,
14.6 Hz), 5.05-5.18 (1H, m), 5.62 (1H, br d, J = 6.4
Hz), 7.00 (2H, t, J = 8.6 Hz), 7.04-7.20 (4H, m),
7.45 (2H, d, J = 8.0 Hz), 7.65-7.72 (2H, m), 7.77-7.
84 (2H, m); IR (KBr) 3229, 1676, 1595 cm ^-1 ; Anal.
Calcd for C ₂₂ H ₁₆ F ₅ NO ₃ S: C, 56.29; H, 3.44; N, 2.9
8. Found: C, 56.15; H, 3.46; N, 3.26. 2) 4-Fluoro-N- [2- (4-fluorophenyl)-
2-hydroxy-1-[[4- (trifluoromethyl) phenyl] methyl] ethyl] benzenesulfonamide 4-fluoro-N- [2- (4-fluorophenyl) -2-oxo-1-[[4- 0.5 g of (trifluoromethyl) phenyl] methyl] ethyl] benzenesulfonamide (1.
Sodium borohydride (45 mg, 1.19 mmol) was added to a methanol (5 ml) solution under ice-cooling, and the mixture was stirred for 1 hour. After adding 1N hydrochloric acid to the reaction solution, the mixture was stirred at room temperature for 10 minutes. The reaction solution was extracted with ethyl acetate, and the extract was washed with water and saturated brine in that order, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1 /
Purification by 2) gave 0.45 g of the desired product (89%, 1/3 mixture of isomers) as crystals. mp 141-161 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 2.30 (3/4
H, d, J = 3.4 Hz), 2.52-2.79 (6 / 4H, m), 3.13 (3 / 4H,
dd, J = 7.0 Hz, 14.0 Hz), 3.59 (1H, ddd, J = 3.6 H
z, 7.4 Hz, 15.8 Hz), 4.75-4.83 (7 / 4H, m), 5.08-5.1
3 (1 / 4H, m), 6.83-7.00 (4H, m), 7.04-7.22 (4H, m),
7.29-7.49 (4H, m); IR (KBr) 3482, 3293cm ^-1

Example 24 1,1-Dimethylethyl (1RS, 2RS) -2- (4-fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl carbamate 1) 4'-fluoroacetophenone (57.8 g,
Sodium hydride (24.5) in a solution of 0.307 mol) and ethanol (1 ml) in diethyl carbonate (300 ml).
g, 60% oily, 0.63 mol). Since heat was gradually generated, the mixture was cooled on ice and then stirred at room temperature for 2 hours. The reaction solution is quenched by adding 6N hydrochloric acid, and the solution is treated with water (300
ml) and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1-5: 1),
Ethyl (4-fluorophenyl) -3-oxopropionate (71.2 g, 89%) was obtained. IRν max ^KBr cm ^-1 : 1744, 1696, 1431, 1325, 1202, 113
^{2, 1069, 1017, 853. 1} H-NMR (CDCl 3) δ: 1.28 (3H × 0.62, t, J = 7.8 H
z), 1.37 (3H × 0.38, t, J = 7.8 Hz), 4.04 (2H ×
0.62, s), 4.25 (2H × 0.62, q, J = 7.8 Hz), 4.31
(2H × 0.38, q, J = 7.8 Hz), 5.75 (1H × 0.38, s),
7.28 (1H × 0.62, s), 7.70 (2H × 0.38, d, J = 8.0
Hz), 7.78 (2H × 0.62, d, J = 8.0 Hz), 7.90 (2H ×
0.38, d, J = 8.0 Hz), 8.08 (2H × 0.62, d, J = 8.
0 Hz). 2) To a solution of ethyl 3- (4-fluorophenyl) -3-oxopropionate (34.7 g, 115.5 mmol) in acetonitrile (300 ml) was added 4-trifluoromethylbenzylbromide (27.6 g, 115.5 mmol) and potassium carbonate (31.9 g, 231 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was washed with water (1
L) and extracted with ethyl acetate (500 ml x 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Hexane was added to the residue, and the precipitated crystals were washed with hexane and washed with ethyl 3- (4-fluorophenyl) -3-oxo-2-((4- (trifluoromethyl) phenyl) methyl) propionate (3
1 g, 76%). mp 56-57 ℃ IRν max ^KBr cm ^-1 : 1738, 1688, 1618, 1599, 1508. Anal.Calcd for C ₁₉ H ₁₆ F ₄ O ₃ : C, 61.96; H, 4.38 Found: C, 61.90; H, 4.43. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 6.8 Hz), 3.38
(2H, d, J = 7.6 Hz), 4.14 (2H, q, J = 6.8 Hz), 4.5
8 (1H, t, J = 7.6 Hz), 7.04-7.20 (2H, m), 7.35 (2
H, d, J = 8.0 Hz), 7.52 (2H, d, J = 8.0 Hz), 7.92-
8.08 (2H, m). 3) 3- (4-Fluorophenyl) -3-oxo-2-
To a solution of ethyl ((4- (trifluoromethyl) phenyl) methyl) propionate (6 g, 16.3 mmol) in methanol (100 ml) was added sodium borohydride (640 mg, 16.9 mmol) under ice-cooling. Stirred for 20 minutes. The reaction solution was poured into 1N hydrochloric acid (50 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1),
(2RS, 3SR) -3- (4-fluorophenyl) -3-
Ethyl hydroxy-2-((4- (trifluoromethyl) phenyl) methyl) propionate (5.1 g, 84%)
Was obtained as a colorless oil. ^{. IRν max KBr cm -1: 1728} , 1607, 1510. Anal Calcd for C 19 H 18 F 4 O 3: C, 61.62; H, 4.90 Found:. C, 61.52; H, 4.88 1 H-NMR (CDCl 3 ) δ: 0.99 (3H, t, J = 7.4 Hz), 2.70-
3.10 (3H, m), 3.13 (1H, d, J = 6.2 Hz), 3.99 (2H,
q, J = 7.4 Hz), 4.76-4.86 (1H, m), 6.98-7.16 (2H,
m), 7.20-7.40 (4H, m), 7.52 (2H, d, J = 8.0 Hz). 4) (2RS, 3SR) -3- (4-fluorophenyl) -3-hydroxy-2-((4 Ethyl-(trifluoromethyl) phenyl) methyl) propionate (4.85)
g, 13.1 mmol) in methanol (20 ml) was added to a 1 N aqueous sodium hydroxide solution (13.1 ml, 1
3.1 mmol) and stirred at room temperature for 6 hours. After evaporating the reaction solution under reduced pressure, the reaction solution was diluted with 1N hydrochloric acid (50 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and recrystallized from ethyl acetate-hexane to give (2RS, 3SR) -3- (4-fluorophenyl)-
3-Hydroxy-2-((4- (trifluoromethyl) phenyl) methyl) propionic acid (3.8 g, 84%) was obtained. mp 136-139 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ2.75 (1H, d
d, J = 5.8 Hz, 13.4 Hz), 2.95 (1H, dd, J = 9.2 Hz,
13.2 Hz), 3.08 (2H, d, J = 8.0 Hz), 4.82 (1H, d,
J = 7.0 Hz), 7.08 (2H, t, J = 8.8 Hz), 7.22 (2H,
d, J = 8.0 Hz), 7.34 (2H, dd, J = 5.3 Hz, 8.8 Hz);
IR (KBr) 3351, 3500-2400, 1713cm ^-1 ; Anal.Calcd fo
r C ₁₇ H ₁₄ F ₄ O ₃ : C, 59.65; H, 4.12.Found: C, 59.52;
H, 4.17.5) (2RS, 3SR) -3- (4-fluorophenyl) -3-hydroxy-2-((4- (trifluoromethyl) phenyl) methyl) propionic acid (3.75 g, 1
1.0 mmol) in tetrahydrofuran (70 ml) in diphenylphosphoryl azide (2.6 ml, 12.
1 mmol) and triethylamine (2.30 ml,
(16.4 mmol) and heated under reflux for 3 hours. The reaction solution was diluted with water (300 ml), and ethyl acetate (200 m
1 × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 1) and recrystallized from ethyl acetate-hexane to give (4RS, 5RS) -5- (4-fluorophenyl)- 4-((4- (trifluoromethyl)
Phenyl) methyl) -1,3-oxazolidine-2-one (3.28 g, 88%) was obtained. mp 83-84 ℃ IRν max ^KBr cm ^-1 : 1755, 1609, 1514, 1420, 1387. Anal.Calcd for C ₁₇ H ₁₃ F ₄ NO ₂ : C, 60.18; H, 3.86; N,
4.13 Found:. C, 60.08; H, 3.56; N, 4.10 1 H-NMR (CDCl 3) δ: 2.90-3.16 (2H, m), 3.95 (1H, dd,
J = 12.8, 6.2 Hz), 5.19 (1H, d, J = 6.2 Hz), 5.73
(1H, brs), 7.00-7.12 (2H, m), 7.12-7.40 (4H, m),
7.60 (2H, d, J = 8.0 Hz). 6) (4RS, 5RS) -5- (4-fluorophenyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidine -2-one (3.19g,
Di-tert-butyl dicarbonate (2.46 g, 11.29 mmol) and 4-dimethylaminopyridine (114 mg, 9.41 mmol) in acetonitrile (30 ml) solution.
(0.94 mmol) and stirred at room temperature for 1 hour. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
ml × 2). Wash the extract with saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, recrystallized from ethyl acetate-hexane, and (4RS, 5RS) -5-
1,4-dimethylethyl (4-fluorophenyl) -2-oxo-4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidine-3-carboxylate (3.8
4 g, 93%). mp 126-127 ° C IRν max ^KBr cm ^-1 : 1817, 1724, 1514, 1325. Anal.Calcd for C ₂₂ H ₂₁ F ₄ NO ₄ : C, 60.14; H, 4.82; N,
3.19 Found: C, 60.05; H, 5.12; N, 3.11. ¹ H-NMR (CDCl ₃ ) δ: 1.58 (9H, s), 3.01 (1H, dd, J =
13.2, 9.8 Hz), 3.51 (1H, dd, J = 13.2, 3.6 Hz), 4.
26-4.38 (1H, m), 5.13 (1H, d, J = 2.6 Hz), 6.80-7.
04 (4H, m), 7.38 (2H, d, J = 8.0 Hz), 7.65 (2H, d,
J = 8.0 Hz). 7) (4RS, 5RS) -5- (4-fluorophenyl) -2-oxo-4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidine-3 To a solution of 1,1-dimethylethyl-carboxylate (3.7 g, 8.42 mmol) in methanol (20 ml) was added sodium hydroxide (0.40 g, 10.10 mmol) in methanol (2 g).
0 ml) solution was gradually added under ice-cooling. After stirring the reaction solution for 1 hour, 1N hydrochloric acid (15 ml) and water (100 m
1) and extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and recrystallized from ethyl acetate-hexane. The title compound (2.24 g, 64%) was obtained. mp 95-96 ℃ IRν max ^KBr cm ^-1 : 1688, 1510. Anal.Calcd for C ₂₁ H ₂₃ F ₄ NO ₃ : C, 61.01; H, 5.61; N,
3.39 Found:. C, 60.92; H, 5.55; N, 3.28 1 H-NMR (CDCl 3) δ: 1.31 (9H, s), 2.80-3.10 (3H, m),
3.80-4.02 (1H, m), 4.62-4.80 (2H, m), 6.96-7.10
(2H, m), 7.22-7.40 (4H, m), 7.55 (2H, d, J = 8.2 H
z).

Example 25 2- (Ethyloxy) -N-((1RS, 2RS) -2-
(4-fluorophenyl) -2-hydroxy-1-((4-
(Trifluoromethyl) phenyl) methyl) ethyl)-
1-Naphthalenecarboxamide 1) 1- (4-Fluorophenyl) -1-oxo-3- (4
-(Trifluoromethyl) phenyl) -2-propylamine hydrochloride (600 mg, 1.73 mmol) and 2-ethyloxy-1-naphthalenecarboxylic acid (411 mg, 1.
90 mmol) of N, N-dimethylformamide (10
1) Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (496 mg, 2.59 mmol), 1-hydroxy-1H-benzotriazole (396 mg, 2.59 mmol) and 1,8 -Diazabicyclo [5.4.0] -7-undecene (0.28 ml,
(1.90 mmol) and stirred overnight. 1 in the reaction solution
A normal hydrochloric acid aqueous solution (10 ml) and water (100 ml) were added, and the mixture was extracted with ethyl acetate (50 ml × 2). The extract was washed with a 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, distilled off under reduced pressure, and recrystallized from ethyl acetate-hexane to give 2- (ethyloxy) -N- (2- ( 4-Fluorophenyl) -2-oxo-1-
((4- (trifluoromethyl) phenyl) methyl) ethyl) -1-naphthalenecarboxamide (670 mg, 7
6%). mp 188-189 ° C IRν max ^KBr cm ^-1 : 1688, 1634, 1597, 1508, 1325. Anal.Calcd for C ₂₉ H ₂₃ F ₄ NO ₃ : C, 68.36; H, 4.55; N,
2.75 Found:. C, 68.25; H, 4.58; N, 2.76 1 H-NMR (CDCl 3) δ: 1, 24 (3H, t, J = 7.0 Hz), 3.20
(1H, dd, J = 14.0, 6.4Hz), 3.46 (1H, dd, J = 14.0,
6.4 Hz), 4.13 (2H, q, J = 7.0 Hz), 6.23 (1H, q, J
= 6.6 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.10-7.56 (9
H, m), 7.60-7.80 (2H, m), 7.85 (1H, d, J = 9.0 H
z), 8.04-8.18 (2H, m). 2) 2- (ethyloxy) -N- (2- (4-fluorophenyl) -2-oxo-1-((4- (trifluoromethyl) phenyl) methyl ) Ethyl) -1-naphthalenecarboxamide (400 mg, 0.79 mmol) in methanol (30 ml) solution.
g, 1.57 mmol) and stirred at room temperature for 30 minutes. Sodium borohydride (30 m
g, 0.79 mmol) and stirred for 1 hour. The reaction solution was poured into 1N hydrochloric acid (30 ml), and ethyl acetate (50 ml) was added.
ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 1) and recrystallized from ethyl acetate-hexane to give the title compound (227 m
g, 57%). mp 186-187 ° C IRν max ^KBr cm ^-1 : 1639, 1512, 1242, 1165. Anal.Calcd for C ₂₉ H ₂₅ F ₄ NO ₃ : C, 68.09; H, 4.93; N,
2.74 Found:. C, 68.04; H, 4.79; N, 2.85 1 H-NMR (CDCl 3) δ: 1.37 (3H, t, 6.8 Hz), 2.84-3.28
(2H, m), 3.34 (1H, d, J = 3.8 Hz), 4.08-4.26 (2H,
m), 4.60-4.84 (2H, m), 6.15 (1H, d, J = 8.6Hz), 6.
96-7.16 (3H, m), 7.20-7.50 (7H, m), 7.58 (2H, d, J
= 8.4 Hz), 7.76 (2H, dd, J = 18.2, 9.2 Hz).

Example 26 N-((1RS, 2RS) -2- (4-fluorophenyl)
2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -1-naphthalenecarboxamide 1) 1,1-dimethylethyl (1RS, 2RS) -2-
(4-fluorophenyl) -2-hydroxy-1-((4-
(Trifluoromethyl) phenyl) methyl) ethyl carbamate (2.1 g, 5.08 mmol) in ethanol (25 ml) was added to a 20% hydrogen chloride ethanol solution (2
5 ml) and heated under reflux for 1 hour. The reaction solution was evaporated under reduced pressure, and the residue was washed with diethyl ether.
S, 2RS) -1- (4-Fluorophenyl) -1-hydroxy-3- (4- (trifluoromethyl) phenyl) -2-
Propylamine hydrochloride (1.7 g, 96%) was obtained. ^{. mp 166-167 ℃ IRν max KBr cm} -1: 1605, 1514, 1497. Anal Calcd for C 16 H 16 ClF 4 NO: C, 54.11; H, 4.71;
N, 3.94 Found:. C, 54.10; H, 4.62; N, 3.83 1 H-NMR (CD 3 OD) δ: 2.98 (2H, d, J = 7.4 Hz), 3.60-
3.78 (1H, m), 4.63 (1H, d, J = 6.2 Hz), 7.04-7.16
(2H, m), 7.36-7.50 (4H, m), 7.61 (2H, d, J = 8.4 H
z). 2) (1RS, 2RS) -1- (4-fluorophenyl) -1-hydroxy-3- (4- (trifluoromethyl)
Phenyl) -2-propylamine hydrochloride (150 mg,
0.43 mmol) in ethyl acetate (5 ml).
Naphthoyl chloride (97 mg, 0.64 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml), and ethyl acetate (5 ml) was added.
0 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purification with ethyl acetate = 4: 1-1: 1)
Recrystallization from hexane gave the title compound (145 mg,
72%). mp 134-135 ℃ IRν max ^KBr cm ^-1 : 1634, 1510. Anal.Calcd for C ₂₇ H ₂₁ F ₄ NO ₂ : C, 69.37; H, 4.53; N,
3.00 Found: C, 69.08; H, 4.80; N, 3.01. ¹ H-NMR (CDCl ₃ ) δ: 3.18-3.30 (3H, m), 4.54-4.72 (1
H, m), 4.92 (1H, brs), 6.20 (1H, d, J = 8.8 Hz), 6.
96-7.14 (2H, m), 7.16-7.70 (11H, m), 7.78-7.90 (2
H, m).

Example 27 N-((1RS, 2RS) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4- (trifluoromethyl)
Benzamide (1RS, 2RS) -1- (4-fluorophenyl) -1-
Hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (150 mg, 0.43
(Mmol) in ethyl acetate (5 ml), 4-trifluorobenzoyl chloride (96 mg, 0.64 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give the title compound (129 mg, 62 mg).
%). mp 162-163 ℃ IRν max ^KBr cm ^-1 : 1653, 1508, 1329. Anal.Calcd for C ₂₄ H ₁₈ F ₇ NO ₂ : C, 59.39; H, 3.74; N,
2.89 Found:. C, 59.20; H, 4.01; N, 2.91 1 H-NMR (CDCl 3) δ: 3.18-3.30 (3H, m), 4.54-4.72 (1
H, m), 4.92 (1H, brs), 6.20 (1H, d, J = 8.8 Hz), 6.
96-7.14 (2H, m), 7.16-7.70 (11H, m), 7.78-7.90 (2
H, m).

Example 28 1,1-Dimethylethyl (1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl carbamate 1) 3- (4-fluorophenyl) -3-oxo-2-
Manganese (II) chloride was added to a methanol (500 ml) solution of ethyl ((4- (trifluoromethyl) phenyl) methyl) propionate (20.8 g, 56.5 mmol).
(14.2 g, 113 mmol) and stirred at room temperature for 30 minutes. Sodium borohydride (4.28 g, 113 mmol) was added to the reaction mixture under ice cooling, and the mixture was stirred for 20 minutes. The reaction solution was poured into 1N hydrochloric acid (300 ml) and extracted with ethyl acetate (500 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give (2
RS, 3RS) -3- (4-Fluorophenyl) -3-hydroxy-2-((4- (trifluoromethyl) phenyl)
Ethyl (methyl) propionate (11.1 g, 53%) was obtained as a colorless oil. ^{. IRν max KBr cm -1: 1726} , 1618, 1607, 1510. Anal Calcd for C 19 H 18 F 4 O 3: C, 61.62; H, 4.90 Found:. C, 61.62; H, 5.06 1 H-NMR ( CDCl ₃ ) δ: 0.91 (3H, t, J = 7.0 Hz), 2.88-
3.10 (4H, m), 3.88 (2H, q, J = 7.0 Hz), 4.98-5.06
(1H, m), 6.96-7.12 (2H, m), 7.20 (2H, d, J = 8.0 H
z), 7.30-7.44 (2H, m), 7.49 (2H, d, J = 8.0 Hz). 2) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((4 Ethyl (-(trifluoromethyl) phenyl) methyl) propionate (11.0
g, 29.7 mmol) in methanol (90 ml) was added to a 1 N aqueous sodium hydroxide solution (59.6 ml, 5 ml).
9.6 mmol) and stirred at room temperature for 6 hours. After distilling off the reaction solution under reduced pressure, the reaction solution was diluted with 1 N hydrochloric acid (100 ml).
Extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and recrystallized from ethyl acetate-hexane to give (2RS, 3RS) -3- (4-fluorophenyl)-
3-Hydroxy-2-((4- (trifluoromethyl) phenyl) methyl) propionic acid (8.6 g, 85%) was obtained. ^{. mp 111-112 ℃ IRν max KBr cm} -1: 1713, 1607, 1512. Anal Calcd for C 17 H 14 O 3 F 4: C, 59.65; H, 4.12 Found:. C, 59.65; H, 4.07 1 H -NMR (CDCl ₃ ) δ: 2.08 (1H, s), 2.94-3.20 (3H, m),
5.04-5.10 (1H, m), 6.98-7.12 (2H, m), 7.18 (2H,
d, J = 8.0 Hz), 7.30-7.42 (2H, m), 7.48 (2H, d, J =
8.0 Hz). 3) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((4- (trifluoromethyl) phenyl) methyl) propionic acid (4.30 g, 1
(2.6 mmol) in tetrahydrofuran (80 ml) in diphenylphosphoryl azide (3.0 ml, 13.
8 mmol) and triethylamine (2.63 ml,
(18.8 mmol) and heated under reflux for 4 hours. The reaction solution was diluted with water (300 ml), and ethyl acetate (200 m
1 × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 1) and recrystallized from ethyl acetate-hexane to give (4RS, 5SR) -5- (4-fluorophenyl)- 4-((4- (trifluoromethyl)
Phenyl) methyl) -1,3-oxazolidin-2-one (3.55 g, 83%) was obtained. mp 154-155 ℃ IRν max ^KBr cm ^-1 : 1755, 1611, 1514, 1235. Anal.Calcd for C ₁₇ H ₁₃ F ₄ NO ₂ : C, 60.18; H, 3.86; N,
4.13 Found: C, 60.20; H, 3.80; N, 4.21. ¹ H-NMR (CDCl ₃ ) δ: 2.20-2.44 (2H, m), 4.26 (1H, q,
J = 8.0 Hz), 5.25 (1H, brs), 5.79 (1H, d, J = 8.0 H
z), 7.06-7.20 (4H, m), 7.28-7.40 (2H, m), 7.54 (2
H, d, J = 8.0 Hz). 4) (4RS, 5SR) -5- (4-fluorophenyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidin-2 -On (3.50g,
10.32 mmol) in acetonitrile (30 ml) was added to di-tert-butyl dicarbonate (2.70 g, 12.39 mmol) and 4-dimethylaminopyridine (126 mM).
g, 1.03 mmol) and stirred at room temperature for 1 hour. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, distilled off under reduced pressure, recrystallized from ethyl acetate-hexane, and purified with (4RS, 5S
R) -5- (4-Fluorophenyl) -2-oxo-4-
((4- (trifluoromethyl) phenyl) methyl)-
There was obtained 1,1-dimethylethyl 1,3-oxazolidine-3-carboxylate (4.09 g, 90%). mp 155-156 ° C IRν max ^KBr cm ^-1 : 1821, 1724, 1514, 1360. Anal.Calcd for C ₂₂ H ₂₁ F ₄ NO ₄ : C, 60.14; H, 4.82; N,
3.19 Found:. C, 60.16; H, 4.84; N, 3.25 1 H-NMR (CDCl 3) δ: 1.48 (9H, s), 2.61 (1H, dd, J =
14.2, 8.4 Hz), 2.91 (1H, dd, J = 14.2, 5.2 Hz), 4.
80 (1H, dd, J = 8.4, 7.0 Hz), 5.68 (1H, d, J = 7.0
Hz), 6.82 (2H, d, J = 8.0 Hz), 6.92-7.06 (2H, m),
7.10-7.24 (2H, m), 7.36 (2H, d, J = 8.0 Hz). 5) (4RS, 5SR) -5- (4-fluorophenyl) -2-oxo-4-((4- (tri Sodium hydroxide (0.44 g, 10%) was added to a methanol (22 ml) solution of 1,1-dimethylethyl (fluoromethyl) phenyl) methyl) -1,3-oxazolidine-3-carboxylate (4.0 g, 9.10 mmol). .92 mmol) of methanol (2
2 ml) solution was gradually added under ice-cooling. After stirring the reaction solution for 3 hours, 1N hydrochloric acid (12 ml) and water (100 m
1) and extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and recrystallized from ethyl acetate-hexane. Gave the title compound (2.90 g, 77%). mp 158-159 ° C IRν max ^KBr cm ^-1 : 3358, 1682, 1532, 1514. Anal.Calcd for C ₂₁ H ₂₃ F ₄ NO ₃ : C, 61.01; H, 5.61; N,
3.39 Found:. C, 60.95; H, 5.59; N, 3.20 1 H-NMR (CDCl 3) δ: 1.32 (9H, s), 2.60-2.90 (2H, m),
3.11 (1H, brs), 4.00-4.20 (1H, m), 4.58 (1H, d, J
= 8.4 Hz), 4.92 (1H, s), 7.02-7.14 (2H, m), 7.22
(2H, d, J = 8.0 Hz), 7.32-7.44 (2H, m), 7.51 (2H,
d, J = 8.0 Hz).

Example 29 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 1) 6,7-dihydro-5H-benzo [a Cyclohepten-1-ylmethanol tert-butyl (6,7-dihydro-5H-benzo [a] cyclohepten-1-ylmethoxy) dimethylsilane (Tetrahedron, 53,
15969-15982 (1990)) 1.079
g (3.740 mmol) of tetrahydrofuran 30 m
1 solution of tetrabutylammonium fluoride in 1.
3.74 ml (3.74 mmol) of a 0 M tetrahydrofuran solution was added, and the mixture was stirred at room temperature for 15 minutes. After concentrating the reaction solution, the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-1).
/ 1) to obtain the desired product. Colorless liquid Yield 0.573g
Yield 88% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.99-2.25 (4H, m), 2.71
(2H, t, J = 6.0 Hz), 4.73 (2H, s), 6.18 (1H, td, J
= 5.5 Hz, 11.6 Hz), 6.73 (1H, d, J = 11.6 Hz), 7.
11-7.25 (3H, m); IR (neat) 3330, 2930, 1449, 1067,
1020, 995, 772 cm ^-1 2) 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid 6,7-dihydro-5H-benzo [a] cycloheptene-1
31.41 g (180.3 mmol) of -ylmethanol
Chromic anhydride 3 in a 500 ml acetone solution under ice-cooling
6.1 g (361 mmol) and 30 ml of concentrated sulfuric acid were added to water 12
A solution dissolved in 0 ml was slowly added dropwise, and after completion of the addition, the mixture was stirred at room temperature for 1 hour. After ice-cooling the reaction solution again,
60 ml of isopropanol was added, and the mixture was stirred for 0.5 hour. The acetone in the reaction solution was distilled off under reduced pressure, diluted with ethyl acetate, washed three times with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from cold diisopropyl ether to obtain the desired product. White crystals Yield 19.78 g Yield 58% mp 146-147 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.08-2.16
(4H, m), 2.70 (2H, t, J = 6.4 Hz), 6.24 (1H, td, J
= 6.4 Hz, 11.1 Hz), 7.14 (1H, d, J = 11.4 Hz), 7.2
3 (1H, t, J = 7.3 Hz), 7.39 (1H, d, J = 7.2 Hz),
7.92 (1H, dd, J = 1.5 Hz, 7.7 Hz); IR (KBr) 3065-25
30, 1686, 1451, 1414, 1300, 1277, 926, 779 cm ^-1 ; A
nal.Calcd for C ₁₂ H ₁₂ O ₂・ 0.1H ₂ O: C, 75.85; H, 6.47.
Found: C, 75.88; H, 6.35. 3) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol (4RS , 5SR) -5- (4-Fluorophenyl) -4-
18.75 g (55.26 mmol) of [4- (trifluoromethyl) benzyl] -1,3-oxazolidin-2-one and 8.84 g (221 mmol) of sodium hydroxide
Was heated to reflux in 100 ml of ethanol and 10 ml of water for 5 hours. The reaction was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Residue is silica gel (APS type)
The product was purified by column chromatography (hexane / ethyl acetate = 1 / 1-ethyl acetate) and crystallized from diethyl ether-hexane to obtain the desired product. White crystals Yield 16.38 g Yield 95% mp 87-88 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.60 (2H, br
s), 2.43 (1H, dd, J = 10.2 Hz, 13.6 Hz), 2.87 (1H,
dd, J = 3.1 Hz, 13.7 Hz), 3.29 (1H, ddd J = 3.3 H
z, 5.2 Hz, 10.3 Hz), 4.66 (1H, d, J = 5.0 Hz), 7.0
8 (2H, t, J = 8.7 Hz), 7.27 (2H, d, J = 8.0 Hz),
7.38 (2H, dd, J = 5.4 Hz, 8.4 Hz), 7.55 (2H, d, J
= 7.6 Hz); IR (neat) 3360-2865, 1508, 1325, 1225,
1163, 1121, 1067, 826 cm ^-1 ; Anal.Calcd for C ₁₆ H ₁₅
F ₄ NO: C, 61.34; H, 4.83; N, 4.47. Found: C, 61.32;
H, 4.62; N, 4.48. 4) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -6,7 -Dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.157 g (0.501 mmol), 94 mg (0.50 mmol) of 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid, 1
-Hydroxybenzotriazole hydrate 77 mg (0.
(50 mmol) was stirred in 10 ml of acetonitrile, and 96 mg (0.50 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added thereto, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 0.134 g
Yield 55% mp 197-198 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 1.
91-2.04 (2H, m), 2.17-2.27 (2H, m), 2.65 2.70 (2H, m
m), 2.83-3.00 (2H, m), 4.62-4.76 (1H, m), 4.97 (1
H, t, J = 4.0 Hz), 5.04 (1H, d, J = 3.8 Hz), 5.84
(1H, td, J = 5.1Hz, 12.2 Hz), 6.11 (1H, d, J = 12.
0 Hz), 6.81 (1H, d, J = 8.8 Hz), 6.91 (1H, dd, J =
1.9 Hz, 7.3 Hz), 7.01-7.14 (4H, m), 7.31 (2H, d, J
= 8.2 Hz), 7.47-7.54 (4H, m); IR (KBr) 3279, 294
0, 1640, 1534, 1514, 1325, 1229, 1163, 1121, 1069,
831 cm ^-1 ; Anal.Calcd for C ₂₈ H ₂₅ F ₄ NO ₂ : C, 69.56;
H, 5.21; N, 2.90. Found: C, 69.41; H, 5.15; N, 2.9
1.

Example 30 4-Fluoro-N-((1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl)- 1-Naphthalenecarboxamide 1) 1,1-dimethylethyl (1RS, 2SR) -2-
(4-fluorophenyl) -2-hydroxy-1-((4-
A 20% ethanol solution of hydrogen chloride (35 ml) was added to a solution of (trifluoromethyl) phenyl) methyl) ethyl carbamate (2.58 g, 6.24 mmol) in ethanol (35 ml), and the mixture was heated under reflux for 30 minutes. The reaction solution was distilled off under reduced pressure, and the residue was washed with diethyl ether.
(1RS, 2SR) -1- (4-fluorophenyl) -1-
Hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (2.05 g, 94%)
I got mp 173-174 ° C IRν max ^KBr cm ^-1 : 3314, 3009, 1611, 1512, 1331. Anal.Calcd for C ₁₆ H ₁₆ ClF ₄ NO ・ 0.5H ₂ O: C, 53.57; H,
4.78; N, 3.90 Found:. C, 53.81; H, 4.81; N, 3.74 1 H-NMR (DMSO-d 6) δ: 2.79 (2H, d, J = 6.6 Hz), 3.64
-3.80 (1H, m), 5.03 (1H, s), 6.30 (1H, d, J = 4.0
Hz), 7.10-7.24 (2H, m), 7.33 (2H, d, J = 8.0Hz),
7.38-7.50 (2H, m), 7.59 (2H, d, J = 8.0 Hz), 8.07
(2H, brs). 2) 4-Fluoro-1-naphthalenecarboxylic acid (163
mg, 0.86 mmol) of tetrahydrofuran (5 m
l) Add oxalyl chloride (0.15 ml, 1.
72 mmol) and N, N-dimethylformamide (0.01 ml) were added, the mixture was stirred at room temperature for 30 minutes, and the reaction solution was distilled off under reduced pressure. (1RS, 2SR) -1- (4-fluorophenyl)-was added to a solution of the residue in ethyl acetate (5 ml).
1-hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (200 mg, 0.57
Mmol) and saturated aqueous sodium bicarbonate (5 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) and recrystallized from ethyl acetate-hexane to give the title compound (214 m
g, 77%). ^{. mp 210-211 ℃ IRν max KBr cm} -1: 3275, 1642, 1626, 1601. Anal Calcd for C 27 H 20 F 5 NO 2: C, 66.80; H, 4.15; N,
2.89 Found:. C, 66.79; H, 4.19; N, 2.82 1 H-NMR (CDCl 3) δ: 2.80-3.16 (2H, m), 3.18 (1H, d,
J = 3.6 Hz), 4.72-4.94 (1H, m), 5.08-5.16 (1H, m),
5.92 (1H, d, J = 8.2 Hz), 7.00-7.70 (13H, m), 8.09
(1H, d, J = 8.0 Hz).

Example 31 4-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -5,6 1,7,8-Tetrahydronaphthalene-1-carboxamide 1) Methyl 4-amino-5,6,7,8-tetrahydronaphthalene-1-carboxylate 4-Nitro-5,6,7,8-tetrahydronaphthalene-1
-Methyl carboxylate (Chem. Abstr., 43,
202f (1949), Chem. Abstr. , 4
3,816b (1949)) 1.816g (7.7
A solution of 20 mmol) in 30 ml of methanol was hydrogenated under normal temperature and pressure until the raw materials disappeared using 0.5 g of 10% palladium / carbon (containing 50% water) as a catalyst. After removing the catalyst by filtration, the filtrate was passed through a short silica gel column chromatography, and the solvent was distilled off under reduced pressure to obtain the desired product. Yellow crystals Yield 1.574 g Yield 99% Recrystallization from ethyl acetate-hexane gave pale yellow crystals. mp 120-121 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 1.68-1.90
(4H, m), 2.44 (2H, t, J = 6.2 Hz), 3.10 (2H, t, J =
6.0 Hz), 3.81 (3H, s), 3.92 (2H, br s), 6.50 (1H,
d, J = 8.4 Hz), 7.69 (1H, d, J = 8.4 Hz); IR (KB
r) 3486, 3374, 2948, 2930, 2868, 1688, 1626, 1590,
1481, 1449, 1431, 1310, 1267, 1253, 1196, 1142, 7
75 cm ^-1 ; Anal.Calcd for C ₁₂ H ₁₅ NO ₂ : C, 70.22; H,
7.37; N, 6.82. Found: C, 70.25; H, 7.33; N, 6.67. 2) Methyl 4-fluoro-5,6,7,8-tetrahydronaphthalene-1-carboxylate 4-amino-5,6, 7,8-tetrahydronaphthalene-1
While stirring 1.210 g (5.895 mmol) of methyl carboxylate and 2 ml of concentrated hydrochloric acid in 20 ml of water, a solution of 0.49 g (7.07 mmol) of sodium nitrite in 1 ml of water was added dropwise under ice-cooling. The mixture was stirred at the same temperature for 10 minutes. Under ice-cooling, 1.48 ml (10.0 mmol) of a 60% aqueous solution of hexafluorophosphoric acid was added to the reaction solution with vigorous stirring, followed by stirring for 0.5 hour. The resulting precipitate was filtered, washed with water and methanol-diethyl ether (1: 4), and dried to obtain a diazonium salt as a white powder. The obtained diazonium salt was heated in 170 ml of liquid paraffin at 170 ° C. for 0.5 hour.
After cooling to room temperature, aqueous sodium hydrogen carbonate solution was added,
Extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 200 / 1-15 / 1) to obtain the desired product. White crystals Yield 0.487 g Yield 40% mp 44-45 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.72-1.83 (4
H, m), 2.74 (2H, br s), 3.08 (2H, br s), 3.86 (3H,
s), 6.87 (1H, t, J = 8.6 Hz), 7.73 (1H, dd, J = 6.
0 Hz, 8.6 Hz); IR (KBr) 2944, 1721, 1582, 1472, 14
33, 1260, 1254,1190, 1157, 1130, 1038, 770 cm ^-1 ; A
nal.Calcd for C ₁₂ H ₁₃ FO ₂ : C, 69.22; H, 6.29. Found:
C, 69.39; H, 6.43. 3) 4-Fluoro-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid 4-fluoro-5,6,7,8-tetrahydronaphthalene-
0.434 g (2.084 mmol) of methyl 1-carboxylate in 10 ml of methanol-10 m in tetrahydrofuran
4.17 ml of 1N aqueous sodium hydroxide solution
(4.17 mmol) and stirred at room temperature overnight. The reaction solution was concentrated, diluted with water, acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from diethyl ether-hexane to obtain the desired product. White crystals Yield 0.308 g Yield 76% mp 172-173 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.74-1.82
(4H, m), 2.76 (2H, brs), 3.16 (2H, br s), 6.91 (1
H, t, J = 8.8 Hz), 7.91 (1H, dd, J = 6.1 Hz, 8.5 H
z); IR (KBr) 3100-2600, 1686, 1588, 1429, 1304, 12
73, 1250, 1188 cm ^-1 ; Anal.Calcd for C ₁₁ H ₁₁ FO ₂ : C,
68.03; H, 5.71. Found: C, 68.10; H, 6.00.4.) 4-Fluoro-N-[(1RS, 2SR) -2- (4-
Fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -5,6,7,8-tetrahydronaphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- ( 0.164 g (0.523 mmol) of 4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 4-fluoro-5,6,7,8-tetrahydronaphthalene-1- Carboxylic acid 0.10 g (0.52 mmol), 1-hydroxybenzotriazole hydrate 80 m
While stirring g (0.52 mmol) in 10 ml of acetonitrile, 0.10 g (0.52 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. . The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White crystal Yield 0.220 g Yield 86% mp 241-242 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 1.
53-1.75 (4H, m), 2.11-2.26 (1H, m), 2.30 2.48 (1H,
m), 2.61-2.67 (2H, m), 2.78-3.02 (2H, m), 4.59-4.
73 (1H, m), 4.95 (1H, t, J = 3.9 Hz), 5.10 (1H, d,
J = 3.6 Hz), 6.69-6.87 (3H, m), 7.06 (2H, t, J =
8.6 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.47-7.54 (4H,
m); IR (KBr) 3272, 2942, 1642, 1514, 1327, 1229, 1
165, 1121,1069, 831 cm ^-1 ; Anal.Calcd for C ₂₇ H ₂₄ F ₅
NO ₂ : C, 66.25; H, 4.94; N, 2.86. Found: C, 66.30;
H, 5.18; N, 2.66.

Example 32 5-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] naphthalene-1- Carboxamide 1) Ethyl 5-nitro-1-naphthoic acid 5-Nitro-1-naphthoic acid (Chem. Pharm. B
ull. , 32, 3968-80 (1984)).
A solution of 5.995 g (27.60 mmol) and 2 ml of concentrated sulfuric acid in 100 ml of ethanol was heated to reflux for 1 day. After concentration, the reaction solution was diluted with ethyl acetate and washed with an aqueous sodium hydrogen carbonate solution and water. The obtained ethyl acetate solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product. Yellow solid Yield: 6.212 g Yield: 92% Recrystallization from ethanol gave a pale yellow powder. mp 92-93 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 1.48 (3H, t,
J = 7.2 Hz), 4.50 (2H, q, J = 7.1 Hz), 7.67 (1H,
dd, J = 7.6 Hz, 8.8 Hz), 7.74 (1H, dd, J = 7.2 Hz,
8.8 Hz), 8.20 (1H, dd, J = 1.1 Hz, 7.7 Hz), 8.29
(1H, dd, J = 1.1Hz, 7.3 Hz), 8.66 (1H, td, J = 1.0
Hz, 8.8 Hz), 9.26 (1H, td, J = 1.0 Hz, 8.6 Hz); I
R (KBr) 1725, 1520, 1354, 1277, 1155, 793, 764 cm
^-1 ; Anal.Calcd for C ₁₃ H ₁₁ NO ₄ : C, 63.67; H, 4.52;
N, 5.71. Found: C, 63.45; H, 4.47; N, 5.69. 2) Ethyl 5-amino-1-naphthoate 3.304 g of ethyl 5-nitro-1-naphthoate (13.
A solution (47 mmol) of ethanol (10 ml) -tetrahydrofuran (20 ml) was hydrogenated under normal temperature and pressure until the raw materials disappeared using 10% palladium / carbon (50% water-containing) 0.5 g as a catalyst. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure. The obtained crude product is purified by silica gel column chromatography (hexane / ethyl acetate =
6 / 1-3 / 1) to obtain the desired product. Yellow liquid yield 2.
797 g 97% yield ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.45 (3H, t, J = 7.1 H
z), 4.16 (2H, br s), 4.47 (2H, q, J = 7.1 Hz), 6.8
5 (1H, dd, J = 0.8 Hz, 7.4 Hz), 7.41 (1H, dd, J =
7.5 Hz, 8.5 Hz), 7.47 (1H, dd, J = 7.2 Hz, 8.6 H
z), 8.05 (1H, td, J = 1.1 Hz, 8.5 Hz), 8.11 (1H, d
d, J = 1.2 Hz, 7.2 Hz), 8.28 (1H, td, J = 0.9 Hz,
8.6 Hz); IR (neat) 3378, 2980, 1705, 1634, 1582, 1
464, 1260, 1213, 1107, 783 cm ^-1 3) Ethyl 5-fluoro-1-naphthoate 1.380 g (6.4 g of ethyl 5-amino-1-naphthoate)
11 mmol) and 0.53 g (7.6 g) of sodium nitrite under ice-cooling while stirring 2 ml of concentrated hydrochloric acid in 15 ml of water.
(9 mmol) was added dropwise and stirred at the same temperature for 10 minutes. Under ice-cooling, 1.61 ml (10.9 mmol) of a 60% aqueous solution of hexafluorophosphoric acid was added to the reaction solution with vigorous stirring, followed by stirring for 0.5 hour. The resulting precipitate was filtered, washed with water and methanol-diethyl ether (1: 4), and dried to obtain a diazonium salt as a brown powder. The obtained diazonium salt was heated in 170 ml of liquid paraffin at 170 ° C. for 0.5 hour. After cooling to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 15/1).
A mixture of ethyl-fluoro-1-naphthoate and liquid paraffin was obtained as a colorless liquid. To a solution of the obtained liquid in 30 ml of ethanol-30 ml of tetrahydrofuran was added 8 ml (8 mmol) of a 1N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, diluted with water, and washed with diethyl ether. The resulting aqueous solution was acidified with 1N hydrochloric acid, the resulting crystals were filtered, washed with water and hexane,
The desired product was obtained. White crystals Yield 0.409 g Yield 34
% Mp 214-216 ° C; ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ 7.44 (1
H, dd, J = 7.8 Hz, 10.4 Hz), 7.60-7.75 (2H, m), 8.2
5 (1H, d, J = 7.0 Hz), 8.32 (1H, d, J = 8.8Hz), 8.
70 (1H, d, J = 8.4 Hz); IR (KBr) 3100-2500, 1678,
1599, 1302, 1246, 1117, 887, 781 cm ^-1 ; Anal.Calcd
for C ₁₁ H ₇ FO ₂ : C, 69.47; H, 3.71. Found: C, 69.24;
H, 3.45. 4) 5-Fluoro-N-[(1RS, 2SR) -2- (4-
Fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4 -(Trifluoromethyl) phenyl] propan-1-ol 0.163 g (0.520 mmol), 5-fluoro-1-naphthoic acid 0.10 g (0.5
80 mg (0.52 mmol) of 1-hydroxybenzotriazole hydrate in 10 ml of acetonitrile
While stirring in 0.1 ml, 0.10 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.
52 mmol) and stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals
Yield 0.216 g Yield 86% mp 222-224 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
93 (1H, dd, J = 10.8 Hz, 14.0 Hz), 3.19 (1H, dd, J
= 3.5 Hz, 14.5 Hz), 4.65-4.80 (1H, m), 4.91 (1H,
t, J = 4.8 Hz), 5.44 (1H, d, J = 4.0 Hz), 7.02-7.2
9 (6H, m), 7.38-7.59 (7H, m), 7.90 (1H, d, J = 9.4
Hz), 8.08 (1H, d, J = 8.4 Hz); IR (KBr) 3283, 164
2, 1537, 1514, 1327, 1248, 1227, 1163, 1121, 1069,
^{. 831, 783cm -1; Anal Calcd} for C 27 H 20 F 5 NO 2: C, 66.80; H, 4.15; N,
2.89. Found: C, 66.65; H, 4.21; N, 2.68.

Example 33 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) ben
[Zyl] ethyl] -5,6,7,8-tetrahydronaphthale
1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophene)
Nyl) -3- [4- (trifluoromethyl) phenyl] p
0.168 g of Lopan-1-ol (0.536 mm
Le), 1,2,3,4-tetrahydronaphthalene-1-ca
Rubonic acid (Tetrahedron, 53, 15969)
-15982 (1990)) 94mg (0.54m
Lmol) 1-hydroxybenzotriazole hydrate 8
2 mg (0.54 mmol) in 10 ml of acetonitrile
1-ethyl-3- (3-dimethylaminopropyl)
Ropyl) carbodiimide hydrochloride 0.10 g (0.54
Mmol) and stirred at room temperature overnight. Acetic acid
Dilute to ethyl, wash with aqueous sodium bicarbonate,
After drying over magnesium sulfate and passing through silica gel,
The medium was distilled off under reduced pressure. The residue obtained is ethyl acetate-hexane.
Crystallization from sun gave the desired product. White crystals Yield
0.161 g yield 64% mp 219-221 ° C;¹H-NMR (CDCl_Three-DMSO-d₆, 200MHz) δ 1.
50-1.73 (4H, m), 2.05-2.35 (2H, m), 2.70 (2H, t, J
 = 6.4 Hz), 2.88 (1H, dd, J = 10.8 Hz, 14.4Hz), 3.
06 (1H, dd, J = 3.8 Hz, 14.0 Hz), 4.55-4.70 (1H,
m), 4.87 (1H, t, J = 4.4 Hz), 5.33 (1H, d, J = 3.6
Hz), 6.74 (1H, dd, J = 2.8 Hz, 5.6 Hz), 6.95-7.09
(4H, m), 7.28-7.37 (3H, m), 7.47-7.54 (4H, m); IR
(KBr) 3330, 1624, 1534, 1329, 1159, 1123, 1069, 83
1 cm^-1; Anal. Calcd for C₂₇H_{twenty five}F _FourNO_Two: C, 68.78; H,
5.34; N, 2.97. Found: C, 68.62; H, 5.38; N, 2.90.

Example 34 4-Chloro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] naphthalene-1- Carboxamide 1) 9.948 g of 4-amino-1-naphthoic acid / hydrochloride 4-amino-1-naphthalenecarbonitrile
(59.14 mmol) and 25 g of potassium hydroxide in water 1
Heated to reflux in 50 ml for 1 day. After cooling the reaction solution to room temperature, it was diluted with 150 ml of water, and the insoluble matter was filtered off. The filtrate was acidified with concentrated hydrochloric acid, and the resulting precipitate was collected by filtration and washed with ethanol and water to obtain the desired product. Brown powder Yield 4.67 g Yield 35% ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ 6.75 (1 H, d, J = 8.4 H)
z), 7.40-7.48 (1H, m), 7.52-7.61 (1H, m), 8.06 (1H,
d, J = 8.6 Hz), 8.16 (1H, d, J = 7.6 Hz), 9.10 (1
H, d, J = 7.8 Hz); IR (KBr) 2838, 1686, 1503, 126
0, 1204, 1094, 766 cm ^-1 2) Methyl 4-chloro-1-naphthoate 2.330 g (1
(0.42 mmol) in 20 ml of conc. The reaction solution was cooled with ice, and cuprous chloride was added to the reaction mixture.
A solution of 57 g (5.73 mmol) in 4 ml of concentrated hydrochloric acid and 50 ml of concentrated hydrochloric acid were added, and the mixture was stirred at 100 ° C. for 4 hours. After cooling to room temperature, the resulting precipitate was collected by filtration and washed with water. The resulting precipitate was stirred overnight at 70 ° C. in 40 ml of a 10% solution of hydrogen chloride in methanol. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate =
9/1), the desired product was obtained. 0.299 g of yellow liquid
Yield 13% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 4.00 (3H, s), 7.58-7.73
(3H, m), 8.09 (1H, d, J = 7.8 Hz), 8.32-8.38 (1H,
m), 8.92-9.01 (1H, m); IR (neat) 1717, 1508,1275,
1246, 1194, 1140, 1024, 787, 766 cm ^-1 3) 4-chloro-1-naphthoic acid 0.299 g of methyl 4-chloro-1-naphthoate (1.3 g)
(55 mmol) in methanol (10 ml) -tetrahydrofuran (5 ml) was added to a 1N aqueous sodium hydroxide solution (2.71).
ml (2.71 mmol) was added and stirred at room temperature overnight. The reaction solution was concentrated, diluted with water, acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from diethyl ether-hexane to obtain the desired product. Light brown crystals Yield 0.234 g Yield 84
% Mp 215-217 ° C .; ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ 7.74-7.8
5 (3H, m), 8.12 (1H, d, J = 7.6 Hz), 8.27 8.35 (1
H, m), 8.91-9.00 (1H, m); IR (KBr) 3100-2500,1690,
1510, 1283, 1252, 785, 762 cm ^-1 ; Anal.Calcd for
C ₁₁ H ₇ ClO ₂・ 0.2H ₂ O: C, 62.85; H, 3.55. Found: C, 62.
99; H, 3.31.4) 4-Chloro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] naphthalene- 1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.155 g (0.495 mmol), 4 -Chloro-1-naphthoic acid 0.10 g (0.49
Mmol) 1-hydroxybenzotriazole hydrate (76 mg, 0.49 mmol) in acetonitrile 10 m
1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 95 mg (0.49
Mmol) and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 0.173 g Yield 70% mp 222-223 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
92 (1H, dd, J = 10.5 Hz, 14.1 Hz), 3.07 (1H, dd, J
= 3.1 Hz, 14.1 Hz), 4.70-4.85 (1H, m), 5.00 (1H,
t, J = 3.8 Hz), 5.23 (1H, d, J = 3.8 Hz), 7.07 (1
H, d, J = 8.8 Hz), 7.13 (2H, t, J = 8.6 Hz), 7.27-
7.62 (11H, m), 8.24 (1H, d, J = 8.4 Hz); IR (KBr)
3274, 1638, 1537, 1514, 1327, 1163, 1125, 1069, 83
^{. 3 cm -1; Anal Calcd for} C 27 H 20 ClF 4 NO 2: C, 64.61;
H, 4.02; N, 2.79.Found: C, 64.26; H, 3.88; N, 2.5
9.

Example 35 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) ben
[Zyl] ethyl] naphthalene-1-carboxamide 1) (1RS, 2SR) -2-amino-1- (4-fluoro)
L-phenyl) -3- [4- (trifluoromethyl) benzyl
Ru] propan-1-ol hydrochloride N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxyethyl-1- [4- (trifluoromethyl
Tert-butyl carbamate 2.5)
8 g (6.24 mmol) in 35 ml ethanol solution
35 ml of a 20% ethanolic hydrogen chloride solution is added and 30 minutes
The mixture was refluxed while heating. The reaction solution was concentrated under reduced pressure, and the residue was
After washing with chill ether, 2.05 g of the desired product (94%)
Was obtained as crystals. mp 173-174 ° C;¹H-NMR (DMSO-d₆, 200MHz) δ 2.79 (2
H, d, J = 6.6 Hz), 3.64-3.80 (1H, m), 5.03 (1H,
s), 6.30 (1H, d, J = 4.0 Hz), 7.10-7.24 (2H, m),
7.33 (2H, d, J = 8.0 Hz), 7.38-7.50 (2H, m), 7.59
(2H, d, J = 8.0 Hz), 8.07 (2H, br s); IR (KBr) 331
4, 3009 cm^-1; Anal. Calcd for C₁₆H₁₆ClF_FourNO ・ 0.5H_TwoO:
 C, 53.57; H, 4.78; N, 3.90. Found: C, 53.81; H,
4.81; N, 3.74.2) N-[(1RS, 2SR) -2- (4-fluorophene)
Nil) -2-hydroxy-1- [4- (trifluoromethyl
L) benzyl] ethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophene)
Nyl) -3- [4- (trifluoromethyl) benzyl] p
Lopan-1-ol hydrochloride 780 mg (1.89 mmol
1) -Naphthoyl chloride in 5 ml of ethyl acetate
0.43 ml (2.84 mmol) and 5 ml of saturated aqueous sodium bicarbonate
Was added and stirred for 30 minutes. Dilute the reaction with water and add acetic acid
Extracted with ethyl. After washing the extract with saturated saline,
It was dried over magnesium sulfate and concentrated under reduced pressure. Remove the residue
Ricagel column chromatography (ethyl acetate / hex
After purifying with sun = 1/2), use ethyl acetate-hexane
To give 354 mg (40%) of the desired product as crystals
I got it. mp 214-216 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 2.89 (1H,
dd, J = 11.0 Hz, 14.0Hz), 3.09 (1H, dd, J = 4.6 H
z, 13.6 Hz), 3.28 (1H, br s), 4.74-4.91 (1H, m), 5.
12 (1H, br s), 5.94 (1H, br d, J = 9.4 Hz), 7.05-
7.24 (2H, m), 7.30-7.66 (11H, m), 7.84 (2H, t, J =
 9.3 Hz); IR (KBr) 3366, 3285, 1636 cm ^-1; Anal. Ca
lcd for C₂₇H_{twenty one}F_FourNO_Two: C, 69.37; H, 4.53; N, 3.00. F
ound: C, 69.17; H, 4.56; N, 2.88.

Example 36 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4-methyl-1-naphthalenecarboxamide (1R, 2S) -2-amino-1- (4-fluorophenyl)- 3- (4- (trifluoromethyl) phenyl) -1-
In a solution of propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml), 4-methyl-1-naphthalenecarboxylic acid (268 mg, 1.44 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. Salt (413 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (220 m
g, 1.44 mmol) and stirred at room temperature overnight.
The reaction solution was diluted with water (100 ml), and ethyl acetate (10 ml) was added.
0 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purification with acetone = 1: 1) and recrystallization from ethyl acetate-hexane gave the title compound (487 mg, 70%). mp 198-199 ℃ IRνmax ^KBr cm ^-1 : 1636, 1620, 1607. Anal.Calcd for C ₂₈ H ₂₃ F ₄ NO ₂ : C, 69.85; H, 4.81; N,
2.91 Found:. C, 69.80; H, 4.92; N, 2.79 1 H-NMR (CDCl 3) δ: 2.58 (3H, s), 2.66-3.06 (1H, m),
3.33 (1H, brs), 4.60-4.80 (1H, m), 4.98-5.06 (1H,
m), 5.80 (1H, d, J = 8.2 Hz), 6.92-7.54 (12H, m),
7.59 (1H, d, J = 8.6 Hz), 7.89 (1H, d, J = 8.2 H
z).

Example 37 5-Chloro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] naphthalene-1- Carboxamide 1) Ethyl 5-chloro-1-naphthoate 1.358 g of ethyl 5-amino-1-naphthoate (6.3 g)
(0.9 mmol) was added dropwise to a solution of 0.52 g (7.57 mmol) of sodium nitrite in 1 ml of water under ice-cooling while stirring in 10 ml of concentrated hydrochloric acid.
Stirred for hours. Cuprous chloride 0.34 g under ice-cooling
(3.47 mmol) in 2 ml of concentrated hydrochloric acid, and 10
Stirred at 0 ° C. for 0.5 hours. After cooling to room temperature, the reaction was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 15/1) to obtain the desired product. Colorless liquid Yield 0.713 g Yield 48% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.47 (3H, t, J = 7.2 H)
z), 4.48 (2H, q, J = 7.3Hz), 7.47-7.66 (3H, m), 8.
22 (1H, dd, J = 1.1 Hz, 7.3 Hz), 8.53 (1H, d, J =
8.6 Hz), 8.85 (1H, d, J = 8.4 Hz); IR (neat) 1717,
1262, 1196, 1142, 789 cm ^-1 2) 5-chloro-1-naphthoic acid 0.713 g of ethyl 5-chloro-1-naphthoate (3.01 g)
38 mmol) in methanol (20 ml) -tetrahydrofuran (10 ml) and 1N aqueous sodium hydroxide solution (4.5).
6 ml (4.56 mmol) was added and stirred overnight at room temperature. The reaction solution was concentrated, diluted with water, and acidified with 1N hydrochloric acid. The resulting precipitate was collected by filtration and washed with water and hexane to obtain the desired product. 0.547 g of white crystals
Yield 87% mp 248-250 ° C; ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ 7.64 (1
H, t, J = 8.0 Hz), 7.74-7.83 (2H, m), 8.23 (1H, d,
J = 6.6 Hz), 8.46 (1H, d, J = 8.6 Hz), 8.84 (1H,
d, J = 8.8 Hz); IR (KBr) 3100-2550, 1678, 1302, 78
3 cm ^-1 ; Anal.Calcd for C ₁₁ H ₇ ClO ₂ : C, 63.94; H, 3.
41. Found: C, 63.96; H, 3.60.3) 5-Chloro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) Benzyl] ethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.163 g (0 .520 mmol) 0.11 g (0.52 mmol) of 5-chloro-1-naphthoic acid
80 mg (0.52 mmol) of 1-hydroxybenzotriazole hydrate in 10 m of acetonitrile
1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.10 g (0.5
2 mmol) and stirred at room temperature overnight. Dilute the reaction solution with ethyl acetate and wash with aqueous sodium hydrogen carbonate,
After drying over anhydrous magnesium sulfate and passing through silica gel,
The solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 0.223 g Yield 85% mp 211-212 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
92 (1H, dd, J = 10.8 Hz, 14.0 Hz), 3.14 (1H, dd, J
= 2.7 Hz, 13.7 Hz), 4.68-4.83 (1H, m), 4.94 (1H,
t, J = 4.5 Hz), 5.36 (1H, d, J = 3.6 Hz), 7.08 (2
H, t, J = 8.8 Hz), 7.17-7.58 (11H, m), 7.75 (1H,
d, J = 10.0 Hz), 8.27 (1H, d, J = 8.4 Hz); IR (KB
r) 3277, 1636, 1537, 1514, 1327, 1229, 1169, 1121,
1069, 1020,833, 785 cm ^-1 ; Anal.Calcd for C ₂₇ H ₂₀ C
lF ₄ NO ₂ : C, 64.61; H, 4.02; N, 2.79. Found: C, 64.4
7; H, 4.00; N, 2.58.

Example 38 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -4-nitro-5,6,7,8-tetrahydronaphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- 0.139 g (0.444 mmol) of (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 4-nitro-5,6,7,8-tetrahydronaphthalene-1 -Carboxylic acid (Chem. Pharm. Bul)
l. , 32, 3968-80 (1984)) 98m
g (0.44 mmol) of 1-hydroxybenzotriazole hydrate (68 mg, 0.44 mmol) in 10 ml of acetonitrile while stirring 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 85 m
g (0.44 mmol) was added and stirred at room temperature overnight.
The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.146 g Yield 64% mp 207-209 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 1.
51-1.75 (4H, m), 2.00-2.15 (1H, m), 2.28 2.43 (1H,
m), 2.80-3.07 (4H, m), 4.62-4.76 (1H, m), 4.93 (1
H, t, J = 4.2 Hz), 5.11 (1H, d, J = 3.6 Hz), 6.89
(1H, d, J = 8.0Hz), 7.08 (2H, t, J = 8.8 Hz), 7.18
(1H, d, J = 9.2 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.4
8-7.54 (5H, m); IR (KBr) 3275, 2944, 1644, 1526, 1
331, 1159, 1127, 1069, 835 cm ^-1 ; Anal.Calcd for C
₂₇ H ₂₄ F ₄ N ₂ O ₄ : C, 62.79; H, 4.68; N, 5.42. Found: C,
62.53; H, 4.49; N, 5.30.

Example 39 6-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] naphthalene-1- Carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.234 g (0.747 mmol), 6-fluoro -1-Naphthoic acid (European Patent EP09
0.147 g (0.75 mmol), 1-hydroxybenzotriazole hydrate 0.1
While stirring 1 g (0.75 mmol) in 10 ml of acetonitrile, 0.14 g (0.75 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. . The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 0.
302g Yield 83% mp 223-224 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200MHz) δ 2.
85-3.08 (2H, m), 4.73-4.87 (1H, m), 5.04 (1H, s),
5.12 (1H, s), 7.05-7.16 (3H, m), 7.21-7.44 (6H,
m), 7.50-7.58 (5H, m), 7.79 (1H, d, J = 8.2 Hz); I
R (KBr) 3268, 1638, 1516, 1325, 1227, 1167, 1121,
^{1069, 864, 829 cm -1;} . Anal Calcd for C 27 H 20 F 5 NO 2 ·
0.1H ₂ O: C, 66.56; H, 4.18; N, 2.87. Found: C, 66.3
8; H, 4.28; N, 3.11.

Example 40 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -5-nitronaphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [ 4- (trifluoromethyl) phenyl] propan-1-ol 0.166 g (0.530 mmol), 5-nitro-1-naphthoic acid 0.12 g (0.53 g)
Mmol) 1-hydroxybenzotriazole hydrate 81 mg (0.53 mmol) in acetonitrile 10m
1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.10 g (0.5
3 mmol) and stirred overnight at room temperature. Dilute the reaction solution with ethyl acetate and wash with aqueous sodium hydrogen carbonate,
After drying over anhydrous magnesium sulfate and passing through silica gel,
The solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 0.258 g Yield 95% mp 211-214 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
85-3.13 (2H, m), 4.74-4.88 (1H, m), 5.00 (1H, t, J
= 4.3 Hz), 5.19 (1H, d, J = 3.6 Hz), 7.10 (2H, t,
J = 8.6 Hz), 7.34-7.42 (4H, m), 7.50-7.70 (7H,
m), 8.15 (1H, dd, J = 1.1 Hz, 7.7 Hz), 8.49 (1H, d,
J = 8.4 Hz); IR (KBr) 3287, 1680, 1526, 1329, 111
5 cm ^-1 ; Anal.Calcd for C ₂₇ H ₂₀ F ₄ N ₂ O ₄・ DMF: C, 61.54;
H, 4.65; N, 7.18.Found: C, 61.24; H, 4.62; N, 7.17.

Example 41 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -1,2,3,4-tetrahydronaphthalene-1-carboxamide 1) 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid Acid 3,4-dihydronaphthalene-1,1 (2H) -dicarboxylate (J. Org. Chem., 54, 271)
3-18 (1989)) 5.129 g (18.56
Mmol), 2.17 g (37.1 mmol) of sodium chloride and 1 ml of water were heated at 180 ° C. for 1.5 days in 10 ml of dimethyl sulfoxide. After cooling to room temperature,
Water was added, and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15/1).
A crude product of ethyl 2,3,4-tetrahydronaphthalene-1-carboxylate was obtained as a yellow liquid. To a solution of the obtained liquid in 20 ml of methanol / 10 ml of tetrahydrofuran was added 30 ml (30 mmol) of a 1N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, diluted with water, and washed with diethyl ether. The resulting aqueous solution is acidified with 1N hydrochloric acid, and the reaction solution is diluted with diethyl ether.
Extracted times. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diethyl ether-hexane to obtain the desired product. White crystals Yield 0.350 g Yield 11% mp 80-82 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.67-2.27 (4
H, m), 2.67-2.93 (2H, m), 3.85 (1H, t, J = 5.5 Hz),
7.08-7.26 (4H, m); IR (KBr) 3065-2500, 1692, 129
8, 1225, 951, 752 cm ^-1 ; Anal.Calcd for C ₁₁ H ₁₂ O ₂ :
C, 74.98; H, 6.86. Found: C, 74.58; H, 7.05.2) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoro Methyl) benzyl] ethyl] -1,2,3,4-tetrahydronaphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) Phenyl] propan-1-ol 0.295 g (0.942 mmol), 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid 0.17 g (0.94 mmol), 1-hydroxybenzotriazole hydrate 0.14 g (0.94 mmol) of 1 in 10 ml of acetonitrile with stirring.
0.18 g (0.94 mmol) of -ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added,
Stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure.
The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 0.359 g Yield 81% mp 205-214 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 1.
35-1.95 (4H, m), 2.59-2.87 (4H, m), 3.45 (1H, t, J
= 6.1 Hz), 4.38-4.49 (1H, m), 4.73 (0.5H, t, J =
4.4 Hz), 4.82 (0.5H, t, J = 4.1 Hz), 5.28 (1H, d,
J = 4.0 Hz), 6.32 (0.5H, d, J = 8.8 Hz), 6.40 (0.5
H, d, J = 8.4 Hz), 6.56 (1H, d, J = 7.4 Hz), 6.91-
7.23 (7H, m), 7.34-7.50 (4H, m); IR (KBr) 3279, 16
47, 1514, 1329, 1167, 1113, 1069 cm ^-1 ; Anal.Calcd
for C ₂₇ H ₂₅ F ₄ NO ₂ : C, 68.78; H, 5.34; N, 2.97. Foun
d: C, 68.62; H, 5.24; N, 2.90.

Example 42 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene-1-carboxamide 1) 6,7,8,9 6,7,8,9-Tetrahydro-5H-benzo [a] cyclohepten-1-ylmethanol (tetrahydro-5H-benzo [a] cycloheptene-1-carboxylic acid)
n, 53, 15969-15982 (1990))
1.232 g (6.990 mmol) of acetone 50m
Chromic anhydride 2.10 g (21.0 g)
(Mmol) and 2 ml of concentrated sulfuric acid in 9 ml of water were slowly added dropwise, and after completion of the addition, the mixture was stirred at room temperature for 2 hours. After the reaction solution was cooled again with ice, isopropanol 5 ml
Was added and the mixture was stirred as it was for 0.5 hour. The reaction solution was diluted with ethyl acetate, washed with water three times, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethanol-water to obtain the desired product. White crystals Yield 0.916 g Yield 69% mp 111-112 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.60-1.90
(6H, m), 2.88 (2H, t, J = 5.5 Hz), 3.17 (2H, t, J =
5.1 Hz), 7.14 (1H, t, J = 7.5 Hz), 7.28 (1H, d, J
= 7.8 Hz), 7.69 (1H, dd, J = 1.5 Hz, 7.7 Hz); IR
(KBr) 3200-2500, 1690, 1437, 1408, 1283, 1273, 91
6, 758 cm ^-1 ; Anal.Calcd for C ₁₂ H ₁₄ O ₂ : C, 75.76; H,
7.42. Found: C, 75.71; H, 7.21.2) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -6,7,8,9-tetrahydro
-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 163 g (0.520 mmol), 99 mg of 6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene-1-carboxylic acid (0.5 mg)
80 mg (0.52 mmol) of 1-hydroxybenzotriazole hydrate in 10 ml of acetonitrile
While stirring in 0.1 ml, 0.10 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.
52 mmol) and stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals
Yield 0.156 g Yield 62% mp 210-211 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 1.
35-1.48 (2H, m), 1.51-1.61 (2H, m), 1.68 1.81 (2H, m
m), 2.39-2.47 (2H, m), 2.69-2.80 (2H, m), 2.85-3.
02 (2H, m), 4.63-4.77 (1H, m), 4.86 (1H, d, J = 3.
8 Hz), 4.98 (1H, t, J = 3.6 Hz), 6.67 (1H, d, J =
9.0 Hz), 6.76 (1H, dd, J = 1.4 Hz, 7.4Hz), 6.94 7.
11 (4H, m), 7.30 (2H, d, J = 8.0 Hz), 7.46-7.53 (4
H, m); IR (KBr) 3335, 2922, 1622, 1532, 1508, 2327,
1171, 1127, 831 cm ^-1 ; Anal.Calcd for C ₂₈ H ₂₇ F ₄ N
O ₂ : C, 69.27; H, 5.61; N, 2.88. Found: C, 69.20;
H, 5.62; N, 2.86.

Example 43 4-Bromo-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] naphthalene-1- Carboxamide 1) 14.98 g of (4-bromo-1-naphthyl) methyl acetate 1-bromo-4-methylnaphthalene (67.
75 mmol), 12.1 g of N-bromosuccinimide
(67.8 mmol) and 50 mg of 2,2'-azobis (isobutyronitrile) in 50 ml of carbon tetrachloride.
The mixture was refluxed for 5 hours. After cooling the reaction solution to room temperature, a white precipitate was removed by filtration, and the precipitate was washed with diethyl ether. The solvent of the collected filtrate was distilled off under reduced pressure to give 1-bromo-4-
A crude product of (bromomethyl) naphthalene was obtained as a pale yellow liquid. The obtained liquid was dissolved in 30 ml of N, N-dimethylformamide, and 11.1 g of sodium acetate (13.
6 mmol) and stirred at 60 ° C. for 6 hours. After cooling to room temperature, the reaction was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 20 / 1-6 / 1) to obtain the desired product. Yellow liquid Yield 14.97 g Yield 79% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.11 (3H, s), 5.53 (2H,
s), 7.40 (1H, d, J = 7.8 Hz), 7.58-7.69 (2H, m),
7.77 (1H, d, J = 7.4 Hz), 7.97-8.05 (1H, m), 8.28-
8.36 (1H, m); IR (neat) 1740, 1381, 1366, 1225, 10
24, 824, 758 cm ^-1 2) (4-bromo-1-naphthyl) methanol 14.97 g of (4-bromo-1-naphthyl) methyl acetate
(53.63 mmol), 3.22 g of sodium hydroxide
(80.4 mmol) in 50 ml of methanol-30 m of water
The mixture was stirred in 30 ml of 1-tetrahydrofuran at room temperature for 30 minutes. The reaction solution was concentrated, diluted with water, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-2 / 1), and crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 11.77
g Yield 93% mp 92-93 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.80 (1H, t,
J = 5.9 Hz), 5.13 (2H, d, J = 5.8 Hz), 7.38 (1H,
d, J = 7.6 Hz), 7.56-7.68 (2H, m), 7.76 (1H, d, J =
7.6 Hz), 8.07-8.15 (1H, m), 8.27-8.35 (1H, m); IR
(KBr) 3214, 1375, 1258, 1073, 997, 822, 748 cm ^-1 ;
_{. Anal Calcd for C 11 H 9} BrO:. C, 55.72; H, 3.83 Foun
d: C, 55.86; H, 3.70.3) 4-Bromo-1-naphthoic acid 1.329 g of (4-bromo-1-naphthyl) methanol
A solution of 1.81 g (18.1 mmol) of chromic anhydride and 2 ml of concentrated sulfuric acid in 9 ml of water was slowly added dropwise to a 50 ml solution of acetone (6.027 mmol) under ice-cooling. For 2 hours. The acetone in the reaction solution was distilled off under reduced pressure, diluted with ethyl acetate, washed three times with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethanol-water to give the desired product. Light brown crystal Yield 1.272 g Yield 84% mp 223-224 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 7.
60-7.69 (2H, m), 7.83 (1H, d, J = 7.8 Hz), 8.06 (1
H, d, J = 8.2 Hz), 8.28-8.36 (1H, m), 8.99-9.08 (1
H, m); IR (KBr) 3100-2500, 1694, 1566, 1508, 1279,
1252, 1190, 903, 785, 762 cm ^-1 ; Anal.Calcd for C
₁₁ H ₇ BrO ₂ : C, 52.62; H, 2.81.Found: C, 52.42; H, 2.
87.4) 4-Bromo-N-[(1RS, 2SR) -2- (4
-Fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [ 0.209 g (0.667 mmol) of 4- (trifluoromethyl) phenyl] propan-1-ol 0.17 g (0.67 g) of 4-bromo-1-naphthoic acid
Mmol) 1-hydroxybenzotriazole hydrate 0.10 g (0.67 mmol) in acetonitrile 10
0.13 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.1 ml) while stirring in 0.1 ml.
67 mmol) and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals
Yield 0.309 g Yield 85% mp 229-231 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
84-3.11 (2H, m), 4.71-4.85 (1H, m), 5.00 (1H, t, J
= 4.0 Hz), 5.24 (1H, d, J = 3.8 Hz), 7.04-7.13 (3
H, m), 7.33-7.60 (10H, m), 7.69 (1H, d, J = 7.4 H
z), 8.20 (1H, d, J = 8.8 Hz); IR (KBr) 3262, 1638,
1537, 1514, 1329, 1163, 1125, 1069, 833, 754 cm ^-1 ;
_{. Anal Calcd for C 27 H 20} BrF 4 NO 2: C, 59.36; H, 3.69;
N, 2.56.Found: C, 59.31; H, 3.84; N, 2.72.

Example 44 2-Cyclopentyl-N-[(1RS, 2SR) -2- (4-
Fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] acetamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoro Methyl) phenyl] propan-1-ol 0.156 g (0.498 mmol), cyclopentyl acetic acid 64 mg (0.50 mmol), 1-hydroxybenzotriazole hydrate 76 m
While stirring g (0.50 mmol) in 10 ml of acetonitrile, 95 mg (0.50 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from hexane to obtain the desired product. White crystals Yield 0.185 g Yield 88% mp 195-196 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 0.
75-1.05 (2H, m), 1.25-1.65 (6H, m), 1.92 2.12 (3H,
m), 2.77-2.81 (2H, m), 4.39-4.52 (1H, m), 4.65 (1
H, d, J = 3.4 Hz), 4.93 (1H, t, J = 3.3 Hz), 6.10
(1H, br d, J = 8.4 Hz), 7.06 (2H, t, J = 8.8 Hz),
7.21 (2H, d, J = 8.0 Hz), 7.39-7.49 (4H, m); IR (K
Br) 3301, 2949, 1645, 1539, 1514, 1327, 1163, 112
5, 1069, 829 cm ^-1 ; Anal.Calcd for C ₂₃ H ₂₅ F ₄ NO ₂ : C,
65.24; H, 5.95; N, 3.31. Found: C, 65.08; H, 5.90;
N, 3.41.

Example 45 3-Cyclopentyl-N-[(1RS, 2SR) -2- (4-
(Fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] propionamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (tri Fluoromethyl) phenyl] propan-1-ol 0.157 g (0.501 mmol) 3-cyclopentylpropionic acid 71 mg (0.
50 mmol) 1-hydroxybenzotriazole hydrate 77 mg (0.50 mmol) was added to acetonitrile 1
While stirring in 0 ml, 96 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.
(50 mmol) and stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from hexane to obtain the desired product. White crystals Yield 0.18
0g Yield 82% mp 169-170 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 0.98 (2H,
br s), 1.35-1.70 (9H, m), 2.07 (2H, dt, J = 2.6 Hz,
7.4 Hz), 2.76 (1H, dd, J = 10.4 Hz, 14.4 Hz), 2.9
0 (1H, dd, J = 4.4 Hz, 14.6 Hz), 3.61 (1H, d, J =
3.6 Hz), 4.36-4.50 (1H, m), 4.97 (1H, t, J = 3.5 H
z), 5.39 (1H, br d, J = 7.8 Hz), 7.08 (2H, t, J =
8.8 Hz), 7.21 (2H, d, J = 7.8 Hz), 7.39 (2H, dd, J
= 5.6 Hz, 8.4 Hz), 7.51 (2H, d, J = 8.0 Hz); IR
(KBr) 3303, 2951, 1645, 1537, 1514, 1327, 1163, 11
23, 1069, 829 cm ^-1 ; Anal.Calcd for C ₂₄ H ₂₇ F ₄ NO ₂ :
C, 65.89; H, 6.22; N, 3.20. Found: C, 65.61; H, 6.
16; N, 3.32.

Example 46 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) ben
[Zyl] ethyl] -1-benzothiophene-3-carboxami
Do (1RS, 2SR) -2-amino-1- (4-fluorophene)
Nyl) -3- [4- (trifluoromethyl) phenyl] p
0.173 g of Lopan-1-ol (0.552 mmol
), 1-benzothiophene-3-carboxylic acid (Synt
h. Commun. , 15, 711-713 (198
4)) 0.10 g (0.55 mmol), 1-hydrido
Roxybenzotriazole hydrate 85mg (0.55m
Lmol) in 10 ml of acetonitrile while stirring.
-Ethyl-3- (3-dimethylaminopropyl) carbodii
0.11 g (0.55 mmol) of mido hydrochloride was added,
Stirred overnight at room temperature. Dilute the reaction solution with ethyl acetate and add
Washed with sodium hydrogen oxyacid solution, anhydrous magnesium sulfate
After drying over and passing through silica gel, the solvent was distilled off under reduced pressure.
The obtained residue was crystallized from diethyl ether-hexane.
To give the desired product. 0.204 g of white crystals
Yield 78% mp 188-189 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 2.88-3.08
(2H, m), 3.64 (1H, d, J = 3.6 Hz), 4.59-4.72 (1H,
m), 5.13 (1H, t, J = 3.2 Hz), 6.04 (1H, d, J = 8.8
Hz), 7.09 (2H, t, J = 8.8 Hz), 7.31-7.60 (9H, m),
7.82-7.92 (2H, m); IR (KBr) 3333, 1622, 1537, 1510,
 1331, 1159, 1123, 1069, 833, 766 cm ^-1; Anal. Calc
d for C_{twenty five}H₁₉F_FourNO_TwoS: C, 63.42; H, 4.04; N, 2.96. Fo
und: C, 63.50; H, 4.10; N, 2.90.

Example 47 N-((1RS, 2SR) -2- (4-fluorophenyl)
Oxalyl chloride was added to a solution of 4-phenylbutyric acid (141 mg, 0.86 mmol) in tetrahydrofuran (5 ml). (0.15 ml, 1.72 mmol) and N, N
-Dimethylformamide (0.01 ml) was added, the mixture was stirred at room temperature for 30 minutes, and the reaction solution was distilled off under reduced pressure. (1RS, 2SR) -1- was added to a solution of the residue in ethyl acetate (5 ml).
(4-Fluorophenyl) -1-hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (200 mg, 0.57 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) were added, and the mixture was added at room temperature. Stirred overnight. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4:
1-1: 1) and recrystallized from ethyl acetate-hexane to give the title compound (179 mg, 68%). mp 150-151 ° C IRν max ^KBr cm ^-1 : 1645, 1508. Anal.Calcd for C ₂₆ H ₂₅ F ₄ NO ₂ : C, 67.96; H, 5.48; N,
3.05 Found:. C, 67.91; H, 5.35; N, 2.98 1 H-NMR (CDCl 3) δ: 1.70-1.90 (2H, m), 2.00-2.14 (2
H, m), 2.51 (2H, t, J = 7.4 Hz), 2.70-2.94 (2H, m),
3.44 (1H, d, J = 3.6 Hz), 4.30-4.56 (1H, m), 4.92
-5.00 (1H, m), 5.38 (1H, d, J = 7.0 Hz), 7.00-7.60
(13H, m).

Example 48 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -3-phenylpropanamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- ( 4- (trifluoromethyl) phenyl) -1
To a solution of -propanol (450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (320 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
1 × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (56
0 mg, 88%). mp 144-145 ℃ IRνmax ^KBr cm ^-1 : 1636, 1541. Anal.Calcd for C ₂₅ H ₂₃ F ₄ NO ₂ : C, 67.41; H, 5.20; N,
3.14 Found:. C, 67.30; H, 5.21; N, 3.38 1 H-NMR (CDCl 3) δ: 2.30-2.44 (2H, m), 2.58-2.94 (4
H, m), 3.29 (1H, d, J = 4.0 Hz), 4.30-4.48 (1H, m),
4.76-7.86 (1H, m), 5.33 (1H, d, J = 8.4 Hz), 6.98
-7.38 (11H, m), 7.46 (2H, d, J = 8.0 Hz).

Example 49 4,4,4-Trifluoro-N-[(1RS, 2SR) -2
-(4-Fluorophenyl) -2-hydroxy-1- [4-
(Trifluoromethyl) benzyl] ethyl] -2-methyl
2-butenamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.154 g (0.492 mmol), 76 mg (0.49 mmol) of 4,4,4-trifluoro-2-methyl-2-butenoic acid and 75 mg (0.49 mmol) of 1-hydroxybenzotriazole hydrate were stirred in 10 ml of acetonitrile for 1-. Ethyl-3
94 mg (0.49 mmol) of-(3-dimethylaminopropyl) carbodiimide hydrochloride was added and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.178 g Yield 81% mp 182-183 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
04 (3H, s), 2.80-2.84 (2H, m), 4.41-4.54 (1H, m),
4.84 (1H, d, J = 3.2 Hz), 4.94 (1H, t, J = 3.3 H)
z), 6.24-6.26 (1H, m), 7.06 (2H, t, J = 8.6 Hz),
7.20 (2H, d, J = 7.8 Hz), 7.33 (1H, d, J = 8.6 H
z), 7.42-7.49 (4H, m); IR (KBr) 3297, 1647,1541, 1
514, 1329, 1167, 1119, 1069, 831 cm ^-1 ; Anal.Calcd
for C ₂₁ H ₁₈ F ₇ NO ₂ : C, 56.13; H, 4.04; N, 3.12. Foun
d: C, 56.02; H, 4.04; N, 2.82.

Example 50 2,3-Dichloro-N-((1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl ) Benzamide (1RS, 2RS) -1- (4-fluorophenyl) -1-
Hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (150 mg, 0.43
2,3-Dichlorobenzoyl chloride (135 mg, 0.64 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) were added to a solution of the resulting mixture in an aqueous solution of ethyl acetate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) and recrystallized from ethyl acetate-hexane to give the title compound (161 mg, 77).
%). mp 187-188 ° C IRνmax ^KBr cm ^-1 : 1647, 1537, 1514. Anal.Calcd for C ₂₃ H ₁₇ Cl ₂ F ₄ NO ₂ : C, 56.81; H, 3.52;
N, 2.88 Found:. C, 56.82; H, 3.38; N, 2.85 1 H-NMR (CDCl 3) δ: 2.80-3.10 (3H, m), 4.60-4.80 (1
H, m), 5.08 (1H, d, J = 3.8 Hz), 6.06 (1H, d, J =
(8.8 Hz), 6.96-7.38 (6H, m), 7.40-7.62 (5H, m).

Example 51 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -6-nitronaphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [ 4- (trifluoromethyl) phenyl] propan-1-ol 0.178 g (0.568 mmol), 6-nitro-1-naphthoic acid (J. Org. Che)
m. , 54, 3596-602 (1989)).
12 g (0.57 mmol) of 1-hydroxybenzotriazole hydrate (87 mg, 0.57 mmol) were stirred in 10 ml of acetonitrile with 1-ethyl-3-ethyl.
0.11 g (0.57 mmol) of (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 0.256 g Yield 88% mp 206-207 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
93 (1H, dd, J = 11.0 Hz, 13.8 Hz), 3.20 (1H, dd, J
= 3.1 Hz, 14.1 Hz), 4.67-4.82 (1H, m), 4.93 (1H,
t, J = 4.7 Hz), 5.44 (1H, d, J = 4.0 Hz), 7.09 (2
H, t, J = 8.6 Hz), 7.38-7.42 (3H, m), 7.51-7.61 (6
H, m), 7.95-8.09 (3H, m), 8.76 (1H, d, J = 2.2 Hz);
IR (KBr) 3297, 1638, 1535, 1346, 1327, 1113, 1069
cm ^-1 ; Anal.Calcd for C ₂₇ H ₂₀ F ₄ N ₂ O ₄ : C, 63.28; H,
3.93; N, 5.47. Found: C, 63.11; H, 3.80; N, 5.34.

Example 52 N-((1RS, 2SR) -2- (4-fluorophenyl)
2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) cyclohexanecarboxamide (1RS, 2SR) -1- (4-fluorophenyl) -1-
Hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (200 mg, 0.57
Cyclohexanecarbonyl chloride (126 mg, 0.86 mmol) and saturated aqueous sodium bicarbonate (5 ml) were added to a solution of the resulting mixture in an aqueous solution of ethyl acetate (5 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with brine, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and recrystallized from ethyl acetate-hexane to give the title compound (1
(66 mg, 69%). mp 203-204 ℃ IRν max ^KBr cm ^-1 : 3275, 1645, 1512. Anal.Calcd for C ₂₃ H ₂₅ F ₄ NO ₂ : C, 65.24; H, 5.95; N,
3.31 Found:. C, 65.14; H, 5.83; N, 3.50 1 H-NMR (CDCl 3) δ: 1.00-1.40 (6H, m), 1.50-1.80 (4
H, m), 1.80-2.10 (1H, m), 2.72-3.00 (2H, m), 3.73
(1H, d, J = 3.6 Hz), 4.32-4.52 (1H, m), 4.94-5.00
(1H, m), 5.36 (1H, d, J = 8.0 Hz), 7.02-7.16 (2H,
m), 7.21 (2H, d, J = 8.4 Hz), 7.30-7.44 (2H, m), 7.
51 (2H, d, J = 8.4 Hz).

Example 53 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -3-oxo-2,3-dihydro
-1H-indene-1-carboxamide (1RS, 2RS) -1- (4-fluorophenyl) -1-
A solution of hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine (150 mg, 0.42 mmol) in acetonitrile (10 ml) was treated with 3-oxo-
2,3-dihydro-1H-indene-1-carboxylic acid (73
mg, 0.42 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (11
9 mg, 0.62 mmol) and 1-hydroxy-1H
-Benzotriazole (63.6 mg, 0.42 mmol) was added and the mixture was stirred at room temperature overnight. The reaction solution was washed with water (50 m
1) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and recrystallized from ethyl acetate-hexane to obtain a highly polar isomer of the title compound (61 mg, 31%). mp 242-243 ℃ IRνmax ^KBr cm ^-1 : 1703, 1649, 1539, 1510. Anal.Calcd for C ₂₆ H ₂₁ F ₄ NO ₃・ 0.1H ₂ O: C, 65.99; H,
4.52; N, 2.96 Found: C, 65.70; H, 4.41; N, 2.83. ¹ H-NMR (CDCl ₃ ) δ: 2.20-2.60 (2H, m), 2.70-3.00 (3
H, m), 3.86-3.98 (1H, m), 4.40-4.62 (1H, m), 4.92-
5.02 (1H, m), 6.46-6.60 (1H, m), 6.60-7.00 (1H,
m), 7.00-7.20 (2H, m), 7.20-7.60 (8H, m), 7.70 (1
H, d, J = 6.2 Hz). At the same time, the less polar isomer of the title compound (74 mg, 3
8%). mp 237-238 ℃ IRνmax ^KBr cm ^-1 : 1715, 1651, 1549, 1513. Anal.Calcd for C ₂₆ H ₂₁ F ₄ NO ₃ : C, 66.24; H, 4.49; N,
2.97 Found:. C, 66.19; H, 4.36; N, 2.90 1 H-NMR (CDCl 3) δ: 2.64-2.92 (4H, m), 3.92-4.00 (1
H, m), 4.36-4.52 (1H, m), 4.83 (1H, d, J = 4.6 H
z), 6.81 (1H, d, J = 7.8 Hz), 7.00-7.22 (5H, m),
7.38-7.58 (5H, m), 7.54 (1H, d, J = 7.0 Hz).

Example 54 4-cyano-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] naphthalene-1- Carboxamide 1) 4- (methoxycarbonyl) -1-naphthoic acid 25.90 g of naphthalene-1,4-dicarboxylic acid (11
9.8 mmol) in 80 ml of tetrahydrofuran-N,
While stirring in 50 ml of N-dimethylformamide,
18.2 g (120 mmol) of 1,8-diazabicyclo [5.4.0] -7-undecene was added at room temperature, and the mixture was stirred for 0.5 hour. 51.0 g of iodomethane was added to the reaction solution.
(359 mmol) was added at room temperature, and the mixture was stirred overnight. The reaction solution was diluted with an aqueous sodium hydrogen carbonate solution and washed with ethyl acetate. The resulting aqueous solution was acidified with concentrated hydrochloric acid and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1), and crystallized from ethyl acetate-hexane to obtain the desired product. Light brown crystal Yield 6.309 g Yield 23% mp 148-150 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 4.
02 (3H, s), 7.59-7.68 (2H, m), 8.09 (1H, d, J = 7.4
Hz), 8.14 (1H, d, J = 7.4 Hz), 8.75-8.84 (1H, m),
8.88-8.96 (1H, m); IR (KBr) 3100-2635, 1723, 170
1, 1291, 1281,1256.1206, 1152, 775 cm ^-1 ; Anal.Ca
lcd for C ₁₃ H ₁₀ O ₄ : C, 67.82; H, 4.38.Found: C, 67.8
2; H, 4.28.2) methyl 4- (aminocarbonyl) -1-naphthoate 2.553 4- (methoxycarbonyl) -1-naphthoic acid
To a solution of g (11.09 mmol) and 2 drops of N, N-dimethylformamide in 40 ml of tetrahydrofuran, 1.93 ml (22.2 mmol) of oxalyl chloride was added dropwise at room temperature, and the mixture was stirred for 0.5 hour. The solvent of the reaction solution was distilled off under reduced pressure to obtain a crude acid chloride product as a liquid. 1.52 g (22.2 mmol) of 15% aqueous ammonia and 1.86 g (22.2 mmol) of sodium hydrogen carbonate dissolved in 40 ml of tetrahydrofuran while stirring under ice-cooling in 40 ml of tetrahydrofuran Was added dropwise, and the mixture was stirred under ice cooling for 0.5 hour and further at room temperature for 0.5 hour. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diethyl ether-hexane to obtain the desired product. Light brown crystal Yield 2.418 g
Yield 95% mp 182-184 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 4.02 (3H,
s), 6.64 (1H, br s), 7.21 (1H, br s), 7.56-7.71 (3
H, m), 8.13 (1H, d, J = 7.8 Hz), 8.34-8.43 (1H,
m), 8.83-8.91 (1H, m); IR (KBr) 3374, 3193, 1719,
1647, 1578, 1279,1250, 1198, 1127, 783 cm ^-1 ; Anal.
Calcd for C ₁₃ H ₁₁ NO ₃ : C, 68.11; H, 4.84; N, 6.11.
Found: C, 67.77; H, 5.20; N, 5.79. 3) Methyl 4-cyano-1-naphthoate 1.7 (methyl) 4- (aminocarbonyl) -1-naphthoate
56 g (7.660 mmol) and 0.68 thionyl chloride
ml (15.3 mmol) in 30 ml toluene
Stirred at C for 30 minutes. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1), and crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 1.021 g Yield 63% mp 109-110 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 4.05 (3H,
s), 7.69-7.80 (2H, M), 7.94 (1H, d, J = 7.6 Hz), 8.
15 (1H, d, J = 7.6 Hz), 8.28-8.36 (1H, m), 8.86-8.9
4 (1H, m); IR (KBr) 2332, 1717, 1298, 1256, 766 cm
^-1 ; Anal.Calcd for C ₁₃ H ₉ NO ₂ : C, 73.92; H, 4.29;
N, 6.63. Found: C, 73.93; H, 4.29; N, 6.6.4. 4) 4-cyano-1-naphthoic acid 0.862 g of methyl 4-cyanonaphthoate (4.081)
Mmol) in methanol (20 ml) -tetrahydrofuran (20 ml) solution.
1 (8.16 mmol) was added and stirred at room temperature overnight.
The reaction solution was concentrated, diluted with water, acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 0.730 g Yield 91% mp 2
37-238 ° C; ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ 7.77-
7.91 (2H, m), 8.14-8.27 (3H, m), 8.83-8.92 (1H,
m); IR (KBr) 3100-2550, 2226, 1698, 1516, 1285, 12
64, 1204, 795, 770 cm ^-1 ; Anal.Calcd for C ₁₂ H ₇ NO ₂ :
C, 73.09; H, 3.58; N, 7.10. Found: C, 72.96; H,
3.42; N, 7.07.5) 4-cyano-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] naphthalene- 1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.155 g (0.495 mmol), 4 0.10 g (0.49-cyano-1-naphthoic acid)
Mmol) 1-hydroxybenzotriazole hydrate (76 mg, 0.49 mmol) in acetonitrile 10 m
1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 94 mg (0.49
Mmol) and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 0.204 g Yield 84% mp 199-201 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
84-2.98 (1H, m), 3.18-3.28 (1H, m), 4.65 4.80 (1H, m
m), 4.85 (1H, t, J = 5.3 Hz), 5.53 (1H, d, J = 4.0
Hz), 7.09 (2H, t, J = 8.8 Hz), 7.17-7.26 (2H, m),
7.37-7.44 (3H, m), 7.52-7.58 (4H, m), 7.64-7.72 (1
H, m), 7.86 (1H, d, J = 7.4 Hz), 8.13-8.22 (2H,
m); IR (KBr) 3283, 2228, 1642, 1539, 1512, 1327, 1
163, 1125,1111, 1069, 839 cm ^-1 ; Anal.Calcd for C
₂₈ H ₂₀ F ₄ N ₂ O ₂・ 0.1H ₂ O: C, 68.04; H, 4.12; N, 5.67. Fou
nd: C, 67.86; H, 4.19; N, 5.55.

Example 55 4-Fluoro-N-((1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) benzamide (1RS, 2SR) -1- (4-fluorophenyl) -1-
Hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (200 mg, 0.57
Mmol) in ethyl acetate (5 ml) in 4-fluorobenzoyl chloride (136 mg, 0.86 mmol)
And saturated aqueous sodium hydrogen carbonate (5 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with brine, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and recrystallized from ethyl acetate-hexane to give the title compound (18
2 mg, 73%). mp 202-203 ℃ IRν max ^KBr cm ^-1 : 3297, 1640, 1607, 1508. Anal.Calcd for C ₂₃ H ₁₈ F ₅ NO ₂ : C, 63.45; H, 4.17; N,
3.22 Found:. C, 63.30; H, 4.26; N, 3.28 1 H-NMR (CDCl 3) δ: 2.80-3.06 (2H, m), 3.43 (1H, d,
J = 3.8 Hz), 4.50-4.70 (1H, m), 5.04-5.14 (1H, m),
6.07 (1H, d, J = 9.0 Hz), 7.00-7.20 (4H, m), 7.20-
7.36 (2H, m), 7.40-7.64 (6H, m).

Example 56 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -6- (methyloxy) -1-naphthalenecarboxamide 6-methoxy-1-naphthalenecarboxylic acid (129 mg,
Oxalyl chloride (0.11 ml, 1.28 mmol) and N, N-dimethylformamide (0.04 mmol) in tetrahydrofuran (5 ml) solution.
1 ml), and the mixture was stirred at room temperature for 30 minutes, and the reaction solution was evaporated under reduced pressure. (1 ml) was added to a solution of the residue in ethyl acetate (5 ml).
RS, 2SR) -1- (4-Fluorophenyl) -1-hydroxy-3- (4- (trifluoromethyl) phenyl) -2
-Propylamine hydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) and recrystallized from ethyl acetate-hexane to give the title compound (148 mg, 69).
%). mp 193-194 ℃ IRν max ^KBr cm ^-1 : 1636, 1512. Anal.Calcd for C ₂₈ H ₂₃ F ₄ NO ₃・ 0.1H ₂ O: C, 67.36; H,
4.68; N, 2.81 Found:. C, 67.24; H, 4.71; N, 2.81 1 H-NMR (CDCl 3) δ: 2.80-3.16 (2H, m), 3.37 (1H, br
s), 3.91 (3H, s), 4.70-4.90 (1H, m), 5.09 (1H, br
s), 5.95 (1H, d, J = 8.4 Hz), 6.98-7.18 (5H, m),
7.20-7.40 (3H, m), 7.40-7.60 (5H, m), 7.75 (1H, d,
J = 8.0 Hz).

Example 57 N-((1RS, 2SR) -2- (4-fluorophenyl)
2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4-quinolinecarboxamide Oxalyl chloride was added to a solution of 4-quinolinecarboxylic acid (111 mg, 0.64 mmol) in tetrahydrofuran (5 ml). (0.11 ml, 1.72 mmol) and N, N-dimethylformamide (0.01 ml) were added, the mixture was stirred at room temperature for 30 minutes, and the reaction solution was distilled off under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) (1RS, 2SR)
-1- (4-Fluorophenyl) -1-hydroxy-3- (4-
(Trifluoromethyl) phenyl) -2-propylamine hydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml) and ethyl acetate (50 ml × 2)
Extracted. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (6
3 mg, 32%). mp 227-228 ° C IRν max ^KBr cm ^-1 : 1644, 1508, 1331. Anal.Calcd for C ₂₆ H ₂₀ F ₄ N ₂ O ₂・ 0.5H ₂ O: C, 65.41; H,
4.43; N, 5.87 Found:. C, 65.31; H, 4.68; N, 5.61 1 H-NMR (CDCl 3) δ: 2.76-2.98 (1H, m), 3.00-3.16 (1
H, m), 4.72-4.92 (1H, m), 5.05 (1H, d, J = 4.0 H
z), 6.60-6.80 (1H, m), 7.02-7.20 (3H, m), 7.22-7.6
0 (8H, m), 7.62-7.78 (1H, m), 8.05 (1H, d, J = 8.4
Hz), 8.82 (1H, brs).

Example 58 3-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] naphthalene-1- Carboxamide 1) Ethyl 3-nitro-1-naphthoate 3-Nitro-1-naphthoic acid (J. Org. Chem.,
54, 3596-602 (1989)) 3.020
g (13.91 mmol) and a solution of concentrated sulfuric acid (1 ml) in ethanol (50 ml) were heated under reflux for 1 day. After concentrating the reaction solution,
Dilute with ethyl acetate and wash with aqueous sodium bicarbonate and water. The obtained ethyl acetate solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diethyl ether-hexane to obtain the desired product. Yellow crystal Yield 3.137 g Yield 92% mp 78-79 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.50 (3H, t,
J = 7.1 Hz), 4.53 (2H, q, J = 7.1 Hz), 7.71 (1H,
ddd, J = 1.0 Hz, 6.8 Hz, 8.2 Hz), 7.83 (1H, ddd, J
= 1.3 Hz, 6.7 Hz, 8.8 Hz), 8.10 (1H, d, J = 8.8 H
z), 8.92 (1H, d, J = 2.6 Hz), 8.96 (1H, d, J = 2.6
Hz), 9.03 (1H, d, J = 8.8 Hz); IR (KBr) 1717, 160
3, 1526, 1453, 1339, 1281, 1240, 1190, 1155, 1140
1024, 795,766 cm ^-1 ; Anal.Calcd for C ₁₃ H ₁₁ NO ₄ : C,
63.67; H, 4.52; N, 5.71. Found: C, 63.64; H, 4.44;
N, 5.64.2) Ethyl 3-amino-1-naphthoate 5.371 g of ethyl 3-nitro-1-naphthoate (21.
A solution of 90 mmol) in 30 ml of ethanol was hydrogenated under normal temperature and pressure until the raw materials disappeared using 0.5 g of 10% palladium / carbon (containing 50% water) as a catalyst. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-3 / 1) to obtain the desired product. Orange liquid Yield 4.681 g Yield 99% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.45 (3H, t, J = 7.1 H)
z), 3.89 (2H, br s), 4.46 (2H, q, J = 7.1 Hz), 7.1
5 (1H, d, J = 2.2 Hz), 7.30-7.45 (2H, m), 7.60-7.6
6 (2H, m), 8.70 (1H, dd, J = 1.6 Hz, 8.2 Hz); IR
(neat) 3465, 3374,2980, 1705, 1626, 1236, 1202 cm
^-1 3) 3-Fluoro-1-naphthoic acid 3-amino-1-ethyl-naphthoic acid 2.318g (10.
77 mmol) and 0.89 g of sodium nitrite (12.
(9 mmol) was added dropwise and stirred at the same temperature for 10 minutes. 2.70 ml (18.3 mmol) of a 60% aqueous solution of hexafluorophosphoric acid was added to the reaction solution under ice cooling.
Was added with vigorous stirring, and the mixture was stirred for 0.5 hour as it was. The resulting precipitate was filtered, washed with water and methanol-diethyl ether (1: 4), and dried to obtain a diazonium salt as a brown powder. The obtained diazonium salt was heated in 170 ml of liquid paraffin at 170 ° C. for 0.5 hour. After cooling to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 15/1) to obtain a mixture of ethyl 3-fluoro-1-naphthoate and liquid paraffin as a pale yellow liquid. The obtained liquid ethanol 3
10 ml (10 mmol) of a 1N aqueous sodium hydroxide solution was added to a 0 ml-tetrahydrofuran 40 ml solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, diluted with water, acidified with diluted hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the desired product. Pale yellow crystal yield 0.629 g yield 31% mp 185-187 ° C; ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ 7.58-7.6
6 (2H, m), 7.94-8.03 (3H, m), 8.82-8.88 (1H, m); I
R (KBr) 3150-2550, 1696, 1682, 1296, 1252, 1221, 7
^{. 50 cm -1; Anal Calcd for} C 11 H 7 FO 2: C, 69.47; H, 3.
71. Found: C, 69.57; H, 3.80.4) 3-Fluoro-N-[(1RS, 2SR) -2- (4-
(Fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4 -(Trifluoromethyl) phenyl] propan-1-ol 0.158 g (0.504 mmol), 3-fluoro-1-naphthoic acid 0.10 g (0.5
0 mmol) 1-hydroxybenzotriazole hydrate 77 mg (0.50 mmol) in acetonitrile 10
While stirring in 0.1 ml, 0.10 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.
(50 mmol) and stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals
Yield 0.199 g Yield 81% mp 223-225 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
92 (1H, dd, J = 11.3 Hz, 14.3 Hz), 3.17 (1H, dd, J
= 3.3 Hz, 13.9 Hz), 4.64-4.80 (1H, m), 4.91 (1H,
t, J = 4.4 Hz), 5.45 (1H, d, J = 4.0 Hz), 6.98 (1
H, dd, J = 2.4 Hz, 8.8 Hz), 7.08 (2H, t, J = 8.8 H
z), 7.21-7.60 (10H, m), 7.74 (1H, d, J = 8.6 Hz),
7.99 (1H, d, J = 10.0 Hz); IR (KBr) 3277, 1642, 16
24, 1537, 1514, 1325, 1231, 1165, 1127, 1069, 831
^{. cm -1; Anal Calcd for C} 27 H 20 F 5 NO 2: C, 66.80; H, 4.
15; N, 2.89. Found: C, 66.66; H, 4.21; N, 2.70.

Example 59 4,4,4-Trifluoro-N-[(1RS, 2SR) -2
-(4-Fluorophenyl) -2-hydroxy-1- [4-
0.170 g of (trifluoromethyl) benzyl] ethyl] butyramide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol ( 0.543 mmol), 77 mg of 4,4,4-trifluorobutanoic acid
(0.54 mmol) 83 mg (0.54 mmol) of 1-hydroxybenzotriazole hydrate in 10 ml of acetonitrile while stirring 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.10.
g (0.54 mmol) was added and stirred at room temperature overnight.
The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.210 g Yield 88% mp 178-179 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
15-2.45 (4H, m), 2.74-2.81 (2H, m), 4.33 4.46 (1H,
m), 4.88 (1H, d, J = 3.2 Hz), 4.92 (1H, t, J = 3.3
Hz), 7.05 (2H, t, J = 8.8 Hz), 7.07 (1H, d, J =
8.8 Hz), 7.20 (2H, d, J = 8.0 Hz), 7.38-7.47 (4H,
m); IR (KBr) 3299, 1655, 1557, 1514, 1329, 1229, 1
107, 1069, 829 cm ^-1 ; Anal.Calcd for C ₂₀ H ₁₈ F ₇ NO ₂ :
C, 54.93; H, 4.15; N, 3.20. Found: C, 54.96; H, 4.2
2; N, 2.95.

Example 60 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4- (methyloxy) benzamide (1RS, 2SR) -1- (4-fluorophenyl) -1-
Hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (200 mg, 0.57
4-anisoyl chloride (146 mg, 0.86 mmol) and saturated aqueous sodium bicarbonate (5 ml) were added to a solution of the resulting solution in an aqueous solution of ethyl acetate (5 mmol) and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml), and ethyl acetate (50 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give the title compound (185 mg, 72%). mp 192-193 ° C IRν max ^KBr cm ^-1 : 1624, 1609, 1539, 1507, 1329. Anal.Calcd for C ₂₄ H ₂₁ F ₄ NO ₃ : C, 64.43; H, 4.73; N,
3.13 Found:. C, 64.44; H, 4.66; N, 3.09 1 H-NMR (CDCl 3) δ: 2.86-3.00 (2H, m), 3.84 (3H, s),
3.80-3.88 (1H, m), 4.50-4.66 (1H, m), 5.06-5.14
(1H, m), 6.00 (1H, d, J = 8.0 Hz), 6.88 (2H, d, J =
8.8 Hz), 7.02-7.14 (2H, m), 7.20-7.30 (2H, m), 7.
36-7.60 (6H, m).

Example 61 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -9-oxo-9H-fluorene
-4-Carboxamide 9-oxo-9H-fluorene-4-carboxylic acid (144 m
g, 0.64 mmol) of tetrahydrofuran (5 m
l) Add oxalyl chloride (0.11 ml, 1.
72 mmol) and N, N-dimethylformamide (0.01 ml) were added, the mixture was stirred at room temperature for 30 minutes, and the reaction solution was distilled off under reduced pressure. (1RS, 2SR) -1- (4-fluorophenyl)-was added to a solution of the residue in ethyl acetate (5 ml).
1-hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (150 mg, 0.43
Mmol) and saturated aqueous sodium hydrogen carbonate (5 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-1: 1) and recrystallized from ethyl acetate-hexane to give the title compound (15
4 mg, 69%). mp 231-232 ℃ IRνmax ^KBr cm ^-1 : 1725, 1638, 1607. Anal.Calcd for C ₃₀ H ₂₁ F ₄ NO ₃ : C, 69.36; H, 4.07; N,
2.70 Found: C, 69.13; H, 4.22; N, 2.53. ¹ H-NMR (CD ₃ OD) δ: 2.78-2.96 (1H, m), 3.49 (1H, d,
J = 13.2 Hz), 4.70-4.80 (2H, m), 6.72 (1H, d, J =
7.4 Hz), 6.89 (1H, d, J = 7.8 Hz), 7.04-7.32 (5H,
m), 7.46-7.66 (8H, m).

Example 62 3,3-Dimethyl-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] butylamide ( 0.168 g (0.536 mmol) of 1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol, 3,3-dimethyl Butanoic acid 62 mg (0.54 mmol), 1-hydroxybenzotriazole hydrate 8
2 mg (0.54 mmol) in 10 ml of acetonitrile
0.10 g (0.54 g) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride while stirring in water.
Mmol) and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from hexane to obtain the desired product. White crystals Yield 0.155 g
Yield 70% mp 140-141 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.81 (9H,
s), 1.87 (1H, d, J = 12.8 Hz), 1.99 (1H, d, J = 1
3.01), 2.71 (1H, dd, J = 10.8 Hz, 14.8 Hz), 2.91
(1H, dd, J = 4.4 Hz, 15.0 Hz), 3.47 (1H, d, J = 3.
6 Hz), 4.32-4.56 (1H, m), 4.97 (1H, t, J = 3.1 Hz),
5.31 (1H, br d, J = 8.4 Hz), 7.07 (2H, t, J = 8.6
Hz), 7.22 (2H, d, J = 8.4 Hz), 7.40 (2H, dd, J =
5.4 Hz, 8.4 Hz), 7.50 (2H, d, J = 8.0 Hz); IR (KB
r) 3337, 2963, 1626, 1534, 1510,1333, 1231, 1159,
1127, 1071, 826 cm ^-1 ; Anal.Calcd for C ₂₂ H ₂₅ F ₄ NO ₂ :
C, 64.22; H, 6.12; N, 3.40. Found: C, 64.03; H, 6.
20; N, 3.16.

Example 63 N-((1RS, 2SR) -2- (4-fluorophenyl)
2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -2-naphthalenecarboxamide (1RS, 2SR) -1- (4-fluorophenyl) -1-
Hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (200 mg, 0.57
2-naphthoyl chloride (164 mg, 0.86 mmol) and saturated aqueous sodium bicarbonate (5 ml) were added to a solution of the resulting compound in an aqueous solution of ethyl acetate (5 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (50 ml), and ethyl acetate (50 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give the title compound (175 mg, 65%). mp 174-175 ° C IRν max ^KBr cm ^-1 : 1640, 1537, 1514. Anal.Calcd for C ₂₇ H ₂₁ F ₄ NO ₂ : C, 69.37; H, 4.53; N,
3.00 Found:. C, 69.23; H, 4.49; N, 2.92 1 H-NMR (CDCl 3) δ: 2.96-3.04 (2H, m), 3.70 (1H, d,
J = 3.6 Hz), 4.58-4.76 (1H, m), 5.12-5.20 (1H, m),
6.26 (1H, d, J = 8.0 Hz), 7.02-7.16 (2H, m), 7.31
(1H, s), 7.40-7.64 (7H, m), 7.80-7.90 (3H, m), 8.0
4 (1H, s).

Example 64 4- (Difluoromethyl) -N-((1S, 2R) -2-
(4-fluorophenyl) -2-hydroxy-1-((4-
(Trifluoromethyl) phenyl) methyl) ethyl)-
1-Naphthalenecarboxamide 1) 4-methyl-1-naphthalenecarboxylic acid (4.14
g, 22.2 mmol) in methanol (50 ml) was added with thionyl chloride (3 ml) and stirred at 60 ° C. overnight. After concentrating the reaction solution, water (100 ml) was added, and the mixture was extracted with ethyl acetate (100 ml × 2). The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give methyl 4-methyl-1-naphthalenecarboxylate (4.32 g, 97%) as a colorless oil. . ^{IRνmax KBr cm -1: 1715, 1591.} 1 H-NMR (CDCl 3) δ: 2.75 (3H, s), 3.99 (3H, s), 7.35
(1H, d, J = 7.6 Hz), 7.50-7.68 (2H, m), 8.00-8.14
(2H, m), 8.92-9.02 (1H, m). 2) Methyl 4-methyl-1-naphthalenecarboxylate (4.23 g, 21.1 mmol) in chloroform (7
0 ml) to a solution of N-bromosuccinimide (4.1 g,
23.2 mmol) and 2,2'-azobis (isobutyronitrile) (175 mg, 1.05 mmol) were added, and the mixture was heated under reflux for 30 minutes. After concentrating the reaction solution, water (100 m
1) and extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (50 ml), sodium acetate (3.46 g, 42.2 mmol) was added, and the mixture was stirred at room temperature for 1 hour and then at 60 ° C. overnight. After concentrating the reaction solution, water (100 ml) was added and ethyl acetate (100 ml × 2).
Extracted. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2
0: 1) to give 4-((acetyloxy) methyl) -1
-Methyl naphthalenecarboxylate (4.1 g, 74%) was obtained. ^{. IRνmax KBr cm -1: 1744,} 1717, 1595, 1518. Anal Calcd for C 15 H 14 O 4: C, 69.76; H, 5.46 Found:. C, 69.63; H, 5.54 1 H-NMR (CDCl 3) δ: 2.14 (3H, s), 4.00 (3H, s), 5.59
(2H, s), 7.52-7.70 (3H, m), 7.98-8.08 (1H, m), 8.
12 (1H, d, J = 7.2 Hz), 8.90-9.00 (1H, m). 3) Methyl 4-((acetyloxy) methyl) -1-naphthalenecarboxylate (3.91 g, 15.1 mmol)
1N aqueous sodium hydroxide solution (15.1 ml, 15.1 mmol) was added to a methanol (20 ml) solution of
Stirred at room temperature for 5 minutes. 1N hydrochloric acid (20 ml) was added to the reaction solution.
And extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 4
There was obtained methyl-(hydroxymethyl) -1-naphthalenecarboxylate (2.78 g, 85%). ^{. IRνmax KBr cm -1: 1715. Anal} Calcd for C 13 H 12 O 3: C, 72.21; H, 5.59 Found:. C, 71.92; H, 5.49 1 H-NMR (CDCl 3) δ: 3.99 (3H, s), 5.16 (2H, s), 7.50
-7.68 (3H, m), 8.00-8.16 (2H, m), 8.88-8.96 (1H,
m). 4) To a solution of methyl 4- (hydroxymethyl) -1-naphthalenecarboxylate (2.0 g, 9.25 mmol) in chloroform (40 ml) was added manganese dioxide (4.0 g), and the mixture was stirred at room temperature for 2 hours. did. Manganese dioxide was filtered from the reaction solution using celite, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) and recrystallized from ethyl acetate-hexane to obtain methyl 4-formyl-1-naphthalenecarboxylate (1.41 g, 85%). Was. ^{. mp 95-96 ℃ IRνmax KBr cm -1} : 1723, 1696. Anal Calcd for C 13 H 10 O 3: C, 72.89; H, 4.71 Found:. C, 72.81; H, 4.87 1 H-NMR (CDCl 3 ) δ: 4.04 (3H, s), 7.60-7.78 (2H, m),
7.98 (1H, d, J = 7.2Hz), 8.17 (1H, d, J = 7.2H
z), 8.76-8.82 (1H, m), 9.20-9.28 (1H, m), 10.47 (1
H, s). 5) Methyl 4-formyl-1-naphthalenecarboxylate (800 mg, 3.73 mmol) in toluene (15 m
1) Add diethylaminosulfur trifluoride (750
ml, 5.1 mmol) and stirred at room temperature overnight. To the reaction solution was added a saturated aqueous sodium bicarbonate solution (10 ml), and ethyl acetate (5 mL) was added.
0 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purified with ethyl acetate = 10: 1) and methyl 4- (difluoromethyl) -1-naphthalenecarboxylate (522 mg, 5
9%). ^{. IRνmax KBr cm -1: 1723. Anal} Calcd for C 13 H 10 F 2 O 2: C, 66.10; H, 4.27 Found:. C, 66.07; H, 4.35 1 H-NMR (CDCl 3) δ: 4.03 ( 3H, s), 7.19 (1H, t, J = 5
5.0 Hz), 7.60-7.70 (2H, m), 7.75 (1H, d, J = 7.8 H
z), 8.10-8.22 (2H, m), 8.86-8.96 (1H, m). 6) A solution of methyl 4- (difluoromethyl) -1-naphthalenecarboxylate (450 mg, 1.91 mmol) in methanol (5 ml) To the mixture was added a 2N aqueous sodium hydroxide solution (1.9 ml, 3.8 mmol), and the mixture was stirred at room temperature overnight. 1N hydrochloric acid (5 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 4
-(Difluoromethyl) -1-naphthalenecarboxylic acid (3
44 mg, 81%). ^{. mp 179-180 ℃ IRνmax KBr cm -1} : 1701. Anal Calcd for C 12 H 8 F 2 O 2: C, 64.87; H, 3.63 Found:. C, 64.76; H, 3.55 1 H-NMR (CDCl 3 ) δ: 7.22 (1H, t, J = 54.8 Hz), 7.62-
7.70 (2H, m), 7.81 (1H, d, J = 7.6 Hz), 8.21 (1H,
d, J = 6.6 Hz), 8.39 (1H, d, J = 7.6 Hz), 9.02-9.1
8 (1H, m). 7) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (4- (trifluoromethyl) phenyl) -1-propanol (300 mg, 0.96 Mmol) in acetonitrile (30 ml) was added to 4- (difluoromethyl) -1-naphthalenecarboxylic acid (213 mg,
0.96 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (275 m
g, 1.44 mmol) and 1-hydroxy-1H-benzotriazole (147 mg, 0.96 mmol) were added and stirred at room temperature overnight. The reaction solution was water (100 ml)
And extracted with ethyl acetate (100 ml × 2).
1N hydrochloric acid, 1N aqueous sodium hydroxide solution,
The extract was washed successively with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give the title compound (4
(10 mg, 83%). mp 212-213 ° C IRνmax ^KBr cm ^-1 : 1640, 1618, 1513. Anal.Calcd for C ₂₈ H ₂₁ F ₆ NO ₂ : C, 64.99; H, 4.09; N,
2.71 Found:. C, 64.77; H, 4.36; N, 2.45 1 H-NMR (CDCl 3) δ: 2.85 (1H, dd, J = 14.6, 11.0 H
z), 3.00-3.16 (2H, m), 4.76-4.92 (1H, m), 5.04-5.1
2 (1H, m), 6.00 (1H, d, J = 9.2 Hz), 6.82-7.66 (14
H, m), 8.10 (1H, d, J = 8.4 Hz).

Example 65 N-((1S, 2R) -2- (4-fluorophenyl) -2-
Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4-((methyloxy) methyl)
1-Naphthalenecarboxamide 1) N, N- of methyl 4- (hydroxymethyl) -1-naphthalenecarboxylate (1.0 g, 4.62 mmol)
Methyl iodide (1 ml) was added to a dimethylformamide (10 ml) solution, and sodium hydride (222 ml) was further added.
g, 5.55 mmol, 60% oil) at 0 ° C.
Stirred at room temperature for 10 minutes. Water (30 ml) was added to the reaction solution, and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1-10: 1) to obtain methyl 4-((methyloxy) methyl) -1-naphthalenecarboxylate (898 mg, 84%). IRνmax ^KBr cm ^-1 : 1717.Anal.Calcd for C ₁₄ H ₁₄ O ₃・ 0.1H ₂ O: C, 72.46; H, 6.1
6 Found: C, 72.66; H, 6.09. ¹ H-NMR (CDCl ₃ ) δ: 3.48 (3H, s), 4.00 (3H, s), 4.94
(2H, s), 7.50-7.68 (3H, m), 8.04-8.18 (2H, m), 8.
90-8.98 (1H, m). 2) To a solution of methyl 4-((methyloxy) methyl) -1-naphthalenecarboxylate (780 mg, 3.38 mmol) in methanol (10 ml) was added a 1 N aqueous solution of sodium hydroxide (6 ml). (.76 ml, 6.76 mmol) and stirred at room temperature overnight. 1N hydrochloric acid (10 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 4-((methyloxy) methyl) -1-naphthalenecarboxylic acid (615 mg, 84%). ^{. mp 133-134 ℃ IRνmax KBr cm -1} : 1694. Anal Calcd for C 13 H 12 O 3: C, 72.21; H, 5.59 Found:. C, 72.10; H, 5.64 1 H-NMR (CDCl 3) δ : 3.52 (3H, s), 4.99 (2H, s), 7.56
-7.70 (3H, m), 8.10-8.18 (1H, m), 8.37 (1H, d, J =
7.2 Hz), 9.10-9.16 (1H, m). 3) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (4- (trifluoromethyl) phenyl) -1-propanol (300 mg, 0.96 mmol) in acetonitrile (30 ml) was added to 4-((methyloxy) methyl) -1-naphthalenecarboxylic acid (207
mg, 0.96 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (27
5 mg, 1.44 mmol) and 1-hydroxy-1H
-Benzotriazole (147 mg, 0.96 mmol) was added and the mixture was stirred at room temperature overnight. The reaction solution was washed with water (100
ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1-2:
Purified in 1) and recrystallized from ethyl acetate-hexane,
The title compound (340 mg, 69%) was obtained. mp 170-171 ° C IRνmax ^KBr cm ^-1 : 1638, 1618, 1607, 1510. Anal.Calcd for C ₂₉ H ₂₅ F ₄ NO ₃ : C, 68.09; H, 4.93; N,
2.74 Found:. C, 67.89; H, 5.05; N, 2.45 1 H-NMR (CDCl 3) δ: 2.82 (1H, dd, J = 14.6, 11.0 H
z), 3.03 (1H, dd, J = 14.6, 4.4 Hz), 3.46 (3H, s),
4.68-4.88 (1H, m), 4.85 (2H, s), 4.92-5.00 (1H,
m), 6.05 (1H, d, J = 8.8 Hz), 7.00-7.16 (3H, m),
7.22-7.62 (10H, m), 8.01 (1H, d, J = 8.4 Hz).

Example 66 N-((1RS, 2SR) -2- (4-fluorophenyl)
Oxalyl chloride was added to a solution of 1-anthracenecarboxylic acid (143 mg, 0.64 mmol) in tetrahydrofuran (5 ml). (0.11 ml, 1.72 mmol) and N, N-dimethylformamide (0.01 ml) were added, the mixture was stirred at room temperature for 30 minutes, and the reaction solution was distilled off under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) was added (1RS, 2
SR) -1- (4-Fluorophenyl) -1-hydroxy-3
-(4- (Trifluoromethyl) phenyl) -2-propylamine hydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml), and ethyl acetate (50 ml) was added.
× 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) and recrystallized from ethyl acetate-hexane to give the title compound (147 mg, 66%). mp 227-228 ℃ IRν max ^KBr cm ^-1 : 1638, 1615, 1514, 1323. Anal.Calcd for C ₃₁ H ₂₃ F ₄ NO ₂ : C, 71.70; H, 4.50; N,
2.70 Found:. C, 71.57; H, 4.41; N, 2.68 1 H-NMR (CDCl 3) δ: 2.90 (1H, dd, J = 13.2, 9.8 Hz),
3.54 (1H, d, J = 13.2Hz), 4.70-4.90 (2H, m), 6.94
(1H, d, J = 7.0 Hz), 7.06-7.20 (2H, m), 7.28-7.40
(1H, m), 7.40-7.78 (9H, m), 7.81 (1H, s), 7.92-8.
06 (2H, m), 8.41 (1H, s).

Example 67 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -2-methylnaphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [ 4- (trifluoromethyl) phenyl] propan-1-ol 0.224 g (0.715 mmol), 2-methyl-1-naphthoic acid 0.13 g (0.71 mmol)
Mmol) 1-hydroxybenzotriazole hydrate (0.11 g, 0.71 mmol) in acetonitrile 10
While stirring in 0.1 ml, 0.14 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.
(71 mmol) and stirred at 70 ° C. for 5 hours. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product is purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1).
/ 1), crystallized from diethyl ether-hexane,
The desired product was obtained. White crystals Yield 0.233 g Yield 68
% Mp 96-98 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.11 (3H,
s), 2.69 (1H, dd, J = 11.1 Hz, 14.5 Hz), 2.99 3.08
(2H, m), 4.96-5.14 (2H, m), 5.88 (1H, d, J = 9.6 H
z), 7.02-7.41 (8H, m), 7.46-7.57 (4H, m), 7.68 7.7
5 (2H, m); IR (KBr) 3241, 3058, 1632, 1510, 1327,
1225, 1163, 1123, 1069, 814 cm ^-1 ; Anal.Calcd for C
₂₈ H ₂₃ F ₄ NO ₂ : C, 69.85; H, 4.81; N, 2.91. Found: C,
69.64; H, 4.72; N, 2.82.

Example 68 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] benzamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl ] Propan-1-ol 0.166 g (0.530 mmol), benzoic acid 65 mg (0.53 mmol), 1-hydroxybenzotriazole hydrate 81 mg (0.53 mmol)
(0.1 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride while stirring in 10 ml of acetonitrile, and stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 0.178 g
Yield 81% mp 193-194 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
86 (1H, dd, J = 4.2 Hz, 14.6 Hz), 2.99 (1H, dd, J
= 10.5 Hz, 14.1 Hz), 4.56-4.69 (1H, m), 5.06 (1H,
t, J = 2.9 Hz), 5.12 (1H, d, J = 3.2 Hz), 7.06 (2
H, t, J = 8.7 Hz), 7.17-7.26 (3H, m), 7.35-7.53 (7
H, m), 7.67 (2H, d, J = 8.0 Hz); IR (KBr) 3303, 16
38, 1534, 1325, 1227, 1167, 1125, 1069, 829, 698 c
m ^-1 ; Anal.Calcd for C ₂₃ H ₁₉ F ₄ NO ₂ : C, 66.18; H, 4.5
9; N, 3.36. Found: C, 66.05; H, 4.51; N, 3.44.

Example 69 N-((1RS, 2SR) -2- (4-fluorophenyl)
2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -2-phenylacetamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (4 -(Trifluoromethyl) phenyl) -1
To a solution of -propanol (450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added phenylacetyl chloride (285 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (578m
g, 93%). mp 173-174 ℃ IRνmax ^KBr cm ^-1 : 1651, 1539, 1514. Anal.Calcd for C ₂₄ H ₂₁ F ₄ NO ₂ : C, 66.82; H, 4.91; N,
3.25 Found:. C, 66.63; H, 4.78; N, 3.19 1 H-NMR (CDCl 3) δ: 2.62 (1H, dd, J = 14.2, 10.6 H
z), 2.81 (1H, dd, J = 14.2, 4.4 Hz), 3.44 (2H, s),
3.50 (1H, d, J = 3.6 Hz), 4.28-4.42 (1H, m), 4.84
4.92 (1H, m), 5.25 (1H, d, J = 8.2 Hz), 6.90-7.10
(6H, m), 7.24-7.36 (5H, m), 7.45 (2H, d, J = 7.6 H
z).

Example 70 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -2,2,2-trifluoroacetamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.155 g (0.495 mmol)
And 83 mg (0.99 mmol) of sodium hydrogen carbonate in 10 ml of tetrahydrofuran were added with 0.08 ml (0.59 mmol) of trifluoroacetic anhydride, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. 0.154 g of white crystals
Yield 76% mp 162-163 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200MHz) δ 2.
81-2.97 (2H, m), 4.31-4.48 (1H, m), 4.85 5.00 (2H, m
m), 7.01-7.11 (2H, m), 7.17 (2H, d, J = 8.0Hz),
7.39-7.47 (4H, m), 7.79-7.92 (1H, m); IR (KBr) 330
1, 1701, 1564, 1514, 1327, 1233, 1182, 1128, 1069,
833 cm ^-1 ; Anal.Calcd for C ₁₈ H ₁₄ F ₇ NO ₂ : C, 52.82;
H, 3.45; N, 3.42. Found: C, 52.98; H, 3.43; N, 3.2
Five.

Example 71 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -2,2,3,3-tetrafluoropropionamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) 0.153 g (0.488 mmol) of -3- [4- (trifluoromethyl) phenyl] propan-1-ol, 2,2,3,3-tetrafluoropropionic acid 7
1 mg (0.49 mmol) of 1-hydroxybenzotriazole hydrate (75 mg, 0.49 mmol) is stirred in 10 ml of acetonitrile with 1-ethyl-3-ethyl.
94 mg (0.49 mmol) of (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1), and crystallized from hexane to obtain the desired product.
White crystals Yield 90 mg Yield 42% mp 164-166 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.66 (1H,
br s), 2.79-2.96 (2H, m), 4.41-4.55 (1H, m), 4.97
(1H, d, J = 4.0 Hz), 5.94 (1H, tt, J = 5.5 Hz, 52.
9 Hz), 6.55 (1H, br d, J = 9.2 Hz), 7.10 (2H, t, J
= 8.6 Hz), 7.18 (2H, d, J = 8.0 Hz), 7.40 (2H, dd,
J = 5.8 Hz, 8.6 Hz), 7.50 (2H, d, J = 8.0 Hz); IR
(KBr) 3304, 1686, 1329, 1231, 1175, 1113, 1069, 82
9 cm ^-1

Example 72 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -1,3-benzodioxole
-5-carboxamide (1RS, 2RS) -1- (4-fluorophenyl) -1-
Hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (150 mg, 0.43
Pivaloyl chloride (119 mg, 0.64 mmol) and saturated aqueous sodium bicarbonate (5 ml) were added to a solution of the resulting compound in an aqueous solution of ethyl acetate (5 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (50 ml) and ethyl acetate (50 ml × 2)
Extracted. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (160 m
g, 81%). mp 180-181 ° C IRνmax ^KBr cm ^-1 : 1640, 1605, 1507, 1485. Anal.Calcd for C ₂₄ H ₁₉ F ₄ NO ₄ : C, 62.47; H, 4.15; N,
3.04 Found:. C, 62.43; H, 4.06; N, 3.06 1 H-NMR (CDCl 3) δ: 2.80-3.06 (2H, m), 3.70 (1H, d,
J = 3.6 Hz), 4.50-4.66 (1H, m), 5.02-5.10 (1H, m),
5.90-6.10 (1H, m), 6.02 (2H, s), 6.77 (1H, d, J =
8.8 Hz), 7.00-7.16 (4H, m), 7.20-7.30 (2H, m), 7.3
6-7.58 (4H, m).

Example 73 4- (4-Fluorophenyl) -N-[(1RS, 2SR)
-2- (4-Fluorophenyl) -2-hydroxy-1- [4-
(Trifluoromethyl) benzyl] ethyl] -5-methyl
2- (1-methylethyl) furan-3-carboxamide 1) 1-fluoro-4- (2-nitro-1-propenyl) benzene 17.02 g of 4-fluorobenzaldehyde (137.
1 mmol), 11.5 g (192 mmol) of acetic acid, 3.70 g (54.9 mmol) of methylamine hydrochloride,
A mixture of 4.50 g (54.9 mmol) of sodium acetate and 41.2 g (549 mmol) of nitroethane was added to 10
Stirred at 0 ° C. for 1.5 hours. The reaction solution was poured into water and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from diethyl ether-hexane to obtain the desired product. Yellow crystal Yield 18.40 g Yield 74% mp 59-61 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.45 (3H,
s), 7.16 (2H, d, J = 8.6Hz), 7.44 (2H, dd, J = 5.4
Hz, 8.8 Hz), 8.06 (1H, s); IR (KBr) 1514, 1318, 1
^{. 225, 982, 847 cm -1} ; Anal Calcd for C 9 H 8 FNO 2: C, 5
9.67; H, 4.45; N, 7.73. Found: C, 59.51; H, 4.39;
N, 7.80. 2) 4- (4-Fluorophenyl) -5-methyl-2- (1
Ethyl 2-methylethyl) furan-3-carboxylate 20.06 g (126.8 mmol) of ethyl isobutyryl acetate and 1-fluoro-4- (2-nitro-1-propenyl)
23.0 g (127 mmol) of benzene in ethanol 1
12.5 ml (127 mmol) of piperidine was added to the 00 ml solution at room temperature, and the mixture was stirred at room temperature overnight and at 80 ° C. for 1 hour. The solvent of the reaction solution was distilled off under reduced pressure, and 50 ml of water and 30 ml of concentrated hydrochloric acid were added to the residue, followed by stirring at room temperature for 1 hour. The reaction solution was extracted twice with ethyl acetate, the collected organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 20/1) to obtain the desired product. Pale yellow solid Yield 5.958 g Yield 16% Recrystallization from cold methanol gave white crystals. mp 27-28 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 1.09 (3H, t,
J = 7.2 Hz), 1.30 (6H, d, J = 7.4 Hz), 2.18 (3H,
s), 3.65-3.79 (1H, m), 4.11 (2H, q, J = 7.2Hz), 7.
04 (2H, t, J = 8.8 Hz), 7.21 (2H, dd, J = 5.6 Hz,
8.8 Hz); IR (neat) 2974, 1707, 1578, 1510, 1221, 1
^{. 149, 1059 cm -1; Anal} Calcd for C 17 H 1 9 FO 3: C, 70.3
3; H, 6.60. Found: C, 70.36; H, 6.53. 3) 4- (4-Fluorophenyl) -5-methyl-2- (1
1.500 g of ethyl 4- (4-fluorophenyl) -5-methyl-2- (1-methylethyl) furan-3-carboxylate
(5.167 mmol) and 1.65 g of sodium hydroxide
(41.3 mmol) in methanol 15 ml-water 5 ml
And stirred at 70 ° C. for 8 hours. The reaction solution was diluted with water, acidified with dilute hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer is dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was crystallized from hexane to obtain the desired product. White crystals Yield 0.958 g Yield 71% mp 176-177 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.28 (6H,
d, J = 7.0 Hz), 2.17 (3H, s), 3.71-3.84 (1H, m),
7.05 (2H, t, J = 8.8 Hz), 7.22 (2H, dd, J = 5.4 H
z, 8.8 Hz); IR (KBr) 3050-2500, 1680, 1512, 1225,
^{. 1074, 845 cm -1; Anal} Calcd for C 15 H 15 FO 3: C, 68.6
9; H, 5.76. Found: C, 68.57; H, 5.84. 4) 4- (4-Fluorophenyl) -N-[(1RS, 2
SR) -2- (4-Fluorophenyl) -2-hydroxy-1
-[4- (Trifluoromethyl) benzyl] ethyl] -5-
Methyl-2- (1-methylethyl) furan-3-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propane-1- All 0.211 g (0.673 mmol), 4- (4-fluorophenyl) -5-methyl-2- (1
-Methylethyl) furan-3-carboxylic acid 0.18g
(0.67 mmol) 1-hydroxybenzotriazole hydrate 0.10 g (0.67 mmol) in 10 ml of acetonitrile while stirring 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0 .1
3 g (0.67 mmol) was added and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product.
White powder Yield 0.288 g Yield 77% mp 134-136 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.19 (3H,
d, J = 7.0 Hz), 1.25 (3H, d, J = 7.0 Hz), 2.09 (3
H, s), 2.38 (1H, dd, J = 10.5 Hz, 14.9 Hz), 2.71
(1H, dd, J = 4.3 Hz, 14.3 Hz), 3.51-3.65 (1H, m),
3.76 (1H, d, J = 4.4 Hz), 4.40-4.53 (1H, m), 4.80
(1H, t, J = 3.3 Hz), 5.19 (1H, d, J = 8.0 Hz), 6.9
0-7.13 (7H, m), 7.23-7.30 (3H, m), 7.45 (2H, d, J
= 8.0 Hz); IR (KBr) 3347, 2973, 2634, 1620, 1605,
1512, 1329, 1223, 1163, 1125, 1069, 839 cm ^-1 ; Ana
l. Calcd for C ₃₁ H ₂₈ F ₅ NO ₃ : C, 66.78; H, 5.06; N, 2.
51. Found: C, 66.43; H, 5.20; N, 2.41.

Example 74 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) [1,1'-biphenyl] -3-
Oxalyl chloride (0.11 ml, 1.72 mmol) and N, N-dimethylformamide (0.01 ml) were added to a solution of carboxamide 3-biphenylcarboxylic acid (127 mg, 0.64 mmol) in tetrahydrofuran (5 ml). After stirring at room temperature for 30 minutes, the reaction solution was distilled off under reduced pressure.
To a solution of the residue in ethyl acetate (5 ml) was added (1RS, 2S
R) -1- (4-Fluorophenyl) -1-hydroxy-3-
(4- (Trifluoromethyl) phenyl) -2-propylamine hydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml), and ethyl acetate (50 ml) was added.
× 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give the title compound (147 mg, 69%). mp 165-166 ℃ IRνmax ^KBr cm ^-1 : 1641, 1539, 1510.Anal.Calcd for C
_{29 H 23 F 4 NO 2:} C, 70.58; H, 4.70; N, 2.84 Found:. C, 70.32; H, 4.80; N, 2.67 1 H-NMR (CDCl 3) δ: 2.90-3.02 (1H, m ), 2.99 (1H, s),
3.64 (1H, d, J = 3.6Hz), 4.50-4.70 (1H, m), 5.08-
5.18 (1H, m), 6.14 (1H, d, J = 6.4 Hz), 7.02-7.18
(2H, m), 7.24-7.34 (2H, m), 7.38-7.58 (11H, m), 7.
70-7.76 (2H, m).

Example 75 4- (Dimethylamino) -N-((1RS, 2SR) -2-
(4-fluorophenyl) -2-hydroxy-1-((4-
(Trifluoromethyl) phenyl) methyl) ethyl)-
1-Naphthalenecarboxamide (1RS, 2RS) -1- (4-fluorophenyl) -1-
4-dimethylaminonaphthalenecarboxylic acid (89 mg, 0.42 mmol) and a solution of hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine (150 mg, 0.42 mmol) in acetonitrile (10 ml) and 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (119 mg, 0.62 mmol) and 1-hydroxy-1H-benzotriazole (63.6 mg, 0.42 mmol) were added, and the mixture was added at room temperature overnight. Stirred. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1).
Recrystallization from hexane gave the title compound (149 mg,
70%). mp 169-170 ℃ IRνmax ^KBr cm ^-1 : 1634, 1578, 1510.Anal. Calcd for C
_{29 H 26 F 4 N 2 O} 2: C, 68.23; H, 5.13; N, 5.49 Found:. C, 68.09; H, 5.11; N, 5.32 1 H-NMR (CDCl 3) δ: 2.88 (6H, s ), 2.76-3.14 (2H, m),
3.71 (1H, d, J = 4.0Hz), 4.66-4.84 (2H, m), 5.04-
5.12 (1H, m), 5.90 (1H, d, J = 8.4 Hz), 6.86 (1H,
d, J = 7.6 Hz), 7.02-7.18 (3H, m), 7.30-7.60 (8H,
m), 7.75 (1H, d, J = 8.4 Hz), 8.17 (1H, d, J = 8.4
Hz).

Example 76 3-Chloro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] naphthalene-1- Carboxamide 1) Ethyl 3-chloro-1-naphthoate 2.317 g of ethyl 3-amino-1-naphthoate (10.
(76 mmol) in concentrated hydrochloric acid (30 ml), a solution of sodium nitrite (0.89 g, 12.9 mmol) in water (2 ml) was added dropwise under ice-cooling.
Stirred for hours. 0.53 g of cuprous chloride under ice-cooling
(5.38 mmol) in 4 ml of concentrated hydrochloric acid was added under ice cooling, and the mixture was stirred at 100 ° C. for 0.5 hour. After cooling to room temperature, the reaction was diluted with water and extracted twice with ethyl acetate.
The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 15).
/ 1) to obtain the desired product. Colorless liquid yield 1.058g
Yield 42% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.47 (3H, t, J = 7.0 H
z), 4.48 (2H, q, J = 7.1Hz), 7.51-7.65 (2H, m), 7.
80 (1H, dd, J = 2.2 Hz, 7.2 Hz), 7.99 (1H, d, J =
2.2 Hz), 8.12 (1H, d, J = 2.2 Hz), 8.87 (1H, dd, J
= 2.2 Hz, 7.4 Hz); IR (KBr) 1717, 1279, 1240, 118
8, 1142 cm ^-1 2) 3-chloro-1-naphthoic acid 1.056 g of ethyl 3-chloro-1-naphthoate (4.5)
00 mmol) in 10 ml of methanol-10 ml of tetrahydrofuran.
0 ml (9.00 mmol) was added and stirred at room temperature overnight. The reaction solution was concentrated, diluted with water, acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 0.769 g Yield 83% mp 217-218 ° C; ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ 7.59-7.7
2 (2H, m), 7.97-8.07 (2H, m), 8.30 (1H, d, J = 2.2
Hz), 8.81-8.86 (1H, m); IR (KBr) 3100-2600,1699,
1285, 1254, 1196, 883, 793, 745 cm ^-1 ; Anal.Calcd
for C ₁₁ H ₇ ClO ₂ : C, 63.94; H, 3.41. Found: C, 64.00;
H, 3.44.3) 3-Chloro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] naphthalene-1- Carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.153 g (0.488 mmol), 3-chloro 0.1-g of 1-naphthoic acid (0.49
Mmol) 1-hydroxybenzotriazole hydrate (75 mg, 0.49 mmol) in acetonitrile 10m
1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 94 mg (0.49
Mmol) and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 0.210 g Yield 86% mp 220-221 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
91 (1H, dd, J = 10.7 Hz, 13.5 Hz), 3.19 (1H, dd, J
= 2.2 Hz, 13.2 Hz), 4.62-4.77 (1H, m), 4.89 (1H,
t, J = 5.0 Hz), 5.50 (1H, d, J = 4.4 Hz), 7.04-7.1
3 (3H, m), 7.22-7.34 (2H, m), 7.38-7.59 (7H, m),
7.73 (1H, d, J = 8.0 Hz), 7.82 (1H, d, J = 2.0 Hz),
8.10 (1H, d, J = 10.0 Hz); IR (KBr) 3285, 1642, 1
541, 1514, 1325, 1163, 1119, 1069, 837 cm ^-1 ; Anal.
_{Calcd for C 27 H 20 ClF 4} NO 2: C, 64.61; H, 4.02; N, 2.7
9. Found: C, 64.82; H, 4.17; N, 2.74.

Example 77 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -2,3-dihydro-1-benzofuran-7-carboxamide 2,3-dihydro-1-benzofuran 7-carboxylic acid ( 10
6 mg, 0.64 mmol) in tetrahydrofuran (5
oxalyl chloride (0.11 ml,
1.72 mmol) and N, N-dimethylformamide (0.01 ml) were added and stirred at room temperature for 30 minutes.
The reaction solution was distilled off under reduced pressure. Ethyl acetate of residue (5 ml)
Add (1RS, 2SR) -1- (4-fluorophenyl) -1-hydroxy-3- (4- (trifluoromethyl)
Phenyl) -2-propylamine hydrochloride (150 mg,
0.43 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (160 mg, 81%). mp 121-122 ℃ IRνmax ^KBr cm ^-1 : 1780, 1644, 1537.Anal.Calcd for C
_{25 H 21 F 4 NO 3:} C, 65.36; H, 4.61; N, 3.05 Found:. C, 65.41; H, 4.38; N, 2.76 1 H-NMR (CDCl 3) δ: 2.76-3.00 (2H, m ), 3.18-3.30 (2
H, m), 4.12 (1H, d, J = 3.6 Hz), 4.48-4.76 (4H, m),
5.08 (1H, s), 6.90-7.16 (2H, m), 7.20-7.52 (6H,
m), 7.60 (1H, d, J = 7.6 Hz), 7.85 (1H, d, J = 7.6 Hz)
Hz).

Example 78 2-Bromo-N-((1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) acetamide (1RS, 2RS) -1- (4-fluorophenyl) -1-
To a solution of hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine (2.0 g, 5.54 mmol) in ethyl acetate (50 ml) was added bromoacetyl bromide (723 ml, 8.30 mmol) and saturated. Aqueous sodium bicarbonate (50 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water (100 ml), and ethyl acetate (200 ml) was added.
1 × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 1) and recrystallized from ethyl acetate-hexane to give the title compound (2.0 g, 83%).
I got mp 151-152 ℃ IRνmax ^KBr cm ^-1 : 1659, 1647, 1547.Anal. Calcd for C
_{18 H 16 BrF 4 NO 2:} C, 49.79; H, 3.71; N, 3.23 Found:. C, 49.80; H, 3.41; N, 3.03 1 H-NMR (CDCl 3) δ: 2.72-2.96 (3H, m ), 3.74 (2H, dd,
J = 18.4, 13.6 Hz), 4.38-4.52 (1H, m), 4.92-5.00
(1H, m), 6.53 (1H, d, J = 8.4 Hz), 7.02-7.18 (2H,
m), 7.22 (2H, d, J = 8.0 Hz), 7.32-7.50 (2H, m),
7.51 (2H, d, J = 8.0 Hz).

Example 79 4-butyl-N-((1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) benzamide Oxalyl chloride (0.15 ml, 1.72 mmol) and N, N-dimethylformamide (0.01 ml) were added to a solution of 4-n-butylbenzoic acid (153 mg, 0.86 mmol) in tetrahydrofuran (5 ml). After stirring at room temperature for 30 minutes, the reaction solution was distilled off under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) (1RS, 2SR)
-1- (4-Fluorophenyl) -1-hydroxy-3- (4-
(Trifluoromethyl) phenyl) -2-propylamine hydrochloride (200 mg, 0.57 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml) and ethyl acetate (50 ml × 2)
Extracted. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
4: 1-1: 1) and recrystallized from ethyl acetate-hexane to give the title compound (172 mg, 64%). mp 171-172 ° C IRν max ^KBr cm ^-1 : 1638, 1609, 1537, 1512.Anal. Calc
_{d for C 27 H 27 F 4} NO 2: C, 68.49; H, 5.75; N, 2.96 Found:. C, 68.46; H, 5.89; N, 2.94 1 H-NMR (CDCl 3) δ: 0.92 (3H, t, J = 7.2 Hz), 1.22-
1.44 (2H, m), 1.48-1.70 (2H, m), 2.63 (2H, t, J =
8.0 Hz), 2.80-3.06 (2H, m), 3.84 (1H, d, J = 3.0 H
z), 4.50-4.70 (1H, m), 5.08 (1H, s), 6.12 (1H, d,
J = 8.2 Hz), 7.00-7.36 (6H, m), 7.38-7.58 (6H, m).

Example 80 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl
Enyl) methyl) ethyl) -8-quinolinecarboxamide (1RS, 2SR) -2-amino-1- (4-fluorophene)
Nyl) -3- (4- (trifluoromethyl) phenyl) -1
Of propanol (450 mg, 1.44 mmol)
8-quinolinecarboxyl in acetonitrile (30 ml) solution
Acid (249 mg, 1.44 mmol) and 1-ethyl-
3- (3-dimethylaminopropyl) carbodiimide salt
Acid salt (413 mg, 2.15 mmol) and 1-hydrido
Roxy-1H-benzotriazole (220 mg, 1.4
4 mmol) and stirred overnight at room temperature. Water
(100 ml) and diluted with ethyl acetate (100 ml ×
Extracted in 2). The extract is washed with a saturated saline solution,
After drying with magnesium acid, it was distilled off under reduced pressure. Silica residue
Gel column chromatography (hexane: ethyl acetate
= 1: 1) and recrystallized from ethyl acetate-hexane
This afforded the title compound (162 mg, 24%). mp 83-84 ℃ IRνmax ^KBr cm ^-1 : 1644, 1574, 1549.Anal.Calcd for C
₂₆ H ₂₀ F _Four N _Two O _Two ・ 1.0H _Two O: C, 64.19; H, 4.56; N, 5.76 Found: C, 64.07; H, 4.39; N, 5.61. ¹ H-NMR (CDCl _Three ) δ: 2.99 (2H, d, J = 7.4 Hz), 4.52
(1H, d, J = 3.6 Hz), 4.70-4.90 (1H, m), 5.12-5.20
(1H, m), 6.96-7.08 (2H, m), 7.31 (2H, d, J = 8.0 H
z), 7.36-7.54 (5H, m), 7.67 (1H, t, J = 7.6 Hz),
7.98 (1H, dd, J = 8.0, 1.8 Hz), 8.28 (1H, dd, J =
8.0, 1.8 Hz), 8.71 (1H, dd, J = 4.0, 1.8Hz), 8.79
(1H, dd, J = 7.4, 1.8 Hz), 11.49 (1H, d, J = 7.6 H
z).

Example 81 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4- (trifluoromethyl)
Benzamide (1RS, 2SR) -1- (4-fluorophenyl) -1-
Hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (200 mg, 0.57
4- (trifluoromethyl) benzoyl chloride (179 mg, 0.
86 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) and recrystallized from ethyl acetate-hexane to give the title compound (17).
(1 mg, 62%). mp 228-229 ℃ IRν max ^KBr cm ^-1 : 3285, 1641, 1329.Anal. Calcd for
_{C 24 H 18 F 7 NO 2} : C, 59.39; H, 3.74; N, 2.89 Found:. C, 59.30; H, 3.74; N, 3.04 1 H-NMR (CDCl 3) δ: 2.90-3.08 (3H, m), 4.56-4.70 (1
H, m), 5.04-5.14 (1H, m), 6.06-6.20 (1H, m), 7.00-
7.20 (2H, m), 7.20-7.34 (2H, m), 7.36-7.56 (4H,
m), 7.60-7.70 (4H, m).

Example 82 N-((1RS, 2SR) -2- (4-fluorophenyl)
2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -2- (1-naphthalenyl) acetamide 1-naphthaleneacetic acid (160 mg, 0.86 mmol)
In a solution of oxalyl chloride (0.15 ml, 1.72 mmol) and N,
Add N-dimethylformamide (0.01 ml)
After stirring at room temperature for 30 minutes, the reaction solution was distilled off under reduced pressure. (1RS, 2SR) -1- was added to a solution of the residue in ethyl acetate (5 ml).
(4-Fluorophenyl) -1-hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (200 mg, 0.57 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) were added, and the mixture was added at room temperature. Stir for 2 hours. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2:
1-1: 1) and recrystallized from ethyl acetate-hexane to give the title compound (175 mg, 64%). mp 186-187 ℃ IRν max ^KBr cm ^-1 : 3285, 1657, 1539, 1512, 1120.Ana
l. Calcd for C ₂₈ H ₂₃ F ₄ NO ₂ : C, 69.85; H, 4.81; N, 2.
91 Found:. C, 69.62; H, 4.68; N, 2.85 1 H-NMR (CDCl 3) δ: 2.40 (1H, dd, J = 14.2, 10.4 H
z), 2.70 (1H, dd, J = 14.2, 4.0 Hz), 3.28 (2H, d,
J = 3.6 Hz), 3.90 (2H, d, J = 2.2 Hz), 4.24-4.40
(1H, m), 4.70-4.84 (1H, m), 5.15 (1H, d, J = 7.8 H
z), 6.78 (2H, d, J = 8.0 Hz), 6.88-7.00 (2H, m), 7.
04-7.20 (3H, m), 7.20-7.34 (2H, m), 7.36-7.60 (3H, m
m), 7.70-7.94 (3H, m).

Example 83 2- (Ethyloxy) -N-((1RS, 2SR) -2-
(4-fluorophenyl) -2-hydroxy-1-((4-
(Trifluoromethyl) phenyl) methyl) ethyl)-
1-Naphthalenecarboxamide 2- (ethyloxy) -N- (2- (4-fluorophenyl) -2-oxo-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -1-naphthalenecarboxamide (400 mg , 0.79 mmol) of methanol (3
Manganese (II) chloride (198 mg,
(1.57 mmol) and stirred at room temperature for 30 minutes. Sodium borohydride (30 mg,
(0.79 mmol) and stirred for 1 hour. The reaction solution was poured into 1N hydrochloric acid (30 ml), and ethyl acetate (50 ml) was added.
× 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Ethyl acetate = 2: 1-1: 1) to give ethyl acetate-
Recrystallized from hexane to give 2- (ethyloxy) -N-
((1RS, 2SR) -2- (4-fluorophenyl) -2
-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -1-naphthalenecarboxamide was obtained. The mother liquor after recrystallization was distilled off under reduced pressure, and the obtained crude crystals were washed with a mixed solvent of hexane: ethyl acetate = 10: 1 to obtain the title compound (37.2 mg, 9%). mp 157-158 ℃ IRν max ^KBr cm ^-1 : 1622, 1510, 1300, 1236.Anal. Calc
d for C ₂₉ H ₂₅ F ₄ NO ₃ : C, 68.09; H, 4.93; N, 2.74 Found: C, 67.96; H, 4.86; N, 2.82. ¹ H-NMR (CDCl ₃ ) δ: 1.38 (3H, t, 7.0 Hz), 2.62-3.10
(2H, m), 3.28 (1H, d, J = 4.0 Hz), 4.06-4.30 (2H,
m), 4.88-5.04 (1H, m), 5.10-5.22 (1H, m), 6.03 (1
H, d, J = 9.6 Hz), 7.00-7.20 (3H, m), 7.20-7.60 (9
H, m), 7.77 (2H, dd, J = 20.0, 8.2 Hz).

Example 84 N-((1RS, 2SR) -2- (4-fluorophenyl)
Oxalyl chloride was added to a solution of 9-anthracenecarboxylic acid (143 mg, 0.64 mmol) in tetrahydrofuran (5 ml). (0.11 ml, 1.72 mmol) and N, N-dimethylformamide (0.01 ml) were added, the mixture was stirred at room temperature for 30 minutes, and the reaction solution was distilled off under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) was added (1RS, 2
SR) -1- (4-Fluorophenyl) -1-hydroxy-3
-(4- (Trifluoromethyl) phenyl) -2-propylamine hydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml), and ethyl acetate (50 ml) was added.
× 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) and recrystallized from ethyl acetate-hexane to give the title compound (136 mg, 61%). mp 251-252 ° C IRν max ^KBr cm ^-1 : 1655, 1514, 1335, 1161, 1111. Anal.Calcd for C ₃₁ H ₂₃ F ₄ NO ₂ : C, 71.95; H, 4.48; N,
2.71 Found:. C, 71.81; H, 4.55; N, 2.74 1 H-NMR (CDCl 3) δ: 2.82 (1H, dd, J = 14.2, 11.8 H
z), 3.59 (1H, d, J = 14.0 Hz), 4.74 (1H, d, J = 8.
0 Hz), 5.16-5.32 (1H, m), 6.57 (1H, d, J = 8.8Hz),
6.76 (1H, d, J = 8.8 Hz), 6.96-7.10 (1H, m), 7.10
-7.30 (3H, m), 7.30-7.46 (2H, m), 7.54-7.76 (6H,
m), 7.84-8.00 (2H, m), 8.42 (1H, s).

Example 85 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -9-oxo-9H-fluorene
-1-Carboxamide 9-oxo-9H-fluorene-1-carboxylic acid (144 m
g, 0.64 mmol) of tetrahydrofuran (5 m
l) Add oxalyl chloride (0.11 ml, 1.
72 mmol) and N, N-dimethylformamide (0.01 ml) were added, the mixture was stirred at room temperature for 30 minutes, and the reaction solution was distilled off under reduced pressure. (1RS, 2SR) -1- (4-fluorophenyl)-was added to a solution of the residue in ethyl acetate (5 ml).
1-hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (150 mg, 0.43
Mmol) and saturated aqueous sodium hydrogen carbonate (5 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane,
The title compound (137 mg, 61%) was obtained. mp 185-186 ° C IRνmax ^KBr cm ^-1 : 1698, 1607, 1574. Anal.Calcd for C ₃₀ H ₂₁ F ₄ NO ₃・ 0.1H ₂ O: C, 69.12; H,
4.10; N, 2.69 Found:. C, 68.98; H, 3.91; N, 2.63 1 H-NMR (CDCl 3) δ: 2.90-3.12 (2H, m), 3.85 (1H, s),
4.64-4.80 (1H, m), 5.20 (1H, s), 7.00-7.16 (2H,
m), 7.20-7.70 (12H, m), 8.12 (1H, dd, J = 7.2, 2.0
Hz), 10.16 (1H, d, J = 7.6 Hz).

Example 86 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -3,5-bis (trifluoromethyl) benzamide (1RS, 2SR) -1- (4-fluorophenyl) -1 -
Hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (150 mg, 0.43
Mmol) in ethyl acetate (5 ml) was added to 3,5-bis (trifluoromethyl) benzoyl chloride (117 m
1,0.64 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give the title compound (73 mg, 31
%). mp 150-151 ° C IRνmax ^KBr cm ^-1 : 1651, 1620, 1543, 1512. Anal.Calcd for C ₂₅ H ₁₇ F ₁₀ NO ₂ : C, 54.26; H, 3.10;
N, 2.53 Found:. C, 54.12; H, 2.95; N, 2.38 1 H-NMR (CDCl 3) δ: 2.80-3.04 (3H, m), 4.60-4.78 (1
H, m), 5.13 (1H, s), 6.24 (1H, d, J = 8.4 Hz), 7.0
2-7.20 (2H, m), 7.20-7.32 (2H, m), 7.40-7.56 (4H, m
m), 7.90-8.02 (3H, m).

Example 87 8-Bromo-N-((1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl)- 1-naphthalenecarboxamide 8-bromo-1-naphthalenecarboxylic acid (161 mg,
Oxalyl chloride (0.11 ml, 1.72 mmol) and N, N-dimethylformamide (0.04 mmol) in tetrahydrofuran (5 ml) solution.
1 ml), and the mixture was stirred at room temperature for 30 minutes, and the reaction solution was evaporated under reduced pressure. (1 ml) was added to a solution of the residue in ethyl acetate (5 ml).
RS, 2SR) -1- (4-Fluorophenyl) -1-hydroxy-3- (4- (trifluoromethyl) phenyl) -2
-Propylamine hydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 1) and recrystallized from ethyl acetate-hexane to give the title compound (67 m
g, 29%). mp 191-192 ° C IRνmax ^KBr cm ^-1 : 1653, 1634, 1510. Anal.Calcd for C ₂₇ H ₂₀ BrF ₄ NO ₂・ 0.2H ₂ O: C, 58.97;
H, 3.74; N, 2.55 Found :. C, 58.73; H, 3.44; N, 2.49 1 H-NMR (CDCl 3) δ: 2.80-3.02 (2H, m), 4.78 (1H, br
s), 5.02-5.20 (1H, m), 5.60-5.80 (1H, m), 7.04-7.20
(2H, m), 7.22-7.44 (5H, m), 7.44-7.70 (4H, m), 7.7
4-7.96 (3H, m).

Example 88 4- (4-Fluorobenzoyl) -N-[(1RS, 2S
R) -2- (4-Fluorophenyl) -2-hydroxy-1-
[4- (trifluoromethyl) benzyl] ethyl] benzenecarboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.224 g (0.715 mmol) 4- (4-fluorobenzoyl) benzoic acid 0.17
g (0.71 mmol) and 0.11 g (0.71 mmol) of 1-hydroxybenzotriazole hydrate in 10 ml of acetonitrile while stirring with 1-ethyl-3- (3- (3-ethyl-3-benzotriazole).
Dimethylaminopropyl) carbodiimide hydrochloride
14 g (0.71 mmol) was added and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product.
White crystals Yield 0.321 g Yield 83% mp 156-157 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
83-3.06 (2H, m), 4.60-4.71 (1H, m), 4.91 (1H, d, J
= 3.2 Hz), 5.08 (1H, t, J = 3.1 Hz), 7.08 (2H, t,
J = 8.6 Hz), 7.14-7.31 (5H, m), 7.45 (2H, d, J =
7.4 Hz), 7.50 (2H, dd, J = 5.6 Hz, 8.8 Hz), 7.77
(4H, s), 7.83 (2H, dd, J = 5.4 Hz, 9.0Hz); IR (KB
r) 3536, 3303, 1644, 1601, 1541, 1507, 1329, 1281,
1225, 1161, 1111, 1069, 864, 849 cm ^-1 ; Anal.Calc
d for C ₃₀ H ₂₂ F ₅ NO ₃・ 0.2H ₂ O: C, 66.35; H, 4.16; N, 2.
58.Found: C, 66.14; H, 4.06; N, 2.57.

Example 89 4-[(Z) -2- (4-chlorophenyl) ethenyl] -N-
[(1RS, 2SR) -2- (4-fluorophenyl) -2
-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] benzenecarboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] 0.245 g (0.782 mmol) of propan-1-ol, 0.20 g (0.78 mmol) of (Z) -4- [2- (4-chlorophenyl) ethenyl] benzoic acid, 1-hydroxybenzotriazole hydrate 0.12 g (0.7
(8 mmol) was stirred in 10 ml of acetonitrile, and 0.15 g (0.78 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added thereto, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. 0.378 g of white crystals
Yield 87% mp 193-194 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200MHz) δ 2.
77-3.03 (2H, m), 4.56-4.69 (1H, m), 4.82 (1H, d, J
= 3.4 Hz), 5.05 (1H, t, J = 2.8 Hz), 6.61 (2H,
s), 6.95 (1H, d, J = 9.0 Hz), 7.06 (2H, t, J = 8.6
Hz), 7.14-7.30 (8H, m), 7.42-7.56 (6H, m); IR (KB
r) 3260, 1642, 1512, 1325, 1165, 1115, 1067, 872,
^{. 826 cm -1; Anal Calcd for} C 31 H 24 ClF 4 NO 2: C, 67.21;
H, 4.37; N, 2.53. Found: C, 67.00; H, 4.42; N, 2.4
8.

Example 90 4- (4-chlorophenoxy) -N-[(1RS, 2SR)
-2- (4-Fluorophenyl) -2-hydroxy-1- [4-
(Trifluoromethyl) benzyl] ethyl] benzenecarboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.235 g (0.750 mmol) 0.19 g of 4- (4-chlorophenoxy) benzoic acid
0.17 g (0.75 mmol) of 1-hydroxybenzotriazole hydrate in 10 ml of acetonitrile was stirred with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0 (0.75 mmol). .1
4 g (0.75 mmol) was added and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product.
White crystals Yield 0.353 g Yield 87% mp 188-189 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
77-3.03 (2H, m), 4.56-4.69 (1H, m), 4.75 (1H, d, J
= 3.2 Hz), 5.06 (1H, t, J = 3.1 Hz), 6.85 (1H, d,
J = 8.4 Hz), 6.95 (2H, d, J = 8.8 Hz), 6.97 (2H,
d, J = 9.2 Hz), 7.07 (2H, t, J = 8.8 Hz), 7.23 (2H,
d, J = 8.0 Hz), 7.33 (2H, d, J = 9.2Hz), 7.43-7.5
1 (4H, m), 7.64 (2H, d, J = 9.2 Hz); IR (KBr) 329
1, 1636,1512, 1487, 1329, 1256, 1121, 1069, 837, 8
28 cm ^-1 ; Anal.Calcd for C ₂₉ H _{2 2} ClF ₄ NO ₃ : C, 64.04;
H, 4.08; N, 2.58. Found: C, 63.86; H, 4.06; N, 2.5
Five.

Example 91 4- (4-fluorophenyl) -N-[(1RS, 2SR)
-2- (4-Fluorophenyl) -2-hydroxy-1- [4-
(Trifluoromethyl) benzyl] ethyl] -5-[(methoxy) methyl] -2-phenylfuran-3-carboxamide 1) 4- (4-fluorophenyl) -5-methyl-2-phenylfuran-3-carboxylic Ethyl benzoylate 12.43 g (64.67 mmol) of ethyl acetate and 11.7 g (64.7 mmol) of 1-fluoro-4- (2-nitro-1-propenyl) benzene in ethanol 6
6.40 ml (64.7 mmol) of piperidine was added to the 0 ml solution at room temperature, and the mixture was stirred at room temperature overnight. Water 5
0 ml and 15 ml of concentrated hydrochloric acid were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted twice with ethyl acetate, the collected organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 20/1) to obtain the desired product.
A pale yellow solid, 7.860 g, 38% yield, was recrystallized from methanol to give a white powder. mp 78-79 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 1.02 (3H, t,
J = 7.1 Hz), 2.30 (3H, s), 4.10 (2H, q, J = 7.1 H
z), 7.09 (2H, t, J = 8.6 Hz), 7.19-7.48 (5H, m), 7.
82 (2H, dd, J = 1.9 Hz, 7.7 Hz); IR (KBr) 1716, 15
10, 1323, 1223,1105 cm ^-1 ; Anal.Calcd for C ₂₀ H ₁₇ FO
₃ : C, 74.06; H, 5.28. Found: C, 73.82; H, 5.35.2) 5-[(acetoxy) methyl] -4- (4-fluorophenyl) -2-phenylfuran-3-carboxylate 19.06 g (58.76 mmol) of ethyl 4- (4-fluorophenyl) -5-methyl-2-phenylfuran-3-carboxylate, 10.5 g of N-bromosuccinimide (5.
8.8 mmol) and a solution of 50 mg of 2,2′-azobis (isobutyronitrile) in 50 ml of carbon tetrachloride were heated under reflux for 0.5 hour. After cooling the reaction solution to room temperature, a white precipitate was removed by filtration, and the precipitate was washed with diethyl ether.
The solvent of the collected filtrate was distilled off under reduced pressure to give 5- (bromomethyl) -4- (4-fluorophenyl) -2-phenylfuran-
The crude product of ethyl 3-carboxylate was obtained as a yellow liquid. The obtained liquid is washed with N, N-dimethylformamide 40
Then, 9.64 g (118 mmol) of sodium acetate was added, and the mixture was stirred at room temperature overnight. The reaction was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to obtain the desired product.
Light yellow solid Yield 17.24 g Yield 77% Recrystallization from diisopropyl ether gave a light brown powder. mp 114-116 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.02 (3H,
t, J = 7.1 Hz), 2.10 (3H, s), 4.11 (2H, q, J = 7.1
Hz), 5.01 (2H, s), 7.11 (2H, t, J = 8.6 Hz), 7.33
(2H, dd, J = 5.6 Hz, 8.8 Hz), 7.42-7.51 (3H, m),
7.81-7.87 (2H, m); IR (KBr) 1740, 1717, 1508, 124
2, 1223, 1130, 1024, 849, 700 cm ^-1 ; Anal.Calcd fo
r C ₂₂ H ₁₉ FO ₅ : C, 69.10; H, 5.01. Found: C, 69.08;
H, 5.07.3) 4- (4-Fluorophenyl) -5-[(methoxy)
Ethyl methyl] -2-phenylfuran-3-carboxylate Ethyl 5-[(acetoxy) methyl] -4- (4-fluorophenyl) -2-phenylfuran-3-carboxylate 4.02
A mixture of 0 g (10.51 mmol) and 50 ml of a 10% solution of hydrogen chloride in methanol was stirred at room temperature for 2.5 days. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to obtain the desired product. Yellow liquid Yield 2.130 g Yield 57% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.02 (3H, t, J = 7.1 H)
z), 3.37 (3H, s), 4.12 (2H, q, J = 7.2 Hz), 4.33
(2H, s), 7.10 (2H, t, J = 8.8 Hz), 7.36 (2H, dd, J
= 5.4 Hz, 8.8 Hz), 7.40-7.49 (3H, m), 7.81-7.89
(2H, m); IR (neat) 1717, 1508, 1223, 1109, 1096 cm
^-14 ) 4- (4-Fluorophenyl) -5-[(methoxy)
Methyl] -2-phenylfuran-3-carboxylic acid ethyl 4- (4-fluorophenyl) -5-[(methoxy) methyl] -2-phenylfuran-3-carboxylate 1.53
5 g (4.332 mmol) and 4.33 ml (8.66 mmol) of a 2N aqueous sodium hydroxide solution in methanol 2
The mixture was stirred in 0 ml at 70 ° C. for 8 hours. The reaction solution was diluted with water, acidified with dilute hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate =
Crystallized from 3 / 1-ethyl acetate) and hexane to give the desired product. Light brown crystal Yield 1.006 g Yield 71% mp 175-176 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 3.36 (3H,
s), 4.31 (2H, s), 7.08 (2H, t, J = 8.8 Hz), 7.35 (2
H, dd, J = 5.6 Hz, 8.8 Hz), 7.41-7.44 (3H, m), 7.78
-7.85 (2H, m); IR (KBr) 3055-2555, 1686, 1508, 122
^{. 5, 1100, 851 cm -1} ; Anal Calcd for C 19 H 15 FO 4: C, 6
9.93; H, 4.63. Found: C, 69.76; H, 4.71.5) 4- (4-Fluorophenyl) -N-[(1RS, 2
SR) -2- (4-Fluorophenyl) -2-hydroxy-1
-[4- (Trifluoromethyl) benzyl] ethyl] -5-
[(Methoxy) methyl] -2-phenylfuran-3-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propane-1- All 0.228 g (0.728 mmol), 4- (4-fluorophenyl) -5-[(methoxy)
Methyl] -2-phenylfuran-3-carboxylic acid 0.24 g
0.17 g (0.73 mmol) of 1-hydroxybenzotriazole hydrate in 10 ml of acetonitrile was stirred with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0 (0.73 mmol). .1
4 g (0.73 mmol) was added and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product.
White crystals Yield 0.341 g Yield 75% mp 204-206 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.48 (1H,
d, J = 4.0 Hz), 2.51-2.70 (2H, m), 3.43 (3H, s),
4.32 (2H, s), 4.51-4.64 (1H, m), 4.75 (1H, t, J =
3.7 Hz), 5.61 (1H, d, J = 8.4 Hz), 6.90-7.00 (4H,
m), 7.09 (2H, t, J = 8.6 Hz), 7.19 (2H, dd, J = 5.2
Hz, 8.6 Hz), 7.30-7.42 (7H, m), 7.56-7.61 (2H,
m); IR (KBr) 3301, 1636, 1512, 1329, 1223, 1163, 1
123, 1094, 1069, 839 cm ^-1 ; Anal.Calcd for C ₃₅ H ₂₈ F
₅ NO ₄ : C, 67.63; H, 4.54; N, 2.25.Found: C, 67.46;
H, 4.71; N, 2.25.

Example 92 4- [2- (4-Chlorophenyl) ethyl] -N-[(1R
S, 2SR) -2- (4-Fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] benzenecarboxamide (1RS, 2SR) -2-amino-1- (4-fluoro 0.219 g (0.699 mmol) of phenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.18 g of 4- [2- (4-chlorophenyl) ethyl] benzoic acid (0. 0.11 g (0.70 mmol) of 1-hydroxybenzotriazole hydrate in 10 ml of acetonitrile while stirring 0.11 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (70 mmol). (0.70 mmol) and stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane,
The desired product was obtained. White crystals Yield 0.345 g Yield 89
% Mp 211-212 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
56-3.06 (6H, m), 4.53-4.66 (1H, m), 5.03 (1H, t, J
= 3.1 Hz), 5.32 (1H, d, J = 3.6 Hz), 7.01-7.27 (9
H, m), 7.36-7.54 (6H, m), 7.60 (2H, d, J = 8.2 H
z); IR (KBr) 3287,1638, 1541, 1512, 1325, 1229, 11
63, 1115, 1067, 837 cm ^-1 ; Anal.Calcd for C ₃₁ H ₂₆ Cl
F ₄ NO ₂ : C, 66.97; H, 4.71; N, 2.52. Found: C, 66.6
5; H, 4.62; N, 2.51.

Example 93 4- [cis-3- (4-chlorophenyl) oxirane-2-
Yl] -N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] benzenecarboxamide (1RS, 2SR) -2-amino 0.264 g (0.843 mmol) of -1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol, cis-4- [3- (4-chlorophenyl) oxirane 2--2-yl] benzoic acid 0.23 g (0.84 mmol), 1-hydroxybenzotriazole hydrate 0.1
While stirring 3 g (0.84 mmol) in 10 ml of acetonitrile, 0.16 g (0.84 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. . The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White powder Yield 0.
288 g yield 60% mp 162-166 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.91 (2H,
d, J = 7.4 Hz), 3.49 (1H, dd, J = 3.5 Hz, 10.5 H
z), 4.36 (2H, s), 4.46-4.63 (1H, m), 5.05 (1H, t, J
= 3.1 Hz), 6.03-6.08 (1H, m), 7.02-7.23 (10H, m),
7.36-7.43 (4H, m), 7.47 (2H, d, J = 8.0 Hz); IR
(KBr) 3289, 1642, 1541, 1510, 1325, 1229, 1163, 11
11, 1067, 1019, 828 cm ^-1 ; Anal.Calcd for C ₃₁ H ₂₄ Cl
F ₄ NO ₃ : C, 65.32; H, 4.24; N, 2.46. Found: C, 65.2
1; H, 4.01; N, 2.44.

Example 94 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -4- (2-phenyl-1,3-dithiolane-
2-yl) benzenecarboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.218 g (0.696 mmol) ), 4- (2-phenyl-1,3-dithiolan-2-yl)
0.21 g (0.70 mmol) of benzoic acid and 0.11 g (0.70 mmol) of 1-hydroxybenzotriazole hydrate were added to 10 ml of acetonitrile while stirring.
0.13 g (0.70 mmol) of -ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added,
Stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure.
The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White amorphous powder Yield 0.3
63 g Yield 87% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.82-2.99 (2H, m), 3.32-
3.51 (4H, m), 3.56 (1H, d, J = 3.6 Hz), 4.54-4.68
(1H, m), 5.06 (1H, t, J = 3.1 Hz), 6.12 (1H, d, J =
8.4 Hz), 7.08 (2H, t, J = 8.6 Hz), 7.22-7.35 (6H,
m), 7.38-7.57 (7H, m), 7.64 (2H, d, J = 8.4 Hz); I
R (KBr) 3241, 1640, 1624, 1541, 1510, 1325, 1223,
1161, 1119, 1067, 829 cm ^-1 ; Anal.Calcd for C ₃₂ H ₂₇
F ₄ NO ₂ S ₂ : C, 64.31; H, 4.55; N, 2.34. Found: C, 64.2
0; H, 4.44; N, 2.60.

Example 95 5- (4-fluorophenyl) -N-[(1RS, 2SR)
-2- (4-Fluorophenyl) -2-hydroxy-1- [4-
(Trifluoromethyl) benzyl] ethyl] -2-methylfuran-3-carboxamide 1) methyl 5- (4-fluorophenyl) -2-methyl-3-furancarboxylate 1,8-diazabicyclo [5.4.0] ] To a solution of 44.2 g (290 mmol) of 7-undecene in 250 ml of toluene was added 33.7 g (290 mmol) of methyl acetoacetate at room temperature, followed by 50.08 g (290.2 mmol) of 2-chloro-4'-fluoroacetophenone. )
Stirred at room temperature for 1 hour. The obtained toluene solution is washed with water
After washing twice, 5 g of p-toluenesulfonic acid monohydrate was added, and the mixture was heated under reflux for 1 hour under dehydration conditions in a reaction vessel equipped with a Dean-Stark trap. The reaction solution was cooled to room temperature, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 20 / 1-9 / 1), and crystallized from cold methanol to obtain the desired product. Yellow crystal Yield 31.26 g Yield 46% mp 96-97 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.64 (3H,
s), 3.85 (3H, s), 6.81 (1H, s), 7.08 (2H, t, J =
8.8 Hz), 7.60 (2H, dd, J = 5.4 Hz, 9.0 Hz); IR (KB
r) 1705, 1501, 1449, 1233, 1105, 1044, 843, 829, 7
79 cm ^-1 ; Anal.Calcd for C ₁₃ H ₁₁ FO ₃ : C, 66.66; H,
4.73. Found: C, 66.63; H, 4.56.2) 5- (4-fluorophenyl) -2-methyl-3-furancarboxylic acid 5- (4-fluorophenyl) -2-methyl-3-furancarboxylic acid 15.36 g (65.58 mmol) of methyl and 5.25 g (131 mmol) of sodium hydroxide were stirred in 100 ml of methanol-50 ml of water at room temperature overnight. The reaction mixture was concentrated, diluted with water, acidified with concentrated hydrochloric acid, and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the desired product. Pale yellow crystal yield 13.42 g yield 93% mp 217-218 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
65 (3H, s), 6.83 (1H, s), 7.07 (2H, t, J = 8.6 Hz),
7.60 (2H, dd, J = 5.0 Hz, 8.8 Hz); IR (KBr) 3100-
2500, 1694, 1505, 1474, 1233, 774 cm ^-1 ; Anal.Calc
d for C ₁₂ H ₉ FO ₃ : C, 65.46; H, 4.12. Found: C, 65.50;
H, 4.15.3) 5- (4-fluorophenyl) -N-[(1RS, 2
SR) -2- (4-Fluorophenyl) -2-hydroxy-1
-[4- (Trifluoromethyl) benzyl] ethyl] -2-
Methylfuran-3-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.219 g (0.699 mmol ), 5- (4-fluorophenyl) -2-methyl-3-furancarboxylic acid 0.15 g (0.70 mmol), 1-hydroxybenzotriazole hydrate 0.11 g (0.7
(0 mmol) was stirred in 10 ml of acetonitrile, and 0.13 g (0.70 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added thereto, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. 0.273 g of white powder
Yield 76% mp 179-181 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.52 (3H,
s), 2.76-2.99 (2H, m), 3.73 (1H, d, J = 3.6 Hz), 4.
51-4.66 (1H, m), 5.08 (1H, t, J = 3.3 Hz), 5.74 (1
H, d, J = 8.2 Hz), 6.35 (1H, s), 7.03-7.15 (4H,
m), 7.24 (2H, d, J = 8.0 Hz), 7.43 (2H, dd, J = 5.4
Hz, 8.8 Hz), 7.49-7.58 (4H, m); IR (KBr) 3266, 16
40, 1510, 1501, 1327, 1233, 1165, 1123, 1069, 837
cm ^-1

Example 96 4-[(Z) -2- (2-chlorophenyl) ethenyl] -N-
[(1RS, 2SR) -2- (4-fluorophenyl) -2
-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] benzenecarboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] 0.208 g (0.664 mmol) of propan-1-ol, 0.17 g (0.66 mmol) of (Z) -4- [2- (2-chlorophenyl) ethenyl] benzoic acid, 1-hydroxybenzotriazole hydrate 0.10g (0.6
(6 mmol) was stirred in 10 ml of acetonitrile, and 0.13 g (0.66 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added thereto, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. 0.312 g of white powder
Yield 85% mp 153-154 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200MHz) δ 2.
81-2.97 (2H, m), 3.60 (1H, d, J = 3.4 Hz), 4.51-4.6
4 (1H, m), 5.06 (1H, s), 6.09 (1H, d, J = 8.4 Hz),
6.68 (1H, d, J = 12.2 Hz), 6.78 (1H, d, J = 12.4
Hz), 6.99-7.26 (9H, m), 7.36-7.50 (7H, m); IR (KBr)
3291, 1638, 1539, 1514, 1325, 1231,1165, 1119, 10
69 cm ^-1 ; Anal.Calcd for C ₃₁ H ₂₄ ClF ₄ NO ₂ : C, 67.21;
H, 4.37; N, 2.53. Found: C, 66.90; H, 4.01; N, 2.3
9.

Example 97 N-[(1RS, 2SR) -2- (4-fluorophenyl)
2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -2-[(phenylthio) methyl] naphthalene-1-carboxamide 1) Methyl 2-methyl-1-naphthoate 2-methyl-1- Oxalyl chloride 7.10 was added to a solution of 7.579 g (40.70 mmol) of naphthoic acid and 3 drops of N, N-dimethylformamide in 40 ml of tetrahydrofuran.
ml (81.4 mmol) was added dropwise at room temperature and stirred for 0.5 hour. The solvent of the reaction solution was distilled off under reduced pressure to obtain a crude acid chloride product as a liquid. 2.47 ml of methanol (6
1.1 mmol), 0.50 g (4.07 mmol) of 4-N, N-dimethylaminopyridine, 8.51 ml (61.1 mmol) of triethylamine in acetonitrile 5
A solution obtained by dissolving the liquid obtained above in 20 ml of acetonitrile was added dropwise to the 0 ml solution under ice cooling, and the mixture was stirred overnight at room temperature. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6).
/ 1) to obtain the desired product. 7.866 g of pale yellow liquid yield
Yield 97% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.51 (3H, s), 4.04 (3H,
s), 7.32 (1H, d, J = 8.4 Hz), 7.41-7.55 (2H, m),
7.77-7.83 (3H, m); IR (neat) 1728, 1435, 1281, 124
4, 1219, 1138, 1051, 814 cm ^-1 2) Methyl 2-[(phenylthio) methyl] -1-naphthoate 1.277 g of methyl 2-methyl-1-naphthoate (6.3 g)
77 mmol), 1.14 g of N-bromosuccinimide
(6.38 mmol), 10 mg of a solution of 2,2′-azobis (isobutyronitrile) in 10 ml of carbon tetrachloride.
The mixture was refluxed for 5 hours. After cooling the reaction solution to room temperature, a white precipitate was removed by filtration, and the precipitate was washed with diethyl ether. The solvent of the collected filtrate was distilled off under reduced pressure to obtain a crude product of methyl 2-bromomethyl-1-naphthoate as a pale yellow liquid. 0.84 g of thiophenol (7.
65 mmol), 1,8-diazabicyclo [5.4.
0] -7-undecene 1.14 ml (7.65 mmol)
And stirred in 20 ml of acetonitrile at room temperature overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 20 / 1-9 / 1) to obtain the desired product. Yellow liquid Yield 1.606 g Yield 82% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 3.99 (3H, s), 4.32 (2H,
s), 7.14-7.35 (5H, m), 7.40-7.56 (3H, m), 7.79-7.88
(3H, m); IR (neat) 1723, 1437, 1287, 1252,1233, 1
209, 1140, 1036, 747 cm -1 3) 2 - [( phenylthio) methyl] -1-naphthoic acid 2 - [(phenylthio) methyl] -1-methyl-naphthoic acid 1.477g (4.789 mmol) and water 2.50 g (62.5 mmol) of sodium oxide was added to 30 m of methanol.
The mixture was heated under reflux in 20 ml of 1-tetrahydrofuran for 6 hours. The reaction solution was concentrated, diluted with water, acidified with concentrated hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1), and crystallized from diethyl ether-hexane to obtain the desired product. Pale yellow crystal yield 0.880 g yield 62% mp 100-101 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 4.47 (2H,
s), 7.16-7.58 (8H, m), 7.81-7.87 (2H, m), 8.13-8.18
(1H, m); IR (KBr) 3100-2600, 1680, 1283, 1262, 75
6, 733 cm ^-1 ; Anal.Calcd for C ₁₈ H ₁₄ O ₂ S: C, 73.44;
H, 4.79. Found: C, 73.17; H, 4.81. 4) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] Ethyl] -2-[(phenylthio) methyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propane-1 0.20 g (0.830 mmol) of 2-ol (0.24 g (0.83 mmol) of 2-[(phenylthio) methyl] -1-naphthoic acid) 0.13 g (0.83 mmol) of 1-hydroxybenzotriazole hydrate Mmol)
Was stirred in 10 ml of acetonitrile while stirring in 1-ethyl-
0.16 g (0.83 mmol) of 3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at 80 ° C. overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1), and crystallized from ethyl acetate-hexane to obtain the desired product. White powder Yield 0.33
7g Yield 69% mp 102-104 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 2.65-2.91
(2H, m), 3.05 (1H, d, J = 4.0 Hz), 3.97-4.17 (1H,
m), 4.35 (1H, br s), 4.92-5.04 (1H, m), 5.14 (1H,
s), 6.21 (1H, d, J = 8.6 Hz), 6.70 (1H, br s), 7.0
3-7.55 (16H, m), 7.73 (2H, d, J = 8.6 Hz); IR (KBr)
3212, 3056, 1628, 1512, 1329, 1227,1165, 1117, 10
^{. 69, 762 cm -1; Anal} Calcd for C 34 H 27 F 4 NO 2 S: C, 69.
26; H, 4.62; N, 2.38. Found: C, 69.45; H, 4.93; N,
2.22.

Example 98 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -1-methyl-1H-indole-3-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl)- 0.172 g (0.549 mmol) of 3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.10 g of 1-methylindole-3-carboxylic acid
(0.55 mmol) 1-Hydroxybenzotriazole hydrate 84 mg (0.55 mmol) in 10 ml of acetonitrile while stirring 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.11.
g (0.55 mmol) was added and stirred at room temperature overnight.
The reaction solution was diluted with ethyl acetate, washed with an aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1).
-1/1) and crystallized from diethyl ether-hexane to obtain the desired product. White crystals Yield 0.183 g Yield 71% mp 129-131 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.91 (1H,
dd, J = 9.5 Hz, 13.9 Hz), 3.01 (1H, dd, J = 5.2 H
z, 14.8 Hz), 3.76 (3H, s), 4.58-4.71 (1H, m), 4.73
(1H, br s), 5.10 (1H, br s), 5.89 (1H, d, J = 7.8
Hz), 7.05 (2H, t, J = 8.8 Hz), 7.11-7.19 (1H, m),
7.23-7.30 (4H, m), 7.36-7.51 (6H, m); IR (KBr) 332
8, 1624, 1545, 1508, 1325, 1229, 1163, 1128, 1067,
747 cm ^-1 ; Anal.Calcd for C ₂₆ H ₂₂ F ₄ N ₂ O ₂ : C, 66.38;
H, 4.71; N, 5.95. Found: C, 66.27; H, 4.71; N, 5.8
2.

Example 99 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -5-phenylpentanamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- ( 4- (trifluoromethyl) phenyl) -1
To a solution of -propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) was added 5-phenylpentanoic acid (257 mg, 1.44 mmol) and 1-ethyl-.
3- (3-dimethylaminopropyl) carbodiimide hydrochloride (413 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.4)
4 mmol) and stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1), and recrystallized from ethyl acetate-hexane to give the title compound (471 mg, 69%). mp 152-153 ℃ IRνmax ^KBr cm ^-1 : 1647, 1549, 1512. Anal.Calcd for C ₂₇ H ₂₇ F ₄ NO ₂ : C, 68.49; H, 5.75; N,
2.96 Found:. C, 68.39; H, 5.52; N, 2.78 1 H-NMR (CDCl 3) δ: 1.40-1.56 (4H, m), 2.00-2.16 (2
H, m), 2.48-2.64 (2H, m), 2.64-2.94 (2H, m), 3.52
(1H, d, J = 3.8 Hz), 4.32-4.50 (1H, m), 4.90-5.00
(1H, m), 5.36 (1H, d, J = 8.4 Hz), 7.00-7.56 (13H,
m).

Example 100 1,1-Dimethylethyl (1S) -2-(((1RS, 2
SR) -2- (4-Fluorophenyl) -2-hydroxy-1
-((4- (trifluoromethyl) phenyl) methyl) ethyl) amino) -2-oxo-1- (phenylmethyl) ethyl carbamate (1RS, 2SR) -2-amino-1- (4-fluorophenyl)- 3- (4- (trifluoromethyl) phenyl) -1
N-tert-butyloxycarbonyl-L-phenylalanine (382 mg, 1.44) was added to a solution of -propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml).
Mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (413 mg, 2.1
5 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) were added and stirred at room temperature overnight. Dilute the reaction with water (100 ml)
Extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (315 mg, 39%). ^{mp 230-231 ℃ IRνmax KBr cm -1:} 1678, 1659, 1524. 1 H-NMR (CDCl 3) δ: 1.36 (9H, s), 2.60-2.90 (4H, m),
3.78-3.90 (4H, m), 4.10-4.40 (2H, m), 4.60-4.68
(1H, m), 5.50 (1H, d, J = 8.8 Hz), 6.96-7.50 (13H,
m).

