JP2818381B2 - 7-Thiaprostaglandins and process for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to novel 7-thiaprostaglandins which have cell migration inhibitory activity and are useful as pharmaceuticals, and to a process for producing them.

[0002]

2. Description of the Related Art Prostaglandins have various physiological actions such as platelet aggregation inhibitory action, vasodilatory action, blood pressure lowering action, gastric acid secretion inhibitory action, smooth muscle contraction action, cytoprotection action, and diuretic action. , Myocardial infarction, angina, arteriosclerosis,
It is a useful compound for treating or preventing hypertension, duodenal ulcer, induction of labor, abortion, etc. Among them Prostaglandin E ₁ is potent platelet aggregation inhibitory action, has a vasodilating effect, it has already been used in clinical.

The 7-thiaprostaglandins E ₁ have an inhibitory action on platelet aggregation, antihypertensive action, antithrombotic, antianginal, antimyocardial infarction, antiarteriosclerosis, and malignant tumor preventive action by vasodilatory action, It is disclosed that it exhibits an antitumor effect (JP-A-53-68753, JP-A-58-110).
562, JP-A-59-29661, JP-A-60-185
761, JP-A-61-204163). It is also known that the 7-thiaprostaglandins E ₁ are useful for neuropathy in diabetes (JP-A-64-52721).

On the other hand, enol butyrate of prostaglandin E ₁ is known as a prostaglandin E ₁ analogue (Japanese Patent Laid-Open No. 5-213862) is a stable in the formulation at a high temperature, prostacyclin Grangen E ₁
It only shows that a biological activity equivalent to that described above can be expected, and there is no suggestion about the biological activity of the compounds of the present invention described below.

[0005] By the way, conventionally, prostaglandin E ₁
As a manufacturing method of the kind, the cyclopentenone derivative having a side chain corresponding to the α-chain, from Organo lithio aluminates of ω-chain moiety, that prostaglandin E ₁ compound with a 2-component coupling type reaction can be synthesized knowledge [MJ Weiss
J. Org. Chem. 44, 1439, (1978)]. Further, as an example of the synthesis by a two-component linking reaction using an organolithiocuprate having an ω chain portion as a nucleophilic reagent, the following method is known [KG Untch et al., J. Am.
hem. Soc. 94, 7826, (1972)], [R. Pappo, PW Col
lins, Tetrahedron Lett. 4217, (1954)], [Kurosumi et al., Ch.
em. Pharm. Bull. 35, 1102, (1982)], [CK Sih,
J. Am. Chem. Soc. 97, 865, (1975)], [Sato et al., JP-A-1-228933].

[0006] Similarly, 7-thiaprostaglandin E ₁
As a method for synthesizing the compounds, a two-component linkage type reaction of a cyclopentenone derivative having a 7-thia-type α-chain and an organolithiocuprate in the ω-chain portion is known [Tanaka et al., C.
hem. Pharm. Bull. 33, 2359, (1985)].

As a method for producing enol butyrate esters of prostaglandins, JP-A-5-213682
The following formula (V)

[0008]

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[0009] A process for the production of According to this, for example, after protecting the hydroxyl group of 1-iodo-3-hydroxy-1-octene and reacting it with alkyllithium to form a 1-lithioalkene, it is reacted with a trialkylphosphine-copper (I) complex to form an organometallic compound. Lithiocuprate, and then the organolithiocuprate was added to a hydroxy-protected 4-hydroxy-2- (6-carboboxyhexyl) -2-cyclopenten-1-one by 1,4
-By conjugate addition, followed by quenching by adding butyric anhydride or butyric halide to the reaction mixture.

[0010]

The problem to be solved by the present invention is that of chemokines such as the monocytic chemoattractant M
An object of the present invention is to provide a novel 7-thiaprostaglandin derivative which inhibits cell migration induced by CP-1 / MCAF and is useful as a therapeutic agent for arteriosclerosis, diabetic vascular disorder and the like.

Here, chemokine (CHEMOKINE)
S; also known as INTERCRINES) is a polypeptide that is produced by activated macrophages and leukocytes in lymphoid tissues and inflammation sites, has a molecular weight of about 10 Kd, has four cysteines, and has basic and heparin-binding properties. Is a general term for inflammatory / immune regulatory factors. Its main activity is cell migration inducing activity, and interleukin-8, MI
P-1α / β (Macrophage Inflammatory Protein-1α / β
Abbreviation), MCP-1 (Monocyte ChemoattractantProtei)
n-1) and a group of cytokines that have been implicated in various chronic / subacute inflammatory diseases.
Family (eg, MICHIEL, D. (1993) BIO
TECHNOLOGY Vol. 11 p. 739, OPPENHEIM, JJ et al. (1991
Year) ANNUALREVIEW OF IMMUNOLOGY Vol. 9 pp. 617-648,
NEOTE, K. et al. (1993) CELL Vol. 72, pp. 415-425, SCHA
LL, TJ (1991) CYTOKINE Vol. 3, pp. 165-183).

Among these, the monosite chemotactic factor MCP
-1 (also known as MCAF (MACROPHAGE CHEMOTACTIC AND ACTI
VATING FACTOR) is a chemokine having monocytic migration activity, which is produced in response to various stimuli from T lymphocytes, macrophages, smooth muscle cells, fibroblasts, vascular endothelial cells, and the like. Such chemokines are involved in vascular restenosis or reocclusion following intimal injury in angioplasty or the like, in which monocytic / macrophage cells are deeply involved in the development of lesions, and porosity in coronary arteries or cervical aorta. To the lesion site in diseases such as stenosis or occlusion of blood vessels mainly due to formation of atherosclerotic lesions, arteriosclerosis occurring in transplanted hearts, rejection of transplanted organs, rheumatoid arthritis, glomerulonephritis, diabetic microangiopathy, etc. It has been strongly suggested that by inducing the accumulation of monocytic / macrophages in blood and activating the monocytic / macrophages further accumulated, they are deeply involved in the development and progression of these lesions (eg, LEONARD). , EJ and YOSHIMU
RA, T. (1990) IMMUNOLOGYTODAY Vol. 11, pages 97 to 10
One page, NELKEN, NA, etc., THE JOURNAL OF CLINICALINVES
TIGATION (1991) 88: 1121-127, KOC
H, AE et al., THE JOUNAL OF CLINICAL INVESTIGATION (1
992) Vol. 90, pages 772 to 779, HANAZAWA, S et al. (1
993) THE JOURNAL OF BIOLOGICAL CHEMISTRY 268
Volume 9526 to 9532, GRAVES, DT et al. AMERICAN
JOURNAL OF PATHOLOGY (1992) Volume 140 pages 9-14
Page, EDGINGTON, SM, BIO / TECHNOLOGY (1993) Vol. 11 6
76-681, ADAMS, DH et al. IMMUNOLOGICAL REVIEWS (19
93) No. 134, pp. 5-19). Such MCP-1
/ Agents that inhibit cell migration induced by MCAF are mainly caused by vascular restenosis or reocclusion following intimal injury in angioplasty, etc., and atherosclerotic lesion formation in coronary arteries or cervical aorta. Is useful as a therapeutic and / or prophylactic agent for vascular stenosis or occlusion, arteriosclerosis occurring in the transplanted heart, diabetic vascular disorder, glomerulonephritis, rheumatoid arthritis, osteoarthritis, transplant organ rejection, etc. There is expected.

[0013]

Means for Solving the Problems The present inventors have conducted intensive studies on the possibility of novel 7-thiaprostaglandins that inhibit cell migration induced by chemokines. Grungins are chemokines,
For example, they have found that they are potent inhibitors of the cell migration triggered by the monocytic migration factor MCP-1 / MCAF, and furthermore, they have found that such compounds suppress intimal thickening that occurs after intimal injury of the blood vessels, The present invention has been reached. It has also been found that the 7-thiaprostaglandins of the present invention have platelet aggregation inhibitory activity.

That is, the present invention relates to the following formula (I)

[0015]

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Wherein R ¹ is a C1-C10 linear or branched alkyl group, a C2-C10 linear or branched alkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C3 To C10 cycloalkyl group, substituted or unsubstituted phenyl (C1 to C2) alkyl group, substituted or unsubstituted phenoxy (C1 to C2)
7) A group that becomes a substituted or unsubstituted amino acid residue including an alkyl group or a carbonyl group of an enol ester. R ² is a hydrogen atom, tri (C1 to C7 hydrocarbon)
It represents a silyl group or a group that forms an acetal bond with an oxygen atom of a hydroxyl group. R ³ is a hydrogen atom, a methyl group,
Or represents a vinyl group. R ⁴ is a C1-C8 linear or branched alkyl group, a C2-C8 linear or branched alkenyl group, a C2-C8 linear or branched alkynyl group, a substituted or unsubstituted phenyl group, A substituted or unsubstituted C3-C10 cycloalkyl group, a C1-C5 alkoxy group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted C3-C10 Or a linear or branched C1-C5 alkyl group, a C2-C5 alkenyl group, or a C2-C5 alkynyl group substituted with a substituted or unsubstituted heterocyclic group. W represents a hydrogen atom, a hydroxyl group, a tri (C1-C7 hydrocarbon) siloxy group, or a group that forms an acetal bond. XY represents an ethylene group, a vinylene group, or an ether bond in which X is an oxygen atom and Y is methylene. Z is CO ₂ R ⁵ or CONR ⁶
Represents R ⁷ . R ⁵ is a hydrogen atom, a linear or branched alkyl group of C1 -C10, straight-chain or branched alkenyl group of C2 -C10, substituted or unsubstituted phenyl group, cycloalkyl substituted or unsubstituted C3~C10 Alkyl group, substituted or unsubstituted phenyl (C1 to C2)
Represents an alkyl group or one equivalent of a cation. R ⁶ ,
R ⁷ is the same or different and represents a hydrogen atom, a C1 to C5 linear or branched alkyl group, or a group which forms a C4 to C6 heterocycle together with the amide nitrogen atom. n represents 0 or 1. Signage - represents a double bond or a single bond. And 7-thiaprostaglandins, which are enantiomers or mixtures thereof in any proportion.

In the 7-thiaprostaglandins represented by the above formula (I), R ¹ is a C1-C10 linear or branched alkyl group, a C2-C10 linear or branched alkenyl group, A substituted or unsubstituted phenyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted phenyl (C1-C
2) alkyl group, substituted or unsubstituted phenoxy (C
1-C7) represents a group that becomes a substituted or unsubstituted amino acid residue including an alkyl group or a carbonyl group of an enol ester. Preferred examples of such a C1-C10 linear or branched alkyl group include a methyl group,
Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl,
Examples include a heptyl group, an octyl group, a nonyl group, and a decyl group. Preferred examples of the C2-C10 linear or branched alkenyl group include a vinyl group, an allyl group, and a 3
-Butenyl group, 2-butenyl group, 4-pentenyl group, 2
A pentenyl group, a prenyl group (3-methyl-2-butenyl group), a 2,4-hexadienyl group, a 2,6-octyldienyl group, a neryl group, a geranyl group, a citronellyl group,
And a farnesyl group and an arachidyl group. Preferred examples of the substituent of the substituted or unsubstituted phenyl group include a halogen atom, a hydroxyl group, C2
A C7 acyloxy group, a C1-C4 alkyl group optionally substituted with a halogen atom, a C1-C4 alkoxy group optionally substituted with a halogen atom, a nitrile group, a nitro group, a carboxyl group, (C1-C6 ) Alkoxycarbonyl group and the like, and these substituents may be substituted at any position of ortho, meta and para on the phenyl group, and may be substituted by a plurality of substituents in any combination. Good. Substituted or unsubstituted C
Preferred examples of the 3- to C10 cycloalkyl group include:
A cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group, a cycloheptyl group, a cyclooctyl group, a cyclodexyl group, etc., which are substituted at any position with a C1 to C5 alkyl group or a C1 to C5 alkoxy group. It may be. Examples of the substituted or unsubstituted phenyl (C1 to C2) alkyl group include a phenyl group substituted or unsubstituted with the same substituent as described above, an α-phenethyl group, a β-phenethyl group, and the like. . Examples of the substituted or unsubstituted phenoxy (C1 to C7) alkyl group include those in which the phenoxy group is substituted or unsubstituted with the same substituent as the phenyl group described above. Furthermore, including the carbonyl group of the enol ester, the amino acid of the group that becomes a substituted or unsubstituted amino acid residue includes alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, Lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine and the like. Among these, R ¹ is preferably a C1-C10 linear or branched alkyl group, or a substituted or unsubstituted phenyl group, and particularly preferably a propyl group.

In the 7-thiaprostaglandins represented by the above formula (I), R ² is a hydrogen atom, tri (C1
(C7 hydrocarbon) represents a silyl group or a group that forms an acetal bond with an oxygen atom of a hydroxyl group. Preferred examples of the tri (C1-C7 hydrocarbon) silyl group include a trimethylsilyl group, a triethylsilyl group, and a tert-
A tri (C1-C4 alkyl) silyl group such as a butyldimethylsilyl group, a diphenyl (C1-C4) alkylsilyl group such as a tert-butyldiphenylsilyl group, or
And a tribenzylsilyl group. Preferred examples of the group that forms an acetal bond together with the oxygen atom of the hydroxyl group include a methoxymethyl group, a 1-ethoxyethyl group,
2-methoxy-2-propyl group, 2-ethoxy-2-propyl group, (2-methoxyethoxy) methyl group, benzyloxymethyl group, 2-tetrahydropyranyl group, 2-
A tetrahydrofuranyl group, a 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hex-4-yl group, and the like. Among them, R ² is particularly preferably a hydrogen atom, a trimethylsilyl group, a 2-tetrahydropyranyl group, or a tert-butyldimethylsilyl group.

In the 7-thiaprostaglandins represented by the above formula (I), R ³ represents a hydrogen atom, a methyl group or a vinyl group, and among them, a hydrogen atom and a methyl group are preferable.

In the 7-thiaprostaglandins represented by the formula (I), R ⁴ is a C1-C8 linear or branched alkyl group, a C2-C8 linear or branched alkenyl group, A C2-C8 linear or branched alkynyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a C1-C5 alkoxy group, and a substituted or unsubstituted aromatic Straight-chain or branched C1-C5 substituted with an aromatic group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted C3-C10 cycloalkyl group, or a substituted or unsubstituted heterocyclic group. Represents an alkyl group, a C2-C5 alkenyl group, and a C2-C5 alkynyl group.

Preferred examples of the C1-C8 linear or branched alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group,
Heptyl group, octyl group, 1-methyl-1-butyl group,
A 2-methylhexyl group, a 2-hexyl group, and a 1,1-dimethylpentyl group are exemplified. Preferred examples of the C2 to C8 linear or branched alkenyl group include an allyl group, a 3-butenyl group, and a 2-butenyl group. A butenyl group, a 4-pentenyl group and a 2-pentenyl group are mentioned, and preferred examples of a C2 to C8 linear or branched alkynyl group are an ethynyl group, a 2-propynyl group, a 1-propynyl group and a 2-alkenyl group.
Butynyl group, 3-butynyl group, 3-hexynyl group, 1-
And a methyl-3-hexynyl group. Further, as preferable examples of the substituent of the substituted phenyl group, the substituents exemplified as the substituent of the substituted phenyl group in R ¹ can be used as they are. Also, substituted or unsubstituted C3
Preferred examples of the -C7 cycloalkyl group include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group, a cycloheptyl group, a cyclooctyl group, a cyclodecyl group, and the like. May be substituted with an alkyl group or a C1 to C5 alkoxy group. A C1-C5 alkoxy group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted C3-
A linear or branched C10 substituted by a C10 cycloalkyl group or a substituted or unsubstituted heterocyclic group;
C1-C5 alkyl group, C2-C5 alkenyl group, C
In the alkynyl group of 2 to C5, C1 as a substituent
Preferred examples of the alkoxy group of C5 to C5 include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group and a hexyloxy group. Preferred examples of the aromatic group as a substituent, can be mentioned phenyl group or a naphthyl group, preferred examples of the cycloalkyl group C3~C10 as a substituent, cycloalkyl group in R ¹ of the Preferred examples can be cited as they are. Preferred examples of the heterocyclic group as a substituent include a thienyl group, a furanyl group, an imidazolyl group, a pyridyl group, and a pyrazinyl group. Among these substituents, an aromatic group, a phenoxy group, and a heterocyclic group are
It may be further substituted, as these substituents, the can be exemplified by the substituents mentioned as substituents for substituted phenyl group in R ^1, also with respect to the position and number of the substituents, in R ¹ What was mentioned as substituted phenyl can be applied as it is. Linear or branched C1-C5 alkyl group, C2-C5
Alkenyl group, C2-C5 alkynyl includes methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group,
Pentyl group, allyl group, 3-butenyl group, 2-butenyl group, 4-pentenyl group, 2-pentenyl group, ethynyl group, 2-propynyl group, 1-propynyl group, 2-butynyl group, 3-butynyl group, etc. Can be mentioned. With respect to these C1 to C5 alkyl groups, C2 to C5 alkenyl groups, and C2 to C5 alkynyl groups, the above substituents may be bonded at any positions. Among these, as R ⁴ , a C3-C8 linear or branched alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, or a linear group substituted with a substituted or unsubstituted aromatic group. A branched or branched C1-C5 alkyl group is preferable, and a pentyl group, a 2-methylhexyl group, a cyclohexyl group, and a substituted or unsubstituted benzyl group are particularly preferable.

In the 7-thiaprostaglandins represented by the above formula (I), W is a hydrogen atom, a hydroxyl group, a tri (C1-C7 hydrocarbon) siloxy group, or
Represents a group that forms an acetal bond. The bird (C1
Preferred examples of the (.C7 hydrocarbon) siloxy group include triphenyl (C1-C4 alkyl) siloxy groups such as trimethylsiloxy group, triethylsiloxy group and tert-butyldimethylsiloxy group, and diphenyl (C1) such as tert-butyldiphenylsiloxy group. To C4) an alkylsiloxy group or a tribenzylsiloxy group. Preferred examples of the group forming an acetal bond include a methoxymethyloxy group, a 1-ethoxyethyloxy group, and a 2-methoxy-2-propyloxy group. Group, 2-ethoxy-2-propyloxy group, (2-methoxyethyloxy) methyloxy group, benzyloxymethyloxy group, 2-tetrahydropyranyloxy group, 2-tetrahydrofuranyloxy group, 6,6-dimethyl- 3-oxa-2-oxobicyclo [3.1.0] Such as tetrakis-4-yloxy group. Among them, W is a hydrogen atom,
Particularly preferred are a hydroxy group, a trimethylsiloxy group, a 2-tetrahydropyranyloxy group and a tert-butyldimethylsiloxy group.

In the 7-thiaprostaglandins represented by the above formula (I), Z represents CO ₂ R ⁵ or CON.
It represents R ⁶ R ^7, R ⁵ is a hydrogen atom, a linear or branched alkyl group of C1 -C10, straight-chain or branched alkenyl group of C2 -C10, substituted or unsubstituted phenyl group, a substituted or unsubstituted A substituted C3-C10 cycloalkyl group, a substituted or unsubstituted phenyl (C1-C10)
2) represents an alkyl group or one equivalent of a cation. Preferred examples of such a C1-C10 linear or branched alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a sec-
Butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like;
Preferred examples of 0 linear or branched alkenyl groups include vinyl, allyl, 3-butenyl, 2-
Butenyl group, 4-pentenyl group, 2-pentenyl group, prenyl group (3-methyl-2-butenyl group), 2,4-hexadienyl group, 2,6-octadienyl group, neryl group, geranyl group, citronellyl group, farnesyl And arachidyl groups. Preferred examples of the substituent of the substituted or unsubstituted phenyl group include a halogen atom, a hydroxyl group, a C2 to C7 acyloxy group, a C1 to C4 alkyl group which may be substituted with a halogen atom, and a halogen atom. C1 to C4 which may be
And a substituted or unsubstituted C3-C10 cycloalkyl group such as a cyclopropyl group and a cyclopentyl group. , Cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclodecyl and the like. Examples of the substituted or unsubstituted phenyl (C1 to C2) alkyl group include a benzyl group substituted or unsubstituted with the same substituent as described above, an α-phenethyl group, a β-phenethyl group, and the like. , One preferred equivalent of the cation is N 2
H ₄ ⁺ , tetramethyl ammonium, monomethyl ammonium, dimethyl ammonium, trimethyl ammonium, benzyl ammonium, phenethyl ammonium,
Ammonium cations such as morpholinium cation, monoethanolammonium and piperidinium cations; alkali metal cations such as Na ⁺ and K ⁺ ; 1/2 Ca
^Examples thereof include divalent or trivalent metal cations such as ²⁺ , 1/2 Mg ²⁺ , 1/2 Zn ²⁺ , and 1/3 Al ³⁺ . Among them, R ² is preferably a hydrogen atom, a C1 to C10 linear or branched alkyl group, a C2 to C10 linear or branched alkenyl group, and particularly preferably a methyl group. R ⁶ and R ⁷ may be the same or different and include a hydrogen atom, a C1 to C5 linear or branched alkyl group, or C4 together with an amide nitrogen atom.
Represents a group forming a heterocyclic ring of C1 to C6, and preferred examples of the linear or branched alkyl group of C1 to C5 include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a sec group. -Butyl group, pentyl group and the like;
As the hetero ring serving as a group forming the hetero ring of C6,
Examples include a pyrrolidine ring, a pyridine ring, a piperazine ring, and a morpholine ring. Among them, R ⁵ and R ⁶ are preferably hydrogen atoms.

Further, in the compound represented by the above formula (I), the configuration of the substituent bonded to the cyclopentanone ring has a configuration derived from natural prostaglandin E _1. Although it is a particularly useful stereoisomer, in the present invention, its enantiomer, which is represented by the following formula (I) ent

[0025]

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[Wherein R ¹ , R ² , R ³ , R ⁴ , W, X-
Y, Z, n, and display - are the same as defined above. ] Or a mixture thereof in any ratio. Further, since carbon substituted by OR ² , R ³ and R ⁴ is an asymmetric carbon, there are two kinds of optical isomers.
Alternatively, it also includes a mixture in any ratio thereof.

