WO2003066578A1 - PROCESS FOR PRODUCING ß-HYDROXYAMINO ACID DERIVATIVE AND INTERMEDIATE THEREFOR - Google Patents

Abstract

A pinene derivative represented by the general formula (I) or a salt thereof; and a process for producing the derivative or salt or a process for producing from the derivative or salt an optionally active 2-(t-butoxycarbonyl)amino-3-hydroxypropanoic acid derivative represented by the general formula (V) (in the formulae, R1 represents alkyl and R2 represents alkyl, alkenyl, alkynyl, a cyclic group, etc.). The 2-(t-butoxycarbonyl)amino-3-hydroxypropanoic acid derivative, which is useful as an important intermediate for medicines, can be efficiently synthesized from the novel intermediate represented by the general formula (I).

Description

 TECHNICAL FIELD The present invention relates to a method for producing a hydroxy-3-amino acid derivative and an intermediate thereof.

 The present invention relates to novel pinene derivatives and salts thereof, methods for producing them, and methods for producing optically active i3-hydroxyamino acid derivatives and salts thereof using the same.

 More specifically, the general formula (I)

(In the formula, R ¹ and R ² represent the same meaning as described below.)

, A salt thereof, a method for producing them, and a general formula (V) using them

(In the formula, R ¹ and R ² represent the same meaning as described below.)

The present invention relates to a method for producing an optically active 1-hydroxyamino acid, particularly a 2- (t-butoxycalponyl) amino- ₃ -hydroxypropanoic acid derivative represented by the formula: Background art j3-Hydroxyamino acid derivatives are generally important compounds as intermediates for pharmaceuticals, and many synthetic methods have been developed. For example, Synthesis, 34-36, (1990) describes a method represented by Reaction Scheme 1. Reaction process formula 1 t-BuOOH / Ti (OPr-i) ₄

L-Jetyl monotartrate

反応工程式 1で示される方法は、 出発原料として 4ーメチルー 2—ペンテ ンー 1一オールを用いる、 （2 S , 3 S ) — 2—ァミノ一 3—ヒ ドロキシー 4 ーメチルペンタン酸の合成方法である。 本発明者らは、 出発原料としてホル ミルシク口へキサンを用いて、 反応工程式 1に示される方法と同様の方法に より、 ( 2 R , 3 R ) — 2—アミノー 3—ヒ ドロキシ一 3—シクロへキシルプ 口パン酸が得られることを確認し、 さらに保護反応を行うことによって、 （2 R， 3 R) - 2- ( t—ブトキシカルポニル） アミノー 3—ヒドロキシー 3 —シク口へキシルプロパン酸が製造できることを確認した （反応工程式 2 )。 反応工程式 2

The method represented by the reaction scheme 1 is a method for synthesizing (2S, 3S) -2-amino-13-hydroxy-4-methylpentanoic acid using 4-methyl-2-penten-1-ol as a starting material. The present inventors have found that (2R, 3R) —2-amino-3-hydroxyl-3 can be obtained by using a formylcyclohexane as a starting material and by a method similar to the method shown in the reaction scheme 1. —Confirmation that cyclohexylbutanoic acid can be obtained, and by carrying out a protective reaction, (2 (R, 3R) -2- (t-butoxycarbonyl) amino-3-hydroxy-3-cyclohexylpropanoic acid was confirmed to be able to be produced (reaction scheme 2). Reaction process formula 2

Ti (OPr-i) ₄

 Cumene hydroperoxide

 D—Jetyl tartrate

モレキュラーンーブ 4A 9 OH

Molecular beam 4A

CH ₂ CI ₂ , -20 ° C

 Process 4 85%

1) S0 ₃ · Py

Triethylamine Ph, NH ₂

 DMSO 5M NaOH

 9.

₂₎ NaCI0 2 COOH Step 6

NaH ₂ P0 ₄ 51%

 2-methyl-2-butene

CH ₃ CN-H ₂ 0

 Process 5 69%

In the 97% reaction scheme, DI BALH represents hydrogenated diisobutylaluminum, THF represents tetrahydrofuran, S0 ₃ · P y represents a sulfur trioxide 'pyridine complex, DMSO represents dimethyl sulfoxide, B oc ₂ 〇 is di - t one Puchinore dicarbonate (di-t-butyl carbonate) Express.

 However, the conventional method described above has the following problems and is not always satisfactory.

 (1) There is a risk of explosion in mass synthesis due to the use of peracid in step 4.

 (2) Step 4 is not suitable for mass synthesis due to the reaction at low temperature

 (3) The oxidation reaction in step 5 has the danger of explosion in mass synthesis.

 (4) The total number of processes is as large as 7 processes.

 (5) Low V, with a total yield of 22.0%.

 Therefore, development of a method for solving the above problems has been desired.

 On the other hand, a method for synthesizing a) 3-hydroxyamino acid derivative using a pinene derivative shown in Reaction Scheme 3 is known (Tetrahedron Letters, 39, 2191-2194 (1 "8),

J. Org. Chem., 59, 3240-3242 (see 199).

Reaction process formula 3

 THF

R = / ^ C ₁₃ H ₂₇ 85%

R = Tetrahedron Letters, 39, 2191-2194 (1998))

R = / ^^ C ₁₃ H ₂ 7 丄 Org. Chem., 59. 3240-3242 (1994) These references describe the reaction for other aldehyde derivatives other than the aldehyde derivative in which R is the above group. Not at all described. Disclosure of the invention The present inventors have conducted intensive research to solve the above-mentioned problems, and as a result, have found a method represented by the following reaction process formula 4. Reaction process formula 4

OH

Hydrolysis COOR ¹

 Hydrolysis

Step 2 Introduction of NH ₂ protecting group

(IV) Process 3

 (V) To explain in more detail,

A binene derivative represented by the general formula (II) and an aldehyde derivative represented by the general formula (ΠΙ) are subjected to an asymmetric aldol reaction at 0 ° C. in dichloromethane in the presence of titanium chloride triethoxide and triethylamine. Indicated by (I) To produce a binene derivative and a salt thereof (Step 1), and subjecting the pinene derivative represented by the general formula (I) and a salt thereof to a hydrolysis reaction in tetrahydrobrane in the presence of 1.2 N hydrochloric acid at room temperature, Producing an optically active hydroxyamino acid derivative represented by the general formula (IV) and a salt thereof (Step 2);

 An optically active hydroxyamino acid derivative represented by the general formula (IV) and a salt thereof are subjected to a hydrolysis reaction in ethanol in the presence of a 1 N aqueous lithium hydroxide solution at room temperature, and further, di-t-butyl dicarbonate is present. Thereafter, the compound is subjected to a protection reaction to produce an optically active 2- (t-butoxycarbonyl) amino-3-hydroxypropanoic acid derivative represented by the general formula (V) and a salt thereof (Step 3).

 However, in step 3, the protection reaction may be performed after the hydrolysis, or the hydrolysis reaction may be performed after the protection reaction.

 According to the method of the present invention, all the problems of the prior art represented by the reaction scheme 2 are solved. That is,

 (1) In all processes, there is no danger of explosion because no peracid is used.

(2) Since there is no low-temperature reaction in all steps, it is advantageous for large-scale synthesis.

 (3) In all processes, there is no oxidation reaction and there is no danger of explosion.

 (4) The total number of processes is three, and the number of processes is shorter than the conventional method.

(5) When R ² is a cyclohexyl group, the total yield is 64.8%, which is higher than the conventional method.

(6) In step 2, (1R, 2R, 5R)-(+) — 2-hydroxy-13-pinanone is recovered, and the recovered compound is reacted again with a glycine derivative to obtain a compound of the general formula (II) ) Can be resynthesized. That is, (1 R, 2R, 5R) one (+) — 2-—hid Mouth xie 3-pinanone can be recovered and reused.

 As described above, the production method of the present invention is more advantageous for mass synthesis than the conventional method.

 Further, the pinene derivative represented by the general formula (I) is a novel compound that has not been known so far, and is a useful intermediate of the production method of the present invention.