Example 101 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -4-methoxynaphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [ 4- (trifluoromethyl) phenyl] propan-1-ol 0.174 g (0.555 mmol), 4-methoxy-1-naphthoic acid 0.11 g (0.5
6 mmol) of 1-hydroxybenzotriazole hydrate (85 mg, 0.56 mmol) in acetonitrile 10
While stirring in 0.1 ml, 0.11 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.
56 mmol) and stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals
Yield 0.209 g Yield 76% mp 227-228 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
88-3.20 (2H, m), 4.00 (3H, s), 4.60-4.75 (1H, m),
4.93 (1H, t, J = 4.2 Hz), 5.49 (1H, d, J = 3.6 H
z), 6.72 (1H, d, J = 8.0 Hz), 7.03-7.19 (3H, m),
7.29-7.71 (10H, m), 8.19 (1H, d, J = 7.8 Hz); IR (K
Br) 3281, 1636, 1588, 1530, 1512, 1327,1265, 1167,
1125, 1069, 839 cm ^-1 ; Anal.Calcd for C ₂₈ H ₂₃ F ₄ N
O ₃ : C, 67.60; H, 4.66; N, 2.82. Found: C, 67.58; H,
4.83; N, 2.73.

Example 102 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -3-nitronaphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [ 4- (trifluoromethyl) phenyl] propan-1-ol 0.174 g (0.555 mmol), 3-nitro-1-naphthoic acid 0.12 g (0.56 g)
Mmol) 1-hydroxybenzotriazole hydrate (85 mg, 0.56 mmol) in acetonitrile 10m
1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.11 g (0.5
6 mmol) and stirred at room temperature overnight. Dilute the reaction solution with ethyl acetate and wash with aqueous sodium hydrogen carbonate,
After drying over anhydrous magnesium sulfate and passing through silica gel,
The solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. Light yellow crystal Yield 0.239 g Yield 84% mp 231-232 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
92 (1H, dd, J = 11.4 Hz, 14.0 Hz), 3.20 (1H, dd, J
= 3.6 Hz, 13.0 Hz), 4.65-4.79 (1H, m), 4.94 (1H,
t, J = 4.5 Hz), 5.53 (1H, d, J = 4.4 Hz), 7.10 (2
H, t, J = 8.6 Hz), 7.36-7.66 (9H, m), 7.95 (1H, d,
J = 2.6 Hz), 8.03 (1H, d, J = 8.0 Hz), 8.18 (1H,
d, J = 9.2 Hz), 8.78 (1H, d, J = 2.2 Hz); IR (KBr)
3283, 1642, 1537, 1327, 1123, 1169, 835 cm ^-1 ; Ana
_{. l Calcd for C 27 H 20} F 4 N 2 O 4: C, 63.28; H, 3.93; N,
5.47. Found: C, 63.23; H, 3.65; N, 5.73.

Example 103 4-[[[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl)
Methyl [benzyl] ethyl] amino] carbonyl] -1-naphthoate (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.287 g (0.916 mmol) 4- (methoxycarbonyl) -1-naphthoic acid
21 g (0.92 mmol) of 1-hydroxybenzotriazole hydrate 0.14 g (0.92 mmol) are stirred in 10 ml of acetonitrile in 1-ethyl-3-ethyl.
0.18 g (0.92 mmol) of (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White amorphous powder Yield 0.449 g Yield 93% ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.92 (1H, dd, J
= 11.0 Hz, 14.0 Hz), 3.17 (1H, dd, J = 3.2 Hz, 14.
0 Hz), 3.99 (3H, s), 4.72-4.85 (1H, m), 4.93 (1H,
d, J = 5.4 Hz), 5.35 (1H, br s), 7.09 (2H, t, J =
8.6 Hz), 7.13 (1H, d, J = 7.4 Hz), 7.26-7.42 (4H,
m), 7.52-7.60 (5H, m), 7.86 (1H, d, J = 9.2 Hz), 8.
03 (1H, d, J = 7.2 Hz), 8.77 (1H, d, J = 8.8 Hz);
IR (KBr) 3283, 1721, 1640, 1512, 1327, 1254, 1163,
1123, 1069, 839 cm ^-1 ; Anal.Calcd for C ₂₉ H ₂₃ F ₄ NO ₄ :
C, 66.28; H, 4.41; N, 2.67. Found: C, 66.06; H,
4.49; N, 2.58.

Example 104 N1-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl)
Benzyl] ethyl] naphthalene-1,4-dicarboxamide 1) 4- (aminocarbonyl) -1-naphthoic acid 4- (aminocarbonyl) -1-methyl naphthoate 0.4
99 g (2.177 mmol) of methanol 20 ml
6.53 ml (6.53 mmol) of a 1N aqueous sodium hydroxide solution was added to a 20 ml solution of tetrahydrofuran, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated, diluted with water, and acidified with diluted hydrochloric acid. The resulting precipitate was collected by filtration and washed with water and hexane to obtain the desired product. White powder Yield 0.340 g Yield 73% mp 294-295 ° C; ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ 7.58-7.7
1 (3H, m), 7.76 (1H, br s), 8.10-8.13 (2H, m), 8.2
5-8.30 (1H, m), 8.84-8.89 (1H, m); IR (KBr) 3191, 3
300-2500, 1694, 1466, 1410, 1368, 1325, 1294, 126
4, 770 cm ^-1 ; Anal.Calcd for C ₁₂ H ₉ NO ₃ : C, 66.97;
H, 4.22; N, 6.51. Found: C, 66.85; H, 4.11; N, 6.6
8.2) N1-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] naphthalene-1,4-dicarboxamide (1RS , 2SR) -2-Amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.154 g (0.492 mmol), 4- (aminocarbonyl) -1-Naphthoic acid 0.1
1 g (0.49 mmol) of 1-hydroxybenzotriazole hydrate (75 mg, 0.49 mmol) is stirred in 10 ml of acetonitrile with stirring in 1-ethyl-3- (3- (3-methyl-3-benzotriazole).
Dimethylaminopropyl) carbodiimide hydrochloride 94
mg (0.49 mmol) was added and stirred at room temperature overnight. The reaction solution was diluted with water, and the resulting precipitate was collected by filtration.
The desired product was obtained by washing with water and diethyl ether. White powder Yield 0.221 g Yield 88% mp 255-256 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
86-2.97 (1H, m), 3.15-3.24 (1H, m), 4.67-4.81 (1H,
m), 4.89 (1H, t, J = 5.0 Hz), 5.46 (1H, d, J = 4.0
Hz), 6.89 (1H, br s), 7.08 (2H, t, J = 8.8 Hz),
7.11 (1H, d, J = 7.0 Hz), 7.29-7.58 (11H, m), 7.94
(1H, d, J = 9.2 Hz), 8.32 (1H, d, J = 8.4 Hz); IR
(KBr) 3283, 1638, 1510, 1329, 1161, 1123, 1069, 83
7 cm ^-1 ; Anal.Calcd for C ₂₈ H ₂₂ F ₄ N ₂ O ₃・ 0.5H ₂ O: C, 6
4.74; H, 4.46; N, 5.39. Found: C, 64.60; H, 4.72;
N, 5.42.

Example 105 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4- (hydroxymethyl)-
1-Naphthalenecarboxamide 1) To a solution of methyl 4- (hydroxymethyl) -1-naphthalenecarboxylate (700 mg, 3.24 mmol) in methanol (10 ml), 1 N aqueous sodium hydroxide solution (3.24 ml, 3.24 mmol) Was added and stirred at room temperature overnight. 1N hydrochloric acid (5 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 4- (hydroxymethyl) -1-naphthalenecarboxylic acid (570 mg, 87%). ^{mp 183-184 ℃ IRνmax KBr cm -1:} 1694, 1593, 1518. 1 H-NMR (CDCl 3) δ: 5.02 (2H, s), 7.54-7.70 (3H, m),
8.04-8.18 (2H, m), 8.86-8.98 (1H, m). 2) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (4- (trifluoromethyl) phenyl ) -1-Propanol (300 mg, 0.96 mmol) in acetonitrile (30 ml) was added to a solution of 4- (hydroxymethyl) -1-naphthalenecarboxylic acid (194 mg,
0.96 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (275 m
g, 1.44 mmol) and 1-hydroxy-1H-benzotriazole (147 mg, 0.96 mmol) were added and stirred at room temperature overnight. The reaction solution was water (100 ml)
And extracted with ethyl acetate (100 ml × 2).
1N hydrochloric acid, 1N aqueous sodium hydroxide solution,
The extract was washed successively with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) and recrystallized from ethyl acetate-hexane to give the title compound (3
(65 mg, 77%). ^{. mp 202-203 ℃ IRνmax KBr cm -1} : 1638, 1618, 1605, 1537. Anal Calcd for C 28 H 23 F 4 NO 3: C, 67.60; H, 4.66; N,
2.82 Found: C, 67.41; H, 4.64; N, 2.53. ¹ H-NMR (CDCl ₃ ) δ: 1.88 (1H, br s), 2.87 (1H, dd, J
= 14.4, 10.6 Hz), 3.09 (1H, dd, J = 14.4, 4.4 H
z), 4.72-4.90 (1H, m), 5.02-5.16 (3H, m), 5.94 (1H,
d, J = 8.0 Hz), 7.04-7.66 (13H, m), 8.02 (1H, d,
J = 8.4 Hz).

Example 106 4-[[[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl)
Benzyl] ethyl] amino] carbonyl] -1-naphthoic acid 4-[[[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl)
1.64 ml (1.64 mmol) of a 1N aqueous sodium hydroxide solution in a solution of 0.216 g (0.411 mmol) of methyl benzyl [ethyl] amino] carbonyl] -1-naphthoate in 5 ml of methanol and 5 ml of tetrahydrofuran.
Was added and stirred at room temperature for 5 hours. The reaction solution was concentrated, diluted with water, and acidified with diluted hydrochloric acid. The resulting precipitate was collected by filtration and washed with water and hexane to obtain the desired product. White powder Yield 0.148 g Yield 70% mp 209-212 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
92 (1H, dd, J = 11.2 Hz, 14.0 Hz), 3.14 (1H, dd, J
= 3.1 Hz, 13.7 Hz), 4.71-4.86 (1H, m), 4.95 (1H, d,
J = 3.6 Hz), 5.31 (1H, br s), 7.09 (2H, t, J = 8.
8 Hz), 7.16 (1H, d, J = 7.4 Hz), 7.31-7.41 (4H,
m), 7.50-7.59 (5H, m), 7.79 (1H, d, J = 9.8 Hz), 8.
08 (1H, d, J = 7.4 Hz), 8.91 (1H, δ, J = 8.8 H
z); IR (KBr) 3281, 1690, 1640, 1532, 1512, 1329, 12
33, 1165, 1125, 1069, 837 cm ^-1 ; Anal.Calcd for C
₂₈ H ₂₁ F ₄ NO ₄・ 1.0H ₂ O: C, 63.52; H, 4.38; N, 2.65. Fou
nd: C, 63.45; H, 4.53; N, 2.49.

Example 107 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -3-phenoxybenzamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (4 -(Trifluoromethyl) phenyl) -1
To a solution of -propanol (400 mg, 1.28 mmol) in acetonitrile (20 ml) was added 3-phenoxybenzoic acid (274 mg, 1.28 mmol) and 1-ethyl-
3- (3-dimethylaminopropyl) carbodiimide hydrochloride (368 mg, 1.92 mmol) and 1-hydroxy-1H-benzotriazole (196 mg, 1.2
(8 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (400 m
g, 61%). ^{. mp 144-145 ℃ IRνmax KBr cm -1} : 1644, 1580, 1510, 1491, 1481. Anal Calcd for C 29 H 23 F 4 NO 3 · 0.1H 2 O: C, 68.13; H,
4.57; N, 2.74 Found:. C, 67.85; H, 4.51; N, 2.53 1 H-NMR (CDCl 3) δ: 2.80-3.00 (2H, m), 3.30-3.70 (1
H, m), 4.50-4.64 (1H, m), 5.05 (1H, d, J = 3.2 H
z), 6.11 (1H, d, J = 8.6 Hz), 6.96-7.52 (17H, m).

Example 108 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4-phenoxybenzamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (4 -(Trifluoromethyl) phenyl) -1
To a solution of -propanol (400 mg, 1.28 mmol) in acetonitrile (20 ml) was added 4-phenoxybenzoic acid (274 mg, 1.28 mmol) and 1-ethyl-
3- (3-dimethylaminopropyl) carbodiimide hydrochloride (368 mg, 1.92 mmol) and 1-hydroxy-1H-benzotriazole (196 mg, 1.2
(8 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (451 m
g, 69%). mp 186-187 ℃ IRνmax ^KBr cm ^-1 : 1622, 1609, 1590, 1532, 1510, 150
1, 1489. ¹ H-NMR (CDCl ₃ ) δ: 2.80-3.02 (2H, m), 3.80-4.00 (1
H, m), 4.50-4.70 (1H, m), 5.06 (1H, d, J = 3.2 H
z), 6.17 (1H, d, J = 8.4 Hz), 6.90-7.60 (17H, m).

Example 109 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -3,3,3-trifluoropropionamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3 -[4- (trifluoromethyl) phenyl] propan-1-ol 0.166 g (0.530 mmol), 3,3,3-trifluoropropionic acid 68 mg
(0.53 mmol) 1-Hydroxybenzotriazole hydrate 81 mg (0.53 mmol) in 10 ml of acetonitrile while stirring 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.10.
g (0.53 mmol) was added and stirred at room temperature overnight.
The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from hexane to obtain the desired product. White crystals Yield 0.185 g Yield 83% mp 179-180 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
79-2.83 (2H, m), 2.90 (1H, d, J = 10.6 Hz), 3.01 (1
H, d, J = 10.6 Hz), 4.35-4.49 (1H, m), 4.64 (1H, d,
J = 3.2 Hz), 4.93 (1H, t, J = 3.4 Hz), 7.06 (2H,
t, J = 8.6 Hz), 7.17-7.21 (3H, m), 7.40-7.47 (4H,
m); IR (KBr) 3308, 1663, 1514, 1327,1238, 1175, 11
13, 1069, 831 cm ^-1 ; Anal.Calcd for C ₁₉ H ₁₆ F ₇ NO ₂ :
C, 53.91; H, 3.81; N, 3.31. Found: C, 53.84; H, 3.
61; N, 3.13.

Example 110 2-Cyclopentyl-N-[(1RS, 2SR) -2- (4-
Fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -2-phenylacetamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4 -(Trifluoromethyl) phenyl] propan-1-ol 0.156 g (0.498 mmol), 2-cyclopentyl-2-phenylacetic acid 0.10 g
(0.50 mmol) 1-hydroxybenzotriazole hydrate (76 mg, 0.50 mmol) was stirred in 10 ml of acetonitrile while stirring 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide.hydrochloride 95 mg.
(0.50 mmol) and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.208 g Yield 84% mp 201-202 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.73-1.08
(2H, m), 1.30-1.70 (6H, m), 2.38-2.93 (4H, m), 3.4
3 (0.5H, d, J = 3.6 Hz), 3.53 (0.5H, d, J = 3.6 H
z), 4.34-4.48 (1H, m), 4.80-4.85 (1H, m), 5.23 (0.
5H, br d, J = 8.4Hz), 5.34 (0.5H, br d, J = 6.6H)
z), 6.88-7.31 (12H, m), 7.43 (1H, d, J = 8.0 Hz); I
R (KBr) 3316, 2957, 1645, 1530, 1514, 1327, 1233,
1167, 1123, 1069, 831 cm ^-1 ; Anal.Calcd for C ₂₉ H ₂₉
F ₄ NO ₂ : C, 69.73; H, 5.85; N, 2.80. Found: C, 69.7
1; H, 5.95; N, 2.63.

Example 111 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) ben
[Zyl] ethyl] -3-nitro-5,6,7,8-tetrahydride
Lonaphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophene)
Nyl) -3- [4- (trifluoromethyl) phenyl] p
Lopan-1-ol 0.150g (0.479mm
Le) 3-nitro-5,6,7,8-tetrahydronaphtha
Ren-1-carboxylic acid (Chem. Pharm. Bul)
l. , 32, 3968-80 (1984)) 0.1
1 g (0.48 mmol), 1-hydroxybenzotri
73 mg (0.48 mmol) of azole hydrate was
While stirring in 10 ml of nitrile, 1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide hydrochloride 92
mg (0.48 mmol) and stirred at room temperature overnight.
Was. Dilute the reaction solution with ethyl acetate and add sodium bicarbonate
Wash with aqueous solution, dry with anhydrous magnesium sulfate, silica gel
Then, the solvent was distilled off under reduced pressure. The resulting residue
Concluded from ethyl acetate-diisopropyl ether-hexane
Crystallization gave the desired product. 0.180 g of white crystals
 Yield 73% mp 216-217 ° C;¹H-NMR (CDCl_Three-DMSO-d₆, 200MHz) δ 1.
49-1.78 (4H, m), 1.97-2.13 (1H, m), 2.36-2.52 (1H,
 m), 2.77-2.93 (3H, m), 3.02 (1H, dd, J = 4.3 Hz,
14.5 Hz), 4.58-4.73 (1H, m), 4.96 (1H, t, J = 4.2
Hz), 5.28 (1H, d, J = 3.6 Hz), 7.08 (2H, t, J = 8.
8 Hz), 7.30-7.56 (6H, m), 7.72 (1H, d, J = 2.2 Hz),
 7.89 (1H, d, J = 2.2 Hz); IR (KBr) 3260, 1642, 15
34, 1514, 1346, 1327, 1231, 1165, 1123, 1067, 837 c
m^-1; Anal. Calcd for C₂₇H_{twenty four}F_FourN _TwoO_Four: C, 62.79; H, 4.
68; N, 5.42. Found: C, 62.68; H, 4.45; N, 5.33.

Example 112 2-Benzyl-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -3,3 -Dimethylbutyramide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.264 g (0.843 mmol), 2-benzyl-3,3-dimethylbutanoic acid 0.17
g (0.84 mmol), 0.10 g (0.84 mmol) of 4-N, N-dimethylaminopyridine and 0.13 g (0.84 mmol) of 1-hydroxybenzotriazole hydrate were stirred in 10 ml of acetonitrile. 1-
0.16 g (0.84 mmol) of ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added,
Stirred at 60 ° C. for 3 days. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.206 g Yield 49% mp 175-176 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.76 (3.5
H, s), 0.90 (5.5 H, s), 1.80-1.93 (1H, m), 2.15-3.0
2 (5H, m), 4.25-4.40 (1H, m), 4.48-4.53 (1H, m), 4.
92-5.04 (1H, m), 6.76-7.45 (13H, m); IR (KBr) 355
1, 2967, 1651, 1507, 1333, 1154, 1127, 1123, 1069,
^{. 835 cm -1; Anal Calcd for} C 29 H 31 F 4 NO 2: C, 69.45;
H, 6.23; N, 2.79.Found: C, 69.09; H, 6.28; N, 2.8
0.

Example 113 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -3,4-dihydro-2H-1,5-benzodioxepin-6-carboxamide 1) Methyl 2,3-dihydroxybenzoate 5.029 g (32.6) of 2,3-dihydroxybenzoic acid
3 mmol) in 80% methanol solution of 10% hydrogen chloride
Heated to reflux in 1 L for 3 days. The solvent of the reaction solution was distilled off under reduced pressure, diluted with water, and extracted with ethyl acetate. The obtained ethyl acetate solution was dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from cold diisopropyl ether-hexane to obtain the desired product. Brown crystals Yield 4.439 g Yield 81% mp 77-78 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 3.96 (3H,
s), 5.65 (1H, s), 6.80 (1H, t, J = 8.1 Hz), 7.11
(1H, dd, J = 1.5 Hz, 7.7 Hz), 7.37 (1H, dd, J = 1.1
Hz, 8.1 Hz), 10.89 (1H, s); IR (KBr) 3465, 3100 2
850, 1674, 1468, 1437, 1321, 1269, 1194, 1152, 107
6, 1009, 837, 758 cm ^-1 ; Anal.Calcd forC ₈ H ₈ O ₄ : C,
57.14; H, 4.80. Found: C, 56.93; H, 4.94. 2) Methyl 3,4-dihydro-2H-1,5-benzodioxepine-6-carboxylate Methyl 2,3-dihydroxybenzoate 870 g (11.12 mmol), 1,3-
2.25 g (11.1 mmol) of dibromopropane and 6.15 g (44.5 mmol) of potassium carbonate were added to N, N-
Stirred in 60 ml of dimethylformamide overnight. The reaction solution was poured into water and extracted twice with ethyl acetate.
The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-3 /
1) The desired product was obtained. Colorless liquid Yield 1.711 g Yield 74% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.18-2.29 (2H, m), 3.89
(3H, s), 4.25 (2H, t, J = 5.7 Hz), 4.30 (2H, t, J =
5.7 Hz), 6.95 (1H, t, J = 7.9 Hz), 7.12 (1H, dd,
J = 1.8 Hz, 8.0 Hz), 7.36 (1H, dd, J = 1.8 Hz, 7.8
Hz); IR (neat) 2953, 1732, 1478, 1454, 1296, 1262,
1225, 1138, 1080, 1044 cm ^-1 3) 3,4-dihydro-2H-1,5-benzodioxepin-6-carboxylic acid 3,4-dihydro-2H-1,5-benzodioxepin- 6-
1.615 g (7.757 mmol) of methyl carboxylate
15.5 ml of a 1N aqueous sodium hydroxide solution (15.
5 mmol) and stirred at room temperature overnight. The reaction solution was concentrated, diluted with water, acidified with dilute hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from hexane to obtain the desired product. White crystals Yield 1.37
6g Yield 91% mp 68-70 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 2.29-2.40 (2
H, m), 4.30 (2H, t, J = 5.8 Hz), 4.52 (2H, t, J =
5.6 Hz), 7.09 (1H, t, J = 7.9 Hz), 7.24 (1H, dd, J
= 2.0 Hz, 8.2 Hz), 7.85 (1H, dd, J = 1.8 Hz, 7.6 H
z); IR (KBr) 3171, 1725, 1478, 1348, 1264, 1022, 7
52 cm ^-1 ; Anal.Calcd for C ₁₀ H ₁₀ O ₄ : C, 61.85; H, 5.1
9. Found: C, 61.77; H, 5.49.4) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -3,4-dihydro-2H-1,5
-Benzodioxepin-6-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol 0.262 g (0 0.836 mmol), 0.16 g (0.84 mmol) of 3,4-dihydro-2H-1,5-benzodioxepin-6-carboxylic acid, 1
-Hydroxybenzotriazole hydrate 0.13g
(0.84 mmol) was stirred in 10 ml of acetonitrile, and 0.16 g (0.84 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added thereto, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.361 g Yield 88% mp 155-156 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.05-2.16
(2H, m), 2.93-2.97 (2H, m), 3.69-3.86 (2H, m), 4.0
9-4.20 (3H, m), 4.55-4.67 (1H, m), 5.10 (1H, t, J =
3.3 Hz), 6.98-7.15 (4H, m), 7.26 (2H, d, J = 7.8
Hz), 7.38-7.52 (4H, m), 7.76 (1H, dd, J = 1.8 Hz,
7.8 Hz), 7.92 (1H, br d, J = 7.8 Hz); IR (KBr) 327
9, 1636, 1541, 1512, 1325, 1264, 1231, 1169, 1121,
1069, 1044, 837 cm ^-1 ; Anal.Calcd for C ₂₆ H ₂₃ F ₄ N
O ₄ : C, 63.80; H, 4.74; N, 2.86. Found: C, 63.63;
H, 4.72; N, 2.80.

Example 114 N-[(1RS, 2SR) -2- (4-fluorophenyl)
Benzyl-2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] carbamate (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl ) Phenyl] propan-1-ol 0.159 g (0.508 mmol)
And 85 mg (1.02 mmol) of sodium hydrogen carbonate in 10 ml of tetrahydrofuran while adding 0.09 ml (0.61 mmol) of benzyl chlorocarbonate,
Stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure.
The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.19
0 g Yield 84% mp 151-152 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.68-2.91
(3H, m), 4.08-4.22 (1H, m), 4.81 (1H, br d, J = 8.
8 Hz), 4.94 (1H, br s), 5.00 (2H, s), 7.06 (2H, t,
J = 8.6 Hz), 7.17-7.40 (9H, m), 7.48 (2H, d, J =
7.8 Hz); IR (KBr) 3337, 1694, 1539, 1327, 1163, 11
21, 1069, 829 cm ^-1 ; Anal.Calcd for C _{2 4} H ₂₁ F ₄ NO ₃ :
C, 64.43; H, 4.73; N, 3.13. Found: C, 64.46; H, 4.
77; N, 2.94.

Example 115 N-[(1RS, 2SR) -2- (4-fluorophenyl)
Ethyl-2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] carbamate (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl ) Phenyl] propan-1-ol 0.401 g (1.280 mmol)
And sodium hydrogencarbonate 0.22 g (2.56 mmol)
Was stirred in 10 ml of tetrahydrofuran-2 ml of water, 0.15 ml (1.54 mmol) of ethyl chlorocarbonate was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. 0.41 white crystals
3g Yield 84% mp 143-144 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.15 (3H,
t, J = 7.0 Hz), 2.67-2.95 (3H, m), 3.93-4.20 (3H,
m), 4.71 (1H, d, J = 8.6 Hz), 4.95 (1H, s), 7.08 (2
H, t, J = 8.6 Hz), 7.21 (2H, d, J = 8.0 Hz), 7.39
(2H, dd, J = 5.5 Hz, 8.5 Hz), 7.51 (2H, d, J = 8.0
Hz); IR (KBr) 3318, 1690, 1547, 1329, 1163, 1117,
1069, 829 cm ^-1 ; Anal.Calcd for C ₁₉ H ₁₉ F ₄ NO ₃ : C, 5
9.22; H, 4.97; N, 3.63. Found: C, 59.28; H, 5.10;
N, 3.63.

Example 116 N-[(1RS, 2SR) -2- (4-fluorophenyl)
Neopentyl 2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] carbamate (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethyl ) Phenyl] propan-1-ol 0.171 g (0.546 mmol)
Then, 0.10 ml (0.65 mmol) of neopentyl chlorocarbonate was added while stirring in 10 ml of tetrahydrofuran and 92 mg (1.09 mmol) of sodium hydrogencarbonate, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from hexane to obtain the desired product. White crystals Yield 0.168 g Yield 72% mp 112-113 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.82 (9H,
s), 2.66-2.92 (3H, m), 3.67 (2H, br s), 4.14 (1H, b
rs), 4.72 (1H, br d, J = 8.2 Hz), 4.95 (1H, br
s), 7.08 (2H, t, J = 8.6 Hz), 7.22 (2H, d, J = 8.0
Hz), 7.39 (2H, dd, J = 5.2 Hz, 8.4 Hz), 7.50 (2H,
d, J = 8.0 Hz); IR (KBr) 3326, 2967, 1690, 1545,
1327, 1127, 1069, 833 cm ^-1 ; Anal.Calcd for C ₂₂ H ₂₅
F ₄ NO ₃ : C, 61.82; H, 5.90; N, 3.28. Found: C, 61.4
7; H, 5.85; N, 3.04.

Example 117 N-((1RS, 2SR) -2- (4-fluorophenyl)
2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -1-naphthalenesulfonamide (1RS, 2SR) -1- (4-fluorophenyl) -1-
Hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (150 mg, 0.43
1 mmol) and 1-naphthalenesulfonyl chloride (107 mg, 0.47 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) were added to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give the title compound (109 mg, 50 mg).
%). mp 176-177 ℃ IRν max ^KBr cm ^-1 : 1508, 1325, 1223, 1161, 1129. Anal.Calcd for C ₂₆ H ₂₁ F ₄ NO ₃ S: C, 62.02; H, 4.20;
N, 2.78 Found:. C, 61.73; H, 4.20; N, 2.74 1 H-NMR (CDCl 3) δ: 2.40-2.62 (2H, m), 2.95 (1H, br
s), 3.56-3.70 (1H, m), 5.15 (2H, s), 6.60 (2H, d, J
= 8.0 Hz), 6.79 (2H, d, J = 8.0 Hz), 6.90-7.04 (2
H, m), 7.20-7.40 (3H, m), 7.40-7.56 (2H, m), 7.70-
7.84 (1H, m), 7.91 (1H, d, J = 8.0 Hz), 8.05 (1H,
d, J = 8.0 Hz), 8.20-8.30 (1H, m).

Example 118 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -N '-(1-naphthalenyl) urea (1RS, 2SR) -1- (4-fluorophenyl) -1-
Hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (150 mg, 0.43
Mmol) in acetonitrile (10 ml) in triethylamine (0.089 ml, 0.64 mmol) and 1-naphthyl isocyanate (0.062 ml, 0.
43 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (50 ml) and ethyl acetate (50 ml × 2)
Extracted. The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (135 mg, 65 mg).
%). mp 222-223 ° C IRν max ^KBr cm ^-1 : 1661, 1638, 1557, 1510. Anal.Calcd for C ₂₇ H ₂₂ F ₄ N ₂ O ₂ : C, 67.21; H, 4.60;
N, 5.81 Found:. C, 67.02; H, 4.47; N, 5.78 1 H-NMR (CDCl 3) δ: 2.47 (1H, dd, J = 14.4, 10.0 H
z), 2.78 (1H, dd, J = 14.4, 3.6 Hz), 4.20-4.40 (3
H, m), 4.91 (1H, br s), 6.36 (1H, s), 6.92-7.10 (5
H, m), 7.22-7.40 (5H, m), 7.40-7.58 (2H, m), 7.74-
7.94 (3H, m).

Example 119 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -N '-(4- (trifluoromethyl) phenyl) urea (1RS, 2SR) -1- (4-fluorophenyl) ) -1-
Hydroxy-3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (150 mg, 0.43
To a solution of (mmol) in acetonitrile (10 ml) were added triethylamine (0.089 ml, 0.64 mmol) and 4-trifluoromethylphenylisocyanate (0.061 ml, 0.43 mmol), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (139 mg, 65%). mp 160-161 ℃ IRν max ^KBr cm ^-1 : 1659, 1605, 1557, 1508. Anal.Calcd for C ₂₄ H ₁₉ F ₇ N ₂ O ₂ : C, 57.60; H, 3.83;
N, 5.60 Found:. C, 57.61; H, 3.59; N, 5.65 1 H-NMR (CDCl 3) δ: 2.60-2.92 (2H, m), 3.50 (1H, br
s), 4.22-4.50 (1H, m), 4.80 (1H, d, J = 8.0 Hz), 5.
01 (1H, s), 6.75 (1H, s), 7.00-7.18 (2H, m), 7.18-
7.60 (10H, m).

Example 120 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -N- (1-naphthalenylmethyl) acetamide 1) (4RS, 5SR) -5- (4-fluorophenyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidine-2-one (1 g, 2.9
5 mmol) of N, N-dimethylformamide (10 m
l) 60% sodium hydride (142 mg, 3.
(54 mmol) and stirred at room temperature for 15 minutes. 1-Naphthylmethyl chloride (480 ml, 3.25) was added to the reaction mixture.
Mmol) and stirred for 1 hour. The reaction solution was diluted with water (10
0 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
4: 1) and recrystallized from diisopropyl ether-hexane to give (4RS, 5SR) -5- (4-fluorophenyl) -3- (1-naphthalenylmethyl) -4-.
((4- (trifluoromethyl) phenyl) methyl)-
1,3-oxazolidine-2-one (1.23 g, 87
%). mp 136-137 ℃ IRνmax ^KBr cm ^-1 : 1748, 1609. Anal.Calcd for C ₂₈ H ₂₁ F ₄ NO ₂ : C, 70.14; H, 4.41; N,
2.92 Found:. C, 70.15; H, 4.23; N, 2.78 1 H-NMR (CDCl 3) δ: 2.34 (1H, dd, J = 14.4, 8.0 Hz),
2.81 (1H, dd, J = 14.4, 5.2 Hz), 3.70-3.84 (1H,
m), 4.24 (1H, d, J = 15.2 Hz), 5.28 (1H, d, J = 7.6
Hz), 5.40 (1H, d, J = 15.2 Hz), 6.48 (2H, d, J =
8.2 Hz), 6.76-7.10 (5H, m), 7.14-7.56 (5H, m), 7.7
0-8.00 (3H, m). 2) (4RS, 5SR) -5- (4-fluorophenyl) -3- (1-naphthalenylmethyl) -4-((4- (trifluoromethyl) phenyl) To a solution of (methyl) -1,3-oxazolidin-2-one (100 mg, 0.21 mmol) in ethanol (2 ml) was added an 8N aqueous sodium hydroxide solution (130 ml), and the mixture was heated under reflux for 4 hours. The reaction solution was diluted with water (50 ml), and ethyl acetate (50 ml ×
Extracted in 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) and recrystallized from diisopropyl ether-hexane to give (1RS, 2SR) -1- (4
-Fluorophenyl) -2-((1-naphthalenylmethyl)
Amino) -3- (4- (trifluoromethyl) phenyl)-
1-propanol (29.6 mg, 31%) was obtained. mp 94-95 ℃ IRνmax ^KBr cm ^-1 : 1605, 1510, 1325. Anal.Calcd for C ₂₇ H ₂₃ F ₄ NO: C, 71.51; H, 5.11; N,
3.09 Found:. C, 71.40; H, 5.07; N, 2.98 1 H-NMR (CDCl 3) δ: 2.45 (2H, d, J = 7.4 Hz), 3.02-
3.14 (1H, m), 3.71 (1H, br s), 4.03 (1H, d, J = 13.
2 Hz), 4.33 (1H, d, J = 13.2 Hz), 5.06 (1H, d, J =
3.6 Hz), 6.92 (2H, d, J = 7.6 Hz), 7.00-7.16 (2H,
m), 7.20-7.58 (9H, m), 7.70-7.88 (2H, m). 3) (1RS, 2SR) -1- (4-fluorophenyl) -2-((1-naphthalenylmethyl) amino ) -3-
To a solution of (4- (trifluoromethyl) phenyl) -1-propanol (100 mg, 0.22 mmol) in ethyl acetate (5 ml) was added acetyl chloride (225 ml, 3.25 ml).
3 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (45 mg, 41%). ^{IRνmax KBr cm -1: 1622, 1508} , 1456. 1 H-NMR (CDCl 3) δ: 2.32 (3H, s), 2.73 (1H, d, J = 1
1.0 Hz), 3.32-3.76 (3H, m), 4.76 (1H, s), 4.82 (1
H, d, J = 15.6 Hz), 6.50-6.64 (2H, m), 6.70-6.84
(2H, m), 7.00-7.18 (3H, m), 7.40-7.60 (6H, m), 7.8
2-8.00 (2H, m).

Example 121 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -N-methyl-1-naphthalenecarboxamide 1) (4RS, 5SR) -5- (4-fluorophenyl) -4- ((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidin-2-one (5 g, 14.
7 mmol) of N, N-dimethylformamide (30 m
l) Add 60% sodium hydride (710 mg, 1
(7.7 mmol) and stirred at room temperature for 15 minutes. Methyl iodide (5 ml, 80 mmol) was added to the reaction solution,
Stir for 1 hour. Dilute the reaction with water (300 ml)
Extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (4RS, 5SR) -5- (4
-Fluorophenyl) -3-methyl-4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidin-2-one (4.76 g, 91%) was obtained. mp 77-78 ℃ IRνmax ^KBr cm ^-1 : 1759, 1609, 1514. Anal.Calcd for C ₁₈ H ₁₅ F ₄ NO ₂ : C, 61.19; H, 4.28; N,
3.96 Found:. C, 61.25; H, 4.21; N, 3.96 1 H-NMR (CDCl 3) δ: 2.45 (1H, dd, J = 14.2, 7.2 Hz),
2.77 (1H, dd, 14.2, 7.2 Hz), 4.30 (1H, q, J = 6.6
Hz), 5.59 (1H, d, J = 8.0 Hz), 6.92 (2H, d, J = 8.
0 Hz), 6.94-7.08 (2H, m), 7.10-7.20 (2H, m), 7.44
(2H, d, J = 8.0 Hz). 2) (4RS, 5SR) -5- (4-fluorophenyl) -3-methyl-4-((4- (trifluoromethyl) phenyl) methyl) -1, 3-Oxazolidin-2-one (4.56 g, 12.9 mmol) in ethanol (20
8N aqueous sodium hydroxide solution (8.07
ml) and heated to reflux for 3 hours. The reaction solution was washed with water (20
0 ml) and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (1RS,
2SR) -1- (4-Fluorophenyl) -2- (methylamino) -3- (4- (trifluoromethyl) phenyl) -1
-Propanol (3.34 mg, 79%) was obtained. mp 79-80 ℃ IRνmax ^KBr cm ^-1 : 1618, 1605, 1510. Anal.Calcd for C ₁₇ H ₁₇ F ₄ NO: C, 62.38; H, 5.23; N,
4.28 Found:. C, 62.38; H, 5.11; N, 4.27 1 H-NMR (CDCl 3) δ: 2.41 (3H, s), 2.44-2.60 (2H, m),
2.84-2.96 (1H, m), 4.94 (1H, d, J = 3.2 Hz), 7.00
-7.12 (2H, m), 7.18 (2H, d, J = 8.0 Hz), 7.32-7.50
(2H, m), 7.52 (2H, d, J = 8.0 Hz). 3) (1RS, 2SR) -1- (4-fluorophenyl) -2- (methylamino) -3- (4- (trifluoro Methyl) phenyl) -1-propanol (150 mg, 0.1 mg).
1-Naphthoyl chloride (76 ml, 0.50 mmol) and a saturated aqueous sodium hydrogen carbonate solution (5 ml) were added to a solution of ethyl acetate (5 ml) in a mixture of 46 mmol) and stirred at room temperature for 6 hours.
The reaction solution was diluted with water (50 ml), and ethyl acetate (50 m
1 × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-1: 1) and recrystallized from ethyl acetate-hexane to give the title compound (166 mg, 75%).
I got mp 196-197 ° C IRνmax ^KBr cm ^-1 : 1605, 1510, 1325. Anal.Calcd for C ₂₈ H ₂₃ F ₄ NO ₂ : C, 69.85; H, 4.81; N,
2.91 Found:. C, 69.76; H, 4.89; N, 2.80 1 H-NMR (CDCl 3) δ: 2.48 (3H, d, J = 4.4 Hz), 3.02-
3.30 (1H, m), 3.60-3.78 (1H, m), 6.08 (1H, d, J =
8.6 Hz), 6.24-6.36 (1H, m), 7.00-7.50 (6H, m), 7.5
8-7.80 (9H, m).

Example 122 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafur
Oroethoxy) benzyl] ethyl] -6,7-dihydro-
5H-benzo [a] cycloheptene-1-carboxamide 1) 3- (4-fluorophenyl) -3-oxo-2- [3
-(1,1,2,2-tetrafluoroethoxy) benzyl
Ethyl propionate 3- (1,1,2,2-tetrafluoroethoxy) tolue
6.70 g (32.2 mmol), N-bromosuccinate
5.73 g (32.2 mmol) of imido, 2,2'-
Azobis (isobutyronitrile) 10mg carbon tetrachloride
The 30 ml solution was heated to reflux for 0.5 hours. Reaction solution at room temperature
After cooling to room temperature, the white precipitate was removed by filtration, and the precipitate was
Washed with ether. The solvent of the collected filtrate was distilled off under reduced pressure.
3- (1,1,2,2-tetrafluoroethoxy)
The crude product of benzyl bromide was obtained as a pale yellow liquid.
6.153 g of ethyl (4-fluorobenzoyl) acetate
(29.27 mmol) 1,2-dimethoxyethane 5
0 ml solution of 60% sodium hydride in ice
1.17 g (29.3 mmol) of the fin suspension are added,
The mixture was stirred for 0.5 hours as it was. This was obtained above 3-
(1,1,2,2-tetrafluoroethoxy) benzyl
A 10 ml solution of bromide in 1,2-dimethoxyethane
The mixture was added at room temperature and stirred at room temperature for 8 hours. Pour the reaction into water,
Extracted twice with ethyl acetate. The collected organic layer is dried over anhydrous sulfuric acid.
The extract was dried over magnesium and the solvent was distilled off under reduced pressure. The residue obtained
The product was purified by silica gel column chromatography.
(Hexane / ethyl acetate = 15 / 1-9 / 1), hexa
The product was crystallized from the compound to give the desired product. White crystals Yield 7.
539 g yield 62% mp 53-54 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 1.12 (3H, t,
 J = 7.1 Hz), 3.34 (2H, d, J = 7.6 Hz), 4.10 (2H,
q, J = 7.1 Hz), 4.56 (1H, t, J = 7.3 Hz), 5.89 (1
H, tt, J = 2.8 Hz, 53.1 Hz), 7.04-7.16 (5H, m), 7.
27 (1H, t, J = 7.7 Hz), 7.99 (2H, dd, J = 5.5 Hz,
8.7 Hz); IR (KBr) 1728, 1682, 1597, 1325, 1275, 12
36, 1205, 1157, 1134, 1100, 847 cm^-1; Anal. Calcd
for C₂₀H₁₇F _FiveO_Four: C, 57.70; H, 4.12. Found: C, 57.7
1; H, 4.15.2) (2RS, 3RS) -3- (4-fluorophenyl)
) -3-Hydroxy-2- [3- (1,1,2,2-tetra
Fluoroethoxy) benzyl] ethyl propionate chloride
4.70 g (34.5 mmol) of zinc was added to diethyl ether
Sodium borohydride with stirring in 80 ml
2.61 g (68.9 mmol) are added at room temperature and
The mixture was further stirred for 2 hours. The mixture is filtered to remove insolubles (die
Butyl ether)
A solution was obtained. To the resulting solution, add 3- (4-fluoro
Phenyl) -3-oxo-2- [3- (1,1,2,2-tet
Lafluoroethoxy) benzyl] ethyl propionate
7.176 g (17.24 mmol) of diethyl ether
30 ml solution at room temperature and stir for 2 hours
Was. Dilute hydrochloric acid is added little by little to the reaction mixture, and excess borohydride is added.
After decomposing the zinc oxide, it was extracted twice with ethyl acetate. gather
The dried organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
I left. The obtained crude product is subjected to silica gel column chromatography.
Purified by chromatography (hexane / ethyl acetate = 6/1)
-3/1) to obtain the desired product. Colorless liquid yield 7.295
g 100% yield¹ H-NMR (CDCl_Three, 200MHz) δ 0.93 (3H, t, J = 7.1 H
z), 2.90-3.04 (4H, m), 3.89 (2H, q, J = 7.1 Hz),
5.02 (1H, t, J = 3.6 Hz), 5.88 (1H, tt, J = 2.9 Hz,
 53.2 Hz), 6.95-7.10 (5H, m), 7.24 (1H, t, J = 7.8
 Hz), 7.37 (2H, dd, J = 5.5 Hz, 8.7 Hz); IR (neat)
 3463, 1725, 1510, 1302, 1279, 1227, 1198, 1159, 1
123, 839 cm^-1 3) (2RS, 3RS) -3- (4-fluorophenyl)
) -3-Hydroxy-2- [3- (1,1,2,2-tetra
Fluoroethoxy) benzyl] propionic acid (2RS,
3RS) -3- (4-Fluorophenyl) -3-hydroxy-
2- [3- (1,1,2,2-tetrafluoroethoxy)
7.252 g of ethyl [benzyl] propionate (17.3 g)
3 mmol) of methanol 30 ml-tetrahydrofura
34.7% 1N aqueous sodium hydroxide solution in 30 ml solution
ml (34.7 mmol) and stirred at room temperature overnight.
Was. The reaction mixture was concentrated, diluted with water, and acidified with 1N hydrochloric acid.
After quenching, it was extracted twice with ethyl acetate. Organic layer collected
Was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Remaining
The distillate was crystallized from hexane to obtain the desired product. White
Crystal yield 5.795 g yield 86% mp 116-117 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 2.92-3.08
(3H, m), 5.06 (1H, s), 5.88 (1H, tt, J = 2.9 Hz, 5
3.2 Hz), 6.94-7.09 (5H, m), 7.23 (1H, t, J = 7.9 H
z), 7.36 (2H, dd, J = 5.4 Hz, 8.6 Hz); IR (KBr) 33
70-2850, 1713, 1229, 1206, 1186, 1115, 841 cm^-1; A
nal.Calcd for C₁₈H₁₅F_FiveO_Four: C, 55.39; H, 3.87. Foun
d: C, 55.51; H, 3.68. 4) (4RS, 5SR) -5- (4-fluorophenyl)
) -4- [3- (1,1,2,2-tetrafluoroethoxy)
B) Benzyl] -1,3-oxazolidin-2-one (2RS, 3RS) -3- (4-fluorophenyl) -3-
Hydroxy-2- [3- (1,1,2,2-tetrafluoro
[Ethoxy] benzyl] propionic acid 4.544 g (1
1.64 mmol) in 40 ml of tetrahydrofuran
2.43 ml of triethylamine (17.5 mmol
3.52 g of diphenylphosphoryl azide (12.
(8 mmol) and heated to reflux overnight. Reaction solvent
Was distilled off under reduced pressure, and the resulting crude product was
Purify by chromatography (hexane / ethyl acetate =
3 / 1-1-1), formed from diethyl ether-hexane
Crystallization gave the desired product. 4.241 g of white crystals
 Yield 94% mp 135-136 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 2.20-2.36
(2H, m), 4.26 (1H, dt, J = 5.5 Hz, 8.6 Hz), 4.97 (1
H, br s), 5.80 (1H, d, J = 8.2 Hz), 5.90 (1H, tt,
J = 2.8 Hz, 53.0 Hz), 6.88 (1H, s), 6.95 (1H, d, J
 = 7.6 Hz), 7.07-7.17 (3H, m), 7.31-7.39 (3H, m);
IR (KBr) 3241, 1740, 1514, 1236, 1223, 1196, 1144,
 1127, 851 cm^-1; Anal. Calcd for C₁₈H₁₄F_FiveNO_Three: C, 5
5.82; H, 3.64; N, 3.62. Found: C, 55.96; H, 3.77;
N, 3.38.5) (1RS, 2SR) -2-amino-1- (4-fluoro
L-phenyl) -3- [3- (1,1,2,2-tetrafluoro
Roethoxy) phenyl] propan-1-ol (4RS, 5SR) -5- (4-fluorophenyl) -4-
[3- (1,1,2,2-tetrafluoroethoxy) benne
Jill] -1,3-oxazolidine-2-one 4.069 g
(10.51 mmol) and 1.68 g of sodium hydroxide
(42.0 mmol) in 30 ml of ethanol-2 ml of water
And heated to reflux for 6 hours. Dilute the reaction with water and add acetic acid
Extracted twice with ethyl. The collected organic layer is dried over anhydrous sodium sulfate.
And dried under reduced pressure. Diisopro residue
Crystallized from pill ether-hexane to obtain the desired product
Was. White crystal yield 2.961 g yield 78% mp 87-88 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 2.38 (1H, d
d, J = 10.4 Hz, 13.8 Hz), 2.81 (1H, dd, J = 3.0 H
z, 14.0 Hz), 3.27 (1H, ddd, J = 3.4 Hz, 4.9 Hz, 1
0.4 Hz), 4.65 (1H, d, J = 5.2 Hz), 5.89 (1H, tt, J
 = 2.8 Hz, 53.1 Hz), 7.00-7.13 (5H, m), 7.30-7.40
 (3H, m); IR (KBr) 3368, 3250-2720, 1508,1211, 119
9, 1127, 1101, 1044 cm^-1; Anal. Calcd for C₁₇H₁₆F_Five
NO_Two: C, 56.51; H, 4.46; N, 3.88. Found: C, 56.43;
H, 4.50; N, 3.58.6) N-[(1RS, 2SR) -2- (4-fluorophene)
Nil) -2-hydroxy-1- [3- (1,1,2,2-tetra
Lafluoroethoxy) benzyl] ethyl] -6,7-dihi
Dro-5H-benzo [a] cycloheptene-1-carboxa
Mid (1RS, 2SR) -2-amino-1- (4-fluorophene)
Nyl) -3- [3- (1,1,2,2-tetrafluoroeth
[Xy) phenyl] propan-1-ol 0.173 g
(0.479 mmol), 6,7-dihydro-5H-ben
90 mg of zo [a] cycloheptene-1-carboxylic acid (0.
48 mmol) 1-hydroxybenzotriazole water
73 mg (0.48 mmol) of acetonitrile 1
While stirring in 0 ml, 1-ethyl-3- (3-dimethyla
Minopropyl) carbodiimide hydrochloride 92 mg (0.
48 mmol) and stirred at room temperature overnight. Reaction solution
Dilute in ethyl acetate and wash with aqueous sodium bicarbonate
Purified, dried over anhydrous magnesium sulfate, passed through silica gel
Thereafter, the solvent was distilled off under reduced pressure. The resulting residue is
Crystallized from pill ether-hexane to obtain the desired product
Was. White crystals Yield 0.216 g Yield 85% mp 176-177 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 1.93-2.05
(2H, m), 2.15-2.24 (2H, m), 2.67 (2H, t, J = 5.8 H
z), 2.78 (1H, dd, J = 10.8 Hz, 14.4 Hz), 3.00 (1H,
 dd, J = 4.2 Hz, 14.4 Hz), 3.61 (1H, d, J = 3.6 H
z), 4.60-4.73 (1H, m), 5.03 (1H, t, J = 3.8 Hz),
5.73 (1H, d, J = 8.2 Hz), 5.88 (1H, tt, J = 2.5 Hz,
 53.1 Hz), 5.92 (1H, td, J = 5.4 Hz, 12.2 Hz), 6.2
0 (1H, d, J = 11.8 Hz), 6.94-7.17 (8H, m), 7.30 (1
H, t, J = 7.8 Hz), 7.43 (2H, dd, J = 5.6 Hz, 8.4 H
z); IR (KBr) 3270, 1640, 1510, 1227, 1198, 1127 cm
^-1; Anal. Calcd for C₂₉H₂₆F_FiveNO_Three: C, 65.53; H, 4.9
3; N, 2.64. Found: C, 65.39; H, 4.84; N, 2.63.

Example 123 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -5,6-dihydronaphthalene-1-carboxamide 1) 5,6-dihydronaphthalene-1-carboxylic acid Methyl acid methyl 8-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carboxylate (Tetrahedron, 5
3, 15969-15982 (1990)) 5.0
29 g (32.63 mmol) was heated to reflux overnight in 80 ml of a 10% methanol solution of hydrogen chloride. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to obtain the desired product. Colorless liquid Yield 0.239
g Yield 17% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.23-2.34 (2H, m), 2.81
(2H, t, J = 8.2 Hz), 3.89 (3H, s), 6.22 (1H, td, J
= 4.8 Hz, 9.7 Hz), 7.14 (1H, t, J = 7.5 Hz), 7.25
(1H, d, J = 7.4 Hz), 7.33 (1H, td, J = 1.6 Hz, 1
0.2 Hz), 7.69 (1H, dd, J = 1.5 Hz, 7.7 Hz); IR (ne
at) 1721, 1264, 1142, 781 cm ^-1 2) 5,6-dihydronaphthalene-1-carboxylic acid methyl 5,6-dihydronaphthalene-1-carboxylate
30 ml of 276 g (1.466 mmol) of methanol
8.80 ml of 1N aqueous sodium hydroxide solution (8.8.
(80 mmol) and stirred at 70 ° C. for 8 hours. The reaction solution was diluted with water, acidified with dilute hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from hexane to obtain the desired product. White crystals Yield 0.15
8g Yield 62% mp 119-120 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 2.25-2.36
(2H, m), 2.83 (2H, t, J = 8.2 Hz), 6.27 (1H, td, J
= 4.8 Hz, 9.7 Hz), 7.19 (1H, t, J = 7.6 Hz), 7.32
(1H, d, J = 7.4 Hz), 7.49 (1H, td, J = 1.6 Hz, 10.
0 Hz), 7.87 (1H, dd, J = 1.3 Hz, 7.9 Hz), 11.60 (1
H, brs); 3) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] Ethyl] -5,6-dihydronaphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) [Phenyl] propan-1-ol 0.203 g
(0.562 mmol), 5,6-dihydronaphthalene-
98 mg (0.56 mmol) of 1-carboxylic acid, 86 mg (0.56 mmol) of 1-hydroxybenzotriazole hydrate were added to 10 ml of acetonitrile while stirring.
0.11 g (0.56 mmol) of -ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added,
Stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure.
The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.24
2g yield 83% mp 165-166 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 2.18-2.28
(2H, m), 2.70-2.85 (3H, m), 3.01 (1H, dd, J = 4.5
Hz, 14.3 Hz), 3.57 (1H, d, J = 3.6 Hz), 4.59-4.73
(1H, m), 5.04 (1H, t, J = 3.8 Hz), 5.67 (1H, d, J
= 8.2 Hz), 5.89 (1H, tt, J = 2.8 Hz, 53.1 Hz), 6.00
(1H, td, J = 9.3 Hz, 9.4 Hz), 6.34 (1H, d, J = 1
0.0 Hz), 6.85 (1H, d, J = 6.6 Hz), 6.99-7.14 (7H,
m), 7.31 (1H, t, J = 7.6 Hz), 7.43 (2H, dd, J = 5.
4 Hz, 8.8 Hz); IR (KBr) 3266, 1640, 1514, 1209, 11
23 cm ^-1 ; Anal.Calcd for C ₂₈ H ₂₄ F ₅ NO ₃ : C, 64.99; H,
4.67; N, 2.71. Found: C, 65.05; H, 4.66; N, 2.75.

Example 124 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene-1-carboxamide ( 0.259 g of 1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol
(0.717 mmol), 6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene-1-carboxylic acid 0.14 g (0.72 mmol), 1-hydroxybenzotriazole hydrate 0.11 g (0.72 mmol)
Was stirred in 10 ml of acetonitrile while stirring in 1-ethyl-
0.14 g (0.72 mmol) of 3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate.
After passing through silica gel, the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.339 g Yield 89% mp 194-195 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.41-1.63
(4H, m), 1.71-1.80 (2H, m), 2.57-2.63 (2H, m), 2.7
2 (1H, dd, J = 10.9 Hz, 14.5 Hz), 2.73-2.79 (2H,
m), 3.03 (1H, dd, J = 3.8 Hz, 14.4 Hz), 3.52 (1H,
d, J = 3.8 Hz), 4.63-4.76 (1H, m), 5.02 (1H, t, J
= 3.8 Hz), 5.60 (1H, d, J = 8.8 Hz), 5.89 (1H, tt,
J = 2.8 Hz, 53.1 Hz), 6.68 (1H, dd, J = 1.5 Hz,
7.4 Hz), 6.93-7.14 (6H, m), 7.26-7.35 (2H, m), 7.4
3 (2H, dd, J = 5.4 Hz, 8.6 Hz); IR (KBr) 3270, 292
6, 1638, 1530, 1514, 1227, 1211, 1125 cm ^-1 ; Anal.
Calcdfor C ₂₉ H ₂₈ F ₅ NO ₃ : C, 65.28; H, 5.29; N, 2.63.
Found: C, 65.23; H, 5.58; N, 2.64.

Example 125 4-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2
2-tetrafluoroethoxy) benzyl] ethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (1,1,2,2-tetrafluoro Ethoxy) phenyl] propan-1-ol 0.165 g
(0.457 mmol) 4-fluoro-1-naphthoic acid 87 mg (0.46 mmol), 1-hydroxybenzotriazole hydrate 70 mg (0.46 mmol) were stirred in 10 ml of acetonitrile with 1-ethyl- 3-
87 mg (0.46 mmol) of (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.198 g Yield 81% mp 186-187 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
89 (1H, dd, J = 10.1 Hz, 14.1 Hz), 3.00 (1H, dd, J
= 4.8 Hz, 14.4 Hz), 4.69-4.84 (1H, m), 5.00-5.06
(2H, m), 5.93 (1H, tt, J = 2.9 Hz, 53.1 Hz), 6.98-
7.57 (13H, m), 7.75 (1H, d, J = 8.0 Hz), 8.06 (1H,
d, J = 7.4 Hz); IR (KBr) 3272, 1640,1624, 1601, 1
535, 1512, 1229, 1198, 1127, 835, 760 cm ^-1 ; Anal.
Calcd forC ₂₈ H ₂₁ F ₆ NO ₃ : C, 63.04; H, 3.97; N, 2.63.
Found: C, 63.05; H, 4.17; N, 2.49.

Example 126 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -5,6,7,8-tetrahydrobenzo [a] cyclooctene-1-carboxamide 1) 7 , 8,9,10-Tetrahydrobenzo [a] cycloocten-5 (6H) -one A solution of 26.16 g (136.1 mmol) of 6-phenylhexanoic acid and 0.1 ml of N, N-dimethylformamide in 130 ml of tetrahydrofuran After 17.8 ml (204 mmol) of oxalyl chloride was added dropwise at room temperature, the mixture was stirred for 0.5 hour. The solvent of the reaction mixture was distilled off under reduced pressure to obtain an acid chloride as a yellow liquid. 250 m of methylene chloride of 36.3 g (272 mmol) of aluminum chloride
While stirring the suspension, a solution of the acid chloride obtained above in 1.2 l of methylene chloride was added dropwise thereto over 3 days. The reaction was quenched by adding water while cooling the reaction mixture with ice. The methylene chloride layer of the mixture was separated, and the aqueous layer was extracted with diethyl ether. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / hexane).
Ethyl acetate = 15 / 1-6 / 1) to give the desired product. Light yellow liquid Yield 16.91 g Yield 71% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.47-1.59 (2H, m), 1.75-
1.91 (4H, m), 2.93 (2H, t, J = 6.8 Hz), 3.05 (2H,
t, J = 6.6 Hz), 7.16-7.44 (3H, m), 7.65 (1H, dd, J
= 1.5 Hz, 7.7 Hz); IR (neat) 2930, 1667, 1445, 126
0,752 cm ^-1 2) 5,6,7,8,9,10-hexahydrobenzo [a] cycloocten-5-ol 7,8,9,10-tetrahydrobenzo [a] cyclooctene-5 ( To a solution of 16.Hg-one (16.91 g, 97.05 mmol) in methanol (100 ml) was added sodium borohydride (3.67 g, 97.1 mmol) little by little under ice-cooling, followed by stirring at room temperature for 1 hour. . The reaction was diluted with water and stirred at room temperature for 0.5 hours. The resulting precipitate was collected and washed with water to obtain the desired product. White crystals Yield 16.5
7g Yield 97% mp 79-80 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 0.87-1.06 (1
H, m), 1.30-1.66 (5H, m), 1.85 (1H, d, J = 2.8 Hz),
1.88-2.00 (1H, m), 2.05-2.22 (1H, m), 2.69-2.86
(2H, m), 5.12-5.21 (1H, m), 7.08-7.30 (3H, m), 7.5
4 (1H, dd, J = 1.4Hz, 7.4Hz); IR (KBr) 3293, 291
7, 1451, 1028, 760 cm ^-1 ; Anal.Calcd for C ₁₂ H ₁₆ O ・
0.1H ₂ O: C, 80.95; H, 9.17. Found: C, 80.93; H, 9.1
4.3) 4- (Hydroxymethyl) -5,6,7,8,9,
10-hexahydrobenzo [a] cycloocten-5-ol 5,6,7,8,9,10-hexahydrobenzo [a]
16.34 g (92.70 mmol) of cycloocten-5-ol and 30.8 g (204 mmol) of N, N, N ', N'-tetramethylethylenediamine in hexane 20
127 ml (204 mmol) of a 1.6 Mn-butyllithium hexane solution was added dropwise to the 0 ml solution under ice-cooling, followed by stirring at 35 ° C. overnight. After cooling the reaction mixture to −78 ° C., 40 g of crushed dry ice was added, and the temperature was raised to room temperature with stirring. The reaction solution was diluted with water, acidified with concentrated hydrochloric acid, and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was passed through silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 6,
A crude product of 7,8,9,10,10a-hexahydro-2H-cycloocta [cd] [2] benzofuran-2-one (15.85 g) was obtained as a yellow liquid. To a suspension of 2.97 g (78.4 mmol) of lithium aluminum hydride in 150 ml of tetrahydrofuran was added dropwise a solution of the above obtained liquid in 100 ml of tetrahydrofuran under ice-cooling, followed by stirring at room temperature for 1 hour. After cooling the reaction solution with ice, 3 ml of water was added.
An excess of lithium aluminum hydride was decomposed by sequentially adding 3 ml of 15% aqueous sodium hydroxide solution and 8 ml of water, and the mixture was stirred at room temperature for 2 hours. The resulting precipitate was removed by filtration, and the precipitate was washed with ethyl acetate. The solvent of the collected filtrate was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-ethyl acetate), and crystallized from diisopropyl ether to obtain the desired product. White crystals Yield 11.7
4g Yield 61% mp 137-138 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 0.66-0.85
(1H, m), 1.24-1.44 (2H, m), 1.55-1.79 (2H, m), 1.9
3-2.11 (3H, m), 2.76-2.84 (2H, m), 2.94 (1H, s), 3.
46 (1H, br s), 4.46 (1H, dd, J = 8.4 Hz, 11.2 Hz),
5.02 (1H, dd, J = 2.9 Hz, 11.7 Hz), 5.44 (1H, t, J
= 8.1 Hz), 7.06-7.23 (3H, m); IR (KBr) 3220, 292
2, 1449, 1053, 1009, 754 cm ^-1 ; Anal.Calcd for C _{13
. H 18 O 2: C,} 75.69; H, 8.80 Found:. C, 75.72; H, 8.99 4) 4 - [[[tert- butyl (dimethyl) silyl]
[Oxy] methyl] -5,6,7,8,9,10-hexahydrobenzo [a] cycloocten-5-ol 4- (hydroxymethyl) -5,6,7,8,9,10-
Hexahydrobenzo [a] cycloocten-5-ol 1
1.51 g (55.80 mmol), 4-N, N-dimethylaminopyridine 0.5 g, triethylamine 9.33
ml (67.0 mmol) of tetrahydrofuran 70 m
To the solution was added 9.25 g (61.4 mmol) of tert-butyldimethylchlorosilane at room temperature, and the mixture was stirred overnight. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-9 / 1) to obtain the desired product. Colorless liquid Yield 17.90 g Yield 100% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.08 (3H, s), 0.14 (3H,
s), 0.91 (9H, s), 1.23-1.57 (2H, m), 1.60-1.77 (2
H, m), 1.91-2.06 (2H, m), 2.86 (2H, t, J = 4.8 H
z), 3.93 (1H, br d, J = 4.8 Hz), 4.79 (1H, d, J =
12.4 Hz), 5.04 (1H, d, J = 12.0 Hz), 5.30-5.40 (1H,
m), 7.07 (1H, dd, J = 2.0 Hz, 7.2 Hz), 7.16 (1H,
t, J = 7.3 Hz), 7.23 (1H, dd, J = 2.0 Hz, 7.4 Hz);
IR (neat) 3412, 2928, 2855, 1472, 1462, 1254, 107
3, 835, 779 cm ^-15 5) tert-butyl (5,6,7,8-tetrahydrobenzo [a] cycloocten-1-ylmethoxy) dimethylsilane 4-[[[tert-butyl (dimethyl) silyl] oxy ] Methyl] -5,6,7,8,9,10-hexahydrobenzo [a] cycloocten-5-ol 17.90 g
(55.84 mmol), 15.6 m of triethylamine
1 (112 mmol) of a methanesulfonyl chloride 9.59 g (83.8 mmol) of acetonitrile 10 in a solution of 0.68 g (5.58 mmol) of 4-N, N-dimethylaminopyridine in 100 ml of acetonitrile under ice-cooling.
The ml solution was added dropwise under ice cooling. To this, lithium chloride 3.5
5 g (83.8 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (80 ml) to give 1,8-diazabicyclo [5.
4.0] -7-undecene (16.7 ml, 112 mmol) was added, and the mixture was stirred at 80 ° C overnight. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 15/1) to obtain the desired product. Colorless liquid Yield 10.94 g Yield 65% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.10 (6H, s), 0.95 (9H,
s), 1.37-1.49 (2H, m), 1.67 (2H, br s), 1.99-2.07
(2H, m), 2.74 (2H, t, J = 5.9 Hz), 4.67 (2H, s), 5.
95 (1H, td, J = 6.7 Hz, 11.5 Hz), 6.32 (1H, d, J =
11.2 Hz), 7.10 (1H, dd, J = 1.3 Hz, 7.5 Hz), 7.22
(1H, t, J = 7.8 Hz), 7.35 (1H, d, J = 7.6 Hz); IR
(neat) 2928, 2855, 1472, 1464, 1254, 1111, 1078, 8
37,777cm ^- 16) 5,6,7,8-tetrahydrobenzo [a] cycloocten-1-ylmethanol tert-butyl (5,6,7,8-tetrahydrobenzo [a] cycloocten-1-ylmethoxy ) A solution of 1.0 M tetrabutylammonium fluoride in tetrahydrofuran in a solution of 10.94 g (36.16 mmol) of dimethylsilane in 100 ml of tetrahydrofuran 43.
4 ml (43.4 mmol) was added and stirred at room temperature for 15 minutes. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-3 / 1) to obtain the desired product. Colorless liquid Yield 5.499 g Yield 81% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.40-1.52 (2H, m), 1.60-
1.74 (3H, m), 2.00-2.11 (2H, m), 2.76 (2H, t, J =
5.8 Hz), 4.68 (2H, d, J = 5.6 Hz), 6.03 (1H, td, J
= 6.7 Hz, 11.7 Hz), 6.50 (1H, d, J = 11.6 Hz), 7.1
4-7.28 (3H, m); IR (neat) 3324, 2926, 2853, 1449, 1
^{065, 1007, 766 cm -1 7} ) 5,6,7,8- tetrahydrobenzo [a] cyclooctene-1-carboxylic acid 5,6,7,8-tetrahydrobenzo [a] cyclooctene-1-ylmethanol A solution obtained by dissolving 7.20 g (72.0 mmol) of chromic anhydride and 6 ml of concentrated sulfuric acid in 20 ml of water was slowly added dropwise to a solution of 5.419 g (28.78 mmol) in 100 ml of acetone under ice-cooling. Thereafter, the mixture was stirred at room temperature for 0.5 hour. After the reaction solution was ice-cooled again, 20 ml of isopropanol was added, and the mixture was added to 0.1 ml.
Stir for 5 hours. The acetone in the reaction solution was distilled off under reduced pressure, diluted with ethyl acetate, washed three times with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 2.413 g Yield 42% mp 164-165 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.46 (2H,
br s), 1.72 (2H, br s), 2.03 (2H, br s), 2.81 (2H,
t, J = 5.8 Hz), 5.98 (1H, td, J = 7.2 Hz, 11.6 H
z), 6.85 (1H, d, J = 11.8 Hz), 7.29 (1H, t, J = 7.
8 Hz), 7.45 (1H, dd, J = 1.4 Hz, 7.8 Hz), 7.94 (1H,
dd, J = 1.4 Hz, 7.8 Hz); IR (KBr) 3080-2520, 169
0, 1451, 1408, 1275, 924, 770 cm ^-1 ; Anal.Calcd fo
r C ₁₃ H ₁₄ O ₂ : C, 77.20; H, 6.98.Found: C, 77.38; H,
7.06.8) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -5 , 6,
7,8-tetrahydrobenzo [a] cyclooctene-1-
Carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol 0.274 g
(0.758 mmol), 5,6,7,8-tetrahydrobenzo [a] cyclooctene-1-carboxylic acid 0.15
g (0.76 mmol) of 0.12 g (0.76 mmol) of 1-hydroxybenzotriazole hydrate in 10 ml of acetonitrile while stirring in 1-ethyl-3- (3- (3-ethyl-3-hydroxybenzotriazole).
Dimethylaminopropyl) carbodiimide hydrochloride
15 g (0.76 mmol) was added and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White powder Yield 0.365 g Yield 86% mp 189-190 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.34-1.49
(2H, m), 1.53-1.73 (2H, m), 1.95-2.06 (2H, m), 2.7
0 (2H, t, J = 5.9 Hz), 2.77 (1H, dd, J = 10.4 Hz,
14.4 Hz), 2.97 (1H, dd, J = 4.2 Hz, 14.4 Hz), 3.91
(1H, br s), 4.58-4.71 (1H, m), 5.04 (1H, t, J =
3.7 Hz), 5.80 (1H, td, J = 6.8 Hz, 11.8Hz), 5.88
(1H, tt, J = 2.9 Hz, 53.0 Hz), 6.01 (1H, d, J = 7.
8 Hz), 6.10 (1H, d, J = 11.8 Hz), 7.00-7.13 (5H,
m), 7.17-7.32 (4H, m), 7.41 (2H, dd, J = 5.5 Hz,
8.5 Hz); IR (KBr) 3272, 2928, 1640, 1535, 1514, 12
25, 1198, 1128, 777 cm ^-1 ; Anal.Calcd for C ₃₀ H ₂₈ F ₅
NO ₃ : C, 66.05; H, 5.17; N, 2.57. Found: C, 65.96;
H, 5.13; N, 2.55.

Example 127 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -8-methyl-6,7-
Dihydro-5H-benzo [a] cycloheptene-1-carboxamide 1) Methyl 6-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene-6-carboxylate 6,7, Flow of 60% sodium hydride in a solution of 24.99 g (156.0 mmol) of 8,9-tetrahydro-5H-benzo [a] cyclohepten-5-one and 42.2 g (468 mmol) of dimethyl carbonate in 150 ml of tetrahydrofuran at room temperature. 12.5 g of paraffin suspension (312
(Mmol) was added and the mixture was heated under reflux for 1 hour. The reaction solution was poured into water, acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15/1) to give 5-oxo-6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene-6-. Methyl carboxylate was obtained as a yellow liquid. 6.86 g (172) of a liquid paraffin suspension of 60% sodium hydride was added to a 250 ml solution of the liquid tetrahydrofuran obtained above under ice-cooling.
Mmol) and the mixture was stirred as it was for 0.5 hour. To the mixture was added 33.2 g (234 mmol) of methyl iodide at 0 ° C.
And stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 20 / 1-6 / 1) to obtain the desired product. Light yellow liquid Yield 35.13 g Yield 97% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.49 (3H, s), 1.69-2.08
(3H, m), 2.25-2.38 (1H, m), 2.70-3.00 (2H, m), 3.6
2 (3H, s), 7.13 (1H, d, J = 7.4 Hz), 7.23-7.46 (3
H, m); IR (neat) 2949, 1740, 1686, 1451, 1262, 123
6, 1215, 963 cm ^-1 2) 6-methyl-6,7,8,9-tetrahydro-5H-
Benzo [a] cyclohepten-5-one 6-methyl-5-oxo-6,7,8,9-tetrahydro-5
35.13 g (151.2 mmol) of methyl H-benzo [a] cycloheptene-6-carboxylate and 50 ml of concentrated hydrochloric acid
Of acetic acid was stirred at 110 ° C. overnight. The reaction solution was concentrated, diluted with water, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to obtain the desired product. Yellow liquid Yield 25.36
g 96% yield ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.22 (3H, d, J = 6.6 H
z), 1.51-2.15 (4H, m), 2.85-3.10 (3H, m), 7.19-7.4
2 (3H, m), 7.67 (1H, dd, J = 1.7 Hz, 7.5 Hz); IR (n
eat) 2932, 1686, 1597, 1448, 1223, 737 cm ^-1 3) 6-methyl-6,7,8,9-tetrahydro-5H-
Benzo [a] cyclohepten-5-ol 24.93 g of 6-methyl-6,7,8,9-tetrahydro-5H-benzo [a] cyclohepten-5-one (143.g)
1 mmol) in 150 ml of methanol under ice-cooling.
Sodium borohydride (5.41 g, 143 mmol)
Was added little by little, and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction solution was distilled off under reduced pressure, water was added, and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to obtain the desired product. Colorless liquid Yield 25.60
g Yield 100% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.85 (1.5 H, d, J = 7.0 H
z), 0.90 (1.5H, d, J = 6.8 Hz), 1.52-2.18 (6H, m),
2.59-2.73 (1H, m), 2.92-3.10 (1H, m), 4.61 (0.5H, d
d, J = 2.2 Hz, 6.8 Hz), 4.89 (0.5H, s), 7.05-7.23
(3H, m), 7.28-7.35 (1H, m); IR (neat) 3382, 2924,
1454, 1034, 747 cm ^-1 4) 4-[[[tert-butyl (dimethyl) silyl]
Oxy] methyl] -6-methyl-6,7,8,9-tetrahydro-5H-benzo [a] cyclohepten-5-ol 6-methyl-6,7,8,9-tetrahydro-5H-benzo [a] 25.17 g of cyclohepten-5-ol (14
2.8 ml) and 47.4 g (314 mmol) of N, N, N ', N'-tetramethylethylenediamine in 250 ml of hexane under ice cooling, 196 ml (314 mmol) of a 1.6 Mn-butyllithium hexane solution. After dropwise addition, the mixture was stirred at 35 ° C. overnight. The reaction mixture was
After cooling to 8 ° C, 30 g of crushed dry ice was added,
The temperature was raised to room temperature with stirring. Dilute the reaction with water,
After acidifying with concentrated hydrochloric acid, the mixture was extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 9-methyl-7,8,9,9a-tetrahydrocyclopenta [cd] [2] benzofuran-2 (6H ) -One crude product (9.06 g) was obtained as a yellow liquid. 1.70 g (44.8 mmol) of lithium aluminum hydride
Was added dropwise to a suspension of 100 ml of tetrahydrofuran in ice-cooled solution under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was ice-cooled, 1.5 ml of water and 1.5 m of a 15% aqueous sodium hydroxide solution were used.
l and 4 ml of water were sequentially added dropwise to decompose excess lithium aluminum hydride, and the mixture was stirred at room temperature for 2 hours.
The resulting precipitate was removed by filtration, and the precipitate was washed with ethyl acetate. The solvent of the collected filtrate was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (hexane / ethyl acetate = 6 / 1-1 / 2) to give 4- (hydroxymethyl) -6-methyl-6,7,8,9-tetrahydro-5.
A crude product of H-benzo [a] cyclohepten-5-ol (8.762 g) was obtained as a colorless liquid. To a solution of the liquid obtained above, 0.2 g of 4-N, N-dimethylaminopyridine and 7.49 ml (53.7 mmol) of triethylamine in 100 ml of tetrahydrofuran, 7.42 g (49.2 mmol) of tert-butyldimethylchlorosilane at room temperature. ) Was added and the mixture was stirred overnight. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-6 / 1) to obtain the desired product. Colorless liquid Yield 14.43 g Yield 32% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.08-0.13 (6H, m), 0.91-
1.16 (12H, m), 1.39-2.11 (5H, m), 2.54-2.70 (2H,
m), 3.18-3.33 (1H, m), 4.57-5.11 (3H, m), 7.04-7.1
4 (3H, m); IR (neat) 3416, 2955, 2928, 2857, 1472,
1462, 1256, 1070, 837, 775 cm -1 5) tert- butyl (8-methyl-6,7-dihydro -
5H-benzo [a] cyclohepten-1-ylmethoxy)
Dimethylsilane 4-[[[tert-butyl (dimethyl) silyl] oxy] methyl] -6-methyl-6,7,8,9-tetrahydro
-5H-benzo [a] cyclohepten-5-ol 14.4
3 g (45.02 mmol), triethylamine 7.5
To a solution of 3 ml (54.0 mmol) of 4-N, N-dimethylaminopyridine 0.55 g (4.50 mmol) of acetonitrile in 50 ml of acetonitrile was cooled under ice-cooling 5.67 g (49.5 mmol) of methanesulfonyl chloride in acetonitrile 1
A 0 ml solution was added dropwise under ice cooling. This is followed by lithium chloride 2.
86 g (67.5 mmol) was added and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into water and extracted twice with ethyl acetate.
The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 50 ml of N, N-dimethylformamide and 13.5 ml of 1,8-diazabicyclo [5.4.0] -7-undecene (90.0 ml)
Mmol) and stirred at 80 ° C. overnight. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 50/1) to obtain the desired product. Colorless liquid Yield 5.608 g Yield 41% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.10 (6H, s), 0.94 (9H,
s), 1.92-2.17 (4H, m), 2.00 (3H, s), 2.60 (2H, t, J
= 6.4 Hz), 4.70 (2H, s), 6.32 (1H, s), 7.04-7.15
(2H, m), 7.32 (1H, d, J = 7.8 Hz); IR (neat) 2928,
2857, 1254, 1109, 1078, 835, 775 cm ^-1 6) 8-Methyl-6,7-dihydro-5H-benzo [a]
Cyclohepten-1-ylmethanol tert-butyl (8-methyl-6,7-dihydro-5H-benzo [a] cyclohepten-1-ylmethoxy) dimethylsilane 5.594 g (18.49 mmol) of tetrahydrofuran in 50 ml of tetrahydrofuran at room temperature. 1.0 M tetrabutylammonium fluoride in tetrahydrofuran solution 2
2.2 ml (22.2 mmol) were added and stirred at room temperature for 15 minutes. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to obtain the desired product. Colorless liquid Yield 3.00
0 g Yield 86% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.59 (1 H, t, J = 6.0 H
z), 1.99-2.19 (4H, m), 2.01 (3H, d, J = 1.6 Hz),
2.62 (2H, t, J = 6.4 Hz), 4.69 (2H, d, J = 5.8 Hz),
6.47 (1H, d, J = 1.6 Hz), 7.11-7.24 (3H, m); IR
(neat) 3333, 2928,1454, 1019 , 791 cm -1 7) 8- methyl-6,7-dihydro -5H- benzo [a]
Cyclohepten-1-carboxylic acid 8-methyl-6,7-dihydro-5H-benzo [a] cyclohepten-1-ylmethanol 2.939 g (15.61
3.90 g (39.0 mmol) of chromic anhydride and 3 ml of concentrated sulfuric acid in a 50 ml acetone solution of
Was dissolved in 10 ml of water, and the solution was slowly added dropwise. After completion of the addition, the mixture was stirred at room temperature for 0.5 hour. After the reaction solution was again ice-cooled, 10 ml of isopropanol was added, and the mixture was stirred for 0.5 hour. The acetone in the reaction solution was distilled off under reduced pressure, diluted with ethyl acetate, washed three times with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 1.086 g Yield 34% mp 139-140 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.96-2.21
(4H, m), 2.05 (3H, d, J = 1.4 Hz), 2.63 (2H, t, J =
6.6 Hz), 6.90 (1H, d, J = 1.2 Hz), 7.191 (1H, t,
J = 7.7 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.90 (1H, d
d, J = 1.3 Hz, 7.9 Hz); IR (KBr) 3055-2530, 1682, 1
449, 1310, 1298, 1277, 1262 cm ^-1 ; Anal.Calcd for
C ₁₃ H ₁₄ O ₂ : C, 77.20; H, 6.98. Found: C, 77.25; H,
7.00.8) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -8 -Methyl-
6,7-dihydro-5H-benzo [a] cycloheptene-1
-Carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol 0.272 g
(0.753 mmol), 8-methyl-6,7-dihydro-
5H-benzo [a] cycloheptene-1-carboxylic acid
15 g (0.75 mmol) of 1-hydroxybenzotriazole hydrate 0.12 g (0.75 mmol) in 10 ml of acetonitrile with stirring in 1-ethyl-3-ethyl.
0.14 g (0.75 mmol) of (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.365 g Yield 89% mp 149-150 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.86 (3H,
s), 1.96-2.14 (4H, m), 2.58 (2H, t, J = 6.1 Hz), 2.
78 (1H, dd, J = 10.1 Hz, 14.5 Hz), 2.97 (1H, dd, J
= 4.6 Hz, 14.4 Hz), 3.93 (1H, br s), 4.57-4.70 (1
H, m), 5.03 (1H, s), 5.87 (1H, tt, J = 3.0 Hz, 52.
9 Hz), 5.89 (1H, s), 6.14 (1H, s), 6.99-7.33 (9H,
m), 7.42 (2H, dd, J = 5.4 Hz, 8.4 Hz); IR (KBr) 32
66, 2938,1638, 1512, 1198, 1128 cm ^-1 ; Anal.Calcd
for C ₃₀ H ₂₈ F ₅ NO ₃ : C, 66.05; H, 5.17; N, 2.57. Found:
C, 66.02; H, 5.28; N, 2.57.

Example 128 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -3,4-dihydro-
2H-1,5-benzodioxepin-6-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) ) Phenyl] propan-1-ol 0.221 g
(0.612 mmol), 3,4-dihydro-2H-1,
0.12 g of 5-benzodioxepin-6-carboxylic acid
(0.61 mmol) 1-Hydroxybenzotriazole hydrate 94 mg (0.61 mmol) in 10 ml of acetonitrile while stirring 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.12
g (0.61 mmol) was added and stirred at room temperature overnight.
The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.261 g Yield 79% mp 147-148 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.04-2.17
(2H, m), 2.82 (1H, dd, J = 9.9 Hz, 14.7 Hz), 2.95
(1H, dd, J = 5.0 Hz, 15.0 Hz), 3.84 (2H, t, J = 5.7
Hz), 4.05-4.22 (2H, m), 4.27 (1H, d, J = 4.2 Hz),
4.58-4.70 (1H, m), 5.09 (1H, t, J = 3.1 Hz), 5.86
(1H, tt, J = 2.8 Hz, 53.0 Hz), 6.97-7.13 (7H, m),
7.26 (1H, t, J = 7.9 Hz), 7.42 (2H, dd, J = 5.2 H
z, 8.6 Hz), 7.77 (1H, dd, J = 2.1 Hz, 7.5 Hz), 7.9
4 (1H, br d, J = 7.0 Hz); IR (KBr) 3283, 1636, 154
7, 1512, 1304, 1264, 1229, 1204, 1125, 1044 cm ^-1 ;
Anal.Calcd for C ₂₇ H ₂₄ F ₅ NO ₅ : C, 60.34; H, 4.50; N,
2.61. Found: C, 60.43; H, 4.46; N, 2.82.

Example 129 N-[(1RS, 2SR) -2- (4-fluorophenyl)
Ethyl-2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] carbamate (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3 -[3- (1,1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol 1.604 g
(4.439 mmol) and 0.75 sodium hydrogen carbonate
g (8.88 mmol) in 30 ml of tetrahydrofuran
0.47 ml of ethyl chlorocarbonate (4.
(88 mmol) and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystal Yield 1.696 g Yield 88% mp 113-114 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.16 (3H,
t, J = 6.9 Hz), 2.68 (1H, dd, J = 9.8 Hz, 14.6 H
z), 2.80 (1H, dd, J = 5.2 Hz, 14.6 Hz), 3.01 (1H,
br s), 3.95-4.17 (3H, m), 4.71 (1H, d, J = 8.8 H
z), 4.93 (1H, s), 5.89 (1H, tt, J = 2.9 Hz, 53.1 H
z), 6.95-7.14 (5H, m), 7.27 (1H, t, J = 7.9 Hz),
7.38 (2H, dd, J = 5.3 Hz, 8.7 Hz); IR (KBr) 3333,
1686, 1541, 1231, 1206, 1132 cm ^-1 ; Anal.Calcd for
C ₂₀ H ₂₀ F ₅ NO ₄ : C, 55.43; H, 4.65; N, 3.23. Found:
C, 55.65; H, 4.41; N, 3.15.

Example 130 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] carbamic acid ter
t-butyl (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol 2.085 g
(5.771 mmol) and 1.51 g (6.92 mmol) of di-tert-butyl dicarbonate were stirred in 50 ml of tetrahydrofuran at room temperature for 1 hour. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was crystallized from hexane to obtain the desired product. White crystals Yield 2.555 g Yield 96% mp 145-146 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.35 (9H,
s), 2.63-2.85 (2H, m), 3.25 (1H, br s), 4.00-4.12
(1H, m), 4.56 (1H, br d, J = 8.8 Hz), 4.92 (1H, br
s), 5.89 (1H, tt, J = 2.8 Hz, 53.1 Hz), 6.97-7.11
(5H, m), 7.27 (1H, t, J = 7.8 Hz), 7.38 (2H, dd,
J = 5.4 Hz, 8.4 Hz); IR (KBr) 3357, 1682, 1532, 12
11, 1123 cm ^-1 ; Anal.Calcd for C ₂₂ H ₂₄ F ₅ NO ₄ : C, 57.
27; H, 5.24; N, 3.04. Found: C, 57.29; H, 5.20; N,
2.96.

Example 131 4-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (1,1,2,2
2-tetrafluoroethoxy) benzyl] ethyl] naphthalene-1-carboxamide 1) 3- (4-fluorophenyl) -3-oxo-2- [4
-(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl propionate 6.73 g (32.3 mmol) of 4- (1,1,2,2-tetrafluoroethoxy) toluene, N-bromosuccinimide 5 .75 g (32.3 mmol), 2,2'-
A solution of 0.2 g of azobis (isobutyronitrile) in 30 ml of carbon tetrachloride was heated under reflux for 0.5 hour. After cooling the reaction solution to room temperature, a white precipitate was removed by filtration, and the precipitate was washed with diethyl ether. The solvent of the collected filtrate was distilled off under reduced pressure to obtain a crude product of 4- (1,1,2,2-tetrafluoroethoxy) benzyl bromide as a pale yellow liquid.
6.177 g of ethyl (4-fluorobenzoyl) acetate
(29.39 mmol) of 1,2-dimethoxyethane 5
To a 0 ml solution was added 1.18 g (29.4 mmol) of a 60% sodium hydride liquid paraffin suspension under ice-cooling.
The mixture was stirred for 0.5 hours as it was. 4-
A solution of (1,1,2,2-tetrafluoroethoxy) benzyl bromide in 10 ml of 1,2-dimethoxyethane was added at room temperature, and the mixture was stirred at room temperature for 8 hours. Pour the reaction into water,
Extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-9 / 1), and crystallized from hexane to obtain the desired product. White crystals Yield 8.
228 g Yield 67% mp 67-68 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.11 (3H, t,
J = 7.1 Hz), 3.32 (2H, d, J = 7.4 Hz), 4.10 (2H,
q, J = 7.1 Hz), 4.55 (1H, t, J = 7.3 Hz), 5.88 (1
H, tt, J = 2.9 Hz, 53.1 Hz), 7.08-7.26 (6H, m), 7.
98 (2H, dd, J = 5.3 Hz, 8.9 Hz); IR (KBr) 1725, 16
76, 1599, 1512, 1304, 1281, 1242, 1215,1202, 1186,
1155, 1115, 1098, 843 cm ^-1 ; Anal.Calcd for C ₂₀ H
₁₇ F ₅ O ₄ : C, 57.70; H, 4.12. Found: C, 57.70; H, 4.2
2.2) Ethyl (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- [4- (1,1,2,2-tetrafluoroethoxy) benzyl] propionate Zinc chloride While stirring 15 g (37.8 mmol) in 80 ml of diethyl ether, 2.86 g (75.6 mmol) of sodium borohydride was added at room temperature, followed by stirring for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. 7.865 g (18.89 mmol) of ethyl 3- (4-fluorophenyl) -3-oxo-2- [4- (1,1,2,2-tetrafluoroethoxy) benzyl] propionate was added to the obtained solution. ) Was added at room temperature, and the mixture was stirred for 2 hours. Dilute hydrochloric acid was added little by little to the reaction solution to decompose excess zinc borohydride, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1).
-3/1) to obtain the desired product. Colorless liquid Yield 7.687
g Yield 97% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.91 (3H, t, J = 7.2 H
z), 2.88-3.03 (4H, m), 3.88 (2H, dq, J = 1.7 Hz,
7.1 Hz), 5.02 (1H, t, J = 3.3 Hz), 5.88 (1H, tt, J
= 2.9 Hz, 53.1 Hz), 7.05 (2H, t, J = 8.8 Hz), 7.0
8 (4H, s), 7.37 (2H, dd, J = 5.6 Hz, 8.8 Hz); IR
(neat) 3468, 1725, 1508, 1306, 1277, 1190,1159, 11
^{23, 837 cm -1 3) (} 2RS, 3RS) -3- (4- fluorophenyl) -3-hydroxy-2- [4- (1,1,2,2-tetrafluoroethoxy) benzyl] propionic acid ( 2RS, 3RS) -3- (4-Fluorophenyl) -3-
7.556 g of ethyl hydroxy-2- [4- (1,1,2,2-tetrafluoroethoxy) benzyl] propionate
To a solution of (18.06 mmol) in 30 ml of methanol-30 ml of tetrahydrofuran was added 36.1 ml (36.1 mmol) of a 1N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, diluted with water, acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from hexane to obtain the desired product. White crystal Yield 6.260 g Yield 89% mp 128-129 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.91-3.07
(3H, m), 5.05 (1H, s), 5.88 (1H, tt, J = 2.8 Hz, 5
3.1 Hz), 7.04 (2H, t, J = 8.6 Hz), 7.07 (4H, s), 7.
35 (2H, dd, J = 5.3 Hz, 8.5 Hz); IR (KBr) 3630, 32
00-2480, 1698,1512, 1283, 1233, 1190, 1128, 1100,
^{. 839 cm -1; Anal Calcd for} C 18 H 15 F 5 O 4: C, 55.39; H,
3.87. Found: C, 55.42; H, 3.71.4) (4RS, 5SR) -5- (4-fluorophenyl) -4- [4- (1,1,2,2-tetrafluoroethoxy) benzyl]- 1,3-oxazolidine-2-one (2RS, 3RS) -3- (4-fluorophenyl) -3-
Hydroxy-2- [4- (1,1,2,2-tetrafluoroethoxy) benzyl] propionic acid 5.072 g (1
2.72 ml (19.5 mmol) of triethylamine and 3.93 g of diphenylphosphoryl azide (14.99 mmol) in 40 ml of tetrahydrofuran solution of 2.99 mmol).
3 mmol) and heated to reflux overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate =
3 / 1-1 / 1) and crystallized from diethyl ether-hexane to obtain the desired product. 4.673 g of white crystals
Yield 93% mp 154-155 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.18-2.35
(2H, m), 4.24 (1H, dt, J = 5.4 Hz, 8.7 Hz), 5.05 (1
H, br s), 5.80 (1H, d, J = 8.0 Hz), 5.90 (1H, tt,
J = 2.8 Hz, 53.1 Hz), 7.05 (2H, t, J = 8.4 Hz), 7.
14 (2H, d, J = 8.8 Hz), 7.15 (2H, d, J = 8.6 Hz),
7.36 (2H, dd, J = 5.2 Hz, 8.6 Hz); IR (KBr) 3258, 1
736, 1510, 1231, 1213, 1192, 1128, 1105 cm ^-1 ; Ana
l. Calcdfor C ₁₈ H ₁₄ F ₅ NO ₃ : C, 55.82; H, 3.64; N, 3.6
2. Found: C, 55.89; H, 3.63; N, 3.44.5) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (1,1,2,2 -Tetrafluoroethoxy) phenyl] propan-1-ol (4RS, 5SR) -5- (4-fluorophenyl) -4-
[4- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,485-oxazolidin-2-one 4.485 g
(11.58 mmol) and 1.85 g of sodium hydroxide
(46.3 mmol) in ethanol 30 ml-water 2 ml
And heated to reflux for 6 hours. The reaction was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel (APS type) column chromatography (hexane / ethyl acetate = 3 / 1-ethyl acetate), and crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 3.447 g Yield 82% mp 78-79 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.36 (1H, d
d, J = 10.5 Hz, 13.7 Hz), 2.80 (1H, dd, J = 3.0 H
z, 13.8 Hz), 3.26 (1H, ddd, J = 3.5 Hz, 4.9 Hz, 1
0.2 Hz), 4.65 (1H, d, J = 4.8 Hz), 5.90 (1H, tt, J
= 3.0 Hz, 53.1 Hz), 7.08 (2H, t, J = 8.6 Hz), 7.1
4 (4H, s), 7.37 (2H, dd, J = 5.6 Hz, 8.4 Hz); IR (K
Br) 3360, 2740, 1508, 1275, 1231, 1215, 1192, 111
9, 1096, 1040, 856 cm ^-1 ; Anal.Calcd for C ₁₇ H ₁₆ F ₅ N
O ₂ : C, 56.51; H, 4.46; N, 3.88. Found: C, 56.52;
H, 4.41; N, 3.66. 6) 4-Fluoro-N-[(1RS, 2SR) -2- (4-
Fluorophenyl) -2-hydroxy-1- [4- (1,
1,2,2-tetrafluoroethoxy) benzyl] ethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (1,1,2,2 2-tetrafluoroethoxy) phenyl] propan-1-ol 0.163 g
(0.451 mmol) 4-fluoro-1-naphthoic acid 86 mg (0.45 mmol), 1-hydroxybenzotriazole hydrate 69 mg (0.45 mmol) in 10 ml of acetonitrile with stirring in 1-ethyl- 3-
86 mg (0.45 mmol) of (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystal Yield 0.212 g Yield 88% mp 192-193 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
87 (1H, dd, J = 10.4 Hz, 14.4 Hz), 2.97 (1H, dd, J
= 4.8 Hz, 13.8 Hz), 4.68-4.82 (1H, m), 5.01-5.08
(2H, m), 5.94 (1H, tt, J = 2.9 Hz, 53.1 Hz), 6.99-
7.12 (6H, m), 7.19-7.26 (3H, m), 7.41-7.58 (4H, m
m), 7.73 (1H, d, J = 8.2 Hz), 8.07 (1H, d, J = 7.8
Hz); IR (KBr) 3285, 1644, 1628, 1601, 1535, 1508,
1314, 1264,1233, 1200, 1127, 1113, 1094, 837 cm ^-1 ;
Anal.Calcd for C ₂₈ H ₂₁ F ₆ NO ₃ : C, 63.04; H, 3.97; N,
2.63. Found: C, 62.98; H, 3.86; N, 2.60.

Example 132 4-Fluoro-N-[(1RS, 2SR) -2- (4-fluoro
L-phenyl) -2-hydroxy-1- [3- (trifluoro
Methoxy) benzyl] ethyl] naphthalene-1-carboxy
Samide 1) 3- (4-Fluorophenyl) -3-oxo-2- [3
-(Trifluoromethoxy) benzyl] propionic acid
4.530 g of ethyl butyl (4-fluorobenzoyl) acetate
(21.55 mmol) of 1,2-dimethoxyethane 5
0 ml solution of 60% sodium hydride in ice
0.86 g (21.6 mmol) of the fin suspension were added,
The mixture was stirred for 0.5 hours as it was. 3- (trifluoromethoate
5.50 g of (xy) benzyl bromide (21.6 mmol
A) in 10 ml of 1,2-dimethoxyethane at room temperature
The mixture was stirred at room temperature for 8 hours. Pour the reaction solution into water and add acetic acid
Extracted twice with ethyl. The collected organic layer is dried over anhydrous magnesium sulfate.
After drying with sodium, the solvent was distilled off under reduced pressure. The resulting residue
Purify by silica gel column chromatography.
Sun / ethyl acetate = 15 / 1-9 / 1), from hexane
Crystallization gave the desired product. White crystal yield 6.824
g yield 82% mp 56-57 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 1.12 (3H, t,
 J = 7.1 Hz), 3.34 (2H, d, J = 7.6 Hz), 4.10 (2H,
q, J = 7.1 Hz), 4.55 (1H, t, J = 7.6 Hz), 7.03-7.1
6 (5H, m), 7.28 (1H, dt, J = 0.7 Hz, 7.7 Hz), 7.98
 (2H, dd, J = 5.3 Hz, 8.9 Hz); IR (KBr) 1717, 168
6, 1599, 1271, 1258, 1236, 1217, 1177,1152 cm^-1; A
nal.Calcd for C₁₉H₁₆F_FourO_Four: C, 59.38; H, 4.20. Foun
d: C, 59.33; H, 4.38.2) (2RS, 3RS) -3- (4-fluorophenyl)
) -3-hydroxy-2- [3- (trifluoromethoxy)
E) Benzyl] ethyl propionate 4.65 g (34.1 mmol) of zinc chloride was added to diethyl ether.
Sodium borohydride while stirring in 50 ml
2.58 g (68.3 mmol) were added at room temperature and the
The mixture was stirred for 2 hours. The insolubles of the mixture are removed by filtration.
Washed with ethyl ether), zinc borohydride in diethyl
An ether solution was obtained. Add 3- (4-fluoro) to the resulting solution.
L-phenyl) -3-oxo-2- [3- (trifluoromethoate
6.559 g of ethyl [xy) benzyl] propionate (1
7.07 mmol) in 30 ml of diethyl ether.
The mixture was added at room temperature and stirred for 2 hours. Dilute hydrochloric acid in the reaction solution
Was added little by little to decompose excess zinc borohydride
Thereafter, the mixture was extracted twice with ethyl acetate. The collected organic layer is anhydrous sulfur
After drying with magnesium acid, the solvent was distilled off under reduced pressure. Got
The crude product is purified by silica gel column chromatography.
(Hexane / ethyl acetate = 6 / 1-3 / 1)
I got something. Colorless liquid Yield 6.574 g Yield 100%¹ H-NMR (CDCl_Three, 200MHz) δ 0.93 (3H, t, J = 7.1 H
z), 2.89 (1H, d, J = 2.8Hz), 2.91-3.07 (3H, m), 3.
88 (2H, q, J = 7.2 Hz), 5.02 (1H, t, J = 3.6Hz),
6.95-7.11 (5H, m), 7.25 (1H, t, J = 7.9 Hz), 7.37
(2H, dd, J = 5.2Hz, 8.4 Hz); IR (neat) 3445, 1728,
 1715, 1512, 1260, 1219, 1161, 839 cm^{- 1} 3) (2RS, 3RS) -3- (4-fluorophenyl)
) -3-hydroxy-2- [3- (trifluoromethoxy)
B) Benzyl] propionic acid (2RS, 3RS) -3- (4-fluorophenyl) -3-
Hydroxy-2- [3- (trifluoromethoxy) benzyl
E) ethyl propionate 6.391 g (16.54 mm
Mol) methanol 30 ml-tetrahydrofuran 20
33.1 ml of 1N aqueous sodium hydroxide solution
(33.1 mmol) and stirred at room temperature overnight. Anti
Concentrate the reaction solution, dilute with water, and acidify the reaction solution with 1N hydrochloric acid.
After that, the mixture was extracted twice with ethyl acetate. Dry the collected organic layer
After drying over sodium sulfate, the solvent was distilled off under reduced pressure. Residue
Crystallization from hexane gave the desired product. White crystals
5.055 g yield 85% mp 108-110 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 2.90-3.10
(3H, m), 5.06 (1H, s), 6.95-7.11 (5H, m), 7.25 (1H,
 t, J = 7.9 Hz), 7.36 (2H, dd, J = 5.6 Hz, 8.8 Hz);
 IR (KBr) 3343, 3020-2550, 1694, 1516, 1283, 1258,
 1238, 1225, 1165, 837 cm^-1; Anal. Calcd for C₁₇H
₁₄F_FourO_Four: C, 56.99; H, 3.94. Found: C, 56.98; H, 3.8
5.4) (4RS, 5SR) -5- (4-fluorophenyl)
) -4- [3- (Trifluoromethoxy) benzyl]-
1,3-oxazolidine-2-one (2RS, 3RS) -3- (4-fluorophenyl) -3-
Hydroxy-2- [3- (trifluoromethoxy) benzyl
Ru] propionic acid 4.649 g (12.98 mmol)
Triethylamine in a 50 ml solution of
2.71 ml (19.5 mmol), diphenylphospho
3.93 g (14.3 mmol) of rilazide were added,
Heated to reflux overnight. The solvent of the reaction solution was distilled off under reduced pressure to obtain
The crude product is purified by silica gel column chromatography.
(Hexane / ethyl acetate = 3 / 1-1 / 1)
Crystallized from tyl ether-hexane to obtain the desired product
Was. White crystals Yield 4.330 g Yield 94% mp 145-146 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 2.21-2.37
(2H, m), 4.26 (1H, dt, J = 6.1 Hz, 8.3 Hz), 5.11 (1
H, br s), 5.80 (1H, d, J = 8.0 Hz), 6.87 (1H, s),
6.96 (1H, d, J = 7.2 Hz), 7.09-7.19 (3H, m), 7.28
7.39 (3H, m); IR (KBr) 3248, 1736, 1516, 1256, 122
7, 1163 cm^-1; Anal. Calcd for C₁₇H₁₃F _FourNO_Three: C, 57.4
7; H, 3.69; N, 3.94. Found: C, 57.54; H, 3.73; N,
4.01 5) (1RS, 2SR) -2-amino-1- (4-fluoro)
L-phenyl) -3- [3- (trifluoromethoxy) fe
Nyl] propan-1-ol (4RS, 5SR) -5- (4-fluorophenyl) -4-
[3- (trifluoromethoxy) benzyl] -1,3-o
4.071 g of oxazolidine-2-one (11.46 mmol
1.83 g (45.8 mmol)
Is heated in 30 ml of ethanol and 2 ml of water for 6 hours.
Refluxed. Dilute the reaction solution with water and extract twice with ethyl acetate
did. Dry the collected organic layer over anhydrous sodium sulfate,
Was distilled off under reduced pressure. Residue is silica gel (APS type)
Purified by column chromatography (hexane / acetic acid
Ethyl = 3 / 1-ethyl acetate) to obtain the desired product. Pale yellow
Liquid Yield 3.722 g Yield 99%¹ H-NMR (CDCl_Three, 200MHz) δ 2.38 (1H, dd, J = 10.3 H
z, 13.9 Hz), 2.82 (1H, dd, J = 3.3 Hz, 13.9 Hz), 3.
27 (1H, ddd, 3.4 Hz, 4.8 Hz, 10.3 Hz), 4.65 (1H, d,
 J = 5.0 Hz), 7.01-7.13 (5H, m), 7.27-7.42 (3H,
m); IR (neat) 2260-2860, 1508, 1260, 1217, 1159 cm
^-1 6) 4-Fluoro-N-[(1RS, 2SR) -2- (4-
Fluorophenyl) -2-hydroxy-1- [3- (trif
Fluoromethoxy) benzyl] ethyl] naphthalene-1-ca
Luboxamide (1RS, 2SR) -2-amino-1- (4-fluorophene)
Nyl) -3- [3- (trifluoromethoxy) phenyl]
0.247 g of propan-1-ol (0.750 mmol
), 0.14 g of 4-fluoro-1-naphthoic acid (0.7
5 mmol) 1-hydroxybenzotriazole hydrate
0.11 g (0.75 mmol) of acetonitrile 1
While stirring in 0 ml, 1-ethyl-3- (3-dimethyla
Minopropyl) carbodiimide hydrochloride 0.14 g
(0.75 mmol) and stirred at room temperature overnight. Anti
Dilute the reaction solution in ethyl acetate and add aqueous sodium hydrogen carbonate
, Dried over anhydrous magnesium sulfate and passed through silica gel.
After that, the solvent was distilled off under reduced pressure. The resulting residue is
Crystallized from propyl ether-hexane to give the desired product
Obtained. White crystals Yield 0.262 g Yield 70% mp 189-190 ° C;¹H-NMR (CDCl_Three-DMSO-d₆, 200MHz) δ 2.
90 (1H, dd, J = 10.7 Hz, 14.3 Hz), 3.04 (1H, dd, J
 = 4.3 Hz, 14.1 Hz), 4.67-4.81 (1H, m), 5.00 (1H,
t, J = 4.0 Hz), 5.21 (1H, d, J = 3.6 Hz), 6.99-7.3
4 (8H, m), 7.39-7.57 (5H, m), 7.69 (1H, d, J = 8.0
 Hz), 8.06 (1H, d, J = 7.2 Hz); IR (KBr) 3268, 164
2, 1624, 1601, 1537, 1512, 1269, 1227, 1173, 835,
760 cm^-1; Anal. Calcd for C₂₇H₂₀F_FiveNO_Three: C, 64.67; H,
 4.02; N, 2.79. Found: C, 64.58; H, 4.05; N, 2.59.

Example 133 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [3- (trifluoromethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a]
Cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (trifluoromethoxy) phenyl]
0.239 g (0.726 mmol) of propan-1-ol, 0.14 g (0.73 mmol) of 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid,
0.11 g of 1-hydroxybenzotriazole hydrate
While stirring (0.73 mmol) in 10 ml of acetonitrile, 0.14 g (0.73 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystal Yield 0.274 g Yield 76% mp 177-178 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 1.
91-2.04 (2H, m), 2.18-2.27 (2H, m), 2.68 (2H, t, J
= 5.9 Hz), 2.78-2.96 (2H, m), 4.60-4.74 (1H, m),
4.93 (1H, d, J = 3.6 Hz), 4.98 (1H, t, J = 3.7 H
z), 5.88 (1H, td, J = 5.3 Hz, 11.9 Hz), 6.18 (1H,
d, J = 12.2 Hz), 6.73 (1H, d, J = 9.2 Hz), 6.92 (1
H, dd, J = 1.9 Hz, 7.3 Hz), 7.01-7.16 (7H, m), 7.2
6 (1H, d, J = 8.8 Hz), 7.49 (2H, dd, J = 5.5 Hz, 8.
5 Hz); IR (KBr) 3268, 1640, 1539,1512, 1269, 1221,
1153 cm ^-1 ; Anal.Calcd for C ₂₈ H ₂₅ F ₄ NO ₃ : C, 67.33;
H, 5.04; N, 2.80.Found: C, 67.22; H, 4.98; N, 2.7
8.

Example 134 4-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethoxy) benzyl] ethyl] naphthalene-1- Carboxamide 1) 3- (4-Fluorophenyl) -3-oxo-2- [4
Ethyl-(trifluoromethoxy) benzyl] propionate 4.140 g of ethyl (4-fluorobenzoyl) acetate
(19.70 mmol) 1,2-dimethoxyethane 5
To a 0 ml solution was added 0.79 g (19.7 mmol) of a 60% sodium hydride liquid paraffin suspension under ice-cooling.
The mixture was stirred for 0.5 hours as it was. A solution of 5.02 g (19.7 mmol) of 4- (trifluoromethoxy) benzyl bromide in 10 ml of 1,2-dimethoxyethane was added at room temperature, and the mixture was stirred at room temperature for 8 hours. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-9 / 1), and crystallized from hexane to obtain the desired product. White crystal yield 5.869
g Yield 78% mp 53.5-54.5 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.11 (3
H, t, J = 7.1 Hz), 3.32 (2H, d, J = 7.4 Hz), 4.10
(2H, q, J = 7.1 Hz), 4.54 (1H, t, J = 7.3 Hz), 7.1
0 (2H, d, J = 8.4 Hz), 7.12 (2H, t, J = 8.6 Hz),
7.25 (2H, d, J = 8.8 Hz), 7.98 (2H, dd, J = 5.2 H
z, 9.0 Hz); IR (KBr) 1732, 1682, 1597, 1507, 1325,
1273, 1236, 1152, 1101, 851 cm ^-1 ; Anal.Calcd for
C ₁₉ H ₁₆ F ₄ O ₄ : C, 59.38; H, 4.20. Found: C, 59.38; H,
4.27.2) Ethyl (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- [4- (trifluoromethoxy) benzyl] propionate 3.98 g (29.2 mmol) of zinc chloride While stirring in 50 ml of diethyl ether, 2.21 g (58.4 mmol) of sodium borohydride was added at room temperature, and the mixture was stirred for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. 5.610 g of ethyl 3- (4-fluorophenyl) -3-oxo-2- [4- (trifluoromethoxy) benzyl] propionate was added to the resulting solution.
(4.60 mmol) in 30 ml of diethyl ether was added at room temperature, and the mixture was stirred for 2 hours. Dilute hydrochloric acid was added little by little to the reaction solution to decompose excess zinc borohydride, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-3 / 1) to obtain the desired product. Colorless liquid Yield 5.601 g Yield 99% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.91 (3H, t, J = 7.2 H)
z), 2.89 (1H, d, J = 2.6Hz), 2.93-3.03 (3H, m), 3.
88 (2H, dq, J = 1.5 Hz, 7.2 Hz), 5.02 (1H, t, J =
3.6 Hz), 7.05 (2H, t, J = 8.8 Hz), 7.09 (4H, s),
7.37 (2H, dd, J = 5.6 Hz, 8.4 Hz); IR (neat) 3445,
1728, 1715, 1510, 1264, 1225, 1161, 839cm -1 3) (2RS, 3RS) -3- (4- fluorophenyl) -3-hydroxy-2- [4- (trifluoromethoxy) benzyl] propionic acid (2RS, 3RS) -3- (4-fluorophenyl) -3-
5.440 g (14.08 mmol) of ethyl hydroxy-2- [4- (trifluoromethoxy) benzyl] propionate in 30 ml of methanol-tetrahydrofuran 20
28.2 ml of 1N aqueous sodium hydroxide solution
(28.2 mmol) and stirred at room temperature overnight. The reaction solution was concentrated, diluted with water, acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from hexane to obtain the desired product. White crystals Yield 4.071 g Yield 80% mp 111-112 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.90-3.10
(3H, m), 5.05-5.08 (1H, m), 7.05 (2H, t, J = 8.4 H
z), 7.08 (4H, s), 7.36 (2H, dd, J = 5.6 Hz, 8.8 H
z); IR (KBr) 3343, 3100-2550, 1692, 1514, 1285, 12
08, 1163, 839 cm ^{- 1} ; Anal.Calcd for C ₁₇ H ₁₄ F ₄ O ₄ : C,
56.99; H, 3.94. Found: C, 56.97; H, 4.05.4. (4RS, 5SR) -5- (4-fluorophenyl) -4- [4- (trifluoromethoxy) benzyl]-
1,3-oxazolidine-2-one (2RS, 3RS) -3- (4-fluorophenyl) -3-
3.637 g (10.15 mmol) of hydroxy-2- [4- (trifluoromethoxy) benzyl] propionic acid
To a solution of the above in 50 ml of tetrahydrofuran were added 2.12 ml (15.2 mmol) of triethylamine and 3.07 g (11.2 mmol) of diphenylphosphoryl azide, and the mixture was heated under reflux overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1), and crystallized from diethyl ether / hexane. I got something. White crystal Yield 3.340 g Yield 93% mp 163-164 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.19-2.35
(2H, m), 4.17-4.29 (1H, m), 4.96 (1H, br s), 5.80
(1H, d, J = 8.2 Hz), 7.02-7.17 (6H, m), 7.36 (2H, d
d, J = 5.2 Hz, 9.0 Hz); IR (KBr) 3243, 1736, 1510,
1275, 1236, 1150 cm ^-1 ; Anal.Calcd for C ₁₇ H ₁₃ F ₄ NO
₃ : C, 57.47; H, 3.69; N, 3.94. Found: C, 57.48; H,
3.58; N, 4.04.5) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4- (trifluoromethoxy) phenyl] propan-1-ol (4RS, 5SR)- 5- (4-fluorophenyl) -4-
[4- (trifluoromethoxy) benzyl] -1,3-oxazolidin-2-one 3.057 g (8.604 mmol) and 1.38 g (34.4 mmol) of sodium hydroxide were added to 30 ml of ethanol and 1.5 ml of water. And heated to reflux for 6 hours. The reaction was diluted with water and extracted twice with ethyl acetate. The collected organic layer is dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel (APS type) column chromatography (hexane /
Crystallization from ethyl acetate = 3 / 1-ethyl acetate) and diisopropyl ether-hexane gave the desired product. White crystal Yield 2.406 g Yield 85% mp 84-85 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.36 (1H, d
d, J = 10.3 Hz, 13.9 Hz), 2.81 (1H, dd, J = 3.3 H
z, 13.5 Hz), 3.26 (1H, ddd, J = 3.3 Hz, 4.8 Hz, 1
0.3 Hz), 4.65 (1H, d, J = 4.8 Hz), 7.07 (2H, t, J
= 8.8 Hz), 7.15 (4H, s), 7.37 (2H, dd, J = 5.2 Hz,
8.4 Hz); IR (KBr) 3350-2750, 1508, 1277,1217, 119
^{. 4, 1165, 1047 cm -1} ; Anal Calcd for C 16 H 15 F 4 NO 2:
C, 58.36; H, 4.59; N, 4.25. Found: C, 58.43; H, 4.5
4; N, 4.31.6.) 4-Fluoro-N-[(1RS, 2SR) -2- (4-
(Fluorophenyl) -2-hydroxy-1- [4- (trifluoromethoxy) benzyl] ethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [4 -(Trifluoromethoxy) phenyl]
0.212 g (0.644 mmol) of propan-1-ol 0.12 g (0.64 g of 4-fluoro-1-naphthoic acid)
4 mmol) and 0.10 g (0.64 mmol) of 1-hydroxybenzotriazole hydrate in acetonitrile 1
0.12 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride while stirring in 0 ml
(0.64 mmol) and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White crystal Yield 0.276 g Yield 86% mp 230-231 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
87 (1H, dd, J = 10.8 Hz, 14.6 Hz), 3.00 (1H, dd, J
= 4.2 Hz, 14.2 Hz), 4.67-4.81 (1H, m), 5.02 (1H,
t, J = 4.1 Hz), 5.19 (1H, d, J = 3.8 Hz), 6.99-7.5
7 (13H, m), 7.67 (1H, d, J = 8.4 Hz), 8.06 (1H, d,
J = 8.0 Hz); IR (KBr) 3281, 1644, 1537, 1512, 126
9, 1227, 1217, 1175, 835 cm ^-1 ; Anal.Calcd for C ₂₇
H ₂₀ F ₅ NO ₃ : C, 64.67; H, 4.02; N, 2.79. Found: C, 64.
57; H, 4.02; N, 2.61.

Example 135 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [4- (trifluoromethoxy) be
[Ndyl] ethyl] -6,7-dihydro-5H-benzo [a]
Cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophene)
Nyl) -3- [4- (trifluoromethoxy) phenyl]
0.238 g of propan-1-ol (0.723 mmol
Le), 6,7-dihydro-5H-benzo [a] cyclohep
0.14 g (0.72 mmol) of ten-1-carboxylic acid,
0.11 g of 1-hydroxybenzotriazole hydrate
(0.72 mmol) in 10 ml of acetonitrile.
While stirring, 1-ethyl-3- (3-dimethylaminopropyl
B) 0.14 g (0.72 mm) carbodiimide hydrochloride
Mol) was added and stirred overnight at room temperature. Ethyl acetate
Diluted with water, washed with aqueous sodium hydrogen carbonate solution,
After drying with magnesium acid and passing through silica gel, the solvent was removed.
It was distilled off under reduced pressure. The resulting residue is
Crystallization from l-hexane gave the desired product. White crystals
 0.279 g yield 77% mp 202-203 ° C;¹H-NMR (CDCl_Three-DMSO-d₆, 200MHz) δ 1.
91-2.04 (2H, m), 2.18-2.27 (2H, m), 2.68 (2H, t, J
 = 5.9 Hz), 2.78-2.92 (2H, m), 4.62-4.72 (1H, m),
4.96-5.02 (2H, m), 5.88 (1H, td, J = 5.3 Hz, 11.7
Hz), 6.17 (1H, d, J = 12.2 Hz), 6.74 (1H, d, J = 1
0.0 Hz), 6.90 (1H, dd, J = 2.0 Hz, 7.6Hz), 7.01-7.
15 (6H, m), 7.22 (2H, d, J = 8.8 Hz), 7.50 (2H, d
d, J = 5.6Hz, 8.6 Hz); IR (KBr) 3272, 1640, 1539,
1512, 1269, 1229, 1202, 1159 cm ^-1; Anal. Calcd for
 C₂₈H_{twenty five}F_FourNO_Three: C, 67.33; H, 5.04; N, 2.80. Found:
C, 67.16; H, 4.94; N, 2.75.

Example 136 N-((1RS, 2SR) -2- (4-fluorophenyl)
2-Hydroxy-1-((3- (trifluoromethyl) phenyl) methyl) ethyl) -1-naphthalenecarboxamide 1) Ethyl 3- (4-fluorophenyl) -3-oxopropionate (10 g, 47.6) Mmol) and 3-trifluoromethylbenzyl chloride (8.33 g, 42.8)
Mmol), potassium carbonate (13.2 g, 95.1 mmol), and acetonitrile (200 ml) in 60 ml.
Stirred at C for 24 hours. The reaction solution was concentrated under reduced pressure, and water (20
0 ml) and extracted with ethyl acetate (200, 100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: toluene = 1: 11-1: 2-
3- (4-fluorophenyl) -3-
Ethyl oxo-2- (3-trifluoromethylbenzyl) propionate (10.2 g, 65%) was obtained as an oil. IRνmax ^Neat cm ^-1 : 1736, 1690, 1599, 1331, 1161, 112
^{7, 1074. 1 H-NMR (} CDCl 3) δ: 1.12 (3H, t, J = 7.1 Hz), 3.38
(2H, d, J = 7.4 Hz), 4.10 (2H, q, J = 7.1 Hz), 4.5
7 (1H, t, J = 7.4 Hz), 7.13 (2H, t, J = 8.8 Hz),
7.35-7.60 (4H, m), 7.95-8.10 (2H, m). 2) To a solution of anhydrous zinc chloride (7.4 g, 54.3 mmol) in diethyl ether (50 ml) was added sodium borohydride (4. 11g, 0.11 mol) and stirred at room temperature for 2 hours. The insoluble material was removed by filtration, and the filtrate was treated with a solution of ethyl 3- (4-fluorophenyl) -3-oxo-2- (3-trifluoromethylbenzyl) propionate (10 g, 27.1 mmol) in diethyl ether (20 ml). Was added and stirred at room temperature for 1 hour. The reaction was quenched by adding 1N hydrochloric acid to the reaction solution, and extracted with ethyl acetate (100 ml). The extract was washed with water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2
0: 1-5: 1) to give (2RS, 3RS) -3-
Ethyl (4-fluorophenyl) -3-hydroxy-2- (3-trifluoromethylbenzyl) propionate (7.9
g, 79%) as a colorless oil. IRνmax ^Neat cm ^-1 : 1717, 1510, 1329, 1161, 1127, 107
^{4, 839. 1 H-NMR (} CDCl 3) δ: 0.92 (3H, t, J = 7.2 Hz), 2.93
(1H, d, J = 2.6 Hz), 2.90-3.12 (3H, m), 3.88 (2H,
q, J = 7.2 Hz), 5.00-5.10 (1H, m), 7.05 (2H, t, J =
8.7 Hz), 7.20-7.55 (6H, m). 3) Ethyl (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- (3-trifluoromethylbenzyl) propionate (7. To a solution of 9 g (21.3 mmol) in methanol (50 ml) was added a 1N aqueous sodium hydroxide solution (42.7 ml, 42.7 mmol) and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with 1N hydrochloric acid (1
00 ml), and then ethyl acetate (200 ml ×
Extracted in 2). The extract was washed with water, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and the residue was crystallized from a mixture of hexane and diethyl ether to give (2RS, 3R
S) -3- (4-Fluorophenyl) -3-hydroxy-2-
(3-Trifluoromethylbenzyl) propionic acid (6.20 g, 85%) was obtained. mp 116-118 ℃ IRνmax ^KBr cm ^-1 : 3424, 1717, 1678, 1514, 1325, 123
8, 1128, 1074, as 839. Elemental analysis _{C 17 H 14 F 4 O 3} , Calcd: C, 59.65; H, 4.12 Found:. C, 59.55; H, 4.10 1 H-NMR (DMSO-d ₆ ) δ: 2.80-2.95 (1H, m), 2.99 (1H,
d, J = 10.4 Hz), 3.15 (1H, d, J = 10.4 Hz), 4.74
(1H, d, J = 6.2 Hz), 5.65-5.90 (1H, br), 7.12 (2H,
t, J = 8.8 Hz), 7.32-7.60 (6H, m). 4) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- (3-trifluoromethylbenzyl) propionic acid (5.85 g, 17.1 mmol)
To a solution of the above in tetrahydrofuran (100 ml) was added diphenylphosphoryl azide (4.78 ml, 22.2 mmol) and triethylamine (3.33 ml, 23.9 mmol). The reaction solution was heated under reflux for 4 hours, cooled, added with water (200 ml), and extracted with ethyl acetate (200 ml). The extract was washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform:
Purification with ethyl acetate = 10: 1-5: 1) gave (4R
S, 5SR) -5- (4-fluorophenyl) -4-((3-
(Trifluoromethyl) phenyl) methyl) -1,3-oxazolidin-2-one (5.30 g, 91%) was obtained as crystals. As mp 177-178 ° C. Elemental analysis _{C 17 H 13 F 4 NO 2} , calc: C, 60.18; H, 3.86 ; N, 4.13 Found:. C, 60.20; H, 3.83; N, 4.09 1 H- NMR (CDCl ₃ ) δ: 2.30-2.45 (2H, m), 4.20-4.40 (1
H, m), 5.11 (1H, brs), 5.80 (1H, d, J = 8.0 Hz), 7.
13 (2H, t, J = 8.6 Hz), 7.15-7.60 (6H, m). 5) (4RS, 5SR) -5- (4-fluorophenyl) -4-((3- (trifluoromethyl) phenyl ) Methyl) -1,3-oxazolidin-2-one (4.0 g, 1
To a solution of (1.8 mmol) in ethanol (80 ml) was added an 8 N aqueous sodium hydroxide solution (7.4 ml, 59 mmol), and the mixture was heated under reflux for 4 hours. After concentrating the reaction solution, the reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2SR)
2-Amino-1- (4-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) -1-propanol (2.
97 g, 80%). ^{. mp 76-77 ℃ IRνmax KBr cm -1} : 1605. Anal Calcd for C 16 H 15 F 4 NO: C, 61.34; H, 4.83; N,
4.47 Found:. C, 61.19; H, 4.82; N, 4.36 1 H-NMR (CDCl 3) δ: 2.42 (1H, dd, J = 13.8, 10.2 H
z), 2.89 (1H, dd, J = 13.8, 3.2 Hz), 3.20-3.38 (1
H, m), 4.66 (1H, d, J = 4.6 Hz), 7.00-7.16 (2H, m),
7.22-7.52 (6H, m). 6) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) -1-propanol (450 mg, 1 (.44 mmol) in ethyl acetate (15 ml), 1-naphthoyl chloride (282 ml, 1.87 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
1 × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (58
2 mg, 87%). mp 158-159 ℃ IRνmax ^KBr cm ^-1 : 1638, 1622, 1534. Anal.Calcd for C ₂₇ H ₂₁ F ₄ NO ₂ : C, 69.37; H, 4.53; N,
3.00 Found:. C, 69.47; H, 4.23; N, 2.97 1 H-NMR (CDCl 3) δ: 2.79 (1H, dd, J = 14.4, 11.0 H
z), 2.97 (1H, dd, J = 14.4, 4.0 Hz), 3.93 (1H, s),
4.70-4.90 (1H, m), 5.18 (1H, s), 5.98 (1H, d, J =
8.2 Hz), 6.92-7.08 (2H, m), 7.10-7.30 (3H, m), 7.3
2-7.80 (8H, m), 7.80-7.96 (2H, m).

Example 137 4-Fluoro-N-((1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-((3- (trifluoromethyl) phenyl) methyl) ethyl)- 1-naphthalenecarboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (3- (trifluoromethyl) phenyl) -1
To a solution of -propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) was added 4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 m
g, 1.44 mmol) and stirred at room temperature overnight.
The reaction solution was diluted with water (100 ml), and ethyl acetate (10 ml) was added.
0 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (490 mg, 70%). mp 193-194 ° C IRνmax ^KBr cm ^-1 : 1642, 1626, 1601, 1514, 1329. Anal.Calcd for C ₂₇ H ₂₀ F ₅ NO ₂ : C, 66.80; H, 4.15; N,
2.89 Found:. C, 66.70; H, 4.11; N, 2.75 1 H-NMR (CDCl 3) δ: 2.89 (1H, dd, J = 14.2, 10.6 H
z), 3.09 (1H, dd, J = 14.2, 4.0 Hz), 3.34 (1H, s),
4.70-4.84 (1H, m), 5.06-5.14 (1H, m), 5.98 (1H,
d, J = 8.8 Hz), 6.92-7.20 (4H, m), 7.40-7.60 (8H,
m), 7.75 (1H, d, J = 8.0 Hz), 8.08 (1H, d, J = 8.0
Hz).

Example 138 N-((1RS, 2SR) -2- (4-fluorophenyl)
2-Hydroxy-1-((3- (trifluoromethyl) phenyl) methyl) ethyl) cyclohexanecarboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (3- (tri Fluoromethyl) phenyl) -1
To a solution of -propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (288 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml), and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
ml × 2). Wash the extract with saturated saline,
After drying over anhydrous magnesium sulfate, the solution was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (5
32 mg, 87%). mp 190-191 ° C IRνmax ^KBr cm ^-1 : 1645, 1541, 1516, 1331. Anal.Calcd for C ₂₃ H ₂₅ F ₄ NO ₂ : C, 65.24; H, 5.95; N,
3.31 Found: C, 65.27; H, 5.92; N, 3.21. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.38 (5H, m), 1.50-1.80 (5
H, m), 1.84-2.06 (1H, m), 2.78 (1H, dd, J = 14.4,
10.2 Hz), 2.93 (1H, dd, J = 14.4, 4.4 Hz), 3.83 (1
H, d, J = 3.2 Hz), 4.30-4.50 (1H, m), 4.97 (1H, br
s), 5.42 (1H, d, J = 8.4 Hz), 7.02-7.18 (2H, m), 7.
24-7.54 (6H, m).

Example 139 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((3- (trifluoromethyl) phenyl) methyl) ethyl) -4-phenylbutyric acid amide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- ( 3- (trifluoromethyl) phenyl) -1
To a solution of -propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) was added 4-phenyl-n-butyric acid (236 mg, 1.44 mmol) and 1-ethyl-3.
-(3-Dimethylaminopropyl) carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44)
Mmol) and stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (432 mg, 65%). mp 110-111 ℃ IRνmax ^KBr cm ^-1 : 1644, 1605, 1510. Anal.Calcd for C ₂₆ H ₂₅ F ₄ NO ₂ : C, 67.96; H, 5.48; N,
3.05 Found:. C, 67.99; H, 5.63; N, 2.96 1 H-NMR (CDCl 3) δ: 1.66-1.90 (2H, m), 1.96-2.16 (2
H, m), 2.40-2.56 (2H, m), 2.68-2.96 (2H, m), 3.56
(1H, d, J = 3.8 Hz), 4.32-4.50 (1H, m), 4.90-5.00
(1H, m), 5.46 (1H, d, J = 8.4 Hz), 7.00-7.50 (13H,
m).

Example 140 N-((1RS, 2SR) -2- (4-fluorophenyl)
2-Hydroxy-1-((2- (trifluoromethyl) phenyl) methyl) ethyl) -1-naphthalenecarboxamide 1) Ethyl 3- (4-fluorophenyl) -3-oxopropionate (18 g, 85.7) Mmol) and 2-trifluoromethylbenzyl chloride (15.0 g, 77.1).
Mmol), potassium carbonate (23.7 g, 0.17 mol) and acetonitrile (200 ml) at 60 ° C.
For 10 hours. The reaction solution was concentrated under reduced pressure, and water (200
ml) and extracted with ethyl acetate (200 ml × 2). After washing the extract with water, drying over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: toluene = 1: 1) to give 3-
Ethyl (4-fluorophenyl) -3-oxo-2- (2-trifluoromethyl) benzylpropionate (22.3
g, 71%) as an oil. IRνmax ^Neat cm ^-1 : 1738, 1690, 1599, 1316, 1159, 112
^{1, 1040, 851. 1 H-} NMR (CDCl 3) δ: 1.11 (3H, t, J = 7.2 Hz), 3.53
(2H, d, J = 7.4 Hz), 4.10 (2H, q, J = 7.2 Hz), 4.6
3 (1H, t, J = 7.2 Hz), 7.10 (2H, t, J = 8.6 Hz),
7.20-7.45 (3H, m), 7.64 (1H, d, J = 7.2 Hz), 7.90-
8.03 (2H, m). 2) To a solution of anhydrous zinc chloride (15.4 g, 0.113 mol) in diethyl ether (200 ml) was added sodium borohydride (9.5 g, 0.226 mol) and room temperature was added. For 2 hours. The insoluble material was removed by filtration, and the filtrate was mixed with ethyl 3- (4-fluorophenyl) -3-oxo-2- (2-trifluoromethyl) benzylpropionate (20.8 g, 5
(6.5 mmol) in diethyl ether (50 ml) and stirred at room temperature for 1 hour. Under ice-cooling, 1N hydrochloric acid was added to the reaction solution to stop the reaction, and water (200 ml) and ethyl acetate (300 ml) were added for extraction. After the extract was washed with water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 20: 1-10: 1).
And purified with ethyl (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- (2-trifluoromethyl) benzylpropionate (16.9 g, 82
%) As a colorless oil. IRνmax ^Neat cm ^-1 : 1715, 1607, 1510, 1316, 1225, 115
^{9, 1121, 1040, 839. 1} H-NMR (CDCl 3) δ: 0.91 (3H, t, J = 7.1 Hz), 2.98-
3.30 (4H, m), 3.88 (2H, q, J = 7.1 Hz), 5.00-5.10
(1H, m), 7.59 (1H, d, J = 7.4 Hz). 3) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- (2-trifluoromethyl) benzylpropion To a solution of ethyl acetate (16.7 g, 45 mmol) in methanol (100 ml) was added a 2N aqueous sodium hydroxide solution (45 ml, 90.2 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with 1 N hydrochloric acid (15
0 ml) and ethyl acetate (150 ml ×
Extracted in 2). The extract was washed with water, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and the residue was crystallized from hexane to give (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- ( There was obtained 2-trifluoromethyl) benzylpropionic acid (12.6 g, 82%). mp 158-159 ℃ IRνmax ^KBr cm ^-1 : 1694, 1514, 1319, 1227, 1115, 104
2, as 839. Elemental analysis _{C 17 H 14 F 4 O 3} , Calcd: C, 59.65; H, 4.12 Found:. C, 59.56; H, 4.07 1 H-NMR (DMSO-d 6) δ: 2.70-2.95 (1H, m), 2.98-3.17
(1H, m), 4.70-4.82 (1H, m), 5.70-5.85 (1H, m), 7.13
(2H, t, J = 9.0 Hz), 7.32-7.50 (4H, m), 7.50-7.70
(2H, m). 4) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- (2-trifluoromethyl) benzylpropionic acid (12.3 g, 35.9 mmol)
To a tetrahydrofuran (100 ml) solution of was added diphenylphosphoryl azide (10.0 ml, 46.7 mmol) and triethylamine (7.0 ml, 50.3 mmol), and the mixture was stirred for 30 minutes. After heating under reflux for further 4 hours, the mixture was allowed to cool, water (200 ml) was added, and the mixture was extracted with ethyl acetate (200 ml). The extract was washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 10: 1-5: 1) to give (4RS, 5SR) -5- (4-fluorophenyl) -4-((2- (trifluoro Methyl) phenyl)
Methyl) -1,3-oxazolidin-2-one (11.8
g, 97%) as crystals. mp 138-140 ° C IRνmax ^KBr cm ^-1 : 1761, 1609, 1514, 1316, 1235, 115
4, 1115, 1063, 964, 833.Calculated for C ₁₇ H ₁₃ F ₄ NO ₂ Calculated: C, 60.18; H, 3.86; N, 4.13 Found: C, 60.18; H, 4.05; N, 4.06. ¹ H-NMR (CDCl ₃ ) δ: 2.20-2.40 (1H, m), 2.50-2.65 (1
H, m), 4.18-4.35 (1H, m), 5.09 (1H, brs), 5.84 (1
H, d, J = 7.6 Hz), 7.10-7.60 (7H, m), 7.66 (1H, d,
J = 8.4 Hz). 5) (4RS, 5SR) -5- (4-fluorophenyl) -4-((2- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidin-2-one (10 .95
g, 32.3 mmol) in an ethanol (200 ml) solution and an 8 N aqueous sodium hydroxide solution (20 ml, 160 ml).
(Mmol) was heated and refluxed for 4 hours. After concentrating the reaction solution, the reaction solution was diluted with water (200 ml), and ethyl acetate (200 m
1 × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2S
R) -2-Amino-1- (4-fluorophenyl) -3- (2-
(Trifluoromethyl) phenyl) -1-propanol (7.56 g, 75%) was obtained. . mp 57-58 ℃ Anal Calcd for C 16 H 15 F 4 NO: C, 61.34; H, 4.83; N,
4.47 Found:. C, 61.52; H, 4.78; N, 4.39 IRνmax KBr cm -1: 1607, 1508, 1316. 1 H-NMR (CDCl 3) δ: 2.34-2.52 (1H, m), 2.90-3.10 ( 1
H, m), 3.30-3.42 (1H, m), 4.74 (1H, d, J = 4.4 H
z), 7.02-7.16 (2H, m), 7.20-7.52 (5H, m), 7.63 (1H,
d, J = 7.6 Hz). 6) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (2- (trifluoromethyl) phenyl) -1-propanol (450 mg, 1. 44 mmol) in ethyl acetate (15 ml) was added with 1-naphthoyl chloride (282 ml, 1.87 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
× 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (536).
mg, 80%). mp 193-194 ° C IRνmax ^KBr cm ^-1 : 1636, 1622, 1607, 1539. Anal.Calcd for C ₂₇ H ₂₁ F ₄ NO ₂ : C, 69.37; H, 4.53; N,
3.00 Found:. C, 69.13; H, 4.37; N, 3.09 1 H-NMR (CDCl 3) δ: 2.90-3.20 (2H, m), 3.33 (1H, d,
J = 3.0 Hz), 4.80-5.00 (1H, m), 5.12-5.20 (1H, m),
6.07 (1H, d, J = 8.8 Hz), 7.00-7.20 (3H, m), 7.24-
7.58 (8H, m), 7.60-7.78 (2H, m), 7.80-7.92 (2H, m
m).

Example 141 4-Fluoro-N-((1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-((2- (trifluoromethyl) phenyl) methyl) ethyl)- 1-naphthalenecarboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (2- (trifluoromethyl) phenyl) -1
To a solution of -propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) was added 4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 m
g, 1.44 mmol) and stirred at room temperature overnight.
The reaction solution was diluted with water (100 ml), and ethyl acetate (10 ml) was added.
0 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
The residue was purified with ethyl acetate = 1: 1) and recrystallized from ethyl acetate-hexane to give the title compound (548 mg, 79%).
I got ^{. mp 200-201 ℃ IRνmax KBr cm -1} : 1640, 1626, 1601, 1537. Anal Calcd for C 27 H 20 F 5 NO 2: C, 66.80; H, 4.15; N,
2.89 Found:. C, 66.67; H, 4.12; N, 2.80 1 H-NMR (CDCl 3) δ: 2.98-3.22 (3H, m), 4.80-4.98 (1
H, m), 5.14-5.20 (1H, m), 6.04 (1H, d, J = 8.4 H
z), 6.96-7.20 (4H, m), 7.26-7.60 (7H, m), 7.65 (1H,
d, J = 7.8 Hz), 7.75 (1H, d, J = 8.4 Hz), 8.08 (1
(H, d, J = 8.2 Hz).

Example 142 N-((1RS, 2SR) -2- (4-fluorophenyl)
2-Hydroxy-1-((2- (trifluoromethyl) phenyl) methyl) ethyl) cyclohexanecarboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (2- (tri Fluoromethyl) phenyl) -1
To a solution of -propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (288 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml), and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
ml × 2). Wash the extract with saturated saline,
After drying over anhydrous magnesium sulfate, the solution was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (4
34 mg, 87%). mp 216-217 ° C IRνmax ^KBr cm ^-1 : 1645, 1607, 1539. Anal.Calcd for C ₂₃ H ₂₅ F ₄ NO ₂ : C, 65.24; H, 5.95; N,
3.31 Found:. C, 64.96; H, 5.92; N, 3.19 1 H-NMR (CDCl 3) δ: 1.00-1.30 (5H, m), 1.40-1.80 (5
H, m), 1.80-2.02 (1H, m), 2.80-3.02 (2H, m), 3.70
(1H, d, J = 3.6 Hz), 4.40-4.60 (1H, m), 4.98-5.06
(1H, m), 5.51 (1H, d, J = 8.2 Hz), 7.00-7.16 (2H,
m), 7.20-7.52 (5H, m), 7.59 (1H, d, J = 7.6 Hz).

Example 143 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((2- (trifluoromethyl) phenyl) methyl) ethyl) -4-phenylbutyric acid amide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- ( 2- (trifluoromethyl) phenyl) -1
To a solution of -propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) was added 4-phenyl-n-butyric acid (236 mg, 1.44 mmol) and 1-ethyl-3.
-(3-Dimethylaminopropyl) carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44)
Mmol) and stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: acetone =
1: 1) and recrystallized from ethyl acetate-hexane to give the title compound (501 mg, 76%). mp 161-162 ° C IRνmax ^KBr cm ^-1 : 1645, 1537, 1514. Anal.Calcd for C ₂₆ H ₂₅ F ₄ NO ₂ : C, 67.96; H, 5.48; N,
3.05 Found:. C, 67.96; H, 5.41; N, 2.94 1 H-NMR (CDCl 3) δ: 1.64-1.84 (2H, m), 1.86-2.12 (2
H, m), 2.38-2.44 (2H, m), 2.91 (2H, d, J = 7.2 H
z), 3.29 (1H, d, J = 3.6 Hz), 4.40-4.60 (1H, m),
4.98-5.06 (1H, m), 5.51 (1H, d, J = 7.6 Hz), 7.00-
7.34 (9H, m), 7.36-7.48 (3H, m), 7.57 (1H, d, J =
7.6 Hz).

Example 144 N-((1RS, 2SR) -2- (4-fluorophenyl)
1-((4-Fluorophenyl) methyl) -2-hydroxyethyl) -1-naphthalenecarboxamide 1) Ethyl 3- (4-fluorophenyl) -3-oxopropionate (20 g, 95.1 mmol) and 4 A mixture of -fluorobenzyl bromide (18.0 g, 85.6 mmol), potassium carbonate (26.3 g, 0.19 mol), and acetonitrile (300 ml) was stirred at 60 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, water (200 ml) was added, and the mixture was extracted with ethyl acetate (200, 100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: toluene = 1: 1-1: 5) to give 2
Ethyl-(4-fluorobenzyl) -3- (4-fluorophenyl) -3-oxopropionate (19.0 g, 63
%) As an oil. IRνmax ^Neat cm ^-1 : 1732, 1688, 1599, 1510, 1159, 85
_{^{1. 1 H-NMR (CDCl 3}} ) δ: 1.12 (3H, t, J = 7.1 Hz), 3.29
(2H, d, J = 7.4 Hz), 4.01 (2H, q, J = 7.1 Hz), 4.5
3 (1H, t, J = 7.4 Hz), 6.88-7.30 (6H, m), 7.90-8.0
8 (2H, m). 2) To a solution of anhydrous zinc chloride (15.4 g, 0.113 mol) in diethyl ether (200 ml) was added sodium borohydride (9.5 g, 0.226 mol), and the mixture was stirred at room temperature. For 2 hours. The insoluble material was removed by filtration, and to the filtrate was added a solution of ethyl 2- (4-fluorobenzyl) -3- (4-fluorophenyl) -3-oxopropionate (18 g, 56.5 mmol) in diethyl ether (50 ml). Stirred at room temperature for 1 hour. Under ice-cooling, 1N hydrochloric acid was added to the reaction solution to stop the reaction. Water (200 ml) and ethyl acetate (200 ml) were added.
l) was added and extracted. The extract was washed with water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-3: 1) to give (2
RS, 3RS) -2- (4-fluorobenzyl) -3- (4-
Ethyl (fluorophenyl) -3-hydroxypropionate (16.8 g, 93%) was obtained as a colorless oil. IRνmax ^Neat cm ^-1 : 1726, 1713, 1605, 1510, 1225, 115
^{9, 1030, 835. 1 H-} NMR (CDCl 3) δ: 0.94 (3H, t, J = 7.0 Hz), 2.80-
3.02 (4H, m), 3.88 (2H, q, J = 7.0 Hz), 4.99 (1H,
d, J = 4.8 Hz), 6.85-7.15 (6H, m), 7.30-7.50 (2H,
m). 3) Ethyl (2RS, 3RS) -2- (4-fluorobenzyl) -3- (4-fluorophenyl) -3-hydroxypropionate (16.5 g, 51.5 mmol) in methanol (50 ml). A 2N aqueous sodium hydroxide solution (51.5 ml, 0.103 mol) was added to the solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was 1N hydrochloric acid (130 ml)
After acidification with, the mixture was extracted with ethyl acetate (200, 100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and the residue was crystallized from hexane to give (2RS, 3RS) -3- (4-fluorophenyl)-
2- (4-Fluorobenzyl) -3-hydroxypropionic acid (14.2 g, 94%) was obtained. mp 169-170 ° C IRνmax ^KBr cm ^-1 : 1692, 1607, 1510, 1231, 1015, 839,
826. As Elemental analysis _{C 16 H 14 F 2 O 3} , Calcd: C, 66.75; H, 4.83 Found:. C, 66.76; H, 4.64 1 H-NMR (DMSO-d 6) δ: 2.70- 2.95 (2H, m), 3.05 (1H,
d, J = 11.0 Hz), 4.60-4.80 (1H, m), 5.65-5.80 (1H,
m), 6.97-7.22 (6H, m), 7.30-7.45 (2H, m), 11.80-1
2.00 (1H, br, OH). 4) (2RS, 3RS) -3- (4-fluorophenyl) -2- (4-fluorobenzyl) -3-hydroxypropionic acid (13.8 g, 47.2 mmol) To a tetrahydrofuran (150 ml) solution of diphenylphosphoryl azide (13.2 ml, 61.4 mmol) and triethylamine (9.2 ml, 66.1 mmol),
Stir for 30 minutes. After heating and refluxing for further 4 hours, the mixture was allowed to cool, water (200 ml) was added, and ethyl acetate (200 m
Extracted in l). The extract was washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, passed through a small amount of silica gel, and evaporated under reduced pressure. The residue was crystallized from hexane-ethyl acetate to give (4RS, 5SR) -5- (4-
Fluorophenyl) -4-((4-fluorophenyl) methyl) -1,3-oxazolidin-2-one (12.8 g,
94%) as crystals. mp 197-198 ° C IRνmax ^KBr cm ^-1 : 1738, 1611, 1510, 1231, 1069, 101
3, 980, 853. Elemental analysis: C ₁₆ H ₁₃ F ₂ NO ₂ Calculated: C, 66.43; H, 4.53; N, 4.84 Found: C, 66.39; H, 4.40; N, 4.79. ¹ H -NMR (CDCl ₃ ) δ: 2.10-2.35 (2H, m), 4.10-4.30 (1
H, m), 4.91 (1H, s), 5.79 (1H, d, J = 7.6 Hz), 6.9
8 (4H, d, J = 7.4 Hz), 7.13 (2H, t, J = 8.4 Hz),
7.30-7.43 (2H, m). 5) (4RS, 5SR) -5- (4-fluorophenyl) -4-((4-fluorophenyl) methyl) -1,3-
To a solution of oxazolidin-2-one (11.87 g, 41.0 mmol) in ethanol (200 ml) was added an 8 N aqueous sodium hydroxide solution (25.6 ml, 205 mmol), and the mixture was heated under reflux for 4 hours. After concentrating the reaction solution, water (20
0 ml) and extracted with ethyl acetate (200 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2SR) -2-amino-1,3-bis (4-fluorophenyl) -1-propanol (9.33 g, 86%). mp 66-67 ℃ IRνmax ^KBr cm ^-1 : 1603, 1510, 1225. Anal.Calcd for C ₁₅ H ₁₅ F ₂ NO: C, 68.43; H, 5.74; N,
5.32 Found:. C, 68.30; H, 5.68; N, 5.17 1 H-NMR (CDCl 3) δ: 2.32 (1H, dd, J = 13.4, 10.2 H
z), 2.77 (1H, dd, J = 13.4, 3.0 Hz), 3.16-3.30 (1
H, m), 4.64 (1H, d, J = 5.2 Hz), 6.90-7.18 (6H, m),
7.30-7.42 (2H, m). 6) (1RS, 2SR) -2-amino-1,3-bis (4
-Fluorophenyl) -1-propanol (450 mg,
1.71 mmol) in ethyl acetate (15 ml).
-Naphthoyl chloride (386 ml, 2.56 mmol)
And a saturated aqueous sodium hydrogen carbonate solution (15 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: acetone = 1: 1) and recrystallized from ethyl acetate-hexane to give the title compound (515 mg, 72%).
I got mp 199-200 ℃ IRνmax ^KBr cm ^-1 : 1640, 1605, 1539, 1510. Anal.Calcd for C ₂₆ H ₂₁ F ₂ NO ₂ : C, 74.81; H, 5.07; N,
3.36 Found:. C, 74.56; H, 5.04; N, 3.27 1 H-NMR (CDCl 3) δ: 2.75 (1H, dd, J = 14.2, 10.6 H
z), 3.01 (1H, dd, J = 14.2, 4.0 Hz), 3.63 (1H, d,
J = 4.0 Hz), 4.68-4.84 (1H, m), 5.04-5.10 (1H, m),
5.89 (1H, d, J = 8.4 Hz), 6.92-7.30 (7H, m), 7.32-
7.52 (5H, m), 7.69 (1H, d, J = 8.2 Hz), 7.78-7.92
(2H, m).

Example 145 4-Fluoro-N-((1RS, 2SR) -2- (4-fluorophenyl) -1-((4-fluorophenyl) methyl)-
2-Hydroxyethyl) -1-naphthalenecarboxamide (1RS, 2SR) -2-amino-1,3-bis (4-fluorophenyl) -1-propanol (450 mg, 1.7
1 mmol) in acetonitrile (30 ml) solution.
Fluoronaphthalenecarboxylic acid (325 mg, 1.71)
Mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (491 mg, 2.5
6 mmol) and 1-hydroxy-1H-benzotriazole (261 mg, 1.71 mmol) were added and stirred at room temperature overnight. Dilute the reaction with water (100 ml)
Extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (571 mg, 77%). ^{. mp 233-234 ℃ IRνmax KBr cm -1} : 1644, 1626, 1601, 1508. Anal Calcd for C 26 H 20 F 3 NO 2: C, 71.72; H, 4.63; N,
3.22 Found:. C, 71.58; H, 4.56; N, 3.12 1 H-NMR (CDCl 3) δ: 2.77 (1H, dd, J = 14.4, 11.0 H
z), 3.03 (1H, dd, J = 14.4, 4.4 Hz), 3.42-3.50 (1
H, m), 4.64-4.84 (1H, m), 5.04-5.12 (1H, m), 5.84
(1H, d, J = 8.4 Hz), 6.92-7.32 (8H, m), 7.40-7.60
(4H, m), 7.74 (1H, d, J = 8.0 Hz), 8.09 (1H, d, J =
8.4 Hz).

Example 146 N-((1RS, 2SR) -2- (4-fluorophenyl)
-1-((4-Fluorophenyl) methyl) -2-hydroxyethyl) cyclohexanecarboxamide (1RS, 2RS) -2-amino-1,3-bis (4-fluorophenyl) -1-propanol (450 mg, 1. 7
Cyclohexanecarbonyl chloride (342 ml, 2.56 mmol) and saturated aqueous sodium bicarbonate (15 ml) were added to a solution of ethyl acetate (15 mmol) in ethyl acetate (15 ml).
Stirred for hours. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (553 mg, 87%). mp 203-204 ℃ IRνmax ^KBr cm ^-1 : 1645, 1537, 1512. Anal.Calcd for C ₂₂ H ₂₅ F ₂ NO ₂ : C, 70.76; H, 6.75; N,
3.75 Found:. C, 70.79; H, 6.80; N, 3.63 1 H-NMR (CDCl 3) δ: 1.02-1.38 (5H, m), 1.50-1.80 (5
H, m), 1.82-2.04 (1H, m), 2.63 (1H, dd, J = 14.4,
10.4 Hz), 2.84 (1H, dd, J = 14.4, 4.4 Hz), 4.06 (1
H, d, J = 4.0 Hz), 4.30-4.46 (1H, m), 4.90-4.96 (1
H, m), 5.29 (1H, d, J = 8.4 Hz), 6.90-7.14 (6H, m),
7.30-7.42 (2H, m).

Example 147 N-((1RS, 2SR) -2- (4-fluorophenyl)
-1-((4-Fluorophenyl) methyl) -2-hydroxyethyl) -4-phenylbutyric acid amide (1RS, 2SR) -2-amino-1,3-bis (4-fluorophenyl) -1-propanol ( 450 mg, 1.7
1 mmol) in acetonitrile (30 ml) solution.
Phenyl-n-butyric acid (280 mg, 1.71 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (491 mg, 2.56 mmol)
And 1-hydroxy-1H-benzotriazole (26
(1 mg, 1.71 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (523 mg, 75%). mp 147-148 ℃ IRνmax ^KBr cm ^-1 : 1645, 1609, 1549. Anal.Calcd for C ₂₅ H ₂₅ F ₂ NO ₂ : C, 73.33; H, 6.15; N,
3.42 Found:. C, 73.34; H, 6.09; N, 3.35 1 H-NMR (CDCl 3) δ: 1.70-1.90 (2H, m), 2.00-2.12 (2
H, m), 2.44-2.58 (2H, m), 2.62 (1H, dd, J = 14.4,
10.4 Hz), 2.80 (1H, dd, J = 14.4, 4.4 Hz), 3.74 (1
H, s), 4.32-4.48 (1H, m), 4.90-4.98 (1H, m), 5.32
(1H, d, J = 7.6 Hz), 6.84-7.16 (8H, m), 7.20-7.42
(5H, m).

Example 148 N-((1RS, 2SR) -2- (4-fluorophenyl)
2-Hydroxy-1-((4- (methyloxy) phenyl) methyl) ethyl) -1-naphthalenecarboxamide 1) Ethyl 3- (4-fluorophenyl) -3-oxopropionate (20 g, 95.1 mmol) ), 4-methoxybenzyl chloride (11.6 ml, 85.6 mmol), potassium carbonate (26.3 g, 0.19 mol), and acetonitrile (300 ml) were stirred at 60 ° C for 6 hours. The reaction solution was concentrated under reduced pressure, water (300 ml) was added, and the mixture was extracted with ethyl acetate (300 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-5: 1) to give 3
Ethyl-(4-fluorophenyl) -3-oxo-2- (4-methoxybenzyl) propionate (26.6 g, 85
%) As an oil. IRνmax ^Neat cm ^-1 : 1734, 1686, 1597, 1514, 1250, 117
9, 1159, 1034, 849, 824. 1 H-NMR (CDCl 3) δ: 1.13 (3H, t, J = 7.2 Hz), 3.26
(2H, d, J = 7.6 Hz), 3.76 (3H, s), 4.10 (2H, q, J
= 7.2 Hz), 4.53 (2H, t, J = 7.2 Hz), 6.79 (2H, d,
J = 8.2 Hz), 6.95-7.20 (3H, m), 7.90-8.10 (2H, m). 2) To a solution of zinc chloride (21.2 g, 0.156 mol) in diethyl ether (200 ml), Sodium chloride (13.1 g, 0.31 mol)
Stirred for hours. The insoluble material was removed by filtration, and the filtrate was treated with 3- (4-fluorophenyl) -3-oxo-2- (4-methoxybenzyl).
Ethyl propionate (25.7 g, 77.8 mmol)
Of diethyl ether (50 ml) was added to the solution at room temperature.
Stirred for hours. Under ice-cooling, 1N hydrochloric acid was added to the reaction solution to stop the reaction. Water (200 ml) and ethyl acetate (200 ml) were added.
l) was added and extracted. The extract was washed with water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-3: 1) to give (2
Ethyl RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- (4-methoxybenzyl) propionate (23.3 g, 90%) was obtained as a colorless oil. IRνmax ^Neat cm ^-1 : 1726, 1607, 1512, 1248, 1223, 117
^{9, 1034, 839. 1 H-} NMR (CDCl 3) δ: 0.95 (3H, t, J = 7.2 Hz), 2.85-
3.00 (3H, m), 3.76 (3H, s, OMe), 3.89 (2H, q, J =
7.2 Hz), 4.95-5.07 (1H, m), 6.70-6.88 (2H, m), 6.9
3-7.12 (4H, m), 7.30-7.47 (2H, m). 3) Ethyl (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- (4-methoxybenzyl) propionate To a solution of (22.8 g, 68.6 mmol) in methanol (100 ml) was added a 2N aqueous solution of sodium hydride (69 ml, 0.137 mol) and the mixture was stirred at room temperature for 4 hours. After acidifying the reaction solution with 6N hydrochloric acid,
Water (300 ml) was added, and ethyl acetate (200 ml ×
Extracted in 2). The extract was washed with water, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and the residue was crystallized from a mixture of hexane and diethyl ether to give (2RS, 3R
S) -3- (4-Fluorophenyl) -3-hydroxy-2-
(4-methoxybenzyl) propionic acid (14.8 g,
71%). mp 96-98 ℃ IRνmax ^KBr cm ^-1 : 1690, 1611, 1514, 1254, 1235, 103
6, as 837. Elemental analysis C ₁₇ H ₁₇ FO _4, Calculated: C, 67.10; H, 5.63 Found:. C, 67.11; H, 5.65 1 H-NMR (DMSO-d 6) δ: 2.70- 2.90 (2H, m), 2.95-3.10
(1H, m), 3.70 (3H, s), 4.60-4.75 (1H, m), 5.60-5.75
(1H, m), 6.79 (2H, d, J = 8.8 Hz), 7.00-7.20 (4H,
m), 7.30-7.45 (2H, m), 11.80-11.95 (1H, br, OH). 4) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- (4-methoxy To a solution of benzyl) propionic acid (13.7 g, 45.0 mmol) in tetrahydrofuran (150 ml), diphenylphosphoryl azide (12.6 ml, 58.5 mmol) and triethylamine (8.78 ml, 63.0 mmol) were added. Stir for 30 minutes. After heating and refluxing for another 4 hours,
After cooling, water (200 ml) was added and ethyl acetate (200 ml) was added.
ml). The extract was washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 4: 1-2: 1) to give (4RS, 5SR) -5- (4-fluorophenyl)-
4-((4- (methyloxy) phenyl) methyl) -1,
3-Oxazolidin-2-one (13.0 g, 96%) was obtained as crystals. mp 125-126 ℃ IRνmax ^KBr cm ^-1 : 1738, 1613, 1514, 1248, 1107, 103
6, 845, 824. As Elemental analysis _{C 17 H 16 FNO 3 · 1} / 4H 2 O, Calculated: C, 66.77; H, 5.44 ; N, 4.58 Found: C, 66.57; H, 5.31 ; N, 4.49. ¹ H-NMR (CDCl ₃ ) δ: 2.10-2.30 (3H, m), 3.78 (3H, s),
4.10-4.30 (1H, m), 4.94 (1H, brs), 5.78 (1H, d, J
= 7.6 Hz), 6.78-6.90 (2H, m), 6.90-7.00 (2H, m),
7.07-7.20 (2H, m), 7.30-7.45 (2H, m). 5) (4RS, 5SR) -5- (4-fluorophenyl) -4-((4- (methyloxy) phenyl) methyl)-
1,3-Oxazolidin-2-one (12.8 g, 42.
To a solution of 5 mmol) in ethanol (200 ml) was added an 8 N aqueous sodium hydroxide solution (26.6 ml, 210 mmol), and the mixture was heated under reflux for 4 hours. After concentrating the reaction solution, the reaction solution was diluted with water (200 ml), and ethyl acetate (200 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2SR)
2-amino-1- (4-fluorophenyl) -3- (4- (methyloxy) phenyl) -1-propanol (10.08
g, 86%). mp 78-79 ℃ IRνmax ^KBr cm ^-1 : 1611, 1603, 1584, 1512. Anal.Calcd for C ₁₆ H ₁₈ FNO ₂ : C, 69.80; H, 6.59; N,
5.09 Found:. C, 69.69; H, 6.65; N, 5.00 1 H-NMR (CDCl 3) δ: 2.27 (1H, dd, J = 13.8, 10.4 H
z), 2.72 (1H, dd, J = 13.8, 3.2 Hz), 3.16-3.28 (1
H, m), 3.78 (3H, s), 4.65 (1H, d, J = 4.6 Hz), 6.78
-6.86 (2H, m), 7.00-7.12 (4H, m), 7.32-7.72 (2H, m
m). 6) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (4- (methyloxy) phenyl) -1
To a solution of -propanol (450 mg, 1.64 mmol) in ethyl acetate (15 ml) was added 1-naphthoyl chloride (369 ml, 2.45 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (622 m
g, 89%). ^{. mp 198-199 ℃ IRνmax KBr cm -1} : 1640, 1611, 1541, 1510. Anal Calcd for C 27 H 24 FNO 3: C, 75.51; H, 5.63; N,
3.26 Found:. C, 75.25; H, 5.88; N, 3.18 1 H-NMR (CDCl 3) δ: 2.69 (1H, dd, J = 14.2, 10.6 H
z), 3.01 (1H, dd, J = 14.2, 4.0 Hz), 3.80 (3H, s),
3.93 (1H, d, J = 4.0 Hz), 4.70-4.88 (1H, m), 5.02-
5.10 (1H, m), 5.82 (1H, d, J = 8.2 Hz), 6.86 (2H,
d, J = 8.6 Hz), 7.00-7.20 (4H, m), 7.20-7.52 (6H,
m), 7.73 (1H, d, J = 8.0 Hz), 7.80-7.92 (2H, m).

Example 149 4-Fluoro-N-((1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-((4- (methyloxy) phenyl) methyl) ethyl) -1 -Naphthalenecarboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (4- (methyloxy) phenyl) -1-propanol (450 mg, 1.64 mmol) in acetonitrile (30 ml) 4-Fluoronaphthalenecarboxylic acid (311 mg, 1.64 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (470 mg, 2.43 mmol) and 1
-Hydroxy-1H-benzotriazole (250 mg,
(1.64 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
1 × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and recrystallized from ethyl acetate-hexane to give the title compound (558 mg, 76%). ^{. mp 210-211 ℃ IRνmax KBr cm -1} : 1640, 1624, 1599, 1539, 1512. Anal Calcd for C 27 H 23 F 2 NO 3: C, 72.47; H, 5.18; N,
3.13 Found: C, 72.39; H, 5.08; N, 3.01. ¹ H-NMR (CDCl ₃ ) δ: 2.70 (1H, dd, J = 14.4, 10.8 H
z), 3.00 (1H, dd, J = 14.4, 4.0 Hz), 3.80 (3H, s),
3.84 (1H, d, J = 3.6 Hz), 4.66-4.84 (1H, m), 5.02-
5.10 (1H, m), 5.81 (1H, d, J = 7.6 Hz), 6.85 (2H,
d, J = 8.8 Hz), 6.92-7.22 (6H, m), 7.40-7.60 (4H,
m), 7.76 (1H, d, J = 8.4 Hz), 8.08 (1H, d, J = 8.0
Hz).

Example 150 N-((1RS, 2SR) -2- (4-fluorophenyl)
2-Hydroxy-1-((4- (methyloxy) phenyl) methyl) ethyl) cyclohexanecarboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (4- (methyloxy ) To a solution of phenyl) -1-propanol (450 mg, 1.64 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (328 ml, 2.45 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (529 m
g, 84%). ^{. mp 193-194 ℃ IRνmax KBr cm -1} : 1647, 1539, 1512. Anal Calcd for C 23 H 28 FNO 3: C, 71.66; H, 7.32; N,
3.63 Found:. C, 71.57; H, 7.40; N, 3.55 1 H-NMR (CDCl 3) δ: 1.02-1.40 (5H, m), 1.54-1.80 (5
H, m), 1.88-2.08 (1H, m), 2.56 (1H, dd, J = 14.4,
10.2 Hz), 2.82 (1H, dd, J = 14.4, 5.2 Hz), 3.78 (3
H, s), 4.30-4.50 (1H, m), 4.45 (1H, d, J = 4.4 H
z), 4.88-4.92 (1H, m), 5.24 (1H, d, J = 7.0 Hz), 6.
81 (2H, d, J = 8.8 Hz), 6.98-7.10 (4H, m), 7.28-7.
40 (2H, m).

Example 151 N-((1RS, 2SR) -2- (4-fluorophenyl)
2-Hydroxy-1-((4- (methyloxy) phenyl) methyl) ethyl) -4-phenylbutyric acid amide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (4 To a solution of-(methyloxy) phenyl) -1-propanol (450 mg, 1.64 mmol) in acetonitrile (30 ml) was added 4-phenyl-n-butyric acid (26
8 mg, 1.64 mmol) and 1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide hydrochloride (4
70 mg, 2.45 mmol) and 1-hydroxy-1
H-benzotriazole (250 mg, 1.64 mmol) was added and the mixture was stirred at room temperature overnight. The reaction solution was washed with water (100
ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 1: 1), and recrystallized from ethyl acetate-hexane to give the title compound (575 mg, 83%). ^{. mp 130-131 ℃ IRνmax KBr cm -1} : 1645, 1607, 1512. Anal Calcd for C 26 H 28 FNO 3: C, 74.09; H, 6.70; N,
3.32 Found:. C, 74.05; H, 6.82; N, 3.24 1 H-NMR (CDCl 3) δ: 1.70-1.90 (2H, m), 2.00-2.12 (2
H, m), 2.40-2.62 (3H, m), 2.80 (1H, dd, J = 14.2,
4.4 Hz), 3.72 (3H, s), 4.05 (1H, d, J = 4.4 Hz),
4.32-4.48 (1H, m), 4.88-4.98 (1H, m), 5.27 (1H, d,
J = 7.2 Hz), 6.79 (2H, d, J = 8.6 Hz), 6.96-7.14
(6H, m), 7.16-7.40 (5H, m).

Example 152 N-[(1RS, 2SR) -1- (4-cyanobenzyl)-
Tert-butyl 2- (4-fluorophenyl) -2-hydroxyethyl] carbamate 1) ethyl 2- (4-cyanobenzyl) -3- (4-fluorophenyl) -3-oxopropionate (4-fluorobenzoyl 15.30 g of ethyl acetate
(72.79 mmol) of 1,2-dimethoxyethane 1
2.91 g (72.8 mmol) of a 60% sodium hydride liquid paraffin suspension was added to the 00 ml solution under ice cooling, and the mixture was stirred for 0.5 hour. A solution of 14.3 g (72.8 mmol) of 4-cyanobenzyl bromide in 50 ml of 1,2-dimethoxyethane was added at room temperature, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography (hexane / toluene =
1 / 1-1 / 1.5) and crystallized from diethyl ether-hexane to obtain the desired product. White crystals Yield 20.6
0g Yield 87% mp 85-86 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 1.12 (3H, t,
J = 7.2 Hz), 3.38 (2H, d, J = 7.2 Hz), 4.10 (2H,
q, J = 7.1 Hz), 4.56 (1H, t, J = 7.5 Hz), 7.14 (2
H, t, J = 8.6 Hz), 7.35 (2H, d, J = 8.0 Hz), 7.56
(2H, d, J = 8.0 Hz), 8.00 (2H, dd, J = 5.4 Hz, 9.0
Hz); IR (KBr) 2230, 1730, 1692, 1599, 1508, 1306,
1285, 1236, 1202, 1161, 851 cm ^-1 ; Anal.Calcd for
C ₁₉ H ₁₆ FNO ₃ : C, 70.14; H, 4.96; N, 4.31. Found: C,
70.20; H, 4.84; N, 4.29.2) (2RS, 3RS) -2- (4-cyanobenzyl)-
Ethyl 3- (4-fluorophenyl) -3-hydroxypropionate While stirring 8.52 g (62.5 mmol) of zinc chloride in 100 ml of diethyl ether, 4.73 g (125 mmol) of sodium borohydride was added at room temperature. The mixture was stirred for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. 10.17 g (31.26 mmol) of ethyl 2- (4-cyanobenzyl) -3- (4-fluorophenyl) -3-oxopropionate was added to the resulting solution.
Was added at room temperature, followed by stirring for 2 hours. Dilute hydrochloric acid was added little by little to the reaction solution to decompose excess zinc borohydride, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-2 / 1) to obtain the desired product. Colorless liquid Yield 4.297 g Yield 42% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.93 (3H, t, J = 7.1 H)
z), 2.82 (1H, d, J = 2.8Hz), 2.89-3.08 (3H, m), 3.
88 (2H, q, J = 7.2 Hz), 5.03 (1H, dd, J = 2.5 Hz,
5.1 Hz), 7.05 (2H, t, J = 8.8 Hz), 7.20 (2H, d, J
= 8.4 Hz), 7.37 (2H, dd, J = 5.2 Hz, 8.4 Hz), 7.53
(2H, d, J = 8.4 Hz); IR (neat) 3484, 2230. 1725,
1607, 1508, 1223, 1179, 1159, 1032, 839 cm -1 3) (2RS, 3RS) -2- (4- cyanobenzyl) -
3- (4-Fluorophenyl) -3-hydroxypropionic acid (2RS, 3RS) -2- (4-cyanobenzyl) -3-
To a solution of 4.145 g (12.66 mmol) of ethyl (4-fluorophenyl) -3-hydroxypropionate in 30 ml of methanol and 20 ml of tetrahydrofuran was added 25.3 ml (25.3 mmol) of a 1N aqueous sodium hydroxide solution, and the mixture was added at room temperature. Stirred overnight. The reaction solution was concentrated, diluted with water, acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from diethyl ether-hexane to obtain the desired product. White crystals
Yield 3.559 g Yield 94% mp 165-168 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
89-3.15 (3H, m), 5.03 (1H, d, J = 5.0 Hz), 7.03 (2
H, t, J = 8.6 Hz), 7.24 (2H, d, J = 8.2 Hz), 7.40
(2H, dd, J = 5.5 Hz, 8.5 Hz), 7.51 (2H, d, J = 8.4
Hz); IR (KBr) 3476, 3152, 2232, 1719, 1678, 1605,
1508, 1406, 1225, 1175, 1157, 845 cm ^{- 1} ; Anal. Cal
_{cd for C 17 H 14 FNO 3} :. C, 68.22; H, 4.71; N, 4.68 Fou
nd: C, 67.98; H, 4.83; N, 4.47.4) (4RS, 5SR) -4- (4-cyanobenzyl)-
5- (4-fluorophenyl) -1,3-oxazolidine-
2-one (2RS, 3RS) -2- (4-cyanobenzyl) -3-
To a solution of 3.385 g (11.31 mmol) of (4-fluorophenyl) -3-hydroxypropionic acid in 50 ml of tetrahydrofuran, 2.36 ml of triethylamine (1
7.0 mmol), diphenylphosphoryl azide 3.4
2 g (12.4 mmol) was added, and the mixture was heated under reflux overnight.
The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / hexane).
Ethyl acetate = 3 / 1-1 / 2) and crystallization from diethyl ether-hexane to give the desired product. White crystals Yield 2.741 g Yield 82% mp 170-173 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.36 (2H,
d, J = 6.6 Hz), 4.27 (1H, dt, J = 7.5 Hz, 7.5 Hz),
5.17 (1H, br s), 5,81 (1H, d, J = 7.8 Hz), 7.13 (2
H, t, J = 8.6 Hz), 7.13 (2H, d, J = 8.0 Hz), 7.35
(2H, dd, J = 5.2 Hz, 8.4 Hz), 7.59 (2H, d, J = 8.0
Hz); IR (KBr) 3324, 2240, 1748, 1514, 1225
cm ^-1 ; Anal. Calcd for C
_{17 H 13 FN 2 O 2:} C, 68.91; H,
4.42; N, 9.45. Found: C,
68.98; H, 4.43; N, 9.33. 5) (4RS, 5SR) -4- (4-cyanobenzyl)-
Tert-Butyl 5- (4-fluorophenyl) -2-oxo-1,3-oxazolidine-3-carboxylate (4RS, 5SR) -4- (4-cyanobenzyl) -5-
(4-Fluorophenyl) -1,3-oxazolidine-2-
2.622 g (8.849 mmol) of di-dicarbonate
2.32 g (10.6 mmol) of tert-butyl, 4-
0.11 g of N, N-dimethylaminopyridine (0.88
(Mmol) in 30 ml of acetonitrile was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystal Yield 3.243 g Yield 92% mp 161-163 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.51 (9H,
s), 2.63 (1H, dd, J = 8.6 Hz, 14.2 Hz), 2.93 (1H, d
d, J = 4.7 Hz, 14.3 Hz), 4.74-4.85 (1H, m), 5.68 (1
H, d, J = 6.6 Hz), 6.80 (2H, d, J = 8.0 Hz), 7.00
(2H, t, J = 8.6 Hz), 7.16 (2H, dd, J = 5.4 Hz, 8.6
Hz), 7.39 (2H, d, J = 8.0 Hz); IR (KBr) 2982, 222
8, 1815, 1721, 1514, 1368, 1152, 1069 cm ^-1 ; Anal.
Calcd for C ₂₂ H ₂₁ FN ₂ O ₄ : C, 66.66; H, 5.34; N, 7.07.
Found: C, 66.76; H, 5.37; N, 7.09.6) N-[(1RS, 2SR) -1- (4-cyanobenzyl) -2- (4-fluorophenyl) -2-hydroxyethyl] carbamic acid tert-butyl (4RS, 5SR) -4- (4-cyanobenzyl) -5-
Tert-Butyl (4-fluorophenyl) -2-oxo-1,3-oxazolidine-3-carboxylate 3.014 g
(7.603 mmol) in methanol (20 ml) -tetrahydrofuran (10 ml) was treated with sodium hydroxide 0.33.
g (8.36 mmol) in 20 ml of methanol was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed with dilute hydrochloric acid, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystal Yield 2.366 g Yield 84% mp 203-204 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.33 (9H,
s), 2.67-2.98 (3H, m), 4.06 (1H, br s), 4.63 (1H, b
rd, J = 8.4 Hz), 4.93 (1H, br s), 7.07 (2H, t, J
= 8.6 Hz), 7.21 (2H, d, J = 8.2 Hz), 7.38 (2H, dd,
J = 5.4 Hz, 8.6 Hz), 7.54 (2H, d, J = 8.4 Hz); IR
(KBr) 3466, 3366, 2236, 1684, 1508,1530, 1221, 11
^{. 71 cm -1; Anal Calcd for} C 21 H 23 FN 2 O 3: C, 68.09; H,
6.26; N, 7.56. Found: C, 68.20; H, 6.18; N, 7.60.

Example 153 N-[(1RS, 2SR) -1- (4-cyanobenzyl)-
2- (4-fluorophenyl) -2-hydroxyethyl]-
4-Fluoronaphthalene-1-carboxamide 1) (1RS, 2SR) -2-amino-3- (4-cyano
Phenyl) -1- (4-fluorophenyl) propane-1-
All N-[(1RS, 2SR) -1- (4-cyanobenzyl)-
2- (4-fluorophenyl) -2-hydroxyethyl] ca
2.199 g of tert-butyl rubamate (5.937)
Mmol), 4 ml of concentrated hydrochloric acid, 30 ml of methanol
A 20 ml solution of lahydrofuran is stirred at 60 ° C. for 30 minutes.
Was. Dilute the reaction solution with water and make it alkaline with potassium carbonate.
And extracted twice with ethyl acetate. The collected organic layer is anhydrous sulfur
The extract was dried over sodium acid and the solvent was distilled off under reduced pressure. Remove the residue
Precipitation from ethyl ether-hexane gave the desired product.
Was. White amorphous powder Yield 1.557 g Yield 9
7%¹ H-NMR (CDCl_Three, 200MHz) δ 2.44 (1H, dd, J = 10.3 H
z, 13.5 Hz), 2.88 (1H, dd, J = 2.9 Hz, 13.9 Hz), 3.
28 (1H, ddd, J = 3.2 Hz, 5.1 Hz, 10.2 Hz), 4.64 (1
H, d, J = 5.2 Hz), 7.08 (2H, t, J = 8.8 Hz), 7.27
(2H, d, J = 8.6Hz), 7.37 (2H, dd, J = 5.6Hz, 8.8
Hz), 7.58 (2H, d, J = 8.0 Hz); IR (KBr) 3350-2750,
 2224, 1605, 1507, 1221, 1044, 828 cm^-1; Anal. Cal
cd for C ₁₆H₁₅FN_TwoO ・ 0.2H_TwoO: C, 70.16; H, 5.67; N, 1
0.23. Found: C, 70.55; H, 5.84; N, 9.95. 2) N-[(1RS, 2SR) -1- (4-cyanobenzy)
) -2- (4-Fluorophenyl) -2-hydroxyethyl
Ru] -4-Fluoronaphthalene-1-carboxamide (1RS, 2SR) -2-amino-3- (4-cyanophenyi)
) -1- (4-Fluorophenyl) propan-1-ol
0.168 g (0.622 mmol), 4-fluoro-1
-Naphthoic acid 0.12 g (0.62 mmol), 1-hydrido
Roxybenzotriazole hydrate 0.10 g (0.62
Mmol) in 10 ml of acetonitrile with stirring
1-ethyl-3- (3-dimethylaminopropyl) carbodi
0.12 g (0.62 mmol) of imide / hydrochloride was added.
And stirred overnight at room temperature. Dilute the reaction solution in ethyl acetate
And washed with aqueous sodium bicarbonate solution, anhydrous magnesium sulfate
After drying with silica and passing through silica gel, the solvent is distilled off under reduced pressure
did. The obtained residue was crystallized from ethyl acetate-hexane.
To give the desired product. 0.217 g of white crystals
Yield 79% mp 248-249 ° C;¹H-NMR (CDCl_Three-DMSO-d₆, 200MHz) δ 2.
93 (1H, dd, J = 11.0 Hz, 14.4 Hz), 3.14 (1H, dd, J
 = 3.4 Hz, 13.6 Hz), 4.64-4.79 (1H, m), 4.94 (1H,
t, J = 4.6 Hz), 5.42 (1H, d, J = 4.2 Hz), 7.02-7.1
2 (3H, m), 7.20 (1H, dd, J = 5.5 Hz, 7.7 Hz), 7.37-
7.58 (9H, m), 7.78 (1H, d, J = 9.4 H), 8.05 (1H,
d, J = 7.6 Hz); IR (KBr) 3476, 3291, 2232, 1642, 1
626, 1603, 1537, 1508, 1225, 847 cm^-1; Anal. Calcd
for C₂₇H₂₀F_TwoN_TwoO_Two: C, 73.29; H, 4.56; N, 6.33. Foun
d: C, 73.08; H, 4.43; N, 6.10.

Example 154 4-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- (4-isopropylbenzyl) ethyl] naphthalene-1-carboxamide 1)
Ethyl 3- (4-fluorophenyl) -2- (4-isopropylbenzyl) -3-oxopropionate 23.21 g of ethyl (4-fluorobenzoyl) acetate
(110.4 mmol) of 1,2-dimethoxyethane 1
To a 50 ml solution was added 4.42 g (110 mmol) of a 60% sodium hydride liquid paraffin suspension under ice cooling.
The mixture was stirred for 0.5 hours as it was. A solution of 18.6 g (110 mmol) of 4-isopropylbenzyl chloride in 50 ml of 1,2-dimethoxyethane was added at room temperature, and the mixture was stirred at 70 ° C. overnight. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-9 / 1) to obtain the desired product. Yellow liquid Yield 21.01 g Yield 56% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.12 (3H, t, J = 7.1 H)
z), 1.20 (6H, d, J = 7.0Hz), 2.78-2.91 (1H, m), 3.
28 (2H, d, J = 7.2 Hz), 4.10 (2H, q, J = 7.1 Hz),
4.55 (1H, t, J = 7.3 Hz), 7.06-7.26 (6H, m), 7.98
(2H, dd, J = 5.7Hz, 8.7 Hz); IR (neat) 2961, 1738,
1688, 1599, 1508, 1271, 1235, 1159, 849 cm ^-1 2) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- (4-isopropylbenzyl)
Ethyl propionate While stirring 8.41 g (61.7 mmol) of zinc chloride in 100 ml of diethyl ether, 4.67 g (123 mmol) of sodium borohydride was added at room temperature, and the mixture was stirred for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. To the resulting solution was added a solution of 10.57 g (30.87 mmol) of ethyl 3- (4-fluorophenyl) -2- (4-isopropylbenzyl) -3-oxopropionate in 50 ml of diethyl ether at room temperature.
The mixture was stirred for 2 hours. Dilute hydrochloric acid was added little by little to the reaction solution to decompose excess zinc borohydride, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-3 / 1) to obtain the desired product. Colorless liquid Yield 8.433 g Yield 79% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.91 (3H, t, J = 7.1 H)
z), 1.20 (6H, d, J = 7.0Hz), 2.71-3.09 (4H, m), 3.
80-4.96 (2H, m), 5.00 (1H, s), 6.94-7.11 (6H, m),
7.37 (2H, dd, J = 5.6 Hz, 8.6 Hz); IR (neat) 3445,
2961, 1726, 1713, 1510, 1225, 1157, 1032, 837 cm
^-1 3) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- (4-isopropyl-benzyl)
Propionic acid (2RS, 3RS) -3- (4-fluorophenyl) -3-
A solution of 8.267 g (24.00 mmol) of ethyl hydroxy-2- (4-isopropylbenzyl) propionate in 40 ml of methanol-50 ml of tetrahydrofuran was added to a solution.
48.0 ml (48.0 mmol) of an N sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, diluted with water, acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from diethyl ether-hexane to obtain the desired product. White crystal Yield 6.275 g Yield 83% mp 147-148 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.21 (6H,
d, J = 7.0 Hz), 2.78-3.09 (4H, m), 5.04 (1H, d, J
= 4.4 Hz), 6.98-7.12 (6H, m), 7.36 (2H, dd, J = 5.2
Hz, 8.6 Hz); IR (KBr) 3330, 3050-2600, 1690, 151
8, 1240, 1221, 1196, 849, 839 cm ^-1 ; Anal.Calcd fo
r C ₁₉ H ₂₁ FO ₃ : C, 72.13; H, 6.69.Found: C, 72.03; H,
6.55.4. 4) (4RS, 5SR) -5- (4-fluorophenyl) -4- (4-isopropylbenzyl) -1,3-oxazolidine-2-one (2RS, 3RS) -3- (4-fluorophenyl) ) -3-
To a solution of 6.128 g (19.37 mmol) of hydroxy-2- (4-isopropylbenzyl) propionic acid in 80 ml of tetrahydrofuran, 4.05 ml of triethylamine was added.
(29.1 mmol) and 5.86 g (21.3 mmol) of diphenylphosphoryl azide, and the mixture was refluxed overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1) and crystallized from toluene-hexane to give the desired product I got White crystal Yield 5.680 g Yield 94% mp 185-186 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.22 (6H,
d, J = 7.0 Hz), 2.10-2.30 (2H, m), 2.80-2.94 (1H,
m), 4.20 (1H, ddd, J = 4.2 Hz, 7.8 Hz, 10.4 Hz), 4.
90 (1H, br s), 5.79 (1H, d, J = 7.6 Hz), 6.95 (2H,
d, J = 8.0 Hz), 7.09-7.18 (4H, m), 7.37 (2H, dd,
J = 5.2 Hz, 8.8 Hz); IR (KBr) 3262, 2961, 1738, 15
14, 1231, 1009, 855 cm ^-1 ; Anal.Calcd for C ₁₉ H ₂₀ FN
O ₂ : C, 72.82; H, 6.43; N, 4.47. Found: C, 72.68;
H, 6.30; N, 4.65.5) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (4-isopropylphenyl) propan-1-ol (4RS, 5SR) -5- (4-fluorophenyl) -4-
(4-isopropylbenzyl) -1,3-oxazolidine-
5.503 g (17.56 mmol) of 2-one and 2.81 g (70.2 mmol) of sodium hydroxide were heated to reflux in 40 ml of ethanol-3 ml of water for 7 hours. The reaction was diluted with water and stirred at room temperature for 10 minutes. The resulting precipitate was collected by filtration and washed with water to obtain the desired product. White crystals Yield 4.097 g Yield 81% mp 74-75 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.23 (6H, d,
J = 6.8 Hz), 2.29 (1H, dd, J = 10.4 Hz, 13.8 Hz),
2.75 (1H, dd, J = 2.8 Hz, 13.2 Hz), 2.80-2.94 (1
H, m), 3.26 (1H, ddd, J = 3.5 Hz, 4.8 Hz, 10.5 H
z), 4.66 (1H, d, J = 5.2 Hz), 7.03-7.17 (6H, m), 7.
37 (2H, dd, J = 5.6 Hz, 8.4 Hz); IR (KBr) 3627, 33
49, 3281, 3150-2700, 1507, 1219, 1042, 855, 924 cm
^-1 ; Anal.Calcd for C ₁₈ H ₂₂ FNO ・ 0.2H ₂ O: C, 74.30; H,
7.76; N, 4.81. Found: C, 74.38; H, 7.80; N, 4.65.6) 4-Fluoro-N-[(1RS, 2SR) -2- (4-
Fluorophenyl) -2-hydroxy-1- (4-isopropylbenzyl) ethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (4-isopropylphenyl) Propane-1-
0.164 g (0.571 mmol) of all, 0.11 g (0.57 mmol) of 4-fluoro-1-naphthoic acid,
87 mg of 1-hydroxybenzotriazole hydrate
(0.57 mmol) was stirred in 10 ml of acetonitrile, and 0.11 g (0.57 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added thereto, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 0.2
11g Yield 80% mp 189-192 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200MHz) δ 1.
23 (6H, d, J = 6.8 Hz), 2.77-3.06 (3H, m), 4.62-4.
76 (1H, m), 4.95 (1H, t, J = 4.2 Hz), 5.33 (1H, d,
J = 4.0 Hz), 6.99-7.24 (8H, m), 7.37-7.65 (6H,
m), 8.04 (1H, d, J = 8.6 Hz); IR (KBr) 3299, 2959,
1642, 1626, 1539, 1512, 1227, 835 cm ^-1 ; Anal.Calcd
for C ₂₉ H ₂₇ F ₂ NO ₂ : C, 75.80; H, 5.92; N, 3.05. Foun
d: C, 75.67; H, 5.77; N, 2.87.

Example 155 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- (4-isopropylbenzyl) ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl ) -3- (4-Isopropylphenyl) propane-1-
0.219 g (0.762 mmol) of all, 6,7-
0.14 g (0.76 mmol) of dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid and 0.12 g (0.76 mmol) of 1-hydroxybenzotriazole hydrate were added to 10 ml of acetonitrile while stirring. 0.15 g (0.76 mmol) of -ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White powder Yield 0.294
g Yield 84% mp 168-169 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.23 (6H,
d, J = 7.0 Hz), 1.95-2.06 (2H, m), 2.14-2.23 (2H,
m), 2.61-2.76 (3H, m), 2.86 (1H, dd, J = 6.6Hz, 1
4.0 Hz), 2.97 (1H, dd, J = 4.4 Hz, 13.6 Hz), 4.14
(1H, d, J = 4.4Hz), 4.61-4.74 (1H, m), 5.02 (1H,
t, J = 3.1 Hz), 5.63 (1H, d, J = 7.8 Hz), 5.93 (1
H, td, J = 5.7 Hz, 11.3 Hz), 6.24 (1H, d, J = 11.8
Hz), 6.89 (1H, d, J = 7.4 Hz), 7.00-7.18 (8H, m),
7.42 (2H, dd, J = 5.4 Hz, 8.6 Hz); IR (KBr) 3291,
1638, 1534, 1512, 1225, 1038, 826 cm ^-1 ; Anal.Calc
_{d for C 30 H 32 FNO 2} :. C, 78.75; H, 7.05; N, 3.06 Foun
d: C, 78.66; H, 6.98; N, 3.06.