Preferred specific examples of the 7-thiaprostaglandins represented by the above (I) of the present invention include the following compounds. 01) (11R, 12S, 13E, 15S) -9-acetoxy-11,15-dihydroxy-7-thiaprostar
8,13-dienoic acid 02) (11R, 12S, 13E, 15S) -9-propionyloxy-11,15-dihydroxy-7-thiaprosta-8,13-dienoic acid 03) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-7-thiaprosta-8,13-dienoic acid 04) (11R, 12S, 13E, 15S) -9-isobutyryloxy-11,15-dihydroxy-7-thiaprosta- 8,13-dienoic acid 05) (11R, 12S, 13E, 15S) -9-valeryloxy-11,15-dihydroxy-7-thiaprosta-8,13-dienoic acid 06) (11R, 12S, 13E, 15S)- 9-isovaleryloxy-11,15-dihydroxy-7-thiaprosta-8,13-dienoic acid 07) (11R, 12S, 13E, 5S) -9-Pivaloyloxy-11,15-dihydroxy-7-thiaprosta-8,13-dienoic acid 08) (11R, 12S, 13E, 15S) -9-Acryloyloxy-11,15-dihydroxy-7-thiaprosta- 8,13-dienoic acid 09) (11R, 12S, 13E, 15S) -9-methacryloyloxy-11,15-dihydroxy-7-thiaprosta-8,13-dienoic acid 10) (11R, 12S, 13E, 15S) -9-crotonoyloxy-11,15-dihydroxy-7-thiaprosta-8,13-dienoic acid 11) (11R, 12S, 13E, 15S) -9-benzoyloxy-11,15-dihydroxy-7-thiaprosta- 8,13-dienoic acid 12) (11R, 12S, 13E, 15S) -9-naphthoyloxy-11,15 Dihydroxy-7-thiaprosta-8,13-dienoic acid 13) (11R, 12S, 13E, 15S) -9-Toluoyloxy-11,15-dihydroxy-7-thiaprosta-8,13-dienoic acid 14) (11R , 12S, 13E, 15S) -9-Cyclohexylcarbonyloxy-11,15-dihydroxy-7-thiaprosta-8,13-dienoic acid 15) (11R, 12S, 13E, 15S, 17R) -9
-Acetoxy-11,15-dihydroxy-17,20
-Dimethyl-7-thiaprosta-8,13-dienoic acid 16) (11R, 12S, 13E, 15S, 17R) -9
-Butyryloxy-11,15-dihydroxy-17,
20-Dimethyl-7-thiaprosta-8,13-dienoic acid 17) (11R, 12S, 13E, 15S, 17S) -9
-Butyryloxy-11,15-dihydroxy-17,
20-dimethyl-7-thiaprosta-8,13-dienoic acid 18) (11R, 12S, 13E, 15S, 17R) -9
-Isobutyryloxy-11,15-dihydroxy-1
7,20-dimethyl-7-thiaprosta-8,13-dienoic acid 19) (11R, 12S, 13E, 15S, 17R) -9
-Pivaloyloxy-11,15-dihydroxy-1
7,20-dimethyl-7-thiaprosta-8,13-dienoic acid 20) (11R, 12S, 13E, 15S, 17R) -9
-Benzoyloxy-11,15-dihydroxy-1
7,20-dimethyl-7-thiaprosta-8,13-dienoic acid

21) (11R, 12S, 13E, 15S)
-9-butyryloxy-11,15-dihydroxy-1
5-methyl-7-thiaprosta-8,13-dienoic acid 22) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-15-cyclopentyl-16,17,18,19,20- Pentanor
7-thiaprosta-8,13-dienoic acid 23) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanor-
7-thiaprosta-8,13-dienoic acid 24) (11R, 12S, 13E, 15R) -9-butyryloxy-11,15-dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanor-
7-thiaprosta-8,13-dienoic acid 25) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-15-phenyl-16,17,18,19,20-pentanor-7- Thiaprosta-8,13-dienoic acid 26) (11R, 12S, 13E, 15S) -9-Butyryloxy-11,15-dihydroxy-16-cyclohexyl-17,18,19,20-tetranor-7-thiaprosta-8, 13-dienoic acid 27) (11R, 12S, 13E, 15R) -9-butyryloxy-11,15-dihydroxy-16-cyclohexyl-17,18,19,20-tetranor-7-thiaprosta-8,13-dienoic acid 28) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16- Enyl-17,18,19,20-tetranor-7-thiaprosta-8,13-dienoic acid 29) (11R, 12S, 13E, 15R) -9-butyryloxy-11,15-dihydroxy-16-phenyl-17, 18,19,20-tetranor-7-thiaprosta-8,13-dienoic acid 30) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-17-phenyl-18,19,20- Trinor-7-thiaprostar
8,13-dienoic acid 31) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-18-phenyl-19,20-dinor-7-thiaprosta-8,13-
Dienoic acid 32) (11R, 12S, 13E, 15R) -9-butyryloxy-11,15-dihydroxy-18-phenyl-19,20-dinor-7-thiaprosta-8,13-
Dienoic acid 33) (11R, 12S, 13E, 15S) -9-Butyryloxy-11,15-dihydroxy-19-phenyl-20-nor-7-thiaprosta-8,13-dienoic acid 34) (11R, 12S, 13E) , 15R) -9-Butyryloxy-11,15-dihydroxy-19-phenyl-20-nor-7-thiaprosta-8,13-dienoic acid 35) (11R, 12S, 13E, 15S) -9-butyryloxy-11, 15-dihydroxy-16,16-diphenyl-17,18,19,20-tetranor-7-
Thiaprosta-8,13-dienoic acid 36) (11R, 12S, 13E, 15R) -9-butyryloxy-11,15-dihydroxy-16,16-diphenyl-17,18,19,20-tetranor-7-
Thiaprosta-8,13-dienoic acid 37) (11R, 12S, 13E, 15S, 16S) -9
-Butyryloxy-11,15-dihydroxy-16-
Phenyl-18,19,20-trinor-7-thiaprosta-8,13-dienoic acid 38) (11R, 12S, 13E, 15S, 16R) -9
-Butyryloxy-11,15-dihydroxy-16-
Phenyl-18,19,20-trinor-7-thiaprosta-8,13-dienoic acid 39) (11R, 12S, 13E, 15R, 16S) -9
-Butyryloxy-11,15-dihydroxy-16-
Phenyl-18,19,20-trinor-7-thiaprosta-8,13-dienoic acid 40) (11R, 12S, 13E, 15R, 16R) -9
-Butyryloxy-11,15-dihydroxy-16-
Phenyl-18,19,20-trinor-7-thiaprosta-8,13-dienoic acid

41) (11R, 12S, 13E, 15S)
-9-butyryloxy-11,15-dihydroxy-1
6-phenyl-16-methyl-18,19,20-trinor-7-thiaprosta-8,13-dienoic acid 42) (11R, 12S, 13E, 15R) -9-butyryloxy-11,15-dihydroxy-16 Phenyl-16-methyl-18,19,20-trinor-7-thiaprosta-8,13-dienoic acid 43) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16-paratolyl- 17,18,19,20-tetranor-7-thiaprosta-8,13-dienoic acid 44) (11R, 12S, 13E, 15R) -9-butyryloxy-11,15-dihydroxy-16-paratolyl-17,18, 19,20-Tetranor-7-thiaprosta-8,13-dienoic acid 45) (11R, 12S, 13E, 15S) -9- Tyryloxy-11,15-dihydroxy-16-methatoryl-17,18,19,20-tetranor-7-thiaprosta-8,13-dienoic acid 46) (11R, 12S, 13E, 15S) -9-butyryloxy-11 15-dihydroxy-16-orthotolyl-17,18,19,20-tetranor-7-thiaprosta-8,13-dienoic acid 47) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy- 16-naphthyl-17,18,19,20-tetranor-7-thiaprosta-8,13-dienoic acid 48) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16- (2 -Chlorophenyl) -17,18,19,20-tetranor-7-thiaprosta-8,13-diene Acid 49) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16- (3-chlorophenyl) -17,18,19,20-tetranor-7-thiaprosta-8,13-diene Acid 50) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16- (4-chlorophenyl) -17,18,19,20-tetranor-7-thiaprosta-8,13-diene Acid 51) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16- (4-nitrophenyl) -17,18,19,20-tetranor-7-thiaprosta-8,13- Dienoic acid 52) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16- (4-nitto (Phenyl) -17,18,19,20-tetranor-7-thiaprosta-8,13-dienoic acid 53) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16- (3- (Methoxyphenyl) -17,18,19,20-tetranor-7-thiaprosta-8,13-dienoic acid 54) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16- ( 4-methoxyphenyl) -17,18,19,20-tetranor-7-thiaprosta-8,13-dienoic acid 55) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16- (3-methoxycarbonylphenyl) -17,18,19,20
-Tetranor-7-thiaprosta-8,13-dienoic acid 56) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16- (4-methoxycarbonylphenyl) -17,18,19 , 20
-Tetranor-7-thiaprosta-8,13-dienoic acid 57) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16- (6-chloro-methatryl) -17,18,19 , 20-Tetranor-7-thiaprosta-8,13-dienoic acid 58) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16- (3-methyl-5-propylphenyl)- 17, 18, 19, 2
0-tetranor-7-thiaprosta-8,13-dienoic acid 59) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16- (3,5
-Dimethylphenyl) -17,18,19,20-tetranor-7-thiaprosta-8,13-dienoic acid 60) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16- ( 3-trifluoromethylphenyl) -17,18,19,20
-Tetranor-7-thiaprosta-8,13-dienoic acid

61) (11R, 12S, 13E, 15S)
-9-butyryloxy-11,15-dihydroxy-1
6- (2-fluoro-3-methoxyphenyl) -17,
18,19,20-tetranor-7-thiaprostar
8,13-dienoic acid 62) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16- (3-fluorophenyl) -17,18,19,20-tetranor-7-thiaprosta -8,13-dienoic acid 63) (11R, 12S, 13E, 15R) -9-butyryloxy-11,15-dihydroxy-16-phenoxy 17,18-19,20-tetranor-7-thiaprosta-8,13- Dienoic acid 64) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-18-oxa-
7-thiaprosta-8,13-dienoic acid 65) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16-furyl-
17,18,19,20-tetranor-7-thiaprosta-8,13-dienoic acid 66) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16-thienyl-17,18, 19,20-tetranor-7-thiaprosta-8,13-dienoic acid 67) (11R, 12S, 13E, 16S) -9-butyryloxy-11,15-dihydroxy-16- (3-thienyl) -17,18, 19,20-tetranor-7-
Thiaprosta-8,13-dienoic acid 68) (11R, 12S, 13E, 16S) -9-Butyryloxy-11,15-dihydroxy-16-pyrrolyl-17,18,19,20-tetranor-7-thiaprosta-8, 13-dienoic acid 69) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16-pyridyl-17,18,19,20-tetranor-7-thiaprosta-8,13-dienoic acid 70) (11R, 12S, 13E, 15S) -9-Butyryloxy-11,15-dihydroxy-16,16-dimethyl-7-thiaprosta-8,13-dienoic acid 71) (11R, 12S, 13E, 15S)- 9-butyryloxy-11,15-dihydroxy-17-methyl-
19,20-dinor-7-thiaprosta-8,13-dienoic acid 72) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-17-methyl-
19,20-dinor-7-thiaprosta-8,13-dienoic acid 73) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16,16,2
0-trimethyl-7-thiaprosta-8,13-dienoic acid 74) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-7-thiaprosta-8,13-diene-18-ic acid 75) (11R, 12S, 13E, 15S) -9-Butyryloxy-11,15-dihydroxy-16,20-dimethyl-7-thiaprosta-8,13-diene-18-
Inic acid 76) (11R, 12S, 13E, 16S) -9-butyryloxy-11,16-dihydroxy-7-thiaprosta-8,13-dienoic acid 77) (11R, 12S, 13E, 16S) -9-butyryloxy- 11,16-dihydroxy-16-methyl-
7-thiaprosta-8,13-dienoic acid 78) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-3-oxa-7
-Tiaprosta-8,13-dienoic acid 79) (11R, 12S, 13E, 15S, 17R) -9
-Butyryloxy-11,15-dihydroxy-17,
20-dimethyl-3-oxa-7-thiaprosta-8,
13-dienoic acid 80) (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-dihydroxy-16-phenyl-17,18,19,20-tetranor-3-oxa-
7-Thiaprosta-8,13-dienoic acid 81) (2E, 11R, 12S, 13E, 15S) -9-
Butyryloxy-11,15-dihydroxy-7-thiaprosta-2,8,13-trienoic acid 82) (2E, 11R, 12S, 13E, 15S, 17)
R) -9-Butyryloxy-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-2,8,
13-trienoic acid 83) (11R, 12S, 15S) -9-butyryloxy-11,15-dihydroxy-7-thia-8-prosenoic acid 84) (11R, 12S, 13E, 15S) -9- (N-
Mendyloxycarbonylphenylalanyloxy)-
11,15-dihydroxy-7-thiaprosta-8,1
3-dienoic acid 85) (11R, 12S, 13E, 15S) -9- (5-
(4-Chlorophenoxy) -1,1-dimethylpentyryloxy) 11,15-dihydroxy-7-thiaprosta-8,13-dienoic acid 86) (12S, 13E, 15S) -9-butyryloxy-15-hydroxy- 7-thiaprosta-8,13-dienoic acid 87) (12S, 13E, 15S, 17R) -9-butyryloxy-15-hydroxy-17,20-dimethyl-
7-thiaprosta-8,13-dienoic acid 88) The enantiomer of the compound of 01) to 87) 89) The methyl ester of the compound of 01) to 88) 90) 01) The ethyl ester of the compound of 88) 91) 01) Butyl ester of the compound of ~ 88) 92) Allyl ester of the compound of 01) ~ 88) 93) benzyl ester of the compound of 01) ~ 88) 94) sodium salt of the compound of 01) ~ 88) 95) 01) ~ 88 )) The compound in which the carboxylic acid at position 1 of the compound is an amide 96) The compound in which the carboxylic acid at position 1 of the compound of 01) to 88) is dimethylamide 97) The compound of the position 1 of the compound of 01) to 88) 98) Compounds in which the carboxylic acid has been converted to diethylamide 98) The hydroxyl group (11-position and 15-position or 16-position) of the compounds of 01) to 88) has a tert-butyldimethylsilyl group and / or a trimethylsilyl group, and / or 2-tetrahydro Examples include ethers protected with a pyranyl group. That, without being limited thereto. In addition, the hydroxyl group (15
And the enantiomers of all of these).

Further, the compound of the present invention represented by the above formula (I)
-A method for producing thiaprostaglandins is also included in the present invention. That is, the following formula (II)

[0032]

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[0033] [wherein, R ^3, R ^4, n, and signage - are as previously defined, R ²¹ is tri (C1 to C7 hydrocarbon) silyl group, or an acetal bond together with an oxygen atom of a hydroxyl group, Represents a group to be formed. M represents a lithium atom or a tri (C1-C6 hydrocarbon) stannyl group. ]
And an organic lithium compound or an organic tin compound represented by the formula: and CuQ [wherein Q represents a halogen atom, a cyano group, a phenylthio group, a 1-pentynyl group, or a 1-hexynyl group. ] And the following formula (III)

[0034]

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Wherein XY is the same as defined above.
W ′ represents a hydrogen atom, a tri (C1 to C7 hydrocarbon) siloxy group, or a group that forms an acetal bond. Z ′ represents CO ₂ R ⁵¹ , where R ⁵¹ is a C1-C10 linear or branched alkyl group, a C2-C10 linear or branched alkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl group, A substituted C3-C10 cycloalkyl group, or a substituted or unsubstituted phenyl (C1-C10)
2) represents an alkyl group. After reacting with represented by 2-organothio-2-cyclopentenone or its enantiomeric or mixtures of them at any ratio in], further, (R ¹ CO) in ₂ O [wherein, R ¹ is the Same as definition. Or R ¹ COCl wherein R ¹ is as defined above. Or the following formula (IV)

[0036]

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Wherein R ¹ is the same as defined above. And subjecting it to at least one of deprotection, hydrolysis, amidation, and salt formation as required, to produce the compound represented by the above formula (I). .

The synthetic route of the 7-thiaprostaglandins of the present invention is illustrated as follows.

[0039]

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[R ¹ , R ²¹ , R ³ , R ⁴ , M, Q, W,
W ', XY, Z, Z', n, and the notation - are the same as defined above. The 2-organothio-2-cyclopentenones of the formula (III) can be obtained by a known method (JP-A-60-185).
No. 761).

In the scheme 1, when a racemate is used as a starting material, an intermediate in the course of the synthesis proceeds stereospecifically through a synthetic route as a mixture of the compound shown in the scheme and its enantiomer. II) or the above formula (II
If any one of the compounds represented by I) is optically active, each stereoisomer can be isolated as a pure product by separation at an appropriate stage.

In the conjugate addition reaction of the first step of the method (Scheme 1) of the present invention, a trivalent organic phosphorus compound such as trialkylphosphine (eg, triethylphosphine, tributylphosphine, etc.), When an alkyl phosphite (for example, trimethyl phosphite, triethyl phosphite, triisobutyl phosphite, tributyl phosphite, or the like), hexamethylphosphorus triamide, triphenylphosphine, or the like is used, the conjugate addition reaction proceeds smoothly. Particularly, tributylphosphine and hexamethylphosphorus triamide are preferably used.

The method of the present invention (Scheme 1) comprises the steps of preparing an organic lithium compound or an organic tin compound represented by the above formula (II) and CuQ (Q) in the presence of an aprotic inert organic solvent.
Is the same as defined above), and after reacting a 2-organothio-2-cyclopentenone represented by the above formula (III), an acid anhydride, an acid chloride,
Alternatively, the reaction is performed by reacting with a mixed acid anhydride.

The 2-organothio-2-cyclopentenone and the organocopper compound undergo a stoichiometric equimolar reaction. Usually, 1 mol of the 2-organothio-2-cyclopentenone is 0.5 to 5.0 times, preferably 0.8 to 2.0
The reaction is carried out by using an organic copper compound in a molar ratio of 1.0 to 1.5 times.

The reaction temperature of the conjugate addition reaction between the 2-organothio-2-cyclopentenones and the organocopper compound is -100 ° C.
A temperature range of from about to 50 ° C, particularly preferably from about -78 ° C to 0 ° C, is employed. The reaction time depends on the reaction temperature,
Normally, it is enough to react at -78 ℃ to -20 ℃ for about 1 hour.

The reaction intermediate obtained by the conjugate addition reaction of 2-organothio-2-cyclopentenones with an organic copper compound and an acid anhydride, an acid chloride or a mixed acid anhydride are stoichiometric. Specifically, an equimolar reaction is performed, but the reaction is usually performed such that an acid anhydride, an acid chloride, or a mixed acid anhydride is excessive. That is, 1.0 to 1 to 1 mol of 2-organothio-2-cyclopentenones.
The reaction is carried out using a 0.0-fold, preferably 2.0 to 5.0-fold molar amount of acid anhydride, acid chloride, or mixed acid anhydride.

The reaction temperature of the reaction between the reaction intermediate obtained by the conjugate addition reaction of a 2-organothio-2-cyclopentenone and an organic copper compound with an acid anhydride, an acid chloride or a mixed acid anhydride is as follows: 30 ° C to 50 ° C, particularly preferably -20
A temperature of about 30 ° C to 30 ° C is adopted. The reaction time varies depending on the reaction temperature, but it is usually sufficient to carry out the reaction at 0 ° C to 20 ° C for about 15 minutes.

The reaction is performed in the presence of an organic solvent. An inert aprotic organic solvent that is liquid at the reaction temperature and does not react with the reaction reagent is used. Such aprotic inert organic solvents include, for example, pentane, hexane, heptane, saturated hydrocarbons such as cyclohexane, benzene, toluene, aromatic hydrocarbons such as xylene, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane , Ether solvents such as diethylene glycol dimethyl ether, hexamethylphosphoric amide (HMP), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), sulfolane, N And a so-called aprotic polar solvent such as -methylpyrrolidone, and the like, and a mixture of two or more solvents. Further, as the aprotic inert organic solvent, the inert solvent used for producing the organic copper compound can be used as it is. That is, in this case, in the reaction system in which the organocopper compound was produced, 2-
The reaction may be carried out by adding an organothio-2-cyclopentenone. The amount of the organic solvent used may be an amount sufficient to allow the reaction to proceed smoothly, and usually 1 to 100
Double volumes, preferably 2 to 20 volumes are used.

The trivalent organophosphorus compound can be present during the preparation of the organocopper compound described above, and the reaction can be carried out by adding 2-organothio-2-cyclopentenones to the system. .

Thus, among the compounds represented by the formula (I), those in which the hydroxyl group is protected and Z is an ester are obtained. Since the production method of the present invention uses a reaction which proceeds stereospecifically, a compound having a configuration represented by the above formula (I) is obtained from a starting material having a configuration represented by the above formula (III). Is obtained, and from the enantiomer of the above formula (III), the enantiomer of the above formula (I) represented by the above formula (I) ent is obtained.

After the reaction, the obtained product is separated and purified from the reaction solution by a usual means. For example, extraction, washing, chromatography or a combination thereof is performed.

Further, the hydroxyl group obtained here is protected,
The compound in which Z is an ester can be subjected to deprotection, hydrolysis, or a salt formation reaction, if necessary.

When Z is an allyl ester (R ⁵¹ = Al
In lyl), an allyl ester can be converted to a carboxylic acid (R ⁵¹ = H) by a hydrogenolysis reaction using a palladium catalyst and formic acid or a salt of formic acid. Here, the obtained carboxylic acid can be further converted to another substituent by performing esterification or amidation.

In the hydrogenolysis reaction of an allyl ester using a palladium catalyst according to the present invention, a zero-valent or divalent complex can be used as a palladium catalyst. For example, tris (dibenzylideneacetone) dipalladium (0 ), Bis [1,2-bis (diphenylphosphino) ethane] palladium (0), tetrakistriphenylphosphinepalladium (II), palladium acetate, bistriphenylphosphinepalladium (II) acetate and the like. In some cases, it is better to add a ligand such as phosphine to the reaction system in order to reduce the amount of the palladium complex required to complete the reaction. In particular, in the case of a palladium complex such as tris (dibenzylideneacetone) dipalladium (0) or palladium acetate in which the complex does not have a phosphine ligand, the reaction is often performed by adding a ligand to the reaction system. Do. Examples of the ligand to be added include triphenylphosphine, diphenylphosphinoethane, tributylphosphine, triethylphosphine, and triethylphosphite. The amount of the palladium complex used for the reaction is based on the allyl ester of the substrate.
0.1 to 50 mol%, and when a ligand is added, the amount to be added is about 0.2 to 8 equivalents to palladium.

The hydrogenolysis reaction of the allyl ester is carried out in the presence of an organic solvent. An inert aprotic organic solvent that is liquid at the reaction temperature and does not react with the reaction reagent is used. Such aprotic inert organic solvents include, for example, pentane, hexane, heptane, saturated hydrocarbons such as cyclohexane, benzene, toluene, aromatic hydrocarbons such as xylene, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane , Ether solvents such as diethylene glycol dimethyl ether, hexamethylphosphoric amide (HMP), N, N-dimethylformamide (DM
F), so-called aprotic polar solvents such as N, N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), sulfolane, N-methylpyrrolidone, and the like, and can be used as a mixed solvent of two or more kinds. It is. The amount of the organic solvent used may be an amount sufficient to allow the reaction to proceed smoothly, and usually 1 to 100 times, preferably 2 to 20 times the volume of the raw material is used.

In the hydrogenolysis reaction of the allyl ester, formic acid is used as a hydrogen source. Therefore, the stoichiometric amount may be equimolar to the allyl ester of the substrate. Used up to 10.0 equivalents. Preferably, 1.0 to 5.0 equivalents are used. When formic acid is used in an actual experiment, a commercially available ammonium salt is used as it is, or the acidity is adjusted by adding a base such as triethylamine to a solvent in which formic acid is dissolved in advance. Basically, the amount of base used is equimolar to formic acid, and the reaction system is neutralized.However, in consideration of acid resistance and base resistance of the reaction substrate, if the conditions do not destroy the compound, ,necessarily,
The condition does not need to be neutral.

The reaction temperature of the hydrogenolysis reaction of the allyl ester is carried out at about 0 to 100 ° C., preferably 15 to 70 ° C.
Do between.

Thus, among the compounds represented by the formula (I), those in which the hydroxyl group is protected and Z is a carboxylic acid are obtained. After the reaction, the resulting product is separated and purified from the reaction solution by means of removal of the catalyst by filtration with florisil or celite, or extraction, washing and chromatography.

The obtained compound wherein Z is a carboxylic acid can be further subjected to a reaction such as esterification or amidation of the carboxylic acid portion, removal of protection of the hydroxyl group, and the like, if necessary. Esterification and amidation of the carboxylic acid moiety can be performed using ordinary chemical reactions.

The removal of the protecting group (W 'and / or R ²¹ ) for the hydroxyl group of the compound may be carried out, for example, when the protecting group forms an acetal bond with the oxygen atom of the hydroxyl group, for example, pyridinium salt of acetic acid or p-toluenesulfonic acid. Or a cation exchange resin as a catalyst, for example, water, tetrahydrofuran,
It is preferably carried out by using dioxane, acetone, acetonitrile or the like as a reaction solvent. Reaction is usually -78 ° C
It is performed for about 10 minutes to 3 days at a temperature range of up to 50 ° C. When the protecting group is a tri (C1-C7 hydrocarbon) silyl group, for example, acetic acid, a pyridinium salt of p-toluenesulfonic acid, tetrabutylammonium fluoride, cesium fluoride, hydrofluoric acid, hydrogen fluoride -The reaction is carried out in the above-mentioned reaction solvent at the same temperature for about the same time using pyridine or the like as a catalyst.

In the case of a compound whose water solubility has been increased by removing a protecting group for a hydroxyl group or the like, the ester hydrolysis reaction of a compound in which Z is an ester is carried out by using an enzyme such as lipase, esterase, etc. In solvents containing water-
It can be carried out in a temperature range of 10 ° C to 60 ° C for about 10 minutes to 24 hours. However, since the enol ester at the 9-position is also hydrolyzed under these conditions, the progress of the reaction is frequently checked, and when the enol ester at the 9-position is hydrolyzed, the carboxyl group at the 1-position is protected. The reaction is stopped without waiting for complete removal of the group (R ⁵ ), and the desired 7-
It is desirable to obtain thiaprostaglandins. As described above, when Z is an allyl ester (R ⁵¹ = Allyl), even when the compound from which the protecting group for the hydroxyl group has been removed, the compound having the protecting group (R ⁵¹ ) is subjected to a hydrogenolysis reaction using a palladium catalyst. Removal can be performed.

According to the present invention, the compound having a carboxyl group obtained by the hydrolysis reaction as described above is then further subjected to a salt formation reaction, if necessary,
The corresponding carboxylate can be obtained. The salt formation reaction is performed by neutralizing a carboxylic acid with a basic compound such as potassium hydroxide, sodium hydroxide, and sodium carbonate in an approximately equivalent amount, or ammonia, trimethylamine, monoethanolamine, and morpholine in a usual manner. Done.