 That is, the present invention

 (1) General formula (I)

(Wherein, R ¹ represents a C 1-8 alkyl group,

R ² is

 (1) C1-8 alkyl group,

 (2) C2-8 alkenyl group,

 (3) C2-8 anolequininole group,

 (4) Cy c 1,

 (5) a C1-8 alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group, which is substituted by Cyc1, or

 (6) The force substituted by the C3-8 cycloalkylidene group, or one of its ring-constituting carbon atoms (excluding the carbon atom having an alkylidene bond) was replaced by an oxygen atom, a nitrogen atom or a sulfur atom Represents a C 1-8 alkyl group substituted with a heterocyclic group,

Cy cl is a 3- to 15-membered C3 to C15 monocyclic, bicyclic or tricyclic carbocycle or 1 to 5 heteroatoms selected from oxygen, nitrogen or sulfur atoms Represents a monocyclic, bicyclic or tricyclic heterocyclic ring, wherein Cy cl is 1 to 5 R ³ May be replaced by

R ³ represents a C 1-8 alkyl group, a C 1-8 alkoxy group, a hydroxyl group, a C 1-8 alkoxy group or a oxo group substituted by a C 1-8 alkoxy group. ) A binene derivative and a salt thereof;

 (2) — General formula (II)

(Wherein, R ¹ has the same meaning as described above.)

And a general formula (III)

R ² — CHO ("I")

(Wherein, R ² has the same meaning as described above.)

Subjecting the aldehyde derivative represented by the above to an asymmetric aldol reaction and, if desired, to a salt conversion reaction, a process for producing a compound represented by the general formula (I) or a salt thereof;

 (3) The compound represented by the general formula (IV) characterized by hydrolyzing the compound represented by the general formula (I) and Z or a salt thereof.

(Wherein, R ¹ and R ² represent the same meaning as described above.)

A method for producing an optically active hydroxyamino acid derivative or a salt thereof represented by:

(4) The compound represented by the general formula (I) is hydrolyzed to obtain the general formula (IV) The compound represented by the general formula (IV) is hydrolyzed by hydrolyzing the compound represented by the general formula (I), or by hydrolyzing the compound represented by the general formula (I). General formula (V) characterized in that the amino group is protected by t-butoxycarpoyl group and further hydrolyzed.

(Wherein, R ² has the same meaning as described above.)

The present invention relates to a method for producing an optically active 2-(-tert-butoxycarbonyl) amino-3-hydroxypropanoic acid derivative represented by the formula: or a salt thereof.

 In the present specification, the Cl8 alkyl group refers to a methyl, ethyl, propyl, butanol, pentyl, hexyl, heptyl, octyl group and isomers thereof.

 In the present specification, a C 28 alkenyl group means a C 28 alkenyl group having 12 double bonds, and specifically, ether, propenyl, butyr, butageninole, penteninole, Pentageninole, hexeninole, hexageninole, heptenyl, heptaenyl, octenyl, octagenyl group and isomers thereof.

 In the present specification, a C 28 alkynyl group means a C 28 alkynyl group having 12 triple bonds, and specifically, ethel, propynyl, butyral, butadininole, pentininole, pentadyninole. Hexidinole, hexadininole, heptinyl, heptadinyl, otatur, octadininole group and isomers thereof.

In the present specification, a C 18 alkoxy group refers to methoxy, ethoxy, Si, butoxy, pentinoleoxy, hexinoleoxy, heptinoleoxy, octyloxy, and isomers thereof.

 As used herein, a C 3-15 monocyclic, bicyclic or tricyclic carbocycle includes a C 3-15 monocyclic, bicyclic or tricyclic carbocyclic aryl, a part or all thereof. Carbocycles, spiro-bonded bicyclic carbocycles and bridged bicyclic carbocycles. For example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentadecane, cyclododecane, cyclotridodecane, cyclotetradecane, cyclopentadecane, cyclopentene, cyclopentene, Cyclohexene, cycloheptene, cyclootathene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, pa-hydropentalene, azulene, phenolic hydrazulene, indene, phenolic hydrazulene Deguchi Indene, indane, naphthalene, dihydrodronaphthalene, tetrahydronaphthalene, nodose. -Hydronaphthalene, heptalene, nodose. -Hydroheptalen, biphenylene, as-indacene, s-indacene, acenaphthylene, asenaphthene, phnoleolene, phenalen, phenanthrene, anthracene, spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] Pendecane, Bicyclo [2.2.1] heptane, Bicyclo [2.2.1] Hepta-2-ene, Bicyclo [3.1.1] heptane, Bicyclo [3.1.1] Hepter 2 — , Bicyclo [2.2.2] octane, bicyclo [2.2.2] octa_2_ene, adamantane, noradamantane and the like.

As used herein, a 3- to 15-membered monocyclic, bicyclic or tricyclic heterocycle containing 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom or a sulfur atom includes: 3- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic aryl containing 1 to 5 heteroatoms selected from oxygen, nitrogen or sulfur, partially or wholly saturated And heterocycles. For example, oxygen atom, nitrogen source 3- to 15-membered monocyclic, bicyclic or tricyclic heteroaryls containing 1 to 5 heteroatoms selected from the group consisting of pyrrole, imidazole, triazole and tetrazole , Pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, chepin, genkixazo / re, isisoxazole, thiazole, isotizazole, franzane, oxazine, oxazine, oxazine. , Xixaziazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoin-donore, indolizine, benzofuran, isobenzofuran, benzothiazephene, isobenzothiophene Dithianaphthalene, indazonole, quinoline, isoquinoline, quinolidine, purine, phthalazine, pteridine, naphthyridin, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazonole, benzimidazonole, chromene, benzoxosepine, benzoxosepine Diazepine, benzocepin, benzothiazepine, benzothiadiazepine, benzoxazepine, benzodiazepine, benzofurazan, benzothiadiazonole, benzotriazolone, canolebazolone, β_carboline, atarizine, phenazine, dibenzofuran, xanthene, dibenzo Thiofen, phenothiazine, phenoxazine, phenoxatiin, thiazulene, phenanthridine, fenan Lorin, Ru include perimidine ring.

Furthermore, a partially or fully saturated 3- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic ring containing 1 to 5 hetero atoms selected from an oxygen atom, a nitrogen atom or a sulfur atom Examples of allyl include aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, virazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, and tetrahydride. Lovirazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, ヽ^0- hydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydrodolazepine, perhydroazepine, dihydrodiazepine, tetrahydrodazepine Pin, Perhydrodazepine, Oxylan, Oxetane, Dihydrofuran, Tetrahydrofuran, Dihydropyran, Tetrahydropyran, Dihydrooxepin, Tetrahydrooxepin, Perhidroxepin, Thiiran, Chetan, Dihydrothiophane, Tetrahydrothiophene, Dihydrothiophene Orchid, dihydrocepin, tetrahydrocepin, perhydrochepin, dihydroxazole, Tetrahydroxazole (oxazolidine), dihydro mouth isoxazole, tetrahydroisoxazole (isoxazolidin), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazonole (isothiazolidine), dihydrofurazan, tetrahydro Drofrazan, dihydrooxazine diazide /, tetrahydroxoxadiazole (oxaziazolidine), dihydroxoxazine, tetrahydroxazine, dihydroxoxadiazine, tetrahydroxoxadiazine, dihydro Xazepine, tetrahydroxazepine, perhydrooxazepine, dihydrooxazedazepine, tetrahydrooxazine diazepine, perhydroxoxazezepine, dihydrothiadiazazo , Tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrodrothazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhidiazine Dorothiadiazepine, monoreforin, chiomo / reforin, oxaxian, indoline, isoindoline, dihydrobenzofuran, perhidrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothifenphen, di. -Hydrobenzon fen, Dihydroisobenzothiophene, perhydroisobenzothiophene, dihydric indazonole, perhydroindazonole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydrosoquinoline, perhydroisoquinoline, dihydrotetralophthalazine Dro phthalazine, c. -Hydrophthalazine, Dihydronaphthyridine, Tetrahydronaphthyridine, Perhydronaphthyridine, Dihydroquinoxaline, Tetrahydroquinoxaline, Perhydroquinoxalin, Dihydroquinazoline, Tetrahydroquinazoline, Perhydroquinazoline, Dihydrocinnoline, Tetrahydranoline , Benzoxathian, dihydrobenzozoxazine, dihydrobenzozothiazine, virazinomorpholine, dihydrobenzoxazonole, ヽ. Hidoro base Nzookisazo one Honoré, dihydro base Nzochia Zonore, Nono ⁰ hydro base Nzochiazonore, dihydric Dorobe emission zone imidazo over Honoré, Nono ⁰ - hydro base emission zone imidazo over Honoré, dihydric mud benzo § Ze pin Tetorahi Dorobe emission zone Azepin , Dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepane, dihydrobenzozoxazepine, tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole, perhydrocanolebasazonole, dihydroacridine, tetrahydroacridine, perhydrofuridine dibenzodiazine Thiofen, tetrahydrodibenzobenzofuran, tetrahydrodibenzothiophene, nordrobenzobenzofuran, ha. -Hydrodibenzothiophene, dioxolane, dioxane, dithiolane, dithiane, dioxindan, benzodioxane, chroman, benzodithiolane, benzodithiane ring and the like.