Example 156 N-((1RS, 2SR) -2- (4-fluorophenyl)
-1-((3-Fluoro-4- (trifluoromethyl) phenyl) methyl) -2-hydroxyethyl) -4-fluoro-
1-Naphthalenecarboxamide 1) To a solution of 3-fluoro-4- (trifluoromethyl) benzoic acid (10.5 g, 50.7 mmol) in tetrahydrofuran (30 ml) was added a 1M borane solution in tetrahydrofuran (63 ml, 63 mmol) and room temperature. For 8 hours. 1N hydrochloric acid (100 ml) was added to the reaction solution,
Extracted with ethyl acetate (300 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and 3-fluoro-4- (trifluoromethyl) benzyl alcohol (10.3 g, 90
% Purity, 94%). ¹ H-NMR (CDCl ₃ ) δ: 1.91 (1H, t, J = 5.4 Hz), 4.78
(2H, d, J = 5.4 Hz), 7.16-7.30 (2H, m), 7.59 (1H,
t, J = 7.6 Hz). 2) Thionyl chloride (18.5 ml, 25 ml) was added to a solution of 3-fluoro-4- (trifluoromethyl) benzyl alcohol (10 g, 52 mmol) in chloroform (20 ml).
(7 mmol) and heated to reflux for 4 hours. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 3-fluoro-4- (trifluoromethyl) benzyl chloride (9.52 g, 87%). Was. ^{IRνmax KBr cm -1: 1634, 1589} , 1512, 1435. 1 H-NMR (CDCl 3) δ: 4.58 (2H, s), 7.20-7.32 (2H, m),
7.60 (1H, t, J = 7.6 Hz). 3) 1,2-Ethyl 3- (4-fluorophenyl) -3-oxopropionate (8.9 g, 42.3 mmol)
Sodium hydride (60% oily, 1.69 g, 42.3 mmol) was added to a dimethoxyethane (50 ml) solution under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. A solution of 3-fluoro-4- (trifluoromethyl) benzyl bromide (9.0 g, 42.3 mmol) in 1,2-dimethoxyethane (50 ml) was added dropwise to the reaction solution, and the reaction solution was allowed to stand at room temperature for 3 hours. Stirred. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene: hexane = 1: 1-toluene) and recrystallized from diisopropyl ether-hexane to give 3- (4-fluorophenyl) -2-((3-fluoro-4- (Trifluoromethyl) phenyl) methyl) -3-
Ethyl oxopropionate (10.8 g, 66%) was obtained. mp 56-57 ℃ IRνmax ^KBr cm ^-1 : 1738, 1688, 1630, 1599, 1508. Anal.Calcd for C ₁₉ H ₁₅ O ₃ F ₅ : C, 59.07; H, 3.91 Found: C, 59.10; H, 3.68 _{^{. 1 H-NMR (CDCl 3}} ) δ: 1.13 (3H, t, J = 7.2 Hz), 3.37
(2H, d, J = 7.2 Hz), 4.12 (2H, q, J = 7.2 Hz), 4.5
7 (1H, t, J = 7.2 Hz), 7.02-7.20 (4H, m), 7.50 (1
H, t, J = 8.0 Hz), 7.96-8.10 (2H, m). 4) To a solution of zinc chloride (7.06 g, 51.8 mmol) in diethyl ether (100 ml) was added sodium borohydride (3.92 g, (103.5 mmol) and stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was added with 3- (4-
A solution of ethyl fluorophenyl) -2-((3-fluoro-4- (trifluoromethyl) phenyl) methyl) -3-oxopropionate (10 g, 25.9 mmol) in diethyl ether (50 ml) was added, and the mixture was added at room temperature. Stir for 30 minutes. Under ice cooling, the reaction solution is quenched by adding 1N hydrochloric acid,
Further, water (200 ml) was added, and ethyl acetate (300 ml) was added.
× 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give (2RS, 3RS) -3- (4-fluorophenyl) -2-((3-fluoro-4- (trifluoromethyl) phenyl) methyl)- Ethyl 3-hydroxypropionate (10.0 g, 99%) was obtained as a colorless oil. ^{. IRνmax KBr cm -1: 1715,} 1632, 1607, 1584. Anal Calcd for C 19 H 17 O 3 F 5: C, 58.77; H, 4.41 Found:. C, 58.54; H, 4.51 1 H-NMR (CDCl ₃ ) δ: 0.95 (3H, t, J = 7.2 Hz), 2.86-
3.10 (4H, m), 3.91 (2H, q, J = 7.2 Hz), 4.98-5.06
(1H, m), 6.90-7.10 (4H, m), 7.30-7.50 (3H, m). 5) (2RS, 3RS) -3- (4-fluorophenyl) -2-((3-fluoro-4 -(Trifluoromethyl)
Ethyl (phenyl) methyl) -3-hydroxypropionate (9.9 g, 25.5 mmol) in methanol (40 m
l) Add 2N aqueous sodium hydroxide solution (25.5
ml, 51.0 mmol) and stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (2RS, 3RS) -3- (4-fluorophenyl) -2.
-((3-Fluoro-4- (trifluoromethyl) phenyl) methyl) -3-hydroxypropionic acid (8.3 g,
90%). mp 74-75 ℃ IRνmax ^KBr cm ^-1 : 1713, 1632, 1607, 1586, 1512, 143
_{^{5. 1 H-NMR (CDCl 3}} ) δ: 2.80-3.16 (3H, m), 5.09 (1H, d,
J = 4.2 Hz), 6.88-7.12 (4H, m), 7.30-7.52 (3H, m). 6) (2RS, 3RS) -3- (4-fluorophenyl) -2-((3-fluoro-4 -(Trifluoromethyl)
(Phenyl) methyl) -3-hydroxypropionic acid (7.
0 g, 19.4 mmol) of tetrahydrofuran (18
0 ml) solution in diphenylphosphoryl azide (4.6).
ml, 21.4 mmol) and triethylamine (4.1
ml, 29.2 mmol) and heated to reflux for 6 hours. After allowing the reaction solution to cool, water (200 ml) was added, and the mixture was extracted with ethyl acetate (200 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and the residue was recrystallized from ethyl acetate-hexane (4R
S, 5SR) -5- (4-fluorophenyl) -4-((3-
Fluoro-4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidin-2-one (5.26 g, 7
6%). mp 122-123 ℃ IRνmax ^KBr cm ^-1 : 1759, 1632, 1611, 1586, 1514, 143
_{. 5. Anal Calcd for C 17 H} 12 O 2 F 5 N: C, 57.15; H, 3.39; N,
3.92 Found:. C, 57.18; H, 3.39; N, 3.75 1 H-NMR (CDCl 3) δ: 2.35 (2H, d, J = 7.4 Hz), 4.22-
4.36 (1H, m), 5.44 (1H, s), 5.80 (1H, d, J = 7.8 H
z), 6.80-6.96 (2H, m), 7.04-7.20 (2H, m), 7.22-7.4
2 (2H, m), 7.46-8.00 (1H, m). 7) (4RS, 5SR) -5- (4-fluorophenyl) -4-((3-fluoro-4- (trifluoromethyl)
Phenyl) methyl) -1,3-oxazolidin-2-one (4.0 g, 11.2 mmol) in ethanol (70 m
l) 8N aqueous sodium hydroxide solution (7.0 m
(1, 56 mmol) and heated to reflux for 6 hours. After concentration, the reaction solution was diluted with water (300 ml) and extracted with ethyl acetate (300 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was recrystallized from ethyl acetate-hexane to give (1
RS, 2SR) -2-Amino-1- (4-fluorophenyl) -3- (3-fluoro-4- (trifluoromethyl) phenyl) -1-propanol (3.21 g, 87%) was obtained. mp 86-87 ℃ IRνmax ^KBr cm ^-1 : 1630, 1590, 1508, 1433, 1331. Anal.Calcd for C ₁₆ H ₁₄ F ₅ NO: C, 58.01; H, 4.26; N,
4.23 Found:. C, 58.02; H, 4.29; N, 4.00 1 H-NMR (CDCl 3) δ: 2.44 (1H, dd, J = 13.6, 10.2 H
z), 2.87 (1H, dd, J = 13.6, 2.6 Hz), 3.22-3.36 (1
H, m), 4.64 (1H, d, J = 5.2 Hz), 6.96-7.16 (4H, m),
7.30-7.42 (2H, m), 7.44-7.58 (1H, m). 8) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (3-fluoro-4- (tri (Fluoromethyl) phenyl) -1-propanol (400 mg, 1.
21 mmol) in acetonitrile (30 ml) solution.
-Fluoronaphthalenecarboxylic acid (230 mg, 1.2
1 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (347 mg, 1.
81 mmol) and 1-hydroxy-1H-benzotriazole (185 mg, 1.21 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (525 mg, 86%). mp 212-213 ° C IRνmax ^KBr cm ^-1 : 1640, 1626, 1599, 1514, 1435, 132
5. Anal.Calcd for C ₂₇ H ₁₉ F ₆ NO ₂・ 0.1H ₂ O: C, 64.19; H,
3.83; N, 2.77 Found:. C, 63.97; H, 3.83; N, 2.52 1 H-NMR (CDCl 3) δ: 2.82-3.16 (3H, m), 4.70-4.90 (1
H, m), 5.12 (1H, d, J = 3.6 Hz), 6.05 (1H, d, J =
8.8 Hz), 7.00-7.30 (6H, m), 7.40-7.62 (5H, m), 7.7
2 (1H, d, J = 8.0 Hz), 8.11 (1H, d, J = 7.8 Hz).

Example 157 N-((1RS, 2SR) -2- (4-fluorophenyl)
-1-((3-Fluoro-4- (trifluoromethyl) phenyl) methyl) -2-hydroxyethyl) -3-phenylpropanamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (3-Fluoro-4- (trifluoromethyl)
To a solution of (phenyl) -1-propanol (400 mg, 1.21 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (269 ml, 1.81 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml), and the mixture was stirred at room temperature overnight. . The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (486 mg, 87%). mp 126-127 ℃ IRνmax ^KBr cm ^-1 : 1632, 1510, 1435, 1325. Anal.Calcd for C ₂₅ H ₂₂ F ₅ NO ₂ : C, 64.79; H, 4.78; N,
3.02 Found:. C, 64.61; H, 4.77; N, 2.80 1 H-NMR (CDCl 3) δ: 2.32-2.44 (2H, m), 2.58-2.80 (2
H, m), 2.88 (2H, t, J = 7.4 Hz), 3.00 (1H, d, J =
4.2 Hz), 4.26-4.42 (1H, m), 4.76-4.84 (1H, m), 5.3
8 (1H, d, J = 8.4 Hz), 6.78-6.90 (2H, m), 7.00-7.5
0 (10H, m).

Example 158 4-Fluoro-N-((1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-((4- (phenyloxy) phenyl) methyl) ethyl) -1 -Naphthalenecarboxamide 1) 4- (phenyloxy) benzoic acid (10.4 g,
48.7 mmol) in tetrahydrofuran (30 ml)
A borane 1M tetrahydrofuran solution (63 ml,
63 mmol) at room temperature and stirred overnight. The reaction solution is quenched by adding 1N hydrochloric acid, and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from hexane to give (4- (phenyloxy) phenyl) methanol (8.51 g, 8
7%). ^{. mp 48-49 ℃ IRνmax KBr cm -1} : 1590, 1507, 1489, 1240. Anal Calcd for C 13 H 12 O 2: C, 77.98; H, 6.04 Found:. C, 77.94; H, 5.74 1 H- NMR (CDCl ₃ ) δ: 1.67 (1H, brs), 4.67 (2H, d, J =
4.0 Hz), 6.96-7.18 (5H, m), 7.22-7.40 (4H, m). 2) (4- (phenyloxy) phenyl) methanol (8 g, 40.0 mmol) in chloroform (20 m
1) Thionyl chloride (36 ml, 500 mmol) was added to the solution.
Was added and heated to reflux overnight. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (ethyl acetate), and 1- (chloromethyl) -4- (phenyloxy)
Benzene (8.1 g, 93%) was obtained. ^{IRνmax KBr cm -1: 1590, 1507} , 1489, 1240. 1 H-NMR (CDCl 3) δ: 3.93 (1H, brs), 4.57 (2H, s), 6.
80-7.40 (9H, m). 3) 1,3-Ethyl 3- (4-fluorophenyl) -3-oxopropionate (6.49 g, 30.9 mmol)
To a solution of -dimethoxyethane (50 ml) was added sodium hydride (60% oily, 1.23 g, 30.9 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 1- in the reaction solution
A solution of (chloromethyl) -4- (phenyloxy) benzene (8.1 g, 37.0 mmol) in 1,2-dimethoxyethane (50 ml) was added dropwise, and the reaction solution was heated to reflux overnight. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene: hexane = 1: 1-toluene) to give 3- (4-fluorophenyl) -3-oxo-2-((4
Ethyl (-(phenyloxy) phenyl) methyl) propionate (7.76 g, crude, 64%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.4 Hz), 3.30
(2H, d, J = 7.6 Hz), 4.12 (2H, q, J = 7.4 Hz), 4.5
6 (1H, t, J = 7.6 Hz), 6.80-7.40 (11H, m), 7.90-8.
08 (2H, m). 4) Sodium borohydride (3.00 g, 79.1 mmol) was added to a solution of zinc chloride (5.39 g, 39.6 mmol) in diethyl ether (100 ml), and the mixture was added at room temperature for 30 minutes. Stirred. The insoluble material was removed by filtration, and the filtrate was added with ethyl 3- (4-fluorophenyl) -3-oxo-2-((4- (phenyloxy) phenyl) methyl) propionate (7.7).
6 g, 19.8 mmol) of diethyl ether (50 m
l) The solution was added and stirred at room temperature for 30 minutes. Under ice-cooling, the reaction solution was quenched by adding 1N hydrochloric acid, and further added with water (200 m 2).
1) and extracted with ethyl acetate (300 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
4: 1-1: 1), and purified by (2RS, 3RS) -3-
(4-fluorophenyl) -3-hydroxy-2-((4-
Ethyl (phenyloxy) phenyl) methyl) propionate (6.66 g, 85%) was obtained as a colorless oil. IRνmax ^KBr cm ^-1 : 1726, 1590, 1507, 1489. ¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, t, J = 7.0 Hz), 2.90-
3.00 (4H, m), 3.91 (2H, q, J = 7.0 Hz), 5.00 (1H, b
rs), 6.82-7.20 (9H, m), 7.24-7.42 (4H, m). 5) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((4- (phenyl Ethyl oxy) phenyl) methyl) propionate (6.6 g, 1
6.7 mmol) in methanol (30 ml).
Normal sodium hydroxide aqueous solution (16.7 ml, 33.4
Mmol) and stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid, and then ethyl acetate (200 ml × 2).
Extracted. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give (2RS, 3RS) -3- (4-)
Fluorophenyl) -3-hydroxy-2-((4- (phenyloxy) phenyl) methyl) propionic acid (5.8
g, 95%). ^{. IRνmax KBr cm -1: 1713,} 1590. Anal Calcd for C 22 H 19 FO 4: C, 72.12; H, 5.23 Found:. C, 72.20; H, 5.23 1 H-NMR (CDCl 3) δ: 2.90- 3.08 (3H, m), 3.92 (1H, s),
5.05 (1H, d, J = 4.4Hz), 6.80-7.20 (9H, m), 7.30-
7.44 (4H, m). 6) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((4- (phenyloxy) phenyl) methyl) propionic acid (5.5 g, 15 2.0 mmol) in tetrahydrofuran (150 ml),
Diphenyl phosphoryl azide (3.56 ml, 16.5
Mmol) and triethylamine (3.15 ml, 22.
(5 mmol) and heated to reflux for 4 hours. After allowing the reaction solution to cool, water (200 ml) was added, and ethyl acetate (200 ml) was added.
1 × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1-1:
Purified in 1) and recrystallized from ethyl acetate-hexane to give (4RS, 5SR) -5- (4-fluorophenyl)-
4-((4- (phenyloxy) phenyl) methyl)-
1,3-Oxazolidin-2-one (3.74 g, 69
%). ^{mp 144-145 ℃ IRνmax KBr cm -1:} 1755, 1590, 1505. 1 H-NMR (CDCl 3) δ: 2.16-2.30 (2H, m), 4.16-4.30 (1
H, m), 5.14 (1H, s), 5.79 (1H, d, J = 8.0 Hz), 6.8
0-7.42 (13H, m). 7) (4RS, 5SR) -5- (4-fluorophenyl) -4-((4- (phenyloxy) phenyl) methyl) -1,3-oxazolidin-2-one (2.5 g, 6.
To a solution of 88 mmol) in ethanol (20 ml) was added an 8 N aqueous sodium hydroxide solution (4.30 ml, 34.4 mmol), and the mixture was heated under reflux for 6 hours. After concentrating the reaction solution,
Dilute with water (100ml) and add ethyl acetate (100ml x
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give (1RS, 2S
R) -2-Amino-1- (4-fluorophenyl) -3- (4-
(Phenyloxy) phenyl) -1-propanol (2.
2 g, 95%). ^{IRνmax KBr cm -1: 1590, 1507} , 1489, 1238. 1 H-NMR (CDCl 3) δ: 2.00-2.40 (2H, m), 3.93 (1H, s),
5.11 (1H, d, J = 7.4 Hz), 6.80-7.40 (13H, m). 8) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (4- (phenyloxy ) Phenyl)-
In a solution of 1-propanol (353 mg, 1.05 mmol) in acetonitrile (20 ml), 4-fluoronaphthalenecarboxylic acid (200 mg, 1.05 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (302 mg, 1.58 mmol) and 1-hydroxy-1H-benzotriazole (161
mg, 1.05 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). Extract solution is 1N hydrochloric acid,
The extract was washed successively with a 1N aqueous sodium hydroxide solution and a saturated saline solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purification with ethyl acetate = 4: 1-1: 1)
Recrystallization from hexane gave the title compound (166 mg,
31%). mp 104-105 ℃ IRνmax ^KBr cm ^-1 : 1644, 1626, 1601, 1590, 1507, 148
_{^{9. 1 H-NMR (CDCl 3}} ) δ: 2.75 (1H, dd, J = 14.4, 11.0 H
z), 3.06 (1H, dd, J = 14.4, 4.0 Hz), 3.64-3.70 (1
H, m), 4.70-4.88 (1H, m), 5.04-5.12 (1H, m), 5.90
(1H, d, J = 8.4 Hz), 6.90-7.60 (17H, m), 7.78-7.86
(1H, m), 8.09 (1H, d, J = 7.8 Hz).

Example 159 N- (1RS, 2SR)-(2- (4-fluorophenyl)
-2-Hydroxy-1-((4- (phenyloxy) phenyl) methyl) ethyl) -3-phenylpropanamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (4 To a solution of-(phenyloxy) phenyl) -1-propanol (550 mg, 1.63 mmol) in ethyl acetate (20 ml) was added 3-phenylpropionyl chloride (360 ml, 2.45 mmol) and saturated aqueous sodium bicarbonate (20 ml). Stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-1: 1), and recrystallized from ethyl acetate-hexane to obtain the title compound (152 mg, 20%). mp 108-110 ° C IRνmax ^KBr cm ^-1 : 1644, 1605, 1507, 1489. ¹ H-NMR (CDCl ₃ ) δ: 2.24-2.40 (2H, m), 2.40-3.00 (5
H, m), 4.30-4.44 (1H, m), 4.76-4.84 (1H, m), 5.69
(1H, d, J = 8.0 Hz), 6.80-7.36 (18H, m).

Example 160 4-Fluoro-N-((1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-((3- (phenyloxy) phenyl) methyl) ethyl) -1 -Naphthalenecarboxamide 1) (3- (phenyloxy) phenyl) methanol (10 g, 49.4 mmol) in chloroform (20 m
1) Thionyl chloride (36 ml, 500 mmol) was added to the solution.
Was added and heated to reflux overnight. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (ethyl acetate), and 1- (chloromethyl) -3- (phenyloxy)
Benzene (10.7 g, 98%) was obtained. ^{IRνmax KBr cm -1: 1584, 1487} , 1445. 1 H-NMR (CDCl 3) δ:. 4.53 (2H, s), 6.80-7.40 (9H, m) 2) 3- (4- fluorophenyl) -3 1,2-Ethyl-oxopropionate (7.2 g, 34.3 mmol)
Sodium hydride (60% oily, 1.37 g, 34.3 mmol) was added to a dimethoxyethane (50 ml) solution under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 1- (chloromethyl) -3- (phenyloxy) benzene (9.0
g, 41.6 mmol) in 1,2-dimethoxyethane (50 ml) was added dropwise and the reaction was heated to reflux overnight. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene: hexane = 1: 1-toluene),
3- (4-fluorophenyl) -3-oxo-2-((3-
Ethyl (phenyloxy) phenyl) methyl) propionate (10.2 g, crude, 76%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.0 Hz), 3.29
(2H, d, J = 7.2 Hz), 4.09 (2H, q, J = 7.0 Hz), 4.5
5 (1H, t, J = 7.2 Hz), 6.70-7.40 (11H, m), 7.90-8.
04 (2H, m). 3) To a solution of zinc chloride (7.08 g, 51.9 mmol) in diethyl ether (100 ml) was added sodium borohydride (3.93 g, 103.9 mmol) and the mixture was added at room temperature for 30 minutes. Stirred. The insoluble material was removed by filtration, and the filtrate was added with 3- (4-
Ethyl fluorophenyl) -3-oxo-2-((3- (phenyloxy) phenyl) methyl) propionate (1
0.2 g, 26.0 mmol) of diethyl ether (5
0 ml) solution and stirred at room temperature for 30 minutes. below freezing,
The reaction solution is quenched by adding 1N hydrochloric acid, and further added with water (20 mL).
0 ml) and extracted with ethyl acetate (300 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate),
(2RS, 3RS) -3- (4-fluorophenyl) -3-
Hydroxy-2-((3- (phenyloxy) phenyl)
Ethyl (methyl) propionate (5.26 g, 51%) was obtained as a colorless oil. ^{IRνmax KBr cm -1: 1728, 1715} , 1582, 1487. 1 H-NMR (CDCl 3) δ: 0.96 (3H, t, J = 7.2 Hz), 2.82-
3.04 (4H, m), 3.89 (2H, q, J = 7.2 Hz), 5.00 (1H, b
rs), 6.78-7.40 (13H, m). 4) Ethyl (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((3- (phenyloxy) phenyl) methyl) propionate (5.26 g, 1
3.3 mmol) in methanol (40 ml).
Normal sodium hydroxide aqueous solution (13.4 ml, 26.8)
Mmol) and stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid, and then ethyl acetate (200 ml × 2).
Extracted. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give (2RS, 3RS) -3- (4-)
Fluorophenyl) -3-hydroxy-2-((3- (phenyloxy) phenyl) methyl) propionic acid (2.3
1 g, 47%). ^{IRνmax KBr cm -1: 1713, 1584} , 1510, 1487. 1 H-NMR (CDCl 3) δ: 2.84-3.06 (4H, m), 5.04 (1H, d,
J = 4.4 Hz), 6.76-7.40 (13H, m). 5) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((3- (phenyloxy) phenyl) methyl) In a solution of propionic acid (2.2 g, 6.00 mmol) in tetrahydrofuran (60 ml), diphenylphosphoryl azide (1.42 ml, 6.60 mmol) and triethylamine (1.26 ml, 9.00 mmol).
(Mmol) was heated and refluxed for 4 hours. After allowing the reaction solution to cool, water (200 ml) was added, and ethyl acetate (200 ml) was added.
× 2). The extract was diluted with 1N hydrochloric acid, saturated aqueous sodium bicarbonate,
The extract was washed successively with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-1: 1) to give (4RS, 5SR) -5- (4-fluorophenyl) -4-((3- (phenyloxy) Phenyl) methyl) -1,3-oxazolidin-2-one (1.69 g, 7
7%). IRνmax ^KBr cm ^-1 : 1759, 1608, 1584. ¹ H-NMR (CDCl ₃ ) δ: 2.10-2.32 (2H, m), 4.16-4.30 (1
H, m), 5.13 (1H, s), 5.77 (1H, d, J = 7.8 Hz), 6.6
0-7.40 (13H, m). 6) (4RS, 5SR) -5- (4-fluorophenyl) -4-((3- (phenyloxy) phenyl) methyl) -1,3-oxazolidin-2-one (877 mg,
8 in a solution of 2.41 mmol) in ethanol (10 ml).
Normal aqueous sodium hydroxide solution (1.51 ml, 12.1
(Mmol) was heated and refluxed for 6 hours. After the reaction solution was concentrated, it was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
1 × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give (1RS, 2
SR) -2-Amino-1- (4-fluorophenyl) -3-
(3- (Phenyloxy) phenyl) -1-propanol (831 mg, 100%) was obtained. ^{IRνmax KBr cm -1: 1582, 1507} , 1487, 1445. 1 H-NMR (CDCl 3) δ: 2.31 (1H, dd, J = 13.6, 10.2 H
z), 2.75 (1H, dd, J = 13.6, 3.0 Hz), 3.18-3.36 (1
H, m), 4.65 (1H, d, J = 4.6 Hz), 6.78-7.40 (13H,
m). 7) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (3- (phenyloxy) phenyl)-
In a solution of 1-propanol (300 mg, 0.89 mmol) in acetonitrile (20 ml), 4-fluoronaphthalenecarboxylic acid (169 mg, 0.89 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (256 mg, 1.33 mmol) and 1-hydroxy-1H-benzotriazole (136
mg, 0.89 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). Extract solution is 1N hydrochloric acid,
The extract was washed successively with a 1N aqueous sodium hydroxide solution and a saturated saline solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purification with ethyl acetate = 4: 1-1: 1)
Recrystallization from hexane gave the title compound (148 mg,
33%). mp 120-121 ℃ IRνmax ^KBr cm ^-1 : 1642, 1626, 1601, 1584. Anal.Calcd for C ₃₂ H ₂₅ F ₂ NO ₃ : C, 75.43; H, 4.95; N,
2.75 Found:. C, 75.33; H, 5.05; N, 2.54 1 H-NMR (CDCl 3) δ: 2.73 (1H, dd, J = 14.4, 10.6 H
z), 3.02 (1H, dd, J = 14.4, 4.0 Hz), 3.60-3.64 (1
H, m), 4.66-4.82 (1H, m), 5.04-5.12 (1H, m), 5.87
(1H, d, J = 8.4 Hz), 6.80-7.36 (13H, m), 7.38-7.62
(4H, m), 7.81 (1H, d, J = 8.0 Hz), 8.09 (1H, d, J
= 7.8 Hz).

Example 161 N- (1RS, 2SR)-(2- (4-fluorophenyl)
-2-Hydroxy-1-((3- (phenyloxy) phenyl) methyl) ethyl) -3-phenylpropanamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (3 To a solution of-(phenyloxy) phenyl) -1-propanol (550 mg, 1.63 mmol) in ethyl acetate (20 ml) was added 3-phenylpropionyl chloride (360 ml, 2.45 mmol) and saturated aqueous sodium bicarbonate (20 ml). Stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-1: 1), and recrystallized from ethyl acetate-hexane to obtain the title compound (422 mg, 55%). ^{mp 91-93 ℃ IRνmax KBr cm -1:} 1645, 1584, 1510, 1487, 1447. 1 H-NMR (CDCl 3) δ: 2.22-2.90 (6H, m), 4.22-4.42 (1
H, m), 4.81 (1H, s), 5.30 (1H, d, J = 8.2 Hz), 6.6
2-7.40 (18H, m).

Example 162 1,1-Dimethylethyl (1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-((5- (trifluoromethyl) -2-furanyl) methyl) ethyl Carbamate 1) Ethyl trifluoroacetoacetate (75 g, 407)
Mmol) of 1,2-dimethoxyethane (200 ml)
Add sodium hydride (60% oily, 16.3 g, 4
(07 mmol) under ice-cooling and stirred at room temperature for 30 minutes.
A solution of chloroacetone (43.3 g, 469 mmol) in 1,2-dimethoxyethane (50 ml) was added dropwise to the reaction solution, potassium iodide (800 mg, 4.8 mmol) was added, and the reaction solution was heated overnight. Refluxed. The reaction solution was poured into water (500 ml), and diethyl ether (50 ml) was added.
0 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was distilled under reduced pressure to give 4-oxo-2- (2,2,2
2-trifluoroacetyl) ethyl valerate (40.5
g, 41%). ^{IRνmax KBr cm -1: 1742, 1723.} 1 H-NMR (CDCl 3) δ: 1.28 (3H, t, J = 7.0 Hz), 2.22
(3H, s), 3.26 (2H, d, J = 7.0 Hz), 4.10-4.50 (3H,
m). bp 110-125 ° C / 0.1 mmHg 2) p-Toluenesulfone was added to a toluene (250 ml) solution of ethyl 4-oxo-2- (2,2,2-trifluoroacetyl) valerate (40 g, 167 mmol). Acid (3
g, 16 mmol) and heated to reflux overnight while removing water with a Dean-Stark apparatus. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography (hexane:
Purified with ethyl acetate = 10: 1) and ethyl 5-methyl-2- (trifluoromethyl) -3-furancarboxylate (25.
8g, 70%). ^{IRνmax KBr cm -1: 1732, 1574.} 1 H-NMR (CDCl 3) δ: 1.35 (3H, t, J = 7.4 Hz), 2.35
(3H, s), 4.32 (2H, q, J = 7.4 Hz), 4.62 (1H, s). 3) Ethyl 5-methyl-2- (trifluoromethyl) -3-furancarboxylate (25 g, 113 mmol) 2) aqueous sodium hydroxide solution (61.9 ml, 123.8 mmol) was added to an ethanol (200 ml) solution of
The mixture was refluxed for 5 minutes. After concentrating the reaction solution, water (150 m
The mixture was diluted in 1), and 6N hydrochloric acid was gradually added until the pH reached about 5. The precipitated crystals were collected by filtration and washed with water to give 5-methyl-2- (trifluoromethyl) -3-furancarboxylic acid (20.5 g, 94%). IRνmax ^KBr cm ^-1 : 1711, 1574. mp 118-119 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.38 (3H, s), 6.52 (1H, s). 4) 5-Methyl-2- (trifluoro To a quinoline (36 ml) solution of (methyl) -3-furancarboxylic acid (20 g, 103 mmol) was added copper (I) sulfate (1 g, 6.3 mmol), and gas was introduced into an oil bath at 230 ° C. while bubbling nitrogen through. Soaked until no more occurs. The evolved gas was collected and redistilled to obtain 2-methyl-5- (trifluoromethyl) furan (8.34 g, 54%). ¹ H-NMR (CDCl ₃ ) δ: 2.34 (3H, s), 6.05 (1H, d, J =
3.4 Hz), 6.60 (1H, d, J = 2.2 Hz) .bp 80-85 ℃ / 760mmHg (Lit.81-82 ℃, J. Hetrocyclic Ch)
em., 5, 95 (1968)) 5) 2-Methyl-5- (trifluoromethyl) furan (4 g, 26.6 mmol) in chloroform (60 m
l) Add N-bromosuccinimide (5.2 g, 2
9.3 mmol) and 2,2′-azobis (isobutyronitrile) (220 mg, 1.33 mmol). The reaction solution was heated under reflux for 15 minutes, cooled, poured into water (200 ml), and extracted with chloroform.
The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 2- (bromomethyl) -5-.
(Trifluoromethyl) furan (4.79 g, 78%)
I got ^{IRνmax KBr cm -1: 1738, 1688} , 1599, 1559. 1 H-NMR (CDCl 3) δ: 4.46 (2H, s), 6.45 (1H, d, J =
3.8 Hz), 6.75 (1H, d, J = 3.8 Hz). 6) Ethyl 3- (4-fluorophenyl) -3-oxopropionate (5.0 g, 24 mmol) in 1,2-dimethoxyethane (40 ml) ) Solution in sodium hydride (6
0% oily, 576 mg, 24 mmol) under ice-cooling,
Stirred at room temperature for 1 hour. A solution of 2- (bromomethyl) -5- (trifluoromethyl) furan (6 g, 26 mmol) in 1,2-dimethoxyethane (50 ml) was added dropwise to the reaction solution, and the reaction solution was stirred at room temperature overnight. The reaction solution was poured into water (200 ml), saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 3-
Ethyl (4-fluorophenyl) -3-oxo-2-((5- (trifluoromethyl) -2-furanyl) methyl) propionate (4.5 g, 52%) was obtained. ^{IRνmax KBr cm -1: 1738, 1688} , 1599, 1559. 1 H-NMR (CDCl 3) δ: 1.16 (3H, t, J = 7.2 Hz), 3.14-
3.50 (2H, m), 4.14 (2H, q, J = 7.2 Hz), 4.73 (1H,
t, J = 7.4 Hz), 6.15 (1H, d, J = 4.0 Hz), 6.60-6.6
6 (1H, m), 7.08-7.30 (3H, m), 7.98-8.10 (2H, m). 7) Boron hydride was added to a solution of zinc chloride (3.35 g, 24.6 mmol) in diethyl ether (70 ml). Sodium (1.86 g, 49.1 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was subjected to ethyl 3- (4-fluorophenyl) -3-oxo-2-((5- (trifluoromethyl) -2-furanyl) methyl) propionate (4.40 g, 12 (0.3 mmol) in diethyl ether (30 ml) and stirred at room temperature for 2 hours. Under ice-cooling, the reaction solution is quenched by adding 1N hydrochloric acid, and water (100 ml) is further added, and ethyl acetate (100 ml × 2) is added.
Extracted. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give (2RS, 3RS) -3- (4
Ethyl-fluorophenyl) -3-hydroxy-2-((5- (trifluoromethyl) -2-furanyl) methyl) propionate (3.46 g, 78%) was obtained. ^{IRνmax KBr cm -1: 1717, 1607} , 1561. 1 H-NMR (CDCl 3) δ: 1.06 (3H, t, J = 7.0 Hz), 2.90-
3.22 (4H, m), 4.00 (2H, q, J = 7.0 Hz), 5.00-5.08
(1H, m), 6.05 (1H, d, J = 3.4 Hz), 6.58-6.64 (1H,
m), 6.98-7.10 (2H, m), 7.30-7.42 (2H, m). 8) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((5- (tri Fluoromethyl) -2-furanyl) methyl) ethyl propionate (3.
3 g, 9.16 mmol) methanol (9.2 ml)
A 2N aqueous sodium hydroxide solution (9.2 ml,
18.4 mmol) and stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid, and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (2RS, 3RS) -3- (4-fluorophenyl) -3.
-Hydroxy-2-((5- (trifluoromethyl) -2-furanyl) methyl) propionic acid (2.43 g, 80%)
I got IRνmax ^KBr cm ^-1 : 1715, 1563, 1513.mp 86-87 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.92-3.22 (3H, m), 5.13 (1H, d,
J = 4.0 Hz), 6.06 (1H, d, J = 3.2 Hz), 6.60-6.68 (1
H, m), 7.00-7.16 (2H, m), 7.30-7.44 (2H, m). 9) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((5- (Trifluoromethyl) -2-furanyl) methyl) propionic acid (2.33)
g, 7.01 mmol) of tetrahydrofuran (60 m
l) Diphenylphosphoryl azide (1.66 m
1, 7.71 mmol) and triethylamine (1.47)
ml, 10.5 mmol) and heated under reflux for 4 hours. After allowing the reaction solution to cool, water (50 ml) was added, and the mixture was extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give (4RS, 5SR) -5- (4-fluorophenyl) -4-((5- (trifluoromethyl) -2-furanyl) methyl) -1,3-oxazolidin-2-one (1.
78 mg, 77%). IRνmax ^KBr cm ^-1 : 1759, 1611, 1559, 1514.mp 177-179 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.30-2.58 (2H, m), 4.32-4.50 (1
H, m), 5.67 (1H, brs), 5.80 (1H, d, J = 8.0 Hz), 6.
00 (1H, d, J = 3.6 Hz), 6.65 (1H, d, J = 2.2 Hz),
7.02-7.20 (2H, m), 7.24-7.40 (2H, m). 10) (4RS, 5SR) -5- (4fluorophenyl) -4-((5- (trifluoromethyl) -2-furanyl) Methyl) -1,3-oxazolidin-2-one (1.6
0 g, 4.86 mmol) of acetonitrile (15 m
l) Di-t-butyl dicarbonate (1.27 g, 5.83) was added to the solution.
Mmol) and dimethylaminopyridine (60 mg,
0.49 mmol) and stirred at room temperature for 30 minutes. After concentration, the reaction solution was diluted with water (30 ml) and extracted with ethyl acetate (30 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and recrystallized from ethyl acetate-hexane to give (4RS, 5SR) -5- (4-fluorophenyl) -2-oxo-4--4-. 1,1-dimethylethyl ((5- (trifluoromethyl) -2-furanyl) methyl) -1,3-oxazolidine-3-carboxylate (1.99
g, 95%). IRνmax ^KBr cm ^-1 : 1823, 1728, 1615, 1559.mp 134-135 ℃ ¹ H-NMR (CDCl ₃ ) δ: 1.55 (9H, s), 2.70-2.98 (2H, m),
4.86-4.98 (1H, m), 5.52 (1H, d, J = 3.2 Hz), 5.70
(1H, d, J = 7.0 Hz), 6.46-6.52 (1H, m), 6.94-7.06
(2H, m), 7.12-7.22 (2H, m). 11) (4RS, 5SR) -5- (4-fluorophenyl) -2-oxo-4-((5- (trifluoromethyl) -2
-Furanyl) methyl) -1,1-dimethylethyl-1,3-oxazolidine-3-carboxylate (1.91 g, 4.45)
Mmol) in methanol (10.7 ml) in 0.5N methanolic sodium hydroxide solution (10.7 ml, 5.0 mL).
(35 mmol) under ice-cooling and stirred at room temperature for 10 minutes.
Water (50 ml) was added to the reaction solution, and ethyl acetate (50 ml) was added.
× 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (1.7
9 g, 100%). IRνmax ^KBr cm ^-1 : 1692, 1561, 1510.mp 111-112 ℃ ¹ H-NMR (CDCl ₃ ) δ: 1.39 (9H, s), 2.78-2.90 (2H, m),
3.12 (1H, brs), 4.02-4.20 (1H, m), 4.76 (1H, d, J
= 8.4 Hz), 4.92 (1H, brs), 6.12 (1H, d, J = 3.0 H
z), 6.62-6.68 (1H, m), 7.00-7.12 (2H, m), 7.28-7.4
2 (2H, m).

Example 163 4-Fluoro-N-((1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-((5- (trifluoromethyl) -2-furanyl) methyl) Ethyl) -1-naphthalenecarboxamide 1) 1,1-dimethylethyl (1RS, 2SR) -2-
(4-fluorophenyl) -2-hydroxy-1-((5-
To (trifluoromethyl) -2-furanyl) methyl) ethyl carbamate (1.70 g, 4.21 mmol) was added trifluoroacetic acid (15 ml) at 0 ° C., and the mixture was stirred for 10 minutes. After concentration, the reaction solution was diluted with water (20 ml) and extracted with ethyl acetate (20 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (5- (trifluoromethyl) -2
-Furanyl) -1-propanol (1.30 g, 100
%). ^{IRνmax KBr cm -1: 1605, 1558} , 1510. 1 H-NMR (CDCl 3) δ: 2.07 (2H, brs), 2.56 (1H, dd, J
= 15.0, 9.8 Hz), 2.78 (1H, dd, J = 15.0, 3.6 Hz),
3.32-3.46 (1H, m), 4.66 (1H, d, J = 4.8 Hz), 6.12
(1H, d, J = 3.4 Hz), 6.62-6.70 (1H, m), 7.00-7.12
(2H, m), 7.30-7.42 (2H, m). 2) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (5- (trifluoromethyl) -2-furanyl ) To a solution of 1-propanol (300 mg, 0.99 mmol) in acetonitrile (20 ml) was added 4-fluoronaphthalenecarboxylic acid (188 mg, 0.99 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. Hydrochloride (283 mg, 1.48 mmol) and 1-hydroxy-1H-benzotriazole (151 mg, 0.99 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give the title compound (1
91 mg, 41%). IRνmax ^KBr cm ^-1 : 1643, 1601, 1512.mp 153-154 ℃ ¹ H-NMR (CDCl ₃ ) δ: 3.54 (2H, d, J = 7.4 Hz), 3.23
(1H, d, J = 3.4 Hz), 4.68-4.86 (1H, m), 5.06-5.12
(1H, m), 6.12-6.28 (2H, m), 6.72 (1H, d, J = 2.2 H
z), 7.00-7.16 (3H, m), 7.32-7.62 (5H, m), 8.00-8.2
0 (2H, m).

Example 164 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((5- (trifluoromethyl) -2
-Furanyl) methyl) ethyl) -3-phenylpropanamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (5- (trifluoromethyl) -2-furanyl) -1- Propanol (300 mg, 099 mmol)
3-Ethylpropionyl chloride (220 ml, 1.48 mmol) and saturated aqueous sodium hydrogen carbonate (10 ml) were added to a solution of the above in ethyl acetate (10 ml), and the mixture was stirred overnight at room temperature.
The reaction solution was diluted with water (100 ml), and ethyl acetate (10 ml) was added.
0 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (321 mg, 75%). IRνmax ^KBr cm ^-1 : 1645, 1559, 1510.mp 91-92 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.32-2.60 (2H, m), 2.73 (2H, d,
J = 7.6 Hz), 2.80-3.00 (2H, m), 3.10 (1H, s), 4.30-
4.48 (1H, m), 4.76-4.84 (1H, m), 5.58 (1H, d, J =
7.6 Hz), 6.00 (1H, d, J = 3.4 Hz), 6.58-6.64 (1H,
m), 6.92-7.10 (2H, m), 7.10-7.36 (7H, m).

Example 165 N-[(1RS, 2SR) -1- [4- (difluoromethyl) benzyl] -2- (4-fluorophenyl) -2-hydroxyethyl] -4-fluoronaphthalene-1-carboxamide 1) Methyl 4- (difluoromethyl) benzoate (Diethylamino) sulfur trifluoride 12.8
g (79.4 mmol) in a 30 ml toluene solution.
At 8.degree. C., 10.86 g of methyl 4-formylbenzoate (6.
(6.15 mmol) in 50 ml of toluene and stirred at room temperature for 3 hours. An aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and after stirring, the toluene layer was separated. The aqueous layer was extracted with ethyl acetate, the collected organic layers were dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 20 / 1-15 / 1) to obtain the desired product. Light yellow solid Yield 9.671 g Yield 79% mp 37-38 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 3.95 (3H,
s), 6.69 (1H, t, J = 56.2 Hz), 7.59 (2H, d, J = 8.
2 Hz), 8.13 (2H, d, J = 8.4 Hz); IR (neat) 1728, 1
437, 1283, 1219, 1113, 1074, 1034, 1020 cm ^-1 ; Ana
l. Calcd for C ₉ H ₈ F ₂ O ₂ : C, 58.07; H, 4.33. Found:
H, 4.24.2) 4- (Difluoromethyl) benzyl alcohol To a suspension of 2.86 g (75.3 mmol) of lithium aluminum hydride in 50 ml of tetrahydrofuran was added 4- (difluoromethyl) benzoate under ice-cooling. 9.34 methyl ester
1 g (50.18 mmol) of tetrahydrofuran 50
The solution was added dropwise and stirred at room temperature for 1 hour. After cooling the reaction solution with ice, 3 ml of water and 3% aqueous solution of 15% sodium hydroxide were added.
Then, 8 ml of water and 8 ml of water were sequentially added dropwise to decompose excess lithium aluminum hydride, and the mixture was stirred at room temperature for 2 hours. The resulting precipitate was removed by filtration, and the precipitate was washed with ethyl acetate. The solvent of the collected filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1) to obtain the desired product. Colorless liquid Yield 7.948 g Yield 100% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.78 (1 H, t, J = 6.0 H)
z), 4.76 (2H, d, J = 5.4Hz), 6.65 (1H, t, J = 56.4
Hz), 7.45 (2H, d, J = 8.6 Hz), 7.52 (2H, d, J = 8.
6 Hz); IR (neat) 3330, 1379, 1221, 1074, 1019 cm ^-1 3) 2- [4- (difluoromethyl) benzyl] -3-
Ethyl (4-fluorophenyl) -3-oxopropionate 4- (difluoromethyl) benzyl alcohol 2.65
g (16.7 mmol), triethylamine 3.50 m
1 (25.1 mmol) in 40 ml of ethyl acetate was added dropwise with a solution of 2.11 g (18.4 mmol) of methanesulfonyl chloride in 10 ml of ethyl acetate under ice-cooling.
Stirred for minutes. The resulting precipitate was removed by filtration, and the precipitate was washed with diethyl ether. The solvent of the collected filtrate was distilled off under reduced pressure to obtain a crude product of methanesulfonic acid ester as a yellow liquid. 0.67 g (16.7 mmol) of a liquid paraffin suspension of 60% sodium hydride in a solution of 3.516 g (16.73 mmol) of ethyl (4-fluorobenzoyl) acetate in 30 ml of 1,2-dimethoxyethane under ice cooling. Was added and the mixture was stirred as it was for 0.5 hour. To this was added a solution of methanesulfonic acid ester obtained above in 10 ml of 1,2-dimethoxyethane at room temperature, and the mixture was stirred at room temperature for 8 hours. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15 /
1-9 / 1) and crystallized from hexane to obtain the desired product. White crystals Yield 3.044 g Yield 52% mp 54-55 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.11 (3H, t,
J = 7.2 Hz), 3.36 (2H, d, J = 7.4 Hz), 4.10 (2H,
q, J = 7.2 Hz), 4.57 (1H, t, J = 7.5 Hz), 6.59 (1
H, t, J = 56.4 Hz), 7.12 (2H, t, J = 8.6 Hz), 7.31
(2H, d, J = 8.4Hz), 7.41 (2H, d, J = 7.8Hz), 8.0
0 (2H, dd, J = 5.4 Hz, 8.8 Hz); IR (KBr) 1721, 168
4, 1597, 1327, 1281, 1231, 1177, 1155, 1024, 847 c
m ^-1 ; Anal.Calcd for C ₁₉ H ₁₇ F ₃ O ₃ : C, 65.14; H, 4.89.
Found: C, 65.21; H, 4.82.4 Ethyl (2RS, 3RS) -2- [4- (difluoromethyl) benzyl] -3- (4-fluorophenyl) -3-hydroxypropionate Zinc chloride 2.17 g While stirring (16.0 mmol) in 50 ml of diethyl ether, 1.21 g (31.9 mmol) of sodium borohydride was added at room temperature, followed by stirring for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. To the resulting solution, 2.794 g of ethyl 2- [4- (difluoromethyl) benzyl] -3- (4-fluorophenyl) -3-oxopropionate (7.
(975 mmol) in 30 ml of diethyl ether was added at room temperature and stirred for 2 hours. After decomposing excess zinc borohydride by adding dilute hydrochloric acid little by little to the reaction solution,
Extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-3 / 1) to obtain the desired product. Colorless liquid Yield 2.800 g Yield 100% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.92 (3H, t, J = 7.1 H)
z), 2.90 (1H, d, J = 2.8Hz), 2.93-3.06 (3H, m), 3.
88 (2H, q, J = 7.2 Hz), 5.02 (1H, dd, J = 2.6 Hz,
4.6 Hz), 6.59 (1H, t, J = 56.6 Hz), 7.05 (2H, t, J
= 8.6 Hz), 7.17 (2H, d, J = 8.0 Hz), 7.34-7.41 (4
H, m); IR (neat) 3445, 1725, 1715, 1510, 1377, 122
^{3, 1026, 839 cm -1 5} ) (2RS, 3RS) -2- [4- ( difluoromethyl) benzyl] -3- (4-fluorophenyl) -3-hydroxypropionic acid (2RS, 3RS)-2- Ethyl [4- (difluoromethyl) benzyl] -3- (4-fluorophenyl) -3-hydroxypropionate 2.739 g (7.774 mmol) of methanol 20 ml-tetrahydrofuran 20 m
15.5 ml of 1N aqueous sodium hydroxide solution (1
5.5 mmol) and stirred overnight at room temperature. The reaction solution was concentrated, diluted with water, acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from hexane to obtain the desired product. White crystal Yield 2.232 g Yield 89% mp 132-133 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.95-3.10
(3H, m), 5.06 (1H, s), 6.60 (1H, t, J = 56.6 Hz),
7.05 (2H, t, J = 8.8 Hz), 7.16 (2H, d, J = 8.0 H
z), 7.33-7.40 (4H, m); IR (KBr) 3349, 3020-2550, 1
694, 1514, 1238, 1022, 841 cm ^-1 ; Anal.Calcd for C
₁₇ H ₁₅ F ₃ O ₃ : C, 62.96; H, 4.66. Found: C, 63.04; H,
4.85. 6) (4RS, 5SR) -4- [4- (difluoromethyl) benzyl] -5- (4-fluorophenyl) -1,3-
Oxazolidin-2-one (2RS, 3RS) -2- [4- (difluoromethyl) benzyl] -3- (4-fluorophenyl) -3-hydroxypropionic acid 2.060 g (6.352 mmol) solution in 40 ml of tetrahydrofuran And triethylamine.
33 ml (9.53 mmol) and 1.92 g (6.99 mmol) of diphenylphosphoryl azide were added, and the mixture was heated under reflux overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1), and crystallized from diethyl ether / hexane. I got something. White crystal Yield 1.888 g Yield 93% mp 161-162 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.22-2.38
(2H, m), 4.25 (1H, dt, J = 4.8 Hz, 8.7 Hz), 5.02 (1
H, br s), 5.80 (1H, d, J = 8.0 Hz), 6.61 (1H, t, J
= 56.4 Hz), 7.09-7.19 (4H, m), 7.34 (2H, dd, J =
5.2 Hz, 8.6 Hz), 7.44 (2H, d, J = 8.0 Hz); IR (KB
r) 3250, 1734, 1516, 1383, 1229, 1076,1032, 849 cm
^-1 ; Anal.Calcd for C ₁₇ H ₁₄ F ₃ NO ₂ : C, 63.55; H, 4.3
9; N, 4.36. Found: C, 63.63; H, 4.42; N, 4.16.7) (1RS, 2SR) -2-amino-3- [4- (difluoromethyl) phenyl] -1- (4-fluoro Phenyl) propan-1-ol (4RS, 5SR) -4- [4- (difluoromethyl) benzyl] -5- (4-fluorophenyl) -1,3-oxazolidin-2-one 1.705 g (5.307 Mmol)
And 0.85 g (21.2 mmol) of sodium hydroxide were heated under reflux in 20 ml of ethanol and 1 ml of water for 6 hours. The reaction was diluted with water and extracted twice with ethyl acetate.
The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 1.2
68g Yield 81% mp 89-90 ° C; ¹ H-NMR (CDCl ₃ , 200MHz) δ 2.40 (1H, d
d, J = 10.3 Hz, 13.1 Hz), 2.84 (1H, d, J = 14.0 H
z), 3.24-3.34 (1H, m), 4.67 (1H, d, J = 4.8 Hz),
6.621 (1H, t, J = 56.6 Hz), 7.08 (2H, t, J = 8.8 H
z), 7.24 (2H, d, J = 8.0 Hz), 7.38 (2H, dd, J = 5.6
Hz, 8.6 Hz), 7.44 (2H, d, J = 8.0 Hz); IR (KBr) 33
50 2870, 1593, 1508, 1381, 1215, 1047, 1001, 829 c
m ^-1 ; Anal.Calcd for C ₁₆ H ₁₆ F ₃ NO: C, 65.08; H, 5.46;
N, 4.74. Found: C, 65.10; H, 5.72; N, 4.47.8) N-[(1RS, 2SR) -1- [4- (difluoromethyl) benzyl] -2- (4-fluorophenyl)- 2-
0.167 g of hydroxyethyl] -4-fluoronaphthalene-1-carboxamide (1RS, 2SR) -2-amino-3- [4- (difluoromethyl) phenyl] -1- (4-fluorophenyl) propan-1-ol (0.566 mmol),
0.11 g (0.57 mmol) of 4-fluoro-1-naphthoic acid, 1-hydroxybenzotriazole hydrate 87
While stirring mg (0.57 mmol) in 10 ml of acetonitrile, 0.11 g (0.57 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. . The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.222 g Yield 84% mp 212-213 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
84-3.05 (2H, m), 4.71-4.85 (1H, m), 4.97-5.16 (2H, m
m), 6.63 (1H, t, J = 56.4 Hz), 6.98-7.63 (14H,
m), 8.06 (1H, d, J = 8.4 Hz); IR (KBr) 3274, 1642,
1626, 1537, 1512,1229, 1030, 837 cm ^-1 ; Anal.Calc
d for C ₂₇ H ₂₁ F ₄ NO ₂ : C, 69.37; H, 4.53; N, 3.00. Fou
nd: C, 69.11; H, 4.72; N, 2.74.

Example 166 N-[(1RS, 2SR) -1- [4- (1,1-difluoroethyl) benzyl] -2- (4-fluorophenyl) -2
-Hydroxyethyl] -4-fluoronaphthalene-1-carboxamide 1) Methyl 4- (1,1-difluoroethyl) benzoate (diethylamino) sulfur trifluoride 10.6
g (66.1 mmol) in 30 ml toluene solution
At 8.degree. C., 10.58 g of methyl 4-acetylbenzoate (5.
(5.04 mmol) in 50 ml of toluene was added, and the mixture was stirred at room temperature for 1 week and at 50 ° C. for 1 day. The reaction mixture was further added with (diethylamino) sulfur trifluoride 5.32.
g (33.0 mmol) was added, and the mixture was stirred at 60 ° C. for 3 days. An aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and after stirring, the toluene layer was separated. The aqueous layer was extracted with ethyl acetate, the collected organic layers were dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to obtain the desired product. Yellow liquid yield 3.95
8 g Yield 34% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.41 (3H, t, J = 7.1 H
z), 1.93 (3H, t, J = 18.1 Hz), 4.40 (2H, q, J = 7.
2 Hz), 7.57 (2H, d, J = 8.0 Hz), 8.10 (2H, d, J =
8.0 Hz); IR (neat) 1721, 1277, 1101 cm ^-1 2) 4- (1,1-difluoroethyl) benzyl alcohol To a suspension of 1.03 g (27.3 mmol) of lithium aluminum hydride in 30 ml of tetrahydrofuran. Under ice cooling, a solution of 3.894 g (18.18 mmol) of methyl 4- (1,1-difluoroethyl) benzoate in 50 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 1 hour. After cooling the reaction solution with ice, 1 ml of water, 1 ml of a 15% aqueous sodium hydroxide solution and 2.5 ml of water are successively added dropwise to decompose excess lithium aluminum hydride and leave it at room temperature for 2 hours.
Stirred for hours. The resulting precipitate was removed by filtration, and the precipitate was washed with ethyl acetate. The solvent of the collected filtrate was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 /
1) The desired product was obtained. Colorless liquid Yield 2.700 g Yield 86% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.72 (1 H, t, J = 5.8 H)
z), 1.92 (3H, t, J = 18.1 Hz), 4.74 (2H, d, J = 6.
0 Hz), 7.42 (2H, d, J = 8.4 Hz), 7.51 (2H, d, J =
8.4 Hz); IR (neat) 3330, 1296, 1175, 918 cm ^-1 3) 2- [4- (1,1-difluoroethyl) benzyl] -3- (4-fluorophenyl) -3-oxopropionic acid Ethyl 4- (1,1-difluoroethyl) benzyl alcohol 2.65 g (15.4 mmol), triethylamine 3.22 ml (23.1 mmol) ethyl acetate 40 m
1.94 g of methanesulfonyl chloride (1
6.9 mmol) in 10 ml of ethyl acetate was added dropwise,
The mixture was stirred for 10 minutes. The resulting precipitate was removed by filtration, and the precipitate was washed with diethyl ether. The solvent of the collected filtrate was distilled off under reduced pressure to obtain a crude product of methanesulfonic acid ester as a yellow liquid. To a solution of 3.235 g (15.39 mmol) of ethyl (4-fluorobenzoyl) acetate in 30 ml of 1,2-dimethoxyethane was added 60% under ice-cooling.
0.62 g of liquid paraffin suspension of sodium hydride
(15.4 mmol) and the mixture was stirred for 0.5 hour. The methanesulfonic acid ester 1,
A 10 ml solution of 2-dimethoxyethane was added at room temperature, and the mixture was stirred at room temperature for 8 hours. The reaction solution was poured into water, and extracted with ethyl acetate.
Extracted times. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-9 / 1), and crystallized from hexane to obtain the desired product. White crystals Yield 2.790 g Yield 50% mp 56-57 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.12 (3H, t,
J = 7.2 Hz), 1.88 (3H, t, J = 18.2 Hz), 3.35 (2H,
d, J = 7.2 Hz), 4.11 (2H, q, J = 7.2 Hz), 4.57 (1
H, t, J = 7.4 Hz), 7.13 (2H, t, J = 8.6 Hz), 7.28
(2H, d, J = 8.0Hz), 7.40 (2H, d, J = 8.0Hz), 8.00
(2H, dd, J = 5.4 Hz, 8.8 Hz); IR (KBr) 1719, 167
8, 1599, 1300, 1231, 1154, 924, 847 cm ^-1 ; Anal.Ca
lcd for C _{2 0} H ₁₉ F ₃ O ₃ : C, 65.93; H, 5.26. Found: C, 6
6.03; H, 5.28.4) (2RS, 3RS) -2- [4- (1,1-difluoroethyl) benzyl] -3- (4-fluorophenyl) -3
Ethyl-hydroxypropionate While stirring 1.91 g (14.0 mmol) of zinc chloride in 50 ml of diethyl ether, 1.06 g (28.1 mmol) of sodium borohydride was added at room temperature, and the mixture was stirred as it was for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. In the obtained solution, 2- [4- (1,
2.556 g of ethyl 1-difluoroethyl) benzyl] -3- (4-fluorophenyl) -3-oxopropionate
(7.015 mmol) in 30 ml of diethyl ether was added at room temperature, and the mixture was stirred for 2 hours. Dilute hydrochloric acid was added little by little to the reaction solution to decompose excess zinc borohydride, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-3 / 1) to obtain the desired product. Colorless liquid Yield 2.615 g Yield 100
% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.92 (3H, t, J = 7.1 H
z), 1.88 (3H, t, J = 18.2 Hz), 2.91 (1H, d, J = 2.
6 Hz), 2.94-3.12 (3H, m), 3.88 (2H, q, J = 7.2Hz),
5.02 (1H, t, J = 3.6 Hz), 7.05 (2H, t, J = 8.6 H
z), 7.14 (2H, d, J = 8.2 Hz), 7.35-7.41 (4H, m); IR
(neat) 3461, 1717, 1510, 1298, 1225, 1177, 1159,
^{837 cm -1 5) (2RS,} 3RS) -2- [4- (1,1- difluoroethyl) benzyl] -3- (4-fluorophenyl) -3
Ethyl 2-hydroxypropionate (2RS, 3RS) -2- [4- (1,1-difluoroethyl) benzyl] -3- (4-fluorophenyl) -3-hydroxypropionate 2.489 g (6.793 mmol) 20 ml of methanol-tetrahydrofuran 2
13.6 ml of 1N aqueous sodium hydroxide solution in 0 ml solution
(13.6 mmol) and stirred at room temperature overnight. The reaction solution was concentrated, diluted with water, acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from hexane to obtain the desired product. White crystal Yield 1.986 g Yield 86% mp 127-128 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.89 (3H,
t, J = 18.1 Hz), 2.89-3.10 (3H, m), 5.06 (1H, d, J
= 3.2 Hz), 7.05 (2H, t, J = 8.7 Hz), 7.13 (2H, d,
J = 8.4 Hz), 7.33-7.39 (4H, m); IR (KBr) 3330, 30
10-2550, 1688, 1518, 1300, 1240, 1225, 1198, 839 c
m ^-1 ; Anal.Calcd for C ₁₈ H ₁₇ F ₃ O ₃ : C, 63.90; H, 5.0
6. Found: C, 64.09; H, 5.03.6) (4RS, 5SR) -4- [4- (1,1-difluoroethyl) benzyl] -5- (4-fluorophenyl)-
1,36-oxazolidin-2-one (2RS, 3RS) -2- [4- (1,1-difluoroethyl) benzyl] -3- (4-fluorophenyl) -3-hydroxypropionic acid 1.836 g (5 1.427 ml) of triethylamine and 1.64 g (5.97 mmol) of diphenylphosphoryl azide were added to a 40 ml solution of tetrahydrofuran, and the mixture was heated under reflux overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1).
1) Crystallization from diethyl ether-hexane gave the desired product. White crystals Yield 1.704 g Yield 94% mp 205-206 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.90 (3H,
t, J = 18.2 Hz), 2.19-2.40 (2H, m), 4.23 (1H, dt,
J = 5.3 Hz, 8.7 Hz), 4.92 (1H, br s), 5.80 (1H, d,
J = 8.0 Hz), 7.09 (2H, d, J = 7.6 Hz), 7.14 (2H,
t, J = 8.8 Hz), 7.37 (2H, dd, J = 5.0 Hz, 8.4 Hz),
7.43 (2H, d, J = 8.8 Hz); IR (KBr) 3245, 1732, 138
5, 1300, 1231, 1107, 1011, 924 cm ^-1 ; Anal.Calcd f
or C ₁₈ H ₁₆ F ₃ NO ₂ : C, 64.47; H, 4.81; N, 4.18. Found:
C, 64.47; H, 4.82; N, 4.02.7) (1RS, 2SR) -2-amino-3- [4- (1,
1-difluoroethyl) phenyl] -1- (4-fluorophenyl) propan-1-ol (4RS, 5SR) -4- [4- (1,1-difluoroethyl) benzyl] -5- (4-fluorophenyl ) -1, 3-
1.557 g (4.643 mmol) of oxazolidine-2-one and 0.74 g (18.6 mmol) of sodium hydroxide were heated to reflux in 20 ml of ethanol-1 ml of water for 6 hours. The reaction was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Residue is silica gel (APS type)
Purification by column chromatography (hexane / ethyl acetate = 3 / 1-ethyl acetate) gave the desired product. Yellow liquid Yield 0.916 g Yield 64% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.91 (3H, t, J = 18.3 H)
z), 2.38 (1H, dd, J = 10.4 Hz, 13.6 Hz), 2.83 (1H,
dd, J = 3.0 Hz, 13.8 Hz), 3.29 (1H, ddd, J = 3.3 H
z, 4.8 Hz, 10.3 Hz), 4.67 (1H, d, J = 5.2 Hz), 7.0
8 (2H, t, J = 8.8 Hz), 7.20 (2H, d, J = 7.6 Hz),
7.38 (2H, dd, J = 5.6 Hz, 8.4 Hz), 7.44 (2H, d, J =
7.6 Hz); IR (neat) 3360-2860, 1605, 1508, 2385, 1
298, 1223,1175, 918, 826 cm ^- 18 18) N-[(1RS, 2SR) -1- [4- (1,1-difluoroethyl) benzyl] -2- (4-fluorophenyl) -2- Hydroxyethyl] -4-fluoronaphthalene-
1-carboxamide (1RS, 2SR) -2-amino-3- [4- (1,1-difluoroethyl) phenyl] -1- (4-fluorophenyl) propan-1-ol 0.173 g (0.559 mmol) ) 4-Fluoro-1-naphthoic acid 0.11 g (0.
86 mg (0.56 mmol) of 1-hydroxybenzotriazole hydrate was dissolved in acetonitrile 1
0.11 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride while stirring in 0 ml
(0.56 mmol) and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether to obtain the desired product. White crystals Yield 0.245 g Yield 91% mp 220-221 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 1.
90 (3H, t, J = 18.1 Hz), 2.84-3.06 (2H, m), 4.69-
4.84 (1H, m), 5.03 (1H, t, J = 3.5 Hz), 5.16 (1H,
d, J = 3.8 Hz), 6.99-7.12 (3H, m), 7.18-7.30 (4H,
m), 7.39-7.65 (7H, m), 8.06 (1H, d, J = 8.4 Hz); I
R (KBr) 3281, 1642, 1626, 1539, 1512, 1298, 1231,
1163, 843, 835, 758 cm -1;. Anal Calcd for C 28 H 23 F 4
NO ₂ : C, 69.85; H, 4.81; N, 2.91. Found: C, 69.70;
H, 4.98; N, 2.84.

Example 167 N-[(1RS, 2SR) -1-[(2,2-difluoro-
1,3-benzodioxol-5-yl) methyl] -2-
(4-Fluorophenyl) -2-hydroxyethyl] -4-
Fluoronaphthalene-1-carboxamide 1) (2,2-difluoro-1,3-benzodioxo)
Ru-5-yl) methanol lithium aluminum hydride
1.86 g (48.9 mmol) of tetrahydrofuran
To a 30 ml suspension was added 2,2-difluoro-1,3 under ice-cooling.
-Benzodioxole-5-carboxylic acid 4.942 g (2
Solution of 4.45 mmol) in 30 ml of tetrahydrofuran
Was added dropwise and stirred at room temperature for 1 hour. The reaction was cooled on ice
Then, 2 ml of water, 2 ml of 15% aqueous sodium hydroxide solution,
5 ml of water is added dropwise to the excess lithium aluminum hydride
The nitrogen was decomposed and the mixture was stirred at room temperature for 2 hours. Arising
The precipitated precipitate was removed by filtration, and the precipitate was washed with ethyl acetate.
The solvent of the collected filtrate was distilled off under reduced pressure. The resulting residue is
Purify by Ricagel column chromatography
Sun / ethyl acetate = 6 / 1-1 / 1) to obtain the desired product.
Colorless liquid yield 3.658 g yield 80%¹ H-NMR (CDCl_Three, 200MHz) δ 1.73 (1H, t, J = 6.0 H
z), 4.68 (2H, d, J = 5.8Hz), 7.02 (1H, d, J = 8.4
Hz), 7.08 (1H, d, J = 8.0 Hz), 7.23 (1H, s); IR (ne
at) 3318, 1501, 1449, 1238, 1148, 1036 cm^-1 2) 2-[(2,2-difluoro-1,3-benzodioxy)
Sole-5-yl) methyl] -3- (4-fluorophenyl)
E) -Ethyl 3-oxopropionate (2,2-difluoro-1,3-benzodioxole-5-
Il) 3.60 g (19.1 mmol) of methanol,
4.00 ml (28.7 mmol) of vinegar
Methanesulfonyl chloride in a 40 ml solution of ethyl acid under ice-cooling
2.41 g (21.1 mmol) of ethyl acetate 10 ml
The solution was added dropwise and stirred for 10 minutes. The resulting precipitate
Was removed by filtration, and the precipitate was washed with diethyl ether.
The solvent of the collected filtrate was distilled off under reduced pressure to give methanesulfonic acid
The crude product of steal was obtained as a yellow liquid. (4-Fluoro
4.024 g (19.14 mi) of ethyl (benzobenzoyl) acetate
Ice) in a 30 ml solution of 1,2-dimethoxyethane
Liquid paraffin suspension of 60% sodium hydride under cooling
0.77 g (19.1 mmol) was added.
Stir for 5 hours. Methanesulfonic acid S obtained above
10 ml solution of ter in 1,2-dimethoxyethane at room temperature
The mixture was stirred at room temperature for 8 hours. Pour the reaction solution into water and add acetic acid
Extracted twice with ethyl. The collected organic layer is dried over anhydrous magnesium sulfate.
After drying with sodium, the solvent was distilled off under reduced pressure. The resulting residue
Purify by silica gel column chromatography.
Sun / ethyl acetate = 15 / 1-9 / 1), from hexane
Crystallization gave the desired product. White crystals Yield 5.047
g yield 69% mp 66-67 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 1.13 (3H, t,
 J = 7.2 Hz), 3.31 (2H, d, J = 7.4 Hz), 4.11 (2H,
q, J = 7.2 Hz), 4.51 (1H, t, J = 7.3 Hz), 6.93-6.9
7 (3H, m), 7.14 (2H, t, J = 8.6 Hz), 8.00 (2H, dd,
 J = 5.4 Hz, 9.0Hz); IR (KBr) 1725, 1682, 1597, 15
01, 1258, 1233, 1150 cm^-1; Anal. Calcd for C₁₉H₁₅F
_ThreeO_Five: C, 60.00; H, 3.98. Found: C, 60.03; H, 4.02. 3) (2RS, 3RS) -2-[(2,2-difluoro-
1,3-benzodioxol-5-yl) methyl] -3-
(4-fluorophenyl) -3-hydroxypropionic acid
Ethyl 3.55 g (25.7 mmol) of zinc chloride was added to diethyl ether.
Sodium borohydride while stirring in 50 ml
1.94 g (51.4 mmol) were added at room temperature and the
The mixture was stirred for 2 hours. The insolubles of the mixture are removed by filtration.
Washed with ethyl ether), zinc borohydride in diethyl
An ether solution was obtained. 2-[(2,2-
Difluoro-1,3-benzodioxol-5-yl) methyl
Ru] -3- (4-Fluorophenyl) -3-oxopropio
4.888 g (12.85 mmol) of ethyl acetate
Add 30 ml of chilled ether solution at room temperature
While stirring. Dilute hydrochloric acid is added to the reaction solution little by little and excess water is added.
After decomposing the zinc borohydride, extract twice with ethyl acetate
Was. Dry the collected organic layer over anhydrous magnesium sulfate,
Was distilled off under reduced pressure. The resulting crude product is passed through a silica gel column.
Purify by chromatography (hexane / ethyl acetate
= 6 / 1-3 / 1) to obtain the desired product. Colorless liquid yield
4.849 g, 99% yield¹ H-NMR (CDCl_Three, 200MHz) δ 0.96 (3H, t, J = 7.1 H
z), 2.82 (1H, d, J = 2.6Hz), 2.85-3.02 (3H, m), 3.
91 (2H, q, J = 7.1 Hz), 4.99 (1H, dd, J = 2.5 Hz,
5.1 Hz), 6.75-6.81 (2H, m), 6.91 (1H, d, J = 8.0 H
z), 7.05 (2H, t, J = 8.6 Hz), 7.36 (2H, dd, J = 5.3
 Hz, 8.7 Hz); IR (neat) 3468, 1725, 1499, 1449, 12
40, 1155, 1036, 839 cm^-1 4) (2RS, 3RS) -2-[(2,2-difluoro-
1,3-benzodioxol-5-yl) methyl] -3-
(4-fluorophenyl) -3-hydroxypropionic acid (2RS, 3RS) -2-[(2,2-difluoro-1,3
-Benzodioxol-5-yl) methyl] -3- (4-fur
3. ethyl (olophenyl) -3-hydroxypropionate
30 ml of 725 g (12.36 mmol) of methanol
-1N sodium hydroxide in 30 ml of tetrahydrofuran solution
24.7 ml (24.7 mmol) of an aqueous solution of
Stirred overnight at room temperature. Concentrate the reaction solution, dilute with water, and add 1N
After acidifying the reaction solution with hydrochloric acid, the mixture was extracted twice with ethyl acetate.
Was. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was removed.
It was distilled off under reduced pressure. The residue was crystallized from hexane,
I got something. White crystals Yield 3.743 g Yield 86% mp 115-117 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 2.97 (3H,
s), 5.03-5.06 (1H, m), 6.76 (1H, dd, J = 1.6 Hz, 8.
2 Hz), 6.80 (1H, s), 6.90 (1H, d, J = 8.2 Hz), 7.0
5 (2H, t, J = 8.6 Hz), 7.36 (2H, dd, J = 5.4 Hz,
8.6 Hz); IR (KBr) 3333, 3100-2550, 1694, 1518, 149
9, 1447, 1273, 1260, 1244, 1163, 1148,841 cm^-1; An
al. Calcd for C₁₇H₁₃F_ThreeO_Five: C, 57.63; H, 3.70. Foun
d: C, 57.64; H, 3.51.5) (4RS, 5SR) -4-[(2,2-difluoro-
1,3-benzodioxol-5-yl) methyl] -5-
(4-Fluorophenyl) -1,3-oxazolidine-2-
ON (2RS, 3RS) -2-[(2,2-difluoro-1,3
-Benzodioxol-5-yl) methyl] -3- (4-fur
Orophenyl) -3-hydroxypropionic acid 3.387
g (9.560 mmol) of tetrahydrofuran 50 m
1.00 ml of triethylamine (14.3 mm
Mol), 2.89 g of diphenylphosphoryl azide (1
(0.5 mmol) and heated to reflux overnight. Reaction solution
The solvent was distilled off under reduced pressure.
Purification by column chromatography (hexane / ethyl acetate
= 3/1-1/1), from diethyl ether-hexane
Recrystallization gave the desired product. White crystals Yield 3.14
4g yield 94% mp 177-178 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 2.16-2.35
(2H, m), 4.13-4.25 (1H, m), 5.10 (1H, br s), 5.79
(1H, d, J = 7.6 Hz), 6.72 (1H, d, J = 8.4 Hz), 6.7
4 (1H, s), 6.98 (1H, d, J = 8.6 Hz), 7.14 (2H, t,
J = 8.6 Hz), 7.36 (2H, dd, J = 5.0 Hz, 8.8 Hz); IR
 (KBr) 3241, 3139, 1736, 1501, 1258, 1238, 1152 cm
^-1; Anal. Calcd for C₁₇H₁₂F_ThreeNO_Four: C, 58.13; H, 3.4
4; N, 3.99.Found: C, 58.16; H, 3.42; N, 3.85. 6) (1RS, 2SR) -2-amino-3- (2,2-di)
Fluoro-1,3-benzodioxol-5-yl) -1-
(4-fluorophenyl) propan-1-ol (4RS, 5SR) -4-[(2,2-difluoro-1,3
-Benzodioxol-5-yl) methyl] -5- (4-fur
(Orophenyl) -1,3-oxazolidin-2-one 2.9
62 g (8.432 mmol) and sodium hydroxide 1.
35 g (33.7 mmol) of ethanol 30 ml-water
The mixture was refluxed for 6 hours in 1.5 ml. Dilute the reaction solution with water
And extracted twice with ethyl acetate. Dry the collected organic layer
After drying over sodium sulfate, the solvent was distilled off under reduced pressure. Residue
Silica gel (APS type) column chromatography
(Hexane / ethyl acetate = 3 / 1-ethyl acetate)
), Crystallized from diisopropyl ether-hexane
Then, the desired product was obtained. White crystals Yield 2.225 g Yield
81% mp 77-78 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 2.36 (1H, d
d, J = 10.1 Hz, 13.7 Hz), 2.81 (1H, dd, J = 3.1 H
z, 13.7 Hz), 3.22 (1H, ddd, J = 3.2 Hz, 5.2 Hz, 1
0.0 Hz), 4.63 (1H, d, J = 5.2 Hz), 6.82-6.87 (2H,
m), 6.97 (1H, d, J = 8.0 Hz), 7.08 (2H, t, J = 8.8
Hz), 7.37 (2H, dd, J = 5.4 Hz, 8.6 Hz); IR (KBr) 33
40-2865, 1501, 1447, 1262, 1242, 1213, 1157, 1063,
 779 cm^-1; Anal. Calcd for C₁₆H₁₄F_ThreeNO_Three: C, 59.08;
H, 4.34; N, 4.31. Found: C, 59.08; H, 4.39; N, 4.1
0.7) N-[(1RS, 2SR) -1-[(2,2-diflu
Oro-1,3-benzodioxol-5-yl) methyl]-
2- (4-fluorophenyl) -2-hydroxyethyl]-
4-Fluoronaphthalene-1-carboxamide (1RS, 2SR) -2-amino-3- (2,2-difluoro
B-1,3-benzodioxol-5-yl) -1- (4-f
Fluorophenyl) propan-1-ol 0.167 g
(0.513 mmol) 4-fluoro-1-naphthoic acid
0.10 g (0.51 mmol), 1-hydroxyben
79 mg (0.51 mmol) of zotriazole hydrate
1-ethyl-3 with stirring in 10 ml of acetonitrile
-(3-Dimethylaminopropyl) carbodiimide / hydrochloric acid
Add 0.10 g (0.51 mmol) of salt and overnight at room temperature
Stirred. Dilute the reaction mixture with ethyl acetate and add sodium hydrogen carbonate
Wash with aqueous solution of lithium, dry over anhydrous magnesium sulfate,
After passing through Licagel, the solvent was distilled off under reduced pressure. Obtained residue
The distillate was crystallized from diisopropyl ether-hexane.
Then, the desired product was obtained. White crystals Yield 0.230 g Yield
90% mp 219-220 ° C;¹H-NMR (CDCl_Three-DMSO-d₆, 200MHz) δ 2.
85 (1H, dd, J = 10.0Hz, 14.4 Hz), 2.97 (1H, dd, J
= 4.2 Hz, 13.8 Hz), 4.64-4.78 (1H, m), 5.01 (1H, t,
 J = 3.8 Hz), 5.10 (1H, d, J = 3.6 Hz), 6.93-7.13
(6H, m), 7.25-7.58 (6H, m), 7.69 (1H, d, J = 8.0 H
z), 8.07 (1H, d, J = 8.0 Hz); IR (KBr) 3266, 1644,
 1626, 1541, 1514, 1497, 1244, 1146 cm^-1; Anal. Ca
lcd for C ₂₇H₁₉F_FourNO_Four: C, 65.19; H, 3.85; N, 2.82. F
ound: C, 65.22; H, 3.87; N, 2.57.

Example 168 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-[[2- (trifluoromethyl)-
Tert-Butyl 1,3-thiazol-5-yl] methyl] ethyl] carbamate 1) 2- (trifluoromethyl) -1,3-thiazole-
Ethyl 5-carboxylate 12.27 g 2,2,2-trifluoroacetamide
(Purity 85%, 80.8 mmol), 15.2 g (80.8 mmol) of ethyl chloroformate acetate potassium salt, and 4.85 g (80.8 mmol) of acetic acid were heated under reflux overnight in 100 ml of ethanol. After evaporating the solvent of the reaction solution under reduced pressure, the reaction solution was diluted with an aqueous solution of sodium hydrogen carbonate,
Extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to obtain the desired product. Yellow liquid Yield 12.72 g Yield 70% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.41 (3H, t, J = 7.1 H)
z), 4.43 (2H, q, J = 7.1Hz), 8.49 (1H, s); IR (nea
t) 1728, 1522, 1304, 1285, 1246, 1196, 1152,1094,
1038 cm ^-1 2) [2- (trifluoromethyl) -1,3-thiazol-5-yl] methanol A suspension of 2.17 g (57.1 mmol) of lithium aluminum hydride in 80 ml of tetrahydrofuran was cooled with ice. 8.57 ethyl ethyl 2- (trifluoromethyl) -1,3-thiazole-5-carboxylate
9 g (38.10 mmol) of tetrahydrofuran 40
The solution was added dropwise and stirred at 0 ° C. for 1 hour. The reaction solution was cooled on ice, and 2 ml of water and 2 m of a 15% aqueous sodium hydroxide solution were used.
1 and 5 ml of water were sequentially added dropwise to decompose excess lithium aluminum hydride, and the mixture was stirred at room temperature for 2 hours.
The resulting precipitate was removed by filtration, and the precipitate was washed with ethyl acetate. The solvent of the collected filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-1 / 1) to obtain the desired product. Brown liquid Yield 5.499 g Yield 79% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.24 (1 H, t, J = 5.7 H)
z), 4.97 (2H, d, J = 5.6Hz), 7.82 (1H, s); IR (nea
t) 3308, 1532, 1456, 1333, 1312, 1196, 1144,1036 c
m ^-1 3) 3- (4-fluorophenyl) -3-oxo-2-
[[2- (trifluoromethyl) -1,3-thiazole-5
Ethyl [-yl] methyl] propionate [2- (trifluoromethyl) -1,3-thiazole-5-
[Il] A solution of 2.61 g (14.3 mmol) of methanol and 2.39 ml (17.1 mmol) of triethylamine in 40 ml of ethyl acetate under ice-cooling 1.80 g (15.7 mmol) of methanesulfonyl chloride in 10 ml of ethyl acetate
The solution was added dropwise and stirred for 10 minutes. The resulting precipitate was removed by filtration, and the precipitate was washed with diethyl ether.
The solvent of the collected filtrate was distilled off under reduced pressure to obtain a crude product of methanesulfonic acid ester as a yellow liquid. 0.57 g (14.3 mmol) of a 60% sodium hydride liquid paraffin suspension in a solution of 2.998 g (14.26 mmol) of ethyl (4-fluorobenzoyl) acetate in 30 ml of 1,2-dimethoxyethane under ice cooling. And add 0.
Stir for 5 hours. To this was added a solution of methanesulfonic acid ester obtained above in 1,2-dimethoxyethane (10 ml) at room temperature, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-6 / 1) to obtain the desired product.
White crystal Yield 4.275 g Yield 80% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.15 (3H, t, J = 7.1 H)
z), 3.61 (2H, d, J = 7.0Hz), 4.15 (2H, q, J = 7.1
Hz), 4.57 (1H, t, J = 7.1 Hz), 7.17 (2H, t, J = 8.6
Hz), 7.70 (1H, s), 8.04 (2H, dd, J = 5.3 Hz, 8.9
Hz); IR (neat) 1740, 1732, 1682, 1599, 1508, 1456,
1329, 1300, 1238, 1194, 1157, 1034, 849 cm -1 4) (1RS, 2RS) -3- (4- fluorophenyl) -3-hydroxy-2 - [[2- (trifluoromethyl) -1 Ethyl 3,3-thiazol-5-yl] methyl] propionate While stirring 2.80 g (20.5 mmol) of zinc chloride in 50 ml of diethyl ether, 1.55 g (41.1 mmol) of sodium borohydride was added at room temperature. The mixture was further stirred for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. 3.856 g of ethyl 3- (4-fluorophenyl) -3-oxo-2-[[2- (trifluoromethyl) -1,3-thiazol-5-yl] methyl] propionate was added to the resulting solution. (10.27 mmol) in 30 ml of diethyl ether was added at room temperature, and the mixture was stirred for 2 hours. Dilute hydrochloric acid was added little by little to the reaction solution to decompose excess zinc borohydride, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-3 / 1) to obtain the desired product. Colorless liquid Yield 1.989 g Yield 51% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.27 (3H, t, J = 7.1 H)
z), 2.64 (1H, d, J = 3.0Hz), 2.98 (1H, ddd, J = 4.
0 Hz, 6.2 Hz, 10.2 Hz), 3.23 (1H, dd, J = 4.2Hz, 1
5.2 Hz), 3.39 (1H, dd, J = 10.2 Hz, 15.2 Hz), 3.99
(2H, q, J = 7.1Hz), 5.03 (1H, dd, J = 2.9 Hz, 6.3
Hz), 7.06 (2H, t, J = 8.6 Hz), 7.36 (2H, dd, J =
5.3 Hz, 8.7 Hz), 7.59 (1H, s); IR (neat) 3409, 172
6, 1510, 1454, 1329, 1300, 1225, 1192, 1150, 1034,
^{839 cm -1 5) (1RS,} 2RS) -3- (4- fluorophenyl) -3-hydroxy-2 - [[2- (trifluoromethyl) -1,3-thiazol-5-yl] methyl] propionic Acid (1RS, 2RS) -3- (4-fluorophenyl) -3-
Hydroxy-2-[[2- (trifluoromethyl) -1,3
1.883 g (4.990 mmol) of ethyl-thiazol-5-yl] methyl] propionate in methanol 20
9.98 ml of 1N aqueous sodium hydroxide solution
(9.98 mmol) and stirred at room temperature overnight. The reaction solution was concentrated, diluted with water, acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1) to obtain the desired product. Light yellow liquid Yield 1.420 g Yield 82% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 3.04 (1H, ddd, J = 4.0 H)
z, 5.8 Hz, 9.7 Hz), 3.18 (1H, dd, J = 3.6 Hz, 15.0
Hz), 3.40 (1H, dd, J = 10.0 Hz, 15.4 Hz), 5.13 (1
H, d, J = 5.4 Hz), 7.08 (2H, t, J = 8.8 Hz), 7.38
(2H, dd, J = 5.4Hz, 8.6 Hz), 7.59 (1H, s); IR (nea
t) 3500-2900, 1715, 1510, 1456, 1331,1300, 1227, 1
196, 1152, 1040, 841 cm -1 6) (4RS, 5SR) -5- (4- fluorophenyl) -4 - [[2- (trifluoromethyl) -1,3-thiazol-5-yl] methyl ] -1,3-Oxazolidine-2-
ON (1RS, 2RS) -3- (4-fluorophenyl) -3-
Hydroxy-2-[[2- (trifluoromethyl) -1,3
-Thiazol-5-yl] methyl] propionic acid 1.31
0 g (1.310 mmol) of tetrahydrofuran 50
0.78 ml (5.63 mmol) of triethylamine and 1.14 g of diphenylphosphoryl azide
(4.13 mmol) and heated to reflux overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1) to obtain the desired product. ¹ H-NMR (CDCl ₃ , 200MHz) δ 2.58 (1H, dd, J = 5.2 H
z, 15.0 Hz), 2.69 (1H, dd, J = 8.8 Hz, 15.0 Hz), 4.
23-4.35 (1H, m), 5.67 (1H, br s), 5.83 (1H, d, J =
7.6 Hz), 7.13 (2H, t, J = 8.6 Hz), 7.32 (2H, dd, J
= 5.2 Hz, 8.8Hz), 7.49 (1H, s); IR (neat) 3272, 1
780-1730, 1514, 1456, 1331, 1300, 1233, 1194, 114
^{8, 1032 cm -1 7) (} 4RS, 5SR) -5- (4- fluorophenyl) -2-oxo-4 - [[2- (trifluoromethyl) -
1,3-thiazol-5-yl] methyl] -1,3-oxazolidin-3-carboxylate tert-butyl (4RS, 5SR) -5- (4-fluorophenyl) -4-
[[2- (trifluoromethyl) -1,3-thiazole-5
-Yl] methyl] -1,3-oxazolidin-2-one
062 g (3.067 mmol), di-tert-dicarbonate
A solution of 0.80 g (3.68 mmol) of butyl and 37 mg (0.31 mmol) of 4-N, N-dimethylaminopyridine in 10 ml of acetonitrile was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. 1.186 g of white crystals
Yield 87% mp 192-193 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.55 (9H,
s), 2.99 (1H, dd, J = 7.4 Hz, 15.0 Hz), 3.09 (1H, d
d, J = 5.2 Hz, 15.4 Hz), 4.75 (1H, dt, J = 4.9 Hz,
14.9 Hz), 5.73 (1H, d, J = 7.0 Hz), 7.04 (1H, s),
7.06 (2H, t, J = 8.6 Hz), 7.22 (2H, dd, J = 5.2 Hz,
8.4 Hz); IR (KBr) 1792, 1370, 1304, 1192, 1163, 1
034 cm ^-1 ; Anal.Calcd for C ₁₉ H ₁₈ F ₄ N ₂ O ₄ S: C, 51.12;
H, 4.06; N, 6.28. Found: C, 50.94; H, 4.10; N, 6.
48.8) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-[[2- (trifluoromethyl) -1,3-thiazol-5-yl] methyl] methyl Ethyl tert-butyl carbamate (4RS, 5SR) -5- (4-fluorophenyl) -2-
Oxo-4-[[2- (trifluoromethyl) -1,3-thiazol-5-yl] methyl] -1,3-oxazolidine-
1.079 g of tert-butyl 3-carboxylate (2.41
0.1 mmol (2.6 mmol) of sodium hydroxide in a solution of 7 mmol) of methanol (10 ml) -tetrahydrofuran (10 ml).
A solution of 6 mmol) in 5 ml of methanol was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.842 g Yield 83% mp 137-138 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.38 (9H,
s), 2.61 (1H, br s), 3.07 (2H, d, J = 7.0 Hz), 3.9
4-4.05 (1H, m), 4.76 (1H, br d, J = 8.4 Hz), 4.91
(1H, br s), 7.08 (2H, t, J = 8.6 Hz), 7.38 (2H, d
d, J = 5.4 Hz, 8.6 Hz), 7.61 (1H, s); IR (KBr) 333
7, 1682, 1532, 1138, 1038 cm ^-1 ; Anal.Calcd for C
₁₈ H ₂₀ F ₄ N ₂ O ₃ S: C, 51.42; H, 4.79; N, 6.66. Found:
C, 51.50; H, 4.70; N, 6.90.

Example 169 4-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-[[2- (trifluoromethyl) -1,3-thiazole- 5-yl] methyl] ethyl] naphthalene-1-carboxamide 1) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [2- (trifluoromethyl) -1,3
-Thiazol-5-yl] propan-1-ol N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-[[2- (trifluoromethyl)-
0.711 g (1.691 mmol) of tert-butyl 1,3-thiazol-5-yl] methyl] ethyl] carbamate and 0.5 ml of concentrated hydrochloric acid in 5 ml of methanol were added.
Heated to reflux for 0 minutes. The reaction was diluted with water, made alkaline with potassium carbonate and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel (APS type) column chromatography (ethyl acetate) to obtain the desired product. Colorless liquid Yield 0.534 g Yield 99% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.82 (1H, dd, J = 9.4 H)
z, 14.8 Hz), 3.08-3.26 (2H, m), 4.56 (1H, d, J = 5.
8 Hz), 7.09 (2H ,, t, J = 8.6 Hz), 7.36 (2H, dd, J =
5.6 Hz, 8.8 Hz), 7.68 (1H, s); IR (neat) 3364, 15
07, 1456, 1331,1300, 1225, 1192, 1144, 1032, 837 c
m ^-1 2) 4-Fluoro-N-[(1RS, 2SR) -2- (4-
Fluorophenyl) -2-hydroxy-1-[[2- (trifluoromethyl) -1,3-thiazol-5-yl] methyl] ethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1 0.226 g of-(4-fluorophenyl) -3- [2- (trifluoromethyl) -1,3-thiazol-5-yl] propan-1-ol
(0.702 mmol) 0.13 g (0.71 mmol) of 4-fluoro-1-naphthoic acid 0.11 g (0.71 mmol) of 1-hydroxybenzotriazole hydrate
Was stirred in 10 ml of acetonitrile while stirring in 1-ethyl-
0.14 g (0.71 mmol) of 3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate.
After passing through silica gel, the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.301 g Yield 87% mp 197-198 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 3.
28 (2H, d, J = 7.0 Hz), 4.62-4.76 (1H, m), 4.97 (1
H, t, J = 3.9 Hz), 5.18 (1H, d, J = 3.2 Hz), 7.08
(2H, t, J = 8.8 Hz), 7.11 (1H, d, J = 9.2 Hz), 7.3
8 (1H, dd, J = 5.4 Hz, 7.8 Hz), 7.47-7.65 (5H, m),
7.68 (1H, s), 7.80-7.86 (1H, m), 8.08-8.12 (1H,
m); IR (KBr) 3264, 1642, 1626, 1601, 1535, 1512, 1
454, 1331, 1300, 1227, 1192, 1140, 1040, 760 cm ^-1 ;
Anal.Calcd for C ₂₄ H ₁₇ F ₅ N ₂ O ₂ S: C, 58.53; H, 3.48;
N, 5.69. Found: C, 58.30; H, 3.68; N, 5.76.

Example 170 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((3- (2,2,2-trifluoroethoxy) phenyl) methyl) ethyl) -4-fluoro-
1-Naphthalenecarboxamide 1) 3-Hydroxytoluene (5.0 g, 46.2 mmol) in N, N-dimethylformamide (50 ml)
Add 2,2,2-trifluoro-1-iodoethane (1
0.7 g, 50.9 mmol) and potassium carbonate (1
(2.8 g, 92.5 mmol) and stirred at 80 ° C. overnight. The reaction solution was diluted with water (200 ml) and extracted with diethyl ether (300 ml × 2). Extract water with water,
The extract was washed successively with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give 3- (2,2,2-trifluoroethoxy) toluene (7.60 g, 86%) as a colorless oil. . IRνmax ^KBr cm ^-1 : 1752, 1680, 1615, 1588, 1487. ¹ H-NMR (CDCl ₃ ) δ: 2.34 (3H, s), 4.33 (2H, q, J =
8.0 Hz), 6.70-6.90 (3H, m), 7.20 (1H, t, J = 7.6 H
z). 2) 3- (2,2,2-trifluoroethoxy) toluene (7.34 g, 38.6 mmol) in carbon tetrachloride (1
00 ml) solution with N-bromosuccinimide (7.56).
g, 42.5 mmol) and 2,2′-azobis (isobutyronitrile) (633 mg, 3.86 mmol), and the mixture was heated under reflux overnight. The insolubles were filtered using celite, and the filtrate was concentrated to prepare a bromo compound. 3-oxo-
Ethyl 3- (4-fluorophenyl) propionate (7.
3g, 34.7 mmol) in 1,2-dimethoxyethane (70 ml) was added to a solution of sodium hydride (60% oily,
(1.39 g, 34.7 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. A solution of the previously synthesized bromo compound in 1,2-dimethoxyethane (20 ml) was dropped into the reaction solution,
The reaction was stirred at room temperature for 1 hour. The reaction solution was washed with water (200 m
1) and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
4: 1) and recrystallized from diisopropyl ether-hexane to give 3- (4-fluorophenyl) -3-oxo-2-((3- (2,2,2-trifluoroethoxy)
Phenyl) methyl) ethyl propionate (4.23 g,
31%). mp 48-49 ° C IRνmax ^KBr cm ^-1 : 1738, 1688, 1599, 1508, 1493, 145
_{. 3. Anal Calcd for C 20 H} 18 F 4 O 4: C, 60.30; H, 4.55 Found:. C, 60.11; H, 4.36 1 H-NMR (CDCl 3) δ: 1.23 (3
H, t, J = 7.0 Hz), 3.30 (2H, d, J = 7.2 Hz), 4.11
(2H, q, J = 7.0 Hz), 4.30 (2H, q, J = 8.0 Hz), 4.5
6 (1H, t, J = 7.2 Hz), 6.70-6.96 (3H, m), 7.06-7.3
0 (3H, m), 7.92-8.10 (2H, m). 3) To a solution of zinc chloride (2.81 g, 20.6 mmol) in diethyl ether (100 ml) was added sodium borohydride (1.56 g, 41.2). Mmol) and stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was treated with 3- (4-fluorophenyl) -3-oxo-2-((3- (2,2,2-
A solution of ethyl trifluoroethoxy) phenyl) methyl) propionate (4.10 g, 10.3 mmol) in diethyl ether (50 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Under ice cooling, the reaction solution is quenched by adding 1N hydrochloric acid,
Further, water (200 ml) was added, and ethyl acetate (300 ml) was added.
× 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purified with ethyl acetate = 4: 1) to give (2RS, 3RS)-
3- (4-fluorophenyl) -3-hydroxy-2-((3
Ethyl-(2,2,2-trifluoroethoxy) phenyl) methyl) propionate (3.51 g, 85%) was obtained as a colorless oil. IRνmax ^KBr cm ^-1 : 1715, 1605, 1590, 1510. Anal.Calcd for C ₂₀ H ₂₀ F ₄ O ₄・ 0.1H ₂ O: C, 59.73; H,
5.06 Found:. C, 59.55; H, 5.06 1 H-NMR (CDCl 3) δ: 0.94 (3H, t, J = 7.0 Hz), 2.88-
3.00 (3H, m), 3.90 (2H, q, J = 7.0 Hz), 4.30 (2H,
q, J = 8.0 Hz), 5.01 (1H, brs), 6.60-6.82 (3H, m),
7.00-7.30 (3H, m), 7.32-7.44 (2H, m). 4) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((3- (2,2, Ethyl 2-trifluoroethoxy) phenyl) methyl) propionate (3.4 g, 8.49 mmol) in methanol (15 m
1) Add 2N aqueous sodium hydroxide solution (8.5 m
1,17.0 mmol) and stirred at room temperature overnight.
The reaction solution was acidified with 1N hydrochloric acid and then ethyl acetate (10%).
0 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane,
(2RS, 3RS) -3- (4-fluorophenyl) -3-
Hydroxy-2-((3- (2,2,2-trifluoroethoxy) phenyl) methyl) propionic acid (2.78 g,
88%). ^{. mp 142-143 ℃ IRνmax KBr cm -1} : 1715, 1607, 1588. Anal Calcd for C 18 H 16 F 4 O 4: C, 58.07; H, 4.33 Found:. C, 58.00; H, 4.27 1 H- NMR (CDCl ₃ ) δ: 2.82-3.10 (3H, m), 4.29 (2H, q,
J = 8.0 Hz), 5.06 (1H, d, J = 4.4 Hz), 6.69 (1H,
s), 6.70-7.02 (2H, m), 7.00-7.24 (3H, m), 7.30-7.4
4 (2H, m). 5) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((3- (2,2,2-trifluoroethoxy) phenyl) methyl) propion Acid (2.
68 g, 7.20 mmol) of tetrahydrofuran (6
0 ml) solution in diphenylphosphoryl azide (1.7).
1 ml, 7.92 mmol) and triethylamine (1.
(51 ml, 10.8 mmol) and heated to reflux for 3 hours. After allowing the reaction solution to cool, water (200 ml) was added, and the mixture was extracted with ethyl acetate (200 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (4RS, 5SR)-
5- (4-fluorophenyl) -4-((3- (2,2,2-
Trifluoroethoxy) phenyl) methyl) -1,3-oxazolidin-2-one (2.31 g, 87%) was obtained. mp 148-149 ° C IRνmax ^KBr cm ^-1 : 1759, 1609, 1590, 1514. Anal.Calcd for C ₁₈ H ₁₅ F ₄ NO ₃ : C, 58.54; H, 4.09; N,
3.79 Found:. C, 58.54; H, 4.01; N, 3.88 1 H-NMR (CDCl 3) δ: 2.12-2.38 (2H, m), 4.16-4.28 (1
H, m), 4.32 (2H, q, J = 8.0 Hz), 5.17 (1H, brs), 5.
79 (1H, d, J = 8.0Hz), 6.62 (1H, d, J = 1.8Hz),
6.72 (1H, d, J = 7.6 Hz), 6.77-6.84 (1H, m), 7.04-
7.42 (5H, m). 6) (4RS, 5SR) -5- (4-fluorophenyl) -4-((3- (2,2,2-trifluoroethoxy)
Phenyl) methyl) -1,3-oxazolidin-2-one (1.2 g, 3.25 mmol) in ethanol (10 m
l) 8N aqueous sodium hydroxide solution (2.0m
1, 16 mmol) and heated to reflux for 2 hours. After concentration, the reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (1R
S, 2SR) -2-Amino-1- (4-fluorophenyl)-
3- (3- (2,2,2-trifluoroethoxy) phenyl) -1-propanol (913 mg, 82%) was obtained. mp 94-95 ° C IRνmax ^KBr cm ^-1 : 1605, 1588, 1508, 1489, 1454 Anal.Calcd for C ₁₇ H ₁₇ F ₄ NO ₂ : C, 59.47; H, 4.99; N,
4.08 Found:. C, 59.34; H, 4.87; N, 4.19 1 H-NMR (CDCl 3) δ: 2.33 (1H, dd, J = 14.0, 10.6 H
z), 2.78 (1H, dd, J = 14.0, 3.0 Hz), 3.20-3.34 (1
H, m), 4.33 (2H, q, J = 8.0 Hz), 4.66 (1H, d, J =
4.6 Hz), 6.70-6.90 (3H, m), 7.00-7.16 (2H, m), 7.2
0-7.30 (1H, m), 7.30-7.44 (2H, m). 7) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (3- (2,2,2 -Trifluoroethoxy) phenyl) -1-propanol (181 mg, 0.1 mg).
53 mmol) in acetonitrile (20 ml) solution.
-Fluoronaphthalenecarboxylic acid (100 mg, 0.5
3 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (151 mg, 0.1 mg).
79 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) were added, and the mixture was stirred at room temperature overnight. Dilute the reaction with water (100 ml)
Extracted with ethyl acetate (100 ml × 2). Extract 1
The mixture was washed successively with normal hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (206 mg, 76%). mp 192-193 ℃ IRνmax ^KBr cm ^-1 : 1642, 1626, 1601, 1512. Anal.Calcd for C ₂₈ H ₂₂ F ₅ NO ₃・ 0.1H ₂ O: C, 65.02;
4.32; N, 2.71 Found: C, 64.89; H, 4.43; N, 2.93. ¹ H-NMR (CDCl ₃ ) δ: 2.78 (1H, dd, J = 14.6, 11.0 H
z), 3.04 (1H, dd, J = 14.6, 4.0 Hz), 4.28 (2H, q,
J = 8.0 Hz), 4.70-4.88 (1H, m), 5.09 (1H, d, J = 3.
8 Hz), 5.90 (1H, d, J = 8.8 Hz), 6.76-7.36 (8H,
m), 7.40-7.60 (4H, m), 7.77 (1H, d, J = 7.6 Hz), 8.
09 (1H, d, J = 7.6 Hz).

Example 171 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((3- (2,2,2-trifluoroethoxy) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR ) -2-Amino-1- (2-fluorophenyl) -3- (3- (2,2,2-trifluoroethoxy)
To a solution of phenyl) -1-propanol (183 mg, 0.53 mmol) in acetonitrile (20 ml) was added 6,7-
Dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (100 mg, 0.53 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (153 mg, 0.80 mmol) and 1 -
Hydroxy-1H-benzotriazole (81 mg, 0.1 mg).
(53 mmol) and stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (225m
g, 82%). ^{mp 172-173 ℃ IRνmax KBr cm -1:} 1636, 1605, 1588, 1510. 1 H-NMR (CDCl 3) δ: 1.90-2.08 (2H, m), 2.10-2.36 (2
H, m), 2.60-2.80 (3H, m), 2.97 (1H, dd, J = 14.2,
4.0 Hz), 3.78 (1H, s), 4.30 (2H, q, J = 8.2 Hz),
4.60-4.76 (1H, m), 5.01 (1H, d, J = 3.2 Hz), 5.75
(1H, d, J = 8.4 Hz), 5.82-6.00 (1H, m), 6.17 (1H,
d, J = 11.8 Hz), 6.77 (1H, s), 6.80-6.92 (1H, m),
6.94-7.30 (7H, m), 7.38-7.50 (2H, m).

Example 172 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((3- (2,2,3,3-tetrafluoropropyloxy) phenyl) methyl) ethyl)-
4-Fluoro-1-naphthalenecarboxamide 1) 3-Hydroxytoluene (5.0 g, 46.2 mmol) in N, N-dimethylformamide (50 ml)
To the solution were added 2,2,3,3-tetrafluoro-1-iodopropane (12.3 g, 50.9 mmol) and potassium carbonate (12.8 g, 92.5 mmol),
And stirred overnight. Dilute the reaction with water (200 ml)
Extracted with diethyl ether (300 ml × 2). The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 10: 1).
To give 3- (2,2,3,3-tetrafluoropropyloxy) toluene (10.0 g, 97%) as a colorless oil. IRνmax ^KBr cm ^-1 : 1607, 1588, 1491, 1458.Anal.Calcd for C ₁₀ H ₁₀ F ₄ O ・ 0.2H ₂ O: C, 53.20; H, 4.
64 Found:. C, 53.01; H, 4.40 1 H-NMR (CDCl 3) δ: 2.34 (3H, s), 4.32 (2H, tt, J =
12.0, 1.6 Hz), 6.07 (1H, tt, J = 53.2, 5.0 Hz), 6.
70-6.90 (3H, m), 7.16-7.24 (1H, m). 2) Tetrachloride of 3- (2,2,3,3-tetrafluoropropyloxy) toluene (7.0 g, 31.5 mmol) N-bromosuccinimide (6.17 g, 34.7 mmol) and 2,2'-azobis (isobutyronitrile) (517 mg, 3.15 mmol) were added to a carbon (100 ml) solution, and the mixture was heated under reflux overnight. The insolubles were filtered using celite, and the filtrate was concentrated to prepare a bromo compound.
To a solution of ethyl 3- (4-fluorophenyl) -3-oxopropionate (5.96 g, 28.4 mmol) in 1,2-dimethoxyethane (60 ml) was added sodium hydride (6 ml).
(0% oily, 1.13 g, 28.4 mmol) under ice-cooling and stirred at room temperature for 30 minutes. A solution of the previously synthesized bromo compound in 1,2-dimethoxyethane (20 ml) was dropped into the reaction solution, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was poured into water (200 ml), and ethyl acetate (200 ml ×
Extracted in 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
The product was purified with ethyl acetate = 4: 1, recrystallized from diisopropyl ether-hexane, and treated with 3- (4-fluorophenyl) -3-oxo-2-((3- (2,2,3,3-tetra Ethyl fluoropropyloxy) phenyl) methyl) propionate (5.63 g, 46%) was obtained. mp 55-56 ° C IRνmax ^KBr cm ^-1 : 1738, 1688, 1599, 1508, 1489, 144
9. Anal.Calcd for C ₂₁ H ₁₉ F ₅ O ₄ : C, 58.61; H, 4.45 Found: C, 58.50; H, 4.41. ¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7.2 Hz), 3.30
(2H, d, J = 7.2 Hz), 4.11 (2H, q, J = 7.2 Hz), 4.2
0-4.38 (2H, m), 4.56 (1H, t, J = 7.2 Hz), 6.05 (1
H, tt, J = 53.0, 5.0 Hz), 6.70-6.88 (2H, m), 6.91
(1H, d, J = 7.2 Hz), 7.06-7.30 (3H, m), 7.92-8.08
(2H, m). 3) To a solution of zinc chloride (3.50 g, 25.6 mmol) in diethyl ether (100 ml) was added sodium borohydride (1.93 g, 51.1 mmol), and the mixture was stirred at room temperature for 30 minutes. did. The insoluble material was removed by filtration, and the filtrate was treated with 3- (4-fluorophenyl) -3-oxo-2-((3- (2,2,2
A solution of ethyl 3,3-tetrafluoropropyloxy) phenyl) methyl) propionate (5.50 g, 12.8 mmol) in diethyl ether (50 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Under ice-cooling, the reaction solution was quenched by adding 1N hydrochloric acid, further added with water (200 ml), and extracted with ethyl acetate (300 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give (2
Ethyl RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((3- (2,2,3,3-tetrafluoropropyloxy) phenyl) methyl) propionate (4.99 g, 90%) as a colorless oil. ^{. IRνmax KBr cm -1: 1725,} 1605, 1588, 1511. Anal Calcd for C 21 H 21 F 5 O 4: C, 58.33; H, 4.90 Found:. C, 58.20; H, 4.92 1 H-NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.0 Hz), 2.89
(1H, d, J = 2.8 Hz), 2.92-3.02 (3H, m), 3.90 (2H,
q, J = 7.0 Hz), 4.29 (2H, t, J = 12.0 Hz), 5.02 (1
H, s), 6.05 (1H, tt, J = 53.0, 5.0 Hz), 6.62-6.82
(3H, m), 7.00-7.24 (3H, m), 7.32-7.44 (2H, m). 4) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((3 To a solution of ethyl-(2,2,3,3-tetrafluoropropyloxy) phenyl) methyl) propionate (4.75 g, 11.0 mmol) in methanol (40 ml) was added 2N aqueous sodium hydroxide solution (11 ml, 22 (1.0 mmol) and stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (100 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (2RS, 3RS) -3- (4-
Fluorophenyl) -3-hydroxy-2-((3- (2,
2,3,3-Tetrafluoropropyloxy) phenyl) methyl) propionic acid (3.91 g, 88%) was obtained. ^{. mp 114-115 ℃ IRνmax KBr cm -1} : 1715, 1607, 1512. Anal Calcd for C 19 H 17 F 5 O 4: C, 56.44; H, 4.24 Found:. C, 56.52; H, 4.35 1 H- NMR (CDCl ₃ ) δ: 2.84-3.08 (3H, m), 4.19-4.37 (2
H, m), 5.06 (1H, d, J = 4.4 Hz), 6.04 (1H, tt, J =
53.0, 5.0 Hz), 6.60-6.68 (1H, m), 6.68-6.80 (2H,
m), 7.00-7.30 (3H, m), 7.30-7.42 (2H, m). 5) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((3- (2 To a solution of (2,3,3-tetrafluoropropyloxy) phenyl) methyl) propionic acid (2.0 g, 4.95 mmol) in tetrahydrofuran (40 ml) was added diphenylphosphoryl azide (1.17 ml, 5.44 mmol). Triethylamine (1.04 ml, 7.43 mmol) was added, and the mixture was heated under reflux for 3 hours. After allowing the reaction solution to cool, water (200 ml) was added, and the mixture was extracted with ethyl acetate (200 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (4R
S, 5SR) -5- (4-fluorophenyl) -4-((3-
(2,2,3,3-tetrafluoropropyloxy) phenyl) methyl) -1,3-oxazolidin-2-one (1.68 g, 85%) was obtained. mp 113-114 ° C IRνmax ^KBr cm ^-1 : 1759, 1608, 1588, 1514. Anal.Calcd for C ₁₉ H ₁₆ F ₅ NO ₃ : C, 56.89; H, 4.02; N,
3.49 Found:. C, 56.99; H, 4.15; N, 3.53 1 H-NMR (CDCl 3) δ: 2.10-2.40 (2H, m), 4.18-4.40 (3
H, m), 5.22 (1H, brs), 5.79 (1H, d, J = 8.4 Hz), 6.
05 (1H, tt, J = 53.2, 5.0 Hz), 6.59 (1H, s), 6.66
6.82 (2H, m), 7.04-7.40 (5H, m). 6) (4RS, 5SR) -5- (4-fluorophenyl) -4-((3- (2,2,3,3-tetrafluoro To a solution of propyloxy) phenyl) methyl) -1,3-oxazolidine-2-one (1.0 g, 2.49 mmol) in ethanol (10 ml) was added an 8 N aqueous sodium hydroxide solution (1.56 ml, 12.5 mmol). Was added and heated under reflux for 3 hours. After concentration, the reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2SR) -2-amino-1- (4-fluorophenyl). ) -3- (3- (2,2,3,3-tetrafluoropropyloxy) phenyl) -1-propanol (82
5 mg, 88%). mp 77-78 ° C IRνmax ^KBr cm ^-1 : 1605, 1586, 1508, 1489. Anal.Calcd for C ₁₈ H ₁₈ F ₅ NO ₂ : C, 57.60; H, 4.83; N,
3.73 Found:. C, 57.62; H, 4.70; N, 3.76 1 H-NMR (CDCl 3) δ: 2.33 (1H, dd, J = 14.0, 10.4 H
z), 2.79 (1H, dd, J = 14.0, 3.0 Hz), 3.22-3.34 (1
H, m), 4.32 (2H, t, J = 12.0 Hz), 4.66 (1H, d, J =
4.8 Hz), 6.06 (1H, tt, J = 53.0, 5.0 Hz), 6.70-6.9
0 (3H, m), 7.00-7.14 (2H, m), 7.20-7.30 (1H, m),
7.30-7.44 (2H, m). 7) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (3- (2,2,3,3-tetrafluoropropyloxy) phenyl ) -1-Propanol (19
7 mg, 0.53 mmol) of acetonitrile (20 m
l) Add 4-fluoronaphthalenecarboxylic acid (100
mg, 0.53 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (15 mg).
1 mg, 0.79 mmol) and 1-hydroxy-1H
-Benzotriazole (81 mg, 0.53 mmol)
Was added and stirred at room temperature overnight. The reaction solution was washed with water (100 m
1) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (240 mg, 84%). mp 160-161 ℃ IRνmax ^KBr cm ^-1 : 1641, 1626, 1601, 1535, 1512. Anal.Calcd for C ₂₉ H ₂₃ F ₆ NO ₃・ 0.2H ₂ O: C, 63.21; H,
4.28; N, 2.54 Found:. C, 62.99; H, 4.39; N, 2.84 1 H-NMR (CDCl 3) δ: 2.79 (1H, dd, J = 14.4, 10.6 H
z), 3.04 (1H, dd, J = 14.4, 4.0 Hz), 4.28 (2H, t,
J = 12.0 Hz), 4.70-4.84 (1H, m), 5.10 (1H, d, J =
4.0 Hz), 5.90 (1H, d, J = 8.4 Hz), 6.01 (1H, tt, J
= 53.0, 5.0 Hz), 6.74-7.30 (8H, m), 7.40-7.60 (4H,
m), 7.77 (1H, d, J = 8.2 Hz), 8.09 (1H, d, J = 7.
6 Hz).

Example 173 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((3- (2,2,3,3-tetrafluoropropyloxy) phenyl) methyl) ethyl)-
6,7-dihydro-5H-benzo [a] cycloheptene-1
-Carboxamide (1RS, 2SR) -2-amino-1- (2-fluorophenyl) -3- (3- (2,2,3,3-tetrafluoropropyloxy) phenyl) -1-propanol (200 m
g, 0.53 mmol) of acetonitrile (20 ml)
6,7-Dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (100 mg, 0.53 mmol) was added to the solution.
And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (153 mg, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) were added, and the mixture was stirred at room temperature overnight. did. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was recrystallized from ethyl acetate-hexane to give the title compound (224 mg, 77%). ^{mp 169-170 ℃ IRνmax KBr cm -1:} 1640, 1605, 1587, 1510. 1 H-NMR (CDCl 3) δ: 1.90-2.08 (2H, m), 2.10-2.28 (2
H, m), 2.60-2.80 (3H, m), 2.97 (1H, dd, J = 14.6,
4.0 Hz), 3.77 (1H, brs), 4.30 (2H, t, J = 12.0 H
z), 4.58-4.76 (1H, m), 5.02 (1H, d, J = 3.6 Hz),
5.70-5.82 (1H, m), 5.84-5.98 (1H, m), 6.04 (1H, t
t, J = 53.0, 5.0 Hz), 6.17 (1H, d, J = 12.0Hz), 6.
75 (1H, s), 6.78-6.90 (2H, m), 6.90-7.30 (6H, m),
7.38-7.50 (2H, m).

Example 174 4-Fluoro-N-((1RS, 2SR) -2-hydroxy-
2-Phenyl-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -1-naphthalenecarboxamide 1) Ethyl 3-oxo-3-phenylpropionate (2
Sodium hydride (60% oily, 5.65 g, 141 mmol) was added to a solution of 8.6 g (145 mmol) in 1,2-dimethoxyethane (150 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. A solution of 4-trifluoromethylbenzyl bromide (33.8 g, 141 mmol) in 1,2-dimethoxyethane (50 ml) was added dropwise to the reaction solution,
The reaction was stirred at room temperature for 2 hours. The reaction solution was washed with water (500 m
1) and extracted with ethyl acetate (500 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene),
Ethyl-oxo-3-phenyl-2-((4- (trifluoromethyl) phenyl) methyl) propionate (45.4
g, 75%) as a yellow oil. ^{IRνmax KBr cm -1: 1738, 1688.} 1 H-NMR (CDCl 3) δ: 1.11 (3H, t, J = 7.2 Hz), 3.39
(2H, d, J = 7.8 Hz), 4.10 (2H, q, J = 7.2 Hz), 4.6
3 (1H, t, J = 8.4 Hz), 7.10-7.64 (7H, m), 7.96 (2
H, d, J = 8.4 Hz). 2) To a solution of zinc chloride (14.7 g, 108 mmol) in diethyl ether (250 ml) was added sodium borohydride (8.2 g, 216 mmol), and the mixture was stirred at room temperature for 2 hours. did. The insoluble material is removed by filtration, and the filtrate is treated with 3-oxo-3-phenyl-2-((4- (trifluoromethyl) phenyl).
A solution of methyl) propionic acid (22 g, 54 mmol) in diethyl ether (50 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Under ice-cooling, the reaction solution was quenched by adding 1N hydrochloric acid, and water (200 ml) was further added thereto.
ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (toluene) to give (2RS, 3RS) -3-hydroxy-3-hydroxy.
Ethyl phenyl-2-((4- (trifluoromethyl) phenyl) methyl) propionate (15.6 g, 83
%) As a colorless oil. ^{. IRνmax KBr cm -1: 1717. Anal} Calcd for C 19 H 19 F 3 O 3: C, 64.77; H, 5.44 Found:. C, 64.65; H, 5.67 1 H-NMR (CDCl 3) δ: 0.91 ( 3H, t, J = 7.2 Hz), 2.96-
3.10 (3H, m), 3.88 (2H, q, J = 7.2 Hz), 5.00-5.08
(1H, m), 7.12-7.56 (9H, m). 3) (2RS, 3RS) -3-hydroxy-3-phenyl
To a solution of ethyl 2--2-((4- (trifluoromethyl) phenyl) methyl) propionate (10.0 g, 28.4 mmol) in methanol (40 ml), a 2N aqueous solution of sodium hydroxide (28.4 ml, 56.4 ml) was added. (8 mmol) and stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml × 2).
The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (2RS, 3RS) -3-hydroxy-3-phenyl-2-((4- (trifluoromethyl)
Phenyl) methyl) propionic acid (7.87 g, 86
%). ^{. mp 138-139 ℃ IRνmax KBr cm -1} : 1694. Anal Calcd for C 17 H 15 F 3 O 3: C, 62.96; H, 4.66 Found:. C, 62.90; H, 4.89 1 H-NMR (CDCl 3 ) δ: 2.90-3.12 (3H, m), 5.11 (1H, d,
J = 3.0 Hz), 7.17 (2H, d, J = 8.0 Hz), 7.30-7.42 (5
H, m), 7.46 (2H, d, J = 8.0 Hz). 4) (2RS, 3RS) -3-hydroxy-3-phenyl
In a solution of 2-((4- (trifluoromethyl) phenyl) methyl) propionic acid (7 g, 21.6 mmol) in tetrahydrofuran (200 ml), diphenylphosphoryl azide (5.12 ml, 23.7 mmol) and triethylamine ( (4.5 ml, 32.4 mmol) and the mixture was refluxed for 4 hours. After allowing the reaction solution to cool, water (200
ml) and extracted with ethyl acetate (200 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (4RS, 5SR) -5-phenyl-4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidin-2-one (6. (5 g, 93%). mp 158-159 ° C IRνmax ^KBr cm ^-1 : 1732.Analyzed Calcd for C ₁₇ H ₁₄ F ₃ NO ₂ : C, 63.55; H, 4.39; N,
4.36 Found: C, 63.38; H, 4.60; N, 4.21. ¹ H-NMR (CDCl ₃ ) δ: 2.22-2.42 (1H, m), 2.37 (1H, s),
4.20-4.34 (1H, m), 5.05 (1H, s), 5.83 (1H, d, J =
8.0 Hz), 7.14 (2H, d, J = 8.0 Hz), 7.30-7.50 (5H,
m), 7.54 (2H, d, J = 8.0 Hz). 5) (4RS, 5SR) -5-phenyl-4-((4-
(Trifluoromethyl) phenyl) methyl) -1,3-oxazolidin-2-one (6.0 g, 18.7 mmol)
8N sodium hydroxide aqueous solution (11.7 ml, 93 mmol) was added to an ethanol (100 ml) solution of
Heated to reflux for an hour. After concentrating the reaction solution, water (300 ml)
And extracted with ethyl acetate (300 ml × 2).
The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (1RS, 2SR) -2-
Amino-1-phenyl-3- (4- (trifluoromethyl)
Phenyl) -1-propanol (4.8 g, 87%) was obtained. mp 64-65 ℃ IRνmax ^KBr cm ^-1 : 1584, 1331. Anal.Calcd for C ₁₆ H ₁₆ F ₃ NO: C, 65.08; H, 5.46; N,
4.74 Found:. C, 65.05; H, 5.65; N, 4.62 1 H-NMR (CDCl 3) δ: 2.45 (1H, dd, J = 13.8, 10.2 H
z), 2.91 (1H, dd, J = 13.8, 2.8 Hz), 3.22-3.36 (1
H, m), 4.65 (1H, d, J = 5.0 Hz), 7.20-7.42 (7H, m),
7.53 (2H, d, J = 8.0 Hz). 6) (1RS, 2SR) -2-amino-1-phenyl-3-
A solution of (4- (trifluoromethyl) phenyl) -1-propanol (500 mg, 1.69 mmol) in acetonitrile (30 ml) was treated with 4-fluoronaphthalenecarboxylic acid (322 mg, 1.69 mmol) and 1-ethyl-
3- (3-dimethylaminopropyl) carbodiimide hydrochloride (487 mg, 2.54 mmol) and 1-hydroxy-1H-benzotriazole (259 mg, 1.6)
9 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (65
0 mg, 84%). mp 217-218 ℃ IRνmax ^KBr cm ^-1 : 1644, 1626, 1601, 1537. Anal.Calcd for C ₂₇ H ₂₁ F ₄ NO ₂ : C, 69.37; H, 4.53; N,
3.00 Found:. C, 69.15; H, 4.59; N, 2.80 1 H-NMR (CDCl 3) δ: 2.89 (1H, dd, J = 14.2, 10.6 H
z), 3.02-3.20 (2H, m), 4.78-4.96 (1H, m), 5.13 (1
H, d, J = 3.8 Hz), 4.97 (1H, d, J = 9.2 Hz), 6.94-
7.08 (1H, m), 7.10-7.70 (13H, m), 8.08 (1H, d, J =
7.6 Hz).

Example 175 N-((1RS, 2SR) -2-hydroxy-2-phenyl-
1-((4- (trifluoromethyl) phenyl) methyl)
Ethyl) -3-phenylpropanamide (1RS, 2SR) -2-amino-1-phenyl-3- (4-
(Trifluoromethyl) phenyl) -1-propanol (500 mg, 1.69 mmol) in ethyl acetate (15 mg).
3-phenylpropionyl chloride (37 ml)
7ml, 2.54mmol) and saturated aqueous sodium bicarbonate (15m
l) was added and the mixture was stirred at room temperature overnight. The reaction solution was washed with water (100
ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (628 mg, 87
%). mp 147-148 ° C IRνmax ^KBr cm ^-1 : 1632, 1547, 1537. Anal.Calcd for C ₂₅ H ₂₄ F ₃ NO ₂ : C, 70.24; H, 5.66; N,
3.28 Found:. C, 70.28; H, 5.85; N, 3.13 1 H-NMR (CDCl 3) δ: 2.38 (2H, t, J = 7.4 Hz), 2.60-
2.80 (2H, m), 2.86 (2H, t, J = 7.4 Hz), 3.08 (1H,
d, J = 4.0 Hz), 4.38-4.50 (1H, m), 4.80-4.88 (1H,
m), 5.34 (1H, d, J = 8.8 Hz), 7.04-7.40 (12H, m),
7.46 (2H, d, J = 8.0 Hz).

Example 176 4-Fluoro-N-((1RS, 2SR) -2- (3-fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl)- 1-Naphthalenecarboxamide 1) To a solution of 3-fluorobenzoic acid (25.5 g, 182 mmol) in tetrahydrofuran (300 ml),
1′-carbonylbis-1H-imidazole (32.4 g,
(200 mmol) and stirred at room temperature for 30 minutes. Monoethyl magnesium malonate (27.1 g,
94.7 mmol) and heated under reflux for 30 minutes. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution, and concentrated hydrochloric acid was further added until the pH of the aqueous layer became acidic.
The reaction solution was extracted with ethyl acetate (200 ml × 2), the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1),
Ethyl 3- (3-fluorophenyl) -3-oxopropionate (34.6 g, 91%) was obtained as a colorless oil. ^{. IRνmax KBr cm -1: 1738,} 1694, 1651, 1589. Anal Calcd for C 11 H 11 FO 3: C, 62.85; H, 5.27 Found:. C, 62.76; H, 5.24 1 H-NMR (CDCl 3) δ: 1.26 (9 / 4H, t, J = 7.0 Hz), 1.34
(3 / 4H, t, J = 7.0 Hz), 3.97 (6 / 4H, s), 4.18-4.32
(2H, m), 5.66 (1 / 4H, s), 7.10-7.76 (4H, m) .2)
Sodium hydride (60% oily, 3.80 g, 95 mmol) was added to a solution of ethyl 3- (3-fluorophenyl) -3-oxopropionate (20 g, 95 mmol) in 1,2-dimethoxyethane (100 ml) using ice. The mixture was added under cooling and stirred at room temperature for 30 minutes. 4-trifluoromethylbenzyl bromide (22.7 g, 95 mmol) in 1,
A solution of 2-dimethoxyethane (50 ml) was added dropwise and the reaction was stirred at room temperature for 4 hours. The reaction solution was water (300 ml)
And extracted with ethyl acetate (500 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (toluene: hexane = 1: 1).
1-toluene) and recrystallized from ethyl acetate-hexane to give 3- (3-fluorophenyl) -3-oxo-2-.
Ethyl ((4- (trifluoromethyl) phenyl) methyl) propionate (28.8 g, 82%) was obtained. mp 50-51 ° C IRνmax ^KBr cm ^-1 : 1738, 1694, 1618, 1590.Anal.Calcd for C ₁₉ H ₁₆ F ₄ O ₃ : C, 61.96; H, 4.38 Found: C, 61.96; H, 4.33. ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.0 Hz), 3.39
(2H, d, J = 7.4 Hz), 4.12 (2H, q, J = 7.0 Hz), 4.5
7 (1H, t, J = 7.4 Hz), 7.22-7.80 (8H, m). 3) To a solution of zinc chloride (14.8 g, 108.6 mmol) in diethyl ether (150 ml) was added sodium borohydride (8. (22 g, 217 mmol) and stirred at room temperature for 30 minutes. The insolubles were removed by filtration, and the filtrate was treated with ethyl 3- (3-fluorophenyl) -3-oxo-2-((4- (trifluoromethyl) phenyl) methyl) propionate (2
0 g, 54.3 mmol) of diethyl ether (50 m
l) The solution was added and stirred at room temperature for 30 minutes. Under ice-cooling, the reaction solution was quenched by adding 1N hydrochloric acid, and further added with water (200 m 2).
1) and extracted with ethyl acetate (300 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
2: 1-1: 1) to give (2RS, 3RS) -3-
(3-fluorophenyl) -3-hydroxy-2-((4-
Ethyl (trifluoromethyl) phenyl) methyl) propionate (19.4 g, 96%) was obtained as a colorless oil. ^{. IRνmax KBr cm -1: 1726,} 1713, 1617, 1593. Anal Calcd for C 19 H 18 F 4 O 3: C, 61.62; H, 4.90 Found:. C, 61.46; H, 4.83 1 H-NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.0 Hz), 2.90-
3.16 (4H, m), 3.91 (2H, q, J = 7.0 Hz), 5.00-5.10
(1H, m), 6.92-7.40 (6H, m), 7.48 (2H, d, J = 8.0 H
z). 4) Ethyl (2RS, 3RS) -3- (3-fluorophenyl) -3-hydroxy-2-((4- (trifluoromethyl) phenyl) methyl) propionate (19 g,
51.3 mmol) in methanol (100 ml) was added to a 2N aqueous sodium hydroxide solution (51 ml, 102 ml).
Mmol) and stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid, and then ethyl acetate (200 ml × 2).
Extracted. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (2RS, 3R
S) -3- (3-Fluorophenyl) -3-hydroxy-2-
((4- (Trifluoromethyl) phenyl) methyl) propionic acid (15.6 g, 89%) was obtained. mp 128-129 ° C IRνmax ^KBr cm ^-1 : 1713, 1618, 1593.Anal.Calcd for C ₁₇ H ₁₄ F ₄ O ₃ : C, 59.65; H, 4.12 Found: C, 59.53; H, 3.85. ¹ H- NMR (CDCl ₃ ) δ: 2.87-3.17 (3H, m), 5.13 (1H, s),
6.90-7.42 (6H, m), 7.47 (2H, d, J = 8.0 Hz). 5) (2RS, 3RS) -3- (3-fluorophenyl) -3-hydroxy-2-((4- (tri (Fluoromethyl) phenyl) methyl) propionic acid (10.0 g, 2
9.2 mmol) in tetrahydrofuran (250 ml)
To the solution was added diphenyl phosphoryl azide (6.9 ml, 3
2.1 mmol) and triethylamine (6.1 ml, 4
(3.8 mmol) and heated to reflux for 4 hours. After allowing the reaction solution to cool, water (200 ml) was added, and ethyl acetate (20 ml) was added.
0 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (4RS, 5SR) -5- (3-fluorophenyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidine-2. -ON (8.
(88 g, 90%). ^{. mp 143-144 ℃ IRνmax KBr cm -1} : 1761, 1618, 1593. Anal Calcd for C 17 H 13 F 4 NO 2: C, 60.18; H, 3.86; N,
4.13 Found:. C, 60.06; H, 3.85; N, 4.06 1 H-NMR (CDCl 3) δ: 2.24-2.48 (2H, m), 4.20-4.36 (1
H, m), 5.03 (1H, s), 5.81 (1H, d, J = 7.6 Hz), 7.0
2-7.22 (5H, m), 7.36-7.50 (1H, m), 7.56 (2H, d, J =
8.0 Hz). 6) (4RS, 5SR) -5- (3-fluorophenyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidin-2-one (7.0 g) , 2
0.6 mmol) in ethanol (100 ml).
A normal aqueous sodium hydroxide solution (12.9 ml, 103 mmol) was added, and the mixture was heated under reflux for 4 hours. After concentrating the reaction solution, the reaction solution was diluted with water (300 ml), and ethyl acetate (300 m
1 × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2S
R) -2-Amino-1- (3-fluorophenyl) -3- (4-
(Trifluoromethyl) phenyl) -1-propanol (5.43 g, 84%) was obtained. ^{. mp 81-82 ℃ IRνmax KBr cm -1} : 1616, 1590. Anal Calcd for C 16 H 15 F 4 NO: C, 61.34; H, 4.83; N,
4.47 Found:. C, 61.31; H, 4.81; N, 4.37 1 H-NMR (CDCl 3) δ: 0.80-1.70 (2H, br), 2.43 (1H, d
d, J = 13.6, 9.8 Hz), 2.83 (1H, dd, J = 13.6, 2.8
Hz), 3.26-3.40 (1H, m), 4.69 (1H, d, J = 4.8Hz),
6.94-7.08 (1H, m), 7.16 (2H, d, J = 8.0 Hz), 7.20-
7.42 (3H, m), 7.55 (2H, d, J = 8.0 Hz). 7) (1RS, 2SR) -2-amino-1- (3-fluorophenyl) -3- (4- (trifluoromethyl) To a solution of (phenyl) -1-propanol (450 mg, 1.44 mmol) in acetonitrile (20 ml) was added 4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. -Hydrochloride (412 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (221 mg, 1.44 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane,
The title compound (573 mg, 82%) was obtained. mp 200-201 ℃ IRνmax ^KBr cm ^-1 : 1644, 1626. Anal.Calcd for C ₂₇ H ₂₀ F ₅ NO ₂・ 0.1H ₂ O: C, 66.56; H,
4.18; N, 2.87 Found:. C, 66.39; H, 3.99; N, 2.97 1 H-NMR (CDCl 3) δ: 2.80-3.12 (2H, m), 3.20-3.50 (1
H, br), 4.72-4.90 (1H, m), 5.15 (1H, d, J = 3.2 H
z), 6.02 (1H, d, J = 8.0 Hz), 6.92-7.62 (12H, m),
7.67 (1H, d, J = 8.0 Hz), 8.08 (1H, d, J = 8.4 H
z).

Example 177 N-((1RS, 2SR) -2- (3-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino- 1- (3-fluorophenyl) -3- (4- (trifluoromethyl) phenyl) -1
6,7-dihydro-5H was added to a solution of -propanol (167 mg, 0.53 mmol) in acetonitrile (20 ml).
-Benzo [a] cycloheptene-1-carboxylic acid (100
mg, 0.53 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (15 mg).
3 mg, 0.80 mmol) and 1-hydroxy-1H
-Benzotriazole (81 mg, 0.53 mmol)
Was added and stirred at room temperature overnight. The reaction solution was washed with water (100 m
1) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (209 mg, 81%). mp 151-152 ° C IRνmax ^KBr cm ^-1 : 1638, 1618, 1590, 1518, 1327. Anal.Calcd for C ₂₈ H ₂₅ F ₄ NO ₂・ 0.2H ₂ O: C, 69.04; H,
5.25; N, 2.88 Found:. C, 68.98; H, 5.16; N, 2.94 1 H-NMR (CDCl 3) δ: 1.90-2.10 (2H, m), 2.12-2.28 (2
H, m), 2.60-2.70 (2H, m), 2.84 (1H, dd, J = 14.4,
10.6 Hz), 3.00 (1H, dd, J = 15.0, 4.0 Hz), 3.61 (1
H, brs), 4.60-4.80 (1H, m), 5.09 (1H, brs), 5.82
(1H, d, J = 8.2 Hz), 5.84-5.98 (1H, m), 6.16 (1H,
d, J = 11.6 Hz), 6.92-7.42 (9H, m), 7.53 (2H, d, J
= 8.0 Hz).

Example 178 N-((1RS, 2SR) -2- (3-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -3-phenylpropanamide (1RS, 2SR) -2-amino-1- (3-fluorophenyl) -3- ( 4- (trifluoromethyl) phenyl) -1
To a solution of -propanol (450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (320 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
1 × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (52
8 mg, 83%). mp 151-152 ℃ IRνmax ^KBr cm ^-1 : 1651, 1620, 1590. Anal.Calcd for C ₂₅ H ₂₃ F ₄ NO ₂ : C, 67.41; H, 5.20; N,
3.14 Found:. C, 67.38; H, 5.05; N, 3.10 1 H-NMR (CDCl 3) δ: 2.36-2.44 (2H, m), 2.60-2.76 (2
H, m), 2.80-2.94 (2H, m), 3.20-3.28 (1H, m), 4.30-
4.48 (1H, m), 4.80-4.90 (1H, m), 5.35 (1H, d, J =
7.8 Hz), 6.92-7.40 (11H, m), 7.46 (2H, d, J = 8.0
Hz).

Example 179 4-Fluoro-N-((1RS, 2SR) -2- (2-fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl)- 1-Naphthalenecarboxamide 1) To a solution of 2-fluorobenzoic acid (25.3 g, 181 mmol) in tetrahydrofuran (300 ml),
1′-carbonylbis-1H-imidazole (32.2 g,
198 mmol) and stirred at room temperature for 30 minutes. Monoethyl magnesium malonate (27.1 g,
94.7 mmol) and heated under reflux for 30 minutes. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution, and concentrated hydrochloric acid was further added until the pH of the aqueous layer became acidic.
The reaction solution was extracted with ethyl acetate (200 ml × 2), the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1),
Ethyl 3- (2-fluorophenyl) -3-oxopropionate (31.9 g, 84%) was obtained as a colorless oil. ^{. IRνmax KBr cm -1: 1748,} 1694, 1651, 1611. Anal Calcd for C 11 H 11 FO 3: C, 62.85; H, 5.27 Found:. C, 62.74; H, 5.24 1 H-NMR (CDCl 3) δ: 1.26 (3H, t, J = 7.2 Hz), 3.99
(8 / 5H, d, J = 3.6 Hz), 4.18-4.30 (2H, m), 5.85 (1/5
H, s), 7.06-7.32 (4H, m), 7.32-7.52 (2 / 5H, m), 7.5
2-7.64 (8 / 5H, m), 7.82-8.02 (2H, m). 2) 1,3-Dimethoxyethane of ethyl 3- (2-fluorophenyl) -3-oxopropionate (20 g, 95 mmol) (100 ml) solution in sodium hydride (6
0% oily, 3.80 g, 95 mmol) under ice-cooling,
Stirred at room temperature for 30 minutes. 4-trifluoromethylbenzyl bromide (22.7 g, 95 mmol) in the reaction solution
Was added dropwise, and the reaction solution was stirred at room temperature for 4 hours. The reaction solution was washed with water (30
0 ml) and extracted with ethyl acetate (500 ml x 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene: hexane = 1: 1-toluene) to give 3- (2-fluorophenyl) -3-oxo-2-((4- (trifluoromethyl)
Phenyl) methyl) ethyl propionate (25.7 g,
73%) as a colorless oil. IRνmax ^KBr cm ^-1 : 1744, 1690.Anal.Calcd for C ₁₉ H ₁₆ F ₄ O ₃ : C, 61.96; H, 4.38 Found: C, 62.04; H, 4.31. ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.0 Hz), 3.24-
3.50 (2H, m), 4.12 (2H, q, J = 7.0 Hz), 4.58 (1H,
t, J = 7.2 Hz), 7.04-7.60 (7H, m), 7.78-7.90 (1H,
m). 3) To a solution of zinc chloride (14.8 g, 108.6 mmol) in diethyl ether (150 ml) was added sodium borohydride (8.22 g, 217 mmol), and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was treated with ethyl 3- (2-fluorophenyl) -3-oxo-2-((4- (trifluoromethyl) phenyl) methyl) propionate (2
0 g, 54.3 mmol) of diethyl ether (50 m
l) The solution was added and stirred at room temperature for 30 minutes. Under ice-cooling, the reaction solution was quenched by adding 1N hydrochloric acid, and further added with water (200 m 2).
1) and extracted with ethyl acetate (300 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
9: 1-4: 1) to give (2RS, 3RS) -3-
(2-fluorophenyl) -3-hydroxy-2-((4-
Ethyl (trifluoromethyl) phenyl) methyl) propionate (16.2 g, 81%) was obtained as a colorless oil. ^{. IRνmax KBr cm -1: 1717,} 1618, 1586. Anal Calcd for C 19 H 18 F 4 O 3: C, 61.62; H, 4.90 Found:. C, 61.51; H, 4.74 1 H-NMR (CDCl 3) δ: 0.96 (3H, t, J = 7.4 Hz), 2.84-
3.20 (3H, m), 3.22 (1H, d, J = 3.8 Hz), 3.94 (2H,
q, J = 7.4 Hz), 5.30-5.40 (1H, m), 6.98-7.38 (5H,
m), 7.40-7.62 (3H, m). 4) (2RS, 3RS) -3- (2-fluorophenyl) -3-hydroxy-2-((4- (trifluoromethyl) phenyl) methyl) propionic acid Ethyl (15.7
g, 42.5 mmol) in methanol (100 ml) was added to a 2N aqueous sodium hydroxide solution (43 ml, 86 ml).
Mmol) and stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid, and then ethyl acetate (200 ml × 2).
Extracted. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (2RS, 3R
S) -3- (2-Fluorophenyl) -3-hydroxy-2-
((4- (Trifluoromethyl) phenyl) methyl) propionic acid (11.7 g, 80%) was obtained. ^{. mp 122-123 ℃ IRνmax KBr cm -1} : 1713, 1491. Anal Calcd for C 17 H 14 F 4 O 3: C, 59.65; H, 4.12 Found:. C, 59.60; H, 4.03 1 H-NMR ( CDCl ₃ ) δ: 2.82-3.12 (2H, m), 3.12-3.30 (1
H, m), 5.44 (1H, d, J = 4.0 Hz), 6.96-7.40 (5H, m),
7.40-7.60 (3H, m). 5) (2RS, 3RS) -3- (2-fluorophenyl) -3-hydroxy-2-((4- (trifluoromethyl) phenyl) methyl) propionic acid (10. 0g, 2
9.2 mmol) in tetrahydrofuran (250 ml)
To the solution was added diphenyl phosphoryl azide (6.9 ml, 3
2.1 mmol) and triethylamine (6.1 ml, 4
(3.8 mmol) and heated to reflux for 4 hours. After allowing the reaction solution to cool, water (200 ml) was added, and ethyl acetate (20 ml) was added.
0 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (4RS, 5SR) -5- (2-fluorophenyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidine-2. -ON (8.
73 g, 88%). ^{. mp 146-147 ℃ IRνmax KBr cm -1} : 1767. Anal Calcd for C 17 H 13 F 4 NO 2: C, 60.18; H, 3.86; N,
4.13 Found:. C, 59.99; H, 3.92; N, 3.90 1 H-NMR (CDCl 3) δ: 2.20-2.60 (2H, m), 4.26-4.46 (1
H, m), 5.06 (1H, s), 6.05 (1H, d, J = 7.8 Hz), 7.0
0-7.70 (8H, m). 6) (4RS, 5SR) -5- (2-fluorophenyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidine-2- ON (7.0 g, 2
0.6 mmol) in ethanol (100 ml).
A normal aqueous sodium hydroxide solution (12.9 ml, 103 mmol) was added, and the mixture was heated under reflux for 6 hours. After concentrating the reaction solution, the reaction solution was diluted with water (300 ml), and ethyl acetate (300 m
1 × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give (1RS, 2SR) -2-amino-1- (2-fluorophenyl) -3- (4- (trifluoromethyl) phenyl) -1-propanol (6.2 g, 96%) as a colorless oil. IRνmax ^KBr cm ^-1 : 1618, 1584, 1487. Anal.Calcd for C ₁₆ H ₁₅ F ₄ NO ・ 0.1H ₂ O: C, 60.99; H,
4.86; N, 4.45 Found:. C, 60.90; H, 4.81; N, 4.20 1 H-NMR (CDCl 3) δ: 1.0-1.8 (2H, br), 2.41 (1H, dd,
J = 13.6, 11.0 Hz), 2.86 (1H, dd, J = 14.0, 2.2 H
z), 3.36-3.48 (1H, m), 5.06 (1H, d, J = 4.4 Hz),
7.00-7.38 (5H, m), 7.48-7.62 (3H, m). 7) (1RS, 2SR) -2-amino-1- (2-fluorophenyl) -3- (4- (trifluoromethyl) phenyl ) To a solution of 1-propanol (450 mg, 1.44 mmol) in acetonitrile (20 ml) was added 4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. Hydrochloride (412 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (221 mg, 1.44 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give the title compound (465 mg, 6
7%). ^{. mp 190-191 ℃ IRνmax KBr cm -1} : 1645, 1628, 1601, 1537. Anal Calcd for C 27 H 20 F 5 NO 2: C, 66.80; H, 4.15; N,
2.89 Found:. C, 66.58; H, 4.12; N, 2.79 1 H-NMR (CDCl 3) δ: 2.94 (1H, dd, J = 14.2, 11.0 H
z), 3.23 (1H, dd, J = 14.2, 4.0 Hz), 3.72 (1H, d,
J = 4.2 Hz), 4.74-4.94 (1H, m), 5.36-5.46 (1H, m),
5.96 (1H, d, J = 8.4 Hz), 6.96-7.74 (13H, m), 8.08
(1H, d, J = 8.4Hz).

Example 180 N-((1RS, 2SR) -2- (2-fluorophenyl)
-2-Hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -3-phenylpropanamide (1RS, 2SR) -2-amino-1- (2-fluorophenyl) -3- ( 4- (trifluoromethyl) phenyl) -1
To a solution of -propanol (450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (320 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
1 × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (49
7 mg, 78%). mp 124-125 ℃ IRνmax ^KBr cm ^-1 : 1651, 1620, 1520. Anal.Calcd for C ₂₅ H ₂₃ F ₄ NO ₂ : C, 67.41; H, 5.20; N,
3.14 Found:. C, 67.30; H, 5.19; N, 2.89 1 H-NMR (CDCl 3) δ: 2.30-2.42 (2H, m), 2.66-2.98 (4
H, m), 3.92-4.04 (1H, m), 4.28-4.46 (1H, m), 5.12-
5.22 (1H, m), 5.39 (1H, d, J = 8.8 Hz), 6.98-7.40
(10H, m), 7.40-7.56 (3H, m).

Example 181 N-((1RS, 2SR) -2- (2,4-difluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4- Fluoro-1-naphthalenecarboxamide 1) 2,4-difluorobenzoic acid (10 g, 63.3)
1,1′-carbonylbis-1H-imidazole (11.3 mmol) in a solution of tetrahydrofuran (150 ml).
g, 69.6 mmol) and stirred at room temperature for 30 minutes. The reaction solution was mixed with monoethyl magnesium malonate (10
g, 34.8 mmol) and stirred at room temperature for 2 hours. Ethyl acetate (50 ml) and water (50 m
l) was added, and concentrated hydrochloric acid was further added until the pH of the aqueous layer became acidic. The reaction solution was extracted with ethyl acetate (200 ml × 2), the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and ethyl 3- (2,4-difluorophenyl) -3-oxopropionate (9.85 g, 74%) was obtained as a brown oil. As obtained. IRνmax ^KBr cm ^-1 : 1746, 1690, 1615, 1507. Anal.Calcd for C ₁₁ H ₁₀ O ₃ F ₂・ 0.1H ₂ O: C, 57.45; H,
4.47 Found:. C, 57.56; H, 4.48 1 H-NMR (CDCl 3) δ: 1.26 (3H × 5/6, t, J = 7.4 Hz),
1.34 (3H × 1/6, t, J = 7.4 Hz), 3.96 (2H × 5/6, d, J
= 4.0 Hz), 4.18-4.32 (2H, m), 5.80 (1H × 1/6, s),
6.80-7.06 (2H, m), 7.80-8.06 (1H, m). 2) 1,3-Ethyl 3- (2,4-difluorophenyl) -3-oxopropionate (9 g, 39.4 mmol)
Sodium hydride (60% oily, 1.58 g, 39.4 mmol) was added to a solution of -dimethoxyethane (50 ml) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. 4-trifluoromethylbenzyl bromide (9.43 g, 3
9.4 mmol) of 1,2-dimethoxyethane (50 m
l) The solution was added dropwise and the reaction was stirred at room temperature for 3 hours. The reaction solution was poured into water (200 ml), and ethyl acetate (20 ml) was added.
0 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene: hexane = 1: 1-toluene) and recrystallized from diisopropyl ether-hexane to give 3-
(2,4-difluorophenyl) -3-oxo-2-((4-
Ethyl (trifluoromethyl) phenyl) methyl) propionate (11.6 g, 77%) was obtained. mp 34-35 ℃ IRνmax ^KBr cm ^-1 : 1742, 1690, 1613, 1593, 1499, 142
_{. 9. Anal Calcd for C 19 H} 15 O 3 F 5: C, 59.07; H, 3.91 Found:. C, 58.86; H, 3.67 1 H-NMR (CDCl 3) δ: 1.13 (3H, t, J = 7.4 Hz), 3.22-
3.50 (2H, m), 4.13 (2H, q, J = 7.4 Hz), 4.53 (1H,
t, J = 7.2 Hz), 6.80-7.02 (2H, m), 7.38 (2H, d, J =
8.0 Hz), 7.52 (2H, d, J = 8.0 Hz), 7.82-8.00 (1H,
m). 3) To a solution of zinc chloride (7.06 g, 51.8 mmol) in diethyl ether (100 ml) was added sodium borohydride (3.92 g, 103.5 mmol), and the mixture was stirred at room temperature for 30 minutes. Remove the insoluble material by filtration, and add 3-
(2,4-difluorophenyl) -3-oxo-2-((4-
A solution of ethyl (trifluoromethyl) phenyl) methyl) propionate (10 g, 25.9 mmol) in diethyl ether (50 ml) was added, and the mixture was stirred at room temperature for 30 minutes.
Under ice-cooling, the reaction solution was quenched by adding 1N hydrochloric acid, and water (200 ml) was further added, and ethyl acetate (300 ml ×
Extracted in 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purified with ethyl acetate = 4: 1) to give (2RS, 3RS)-
3- (2,4-difluorophenyl) -3-hydroxy-2-
Ethyl ((4- (trifluoromethyl) phenyl) methyl) propionate (8.23 g, 82%) was obtained as a colorless oil. IRνmax ^KBr cm ^-1 : 1713, 1618, 1505, 1420. Anal.Calcd for C ₁₉ H ₁₇ O ₃ F ₅・ 0.2H ₂ O: C, 58.23; H,
4.47 Found:. C, 58.04; H, 4.60 1 H-NMR (CDCl 3) δ: 0.97 (3H, t, J = 7.0 Hz), 2.80-
3.18 (3H, m), 3.25 (1H, d, J = 3.6 Hz), 3.95 (2H,
q, J = 7.0 Hz), 5.28-5.38 (1H, m), 6.72-7.00 (2H,
m), 7.18 (2H, d, J = 8.0 Hz), 7.48 (2H, d, J = 8.0
Hz), 7.40-7.60 (1H, m). 4) (2RS, 3RS) -3- (2,4-difluorophenyl) -3-hydroxy-2-((4- (trifluoromethyl) phenyl) methyl) Ethyl propionate (8.1
g, 20.8 mmol) in a methanol (40 ml) solution.
(1.6 mmol) and stirred at room temperature overnight. After the reaction solution was acidified with 1N hydrochloric acid, ethyl acetate (200 ml) was added.
× 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (2RS,
3RS) -3- (2,4-difluorophenyl) -3-hydroxy-2-((4- (trifluoromethyl) phenyl)
Methyl) propionic acid (6.0 g, 80%) was obtained. ^{. mp 120-121 ℃ IRνmax KBr cm -1} : 1713, 1620, 1505, 1418. Anal Calcd for C 17 H 13 O 3 F 5: C, 56.57; H, 3.64 Found:. C, 56.68; H, 3.59 1 _{H-NMR (CDCl 3) δ} : 2.84-3.24 (3H, m), 5.38 (1H, d,
J = 4.0 Hz), 6.70-6.98 (2H, m), 7.16 (2H, d, J = 8.
0 Hz), 7.46 (2H, d, J = 8.0 Hz), 7.50-7.58 (1H, m). 5) (2RS, 3RS) -3- (2,4-difluorophenyl) -3-hydroxy-2- ((4- (trifluoromethyl) phenyl) methyl) propionic acid (5.0 g, 1
3.9 mmol) in tetrahydrofuran (150 ml)
To the solution was added diphenylphosphoryl azide (3.3 ml, 1
5.3 mmol) and triethylamine (2.9 ml, 2
(0.8 mmol) and heated to reflux for 6 hours. After allowing the reaction solution to cool, water (200 ml) was added, and ethyl acetate (20 ml) was added.
0 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and the residue was recrystallized from ethyl acetate-hexane (4RS, 5SR).
-5- (2,4-Difluorophenyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidin-2-one (3.86 g, 78%) was obtained. ^{. mp 147-148 ℃ IRνmax KBr cm -1} : 1767, 1622, 1607, 1507. Anal Calcd for C 17 H 12 O 2 F 5 N: C, 57.15; H, 3.39; N,
3.92 Found:. C, 57.12; H, 3.12; N, 3.63 1 H-NMR (CDCl 3) δ: 2.24-2.56 (2H, m), 4.28-4.44 (1
H, m), 5.12 (1H, s), 5.99 (1H, d, J = 7.6 Hz), 6.7
8-6.92 (1H, m), 6.92-7.08 (1H, m), 7.17 (2H, d, J =
7.6 Hz), 7.50-7.64 (3H, m). 6) (4RS, 5SR) -5- (2,4-difluorophenyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1, 3-oxazolidine-2-one (3.5
g, 9.8 mmol) in ethanol (60 ml) was added with 8N aqueous sodium hydroxide solution (6.1 ml, 49 mmol), and the mixture was refluxed for 6 hours. After concentrating the reaction solution,
Dilute with water (300ml) and add ethyl acetate (300ml x
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2SR)
-2-Amino-1- (2,4-difluorophenyl) -3-
(4- (Trifluoromethyl) phenyl) -1-propanol (2.27 g, 70%) was obtained. ^{. mp 99-100 ℃ IRνmax KBr cm -1} : 1618, 1501, 1427, 1420. Anal Calcd for C 16 H 14 OF 5 N: C, 58.01; H, 4.26; N,
4.23 Found:. C, 58.09; H, 4.14; N, 4.07 1 H-NMR (CDCl 3) δ: 2.39 (1H, dd, J = 14.0, 10.6 H
z), 2.83 (1H, dd, J = 14.0, 3.0 Hz), 3.36-3.48 (1
H, m), 5.01 (1H, d, J = 4.4 Hz), 6.78-7.00 (2H, m),
7.24 (2H, d, J = 8.0 Hz), 7.54 (2H, d, J = 8.0 H
z), 7.50-7.62 (1H, m). 7) (1RS, 2SR) -2-amino-1- (2,4-difluorophenyl) -3- (4- (trifluoromethyl)
To a solution of (phenyl) -1-propanol (400 mg, 1.21 mmol) in acetonitrile (30 ml) was added 4-fluoronaphthalenecarboxylic acid (230 mg, 1.21 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. -Hydrochloride (347 mg, 1.81 mmol) and 1-hydroxy-1H-benzotriazole (185 mg, 1.21 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane,
The title compound (538 mg, 89%) was obtained. mp 194-195 ° C IRνmax ^KBr cm ^-1 : 1645, 1622, 1601, 1537, 1507. Anal.Calcd for C ₂₇ H ₁₉ O ₂ F ₆ N: C, 64.42; H, 3.80; N,
2.78 Found:. C, 64.14; H, 3.59; N, 2.63 1 H-NMR (CDCl 3) δ: 2.92 (1H, dd, J = 14.6, 11.2 H
z), 3.19 (1H, dd, J = 14.6, 3.8 Hz), 3.88 (1H, br
s), 4.70-4.88 (1H, m), 5.33 (1H, d, J = 4.0 Hz),
5.96 (1H, d, J = 8.8 Hz), 6.78-7.18 (4H, m), 7.22-
7.70 (8H, m), 8.08 (1H, d, J = 8.4 Hz).

Example 182 N-((1RS, 2SR) -2- (2,4-difluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -3- Phenylpropanamide Acetic acid of (1RS, 2SR) -2-amino-1- (2,4-difluorophenyl) -3- (4- (trifluoromethyl) phenyl) -1-propanol (400 mg, 1.21 mmol) To the ethyl (20 ml) solution were added 3-phenylpropionyl chloride (269 ml, 1.81 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was recrystallized from ethyl acetate-hexane to give the title compound (498 mg, 89%). mp 126-127 ℃ IRνmax ^KBr cm ^-1 : 1645, 1620, 1503, 1427. Anal.Calcd for C ₂₅ H ₂₂ O ₂ F ₅ N: C, 64.79; H, 4.78; N,
3.02 Found:. C, 64.82; H, 4.57; N, 2.86 1 H-NMR (CDCl 3) δ: 2.30-2.46 (2H, m), 2.64-2.92 (4
H, m), 4.11 (1H, d, J = 4.0 Hz), 4.22-4.38 (1H, m),
5.04-5.14 (1H, m), 5.39 (1H, d, J = 8.0 Hz), 6.70
-6.92 (2H, m), 7.02-7.52 (10H, m).

Example 183 N-((1RS, 2SR) -2- (3,4-difluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4- Fluoro-1-naphthalenecarboxamide 1) 3,4-difluorobenzoic acid (10 g, 63.3)
1,1′-carbonylbis-1H-imidazole (11.3 mmol) in a solution of (1 mmol) in tetrahydrofuran (300 ml).
g, 69.6 mmol) and stirred at room temperature for 30 minutes. The reaction solution was mixed with monoethyl magnesium malonate (10
g, 34.8 mmol) and stirred at room temperature for 2 hours. Ethyl acetate (50 ml) and water (50 m
l) was added, and concentrated hydrochloric acid was further added until the pH of the aqueous layer became acidic. The reaction solution was extracted with ethyl acetate (200 ml × 2), the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and ethyl 3- (3,4-difluorophenyl) -3-oxopropionate (10.3 g, 77%) was added as a brown oil. As obtained. ^{. IRνmax KBr cm -1: 1742,} 1694, 1613, 1520, 1433. Anal Calcd for C 11 H 10 O 3 F 2: C, 57.90; H, 4.42 Found:. C, 57.78; H, 4.56 1 H-NMR (CDCl ₃ ) δ: 1.26 (3H × 4/5, t, J = 7.4 Hz),
1.33 (3H × 1/5, t, J = 7.4 Hz), 3.94 (2H × 4/5, s),
4.10-4.32 (2H, m), 5.60 (1H × 1/5, s), 7.12-7.34 (1
H, m), 7.48-7.86 (2H, m). 2) 1,2 of ethyl 3- (3,4-difluorophenyl) -3-oxopropionate (9 g, 39.4 mmol).
Sodium hydride (60% oily, 1.58 g, 39.4 mmol) was added to a solution of -dimethoxyethane (50 ml) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. 4-trifluoromethylbenzyl bromide (9.43 g, 3
9.4 mmol) of 1,2-dimethoxyethane (50 m
l) The solution was added dropwise and the reaction was stirred at room temperature for 3 hours. The reaction solution was poured into water (200 ml), and ethyl acetate (20 ml) was added.
0 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene: hexane = 1: 1) and recrystallized from diisopropyl ether-hexane to give 3- (3,4-difluorophenyl) -3-oxo-2-((4- Ethyl (trifluoromethyl) phenyl) methyl) propionate (1
0.9 g, 71%). mp 48-49 ° C IRνmax ^KBr cm ^-1 : 1738, 1694, 1615, 1518, 1429. Anal.Calcd for C ₁₉ H ₁₅ O ₃ F ₅ : C, 59.07; H, 3.91 Found: C, 59.06; H, 3.87 _{^{. 1 H-NMR (CDCl 3}} ) δ: 1.30 (3H, t, J = 7.2 Hz), 3.38
(2H, d, J = 7.2 Hz), 4.11 (2H, q, J = 7.2 Hz), 4.5
3 (1H, t, J = 7.2 Hz), 7.16-7.30 (1H, m), 7.34 (2
H, d, J = 8.0 Hz), 7.53 (2H, d, J = 8.0 Hz), 7.70-
7.90 (2H, m). 3) To a solution of zinc chloride (7.06 g, 51.8 mmol) in diethyl ether (100 ml) was added sodium borohydride (3.92 g, 103.5 mmol), and the mixture was stirred at room temperature for 30 minutes. Stirred. Remove the insoluble material by filtration, and add 3-
(3,4-difluorophenyl) -3-oxo-2-((4-
A solution of ethyl (trifluoromethyl) phenyl) methyl) propionate (10 g, 25.9 mmol) in diethyl ether (50 ml) was added, and the mixture was stirred at room temperature for 30 minutes.
Under ice-cooling, the reaction solution was quenched by adding 1N hydrochloric acid, and water (200 ml) was further added, and ethyl acetate (300 ml ×
Extracted in 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purified with ethyl acetate = 4: 1) to give (2RS, 3RS)-
3- (3,4-difluorophenyl) -3-hydroxy-2-
Ethyl ((4- (trifluoromethyl) phenyl) methyl) propionate (9.84 g, 98%) was obtained as a colorless oil. ^{. IRνmax KBr cm -1: 1715,} 1620, 1520, 1435. Anal Calcd for C 19 H 17 O 3 F 5 · 0.2H 2 O: C, 58.23; H,
4.47 Found:. C, 58.07; H, 4.41 1 H-NMR (CDCl 3) δ: 0.95 (3H, t, J = 7.2 Hz), 2.86-
3.12 (4H, m), 3.91 (2H, q, J = 7.2 Hz), 5.00-5.05
(1H, m), 7.04-7.34 (5H, m), 7.49 (2H, d, J = 8.0 H
z). 4) Ethyl (2RS, 3RS) -3- (3,4-difluorophenyl) -3-hydroxy-2-((4- (trifluoromethyl) phenyl) methyl) propionate (9.7
g, 25.0 mmol) in a solution of methanol (40 ml) in 2N aqueous sodium hydroxide (25 ml, 50.50 g).
0 mmol) and stirred at room temperature overnight. Reaction solution 1
After acidification with normal hydrochloric acid, ethyl acetate (200 ml ×
Extracted in 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (2RS,
3RS) -3- (3,4-Difluorophenyl) -3-hydroxy-2-((4- (trifluoromethyl) phenyl)
Methyl) propionic acid (6.7 g, 74%) was obtained. ^{mp 76-77 ℃ IRνmax KBr cm -1:} 1713, 1620, 1520, 1435. 1 H-NMR (CDCl 3) δ: 2.90-3.18 (3H, m), 5.07 (1H, s),
7.04-7.34 (5H, m), 7.49 (2H, d, J = 8.0 Hz). 5) (2RS, 3RS) -3- (3,4-difluorophenyl) -3-hydroxy-2-((4- (Trifluoromethyl) phenyl) methyl) propionic acid (5.0 g, 1
3.9 mmol) in tetrahydrofuran (150 ml)
To the solution was added diphenylphosphoryl azide (3.3 ml, 1
5.3 mmol) and triethylamine (2.9 ml, 2
(0.8 mmol) and heated to reflux for 6 hours. After allowing the reaction solution to cool, water (200 ml) was added, and ethyl acetate (20 ml) was added.
0 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and the residue was recrystallized from ethyl acetate-hexane (4RS, 5SR).
This gave -5- (3,4-difluorophenyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidin-2-one (3.81 g, 77%). ^{. mp 157-158 ℃ IRνmax KBr cm -1} : 1761, 1617, 1524. Anal Calcd for C 17 H 12 O 2 F 5 N: C, 57.15; H, 3.39; N,
3.92 Found:. C, 57.12; H, 3.26; N, 3.76 1 H-NMR (CDCl 3) δ: 2.24-2.44 (2H, m), 4.20-4.38 (1
H, m), 5.31 (1H, s), 5.76 (1H, d, J = 7.6 Hz), 7.0
4-7.30 (5H, m), 7.55 (2H, d, J = 8.0 Hz). 6) (4RS, 5SR) -5- (3,4-difluorophenyl) -4-((4- (trifluoromethyl ) Phenyl) methyl) -1,3-oxazolidin-2-one (3.5
g, 9.8 mmol) in ethanol (60 ml) was added with 8N aqueous sodium hydroxide solution (6.1 ml, 49 mmol), and the mixture was refluxed for 6 hours. After concentrating the reaction solution,
Dilute with water (300ml) and add ethyl acetate (300ml x
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2SR)
-2-Amino-1- (3,4-difluorophenyl) -3-
(4- (Trifluoromethyl) phenyl) -1-propanol (2.43 g, 75%) was obtained. ^{. mp 99-100 ℃ IRνmax KBr cm -1} : 1618, 1576, 1518, 1429. Anal Calcd for C 16 H 14 OF 5 N: C, 58.01; H, 4.26; N,
4.23 Found:. C, 58.01; H, 3.97; N, 4.05 1 H-NMR (CDCl 3) δ: 2.41 (1H, dd, J = 14.0, 10.4 H
z), 2.79 (1H, dd, J = 14.0, 3.0 Hz), 3.22-3.36 (1
H, m), 4.66 (1H, d, J = 4.8 Hz), 7.04-7.32 (5H, m),
7.55 (2H, d, J = 8.2 Hz). 7) (1RS, 2SR) -2-amino-1- (3,4-difluorophenyl) -3- (4- (trifluoromethyl)
To a solution of (phenyl) -1-propanol (400 mg, 1.21 mmol) in acetonitrile (30 ml) was added 4-fluoronaphthalenecarboxylic acid (230 mg, 1.21 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. -Hydrochloride (347 mg, 1.81 mmol) and 1-hydroxy-1H-benzotriazole (185 mg, 1.21 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane,
The title compound (522 mg, 86%) was obtained. mp 197-198 ° C IRνmax ^KBr cm ^-1 : 1642, 1626, 1601, 1522, 1424. Anal.Calcd for C ₂₇ H ₁₉ O ₂ F ₆ N: C, 64.42; H, 3.80; N,
2.78 Found:. C, 64.20; H, 3.68; N, 2.69 1 H-NMR (CDCl 3) δ: 2.80-3.10 (2H, m), 4.64-4.84 (1
H, m), 5.06-5.18 (1H, m), 6.01 (1H, d, J = 8.8 H
z), 6.94-7.72 (12H, m), 8.09 (1H, d, J = 8.8 Hz).

Example 184 N-((1RS, 2SR) -2- (3,4-difluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -3- Phenylpropanamide Acetic acid of (1RS, 2SR) -2-amino-1- (3,4-difluorophenyl) -3- (4- (trifluoromethyl) phenyl) -1-propanol (400 mg, 1.21 mmol) To the ethyl (20 ml) solution were added 3-phenylpropionyl chloride (269 ml, 1.81 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was recrystallized from ethyl acetate-hexane to give the title compound (471 mg, 84%). mp 114-115 ℃ IRνmax ^KBr cm ^-1 : 1647, 1620, 1518, 1433. Anal.Calcd for C ₂₅ H ₂₂ O ₂ F ₅ N: C, 64.79; H, 4.78; N,
3.02 Found:. C, 64.88; H, 4.59; N, 2.90 1 H-NMR (CDCl 3) δ: 2.26-2.50 (2H, m), 2.58-2.80 (2
H, m), 2.82-2.96 (2H, m), 3.36 (1H, brs), 4.22-4.4
0 (1H, m), 4.81 (1H, d, J = 2.6 Hz), 5.34 (1H, d,
J = 7.2 Hz), 6.98-7.38 (10H, m), 7.47 (2H, d, J =
8.0 Hz).

Example 185 N-((1RS, 2SR) -2-hydroxy-2- (1-naphthalenyl) -1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -1-naphthalenecarboxamide 1 ) 1'-acetonaphthone (28.29 g, 0.16
Sodium hydride (13.3) in a solution of ethanol (0.5 ml) and diethyl carbonate (200 ml) in ethanol (0.5 ml).
g, 60% oily, 0.332 mol) was added little by little, and 8
Stirred at 0 ° C. for 1.5 hours. The reaction was poured into water, acidified with dilute hydrochloric acid and extracted twice with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1-6: 1) to give (1-
Naphthoyl) ethyl acetate (38.14 g, 95%) was obtained as a yellow liquid. ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.21 (2.4H, t, J = 7.2
Hz), 1.36 (0.6H, t, J = 7.1 Hz), 4.11 (1.6H, s), 4.
20 (1.6H, q, J = 7.2 Hz), 4.31 (0.4H, q, J = 7.1 H
z), 5.50 (0.2H, s), 7.44-7.67 (4H, m), 7.86-7.95
(2H, m), 8.03 (1H, d, J = 8.0 Hz), 8.75 (1H, d, J
= 8.4 Hz); IR (neat) 1740, 1682, 1315,1211, 802, 7
75 cm ^-1 2) Ethyl (1-naphthoyl) acetate (10.2 g, 3
9.9 mmol) in acetonitrile (100 ml) was added to 4- (trifluoromethyl) benzylbromide (9.9).
(54 g, 39.9 mmol) and stirred at room temperature overnight. After concentration, the reaction solution was diluted with water (500 ml) and extracted with ethyl acetate (300 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: toluene = 1: 1). To a solution of the obtained crude product of the monoalkyl compound (7.46 g, 18.63 mmol) in ether (100 ml), zinc chloride (5.07 g, 37.3 mmol) and sodium borohydride (2.82 g, 74.5 mmol) of Zn (NH ₄ ) ₂ in ether (100 ml) and stirred at room temperature for 30 minutes. The reaction solution was poured into a 1N aqueous hydrochloric acid solution (100 ml), and ethyl acetate (300 ml × 2) was added.
Extracted. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene). To a solution of the obtained crude product of the reduced form (3.74 g, 9.29 mmol) in methanol (40 ml) was added a 1 N aqueous sodium hydroxide solution (20 ml, 20 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with a 1N aqueous hydrochloric acid solution (40
ml) and extracted with ethyl acetate (100 ml x 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (2RS, 3RS)
-3-Hydroxy-3- (1-naphthalenyl) -2-((4-
(Trifluoromethyl) phenyl) methyl) propionic acid (2.48 g, 16%) was obtained. mp 151-152 ℃ IRνmax ^KBr cm ^-1 : 1713. Anal.Calcd for C ₂₁ H ₁₇ F ₃ O ₃・ 0.1H ₂ O: C, 67.05; H,
4.61 Found:. C, 67.02; H, 4.45 1 H-NMR (CDCl 3) δ: 2.87 (1H, d, J = 14.0 Hz), 3.10-
3.40 (2H, m), 6.04 (1H, d, J = 2.8 Hz), 6.98 (2H,
d, J = 8.0 Hz), 7.34 (2H, d, J = 8.0 Hz), 7.42-7.6
2 (3H, m), 7.72-7.98 (3H, m), 8.03 (1H, d, J = 9.2
Hz). 3) (2RS, 3RS) -3-hydroxy-3- (1-naphthalenyl) -2-((4- (trifluoromethyl) phenyl) methyl) propionic acid (2.64 g, 7.05 mmol) Was added to a solution of diphenylphosphoryl azide (1.67 ml, 7.76 mmol) and triethylamine (1.5 ml, 10.6) in tetrahydrofuran (50 ml).
(Mmol) was added and the mixture was heated under reflux for 1 hour. The reaction solution was diluted with water (300 ml), and ethyl acetate (200 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (4RS, 5SR)
-5- (1-Naphthalenyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidine-2-
ON (2.19 g, 84%) was obtained. mp 202-203 ℃ IRνmax ^KBr cm ^-1 : 1761. Anal.Calcd for C ₂₁ H ₁₆ F ₃ NO ₂ : C, 67.92; H, 4.34; N,
3.77 Found:. C, 67.90; H, 4.15; N, 3.63 1 H-NMR (CDCl 3) δ: 2.15 (1H, dd, J = 13.6, 4.4 Hz),
2.37 (1H, dd, J = 13.6, 10.2 Hz), 4.46-4.64 (1H,
m), 5.38 (1H, brs), 6.53 (1H, d, J = 7.6 Hz), 6.97
(2H, d, J = 8.0 Hz), 7.39 (2H, d, J = 8.0 Hz), 7.39
46-7.80 (4H, m), 7.80-8.00 (3H, m). 4) (4RS, 5SR) -5- (1-naphthalenyl) -4
-((4- (trifluoromethyl) phenyl) methyl)-
1,3-Oxazolidin-2-one (2.10 g, 5.6
To a solution of 6 mmol) in ethanol (30 ml) was added an 8 N aqueous sodium hydroxide solution (3.53 ml, 28.3 mmol), and the mixture was heated under reflux for 1 hour. After concentrating the reaction solution, the reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. HCl / ethyl acetate solution was added to a solution of the residue in ethyl acetate (100 ml), the solvent was concentrated, and the obtained crude crystals were washed with ether, and (1RS, 2SR) -1-hydroxy-1- (1-naphthalenyl). ) -3- (4- (Trifluoromethyl) phenyl) -2-propylamine hydrochloride (1.56 g, 72%)
I got mp 229-230 ° C IRνmax ^KBr cm ^-1 : 1761. Anal.Calcd for C ₂₀ H ₁₉ ClF ₃ NO ・ 0.1H ₂ O: C, 62.62; H,
5.04; N, 3.65 Found:. C, 62.44; H, 5.07; N, 3.88 1 H-NMR (CD 3 OD) δ: 2.80-3.04 (2H, m), 3.96-4.10 (1
H, m), 5.93 (1H, d, J = 2.6 Hz), 7.02 (2H, d, J =
8.0 Hz), 7.37 (2H, d, J = 8.0 Hz), 7.46-7.62 (3H,
m), 7.78-7.96 (3H, m), 8.07 (1H, d, J = 8.0 Hz). 5) (1RS, 2SR) -1-hydroxy-1- (1-naphthalenyl) -3- (4- ( (Trifluoromethyl) phenyl) -2-propylamine hydrochloride (150 mg, 0.39
(1 mmol)) in ethyl acetate (5 ml), 1-naphthoyl chloride (89 ml, 0.59 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml), and ethyl acetate (50 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (172
mg, 88%). mp 217-218 ° C IRνmax ^KBr cm ^-1 : 1615, 1591, 1537, 1526. Anal.Calcd for C ₃₁ H ₂₄ F ₃ NO ₂ : C, 74.54; H, 4.84; N,
2.80 Found:. C, 74.33; H, 4.96; N, 2.76 1 H-NMR (CDCl 3) δ: 2.80-3.14 (3H, m), 4.94-5.12 (1
H, m), 6.04 (1H, brs), 6.32 (1H, d, J = 8.8 Hz), 7.
17 (2H, d, J = 8.2 Hz), 7.20-8.00 (15H, m), 8.45 (1
(H, d, J = 8.4 Hz).

Example 186 4-Fluoro-N-((1RS, 2SR) -2-hydroxy-
2- (1-naphthalenyl) -1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -1-naphthalenecarboxamide 4-fluoronaphthalene-1-carboxylic acid (112 mg,
Oxalyl chloride (0.10 ml, 1.18 mmol) and N, N-dimethylformamide (0.09 mmol) in a solution of 0.59 mmol) in tetrahydrofuran (5 ml).
1 ml), and the mixture was stirred at room temperature for 30 minutes, and the reaction solution was evaporated under reduced pressure. (1 ml) was added to a solution of the residue in ethyl acetate (5 ml).
RS, 2SR) -1-Hydroxy-1- (1-naphthalenyl) -3- (4- (trifluoromethyl) phenyl) -2-
Propylamine hydrochloride (150 mg, 0.39 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give the title compound (147 mg, 72).
%). ^{. mp 195-196 ℃ IRνmax KBr cm -1} : 1644, 1620, 1514. Anal Calcd for C 31 H 23 F 4 NO 2: C, 71.95; H, 4.48; N,
2.71 Found:. C, 71.67; H, 4.63; N, 2.56 1 H-NMR (CDCl 3) δ: 2.78 (1H, d, J = 3.0 Hz), 2.80-
3.16 (2H, m), 4.96-5.14 (1H, m), 6.05 (1H, s), 6.27
(1H, d, J = 8.8 Hz), 6.98-7.10 (1H, m), 7.14-7.30
(3H, m), 7.40-8.00 (11H, m), 8.09 (1H, d, J = 8.4
Hz), 8.44 (1H, d, J = 8.4 Hz).

Example 187 N-((1RS, 2SR) -2-hydroxy-2- (1-naphthalenyl) -1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -2-naphthalenecarboxamide ( 1RS, 2SR) -1-hydroxy-1- (1-naphthalenyl) -3- (4- (trifluoromethyl) phenyl) -2
To a solution of -propylamine hydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) was added 2-naphthoyl chloride (112 mg, 0.59 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was ethyl acetate-
Recrystallization from hexane gave the title compound (160 mg,
82%). mp 251-252 ° C IRνmax ^KBr cm ^-1 : 1644, 1620. Anal.Calcd for C ₃₁ H ₂₄ F ₃ NO ₂ : C, 74.54; H, 4.84; N,
2.80 Found:. C, 74.25; H, 4.56; N, 2.75 1 H-NMR (CDCl 3) δ: 2.82-3.30 (3H, m), 4.80-5.00 (1
H, m), 6.08 (1H, s), 6.59 (1H, d, J = 7.4 Hz), 7.1
5 (2H, d, J = 8.2 Hz), 7.40 (2H, d, J = 8.2 Hz),
7.50-7.80 (6H, m), 7.80-7.98 (6H, m), 8.12 (1H,
s), 8.45 (1H, d, J = 8.4 Hz).

Example 188 4-Fluoro-N-((1RS, 2SR) -2-hydroxy-
2- (1-naphthalenyl) -1-((4- (trifluoromethyl) phenyl) methyl) ethyl) benzamide (1RS, 2SR) -1-hydroxy-1- (1-naphthalenyl) -3- (4- ( Trifluoromethyl) phenyl) -2
To a solution of -propylamine hydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) was added 4-fluorobenzoyl chloride (70 ml, 0.59 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml), and ethyl acetate (50 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (152
mg, 83%). ^{. mp 194-195 ℃ IRνmax KBr cm -1} : 1638, 1605, 1539, 1501. Anal Calcd for C 27 H 21 F 4 NO 2: C, 69.37; H, 4.53; N,
3.00 Found:. C, 69.32; H, 4.54; N, 2.94 1 H-NMR (CDCl 3) δ: 2.80-3.18 (3H, m), 4.76-4.92 (1
H, m), 5.98 (1H, brs), 6.40 (1H, d, J = 8.4 Hz), 7.
00-7.14 (4H, m), 7.38 (2H, d, J = 8.4 Hz), 7.46-7.
70 (5H, m), 7.80-7.96 (3H, m), 8.38 (1H, d, J = 8.
4 Hz).

Example 189 N-((1RS, 2SR) -2-hydroxy-2- (1-naphthalenyl) -1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4- (trifluoro Methyl) benzamide (1RS, 2SR) -1-hydroxy-1- (1-naphthalenyl) -3- (4- (trifluoromethyl) phenyl) -2
To a solution of -propylamine hydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) was added 4-trifluoromethylbenzoyl chloride (87.5 ml, 0.59 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml), and the mixture was added at room temperature. Stirred overnight. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was recrystallized from ethyl acetate-hexane to give the title compound (178 mg, 88%). mp 232-233 ℃ IRνmax ^KBr cm ^-1 : 1644, 1534. Anal.Calcd for C ₂₈ H ₂₁ F ₆ NO ₂ : C, 64.99; H, 4.09; N,
2.71 Found:. C, 64.77; H, 3.93; N, 2.55 1 H-NMR (CDCl 3) δ: 2.68-2.74 (1H, m), 2.80-3.20 (2
H, m), 4.82-5.00 (1H, m), 6.00 (1H, s), 6.39 (1H,
d, J = 8.4 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.40 (2
H, d, J = 8.4 Hz), 7.50-7.78 (7H, m), 7.82-7.98 (3
H, m), 8.39 (1H, d, J = 8.0 Hz).

Example 190 N-((1RS, 2SR) -2-hydroxy-2- (1-naphthalenyl) -1-((4- (trifluoromethyl) phenyl) methyl) ethyl) cyclohexanecarboxamide (1RS, 2SR ) -1-Hydroxy-1- (1-naphthalenyl) -3- (4- (trifluoromethyl) phenyl) -2
To a solution of -propylamine hydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were added cyclohexanecarbonyl chloride (87.8 ml, 0.59 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (50 ml), and ethyl acetate (5 ml) was added.
0 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
The residue was purified with ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give the title compound (141 mg, 79%). ^{. mp 156-157 ℃ IRνmax KBr cm -1} : 1645, 1508. Anal Calcd for C 27 H 28 F 3 NO 2: C, 71.19; H, 6.20; N,
3.07 Found:. C, 71.14; H, 6.43; N, 3.06 1 H-NMR (CDCl 3) δ: 1.00-1.44 (5H, m), 1.50-1.80 (5
H, m), 1.86-2.10 (1H, m), 2.70-3.10 (2H, m), 3.15
(1H, d, J = 3.0 Hz), 4.52-4.70 (1H, m), 5.74 (1H,
d, J = 8.0 Hz), 5.84 (1H, s), 7.05 (2H, d, J = 8.2
Hz), 7.39 (2H, d, J = 8.2 Hz), 7.44-7.70 (3H, m),
7.78-7.98 (3H, m), 8.29 (1H, d, J = 8.4 Hz).

Example 191 N-((1RS, 2SR) -2-hydroxy-2- (1-naphthalenyl) -1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4- (2- Thienyl) butyric acid amide In a solution of 4- (2-thienyl) butyric acid (86 ml, 0.59 mmol) in tetrahydrofuran (5 ml), oxalyl chloride (0.10 ml, 1.18 mmol) and N, N-dimethylformamide (0. 01 ml), and the mixture was stirred at room temperature for 30 minutes, and the reaction solution was distilled off under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) (1RS, 2SR)
-1-Hydroxy-1- (1-naphthalenyl) -3- (4- (trifluoromethyl) phenyl) -2-propylamine hydrochloride (150 mg, 0.39 mmol) and saturated aqueous sodium bicarbonate (5 ml) were added. Stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was ethyl acetate-
Recrystallization from hexane gave the title compound (110 mg,
56%). mp 139-140 ℃ IRνmax ^KBr cm ^-1 : 1651, 1644, 1514. Anal.Calcd for C ₂₈ H ₂₆ F ₃ NO ₂ S ・ 0.1H ₂ O: C, 67.34; H,
5.29; N, 2.80 Found:. C, 67.18; H, 5.44; N, 2.69 1 H-NMR (CDCl 3) δ: 1.80-2.00 (2H, m), 2.02-2.30 (2
H, m), 2.60-3.04 (5H, m), 4.58-4.76 (1H, m), 5.75
(1H, d, J = 8.4 Hz), 5.85 (1H, s), 6.64-6.70 (1H,
m), 6.86-6.96 (1H, m), 7.00-7.18 (3H, m), 7.36-7.7
0 (5H, m), 7.76-7.96 (3H, m), 8.30 (1H, d, J = 8.4
Hz).

Example 192 4-Fluoro-N-((1RS, 2SR) -2-hydroxy-
2- (4-Methoxyphenyl) -1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -1-naphthalenecarboxamide 1) 4-methoxybenzoic acid (26.2 g, 172 mmol) in tetrahydrofuran (150 ml) ) 1
1′-carbonylbis-1H-imidazole (30.7 g,
189 mmol) and stirred at room temperature for 5 hours. Monoethyl magnesium malonate (27.1 g,
94.7 mmol) and stirred at 60 ° C. for 2 hours.
Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution.
And concentrated hydrochloric acid was further added until the pH of the aqueous layer became acidic. The reaction solution was extracted with ethyl acetate (200 ml × 2),
The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and ethyl 3- (4-methoxyphenyl) -3-oxopropionate (37.6 g, 94% w / w, 92%). Was obtained as a colorless oil. ^{. IRνmax KBr cm -1: 1738,} 1682, 1601, 1576. Anal Calcd for C 12 H 14 O 4: C, 64.85; H, 6.35 Found:. C, 64.93; H, 6.26 1 H-NMR (CDCl 3) δ: 1.26 (3H, t, J = 7.0 Hz), 3.85
(3 / 10H, s), 3.88 (27 / 10H, s), 3.94 (18 / 10H, s), 4.
21 (2H, q, J = 7.0 Hz), 5.58 (1 / 10H, s), 6.90-7.00
(2H, m), 7.70-7.78 (2 / 10H, m), 7.88-7.98 (18 / 10H,
m). 2) 4-Trifluoromethylbenzyl bromide (20.2 g, 84.6) in a solution of ethyl 3- (4-methoxyphenyl) -3-oxopropionate (20 g, 84.6 mmol) in acetonitrile (200 ml). Mmol) and potassium carbonate (23.4 g, 169 mmol)
The mixture was stirred at 60 ° C. for 2 hours. After evaporating the reaction solution under reduced pressure, the reaction solution was diluted with water (500 ml), and ethyl acetate (500 ml ×
Extracted in 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (toluene:
Purification with hexane = 1: 1-toluene) and ethyl 3- (4-methoxyphenyl) -3-oxo-2-((4- (trifluoromethyl) phenyl) methyl) propionate (19.
2g, 56%) as a colorless oil. ^{. IRνmax KBr cm -1: 1732,} 1682, 1601, 1576. Anal Calcd for C 20 H 19 F 3 O 4: C, 63.15; H, 5.03 Found:. C, 63.14; H, 4.83 1 H-NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.4 Hz), 3.37
(2H, d, J = 7.2 Hz), 3.85 (3H, s), 4.10 (2H, q, J
= 7.4 Hz), 4.58 (1H, t, J = 7.2 Hz), 6.92 (2H, d,
J = 8.8 Hz), 7.35 (2H, d, J = 8.0 Hz), 7.51 (2H,
d, J = 8.0 Hz), 7.95 (2H, d, J = 8.8 Hz). 3) Sodium borohydride (6.85 g) was added to a solution of zinc chloride (12.3 g, 90.4 mmol) in diethyl ether (150 ml). , 181 mmol) and stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was treated with ethyl 3- (4-methoxyphenyl) -3-oxo-2-((4- (trifluoromethyl) phenyl) methyl) propionate (1
7.2 g, 45.2 mmol) of diethyl ether (5
0 ml) solution and stirred at room temperature for 30 minutes. below freezing,
The reaction solution is quenched by adding 1N hydrochloric acid, and further added with water (20 mL).
0 ml) and extracted with ethyl acetate (300 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
4: 1-2: 1) and purified with ethyl (2RS, 3RS) -3-hydroxy-3- (4-methoxyphenyl) -2-((4- (trifluoromethyl) phenyl) methyl) propionate ( 15.1 g, 87%) as a colorless oil. IRνmax ^KBr cm ^-1 : 1728, 1615, 1586, 1514.Anal.Calcd for C ₂₀ H ₂₁ F ₃ O ₄ : C, 62.82; H, 5.54 Found: C, 62.71; H, 5.42. ¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7.0 Hz), 2.72
(1H, d, J = 2.6 Hz), 2.90-3.10 (3H, m), 3.81 (3H,
s), 3.87 (2H, q, J = 7.0 Hz), 4.96-5.04 (1H, m), 6.
89 (2H, d, J = 8.8 Hz), 7.22 (2H, d, J = 8.0 Hz),
7.31 (2H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.0 Hz). 4) (2RS, 3RS) -3-hydroxy-3- (4-methoxyphenyl) -2-((4 -(Trifluoromethyl)
Phenyl) methyl) ethyl propionate (14.7 g,
38.4 mmol) in methanol (60 ml)
A 2N aqueous sodium hydroxide solution (38.5 ml, 77 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (2RS, 3RS)
-3-Hydroxy-3- (4-methoxyphenyl) -2-
((4- (Trifluoromethyl) phenyl) methyl) propionic acid (11.7 g, 86%) was obtained. mp 113-114 ° C IRνmax ^KBr cm ^-1 : 1715, 1614, 1514.Anal.Calcd for C ₁₈ H ₁₇ F ₃ O ₄ : C, 61.02; H, 4.84 Found: C, 61.03; H, 4.85. ¹ H- NMR (CDCl ₃ ) δ: 3.03 (3H, s), 3.80 (3H, s), 4.98
-5.06 (1H, m), 6.89 (2H, d, J = 8.8 Hz), 7.19 (2H,
d, J = 8.0 Hz), 7.29 (2H, d, J = 8.8 Hz), 7.47 (2
H, d, J = 8.0 Hz). 5) (2RS, 3RS) -3-hydroxy-3- (4-methoxyphenyl) -2-((4- (trifluoromethyl)
Phenyl) methyl) propionic acid (10.0 g, 28.
Diphenylphosphoryl azide (6.7 ml, 31.2 mmol) in a solution of tetrahydrofuran (250 ml).
1 mmol) and triethylamine (5.9 ml, 42.
(3 mmol) and heated to reflux for 4 hours. After allowing the reaction solution to cool, water (200 ml) was added, and ethyl acetate (200 ml) was added.
1 × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (4RS, 5SR) -5- (4-methoxyphenyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidine-2. -ON (9.8
9g, 99%). mp 164-165 ℃ IRνmax ^KBr cm ^-1 : 1755, 1615, 1516. Anal.Calcd for C ₁₈ H ₁₆ F ₃ NO ₃ : C, 61.54; H, 4.59; N,
3.99 Found: C, 61.25; H, 4.50; N, 3.82. ¹ H-NMR (CDCl ₃ ) δ: 2.37 (2H, d, J = 7.4 Hz), 3.83
(3H, s), 4.23 (1H, q, J = 7.8 Hz), 5.32 (1H, brs),
5.75 (1H, d, J = 7.8 Hz), 6.88-7.00 (2H, m), 7.11
(2H, d, J = 8.0 Hz), 7.20-7.32 (2H, m), 7.52 (2H,
d, J = 8.0 Hz). 6) (4RS, 5SR) -5- (4-methoxyphenyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidin-2-one (7.0 g, 1
9.9 mmol) in ethanol (100 ml).
Normal aqueous sodium hydroxide solution (12.45 ml, 99.
6 mmol) and heated under reflux for 4 hours. After concentrating the reaction solution, the reaction solution was diluted with water (300 ml) and ethyl acetate (300 ml).
ml × 2). Wash the extract with saturated saline,
After drying over anhydrous magnesium sulfate, the solution was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2
SR) -2-Amino-1- (4-methoxyphenyl) -3-
(4- (trifluoromethyl) phenyl) -1-propanol (5.87 g, 91%) was obtained. mp 116-117 ℃ IRνmax ^KBr cm ^-1 : 1614, 1584, 1514. Anal.Calcd for C ₁₇ H ₁₈ F ₃ NO ₂ : C, 62.76; H, 5.58; N,
4.31 Found:. C, 62.74; H, 5.58; N, 4.23 1 H-NMR (CDCl 3) δ: 1.40-1.80 (2H, br), 2.45 (1H, d
d, J = 13.6, 10.0 Hz), 2.95 (1H, dd, J = 13.6, 3.2
Hz), 3.18-3.34 (1H, m), 3.82 (3H, s), 4.58 (1H, d,
J = 5.0 Hz), 6.92 (2H, d, J = 8.8 Hz), 7.22-7.38
(4H, m), 7.54 (2H, d, J = 8.4 Hz). 7) (1RS, 2SR) -2-amino-1- (4-methoxyphenyl) -3- (4- (trifluoromethyl) phenyl ) To a solution of 1-propanol (450 mg, 1.38 mmol) in acetonitrile (20 ml) was added 4-fluoronaphthalenecarboxylic acid (263 mg, 1.38 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. Hydrochloride (397 mg, 2.08 mmol) and 1-hydroxy-1H-benzotriazole (212 mg, 1.38 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane,
The title compound (558 mg, 81%) was obtained. mp 184-185 ℃ IRνmax ^KBr cm ^-1 : 1643, 1626, 1601.Anal.Calcd for C ₂₈ H ₂₃ F ₄ NO ₃ : C, 67.60; H, 4.66; N,
2.82 Found:. C, 67.37; H, 4.49; N, 2.87 1 H-NMR (CDCl 3) δ: 2.83 (1H, dd, J = 14.4, 10.6 H
z), 3.07 (1H, dd, J = 14.4, 4.0 Hz), 3.81 (3H, s),
4.70-4.90 (1H, m), 4.99 (1H, d, J = 3.6 Hz), 6.05
(1H, d, J = 8.8 Hz), 6.88-7.00 (3H, m), 7.04-7.16
(1H, m), 7.24-7.44 (5H, m), 7.44-7.60 (4H, m), 8.0
5 (1H, d, J = 8.0 Hz).