[0063]

【Example】

[Example 1] (11R, 12S, 13E, 15S, 17R) -9-B
Tyryloxy-11,15-bis (tert-butyl dimethyl
Lucyloxy) -17,20-dimethyl-7-thiapros
Synthesis of Methyl 8,13-dienoate (R ¹ = Pr, R ² = ^t B
uMe ₂ Si, R ³ = H, R ⁴ = 2-Me-hexyl, W = ^t BuMe ₂ SiO, XY = CH ₂ -C
H ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0064]

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(1E, 3S, 5R) -1-Iodo-3-
(Tert-butyldimethylsiloxy) -5-methyl-1-
A solution of nonene (476 mg, 1.2 mmol) in ether (3 ml) was added.
After cooling to -78 ° C, tert-butyllithium (1.54
mol / l, 1.56 ml, 2.4 mmol) and keep at -78 ° C. 2
Stirred for hours. In addition, 174 mg of hexine copper and ether of hexamethylphosphorus triamide (436 μl)
(6 ml) The solution was added, and the mixture was stirred at −78 ° C. for another 1 hour to produce a copper reagent. (4)
R) -tert-butyldimethylsiloxy-2- (5-methoxycarbonylpentylthio) -2-cyclopentene-
1-one (373 mg, 1 mmol) in tetrahydrofuran (20
ml) solution was added dropwise. The reaction mixture is kept at -78 ° C for 15 minutes, then the reaction temperature is raised to -40 to -3
The mixture was stirred at 0 ° C for 1 hour. Further, at 0 ° C, butyric anhydride (441 μ
l) was added, and the mixture was stirred for 15 minutes while raising the reaction temperature to room temperature. The reaction solution was poured into saturated ammonium sulfate (40 ml), the mixture was separated, the aqueous layer was extracted with ether, and the extract and the organic layer were combined and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure and purified by silica gel column chromatography (5 to 10% ethyl acetate / hexane) to give (11R, 12S, 13E, 15E).
S, 17R) -9-Butyryloxy-11,15-bis (tert-butyldimethylsiloxy) -17,20-dimethyl-7-thiaprosta-8,13-dienoic acid methyl ester
(428 mg, 60%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s), 0.05 (s) ... 12 H 0.87 (s, 9H) 0.8-1.0 (m, 6H) 0.89 (s, 9H) 1.00 (t, J = 7.3 Hz, 3H) 1.0-1.8 (m, 17H) 2.30 (t, J = 7.6 Hz, 2H) 2.42 (t, J = 7.3 Hz, 2H) 2.3-2.7 (m, 3H) 2.92 ( dd, J = 16.3 & 6.8 Hz, 1H) 3.12 (d, J = 7.9 Hz, 1H) 3.66 (s, 3H) 4.1-4.2 (m, 2H) 5.43 (dd, J = 15.5 & 8.6 Hz, 1H) 5.62 (dd, J = 15.3 & 6.1 Hz, 1H)

[Example 2](11R, 12S, 13E, 15S, 17R) -9-B
Tyryloxy-11,15-dihydroxy-17,20
-Dimethyl-7-thiaprosta-8,13-dienoic acid
Synthesis of chill (R¹= Pr, R^Two= H, R^Three= H, R^Four= 2-Me-hexyl, W =
OH, X-Y = CH_Two-CH _Two, Z = CO_TwoMe, n = 0,-= trans-CH = CH)

[0068]

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A solution of acetonitrile (3 ml) and pyridine (0.1 ml) cooled with ice was added to a hydrogen fluoride pyridine solution (0.3 ml).
l) and (11R, 12S, 13E, 15S, 17
R) -9-Butyryloxy-11,15-bis (tert-
Butyldimethylsiloxy) -17,20-dimethyl-7
-Methyl thiaprosta-8,13-dienoate (214 mg)
Of pyridine (50 μl) was added. The ice bath was removed, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into a mixture of ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate. The desired product was extracted from the mixture with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and purified by silica gel column chromatography (40 to 50% ethyl acetate / hexane).
(11R, 12S, 13E, 15S, 17R) -9-butyryloxy-11,15-dihydroxy-17,20
Methyl -dimethyl-7-thiaprosta-8,13-dienoate (119 mg, 82%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.8-1.0 (m, 6H) 1.00 (t, J = 7.4 Hz, 3H) 1.0-1.8 (m, 17H) 2.30 (t, J = 7.4 Hz, 2H) 2.43 (t, J = 7.4 Hz, 2H) 2.3-2.7 (m, 3H) 2.89 (ddd, J = 16.5 & 6.9 & 1.3 Hz, 1H) 3.20 (dd, J = 8.1 & 3.5 Hz, 1H ) 3.67 (s, 3H) 4.1-4.3 (m, 2H) 5.55 (dd, J = 15.3 & 8.1 Hz, 1H) 5.68 (dd, J = 15.3 & 6.4 Hz, 1H)

Example 3 (11R, 12S, 13E, 15S, 17R) -9-B
Tyloxy-11,15-dihydroxy-17,20-di
Synthesis of methyl-7-thiaprosta-8,13-dienoic acid (R ¹ = Pr, R ² = H, R ³ = H, R ⁴ = 2-Me-hexyl, W = OH, XY = CH
₂ -CH ₂ , Z = CO ₂ H, n = 0, - = trans-CH = CH)

[0072]

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(11R, 12S, 13E, 15S, 17
S) -9-Butyloxy-11,15-dihydroxy-1
Methyl 7,20-dimethyl-7-thiaprosta-8,13-dienoate (51 mg, 0.11 mmol) in acetone (1 ml)
And pH 8 phosphate buffer (10 ml) was added thereto. Further, an esterase (from Porcine Liver Sigma, 114 μl) was added, followed by stirring at room temperature for 5 hours. With the methyl ester still remaining, the reaction solution was ice-cooled, adjusted to pH 4 with dilute hydrochloric acid, and saturated with ammonium sulfate. The mixture was extracted with ethyl acetate, and the extract was dried.
It was concentrated under reduced pressure. The concentrate was purified by thin-layer chromatography (developing solution: ethyl acetate, Rf = 0.2), (11R, 1
2S, 13E, 15S, 17S) -9-butyroxy-1
1,15-dihydroxy-17,20-dimethyl-7-
Thiaprosta-8,13-dienoic acid (7 mg, 14%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.8-1.0 (m, 6H) 1.00 (t, J = 7.4 Hz, 3H) 1.0-1.8 (m, 17H) 2.30 (t, J = 7.4 Hz, 2H) 2.43 (t, J = 7.4 Hz, 2H) 2.3-2.7 (m, 3H) 2.89 (ddd, J = 16.5 & 6.9 & 1.3 Hz, 1H) 3.20 (dd, J = 8.1 & 3.5 Hz, 1H ) 4.1-4.3 (m, 2H) 5.55 (dd, J = 15.3 & 8.1 Hz, 1H) 5.68 (dd, J = 15.3 & 6.4 Hz, 1H)

Example 4 (11R, 12S, 13E, 15S, 17R) -9-A
Cetoxy-11,15-bis (tert-butyldimethylsi
Roxy) -17,20-dimethyl-7-thiaprostar
Synthesis of methyl 8,13-dienoate (R ¹ = Me, R ² = ^t BuMe ₂
Si, R ³ = H, R ⁴ = 2-Me-hexyl, W = ^t BuMe ₂ SiO, XY = CH ₂ -CH ₂ ,
Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0076]

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As raw materials and reagents, (1E, 3S, 5
R) -1-Iodo-3- (tert-butyldimethylsiloxy) -5-methyl-1-nonene (476 mg, 1.2 mmol), t
ert-butyl lithium (1.54 mol / l, 1.56 ml, 2.4 mm
ol), hexine copper 174 mg, hexamethylphosphorous triamide (436 μl), (4R) -tert-butyldimethylsiloxy-2- (5-methoxycarbonylpentylthio)
-2-cyclopenten-1-one (373 mg, 1 mmol),
Using acetic anhydride (255 μl), the same operation as in Example 1 was performed to obtain (11R, 12S, 13E, 15S, 17R) -9.
-Methyl -acetoxy-11,15-bis (tert-butyldimethylsiloxy) -17,20-dimethyl-7-thiaprosta-8,13-dienoate (484 mg, 71%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.02 (s), 0.03 (s) ... 12 H 0.8-0.9 (m, 6H) 0.86 (s, 9H) 0.87 (s, 9H) 1.0 -1.7 (m, 15H) 2.16 (s, 3H) 2.28 (t, J = 7.4 Hz, 2H) 2.3-2.7 (m, 3H) 2.91 (ddd, J = 1.4 & 6.7 & 16.4 Hz, 1H) 3.10 (d , J = 6.6 Hz, 1H) 3.64 (s, 3H) 4.0-4.2 (m, 2H) 5.41 (dd, J = 8.6 & 15.8 Hz, 1H) 5.60 (dd, J = 6.1 & 15.3 Hz, 1H)

Embodiment 5 (11R, 12S, 13E, 15S, 17R) -9-A
Sethoxy-11,15-dihydroxy-17,20-di
Methyl methyl 7-thiaprosta-8,13-dienoate
Synthesis ^{(R 1 = Me, R 2} = H, R 3 = H, R 4 = 2-Me-hexyl, W = OH,
XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH

[0080]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.6 ml), (11R, 12S, 13E, 15
S, 17R) -9-acetoxy-11,15-bis (te
(rt-butyldimethylsiloxy) -17,20-dimethyl-7-thiaprosta-8,13-dienoic acid methyl ester (484
mg), the same operation as in Example 2 was performed, and (11R,
12S, 13E, 15S, 17R) -9-acetoxy-
11,15-dihydroxy-17,20-dimethyl-7
-Methyl thiaprosta-8,13-dienoate (179 mg,
56%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.8-1.0 (m, 6H) 1.1-1.7 (m, 15H) 2.19 (s, 3H) 2.31 (t, J = 7.4 Hz, 2H) 2.4 -2.8 (m, 3H) 2.91 (ddd, J = 1.1 & 6.8 & 16.4 Hz, 1H) 3.20 (dd, J = 3.3 & 8.3 Hz, 1H) 3.67 (s, 3H) 4.1-4.3 (m, 2H) 5.56 (dd, J = 8.1 & 15.3 Hz, 1H) 5.68 (dd, J = 6.6 & 15.5 Hz, 1H)

[Embodiment 6](11R, 12S, 13E, 15S, 17R) -9-b
Sobutyryloxy-11,15-bis (tert-butyldi
Methylsiloxy) -17,20-dimethyl-7-thiap
Synthesis of methyl roster-8,13-dienoate (R¹=ⁱPr,
R^Two=^tBuMe_TwoSi, R ^Three= H, R^Four= 2-Me-hexyl, W =^tBuMe_TwoSiO, X-Y
= CH_Two-CH_Two, Z = CO_TwoMe, n = 0,-= trans-CH = CH)

[0084]

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As raw materials and reagents, (1E, 3S, 5
R) -1-Iodo-3- (tert-butyldimethylsiloxy) -5-methyl-1-nonene (476 mg, 1.2 mmol), t
ert-butyl lithium (1.54 mol / l, 1.56 ml, 2.4 mm
ol), hexine copper 174 mg, hexamethylphosphorous triamide (436 μl), (4R) -tert-butyldimethylsiloxy-2- (5-methoxycarbonylpentylthio)
-2-cyclopenten-1-one (373 mg, 1 mmol),
The same operation as in Example 1 was performed using isobutyric anhydride (448 μl) to obtain (11R, 12S, 13E, 15S, 17
R) -9-isobutyryloxy-11,15-bis (te
(rt-butyldimethylsiloxy) -17,20-dimethyl-7-thiaprosta-8,13-dienoic acid methyl (466
mg, 65%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s), 0.05 (s) ... 12 H 0.8-0.9 (m, 6H) 0.88 (s, 9H) 0.89 (s, 9H) 1.1 -1.7 (m, 15H) 1.24 (d, J = 6.9 Hz, 3H) 1.25 (d, J = 6.9 Hz, 3H) 2.30 (t, J = 7.6 Hz, 2H) 2.3-2.8 (m, 4H) 2.91 ( ddd, J = 1.3 & 6.6 & 16.2 Hz, 1H) 3.12 (d, J = 8.6 Hz, 1H) 3.66 (s, 3H) 4.1-4.2 (m, 2H) 5.43 (dd, J = 8.6 & 15.2 Hz, 1H) ) 5.62 (dd, J = 5.9 & 15.5 Hz, 1H)

Embodiment 7 (11R, 12S, 13E, 15S, 17R) -9-A
Sobutyryloxy-11,15-dihydroxy-17,
20-dimethyl-7-thiaprosta-8,13-diene
Synthesis of methyl acid salt (R ¹ = ⁱ Pr, R ² = H, R ³ = H, R ⁴ = 2-Me-hexy
l, W = ^t BuMe ₂ SiO, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = tran
s-CH = CH)

[0088]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.6 ml), (11R, 12S, 13E, 15S, 1
7R) -9-Isobutyryloxy-11,15-bis (tert-butyldimethylsiloxy) -17,20-dimethyl-7-thiaprosta-8,13-dienoic acid methyl ester
(466 mg), and the same operation as in Example 2 was performed.
(11R, 12S, 13E, 15S, 17R) -9-isobutyryloxy-11,15-dihydroxy-17,
Methyl 20-dimethyl-7-thiaprosta-8,13-dienoate (192 mg, 64%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.8-1.0 (m, 6H) 1.1-1.7 (m, 15H) 1.25 (d, J = 6.9 Hz, 6H) 2.31 (t, J = 7.4 Hz, 2H) 2.4-2.8 (m, 4H) 2.90 (ddd, J = 1.2 & 6.8 & 16.3 Hz, 1H) 3.21 (dd, J = 3.1 & 8.1 Hz, 1H) 3.67 (s, 3H) 4.1-4.3 ( m, 2H) 5.56 (dd, J = 8.1 & 15.3 Hz, 1H) 5.68 (dd, J = 6.4 & 15.3 Hz, 1H)

[Embodiment 8] (11R, 12S, 13E, 15S, 17R) -9-pi
Baroyloxy-11,15-bis (tert-butyldim
Tylsiloxy) -17,20-dimethyl-7-thiapro
Synthesis of methyl star 8,13-dienoate (R ¹ = ^t Bu, R ²
= ^t BuMe ₂ Si, R ³ = H, R ⁴ = 2-Me-hexyl, W = ^t BuMe ₂ SiO, XY = C
H ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0092]

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As raw materials and reagents, (1E, 3S, 5R)
-1-Iodo-3- (tert-butyldimethylsiloxy)
-5-methyl-1-nonene (476 mg, 1.2 mmol), tert
-Butyl lithium (1.54 mol / l, 1.56 ml, 2.4 mmo
l), hexine copper 174 mg, hexamethylphosphorous triamide (436 μl), (4R) -tert-butyldimethylsiloxy-2- (5-methoxycarbonylpentylthio)
-2-cyclopenten-1-one (373 mg, 1 mmol),
The same operation as in Example 1 was performed using pivalic anhydride (534 μl) to obtain (11R, 12S, 13E, 15S, 17
R) -9-pivaloyloxy-11,15-bis (tert
-Butyldimethylsiloxy) -17,20-dimethyl-
Methyl 7-thiaprosta-8,13-dienoate (564 m
g, 78%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s), 0.05 (s) ... 12 H 0.8-1.0 (m, 6H) 0.88 (s, 9H) 0.89 (s, 9H) 1.1 -1.7 (m, 15H) 1.28 (s, 9H) 2.30 (t, J = 7.6 Hz, 2H) 2.3-2.7 (m, 3H) 2.89 (ddd, J = 1.3 & 6.9 & 16.2 Hz, 1H) 3.12 (d , J = 8.3 Hz, 1H) 3.66 (s, 3H) 4.0-4.2 (m, 2H) 5.43 (dd, J = 8.7 & 15.3 Hz, 1H) 5.62 (dd, J = 6.3 & 15.5 Hz, 1H)

[Embodiment 9] (11R, 12S, 13E, 15S, 17R) -9-pi
Valoyloxy-11,15-dihydroxy-17,2
0-dimethyl-7-thiaprosta-8,13-dienoic acid
Synthesis of methyl (R ¹ = ^t Bu, R ² = H, R ³ = H, R ⁴ = 2-Me-hexyl,
W = OH, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH
)

[0096]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.7 ml), (11R, 12S, 13E, 15S, 1
7R) -9-pivaloyloxy-11,15-bis (te
(rt-butyldimethylsiloxy) -17,20-dimethyl-7-thiaprosta-8,13-dienoic acid methyl (564
mg), the same operation as in Example 2 was performed, and (11)
R, 13E, 15S, 17R) -9-pivaloyloxy-11,15-dihydroxy-17,20-dimethyl-
Methyl 7-thiaprosta-8,13-dienoate (211 m
g, 55%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.8-1.0 (m, 6H) 1.1-1.7 (m, 15H) 1.29 (s, 9H) 2.31 (t, J = 7.6 Hz, 2H) 2.4 -2.8 (m, 3H) 2.94 (dd, J = 6.3 & 16.5 Hz, 1H) 3.22 (d, J = 7.6 Hz, 1H) 3.67 (s, 3H) 4.1-4.3 (m, 2H) 5.57 (dd, J = 8.2 & 15.5 Hz, 1H) 5.72 (dd, J = 5.9 & 15.5 Hz, 1H)

Embodiment 10 (11R, 12S, 13E, 15S, 17R) -9-B
Tyryloxy-11,15-bis (t-butyldimethylsi
Roxy) -17,20-dimethyl-7-thiaprostar
Synthesis of butyl 8,13-dienoate (R ¹ = Pr, R ² = ^t BuMe ₂
Si, R ³ = H, R ⁴ = 2-Me-hexyl, W = ^t BuMe ₂ SiO, XY = CH ₂ -CH ₂ ,
Z = CO ₂ Bu, n = 0, - = trans-CH = CH)

[0100]

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As raw materials and reagents, (1E, 3S, 5R)
-1-Iodo-3- (tert-butyldimethylsiloxy)
-5-methyl-1-nonene (120 mg, 0.302 mmol), ter
t-butyl lithium (1.54 mol / l, 392 μl, 0.302 mm
ol), hexine copper 43.6 mg, hexamethylphosphorous triamide (110 μl), (4R) -tert-butyldimethylsiloxy-2- (5-butoxycarbonylpentylthio) -2-cyclopenten-1-one (104 mg, 0.251
mmol) and butyric anhydride (111 μl), and the same operation as in Example 1 was performed to obtain (11R, 12S, 13E, 15S, 1
7R) -9-butyryloxy-11,15-bis (tert
-Butyldimethylsiloxy) -17,20-dimethyl-
7-thiaprostar-8,13-butyl dienoate (138 m
g, 73%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.03 (s), 0.04 (s) ... 12 H 0.8-0.9 (m, 6H) 0.86 (s, 9H) 0.88 (s, 9H) 0.92 (t, J = 7.3 Hz, 3H) 0.99 (t, J = 7.4 Hz, 3H) 1.0-1.8 (m, 21H) 2.27 (t, J = 7.6 Hz, 2H) 2.3-2.7 (m, 3H) 2.41 ( t, J = 7.3 Hz, 2H) 2.91 (ddd, J = 1.3 & 6.6 & 16.2 Hz, 1H) 3.10 (d, J = 8.6 Hz, 1H) 4.0-4.2 (m, 2H) 4.05 (t, J = 6.8 Hz, 2H) 5.42 (dd, J = 8.6 & 15.2 Hz, 1H) 5.60 (dd, J = 5.9 & 15.5 Hz, 1H)

[Embodiment 11](11R, 12S, 13E, 15S, 17R) -9-B
Tyryloxy-11,15-dihydroxy-17,20
-Dimethyl-7-thiaprosta-8,13-dienoic acid
Synthesis of chill (R¹= Pr, R^Two= H, R^Three= H, R^Four= 2-Me-hexyl, W =
OH, X-Y = CH_Two-CH _Two, Z = CO_TwoBu, n = 0,-= trans-CH = CH)

[0104]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.2 ml), (11R, 12S, 13E, 15S, 1
7R) -9-butyryloxy-11,15-bis (tert
-Butyldimethylsiloxy) -17,20-dimethyl-
7-thiaprostar-8,13-butyl dienoate (138 m
g), the same operation as in Example 2 was performed, and (11R,
12S, 13E, 15S, 17R) -9-Butyryloxy-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-butyl butylate (69 m
g, 72%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.8-1.0 (m, 6H) 0.94 (t, J = 7.3 Hz, 3H) 1.01 (t, J = 7.3 Hz, 3H) 1.1-1.8 ( m, 21H) 2.29 (t, J = 7.4 Hz, 2H) 2.4-2.8 (m, 3H) 2.44 (t, J = 7.4 Hz, 2H) 2.96 (ddd, J = 1.2 & 6.3 & 16.2 Hz, 1H) 3.21 (d, J = 10.2 Hz, 1H) 4.07 (t, J = 6.6 Hz, 2H) 4.1-4.3 (m, 2H) 5.57 (dd, J = 8.1 & 15.7 Hz, 1H) 5.60 (dd, J = 5.9 & (15.5 Hz, 1H)

[Embodiment 12](11R, 12S, 13E, 15S) -9-butyryl
Xy-11,15-bis (tert-butyldimethylsiloxy)
B) of methyl 7-thiaprosta-8,13-dienoate
Synthesis (R¹= Pr, R^Two=^tBuMe_TwoSi, R^Three= H, R^Four= Pentyl, W =^tBu
Me_TwoSiO, X-Y = CH _Two-CH_Two, Z = CO_TwoMe, n = 0,-= trans-CH = CH
 )

[0108]

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(1E, 3S) -1-
Iodo-3- (tert-butyldimethylsiloxy) -1-
Octene (442 mg, 1.2 mmol), tert-butyllithium
(1.54 mol / l, 1.56 ml, 2.4 mmol), hexine copper 174
mg, hexamethylphosphorous triamide (436 μl),
(4R) -tert-butyldimethylsiloxy-2- (5-
(Methoxycarbonylpentylthio) -2-cyclopenten-1-one (373 mg, 1.0 mmol), butyric anhydride (441 μl)
Using l), the same operation as in Example 1 was performed, and (11R,
12S, 13E, 15S) -9-butyryloxy-1
1,15-bis (tert-butyldimethylsiloxy) -7
-Methyl thiaprosta-8,13-dienoate (538 mg,
79%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s), 0.05 (s) ... 12 H 0.8-1.0 (m, 3H) 0.87 (s, 9H) 0.89 (s, 9H) 1.00 (t, J = 7.3 Hz, 3H) 1.0-1.7 (m, 16H) 2.30 (t, J = 7.6 Hz, 2H) 2.3-2.7 (m, 3H) 2.42 (t, J = 7.3 Hz, 2H) 2.91 ( ddd, J = 1.3 & 6.8 & 16.3 Hz, 1H) 3.12 (d, J = 5.9 Hz, 1H) 3.66 (s, 3H) 4.0-4.2 (m, 2H) 5.43 (dd, J = 8.7 & 15.3 Hz, 1H ) 5.57 (dd, J = 5.8 & 15.3 Hz, 1H)

[Embodiment 13](11R, 12S, 13E, 15S) -9-butyryl
Xy-11,15-dihydroxy-7-thiaprostar
Synthesis of methyl 8,13-dienoate (R¹= Pr, R ^Two= H, R^Three=
H, R^Four= Pentyl, W = OH, X-Y = CH_Two-CH_Two, Z = CO_TwoMe, n = 0,-=
trans-CH = CH)

[0112]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.7 ml) was added, and (11R, 12S, 13E, 15E) was added.
S) -9-Butyryloxy-11,15-bis (tert-
Butyldimethylsiloxy) -7-thiaprosta-8,1
The same operation as in Example 2 was performed using methyl 3-dienoate (538 mg) to obtain (11R, 12S, 13E, 15S).
-9-butyryloxy-11,15-dihydroxy-7
Methyl thiaprosta-8,13-dienoate (287 mg,
80%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.89 (t, J = 6.6 Hz, 3H) 1.01 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 16H) 2.31 (t, J = 7.3 Hz, 2H) 2.4-2.8 (m, 3H) 2.43 (t, J = 7.3 Hz, 2H) 2.96 (dd, J = 6.3 & 16.5 Hz, 1H) 3.22 (d, J = 8.3 Hz, 1H) 3.67 (s, 3H) 4.0-4.2 (m, 2H) 5.56 (dd, J = 7.9 & 15.5 Hz, 1H) 5.70 (dd, J = 6.3 & 15.5 Hz, 1H)

[Embodiment 14](11R, 12S, 13E, 15S) -9-butyryl
Xy-11,15-bis ( tert-butyldimethylsiloxy
B) -15-cyclopentyl-16,17,18,1
9,20-pentanor-7-thiaprosta-8,13-
Synthesis of methyl dienoate (R¹= Pr, R^Two=^tBuMe_TwoSi, R^Three= H,
R^Four= cyclo-Pentyl, W =^tBuMe_TwoSiO, X-Y = CH_Two-CH_Two, Z = CO_TwoM
e, n = 0,-= trans-CH = CH)