 In the present specification, the C3-8 cycloalkylidene group represents a cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene or cyclootatilidene group.

In the present specification, one of the carbon atoms constituting the ring of the C 3-8 cycloalkylidene group (α Excludes carbon atoms having a alkylidene bond. A heterocyclic group in which is replaced by an oxygen atom, a nitrogen atom or a sulfur atom is a divalent group formed by losing two hydrogen atoms from one of the ring-constituting carbon atoms on the heterocyclic ring. Examples of the hetero ring include oxetane, oxolan, perhydropyran, chetan, thiolan, thiane, azetidine, pyrrolidine, and piperidine ring.

In the present invention, R ¹ is preferably a C 1-4 alkyl group, particularly preferably a methyl and ethyl group.

In the present invention, R ² is preferably substituted with a Cl-8 alkyl group, a C1-8 alkyl group substituted by Cycl, Cyc1, or a C3-8 cycloalkylidene group or the heterocyclic group. C 1-8 alkyl group, particularly preferably 2-methylpropyl group, 1-ethylpropyl group, cyclopropynole group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptinol group, cyclopentene_ 4-Inole group, Cyclohexene-1-yl group, 4-Methyl / Recyclohexyl group, 4-Hydroxycyclohexyl group, 4-Methoxymethyloxy hexyl group, 4-Methoxy methoxy group Xyl group, 4-ethoxycyclohexyl group, cyclohexylmethynole group, adamantane-11-yl group, phenyl group, 2,6-dimethylphenyl group, 1- Cyl-11 phenylethyl group, 2-phenylethyl group, 1,4-benzodioxane-1-yl group, furan-3-yl group, tetrahydropyran-14-yl group, tetrahydropyran-14-fluoromethyl group, 3,5 , 6-trihydropyran-1-ylidenemethyl group, 1,3-dithiane-12-inole group, thiane-4-yl group, and thiane-1,1-dione-14-yl group. Most preferred are cyclopentyl, cyclohexyl, cycloheptyl, tetrahydropyran-41-yl, 4-methoxymethyloxycyclohexyl or 4-hydroxycyclohexyl. is there.

In this specification, the symbols No,

Indicates that it is connected to the other side of the paper (that is, α-configuration),

 No

Indicates that it is connected to the near side of the page (that is, one arrangement),

Represents α-,] 3- or a mixture thereof, or represents a Ε-form, a Ζ-form or a mixture thereof,

Represents a mixture of the _α -configuration and the] 3-configuration.

 In the present invention, all isomers are included unless otherwise indicated. For example, the alkyl group, alkoxy group and alkylene group include straight-chain and branched-chain ones. Furthermore, isomers in double bonds, rings and condensed rings (Ε, 環, cis, trans), isomers due to the presence of asymmetric carbon (R, S, α, β, enantiomer, diastereomer), optical rotation Optically active isomers (D, L, d, 1), polar compounds (high polar, low polar) by chromatographic separation, equilibrium compounds, mixtures of these in any proportion, and racemic mixtures Included in the invention.

[Method for producing the compound of the present invention]

 The compound of the present invention represented by the general formula (I) can be produced by the following methods or the methods described in Examples.

General formula (I) , COOR,

(I)

 OH OH

(Wherein, R ¹ and R ² have the same meanings as described above) and their salts represented by general formula (II)

(II)

(式中、 R ¹は前記と同じ意味を表わす。）

(Wherein, R ¹ has the same meaning as described above.)

And a general formula (III)

R ² — CHO (III)

(Wherein, R ² has the same meaning as described above.)

Can be produced by subjecting an aldehyde derivative represented by the following to an asymmetric aldol reaction.

 This asymmetric aldol reaction is known. For example, an organic metal reagent (titanium chloride triethoxide, titanium chloride triisopropoxide, titanium dichloride diisopropoxide, dimethyl alcohol) in an organic solvent (dichloromethane, chlorophonolem, tetrahydrofuran, etc.) Aluminum chloride, etc.), bases (triethylamine, lithium disopropion / reamine, t_butylmagnesium chloride, 1,8,1 diazabisic [5.4.0] ) In the presence, at a temperature of 0 to 20 ° C.

The optically active 2_ (t-butoxycarbonyl) amino-3-hydroxypropanoic acid derivative represented by the general formula (V) can be prepared from the pinene derivative represented by the formula (I) and a salt thereof by the following method or It can be produced by the method described in the examples. General formula (IV)

(Wherein, R ¹ and R ² have the same meanings as described above), and the optically active hydroxyamino acid derivatives and salts thereof are represented by the general formula (I) produced by the method described above. By subjecting the obtained binene derivatives and their salts to a hydrolysis reaction.

 This hydrolysis reaction is known and is carried out under acidic conditions. For example, in an organic solvent (tetrahydrofuran, dioxane, ethanol, methanol, etc.), an acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, boric acid, citric acid, ammonium acetate, etc.) or a mixture thereof, It is performed at a temperature of 100 ° C.

 General formula (V)

(Wherein R ² has the same meaning as described above.) The optically active 2_ (t-butoxycarbonyl) amino-3-hydroxypropanoic acid derivative represented by the general formula (IV) ), The carboxylic acid ester moiety of the optically active hydroxyamino acid derivative or a salt thereof is hydrolyzed, and the amino group is further protected with a t-butoxycarbyl group. .

In this reaction step, the protection reaction is performed even if the protection reaction is performed after hydrolysis. After that, a hydrolysis reaction may be performed.

 This hydrolysis reaction is known and is carried out under alkaline conditions. For example, in organic solvents (methanol, ethanol, tetrahydrofuran, dioxane, 1,2-dimethoxetane, etc.), alkali metal hydroxides (sodium hydroxide, hydroxide hydroxide, lithium hydroxide, etc.), alkaline hydroxides Use an earth metal hydroxide (barium hydroxide, canoleum hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution or a mixture thereof at a temperature of 0 to 40 ° C. Done.

 This protection reaction is well known, and includes a base (sodium hydroxide, potassium hydroxide, lithium hydroxide, triethynoleamine, dimethylamino) in a water-miscible organic solvent (dioxane, acetate, etc.) and a mixture with water. The reaction is performed at a temperature of 0 to 40 ° C. in the presence of a protecting reagent such as pyridine and di-t-butyl dicarbonate.

 The alkaline hydrolysis reaction and the protection reaction can be performed in one pot. That is, for example, in an organic solvent (methanol, ethanol, tetrahydrofuran, dioxane, etc.), an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide The reaction is carried out at a temperature of 0 to 40 ° C. using sodium hydroxide (potassium hydroxide, calcium calcium hydroxide, etc.) or a carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof. Thereafter, the reaction mixture is treated with ge-butyl dicarbonate at a temperature of 0 to 40 ° C.

 The protection reaction with di-t-butoxycarbon group is not limited to the reaction using di-t-butyl dicarbonate. For example, the one described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991 can be used.

Of the compounds of the general formula (II) used as starting materials, R ¹ The compound that is tyl is known and has a CAS Registry Number of 90473-01-1. The aldehyde derivative represented by the general formula (III) is a known compound or can be produced by a known method. For example, the CAS registration number for formylcyclohexane where R ² is a cyclohexyl group is 2043-61-0. The product of each reaction may be isolated, washed, dried and purified for each step and used in the next reaction, or the procedure may not be performed at all or may be stopped at an appropriate stage. The process may proceed. The reaction product in each reaction is purified by conventional purification means, for example, distillation under normal pressure or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, column chromatography, washing, and recrystallization. Can be purified. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail by reference examples and examples, but the present invention is not limited thereto.

 The solvent in the column indicated by the chromatographic separation and the force in the TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio.