Example 193 N-((1RS, 2SR) -2-hydroxy-2- (4-methoxyphenyl) -1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -3-phenylpropane Amido (1RS, 2SR) -2-amino-1- (4-methoxyphenyl) -3- (4- (trifluoromethyl) phenyl) -1
To a solution of -propanol (450 mg, 1.38 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (308 ml, 2.07 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
1 × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (57
4 mg, 91%). mp 116-117 ° C IRνmax ^KBr cm ^-1 : 1645, 1615. Anal.Calcd for C ₂₆ H ₂₆ F ₃ NO ₃ : C, 68.26; H, 5.73; N,
3.06 Found:. C, 68.10; H, 5.99; N, 2.99 1 H-NMR (CDCl 3) δ: 2.37 (2H, t, J = 7.2 Hz), 2.60-
2.90 (4H, m), 3.04-3.20 (1H, m), 3.81 (3H, s), 4.32
-4.50 (1H, m), 4.72-4.84 (1H, m), 5.35 (1H, d, J =
8.4 Hz), 6.88 (2H, d, J = 8.8 Hz), 7.08-7.40 (9H,
m), 7.46 (2H, d, J = 8.0 Hz).

Example 194 N-[(1RS, 2SR) -2- (4-chlorophenyl)-
2-hydroxy-1- [4- (trifluoromethyl) benzyl
[Ethyl] -4-fluoronaphthalene-1-carboxami
1) Ethyl (4-chlorobenzoyl) acetate 15.77 g (100.7 mmol) of 4-chlorobenzoic acid
1,1′-) in 100 ml of tetrahydrofuran
18.0 g of carbonyldiimidazole (111 mmol
) Was added at room temperature, and the mixture was stirred as it was for 6 hours. This mixture
To the product, malonic acid monoethyl ester monomagnesium salt 1
At room temperature, add 5.9 g (55.4 mmol) at 60 ° C.
Stir for 3 hours. Dilute the reaction with ethyl acetate and water and concentrate.
After acidifying the reaction solution with hydrochloric acid, the ethyl acetate layer was separated,
The aqueous layer was extracted with ethyl acetate. The collected organic layer is sulfuric anhydride
After drying with sodium, the solvent was distilled off under reduced pressure. Obtained crude
The product is purified by silica gel column chromatography.
(Hexane / ethyl acetate = 6/1) to obtain the desired product.
Red liquid Yield 19.64 g Yield 86%¹ H-NMR (CDCl_Three, 200MHz) δ 1.26 (2.4H, t, J = 7.4H
z), 1.34 (0.6H, t, J = 7.0 Hz), 3.97 (1.6H, s), 4.2
2 (1.6H, q, J = 7.1 Hz), 4.27 (0.4H, q, J = 7.1 H
z), 5.64 (0.2H, s), 7.40 (0.4H, d, J = 8.8 Hz), 7.
46 (1.6H, d, J = 8.6 Hz), 7.72 (0.4H, d, J = 8.6 H
z), 7.90 (1.6H, d, J = 8.0 Hz); IR (neat) 1742, 16
90, 1622, 1590, 1325, 1265, 1200, 1092, 1013 cm^-1 2) 3- (4-chlorophenyl) -3-oxo-2- [4-
Ethyl (trifluoromethyl) benzyl] propionate 14.28 g of ethyl (4-chlorobenzoyl) acetate (6
3.00 mmol) of 1,2-dimethoxyethane 100
liquid paraffin of 60% sodium hydride under ice-cooling
2.52 g (63.0 mmol) of the
The mixture was stirred for 0.5 hours as it was. 4- (trifluoromethy
G) Benzyl bromide 15.1 g (63.0 mmol)
Of 1,2-dimethoxyethane at room temperature.
And stirred at room temperature for 6 hours. Pour the reaction mixture into water and add
Extracted twice with chill. The collected organic layer is dried over anhydrous magnesium sulfate.
And dried under reduced pressure. The resulting residue is
Purified by Ricagel column chromatography (hexa
Ethyl acetate / ethyl acetate = 15 / 1-9 / 1)
Crystallization gave the desired product. 18.87 g of white crystals
 Yield 78% mp 69-70 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 1.12 (3H, t,
 J = 7.1 Hz), 3.38 (2H, d, J = 7.4 Hz), 4.10 (2H,
q, J = 7.3 Hz), 4.56 (1H, t, J = 7.5 Hz), 7.34 (2
H, d, J = 8.0 Hz), 7.43 (2H, d, J = 8.8 Hz), 7.52
(2H, d, J = 8.0 Hz), 7.90 (2H, d, J = 8.4 Hz); IR
(KBr) 1717, 1690, 1590, 1329, 1283, 1229, 1179, 11
57, 1111, 1092, 1071, 845, 828 cm^-1; Anal. Calcd f
or C₁₉H₁₆ClF_ThreeO_Three: C, 59.31; H, 4.19. Found: C, 59.2
9; H, 4.05.3. (2RS, 3RS) -3- (4-chlorophenyl)-
3-hydroxy-2- [4- (trifluoromethyl) benzyl
Ethyl] propionate 7.18 g (52.7 mmol) of zinc chloride in diethyl ether
Sodium borohydride while stirring in 100 ml
3.98 g (105 mmol) were added at room temperature.
The mixture was stirred for 2 hours. The insolubles of the mixture are removed by filtration.
Washed with ethyl ether), zinc borohydride in diethyl
An ether solution was obtained. To the resulting solution, add 3- (4-chloro
Phenyl) -3-oxo-2- [4- (trifluoromethyl
L) benzyl] ethyl propionate 10.13 g (2
(6.33 mmol) in 50 ml of diethyl ether.
The mixture was added at room temperature and stirred for 2 hours. Dilute hydrochloric acid in the reaction solution
Was added little by little to decompose excess zinc borohydride
Thereafter, the mixture was extracted twice with ethyl acetate. The collected organic layer is anhydrous sulfur
After drying with magnesium acid, the solvent was distilled off under reduced pressure. Got
The crude product is purified by silica gel column chromatography.
(Hexane / ethyl acetate = 9 / 1-3 / 1)
I got something. Colorless liquid Yield 9.971 g 98% yield¹ H-NMR (CDCl_Three, 200MHz) δ 0.93 (3H, t, J = 7.1 H
z), 2.90-3.14 (4H, m), 3.90 (2H, q, J = 7.1 Hz),
5.04 (1H, dd, J = 3.0 Hz, 4.8 Hz), 7.19 (2H, d, J =
 8.2 Hz), 7.34 (4H, s), 7.48 (2H, d, J = 8.2 Hz);
IR (neat) 3466, 1715, 1325, 1163, 1125, 1109, 106
9, 1019, 829 cm^-1 4) (2RS, 3RS) -3- (4-chlorophenyl)-
3-hydroxy-2- [4- (trifluoromethyl) benzyl
] Propionic acid (2RS, 3RS) -3- (4-chlorophenyl) -3-h
Droxy-2- [4- (trifluoromethyl) benzyl]
9.756 g of ethyl propionate (25.22 mmol
M) -methanol 40 ml-tetrahydrofuran 40 m
1N aqueous sodium hydroxide solution 50.4 ml (5
0.4 mmol) and stirred at room temperature overnight. Reaction liquid
Was concentrated, diluted with water, and the reaction solution was acidified with 1N hydrochloric acid.
Thereafter, the mixture was extracted twice with ethyl acetate. The collected organic layer is anhydrous sulfur
The extract was dried over sodium acid and the solvent was distilled off under reduced pressure. Remove the residue
Crystallized from ethyl ether-hexane to obtain the desired product
Was. White crystals Yield 7.152 g Yield 79% mp 100-101 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 2.94-3.13
(3H, m), 5.09 (1H, t, J = 2.2 Hz), 7.18 (2H, d, J =
 7.6 Hz), 7.34 (4H, s), 7.48 (2H, d, J = 8.0 Hz);
IR (KBr) 3400-2550, 1696, 1323, 1167, 1130, 1119,
1107, 828 cm^-1; Anal. Calcd for C₁₇H₁₄ClF_ThreeO_Three: C, 5
6.92; H, 3.93. Found: C, 56.98; H, 3.73.5) (4RS, 5SR) -5- (4-chlorophenyl)-
4- [4- (trifluoromethyl) benzyl] -1,3-o
Oxazolidine-2-one (2RS, 3RS) -3- (4-chlorophenyl) -3-h
Droxy-2- [4- (trifluoromethyl) benzyl]
6.931 g (19.32 mmol) of propionic acid
3. Triethylamine in 80 ml solution of trahydrofuran.
04 ml (29.0 mmol), diphenylphosphoryl
Add 5.85 g (21.3 mmol) of azide and add overnight.
Heated to reflux. The solvent of the reaction solution was distilled off under reduced pressure to obtain a crude product.
The product is purified by silica gel column chromatography.
(Hexane / ethyl acetate = 3 / 1-1 / 1), ethyl acetate
Crystallization from l-hexane gave the desired product. White crystals
 6.120 g yield 89% mp 159-160 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 2.24-2.40
(2H, m), 4.20-4.32 (1H, m), 5.02 (1H, br s), 5.80
(1H, d, J = 8.2 Hz), 7.15 (2H, d, J = 8.0 Hz), 7.3
2 (2H, d, J = 8.4 Hz), 7.42 (2H, d, J = 8.4 Hz),
7.55 (2H, d, J = 8.0 Hz); IR (KBr) 3248, 1736, 132
7, 1167, 1138, 1109, 1096, 1067 cm^-1; Anal. Calcd
for C₁₇H₁₃ClF_ThreeNO_Two: C, 57.40; H, 3.68; N, 3.94. Fou
nd: C, 57.41; H, 3.58; N, 3.85. 6) (1RS, 2SR) -2-amino-1- (4-chloro)
Phenyl) -3- [4- (trifluoromethyl) phenyl
Ru] propan-1-ol (4RS, 5SR) -5- (4-chlorophenyl) -4-
[4- (trifluoromethyl) benzyl] -1,3-oxo
5.902 g of sazolidine-2-one (16.59 mmol
) And 2.65 g of sodium hydroxide (66.4 mmol
7) in 40 ml of ethanol-2.5 ml of water for 7 hours
Heated to reflux. Dilute the reaction with water and leave for 10 minutes
Stirred. The resulting precipitate is collected by filtration, washed with water,
The desired product was obtained. White crystals Yield 4.902 g Yield 90
% Mp 103-105 ° C;¹H-NMR (CDCl_Three, 200MHz) δ 2.41 (1H,
dd, J = 10.3 Hz, 13.5Hz), 2.83 (1H, dd, J = 3.1 H
z, 13.7 Hz), 3.29 (1H, ddd, J = 3.3 Hz, 4.9Hz, 10.
5 Hz), 4.66 (1H, d, J = 4.8 Hz), 7.25 (2H, d, J =
8.0 Hz), 7.31-7.40 (4H, m), 7.54 (2H, d, J = 8.0 H
z); IR (KBr) 3150-2760, 1329, 1165, 1130, 1115, 10
69, 1042, 851 cm^-1; Anal. Calcd for C₁₆H₁₅ClF_ThreeNO:
C, 58.28; H, 4.59; N, 4.25. Found: C, 58.03; H, 4.7
2; N, 4.16.7) N-[(1RS, 2SR) -2- (4-chlorophenyl)
) -2-Hydroxy-1- [4- (trifluoromethyl)
[Benzyl] ethyl] -4-fluoronaphthalene-1-carbo
Oxamide (1RS, 2SR) -2-amino-1- (4-chlorophenyi)
) -3- [4- (Trifluoromethyl) phenyl] pro
0.173 g (0.525 mmol) of pan-1-ol,
0.10 g of 4-fluoro-1-naphthoic acid (0.52 mm
Mol) 1-hydroxybenzotriazole hydrate 80
mg (0.52 mmol) in 10 ml of acetonitrile
1-ethyl-3- (3-dimethylaminopro
Pill) 0.10 g (0.52 mi) carbodiimide hydrochloride
Lmol) and stirred overnight at room temperature. The reaction solution was
Dilute to chill, wash with aqueous sodium bicarbonate, anhydrous
After drying over magnesium sulfate and passing through silica gel, the solvent
Was distilled off under reduced pressure. The obtained residue is ethyl acetate-hexa.
The product was crystallized from the compound to give the desired product. White crystals Yield 0.
216 g yield 82% mp 203-204 ° C;¹H-NMR (CDCl_Three-DMSO-d₆, 200MHz) δ 2.
93 (1H, dd, J = 10.6 Hz, 14.4 Hz), 3.11 (1H, dd, J
 = 3.1 Hz, 13.3 Hz), 4.66-4.81 (1H, m), 4.95 (1H,
t, J = 4.6 Hz), 5.43 (1H, d, J = 4.0 Hz), 7.05 (1
H, dd, J = 7.7 Hz, 9.9 Hz), 7.20 (1H, dd, J = 5.5
Hz, 8.1 Hz), 7.33-7.57 (11H, m), 7.71 (1H, d, J =
9.6 Hz), 8.05 (1H, d, J = 8.4 Hz); IR (KBr) 3343,
1638, 1620,1601, 1534, 1327, 1159, 1125, 1069, 833
 cm^-1; Anal. Calcd for C₂₇H₂₀ClF _FourNO_Two: C, 64.61; H,
 4.02; N, 2.79. Found: C, 64.42; H, 3.98; N, 2.61.

Example 195 4-Fluoro-N-((1RS, 2SR) -2- (3-furanyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -1 -Naphthalenecarboxamide 1) To a solution of 3-furancarboxylic acid (25.5 g, 227 mmol) in tetrahydrofuran (200 ml),
1′-carbonylbis-1H-imidazole (40.5 g,
(250 mmol) and stirred at 60 ° C. for 2 hours. Monoethyl magnesium malonate (35.8) was added to the reaction solution.
g, 125 mmol) and heated to reflux for 30 minutes. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution, and concentrated hydrochloric acid was further added until the pH of the aqueous layer became acidic. The reaction solution was extracted with ethyl acetate (200 ml × 2),
The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give ethyl 3- (3-furanyl) -3-oxopropionate (42 g, 100%) as a colorless oil. ^{. IRνmax KBr cm -1: 1738,} 1682. Anal Calcd for C 9 H 10 O 4 · 0.1H 2 O: C, 58.76; H, 5.59 Found:. C, 58.90; H, 5.56 1 H-NMR (CDCl 3 ) δ: 1.27 (3H, t, J = 7.0 Hz), 3.78
(18 / 10H, s), 4.21 (2H, q, J = 7.0 Hz), 5.37 (1 / 10H,
s), 6.57 (1 / 10H, s), 6.79 (9 / 10H, s), 7.40-7.50
(1H, m), 7.90 (1 / 10H, s), 8.11 (9 / 10H, s). 2) Ethyl 3- (3-furanyl) -3-oxopropionate (20 g, 110 mmol) Sodium hydride (60% oily, 4.4 g, 110 mmol) was added to a solution of -dimethoxyethane (100 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. A solution of 4-trifluoromethylbenzyl bromide (26.2 g, 110 mmol) in 1,2-dimethoxyethane (50 ml) was added dropwise to the reaction solution.
The reaction was stirred at room temperature for 3 hours. The reaction solution was washed with water (300 m
1) and extracted with ethyl acetate (500 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give 3- (3-
Ethyl furanyl) -3-oxo-2-((4- (trifluoromethyl) phenyl) methyl) propionate (28.8
g, 77%). ^{. mp 55-56 ℃ IRνmax KBr cm -1} : 1738, 1682. Anal Calcd for C 17 H 15 F 3 O 4: C, 60.00; H, 4.44 Found:. C, 59.89; H, 4.38 1 H-NMR ( CDCl ₃ ) δ: 1.16 (3H, t, J = 7.0 Hz), 3.35
(2H, d, J = 7.6 Hz), 4.06-4.24 (3H, m), 6.76-6.80
(1H, m), 7.34 (2H, d, J = 8.0 Hz), 7.40-7.48 (1H,
m), 7.53 (2H, d, J = 8.0 Hz), 8.09 (1H, s). 3) To a solution of zinc chloride (16.0 g, 117 mmol) in diethyl ether (250 ml) was added sodium borohydride (8.9 g). , 235 mmol) and stirred at room temperature for 2 hours. The insoluble material was removed by filtration, and the filtrate was treated with ethyl 3- (3-furanyl) -3-oxo-2-((4- (trifluoromethyl) phenyl) methyl) propionate (20 g, 58.
(8 mmol) in diethyl ether (50 ml) and stirred at room temperature for 30 minutes. The reaction solution was quenched by adding 1N hydrochloric acid under ice-cooling, and water (200 ml) was further added.
Extracted with ethyl acetate (300 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give (2RS, 3RS) -3- (3-furanyl) -3-hydroxy-2-((4- (trifluoro Methyl) phenyl) methyl) ethyl propionate (19.7
g, 98%) as a colorless oil. ^{. IRνmax KBr cm -1: 1728. Anal} Calcd for C 17 H 17 F 3 O 4: C, 59.65; H, 5.01 Found:. C, 59.35; H, 5.19 1 H-NMR (CDCl 3) δ: 1.00 ( 3H, t, J = 7.2 Hz), 2.80
(1H, d, J = 3.8 Hz), 2.86-3.14 (3H, m), 3.96 (2H,
q, J = 7.2 Hz), 5.01 (1H, t, J = 4.0 Hz), 6.40 (1
H, s), 7.25 (2H, d, J = 8.0 Hz), 7.38-7.60 (4H,
m). 4) Ethyl (2RS, 3RS) -3- (3-furanyl) -3-hydroxy-2-((4- (trifluoromethyl) phenyl) methyl) propionate (19.0 g, 55.5 g).
To a solution of 5 mmol) in methanol (100 ml) was added a 2 N aqueous solution of sodium hydroxide (55.5 ml, 111 mmol) and the mixture was stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane (2R
S, 3RS) -3- (3-Furanyl) -3-hydroxy-2-
((4- (trifluoromethyl) phenyl) methyl) propionic acid (15.1 g, 86%) was obtained. ^{. mp 104-105 ℃ IRνmax KBr cm -1} : 1713. Anal Calcd for C 15 H 13 F 3 O 4: C, 57.33; H, 4.17 Found:. C, 57.42; H, 4.15 1 H-NMR (CDCl 3 ) δ: 2.90-3.20 (3H, m), 5.02 (1H, d,
J = 4.0 Hz), 6.39 (1H, s), 7.26 (2H, d, J = 8.2 H
z), 7.40-7.50 (2H, m), 7.52 (2H, d, J = 8.2 Hz). 5) (2RS, 3RS) -3- (3-furanyl) -3-hydroxy-2-((4- In a solution of (trifluoromethyl) phenyl) methyl) propionic acid (10.0 g, 31.8 mmol) in tetrahydrofuran (250 ml), diphenylphosphoryl azide (7.5 ml, 35.0 mmol) and triethylamine (6.7 ml, 47). (0.7 mmol) and heated under reflux for 4 hours. After allowing the reaction solution to cool,
Add water (200 ml) and add ethyl acetate (200 ml ×
Extracted in 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (4RS, 5SR) -5- (3-furanyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidine-2-. ON (8.2
(5 g, 83%). ^{. mp 111-112 ℃ IRνmax KBr cm -1} : 1759. Anal Calcd for C 15 H 12 F 3 NO 3: C, 57.88; H, 3.89; N,
4.50 Found:. C, 57.94; H, 3.97; N, 4.38 1 H-NMR (CDCl 3) δ: 2.48-2.72 (2H, m), 4.12-4.28 (1
H, m), 5.09 (1H, brs), 5.75 (1H, d, J = 7.8 Hz), 6.
47 (1H, s), 7.22 (2H, d, J = 8.0 Hz), 7.48-7.62 (4
H, m). 6) (4RS, 5SR) -5- (3-furanyl) -4-
((4- (trifluoromethyl) phenyl) methyl)-
1,3-oxazolidine-2-one (7.0 g, 22.5
8 mmol sodium hydroxide aqueous solution (14.0 ml, 112.5 mmol) was added to an ethanol (100 ml) solution of the resultant solution, and the mixture was refluxed for 3 hours. After concentrating the reaction solution,
Dilute with water (300ml) and add ethyl acetate (300ml x
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2SR)
-2-amino-1- (3-furanyl) -3- (4- (trifluoromethyl) phenyl) -1-propanol (5.54 g,
86%). mp 91-92 ° C IRνmax ^KBr cm ^-1 : 1572, 1500, 1331. Anal.Calcd for C ₁₄ H ₁₄ F ₃ NO ₂ : C, 58.95; H, 4.95; N,
4.91 Found:. C, 58.91; H, 5.08; N, 4.78 1 H-NMR (CDCl 3) δ: 2.49 (1H, dd, J = 13.6, 9.8 Hz),
2.96 (1H, dd, J = 14.0, 3.6 Hz), 3.20-3.32 (1H,
m), 4.62 (1H, d, J = 5.2 Hz), 6.44 (1H, s), 7.30
(2H, d, J = 8.0 Hz), 7.40-7.50 (2H, m), 7.56 (2H,
d, J = 8.0 Hz). 7) (1RS, 2SR) -2-amino-1- (3-furanyl) -3- (4- (trifluoromethyl) phenyl) -1-
To a solution of propanol (500 mg, 1.75 mmol) in acetonitrile (30 ml) was added 4-fluoronaphthalenecarboxylic acid (333 mg, 1.75 mmol) and 1
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (504 mg, 2.63 mmol) and 1-hydroxy-1H-benzotriazole (268 m
g, 1.75 mmol) and stirred at room temperature overnight.
The reaction solution was diluted with water (100 ml), and ethyl acetate (10 ml) was added.
0 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to obtain the title compound (573 mg, 71%). mp 206-207 ℃ IRνmax ^KBr cm ^-1 : 1644, 1626, 1601, 1537, 1329. Anal.Calcd for C ₂₅ H ₁₉ F ₄ NO ₃ : C, 65.64; H, 4.19; N,
3.06 Found:. C, 65.49; H, 4.37; N, 2.91 1 H-NMR (CDCl 3) δ: 2.89 (1H, dd, J = 14.2, 10.2 H
z), 3.15 (1H, dd, J = 14.2, 4.2 Hz), 3.24 (1H, br
s), 4.70-4.88 (1H, m), 5.03 (1H, d, J = 3.2 Hz),
6.02 (1H, d, J = 8.6 Hz), 6.51 (1H, s), 6.92-7.08
(1H, m), 7.12-7.24 (1H, m), 7.30-7.62 (8H, m), 7.7
0 (1H, d, J = 8.4 Hz), 8.08 (1H, d, J = 8.2 Hz).

Example 196 N-((1RS, 2SR) -2- (3-furanyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl)
Methyl) ethyl) -3-phenylpropanamide (1RS, 2SR) -2-amino-1- (3-furanyl) -3
To a solution of-(4- (trifluoromethyl) phenyl) -1-propanol (500 mg, 1.75 mmol) in ethyl acetate (20 ml) was added 3-phenylpropionyl chloride (390 ml, 2.63 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml). ) Was added and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (650 m
g, 89%). mp 134-135 ℃ IRνmax ^KBr cm ^-1 : 1645, 1520. Anal.Calcd for C ₂₃ H ₂₂ F ₃ NO ₃ : C, 66.18; H, 5.31; N,
3.36 Found:. C, 66.18; H, 5.40; N, 3.22 1 H-NMR (CDCl 3) δ: 2.39 (2H, t, J = 7.0 Hz), 2.64-
2.92 (4H, m), 3.08-3.36 (1H, m), 4.26-4.44 (1H, m),
4.75 (1H, s), 5.30-5.50 (1H, m), 6.31 (1H, s), 7.0
6-7.34 (7H, m), 7.38 (2H, d, J = 6.8 Hz), 7.49 (2
(H, d, J = 8.2 Hz).

Example 197 N-[(1RS, 2RS) -2- (5-chloro-2-thienyl) -2-hydroxy-1- [4- (trifluoromethyl)
Benzyl] ethyl] -4-fluoronaphthalene-1-carboxamide 1) ethyl 3- (5-chloro-2-thienyl) -3-oxopropionate 10.12 g (6
To a solution of 2.24 mmol) in 80 ml of tetrahydrofuran was added 11.1 g (6,1'-carbonyldiimidazole).
(8.5 mmol) at room temperature and stirred for 6 hours. 9.81 g (34.2 mmol) of malonic acid monoethyl ester monomagnesium salt was added to this mixture at room temperature, and the mixture was stirred at 60 ° C. for 3 hours. After diluting the reaction solution with ethyl acetate and water and acidifying the reaction solution with concentrated hydrochloric acid, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to obtain the desired product. Dark red liquid Yield 13.89 g Yield 96
% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.27 (3H, t, J = 7.2 H
z), 3.85 (2H, s), 4.21 (2H, q, J = 7.1 Hz), 6.99
(1H, d, J = 4.0 Hz), 7.53 (1H, d, J = 4.0 Hz); IR
(neat) 1738, 1667, 1418, 1329, 1215, 1017 cm ^-1 2) 3- (5-chloro-2-thienyl) -3-oxo-2-
Ethyl [4- (trifluoromethyl) benzyl] propionate 13.57 g (58.32 mmol) of ethyl 3- (5-chloro-2-thienyl) -3-oxopropionate in 1,2-
2.33 g of a liquid paraffin suspension of 60% sodium hydride in a 100 ml dimethoxyethane solution under ice-cooling (58.
3 mmol), and the mixture was stirred as it was for 0.5 hour. 4
13.9 g of-(trifluoromethyl) benzyl bromide
(58.3 mmol) of 1,2-dimethoxyethane 20
ml solution was added at room temperature and stirred at room temperature for 6 hours. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-9 /
1) Crystallized from hexane to obtain the desired product. White crystals Yield 18.30 g Yield 80% mp 87-88 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.16 (3H, t,
J = 7.2 Hz), 3.36 (2H, d, J = 7.8 Hz), 4.14 (2H,
q, J = 7.2 Hz), 4.35 (1H, t, J = 7.5 Hz), 6.94 (1
H, d, J = 4.0 Hz), 7.33 (2H, d, J = 8.0 Hz), 7.53
(2H, d, J = 8.4 Hz), 7.55 (1H, d, J = 4.0 Hz); IR
(KBr) 1721, 1659, 1418, 1329, 1285, 1236, 1155, 11
^{. 19, 1071 cm -1; Anal} Calcd for C 17 H 14 ClF 3 O 3 S: C, 5
2.25; H, 3.61. Found: C, 52.22; H, 3.42.3) (2RS, 3RS) -3- (5-Chloro-2-thienyl) -3-hydroxy-2- [4- (trifluoromethyl)
Ethyl benzyl] propionate While stirring 6.47 g (47.5 mmol) of zinc chloride in 100 ml of diethyl ether, 3.59 g (94.9 mmol) of sodium borohydride was added at room temperature, and the mixture was stirred for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. 9.272 g of ethyl 3- (5-chloro-2-thienyl) -3-oxo-2- [4- (trifluoromethyl) benzyl] propionate was added to the resulting solution.
(23.73 mmol) in 50 ml of diethyl ether was added at room temperature, and the mixture was stirred for 2 hours. Dilute hydrochloric acid was added little by little to the reaction solution to decompose excess zinc borohydride, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-3 / 1) to obtain the desired product. Colorless liquid Yield 9.093 g Yield 98% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.99 (3H, t, J = 7.1 H)
z), 2.96-3.16 (4H, m), 3.96 (2H, q, J = 7.1 Hz),
5.15 (1H, t, J = 4.2 Hz), 6.76 (1H, d, J = 3.8Hz),
6.79 (1H, d, J = 3.6 Hz), 7.26 (2H, d, J = 8.2 H
z), 7.52 (2H, d, J = 8.0 Hz); IR (neat) 3459, 1715,
1325, 1163, 1125, 1109, 1069, 1020 cm -1 4) (2RS, 3RS) -3- (5- chloro-2-thienyl) -3-hydroxy-2- [4- (trifluoromethyl)
Benzyl] propionic acid (2RS, 3RS) -3- (5-chloro-2-thienyl) -3
Ethyl -hydroxy-2- [4- (trifluoromethyl) benzyl] propionate 8.878 g (22.60 mmol) in methanol 30 ml-tetrahydrofuran 30
45.2 ml of 1N aqueous sodium hydroxide solution
(45.2 mmol) and stirred at room temperature overnight. The reaction solution was concentrated, diluted with water, acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from diethyl ether-hexane to obtain the desired product. White crystals Yield 7.092 g Yield 86% mp 150-151 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 3.06-3.15
(3H, m), 5.17 (1H, d, J = 4.8 Hz), 6.79 (2H, s), 7.
27 (2H, d, J = 8.0 Hz), 7.53 (2H, d, J = 8.4 Hz);
IR (KBr) 3382, 3050-2650, 1698, 1333, 1159, 1130,
^{1111, 1071, 802cm -1;.} Anal Calcd for C 15 H 12 ClF 3 O
_{3 S:. C, 49.39;} H, 3.32 Found:. C, 49.40; H, 3.29 5) (4RS, 5RS) -5- (5- chloro-2-thienyl) -4- [4- (trifluoromethyl ) Benzyl] -1,
3-oxazolidine-2-one (2RS, 3RS) -3- (5-chloro-2-thienyl) -3
6.918 g (18.97 mmol) of -hydroxy-2- [4- (trifluoromethyl) benzyl] propionic acid
3.97 ml (28.4 mmol) of triethylamine and 5.74 g (20.9 mmol) of diphenylphosphoryl azide were added to a solution of the above in 80 ml of tetrahydrofuran, and the mixture was refluxed overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1), and crystallized from diethyl ether / hexane. I got something. White crystal Yield 5.985 g Yield 87% mp 127-128 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.54-2.75
(2H, m), 4.25 (1H, ddd, 4.7 Hz, 8.0 Hz, 10.1 Hz),
5.10 (1H, br s), 5.72 (1H, d, J = 7.6 Hz), 6.89 (2
H, s), 7.22 (2H, d, J = 8.0 Hz), 7.58 (2H, d, J =
8.6 Hz); IR (KBr) 3248, 1736, 1327, 1159, 1127, 10
^{. 69 cm -1; Anal Calcd for} C 15 H 11 ClF 3 NO 2 S: C, 49.80;
H, 3.06; N, 3.87. Found: C, 49.77; H, 2.95; N, 3.
65.6) (1RS, 2RS) -2-amino-1- (5-chloro-
2-thienyl) -3- [4- (trifluoromethyl) phenyl] propan-1-ol (4RS, 5RS) -5- (5-chloro-2-thienyl) -4
2.951 g (8.157 mmol) of-[4- (trifluoromethyl) benzyl] -1,3-oxazolidin-2-one and 1.31 g (32.6 mmol) of sodium hydroxide in 30 ml of ethanol and 1. The mixture was heated under reflux in 5 ml for 7 hours. The reaction was diluted with brine and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified on silica gel (APS
Type) Purification by column chromatography (hexane / ethyl acetate = 3 / 1-ethyl acetate), and ethyl acetate-
Crystallization from hexane gave the desired product. White crystal Yield 1.318 g Yield 48% mp 86-87 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.49 (1H, d
d, J = 9.7 Hz, 13.7 Hz), 2.92 (1H, dd, J = 3.9 Hz,
13.7 Hz), 3.28-3.38 (1H, m), 4.77 (1H, d, J = 4.8
Hz), 6.79 (1H, d, J = 3.8 Hz), 6.83 (1H, d, J = 3.
6 Hz), 7.30 (2H, d, J = 8.6 Hz), 7.57 (2H, d, J =
8.0 Hz); IR (KBr) 3100-2700, 1327, 1163, 1117, 106
9, 1038, 802 cm ^-1 ; Anal.Calcd for C ₁₄ H ₁₃ ClF ₃ NOS:
C, 50.08; H, 3.90; N, 4.17. Found: C, 49.99; H, 3.9
2; N, 4.11.7) N-[(1RS, 2RS) -2- (5-chloro-2-thienyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -4- Fluoronaphthalene-1-carboxamide (1RS, 2RS) -2-amino-1- (5-chloro-2-thienyl) -3- [4- (trifluoromethyl) phenyl]
0.168 g (0.500 mmol) of propan-1-ol 0.10 g (0.50 mmol) of 4-fluoro-1-naphthoic acid
0 mmol) 1-hydroxybenzotriazole hydrate 77 mg (0.50 mmol) in acetonitrile 10
While stirring in 0.1 ml, 0.10 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.
(50 mmol) and stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals
Yield 0.186 g Yield 73% mp 201-203 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ 2.
95 (1H, dd, J = 10.6 Hz, 14.0 Hz), 3.21 (1H, dd, J
= 2.8 Hz, 14.6 Hz), 4.66-4.80 (1H, m), 5.10 (1H,
t, J = 4.7 Hz), 5.86 (1H, d, J = 4.4 Hz), 6.85 (1
H, d, J = 3.6 Hz), 6.91 (1H, d, J = 4.0 Hz), 7.07
(1H, dd, J = 7.9 Hz, 10.1 Hz), 7.28 (1H, dd, J =
5.4 Hz, 8.0 Hz), 7.39-7.64 (7H, m), 7.79 (1H, d, J
= 9.6 Hz), 8.06 (1H, d, J = 7.8 Hz); IR (KBr) 327
5, 1644, 1626, 1537, 1325, 1167, 1121, 1069, 760 c
m ^-1 ; Anal.Calcd for C ₂₅ H ₁₈ ClF ₄ NO ₂ S: C, 59.12; H,
3.57; N, 2.76.Found: C, 59.05; H, 3.47; N, 2.49.

Example 198 N-[(1RS, 2RS) -2- (5-chloro-2-thienyl) -2-hydroxy-1- [4- (trifluoromethyl)
Benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2RS) -2-amino-1- (5-chloro-2-thienyl) -3- [4- ( Trifluoromethyl) phenyl]
0.235 g (0.700 mmol) of propan-1-ol, 0.13 g (0.70 mmol) of 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid,
0.11 g of 1-hydroxybenzotriazole hydrate
While stirring (0.70 mmol) in 10 ml of acetonitrile, 0.13 g (0.70 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystal Yield 0.298 g Yield 84% mp 184-185 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.94-2.06
(2H, m), 2.15-2.24 (2H, m), 2.67 (2H, t, J = 5.8 H
z), 2.86 (1H, dd, J = 10.5 Hz, 14.5 Hz), 3.09 (1H,
dd, J = 4.5 Hz, 14.1 Hz), 4.25 (1H, d, J = 4.0 H
z), 4.63-4.76 (1H, m), .15 (1H, t, J = 3.8 Hz), 5.
83 (1H, d, J = 8.8 Hz), 5.91 (1H, td, J = 5.3 Hz, 1
1.8 Hz), 6.19 (1H, d, J = 11.8 Hz), 6.84 (2H, s),
7.00-7.21 (3H, m), 7.33 (2H, d, J = 8.0 Hz), 7.57
(2H, d, J = 8.0 Hz); IR (KBr) 3283, 1638, 1526, 13
27, 1161, 1125, 1069 cm ^-1 ; Anal.Calcd for C ₂₆ H ₂₃ C
lF ₃ NO ₂ S: C, 61.72; H, 4.58; N, 2.77. Found: C, 61.
57; H, 4.35; N, 2.71.

Example 199 1,1-Dimethylethyl (1RS, 2SR) -2-hydroxy-2- (4-pyridyl) -1-((4- (trifluoromethyl) phenyl) methyl) ethyl carbamate 1) 4 To a solution of 1-pyridinecarboxylic acid (50.0 g, 406 mmol) in tetrahydrofuran (250 ml) was added 1,1′-carbonylbis-1H-imidazole (72.5 g).
g, 447 mmol) and stirred at room temperature for 30 minutes.
Monoethyl magnesium malonate (82.9) was added to the reaction mixture.
g, 487 mmol) and heated under reflux for 30 minutes. Ethyl acetate (200 ml) and water (200 m
l) was added, and citric acid was further added until the pH of the aqueous layer reached 7. The reaction solution was extracted with ethyl acetate (400 ml × 2), the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was washed with diisopropyl ether-hexane and recrystallized from diisopropyl ether-hexane to obtain ethyl 3-oxo-3- (4-pyridyl) propionate (13.3 g, 17%). mp 60-61 ℃ IRνmax ^KBr cm ^-1 : 1744, 1699, 1651, 1634, 1595, 155
_{. 3. Anal Calcd for C 10 H} 11 NO 3: C, 62.17; H, 5.74; N,
7.25 Found:. C, 62.17; H, 5.86; N, 7.22 1 H-NMR (CDCl 3) δ: 1.26 (3 / 7H, t, J = 7.2 Hz), 1.35
(18 / 7H, t, J = 7.2 Hz), 4.00 (2 / 7H, s), 4.18-4.40
(2H, m), 5.77 (6 / 7H, s), 7.61 (12 / 7H, d, J = 4.8 H
z), 7.74 (2 / 7H, d, J = 4.8 Hz), 8.71 (12 / 7H, d, J
= 4.8 Hz), 8.83 (2 / 7H, d, J = 4.8 Hz), 12.44 (6 / 7H,
s). 2) To a solution of ethyl 3-oxo-3- (4-pyridyl) propionate (13.9 g, 72.0 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (6).
(0% oily, 2.88 g, 72.0 mmol) under ice-cooling and stirred at room temperature for 30 minutes. A solution of 4-trifluoromethylbenzyl bromide (17.2 g, 72.0 mmol) in 1,2-dimethoxyethane (50 ml) was added dropwise to the reaction solution, and the reaction solution was stirred at room temperature for 4 hours. The reaction solution was poured into water (300 ml), and ethyl acetate (500 ml ×
Extracted in 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purified with ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give 3-oxo-3- (4-pyridyl) -2-.
Ethyl ((4- (trifluoromethyl) phenyl) methyl) propionate (10.9 g, 43%) was obtained. mp 64-65 ° C IRνmax ^KBr cm ^-1 : 1738, 1699. Anal.Calcd for C ₁₈ H ₁₆ F ₃ NO ₃ : C, 61.54; H, 4.59; N,
3.99 Found: C, 61.61; H, 4.44; N, 3.93. ¹ H-NMR (CDCl ₃ ) δ: 1.11 (3H, t, J = 7.0 Hz), 3.39
(2H, d, J = 7.4 Hz), 4.11 (2H, q, J = 7.0 Hz), 4.5
6 (1H, t, J = 7.4 Hz), 7.35 (2H, d, J = 8.0 Hz),
7.54 (2H, d, J = 8.0 Hz), 7.66-7.78 (2H, m), 8.76-
8.88 (2H, m). 3) Sodium borohydride (4.53 g, 120 mmol) was added to a solution of zinc chloride (8.14 g, 59.8 mmol) in diethyl ether (200 ml), and the mixture was stirred at room temperature for 30 minutes. . The insoluble material is removed by filtration, and the filtrate is treated with 3-oxo-3.
-(4-pyridyl) -2-((4- (trifluoromethyl)
Phenyl) methyl) ethyl propionate (10.5 g,
(29.9 mmol) in diethyl ether (50 ml) was added and stirred at room temperature for 30 minutes. Add 1 reaction solution under ice-cooling.
The mixture was quenched by addition of normal hydrochloric acid, and saturated aqueous sodium hydrogen carbonate was further added until the pH reached 8, followed by extraction with ethyl acetate (300 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from diisopropyl ether-hexane to give (2RS, 3RS) -3-hydroxy-3- (4-pyridyl) -2-((4- ( Trifluoromethyl) phenyl)
Ethyl (methyl) propionate (9.52 g, 90%) was obtained. ^{mp 78-80 ℃ IRνmax KBr cm -1:} 1726, 1630, 1618. 1 H-NMR (CDCl 3) δ: 0.98 (3H, t, J = 7.4 Hz), 2.72-
2.82 (1H, m), 2.90-3.20 (2H, m), 3.58 (1H, d, J =
2.6 Hz), 3.97 (2H, q, J = 7.4 Hz), 5.21 (1H, s), 7.
16 (2H, d, J = 8.0 Hz), 7.40-7.70 (4H, m), 8.59 (2
H, d, J = 6.2 Hz). 4) Ethyl (2RS, 3RS) -3-hydroxy-3- (4-pyridyl) -2-((4- (trifluoromethyl) phenyl) methyl) propionate (9 .36 g, 26.
To a solution of 5 mmol) in methanol (40 ml) was added a 2N aqueous sodium hydroxide solution (26 ml, 52 mmol), and the mixture was stirred at room temperature overnight. After the reaction solution was acidified with 1N hydrochloric acid, the pH was adjusted to 6 by adding saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. (2RS, 3RS) -3-hydroxy-3- (4-
Pyridyl) -2-((4- (trifluoromethyl) phenyl) methyl) propionic acid (7.8 g, 90%) was obtained. ^{IRνmax KBr cm -1: 1725. 1 H} -NMR (CD 3 OD) δ: 3.10-3.24 (3H, m), 5.26 (1H, d,
J = 4.8 Hz), 7.34 (2H, d, J = 8.0 Hz), 7.49 (2H, d,
J = 8.0 Hz), 8.07 (2H, d, J = 6.6 Hz), 8.73 (2H,
d, J = 6.6 Hz). 5) (2RS, 3RS) -3-hydroxy-3- (4-pyridyl) -2-((4- (trifluoromethyl) phenyl) methyl) propionic acid (7.8 g, To a solution of 24.0 mmol) in tetrahydrofuran (100 ml) was added diphenylphosphoryl azide (4.6 ml, 21.3 mmol) and triethylamine (6.76 ml, 48.4 mmol), and the mixture was heated under reflux overnight. After allowing the reaction solution to cool, water (200 ml) was added, and ethyl acetate (200 ml × 2) was added.
Extracted. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
1: 1) and recrystallized from diisopropyl ether-hexane to give (4RS, 5SR) -5- (4-pyridyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3- Oxazolidin-2-one (2.50 g,
58%). mp 212-213 ℃ IRνmax ^KBr cm ^-1 : 1755, 1609. Anal.Calcd for C ₁₆ H ₁₃ F ₃ N ₂ O ₂ : C, 59.63; H, 4.07;
N, 8.69 Found:. C, 59.71; H, 3.99; N, 8.56 1 H-NMR (CDCl 3) δ: 2.20-2.48 (2H, m), 4.26-4.38 (1
H, m), 5.33 (1H, brs), 5.80 (1H, d, J = 8.2 Hz), 7.
16 (2H, d, J = 8.0 Hz), 7.33 (2H, d, J = 6.0 Hz),
7.56 (2H, d, J = 8.0 Hz), 7.68 (2H, d, J = 6.0 H
z). 6) (4RS, 5SR) -5- (4-pyridyl) -4-
((4- (trifluoromethyl) phenyl) methyl)-
1,3-oxazolidine-2-one (500 mg, 1.5
To a solution of 5 mmol) in acetonitrile (5 ml) were added di-t-butyl dicarbonate (406 mg, 1.86 mmol) and dimethylaminopyridine (19.6 mg, 0.16 mmol), and the mixture was stirred at room temperature for 1 hour. Water (2
0 ml) and extracted with ethyl acetate (20 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (4RS, 5SR) -2-oxo-5-.
There was obtained 1,1-dimethylethyl (571 mg, 87%) of (4-pyridyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidine-3-carboxylate. mp 166-168 ° C IRνmax ^KBr cm ^-1 : 1821, 1726. Anal.Calcd for C ₂₁ H ₂₁ F ₃ N ₂ O ₄ : C, 59.71; H, 5.01;
N, 6.63 Found:. C, 59.65; H, 5.05; N, 6.34 1 H-NMR (CDCl 3) δ: 1.48 (9H, s), 2.61 (1H, dd, J =
14.2, 8.0 Hz), 2.91 (1H, dd, J = 14.2, 5.4 Hz), 4.
80-4.98 (1H, m), 5.67 (1H, d, J = 7.0 Hz), 6.84 (2
H, d, J = 8.0 Hz), 7.13 (2H, d, J = 6.0 Hz), 7.37
(2H, d, J = 8.0 Hz), 8.54 (2H, d, J = 6.0 Hz). 7) (4RS, 5SR) -2-oxo-5- (4-pyridyl) -4-((4- ( Trifluoromethyl) phenyl) methyl) -1,3-oxazolidine-3-carboxylic acid 1,1-
A methanol solution (2.8 ml, 1.40 mmol) of 0.5N sodium hydroxide was added to methanol (2.8 ml) of dimethylethyl (500 mg, 1.18 mmol), and the mixture was stirred at room temperature for 1 hour. Water (20 ml) was added to the reaction solution, and extracted with ethyl acetate (20 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (391 mg, 83%). ^{mp 198-200 ℃ IRνmax KBr cm -1:} 1682, 1605, 1528. 1 H-NMR (CDCl 3) δ: 1.35 (9H, s), 2.72-2.82 (2H, m),
3.61 (1H, brs), 4.11 (1H, brs), 4.65 (1H, d, J =
8.6 Hz), 4.99 (1H, s), 7.20 (2H, d, J = 8.0Hz), 7.
36 (2H, d, J = 6.0 Hz), 7.51 (2H, d, J = 8.0 Hz),
8.61 (2H, d, J = 6.0 Hz).

Example 200 4-Fluoro-N-((1S, 2R) -2-hydroxy-2-
(4-pyridyl) -1-((4- (trifluoromethyl) phenyl
Enyl) methyl) ethyl) -1-naphthalenecarboxami
1) 1,1-dimethylethyl (1RS, 2SR) -2-
Hydroxy-2- (4-pyridyl) -1-((4- (trifur
Oromethyl) phenyl) methyl) ethyl carbamate
(300 mg, 0.76 mmol) in trifluoroacetic acid
(3 ml) was added and stirred at room temperature for 10 minutes. 1 in the reaction solution
N sodium hydroxide aqueous solution (10 ml) was added, and
Extracted with chill (20 ml × 2). Extracts were washed with saturated saline
, Dried over anhydrous magnesium sulfate and evaporated under reduced pressure.
Was. The residue was purified from ethyl acetate-diisopropyl ether.
After recrystallization, (1RS, 2SR) -2-amino-1- (4-
Pyridyl) -3- (4- (trifluoromethyl) phenyl
L) -1-Propanol (135 mg, 60%) was obtained. mp 97-98 ℃ IRνmax ^KBr cm ^-1 : 1603, 1418. ¹ H-NMR (CDCl _Three ) δ: 2.43 (1H, dd, J = 13.6, 10.6 H
z), 2.71 (1H, dd, J = 13.6, 2.8 Hz), 3.30-3.42 (1
H, m), 4.74 (1H, d, J = 4.4 Hz), 7.23 (2H, d, J =
8.2 Hz), 7.35 (2H, d, J = 6.0 Hz), 7.55 (2H, d, J
= 8.2 Hz), 8.62 (2H, d, J = 6.0 Hz). 2) (1RS, 2SR) -2-amino-1- (4-pyridyl)
) -3- (4- (trifluoromethyl) phenyl) -1-
Acetal of propanol (70 mg, 0.24 mmol)
4-Fluoronaphthalene carb in nitrile (5ml) solution
Boric acid (45 mg, 0.24 mmol) and 1-ethyl
3- (3-dimethylaminopropyl) carbodiimide
Hydrochloride (68 mg, 0.35 mmol) and 1-
Droxy-1H-benzotriazole (36 mg, 0.2
4 mmol) and stirred overnight at room temperature. Water
(100 ml) and diluted with ethyl acetate (100 ml ×
Extracted in 2). Extract solution is 1N hydrochloric acid, 1N hydroxide
Wash sequentially with aqueous thorium solution and saturated saline,
After drying with gnesium, it was distilled off under reduced pressure. Silica gel residue
Purified by column chromatography (ethyl acetate)
Recrystallized from ethyl acid-diisopropyl ether,
The title compound (55 mg, 50%) was obtained. mp 239-243 ℃ IRνmax ^KBr cm ^-1 : 1638, 1620, 1603. ¹ H-NMR (CDCl _Three + CD _Three OD) δ: 2.80-3.00 (2H, m), 4.70-4.
92 (1H, m), 5.05 (1H, brs), 7.00-7.60 (13H, m), 8.0
7 (1H, d, J = 8.4 Hz), 8.50-8.62 (2H, m).

Example 201 1,1-Dimethylethyl (1RS, 2SR) -2- (6-chloro-3-pyridyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl Carbamate 1) 6-chloro-3-pyridinecarboxylic acid (10 g, 6
3.5 mmol) of tetrahydrofuran (150 ml)
Add 1,1'-carbonylbis-1H-imidazole (1
(1.3 g, 69.8 mmol) and heated under reflux for 30 minutes. After cooling the reaction solution, monoethyl magnesium malonate (10 g, 34.9 mmol) was added, and the mixture was added at room temperature for 30 minutes.
Minutes. Water (200 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 ml × 2). The extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and ethyl 3- (6-chloro-3-pyridyl) -3-oxopropionate (9.
(28 g, 64%) as a brown oil. ^{IRνmax KBr cm -1: 1740, 1694} , 1628, 1584. 1 H-NMR (CDCl 3) δ: 1.16 (3H × 3/5, t, J = 7.4 Hz),
1.24 (3H × 2/5, t, J = 7.0 Hz), 3.88 (2H × 3/5, s),
4.04-4.24 (2H, m), 5.58 (1H × 2/5, s), 7.29 (1H × 2 /
5, d, J = 8.0 Hz), 7.37 (1H × 3/5, d, J = 8.0 Hz),
7.90 (1H × 2/5, dd, J = 8.0, 2.6 Hz), 8.11 (1H × 3 /
5, dd, J = 8.0, 2.6 Hz), 8.66 (1H × 2/5, d, J = 2.6
Hz), 8.81 (1H × 3/5, d, J = 2.6 Hz). 2) Ethyl 3- (6-chloro-3-pyridyl) -3-oxopropionate (9.0 g, 39.5 mmol) 1,2
Sodium hydride (60% oil, 1.58 g, 39.5 mmol) was added to a solution of -dimethoxyethane (50 ml) under ice cooling, and the mixture was stirred at room temperature for 2 hours. 4-trifluoromethylbenzyl bromide (9.45 g, 3
9.5 mmol) of 1,2-dimethoxyethane (50 m
l) The solution was added dropwise and the reaction was stirred at room temperature overnight. The reaction solution was poured into water (200 ml), and a saturated aqueous solution of sodium bicarbonate was added.
Extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene: ethyl acetate = 1: 1) to give 3- (6-chloro-3-pyridyl) -3-oxo-2-((4-
Ethyl (trifluoromethyl) phenyl) methyl) propionate (14.2 g, 93%) was obtained as a colorless oil. IRνmax ^KBr cm ^-1 : 1740, 1694, 1582. ¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7.0 Hz), 3.40
(2H, d, J = 7.4 Hz), 4.12 (2H, q, J = 7.0 Hz), 4.5
4 (1H, t, J = 7.4 Hz), 7.35 (2H, d, J = 8.4 Hz),
7.44 (1H, d, J = 7.0 Hz), 7.53 (2H, d, J = 8.4 H
z), 8.16-8.24 (1H, m), 8.95 (1H, d, J = 2.6 Hz). 3) Sodium borohydride was added to a solution of zinc chloride (9.89 g, 72.6 mmol) in diethyl ether (150 ml). (5.49 g, 145 mmol) and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was treated with ethyl 3- (6-chloro-3-pyridyl) -3-oxo-2-((4- (trifluoromethyl) phenyl) methyl) propionate (1).
4 g, 36.3 mmol) of diethyl ether (50 m
l) The solution was added and stirred at room temperature for 30 minutes. Under ice-cooling, the reaction solution was quenched by adding 1N hydrochloric acid, and further added with water (200 m 2).
1) and extracted with ethyl acetate (300 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give (2RS, 3RS) -3- (6-chloro-3-pyridyl) -3-hydroxy-2-((4 Ethyl-(trifluoromethyl) phenyl) methyl) propionate (9.32 g, 66%) was obtained as a colorless oil. ^{IRνmax KBr cm -1: 1728, 1618} , 1588, 1568. 1 H-NMR (CDCl 3) δ: 0.95 (3H, t, J = 7.0 Hz), 2.92-
3.18 (3H, m), 3.35 (1H, d, J = 2.4 Hz), 3.92 (2H,
q, J = 7.0 Hz), 5.04-5.12 (1H, m), 7.20 (2H, d, J =
8.2 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.50 (2H, d, J
= 8.2 Hz), 7.73 (1H, dd, J = 8.8, 2.8 Hz), 8.38 (1
H, d, J = 8.4 Hz). 4) (2RS, 3RS) -3- (6-chloro-3-pyridyl) -3-hydroxy-2-((4- (trifluoromethyl) phenyl) methyl) propion Ethyl acid (9.0
g, 23.2 mmol) in methanol (23 ml).
6.4 mmol) and stirred at room temperature overnight. After the reaction solution was acidified with 1N hydrochloric acid, the pH was adjusted to 8 by adding saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane (2RS, 3
RS) -3- (6-Chloro-3-pyridyl) -3-hydroxy-
2-((4- (trifluoromethyl) phenyl) methyl)
Propionic acid (7.4 g, 89%) was obtained. mp 145-146 ° C IRνmax ^KBr cm ^-1 : 1715, 1591, 1464. Anal.Calcd for C ₁₆ H ₁₃ NO ₃ ClF ₃ : C, 53.42; H, 3.64;
N, 3.89 Found:. C, 53.48; H, 3.93; N, 3.66 1 H-NMR (CDCl 3) δ: 2.90-3.20 (3H, m), 5.11 (1H, d,
J = 4.4 Hz), 7.24 (2H, d, J = 8.4 Hz), 7.33 (1H, d,
J = 8.2 Hz), 7.49 (2H, d, J = 8.4 Hz), 7.78 (1H,
dd, J = 8.2, 2.2 Hz), 8.35 (1H, d, J = 2.2 Hz). 5) (2RS, 3RS) -3- (6-chloro-3-pyridyl) -3-hydroxy-2-(( 4- (trifluoromethyl) phenyl) methyl) propionic acid (5.0 g, 1
3.9 mmol) in tetrahydrofuran (150 ml)
To the solution was added diphenylphosphoryl azide (3.3 ml, 1
5.3 mmol) and triethylamine (2.9 ml, 2
(0.9 mmol) and heated to reflux for 1 hour. After allowing the reaction solution to cool, water (200 ml) was added, and ethyl acetate (20 ml) was added.
0 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate).
Recrystallized from hexane to give (4RS, 5SR) -5- (6
-Chloro-3-pyridyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidin-2-one (4.29 g, 87%) was obtained. ^{. mp 176-177 ℃ IRνmax KBr cm -1} : 1767, 1590, 1568. Anal Calcd for C 16 H 12 N 2 O 2 ClF 3: C, 53.87; H, 3.39;
N, 7.85 Found:. C, 53.86; H, 3.57; N, 7.66 1 H-NMR (CDCl 3) δ: 2.22-2.50 (2H, m), 4.26-4.40 (1
H, m), 5.16 (1H, brs), 5.84 (1H, d, J = 8.0 Hz), 7.
16 (2H, d, J = 8.0 Hz), 7.43 (1H, d, J = 8.2 Hz),
7.57 (2H, d, J = 8.0 Hz), 7.73 (1H, dd, J = 8.2,
2.6 Hz), 8.41 (1H, d, J = 2.6 Hz). 6) (4RS, 5SR) -5- (6-chloro-3-pyridyl) -4-((4- (trifluoromethyl) phenyl) methyl ) -1,3-Oxazolidin-2-one (500 mg,
To a solution of 1.40 mmol) in acetonitrile (5 ml) was added di-t-butyl dicarbonate (367 mg, 1.68 mmol).
And dimethylaminopyridine (17 mg, 0.14 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated, it was diluted with water (20 ml), and ethyl acetate (20 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (4RS, 5SR)-
5- (6-chloro-3-pyridyl) -2-oxo-4-((4-
There was obtained 1,1-dimethylethyl (trifluoromethyl) phenyl) methyl) -1,3-oxazolidine-3-carboxylate (1.19 g, 93%). mp 170-174 ℃ IRνmax ^KBr cm ^-1 : 1821, 1723, 1464, 1362. Anal.Calcd for C ₂₁ H ₂₀ N ₂ O ₄ ClF ₃ : C, 55.21; H, 4.41;
N, 6.13 Found:. C, 55.44; H, 4.28; N, 6.22 1 H-NMR (CDCl 3) δ: 1.49 (9H, s), 2.60 (1H, dd, J =
14.2, 8.8 Hz), 3.01 (1H, dd, J = 14.2, 5.2 Hz), 4.
82-4.96 (1H, m), 5.70 (1H, d, J = 7.0 Hz), 6.85 (2
H, d, J = 8.0 Hz), 7.18 (1H, d, J = 8.4 Hz), 7.36-
7.46 (3H, m), 8.27 (1H, d, J = 2.2 Hz). 7) (4RS, 5SR) -5- (6-chloro-3-pyridyl) -2-oxo-4-((4- ( 0.5N sodium hydroxide in methanol (3.1 ml) of 1,1-dimethylethyl (trifluoromethyl) phenyl) methyl) -1,3-oxazolidine-3-carboxylate (600 mg, 1.31 mmol) (3.1 ml, 1.55 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water (50 ml) was added to the reaction solution, and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was ethyl acetate-
Recrystallization from hexane gave the title compound (321 mg, 5
7%). ^{mp 157-158 ℃ IRνmax KBr cm -1:} 1682, 1618, 1588, 1522. 1 H-NMR (CDCl 3) δ: 1.34 (9H, s), 2.70-2.90 (2H, m),
3.85 (1H, brs), 4.09 (1H, brs), 4.62 (1H, d, J =
8.8 Hz), 4.96 (1H, s), 7.24 (2H, d, J = 8.0Hz), 7.
35 (1H, d, J = 8.0 Hz), 7.53 (2H, d, J = 8.0 Hz),
7.73 (1H, dd, J = 8.0, 2.6 Hz), 8.4 (1H, d, J = 2.6
Hz).

Example 202 N-((1RS, 2SR) -2- (6-chloro-3-pyridyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4 -Fluoro-1-naphthalenecarboxamide 1) 1,1-dimethylethyl (1RS, 2SR) -2-
(6-chloro-3-pyridyl) -2-hydroxy-1-((4-
To (trifluoromethyl) phenyl) methyl) ethyl carbamate (880 mg, 2.04 mmol) was added trifluoroacetic acid (8 ml) at 0 ° C., and the mixture was stirred for 10 minutes. After concentration, the reaction solution was diluted with water (20 ml) and extracted with ethyl acetate (20 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give (1RS, 2SR) -2-amino-1- (6-chloro-
There was obtained 3-pyridyl) -3- (4- (trifluoromethyl) phenyl) -1-propanol (602 mg, 89%). mp 103-104 ° C IRνmax ^KBr cm ^-1 : 1588, 1568, 1460. Anal.Calcd for C ₁₅ H ₁₄ N ₂ OClF ₃ : C, 54.47; H, 4.27;
N, 8.47 Found:. C, 54.57; H, 4.19; N, 8.39 1 H-NMR (CDCl 3) δ: 2.42 (1H, dd, J = 13.6, 10.4 H
z), 2.76 (1H, dd, J = 13.6, 3.0 Hz), 3.30-3.44 (1
H, m), 4.76 (1H, d, J = 4.4 Hz), 7.24 (2H, d, J =
8.4 Hz), 7.36 (1H, d, J = 8.4 Hz), 7.55 (2H, d, J
= 8.4 Hz), 7.75 (1H, dd, J = 8.4, 2.2 Hz). 2) (1RS, 2SR) -2-amino-1- (6-chloro-
4-Fluoronaphthalenecarboxylic acid (144 mg, 0.76 mmol) in a solution of 3-pyridyl) -3- (4- (trifluoromethyl) phenyl) -1-propanol (250 mg, 0.76 mmol) in acetonitrile (15 ml) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (218 mg, 1.14 mmol) and 1-hydroxy-1H-benzotriazole (116 mg, 0.76 mmol) were added, and the mixture was stirred at room temperature overnight. did. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (324 mg, 85%). mp 188-189 ℃ IRνmax ^KBr cm ^-1 : 1642, 1626, 1601, 1534, 1462. Anal.Calcd for C ₂₆ H ₁₉ N ₂ O ₂ ClF ₄・ 0.2H ₂ O: C, 61.66;
H, 3.86; N, 5.53 Found :. C, 61.56; H, 3.91; N, 5.37 1 H-NMR (CDCl 3) δ: 2.89 (1H, dd, J = 14.6, 11.0 H
z), 3.08 (1H, dd, J = 14.6, 4.4 Hz), 4.04 (1H, br
s), 4.68-4.84 (1H, m), 5.13 (1H, d, J = 3.6 Hz),
6.04 (1H, d, J = 8.4 Hz), 6.92-7.20 (2H, m), 7.22-
7.70 (8H, m), 7.82 (1H, dd, J = 8.0, 2.6 Hz), 8.09
(1H, d, J = 8.0 Hz), 8.44 (1H, d, J = 2.6 Hz).

Example 203 N-((1RS, 2SR) -2- (6-chloro-3-pyridyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -3 -Phenylpropanamide (1RS, 2SR) -2-amino-1- (6-chloro-3-pyridyl) -3- (4- (trifluoromethyl) phenyl)-
To a solution of 1-propanol (250 mg, 0.76 mmol) in ethyl acetate (10 ml) was added 3-phenylpropionyl chloride (168 ml, 1.13 mmol) and saturated aqueous sodium hydrogen carbonate (10 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
ml × 2). Wash the extract with saturated saline,
After drying over anhydrous magnesium sulfate, the solution was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (3
02 mg, 86%). mp 149-150 ° C IRνmax ^KBr cm ^-1 : 1651, 1541, 1456. Anal.Calcd for C ₂₄ H ₂₂ N ₂ O ₂ ClF ₃ : C, 62.27; H, 4.79;
N, 6.05 Found:. C, 62.44; H, 4.96; N, 6.05 1 H-NMR (CDCl 3) δ: 2.30-2.50 (2H, m), 2.60-2.92 (4
H, m), 3.90 (1H, s), 4.24-4.40 (1H, m), 4.80-4.90
(1H, m), 5.36 (1H, d, J = 8.2 Hz), 7.00-7.40 (8H,
m), 7.48 (2H, d, J = 8.0 Hz), 7.56 (1H, dd, J = 8.
0, 2.6 Hz), 8.32 (1H, d, J = 2.2 Hz).

Example 204 1,1-Dimethylethyl (1RS, 2RS) -2- (6-chloro-2-pyridyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl Carbamate 1) 6-chloro-2-pyridinecarboxylic acid (10 g, 6
3.5 mmol) of tetrahydrofuran (150 ml)
Add 1,1'-carbonylbis-1H-imidazole (1
(1.3 g, 69.8 mmol) and heated under reflux for 30 minutes. After cooling the reaction solution, monoethyl magnesium malonate (10 g, 34.9 mmol) was added, and the mixture was added at room temperature for 30 minutes.
Minutes. Water (200 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 ml × 2). The extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and ethyl 3- (6-chloro-2-pyridyl) -3-oxopropionate (7.
96 g, 55%) as a brown oil. IRνmax ^KBr cm ^-1 : 1738, 1713, 1651, 1645. Anal.Calcd for C ₁₀ H ₁₀ NO ₃ Cl: C, 52.76; H, 4.43; N,
6.15 Found:. C, 52.63; H, 4.55; N, 6.02 1 H-NMR (CDCl 3) δ: 1.20-1.40 (3H, m), 4.15 (2H × 2 /
3, s), 4.14-4.32 (2H, m), 6.35 (1H × 1/3, s), 7.37
(1H × 1/3, d, J = 6.6 Hz), 7.53 (1H × 2/3, d, J = 7.0
Hz), 7.70-8.02 (2H, m), 12.31 (1H × 1/3, s). 2) Ethyl 3- (6-chloro-2-pyridyl) -3-oxopropionate (7.6 g, 33.3 g). 4 mmol) 1,2
Sodium hydride (60% oily, 1.34 g, 33.4 mmol) was added to a solution of -dimethoxyethane (50 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. 4-trifluoromethylbenzyl bromide (7.98 g, 3
3.4 mmol) of 1,2-dimethoxyethane (50 m
l) The solution was added dropwise and the reaction was stirred at room temperature overnight. The reaction solution was poured into water (200 ml), and a saturated aqueous solution of sodium bicarbonate was added.
Extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene), and ethyl 3- (6-chloro-2-pyridyl) -3-oxo-2-((4- (trifluoromethyl) phenyl) methyl) propionate (13. 0
g, 100%) as a colorless oil. ^{IRνmax KBr cm -1: 1732, 1709} , 1576, 1563. 1 H-NMR (CDCl 3) δ: 1.14 (3H, t, J = 7.0 Hz), 3.24-
3.50 (2H, m), 4.02-4.20 (2H, m), 4.99 (1H, t, J =
7.2 Hz), 7.42 (2H, d, J = 8.0 Hz), 7.52 (2H, d, J =
8.0 Hz), 7.81 (1H, t, J = 8.0 Hz), 7.97 (1H, d, J
= 6.6 Hz). 3) To a solution of zinc chloride (9.0 g, 66.15 mmol) in diethyl ether (200 ml) was added sodium borohydride (5.0 g, 132 mmol), and the solution was added at room temperature for 3 hours.
Stirred for 0 minutes. The insoluble material was removed by filtration to prepare a zinc borohydride solution in diethyl ether. Ethyl 3- (6-chloro-2-pyridyl) -3-oxo-2-((4- (trifluoromethyl) phenyl) methyl) propionate (12.7
g, 33.1 mmol) in diethyl ether (100 m
l) The solution of zinc borohydride in diethyl ether previously prepared was slowly added dropwise to the solution at -20 ° C. After stirring the reaction solution at −20 ° C. for 30 minutes, the reaction solution was quenched by adding 1N hydrochloric acid, further added with water (200 ml), and extracted with ethyl acetate (300 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 3-
(6-chloro-2-pyridyl) -3-hydroxy-2-((4-
Ethyl (trifluoromethyl) phenyl) methyl) propionate (4.1 g, 32%, (2RS, 3RS) form:
(2RS, 3SR) form = 1: 1, crude) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.95-1.10 (3H, m), 2.80-3.40 (3
H, m), 3.82-4.08 (2H, m), 4.78 (1H × 1/2, dd, J =
9.6, 4.4 Hz), 5.08 (1H × 1/2, t, J = 5.0 Hz), 7.10-
7.70 (7H, m). 4) 3- (6-Chloro-2-pyridyl) -3-hydroxy-
2-((4- (trifluoromethyl) phenyl) methyl)
To a solution of ethyl propionate (4.1 g, 10.7 mmol) in methanol (20 ml) was added a 2N aqueous sodium hydroxide solution (10.7 ml, 21.4 mmol), and the mixture was stirred at room temperature overnight. After the reaction solution was acidified with 1N hydrochloric acid, the pH was adjusted to 8 by adding saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give 3- (6-chloro-2-pyridyl) -3-hydroxy-2-((4- (trifluoromethyl) phenyl)
Methyl) propionic acid (3.3 g, 86%, (2RS,
3RS) form: (2RS, 3SR) form = 1: 1) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.20-2.60 (1H, m), 2.80-3.30 (2
H, m), 4.73 (1H × 1/2, d, J = 7.4 Hz), 5.30 (1H × 1 /
2, s), 6.64-7.40 (7H, m). 5) 3- (6-Chloro-2-pyridyl) -3-hydroxy-
2-((4- (trifluoromethyl) phenyl) methyl)
To a solution of propionic acid (3.1 g, 8.6 mmol) in tetrahydrofuran (100 ml) were added diphenylphosphoryl azide (2.0 ml, 9.5 mmol) and triethylamine (1.8 ml, 12.9 mmol) for 1 hour. Heated to reflux. After allowing the reaction solution to cool, water (150 ml) was added, and the mixture was extracted with ethyl acetate (150 ml × 2). The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give 5- (6-chloro-2-pyridyl) -4-((4- (trifluoromethyl)
Phenyl) methyl) -1,3-oxazolidin-2-one (1.18 g, 38%, (4RS, 5RS) form: (4R
(S, 5SR) form = 3: 2) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.18 (1H × 3/5, dd, J = 13.4, 7.0
Hz), 2.62 (1H × 3/5, dd, J = 13.4, 3.8 Hz), 3.05
(1H × 2/5, dd, J = 13.4, 9.2 Hz), 3.36 (1H × 2/5, d
d, J = 13.4, 4.4 Hz), 4.16-4.30 (1H × 2/5, m), 4.40
-4.56 (1H × 3/5, m), 5.19 (1H × 3/5, s), 5.29 (1H × 2
/ 5, d, J = 5.0 Hz), 5.37 (1H × 2/5, s), 5.83 (1H × 3
/ 5, d, J = 8.0 Hz), 7.10-7.82 (7H, m). 6) 5- (6-Chloro-2-pyridyl) -4-((4- (trifluoromethyl) phenyl) methyl)- 1,3-oxazolidine-2-one (1.08 g, 1.40 mmol,
(4RS, 5RS) body: (4RS, 5SR) body = 3:
2) Di-t-dicarbonate was added to acetonitrile (10 ml) solution.
Butyl (793 mg, 3.63 mmol) and dimethylaminopyridine (37 mg, 0.30 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction solution, water (20
ml) and extracted with ethyl acetate (20 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluting with hexane: ethyl acetate = 4: 1, and recrystallized from diisopropyl ether-hexane to give (4RS, 5SR) -5- (6-chloro-2-pyridyl) -2-. There was obtained 1,1-dimethylethyl oxo-4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidine-3-carboxylate (300 mg, 22%). IRνmax ^KBr cm ^-1 : 1817, 1726, 1566.mp 125-126 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.55 (9H, s), 3.24 (1H, dd, J =
13.6, 8.0 Hz), 3.44 (1H, dd, J = 13.6, 4.4 Hz), 4.
76-4.86 (1H, m), 5.13 (1H, d, J = 2.6 Hz), 7.22-7.
32 (2H, m), 7.40 (2H, d, J = 8.0 Hz), 7.62 (2H, d,
J = 8.0 Hz), 7.66 (1H, t, J = 7.8 Hz). Further elute with hexane: ethyl acetate = 1: 1 and recrystallize from ethyl acetate-hexane (4RS, 5RS).
-5- (6-chloro-2-pyridyl) -2-oxo-4-((4-
There was obtained (1-dimethylethyl (trifluoromethyl) phenyl) methyl) -1,3-oxazolidine-3-carboxylate (735 mg, 53%). IRνmax ^KBr cm ^-1 : 1823, 1726, 1566.mp 166-167 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.65 (1H, dd, J =
14.0, 8.0 Hz), 2.89 (1H, dd, J = 14.0, 5.4 Hz), 5.
02-5.16 (1H, m), 5.66 (1H, d, J = 6.6 Hz), 6.88 (2
H, d, J = 8.2 Hz), 7.26 (1H, d, J = 8.2 Hz), 7.40
(2H, d, J = 8.0Hz), 7.50 (1H, d, J = 7.6Hz), 7.73
(1H, t, J = 7.8 Hz). 7) (4RS, 5RS) -5- (6-chloro-2-pyridyl) -2-oxo-4-((4- (trifluoromethyl) phenyl) methyl) 0.5N sodium hydroxide methanol solution (3.5 ml, 1.75) in methanol (3.5 ml) of 1,1-dimethylethyl-1,3-oxazolidine-3-carboxylate (677 mg, 1.46 mmol) (Mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water (50 ml) was added to the reaction solution, and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from diisopropyl ether-hexane to give the title compound (550 mg, 57%). IRνmax ^KBr cm ^-1 : 1682, 1530.mp 159-160 ℃ ¹ H-NMR (CDCl ₃ ) δ: 1.36 (9H, s), 2.67 (1H, dd, J =
15.0, 5.8 Hz), 2.87 (1H, dd, J = 15.0, 8.4 Hz), 4.
12-4.30 (1H, m), 4.60 (1H, d, J = 5.6 Hz), 4.90-5.
10 (2H, m), 7.19 (2H, d, J = 7.8 Hz), 7.20-7.32 (2
H, m), 7.45 (2H, d, J = 7.8 Hz), 7.61 (1H, t, J =
8.0 Hz).

Example 205 N-((1RS, 2RS) -2- (6-chloro-2-pyridyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -4 -Fluoro-1-naphthalenecarboxamide 1) 1,1-dimethylethyl (1RS, 2RS) -2-
(6-chloro-2-pyridyl) -2-hydroxy-1-((4-
To (trifluoromethyl) phenyl) methyl) ethyl carbamate (500 mg, 1.16 mmol) was added trifluoroacetic acid (8 ml) at 0 ° C., and the mixture was stirred for 10 minutes. After concentration, the reaction solution was diluted with water (20 ml) and extracted with ethyl acetate (20 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (1RS, 2RS) -2-amino-1- (6-chloro-2-
-Pyridyl) -3- (4- (trifluoromethyl) phenyl) -1-propanol (302 mg, 79%) was obtained. IRνmax ^KBr cm ^-1 : 1757, 1586, 1563.mp 89-90 ℃ ¹ H-NMR (CDCl ₃ ) δ: 2.54 (1H, dd, J = 13.6, 9.8 Hz),
2.77 (1H, d, J = 13.0Hz), 3.44-3.58 (1H, m), 4.74
(1H, d, J = 4.4 Hz), 7.16-7.32 (3H, m), 7.57 (1H,
d, J = 7.4 Hz), 7.52 (2H, d, J = 7.4 Hz), 7.62-7.
74 (1H, m). 2) (1RS, 2RS) -2-amino-1- (6-chloro-
4-Fluoronaphthalenecarboxylic acid (144 mg, 0.76 mmol) in a solution of 2-pyridyl) -3- (4- (trifluoromethyl) phenyl) -1-propanol (250 mg, 0.76 mmol) in acetonitrile (15 ml) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (218 mg, 1.14 mmol) and 1-hydroxy-1H-benzotriazole (116 mg, 0.76 mmol) were added, and the mixture was stirred at room temperature overnight. did. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give the title compound (2
67 mg, 70%). ^{mp 225-226 ℃ IRνmax KBr cm -1:} 1639, 1624. 1 H-NMR (CDCl 3) δ: 2.83 (1H, dd, J = 14.0, 5.2 Hz),
3.02 (1H, dd, J = 14.0, 9.6 Hz), 4.74 (1H, d, J =
5.6 Hz), 4.80-5.00 (1H, m), 5.10-5.20 (1H, m), 6.4
6 (1H, d, J = 8.6 Hz), 7.00-7.12 (1H, m), 7.20-7.6
0 (9H, m), 7.64-7.76 (1H, m), 7.84 (1H, d, J = 7.6
Hz), 8.11 (1H, d, J = 8.0 Hz).

Example 206 1,1-Dimethylethyl (1RS, 2SR) -2- (6-chloro-2-pyridyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl Carbamate (4RS, 5SR) -5- (6-chloro-2-pyridyl) -2
-Oxo-4-((4- (trifluoromethyl) phenyl)
Methyl) -1,3-oxazolidine-3-carboxylic acid 1,1
To a solution of -dimethylethyl (237 mg, 0.52 mmol) in methanol (1.25 ml) was added a 0.5 N solution of sodium hydroxide in methanol (1.25 ml, 0.62 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. did. Water (50 ml) was added to the reaction solution, and extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was ethyl acetate-
Recrystallized from hexane to give the title compound (150 mg, 6
7%). IRνmax ^KBr cm ^-1 : 1694, 1505.mp 134-135 ℃ ¹ H-NMR (CDCl ₃ ) δ: 1.24 (9H, s), 3.13 (2H, d, J =
(7.8 Hz), 4.10-4.30 (1H, m), 4.62-4.90 (2H, m), 7.20
-7.30 (2H, m), 7.30-7.52 (2H, m), 7.56-7.72 (3H,
m).

Example 207 N-((1RS, 2SR) -2-hydroxy-2- (4-phenoxyphenyl) -1-((4- (trifluoromethyl)
Phenyl) methyl) ethyl) -4-fluoro-1-naphthalenecarboxamide 1) 3-phenoxybenzoic acid (13.5 g, 63.0)
1,1′-carbonylbis-1H-imidazole (11.2 mmol) in a solution of tetrahydrofuran (150 ml).
g, 69.3 mmol) and stirred at room temperature for 30 minutes. The reaction solution was mixed with monoethyl magnesium malonate (10
g, 34.8 mmol) and stirred at room temperature for 2 hours. Ethyl acetate (50 ml) and water (50 m
l) was added, and concentrated hydrochloric acid was further added until the pH of the aqueous layer became acidic. The reaction solution was extracted with ethyl acetate (200 ml × 2), the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give ethyl 3-oxo-3- (4-phenoxyphenyl) propionate (17.9 g, 100%) as a brown oil. Was. IRνmax ^KBr cm ^-1 : 1744, 1694, 1582, 1489, 1439.Anal.Calcd for C ₁₇ H ₁₆ O ₄・ 0.1H ₂ O: C, 71.37; H, 5.7
0 Found: C, 71.11; H, 5.89. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.40 (3H, m), 3.95 (2H × 4 /
5, s), 4.12-4.30 (2H, m), 5.62 (1H × 1/5, s), 7.02
(2H, d, J = 7.4 Hz), 7.04-7.30 (2H, m), 7.30-7.60
(4H, m), 7.66 (1H, d, J = 7.6 Hz). 2) 1,2-Ethyl 3-oxo-3- (4-phenoxyphenyl) propionate (15 g, 52.8 mmol)
Sodium hydride (60% oily, 2.11 g, 52.8 mmol) was added to a dimethoxyethane (100 ml) solution under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 4-trifluoromethylbenzyl bromide (12.6 g, 5
2.8 mmol) of 1,2-dimethoxyethane (50 m
l) The solution was added dropwise and the reaction was stirred at room temperature for 4 hours. The reaction solution was poured into water (200 ml), and ethyl acetate (20 ml) was added.
0 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 3
-Oxo-3- (4-phenoxyphenyl) -2-((4-
Ethyl (trifluoromethyl) phenyl) methyl) propionate (15.4 g, 66%) was obtained. mp 77-78 ℃ IRνmax ^KBr cm ^-1 : 1738, 1694, 1582, 1489, 1437. Anal.Calcd for C ₂₅ H ₂₁ F ₃ O ₄ : C, 67.87; H, 4.78 Found: C, 67.92; H, 4.89 _{^{. 1 H-NMR (CDCl 3}} ) δ: 1.10 (3H, t, J = 7.4 Hz), 3.35
(1H, d, J = 7.4 Hz), 4.09 (2H, q, J = 7.4 Hz), 4.5
3 (1H, t, J = 7.4 Hz), 6.94-7.04 (2H, m), 7.10-7.7
0 (11H, m). 3) To a solution of zinc chloride (7.39 g, 54.2 mmol) in diethyl ether (150 ml) was added sodium borohydride (4.11 g, 108.5 mmol) and the mixture was stirred at room temperature for 30 minutes. Stirred. The insolubles were removed by filtration, and the filtrate was treated with ethyl 3-oxo-3- (4-phenoxyphenyl) -2-((4- (trifluoromethyl) phenyl) methyl) propionate (10 g, 25.9 mmol). Diethyl ether (5
0 ml) solution and stirred at room temperature for 30 minutes. below freezing,
The reaction solution is quenched by adding 1N hydrochloric acid, and further added with water (20 mL).
0 ml) and extracted with ethyl acetate (300 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate),
Ethyl (2RS, 3RS) -3-hydroxy-3- (4-phenoxyphenyl) -2-((4- (trifluoromethyl) phenyl) methyl) propionate (12.0 g, 10
0%) as a colorless oil. IRνmax ^KBr cm ^-1 : 1728, 1713, 1584, 1487, 1447.Anal.Calcd for C ₂₅ H ₂₃ F ₃ O ₄ : C, 67.56; H, 5.22 Found: C, 67.46; H, 5.20 ¹ H-NMR ( CDCl ₃ ) δ: 0.94 (3H, t, J = 7.2 Hz), 2.90-
3.12 (4H, m), 3.90 (2H, q, J = 7.2 Hz), 4.98-5.08
(1H, m), 6.90-7.40 (11H, m), 7.48 (2H, d, J = 8.0 H
z). 4) Ethyl (2RS, 3RS) -3-hydroxy-3- (4-phenoxyphenyl) -2-((4- (trifluoromethyl) phenyl) methyl) propionate (11.8
g, 26.6 mmol) in methanol (40 ml) was added to a 2N aqueous sodium hydroxide solution (26.6 ml, 5 ml).
3.2 mmol) and stirred at room temperature for 4 hours. After the reaction solution was acidified with 1N hydrochloric acid, ethyl acetate (200 m
1 × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (2R
S, 3RS) -3-Hydroxy-3- (4-phenoxyphenyl) -2-((4- (trifluoromethyl) phenyl)
Methyl) propionic acid (9.0 g, 81%) was obtained. mp 128-129 ℃ IRνmax ^KBr cm ^-1 : 1713, 1586, 1489, 1447.Anal.Calcd for C ₂₃ H ₁₉ F ₃ O ₄ : C, 66.34; H, 4.60 Found: C, 66.41; H, 4.58. ¹ H-NMR (CDCl ₃ ) δ: 2.86-3.14 (3H, m), 5.10 (1H, s),
6.90-7.02 (3H, m), 7.02-7.22 (5H, m), 7.22-7.40
(3H, m), 7.47 (2H, d, J = 8.0 Hz). 5) (2RS, 3RS) -3-hydroxy-3- (4-phenoxyphenyl) -2-((4- (trifluoromethyl) Phenyl) methyl) propionic acid (7.0 g, 1
6.8 mmol) in tetrahydrofuran (180 ml)
To the solution was added diphenylphosphoryl azide (4.0 ml, 1 ml).
8.5 mmol) and triethylamine (3.5 ml, 2
(5.2 mmol) and heated to reflux for 6 hours. After allowing the reaction solution to cool, water (200 ml) was added, and ethyl acetate (20 ml) was added.
0 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and the residue was recrystallized from ethyl acetate-hexane (4RS, 5SR).
This gave -5- (4-phenoxyphenyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidin-2-one (6.40 g, 92%). mp 110-111 ° C IRνmax ^KBr cm ^-1 : 1759, 1617, 1586, 1489. Anal.Calcd for C ₂₃ H ₁₈ F ₃ NO ₃ : C, 66.82; H, 4.39; N,
3.39 Found:. C, 66.78; H, 4.25; N, 3.14 1 H-NMR (CDCl 3) δ: 2.30-2.50 (2H, m), 4.18-4.30 (1
H, m), 5.22 (1H, s), 5.77 (1H, d, J = 8.0 Hz), 6.9
6-7.04 (4H, m), 7.04-7.20 (4H, m), 7.30-7.44 (3H,
m), 7.55 (2H, d, J = 8.0 Hz). 6) (4RS, 5SR) -5- (4-phenoxyphenyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1, 3-Oxazolidin-2-one (6.0 g, 1
4.5 mmol) in ethanol (100 ml).
A normal aqueous sodium hydroxide solution (9.0 ml, 72 mmol) was added, and the mixture was heated under reflux for 4 hours. After the reaction solution was concentrated, it was diluted with water (300 ml), and ethyl acetate (300 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give (1RS, 2S
R) -2-Amino-1- (4-phenoxyphenyl) -3-
(4- (Trifluoromethyl) phenyl) -1-propanol (4.21 g, 75%) was obtained as a colorless oil.
A part was converted into a hydrochloride and recrystallized from ethanol-ether, and the elemental analysis value was measured. IRνmax ^KBr cm ^-1 : 1584, 1489, 1443, 1418. Anal.Calcd for C ₂₂ H ₂₁ ClF ₃ NO ₂・ 0.2H ₂ O: C, 61.82;
H, 5.04; N, 3.28 Found :. C, 61.83; H, 5.26; N, 3.24 1 H-NMR (CDCl 3) δ: 2.44 (1H, dd, J = 14.2, 10.2 H
z), 2.86 (1H, dd, J = 14.0, 2.8 Hz), 3.20-3.36 (1
H, m), 4.64 (1H, d, J = 4.8 Hz), 6.90-7.20 (6H, m),
7.20-7.42 (5H, m), 7.53 (2H, d, J = 8.0 Hz). 7) (1RS, 2SR) -2-amino-1- (4-phenoxyphenyl) -3- (4- (trifluoro Methyl) phenyl) -1-propanol (400 mg, 1.03 mmol) in acetonitrile (30 ml) solution of 4-fluoronaphthalenecarboxylic acid (196 mg, 1.03 mmol) and 1-ethyl-3- (3-dimethylaminopropyl ) Carbodiimide hydrochloride (247 mg, 1.55 mmol) and 1-hydroxy-1H-benzotriazole (158 mg, 1.03 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane,
The title compound (446 mg, 77%) was obtained. ^{. mp 184-185 ℃ IRνmax KBr cm -1} : 1642, 1537, 1489. Anal Calcd for C 33 H 25 F 4 NO 3: C, 70.83; H, 4.50; N,
2.50 Found:. C, 70.65; H, 4.56; N, 2.44 1 H-NMR (CDCl 3) δ: 2.88 (1H, dd, J = 14.4, 10.6 H
z), 3.08 (1H, dd, J = 14.4, 4.0 Hz), 4.76-4.94 (1
H, m), 5.09 (1H, s), 6.04 (1H, d, J = 8.8 Hz), 6.95
-7.50 (14H, m), 7.50-7.60 (3H, m), 7.66 (1H, d, J
= 8.0 Hz), 8.10 (1H, d, J = 8.4 Hz).

Example 208 N-((1RS, 2SR) -2-hydroxy-2- (4-phenoxyphenyl) -1-((4- (trifluoromethyl)
(Phenyl) methyl) ethyl) -3-phenylpropanamide (1RS, 2SR) -2-amino-1- (4-phenoxyphenyl) -3- (4- (trifluoromethyl) phenyl)-
To a solution of 1-propanol (400 mg, 1.03 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (230 ml, 1.55 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
ml × 2). Wash the extract with saturated saline,
After drying over anhydrous magnesium sulfate, the solution was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (4
72 mg, 88%). mp 134-135 ℃ IRνmax ^KBr cm ^-1 : 1645, 1584, 1489, 1445. Anal.Calcd for C ₃₁ H ₂₈ F ₃ NO ₃ : C, 71.66; H, 5.43; N,
2.70 Found:. C, 71.50; H, 5.47; N, 2.43 1 H-NMR (CDCl 3) δ: 2.37 (2H, t, J = 7.6 Hz), 2.58-
2.78 (2H, m), 2.85 (2H, t, J = 7.6 Hz), 3.20 (1H,
d, J = 3.8 Hz), 4.30-4.48 (1H, m), 4.78-4.84 (1H,
m), 5.37 (1H, d, J = 8.4 Hz), 6.90-7.20 (10H, m),
7.20-7.40 (6H, m), 7.45 (2H, d, J = 8.4 Hz).

Example 209 N-((1RS, 2SR) -2-hydroxy-2- (4-phenoxyphenyl) -1-((4- (trifluoromethyl)
Phenyl) methyl) ethyl) -4-fluoro-1-naphthalenecarboxamide 1) 4-phenoxybenzoic acid (10.4 g, 48.7)
1,1′-carbonylbis-1H-imidazole (8.68 mmol) in a solution of (1 mmol).
g, 53.6 mmol) and stirred at room temperature for 30 minutes. Monoethyl malonate magnesium salt (7.
67 g, 26.8 mmol) and stirred at room temperature for 2 hours. Ethyl acetate (50 ml) and water (50
ml), and concentrated hydrochloric acid was further added until the pH of the aqueous layer became acidic. The reaction solution was extracted with ethyl acetate (200 ml × 2), the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel column chromatography of the residue (hexane: ethyl acetate = 4: 1)
To give ethyl 3-oxo-3- (4-phenoxyphenyl) propionate (12.9 g, 93%) as a brown oil. ^{. IRνmax KBr cm -1: 1738,} 1682, 1586, 1505, 1489. Anal Calcd for C 17 H 16 O 4: C, 71.82; H, 5.67 Found:. C, 71.63; H, 5.56 1 H-NMR (CDCl ₃ ) δ: 1.20-1.38 (3H, m), 3.95 (2H × 5 /
6, s), 4.16-4.32 (2H, m), 5.60 (1H × 1/6, s), 6.94-
7.12 (4H, m), 7.12-7.28 (1H, m), 7.32-7.48 (2H,
m), 7.72-7.80 (2H × 1/6, m), 7.88-8.00 (2H × 5/6,
m). 2) 1,2-Ethyl 3-oxo-3- (4-phenoxyphenyl) propionate (12 g, 42.2 mmol)
Sodium hydride (60% oily, 1.69 g, 42.2 mmol) was added to a dimethoxyethane (80 ml) solution under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 4-trifluoromethylbenzyl bromide (10.1 g, 42.
2 mmol) of 1,2-dimethoxyethane (50 ml)
The solution was added dropwise and the reaction was stirred at room temperature for 4 hours. The reaction solution was poured into water (200 ml), and ethyl acetate (200 ml) was added.
1 × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give ethyl 3-oxo-3- (4-phenoxyphenyl) -2-((4- (trifluoromethyl) phenyl) methyl) propionate (14.0 g, 75% ) Got. mp 67-68 ℃ IRνmax ^KBr cm ^-1 : 1738, 1682, 1586, 1505, 1489.Anal.Calcd for C ₂₅ H ₂₁ F ₃ O ₄ : C, 67.87; H, 4.78 Found: C, 67.88; H, 4.89 _{^{. 1 H-NMR (CDCl 3}} ) δ: 1.13 (3H, t, J = 7.2 Hz), 3.37
(2H, d, J = 7.2 Hz), 4.11 (2H, q, J = 7.2 Hz), 4.5
7 (1H, t, J = 7.2 Hz), 6.90-7.10 (4H, m), 7.12-7.2
6 (1H, m), 7.30-7.48 (4H, m), 7.51 (2H, d, J = 8.2
Hz), 7.90-8.00 (2H, m). 3) To a solution of zinc chloride (7.39 g, 54.2 mmol) in diethyl ether (150 ml) was added sodium borohydride (4.11 g, 108.5 mmol). And stirred at room temperature for 30 minutes. The insolubles were removed by filtration, and the filtrate was treated with ethyl 3-oxo-3- (4-phenoxyphenyl) -2-((4- (trifluoromethyl) phenyl) methyl) propionate (12 g, 27.1 mmol). Diethyl ether (5
0 ml) solution and stirred at room temperature for 30 minutes. below freezing,
The reaction solution is quenched by adding 1N hydrochloric acid, and further added with water (20 mL).
0 ml) and extracted with ethyl acetate (300 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate),
Ethyl (2RS, 3RS) -3-hydroxy-3- (4-phenoxyphenyl) -2-((4- (trifluoromethyl) phenyl) methyl) propionate (11.9 g, 99
%) As a colorless oil. ^{. IRνmax KBr cm -1: 1728,} 1618, 1590, 1507, 1489. Anal Calcd for C 25 H 23 F 3 O 4: C, 67.56; H, 5.22 Found:. C, 67.40; H, 5.04 1 H-NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.2 Hz), 2.85
(1H, d, J = 2.6 Hz), 2.90-3.12 (3H, m), 3.89 (2H,
q, J = 7.2 Hz), 4.98-5.06 (1H, m), 6.94-7.04 (4H,
m), 7.04-7.18 (1H, m), 7.22 (2H, d, J = 8.0 Hz),
7.30-7.42 (4H, m), 7.49 (2H, d, J = 8.0 Hz). 4) (2RS, 3RS) -3-hydroxy-3- (4-phenoxyphenyl) -2-((4- (tri Fluoromethyl) phenyl) methyl) ethyl propionate (11.5
g, 25.9 mmol) in methanol (40 ml) was added to a 2N aqueous sodium hydroxide solution (25.9 ml, 55.9 ml).
(1.8 mmol) and stirred at room temperature overnight. After the reaction solution was acidified with 1N hydrochloric acid, ethyl acetate (200 ml) was added.
× 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (2RS,
3RS) -3-Hydroxy-3- (4-phenoxyphenyl) -2-((4- (trifluoromethyl) phenyl) methyl) propionic acid (9.65 g, 90%) was obtained. mp 140-141 ℃ IRνmax ^KBr cm ^-1 : 1715, 1590, 1489.Anal.Calcd for C ₂₃ H ₁₉ F ₃ O ₄ : C, 66.34; H, 4.60 Found: C, 66.36; H, 4.49. ¹ H- NMR (CDCl ₃ ) δ: 2.98-3.10 (3H, m), 5.08 (1H, s),
6.92-7.04 (4H, m), 7.04-7.30 (3H, m), 7.30-7.40
(4H, m), 7.48 (2H, d, J = 8.2 Hz). 5) (2RS, 3RS) -3-hydroxy-3- (4-phenoxyphenyl) -2-((4- (trifluoromethyl) Phenyl) methyl) propionic acid (7.0 g, 1
6.8 mmol) in tetrahydrofuran (180 ml)
To the solution was added diphenylphosphoryl azide (4.0 ml, 1 ml).
8.5 mmol) and triethylamine (3.5 ml, 2
(5.2 mmol) and heated to reflux for 6 hours. After allowing the reaction solution to cool, water (200 ml) was added, and ethyl acetate (20 ml) was added.
0 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate).
Recrystallized from hexane to give (4RS, 5SR) -5- (4
-Phenoxyphenyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1,3-oxazolidin-2-one (6.40 g, 92%) was obtained. mp 162-163 ° C IRνmax ^KBr cm ^-1 : 1759, 1617, 1591, 1508, 1489. Anal.Calcd for C ₂₃ H ₁₈ F ₃ NO ₃ : C, 66.82; H, 4.39; N,
3.39 Found:. C, 66.94; H, 4.17; N, 3.39 1 H-NMR (CDCl 3) δ: 2.30-2.50 (2H, m), 4.20-4.32 (1
H, m), 5.11 (1H, brs), 5.80 (1H, d, J = 7.8 Hz), 6.
90-7.10 (4H, m), 7.10-7.22 (3H, m), 7.22-7.50 (4H, m
m), 7.56 (2H, d, J = 8.0 Hz). 6) (4RS, 5SR) -5- (4-phenoxyphenyl) -4-((4- (trifluoromethyl) phenyl) methyl) -1, 3-Oxazolidin-2-one (6.0 g, 1
4.5 mmol) in ethanol (100 ml).
A normal aqueous sodium hydroxide solution (9.0 ml, 72 mmol) was added, and the mixture was heated under reflux for 4 hours. After the reaction solution was concentrated, it was diluted with water (300 ml), and ethyl acetate (300 ml ×
Extracted in 2). The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2SR) -2-.
Amino-1- (4-phenoxyphenyl) -3- (4- (trifluoromethyl) phenyl) -1-propanol (5.0
3g, 90%). mp 114-115 ° C IRνmax ^KBr cm ^-1 : 1590, 1507, 1489. Anal.Calcd for C ₂₂ H ₂₀ F ₃ NO ₂ : C, 68.21; H, 5.20; N,
3.62 Found:. C, 68.12; H, 5.27; N, 3.58 1 H-NMR (CDCl 3) δ: 2.46 (1H, dd, J = 13.6, 10.2 H
z), 2.94 (1H, dd, J = 13.6, 2.8 Hz), 3.24-3.38 (1
H, m), 4.65 (1H, d, J = 5.0 Hz), 6.98-7.18 (5H, m),
7.22-7.42 (6H, m), 7.55 (2H, d, J = 8.0 Hz). 7) (1RS, 2SR) -2-amino-1- (4-phenoxyphenyl) -3- (4- (trifluoro Methyl) phenyl) -1-propanol (400 mg, 1.03 mmol) in acetonitrile (30 ml) solution of 4-fluoronaphthalenecarboxylic acid (196 mg, 1.03 mmol) and 1-ethyl-3- (3-dimethylaminopropyl ) Carbodiimide hydrochloride (297 mg, 1.55 mmol) and 1-hydroxy-1H-benzotriazole (158 mg, 1.03 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane,
The title compound (520 mg, 90%) was obtained. mp 205-210 ° C IRνmax ^KBr cm ^-1 : 1644, 1626, 1599, 1510. Anal.Calcd for C ₃₃ H ₂₅ F ₄ NO ₃ : C, 70.83; H, 4.50; N,
2.50 Found:. C, 70.59; H, 4.50; N, 2.57 1 H-NMR (CDCl 3) δ: 2.89 (1H, dd, J = 14.2, 11.0 H
z), 3.06-3.24 (2H, m), 4.78-4.90 (1H, m), 5.09 (1
H, d, J = 4.0 Hz), 5.97 (1H, d, J = 9.0 Hz), 6.96-
7.20 (7H, m), 7.30-7.68 (11H, m), 8.08 (1H, d, J =
8.0 Hz).

Example 210 N-((1RS, 2SR) -2-hydroxy-2- (4-phenoxyphenyl) -1-((4- (trifluoromethyl)
(Phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-phenoxyphenyl) -3- (4- (tri Fluoromethyl) phenyl)-
6,7-dihydro-5 was added to a solution of 1-propanol (206 mg, 0.53 mmol) in acetonitrile (20 ml).
H-benzo [a] cycloheptene-1-carboxylic acid (10
0 mg, 0.53 mmol) and 1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide hydrochloride (1
53 mg, 0.80 mmol) and 1-hydroxy-1
H-benzotriazole (81 mg, 0.53 mmol) was added and the mixture was stirred at room temperature overnight. The reaction solution was washed with water (100
ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (268 mg, 90%).
I got ^{mp 191-192 ℃ IRνmax KBr cm -1:} 1642, 1590, 1507, 1489, 1327. 1 H-NMR (CDCl 3) δ: 1.90-2.06 (2H, m), 2.10-2.26 (2
H, m), 2.60-2.70 (2H, m), 2.85 (1H, dd, J = 14.4,
11.0 Hz), 3.07 (1H, dd, J = 14.4, 3.4 Hz), 3.42 (1
H, brs), 4.64-4.84 (1H, m), 5.03 (1H, d, J = 4.0 H
z), 5.80 (1H, d, J = 9.6 Hz), 5.80-5.96 (1H, m), 6.
13 (1H, d, J = 11.8 Hz), 6.90-7.20 (8H, m), 7.20-
7.50 (6H, m), 7.54 (2H, d, J = 8.2 Hz).

Example 211 N-((1RS, 2SR) -2-hydroxy-2- (4-phenoxyphenyl) -1-((4- (trifluoromethyl)
(Phenyl) methyl) ethyl) -3-phenylpropanamide (1RS, 2SR) -2-amino-1- (4-phenoxyphenyl) -3- (4- (trifluoromethyl) phenyl)-
To a solution of 1-propanol (400 mg, 1.03 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (230 ml, 1.55 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
ml × 2). Wash the extract with saturated saline,
After drying over anhydrous magnesium sulfate, the solution was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (4
(16 mg, 78%). mp 133-134 ℃ IRνmax ^KBr cm ^-1 : 1645, 1590, 1507, 1489. Anal.Calcd for C ₃₁ H ₂₈ F ₃ NO ₃ : C, 71.66; H, 5.43; N
2.70 Found:. C, 71.84; H, 5.26; N, 2.69 1 H-NMR (CDCl 3) δ: 2.32-2.42 (2H, m), 2.60-2.90 (4
H, m), 3.14-3.22 (1H, m), 4.32-4.50 (1H, m), 4.78-
4.86 (1H, m), 5.36 (1H, d, J = 8.4 Hz), 6.92-7.04
(4H, m), 7.06-7.40 (7H, m), 7.47 (2H, d, J = 8.0 H
z).

Example 212 N-((1RS, 2SR) -1-((4-fluorophenyl) methyl) -2-hydroxy-2- (4- (trifluoromethyl) phenyl) ethyl) -1-naphthalenecarboxamide 1) 4-trifluoromethylacetophenone (57.
8 g, 0.307 mol) and ethanol (1 ml) in diethyl carbonate (300 ml).
(4.5 g, 60% oily, 0.63 mol) was added in small portions. Since the mixture gradually generated heat, the mixture was cooled on ice and then stirred at room temperature for 2 hours. The reaction was stopped by adding 6N hydrochloric acid to the reaction solution,
After dilution with water (300 ml), ethyl acetate (200 m
1 × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5).
0: 1-5: 1) and ethyl 3-oxo-3- (4-trifluoromethylphenyl) propionate (71.
2 g, 89%). IRνmax ^Neat cm ^-1 : 1744, 1696, 1431, 1325, 1202, 113
^{2, 1069, 1017, 853. 1} H-NMR (CDCl 3) δ: 1.28 (3H × 0.62, t, J = 7.8 Hz, k
eto), 1.37 (3H × 0.38, t, J = 7.8 Hz, enol), 4.04 (2
H × 0.62, s, keto), 4.25 (2H, × 0.62, q, J = 7.8 Hz,
keto), 4.31 (2H, × 0.38, q, J = 7.8 Hz, enol), 5.
75 (1H × 0.38, s, enol), 7.28 (1H × 0.62, s, keto),
7.70 (2H × 0.38, d, J = 8.0 Hz, enol), 7.78 (2H × 0.
62, d, J = 8.0 Hz, keto), 7.90 (2H × 0.38, d, J =
8.0 Hz), 8.08 (2H x 0.62, d, J = 8.0 Hz). 2) Ethyl 3-oxo-3- (4-trifluoromethylphenyl) propionate (38.2 g, 0.147 mol) and 4- Fluorobenzyl bromide (25 g, 0.1
3 mol), potassium carbonate (36.6 g, 0.26 mol), and acetonitrile (500 ml) at 60 ° C.
For 3 hours. The reaction solution was concentrated under reduced pressure, and water (500 m
l) was added and extracted with ethyl acetate (500, 200 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 50: 1-10:
Purified with 1, hexane: toluene = 1: 1) and crystallized from cold hexane to give 2-((4-fluorophenyl) methyl) -3-oxo-3- (4- (trifluoromethyl) phenyl) Ethyl propionate (29.5 g, 55%) was obtained. mp 52-53 ° C IRνmax ^KBr cm ^-1 : 1723, 1692, 1514, 1323, 1231, 113
0, 1067, 853, as 824. Elemental analysis _{C 19 H 16 F 4 O 3} , Calcd: C, 61.96; H, 4.38 Found:. C, 61.97; H, 4.14 1 H-NMR (CDCl 3) δ: 1.12 (3H, t, J = 7.1 Hz), 3.31
(2H, d, J = 7.6 Hz), 4.10 (2H, q, J = 7.1 Hz), 4.5
6 (1H, t, J = 7.3 Hz), 6.88-8.03 (2H, m), 7.12-7.3
2 (2H, m), 7.71 (2H, t, J = 8.0 Hz), 8.04 (2H, d,
J = 8.0 Hz). 3) To a solution of zinc chloride (21.54 g, 158 mmol) in ether (500 ml) was added sodium borohydride (11.96 g, 316 mmol), and the mixture was added at room temperature for 30 minutes.
After stirring for minutes, the precipitated salt was filtered. 2- in the filtrate
((4-fluorophenyl) methyl) -3-oxo-3-
Ether of ethyl (4- (trifluoromethyl) phenyl) propionate (28 g, 79 mmol) (200 m
l) The solution was gradually added under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction solution was poured into a 1N aqueous hydrochloric acid solution (500 ml),
Extracted with ethyl acetate (500 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give (2R
S, 3RS) -2-((4-Fluorophenyl) methyl)-
Ethyl 3-hydroxy-3- (4- (trifluoromethyl) phenyl) propionate (28 g, 100%) was obtained as a colorless oil. IRνmax ^KBr cm ^-1 : 1713, 1510.Anal.Calcd for C ₁₉ H ₁₈ F ₄ O ₃ : C, 61.62; H, 4.90 Found: C, 61.51; H, 4.87. ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, t, J = 7.4 Hz), 2.80-
3.06 (3H, m), 3.15 (1H, d, J = 2.6 Hz), 3.91 (2H,
q, J = 7.4 Hz), 5.11 (1H, brs), 6.84-7.06 (4H, m),
7.52 (2H, d, J = 8.4 Hz), 7.63 (2H, d, J = 8.4 H
z). 4) Ethyl (2RS, 3RS) -2-((4-fluorophenyl) methyl) -3-hydroxy-3- (4- (trifluoromethyl) phenyl) propionate (27.5 g,
74.3 mmol) in methanol (300 ml) was added to a 1 N aqueous sodium hydroxide solution (150 ml, 15 ml).
0 mmol) and stirred at room temperature overnight. Reaction solution 1
Pour into a normal aqueous hydrochloric acid solution (180 ml) and add ethyl acetate (3
00 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (2R
S, 3RS) -2-((4-Fluorophenyl) methyl)-
3-Hydroxy-3- (4- (trifluoromethyl) phenyl) propionic acid (22.45 g, 88%) was obtained. ^{. mp 120-121 ℃ IRνmax KBr cm -1} : 1713. Anal Calcd for C 17 H 14 F 4 O 3: C, 59.65; H, 4.12 Found:. C, 59.56; H, 4.03 1 H-NMR (CDCl 3 ) δ: 2.90-3.10 (3H, m), 5.16 (1H, d,
J = 3.6 Hz), 6.82-7.12 (4H, m), 7.52 (2H, d, J = 8.
0 Hz), 7.63 (2H, d, J = 8.0 Hz). 5) (2RS, 3RS) -2-((4-fluorophenyl) methyl) -3-hydroxy-3- (4- (trifluoromethyl) Phenyl) propionic acid (21.0 g, 61.
35 mmol) in tetrahydrofuran (500 ml) was added to diphenylphosphoryl azide (14.5 ml, 6 ml).
7.5 mmol) and triethylamine (12.9 m
(1, 92 mmol) and heated to reflux for 3 hours. The reaction solution was diluted with water (500 ml), and ethyl acetate (500 m
1 × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give (4R
S, 5SR) -4-((4-Fluorophenyl) methyl)-
5- (4- (Trifluoromethyl) phenyl) -1,3-oxazolidin-2-one (19.24 g, 92%) was obtained. mp 160-161 ℃ IRνmax ^KBr cm ^-1 : 1738, 1508. Anal.Calcd for C ₁₇ H ₁₃ F ₄ NO ₂ : C, 60.18; H, 3.86; N,
4.13 Found:. C, 60.01; H, 3.99; N, 4.06 1 H-NMR (CDCl 3) δ: 2.10-2.34 (2H, m), 4.20-4.34 (1
H, m), 5.11 (1H, s), 5.86 (1H, d, J = 7.8 Hz), 6.9
7 (4H, d, J = 9.0 Hz), 7.51 (2H, d, J = 8.2 Hz),
7.70 (2H, d, J = 8.2 Hz). 6) (4RS, 5SR) -4-((4-fluorophenyl) methyl) -5- (4- (trifluoromethyl) phenyl) -1,3-oxazolidine -2-one (18 g, 53.
To a solution of 1 mmol) in ethanol (300 ml) was added an 8 N aqueous sodium hydroxide solution (19.9 ml, 159 mmol), and the mixture was refluxed for 4 hours. After the reaction solution was concentrated, it was diluted with water (300 ml), and ethyl acetate (300 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2SR)
2-amino-3- (4-fluorophenyl) -1- (4- (trifluoromethyl) phenyl) -1-propanol (1
4.1 g, 85%). mp 130-131 ° C IRνmax ^KBr cm ^-1 : 1618, 1601, 1588. Anal.Calcd for C ₁₆ H ₁₅ F ₄ NO: C, 61.34; H, 4.83; N,
4.47 Found:. C, 61.23; H, 4.72; N, 4.41 1 H-NMR (CDCl 3) δ: 2.32 (1H, dd, J = 14.0, 10.6 H
z), 2.68 (1H, dd, J = 14.0, 3.4 Hz), 3.20-3.36 (1
H, m), 4.76 (1H, d, J = 4.4 Hz), 6.90-7.16 (4H, m),
7.52 (2H, d, J = 8.2 Hz), 7.65 (2H, d, J = 8.2 H
z). 7) Acetic acid of (1RS, 2SR) -2-amino-3- (4-fluorophenyl) -1- (4- (trifluoromethyl) phenyl) -1-propanol (450 mg, 1.44 mmol) 1-Naphthoyl chloride (282 ml, 1.87 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) were added to the ethyl (15 ml) solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
1 × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (6
14 mg, 91%). mp 207-208 ℃ IRνmax ^KBr cm ^-1 : 1640. Anal.Calcd for C ₂₇ H ₂₁ F ₄ NO ₂ : C, 69.37; H, 4.53; N,
3.00 Found:. C, 69.21; H, 4.46; N, 2.87 1 H-NMR (CDCl 3) δ: 2.92 (1H, dd, J = 14.2, 10.4 H
z), 3.13 (1H, dd, J = 14.2, 4.0 Hz), 3.39 (1H, s),
4.72-4.90 (1H, m), 5.13 (1H, s), 5.98 (1H, d, J =
8.4 Hz), 7.04-7.60 (12H, m), 7.70-7.92 (3H, m).

Example 213 4-Fluoro-N-((1RS, 2SR) -1-((4-fluorophenyl) methyl) -2-hydroxy-2- (4- (trifluoromethyl) phenyl) ethyl)- 1-naphthalenecarboxamide (1RS, 2SR) -2-amino-3- (4-fluorophenyl) -1- (4- (trifluoromethyl) phenyl) -1
To a solution of -propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) was added 4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 m
g, 1.44 mmol) and stirred at room temperature overnight.
The reaction solution was diluted with water (100 ml), and ethyl acetate (10 ml) was added.
0 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (430 mg, 62%). mp 235-236 ° C IRνmax ^KBr cm ^-1 : 1651, 1605, 1510. Anal.Calcd for C ₂₇ H ₂₀ F ₅ NO ₂ : C, 66.80; H, 4.15; N,
2.89 Found:. C, 66.59; H, 4.25; N, 2.90 1 H-NMR (CDCl 3) δ: 2.79 (1H, dd, J = 14.2, 11.0 H
z), 2.98 (1H, dd, J = 14.2, 4.4 Hz), 3.75 (1H, s),
4.70-4.88 (1H, m), 5.18-5.22 (1H, m), 5.91 (1H, m
d, J = 8.4 Hz), 6.92-7.10 (3H, m), 7.12-7.22 (3H,
m), 7.40-7.80 (7H, m), 8.10 (1H, d, J = 8.4 Hz).

Example 214 N-((1RS, 2SR) -1-((4-fluorophenyl) methyl) -2-hydroxy-2- (4- (trifluoromethyl) phenyl) ethyl) cyclohexanecarboxamide (1RS, 2SR) -2-Amino-3- (4-fluorophenyl) -1- (4- (trifluoromethyl) phenyl) -1
To a solution of -propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (288 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml), and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
ml × 2). Wash the extract with saturated saline,
After drying over anhydrous magnesium sulfate, the solution was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (550 mg, 90%). mp 220-221 ℃ IRνmax ^KBr cm ^-1 : 1645, 1510, 1329. Anal.Calcd for C ₂₃ H ₂₅ F ₄ NO ₂ : C, 65.24; H, 5.95; N,
3.31 Found:. C, 65.07; H, 5.85; N, 3.22 1 H-NMR (CDCl 3) δ: 1.04-1.40 (5H, m), 1.50-1.80 (5
H, m), 1.82-2.10 (1H, m), 2.66 (1H, dd, J = 14.4,
10.8 Hz), 2.83 (1H, dd, J = 14.4, 4.6 Hz), 4.34-4.
50 (2H, m), 5.04 (1H, brs), 5.36 (1H, d, J = 7.4 H
z), 6.90-7.12 (4H, m), 7.52 (2H, d, J = 8.0 Hz),
7.66 (2H, d, J = 8.0 Hz).

Example 215 N-((1RS, 2SR) -1-((4-fluorophenyl) methyl) -2-hydroxy-2- (4- (trifluoromethyl) phenyl) ethyl) -4-phenylbutyric acid Amido (1RS, 2SR) -2-amino-3- (4-fluorophenyl) -1- (4- (trifluoromethyl) phenyl) -1
To a solution of -propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) was added 4-phenyl-n-butyric acid (236 mg, 1.44 mmol) and 1-ethyl-3.
-(3-Dimethylaminopropyl) carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44)
Mmol) and stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (450 mg, 68%). mp 155-156 ° C IRνmax ^KBr cm ^-1 : 1645, 1537, 1510. Anal.Calcd for C ₂₆ H ₂₅ F ₄ NO ₂ : C, 67.96; H, 5.48; N,
3.05 Found:. C, 67.98; H, 5.68; N, 3.06 1 H-NMR (CDCl 3) δ: 1.70-1.90 (2H, m), 2.00-2.20 (2
H, m), 2.44-2.60 (2H, m), 2.62-2.84 (2H, m), 4.10
(1H, d, J = 4.0 Hz), 4.32-4.48 (1H, m), 4.98-5.06
(1H, m), 5.40 (1H, d, J = 7.6 Hz), 6.86-7.14 (6H,
m), 7.16-7.34 (3H, m), 7.51 (2H, d, J = 8.0 Hz),
7.63 (2H, d, J = 8.0 Hz).

Example 216 N-[(1RS, 2SR) -2- (4-chlorophenyl)-
2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
5H-benzo [a] cycloheptene-1-carboxamide 1) 3- (4-chlorophenyl) -3-oxo-2- [3-
(1,1,2,2-tetrahydroethoxy) benzyl]
Ethyl propionate 3- (1,1,2,2-tetrahydroethoxy) toluene (7.43 ml, 44 mmol) in carbon tetrachloride (30 m
1) Add N-bromosuccinimide (7.83 g,
44 mmol) and 2,2'-azobisisobutyronitrile (0.2 g) were added, and the mixture was heated under reflux for 30 minutes. After the reaction solution was cooled, insolubles were removed and washed with diethyl ether. The filtrate was distilled off under reduced pressure to obtain 3- (1,1,2,2-tetrahydroethoxy) -1-bromomethylbenzene.
Ethyl 3- (4-chlorophenyl) -3-oxopropionate (9.07 g, 40 mmol) was dissolved in dimethoxyethane (100 ml), and sodium hydride (1.6 g, 60% oily, 40 mmol) was added under ice cooling. Was added and stirred for 1 hour. The solution of 3- (1,1,2,2-tetrahydroethoxy) -1-bromomethylbenzene obtained above in dimethoxyethane (20 ml) was added dropwise thereto, and the mixture was stirred at room temperature for 15 hours. Water (100 ml) was added to the reaction solution, and extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 20: 1-4: 1), crystallized from hexane to give 3- (4-chlorophenyl) -3-oxo-2- [3-
(1,1,2,2-tetrahydroethoxy) benzyl]
Ethyl propionate (7.85 g, 45%) was obtained. mp 60-61 ° C IRνmax ^KBr cm ^-1 : 1723, 1684, 1590, 1325, 1275, 1231,
1200, 1134, 1096. Calculated as elemental analysis C ₂₀ H ₁₇ ClF ₄ O ₄ : C, 55.50; H, 3.9
6, actual value: C, 55.55; H, 3.83 ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.2 Hz), 3.33 (2
H, d, J = 8.0 Hz), 4.10 (2H, q, J = 7.2 Hz), 4.55
(1H, t, J = 7.0 Hz), 5.89 (1H, tt, J = 53.1 Hz, 2.
2 Hz), 7.00-7.20 (3H, m), 7.20-7.35 (1H, m), 7.42
(2H, d, J = 8.0 Hz), 7.89 (2H, d, J = 8.0 Hz). 2) (2RS, 3RS) -3- (4-chlorophenyl)-
Ethyl 3-hydroxy-2- [3- (1,1,2,2-tetrahydroethoxy) benzyl] propionate Hydrogenation to a suspension of anhydrous zinc chloride (4.09 g, 30 mmol) in diethyl ether (100 ml). Sodium boron (2.53 g, 60 mmol) was added in small portions,
Stir for 2 hours. The insolubles were removed by filtration and washed with diethyl ether. The filtrate was cooled with ice, and ethyl 3- (4-chlorophenyl) -3-oxo-2- [3- (1,1,2,2-tetrahydroethoxy) benzyl] propionate (6.5) was added thereto.
g, 15 mmol) in diethyl ether (20 ml). After stirring at room temperature for 1 hour, the mixture was cooled again on ice and
The reaction was stopped with normal hydrochloric acid. The obtained mixture was extracted with ethyl acetate (100 ml × 2), washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel chromatography of the residue (hexane: ethyl acetate = 10: 1)
-3: 1) and purified by (2RS, 3RS) -3- (4-
Chlorophenyl) -3-hydroxy-2- [3- (1,1,
Ethyl 2,2-tetrahydroethoxy) benzyl] propionate (6.5 g, 99%) was obtained as a colorless oil. IRνmax ^Neat cm ^-1 : 1723, 1489, 1302, 1277, 1198, 112
^{3, 1094. 1 H-NMR (} CDCl 3) δ: 0.94 (3H, t, J = 7.2 Hz), 2.90-3.1
0 (3H, m), 3.90 (2H, d, J = 7.2 Hz), 5.02 (1H, b
r), 5.88 (1H, tt, J = 53.1 Hz, 2.3 Hz), 6.90-7.10
(3H, m), 7.22 (1H, d, J = 7.6 Hz), 7.27 (1H, d, J
= 3.4 Hz). 3) (2RS, 3RS) -3- (4-chlorophenyl)-
3-hydroxy-2- [3- (1,1,2,2-tetrahydroethoxy) benzyl] propionic acid (2RS, 3RS) -3- (4-chlorophenyl) -3-hydroxy-2- [3- (1 , 1,2,2-Tetrahydroethoxy) benzyl] ethyl propionate (6.45 g, 1
To a solution of 4.8 mmol) in methanol (30 ml) was added a 2N aqueous sodium hydroxide solution (14.8 ml, 29.6 mmol) and the mixture was stirred at room temperature for 4 hours. The reaction solution was acidified by adding 1N hydrochloric acid (100 ml), and extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from hexane to give (2RS, 3RS)-
3- (4-chlorophenyl) -3-hydroxy-2- [3-
(1,1,2,2-tetrahydroethoxy) benzyl]
Propionic acid (5.39 g, 89%) was obtained. mp 88-90 ° C IRνmax ^KBr cm ^-1 : 1694, 1489, 1277, 1206, 1127. Calculated as C ₁₈ H ₁₅ ClF ₄ O ₄ : C, 53.15; H, 3.7
2, found: C, 53.26; H, 3.87 ¹ H-NMR (CDCl ₃ ) δ: 2.80-3.10 (3H, m), 5.07 (1H, d, J
= 3.6 Hz), 5.88 (1H, tt, J = 53.1 Hz, 2.6 Hz), 6.9
0-7.15 (4H, m), 7.20-7.35 (4H, m). 4) (4RS, 5SR) -5- (4-chlorophenyl)-
4- [3- (1,1,2,2-tetrahydroethoxy) benzyl] -1,3-oxazolidin-2-one (2RS, 3RS) -3- (4-chlorophenyl) -3-hydroxy-2- [ 3- (1,1,2,2-tetrahydroethoxy) benzyl] propionic acid (5.39 g, 13.3
Mmol) in a solution of diphenylphosphoryl azide (3.70 ml, 17.2).
Mmol) and triethylamine (2.59 ml, 18.
6 mmol) and stirred at room temperature for 1 hour. afterwards,
After heating under reflux for 3 hours, the reaction solution was concentrated under reduced pressure and water (10
0 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1-1: 1), and the precipitated crystals were collected by filtration by adding hexane.
S, 5SR) -5- (4-Chlorophenyl) -4- [3-
(1,1,2,2-tetrahydroethoxy) benzyl]-
1,3-Oxazolidin-2-one (4.65 g, 87
%). mp 134-135 ℃ IRνmax ^KBr cm ^-1 : 3243, 1740, 1489, 1447, 1343, 1273,
1238, 1198, 1125, as 1088. Elemental analysis _{C 18 H 14 ClF 4 NO 3} , Calcd: C, 53.55; H, 3 .
49; N, 3.47, Found:. C, 53.56; H, 3.28; N, 3.48 1 H-NMR (CDCl 3) δ: 2.18-2.40 (2H, m), 4.20-4.35 (1H,
m), 5.05 (1H, br s), 5.79 (1H, d, J = 8.0 Hz), 5.9
0 (1H, tt, J = 54.8 Hz, 2.6 Hz), 6.85-7.00 (2H,
m), 7.05-7.20 (1H, m), 7.20-7.50 (5H, m). 5) (1RS, 2SR) -2-amino-1- (4-chlorophenyl) -3- [3- (1,1 , 2,2-Tetrahydroethoxy) phenyl] -1-propanol (4RS, 5SR) -5- (4-chlorophenyl) -4-
[3- (1,1,2,2-tetrahydroethoxy) benzyl] -1,3-oxazolidin-2-one (4.35 g, 1
0.8 mmol) in ethanol (20 ml)
Normal sodium hydroxide aqueous solution (5.39 ml, 43.1
(Mmol) and heated to reflux for 6 hours. The reaction solution was concentrated under reduced pressure, water (100 ml) was added, and ethyl acetate (100
ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from a mixture of hexane and diethyl ether to give (1R
S, 2SR) -2-Amino-1- (4-chlorophenyl) -3
There was obtained-[3- (1,1,2,2-tetrahydroethoxy) phenyl] -1-propanol (3.61 g, 89%). ^{mp 96-97 ℃ IRνmax KBr cm -1:} 1611, 1588, 1489, 1308, 1196, as 1119. Elemental analysis _{C 17 H 16 ClF 4 NO 2} , calc: C, 54.05; H, 4 .
27; N, 3.71, Found:. C, 54.08; H, 4.34; N, 3.75 1 H-NMR (CDCl 3) δ: 2.36 (1H, dd, J = 13.6 Hz, 10.2 H
z), 2.77 (1H, dd, J = 13.6 Hz, 3.2 Hz), 3.20-3.40
(1H, m), 4.66 (1H, d, J = 4.6 Hz), 5.89 (1H, tt, J
= 53.0 Hz, 2.5 Hz), 6.99 (1H, s), 7.00-7.15 (2H,
m), 7.20-7.40 (5H, m). 6) N-[(1RS, 2SR) -2- (4-chlorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetra Fluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-chlorophenyl) -3- [3- (1 , 1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol 0.280 g (0.
741 mmol), 0.14 g of 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (0.14 g).
0.11 g (0.74 mmol) of 1-hydroxybenzotriazole hydrate 0.14 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride while stirring in 10 ml of acetonitrile.
(0.74 mmol) and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White powder Yield 0.373 g Yield 92% mp 182-183 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.93-2.06
(2H, m), 2.15-2.24 (2H, m), 2.67 (2H, t, J = 6.1 H
z), 2.78 (1H, dd, J = 10.9 Hz, 14.9 Hz), 2.98 (1H,
dd, J = 4.2 Hz, 14.6 Hz), 3.71 (1H, d, J = 3.6 H
z), 4.60-4.73 (1H, m), 5.04 (1H, t, J = 3.7 Hz),
5.74 (1H, d, J = 8.4 Hz), 5.89 (1H, tt, J = 2.7 Hz,
53.0 Hz), 5.93 (1H, td, J = 5.6 Hz, 11.0 Hz), 6.2
1 (1H, d, J = 11.6 Hz), 6.95-7.18 (6H, m), 7.31-7.4
3 (5H, m); IR (KBr) 3270, 2940,1640, 1537, 1198, 1
125 cm ^-1 ; Anal.Calcd for C ₂₉ H ₂₆ ClF ₄ NO ₃ : C, 63.56;
H, 4.78; N, 2.56.Found: C, 63.51; H, 4.69; N, 2.5
2.

Example 217 N-((1RS, 2SR) -2-hydroxy-2- (4- (phenyloxy) phenyl) -1-((3-((1,1,1
2,2-tetrafluoroethyl) oxy) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 1) 3- (1,1,2,2-tetrafluoroethoxy) )
N-bromosuccinimide (7.3 g) was added to a solution of toluene (7.8 g, 37.5 mmol) in carbon tetrachloride (80 ml).
3g, 41.2 mmol) and 2,2'-azobis (isobutyronitrile) (300 mg, 1.87 mmol)
Was added and heated under reflux for 6 hours. After cooling, the reaction solution was filtered, and the filtrate was concentrated to prepare 3- (1,1,2,2-tetrafluoroethoxy) -α-bromotoluene. 3- (4-
A solution of ethyl phenoxyphenyl) -3-oxopropionate (10.7 g, 37.5 mmol) in 1,2-dimethoxyethane (120 ml) was treated with sodium hydride (60 ml).
% Oily, 1.50 g, 37.5 mmol) under ice-cooling and stirred at room temperature for 30 minutes. 1,2-Dimethoxyethane of 3- (1,1,2,2-tetrafluoroethoxy) -α-bromotoluene previously prepared in the reaction solution (10 ml)
The solution was added dropwise and the reaction was stirred at room temperature for 1 hour. The reaction solution was poured into water (100 ml), and ethyl acetate (100 m
1 × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene) to give 3-oxo-3- (4-phenyloxyphenyl) -2-((3-((1,1,2,2-tetrafluoroethyl) oxy) Ethyl phenyl) methyl) propionate (9.92 g, 54%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7.0 Hz), 3.33
(2H, d, J = 6.8 Hz), 4.11 (2H, q, J = 7.0 Hz), 4.5
6 (1H, t, J = 7.6 Hz), 5.88 (1H, tt, J = 53.0, 2.8
Hz), 6.90-7.48 (11H, m), 7.90-8.02 (2H, m) .IRνmax ^KBr cm ^-1 : 1738, 1682, 1605, 1586, 1505, 148
9, 1449, 1420. Anal.Calcd for C ₂₆ H ₂₂ F ₄ O ₅・ 0.3H ₂ O: C, 62.98; H,
4.59 Found: C, 62.84; H, 4.46.2) To a solution of zinc chloride (5.34 g, 39.2 mmol) in diethyl ether (120 ml) was added sodium borohydride (2.97 g, 78.4 mmol). Stirred at room temperature for 30 minutes. Remove the insoluble material by filtration and add 3-oxo- to the filtrate.
3- (4-phenyloxyphenyl) -2-((3-
((1,1,2,2-tetrafluoroethyl) oxy)
Phenyl) methyl) ethyl propionate (9.61 g,
(19.6 mmol) in diethyl ether (60 ml) was added and stirred at room temperature for 30 minutes. Add 1 reaction solution under ice-cooling.
The mixture was quenched by the addition of normal hydrochloric acid, water (150 ml) was added, and the mixture was extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give (2RS, 3RS) -3-hydroxy-3- (4-
(Phenyloxy) phenyl) -2-((3-((1,
Ethyl 1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) propionate (6.50 g, 67
%) As a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.0 Hz), 2.90-
3.10 (4H, m), 3.89 (2H, q, J = 7.0 Hz), 4.98-5.06
(1H, m), 5.89 (1H, tt, J = 53.0, 2.8 Hz), 6.92-7.4
2 (13H, m) .IRνmax ^KBr cm ^-1 : 1725, 1611, 1590, 1507, 1489, 144
9. Anal. Calcd for C ₂₆ H ₂₄ F ₄ O ₅ : C, 63.41; H, 4.91 Found: C, 63.32; H, 4.97. 3) (2RS, 3RS) -3-hydroxy-3- (4-
(Phenyloxy) phenyl) -2-((3-((1,
Ethyl 1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) propionate (6.14 g, 12.
To a solution of 5 mmol) in methanol (30 ml) was added a 2N aqueous sodium hydroxide solution (12.5 ml, 25.0 mmol) and the mixture was stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (2RS, 3RS)
3-Hydroxy-3- (4- (phenyloxy) phenyl) -2-((3-((1,1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) propionic acid (4.
51 g, 89%). ¹ H-NMR (CDCl ₃ ) δ: 2.94-3.10 (3H, m), 5.07 (1H, d,
J = 4.2 Hz), 5.87 (1H, t, J = 53.0, 3.0 Hz), 6.92-
^{7.40 (13H, m) IRνmax KBr} cm -1: 1711, 1613, 1590, 1508, 1489. mp 109-110 ℃ Anal Calcd for C 24 H 20 F 4 O 5:.. C, 62.07; H, 4.34 Found: C, 62.09; H, 4.42.4) (2RS, 3RS) -3-hydroxy-3- (4-
(Phenyloxy) phenyl) -2-((3-((1,
To a solution of 1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) propionic acid (4.3 g, 10.6 mmol) in tetrahydrofuran (80 ml) was added diphenylphosphoryl azide (2.52 ml, 11.7 mmol). Triethylamine (2.23 ml, 16.0 mmol) was added, and the mixture was heated under reflux for 2 hours. After allowing the reaction solution to cool,
Water (200 ml) was added and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-1: 1) and recrystallized from ethyl acetate-hexane to give (4.
RS, 5SR) -5- (4- (phenyloxy) phenyl) -4-((3-((1,1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) -1,3-oxazolidine- 2-One (3.92 g, 80%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.24-2.44 (2H, m), 4.18-4.32 (1
H, m), 5.08 (1H, brs), 5.79 (1H, d, J = 8.0 Hz), 5.
90 (1H, tt, J = 53.0, 3.0 Hz), 6.86-7.20 (8H, m),
7.22-7.42 (5H, m) .IRνmax ^KBr cm ^-1 : 1759, 1612, 1590, 1508, 1489.mp 90-91 ° C Anal.Calcd for C ₂₄ H ₁₉ F ₄ NO ₄ : C, 62.47; H, 4.15 ; N,
3.04 Found: C, 62.54; H, 4.05; N, 3.04.5) (4RS, 5SR) -5- (4- (phenyloxy) phenyl) -4-((3-((1,1,2,2 -Tetrafluoroethyl) oxy) phenyl) methyl) -1,3-
To a solution of oxazolidine-2-one (3.7 g, 8.02 mmol) in ethanol (10 ml) was added an 8 N aqueous sodium hydroxide solution (5.0 ml, 40 mmol), and the solution was added.
Heated to reflux for an hour. After concentrating the reaction solution, water (100 ml)
And extracted with ethyl acetate (100 ml × 2).
The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2SR) -2-amino-1- (4
-(Phenyloxy) phenyl) -3- (3-((1,1,
2,2-tetrafluoroethyl) oxy) phenyl) -1
-Propanol (3.05 g, 87%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.00 (2H, br), 2.41 (1H, d
d, J = 13.8, 10.2 Hz), 2.88 (1H, dd, J = 13.8, 3.2
Hz), 3.22-3.38 (1H, m), 4.65 (1H, d, J = 5.2Hz),
5.89 (1H, tt, J = 53.0, 3.0 Hz), 6.98-7.18 (8H,
m), 7.28-7.42 (5H, m) .IRνmax ^KBr cm ^-1 : 1611, 1590, 1507, 1489, 1449.mp 85-86 ° C Anal.Calcd for C ₂₃ H ₂₁ F ₄ NO ₃ : C, 63.44; H, 4.86; N,
3.22 Found: C, 63.44; H, 4.76; N, 3.22.6) (1RS, 2SR) -2-amino-1- (4- (phenyloxy) phenyl) -3- (3-((1,1, 2,2-
A solution of 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (130 mg,
0.69 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (198 m
g, 1.03 mmol) and 1-hydroxy-1H-benzotriazole (106 mg, 0.69 mmol) were added and stirred at room temperature overnight. The reaction solution was water (100 ml)
And extracted with ethyl acetate (100 ml × 2).
1N hydrochloric acid, 1N aqueous sodium hydroxide solution,
The extract was washed successively with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (285 mg, 68%). ¹ H-NMR (CDCl ₃ ) δ: 1.90-2.10 (2H, m), 2.12-2.28 (2
H, m), 2.60-2.72 (2H, m), 2.8 (1H, dd, J = 14.8, 1
0.4 Hz), 3.04 (1H, dd, J = 14.8, 4.0 Hz), 3.53 (1
H, s), 4.60-4.80 (1H, m), 5.02 (1H, s), 5.75 (1H,
d, J = 8.4 Hz), 5.89 (1H, tt, J = 53.0, 2.8 Hz),
5.90-6.00 (1H, m), 6.23 (1H, d, J = 11.8Hz), 6.90-
7.20 (12H, m), 7.22-7.48 (4H, m) .IRνmax ^KBr cm ^-1 : 1640, 1590, 1507, 1489, 1449.mp 95-96 ℃

Example 218 N-((1RS, 2SR) -2- (4-((4-chloro-3-
Ethylphenyl) oxy) phenyl) -2-hydroxy-
1-((3-((1,1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 1) 4- Fluoroacetophenone (13.8 g, 10
0 mmol) of N, N-dimethylacetamide (100
ml) solution in 4-chloro-3-ethylphenol (15.
6 g, 100 mmol) and potassium carbonate (16.6).
g, 120 mmol) and heated under reflux for 10 hours.
After concentration, the reaction solution was diluted with water (300 ml) and extracted with ethyl acetate (300 ml × 2). The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give 4-
((4-Chloro-3-ethylphenyl) oxy) acetophenone (24.2 g, 88%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.4 Hz), 2.58
(3H, s), 2.74 (2H, q, J = 7.4 Hz), 6.84 (1H, dd, J
= 8.8, 3.0 Hz), 6.94-7.04 (3H, m), 7.34 (1H, d, J =
.. 8.8 Hz), 7.90-8.00 ( 2H, m) IRνmax KBr cm -1: 1682, 1595, 1574, 1503, 1472. Anal Calcd for C 16 H 15 ClO 2: C, 69.95; H, 5.50 Found: C H, 5.65 2) 4-((4-chloro-3-ethylphenyl) oxy)
To a solution of acetophenone (24.2 g, 88.2 mmol) in diethyl carbonate (100 ml) was added ethanol (0.3 mM).
l) and sodium hydride (60% oily,
(7.06 g, 176 mmol) and stirred at room temperature for 2 hours. The reaction solution is quenched by adding 6N hydrochloric acid, and the solution
00 ml) and extracted with ethyl acetate (300 ml × 2). The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
50: 1-5: 1) to give 3- (4-((4-chloro-3
Ethyl -ethylphenyl) oxy) phenyl) -3-oxopropionate (29.3 g, 96%) was obtained as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 1.08-1.20 (6H, m), 2.68-2.82 (2
H, m), 3.95 (2H × 7/8, s), 4.14-4.30 (2H, m), 5.60
(1H × 1/8, s), 6.80-6.90 (1H, m), 6.92-7.04 (3H,
m), 7.32 (1H × 1/8, d, J = 8.4 Hz), 7.35 (1H × 7/8,
d, J = 8.4 Hz), 7.75 (2H × 1/8, d, J = 9.2 Hz), 7.9
3 (2H × 7/8, d, J = 9.2 Hz) .IRνmax ^KBr cm ^-1 : 1744, 1682, 1595, 1576, 1505, 147
2, 1410. Anal. Calcd for C ₁₉ H ₁₉ F ₅ ClO ₄ : C, 65.80; H, 5.52 Found: C, 65.98; H, 5.53.3. 3) 3- (1,1,2,2-tetrafluoroethoxy) )
To a solution of toluene (6.0 g, 28.8 mmol) in carbon tetrachloride (60 ml) was added N-bromosuccinimide (5.6).
5g, 31.7 mmol) and 2,2'-azobis (isobutyronitrile) (237 mg, 1.44 mmol)
Was added and heated under reflux for 6 hours. After cooling, the reaction solution was filtered, and the filtrate was concentrated to prepare 3- (1,1,2,2-tetrafluoroethoxy) -α-bromotoluene. 3- (4-
Ethyl ((4-chloro-3-ethylphenyl) oxy) phenyl) -3-oxopropionate (10 g, 28.8)
Mmol) 1,2-dimethoxyethane (100 ml)
Add sodium hydride (60% oily, 1.15 g, 2
(8.8 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 1,2- (1,1,2,2-tetrafluoroethoxy) -α-bromotoluene prepared in advance in the reaction solution
A solution of dimethoxyethane (10 ml) was added dropwise, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was poured into water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene) to give 3- (4-
Ethyl ((4-chloro-3-ethylphenyl) oxy) phenyl) -3-oxo-2-((3-((1,1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) propionate ( 9.26 g, 58%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7.0 Hz), 1.22
(3H, t, J = 7.6 Hz), 2.74 (2H, q, J = 7.6 Hz), 3.3
3 (2H, d, J = 7.2 Hz), 4.11 (2H, q, J = 7.0 Hz),
4.56 (1H, t, J = 7.2 Hz), 5.88 (1H, tt, J = 53.2,
2.8 Hz), 6.83 (1H, dd, J = 8.6, 3.0 Hz), 6.90-7.38
(8H, m), 7.90-8.00 (2H, m) .IRνmax ^KBr cm ^-1 : 1738, 1682, 1595, 1576, 1505, 147
_{. 2. Anal Calcd for C 28 H} 25 ClF 4 O 5: C, 60.82; H, 4.56 Found:. C, 60.79; H, 4.38 4) in diethyl ether of zinc chloride (4.44 g, 32.6 mmol) ( Sodium borohydride (2.46 g, 65.1 mmol) was added to the solution (100 ml) and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was added with 3- (4-
Ethyl ((4-chloro-3-ethylphenyl) oxy) phenyl) -3-oxo-2-((3-((1,1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) propionate ( (9.0 g, 16.3 mmol) in diethyl ether (50 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Under ice cooling, the reaction solution is quenched by adding 1N hydrochloric acid,
Further, water (150 ml) was added, and ethyl acetate (200 ml) was added.
× 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purified with ethyl acetate = 4: 1) to give (2RS, 3RS)-
3- (4-((4-chloro-3-ethylphenyl) oxy)
Phenyl) -3-hydroxy-2-((3-((1,1,
Ethyl 2,2-tetrafluoroethyl) oxy) phenyl) methyl) propionate (6.79 g, 75%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, t, J = 7.0 Hz), 1.21
(3H, t, J = 7.6 Hz), 2.72 (2H, q, J = 7.6 Hz), 2.9
0-3.10 (4H, m), 3.90 (2H, q, J = 7.0 Hz), 4.93 (1
H, brs), 5.89 (1H, tt, J = 53.0, 3.0 Hz), 6.76 (1
H, dd, J = 8.8, 3.0Hz), 6.82-7.10 (6H, m), 7.20-7.
^{42 (4H, m) IRνmax KBr} cm -1: 1726, 1611, 1588, 1507, 1474. Anal Calcd for C 28 H 27 ClF 4 O 5:.. C, 60.60; H, 4.90 Found: C, 60.53; H , 4.90.5) (2RS, 3RS) -3- (4-((4-chloro-3-
Ethylphenyl) oxy) phenyl) -3-hydroxy-
Ethyl 2-((3-((1,1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) propionate (6.6 g, 11.9 mmol) in methanol (30 m
1) Add 2N aqueous sodium hydroxide solution (11.9) to the solution.
ml, 23.8 mmol) and stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from hexane to give (2R
S, 3RS) -3- (4-((4-Chloro-3-ethylphenyl) oxy) phenyl) -3-hydroxy-2-((3-
((1,1,2,2-tetrafluoroethyl) oxy)
Phenyl) methyl) propionic acid (5.28 g, 84
%). ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.6 Hz), 2.71
(2H, q, J = 7.6 Hz), 2.92-3.10 (3H, m), 5.07 (1H,
d, J = 4.0 Hz), 5.87 (1H, tt, J = 53.0, 3.0 Hz),
6.75 (1H, dd, J = 8.4, 3.0 Hz), 6.88-7.10 (6H, m),
7.20-7.40 (4H, m) .IRνmax ^KBr cm ^-1 : 1713, 1611, 1599, 1507, 1472.mp 75-76 ° C Anal.Calcd for C ₂₆ H ₂₃ ClF ₄ O ₅ : C, 59.27; H, 4.40 Found: C, 59.22; H, 4.43.6) (2RS, 3RS) -3- (4-((4-chloro-3-
Ethylphenyl) oxy) phenyl) -3-hydroxy-
2-((3-((1,1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) propionic acid (5.1
8 g, 9.83 mmol) of tetrahydrofuran (75
ml) solution in diphenylphosphoryl azide (2.33).
ml, 10.8 mmol) and triethylamine (2.0
(6 ml, 14.8 mmol) was added and the mixture was refluxed for 2 hours. After allowing the reaction mixture to cool, water (200 ml) was added, and the mixture was extracted with ethyl acetate (100 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give (4RS, 5S
R) -5- (4-((4-Chloro-3-ethylphenyl) oxy) phenyl) -4-((3-((1,1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) -1,3-
Oxazolidin-2-one (4.56 g, 89%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.6 Hz), 2.20-
2.44 (2H, m), 2.73 (2H, q, J = 7.6 Hz), 4.18-4.32
(1H, m), 4.98 (1H, s), 5.80 (1H, d, J = 7.8 Hz),
5.90 (1H, tt, J = 53.0, 3.0 Hz), 6.80 (1H, dd, J =
8.4, 3.0 Hz), 6.88-7.20 (5H, m), 7.22-7.44 (5H,
^{.. m) IRνmax KBr cm -1} : 1759, 1612, 1588, 1508, 1472. mp 100-101 ℃ Anal Calcd for C 26 H 22 ClF 4 NO 4: C, 59.61; H, 4.23;
N, 2.67 Found: C, 59.67; H, 4.27; N, 2.76.7) (4RS, 5SR) -5- (4-((4-chloro-3-
Ethylphenyl) oxy) phenyl) -4-((3-
((1,1,2,2-tetrafluoroethyl) oxy)
Phenyl) methyl) -1,3-oxazolidin-2-one (4.3 g, 8.21 mmol) in ethanol (20 m
l) 8N aqueous sodium hydroxide solution (5.13 m
(4,11.1 mmol) and heated to reflux for 4 hours.
After concentration, the reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and then distilled off under reduced pressure.
(1RS, 2SR) -2-amino-1- (4-((4-chloro
-3-Ethylphenyl) oxy) phenyl) -3- (3-
((1,1,2,2-tetrafluoroethyl) oxy)
Phenyl) -1-propanol (3.64 g, 89%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.6 Hz), 2.41
(1H, dd, J = 13.6, 10.2Hz), 2.72 (2H, q, J = 7.6H
z), 2.87 (1H, dd, J = 13.6, 3.2 Hz), 4.65 (1H, d,
J = 5.2 Hz), 5.90 (1H, tt, J = 53.0, 3.0 Hz), 6.78
(1H, dd, J = 8.4, 3.0 Hz), 6.88-7.18 (6H, m), 7.2
8-7.40 (4H, m) .IRνmax ^KBr cm ^-1 : 1611, 1586, 1505, 1472, 1412. Anal.Calcd for C ₂₅ H ₂₄ ClF ₄ NO ₃ : C, 60.31; H, 4.86;
N, 32.81 Found: C, 60.31; H, 5.18; N, 2.85.8) (1RS, 2SR) -2-amino-1- (4-((4-
Chloro-3-ethylphenyl) oxy) phenyl) -3-
(3-((1,1,2,2-tetrafluoroethyl) oxy) phenyl) -1-propanol (300 mg, 0.6
0 mmol) in acetonitrile (16 ml) solution.
7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (114 mg, 0.60 mmol) and 1-
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (174 mg, 0.91 mmol) and 1-hydroxy-1H-benzotriazole (92 mg,
(0.60 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
1 × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (318
mg, 79%). ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.2 Hz), 1.90-
2.08 (2H, m), 2.10-2.26 (2H, m), 2.60-2.84 (5H, m),
3.02 (1H, dd, J = 14.6, 4.0 Hz), 3.50-3.90 (1H, b
r), 4.60-4.78 (1H, m), 5.01 (1H, d, J = 3.6 Hz),
5.60-6.22 (4H, m), 6.77 (1H, dd, J = 8.8, 3.0 Hz),
6.84-7.20 (9H, m), 7.28 (2H, d, J = 7.8 Hz), 7.41
.. (2H, d, J = 8.8 Hz) IRνmax KBr cm -1: 1613, 1588, 1505, 1472, 1453. mp 116-117 ℃ Anal Calcd for C 37 H 34 ClF 4 NO 4: C, 66.51; H , 5.13;
N, 2.10 Found: C, 66.22; H, 5.24; N, 2.25.

Example 219 1,1-Dimethylethyl (1RS, 2SR) -2- (2-fluoropyridin-4-yl) -2-hydroxy-1-((3-
(1,1,2,2-tetrafluoroethoxy) phenyl) methyl) ethyl carbamate 1) 2-amino-4-methylpyridine (100 g, 92
5 mmol) of 42% tetrafluoroboric acid (400 m
l) A solution of sodium nitrite (64 g, 927 mmol) in water (100 ml) was gradually added to the solution while cooling with dry ice-acetone so that the internal temperature did not exceed 10 ° C. After stirring the reaction solution at 45 ° C. for 30 minutes, an 8 N aqueous sodium hydroxide solution (100 ml) was gradually added thereto, and the mixture was extracted with diethyl ether (300 ml × 2). After the extract was concentrated under reduced pressure, the residue was distilled to obtain 2-fluoro-4-methylpyridine (48 g). Potassium permanganate (1
00g, 632 mmol) in water (1.2 L)
And heated to 2-fluoro-4-methylpyridine (48
g) was added and the mixture was heated under reflux for 1 hour. Insolubles were filtered from the reaction solution through celite, the filtrate was concentrated to 200 ml, and 6N hydrochloric acid was added until the pH was about 3. The precipitated crystals were collected by filtration to obtain 2-fluoro-4-pyridinecarboxylic acid (19.8 g, 32%). ¹ H-NMR (CDCl ₃ ) δ: 7.50 (1H, s), 7.75 (1H, d, J =
5.0 Hz), 8.40 (1H, d, J = 5.0 Hz) .IRνmax ^KBr cm ^-1 : 3100, 1730, 1620.mp 258-260 ℃ Anal.Calcd for C ₆ H ₄ FNO ₂ : C, 51.07; H, 2.86; N, 9.
93 Found: C, 50.77; H, 2.80; N, 10.04.2) 2-Fluoro-4-pyridinecarboxylic acid (10 g,
70.9 mmol) of tetrahydrofuran (150 m
l) 1,1′-Carbonylbis-1H-imidazole (12.7 g, 78.0 mmol) was added to the solution, and the mixture was heated under reflux for 30 minutes. After cooling the reaction solution, monoethyl magnesium malonate (11.2 g, 39.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. 1N hydrochloric acid (200m
l), and extracted with ethyl acetate (200 ml × 2).
The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from hexane to give ethyl 3- (2-fluoro-4-pyridyl) -3-oxopropionate (7.32 g,
49%). ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.40 (3H, m), 3.98 (2H × 1 /
5, s), 4.18-4.40 (2H, m), 5.76 (1H × 4/5, s), 7.26
(1H × 4/5, s), 7.40 (1H × 1/5, s), 7.50 (1H × 4/5, d,
J = 7.4 Hz), 7.63 (1H × 1/5, d, J = 7.4 Hz), 8.32
(1H × 4/5, d, J = 7.0 Hz), 8.43 (1H × 1/5, d, J = 7.0
.. Hz), 12.44 (1H × 4/5, s) IRνmax KBr cm -1: 1744, 1705, 1651, 1607, 1563. mp 66-67 ℃ Anal Calcd for C 10 H 10 FNO 3: C, 56.87; H, 4.77; N,
6.63 Found: C, 56.92; H, 4.69; N, 6.82. 3) 3- (1,1,2,2-tetrafluoroethoxy)
To a solution of toluene (3.80 g, 18.2 mmol) in carbon tetrachloride (50 ml) was added N-bromosuccinimide (3.
54 g, 19.9 mmol) and 2,2′-azobis (isobutyronitrile) (136 mg, 0.83 mmol) were added, and the mixture was heated under reflux for 4 hours. After cooling, the reaction solution was filtered, and the filtrate was concentrated to prepare 3- (1,1,2,2-tetrafluoroethoxy) -α-bromotoluene. 3-
Ethyl (2-fluoropyridin-4-yl) -3-oxopropionate (3.5 g, 16.6 mmol) in 1,2-
Sodium hydride (60% oily, 0.66 g, 16.6 mmol) was added to a dimethoxyethane (35 ml) solution under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 3- (1,1,2,2-tetrafluoroethoxy)-previously prepared in the reaction solution
1,2-dimethoxyethane of α-bromotoluene (5 m
l) The solution was added dropwise and the reaction was stirred at room temperature for 1 hour. The reaction solution was poured into water (100 ml), and ethyl acetate (10 ml) was added.
0 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene: hexane = 1: 1) to give 3- (2-fluoropyridin-4-yl) -3-oxo-2-((3- (1,
Ethyl 1,2,2-tetrafluoroethoxy) phenyl) methyl) propionate (4.78 g, 69%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.0 Hz), 3.35
(2H, d, J = 7.4 Hz), 4.13 (2H, q, J = 7.0 Hz), 4.4
4-4.56 (1H, m), 5.90 (1H, tt, J = 53.0, 3.0 Hz),
7.00-7.38 (5H, m) .IRνmax ^KBr cm ^-1 : 1740, 1703, 1607, 1588, 1566.Anal.Calcd for C ₁₉ H ₁₆ F ₅ NO ₄ : C, 54.68; H, 3.86; N,
3.36 Found: C, 54.44; H, 3.76; N, 3.55.4) In a solution of zinc chloride (3.12 g, 22.9 mmol) in diethyl ether (100 ml), sodium borohydride (1.74 g, 45.8 mmol) was added. ) And stirred at room temperature for 30 minutes. The insolubles were removed by filtration, and the filtrate was treated with 3- (2-fluoropyridin-4-yl) -3-oxo-2-((3-
Ethyl (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) propionate (4.78 g, 11.
(5 mmol) in diethyl ether (30 ml) and stirred at room temperature for 30 minutes. Under ice cooling, the reaction solution was quenched by adding 1N hydrochloric acid, and water (100 ml) was further added.
Extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 3- (2-fluoropyridin-4-yl) -3-hydroxy-2-((3- (1,1,1,2 Ethyl 2,2-tetrafluoroethoxy) phenyl) methyl) propionate ((2R
(S, 3RS) body: (2RS, 3SR) body = 9: 1,4.
(05 g, 84%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.92-1.06 (3H, m), 2.70-3.10 (3
H, m), 3.54 (1H, dd, J = 2.6 Hz), 3.90-4.04 (2H,
m), 4.77 (1H × 1/10, dd, J = 8.8, 3.4 Hz), 5.13 (1H
× 9/10, s), 5.89 (1H, tt, J = 53.0, 3.0 Hz), 6.90-
7.30 (7H, m), 8.16-8.24 (1H, m) IRνmax KBr cm -1: 1728, 1615, 1588, 1572, 1487. Anal Calcd for C 19 H 18 F 5 NO 4:.. C, 54.42; H , 4.33; N,
3.34 Found: C, 54.37; H, 4.39; N, 3.35.5) (2RS, 3RS) -3- (2-fluoropyridine-
4-yl) -3-hydroxy-2-((3- (1,1,2,2
Ethyl-tetrafluoroethoxy) phenyl) methyl) propionate (3.8 g, 9.06 mmol, (2R
To a solution of (S, 3RS) form: (2RS, 3SR) form = 9: 1) in methanol (20 ml), 2N aqueous sodium hydroxide solution (9.1 ml, 18.2 mmol) was added and stirred at room temperature for 2 hours. . The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (2RS, 3RS) -3- (2-fluoropyridin-4-yl) -3-hydroxy-2-((3-
(1,1,2,2-tetrafluoroethoxy) phenyl) methyl) propionic acid (2.14 g, 60%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.74-2.92 (1H, m), 2.98-3.16 (2
H, m), 5.18 (1H, d, J = 3.2 Hz), 5.88 (1H, tt, J =
53.0, 3.0 Hz), 6.90-7.10 (4H, m), 7.16-7.30 (2H,
m), 8.17 (1H, d, J = 5.2 Hz) .IRνmax ^KBr cm ^-1 : 1717, 1615, 1588, 1570.mp 134-135 ℃ Anal. Calcd for C ₁₇ H ₁₄ F ₅ NO ₄ : C, 52.18 ; H, 3.61; N,
3.58 Found: C, 52.20; H, 3.51; N, 3.58. 6) (2RS, 3RS) -3- (2-fluoropyridine-
4-yl) -3-hydroxy-2-((3- (1,1,2,2
To a solution of -tetrafluoroethoxy) phenyl) methyl) propionic acid (2.0 g, 5.11 mmol) in tetrahydrofuran (50 ml) was added diphenylphosphoryl azide (1.21 ml, 5.62 mmol) and triethylamine (1.07 ml, 7 .67 mmol) and heated to reflux for 2 hours. After allowing the reaction mixture to cool, water (200 ml) was added, and the mixture was extracted with ethyl acetate (100 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purification with ethyl acetate = 1: 1) and recrystallization from ethyl acetate-hexane gave (4RS, 5SR) -5- (2-fluoropyridin-4-yl) -4-((3- (1,1 , 2,2-
Tetrafluoroethoxy) phenyl) methyl) -1,3-
Oxazolidin-2-one (1.36 g, 69%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.27 (1H, dd, J = 14.0, 10.2 H
z), 2.41 (1H, dd, J = 14.0, 4.4 Hz), 4.28-4.42 (1
H, m), 5.49 (1H, s), 5.81 (1H, d, J = 8.0 Hz), 5.91
(1H, tt, J = 53.0, 2.6 Hz), 6.90-7.40 (6H, m), 8.
30 (1H, d, J = 5.2Hz) IRνmax KBr cm -1:. 1771, 1615, 1588, 1574, 1489. mp 118-119 ℃ Anal Calcd for C 17 H 13 F 5 N 2 O 3:. C, 52.59; H, 3.37;
N, 7.21 Found: C, 52.70; H, 3.20; N, 7.20.7) (4RS, 5SR) -5- (2-fluoropyridine-
Acetonitrile of 4-yl) -4-((3- (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) -1,3-oxazolidin-2-one (1.25 g, 3.22 mmol) (20 ml) solution in di-t-butyl dicarbonate (0.
84 g, 3.86 mmol) and dimethylaminopyridine (39 mg, 0.32 mmol).
Stirred for hours. Water (50 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give ethyl acetate-
Recrystallized from hexane, (4RS, 5SR) -5- (2
-Fluoropyridin-4-yl) -2-oxo-4-((3-
1,1-Dimethylethyl (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) -1,3-oxazolidine-3-carboxylate (1.41 g, 89%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s), 2.60 (1H, dd, J =
14.2, 8.8 Hz), 2.95 (1H, dd, J = 14.2, 4.6 Hz), 4.
82-4.98 (1H, m), 5.67 (1H, d, J = 7.0 Hz), 5.90 (1
H, tt, J = 53.0, 3.0 Hz), 6.54 (1H, d, J = 7.4 H
z), 6.73 (1H, s), 6.82 (1H, s), 6.94 (1H, d, J = 5.
0 Hz), 6.98-7.20 (2H, m), 8.09 (1H, d, J = 5.2 Hz) .IRνmax ^KBr cm ^-1 : 1821, 1726, 1615, 1588, 1574, 148
9, 1416.mp 113-114 ℃ Anal.Calcd for C ₂₂ H ₂₁ F ₅ N ₂ O ₅ : C, 54.10; H, 4.33;
N, 5.74 Found: C, 54.10; H, 4.21; N, 5.72.8) (4RS, 5SR) -5- (2-fluoropyridine-
1,1-dimethylethyl 4-yl) -2-oxo-4-((3- (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) -1,3-oxazolidine-3-carboxylate ( 1.30 g, 2.66 mmol) of methanol (7 m
l) To the solution was added 0.5N sodium hydroxide in methanol (6.39 ml, 3.19 mmol), and the mixture was added at room temperature for 1 hour.
Stirred for 0 minutes. Water (50 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (1.08 g, 88%). ¹ H-NMR (CDCl ₃ ) δ: 1.37 (9H, s), 2.60-2.80 (2H, m),
3.82-4.10 (2H, m), 4.68 (1H, d, J = 8.0 Hz), 5.01
(1H, s), 5.89 (1H, tt, J = 53.0, 3.0 Hz), 6.92-7.
12 (4H, m), 7.18-7.32 (2H, m), 8.20 (1H, d, J = 5.
0 Hz) .IRνmax ^KBr cm ^-1 : 1752, 1694, 1615, 1570, 1512, 148
9, 1449, 1412.mp 143-144 ℃ Anal.Calcd for C ₂₁ H ₂₃ F ₅ N ₂ O ₄ : C, 54.55; H, 5.01;
N, 6.06 Found: C, 54.32; H, 4.86; N, 6.07.

Example 220 N-((1RS, 2SR) -2- (2-fluoropyridine-
4-yl) -2-hydroxy-1-((3- (1,1,2,2
-Tetrafluoroethoxy) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 1) 1,1-dimethylethyl (1RS, 2SR) -2- (2-fluoropyridine -4-yl) -2-hydroxy-1-((3- (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) ethylcarbamate (0.8 g, 1.73 mmol) was added to trifluoroacetic acid ( 10 ml) and stirred at room temperature for 10 minutes. After concentrating the reaction solution under reduced pressure, a 1N aqueous sodium hydroxide solution (10
ml) and extracted with ethyl acetate (20 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2SR) -2-amino-1-amino.
(2-Fluoropyridin-4-yl) -3- (3- (1,1,
2,2-Tetrafluoroethoxy) phenyl) -1-propanol (0.59 g, 93%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.40 (1H, dd, J = 13.6, 10.6 H
z), 2.63 (1H, dd, J = 13.6, 3.2 Hz), 3.32-3.48 (1
H, m), 4.79 (1H, d, J = 4.0 Hz), 5.92 (1H, tt, J =
53.0, 3.0 Hz), 6.92-7.40 (6H, m), 8.24 (1H, d, J =
5.2 Hz) .IRνmax ^KBr cm ^-1 : 1613, 1588, 1568, 1487, 1449, 141
0.mp 119-120 ℃ Anal. Calcd for C ₁₆ H ₁₅ F ₅ N ₂ O ₂ : C, 53.04; H, 4.17;
N, 7.73 Found: C, 52.91; H, 4.08; N, 7.60.2) (1RS, 2SR) -2-amino-1- (2-fluoropyridin-4-yl) -3- (3- (1, 1,2,2-tetrafluoroethoxy) phenyl) -1-propanol (3
00 mg, 0.83 mmol) of acetonitrile (20
ml) solution, 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (156 mg, 0.83 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (238 mg) , 1.24 mmol) and 1-hydroxy-1H-benzotriazole (127 mg, 0.83 mmol) were added and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane,
The title compound (347 mg, 79%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.90-2.08 (2H, m), 2.10-2.26 (2
H, m), 2.60-2.72 (2H, m), 2.80-2.92 (2H, m), 4.40-
4.70 (2H, m), 5.11 (1H, d, J = 2.6 Hz), 5.89 (1H, t
t, J = 53.0, 3.0 Hz), 5.90-6.10 (2H, m), 6.24 (1H,
d, J = 11.6 Hz), 6.92-7.38 (9H, m), 8.08 (1H, d,
J = 5.2 Hz) .IRνmax ^KBr cm ^-1 : 1636, 1615, 1588, 1570, 1516, 144
9, 1412.mp 159-160 ℃ Anal. Calcd for C ₂₈ H ₂₅ F ₅ N ₂ O ₃・ 0.2H ₂ O: C, 62.73; H,
4.78; N, 5.23 Found: C, 62.64; H, 4.80; N, 5.37.

Example 221 1,1-Dimethylethyl (1RS, 2RS) -2- (6-fluoropyridin-2-yl) -2-hydroxy-1-((3-
(1,1,2,2-tetrafluoroethoxy) phenyl) methyl) ethyl carbamate 1) 2-amino-6-methylpyridine (75 g, 693)
Mmol) of 42% tetrafluoroboric acid (291 m
l) A solution of sodium nitrite (47.8 g, 693 mmol) in water (100 ml) was gradually added to the solution while cooling with dry ice-acetone so that the internal temperature did not exceed 10 ° C. After stirring the reaction solution at 45 ° C. for 30 minutes, an 8 N aqueous sodium hydroxide solution (100 ml) was gradually added thereto, and the mixture was extracted with diethyl ether (300 ml × 2). After the extract was concentrated under reduced pressure, the residue was distilled to obtain 2-fluoro-6-methylpyridine (27.9 g). A solution of potassium permanganate (100 g, 632 mmol) in water (1.2 L) was heated to 80 ° C., 2-fluoro-6-methylpyridine (27.9 g) was added, and the mixture was heated under reflux for 4 hours. Insolubles were filtered from the reaction solution through celite, the filtrate was concentrated to 200 ml, and 6N hydrochloric acid was added until the pH was about 3. The precipitated crystals were collected by filtration to obtain 6-fluoro-2-pyridinecarboxylic acid (5.84 g, 14%). ¹ H-NMR (CDCl ₃ ) δ: 7.26 (1H, d, J = 7.2 Hz), 7.36
.. (1H, s), 8.00-8.30 (1H, m) IRνmax KBr cm -1: 3100, 1730, 1620. mp 248-250 ℃ Anal Calcd for C 6 H 4 FNO 2: C, 51.07; H, 2.86 ; N, 9.
93 Found: C, 51.10; H, 2.81; N, 9.87. 2) 6-Fluoro-2-pyridinecarboxylic acid (15.0
g, 106.3 mmol) of tetrahydrofuran (20
0 ml) to the solution, 1,1'-carbonylbis-1H-imidazole (19.0 g, 116.9 mmol) was added.
Heated to reflux for a minute. After cooling the reaction solution, monoethyl magnesium malonate (16.8 g, 58.5 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. 1N hydrochloric acid (20
0 ml), and the mixture was extracted with ethyl acetate (200 ml × 2). The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and ethyl 3- (6-fluoro-2-pyridyl) -3-oxopropionate (20.16 g, 90%) was obtained as a brown oil. Obtained as a product. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.40 (3H, m), 4.13 (2H × 2 /
3, s), 4.14-4.34 (2H, m), 6.30 (1H × 1/3, s), 6.96-
7.04 (1H × 1/3, m), 7.12-7.24 (1H × 2/3, m), 7.78-8.
04 (2H, m), 12.32 (1H × 1/3, s) .IRνmax ^KBr cm ^-1 : 1744, 1709, 1651, 1593, 1578, 145
_{. 3. Anal Calcd for C 10 H} 10 FNO 3: C, 56.87; H, 4.77 Found: C, 56.74; H, 4.73 3) 3- (1,1,2,2- tetrafluoroethoxy)
To a solution of toluene (7.51 g, 35.6 mmol) in carbon tetrachloride (100 ml) was added N-bromosuccinimide (7.60 g, 42.7 mmol) and 2,2′-azobis (isobutyronitrile) (290 mg, (1.78 mmol) and heated to reflux for 4 hours. After cooling, the reaction solution was filtered, and the filtrate was concentrated to prepare 3- (1,1,2,2-tetrafluoroethoxy) -α-bromotoluene. 3
1,2- (6-fluoropyridin-2-yl) -3-oxopropionate ethyl (7.51 g, 35.6 mmol)
Sodium hydride (60% oily, 1.42 g, 35.6 mmol) was added to a solution of -dimethoxyethane (70 ml) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. 3- (1,1,2,2-tetrafluoroethoxy) previously prepared in the reaction solution
1,2-dimethoxyethane of -α-bromotoluene (10
ml) solution was added dropwise and the reaction was stirred at room temperature for 1 hour.
The reaction solution was poured into water (100 ml), and ethyl acetate (1
00 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene: hexane = 1: 1) to give 3- (6-fluoropyridin-2-yl) -3-oxo-2-((3- (1,
Ethyl 1,2,2-tetrafluoroethoxy) phenyl) methyl) propionate (7.74 g, 52%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 9.0 Hz), 3.20-
3.44 (2H, m), 4.11 (2H, q, J = 9.0 Hz), 4.98 (1H,
t, J = 7.4 Hz), 5.89 (1H, tt, J = 53.0, 3.0 Hz),
7.00-7.32 (5H, m), 7.90-8.04 (2H, m) .IRνmax ^KBr cm ^-1 : 1732, 1705, 1593, 1453.Anal.Calcd for C ₁₉ H ₁₆ F ₅ NO ₄ : C, 54.68; H , 3.86; N,
3.36 Found: C, 54.55; H, 3.92; N, 3.51.4) In a solution of zinc chloride (4.19 g, 30.7 mmol) in diethyl ether (100 ml), sodium borohydride (2.33 g, 61.4 mmol) was added. ) And stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was treated with 3- (6-fluoropyridin-2-yl) -3-oxo-2-((3-
Ethyl (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) propionate (6.41 g, 15.
4 mmol) in diethyl ether (50 ml).
The mixture was added at 78 ° C and stirred for 30 minutes. The reaction solution was quenched by the addition of 1N hydrochloric acid, water (100 ml) was added, and the mixture was extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1),
3- (6-fluoropyridin-2-yl) -3-hydroxy-
Ethyl 2-((3- (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) propionate ((2R
(S, 3RS) body: (2RS, 3SR) body = 6: 1,5.
(70 g, 88%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.96-1.00 (3H, m), 2.87 (1H, dd,
J = 5.0 Hz), 2.96-3.14 (1H, m), 3.20-3.40 (1H,
m), 3.76 (1H, d, J = 5.6 Hz), 3.90-4.04 (2H, m),
4.76 (1H × 1/7, dd, J = 9.6, 4.4 Hz), 5.00-5.08 (1H
× 6/7, m), 5.89 (1H, tt, J = 53.0, 3.0 Hz), 6.83
(1H, dd, J = 8.0, 2.6 Hz), 6.90-7.36 (5H, m), 7.70-
7.86 (1H, m) .IRνmax ^KBr cm ^-1 : 1728, 1607, 1578, 1454.Anal.Calcd for C ₁₉ H ₁₈ F ₅ NO ₄ : C, 54.42; H, 4.33; N,
3.34 Found: C, 54.34; H, 4.37; N, 3.29.5) (2RS, 3RS) -3- (6-fluoropyridine-
2-yl) -3-hydroxy-2-((3- (1,1,2,2
-Tetrafluoroethoxy) phenyl) methyl) ethyl propionate (5.5 g, 13.1 mmol, (2R
To a solution of (S, 3RS) form: (2RS, 3SR) form = 6: 1) in methanol (25 ml), 2N aqueous sodium hydroxide solution (13.1 ml, 26.2 mmol) was added and stirred at room temperature for 2 hours. . The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (2RS, 3RS) -3- (6-fluoropyridin-2-yl) -3-hydroxy-2-((3-
(1,1,2,2-tetrafluoroethoxy) phenyl) methyl) propionic acid (3.82 g, 74%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.85 (1H, dd, J = 14.0, 5.2 Hz),
3.08 (1H, dd, J = 14.0, 9.0 Hz), 3.26-3.38 (1H,
m), 5.12 (1H, d, J = 4.4 Hz), 5.88 (1H, tt, J = 53.
0, 3.0 Hz), 6.81 (1H, dd, J = 8.2, 2.6 Hz), 6.90-
7.04 (3H, m), 7.18 (1H, d, J = 7.6 Hz), 7.27 (1H,
. dd, J = 7.2, 2.2 Hz), 7.70-7.82 (1H, m) IRνmax KBr cm -1:. 1713, 1609, 1580, 1489, 1456. mp 103-104 ℃ Anal Calcd for C 17 H 14 F 5 NO ₄ : C, 52.18; H, 3.61; N,
3.58 Found: C, 52.16; H, 3.57; N, 3.57.6.) (2RS, 3RS) -3- (6-fluoropyridine-)
2-yl) -3-hydroxy-2-((3- (1,1,2,2
To a solution of -tetrafluoroethoxy) phenyl) methyl) propionic acid (3.6 g, 9.20 mmol) in tetrahydrofuran (90 ml), diphenylphosphoryl azide (2.18 ml, 10.1 mmol) and triethylamine (1.93 ml, 13 (0.8 mmol) and heated under reflux for 2 hours. After allowing the reaction mixture to cool, water (200 ml) was added, and the mixture was extracted with ethyl acetate (100 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purification with ethyl acetate = 1: 1) and recrystallization from ethyl acetate-hexane gave (4RS, 5RS) -5- (6-fluoropyridin-2-yl) -4-((3- (1,1 , 2,2-
Tetrafluoroethoxy) phenyl) methyl) -1,3-
Oxazolidin-2-one (2.34 g, 65%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.14 (1H, dd, J = 13.6, 9.0 Hz),
2.58 (1H, dd, J = 13.6, 3.2 Hz), 4.36-4.50 (1H,
m), 5.13 (1H, s), 5.78 (1H, d, J = 8.0 Hz), 5.91
(1H, tt, J = 53.0, 3.0 Hz), 6.90-7.20 (4H, m), 7.2
6-7.42 (1H, m), 7.52 (1H, d, J = 5.2 Hz), 7.86-8.0
0 (1H, m) .IRνmax ^KBr cm ^-1 : 1767, 1607, 1584, 1489, 1458, 144
7.mp 118-119 ℃ Anal.Calcd for C ₁₇ H ₁₃ F ₅ N ₂ O ₃ : C, 52.59; H, 3.37;
N, 7.21 Found: C, 52.60; H, 3.31; N, 7.35.7) (4RS, 5RS) -5- (6-fluoropyridine-
Acetonitrile of 2-yl) -4-((3- (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) -1,3-oxazolidin-2-one (2.2 g, 5.67 mmol) (20 ml) solution in di-t-butyl dicarbonate (1.4).
8 g, 6.80 mmol) and dimethylaminopyridine (70 mg, 0.57 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water (50 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give (4RS, 5RS) -5- (6-fluoropyridin-2-yl) -2. -Oxo-4-((3-
1,1-Dimethylethyl (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) -1,3-oxazolidine-3-carboxylate (2.59 g, 94%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.65 (1H, dd, J =
14.2, 7.4 Hz), 2.84 (1H, dd, J = 14.2, 5.8 Hz), 4.
97-5.08 (1H, m), 5.61 (1H, d, J = 6.4 Hz), 5.88 (1
H, tt, J = 53.0, 3.0 Hz), 6.53 (1H, s), 6.75 (1H,
d, J = 7.6 Hz), 6.88 (1H, dd, J = 8.0, 2.6 Hz), 7.0
2 (1H, d, J = 9.6 Hz), 7.10-7.22 (1H, m), 7.43 (1H,
dd, J = 7.4, 2.6 Hz), 7.80-7.94 (1H, m).
^KBr cm ^-1 : 1823, 1728, 1607, 1584, 1460, 1447.mp 96-97 ° C Anal.Calcd for C ₂₂ H ₂₁ F ₅ N ₂ O ₅ : C, 54.10; H, 4.33;
N, 5.74 Found: C, 54.14; H, 4.25; N, 5.78.8) (4RS, 5RS) -5- (6-fluoropyridine-
1,1-dimethylethyl 2-yl) -2-oxo-4-((3- (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) -1,3-oxazolidine-3-carboxylate ( 2.40 g (4.91 mmol) of methanol (12
0.5N sodium hydroxide in methanol (11.8 ml, 5.90 mmol) was added to the mixture at room temperature.
Minutes. Water (50 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was recrystallized from ethyl acetate-hexane to give the title compound (1.92 g, 84%). ¹ H-NMR (CDCl ₃ ) δ: 1.37 (9H, s), 2.65 (1H, dd, J =
13.6, 5.0 Hz), 2.85 (1H, dd, J = 13.6, 9.0 Hz), 4.
08-4.30 (1H, m), 4.45 (1H, d, J = 6.0 Hz), 4.88-5.
02 (2H, m), 5.89 (1H, tt, J = 53.0, 3.0 Hz), 6.85
(1H, dd, J = 8.0, 2.2 Hz), 6.90-7.10 (3H, m), 7.10
-7.32 (2H, m), 7.70-7.86 (1H, m) .IRνmax ^KBr cm ^-1 : 1682, 1607, 1576, 1532, 1487, 145
4.mp 140-141 ℃ Anal. Calcd for C ₂₁ H ₂₃ F ₅ N ₂ O ₄ : C, 54.55; H, 5.01;
N, 6.06 Found: C, 54.27; H, 4.71; N, 6.12.

Example 222 N-((1RS, 2RS) -2- (6-fluoropyridine-
2-yl) -2-hydroxy-1-((3- (1,1,2,2
-Tetrafluoroethoxy) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 1) 1,1-dimethylethyl (1RS, 2RS) -2-
(6-fluoropyridin-2-yl) -2-hydroxy-1-
((3- (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) ethyl carbamate (1.6 g, 3.
Trifluoroacetic acid (20 ml) was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. After concentrating the reaction solution under reduced pressure, 1
An aqueous solution of N sodium hydroxide (10 ml) was added, and the mixture was extracted with ethyl acetate (20 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and then distilled off under reduced pressure.
(1RS, 2RS) -2-amino-1- (6-fluoropyridin-2-yl) -3- (3- (1,1,2,2-tetrafluoroethoxy) phenyl) -1-propanol (1. 3
g, 100%). ¹ H-NMR (CDCl ₃ ) δ: 2.47 (1H, dd, J = 13.8, 10.0 H
z), 2.73 (1H, dd, J = 13.8, 3.4 Hz), 3.40-3.54 (1
H, m), 4.70 (1H, d, J = 4.4 Hz), 5.90 (1H, tt, J =
53.0, 3.0 Hz), 6.86 (1H, dd, J = 8.0, 2.6 Hz), 6.9
6-7.18 (3H, m), 7.20-7.40 (2H, m), 7.78-7.92 (1H,
m) .IRνmax ^KBr cm ^-1 : 1755, 1607, 1578, 1489, 1454. Anal.Calcd for C ₁₆ H ₁₅ F ₅ N ₂ O ₂ : C, 53.04; H, 4.17;
N, 7.73 Found: C, 53.19; H, 4.40; N, 7.51.2) (1RS, 2RS) -2-amino-1- (6-fluoropyridin-2-yl) -3- (3- (1,1 1,2,2-tetrafluoroethoxy) phenyl) -1-propanol (3
00 mg, 0.83 mmol) of acetonitrile (20
ml) solution, 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (156 mg, 0.83 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (238 mg) , 1.24 mmol) and 1-hydroxy-1H-benzotriazole (127 mg, 0.83 mmol) were added and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane,
The title compound (293 mg, 66%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.92-2.10 (2H, m), 2.12-2.26 (2
H, m), 2.60-2.70 (2H, m), 2.81 (1H, dd, J = 14.6,
5.2 Hz), 3.03 (1H, dd, J = 14.6, 9.8 Hz), 4.66-4.8
2 (1H, m), 4.84 (1H, d, J = 5.8 Hz), 5.02-5.10 (1
H, m), 5.89 (1H, tt, J = 53.0, 3.0 Hz), 5.90-6.02
(1H, m), 6.18-6.32 (2H, m), 6.86 (1H, dd, J = 8.0,
2.6 Hz), 7.00-7.30 (7H, m), 7.42 (1H, dd, J = 7.
4, 2.2 Hz), 7.76-7.90 (1H, m). IRνmax ^KBr cm ^-1 : 1642, 1607, 1578, 1516, 1454.mp 151-152 ° C Anal.Calcd for C ₂₈ H ₂₅ F ₅ N ₂ O ₃・ 0.2H ₂ O: C, 62.73; H,
4.78; N, 5.23 Found: C, 62.75; H, 4.75; N, 5.31.

Example 223 1,1-Dimethylethyl (1RS, 2SR) -2- (6-fluoropyridin-3-yl) -2-hydroxy-1-((3-
(1,1,2,2-tetrafluoroethoxy) phenyl) methyl) ethyl carbamate 1) 2-amino-5-methylpyridine (75 g, 693)
Mmol) of 42% tetrafluoroboric acid (291 m
l) A solution of sodium nitrite (47.8 g, 693 mmol) in water (100 ml) was gradually added to the solution while cooling with dry ice-acetone so that the internal temperature did not exceed 10 ° C. After stirring the reaction solution at 45 ° C. for 30 minutes, an 8 N aqueous sodium hydroxide solution (100 ml) was gradually added thereto, and the mixture was extracted with diethyl ether (300 ml × 2). After the extract was concentrated under reduced pressure, the residue was distilled to obtain 2-fluoro-5-methylpyridine (30.4 g). A solution of potassium permanganate (100 g, 632 mmol) in water (1.2 L) was heated to 80 ° C., 2-fluoro-5-methylpyridine (30.4 g, 274 mmol) was added, and the mixture was heated under reflux for 4.5 hours. did. Insolubles were filtered from the reaction solution through celite, the filtrate was concentrated to 200 ml, and 6N hydrochloric acid was added until the pH was about 3. The precipitated crystals were collected by filtration, and 6-fluoro-3-pyridinecarboxylic acid (10.58 g, 11
%). mp 151-152 ° C IRνmax ^KBr cm ^-1 : 3100, 1730, 1620. Anal.Calcd for C ₆ H ₄ FNO ₂ : C, 51.07; H, 2.86; N, 9.
93 Found:. C, 50.78; H, 2.72; N, 9.87 1 H-NMR (CDCl 3) δ: 7.07 (1H, dd, J = 8.8, 2.8 Hz),
8.40-8.52 (1H, m), 8.90-9.04 (1H, m). 2) 6-Fluoro-3-pyridinecarboxylic acid (9.5
g, 67.3 mmol) of tetrahydrofuran (150
ml) solution, 1,1′-carbonylbis-1H-imidazole (12.0 g, 74.1 mmol) was added, and the mixture was stirred at 80 ° C. for 10 minutes. After cooling the reaction solution to room temperature, monoethyl magnesium malonate (10.6 g, 37.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate (100 ml) and water (100 ml) were added to the reaction solution, and concentrated hydrochloric acid was further added until the pH of the aqueous layer became acidic. The reaction solution was extracted with ethyl acetate (200 ml × 2), the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 3- (6-
Ethyl fluoropyridin-3-yl) -3-oxopropionate (9.74 g, 68%) was obtained as a brown oil. IRνmax ^KBr cm ^-1 : 1738, 1694, 1634, 1593, 1485.Anal.Calcd for C ₁₀ H ₁₀ NO ₃ F: C, 56.87; H, 4.77; N,
6.63 Found:. C, 56.79; H, 4.78; N, 6.84 1 H-NMR (CDCl 3) δ: 1.27 (3H × 5/7, t, J = 7.0 Hz),
1.35 (3H × 2/7, t, J = 7.4 Hz), 3.99 (2H × 5/7, s),
4.16-4.36 (2H, m), 5.65 (1H × 2/7, s), 6.96-7.10 (1
H, m), 8.16 (1H × 2/7, td, J = 9.0, 3.8 Hz), 8.39
(1H × 5/7, td, J = 9.0, 3.8 Hz), 8.64 (1H × 2/7, d, J
= 3.8 Hz), 8.81 (1H × 5/7, d, J = 3.8 Hz). 3) 3- (1,1,2,2-tetrafluoroethoxy)
To a solution of toluene (15 g, 72.1 mmol) in chloroform (200 ml) was added N-bromosuccinimide (1
4.11 g (79.3 mmol) and 2,2′-azobis (isobutyronitrile) (590 mg, 3.60 mmol) were added and heated under reflux for 30 minutes. After cooling the reaction solution,
Water (100 ml) was added, and the mixture was extracted with chloroform. The extract was washed successively with water (100 ml) and saturated saline (100 ml), dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give 3- (1,1).
(1,2,2-tetrafluoroethoxy) -α-bromotoluene (19.4 g, purity 56%, 53%) was obtained. This compound was used for the next reaction without further purification. 4) Ethyl 3- (6-fluoropyridin-3-yl) -3-oxopropionate (3.83 g, 18.1 mmol)
To a solution of the above in 1,2-dimethoxyethane (30 ml) was added sodium hydride (60% oil, 725 mg, 18.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 3- (1,1,2,2-tetrafluoroethoxy) -α-
A solution of bromotoluene (9.30 g, purity 56%, 18.1 mmol) in 1,2-dimethoxyethane (10 ml) was added dropwise, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was poured into water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (toluene-
Purification with toluene: ethyl acetate = 5: 1) and purification of 3- (6-fluoropyridin-3-yl) -3-oxo-2-((3-
Ethyl (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) propionate (6.67 g, 88
%) As a colorless oil. IRνmax ^KBr cm ^-1 : 1738, 1694, 1590, 1487.Anal.Calcd for C ₁₉ H ₁₆ F ₅ NO ₄ : C, 54.68; H, 3.86; N,
3.36 Found: C, 54.56; H, 4.13; N, 3.51. ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.0 Hz), 3.36
(2H, d, J = 7.4 Hz), 4.13 (2H, q, J = 7.0 Hz), 4.5
4 (1H, d, J = 7.4 Hz), 5.89 (1H, tt, J = 53.0, 2.8
Hz), 6.98-7.20 (4H, m), 7.20-7.36 (1H, m), 8.35
(1H, td, J = 8.4,2.4 Hz), 8.82 (1H, d, J = 2.4 H
z). 5) To a solution of zinc chloride (4.25 g, 31.2 mmol) in diethyl ether (100 ml) was added sodium borohydride (2.36 g, 62.3 mmol), and the mixture was stirred at room temperature for 30 minutes. The insolubles were removed by filtration, and the filtrate was treated with 3- (6-fluoropyridin-3-yl) -3-oxo-2-((3-
Ethyl (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) propionate (6.50 g, 15.
(6 mmol) in diethyl ether (50 ml) and stirred at room temperature for 30 minutes. Under ice cooling, the reaction solution was quenched by adding 1N hydrochloric acid, and water (100 ml) was further added.
Extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1-1: 1)
And purified with (2RS, 3RS) -3- (6-fluoropyridin-3-yl) -3-hydroxy-2-((3- (1,1,
2,2-tetrafluoroethoxy) phenyl) methyl)
Ethyl propionate ((1RS, 2SR) form: (1R
(S, 2RS) form = 10: 1, 5.15 g, 79%) as a colorless oil. IRνmax ^KBr cm ^-1 : 1728, 1601, 1487. Anal.Calcd for C ₁₉ H ₁₈ F ₅ NO ₄・ 0.1H ₂ O: C, 54.19; H,
4.35; N, 3.33 Found:. C, 54.10; H, 4.20; N, 3.39 1 H-NMR (CDCl 3) δ: 0.95 (3H × 10/11, t, J = 7.0 Hz),
1.02 (3H × 1/11, t, J = 7.4 Hz), 2.80-3.16 (3H, m),
3.23 (1H, d, J = 3.0 Hz), 3.84-4.00 (2H, m), 4.80
-4.90 (1H × 1/11, m), 5.09 (1H × 10/11, s), 5.89 (1
H, tt, J = 53.0,3.0 Hz), 6.90-7.12 (4H, m), 7.20-
7.30 (1H, m), 7.86 (1H, td, J = 8.2, 2.6 Hz), 8.16
-8.24 (1H, m). 6) (2RS, 3RS) -3- (6-fluoropyridine-
3-yl) -3-hydroxy-2-((3- (1,1,2,2
Ethyl-tetrafluoroethoxy) phenyl) methyl) propionate (5.0 g, 11.9 mmol, (2R
To a solution of (S, 3SR) form: (2RS, 3RS) form = 10: 1) in methanol (20 ml), 2N aqueous sodium hydroxide solution (11.9 ml, 23.8 mmol) was added and stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give (2RS, 3
RS) -3- (6-Fluoropyridin-3-yl) -3-hydroxy-2-((3- (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) propionic acid (3.75)
g, (2RS, 3SR) body: (2RS, 3RS) body = 1
(0: 1, 80%) as amorphous. IRνmax ^KBr cm ^-1 : 1715, 1607, 1593, 1487.Anal.Calcd for C ₁₇ H ₁₄ F ₅ NO ₄ : C, 52.18; H, 3.61; N,
3.58 Found:. C, 52.13; H, 3.43; N, 3.57 1 H-NMR (CDCl 3) δ: 2.80-3.12 (3H, m), 4.85 (1H × 1/1
1, d, J = 5.2 Hz), 5.10 (1H × 10/11, s), 6.88-7.12
(4H, m), 7.22 (1H, t, J = 7.6 Hz), 7.87 (1H, td, J
= 7.6, 2.2 Hz), 8.14 (1H, s). 7) (2RS, 3RS) -3- (6-fluoropyridine-
3-yl) -3-hydroxy-2-((3- (1,1,2,2
-Tetrafluoroethoxy) phenyl) methyl) propionic acid (3.6 g, 9.20 mmol, (2RS, 3S
R) form: (2RS, 3RS) form = 10: 1) to a tetrahydrofuran (90 ml) solution was added diphenylphosphoryl azide (2.18 ml, 10.1 mmol) and triethylamine (1.93 ml, 13.8 mmol). ,
The mixture was refluxed for 30 minutes. After allowing the reaction solution to cool, water (200 m
1) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give (4RS, 5
SR) -5- (6-Fluoropyridin-3-yl) -4-
((3- (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) -1,3-oxazolidin-2-one (3.31 g, (4RS, 5SR) form: (4RS, 5R)
S) form = 10: 1, 93%) was obtained as amorphous. IRνmax ^KBr cm ^-1 : 1767, 1603, 1489. Anal.Calcd for C ₁₇ H ₁₃ F ₅ N ₂ O ₃ : C, 52.59; H, 3.37;
N, 7.21 Found:. C, 52.46; H, 3.55; N, 7.03 1 H-NMR (CDCl 3) δ: 2.34 (1H, d, J = 4.0 Hz), 2.38
(1H, s), 4.04-4.20 (1H × 1/11, m), 4.28-4.42 (1H × 1
0/11, m), 5.25 (1H × 1/11, s), 5.29 (1H × 10/11, s),
5.84 (1H, d, J = 8.0 Hz), 5.91 (1H, tt, J = 53.0,
3.0 Hz), 6.86-7.18 (4H, m), 7.22-7.40 (1H, m), 7.
60-7.78 (1H × 1/11, m), 7.85 (1H × 10/11, td, J = 8.
2, 2.6 Hz), 8.02 (1H × 1/11, s), 8.22 (1H × 10/11,
s). 8) (4RS, 5SR) -5- (6-fluoropyridine-
Acetonitrile of 3-yl) -4-((3- (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) -1,3-oxazolidin-2-one (3.10 g, 7.98 mmol) (30 ml) solution in di-t-butyl dicarbonate (2.
09 g, 9.58 mmol) and dimethylaminopyridine (97 mg, 0.80 mmol) were added at room temperature.
Stirred for hours. Water (50 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give ethyl acetate-
Recrystallized from hexane to give (4RS, 5SR) -5- (6
-Fluoropyridin-3-yl) -2-oxo-4-((3-
There was obtained 1,1-dimethylethyl (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) -1,3-oxazolidine-3-carboxylate (2.55 g, 65%). mp 138-139 ° C IRνmax ^KBr cm ^-1 : 1821, 1725, 1603. Anal.Calcd for C ₂₂ H ₂₁ F ₅ N ₂ O ₅ : C, 54.10; H, 4.33;
N, 5.74 Found:. C, 54.14; H, 4.41; N, 5.77 1 H-NMR (CDCl 3) δ: 1.54 (9H, s), 2.06 (1H, dd, J =
14.2, 9.6 Hz), 3.04 (1H, dd, J = 14.2, 4.0 Hz), 4.
82-4.96 (1H, m), 5.72 (1H, d, J = 6.8 Hz), 5.89 (1
H, tt, J = 53.0, 3.0 Hz), 6.52-6.62 (2H, m), 6.81
(1H, dd, J = 8.4, 2.8 Hz), 6.94-7.04 (1H, m), 7.04
-7.20 (1H, m), 7.53 (1H, td, J = 8.0,2.6 Hz), 8.05
(1H, d, J = 2.0 Hz). 9) (4RS, 5SR) -5- (6-fluoropyridine-
1,1-dimethylethyl 3-yl) -2-oxo-4-((3- (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) -1,3-oxazolidine-3-carboxylate 2.40 g (4.91 mmol) of methanol (12
0.5N sodium hydroxide in methanol (11.8 ml, 5.90 mmol) was added to the mixture at room temperature.
Minutes. Water (50 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was recrystallized from ethyl acetate-hexane to give the title compound (1.98 g, 87%). mp 128-129 ° C IRνmax ^KBr cm ^-1 : 1694, 1601, 1487. Anal.Calcd for C ₂₁ H ₂₃ F ₅ N ₂ O ₄ : C, 54.55; H, 5.01;
N, 6.06 Found:. C, 54.49; H, 5.01; N, 6.23 1 H-NMR (CDCl 3) δ: 1.34 (9H, s), 2.62-2.90 (2H, m),
3.92 (1H, brs), 3.98-4.16 (1H, m), 4.62 (1H, d, J
= 7.4 Hz), 4.94 (1H, s), 5.90 (1H, tt, J = 53.0,
3.0 Hz), 6.90-7.12 (4H, m), 7.22-7.32 (1H, m), 7.8
0-7.92 (1H, m), 8.21 (1H, s).