[0116]

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As raw materials and reagents, (1E, 3S) -1-
Iodo-3- (tert-butyldimethylsiloxy) -3-
Cyclopentyl-1-propene (440 mg, 1.2 mmol), t
ert-butyl lithium (1.54 mol / l, 1.56 ml, 2.4 mm
ol), hexine copper 174 mg, hexamethylphosphorous triamide (436 μl), (4R) -tert-butyldimethylsiloxy-2- (5-methoxycarbonylpentylthio)
-2-cyclopenten-1-one (373 mg, 1.0 mmo
l) and butyric anhydride (441 μl), the same operation as in Example 1 was performed to obtain (11R, 12S, 13E, 15S) -9-
Butyryloxy-11,15-bis (tert-butyldimethylsiloxy) -15-cyclopentyl-16,17,
18,19,20-pentanor-7-thiaprostar
Methyl 8,13-dienoate (321 mg, 47%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.02 (s), 0.04 (s), 0.05 (s) ... 12H 0.88 (s, 9H) 0.89 (s, 9H) 1.00 (t, J = 7.4 Hz, 3H) 1.2-2.0 (m, 17 H) 2.30 (t, J = 7.4 Hz, 2H) 2.3-2.7 (m, 3H) 2.42 (t, J = 7.3 Hz, 2H) 2.95 (ddd, J = 1.3 & 6.4 & 16.3 Hz, 1H) 3.11 (d, J = 7.6 Hz, 1H) 3.66 (s, 3H) 3.90 (dd, J = 6.6 & 6.6 Hz, 1H) 4.0-4.2 (m, 1H) 5.41 ( dd, J = 8.6 & 15.5 Hz, 1H) 5.62 (dd, J = 6.4 & 15.3 Hz, 1H)

Example 15 (11R, 12S, 13E, 15S) -9-butyryl
Xy-11,15-dihydroxy-15-cyclopentene
-16,17,18,19,20-Pentanol-7-
Synthesis of methyl thiaprosta-8,13-dienoate (R ¹
= Pr, R ² = H, R ³ = H, R ⁴ = cyclo-Pentyl, W = OH, XY = CH ₂ -CH
₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0120]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.4 ml), (11R, 12S, 13E, 15S)-
9-butyryloxy-11,15-bis (tert-butyldimethylsiloxy) -15-cyclopentyl-16,1
The same operation as in Example 2 was carried out using methyl 7,18,19,20-pentanor-7-thiaprosta-8,13-dienoate (321 mg) to obtain (11R, 12S, 13E,
15S) -9-Butyryloxy-11,15-dihydroxy-15-cyclopentyl-16,17,18,1
9,20-pentanor-7-thiaprosta-8,13-
Methyl dienoate (140 mg, 66%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.2-2.1 (m, 17 H) 2.31 (t, J = 7.4 Hz, 2H) 2.4-2.8 (m, 3H) 2.43 (t, J = 7.3 Hz, 2H) 2.95 (ddd, J = 1.3 & 6.6 & 16.5 Hz, 1H) 3.11 (d, J = 2.5 & 8.3 Hz, 1H) 3.67 (s, 3H) 3.91 (dd, J = 7.3 & 7.3 Hz, 1H) 4.1-4.2 (m, 1H) 5.57 (dd, J = 7.9 & 15.5 Hz, 1H) 5.71 (dd, J = 6.6 & 15.5 Hz, 1H)

[Embodiment 16](11R, 12S, 13E, 15S) -9-butyryl
Xy-11,15-bis (tert-butyldimethylsiloxy)
B) -15-cyclohexyl-16,17,18,1
9,20-pentanor-7-thiaprosta-8,13-
Synthesis of methyl dienoate (R¹= Pr, R^Two=^tBuMe_TwoSi, R^Three= H,
R^Four= cyclo-Hexyl, W =^tBuMe_TwoSiO, X-Y = CH_Two-CH_Two, Z = CO_TwoMe,
 n = 0,-= trans-CH = CH)

[0124]

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As raw materials and reagents, (1E, 3S) -1-
Iodo-3- (tert-butyldimethylsiloxy) -3-
Cyclohexyl-1-propene (150 mg, 0.4 mmol), t
ert-butyl lithium (1.50 mol / l, 0.53 ml, 0.79 mm
ol), hexyne copper (58 mg), hexamethylphosphorus triamide (145 μl), (4R) -4- (tert-butyldimethylsiloxy) -2- (5-methoxycarbonylpentylthio) -2-cyclopentene-1 −one (124 mg,
0.33 mmol) and butyric anhydride (147 μl) were used to carry out the same operation as in Example 1 to obtain (11R, 12S, 13E, 15E).
S) -9-Butyryloxy-11,15-bis (tert-
Butyldimethylsiloxy) -15-cyclohexyl-1
There was obtained methyl 6,17,18,19,20-pentanor-7-thiaprosta-8,13-dienoate (133 mg, 48%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.01 (s), 0.03 (s) ... 12H 0.88 (s, 9H) 0.89 (s, 9H) 1.00 (t, J = 7.5 Hz, 3H ) 1.1-1.9 (m, 19 H) 2.30 (t, J = 7.6 Hz, 2H) 2.3-2.7 (m, 3H) 2.42 (t, J = 7.5 Hz, 2H) 2.94 (ddd, J = 1.0 & 6.6 & 16.2 Hz, 1H) 3.13 (d, J = 8.5 Hz, 1H) 3.66 (s, 3H) 3.82 (t, J = 6.0 Hz, 1H) 4.0-4.2 (m, 1H) 5.38 (dd, J = 8.5 & 15.5 Hz, 1H) 5.60 (dd, J = 6.3 & 15.5 Hz, 1H)

Example 17 (11R, 12S, 13E, 15S) -9-butyryl
Xy-11,15-dihydroxy-15-cyclohexyl
-16,17,18,19,20-Pentanol-7-
Synthesis of methyl thiaprosta-8,13-dienoate (R ¹
= Pr, R ² = H, R ³ = H, R ⁴ = cyclo-Hexyl, W = OH, XY = CH ₂ -C
H ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0128]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.2 ml), (11R, 12S, 13E, 15S)-
9-butyryloxy-11,15-bis (tert-butyldimethylsiloxy) -15-cyclohexyl-16,1
The same operation as in Example 2 was performed using methyl 7,18,19,20-pentanor-7-thiaprosta-8,13-dienoate (130 mg) to obtain (11R, 12S, 13E,
15S) -9-Butyryloxy-11,15-dihydroxy-15-cyclohexyl-16,17,18,1
9,20-pentanor-7-thiaprosta-8,13-
Methyl dienoate (60 mg, 67%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 1.01 (t, J = 7.5 Hz, 3H) 0.9-1.9 (m, 19 H) 2.31 (t, J = 7.5 Hz, 2H) 2.43 (t , J = 7.5 Hz, 2H) 2.5-2.8 (m, 3H) 2.94 (ddd, J = 1.2 & 6.6 & 16.5 Hz, 1H) 3.22 (dd, J = 2.5 & 8.2 Hz, 1H) 3.67 (s, 3H) 3.85 (dd, t = 6.6 Hz, 1H) 4.1-4.2 (m, 1H) 5.53 (dd, J = 7.9 & 15.5 Hz, 1H) 5.68 (dd, J = 6.6 & 15.5 Hz, 1H)

[Embodiment 18](11R, 12S, 13E, 15R) -9-butyryl
Xy-11,15-bis (tert-butyldimethylsiloxy)
B) -15-cyclohexyl-16,17,18,1
9,20-pentanor-7-thiaprosta-8,13-
Synthesis of methyl dienoate (R¹= Pr, R^Two=^tBuMe_TwoSi, R^Three= H,
R^Four= cyclo-Hexyl, W =^tBuMe_TwoSiO, X-Y = CH_Two-CH_Two, Z = CO_TwoMe,
 n = 0,-= trans-CH = CH)

[0132]

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As raw materials and reagents, (1E, 3R) -1-
Iodo-3- (tert-butyldimethylsiloxy) -3-
Cyclohexyl-1-propene (457 mg, 1.2 mmol), t
ert-butyl lithium (1.54 mol / l, 1.56 ml, 2.4 mmo
l), hexyne copper (174 mg), hexamethylphosphorous triamide (436 μl), (4R) -tert-butyldimethylsiloxy-2- (5-methoxycarbonylpentylthio) -2-cyclopenten-1-one (373 mg, 1.0 mm
ol) and butyric anhydride (441 μl), and the same operation as in Example 1 was performed to obtain (11R, 12S, 13E, 15R) -9.
-Butyryloxy-11,15-bis (tert-butyldimethylsiloxy) -15-cyclohexyl-16,1
There was obtained methyl 7,18,19,20-pentanor-7-thiaprosta-8,13-dienoate (80 mg, 12%).

[0134] ^{1 H-NMR (270 MHz,} δppm, CDCl 3) 0.02 (s), 0.03 (s), 0.04 (s) ...... 12H 0.88 (s, 9H) 0.89 (s, 9H) 1.00 (t, J = 7.4 Hz, 3H) 1.1-1.9 (m, 19 H) 2.30 (t, J = 7.4 Hz, 2H) 2.3-2.7 (m, 3H) 2.42 (t, J = 7.4 Hz, 2H) 2.90 (ddd, J = 1.3 & 6.9 & 16.2 Hz, 1H) 3.13 (dd, J = 2.6 & 8.6 Hz, 1H) 3.66 (s, 3H) 3.81 (dd, J = 6.3 & 6.3 Hz, 1H) 4.11 (ddd, J = 3.3 & 3.6 & 6.6 Hz, 1H) 5.39 (dd, J = 8.6 & 15.2 Hz, 1H) 5.59 (dd, J = 6.9 & 15.5 Hz, 1H)

Example 19 (11R, 12S, 13E, 15R) -9-butyrylthio
Xy-11,15-dihydroxy-15-cyclohexyl
-16,17,18,19,20-Pentanol-7-
Synthesis of methyl thiaprosta-8,13-dienoate (R ¹
= Pr, R ² = H, R ³ = H, R ⁴ = cyclo-Hexyl, W = OH, XY = CH ₂ -C
H ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0136]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.1 ml), (11R, 12S, 13E, 15R)-
9-butyryloxy-11,15-bis (tert-butyldimethylsiloxy) -15-cyclohexyl-16,1
The same operation as in Example 2 was carried out using methyl 7,18,19,20-pentanor-7-thiaprosta-8,13-dienoate (80 mg) to give (11R, 12S, 13E, 1
5R) -9-butyryloxy-11,15-dihydroxy-15-cyclohexyl-16,17,18,19,
There was obtained methyl 20-pentanor-7-thiaprosta-8,13-dienoate (32 mg, 59%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.1-1.9 (m, 19 H) 2.31 (t, J = 7.4 Hz, 2H) 2.3-2.8 (m, 3H) 2.44 (t, J = 7.3 Hz, 2H) 2.90 (ddd, J = 1.3 & 6.4 & 16.7 Hz, 1H) 3.23 (dd, J = 1.3 & 7.9 Hz, 1H) 3.67 (s, 3H) 3.86 (dd, J = 6.4 & 6.4 Hz, 1H) 4.1-4.2 (m, 1H) 5.55 (dd, J = 8.3 & 15.5 Hz, 1H) 5.59 (dd, J = 6.6 & 15.5 Hz, 1H)

Example 20 (11R, 12S, 13E, 15S) -9-benzoyl
Oxy-11,15-bis (tert-butyldimethylsilo
Xy) -7-thiaprosta-8,13-dienoic acid methyl ester
Synthesis ^{(R 1 = Ph, R 2} = t BuMe 2 Si, R 3 = H, R 4 = Pentyl, W = t
BuMe ₂ SiO, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = C
H)

[0140]

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As raw materials and reagents, (1E, 3S) -1-
Iodo-3- (tert-butyldimethylsiloxy) -1-
Octene (442 mg, 1.2 mmol), tert-butyllithium
(1.54 mol / l, 1.56 ml, 2.4 mmol), hexyne copper (174
mg), hexamethylphosphorous triamide (436 μl),
(4R) -tert-butyldimethylsiloxy-2- (5-
(Methoxycarbonylpentylthio) -2-cyclopenten-1-one (373 mg, 1.0 mmol), benzoic anhydride (6
(61 mg) and the same operation as in Example 1 was carried out.
1R, 12S, 13E, 15S) -9-Benzoyloxy-11,15-bis (tert-butyldimethylsiloxy) -7-thiaprosta-8,13-dienoic acid methyl
(239 mg, 33%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.06 (s), 0.07 (s), 0.07 (s) ... 12H 0.8-1.0 (m, 3H) 0.89 (s, 9H) 0.91 (s , 9H) 1.00 (t, J = 7.3 Hz, 3H) 1.2-1.7 (m, 14H) 2.25 (t, J = 7.6 Hz, 2H) 2.4-2.8 (m, 3H) 3.07 (ddd, J = 1.6 & 5.4 & 16.2 Hz, 1H) 3.19 (d, J = 8.6 Hz, 1H) 3.65 (s, 3H) 4.11 (dd, J = 5.8 & 11.7 Hz, 1H) 4.20 (ddd, J = 3.3 & 3.3 & 6.6 Hz, 1H ) 5.48 (dd, J = 8.4 & 15.7 Hz, 1H) 5.60 (dd, J = 5.8 & 15.3 Hz, 1H) 7.47 (dd, J = 7.2 & 7.9 Hz, 2H) 7.60 (dd, J = 6.2 & 7.3 Hz) , 1H) 8.12 (d, J = 7.3 Hz, 2H)

Example 21 (11R, 12S, 13E, 15S) -9-benzoyl
Oxy-11,15-dihydroxy-7-thiaprosta
Synthesis of methyl -8,13-dienoate (R ¹ = Ph, R ² = H, R ³
= H, R ⁴ = Pentyl, W = OH, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, -
= trans-CH = CH)

[0144]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.3 ml), (11R, 12S, 13E, 15S)-
9-benzoyloxy-11,15-bis (tert-butyldimethylsiloxy) -7-thiaprosta-8,13-
The same operation as in Example 2 was carried out using methyl dienoate (239 mg) to give (11R, 13E, 15S) -9-benzoyloxy-11,15-dihydroxy-7-thiaprosta-8,13-dienoic acid. Methyl (144 mg, 86%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.89 (t, J = 6.8 Hz, 3H) 1.2-1.7 (m, 14H) 2.26 (t, J = 7.4 Hz, 2H) 2.5-2.8 ( m, 3H) 3.11 (dd, J = 5.3 & 16.3 Hz, 1H) 3.28 (d, J = 10.9 Hz, 1H) 3.65 (s, 3H) 4.14 (dd, J = 6.3 & 12.5 Hz, 1H) 4.24 (ddd , J = 3.0 & 3.3 & 6.2 Hz, 1H) 5.61 (dd, J = 8.4 & 15.7 Hz, 1H) 5.75 (dd, J = 6.3 & 15.5 Hz, 1H) 7.49 (dd, J = 7.3 & 7.9 Hz, 2H ) 7.62 (dd, J = 6.3 & 7.6 Hz, 1H) 8.11 (d, J = 7.3 Hz, 2H)

Example 22 (11R, 12S, 13E, 16S) -9-butyryl
Xy-11- (tert-butyldimethylsiloxy) -16
-(Trimethylsiloxy) -16-methyl-7-thiap
Synthesis of methyl roster-8,13-dienoate (R ¹ = Pr, R
² = ^t BuMe ₂ Si, R ³ = Me, R ⁴ = Bu, W = ^t BuMe ₂ SiO, XY = CH ₂ -C
H ₂ , Z = CO ₂ Me, n = 1, - = trans-CH = CH)

[0148]

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As raw materials and reagents, (1E, 4S) -1-
Iodo-4-methyl-4- (trimethylsiloxy) -1
-Octene (408 mg, 1.2 mmol), tert-butyl lithium (1.54 mol / l, 1.56 ml, 2.4 mmol), hexyne copper (1
74 mg), hexamethylphosphorous triamide (436 μ
l), (4R) -tert-butyldimethylsiloxy-2-
(5-methoxycarbonylpentylthio) -2-cyclopenten-1-one (373 mg, 1.0 mmol), butyric anhydride (44
(1 μl) and the same operation as in Example 1 was carried out.
R, 12S, 13E, 16S) -9-butyryloxy-
There was obtained methyl 11- (tert-butyldimethylsiloxy) -16- (trimethylsiloxy) -16-methyl-7-thiaprosta-8,13-dienoate (226 mg, 35%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s), 0.10 (s) ... 15H 0.8-1.0 (m, 3H) 0.87 (s, 9H) 1.00 (t, J = 7.4 Hz , 3H) 1.17 (s, 3H) 1.2-1.8 (m, 14H) 2.0-2.8 (m, 9H) 2.88 (dd, J = 6.6 & 16.5 Hz, 1H) 3.13 (d, J = 6.4 Hz, 1H) 3.67 (s, 3H) 4.1-4.2 (m, 1H) 5.1-5.4 (m, 1H) 5.5-5.7 (m, 1H)

Example 23 (11R, 12S, 13E, 16S) -9-butyryl
Xy-11,16-dihydroxy-16-methyl-7-
Synthesis of methyl thiaprosta-8,13-dienoate (R ¹
= Pr, R ² = H, R ³ = Me, R ⁴ = Bu, W = OH, XY = CH ₂ -CH ₂ , Z = CO ₂ M
e, n = 1, - = trans-CH = CH)

[0152]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.1 ml), (11R, 12S, 13E, 16S)-
Methyl 9-butyryloxy-11- (tert-butyldimethylsiloxy) -16- (trimethylsiloxy) -16-methyl-7-thiaprosta-8,13-dienoate (19
mg), the same operation as in Example 2 was performed, and (11)
R, 12S, 13E, 16S) -9-butyryloxy-
There was obtained methyl 11,16-dihydroxy-16-methyl-7-thiaprosta-8,13-dienoate (5 mg, 37%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.91 (t, J = 6.9 Hz, 3H) 1.00 (t, J = 7.4 Hz, 3H) 1.16 (s, 3H) 1.2-1.8 (m, 14 H) 2.20 (d, J = 7.3 Hz, 2H) 2.31 (t, J = 7.3 Hz, 2H) 2.43 (t, J = 7.4 Hz, 2H) 2.5-2.8 (m, 3H) 2.95 (ddd, J = 1.3 & 6.6 & 16.5 Hz, 1H) 3.22 (d, J = 6.3 Hz, 1H) 3.67 (s, 3H) 4.18 (dt, J = 3.3 & 3.3 Hz, 1H) 5.41 (dd, J = 8.6 & 15.2 Hz, 1H) 5.72 (dt, J = 15.2 & 7.3 Hz, 1H)

[Embodiment 24](11R, 12S, 13E, 15S) -9-butyryl
Xy-11,15-bis (tert-butyldimethylsiloxy)
B) Allyl -7-thiaprosta-8,13-dienoate
Synthesis (R¹= Pr, R^Two=^tBuMe_TwoSi, R^Three= H, R^Four= Pentyl, W =^tBu
Me_TwoSiO, X-Y = CH _Two-CH_Two, Z = CO_Two-Allyl, n = 0,-= trans-CH
= CH)

[0156]

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As raw materials and reagents, (1E, 3S) -1-
Iodo-3- (tert-butyldimethylsiloxy) -1-
Octene (1.31 g, 3.57 mmol), tert-butyllithium
(1.57 mol / l, 4.55 ml, 7.13 mmol), hexyne copper (51
6 mg), hexamethylphosphorous triamide (1.30 m
l), (4R) -4- (tert-butyldimethylsiloxy)
-2- (5-allyloxycarbonylpentylthio)-
2-cyclopenten-1-one (1.19 g, 2.97 mmol),
The same operation as in Example 1 was performed using butyric anhydride (1.31 ml) to obtain (11R, 12S, 13E, 15S) -9-butyryloxy-11,15-bis (tert-butyldimethylsiloxy) -7-thiaplasta. Allyl -8,13-dienoate (1.63 mg, 77%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s), 0.05 (s) ... 12 H 0.8-0.9 (m, 3H) 0.87 (s, 9H) 0.89 (s, 9H) 1.00 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 16H) 2.32 (t, J = 7.4 Hz, 2H) 2.4-2.7 (m, 3H) 2.42 (t, J = 7.4 Hz, 2H) 2.91 ( ddd, J = 1.5 & 6.8 & 16.2 Hz, 1H) 3.12 (dd, J = 2.6 & 8.6 Hz, 1H) 4.0-4.2 (m, 2H) 4.57 (dt, J = 5.9 & 1.3 Hz, 2H) 5.23 (dd , J = 1.3 & 10.6 Hz, 1H) 5.31 (dd, J = 1.7 & 17.2 Hz, 1H) 5.43 (dd, J = 8.6 & 16.2 Hz, 1H) 5.62 (dd, J = 5.9 & 15.5 Hz, 1H) 5.8 -6.0 (m, 1H)

Example 25 (11R, 12S, 13E, 15S) -9-butyryl
Xy-11,15-bis (tert-butyldimethylsiloxy)
B) Synthesis of -7-thiaprosta-8,13-dienoic acid
(R ¹ = Pr, R ² = ^t BuMe ₂ Si, R ³ = H, R ⁴ = Pentyl, W = ^t BuMe ₂ Si
O, XY = CH ₂ -CH ₂ , Z = CO ₂ H, n = 0, - = trans-CH = CH

[0160]

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To a solution of palladium acetate (52 mg) and tributylphosphine (229 μl) in tetrahydrofuran (20 ml) was added a solution of formic acid (347 μl) and triethylamine (57.3 μl) in tetrahydrofuran (10 ml). Furthermore, (11
R, 12S, 13E, 15S) -9-butyryloxy-
11,15-bis (tert-butyldimethylsiloxy)-
Allyl 7-thiaprosta-8,13-dienoate (1.63
g) in tetrahydrofuran (10 ml) was added and refluxed for 1 hour. After cooling, the reaction solution was passed through a short florisil column to remove the catalyst. The solution was concentrated under reduced pressure, and purified by silica gel column chromatography (10 to 20% ethyl acetate / hexane) to give (11R, 12S, 13
E, 15S) -9-Butyryloxy-11,15-bis (tert-butyldimethylsiloxy) -7-thiaprosta-8,13-dienoic acid (1.41 g, 91%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s), 0.05 (s) ... 12 H 0.8-0.9 (m, 3H) 0.88 (s, 9H) 0.89 (s, 9H) 1.00 (t, J = 7.3 Hz, 3H) 1.2-1.8 (m, 16H) 2.34 (t, J = 7.2 Hz, 2H) 2.4-2.8 (m, 3H) 2.42 (t, J = 7.4 Hz, 2H) 2.92 ( ddd, J = 1.7 & 5.3 & 16.5 Hz, 1H) 3.13 (dd, J = 6.9 Hz, 1H) 4.0-4.2 (m, 2H) 5.43 (dd, J = 8.6 & 16.2 Hz, 1H) 5.62 (dd, J = 5.6 & 15.5 Hz, 1H)

[Example 26](11R, 12S, 13E, 15S) -9-butyryl
Xy-11,15-dihydroxy-7-thiaprostar
Synthesis of 8,13-dienoic acid (R¹= Pr, R^Two= H, R ^Three= H, R^Four=
Pentyl, W = OH, X-Y = CH_Two-CH_Two, Z = CO_TwoH, n = 0,-= trans-C
H = CH)

[0164]

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To a solution of ice-cooled acetonitrile (1 ml) and pyridine (0.1 ml) was added a solution of hydrogen fluoride in pyridine (0.1 ml).
ml) and (11R, 12S, 13E, 15S) -9
A solution of -butyryloxy-11,15-bis (tert-butyldimethylsiloxy) -7-thiaprosta-8,13-dienoic acid (79 mg) in pyridine (0.1 ml) was added. The ice bath was removed, and the mixture was stirred at room temperature for 20 hours. The reaction solution was poured into a mixture of ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate. The desired product was extracted from the mixture with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, preparative TLC
(Merck TLC plate silica gel 60 F ₂₅₄ , 20 × 20 cm, l
ayer thickness 0.25 mm, 2 plates, purified with ethyl acetate: hexane = 4: 1) and (11R, 12S, 13E, 15)
S) -9-Butyryloxy-11,15-dihydroxy-7-thiaprosta-8,13-dienoic acid (17 mg, 33
%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.8-1.1 (m, 6H) 1.2-1.8 (m, 16H) 2.34 (t, J = 7.1 Hz, 2H) 2.4-2.8 (m, 3H ) 2.44 (t, J = 7.4 Hz, 2H) 2.96 (dd, J = 6.3 & 16.2 Hz, 1H) 3.23 (d, J = 7.6 Hz, 1H) 4.0-4.2 (m, 2H) 5.56 (dd, J = 7.9 & 15.5 Hz, 1H) 5.70 (dd, J = 6.6 & 15.5 Hz, 1H)

Example 27 (11R, 12S, 13E, 15S) -9-butyryl
Xy-11,15-bis (tert-butyldimethylsiloxy)
B) -18-oxa-7-thiaprosta-8,13-di
Synthesis of methyl enoate (R ¹ = Pr, R ² = ^t BuMe ₂ Si, R ³ = H, R ⁴
= 2-Ethoxyethyl, W = ^t BuMe ₂ SiO, XY = CH ₂ -CH ₂ , Z = CO ₂ Me,
n = 0, - = trans-CH = CH)

[0168]

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As raw materials and reagents, (1E, 3S) -1-
Iodo-3- (tert-butyldimethylsiloxy) -5
Ethoxy-1-pentene (444 mg, 1.2 mmol), tert-
Butyllithium (1.54 mol / l, 1.56 ml, 2.4 mmol),
Hexin copper (174 mg), hexamethylphosphorus triamide (436 μl), (4R) -4- (tert-butyldimethylsiloxy) -2- (5-methoxycarbonylpentylthio) -2-cyclopenten-1-one ( 373 mg, 1.0
mmol) and butyric anhydride (441 μl), and the same operation as in Example 1 was performed to obtain (11R, 12S, 13E, 15S)-
Methyl 9-butyryloxy-11,15-bis (tert-butyldimethylsiloxy) -18-oxa-7-thiaprosta-8,13-dienoate (192 mg, 28%) was obtained.