 The solvent in the parenthesis shown in the NMR indicates the solvent used for the measurement. Reference example 1

グリシンェチルエステル .塩酸塩 (9. 21 g) のベンゼン （50m l) 懸 濁液にトリェチルァミン （9.2m l) を加えた。 混合物を 70 °Cで 10分間 撹拌した。 混合物に、 （1R， 2R， 5R) — 2—ヒドロキシ一 3_ピナノン ( 5. 55 g、 99 % e . e . ) と三フッ化ホゥ素 ·エーテル錯体 （ 90 1 ) を加えた。 反応混合物を Dean-Starkを用いて、 2時間還流した。 析出した不 溶物をろ過し、 ろ液を濃縮した。 得られた残渣をシリカゲルカラムクロマト グラフィー （へキサン：酢酸ェチノレ = 2 : 1→1 : 1→1 : 2→0 : 1) に よって精製し、 以下の物性値を有する標題化合物 （8.23 g、 99%) を得 た。 Ethyl N-[(1R, 2R, 5R) 1-2-Hydroxy-2,6,6-trimethylbicyclo mouth [3.1.1] Heptoto-3-ylidene] glycinate

Glycineethyl ester. To a suspension of hydrochloride (9.21 g) in benzene (50 ml) was added triethylamine (9.2 ml). The mixture was stirred at 70 ° C for 10 minutes. To the mixture were added (1R, 2R, 5R) -2-hydroxy-13-pinanone (5.55 g, 99% e.e.) and a boron trifluoride / ether complex (901). The reaction mixture was refluxed for 2 hours using Dean-Stark. The precipitated insolubles were filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1 → 1: 2 → 0: 1) to give the title compound (8.23 g, 99%) having the following physical data. %).

 TLC: R f 0.54 (hexane: ethyl acetate = 1: 2);

_{NMR (CDC1 3): δ 4.23} (q, J = 6.9 Hz, 2H), 4.17-4.16 (m, 2H), 2.67 (brs, IH), 2.54-2.46 (m, 2H), 2.35 (m, IH) , 2.11-2.01 (m, 2H), 1.90 (brs, IH), 1.52 (s, 3H), 1.33 (s, 3H), 1.30 (t, J = 6.9 Hz, 3H), 0.88 (s, 3H). Example 1

Ethyl (3 R) 13-cyclohexyl mono-N— [(1 R, 2 R, 5 R) — 2-hydroxy-2,6,6-trimethylbicyclo [3.1.1] heptoh 3-ylidene] D-Selinate

Compound (253mg) produced in Reference Example 1 in dichloromethane (1.5ml) To the solution was added a solution of titanium chloride triethoxide (218 mg) in dichloromethane (1 ml) at 0 ° C. under an argon atmosphere. To this solution were added formic acid hexane (218 mg) and triethylamine (0.28 ml). The reaction mixture was stirred at the same temperature for 4 hours. The reaction mixture was poured into a saturated aqueous sodium chloride solution, the precipitated insolubles were filtered, and the filtrate was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 → 3: 1) to give the compound of the present invention (309 mg, 84%) having the following physical data.

 However, because titanium chloride triethoxide contained titanium chloride triisopropoxide, transesterified isopropyl ester was mixed in the product. Ethyl ester form: isopropyl ester form = 14.3: 1. The yield was calculated in consideration of this production ratio. TLC: R f 0.23 (hexane: ethyl acetate = 3: 1);

_{NMR (CDC1 3): δ 4.24} (d, J = 6.9 Hz, 1H), 4.19 (q, J = 6.9 Hz, 2H), 3.85 (m, 1H), 3.15 (brs, 1H), 2.65-2.50 (m , 2H), 2.40-2.32 (m, 2H), 2.11-2.02 (m, 2H), 1.85-1.10 (m, 12H), 1.50 (s, 3H), 1.33 (s, 3H), 1.25 (t, J = 6.9 Hz, 3H), 0.87 (s, 3H). Example 1 (1) to 1 (27)

 The same operation as in Example 1 was carried out using the corresponding aldehyde derivative instead of formyl hexane, to obtain the present compound shown below. Example 1 (1)

Ethyl (3 R)-3-(2-Methylpropyl) — N— [(1 R, 2 R, 5 R) — 2-Hydroxy 2, 6, 6—Trimethinolevisic [3.1.1 ] Hept—3-ylidene] D-serinate

TLC: R f 0.23 (hexane: ethyl acetate = 2: 1);

 NMR (DMSO-de): δ 4.51 (br, IH), 4.21-4.06 (m, 3H), 3.50 (br, IH), 2.70 (br, IH), 2.26 (m, IH), 2.00 (m, IH ), 1.93 (m, IH), 1.78 (m, IH), 1.59-1.49 (m, 6H), 1.27 (s, 3H), 1.17 (t, J = 7.0Hz, 3H), 0.90 (d, J = 6.5Hz, 3H), 0.87 (d, J = 6.5Hz, 3H), 0.77 (s.3H). Example 1 (2)

Ethyl (3 R)-3-(1,3-dithiane-1-yl) — N— [(1 R, 2 R, 5 R) 1-2-hydroxy-1,2,6,6-trimethylbicyclo [3 1.1] Heptot 3 _ylidene] D-Selynate

 TLC: R f 0.54 (hexane: ethyl acetate = 1: 1);

NMR (DMSO-d ₆ ): δ 5.61 (d, J = 6.5 Hz, IH), 4.70 (s, IH), 4.39 (m, IH), 4.22 (d, J = 8.5 Hz, IH), 4.11 (d , J = 2.5Hz, IH), 4.10-3.96 (m, 2H), 3.00-2.77 (m, 4H), 2.69-2.59 (m, 2H), 2.17 (m, IH), 1.98-1.85 (m, 3H ), 1.73 (m, IH), 1.50 (d, J = lO.OHz, IH), 1.31 (s, 3H), 1.24 (s, 3H), 1.12 (t, J = 7.0Hz, 3H), 0.72 ( s.3H). Example 1 (3)

Ethyl (3R) —3— (1,4-cis-1-4-methylcyclohexane) N ― [(1 R, 2 R, 5R) —2—Hydroxy 2,66-trimethinolevisic Mouth [3.1.1] Heptoh 3-ylidene] —D—Selinate

 TLC R f 0.33 (ethyl hexane acetate = 2: 1);

NMR (DMSO-de) δ 4.56 (d, J = 6.5 Hz, IH), 4.41 (s, IH), 4.10 (m, IH), 4.04 (q, J = 7.0 Hz, 2H), 3.86 (m, IH ), 2.45 (m, IH), 2.18 (m, IH), 1.94 (m, IH), 1.87 (m, IH), 1.76 (m, IH), 1.54-1.10 (m, 11H), 1.32 (s, 3H), 1.24 (s, 3H), 1.13 (t, J = 7.0Hz, 3H), 0.89 (d, J = 7.0Hz, 3H), 0.73 (s.3H) ₀ Example 1 (4)

Echinole (3 R) — 3- (1,4-trans-1-4-methynolecyclohexane) -N- [(1 R, 2 R, 5 R) 1-2-hydroxy-1 2,6,6-trimethinolebi cyclo [3 . 1. 1] Heptot 3_ylidene] —D—Selynate

 TLC R f 0.58 (hexane: ethyl acetate = 1: 1);

NMR (DMSO-de) δ 4.58 (d, J = 6.5Hz, IH), 4.42 (s, IH), 4.09-3.98 (m, 3H), 3.83 (m, IH), 2.58-2.42 (m, 2H) , 2.18 (m, IH), 1.92 (m, IH), 1.87 (m, IH), 1.70-1.55 (m, 2H), 1.48-1.00 (m, 5H), 1.30 (s, 3H), 1.24 (s , 3H), 1.12 (t, J = 7.0Hz, 3H), 0.98-0.75 (m, 4H), 0.81 (d, J = 6.5Hz, 3H), 0.72 (s.3H). Example 1 (5) Ethyl (3R) — 3-cyclopropyl-1-N_ [(1 R, 2 R, 5 R) 1-2-hydroxy-1,2,6,6-trimethinolebicyclo [3.1.1] heptoh-3-ylidene] —D—Selinate

T L C ： R f 0.40 (クロ口ホルム ： メタノ一ル= 9 : 1) ;

TLC: R f 0.40 (cloth form: methanol = 9: 1);