Example 224 N-((1RS, 2SR) -2- (6-fluoropyridine-
3-yl) -2-hydroxy-1-((3- (1,1,2,2
-Tetrafluoroethoxy) phenyl) methyl) ethyl) -4-fluoro-1-naphthalenecarboxamide 1) 1,1-dimethylethyl (1RS, 2SR) -2-
(6-fluoropyridin-3-yl) -2-hydroxy-1-
((3- (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) ethyl carbamate (1.0 g, 2.
(16 mmol) was added with trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 10 minutes. After concentrating the reaction solution under reduced pressure, 1
An aqueous solution of N sodium hydroxide (10 ml) was added, and the mixture was extracted with ethyl acetate (20 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2SR) -2-amino-1- (6-fluoropyridin-3-yl) -3- (3- (1,1,2,2-tetra (Fluoroethoxy) phenyl) -1-propanol (750m
g, 96%). mp 103-104 ° C IRνmax ^KBr cm ^-1 : 1597, 1485, 1449, 1399. Anal.Calcd for C ₁₆ H ₁₅ F ₅ N ₂ O ₂ : C, 53.04; H, 4.17;
N, 7.73 Found:. C, 52.97; H, 4.17; N, 7.84 1 H-NMR (CDCl 3) δ: 2.38 (1H, dd, J = 13.4, 10.4 H
z), 2.74 (1H, dd, J = 13.4, 3.0 Hz), 3.28-3.40 (1
H, m), 4.76 (1H, d, J = 4.4 Hz), 5.90 (1H, tt, J =
53.0, 3.0 Hz), 6.90-7.12 (4H, m), 7.22-7.40 (1H,
m), 7.88 (1H, td, J = 8.2, 2.6 Hz), 8.23 (1H, s). 2) (1RS, 2SR) -2-amino-1- (6-fluoropyridin-3-yl) -3 -(3- (1,1,2,2-tetrafluoroethoxy) phenyl) -1-propanol (1
91 mg, 0.53 mmol) of acetonitrile (20
ml) solution with 4-fluoronaphthalenecarboxylic acid (10
0 mg, 0.53 mmol) and 1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide hydrochloride (1
51 mg, 0.79 mmol) and 1-hydroxy-1
H-benzotriazole (81 mg, 0.53 mmol) was added and the mixture was stirred at room temperature overnight. The reaction solution was washed with water (100
ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (130 mg, 48%).
I got mp 148-149 ° C IRνmax ^KBr cm ^-1 : 1640, 1626, 1601, 1514, 1485. Anal.Calcd for C ₂₇ H ₂₀ F ₆ N ₂ O ₃ : C, 60.68; H, 3.77;
N, 5.24 Found:. C, 60.87; H, 3.87; N, 5.11 1 H-NMR (CDCl 3) δ: 2.84 (1H, dd, J = 14.2, 10.6 H
z), 3.09 (1H, dd, J = 14.2, 4.0 Hz), 4.02 (1H, br
s), 4.64-4.82 (1H, m), 5.15 (1H, d, J = 4.0 Hz),
5.89 (1H, tt, J = 53.0, 3.0 Hz), 5.97 (1H, d, J =
8.4 Hz), 6.90-7.70 (9H, m), 7.78-7.90 (1H, m), 7.9
7 (1H, td, J = 8.0, 2.2 Hz), 8.09 (1H, d, J = 7.2 H
z), 8.26 (1H, s).

Example 225 N-((1RS, 2SR) -2- (6-fluoropyridine-
3-yl) -2-hydroxy-1-((3- (1,1,2,2
-Tetrafluoroethoxy) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- (6-fluoropyridin-3-yl ) -3- (3- (1,1,2,2-tetrafluoroethoxy) phenyl) -1-propanol (193 m
g, 0.53 mmol) of acetonitrile (20 ml)
6,7-Dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (100 mg, 0.53 mmol) was added to the solution.
And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (153 mg, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) were added, and the mixture was stirred at room temperature overnight. did. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was recrystallized from ethyl acetate-hexane to give the title compound (232 mg, 82%). mp 140-142 ° C IRνmax ^KBr cm ^-1 : 1636, 1597, 1487. ¹ H-NMR (CDCl ₃ ) δ: 1.90-2.10 (2H, m), 2.10-2.28 (2
H, m), 2.58-2.72 (2H, m), 2.79 (1H, dd, J = 14.4,
10.8 Hz), 3.03 (1H, dd, J = 14.4, 4.0 Hz), 4.26 (1
H, brs), 4.58-4.74 (1H, m), 5.07 (1H, d, J = 3.6 H
z), 5.80 (1H, d, J = 7.6 Hz), 5.89 (1H, tt, J = 53.
0, 3.0 Hz), 5.90-6.00 (1H, m), 6.10-6.24 (1H, m),
6.90-7.22 (7H, m), 7.22-7.40 (1H, m), 7.94 (1H, t
d, J = 8.0, 2.2 Hz), 8.23 (1H, s).

Example 226 N-[(1RS, 2SR) -2- (4-fluorophenyl)
Optical Resolution of 2--2-Hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] naphthalene-1-carboxamide The racemate was converted to an optically active column (Chiralcel OD, 50 mm ID).
× 500 mmL) by high-performance liquid chromatography (mobile phase: hexane / ethanol = 9 /
After 1), recrystallization from ethanol yielded each optical isomer. (1R, 2S) form mp 239-240 ° C .; [α] _D ²⁰ + 37.3 ° (c = 0.507, MeOH); ¹ H
-NMR (CDCl ₃ -CD ₃ OD, 200MHz) δ 2.85 (1H, dd, J = 1
0.8 Hz, 14.0 Hz), 3.08 (1H, dd, J = 3.6 Hz, 13.8 H
z), 4.72-4.87 (1H, m), 5.02 (1H, d, J = 4.6 Hz),
6.79 (1H, br d, J = 8.8 Hz), 7.10 (2H, t, J = 8.6 H
z), 7.21 (1H, d, J = 7.0 Hz), 7.30-7.57 (10H, m),
7.77-7.88 (2H, m); IR (KBr) 3268, 1638, 1534, 151
4, 1325, 1229, 1163, 1123, 1069, 831 cm ^-1 ; Anal. C
alcd for C ₂₇ H ₂₁ F ₄ NO ₂ : C, 69.37; H, 4.53; N, 3.00. F
ound: C, 69.30; H, 4.27; N, 2.76. (1S, 2R) form mp 238-239 ° C; [α] _D ²⁰ -37.9 ° (c = 0.508, MeOH); ¹
H-NMR (CDCl ₃ -CD ₃ OD, 200MHz) δ 2.85 (1H, dd, J = 1
1.4 Hz, 14.2 Hz), 3.09 (1H, dd, J = 3.9 Hz, 13.7 H
z), 4.72-4.86 (1H, m), 5.01 (1H, d, J = 4.8 Hz),
6.90 (1H, br d, J = 9.6 Hz), 7.11 (2H, t, J = 8.8 H
z), 7.20 (1H, dd, J = 1.2 Hz, 7.0 Hz), 7.29-7.57 (1
0H, m), 7.79-7.88 (2H, m); IR (KBr) 3279, 1638, 15
34, 1514, 1325, 1229, 1163, 1123, 1069, 833 cm ^-1 ; A
nal.Calcd for C ₂₇ H ₂₁ F ₄ NO ₂ : C, 69.37; H, 4.53; N,
3.00. Found: C, 69.28; H, 4.50; N, 2.98.

Example 227 4-Fluoro-N-[(1RS, 2SR) -2- (4-fluoro
Rophenyl) -2-hydroxy-1- [4- (trifluoro
Methyl) benzyl] ethyl] naphthalene-1-carbox
Optical Resolution of Mid Racemate is converted to an optically active column (Chiral Cell OD, 50mmID
× 500mmL) for high performance liquid chromatography
More optical resolution (mobile layer: hexane / ethanol = 95 /
5) After ethanol-diisopropyl ether
Recrystallization afforded each optical isomer. (1R, 2S) form mp 251-252 ° C; [α]_D ²⁰ + 33.4 ° (c = 0.499, MeOH);¹
H-NMR (CDCl_Three-DMSO-d₆, 200MHz) δ 2.92 (1H, dd, J =
11.0 Hz, 13.8 Hz), 3.19 (1H, dd, J = 3.3 Hz, 14.3
Hz), 4.62-4.76 (1H, m), 4.89 (1H, t, J = 5.2 Hz),
5.49 (1H, d, J = 4.4 Hz), 7.01-7.18 (4H, m), 7.32-
7.42 (4H, m), 7.48-7.60 (5H, m), 7.91 (1H, d, J =
9.6 Hz), 8.03 (1H, d, J = 8.6 Hz); IR (KBr) 3275,
1642, 1626, 1539, 1514, 1327, 1229, 1167, 1125, 10
69, 835 cm^-1; Anal. Calcd for C ₂₇H₂₀F_FiveNO_Two: C, 66.8
0; H, 4.15; N, 2.89. Found: C, 66.55; H, 4.16; N,
2.76. (1S, 2R) form mp 252-253 ° C; [α]_D ²⁰ -33.9 ° (c = 0.504, MeOH);¹
H-NMR (CDCl_Three-DMSO-d₆, 200MHz) δ 2.93 (1H, dd, J =
11.0 Hz, 14.0 Hz), 3.15 (1H, dd, J = 3.2 Hz, 14.0
Hz), 4.66-4.79 (1H, m), 4.93 (1H, t, J = 4.8 Hz),
5.42 (1H, d, J = 3.6 Hz), 7.01-7.21 (4H, m), 7.34-
7.60 (9H, m), 7.78 (1H, d, J = 9.6 Hz), 8.04 (1H,
d, J = 8.2 Hz); IR (KBr) 3275, 1642, 1626, 1539, 1
514, 1327, 1227, 1167, 1125, 1069, 835 cm^-1; Anal.
 Calcd for C₂₇H₂₀F_FiveNO_Two: C, 66.80; H, 4.15; N, 2.8
9. Found: C, 66.69; H, 4.09; N, 2.82.

Example 228 4-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2
Optical Resolution of 2-Tetrafluoroethoxy) benzyl] ethyl] naphthalene-1-carboxamide The racemate was converted to an optically active column (Chiralcel OD, 50 mm ID).
× 500 mmL) by high-performance liquid chromatography (mobile layer: hexane / ethanol = 95 /
After 5), recrystallization from ethyl acetate-diisopropyl ether-hexane gave each optical isomer. (1R, 2S) form mp 213-214 ° C .; [α] _D ²⁰ + 20.6 ° (c = 0.506, MeOH); ¹
H-NMR (CDCl ₃ -DMSO-d ₆ , 200MHz) δ 2.82-3.03 (2H, m),
4.70-4.84 (2H, m), 5.07 (1H, t, J = 3.3 Hz), 5.90
(1H, tt, J = 2.8 Hz, 53.0 Hz), 6.92 (1H, d, J =
9.4 Hz), 6.98-7.33 (8H, m), 7.42-7.57 (4H, m), 7.7
9 (1H, d, J = 8.4 Hz), 8.07 (1H, d, J = 7.4 Hz); IR
(KBr) 3270, 1642, 1624, 1601, 1537, 1512, 1235, 1
198, 1127, 835, 760 cm ^-1 ; Anal.Calcd for C ₂₈ H ₂₁ F ₆
NO ₃ : C, 63.04; H, 3.97; N, 2.63. Found: C, 62.87;
H, 3.84; N, 2.64. (1S, 2R) form mp 213-214 ° C; [α] _D ²⁰ -20.6 ° (c = 0.520, MeOH); ¹
H-NMR (CDCl ₃ -DMSO-d ₆ , 200MHz) δ 2.82-3.03 (2H, m),
4.70-4.85 (2H, m), 5.07 (1H, t, J = 3.7 Hz), 5.90
(1H, tt, J = 2.9 Hz, 53.0 Hz), 6.92 (1H, d, J =
8.8 Hz), 6.98-7.33 (8H, m), 7.40-7.58 (4H, m), 7.8
0 (1H, d, J = 8.0 Hz), 8.07 (1H, d, J = 7.8 Hz); IR
(KBr) 3272, 1642, 1624, 1601, 1537, 1512, 1235, 1
198, 1127, 835, 760 cm ^-1 ; Anal.Calcd for C ₂₈ H ₂₁ F ₆
NO ₃ : C, 63.04; H, 3.97; N, 2.63. Found: C, 62.97;
H, 3.87; N, 2.57.

Example 229 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
Optical Resolution of 5H-Benzo [a] cycloheptene-1-carboxamide The racemate was converted to an optically active column (Chiral Cell OD, 50 mm ID).
× 500 mmL) by high-performance liquid chromatography (mobile layer: hexane / ethanol = 95 /
After 5), recrystallization from ethyl acetate-diisopropyl ether-hexane gave each optical isomer. (1R, 2S) form mp 199-200 ° C .; [α] _D ²⁰ + 20.3 ° (c = 0.536, MeOH); ¹
H-NMR (CDCl ₃ , 200MHz) δ 1.93-2.06 (2H, m), 2.15-2.
24 (2H, m), 2.67 (2H, t, J = 5.7 Hz), 2.79 (1H, dd,
J = 10.8 Hz, 14.4 Hz), 3.00 (1H, dd, J = 3.7 Hz,
14.5 Hz), 3.59 (1H, d, J = 3.6 Hz), 4.60-4.74 (1H,
m), 5.04 (1H, t, J = 3.7 Hz), 5.72 (1H, d, J = 8.8
Hz), 5.89 (1H, tt, J = 2.8 Hz, 53.0 Hz), 5.91 (1H,
td, J = 5.3 Hz, 11.6 Hz), 6.21 (1H, d, J = 11.6 H
z), 6.95-7.17 (8H, m), 7.31 (1H, t, J = 8.0 Hz), 7.
44 (2H, dd, J = 5.3 Hz, 8.7 Hz); IR (KBr) 3264, 16
40, 1512, 1227, 1198, 1128 cm ^-1 ; Anal.Calcd for C
₂₉ H ₂₆ F ₅ NO ₃ : C, 65.53; H, 4.93; N, 2.64. Found: C, 6
5.52; H, 4.85; N, 2.63. (1S, 2R) form mp 200-201 ° C .; [α] _D ²⁰ -20.8 ° (c = 0.544, MeOH); ¹
H-NMR (CDCl ₃ , 200MHz) δ 1.93-2.06 (2H, m), 2.15-2.
24 (2H, m), 2.67 (2H, t, J = 5.8 Hz), 2.79 (1H, dd,
J = 10.6 Hz, 14.6 Hz), 3.00 (1H, dd, J = 4.3 Hz,
14.7 Hz), 3.59 (1H, d, J = 3.8 Hz), 4.60-4.74 (1H,
m), 5.04 (1H, t, J = 3.7 Hz), 5.72 (1H, d, J = 8.8
Hz), 5.89 (1H, tt, J = 3.0 Hz, 53.1 Hz), 5.91 (1H,
td, J = 5.3 Hz, 12.0 Hz), 6.21 (1H, d, J = 12.0 H
z), 6.95-7.17 (8H, m), 7.31 (1H, t, J = 7.6 Hz), 7.
44 (2H, dd, J = 5.4 Hz, 8.6 Hz); IR (KBr) 3264, 16
37, 1512, 1227, 1198, 1130 cm ^-1 ; Anal.Calcd for C
₂₉ H ₂₆ F ₅ NO ₃ : C, 65.53; H, 4.93; N, 2.64. Found: C, 6
5.56; H, 4.87; N, 2.64.

Example 230 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((5-methyl-3- (1,1,2,2
2-tetrafluoroethoxy) phenyl) methyl) ethyl) -4-fluoro-1-naphthalenecarboxamide 1) 3,5-dimethyl-1- (1,1,2,2-tetrafluoropropyloxy) benzene (8.22 g, 32.
N-bromosuccinimide (6.42 g, 36.1 mmol) in a solution of 8 mmol) in carbon tetrachloride (100 ml).
And 2,2′-azobis (isobutyronitrile) (2
(70 mg, 1.64 mmol) and heated to reflux overnight. The insolubles were filtered using Celite, the filtrate was concentrated,
The bromo form was prepared. 3- (4-fluorophenyl) -3-
Sodium hydride (60% oily, 1.18 g, 29.5) was added to a solution of ethyl oxopropionate (6.20 g, 29.5 mmol) in 1,2-dimethoxyethane (60 ml).
(Mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. A solution of the previously synthesized bromo compound in 1,2-dimethoxyethane (20 ml) was dropped into the reaction solution, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene: hexane = 1: 1-ethyl acetate), recrystallized from ethyl acetate-hexane, and
(4-fluorophenyl) -2-((3-methyl-5- (1,
Ethyl 1,2,2-tetrafluoroethoxy) phenyl) methyl) -3-oxopropionate (6.68 g, 53
%). ^{. mp 56-57 ℃ IRνmax KBr cm -1} : 1738, 1688, 1599, 1508. Anal Calcd for C 21 H 19 F 5 O 4: C, 58.12; H, 4.50 Found:. C, 57.94; H, 4.27 1 H-NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7.0 Hz), 2.30
(3H, s), 3.28 (2H, d, J = 7.4 Hz), 4.12 (2H, q, J =
7.0 Hz), 4.54 (1H, t, J = 7.4 Hz), 5.87 (1H, tt,
J = 53.0, 3.0 Hz), 6.87 (2H, s), 6.94 (1H, s), 7.1
2 (2H, t, J = 8.4 Hz), 7.92-8.06 (2H, m). 2) To a solution of zinc chloride (4.12 g, 30.2 mmol) in diethyl ether (100 ml) was added sodium borohydride (2. (29 g, 60.4 mmol) and stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was added with 3- (4-fluorophenyl) -2-((5-methyl-3- (1,1,1).
2,2-tetrafluoroethoxy) phenyl) methyl)-
Ethyl 3-oxopropionate (6.50 g, 15.1)
Mmol) in diethyl ether (50 ml) and stirred at room temperature for 30 minutes. Under ice-cooling, the reaction solution was quenched by adding 1N hydrochloric acid, further added with water (200 ml), and extracted with ethyl acetate (300 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1),
(2RS, 3RS) -3- (4-fluorophenyl) -3-
Ethyl hydroxy-2-((5-methyl-3- (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) propionate (6.56 g, 100%) was obtained as a colorless oil. IRνmax ^KBr cm ^-1 : 1715, 1605, 1512. Anal.Calcd for C ₂₁ H ₂₁ F ₅ O ₄・ 0.3H ₂ O: C, 57.62; H,
4.97 Found: C, 57.54; H, 4.85. ¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.0 Hz), 2.29
(3H, s), 2.92-3.02 (4H, m), 3.89 (2H, q, J = 7.0 H
z), 5.00 (1H, s), 5.86 (1H, tt, J = 53.0, 3.0Hz),
6.72-6.86 (3H, m), 7.00-7.10 (2H, m), 7.30-7.42 (2
H, m). 3) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((5-methyl-3- (1,1,
To a methanol (50 ml) solution of ethyl 2,2-trifluoroethoxy) phenyl) methyl) propionate (6.30 g, 14.6 mmol) was added a 2N aqueous sodium hydroxide solution (14.6 ml, 29.2 mmol). In addition, the mixture was stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (100 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from diethyl ether-hexane to give (2RS, 3RS) -3- (4
-Fluorophenyl) -3-hydroxy-2-((5-methyl
-3- (1,1,2,2-Trifluoroethoxy) phenyl) methyl) propionic acid (6.0 g, 100%) was obtained. ^{. mp 82-83 ℃ IRνmax KBr cm -1} : 1713, 1607, 1512. Anal Calcd for C 19 H 17 F 5 O 4: C, 56.19; H, 4.26 Found:. C, 56.05; H, 4.13 1 H- NMR (CDCl ₃ ) δ: 2.27 (3H, s), 2.80-3.08 (3H, m),
5.06 (1H, d, J = 4.0Hz), 5.86 (1H, tt, J = 53.0,
2.8 Hz), 6.76 (2H, d, J = 6.6 Hz), 6.84 (1H, s),
6.98-7.12 (2H, m), 7.30-7.42 (2H, m). 4) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((5-methyl-3- ( 1,1,
2,2-tetrafluoroethoxy) phenyl) methyl)
To a solution of propionic acid (5.8 g, 14.3 mmol) in tetrahydrofuran (100 ml), diphenylphosphoryl azide (3.4 ml, 15.8 mmol) and triethylamine (3.0 ml, 21.5 mmol) were added.
The mixture was refluxed for 30 minutes. After allowing the reaction solution to cool, water (200 m
1) and extracted with ethyl acetate (200 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1).
Recrystallized from hexane, (4RS, 5SR) -5-
(4-fluorophenyl) -4-((5-methyl-3- (1,
1,2,2-tetrafluoroethoxy) phenyl) methyl) -1,3-oxazolidin-2-one (4.1 g, 71
%). mp 107-108 ° C IRνmax ^KBr cm ^-1 : 1761, 1611, 1597, 1514. Anal.Calcd for C ₁₉ H ₁₆ F ₅ NO ₃ : C, 56.86; H, 4.02; N,
3.49 Found:. C, 56.64; H, 4.01; N, 3.58 1 H-NMR (CDCl 3) δ: 1.16-2.40 (2H, m), 2.32 (3H, s),
4.18-4.32 (1H, m), 5.12 (1H, brs), 5.79 (1H, d, J
= 7.8 Hz), 5.89 (1H, tt, J = 53.0, 3.0 Hz), 6.70
(2H, d, J = 8.0 Hz), 6.91 (1H, s), 7.04-7.20 (2H,
m), 7.30-7.42 (2H, m). 5) (4RS, 5SR) -5- (4-fluorophenyl) -4-((5-methyl-3- (1,1,2,2-tetrafluoro To a solution of (ethoxy) phenyl) methyl) -1,3-oxazolidin-2-one (3.0 g, 7.48 mmol) in ethanol (30 ml) was added an 8 N aqueous sodium hydroxide solution (4.7 ml, 37.4 mmol). The mixture was heated under reflux for 3 hours. After concentration, the reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2SR) -2-amino-1- (4-fluorophenyl). ) -3- (5-Methyl-3- (1,1,2,2-tetrafluoroethoxy) phenyl) -1-propanol (2.34 g, 83%) was obtained. mp 96-98 ° C IRνmax ^KBr cm ^-1 : 1617, 1595, 1508, 1458. Anal.Calcd for C ₁₈ H ₁₈ F ₅ NO ₂ : C, 57.60; H, 4.83; N,
3.73 Found:. C, 57.59; H, 4.79; N, 3.73 1 H-NMR (CDCl 3) δ: 2.20-2.50 (1H, m), 2.32 (3H, s),
2.76 (1H, dd, J = 13.4, 3.2 Hz), 3.20-3.32 (1H,
m), 4.65 (1H, d, J = 4.8 Hz), 5.88 (1H, tt, J = 53.
0, 3.0 Hz), 6.80 (1H, s), 6.82-6.90 (2H, m), 7.00-
7.12 (2H, m), 7.30-7.42 (2H, m). 6) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (5-methyl-3- (1,1 In a solution of (2,2,2-tetrafluoroethoxy) phenyl) -1-propanol (197 mg, 0.53 mmol) in acetonitrile (20 ml), 4-fluoronaphthalenecarboxylic acid (100 mg, 0.53 mmol) and 1-ethyl-3
-(3-Dimethylaminopropyl) carbodiimide hydrochloride (151 mg, 0.79 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was washed with water (1
00 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (234 mg, 81
%). mp 189-190 ℃ IRνmax ^KBr cm ^-1 : 1642, 1626, 1601, 1512. Anal.Calcd for C ₂₉ H ₂₃ F ₆ NO ₃・ 0.1H ₂ O: C, 63.41; H,
4.25; N, 2.55 Found:. C, 63.22; H, 4.24; N, 2.77 1 H-NMR (CDCl 3) δ: 2.29 (3H, s), 2.77 (1H, dd, J =
14.0, 11.0 Hz), 3.00 (1H, dd, J = 14.0, 4.0 Hz),
4.62-4.82 (1H, m), 5.07 (1H, d, J = 3.6 Hz), 5.87
(1H, tt, J = 53.0, 3.0 Hz), 5.95 (1H, d, J = 8.8 H
z), 6.80-7.20 (7H, m), 7.38-7.60 (4H, m), 7.80 (1
H, d, J = 8.0 Hz), 8.08 (1H, d, J = 7.6Hz).

Example 231 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((5-methyl-3- (1,1,2,2
2-tetrafluoroethoxy) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- (2-fluorophenyl) -3 -(5-Methyl-3- (1,1,2,2-tetrafluoroethoxy) phenyl) -1-propanol (200
mg, 0.53 mmol) of acetonitrile (20 m
l) To a solution, 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (100 mg, 0.53 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (153 mg) , 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) were added and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was recrystallized from ethyl acetate-hexane to give the title compound (228 mg, 78%). ^{mp 175-176 ℃ IRνmax KBr cm -1:} 1636, 1510, 1449. 1 H-NMR (CDCl 3) δ: 1.90-2.10 (2H, m), 2.10-2.28 (2
H, m), 2.31 (3H, s), 2.60-2.82 (3H, m), 3.87 (1H,
brs), 4.56-4.72 (1H, m), 5.01 (1H, d, J = 3.8Hz),
5.76 (1H, d, J = 8.4 Hz), 5.87 (1H, tt, J = 53.0,
3.0 Hz), 5.90-6.00 (1H, m), 6.22 (1H, d, J = 11.6
Hz), 6.82 (1H, s), 6.84-7.20 (7H, m), 7.36-7.50 (2
H, m).

Example 232 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4-chloro-3- (1,1,2,2
2-tetrafluoroethoxy) phenyl) methyl) ethyl) -4-fluoro-1-naphthalenecarboxamide 1) 4-chloro-3- (1,1,2,2-tetrafluoropropyloxy) toluene (7.63 g, 28 N-bromosuccinimide (5.54 g, 31.1 mmol) and 2,2′-azobis (isobutyronitrile) (255 mg, 1.56 g) in a solution of 0.3 mmol, 90% purity) in carbon tetrachloride (100 ml). Mmol) and heated to reflux overnight. The insolubles were filtered using celite, and the filtrate was concentrated to prepare a bromo compound. Ethyl 3- (4-fluorophenyl) -3-oxopropionate (5.35 g, 2
5.5 mmol) of 1,2-dimethoxyethane (50 m
l) Add sodium hydride (60% oil, 1.02
g, 25.5 mmol) under ice-cooling and stirred at room temperature for 30 minutes. In the reaction solution, the 1,2-
A solution of dimethoxyethane (20 ml) was added dropwise and the reaction was stirred at room temperature for 1 hour. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene: hexane = 1: 1-ethyl acetate) and recrystallized from ethyl acetate-hexane to give 2-((4-chloro-3- (1,1,2,2, Ethyl 2-tetrafluoroethoxy) phenyl) methyl) -3- (4-fluorophenyl) -3-oxopropionate (6.
71 g, 56%). ^{. mp 73-74 ℃ IRνmax KBr cm -1} : 1738, 1688, 1599. Anal Calcd for C 20 H 16 ClF 5 O 4: C, 53.29; H, 3.58 Found:. C, 53.38; H, 3.35 1 H- NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7.0 Hz), 3.32
(2H, d, J = 7.2 Hz), 4.11 (2H, q, J = 7.0 Hz), 4.5
4 (1H, t, J = 7.2 Hz), 5.97 (1H, tt, J = 53.2, 3.0
Hz), 7.06-7.40 (5H, m), 7.92-8.08 (2H, m). 2) To a solution of zinc chloride (4.0 g, 29.3 mmol) in diethyl ether (100 ml) was added sodium borohydride (2. (22 g, 58.6 mmol) and stirred at room temperature for 30 minutes. The insolubles were removed by filtration, and the filtrate was treated with 2-((4-chloro-3- (1,1,2,2-tetrafluoroethoxy).
Phenyl) methyl) -3- (4-fluorophenyl) -3-
A solution of ethyl oxopropionate (6.60 g, 14.6 mmol) in diethyl ether (50 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Under ice-cooling, the reaction solution was quenched by adding 1N hydrochloric acid, further added with water (200 ml), and extracted with ethyl acetate (300 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give (2
RS, 3RS) -2-((4-chloro-3- (1,1,2,
2-tetrafluoroethoxy) phenyl) methyl) -3-
Ethyl (4-fluorophenyl) -3-hydroxypropionate (5.85 g, 88%) was obtained as a colorless oil. ^{. IRνmax KBr cm -1: 1717,} 1605, 1510, 1487. Anal Calcd for C 20 H 18 ClF 5 O 4: C, 53.05; H, 4.01 Found:. C, 53.17; H, 4.13 1 H-NMR (CDCl ₃ ) δ: 0.95 (3H, t, J = 7.0 Hz), 2.84-
3.04 (4H, m), 3.89 (2H, q, J = 7.0 Hz), 4.98-5.06
(1H, m), 5.96 (1H, tt, J = 53.0, 3.4 Hz), 6.92-7.1
0 (4H, m), 7.30-7.44 (3H, m). 3) (2RS, 3RS) -2-((4-chloro-3-
(1,1,2,2-trifluoroethoxy) phenyl)
To a solution of ethyl (methyl) -3- (4-fluorophenyl) -3-hydroxypropionate (5.60 g, 12.37 mmol) in methanol (50 ml) was added 2N aqueous sodium hydroxide solution (12.3 ml, 24.6). Mmol) and stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (100 ml × 2).
The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from diethyl ether-hexane to give (2RS, 3RS)-
2-((4-chloro-3- (1,1,2,2-trifluoroethoxy) phenyl) methyl) -3- (4-fluorophenyl) -3-hydroxypropionic acid (4.12 g, 78
%). ^{. mp 121-122 ℃ IRνmax KBr cm -1} : 1713, 1607, 1512, 1489. Anal Calcd for C 18 H 14 ClF 5 O 4: C, 50.90; H, 3.32 Found:. C, 50.92; H, 3.07 1 H-NMR (CDCl ₃ ) δ: 2.90-3.06 (3H, m), 5.07 (1H, s),
5.96 (1H, tt, J = 53.0, 3.2 Hz), 6.94 (1H, dd, J
= 8.2, 2.0 Hz), 7.00-7.12 (3H, m), 7.24-7.40 (3H,
m). 4) (2RS, 3RS) -2-((4-chloro-3-
(1,1,2,2-tetrafluoroethoxy) phenyl) methyl) -3- (4-fluorophenyl) -3-hydroxypropionic acid (2.0 g, 4.71 mmol) in tetrahydrofuran (40 ml) solution Diphenylphosphoryl azide (1.12 ml, 5.18 mmol) and triethylamine (0.99 ml, 7.07 mmol) were added, and the mixture was heated under reflux for 3 hours. After allowing the reaction solution to cool, water (20
0 ml) and extracted with ethyl acetate (200 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give (4RS, 5
SR) -4-((4-Chloro-3- (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) -5- (4-fluorophenyl) -1,3-oxazolidin-2-one ( 1.
72 g, 87%) as a colorless oil. ^{. IRνmax KBr cm -1: 1759,} 1514, 1489. Anal Calcd for C 18 H 13 ClF 5 NO 3: C, 51.26; H, 3.11;
N, 3.32 Found:. C, 51.16; H, 3.13; N, 3.24 1 H-NMR (CDCl 3) δ: 2.30 (2H, d, J = 6.8 Hz), 4.25
(1H, q, J = 6.8 Hz), 5.30 (1H, brs), 5.80 (1H, d,
J = 8.0 Hz), 5.98 (1H, tt, J = 53.0, 3.0 Hz), 6.89
(1H, dd, J = 8.0, 2.0 Hz), 6.99 (1H, s), 7.06-7.20
(2H, m), 7.30-7.42 (3H, m). 5) (4RS, 5SR) -4-((4-chloro-3-
(1,1,2,2-tetrafluoroethoxy) phenyl) methyl) -5- (4-fluorophenyl) -1,3-oxazolidin-2-one (1.42 g, 3.37 mmol) in ethanol (20 ml) )) An 8 N aqueous sodium hydroxide solution (2.1 ml, 16.9 mmol) was added to the solution, and the mixture was heated under reflux for 3 hours. After concentrating the reaction solution, water (100
ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2SR) -2-amino-3-amino-3-hexane.
(4-Chloro-3- (1,1,2,2-tetrafluoroethoxy) phenyl) -1- (4-fluorophenyl) -1-propanol (1.17 g, 88%) was obtained. ^{. mp 109-110 ℃ IRνmax KBr cm -1} : 1605, 1508, 1489. Anal Calcd for C 17 H 15 ClF 5 NO 2: C, 51.59; H, 3.82;
N, 3.54 Found:. C, 51.62; H, 3.78; N, 3.55 1 H-NMR (CDCl 3) δ: 2.39 (1H, dd, J = 14.0, 10.0 H
z), 2.81 (1H, dd, J = 14.0, 3.4 Hz), 3.18-3.32 (1
H, m), 4.63 (1H, d, J = 5.2 Hz), 5.98 (1H, tt, J =
53.0, 3.0 Hz), 7.00-7.20 (4H, m), 7.30-7.44 (3H,
m). 6) (1RS, 2SR) -2-amino-3- (4-chloro-
To a solution of 3- (1,1,2,2-tetrafluoroethoxy) phenyl) -1- (4-fluorophenyl) -1-propanol (208 mg, 0.53 mmol) in acetonitrile (20 ml) was added 4-fluoronaphthalenecarboxylic acid. Acid (100 mg, 0.53 mmol) and 1-ethyl-3
-(3-Dimethylaminopropyl) carbodiimide hydrochloride (151 mg, 0.79 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was washed with water (1
00 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (273 mg, 91
%). ^{mp 206-207 ℃ IRνmax KBr cm -1:} 1642, 1626, 1601, 1512. 1 H-NMR (CDCl 3) δ: 2.84 (1H, dd, J = 14.2, 10.6 H
z), 3.02 (1H, dd, J = 14.2, 4.2 Hz), 4.68-4.84 (1
H, m), 5.07 (1H, d, J = 4.0 Hz), 5.95 (1H, tt, J =
53.0, 3.0 Hz), 5.99 (1H, d, J = 9.0 Hz), 6.92-7.30
(6H, m), 7.30-7.60 (5H, m), 7.73 (1H, d, J = 8.2
Hz), 8.08 (1H, d, J = 8.2 Hz).

Example 233 N-((1RS, 2SR) -1-((4-chloro-3- (1,1
1,2,2-tetrafluoroethoxy) phenyl) methyl) ethyl) -2- (4-fluorophenyl) -2-hydroxy-6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-3- (4-chloro-3-
6,7-Dihydro-5H was added to a solution of (1,1,2,2-tetrafluoroethoxy) phenyl) -1- (2-fluorophenyl) -1-propanol (210 mg, 0.53 mmol) in acetonitrile (20 ml). -Benzo [a] cycloheptene-1-carboxylic acid (100 mg,
0.53 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (153 m
g, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) were added and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed sequentially with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (213 mg, 71%). mp 174-175 ° C IRνmax ^KBr cm ^-1 : 1640, 1508, 1489. ¹ H-NMR (CDCl ₃ ) δ: 1.90-2.10 (2H, m), 2.12-2.26 (2
H, m), 2.60-2.72 (2H, m), 2.78 (1H, dd, J = 14.6,
10.4 Hz), 2.96 (1H, dd, J = 14.6, 4.4 Hz), 3.40 (1
H, brs), 4.58-4.72 (1H, m), 5.01 (1H, d, J = 4.0 H
z), 5.80 (1H, d, J = 8.8 Hz), 5.82-5.98 (1H, m), 5.
95 (1H, tt, J = 53.0, 3.0 Hz), 6.16 (1H, d, J = 1
1.6 Hz), 6.92-7.20 (7H, m), 7.32-7.50 (3H, m).

Example 234 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-((4-methyl-3-((1,1,
2,2-tetrafluoroethyl) oxy) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 1) Lithium aluminum hydride (1.02 g, 2
6.8 mmol) in tetrahydrofuran (100 ml)
Ethyl 4-methyl-3-((1,1,2,2-tetrafluoroethyl) oxy) benzoate (5.0 g, 17.
(8 mmol) in tetrahydrofuran (20 ml) was added under ice cooling. After stirring the reaction solution at room temperature for 30 minutes, a 1 N aqueous sodium hydroxide solution (20 ml) was added, and the mixture was filtered using celite. After the filtrate was concentrated, water was added, and the mixture was extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
-Methyl-3-((1,1,2,2-tetrafluoroethyl) oxy) phenyl) methanol (4.45 g, 10
0%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 2.27 (3H, s), 4.67 (2H, s), 5.94
(1H, tt, J = 53.0, 2.6 Hz), 7.14-7.28 (3H, m) .IRνmax ^KBr cm ^-1 : 1584, 1508, 1456, 1418.Anal.Calcd for C ₁₀ H ₁₀ F ₄ O ₂ : C H, 4.23 Found: C, 50.44; H, 4.18.2) (4-Methyl-3-((1,1,2,2-tetrafluoroethyl) oxy) phenyl) methanol (4.26)
methanesulfonyl chloride (2.25 g, 19.7 mmol) and triethylamine (3.0 ml, 21.g, 17.9 mmol) in ethyl acetate (60 ml).
(5 mmol) at 0 ° C. and stirred for 30 minutes. The insoluble material was filtered, and the filtrate was concentrated to prepare a mesyl compound. 3- (4-
Sodium hydride (60%) was added to a solution of ethyl (fluorophenyl) -3-oxopropionate (3.76 g, 17.9 mmol) in 1,2-dimethoxyethane (40 ml).
Oily, 0.72 g, 17.9 mmol) under ice cooling.
Stirred at room temperature for 30 minutes. A solution of the previously synthesized mesyl compound in 1,2-dimethoxyethane (20 ml) was added dropwise to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was water (200 ml)
And extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene) and recrystallized from hexane to give 3- (4-fluorophenyl)-
Ethyl 2-((4-methyl-3-((1,1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) -3-oxopropionate (4.91 g, 64%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7.0 Hz), 2.21
(3H, s), 3.30 (2H, d, J = 7.4 Hz), 4.10 (2H, q, J =
7.0 Hz), 4.54 (1H, t, J = 7.4 Hz), 5.92 (1H, tt,
J = 53.0, 2.8 Hz), 7.00-7.20 (5H, m), 7.94-8.04 (2
H, m) .IRνmax ^KBr cm ^-1 : 1736, 1688, 1599, 1508, 1447, 141
2. mp 52-53 ° C Anal. Calcd for C ₂₁ H ₁₉ F ₅ O ₄ : C, 58.61; H, 4.45 Found: C, 58.61; H, 4.55.3.) Zinc chloride (3.04 g, 22.3 mmol) ) In diethyl ether (70 ml) was added with sodium borohydride (1.69 g, 44.6 mmol), and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was treated with 3- (4-fluorophenyl) -2-((4-methyl-3-((1,1,1
Ethyl 2,2-tetrafluoroethyl) oxy) phenyl) methyl) -3-oxopropionate (4.8 g, 1
(1.2 mmol) in diethyl ether (50 ml) and stirred at room temperature for 30 minutes. Under ice-cooling, the reaction solution was quenched by adding 1N hydrochloric acid, further added with water (100 ml), and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((4-methyl-3- ((1,
Ethyl 1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) propionate (4.69 g, 97
%) As a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.4 Hz), 2.21
(3H, s), 2.80-3.10 (3H, m), 3.89 (2H, q, J = 7.4 H
z), 4.96-5.02 (1H, m), 5.92 (1H, tt, J = 52.2, 2.6
Hz), 6.86-7.12 (5H, m), 7.30-7.42 (2H, m) .IRνmax ^KBr cm ^-1 : 1717, 1605, 1580, 1510, 1447.Anal.Calcd for C ₂₁ H ₂₁ F ₅ O ₄ : C, 58.33; H, 4.90 Found: C, 58.29; H, 4.88. 4) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((4-methyl-3-(( 1,
Ethyl 1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) propionate (4.5 g, 10.4)
2 mmol sodium hydroxide aqueous solution (10.4 ml, 20.8 mmol) was added to a methanol (20 ml) solution and stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (2R
S, 3RS) -3- (4-Fluorophenyl) -3-hydroxy-2-((4-methyl-3-((1,1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) propionic acid (3.56 g, 85%). ¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, s), 2.80-3.02 (3H, m),
5.04 (1H, d, J = 3.8Hz), 5.90 (1H, tt, J = 53.0,
2.6 Hz), 6.84-7.12 (5H, m), 7.30-7.40 (2H, m) .IRνmax ^KBr cm ^-1 : 1713, 1607, 1510, 1449, 1422.mp 102-103 ℃ Anal.Calcd for C ₁₉ H ₁₇ F ₅ O ₄ : C, 56.44; H, 4.24 Found: C, 56.56; H, 4.20.5) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-((4- Methyl-3-((1,
To a solution of 1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) propionic acid (3.3 g, 8.16 mmol) in tetrahydrofuran (60 ml) was added diphenylphosphoryl azide (1.93 ml, 8.98 mmol). Triethylamine (1.71 ml, 12.2 mmol) was added, and the mixture was heated under reflux for 2 hours. After allowing the reaction solution to cool,
Water (200 ml) was added and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give (4RS, 5SR) -5- (4-fluorophenyl) -4-((4-methyl-3- ((1,1,
2,2-tetrafluoroethyl) oxy) phenyl) methyl) -1,3-oxazolidin-2-one (2.97 g,
91%). ¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, s), 2.12-2.30 (2H, m),
4.18-4.30 (1H, m), 5.21 (1H, s), 5.78 (1H, d, J =
8.0 Hz), 5.93 (1H, tt, J = 53.0, 2.6 Hz), 6.80-6.
90 (2H, m), 7.04-7.20 (3H, m), 7.30-7.42 (2H, m) .IRνmax ^KBr cm ^-1 : 1759, 1609, 1580, 1514, 1422.mp 112-113 ℃ Anal.Calcd for C ₁₉ H ₁₆ F ₅ NO ₃ : C, 56.86; H, 4.02; N,
3.49 Found: C, 56.87; H, 3.91; N, 3.59.6) (4RS, 5SR) -5- (4-fluorophenyl) -4-((4-methyl-3-((1,1,2, 2-tetrafluoroethyl) oxy) phenyl) methyl) -1,3-
To a solution of oxazolidine-2-one (2.7 g, 6.73 mmol) in ethanol (10 ml) was added an 8 N aqueous sodium hydroxide solution (4.2 ml, 33.6 mmol), and the mixture was heated under reflux for 4 hours. After concentrating the reaction solution, water (100
ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS, 2SR) -2-amino-1-amino.
(4-fluorophenyl) -3- (4-methyl-3-((1,
There was obtained 1,2,2-tetrafluoroethyl) oxy) phenyl) -1-propanol (2.25 g, 89%). ¹ H-NMR (CDCl ₃ ) δ: 2.24 (3H, s), 2.33 (1H, dd, J =
14.0, 10.6 Hz), 2.77 (1H, dd, J = 14.0, 3.2 Hz),
3.20-3.32 (1H, m), 4.65 (1H, d, J = 4.8 Hz), 5.93
(1H, tt, J = 53.0, 3.0 Hz), 6.92-7.18 (5H, m), 7.3
0-7.42 (2H, m) .IRνmax ^KBr cm ^-1 : 1605, 1582, 1508.mp 112-113 ℃ Anal. Calcd for C ₁₈ H ₁₈ F ₅ NO ₂ : C, 57.60; H, 4.83; N,
3.73 Found: C, 57.59; H, 4.75; N, 3.73.7) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (4-methyl-3-((1,1 , 2,2-
A solution of tetrafluoroethyl) oxy) phenyl) -1-propanol (300 mg, 0.80 mmol) in acetonitrile (20 ml) was prepared by adding 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (150 mg,
0.80 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (230 m
g, 1.20 mmol) and 1-hydroxy-1H-benzotriazole (123 mg, 0.80 mmol) were added and stirred at room temperature overnight. The reaction solution was water (100 ml)
And extracted with ethyl acetate (100 ml × 2).
1N hydrochloric acid, 1N aqueous sodium hydroxide solution,
The extract was washed successively with saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (363 mg, 83%). ¹ H-NMR (CDCl ₃ ) δ: 1.90-2.08 (2H, m), 2.12-2.30 (2
H, m), 2.24 (3H, s), 2.60-2.80 (3H, m), 2.95 (1H,
dd, J = 15.0, 4.0 Hz), 4.60-4.76 (1H, m), 5.00 (1
H, d, J = 3.6 Hz), 5.60-6.24 (4H, m), 6.94-7.20 (8
. H, m), 7.38-7.48 ( 2H, m) IRνmax KBr cm -1:. 1640, 1607, 1508, 1447, 1424. mp 168-169 ℃ Anal Calcd for C 30 H 28 F 5 NO 3 · 0.1H ₂ O: C, 65.83; H,
5.19; N, 2.56 Found: C, 65.60; H, 4.89; N, 2.82.

Example 235 N-｛(1RS, 2SR) -2- (3-fluorophenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro-
5H-benzo [a] [7] annulene-1-carboxamide 1) 3- (3-fluorophenyl) -3-oxo-2- [3
Ethyl-(1,1,2,2-tetrafluoroethoxy) benzyl] propanoate Ethyl acetate of 3- (1,1,2,2-tetrafluoroethoxy) toluene (8.91 g, 42.8 mmol)
00 ml) solution with N-bromosuccinimide (8.35).
g, 46.9 mmol) and 2,2'-azobis (isobutyronitrile) (335 mg, 2.04 mmol)
Was added and heated under reflux for 5 hours. After concentrating the reaction solution, the crystals were filtered with hexane, and the filtrate was concentrated to give 3- (1,1,2,2,3).
2-Tetrafluoroethoxy) -α-bromotoluene was prepared. Ethyl 3- (3-fluorophenyl) -3-oxopropanoate (8.57 g, 40.8 mmol) in 1,2
Sodium hydride (60% oily, 1.63 g, 40.8 mmol) was added to a solution of -dimethoxyethane (80 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 3- (1,1,2,2-tetrafluoroethoxy) previously prepared in the reaction solution
1,2-dimethoxyethane of -α-bromotoluene (10
ml) solution was added dropwise and the reaction was stirred at room temperature overnight. The reaction solution was poured into water (100 ml), and ethyl acetate (10 ml) was added.
0 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-6: 1) and recrystallized from ethyl acetate-hexane to give the desired product (8.86).
g, 52%). ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.2 Hz), 3.33 (2
H, d, J = 7.5 Hz), 4.02-4.18 (2H, m), 4.54 (1H, t,
J = 7.2 Hz), 5.89 (1H, tt, J = 53.1, 2.7 Hz), 7.0
2-7.10 (2H, m), 7.14 (1H, d, J = 7.8 Hz), 7.26-7.3
2 (2H, m), 7.38-7.48 (1H, m), 7.60-7.68 (1H, m),
7.72 (1H, d, J = 7.8 Hz) .IRν max ^KBr cm ^-1 : 1738, 1694, 1613, 1590, 1487, 144
. 5. mp 52-53 ℃ Anal Calcd for C 20 H 17 O 4 F 5: C, 57.70; H, 4.12 Found:. C, 57.72; H, 4.13 2) (2RS, 3RS) -3- (3- Ethyl fluorophenyl) -3-hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoate A solution of zinc chloride (5.60 g, 41.1 mmol) in diethyl ether (140 ml) Sodium borohydride (3.11 g, 82.2 mmol) was added to the mixture at room temperature.
Minutes. The insoluble material was removed by filtration, and the filtrate was mixed with ethyl 3- (3-fluorophenyl) -3-oxo-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoate (8.56 g). , 20.6 mmol) in diethyl ether (50 ml) was added at 0 ° C. and stirred for 30 minutes. The reaction was quenched by adding 1N hydrochloric acid to the reaction solution, and further added with water (100
ml) and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
4: 1) to give the desired product (7.04 g, 82%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, t, J = 7.0 Hz), 2.86-3.0
6 (3H, m), 3.10 (1H, d, J = 3.0 Hz), 3.92 (2H, q,
J = 7.0 Hz), 5.06 (1H, s), 5.88 (1H, tt, J = 53.0,
3.0Hz), 6.90-7.08 (4H, m), 7.10-7.40 (4H, m) .IRν max ^KBr cm ^-1 : 1724, 1715, 1614, 1591, 1489, 145
_{. 1. Anal Calcd for C 20 H} 19 O 4 F 5: C, 57.42; H, 4.58 Found:. C, 57.36; H, 4.55 3) (2RS, 3RS) -3- (3- fluorophenyl) -3 -Hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoic acid (2RS, 3RS) -3- (3-fluorophenyl) -3-
Ethyl hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoate (6.92 g,
16.5 mmol) in methanol (50 ml)
2N aqueous sodium hydroxide solution (16.5 ml, 33.
0 mmol) and stirred at room temperature for 2 hours. After the reaction solution was acidified with 1N hydrochloric acid, ethyl acetate (200 ml ×
Extracted in 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain the desired product (4.28 g, 66%). ¹ H-NMR (CDCl ₃ ) δ: 2.80-3.16 (3H, m), 5.14 (1H, d, J
= 3.6 Hz), 5.90 (1H, tt, J = 53.0, 3.0 Hz), 6.90-
7.40 (8H, m) .IRν max ^KBr cm ^-1 : 1713, 1615, 1591, 1489, 1451.mp 116-117 ℃ Anal.Calcd for C ₁₈ H ₁₅ O ₄ F ₅ : C, 55.39; H, 3.87 Found : C, 55.42; H, 3.86. 4) (4RS, 5SR) -5- (3-fluorophenyl) -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3 -Oxazolidin-2-one (2RS, 3RS) -3- (3-fluorophenyl) -3-
Hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoic acid (4.15 g, 10.
6 mmol) in tetrahydrofuran (80 ml) was added to diphenylphosphoryl azide (2.52 ml, 1).
1.7 mmol) and triethylamine (2.23 ml,
16.0 mmol) and heated to reflux for 3 hours. After allowing the reaction solution to cool, water (200 ml) was added, and ethyl acetate (1 mL) was added.
00 ml × 2). The extract was washed successively with 1N hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the desired product (3.4).
(6 g, 84%). ¹ H-NMR (CDCl ₃ ) δ: 2.20-2.40 (2H, m), 4.20-4.30 (1H,
m), 5.17 (1H, s), 5.80 (1H, d, J = 7.8 Hz), 5.90 (1
H, tt, J = 53.1, 2.7 Hz), 6.89 (1H, s), 6.96 (1H,
d, J = 8.1 Hz), 7.04-7.20 (4H, m), 7.24-7.36 (1H,
m), 7.36-7.46 (1H, m) .IRν max ^KBr cm ^-1 : 1767, 1615, 1593, 1489, 1453.mp 110-111 ℃ Anal.Calcd for C ₁₈ H ₁₄ NO ₃ F ₅ : C, 55.82 ; H, 3.64; N,
3.62 Found: C, 55.81; H, 3.62; N, 3.58.5) (1RS, 2SR) -2-amino-1- (3-fluorophenyl) -3- [3- (1,1,2,2- Tetrafluoroethoxy) phenyl] propan-1-ol (4RS, 5SR) -5- (3-fluorophenyl) -4-
[3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidin-2-one (3.30 g,
8.52 mmol) in ethanol (12 ml).
A normal aqueous sodium hydroxide solution (5.3 ml, 42 mmol) was added, and the mixture was refluxed for 5 hours. After concentrating the reaction solution, the reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed with saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to obtain the desired product (2.60 g, 84%). ¹ H-NMR (CDCl ₃ ) δ: 1.85 (2H, brs), 2.38 (1H, dd, J =
13.8, 10.6 Hz), 2.77 (1H, dd, J = 13.8, 3.4 Hz),
3.24-3.36 (1H, m), 4.69 (1H, d, J = 4.8 Hz), 5.89
(1H, tt, J = 53.0, 3.0 Hz), 6.94-7.22 (5H, m), 7.2
2-7.40 (3H, m) .IRν max ^KBr cm ^-1 : 1613, 1590, 1487, 1449, 1304, 127
9.mp 51-52 ℃ Anal. Calcd for C ₁₇ H ₁₆ NO ₂ F ₅ : C, 56.51; H, 4.46; N,
3.88 Found: C, 56.42; H, 4.39; N, 3.72.6) N-{(1RS, 2SR) -2- (3-fluorophenyl) -2-hydroxy-1- [3- (1,1,2 , 2-Tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro-5H-benzo [a] [7] annulene-1-carboxamide (1RS, 2SR) -2-amino-1- (3-fluorophenyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol (448 mg,
1.24 mmol) in acetonitrile (20 ml) was added to 6,7-dihydro-5H-benzo [a] cycloheptene-
1-carboxylic acid (234 mg, 1.24 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (357 mg, 1.86 mmol) and 1-hydroxybenzotriazole hydrate (190
mg, 1.24 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). Extract solution is 1N hydrochloric acid,
The extract was washed sequentially with a 1N aqueous sodium hydroxide solution and a saturated saline solution, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain the desired product (444 mg, 67%). ¹ H-NMR (CDCl ₃ ) δ: 1.94-2.06 (2H, m), 2.16-2.24 (2H,
m), 2.62-2.68 (2H, m), 2.79 (1H, dd, J = 14.7, 10.8
Hz), 2.96 (1H, dd, J = 14.7, 4.2 Hz), 4.60-4.74
(1H, m), 5.07 (1H, d, J = 3.3 Hz), 5.81 (1H, d, J
= 8.1 Hz), 5.88 (1H, tt, J = 53.1, 3.0 Hz), 5.90-6.
00 (1H, m), 6.23 (1H, d, J = 11.7 Hz), 6.94-7.40
(11H, m) .IRν max ^KBr cm ^-1 : 1634, 1615, 1590, 1514, 1489, 145
1.mp 150-155 ℃ Anal. Calcd for C ₂₉ H ₂₆ NO ₃ F ₅ : C, 65.53; H, 4.93; N,
2.64 Found: C, 65.25; H, 4.95; N, 2.66.

Example 236 N-｛(1RS, 2SR) -2- [4- (benzyloxy)
Phenyl] -2-hydroxy-1- [3- (1,1,2,2-
Tetrafluoroethoxy) benzyl] ethyl} -6,7-
Dihydro-5H-benzo [a] [7] annulene-1-carboxamide 1) 4-benzyloxyacetophenone Potassium carbonate (5 ml) was added to a solution of 4-hydroxyacetophenone (25 g, 184 mmol) in acetone (500 ml).
0.7 g, 367 mmol) and benzyl bromide (32 g, 187 mmol) were added, and the mixture was stirred at room temperature overnight. After concentration, the reaction solution was diluted with water (500 ml) and extracted with ethyl acetate (500 ml × 2). The extract is washed sequentially with water and saturated saline, and dried (anhydrous magnesium sulfate)
After that, it was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain the desired product (36.8 g, 89%). ¹ H-NMR (CDCl ₃ ) δ: 2.56 (3H, s), 5.13 (2H, s), 7.01
(2H, d, J = 9.0 Hz), 7.30-7.44 (5H, m), 7.94 (2H,
d, J = 9.0 Hz) .IRν max ^KBr cm ^-1 : 1674, 1601, 1576, 1508, 1454, 142
. 0. mp 87-88 ℃ Anal Calcd for C 15 H 14 O 2 C, 79.62; H, 6.24 Found:. C, 79.68; H, 6.23 2) 3- [4- ( benzyloxy) phenyl] -3- Ethyl oxopropanoate Ethanol (0.6 ml) was added to a solution of 4-benzyloxyacetophenone (36 g, 159 mmol) in diethyl carbonate (200 ml), and sodium hydride (6 ml) was added under ice cooling.
(0% oily, 12.7 g, 318 mmol) and stirred at room temperature for 2 hours. 6N hydrochloric acid was added to the reaction solution to stop the reaction, water (500 ml) was added, and ethyl acetate (500 ml ×
Extracted in 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to obtain the desired product (49.3 g, 100%). ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.2 Hz), 3.94 (2
H, s), 4.21 (2H, q, J = 7.2 Hz), 5.14 (2H, s), 6.98
-7.06 (2H, m), 7.30-7.48 (5H, m), 7.88-7.96 (2
H, m). IRν max ^KBr cm ^-1 : 1740, 1678, 1601, 1576, 1510.mp 53-54 ° C Anal.Calcd for C ₁₈ H ₁₈ O ₄ C, 72.47; H, 6.08 Found: C, 72.56; H, 6.10.3 ) Ethyl 3- [4- (benzyloxy) phenyl] -3-oxo-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoate -Tetrafluoroethoxy) toluene (27.8 g, 133 mmol) in ethyl acetate (25
0 ml) solution with N-bromosuccinimide (26.1).
g, 147 mmol) and 2,2′-azobis (isobutyronitrile) (440 mg, 2.67 mmol) were added, and the mixture was refluxed for 5 hours. After concentrating the reaction solution, the crystals were filtered with hexane, and the filtrate was concentrated to give 3- (1,1,2,2-
Tetrafluoroethoxy) -α-bromotoluene was prepared. To a solution of ethyl 3- [4- (benzyloxy) phenyl] -3-oxopropanoate (37.8 g, 127 mmol) in 1,2-dimethoxyethane (250 ml) was added sodium hydride (60% oil, 5.07 g, (127 mmol) under ice-cooling and stirred at room temperature for 30 minutes. The previously prepared solution of 3- (1,1,2,2-tetrafluoroethoxy) -α-bromotoluene in 1,2-dimethoxyethane (50 ml) was added dropwise to the reaction solution, and the reaction solution was allowed to stand at room temperature overnight. Stirred. The reaction solution was poured into water (500 ml) and extracted with ethyl acetate (500 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-1: 1) and recrystallized from ethyl acetate-hexane to give the desired product (4.
(3.4 g, 68%). ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.0 Hz), 3.20-3.4
2 (2H, m), 4.09 (2H, q, J = 7.0 Hz), 4.56 (1H, t,
J = 7.4 Hz), 5.12 (2H, s), 5.88 (1H, tt, J = 53.0,
3.0Hz), 6.92-7.50 (11H, m), 7.88-8.00 (2H, m) .IRν max ^KBr cm ^-1 : 1732, 1680, 1601, 1576, 1510, 145
4, 1422. mp 71-72 ° C Anal. Calcd for C ₂₇ H ₂₄ O ₅ F ₄ C, 64.28; H, 4.80 Found: C, 64.47; H, 4.78. 4) (2RS, 3RS) -3- [4 -(Benzyloxy) phenyl] -3-hydroxy-2- [3- (1,1,
Ethyl 2,2-tetrafluoroethoxy) benzyl] propanoate To a solution of zinc chloride (18.9 g, 139 mmol) in diethyl ether (500 ml) was added sodium borohydride (10.5 g, 278 mmol) for 30 minutes at room temperature. Stirred. The insoluble material was removed by filtration, and the filtrate was subjected to 3- [4- (benzyloxy) phenyl] -3-oxo-2- [3- (1,1,1).
A solution of ethyl 2,2-tetrafluoroethoxy) benzyl] propanoate (35.0 g, 69.4 mmol) in diethyl ether (200 ml) was added at 0 ° C., and the mixture was stirred for 30 minutes. 1N hydrochloric acid was added to the reaction solution to stop the reaction, water (500 ml) was further added, and ethyl acetate (500 ml ×
Extracted in 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to obtain the desired product (30.3 g, 86%). ¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7.0 Hz), 2.77 (1
H, d, J = 2.8 Hz), 2.90-3.08 (3H, m), 3.87 (2H, q,
J = 7.0 Hz), 4.92-5.00 (1H, m), 5.06 (2H, s), 5.8
8 (1H, tt, J = 53.0, 3.0 Hz), 6.92-7.08 (5H, m),
7.20-7.50 (8H, m) .IRν max ^KBr cm ^-1 : 1725, 1611, 1586, 1512, 1487, 145
. 4. mp 67-68 ℃ Anal Calcd for C 27 H 26 O 5 F 4 C, 64.03; H, 5.17 Found:. C, 64.02; H, 5.15 5) (2RS, 3RS) -3- [4- ( Benzyloxy) phenyl] -3-hydroxy-2- [3- (1,1,
2,2-Tetrafluoroethoxy) benzyl] propanoic acid (2RS, 3RS) -3- [4- (benzyloxy) phenyl] -3-hydroxy-2- [3- (1,1,2,2-tetrafluoro) Ethoxy) benzyl] ethyl propanoate (2
5.0 g, 49.4 mmol) of methanol (200 m
l) A 2N aqueous sodium hydroxide solution (49.0) was added to the solution.
ml, 98.0 mmol) and stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid, and then extracted with ethyl acetate (500 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to obtain the desired product (21 g, 89%). ¹ H-NMR (CDCl ₃ ) δ: 2.90-3.08 (3H, m), 5.02 (1H, d, J
= 3.9 Hz), 5.05 (2H, s), 5.86 (1H, tt, J = 53.1,
3.0Hz), 6.90-7.48 (13H, m) .IRν max ^KBr cm ^-1 : 1709, 1611, 1586, 1512, 1489, 145
4. mp 76-77 ° C Anal. Calcd for C ₂₅ H ₂₂ O ₅ F ₄ C, 62.76; H, 4.63 Found: C, 62.98; H, 4.57.6) (4RS, 5SR) -5- [4- ( Benzyloxy) phenyl] -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine-2-
On (2RS, 3RS) -3- [4- (benzyloxy) phenyl] -3-hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoic acid (21.0
g, 43.9 mmol) of tetrahydrofuran (300
ml) solution in diphenylphosphoryl azide (10.4
ml, 48.3 mmol) and triethylamine (9.2).
ml, 65.9 mmol) and heated to reflux for 2 hours. After allowing the reaction solution to cool, water (400 ml) was added, and the mixture was extracted with ethyl acetate (200 ml × 2). The extract was washed successively with 1N hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and recrystallized from ethyl acetate-hexane to obtain the desired product (16.4 g, 79%). ¹ H-NMR (CDCl ₃ ) δ: 2.22-2.40 (2H, m), 4.16-4.30 (1H,
m), 5.08 (2H, s), 5.25 (1H, s), 5.75 (1H, d, J = 8.
0 Hz), 5.89 (1H, tt, J = 53.0, 3.0 Hz), 6.80-7.50
(13H, m) .IRν max ^KBr cm ^-1 : 1759, 1613, 1588, 1514, 1489, 145
4.mp 115-116 ℃ Anal. Calcd for C ₂₅ H ₂₁ NO ₄ F ₄ : C, 63.16; H, 4.45; N,
2.95 Found: C, 62.89; H, 4.48; N, 2.5.7. 7) (1RS, 2SR) -2-amino-1- [4- (benzyloxy) phenyl] -3- [3- (1,1,2 , 2-Tetrafluoroethoxy) phenyl] propan-1-ol (4RS, 5SR) -5- [4- (benzyloxy) phenyl] -4- [3- (1,1,2,2-tetrafluoroethoxy) Benzyl] -1,3-oxazolidin-2-one (2.50 g, 5.26 mmol) in ethanol (30
8N aqueous sodium hydroxide solution (2 ml,
(16 mmol) and heated under reflux for 5 hours. After the reaction solution was concentrated, it was diluted with water (100 ml), and ethyl acetate (10 ml) was added.
0 ml × 2). The extract was washed with brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure to give the desired product (2.4 g, 100%). ¹ H-NMR (CDCl ₃ ) δ: 1.69 (2H, brs), 2.40 (1H, dd, J =
13.8, 10.2 Hz), 2.90 (1H, dd, J = 13.8, 3.0 Hz),
3.22-3.30 (1H, m), 4.59 (1H, d, J = 5.4 Hz), 5.08
(2H, s), 5.89 (1H, tt, J = 53.1, 3.0 Hz), 6.96-7.1
.. 0 (5H, m) , 7.26-7.50 (8H, m) IRν max KBr cm -1: 1611, 1586, 1510, 1487, 1454. Anal Calcd for C 24 H 23 NO 3 F 4: C, 64.14; H, 5.16; N,
3.12 Found: C, 63.87; H, 5.20; N, 2.96.8) N-{(1RS, 2SR) -2- [4- (benzyloxy) phenyl] -2-hydroxy-1- [3- (1, 1,
2,2-tetrafluoroethoxy) benzyl] ethyl｝-
6,7-dihydro-5H-benzo [a] [7] annulene-
1-carboxamide (1RS, 2SR) -2-amino-1-
[4- (benzyloxy) phenyl] -3- [3- (1,
6,7-Dihydro-5H was added to a solution of 1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol (617 mg, 1.37 mmol) in acetonitrile (20 ml).
-Benzo [a] cycloheptene-1-carboxylic acid (258
mg, 1.37 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (39
4 mg, 2.06 mmol) and 1-hydroxybenzotriazole hydrate (210 mg, 1.37 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was washed with water (100
ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the desired product (474 mg, 56%). ¹ H-NMR (CDCl ₃ ) δ: 1.94-2.04 (2H, m), 2.12-2.24 (2H,
m), 2.62-2.70 (2H, m), 2.78 (1H, dd, J = 14.7, 10.5
Hz), 3.02 (1H, dd, J = 14.7, 4.2 Hz), 3.40 (1H, br
s), 4.64-4.76 (1H, m), 4.97 (1H, d, J = 3.9 Hz),
5.07 (2H, s), 5.72 (1H, d, J = 9.9 Hz), 5.70-6.08
(2H, m), 6.19 (1H, d, J = 11.7 Hz), 6.92-7.18 (8H,
. m), 7.26-7.48 (8H, m) IRν max KBr cm -1:. 1644, 1613, 1586, 1510, 1454. mp 115-116 ℃ Anal Calcd for C 36 H 33 NO 4 F 4 · 0.1H 2 O: C, 69.58; H,
5.38; N, 2.25 Found: C, 69.45; H, 5.40; N, 2.27.

Example 237 N-{(1RS, 2SR) -2- (3-chlorophenyl)-
2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro-
5H-benzo [a] [7] annulene-1-carboxamide 1) Ethyl 3- (3-chlorophenyl) -3-oxopropanoate A solution of 3-chloroacetophenone (23.9 g, 154 mmol) in diethyl carbonate (150 ml). Ethanol (0.3 ml) was added, and sodium hydride (60
% Oily, 12.4 g, 309 mmol) and stirred at room temperature for 2 hours. 6N hydrochloric acid was added to the reaction solution to stop the reaction, water (500 ml) was added, and ethyl acetate (500 ml ×
Extracted in 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1-5: 1) to obtain the desired product (24.8 g, 71%). ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.40 (3H, m), 3.97 (2H × 3/4,
s), 4.16-4.32 (2H, m), 5.65 (1H × 1/4, s), 7.30-7.50
(1H, m), 7.54-7.68 (1H, m), 7.76-7.84 (1H, m), 7.9
0-7.96 (1H, m) .IRν max ^KBr cm ^-1 : 1740, 1694, 1651, 1628, 1568, 147
_{. 4. Anal Calcd for C 11 H} 11 O 3 Cl: C, 58.29; H, 4.89 Found:. C, 58.54; H, 4.84 2) 3- (3- chlorophenyl) -3-oxo-2- [3-
Ethyl (1,1,2,2-tetrafluoroethoxy) benzyl] propanoate ethyl 3- (1,1,2,2-tetrafluoroethoxy) toluene (10.2 g, 49.0 mmol) in ethyl acetate (8
0 ml) to a solution of N-bromosuccinimide (9.6 g,
53.9 mmol) and 2,2′-azobis (isobutyronitrile) (161 mg, 0.98 mmol) were added, and the mixture was heated under reflux for 5 hours. After concentrating the reaction solution, the crystals were filtered with hexane, and the filtrate was concentrated to prepare 3- (1,1,2,2-tetrafluoroethoxy) -α-bromotoluene. To a solution of ethyl 3- (3-chlorophenyl) -3-oxopropanoate (10.0 g, 44.1 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% oily, 1.76 g, 44.50 g). (1 mmol) under ice-cooling and stirred at room temperature for 30 minutes. 3- (1,1,2,2-tetrafluoroethoxy)-previously prepared in the reaction solution
1,2-dimethoxyethane of α-bromotoluene (50 m
l) The solution was added dropwise and the reaction was stirred at room temperature overnight. The reaction solution was poured into water (300 ml), and ethyl acetate (300 ml) was added.
ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-1: 1) to obtain the desired product (7.5 g, 39%). ¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7.2 Hz), 3.33 (2
H, d, J = 7.4 Hz), 4.02-4.20 (2H, m), 4.54 (1H, t,
J = 7.2 Hz), 5.89 (1H, tt, J = 53.0, 3.0 Hz), 7.0
0-7.20 (2H, m), 7.20-7.46 (2H, m), 7.50-7.60 (1H,
m), 7.78-7.84 (1H, m), 7.90-7.98 (1H, m). IRν max ^KBr cm ^-1 : 1738, 1694, 1613, 1588, 1572. -Chlorophenyl)-
Ethyl 3-hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoate Boron hydride in a solution of zinc chloride (4.66 g, 34.2 mmol) in diethyl ether (100 ml) Add sodium (2.59 g, 68.4 mmol) and add 30
Minutes. The insolubles were removed by filtration, and the filtrate was treated with ethyl 3- (3-chlorophenyl) -3-oxo-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoate (7.
40 g, 17.1 mmol) of diethyl ether (30
ml) solution was added at 0 ° C. and stirred for 30 minutes. 1N hydrochloric acid was added to the reaction solution to stop the reaction, and water (100 ml) was further added.
And extracted with ethyl acetate (100 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4:
Purification in 1) gave the desired product (6.6 g, 89%). ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, t, J = 7.2 Hz), 2.90-3.0
8 (3H, m), 3.10-3.16 (1H, m), 3.91 (2H, q, J = 7.2
Hz), 5.02 (1H, s), 5.88 (1H, tt, J = 53.1,3.0 H
z), 6.92-7.08 (3H, m), 7.20-7.32 (4H, m), 7.42 (1
H, s) .IRν max ^KBr cm ^-1 : 1725, 1613, 1588, 1487, 1449.Anal.Calcd for C ₂₀ H ₁₉ O ₄ ClF ₄ : C, 55.25; H, 4.40 Found: C, 58.33; H, 4.43. 4) (2RS, 3RS) -3- (3-chlorophenyl)-
3-hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoic acid (2RS, 3RS) -3- (3-chlorophenyl) -3-hydroxy-2- [3- ( Ethyl 1,1,2,2-tetrafluoroethoxy) benzyl] propanoate (6.08 g, 1
4.0 mmol) in methanol (30 ml).
A normal aqueous sodium hydroxide solution (14 ml, 28 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the desired product (4.6).
g, 81%). ¹ H-NMR (CDCl ₃ ) δ: 2.80-3.12 (3H, m), 5.11 (1H, d, J
= 3.6 Hz), 5.88 (1H, tt, J = 53.2, 3.0 Hz), 6.90-
7.10 (3H, m), 7.18-7.32 (4H, m), 7.42 (1H, s) .IRν max ^KBr cm ^-1 : 1713, 1613, 1588, 1489, 1451.mp
.. 94-95 ℃ Anal Calcd for C 18 H 15 O 4 F 4: C, 53.15; H, 3.72 Found: C, 53.03; H, 3.69 5) (4RS, 5SR) -5- (3- chlorophenyl) -
4- [3- (1,1,2,2-tetrafluoroethoxy)
Benzyl] -1,3-oxazolidin-2-one (2RS, 3RS) -3- (3-chlorophenyl) -3-hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] Propanoic acid (4.50 g, 11.1)
Mmol) in tetrahydrofuran (90 ml).
Diphenyl phosphoryl azide (2.62 ml, 12.2
Mmol) and triethylamine (2.32 ml, 16.
6 mmol) and heated under reflux for 4 hours. After allowing the reaction mixture to cool, water (200 ml) was added thereto, and ethyl acetate (100 ml) was added.
1 × 2). The extract was washed successively with 1N hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and neutral alumina column chromatography (ethyl acetate), and recrystallized from ethyl acetate-hexane to obtain the desired product (4.70 g, 100%). ¹ H-NMR (CDCl ₃ ) δ: 2.20-2.42 (2H, m), 4.20-4.34 (1H,
m), 5.06 (1H, s), 5.78 (1H, d, J = 8.0 Hz), 5.90 (1
H, tt, J = 53.0, 2.6 Hz), 6.89 (1H, s), 6.96 (1H,
d, J = 7.6 Hz), 7.06-7.18 (1H, m), 7.20-7.44 (5H,
^{.. m) IRν max KBr cm} -1: 1767, 1613, 1588, 1489, 1435. mp 102-103 ℃ Anal Calcd for C 18 H 14 NO 3 ClF 4: C, 53.55; H, 3.49;
N, 3.47 Found: C, 53.57; H, 3.55; N, 3.38.6) (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- [3- (1,1,2,2 -Tetrafluoroethoxy) phenyl] propan-1-ol (4RS, 5SR) -5- (3-chlorophenyl) -4-
[3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidin-2-one (3.70 g,
8.16 mmol) in ethanol (30 ml)
A normal aqueous sodium hydroxide solution (5.7 ml, 46 mmol) was added, and the mixture was heated under reflux for 3 hours. After concentrating the reaction solution, the reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed with brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure to give the desired product (3.
0 g, 87%). ¹ H-NMR (CDCl ₃ ) δ: 2.38 (1H, dd, J = 14.0, 10.2 Hz),
2.77 (1H, dd, J = 14.0, 3.0 Hz), 3.24-3.36 (1H,
m), 4.67 (1H, d, J = 4.8 Hz), 5.90 (1H, tt, J = 53.
0, 3.0 Hz), 6.94-7.18 (3H, m), 7.22-7.43 (5H, m). IRν max ^KBr cm ^-1 : 1613, 1586, 1487, 1449, 1431. 7) N- ｛(1RS, 2SR) ) -2- (3-Chlorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro-5H-benzo [a] [ 7] annulene-1-carboxamide (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol (448 mg, 1.
6,7-dihydro-5H-benzo [a] cycloheptene-1 in a solution of 24 mmol) in acetonitrile (20 ml).
-Carboxylic acid (234 mg, 1.24 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (357 mg, 1.86 mmol) and 1-hydroxybenzotriazole hydrate (190 m
g, 1.24 mmol) and stirred at room temperature overnight.
The reaction solution was diluted with water (100 ml), and ethyl acetate (10 ml) was added.
0 ml × 2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the desired product (44).
4 mg, 67%). ¹ H-NMR (CDCl ₃ ) δ: 1.92-2.04 (2H, m), 2.10-2.24 (2H,
m), 2.60-2.70 (2H, m), 2.73-2.82 (1H, m), 2.90-3.00
(1H, m), 3.87 (1H, d, J = 3.6 Hz), 4.60-4.70 (1H,
m), 5.00-5.06 (1H, m), 5.70-6.08 (2H, m), 5.80 (1
H, d, J = 8.4 Hz), 6.22 (1H, d, J = 11.7 Hz), 6.92
-7.18 (6H, m), 7.22-7.36 (4H, m), 7.47 (1H, s) .IRν max ^KBr cm ^-1 : 1634, 1588, 1514, 1451, 1302.mp 160-161 ℃ Anal. C ₂₉ H ₂₆ NO ₃ ClF ₄ : C, 63.56; H, 4.78;
N2.56 Found: C, 63.40; H, 4.65; N, 2.42.

Example 238 (1RS, 2SR) -2- (4-fluorophenyl) -2-
Tert-butyl hydroxy-1-{[6- (1,1,2,2-tetrafluoroethoxy) pyridin-2-yl] methyl} ethylcarbamate 1) [6- (1,1,2,2-tetra Fluoroethoxy) pyridin-2-yl] methanol Red was added to a solution of ethyl 6- (1,1,2,2-tetrafluoroethoxy) pyridine-2-carboxylate (5.65 g, 21.2 mmol) in tetrahydrofuran (60 ml). -
Al® (6.11 g, 21.2 mmol) was added. After stirring the reaction solution at room temperature for 30 minutes, acetone (2 m
l) was added. Water (100 ml) was added to the reaction solution, and extracted with ethyl acetate (100 ml × 2). The extract is washed sequentially with water and saturated saline, and dried (anhydrous magnesium sulfate)
After that, it was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product (4.2 g, 88%). ¹ H-NMR (CDCl ₃ ) δ: 3.02 (1H, brs), 4.74 (2H, s), 6.17
(1H, tt, J = 53.0, 3.8 Hz), 6.96 (1H, d, J = 8.2
Hz), 7.23 (1H, d, J = 8.2 Hz), 7.79 (1H, t, J = 7.8
Hz). IRν max ^KBr cm ^-1 : 1607, 1580, 1443, 135.2 2) 3- (4-Fluorophenyl) -3-oxo-2-
{[6- (1,1,2,2-tetrafluoroethoxy) pyridin-2-yl] methyl} ethyl propanoate [6- (1,1,2,2-tetrafluoroethoxy) pyridin-2-yl] To a solution of methanol (4.14 g, 18.39 mmol) in ethyl acetate (50 ml) was added methanesulfonyl chloride (2.32 g, 20.23 mmol) and triethylamine (3.08 ml, 22.07 mmol).
Was added and stirred at room temperature for 2 hours. The insolubles were filtered, and the filtrate was distilled off under reduced pressure to prepare a mesyl compound. Ethyl 3- (4-fluorophenyl) -3-oxopropanoate (3.87 g, 1
8.4 mmol) of 1,2-dimethoxyethane (40 m
l) Sodium hydride (740 mg, 60% oily, 18.4 mmol) was added to the solution, and the mixture was stirred at room temperature for 2 hours. The 1,2-dimethoxyethane (10 ml) solution of the mesyl compound previously prepared was added dropwise to the reaction solution, and the reaction solution was stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (100 ml × 2). Extract water with water,
The extract was washed successively with a saturated saline solution, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1-2:
Purification in 1) gave the desired product (1.46 g, 19%). ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.0 Hz), 3.47 (2
H, d, J = 7.4 Hz), 4.13 (2H, q, J = 7.0 Hz), 5.08
(1H, t, J = 7.2 Hz), 6.12 (1H, tt, J = 53.0,3.6 H
z), 6.83 (1H, d, J = 8.0 Hz), 7.06-7.22 (3H, m),
7.60-7.72 (1H, m), 8.02-8.18 (2H, m) .IRν max ^KBr cm ^-1 : 1738, 1688, 1601, 1578, 1508, 145
6, 1441.3) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-{[6- (1,1,2,2-tetrafluoroethoxy) pyridin-2-yl] Methyl ethyl propanoate To a solution of zinc chloride (915 mg, 6.71 mmol) in diethyl ether (20 ml) was added sodium borohydride (508 mg, 13.4 mmol), and the mixture was added at room temperature for 30 minutes.
Minutes. The insoluble material is removed by filtration, and the filtrate is treated with 3- (4-fluorophenyl) -3-oxo-2-{[6- (1,1,2,2-tetrafluoroethoxy) pyridin-2-yl] methyl}. A solution of ethyl propanoate (1.40 g, 3.35 mmol) in diethyl ether (10 ml) was added at 0 ° C.
Minutes. The reaction was stopped by adding 1N hydrochloric acid to the reaction solution.
Further, water (50 ml) was added, and ethyl acetate (50 ml ×
Extracted in 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-1: 1) to obtain the desired product (1.28 g, 91%). ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, t, J = 7.2 Hz), 2.92-3.1
0 (1H, m), 3.18-3.30 (2H, m), 3.43 (1H, d, J = 3.3
Hz), 3.92-4.06 (2H, m), 5.04-5.10 (1H, m), 6.26 (1
H, tt, J = 53.1, 3.9 Hz), 6.84 (1H, d, J = 8.4 H
z), 6.96-7.06 (3H, m), 7.32-7.40 (2H, m), 7.64 (1
H, t, J = 8.1 Hz) .IRν max ^KBr cm ^-1 : 1728, 1605, 1576, 1512, 1456, 144
3. Anal.Calcd for C ₁₉ H ₁₈ NO ₄ F ₅ : C, 54.42; H, 4.33; N,
3.34 Found: C, 54.55; H, 4.16; N, 3.22.4) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-｛[6- (1,1,2,2 -Tetrafluoroethoxy) pyridin-2-yl] methyl} propanoic acid (2RS, 3RS) -3- (4-fluorophenyl) -3-
To a solution of ethyl hydroxy-2-{[6- (1,1,2,2-tetrafluoroethoxy) pyridin-2-yl] methyl} propanoate (1.28 g, 3.05 mmol) in methanol (6 ml), A 2N aqueous sodium hydroxide solution (3.05 ml, 6.1 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction solution was acidified with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate (50 ml × 2).
The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate), and then distilled off under reduced pressure to obtain the desired product (1.20 g, 10
0%). ¹ H-NMR (CDCl ₃ ) δ: 2.82-3.10 (1H, m), 3.18-3.32 (2H,
m), 5.24 (1H, d, J = 3.9 Hz), 6.14 (1H, tt, J = 5
3.4, 3.6 Hz), 6.84-7.08 (4H, m), 7.28-7.40 (2H,
m), 7.62-7.70 (1H, m) .IRν max ^KBr cm ^-1 : 1713, 1605, 1578, 1512, 1456, 144
3.5) (4RS, 5SR) -5- (4-fluorophenyl) -4-{[6- (1,1,2,2-tetrafluoroethoxy) pyridin-2-yl] methyl} -1,3 -Oxazolidin-2-one (2RS, 3RS) -3- (4-fluorophenyl) -3-
To a solution of hydroxy-2-{[6- (1,1,2,2-tetrafluoroethoxy) pyridin-2-yl] methyl} propanoic acid (1.20 g, 3.07 mmol) in tetrahydrofuran (20 ml) was added diphenyl. Phosphoryl azide (730 μl, 3.37 mmol) and triethylamine (706 μl, 5.06 mmol) were added, and the mixture was heated under reflux for 4 hours. After allowing the reaction mixture to cool, water (100 ml) was added, and the mixture was extracted with ethyl acetate (50 ml × 2). The extract was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3:
1-1: 1) to give the desired product (808 mg, 68%)
I got ¹ H-NMR (CDCl ₃ ) δ: 2.39 (1H, dd, J = 15.8, 4.0 Hz),
2.58 (1H, dd, J = 15.8,10.2 Hz), 4.52-4.66 (1H,
m), 5.81 (1H, d, J = 8.0 Hz), 6.03 (1H, tt, J = 53.
2, 3.0 Hz), 6.80 (1H, d, J = 7.2 Hz), 6.88 (1H, d,
J = 8.2 Hz), 7.00-7.16 (2H, m), 7.24-7.40 (2H,
m), 7.63 (1H, t, J = 8.0 Hz) .IRν max ^KBr cm ^-1 : 1761, 1607, 1576, 1514, 1456, 144
1.6) (4RS, 5SR) -5- (4-fluorophenyl) -2-oxo-4-{[6- (1,1,2,2-tetrafluoroethoxy) pyridin-2-yl] methyl} -1,3-
Tert-Butyl oxazolidine-3-carboxylate (4RS, 5SR) -5- (4-fluorophenyl) -4-
{[6- (1,1,2,2-tetrafluoroethoxy) pyridin-2-yl] methyl} -1,3-oxazolidine-2-
(808 mg, 2.08 mmol) in acetonitrile (20 ml) was added to di-tert-butyl dicarbonate (54 ml).
5 mg, 2.50 mmol) and 4-N, N-dimethylaminopyridine (25.6 mg, 0.21 mmol) were added, and the mixture was stirred at room temperature for 6 hours. Water (50 ml) in the reaction solution
And extracted with ethyl acetate (50 ml × 2). The extract was washed with brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the desired product (850 g, 84%). ¹ H-NMR (CDCl ₃ ) δ: 1.53 (9H, s), 2.70 (1H, dd, J = 1
4.8, 10.0 Hz), 3.12 (1H, dd, J = 14.8, 3.4 Hz), 5.
30-5.42 (1H, m), 5.70 (1H, d, J = 7.4 Hz), 6.20 (1
H, d, J = 7.2 Hz), 6.22 (1H, tdd, J = 53.4, 4.4,
3.0 Hz), 6.68-6.88 (3H, m), 6.98-7.10 (2H, m), 7.30
-7.40 (1H, m) .IRν max ^KBr cm ^-1 : 1821, 1725, 1607, 1578, 1514, 145
6, 1443, 1370. Anal.Calcd for C ₂₂ H ₂₁ F ₅ N ₂ O ₅ : C, 54.10; H, 4.33;
N, 5.74 Found: C, 54.06; H, 4.23; N, 5.52.7) (1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-{[6- (1,1,2 Tert-butyl (2,2-tetrafluoroethoxy) pyridin-2-yl] methyldiethylcarbamate (4RS, 5SR) -5- (4-fluorophenyl) -2-
Tert-Butyl oxo-4-{[6- (1,1,2,2-tetrafluoroethoxy) pyridin-2-yl] methyl} -1,3-oxazolidine-3-carboxylate (840 mg,
1.72 mmol) in methanol (4 ml) in 0.5N sodium hydroxide in methanol (4.12 ml,
2.06 mmol) and stirred at room temperature for 15 minutes. Water (50 ml) was added to the reaction solution, and ethyl acetate (50 ml ×
Extracted in 2). The extract was washed with brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1), and recrystallized from ethyl acetate-hexane to obtain the desired product (390 mg, 49%). ¹ H-NMR (CDCl ₃ ) δ: 1.37 (9H, s), 2.90-3.02 (2H, m),
3.85 (1H, brs), 4.16-4.30 (1H, m), 4.89 (1H, brs),
5.26 (1H, d, J = 7.2 Hz), 6.19 (1H, tt, J = 53.0,
3.6 Hz), 6.91 (1H, d, J = 8.0 Hz), 7.00-7.14 (3H,
m), 7.34-7.44 (2H, m), 7.71 (1H, t, J = 8.0 Hz) .IRν max ^KBr cm ^-1 : 1694, 1605, 1578, 1510, 1456, 144
1.mp 109-110 ℃ Anal. Calcd for C ₂₁ H ₂₃ F ₅ N ₂ O ₄・ 0.1H ₂ O: C, 54.34; H,
5.03; N, 6.03 Found: C, 54.12; H, 4.93; N, 5.87.

Example 239 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-{[6- (1,1,2,2-tetrafluoroethoxy) pyridin-2-yl] methyl} ethyl)
-6,7-Dihydro-5H-benzo [a] [7] annulene
-1-Carboxamide (1RS, 2SR) -2- (4-fluorophenyl) -2-
Tert-butyl hydroxy-1-{[6- (1,1,2,2-tetrafluoroethoxy) pyridin-2-yl] methyl} ethylcarbamate (300 mg, 0.65 mmol) in trifluoroacetic acid (3 ml) At 0 ° C.
Stirred at C for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml × 2). The extract was washed with brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The solution of the residue in acetonitrile (25 ml)
7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (122 mg, 0.65 mmol) and 1-
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (187 mg, 0.97 mmol) and 1-hydroxybenzotriazole hydrate (99 mg,
(0.65 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
1 × 2). The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 1) and recrystallized from ethyl acetate-hexane to give the desired product (196).
mg, 57%). ¹ H-NMR (CDCl ₃ ) δ: 1.92-2.06 (2H, m), 2.14-2.24 (2H,
m), 2.62-2.70 (2H, m), 3.06 (1H, dd, J = 15.0, 6.9
Hz), 3.16 (1H, dd, J = 15.0, 5.1 Hz), 4.34 (1H, d,
J = 5.1 Hz), 4.70-4.82 (1H, m), 5.00 (1H, t, J =
4.8 Hz), 5.88-6.26 (3H, m), 6.44 (1H, d, J = 7.8 H
z), 6.93 (1H, d, J = 7.8 Hz), 7.00-7.12 (4H, m),
7.12-7.20 (2H, m), 7.40-7.50 (2H, m), 7.72 (1H, t,
J = 7.5 Hz) .IRν max ^KBr cm ^-1 : 1645, 1605, 1576, 1508, 1456, 144
1.mp 134-135 ℃ Anal.Calcd for C ₂₈ H ₂₅ N ₂ O ₃ F ₅・ 0.1H ₂ O: C, 62.94; H,
4.75; N, 5.24 Found: C, 62.84; H, 4.77; N, 5.16.

Example 240 N-｛(1RS, 2SR) -2- [3- (benzyloxy)
Phenyl] -2-hydroxy-1- [3- (1,1,2,2-
Tetrafluoroethoxy) benzyl] ethyl} -6,7-
Dihydro-5H-benzo [a] [7] annulene-1-carboxamide 1) 3-Benzyloxyacetophenone Potassium carbonate (154) was added to a solution of 3-hydroxyacetophenone (101 g, 744 mmol) in acetone (1 L).
g, 1.12 mol) and benzyl bromide (130
g, 759 mmol) and stirred at room temperature overnight. After concentration, the reaction solution was diluted with water (500 ml) and extracted with ethyl acetate (500 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-4: 1) to obtain the desired product (128 g, 76%). ¹ H-NMR (CDCl ₃ ) δ: 2.58 (3H, s), 5.11 (2H, s), 7.14-
7.20 (1H, m), 7.30-7.48 (6H, m), 7.54-7.60 (2H, m) .IRν max ^KBr cm ^-1 : 1684, 1593, 1582, 1497, 1483, 143
9. Anal. Calcd for C ₁₅ H ₁₄ O ₂ : C, 79.62; H, 6.24 Found: C, 79.44; H, 6.22.2. 2) Ethyl 3- [3- (benzyloxy) phenyl] -3-oxopropanoate Ethanol (1.5 ml) was added to a solution of 3-benzyloxyacetophenone (90 g, 400 mmol) in diethyl carbonate (500 ml), and sodium hydride (6 ml) was added under ice-cooling.
(0% oily, 31.8 g, 800 mmol) and stirred at room temperature for 4 hours. 6N hydrochloric acid was added to the reaction solution to stop the reaction, water (500 ml) was added, and ethyl acetate (500 ml ×
Extracted in 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1-10: 1) to obtain the desired product (107 g, 90%). ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.38 (3H, m), 3.96 (2H × 6/7,
s), 4.18-4.32 (2H, m), 5.09 (2H × 1/7, s), 5.11 (2H
× 6/7, s), 5.65 (1H × 1/7, s), 7.02-7.60 (9H, m) .IRν max ^KBr cm ^-1 : 1740, 1688, 1582, 1485, 1441. Anal.Calcd for C ₁₅ H ₁₄ O ₂ : C, 72.47; H, 6.08 Found: C, 72.77; H, 6.01.3) 3- [3- (benzyloxy) phenyl] -3-oxo-2- [3- (1,1 Ethyl [2,2,2-tetrafluoroethoxy) benzyl] propanoate [3- (1,1,2,2-tetrafluoroethoxy) phenyl] methanol (7.91 g, 35.3 mmol) in ethyl acetate (100 ml) To the mixture was added methanesulfonyl chloride (3.00 ml, 38.8 mmol) and triethylamine (5.91 ml, 42.4 mmol), and the mixture was stirred at room temperature for 2 hours. The insolubles were filtered, and the filtrate was distilled off under reduced pressure to prepare a mesyl compound. Ethyl 3- [3- (benzyloxy) phenyl] -3-oxopropanoate (10 g, 33.
5 mmol) of 1,2-dimethoxyethane (80 ml)
Add sodium hydride (1.34 g, 60% oily, 3
(3.5 mmol) and stirred at room temperature for 3 hours. The 1,2-dimethoxyethane (10 ml) solution of the mesyl compound previously prepared was added dropwise to the reaction solution, and the reaction solution was stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (300 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-1: 1) to obtain the desired product (19.0 g). ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.0 Hz), 3.32 (2
H, d, J = 7.4 Hz), 4.09 (2H, q, J = 7.0 Hz), 4.56
(1H, t, J = 7.4 Hz), 5.09 (2H, s), 5.88 (1H, tt, J
= 53.2, 3.0 Hz), 7.00-7.60 (13H, m). 4) (2RS, 3RS) -3- [3- (benzyloxy) phenyl] -3-hydroxy-2- [3- (1,1,
Ethyl 2,2-tetrafluoroethoxy) benzyl] propanoate To a solution of zinc chloride (9.14 g, 67.0 mmol) in diethyl ether (100 ml) was added sodium borohydride (5.07 g, 134 mmol) at room temperature. Stir for 30 minutes. The insoluble material was removed by filtration, and the filtrate was subjected to 3- [3- (benzyloxy) phenyl] -3-oxo-2- [3- (1,1,1).
A solution of ethyl 2,2-tetrafluoroethoxy) benzyl] propanoate (19.0 g, 33.5 mmol) in diethyl ether (200 ml) was added at 0 ° C., and the mixture was stirred for 30 minutes. 1N hydrochloric acid was added to the reaction solution to stop the reaction, water (500 ml) was further added, and ethyl acetate (500 ml ×
Extracted in 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-ethyl acetate) to obtain the desired product (10.7 g, crude). 5) (2RS, 3RS) -3- [3- (benzyloxy) phenyl] -3-hydroxy-2- [3- (1,1,
2,2-Tetrafluoroethoxy) benzyl] propanoic acid (2RS, 3RS) -3- [3- (benzyloxy) phenyl] -3-hydroxy-2- [3- (1,1,2,2-tetrafluoro Ethoxy) benzyl] ethyl propanoate (1
0.7 g, 21.2 mmol, crude) of methanol (5
0 ml) solution and 2N aqueous sodium hydroxide solution (21 ml).
ml, 42 mmol) and stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid, and then ethyl acetate (50 m
1 × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure.
The obtained crystals were washed with hexane to give the desired product (7.90).
g, 3 steps, 49%). ¹ H-NMR (CDCl ₃ ) δ: 2.80-3.08 (3H, m), 5.06 (2H, s),
5.00-5.10 (1H, m), 5.86 (1H, tt, J = 53.2, 2.8 Hz),
6.86-7.10 (6H, m), 7.10-7.50 (7H, m) IRν max KBr cm -1:.. 1713, 1588, 1489, 1451. mp 103-104 ℃ Anal Calcd for C 25 H 22 O 5 F 4 : C, 62.76; H, 4.63 Found: C, 63.01; H, 4.58.6) (4RS, 5SR) -5- [3- (benzyloxy) phenyl] -4- [3- (1,1,2, 2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine-2-
ON (2RS, 3RS) -3- [3- (benzyloxy) phenyl] -3-hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoic acid (7.8
g, 16.3 mmol) of tetrahydrofuran (100
ml) solution in diphenylphosphoryl azide (3.86).
ml, 17.9 mmol) and triethylamine (3.4
(2 ml, 24.5 mmol), and the mixture was heated under reflux for 4 hours. After allowing the reaction mixture to cool, water (100 ml) was added, and the mixture was extracted with ethyl acetate (100 ml × 2). The extract was washed successively with 1N hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain the desired product (6.72 g, 87%). ¹ H-NMR (CDCl ₃ ) δ: 2.10-2.38 (2H, m), 4.10-4.28 (1H,
m), 5.05 (1H, brs), 5.10 (2H, s), 5.77 (1H, d, J =
7.6 Hz), 5.90 (1H, tt, J = 53.2, 2.8 Hz), 6.80-7.
38 (6H, m), 7.20-7.50 (7H, m) .IRν max ^KBr cm ^-1 : 1759, 1613, 1588, 1489, 1451.mp 97-99 ° C Anal.Calcd for C ₂₅ H ₂₁ NO ₄ F ₄ : C, 63.16; H, 4.45;
N, 2.95 Found: C, 62.91; H, 4.30; N, 2.85.7) (1RS, 2SR) -2-amino-1- (3- (benzyloxy) phenyl) -3- (3-((1, 1,2,2-
(Tetrafluoroethyl) oxy) phenyl) -1-propanol (4RS, 5SR) -5- [3- (benzyloxy) phenyl] -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-Oxazolidin-2-one (6.5 g, 13.7 mmol) in ethanol (70 m
l) 8N aqueous sodium hydroxide solution (5.13 m
(1, 41 mmol) and heated to reflux for 4 hours. After concentration, the reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated saline, dried (anhydrous magnesium sulfate), and evaporated under reduced pressure.
The desired product (6.26 g, 100%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.36 (1H, dd, J = 14.0, 10.4 Hz),
2.82 (1H, dd, J = 14.0, 3.0 Hz), 3.20-3.32 (1H,
m), 4.63 (1H, d, J = 4.8 Hz), 5.10 (2H, s), 5.89
(1H, tt, J = 53.0, 3.0 Hz), 6.90-7.12 (6H, m), 7.2
4-7.48 (7H, m) IRν max KBr cm -1: 1740, 1609, 1586, 1487, 1449. Anal Calcd for C 24 H 23 NO 3 F 4:.. C, 64.14; H, 5.16;
N, 3.12 Found: C, 63.87; H, 5.26; N, 2.93.8) N-{(1RS, 2SR) -2- [3- (benzyloxy) phenyl] -2-hydroxy-1- [3- ( 1,1,
2,2-tetrafluoroethoxy) benzyl] ethyl｝-
6,7-dihydro-5H-benzo [a] [7] annulene-
1-carboxamide (1RS, 2SR) -2-amino-1- (3- (benzyloxy) phenyl) -3- (3-((1,1,2,2-tetrafluoroethyl) oxy) phenyl) -1 To a solution of -propanol (405 mg, 0.90 mmol) in acetonitrile (30 ml) was added 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (170 mg,
0.90 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (259 m
g, 1.35 mmol) and 1-hydroxybenzotriazole hydrate (138 mg, 0.90 mmol) were added and stirred at room temperature overnight. The reaction solution was water (100 ml)
And extracted with ethyl acetate (100 ml × 2).
1N hydrochloric acid, 1N aqueous sodium hydroxide solution,
The extract was washed successively with a saturated saline solution, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1-1:
Purification in 1) and recrystallization from ethyl acetate-hexane gave the desired product (407 mg, 73%). ¹ H-NMR (CDCl ₃ ) δ: 1.92-2.02 (2H, m), 2.12-2.20 (2H,
m), 2.60-2.70 (2H, m), 2.74 (1H, dd, J = 14.4, 10.5
Hz), 2.96 (1H, dd, J = 14.4, 3.9 Hz), 3.49 (1H, d,
J = 3.6 Hz), 4.64-4.76 (1H, m), 5.00-5.10 (3H,
m), 5.76 (1H, d, J = 8.7 Hz), 5.68-6.08 (2H, m), 6.
23 (1H, d, J = 11.7 Hz), 6.90-7.18 (9H, m), 7.24-
7.44 (7H, m) .IRν max ^KBr cm ^-1 : 1640, 1611, 1588, 1510, 1489, 144
9. mp 128-129 ℃ Anal. Calcd for C ₃₆ H ₃₃ NO ₄ F ₄ : C, 69.78; H, 5.37;
N, 2.26 Found: C, 69.62; H, 5.34; N, 2.03.

Example 241 N-{(1RS, 2SR) -2-hydroxy-2- (4-hydroxyphenyl) -1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro
-5H-benzo [a] [7] annulene-1-carboxamide 1) 4-{(1RS, 2SR) -2-amino-1-hydroxy-3- [3- (1,1,2,2-tetrafluoro Ethoxy) phenyl] propyl} phenol (1RS, 2SR) -2-amino-1- [4- (benzyloxy) phenyl] -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propane -1-all (2.
60 g, 5.79 mmol) of ethanol (20 ml)
Add 10% palladium / carbon (50% water content, 260m
g) was added, and the mixture was stirred overnight under a hydrogen stream. The catalyst was removed from the reaction solution using celite, and the filtrate was concentrated. The residue is neutral alumina column chromatography (ethanol)
Then, the target product (0.80 g, 39%) was obtained as an amorphous substance. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (1H, dd, J = 13.6, 10.0 Hz),
2.97 (1H, dd, J = 13.6, 2.6 Hz), 3.16-3.28 (1H,
m), 4.55 (1H, d, J = 5.4 Hz), 5.89 (1H, tt, J = 53.
2, 3.0 Hz), 6.75 (2H, d, J = 8.0 Hz), 7.00-7.34 (6
H, m) .IRν max ^KBr cm ^-1 : 1613, 1588, 1514, 1489, 1449.Anal.Calcd for C ₁₇ H ₁₇ NO ₃ F ₄・ 0.5H ₂ O: C, 55.44; H,
4.92; N, 3.80 Found: C, 55.41; H, 4.83; N, 3.61.2) N-｛(1RS, 2SR) -2-hydroxy-2-
(4-hydroxyphenyl) -1- [3- (1,1,2,2
-Tetrafluoroethoxy) benzyl] ethyl} -6,7
-Dihydro-5H-benzo [a] [7] annulene-1-carboxamide 4-{(1RS, 2SR) -2-amino-1-hydroxy-3
-[3- (1,1,2,2-tetrafluoroethoxy) phenyl] propyl} phenol (125 mg, 0.35
Mmol) in acetonitrile (30 ml) solution.
-Dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (66 mg, 0.35 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (100 mg, 0.52 mmol) and 1-
Hydroxybenzotriazole hydrate (53 mg, 0.
(35 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline, and dried (anhydrous magnesium sulfate).
After that, it was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1),
Recrystallize from chloroform-hexane to obtain the desired product (1
(62 mg, 88%). ¹ H-NMR (CDCl ₃ ) δ: 1.90-2.08 (2H, m), 2.10-2.22 (2H,
m), 2.58-2.70 (2H, m), 2.80 (1H, dd, J = 14.4, 10.0
Hz), 3.06 (1H, dd, J = 14.4, 4.0 Hz), 3.24 (1H, br
s), 4.64-4.82 (1H, m), 4.88 (1H, brs), 5.73 (1H,
d, J = 8.8 Hz), 5.60-6.20 (3H, m), 6.82 (2H, d, J =
. 8.4 Hz), 6.86-7.18 (5H , m), 7.22-7.40 (3H, m) IRν max KBr cm -1:. 1732, 1615, 1588, 1516, 1451. mp 167-168 ℃ Anal Calcd for C 29 H ₁₇ NO ₄ F ₄・ 0.2H ₂ O: C, 65.34; H,
5.18; N, 2.63 Found: C, 65.11; H, 4.99; N, 2.42.

Example 242 N-{(1RS, 2SR) -2-hydroxy-2- (4-methoxyphenyl) -1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro-
5H-benzo [a] [7] annulene-1-carboxamide N-{(1RS, 2SR) -2-hydroxy-2- (4-hydroxyphenyl) -1- [3- (1,1,2,2- Tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro
-5H-benzo [a] [7] annulene-1-carboxamide (400 mg, 0.755 mmol) in N, N-dimethylformamide (15 ml) was dissolved in potassium carbonate (3 ml).
13 mg, 2.27 mmol) and methyl iodide (2
ml) and stirred at room temperature overnight. The reaction solution was diluted with water (10
0 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), and recrystallized from ethyl acetate-hexane to obtain the desired product (80 mg, 19%). ¹ H-NMR (CDCl ₃ ) δ: 1.90-2.06 (2H, m), 2.08-2.24 (2H,
m), 2.58-2.72 (2H, m), 2.78 (1H, dd, J = 14.2, 10.2
Hz), 3.02 (1H, dd, J = 14.2, 4.0 Hz), 3.38 (1H, br
s), 3.82 (3H, s), 4.60-4.78 (1H, m), 4.94-5.00 (1
H, m), 5.73 (1H, d, J = 8.4 Hz), 5.60-6.24 (3H,
. m), 6.84-7.20 (8H, m), 7.20-7.46 (3H, m) IRν max KBr cm -1:. 1645, 1613, 1512, 1449. mp 151-152 ℃ Anal Calcd for C 30 H 29 NO ₄ F ₄・ 0.1H ₂ O: C, 66.07; H,
5.39; N, 2.57 Found: C, 65.92; H, 5.23; N, 2.51.

Example 243 N-{(1RS, 2SR) -2-hydroxy-2- (4-isopropoxyphenyl) -1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl {-6,7-dihydro-5H-benzo [a] [7] annulene-1-carboxamide N-{(1RS, 2SR) -2-hydroxy-2- (4-hydroxyphenyl) -1- [3- ( 1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro
-5H-benzo [a] [7] annulene-1-carboxamide (400 mg, 0.755 mmol) in N, N-dimethylformamide (15 ml) was dissolved in potassium carbonate (3 ml).
13 mg, 2.27 mmol) and 2-iodopropane (226 μl, 2.27 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract is washed sequentially with water and saturated saline, and dried (anhydrous magnesium sulfate)
After that, it was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1),
Recrystallization from ethyl acetate-hexane gave the desired product (28
7 mg, 66%). ¹ H-NMR (CDCl ₃ ) δ: 1.33 (3H, s), 1.36 (3H, s), 1.90-
2.08 (2H, m), 2.10-2.26 (2H, m), 2.78 (1H, dd, J =
14.6, 10.2 Hz), 3.03 (1H, dd, J = 14.2, 4.0Hz), 3.
33 (1H, d, J = 3.4 Hz), 4.48-4.62 (1H, m), 4.62-4.
80 (1H, m), 4.92-5.00 (1H, m), 5.72 (1H, d, J = 8.
4 Hz), 5.60-6.24 (3H, m), 6.84-7.20 (8H, m), 7.20-
7.40 (3H, m) IRν max KBr cm -1:. 1641, 1613, 1588, 1508, 1451. mp 134-135 ℃ Anal Calcd for C 32 H 33 NO 4 F 4 · 0.2H 2 O:. C, 66.82 ; H,
5.85; N, 2.44 Found: C, 66.72; H, 5.85; N, 2.52.

Example 244 N-｛(1RS, 2SR) -2- (4-butoxyphenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro-
5H-benzo [a] [7] annulene-1-carboxamide N-{(1RS, 2SR) -2-hydroxy-2- (4-hydroxyphenyl) -1- [3- (1,1,2,2- Tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro
-5H-benzo [a] [7] annulene-1-carboxamide (400 mg, 0.755 mmol) in N, N-dimethylformamide (15 ml) was dissolved in potassium carbonate (3 ml).
13 mg, 2.27 mmol) and 1-iodobutane (417 mg, 2.27 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain the desired product (298 mg, 67%). ¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, t, J = 7.4 Hz), 1.40-1.6
0 (2H, m), 1.68-1.88 (2H, m), 1.90-2.10 (2H, m),
2.12-2.28 (2H, m), 2.60-2.72 (2H, m), 2.77 (1H, d
d, J = 14.6, 10.6 Hz), 3.02 (1H, dd, J = 14.6, 4.0
Hz), 3.36 (1H, d, J = 3.6 Hz), 3.96 (2H, t, J = 6.
4 Hz), 4.62-4.78 (1H, m), 4.96 (1H, t, J = 4.0 Hz),
5.72 (1H, d, J = 8.6 Hz), 5.60-6.22 (3H, m), 6.86
-7.20 (7H, m), 7.22-7.40 (4H, m) IRν max KBr cm -1:.. 1644, 1613, 1586, 1512, 1449. mp 126-127 ℃ Anal Calcd for C 33 H 35 NO 4 F ₄ : C, 67.68; H, 6.02; N,
2.39 Found: C, 67.64; H, 6.04; N, 2.23.

Example 245 N-{(1RS, 2SR) -2- {4-[(4-fluorobenzyl) oxy] phenyl} -2-hydroxy-1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro-5H-benzo [a]
[7] Annulene-1-carboxamide N-{(1RS, 2SR) -2-hydroxy-2- (4-hydroxyphenyl) -1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] Ethyl｝ -6,7-dihydro
-5H-benzo [a] [7] annulene-1-carboxamide (400 mg, 0.755 mmol) in N, N-dimethylformamide (15 ml) was dissolved in potassium carbonate (3 ml).
13 mg, 2.27 mmol) and 4-fluorobenzyl bromide (428 mg, 2.27 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain the desired product (381 mg, 79%). ¹ H-NMR (CDCl ₃ ) δ: 1.90-2.08 (2H, m), 2.10-2.26 (2H,
m), 2.60-2.76 (2H, m), 2.77 (1H, dd, J = 14.6, 10.2
Hz), 3.02 (1H, dd, J = 14.6, 4.0 Hz), 3.43 (1H, d,
J = 3.4 Hz), 4.80-4.98 (1H, m), 4.97 (1H, t, J =
4.0 Hz), 5.02 (2H, s), 5.74 (1H, d, J = 8.4 Hz), 5.
60-6.24 (3H, m), 6.90-7.20 (10H, m), 7.24-7.48 (8
.. H, m) IRν max KBr cm -1: 1644, 1611, 1586, 1512, 1449. mp 144-145 ℃ Anal Calcd for C 36 H 32 NO 4 F 5: C, 67.81; H, 5.06; N,
2.20 Found: C, 67.69; H, 4.95; N, 1.98.

Example 246 N-{(1RS, 2SR) -2- [4- (cyclohexylmethoxy) phenyl] -2-hydroxy-1- [3- (1,
1,2,2-tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro-5H-benzo [a] [7] annulene-1-carboxamide N-{(1RS, 2SR) -2-hydroxy-2- (4-Hydroxyphenyl) -1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro
-5H-benzo [a] [7] annulene-1-carboxamide (400 mg, 0.755 mmol) in N, N-dimethylformamide (15 ml) was dissolved in potassium carbonate (3 ml).
13 mg, 2.27 mmol) and (bromomethyl)
Cyclohexane (401 mg, 2.27 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
Purification in 1) and recrystallization from ethyl acetate-hexane gave the desired product (129 mg, 27%). ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.45 (6H, m), 1.66-2.10 (7H,
m), 2.12-2.28 (2H, m), 2.60-2.72 (2H, m), 2.79 (1H,
dd, J = 14.8, 10.6 Hz), 3.03 (1H, dd, J = 14.8, 4.
0 Hz), 3.38 (1H, d, J = 3.4 Hz), 3.77 (2H, d, J =
5.8 Hz), 4.64-4.80 (1H, m), 4.90-5.02 (1H, m), 5.7
4 (1H, d, J = 8.8 Hz), 5.62-6.24 (3H, m), 6.88-7.2
0 (7H, m), 7.20-7.42 (4H, m) IRν max KBr cm -1:.. 1644, 1613, 1586, 1512, 1451. mp 141-142 ℃ Anal Calcd for C 36 H 39 NO 4 F 4 : C, 69.11; H, 6.28; N,
2.24 Found: C, 69.05; H, 6.47; N, 2.14.

Example 247 N-｛(1RS, 2SR) -2-hydroxy-2- [4- (3
-Phenoxypropoxy) phenyl] -1- [3- (1,
1,2,2-tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro-5H-benzo [a] [7] annulene-1-carboxamide N-{(1RS, 2SR) -2-hydroxy-2- (4-Hydroxyphenyl) -1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro
-5H-benzo [a] [7] annulene-1-carboxamide (400 mg, 0.755 mmol) in N, N-dimethylformamide (15 ml) was dissolved in potassium carbonate (3 ml).
13 mg, 2.27 mmol) and 3-phenoxy-1
-Bromopropane (487 mg, 2.27 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was water (100 ml)
And extracted with ethyl acetate (100 ml × 2).
The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2:
Purification in 1) and recrystallization from ethyl acetate-hexane gave the desired product (245 mg, 50%). ¹ H-NMR (CDCl ₃ ) δ: 1.92-2.02 (2H, m), 2.12-2.22 (2H,
m), 2.22-2.32 (2H, m), 2.62-2.70 (2H, m), 2.76 (1H,
dd, J = 14.4, 10.2 Hz), 3.00 (1H, dd, J = 14.4, 3.
9 Hz), 3.39 (1H, d, J = 3.6 Hz), 4.14-4.22 (4H,
m), 4.64-4.76 (1H, m), 4.96-5.00 (1H, m), 5.68-6.1
0 (3H, m), 6.19 (1H, d, J = 11.7 Hz), 6.88-7.00 (6
H, m), 7.00-7.16 (5H, m), 7.24-7.40 (5H, m) .IRν max ^KBr cm ^-1 : 1644, 1613, 1601, 1588, 1512, 149
. 9. mp 142-143 ℃ Anal Calcd for C 38 H 37 NO 5 F 4: C, 68.77; H, 5.62; N,
2.11 Found: C, 68.67; H, 5.38; N, 1.92.

Example 248 4-[(4-{(1RS, 2SR) -2-[(6,7-dihydro-5H-benzo [a] [7] annulen-1-ylcarbonyl) amino] -1-] Hydroxy-3- [3- (1,1,
2,2-Tetrafluoroethoxy) phenyl] propyl {phenoxy) methyl] methyl benzoate N-{(1RS, 2SR) -2-hydroxy-2- (4-hydroxyphenyl) -1- [3- (1,1 , 2,2-Tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro
To a solution of -5H-benzo [a] [7] annulene-1-carboxamide (600 mg, 1.13 mmol) in N, N-dimethylformamide (20 ml) was added potassium carbonate (47 ml).
0 mg, 3.40 mmol) and methyl 4- (bromomethyl) benzoate (780 mg, 3.40 mmol)
Was added and stirred at room temperature overnight. The reaction solution was washed with water (100 m
1) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
4: 1-2: 1) and recrystallized from ethyl acetate-hexane to give the desired product (361 mg, 47%). ¹ H-NMR (CDCl ₃ ) δ: 1.90-2.08 (2H, m), 2.10-2.24 (2H,
m), 2.60-2.70 (2H, m), 2.78 (1H, dd, J = 14.2, 10.4
Hz), 3.02 (1H, dd, J = 14.2, 4.0 Hz), 3.39 (1H,
s), 3.92 (3H, s), 4.60-4.80 (1H, m), 4.98 (1H, s),
5.13 (2H, s), 5.72 (1H, d, J = 8.8 Hz), 5.60-6.24
(3H, m), 6.90-7.18 (8H, m), 7.20-7.36 (1H, m), 7.3
8 (2H, d, J = 8.4 Hz), 7.51 (2H, d, J = 8.0 Hz),
8.06 (2H, d, J = 8.0 Hz) .IRν max ^KBr cm ^-1 : 1719, 1640, 1613, 1586, 1510, 143
7.mp 169-170 ℃ Anal. Calcd for C ₃₈ H ₃₅ F ₄ NO ₆ : C, 67.35; H, 5.21; N,
2.07 Found: C, 67.19; H, 4.94; N, 1.83.

Example 249 (4-{(1RS, 2SR) -2-[(6,7-dihydro-
5H-benzo [a] [7] annulen-1-ylcarbonyl) amino] -1-hydroxy-3- [3- (1,1,2,2
2-Tetrafluoroethoxy) phenyl] propyl {phenoxy) ethyl acetate N-{(1RS, 2SR) -2-hydroxy-2- (4-hydroxyphenyl) -1- [3- (1,1,2,2- Tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro
To a solution of -5H-benzo [a] [7] annulene-1-carboxamide (600 mg, 1.13 mmol) in N, N-dimethylformamide (20 ml) was added potassium carbonate (47 ml).
0 mg, 3.40 mmol) and ethyl bromoacetate (570 mg, 3.40 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give the desired product (167).
mg, 24%). ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.2 Hz), 1.90-2.0
8 (2H, m), 2.12-2.24 (2H, m), 2.58-2.70 (2H, m),
2.77 (1H, dd, J = 14.1, 10.8 Hz), 3.00 (1H, dd, J
= 14.1, 3.9 Hz), 3.48 (1H, d, J = 3.6 Hz), 4.28 (2
H, q, J = 7.2 Hz), 4.63 (2H, s), 4.60-4.76 (1H,
m), 4.96-5.06 (1H, m), 5.70-6.10 (3H, m), 6.21 (1H,
d, J = 11.7 Hz), 6.88-7.20 (8H, m), 7.26-7.38 (1
H, m), 7.38 (2H, d, J = 8.7 Hz) .IRν max ^KBr cm ^-1 : 1755, 1645, 1613, 1588, 1512, 144
9.mp 125-126 ℃ Anal.Calcd for C ₃₃ H ₃₃ F ₄ NO ₆ : C, 64.38; H, 5.40; N,
2.28 Found: C, 64.15; H, 5.36; N, 2.02.

Example 250 4-[(4-｛(1RS, 2SR) -2-[(6,7-diethyl
Dro-5H-benzo [a] [7] annulen-1-ylcar
Bonyl) amino] -1-hydroxy-3- [3- (1,1,
2,2-tetrafluoroethoxy) phenyl] propi
[Ruphenoxy) methyl] benzoic acid 4-[(4-{(1RS, 2SR) -2-[(6,7-dihi)
Dro-5H-benzo [a] [7] annulen-1-ylcar
Bonyl) amino] -1-hydroxy-3- [3- (1,1,
2,2-tetrafluoroethoxy) phenyl] propi
Ruphenoxy) methyl] methyl benzoate (260m
g, 0.384 mmol) in methanol (10 ml)
A 2N aqueous sodium hydroxide solution (0.38 ml,
(0.76 mmol) and stirred at 60 ° C. overnight. Anti
The reaction solution was acidified with 1N hydrochloric acid, and then ethyl acetate (100
ml × 2). Extract with water and saturated saline
Wash, dry (anhydrous magnesium sulfate) and evaporate under reduced pressure
Was. The residue was recrystallized from ethyl acetate-hexane,
The desired product (209 mg, 82%) was obtained. ¹ H-NMR (CDCl _Three ) δ: 1.90-2.06 (2H, m), 2.10-2.26 (2H,
m), 2.60-2.80 (2H, m), 2.77 (1H, dd, J = 14.6, 10.6
Hz), 3.03 (1H, dd, J = 14.6, 4.4 Hz), 4.62-4.80
(1H, m), 4.99 (1H, d, J = 3.6 Hz), 5.15 (2H, s),
5.75 (1H, d, J = 8.8 Hz), 5.58-6.24 (3H, m), 6.90-
7.20 (8H, m), 7.20-7.40 (1H, m), 7.39 (2H, d, J =
8.4 Hz), 7.54 (2H, d, J = 8.4 Hz), 8.12 (2H, d, J
= 8.2 Hz) .IRν max ^KBr cm ^-1 : 1696, 1640, 1613, 1586, 1510, 148
9, 1449.mp 190-191 ℃ Anal.Calcd for C ₃₇ H ₃₃ F _Four NO ₆ : C, 66.96; H, 5.01; N,
2.11 Found: C, 66.86; H, 4.88; N, 2.01.

Example 251 (4-{(1RS, 2SR) -2-[(6,7-dihydro-
5H-benzo [a] [7] annulen-1-ylcarbonyl) amino] -1-hydroxy-3- [3- (1,1,2,2
2-tetrafluoroethoxy) phenyl] propyl {phenoxy) acetic acid (4-{(1RS, 2SR) -2-[(6,7-dihydro-
5H-benzo [a] [7] annulen-1-ylcarbonyl) amino] -1-hydroxy-3- [3- (1,1,2,2
To a solution of ethyl 2-tetrafluoroethoxy) phenyl] propyl @ phenoxy) acetate (100 mg, 0.163 mmol) in methanol (20 ml) was added a 2N aqueous sodium hydroxide solution (0.16 ml, 0.32 mmol), and the mixture was stirred at room temperature. Stirred overnight. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (100 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1).
-Ethyl acetate-methanol = 10: 1) and recrystallized from ethyl acetate-hexane to give the desired product (87 mg,
91%). ¹ H-NMR (CDCl ₃ ) δ: 1.86-2.04 (2H, m), 2.10-2.24 (2H,
m), 2.58-2.70 (2H, m), 2.75 (1H, dd, J = 14.6, 10.6
Hz), 2.98 (1H, dd, J = 14.6, 3.6 Hz), 4.50-4.96
(5H, m), 4.96 (1H, d, J = 3.8 Hz), 5.58-6.20 (4H,
. m), 6.82-7.20 (8H, m), 7.20-7.40 (3H, m) IRν max KBr cm -1:. 1744, 1640, 1613, 1588, 1512. mp 119-120 ℃ Anal Calcd for C 31 H ₂₉ NO ₆ F ₄・ 0.2H ₂ O: C, 62.99; H,
5.01; N, 2.37 Found: C, 62.82; H, 5.13; N, 2.32.

Example 252 N-{(1RS, 2SR) -2-hydroxy-2- (3-hydroxyphenyl) -1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro
-5H-benzo [a] [7] annulene-1-carboxamide 1) 3-{(1RS, 2SR) -2-amino-1-hydroxy-3- [3- (1,1,2,2-tetrafluoro) Ethoxy) phenyl] propyl} phenol (1RS, 2SR) -2-amino-1- [3- (benzyloxy) phenyl] -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propane -1-all (5.
50 g, 12.23 mmol) of ethanol (100 m
l) Add 10% palladium / carbon (50% water, 50%
0 mg) and stirred overnight under a stream of hydrogen. The catalyst was removed from the reaction solution using celite, and the filtrate was concentrated to give the desired product (4.04 g, 92%, crude). For data acquisition, a portion was purified by alumina column chromatography (ethanol) and recrystallized from diisopropyl ether-hexane. ¹ H-NMR (CDCl ₃ ) δ: 2.47 (1H, t, J = 12.6 Hz), 2.99 (1
H, d, J = 13.5 Hz), 3.22 (2H, s), 3.33 (2H, brs),
4.56 (1H, d, J = 3.4 Hz), 5.88 (1H, t, J = 53.1 H
.. z), 6.70-7.40 (8H , m) IRν max KBr cm -1: 1586, 1487, 1456. mp 130-131 ℃ Anal Calcd for C 17 H 17 F 4 NO 3: C, 56.83; H, 4.77 ; N,
3.90 Found: C, 56.73; H, 4.59; N, 3.79. 2) N-｛(1RS, 2SR) -2-hydroxy-2-
(3-hydroxyphenyl) -1- [3- (1,1,2,2
-Tetrafluoroethoxy) benzyl] ethyl} -6,7
-Dihydro-5H-benzo [a] [7] annulene-1-carboxamide 3-{(1RS, 2SR) -2-amino-1-hydroxy-3
-[3- (1,1,2,2-tetrafluoroethoxy) phenyl] propyl} phenol (2.89 g, 8.04
Mmol) in acetonitrile (50 ml) solution.
-Dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (1.51 g, 8.04 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.31 g, 12.1 g). 06 mmol) and 1-hydroxybenzotriazole hydrate (1.23
g, 8.04 mmol) and stirred at room temperature overnight.
The reaction solution was diluted with water (200 ml), and ethyl acetate (20 ml) was added.
0 ml × 2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1-
1: 1) to give the desired product (2.75 g, 65%) as an amorphous product. ¹ H-NMR (CDCl ₃ ) δ: 1.88-2.00 (2H, m), 2.08-2.18 (2H,
m), 2.54-2.64 (2H, m), 2.74 (1H, dd, J = 14.4, 10.5
Hz), 2.98 (1H, dd, J = 14.4, 7.5 Hz), 4.07 (1H, br
s), 4.64-4.78 (1H, m), 4.86-4.92 (1H, m), 5.66-6.0
4 (4H, m), 6.72-6.80 (1H, m), 6.84-7.28 (9H, m),
7.58 (1H, brs) IRν max KBr cm -1: 1636, 1588, 1520, 1489, 1453. Anal Calcd for C 29 H 27 NO 4 F 4 · 0.2H 2 O:.. C, 65.34; H,
5.18; N, 2.63 Found: C, 65.27; H, 5.34; N, 2.45.

Example 253 N-{(1RS, 2SR) -2-hydroxy-2- (3-methoxyphenyl) -1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro-
5H-benzo [a] [7] annulene-1-carboxamide N-{(1RS, 2SR) -2-hydroxy-2- (3-hydroxyphenyl) -1- [3- (1,1,2,2- Tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro
-5H-benzo [a] [7] annulene-1-carboxamide (400 mg, 0.755 mmol) in N, N-dimethylformamide (15 ml) was dissolved in potassium carbonate (3 ml).
13 mg, 2.27 mmol) and methyl iodide (2
ml) and stirred at room temperature overnight. The reaction solution was diluted with water (10
0 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) and recrystallized from ethyl acetate-hexane to obtain the desired product (115 mg, 28%). ¹ H-NMR (CDCl ₃ ) δ: 1.90-2.06 (2H, m), 2.12-2.26 (2H,
m), 2.60-2.70 (2H, m), 2.79 (1H, dd, J = 14.2, 10.6
Hz), 3.00 (1H, dd, J = 14.2, 4.0 Hz), 3.47 (1H, d,
J = 3.6 Hz), 3.81 (3H, s), 4.64-4.80 (1H, m), 5.0
0-5.06 (1H, m), 5.79 (1H, d, J = 8.4 Hz), 5.60-6.2
6 (3H, m), 6.80-6.90 (1H, m), 6.90-7.20 (7H, m),
7.20-7.38 (3H, m) .IRν max ^KBr cm ^-1 : 1640, 1611, 1588, 1514, 1489, 145
3, 1439.mp 155-156 ℃ Anal.Calcd for C ₃₀ H ₂₉ F ₄ NO ₄ : C, 66.29; H, 5.38; N,
2.58 Found: C, 66.06; H, 5.08; N, 2.36.

Example 254 (1RS, 2RS) -2-hydroxy-2- (5-phenoxypyridin-2-yl) -1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl Carbamic acid t
tert-butyl 1) 2-Methyl-5-phenoxypyridine 6-methylpyridin-3-ol (25.2 g, 231 mmol) in N, N-dimethylformamide (100 m
l) Add tert-butoxy potassium (25.9 g,
231 mmol) and stirred at room temperature for 1 hour. After the reaction solution was distilled off under reduced pressure, N, N-dimethylformamide (10
0 ml) and copper powder (3.7 g, 58 mmol)
And bromobenzene (36.3 g, 231 mmol)
And stirred at 120 ° C. overnight. Methanol was added to the reaction solution, the insolubles were filtered through celite, and the filtrate was washed with water (500 m
1) and extracted with ethyl acetate (500 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
4: 1) to give the desired product (31 g, 72%). ¹ H-NMR (CDCl ₃ ) δ: 2.55 (3H, s), 6.94-7.04 (2H, m),
7.06-7.40 (5H, m), 8.30 (1H, d, J = 2.4 Hz) .IRν max ^KBr cm ^-1 : 1603, 1590, 1574, 1483, 1385.Analytical calculation for C ₁₂ H ₁₁ NO: C, 77.81; H, 5.99; N, 7.
56 Found: C, 77.51; H, 5.99; N, 7.4.1.2. 5-Phenoxypyridine-2-carboxylic acid Selenium dioxide was added to a solution of 2-methyl-5-phenoxypyridine (30 g, 162 mmol) in pyridine (90 ml). (18.0 g, 162 mmol) was added and the mixture was stirred at 110 ° C. overnight. The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was diluted with chloroform (300 ml),
Wash sequentially with 0.2N aqueous hydrochloric acid, water and saturated saline,
After drying (anhydrous magnesium sulfate), the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give the desired product (10.1 g, 29
%). ¹ H-NMR (CDCl ₃ ) δ: 7.04-7.18 (2H, m), 7.20-7.54 (4H,
m), 8.18 (1H, d, J = 8.4 Hz), 8.43 (1H, d, J = 2.6
.. Hz), 9.59 (1H , brs) IRν max KBr cm -1: 1705, 1574, 1489. mp 149-150 ℃ Anal Calcd for C 12 H 9 NO 3: C, 66.97; H, 4.22; N, 6 .
51, Found: C, 66.99; H, 4.04; N, 6.42. 3) Benzyl 3-oxo-3- (5-phenoxypyridin-2-yl) propanoate 5-phenoxypyridine-2-carboxylic acid (10 g, 4
6.5 mmol) of tetrahydrofuran (150 ml)
N, N'-carbonyldiimidazole (8.29 g,
51.1 mmol) and heated under reflux for 1 hour. After the reaction solution was cooled to room temperature, malonic acid monobenzylmagnesium salt (10.5 g, 25.6 mmol) was added, and the mixture was refluxed for 2 hours. After concentrating the reaction solution, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2:
Purification in 1) gave the desired product (11.2 g, 76%). ¹ H-NMR (CDCl ₃ ) δ: 4.19 (2H, s), 5.18 (2H, s), 7.00-
7.50 (11H, m), 8.04 (1H, d, J = 8.8 Hz), 8.28 (1H,
d, J = 3.0 Hz) .IRν max ^KBr cm ^-1 : 1740, 1699, 1640, 1570, 1489, 147
2.4) Benzyl 3-oxo-3- (5-phenoxypyridin-2-yl) -2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoate [3- (1, 1,2,2-Tetrafluoroethoxy) phenyl] methanol (8.29 g, 37.0 mmol) in ethyl acetate (100 ml) was treated with methanesulfonyl chloride (3.15 ml, 40.68 mmol) and triethylamine (6.19 ml). , 44.4 mmol).
Stirred at room temperature for 2 hours. The insolubles were filtered, and the filtrate was distilled off under reduced pressure to prepare a mesyl compound. Benzyl 3-oxo-3- (5-phenoxypyridin-2-yl) propanoate (11.2
g, 35.1 mmol) in 1,2-dimethoxyethane (80 ml) was added to sodium hydride (1.41 g, 6 ml).
(0% oily, 35.1 mmol) and stirred at room temperature for 1 hour. A solution of the previously prepared mesyl compound in 1,2-dimethoxyethane (10 ml) was added dropwise to the reaction solution.
Stirred at 0 ° C. overnight. The reaction solution was acidified with 1N hydrochloric acid, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and ethyl acetate (300 ml ×
Extracted in 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the desired product (9.32).
g, 48%, crude). This compound was used crude in the next reaction. 5) 3-Hydroxy-3- (5-phenoxypyridine-2-
Yl) -2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] benzyl benzylpropanoate Sodium borohydride in a solution of zinc chloride (4.57 g, 33.6 mmol) in diethyl ether (100 ml) (2.54 g, 67.1 mmol) at room temperature.
Minutes. The insolubles are removed by filtration and the filtrate is treated with 3-oxo-3-.
(5-phenoxypyridin-2-yl) -2- [3- (1,
A solution of benzyl 1,2,2-tetrafluoroethoxy) benzyl] propanoate (9.32 g, 16.8 mmol, crude) in diethyl ether (100 ml) was added at 0 ° C., and the mixture was stirred for 30 minutes. The reaction solution was quenched with 1N hydrochloric acid, neutralized with saturated aqueous sodium hydrogen carbonate, and further added with water (200 ml).
And extracted with ethyl acetate (500 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1).
-1: 1) to give the desired product (5.07 g, 54%, crude). This compound was used crude in the next reaction. 6) 3-Hydroxy-3- (5-phenoxypyridine-2-
Yl) -2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoic acid 3-hydroxy-3- (5-phenoxypyridin-2-yl)
-2- [3- (1,1,2,2-tetrafluoroethoxy)
Benzyl] benzyl propanoate (5.07 g, 9.09
Mmol, crude) in ethanol (500 ml)
10% palladium / carbon (50% water content) (500mg)
Was added, and the mixture was stirred overnight under a 1 atm hydrogen stream. The reaction solution was filtered through celite, and the filtrate was concentrated to give the desired product (4.22 g,
100%, crude). This compound was used crude in the next reaction. 7) 5- (5-phenoxypyridin-2-yl) -4- [3
-(1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine-2-one 3-hydroxy-3- (5-phenoxypyridin-2-yl)
-2- [3- (1,1,2,2-tetrafluoroethoxy)
To a solution of [benzyl] propanoic acid (4.22 g, 9.07 mmol, crude) in tetrahydrofuran (200 ml) was added diphenylphosphoryl azide (2.15 ml, 9.9 ml).
97 mmol) and triethylamine (1.90 mmol, 13.6 mmol) were added, and the mixture was heated under reflux for 3 hours.
After allowing the reaction mixture to cool, water (100 ml) was added, and the mixture was extracted with ethyl acetate (100 ml × 2). Extract solution is 1N hydrochloric acid,
Wash sequentially with aqueous sodium hydrogen carbonate solution and saturated saline,
After drying (anhydrous magnesium sulfate), the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 1) to give the desired product (4R
S, 5RS) form (1.06 g, high polarity component, 25%) and (4RS, 5SR) form (1.94 g, low polarity component,
46%, recrystallized from hexane-ethyl acetate). (4RS, 5RS) form: ¹ H-NMR (CDCl ₃ ) δ: 2.04-2.22 (1
H, m), 2.53 (1H, dd, J = 14.0, 3.4 Hz), 4.38-4.50
(1H, m), 5.12 (1H, s), 5.87 (1H, d, J = 8.4Hz), 5.
90 (1H, tt, J = 53.2, 3.0 Hz), 6.90-7.48 (10H, m),
7.54 (1H, d, J = 8.4 Hz), 8.39 (1H, d, J = 2.6 H
z). IRν max ^KBr cm ^-1 : 1761, 1588, 1574, 1487. (4RS, 5SR) form: ¹ H-NMR (CDCl ₃ ) δ: 2.98 (1H, d
d, J = 13.6, 9.2 Hz), 3.28 (1H, dd, J = 13.6, 4.4
Hz), 4.20-4.34 (1H, m), 5.12 (1H, brs), 5.32 (1H,
d, J = 5.4 Hz), 5.91 (1H, tt, J = 53.2, 3.0 Hz),
7.00-7.48 (11H, m), 8.38 (1H, d, J = 2.4 Hz) .IRν max ^KBr cm ^-1 1761, 1588, 1576, 1489.mp 87-88 ℃ Anal. Calcd for C ₂₃ H ₁₈ F ₄ N ₂ O ₄ : C, 59.74; H, 3.92;
N, 6.06 Found: C, 59.70; H, 3.81; N, 6.03.8) (4RS, 5RS) -2-oxo-5- (5-phenoxypyridin-2-yl) -4- [3- (1, Tert-Butyl (1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine-3-carboxylate (4RS, 5RS) -5- (5-phenoxypyridine-2-
Yl) -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidin-2-one (1.01 g, 2.18 mmol) in acetonitrile (15 ml). Di-tert-butyl dicarbonate (571
mg, 2.62 mmol) and 4-N, N-dimethylpyridine (26.9 mg, 0.22 mmol), and the mixture was stirred at room temperature for 1 hour. Water (50 ml) was added to the reaction solution,
Extracted with ethyl acetate (50 ml × 2). Extract water with water,
The extract was washed successively with a saturated saline solution, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 10: 1-1:
Purified in 1) and recrystallized from ethyl acetate-hexane,
The desired product (1.07 g, 87%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.66 (1H, dd, J = 1
4.2, 7.4 Hz), 2.83 (1H, dd, J = 14.2, 5.8 Hz), 5.02
(1H, q, J = 7.0 Hz), 5.70 (1H, d, J = 7.0 Hz), 5.
88 (1H, tt, J = 53.0, 3.0 Hz), 6.60 (1H, s), 6.76
(1H, d, J = 7.6Hz), 6.98-7.10 (3H, m), 7.10-7.32
(3H, m), 7.34-7.50 (3H, m), 8.18 (1H, d, J = 3.0 H
z) .IRν max ^KBr cm ^-1 : 1825, 1725, 1588, 1574, 1489.mp 113-114 ℃ Anal. Calcd for C ₂₈ H ₂₆ N ₂ O ₆ F ₄ : C, 59.79; H, 4.66;
N, 4.98 Found: C, 59.75; H, 4.58; N, 4.0.9. 9) (1RS, 2RS) -2-hydroxy-2- (5-phenoxypyridin-2-yl) -1- [3- (1, 1,2,
Tert-Butyl 2-tetrafluoroethoxy) benzyl] ethylcarbamate (4RS, 5RS) -2-oxo-5- (5-phenoxypyridin-2-yl) -4- [3- (1,1,2,2 -Tetrafluoroethoxy) benzyl] -1,3-oxazolidine-
Tert-Butyl 3-carboxylate (1.00 g, 1.78)
0.5N sodium hydroxide in methanol (12 ml) (4.3 ml, 2.13).
(Mmol) was added and stirred at room temperature for 1 hour. Water (50 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 2). The extract was washed with brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Ethyl acetate-residue
Recrystallization from hexane gave the desired product (0.81 g, 85
%). ¹ H-NMR (CDCl ₃ ) δ: 1.37 (9H, s), 2.58 (1H, dd, J = 1
4.6, 5.4 Hz), 2.78 (1H, dd, J = 14.6, 8.8 Hz), 4.10
-4.30 (1H, m), 4.76 (1H, d, J = 5.6 Hz), 4.84-4.96
(1H, m), 5.13 (1H, d, J = 9.0 Hz), 5.89 (1H, tt,
J = 53.0, 3.0 Hz), 6.90-7.10 (5H, m), 7.12-7.30 (4
. H, m), 7.30-7.48 ( 2H, m), 8.32 (1H, s) IRν max KBr cm -1:. 1694, 1588, 1483. mp 129-130 ℃ Anal Calcd for C 27 H 28 F 4 N ₂ O ₅ : C, 60.44; H, 5.26;
N, 5.22 Found: C, 60.21; H, 5.23; N, 5.22.

Example 255 N-{(1RS, 2RS) -2-hydroxy-2- (5-phenoxypyridin-2-yl) -1- [3- (1,1,2,2-
Tetrafluoroethoxy) benzyl] ethyl} -6,7-
Dihydro-5H-benzo [a] [7] annulene-1-carboxamide (1RS, 2RS) -2-hydroxy-2- (5-phenoxypyridin-2-yl) -1- [3- (1,1,1,2 , 2-Tetrafluoroethoxy) benzyl] ethylcarbamic acid t
Trifluoroacetic acid (5 ml) was added to tert-butyl (300 mg, 0.56 mmol), and the mixture was stirred at 0 ° C. for 10 minutes. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and ethyl acetate (20 m
1 × 2). The extract was washed with brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. To a solution of the residue in acetonitrile (20 ml) was added 6,7-dihydro-5.
H-benzo [a] cycloheptene-1-carboxylic acid (10
5 mg, 0.56 mmol) and 1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide hydrochloride (1
61 mg, 0.84 mmol) and 1-hydroxybenzotriazole hydrate (86 mg, 0.56 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was washed with water (100
ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), and recrystallized from ethyl acetate-hexane to obtain the desired product (140 mg, 41%). ¹ H-NMR (CDCl ₃ ) δ: 1.92-2.12 (2H, m), 2.18-2.30 (2H,
m), 2.64-2.80 (3H, m), 2.94 (1H, dd, J = 14.8, 9.6
Hz), 4.78-4.92 (1H, m), 4.96 (1H, d, J = 5.4 Hz),
5.02-5.10 (1H, m), 5.91 (1H, tt, J = 53.0, 3.0 H
z), 5.94-6.04 (1H, m), 6.30-6.44 (2H, m), 7.00-7.5
0 (14H, m), 8.34 (1H, d, J = 2.6 Hz) IRν max KBr cm -1:.. 1638, 1588, 1572, 1483. mp 147-148 ℃ Anal Calcd for C 34 H 30 F 4 N ₂ O ₄ : C, 67.32; H, 4.98;
N, 4.62 Found: C, 67.16; H, 4.79; N, 4.52.

Example 256 4-Fluoro-N-｛(1RS, 2RS) -2-hydroxy-
2- (5-phenoxypyridin-2-yl) -1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -1-naphthamide (1RS, 2RS) -2-hydroxy-2- (5-phenoxypyridin-2-yl) -1- [3- ( 1,1,2,2-tetrafluoroethoxy) benzyl] ethylcarbamic acid t
Trifluoroacetic acid (5 ml) was added to tert-butyl (300 mg, 0.56 mmol), and the mixture was stirred at 0 ° C. for 10 minutes. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and ethyl acetate (20 m
1 × 2). The extract was washed with brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. To a solution of the residue in acetonitrile (20 ml) was added 4-fluoronaphthalenecarboxylic acid (106 mg, 0.56 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (161 mg, 0.84 mmol) and 1-hydroxybenzotriazole hydrate (86m
g, 0.56 mmol) and stirred at room temperature overnight.
The reaction solution was diluted with water (100 ml), and ethyl acetate (10 ml) was added.
0 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1),
Recrystallization from hexane gave the desired product (133 mg, 39 mg).
%). ¹ H-NMR (CDCl ₃ ) δ: 2.72 (1H, dd, J = 14.4, 4.5 Hz),
2.92 (1H, dd, J = 14.7,9.6 Hz), 4.88-5.00 (2H, m),
5.10-5.16 (1H, m), 5.88 (1H, tt, J = 53.1,3.0 H
z), 6.55 (1H, d, J = 9.0 Hz), 7.00-7.60 (15H, m),
7.98 (1H, d, J = 8.1 Hz), 8.10 (1H, d, J = 8.1 Hz),
8.34 (1H, d, J = 2.7 Hz) .IRν max ^KBr cm ^-1 : 1642, 1626, 1601, 1586, 1535, 148
5.mp 146-147 ℃ Anal. Calcd for C ₃₃ H ₂₅ F ₅ N ₂ O ₄ : C, 65.13; H, 4.14;
N, 4.60 Found: C, 64.99; H, 4.11; N, 4.53.

Example 257 (1RS, 2SR) -2-hydroxy-2- [4- (pyridin-2-yloxy) phenyl] -1- [3- (1,1,1
Tert-Butyl 2,2-tetrafluoroethoxy) benzyl] ethylcarbamate 1) Benzyl 4- (pyridin-2-yloxy) benzoate Benzyl 4-hydroxybenzoate (25.3 g, 111
Mmol) of N, N-dimethylformamide (60 m
l) Add tert-butoxy potassium (12.4 g,
111 mmol) and stirred at room temperature for 1 hour. After evaporating the reaction solution under reduced pressure, 2-bromopyridine (24.5 g, 1
55 mmol) and copper powder (1.76 g, 27.7 mmol) and N, N-dimethylformamide (80 m
l) was added and the mixture was stirred at 120 ° C for 8 hours. After the reaction solution was filtered using Celite, the filtrate was distilled off under reduced pressure. Water (500 ml) was added to the residue, and the mixture was extracted with ethyl acetate (500 ml). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1), and recrystallized from ethyl acetate-hexane to obtain the desired product (25.5 g, 73%). ¹ H-NMR (CDCl ₃ ) δ: 5.36 (2H, s), 6.97 (1H, d, J = 8.4
Hz), 7.00-7.10 (1H, m), 7.16-7.22 (2H, m), 7.30-
7.48 (5H, m), 7.68-7.78 (1H, m), 8.08-8.16 (2H,
m), 8.18-8.24 (1H, m) .IRν max ^KBr cm ^-1 : 1717, 1589, 1574, 1505, 1466, 142
. 9. mp 68-69 ℃ Anal Calcd for C 19 H 15 NO 3: C, 74.74; H, 4.95; N,
4.59 Found: C, 74.90; H, 5.14; N, 4.67. 2) 4- (Pyridin-2-yloxy) benzoic acid 4- (Pyridin-2-yloxy) benzyl benzoate (2
4.8 g, 81.5 mmol) of ethanol (300 m
l) 10% palladium / carbon (50% water-containing) in solution
(2.0 g), and the mixture was stirred at 80 ° C. overnight under a hydrogen stream. The reaction solution was filtered using celite, and the filtrate was concentrated. The residue was recrystallized from ethanol to give the desired product (1
4.1 g, 80%). ¹ H-NMR (CDCl ₃ ) δ: 7.04-7.20 (2H, m), 7.20-7.52 (4H,
m), 8.18 (1H, d, J = 8.4 Hz), 8.43 (1H, d, J = 2.6
Hz), 9.59 (1H, brs) .IRν max ^KBr cm ^-1 : 1682, 1599, 1588, 1570, 1508.mp 175-176 ° C Anal.Calcd for C ₁₂ H ₉ NO ₃ : C, 66.97; H, 4.22 ; N, 6.
51 Found: C, 66.78; H, 3.94; N, 6.37. 3) 3-oxo-3- [4- (pyridin-2-yloxy)
Benzyl phenyl] propanoate 4- (pyridin-2-yloxy) benzoic acid (20 g, 9
2.9 mmol) in tetrahydrofuran (300 ml)
N, N'-carbonyldiimidazole (16.6 g,
(102 mmol) and heated under reflux for 1 hour. After the reaction solution was cooled to room temperature, malonic acid monobenzylmagnesium salt (21 g, 51.2 mmol) was added, and the mixture was heated under reflux for 2 hours. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product (20.6 g, 64%). ¹ H-NMR (CDCl ₃ ) δ: 4.03 (2H, s), 5.17 (2H, s), 6.90-
7.50 (7H, m), 7.70-7.88 (2H, m), 7.90-8.02 (2H, m),
8.10-8.24 (2H, m) .IRν max ^KBr cm ^-1 : 1740, 1684, 1590, 1572, 1505, 146
6, 1429. Anal.Calcd for C ₂₁ H ₁₇ NO ₄ : C, 72.61; H, 4.93; N,
4.03 Found: C, 72.48; H, 4.88; N, 4.06.4. 4) 3-oxo-3- [4- (pyridin-2-yloxy)
Phenyl] -2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] benzyl propanoate [3- (1,1,2,2-tetrafluoroethoxy) phenyl] methanol (6.79 g, Methanesulfonyl chloride (2.58 ml, 33.3 mmol) and triethylamine (5.07 ml, 36.4 mmol) were added to a solution of 30.3 mmol) in ethyl acetate (100 ml), and the mixture was stirred at room temperature for 2 hours. The insolubles were filtered, and the filtrate was distilled off under reduced pressure to prepare a mesyl compound. 3-oxo-3- [4- (pyridine
-2-yloxy) phenyl] benzyl propanoate (10
g, 28.8 mmol) in 1,2-dimethoxyethane (80 ml) was added to sodium hydride (1.15 g, 6
0% oily, 28.8 mmol) and stirred at room temperature for 1 hour. The 1,2-dimethoxyethane (10 ml) solution of the previously prepared mesyl compound was added dropwise to the reaction solution, and the reaction solution was
Stirred at 0 ° C. overnight. The reaction solution was acidified with 1N hydrochloric acid, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and ethyl acetate (300 ml ×
Extracted in 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the desired product (13.0).
g, 74%). ¹ H-NMR (CDCl ₃ ) δ: 3.35 (2H, d, J = 7.5 Hz), 4.63 (1
H, t, J = 7.5 Hz), 5.08 (2H, s), 5.88 (1H, tt, J =
53.1, 3.0 Hz), 6.98-7.20 (13H, m), 7.72-7.80 (1H,
m), 7.96-8.02 (2H, m), 8.20-8.26 (1H, m). IRν max ^KBr cm ^-1 : 1738, 1684, 1590, 15580. 5) (2RS, 3RS) -3-hydroxy-3- [4-
(Pyridin-2-yloxy) phenyl] -2- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] benzyl benzyl propanate Sodium borohydride (1.77 g, 67.1) was added to a solution of zinc chloride (3.19 g, 23.4 mmol) in diethyl ether (100 ml). Mmol) at room temperature for 30 minutes.
Minutes. The insolubles are removed by filtration and the filtrate is treated with 3-oxo-3-.
[4- (Pyridin-2-yloxy) phenyl] -2- [3-
A solution of benzyl (1,1,2,2-tetrafluoroethoxy) benzyl] propanoate (6.5 g, 11.7 mmol) in diethyl ether (50 ml) was added at 0 ° C., and the mixture was stirred for 30 minutes. The reaction solution was quenched with 1N hydrochloric acid, neutralized with saturated aqueous sodium hydrogen carbonate, further added with water (200 ml), and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1-
1: 1) to give the desired product (4.78 g, 73%). ¹ H-NMR (CDCl ₃ ) δ: 2.83 (1 H, d, J = 3.0 Hz), 2.96-3.2
0 (3H, m), 4.84 (2H, s), 4.98-5.04 (1H, m), 5.88
(1H, tt, J = 53.2, 3.0 Hz), 6.88-7.30 (13H, m), 7.
30-7.44 (2H, m), 7.62-7.76 (1H, m), 8.16-8.22 (1H,
m). IRν max ^KBr cm ^-1 : 1728, 1593, 1507, 1468, 142.9 6) (2RS, 3RS) -3-hydroxy-3- [4-
(Pyridin-2-yloxy) phenyl] -2- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] propanoic acid (2RS, 3RS) -3-hydroxy-3- [4- (pyridin-2-yloxy) phenyl] -2- [3- (1, 1,
To a solution of benzyl 2,2-tetrafluoroethoxy) benzyl] propanoate (4.99 g, 8.95 mmol) in ethanol (500 ml) was added 10% palladium / carbon (50% water content, 500 mg), and a 1 atm hydrogen stream was added. Stirred under for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain the desired product (4.50 g, 100%, crude). This compound was used crude in the next reaction. ¹ H-NMR (CDCl ₃ ) δ: 2.90-3.10 (3H, m), 3.83 (1H, brs),
5.01 (1H, d, J = 3.0Hz), 5.87 (1H, tt, J = 53.0,
3.0 Hz), 6.86-7.16 (7H, m), 7.18-7.30 (1H, m), 7.40
(2H, d, J = 8.4 Hz), 7.64-7.76 (1H, m), 8.14 (1H,
d, J = 3.8 Hz). IRν max ^KBr cm ^-1 : 1717, 1597, 1508, 1470, 141.7. (4) (4RS, 5SR) -5- [4- (pyridin-2-yloxy) phenyl] -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidin-2-one (2RS, 3RS) -3-hydroxy-3- [4- (pyridin-2-yloxy) Phenyl] -2- [3- (1,1,
In a solution of 2,2-tetrafluoroethoxy) benzyl] propanoic acid (4.49 g, 9.65 mmol, crude) in tetrahydrofuran (60 ml), diphenylphosphoryl azide (2.29 ml, 10.6 mmol) and triethylamine (2. 02 mmol, 14.5 mmol) and heated under reflux for 2 hours. After allowing the reaction solution to cool, water (100
ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with an aqueous solution of sodium hydrogen carbonate and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 1),
Recrystallization from ethyl acetate-hexane gave the desired product (3.
56 g, 80%). ¹ H-NMR (CDCl ₃ ) δ: 2.28-2.44 (2H, m), 4.20-4.30 (1H,
m), 5.20-5.30 (1H, m), 5.81 (1H, d, J = 7.5 Hz), 5.
90 (1H, tt, J = 53.1, 2.7 Hz), 6.84-7.00 (3H, m),
7.00-7.38 (5H, m), 7.39 (2H, d, J = 8.4 Hz), 7.68-
7.78 (1H, m), 8.16-8.24 (1H, m) .IRν max ^KBr cm ^-1 : 1753, 1589, 1508, 1489, 1468, 143
1.mp 99-100 ℃ Anal.Calcd for C ₂₃ H ₁₈ N ₂ O ₄ F ₄ : C, 59.74; H, 3.92;
N, 6.06 Found: C, 59.60; H, 3.85; N, 6.11.8) (4RS, 5SR) -2-oxo-5- [4- (pyridin-2-yloxy) phenyl] -4- [3- ( 1,1,
2,2-tetrafluoroethoxy) benzyl] -1,3-
Tert-Butyl oxazolidine-3-carboxylate (4RS, 5SR) -5- [4- (pyridin-2-yloxy) phenyl] -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine-2-
To a solution of ON (3.3 g, 7.14 mmol) in acetonitrile (50 ml) was added di-tert-butyl dicarbonate (1.8).
7 g, 8.56 mmol) and 4-N, N-dimethylpyridine (87 mg, 0.71 mmol) were added, and the mixture was stirred at room temperature for 15 minutes. Water (100 ml) was added to the reaction solution, and extracted with ethyl acetate (100 ml × 2). Extract water with water,
The extract was washed successively with a saturated saline solution, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1-1:
Purified in 1) and recrystallized from ethyl acetate-hexane,
The desired product (3.46 g, 86%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.67 (1H, dd, J = 1
4.2, 8.4 Hz), 2.89 (1H, dd, J = 14.2, 4.8 Hz), 4.72
-4.84 (1H, m), 5.71 (1H, d, J = 7.0 Hz), 5.89 (1H,
tt, J = 53.1, 3.0 Hz), 6.59 (1H, d, J = 7.6 Hz),
6.66 (1H, s), 6.88-7.28 (8H, m), 7.64-7.78 (1H,
. m), 8.16-8.22 (1H, m) IRν max KBr cm -1: 1817, 1719, 1595, 1510, 1468. mp 123-124 ℃ Anal Calcd for C 28 H 26 N 2 O 6 F 4:. C , 59.79; H, 4.66;
N, 4.98 Found: C, 59.83; H, 4.68; N, 4.99.9) (1RS, 2SR) -2-hydroxy-2- [4-
(Pyridin-2-yloxy) phenyl] -1- [3-
Tert-Butyl (1,1,2,2-tetrafluoroethoxy) benzyl] ethylcarbamate (4RS, 5SR) -2-oxo-5- [4- (pyridine-2
-Yloxy) phenyl] -4- [3- (1,1,2,2-
Tert-butyl tetrafluoroethoxy) benzyl] -1,3-oxazolidine-3-carboxylate (3.00 g,
5.33 mmol) in methanol (20 ml).
Normal methanol solution of sodium hydroxide (12.8m
1,6.4 mmol) and stirred at room temperature for 1 hour. Water (100 ml) was added to the reaction solution, and ethyl acetate (100 m
1 × 2). The extract was washed with brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the desired product (2.6).
7g, 93%). ¹ H-NMR (CDCl ₃ ) δ: 1.35 (9H, m), 2.64-2.80 (1H, m),
2.85 (1H, dd, J = 15.0,4.2 Hz), 3.23 (1H, s), 4.12
(1H, s), 4.64 (1H, d, J = 8.4 Hz), 4.93 (1H, s),
5.89 (1H, tt, J = 53.1, 3.0 Hz), 6.92 (1H, d, J =
8.4 Hz), 6.96-7.10 (4H, m), 7.10-7.20 (2H, m), 7.2
0-7.36 (1H, m), 7.38-7.46 (2H, m), 7.66-7.72 (1H,
m), 8.18-8.24 (1H, m) .IRν max ^KBr cm ^-1 : 1696, 1590, 1574, 1507, 1468, 143
1.mp 130-131 ℃ Anal. Calcd for C ₂₇ H ₂₈ F ₄ N ₂ O ₅ : C, 60.44; H, 5.26;
N, 5.22 Found: C, 60.36; H, 5.06; N, 5.23.

Example 258 N-{(1RS, 2SR) -2-hydroxy-2- [4- (pyridin-2-yloxy) phenyl] -1- [3- (1,
1,2,2-tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro-5H-benzo [a] [7] annulene-1-carboxamide (1RS, 2SR) -2-hydroxy-2- [4- (Pyridin-2-yloxy) phenyl] -1- [3- (1,1,
Trifluoroacetic acid (10 ml) was added to tert-butyl 2,2-tetrafluoroethoxy) benzyl] ethylcarbamate (500 mg, 0.93 mmol), and the mixture was added at 0 ° C.
For 10 minutes. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (30 ml × 2). The extract was washed with brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The solution of the residue in acetonitrile (20 ml)
7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (175 mg, 0.93 mmol) and 1-
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (268 mg, 1.40 mmol) and 1-hydroxybenzotriazole hydrate (143 m
g, 0.93 mmol) and stirred at room temperature overnight.
The reaction solution was diluted with water (150 ml), and ethyl acetate (10 ml) was added.
0 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-1: 1) and recrystallized from ethyl acetate-hexane to give the desired product (181 m
g, 32%). ¹ H-NMR (CDCl ₃ ) δ: 1.90-2.08 (2H, m), 2.10-2.24 (2H,
m), 2.60-2.70 (2H, m), 2.82 (1H, dd, J = 14.6, 10.6
Hz), 3.04 (1H, dd, J = 14.6, 4.0 Hz), 3.71 (1H, d,
J = 3.4 Hz), 4.62-4.80 (1H, m), 5.00-5.08 (1H,
m), 5.60-6.20 (2H, m), 6.23 (1H, d, J = 11.6 Hz),
6.84-7.20 (10H, m), 7.20-7.38 (1H, m), 7.48 (2H, d,
J = 8.4 Hz), 7.64-7.76 (1H, m), 8.16-8.24 (1H,
^{.. m) IRν max KBr cm} -1: 1644, 1590, 1507, 1468, 1429. mp 160-161 ℃ Anal Calcd for C 34 H 30 F 4 N 2 O 4: C, 67.32; H, 4.98;
N, 4.62 Found: C, 67.09; H, 4.96; N, 4.56.

Example 259 4-Fluoro-N-｛(1RS, 2SR) -2-hydroxy-
2- [4- (pyridin-2-yloxy) phenyl] -1-
[3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -1-naphthamide (1RS, 2SR) -2-hydroxy-2- [4- (pyridin-2-yloxy) phenyl] -1 -[3- (1,1,
Trifluoroacetic acid (10 ml) was added to tert-butyl 2,2-tetrafluoroethoxy) benzyl] ethylcarbamate (500 mg, 0.93 mmol), and the mixture was added at 0 ° C.
For 10 minutes. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (30 ml × 2). The extract was washed with brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. 4-to the solution of the residue in acetonitrile (20 ml)
Fluoronaphthalenecarboxylic acid (177 mg, 0.93
Mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (268 mg, 1.4).
0 mmol) and 1-hydroxybenzotriazole hydrate (143 mg, 0.93 mmol) were added, and the mixture was stirred at room temperature overnight. Dilute the reaction with water (150 ml)
Extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1-1:
Purification in 1) and recrystallization from ethyl acetate-hexane gave the desired product (312 mg, 55%). ¹ H-NMR (CDCl ₃ ) δ: 2.88 (1H, dd, J = 14.4, 10.8 Hz),
3.11 (1H, dd, J = 14.4, 4.2 Hz), 3.59 (1H, s), 4.7
6-4.90 (1H, m), 5.08 (1H, s), 5.88 (1H, tt, J = 53.
1, 2.7 Hz), 6.05 (1H, d, J = 7.8 Hz), 6.90-7.10 (3
H, m), 7.10-7.22 (6H, m), 7.22-7.38 (1H, m), 7.40-
7.60 (4H, m), 7.64-7.74 (1H, m), 7.84 (1H, d, J =
8.4 Hz), 8.07 (1H, d, J = 8.1 Hz), 8.14-8.20 (1H,
m) .IRν max ^KBr cm ^-1 : 1715, 1644, 1597, 1508, 1468, 143
1.mp 176-177 ℃ Anal. Calcd for C ₃₃ H ₂₅ N ₂ O ₄ F ₅・ 1.0H ₂ O: C, 63.26; H,
4.34; N, 4.47 Found: C, 63.41; H, 4.07; N, 4.57.

Example 260 (1RS, 2SR) -2-hydroxy-2- [4- (pyridin-3-yloxy) phenyl] -1- [3- (1,1,
Tert-Butyl 2,2-tetrafluoroethoxy) benzyl] ethylcarbamate 1) Benzyl 4- (pyridin-3-yloxy) benzoate Benzyl 4-hydroxybenzoate (25.0 g, 110
Mmol) of N, N-dimethylformamide (60 m
l) Potassium tert-butoxide (12.3 g,
(110 mmol) and stirred at room temperature for 1 hour. After evaporating the reaction solution under reduced pressure, 3-bromopyridine (25.0 g, 1
10 mmol) and copper powder (1.76 g, 27.2 mmol) and N, N-dimethylformamide (80 m
l) was added and the mixture was stirred at 120 ° C for 8 hours. After the reaction solution was filtered using Celite, the filtrate was distilled off under reduced pressure. Water (500 ml) was added to the residue, and the mixture was extracted with ethyl acetate (500 ml). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-2: 1) to give the desired product (18.0 g,
54%, crude). ¹ H-NMR (CDCl ₃ ) δ: 5.36 (2H, s), 6.96-7.06 (2H, m),
7.26-7.50 (7H, m), 8.04-8.12 (2H, m), 8.46 (2H, br
s) .IRν max ^KBr cm ^-1 : 1717, 1605, 1574, 1505, 1474, 142
4.2) 4- (Pyridin-3-yloxy) benzoic acid Benzyl 4- (pyridin-3-yloxy) benzoate (1
8.0 g, 5.90 mmol) of ethanol (300 m
l) 10% palladium on carbon (50% water, 2.
0 g), and the mixture was stirred at 80 ° C. overnight under a hydrogen stream. The reaction solution was filtered using celite, and the filtrate was concentrated. The residue was recrystallized from ethanol-hexane to obtain the desired product (11.2 g, 88%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.10 (2H, d, J = 8.8 Hz), 7.42-
7.66 (2H, m), 7.98 (2H, d, J = 8.8 Hz), 8.47 (2H,
s) .IRν max ^KBr cm ^-1 : 1690, 1597, 1574.mp 204-205 ° C Anal.Calcd for C ₁₂ H ₉ NO ₃ : C, 66.97; H, 4.22; N, 6.
51 Found: C, 66.88; H, 4.15; N, 6.42. 3) 3-oxo-3- [4- (pyridin-3-yloxy)
Benzyl phenyl] propanoate 4- (pyridin-3-yloxy) benzoic acid (11.2
g, 52.0 mmol) of tetrahydrofuran (160
ml) with N, N'-carbonyldiimidazole (9.2
(8 g, 57.3 mmol) and heated under reflux for 3 hours. After the reaction solution was cooled to room temperature, malonic acid monobenzylmagnesium salt (11.7 g, 28.6 mmol) was added, and the mixture was heated under reflux for 2 hours. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product (14.1 g, 78).
%). ¹ H-NMR (CDCl ₃ ) δ: 4.02 (2H, s), 5.20 (2H, s), 6.94-
7.08 (2H, m), 7.30-7.48 (6H, m), 7.90-7.96 (2H, m),
8.40-8.52 (3H, m) .IRν max ^KBr cm ^-1 : 1740, 1682, 1601, 1574, 1505, 147
3, 1424. 4) 3-Oxo-3- [4- (pyridin-3-yloxy)
Phenyl] -2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] benzyl propanoate [3- (1,1,2,2-tetrafluoroethoxy) phenyl] methanol (4.97 g, To a solution of 22.2 mmol) in ethyl acetate (100 ml) were added methanesulfonyl chloride (1.87 ml, 24.2 mmol) and triethylamine (3.65 ml, 26.2 mmol), and the mixture was stirred at room temperature for 2 hours. The insolubles were filtered, and the filtrate was distilled off under reduced pressure to prepare a mesyl compound. 3-oxo-3- [4- (pyridine
Benzyl-3-yloxy) phenyl] propanoate (7
g, 20.2 mmol) in 1,2-dimethoxyethane (80 ml).
(0% oily, 20.2 mmol) and stirred at room temperature for 1 hour. The 1,2-dimethoxyethane (10 ml) solution of the previously prepared mesyl compound was added dropwise to the reaction solution, and the reaction solution was
Stirred at 0 ° C. overnight. The reaction solution was acidified with 1N hydrochloric acid, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and ethyl acetate (300 ml ×
Extracted in 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the desired product (6.0 g,
54%, crude). ¹ H-NMR (CDCl ₃ ) δ: 3.35 (2H, d, J = 7.6 Hz), 4.60 (1
H, t, J = 7.6 Hz), 5.08 (2H, s), 5.88 (1H, tt, J =
53.0, 3.0 Hz), 6.90-7.40 (13H, m), 7.86-7.98 (2H,
m), 8.40-8.52 (2H, m) .IRν max ^KBr cm ^-1 : 1740, 1684, 1601, 1574, 1505, 147
3, 1424.5) (2RS, 3RS) -3-hydroxy-3- [4-
(Pyridin-3-yloxy) phenyl] -2- [3-
Benzyl (1,1,2,2-tetrafluoroethoxy) benzyl] propanoate Sodium borohydride (1.64 g, 43.3) was added to a solution of zinc chloride (2.95 g, 21.6 mmol) in diethyl ether (100 ml). Mmol) at room temperature for 30 minutes.
Minutes. The insolubles are removed by filtration and the filtrate is treated with 3-oxo-3-.
[4- (Pyridin-3-yloxy) phenyl] -2- [3-
A solution of benzyl (1,1,2,2-tetrafluoroethoxy) benzyl] propanoate (6.0 g, 10.8 mmol, crude) in diethyl ether (50 ml) was added at 0 ° C.
And stirred for 30 minutes. The reaction solution was quenched with 1N hydrochloric acid, neutralized with saturated aqueous sodium hydrogen carbonate, and further added with water (200 ml).
l) was added, and the mixture was extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
2: 1) and recrystallized from ethyl acetate-hexane to give the desired product (3.13 g, 73%). ¹ H-NMR (CDCl ₃ ) δ: 2.92-3.14 (4H, m), 4.86 (2H, d, J
= 3.3 Hz), 5.03 (1H, s), 5.88 (1H, tt, J = 53.1,
3.0 Hz), 6.90-7.08 (7H, m), 7.18-7.32 (6H, m), 7.3
6 (2H, d, J = 8.4 Hz), 8.34-8.40 (2H, m) .IRν max ^KBr cm ^-1 : 1730, 1611, 1576, 1507, 1478, 145
1, 1426.mp 120-122 ℃ Anal.Calcd for C ₃₀ H ₂₅ NO ₅ F ₄ : C, 64.86; H, 4.54; N,
2.52 Found: C, 64.91; H, 4.75; N, 2.56.6) (2RS, 3RS) -3-hydroxy-3- [4-
(Pyridin-3-yloxy) phenyl] -2- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] propanoic acid (2RS, 3RS) -3-hydroxy-3- [4- (pyridin-3-yloxy) phenyl] -2- [3- (1, 1,
To a solution of benzyl 2,2-tetrafluoroethoxy) benzyl] propanoate (3.00 g, 5.38 mmol) in ethanol (200 ml) was added 10% palladium / carbon (50% water content, 300 mg), and a 1 atm hydrogen stream was added. Stirred under for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain the desired product (2.8 g, 100%, crude).
This compound was used crude in the next reaction. ¹ H-NMR (CDCl ₃ ) δ: 2.92-3.10 (3H, m), 5.05 (1H, m),
5.88 (1H, tt, J = 53.0,3.0 Hz), 6.96-7.16 (5H, m),
7.20-7.48 (5H, m), 8.20-8.32 (2H, m) .IRν max ^KBr cm ^-1 : 1711, 1611, 1578, 1507, 1480, 142
7.7) (4RS, 5SR) -5- [4- (pyridin-3-yloxy) phenyl] -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3- Oxazolidin-2-one (2RS, 3RS) -3-hydroxy-3- [4- (pyridin-3-yloxy) phenyl] -2- [3- (1,1,
In a solution of (2,2-tetrafluoroethoxy) benzyl] propanoic acid (2.83 g, 6.08 mmol, crude) in tetrahydrofuran (100 ml), diphenylphosphoryl azide (1.44 ml, 6.69 mmol) and triethylamine (1. (27 mmol, 9.12 mmol), and the mixture was heated under reflux for 1 hour. After allowing the reaction solution to cool, water (10
0 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with an aqueous solution of sodium hydrogen carbonate and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-1: 1),
Recrystallization from ethyl acetate-hexane gave the desired product (3.
56 g, 73%). ¹ H-NMR (CDCl ₃ ) δ: 2.24-2.42 (2H, m), 4.22-4.32 (1H,
m), 5.12-5.22 (1H, m), 5.80 (1H, d, J = 7.8 Hz), 5.
90 (1H, tt, J = 53.1, 2.7 Hz), 6.89 (1H, s), 6.96
(1H, d, J = 7.8 Hz), 7.00-7.18 (3H, m), 7.26-7.40
(5H, m), 8.18-8.24 (2H, m) .IRν max ^KBr cm ^-1 : 1759, 1613, 1576, 1508, 1478, 142
4.mp 123-124 ℃ Anal. Calcd for C ₂₃ H ₁₈ N ₂ O ₄ F ₄ : C, 59.74; H, 3.92;
N, 6.06 Found: C, 59.60; H, 3.85; N, 6.11.8) (4RS, 5SR) -2-oxo-5- [4- (pyridin-3-yloxy) phenyl] -4- [3- ( 1,1,
2,2-tetrafluoroethoxy) benzyl] -1,3-
Tert-Butyl oxazolidine-3-carboxylate (4RS, 5SR) -5- [4- (pyridin-3-yloxy) phenyl] -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine-2-
To a solution of ON (1.80 g, 3.89 mmol) in acetonitrile (40 ml) was added di-tert-butyl dicarbonate (1.
02 g, 4.67 mmol) and 4-N, N-dimethylpyridine (47 mg, 0.39 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water (100 ml) was added to the reaction solution,
Extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1-1:
Purified in 1) and recrystallized from ethyl acetate-hexane,
The desired product (1.87 g, 85%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s), 2.65 (1H, dd, J = 1
4.2, 8.8 Hz), 2.93 (1H, dd, J = 14.2, 4.4 Hz), 4.76
-4.88 (1H, m), 5.69 (1H, d, J = 7.0 Hz), 5.91 (1H,
tt, J = 53.0, 3.0 Hz), 6.58 (1H, s), 6.66 (1H, d,
J = 7.6 Hz), 6.84-7.04 (3H, m), 7.08-7.20 (3H,
m), 7.26-7.36 (2H, m), 8.36-8.44 (2H, m) .IRν max ^KBr cm ^-1 : 1819, 1721, 1613, 1578, 1508, 147
6, 1424.mp 146-147 ° C Anal.Calcd for C ₂₈ H ₂₆ N ₂ O ₆ F ₄ : C, 59.79; H, 4.66;
N, 4.98 Found: C, 59.83; H, 4.65; N, 4.84. 9) (1RS, 2SR) -2-hydroxy-2- [4-
(Pyridin-3-yloxy) phenyl] -1- [3-
Tert-Butyl (1,1,2,2-tetrafluoroethoxy) benzyl] ethylcarbamate (4RS, 5SR) -2-oxo-5- [4- (pyridine-3
-Yloxy) phenyl] -4- [3- (1,1,2,2-
Tert-butyl tetrafluoroethoxy) benzyl] -1,3-oxazolidine-3-carboxylate (1.70 g,
3.02 mmol) in methanol (10 ml).
Normal methanol solution of sodium hydroxide (7.26 m
1, 3.63 mmol) and stirred at room temperature for 1 hour.
Water (100 ml) was added to the reaction solution, and ethyl acetate (100 ml) was added.
ml × 2). Wash the extract with saturated saline,
After drying (anhydrous magnesium sulfate), the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the desired product (1.
39 g, 86%). ¹ H-NMR (CDCl ₃ ) δ: 1.35 (9H, s), 2.60-2.84 (2H, m),
3.45 (1H, s), 4.02-4.16 (1H, m), 4.63 (1H, d, J =
8.4 Hz), 4.93 (1H, s), 5.90 (1H, tt, J = 52.8, 3.0
Hz), 6.96-7.10 (5H, m), 7.24-7.34 (3H, m), 7.41
(2H, d, J = 8.4 Hz), 8.34-8.44 (2H, m) .IRν max ^KBr cm ^-1 : 1698, 1576, 1505, 1478.mp 123-124 ℃ Anal. Calcd for C ₂₇ H ₂₈ F ₄ N ₂ O ₅ : C, 60.44; H, 5.26;
N, 5.22 Found: C, 60.24; H, 5.45; N, 5.15.

Example 261 N-{(1RS, 2SR) -2-hydroxy-2- [4- (pyridin-3-yloxy) phenyl] -1- [3- (1,
1,2,2-tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro-5H-benzo [a] [7] annulene-1-carboxamide (1RS, 2SR) -2-hydroxy-2- [4- (Pyridin-3-yloxy) phenyl] -1- [3- (1,1,
Trifluoroacetic acid (10 ml) was added to tert-butyl 2,2-tetrafluoroethoxy) benzyl] ethylcarbamate (500 mg, 0.93 mmol), and the mixture was added at 0 ° C.
For 10 minutes. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (30 ml × 2). The extract was washed with brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The solution of the residue in acetonitrile (20 ml)
7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (175 mg, 0.93 mmol) and 1-
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (268 mg, 1.40 mmol) and 1-hydroxybenzotriazole hydrate (143 m
g, 0.93 mmol) and stirred at room temperature overnight.
The reaction solution was diluted with water (150 ml), and ethyl acetate (10 ml) was added.
0 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-ethyl acetate),
Recrystallization from ethyl acetate-hexane gave the desired product (31
7 mg, 56%). ¹ H-NMR (CDCl ₃ ) δ: 1.90-2.08 (2H, m), 2.10-2.28 (2H,
m), 2.60-2.70 (2H, m), 2.81 (1H, dd, J = 14.8, 10.2
Hz), 3.02 (1H, dd, J = 14.8, 4.0 Hz), 3.97 (1H,
s), 4.60-4.80 (1H, m), 5.00-5.08 (1H, m), 5.60-6.1
8 (2H, m), 6.21 (1H, d, J = 11.8 Hz), 6.90-7.20 (8
H, m), 7.20-7.40 (3H, m), 7.40-7.52 (2H, m), 8.35
. (2H, s) IRν max KBr cm -1: 1642, 1613, 1576, 1505, 1478, 142
. 6. mp 133-134 ℃ Anal Calcd for C 34 H 30 F 4 N 2 O 4: C, 67.12; H, 5.00;
N, 4.60 Found: C, 66.98; H, 4.85; N, 4.61.

Example 262 4-Fluoro-N-｛(1RS, 2SR) -2-hydroxy-
2- [4- (pyridin-3-yloxy) phenyl] -1-
[3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -1-naphthamide (1RS, 2SR) -2-hydroxy-2- [4- (pyridin-3-yloxy) phenyl] -1 -[3- (1,1,
Trifluoroacetic acid (10 ml) was added to tert-butyl 2,2-tetrafluoroethoxy) benzyl] ethylcarbamate (500 mg, 0.93 mmol), and the mixture was added at 0 ° C.
For 10 minutes. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (30 ml × 2). The extract was washed with brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. 4-to the solution of the residue in acetonitrile (20 ml)
Fluoronaphthalenecarboxylic acid (177 mg, 0.93
Mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (268 mg, 1.4).
0 mmol) and 1-hydroxybenzotriazole hydrate (143 mg, 0.93 mmol) were added, and the mixture was stirred at room temperature overnight. Dilute the reaction with water (150 ml)
Extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1-1:
Purification in 1) and recrystallization from ethyl acetate-hexane gave the desired product (347 mg, 61%). ¹ H-NMR (CDCl ₃ ) δ: 2.89 (1H, dd, J = 14.6, 10.6 Hz),
3.12 (1H, dd, J = 14.6, 4.0 Hz), 3.59 (1H, s), 4.7
0-4.90 (1H, m), 5.14 (1H, s), 5.91 (1H, tt, J = 53.
0, 3.0 Hz), 6.00 (1H, d, J = 8.4 Hz), 6.90-7.65 (1
4H, m), 7.88 (1H, d, J = 8.0 Hz), 8.11 (1H, d, J =
8.0Hz), 8.41 (2H, brs) .IRν max ^KBr cm ^-1 : 1642, 1626, 1582, 1505, 1480, 142
6. mp 183-184 ℃ Anal. Calcd for C ₃₃ H ₂₅ F ₅ N ₂ O ₄ : C, 65.13; H, 4.14;
N, 4.60 Found: C, 65.03; H, 4.01; N, 4.35.

Example 263 4-Fluoro-N-｛(1RS, 2SR) -2- (3-fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2
2-tetrafluoroethoxy) benzyl] ethyl} -1-
Naphthamide (1RS, 2SR) -2-amino-1- (3-fluorophenyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol (300 mg,
0.83 mmol) in acetonitrile (20 ml) was added to 4-fluoronaphthalenecarboxylic acid (156 mg,
0.83 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (239 m
g, 1.25 mmol) and 1-hydroxybenzotriazole hydrate (127 mg, 0.83 mmol) were added and stirred at room temperature overnight. The reaction solution was water (100 ml)
And extracted with ethyl acetate (100 ml × 2).
The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4:
1-2: 1) and recrystallized from ethyl acetate-hexane to give the desired product (283 mg, 64%). ¹ H-NMR (CDCl ₃ ) δ: 2.85 (1H, dd, J = 14.6, 10.6 Hz),
3.03 (1H, dd, J = 14.6, 4.4 Hz), 3.60 (1H, d, J =
3.8 Hz), 4.68-4.86 (1H, m), 5.10-5.20 (1H, m), 5.8
8 (1H, tt, J = 53.0, 3.0 Hz), 5.99 (1H, d, J = 8.4
Hz), 6.92-7.60 (12H, m), 7.84 (1H, d, J = 8.0 Hz),
8.08 (1H, d, J = 7.8 Hz) IRν max KBr cm -1:.. 1642, 1626, 1601, 1590, 1539. mp 175-176 ℃ Anal Calcd for C 28 H 21 F 6 NO 3 · 0.1H 2 O: C, 62.83; H,
3.99; N, 2.62 Found: C, 62.62; H, 3.79; N, 2.52.

Example 264 4-Fluoro-N-｛(1RS, 2SR) -2- (3-chlorophenyl) -2-hydroxy-1- [3- (1,1,2,2-
Tetrafluoroethoxy) benzyl] ethyl} -1-naphthamide (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] Propan-1-ol (300 mg, 0.1 mg).
79 mmol) in acetonitrile (20 ml) solution.
-Fluoronaphthalenecarboxylic acid (151 mg, 0.7
9 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (228 mg, 1.
19 mmol) and 1-hydroxybenzotriazole hydrate (122 mg, 0.79 mmol) were added and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-ethyl acetate) and recrystallized from ethyl acetate-hexane to obtain the desired product (163 mg, 37%). ¹ H-NMR (CDCl ₃ ) δ: 2.84 (1H, dd, J = 14.4, 10.8 Hz),
3.01 (1H, dd, J = 14.4, 4.2 Hz), 3.73 (1H, d, J =
(3.9 Hz), 4.68-4.80 (1H, m), 5.06-5.12 (1H, m), 5.8
8 (1H, tt, J = 52.8, 3.0 Hz), 6.02 (1H, d, J = 8.7
Hz), 6.92-7.00 (1H, m), 7.06 (1H, s), 7.08-7.18 (3
H, m), 7.24-7.40 (4H, m), 7.40-7.58 (3H, m), 7.80
. (1H, d, J = 8.4 Hz), 8.07 (1H, d, J = 8.1 Hz) IRν max KBr cm -1:. 1642, 1626, 1601, 1537. mp 177-178 ℃ Anal Calcd for C 28 H ₂₁ ClF ₅ NO ₃ : C, 61.15; H, 3.85;
N, 2.55 Found: C, 61.09; H, 3.70; N, 2.49.

Example 265 4-Fluoro-N-｛(1RS, 2SR) -2- (2-fluoropyridin-4-yl) -2-hydroxy-1- [3- (1,
1,2,2-tetrafluoroethoxy) benzyl] ethyl} -1-naphthamide (1RS, 2SR) -2-amino-1- (2-fluoropyridin-4-yl) -3- [3- (1,1 , 2,2-Tetrafluoroethoxy) phenyl] propan-1-ol (194
mg, 0.54 mmol) of acetonitrile (20 m
l) Add 4-fluoronaphthalenecarboxylic acid (101
mg, 0.54 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (15 mg).
4 mg, 0.80 mmol) and 1-hydroxybenzotriazole hydrate (82 mg, 0.54 mmol)
Was added and stirred at room temperature overnight. The reaction solution was washed with water (100 m
1) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
2: 1-ethyl acetate) and recrystallized from ethyl acetate-hexane to give the desired product (189 mg, 66%). ¹ H-NMR (CDCl ₃ ) δ: 2.80-3.02 (2H, m), 4.39 (1H, s),
4.62-4.80 (1H, m), 5.18 (1H, s), 5.60-6.20 (1H, m),
6.27 (1H, d, J = 7.4 Hz), 6.90-7.20 (6H, m), 7.20
-7.40 (2H, m), 7.42-7.62 (2H, m), 7.88 (1H, d, J =
. 8.0 Hz), 8.02-8.20 (2H , d, J = 6.2 Hz) IRν max KBr cm -1:. 1642, 1615, 1601, 1585. mp 170-171 ℃ Anal Calcd for C 27 H 20 F 6 N 2 O ₃・ 0.2H ₂ O: C, 60.27; H,
3.82; N, 5.21 Found: C, 60.04; H, 3.63; N, 5.20.

Example 266 4-Fluoro-N-｛(1RS, 2RS) -2- (6-fluoropyridin-2-yl) -2-hydroxy-1- [3- (1,1
1,2,2-tetrafluoroethoxy) benzyl] ethyl} -1-naphthamide (1RS, 2RS) -2-amino-1- (6-fluoropyridin-2-yl) -3- [3- (1,1 , 2,2-Tetrafluoroethoxy) phenyl] propan-1-ol hydrochloride (300 mg, 0.75 mmol) in acetonitrile (20 ml) solution was treated with 4-fluoronaphthalenecarboxylic acid (141 mg, 0.75 mmol), 1- Ethyl-3-
(3-Dimethylaminopropyl) carbodiimide hydrochloride (216 mg, 1.13 mmol), 1-hydroxybenzotriazole hydrate (115 mg, 0.75 mmol) and triethylamine (1.03 ml, 0.7
(5 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-ethyl acetate) and recrystallized from ethyl acetate-hexane to give the desired product (306 m
g, 76%). ¹ H-NMR (CDCl ₃ ) δ: 2.82 (1H, dd, J = 14.4, 5.0 Hz),
3.02 (1H, dd, J = 14.4,9.8 Hz), 4.67 (1H, d, J =
5.4 Hz), 4.80-4.96 (1H, m), 5.10-5.20 (1H, m), 5.8
8 (1H, tt, J = 53.0, 3.0 Hz), 6.42 (1H, d, J = 8.8
Hz), 6.89 (1H, dd, J = 8.2, 2.6 Hz), 7.00-7.20 (4
H, m), 7.20-7.40 (2H, m), 7.40-7.62 (3H, m), 7.78-
7.94 (1H, m), 7.97 (1H, d, J = 8.4 Hz), 8.10 (1H,
d, J = 7.2Hz) .IRν max ^KBr cm ^-1 : 1642, 1626, 1603, 1578, 1535, 145
. 4. mp 185-186 ℃ Anal Calcd for C 27 H 20 F 6 N 2 O 3: C, 60.68; H, 3.77;
N, 5.24 Found: C, 60.40; H, 3.61; N, 5.14.