[0170] ^{1 H-NMR (270 MHz,} δppm, CDCl 3) 0.04 (s), 0.06 (s) ...... 12H 0.87 (s, 9H) 0.90 (s, 9H) 1.00 (t, J = 7.4 Hz, 3H ) 1.19 (t, J = 6.9 Hz, 3H) 1.2-1.8 (m, 10 H) 2.30 (t, J = 7.4 Hz, 2H) 2.4-2.8 (m, 3H) 2.42 (t, J = 7.4 Hz, 2H ) 2.91 (ddd, J = 1.6 & 6.6 & 16.2 Hz, 1H) 3.12 (d, J = 5.9 Hz, 1H) 3.4-3.6 (m, 4H) 3.66 (s, 3H) 4.1-4.2 (m, 1H) 4.28 (dt, J = 5.9 & 6.3 Hz, 1H) 5.46 (dd, J = 8.7 & 15.3 Hz, 1H) 5.63 (dd, J = 5.8 & 15.3 Hz, 1H)

Example 28 (11R, 12S, 13E, 15S) -9-butyryl
Xy-11,15-dihydroxy-18-oxa-7-
Synthesis of methyl thiaprosta-8,13-dienoate (R ¹
= Pr, R ² = H, R ³ = H, R ⁴ = 2-Ethoxyethyl, W = OH, XY = CH ₂ -C
H ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0172]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.2 ml), (11R, 12S, 13E, 15S)-
The same operation as in Example 2 was carried out using methyl 9-butyryloxy-11,15-bis (tert-butyldimethylsiloxy) -18-oxa-7-thiaprosta-8,13-dienoate (192 mg). (11R, 13E, 15S)
-9-butyryloxy-11,15-dihydroxy-1
Methyl 8-oxa-7-thiaprosta-8,13-dienoate (115 mg, 89%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 1.00 (t, J = 7.4 Hz, 3H) 1.20 (t, J = 6.9 Hz, 3H) 1.3-1.9 (m, 10 H) 2.31 (t , J = 7.4 Hz, 2H) 2.4-2.8 (m, 3H) 2.43 (t, J = 7.4 Hz, 2H) 2.90 (ddd, J = 1.3 & 6.9 & 16.2 Hz, 1H) 3.21 (dd, J = 3.3 & 7.9 Hz, 1H) 3.49 (q, J = 6.9 Hz, 2H) 3.5-3.7 (m, 2H) 3.67 (s, 3H) 4.1-4.2 (m, 1H) 4.32 (dt, J = 5.6 & 5.8 Hz, 1H ) 5.60 (dd, J = 7.9 & 15.5 Hz, 1H) 5.70 (dd, J = 5.9 & 15.2 Hz, 1H)

[Example 29] (11R, 12S, 13E, 15S, 17R) -9-B
Nzoyloxy-11,15-bis (tert-butyldim
Tylsiloxy) -17,20-dimethyl-7-thiapro
Synthesis of methyl star 8,13-dienoate (R ¹ = Ph, R ² =
^t BuMe ₂ Si, R ³ = H, R ⁴ = 2-Me-hexyl, W = ^t BuMe ₂ SiO, XY = CH
₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0176]

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As a raw material, (1E, 3S, 5R) -1-
Iodo-3- (tert-butyldimethylsiloxy) -5
Methyl-1-nonene (476 mg, 1.2 mmol), tert-butyllithium (1.54 mol / l, 1.56 ml, 2.4 mmol), hexine copper (174 mg), hexamethylphosphorous triamide
(436 μl), (4R) -4- (tert-butyldimethylsiloxy) -2- (5-methoxycarbonylpentylthio) -2-cyclopenten-1-one (373 mg, 1.0 mm
ol) and benzoic anhydride (611 mg), and the same operation as in Example 1 was carried out to obtain (11R, 12S, 13E, 15S,
17R) -9-Benzoyloxy-11,15-bis (tert-butyldimethylsiloxy) -17,20-dimethyl-7-thiaprosta-8,13-dienoic acid methyl
(734 mg, 98%).

[0178] ^{1 H-NMR (270 MHz,} δppm, CDCl 3) 0.06 (s), 0.06 (s), 0.07 (s), 0.08 (s) ...... 12H 0.8 - 1.0 (m, 6H) 0.90 (s, 9H) 0.90 (s, 9H) 1.0-1.7 (m, 15 H) 2.25 (t, J = 7.4 Hz, 2H) 2.5-2.8 (m, 3H) 3.08 (dd, J = 5.5 & 16.2 Hz, 1H) 3.18 (d, J = 6.3 Hz, 1H) 3.64 (s, 3H) 4.1-4.2 (m, 1H) 5.48 (dd, J = 8.6 & 15.5 Hz, 1H) 5.67 (dd, J = 6.1 & 15.3 Hz, 1H) 7.47 (t, J = 7.6 Hz, 2H) 7.60 (t, J = 7.4 Hz, 1H) 8.12 (d, J = 7.3 Hz, 2H)

Embodiment 30 (11R, 12S, 13E, 15S, 17R) -9-B
Nzoyloxy-11,15-dihydroxy-17,2
0-dimethyl-7-thiaprosta-8,13-dienoic acid
Synthesis of methyl (R ¹ = Ph, R ² = H, R ³ = H, R ⁴ = 2-Me-hexyl,
W = OH, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0180]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.7 ml), (11R, 12S, 13E, 15S, 1
7R) -9-benzoyloxy-11,15-bis (te
(rt-butyldimethylsiloxy) -17,20-dimethyl-7-thiaprosta-8,13-dienoic acid methyl (734
mg), the same operation as in Example 2 was performed, and (11)
R, 12S, 13E, 15S, 17R) -9-Benzoyloxy-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoic acid methyl (141 mg, 28%) was obtained.

¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 0.89 (t, J = 6.3 Hz, 3H) 0.92 (d, J = 6.3 Hz, 9H) 1.1-1.7 (m, 15 H) 2.26 (t , J = 7.4 Hz, 2H) 2.5-2.8 (m, 3H) 3.10 (dd, J = 6.8 & 16.7 Hz, 1H) 3.28 (d, J = 5.6 Hz, 1H) 3.65 (s, 3H) 4.2-4.3 ( m, 1H) 5.63 (dd, J = 8.1 & 15.3 Hz, 1H) 5.76 (dd, J = 6.3 & 15.5 Hz, 1H) 7.49 (t, J = 7.8 Hz, 2H) 7.62 (t, J = 7.3 Hz, 1H) 8.11 (d, J = 7.3 Hz, 2H)

[Example 31](11R, 12S, 13E, 15S) -9- (N-ben
(Dyloxycarbonylphenylalanyloxy) -1
1,15-bis (tert-butyldimethylsiloxy) -7
Synthesis of Methyl Thiaprosta-8,13-dienoate 
(R¹= 1- (Cbz-NH) -2-Ph-ethyl, R^Two=^tBuMe_TwoSi, R^Three= H, R^Four=
Pentyl, W =^tBuMe_TwoSiO, X-Y = CH_Two-CH_Two, Z = CO_TwoMe, n = 0,-
= trans-CH = CH)

[0184]

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(1E, 3S) -1-iodo-3- (tert
-Butyldimethylsiloxy) -1-octene (221 mg,
After cooling a solution of 0.6 mmol) in ether (1.5 ml) to -78 ° C, tert-butyllithium (1.50 mol / l, 0.
80 ml, 1.2 mmol) and stirred at −78 ° C. for 2 hours. Further, a solution of hexyne copper (87 mg) and hexamethylphosphorus triamide (218 μl) in ether (3 ml) was added thereto, and the mixture was further stirred at −78 ° C. for 1 hour to produce a copper reagent. Into the obtained copper reagent, (4R) -tert-butyldimethylsiloxy-2- (5-methoxycarbonylpentylthio) -2-cyclopenten-1-one (187
mg, 0.5 mmol) in tetrahydrofuran (10 ml) was added dropwise. The reaction mixture was kept at −78 ° C. for 15 minutes, and then the reaction temperature was increased and stirred at −50 to −30 ° C. for 1 hour. Furthermore, a mixed acid anhydride of N-benzyloxycarbonylphenylalanine separately prepared at −30 ° C. (1.35 m
mol) in tetrahydrofuran (6 ml), and the mixture was stirred for 15 hours while raising the reaction temperature to room temperature. The reaction solution was poured into saturated ammonium sulfate (40 ml), the mixture was separated, the aqueous layer was extracted with ether, and the extract and the organic layer were combined and dried over anhydrous magnesium sulfate.
The solution was concentrated under reduced pressure and purified by silica gel column chromatography (10% ethyl acetate / hexane).
Methyl 1R, 13E, 15S) -9- (N-benzyloxycarbonylphenylalanyloxy) -11,15-bis (tert-butyldimethylsiloxy) -7-thiaprosta-8,13-dienoate (148 mg, 33 %).
A mixed acid anhydride of N-benzyloxycarbonylphenylalanine was prepared as follows. A solution of N-benzyloxycarbonylphenylalanine (414 mg, 1.35 mmol) in tetrahydrofuran (6 ml) was stirred at -15 ° C.
And cooled. N-methylmorpholine (137 mg, 1.35 mmo
l), and then isobutyl chloroformate (184 mg, 1.35 mmo
l) was added, and the mixture was stirred at −15 ° C. for 30 minutes. The resulting precipitate was removed and used for the reaction.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.06 (s), 0.06 (s) ... 12 H 0.88 (s, 9H) 0.90 (s, 9H) 1.1-1.8 (m, 18H) 2.28 (t, J = 7.6 Hz, 2H) 2.3-3.0 (m, 4H) 3.1-3.4 (m, 2H) 3.64 (s, 3H) 4.0-4.2 (m, 2H) 4.7-4.8 (m, 1H) 5.09 ( d, J = 13.0 Hz, 2H) 5.21 (d, J = 8.5 Hz, 1H) 5.44 (dd, J = 7.9 & 15.5 Hz, 1H) 5.62 (dd, J = 5.3 & 15.5 Hz, 1H) 7.1-7.4 ( m, 11H)

[Example 32](11R, 12S, 13E, 15S) -9- (N-ben
(Dyloxycarbonylphenylalanyloxy) -1
1,15-dihydroxy-7-thiaprosta-8,13
-Synthesis of methyl dienoate (R¹= 1- (Cbz-NH) -2-Ph-ethy
l, R^Two= H, R^Three= H, R^Four= Pentyl, W = OH, X-Y = CH_Two-CH_Two, Z = CO_Two
Me, n = 0,-= trans-CH = CH)

[0188]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.3 ml), (11R, 12S, 13E, 15S)-
Using 9- (N-benzyloxycarbonylphenylalanyloxy) -11,15-bis (tert-butyldimethylsiloxy) -7-thiaprosta-8,13-dienoate (140 mg), (11R, 12S , 13E, 1
5S) -9- (N-Benzyloxycarbonylphenylalanyloxy) -11,15-dihydroxy-7-thiaprosta-8,13-dienoic acid methyl ester (53 mg, 51%)
I got

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.89 (t, J = 7.0 Hz, 3H) 1.1-2.1 (m, 14H) 2.28 (t, J = 7.2 Hz, 2H) 2.4-3.0 ( m, 5H) 3.1-3.4 (m, 3H) 3.64 (s, 3H) 4.1-4.2 (m, 2H) 4.7-4.8 (m, 1H) 5.09 (d, J = 3.0 Hz, 2H) 5.28 (d, J = 7.9 Hz, 1H) 5.55 (dd, J = 7.9 & 15.5 Hz, 1H) 5.68 (dd, J = 6.4 & 15.5 Hz, 1H) 7.1-7.4 (m, 10H)

Example 33 (11R, 12S, 15S) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15- (2-teto
Lahydropyranyloxy) -7-thia-8-prosten
Synthesis of methyl acid (R ¹ = Pr, R ² = THP, R ³ = H, R ⁴ = Pentyl,
W = ^t BuMe ₂ SiO, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = CH ₂ -C
H ₂₎

[0192]

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As a raw material and a reagent, 1-iodo-3- (2
-Tetrahydropyranyloxy) -octane (263 mg,
0.773 mmol), tert-butyllithium (1.54 mol / l,
1.0 ml, 1.55 mmol), copper hexine (112 mg), hexamethylphosphorus triamide (281 μl), (4R) -4-
(Tert-butyldimethylsiloxy) -2- (5-methoxycarbonylpentylthio) -2-cyclopentene-1
The same operation as in Example 1 was performed using -one (240 mg, 0.644 mmol) and butyric anhydride (284 μl) to obtain (11R, 12
(S, 15S) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15- (2-tetrahydropyranyloxy) -7-thia-8-prostenate methyl (171
mg, 40%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.06 (s, 3H) 0.07 (s, 3H) 0.8-0.9 (m, 3H) 0.88 (s, 9H) 1.00 (t, J = 7.3 Hz , 3H) 1.2-1.8 (m, 20H) 2.30 (t, J = 7.4 Hz, 2H) 2.4-2.8 (m, 4H) 2.42 (t, J = 7.4 Hz, 2H) 2.8-3.0 (m, 1H) 3.3 -3.5 (m, 1H) 3.5-3.7 (m, 1H) 3.66 (s, 3H) 3.8-4.0 (m, 1H) 4.0-4.2 (m, 1H) 4.5-4.7 (m, 1H)

Example 34 (11R, 12S, 15S) -9-butyryloxy-1
1,15-dihydroxy-7-thia-8-prostenic acid
Synthesis of methyl (R ¹ = Pr, R ² = H, R ³ = H, R ⁴ = Pentyl, W = O
H, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = CH ₂ -CH ₂ )

[0196]

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To a solution of ice-cooled acetonitrile (2 ml) and pyridine (0.2 ml) was added a hydrogen fluoride pyridine solution (0.2 ml).
ml), and (11R, 12S, 15S) -9-butyryloxy-11-tert-butyldimethylsiloxy-15
-(2-tetrahydropyranyloxy) -7-thia-8
-Methyl prostenate (171 mg) in pyridine (0.2 ml)
The solution was added. The ice bath was removed, and the mixture was stirred at room temperature for 20 hours. The reaction solution was poured into a mixture of ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate. The desired product was extracted from the mixture with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and tetrahydrofuran (4 ml) was added to form a solution. Then, water (2 ml) and acetic acid (8 ml) were added, and the mixture was stirred at 45 ° C for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and purified by silica gel column chromatography (40 to 50% ethyl acetate / hexane).
R, 12S, 15S) -9-Butyryloxy-11,1
Methyl 5-hydroxy-7-thia-8-prostenate (85 mg, 71%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.89 (t, J = 6.6 Hz, 3H) 1.00 (t, J = 7.4 Hz, 3H) 1.2-1.9 (m, 20 H) 2.31 (t , J = 7.4 Hz, 2H) 2.4-2.8 (m, 4H) 2.42 (t, J = 7.4 Hz, 2H) 2.96 (ddt, J = 6.6 & 16.8 & 1.0 Hz, 1H) 3.5-3.7 (m, 1H) 3.67 (s, 3H) 4.1-4.2 (m, 1H)

[Reference Example 1](3S, 4R) -4- (tert-butyldimethylsiloxy
B) -1-butyryloxy-2- (5-methoxycarbo)
Nilpentylthio) -3- (trans-2-tributyls
Synthesis of (tanylvinyl) -1-cyclopentene

[0200]

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To a suspension of ice-cooled cuprous cyanide (1.88 g) in tetrahydrofuran (35 ml) was added methyllithium.
(1.25 mol / l, 37 ml) was added, and the reaction solution was warmed to room temperature. Further, tetra-1,2-bis (tributylstannyl) ethylene (14.4 g) in tetrahydrofuran (35 ml) was added thereto, and the mixture was further stirred at room temperature for 1.5 hours to produce a copper reagent. The resulting copper reagent was cooled to -78 ° C and (4R) -tert-butyldimethylsiloxy-2
-(5-Methoxycarbonylpentylthio) -2-cyclopenten-1-one (5.60 g) in tetrahydrofuran
(30 ml) solution was added dropwise. Let this reaction take 1 hour-
The temperature was raised to 35 ° C., and the mixture was stirred for 30 minutes. Further, butyric anhydride (8.60 ml) was added to the reaction solution, and the mixture was stirred for 3 hours while raising the reaction temperature to room temperature. The reaction solution was mixed with a saturated ammonium sulfate aqueous solution and concentrated ammonium water (9:
1,300 ml). The mixture was extracted with ether, and the extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (3 to 5% ethyl acetate / hexane) to give (3S, 4R) -4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonyl). (Pentylthio) -3- (trans-2-tributylstannylvinyl) -1-cyclopentene (10.5
g, 92%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.00 (s, 6H) 0.84 (s, 9H) 0.85 (t, J = 7.0 Hz, 9H) 0.97 (t, J = 7.4 Hz, 3H) 1.1-1.8 (m, 26H) 2.26 (t, J = 7.5 Hz, 2H) 2.39 (t, J = 7.5 Hz, 2H) 2.4-2.7 (m, 3H) 2.81 (dd, J = 6.9 & 16.5 Hz, 1H ) 3.1-3.2 (m, 1H) 3.63 (s, 3H) 4.1-4.2 (m, 1H) 5.80 (dd, J = 8.2 & 18.8 Hz, 1H) 6.09 (d, J = 18.8 Hz, 1H)

[Reference Example 2](3S, 4R) -4- (tert-butyldimethylsiloxy
B) -1-butyryloxy-2- (5-methoxycarbo)
Nilpentylthio) -3- (trans-2-iodovini
L) Synthesis of 1-cyclopentene

[0204]

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(3S, 4R) -4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio) -3- (trans-2-tributylstannylvinyl) -1-cyclopentene (8.74
To a solution of g) in ether (90 ml) was added iodine (2.92 g), and the mixture was stirred at room temperature for 1 hour. After a saturated aqueous solution of sodium thiosulfate (50 ml) was added to the reaction solution, ether extraction was performed. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
(3S, 4R) -4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio) -3- (trans-2-iodovinyl) -1-cyclopentene (6.44 g, 94%) ).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.05 (s, 6H) 0.87 (s, 9H) 1.00 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 8H) 2.31 (t , J = 7.3 Hz, 2H) 2.4-2.7 (m, 3H) 2.42 (t, J = 7.4 Hz, 2H) 2.84 (dd, J = 6.9 & 16.5 Hz, 1H) 3.1-3.2 (m, 1H) 3.67 ( s, 3H) 4.0-4.2 (m, 1H) 6.28 (d, J 14.5 Hz, 1H) 6.45 (dd, J = 8.3 & 14.5 Hz, 1H)

[Embodiment 35](11R, 12S, 13E) -9-butyryloxy-1
1,15-bis (tert-butyldimethylsiloxy) -1
7-phenyl-18,19,20-trinor-7-thia
Synthesis of methyl prostar-8,13-dienoate (R¹= Pr,
 R^Two= H, R^Three= H, R ^Four= 2-Phenylethyl, W =^tBuMe_TwoSiO, X-Y = CH
_Two-CH_Two, Z = CO_TwoMe, n = 0,-= trans-CH = CH)

[0208]

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A suspension of cuprous cyanide (63 mg) in tetrahydrofuran (1 ml) was cooled on ice, and methyllithium (1.25 ml) was added.
ol / l, 1.23 ml) and brought to room temperature with stirring. There, (1E) -1-tributylstannio-3- (te
(rt-butyldimethylsiloxy) -5-phenyl-1-pentene (447 mg, 0.79 mmol) in tetrahydrofuran (1.
5 ml) solution and stirred at room temperature for 1.5 hours to produce a copper reagent. The obtained copper reagent was cooled to -78 ° C, and (4R) -tert-butyldimethylsiloxy-2-
A solution of (5-methoxycarbonylpentylthio) -2-cyclopenten-1-one (186 mg, 0.5 mmol) in tetrahydrofuran (1.5 ml) was added dropwise. The reaction mixture was immediately heated to -35 ° C and stirred at -35 ° C for 30 minutes. Then add butyric anhydride (286 μl) to the reaction mixture at -35 ° C.
Was added, and the mixture was stirred for 1.5 hours while raising the reaction temperature to room temperature. The reaction solution was poured into a mixture of saturated ammonium sulfate and concentrated aqueous ammonia (9: 1, 40 ml), the mixture was separated, the aqueous layer was extracted with ether, and the extract and the organic layer were combined. Dry over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure and purified by silica gel column chromatography (4% ethyl acetate / hexane) to give (11R,
12S, 13E) -9-butyryloxy-11,15-
Bis (tert-butyldimethylsiloxy) -17-phenyl-18,19,20-trinor-7-thiaprostar
Methyl 8,13-dienoate (322 mg, 90%) was obtained.

Incidentally, the obtained (11R, 12S,
13E) -9-Butyryloxy-11,15-bis (te
rt-butyldimethylsiloxy) -17-phenyl-1
8,19,20-trinor-7-thiaprosta-8,1
Methyl 3-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s), 0.05 (s), 0.05 (s), 0.06 (s) ... 12H 0.87 (s, 9H) 0.90 (s, 9H) 1.00 (t, J = 7.4 Hz, 3H) 1.5-1.8 (m, 12H) 2.1-2.3 (m, 2H) 2.3-2.7 (m, 3H) 2.7-3.0 (m, 1H) 3.14 (d, J = 10.0 Hz, 1H) 3.65 (s, 3H) 4.0-4.2 (m, 1H) 5.3-5.5 (m, 1H) 5.62 (dd, J = 6.3 & 15.2 Hz, 1H) 7.0-7.3 (m, 5H)

[Embodiment 36](11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-17-phenyl-18,1
9,20-trinor-7-thiaprosta-8,13-di
Synthesis of methyl enoate (R¹= Pr, R^Two= H, R^Three= H, R^Four= 2-Phen
ylethyl, W = OH, X-Y = CH_Two-CH_Two, Z = CO_TwoMe, n = 0,-= trans
-CH = CH)

[0213]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.5 ml), (11R, 12S, 13E) -9-butyryloxy-11,15-bis (tert-butyldimethylsiloxy) -17-phenyl-18,19 Methyl 20,20-trinor-7-thiaprosta-8,13-dienoate
(300 mg), and the same operation as in Example 2 was performed.
(11R, 13E) -9-butyryloxy-11,15
Dihydroxy-17-phenyl-18,19,20-
Two isomers of methyl trinor-7-thiaprosta-8,13-dienoate having different configurations at the 15-position were separately obtained (low-polarity compound: 71 mg, 34%; high-polarity compound: 101 m)
g, 50%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.2 Hz, 3H) 1.2-1.9 (m, 10 H) 2.15 (d, J = 6.3 Hz, 1H) 2.29 (t, J = 7.3 Hz, 2H) 2.43 (t, J = 7.5 Hz, 2H) 2.5-2.8 (m, 4H) 2.96 (dd, J = 6.3 & 16.5 Hz, 1H) 3.23 (d, J = 7.9 Hz, 1H) 3.66 (s, 3H) 4.1-4.2 (m, 2H) 5.59 (dd, J = 7.9 & 15.5 Hz, 1H) 5.76 (dd, J = 6.0 & 15.5 Hz, 1H) 7.1-7.3 ( m, 5H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.2-2.0 (m, 10 H) 2.28 (t, J = 7.6 Hz, 2H) 2.43 (t, J = 7.6 Hz, 2H) 2.5-2.8 (m, 5H) 2.94 (ddd, J = 6.6 & 16.5 Hz, 1H) 3.22 (dd, J = 2.7 & 8.2 Hz, 1H) 3.67 (s , 3H) 4.1-4.2 (m, 2H) 5.58 (dd, J = 8.3 & 15.5 Hz, 1H) 5.73 (dd, J = 6.5 & 15.5 Hz, 1H) 7.1-7.4 (m, 5H)

[Example 37](11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-16-phenyl-17,18,19,20-tetrano
Synthesis of methyl methyl 7-thiaprosta-8,13-dienoate
Success (R¹= Pr, R ^Two= H, R^Three= H, R^Four= Benzyl, W =^tBuMe_TwoSiO, X
-Y = CH_Two-CH_Two, Z = CO_TwoMe, n = 0,-= trans-CH = CH)

[0218]

Embedded image

Chromium (II) chloride (344 mg) and nickel chloride (0.3 mg) were added to dimethylformamide (3.0).
ml), and stirred at room temperature with (3S, 4R)-
4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio)
-3- (trans-2-iodovinyl) -1-cyclopentene (418 mg) and phenylacetaldehyde (16
8 mg) in dimethylformamide (2.0 ml) was added. After stirring at room temperature for an additional 2.5 hours, water (70 ml) was added, and the mixture was separated.
ml × 3). The organic layers were combined, washed with brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained yellow oil was purified by silica gel column chromatography (15% ethyl acetate / hexane).
(11R, 12S, 13E) -9-butyryloxy-1
Methyl 1-tert-butyldimethylsiloxy-15-hydroxy-16-phenyl-17,18,19,20-tetranor-7-thiaprosta-8,13-dienoate (2
(68 mg, 65%).