 NMR (DMSO-de): δ 4.63 (d, J = 8.0 Hz, IH), 4.47 (s, IH), 4.10 (d, J = 6.5 Hz, IH), 4.05 (q, J = 7.0 Hz, IH) , 4.04 (q, J = 7.0Hz, IH), 3.49 (q, J = 6.5Hz, IH), 2.53 (dd, J = 18.0, 2.5Hz, IH), 2.40 (dt, J = 18.0, 1.5Hz, (IH), 2.18 (m, IH), 1.93 (m, IH), 1.89 (q, J = 6.0Hz, IH), 1.52 (d, J = 10.5Hz, IH), 1.35 (s, 3H), 1.24 ( s, 3H), 1.14 (t, J = 7.0Hz, 3H), 1.08 (m, IH), 0.76 (s, 3H), 0.31-0.25 (m.4H). Example 1 (6)

Ethyl (3R) —3-cyclobutyl-N— [(1R, 2R, 5R) — 2-hydroxy-1,2,6,6-trimethinolevicik mouth [3.1.1] Heptoh-3-ylidene] D—Selinate

TLC: R f 0.39 (hexane: ethyl acetate = 1: 1);

NMR (DMSO-d ₆ ): δ 4.67 (d, J = 7.0 Hz, IH), 4.47 (s, IH), 4.07-3.98 (m, 3H), 3.85 (m, IH), 2.53 (m, IH) , 2.43-2.41 (m, 2H), 2.17 (m, IH), 1.97-1.57 (m, 8H), 1.51 (d, J = 10.5Hz, IH), 1.31 (s, 3H), 1.23 (s, 3H ), 1.13 (t, J = 7.0Hz, 3H), 0.72 (s.3H). Example 1 (7)

Ethyl (3R) —3—Feniru N — [(1 R, 2 R, 5 R) —2-Hydroxy-1,2,6,6-trimethylbisic mouth [3.1.1] Hept-1 3 —Iridene] D-Selynate

 TLC: R f 0.11 (hexane: ethyl acetate = 1: 1), Example 1 (8)

Ethyl (3R) _3— (2, 6—Jell) 1 N— [(1 R, 2 R, 5 R) 1—2-Hydroxy 1 2,6,6 Trimethinolevisic mouth [3.1.1] Heptaw 3-Ylidene] D-Serinet

 TLC: R f 0.69 (hexane: ethyl acetate = 1: 1). Example 1 (9)

Ethyl (3R) — 3- (cyclohexene-1-yl) 1 N— [(1 R, 2 R, 5 R) —2-hydroxy 2,6,6-trimethylbicyclo [3.1.1] ] Heptaw 3-ylidene] D-Selynate I NO COOC ₂ H ₅

TLC: R f 0.25 (hexane: ethyl acetate = 2: 1).

Example 1 (1 0)

Ethyl (3 R) — 3 -— (1-Ethylpropyl) mono N_ [(1 R, 2R, 5 R) — 2-Hydroxy-1, 2, 6, 6-trimethinolebicyclo [3.1.1] hept — 3—Ilidene] —D—Selenate

TLC: R f 0.31 (hexane: ethyl acetate = 3: 1).

Example 1 (1 1)

Ethyl (3 R) — 3— (Tian-1-yl) -N- [(1 R, 2 R, 5 R) 1-2—Hydroxy 2,6,6_ trimethinorevitik mouth [3.1. . 1] Hept —3—Ilidene] —D—Selinate

 TLC: Rf 0.47 (hexane: ethyl acetate:).

Example 1 (1 2) Ethyl (3 R) 1—3—Heptyl heptyl—N— [(1 R, 2 R, 5 R) 1-2 Hydroxy 2, 6, 6—Trimethylbisic mouth [3.1.1] Heptoh 3 ylidene] —D—Selinate

TLC: R f 0.37 (hexane: ethyl acetate = 3: 1). Example 1 (13)

Ethyl (3 R) — 3 -— (1-Methinole 1-phenylenoleethyl) —N — [(1 R, 2 R, 5 R) —2-Hydroxy 2,6,6-trimethinolebicyclo [3.1.1. 1] Heptot 3 _ylidene] —D-serinate

TLC: R f 0.34 (hexane: ethyl acetate = 2: 1). Example 1 (14)

Ethyl (3R) —3— (1,4-benzodioxane-6_yl) -1-N— [(R, 2 R, 5 R) — 2-hydroxy-1 2,6,6-trimethinolebicyclo [3 1. 1] Heptaw 3-Ilidene] D-Selynate

 TLC: R f 0.57 (hexane: ethyl acetate = 2), Example 1 (15)

Ethyl (3 R)-3-(3,5,6-Trihydridopyran-1 4-ylidenemethyl) 1 N— [(1 R, 2 R, 5 R) 1 2-Hydroxy 2,6,6-Trimethinolebicyclo [3.1.1] Heptaw 3-ylidene] -D-serinate

TLC: R f 0.26 (hexane: ethyl acetate = 1: 4). Example 1 (16)

Ethyl (3 R)-3-(furan 3-yl) -N- [(1 R, 2 R, 5 R) — 2-hydroxy _ 2,6,6-trimethylbicyclo [3.1.1 ] Hept-1-3-ylidene] 1-D-serinate

TLC: R f 0.40 (hexane: ethyl acetate = 1: 1) ₍ Example 1 (17)

Echinole (3 R)-3-(Six-mouth pentene-1-4-inole) -N- [(1 R, 2 R, 5 R) -2-hydroxy-1,2,6,6-trimethinolebicyclo [3.1 . 1] Heptoh 3-ylidene] —D-serinate

TLC: R f 0.38 (dichloromethane: methanol = 10: 1). Example 1 (18)

Ethyl (3 R) — 3— (tetrahydropyran-1 4-yl) 1N— [(1 R, 2 R, 5 R) — 2-hydroxy 2,6,6-trimethylbicyclo [3.1.1] ] Hept _ 3 -ylidene] -D-serinate

 TLC: Rf 0.15 (hexane: ethyl acetate = 1: 1). Example 1 (19)

Ethyl (3R) —3— (1,4-cis-14-methoxycyclohexyl) -1-N — [(1R, 2R, 5R) —2-hydroxy 2,6,6-trimethylbicyclo [3. 1. 1] Heptot 3— ^ f redene] —D—serinate

 TLC: R f 0.52 (dichloromethane: methanol = 20: 1, twice). Example 1 (20)

Ethyl (3R) —3— (1,4-trans-4-methoxycyclohexyl) -N- [(1 R, 2 R, 5 R) — 2-hydroxy-1,2,6,6-trimethinolecyclo [3 1.1] Heptot 3 _ylidene] D-Selynate

 TLC: R f 0.50 (dichloromethane: methanol = 20: 1, twice). Example 1 (21)

Etinole (3 R)-3-(1,4-cis-1-4-ethoxycyclohexinole) 1 N— [(1 R, 2 R, 5 R) — 2-hydroxy 2,6,6-trimethinorebicyclo [3. 1. 1] Heptot 3-ylidene] —D-serinate

 TLC: R f 0.64 (dichloromethane: methanol = 20: 1, twice) 'Example 1 (22)

Etchinole (3R)-3-(1,4-trans-1-ethoxycyclohexynole) 1 N — [(1R, 2R, 5R) _2—Hydroxy 2,6,6-trimethinolebicyclo [3.1.1] heptoh 3 _ylidene] 1 D—Selinate

 TLC: R f 0.60 (dichloromethane: methanol = 20: 1, twice). Example 1 (23)

Ethyl (3R) — 3— (Adamantane 11-yl) -N- [(1R, 2 R, 5 R) _ 2—Hydroxy-1 2, 6, 6—Trimethinolevisic mouth [3.1. 1] Heptoh 3-ylidene] —D-serinate

 TLC: R f 0.47 (hexane: ethyl acetate = 3: 1). Example 1 (24)

Ethyl (3R) — 3— (2-Phenylethyl) -N- [(1 R, 2 R, 5 R) —2-Hydroxy-1,2,6,6-trimethylbicyclo [3.1.1] Hept-1-3 —Ilidene] —D—Selenate

 TLC: R f 0.50 (hexane ethyl acetate:). Example 1 (25)

Ethyl (3R) —3-cyclo'-xinolemethinoleone N— [(1R, 2R, 5R) _2—hydroxy 2,66-trimethinolebicyclo [3.1.1] hept —3—ylidene ] —D—Serine

TLC R f 0.59 (hexane ethinol acetate: Example 1 (26)

Ethyl (3 R) — 3— (1 4 1 cis 1 4 — methoxymethinoleoxycyclohexyl) 1 N— [(1 R, 2 R, 5 R) _ 2 —hydroxy 2, 6, 6— Trimethinolebicyclo [3.1.1] heptose 3-ylidene] D-serinate

TLC R f 0.40 (dichloromethane methanol = 20 1), Example 1 (27)

Ethyl (3 R)-3-(1,4 -trans- 1-4-methoxymethyloxyhexyl) -N- [(1 R, 2 R, 5 R) _ 2 -hydroxy _ 2, 6, 6 Monotrimethylbis [3.1.1] Heptoh 3 f redene] — D-Serineate

 TLC: Rf 0.34 (dichloromethane: methanol = 20: 1). Example 2

Ethyl (2R, 3R) — 2-amino-3-hydroxy_3-cyclohexylpropionate ■ hydrochloride

 To a solution of the compound produced in Example 1 (30 Omg) in tetrahydrofuran (2.4 ml) was added 1.2 N hydrochloric acid (5.5 ml). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 70: 1 → 20: 1 → 10: 1) to give the compound of the present invention (196 mg, 95%) having the following physical data. I got Pinanone (65 mg, 47%) was recovered.