Example 267 4-Fluoro-N-｛(1RS, 2SR) -2-hydroxy-
2- (4-phenoxyphenyl) -1- [3- (1,1,
2,2-tetrafluoroethoxy) benzyl] ethyl｝-
1-Naphthamide (1RS, 2SR) -2-amino-1- (4-phenoxyphenyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol (300 mg,
0.69 mmol) in acetonitrile (20 ml) was added to 4-fluoronaphthalenecarboxylic acid (131 mg,
0.69 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (198 m
g, 1.03 mmol) and 1-hydroxybenzotriazole hydrate (105 mg, 0.69 mmol) were added and stirred at room temperature overnight. The reaction solution was water (100 ml)
And extracted with ethyl acetate (100 ml × 2).
The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2:
The residue was purified with 1-ethyl acetate) and recrystallized from ethyl acetate-hexane to give the desired product (286 mg, 68%). ¹ H-NMR (CDCl ₃ ) δ: 2.85 (1H, dd, J = 14.4, 10.8 Hz),
3.10 (1H, dd, J = 14.4, 4.2 Hz), 3.41 (1H, d, J =
3.0 Hz), 4.72-4.86 (1H, m), 5.04-5.10 (1H, m), 5.8
8 (1H, tt, J = 52.8, 3.0 Hz), 5.95 (1H, d, J = 8.7
Hz), 6.94-7.04 (5H, m), 7.06-7.20 (5H, m), 7.28-7.
40 (3H, m), 7.40-7.60 (4H, m), 7.81 (1H, d, J = 8.
4 Hz), 8.08 (1H, d, J = 8.1 Hz) .IRν max ^KBr cm ^-1 : 1644, 1626, 1599, 1590, 1537, 150
8, 1489.mp 155-156 ℃ Anal.Calcd for C ₃₄ H ₂₆ F ₅ NO ₄ : C, 67.21; H, 4.31; N,
2.31 Found: C, 67.02; H, 4.27; N, 2.21.

Example 268 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- {3-[(trifluoromethyl) thio] benzyl} ethyl) -6,7-dihydro-5H-benzo [a] [7] annulene-1-carboxamide 1) 3- (4-) Fluorophenyl) -3-oxo-2- ｛3
-[(Trifluoromethyl) thio] benzyl} propanoate ethyl 3-[(trifluoromethyl) thio] benzyl alcohol (4.82 g, 23.1 mmol) in ethyl acetate (6
Methanesulfonyl chloride (2.92 g, 2 ml).
5.5 mmol) and triethylamine (3.87 m
1,27.8 mmol) and stirred at room temperature for 2 hours. The insolubles were filtered, and the filtrate was distilled off under reduced pressure to prepare a mesyl compound. Ethyl 3- (4-fluorophenyl) -3-oxopropanoate (4.87 g, 23.2 mmol) in 1,2-
Sodium hydride (0.93 g, 60% oily, 23.2 mmol) was added to a dimethoxyethane (50 ml) solution, and the mixture was stirred at room temperature for 1 hour. The 1,2-dimethoxyethane (10 ml) solution of the mesyl compound previously prepared was added dropwise to the reaction solution, and the reaction solution was stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate (300 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give the desired product (5.67 g, 6
1%). ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.2 Hz), 3.26-7.4
2 (2H, m), 4.11 (2H, q, J = 7.2 Hz), 4.56 (1H, t,
J = 7.5 Hz), 7.06-7.16 (2H, m), 7.26-7.38 (2H, m),
7.44-7.54 (2H, m), 7.94-8.02 (2H, m) IRν max KBr cm -1:.. 1738, 1688, 1599, 1508. mp 72-73 ℃ Anal Calcd for C 19 H 16 F 3 O 3 S, C, 57.00; H, 4.03 Found: C, 56.99; H, 4.06.2) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- {3-[(trifluoromethyl ) Thio] benzyl @ ethyl propanoate To a solution of zinc chloride (3.74 g, 27.4 mmol) in diethyl ether (100 ml) was added sodium borohydride (2.08 g, 54.8 mmol), and the mixture was added at room temperature for 30 minutes.
Minutes. The insoluble material was removed by filtration, and the filtrate was subjected to ethyl 3- (4-fluorophenyl) -3-oxo-2- {3-[(trifluoromethyl) thio] benzyl} propanoate (5.5 g, 1
(3.7 mmol) in diethyl ether (50 ml) was added at 0 ° C., and the mixture was stirred for 30 minutes. The reaction solution was quenched with 1N hydrochloric acid, neutralized with saturated aqueous sodium hydrogen carbonate, and further added with water (2%).
00 ml) and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the desired product (5.40 g, 98%).
%). ¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7.2 Hz), 2.88-3.1
0 (4H, m), 3.87 (2H, q, J = 7.2 Hz), 5.02 (1H, d,
J = 4.8 Hz), 6.98-7.12 (2H, m), 7.18-7.52 (6H, m). IRν max ^KBr cm ^-1 : 1725, 1605, 1510.3) (2RS, 3RS) -3- (4- (Fluorophenyl) -3-hydroxy-2- {3-[(trifluoromethyl) thio] benzyl} propanoic acid (2RS, 3RS) -3- (4-fluorophenyl) -3-
Hydroxy-2- {3-[(trifluoromethyl) thio]
Benzyl ethyl propanoate (5.30 g, 13.17)
A 2N aqueous solution of sodium hydroxide (13.2 ml, 26.4 mmol) was added to a methanol (150 ml) solution of the above (mole), and the mixture was stirred at room temperature overnight. After concentrating the reaction solution,
After adding normal hydrochloric acid to make it acidic, ethyl acetate (200 ml)
× 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain the desired product (3.98 g, 81%). ¹ H-NMR (CDCl ₃ ) δ: 2.90-3.10 (3H, m), 5.07 (1H, s),
6.98-7.10 (2H, m), 7.12-7.42 (5H, m), 7.47 (1H, d,
.. J = 7.4 Hz) IRν max KBr cm -1: 1712, 1607. mp 121-122 ℃ Anal Calcd for C 17 H 14 O 3 SF 4: C, 54.54; H, 3.77 Found: C, 54.58; H, 3.80.5) (4RS, 5SR) -5- (4-Fluorophenyl) -4- {3-[(trifluoromethyl) thio] benzyl} -1,3-oxazolidin-2-one (2RS, 3RS)- 3- (4-fluorophenyl) -3-
Hydroxy-2- {3-[(trifluoromethyl) thio]
To a solution of benzyl dipropanoic acid (3.9 g, 10.42 mmol) in tetrahydrofuran (150 ml), diphenylphosphoryl azide (2.47 ml, 11.5 mmol) and triethylamine (2.18 ml, 15.6 mmol) were added. The mixture was refluxed for 1 hour. After allowing the reaction solution to cool, it was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-ethyl acetate) and recrystallized from ethyl acetate-hexane to obtain the desired product (3.45 g, 89%). ¹ H-NMR (CDCl ₃ ) δ: 2.31 (1H, d, J = 3.0 Hz), 2.35 (1
H, s), 4.20-4.34 (1H, m), 5.13 (1H, brs), 5.79 (1
H, d, J = 7.8 Hz), 7.04-7.20 (3H, m), 7.20-7.44 (4
. H, m), 7.54 ( 1H, d, J = 7.6 Hz) IRν max KBr cm -1:. 1755, 1609, 1595, 1514. mp 132-133 ℃ Anal Calcd for C 17 H 13 NO 2 SF 4: C, 54.98; H, 3.53;
N, 3.77 Found: C, 55.28; H, 3.47; N, 3.98.6) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- {3-[(trifluoromethyl) thio ] Phenyl} propan-1-ol (4RS, 5SR) -5- (4-fluorophenyl) -4-
{3-[(trifluoromethyl) thio] benzyl} -1,
To a solution of 3-oxazolidin-2-one (1.30 g, 3.50 mmol) in ethanol (3 ml) was added an 8 N aqueous sodium hydroxide solution (1.31 ml, 10.5 mmol) and the mixture was stirred at 80 ° C. for 4 hours. did. Water (20m
l) was added, and the mixture was extracted with ethyl acetate (50 ml × 2).
The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and then distilled off under reduced pressure to obtain the desired product (0.8 g, 77 g).
%). ¹ H-NMR (CDCl ₃ ) δ: 1.80-2.30 (2H, m), 2.42 (1H, dd, J
= 13.6, 10.2 Hz), 2.83 (1H, dd, J = 14.0, 2.6 H
z), 3.20-3.40 (1H, m), 4.69 (1H, d, J = 4.8 Hz),
7.00-7.20 (2H, m), 7.20-7.56 (6H, m). IRν max ^KBr cm ^-1 : 1752, 1605, 1508, 1476. 7) N-((1RS, 2SR) -2- (4-fluoro Phenyl) -2-hydroxy-1- {3-[(trifluoromethyl) thio] benzyl} ethyl) -6,7-dihydro-5H-
Benzo [a] [7] annulene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- {3-[(trifluoromethyl) thio] phenyl} propane-1- To a solution of all (450 mg, 1.51 mmol) in acetonitrile (20 ml) was added 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (284 mg, 1.51 mmol) and 1-ethyl-
3- (3-dimethylaminopropyl) carbodiimide hydrochloride (435 mg, 2.27 mmol) and 1-hydroxybenzotriazole hydrate (231 mg, 1.5
(1 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-ethyl acetate) and recrystallized from ethyl acetate-hexane to give the desired product (396 m
g, 51%). ¹ H-NMR (CDCl ₃ ) δ: 1.90-2.08 (2H, m), 2.12-2.24 (2H,
m), 2.60-2.72 (2H, m), 2.81 (1H, dd, J = 14.7, 10.5
Hz), 3.00 (1H, dd, J = 14.7, 4.2 Hz), 3.52 (1H, d,
J = 3.6 Hz), 4.62-4.74 (1H, m), 5.00-5.08 (1H,
m), 5.77 (1H, d, J = 8.7 Hz), 5.88-5.96 (1H, m), 6.
19 (1H, d, J = 12.0 Hz), 6.90-7.00 (1H, m), 7.00-
7.20 (4H, m), 7.30-7.60 (6H, m) .IRν max ^KBr cm ^-1 : 1638, 1512.mp 163-164 ℃ Anal. Calcd for C ₂₈ H ₂₅ F ₄ NO ₂ S: C, 65.23; H, 4.89;
N, 2.72; S, 6.22 Found: C, 65.02; H, 5.02; N, 2.79; S, 6.22.

Example 269 4-Fluoro-N-((1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- {3-[(trifluoromethyl) thio] benzyl} ethyl)- 1-Naphthamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- {3-[(trifluoromethyl) thio] phenyl} propan-1-ol (450 mg, 1.51 mmol) To acetonitrile (20 ml) solution of 4-fluoronaphthalenecarboxylic acid (287 mg, 1.51 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (435 mg, 2.27 mmol) and 1- Hydroxybenzotriazole hydrate (231 mg, 1.51 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract is washed sequentially with water and saturated saline, and dried (anhydrous magnesium sulfate)
After that, it was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-ethyl acetate) and recrystallized from ethyl acetate-hexane to obtain the desired product (447 mg, 57%). ¹ H-NMR (CDCl ₃ ) δ: 2.85 (1H, dd, J = 15.2, 10.8 Hz),
3.04 (1H, dd, J = 15.0, 3.9 Hz), 3.43 (1H, d, J =
3.6 Hz), 4.70-4.82 (1H, m), 5.04-5.10 (1H, m), 5.9
8 (1H, d, J = 9.3 Hz), 6.92-7.02 (1H, m), 7.02-7.1
2 (3H, m), 7.30-7.58 (8H, m), 7.77 (1H, d, J = 8.7
. Hz), 8.08 (1H, d, J = 8.4 Hz) IRν max KBr cm -1:. 1642, 1626, 1601, 1537, 1512. mp 192-193 ℃ Anal Calcd for C 27 H 20 F 5 NO 2 S : C, 62.66; H, 3.90;
N, 2.71; S, 6.20 Found: C, 62.56; H, 3.86; N, 2.66; S, 6.34.

Example 270 N-｛(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] ethyl} -6,7-dihydro-5H- Benzo [a] [7] annulene-1-carboxamide 1) 2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-carboxylic acid 2,2,3,3-carboxylic acid Tetrafluoro-2,3-dihydro-1,
4-benzodioxin-6-carbonitrile (5.0 g,
Concentrated hydrochloric acid (20 ml) was added to a solution of acetic acid (21.44 mmol) in acetic acid (20 ml), and the mixture was refluxed overnight. After concentrating the reaction solution, the precipitated crystals were collected by filtration and washed with water to obtain the desired product (4.
76 g, 88%). _{^{1 H-NMR (CDCl 3)}} δ: 7.26 (1H, d, J = 8.7 Hz), 7.90-8.0
0 (2H, m), 11.00-11.80 (1H, br) .IRν max ^KBr cm ^-1 : 1726, 1701, 1624, 1597, 1508.mp 103-104 ° C Anal.Calcd for C ₉ H ₄ O ₄ F ₄ : C, 42.88; H, 1.60 Found: C, 43.13; H, 1.60. 2) (2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methanol Lithium aluminum hydride (1.40 g, 36.89)
Mmol) in 2,2,3,3-tetrafluoro-2,3-dihydro-1,2.
4-benzodioxin-6-carboxylic acid (4.65 g, 1
(8.44 mmol) at 0 ° C. After stirring the reaction solution at 0 ° C. for 10 minutes, a 1 N aqueous solution of sodium hydroxide was added. The filtrate was concentrated after filtering an insoluble matter through celite. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the desired product (3.
54 g, 81%). ¹ H-NMR (CDCl ₃ ) δ: 1.87 (1H, t, J = 6.0 Hz), 4.69 (2
H, d, J = 6.0 Hz), 7.08-7.20 (3H, m). IRν max ^KBr cm ^-1 : 1611, 1510, 1441. 3) 3- (4-Fluorophenyl) -3-oxo-2-
[(2,2,3,3-tetrafluoro-2,3-dihydro-
1,4-benzodioxin-6-yl) methyl] ethyl propanoate (2,2,3,3-tetrafluoro-2,3-dihydro-
1,4-benzodioxin-6-yl) methanol (3.
48 g, 14.6 mmol) of ethyl acetate (100 m
l) Add methanesulfonyl chloride (1.25 ml, 1
6.1 mmol) and triethylamine (3.05 m
1,21.9 mmol) and stirred at room temperature for 2 hours. The insolubles were filtered, and the filtrate was distilled off under reduced pressure to prepare a mesyl compound. 1,3-Ethyl 3- (4-fluorophenyl) -3-oxopropanoate (3.07 g, 14.6 mmol)
Sodium hydride (0.58 g, 60% oily, 14.6 mmol) was added to a dimethoxyethane (20 ml) solution, and the mixture was stirred at room temperature for 1 hour. The 1,2-dimethoxyethane (10 ml) solution of the mesyl compound previously prepared was added dropwise to the reaction solution, and the reaction solution was stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate (300 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give the desired product (4.49 g, 7
1%). ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.2 Hz), 3.30 (2
H, d, J = 7.5 Hz), 4.11 (2H, q, J = 7.2 Hz), 4.51
(1H, t, J = 7.5 Hz), 7.03 (3H, s), 7.08-7.20 (2H,
m), 7.96-8.04 (2H, m) .IRν max ^KBr cm ^-1 : 1736, 1688, 1599, 1508.mp 83-84 ℃ Anal. Calcd for C ₂₀ H ₁₅ O ₅ F ₅ : C, 55.82; H , 3.51 Found: C, 55.87; H, 3.42.4.4) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-[(2,2,3,3-tetrafluoro-2, 3-dihydro-1,4-benzodioxin-6-
Yl) methyl] ethyl propanoate To a solution of zinc chloride (2.79 g, 20.5 mmol) in diethyl ether (100 ml) was added sodium borohydride (1.55 g, 40.9 mmol), and the mixture was added at room temperature for 30 minutes.
Minutes. The insoluble material was removed by filtration, and the filtrate was treated with 3- (4-fluorophenyl) -3-oxo-2-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin. -
6-yl) methyl] ethyl propanoate (4.4 g, 1
(0.2 mmol) in diethyl ether (50 ml) was added at 0 ° C. and stirred for 30 minutes. The reaction solution was quenched with 1N hydrochloric acid, neutralized with saturated aqueous sodium hydrogen carbonate, and further added with water (2%).
00 ml) and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate), and then distilled off under reduced pressure to obtain the desired product (4.4).
0 g, 100%). ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, t, J = 7.2 Hz), 2.84-3.0
2 (4H, m), 3.80-4.00 (2H, m), 4.96-5.04 (1H, m),
6.84-6.90 (2H, m), 6.96-7.10 (3H, m), 7.30-7.40 (2
H, m). IRν max ^KBr cm ^-1 : 1725, 1607, 1510. Anal. Calcd for C ₂₀ H ₁₇ O ₅ F ₅ : C, 55.56; H, 3.96 Found: C, 55.33; H, 3.97.5) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-
Yl) methyl] propanoic acid (2RS, 3RS) -3- (4-fluorophenyl) -3-
Hydroxy-2-[(2,2,3,3-tetrafluoro-
2,3-dihydro-1,4-benzodioxin-6-yl)
To a solution of ethyl [methyl] propanoate (4.20 g, 9.71 mmol) in methanol (20 ml) was added a 2N aqueous sodium hydroxide solution (9.7 ml, 19.4 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, acidified with 1N hydrochloric acid, and extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the desired product (3.50).
g, 89%). ¹ H-NMR (CDCl ₃ ) δ: 2.84-3.10 (3H, m), 5.08 (1H, s),
6.80-6.92 (2H, m), 6.92-7.12 (3H, m), 7.26-7.42 (2
.. H, m) IRν max KBr cm -1: 1752, 1676. mp 90-91 ℃ Anal Calcd for C 18 H 13 O 5 F 5: C, 53.48; H, 3.24 Found: C, 53.48; H, 3.18 .6) (4RS, 5SR) -5- (4-fluorophenyl) -4-[(2,2,3,3-tetrafluoro-2,3-
Dihydro-1,4-benzodioxin-6-yl) methyl]
-1,3-oxazolidine-2-one (2RS, 3RS) -3- (4-fluorophenyl) -3-
Hydroxy-2-[(2,2,3,3-tetrafluoro-
2,3-dihydro-1,4-benzodioxin-6-yl)
To a solution of [methyl] propanoic acid (3.3 g, 8.16 mmol) in tetrahydrofuran (120 ml) was added diphenylphosphoryl azide (1.94 ml, 8.98 mmol).
And triethylamine (1.71 ml, 12.2 mmol) were added, and the mixture was heated under reflux for 1 hour. After allowing the reaction solution to cool, it was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to obtain the desired product (2.74 g, 84%). ¹ H-NMR (CDCl ₃ ) δ: 2.20-2.40 (2H, m), 4.18-4.30 (1H,
m), 5.28 (1H, brs), 5.79 (1H, d, J = 8.2 Hz), 6.77
(1H, s), 6.81 (1H, d, J = 8.8 Hz), 7.00-7.20 (3H,
m), 7.20-7.40 (2H, m) .IRν max ^KBr cm ^-1 : 1751, 1736, 1611, 1513.mp 191-192 ° C Anal.Calcd for C ₁₈ H ₁₂ F ₅ NO ₄ : C, 53.88; H , 3.01; N,
3.49 Found: C, 54.06; H, 3.22; N, 3.60.7) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (2,2,3,3-tetrafluoro-
2,3-dihydro-1,4-benzodioxin-6-yl)
Propan-1-ol (4RS, 5SR) -5- (4-fluorophenyl) -4-
[(2,2,3,3-tetrafluoro-2,3-dihydro-
1,4-benzodioxin-6-yl) methyl] -1,3-
To a solution of oxazolidin-2-one (1.50 g, 3.74 mmol) in ethanol (10 ml) was added an 8 N aqueous sodium hydroxide solution (1.40 ml, 11.2 mmol), and the mixture was stirred at 80 ° C. overnight. Water (20 ml) in the reaction solution
And extracted with ethyl acetate (50 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain the desired product (0.81 g, 58%). ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.60 (2H, br), 2.36 (1H, dd,
J = 14.0, 10.2 Hz), 2.80 (1H, dd, J = 14.0, 2.8 H
z), 3.18-3.30 (1H, m), 4.62 (1H, d, J = 5.2 Hz),
6.90-7.00 (2H, m), 7.00-7.14 (3H, m), 7.30-7.42 (2
H, m) .IRν max ^KBr cm ^-1 : 1605, 1508, 1279, 1219.mp 87-88 ℃ Anal. Calcd for C ₁₇ H ₁₄ F ₅ NO ₃ : C, 54.41; H, 3.76; N,
3.73 Found: C, 54.40; H, 3.66; N, 3.66.8) N-{(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-[(2,2,3,3 -Tetrafluoro-2,3-dihydro-1,4-benzodioxin-
6-yl) methyl] ethyl} -6,7-dihydro-5H-benzo [a] [7] annulene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (2,2,3,3-tetrafluoro-2,3-
Dihydro-1,4-benzodioxin-6-yl) propane
To a solution of -1-ol (250 mg, 0.67 mmol) in acetonitrile (20 ml) was added 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (125 ml).
g, 0.67 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (191)
mg, 1.00 mmol) and 1-hydroxybenzotriazole hydrate (102 mg, 0.67 mmol)
Was added and stirred at room temperature overnight. The reaction solution was washed with water (100 m
1) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate),
Recrystallization from ethyl acetate-hexane gave the desired product (25
7 mg, 69%). ¹ H-NMR (CDCl ₃ ) δ: 1.90-2.10 (2H, m), 2.12-2.26 (2H,
m), 2.60-2.74 (2H, m), 2.79 (1H, dd, J = 14.6, 10.2
Hz), 2.95 (1H, dd, J = 14.6, 4.4 Hz), 3.35 (1H, d,
J = 3.8 Hz), 4.50-4.70 (1H, m), 4.98-5.08 (1H,
m), 5.78 (1H, d, J = 8.8 Hz), 5.84-6.00 (1H, m), 6.
19 (1H, d, J = 11.6 Hz), 6.90-7.20 (8H, m), 7.38-
7.50 (2H, m) .IRν max ^KBr cm ^-1 : 1636, 1607, 1510.mp 184-185 ° C Anal.Calcd for C ₂₉ H ₂₄ NO ₄ F ₅ : C, 63.85; H, 4.43; N,
2.57 Found: C, 63.79; H, 4.70; N, 2.64.

Example 271 4-Fluoro-N-｛(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-[(2,2,3,3-
Tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] ethyl} -1-naphthamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- ( 2,2,3,3-tetrafluoro-2,3-
Dihydro-1,4-benzodioxin-6-yl) propane
To a solution of -1-ol (250 mg, 0.67 mmol) in acetonitrile (20 ml) was added 4-fluoronaphthalenecarboxylic acid (127 mg, 0.67 mmol) and 1-ol.
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (191 mg, 1.00 mmol) and 1-hydroxybenzotriazole hydrate (102 m
g, 0.67 mmol) and stirred at room temperature overnight.
The reaction solution was diluted with water (100 ml), and ethyl acetate (10 ml) was added.
0 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to obtain the desired product (290 mg, 80%). ¹ H-NMR (CDCl ₃ ) δ: 2.84 (1H, dd, J = 14.6, 10.6 Hz),
3.02 (1H, dd, J = 14.6, 4.0 Hz), 3.27 (1H, s), 4.6
4-4.82 (1H, m), 5.09 (1H, s), 6.04 (1H, d, J = 9.0
Hz), 6.90-7.22 (7H, m), 7.36-7.66 (4H, m), 7.77 (1
H, d, J = 8.0 Hz), 8.01 (1H, d, J = 8.2 Hz) .IRν max ^KBr cm ^-1 : 1642, 1626, 1603, 1534, 1512.mp 193-194 ℃ Anal. Calcd for C ₂₈ H ₁₉ NO ₄ F ₆ : C, 61.43; H, 3.50; N,
2.56 Found: C, 61.32; H, 3.57; N, 2.58.

Example 272 N-[(1RS, 2SR) -1- (4-tert-butylbenzyl) -2- (3-chlorophenyl) -2-hydroxyethyl] -6,7-dihydro-5H-benzo [ a] [7] Annulene-1-carboxamide 1) Ethyl 2- (4-tert-butylbenzyl) -3- (3-chlorophenyl) -3-oxopropanoate (4-tert-butylphenyl) methanol (14.1)
g, 86.0 mmol) in acetic acid (200 ml) in methanesulfonyl chloride (7.47 ml, 94.6 mmol) and triethylamine (18.0 ml, 128.0 mmol).
9 mmol) and stirred at room temperature for 2 hours. The insolubles were filtered, and the filtrate was distilled off under reduced pressure to prepare a mesyl compound. 3-
To a solution of ethyl (3-chlorophenyl) -3-oxopropanoate (19.5 g, 86.0 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (3.
44 g, 60% oily, 86.0 mmol) and stirred at room temperature for 1 hour. The 1,2-dimethoxyethane (10 ml) solution of the previously prepared mesyl compound was added dropwise to the reaction solution,
The reaction was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (300 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
4: 1) to give the desired product (31.1 g, 97%). ¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7.0 Hz), 1.28 (9
H, s), 3.29 (2H, d, J = 7.4 Hz), 4.11 (2H, q, J =
7.0 Hz), 4.54 (1H, t, J = 7.4 Hz), 7.08-7.18 (2H,
m), 7.22-7.44 (3H, m), 7.48-7.56 (1H, m), 7.81 (1
H, dt, J = 7.6, 1.6 Hz), 7.89 (1H, t, J = 1.8 Hz) .IRν max ^KBr cm ^-1 : 1738, 1694, 1570. Anal.Calcd for C ₂₂ H ₂₅ ClO ₃ 0.1H ₂ O: C, 70.53; H, 6.
77 Found: C, 70.38; H, 7.02.2) Ethyl (2RS, 3RS) -2- (4-tert-butylbenzyl) -3- (3-chlorophenyl) -3-hydroxypropanoate Zinc chloride (22.3 g) , 163.6 mmol) in diethyl ether (500 ml) was added with sodium borohydride (12.4 g, 327.2 mmol) and stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was 2- (4-te)
rt-butylbenzyl) -3- (3-chlorophenyl) -3-
A solution of ethyl oxopropanoate (30.5 g, 81.8 mmol) in diethyl ether (200 ml) was added at 0 ° C., and the mixture was stirred for 30 minutes. 1N hydrochloric acid was added to the reaction solution to stop the reaction, water (200 ml) was further added, and the mixture was extracted with ethyl acetate (200 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure to obtain the desired product (26.8 g, 87%). ¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 7.0 Hz), 1.27 (9
H, s), 2.80-3.00 (3H, m), 3.14 (1H, d, J = 3.0 H
z), 3.80-4.00 (2H, m), 4.96-5.04 (1H, m), 7.01 (2H,
. d, J = 8.4 Hz) , 7.18-7.30 (5H, m), 7.41 (1H, s) IRν max KBr cm -1:. 1728, 1713, 1597, 1574. Anal Calcd for C 22 H 27 ClO 3 0.5 _{H 2 O: C, 68.83;} H, 7.
34 Found: C, 68.71; H, 7.32. 3) (2RS, 3RS) -2- (4-tert-butylbenzyl) -3- (3-chlorophenyl) -3-hydroxypropanoic acid (2RS, 3RS) -2 To a solution of ethyl 2- (4-tert-butylbenzyl) -3- (3-chlorophenyl) -3-hydroxypropanoate (26.5 g, 70.7 mmol) in methanol (200 ml) was added a 2N aqueous sodium hydroxide solution (70 ml, 140 mmol) and stirred overnight at room temperature. The reaction solution was concentrated, acidified with 1N hydrochloric acid, and extracted with ethyl acetate (500 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain the desired product (15.0 g, 59%). ¹ H-NMR (CDCl ₃ ) δ: 1.28 (9H, s), 2.80-3.10 (3H, m),
5.08 (1H, d, J = 4.0 Hz), 7.00 (2H, d, J = 8.4 H
. z), 7.20-7.30 (5H, m), 7.41 (1H, s) IRν max KBr cm -1: 1713, 1599, 1576. mp 117-118 ℃ Anal Calcd for C 20 H 23 ClO 3:. C, 69.26; H, 6.68 Found: C, 69.18; H, 6.68. 4) (4RS, 5SR) -4- (4-tert-butylbenzyl) -5- (3-chlorophenyl) -1,3-oxazolidine-2- Diphenyl was added to a solution of (2RS, 3RS) -2- (4-tert-butylbenzyl) -3- (3-chlorophenyl) -3-hydroxypropanoic acid (14.5 g, 40.6 mmol) in tetrahydrofuran (400 ml). Phosphoryl azide (9.63 ml, 44.7 mmol) and triethylamine (8.50 ml, 60.9 mmol) were added and 1
Heated to reflux for an hour. After allowing the reaction solution to cool, it was evaporated under reduced pressure. Water (500 ml) was added to the residue, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was washed with ethyl acetate, and the desired product (9.6 g,
69%). ¹ H-NMR (CDCl ₃ ) δ: 1.29 (9H, s), 2.04-2.36 (2H, m),
4.16-4.30 (1H, m), 5.03 (1H, brs), 5.76 (1H, d, J =
7.6 Hz), 6.96 (2H, d, J = 8.4 Hz), 7.24-7.40 (6H,
m) .IRν max ^KBr cm ^-1 : 1734.mp 215-216 ° C Anal.Calcd for C ₂₀ H ₂₂ Cl NO ₂ : C, 69.86; H, 6.45;
N, 4.07 Found: C, 69.65; H, 6.46; N, 4.10. 5) (1RS, 2SR) -2-amino-3- (4-ter
t-butylphenyl) -1- (3-chlorophenyl) propan-1-ol (4RS, 5SR) -4- (4-tert-butylbenzyl) -5- (3-chlorophenyl) -1,3-oxazolidine-2 To a solution of -one (9.50 g, 27.6 mmol) in ethanol (70 ml) was added an 8N aqueous sodium hydroxide solution (17.3 ml, 138 mmol), and the mixture was stirred at 80 ° C overnight. Water (20 ml) was added to the reaction solution, and extracted with ethyl acetate (50 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure to obtain the desired product (8.82 g, 100%). ¹ H-NMR (CDCl ₃ ) δ: 1.30 (9H, s), 2.31 (1H, dd, J = 1
4.0, 10.6 Hz), 2.73 (1H, dd, J = 14.0, 3.4 Hz), 3.
22-3.34 (1H, m), 4.67 (1H, d, J = 4.8 Hz), 7.05 (2
H, d, J = 8.0 Hz), 7.24-7.36 (5H, m), 7.42 (1H,
s). IRν max ^KBr cm ^-1 : 1597, 1574, 1512, 1474. 6) N-[(1RS, 2SR) -1- (4-tert-butylbenzyl) -2- (3-chlorophenyl) -2- Hydroxyethyl] -6,7-dihydro-5H-benzo [a]
[7] Annulene-1-carboxamide (1RS, 2SR) -2-amino-3- (4-tert-butylphenyl) -1- (3-chlorophenyl) propane-1-
To a solution of all (355 mg, 1.17 mmol) in acetonitrile (20 ml) was added 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (220 mg,
1.17 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (336 m
g, 1.76 mmol) and 1-hydroxybenzotriazole hydrate (179 mg, 1.17 mmol) were added and stirred at room temperature overnight. The reaction solution was water (100 ml)
And extracted with ethyl acetate (100 ml × 2).
The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4:
1-2: 1) and recrystallized from ethyl acetate-hexane to give the desired product (348 mg, 64%). ¹ H-NMR (CDCl ₃ ) δ: 1.30 (9H, s), 1.90-2.08 (2H, m),
2.10-2.24 (2H, m), 2.60-2.78 (3H, m), 2.96 (1H, d
d, J = 14.4, 4.8 Hz), 4.35 (1H, d, J = 4.4 Hz), 4.
60-4.76 (1H, m), 4.98-5.06 (1H, m), 5.67 (1H, d, J
= 7.8 Hz), 5.88-6.02 (1H, m), 6.28 (1H, d, J = 1
1.8 Hz), 6.88 (1H, dd, J = 7.4, 1.4 Hz), 6.98-7.18
(4H, m), 7.20-7.38 (8H, m), 7.47 (1H, s) .IRν max ^KBr cm ^-1 : 1633, 1514.mp 142-143 ° C Anal.Calcd for C ₃₁ H ₃₄ Cl NO ₂ : C, 76.29; H, 7.02;
N, 2.87 Found: C, 76.19; H, 7.15; N, 2.83.

Example 273 N-[(1RS, 2SR) -1- (4-tert-butylbenzyl) -2- (3-chlorophenyl) -2-hydroxyethyl] -4-fluoro-1-naphthamide (1RS, 2SR) -2-Amino-3- (4-tert-butylphenyl) -1- (3-chlorophenyl) propane-1-
In a solution of all (355 mg, 1.17 mmol) in acetonitrile (20 ml), 4-fluoronaphthalenecarboxylic acid (223 mg, 1.17 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (336 mg) , 1.76 mmol) and 1-
Hydroxybenzotriazole hydrate (179 mg,
1.17 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
1 × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-2: 1) and recrystallized from ethyl acetate-hexane to give the desired product (333 mg,
61%). ¹ H-NMR (CDCl ₃ ) δ: 2.74 (1H, dd, J = 14.4, 11.0 Hz),
3.02 (1H, dd, J = 14.4, 4.4 Hz), 4.15 (1H, d, J =
4.4 Hz), 4.70-4.86 (1H, m), 5.04-5.12 (1H, m), 5.8
5 (1H, d, J = 8.0 Hz), 6.90-7.20 (4H, m), 7.24-7.6
0 (8H, m), 7.89 (1H, d, J = 7.6 Hz), 8.07 (1H, d, J
= 8.0 Hz) IRν max ^KBr cm ^-1 : 1640, 1624, 1599, 1580, 1514.mp 144-145 ° C Anal.Calcd for C ₃₀ H ₂₉ Cl FNO ₂・ 0.1H ₂ O: C, 73.27; H,
5.98; N, 2.85 Found: C, 73.05; H, 5.74; N, 3.09.

Example 274 N-[(1RS, 2SR) -1- (4-tert-butylbenzyl) -2- (3-chlorophenyl) -2-hydroxyethyl] -5-chloro-1-naphthamide (1RS, 2SR) -2-Amino-3- (4-tert-butylphenyl) -1- (3-chlorophenyl) propane-1-
To a solution of all (1.0 g, 3.15 mmol) in acetonitrile (40 ml) was added 5-chloronaphthalenecarboxylic acid (651 mg, 3.15 mmol) and 1-ethyl-3.
-(3-Dimethylaminopropyl) carbodiimide hydrochloride (725 mg, 3.78 mmol) and 1-hydroxybenzotriazole hydrate (482 mg, 3.15)
Mmol) and stirred overnight at room temperature. The reaction solution was diluted with water (200 ml), and ethyl acetate (200 ml ×
Extracted in 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-1: 1) and recrystallized from ethyl acetate-hexane to give the desired product (1.04 g,
66%). ¹ H-NMR (CDCl ₃ ) δ: 1.31 (9H, s), 2.74 (1H, dd, J = 1
4.2, 11.0 Hz), 3.01 (1H, dd, J = 14.2, 4.4 Hz), 3.
98 (1H, d, J = 4.4 Hz), 4.70-4.88 (1H, m), 5.02-5.
10 (1H, m), 5.90 (1H, d, J = 8.0 Hz), 7.13 (2H, d,
J = 8.4 Hz), 7.22-7.60 (10H, m), 7.73 (1H, d, J =
. 8.8 Hz), 8.31 (1H , d, J = 8.4 Hz) IRν max KBr cm -1: 1636, 1572, 1518. mp 112-113 ℃ Anal Calcd for C 30 H 29 Cl 2 NO 2:. C, 71.15 ; H, 5.77;
N, 2.77 Found: C, 71.10; H, 5.83; N, 2.56.

Example 275 N-[(1RS, 2SR) -1- (4-tert-butylbenzyl) -2- (3-chlorophenyl) -2-hydroxyethyl] -5-fluoro-1-naphthamide (1RS, 2SR) -2-Amino-3- (4-tert-butylphenyl) -1- (3-chlorophenyl) propane-1-
In a solution of all (300 mg, 0.94 mmol) in acetonitrile (20 ml), 5-fluoronaphthalenecarboxylic acid (180 mg, 0.94 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (217 mg) , 1.13 mmol) and 1-
Hydroxybenzotriazole hydrate (145 mg,
0.94 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
1 × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and recrystallized from ethyl acetate-hexane to give the desired product (0.24 g, 53%).
I got ¹ H-NMR (CDCl ₃ ) δ: 1.31 (9H, s), 2.74 (1H, dd, J = 1
4.2, 10.6 Hz), 3.01 (1H, dd, J = 14.2, 4.4 Hz), 4.
02 (1H, s), 4.70-4.88 (1H, m), 5.07 (1H, t, J = 4.0
Hz), 5.89 (1H, d, J = 7.0 Hz), 7.04-7.20 (4H, m),
7.22-7.44 (7H, m), 7.50 (1H, s), 7.60 (1H, d, J =
. 8.4 Hz), 8.12 (1H , d, J = 8.4 Hz) IRν max KBr cm -1: 1636, 1595, 1584, 1520, 1507. mp 102-103 ℃ Anal Calcd for C 30 H 29 ClFNO 2:. C , 72.47; H, 6.04;
N, 2.82 Found: C, 72.47; H, 6.23; N, 2.60.

Example 276 1) 2- (4-tert-butoxylbenzyl) -3-
Ethyl (3-chlorophenyl) -3-oxopropanoate (4-tert-butoxyphenyl) methanol (5.0
g, 27.7 mmol) in acetic acid (70 ml) in methanesulfonyl chloride (2.36 ml, 30.5 mmol) and triethylamine (5.8 ml, 41.6).
Mmol) and stirred at room temperature for 2 hours. The insolubles were filtered, and the filtrate was distilled off under reduced pressure to prepare a mesyl compound. 3- (3-
Ethyl chlorophenyl) -3-oxopropanoate (6.2
9g, 27.7 mmol) in 1,2-dimethoxyethane (50 ml).
(0% oily, 27.7 mmol) and stirred at room temperature for 1 hour. The 1,2-dimethoxyethane (10 ml) solution of the mesyl compound previously prepared was added dropwise to the reaction solution, and the reaction solution was stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (300 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product (8.26 g, 77%, crude). 2) Ethyl (2RS, 3RS) -2- (4-tert-butoxylbenzyl) -3- (3-chlorophenyl) -3-hydroxypropanoate Diethyl ether of zinc chloride (5.79 g, 42.5 mmol) Sodium borohydride (3.22 g, 85.0 mmol) was added to the solution at room temperature for 30 minutes.
Minutes. The insolubles were removed by filtration, and the filtrate was treated with 2- (4-tert-
-Butoxylbenzyl) -3- (3-chlorophenyl) -3-
A solution of ethyl oxopropanoate (8.26 g, 21.2 mmol) in diethyl ether (100 ml) was added at 0 ° C., and the mixture was stirred for 30 minutes. 1N hydrochloric acid was added to the reaction solution to stop the reaction, water (200 ml) was further added, and the mixture was extracted with ethyl acetate (200 ml × 2). The extract was washed with water and brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-2: 1) to give the desired product (7.12 g, 86%). ¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.0 Hz), 1.30 (9
H, s), 2.80-3.00 (3H, m), 3.12-3.22 (1H, m), 3.89
(2H, q, J = 7.0 Hz), 5.01 (1H, s), 6.80-6.88 (2H,
m), 6.92-7.00 (2H, m), 7.20-7.30 (3H, m), 7.42 (1
H, s). IRν max ^KBr cm ^-1 : 1726, 1609, 1597, 1574, 1507.3. (3) (2RS, 3RS) -2- (4-tert-butoxylbenzyl) -3- (3-chlorophenyl)- Ethyl 3-hydroxypropanoate (2RS, 3RS) -2- (4-tert-butoxylbenzyl) -3- (3-chlorophenyl) -3-hydroxypropanoate (7.12 g, 18.2 mmol) in methanol ( 2N aqueous sodium hydroxide solution (18.2 ml, 36.4 mmol) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, acidified with 1N hydrochloric acid, and extracted with ethyl acetate (200 ml × 2).
The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Ethyl acetate-residue
Recrystallization from hexane gave the desired product (4.70 g, 82
%). ¹ H-NMR (CDCl ₃ ) δ: 1.29 (9H, s), 2.80-3.02 (3H, m),
5.06 (1H, d, J = 4.4 Hz), 6.80-6.90 (2H, m), 6.90-
7.02 (2H, m), 7.20-7.30 (3H, m), 7.42 (1H, s). IRν max ^KBr cm ^-1 : 1713, 1705. mp 81-82 ° C 4) (4RS, 5SR) -4- 4-tert-butoxylbenzyl) -5- (3-chlorophenyl) -1,3-oxazolidin-2-one (2RS, 3RS) -2- (4-tert-butoxylbenzyl) -3- (3-chlorophenyl In a solution of) -3-hydroxypropanoic acid (4.50 g, 14.3 mmol) in tetrahydrofuran (150 ml), diphenylphosphoryl azide (3.39 ml, 15.7 mmol) and triethylamine (3.00 ml, 21.4 mmol). And add
The mixture was refluxed for 1 hour. After allowing the reaction solution to cool, it was evaporated under reduced pressure.
Water (200 ml) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Hexane residue
-Recrystallized from ethyl acetate to give the desired product (4.01 g, 80%)
I got ¹ H-NMR (CDCl ₃ ) δ: 1.32 (9H, s), 2.18 (1H, dd, J = 1
3.8, 11.1 Hz), 2.28 (1H, dd, J = 13.8, 3.9 Hz), 4.
18-4.28 (1H, m), 4.95 (1H, s), 5.76 (1H, d, J = 7.8
Hz), 6.90-6.98 (2H, m), 7.24-7.30 (2H, m), 7.30-
7.40 (4H, m) .IRν max ^KBr cm ^-1 : 1734, 1507, 1476, 1435, 1391, 136
4.mp 165-166 ℃ Anal. Calcd for C ₂₀ H ₂₂ NO ₃ Cl: C, 66.75; H, 6.16; N,
3.89 Found: C, 66.65; H, 6.26; N, 3.69.5) (1RS, 2SR) -2-amino-3- (4-ter
t-butoxylphenyl) -1- (3-chlorophenyl) propan-1-ol (4RS, 5SR) -4- (4-tert-butoxylbenzyl) -5- (3-chlorophenyl) -1,3-oxazolidine To a solution of -2-one (3.80 g, 10.6 mmol) in ethanol (20 ml) was added an 8 N aqueous sodium hydroxide solution (3.96 ml, 31.7 mmol), and the mixture was heated at 80 ° C.
For 6 hours. Water (20 ml) was added to the reaction solution,
Extracted with ethyl acetate (50 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the desired product (2.67 g, 76%). ¹ H-NMR (CDCl ₃ ) δ: 1.32 (9H, s), 2.30 (1H, dd, J = 1
3.8, 10.4 Hz), 2.70 (1H, dd, J = 13.8, 3.4 Hz), 3.
22-3.34 (1H, m), 4.67 (1H, d, J = 4.8 Hz), 6.86-6.
96 (2H, m), 6.96-7.06 (2H, m), 7.20-7.34 (3H, m),
7.42 (1H, s) .IRν max ^KBr cm ^-1 : 1574,1507,1476,1366.mp 93-94 ° C Anal.Calcd for C ₁₉ H ₂₄ NO ₂ Cl: C, 68.35; H, 7.25; N,
4.20 Found: C, 68.21; H, 7.28; N, 4.18.6) N-[(1RS, 2SR) -1- (4-tert-butoxylbenzyl) -2- (3-chlorophenyl) -2-hydroxyethyl ] -6,7-Dihydro-5H-benzo [a]
[7] Annulene-1-carboxamide (1RS, 2SR) -2-amino-3- (4-tert-butoxylphenyl) -1- (3-chlorophenyl) propane-
To a solution of 1-ol (300 mg, 0.90 mmol) in acetonitrile (20 ml) was added 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (169 m
g, 0.90 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (258
mg, 1.35 mmol) and 1-hydroxybenzotriazole hydrate (138 mg, 0.90 mmol)
Was added and stirred at room temperature overnight. The reaction solution was washed with water (100 m
1) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
4: 1-2: 1) and recrystallized from ethyl acetate-hexane to give the desired product (351 mg, 77%). ¹ H-NMR (CDCl ₃ ) δ: 1.32 (9H, s), 1.90-2.08 (2H, m),
2.12-2.24 (2H, m), 2.60-2.76 (3H, m), 2.94 (1H, d
d, J = 14.6, 4.4 Hz), 4.32 (1H, d, J = 4.0 Hz), 4.
58-4.72 (1H, m), 5.00-5.08 (1H, m), 5.73 (1H, d, J
= 7.6 Hz), 5.92-6.08 (1H, m), 6.33 (1H, d, J = 1
2.0 Hz), 6.88-7.20 (7H, m), 7.24-7.36 (3H, m), 7.4
7 (1H, s) .IRν max ^KBr cm ^-1 : 1640, 1507.mp 180-181 ° C Anal.Calcd for C ₃₁ H ₃₄ NO ₃ Cl: C, 73.87; H, 6.80; N,
2.78 Found: C, 73.62; H, 6.81; N, 2.85.

Example 277 N-[(1RS, 2SR) -1- (4-tert-butoxylbenzyl) -2- (3-chlorophenyl) -2-hydroxyethyl] -4-fluoro-1-naphthamide (1RS , 2SR) -2-Amino-3- (4-tert-butoxylphenyl) -1- (3-chlorophenyl) propane-
To a solution of 1-ol (300 mg, 0.90 mmol) in acetonitrile (20 ml) was added 4-fluoronaphthalenecarboxylic acid (171 mg, 0.90 mmol) and 1-ol.
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (258 mg, 1.35 mmol) and 1-hydroxybenzotriazole hydrate (138 m
g, 0.90 mmol) and stirred at room temperature overnight.
The reaction solution was diluted with water (100 ml), and ethyl acetate (10 ml) was added.
0 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-2: 1) and recrystallized from ethyl acetate-hexane to give the desired product (278 m
g, 61%). ¹ H-NMR (CDCl ₃ ) δ: 1.32 (9H, s), 2.73 (1H, dd, J = 1
4.6, 11.0 Hz), 3.01 (1H, dd, J = 14.6, 4.4 Hz), 4.
13 (1H, d, J = 4.0 Hz), 4.66-4.82 (1H, m), 5.10 (1
H, s), 5.87 (1H, d, J = 8.6 Hz), 6.90-7.02 (3H,
m), 7.04-7.16 (3H, m), 7.26-7.38 (3H, m), 7.44-7.60
(3H, m), 7.95 (1H, d, J = 7.6 Hz), 8.02-8.10 (1H,
^{.. m) IRν max KBr cm} -1: 1640, 1626, 1599, 1582, 1507. mp 161-162 ℃ Anal Calcd for C 30 H 29 NO 3 ClF: C, 71.21; H, 5.78;
N, 2.77 Found: C 71.10; H, 5.94; N, 2.53.

Example 278 N-[(1RS, 2SR) -1- (4-tert-butoxylbenzyl) -2- (3-chlorophenyl) -2-hydroxyethyl] -5-chloro-1-naphthamide (1RS , 2SR) -2-Amino-3- (4-tert-butoxylphenyl) -1- (3-chlorophenyl) propane-
In a solution of 1-ol (300 mg, 0.90 mmol) in acetonitrile (20 ml), 5-chloronaphthalenecarboxylic acid (186 mg, 0.90 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (258 mg, 1.35 mmol) and 1
-Hydroxybenzotriazole hydrate (138 mg,
(0.90 mmol) and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml), and ethyl acetate (100 ml) was added.
1 × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-2: 1) and recrystallized from ethyl acetate-hexane to give the desired product (136 mg,
29%). ¹ H-NMR (CDCl ₃ ) δ: 1.32 (9H, s), 2.72 (1H, dd, J = 1
4.4, 11.0 Hz), 3.00 (1H, dd, J = 14.4, 4.0 Hz), 3.
96 (1H, d, J = 3.6 Hz), 4.70-4.84 (1H, m), 5.09 (1
H, s), 5.90 (1H, d, J = 8.2 Hz), 6.93 (2H, d, J =
8.4 Hz), 7.10 (2H, d, J = 8.4 Hz), 7.14-7.62 (8H,
m), 7.78 (1H, d, J = 8.4 Hz), 8.32 (1H, d, J = 8.4
Hz) .IRν max ^KBr cm ^-1 : 1638, 1572, 1507.mp 132-133 ℃ Anal. Calcd for C ₃₀ H ₂₉ NO ₃ Cl ₂ : C, 68.97; H, 5.59;
N, 2.68 Found: C, 68.68; H, 5.69; N, 2.53.

Example 279 (1RS, 2SR) -2- (4-fluorophenyl) -2-
Tert-butyl hydroxy-1- {3-[(trifluoromethyl) sulfonyl] benzyl} ethylcarbamate 1) (4RS, 5SR) -5- (4-fluorophenyl) -2-oxo-4- {3- [ Tert-Butyl (trifluoromethyl) thio] benzyl} -1,3-oxazolidine-3-carboxylate (4RS, 5RS) -5- (4-fluorophenyl) -4-
{3-[(trifluoromethyl) thio] benzyl} -1,
To a solution of 3-oxazolidine-2-one (2.06 g, 5.55 mmol) in acetonitrile (20 ml) was added dicarbonate.
-tert-butyl (1.45 g, 6.66 mmol) and 4-N, N-dimethylpyridine (68 mg, 0.56
Mmol) and stirred at room temperature for 1 hour. Water (100 ml) was added to the reaction solution, and ethyl acetate (100 ml × 2) was added.
Extracted. The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-1: 1) and recrystallized from ethyl acetate-hexane to obtain the desired product (2.17 g, 83%). ¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s), 2.62 (1H, dd, J = 1
4.4, 9.0 Hz), 2.96 (1H, dd, J = 14.4, 4.0 Hz), 4.76
-4.88 (1H, m), 5.67 (1H, d, J = 6.8 Hz), 6.73 (1H,
d, J = 7.8 Hz), 6.82-7.00 (3H, m), 7.04-7.20 (3H,
m), 7.39 (1H, d, J = 7.8 Hz) .IRν max ^KBr cm ^-1 : 1823, 1725, 1611, 1597, 1514.mp 112-113 ℃ Anal.Calcd for C ₂₂ H ₂₁ NO ₄ SF ₄ : C, 56.05; H, 4.49;
N, 2.97 Found: C, 56.08; H, 4.56; N, 2.98.2) (4RS, 5SR) -5- (4-fluorophenyl) -2-oxo-4- {3-[(trifluoromethyl) sulfonyl Tert-Butyl benzyl} -1,3-oxazolidine-3-carboxylate (4RS, 5SR) -5- (4-fluorophenyl) -2-
Oxo-4- {3-[(trifluoromethyl) thio] benzyl} -1,3-oxazolidine-3-carboxylic acid tert
To a solution of -butyl (1.0 g, 2.12 mmol) in acetonitrile (100 ml) was added sodium periodate (1.
36 g, 6.36 mmol) of an aqueous solution (50 ml) was added. After stirring the reaction solution for 10 minutes, ruthenium chloride (41 m
g, 0.21 mmol) and stirred overnight. After concentrating the reaction solution, water (100 ml) was added and ethyl acetate (20 ml) was added.
0 ml × 2). The extract was washed with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane,
The desired product (0.93 g, 87%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s), 2.76 (1H, dd, J = 1
4.6, 9.2 Hz), 3.03 (1H, dd, J = 14.6, 4.0 Hz), 4.78
-4.92 (1H, m), 5.70 (1H, d, J = 6.8 Hz), 6.90-7.20
(5H, m), 7.30-7.44 (2H, m), 7.79 (1H, d, J = 8.2
Hz) .IRν max ^KBr cm ^-1 : 1817, 1725, 1611, 1514.mp 158-159 ℃ Anal. Calcd for C ₂₂ H ₂₁ NO ₆ SF ₄ : C, 52.48; H, 4.20;
N, 2.78; F, 15.09; S, 6.37 Found: C, 52.51; H, 4.00; N, 2.55; F, 15.06; S,
6.40. 3) (1RS, 2SR) -2- (4-Fluorophenyl) -2-hydroxy-1- {3-[(trifluoromethyl) sulfonyl] benzyl} ethylcarbamic acid ter
t-butyl (4RS, 5SR) -5- (4-fluorophenyl) -2-
To a solution of tert-butyl oxo-4- {3-[(trifluoromethyl) sulfonyl] benzyl} -1,3-oxazolidine-3-carboxylate (0.90 g, 1.79 mmol) in methanol (10 ml) was added a solution of 0.1 g in methanol (10 ml). A methanol solution of 5N sodium hydroxide (10.8 ml, 5.40 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Water (50m
1) and extracted with ethyl acetate (100 ml × 2). The extract was washed with brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain the desired product (0.72 g, 84%). ¹ H-NMR (CDCl ₃ ) δ: 1.31 (9H, s), 2.74-3.00 (3H, m),
3.96-4.16 (1H, m), 4.69 (1H, d, J = 8.4 Hz), 4.95
(1H, s), 7.02-7.14 (2H, m), 7.32-7.44 (2H, m), 7.5
0-7.64 (2H, m), 7.77 (1H, s), 7.87 (1H, d, J = 6.6
Hz) .IRν max ^KBr cm ^-1 : 1694, 1510, 1368.mp 152-153 ℃ Anal. Calcd for C ₂₁ H ₂₃ NO ₅ SF ₄ : C, 52.83; H, 4.86;
N, 2.93 Found: C, 52.67; H, 4.74; N, 2.97.

Example 280 N-((1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- {3-[(trifluoromethyl) sulfonyl] benzyl} ethyl) -6,7-dihydro-5H-
Benzo [a] [7] annulene-1-carboxamide 1) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- {3-[(trifluoromethyl) sulfonyl] phenyl} propane- 1-ol (1RS, 2SR) -2- (4-fluorophenyl) -2-
Trifluoroacetic acid (5 ml) was added to tert-butyl hydroxy-1- {3-[(trifluoromethyl) sulfonyl] benzyl} ethylcarbamate (620 mg, 1.30 mmol), and the mixture was stirred at 0 ° C. for 10 minutes. After concentrating the reaction solution, saturated aqueous sodium hydrogen carbonate was added, and ethyl acetate (30 ml × 2) was added.
Extracted. The extract was washed with brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure to give the desired product (0.52 g,
100%). ¹ H-NMR (CDCl ₃ ) δ: 2.55 (1H, dd, J = 13.8, 9.9 Hz),
2.98 (1H, dd, J = 13.8,3.0 Hz), 3.22-3.36 (1H, m),
4.63 (1H, d, J = 5.1 Hz), 7.02-7.12 (2H, m), 7.30
-7.42 (2H, m), 7.52-7.70 (2H, m), 7.85 (1H, s), 7.
90 (1H, d, J = 8.4 Hz). IRν max ^KBr cm ^-1 : 1603, 1508, 1431, 1366. 2) N-((1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy -1- {3-[(Trifluoromethyl) sulfonyl] benzyl} ethyl) -6,7-dihydro
-5H-benzo [a] [7] annulene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- {3-[(trifluoromethyl) sulfonyl] phenyl} propane -1-ol (260 mg, 0.
6,7-dihydro-5H-benzo [a] cycloheptene-1 in a solution of 69 mmol) in acetonitrile (20 ml).
-Carboxylic acid (130 mg, 0.69 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (198 mg, 1.03 mmol) and 1-hydroxybenzotriazole hydrate (105 m
g, 0.69 mmol) and stirred at room temperature overnight.
The reaction solution was diluted with water (100 ml), and ethyl acetate (10 ml) was added.
0 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-2: 1) and recrystallized from ethyl acetate-hexane to give the desired product (252 m 2).
g, 67%). ¹ H-NMR (CDCl ₃ ) δ: 1.90-2.06 (2H, m), 2.12-2.26 (2H,
m), 2.60-2.70 (2H, m), 2.90-3.20 (3H, m), 4.60-4.80
(1H, m), 5.04 (1H, s), 5.82-5.98 (2H, m), 6.13 (1
H, d, J = 11.8 Hz), 6.95 (1H, dd, J = 7.4, 1.8 H
z), 7.00-7.20 (4H, m), 7.40-7.50 (2H, m), 7.52-7.6
4 (1H, m), 7.70 (1H, d, J = 7.6 Hz), 7.81 (1H, s),
7.89 (1H, d, J = 7.8 Hz) IRν max KBr cm -1: 1638, 1508, 1449, 1366. mp 156-157 ℃ Anal Calcd for C 28 H 25 NO 4 SF 4:.. C, 61.42; H , 4.60;
N, 2.56 Found: C, 61.25; H, 4.57; N, 2.57.

Example 281 4-Fluoro-N-((1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- {3-[(trifluoromethyl) sulfonyl] benzyl} ethyl)- 1-Naphthamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- {3-[(trifluoromethyl) sulfonyl] phenyl} propan-1-ol (260 mg, 0.
69 mmol) in acetonitrile (20 ml) solution.
-Fluoronaphthalenecarboxylic acid (131 mg, 0.6
9 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (198 mg, 1.
03 mmol) and 1-hydroxybenzotriazole hydrate (105 mg, 0.69 mmol) were added and stirred at room temperature overnight. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed successively with water and saturated saline, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1-
2: 1) and recrystallized from ethyl acetate-hexane to give the desired product (218 mg, 58%). ¹ H-NMR (CDCl ₃ ) δ: 2.84-3.20 (3H, m), 4.70-4.86 (1H,
m), 5.09 (1H, s), 6.10 (1H, d, J = 9.0 Hz), 6.96-7.
24 (4H, m), 7.40-7.62 (5H, m), 7.64-7.80 (2H, m),
7.84-7.94 (2H, m), 8.08 (1H, d, J = 7.6 Hz) IRν max KBr cm -1:.. 1642, 1626, 1601, 1514, 1369. mp 157-158 ℃ Anal Calcd for C 27 H ₂₀ NO ₄ SF ₅ : C, 59.01; H, 3.67;
N, 2.55 Found: C, 58.88; H, 3.64; N, 2.53.

Example 282 N-[(1RS, 2SR) -2- (4-fluorophenyl)
2-Hydroxy-1- (3-isopropoxybenzyl) ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 1) Ethyl 3-isopropyloxybenzoate Ethyl 3-hydroxybenzoate ( 15.2 g, 0.10
Mol) N, N-dimethylformamide (100 ml)
Add isopropyl bromide (12.1 ml, 0.13 mol) and sodium iodide (19.5 g, 0.13 mol) to the solution.
Was added and stirred at 70 ° C. for 15 hours. Add water (50
0 ml) and extracted with ethyl acetate (500, 200 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1) to give the desired product (12.4 g, 64%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.35 (6H, d, J = 6.2 Hz), 3.90 (3H,
s), 4.55-4.65 (1H, m), 7.07 (1H, dd, J = 8.2, 1.8 H
z), 7.33 (1H, t, J = 8.2 Hz), 7.50-7.70 (2H, m). 2) 3-isopropyloxybenzyl alcohol ethyl 3-isopropyloxybenzoate (12.0 g,
61.8 mmol) of tetrahydrofuran (100 m
1) Lithium aluminum hydride (3.
52 g, 92.7 mmol) were added in small portions. After stirring at room temperature for 1 hour, water (10 ml) was added under ice cooling to decompose. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to give the desired product (10.0 g, 9 g).
7%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (6H, d, J = 6.4 Hz), 4.50-
4.65 (1H, m), 4.66 (1H, d, J = 6.2 Hz), 6.78-6.90 (1
H, m), 6.90-7.00 (2H, m), 7.26 (1H, t, J = 8.2 Hz). 3) 3- (4-Fluorophenyl) -3-oxo-2- [3
-(Isopropyloxy) benzyl] ethyl propanoate 3-isopropyloxybenzyl alcohol (7.31
g, 44 mmol) in ethyl acetate (50 ml).
Under ice cooling, methanesulfonyl chloride (3.56 ml, 46 mmol) and triethylamine (6.69 ml, 48 mmol) were added, and the mixture was stirred at room temperature for 2.5 hours. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain mesylate. Ethyl 3- (4-fluorophenyl) -3-oxopropanoate (8.4
1 g, 40 mmol) of dimethoxyethane (50 ml)
To the solution was added sodium hydride (1.60 g, 60%
(Oily, 40 mmol) and stirred for 1 hour. A solution of the mesylate obtained above in dimethoxyethane (20 ml) was added dropwise thereto, and the mixture was stirred at room temperature for 10 hours. Water (2
00 ml) and extracted with ethyl acetate (200 ml). After washing the extract with water and drying over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1-5: 1) to obtain the desired product (12.5 g, 87%). IRνmax ^Neat cm ^-1 : 1736, 1688, 1599, 1508, 1258, 123
^{3, 1157. 1 H-NMR (} CDCl 3) δ: 1.13 (3H, t, J = 7.2 Hz), 1.30 (6
H, d, J = 6.2 Hz), 3.28 (2H, d, J = 7.4 Hz), 4.15 (2
H, q, J = 7.2 Hz), 4.57 (1H, d, J = 7.8 Hz), 4.40-
4.60 (1H, m), 6.60-6.80 (3H, m), 7.00-7.25 (3H, m),
7.90-8.10 (2H, m). 4) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- [3- (isopropyloxy)
Ethyl benzyl] propanoate To a suspension of anhydrous zinc chloride (9.12 g, 67.0 mmol) in diethyl ether (100 ml) was added sodium borohydride (5.07 g, 134 mmol) little by little and stirred for 2 hours. did. The insolubles were removed by filtration and washed with diethyl ether. The filtrate was ice-cooled, and ethyl 3- (4-fluorophenyl) -3-oxo-2- [3- (isopropyloxy) benzyl] propanoate (12.0 g, 33.0 g) was added.
(5 mmol) in diethyl ether (20 ml) was added. After stirring at room temperature for 2 hours, the mixture was ice-cooled again and the reaction was stopped with 1N hydrochloric acid. The mixture was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1) to give the desired product (10 g, 83%) as a colorless oil. ^{IRνmax Neat cm -1: 1728, 1603} , 1510, 1260, 1157. 1 H-NMR (CDCl 3) δ: 0.94 (3H, t, J = 7.2 Hz), 1.30 (6
H, d, J = 6.2 Hz), 2.80-3.00 (4H, m), 3.89 (2H, d, J
= 7.2 Hz), 4.40-4.60 (1H, m), 5.01 (1H, s), 6.58-6.
75 (3H, m), 6.98-7.20 (3H, m), 7.30-7.45 (2H, m). 5) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- [3 -(Isopropyloxy)
Benzyl] propanoic acid (2RS, 3RS) -3- (4-fluorophenyl) -3-
Ethyl hydroxy-2- [3- (isopropyloxy) benzyl] propanoate (9.8 g, 27.2 mmol)
2N aqueous sodium hydroxide solution (27.2 ml, 54.4 mmol) was added to a methanol (50 ml) solution and the mixture was stirred at room temperature for 3 hours. 6N hydrochloric acid (100m
l) to make it acidic, and then ethyl acetate (200, 10
0 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from hexane to give the desired product (7.44 g, 82%). mp 101-102 ℃ IRνmax ^KBr cm ^-1 : 1694, 1514, 1451, 1292, 1260, 1229,
. 1152, 1119. Anal Calcd for C 19 H 21 FO 4 (MW332.37) Calcd: C, 68.66; H, 6.37 Found: C, 68.52; H, 6.37 1 H-NMR (CDCl 3) δ: 1.29 (6H , d, J = 6.2 Hz), 2.80-3.
15 (3H, m), 4.40-4.60 (1H, m), 5.00-5.10 (1H, m), 6.5
5-6.80 (3H, m), 6.95-7.20 (3H, m), 7.30-7.45 (2H, m). 6) (4RS, 5SR) -5- (4-fluorophenyl) -4- [3- ( Isopropyloxy) benzyl] -1,
3-oxazolidine-2-one (2RS, 3RS) -3- (4-fluorophenyl) -3-
In a solution of hydroxy-2- [3- (isopropyloxy) benzyl] propanoic acid (7.14 g, 21.5 mmol) in tetrahydrofuran (100 ml), diphenylphosphoryl azide (6.0 ml, 27.9 mmol) and triethylamine (4 .19 ml, 30.1 mmol) and stirred at room temperature for 1 hour. After heating under reflux for 5 hours, the reaction solution was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate (100 ml).
And extracted with ethyl acetate (200 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1-2: 1) to obtain the desired product (14.7 g, 91%). mp 114-115 ° C IRνmax ^KBr cm ^-1 : 1738, 1582, 1514, 1385, 1248, 1227,
_{. 1157. Anal Calcd for C 19 H} 20 FNO 3 (MW329.36) Calcd: C, 69.29; H, 6.12; N, 4.25 Found:. C, 69.27; H, 6.16; N, 4.26 1 H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J = 6.0 Hz), 2.05-2.
35 (2H, m), 4.15-4.60 (1H, m), 4.96 (1H, brs), 5.78 (1
H, d, J = 7.6 Hz), 6.50-6.65 (2H, m), 6.70-6.80 (1H,
m), 7.00-7.25 (3H, m), 7.30-7.45 (2H, m). 7) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (isopropyloxy ) Phenyl] -1-propanol (4RS, 5SR) -5- (4-fluorophenyl) -4-
[3- (isopropyloxy) benzyl] -1,3-oxazolidine-2-one (5.85 g, 17.8 mmol)
To a solution of the above in ethanol (30 ml) was added an 8 N aqueous sodium hydroxide solution (8.9 ml, 71.0 mmol), and the mixture was refluxed for 5 hours. The reaction solution was concentrated under reduced pressure, and water (100
ml) and extracted with ethyl acetate (100 ml × 2). After washing the extract with water and drying over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue was crystallized from hexane-diethyl ether to obtain the desired product (5.0 g, 93%). mp 98-99 ℃ IRνmax ^KBr cm ^-1 : 3364, 1605, 1582, 1508, 1252, 1211,
. 1154, 1044. Anal Calcd for C 18 H 22 FNO 2 (MW303.37) Calcd: C, 71.26; H, 7.31; N, 4.62 Found:. C, 71.30; H, 7.46; N, 4.55 1 H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J = 6.0 Hz), 2.28 (1
H, dd, J = 13.6, 10.2 Hz), 2.73 (1H, dd, J = 13.6,
3.0 Hz), 3.20-3.40 (1H, m), 4.45-4.60 (1H, m), 4.67 (1
H, d, J = 4.8 Hz), 6.60-6.80 (3H, m), 7.00-7.45 (5H,
m). 8) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- (3-isopropoxybenzyl) ethyl] -6,7-dihydro-5H-benzo [a Cyclohepten-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (isopropyloxy) phenyl] -1
-Propanol (0.46 g, 1.5 mmol) and 6,
To a solution of 7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (0.34 g, 1.8 mmol) in acetonitrile (20 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide.hydrochloride Salt (0.36
g, 2.1 mmol) and 1-hydroxybenzotriazole hydrate (0.32 g, 2.1 mmol) were added and stirred at room temperature for 5 hours. Water (100 ml) was added to the reaction solution, and extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1) to give the desired product (0.5%).
(5 g, 77%) as crystals. ^{. mp 161-162 ℃ IRνmax KBr cm -1} : 3274, 1638, 1510, 1258, 1225, 833. Anal Calcd for C 30 H 32 FNO 3 (MW473.58) Calcd: C, 76.08; H, 6.81; N, 2.96 Found:. C, 76.10; H, 6.73; N, 2.89 1 H-NMR (CDCl 3) δ: 1.30 (6H, d, J = 6.0 Hz), 1.90-2.
10 (2H, m), 2.10-2.30 (2H, m), 2.60-2.80 (2H, m), 2.9
6 (1H, dd, J = 14.0, 4.4 Hz), 4.10 (1H, d, J = 4.4 H
z), 4.40-4.60 (1H, m), 4.60-4.80 (1H, m), 5.00-5.10
(1H, m), 5.66 (1H, d, J = 7.8 Hz), 5.90-6.00 (1H, m),
6.40 (1H, d, J = 11.8 Hz), 6.65-6.85 (3H, m), 6.95-
7.25 (7H, m), 7.35-7.50 (2H, m).

Example 283 4-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- (3-isopropoxybenzyl) ethyl] -1-naphthamide (1RS, 2SR) -2-Amino-1- (4-fluorophenyl) -3- [3- (isopropyloxy) phenyl] -1
-Propanol (0.46 g, 1.5 mmol) and 4-fluoronaphthalene-1-carboxylic acid (0.34 g, 1.8
Mmol) in acetonitrile (20 ml).
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.36 g, 2.1 mmol) and 1-hydroxybenzotriazole hydrate (0.32 g, 2.
(1 mmol) and stirred at room temperature for 5 hours. Water (100 ml) was added to the reaction solution, and ethyl acetate (100 ml ×
Extracted in 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel chromatography (chloroform: ethyl acetate = 10:
Purification in 1) gave the desired product (0.65 g, 91%) as crystals. mp 190-191 ° C IRνmax ^KBr cm ^-1 : 3281, 1640, 1624, 1539, 1514, 1256,
1229. Anal.Calcd for C ₂₉ H ₂₇ F ₂ NO ₃ (MW475.53) Calcd: C, 73.25; H, 5.72; N, 2.95 Found: C, 72.87; H, 5.57; N, 2.84. ¹ H-NMR (CDCl ₃ -DMSO-d ₆ (1drop)) δ: 1.26 (6H, d, J =
6.0 Hz), 2.70-3.00 (2H, m), 4.40- 4.60 (1H, m), 4.65-
4.85 (1H, m), 4.95-5.10 (2H, m), 6.70-6.85 (3H, m),
6.85-7.60 (10H, m), 7.74 (1H, d, J = 6.8 Hz), 8.06 (1
(H, d, J = 7.6 Hz).

Example 284 4-Fluoro-N-[(1RS, 2SR) -1- (3-ter
t-Butyloxybenzyl) ethyl] -2- (4-fluorophenyl) -2-hydroxy-1-naphthamide 1) Ethyl 3-tert-butyloxybenzoate Ethyl 3-hydroxybenzoate (20 g, 0.13 mol) Isobutene (about 30 g) and concentrated sulfuric acid (0.5 ml) were added to a dichloromethane (200 ml) solution and left for 2 days. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel chromatography (hexane: ethyl acetate = 10:
Purification in 1) gave the desired product (17.3 g, 63%) as an oil. _{^{1 H-NMR (CDCl 3)}} δ: 1.37 (9H, s, Bu t), 3.91 (3H, s),
7.15-7.25 (1H, m), 7.33 (1H, t, J = 7.9 Hz), 7.65-7.
70 (1H, m), 7.76 (1H, d, J = 7.9 Hz). 2) 3-tert-butyloxybenzyl alcohol ethyl 3-tert-butyloxybenzoate (16.7)
g, 80 mmol) of tetrahydrofuran (100 m
1) Lithium aluminum hydride (4.
55 g, 120 mmol) were added in small portions. 1 at room temperature
After stirring for an hour, water (10 ml) was added under ice cooling to decompose. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1-2: 1) to give the desired product (12.8).
g, 88%) as an oil. _{^{1 H-NMR (CDCl 3)}} δ: 1.35 (9H, s, Bu t), 4.66 (2H, d, H =
6.0 Hz), 6.93 (1H, m), 7.00 (1H, brs), 7.07 (1H, d, J
= 7.4 Hz), 7.25 (1H, t, J = 7.4 Hz). 3) 3- (4-Fluorophenyl) -2- [3- (ter
[tert-butyloxy) benzyl] ethyl 3-oxopropanoate 3-tert-butyloxybenzyl alcohol (10.
Methanesulfonyl chloride (4.88 ml, 63 mmol) in a solution of 8 g (60 mmol) in ethyl acetate (100 ml) under ice cooling.
Mmol) and triethylamine (9.2 ml, 66 mmol) were added and stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain mesylate. Ethyl 3- (4-fluorophenyl) -3-oxopropanoate (12.
6 g, 60 mmol) of dimethoxyethane (100 m
1) Add sodium hydride (2.4 g, 60
% Oily, 60 mmol) and stirred for 10 minutes. The dimethoxyethane of the mesylate obtained above (20 m
l) The solution was added dropwise and stirred at room temperature for 4 hours. Water (200 ml) was added to the reaction solution, and ethyl acetate (200 ml × 2) was added.
Extracted. The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1) to obtain the desired product (20.1 g, 90%). IRνmax ^Neat cm ^-1 : 1740, 1686, 1599, 1508, 1485, 136
^{6, 1233, 1152. 1 H-} NMR (CDCl 3) δ: 1.13 (3H, t, J = 7.0 Hz), 1.28 (9
^{H, s, Bu t),} 3.29 (2H, d, J = 7.4 Hz), 4.10 (2H, q,
J = 7.0 Hz), 4.56 (1H, t, J = 7.4 Hz), 6.67-6.90 (2
H, m), 6.95 (1H, d, J = 7.6 Hz), 7.05-7.20 (3H, m),
7.90-8.05 (2H, m). 4) (2RS, 3RS) -2- [3- (tert-butyloxy) benzyl] -3- (4-fluorophenyl) -3-
Ethyl hydroxypropanoate To a suspension of anhydrous zinc chloride (8.17 g, 60 mmol) in diethyl ether (100 ml) was added sodium borohydride (4.54 g, 120 mmol) little by little, and the mixture was stirred for 2 hours. The insolubles were removed by filtration and washed with diethyl ether. The filtrate was cooled on ice, and ethyl 3- (4-fluorophenyl) -2- [3- (tert-butyloxy) benzyl] -3-oxopropanoate (10.8 g, 30 mmol) in diethyl ether (20 ml) was added. The solution was added. After stirring at room temperature for 1 hour, the mixture was ice-cooled again and the reaction was stopped with water. The mixture was washed with a 5% aqueous solution of potassium hydrogen sulfate and water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1) to give the desired product (8.9 g,
79%) as a colorless oil. IRνmax ^Neat cm ^-1 : 1728, 1605, 1510, 1260, 1225, 117
^{9, 1154. 1 H-NMR (} CDCl 3) δ: 0.93 (3H, t, J = 7.2 Hz), 1.31 (9
^{H, s, Bu t),} 2.90-3.05 (3H, m), 3.87 (2H, d, J = 7.2
Hz), 4.95-5.10 (1H, m), 6.70-6.80 (1H, m), 6.80 (1H, m
d, J = 7.8 Hz), 7.00-7.20 (3H, m), 7.30-7.45 (2H,
m). 5) (4RS, 5SR) -4- [3- (tert-butyloxy) benzyl] -5- (4-fluorophenyl) -1,
Ethyl 3-oxazolidin-2-one (2RS, 3RS) -2- [3- (tert-butyloxy) benzyl] -3- (4-fluorophenyl) -3-hydroxypropanoate (8.8 g, 23.5 mmol) ) Was added to a methanol (100 ml) solution, and a 2N aqueous sodium hydroxide solution (23.5 ml, 47 mmol) was added thereto, followed by stirring at room temperature for 3 hours. The reaction solution was acidified by adding a 5% aqueous solution of potassium hydrogen sulfate (100 ml), and extracted with ethyl acetate (200 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from hexane to give (2RS, 3RS) -2- [3
-(Tert-Butyloxy) benzyl] -3- (4-fluorophenyl) -3-hydroxypropanoic acid was obtained. To a solution of the compound obtained above in tetrahydrofuran (150 ml) was added diphenylphosphoryl azide (6.57 ml, 30.6 ml).
Mmol) and triethylamine (4.59 ml, 32.
9 mmol) and stirred at room temperature for 1 hour. afterwards,
After heating under reflux for 2 hours, the reaction solution was concentrated under reduced pressure and water (20
0 ml) and extracted with ethyl acetate (200 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1-2: 1) to obtain the desired product (6.92 g, 86%). mp 131-132 ℃ IRνmax ^KBr cm ^-1 : 1742, 1603, 1514, 1364, 1240, 1223,
_{. 1148. Anal Calcd for C 20 H} 22 FNO 3 (MW343.40) Calcd: C, 69.95; H, 6.46; N, 4.08 Found:. C, 69.96; H, 6.38; N, 4.11 1 H-NMR (CDCl _{3) δ: 1.33 (9H,} s, Bu t), 2.10-2.40 (2H,
m), 4.15-4.30 (1H, m), 4.91 (1H, brs), 5.79 (1H, d, J
= 7.8 Hz), 6.60-6.80 (2H, m), 6.80-6.95 (1H, m), 7.05
-7.25 (3H, m), 7.30-7.50 (2H, m). 6) (1RS, 2SR) -2-amino-3- [3- (te
rt-butyloxy) phenyl] -1- (4-fluorophenyl) -1-propanol (4RS, 5SR) -4- [3- (tert-butyloxy) benzyl] -5- (4-fluorophenyl) -1,3 -
To a solution of oxazolidin-2-one (6.6 g, 19.2 mmol) in ethanol (30 ml) was added an 8 N aqueous sodium hydroxide solution (9.6 ml, 76.9 mmol), and the mixture was heated under reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and water (1
50 ml) and extracted with ethyl acetate (200 ml). After washing the extract with water and drying over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue was crystallized from hexane-diethyl ether to obtain the desired product (5.86 g, 96%). mp 132-133 ℃ IRνmax ^KBr cm ^-1 : 3362, 3295, 1601, 1582, 1507, 1485,
. 1363, 1208, 1152, 1036. Anal Calcd for C 19 H 24 FNO 2 (MW317.40) Calcd: C, 71.90; H, 7.62; N, 4.41 Found: C, 71.69; H, 7.65; N, 4.35. _{^{1 H-NMR (CDCl 3)}} δ: 1.33 (9H, s, Bu t), 2.29 (1H, dd, J
= 14.0, 10.2 Hz), 2.74 (1H, dd, J = 14.0, 3.0 Hz),
3.20-3.35 (1H, m), 4.66 (1H, d, J = 5.2 Hz), 6.75-6.
90 (3H, m), 7.70-7.25 (3H, m), 7.30-7.45 (2H, m). 7) 4-Fluoro-N-[(1RS, 2SR) -1- (3-
tert-butyloxybenzyl) ethyl] -2- (4-fluorophenyl) -2-hydroxy-1-naphthamide (1RS, 2SR) -2-amino-3- [3- (tert-butyloxy) phenyl] -1- (4-fluorophenyl)-
1-propanol (1.59 g, 5.0 mmol) and 4-
Fluoronaphthalene-1-carboxylic acid (1.14 g, 6.
0 mmol) in acetonitrile (30 ml) solution.
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.20 g, 7.0 mmol) and 1-hydroxybenzotriazole hydrate (1.07 g, 7.
0 mmol) and stirred at room temperature for 5 hours. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ethyl acetate = 10: 1) to obtain the desired product (2.27 g, 93%) as crystals. mp 180-181 ° C IRνmax ^KBr cm ^-1 : 3420, 3312, 1644, 1539, 1508, 1223,
1150.Anal.Calcd for C ₃₀ H ₂₉ F ₂ NO ₃ (MW489.55) Calcd: C, 73.60; H, 5.97; N, 2.86 Found: C, 73.61; H, 6.00; N, 2.76. ¹ H-NMR _{(CDCl 3) δ: 1.28 (} 9H, s, Bu t), 2.73 (1H, dd, J
= 14.1, 10.6 Hz), 3.03 (1H, dd, J = 14.4, 4.4 Hz),
3.90 (1H, d, J = 3.6 Hz), 4.70-4.90 (1H, m), 5.00-5.
15 (1H, m), 5.85 (1H, brd, J = 4.4 Hz), 6.80-7.30 (8
H, m), 7.4-7.60 (4H, m), 7.83 (1H, d, J = 8.0 Hz),
8.08 (1H, d, J = 7.2 Hz).

Example 285 N-[(1RS, 2SR) -1- (3-tert-butyloxybenzyl) ethyl] -2- (4-fluorophenyl)-
2-hydroxy-6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-3- [3- (tert-butyloxy) phenyl] -1- (4-fluoro Phenyl)-
1-propanol (0.48 g, 1.5 mmol) and 6,7-dihydro-5H-benzo [a] cycloheptene-1
To a solution of -carboxylic acid (0.34 g, 1.8 mmol) in acetonitrile (20 ml) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.3
6 g, 2.1 mmol) and 1-hydroxybenzotriazole hydrate (0.32 g, 2.1 mmol) were added, and the mixture was stirred at room temperature for 5 hours. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 m). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1-3: 1) to give the desired product (0.63 g, 86%) as crystals. mp 149-150 ℃ IRνmax ^KBr cm ^-1 : 3303, 1638, 1537, 1512, 1443, 1256,
. 1225, 1150, 1032. Anal Calcd for C 31 H 34 FNO 3 (MW487.61) Calcd: C, 76.36; H, 7.03; N, 2.87 Found:. C, 76.29; H, 7.20; N, 2.80 1 H _{-NMR (CDCl 3) δ: 1.30} (9H, s, Bu t), 1.90-2.10 (2H,
m), 2.10-2.30 (2H, m), 2.60-2.80 (2H, m), 2.96 (1H, d
d, J = 7.3, 4.4 Hz), 4.06 (1H, d, J = 4.0 Hz), 4.60
-4.80 (1H, m), 5.01 (1H, t, J = 3.7 Hz), 5.65 (1H, br
d, J = 8.0 Hz), 5.90-6.05 (1H, m), 6.25 (1H, d, J = 1
1.4 Hz), 6.78-7.30 (9H, m), 7.30-7.50 (2H, m).

Example 286 4-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- (3-hydroxybenzyl) ethyl] -1-naphthamide 4-fluoro- N-[(1RS, 2SR) -1- (3-ter
t-butyloxybenzyl) ethyl] -2- (4-fluorophenyl) -2-hydroxy-1-naphthamide (0.30
g, 0.61 mmol) of tetrahydrofuran (10 m
l) Add trifluoroacetic acid (5 ml) to the solution and add 50 ml
Stirred at C for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (chloroform: ethyl acetate = 5: 1) to obtain the desired product (0.18 g, 68%).
Was obtained as crystals. mp 179-180 ℃ IRνmax ^KBr cm ^-1 : 1644, 1601, 1537, 1512, 1262, 1231,
. 1157, 1053. Anal Calcd for C 26 H 21 F 2 NO 3 (MW433.45) Calcd: C, 72.05; H, 4.88; N, 3.23 Found:. C, 71.61; H, 5.14; N, 3.07 1 H -NMR (CDCl ₃ ) δ: 2.50-2.75 (2H, m), 3.10-3.30 (1H,
m), 4.30-4.55 (1H, m), 4.55-4.65 (1H, m), 5.73 (1H,
d, J = 4.4 Hz), 6.60-6.75 (3H, m), 7.00-7.70 (9H,
m), 7.99 (1H, d, J = 7.6 Hz), 8.25-8.40 (1H, m), 9.2
1 (1H, s).

Example 287 N-[(1RS, 2SR) -2- (4-fluorophenyl)
Benzyl-2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] carbamate (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3 -0.278 g of-[3- (1,1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol
(0.769 mmol) and sodium hydrogen carbonate 0.13
g (1.54 mmol) in 10 ml of tetrahydrofuran
0.12m at room temperature with stirring in the benzyl carbonate
(0.85 mmol) was allowed to stir for 3 hours.
The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.344 g Yield 90% mp 136-137 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.64-2.91
(3H, m), 4.09-4.20 (1H, m), 4.82 (1H, br d, J =
9.2 Hz), 4.85-5.04 (3H, m), 5.88 (1H, tt, J = 2.9 H
z, 53.1 Hz), 6.96-7.09 (5H, m), 7.21-7.39 (8H, m);
IR (KBr) 3326,1692, 1545, 1198, 1115 cm ^-1 ; Anal.
Calcd for C ₂₅ H ₂₂ F ₅ NO ₄ : C, 60.61; H, 4.48; N, 2.83.
Found: C, 60.81; H, 4.53; N, 2.99.

Example 288 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,6-dimethyl-
6,7-dihydro-5H-benzo [a] cycloheptene-1
-Carboxamide 1) Ethyl (E) -4,4-dimethyl-5-phenyl-2-pentenoate Liquid paraffin suspension of 60% sodium hydride 17.
8 g (445 mmol) was suspended in 300 ml of toluene, a solution of 99.8 g (445 mmol) of ethyl diethylphosphonoacetate in 50 ml of toluene was added at room temperature, and the mixture was stirred for 30 minutes. To this, 2,2-dimethyl-3-phenylpropanal (Tetrahedron Lett., 12
73-1275 (1973)) 60.16 g (37
(0.8 mmol) in 50 ml of toluene was added dropwise and stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted twice with diethyl ether. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 20 / 1-9 / 1) to obtain the desired product. Colorless liquid Yield 55.97 g Yield 65% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.06 (6H, s), 1.29 (3H,
t, J = 7.2 Hz), 2.66 (2H, s), 4.19 (2H, q, J = 7.1
Hz), 5.63 (1H, d, J = 16.2 Hz), 7.03 (1H, d, J = 1
6.2 Hz), 7.06-7.10 (2H, m), 7.20-7.38 (3H, m); IR
(neat) 2963, 1717, 1310, 1167, 1038, 702 cm ^-1 2) Ethyl 4,4-dimethyl-5-phenylpentanoate Ethyl (E) -4,4-dimethyl-5-phenyl-2-pentenoate A solution of 55.97 g (240.9 mmol) in 150 ml of ethanol was hydrogenated overnight at room temperature and normal pressure using 5 g of 10% palladium / carbon (containing 50% water) as a catalyst.
The catalyst in the reaction solution was filtered off, and the catalyst was washed with ethanol.
The solvent of the collected filtrate was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-9 / 1) to obtain the desired product. Colorless liquid Yield 45.47 g Yield 81% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.86 (6H, s), 1.26 (3H,
t, J = 7.2 Hz), 1.56-1.64 (2H, m), 2.30-2.38 (2H,
m), 2.51 (2H, s), 4.13 (2H, q, J = 7.1 Hz), 7.10-
7.15 (2H, m), 7.20-7.32 (3H, m); IR (neat) 2961, 1
736, 1171, 704 cm ^-1 3) Ethyl 4,4-dimethyl-5-phenylpentanoate Ethyl 4,4-dimethyl-5-phenylpentanoate 45.
47 g (194.0 mmol), sodium hydroxide 1
A mixture of 5.5 g (388 mmol), 200 ml of water, 200 ml of methanol and 100 ml of tetrahydrofuran was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, it was diluted with water. This was washed with diethyl ether, acidified with concentrated hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product. Colorless liquid Yield 38.35 g 96% yield ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.88 (6H, s), 1.57-1.65
(2H, m), 2.35-2.43 (2H, m), 2.52 (2H, s), 7.10-7.
15 (2H, m), 7.21-7.32 (3H, m); IR (neat) 3100-285
0, 1715, 1452, 1416, 1302, 702 cm ^-1 4) 8,8-dimethyl-6,7,8,9-tetrahydro-
38.30 g of 5H-benzo [a] cyclohepten-5-one 4,4-dimethyl-5-phenylpentanoic acid
(185.7 mmol) and 24.3 ml (279 mmol) of oxalyl chloride were added dropwise to a solution of 0.1 ml of N, N-dimethylformamide in 150 ml of tetrahydrofuran at room temperature, followed by stirring for 0.5 hour. The solvent of the reaction mixture was distilled off under reduced pressure to obtain an acid chloride as a yellow liquid.
While stirring a suspension of 49.5 g (371 mmol) of aluminum chloride in 250 ml of methylene chloride, a solution of the acid chloride obtained above in 800 ml of methylene chloride was added dropwise thereto over 2 days. While cooling the reaction solution with ice, water was added to stop the reaction. The methylene chloride layer of the mixture was separated, and the aqueous layer was extracted with diethyl ether. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-6 / 1) to obtain the desired product. Yellow liquid Yield 29.55 g Yield 85% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.02 (6H, s), 1.45-1.51
(2H, m), 2.62 (2H, s), 2.63-2.69 (2H, m), 7.12 (1
H, dd, J = 1.0 Hz, 7.2 Hz), 7.31 (1H, dt, J = 1.5 H
z, 7.5 Hz), 7.43 (1H, dt, J = 1.6 Hz, 7.5 Hz), 7.7
2 (1H, dd, J = 1.4 Hz, 7.4 Hz); IR (neat) 2953, 292
8, 1682, 1601, 1468, 1289, 770 cm ^-1 5) 8,8-dimethyl-6,7,8,9-tetrahydro-
5H-benzo [a] cyclohepten-5-ol 8,8-dimethyl-6,7,8,9-tetrahydro-5H-
Benzo [a] cyclohepten-5-one 29.20 g (1
To a solution of 55.1 mmol) in 150 ml of methanol was added little by little 5.87 g (155 mmol) of sodium borohydride under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-6).
/ 1) to obtain the desired product. 28.96 g of yellow liquid
Yield 98% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.72 (3H, s), 0.94 (3H,
s), 1.54-1.97 (4H, m), 1.78 (1H, d, J = 4.0 Hz),
2.67 (2H, br s), 4.85-4.93 (1H, m), 7.02 (1H, dd,
J = 1.6 Hz, 7.2 Hz), 7.11-7.23 (2H, m), 7.42 (1H,
d, J = 7.0 Hz); IR (neat) 3353, 2951, 2928, 1456, 1
^{044, 756 cm -1 6) 4-} ( hydroxymethyl) -8,8-dimethyl-6,
7,8,9-tetrahydro-5H-benzo [a] cyclohepten-5-ol 8,8-dimethyl-6,7,8,9-tetrahydro-5H-
Benzo [a] cyclohepten-5-ol 28.72 g
(150.9 mmol) and 50.1 ml (332 mmol) of N, N, N ', N'-tetramethylethylenediamine in 200 ml of hexane under ice-cooling to 1.6 Mn.
After dropping 208 ml (332 mmol) of a hexane solution of -butyllithium, the mixture was stirred at 35 ° C overnight. After cooling the reaction mixture to −78 ° C.,
g was added and the temperature was raised to room temperature with stirring. The reaction mixture was diluted with water, acidified with concentrated hydrochloric acid, and extracted three times with ethyl acetate. The collected organic layer is dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The obtained crude product is subjected to silica gel column chromatography (hexane / ethyl acetate = 6 /
7,7-dimethyl-7,8,9,9a-tetrahydrocyclohepta [cd] [2] benzofuran-2
The crude product of (6H) -one (31.00 g) was obtained as a yellow wet solid. Lithium aluminum hydride5.
73 g (151 mmol) of tetrahydrofuran 200
A 100 ml solution of the solid obtained above in tetrahydrofuran was added dropwise to the ml suspension under ice cooling, and the mixture was stirred at room temperature for 1 hour.
After cooling the reaction solution with ice, 6 ml of water, 6 ml of a 15% aqueous sodium hydroxide solution and 15 ml of water are sequentially added dropwise to decompose excess lithium aluminum hydride and leave it at room temperature for 2 hours.
Stirred for hours. The resulting precipitate was removed by filtration, and the precipitate was washed with ethyl acetate. The solvent of the collected filtrate was distilled off under reduced pressure.
The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-1 /
2) Crystallized from hexane to obtain the desired product. White crystals Yield 19.15 g Yield 58% mp 107-108 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.76 (3H,
s), 0.99 (3H, s), 1.16-1.28 (1H, m), 1.68-1.82 (1
H, m), 1.91-2.03 (2H, m), 2.30 (1H, d, J = 13.6 H
z), 2.63 (1H, br t, J = 5.3 Hz), 2.93 (1H, br s),
3.22 (1H, d, J = 13.8 Hz), 4.58 (1H, dd, J = 5.3 H
z, 11.9 Hz), 4.85 (1H, dd, J = 5.7 Hz, 11.9 Hz), 5.
24-5.32 (1H, m), 7.00-7.06 (1H, m), 7.08-7.17 (2H, m
m); IR (KBr) 3312, 2951, 1402, 1016, 997, 762 cm
^-1 ; Anal.Calcd for C ₁₄ H ₂₀ O ₂ : C, 76.33; H, 9.15. Fo
und: C, 76.37; H, 9.28.7) 4-[[[tert-butyl (dimethyl) silyl]
[Oxy] methyl] -8,8-dimethyl-6,7,8,9-tetrahydro-5H-benzo [a] cyclohepten-5-ol 4- (hydroxymethyl) -8,8-dimethyl-6,7,
18.87 g (85.65 mmol) of 8,9-tetrahydro-5H-benzo [a] cyclohepten-5-ol, 4
To a solution of 0.5 g of -N, N-dimethylaminopyridine and 14.3 ml (103 mmol) of triethylamine in 100 ml of tetrahydrofuran was added 14.2 g (94.2 mmol) of tert-butyldimethylchlorosilane at room temperature, and the mixture was stirred overnight. . The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-9 / 1) to obtain the desired product. Colorless liquid Yield 28.90 g Yield 100% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.08 (3H, s), 0.11 (3H,
s), 0.76 (3H, s), 0.90 (9H, s), 0.99 (3H, s), 1.1
6-1.30 (1H, m), 1.67-1.80 (1H, m), 1.88-2.05 (2H,
m), 2.30 (1H, d, J = 13.6 Hz), 3.02 (1H, br s), 3.
23 (1H, d, J = 14.0 Hz), 4.64 (1H, d, J = 11.8 H
z), 4.94 (1H, d, J = 12.0 Hz), 5.23-5.31 (1H, m),
6.98-7.04 (1H, m), 7.06-7.15 (2H, m); IR (neat) 33
91, 2951, 2928, 2857, 1470, 1254, 1076, 837, 775 c
m ^- 18) tert-butyl (6,6-dimethyl-6,7-dihydro-5H-benzo [a] cyclohepten-1-ylmethoxy) dimethylsilane 4-[[[tert-butyl (dimethyl) silyl] oxy] Methyl] -8,8-dimethyl-6,7,8,9-tetrahydro-5H-benzo [a] cyclohepten-5-ol 2
Methanesulfonyl chloride 14 was added to a solution of 8.90 g (86.38 mmol), 24.1 ml (173 mmol) of triethylamine and 1.06 g (8.64 mmol) of 4-N, N-dimethylaminopyridine in 100 ml of acetonitrile under ice-cooling. A solution of 2.8 g (130 mmol) in 10 ml of acetonitrile was added dropwise under ice cooling. To this, 5.49 g (130 mmol) of lithium chloride was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 100 ml of N, N-dimethylformamide, 25.8 ml (173 mmol) of 1,8-diazabicyclo [5.4.0] -7-undecene was added, and the mixture was stirred at 80 ° C. overnight. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 15/1) to obtain the desired product. Light yellow liquid Yield 10.25 g Yield 38% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.09 (6H, s), 0.94 (9H,
s), 1.01 (6H, s), 1.65 (2H, d, J = 7.0 Hz), 2.32
(2H, s), 4.71 (2H, s), 6.25 (1H, td, J = 7.0Hz, 1
0.7 Hz), 6.64 (1H, d, J = 10.8 Hz), 7.07 (1H, d, J
= 8.8 Hz), 7.17 (1H, t, J = 7.5 Hz), 7.37 (1H, d,
J = 8.0 Hz); IR (neat) 2953, 2928, 1464, 1256, 111
1, 1074, 837, 775 cm- ¹ 9) 6,6-dimethyl-6,7-dihydro-5H-benzo [a] cyclohepten-1-ylmethanol tert-butyl (6,6-dimethyl-6,7- Dihydro-
5H-benzo [a] cyclohepten-1-ylmethoxy)
To a solution of 7.306 g (23.08 mmol) of dimethylsilane in 30 ml of tetrahydrofuran was added 27.7 ml (27.7 mmol) of a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran at room temperature, followed by stirring at room temperature for 15 minutes. The reaction solution was poured into water, and extracted with ethyl acetate.
Extracted times. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-3 / 1) to obtain the desired product. Colorless liquid Yield 4.484 g Yield 96% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.02 (6H, s), 1.59 (1H,
t, J = 5.9 Hz), 1.67 (2H, d, J = 7.4 Hz), 2.35 (2
H, s), 4.70 (2H, d, J = 6.2 Hz), 6.32 (1H, td, J =
7.0 Hz, 10.6 Hz), 6.79 (1H, d, J = 10.6 Hz), 7.11
-7.31 (3H, m); IR (neat) 3318, 2951, 1454, 774 cm
^-1 10) 6,6-Dimethyl-6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid 6,6-dimethyl-6,7-dihydro-5H-benzo [a]
4.429 g of cyclohepten-1-ylmethanol (2
A solution of 5.47 g (53.7 mmol) of chromic anhydride and 4 ml of concentrated sulfuric acid in 15 ml of water was slowly added dropwise to a solution of 1.90 mmol) in acetone under ice-cooling. Stir for 1.5 hours. After ice-cooling the reaction solution again, 20 ml of isopropanol was added,
The mixture was stirred for 0.5 hours as it was. The acetone in the reaction solution was distilled off under reduced pressure, diluted with ethyl acetate, washed three times with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. Yellow crystals Yield 3.087 g Yield 65% mp 132-134 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.03 (6H,
s), 1.66 (2H, d, J = 7.4 Hz), 2.37 (2H, s), 6.33
(1H, td, J = 7.3 Hz, 10.6 Hz), 7.23 (1H, d, J = 10.
6 Hz), 7.26 (1H, t, J = 7.5 Hz), 7.39 (1H, dd, J =
1.3 Hz, 7.5 Hz), 8.00 (1H, dd, J = 1.5 Hz, 7.6 H
z); IR (KBr) 3050-2550, 1682, 1464, 1451, 1308, 12
79, 775 cm ^-1 ; Anal.Calcd for C ₁₄ H ₁₆ O ₂ : C, 77.75;
H, 7.46. Found: C, 77.97; H, 7.57.11) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2, 2-tetrafluoroethoxy) benzyl] ethyl] -6,6-dimethyl-6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluoro Phenyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol 0.367 g
(1.016 mmol), 0.22 g (1.02 mmol) of 6,6-dimethyl-6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid, 1-hydroxybenzotriazole hydrate 0 0.16 g (1.02 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added while stirring 0.16 g (1.02 mmol) of 0.16 g (1.02 mmol) in 10 ml of acetonitrile, and the mixture was stirred at room temperature overnight. did. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. 0.443 white powder yield
g Yield 78% mp 115-116 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 0.99 (6H,
s), 1.64 (2H, d, J = 7.2 Hz), 2.29 (2H, s), 2.79
(1H, dd, J = 10.4 Hz, 14.6 Hz), 2.98 (1H, dd, J =
4.1 Hz, 14.6 Hz), 3.78 (1H, d, J = 4.2 Hz), 4.59-
4.68 (1H, m), 5.04 (1H, t, J = 3.8 Hz), 5.76 (1H,
d, J = 8.4 Hz), 5.89 (1H, tt, J = 2.8 Hz, 53.0 H
z), 6.13 (1H, td, J = 7.1 Hz, 10.6 Hz), 6.34 (1H,
d, J = 10.5 Hz), 7.01-7.14 (7H, m), 7.17-7.22 (1H,
m), 7.30 (1H, t, J = 7.8 Hz), 7.42 (2H, dd, J = 5.
3 Hz, 8.6 Hz); IR (KBr) 3287, 1638, 1512, 1227, 12
^{. 00, 1125 cm -1; Anal} Calcd for C 31 H 30 F 5 NO 3: C, 66.
54; H, 5.40; N, 2.50. Found: C, 66.47; H, 5.46; N,
2.49.

Example 289 N-[(1RS, 2RS) -2- (5-chloro-2-thienyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl ] Ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 1) 3- (5-chloro-2-thienyl) -3-oxo-2-
Ethyl [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propionate 12.5 g (60.0 mmol) of 3- (1,1,2,2-tetrafluoroethoxy) toluene, N-bromo 10.7 g (60.0 mmol) of succinimide, 2,2'-
A solution of 30 mg of azobis (isobutyronitrile) in 30 ml of carbon tetrachloride was heated under reflux for 0.5 hour. After cooling the reaction solution to room temperature, a white precipitate was removed by filtration, and the precipitate was washed with diethyl ether. The solvent of the collected filtrate was distilled off under reduced pressure to obtain a crude product of 3- (1,1,2,2-tetrafluoroethoxy) benzyl bromide as a pale yellow liquid. 3
Liquid paraffin suspension of 60% sodium hydride in a solution of 11.63 g (49.98 mmol) of ethyl-(5-chloro-2-thienyl) -3-oxopropionate in 50 ml of 1,2-dimethoxyethane under ice-cooling 2.00 g (50.0 mmol) was added, and the mixture was stirred as it was for 0.5 hour. The 3- (1,1,2,2-tetrafluoroethoxy) benzyl bromide obtained above was treated with 1,2-dimethoxyethane 10
ml solution was added at room temperature and stirred at room temperature for 8 hours. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-9 /
1) Crystallized from hexane to obtain the desired product. White crystals Yield 12.58 g Yield 57% mp 49-51 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.16 (3H,
t, J = 7.2 Hz), 3.27 (1H, dd, J = 7.5 Hz, 14.1 H
z), 3.36 (1H, dd, J = 7.5 Hz, 14.1 Hz), 4.13 (2H,
q, J = 7.1 Hz), 4.34 (1H, t, J = 7.5 Hz), 5.89 (1
H, tt, J = 2.9 Hz, 53.1 Hz), 6.93 (1H, d, J = 4.2
Hz), 7.04-7.14 (3H, m), 7.23-7.32 (1H, m), 7.53 (1
H, d, J = 4.0 Hz); IR (KBr) 1725, 1661, 1434, 121
^{. 5, 1148, 1132 cm -1} ; Anal Calcd for C 18 H 15 ClF 4 O 4 S:
H, 3.45. Found: C, 49.24; H, 3.20.2) (2RS, 3RS) -3- (5-chloro-2-thienyl) -3-hydroxy-2- [3- (1, Ethyl 1,2,2-tetrafluoroethoxy) benzyl] propionate While stirring 7.76 g (57.0 mmol) of zinc chloride in 150 ml of diethyl ether, 4.31 g (114 mmol) of sodium borohydride was added at room temperature. The mixture was stirred for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. To the resulting solution, add 3- (5-chloro
-2-thienyl) -3-oxo-2- [3- (1,1,2,2-
12.50 g (28.48 mmol) of ethyl tetrafluoroethoxy) benzyl] propionate was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Dilute hydrochloric acid was added little by little to the reaction solution to decompose excess zinc borohydride, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-1 / 1) to obtain the desired product.
Colorless liquid Yield 12.70 g Yield 100% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.00 (3H, t, J = 7.2 H)
z), 2.95-3.09 (3H, m), 3.14 (1H, d, J = 3.6 Hz), 3.
96 (2H, q, J = 7.2 Hz), 5.14 (1H, t, J = 3.9Hz),
5.90 (1H, tt, J = 2.9 Hz, 53.1 Hz), 6.75 (1H, d, J
= 4.0 Hz), 6.79 (1H, d, J = 4.0 Hz), 7.00 (1H, s),
7.06 (2H, d, J = 7.8 Hz), 7.28 (1H, t, J = 7.9 H
z); IR (neat) 3463, 1725, 1451, 1302, 1277, 1198,
^{1125, 801cm -1 3) (2RS} , 3RS) -3- (5- chloro-2-thienyl) -3-hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propionic Acid (2RS, 3RS) -3- (5-chloro-2-thienyl) -3
Ethyl ethyl-hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propionate 14.27
g (32.37 mmol), sodium hydroxide 2.39
g (64.7 mmol), a mixture of 50 ml of methanol and 50 ml of tetrahydrofuran were stirred at room temperature for 6 hours. The reaction solution was concentrated, diluted with water, acidified with dilute hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from diethyl ether-hexane to obtain the desired product. White crystals Yield 9.181 g Yield 69% mp 105-106 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 3.03-3.11
(3H, m), 5.15-5.17 (1H, m), 5.89 (1H, tt, J = 2.9
Hz, 53.1 Hz), 6.76 (1H, d, J = 3.9 Hz), 6.79 (1H,
d, J = 3.6 Hz), 7.01 (1H, s), 7.06 (2H, d, J = 8.
7 Hz), 7.27 (1H, t, J = 7.8 Hz); IR (KBr) 3358, 310
0-2550, 1692, 1453, 1287, 1204, 1117,801 cm ^-1 ; Ana
l. Calcd for C ₁₆ H ₁₃ ClF ₄ O ₄ S: C, 46.56; H, 3.17. Fou
nd: C, 46.59; H, 3.20.4) (4RS, 5RS) -5- (5-chloro-2-thienyl) -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine-2-one (2R
8.996 g (21.7) of S, 3RS) -3- (5-chloro-2-thienyl) -3-hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propionic acid
To a solution of 9 mmol) in 80 ml of tetrahydrofuran were added 3.65 ml (26.2 mmol) of triethylamine and 6.60 g (24.0 mmol) of diphenylphosphoryl azide, and the mixture was heated under reflux overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-
1/1) to obtain the desired product. Brown liquid yield 8.480g
Yield 95% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.55 (1H, dd, J = 9.8 H
z, 14.0 Hz), 2.66 (1H, dd, J = 4.6 Hz, 13.4 Hz), 4.
20-4.31 (1H, m), 5.19 (1H, br s), 5.86 (1H, d, J =
7.6 Hz), 5.91 (1H, tt, J = 2.8 Hz, 53.0 Hz), 6.87
(2H, s), 6.94 (1H, s), 7.01 (1H, d, J = 7.6 Hz), 7.
13 (1H, dd, J = 1.2 Hz, 8.2 Hz), 7.34 (1H, t, J =
7.9 Hz); IR (neat) 3274, 1761, 1451, 1196, 1119, 1
^{001 cm - 1 5) (1RS} , 2RS) -2- amino-1- (5-chloro -
2-thienyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol (4RS, 5RS) -5- (5-chloro-2-thienyl) -4
-[3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidin-2-one 8.480 g
(20.69 mmol) and 3.31 g of sodium hydroxide
(82.8 mmol) in 40 ml of ethanol-3 ml of water
And heated under reflux for 4 hours. Dilute the reaction with saline,
Extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel (APS type) column chromatography (hexane / ethyl acetate = 3 / 1-ethyl acetate),
The desired product was obtained. Yellow liquid Yield 7.648 g Yield 96
% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.45 (1H, dd, J = 9.8 H
z, 13.8 Hz), 2.86 (1H, dd, J = 4.1 Hz, 13.5 Hz), 3.
27-3.36 (1H, m), 4.76 (1H, d, J = 4.8 Hz), 5.91 (1
H, tt, J = 2.7 Hz, 53.1 Hz), 6.78 (1H, d, J = 3.6
Hz), 6.83 (1H, d, J = 3.6 Hz), 7.06 (2H, d, J = 7.4
Hz), 7.12 (1H, d, J = 1.6 Hz), 7.32 (1H, t, J = 7.
8 Hz); IR (neat) 3360-2860, 1586, 1487, 1451, 130
2, 1279,1196, 1121, 801 cm -1 6) N - [(1RS, 2RS) -2- (5- chloro-2-thienyl) -2-hydroxy-1- [3- (1,1,2 , 2-Tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2RS) -2-amino-1- (5-chloro-2-thienyl) 0.582 g of -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol
(1.516 mmol), 0.29 g of 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid
(1.52 mmol) 1-Hydroxybenzotriazole hydrate 0.23 g (1.52 mmol) in 10 ml of acetonitrile while stirring 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0 .2
9 g (1.52 mmol) was added and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White powder Yield 0.623 g Yield 74% mp 177-178 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.95-2.07
(2H, m), 2.16-2.25 (2H, m), 2.68 (2H, t, J = 5.9
Hz), 2.80 (1H, dd, J = 10.4 Hz, 14.6 Hz), 3.06 (1
H, dd, J = 4.8 Hz, 14.2 Hz), 4.40 (1H, d, J = 4.2
Hz), 4.62-4.76 (1H, m), 5.15 (1H, t, J = 3.6 Hz),
5.81 (1H, d, J = 7.6 Hz), 5.90 (1H, tt, J = 2.9 Hz,
53.1 Hz), 5.96 (1H, td, J = 5.3 Hz, 11.6 Hz), 6.2
7 (1H, d, J = 11.8 Hz), 6.83 (2H, s), 7.02-7.21 (6
H, m), 7.35 (1H, t, J = 7.7 Hz); IR (KBr) 3264, 164
0, 1537, 1451, 1202, 1117 cm ^-1 ; Anal.Calcd for C
₂₇ H _{2 4} ClF ₄ NO ₃ S: C, 58.54; H, 4.37; N, 2.53. Found:
C, 58.29; H, 4.36; N, 2.47.

Example 290 N-[(1RS, 2SR) -2- (4-bromophenyl)-
2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
5H-benzo [a] cycloheptene-1-carboxamide 1) Ethyl 3- (4-bromophenyl) -3-oxopropanoate 4-bromoacetophenone (80 g, 0.40 mol), ethanol (1 ml), diethyl carbonate (350 ml) Sodium hydride (32 g, 60% oil) was added little by little to the mixture under ice cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was cooled to 0 ° C., 6N hydrochloric acid (200 ml) was added, and the mixture was extracted with ethyl acetate (200, 100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1-5: 1) to give the desired product (108.9 g, quantitative) as an oil. IRνmax ^Neat cm ^-1 : 1742, 1688, 1586, 1424, 1323, 126
^{4, 1200, 1073, 1009. 1} H-NMR (CDCl 3) δ: 1.26 (3H × 3/4, t, J = 7.2 Hz),
1.31 (3H × 1/4, t, J = 7.2 Hz), 3.96 (2H × 3/4, s), 4.
21 (2H x 3/4, q, J = 7.2 Hz), 4.27 (2H x 1/4, q, J = 7.
2 Hz), 5.65 (1H x 1/4, s), 7.50-7.70 (2H x 5/4, m), 7.
75-7.90 (2H × 3/4, m). 2) 3- (4-bromophenyl) -3-oxo-2- [3-
Ethyl (1,1,2,2-tetrafluoroethoxy) benzyl] propanoate Ethyl acetate of 3- (1,1,2,2-tetrafluoroethoxy) toluene (25 g, 0.12 mol) (400 m
1) Add N-bromosuccinimide (21.4,
0.12 mol) and 2,2'-azobisisobutyronitrile (0.2 g) were added, and the mixture was heated under reflux for 2.5 hours. After the reaction solution was concentrated under reduced pressure, diethyl ether and hexane were added to remove insolubles, and washed with diethyl ether. The filtrate was distilled off under reduced pressure to obtain 3- (1,1,2,2-tetrafluoroethoxy) -1-bromomethylbenzene. 3- (4-
Ethyl bromophenyl) -3-oxopropanoate (27.
1 g, 100 mmol) of dimethoxyethane (150 m
l) Add sodium hydride (4.0 g, 60
% Oily, 0.1 mol) and stirred for 1 hour. The dimethoxyethane (2) of 3- (1,1,2,2-tetrafluoroethoxy) -1-bromomethylbenzene obtained above was added thereto.
0 ml) solution was added dropwise and stirred at room temperature for 15 hours. Water (300 ml) was added to the reaction solution, and ethyl acetate (200 ml) was added.
× 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel chromatography (hexane: toluene = 1: 2-1: 1).
Purified in 5) and crystallized from hexane to give the desired product (2
1.1 g, 44%). mp 48-49 ° C IRνmax ^KBr cm ^-1 : 1721, 1684, 1588, 1277, 1198, 1134,
845.Analyzed Calcd for C ₂₀ H ₁₇ BrF ₄ O ₄ (MW477.24) Calcd: C, 50.33; H, 3.96 Found: C, 55.55; H, 3.83 ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H , t, J = 7.2 Hz), 3.33 (2
H, d, J = 8.0 Hz), 4.10 (2H, q, J = 7.2 Hz), 4.55 (1
H, t, J = 7.0 Hz), 5.89 (1H, tt, J = 53.1, 2.2Hz),
7.00-7.20 (3H, m), 7.20-7.35 (1H, m), 7.42 (2H, d, J
= 8.0 Hz), 7.89 (2H, d, J = 8.0 Hz). 3) (2RS, 3RS) -3- (4-bromophenyl)-
Ethyl 3-hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoate To a suspension of anhydrous zinc chloride (11.4 g, 83.8 mmol) in diethyl ether (200 ml). Then, sodium borohydride (6.34 g, 168 mmol) was added little by little, and the mixture was stirred for 2 hours. The insolubles were removed by filtration and washed with diethyl ether. The filtrate was ice-cooled, and ethyl 3- (4-bromophenyl) -3-oxo-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoate (2
0 g, 41.9 mmol) of diethyl ether (50 m
l) The solution was added. After stirring at room temperature for 2 hours, the mixture was ice-cooled again and the reaction was stopped with 2N hydrochloric acid. The obtained mixture was extracted with ethyl acetate (200, 100 ml), washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel (hexane: ethyl acetate =
5: 1-2: 1) to give the desired product (20 g, quantitative) as a colorless oil. IRνmax ^Neat cm ^-1 : 1715, 1590, 1487, 1302, 1279, 119
^{8, 1123, 1011. 1 H-} NMR (CDCl 3) δ: 0.95 (3H, t, J = 7.2 Hz), 2.90-
3.15 (4H, m), 3.90 (2H, d, J = 7.2 Hz), 5.02 (1H, b
r), 5.89 (1H, tt, J = 53.1, 2.8 Hz), 6.90-7.15 (3H,
m), 7.20-7.40 (3H, m), 7.40-7.60 (2H, m). 4) (2RS, 3RS) -3- (4-bromophenyl)-
3-hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoic acid (2RS, 3RS) -3- (4-bromophenyl) -3-hydroxy-2- [3- Ethyl (1,1,2,2-tetrafluoroethoxy) benzyl] propanoate (19.5 g, 4
0.7 mmol) in methanol (100 ml).
Normal sodium hydroxide aqueous solution (40.7 ml, 81.4
Mmol) and stirred at room temperature for 2.5 hours. The reaction solution was acidified by adding 6N hydrochloric acid (50 ml), and then extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from hexane to give the desired product (16.7).
g, 91%). ^{. mp 85-86 ℃ IRνmax KBr cm -1} : 1696, 1487, 1279, 1206, 1127. Anal Calcd for C 18 H 15 BrF 4 O 4 (MW451.21) Calcd: C, 47.91; H, 3.35 Found: C , 47.97; H, 3.33 ¹ H-NMR (CDCl ₃ ) δ: 2.85-3.15 (3H, m), 5.06 (1H, d, J
= 3.8 Hz), 5.88 (1H, tt, J = 53.1, 2.8 Hz), 6.90-
7.15 (3H, m), 7.20-7.40 (2H, m), 7.49 (2H, d, J = 8.4
Hz). 5) (4RS, 5SR) -5- (4-bromophenyl)-
4- [3- (1,1,2,2-tetrafluoroethoxy)
Benzyl] -1,3-oxazolidin-2-one (2RS, 3RS) -3- (4-bromophenyl) -3-hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl ] Propanoic acid (16.2 g, 35.9)
Mmol) in a solution of diphenylphosphoryl azide (10.0 ml, 46.7).
Mmol) and triethylamine (7.0 ml, 50.3)
Mmol) and stirred at room temperature for 1 hour. Then 2
After heating under reflux for a period of time, the reaction solution was concentrated under reduced pressure and water (100
ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel (hexane: ethyl acetate =
3: 1-1: 1), and the precipitated crystals were added with hexane and collected by filtration to obtain the desired product (14.7 g, 91%). ^{. mp 136-137 ℃ IRνmax KBr cm -1} : 1738, 1489, 1200, 1125, 848. Anal Calcd for C 18 H 14 BrF 4 NO 3 (MW448.21) Calcd: C, 48.24; H, 3.15; N, 3.13 Found:. C, 48.30; H, 2.87; N, 3.14 1 H-NMR (CDCl 3) δ: 2.15-2.40 (2H, m), 4.20-4.35 (1H,
m), 5.03 (1H, brs), 5.77 (1H, d, J = 8.0 Hz), 5.90
(1H, tt, J = 53.2, 2.7 Hz), 6.87 (1H, s), 6.94 (1H,
d, J = 7.6 Hz), 7.05-7.15 (1H, m), 7.20-7.40 (3H,
m), 7.55-7.65 (2H, m). 6) (1RS, 2SR) -2-amino-1- (4-bromophenyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) ) Phenyl] -1-propanol (4RS, 5SR) -5- (4-bromophenyl) -4-
[3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidin-2-one (14.0 g,
31.2 mmol) in ethanol (50 ml)
8N aqueous sodium hydroxide solution (15.6 ml, 125
(Mmol) was added and heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, water (200 ml) was added, and ethyl acetate (200 ml) was added.
ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Hexane residue
Crystallization from diethyl ether gave the desired product (12.8).
g, 97%). mp 84-86 ℃ IRνmax ^KBr cm ^-1 : 3362, 1611, 1588, 1485, 1308, 1196,
. 1119, 1034, 1007. Anal Calcd for C 17 H 16 BrF 4 NO 2 (MW422.21) Calcd: C, 48.36; H, 3.82; N, 3.32 Found: C, 48.59; H, 3.57; N, 3.37. ¹ H-NMR (CDCl ₃ ) δ: 2.36 (1H, dd, J = 13.4, 10.6 Hz),
2.76 (1H, dd, J = 13.4, 3.4 Hz), 3.20-3.40 (1H, m),
4.65 (1H, d, J = 4.8 Hz), 5.91 (1H, tt, J = 53.1,
2.8 Hz), 6.99 (1H, s), 7.06 (2H, t, J = 6.6 Hz), 7.2
0-7.40 (3H, m), 7.51 (2H, d, J = 8.6 Hz). 7) N-[(1RS, 2SR) -2- (4-bromophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- (4- 5.647 g of bromophenyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] -1-propanol (13.
37 mmol), 6,7-dihydro-5H-benzo [a]
2.52 g (13.4 mmol) of cycloheptene-1-carboxylic acid and 2.05 g (13.4 mmol) of 1-hydroxybenzotriazole hydrate were added to acetonitrile 40
2.56 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1 ml)
3.4 mmol) and stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The residue obtained is ethyl acetate
Crystallization from -diisopropyl ether-hexane gave the desired product. White powder Yield 7.306 g Yield 92% mp 184-185 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.95-2.04
(2H, m), 2.16-2.23 (2H, m), 2.66 (2H, t, J = 5.9
Hz), 2.77 (1H, dd, J = 10.7 Hz, 14.6 Hz), 2.97 (1
H, dd, J = 4.1 Hz, 14.6 Hz), 3.76 (1H, d, J = 3.9
Hz), 4.61-4.70 (1H, m), 5.02 (1H, t, J = 3.9 Hz),
5.75 (1H, d, J = 8.4 Hz), 5.89 (1H, tt, J = 2.8 Hz,
53.1 Hz), 5.92 (1H, td, J = 5.9 Hz, 11.4 Hz), 6.2
0 (1H, d, J = 11.7 Hz), 6.96 (1H, dd, J = 1.5 Hz,
7.8 Hz), 7.01 (1H, s), 7.03-7.17 (4H, m), 7.30 (1H,
t, J = 7.8 Hz), 7.34 (2H, d, J = 8.1 Hz), 7.51 (2
H, d, J = 8.4 Hz); IR (KBr) 3260, 1640, 1532, 1487,
1198, 1125 cm ^-1 ; Anal.Calcd for C ₂₉ H ₂₆ BrF ₄ NO ₃ : C,
58.80; H, 4.42; N, 2.36. Found: C, 58.75; H, 4.43;
N, 2.35.

Example 291 N-[(1RS, 2SR) -2- (1,1′-biphenyl-
4-yl) -2-hydroxy-1- [3- (1,1,2,2-
Tetrafluoroethoxy) benzyl] ethyl] -6,7-
Dihydro-5H-benzo [a] cycloheptene-1-carboxamide N-[(1RS, 2SR) -2- (4-bromophenyl)-
2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
0.511 g (0.863 mmol) of 5H-benzo [a] cycloheptene-1-carboxamide, 0.16 g (1.29 mmol) of phenylboronic acid, 0.10 g of tetrakis (triphenylphosphine) palladium (0)
(0.086 mmol) and 0.18 g of sodium carbonate
(1.73 mmol) was stirred in 8 ml of toluene-8 ml of water at 90 ° C. for 1 day. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1), and crystallized from diisopropyl ether to obtain the desired product. White powder Yield 0.26
9g Yield 53% mp 122-123 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.96-2.05
(2H, m), 2.14-2.24 (2H, m), 2.66 (2H, t, J = 5.8
Hz), 2.83 (1H, dd, J = 10.8 Hz, 14.6 Hz), 3.06 (1
H, dd, J = 4.5 Hz, 14.7 Hz), 3.60 (1H, d, J = 3.6
Hz), 4.72-4.82 (1H, m), 5.11 (1H, t, J = 3.7 Hz),
5.80 (1H, d, J = 8.0 Hz), 5.88 (1H, tt, J = 3.0 Hz,
53.1 Hz), 5.91 (1H, td, J = 5.4 Hz, 11.6 Hz), 6.2
3 (1H, d, J = 11.6 Hz), 6.97-7.17 (6H, m), 7.31-7.6
4 (10H, m); IR (KBr) 3250, 1634, 1530, 1487, 1285,
1194, 1115, 770, 700 cm ^-1 ; Anal.Calcd for C ₃₅ H ₃₁
F ₄ NO ₃・ 0.1H ₂ O ・ 0.5i-Pr ₂ O: C, 71.04; H, 5.99; N, 2.1
8. Found: C, 70.75; H, 5.99; N, 2.23.

Example 292 N-[(1RS, 2SR) -2-hydroxy-1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] -2- [4- (3-thienyl) phenyl] ethyl]-
6,7-dihydro-5H-benzo [a] cycloheptene-1
-Carboxamide N-[(1RS, 2SR) -2- (4-bromophenyl)-
2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
0.519 g (0.876 mmol) of 5H-benzo [a] cycloheptene-1-carboxamide, thiophen-3-
0.17 g (1.31 mmol) of boronic acid, tetrakis (triphenylphosphine) palladium (0) 0.10
g (0.088 mmol) and 0.19 g of sodium carbonate
(1.75 mmol) was stirred at 90 ° C. for 1 day in 8 ml of toluene and 8 ml of water. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1), and crystallized from ethyl acetate / diisopropyl ether / hexane to obtain the desired product. Light brown powder Yield 0.334 g Yield 64% mp 178-179 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.92-2.04
(2H, m), 2.14-2.23 (2H, m), 2.66 (2H, t, J = 5.9
Hz), 2.81 (1H, dd, J = 10.5 Hz, 14.7 Hz), 3.03 (1
H, dd, J = 4.6 Hz, 14.4 Hz), 3.63 (1H, d, J = 3.6
Hz), 4.67-4.81 (1H, m), 5.07 (1H, t, J = 3.7 Hz),
5.80 (1H, d, J = 8.4 Hz), 5.88 (1H, tt, J = 2.9 Hz,
53.1 Hz), 5.90 (1H, td, J = 5.0 Hz, 12.2 Hz), 6.2
2 (1H, d, J = 11.8 Hz), 6.95-7.17 (6H, m), 7.26-7.5
0 (6H, m), 7.62 (2H, d, J = 8.2Hz); IR (KBr) 3283,
2936, 1640, 1532, 1200, 1123, 783 cm ^-1 ; Anal. Cal
_{cdfor C 33 H 29 F 4 NO} 3 S:. C, 66.54; H, 4.91; N, 2.35 Fo
und: C, 66.37; H, 4.86; N, 2.28.

Example 293 N-[(1RS, 2SR) -2- (2′-chloro [1,1 ′]
-Biphenyl] -4-yl) -2-hydroxy-1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide N-[(1RS, 2SR) -2- (4-bromo Phenyl)-
2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
0.529 g (0.893 mmol) of 5H-benzo [a] cycloheptene-1-carboxamide, 0.42 g (2.68 mmol) of 2-chlorophenylboronic acid, tetrakis (triphenylphosphine) palladium (0).
20 g (0.18 mmol) and 0.38 sodium carbonate
g (3.58 mmol) was stirred in 8 ml of toluene-8 ml of water at 90 ° C. for 2 days. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1), and crystallized from diisopropyl ether / hexane to obtain the desired product. White powder Yield 0.203 g Yield 36% mp 172-173 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.95-2.04
(2H, m), 2.16-2.22 (2H, m), 2.66 (2H, t, J = 5.9
Hz), 2.86 (1H, dd, J = 10.8 Hz, 14.4 Hz), 3.07 (1
H, dd, J = 4.5 Hz, 14.7 Hz), 3.62 (1H, d, J = 3.9
Hz), 4.72-4.81 (1H, m), 5.11 (1H, t, J = 3.9 Hz),
5.83 (1H, d, J = 8.4 Hz), 5.89 (1H, tt, J = 2.9 Hz,
53.0 Hz), 5.93 (1H, td, J = 5.7 Hz, 11.6 Hz), 6.2
5 (1H, d, J = 11.7 Hz), 6.96-7.16 (6H, m), 7.26-7.3
6 (4H, m), 7.46-7.54 (5H, m); IR (KBr) 3753, 3233,
3061, 1640, 1306, 1198, 1123, 1030, 762 cm ^-1 ; Ana
_{l.Calcd for C 35 H 30 ClF 4} NO 3: C, 67.36; H, 4.85; N,
2.24. Found: C, 66.99; H, 5.05; N, 2.08.

Example 294 N-[(1RS, 2SR) -2- (4'-chloro [1,1 '
-Biphenyl] -4-yl) -2-hydroxy-1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide N-[(1RS, 2SR) -2- (4-bromo Phenyl)-
2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
0.500 g (0.844 mmol) of 5H-benzo [a] cycloheptene-1-carboxamide, 0.26 g (1.69 mmol) of 4-chlorophenylboronic acid, tetrakis (triphenylphosphine) palladium (0).
20 g (0.17 mmol) and sodium carbonate 0.27
g (2.53 mmol) in 10 ml of toluene and 10 m of water
and stirred at 90 ° C. for 2 days. Pour the reaction into water,
Extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane /
Crystallization from ethyl acetate = 3 / 1-1 / 1) and diisopropyl ether / hexane gave the desired product. Light brown crystal Yield 0.136 g Yield 26% mp 167-168 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.95-2.03
(2H, m), 2.15-2.22 (2H, m), 2.66 (2H, t, J = 5.9
Hz), 2.83 (1H, dd, J = 10.7 Hz, 14.6 Hz), 3.04 (1
H, dd, J = 4.1 Hz, 14.9 Hz), 3.63 (1H, d, J = 3.6
Hz), 4.71-4.79 (1H, m), 5.11 (1H, t, J = 3.8 Hz),
5.80 (1H, d, J = 8.4 Hz), 5.88 (1H, tt, J = 2.9 Hz,
53.1 Hz), 5.90 (1H, td, J = 5.7 Hz, 11.4 Hz), 6.2
3 (1H, d, J = 12.0 Hz), 6.96-7.16 (6H, m), 7.30 (1
H, t, J = 8.0 Hz), 7.41 (2H, d, J = 8.7 Hz), 7.50-
7.59 (6H, m); IR (KBr) 3289, 2932, 1638, 1530, 148
7, 1204, 1123, 1096, 818 cm ^-1 ; Anal.Calcd for C ₃₅
H ₃₀ ClF ₄ NO ₃ : C, 67.36; H, 4.85; N, 2.24. Found: C,
67.37; H, 4.87; N, 2.15.

Example 295 N-[(1RS, 2SR) -2- (3′-chloro [1,1 ′]
-Biphenyl] -4-yl) -2-hydroxy-1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide N-[(1RS, 2SR) -2- (4-bromo Phenyl)-
2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
0.500 g (0.844 mmol) of 5H-benzo [a] cycloheptene-1-carboxamide, 0.26 g (1.69 mmol) of 3-chlorophenylboronic acid, tetrakis (triphenylphosphine) palladium (0).
20 g (0.17 mmol) and sodium carbonate 0.27
g (2.53 mmol) in 10 ml of toluene and 10 m of water
and stirred at 90 ° C. for 2 days. Pour the reaction into water,
Extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane /
Crystallization from ethyl acetate = 3 / 1-1 / 1) and diisopropyl ether / hexane gave the desired product. Light brown crystal Yield 0.165 g Yield 31% mp 131-132 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.95-2.03
(2H, m), 2.16-2.22 (2H, m), 2.67 (2H, t, J = 5.9
Hz), 2.83 (1H, dd, J = 10.5 Hz, 14.4 Hz), 3.03 (1
H, dd, J = 4.2 Hz, 14.7 Hz), 3.66 (1H, d, J = 3.9
Hz), 4.70-4.79 (1H, m), 5.11 (1H, t, J = 3.8 Hz),
5.80 (1H, d, J = 8.1 Hz), 5.88 (1H, tt, J = 2.9 Hz,
53.0 Hz), 5.91 (1H, td, J = 5.7 Hz, 11.4 Hz), 6.2
3 (1H, d, J = 11.7 Hz), 6.98-7.17 (6H, m), 7.28-7.4
3 (3H, m), 7.46-7.60 (6H, m); IR (KBr) 3270, 2938,
1640, 1514, 1200, 1125, 783 cm ^-1 ; Anal.Calcd for
C _{3 5} H ₃₀ ClF ₄ NO ₃ : C, 67.36; H, 4.85; N, 2.24. Found:
C, 67.42; H, 4.80; N, 2.10.

Example 296 N-[(1RS, 2SR) -2-hydroxy-2- (2'-methoxy [1,1'-biphenyl] -4-yl) -1- [3-]
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide N-[(1RS, 2SR) -2- (4-bromo Phenyl)-
2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
0.530 g (0.895 mmol) of 5H-benzo [a] cycloheptene-1-carboxamide, 0.20 g (1.34 mmol) of 2-methoxyphenylboronic acid, tetrakis (triphenylphosphine) palladium (0)
0.10 g (0.089 mmol) and 0.19 g (1.79 mmol) of sodium carbonate were stirred at 90 ° C. for 1 day in 8 ml of toluene and 8 ml of water. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1), and crystallized from ethyl acetate / diisopropyl ether / hexane to obtain the desired product. White powder Yield 0.307 g Yield 55% mp 148-150 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.95-2.05
(2H, m), 2.16-2.22 (2H, m), 2.66 (2H, t, J = 5.7
Hz), 2.85 (1H, dd, J = 10.7 Hz, 14.9 Hz), 3.08 (1
H, dd, J = 4.2 Hz, 14.7 Hz), 3.48 (1H, d, J = 3.9
Hz), 3.82 (3H, s), 4.74-4.82 (1H, m), 5.09 (1H, t,
J = 3.6 Hz), 5.79 (1H, d, J = 8.7 Hz), 5.89 (1H, t
t, J = 2.9 Hz, 53.1 Hz), 5.91 (1H, td, J = 5.5 Hz,
11.2 Hz), 6.24 (1H, d, J = 11.7 Hz), 6.97-7.18 (8
H, m), 7.28-7.36 (3H, m), 7.49 (2H, d, J = 8.1 H
z), 7.57 (2H, d, J = 8.1 Hz); IR (KBr) 3264, 2938,
1638,1528, 1487, 1275, 1190, 1117, 762 cm ^-1 ; Ana
l. Calcd for C ₃₆ H ₃₃ F ₄ NO ₄・ 0.2H ₂ O: C, 69.38; H, 5.4
0; N, 2.25. Found: C, 69.11; H, 5.33; N, 2.05.

Example 297 N-[(1RS, 2SR) -2-hydroxy-2- (4′-methoxy [1,1′-biphenyl] -4-yl) -1- [3-]
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide N-[(1RS, 2SR) -2- (4-bromo Phenyl)-
2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
0.5H g (0.844 mmol) of 5H-benzo [a] cycloheptene-1-carboxamide, 0.26 g (1.69 mmol) of 4-methoxyphenylboronic acid, tetrakis (triphenylphosphine) palladium (0)
0.20 g (0.17 mmol) and sodium carbonate 0.1.
27 g (2.53 mmol) of toluene 10 ml-water 1
Stir in 0 ml at 90 ° C. for 1 day. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1), and crystallized from diisopropyl ether / hexane to obtain the desired product. White crystal Yield 0.310 g Yield 59% mp 162-163 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.94-2.03
(2H, m), 2.15-2.22 (2H, m), 2.66 (2H, t, J = 5.9
Hz), 2.83 (1H, dd, J = 10.7 Hz, 14.6 Hz), 3.05 (1
H, dd, J = 4.2 Hz, 14.7 Hz), 3.54 (1H, d, J = 3.6
Hz), 3.86 (3H, s), 4.73-4.81 (1H, m), 5.09 (1H, t,
J = 3.9 Hz), 5.78 (1H, d, J = 8.7 Hz), 5.88 (1H, t
t, J = 2.9 Hz, 53.1 Hz), 5.90 (1H, td, J = 5.7 Hz,
11.4 Hz), 6.23 (1H, d, J = 11.7 Hz), 6.96-7.16 (8
H, m), 7.30 (1H, t, J = 8.0 Hz), 7.49-7.59 (6H, m);
IR (KBr) 3299, 2930, 1638, 1530, 1503, 1277, 122
9, 1198, 1125, 820 cm ^-1 ; Anal.Calcd for C ₃₆ H ₃₃ F ₄ N
O ₄ : C, 69.78; H, 5.37; N, 2.26. Found: C, 69.69; H,
5.17; N, 2.10.

Example 298 N-[(1RS, 2SR) -2-hydroxy-2- (3′-me
Toxi [1,1'-biphenyl] -4-yl) -1- [3-
(1,1,2,2-tetrafluoroethoxy) benzene
[Ethyl] -6,7-dihydro-5H-benzo [a] cycl
Roheptene-1-carboxamide N-[(1RS, 2SR) -2- (4-bromophenyl)-
2-hydroxy-1- [3- (1,1,2,2-tetrafur
Oroethoxy) benzyl] ethyl] -6,7-dihydro-
5H-benzo [a] cycloheptene-1-carboxamide
0.500 g (0.844 mmol), 3-methoxyph
0.26 g (1.69 mmol) of phenylboronic acid, tet
Lakis (triphenylphosphine) palladium (0)
0.20 g (0.17 mmol) and sodium carbonate 0.1.
27 g (2.53 mmol) of toluene 10 ml-water 1
Stir in 0 ml at 90 ° C. for 1 day. Pour the reaction solution into water
And extracted twice with ethyl acetate. The collected organic layer is anhydrous sulfur
The extract was dried over sodium acid and the solvent was distilled off under reduced pressure. Remove the residue
Purified by Ricagel column chromatography (hexa
/ Ethyl acetate = 3 / 1-1 / 1), diisopropyl
Crystallization from ether-hexane gave the desired product. White
Crystal yield 0.241 g yield 46% mp 79-81 ° C;¹H-NMR (CDCl_Three, 300 MHz) δ 1.95-2.03
(2H, m), 2.16-2.22 (2H, m), 2.66 (2H, t, J = 5.7 H
z), 2.83 (1H, dd, J = 10.5 Hz, 14.7 Hz), 3.05 (1H,
dd, J = 4.1 Hz, 14.6 Hz), 3.60 (1H, d, J = 3.9 H
z), 3.87 (3H, s), 4.73-4.80 (1H, m), 5.10 (1H, t, J
 = 3.8 Hz), 5.79 (1H, d, J = 8.4 Hz), 5.88 (1H, t
t, J = 2.9 Hz, 53.0 Hz), 5.91 (1H, td, J = 5.7 Hz,
 11.4 Hz), 6.23 (1H, d, J = 11.7 Hz), 6.91 (1H, d
d, J = 2.1 Hz, 7.8 Hz), 6.99 (1H, dd, J = 1.5 Hz,
7.5 Hz), 7.03-7.20 (7H, m), 7.30 (1H, t, J = 7.8 H
z), 7.37 (1H, t, J = 8.0 Hz), 7.52 (2H, d, J = 8.1
 Hz), 7.61 (2H, d, J = 8.1 Hz); IR (KBr) 3268, 293
2, 1638, 1518, 1483, 1298, 1277, 1194, 1121, 779 c
m ^-1; Anal. Calcd for C₃₆H₃₃F_FourNO_Four: C, 69.78; H, 5.3
7; N, 2.26. Found: C, 69.76; H, 5.70; N, 2.07.

Example 299 N-[(1RS, 2SR) -2- (4'-formyl [1,
1'-biphenyl] -4-yl) -2-hydroxy-1- [3-
(1,1,2,2-tetrafluoroethoxy) benzene
[Ethyl] -6,7-dihydro-5H-benzo [a] cycl
Roheptene-1-carboxamide N-[(1RS, 2SR) -2- (4-bromophenyl)-
2-hydroxy-1- [3- (1,1,2,2-tetrafur
Oroethoxy) benzyl] ethyl] -6,7-dihydro-
5H-benzo [a] cycloheptene-1-carboxamide
0.822 g (1.388 mmol), 4-formylph
0.31 g (2.08 mmol) of phenylboronic acid, tet
Lakis (triphenylphosphine) palladium (0)
0.16 g (0.14 mmol) and sodium carbonate 0.1.
29 g (2.78 mmol) of toluene 10 ml-water 1
Stir in 0 ml at 90 ° C. for 1 day. Pour the reaction solution into water
And extracted twice with ethyl acetate. The collected organic layer is anhydrous sulfur
The extract was dried over sodium acid and the solvent was distilled off under reduced pressure. Remove the residue
Purified by Ricagel column chromatography (hexa
/ Ethyl acetate = 3 / 1-1 / 1), diisopropyl
Crystallization from ether-hexane gave the desired product. White
Powder Yield 0.214 g Yield 25% mp 174-176 ° C;¹H-NMR (CDCl_Three, 300 MHz) δ 1.97-2.04
 (2H, m), 2.16-2.22 (2H, m), 2.67 (2H, t, J = 5.9
Hz), 2.85 (1H, dd, J = 10.5 Hz, 14.7 Hz), 3.04 (1
H, dd, J = 3.8 Hz, 14.3 Hz), 3.69 (1H, d, J = 3.9
Hz), 4.72-4.80 (1H, m), 5.14 (1H, t, J = 3.5 Hz),
5.81 (1H, d, J = 8.4 Hz), 5.88 (1H, tt, J = 2.6 Hz,
 53.0 Hz), 5.91 (1H, td, J = 5.6 Hz, 11.4 Hz), 6.2
4 (1H, d, J = 11.7 Hz), 6.98-7.17 (6H, m), 7.31 (1
H, t, J = 7.8 Hz), 7.58 (2H, d, J = 8.1 Hz), 7.67
(2H, d, J = 8.4 Hz), 7.77 (2H, d, J = 8.1 Hz), 7.9
7 (2H, d, J = 8.1 Hz), 10.06 (1H, s); IR (KBr) 332
4, 2940, 1701, 1626, 1605,1532, 1308, 1275, 1200,
1119, 806, 774 cm^-1; Anal. Calcd for C₃₆H₃₁F_FourNO _Four:
C, 70.01; H, 5.06; N, 2.27. Found: C, 69.89; H, 5.
19; N, 2.01.

Example 300 N-[(1RS, 2SR) -2- (3′-formyl [1,
1'-biphenyl] -4-yl) -2-hydroxy-1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide N-[(1RS, 2SR) -2- (4-bromo Phenyl)-
2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
0.812 g (1.371 mmol) of 5H-benzo [a] cycloheptene-1-carboxamide, 0.41 g (2.74 mmol) of 3-formylphenylboronic acid, tetrakis (triphenylphosphine) palladium (0)
0.32 g (0.27 mmol) and sodium carbonate 0.1.
44 g (4.11 mmol) of toluene 10 ml-water 1
Stir in 0 ml at 90 ° C. for 1 day. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1), and crystallized from diisopropyl ether / hexane to obtain the desired product. Light brown powder Yield 0.285 g Yield 34% mp 103-105 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.95-2.04
(2H, m), 2.16-2.22 (2H, m), 2.67 (2H, t, J = 5.9
Hz), 2.84 (1H, dd, J = 10.8 Hz, 14.7 Hz), 3.05 (1
H, dd, J = 4.2 Hz, 14.4 Hz), 3.67 (1H, d, J = 3.9
Hz), 4.71-4.80 (1H, m), 5.14 (1H, t, J = 3.9 Hz),
5.81 (1H, d, J = 8.4 Hz), 5.89 (1H, tt, J = 2.8 Hz,
53.0 Hz), 5.91 (1H, td, J = 5.4 Hz, 12.9 Hz), 6.2
5 (1H, d, J = 12.0 Hz), 6.98-7.17 (6H, m), 7.31 (1
H, t, J = 8.0 Hz), 7.57-7.67 (5H, m), 7.88 (2H, d
d, J = 2.1 Hz, 7.2 Hz), 8.12 (1H, s), 10.10 (1H,
s); IR (KBr) 3264, 2938, 1701, 1640, 1518, 1449, 13
04, 1279, 1198, 1123, 793 cm ^-1 ; Anal.Calcd for C
₃₆ H ₃₁ F ₄ NO ₄ : C, 70.01; H, 5.06; N, 2.27. Found: C, 7
0.08; H, 5.19; N, 2.16.

Example 301 N-[(1RS, 2SR) -2- (2′-formyl [1,
1'-biphenyl] -4-yl) -2-hydroxy-1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide N-[(1RS, 2SR) -2- (4-bromo Phenyl)-
2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
0.812 g (1.371 mmol) of 5H-benzo [a] cycloheptene-1-carboxamide, 0.41 g (2.74 mmol) of 2-formylphenylboronic acid, tetrakis (triphenylphosphine) palladium (0)
0.32 g (0.27 mmol) and sodium carbonate 0.1.
44 g (4.11 mmol) of toluene 10 ml-water 1
Stir in 0 ml at 90 ° C. for 1 day. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1), and crystallized from diisopropyl ether / hexane to obtain the desired product. Light brown crystal Yield 0.423 g Yield 50% mp 195-196 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.96-2.04
(2H, m), 2.16-2.22 (2H, m), 2.67 (2H, t, J = 5.9
Hz), 2.86 (1H, dd, J = 10.5 Hz, 14.7 Hz), 3.06 (1
H, dd, J = 4.4 Hz, 14.6 Hz), 3.77 (1H, d, J = 3.9
Hz), 4.72-4.81 (1H, m), 5.16 (1H, t, J = 3.6 Hz),
5.85 (1H, d, J = 8.4 Hz), 5.90 (1H, tt, J = 2.7 Hz,
53.0 Hz), 5.93 (1H, td, J = 5.7 Hz, 11.4 Hz), 6.2
6 (1H, d, J = 11.7 Hz), 6.98-7.18 (6H, m), 7.32 (1
H, t, J = 7.8 Hz), 7.40-7.68 (7H, m), 8.04 (1H, d,
J = 8.1 Hz), 9.99 (1H, s); IR (KBr) 3227, 2930, 1
688,1636, 1304, 1198, 1123, 770 cm ^-1 ; Anal.Calcd
for C ₃₆ H ₃₁ F ₄ NO ₄ : C, 70.01; H, 5.06; N, 2.27. Foun
d: C, 70.00; H, 5.13; N, 2.20.

Example 302 N-[(1RS, 2SR) -2- [2 ′-(hydroxymethyl) [1,1′-biphenyl] -4-yl] -2-hydroxy-1- [3- (1 , 1,2,2-Tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide N-[(1RS, 2SR) -2- (2'-formyl [ 1,
1'-biphenyl] -4-yl) -2-hydroxy-1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 168 mg (0.272
Sodium borohydride (10 mg, 0.27 mmol) was added to a 3 ml solution of
The mixture was stirred for 0.5 hours as it was. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was stirred for 1 hour. The resulting precipitate was collected and washed with water and diisopropyl ether-hexane to obtain the desired product. White powder yield 137mg
Yield 81% mp 152-154 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.60 (1H,
t, J = 5.7 Hz), 1.95-2.04 (2H, m), 2.16-2.22 (2H,
m), 2.64-2.69 (2H, m), 2.86 (1H, dd, J = 10.7 Hz,
14.9 Hz), 3.08 (1H, dd, J = 4.1 Hz, 14.6 Hz), 3.6
2 (1H, d, J = 3.0 Hz), 4.62 (2H, d, J = 5.4 Hz),
4.72-4.80 (1H, m), 5.11 (1H, t, J = 3.8Hz), 5.82
(1H, d, J = 8.7 Hz), 5.90 (1H, tt, J = 2.7 Hz, 53.
0 Hz), 5.93 (1H, td, J = 5.8 Hz, 11.6 Hz), 6.25 (1
H, d, J = 11.7 Hz), 6.98 (1H, dd, J = 1.5 Hz, 7.5 H
z), 7.04-7.17 (5H, m), 7.27-7.43 (6H, m), 7.51-7.5
8 (3H, m); IR (KBr) 3289, 1638, 1526, 1200, 1125,
1036, 762 cm ^-1 ; Anal.Calcd for C ₃₆ H ₃₃ F ₄ NO ₄ : C, 6
9.78; H, 5.37; N, 2.26. Found: C, 69.47; H, 5.39;
N, 2.16.

Example 303 N-[(1RS, 2SR) -2- [3 ′-(hydroxymethyl) [1,1′-biphenyl] -4-yl] -2-hydroxy-1- [3- (1 , 1,2,2-Tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide N-[(1RS, 2SR) -2- (3′-formyl [ 1,
1'-biphenyl] -4-yl) -2-hydroxy-1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 123 mg (0.199
(Mmol) in a solution of methanol (3 ml) at room temperature, and 8 mg (0.20 mmol) of sodium borohydride was added thereto, followed by stirring for 0.5 hour. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was stirred for 1 hour. The resulting precipitate was collected and washed with water and diisopropyl ether-hexane to obtain the desired product. White powder Yield 101 mg Yield 82% mp 178-179 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.74 (1H,
t, J = 5.3 Hz), 1.95-2.03 (2H, m), 2.16-2.22 (2H,
m), 2.66 (2H, t, J = 5.9 Hz), 2.83 (1H, dd, J = 1
0.4 Hz, 14.6 Hz), 3.05 (1H, dd, J = 4.2 Hz, 14.4 H
z), 3.60 (1H, d, J = 3.9 Hz), 4.72-4.80 (1H, m), 4.
78 (2H, d, J = 4.2 Hz), 5.11 (1H, t, J = 3.6 Hz),
5.79 (1H, d, J = 8.4 Hz), 5.88 (1H, tt, J = 3.2 H
z, 53.0 Hz), 5.91 (1H, td, J = 5.9 Hz, 11.7 Hz),
6.24 (1H, d, J = 12.0 Hz), 6.98-7.16 (6H, m), 7.26
-7.64 (9H, m); IR (KBr) 3268, 1638, 1532, 1198, 11
27, 787 cm ^-1 ; Anal.Calcd for C ₃₆ H ₃₃ F ₄ NO ₄ : C, 69.7
8; H, 5.37; N, 2.26. Found: C, 69.47; H, 5.22; N,
2.15.

Example 304 N-[(1RS, 2SR) -2- [4 ′-(hydroxymethyl) [1,1′-biphenyl] -4-yl] -2-hydroxy-1- [3- (1 , 1,2,2-Tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide N-[(1RS, 2SR) -2- (4'-formyl [ 1,
1'-biphenyl] -4-yl) -2-hydroxy-1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 107 mg (0.173
7 mmol (0.17 mmol) of sodium borohydride was added to a 3 ml solution of methanol (3 mmol) in methanol at room temperature, and the mixture was stirred as it was for 0.5 hour. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was stirred for 1 hour. The resulting precipitate was collected and washed with water and diisopropyl ether-hexane to obtain the desired product. White powder Yield 85 mg Yield 80% mp 189-191 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
1.95-2.01 (2H, m), 2.14-2.24 (2H, m), 2.67 (2H, t,
J = 5.6 Hz), 2.89 (1H, dd, J = 11.0 Hz, 14.3Hz),
2.98 (1H, dd, J = 4.1 Hz, 14.6 Hz), 3.69 (1H, br
s), 4.72 (2H, d, J = 5.1 Hz), 4.72-4.81 (1H, m), 4.
87 (1H, d, J = 2.7 Hz), 5.06 (1H, t, J = 3.5 Hz),
5.87 (1H, td, J = 5.7 Hz, 11.6 Hz), 5.92 (1H, tt,
J = 2.9 Hz, 53.1 Hz), 6.20 (1H, d, J = 12.3 Hz),
6.69 (1H, d, J = 8.7 Hz), 6.96 (1H, d, J = 7.5 H
z), 7.02-7.16 (5H, m), 7.27 (1H, t, J = 7.8 Hz),
7.46 (2H, d, J = 7.8 Hz), 7.56-7.63 (6H, m); IR (K
Br) 3268, 1636, 1520, 1206, 1119 cm ^-1 ; Anal.Calcd
for C ₃₆ H ₃₃ F ₄ NO ₄ : C, 69.78; H, 5.37; N, 2.26. Foun
d: C, 69.53; H, 5.24; N, 2.14.

Example 305 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -5,5-dimethyl-
6,7-dihydro-5H-benzo [a] cycloheptene-1
-Carboxamide 1) 3-Methyl-3-phenylbutanoic acid 9.56 g (393 mmol) of powdered magnesium and 1 fragment of iodine were stirred in 10 ml of tetrahydrofuran while stirring 1-chloro-2-methyl-2-phenylpropane 2
A solution of 6.53 g (157.3 mmol) and 29.6 g (157 mmol) of 1,2-dibromoethane in 100 ml of tetrahydrofuran was added dropwise at a rate at which the reaction solution was slowly refluxed. After completion of the dropwise addition, the mixture was stirred at 60 ° C. for 4 hours. The reaction was cooled to -78 ° C and crushed dry ice 50
g was carefully added, and the temperature of the reaction solution was gradually raised to room temperature while stirring. The reaction solution was diluted with water, acidified with concentrated hydrochloric acid, and extracted twice with ethyl acetate. The solvent of the collected organic layer was distilled off under reduced pressure. The obtained residue was treated with sodium hydroxide (6 g).
And 200 ml of water. The resulting aqueous solution was washed with diethyl ether-hexane, acidified with concentrated hydrochloric acid,
Extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product. Yellow liquid Yield 20.83 g Yield 74% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.47 (6H, s), 2.65 (2H,
s), 7.17-7.40 (5H, m), 10.48 (1H, br s); IR (nea
t) 2967, 1699, 1634, 1260, 1167, 772, 700 cm ^{- 1} 2) 3-Methyl-3-phenyl-1-butanol A suspension of 8.62 g (228 mmol) of lithium aluminum hydride in 200 ml of tetrahydrofuran was Under ice-cooling, 20.26 g of 3-methyl-3-phenylbutanoic acid (1
(13.7 mmol) in 100 ml of tetrahydrofuran was added dropwise and stirred overnight at room temperature. After cooling the reaction solution with ice, 8 ml of water, 8 ml of 15% aqueous sodium hydroxide solution,
Excess lithium aluminum hydride was decomposed by sequentially adding 20 ml of water dropwise, and the mixture was stirred at room temperature for 2 hours. The resulting precipitate was removed by filtration, and the precipitate was washed with ethyl acetate. The solvent of the collected filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain the desired product. Colorless liquid Yield 18.09 g Yield 97% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.00 (1 H, t, J = 5.3 H)
z), 1.35 (6H, s), 1.95 (2H, t, J = 7.4 Hz), 3.44-3.
54 (2H, m), 7.14-7.40 (5H, m); IR (neat) 3333, 296
5, 1497, 1445, 1057, 1022, 764, 700 cm ^-1 3) 18.09 g of 3,5-dimethyl-5-phenyl-2-pentanoic acid 3-methyl-3-phenyl-1-butanol
(110.1 mmol), triethylamine 23.0 m
1 (165 mmol) in 150 ml of ethyl acetate was added dropwise with a solution of 15.1 g (132 mmol) of methanesulfonyl chloride in 30 ml of ethyl acetate under ice-cooling.
Stirred for minutes. The resulting precipitate (triethylamine hydrochloride)
Was filtered off and the precipitate was washed with ethyl acetate. The collected ethyl acetate solution was concentrated under reduced pressure to obtain a crude product of mesylate as a yellow liquid. 22.8 g of diethyl malonate
To a solution of (132 mmol) in 100 ml of tetrahydrofuran was slowly added 5.29 g (132 mmol) of a 60% sodium hydride paraffin suspension under ice-cooling, followed by stirring for 0.5 hour. To this, a solution of the liquid obtained above in 50 ml of tetrahydrofuran was added dropwise at room temperature, and the mixture was stirred at 60 ° C. overnight. After adding water to the reaction solution and stirring, the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-6 / 1), and diethyl (3-methyl-3-phenylbutyl) malonate (31.8 g) was added as a colorless liquid. As obtained. The liquid obtained above and 50 ml of concentrated hydrochloric acid were stirred in 100 ml of acetic acid at 100 ° C. overnight. After evaporating the reaction solution under reduced pressure, the obtained residue was stirred at 175 ° C for 4 hours to obtain the desired product. Yellow liquid Yield 18.86 g Yield 83% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.21-1.47 (2H, m), 1.31
(6H, s), 1.63-1.69 (2H, m), 2.25 (2H, t, J = 7.3
Hz), 7.14-7.23 (1H, m), 7.29-7.35 (4H, m); IR (nea
t) 2963, 1709, 1279, 766, 700 cm ^-1 4) 9,9-dimethyl-6,7,8,9-tetrahydro-
5H-benzo [a] cyclohepten-5-one 5,5-dimethyl-5-phenyl-2-pentanoic acid 18.8
To a solution of 6 g (91.43 mmol) and 2 drops of N, N-dimethylformamide in 100 ml of tetrahydrofuran was added dropwise 12.0 ml (137 mmol) of oxalyl chloride at room temperature, followed by stirring for 0.5 hour. The solvent of the reaction mixture was distilled off under reduced pressure to obtain an acid chloride as a yellow liquid. While stirring a suspension of 24.4 g (183 mmol) of aluminum chloride in 100 ml of methylene chloride, a solution of the acid chloride obtained above in 400 ml of methylene chloride was added dropwise thereto over 2 days. While cooling the reaction solution with ice, water was added to stop the reaction. The methylene chloride layer of the mixture was separated, and the aqueous layer was extracted with diethyl ether. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-6 / 1) to obtain the desired product. Yellow liquid Yield 5.780 g Yield 34% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.36 (6H, s), 1.83-2.02
(4H, m), 2.75 (2H, t, J = 6.8 Hz), 7.21-7.29 (1H,
m), 7.36-7.43 (3H, m); IR (neat) 2965, 1684, 1597,
1456, 1250, 764 cm ^-1 5) 9,9-dimethyl-6,7,8,9-tetrahydro-
5H-benzo [a] cyclohepten-5-ol 9,9-dimethyl-6,7,8,9-tetrahydro-5H-
5.780 g of benzo [a] cyclohepten-5-one (3
To a solution of 0.70 mmol) in 40 ml of methanol was added little by little 1.16 g (30.7 mmol) of sodium borohydride under ice-cooling, followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, diluted with water, and extracted twice with ethyl acetate. The collected organic layer is dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-6 / 1) to obtain the desired product. Yellow liquid Yield 5.245 g Yield 90% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.33 (3H, s), 1.45 (3H,
s), 1.61-1.94 (5H, m), 1.76 (1H, d, J = 4.5 Hz),
2.01-2.10 (1H, m), 5.15-5.20 (1H, m), 7.19-7.25 (2
H, m), 7.39-7.44 (1H, m), 7.58-7.62 (1H, m); IR (n
eat) 3335, 2926,1476, 1443, 1362, 1030, 760 cm -1 6) 4- bromo-9,9-dimethyl-6,7,8,9-tetrahydro -5H- benzo [a] cycloheptene-5- All 9,9-dimethyl-6,7,8,9-tetrahydro-5H-
Benzo [a] cyclohepten-5-ol 5.128 g
(26.95 mmol) and 6.89 g (59.3 mmol) of N, N, N ', N'-tetramethylethylenediamine in 100 ml of hexane under ice-cooling, 1.6 Mn.
37.1 ml of a hexane solution of -butyllithium (59.
(3 mmol) was added dropwise, followed by stirring at 35 ° C. overnight. After cooling the reaction mixture to −78 ° C., 14.0 g (53.9 mmol) of 1,2-dibromotetrafluoroethane was added, the temperature was raised to room temperature with stirring, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted twice with ethyl acetate.
The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product is purified by silica gel column chromatography (hexane / ethyl acetate = 1).
5/1), the desired product was obtained. 4.614 g of a yellow solid
The crystals were recrystallized from hexane to give white crystals. mp 91-92 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.38 (3H,
s), 1.40 (3H, s), 1.54-1.62 (1H, m), 1.71-1.88 (2
H, m), 2.05-2.36 (3H, m), 2.22 (1H, d, J = 4.8Hz),
5.56-5.59 (1H, m), 7.05 (1H, t, J = 8.0 Hz), 7.42
-7.45 (2H, m); IR (KBr) 3354, 2955, 1447, 945, 918,
775, 747 cm ^-1 ; Anal.Calcd for C ₁₃ H ₁₇ BrO: C, 58.0
1; H, 6.37. Found: C, 58.34; H, 6.51.7. 1) 1-Bromo-5,5-dimethyl-6,7-dihydro-5
3. H-benzo [a] cycloheptene 4-bromo-9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzo [a] cyclohepten-5-ol
A solution of 402 g (16.35 mmol) and 0.31 g (1.64 mmol) of p-toluenesulfonic acid monohydrate in 80 ml of toluene was heated in a reaction vessel equipped with a Dean-Stark trap for 0.5 hour under dehydrating conditions. Refluxed.
After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane) to obtain the desired product. Colorless liquid Yield 3.887 g Yield 95% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.34 (6H, s), 1.83 (2H,
t, J = 6.8 Hz), 2.42-2.52 (2H, m), 6.05 (1H, td,
J = 4.4 Hz, 12.5 Hz), 6.91 (1H, td, J = 1.9Hz), 6.
98 (1H, t, J = 8.0 Hz), 7.33 (1H, d, J = 7.8 Hz),
7.49 (1H, dd, J = 1.3 Hz, 7.9 Hz); IR (neat) 2965,
2919, 1454, 1420, 1404, 885, 766 cm - 1 8) 5,5- dimethyl-6,7-dihydro -5H- benzo [a] cycloheptene-1-carboxylic acid 1-bromo-5,5-dimethyl - To a solution of 3.879 g (15.44 mmol) of 6,7-dihydro-5H-benzo [a] cycloheptene in 30 ml of diethyl ether was added -78 ° C.
1.6 Mn-butyllithium hexane solution 11.6
After dropwise addition of 1 ml (18.5 mmol), the mixture was stirred at room temperature for 4 hours. After cooling the reaction mixture to −78 ° C., 5 g of crushed dry ice was added, and the temperature was raised to room temperature with stirring. The reaction mixture was diluted with water, washed with diethyl ether, acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude crystals were washed with hexane to obtain the desired product. White crystals Yield 1.540 g Yield 4
6% mp 165-166 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.37 (6H,
s), 1.89 (2H, t, J = 6.6 Hz), 2.44-2.54 (2H, m),
6.08 (1H, td, J = 4.4 Hz, 12.4 Hz), 6.92 (1H, td,
J = 2.0 Hz, 12.3 Hz), 7.22 (1H, t, J = 7.9 Hz), 7.
57 (1H, dd, J = 1.2 Hz, 8.0 Hz), 7.66 (1H, dd, J =
1.4 Hz, 7.6 Hz); IR (KBr) 3050-2650,1688, 1426, 13
06, 1279, 775, 764 cm ^-1 ; Anal.Calcd for C ₁₄ H ₁₆ O ₂ :
C, 77.75; H, 7.46. Found: C, 77.99; H, 7.34.9) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1, 1,2,2-tetrafluoroethoxy) benzyl] ethyl] -5,5-dimethyl-6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- 0.379 g of (4-fluorophenyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol
(1.049 mmol), 0.23 g (1.05 mmol) of 5,5-dimethyl-6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid, 1-hydroxybenzotriazole hydrate 0 While stirring 0.16 g (1.05 mmol) in 10 ml of acetonitrile, 0.20 g (1.05 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. did. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White powder Yield 0.545 g Yield 93% mp 101-104 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.28 (6H,
s), 1.76 (2H, t, J = 6.6 Hz), 2.36-2.45 (2H, m),
2.74 (1H, dd, J = 10.6 Hz, 14.2 Hz), 3.00 (1H, dd,
J = 3.8 Hz, 14.4 Hz), 3.45 (1H, br s), 4.65-4.79
(1H, m), 5.01 (1H, d, J = 3.6 Hz), 5.69 (1H, d, J
= 9.4 Hz), 5.74 (1H, td, J = 4.2 Hz, 12.3 Hz), 5.8
9 (1H, tt, J = 2.9 Hz, 53.3 Hz), 6.12 (1H, d, J =
13.2 Hz), 6.77 (1H, d, J = 6.6 Hz), 7.02-7.15 (6H,
m), 7.26-7.40 (2H, m), 7.45 (2H, dd, J = 5.3 Hz,
8.7 Hz); IR (KBr) 3357, 2965, 1638, 1505, 1227, 11
^{. 98,1130 cm -1; Anal Calcd for} C 31 H 30 F 5 NO 3: C, 66.5
4; H, 5.40; N, 2.50. Found: C, 66.30; H, 5.50; N,
2.60.

Example 306 N-[(1RS, 2SR) -2-hydroxy-2- [4- (methylsulfonyl) phenyl] -1- [3- (1,1,2,2
2-tetrafluoroethoxy) benzyl] ethyl] -6
7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 1) Ethyl 3- [4- (methylsulfonyl) phenyl] -3-oxopropanoate 4- (methylsulfonyl) acetophenone (10 g, 4
2.2 mmol), a mixture of ethanol (0.2 ml) and diethyl carbonate (50 ml) was mixed with sodium hydride (3.
(37 g, 60% oily, 84.4 mmol) was added little by little, and the mixture was stirred at room temperature for 2 hours and at 60 ° C for 1 hour. The reaction solution was cooled, 1N hydrochloric acid (30 ml) was added, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel chromatography (hexane: ethyl acetate = 3:
Purification in 1) gave the desired product (3.76 g, 33%) as crystals. mp 50-52 ° C IRνmax ^KBr cm ^-1 : 1738, 1622, 1427, 1304, 1250, 1198,
_{1148, 1090. Anal Calcd for C 12} H 14 O 5 S (MW270.30) Calcd:. C, 53.32; H, 5.22 Found:. C, 53.46; H, 5.25 1 H-NMR (CDCl 3) δ: 1.27 (3H × 1/2, t, J = 7.1 Hz), 1.
36 (3H × 1/2, t, J = 7.1Hz), 3.08 (3H × 1/2, s), 3.10
(3H × 1/2, s), 4.04 (2H × 1/2, q, J = 7.1 Hz), 4.23 (2H
× 1/2, q, J = 7.1 Hz), 5.76 (1H × 1/2, s), 7.95-8.20
(4H, m). 2) Ethyl 3- [4- (methylsulfonyl) phenyl] -3-oxo-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoate 3- ( To a solution of 1,1,2,2-tetrafluoroethoxy) toluene (2.84 ml, 16.8 mmol) in ethyl acetate (30 ml) was added N-bromosuccinimide (3.
(0 g, 16.8 mmol) and 2,2'-azobisisobutyronitrile (0.1 g) were added and the mixture was refluxed for 2 hours.
After the reaction solution was concentrated under reduced pressure, diethyl ether and hexane were added to remove insolubles, and washed with diethyl ether. The filtrate was distilled off under reduced pressure to obtain 3- (1,1,2,2-tetrafluoroethoxy) -1-bromomethylbenzene.
Ethyl 3- [4- (methylsulfonyl) phenyl] -3-oxopropanoate (3.5 g, 13.0 mmol) in 1,
Sodium hydride (0.52 g, 60% oily, 13.0 mmol) was added to a solution of 2-dimethoxyethane (30 ml) under ice cooling, and the mixture was stirred for 10 minutes. This was obtained above 3-
1,2-dimethoxyethane of (1,1,2,2-tetrafluoroethoxy) -1-bromomethylbenzene (5 m
l) The solution was added dropwise and stirred at room temperature for 4 hours. Water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1-2: 1) to give the desired product (3.03 g, 49%) as an oil. IRνmax ^Neat cm ^-1 : 1738, 1694, 1319, 1302, 1196, 115
^{4, 1121. 1 H-NMR (} CDCl 3) δ: 1.13 (3H, t, J = 7.1 Hz), 3.07 (3
H, s), 3.37 (2H, d, J = 7.6 Hz), 4.11 (2H, q, J = 7.1
Hz), 4.60 (1H, t, J = 7.6 Hz), 5.89 (1H, tt, J = 53.
2, 3.0 Hz), 7.00-7.35 (4H, m), 7.95-8.20 (4H, m). 3) (2RS, 3RS) -3- [4- (methylsulfonyl) phenyl] -3-hydroxy-2- [3- (1,1,
Ethyl 2,2-tetrafluoroethoxy) benzyl] propanoate To a suspension of anhydrous zinc chloride (1.72 g, 12.6 mmol) in diethyl ether (20 ml) was added sodium borohydride (0.95 g, 25.2 mmol). ) Was added in small portions and stirred for 1 hour. The insolubles were removed by filtration and washed with diethyl ether. The filtrate was cooled on ice, and 3- [4- (methylsulfonyl) phenyl] -3-oxo-2- [3- (1,
A solution of ethyl 1,2,2-tetrafluoroethoxy) benzyl] propanoate (3.0 g, 6.30 mmol) in diethyl ether (10 ml) was added. After stirring at room temperature for 1 hour, the mixture was ice-cooled again and the reaction was stopped with 1N hydrochloric acid. The obtained mixture was extracted with ethyl acetate (100 ml), washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1-1: 1) to give the desired product (2.
(60 g, 86%) as a colorless oil. ^{IRνmax Neat cm -1: 1726, 1306} , 1198, 1152, 1090, 774. 1 H-NMR (CDCl 3) δ: 0.97 (3H, t, J = 7.1 Hz), 2.80-3.
10 (3H, m), 3.06 (3H, s), 3.35 (1H, d, J = 2.6 Hz),
3.95 (2H, d, J = 7.1 Hz), 5.15-5.25 (1H, m), 5.89 (1
H, tt, J = 53.1, 3.0 Hz), 6.85-7.10 (3H, m), 7.21 (1
H, d, J = 7.6 Hz), 7.61 (2H, d, J = 8.6 Hz), 7.94 (2
H, d, J = 8.6 Hz). 4) (2RS, 3RS) -3- [4- (methylsulfonyl) phenyl] -3-hydroxy-2- [3- (1,1,
2,2-Tetrafluoroethoxy) benzyl] propanoic acid (2RS, 3RS) -3- [4- (methylsulfonyl) phenyl] -3-hydroxy-2- [3- (1,1,2,2-tetrafluoro Ethoxy) benzyl] ethyl propanoate (2.55 g, 5.33 mmol) in ethanol (20
1N sodium hydroxide aqueous solution (10.7 ml)
ml, 10.7 mmol) and stirred at room temperature for 1 hour. The reaction mixture was acidified with 1N hydrochloric acid (30 ml), and extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give the desired product (2.30 g, 96%) as an oil. IRνmax ^Neat cm ^-1 : 1715, 1302, 1198, 1148, 1121, 109
^{0, 961. 1 H-NMR (} CDCl 3) δ: 2.80-3.05 (2H, m), 3.05 (3H, s),
3.08 (1H, d, J = 4.0 Hz), 5.22 (1H, d, J = 4.0 H
z), 5.89 (1H, tt, J = 53.0, 2.8 Hz), 6.90-7.10 (3H,
m), 7.22 (1H, d, J = 8.0 Hz), 7.60 (2H, d, J = 8.2 H
z), 7.90 (2H, d, J = 8.2 Hz). 5) (4RS, 5SR) -5- [4- (methylsulfonyl) phenyl] -4- [3- (1,1,2,2-tetra Fluoroethoxy) benzyl] -1,3-oxazolidine-2-
On (2RS, 3RS) -3- [4- (methylsulfonyl) phenyl] -3-hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propanoic acid (2.2
0 g, 4.88 mmol) of tetrahydrofuran (20
ml) solution into diphenylphosphoryl azide (1.37 m
1, 6.35 mmol) and triethylamine (0.95
ml, 6.84 mmol) and stirred at room temperature for 1 hour. Then, after heating and refluxing for 1 hour, water (100 ml)
And extracted with ethyl acetate (100 ml × 2). The extract was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1-1: 3), and the precipitated crystals were added to hexane and collected by filtration to obtain the desired product (2.07 g, 95%). . ^{. mp 123-125 ℃ IRνmax KBr cm -1} : 1740, 1588, 1314, 1152, 1115, 959. Anal Calcd for C 19 H 17 F 4 NO 5 S (MW447.40) Calcd: C, 51.01; H, 3.83 ; N, 3.13 Found:. C , 50.87; H, 3.68; N, 2.98 1 H-NMR (CDCl 3) δ: 2.20-2.40 (2H, m), 3.10 (3H, s),
4.25-4.45 (1H, m), 5.10 (1H, s), 5.89 (1H, d, J = 7.8
Hz), 5.90 (1H, tt, J = 53.2, 3.0 Hz), 6.80-7.00 (2
H, m), 7.10-7.20 (1H, m), 7.34 (1H, d, J = 8.0 Hz),
7.60 (2H, d, J = 8.0 Hz). 6) (1RS, 2SR) -2-amino-1- [4- (methylsulfonyl) phenyl] -3- [3- (1,1,2,2-
Tetrafluoroethoxy) phenyl] -1-propanol (4RS, 5SR) -5- [4- (methylsulfonyl) phenyl] -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1 , 3-Oxazolidin-2-one (1.80 g, 4.02 mmol) in ethanol (20
ml) solution, 8N aqueous sodium hydroxide solution (1.5
(1 ml, 12.07 mmol) and the mixture was heated under reflux for 3 hours. Water (100 ml) was added to the reaction solution, and extracted with ethyl acetate (200 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from hexane-diethyl ether to obtain the desired product (1.49 g, 86%). mp 93-95 ° C IRνmax ^KBr cm ^-1 : 1586, 1298, 1200, 1148, 1117, 766. Anal.Calcd for C ₁₈ H ₁₉ F ₄ NO ₄ S ・ 1 / 2H ₂ O (MW430.42) Calcd: C , 50.22; H, 4.68; N , 3.25 Found:. C, 50.11; H, 4.43; N, 3.10 1 H-NMR (CDCl 3) δ: 2.37 (1H, dd, J = 13.6, 10.2 Hz),
2.66 (1H, dd, J = 13.6, 2.8 Hz), 3.08 (3H, s), 3.30
-3.50 (1H, m), 4.81 (1H, d, J = 4.4 Hz), 5.90 (1H, t
t, J = 53.1, 2.5 Hz), 6.9-7.20 (3H, m), 7.30-7.40 (1
H, m), 7.62 (2H, d, J = 8.2 Hz), 7.96 (2H, d, J = 8.
2 Hz). 7) N-[(1RS, 2SR) -2-hydroxy-2-
[4- (methylsulfonyl) phenyl] -1- [3- (1,
1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- [4- (methylsulfonyl) ) Phenyl] -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] -1-propanol 0.3
01g (0.714 mmol), 6,7-dihydro-5H
-Benzo [a] cycloheptene-1-carboxylic acid 0.13
g (0.71 mmol) and 0.11 g (0.71 mmol) of 1-hydroxybenzotriazole hydrate in 10 ml of acetonitrile while stirring with 1-ethyl-3- (3- (3-ethyl-3-benzotriazole).
Dimethylaminopropyl) carbodiimide hydrochloride
14 g (0.71 mmol) was added and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-ethyl acetate), and crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White powder yield 0.2
93g yield 69% mp 154-157 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.93-2.06
(2H, m), 2.15-2.24 (2H, m), 2.67 (2H, t, J = 5.6
Hz), 2.80 (1H, dd, J = 11.8 Hz, 14.6 Hz), 2.95 (1
H, dd, J = 4.6 Hz, 14.4 Hz), 3.06 (3H, s), 4.22 (1
H, d, J = 4.2 Hz), 4.62-4.75 (1H, m), 5.19 (1H, t,
J = 3.5 Hz), 5.86 (1H, d, J = 8.2 Hz), 5.89 (1H, t
t, J = 3.0 Hz, 53.1 Hz), 5.95 (1H, td, J = 5.5 Hz,
11.8 Hz), 6.25 (1H, d, J = 12.0 Hz), 6.97-7.35 (7
H, m), 7.67 (2H, d, J = 8.4 Hz), 7.93 (2H, d, J =
8.0 Hz); IR (KBr) 3486, 3330, 2932, 1645, 1532, 13
02,1271, 1200, 1146, 1123, 768 cm ^-1 ; Anal.Calcd f
or CHFNOS ・ 0.5H ₂ O: C, 59.99; H, 5.03; N, 2.33. Foun
d: C, 60.02; H, 4.88; N, 2.48.

Example 307 1- (2-Ethylbutyl) -N-[(1RS, 2SR) -2-
(4-Fluorophenyl) -2-hydroxy-1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] cyclohexanecarboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (1,1,2,2 0.335 g of 2-tetrafluoroethoxy) phenyl] propan-1-ol
(0.927 mmol), 0.22 g (1.02 mmol) of 1- (2-ethylbutyl) cyclohexanecarboxylic acid, 0.11 g of 4-N, N-dimethylaminopyridine
0.14 g (0.93 mmol) of 1-hydroxybenzotriazole hydrate (0.93 mmol) in 10 ml of acetonitrile while stirring 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. 18
g (0.93 mmol) was added and the mixture was stirred at 80 ° C. for 1 day. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-2 /
1) The desired product was obtained. Colorless liquid Yield 0.416 g Yield 81% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 0.69-0.75 (6H, m), 0.96
-1.47 (15H, m), 1.64-1.76 (2H, m), 2.67 (1H, dd, J
= 11.0 Hz, 14.6 Hz), 4.1 Hz, 14.6 Hz), 4.03 (1H,
d, J = 4.2 Hz), 4.42-4.50 (1H, m), 4.98 (1H, t, J
= 3.0 Hz), 5.60 (1H, d, J = 7.2 Hz), 5.88 (1H, tt,
J = 2.9 Hz, 53.1 Hz), 6.97 (1H, s), 7.04-7.11 (4H,
m), 7.28 (1H, t, J = 8.0 Hz), 7.40 (2H, dd, J =
5.3 Hz, 8.6 Hz); IR (neat) 3378, 2932, 2861, 1636,
1609, 1508, 1449, 1304, 1279, 1223, 1196, 1123 cm
^-1

Example 308 4-[(1RS, 2SR) -2-[(tert-butoxycarbonyl) amino] -1-hydroxy-3- [3- (1,
Methyl 1,2,2-tetrafluoroethoxy) phenyl] propyl] benzoate 1) 3- [4- (methoxycarbonyl) phenyl] -3-
Benzyl oxopropionate 50.95 g of 4- (methoxycarbonyl) benzoic acid (2
52.8 g of 1,1'-carbonyldiimidazole was added to a solution of 82.8 mmol) in 400 ml of tetrahydrofuran.
(311 mmol) was added at room temperature, and the mixture was stirred as it was for 2 hours. 200 ml of dimethyl sulfoxide was added to this mixture,
Malonic acid monobenzyl ester monopotassium salt 78.8
g (339 mmol), magnesium chloride 16.2 g
(170 mmol) at room temperature and stirred at room temperature overnight. After diluting the reaction solution with ethyl acetate and water and acidifying the reaction solution with concentrated hydrochloric acid, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-2 / 1) to obtain the desired product. Light yellow solid Yield: 31.19 g Yield: 35% Recrystallization from ethyl acetate-diethyl ether-hexane gave pale yellow crystals. mp 74-75 ° C; ¹ H-NMR (CDCl ₃ , 2
00 MHz) δ 3.94 (1.2H, s), 3.96 (1.8H, s), 4.07
(1.2 Hz, s), 5.20 (1.2H, s), 5.27 (0.8H, s), 5.80
(0.4H, s), 7.22-7.43 (5H, m), 7.84 (0.8H, d, J = 8.8
Hz), 7.97 (1.2H, d, J = 8.4 Hz), 8.08 (0.8H, d, J
= 8.0 Hz), 8.12 (1.2H, d, J = 8.8 Hz); IR (KBr) 1
721, 1281, 1211, 1204, 1109, 818, 731 cm ^-1 ; Anal.
Calcd for C ₁₈ H ₁₆ O ₅ : C, 69.22; H, 5.16. Found: C, 6
9.40; H, 5.24.2) 3- [4- (methoxycarbonyl) phenyl] -3-
Benzo oxo-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propionate 48.4 g (233 mmol) of 3- (1,1,2,2-tetrafluoroethoxy) toluene, N -Bromosuccinimide (41.4 g, 233 mmol) and 2,2'-azobis (isobutyronitrile) 0.1 g
The mixture was heated under reflux in 0 ml for 0.5 hours. After cooling the reaction solution to room temperature, a white precipitate was removed by filtration, and the precipitate was washed with diethyl ether. The solvent of the collected filtrate was distilled off under reduced pressure,
A crude product of 3- (1,1,2,2-tetrafluoroethoxy) benzyl bromide was obtained as a pale yellow liquid. 3-
Liquid paraffin suspension 8 of 60% sodium hydride in a solution of 66.08 g (211.6 mmol) of benzyl [4- (methoxycarbonyl) phenyl] -3-oxopropionate in 200 ml of 1,2-dimethoxyethane 8 under ice-cooling .
89 g (222 mmol) was added, and the mixture was stirred as it was for 0.5 hour. To this was added a solution of 3- (1,1,2,2-tetrafluoroethoxy) benzyl bromide obtained above in 50 ml of 1,2-dimethoxyethane at room temperature, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water and extracted twice with ethyl acetate.
The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 /
1-2 / 1) to obtain the desired product. Pale yellow liquid yield 98.
99 g Yield 90% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 3.36 (2H, d, J = 7.2 H
z), 3.95 (3H, s), 4.63 (1H, t, J = 7.4 Hz), 5.03 (1
H, d, J = 16.8 Hz), 5.08 (1H, d, J = 15.9 Hz), 5.8
8 (1H, tt, J = 2.7 Hz, 53.1 Hz), 7.01-7.49 (9H,
m), 7.93 (2H, d, J = 8.4 Hz), 8.05 (2H, d, J = 8.1
Hz); IR (neat) 1728 , 1694, 1281, 1196,1119 cm -1 3) (2RS, 3RS) -3- hydroxy-3- [4-
(Methoxycarbonyl) phenyl] -2- [3- (1,
1,2,2-Tetrafluoroethoxy) benzyl] benzyl benzyl propionate While stirring 25.0 g (382 mmol) of zinc chloride in 250 ml of diethyl ether, 28.9 g (764 mmol) of sodium borohydride was added at room temperature, and the mixture was allowed to stand. Stir for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. The resulting solution was added to 3- [4- (methoxycarbonyl) phenyl] -3-oxo-2- [3- (1,
98.98 g (190.9 mmol) of benzyl 1,2,2-tetrafluoroethoxy) benzyl] propionate
Is added dropwise under ice-cooling to a 100 ml solution of diethyl ether.
The mixture was stirred for 1 hour. Dilute hydrochloric acid was added little by little to the reaction solution to decompose excess zinc borohydride, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-2 / 1) to obtain the desired product. Colorless liquid Yield 69.90 g Yield 70% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.93-3.10 (4H, m), 3.92
(3H, s), 4.83 (1H, d, J = 12.3 Hz), 4.89 (1H, d, J
= 12.3 Hz), 5.11 (1H, t, J = 3.6 Hz), 5.87 (1H, t
t, J = 2.9 Hz, 53.2 Hz), 6.91-7.03 (5H, m), 7.16-
7.38 (4H, m), 7.44 (2H, d, J = 8.4 Hz), 7.99 (2H,
d, J = 8.4 Hz); IR (neat) 3480, 1723,1281, 1196, 1
^{119 cm -1 4) (4RS,} 5SR) -5- [4- ( methoxycarbonyl) phenyl] -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine -
2-one (2RS, 3RS) -3-hydroxy-3- [4- (methoxycarbonyl) phenyl] -2- [3- (1,1,2,2-
A solution of 69.90 g (134.3 mmol) of benzyl tetrafluoroethoxy) benzyl] propionate in 200 ml of ethanol was hydrogenated overnight at room temperature and normal pressure using 5 g of 10% palladium / carbon (containing 50% water) as a catalyst. After removing the catalyst by filtration, washing with ethanol, the solvent of the collected filtrate was distilled off under reduced pressure to obtain crude (2RS, 3RS)
3-Hydroxy-3- [4- (methoxycarbonyl) phenyl] -2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propionic acid was obtained as a colorless foam. The foam obtained above was dissolved in 150 ml of tetrahydrofuran, 22.5 ml (161 mmol) of triethylamine and 40.7 g of diphenylphosphoryl azide (148)
Mmol) and stirred at 70 ° C. overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate =
3 / 1-ethyl acetate), N, N-dimethylformamide-
Crystallization from diisopropyl ether gave the desired product. White powder Yield 40.33 g Yield 70% mp 155-158 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.17-2.34
(2H, m), 3.95 (3H, s), 4.25-4.36 (1H, m), 5.07 (1
H, br s), 5.87 (1H, d, J = 7.8 Hz), 5.89 (1H, tt,
J = 2.8 Hz, 53.0 Hz), 6.85 (1H, s), 6.94 (1H, d, J
= 7.8 Hz), 7.10 (1H, d, J = 8.4 Hz), 7.30 (1H, t,
J = 8.0 Hz), 7.46 (2H, d, J = 8.0 Hz), 8.11 (2H,
d, J = 8.4 Hz); IR (KBr) 3250, 1736, 1279, 1206, 1
113 cm ^-1 ; Anal.Calcd for C ₂₀ H ₁₇ F ₄ NO ₅・ 0.5DMF: C, 55.6
7; H, 4.45; N, 4.53.Found: C, 55.60; H, 4.18; N, 4.8
3.5) (4RS, 5SR) -5- [4- (methoxycarbonyl) phenyl] -2-oxo-4- [3- (1,1,2,2
Tert-Butyl 2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine-3-carboxylate (4RS, 5SR) -5- [4- (methoxycarbonyl)
20.04 g (46.89 mmol) of phenyl] -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidin-2-one, di-te dicarbonate
tert-butyl 12.3 g (56.3 mmol), 4-N,
A solution of 0.57 g (4.69 mmol) of N-dimethylaminopyridine in 150 ml of acetonitrile was stirred at room temperature overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-2 / 1), and crystallized from ethyl acetate-diisopropyl ether-hexane. The desired product was obtained. White crystals Yield 21.14 g Yield 86% mp 140-141 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.52 (9H,
s), 2.59 (1H, dd, J = 8.9 Hz, 14.3 Hz), 2.91 (1H,
dd, J = 4.2 Hz, 14.1 Hz), 3.93 (3H, s), 4.81-4.88
(1H, m), 5.73 (1H, d, J = 6.9 Hz), 5.85 (1H, tt, J
= 2.9 Hz, 53.1 Hz), 6.35 (1H, s), 6.62 (1H, d, J =
7.5 Hz), 6.95 (1H, d, J = 8.7 Hz), 7.06 (1H, t, J
= 8.0 Hz), 7.24 (2H, d, J = 8.1 Hz), 7.93 (2H, d,
J = 8.7Hz); IR (KBr) 1786, 1717, 1360, 1331, 1281,
1200, 1113, 1071 cm ^-1 ; Anal.Calcd for C ₂₅ H ₂₅ F ₄ NO
₇ : C, 56.93; H, 4.78; N, 2.66. Found: C, 57.05; H,
4.76; N, 2.71.6) 4-[(1RS, 2SR) -2-[(tert-butoxycarbonyl) amino] -1-hydroxy-3- [3-
Methyl (1,1,2,2-tetrafluoroethoxy) phenyl] propyl] benzoate (4RS, 5SR) -5- [4- (methoxycarbonyl)
Tert-butyl phenyl] -2-oxo-4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine-3-carboxylate 20.82 g (3
1.66 g of sodium hydroxide was added to a solution of 9.47 mmol) in 50 ml of methanol and 100 ml of tetrahydrofuran.
A solution of (41.4 mmol) in methanol (20 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 16.05 g Yield 81% mp 148-150 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.36 (9H,
s), 2.73 (2H, d, J = 6.0 Hz), 3.45 (1H, br s), 3.9
3 (3H, s), 4.05-4.11 (1H, m), 4.61 (1H, brd, J =
8.4 Hz), 5.03 (1H, br s), 5.89 (1H, tt, J = 2.9 H
z, 53.1 Hz), 6.94 (1H, s), 7.00 (1H, d, J = 7.5 H
z), 7.05 (1H, dd, J = 1.4 Hz, 8.3 Hz), 7.26 (1H, t,
J = 8.0 Hz), 7.49 (2H, d, J = 8.1 Hz), 8.05 (2H,
d, J = 8.4Hz); IR (KBr) 3330, 3206, 1721, 1678, 15
51, 1300, 1283, 1202, 1175, 1113, 1098 cm ^-1 ; Anal.
_{Calcd for C 24 H 27 F 4} NO 6: C, 57.48; H, 5.43; N, 2.7
9.Found: C, 57.43; H, 5.71; N, 2.62.