Note that (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16-phenyl-
Methyl 17,18,19,20-tetranor-7-thiaprosta-8,13-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s, 6H) 0.88 (s, 9H) 1.01 (t, J = 7.3 Hz, 3H) 1.2-1.75 (m, 10H) 2.30 ( t, J = 7.4 Hz, 2H) 2.35-2.45 (m, 1H) 2.42 (t, J = 7.3 Hz, 2H) 2.7-2.9 (m, 3H) 3.1 (d-like, J = 8.0 Hz, 1H) 3.66 (s, 3H) 4.0-4.1 (m, 1H) 4.3-4.4 (m, 1H) 5.45-5.6 (m, 1H) 5.65-5.8 (m, 1H) 7.1-7.3 (m, 5H)

[Embodiment 38](11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-16-phenyl-17,1
8,19,20-tetranor-7-thiaprosta-8,
Synthesis of methyl 13-dienoate (R¹= Pr, R^Two= H, R^Three= H, R
^Four= Benzyl, W = OH, X-Y = CH_Two-CH_Two, Z = CO_TwoMe, n = 0,-= trans
-CH = CH)

[0223]

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As raw materials and reagents, a solution of hydrogen fluoride in pyridine (0.5 ml), (11R, 12S, 13E) -9-butyryloxy-11-tert-butyldimethylsiloxy-1
5-hydroxy-16-phenyl-17,18,19,
The same operation as in Example 2 was carried out using methyl 20-tetranor-7-thiaprosta-8,13-dienoate (260 mg) to give (11R, 12S, 13E) -9-butyryloxy-11,15-dihydroxy. -16-phenyl-1
Two isomers having different configurations at the 15-position of methyl 7,18,19,20-tetranor-7-thiaprosta-8,13-dienoate were separately obtained (low-polar compound: 75 mg, 3 mg).
6%; highly polar compound: 79 mg, 38%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.3-1.8 (m, 8H) 1.86 (br.d, J = 3.9 Hz) , 1H) 2.06 (d-like, J = 6.3 Hz, 1H) 2.31 (t, J = 7.3 Hz, 2H) 2.4-2.8 (m, 3H) 2.43 (t, J = 7.3 Hz, 2H) 2.85 (dd, J = 2.5 & 6.8 Hz, 2H) 2.93 (d, J = 8.0 Hz, 1H) 3.18 (dd, J = 1.9 & 8.1 Hz, 1H) 3.66 (s, 3H) 3.99 (m, 1H) 4.38 (m, 1H) ) 5.50 (ddd, J = 1.0 & 8.2 & 15.5 Hz, 1H) 5.75 (ddd, J = 0.7 & 6.3 & 15.5 Hz, 1H) 7.1-7.4 (m, 5H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.3-1.8 (m, 8H) 1.82 (br.1H) 2.3 (br. 1H) 2.30 (t, J = 7.3 Hz, 2H) 2.4-2.7 (m, 3H) 2.44 (t, J = 7.2 Hz, 2H) 2.7-3.0 (m, 3H) 3.19 (d-like, J = 6.2 Hz , 1H) 3.66 (s, 3H) 4.08 (br.1H) 4.38 (m, 1H) 5.57 (dd, J = 7.2 & 15.5 Hz, 1H) 5.75 (dd, J = 6.0 & 15.5 Hz, 1H) 7.1-7.4 (m, 5H)

Example 39 (11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-16,16,20-trimethyl-7-thiaprostar
Synthesis of methyl 8,13-dienoate (R ¹ = Pr, R ² = H, R ³ =
H, R ⁴ = 1,1-Dimethylhexyl, W = ^t BuMe ₂ SiO, XY = CH ₂ -CH ₂ ,
Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0228]

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Chromium (II) chloride (34)
4 mg), nickel chloride (0.3 mg), (3S, 4R) -4-
(Tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio) -3
-(Trans-2-iodovinyl) -1-cyclopentene
(418 mg), 2,2-dimethylheptane aldehyde (199
mg), the same operation as in Example 37 was performed, and (11)
R, 12S, 13E) -9-butyryloxy-11-te
rt-butyldimethylsiloxy-15-hydroxy-1
6,16,20-trimethyl-7-thiaprosta-8,
Methyl 13-dienoate (103 mg, 24%) was obtained.

Note that (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16,16,20
Methyl trimethyl-7-thiaprosta-8,13-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.05 (s, 6H) 0.85 (s, 3H) 0.88 (s, 3H) 0.90 (t, J = 7.7 Hz, 3H) 0.91 (s, 9H ) 1.1-1.8 (m, 16 H) 2.30 (t, J = 7.4 Hz, 2H) 2.3-2.7 (m, 3H) 2.42 (t, J = 7.3 Hz, 2H) 2.8-2.9 (m, 1H) 3.1- 3.2 (m, 1H) 3.67 (s, 3H) 3.83 (d-like, J = 6.9 Hz, 1H) 4.0-4.2 (m, 1H) 5.4-5.6 (m, 1H) 5.6-5.8 (m, 1H)

Example 40 (11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-16,16,20-trimethyl
Synthesis of methyl methyl 7-thiaprosta-8,13-dienoate
Formed ^{(R 1 = Pr, R 2} = H, R 3 = H, R 4 = 1,1-Dimethylhexyl, W = O
H, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0233]

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As a raw material, a hydrogen fluoride-pyridine solution
(0.25 ml), (11R, 12S, 13E) -9-butyryloxy-11-tert-butyldimethylsiloxy-15
-Hydroxy-16,16,20-trimethyl-7-thiaprosta-8,13-dienoate (100 mg) was used to carry out the same operation as in Example 2 to give (11R, 12
The two stereoisomers at the 15-position of methyl (S, 13E) -9-butyryloxy-11,15-dihydroxy-16,16,20-trimethyl-7-thiaprosta-8,13-dienoate were obtained separately ( Low polar compounds: 26 mg, 3
3%; highly polar compound: 28 mg, 35%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.85 (s, 3H) 0.8-0.9 (m, 3H) 0.88 (s, 3H) 1.00 (t, J = 7.4 Hz, 3H) 1.1-1.8 (m, 16H) 2.11 (d-like, J = 7.0 Hz, 1H) 2.31 (t, J = 7.3 Hz, 2H) 2.4-2.8 (m, 3H) 2.44 (t, J = 7.3 Hz , 2H) 2.97 (ddd, J = 1.3 & 6.3 & 16.5 Hz, 1H) 3.25 (d-like, J = 8.3 Hz, 1H) 3.67 (s, 3H) 3.8-3.9 (m, 1H) 4.1-4.2 (m , 1H) 5.58 (dd, J = 7.9 & 15.5 Hz, 1H) 5.79 (dd, J = 6.9 & 15.5 Hz, 1H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.85 (s, 3H) 0.8-0.9 (m, 3H) 0.88 (s, 3H) 1.01 (t, J = 7.4 Hz, 3H) 1.1-1.8 (m, 16H) 2.18 (d-like, J = 7.3 Hz, 1H) 2.31 (t, J = 7.3 Hz, 2H) 2.4-2.8 (m, 3H) 2.43 (t, J = 7.3 Hz , 2H) 2.97 (ddd, J = 1.3 & 6.6 & 16.5 Hz, 1H) 3.23 (d-like, J = 7.6 Hz, 1H) 3.67 (s, 3H) 3.82 (d-like, J = 6.9 Hz, 1H) 4.15 (m, 1H) 5.56 (dd, J = 7.6 & 15.5 Hz, 1H) 5.77 (dd, J = 6.7 & 15.5 Hz, 1H)

Example 41 (11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-16-methyl-16-phenyl-18,19,20-
Trinor-7-thiaprosta-8,13-dienoic acid methyl
Synthesis of Le ^{(R 1 = Pr, R 2} = H, R 3 = H, R 4 = 1-Ph-1-Me-ethyl,
W = ^t BuMe ₂ SiO, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = trans-C
H = CH)

[0238]

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As a raw material and a reagent, chromium (II) chloride (63
0 mg), nickel chloride (0.1 mg), (3S, 4R) -4-
(Tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio) -3
-(Trans-2-iodovinyl) -1-cyclopentene
(418 mg), dimethylphenylacetaldehyde (311 m
g), the same operation as in Example 37 was performed, and (1)
1R, 12S, 13E) -9-Butyryloxy-11-
tert-butyldimethylsiloxy-15-hydroxy-1
Methyl 6-methyl-16-phenyl-18,19,20-trinor-7-thiaprosta-8,13-dienoate
(214 mg, 24%).

The (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16-methyl-1
Methyl 6-phenyl-18,19,20-trinor-7-thiaprosta-8,13-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.02 (s, 3H) 0.03 (s, 3H) 0.84 (s), 0.87 (s) ... 9H 1.00 (t, J = 7.4 Hz, 3H ) 1.2-1.8 (m, 8H) 1.34 (s, 3H) 1.35 (s, 3H) 2.29 (t, J = 7.3 Hz, 2H) 2.3-2.7 (m, 3H) 2.43 (t, J = 7.3 Hz, 2H) 2.87 (ddd, J = 1.3 & 6.9 & 16.5 Hz, 1H) 3.09 (br.d, J = 7.3 Hz, 1H) 3.66 (s, 3H) 5.4-5.7 (m, 2H) 7.1-7.5 (m, 5H)

Example 42 (11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-16-methyl-16-phenyl
Ru-18,19,20-trinor-7-thiaprostar
Synthesis of methyl 8,13-dienoate (R ¹ = Pr, R ² = H, R ³ =
H, R ⁴ = 1-Ph-1-Me-ethyl, W = OH, XY = CH ₂ -CH ₂ , Z = CO ₂ Me,
n = 0, - = trans-CH = CH)

[0243]

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(11R, 12S, 13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15
-Hydroxy-16-methyl-16-phenyl-18,
19,20-trinor-7-thiaprosta-8,13-
To a solution of methyl dienoate (180 mg) in methanol (4.0 ml) was added paratoluenesulfonate of pyridine bound to the polymer (280 mg), and the mixture was stirred at 40 ° C for 2 hours. The reaction solution was filtered to remove insolubles, concentrated under reduced pressure, and purified by silica gel column chromatography (40% ethyl acetate / hexane) to give (11R, 12S, 13E) -9-butyryloxy-11,15-dihydroxy- 16-methyl-16-phenyl-18,19,20-trinor-7-
The two isomers for the configuration at position 15 of methyl thiaprosta-8,13-dienoate were obtained separately (low polar compound: 34 mg, 23%; high polar compound: 48 mg, 33%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.00 (t, J = 7.4 Hz, 3H) 1.34 (s, 3H) 1.37 (s, 3H) 1.2-1.8 (m, 8H) 1.98 (d-like, J = 7.0 Hz, 1H) 2.30 (t, J = 7.4 Hz, 2H) 2.4-2.7 (m, 3H) 2.42 (t, J = 7.4 Hz, 1H) 2.88 (ddd, J = 1.3 & 6.3 & 16.5 Hz, 1H) 3.13 (dd, J = 3.0 & 8.2 Hz, 1H) 3.66 (s, 3H) 3.9-4.0 (m, 1H) 4.1-4.3 (m, 1H) 5.46 (dd, J = 8.2 & 15.5 Hz, 1H) 5.60 (dd, J = 6.2 & 15.5 Hz, 1H) 7.1-7.5 (m, 5H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.00 (t, J = 7.4 Hz, 3H) 1.34 (s, 3H) 1.35 (s, 3H) 1.2-1.8 (m, 8H) 2.18 (br. 1H) 2.30 (t, J = 7.4 Hz, 2H) 2.4-2.7 (m, 3H) 2.43 (t, J = 7.4 Hz, 1H) 2.90 (dd, J = 6.3 & 16.5 Hz, 1H ) 3.16 (d-like, J = 7.2 Hz, 1H) 3.66 (s, 3H) 4.05 (br.1H) 4.13 (br.1H) 5.4-5.7 (m, 2H) 7.1-7.5 (m, 5H)

[Embodiment 43](11R, 12S, 13E, 16R) -9-butyryl
Xy-11-tert-butyldimethylsiloxy-15-h
Droxy-16-phenyl-18,19,20-trino
Synthesis of methyl methyl 7-thiaprosta-8,13-dienoate
Success (R¹= Pr, R ^Two= H, R^Three= H, R^Four= 1-Ph-ethyl, W =^tBuMe_TwoSi
O, X-Y = CH_Two-CH_Two, Z = CO_TwoMe, n = 0,-= trans-CH = CH)

[0248]

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Chromium (II) chloride (43)
0 mg), nickel chloride (0.1 mg), (3S, 4R) -4
-(Tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio)-
The same operation as in Example 37 was performed using 3- (trans-2-iodovinyl) -1-cyclopentene (418 mg) and (R) -methylphenylacetaldehyde (186 mg) to obtain (11R, 12S, 13E). , 16R) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15
-Hydroxy-16-phenyl-18,19,20-trinor-7-thiaprosta-8,13-dienoic acid methyl
(259 mg, 61%).

The (11R, 12S,
13E, 16R) -9-butyryloxy-11-tert-
Methyl butyldimethylsiloxy-15-hydroxy-16-phenyl-18,19,20-trinor-7-thiaprosta-8,13-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (400 MHz, δppm, CDCl ₃ ) -0.01 (s, 3H) 0.03 (s, 3H) 0.84 (s), 0.87 (s) 9H 0.98 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 11 H) 2.28 (t, J = 7.3 Hz, 2H) 2.3-3.2 (m, 6H) 2.41 (t, J = 7.3 Hz, 2H) 3.65 (s, 3H) 3.95 (m , 1H) 4.2 (m, 1H) 5.4-5.8 (m, 2H) 7.1-7.4 (m, 5H)

Example 44 (11R, 12S, 13E, 16R) -9-butyryl
Xy-11,15-dihydroxy-16-phenyl-1
8,19,20-trinor-7-thiaprosta-8,1
Synthesis of methyl 3 -dienoate (R ¹ = Pr, R ² = H, R ³ = H, R ⁴ =
1-Ph-ethyl, W = OH, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = tr
ans-CH = CH)

[0253]

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As raw materials and reagents, a hydrogen fluoride-pyridine solution (0.5 ml), (11R, 12S, 13E, 16R)
-9-butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16-phenyl-18,1
The same operation as in Example 2 was performed using methyl 9,20-trinor-7-thiaprosta-8,13-dienoate (247 mg) to give (11R, 12S, 13E, 16R) -9.
-Butyryloxy-11,15-dihydroxy-16-
Two isomers of methyl phenyl-18,19,20-trinor-7-thiaprosta-8,13-dienoate having different configurations at the 15-position were separately obtained (low polar compound: 28 m
g, 19%; highly polar compound: 109 mg, 54%).

[Low Polarity Compound] ¹ H-NMR (400 MHz, δ ppm, CDCl ₃ ) 1.00 (dt, J = 6.3 & 7.4 Hz, 3H) 1.2-1.8 (m, 8H) 1.27 (d, J = 6.8 Hz) , 3H) 2.3-3.3 (m, 8H) 2.32 (t, J = 7.3 Hz, 2H) 3.66 (s), 3.67 (s) ... 3H 3.7-4.2 (m, 2H) 5.37 (dd, J = 8.8 & 15.6 Hz, 0.5H) 5.5-5.7 (m, 1H) 5.72 (dd, J = 8.8 & 15.6 Hz, 0.5H) 7.1-7.4 (m, 5H)

[Highly Polar Compound] ¹ H-NMR (400 MHz, δppm, CDCl ₃ ) 1.01 (t, J = 7.3 Hz, 3H) 1.3-1.7 (m, 6H) 1.33 (d, J = 6.8 Hz, 3H) ) 1.74 (d, J = 7.3 Hz, 3H) 2.24 (br.1H) 2.30 (t, J = 7.3 Hz, 2H) 2.3-2.5 (m, 2H) 2.43 (t, J = 7.3 Hz, 2H) 2.58 ( dq, J = 7.8 & 6.3 Hz, 1H) 2.83 (ddd, J = 1.4 & 6.7 & 16.5 Hz, 1H) 2.91 (t-like, J = 6.5 Hz, 1H) 3.13 (br.d, J = 5.5 Hz, 1H) 3.66 (s, 3H) 3.96 (br.1H) 4.22 (br.t, J = 5.8 Hz, 1H) 5.50 (dd, J = 7.5 & 15.5 Hz, 1H) 5.58 (dd, J = 6.4 & 15.5 Hz , 1H) 7.1-7.4 (m, 5H)

[Embodiment 45](11R, 12S, 13E, 16S) -9-butyryl
Xy-11-tert-butyldimethylsiloxy-15-h
Droxy-16-phenyl-18,19,20-trino
Synthesis of methyl methyl 7-thiaprosta-8,13-dienoate
Success (R¹= Pr, R ^Two= H, R^Three= H, R^Four= 1-Ph-ethyl, W =^tBuMe_TwoSi
O, X-Y = CH_Two-CH_Two, Z = CO_TwoMe, n = 0,-= trans-CH = CH)

[0258]

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Chromium (II) chloride (78)
9 mg), nickel chloride (0.1 mg), (3S, 4R) -4-
(Tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio) -3
-(Trans-2-iodovinyl) -1-cyclopentene
(418 mg), (S) -methylphenylacetaldehyde
(186 mg), and the same operation as in Example 37 was performed.
Methyl (11R, 12S, 13E, 16S) -9-butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16-phenyl-18,19,20-trinor-7-thiaprosta-8,13-dienoate ( 27
6 mg, 65%).

The (11R, 12S,
13E, 16S) -9-Butyryloxy-11-tert-
Methyl butyldimethylsiloxy-15-hydroxy-16-phenyl-18,19,20-trinor-7-thiaprosta-8,13-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (400 MHz, δppm, CDCl ₃ ) 0.00 (s, 6H) 0.86 (s, 9H) 1.00 (t, J = 7.5 Hz, 3H) 1.2-1.8 (m, 8H) 1.51 (d , J = 1.0 Hz, 3H) 2.29 (t, J = 7.3 Hz, 2H) 2.3-3.2 (m, 6H) 2.42 (t, J = 7.3 Hz, 2H) 3.66 (s, 3H) 3.97 (m, 1H) 4.23 (m, 1H) 5.47 (m, 1H) 5.5-5.8 (m, 1H) 7.1-7.4 (m, 5H)

Example 46 (11R, 12S, 13E, 16S) -9-butyryl
Xy-11,15-dihydroxy-16-phenyl-1
8,19,20-trinor-7-thiaprosta-8,1
Synthesis of methyl 3 -dienoate (R ¹ = Pr, R ² = H, R ³ = H, R ⁴ =
1-Ph-ethyl, W = OH, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = tr
ans-CH = CH)

[0263]

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As a raw material and a reagent, a hydrogen fluoride-pyridine solution (0.5 ml), (11R, 12S, 13E, 16S)
-9-butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16-phenyl-18,1
The same operation as in Example 2 was performed using methyl 9,20-trinor-7-thiaprosta-8,13-dienoate (270 mg) to obtain (11R, 12S, 13E, 16S) -9-
Two isomers of methyl butyryloxy-11,15-dihydroxy-16-phenyl-18,19,20-trinor-7-thiaprosta-8,13-dienoate having different configurations at the 15-position were separately obtained (low Polar compound: 142 m
g, 64%; highly polar compound: 38 mg, 17%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.00 (t, J = 7.3 Hz, 3H) 1.3-1.8 (m, 8H) 1.36 (d, J = 7.0 Hz, 3H) ) 1.85 (br. 1H) 2.30 (t, J = 7.3 Hz, 2H) 2.3-2.7 (m, 3H) 2.41 (t, J = 7.3 Hz, 2H) 2.7-2.9 (m, 2H) 3.07 (dd, J = 3.0 & 8.6 Hz, 1H) 3.67 (s, 3H) 3.78 (br.1H) 4.19 (t-like, J = 5.0 Hz, 1H) 5.37 (dd, J = 8.2 & 15.5 Hz, 1H) 5.58 (dd, J = 6.6 & 15.5 Hz, 1H) 7.1-7.4 (m, 5H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.3 Hz, 3H) 1.2-1.8 (m, 8H) 1.26 (d, J = 7.0 Hz, 3H ) 2.31 (t, J = 7.4 Hz, 2H) 2.3-3.0 (m, 5H) 2.44 (t, J = 7.3 Hz, 2H) 3.1-3.3 (m, 1H) 3.66 (s, 3H) 4.0-4.3 (m , 2H) 5.4-5.8 (m, 2H) 7.1-7.4 (m, 5H)

Example 47 (11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-16,16-diphenyl-17,18,19,20-
Tetranor-7-thiaprosta-8,13-dienoic acid
Synthesis of tyl (R ¹ = Pr, R ² = H, R ³ = H, R ⁴ = Benzhydryl, W =
^t BuMe ₂ SiO, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = trans-CH =
CH)

[0268]

Embedded image

Chromium (II) chloride (55)
0 mg), nickel chloride (0.3 mg), (3S, 4R) -4-
(Tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio) -3
-(Trans-2-iodovinyl) -1-cyclopentene
(418 mg) and diphenylacetaldehyde (275 mg), and the same operation as in Example 37 was performed.
S, 13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16,16-
Diphenyl-17,18,19,20-tetranor-7
-Methyl thiaprosta-8,13-dienoate (137 mg,
29%).