TLC: R f 0.25 (dichloromethane: methanol: = 10: 1);

NMR (CD ₃ OD): δ 4.34-4.16 (m, 2H), 3.92 (d. J = 3.3 Hz, 1H), 3.46 (dd, J = 8.7, 3.3 Hz, IH), 2.02 (m, IH), 1.90-1.55 (m, 5H), 1.40-0.90 (m, 5H), 1.31 (t, J = 6.9 Hz, 3H). Example 3

 (2 R, 3 R) —2— (t-butoxycarbonyl) amino-3-hydroxy-1-hexoxy hexinolepropanoic acid

To a solution of the compound produced in Example 2 (190 mg) in ethanol (8 ml) was added a 1N aqueous solution of lithium hydroxide (1.8 ml). The reaction mixture was stirred at room temperature for 3.5 hours. Di-tert-butyl dicarbonate (0.24 m 1) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water and washed with t-butyl methyl ether. To the aqueous layer was added a 5% aqueous hydrogen sulfate aqueous solution until the pH reached 3. The aqueous layer was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to give the compound of the present invention (175 mg, 81 ° / ₀ , 97.3% ee) having the following physical data. .

TLC: R f 0.81 (dichloromethane: methanol: acetic acid = 10: 2: 1); NMR (CD ₃ OD): δ 4.28 (d, J = 6.0 Hz, IH), 3.47 (t, J = 6.0 Hz, IH) , 1.95-0.95 (m, 11H), 1.44 (s, 9H).

HPLC conditions:

 Column used: CHIRALPAKAS (Daicel);

Flow rate used: 1 m 1 Z min; Solvent used: Hexane_2-propyl alcohol / trifluoroacetic acid = 90/1 0 / 0.1;

 Temperature: 25 ° C;

 Detection: UV 210 nm;

HP LC retention time: 15 minutes. Example 3 (1) to 3 (2 5)

 Using the compounds produced in Examples 1 (1) to 1 (25), the same operation as in Example 2 → Example 3 was performed to obtain the present invention compound shown below. Example 3 (1)

 (2 R, 3 R) — 2- (t-butoxycarbonyl) amino-3-hydroxy—3—5-methylhexanoic acid

TLC: R f 0.55 (cloth form: methanol: acetic acid = 10: 1: 1); NMR (DMSO-d ₆ ): δ 12.37 (br, IH), 6.76 (d. J = 8.5 Hz, IH), 4.81 (br, IH), 3.88 (dd, J = 8.5, 5.0Hz, IH), 3.72 (m, IH), 1.71 (m, IH), 1.39 (m, IH), 1.37 (s, 9H), 1.15 (m, IH), 0.85 (d, J = 6.5 Hz, 3H), 0.82 (d, J = 6.5 Hz, 3H). Example 3 (2)

(2 R, 3 R) -1- (t-butoxycarbonyl) amino-3-hydroxy-3- (1,3-dithiane-2-yl) propanoic acid

TLC: R f 0.55 (cloth form: methanol: acetic acid = 10: 1: 1); NMR (DMSO-d ₆ ): δ 12.52 (br s, IH), 6.85 (d. J = 9.0 Hz, IH), 5.65 (br s, IH), 4.34 (dd, J = 9.0, 6.0Hz, IH), 4.09 (d, J = 6.0Hz, IH), 3.94 (dd, J = 6.0, 6.0Hz, IH), 3.00- 2.86 (m, 2H), 2.79-2.56 (m, 2H), 1.93 (m, IH), 1.78 (m, 1H), 1.37 (s, 9H). Example 3 (3)

 (2 R, 3 R) -2- (t-butoxycarbonyl) amino-3-hydroxy-3-(1,4-cis-14-methynolecyclohexane)

TLC: R f 0.59 (form: methanol: acetic acid = 10: 1: 1); NMR (DMSO-d ₆ ): δ 12.3 (br, IH), 6.73 (d. J = 9.0 Hz, IH), 4.89 (br, IH), 4.04 (dd, J = 9.0, 5.5Hz, IH), 3.51 (t, J = 5.5Hz, IH), 1.80-1.25 (m, 10H), 1.37 (s, 9H), 0.88 ( d, J = 7.0 Hz, 3H). Example 3 (4)

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TLC: R f 0.53 (cloth form: methanolic: acetic acid = 10: 1: 1); NMR (DMSO-d ₆ ): δ 12.33 (br, IH), 6.68 (d. J = 9.0Hz, IH) , 3.80 (dd, J = 9.0, 5.5Hz, IH), 3.56 (dd, J = 8.0, 5.5Hz, IH), 1.89-1.62 (m, 7H), 1.36 (s, 9H). Example 3 (7)

 (2 R, 3 R) 2- (t-butoxycarbonyl) amino-3-hydroxy-3--3-phenic acid

TLC: R f 0.82 (dichloromethane: methanol: acetic acid = 10: 2: 1); NMR (CD ₃ OD): δ 7.40-7.20 (m, 5H), 4.92 (d, J-6.9 Hz, IH), 4.40 ( d, J = 6.9 Hz, IH), 1.33 (s, 9H). Example 3 (8)

(2R, 3 R) —2— (t-butoxycarbonyl) amino-3-hydroxy—3— (2,6-dimethylphenyl) propanoic acid

TLC: R f 0.83 (dichloromethane: methanol: acetic acid = 10: 2: 1); NMR (CD ₃ OD): δ 7.10 (m, 3H), 5.30 (d, J = 9.6 Hz, IH), 4.72 (d, J-9.6 Hz, IH), 2.49 (s, 6H), 1.21 (s, 9H. Embodiment 3 (9)

 (2 R, 3 R) —2— (t-butoxycarbol) amino-3-hydroxy-13- (cyclohexene-4-yl) propanoic acid

TLC: R f 0.91 (dichloromethane: methanol: acetic acid = 10: 2: 1); NMR (CD ₃ OD): δ 5.66 (brs, 2H), 4.29 (m, IH), 3.61-3.50 (m, IH), 2.25-1.75 (m, 6H), 1.44 (s, 9H), 1.23 (m, 1H). Example 3 (10)

(2R, 3R) -2- (t-butoxycarbonyl) amino-3-hydroxy-3- (1-ethylpropyl) propanoic acid

TLC: R f 0.99 (dichloromethane: methanol: acetic acid = 10: 2: 1); NMR (CD ₃ OD): δ 4.27 (d, J = 6.6 Hz, IH), 3.73 (dd, J = 6.6, 5.1 Hz, IH), 1.65-1.21 (m, 5H), 1.44 (s, 9H), 0.94-0.86 (m, 6H). Example 3 (11)

 (2 R, 3 R) -2- (t-butoxycarboel) amino-3 -hydroxy —3-(thian 41-yl) propanoic acid

TLC: R f 0.98 (dichloromethane: methanol: acetic acid = 10: 2: 1); NMR (CD ₃ OD): δ 4.26 (d, J = 6.3 Hz, IH), 3.51 (t, J = 6.3 Hz, IH) , 2.74-2.55 (m, 4H), 2.18 (m, IH), 2.03 (m, IH), 1.70-1.35 (m, 2H), 1.44 (s, 9H). Example 3 (12)

(2 R, 3 R) -2- (t-butoxycarboel) amino-3-hydroxy-1 3-cyclohexyl heptinolepropanoic acid

 T LC: R f 0.85 (n-butanol: acetic acid: water = 4: 2: 1);

NMR (CD ₃ OD): δ 5.49 (m, IH), 4.42 (m, IH), 3.56 (m, IH), 1.88-1.22 (m,

21H);