Example 309 4-[(1RS, 2SR) -2-[(6,7-dihydro-5
H-benzo [a] cyclohepten-1-ylcarbonyl)
Amino] -1-hydroxy-3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propyl] methyl benzoate 1) 4-[(1RS, 2SR) -2-amino-1-hydroxy Methyl-3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propyl] benzoate 4-[(1RS, 2SR) -2-[(tert-butoxycarbonyl) amino] -1-hydroxy -3- [3- (1,
A solution of 15.72 g (31.35 mmol) of methyl 1,2,2-tetrafluoroethoxy) phenyl] propyl] benzoate and 10 ml of concentrated hydrochloric acid in 150 ml of methanol was prepared.
Stirred at 0 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, diluted with water, made alkaline with potassium carbonate, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 12.27 g Yield 98% mp 100-101 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.37 (1H,
dd, J = 10.5 Hz, 13.8Hz), 2.72 (1H, dd, J = 3.2 H
z, 13.7 Hz), 3.34 (1H, ddd, J = 3.4 Hz, 4.3Hz, 10.
4 Hz), 3.93 (3H, s), 4.77 (1H, d, J = 4.5 Hz), 5.8
9 (1H, tt, J = 2.8 Hz, 53.3 Hz), 6.97 (1H, s), 7.02
-7.09 (2H, m), 7.29 (1H, t, J = 7.8Hz), 7.48 (2H,
d, J = 8.1 Hz), 8.06 (2H, d, J = 8.4 Hz); IR (KBr)
3150-2850, 1725, 1281, 1198, 1111 cm ^-1 ; Anal.
cd for C ₁₉ H ₁₉ F ₄ NO ₄ : C, 56.86; H, 4.77; N, 3.49. Fo
und: C, 56.68; H, 4.92; N, 3.26.2) 4-[(1RS, 2SR) -2-[(6,7-dihydro-5H-benzo [a] cyclohepten-1-ylcarbonyl) amino] -1-Hydroxy-3- [3- (1,1,2,2
Methyl 2-tetrafluoroethoxy) phenyl] propyl] benzoate 4-[(1RS, 2SR) -2-amino-1-hydroxy-3
Methyl-[3- (1,1,2,2-tetrafluoroethoxy) phenyl] propyl] benzoate (10.80 g (2
6.91 mmol), 5.06 g of 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (2
4.12 g (26.9 mmol) of 1-hydroxybenzotriazole hydrate in 10 ml of acetonitrile while stirring 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. 16g
(26.9 mmol) was added and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether to obtain the desired product. White crystals Yield 13.24 g Yield 86% mp 137-138 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.98-2.04
(2H, m), 2.16-2.22 (2H, m), 2.66 (2H, t, J = 5.9
Hz), 2.80 (1H, dd, J = 10.8 Hz, 14.4 Hz), 2.95 (1
H, dd, J = 4.4 Hz, 14.6 Hz), 3.86 (1H, d, J = 4.2
Hz), 3.93 (3H, s), 4.66-4.72 (1H, m), 5.15 (1H, t,
J = 3.8 Hz), 5.79 (1H, d, J = 8.4 Hz), 5.88 (1H, t
t, J = 2.9 Hz, 53.1 Hz), 5.92 (1H, td, J = 5.7 Hz,
11.4 Hz), 6.23 (1H, d, J = 11.4 Hz), 6.97-7.11 (5
H, m), 7.16 (1H, dd, J = 1.1 Hz, 7.4 Hz), 7.29 (1H,
t, J = 8.0 Hz), 7.55 (2H, d, J = 8.4 Hz), 8.06 (2
H, d, J = 8.1 Hz); IR (KBr) 3256, 2934, 1719, 1636,
1528, 1439, 1285, 1194,1115, 775 cm ^-1 ; Anal.Calc
d for C ₃₁ H ₂₉ F ₄ NO ₅ : C, 65.14; H, 5.11; N, 2.45. Fou
nd: C, 64.98; H, 5.39; N, 2.35.

Example 310 4-[(1RS, 2SR) -2-[(6,7-dihydro-5
H-benzo [a] cyclohepten-1-ylcarbonyl)
Amino] -1-hydroxy-3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propyl] benzoic acid 4-[(1RS, 2SR) -2-[(6,7-dihydro- 5
H-benzo [a] cyclohepten-1-ylcarbonyl)
A solution of 12.93 g (22.62 mmol) of methyl [amino] -1-hydroxy-3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propyl] benzoate in a solution of 40 ml of methanol and 50 ml of tetrahydrofuran was added. 67.9 ml (67.9 mmol) of a normal aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated, diluted with water, acidified with dilute hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid is ethyl acetate-
The desired product was obtained by washing with diisopropyl ether. White powder Yield 10.52 g Yield 83% mp 210-211 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
1.92-2.00 (2H, m), 2.18-2.26 (2H, m), 2.65-2.69 (2
H, m), 2.82-2.93 (2H, m), 4.64-4.74 (1H, m), 5.03
(1H, d, J = 3.6 Hz), 5.31 (1H, br s), 5.85 (1H, t
d, J = 5.3 Hz, 11.8 Hz), 5.98 (1H, tt, J = 3.0 Hz,
53.1 Hz), 6.14 (1H, d, J = 11.7 Hz), 6.89 (1H, d
d, J = 1.5 Hz, 7.8 Hz), 7.01-7.13 (5H, m), 7.26 (1
H, t, J = 8.1Hz), 7.61 (2H, d, J = 8.4 Hz), 8.05
(2H, d, J = 8.1 Hz); IR (KBr) 3268,3020-2860, 168
6, 1640, 1279, 1202, 1123 cm ^-1 ; Anal.Calcd for C
₃₀ H ₂₇ F ₄ NO ₅ : C, 64.63; H, 4.88; N, 2.51. Found: C,
64.50; H, 4.80; N, 2.39.

Example 311 N-[(1RS, 2SR) -2- [4- (aminocarbonyl) phenyl] -2-hydroxy-1- [3- (1,1,
2,2-tetrafluoroethoxy) benzyl] ethyl]-
6,7-dihydro-5H-benzo [a] cycloheptene-1
-Carboxamide 4-[(1RS, 2SR) -2-[(6,7-dihydro-5
H-benzo [a] cyclohepten-1-ylcarbonyl)
Amino] -1-hydroxy-3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propyl] benzoic acid 0.284 g (0.509 mmol), 1-hydroxybenzotriazole hydrate 86 mg (0.56 mmol) was stirred in 10 ml of acetonitrile-2 ml of N, N-dimethylformamide while stirring 0.11 of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride.
g (0.56 mmol) was added and the mixture was stirred at room temperature for 0.5 hour. 54 mg (1.02 mmol) of ammonium chloride and 0.21 ml (1.53 mmol) of triethylamine were added thereto, and the mixture was stirred at room temperature for 1 hour. An aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was stirred at room temperature for 0.5 hour. The resulting precipitate was collected and washed with water and diisopropyl ether-hexane to obtain the desired product. White powder Yield 0.227 g Yield 80% mp 197-199 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
1.91-1.99 (2H, m), 2.20-2.25 (2H, m), 2.67 (2H, t,
J = 5.6 Hz), 2.81-2.95 (2H, m), 4.64-4.73 (1H,
m), 5.01 (1H, d, J = 4.2 Hz), 5.35 (1H, br s), 5.8
4 (1H, td, J = 5.1Hz, 11.7 Hz), 6.00 (1H, tt, J =
2.9 Hz, 53.0 Hz), 6.11 (1H, d, J = 12.0Hz), 6.29
(1H, br s), 6.87 (1H, dd, J = 1.5 Hz, 7.5 Hz), 7.0
0-7.14 (5H, m), 7.22-7.29 (2H, m), 7.61 (2H, d, J =
8.1 Hz), 7.91 (2H, d, J = 8.4 Hz); IR (KBr) 3310,
1636, 1615, 1524, 1206, 1121, 777 cm ^-1 ; Anal.
cd for C ₃₀ H ₂₈ F ₄ N ₂ O ₄・ 0.5H ₂ O: C, 63.71; H, 5.17; N,
4.95. Found: C, 63.68; H, 5.30; N, 4.88.

Example 312 N-[(1RS, 2SR) -2- [4-[(dimethylamino) carbonyl] phenyl] -2-hydroxy-1- [3-
Example 3 using dimethylamine hydrochloride as (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide amine
In the same manner as in Example 11, 0.244 g (82%) of the target product was obtained as a white powder. mp 165-166 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.96-2.05
(2H, m), 2.16-2.22 (2H, m), 2.66 (2H, t, J = 5.9
Hz), 2.75 (1H, dd, J = 10.8 Hz, 14.7 Hz), 2.93 (1
H, dd, J = 3.9 Hz, 15.6 Hz), 2.97 (3H, s), 3.11 (3
H, s), 4.41 (1H, d, J = 4.2 Hz), 4.67-4.74 (1H, m),
5.03 (1H, t, J = 3.8 Hz), 5.86 (1H, d, J = 8.4 H
z), 5.89 (1H, tt, J = 2.7 Hz, 53.1 Hz), 5.94 (1H,
td, J = 5.6Hz, 11.3 Hz), 6.26 (1H, d, J = 12.0 H
z), 6.99-7.17 (6H, m), 7.29 (1H, t, J = 8.1 Hz),
7.38 (2H, d, J = 8.1 Hz), 7.45 (2H, d, J = 8.1 H)
z); IR (KBr) 3326, 2942, 1638, 1620, 1518, 1194, 1
115 cm ^-1 ; Anal.Calcd for C ₃₂ H _{3 2} F ₄ N ₂ O ₄ : C, 65.74;
H, 5.52; N, 4.79.Found: C, 65.58; H, 5.63; N, 4.8
1.

Example 313 N-[(1RS, 2SR) -2-hydroxy-2- [4- (piperidinocarbonyl) phenyl] -1- [3- (1,1,
2,2-tetrafluoroethoxy) benzyl] ethyl]-
6,7-dihydro-5H-benzo [a] cycloheptene-1
-In the same manner as in Example 311, using piperidine as the carboxamidoamine, 0.275 g (86%) of the desired product
Was obtained as white crystals. mp 176-177 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.51 (2H,
br s), 1.68 (4H, br s), 1.96-2.04 (2H, m), 2.16-
2.22 (2H, m), 2.66 (2H, t, J = 5.9 Hz), 2.75 (1H, d
d, J = 10.7 Hz, 14.6 Hz), 2.95 (1H, dd, J = 3.9 H
z, 14.7 Hz), 3.32 (2H, br s), 3.70 (2H, br s), 4.36
(1H, d, J = 3.6 Hz), 4.67-4.75 (1H, m), 5.03 (1H,
t, J = 3.8 Hz), 5.82 (1H, d, J = 8.1 Hz), 5.89 (1
H, tt, J = 2.9 Hz, 53.2 Hz), 5.94 (1H, td, J = 5.7
Hz, 11.3 Hz), 6.25 (1H, d, J = 11.7 Hz), 6.99-7.17
(6H, m), 7.29 (1H, t, J = 7.8 Hz), 7.36 (2H, d, J
= 8.1 Hz), 7.45 (2H, d, J = 8.1 Hz); IR (KBr) 3430,
3328, 2940, 2863, 1640, 1516, 1437, 1277, 1209, 1
123, 768 cm ^-1 ; Anal.Calcd for C ₃₅ H ₃₆ F ₄ N ₂ O ₄ : C, 67.
30; H, 5.81; N, 4.48. Found: C, 67.20; H, 5.78; N,
4.47.

Example 314 N-[(1RS, 2SR) -2- [4- (anilinocarbonyl) phenyl] -2-hydroxy-1- [3- (1,1,1
2,2-tetrafluoroethoxy) benzyl] ethyl]-
6,7-dihydro-5H-benzo [a] cycloheptene-1
-Carboxamide Using aniline as the amine, 0.275 g (85%) of the desired product was obtained as a white powder in the same manner as in Example 311. mp 205-206 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
1.94-2.00 (2H, m), 2.19-2.25 (2H, m), 2.67 (2H, t,
J = 5.4 Hz), 2.88 (2H, d, J = 7.5 Hz), 4.68-4.76
(1H, m), 5.06 (1H, t, J = 3.5 Hz), 5.25 (1H, d, J
= 3.6 Hz), 5.88 (1H, td, J = 5.6 Hz, 11.4 Hz), 5.9
5 (1H, tt, J = 2.9 Hz, 53.0 Hz), 6.17 (1H, d, J =
11.4 Hz), 6.92 (1H, dd, J = 1.1 Hz, 7.4 Hz), 7.01-
7.13 (7H, m), 7.27 (1H, t, J = 8.3 Hz), 7.35 (2H,
t, J = 7.8 Hz), 7.64 (2H, d, J = 8.4 Hz), 7.76 (2H,
d, J = 7.8 Hz), 7.99 (2H, d, J = 8.4 Hz), 9.31 (1
H, s); IR (KBr) 3297, 2938, 1647, 1532, 1507, 144
3, 1323, 1200, 1121, 752, 694 cm ^-1 ; Anal.Calcd fo
r C ₃₆ H ₃₂ F ₄ N ₂ O ₄ : C, 68.35; H, 5.10; N, 4.43. Found:
C, 68.10; H, 5.07; N, 4.42.

Example 315 N-[(1RS, 2SR) -2-hydroxy-2- [4-
[(Isopropylamino) carbonyl] phenyl] -1-
[3- (1,1,2,2-tetrafluoroethoxy) benne
[Zyl] ethyl] -6,7-dihydro-5H-benzo [a] si
Example 311 Using isopropylamine as cloheptene-1-carboxamide amine
0.258 g (84%) of the target product was obtained as white powder
I got it at the end. mp 215-217 ° C;¹H-NMR (CDCl_Three-DMSO-d₆, 300 MHz) δ
1.27 (6H, d, J = 6.6 Hz), 1.93-2.02 (2H, m), 2.19-
2.25 (2H, m), 2.67 (2H, t, J = 5.1 Hz), 2.85 (2H, m
d, J = 7.5 Hz), 4.25-4.32 (1H, m), 4.67-4.75 (1H,
m), 5.06 (2H, s), 5.88 (1H, td, J = 5.7 Hz, 11.4 H
z), 5.92 (1H, tt, J = 3.0 Hz, 53.0 Hz), 6.18 (1H,
d, J = 12.0 Hz), 6.46 (1H, d, J = 7.8 Hz), 6.80 (1
H, d, J = 9.0 Hz), 6.94 (1H, dd, J = 1.2 Hz, 7.5 H
z), 7.01-7.14 (5H, m), 7.26 (1H, t, J = 7.8 Hz), 7.
58 (2H, d, J = 8.4 Hz), 7.80 (2H, d, J = 8.4 Hz);
IR (KBr) 3295, 2971, 2930, 1638, 1537, 1213, 1123
cm^-1; Anal. Calcd for C₃₃H ₃₄F_FourN_TwoO_Four: C, 66.21; H,
5.72; N, 4.68. Found: C, 66.00; H, 5.50; N, 4.65.

Example 316 N-[(1RS, 2SR) -2- [4-[(benzylamino) carbonyl] phenyl] -2-hydroxy-1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide Using benzylamine as the amine, in the same manner as in Example 311, 0.297 g (90%) of the desired product was obtained as a white powder. mp 216-217 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
1.91-1.99 (2H, m), 2.19-2.24 (2H, m), 2.67 (2H, t,
J = 5.9 Hz), 2.86-2.89 (2H, m), 4.62 (2H, d, J =
6.0 Hz), 4.65-4.71 (1H, m), 5.01 (1H, t, J = 3.8 H
z), 5.30 (1H, d, J = 3.3 Hz), 5.84 (1H, td, J = 5.5
Hz, 11.3 Hz), 5.99 (1H, tt, J = 2.8 Hz, 52.9 Hz),
6.11 (1H, d, J = 12.0 Hz), 6.88 (1H, dd, J = 1.2
Hz, 7.5 Hz), 7.00-7.05 (3H, m), 7.11 (2H, d, J =
9.9 Hz), 7.17-7.39 (7H, m), 7.60 (2H, d, J = 8.1 H
z), 7.93 (2H, d, J = 8.1 Hz), 8.05 (1H, t, J = 5.6
Hz); IR (KBr) 3297, 2932, 1638, 1615, 1537, 1200,
1130, 698 cm ^-1 ; Anal.Calcd for C ₃₇ H ₃₄ F ₄ N ₂ O ₄ : C, 6
8.72; H, 5.30; N, 4.33. Found: C, 68.59; H, 5.06;
N, 4.22.

Example 317 N-[(1RS, 2SR) -2- [4-[(butylamino)
Carbonyl] phenyl] -2-hydroxy-1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide Using butylamine as the amine, the same procedure as in Example 311 was carried out. 0.284 g (91%) of the product as a white powder. mp 207-208 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
0.96 (3H, t, J = 7.4 Hz), 1.35-1.48 (2H, m), 1.56-
1.66 (2H, m), 1.94-2.01 (2H, m), 2.20-2.26 (2H, m
m), 2.68 (2H, t, J = 6.0 Hz), 2.87 (2H, d, J = 8.4
Hz), 3.42 (2H, q, J = 6.7 Hz), 4.64-4.72 (1H, m),
5.03 (1H, t, J = 3.8 Hz), 5.23 (1H, d, J = 3.6 Hz),
5.86 (1H, td, J = 5.2 Hz, 12.1 Hz), 5.97 (1H, tt,
J = 2.9 Hz, 53.0 Hz), 6.14 (1H, d, J = 11.7 Hz),
6.90 (1H, dd, J = 1.2 Hz, 7.5 Hz), 7.01-7.17 (7H,
m), 7.26 (1H, t, J = 8.3 Hz), 7.59 (2H, d, J = 7.8
Hz), 7.84 (2H, d, J = 8.4 Hz); IR (KBr) 3308, 293
4, 1640, 1612, 1537, 1201,1128, 696 cm ^-1 ; Anal.Ca
lcd for C ₃₄ H ₃₆ F ₄ N ₂ O ₄ : C, 66.66; H, 5.92; N, 4.57.
Found: C, 66.44; H, 5.88; N, 4.40.

Example 318 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -4-methyl-6,7-
Dihydro-5H-benzo [a] cycloheptene-1-carboxamide 1) (E) -5- (2-methylphenyl) -3-oxo-4
50.71 g (312.7 mmol) of ethyl 2-pentenoate 2-methylcinnamic acid
Was added to a solution of 500 ml of tetrahydrofuran at room temperature, and the mixture was stirred as it was for 1 hour. 58.5 g of monoethyl malonate monopotassium salt was added to this mixture.
(344 mmol) and 16.4 g of magnesium chloride
(172 mmol) at room temperature and stirred at 60 ° C. overnight. After diluting the reaction solution with ethyl acetate and water and acidifying the reaction solution with concentrated hydrochloric acid, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-6 / 1) to obtain the desired product. Yellow liquid Yield 37.24 g Yield 51% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.29 (1.2 H, t, J = 7.1)
Hz), 1.32 (1.8H, t, J = 7.1 Hz), 2.43 (1.8H, s), 2.
45 (1.2H, s), 3.70 (0.8H, s), 4.23 (0.8H, q, J =
7.2 Hz), 4.24 (1.2H, q, J = 7.1 Hz), 5.17 (0.6H,
s), 6.36 (0.6H, dd, J = 1.4 Hz, 15.8 Hz), 6.74 (0.
4H, d, J = 15.8 Hz), 7.15-7.35 (3H, m), 7.52-7.61
(1H, m), 7.70 (0.6H, d, J = 15.8 Hz), 7.93 (0.4H,
d, J = 16.2Hz); IR (neat) 2980, 1740, 1636, 1595,
1420, 1236, 1148, 1038, 754 cm ^-1 2) Ethyl 5- (2-methylphenyl) pentanoate 37.24 g of ethyl (E) -5- (2-methylphenyl) -3-oxo-4-pentenoate To a solution of (160.3 mmol) in 100 ml of ethanol, 3.03 g (80.2 mmol) of sodium borohydride was added little by little under ice-cooling, followed by stirring for 10 minutes. The reaction was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain (E) -3-
A crude product of ethyl hydroxy-5- (2-methylphenyl) penta-4-enoate was obtained as a yellow liquid. The liquid obtained above and 33.5 ml (240 mmol) of triethylamine
Was added dropwise to a solution of the above in 180 ml of ethyl acetate under ice-cooling, and methanesulfonyl chloride (22.0 g, 192 mmol) was added dropwise under ice-cooling, followed by stirring for 15 minutes. The resulting precipitate (triethylamine hydrochloride) was removed by filtration, and the precipitate was washed with ethyl acetate. The collected ethyl acetate solution was concentrated under reduced pressure.
The obtained residue was dissolved in 200 ml of tetrahydrofuran, 28.8 ml (192 mmol) of 1,8-diazabicyclo [5.4.0] -7-undecene was added, and the mixture was stirred at room temperature for 0.5 hour. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / hexane).
Ethyl acetate = 15 / 1-9 / 1) 5- (2-methylphenyl) penta-2,4-dienoate ((2E, 4E)
And a mixture of the (2Z, 4E) form) as a yellow liquid. Using a solution of the liquid obtained above in 40 ml of ethanol with 1.5 g of 10% palladium / carbon (containing 50% water) as a catalyst,
Hydrogenation was performed under normal temperature and normal pressure until the raw materials disappeared. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-6 / 1) to obtain the desired product. Colorless liquid Yield 13.92 g Yield 39% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.25 (3H, t, J = 7.2 H)
z), 1.52-1.80 (4H, m), 2.30 (3H, s), 2.34 (2H, t, J
= 7.0 Hz), 2.61 (2H, t, J = 7.6 Hz), 4.12 (2H, q,
J = 7.2 Hz), 7.12 (4H, s); IR (neat) 2938, 1736,
1181, 745 cm ^-1 3) Ethyl 5- (2-methylphenyl) pentanoate 13.92 Ethyl 5- (2-methylphenyl) pentanoate
g (63.18 mmol), sodium hydroxide 5.05
g (126 mmol), water 30 ml, methanol 50 m
1 and a mixture of 50 ml of tetrahydrofuran were stirred at room temperature overnight. The reaction solution was concentrated, diluted with water, washed with diethyl ether, and the obtained aqueous solution was acidified with concentrated hydrochloric acid, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product. White crystals Yield 12.04 g Yield 99% mp 57-58 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.54-1.82
(4H, m), 2.30 (3H, s), 2.40 (2H, t, J = 7.1 Hz), 2.
62 (2H, t, J = 7.6 Hz), 7.12 (4H, s); IR (KBr) 307
0-2520, 1698, 1462, 1437, 1406, 1329, 1289, 1260,
1208, 941, 739 cm ^-1 4) 1-methyl-6,7,8,9-tetrahydro-5H-
Benzo [a] cyclohepten-5-one 11.92 g of 5- (2-methylphenyl) pentanoic acid (6.
2.00 mmol), N, N-dimethylformamide 2
8.11 ml (93.0 mmol) of oxalyl chloride was added dropwise to a solution of the drops in 50 ml of tetrahydrofuran at room temperature, followed by stirring for 0.5 hour. The solvent of the reaction mixture was distilled off under reduced pressure to obtain an acid chloride as a yellow liquid. While stirring a suspension of 16.5 g (124 mmol) of aluminum chloride in 100 ml of methylene chloride, a solution of the acid chloride obtained above in 250 ml of methylene chloride was added dropwise over 1 day. While cooling the reaction solution with ice, water was added to stop the reaction. The methylene chloride layer of the mixture was separated, and the aqueous layer was extracted with diethyl ether. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to obtain the desired product. Light yellow solid Yield 10.14 g Yield 94% Recrystallization from hexane gave white crystals. mp 65-66 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.69-1.91
(4H, m), 2.37 (3H, s), 2.67 (2H, t, J = 5.9 Hz), 2.
88 (2H, t, J = 6.2 Hz), 7.17 (1H, t, J = 7.5Hz),
7.30 (1H, d, J = 6.6 Hz), 7.44 (1H, d, J = 7.4 H
z); IR (KBr) 2940,1671, 1586, 1460, 1271, 793 c
m ^-1 ; Anal.Calcd for C ₁₂ H ₁₄ O: C, 82.72; H, 8.10. Fo
und: C, 82.68; H, 8.15.5) 1-methyl-6,7,8,9-tetrahydro-5H-
Benzo [a] cyclohepten-5-ol 9.797 g (56.2) of 1-methyl-6,7,8,9-tetrahydro-5H-benzo [a] cyclohepten-5-one
2.13 g (56.2 mmol) of sodium borohydride in a solution of methanol (3 mmol) in 40 ml of methanol under ice-cooling.
Was added little by little, and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1), and crystallized from ethyl acetate-hexane to obtain the desired product. White crystals Yield 8.345 g Yield 84% mp 109-110 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.30-1.42
(1H, m), 1.66-1.86 (4H, m), 1.91-2.05 (2H, m), 2.
32 (3H, s), 2.57 (1H, dd, J = 11.1 Hz, 12.9Hz), 3.
08 (1H, ddd, J = 1.6 Hz, 7.9 Hz, 14.5 Hz), 5.01 (1
H, dd, J = 3.6Hz, 9.0 Hz), 7.06 (1H, dd, J = 1.7 H
z, 7.7 Hz), 7.11 (1H, t, J = 7.4 Hz), 7.32 (1H, d,
J = 6.9 Hz); IR (KBr) 3293, 3189, 2928, 1466, 143
9, 1096,1049, 781, 747 cm ^-1 ; Anal.Calcd for C ₁₂ H
₁₆ O: C, 81.77; H, 9.15. Found: C, 81.73; H, 8.93. 6) 4-Bromo-1-methyl-6,7,8,9-tetrahydro-5H-benzo [a] cycloheptene-5 -All 1-methyl-6,7,8,9-tetrahydro-5H-benzo [a] cyclohepten-5-ol 8.193 g (46.
To a solution of 48 mmol) and 11.9 g (102 mmol) of N, N, N ', N'-tetramethylethylenediamine in 100 ml of hexane, 63.9 ml (102 mmol) of a 1.6 Mn-butyllithium hexane solution under ice-cooling. After dropwise addition, the mixture was stirred at 35 ° C. overnight. The reaction mixture was
After cooling to 8 ° C., 24.2 g (93.0 mmol) of 1,2-dibromotetrafluoroethane was added, the temperature was raised to room temperature with stirring, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 15/1) to obtain the desired product. Yellow solid Yield 6.439 g Yield 54% Recrystallization from hexane gave white crystals. mp 74-75 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.25-1.44
(1H, m), 1.57-2.23 (6H, m), 2.26 (3H, s), 2.88 (1H,
ddd, J = 1.7 Hz, 6.8 Hz, 14.3 Hz), 3.26 (1H, dt,
J = 1.8 Hz, 13.0 Hz), 5.65-5.71 (1H, m), 6.90 (1H,
d, J = 8.2 Hz), 7.26 (1H, d, J = 8.0 Hz); IR (KBr)
3326, 2930, 1456, 1090, 1049, 995, 930, 856, 806
cm ^-1 ; Anal.Calcd for C ₁₂ H ₁₅ BrO: C, 56.49; H, 5.9
3. Found: C, 56.48; H, 5.83.7) 1-bromo-4-methyl-6,7-dihydro-5H-benzo [a] cycloheptene 4-bromo-1-methyl-6,7,8,9 -Tetrahydro-5
H-benzo [a] cyclohepten-5-ol 6.213
g (24.35 mmol), 0.46 g (2.44 mmol) of p-toluenesulfonic acid monohydrate in toluene 10
The 0 ml solution was heated to reflux for 0.5 hours in a reaction vessel fitted with a Dean-Stark trap. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane) to obtain the desired product. Colorless liquid Yield 2.485 g Yield 43% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.99-2.13 (4H, m), 2.31
(3H, s), 2.64 (2H, t, J = 6.3 Hz), 6.22 (1H, td, J
= 6.2 Hz, 11.2 Hz), 6.71 (1H, d, J = 11.1Hz), 6.9
0 (1H, d, J = 8.1 Hz), 7.31 (1H, d, J = 8.1 Hz); I
R (neat) 2930,1451, 1127, 802, 779 cm -1 8) 4- methyl-6,7-dihydro -5H- benzo [a]
Cycloheptene-1-carboxylic acid 1-bromo-4-methyl-6,7-dihydro-5H-benzo [a] cycloheptene 2.485 g (10.48 mmol) of diethyl ether in 30 ml of 1.6 M at −78 ° C. 9.82m of hexane solution of -butyllithium
After the dropwise addition of 1 (15.7 mmol), the mixture was stirred at room temperature for 4 hours. After cooling the reaction mixture to −78 ° C., 5 g of crushed dry ice was added, and the temperature was raised to room temperature with stirring. The reaction solution was diluted with water, washed with diethyl ether, and the obtained aqueous solution was acidified with 1N hydrochloric acid, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude crystals were washed with hexane to obtain the desired product. White crystals Yield 1.080 g Yield 51% mp 152-153 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.91-2.18
(4H, m), 2.43 (3H, s), 2.66 (2H, t, J = 6.6 Hz),
6.26 (1H, td, J = 6.6 Hz, 11.0 Hz), 7.13 (1H, d, J
= 7.8 Hz), 7.21 (1H, d, J = 11.0 Hz), 7.85 (1H,
d, J = 8.2 Hz); IR (KBr) 3044-2510, 1686, 1300, 12
71, 1258 cm ^-1 ; Anal.Calcd for C ₁₃ H ₁₄ O ₂ : C, 77.20;
H, 6.98. Found: C, 76.98; H, 7.03.9) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2, 2-tetrafluoroethoxy) benzyl] ethyl] -4-methyl-
6,7-dihydro-5H-benzo [a] cycloheptene-1
-Carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol 0.366 g
(1.013 mmol), 4-methyl-6,7-dihydro-
5H-benzo [a] cycloheptene-1-carboxylic acid
20 g (1.01 mmol) and 0.16 g (1.01 mmol) of 1-hydroxybenzotriazole hydrate are stirred in 10 ml of acetonitrile with 1-ethyl-3-ethyl.
0.19 g (1.01 mmol) of (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.46
1g Yield 83% mp 177-178 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.95-2.07
(4H, m), 2.33 (3H, s), 2.59 (2H, t, J = 5.7 Hz),
2.78 (1H, dd, J = 10.7 Hz, 14.6 Hz), 2.98 (1H, dd,
J = 4.2 Hz, 14.4 Hz), 3.90 (1H, d, J = 3.9 Hz),
4.58-4.67 (1H, m), 5.03 (1H, t, J = 3.6 Hz), 5.74
(1H, d, J = 7.5 Hz), 5.89 (1H, tt, J = 2.8 Hz, 53.0
Hz), 6.02 (1H, td, J = 6.2 Hz, 11.3 Hz), 6.29 (1
H, d, J = 11.1 Hz), 6.96-7.11 (7H, m), 7.29 (1H,
t, J = 7.8 Hz), 7.42 (2H, dd, J = 5.4 Hz, 8.7 Hz);
IR (KBr) 3279, 1638, 1512, 1200, 1127 cm ^-1 ; Anal.
Calcdfor C ₃₀ H ₂₈ F ₅ NO ₃ : C, 66.05; H, 5.17; N, 2.57.
Found: C, 66.03; H, 5.21; N, 2.52.

Example 319 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-[[3- (1,1,2,2-tetrafluoroethoxy) isoxazol-5-yl] methyl]
Tert-Butyl ethyl] carbamate 1) 3- (4-fluorophenyl) -3-oxo-2-
Ethyl [[3- (1,1,2,2-tetrafluoroethoxy) isoxazol-5-yl] methyl] propionate 3- (1,1,2,2-tetrafluoroethoxy) -5-isoxazolecarboxylic acid 1.975 g of methyl acid salt (8.1
24 mmol) in 30 ml of methanol under ice-cooling.
After adding 0.40 g (10.6 mmol) of sodium borohydride little by little, the mixture was stirred at room temperature overnight. Dilute hydrochloric acid was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour, and then extracted three times with ethyl acetate. After drying the collected organic layer over anhydrous magnesium sulfate and passing through silica gel, the solvent was distilled off under reduced pressure.
A crude product of [3- (1,1,2,2-tetrafluoroethoxy) isoxazol-5-yl] methanol was obtained as a yellow liquid (1.72 g). To a solution of 1.70 ml (12.2 mmol) of the above-obtained liquid, triethylamine, in 40 ml of ethyl acetate, was added 0.75 methanesulfonyl chloride under ice cooling.
ml (9.75 mmol) was added dropwise and stirred for 10 minutes. The resulting precipitate was removed by filtration, and the precipitate was washed with ethyl acetate. The solvent of the collected filtrate was distilled off under reduced pressure to obtain a crude product of methanesulfonic acid ester as a yellow liquid. 1.88 g of ethyl (4-fluorobenzoyl) acetate
(8.94 mmol) of 1,2-dimethoxyethane 30
0.36 g (8.94 mmol) of a 60% sodium hydride liquid paraffin suspension was added to the ml solution under ice-cooling, and the mixture was stirred for 0.5 hour as it was. To this was added a solution of methanesulfonic acid ester obtained above in 1,2-dimethoxyethane (10 ml) at room temperature, and the mixture was stirred at 70 ° C. for 4 hours. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-6 / 1) to obtain the desired product. Pale yellow liquid yield 2.418 g yield 73
% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.16 (3H, t, J = 7.2 H
z), 3.46 (2H, d, J = 7.4 Hz), 4.16 (2H, q, J = 7.1
Hz), 4.77 (1H, t, J = 7.4 Hz), 6.00 (1H, tt, J =
3.3 Hz, 52.7 Hz), 6.07 (1H, s), 7.18 (2H, t, J =
8.7 Hz), 8.06 (2H, dd, J = 5.3 Hz, 8.9 Hz); IR (nea
t) 1738, 1690, 1601, 1447, 1283, 1233,1182, 1159 c
m- ¹ 2) (2RS, 3SR) -3- (4-fluorophenyl) -3-hydroxy-2-[[3- (1,1,2,2-tetrafluoroethoxy) isoxazol-5-yl] Ethyl methyl] propionate While stirring 6.35 g (46.6 mmol) of zinc chloride in 100 ml of diethyl ether, 3.53 g (93.2 mmol) of sodium borohydride was added at room temperature, and the mixture was stirred for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. The resulting solution was added to 3- (4-fluorophenyl) -3-oxo-2-[[3- (1,1,
2,2-tetrafluoroethoxy) isoxazole-5
2.372 g of ethyl -yl] methyl] propionate
A solution of (5.824 mmol) in 30 ml of diethyl ether was added under ice-cooling, and the mixture was refluxed for 4 hours. Dilute hydrochloric acid was added little by little to the reaction solution to decompose excess zinc borohydride, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-3 / 1) to obtain the desired product. Colorless liquid Yield 1.402 g Yield 59% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.11 (3H, t, J = 7.1 H)
z), 2.72 (1H, d, J = 3.0 Hz), 2.98-3.26 (3H, m),
4.02-4.11 (2H, m), 5.11 (1H, dd, J = 3.3 Hz, 5.1 H
z), 5.93 (1H, s), 6.00 (1H, tt, J = 3.3 Hz, 52.7 H
z), 7.06 (2H, t, J = 8.7 Hz), 7.36 (2H, dd, J = 5.3
Hz, 8.6 Hz); IR (neat) 3465, 1728, 1609, 1512, 14
49, 1225, 1184, 1146 cm -1 3) (4RS, 5SR) -5- (4- fluorophenyl) -4 - [[3- (1,1,2,2-tetrafluoroethoxy) isoxazole -5 -Yl] methyl] -1,3-oxazolidin-2-one (2RS, 3SR) -3- (4-fluorophenyl) -3-
1N water was added to a solution of 1.402 g (3.425 mmol) of ethyl hydroxy-2-[[3- (1,1,2,2-tetrafluoroethoxy) isoxazol-5-yl] methyl] propionate in 30 ml of methanol. 6.85 ml (6.85 mmol) of an aqueous sodium oxide solution was added, and the mixture was added at room temperature for 2 hours.
Stirred for hours. The reaction solution was concentrated, diluted with water, acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate.
The collected organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give (2RS, 3SR) -3- (4-fluorophenyl) -3-hydroxy-2-[[3- (1,1,2 A crude product of 2,2-tetrafluoroethoxy) isoxazol-5-yl] methyl] propionic acid was obtained as a colorless liquid. 0.57 ml (4.11 mmol) of triethylamine was added to a solution of the liquid obtained above in 30 ml of tetrahydrofuran,
1.04 g (3.77 mmol) of diphenylphosphoryl azide was added, and the mixture was stirred at 70 ° C. overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3).
/ 1-1 / 1) and crystallized from diethyl ether-hexane to obtain the desired product. White crystals Yield 0.921 g Yield 71% mp 124-125 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.48 (1H,
dd, J = 5.3 Hz, 15.5Hz), 2.59 (1H, dd, J = 8.4 H
z, 15.6 Hz), 4.45-4.53 (1H, m), 5.52 (1H, brs), 5.
83 (1H, s), 6.00 (1H, tt, J = 3.2 Hz, 52.7 Hz), 7.
12 (2H, t, J = 8.6 Hz), 7.32 (2H, dd, J = 5.3 Hz,
8.3 Hz); IR (KBr) 3156, 1755, 1447, 1235, 1209, 11
50,1119 cm ^-1 ; Anal.Calcd for C ₁₅ H ₁₁ F ₅ N ₂ O ₄ : C, 47.
63; H, 2.93; N, 7.41. Found: C, 47.60; H, 2.98; N,
7.21.4) (4RS, 5SR) -5- (4-fluorophenyl) -2-oxo-4-[[3- (1,1,2,2-tetrafluoroethoxy) isoxazol-5-yl] methyl ]
Tert-Butyl-1,3-oxazolidine-3-carboxylate (4RS, 5SR) -5- (4-fluorophenyl) -4-
0.866 g (2.289 mmol) of [[3- (1,1,2,2-tetrafluoroethoxy) isoxazol-5-yl] methyl] -1,3-oxazolidin-2-one, di-dicarbonate tert-butyl 0.60 g (2.75 mmol), 4-N, N-dimethylaminopyridine 28 mg
(0.23 mmol) in 10 ml of acetonitrile was stirred at room temperature overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate) and crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.785 g Yield 72% mp 177-178 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.55 (9H,
s), 2.81 (1H, dd, J = 9.3 Hz, 15.6 Hz), 3.01 (1H,
ddd, J = 1.0 Hz, 4.6 Hz, 15.4 Hz), 4.96-5.03 (1H,
m), 5.36 (1H, s), 5.72 (1H, d, J = 7.2 Hz), 5.97
(1H, tt, J = 3.3Hz, 52.8 Hz), 7.04 (2H, t, J = 8.6
Hz), 7.23 (2H, dd, J = 5.3 Hz, 8.6 Hz); IR (KBr)
1802, 1372, 1298, 1163 cm ^-1 ; Anal.Calcd for C ₂₀ H
₁₉ F ₅ N ₂ O ₆ : C, 50.22; H, 4.00; N, 5.86. Found: C, 50.
16; H, 3.79; N, 5.88. 5) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-[[3- (1,1,2,2-tetra Tert-Butyl fluoroethoxy) isoxazol-5-yl] methyl] ethyl] carbamate (4RS, 5SR) -5- (4-fluorophenyl) -2-
Oxo-4-[[3- (1,1,2,2-tetrafluoroethoxy) isoxazol-5-yl] methyl] -1,3-
Tert-butyl oxazolidine-3-carboxylate 0.7
35 g (1.536 mmol) of tetrahydrofuran 1
To a 0 ml solution was added a solution of 61 mg (1.54 mmol) of sodium hydroxide in 2 ml of methanol under ice-cooling.
Stirred for 0 minutes. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystal Yield 0.626 g Yield 90% mp 114-115 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.39 (9H,
s), 2.69 (1H, br d, J = 2.7 Hz), 2.86 (1H, dd, J =
4.2 Hz, 15.3 Hz), 3.01 (1H, dd, J = 10.7 Hz, 15.5
Hz), 4.09-4.18 (1H, m), 4.89 (1H, br d, J = 7.5 H
z), 4.94 (1H, br s), 6.00 (1H, tt, J = 3.4 Hz, 52.
7 Hz), 6.03 (1H, s), 7.08 (2H, t, J = 8.7 Hz), 7.38
(2H, dd, J = 5.1 Hz, 8.4 Hz); IR (KBr) 3360, 168
0, 1530,1449, 1190, 1125 cm ^-1 ; Anal.Calcd for C ₁₉
H ₂₁ F ₅ N ₂ O ₅ : C, 50.45; H, 4.68; N, 6.19. Found: C, 5
0.32; H, 4.58; N, 6.25.

Example 320 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-[[3- (1,1,2,2-tetrafluoroethoxy) isoxazol-5-yl] methyl]
Ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1-[[3- (1,1,2,2-tetrafluoroethoxy) isoxazol-5-yl] methyl]
0.291 g of tert-butyl ethyl] carbamate
(0.643 mmol), a solution of 0.2 ml of concentrated hydrochloric acid in 5 ml of methanol was stirred for 0.5 hour at 60 ° C. The reaction was diluted with water, made alkaline with potassium carbonate and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and (1RS, 2SR) -2-
Amino-1- (4-fluorophenyl) -3- [3- (1,
The crude product of 1,2,2-tetrafluoroethoxy) isoxazol-5-yl] propan-1-ol was obtained as a white solid (0.227 g). The solid obtained above, 6,7
0.13 g (0.71 mmol) of 1-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid, 0.10 g (0.71 mmol) of 1-hydroxybenzotriazole hydrate were stirred in 10 ml of acetonitrile. 1-
0.14 g (0.71 mmol) of ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added,
Stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / hexane).
Crystallization from ethyl acetate = 3 / 1-1 / 1) and diisopropyl ether / hexane gave the desired product. White powder Yield 0.251 g Yield 75% mp 127-128 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.98-2.06
(2H, m), 2.20-2.26 (2H, m), 2.67-2.71 (2H, m), 3.
01 (1H, dd, J = 4.2 Hz, 15.9 Hz), 3.12 (1H, d, J =
3.9 Hz), 3.16 (1H, dd, J = 10.2 Hz, 16.2 Hz), 4.61
-4.70 (1H, m), 5.02 (1H, t, J = 3.9 Hz), 6.00 (1H,
tt, J = 3.3 Hz, 52.5 Hz), 6.03 (1H, td, J = 5.6 Hz,
11.7 Hz), 6.11 (1H, s), 6.15 (1H, d, J = 8.7 Hz),
6.33 (1H, d, J = 11.7 Hz), 7.05-7.14 (4H, m), 7.1
6-7.22 (1H, m), 7.42 (2H, dd, J = 5.3 Hz, 8.9 Hz);
IR (KBr) 3289, 1640, 1514, 1449, 1188, 1146 cm ^-1 ; A
nal.Calcd for C ₂₆ H ₂₃ F ₅ N ₂ O ₄ : C, 59.77; H, 4.44; N,
5.36. Found: C, 59.82; H, 4.48; N, 5.34.

Example 321 N-[(1RS, 2SR) -2- [4-[(tert-butoxycarbonyl) amino] phenyl] -2-hydroxy-
1- [3- (1,1,2,2-tetrafluoroethoxy)
Benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 4-[(1RS, 2SR) -2-[(6,7-dihydro-5
H-benzo [a] cyclohepten-1-ylcarbonyl)
Triethylamine 1 was added to a solution of 3.283 g (5.888 mmol) of amino] -1-hydroxy-3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propyl] benzoic acid in 60 ml of tert-butyl alcohol. .23
ml (8.83 mmol) and 1.78 g (6.48 mmol) of diphenylphosphoryl azide.
Stirred for days. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane-hexane / ethyl acetate = 1/1) and crystallized from diisopropyl ether-hexane to obtain the desired product.
White powder Yield 2.714g yield ^{73% mp 153-156 ℃; 1 H} -NMR (CDCl 3, 300 MHz) δ 1.52 (9H,
s), 1.95-2.03 (2H, m), 2.16-2.23 (2H, m), 2.66 (2
H, t, J = 5.7 Hz), 2.75 (1H, dd, J = 10.5 Hz, 14.4
Hz), 2.99 (1H, dd, J = 3.6 Hz, 14.4 Hz), 3.57 (1
H, d, J = 3.6 Hz), 4.65-4.75 (1H, m), 5.00 (1H, t,
J = 3.6 Hz), 5.74 (1H, d, J = 8.4 Hz), 5.89 (1H, t
t, J = 2.9 Hz, 53.0 Hz), 5.91 (1H, td, J = 5.6 Hz,
11.4 Hz), 6.22 (1H, d, J = 12.0 Hz), 6.52 (1H, s),
6.95-7.16 (6H, m), 7.30 (1H, t, J = 7.8 Hz), 7.38
(4H, s); IR (KBr) 3314, 1694, 1676, 1636, 1532, 1
314, 1211, 1161, 1115 cm ^-1 ; Anal.Calcd for C ₃₄ H ₃₆
F ₄ N ₂ O ₅・ DMF: C, 63.33; H, 6.18; N, 5.99. Found: C, 63.3
0; H, 6.07; N, 5.84.

Example 322 N-[(1RS, 2SR) -2- (4-aminophenyl)-
2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
5H-benzo [a] cycloheptene-1-carboxamide N-[(1RS, 2SR) -2- [4-[(tert-butoxycarbonyl) amino] phenyl] -2-hydroxy-
1- [3- (1,1,2,2-tetrafluoroethoxy)
[Benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 1.547 g
(2.461 mmol), a solution of 0.5 ml of concentrated hydrochloric acid in 10 ml of methanol was stirred at 60 ° C. for 2 hours. The reaction was diluted with water, made alkaline with potassium carbonate and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1-1-1 / 3), and diisopropyl ether-
Crystallization from hexane gave the desired product. Light brown powder
Yield 0.150 g Yield 12% mp 153-155 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.94-2.03
(2H, m), 2.15-2.23 (2H, m), 2.66 (2H, t, J = 5.9
Hz), 2.77 (1H, dd, J = 10.2 Hz, 14.7 Hz), 3.03 (1
H, dd, J = 4.2 Hz, 14.4 Hz), 3.19 (1H, d, J = 3.9
Hz), 3.70 (2H, brs), 4.65-4.74 (1H, m), 4.90 (1H,
t, J = 3.8 Hz), 5.71 (1H, d, J = 8.4 Hz), 5.89 (1
H, tt, J = 2.9 Hz, 53.1 Hz), 5.91 (1H, td, J = 5.3
Hz, 11.7 Hz), 6.20 (1H, d, J = 11.7 Hz), 6.69 (2
H, d, J = 8.1 Hz), 6.97 (1H, dd, J = 1.4 Hz, 7.7 H
z), 7.03-7.15 (5H, m), 7.21-7.32 (3H, m); IR (KBr)
3270,1642, 1518, 1275, 1198, 1125 cm ^-1 ; Anal.
cd for C ₂₉ H ₂₈ F ₄ N ₂ O ₃ : C, 65.90; H, 5.34; N, 5.30. F
ound: C, 65.68; H, 5.15; N, 5.02.

Example 323 N-[(1RS, 2SR) -2- (4-fluorophenyl)
2-Hydroxy-1- (3-isopropylbenzyl) ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 1) 3-isopropylbenzyl alcohol 3.33 g (137 mmol) of powdered magnesium While stirring 1 piece of iodine in 10 ml of tetrahydrofuran, 10.91 g of 3-isopropylbromobenzene
(54.80 mmol), 1,2-dibromoethane 1
0.3 g (54.8 mmol) of tetrahydrofuran 1
The 00 ml solution was slowly added dropwise. After dropping, 70
Stirred at C for 1 hour. The reaction was cooled to -78 ° C,
10 g of crushed dry ice was carefully added, and the reaction solution was gradually heated to room temperature while stirring. The reaction solution was diluted with water, acidified with concentrated hydrochloric acid, and extracted twice with ethyl acetate. The solvent of the collected organic layer was distilled off under reduced pressure to obtain a crude product of 3-isopropylbenzoic acid as a yellow liquid. To a suspension of 3.12 g (82.2 mmol) of lithium aluminum hydride in 100 ml of tetrahydrofuran was added dropwise a solution of the liquid obtained above in 50 ml of tetrahydrofuran under ice-cooling.
Stirred at room temperature for 1 hour. The reaction solution was cooled on ice and 3 ml of water was added.
Excess lithium aluminum hydride was decomposed by sequentially adding 3 ml of a 15% aqueous sodium hydroxide solution and 7.5 ml of water dropwise, and the mixture was stirred at room temperature for 1 hour. The resulting precipitate was removed by filtration, and the precipitate was washed with ethyl acetate. The solvent of the collected filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-3 / 1) to obtain the desired product. Yellow liquid
Yield 5.610 g Yield 68% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.26 (6H, d, J = 7.0 H)
z), 1.64 (1H, t, J = 5.9 Hz), 2.85-2.99 (1H, m),
4.68 (2H, d, J = 5.6 Hz), 7.15-7.34 (4H, m); IR (n
eat) 3320, 2961, 1464, 1017, 791, 704 cm ^-1 2) Ethyl 3- (4-fluorophenyl) -2- (3-isopropylbenzyl) -3-oxopropionate 2.595 g of 3-isopropylbenzyl alcohol (1
7.27 mmol), 3.61 ml of triethylamine
(25.9 mmol) of 30 ml of ethyl acetate was added dropwise with a solution of 2.37 g (20.7 mmol) of methanesulfonyl chloride in 10 ml of ethyl acetate under ice-cooling.
Stirred for minutes. The resulting precipitate was removed by filtration, and the precipitate was washed with ethyl acetate. The solvent of the collected filtrate was distilled off under reduced pressure,
The crude product of methanesulfonic acid ester was obtained as a yellow liquid. Ethyl (4-fluorobenzoyl) acetate 3.63
g (17.3 mmol) of 1,2-dimethoxyethane 3
0.69 g (17.3 mmol) of a liquid paraffin suspension of 60% sodium hydride was added to the 0 ml solution under ice cooling,
The mixture was stirred for 0.5 hours as it was. 10 ml of 1,2-dimethoxyethane of the methanesulfonate obtained above
The solution was added at room temperature and stirred at 60 ° C. overnight. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-6 / 1) to obtain the desired product. Light yellow liquid Yield 5.108 g Yield 86
% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.13 (3H, t, J = 7.2 H
z), 1.18 (6H, d, J = 7.0 Hz), 2.76-2.90 (1H, m),
3.30 (1H, d, J = 7.4 Hz), 3.31 (1H, d, J = 7.4 Hz),
4.11 (2H, q, J = 7.1 Hz), 4.57 (1H, t, J = 7.3 H
z), 7.00-7.22 (6H, m), 7.96 (2H, dd, J = 5.4 Hz, 9.
0 Hz); IR (neat) 2961, 1738, 1688, 1599, 1507, 127
^{1, 1233, 1159 cm -1 3} ) (2RS, 3RS) -3- (4- fluorophenyl) -3-hydroxy-2- (3-isopropyl-benzyl)
Ethyl propionate While stirring 3.99 g (29.3 mmol) of zinc chloride in 30 ml of diethyl ether, 2.22 g (58.6 mmol) of sodium borohydride was added at room temperature, and the mixture was stirred as it was for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. To the resulting solution, a solution of 5.016 g (14.65 mmol) of ethyl 3- (4-fluorophenyl) -2- (3-isopropylbenzyl) -3-oxopropionate in 30 ml of diethyl ether was added under ice-cooling.
Stirred at 0 ° C. for 20 minutes. Dilute hydrochloric acid was added little by little to the reaction solution to decompose excess zinc borohydride, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-3 / 1) to obtain the desired product. Colorless liquid Yield 4.166 g Yield 83% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 0.91 (3H, t, J = 7.2 H)
z), 1.20 (6H, d, J = 7.2 Hz), 2.78-2.87 (1H, m),
2.91-3.00 (4H, m), 3.87 (2H, q, J = 7.2 Hz), 5.01
(1H, t, J = 3.3 Hz), 6.89-6.93 (2H, m), 7.02-7.08
(3H, m), 7.16 (1H, t, J = 7.5 Hz), 7.38 (2H, dd, J
= 5.7 Hz, 8.7 Hz); IR (neat) 3466, 2961, 1726, 171
3, 1605, 1510, 1375, 1225, 1179, 1157, 1032, 837 c
m ^- 14) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- (3-isopropylbenzyl)
Propionic acid (2RS, 3RS) -3- (4-fluorophenyl) -3-
Ethyl hydroxy-2- (3-isopropylbenzyl) propionate 4.166 g (12.10 mmol), sodium hydroxide 0.97 g (24.2 mmol), methanol 30 ml, water 30 ml, tetrahydrofuran 30 m
The mixture was stirred at 60 ° C. for 6 hours. The reaction mixture was concentrated, diluted with water, and acidified with 1N hydrochloric acid.
Extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 3.208 g Yield 84% mp 102-104 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.19 (6H,
d, J = 6.9 Hz), 2.77-2.86 (1H, m), 2.89-3.07 (3H,
m), 5.04 (1H, d, J = 4.8 Hz), 6.88-6.91 (2H, m),
7.01-7.07 (3H, m), 7.15 (1H, t, J = 7.5 Hz), 7.36
(2H, dd, J = 5.6Hz, 8.6 Hz); IR (KBr) 3341, 3100-2
550, 1694, 1514, 1229, 1020, 837, 785, 702 cm ^-1 ; A
nal.Calcd for C ₁₉ H ₂₁ FO ₃ : C, 72.13; H, 6.69. Foun
d: C, 72.02; H, 6.64.5) (4RS, 5SR) -5- (4-fluorophenyl) -4- (3-isopropylbenzyl) -1,3-oxazolidin-2-one (2RS, 3RS) -3- (4-Fluorophenyl) -3-
1.58 ml of triethylamine was added to a solution of 2.982 g (9.426 mmol) of hydroxy-2- (3-isopropylbenzyl) propionic acid in 50 ml of tetrahydrofuran.
(11.3 mmol) and 2.85 g (10.4 mmol) of diphenylphosphoryl azide, and the mixture was stirred at 65 ° C. overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1), and crystallized from diisopropyl ether / hexane. I got something. White crystal Yield 2.680 g Yield 91% mp 153-154 ° C .; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.21 (6H,
d, J = 6.9 Hz), 2.19 (1H, dd, J = 10.8 Hz, 13.8 H
z), 2.28 (1H, dd, J = 4.1 Hz, 13.7 Hz), 2.77-2.91
(1H, m), 4.24 (1H, ddd, J = 3.7 Hz, 8.2 Hz, 11.2 H
z), 4.94 (1H, brs), 5.79 (1H, d, J = 8.1 Hz), 6.84
-6.87 (2H, m), 7.09-7.24 (4H, m), 7.38 (2H, dd, J
= 5.3 Hz, 8.6 Hz); IR (KBr) 3306, 2969, 1759, 172
3, 1701, 1510, 1424, 1225, 1078, 1007 cm ^-1 ; Anal.
_{Calcd for C 19 H 20 FNO 2} :. C, 72.82; H, 6.43; N, 4.47 F
ound: C, 72.81; H, 6.60; N, 4.41.6) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (3-isopropylphenyl) propan-1-ol (4RS , 5SR) -5- (4-Fluorophenyl) -4-
(3-isopropylbenzyl) -1,3-oxazolidine-
2.453 g (7.828 mmol) of 2-one and 1.25 g (31.3 mmol) of sodium hydroxide were heated to reflux in 25 ml of ethanol-1.5 ml of water for 3 hours.
The reaction was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, passed through APS-silica gel, and the solvent was distilled off under reduced pressure. The residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystal Yield 1.999 g Yield 89% mp 88-90 ° C .; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.23 (6H,
d, J = 6.6 Hz), 2.30 (1H, dd, J = 10.4 Hz, 13.4 H
z), 2.77 (1H, dd, J = 3.3 Hz, 13.5 Hz), 2.82-2.91
(1H, m), 3.29 (1H, ddd, J = 3.3 Hz, 5.0 Hz, 10.4 H
z), 4.67 (1H, d, J = 5.1 Hz), 6.94-6.98 (2H, m), 7.
05-7.11 (3H, m), 7.22 (1H, t, J = 7.4 Hz), 7.38 (2
H, dd, J = 5.6 Hz, 8.6 Hz); IR (KBr) 3150-2780, 15
08, 1215, 1046, 980, 818, 710 cm ^-1 ; Anal.Calcd fo
r C ₁₈ H ₂₂ FNO: C, 75.23; H, 7.72; N, 4.87. Found: C,
75.33; H, 7.82; N, 4.78.7) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- (3-isopropylbenzyl) ethyl] -6,7-dihydro -5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- (3-isopropylphenyl) propane-1-
All 0.250 g (0.870 mmol), 6,7-
0.16 g (0.87 mmol) of dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid and 0.13 g (0.87 mmol) of 1-hydroxybenzotriazole hydrate were added to 10 ml of acetonitrile while stirring. 0.17 g (0.87 mmol) of -ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.330
g Yield 83% mp 165-167 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.20 (6H,
d, J = 6.9 Hz), 1.94-2.03 (2H, m), 2.14-2.22 (2H,
m), 2.66 (2H, t, J = 5.9 Hz), 2.68 (1H, dd, J = 1
1.1 Hz, 14.1 Hz), 2.80-2.89 (1H, m), 2.99 (1H, dd,
J = 4.5 Hz, 14.1 Hz), 4.18 (1H, d, J = 3.9 Hz),
4.64-4.73 (1H, m), 5.02 (1H, t, J = 3.6Hz), 5.65
(1H, d, J = 7.5 Hz), 5.91 (1H, td, J = 5.6 Hz, 11.
2 Hz), 6.24 (1H, d, J = 11.7 Hz), 6.89 (1H, dd, J =
0.9 Hz, 7.2 Hz), 6.98-7.15 (7H, m), 7.22 (1H, t, J
= 8.0 Hz), 7.43 (2H, dd, J = 5.4 Hz, 8.7 Hz); IR
(KBr) 3281, 2961, 2942, 1640, 1510, 1225, 833, 704
cm ^-1 ; Anal.Calcd for C _{3 0} H ₃₂ FNO ₂ : C, 78.75; H, 7.
05; N, 3.06. Found: C, 78.66; H, 7.15; N, 2.98.

Example 324 4-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- (3-isopropylbenzyl) ethyl] naphthalene-1-carboxamide (1R
S, 2SR) -2-Amino-1- (4-fluorophenyl)-
0.250 g (0.870 mmol) of 3- (3-isopropylphenyl) propan-1-ol, 4-fluoro-1
-Naphthoic acid 0.17 g (0.87 mmol), 1-hydroxybenzotriazole hydrate 0.13 g (0.87 g)
(Mmol) was added to 10 ml of acetonitrile while 0.17 g (0.87 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.355 g Yield 89% mp 159-160 ° C .; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.18 (3H,
d, J = 7.2 Hz), 1.19 (3H, d, J = 7.2 Hz), 2.73 (1
H, dd, J = 11.1 Hz, 14.4 Hz), 2.80-2.89 (1H, m), 3.
06 (1H, dd, J = 4.2 Hz, 14.4 Hz), 4.02 (1H, d, J =
4.2 Hz), 4.74-4.83 (1H, m), 5.08 (1H, t, J = 3.9
Hz), 5.81 (1H, d, J = 7.8 Hz), 6.96 (1H, dd, J =
8.1 Hz, 9.9 Hz), 7.01-7.15 (6H, m), 7.25 (1H, t, J
= 7.5 Hz), 7.42-7.47 (3H, m), 7.54 (1H, t, J = 8.
1 Hz), 7.80 (1H, d, J = 8.4 Hz), 8.07 (1H, d, J =
8.4 Hz); IR (KBr) 3272, 2965, 1640, 1626, 1601, 15
39,1512, 1329, 1264, 1229, 1051, 833, 760 cm ^-1 ; An
al. Calcd for C ₂₉ H ₂₇ F ₂ NO ₂・ 0.1H ₂ O: C, 75.50; H, 5.9
4; N, 3.04. Found: C, 75.24; H, 5.94; N, 3.44.

Example 325 N-[(1RS, 2SR) -2- (4-formylphenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] carbamic acid ter
t-butyl 1) (4RS, 5SR) -5- [4- (hydroxymethyl) phenyl] -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine- 2-
ON (4RS, 5SR) -5- [4- (methoxycarbonyl)
Phenyl] -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidin-2-one 1.518 g (3.552 mmol) and 1.34 g of sodium borohydride A solution of (35.5 mmol) in 3 ml of methanol-50 ml of tetrahydrofuran was heated to reflux for 6 hours. After the reaction solution was cooled to room temperature, dilute hydrochloric acid was added little by little, and the mixture was stirred at room temperature for 0.5 hour.
Extracted times. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 1-1 / 2), and diisopropyl ether-
Crystallization from hexane gave the desired product. White crystals Yield 0.899 g Yield 63% mp 124-125 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.75 (1H,
t, J = 5.9 Hz), 2.26 (1H, dd, J = 10.2 Hz, 13.8 H
z), 2.33 (1H, dd, J = 4.5 Hz, 13.8 Hz), 4.22-4.29
(1H, m), 4.75 (2H, d, J = 6.0 Hz), 4.94 (1H, br
s), 5.83 (1H, d, J = 8.1 Hz), 5.90 (1H, tt, J = 2.8
Hz, 53.0 Hz), 6.85 (1H, s), 6.96 (1H, d, J = 7.8 H
z), 7.10 (1H, dd, J = 1.1 Hz, 8.3 Hz), 7.31 (1H,
t, J = 8.0Hz), 7.37 (2H, d, J = 8.1 Hz), 7.45 (2H,
d, J = 8.4 Hz); IR (KBr) 3243,1746, 1208, 1123 cm
^-1 ; Anal.Calcd for C ₁₉ H ₁₇ F ₄ NO ₄ : C, 57.15; H, 4.2
9; N, 3.51. Found: C, 56.95; H, 4.05; N, 3.40. 2) 4-[(4RS, 5SR) -2-oxo-4- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidin-5-yl] benzaldehyde To a solution of 5.58 g (44.0 mmol) of oxalyl chloride in 100 ml of tetrahydrofuran was added dimethylsulfoxide 6 at -78 ° C. A solution of .24 ml (88.0 mmol) in 30 ml of tetrahydrofuran was added dropwise. After stirring for 5 minutes, (4RS, 5SR) -5- [4- (hydroxymethyl) phenyl] -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine -2-
A solution of 11.71 g (29.32 mmol) of ON in 50 ml of tetrahydrofuran-70 ml of dichloromethane-30 ml of dimethylsulfoxide was added at -78 ° C, and the mixture was stirred for 15 minutes. 24.5 ml of triethylamine (176
Mmol) and the temperature was raised to room temperature. The reaction mixture was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained crude product was crystallized from diisopropyl ether-hexane to obtain the desired product. Pale yellow crystal yield 11.39 g yield 98% mp 132-133 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.26 (1H,
dd, J = 9.9 Hz, 13.5Hz), 2.33 (1H, dd, J = 4.8 H
z, 13.8 Hz), 4.30-4.37 (1H, m), 5.10 (1H, brs), 5.
89 (1H, d, J = 8.1 Hz), 5.89 (1H, tt, J = 2.8 Hz,
53.1 Hz), 6.85 (1H, s), 6.94 (1H, d, J = 7.8 Hz),
7.11 (1H, dd, J = 1.2 Hz, 8.1 Hz), 7.30 (1H, t, J
= 8.0 Hz), 7.57 (2H, d, J = 7.8 Hz), 7.96 (2H, d,
J = 8.4 Hz), 10.06 (1H, s); IR (KBr) 3243, 3144, 1
742, 1703, 1238, 1198, 1144, 1121, 1090 cm ^-1 ; Ana
_{. l Calcd for C 19 H 15} F 4 NO 4: C, 57.44; H, 3.81; N, 3.
53.Found: C, 57.28; H, 3.87; N, 3.39. 3) (4RS, 5SR) -5- (4-formylphenyl) -2-oxo-4- [3- (1,1,2,2 -Tetrafluoroethoxy) benzyl] -1,3-oxazolidine-3-
Tert-Butyl carboxylate 4-[(4RS, 5SR) -2-oxo-4- [3- (1,
1,2,2-tetrafluoroethoxy) benzyl] -1,
3-Oxazolidin-5-yl] benzaldehyde
A solution of 29 g (28.41 mmol), 7.44 g (34.1 mmol) of di-tert-butyl dicarbonate, 0.35 g (2.84 mmol) of 4-N, N-dimethylaminopyridine in 50 ml of acetonitrile at room temperature. Stirred overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-2 / 1), and crystallized from ethyl acetate-diisopropyl ether-hexane. The desired product was obtained. White crystal Yield 12.38 g Yield 88% mp 143-144 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.53 (9H,
s), 2.59 (1H, dd, J = 8.9 Hz, 14.6 Hz), 2.94 (1H,
dd, J = 4.4 Hz, 14.3 Hz), 4.85-4.91 (1H, m), 5.75
(1H, d, J = 6.9 Hz), 5.84 (1H, tt, J = 2.9 Hz, 53.
1 Hz), 6.37 (1H, s), 6.60 (1H, d, J = 7.8 Hz), 6.9
4 (1H, dd, J = 1.4 Hz, 8.0 Hz), 7.05 (1H, t, J = 8.
0 Hz), 7.34 (2H, d, J = 8.1 Hz), 7.77 (2H, d, J =
8.7 Hz), 9.99 (1H, s); IR (KBr) 1804, 1690, 1364, 1
348, 1304, 1196, 1155, 1121,1092, 1061 cm ^-1 ; Anal.
Calcd for C ₂₄ H ₂₃ F ₄ NO ₆ : C, 57.95; H, 4.66; N, 2.8
2. Found: C, 57.88; H, 4.49; N, 2.71.4) N-[(1RS, 2SR) -2- (4-formylphenyl) -2-hydroxy-1- [3- (1,1, Tert-Butyl 2,2-tetrafluoroethoxy) benzyl] ethyl] carbamate (4RS, 5SR) -5- (4-formylphenyl) -2-
Tert-Butyl oxo-4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine-3-carboxylate 12.20 g (24.53 mmol) of methanol 20 ml-tetrahydrofuran 50m
To this solution, a solution of 1.03 g (25.8 mmol) of sodium hydroxide in 15 ml of methanol was added under ice-cooling.
Stirred for hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The residue obtained is ethyl acetate
Crystallization from -diisopropyl ether-hexane gave the desired product. White crystals Yield 8.681 g Yield 75% mp 140-142 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.36 (9H,
s), 2.75 (2H, d, J = 7.5 Hz), 3.54 (1H, br s), 4.0
4-4.13 (1H, m), 4.63 (1H, br d, J = 8.1 Hz), 5.06
(1H, br s), 5.89 (1H, tt, J = 2.9 Hz, 53.0 Hz), 6.
94 (1H, s), 7.00 (1H, d, J = 7.8 Hz), 7.06 (1H, d
d, J = 1.4 Hz, 8.3 Hz), 7.26 (1H, t, J = 8.0 Hz),
7.59 (2H, d, J = 8.4 Hz), 7.90 (2H, d, J = 8.1 H
z), 10.03 (1H, s); IR (KBr) 3358, 1684, 1530, 127
7, 1211, 1169, 1125 cm ^-1 ; Anal.Calcd for C ₂₃ H ₂₅ F ₄
NO ₅・ 0.5H ₂ O: C, 57.50; H, 5.45; N, 2.92. Found: C,
57.33; H, 5.27; N, 2.89.

Example 326 N-[(1RS, 2SR) -2- (4-formylphenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
5H-benzo [a] cycloheptene-1-carboxamide N-[(1RS, 2SR) -2- (4-formylphenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] carbamic acid ter
A solution of 8.465 g (17.96 mmol) of t-butyl and 20 ml of trifluoroacetic acid in 20 ml of tetrahydrofuran was stirred at 50 ° C. for 0.5 hour. After evaporating the reaction solution under reduced pressure, the solution was diluted with water, made alkaline with potassium carbonate, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a brown liquid. 3.38 g (18.0 mmol) of the liquid obtained above, 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid, 1-hydroxybenzotriazole hydrate 2.7
While stirring 5 g (18.0 mmol) in 60 ml of acetonitrile, 3.44 g (18.0 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature for 3 days. . The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2 / 1-3 / 2), and crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White crystals Yield 4.388 g Yield 45% mp 164-166 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.96-2.04
(2H, m), 2.15-2.22 (2H, m), 2.66 (2H, t, J = 6.0
Hz), 2.82 (1H, dd, J = 10.8 Hz, 14.4 Hz), 2.96 (1
H, dd, J = 4.4 Hz, 14.6 Hz), 3.96 (1H, d, J = 3.9
Hz), 4.65-4.74 (1H, m), 5.18 (1H, t, J = 3.8 Hz),
5.82 (1H, d, J = 7.8 Hz), 5.88 (1H, tt, J = 2.7 Hz,
53.0 Hz), 5.93 (1H, td, J = 5.7 Hz, 11.4 Hz), 6.2
3 (1H, d, J = 11.7 Hz), 6.97-7.11 (5H, m), 7.17 (1
H, d, J = 7.2 Hz), 7.30 (1H, t, J = 8.1 Hz), 7.66
(2H, d, J = 8.4 Hz), 7.91 (2H, d, J = 8.1 Hz), 10.
03 (1H, s); IR (KBr) 3503, 3252, 1694, 1636, 1537,
1285, 1190, 1107, 775 cm ^{- 1} ; Anal.Calcd for C ₃₀ H
₂₇ F ₄ NO ₄ : C, 66.54; H, 5.03; N, 2.59. Found: C, 66.
20; H, 5.00; N, 2.32.

Example 327 N-[(1RS, 2SR) -2- (4-formylphenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
0.300 g (0.554 mmol) of 5H-benzo [a] cycloheptene-1-carboxamide, piperidine 0.1.
11 ml (1.1 mmol), acetic acid 0.06 ml (1.
(1 mmol) in 10 ml of methanol was stirred at room temperature for 1 hour, and then 70 mg of sodium cyanoborohydride
(1.1 mmol) was added at room temperature and stirred at room temperature overnight. The reaction mixture was poured into aqueous sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3: 2-chloroform / methanol = 20/1), and precipitated from hexane to obtain three kinds of products. N-[(1RS, 2SR) -2-hydroxy-2
-[4- (Piperidinomethyl) phenyl] -1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide White powder Yield 0.127 g Yield 38% mp 104-106 ° C ; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.40-1.46
(2H, m), 1.53-1.60 (4H, m), 1.94-2.02 (2H, m), 2.
15-2.22 (2H, m), 2.37 (4H, br s), 2.65 (2H, t, J =
5.6 Hz), 2.79 (1H, dd, J = 10.7 Hz, 14.9 Hz), 3.00
(1H, dd, J = 4.5 Hz, 14.7 Hz), 3.46 (2H, s), 3.67
(1H, br s), 4.68-4.75 (1H, m), 5.01 (1H, d, J = 3.
6 Hz), 5.81 (1H, d, J = 8.4 Hz), 5.88 (1H, tt, J =
2.7 Hz, 53.1 Hz), 5.90 (1H, td, J = 5.1 Hz, 12.3 H
z), 6.19 (1H, d, J = 12.0 Hz), 6.95 (1H, dd, J =
1.2 Hz, 7.8 Hz), 7.01-7.15 (5H, m), 7.26-7.33 (3H,
m), 7.39 (2H, d, J = 8.1 Hz); IR (KBr) 3258, 293
2, 1632, 1535, 1285, 1198, 1113 cm ^-1 ; Anal.Calcd
for C ₃₅ H ₃₈ F ₄ N ₂ O ₃・ 1.0H ₂ O: C, 66.86; H, 6.41; N, 4.4
6. Found: C, 66.55; H, 6.35; N, 4.54. N-[(1RS, 2SR) -2- [4- [cyano (piperidino) methyl] phenyl] -2-hydroxy-1- [3-.
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide White powder Yield 35 mg mp 152-154 ° C .; ¹ H-NMR ( (CDCl ₃ , 300 MHz) δ 1.43-1.67
(6H, m), 1.96-2.04 (2H, m), 2.16-2.22 (2H, m), 2.
51 (4H, br s), 2.66 (2H, t, J = 5.9 Hz), 2.74-2.84
(1H, m), 2.94-3.02 (1H, m), 3.78 (0.5H, d, J = 3.
9 Hz), 3.81 (0.5H, d, J = 4.2 Hz), 4.67-4.74 (1H,
m), 4.81 (1H, s), 5.06-5.93 (1H, m), 5.79-5.84 (1
H, m), 5.88-5.96 (1H, m), 5.89 (1H, tt, J = 2.9 H
z, 53.0 Hz), 6.17-6.24 (1H, m), 6.94-7.17 (6H, m),
7.29 (1H, t, J = 7.8 Hz), 7.48 (2H, d, J = 8.7 H
z), 7.55 (2H, d, J = 8.4 Hz); IR (KBr) 3353, 2940,
1638,1522, 1202, 1121 cm ^-1 ; Anal.Calcd for C ₃₆ H
₃₇ F ₄ N ₃ O ₃ : C, 68.02; H, 5.87; N, 6.61. Found: C, 67.
81; H, 6.02; N, 6.54. N-[(1RS, 2SR) -2-hydroxy-2- [4- (hydroxymethyl) phenyl] -1- [3- (1,1,2,
2-tetrafluoroethoxy) benzyl] ethyl] -6
7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide White powder Yield 41 g mp 151-152 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.75 (1H,
t, J = 5.7 Hz), 1.96-2.04 (2H, m), 2.16-2.22 (2H,
m), 2.66 (2H, t, J = 5.9 Hz), 2.78 (1H, dd, J = 1
0.8 Hz, 14.7 Hz), 2.99 (1H, dd, J = 4.1 Hz, 14.6 H
z), 3.61 (1H, d, J = 4.2 Hz), 4.68-4.75 (1H, m), 4.
71 (2H, d, J = 6.0 Hz), 5.06 (1H, t, J = 3.6 Hz),
5.77 (1H, d, J = 8.1 Hz), 5.89 (1H, tt, J = 2.9 H
z, 53.0 Hz), 5.91 (1H, td, J = 5.4 Hz, 11.7 Hz),
6.22 (1H, d, J = 11.4 Hz), 6.96-7.16 (6H, m), 7.29
(1H, t, J = 8.0 Hz), 7.38 (2H, d, J = 8.1 Hz), 7.
46 (2H, d, J = 7.8 Hz); IR (KBr) 3270, 2932, 1638,
1522, 1202, 1123 cm ^-1 ; Anal.Calcd for C ₃₀ H ₂₉ F ₄ NO
₄・ 0.1H ₂ O: C, 66.07; H, 5.40; N, 2.57. Found: C, 6
5.88; H, 5.29; N, 2.47.

Example 328 N-[(1RS, 2SR) -2- (6-chloropyridine-3-
Tert-Butyl yl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] carbamate 1) 3- (6-chloropyridin-3-yl) -3 -Oxo-
2- [3- (1,1,2,2-tetrafluoroethoxy)
Benzyl] ethyl propionate 3- (1,1,2,2-tetrafluoroethoxy) benzyl alcohol 10.5 g (46.8 mmol) and triethylamine 7.83 ml (56.2 mmol) in 80 ml of ethyl acetate are ice-cooled. Methanesulfonyl chloride 5.9
A solution of 0 g (51.5 mmol) in 20 ml of ethyl acetate was added dropwise, and the mixture was stirred for 10 minutes. The resulting precipitate was removed by filtration, and the precipitate was washed with diethyl ether. The solvent of the collected filtrate was distilled off under reduced pressure to obtain a crude product of methanesulfonic acid ester as a yellow liquid. Ethyl 3- (6-chloropyridin-3-yl) -3-oxopropionate 10.6
To a solution of 6 g (46.83 mmol) in 1,2-dimethoxyethane (100 ml) was added 1.87 g (46.8 mmol) of a 60% sodium hydride liquid paraffin suspension under ice cooling, and the mixture was stirred for 0.5 hour. . The methanesulfonic acid ester of 1,2-dimethoxyethane 1 obtained above was added thereto.
0 ml solution was added at room temperature and stirred at 60 ° C. overnight. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-6 /
1) The desired product was obtained. 17.22g pale yellow liquid yield
Yield 85% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.14 (3H, t, J = 7.2 H
z), 3.36 (2H, d, J = 7.2 Hz), 4.12 (2H, q, J = 7.1
Hz), 4.52 (1H, t, J = 7.4 Hz), 5.89 (1H, t, J = 2.
8 Hz, 53.2 Hz), 7.05-7.07 (2H, m), 7.13 (1H, d, J
= 7.8 Hz), 7.29 (1H, t, J = 8.3 Hz), 7.42 (1H, dd,
J = 0.8 Hz, 8.3 Hz), 8.16 (1H, dd, J = 2.6 Hz, 8.3
Hz), 8.92 (1H, dd, J = 0.8 Hz, 2.7 Hz); IR (neat)
1738, 1694, 1582, 1364, 1302, 1277, 1196, 1113 cm
^-1 2) (2RS, 3RS) -3- (6-chloropyridine-3)
Ethyl -yl) -3-hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propionate 10.8 g (79.0 mmol) of zinc chloride were stirred in 50 ml of diethyl ether. While stirring, 5.98 g (158 mmol) of sodium borohydride was added at room temperature, and the mixture was stirred for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. To the resulting solution was added 3- (6-chloropyridin-3-yl) -3-oxo-2- [3- (1,1,2,2
A solution of 17.14 g (39.51 mmol) of ethyl 2-tetrafluoroethoxy) benzyl] propionate in 50 ml of diethyl ether was added under ice-cooling, and the mixture was stirred for 20 minutes. Dilute hydrochloric acid was added little by little to the reaction solution to decompose excess zinc borohydride, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-2 / 1) to obtain the desired product. Light yellow liquid Yield 13.52 g Yield 79% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 0.97 (3H, t, J = 7.1 H)
z), 2.90-3.07 (3H, m), 3.28 (1H, d, J = 3.0 Hz), 3.
93 (2H, q, J = 7.2 Hz), 5.10 (1H, t, J = 3.3Hz),
5.89 (1H, tt, J = 2.8 Hz, 53.2 Hz), 6.95 (1H, s),
6.98-7.07 (2H, m), 7.27 (1H, t, J = 7.8 Hz), 7.33
(1H, d, J = 8.4 Hz), 7.73 (1H, ddd, J = 0.5 Hz, 2.5
Hz, 8.3 Hz), 8.39 (1H, dd, J = 0.9 Hz, 2.1 Hz); I
R (neat) 3353, 1728, 1588, 1460, 1375, 1302, 1279,
1198, 1119, 1026 cm ^-1 3) (2RS, 3RS) -3- (6-chloropyridine-3)
-Yl) -3-Hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propionic acid (2RS, 3RS) -3- (6-chloropyridin-3-yl) -3 Ethyl 2-hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propionate 1
3.52 g (31.02 mmol), sodium hydroxide 2.48 g (62.0 mmol), methanol 50 m
l, a mixture of 20 ml of tetrahydrofuran and 50 ml of water were stirred at room temperature for 2 hours. Concentrate the reaction, dilute with water,
After acidifying the reaction solution with hydrochloric acid, it was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from diisopropyl ether-hexane to obtain the desired product. Pale yellow crystal yield 11.32 g yield 90% mp 88-91 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.92-3.11
(3H, m), 5.10 (1H, d, J = 4.5 Hz), 5.88 (1H, tt, J
= 2.9 Hz, 53.1 Hz), 6.99-7.10 (3H, m), 7.23 (1H, t,
J = 7.8 Hz), 7.31 (1H, d, J = 8.1 Hz), 7.77 (1H,
dd, J = 2.4 Hz, 8.4 Hz), 8.34 (1H, d, J = 2.4 Hz);
IR (KBr) 3364, 2900-2400, 1686, 1590, 1462, 1316,
1279, 1227, 1202, 1113, 1082 cm ^-1 ; Anal.Calcd for
C ₁₇ H ₁₄ ClF ₄ NO ₄ : C, 50.08; H, 3.46; N, 3.44. Found:
C, 50.01; H, 3.53; N, 3.42.4) (4RS, 5S
R) -5- (6-Chloropyridin-3-yl) -4- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine-2-one (2RS, 3RS) -3- (6-chloropyridin-3-yl) -3-hydroxy-2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propionic acid 10.94
g (26.83 mmol) of tetrahydrofuran 80m
4.49 ml (32.2 mmol) of triethylamine and 8.12 g of diphenylphosphoryl azide (2
9.5 mmol) and stirred at 65 ° C. overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1), and crystallized from diisopropyl ether / hexane. I got something. White crystals Yield 8.107 g Yield 75% mp 131-132 ° C .; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.31 (1H,
dd, J = 10.5 Hz, 13.8Hz), 2.38 (1H, dd, J = 5.1 H
z, 13.8 Hz), 4.30-4.38 (1H, m), 5.23 (1H, s), 5.83
(1H, d, J = 7.8 Hz), 5.91 (1H, tt, J = 2.9 Hz, 5
3.0 Hz), 6.89 (1H, s), 6.93 (1H, d, J = 7.8 Hz),
7.13 (1H, d, J = 8.1 Hz), 7.32 (1H, t, J = 7.8 Hz),
7.42 (1H, d, J = 8.4 Hz), 7.71 (1H, dd, J = 2.4 H
z, 8.4 Hz), 8.39 (1H, d, J = 2.4 Hz); IR (KBr) 325
2, 1740, 1208, 1134, 1105, 758 cm ^-1 ; Anal.Calcd f
or C ₁₇ H ₁₃ ClF ₄ N ₂ O ₃ : C, 50.45; H, 3.24; N, 6.92. Fou
nd: C, 50.41; H, 3.04; N, 6.955.5) (4RS, 5SR) -5- (6-chloropyridine-3)
-Yl) -2-oxo-4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine
Tert-Butyl-3-carboxylate (4RS, 5SR) -5- (6-chloropyridin-3-yl) -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1, 3-Oxazolidin-2-one 7.8
A solution of 89 g (19.49 mmol), 5.10 g (23.4 mmol) of di-tert-butyl dicarbonate and 0.24 g (1.95 mmol) of 4-N, N-dimethylaminopyridine in 80 ml of acetonitrile at room temperature. Stirred overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1), and crystallized from diisopropyl ether-hexane to give the desired product. I got White crystals Yield 9.444 g Yield 96% mp 130-131 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.54 (9H,
s), 2.58 (1H, dd, J = 9.7 Hz, 14.5 Hz), 3.03 (1H,
dd, J = 4.2 Hz, 14.2 Hz), 4.83-4.93 (1H, m), 5.70
(1H, d, J = 7.0 Hz), 5.90 (1H, tt, J = 2.6 Hz, 53.
0 Hz), 6.52-6.57 (2H, m), 7.01 (1H, br d, J = 8.2
Hz), 7.11 (1H, d, J = 7.2 Hz), 7.19 (1H, d, J = 8.
4 Hz), 7.39 (1H, dd, J = 2.6 Hz, 8.4 Hz), 8.19 (1
H, d, J = 1.8 Hz); IR (KBr) 2988, 1796, 1730, 1366,
1343, 1319, 1204, 1154, 1115,1074, 1024, 845, 760
cm ^-1 ; Anal.Calcd for C ₂₂ H ₂₁ ClF ₄ N ₂ O ₅ : C, 52.34;
H, 4.19; N, 5.55.Found: C, 52.27; H, 4.03; N, 5.3
5.6) N-[(1RS, 2SR) -2- (6-chloropyridin-3-yl) -2-hydroxy-1- [3- (1,1,2,2
Tert-Butyl 2-tetrafluoroethoxy) benzyl] ethyl] carbamate (4RS, 5SR) -5- (6-chloropyridin-3-yl) -2-oxo-4- [3- (1,1,2,2 2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine-3-
9.144 g of tert-butyl carboxylate (18.11
0.76 g of sodium hydroxide (19.0 mmol) in a solution of 10 ml of methanol in 50 ml of tetrahydrofuran.
(Mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. Dilute the reaction in ethyl acetate,
After washing with water, drying over anhydrous magnesium sulfate and passing through silica gel, the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White crystals Yield 8.441 g Yield 97% mp 119-121 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.36 (9H,
s), 2.70-2.85 (2H, m), 3.86 (1H, br s), 4.00-4.09
(1H, m), 4.55 (1H, d, J = 8.1 Hz), 4.95 (1H, s),
5.90 (1H, tt, J = 2.8 Hz, 53.1 Hz), 6.98 (1H, s),
7.03 (1H, d, J = 7.8 Hz), 7.08 (1H, d, J = 7.8 Hz),
7.26-7.36 (2H, m), 7.73 (1H, dd, J = 2.3 Hz, 8.0 H
z), 8.39 (1H, d, J = 1.8 Hz); IR (KBr) 3378, 3175,
2982, 1682, 1524, 1460, 1196, 1125, 1105 cm ^-1 ; An
al. Calcd for C ₂₁ H ₂₃ ClF ₄ N ₂ O ₄ : C, 52.67; H, 4.84; N,
5.85. Found: C, 52.95; H, 4.88; N, 5.83.

Example 329 N-[(1RS, 2SR) -2- (6-chloropyridine-3-
Yl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 1) ( 1RS, 2SR) -2-amino-1- (6-chloropyridin-3-yl) -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol N- [ (1RS, 2SR) -2- (6-chloropyridine-3-
8.196 g (17.12 mmol) of tert-butyl yl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] carbamate
And 20 ml of trifluoroacetic acid were stirred at room temperature for 1 hour. After evaporating the reaction solution under reduced pressure, the solution was diluted with water, made alkaline with potassium carbonate, and extracted twice with ethyl acetate.
The collected organic layer was dried over anhydrous sodium sulfate, passed through APS-silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystal Yield 6.118 g Yield 94% mp 97-98 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.37 (1H, d
d, J = 10.4 Hz, 13.7 Hz), 2.70 (1H, dd, J = 3.2 H
z, 14.0 Hz), 3.34 (1H, ddd, J = 3.5 Hz, 4.2 Hz, 1
0.1 Hz), 3.58 (1H, br s), 4.75 (1H, d, J = 4.2 H
z), 5.90 (1H, tt, J = 2.9 Hz, 53.1 Hz), 6.98 (1H,
s), 7.04 (1H, d, J = 7.5 Hz), 7.09 (1H, d, J = 8.1
Hz), 7.31 (1H, t, J = 7.8 Hz), 7.36 (1H, d, J = 8.
1 Hz), 7.75 (1H, dd, J = 2.6 Hz, 8.3 Hz), 8.40 (1
H, d, J = 2.4 Hz); IR (KBr) 3358, 3065-2755, 1588,
1568, 1454, 1279, 1202, 1119, 1100, 1047 cm ^-1 ; An
al. Calcd for C ₁₆ H ₁₅ ClF ₄ N ₂ O ₂ : C, 50.74; H, 3.99;
N, 7.40. Found: C, 50.60; H, 3.72; N, 7.13.2) N-[(1RS, 2SR) -2- (6-chloropyridin-3-yl) -2-hydroxy-1- [3 -(1,1,2,
2-tetrafluoroethoxy) benzyl] ethyl] -6
7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- (6-chloropyridin-3-yl) -3- [3- (1,1,2,2 2-tetrafluoroethoxy) phenyl] propan-1-ol 1.000
g (2.640 mmol), 0.50 g of 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid
(2.64 mmol) 1-Hydroxybenzotriazole hydrate 0.40 g (2.64 mmol) in 20 ml of acetonitrile while stirring 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0 .5
1 g (2.64 mmol) was added and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystal Yield 1.311 g Yield 91% mp 170-172 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.96-2.05
(2H, m), 2.14-2.22 (2H, m), 2.66 (2H, t, J = 6.0
Hz), 2.79 (1H, dd, J = 11.0 Hz, 14.3 Hz), 3.01 (1
H, dd, J = 4.2 Hz, 14.4 Hz), 4.29 (1H, d, J = 3.9
Hz), 4.61-4.69 (1H, m), 5.08 (1H, t, J = 3.9 Hz),
5.76 (1H, d, J = 7.8 Hz), 5.90 (1H, tt, J = 2.8 Hz,
53.0 Hz), 5.94 (1H, td, J = 5.8 Hz, 11.7 Hz), 6.1
9 (1H, d, J = 11.4 Hz), 6.96 (1H, dd, J = 1.5 Hz,
7.8 Hz), 7.03-7.18 (5H, m), 7.33 (1H, t, J = 8.0 H
z), 7.35 (1H, d, J = 8.1 Hz), 7.81 (1H, dd, J = 2.
4 Hz, 8.4 Hz), 8.42 (1H, d, J = 2.7 Hz); IR (KBr)
3247, 1634, 1530, 1462, 1277, 1198, 1121 cm ^-1 ; Ana
l. Calcd for C ₂₈ H ₂₅ ClF ₄ N ₂ O ₃ : C, 61.26; H, 4.59; N,
5.10. Found: C, 61.32; H, 4.75; N, 5.07.

Example 330 N-[(1RS, 2SR) -2-hydroxy-2- (6-phenylpyridin-3-yl) -1- [3- (1,1,2,2-tetrafluoroethoxy) Benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide N-[(1RS, 2SR) -2- (6-chloropyridine-3-
Il) -2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 0.523 g (0.953 mmol), phenylboronic acid 0.35 g (2.86 mmol), tetrakis (triphenylphosphine) palladium (0) 0.22
g (0.19 mmol) and 0.40 g of sodium carbonate
(3.81 mmol) in 10 ml of toluene and 10 ml of water
And stirred at 110 ° C. for 3 days. Pour the reaction into water,
Extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane /
Crystallization from ethyl acetate = 3 / 1-1 / 1) and diisopropyl ether / hexane gave the desired product. Light brown powder Yield 0.344 g Yield 61% mp 174-175 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.95-2.03
(2H, m), 2.14-2.20 (2H, m), 2.66 (2H, t, J = 5.9
Hz), 2.82 (1H, dd, J = 10.7 Hz, 14.0 Hz), 3.07 (1
H, dd, J = 4.1 Hz, 14.9 Hz), 4.25 (1H, d, J = 3.9
Hz), 4.70-4.79 (1H, m), 5.12 (1H, t, J = 3.3 Hz),
5.79 (1H, d, J = 8.4 Hz), 5.89 (1H, tt, J = 2.7 Hz,
53.0 Hz), 5.91 (1H, td, J = 5.5 Hz, 11.4 Hz), 6.2
1 (1H, d, J = 11.7 Hz), 6.98 (1H, dd, J = 1.0 Hz,
7.5 Hz), 7.03-7.17 (5H, m), 7.32 (1H, t, J = 8.0 H
z), 7.40-7.52 (3H, m), 7.75 (1H, d, J = 8.1 Hz),
7.90 (1H, dd, J = 2.3 Hz, 8.3 Hz), 7.99 (2H, dd, J
= 2.1 Hz, 8.7 Hz), 8.70 (1H, d, J = 2.1 Hz); IR (K
Br) 3270, 2932, 1640, 1518, 1478, 1277, 1200, 112
3, 743, 694 cm ^-1 ; Anal.Calcd for C ₃₄ H ₃₀ F ₄ N ₂ O ₃ : C,
69.14; H, 5.12; N, 4.74. Found: C, 69.04; H, 5.0
4; N, 4.71.

Example 331 N-[(1RS, 2SR) -2- (6-chloropyridine-3-
Yl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -4-fluoronaphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (6-chloropyridin-3-yl) -3- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] propan-1-ol 1.000
g (2.640 mmol), 0.50 g (2.64 mmol) of 4-fluoro-1-naphthoic acid and 0.40 g (2.64 mmol) of 1-hydroxybenzotriazole hydrate were stirred in 20 ml of acetonitrile. While adding 0.51 g (2.64 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 1.338
g Yield 92% mp 185-187 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
2.91 (1H, dd, J = 10.8Hz, 14.1 Hz), 3.17 (1H, dd,
J = 3.8 Hz, 14.0 Hz), 4.68-4.78 (1H, m), 4.95 (1H,
t, J = 5.0 Hz), 5.61 (1H, d, J = 4.2 Hz), 6.00 (1
H, tt, J = 2.9 Hz, 53.0 Hz), 7.03 (1H, dd, J = 7.7
Hz, 10.1 Hz), 7.08-7.23 (4H, m), 7.29-7.38 (2H,
m), 7.42-7.56 (3H, m), 7.85 (1H, d, J = 9.3 Hz, 7.
93 (1H, dd, J = 2.4 Hz, 8.1 Hz), 8.05 (1H, d, J =
8.1 Hz), 8.49 (1H, d, J = 2.1 Hz); IR (KBr) 3291,
1638, 1624, 1539, 1456, 1196, 1125, 837, 766 cm ^-1 ;
_{. Anal Calcd for C 27 H 20} ClF 5 N 2 O 3: C, 58.87; H, 3.6
6; N, 5.08. Found: C, 58.84; H, 3.59; N, 5.13.

Example 332 4-Fluoro-N-[(1RS, 2SR) -2-hydroxy-
2- (6-phenylpyridin-3-yl) -1- [3- (1,
1,2,2-tetrafluoroethoxy) benzyl] ethyl] naphthalene-1-carboxamide N-[(1RS, 2SR) -2- (6-chloropyridine-3-
Yl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -4-fluoronaphthalene-1-carboxamide 0.516 g (0.93 g)
7 mmol), 0.34 g (2.81) of phenylboronic acid
Mmol), 0.22 g (0.19 mmol) of tetrakis (triphenylphosphine) palladium (0) and 0.40 g (3.74 mmol) of sodium carbonate were stirred at 110 ° C. for 3 days in 10 ml of toluene and 10 ml of water. . The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-ethyl acetate), and crystallized from diisopropyl ether-hexane to obtain the desired product. Brown amorphous powder Yield 0.154g
Yield 28% ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ 2.95 (1H, dd, J
= 10.8 Hz, 14.4 Hz), 3.10 (1H, dd, J = 3.6 Hz, 14.
1 Hz), 4.82-4.90 (1H, m), 5.12 (1H, t, J = 3.9 Hz),
5.32 (1H, d, J = 3.9 Hz), 5.92 (1H, tt, J = 2.8 H
z, 53.1 Hz), 7.02 (1H, dd, J = 7.8 Hz, 10.2 Hz),
7.09 (1H, d, J = 7.8 Hz), 7.15 (1H, s), 7.19-7.53
(9H, m), 7.73 (1H, d, J = 9.0 Hz), 7.78 (1H, d, J
= 8.4 Hz), 7.97-8.07 (4H, m), 8.82 (1H, d, J = 2.4
Hz); IR (KBr) 3289, 1644, 1601, 1532, 1476, 1264,
1236, 1202, 1123, 758 cm ^-1 ; Anal.Calcd for C ₃₃ H
₂₅ F ₅ N ₂ O ₃ : C, 66.89; H, 4.25; N, 4.73. Found: C, 6
6.57; H, 4.13; N, 4.82.

Example 333 5-Chloro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2-
Tetrafluoroethoxy) benzyl] ethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (1,1,2,2-tetrafluoroethoxy) Phenyl] propan-1-ol 0.200 g
(0.554 mmol) 5-chloro-1-naphthoic acid 0.11 g (0.55 mmol) 1-hydroxybenzotriazole hydrate 85 mg (0.55 mmol) in 10 ml of acetonitrile with stirring 1-. Ethyl-3
0.11 g (0.55 mmol) of-(3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White powder Yield 0.25
8g Yield 85% mp 174-175 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
2.87 (1H, dd, J = 10.7Hz, 14.9 Hz), 2.98 (1H, dd,
J = 4.7 Hz, 14.0 Hz), 4.64 (1H, d, J = 3.3 Hz), 4.
75-4.84 (1H, m), 5.06 (1H, t, J = 4.1 Hz), 5.90 (1
H, tt, J = 2.9 Hz, 53.3 Hz), 6.93 (1H, d, J = 9.3
Hz), 7.04-7.16 (5H, m), 7.26-7.32 (3H, m), 7.45-7.6
2 (5H, m), 8.31 (1H, d, J = 8.4 Hz); IR (KBr) 327
0, 1634, 1537, 1512, 1227, 1192, 1119, 785 cm ^-1 ; A
nal.Calcd for C ₂₈ H ₂₁ ClF ₅ NO ₃ : C, 61.16; H, 3.85; N,
2.55. Found: C, 61.23; H, 3.86; N, 2.39.

Example 334 5-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2
2-tetrafluoroethoxy) benzyl] ethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (1,1,2,2-tetrafluoro Ethoxy) phenyl] propan-1-ol 0.200 g
(0.554 mmol) 5-fluoro-1-naphthoic acid 0.11 g (0.55 mmol), 1-hydroxybenzotriazole hydrate 85 mg (0.55 mmol) in 10 ml of acetonitrile with stirring. Ethyl-3
0.11 g (0.55 mmol) of-(3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White powder Yield 0.24
0 g Yield 81% mp 178-180 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
2.89 (1H, dd, J = 10.7Hz, 14.6 Hz), 2.98 (1H, dd,
J = 4.5 Hz, 14.7 Hz), 4.73 (1H, d, J = 3.6 Hz), 4.
75-4.84 (1H, m), 5.07 (1H, t, J = 3.8 Hz), 5.90 (1
H, tt, J = 2.9 Hz, 53.1 Hz), 6.98 (1H, d, J = 9.0
Hz), 7.05-7.17 (6H, m), 7.26-7.35 (3H, m), 7.41-7.5
5 (4H, m), 8.12 (1H, d, J = 8.4 Hz); IR (KBr) 327
5, 1640, 1541, 1512, 1250, 1229, 1198, 1128, 785 c
m ^-1 ; Anal.Calcd for C ₂₈ H ₂₁ F ₆ NO ₃ : C, 63.04; H, 3.9
7; N, 2.63. Found: C, 63.09; H, 4.24; N, 2.56.

Example 335 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [3- (2,3,3-trifluoro-
1-propenyl) benzyl] ethyl] -6,7-dihydro-
5H-benzo [a] cyclohepten-1-carboxamide 1) 2,2,3,3-tetrafluoro-1- (3-methylphenyl) propan-1-one magnesium 14.1 g (579 mmol), iodine 1
While stirring the fragments in 100 ml of diethyl ether, a solution of 90.0 g (526 mmol) of 3-methylbromobenzene in 200 ml of diethyl ether was slowly added dropwise at room temperature. After completion of the addition, the mixture was stirred at room temperature overnight. The reaction solution was cooled to -78 ° C, a solution of 25.61 g (175.4 mmol) of 2,2,3,3-tetrafluoropropionic acid in 100 ml of diethyl ether was added dropwise, and the mixture was refluxed for 4 hours. 1N hydrochloric acid was added dropwise to the reaction solution under ice cooling. The diethyl ether layer was separated, and the aqueous layer was extracted with diethyl ether. The collected diethyl ether solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-hexane / ethyl acetate = 15/1),
The desired product was obtained. Light yellow liquid Yield 27.97 g Yield 7
2% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.45 (3H, s), 6.29 (1H,
tt, J = 5.5 Hz, 53.6Hz), 7.42 (1H, dt, J = 1.2 H
z, 7.4 Hz), 7.51 (1H, dd, J = 0.6 Hz, 7.8 Hz), 7.8
9-7.92 (2H, m); IR (neat) 1698, 1240, 1142, 1115,
1092, 789, 770,743 cm ^-1 2) 2,2,3,3-tetrafluoro-1- (3-methylphenyl) propan-1-ol 2,2,3,3-tetrafluoro-1- (3- 9.11 g (41.4 mmol) of methylphenyl) propan-1-one
Then, 0.76 g (20 mmol) of sodium borohydride was added little by little to a 50 ml solution of methanol under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-3 / 1) to obtain the desired product. Colorless liquid
Yield 6.131 g Yield 67% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 2.35 (1H, d, J = 4.8 H)
z), 2.39 (3H, s), 4.95-5.10 (1H, m), 5.97 (1H, dd
t, J = 3.3 Hz, 8.1 Hz, 53.2 Hz), 7.21-7.36 (4H,
m); IR (neat) 3426, 1240, 1161, 1107, 1059, 762, 7
43 cm ^-1 3) O-phenyl O- [2,2,3,3-tetrafluoro-1- (3-methylphenyl) propyl] thioacetate 2,2,3,3-tetrafluoro-1- (3 3.814 g (17.17 mmol) of -methylphenyl) propan-1-ol and 3.26 g of phenylchlorothionoformate
(18.9 mmol) in a solution of acetonitrile in 40 ml of 4.62 g of 4-N, N-dimethylaminopyridine (37.
(8 mmol) under ice-cooling and stirred at room temperature overnight. The resulting precipitate was removed by filtration and washed with acetonitrile. The solvent of the collected filtrate was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-6 / 1) to obtain the desired product. Colorless liquid Yield 6.189 g Yield 100% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.41 (3H, s), 5.89 (1H,
tt, J = 5.0 Hz, 53.0Hz), 6.56 (1H, dd, J = 10.7 H
z, 14.0 Hz), 7.08 (2H, d, J = 7.5 Hz), 7.21-7.49
(7H, m); IR (neat) 1591, 1489, 1279, 1211, 1127, 1
107, 1065, 774,689 cm ^-1 4) 1-methyl-3- (2,2,3,3-tetrafluoropropyl) benzene O-phenyl O- [2,2,3,3-tetrafluoro-1 thioacetate -(3-Methylphenyl) propyl] 6.189
g (17.27 mmol), tributyltin hydride 7.
A solution of 49 g (25.7 mmol) and 0.56 g (3.43 mmol) of 2,2′-azobis (isobutyronitrile) in 50 ml of benzene was stirred at 80 ° C. for 6 hours. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane) to obtain the desired product. Colorless liquid, yield 1.4
12 g Yield 40% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.36 (3H, s), 3.24 (2H,
t, J = 17.7 Hz), 5.69 (1H, tt, J = 3.5 Hz, 53.7 H
z), 7.08-7.15 (3H, m), 7.23 (1H, d, J = 7.8Hz); IR
(neat) 1165, 1101, 1057 cm ^-15 ) 3- (4-fluorophenyl) -2- [3- (2,
2,3,3-tetrafluoropropyl) benzyl] -3-
Ethyl oxopropionate 1.363 g (6.611 mmol) of 1-methyl-3- (2,2,3,3-tetrafluoropropyl) benzene, N
-Bromosuccinimide 1.18 g (6.61 mmol), 2,2'-azobis (isobutyronitrile) 30
A solution of mg of carbon tetrachloride in 20 ml was heated to reflux for 1.5 hours. After cooling the reaction solution to room temperature, a white precipitate was removed by filtration, and the precipitate was washed with hexane. The solvent of the collected filtrate was distilled off under reduced pressure to obtain a crude product of 3- (2,2,3,3-tetrafluoropropyl) benzyl bromide as a colorless liquid. 1.39 g of ethyl (4-fluorobenzoyl) acetate
(6.61 mmol) of 1,2-dimethoxyethane 30
To the ml solution was added 0.26 g (6.61 mmol) of a 60% sodium hydride liquid paraffin suspension under ice cooling, and the mixture was stirred for 0.5 hour as it was. The 3- (2,
A solution of 2,3,3-tetrafluoropropyl) benzyl bromide in 10 ml of 1,2-dimethoxyethane was added at room temperature, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-9 / 1) to obtain the desired product. Yellow liquid Yield 1.849 g Yield 68% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.12 (3H, t, J = 7.1 H)
z), 3.22 (2H, t, J = 18.0 Hz), 3.32 (1H, d, J = 7.
5 Hz), 3.33 (1H, d, J = 7.2 Hz), 4.10 (2H, dq, J =
1.7 Hz, 7.2 Hz), 4.56 (1H, t, J = 7.7 Hz), 5.63
(1H, tt, J = 3.3 Hz, 53.6 Hz), 7.08-7.24 (6H, m),
7.97 (2H, dd, 5.6 Hz, 8.9 Hz); IR (neat) 1738, 168
8, 1599, 1508, 1233, 1159, 1101, 849 cm -1 6) (2RS, 3RS) -3- (4- fluorophenyl) -3-hydroxy-2- [3- (2,2,3,3 -Tetrafluoropropyl) benzyl] ethyl propionate Zinc chloride (1.22 g, 8.92 mmol) was stirred in diethyl ether (30 ml) while sodium borohydride (0.68 g, 17.8 mmol) was added at room temperature. Stirred for hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. 1.849 g (4.462 mmol) of ethyl 3- (4-fluorophenyl) -2- [3- (2,2,3,3-tetrafluoropropyl) benzyl] -3-oxopropionate was added to the resulting solution. ) In 20 ml of diethyl ether was added under ice-cooling, and the mixture was stirred for 20 minutes. Dilute hydrochloric acid was added little by little to the reaction solution to decompose excess zinc borohydride, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 /
1) The desired product was obtained. Colorless liquid Yield 1.378 g Yield 74% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 0.91 (3H, t, J = 7.1 H)
z), 2.92 (1H, d, J = 2.7 Hz), 2.98 (2H, s), 3.20
(2H, t, J = 17.9 Hz), 3.87 (2H, dq, J = 2.0 Hz, 7.
2 Hz), 5.01 (1H, t, J = 3.6 Hz), 5.66 (1H, tt, J =
3.3 Hz, 53.7 Hz), 7.01-7.11 (5H, m), 7.22 (1H, t,
J = 7.5 Hz), 7.37 (2H, dd, J = 5.3 Hz, 8.6 Hz); IR
(neat) 3445, 1715, 1607, 1512, 1375, 1346, 1223, 1
159, 1100, 1057, 839 cm ^- 17 17) (4RS, 5SR) -5- (4-fluorophenyl) -4- [3- (2,2,3,3-tetrafluoropropyl) benzyl] -1, 3-oxazolidine-2-one (2RS, 3RS) -3- (4-fluorophenyl) -3-
1.378 g of ethyl hydroxy-2- [3- (2,2,3,3-tetrafluoropropyl) benzyl] propionate
(3.309 mmol), 0.26 g of sodium hydroxide
(6.62 mmol), 10 ml of methanol, 5 m of water
1 and a mixture of 10 ml of tetrahydrofuran were stirred at room temperature overnight. The reaction solution was concentrated, diluted with water, acidified with 1N hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- [3- (2,2,3, A crude product of [3-tetrafluoropropyl) benzyl] propionic acid was obtained as a liquid. To a solution of the liquid obtained above in 30 ml of tetrahydrofuran, 0.55 ml of triethylamine (3.9
7 mmol), 1.00 g of diphenylphosphoryl azide
(3.64 mmol) and stirred at 65 ° C. overnight.
The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / hexane).
Crystallization from ethyl acetate = 3 / 1-1 / 1) and diisopropyl ether / hexane gave the desired product. White crystals Yield 1.022 g Yield 80% mp 91-93 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.24 (1H, d
d, J = 10.1 Hz, 14.0 Hz), 2.31 (1H, dd, J = 4.8 H
z, 13.5 Hz), 3.22 (2H, t, J = 17.9 Hz), 4.21-4.28
(1H, m), 5.15 (1H, s), 5.72 (1H, tt, J = 3.0 Hz, 5
3.9 Hz), 5.79 (1H, d, J = 7.8 Hz), 6.95 (1H, s),
6.99 (1H, d, J = 7.8 Hz), 7.10-7.18 (3H, m), 7.28
(1H, t, J = 7.7 Hz), 7.36 (2H, dd, J = 5.1 Hz, 8.4
Hz); IR (KBr) 3241, 1757, 1740, 1512, 1343, 1223,
1167, 1094, 1051, 835, 712 cm ^-1 ; Anal.Calcd for C
₁₉ H ₁₆ F ₅ NO ₂ : C, 59.22; H, 4.19; N, 3.63. Found: C,
59.20; H, 4.22; N, 3.66.8) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (2,3,3-trifluoro-1-)
Propenyl) phenyl] propan-1-ol (4RS, 5SR) -5- (4-fluorophenyl) -4-
0.880 g of [3- (2,2,3,3-tetrafluoropropyl) benzyl] -1,3-oxazolidin-2-one
(2.284 mmol) and 0.37 g of sodium hydroxide
(9.14 mmol) in 10 ml ethanol-0.5 water
The mixture was heated under reflux for 3 hours. Dilute the reaction with water,
Extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, passed through APS-silica gel, and the solvent was distilled off under reduced pressure. The residue was crystallized from ethyl acetate-diethyl ether-hexane to obtain the desired product. White crystals Yield 0.462 g Yield 60% mp 98-99 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.36 (1H, d
d, J = 10.2 Hz, 13.5 Hz), 2.81 (1H, dd, J = 3.3 H
z, 13.8 Hz), 3.26-3.32 (1H, m), 4.67 (1H, d, J = 4.
8 Hz), 6.07 (1H, d, J = 37.2 Hz), 6.15 (1H, dt, J
= 7.2 Hz, 53.8 Hz), 7.05-7.14 (3H, m), 7.28-7.43
(5H, m); IR (KBr) 3100-2750, 1508, 1406, 1362, 122
3, 1103, 1042 cm ^-1 ; Anal.Calcd for C ₁₈ H ₁₇ F ₄ NO: C,
63.71; H, 5.05; N, 4.13. Found: C, 63.49; H, 5.07;
N, 4.12.9) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (2,3,3-trifluoro-1-propenyl) benzyl] ethyl ] -6,7-Dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (2,3,3- 0.100 g of trifluoro-1-propenyl) phenyl] propan-1-ol
(0.295 mmol), 55 mg of 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (0.
29 mmol) 1-hydroxybenzotriazole hydrate (45 mg, 0.29 mmol) in acetonitrile 1
While stirring in 0 ml, 56 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.
29 mmol) and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White powder Yield 0.122 g Yield 81% mp 165-167 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.95-2.03
(2H, m), 2.16-2.22 (2H, m), 2.66 (2H, t, J = 6.2
Hz), 2.76 (1H, dd, J = 10.8 Hz, 14.7 Hz), 3.00 (1
H, dd, J = 4.4 Hz, 14.6 Hz), 3.69 (1H, d, J = 4.2
Hz), 4.64-4.73 (1H, m), 5.04 (1H, t, J = 3.9 Hz),
5.72 (1H, d, J = 8.1 Hz), 5.89 (1H, td, J = 5.6 Hz,
11.3 Hz), 6.06 (1H, d, J = 37.2 Hz), 6.14 (1H, d
t, J = 7.2Hz, 53.7 Hz), 6.17 (1H, d, J = 11.7 Hz),
6.97 (1H, dd, J = 1.5 Hz, 7.8 Hz), 7.03-7.19 (5H,
m), 7.29-7.34 (2H, m), 7.41-7.48 (3H, m); IR (KB
r) 3272, 2938, 1638, 1512, 1345, 1227, 1182, 1101,
^{. 1038, 772 cm -1; Anal} Calcd for C 30 H 27 F 4 NO 2: C, 7
0.72; H, 5.34; N, 2.75. Found: C, 70.43; H, 5.26;
N, 2.71.

Example 336 4-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (2,3,3-trifluoro-1-propenyl) ) Benzyl] ethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (2,3,3-trifluoro-1-propenyl) phenyl] 0.100 g of propan-1-ol
(0.295 mmol) 56 mg (0.29 mmol) of 4-fluoro-1-naphthoic acid, 45 mg (0.29 mmol) of 1-hydroxybenzotriazole hydrate in 10 ml of acetonitrile with stirring in 1-ethyl- 3-
56 mg (0.29 mmol) of (3-dimethylaminopropyl) carbodiimide hydrochloride was added and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White powder Yield 0.122 g Yield 81% mp 184-185 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.81 (1H,
dd, J = 10.7 Hz, 14.3Hz), 3.06 (1H, dd, J = 4.1 H
z, 14.6 Hz), 3.49 (1H, d, J = 3.3 Hz), 4.73-4.82
(1H, m), 5.10 (1H, t, J = 3.8 Hz), 5.89 (1H, d, J
= 8.1 Hz), 6.05 (1H, d, J = 37.2 Hz), 6.12 (1H, dt,
J = 7.2 Hz, 53.7 Hz), 7.01 (1H, dd, J = 7.7 Hz, 1
0.1 Hz), 7.09 (2H, t, J = 8.6 Hz), 7.16-7.57 (9H,
m), 7.75 (1H, d, J = 8.7 Hz), 8.08 (1H, d, J = 8.4
Hz); IR (KBr) 3275, 1642, 1512, 1229, 1051, 837, 7
60 cm ^-1 ; Anal.Calcd for C ₂₉ H ₂₂ F ₅ NO ₂ : C, 68.10; H,
4.34; N, 2.74. Found: C, 67.77; H, 4.19; N, 2.74.

Example 337 N-[(1RS, 2SR) -2- (4-fluorophenyl)
Tert--2-Hydroxy-1- [3- (2,2,3,3-tetrafluoropropyl) benzyl] ethyl] carbamic acid
t-butyl 1) (4RS, 5SR) -5- (4-fluorophenyl) -2-oxo-4- [3- (2,2,3,3-tetrafluoropropyl) benzyl] -1,3-oxazolidine -3-
Tert-Butyl carboxylate (4RS, 5SR) -5- (4-fluorophenyl) -4-
[3- (2,2,3,3-tetrafluoropropyl) benzyl] -1,368-oxazolidine-2-one 2.368 g
(6.145 mmol), 1.61 g (7.37 mmol) of di-tert-butyl dicarbonate, 75 mg (0.61 mmol) of 4-N, N-dimethylaminopyridine in 30 ml of acetonitrile were stirred at room temperature overnight. did. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1) to obtain the desired product. Light yellow liquid Yield 3.014 g Yield 100% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.51 (9H, s), 2.57 (1H,
dd, J = 9.0 Hz, 14.0Hz), 2.90 (1H, dd, J = 4.4 H
z, 14.4 Hz), 3.11 (2H, br t, J = 18.3 Hz), 4.77-4.
87 (1H, m), 5.67 (1H, d, J = 8.0 Hz), 5.69 (1H, t
t, J = 3.2 Hz, 53.8 Hz), 6.60-6.64 (2H, m), 6.93
(2H, t, J = 8.6 Hz), 7.03-7.16 (4H, m); IR (neat) 2
982, 1817, 1723, 1514, 1360, 1302, 1227, 1155, 110
^{1, 1067 cm - 1 2)} N - [(1RS, 2SR) -2- (4- fluorophenyl) -2-hydroxy-1- [3- (2,2,3,3-tetrafluoro propyl) benzyl] Ethyl tert-butyl carbamate (4RS, 5SR) -5- (4-fluorophenyl) -2-
To a solution of 3.014 g (6.209 mmol) of tert-butyl oxo-4- [3- (2,2,3,3-tetrafluoropropyl) benzyl] -1,3-oxazolidine-3-carboxylate in 30 ml of tetrahydrofuran was added. 0.26 g (6.52 mmol) of sodium hydroxide in methanol 10
The solution was added under ice-cooling and stirred at 0 ° C. for 0.5 hour. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White crystal Yield 2.367 g Yield 83% mp 168-169 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
1.30 (9H, s), 2.64-2.78 (2H, m), 3.21 (2H, t, J = 1
7.7 Hz), 4.05 (1H, br s), 4.54 (1H, s), 4.87 (1H, b
rs), 5.08 (1H, br d, J = 8.4 Hz), 5.70 (1H, tt, J
= 3.9 Hz, 53.4Hz), 7.01-7.10 (5H, m), 7.21 (1H,
t, J = 7.7 Hz), 7.41 (2H, dd, J = 5.6Hz, 8.6 Hz);
IR (KBr) 3349, 1680, 1535, 1227, 1173, 1113, 1007,
837 cm ^{- 1} ; Anal.Calcd for C ₂₃ H ₂₆ F ₅ NO ₃ : C, 60.13;
H, 5.70; N, 3.05. Found: C, 60.04; H, 5.73; N, 2.9
1.

Example 338 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [3- (2,2,3,3-tetrafluoropropyl) benzyl] ethyl] -6,7-dihydro-
5H-benzo [a] cycloheptene-1-carboxamide 1) (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (2,2,3,3-tetrafluoropropyl) Phenyl] propan-1-ol N-[(1RS, 2SR) -2- (4-fluorophenyl)
Tert--2-Hydroxy-1- [3- (2,2,3,3-tetrafluoropropyl) benzyl] ethyl] carbamic acid
A mixture of 2.188 g (4.762 mmol) of t-butyl and 10 ml of trifluoroacetic acid was stirred at room temperature for 1 hour. After evaporating the reaction solution under reduced pressure, the solution was diluted with water, made alkaline with potassium carbonate, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and passed through APS-silica gel, and then the solvent was distilled off under reduced pressure to obtain the desired product.
Yellow liquid Yield 1.720 g Yield 100% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.35 (1H, dd, J = 10.4)
Hz, 13.7 Hz), 2.80 (1H, dd, J = 3.3 Hz, 13.5 Hz),
3.24 (2H, t, J = 18.6 Hz), 3.25-3.29 (1H, m), 4.66
(1H, d, J = 4.8 Hz), 5.70 (1H, tt, J = 3.2 Hz, 5
3.8 Hz), 7.04-7.16 (5H, m), 7.28 (1H, t, J = 7.7 H
z), 7.37 (2H, dd, J = 5.4 Hz, 8.7 Hz); IR (neat) 33
65-2860, 1605, 1508, 1223, 1157, 1101, 1057, 837 c
m ^- 12) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (2,2,3,3-tetrafluoropropyl) benzyl] ethyl]- 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (2,2,3,3- Tetrafluoropropyl) phenyl] propan-1-ol 0.300 g
(0.835 mmol), 0.16 g of 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid
0.18 g (0.83 mmol) of 1-hydroxybenzotriazole hydrate in 10 ml of acetonitrile was stirred with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0 (0.83 mmol). .1
6 g (0.83 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. 0.325 g of white powder
Yield 74% mp 165-166 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.95-2.04
(2H, m), 2.16-2.22 (2H, m), 2.64-2.68 (2H, m), 2.
74 (1H, dd, J = 10.5 Hz, 14.4 Hz), 2.99 (1H, dd, J
= 4.1 Hz, 14.6 Hz), 3.22 (2H, t, J = 18.0 Hz), 3.7
5 (1H, d, J = 3.9 Hz), 4.65-4.74 (1H, m), 5.02 (1
H, t, J = 3.9 Hz), 5.68 (1H, tt, J = 3.4 Hz, 53.7
Hz), 5.70 (1H, d, J = 9.0 Hz), 5.91 (1H, td, J =
5.5 Hz, 11.7 Hz), 6.21 (1H, d, J = 11.7 Hz), 6.91
(1H, d, J = 7.8 Hz), 7.02-7.10 (4H, m), 7.14-7.17
(3H, m), 7.7.28 (1H, t, J = 7.2 Hz), 7.43 (2H, dd,
J = 5.3 Hz, 8.6 Hz); IR (KBr) 3281, 1638, 1514, 12
29, 1105, 835 cm ^-1 ; Anal.Calcd for C ₃₀ H ₂₈ F ₅ NO ₂ : C,
68.04; H, 5.33; N, 2.65. Found: C, 67.89; H, 5.3
4; N, 2.47.

Example 339 4-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (2,2,3,
3-tetrafluoropropyl) benzyl] ethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (2,2,3,3-tetrafluoro Propyl) phenyl] propan-1-ol 0.300 g
(0.835 mmol) 4-fluoro-1-naphthoic acid 0.16 g (0.83 mmol) 1-hydroxybenzotriazole hydrate 0.13 g (0.83 mmol)
Was stirred in 10 ml of acetonitrile while stirring in 1-ethyl-
0.16 g (0.83 mmol) of 3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate.
After passing through silica gel, the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White powder Yield 0.3
49g Yield 79% mp 172-173 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
2.86 (1H, dd, J = 10.7Hz, 14.3 Hz), 2.97 (1H, dd,
J = 4.2 Hz, 14.1 Hz), 3.20 (2H, t, J = 17.9Hz), 4.
73-4.82 (1H, m), 4.92 (1H, d, J = 3.6 Hz), 5.06 (1
H, t, J = 3.5 Hz), 5.69 (1H, tt, J = 3.5 Hz, 53.5
Hz), 6.90 (1H, d, J = 9.0 Hz), 7.01 (1H, dd, J =
7.7 Hz, 10.1 Hz), 7.08 (2H, t, J = 8.4 Hz), 7.14-
7.29 (5H, m), 7.43 (1H, t, J = 7.5 Hz), 7.50-7.55
(3H, m), 7.73 (1H, d, J = 8.4 Hz), 8.06 (1H, d, J
= 8.1 Hz); IR (KBr) 3274, 1644, 1539, 1514, 1236,
1103,1055, 837, 760 cm ^-1 ; Anal.Calcd for C ₂₉ H ₂₃ F ₆
NO ₂ : C, 65.54; H, 4.36; N, 2.64. Found: C, 65.53;
H, 4.39; N, 2.34.

Example 340 5-Chloro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (2,2,3,3-
Tetrafluoropropyl) benzyl] ethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (4-fluorophenyl) -3- [3- (2,2,3,3-tetrafluoropropyl) Phenyl] propan-1-ol 0.300 g
(0.835 mmol) 0.16 g (0.83 mmol) of 5-chloro-1-naphthoic acid 0.13 g (0.83 mmol) of 1-hydroxybenzotriazole hydrate
Was stirred in 10 ml of acetonitrile while stirring in 1-ethyl-
0.16 g (0.83 mmol) of 3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1), and crystallized from ethyl acetate / diisopropyl ether / hexane to obtain the desired product. White crystals Yield 0.285 g Yield 62% mp 174-175 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
2.85 (1H, dd, J = 11.0Hz, 14.3 Hz), 2.98 (1H, dd,
J = 3.6 Hz, 14.7 Hz), 3.21 (2H, t, J = 18.0Hz), 4.
75-4.85 (1H, m), 4.90 (1H, d, J = 3.6 Hz), 5.05 (1
H, t, J = 3.5 Hz), 5.69 (1H, tt, J = 3.6 Hz, 53.7
Hz), 7.00 (1H, d, J = 9.0 Hz), 7.05-7.29 (8H, m),
7.45-7.56 (5H, m), 8.30 (1H, d, J = 8.4 Hz); IR (K
Br) 3275,1638, 1539, 1514, 1233, 1100, 837, 785, 7
08 cm ^-1 ; Anal.Calcd for C ₂₉ H _{2 3} ClF ₅ NO ₂ : C, 63.57;
H, 4.23; N, 2.56. Found: C, 63.59; H, 4.14; N, 2.6
8.

Example 341 N-[(1RS, 2SR) -1- [3- (1,2-difluoro-2-methylpropyl) benzyl] -2- (4-fluorophenyl) -2-hydroxyethyl] carbamine Acid ter
t-Butyl 1) Ethyl 2-methyl-2- (3-methylphenyl) propionate A solution of 30.92 g (173.5 mmol) of ethyl 3-tolylacetate in 150 ml of N, N-dimethylformamide under ice cooling with 60% hydrogen 15.3 g (382 mmol) of a liquid paraffin suspension of sodium chloride was added, and the mixture was stirred at room temperature for 0.5 hour. 32.2 ml of methyl iodide (520
(Mmol) at 0 ° C and stirred overnight at room temperature. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 50 / 1-15 /
1) The desired product was obtained. Colorless liquid Yield 30.22 g Yield 84% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.19 (3H, t, J = 7.1 H)
z), 1.56 (6H, s), 2.35 (3H, s), 4.12 (2H, q, J = 7.
2 Hz), 7.03-7.22 (4H, m); IR (neat) 2976, 1730, 12
52, 1146, 702 cm ^-1 2) 2-Methyl-2- (3-methylphenyl) propane-
1-ol To a suspension of 3.52 g (92.9 mmol) of lithium aluminum hydride in 150 ml of tetrahydrofuran was added 19.16 g (92.88 g) of ethyl 2-methyl-2- (3-methylphenyl) propionate under ice-cooling. (Mmol) was added dropwise and stirred at room temperature for 1 hour. After the reaction solution was cooled with ice, 3.5 ml of water, 3.5 ml of a 15% aqueous sodium hydroxide solution and 9 ml of water were sequentially added dropwise to decompose excess lithium aluminum hydride and stirred at room temperature for 2 hours. The resulting precipitate was removed by filtration, and the precipitate was washed with ethyl acetate. The solvent of the collected filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate =
6/1) to obtain the desired product. Colorless liquid Yield 12.99g
Yield 85% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.22 (1H, t, J = 6.6 H
z), 1.33 (6H, s), 2.36 (3H, s), 3.61 (2H, d, J = 6.
9 Hz), 7.04 (1H, d, J = 7.2 Hz), 7.17-7.27 (3H,
m); tetrahydrofuran 150ml solution of IR (neat) 3370, 2963, 1042, 783, 704 cm -1 3) 2- methyl-2- (3-methylphenyl) propanal oxalyl chloride 15.1 g (119 mmol) - At 78 ° C., a solution of 16.8 ml (237 mmol) of dimethyl sulfoxide in 50 ml of tetrahydrofuran was added dropwise. After stirring for 5 minutes,
A solution of 12.99 g (79.09 mmol) of 2-methyl-2- (3-methylphenyl) propan-1-ol in 80 ml of tetrahydrofuran was added at -78 ° C, and the mixture was stirred for 15 minutes. To this, 66.1 ml (475 mmol) of triethylamine was added, and the temperature was raised to room temperature. The reaction mixture was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 15/1) to obtain the desired product. Light yellow liquid Yield 11.72 g Yield 91% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.45 (6H, s), 2.36 (3H,
s), 7.07-7.7.12 (3H, m), 7.27 (1H, t, J = 8.0 Hz),
9.49 (1H, s); IR (neat) 2975, 1728, 785, 704 cm ^-14 ) 1- (1,2-difluoro-2-methylpropyl)-
3-methylbenzene (diethylamino) sulfur trifluoride 7.31
g (45.4 mmol) in 20 ml of methylene chloride at -78 ° C. was added with a solution of 7.360 g (45.37 mmol) of 2-methyl-2- (3-methylphenyl) propanal in 10 ml of methylene chloride at room temperature. Stirred at room temperature for 0.5 hour. Water was added to the reaction solution, and after stirring, the methylene chloride layer was separated. The aqueous layer was extracted with diethyl ether, the collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-hexane / ethyl acetate = 30/1) to obtain the desired product. Colorless liquid, yield 2.74
7 g Yield 33% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.33 (3H, dd, J = 1.5 H
z, 16.2 Hz), 1.40 (3H, dd, J = 2.0 Hz, 16.4 Hz), 2.
37 (3H, s), 5.29 (1H, dd, J = 13.8 Hz, 45.3Hz), 7.
14-7.18 (3H, m), 7.27 (1H, t, J = 7.8 Hz); IR (nea
t) 2988, 1387,1157, 1036, 775, 702 cm -1 5) 2- [3- (1,2- difluoro-2-methylpropyl) benzyl] -3- (4-fluorophenyl) -3-oxo Ethyl propionate 2.747 g (14.91 mmol) of 1- (1,2-difluoro-2-methylpropyl) -3-methylbenzene, N-
2.65 g (14.9 mmol) of bromosuccinimide, 0.2% of 2,2'-azobis (isobutyronitrile).
A solution of 1 g of carbon tetrachloride in 30 ml was refluxed under heating for 1.5 hours. After cooling the reaction solution to room temperature, a white precipitate was removed by filtration, and the precipitate was washed with hexane. The solvent of the collected filtrate was distilled off under reduced pressure to obtain a crude product of 3- (1,2-difluoro-2-methylpropyl) benzyl bromide as a yellow liquid. 3.13 g of ethyl (4-fluorobenzoyl) acetate
(14.9 mmol) of 1,2-dimethoxyethane 40
0.60 g (14.9 mmol) of a 60% sodium hydride liquid paraffin suspension was added to the ml solution under ice cooling, and the mixture was stirred for 0.5 hour as it was. To this, the liquid 1 obtained above
A solution of 10 ml of 2-dimethoxyethane was added at room temperature, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-9 / 1) to obtain the desired product. Yellow liquid Yield 3.484 g Yield 60% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.12 (3H, t, J = 7.1 H)
z), 1.23-1.39 (6H, m), 3.34 (1H, d, J = 7.5 Hz), 3.
35 (1H, d, J = 7.2 Hz), 4.10 (2H, q, J = 7.1Hz),
4.55 (0.5H, t, J = 7.7 Hz), 4.58 (0.5H, t, J = 7.5
Hz), 5.25 (0.5H, dd, J = 14.1 Hz, 45.0 Hz), 5.26
(0.5H, dd, J = 13.4 Hz, 45.2 Hz), 7.10 (2H, t, J =
8.4 Hz), 7.16-7.24 (4H, m), 7.97 (2H, dd, J = 5.4
Hz, 9.0 Hz); IR (neat) 2986, 1736, 1686, 1599, 150
8, 1269, 1236, 1159, 1032, 849cm -1 6) (2RS, 3RS) -2- [3- (1,2- difluoro-2-methylpropyl) benzyl] -3- (4-fluorophenyl) - Ethyl 3-hydroxypropionate While stirring 2.37 g (17.4 mmol) of zinc chloride in 50 ml of diethyl ether, 1.32 g (34.8 mmol) of sodium borohydride was added at room temperature, and the mixture was stirred for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. In the obtained solution, 2- [3- (1,
2-difluoro-2-methylpropyl) benzyl] -3-
A solution of 3.412 g (8.695 mmol) of ethyl (4-fluorophenyl) -3-oxopropionate in 20 ml of diethyl ether was added under ice-cooling, and the mixture was stirred for 20 minutes. Dilute hydrochloric acid was added little by little to the reaction solution to decompose excess zinc borohydride, and then extracted twice with ethyl acetate.
The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3).
/ 1) to obtain the desired product. Colorless liquid, yield 2.919 g
Yield 85% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.92 (3H, t, J = 7.1 H
z), 1.25-1.42 (6H, m), 2.89-2.93 (1H, m), 2.96-3.05
(3H, m), 3.86 (2H, q, J = 7.1 Hz), 5.00 (1H, t, J
= 3.7 Hz), 5.24 (1H, dd, J = 14.2 Hz, 45.2 Hz),
7.00-7.29 (6H, m), 7.37 (2H, dd, J = 5.2 Hz, 8.8 H
z); IR (neat) 3445, 2986, 1728, 1605, 1510, 1375,
1225, 1159, 1032, 839 cm ^- 17 17) (4RS, 5SR) -4- [3- (1,2-difluoro-2-methylpropyl) benzyl] -5- (4-fluorophenyl) -1,3 -Oxazolidin-2-one (2RS, 3RS) -2- [3- (1,2-difluoro-2-
Methylpropyl) benzyl] 2.849 g of ethyl 3- (4-fluorophenyl) -3-hydroxypropionate
(7.223 mmol), 0.58 g of sodium hydroxide
(14.4 mmol), methanol 10 ml, water 10 m
1 and a mixture of 10 ml of tetrahydrofuran were stirred at room temperature overnight. The reaction mixture was concentrated, diluted with water, acidified with hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
(2RS, 3RS) -2- [3- (1,2-difluoro-2-
A crude product of [methylpropyl) benzyl] -3- (4-fluorophenyl) -3-hydroxypropionic acid was obtained as a liquid. To a solution of the liquid obtained above in 40 ml of tetrahydrofuran, 1.21 ml (8.67 mmol) of triethylamine and 2.19 g of diphenylphosphoryl azide (7.9 g)
5 mmol) and stirred at 65 ° C. overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1) to obtain the desired product. White solid Yield 2.245 g Yield 86% mp 130-131 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.28-1.41
(6H, m), 2.20-2.36 (2H, m), 4.21-4.30 (1H, m), 4.
97 (1H, s), 5.24 (0.5H, dd, J = 13.7 Hz, 44.9 Hz),
5.25 (0.5H, dd, J = 14.0 Hz, 45.2 Hz), 5.80 (1H,
d, J = 8.1 Hz), 7.01-7.39 (8H, m); IR (KBr) 3250, 1
742, 1514, 1236, 1223, 1022, 849 cm ^-1 ; Anal.Calcd
for C ₂₀ H ₂₀ F ₃ NO ₂・ 0.1H ₂ O: C, 65.78; H, 5.58; N, 3.8
4. Found: C, 65.64; H, 5.50; N, 3.96.8) (4RS, 5SR) -4- [3- (1,2-difluoro-2-methylpropyl) benzyl] -5- (4-fluoro Tert-Butyl (phenyl) -2-oxo-1,3-oxazolidine-3-carboxylate (4RS, 5SR) -4- [3- (1,2-difluoro-2-
Methylpropyl) benzyl] -5- (4-fluorophenyl) -1,3-oxazolidine-2-one 2.124 g
(5.845 mmol), 1.53 g (7.01 mmol) of di-tert-butyl dicarbonate and a solution of 71 mg (0.58 mmol) of 4-N, N-dimethylaminopyridine in 40 ml of acetonitrile were stirred at room temperature overnight. did. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-2 / 1) to obtain the desired product. Light yellow liquid Yield 2.633 g Yield 97% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.24-1.38 (6H, m), 1.49
(4.5H, s), 1.53 (4.5H, s), 2.55-2.64 (1H, m), 2.8
5-2.96 (1H, m), 4.79-4.86 (1H, m), 5.10 (0.5H, dd,
J = 13.2 Hz, 45.0 Hz), 5.17 (0.5H, dd, J = 14.6 H
z, 45.2 Hz), 5.66 (0.5H, d, J = 7.2 Hz), 5.67 (0.5
H, d, J = 6.6 Hz), 6.59-6.65 (1H, m), 6.67 (0.5H,
s), 6.82 (0.5H, s), 6.91-6.98 (2H, m), 7.04-7.17
(4H, m); IR (neat) 2984, 1817, 1723, 1514, 1358, 13
08, 1229, 1155, 1069 cm -1 9) N - [(1RS, 2SR) -1- [3- (1,2- difluoro-2-methylpropyl) benzyl] -2- (4-fluorophenyl) - Tert-Butyl 2-hydroxyethyl] carbamate (4RS, 5SR) -4- [3- (1,2-difluoro-2-
Methylpropyl) benzyl] 2.584 g (5.575 mmol) of tert-butyl-5- (4-fluorophenyl) -2-oxo-1,3-oxazolidine-3-carboxylate
To a solution of the above in 20 ml of tetrahydrofuran was added a solution of 0.22 g (5.57 mmol) of sodium hydroxide in 5 ml of methanol under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure to obtain the desired product. White solid Yield 2.300 g Yield 94% mp 148-149 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.28-1.41
(6H, m), 1.34 (9H, s), 2.65 (1H, dd, J = 10.1 Hz,
14.3 Hz), 2.80 (1H, dd, J = 4.7 Hz, 14.3 Hz), 3.3
8 (1H, br s), 4.09 (1H, br s), 4.50 (1H, br d, J =
6.9 Hz), 4.90 (1H, br s), 5.27 (1H, dd, J = 13.7
Hz, 45.2 Hz), 7.07 (2H, t, J = 8.7 Hz), 7.11-7.13
(2H, m), 7.18-7.31 (2H, m), 7.37 (2H, dd, J = 5.6
Hz, 8.6 Hz); IR (KBr) 3366, 2988, 1682, 1532, 151
4, 1225, 1171, 1007 cm ^-1 ; Anal.Calcd for C ₂₄ H ₃₀ F ₃
NO ₃ : C, 65.89; H, 6.91; N, 3.20. Found: C, 65.62;
H, 6.88; N, 3.22.

Example 342 N-[(1RS, 2SR) -1- [3- (1,2-difluoro-2-methylpropyl) benzyl] -2- (4-fluorophenyl) -2-hydroxyethyl]- 6,7-dihydro-
5H-benzo [a] cycloheptene-1-carboxamide 1) (1RS, 2SR) -2-amino-3- [3- (1,
2-difluoro-2-methylpropyl) phenyl] -1-
(4-Fluorophenyl) propan-1-ol N-[(1RS, 2SR) -1- [3- (1,2-difluoro-2-methylpropyl) benzyl] -2- (4-fluorophenyl) -2 -Hydroxyethyl] carbamic acid ter
A mixture of 2.139 g (4.889 mmol) of t-butyl and 10 ml of trifluoroacetic acid was stirred at room temperature for 1 hour. After evaporating the reaction solution under reduced pressure, the solution was diluted with water, made alkaline with potassium carbonate, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and passed through APS-silica gel, and then the solvent was distilled off under reduced pressure to obtain the desired product.
Light yellow liquid Yield 1.650 g Yield 100% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.31 (3H, d, J = 15.3 H)
z), 1.38 (3H, d, J = 14.7 Hz), 2.36 (1H, dd, J = 1
0.2 Hz, 13.5 Hz), 2.81 (1H, dd, J = 3.2 Hz, 13.4 H
z), 3.25-3.32 (1H, m), 4.66 (1H, d, J = 4.8 Hz),
5.28 (1H, dd, J = 13.8 Hz, 45.3 Hz), 7.08 (2H, t, J
= 8.7 Hz), 7.11-7.33 (4H, m), 7.37 (2H, dd, J =
5.6 Hz, 8.6 Hz); IR (neat) 3360-2860, 1605, 1508,
1387, 1373,1223, 1157, 1034, 839 cm- ¹ 2) N-[(1RS, 2SR) -1- [3- (1,2-difluoro-2-methylpropyl) benzyl] -2- (4- Fluorophenyl) -2-hydroxyethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-3- [3- (1,2-difluoro-2 -Methylpropyl) phenyl] -1- (4-fluorophenyl) propan-1-ol 0.200 g (0.
593 mmol), 0.11 g of 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (0.15 g).
59 mg) of 1-hydroxybenzotriazole hydrate (91 mg, 0.59 mmol) was added to acetonitrile 1
0.11 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride while stirring in 0 ml
(0.59 mmol) and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1).
/ 1) and crystallized from diisopropyl ether-hexane to obtain the desired product. White powder Yield 0.184 g Yield 61% mp 102-104 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.25-1.39
(6H, m), 1.95-2.03 (2H, m), 2.16-2.22 (2H, m), 2.
66 (2H, t, J = 5.7 Hz), 2.69-2.82 (1H, m), 2.98-3.
03 (1H, m), 3.79 (0.5H, d, J = 3.9 Hz), 3.82 (0.5
H, d, J = 3.9 Hz), 4.65-4.74 (1H, m), 5.02 (1H, t,
J = 3.6 Hz), 5.24 (0.5H, dd, J = 14.0Hz, 45.2 H
z), 5.27 (0.5H, dd, J = 13.5 Hz, 45.0 Hz), 5.70 (1
H, d, J = 8.7 Hz), 5.88-5.96 (1H, m), 6.20 (1H, d,
J = 12.3 Hz), 6.91-6.95 (1H, m), 7.02-7.34 (8H,
m), 7.43 (2H, dd, J = 5.3 Hz, 8.6 Hz); IR (KBr) 32
95, 2938, 1638, 1510, 1225, 1034, 772 cm ^-1 ; Anal.
Calcd for C ₃₁ H ₃₂ F ₃ NO ₂・ 0.1H ₂ O: C, 73.09; H, 6.37; N,
2.75. Found: C, 72.87; H, 6.31; N, 2.62.

Example 343 4-Fluoro-N-[(1RS, 2SR) -1- [3- (1,
2-difluoro-2-methylpropyl) benzyl] -2-
(4-Fluorophenyl) -2-hydroxyethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-3- [3- (1,2-difluoro-2-methylpropyl) phenyl] -1- ( 0.200 g of 4-fluorophenyl) propan-1-ol (0.
593 mmol) 4-fluoro-1-naphthoic acid 0.1
1 g (0.59 mmol), 91 mg (0.59 mmol) of 1-hydroxybenzotriazole hydrate were stirred in 10 ml of acetonitrile while stirring 1-ethyl-3- (3- (3-methyl-3-hydroxybenzotriazole).
Dimethylaminopropyl) carbodiimide hydrochloride
11 g (0.59 mmol) was added and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 /
1-1-1) and crystallization from diisopropyl ether-hexane to obtain the desired product. 0.218 g of white powder
Yield 72% mp 163-165 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.24-1.38
(6H, m), 2.74-2.87 (1H, m), 3.07 (1H, dd, J = 4.1
Hz, 14.3 Hz), 3.62-3.64 (1H, m), 4.74-4.83 (1H,
m), 5.07 (0.5H, t, J = 4.1 Hz), 5.08 (0.5H, t, J =
3.9 Hz), 5.22 (0.5H, dd, J = 14.9 Hz, 45.2 Hz),
5.27 (0.5H, dd, J = 13.4 Hz, 44.9 Hz), 5.86 (0.5H,
d, J = 8.1 Hz), 5.88 (0.5H, d, J = 8.1 Hz), 6.96-
7.37 (8H, m), 7.43-7.57 (4H, m), 7.77-7.84 (1H,
m), 8.08 (1H, d, J = 8.1 Hz); IR (KBr) 3291, 1642,
1626, 1512, 1231, 837, 768 cm ^-1 ; Anal.Calcd for
C ₃₀ H ₂₇ F ₄ NO ₂・ 0.2H ₂ O: C, 70.22; H, 5.38; N, 2.73. Fo
und: C, 69.96; H, 5.24; N, 2.70.

Example 344 N-[(1RS, 2SR) -2- (3-chlorophenyl)-
2-hydroxy-1- (4-neopentylbenzyl) ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 1) 4-neopentylbenzoic acid 4.43 g (33.2 mmol) of aluminum chloride )), A solution of 6.04 g (33.2 mmol) of trichloroacetyl chloride in 10 ml of methylene chloride was added dropwise at -78 ° C while stirring. Reaction solution 1
After stirring for 5 minutes, the temperature was raised to −50 ° C., a solution of 4.922 g (33.20 mmol) of neopentylbenzene in 10 ml of methylene chloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water, the methylene chloride layer of the mixture was separated, and the aqueous layer was extracted with diethyl ether. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 30 ml of tetrahydrofuran, a solution of 3.73 g (66.4 mmol) of potassium hydroxide in 40 ml of water was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was diluted with diethyl ether and water, and the aqueous layer was separated. The resulting aqueous solution was acidified with concentrated hydrochloric acid and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product. Brown crystals Yield 5.34
Recrystallization from 3 g of 84% diisopropyl ether-hexane gave 3 g of white crystals. mp 193-194 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 0.92 (9H,
s), 2.58 (2H, s), 2.24 (2H, d, J = 8.1 Hz), 8.02
(2H, d, J = 8.4 Hz), 8.02 (1H, br s); IR (KBr) 310
0-2550, 1682, 1426, 1319, 1296, 951, 731 cm ^-1 ; Ana
l. Calcd for C ₁₂ H ₁₆ O ₂ : C, 74.97; H, 8.39. Found:
H, 8.47.2) 4-Neopentylbenzyl alcohol To a suspension of 1.13 g (29.9 mmol) of lithium aluminum hydride in 50 ml of tetrahydrofuran was added 3.830 g of 4-neopentylbenzoic acid under ice-cooling. 19.9
(2 mmol) in 30 ml of tetrahydrofuran was added dropwise and stirred at room temperature overnight. After cooling the reaction mixture with ice, 1 m of water
1, 15% aqueous sodium hydroxide solution 1 ml, water 2.5 m
1 was sequentially added dropwise to decompose excess lithium aluminum hydride and stirred at room temperature for 2 hours. The resulting precipitate was removed by filtration, and the precipitate was washed with ethyl acetate. The solvent of the collected filtrate was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / hexane).
Ethyl acetate = 6 / 1-3 / 1) to obtain the desired product. Yellow liquid Yield 2.446 g Yield 69% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 0.90 (9H, s), 1.62 (1H,
t, J = 5.9 Hz), 2.49 (2H, s), 4.67 (2H, d, J = 5.7
Hz), 7.12 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J =
7.8 Hz); IR (neat) 3330, 2951, 1364, 1017 cm ^-1 3) ethyl 3- (3-chlorophenyl) -2- (4-neopentylbenzyl) -3-oxopropionate 4-neopentylbenzyl alcohol 2.446 g (1
3.72 mmol), 2.87 ml of triethylamine
(20.6 mmol) in 50 ml of ethyl acetate was added dropwise with a solution of 1.89 g (16.5 mmol) of methanesulfonyl chloride in 10 ml of ethyl acetate under ice-cooling.
Stirred for minutes. The resulting precipitate was removed by filtration, and the precipitate was washed with diethyl ether. The solvent of the collected filtrate was distilled off under reduced pressure to obtain a crude product of methanesulfonic acid ester as a yellow liquid. 2. ethyl (3-chlorobenzoyl) acetate
To a solution of 11 g (13.7 mmol) in 1,2-dimethoxyethane (20 ml) was added 0.55 g (13.7 mmol) of a 60% sodium hydride liquid paraffin suspension under ice cooling, and the mixture was stirred for 0.5 hour. . The methanesulfonic acid ester of 1,2-dimethoxyethane 20 obtained above was added to this.
ml solution was added at room temperature and stirred at room temperature for 3 days. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15/1) to obtain the desired product. Light yellow liquid Yield 4.648 g Yield 88% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 0.85 (9H, s), 1.13 (3H,
t, J = 7.1 Hz), 2.42 (2H, s), 3.28-3.31 (2H, m),
4.07-4.15 (2H, m), 4.55 (1H, t, J = 7.4 Hz), 7.00
(2H, d, J = 7.8 Hz), 7.09 (2H, d, J = 8.1 Hz), 7.3
6 (1H, t, J = 7.7 Hz), 7.51 (1H, ddd, J = 1.1 Hz,
1.9 Hz, 8.0 Hz), 7.78 (1H, ddd, J = 1.1 Hz, 1.7 H
z, 7.7 Hz), 7.89 (1H, t, J = 1.8 Hz); IR (neat) 29
53, 1738, 1694, 1229 cm -1 4) (2RS, 3RS) -3- (3- chlorophenyl) -
Ethyl 3-hydroxy-2- (4-neopentylbenzyl) propionate While stirring 3.22 g (23.6 mmol) of zinc chloride in 30 ml of diethyl ether, 1.78 g (47.2 mmol) of sodium borohydride was added. The mixture was added at room temperature and stirred for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. To the obtained solution, a solution of 4.564 g (11.80 mmol) of ethyl 3- (3-chlorophenyl) -2- (4-neopentylbenzyl) -3-oxopropionate in 30 ml of diethyl ether was added under ice-cooling. ,
The mixture was stirred for 20 minutes as it was. Dilute hydrochloric acid was added little by little to the reaction solution to decompose excess zinc borohydride, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-6 / 1) to obtain the desired product.
Colorless liquid Yield 3.828 g Yield 83% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.86 (9H, s), 0.95 (3H,
t, J = 7.2 Hz), 2.42 (2H, s), 2.84-3.00 (3H, m),
3.13 (1H, d, J = 2.6 Hz), 3.91 (2H, q, J = 7.1 H
z), 5.03 (1H, t, J = 3.1 Hz), 6.98 (4H, s), 7.26
(3H, s), 7.42 (1H, s); IR (neat) 3468, 2951, 1726,
1709, 1476, 1375, 1364, 1236, 1184, 1032cm -1 5) (4RS, 5SR) -5- (3- chlorophenyl) -
Ethyl 4- (4-neopentylbenzyl) -1,3-oxazolidin-2-one (2RS, 3RS) -3- (3-chlorophenyl) -3-hydroxy-2- (4-neopentylbenzyl) propionate 3 0.756 g (9.657 mmol), sodium hydroxide 0.77 g (19.3 mmol), methanol 20 ml, water 10 ml, tetrahydrofuran 20 ml
Was stirred overnight at room temperature. The reaction mixture was concentrated, diluted with water, acidified with hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer is dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure to obtain a crude product of (2RS, 3RS) -3- (3-chlorophenyl) -3-hydroxy-2- (4-neopentylbenzyl) propionic acid as a white solid. 1.62 ml (11.6 mmol) of triethylamine was added to a solution of the solid obtained above in 30 ml of tetrahydrofuran,
2.92 g (10.6 mmol) of diphenylphosphoryl azide was added and stirred at 65 ° C. overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3).
/ 1-1-1), ethyl acetate-diisopropyl ether-
Crystallization from hexane gave the desired product. White crystals Yield 2.517 g Yield 73% mp 197-198 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.87 (9H,
s), 2.18 (1H, dd, J = 11.0 Hz, 13.6 Hz), 2.30 (1H,
dd, J = 4.0 Hz, 13.8 Hz), 2.44 (2H, s), 4.18-4.30
(1H, m), 4.99 (1H, br s), 5.76 (1H, d, J = 8.2 H
z), 6.92 (2H, d, J = 8.0 Hz), 7.04 (2H, d, J = 8.0
Hz), 7.24-7.38 (4H, m); IR (KBr) 3268, 2959, 1740,
1240, 1017, 791 cm ^-1 ; Anal.Calcd for C ₂₁ H ₂₄ ClN
O ₂ : C, 70.48; H, 6.76; N, 3.91. Found: C, 70.56;
H, 7.00; N, 3.62.6) (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- (4-neopentylphenyl) propane-
1-ol (4RS, 5SR) -5- (3-chlorophenyl) -4-
(4-neopentylbenzyl) -1,3-oxazolidine-
2.335 g (6.525 mmol) of 2-one and 1.04 g (26.1 mmol) of sodium hydroxide were heated to reflux in 30 ml of ethanol-1 ml of water for 5 hours. The reaction solution was diluted with water and stirred as it was for 0.5 hour. The resulting precipitate was collected and washed with water and diisopropyl ether-hexane to obtain the desired product. White powder Yield 1.814 g
Yield 84% mp 118-120 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 0.88 (9H,
s), 2.31 (1H, dd, J = 10.5 Hz, 13.8 Hz), 2.45 (2H,
s), 2.72 (1H, dd, J = 3.3 Hz, 13.8 Hz), 3.29 (1H,
ddd, J = 3.3 Hz, 4.8 Hz, 10.5 Hz), 4.67 (1H, d, J
= 4.5 Hz), 7.00-7.06 (5H, m), 7.24-7.32 (2H, m),
7.42 (1H, s); IR (KBr) 3130-2770, 2953, 1576, 147
6, 1420, 1364, 1192, 1040, 949, 855, 779, 729 c
m ^-1 ; Anal.Calcd for C ₂₀ H ₂₆ ClNO: C, 72.38; H, 7.9
0, N, 4.22. Found: C, 72.24; H, 7.97; N, 4.02.7) N-[(1RS, 2SR) -2- (3-chlorophenyl) -2-hydroxy-1- (4-neopentyl) Benzyl)
Ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- (4-neopentylphenyl) propane-1 0.300 g (0.904 mmol), 0.17 g (0.90 mmol) of 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid, 1-hydroxybenzotriazole hydrate. 14 g (0.90 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.17 was stirred in 10 ml of acetonitrile-2 ml of N, N-dimethylformamide while stirring.
g (0.90 mmol) was added and stirred at room temperature overnight.
The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White powder Yield 0.377 g Yield 83% mp 147-149 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 0.88 (9H,
s), 1.95-2.04 (2H, m), 2.17-2.23 (2H, m), 2.46 (2
H, s), 2.62-2.71 (3H, m), 2.97 (1H, dd, J = 4.2 Hz,
14.4 Hz), 4.38 (1H, d, J = 4.2 Hz), 4.63-4.72 (1
H, m), 5.04 (1H, t, J = 3.8 Hz), 5.69 (1H, d, J =
7.5 Hz), 5.99 (1H, td, J = 5.4 Hz, 12.0 Hz), 6.33
(1H, d, J = 11.7 Hz), 6.88 (1H, dd, J = 1.2 Hz, 7.
5 Hz), 7.01 (1H, t, J = 7.5 Hz), 7.05 (4H, s), 7.1
4 (1H, d, J = 6.3 Hz), 7.27-7.35 (3H, m), 7.48 (1H,
s); IR (KBr) 3376, 3331, 2959, 1626, 1528, 779, 7
66cm ^-1 ; Anal.Calcd for C ₃₂ H ₃₆ ClNO ₂ : C, 76.55; H,
7.23; N, 2.79. Found: C, 76.38; H, 7.19; N, 2.52.

Example 345 4-Fluoro-N-[(1RS, 2SR) -2- (3-chlorophenyl) -2-hydroxy-1- (4-neopentylbenzyl) ethyl] naphthalene-1-carboxamide (1RS, 0.300 g (0.904 mmol) of 2SR) -2-amino-1- (3-chlorophenyl) -3- (4-neopentylphenyl) propan-1-ol 0.17 g of 4-fluoro-1-naphthoic acid (0.90 mmol), 1
-Hydroxybenzotriazole hydrate 0.14g
(0.90 mmol) in acetonitrile 10 ml-N,
While stirring in 2 ml of N-dimethylformamide, 0.17 g (0.90 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was purified with ethyl acetate-diisopropyl ether-
Crystallization from hexane gave the desired product. White powder Yield 0.300 g Yield 66% mp 150-151 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 0.89 (9H,
s), 2.48 (2H, s), 2.73 (1H, dd, J = 11.3 Hz, 14.6
Hz), 3.04 (1H, dd, J = 4.2 Hz, 14.4 Hz), 4.19 (1
H, d, J = 4.5 Hz), 4.72-4.81 (1H, m), 5.11 (1H, t,
J = 3.9 Hz), 5.86 (1H, d, J = 8.1 Hz), 6.94 (1H,
dd, J = 8.1 Hz, 9.9 Hz), 7.04-7.12 (5H, m), 7.27-7.
40 (3H, m), 7.46-7.58 (3H, m), 7.94 (1H, d, J = 8.
1 Hz), 8.08 (1H, d, J = 7.5 Hz); IR (KBr) 3275, 29
55, 1642, 1626, 1541, 1426, 1264, 1236, 1051, 760
cm ^-1 ; Anal.Calcd for C ₃₁ H ₃₁ ClFNO ₂ : C, 73.87; H,
6.20; N, 2.78.Found: C, 73.69; H, 6.02; N, 2.59.

Example 346 5-Chloro-N-[(1RS, 2SR) -2- (3-chlorofurf
Enyl) -2-hydroxy-1- (4-neopentylbenzy
Ru) ethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (3-chlorophenyl)
) -3- (4-neopentylphenyl) propane-1-o
0.300 g (0.904 mmol), 5-chloro-
0.19 g (0.90 mmol) of 1-naphthoic acid
0.14 g of droxybenzotriazole hydrate (0.9
0 mmol) in 10 ml of acetonitrile-N, N-dimethyl
1-ethyl-3- while stirring in 2 ml of formamide
(3-dimethylaminopropyl) carbodiimide / hydrochloric acid
Add 0.17 g (0.90 mmol) of salt and allow to stand at room temperature overnight
Stirred. Dilute the reaction mixture with ethyl acetate and add sodium hydrogen carbonate
Wash with aqueous solution of lithium, dry over anhydrous magnesium sulfate,
After passing through Licagel, the solvent was distilled off under reduced pressure. Obtained residue
The distillate was extracted with ethyl acetate-diisopropyl ether-hexane
Further crystallization gave the desired product. White crystals Yield 0.3
67g yield 78% mp 168-169 ° C;¹H-NMR (CDCl_Three-DMSO-d₆, 200 MHz) δ
0.88 (9H, s), 2.46 (2H, s), 2.81 (1H, dd, J = 10.6
Hz, 14.6 Hz), 2.94 (1H, dd, J = 4.6 Hz, 14.4Hz),
4.72-4.86 (1H, m), 5.04-5.11 (2H, m), 6.97-7.14 (5
H, m), 7.23-7.37 (4H, m), 7.42-7.58 (4H, m), 7.67
(1H, d, J = 8.4 Hz), 8.29 (1H, d, J = 8.6 Hz); IR
(KBr) 3272, 2957, 1636, 1537, 785 cm^-1; Anal. Calc
d for C₃₁H ₃₁Cl_TwoNO_Two: C, 71.54; H, 6.00; N, 2.69. Fo
und: C, 71.63; H, 6.09; N, 2.58.

Example 347 N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxyethyl-1- [3- (2,2,3,3-tetrafluoropropionyl) benzyl]] carbamic acid
ert-butyl 1) 3- (4-fluorophenyl) -2- [3- (2,
2,3,3-tetrafluoropropionyl) benzyl]-
Ethyl 3-oxopropionate 7.484 g (33.99 mmol) of 2,2,3,3-tetrafluoro-1- (3-methylphenyl) propan-1-one, 6.05 g of N-bromosuccinimide (34. 0
Mmol) and 0.2 g of 2,2'-azobis (isobutyronitrile) in 40 ml of carbon tetrachloride were heated under reflux for 1.5 hours. After cooling the reaction solution to room temperature, a white precipitate was removed by filtration, and the precipitate was washed with hexane. The solvent of the collected filtrate was distilled off under reduced pressure to obtain a pale yellow liquid. 1.34 g (34.0 mmol) of ethyl (4-fluorobenzoyl) acetate in 50 ml of 1,2-dimethoxyethane in a liquid paraffin suspension of 60% sodium hydride under ice-cooling 1.3
6 g (34.0 mmol) was added, and the mixture was stirred for 0.5 hour. A solution of the liquid obtained above in 30 ml of 1,2-dimethoxyethane was added thereto at room temperature, and the mixture was stirred at room temperature overnight.
The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-
9/1), the desired product was obtained. 6.608 g of yellow liquid
Yield 45% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.12 (3H, t, J = 7.2 H
z), 3.41 (2H, d, J = 7.5 Hz), 3.40-4.15 (2H, m),
4.59 (1H, t, J = 7.4 Hz), 6.28 (1H, tt, J = 5.6 H
z, 52.5 Hz), 7.13 (2H, t, J = 8.7 Hz), 7.44 (1H,
t, J = 8.0 Hz), 7.59 (1H, d, J = 7.5 Hz), 7.93-7.96
(2H, m), 8.01 (2H, dd, J = 5.6 Hz, 8.9 Hz); IR (n
eat) 1736, 1686, 1599, 1508, 1302, 1273, 1238, 115
9, 1115, 849 cm ^-1 2) (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- [3- (2,2,3,3-tetrafluoro-1-hydroxypropyl) Ethyl benzyl] propionate While stirring 4.16 g (30.5 mmol) of zinc chloride in 50 ml of diethyl ether, 2.31 g (61.1 mmol) of sodium borohydride was added at room temperature, and the mixture was stirred as it was for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. To the resulting solution, 6.540 g (15.27 mmol) of ethyl 3- (4-fluorophenyl) -2- [3- (2,2,3,3-tetrafluoropropionyl) benzyl] -3-oxopropionate ) Was added under ice-cooling, and the mixture was stirred for 20 minutes. Dilute hydrochloric acid was added little by little to the reaction solution to decompose excess zinc borohydride, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1) to obtain the desired product. Light yellow liquid Yield 5.958 g Yield 90% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 0.90 (3H, t, J = 7.1 H)
z), 2.78 (1H, s), 2.93-3.03 (4H, m), 3.78-3.89 (2
H, m), 4.93-5.03 (2H, m), 5.96 (1H, ddt, J = 2.4 H
z, 8.5 Hz, 53.2 Hz), 7.03 (2H, t, J = 8.7 Hz), 7.1
1-7.15 (1H, m), 7.19 (1H, d, J = 7.2 Hz), 7.24-7.2
8 (2H, m), 7.34 (2H, dd, J = 5.4 Hz, 9.0Hz); IR (n
eat) 3418, 1715, 1607, 1512, 1377, 1229, 1186, 115
9, 1100, 1057, 839 cm ^-1 3) (4RS, 5SR) -5- (4-fluorophenyl) -4- [3- (2,2,3,3-tetrafluoro-1-hydroxypropyl) benzyl ] -1,3-oxazolidine
-2-one (2RS, 3RS) -3- (4-fluorophenyl) -3-
Hydroxy-2- [3- (2,2,3,3-tetrafluoro
5.878 g (13.59 mmol) of ethyl 1-hydroxypropyl) benzyl] propionate, 1.09 g (27.2 mmol) of sodium hydroxide, methanol 20
A mixture of 30 ml of water, 30 ml of water and 20 ml of tetrahydrofuran was stirred at room temperature overnight. Concentrate the reaction, dilute with water,
After acidifying the reaction solution with hydrochloric acid, it was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and (2RS, 3RS) -3- (4-fluorophenyl) -3-hydroxy-2- [3- (2,2,3, 3-
A crude product of tetrafluoro-1-hydroxypropyl) benzyl] propionic acid was obtained as a liquid. To a solution of the liquid obtained above in 50 ml of tetrahydrofuran, 2.27 ml (16.3 mmol) of triethylamine and 4.12 g (15.0 mmol) of diphenylphosphoryl azide were added.
Stirred at 5 ° C. overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 2).
The desired product was obtained. Light yellow liquid Yield 5.001 g Yield 9
2% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.14-2.38 (2H, m), 4.17
-4.25 (1H, m), 4.34-4.42 (0.5H, m), 4.87-4.89 (0.5
H, m), 4.96 (0.5H, br s), 5.02 (0.5H, br s), 5.73
(0.5H, d, J = 8.7 Hz), 5.78 (0.5H, d, J = 8.7 Hz),
6.08 (1H, dt, J = 9.7 Hz, 53.4 Hz), 6.85 (0.5H,
s), 6.99-7.36 (7.5H, m); IR (neat) 3304, 1744, 151
4, 1236, 1101, 1067, 735 cm -1 4) (4RS, 5SR) -5- (4- fluorophenyl) -4- [3- (2,2,3,3-tetrafluoro-propionyl) benzyl] - 1,3-oxazolidine-2-one (4RS, 5SR) -5- (4-fluorophenyl) -4-
5.779 g (14.40 mmol) of [3- (2,2,3,3-tetrafluoro-1-hydroxypropyl) benzyl] -1,3-oxazolidin-2-one and 16.1 ml (115 mmol) of triethylamine Was stirred in 20 ml of dimethyl sulfoxide, a solution of 9.17 g (57.6 mmol) of sulfur trioxide pyridine complex in 30 ml of dimethyl sulfoxide was added at room temperature, and the mixture was stirred overnight as it was. The reaction mixture was poured into water, acidified with concentrated hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2 / 1-1 / 1) to obtain the desired product. Yellow solid Yield 3.772 g Yield 66% Recrystallization from diisopropyl ether gave a white powder. mp 149-150 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.41 (2H,
d, J = 7.5 Hz), 4.31 (1H, q, J = 7.4 Hz), 5.69 (1
H, s), 5.79 (1H, d, J = 8.1 Hz), 6.27 (1H, tt,
J = 5.4 Hz, 52.6 Hz), 7.1
6. 1 (2H, t, J = 8.6 Hz);
31-7.36 (3H, m), 7.46 (1
H, t, J = 7.7 Hz), 7.68
(1H, s), 7.96 (1H, d, J =
8.1 Hz); IR (KBr) 3250, 1
740, 1690, 1516, 1240, 11
15, 1096 cm ^-1 ; Anal. Calc
_{d for C 19 H 14 F 5} NO 3: C, 57.
15; H, 3.53; N, 3.51. Fou
nd: C, 57.12; H, 3.57; N,
3.41. 5) (4RS, 5SR) -5- (4-fluorophenyl) -2-oxo-4- [3- (2,2,3,3-tetrafluoropropionyl) benzyl] -1,3-oxazolidine
Tert-Butyl-3-carboxylate (4RS, 5SR) -5- (4-fluorophenyl) -4-
[3- (2,2,3,3-tetrafluoropropionyl)
Benzyl] -1,3-oxazolidin-2-one 2.199
g (5.507 mmol), 1.44 g (6.61 mmol) of di-tert-butyl dicarbonate, a solution of 67 mg (0.55 mmol) of 4-N, N-dimethylaminopyridine in 30 ml of acetonitrile at room temperature overnight. Stirred. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) and crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 2.178 g
Yield 79% mp 116-118 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.52 (9H,
s), 2.69 (1H, dd, J = 9.0 Hz, 14.4 Hz), 2.99 (1H,
dd, J = 4.1 Hz, 14.3 Hz), 4.83 (1H, ddd, J = 4.4 H
z, 7.1 Hz, 9.2 Hz), 5.68 (1H, d, J = 7.2 Hz), 6.27
(1H, tt, J = 5.6 Hz, 52.5 Hz), 6.94 (2H, t, J =
8.7 Hz), 7.04 (1H, d, J = 7.8 Hz), 7.13 (2H, dd, J
= 5.1 Hz, 8.4 Hz), 7.28 (1H, t, J = 8.0 Hz), 7.33
(1H, s), 7.84 (1H, d, J = 8.1 Hz); IR (KBr) 1806,
1701, 1516, 1372, 1159, 1113, 1076 cm ^-1 ; Anal. Cal
cd for C ₂₄ H ₂₂ F ₅ NO ₅ : C, 57.72; H, 4.44; N, 2.80. Fo
und: C, 57.66; H, 4.41; N, 2.6.6. 6) N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxyethyl-1- [3- (2,2,3 ,
3-tetrafluoropropionyl) benzyl]] tert-butyl carbamate (4RS, 5SR) -5- (4-fluorophenyl) -2-
To a solution of 2.030 g (4.065 mmol) of tert-butyl oxo-4- [3- (2,2,3,3-tetrafluoropropionyl) benzyl] -1,3-oxazolidine-3-carboxylate in 20 ml of tetrahydrofuran 0.16 g (4.06 mmol) of sodium hydroxide in methanol 1
A 0 ml solution was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White powder Yield 1.692 g 88% mp 157-158 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.31 (9H,
s), 2.76 (1H, dd, J = 9.9 Hz, 14.4 Hz), 2.86 (1H,
dd, J = 4.2 Hz, 14.1 Hz), 3.07 (1H, s), 4.04-4.13
(1H, m), 4.65 (1H, br d, J = 9.3 Hz), 4.94 (1H,
s), 6.29 (1H ,, tt, J = 5.6 Hz, 52.5 Hz), 7.08 (2H,
t, J = 8.7 Hz), 7.34-7.48 (4H, m), 7.81 (1H, s),
7.93 (1H, d, J = 6.9 Hz); IR (KBr) 3353, 1682, 153
4, 1514, 1242, 1225, 1171, 1113, 1005 cm ^-1 ; Anal.
Calcd for C ₂₃ H ₂₄ F ₅ NO ₄ : C, 58.35; H, 5.11; N, 2.96.
Found: C, 58.12; H, 4.94; N, 2.79.

Example 348 4-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (2,2,3,
3-tetrafluoropropionyl) benzyl] ethyl]
Naphthalene-1-carboxamide N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxyethyl-1- [3- (2,2,3,3-tetrafluoropropionyl) benzyl]] carbamic acid
A solution of 0.423 g (0.893 mmol) of tert-butyl in 5 ml of trifluoroacetic acid was stirred at room temperature for 15 minutes. After evaporating the reaction solution under reduced pressure, the solution was diluted with water, made alkaline with potassium carbonate, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale yellow liquid. The liquid obtained above, 4-fluoro-1
-Naphthoic acid 0.17 g (0.89 mmol), 1-hydroxybenzotriazole hydrate 0.14 g (0.89
(Mmol) was added to 15 ml of acetonitrile, and 0.17 g (0.89 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added thereto, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2 / 1-1 / 1), and crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.364 g Yield 75% mp 160-162 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
2.94 (1H, dd, J = 10.5Hz, 14.4 Hz), 3.01 (1H, dd,
J = 5.1 Hz, 14.1 Hz), 4.66 (1H, d, J = 3.6 Hz), 4.
74-4.83 (1H, m), 5.07 (1H, t, J = 3.6 Hz), 6.26 (1
H, tt, J = 5.6 Hz, 52.5 Hz), 6.97-7.11 (4H, m), 7.
24 (1H, dd, J = 5.3 Hz, 8.0 Hz), 7.38-7.61 (6H,
m), 7.68 (1H, d, J = 8.7 Hz), 7.90 (1H, s), 7.96
(1H, d, J = 8.1 Hz), 8.06 (1H, d, J = 8.1 Hz); IR
(KBr) 3277, 1703, 1644, 1626, 1601,1512, 1231, 111
3, 835, 762 cm ^-1 ; Anal.Calcd for C ₂₉ H ₂₁ F ₆ NO ₃ : C,
63.86; H, 3.88; N, 2.57. Found: C, 63.49; H, 3.49;
N, 2.45.

Example 349 4-Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- [1- (1,1,1
2,2-tetrafluoroethyl) vinyl] benzyl] ethyl] naphthalene-1-carboxamide 0.36 g of methyltriphenylphosphonium bromide (1.
(0.1 mmol) of potassium tert-butoxide (1.00 mmol) in a solution of
Mmol) and stirred for 0.5 h. In addition, 4-
Fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (2,2,3,3-
A solution of 0.181 g (0.332 mmol) of tetrafluoropropionyl) benzyl] ethyl] naphthalene-1-carboxamide in 10 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / hexane).
Ethyl acetate = 2 / 1-1 / 1) and crystallization from diisopropyl ether-hexane gave the desired product. White solid Yield 0.146 g Yield 81% mp 162-163 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ
2.86 (1H, dd, J = 10.6Hz, 14.2 Hz), 2.99 (1H, dd,
J = 6.6 Hz, 14.2 Hz), 4.73-4.86 (1H, m), 5.01-5.06
(2H, m), 5.63 (1H, s), 5.75 (1H, tt, J = 4.6 Hz,
53.2 Hz), 5.87 (1H, t, J = 1.7 Hz), 6.96-7.27 (9H,
m), 7.37-7.57 (4H, m), 7.67 (1H, d, J = 8.6 Hz),
8.06 (1H, d, J = 8.4 Hz); IR (KBr) 3262, 1642, 162
6, 1601, 1537, 1510, 1264, 1229, 1111, 1053, 833,
758 cm ^-1 ; Anal.Calcd for C ₃₀ H ₂₃ F ₆ NO ₂・ 0.3H ₂ O: C, 6
5.64; H, 4.33; N, 2.55. Found: C, 65.53; H, 4.04;
N, 2.37.

Example 350 5-Chloro-N-[(1RS, 2SR) -2- (4-fluoro
Phenyl) -2-hydroxy-1- [3- (2,2,3,3-
Tetrafluoropropionyl) benzyl] ethyl] naph
Taren-1-carboxamide N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxyethyl-1- [3- (2,2,3,3-tet
Lafluoropropionyl) benzyl]] carbamic acid t
0.462 g (0.976 mmol) of tert-butyl
A solution of 5 ml of trifluoroacetic acid was stirred at room temperature for 15 minutes.
Was. After distilling off the reaction solution under reduced pressure, it was diluted with water, and potassium carbonate was added.
The mixture was made alkaline with a solvent and extracted twice with ethyl acetate. gather
The dried organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
This gave a pale yellow liquid. The liquid obtained above, 5-chloro-1-
0.20 g (0.98 mmol) of naphthoic acid, 1-hydr
Roxybenzotriazole hydrate 0.15 g (0.98
Mmol) in 15 ml of acetonitrile with stirring
1-ethyl-3- (3-dimethylaminopropyl) carbodi
0.19 g (0.98 mmol) of imide / hydrochloride was added.
And stirred overnight at room temperature. Dilute the reaction solution in ethyl acetate
And washed with aqueous sodium bicarbonate solution, anhydrous magnesium sulfate
After drying with sodium, the solvent was distilled off under reduced pressure. The resulting residue
Purify by silica gel column chromatography.
Sun / ethyl acetate = 2 / 1-1 / 1), diisopropyl
Crystallization from ether-hexane gave the desired product. White
Color crystal yield 0.429 g yield 78% mp 154-155 ° C;¹H-NMR (CDCl_Three-DMSO-d₆, 300 MHz) δ
2.94 (1H, dd, J = 10.7Hz, 14.0 Hz), 3.04 (1H, dd,
J = 4.1 Hz, 14.0 Hz), 4.75-4.85 (1H, m), 4.87 (1H,
 d, J = 3.6 Hz), 5.05 (1H, t, J = 3.9 Hz), 6.28 (1
H, tt, J = 5.5 Hz, 52.4 Hz), 7.09 (2H, t, J = 8.6
Hz), 7.23 (1H, t, J = 8.0 Hz), 7.33 (1H, t, J = 9.
0 Hz), 7.44-7.56 (6H, m), 7.61 (1H, d, J = 7.5 H
z), 7.91 (1H, s), 7.98 (1H, t, J = 8.4 Hz), 8.30
(1H, d, J = 8.1 Hz); IR (KBr) 3279,1703, 1640, 153
7, 1512, 1231, 1113, 787 cm^-1; Anal. Calcd for C₂₉
H_{twenty one}ClF _FiveNO_Three・ 0.5H_TwoO: C, 61.01; H, 3.88; N, 2.45. Fou
nd: C, 61.21; H, 3.96; N, 2.82.

Example 351 5-Chloro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- [1- (1,1,1
2,2-tetrafluoroethyl) vinyl] benzyl] ethyl] naphthalene-1-carboxamide 0.39 g of methyltriphenylphosphonium bromide (1.
0.12 g (1.10 mmol) of potassium tert-butoxide in a solution of 10 mmol) in 15 ml of tetrahydrofuran at room temperature.
Mmol) and stirred for 0.5 h. In addition, 5-
Chloro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (2,2,3,3-tetrafluoropropionyl) benzyl] ethyl] naphthalene-1- A solution of 0.206 g (0.367 mmol) of carboxamide in 10 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was poured into water, and extracted with ethyl acetate.
Extracted times. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2 / 1-1 / 1), and diisopropyl ether-
Crystallization from hexane gave the desired product. White powder Yield 0.100 g Yield 49% mp 162-163 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 2.81 (1H,
dd, J = 10.7 Hz, 14.3Hz), 3.08 (1H, dd, J = 4.2 H
z, 14.1 Hz), 3.28 (1H, d, J = 3.6 Hz), 4.79-4.89
(1H, m), 5.08 (1H, t, J = 3.8 Hz), 5.63 (1H, s),
5.72 (1H, tt, J = 4.0 Hz, 53.4 Hz), 5.89 (1H, s),
7.10 (2H, t, J = 8.7 Hz), 7.18-7.32 (7H, m), 7.43-
7.50 (3H, m), 7.57 (1H, d, J = 8.4 Hz), 7.59 (1H,
d, J = 8.4 Hz), 8.33 (1H, d, J = 8.4 Hz); IR (KBr)
3621, 3248, 1638, 1541, 1508, 1223, 1101, 789 cm ^-1

Example 352 N-[(1RS, 2SR) -2- (3-chlorophenyl)-
Tert- 1- [4- (2,2-Difluoro-3-methylbutyl) benzyl] -2-hydroxyethyl] carbamic acid
Butyl 1) 3-Methyl-1- (4-methylphenyl) butane-2-
On magnesium 22.5 g (925 mmol), iodine 1
While stirring the fragments in 400 ml of diethyl ether, a solution of 65.0 g (463 mmol) of 4-methylbenzyl chloride in 500 ml of diethyl ether was slowly added dropwise at room temperature. After the addition was completed, the mixture was stirred at room temperature for 0.5 hour. 21.31 g of isobutyronitrile (3.
(08.3 mmol) in 100 ml of diethyl ether was added dropwise under ice-cooling, and the mixture was stirred at room temperature overnight. 1N hydrochloric acid was added dropwise to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 1 hour. The diethyl ether layer of the mixture was separated, and the aqueous layer was extracted with diethyl ether. After drying the collected organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-9 / 1) to obtain the desired product. Light yellow liquid Yield 52.64 g Yield 97% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.09 (6H, d, J = 6.9 H)
z), 2.33 (3H, s), 2.67-2.77 (1H, m), 3.70 (2H, s),
7.08 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 7.8 H
z); IR (neat) 2971, 1713, 1514, 1464, 1042, 781 cm
^-12 ) 4- (2,2-difluoro-3-methylbutyl) toluene 3-methyl-1- (4-methylphenyl) butan-2-one 2
A mixture of 5.00 g (141.8 mmol) and 25.1 g (156 mmol) of (diethylamino) sulfur trifluoride was stirred at room temperature overnight. The reaction solution was poured into ice water, stirred, and extracted twice with diethyl ether.
The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-hexane / ethyl acetate = 20/1) to obtain the desired product. Colorless liquid Yield 8.562 g Yield 31% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.04 (6H, d, J = 6.9 H)
z), 1.91-2.05 (1H, m), 2.33 (3H, s), 3.09 (2H, t, J
= 17.0 Hz), 7.12 (2H, d, J = 8.1 Hz), 7.17 (2H, d,
J = 8.4 Hz); IR (neat) 2975, 1514, 999 cm ^-1 3) (4RS, 5SR) -5- (3-chlorophenyl)-
Tert-Butyl 4- [4- (2,2-difluoro-3-methylbutyl) benzyl] -2-oxo-1,3-oxazolidine-3-carboxylate 4- (2,2-difluoro-3-methylbutyl) toluene 4.06 g, N-bromosuccinimide 3.64 g (2
0.5 mmol) and a solution of 30 mg of 2,2′-azobis (isobutyronitrile) in 30 ml of carbon tetrachloride were heated under reflux for 1.5 hours. After cooling the reaction solution to room temperature, a white precipitate was removed by filtration, and the precipitate was washed with hexane. The solvent of the collected filtrate was distilled off under reduced pressure to obtain a yellow liquid. Liquid paraffin suspension of 60% sodium hydride in a solution of 4.64 g (20.5 mmol) of ethyl (3-chlorobenzoyl) acetate in 40 ml of 1,2-dimethoxyethane under ice-cooling 0.8
2 g (20.5 mmol) was added, and the mixture was stirred as it was for 0.5 hour. A solution of the liquid obtained above in 1,2-dimethoxyethane (20 ml) was added thereto at room temperature, and the mixture was stirred at room temperature overnight.
The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was passed through silica gel column chromatography (hexane / ethyl acetate = 15 / 1-9 / 1) to give 3- (3-chlorophenyl) -2- [4- (2,2-difluoro-3-methylbutyl). ) Benzyl] -3-oxopropionate as a yellow liquid. While stirring 2.49 g (18.3 mmol) of zinc chloride in 30 ml of diethyl ether, 1.38 g (36.6 mmol) of sodium borohydride was added at room temperature, and the mixture was stirred for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. To the obtained solution, a solution of the above obtained liquid in 20 ml of diethyl ether was added under ice-cooling, and the mixture was stirred for 20 minutes. Dilute hydrochloric acid was added little by little to the reaction solution to decompose excess zinc borohydride, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (hexane / ethyl acetate = 9).
/ 1-6 / 1) to give ethyl (2RS, 3RS) -3- (3-chlorophenyl) -2- [4- (2,2-difluoro-3-methylbutyl) benzyl] -3-hydroxypropionate. The crude product was obtained as a yellow liquid. The liquid obtained above, 1
9.26 ml (9.26 mmol) of a normal aqueous sodium hydroxide solution, 20 ml of methanol, and tetrahydrofuran 2
0 ml of the mixture was stirred at room temperature overnight. Concentrate the reaction solution,
The mixture was diluted with water, acidified with hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give (2RS, 3RS) -3-.
(3-chlorophenyl) -2- [4- (2,2-difluoro-
The crude product of 3-methylbutyl) benzyl] -3-hydroxypropionic acid was obtained as a yellow solid. 0.77 ml (5.56 mmol) of triethylamine and 1.40 g (5.09 mmol) of diphenylphosphoryl azide were added to a solution of the solid obtained above in 40 ml of tetrahydrofuran.
Stirred at 5 ° C. overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was passed through silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1) to give (4R
S, 5SR) -5- (3-Chlorophenyl) -4- [4-
(2,2-difluoro-3-methylbutyl) benzyl]-
The crude product of 1,3-oxazolidin-2-one was obtained as a white solid. A solution of the solid obtained above, 0.69 g (3.18 mmol) of di-tert-butyl dicarbonate, 32 mg (0.27 mmol) of 4-N, N-dimethylaminopyridine in 30 ml of acetonitrile was stirred at room temperature overnight. . The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-6 / 1) to obtain the desired product. Light yellow liquid Yield 0.684 g Yield 7% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.03 (6H, d, J = 6.9 H)
z), 1.49 (9H, s), 1.88-2.02 (1H, m), 2.57 (1H, dd,
J = 8.7 Hz, 14.1 Hz), 2.86 (1H, dd, J = 4.7Hz, 1
4.3 Hz), 3.02 (2H, t, J = 17.3 Hz), 4.82 (1H, ddd,
J = 4.9 Hz, 7.1Hz, 8.5 Hz), 5.64 (1H, d, J = 7.2
Hz), 6.63 (2H, d, J = 7.8 Hz), 6.99-7.05 (3H, m),
7.15-7.20 (2H, m), 7.27 (1H, d, J = 8.1 Hz); IR (n
eat) 2980,1809, 1728, 1360, 1312, 1155, 1071, 733
cm ^- 14) N-[(1RS, 2SR) -2- (3-chlorophenyl) -1- [4- (2,2-difluoro-3-methylbutyl)
[Benzyl] -2-hydroxyethyl] carbamic acid ter
t-butyl (4RS, 5SR) -5- (3-chlorophenyl) -4-
0.684 g (1.385 mmol) of tert-butyl [4- (2,2-difluoro-3-methylbutyl) benzyl] -2-oxo-1,3-oxazolidine-3-carboxylate
Was added to a solution of sodium hydroxide in 20 ml of tetrahydrofuran, and a solution of 58 mg (1.45 mmol) of sodium hydroxide in 2 ml of methanol was added under ice-cooling, followed by stirring for 0.5 hour. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure.
The obtained residue is ethyl acetate-diisopropyl ether-
Crystallization from hexane gave the desired product. White powder Yield 0.524 g Yield 81% mp 139-141 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.03 (6H,
d, J = 6.8 Hz), 1.37 (9H, s), 1.85-2.06 (1H, m),
2.64 (1H, dd, J = 10.2 Hz, 14.6 Hz), 2.75 (1H, dd,
J = 5.4 Hz, 14.6 Hz), 3.09 (2H, t, J = 17.0 Hz),
3.63 (1H, br s), 4.12 (1H, br s), 4.53 (1H, br d, J
= 6.2 Hz), 4.91 (1H, br s), 7.07 (2H, d, J = 8.0
Hz), 7.19 (2H, d, J = 8.0 Hz), 7.28 (3H, s), 7.41
(1H, s); IR (KBr) 3358, 2984, 1682, 1530, 1167, 100
^{. 9 cm -1; Anal Calcd for} C 25 H 32 ClF 2 NO 3: C, 64.16;
H, 6.89; N, 2.99. Found: C, 64.21; H, 6.90; N, 3.0
1.

Example 353 N-[(1RS, 2SR) -2- (3-chlorophenyl)-
1- [4- (2,2-difluoro-3-methylbutyl) benzyl] -2-hydroxyethyl] -4-fluoronaphthalene
-1-Carboxamide N-[(1RS, 2SR) -2- (3-chlorophenyl)-
Tert- 1- [4- (2,2-Difluoro-3-methylbutyl) benzyl] -2-hydroxyethyl] carbamic acid
A solution of 0.200 g (0.427 mmol) of butyl in 2 ml of trifluoroacetic acid was stirred at room temperature for 15 minutes. After evaporating the reaction solution under reduced pressure, the solution was diluted with water, made alkaline with potassium carbonate, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a white solid. 81 mg (0.43 mmol) of the solid obtained above, 4-fluoro-1-naphthoic acid, 65 mg (0.43 mmol) of 1-hydroxybenzotriazole hydrate were stirred in 10 ml of acetonitrile with 1-ethyl-3. -
82 mg (0.43 mmol) of (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography (hexane / ethyl acetate =
2 / 1-1-1) and crystallized from diisopropyl ether-hexane to give the desired product. White crystals Yield 0.15
3g Yield 66% mp 181-182 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 200 MHz) δ
1.02 (3H, d, J = 7.0 Hz), 1.02 (3H, d, J = 6.8 H
z), 1.86-2.06 (1H, m), 2.80-2.97 (2H, m), 3.09 (2H,
t, J = 17.2 Hz), 4.68-4.82 (1H, m), 5.07 (1H, t,
J = 4.0 Hz), 5.19 (1H, d, J = 3.6 Hz), 6.98-7.37 (9
H, m), 7.40-7.58 (4H, m), 7.82 (1H, d, J = 8.2 Hz),
8.06 (1H, d, J = 8.4 Hz); IR (KBr) 3297, 1640, 15
34, 1264,1057, 774, 760 cm ^-1 ; Anal.Calcd for C ₃₁ H
₂₉ ClF ₃ NO ₂ : C, 68.95; H, 5.41; N, 2.59. Found: C, 6
8.88; H, 5.33; N, 2.55.

Example 354 5-Chloro-N-[(1RS, 2SR) -2- (3-chlorophenyl) -1- [4- (2,2-difluoro-3-methylbutyl) benzyl] -2-hydroxyethyl ] Naphthalene-1-
Carboxamide N-[(1RS, 2SR) -2- (3-chlorophenyl)-
Tert- 1- [4- (2,2-Difluoro-3-methylbutyl) benzyl] -2-hydroxyethyl] carbamic acid
A solution of 0.200 g (0.427 mmol) of butyl in 2 ml of trifluoroacetic acid was stirred at room temperature for 15 minutes. After evaporating the reaction solution under reduced pressure, the solution was diluted with water, made alkaline with potassium carbonate, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a white solid. The solid obtained above, 5-chloro-1-naphthoic acid 8
8 mg (0.43 mmol) of 1-hydroxybenzotriazole hydrate 65 mg (0.43 mmol) are stirred in 10 ml of acetonitrile with 1-ethyl-3-ethyl.
82 mg (0.43 mmol) of (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography (hexane / ethyl acetate =
2 / 1-1-1) and crystallized from diisopropyl ether-hexane to give the desired product. White crystals Yield 0.17
8g Yield 75% mp 170-171 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
1.02 (3H, d, J = 6.9 Hz), 1.03 (3H, d, J = 6.9 H
z), 1.89-2.03 (1H, m), 2.86 (1H, dd, J = 10.8 Hz,
14.1 Hz), 2.95 (1H, dd, J = 4.5 Hz, 14.4 Hz), 3.10
(2H, t, J = 17.4 Hz), 4.73-4.82 (1H, m), 5.05 (1
H, t, J = 3.8 Hz), 5.19 (1H, d, J = 3.9 Hz), 7.16-
7.38 (8H, m), 7.44-7.58 (5H, m), 7.64 (1H, d, J =
8.7 Hz), 8.29 (1H, d, J = 8.7 Hz); IR (KBr) 3272, 1
638, 1535, 1202, 785 cm ^-1 ; Anal.Calcd for C ₃₁ H ₂₉ C
l ₂ F ₂ NO ₂ : C, 66.91; H, 5.25; N, 2.52. Found: C, 67.
01; H, 5.27; N, 2.41.