The (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16,16-diphenyl-17,18,19,20-tetranor-7-thiaprosta-8,13-dienoic acid methyl It is a diastereomeric mixture for the configuration of the hydroxyl group.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) -0.04 (s, 3H) -0.03 (s, 3H) 0.84 (d, J = 3.0 Hz, 9H) 1.26 (t, J = 7.1 Hz, 3H) 1.3-1.8 (m, 9H) 2.2-2.9 (m, 8H) 3.01 (br.d, J = 6.6 Hz, 1H) 3.67 (s, 3H) 3.8-4.1 (m, 2H) 4.8-5.0 (m , 1H) 5.4-5.8 (m, 2H) 7.1-7.4 (m, 10H)

Example 48 (11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-16,16-diphenyl-1
7,18,19,20-tetranor-7-thiaprosta
Synthesis of methyl -8,13-dienoate (R ¹ = Pr, R ² = H, R
³ = H, R ⁴ = Benzhydryl, W = OH, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n =
0, - = trans-CH = CH)

[0273]

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As a raw material and a reagent, a hydrogen fluoride-pyridine solution (0.25 ml), (11R, 12S, 13E) -9-butyryloxy-11-tert-butyldimethylsiloxy-
15-hydroxy-16,16-diphenyl-17,1
8,19,20-tetranor-7-thiaprosta-8,
The same operation as in Example 2 was performed using methyl 13-dienoate (137 mg) to give (11R, 12S, 13E) -9-
Butyryloxy-11,15-dihydroxy-16,1
15-Methyl 6-diphenyl-17,18,19,20-tetranor-7-thiaprosta-8,13-dienoate
Two isomers having different configurations at different positions were obtained separately (low-polarity compound: 31 mg, 27%; high-polarity compound: 32 mg, 28)
%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 0.99 (t, J = 7.2 Hz, 3H) 1.3-1.9 (m, 8H) 2.29 (t, J = 7.2 Hz, 2H ) 2.2-2.8 (m, 5H) 2.41 (t, J = 7.3 Hz, 1H) 3.04 (ddd, J = 1.4 & 3.6 & 8.6 Hz, 1H) 3.66 (s, 3H) 3.99 (d, J = 8.9 Hz, 1H) 4.8-5.0 (m, 1H) 5.45 (dd, J = 8.5 & 15.4 Hz, 1H) 5.64 (dd, J = 6.6 & 15.4 Hz, 1H) 7.1-7.5 (m, 10H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.00 (t, J = 7.3 Hz, 3H) 1.2-1.9 (m, 8H) 2.28 (t, J = 7.3 Hz, 2H ) 2.1-2.5 (m, 4H) 2.42 (t, J = 7.2 Hz, 2H) 2.73 (dd, J = 6.5 & 16.5 Hz, 1H) 3.08 (d-like, J = 5.0 Hz, 1H) 3.66 (s, 3H) 3.8-3.9 (br.1H) 3.99 (d, J = 8.0 Hz, 1H) 4.8-4.9 (m, 1H) 5.63 (t-like, J = 5.3 Hz, 2H) 7.1-7.4 (m, 10H)

Example 49 (11R, 12S, 13E, 15S, 17R) -9-B
Tyryloxy-11,15-bis (tert-butyl dimethyl
Lucyloxy) -17,20-dimethyl-3-oxa-7
Synthesis of Methyl Thiaprosta-8,13-dienoate
(R ¹ = Pr, R ² = ^t BuMe ₂ Si, R ³ = H, R ⁴ = 2-Me-hexyl, W = ^t BuMe
₂ SiO, XY = O-CH ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0278]

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As raw materials and reagents, (1E, 3S, 5R)
-1-Iodo-3- (tert-butyldimethylsiloxy)
-5-methyl-1-nonene (476 mg, 1.2 mmol), tert
-Butyl lithium (1.54 mol / l, 1.56 ml, 2.4 mmo
l), Hexin copper (174 mg), hexamethylphosphorous triamide (436 μl), (4R) -4- (tert-butyldimethylsiloxy) -2- (5-methoxycarbonyl-4)
-Oxa-pentylthio) -2-cyclopentene-1-
The same operation as in Example 1 was performed using ON (375 mg, 1.0 mmol) and butyric anhydride (441 μl) to obtain (11R, 12S,
13E, 15S, 17R) -9-butyryloxy-1
1,15-bis (tert-butyldimethylsiloxy) -1
7,20-dimethyl-3-oxa-7-thiaprostar
Methyl 8,13-dienoate (524 mg, 73%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s), 0.05 ... 12H 0.8-1.0 (m, 6H) 0.87 (s, 9H) 0.89 (s, 9H) 1.00 (t, J = 7.3 Hz, 3H) 1.0-1.9 (m, 13H) 2.3-2.5 (m, 1H) 2.42 (t, J = 7.4 Hz, 2H) 2.5-2.8 (m, 2H) 2.92 (dd, J = 6.8 & 16.3 Hz, 1H) 3.13 (d, J = 6.3 Hz, 1H) 3.5-3.6 (m, 2H) 3.75 (s, 3H) 4.07 (s, 2H) 4.1-4.2 (m, 1H) 5.43 (dd, J = 8.6 & 15.5 Hz, 1H) 5.63 (dd, J = 6.1 & 15.3 Hz, 1H)

[Example 50] (11R, 12S, 13E, 15S, 17R) -9-B
Tyryloxy-11,15-dihydroxy-17,20
-Dimethyl-3-oxa-7-thiaprosta-8,13
-Synthesis of methyl dienoate (R ¹ = Pr, R ² = H, R ³ = H, R ⁴ = 2-
Me-hexyl, W = OH, XY = O-CH ₂ , Z = CO ₂ Me, n = 0, - = trans-
CH = CH)

[0282]

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A solution of hydrogen fluoride in pyridine (50 μl) was added to an ice-cooled solution of acetonitrile (0.5 ml) and pyridine (50 μl).
l) and (11R, 12S, 13E, 15S, 17
R) -9-Butyryloxy-11,15-bis (tert-
Butyldimethylsiloxy) -17,20-dimethyl-3
A solution of methyl-oxa-7-thiaprosta-8,13-dienoate (52 mg) in pyridine (50 μl) was added. The ice bath was removed, and the mixture was stirred at room temperature for 20 hours. The reaction solution was poured into a mixture of ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate. The desired product was extracted from the mixture with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, preparative TLC
(Merck TLC plate silica gel 60 F ₂₅₄ , 20 × 20 cm, l
ayer thickness 0.25 mm, 3 plates, purified by ethyl acetate: hexane = 4: 1) and purified by (11R, 12S, 13E, 15)
(S, 17R) -9-Butyryloxy-11,15-dihydroxy-17,20-dimethyl-3-oxa-7-thiaprosta-8,13-dienoic acid methyl ester (22 mg, 63
%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.8-1.0 (m, 6H) 1.00 (t, J = 7.4 Hz, 3H) 1.0-1.9 (m, 13 H) 2.4-2.6 (m, 1H) 2.43 (t, J = 7.3 Hz, 2H) 2.6-2.9 (m, 2H) 2.92 (dd, J = 6.6 & 16.5 Hz, 1H) 3.27 (d, J = 8.2 Hz, 1H) 3.5-3.7 (m , 2H) 3.75 (s, 3H) 4.07 (s, 2H) 4.1-4.3 (m, 1H) 5.58 (dd, J = 8.1 & 15.3 Hz, 1H) 5.72 (dd, J = 6.1 & 15.3 Hz, 1H)

Example 51 (11R, 12S, 13E, 15S) -9-butyryl
Xy-11,15-bis (tert-butyldimethylsiloxy)
B) -16-phenyl-17,18,19,20-tetra
Lanor-3-oxa-7-thiaprosta-8,13-di
Synthesis of methyl enoate (R ¹ = Pr, R ² = ^t BuMe ₂ Si, R ³ = H, R ⁴
= Benzyl, W = ^t BuMe ₂ SiO, XY = O-CH ₂ , Z = CO ₂ Me, n = 0, - =
trans-CH = CH)

[0286]

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As a raw material and a reagent, (1E, 3S) -1-
Iodo-3- (tert-butyldimethylsiloxy) -4-
Phenyl-1-butene (466 mg, 1.2 mmol), tert-butyllithium (1.54 mol / l, 1.56 ml, 2.4 mmol), copper hexine (174 mg), hexamethylphosphorous triamide
(436 μl), (4R) -4- (tert-butyldimethylsiloxy) -2- (5-methoxycarbonyl-4-oxa-
(Pentylthio) -2-cyclopenten-1-one (375
mg, 1.0 mmol) and butyric anhydride (442 μl), and the same operation as in Example 1 was performed to obtain (11R, 12S, 13E, 1E).
5S) -9-butyryloxy-11,15-bis (tert
-Butyldimethylsiloxy) -16-phenyl-17,
Methyl 18,19,20-tetranor-3-oxa-7-thiaprosta-8,13-dienoate (238 mg, 34%)
I got

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s, 12H) 0.83 (s, 9H) 0.87 (s, 9H) 1.00 (t, J = 7.4 Hz, 3H) 1.6-2.0 (m , 4H) 2.3-2.5 (m, 1H) 2.43 (t, J = 7.3 Hz, 2H) 2.5-3.0 (m, 2H) 3.11 (br.d, J = 6.6 Hz, 1H) 3.5-3.7 (m, 2H) ) 3.74 (s, 3H) 4.0-4.2 (m, 1H) 4.06 (s, 2H) 4.27 (dt, J = 5.9 & 5.9 Hz, 1H) 5.47 (dd, J = 8.4 & 16.3 Hz, 1H) 5.65 (dd , J = 5.6 & 15.5 Hz, 1H) 7.1-7.3 (m, 5H)

Example 52 (11R, 12S, 13E, 15S) -9-butyryl
Xy-11,15-dihydroxy-16-phenyl-1
7,18,19,20-tetranor-3-oxa-7-
Synthesis of methyl thiaprosta-8,13-dienoate (R ¹
= Pr, R ² = H, R ³ = H, R ⁴ = Benzyl, W = OH, XY = O-CH ₂ , Z = CO ₂
Me, n = 0, - = trans-CH = CH)

[0290]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.25 ml), (11R, 12S, 13E, 15
S) -9-Butyryloxy-11,15-bis (tert-
Butyldimethylsiloxy) -16-phenyl-17,1
Using methyl 8,19,20-tetranor-3-oxa-7-thiaprosta-8,13-dienoate (238 mg),
The same operation as in Example 2 was performed, and (11R, 12S, 13
E, 15S) -9-Butyryloxy-11,15-dihydroxy-16-phenyl-17,18,19,20-
Tetranor-3-oxa-7-thiaprosta-8,13
-Methyl dienoate (122 mg, 76%) was obtained.

¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.5-1.9 (m, 4H) 2.3-2.5 (m, 1H) 2.44 (t, J = 7.3 Hz, 2H) 2.6-3.0 (m, 5H) 3.26 (br.d, J = 8.3 Hz, 1H) 3.58 (dt, J = 1.4 & 5.9 Hz, 2H) 3.74 (s, 3H) 4.0-4.2 (m , 1H) 4.06 (s, 2H) 4.37 (dt, J = 6.3 & 6.6 Hz, 1H) 5.57 (dd, J = 8.1 & 15.3 Hz, 1H) 5.72 (dd, J = 5.9 & 15.5 Hz, 1H) 7.2- 7.4 (m, 5H)

[Example 53] (2E, 11R, 12S, 13E, 15S, 17R)
9-butyryloxy-11,15-bis (tert-butyl
Dimethylsiloxy) -17,20-dimethyl-7-thia
Synthesis of Prosta-2,8,13-methyl trienoate
(R ¹ = Pr, R ² = ^t BuMe ₂ Si, R ³ = H, R ⁴ = 2-Me-hexyl, W = ^t BuMe
₂ SiO, XY = trans-CH = CH, Z = CO ₂ Me, n = 0, - = trans-CH = C
H)

[0294]

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As raw materials and reagents, (1E, 3S, 5R)
-1-Iodo-3- (tert-butyldimethylsiloxy)
-5-methyl-1-nonene (476 mg, 1.2 mmol), tert
-Butyl lithium (1.54 mol / l, 1.56 ml, 2.4 mmo
l), hexine copper (174 mg), hexamethylphosphorustriamide (436 μl), (4R) -4- (tert-butyldimethylsiloxy) -2- (5-methoxycarbonyl-4)
-Trans-pentenylthio) -2-cyclopentene-1-
(2E, 11R, 1 mmol) in the same manner as in Example 1 using ON (371 mg, 1.0 mmol) and butyric anhydride (442 μl).
2S, 13E, 15S, 17R) -9-butyryloxy-11,15-bis (tert-butyldimethylsiloxy)
-17,20-dimethyl-7-thiaprosta-2,8,
Methyl 13-trienoate (232 mg, 33%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.03 (s), 0.05 ... 12H 0.8-1.0 (m, 6H) 0.87 (s, 9H) 0.89 (s, 9H) 1.00 (t, J = 7.4 Hz, 3H) 1.0-1.8 (m, 13H) 2.2-2.6 (m, 4H) 2.42 (t, J = 7.4 Hz, 2H) 2.6-2.8 (m, 1H) 2.92 (ddd, J = 1.3 & 6.6 & 16.5 Hz, 1H) 3.10 (d, J = 8.6 Hz, 1H) 3.72 (s, 3H) 4.1-4.2 (m, 2H) 5.42 (dd, J = 8.6 & 15.5 Hz, 1H) 5.61 (dd, J = 5.9 & 15.5 Hz, 1H) 5.83 (d, J = 15.5 Hz, 1H) 6.92 (dt, J = 15.5 & 6.9 Hz

[Embodiment 54](2E, 11R, 12S, 13E, 15S, 17R)-
9-butyryloxy-11,15-dihydroxy-1
7,20-dimethyl-7-thiaprosta-2,8,13
-Synthesis of methyl trienoate (R¹= Pr, R^Two= H, R^Three= H, R^Four=
2-Me-hexyl, W = OH, X-Y = trans-CH = CH, Z = CO_TwoMe, n = 0,-
= trans-CH = CH)

[0298]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.2 ml), (2E, 11R, 12S, 13E,
15S, 17R) -9-butyryloxy-11,15-
Bis (tert-butyldimethylsiloxy) -17,20-
The same operation as in Example 2 was carried out using methyl dimethyl-7-thiaprosta-2,8,13-trienoate (232 mg) to obtain (2E, 11R, 12S, 13E, 15S, 17).
R) -9-Butyryloxy-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-2,8,
Methyl 13-trienoate (145 mg, 92%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.8-1.0 (m, 6H) 1.01 (t, J = 7.4 Hz, 3H) 1.1-1.4 (m, 6H) 1.4-1.8 (m, 7H) ) 2.2-2.8 (m, 5H) 2.44 (t, J = 7.4 Hz, 2H) 2.96 (dd, J = 6.3 & 17.2 Hz, 1H) 3.20 (d, J = 5.9 Hz, 1H) 3.71 (s, 3H) 4.1-4.3 (m, 2H) 5.57 (dd, J = 8.1 & 15.3 Hz, 1H) 5.70 (dd, J = 5.9 & 15.5 Hz, 1H) 5.85 (d, J = 15.5 Hz, 1H) 6.92 (dt, J = 15.8 & 7.1 Hz, 1H)

Example 55 (11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-16- (3-chlorophenyl) -17,18,19,
20-tetranor-7-thiaprosta-8,13-die
Synthesis of methyl phosphate (R ¹ = Pr, R ² = ^t BuMe ₂ Si, R ³ = H, R ⁴ = 3
-Chlorobenzyl, W = ^t BuMe ₂ SiO, XY = CH ₂ -CH ₂ , Z = CO ₂ Me,
n = 0, - = trans-CH = CH)

[0302]

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Chromium (II) chloride (100
mg), nickel chloride (0.1 mg), (3S, 4R) -4-
(Tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio) -3
-(Trans-2-iodovinyl) -1-cyclopentene
(76 mg), 3-chlorophenylacetaldehyde (50 m
g), the same operation as in Example 37 is performed, and (11)
R, 12S, 13E) -9-butyryloxy-11-te
rt-butyldimethylsiloxy-15-hydroxy-16
-(3-chlorophenyl) -17,18,19,20-
Methyl tetranor-7-thiaprosta-8,13-dienoate (14 mg, 14%) was obtained.

Incidentally, the obtained (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (3-chlorophenyl) -17,18,19,20-tetranor-
Methyl 7-thiaprosta-8,13-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.03 (s), 0.03 (s) 6H 0.87 (s, 9H) 1.01 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m , 8 H) 2.30 (t, J = 7.4 Hz, 2H) 2.3-2.8 (m, 3H) 2.43 (t, J = 7.4 Hz, 2H) 2.8-3.0 (m, 3H) 3.0-3.2 (m, 1H) 3.66 (s, 3H) 4.0-4.1 (m, 1H) 4.3-4.4 (m, 1H) 5.56 (dd, J = 8.4 & 15.3 Hz, 1H) 5.6-5.8 (m, 1H) 7.0-7.4 (m, 4H) )

[Embodiment 56](11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-16- (3-chlorophenyi
Le) -17,18,19,20-tetranor-7-thia
Synthesis of methyl prostar-8,13-dienoate (R¹= Pr,
 R^Two= H, R^Three= H, R^Four= 3-Chlorobenzyl, W = OH, X-Y = CH_Two-CH_Two,
 Z = CO_TwoMe, n = 0,-= trans-CH = CH)

[0307]

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As a raw material and a reagent, a hydrogen fluoride-pyridine solution (0.1 ml), (11R, 12S, 13E) -9-butyryloxy-11-tert-butyldimethylsiloxy-
15-hydroxy-16- (3-chlorophenyl) -1
The same operation as in Example 2 was performed using methyl 7,18,19,20-tetranor-7-thiaprosta-8,13-dienoate (14 mg) to obtain (11R, 12S, 13E)-
9-butyryloxy-11,15-dihydroxy-16
-(3-chlorophenyl) -17,18,19,20-
The two isomers for the configuration at position 15 of methyl tetranor-7-thiaprosta-8,13-dienoate were obtained separately (low polar compound: 4 mg, 35%; high polar compound: 4
mg, 35%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 8H) 2.31 (t, J = 7.3 Hz, 2H) 2.3-2.8 (m, 3H) 2.43 (t, J = 7.3 Hz, 2H) 2.8-3.0 (m, 3H) 3.20 (d, J = 6.6 Hz, 1H) 3.66 (s, 3H) 4.0-4.1 ( m, 1H) 4.36 (dt, J = 6.3 & 6.3 Hz, 1H) 5.51 (dd, J = 8.3 & 15.5 Hz, 1H) 5.74 (dd, J = 6.6 & 15.8 Hz, 1H) 7.0-7.3 (m, 4H )

[Highly Polar Compound] ¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 8H) 2.31 (t, J = 7.4 Hz, 2H) 2.4-2.7 (m, 3H) 2.44 (t, J = 7.4 Hz, 2H) 2.83 (d, J = 6.9 Hz, 2H) 2.93 (ddd, J = 1.3 & 6.3 & 16.5 Hz, 1H) 3.20 (d , J = 7.9 Hz, 1H) 3.66 (s, 3H) 4.0-4.1 (m, 1H) 4.37 (dt, J = 6.3 & 5.9 Hz, 1H) 5.56 (dd, J = 7.9 & 15.2 Hz, 1H) 5.74 ( dd, J = 6.3 & 15.5 Hz, 1H) 7.0-7.2 (m, 1H) 7.2-7.3 (m, 3H)

Example 57 (11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-16- (4-chlorophenyl) -17,18,19,
20-tetranor-7-thiaprosta-8,13-die
Synthesis of methyl phosphate (R ¹ = Pr, R ² = ^t BuMe ₂ Si, R ³ = H, R ⁴ = 4
-Chlorobenzyl, W = ^t BuMe ₂ SiO, XY = CH ₂ -CH ₂ , Z = CO ₂ Me,
n = 0, - = trans-CH = CH)

[0312]

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Chromium (II) chloride (307) was used as a raw material and a reagent.
mg), nickel chloride (0.1 mg), (3S, 4R) -4-
(Tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio) -3
-(Trans-2-iodovinyl) -1-cyclopentene
(235 mg), 4-chlorophenylacetaldehyde (155
The same operation as in Example 37 was carried out using
1R, 12S, 13E) -9-Butyryloxy-11-
tert-butyldimethylsiloxy-15-hydroxy-1
6- (4-chlorophenyl) -17,18,19,20
-Methyl tetranor-7-thiaprosta-8,13-dienoate (191 mg, 61%) was obtained.

Note that the obtained (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (4-chlorophenyl) -17,18,19,20-tetranor-
Methyl 7-thiaprosta-8,13-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 0.03 (s), 0.03 (s) 6H 0.87 (s, 9H) 1.01 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m , 8 H) 2.30 (t, J = 7.4 Hz, 2H) 2.3-2.7 (m, 3H) 2.43 (t, J = 7.3 Hz, 2H) 2.7-3.0 (m, 3H) 3.12 (br.d, J = 8.3 Hz, 1H) 3.66 (s, 3H) 4.0-4.1 (m, 1H) 4.3-4.4 (m, 1H) 5.55 (dd, J = 8.3 & 15.5 Hz, 1H) 5.6-5.8 (m, 1H) 7.1- 7.3 (m, 4H)

[Example 58](11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-16- (4-chlorophenyl
Le) -17,18,19,20-tetranor-7-thia
Synthesis of methyl prostar-8,13-dienoate (R¹= Pr,
 R^Two= H, R^Three= H, R^Four= 4-Chlorobenzyl, W = OH, X-Y = CH_Two-CH_Two,
 Z = CO_TwoMe, n = 0,-= trans-CH = CH)

[0317]

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As a raw material and a reagent, a hydrogen fluoride-pyridine solution (0.2 ml), (11R, 12S, 13E) -9-butyryloxy-11-tert-butyldimethylsiloxy-
15-hydroxy-16- (4-chlorophenyl) -1
The same operation as in Example 2 was carried out using methyl 7,18,19,20-tetranor-7-thiaprosta-8,13-dienoate (191 mg) to give (11R, 12S, 13E)
-9-butyryloxy-11,15-dihydroxy-1
6- (4-chlorophenyl) -17,18,19,20
The two isomers for the configuration at position 15 of methyl-tetranor-7-thiaprosta-8,13-dienoate were obtained separately (low-polarity compound: 64 mg, 41%; high-polarity compound: 52 mg, 33 %).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 8H) 2.31 (t, J = 7.3 Hz, 2H) 2.4-2.8 (m, 3H) 2.44 (t, J = 7.4 Hz, 2H) 2.82 (d, J = 6.6 Hz, 2H) 2.92 (dd, J = 5.3 & 16.5 Hz, 1H) 3.19 (d, J = 7.6 Hz, 1H) 3.66 (s, 3H) 4.0-4.1 (m, 1H) 4.34 (dt, J = 6.2 & 6.6 Hz, 1H) 5.53 (dd, J = 8.1 & 15.7 Hz, 1H) 5.74 (dd, J = 5.9 & 15.5 Hz, 1H) 7.15 (d, J = 8.3 Hz, 2H) 7.26 (d, J = 8.3 Hz, 2H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 8H) 2.31 (t, J = 7.3 Hz, 2H) 2.4-2.7 (m, 3H) 2.44 (t, J = 7.4 Hz, 2H) 2.8-2.9 (m, 2H) 2.92 (dd, J = 6.3 & 16.8 Hz, 1H) 3.20 (br.d, J = 7.9 Hz, 1H) 3.66 (s, 3H) 4.0-4.2 (m, 1H) 4.34 (dt, J = 6.3 & 6.6 Hz, 1H) 5.56 (dd, J = 7.9 & 15.5 Hz, 1H) 5.73 (dd, J = 5.8 & 15.7 Hz, 1H) 7.16 (d, J = 8.3 Hz, 2H) 7.26 (d, J = 8.3 Hz, 2H)

Example 59 (11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-16- (4-nitrophenyl) -17,18,19,
20-tetranor-7-thiaprosta-8,13-die
Synthesis of methyl phosphate (R ¹ = Pr, R ² = ^t BuMe ₂ Si, R ³ = H, R ⁴ = 4
-Nitrobenzyl, W = ^t BuMe ₂ SiO, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n
= 0, - = trans-CH = CH)

[0322]

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As a raw material and a reagent, chromium (II) chloride (135)
mg), nickel chloride (0.1 mg), (3S, 4R) -4-
(Tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio) -3
-(Trans-2-iodovinyl) -1-cyclopentene
(103 mg), 4-nitrophenylacetaldehyde (73 m
g), the same operation as in Example 37 is performed, and (11)
R, 12S, 13E) -9-butyryloxy-11-te
rt-butyldimethylsiloxy-15-hydroxy-16
-(4-nitrophenyl) -17,18,19,20-
Methyl tetranor-7-thiaprosta-8,13-dienoate (17 mg, 12%) was obtained.