Specific rotation: [] _D -11.09 (cl.06, methanol). Example 3 (1 3)

 (2 R, 3 R) — 2— (t-butoxycarbonyl) amino-3-hydroxy— 3— (1-methyl-1-phenylethyl) propanoic acid

TLC: R f 0.96 (dichloromethane: methanol: acetic acid = 10: 2: 1); NMR (CD ₃ OD): δ 7.40-7.38 (m, 2H), 7.30-7.25 (m, 2H), 7.15 (m, IH), 4.16 (d, J = 7.2 Hz, IH), 3.99 (d, J = 7.2 Hz, IH), 1.37 (s, 3H), 1.35 (s, 3H), 1.33 (s, 9H). Example 3 (1 4)

(2 R, 3 R) — 2- (1-butoxycarbonyl) amino-3-hydroxy-3--3- (1,4-benzodioxane-1 6-inole) propanoic acid O CH ₃

TLC: R f 0.91 (dichloromethane: methanol: acetic acid = 10: 2: 1); NMR (CD ₃ OD): δ 6.87-6.75 (m, 3H), 4.80 (d, J = 7.2 Hz, IH), 4.33 ( d, J = 7.2 Hz, IH), 4.20 (s, 4H), 1.35 (s, 9H). Example 3 (15)

 (2 R, 3 R) 1-2- (t-butoxycarbonyl) amino-3-hydroxy-1 3- (3,5,6-trihydropyran-14-ylidenemethinole) propanoic acid

TLC ： R f 0.69 (ジクロロメタン： メタノール：酢酸 = 10 : 2 : 1) ; NMR (CD₃OD) ： δ 5.48 (brs, IH), 5.34 (d， J = 8.7 Hz, IH), 4.77 (brs, IH), 4.42 (brs, IH), 4.20 (brs, IH), 3.80-3.60 (m, 4H), 2.40-2.20 (m, 4H), 1.46 (s, 9H)。 実施例 3 (16)

TLC: R f 0.69 (dichloromethane: methanol: acetic acid = 10: 2: 1); NMR (CD ₃ OD): δ 5.48 (brs, IH), 5.34 (d, J = 8.7 Hz, IH), 4.77 (brs, IH), 4.42 (brs, IH), 4.20 (brs, IH), 3.80-3.60 (m, 4H), 2.40-2.20 (m, 4H), 1.46 (s, 9H). Example 3 (16)

(2 R, 3R) — 2-— (t-butoxycarbonyl) amino-3-hydroxy-3- (furan-3-yl) propanoic acid

TLC: R f 0.84 (dichloromethane: methanol: acetic acid = 10: 2: 1); NMR (CD ₃ OD): δ 7.44 (d, J = 8.1 Hz, 2H), 6.43 (s, 1H), 4.93 (d, J = 6.9 Hz, 1H), 4.38 (d, J = 6.9 Hz, 1H), 1.39 (s, 9H). Example 3 (17)

 (2R, 3R) -2- (t-butoxycarbonyl) amino-3-hydroxy-13- (cyclopentene-4-yl) propanoic acid

TLC: R f 0.64 (dichloromethane: methanol: acetic acid = 10: 2: 1); NMR (CD ₃ OD): δ 5.68-5.64 (m, 2H), 4.20 (d, J = 4.2 Hz, 1H), 3.68 ( dd, J = 8.4, 4.2 Hz, 1H), 2.65-2.10 (m, 5H), 1.44 (s, 9H);

Specific rotation: [a] _D -17.99 (c 1.025, methanol). Example 3 (18)

( - , ^ 4 ー ) -Ζ- (Ή S 'Ή Ζ) 91 (2R, 3R) -2- (t-butoxycarbol) amino-3-hydroxy-1-3- (tetrahydropyran -4-yl) propanoic acid Eve. , / (4 // c, ^ a /, — one 4-'τ)-ε-

(-, ^ 4 ー) -Ζ- (Ή S 'Ή Ζ) 91

 (02) ε \ mm

° (Η6 's) 1 / Ί' (Η6 '∞) 8Π-66 Ι

'(ΗΙ' ∞) s · ε X 's) ςυι ^£ (ΗΙ ¾ 9 · ε' (ΗΙ 'ω) εε §: (αο ^ε αο) ΉΙΛΙΝ

 • (T: 0 τ = Λ ί ≠: ^^ 800 J Η: つ [丄 01

 蠲 a a (Λ, ί ^ τχ ^ ^ -Λ 1 ー / ^ 1 'τ)-ε-^ τχ ^ 3— ε— / 4-^) — Ζ_ (Η ε' Ή Ζ)

 (6 τ) ε mm

. 1 ", 086'0.) 98 SI- ^α [»]:

: (Η6 'S)' (ΕΚ ^£ UI) οε ι-οοτ '(HZ: ^£ m) ιε'ε- ^ ε' (HI ¾H Υζ

'S' = ί 'ΡΡ) OS' (HZ ¾ 06- ^£ -00 ^£ (Hl ^£ ΖΗ1 / 1 / ς = Γ ^£ p) 93 9 '■ (aO ^e Q3)

CZT0 / C0df / X3d 8.S990 / C0 OAV

 TLC: R f 0.07 (dichloromethane: methanol = 10: 1);

NMR (CD ₃ OD): δ 4.25 (m, IH), 3.49 (m, IH), 3.33 (s, 3H), 3.12 (m, 1H),

2.11-1.01 (m, 9H), 1.44 (s, 9H). Example 3 (21)

 (2R, 3R) -2- (t-butoxycarbonyl) amino-3-hydroxy (-3-, 1-cis-4-ethoxycyclohexyl) propanoic acid

TLC: R f 0.85 (n-butanol: acetic acid: water = 4: 2: 1);

NMR (CD ₃ OD): δ 4.30 (m, IH), 3.54-3.48 (m, 2H), 3.46 (q, J = 7.2 Hz, 2H), 1.91-1.88 (m, 2H), 1.65-1.39 (m , 7H), 1.44 (s, 9H), 1.71 (t, J = 7.2 Hz, 3H). Example 3 (22)

(2R, 3R) -2- (t-butoxycarbol) amino-3-hydroxy-3- (1,4-trans-4-ethoxycyclohexanol) propanoic acid C ₂ H ₅ 0,

O CH ₃

 TLC: R f 0.88 (n-butanol: acetic acid: water = 4: 2: 1);

NMR (CD ₃ OD): δ 4.24 (m, IH), 3.54 (q, J = 7.2 Hz, 2H), 3.47 (m, IH), 3.23 (m,

IH), 2.06-1.10 (m, 9H), 1.44 (s, 9H), 1.16 (t, J = 7.2 Hz, 3H). Example 3 (23)

 (2 R, 3 R) -2- (t-butoxycarboyl) amino-3-hydroxy

3-(Adamantane 1 1-Inore) Propane Fuji

_{NMR (CDC1 3): δ 5.54} (m, IH), 4.43 (m, IH), 3.32 Cm, IH), 2.00-1.27 (m, 24H). Example 3 (24)

 (2 R, 3 R) -1- (t-butoxycarbonyl) amino-3-hydroxy-1- (2-phenylethyl) propanoic acid

TLC: R f 0.82 (dichloromethane: methanol: acetic acid: 0: 2 NMR (CDCI3): δ 7.31-7.19 (m, 5H), 5.43 (m, IH), 4.34 (m, 1H), 3.92 (m, IH), 2.70 (m, IH), 2.00-1.78 (m, 3H ), 1.45 (s, 9H). Example 3 (25)

 (2R, 3R) -2- (t-butoxycarbonyl) amino-3-hydroxy-1-hexylhexylmethylpropanoic acid

TLC: R f 0.94 (n-butanol: acetic acid: water = 4: 2: 1);

_{NMR (CD 3 OD): 8} 4.14 (m, IH), 3.95 (m, IH), 1.85-1.15 (m, 11H), 1.44 (s, 9H), 1.03-0.83 (n, 2H;). Example 4 (1) or 4 (2)

 Using the compound prepared in Example 1 (26) or 1 (27), the same operation as in Example 2 → Example 3 was performed to obtain the present compound shown below. Example 4 (1)

(2R, 3R) -2- (t-butoxycarbol) amino-3-hydroxy- 3- (1,4-cis-14-hydroxycyclohexynole) propanoic acid

 TLC: R f 0.62 (n-butanol: acetic acid: water = 4: 2: 1);

NMR (CD ₃ OD): 8 4.32 (d, J = 4.5 Hz, IH), 3.91 (m, IH), 3.55 (m, IH),

1.97-1.43 (m, 9H), 1.44 (s.9H). Example 4 (2)

 (2R, 3R) -2- (t-butoxycarbonyl) amino-3-hydroxy-13- (1,4-trans-4-hydroxycyclohexyl) propanoic acid

TLC: R f 0.64 (n-butanol: acetic acid: water = 4: 2: 1);

NMR (CD ₃ OD): δ 4.25 (d, J = 5.4 Hz, IH), 3.50-3.42 (m, 2H), 1.98-1.92 (m, 4H), 1.84-1.77 (m, IH), 1.60-1.50 (m, 2H), 1.44 (s, 9H), 1.28-1.12 (m, 2H).