Example 355 4-Fluoro-N-[(1RS, 2SR) -2- (3-chlorophenyl) -2-hydroxy-1- [4- (tert-pentyl) benzyl] ethyl] naphthalene-1-carboxamide 1) 4- (tert-pentyl) benzyl alcohol 10.04 g of tert-pentylbenzene (67.72)
Mmol) and 9.49 g of hexamethylenetetramine (6
(7.7 mmol) in 100 ml of trifluoroacetic acid was stirred at 90 ° C. overnight. After evaporating the reaction solution under reduced pressure, the solution was diluted with water, made alkaline with potassium carbonate, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of 4- (tert-pentyl) benzaldehyde as a dark brown liquid. To a solution of the liquid obtained above in 100 ml of methanol, 1.28 g (33.9 mmol) of sodium borohydride was added little by little under ice-cooling, followed by stirring at room temperature overnight. After concentrating the reaction solution, it was diluted with water and extracted twice with diethyl ether. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-6).
/ 1) to obtain the desired product. Yellow liquid yield 10.83g
Yield 74% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 0.68 (3H, t, J = 7.4 H
z), 1.28 (6H, s), 1.65 (2H, q, J = 7.4 Hz), 4.66 (2
H, d, J = 5.7 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.33
(2H, d, J = 8.7 Hz); IR (neat) 3281, 2965, 1462, 1
015 cm ^-1 2) 3- (3-chlorophenyl) -3-oxo-2- [4-
(Tert-Pentyl) benzyl] ethyl propionate 4- (tert-pentyl) benzyl alcohol 4.07
5 g (22.86 mmol), triethylamine 4.7
A solution of 3.14 g (27.4 mmol) of methanesulfonyl chloride in 10 ml of ethyl acetate was added dropwise to a solution of 8 ml (34.3 mmol) of ethyl acetate in 50 ml under ice-cooling, and the mixture was stirred for 10 minutes. The resulting precipitate was removed by filtration, and the precipitate was washed with diethyl ether. The solvent of the collected filtrate was distilled off under reduced pressure to obtain a crude product of methanesulfonic acid ester as a yellow liquid. 0.91 g (22.9 mmol) of a 60% sodium hydride liquid paraffin suspension in a solution of 5.18 g (22.9 mmol) of ethyl (3-chlorobenzoyl) acetate in 40 ml of 1,2-dimethoxyethane under ice-cooling
Was added and the mixture was stirred as it was for 0.5 hour. A solution of the methanesulfonic acid ester obtained above in 1,2-dimethoxyethane (20 ml) was added thereto at room temperature, and the mixture was stirred at 50 ° C. overnight. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 15/1),
The desired product was obtained. Yellow liquid Yield 6.969 g Yield 79
% ¹ H-NMR (CDCl ₃ , 300 MHz) δ 0.62 (3H, t, J = 7.4 H
z), 1.12 (3H, t, J = 7.2 Hz), 1.23 (6H, s), 1.59
(2H, q, J = 7.4 Hz), 3.26 (1H, dd, J = 7.5 Hz, 14.1
Hz), 3.32 (1H, dd, J = 7.2 Hz, 14.4 Hz), 4.10 (1
H, q, J = 7.0 Hz), 4.11 (1H, q, J = 7.2 Hz), 4.54
(1H, t, J = 7.4 Hz), 7.13 (2H, d, J = 8.4 Hz), 7.2
1 (2H, d, J = 8.4 Hz), 7.36 (1H, t, J = 8.0 Hz),
7.51 (1H, dd, J = 1.2 Hz, 7.8 Hz), 7.78 (1H, dd, J
= 1.5 Hz, 7.8 Hz), 7.89 (1H, t, J = 1.8 Hz); IR (ne
at) 2965, 1736, 1692, 1229 cm -1 3) (2RS, 3RS) -3- (3- chlorophenyl) -
Ethyl 3-hydroxy-2- [4- (tert-pentyl) benzyl] propionate While stirring 4.91 g (36.0 mmol) of zinc chloride in 50 ml of diethyl ether, 2.73 g (72.0 g) of sodium borohydride was stirred. (Mmol) at room temperature and stirred for 2 hours. The insoluble matter of the mixture was removed by filtration (washed with diethyl ether) to obtain a diethyl ether solution of zinc borohydride. The resulting solution was added to 3- (3-chlorophenyl) -3-oxo-2- [4- (tert-pentyl)
6.969 g of ethyl benzyl] propionate (18.0
(1 mmol) in 30 ml of diethyl ether was added under ice-cooling, and the mixture was stirred as it was for 20 minutes. After decomposing excess zinc borohydride by adding dilute hydrochloric acid little by little to the reaction solution,
Extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 15 / 1-6 / 1) to obtain the desired product. Yellow liquid Yield 6.751 g Yield 96% ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.63 (3H, t, J = 7.4 H)
z), 0.923 (3H, t, J = 7.1 Hz), 1.23 (6H, s), 1.59
(2H, q, J = 7.4 Hz), 2.84-2.99 (3H, m), 3.13 (1H,
d, J = 3.0 Hz), 3.90 (1H, q, J = 7.2 Hz), 3.91 (1
H, q, J = 7.4 Hz), 5.02 (1H, t, J = 3.1 Hz), 7.00
(2H, d, J = 8.0 Hz), 7.18 (2H, d, J = 8.0 Hz), 7.2
6 (3H, s), 7.42 (1H, s); IR (neat) 3480, 2965, 172
8, 1715, 1375, 1192, 1159, 1032, 789 cm -1 4) (4RS, 5SR) -5- (3- chlorophenyl) -
4- [4- (tert-pentyl) benzyl] -1,3-oxazolidin-2-one (2RS, 3RS) -3- (3-chlorophenyl) -3-hydroxy-2- [4- (tert-pentyl) A mixture of 6.650 g (17.10 mmol) of ethyl benzyl] propionate, 1.37 g (34.2 mmol) of sodium hydroxide, 20 ml of methanol, 20 ml of water and 20 ml of tetrahydrofuran was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with water, acidified with hydrochloric acid, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and (2RS, 3R
S) -3- (3-Chlorophenyl) -3-hydroxy-2-
A crude product of [4- (tert-pentyl) benzyl] propionic acid was obtained as a white solid. To a solution of the solid obtained above in 70 ml of tetrahydrofuran was added 2.86 of triethylamine.
ml (20.5 mmol) and 5.18 g (18.8 mmol) of diphenylphosphoryl azide were added, and the mixture was stirred at 65 ° C overnight. The solvent of the reaction solution was distilled off under reduced pressure, and diluted with ethyl acetate. The obtained ethyl acetate solution was washed with water, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with diisopropyl ether to obtain the desired product. White crystals Yield 4.312 g Yield 71% mp 223-224 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
0.65 (3H, t, J = 7.4 Hz), 1.24 (6H, s), 1.60 (2H,
q, J = 7.4 Hz), 2.30 (1H, dd, J = 6.3 Hz, 14.1 H
z), 2.37 (1H, dd, J = 9.0 Hz, 14.4 Hz), 4.33-4.41
(1H, m), 5.70 (1H, d, J = 7.8 Hz), 6.84-6.87 (3H,
m), 7.15-7.23 (3H, m), 7.27-7.33 (3H, m); IR (KBr)
3247, 2965, 1738, 1240, 1019 cm ^-1 ; Anal.Calcd for
C ₂₁ H ₂₄ ClNO ₂ : C, 70.48; H, 6.76; N, 3.91. Found:
C, 70.35; H, 6.59; N, 3.77.5) (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- [4- (tert-pentyl) phenyl]
Propan-1-ol (4RS, 5SR) -5- (3-chlorophenyl) -4-
[4- (tert-pentyl) benzyl] -1,4-oxazolidin-2-one 4.046 g (11.31 mmol)
And 1.81 g (45.2 mmol) of sodium hydroxide were heated under reflux for 5 hours in 40 ml of ethanol and 2 ml of water. The reaction solution was diluted with water and stirred as it was for 0.5 hour. Collect the resulting precipitate, add water and diisopropyl ether
Washing with hexane gave the desired product. White crystal yield 2.833 g yield 76% mp 86-87 ° C .; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 0.66 (3H,
t, J = 7.3 Hz), 1.26 (6H, s), 1.61 (2H, q, J = 7.4
Hz), 2.30 (1H, dd, J = 10.2 Hz, 14.0 Hz), 2.72 (1
H, dd, J = 3.2 Hz, 13.6 Hz), 3.30 (1H, ddd, J = 3.
5 Hz, 4.7 Hz, 10.4 Hz), 4.67 (1H, d, J = 4.8 Hz),
7.05 (2H, d, J = 8.4 Hz), 7.22-7.30 (5H, m), 7.42
(1H, s); IR (KBr) 3400-2700, 1576, 1474, 1460, 142
0, 1044, 781 cm ^-1 ; Anal.Calcd for C ₂₀ H ₂₆ ClNO ・ 0.1H
₂ O: C, 71.99; H, 7.91; N, 4.20. Found: C, 71.96;
H, 7.85; N, 4.14.6) 4-Fluoro-N-[(1RS, 2SR) -2- (3-
Chlorophenyl) -2-hydroxy-1- [4- (tert-
Pentyl) benzyl] ethyl] naphthalene-1-carboxamide (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- [4- (tert-pentyl) phenyl] propan-1-ol 0.300 g ( 0.904 mmol), 4
-Fluoro-1-naphthoic acid 0.17 g (0.90 mmol), 1-hydroxybenzotriazole hydrate 0.1
4 g (0.90 mmol) of acetonitrile 10 ml
While stirring in 2 ml of N, N-dimethylformamide, 0.17 g (0.90 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White amorphous powder Yield 0.381 g Yield 84% ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ 0.64 (3H, t, J
= 7.5 Hz), 1.25 (6H, s), 1.61 (2H, q, J = 7.5 Hz),
2.84 (1H, dd, J = 10.5 Hz, 14.4 Hz), 2.93 (1H, d
d, J = 4.2 Hz, 14.4 Hz), 4.72-4.81 (1H, m), 5.05
(1H, t, J = 3.6 Hz), 5.28 (1H, d, J = 3.6 Hz), 7.0
0 (1H, dd, J = 8.1 Hz, 10.2 Hz), 7.12-7.35 (8H,
m), 7.41-7.58 (4H, m), 7.82 (1H, d, J = 8.1 Hz),
8.05 (1H, d, J = 8.1 Hz); IR (KBr) 3414, 3250, 296
5, 1638, 1628, 1599, 1514, 1262, 1233, 766 cm ^-1 ; A
nal.Calcd for C ₃₁ H ₃₁ ClFNO ₂ : C, 73.87; H, 6.20; N,
2.78. Found: C, 73.53; H, 6.13; N, 2.84.

Example 356 5-Chloro-N-[(1RS, 2SR) -2- (3-chlorophenyl) -2-hydroxy-1- [4- (tert-pentyl) benzyl] ethyl] naphthalene-1-carboxamide 0.300 g (0.904 mmol) of (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- [4- (tert-pentyl) phenyl] propan-1-ol, 5
-Chloro-1-naphthoic acid 0.19 g (0.90 mmol), 1-hydroxybenzotriazole hydrate 0.1
4 g (0.90 mmol) of acetonitrile 10 ml
While stirring in 2 ml of N, N-dimethylformamide, 0.17 g (0.90 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethyl acetate-diisopropyl ether-hexane to obtain the desired product. White amorphous powder Yield 0.363 g Yield 77% ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ 0.64 (3H, t, J
= 7.4 Hz), 1.26 (6H, s), 1.62 (2H, q, J = 7.4 Hz),
2.83 (1H, dd, J = 11.0 Hz, 14.6 Hz), 2.95 (1H, d
d, J = 4.2 Hz, 14.7 Hz), 4.73-4.82 (1H, m), 5.03
(1H, t, J = 3.9 Hz), 5.26 (1H, d, J = 3.9 Hz), 7.1
6 (2H, d, J = 8.4 Hz), 7.22-7.36 (7H, m), 7.42-7.4
9 (2H, m), 7.55 (1H, d, J = 7.5 Hz), 7.58 (1H, s),
7.65 (1H, d, J = 8.4 Hz), 8.28 (1H, d, J = 8.7 H
z); IR (KBr) 3262, 2963, 1636, 1516, 785 cm ^-1 ; Ana
l. Calcd for C ₃₁ H ₃₁ Cl ₂ NO ₂ : C, 71.54; H, 6.00; N,
2.69. Found: C, 71.24; H, 6.11; N, 2.42.

Example 357 N-[(1RS, 2SR) -1- (4-tert-butylbenzyl) -2- (4-fluorophenyl) -2-hydroxyethyl] -4-fluoro-1-naphthamide 1) Ethyl 2- [4- (tert-butyl) benzyl]-
3- (4-fluorophenyl) -3-oxopropionate p-tert-butylbenzyl alcohol (5 ml, 2
To a solution of 8.2 mmol) in ethyl acetate (60 ml) was added triethylamine (5.9 ml, 42.3 mmol), and methanesulfonyl chloride (2.4 ml, 3 ml) was added under ice-cooling.
1.0 mmol) was added dropwise, and the mixture was stirred for 1 hour.
The precipitated crystals were filtered, and the filtrate was concentrated to obtain a mesylate. This was used for the next reaction as it was. Ethyl 3- (4-
Fluorophenyl) -3-oxopropionate (5.6
8 g, 27 mmol) of dimethoxyethane (50 ml)
The solution was cooled on ice and sodium hydride (60%, 1.13
g, 28 mmol), and the mixture was stirred under ice-cooling for 30 minutes. Then, a solution of mesylate in dimethoxyethane (30 ml) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction was quenched with 1N hydrochloric acid and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1, 8: 1) to give ethyl 2- [4- (te
rt-butyl) benzyl] -3- (4-fluorophenyl)
-3-Oxopropionate (8.97 g, 93%) was obtained as a colorless transparent oil. IRνmax ^KBr (cm ^-1 ): 1736, 1685, 1599, 1508, 1267, 1
234, 1159 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.11 (3H, t, J = 4.8 Hz) 1.2
7 (9H, s) 3.28 (1H, dd, J = 2.0, 4.8 Hz) 4.10 (2H,
q, J = 4.8 Hz) 4.56 (1H, t, J = 4.8 Hz) 7.07-7.15
(4H, m) 7.27 (2H, d, J = 5.4 Hz) 7.95-8.00 (2H,
m). 2) Ethyl (2RS, 3RS) -2- [4- (tert-
Butyl) benzyl] -3- (4-fluorophenyl) -3-
Hydroxypropionate Sodium borohydride (3.6) was added to an ether suspension (80 ml) of zinc chloride (6.59 g, 48.3 mmol).
(6 g, 96.6 mmol) at room temperature and stirred for 2 hours. Then, ethyl 2- [4- (tert-butyl) benzyl] -3- (4-fluorophenyl) -3-oxopropionate (8.61 g, 24.15 mmol)
Was added and stirred at room temperature for 15 minutes. The reaction was terminated with 1N hydrochloric acid, diluted with ethyl acetate, and washed with water. After drying over anhydrous magnesium sulfate,
Filtration and concentration under reduced pressure. The residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 8: 1, 5: 1).
And purified with ethyl (2RS, 3RS) -2- [4- (te
rt-butyl) benzyl] -3- (4-fluorophenyl)
-3-Hydroxypropionate (8.00 g, 92%)
Was obtained as a colorless transparent oil. IRνmax ^KBr (cm ^-1 ): 3452, 1726, 1604, 1510, 1464, 13
94, 1373, 1224, 1157,1030 ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.89 (3H, t, J = 7.4 Hz) 1.
27 (9H, s) 2.95 (2H, s) 3.04 (1H, d, J = 3.0 Hz)
3.87-3.95 (2H, m) 4.99 (1H, s) 6.97-7.07 (4H, m) 7.
21-7.28 (2H, m) 7.32-7.39 (2H, m). 3) (2RS, 3RS) -2- [4- (tert-butyl) benzyl] -3- (4-fluorophenyl) -3-hydroxy Ethyl propionate 2- [4- (tert-butyl) benzyl] -3-
To a solution of (4-fluorophenyl) -3-oxopropionate (7.43 g, 20.7 mmol) in tetrahydrofuran-methanol (20 ml to 20 ml) was added 2N sodium hydroxide at room temperature, and the mixture was stirred at room temperature overnight. . After completion of the reaction, the organic solvent was distilled off under reduced pressure, the aqueous layer was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Hexane-
Recrystallization from ethyl acetate gave (2RS, 3RS) -2-
[4- (tert-butyl) benzyl] -3- (4-fluorophenyl) -3-hydroxypropionic acid (5.51
g, 81%) as colorless crystals. mp 102-104 ℃ IRνmax ^KBr (cm ^-1 ): 2500-3300, 1709, 1606, 1510, 122
6, 1159, 839 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.27 (9H, s) 2.85-3.02 (3H,
m) 5.04 (1H, d, J = 4.4 Hz) 6.98-7.06 (4H, m) 7.2
2-7.27 (2H, m) 7.31-7.38 (2H, m). 4) (4RS, 5SR) -4- [4- (tert-butyl) benzyl] -5- (4-fluorophenyl) -1,3 -
Oxazolidine-2-one (2RS, 3RS) -2- [4- (tert-butyl) benzyl] -3- (4-fluorophenyl) -3-hydroxypropionic acid (5.07 g, 15.3 mmol) in tetrahydrofuran (150 ml) solution, triethylamine (3.2 ml, 22.95 mmol) and diphenylphosphoric azide (3.63 ml, 16.8 mmol) were added,
The mixture was refluxed for 5 hours. After the solvent was distilled off, the residue was passed through a silica gel column and purified by recrystallization (hexane-ethyl acetate) to give (4RS, 5SR) -4- [4- (tert-butyl).
Benzyl] -5- (4-fluorophenyl) -1,3-oxazolidin-2-one (3.98 g, 79%) was obtained as colorless crystals. mp 218-219 ℃ IRνmax ^KBr (cm ^-1 ): 3284, 1736, 1610, 1514, 1363, 1
230 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.28 (9H, s) 2.10-2.86 (2H,
m) 4.15-4.26 (1H, m) 4.95 (1H, s) 5.78 (1H, d, J =
(7.6 Hz) 6.95 (2H, d, J = 8.4 Hz) 7.08-7.18 (2H, m)
7.26-7.40 (4H, m). 5) (1RS, 2RS) -2-amino-3- [4- (te
rt-butyl) benzyl] -1- (4-fluorophenyl)
Propan-1-ol (4RS, 5SR) -4- [4- (tert-butyl) benzyl] -5- (4-fluorophenyl) -1,3-oxazolidin-2-one (3.80 g, 11.6 Mmol) in an ethanol solution of 8N sodium hydroxide solution (7.3).
ml, 58.4 mmol) and heated under reflux for 5 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate.
The organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) and (1RS, 2R
S) -2-Amino-3- [4- (tert-butyl) benzyl] -1- (4-fluorophenyl) propan-1-ol (2.57 g, 74%) was obtained as colorless crystals. mp 139-140 ℃ IRνmax ^KBr (cm ^-1 ): 2500-3300, 1603, 1508, 1363, 122
4, 1155, 1043 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.29 (9H, s) 2.06 (2H, br)
2.30 (1H, dd, J = 10.4, 13.6 Hz) 2.72 (1H, dd, J =
3.4, 14.0 Hz) 3.26 (1H, ddd, J = 3.8, 4.8,10.6 H
z) 4.69 (1H, d, J = 4.8 Hz) 7.01-7.10 (4H, m) 7.25
-7.40 (4H, m). 6) N-[(1RS, 2SR) -1- (4-tert-butylbenzyl) -2- (4-fluorophenyl) -2-hydroxyethyl] -4-fluoro-1 -Naphthamide acetonitrile of (1RS, 2RS) -2-amino-3- [4- (tert-butyl) benzyl] -1- (4-fluorophenyl) propan-1-ol (0.30 g, 0.998 mmol) (10 ml) solution was added 4-fluoronaphthalene-1-carboxylic acid (0.20 g, 1.05 mmol),
1-hydroxybenzotriazole monohydrate (0.16
g, 1.05 mmol) and finally 1-ethyl-3-
(3-Dimethylaminopropyl) carbodiimide hydrochloride (0.20 g, 1.05 mmol) was added, and
Stirred for hours. Dilute with ethyl acetate, add saturated aqueous sodium bicarbonate, water,
After washing with saturated saline and drying over anhydrous magnesium sulfate,
Filtration and concentration under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1, 3: 2).
1) Then, the product was purified by recrystallization (hexane-ethyl acetate) to give N-[(1RS, 2SR) -1- (4-tert-butylbenzyl) -2- (4-fluorophenyl) -2-hydroxyethyl. ] -4-Fluoro-1-naphthamide (0.30
g, 64%) as colorless crystals. mp 149-150 ° C. Elemental analysis C ₃₀ H ₂₉ NO ₂ F ₂ Calculated: C, 76.09; H, 6.17 ; N, 2.96 Found: C, 76.07; H, 6.09 ; N, 2.92 IRνmax KBr (cm - ¹ ): 3263, 1639, 1601, 1510, 1263, 1
226, 1051, 835 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.31 (9H, s) 2.72 (1H, dd,
J = 10.6, 14.4 Hz) 3.03 (1H, dd, J = 4.4, 14.2 Hz)
4.70-4.84 (1H, m) 5.04-5.08 (1H, m) 5.83 (1H, d,
J = 8.0 Hz) 6.90-7.15 (6H, m) 7.31-7.57 (6H, m) 7.
85 (1H, d, J = 8.0 Hz) 8.97 (1H, d, J = 7.6 Hz).

Example 358 N-[(1RS, 2SR) -1- (4-tert-butylbenzyl) -2- (4-fluorophenyl) -2-hydroxyethyl] -6,7-dihydro-5H-benzo [A] Cycloheptene-1-carboxamide (1RS, 2RS) -2-amino-3- [4- (tert-butyl) benzyl] -1- (4-fluorophenyl) propan-1-ol (0.41 g, 1 .36 mmol) in acetonitrile (10 ml) was added to 6,7-dihydro-5H-
Benzo [a] cycloheptene-1-carboxylic acid (0.20
g, 1.05 mmol) and 1-hydroxybenzotriazole monohydrate (0.16 g, 1.05 mmol), and finally 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0%). .20 g, 1.05 mmol) and stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1, 2: 1), and then recrystallized (hexane-ethyl acetate).
Ethyl acetate) and purified by N-[(1RS, 2SR) -1-
(4-tert-butylbenzyl) -2- (4-fluorophenyl) -2-hydroxyethyl] -6,7-dihydro-5
H-benzo [a] cycloheptene-1-carboxamide (0.43 g, 67%) was obtained as colorless crystals. mp 140-142 ° C Elemental analysis: C ₃₁ H ₃₄ NO ₂・ 0.25H ₂ O Calculated: C, 78.20; H, 7.30; N, 2.94 Found: C, 78.16; H, 7.20; N, 2.86 IRνmax ^KBr (cm ^-1 ): 1637, 1508, 1363, 1222, 1155 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.29 (9H, s) 1.96-2.04 (2H,
m) 2.13-2.23 (2H, m) 2.62-2.73 (3H, m) 2.96 (1H, d
d, J = 4.4, 14.6 Hz) 4.17 (1H, d, J = 3.2 Hz) 4.99
-5.01 (1H, m) 5.63 (1H, d, J = 7.6 Hz) 5.90 (1H, d
t, J = 5.6, 11.4Hz) 6.24 (1H, d, J = 11.8 Hz) 6.87
(1H, d, J = 1.0 Hz) 7.01-7.16 (5H, m) 7.25-7.33
(3H, m) 7.38-7.45 (2H, m).

Example 359 N-[(1RS, 2SR) -1- [3- (1,1-difluoroethyl) benzyl] -2- (4-fluorophenyl) -2
-Hydroxyethyl] -4-fluoro-1-naphthamide 1) 3- (1,1-difluoroethyl) benzonitrile Nascol containing 3-acetylbenzophenone (5.81 g, 40.0 mmol) was added with bis (2- Methoxyethyl) aminosulfur trifluoride (12.5m
1,67.8 mmol) was added dropwise and ethanol (0.4%) was added.
6 ml, 8.14 mmol) was slowly added dropwise.
Stirred at 85 ° C. overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ether. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ether = 10: 1,
8: 1, 5: 1) to give 3- (1,1-difluoroethyl) benzonitrile (5.16 g, 77%) as a clear, colorless oil. IRνmax ^KBr (cm ^-1 ): 2223, 1485, 1429, 1386, 1304, 1
186 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.93 (3H, t, J = 18.3 Hz) 7.
55-7.60 (1H, m) 7.72-7.80 (3H, m). 2) 3- (1,1-difluoroethyl) benzoic acid 3- (1,1-difluoroethyl) benzonitrile (5.
10 g, 30.5 mmol) in water (100 ml)
To the mixture was added sodium hydroxide (3.05 g, 76.25 mmol), and the mixture was stirred at 100 ° C for 5 hours. After completion of the reaction, the mixture was acidified with 6N hydrochloric acid and extracted with ethyl acetate.
The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 3- (1,1-difluoroethyl) benzoic acid (5.10 g, 90%) as colorless crystals. Was. mp 96-97 ℃ IRνmax ^KBr (cm ^-1 ): 2500-3300, 1689, 1616, 1423, 13
85, 1323, 1278, 1263,1176 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.97 (3H, t, J = 18.4 Hz)
7.52-7.65 (1H, m) 7.76-7.79 (1H, m) 8.17-8.34 (2H,
m). 3) 3- (1,1-Difluoroethyl) benzyl alcohol 3- (1,1-Difluoroethyl) benzyl alcohol was added to an ether suspension (100 ml) of lithium aluminum hydride (2.24 g, 54.4 mmol).
1-difluoroethyl) benzonitrile (5.48 g,
(29.4 mmol) in ether (50 m) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 4 hours. After the completion of the reaction, water (2.24 ml), a 15% aqueous sodium hydroxide solution (2.24 ml) and water (6.72 ml) were slowly added dropwise in succession under ice cooling. The resulting solid is filtered through Celite,
Washed with ethyl acetate. The filtrate is concentrated, and the residue is subjected to silica gel column chromatography (hexane: ethyl acetate =
Purification by 3: 1, 1: 1) afforded 3- (1,1-difluoroethyl) benzyl alcohol (3.82 g, 75%) as a clear, colorless oil. IRνmax ^KBr (cm ^-1 ): 3292, 1439, 1389, 1305, 1180, 11
43 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.91 (3H, t, J = 17.8 Hz)
2.08 (1H, s) 4.71 (2H, s) 7.41-7.44 (3H, m) 7.50 (1
H, s). 4) Ethyl 2- [3- (1,1-difluoroethyl) benzyl] -3- (4-fluorophenyl) -3-oxopropionate 3- (1,1-difluoroethyl) benzyl The alcohol (3.71 ml, 21.5 mmol) in ethyl acetate (5
0ml) solution in triethylamine (4.5ml, 32.
Methanesulfonyl chloride (1.83 ml, 23.6 mmol) was added dropwise under ice-cooling, and the mixture was stirred for 45 minutes. The precipitated crystals were filtered, and the filtrate was concentrated to obtain mesylate. This was used for the next reaction as it was. A solution of ethyl 3- (4-fluorophenyl) -3-oxopropionate (4.52 g, 21.5 mmol) in dimethoxyethane (50 ml) was cooled with ice, and sodium hydride (60%, 0.86 g, 21%) was added. After stirring for 30 minutes under ice-cooling, a solution of mesylate in dimethoxyethane (50 ml) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched with 1N hydrochloric acid, diluted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1, 5: 1) to give ethyl 2- [3- (1,1).
-Difluoroethyl) benzyl] -3- (4-fluorophenyl) -3-oxopropionate (7.31 g, 93
%) As a clear, colorless oil. IRνmax ^KBr (cm ^-1 ): 1736, 1685, 1508, 1446, 1385, 1
304, 1234, 1159 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.12 (3H, t, J = 7.2 Hz) 1.8
6 (3H, t, J = 18.3 Hz) 3.35 (2H, dd, J = 2.7, 7.2 H
z) 4.10 (2H, q, J = 7.2 Hz) 4.57 (1H, t, J = 7.5 H
z) 7.08-7.15 (2H, m) 7.26-7.35 (4H, m) 7.96-8.01
(2H, m). 5) Ethyl (2RS, 3RS) -2- [3- (1,1-difluoroethyl) benzyl] -3- (4-fluorophenyl) -3-hydroxypropionate Zinc chloride (5 Sodium borohydride (2.9 ml) in an ether suspension (40 ml) of 0.35 g (39.2 mmol).
(7 g, 78.4 mmol) at room temperature and stirred for 2 hours. The insolubles were filtered off and the filtrate was added with ethyl 2- [3-
(1,1-difluoroethyl) benzyl] -3- (4-fluorophenyl) -3-oxopropionate (7.16
g, 19.6 mmol) in ether (40 ml) was added and stirred at room temperature for 1.5 hours. The reaction was terminated with 1N hydrochloric acid, diluted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1, 4: 1), and ethyl (2RS, 3RS) -2- [3- (1,1-difluoroethyl) benzyl] -3- ( 4-Fluorophenyl) -3-hydroxypropionate (6.24 g, 87%) was obtained as a clear, colorless oil. IRνmax ^KBr (cm ^-1 ): 1728, 1604, 1510, 1446, 1385, 13
04 ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.91 (3H, t, J = 7.4 Hz) 1.8
7 (3H, t, J = 17.6 Hz) 2.90-3.05 (4H, m) 3.87 (1H,
q, J = 7.8 Hz) 4.99-5.02 (1H, m) 6.98-7.40 (8H, m). 6) (2RS, 3RS) -2- [3- (1,1-difluoroethyl) benzyl] -3- (4-fluorophenyl) -3
Ethyl 2-hydroxypropionate (2RS, 3RS) -2- [3- (1,1-difluoroethyl) benzyl] -3- (4-fluorophenyl) -3
-Hydroxypropionate (5.97 g, 17.6 mmol) in tetrahydrofuran-ethanol (30 ml-
20 ml) solution at room temperature with 2N sodium hydroxide (1
(8 ml, 36 mmol) and stirred at room temperature overnight.
After completion of the reaction, the organic solvent was distilled off under reduced pressure, the aqueous layer was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Hexane
-Recrystallize with ethyl acetate to give (2RS, 3RS) -2-
[3- (1,1-difluoroethyl) benzyl] -3- (4
-Fluorophenyl) -3-hydroxypropionic acid (4.48 g, 82%) was obtained as colorless crystals. mp 132-133 ℃ IRνmax ^KBr (cm ^-1 ): 2800-3300, 1709, 1606, 1512, 138
5, 1304, 1226, 1178 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.85 (3H, t, J = 18.2 Hz) 3.
01 (3H, m) 5.06 (1H, s) 6.99-7.39 (8H, m). 7) (4RS, 5SR) -4- [3- (1,1-difluoroethyl) benzyl] -5- (4- Fluorophenyl)-
1,3-Oxazolidin-2-one (2RS, 3RS) -2- [3- (1,1-difluoroethyl) benzyl] -3- (4-fluorophenyl) -3-hydroxypropionic acid (4.22 g, 13.6 mmol)
Of triethylamine (2.85 ml, 20.4 mmol) and azide diphenylphosphoric acid (3.23 ml, 14.96 mmol) in a tetrahydrofuran (130 ml) solution of
Was added and heated under reflux for 5 hours. The solvent was distilled off, diluted with ethyl acetate, and washed with water, saturated aqueous sodium hydrogen carbonate and saturated saline.
The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Recrystallized with hexane-ethyl acetate, (4R
S, 5SR) -4- [3- (1,1-difluoroethyl) benzyl] -5- (4-fluorophenyl) -1,3-oxazolidin-2-one (3.99 g, 95%) as colorless crystals. As obtained. mp 143-144 ℃ IRνmax ^KBr (cm ^-1 ): 3231, 1763, 1608, 1512, 1386, 13
00, 1230 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.88 (3H, t, J = 18.4 Hz)
2.29-2.38 (2H, m) 4.22-4.33 (1H, m) 5.17 (1H, s)
5.79 (1H, d, J = 8.0 Hz) 7.06-7.18 (4H, m) 7.29-7.
39 (4H, m). 8) (1RS, 2SR) -2-amino-3- [3- (1,
1-difluoroethyl) phenyl] -1- (4-fluorophenyl) -1-propanol (4RS, 5SR) -4- [3- (1,1-difluoroethyl) benzyl] -5- (4-fluorophenyl) -1,3-
To a solution of oxazolidin-2-one (3.83 g, 12.5 mmol) in ethanol (100 ml) was added an 8 N aqueous sodium hydroxide solution (7.8 ml, 39.0 mmol), and the mixture was heated under reflux for 5 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give (1RS, 2SR) -2-amino-3- [3- (1,1-
[Difluoroethyl) phenyl] -1- (4-fluorophenyl) -1-propanol (3.08 g, 88%) was obtained as colorless crystals. mp 101-102 ° C IRνmax ^KBr (cm ^-1 ): 3363, 1604, 1508, 1448, 1385, 13
02, 1224, 1176 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.89 (3H, t, J = 18.4 Hz)
2.39 (1H, dd, J = 10.4,13.6 Hz) 2.82 (1H, dd, J =
3.0, 13.6 Hz) 3.25-3.34 (1H, m) 4.69 (1H, d, J = 5.
0 Hz) 7.03-7.11 (2H, m) 7.11-7.21 (1H, m) 7.26-7.4
1 (5H, m). 9) N-[(1RS, 2SR) -1- [3- (1,1-difluoroethyl) benzyl] -2- (4-fluorophenyl) -2-hydroxyethyl] -4 -Fluoro-1-naphthamide (1RS, 2SR) -2-amino-3- [3- (1,1-difluoroethyl) phenyl] -1- (4-fluorophenyl) -1-propanol (0.40 g, 1 .42 mmol) in acetonitrile (10 ml) solution in 4-fluoronaphthalene-1-carboxylic acid (0.283 g, 1.49 mmol), 1-hydroxybenzotriazole monohydrate (0.22 g, 1.49 mmol) And finally 1-
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.27 g, 1.49 mmol) was added,
Stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1,
2: 1) and then purified by recrystallization (hexane-ethyl acetate) to give N-[(1RS, 2SR) -1- [3- (1,1-
Difluoroethyl) benzyl] -2- (4-fluorophenyl) -2-hydroxyethyl] -4-fluoro-1-naphthamide (0.52 g, 81%) was obtained as colorless crystals. mp 182-183 ° C. Elemental analysis C ₂₈ H ₂₃ NO ₂ F ₄ Calculated: C, 69.85; H, 4.81 ; N, 2.91 Found: C, 69.86; H, 4.75 ; N, 2.74 IRνmax KBr (cm - ¹ ): 3277, 1641, 1626, 1601, 1512, 14
25, 1307, 1230 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.84 (3H, t, J = 18.0 Hz) 2.
84 (1H, dd, J = 10.2, 14.1 Hz) 3.07 (1H, dd, J = 4.
2, 14.7 Hz) 3.55 (1H, s) 4.72-4.81 (1H, m) 5.08 (1
H, s) 5.92 (1H, d, J = 8.7 Hz) 6.98 (1H, dd, J =
8.1, 9.9 Hz) 7.05-7.15 (3H, m) 7.27-7.48 (7H, m)
7.50-7.55 (1H, m) 7.75 (1H, d, J = 8.7Hz) 8.07 (1
(H, d, J = 8.7 Hz).

Example 360 N-[(1RS, 2SR) -1- [3- (1,1-difluoroethyl) benzyl] -2- (4-fluorophenyl) -2
-Hydroxyethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-3- [3- (1,1-difluoroethyl) phenyl] -1- To a solution of (4-fluorophenyl) -1-propanol (0.40 g, 1.42 mmol) in acetonitrile (10 ml) was added 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (0.28 g, 1.49 mmol), 1-hydroxybenzotriazole monohydrate (0.22 g, 1.49 mmol) and finally 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.27 g) , 1.
49 mmol) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Ethyl acetate = 5: 1, 2: 1), then purified by recrystallization (hexane-ethyl acetate) to give N-[(1RS, 2SR)
-1- [3- (1,1-difluoroethyl) benzyl] -2-
(4-Fluorophenyl) -2-hydroxyethyl] -6
7-Dihydro-5H-benzo [a] cycloheptene-1-carboxamide (0.50 g, 78%) was obtained as colorless crystals. mp 170-171 ° C IRνmax ^KBr (cm ^-1 ): 1639, 1510, 1448, 1385, 1305, 12
22, 1174, 1086 Elemental analysis: C ₂₉ H ₂₈ NO ₂ F ₃ Calculated: C, 72.64; H, 5.89; N, 2.92 Found: C, 72.61; H, 5.91; N, 2.65 ¹ H-NMR ( CDCl ₃ ) δ (ppm) 1.87 (3H, t, J = 18.3 Hz)
1.96-2.04 (2H, m) 2.15-2.21 (2H, m) 2.63-2.67 (2H, m
m) 2.78 (1H, dd, J = 10.8, 14.4 Hz) 3.01 (1H, dd,
J = 4.5, 14.7 Hz) 3.70 (1H, d, J = 3.3 Hz) 4.65-
4.72 (1H, m) 5.03 (1H, t, J = 3.9 Hz) 5.72 (1H, d,
J = 7.8 Hz) 5.90 (1H, dt, J = 5.1, 12.0Hz) 6.16 (1
H, d, J = 11.7 Hz) 6.93 (1H, dd, J = 1.2, 7.5 Hz)
7.04-7.15 (4H, m) 7.25-7.31 (2H, m) 7.34-7.38 (2H, m
m) 7.41-7.46 (2H, m).

Example 361 Tert-butyl (1RS, 2RS) -2-hydroxy-2
-(2-Phenyl-1,3-thiazol-4-yl) -1- [3
-(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl carbamate 1) ethyl 3-oxo-3- (2-phenyl-1,3-thiazol-4-yl) propionate 2-phenyl-1,3 -Thiazole-4-carboxylic acid (1
g, 4.87 mmol) in tetrahydrofuran (10 m
l) N, N'-carbonyldiimidazole (0.8
7g, 5.37 mmol) and stirred at room temperature for 3 hours to prepare an imidazolide solution. Ethyl hydrogen malonate (0.78 g,
5.84 mmol) in tetrahydrofuran (10 ml)
Add magnesium ethoxide (0.34 g, 2.92) to the solution.
Mmol), and the mixture was stirred at room temperature for 1 hour, and then the solvent was concentrated under reduced pressure to obtain a pale yellow amorphous powder. The previously prepared imidazolide solution was added dropwise thereto, and the mixture was stirred at room temperature overnight. Diluted with ethyl acetate, 1M potassium bisulfate,
The extract was washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
4: 1) to give ethyl 3-oxo-3- (2-phenyl)
-1,3-thiazol-4-yl) propionate (1.2
9g, 96%) as colorless crystals. mp 66-68 ℃ IRνmax ^KBr (cm ^-1 ): 3117, 1739, 1693, 1628, 1483, 1
304, 1219, 1153, 1028 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.24, 1.34 (3H, each t, J =
7.0, 7.2 Hz respectively) 4.15 (1.2H, s) 4.21, 4.
28 (2H, each q, J = 6.8, 7.2 Hz respectively) 6.21
(0.4H, s) 7.41-7.49 (3H, m) 7.83 (0.4H, s) 7.93-
7.99 (2H, m) 8.19 (0.6H, s) 12.16 (0.4H, s) 2) Ethyl 3-oxo-3- (2-phenyl-1,3-thiazol-4-yl) -2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propionate 3- (1,1,2,2-tetrafluoroethoxy) benzyl alcohol (5.53 ml, 24.7 mmol) solution in ethyl acetate (50 ml) To triethylamine (5.2
methanesulfonyl chloride (2.1 ml, 27.17 mmol) under ice cooling.
Was added dropwise, and the mixture was stirred as it was for 30 minutes. The precipitated crystals were filtered, and the filtrate was concentrated to obtain mesylate. This was used for the next reaction as it was. A solution of ethyl 3-oxo-3- (2-phenyl-1,3-thiazol-4-yl) propionate (6.80 g, 24.7 mmol) in dimethoxyethane (50 ml) was cooled on ice, and sodium hydride (60%) was added.
%, 0.99 g, 24.7 mmol), and the mixture was stirred under ice-cooling for 30 minutes, and then dimethoxyethane of mesylate (5%) was added.
0 ml) solution and stirred at room temperature overnight. After completion of the reaction, the reaction is quenched with 1N hydrochloric acid, diluted with ethyl acetate,
Washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 10: 1,
5: 1) to give ethyl 3-oxo-3- (2-phenyl)
-1,3-thiazol-4-yl) -2- [3- (1,1,
2,2-Tetrafluoroethoxy) benzyl] propionate (8.65 g, 73%) was obtained as a pale yellow oil. IRνmax ^KBr (cm ^-1 ): 1736, 1691, 1612, 1587, 1487, 14
67, 1444, 1197, 1122 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.12 (3H, t, J = 7.2 Hz) 3.
37 (2H, m) 4.12 (2H, q, J = 7.0 Hz) 4.84 (1H, dd,
J = 7.0, 7.8 Hz) 5.87 (1H, dt, J = 2.8, 53.0Hz) 7.
02-7.06 (1H, m) 7.18-7.32 (3H, m) 7.44-7.51 (3H,
m) 7.94-7.98 (2H, m) 8.19 (1H, s). 3) Ethyl 3-hydroxy-3- (2-phenyl-1,3-
Thiazol-4-yl) -2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propionate Boron hydride was added to an ether suspension (50 ml) of zinc chloride (3.41 g, 25 mmol). Sodium (1.89
g, 50 mmol) at room temperature and stirred for 2 hours. The insolubles were filtered off and the filtrate was added to ethyl 3-oxo-3-
(2-phenyl-1,3-thiazol-4-yl) -2- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] propionate (6.01 g, 12.5 mmol)
Of ether (40 ml) was added under ice-cooling.
Stirred for hours. The reaction was terminated with 1N hydrochloric acid, diluted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1, 4: 1) to give ethyl 3-hydroxy-3.
-(2-phenyl-1,3-thiazol-4-yl) -2- [3
-(1,1,2,2-Tetrafluoroethoxy) benzyl] propionate (4.61 g, 76%) was obtained as a colorless transparent oil. IRνmax ^KBr (cm ^-1 ): 1726, 1612, 1587, 1460, 1302, 1
277, 1197, 1120 ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.96-107 (3H, m) 2.93-3.15
(2H, m) 3.36-3.49 (1H, m) 3.54 (0.74H, d, J = 5.2 H
z) 3.69 (0.26H, d, J = 9.4 Hz) 3.99, 4.01 (2H, eac
hq, J = 6.8, 7.0 Hz) 4.94 (0.26H, dd, J = 5.6, 9.
6 Hz) 5.18-5.23 (0.74H, m) 5.85, 5.89 (1H, each dt,
J = 3.0, 53.0 Hz) 6.99-7.32 (5H, m) 7.39-7.47 (3H,
m) 7.89-7.95 (2H, m). (The ratio of syn to anti was determined to be 2.8: 1 based on the integration ratio of the peaks at 4.94 ppm and 5.18-5.23 ppm.) 4) 3-Hydroxy-3- (2- Ethyl phenyl-1,3-thiazol-4-yl) -2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propionate 3-hydroxy-3- (2-phenyl-1,3 -Thiazol-4-yl) -2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propionate (6.28
g, 13.0 mmol) in tetrahydrofuran-ethanol (20 ml-20 ml) was added 2N sodium hydroxide (17 ml, 34 mmol) at room temperature and stirred at room temperature overnight. After completion of the reaction, the organic solvent was distilled off under reduced pressure.
Diluted with water. The aqueous layer was washed with ether, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and then 3-hydroxy-3- (2-phenyl-1,3-thiazol-4-yl) -2- [3- (1,1,2, 2-Tetrafluoroethoxy) benzyl] propionic acid (5.51 g, 93%) was obtained as a pale yellow oil. IRνmax ^KBr (cm ^-1 ): 250-3300, 1707, 1612, 1587, 145
8, 1278, 1197, 1120 ¹ H-NMR (CDCl ₃ ) δ (ppm) 2.85-3.14 (2H, m) 3.39-3.52
(1H, m) 4.93 (0.33H, d, J = 5.8 Hz) 5.24 (0.66H,
d, J = 4.4 Hz) 5.81, 5.85 (1H, dt, J = 3.0, 53.0 H
z, J = 3.0, 56.0 Hz respectively) 6.98-7.31 (5H,
m) 7.39-7.45 (3H, m) 7.82-7.89 (2H, m). (The ratio of syn to anti was determined to be 2: 1 from the integration ratio of the peaks at 4.93 ppm and 5.24 ppm.) 5) 5- ( 2-phenyl-1,3-thiazol-4-yl)
-4- [3- (1,1,2,2-tetrafluoroethoxy)
Benzyl] -1,3-oxazolidin-2-one 3-hydroxy-3- (2-phenyl-1,3-thiazole-
4-yl) -2- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] propionic acid (5.23 g, 1
1.48 mmol) of tetrahydrofuran (120 m
l) Add triethylamine (2.40 ml, 17.2) to the solution.
2 mmol), diphenylphosphate azide (2.73 m
1, 12.63 mmol) and heated under reflux for 5 hours. The solvent was distilled off and diluted with ethyl acetate. Washed with water, saturated aqueous sodium bicarbonate, and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
3: 1, 1: 1) and purified by 5- (2-phenyl-1,3-
Thiazol-4-yl) -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidin-2-one (4.57 g, 88%) as a pale yellow oil Obtained. IRνmax ^KBr (cm ^-1 ): 3260, 1761, 1612, 1587, 1462, 1
302, 1277, 1197, 1120 ¹ H-NMR (CDCl ₃ ) δ (ppm) 2.33 (0.66H, dd, J = 11.0,
13.8 Hz) 2.71 (0.66H, dd, J = 4.0, 14.0 Hz) 3.01
(0.33H, dd, J = 8.8, 13.8 Hz) 3.26 (0.33H, dd, J =
5.0, 13.4 Hz) 4.27-4.51 (1H, m) 5.20 (0.66H, m)
5.42 (0.33H, d, J = 5.5 Hz) 5.30-5.50 (0.33H, br)
5.61-5.65 (0.25H, m) 5.87-5.91 (0.5H, m) 6.00 (0.66
(H, d, J = 8.2 Hz) 6.13-6.16 (0.25H, m) 6.95-7.19
(3H, m) 7.19-7.47 (5H, m) 7.90-7.95 (2H, m). 6) tert-butyl (4RS, 5RS) -2-oxo-
5- (2-phenyl-1,3-thiazol-4-yl) -4-
[3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine-3-carboxylate 5- (2-phenyl-1,3-thiazol-4-yl) -4-
[3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidin-2-one (4.43 g,
9.79 mmol) in acetonitrile (50 ml) was added to a solution of di-tert-butyl-dicarbonate (2.58 g,
11.8 mmol) and 4- (dimethylamino) pyridine (0.12 g, 0.98 mmol) were added in that order, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, the residue was purified by flash column chromatography (hexane: ethyl acetate: toluene = 4: 1: 1), and tert-butyl (4R
S, 5RS) -2-Oxo-5- (2-phenyl-1,3-thiazol-4-yl) -4- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -1, 3-oxazolidine
-3-Carboxylate (3.40 g, 63%) was obtained as a pale yellow oil. Thin (4RS, 5RS) body (more polar) IRνmax ^KBr (cm ^-1 ): 1824, 1724, 1612, 1587, 1489, 1
464, 1356, 1116 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.49 (9H, s) 2.78 (1H, dd,
J = 8.2, 14.0 Hz) 2.94 (1H, dd, J = 4.6, 13.8 Hz)
4.98-5.08 (1H, m) 5.79-5.83 (1H, m) 5.82 (1H, dt,
J = 3.0, 53.0 Hz) 6.69 (2H, d, J = 7.4 Hz) 6.81 (1
H, d, J = 8.0 Hz) 6.99-7.07 (1H, m) 7.15-7.29 (1H,
m) 7.34-7.43 (3H, m) 7.68-7.73 (2H, m). Anti (4RS, 5SR) form (less polar) IRνmax ^KBr (cm ^-1 ): 1871, 1724, 1612, 1587, 1489, 1
464, 1356, 1116 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.59 (9H, s) 3.06 (1H, dd,
J = 8.8, 13.6 Hz) 3.44 (1H, dd, J = 4.2, 14.0 Hz)
4.73-4.81 (1H, m) 5.28 (1H, dd, J = 1.2, 3.0 Hz)
5.90 (1H, dt, J = 2.8, 53.0 Hz) 7.18-7.25 (4H, m)
7.34-7.45 (4H, m) 7.82-7.87 (2H, m). 7) tert-butyl (1RS, 2RS) -2-hydroxy-2- (2-phenyl-1,3-thiazol-4-yl)-
1- [3- (1,1,2,2-tetrafluoroethoxy)
[Benzyl] ethylcarbamate tert-butyl (4RS, 5RS) -2-oxo-5-
(2-phenyl-1,3-thiazol-4-yl) -4- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] -1,3-oxazolidine-3-carboxylate (3.17 g, 5.74 mmol) in methanol (60
1N sodium hydroxide (6.9 ml,
6.9 mmol) and stirred at room temperature overnight. After dilution with water, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by recrystallization (hexane-ethyl acetate) and tert-butyl (1RS, 2RS) -2-hydroxy-2- (2-phenyl-1,3-thiazol-4-yl)-.
1- [3- (1,1,2,2-tetrafluoroethoxy)
[Benzyl] ethyl carbamate (1.72 g, 57%)
Was obtained as colorless crystals. mp 127-128 ℃ IRνmax ^KBr (cm ^-1 ): 3341, 1691, 1612, 1587, 1508, 1
558, 1367, 1278, 1195,1167, 1122 ¹ H-NMR (CD ₃ OD) δ (ppm): 1.39 (9H, s) 2.80 (1H, d
d, J = 6.0, 14.1 Hz) 2.92 (1H, dd, J = 8.7, 14.1 H
z) 3.96 (1H, d, J = 6.0 Hz) 4.29-4.34 (1H, m) 4.97
(1H, s) 5.22 (1H, d, J = 5.8 Hz) 5.88 (1H, dt, J =
2.7, 53.7 Hz) 7.07 (2H, s) 7.12 (1H, d, J = 7.2 H
z) 7.24-7.30 (2H, m) 7.44-7.46 (3H, m) 7.95-7.98 (2
H, m).

Example 362 4-Fluoro-N-｛(1RS, 2RS) -2-hydroxy-
2- (2-phenyl-1,3-thiazol-4-yl) -1-
[3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -1-naphthamide 1) (1RS, 2RS) -2-amino-1- (2-phenyl-1,3-thiazole-4) -Il) -3- [3- (1,1,
2,2-tetrafluoroethoxy) phenyl] -1-propanol tert-butyl (1RS, 2RS) -2-hydroxy-2
-(2-Phenyl-1,3-thiazol-4-yl) -1- [3
To a solution of-(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl carbamate (1.67 g, 3.17 mmol) in chloroform (20 ml) was added trifluoroacetic acid (20 ml), and the mixture was stirred at room temperature for 1 hour. . After concentration under reduced pressure, water was added to the residue, and the mixture was basified with saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give (1RS, 2RS) -2-amino-1- (2-phenyl-1,3-thiazol-4-yl)-.
3- [3- (1,1,2,2-tetrafluoroethoxy)
[Phenyl] -1-propanol (1.17 g, 87%) was obtained as colorless crystals. mp 128-130 ° C IRνmax ^KBr (cm ^-1 ): 3300, 1676, 1462, 1199, 1126 ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.76 (1H, dd, J = 7.8, 1
4.1 Hz) 3.00 (1H, dd, J = 6.3, 14.1 Hz) 3.77-3.83
(1H, m) 4.93 (1H, dd, J = 0.9, 4.2 Hz) 6.27 (1H, d
t, J = 3.0, 52.5 Hz) 7.07 (1H, d, J = 8.1 Hz) 7.16
-7.20 (2H, m) 7.33 (1H, t, J = 7.8 Hz) 7.46-7.49
(4H, m) 7.93-7.97 (2H, m). 2) 4-Fluoro-N-｛(1RS, 2RS) -2-hydroxy-2- (2-phenyl-1,3-thiazol-4-yl) -1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -1-naphthamide (1RS, 2RS) -2-amino-1- (2-phenyl-1,1
3-thiazol-4-yl) -3- [3- (1,1,2,2-
4-Fluoronaphthalene-1-carboxylic acid (133 mg, 0.70 mmol) in a solution of tetrafluoroethoxy) phenyl] -1-propanol (311 mg, 0.73 mmol) in N, N-dimethylformamide (10 ml),
1-hydroxybenzotriazole monohydrate (112m
g, 0.73 mmol) and finally 1-ethyl-3-
(3-Dimethylaminopropyl) carbodiimide hydrochloride (140 mg, 0.73 mmol) was added, and the mixture was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1, 1: 2),
Then, it is purified by recrystallization (hexane-ethyl acetate) and
Fluoro-N-｛(1RS, 2RS) -2-hydroxy-2-
(2-phenyl-1,3-thiazol-4-yl) -1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl} -1-naphthamide (217 mg, 52%)
Was obtained as colorless crystals. mp 148-150 ° C IRνmax ^KBr (cm ^-1 ): 3258, 1641, 1514, 1462, 1197, 1
124 Elemental analysis: C ₃₁ H ₂₃ N ₂ O ₃ SF ₅ Calculated: C, 62.20; H, 3.87; N, 4.68 Found: C, 62.06; H, 3.78; N, 4.63 ¹ H-NMR (CDCl ₃ ) δ (ppm) 2.95 (1H, dd, J = 6.0, 13.6
Hz) 3.13 (1H, dd, J = 5.6, 14.0 Hz) 3.95 (1H, d, J
= 6.0 Hz) 4.89-5.02 (1H, m) 5.08-512 (1H, m) 5.87
(1H, dt, J = 2.8, 53.0 Hz) 6.99-7.08 (4H, m) 7.21-
7.59 (8H, m) 7.81-7.86 (2H, m) 8.09-8.15 (2H, m).

Example 363 N-{(1RS, 2RS) -2-hydroxy-2- (2-phenyl-1,3-thiazol-4-yl) -1- [3- (1,
1,2,2-tetrafluoroethoxy) benzyl] ethyl} -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (1RS, 2RS) -2-amino-1- (2-phenyl-1 ,
3-thiazol-4-yl) -3- [3- (1,1,2,2-
Tetrafluoroethoxy) phenyl] -1-propanol (310 mg, 0.73 mmol) in acetonitrile (10 ml) was treated with 6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (132 mg,
0.70 mmol), 1-hydroxybenzotriazole monohydrate (112 mg, 0.73 mmol) was added,
Finally, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (140 mg, 0.73 mmol)
Was added and stirred at room temperature for 3 days. Diluted with ethyl acetate,
The extract was washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
5: 1, 2: 1) and then purified by recrystallization (hexane-ethyl acetate) to give N-{(1RS, 2RS) -2-hydroxy-2- (2-phenyl-1,3-thiazole-4). -Il)-
1- [3- (1,1,2,2-tetrafluoroethoxy)
Benzyl] ethyl} -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (247 m
g, 59%) as colorless crystals. mp 137-138 ° C Elemental analysis: C ₃₂ H ₂₈ N ₂ O ₃ SF ₅ Calculated: C, 64.42; H, 4.73; N, 4.70 Found: C, 64.34; H, 4.64; N, 4.55 IRνmax ^KBr ( cm ^-1 ): 3265, 1641, 1512, 1304, 1195, 11
22 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.96-2.05 (2H, m) 2.12-2.22
(2H, m) 2.64-2.70 (2H, m) 3.00 (1H, dd, J = 6.2,
14.2 Hz) 3.14 (1H, dd, J = 8.6, 13.8 Hz) 4.34 (1H,
d, J = 5.8 Hz) 4.75-4.89 (1H, m) 5.08 (1H, dd, J
= 2.6, 5.4 Hz) 5.88 (1H, dt, J = 3.0, 53.0 Hz) 5.9
4 (1H, dt, J = 5.6, 11.6 Hz) 6.36 (1H, d, J = 11.8
Hz) 6.50 (1H, d, J = 8.0 Hz) 7.04-7.34 (8H, m) 7.4
2-7.47 (3H, m) 7.89-7.93 (2H, m).

Example 364 N-[(1RS, 2SR) -1- (4-tert-butylbenzyl) -2- (4-fluorophenyl) -2-hydroxyethyl] -5-fluoro-1-naphthamide (1RS , 2RS) -2-Amino-3- [4- (tert-butyl) benzyl] -1- (4-fluorophenyl) propan-1-ol (0.22 g, 0.70 mmol) N,
To a solution of N-dimethylformamide (10 ml) was added 5-fluoronaphthalene-1-carboxylic acid (122 mg, 0.64 mmol) and 1-hydroxybenzotriazole monohydrate (108 mg, 0.70 mmol). -
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (134 mg, 0.70 mmol) was added,
Stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2:
1) Then, the product was purified by recrystallization (hexane-ethyl acetate) to give N-[(1RS, 2SR) -1- (4-tert-butylbenzyl) -2- (4-fluorophenyl) -2-hydroxyethyl. ] -5-Fluoro-1-naphthamide (153m
g, 50%) as colorless crystals. mp 148-149 ° C. Elemental analysis C ₃₀ H ₂₉ NO ₂ F ₂ Calculated: C, 76.09; H, 6.17 ; N, 2.96 Found: C, 76.02; H, 6.16 ; N, 2.78 IRνmax KBr (cm - ¹ ): 3267, 1637, 1508, 1412, 1244, 1
224 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.31 (9H, s) 2.73 (1H, dd,
J = 10.8, 14.4 Hz) 3.03 (1H, dd, J = 4.5, 14.4 Hz)
3.82 (1H, d, J = 2.6 Hz) 4.77-4.84 (1H, m) 5.06-5.
08 (1H, m) 5.84 (1H, d, J = 5.6 Hz) 7.04-7.17 (6H,
m) 7.26-7.57 (6H, m) 7.59 (1H, d, J = 5.6 Hz) 8.1
4 (1H, d, J = 5.4 Hz).

Example 365 N-[(1RS, 2SR) -1- (4-tert-butylbenzyl) -2- (4-fluorophenyl) -2-hydroxyethyl] -5-chloro-1-naphthamide (1RS , 2RS) -2-Amino-3- [4- (tert-butyl) benzyl] -1- (4-fluorophenyl) propan-1-ol (0.34 g, 1.1 mmol) N, N
5-Chloronaphthalene-1-carboxylic acid (208 mg, 1.0 mmol) and 1-hydroxybenzotriazole monohydrate (1
70 mg, 1.1 mmol) and finally 1-ethyl-
3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (210 mg, 1.1 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1), and then
The product was purified by recrystallization (hexane-ethyl acetate) and N-[(1R
S, 2SR) -1- (4-tert-butylbenzyl) -2-
(4-Fluorophenyl) -2-hydroxyethyl] -5-
Chloro-1-naphthamide (265 mg, 57%) was obtained as colorless crystals. Elemental analysis: C ₃₀ H ₂₉ NO ₂ ClF ₂ Calculated: C, 73.53; H, 5.97; N, 2.86 Found: C, 73.68; H, 5.93; N, 2.75 IRνmax ^KBr (cm ^-1 ): 3261, 1637, 1508, 1222, 1157 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.31 (9H, s) 2.72 (1H, dd,
J = 10.6, 14.2 Hz) 3.03 (1H, dd, J = 4.4, 14.4 Hz)
3.73 (1H, d, J = 3.6 Hz) 4.72-4.86 (1H, m) 5.03-5.
07 (1H, m) 5.83 (1H, d, J = 8.4 Hz) 7.01-7.13 (5H,
m) 7.15-7.47 (6H, m) 7.56 (1H, dd, J = 1.0, 7.6 H
z) 7.70 (1H, d, J = 8.8 Hz) 8.31 (1H, d, J = 8.4 H
z).

Example 366 N-[(1RS, 2SR) -1- [3- (neopentyloxy) benzyl] -2- (3-chlorophenyl) -2-hydroxyethyl] -4-fluoro-1-naphthamide 1 ) Methyl 3- (neopentyloxy) benzoate Methyl 3-hydroxybenzoate (7.68 g, 5
0.5 mmol) of N, N-dimethylformamide (1
00 ml) solution and potassium carbonate (13.96 g, 101
Mmol) and neopentyl iodide (10 g, 50.5 mmol) were added and stirred at 100 ° C. overnight. The mixture was diluted with ethyl acetate and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
20: 1 and 10: 1) to give methyl 3- (neopentyloxy) benzoate (4.69 g, 42%) as a clear, colorless oil. IRνmax ^KBr (cm ^-1 ): 1724, 1601, 1587, 1489, 1477, 1
444, 1400, 1365, 1292,1278, 1224 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.04 (9H, s) 3.63 (2H, s) 3.
91 (3H, s) 7.10 (1H, ddd, J = 0.8, 2.6, 8.2 Hz) 7.
32 (1H, t, J = 7.8 Hz) 7.54-7.56 (1H, m) 7.60 (1H,
dt, J = 1.4, 7.8 Hz). 2) 3- (neopentyloxy) benzyl alcohol methyl 3- (neopentyloxy) benzoate (4.
51 g, 20.3 mmol) of tetrahydrofuran (1
Lithium aluminum hydride (1.93 g, 50.75 mmol) was added little by little to the solution under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water (2 ml), a 15% aqueous sodium hydroxide solution (2 ml) and water (6 ml) were slowly added in that order under ice cooling, and the resulting solid was filtered through celite.
After washing well with ethyl acetate, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 3- (neopentyloxy) benzyl alcohol (3.81 g, 97%) as a colorless transparent oil. IRνmax ^KBr (cm ^-1 ): 3231, 1601, 1585, 1489, 1477, 14
48, 1400, 1363, 1259,1155 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.03 (9H, s) 1.81 (1H, br)
3.59 (2H, s) 4.65 (2H, s) 6.80-6.93 (3H, m) 7.25 (1
H, t, J = 7.6 Hz). 3) 6-ethyl 2- [3- (neopentyloxy) benzyl] -3- (3-chlorophenyl) -3-oxopropionate 3- (neopentyloxy) benzyl Alcohol (3.
76 g, 19.4 mmol) of ethyl acetate (40 ml)
Triethylamine (4.06 ml, 29.1 mmol) was added to the solution, and methanesulfonyl chloride (1.65 ml, 21.34 mmol) was added dropwise under ice-cooling, followed by stirring for 45 minutes. The precipitated crystals were filtered, and the filtrate was concentrated to obtain mesylate. This was used for the next reaction as it was. A solution of ethyl 3- (3-chlorophenyl) -3-oxopropionate (4.40 g, 19.4 mmol) in dimethoxyethane (40 ml) was ice-cooled and sodium hydride (60%, 0.78 g, 19.30 g). 4 mmol), and the mixture was stirred under ice-cooling for 30 minutes, and then a solution of mesylate in dimethoxyethane (30 ml) was added, followed by stirring at room temperature overnight. After completion of the reaction, the reaction was quenched with 1N hydrochloric acid, diluted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1, 7: 1), and ethyl 2- [3- (neopentyloxy) benzyl] -3- (3-chlorophenyl) -3-oxopro. Pionate (7.11 g, 91%)
Was obtained as a pale yellow oil. IRνmax ^KBr (cm ^-1 ): 1736, 1691, 1585, 1475, 1448, 1
365, 1255, 1226, 1159 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.01 (9H, s) 1.14 (3H, t, J
= 7.2 Hz) 3.28 (2H, d, J = 7.4 Hz) 3.52 (2H, s)
4.12 (2H, q, J = 6.8 Hz) 4.55 (1H, t, J = 7.4Hz)
6.69-6.78 (3H, m) 7.11-7.18 (1H, m) 7.33-7.41 (1H, m
m) 7.49-7.55 (1H, m) 7.82 (1H, dt, J = 1.0, 7.6 H
z) 7.90-7.92 (1H, m). 4) Ethyl (2RS, 3RS) -2- [3- (neopentyloxy) benzyl] -3- (3-chlorophenyl) -3
-Hydroxypropionate Sodium borohydride (2.6) was added to an ether suspension (60 ml) of zinc chloride (4.75 g, 34.8 mmol).
(4 g, 69.6 mmol) at room temperature and stirred for 2 hours. The insolubles were filtered off and the filtrate was added with ethyl 2- [3-
(Neopentyloxy) benzyl] -3- (3-chlorophenyl) -3-oxopropionate (2.64 g, 6
9.6 mmol) in ether (40 ml)
Stirred at room temperature for 1 hour. Terminate the reaction with 1N hydrochloric acid,
The mixture was diluted with ethyl acetate and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1, 3: 1) to give ethyl (2R
S, 3RS) -2- [3- (Neopentyloxy) benzyl] -3- (3-chlorophenyl) -3-hydroxypropionate (5.82 g, 81%) was obtained as a colorless transparent oil. IRνmax ^KBr (cm ^-1 ): 3472, 1726, 1599, 1583, 1477, 1
448, 1400, 1257, 1159 ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.98 (3H, t, J = 7.4 Hz) 1.
01 (9H, s) 2.84-2.99 (3H, m) 3.10 (1H, d, J = 2.4
Hz) 3.93 (2H, q, J = 7.4 Hz) 5.01 (1H, t, J = 3.0 H
z) 6.61-6.72 (3H, m) 7.08-7.15 (1H, m) 7.25-7.28
(3H, m) 7.41 (1H, s). 5) (4RS, 5SR) -4- [3- (neopentyloxy) benzyl] -5- (3-chlorophenyl) -1,3-
Oxazolidin-2-one Ethyl (2RS, 3RS) -2- [3- (neopentyloxy) benzyl] -3- (3-chlorophenyl) -3-hydroxypropionate (5.71 g, 14.1 mmol) Tetrahydrofuran-ethanol (15ml-15
2N sodium hydroxide (15 m
1, 30 mmol) and stirred at room temperature overnight. After completion of the reaction, the organic solvent was distilled off under reduced pressure, the aqueous layer was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a colorless transparent oil. The oil obtained above in tetrahydrofuran (150
ml) solution in triethylamine (2.95 ml, 21.
15 mmol), azide diphenylphosphate (3.35 m
1, 15.51 mmol) and heated to reflux for 4 hours. The solvent was distilled off, diluted with ethyl acetate, and washed with water, saturated aqueous sodium hydrogen carbonate and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Recrystallization from hexane-ethyl acetate gave (4RS, 5SR) -4- [3-
(Neopentyloxy) benzyl] -5- (3-chlorophenyl) -1,3-oxazolidin-2-one (4.15
g, 79%) as colorless crystals. mp 141-142 ℃ IRνmax ^KBr (cm ^-1 ): 3248, 1763, 1601, 1583, 1477, 14
00, 1363 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.02 (9H, s) 2.15 (1H, dd,
J = 10.8, 13.2 Hz) 2.29 (1H, dd, J = 4.2, 14.1 Hz)
3.54 (2H, s) 4.21-4.28 (1H, m) 4.99 (1H, s) 5.76
(1H, d, J = 7.8 Hz) 6.57-6.62 (2H, m) 6.76 (1H, d
d, J = 2.1, 7.8 Hz) 7.16-7.21 (1H, m) 7.26-7.28 (1
H, m) 7.34-7.39 (3H, m). 6) (1RS, 2SR) -2-amino-3- [3- (neopentyloxy) phenyl] -1- (3-chlorophenyl) -1-propanol ( 4RS, 5SR) -4- [3- (neopentyloxy)
Benzyl] -5- (3-chlorophenyl) -1,3-oxazolidin-2-one (4.0 g, 10.7 mmol) in ethanol (80 ml) was treated with an 8N aqueous sodium hydroxide solution (6.7 ml, 53.50 ml). (5 mmol) and heated under reflux for 5 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate), and (1R
(S, 2SR) -2-Amino-3- [3- (neopentyloxy) phenyl] -1- (3-chlorophenyl) -1-propanol (2.95 g, 79%) was obtained as colorless crystals. mp 115-116 ℃ IRνmax ^KBr (cm ^-1 ): 3300, 1599, 1583, 1477, 1448, 1
400, 1363, 1255, 1159,1053 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.02 (9H, s) 2.29 (1H, dd,
J = 10.4, 13.6 Hz) 2.72 (1H, dd, J = 3.0, 13.6 Hz)
3.30 (1H, dt, J = 3.8, 14.4 Hz) 3.55 (2H, s) 4.66
(1H, d, J = 4.8 Hz) 6.67-6.77 (3H, m) 7.14-7.30
(4H, m) 7.41 (1H, s). 7) N-[(1RS, 2SR) -1- [3- (neopentyloxy) benzyl] -2- (3-chlorophenyl) -2-
Hydroxyethyl] -4-fluoro-1-naphthamide (1RS, 2SR) -2-amino-3- [3- (neopentyloxy) phenyl] -1- (3-chlorophenyl) -1-
N in propanol (0.30 g, 0.86 mmol)
To a solution of N-dimethylformamide (5 ml) was added 4-fluoronaphthalene-1-carboxylic acid (0.17 g, 0.90 mmol) and 1-hydroxybenzotriazole monohydrate (0.138 g, 0.90 mmol). And finally one
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.173 g, 0.90 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate), and N-[(1RS, 2SR)-
1- [3- (neopentyloxy) benzyl] -2- (3-
Chlorophenyl) -2-hydroxyethyl] -4-fluoro
-1-Naphthamide (0.354 g, 79%) was obtained as colorless crystals. mp 165-166 ° C IRνmax ^KBr (cm ^-1 ): 3263, 1639, 1599, 1583, 1518, 14
77, 1448, 1400, 1259 ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.99 (9H, s) 2.73 (1H, dd,
J = 11.0, 14.4 Hz) 3.01 (1H, dd, J = 4.0, 14.4 Hz)
3.52 (2H, dd, J = 8.6, 11.4 Hz) 4.17 (1H, br) 4.7
0-4.81 (1H, m) 5.09 (1H, s) 5.87 (1H, d, J = 7.2 H
z) 6.74-6.83 (3H, m) 7.00 (1H, dd, J = 7.6, 9.8 H
z) 7.18-7.36 (5H, m) 7.41-7.57 (3H, m) 7.80 (1H, d,
J = 7.6 Hz) 8.07 (1H, d, J = 7.6 Hz).

Example 367 N-[(1RS, 2SR) -1- [3- (neopentyloxy) benzyl] -2- (3-chlorophenyl) -2-hydroxyethyl] -5-chloro-1-naphthamide ( 1RS, 2SR) -2-amino-3- [3- (neopentyloxy) phenyl] -1- (3-chlorophenyl) -1-
N in propanol (0.30 g, 0.86 mmol)
To a solution of N-dimethylformamide (5 ml) was added 5-chloronaphthalene-1-carboxylic acid (0.186 g, 0.90 mmol) and 1-hydroxybenzotriazole monohydrate (0.138 g, 0.90 mmol). And finally one
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.173 g, 0.90 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate), and N-[(1RS, 2SR)-
1- [3- (neopentyloxy) benzyl] -2- (3-
Chlorophenyl) -2-hydroxyethyl] -5-chloro-
1-Naphthamide (0.350 g, 76%) was obtained as colorless crystals. mp 142-143 ℃ IRνmax ^KBr (cm ^-1 ): 3252, 1637, 1518, 1477, 1448, 1
398, 1363, 1255, 1159,1059, 1022 ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.99 (9H, s) 2.71 (1H, dd,
J = 11.0, 14.4 Hz) 2.98 (1H, dd, J = 4.2, 14.4 Hz)
3.51 (2H, dd, J = 8.8, 11.6 Hz) 4.05 (1H, br) 4.7
0-4.79 (1H, m) 5.04 (1H, d, J = 3.4 Hz) 5.97 (1H, m
d, J = 7.6 Hz) 6.72-6.81 (3H, m) 7.16-7.62 (10H,
m) 8.28 (1H, d, J = 8.4 Hz).

Example 368 N-[(1RS, 2SR) -1- [3- (neopentyloxy) benzyl] -2- (3-chlorophenyl) -2-hydroxyethyl] -6,7-dihydro-5H- Benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-3- [3- (neopentyloxy) phenyl] -1- (3-chlorophenyl) -1-
N in propanol (0.40 g, 0.86 mmol)
6,7-Dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (0.17 g, 0.90 mmol) and 1-hydroxybenzotriazole monohydrate (0.1 ml) in N-dimethylformamide (5 ml) solution. 138 g, 0.90 mmol) and finally 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.173 g,
0.90 mmol) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, 0: 1) and then recrystallized (hexane-ethyl acetate) to give N-[(1RS, 2
SR) -1- [3- (Neopentyloxy) benzyl] -2
-(3-chlorophenyl) -2-hydroxyethyl] -6
7-Dihydro-5H-benzo [a] cycloheptene-1-carboxamide (0.174 g, 39%) was obtained as colorless crystals. mp 128-129 ° C IRνmax ^KBr (cm ^-1 ): 3265, 1633, 1599, 1585, 1514, 14
77, 1450, 1363, 1255,1159 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.01 (9H, s) 1.99-2.01 (1H,
m) 2.14-2.20 (1H, m) 2.63-2.73 (3H, m) 2.94 (1H, d
d, J = 3.8, 13.6 Hz) 3.54 (2H, s) 4.33 (1H, d, J =
4.4 Hz) 4.65 (1H, m) 5.03 (1H, br) 5.71 (1H, d, J
= 6.6 Hz) 5.90-6.01 (1H, m) 6.26 (1H, d, J = 11.6
(Hz) 6.71-6.78 (3H, m) 7.02-7.30 (7H, m).

Example 369 N-[(1RS, 2SR) -1- [3- (tert-butyl) benzyl] -2- (3-chlorophenyl) -2-hydroxyethyl] -4-fluoro-1-naphthamide 1 3-tert-butylphenyltrifluoromethanesulfonate N-ethyldiisopropylamine (17.5 ml, 100 mmol) in a solution of 3-tert-butylphenol 1 (15 g, 100 mmol) in dichloromethane (300 ml), N-phenyltrifluoromethanesulfonimide (44.7 g, 125 mmol) and stirred at room temperature overnight. The dichloromethane was distilled off under reduced pressure, diluted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3
0: 1) to give 3-tert-butylphenyltrifluoromethanesulfonate (7.17 g, 25%) as a clear, colorless oil. IRνmax ^KBr (cm ^-1 ): 1612, 1577, 1489, 1423, 1246, 12
15, 1145, 925 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.33 (9H, s) 7.06-7.10 (1H,
m) 7.24-7.25 (1H, m) 7.33-7.42 (2H, m). 2) 3-tert-butylbenzylbenzonitrile acetonitrile of 3-tert-butylphenyltrifluoromethanesulfonate (6.17 g, 21.9 mmol) (80 ml) solution in sodium cyanide (2.15
g, 43.8 mmol), copper iodide (0.42 g, 2.
19 mmol) and tetrakis (triphenylphosphine) palladium (1.27 g, 1.1) under a nitrogen stream.
(0 mmol) and heated to reflux for 5 hours. After dilution with ethyl acetate, insolubles were filtered through celite, and the filtrate was washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ether = 1: 0, 20: 1),
To give 3-tert-butylbenzylbenzonitrile (4.13 g) as a colorless transparent oil. Although this substance contained impurities, it was used for the next reaction as it was. IRνmax ^KBr (cm ^-1 ): 2229, 1599, 1579, 1485, 1417, 1
365, 1273, 1113 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.32 (9H, s) 7.33-7.35 (2H,
m) 7.39-7.50 (1H, m) 7.60-7.66 (1H, m). 3) 3-tert-butylbenzoic acid 3-tert-butylbenzylbenzonitrile (4.13
g, 21.9 mmol) in water (80 ml) was added with sodium hydroxide (2.19 g, 54.8 mmol) and heated under reflux overnight. After completion of the reaction, the reaction mixture was diluted with water, and the aqueous layer was washed with ether. Then, the aqueous layer was acidified with 6N hydrochloric acid and extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate,
After filtration and concentration under reduced pressure, 3-tert-butylbenzoic acid (3.
23 g, 83% in 2 steps) were obtained as colorless crystals. mp 96-97 ℃ IRνmax ^KBr (cm ^-1 ): 2500-3300, 1693, 1604, 1585, 144
0, 1412, 1286, 1259 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.36 (9H, s) 7.41 (1H, t,
J = 7.5 Hz) 7.65 (1H, ddd, J = 1.5, 2.1, 7.8 Hz)
7.94 (1H, dt, J = 1.5, 7.8 Hz) 8.16 (1H, t, J = 1.8
4) 3-tert-butylbenzyl alcohol A solution of lithium aluminum hydride (1.38 g, 36.2 mmol) in ether suspension (40 ml) was 3-tert-butylbenzyl alcohol.
A solution of butylbenzoic acid (3.13 g, 17.6 mmol) in ether (40 m) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water (1.38 ml), 15% aqueous sodium hydroxide solution (1.38 ml), water (4.2 m)
1) was slowly added dropwise under ice-cooling. The resulting solid was filtered through celite and washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1, 4: 1) to give 3-t
tert-butylbenzyl alcohol (2.59 g, 90
%) As a clear, colorless oil. IRνmax ^KBr (cm ^-1 ): 3277, 1606, 1489, 1363, 1275, 12
03, 1016 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.32 (9H, s) 1.85 (1H, s) 4.
66 (2H, s) 7.14-7.19 (1H, m) 7.29-7.38 (3H, m). 5) Ethyl 2- [3- (tert-butyl) benzyl]-
3- (3-chlorophenyl) -3-oxopropionate 3-tert-butylbenzyl alcohol (2.50 g,
Triethylamine (3.18 ml, 22.8 mmol) was added to a solution of 15.2 mmol) in ethyl acetate (30 ml), and methanesulfonyl chloride (1.29 mmol) was added under ice-cooling.
1, 16.72 mmol) was added dropwise, followed by stirring for 1 hour. The precipitated crystals were filtered, and the filtrate was concentrated to obtain mesylate. This was used for the next reaction as it was. A solution of ethyl 3- (3-chlorophenyl) -3-oxopropionate (3.45 g, 15.2 mmol) in dimethoxyethane (30 ml) was cooled on ice, and sodium hydride (60 ml) was added.
%, 0.61 g, 15.2 mmol), and the mixture was stirred under ice-cooling for 30 minutes, and then dimethoxyethane of mesylate (2
5 ml) solution and stirred at room temperature overnight. After completion of the reaction, the reaction is quenched with 1N hydrochloric acid, diluted with ethyl acetate,
Washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 10: 1,
8: 1) to give ethyl 2- [3- (tert-butyl) benzyl] -3- (3-chlorophenyl) -3-oxopropionate (5.01 g, 88%) as a pale yellow oil. Was. IRνmax ^KBr (cm ^-1 ): 1739, 1691, 1572, 1475, 1423, 1
365, 1228 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.13 (3H, t, J = 7.0 Hz) 1.
25 (9H, s) 3.32 (2H, dd, J = 2.2, 7.8 Hz) 4.12 (2
H, dq, J = 1.8, 7.4 Hz) 4.55 (1H, t, J = 7.4Hz) 6.
98-7.03 (1H, m) 7.18-7.21 (3H, m) 7.29-7.39 (1H, m
m) 7.48-7.53 (1H, m) 7.77 (1H, dt, J = 1.6, 7.8 Hz)
7.85-7.87 (1H, m). 6) Ethyl (2RS, 3RS) -2- [3- (tert-
Butyl) benzyl] -3- (3-chlorophenyl) -3-hydroxypropionate Sodium borohydride (2.0 ml) was added to an ether suspension (50 ml) of zinc chloride (3.60 g, 26.4 mmol).
g, 52.8 mmol) at room temperature and stirred for 2 hours. The insolubles were filtered off and the filtrate was added with ethyl 2- [3-
(Tert-butyl) benzyl] -3- (3-chlorophenyl) -3-oxopropionate (4.91 g, 13.2)
(Mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was terminated with 1N hydrochloric acid, diluted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1, 3: 1) to give ethyl (2RS, 3
RS) -2- [3- (tert-butyl) benzyl] -3-
(3-Chlorophenyl) -3-hydroxypropionate (4.16 g, 82%) was obtained as a clear, colorless oil. IRνmax ^KBr (cm ^-1 ): 3456, 1728, 1599, 1477, 1373, 13
46, 1180, 1032 ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.92 (3H, t, J = 7.0 Hz) 1.
27 (9H, s) 2.88-3.02 (3H, m) 3.14 (1H, d, J = 3.0
Hz) 3.88 (2H, q, J = 7.4 Hz) 4.99-5.01 (1H, m) 6.86
-6.91 (1H, m) 7.07 (1H, s) 7.15-7.18 (2H, m) 7.25-
7.27 (3H, m) 7.41 (1H, s). 7) (4RS, 5SR) -4- [3- (tert-butyl) benzyl] -5- (3-chlorophenyl) -1,3-oxazolidine-2- On ethyl (2RS, 3RS) -2- [3- (tert-butyl) benzyl] -3- (3-chlorophenyl) -3-hydroxypropionate (4.05 g, 10.8 mmol)
Of tetrahydrofuran-ethanol (10ml-10m
l) Add 2N sodium hydroxide (11m
1,22 mmol) and stirred at room temperature overnight. After completion of the reaction, the organic solvent was distilled off under reduced pressure, the aqueous layer was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a colorless transparent oil. The oil obtained above in tetrahydrofuran (100
ml) solution in triethylamine (2.26 ml, 16.
2 mmol), azide diphenylphosphate (2.56 m
1, 11.88 mmol) and heated to reflux for 4 hours. The solvent was distilled off, diluted with ethyl acetate, and washed with water, saturated aqueous sodium hydrogen carbonate and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Recrystallization from hexane-ethyl acetate gave (4RS, 5SR) -4- [3-
(Tert-butyl) benzyl] -5- (3-chlorophenyl) -1,3-oxazolidin-2-one (2.47 g, 6
0%) as colorless crystals. mp 136-137 ℃ IRνmax ^KBr (cm ^-1 ): 3263, 1763, 1601, 1477, 1433, 13
63, 1234 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.28 (9H, s) 2.20 (1H, dd,
J = 11.1, 13.8 Hz) 2.32 (1H, dd, J = 3.9, 13.8 Hz)
4.23-4.30 (1H, m) 4.99 (1H, s) 5.77 (1H, d, J = 8.
1 Hz) 6.85 (1H, d, J = 7.2 Hz) 7.01 (1H, s) 7.19-
7.31 (3H, m) 7.34-7.40 (3H, m). 8) (1RS, 2SR) -2-amino-3- [3- (te
rt-butyl) phenyl] -1- (3-chlorophenyl)-
1-propanol (4RS, 5SR) -4- [3- (tert-butyl) benzyl] -5- (3-chlorophenyl) -1,3-oxazolidin-2-one (2.36 g, 6.86 mmol) An 8 N aqueous sodium hydroxide solution (4.3 ml, 34.3 mmol) was added to an ethanol (60 ml) solution, and the mixture was heated under reflux for 5 hours. After completion of the reaction, ethanol was distilled off under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give (1RS, 2SR) -2-amino-
3- [3- (tert-butyl) phenyl] -1- (3-chlorophenyl) -1-propanol (1.21 g, 55%)
Was obtained as colorless crystals. mp 102-103 ℃ IRνmax ^KBr (cm ^-1 ): 3063, 1597, 1576, 1476, 1429, 1
363, 1199 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.30 (9H, s) 2.32
(1H, dd, J = 10.4, 13.6 Hz) 2.75 (1H, dd, J = 3.2,
13.8 Hz) 3.31 (1H, dt, J = 4.0, 9.6 Hz) 4.68 (1H,
d, J = 4.8 Hz) 6.94-6.96 (1H, m) 7.13 (1H, s) 7.21
-7.31 (5H, m) 7.42 (1H, s) 9) N-[(1RS, 2SR) -1- [3- (tert-
Butyl) benzyl] -2- (3-chlorophenyl) -2-hydroxyethyl] -4-fluoro-1-naphthamide (1RS, 2SR) -2-amino-3- [3- (tert-butyl) phenyl] -1 N, N of-(3-chlorophenyl) -1-propanol (0.30 g, 0.944 mmol)
To a solution of -dimethylformamide (5 ml) was added 4-fluoronaphthalene-1-carboxylic acid (0.189 g, 0.99 mmol) and 1-hydroxybenzotriazole monohydrate (0.152 g, 0.99 mmol), Finally one
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.190 g, 0.99 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
1,0: 1) and then purified by recrystallization (hexane-ethyl acetate) to give N-[(1RS, 2SR) -1- [3- (t
tert-butyl) benzyl] -2- (3-chlorophenyl)
[-2-Hydroxyethyl] -4-fluoro-1-naphthamide (0.245 g, 53%) was obtained as colorless crystals. mp 76-78 ℃ IRνmax ^KBr (cm ^-1 ): 3312, 1639, 1599, 1516, 1425, 1
261, 1236, 1201, 1051 ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.99 (9H, s) 2.73 (1H, dd,
J = 11.0, 14.4 Hz) 3.01 (1H, dd, J = 4.0, 14.4 Hz)
3.52 (2H, dd, J = 8.6, 11.4 Hz) 4.17 (1H, br) 4.7
0-4.81 (1H, m) 5.09 (1H, s) 5.87 (1H, d, J = 7.2 H
z) 6.74-6.83 (3H, m) 7.00 (1H, dd, J = 7.6, 9.8 H
z) 7.18-7.36 (5H, m) 7.41-7.57 (3H, m) 7.80 (1H, d,
J = 7.6 Hz) 8.07 (1H, d, J = 7.6 Hz).

Example 370 N-[(1RS, 2SR) -1- [3- (tert-butyl) benzyl] -2- (3-chlorophenyl) -2-hydroxyethyl] -6,7-dihydro-5H- Benzo [a] cycloheptene-1-carboxamide (1RS, 2SR) -2-amino-3- [3- (tert-butyl) phenyl] -1- (3-chlorophenyl) -1-propanol (0.30 g, 0. 944 mmol) N, N
6,7-Dihydro-5H-benzo [a] cycloheptene-1-carboxylic acid (0.187 g, 0.99 mmol), 1-hydroxybenzotriazole monohydrate (.152 g, 0.99 mmol) and finally 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.190 g,
0.99 mmol) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, 0: 1) and then recrystallized (hexane-ethyl acetate) to give N-[(1RS, 2
SR) -1- [3- (tert-butyl) benzyl] -2-
(3-Chlorophenyl) -2-hydroxyethyl] -6,7
-Dihydro-5H-benzo [a] cycloheptene-1-carboxamide (0.230 g, 50%) was obtained as colorless crystals. mp 104-105 ℃ IRνmax ^KBr (cm ^-1 ): 3300, 1635, 1514, 1425, 1363, 1
298, 1273, 1197, 1103, 1076 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.27 (9H, s) 1.95-2.01 (2H,
m) 2.14-2.20 (2H, m) 2.63-2.75 (3H, m) 297 (1H, d
d, J = 4.0, 14.2 Hz) 4.36 (1H, s) 4.67-4.69 (1H,
m) 5.02 (1H, s) 5.69 (1H, d, J = 7.4 Hz) 5.87-5.98
(1H, m) 6.26 (1H, d, J = 12.0 Hz) 6.86-7.30 (10H,
m) 7.47 (1H, s).

Example 371 N-[(1RS, 2SR) -1- [3- (tert-butyl) benzyl] -2- (3-chlorophenyl) -2-hydroxyethyl] -5-chloro-1-naphthamide ( 1RS, 2SR) -2-Amino-3- [3- (tert-butyl) phenyl] -1- (3-chlorophenyl) -1-propanol (0.313 g, 0.985 mmol) N,
To a solution of N-dimethylformamide (5 ml) was added 5-chloronaphthalene-1-carboxylic acid (0.214 g, 1.04 mmol) and 1-hydroxybenzotriazole monohydrate (0.160 g, 1.04 mmol). And finally one
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.20 g, 1.04 mmol) was added,
Stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Recrystallize the residue (hexane
-Ethyl acetate) to give N-[(1RS, 2SR) -1-]
[3- (tert-Butyl) benzyl] -2- (3-chlorophenyl) -2-hydroxyethyl] -5-chloro-1-naphthamide (0.307 g, 62%) was obtained as colorless crystals. mp 91-93 ° C IRνmax ^KBr (cm ^-1 ): 3267, 1631, 1572, 1518, 1203, 1
037 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.25 (9H, s) 2.74 (1H, dd, J
= 11.0, 14.4 Hz) 3.05 (1H, dd, J = 4.0, 14.2 Hz)
4.02 (1H, d, J = 4.4 Hz) 4.77-4.86 (1H, m) 5.05-5.
09 (1H, m) 5.87 (1H, d, J = 7.8 Hz) 7.01 (1H, d, J
= 7.4 Hz) 7.12-7.66 (12H, m) 8.29 (1H, d, J = 8.8
Hz).

Example 372 tert-Butyl (1RS, 2SR) -2- (3-chlorophenyl) -2-hydroxy-1- [4- (2,2,3,3,3
3-Pentafluoropropyl) benzyl] ethyl carbamate 1) 2,2,3,3,3-Pentafluoro-1- (4-methylphenyl) propan-1-ol Magnesium (12.2.
g, 502 mmol) and ether (100 ml), a solution of 4-bromotoluene (56.1 ml, 456 mmol) in ether (200 ml) was added dropwise, and the mixture was heated under reflux for 1.5 hours. The reaction vessel was cooled in a dry ice-acetone bath, and pentafluoropropionic acid (25 g, 15
2 mmol) in ether (100 ml) was added dropwise,
After slowly returning to room temperature, the mixture was heated under reflux for 3 hours and stirred at room temperature overnight. The reaction mixture was ice-cooled and quenched with 3N hydrochloric acid. Dilute with ethyl acetate and separate the organic layer,
The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
0, 30: 1) to obtain a colorless transparent oil. This was dissolved in methanol, and sodium borohydride was added under ice cooling. It returned to room temperature and stirred for 1 hour. After completion of the reaction, the reaction was quenched with 6N hydrochloric acid and extracted with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 10:
1,5: 1) to give 2,2,3,3,3-pentafluoro-1- (4-methylphenyl) propan-1-ol (20.28 g, 56%) as a colorless transparent oil. Was. IRνmax ^KBr (cm ^-1 ): 3400, 1616, 1518, 1363, 1331, 1
213, 1184, 1132 ¹ H-NMR (CDCl ₃ ) δ (ppm) 2.37 (3H, s) 2.50 (1H, d, J
= 4.8 Hz) 4.98-5.13 (1H, m) 7.21 (2H, d, J = 8.4
Hz) 7.33 (2H, d, J = 8.0 Hz). 2) O-phenyl O- [2,2,3,3,3-pentafluoro-1- (4-methylphenyl) propyl] carbonothionate 2, 2,3,3,3-pentafluoro-1- (4-methylphenyl) propan-1-ol (15.93 g, 66.3)
Triethylamine (13.9 ml, 99.45 mmol) was added to a solution of ethyl chlorophenylthionoformate (10. mmol) in ethyl acetate (200 ml).
1 ml, 72.8 mmol) and stirred for 2 hours under ice cooling. The precipitated solid was removed by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 30:
Purified in 1), O-phenyl O- [2,2,3,3,3-
Pentafluoro-1- (4-methylphenyl) propyl]
Carbonothionate (22.82 g, 91%) was obtained as a clear, colorless oil. IRνmax ^KBr (cm ^-1 ): 1616, 1591, 1518, 1491, 1290, 11
92, 1143 ¹ H-NMR (CDCl ₃ ) δ (ppm) 2.39 (3H, s) 6.67 (1H, dd,
J = 7.5, 16.5 Hz) 7.05 (2H, d, J = 8.1 Hz) 7.24-7.3
1 (3H, m) 7.37-7.42 (4H, m). 3) 4- (2,2,3,3,3-pentafluoropropyl) toluene O-phenyl O- [2,2,3,3,3 -Pentafluoro-
1- (4-Methylphenyl) propyl] carbonothionate (16.55 g, 44.0 mmol) in benzene (1
To the solution, 2,2′-azobisisobutyronitrile (1.45 g, 8.8 mmol) and tri-n-butyltin hydride (17.8 ml, 66.0 mmol) were added.
Stirred at 0 ° C. for 5 hours. After completion of the reaction, benzene was distilled off under reduced pressure and purified by silica gel column chromatography (hexane), and 4- (2,2,3,3,3-pentafluoropropyl) toluene (11.13 g,) was added to a colorless transparent oil. As obtained. Although this contains some impurities considered to be tin compounds, it was used for the next reaction as it was. IRνmax ^KBr (cm ^-1 ): 1518, 1464, 1377, 1315, 1203, 11
18, 1080, 1030 ¹ H-NMR (CDCl ₃ ) δ (ppm) 2.34 (3H, s) 3.26 (2H, t, J
= 18.8 Hz) 7.16 (4H, s). 4) 1- (Bromomethyl) -4- (2,2,3,3,3-
Pentafluoropropyl) benzene To a solution of 4- (2,2,3,3,3-pentafluoropropyl) toluene (9.97 g, 39.4 mmol) in carbon tetrachloride (300 ml), 2,2′-azobisisopropane Butyronitrile (0.33 g, 197 mmol) and N-bromosuccinimide (8.50 g, 47.3 mmol) were added,
Heated to reflux overnight. After cooling to room temperature, insolubles were filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 0, 50: 1, 20:
Purified in 1), 1- (bromomethyl) -4- (2,2,
3,3,3-pentafluoropropyl) benzene (3.
66 g, 31% (yield in two steps) were obtained as colorless crystals. mp 62-63 ℃ IRνmax ^KBr (cm ^-1 ): 1518, 1437, 1323, 1190, 1101, 10
70, 1045 ¹ H-NMR (CDCl ₃ ) δ (ppm) 3.31 (2H, t, J = 17.8 Hz)
7.27 (2H, d, J = 8.0 Hz) 7.40 (2H, d, J = 8.4 Hz). 5) Ethyl 3- (3-chlorophenyl) -3-oxo-2-
[4- (2,2,3,3,3-pentafluoropropyl)
Benzyl] propionate Ethyl 3- (3-chlorophenyl) -3-oxopropionate (2.74 g, 12.08 mmol) in dimethoxyethane (30 ml) was ice-cooled and sodium hydride (60%, 0.49 g) , 12.08 mmol)
After stirring for 30 minutes under ice cooling, 1- (bromomethyl) -4-
A solution of (2,2,3,3,3-pentafluoropropyl) benzene (3.66 g, 12.08 mmol) in dimethoxyethane (15 ml) was added, and the mixture was stirred at room temperature overnight.
After completion of the reaction, the reaction was quenched with 0.5N hydrochloric acid, diluted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1, 10: 1), and ethyl 3- (3-chlorophenyl) -3-oxo-2- [4- (2,2,3,3) was used. ,
[3-Pentafluoropropyl) benzyl] propionate (4.64 g, 86%) was obtained as colorless crystals. mp 81-82 ℃ IRνmax ^KBr (cm ^-1 ): 1738, 1693, 1572, 1425, 1317, 11
95, 1028 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.11 (3H, t, J = 7.2 Hz) 3.
25 (2H, t, J = 18.3 Hz) 3.32 (2H, d, J = 7.2 Hz)
4.05-4.14 (2H, m) 4.54 (1H, t, J = 7.5 Hz) 7.16-7.
23 (4H, m) 7.37 (1H, t, J = 8.1 Hz) 7.51-7.54 (1H,
m) 7.77-7.81 (1H, m) 7.90-7.92 (1H, m). 6) Ethyl (2RS, 3RS) -3- (3-chlorophenyl) -3-hydroxy-2- [4- (2,2, 3,3,3-
[Pentafluoropropyl) benzyl] propionate An ether suspension (30 ml) of zinc chloride (2.70 g, 19.84 mmol) was added to sodium borohydride (1.
50 g, 39.68 mmol) at room temperature.
Stirred for hours. The insoluble material is filtered, and the filtrate is ethyl 3-
(3-chlorophenyl) -3-oxo-2- [4- (2,2,
A solution of (3,3,3-pentafluoropropyl) benzyl] propionate (4.45 g, 9.92 mmol) in ether (20 ml) was added, and the mixture was stirred at room temperature for 1 hour. 1
Terminate the reaction with normal hydrochloric acid, dilute with ethyl acetate, add water,
Washed with saturated saline. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 10: 1,
5: 1) to give ethyl (2RS, 3RS) -3- (3
-Chlorophenyl) -3-hydroxy-2- [4- (2,2,
[3,3,3-pentafluoropropyl) benzyl] propionate (3.95 g, 89%) was obtained as a colorless transparent oil. IRνmax ^KBr (cm ^-1 ): 3450, 1709, 1576, 1518, 1435, 13
15, 1195, 1113, 1030 ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.91 (3H, t, J = 7.0 Hz) 2.
87-3.02 (3H, m) 3.18 (1H, d, J = 2.6 Hz) 3.25 (2H, m
t, J = 18.2 Hz) 3.88 (2H, q, J = 6.8 Hz) 5.02 (1
H, d, J = 1.8 Hz) 7.04-7.17 (4H, m) 7.26-7.28 (3H,
m) 7.41-7.42 (1H, m). 7) (2RS, 3RS) -3- (3-chlorophenyl)-
Ethyl 3-hydroxy-2- [4- (2,2,3,3,3-pentafluoropropyl) benzyl] propionate (2RS, 3RS) -3- (3-chlorophenyl)-
3-hydroxy-2- [4- (2,2,3,3,3-pentafluoropropyl) benzyl] propionate (3.8
To a solution of 4 g (8.52 mmol) in tetrahydrofuran-ethanol (20 ml-20 ml) was added 1N sodium hydroxide (17 ml, 17 mmol) at room temperature, and the mixture was stirred at room temperature overnight. After completion of the reaction, the organic solvent was distilled off under reduced pressure, the aqueous layer was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Recrystallize with hexane-ethyl acetate,
(2RS, 3RS) -3- (3-chlorophenyl) -3-hydroxy-2- [4- (2,2,3,3,3-pentafluoropropyl) benzyl] propionic acid (2.85 g, 7
9%) as colorless crystals. mp 150-151 ℃ IRνmax ^KBr (cm ^-1 ): 2500-3300, 1693, 1433, 1315, 12
38, 1194, 1103, 1078,1030 ¹ H-NMR (CDCl ₃ ) δ (ppm) 2.87-3.05 (3H, m) 3.24 (2H,
t, J = 18.4 Hz) 5.09 (1H, d, J = 4.0 Hz) 7.05 (2H,
d, J = 8.0 Hz) 7.14 (2H, d, J = 8.4 Hz) 7.24-7.29
(3H, m) 7.41 (1H, s). 8) (4RS, 5SR) -5- (3-chlorophenyl)-
4- [4- (2,2,3,3,3-pentafluoropropyl) benzyl] -1,3-oxazolidin-2-one (2RS, 3RS) -3- (3-chlorophenyl) -3-hydroxy- 2- [4- (2,2,3,3,3-pentafluoropropyl) benzyl] propionic acid (2.75 g,
6.50 mmol) in tetrahydrofuran (70 ml)
Triethylamine (1.36 ml, 9.75 mmol), diphenylphosphoric azide (1.54 ml, 7.7 ml) were added to the solution.
(15 mmol) and heated under reflux for 4 hours. The solvent was distilled off, diluted with ethyl acetate, and washed with water, saturated aqueous sodium hydrogen carbonate and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Recrystallization from hexane-ethyl acetate gave (4RS, 5SR) -5- (3-chlorophenyl) -4- [4- (2,2,3,3,3-pentafluoropropyl) benzyl] -1,3. -Oxazolidin-2-one (2.54 g, 93%) was obtained as colorless crystals. mp 137-138 ℃ IRνmax ^KBr (cm ^-1 ): 3234, 1761, 1435, 1317, 1194, 10
30, 912 ¹ H-NMR (CDCl ₃ ) δ (ppm) 2.17-2.36 (2H, m) 3.28 (2H,
(t, J = 18.6 Hz) 4.19-4.30 (1H, m) 4.95 (1H, s) 5.
77 (1H, d, J = 8.2 Hz) 7.03 (2H, d, J = 7.6Hz) 7.2
9-7.38 (3H, m). 9) tert-Butyl (4RS, 5SR) -5- (3-chlorophenyl) -2-oxo-4- [4- (2,2,3,
3,3-pentafluoropropyl) benzyl] -1,3-
Oxazolidine-3-carboxylate (4RS, 5SR) -5- (3-chlorophenyl) -4-
[4- (2,2,3,3,3-pentafluoropropyl)
Benzyl] -1,3-oxazolidin-2-one (2.43
g, 5.79 mmol) of acetonitrile (40 ml)
Di-tert-butyl dicarbonate (1.52
g, 6.95 mmol) and 4- (dimethylamino) pyridine (71 mg, 0.579 mmol) were added in this order, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, recrystallized from hexane-ethyl acetate, and tert-butyl (4RS, 5
SR) -5- (3-Chlorophenyl) -2-oxo-4- [4-
(2,2,3,3,3-pentafluoropropyl) benzyl] -1,3-oxazolidine-3-carboxylate (2.77 g, 92%) was obtained as colorless crystals. ^{mp 136-138 ℃ IRνmax KBr (cm -1} ): 1813, 1724, 1358, 1315, 1251, 11
95, 157, 1076, 1028 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.49 (9H, s) 2.58 (1H, dd,
J = 8.8, 14.4 Hz) 2.88 (1H, dd, J = 4.6, 14.4 Hz)
3.21 (2H, t, J = 18.4H) 4.77-4.87 (1H, m) 5.64 (1
(H, d, J = 7.0 Hz) 6.67 (2H, d, J = 8.0 Hz) 6.99-7.
03 (3H, m) 7.12-7.19 (2H, m) 7.24-7.30 (1H, m). 10) tert-Butyl (1RS, 2SR) -2- (3-
Chlorophenyl) -2-hydroxy-1- [4- (2,2,
3,3,3-pentafluoropropyl) benzyl] ethylcarbamate tert-butyl (4RS, 5SR) -5- (3-chlorophenyl) -2-oxo-4- [4- (2,2,3,3,3 -Pentafluoropropyl) benzyl] -1,3-oxazolidine-3-carboxylate (2.66 g, 5.12 mmol) in methanol-tetrahydrofuran (20 ml-2)
0 ml) solution in 1N sodium hydroxide (6.2 ml,
6.2 mmol) and stirred at room temperature overnight. After dilution with water, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate), and tert-butyl (1RS, 2SR) -2- (3-chlorophenyl) -2-hydroxy-1- [4- (2,2,2
[3,3,3-pentafluoropropyl) benzyl] ethyl carbamate (2.11 g, 83%) was obtained as colorless crystals. mp 156-157 ℃ IRνmax ^KBr (cm ^-1 ): 3348, 1682, 1531, 1444, 1311, 12
44, 1178, 1032 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.34 (9H, s) 2.59-2.79 (2
(H, m) 3.26 (2H, t, J = 18.4 Hz) 3.49 (1H, br) 4.09
(1H, br) 4.55 (1H, d, J = 7.6 Hz) 4.91 (1H, br) 7.0
8-7.20 (4H, m) 7.26-7.29 (3H, m) 7.1 (1H, s).

Example 373 N-[(1RS, 2SR) -1- [4- (2,2,3,3,3)
3-Pentafluoropropyl) benzyl] -2- (3-chlorophenyl) -2-hydroxyethyl] -4-fluoro-1-
Naphthamide 1) (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- [4- (2,2,3,3,3-pentafluoropropyl) phenyl] -1-propanol tert-butyl (1RS, 2SR) -2- (3-chlorophenyl) -2-hydroxy-1- [4- (2,2,3,3
To a solution of [3-pentafluoropropyl) benzyl] ethyl carbamate (2.00 g, 4.05 mmol) in chloroform (20 ml) was added trifluoroacetic acid (20 ml), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water was added to the residue, and the mixture was basified with saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- [4- (2,2,3,3,3-pentafluoro). Propyl) phenyl] -1-propanol (1.0
8g, 68%) as colorless crystals. mp 109-110 ℃ IRνmax ^KBr (cm ^-1 ): 3000-3300, 1576, 1518, 1433, 13
17, 1078, 1028 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.60 (2H, br) 2.35 (1H, d
d, J = 10.2, 13.4 Hz) 2.75 (1H, dd, J = 3.0, 13.6 H
z) 3.18-3.36 (3H, m) 4.66 (1H, d, J = 4.8 Hz) 7.10
-7.35 (7H, m) 7.41 (1H, s). 2) N-[(1RS, 2SR) -1- [4- (2,2,
3,3,3-pentafluoropropyl) benzyl] -2-
(3-Chlorophenyl) -2-hydroxyethyl] -4-fluoro-1-naphthamide 4-fluoronaphthalene-1-carboxylic acid (153 mg,
0.801 mmol) in N, N-dimethylformamide (5 ml) was added to a solution of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (154 g, 0.80 mmol).
1 mmol), 1-hydroxybenzotriazole monohydrate (123 mg, 0.801 mmol), and finally (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- [4- ( 2,2,3,3,3-pentafluoropropyl) phenyl] -1-propanol (0.30 g,
(0.763 mmol) and stirred at room temperature overnight. It was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, dried over anhydrous magnesium sulfate, filtered through a glass filter filled with silica gel, washed with ethyl acetate, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-[(1RS, 2SR) -1- [4- (2,2,2).
3,3,3-pentafluoropropyl) benzyl] -2-
(3-Chlorophenyl) -2-hydroxyethyl] -4-fluoro-1-naphthamide (0.284 g, 66%) was obtained as colorless crystals. mp 191-192 ° C. Elemental analysis C ₂₉ H ₂₂ NO ₂ ClF ₆ Calculated: C, 61.55; H, 3.92 ; N, 2.47 Found: C, 61.27; H, 3.75 ; N, 2.45 IRνmax KBr (cm - ¹ ): 3265, 1641, 1626, 1516, 1425, 1
236, 1178, 1032 ¹ H-NMR (CDCl ₃ ) δ (ppm) 2.80 (1H, dd, J = 10.8, 14.
1 Hz) 3.02 (1H, dd, J = 4.2, 14.4 Hz) 3.29 (2H, t,
J = 18.0 Hz) 3.91 (1H, s) 4.70-4.77 (1H, m) 5.10 (1
(H, d, J = 2.2 Hz) 5.95 (1H, d, J = 8.1 Hz) 6.90-6.
96 (1H, m) 7.03 (1H, dd, J = 5.4, 7.8 Hz) 7.17-7.3
6 (7H, m) 7.43-7.56 (3H, m) 7.88 (1H, d, J = 8.4 H
z) 8.07 (1H, d, J = 8.4 Hz).

Example 374 N-[(1RS, 2SR) -1- [4- (2,2,3,3,3)
3-Pentafluoropropyl) benzyl] -2- (3-chlorophenyl) -2-hydroxyethyl] -6,7-dihydro
-5H-benzo [a] cycloheptene-1-carboxamide 6,7-dihydro-5H-benzo [a] cycloheptene-1
To a solution of -carboxylic acid (151 mg, 0.801 mmol) in N, N-dimethylformamide (5 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (154 g, 0.801 mmol), 1 -Hydroxybenzotriazole monohydrate (123 mg, 0.
801 mmol), and (1RS, 2SR)-
2-amino-1- (3-chlorophenyl) -3- [4- (2,
2,3,3,3-pentafluoropropyl) phenyl]-
1-propanol (0.30 g, 0.763 mmol)
Was added and stirred at room temperature overnight. It was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, dried over anhydrous magnesium sulfate, filtered through a glass filter filled with silica gel, washed with ethyl acetate, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) and N-[(1R
(S, 2SR) -1- [4- (2,2,3,3,3-pentafluoropropyl) benzyl] -2- (3-chlorophenyl) -2-hydroxyethyl] -6,7-dihydro-5H- Benzo [a] cycloheptene-1-carboxamide (0.2
(84 g, 66%) as colorless crystals. mp 176-177 ° C. Elemental analysis C ₃₀ H ₂₇ NO ₂ ClF ₅ Calculated: C, 63.89; H, 4.83 ; N, 2.48 Found: C, 63.70; H, 4.85 ; N, 2.22 IRνmax KBr (cm - ¹ ): 3281, 1635, 1518, 1433, 1315, 11
97, 1030 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.95-2.04 (2H, m) 2.16-2.28
(2H, m) 2.64-2.68 (2H, m) 2.75 (1H, dd, J = 11.1,
14.7 Hz) 2.97 (1H, dd, J = 4.5, 14.7 Hz) 3.28 (2
(H, t, J = 18.3 Hz) 4.01 (1H, br) 4.62-4.71 (1H, m)
5.05 (1H, d, J = 2.7 Hz) 5.74 (1H, d, J = 7.8 Hz)
5.95 (1H, dt, J = 5.7, 11.4 Hz) 6.29 (1H, d, J = 1
1.7 Hz) 6.88 (1H, dd, J = 1.2, 7.2 Hz) 7.03 (1H,
t, J = 7.8Hz) 7.0-7.36 (8H, m) 7.48 (1H, s).

Example 375 N-[(1RS, 2SR) -1- [4- (2,2,3,3,3)
[3-pentafluorophenyl) benzyl] -2- (3-chlorophenyl) -2-hydroxyethyl] -5-chloro-1-naphthamide 5-chloronaphthalene-1-carboxylic acid (176 mg,
0.849 mmol) in N, N-dimethylformamide (5 ml) was added to 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (163 mg, 0.8 ml).
49 mmol) 1-hydroxybenzotriazole 1
Hydrate (130 mg, 0.849 mmol) was added, and finally (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- [4- (2,2,3,3-3- Pentafluoropropyl) phenyl] -1-propanol (318m
g, 0.809 mmol) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, filtered through a glass filter filled with silica gel, washed with ethyl acetate, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-[(1RS, 2SR) -1- [4-
(2,2,3,3,3-pentafluorophenyl) benzyl] -2- (3-chlorophenyl) -2-hydroxyethyl] -5-chloro-1-naphthamide (330 mg, 70
%) As colorless crystals. mp 216-217 ° C Elemental analysis: C ₂₉ H ₂₂ NO ₂ Cl ₂ F ₅ Calculated: C, 59.81; H, 3.81; N, 2.41 Found: C, 59.75; H, 3.81; N, 2.41 IRνmax ^KBr ( cm ^-1 ): 3260, 1637, 1539, 1319, 1180, 11
18, 1030 ¹ H-NMR (CDCl ₃ ) δ (ppm) 2.80 (1H, dd, J = 11.0, 14.
4 Hz) 3.02 (1H, dd, J = 4.0, 14.6 Hz) 3.30 (2H, t,
J = 18.2 Hz) 3.74 (1H, br) 4.72-4.84 (1H, m) 5.09
(1H, s) 5.96 (1H, d, J = 8.6 Hz) 7.11-7.58 (12H,
m) 7.74 (1H, d, J = 8.8 Hz) 8.31 (1H, d, J = 8.4 H
z).

Example 376 N-{(1RS, 2SR) -2- (3-chlorophenyl)-
1-[(3,3-Dimethyl-2,3-dihydro-1-benzofuran-5-yl) methyl] -2-hydroxyethyl} -4-fluoro-1-naphthamide 1) 2-bromo-4-methyl- 1-[(2-Methyl-2-propenyl) oxy] benzene Potassium carbonate (17.2 g, 124 ml) was added to a solution of 2-bromo-p-cresol (10 ml, 82.7 mmol) in N, N-dimethylformamide (200 ml). Mmol), methallyl chloride (9.8 ml, 99.2 mmol),
Stirred at 100 ° C. overnight. The mixture was diluted with ethyl acetate and washed with water and saturated saline. After drying over anhydrous magnesium sulfate,
Filtration and concentration under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1), and 2-bromo-4-methyl-1-[(2-methyl-2-propenyl) oxy] benzene (19.67 g, 99%) ) Was obtained as a clear, colorless oil. IRνmax ^KBr (cm ^-1 ): 1658, 1604, 1494, 1452, 1377, 1
286, 1251, 1230, 1207,1153 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.84 (3H, s) 2.25 (3H, s)
4.45 (2H, s) 4.98-5.00 (1H, m) 5.13-5.14 (1H, m) 6.
56 (1H, d, J = 8.4 Hz) 6.99-7.03 (1H, m) 7.35-7.36
(1H, m). 2) 3,3,5-trimethyl-2,3-dihydro-1-benzofuran 2-bromo-4-methyl-1-[(2-methyl-2-propenyl) oxy] benzene (5 0.0 g, 20.7 mmol)
2,2'-azobisisobutyronitrile (1.45 g, 8.8 mmol) and tri-n-butyltin hydride (8.34 ml, 31 mmol) in a toluene (100 ml) solution of
Was added and heated to reflux overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0, 50: 1).
3,5-Trimethyl-2,3-dihydro-1-benzofuran (3.70 g, 100%) was obtained as a clear, colorless oil. IRνmax ^KBr (cm ^-1 ): 1612, 1489, 1464, 1192, 991 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.32 (6H, s) 2.29 (3H, s)
4.20 (2H, s) 6.67 (1H, d, J = 8.4 Hz) 6.90-6.92 (2
H, m). 3) Ethyl 3- (3-chlorophenyl) -2-[(3,3
-Dimethyl-2,3-dihydro-1-benzofuran-5-yl) methyl] -3-oxopropionate 3,3,5-trimethyl-2,3-dihydro-1-benzofuran (9.42 g, 58 mmol) ) Carbon tetrachloride (30
0 ml) solution, 2,2'-azobisisobutyronitrile (0.48 g, 2.9 mmol) and N-bromosuccinimide (10.84 g, 60.9 mmol) were added, and the mixture was heated under reflux overnight. After cooling to room temperature, insolubles were filtered and concentrated under reduced pressure to obtain a bromine. A solution of ethyl 3- (3-chlorophenyl) -3-oxopropionate (13.15 g, 58 mmol) in dimethoxyethane (100 ml) was ice-cooled, and sodium hydride (60%, 2.32 g, 58 mmol) was added. After stirring for 30 minutes under ice-cooling, bromine (5
(8 mmol) in dimethoxyethane (150 ml) and stirred overnight at room temperature. After completion of the reaction, the reaction was quenched with 0.5N hydrochloric acid, diluted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, filtration,
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1, 15: 1), and ethyl 3- (3-chlorophenyl) -2-[(3,
3-dimethyl-2,3-dihydro-1-benzofuran-5-yl) methyl] -3-oxopropionate (14.04
g, 63%) as a pale yellow oil. IRνmax ^KBr (cm ^-1 ): 1738, 1693, 1612, 1572, 1487, 1
469, 1423, 1365, 1228,1192 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.14 (3H, t, J = 7.0 Hz) 1.2
4 (3H, s) 1.28 (3H, s) 3.27 (2H, dd, J = 1.8, 7.6 H
z) 4.06-4.17 (4H, q, J = 7.2 Hz) 6.65 (1H, d, J =
8.0 Hz) 6.89-6.90 (1H, m) 6.95 (1H, dd, J = 1.8,
8.0 Hz) 7.36 (1H, t, J = 8.0 Hz) 7.51 (1H, ddd, J
= 1.2, 2.2, 8.0 Hz) 7.77 (1H, dt, J = 1.0, 7.6 Hz)
7.85-7.86 (1H, m). 4) Ethyl (2RS, 3RS) -3- (3-chlorophenyl) -2-[(3,3-dimethyl-2,3-dihydro-1-)
Benzofuran-5-yl) methyl] -3-hydroxypropionate Sodium borohydride (5.10 g) was added to an ether suspension (140 ml) of zinc chloride (9.90 g, 72.6 mmol).
50 g, 145.2 mmol) at room temperature.
Stirred for hours. The insoluble material is filtered, and the filtrate is ethyl 3-
(3-chlorophenyl) -2-[(3,3-dimethyl-2,2
3-dihydro-1-benzofuran-5-yl) methyl] -3-
A solution of oxopropionate (14.04 g, 36.3 mmol) in ether (50 ml) was added, and the mixture was added at room temperature for 1.5 hours.
Stirred for hours. The reaction was terminated with 3N hydrochloric acid, diluted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1, 5: 1) to give ethyl (2RS, 3R).
S) -3- (3-Chlorophenyl) -2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl) methyl] -3-hydroxypropionate (12.07 g, 8
6%) as a pale yellow oil. IRνmax ^KBr (cm ^-1 ): 3460, 1726, 1487, 1467, 1373, 1
190, 1032, 987 ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.95 (3H, t, J = 7.0 Hz) 1.
27 (3H, s) 1.29 (3H, s) 2.89-2.97 (3H, m) 3.18 (1
H, d, J = 2.4 Hz) 3.90 (2H, q, J = 7.0 Hz) 4.18 (2
(H, s) 4.98-4.99 (1H, m) 6.03 (1H, d, J = 8.2 Hz)
6.78-6.84 (2H, m) 7.24-7.28 (3H, m) 7.40-7.42 (1H,
m). 5) (4RS, 5SR) -5- (3-chlorophenyl)-
4-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl) methyl] -1,3-oxazolidin-2-one ethyl (2RS, 3RS) -3- (3-chlorophenyl) -
2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl) methyl] -3-hydroxypropionate (11.44 g, 29.4 mmol) in tetrahydrofuran-ethanol (60 ml- 60 ml) solution at room temperature
Normal sodium hydroxide (60 ml, 60 mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the organic solvent was distilled off under reduced pressure, the aqueous layer was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a colorless transparent oil. To this tetrahydrofuran (300 ml) solution were added triethylamine (6.2 ml, 44.1 mmol) and diphenylphosphoric azide (7.6 ml, 35.3 mmol), and the mixture was heated under reflux for 4 hours. Evaporate the solvent, dilute with ethyl acetate,
Washed with water, saturated aqueous sodium bicarbonate, and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Recrystallization with hexane-ethyl acetate gave (4RS, 5SR)-
5- (3-chlorophenyl) -4-[(3,3-dimethyl-
2,3-dihydro-1-benzofuran-5-yl) methyl]-
1,3-oxazolidine-2-one (8.11 g, 77
%) As colorless crystals. mp 183-184 ° C IRνmax ^KBr (cm ^-1 ): 3271, 1759, 1489, 1236, 1194 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.29, 1.30 (each s, 6H) 2.1
5 (1H, dd, J = 11.4, 13.8 Hz) 2.27 (1H, dd, J = 3.
9, 13.8 Hz) 4.18-4.25 (3H, m) 4.98 (1H, s) 5.75 (1
(H, d, J = 7.8 Hz) 6.68 (1H, d, J = 8.1 Hz) 6.74-6.
79 (2H, m) 7.25-7.28 (1H, m) 7.34-7.39 (3H, m). 6) (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- (3,3- Dimethyl-2,3-dihydro-1
-Benzofuran-5-yl) -1-propanol (4RS, 5SR) -5- (3-chlorophenyl) -4-
[(3,3-Dimethyl-2,3-dihydro-1-benzofuran-5-yl) methyl] -1,3-oxazolidin-2-one (5.33 g, 14.9 mmol) in ethanol (10
0 ml) solution to an 8N aqueous sodium hydroxide solution (9.3 ml).
ml, 74.5 mmol) and heated under reflux for 5 hours. After completion of the reaction, ethanol was distilled off under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, filtered,
It was concentrated under reduced pressure. Recrystallize the residue (hexane-ethyl acetate)
And purified by (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- (3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -1-propanol ( 3.
(68 g, 74%) as colorless crystals. mp 83-86 ℃ IRνmax ^KBr (cm ^-1 ): 3000-3300, 1597, 1574, 1487, 14
69, 1192, 1076, 987 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.30 (3H, s) 1.31 (3H, s)
2.28 (1H, dd, J = 7.5,13.8 Hz) 2.70 (1H, dd, J =
(3.3, 13.8 Hz) 3.21-3.27 (1H, m) 4.20 (2H, s) 4.66
(1H, d, J = 5.1 Hz) 6.69 (1H, d, J = 7.8 Hz) 6.84-
6.88 (2H, m) 7.24-7.33 (3H, m) 7.41 (1H, s). 7) N-｛(1RS, 2SR) -2- (3-chlorophenyl) -1-[(3,3-dimethyl- 2,3-dihydro-1-benzofuran-5-yl) methyl] -2-hydroxyethyl
4-Fluoro-1-naphthamide 4-fluoronaphthalene-1-carboxylic acid (242 mg,
To a solution of 1.27 mmol) in N, N-dimethylformamide (10 ml) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (243 mg, 1.
27 mmol) 1-hydroxybenzotriazole 1
Hydrate (195 mg, 1.27 mmol) was added, and finally (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- (3,3-dimethyl-2,3-dihydro-1). -Benzofuran-5-yl) -1-propanol (0.40 g,
1.21 mmol) and stirred at room temperature overnight. It was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, dried over anhydrous magnesium sulfate, filtered through a glass filter filled with silica gel, washed with ethyl acetate, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-{(1RS, 2SR) -2- (3-chlorophenyl) -1-[(3,3-dimethyl-2,3-dihydro-1-).
Benzofuran-5-yl) methyl] -2-hydroxyethyl} -4-fluoro-1-naphthamide (383 mg, 68
%) As colorless crystals. mp 131-133 ° C Elemental analysis: C ₃₀ H ₂₇ NO ₃ Cl ・ H ₂ O Calculated: C, 71.63; H, 5.81; N, 2.78 Found: C, 71.28; H, 5.54; N, 2.79 IRνmax ^KBr (cm ^-1 ): 3281, 1641, 1626, 1518, 1487, 14
64, 1425, 1261, 1236,1194 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.22 (3H, s) 1.27 (3H, s)
2.71 (1H, dd, J = 11.1,14.7 Hz) 3.00 (1H, dd, J =
4.2, 14.4 Hz) 4.12 (1H, d, J = 4.2 Hz) 4.21 (2H, d,
J = 0.9 Hz) 4.69-4.78 (1H, m) 5.08-5.10 (1H, m)
5.83 (1H, d, J = 7.5 Hz) 6.72 (1H, d, J = 8.4 Hz)
6.91-7.02 (3H, m) 7.16 (1H, dd, J = 5.4, 7.8 Hz)
7.27-7.38 (3H, m) 7.45-7.57 (3H, m) 7.80 (1H, d, J
= 8.1 Hz) 8.07 (1H, d, J = 7.8 Hz).

Example 377 N-{(1RS, 2SR) -2- (3-chlorophenyl)-
1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl) methyl] -2-hydroxyethyl} -6
7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 6,7-dihydro-5H-benzo [a] cycloheptene-1
-Carboxylic acid (239 mg, 1.27 mmol) N,
N-dimethylformamide (5 ml) solution in 1-ethyl
-3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (243 mg, 1.27 mmol), 1-hydroxybenzotriazole monohydrate (195 mg, 1.27
Mmol) and finally (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- (3,3-dimethyl-
2,3-Dihydro-1-benzofuran-5-yl) -1-propanol (0.40 g, 1.21 mmol) was added, and the mixture was stirred at room temperature overnight. Dilute with ethyl acetate, add saturated aqueous sodium bicarbonate,
After washing with water and saturated saline and drying over anhydrous magnesium sulfate, the mixture was filtered through a glass filter filled with silica gel, washed with ethyl acetate, and concentrated under reduced pressure. The residue is purified by recrystallization (hexane-ethyl acetate) and N-｛(1RS, 2SR)
-2- (3-chlorophenyl) -1-[(3,3-dimethyl-
2,3-dihydro-1-benzofuran-5-yl) methyl]-
2-hydroxyethyl} -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide (326 m
g, 54%) as colorless crystals. mp 149-150 ° C Elemental analysis: C ₃₁ H ₃₂ NO ₃ Cl ・ 0.5H ₂ O Calculated: C, 72.86; H, 6.51; N, 2.74 Found: C, 73.04; H, 6.26; N, 3.04 IRνmax ^KBr (cm ^-1 ): 3304, 1635, 1514, 1487, 1192, 1
076, 987, 910 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.28 (6H, s) 1.98-2.01 (2H,
m) 2.16-2.21 (2H, m) 2.58-2.69 (3H, m) 2.87-2.95
(1H, m) 4.20 (2H, s) 4.62 (1H, br) 5.00 (1H, s) 5.7
1 (1H, d, J = 7.4 Hz) 5.89-6.00 (1H ,, m) 6.26 (1H,
d, J = 11.8 Hz) 6.68 (1H, d, J = 8.8 Hz) 6.88-7.1
6 (5H, m) 7.26-7.30 (3H, m) 7.46 (1H, s)

Example 378 5-Chloro-N-｛(1RS, 2SR) -2- (3-chlorophenyl) -1-[(3,3-dimethyl-2,3-dihydro-1
-Benzofuran-5-yl) methyl] -2-hydroxyethyl} -1-naphthamide 5-chloronaphthalene-1-carboxylic acid (260 mg,
1.26 mmol) in N, N-dimethylformamide (5 ml) was added to 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (242 mg, 1.2 mg).
6 mmol), 1-hydroxybenzotriazole monohydrate (193 mg, 1.26 mmol) and finally (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- (3,3 -Dimethyl-2,3-dihydro-1-benzofuran-5-yl) -1-propanol (0.40 g,
1.20 mmol) and stirred overnight at room temperature. It was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, dried over anhydrous magnesium sulfate, filtered through a glass filter filled with silica gel, washed with ethyl acetate, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give 5-chloro-N-｛(1RS, 2SR) -2- (3-
Chlorophenyl) -1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl) methyl] -2-hydroxyethyl} -1-naphthamide (473 mg, 76%)
Was obtained as colorless crystals. mp 191-192 ° C. Elemental analysis C ₃₀ H ₂₇ NO ₃ Cl ₂ Calculated: C, 69.23; H, 5.23 ; N, 2.69 Found: C, 69.02; H, 5.04 ; N, 2.71 IRνmax KBr (cm - ¹ ): 3271, 1639, 1572, 1520, 1487, 11
94, 908 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.23 (3H, s) 1.26 (3H, s) 2.
70 (1H, dd, J = 11.0,14.6 Hz) 2.99 (1H, dd, J = 4.
4, 14.8 Hz) 4.21 (2H, s) 4.71-4.78 (1H, m) 5.07 (1
H, d, J = 3.2 Hz) 5.86 (1H, d, J = 8.2 Hz) 6.71 (1
H, d, J = 8.8 Hz) 6.90-6.93 (2H, m) 7.22-7.64 (9H,
m) 8.31 (1H, d, J = 8.4 Hz).

Example 379 N-{(1RS, 2SR) -2- (3-chlorophenyl)-
1- [4- (1,1-difluoro-2,2-dimethylpropyl) benzyl] -2-hydroxyethyl {-4-fluoro-
1-Naphthamide 1) 2,2-dimethyl-1- (4-methylphenyl) -1-
Propanone In a three-necked flask, a suspension of ether (200 ml) of magnesium (7.14 g, 294 mmol) was added to ether (10 ml) of p-bromotoluene (34 ml, 276 mmol).
0 ml) solution was added dropwise and heated under reflux for 1.5 hours. Then, at room temperature, trimethylacetonitrile (25 ml, 2
26 mmol) in ether (100 ml)
Stir for 2 hours. Then, the mixture was ice-cooled, 6N hydrochloric acid was added dropwise, and the mixture was stirred for 30 minutes at room temperature. Diluted with ether, water,
Washed with saturated saline. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 0, 1
0: 1) to give 2,2-dimethyl-1- (4-methylphenyl) -1-propanone (10.94 g, 27%) as a colorless transparent oil. IRνmax ^KBr (cm ^-1 ): 1672, 1608, 1477, 1396, 1365, 1
278, 960 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.35 (9H, s) 2.38 (3H, s) 7.2
0 (2H, d, J = 8.1 Hz) 7.66 (2H, d, J = 8.4 Hz). 2) 1- (1,1-Difluoro-2,2-dimethylpropyl) -4-methylbenzene 2,2- Bis (2-methoxyethyl) aminosulfur trifluoride (10 g, 45.2 mmol) was added to nascol containing dimethyl-1- (4-methylphenyl) -1-propanone (4.69 g, 26.6 mmol). The mixture was added dropwise and stirred at 80-85 ° C overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane),
1- (1,1-difluoro-2,2-dimethylpropyl)-
4-Methylbenzene (5.16 g, 77%) was obtained as a clear, colorless oil. IRνmax ^KBr (cm ^-1 ): 1618, 1518, 1485, 1464, 1308, 128
6, 1259, 1209, 1093, 1072, 976 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.02 (9H, s) 2.37 (3H, s)
7.15-7.19 (2H, m) 7.31 (2H, d, J = 8.4 Hz). 3) Ethyl 3- (3-chlorophenyl) -2- [4-
(1,1-Difluoro-2,2-dimethylpropyl) benzyl] -3-oxopropionate 1- (1,1-difluoro-2,2-dimethylpropyl)-
4-methylbenzene (4.52 g, 22.8 mmol)
2,2′-azobisisobutyronitrile (188 mg, 1.14 mmol) in a solution of
N-Bromosuccinimide (4.06 g, 22.8 mmol) was added, and the mixture was heated under reflux overnight. After cooling to room temperature, insolubles were filtered and concentrated under reduced pressure. Bromine was obtained. This was used for the next reaction as it was. Ethyl 3- (3-chlorophenyl) -3-oxopropionate (5.17 g, 22.8)
(Mmol) of dimethoxyethane (60 ml) was cooled on ice, and sodium hydride (60%, 0.92 g, 22.8) was added.
Mmol), and the mixture was stirred under ice-cooling for 15 minutes, and then brominated (22.8 mmol) in dimethoxyethane (40 ml).
The solution was added and stirred at room temperature overnight. After completion of the reaction, the reaction was quenched with 1N hydrochloric acid, diluted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 20: 1, 15:15).
Purified in 1), and ethyl 3- (3-chlorophenyl) -2-
[4- (1,1-difluoro-2,2-dimethylpropyl)
Benzyl] -3-oxopropionate (7.44 g, 7
7%) as a pale yellow oil. IRνmax ^KBr (cm ^-1 ): 1736, 1691, 1570, 1483, 1425, 1
367, 1259, 1093, 1072 ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.99 (9H, s) 1.12 (3H, t, J
= 6.9 Hz) 3.34 (2H, d, J = 7.5 Hz) 3.96-4.15 (2H,
m) 4.56 (1H, t, J = 7.2 Hz) 7.21-7.45 (5H, m) 7.50
-7.55 (1H, m) 7.78-7.90 (1H, m) 7.90-7.92 (1H, m). 4) Ethyl (2RS, 3RS) -3- (3-chlorophenyl) -3-hydroxy-2- [4- (1,1-difluoro-
2,2-Dimethylpropyl) benzyl] propionate Sodium borohydride (2.7) was added to an ether suspension (70 ml) of zinc chloride (4.94 g, 36.2 mmol).
(4 g, 72.4 mmol) at room temperature and stirred for 2 hours. The insolubles were filtered, and the filtrate was treated with ethyl 3- (3-
Chlorophenyl) -2- [4- (1,1-difluoro-2,
A solution of 2-dimethylpropyl) benzyl] -3-oxopropionate (7.59 g, 18.1 mmol) in ether (50 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was terminated with 1N hydrochloric acid, diluted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate,
Filtration and concentration under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 15: 1, 10:
1,5: 1) and purified by ethyl (2RS, 3RS) -3-
(3-chlorophenyl) -3-hydroxy-2- [4- (1,
1-difluoro-2,2-dimethylpropyl) benzyl]
Propionate (6.12 g, 80%) was obtained as a pale yellow oil. IRνmax ^KBr (cm ^-1 ): 3454, 1712, 1616, 1597, 1576, 1
483, 1398, 1371, 1398, 1286, 1259, 1190 ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.94 (3H, t, J = 7.2 Hz) 1.
00 (9H, s) 2.90-3.04 (2H, m) 3.11 (1H, d, J = 1.8
Hz) 3.90 (2H, q, J = 7.0 Hz) 5.03 (1H, d, J = 2.2 H
z) 7.09 (2H, d, J = 8.0 Hz) 7.25-7.29 (5H, m) 7.42
(1H, s). 5) (2RS, 3RS) -3- (3-chlorophenyl)-
3-hydroxy-2- [4- (1,1-difluoro-2,2-
Dimethylpropyl) benzyl] ethyl propionate (2RS, 3RS) -3- (3-chlorophenyl)-
3-hydroxy-2- [4- (1,1-difluoro-2,2-
Dimethylpropyl) benzyl] propionate (5.8
To a solution of 8 g (13.8 mmol) in tetrahydrofuran-ethanol (30 ml-30 ml) was added 1N sodium hydroxide (28 ml, 28 mmol) at room temperature, and the mixture was stirred at room temperature overnight. After completion of the reaction, the organic solvent was distilled off under reduced pressure, the aqueous layer was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Recrystallize with hexane-ethyl acetate,
(2RS, 3RS) -3- (3-chlorophenyl) -3-hydroxy-2- [4- (1,1-difluoro-2,2-dimethylpropyl) benzyl] propionic acid (4.24 g, 7
7%) as colorless crystals. mp 141-142 ℃ IRνmax ^KBr (cm ^-1 ): 2500-3300, 1709, 1599, 1574, 14
83, 1413, 1398, 1369, 1286, 1259 ¹ H-NMR (CDCl ₃ ) δ (ppm) 0.99 (9H, s) 2.90-3.05 (3H,
m) 5.10 (1H, d, J = 3.6 Hz) 7.07 (2H, d, J = 8.1
Hz) 7.25-7.28 (5H, m) 7.42 (1H, s). 6) (4RS, 5SR) -5- (3-chlorophenyl)-
4- [4- (1,1-difluoro-2,2-dimethylpropyl) benzyl] -1,3-oxazolidin-2-one (2RS, 3RS) -3- (3-chlorophenyl) -3-hydroxy-2 -[4- (1,1-difluoro-2,2-dimethylpropyl) benzyl] propionic acid (4.09 g, 1
0.3 mmol) of tetrahydrofuran (100 ml)
Triethylamine (2.16 ml, 15.45 mmol), diphenylphosphoric azide (2.67 ml, 1
(2.36 mmol) and heated to reflux for 4 hours. The solvent was distilled off, diluted with ethyl acetate, and washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Recrystallization from hexane-ethyl acetate gave (4RS, 5SR) -5- (3-chlorophenyl) -4- [4- (1,1-difluoro-2,2-
Dimethylpropyl) benzyl] -1,3-oxazolidine
-2-One (3.97 g, 98%) was obtained as colorless crystals. mp 188-190 ℃ IRνmax ^KBr (cm ^-1 ): 3246, 1739, 1437, 1369, 1286, 12
38, 1078 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.01 (9H, s) 2.27 (1H, dd,
J = 10.8, 13.1 Hz) 2.36 (1H, dd, J = 4.2, 12.8 Hz)
4.23-4.31 (1H, m) 5.09 (1H, s) 5.77 (1H, d, J = 8.
1 Hz) 7.05 (2H, d, J = 8.1 Hz) 7.24-7.29 (1H, m)
7.32-7.38 (5H, m). 7) (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- [4- (1,1-difluoro-2,2-dimethylpropyl) phenyl] -1-propanol (4RS, 5SR) -5- (3-chlorophenyl) -4-
[4- (1,1-difluoro-2,2-dimethylpropyl)
Benzyl] -1,3-oxazolidin-2-one (3.82
g, 9.70 mmol) in an ethanol (100 ml) solution and an 8 N aqueous sodium hydroxide solution (6.1 ml, 4 ml).
(8.5 mmol) and heated to reflux for 4 hours. After completion of the reaction, ethanol was distilled off under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate),
(1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- [4- (1,1-difluoro-2,2-dimethylpropyl) phenyl] -1-propanol (2.56 g, 7
2%) as colorless crystals. mp 105-107 ℃ IRνmax ^KBr (cm ^-1 ): 3352, 1597, 1483, 1286, 1259, 1
093, 1068, 1037, 1008,978 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.02 (9H, s) 2.38 (1H, dd,
J = 10.6, 13.6 Hz) 2.80 (1H, dd, J = 2.8, 13.2 Hz)
3.27-3.36 (1H, m) 4.68 (1H, d, J = 4.8 Hz) 7.15 (2
H, d, J = 8.2 Hz) 7.26-7.35 (5H, m) 7.42 (1H, s). 8) N-｛(1RS, 2SR) -2- (3-chlorophenyl) -1- [4- (1 , 1-Difluoro-2,2-dimethylpropyl) benzyl] -2-hydroxyethyl} -4-fluoro-1-naphthamide 4-fluoronaphthalene-1-carboxylic acid (216 mg,
1.15 mmol) in N, N-dimethylformamide (5 ml) solution, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (220 mg, 1.1
5 mmol), 1-hydroxybenzotriazole monohydrate (176 mg, 1.15 mmol) and finally (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- [4- ( 1,1-difluoro-2,2-dimethylpropyl) phenyl] -1-propanol (0.40 g,
(1.09 mmol) and stirred at room temperature overnight. It was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, dried over anhydrous magnesium sulfate, filtered through a glass filter filled with silica gel, washed with ethyl acetate, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-｛(1RS, 2SR) -2- (3-chlorophenyl) -1- [4- (1,1-difluoro-2,2-dimethylpropyl). [Benzyl] -2-hydroxyethyl} -4-fluoro-1-naphthamide (289 mg, 49%) was obtained as colorless crystals. mp 104-106 ℃ IRνmax ^KBr (cm ^-1 ): 3244, 1639, 1626, 1599, 1516, 1
425, 1286, 1261, 1091,1072, 1008, 978 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.01 (9H, s) 2.82 (1H, dd,
J = 11.0, 14.4 Hz) 3.03 (1H, dd, 4.4, 14.4 Hz) 3.8
5 (1H, s) 4.72-4.81 (1H, m) 5.10 (1H, d, J = 3.4 H
z) 5.98 (1H, d, J = 8.4 Hz) 6.93 (1H, dd, J = 7.6,
9.8 Hz) 7.10 (1H, dd, J = 5.0, 7.6 Hz) 7.19-7.56
(10H, m) 7.75 (1H, d, J = 7.6 Hz) 8.06 (1H, d, J =
8.0 Hz).

Example 380 N-{(1RS, 2SR) -2- (3-chlorophenyl)-
1- [4- (1,1-difluoro-2,2-dimethylpropyl) benzyl] -2-hydroxyethyl} -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide 6,7-dihydro -5H-benzo [a] cycloheptene-1
-Carboxylic acid (216 mg, 1.15 mmol) N,
N-dimethylformamide (5 ml) solution in 1-ethyl
-3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (220 mg, 1.15 mmol), 1-hydroxybenzotriazole monohydrate (176 mg, 1.15)
Mmol) and finally (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- [4- (1,1-difluoro-2,2-dimethylpropyl) phenyl] -1-propanol (0.40 g, 1.09 mmol) and the mixture was stirred at room temperature overnight. Dilute with ethyl acetate, add saturated aqueous sodium bicarbonate,
After washing with water and saturated saline and drying over anhydrous magnesium sulfate, the mixture was filtered through a glass filter filled with silica gel, washed with ethyl acetate, and concentrated under reduced pressure. The residue is purified by recrystallization (hexane-ethyl acetate) and N-｛(1RS, 2SR)
-2- (3-chlorophenyl) -1- [4- (1,1-difluoro-2,2-dimethylpropyl) benzyl] -2-hydroxyethyl} -6,7-dihydro-5H-benzo [a] cycloheptene -1-carboxamide (316 mg, 54%)
Was obtained as colorless crystals. mp 119-120 ℃ IRνmax ^KBr (cm ^-1 ): 3265, 1635, 1516, 1485, 1286, 12
59 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.28 (6H, s) 1.98-2.01 (2H,
m) 2.16-2.21 (2H, m) 2.58-2.69 (3H, m) 2.87-2.95
(1H, m) 4.20 (2H, s) 4.62 (1H, br) 5.00 (1H, s) 5.7
1 (1H, d, J = 7.4 Hz) 5.89-6.00 (1H ,, m) 6.26 (1H,
d, J = 11.8 Hz) 6.68 (1H, d, J = 8.8 Hz) 6.88-7.1
6 (5H, m) 7.26-7.30 (3H, m) 7.46 (1H, s)

Example 381 5-Chloro-N-{(1RS, 2SR) -2- (3-chlorophenyl) -1- [4- (1,1-difluoro-2,2-dimethylpropyl) benzyl] -2 -Hydroxyethyl} -1-naphthamide 5-chloronaphthalene-1-carboxylic acid (238 mg,
1.15 mmol) in N, N-dimethylformamide (5 ml) solution, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (220 mg, 1.1
5 mmol), 1-hydroxybenzotriazole monohydrate (176 mg, 1.15 mmol) and finally (1RS, 2SR) -2-amino-1- (3-chlorophenyl) -3- [4- ( 1,1-difluoro-2,2-dimethylpropyl) phenyl] -1-propanol (0.40 g,
(1.09 mmol) and stirred at room temperature overnight. It was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, dried over anhydrous magnesium sulfate, filtered through a glass filter filled with silica gel, washed with ethyl acetate, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give 5-chloro-N-｛(1RS, 2SR) -2- (3-
Chlorophenyl) -1- [4- (1,1-difluoro-2,
2-Dimethylpropyl) benzyl] -2-hydroxyethyl} -1-naphthamide (252 mg, 42%) was obtained as colorless crystals. mp 99-101 ℃ IRνmax ^KBr (cm ^-1 ): 3260, 1635, 1521, 1286, 1093, 1
072, 1037, 1008, 978,908 ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.01 (9H, s) 2.79 (1H, dd,
J = 11.1, 14.4 Hz) 3.02 (1H, dd, J = 3.6, 14.1 Hz)
4.74-4.82 (1H, m) 5.07 (1H, d, J = 3.6 Hz) 6.02 (1
H, d, J = 8.7 Hz) 7.15-7.41 (10H, m) 7.53-7.57 (3
H, m) 8.28 (1H, d, J = 8.7 Hz).

Example 382 Acetic acid (1RS, 2SR) -2-[(6,7-dihydro-5H
-Benzo [a] cyclohepten-1-ylcarbonyl) amino] -1- (4-fluorophenyl) -3- [3- (1,
1,2,2-tetrafluoroethoxy) phenyl] propyl N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
0.359 g (0.675 mmol) of 5H-benzo [a] cycloheptene-1-carboxamide, 2 m of acetic anhydride
l, 5 ml of pyridine was stirred at 100 ° C. overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate) and crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.347 g Yield 90% mp 176-177 ° C; ¹ H-NMR (CDCl ₃ , 200 MHz) δ 1.91-2.05
(2H, m), 2.15 (3H, s), 2.13-2.32 (2H, m), 2.63-2.
66 (2H, m), 2.71 (1H, dd, J = 10.2 Hz, 15.2Hz), 3.
07 (1H, dd, J = 4.3 Hz, 14.7 Hz), 4.89-5.03 (1H,
m), 5.51 (1H, d, J = 9.6 Hz), 5.89 (1H, tt, J = 2.9
Hz, 53.0 Hz), 5.81-6.06 (3H, m), 6.82 (1H, dd, J
= 2.0 Hz, 7.2 Hz), 6.97-7.15 (7H, m), 7.32 (1H, t,
J = 7.9Hz), 7.41 (2H, dd, J = 5.4Hz, 8.6Hz); IR
(KBr) 3241, 1746, 1642, 1512,1275, 1236, 1113, 77
2 cm ^-1 ; Anal.Calcd for C ₃₁ H ₂₈ F ₅ NO ₄ : C, 64.92; H,
4.92; N, 2.44. Found: C, 64.87; H, 4.84; N, 2.30.

Example 383 Succinic acid (1RS, 2SR) -2-[(6,7-dihydro-
5H-benzo [a] cyclohepten-1-ylcarbonyl) amino] -1- (4-fluorophenyl) -3- [3-
(1,1,2,2-tetrafluoroethoxy) phenyl] propyl methyl N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
0.31 g (0.566 mmol) of 5H-benzo [a] cycloheptene-1-carboxamide, 0.10 ml (0.85 mmol) of monomethyl succinate monochloride,
0.14 g of 4-N, N-dimethylaminopyridine (1.1
(3 mmol) in 15 ml of acetonitrile was stirred at 80 ° C. for 2 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-2 / 1) to obtain the desired product. White solid Yield 0.365 g Yield 100% Recrystallization from ethyl acetate-hexane gave white crystals. mp 170-171 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.92-2.00
(2H, m), 2.18-2.24 (2H, m), 2.61-2.81 (7H, m), 3.
02 (1H, dd, J = 4.2 Hz, 14.4 Hz), 3.50 (3H, s), 4.8
7-4.97 (1H, m), 5.85 (1H, td, J = 5.2 Hz, 11.9 H
z), 5.89 (1H, tt, J = 2.8 Hz, 53.0 Hz), 5.90 (1H,
d, J = 9.9 Hz), 6.03 (1H, d, J = 12.0 Hz), 6.16 (1
H, d, J = 4.8 Hz), 6.86 (1H, dd, J = 1.5 Hz, 7.5 H
z), 6.99-7.13 (7H, m), 7.30 (1H, t, J = 8.0 Hz),
7.43 (2H, dd, J = 5.3 Hz, 8.6 Hz); IR (KBr) 3239, 1
742, 1640, 1512, 1223, 1165, 1128 cm ^-1 ; Anal.Calc
d forC ₃₄ H ₃₂ F ₅ NO ₆ : C, 63.25; H, 5.00; N, 2.17. Foun
d: C, 63.21; H, 5.03; N, 2.13.

Example 384 Succinic acid (1RS, 2SR) -2-[(6,7-dihydro-
5H-benzo [a] cyclohepten-1-ylcarboni
Ru) amino] -1- (4-fluorophenyl) -3- [3-
(1,1,2,2-tetrafluoroethoxy) phenyl
] Propyl hydrogen N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafur
Oroethoxy) benzyl] ethyl] -6,7-dihydro-
5H-benzo [a] cycloheptene-1-carboxamide
0.566 g (1.065 mmol) and chlorinated succinate
0.41 g (2.66 mmol) of acetonitrile 3
To a 0 ml solution was added 4-N, N-dimethylaminopyridine.
26 g (2.13 mmol) were added and stirred at 70 ° C. for 3 hours.
Stirred. After cooling the reaction solution to room temperature, 30 ml of water was added.
Then, the mixture was stirred for 0.5 hour. Acidify with dilute hydrochloric acid
And extracted twice with ethyl acetate. The collected organic layer
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Profit
The crude product was purified by silica gel column chromatography.
(Hexane / ethyl acetate = 1 / 1-ethyl acetate)
), Crystallized from diisopropyl ether-hexane
Then, the desired product was obtained. Light brown powder Yield 0.466 g
Rate 69% mp 154-155 ° C;¹H-NMR (CDCl_Three, 300 MHz) δ 1.92-2.01
 (2H, m), 2.17-2.23 (2H, m), 2.58-2.77 (7H, m), 3.
04 (1H, dd, J = 3.8 Hz, 14.3 Hz), 4.89-4.99 (1H,
m), 5.71 (1H, d, J = 9.3 Hz), 5.85 (1H, td, J = 5.
1 Hz, 11.7 Hz), 5.89 (1H, tt, J = 2.9 Hz, 53.1 H
z), 6.00 (1H, d, J = 11.7 Hz), 6.06 (1H, d, J = 5.4
 Hz), 6.84 (1H, dd, J = 1.4 Hz, 7.7 Hz), 6.98-7.13
 (7H, m), 7.30 (1H, t, J = 7.8 Hz), 7.41 (2H, dd,
J = 5.3 Hz, 8.6 Hz); IR (KBr) 3243, 3067, 2940, 17
34, 1640, 1512, 1211, 1155, 1123 cm^-1; Anal. Calcd
 for C ₃₃H₃₀F_FiveNO₆・ 0.5H_TwoO: C, 61.87; H, 4.88; N, 2.1
9. Found: C, 61.78; H, 4.77; N, 2.15.

Example 385 Sodium succinate (1RS, 2SR) -2-[(6,7
-Dihydro-5H-benzo [a] cyclohepten-1-ylcarbonyl) amino] -1- (4-fluorophenyl) -3
-[3- (1,1,2,2-tetrafluoroethoxy) phenyl] propyl succinic acid (1RS, 2SR) -2-[(6,7-dihydro-
5H-benzo [a] cyclohepten-1-ylcarbonyl) amino] -1- (4-fluorophenyl) -3- [3-
To a solution of 165 mg (0.261 mmol) of (1,1,2,2-tetrafluoroethoxy) phenyl] propyl hydrogen in 2 ml of tetrahydrofuran was added 0.26 ml (0.26 mmol) of a 1 N aqueous sodium hydroxide solution,
Stir at room temperature for 5 minutes. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was crystallized from ethanol-hexane to obtain the desired product. Light brown powder Yield 130 mg Yield 76% mp 165-170 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.92-2.00
(2H, m), 2.17-2.23 (2H, m), 2.60-2.75 (7H, m), 3.
03 (1H, dd, J = 3.9 Hz, 14.1 Hz), 4.90-5.00 (1H,
m), 5.66 (1H, d, J = 9.6 Hz), 5.85 (1H, td, J = 5.
3 Hz, 10.5 Hz), 5.89 (1H, tt, J = 2.9 Hz, 53.0 H
z), 6.01 (1H, d, J = 12.0 Hz), 6.04 (1H, d, J = 5.1
Hz), 6.83 (1H, dd, J = 1.5 Hz, 7.5 Hz), 6.99-7.13
(7H, m), 7.29 (1H, t, J = 7.8 Hz), 7.40 (2H, dd,
J = 5.3 Hz, 8.9 Hz); IR (KBr) 3400-2900, 1730, 164
0, 1534, 1514, 1200, 1159, 1128 cm ^-1 ; Anal.Calcd
for C _{3 3} H ₂₉ F ₅ NO ₆ Na ・ 2.0H ₂ O: C, 57.48; H, 4.82; N, 2.
03. Found: C, 57.49; H, 4.46; N, 1.88.

Example 386 N- (tert-butoxycarbonyl) glycine (1R
S, 2SR) -2-[(6,7-dihydro-5H-benzo [a] cyclohepten-1-ylcarbonyl) amino]-
1- (4-fluorophenyl) -3- [3- (1,1,2,2
2-tetrafluoroethoxy) phenyl] propyl ester N-[(1RS, 2SR) -2- (4-fluorophenyl)
-2-Hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro-
0.34 g (0.572 mmol) of 5H-benzo [a] cycloheptene-1-carboxamide, 0.12 g (0.69 mmol) of BOC-glycine 0.14 g (1.14 g) of 4-N, N-dimethylaminopyridine Mmol), 1
A solution of 0.16 g (0.86 mmol) of -ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride in 10 ml of acetonitrile was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure to obtain the desired product. White solid Yield: 0.411 g Yield: 100% Crystallization from diisopropyl ether-hexane gave a white powder. mp 151-152 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.41 (9H,
s), 1.93-2.01 (2H, m), 2.18-2.24 (2H, m), 2.66 (2
H, t, J = 5.9 Hz), 2.70 (1H, dd, J = 10.5 Hz, 14.4
Hz), 3.04 (1H, dd, J = 4.1 Hz, 14.3 Hz), 3.91-4.0
6 (2H, m), 4.91-5.00 (1H, m), 5.07 (1H, br t, J =
4.5 Hz), 5.68 (1H, d, J = 9.9 Hz), 5.86 (1H, td, J
= 5.4 Hz, 12.0 Hz), 5.89 (1H, tt, J = 2.9 Hz, 53.
1 Hz), 6.02 (1H, d, J = 11.7 Hz), 6.11 (1H, d, J =
5.4 Hz), 6.87 (1H, d, J = 7.2 Hz), 7.01-7.13 (7H,
m), 7.31 (1H, t, J = 8.0 Hz), 7.41 (2H, dd, J =
5.4 Hz, 8.7 Hz); IR (KBr) 3370, 3310, 2936, 1750,
1684, 1638, 1512, 1225, 1196, 1157, 1125 cm ^-1 ; Ana
l. Calcd for C ₃₆ H ₃₇ F ₅ N ₂ O ₆ : C, 62.79; H, 5.42; N, 4.
07. Found: C, 62.60; H, 5.49; N, 4.00.

Example 387 Glycine (1RS, 2SR) -2-[(6,7-dihydro-
5H-benzo [a] cyclohepten-1-ylcarbonyl) amino] -1- (4-fluorophenyl) -3- [3-
(1,1,2,2-tetrafluoroethoxy) phenyl] propyl ester hydrochloride N- (tert-butoxycarbonyl) glycine (1R
S, 2SR) -2-[(6,7-dihydro-5H-benzo [a] cyclohepten-1-ylcarbonyl) amino]-
1- (4-fluorophenyl) -3- [3- (1,1,2,2
0.351 g (0.510 mmol) of 2-tetrafluoroethoxy) phenyl] propyl ester, concentrated hydrochloric acid 0.1%.
A mixture of 3 ml and 8 ml of methanol was stirred at 50 ° C. for 1 hour. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was crystallized from diethyl ether to obtain the desired product. White powder Yield 0.270 g Yield 85% mp 174-177 ° C. (dec.); ¹ H-NMR (CD ₃ OD, 300 MHz) δ 1.8
8-1.96 (2H, m), 2.19-2.24 (2H, m), 2.63-2.72 (3H,
m), 3.24 (1H, dd, J = 3.3 Hz, 14.1 Hz), 3.90 (1H,
d, J = 17.1 Hz), 3.99 (1H, d, J = 17.1 Hz), 4.86-
4.98 (1H, m), 5.69-5.79 (2H, m), 6.04 (1H, d, J =
6.9 Hz), 6.24 (1H, tt, J = 2.9 Hz, 52.6Hz), 6.59
(1H, dd, J = 1.2 Hz, 7.5 Hz), 7.00 (1H, t, J = 7.4
Hz), 7.10-7.17 (5H, m), 7.23 (1H, d, J = 7.8 Hz),
7.38 (1H, t, J = 7.8 Hz), 7.55 (2H, dd, J = 5.3 H
z, 8.9 Hz); IR (KBr) 3283, 3100-2800, 1744, 1640,
1514,1271, 1233, 1200, 1125 cm ^-1 ; Anal.Calcd for
C ₃₁ H ₃₀ ClF ₅ N ₂ O ₄・ 0.5H ₂ O: C, 58.72; H, 4.93; N, 4.42.
Found: C, 58.46; H, 4.84; N, 4.51.

Example 388 Succinic acid (1RS, 2SR) -2-[(4-fluoro-1-
Naphthoyl) amino] -1- (4-fluorophenyl) -3
-[3- (1,1,2,2-tetrafluoroethoxy) phenyl] propyl hydrogen 4-fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [ 3- (1,1,2,2
4-N, N-dimethyl was added to a solution of 0.664 g (1.245 mmol) of 2-tetrafluoroethoxy) benzyl] ethyl] naphthalene-1-carboxamide and 0.48 g (3.11 mmol) of succinic chloride in 30 ml of acetonitrile. Aminopyridine 0.30 g (2.49 mmol)
Was added and stirred at 70 ° C. for 3 hours. After the reaction solution was cooled to room temperature, 30 ml of water was added and the mixture was stirred for 0.5 hour. This was acidified with diluted hydrochloric acid, and then extracted twice with ethyl acetate. The collected organic layer is dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 1-ethyl acetate), and diisopropyl ether-
Crystallization from hexane gave the desired product. Light brown powder
Yield 0.438 g Yield 56% mp 181-182 ° C .; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
2.70-2.76 (4H, m), 2.84 (1H, dd, J = 11.7 Hz, 14.4
Hz), 3.07 (1H, dd, J = 3.9 Hz, 14.4 Hz), 4.93-5.02
(1H, m), 5.94 (1H, tt, J = 2.9 Hz, 53.0 Hz), 6.27
(1H, d, J = 5.4Hz), 7.01-7.32 (8H, m), 7.40-7.53
(5H, m), 8.03 (1H, d, J = 9.0 Hz); IR (KBr) 3308, 3
100-2800, 1740, 1723, 1640, 1624, 1530, 1516, 123
5, 1179,1119 cm ^-1 ; Anal.Calcd for C ₃₂ H ₂₅ F ₆ NO ₆ : C,
60.67; H, 3.98; N, 2.21. Found: C, 60.37; H, 3.7
6; N, 2.05.

Example 389 Sodium succinate (1RS, 2SR) -2-[(4-fluoro-1-naphthoyl) amino] -1- (4-fluorophenyl) -3- [3- (1,1,2 , 2-Tetrafluoroethoxy) phenyl] propyl succinic acid (1RS, 2SR) -2-[(4-fluoro-1-
Naphthoyl) amino] -1- (4-fluorophenyl) -3
To a solution of 242 mg (0.382 mmol) of-[3- (1,1,2,2-tetrafluoroethoxy) phenyl] propyl hydrogen in 2 ml of tetrahydrofuran was added 0.38 ml (0.38 mmol) of a 1 N aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 5 minutes. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was crystallized from ethanol-hexane to obtain the desired product. Light brown powder Yield 165 mg Yield 66% mp 192-198 ° C .; ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ 2.42-2.
64 (4H, m), 2.81 (1H, dd, J = 11.7 Hz, 13.2 Hz), 3.
08 (1H, dd, J = 2.1 Hz, 13.5 Hz), 4.68-4.79 (1H,
m), 5.93 (1H, d, J = 6.9 Hz), 6.73 (1H, tt, J = 2.
9 Hz, 51.8 Hz), 7.08-7.42 (10H, m), 7.50 (2H, dd, J
= 5.7 Hz, 8.4 Hz), 7.58 (1H, t, J = 7.4 Hz), 8.01
(1H, d, J = 8.7 Hz), 8.73 (1H, d, J = 9.3 Hz); IR
(KBr) 3304, 1738, 1842, 1574, 1530, 1514, 1119 cm
^-1 ; Anal.Calcd for C ₃₂ H ₂₄ F ₆ NO ₆ Na ・ 1.0H ₂ O: C, 57.0
6; H, 3.89; N, 2.08. Found: C, 56.79; H, 3.86; N,
1.90.

Example 390 N- (tert-butoxycarbonyl) glycine (1R
S, 2SR) -2-[(4-Fluoro-1-naphthoyl) amino] -1- (4-fluorophenyl) -3- [3- (1,
1,2,2-tetrafluoroethoxy) phenyl] propyl ester 4-fluoro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1, 2,
0.486 g (0.911 mmol) of 2-tetrafluoroethoxy) benzyl] ethyl] naphthalene-1-carboxamide, 0.19 g (1.09 mmol) of BOC-glycine, 0.22 g of 4-N, N-dimethylaminopyridine
(1.82 mmol) 0.26 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
A solution of (1.37 mmol) in 20 ml of acetonitrile was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through silica gel, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from diisopropyl ether-hexane to obtain the desired product. White powder Yield 0.582 g Yield 93% mp 126-127 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.33 (9H,
s), 2.81 (1H, dd, J = 11.0 Hz, 14.6 Hz), 3.10 (1H,
dd, J = 3.9 Hz, 14.4 Hz), 3.93 (1H, dd, J = 6.0 H
z, 17.4 Hz), 4.04 (1H, dd, J = 5.9 Hz, 1.9 Hz), 4.
98-5.09 (2H, m), 5.88 (1H, tt, J = 2.8 Hz, 53.2 H
z), 6.08 (1H, d, J = 9.9 Hz), 6.26 (1H, d, J = 3.9
Hz), 7.00 (1H, dd, J = 7.8 Hz, 9.9 Hz), 7.08-7.19
(6H, m), 7.32 (1H, t, J = 8.0 Hz), 7.40-7.54 (4H,
m), 7.62 (1H, d, J = 7.8 Hz), 8.06 (1H, d, J = 7.8
Hz); IR (KBr) 3360, 3297, 2982, 1746, 1682, 1642,
1530, 1514, 1227, 2300, 1161, 1125 cm ^-1 ; Anal.Ca
lcd for C ₃₅ H ₃₂ F ₆ N ₂ O ₆ : C, 60.87; H, 4.67; N, 4.06. F
ound: C, 60.73; H, 4.65; N, 4.05.

Example 391 Glycine (1RS, 2SR) -2-[(4-fluoro-1-
Naphthoyl) amino] -1- (4-fluorophenyl) -3
-[3- (1,1,2,2-tetrafluoroethoxy) phenyl] propyl ester hydrochloride N- (tert-butoxycarbonyl) glycine (1R
S, 2SR) -2-[(4-Fluoro-1-naphthoyl) amino] -1- (4-fluorophenyl) -3- [3- (1,
A mixture of 0.404 g (0.585 mmol) of 1,2,2-tetrafluoroethoxy) phenyl] propyl ester, 0.4 ml of concentrated hydrochloric acid and 6 ml of methanol was stirred at 50 ° C. for 1 hour. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was crystallized from diethyl ether to obtain the desired product. White powder Yield 0.331 g Yield 90% mp 209-212 ° C (dec.); ¹ H-NMR (CD ₃ OD, 300 MHz) δ 2.7
8 (1H, dd, J = 11.9 Hz, 14.3 Hz), 3.33 (1H, dd, J
= 3.9 Hz, 14.3 Hz), 3.95 (1H, d, J = 17.4 Hz), 4.0
4 (1H, d, J = 17.4 Hz), 4.98-5.06 (1H, m), 6.08 (1
H, d, J = 7.5 Hz), 6.249 (1H, tt, J = 2.9 Hz, 52.7
Hz), 7.00 (1H, dd, J = 5.4 Hz, 8.1 Hz), 7.07 (1H,
dd, J = 7.7 Hz, 10.1 Hz), 7.14-7.28 (6H, m), 7.36
-7.41 (2H, m), 7.51-7.61 (3H, m), 8.03 (1H, d, J =
8.4 Hz); IR (KBr) 3301, 3100-2800, 1740, 1644, 151
4, 1275, 1235, 1206, 1121 cm ^-1 ; Anal.Calcd for C
_{30 H 2 5 ClF 6 N 2} O 4 · 0.5H 2 O: C, 56.66; H, 4.12; N, 4.40.
Found: C, 56.81; H, 4.35; N, 4.62.

Example 392 (1RS, 2SR) -3- (4-tert-butylphenyl) -2-[(5-chloro-1-naphthoyl) amino] -1- (4-fluorophenyl) propyl hydrogen succinate 0.499 g of N-[(1RS, 2SR) -1- (4-tert-butylbenzyl) -2- (3-chlorophenyl) -2-hydroxyethyl] -5-chloro-1-naphthamide (0.
985 mmol) and 0.38 g of succinic chloride (2.
46 mmol) in 30 ml of acetonitrile
0.24 g of N, N-dimethylaminopyridine (1.97
Mmol) and stirred at 70 ° C. for 3 hours. After cooling the reaction solution to room temperature, 30 ml of water was added, and
Stirred for hours. This was acidified with diluted hydrochloric acid, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2 / 1-1 / 1), and crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.325 g Yield 54% mp 161-162 ° C; ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.31 (9H,
s), 2.63-2.84 (5H, m), 3.02 (1H, dd, J = 4.1 Hz,
14.0 Hz), 4.98-5.06 (1H, m), 5.97 (1H, d, J = 9.3 H
z), 6.21 (1H, d, J = 4.8 Hz), 7.11 (2H, d, J = 8.4
Hz), 7.18-7.54 (11H, m), 8.28 (1H, d, J = 8.7 Hz);
IR (KBr) 3300-3020, 2961, 1734, 1644, 1532, 1213,
1165, 783 cm ^-1 ; Anal.Calcd for C ₃₄ H ₃₃ Cl ₂ NO ₅・ 0.5H
₂ O: C, 66.34; H, 5.57; N, 2.28. Found: C, 66.28;
H, 5.34; N, 2.28.

Example 393 Sodium succinate (1RS, 2SR) -3- (4-te)
rt-butylphenyl) -2-[(5-chloro-1-naphthoyl) amino] -1- (4-fluorophenyl) propyl (1RS, 2SR) -3- (4-tert-butylphenyl) -2 succinate -[(5-Chloro-1-naphthoyl) amino] -1- (4-fluorophenyl) propyl hydrogen 217
mg (0.358 mmol) of tetrahydrofuran 3m
0.36 ml of 1N aqueous sodium hydroxide solution
(0.36 mmol) and stirred at room temperature for 5 minutes. The solvent of the reaction solution was distilled off under reduced pressure.
Crystallization from -diethyl ether-hexane gave the desired product. White powder Yield 200 mg Yield 89% mp 174-178 ° C .; ¹ H-NMR (CDCl ₃ -CD ₃ OD, 300 MHz) δ 1.3
0 (9H, s), 2.53-2.58 (2H, m), 2.65-2.83 (3H, m),
3.00 (1H, dd, J = 2.7 Hz, 14.4 Hz), 4.89-4.98 (1H,
m), 6.17 (1H, d, J = 4.8 Hz), 7.12 (2H, d, J = 8.4
Hz), 7.20-7.54 (11H, m), 8.28 (1H, d, J = 8.4 Hz);
IR (KBr) 3245, 2965, 1730, 1640, 1574, 1418, 115
7, 785 cm ^-1 ; Anal.Calcd for C ₃₄ H ₃₂ Cl ₂ NO ₅ Na ・ 1.0H
₂ O: C, 63.16; H, 5.30; N, 2.17. Found: C, 62.93;
H, 5.57; N, 2.04.

Example 394 (1RS, 2SR) -2-succinic acid-2-[(5-chloro-1-naphthoyl) amino] -1- (4-fluorophenyl) -3-
[4- (trifluoromethyl) phenyl] propyl hydrogen 5-chloro-N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] To a solution of 0.549 g (1.094 mmol) of ethyl] naphthalene-1-carboxamide and 0.42 g (2.73 mmol) of succinic chloride in 30 ml of acetonitrile, 0.27 g of 4-N, N-dimethylaminopyridine (2. 19 mmol) and stirred at 70 ° C. for 3 hours. After the reaction solution was cooled to room temperature, 30 ml of water was added and the mixture was stirred for 0.5 hour. This was acidified with diluted hydrochloric acid, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2 / 1-1 / 1).
1) Crystallized from diisopropyl ether-hexane to obtain the desired product. White crystals Yield 0.408 g Yield 62% mp 228-229 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
2.65-2.79 (4H, m), 2.87 (1H, dd, J = 11.7 Hz, 13.5
Hz), 3.13 (1H, dd, J = 3.3 Hz, 14.1 Hz), 4.94-5.04
(1H, m), 6.21 (1H, d, J = 6.0 Hz), 7.08-7.23 (5H,
m), 7.38 (2H, d, J = 7.8 Hz), 7.47-7.54 (6H, m),
7.75 (1H, d, J = 9.6 Hz), 8.25 (1H, d, J = 8.4 Hz);
IR (KBr) 3300-2640, 1730, 1636, 1528, 1510, 1323,
1221, 1177, 1155, 1109 cm ^-1 ; Anal.Calcd for C ₃₁ H
₂₄ ClF ₄ NO ₅・ 0.3H ₂ O: C, 61.30; H, 4.08; N, 2.31. Foun
d: C, 61.21; H, 3.72; N, 2.36.

Example 395 Sodium succinate (1RS, 2SR) -2-[(5-chloro-1-naphthoyl) amino] -1- (4-fluorophenyl) -3- [4- (trifluoromethyl) phenyl ] Propyl (1RS, 2SR) -2-[(5-chloro-1-naphthoyl) amino] -1- (4-fluorophenyl) -3-succinate
To a solution of 214 mg of [4- (trifluoromethyl) phenyl] propyl hydrogen in 3 ml of tetrahydrofuran was added 0.36 ml (0.36 mmol) of a 1N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 5 minutes. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was crystallized from methanol-diethyl ether-hexane to obtain the desired product. Light yellow amorphous powder Yield 132 mg ¹ H-NMR (CDCl ₃ -DMSO-d ₆ -CD ₃ OD, 300 MHz) δ 2.54-2.79
(4H, m), 2.91 (1H, dd, J = 11.7 Hz, 14.1 Hz), 3.0
8 (1H, dd, J = 2.6 Hz, 14.0 Hz), 4.86-4.93 (1H,
m), 6.18 (1H, d, J = 5.7 Hz), 7.04-7.22 (4H, m),
7.26 (1H, d, J = 6.6 Hz), 7.39 (2H, d, J = 8.4 H
z), 7.47-7.55 (6H, m), 8.26 (1H, d, J = 8.1Hz); IR
(KBr) 3650-2940, 1730, 1640, 1574, 1539, 1512, 13
^{27, 1159, 1123cm -1;.} Anal Calcd for C 31 H 23 ClF 4 NO 5 N
a ・ 1.1H ₂ O: C, 57.84; H, 3.95; N, 2.18. Found: C, 5
7.68; H, 3.97; N, 2.13.

Example 396 (1RS, 2SR) -1- (4-Fluorophenyl) -2-[(4-fluoro-1-naphthoyl) amino] -3 succinate
-(2,2,3,3-tetrafluoro-2,3-dihydro-
1,4-benzodioxin-6-yl) propyl hydrogen 4-fluoro-N-{(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1-[(2,2,3,3 -
Tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] ethyl} -1-naphthamide
278 g (0.508 mmol) and 0.20 g (1.27 mmol) of succinic chloride in acetonitrile 30
0.1 ml of 4-N, N-dimethylaminopyridine
2 g (1.02 mmol) was added, and the mixture was stirred at 70 ° C. for 3 hours. After cooling the reaction solution to room temperature, 30 ml of water was added,
The mixture was stirred for 0.5 hours as it was. This was acidified with diluted hydrochloric acid, and then extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2 / 1-1 / 1), and crystallized from diisopropyl ether-hexane to obtain the desired product. White crystal Yield 0.184 g Yield 56% mp 196-197 ° C; ¹ H-NMR (CDCl ₃ -DMSO-d ₆ , 300 MHz) δ
2.71-2.75 (4H, m), 2.78 (1H, dd, J = 11.4 Hz, 14.4
Hz), 2.98 (1H, dd, J = 3.6 Hz, 14.7 Hz), 4.89-4.98
(1H, m), 6.33 (1H, d, J = 4.5 Hz), 7.01-7.16 (6H,
m), 7.27 (1H, dd, J = 5.4 Hz, 8.1 Hz), 7.38-7.54
(6H, m), 8.05 (1H, d, J = 7.8 Hz); IR (KBr) 3285-26
20, 1728, 1512, 1279, 1223, 1159, 1084 cm ^-1 ; Anal.
Calcd for C ₃₂ H ₂₃ F ₆ NO ₇・ 0.5H ₂ O: C, 58.54; H, 3.68;
N, 2.13. Found: C, 58.76; H, 3.85; N, 2.31.

Example 397 Sodium succinate (1RS, 2SR) -1- (4-fluorophenyl) -2-[(5-fluoro-1-naphthoyl)
Amino] -3- (2,2,3,3-tetrafluoro-2,3
-Dihydro-1,4-benzodioxin-6-yl) propyl succinic acid (1RS, 2SR) -1- (4-fluorophenyl) -2-[(4-fluoro-1-naphthoyl) amino] -3
-(2,2,3,3-tetrafluoro-2,3-dihydro-
1,4-benzodioxin-6-yl) propyl hydrogen 14
0.25 ml (0.22 mmol) of 1N aqueous sodium hydroxide solution in 5 ml of a solution of 5 mg of tetrahydrofuran
Was added and stirred at room temperature for 5 minutes. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was crystallized from methanol-diethyl ether-hexane to obtain the desired product. White powder Yield 79 mg ¹ H-NMR (CDCl ₃ -DMSO-d ₆ -CD ₃ OD, 300 MHz) δ 2.54-2.76
(4H, m), 2.85 (1H, dd, J = 11.6 Hz, 14.3 Hz), 2.9
8 (1H, dd, J = 3.5 Hz, 14.3 Hz), 4.80-4.86 (1H,
m), 6.21 (1H, d, J = 4.8 Hz), 7.03-7.14 (6H, m),
7.25 (1H, dd, J = 5.4 Hz, 7.8 Hz), 7.40 (1H, dd, J
= 6.5 Hz, 8.6 Hz), 7.50-7.53 (4H, m), 8.04 (1H,
d, J = 8.7 Hz); IR (KBr) 3630-2930, 1728, 1642, 16
01, 1574, 1512, 1279, 1227, 1157, 1084 cm ^-1 ; Anal.
Calcd for C ₃₂ H ₂₂ F ₆ NO ₇ Na ・ 1.5H ₂ O: C, 55.18; H, 3.62;
N, 2.01. Found: C, 55.41; H, 3.67; N, 2.00.

[0530]

The compounds (I) and (I ') of the present invention have excellent cholesteryl ester transfer protein inhibitory activity and the like, and pharmaceutical preparations containing these compounds can be used, for example, as lipid-lowering agents and the like. It can be used safely and advantageously.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) / 351 4C206 31/357 31/357 4H006 31/36 31/36 31/381 31/381 31/42 31/42 31/426 31/426 31/44 31/44 31/4409 31/4409 31/47 31 / 47 A61P 3/06 A61P 3/06 9/04 9/04 9/10 9/10 43/00 111 43/00 111 123 123 123 C07C 233/19 C07C 233/19 233/21 233/21 233/22 233 / 22 233/60 233/60 233/63 233/63 233/73 233/73 235/48 235/48 235/66 235/66 235/82 235/82 235/84 235/84 237/48 237/48 255/57 255/57 255/60 255/60 271/16 271/16 271/22 271/22 275/28 275/28 311/17 311/17 323/40 323/40 323/60 323/60 C07D 213 / 40 C07D 213/40 213/61 213/61 213/64 213/64 213/65 2 13/65 215/50 215/50 261/12 261/12 277/28 277/28 307/52 307/52 307/54 307/54 307/79 307/79 309/38 309/38 317/46 317 / 46 317/68 317/68 319/20 319/20 321/10 321/10 333/24 333/24 333/54 333/54 333/68 333/68 // C07M 7:00 C07M 7:00 9:00 9:00 (72) Inventor Toshihiro Yamamoto 1-7-7-1 Yamada Nishi, Suita-shi, Osaka F-term (reference) 4C022 AA05 4C023 EA11 4C033 AD10 4C037 AA01 HA30 PA01 4C055 AA01 BA01 BA02 BA03 BA13 BA28 BA42 BB04 BB07 CA01 CA02 CA42 CB04 DA01 DA08 DA28 FA03 4C056 AA01 AB01 AC01 AD01 AE03 AF05 4C062 CC41 4C086 AA01 AA02 AA03 BA02 BA03 BA06 BA07 BA08 BA13 BA15 BA16 BA17 BC29 BC67 BC82 MA01 MA04 NA14 NA15 ZA36 ZC31 ZA33 A03A03 A02A03 ZC33 ZC41 4H006 AA01 AA03 AB20 AB23 BJ20 BJ30 BJ50 BM10 BM30 BM71 BM72 BM73 BN10 BP30 BP60 BR60 BR70 BT12 BV22 BV42 BV53 BV62 BV72 RA10 RA12 TA04 TB40 TB52

Claims (58)

[Claims] (1) Formula (1) [Wherein, Ar ¹ represents an aromatic ring group which may have a substituent, Ar ² represents an aromatic ring group having a substituent, OR ″ represents a hydroxyl group which may be protected, and R represents an acyl group. And R ′ represents a hydrogen atom or a hydrocarbon group which may have a substituent. Or a salt thereof (provided that benzyl- [2 (S) -hydroxy-2-thiazol-2-yl-
1 (S)-(4-trifluoromethyl-benzyl) -ethyl] -carbamic acid tert-butyl ester). 2. The compound according to claim 1, wherein Ar ¹ is an optionally substituted 5- or 6-membered aromatic ring group. 3. The compound according to claim 1, wherein Ar ¹ is a phenyl group which may have a substituent. 4. The compound according to claim 1, wherein Ar ² is a 5- or 6-membered aromatic ring group having a substituent. 5. The compound according to claim 1, wherein Ar ² is a phenyl group having a substituent. 6. R is a group represented by the formula R ^1N CO— (R ^1N represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent). A compound according to claim 1. 7. The compound according to claim 6, wherein R ^1N is a cyclic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent. 8. The compound according to claim 1, wherein R ″ is a hydrogen atom or an acyl group. 9. R ″ is represented by the formula R ^1O CO—, wherein R ^1O represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent. Claim 1 which is a group
A compound as described. 10. The compound according to claim 8, wherein R ^1O is an alkyl group which may have a substituent. 11. The compound according to claim 1, wherein R ″ is a hydrogen atom. 12. The compound according to claim 1, wherein R ′ is a hydrogen atom. 13. A group in which R is represented by the formula R ^1N CO— (R ^1N represents a cyclic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent). And
The compound according to claim 1, wherein R ″ is a hydrogen atom and R ′ is a hydrogen atom. 14. Ar ¹ is a substituent selected from a halogen atom, a lower alkyl group which may be halogenated, a lower alkoxy group which may be halogenated, and an aryloxy group which may have a substituent. A 5- or 6-membered aromatic ring group which may have a substituent, wherein Ar ² is a substituent selected from a halogen atom, a lower alkyl group which may be halogenated, and a lower alkoxy group which may be halogenated. A 5- or 6-membered aromatic ring group having
May have a substituent selected from a halogen atom, an optionally halogenated C _1-6 alkoxy and an optionally halogenated C _1-6 alkyl.
_1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, C _6-10 aryl-carbonyl, dihydronaphthalenecarbonyl, tetrahydronaphthalenecarbonyl, benzocycloheptenecarbonyl or benzocyclooctenecarbonyl, wherein R '' is a hydrogen atom The compound according to claim 1, wherein R 'is a hydrogen atom. 15. The compound according to claim 14, wherein the 5- or 6-membered aromatic ring group is a phenyl group, a pyridyl group, a thienyl group, a furyl group or a thiazolyl group. 16. The 5- or 6-membered aromatic ring group is a phenyl group, a pyridyl group or a thienyl group, and R is a halogen atom, an optionally halogenated C _1-6 alkoxy and an optionally halogenated group. C _1-6 good naphthalene carbonyl optionally having respective selected substituents from alkyl, dihydronaphthalene carbonyl, tetrahydronaphthalene carbonyl, benzocycloheptene carbonyl or compound of claim 14 wherein the benzocyclooctene carbonyl. 17. N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [4- (trifluoromethyl) benzyl] ethyl] -6,7-dihydro-5
H-benzo [a] cycloheptene-1-carboxamide,
4-fluoro-N-((1R, 2S) -2- (4-fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -1-naphthalenecarboxamide, N -[(1R, 2S) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7-dihydro- 5H-benzo [a] cycloheptene-1-carboxamide, N-[(1RS, 2SR) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoro Ethoxy) benzyl] ethyl] -5,6-dihydronaphthalene-1-carboxamide, N-[(1R
S, 2SR) -2- (4-Fluorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -6,7,8,9-tetrahydro
-5H-benzo [a] cycloheptene-1-carboxamide, 4-fluoro-N-[(1R, 2S) -2- (4-fluorophenyl) -2-hydroxy-1- [3- (1,1,2 ,
2-tetrafluoroethoxy) benzyl] ethyl] naphthalene-1-carboxamide, N-[(1RS, 2SR)-
2- (4-fluorophenyl) -2-hydroxy-1- [3-
(1,1,2,2-tetrafluoroethoxy) benzyl] ethyl] -5,6,7,8-tetrahydrobenzo [a] cyclooctene-1-carboxamide, N-[(1
RS, 2SR) -2- (4-Fluorophenyl) -2-hydroxy-1- (4-isopropylbenzyl) ethyl] -6
7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-((1RS, 2SR) -2- (3-fluorophenyl) -2-hydroxy-1-((4- (trifluoromethyl) phenyl ) Methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-((1RS, 2SR) -2-hydroxy-2-
(4-phenoxyphenyl) -1-((4- (trifluoromethyl) phenyl) methyl) ethyl) -6,7-dihydro
-5H-benzo [a] cycloheptene-1-carboxamide, N-[(1RS, 2SR) -2- (4-chlorophenyl) -2-hydroxy-1- [3- (1,1,2,2-tetrafluoro) Ethoxy) benzyl] ethyl] -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-((1RS, 2SR) -2-hydroxy-2- (4-
(Phenyloxy) phenyl) -1-((3-((1,
1,2,2-tetrafluoroethyl) oxy) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-((1
RS, 2SR) -2- (4-((4-chloro-3-ethylphenyl) oxy) phenyl) -2-hydroxy-1-((3-
((1,1,2,2-tetrafluoroethyl) oxy)
Phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-
((1RS, 2SR) -2- (2-fluoropyridine-4-
Yl) -2-hydroxy-1-((3- (1,1,2,2-tetrafluoroethoxy) phenyl) methyl) ethyl)-
6,7-dihydro-5H-benzo [a] cycloheptene-1
-Carboxamide, N-((1RS, 2RS) -2- (6-
Fluoropyridin-2-yl) -2-hydroxy-1-((3
-(1,1,2,2-tetrafluoroethoxy) phenyl) methyl) ethyl) -6,7-dihydro-5H-benzo [a] cycloheptene-1-carboxamide, N-[(1
RS, 2SR) -1- (4-tert-butylbenzyl) -2- (3-chlorophenyl) -2-hydroxyethyl] -5-chloro-1-naphthamide, 4-fluoro-N-{(1RS, 2SR) -2- (4-Fluorophenyl) -2-hydroxy-1-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] ethyl} The compound according to claim 1, which is -1-naphthamide or a salt thereof. 18. The formula: [Wherein, Ar ¹ represents an aromatic ring group which may have a substituent, Ar ² represents an aromatic ring group having a substituent, OR ″ represents a hydroxyl group which may be protected, and R represents an acyl group. And R ′ represents a hydrogen atom or a hydrocarbon group which may have a substituent. (Provided that benzyl- [2 (S) -hydroxy-2-thiazol-2-yl-1 (S)-(4-trifluoromethyl-benzyl) -ethyl] is used). -Excluding carbamic acid tert-butyl ester). 19. A compound of the formula [Wherein, Ar ¹ represents an aromatic ring group which may have a substituent, Ar ² represents an aromatic ring group having a substituent, OR ″ represents a hydroxyl group which may be protected, and R represents an acyl group. And R ′ represents a hydrogen atom or a hydrocarbon group which may have a substituent. Or a salt thereof, or a prodrug thereof. 20. The composition according to claim 19, which is a cholesteryl ester transfer protein inhibitor. 21. The composition according to claim 19, which is a high-density lipoprotein-cholesterol increasing agent. 22. The composition according to claim 19, which is a low-density lipoprotein-cholesterol lowering agent. 23. The composition according to claim 19, which is an extremely low density lipoprotein-cholesterol lowering agent. 24. The method according to claim 1, which is a triglyceride lowering agent.
9. The composition according to 9. (25) The composition according to the above (19), which is an agent for preventing or treating acute coronary syndrome. 26. The composition according to claim 19, which is an agent for preventing or treating acute myocardial infarction. 27. The composition according to claim 19, which is a preventive or therapeutic agent for unstable angina. 28. The composition according to claim 19, which is an agent for preventing or treating arterial restenosis after PTCA or stent implantation. (29) The composition according to the above (19), which is an agent for preventing or treating peripheral arterial occlusion. 30. The method according to claim 1, which is a preventive or therapeutic agent for hyperlipidemia.
9. The composition according to 9. (31) the agent for preventing or treating cerebral infarction;
A composition as described. 32. The method according to claim 19, which is an agent for preventing or treating stroke.
A composition as described. 33. The composition according to claim 19, which is an agent for inhibiting the progression of atherosclerotic lesions. 34. The formula [Wherein, Ar ¹ represents an aromatic ring group which may have a substituent, Ar ^{2 ′} represents an aromatic ring group which may have a substituent;
R ″ represents a hydroxyl group which may be protected, R represents an acyl group, and R ′ represents a hydrogen atom or a hydrocarbon group which may have a substituent. A cholesteryl ester transfer protein inhibitor comprising the compound represented by the formula: or a salt thereof, or a prodrug thereof. 35. The method according to claim 3, which is an agent for preventing or treating hyperlipidemia.
4. The agent according to 4. 36. The agent according to claim 34, which is a preventive or therapeutic agent for acute coronary syndrome. 37. The agent according to claim 34, which is a preventive or therapeutic agent for acute myocardial infarction. 38. The agent according to claim 34, which is a preventive or therapeutic agent for unstable angina. 39. The agent according to claim 34, which is a preventive or therapeutic agent for arterial restenosis after PTCA or stent implantation. (40) the agent of the above (34), which is a prophylactic or therapeutic agent for peripheral arterial occlusion; 41. The agent according to claim 34, which is a prophylactic or therapeutic agent for cerebral infarction.
Agents as described. 42. The preventive and therapeutic agent for stroke.
Agents as described. 43. The agent according to claim 34, which is an agent for inhibiting the progression of atherosclerotic lesions. 44. A method for inhibiting cholesteryl ester transfer protein in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal. 45. A method for preventing or treating hyperlipidemia in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal. 46. Use of the compound according to claim 1 or a salt thereof for the manufacture of a medicament for inhibiting cholesteryl ester transfer protein. 47. Use of the compound according to claim 1 or a salt thereof for the manufacture of a medicament for preventing or treating hyperlipidemia. 48. A method for preventing or treating acute coronary syndrome in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal. 49. A method for preventing or treating acute myocardial infarction in a mammal, which comprises administering an effective amount of the compound of claim 1 or a salt thereof to the mammal. 50. A method for preventing or treating unstable angina in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal. 51. A method for preventing or treating coronary restenosis after PTCA or stent implantation in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal. 52. A method for preventing or treating peripheral arterial occlusion in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal. 53. A method for preventing or treating cerebral infarction in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal. 54. A method for preventing or treating stroke in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal. 55. A method for inhibiting the progression of atherosclerotic lesions in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal. 56. A cholesteryl ester transfer protein in a mammal, which comprises administering an effective amount of the compound represented by the formula (I ′) according to claim 34, a salt thereof, or a prodrug thereof to the mammal. Inhibition method. 57. Use of the compound represented by the formula (I ') according to claim 34, a salt thereof, or a prodrug thereof for the manufacture of a medicament for inhibiting cholesteryl ester transfer protein. 58. The formula A compound represented by the formula [wherein the symbols are as defined in claim 1] or a salt thereof is subjected to an acylation reaction to obtain a compound represented by the formula: The method for producing a compound according to claim 1 or a salt thereof, wherein a compound represented by the formula [Symbols are as defined in claim 1] or a salt thereof is obtained, and if necessary, the compound is subjected to a hydroxyl group protection reaction. .