Claims

Wherein R 1 represents a C 1-8 alkyl group, and R 2 represents  (1) C1-8 alkyl group,  (2) C2-8 alkenyl group,  (3) C2-8 alkyl group,  (4) C y c 1,  (5) a C1-8 alkyl group, a C2-8 alkenyl group or a C2-8 quinolene group, which is substituted by Cyc1, or  (6) Substituted with a C3-8 cycloalkylidene group or one of its ring-constituting carbon atoms (excluding carbon atoms having an alkylidene bond) replaced with an oxygen, nitrogen or sulfur atom Represents a C 1-8 alkyl group substituted with a heterocyclic group, Cy cl is a C 3-15 monocyclic, bicyclic or tricyclic carbocyclic ring, or 3- to 15-membered containing 1 to 5 heteroatoms selected from oxygen, nitrogen or sulfur atoms Represents a monocyclic, bicyclic or tricyclic heterocyclic ring, wherein Cy cl may be substituted by 1 to 5 R ³ , R ³ represents a C L～8 alkyl group, C L～8 alkoxy group, hydroxyl group, C l~8 C 1~ 8 alkoxy group or Okiso group alkoxy group is substituted. ) Or a salt thereof. 2. R ² is 2-methylpropyl, 1-ethylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentene-4-yl, cyclohexene 4-yl group, 4-methylcyclohexyl group, 4-hydroxycyclohexyl group, 4_methoxymethylenoxycyclohexynole group, 4-methoxycyclohexynole group, 4-ethoxycyclohexyl group, Cyclic hexylmethyl group, adamantane-1-yl group, pheninole group, 2,6-dimethinolephenyl group, 1-methynole-1-1-phenylinoleethyl group, 2-phenylenyl group, 1,4-benzodioxane-16- Yl, trifluoro-3-yl, tetrahydropyran -4-yl, tetrahydropyran-4-inolemethyl, 3,5,6-trihydro Run _4_ ylidene group, 1, 3-dithiane _ 2 I group, thian _ 4 _ I group or Chian 1, 1 compound or salt thereof according to claim 1, wherein-dione is an 4 Iru group. 3. R ² is a pentynole group, a cyclohexynole group, a heptyl group, a 4-hydroxycyclohexyl group, a 4-methoxymethyloxy hexyl group, or a tetrahydropyran 3. The compound according to claim 2, which is a fluor group, or a salt thereof. 4. General formula (II), NO COOR ¹  (Π)  OH (In the formula, R ¹ has the same meaning as described in claim 1.) And a general formula (ΙΠ) R ² — CHO (ΠΙ) (Wherein, R ² has the same meaning as described in claim 1). An aldehyde derivative represented by the formula (1) is subjected to an asymmetric aldol reaction and, if desired, to a salt conversion reaction. I)

(Wherein, R ¹ and R ² represent the same meaning as described above.) Or a method for producing a salt thereof. 5. R ² is 2-methylpropyl group, 1-ethylpropyl group, cyclopropyl group, cyclopentinole group, cyclopentinole group, cyclohexinole group, cycloheptinole group, cyclopentene-4-ynole group, cyclohexene I 4-Inole group, 4-methylcyclohexyl group, 4-hydroxycyclohexyl group, 4-methoxymethylcyclohexyl group, 4-methoxycyclohexyl group, 4-ethoxycyclohexyl group, Silk mouth Xylmethyl group, adamantane-11-yl group, phenyl group, 2,6-dimethylphenyl group, 1-methynole-11-phenylenolethione group, 2-phenylenoletinole group, 1,4-benzodioxane-16-ynolele group , A trifluoro-3-yl group, a tetrahydropyran-4-yl group, a tetrahydropyran-14-ylmethyl group, 3, 5, 6 Tri ratio Doropiran one 4-Iridenmechiru group, 1, 3-dithiane one 2-I group, thian one 4 Iru group, thian one 1, 1 - dione one 4 Iru manufacturing method in the range 4 according claims a group. 6. R ² is a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4-hydroxycyclyl hexyl group, a 4-methoxymethynoleoxycyclyl hexyl group, or a tetrahydropyran-1-yl group The production method according to claim 5. 7. General formula (I) (I)

(Wherein, R ¹ and R ² have the same meanings as described in claim 1). A compound represented by the general formula (IV):

(Wherein, R ¹ and R ² represent the same meaning as described above.) A method for producing an optically active hydroxyamino acid derivative or a salt thereof represented by the formula: 8. R ² is 2-methylpropyl group, 1-ethylpropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclopentene 1-4-inole group, cyclohexyl Xen-1-yl, 4-methylcyclohexyl, 4-hydroxycyclohexyl, 4-methoxymethyloxyhexyl, 4-methoxycyclohexynole, 4-ethoxycyclohexyl Hexinolemethynole group, adamantane-11-inole group, phenyl group, 2,6-dimethylphenyl group, 1-methynole-11-phenylenoletinole group, 2-phenylenyl group, 1,4-benzodioxane-16- Yl, furan-3-yl, tetrahydropyran-14-inole, tetrahydropyran-14-ylmethyl, 3,5,6-tri 8. The production method according to claim 7, which is a hydropyran-14-ylidenemethynole group, a 1,3-dithiane-12-yl group, a thian-14-yl group, or a thian-1,1-dione-14-yl group. 9. R ² is a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4-hydroxycyclohexyl group, a 4-methoxymethinoleoxycyclohexynole group, or a tetrahydropyran-1-yl group 9. The production method according to claim 8. 0. General formula (I)

(Wherein R ¹ and R ² have the same meanings as described in claim 1). The compound represented by the formula (IV)

(Wherein, R ¹ and R ² represent the same meaning as described above.) Wherein the compound represented by the formula is hydrolyzed, and the amino group is further protected by a t-butoxycarbonyl group.

(Wherein, R ² has the same meaning as described above.) A method for producing an optically active 2-((t-butoxycarbonyl) amino-3-hydro: acid derivative or a salt thereof represented by the formula: 1 1-General formula (I)

(Wherein R ¹ and R ² have the same meanings as described in claim 1). The compound represented by the formula (IV)

(Wherein, R ¹ and R ² represent the same meaning as described above.) Wherein the amino group of the compound represented by the formula is protected by a t-butoxycarbonyl group, and further hydrolyzed.

(Wherein, R ² has the same meaning as described above.) A method for producing an optically active 2-(-tert-butoxycarbonyl) amino-3-hydroxypropanoic acid derivative or a salt thereof represented by the formula: 12. R ² is 2-methylpropyl group, 1-ethylpropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptinol group, cyclopentene 4-ynole group, cyclohexene 1-4-inole Group, 4-methylcyclohexyl group, 4-hydroxycyclohexyl group, 4-methoxy Methylenoxyoxyhexyl group, 4-methoxyhexyl group, 4-ethoxyhexyl group, hexanoxyhexolemethyl group, adamantane-11-inole group, pheninole group, 2,6-dimethinolefe 2-norethyl group, 1-methyl-1-phenylinoletinole group, 2-phenylethyl group, 1,4-benzodioxane-1-6-yl group, furan-3-ynole group, tetrahydropyran-4-yi group, tetrahydrosilane 1-4-ylmethyl group, 3,5,6_trihydridopyran-1-4-ylidenemethyl group, 1,3-dithiane-2-yl group, thiane-4-yl group, thiane-1,1-dione-1 4 12. The production method according to claim 10 or 11, which is a methyl group. 13. R ² is a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a tetrahydropyran-1-yl group, a 4-hexoxymethinoleoxycyclyl hexyl group or a 4-hydroxycyclohexyl group The production method according to claim 12.