Note that the obtained (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (4-nitrophenyl) -17,18,19,20-tetranor-
Methyl 7-thiaprosta-8,13-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.02 (s), 0.03 (s) 6H 0.87 (s, 9H) 1.01 (t, J = 6.3 Hz, 3H) 1.2-1.8 (m , 8 H) 2.30 (t, J = 7.3 Hz, 2H) 2.3-2.7 (m, 3H) 2.43 (t, J = 6.9 Hz, 2H) 2.8-3.2 (m, 4H) 3.66 (s, 3H) 4.0- 4.2 (m, 1H) 4.3-4.5 (m, 1H) 5.3-5.8 (m, 2H) 7.40 (d, J = 8.9 Hz, 2H) 8.1-8.3 (m, 2H)

[Example 60](11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-16- (4-nitrophenyi
Le) -17,18,19,20-tetranor-7-thia
Synthesis of methyl prostar-8,13-dienoate (R¹= Pr,
 R^Two= H, R^Three= H, R^Four= 4-Nitrobenzyl, W = OH, X-Y = CH_Two-CH_Two,
Z = CO_TwoMe, n = 0,-= trans-CH = CH)

[0327]

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As a raw material and a reagent, a hydrogen fluoride-pyridine solution (0.1 ml), (11R, 12S, 13E) -9-butyryloxy-11-tert-butyldimethylsiloxy-
15-hydroxy-16- (4-nitrophenyl) -1
The same operation as in Example 2 was carried out using methyl 7,18,19,20-tetranor-7-thiaprosta-8,13-dienoate (17 mg) to give (11R, 12S, 13E)-
9-butyryloxy-11,15-dihydroxy-16
-(4-nitrophenyl) -17,18,19,20-
The two isomers for the configuration at position 15 of methyl tetranor-7-thiaprosta-8,13-dienoate were obtained separately (low polarity compound: 6 mg, 44%; high polarity compound: 5).
mg, 38%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 8H) 2.31 (t, J = 7.3 Hz, 2H) 2.4-2.8 (m, 3H) 2.44 (t, J = 7.4 Hz, 2H) 2.8-3.0 (m, 1H) 2.96 (d, J = 6.3 Hz, 2H) 3.20 (br.d, J = 6.9 Hz , 1H) 3.66 (s, 3H) 4.0-4.1 (m, 1H) 4.41 (dt, J = 6.2 & 6.6 Hz, 1H) 5.56 (dd, J = 7.9 & 16.2 Hz, 1H) 5.76 (dd, J = 6.4 & 15.4 Hz, 1H) 7.40 (d, J = 8.9 Hz, 2H) 8.15 (d, J = 8.6 Hz, 2H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 8H) 2.31 (t, J = 7.4 Hz, 2H) 2.4-2.8 (m, 3H) 2.44 (t, J = 7.4 Hz, 2H) 2.8-3.0 (m, 1H) 2.96 (d, J = 6.6 Hz, 2H) 3.20 (br.d, J = 7.3 Hz , 1H) 3.66 (s, 3H) 4.0-4.2 (m, 1H) 4.42 (dt, J = 6.3 & 6.6 Hz, 1H) 5.58 (dd, J = 7.9 & 15.1 Hz, 1H) 5.75 (dd, J = 6.3 & 15.5 Hz, 1H) 7.40 (d, J = 8.6 Hz, 2H) 8.15 (d, J = 8.6 Hz, 2H)

Example 61 (11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-15-phenyl-16,17,18,19,20-pe
Methanol-7-thiaprosta-8,13-dienoic acid methyl ester
Synthesis of Le ^{(R 1 = Pr, R 2} = H, R 3 = H, R 4 = Ph, W = t BuMe 2 SiO,
(XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0332]

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As the raw materials and reagents, (3S, 4R)-
4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio)
As in Example 37, using -3- (trans-2-iodovinyl) -1-cyclopentene (323 mg), chromium (II) chloride (325 mg), nickel chloride (0.1 mg), and benzaldehyde (115 mg). (11R, 12)
S, 13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-15-phenyl-16,17,18,19,20-pentanor-7-
Methyl thiaprosta-8,13-dienoate (188 mg, 6
0%).

Note that the (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-15-phenyl-
Methyl 16,17,18,19,20-pentanor-7-thiaprosta-8,13-dienoate is a diastereomeric mixture for the configuration of the hydroxyl group at position 15.

¹ H-NMR (270 MHz, δppm, CDCl ₃ )-0.07 (s, 3 / 2H)-0.03 (s, 3 / 2H) 0.02 (s, 3 / 2H) 0.03 (s, 3 / 2H) 0.81 (s, 9 / 2H) 0.86 (s, 9 / 2H) 1.00 (t, J = 6.6 Hz, 3H) 1.2-1.8 (m, 8H) 1.9-2.08 (m, 1 / 2H) 2.2-2.7 (m , 7H) 2.8-2.92 (m, 1H) 3.15-3.25 (m, 1H) 3.66 (s, 3H) 4.1-4.24 (m, 1H) 5.17-5.28 (m, 1H) 5.62-5.74 (m, 1H) 5.82 -5.95 (m, 1H) 7.25-7.45 (m, 5H)

[Example 62](11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-15-phenyl-16,1
7,18,19,20-pentanor-7-thiaprosta
Synthesis of methyl -8,13-dienoate (R¹= Pr, R^Two= H, R
^Three= H, R^Four= Ph, W = OH, X-Y = CH_Two-CH_Two, Z = CO_TwoMe, n = 0,-= tra
ns-CH = CH)

[0337]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.4 ml), (11R, 12S, 13E) -9-
Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-15-phenyl-16,17,1
8,19,20-pentanor-7-thiaprosta-8,
The same operation as in Example 2 was performed using methyl 13-dienoate (185 mg) to give (11R, 12S, 13E) -9.
-Butyryloxy-11,15-dihydroxy-15-
Methyl phenyl-16,17,18,19,20-pentanor-7-thiaprosta-8,13-dienoate (129
mg, 90%).

Incidentally, the obtained (11R, 12S,
13E) -9-Butyryloxy-11,15-dihydroxy-15-phenyl-16,17,18,19,20
Methyl -pentanor-7-thiaprosta-8,13-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 1.00 (t, J = 7.3 Hz, 3H) 1.2-1.8 (m, 8H) 2.1-2.75 (m, 7H) 2.9-3.03 (m, 1H ) 3.22-3.29 (m, 1H) 3.66 (s, 3H) 4.15-4.24 (br, 1H) 5.19-5.27 (m, 1H) 5.65-5.78 (m, 1H) 5.85-5.98 (m, 1H) 7.25-7.42 (m, 5H)

Example 63 (11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-18-phenyl-19,20-dinor-7-thiapro
Synthesis of methyl star 8,13-dienoate (R ¹ = Pr, R ² =
H, R ³ = H, R ⁴ = Phenylpropyl, W = ^t BuMe ₂ SiO, XY = CH ₂ -C
H ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0342]

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(3S, 4R)-
4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio)
-3- (trans-2-iodovinyl) -1-cyclopentene (433 mg), chromium (II) chloride (440 mg), nickel chloride (0.1 mg) and 4-phenyl-butyraldehyde (2 mg)
20 mg) and the same operation as in Example 37 was performed.
(11R, 12S, 13E) -9-butyryloxy-1
Methyl 1-tert-butyldimethylsiloxy-15-hydroxy-18-phenyl-19,20-dinor-7-thiaprosta-8,13-dienoate (325 mg, 72%) was obtained.

Incidentally, the (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-18-phenyl-
Methyl 19,20-dinor-7-thiaprosta-8,13-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (270 MHz, δppm, CDCl ₃ )-0.02 (s, 3H) 0.01 (s, 3H) 0.83 (s), 0.84 (s) 9H 0.97 (t, J = 7.5 Hz, 3H) 1.25-1.8 (m, 10H) 2.25 (dt, J = 7.5 & 1.6 Hz, 2H) 2.39 (t, J = 7.4 Hz, 2H) 2.4-2.65 (m, 5H) 2.83 (ddd, J = 16.2 & 6.9 & 1.3 Hz, 1H) 3.11 (dd, J = 8.2 & 3.6 Hz, 1H) 3.63 (s, 3H) 4.0-4.18 (m, 2H) 5.50 (ddd, J = 15.9 & 8.6 & 3.0 Hz, 1H) 5.64 (dd, J = 15.9 & 5.9 Hz, 1H) 7.08-7.3 (m, 5H)

[Example 64](11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-18-phenyl-19,20
-Dinor-7-thiaprosta-8,13-dienoic acid methyl
Synthesis (R¹= Pr, R^Two= H, R^Three= H, R^Four= Phenylpropyl, W =
OH, X-Y = CH_Two-CH _Two, Z = CO_TwoMe, n = 0,-= trans-CH = CH)

[0347]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.5 ml), (11R, 12S, 13E) -9-
Methyl butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-18-phenyl-19,20-dinor-7-thiaprosta-8,13-dienoate
(305 mg), and the same operation as in Example 2 was performed.
(11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-18-phenyl-19,20
The two isomers for the 15-position configuration of methyl-dinor-7-thiaprosta-8,13-dienoate were obtained separately (low-polarity compound: 94 mg, 38%; high-polarity compound: 91).
mg, 37%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.5 Hz, 3H) 1.3-1.8 (m, 10H) 2.30 (t, J = 7.3 Hz, 2H ) 2.43 (t, J = 7.3 Hz, 2H) 2.45-2.7 (m, 5H) 2.95 (ddd, J = 16.5 & 6.6 & 1.3 Hz, 1H) 3.20 (d-like, J = 5.3 Hz, 1H) 3.66 ( s, 3H) 4.1-4.2 (m, 2H) 5.54 (dd, J = 15.5 & 7.9 Hz, 1H) 5.70 (dd, J = 15.5 & 6.3 Hz, 1H) 7.14-7.3 (m, 5H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 1.01 (t, J = 7.5 Hz, 3H) 1.3-1.8 (m, 10H) 2.29 (t, J = 7.3 Hz, 2H ) 2.43 (t, J = 7.3 Hz, 2H) 2.40-2.7 (m, 5H) 2.94 (ddd, J = 16.5 & 6.6 & 1.3 Hz, 1H) 3.20 (dd, J = 6.6 & 2.6 Hz, 1H) 3.66 ( s, 3H) 4.1-4.2 (m, 2H) 5.55 (dd, J = 15.8 & 7.9 Hz, 1H) 5.68 (dd, J = 15.8 & 6.3 Hz, 1H) 7.1-7.3 (m, 5H)

Example 65 (11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-16- (4-methylphenyl) -17,18,19,
20-tetranor-7-thiaprosta-8,13-die
Synthesis of methyl phosphate (R ¹ = Pr, R ² = H, R ³ = H, R ⁴ = 4-Me-Ben
zyl, W = ^t BuMe ₂ SiO, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = tra
ns-CH = CH)

[0352]

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As raw materials and reagents, (3S, 4R)-
4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio)
Using -3- (trans-2-iodovinyl) -1-cyclopentene (433 mg), chromium (II) chloride (440 mg), nickel chloride (0.1 mg) and (4-methylphenyl) acetaldehyde (195 mg), By the same operation as in Example 37, (11R, 12S, 13E) -9-butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (4-methylphenyl) -17,18,1
9,20-tetranor-7-thiaprosta-8,13-
Methyl dienoate (320 mg, 72%) was obtained.

Incidentally, the (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (4-methylphenyl) -17,18,19,20-tetranor-
Methyl 7-thiaprosta-8,13-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.03 (s, 6H) 0.87 (s, 9H) 1.00 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 8H) 2.29 (t , J = 7.6 Hz, 2H) 2.31 (s, 3H) 2.42 (t, J = 7.3 Hz, 2H) 2.3-2.9 (m, 6H) 3.15 (br-d, J = 8 Hz, 1H) 3.65 (s, 3H) 4.05 (m, 1H) 4.35 (m, 1H) 5.45-5.8 (m, 2H) 7.11 (s, 4H)

[Example 66](11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-16- (4-methylphenyi
Le) -17,18,19,20-tetranor-7-thia
Synthesis of methyl prostar-8,13-dienoate (R¹= Pr,
 R^Two= H, R^Three= H, R^Four= 4-Me-Benzyl, W = OH, X-Y = CH_Two-CH_Two, Z =
CO_TwoMe, n = 0,-= trans-CH = CH)

[0357]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.5 ml), (11R, 12S, 13E) -9-
Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (4-methylphenyl)-
The same operation as in Example 2 was performed using methyl 17,18,19,20-tetranor-7-thiaprosta-8,13-dienoate (300 mg) to give (11R, 12S, 13).
E) -9-Butyryloxy-11,15-dihydroxy-16- (4-methylphenyl) -17,18,19,
The two isomers for the 15-position configuration of methyl 20-tetranor-7-thiaprosta-8,13-dienoate were obtained separately (low-polarity compound: 73 mg, 30%; high-polarity compound: 83 mg, 34%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.3 Hz, 3H) 1.2-1.8 (m, 8H) 1.87 (br, 1H) 2.16 (br, 1H) 2.30 (t, J = 7.3 Hz, 2H) 2.32 (s, 3H) 2.43 (t, J = 7.3 Hz, 2H) 2.35-2.70 (m, 3H) 2.80 (d, J = 6.6 Hz, 2H) 2.90 (dd, J = 16.5 & 6.3 Hz, 1H) 3.18 (br-d, J = 7.9 Hz, 1H) 3.66 (s, 3H) 4.03 (m, 1H) 4.35 (m, 1H) 5.50 (ddd, J = 15.5 & 8.2 & 1.0 Hz, 1H) 5.72 (dd, J = 15.5 & 5.9 Hz, 1H) 7.10 (s, 4H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.3 Hz, 3H) 1.2-1.9 (m, 9H) 2.30 (t, J = 7.5 Hz, 2H ) 2.32 (s, 3H) 2.44 (t, J = 7.3 Hz, 2H) 2.35-3.0 (m, 5H) 3.20 (br-d, J = 8 Hz, 1H) 3.66 (s, 3H) 4.10 (m, 1H) ) 4.34 (m, 1H) 5.57 (dd, J = 15.5 & 8.2 Hz, 1H) 5.75 (dd, J = 15.5 & 5.9 Hz, 1H) 7.10 (s, 4H)

Example 67 (11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-16- (3-thienyl) -17,18,19,20-
Tetranor-7-thiaprosta-8,13-dienoic acid
Synthesis of tyl (R ¹ = Pr, R ² = H, R ³ = H, R ⁴ = 3-Thienyl, W =
^t BuMe ₂ SiO, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = C
H)

[0362]

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As raw materials and reagents, (3S, 4R)-
4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio)
-3- (trans-2-iodovinyl) -1-cyclopentene (418 mg), chromium (II) chloride (4.20 g), nickel chloride (0.1 mg) and 3-thienylacetaldehyde (176
mg), and the same operation as in Example 37 was performed, to obtain (11).
R, 12S, 13E) -9-butyryloxy-11-te
rt-butyldimethylsiloxy-15-hydroxy-16
Methyl-(3-thienyl) -17,18,19,20-tetranor-7-thiaprosta-8,13-dienoate
(267 mg, 64%).

Incidentally, the obtained (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (3-thienyl) -17,18,19,20-tetranor-7-thiaprosta-8,13-methyl methyl Is a mixture of diastereomers for the configuration of the hydroxyl group at the position.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.03 (s, 6H) 0.87 (s, 9H) 1.00 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 8H) 2.29 (t , J = 7.6 Hz, 2H) 2.42 (t, J = 7.4 Hz, 2H) 2.4-2.65 (m, 3H) 2.75-2.9 (m, 3H) 3.10 (br-d, J = 8 Hz, 1H) 3.66 ( s, 3H) 4.0-4.15 (m, 1H) 4.3-4.4 (m, 1H) 5.5-5.75 (m, 2H) 7.00 (dd, J = 4.9 & 1.0 Hz, 1H) 7.06 (d, J = 2.0 Hz, 1H) 7.22 (m, 1H)

Example 68 (11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-16- (3-thienyl) -1
7,18,19,20-tetranor-7-thiaprosta
Synthesis of methyl -8,13-dienoate (R ¹ = Pr, R ² = H, R
³ = H, R ⁴ = 4-Me-Benzyl, W = OH, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n
= 0, - = trans-CH = CH)

[0367]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.5 ml), (11R, 12S, 13E) -9-
Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (3-thienyl) -17,
18,19,20-tetranor-7-thiaprostar
The same operation as in Example 2 was performed using methyl 8,13-dienoate (260 mg) to give (11R, 12S, 13E)
-9-butyryloxy-11,15-dihydroxy-1
The two isomers for the configuration at the 15-position of methyl 6- (3-thienyl) -17,18,19,20-tetranor-7-thiaprosta-8,13-dienoate were obtained separately (low polar compounds : 47 mg, 22%; Highly polar compound: 64
mg, 30%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 8H) 1.99 (d, J = 3.9 Hz, 1H) ) 2.10 (d, J = 5.9 Hz, 1H) 2.31 (t, J = 7.4 Hz, 2H) 2.43 (t, J = 7.3 Hz, 2H) 2.4-2.7 (m, 3H) 2.86-2.96 (m, 1H) 2.89 (d, J = 6.6 Hz, 1H) 3.20 (br-d, J = 8.2 Hz, 1H) 3.66 (s, 3H) 4.0-4.1 (m, 1H) 4.3-4.45 (m, 1H) 5.54 (dd, J = 15.5 & 8.3 Hz, 1H) 5.75 (dd, J = 15.5 & 6.3 Hz, 1H) 6.98 (dd, J = 4.7 & 1.2 Hz, 1H) 7.05-7.06 (m, 1H) 7.25-7.29 (m, 1H )

[Highly Polar Compound] ¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 8H) 1.95 (br, 1H) 2.31 (t, J = 7.3 Hz, 2H) 2.44 (t, J = 7.3 Hz, 2H) 2.3-2.75 (m, 4H) 2.8-3.0 (m, 3H) 3.19 (dd, J = 7.9 & 2.6 Hz, 1H) 3.66 (s , 3H) 4.05-4.15 (m, 1H) 4.3-4.42 (m, 1H) 5.59 (dd, J = 15.5 & 8.3 Hz, 1H) 5.74 (dd, J = 15.5 & 6.2 Hz, 1H) 6.99 (dd, J = 5.0 & 1.0 Hz, 1H) 7.06 (d, J = 2.0 Hz, 1H) 7.26-7.28 (m, 1H)

[Example 69](11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-16- (3-methylphenyl) -17,18,19,
20-tetranor-7-thiaprosta-8,13-die
Synthesis of methyl phosphate (R¹= Pr, R^Two= H, R^Three= H, R^Four= 3-Me-Be
nzyl, W =^tBuMe_TwoSiO, X-Y = CH_Two-CH_Two, Z = CO _TwoMe, n = 0,-= tr
ans-CH = CH)

[0372]

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As raw materials and reagents, (3S, 4R)-
4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio)
Using -3- (trans-2-iodovinyl) -1-cyclopentene (418 mg), chromium (II) chloride (440 mg), nickel chloride (0.1 mg) and (3-methylphenyl) acetaldehyde (188 mg), By the same operation as in Example 37, (11R, 12S, 13E) -9-butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (3-methylphenyl) -17,18,1
9,20-tetranor-7-thiaprosta-8,13-
Methyl dienoate (234 mg, 55%) was obtained.

Incidentally, the obtained (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (3-methylphenyl) -17,18,19,20-tetranor-
Methyl 7-thiaprosta-8,13-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.03 (s, 6H) 0.87 (s, 9H) 1.00 (t, J = 7.4 Hz, 3H) 1.3-1.8 (m, 8H) 2.29 (t , J = 7.6 Hz, 2H) 2.33 (s, 3H) 2.42 (t, J = 7.3 Hz, 2H) 2.4-2.9 (m, 6H) 3.15 (br-d, J = 10 Hz, 1H) 3.65 (s, 3H) 4.05 (m, 1H) 4.35 (m, 1H) 5.5-5.65 (m, 1H) 5.68-5.80 (m, 1H) 6.95-7.05 (m, 3H) 7.19 (t, J = 7.6 Hz, 1H)

[Example 70](11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-16- (3-methylphenyi
Le) -17,18,19,20-tetranor-7-thia
Synthesis of methyl prostar-8,13-dienoate (R¹= Pr,
 R^Two= H, R^Three= H, R^Four= 3-Me-Benzyl, W = OH, X-Y = CH_Two-CH_Two, Z =
CO_TwoMe, n = 0,-= trans-CH = CH)

[0377]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.5 ml), (11R, 12S, 13E) -9-
Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (3-methylphenyl)-
The same operation as in Example 2 was carried out using methyl 17,18,19,20-tetranor-7-thiaprosta-8,13-dienoate (225 mg) to give (11R, 12S, 13).
E) -9-Butyryloxy-11,15-dihydroxy-16- (3-methylphenyl) -17,18,19,
The two isomers for the 15-position configuration of methyl 20-tetranor-7-thiaprosta-8,13-dienoate were obtained separately (low-polarity compound: 65 mg, 36%; high-polarity compound: 73 mg, 40%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.5 Hz, 3H) 1.3-1.8 (m, 8H) 1.87 (br, 1H) 2.06 (br, 1H) 2.30 (t, J = 7.3 Hz, 2H) 2.33 (s, 3H) 2.43 (t, J = 7.3 Hz, 2H) 2.35-2.73 (m, 3H) 2.81 (d, J = 6.9 Hz, 2H) 2.90 (ddd, J = 16.5 & 6.6 & 1.2 Hz, 1H) 3.19 (dd, J = 8.3 & 2.0 Hz, 1H) 3.66 (s, 3H) 3.95-4.05 (br, 1H) 4.3-4.43 (m, 1H) 5.52 (ddd, J = 16.5 & 8.2 & 1.0 Hz, 1H) 5.75 (dd, J = 16.5 & 6.2 Hz, 1H) 6.95-7.08 (m, 3H) 7.19 (t, J = 7.5 Hz, 1H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.3-1.8 (m, 8H) 1.9 (br, 1H) 2.30 (t, J = 7.4 Hz, 2H) 2.33 (s, 3H) 2.44 (t, J = 7.4 Hz, 2H) 2.35-2.95 (m, 5H) 3.19 (dd, J = 8.1 & 2.5 Hz, 1H) 3.66 (s, 3H) ) 4.02-4.12 (br, 1H) 4.3-4.44 (m, 1H) 5.57 (ddd, J = 16.2 & 8.3 & 1.0 Hz, 1H) 5.75 (dd, J = 16.2 & 6.0 Hz, 1H) 6.95-7.07 (m , 3H) 7.19 (t, J = 7.5 Hz, 1H)

[Example 71](11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-16- (2-methylphenyl) -17,18,19,
20-tetranor-7-thiaprosta-8,13-die
Synthesis of methyl phosphate (R¹= Pr, R^Two= H, R^Three= H, R^Four= 2-Me-Be
nzyl, W =^tBuMe_TwoSiO, X-Y = CH_Two-CH_Two, Z = CO _TwoMe, n = 0,-= tr
ans-CH = CH)

[0382]

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As raw materials and reagents, (3S, 4R)-
4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio)
Using -3- (trans-2-iodovinyl) -1-cyclopentene (418 mg), chromium (II) chloride (427 mg), nickel chloride (0.1 mg) and (2-methylphenyl) acetaldehyde (188 mg), The same operation as in Example 37 was performed, and (11R, 12S, 13E) -9-butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (2-methylphenyl) -17,18,1
9,20-tetranor-7-thiaprosta-8,13-
Methyl dienoate (330 mg, 96%) was obtained.

Note that the (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (2-methylphenyl) -17,18,19,20-tetranor-
Methyl 7-thiaprosta-8,13-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s, 6H) 0.88 (s, 9H) 1.01 (t, J = 7.4 Hz, 3H) 1.3-1.8 (m, 8H) 2.30 (t , J = 7.6 Hz, 2H) 2.34 (s, 3H) 2.43 (t, J = 7.3 Hz, 2H) 2.3-2.9 (m, 6H) 3.14 (br-d, J = 8 Hz, 1H) 3.66 (s, 3H) 4.0-4.1 (m, 1H) 4.25-4.4 (m, 1H) 5.45-5.6 (m, 1H) 5.67-5.80 (m, 1H) 7.0-7.2 (m, 4H)

[Example 72](11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-16- (2-methylphenyi
Le) -17,18,19,20-tetranor-7-thia
Synthesis of methyl prostar-8,13-dienoate (R¹= Pr,
 R^Two= H, R^Three= H, R^Four= 2-Me-Benzyl, W = OH, X-Y = CH_Two-CH_Two, Z =
CO_TwoMe, n = 0,-= trans-CH = CH)

[0387]

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As raw materials and reagents, a pyridine solution of hydrogen fluoride (0.6 ml), (11R, 12S, 13E) -9-
Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (2-methylphenyl)-
The same operation as in Example 2 was carried out using methyl 17,18,19,20-tetranor-7-thiaprosta-8,13-dienoate (330 mg) to obtain (11R, 12S, 13
E) -9-Butyryloxy-11,15-dihydroxy-16- (2-methylphenyl) -17,18,19,
The two isomers for the 15-position configuration of methyl 20-tetranor-7-thiaprosta-8,13-dienoate were obtained separately (low-polarity compound: 69 mg, 21%; high-polarity compound: 80 mg, twenty four %).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.5 Hz, 3H) 1.3-1.8 (m, 8H) 1.90 (br-d, J = 3.7 Hz) , 1H) 2.07 (br, 1H) 2.31 (t, J = 7.4 Hz, 2H) 2.34 (s, 3H) 2.43 (t, J = 7.3 Hz, 2H) 2.4-2.7 (m, 3H) 2.78-2.97 (m , 3H) 3.17 (dd, J = 8.2 & 2.0 Hz, 1H) 3.66 (s, 3H) 3.9-4.0 (br, 1H) 4.3-4.42 (m, 1H) 5.47 (ddd, J = 16.5 & 8.2 & 1.0 Hz , 1H) 5.76 (dd, J = 16.5 & 6.7 Hz, 1H) 7.10-7.19 (m, 4H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.3-1.8 (m, 8H) 1.95 (br, 1H) 2.30 (t, J = 7.6 Hz, 2H) 2.34 (s, 3H) 2.44 (t, J = 7.4 Hz, 2H) 2.4-2.7 (m, 3H) 2.85 (d, J = 6.5 Hz, 2H) 2.8-2.95 (m, 2H ) 3.19 (dd, J = 8.1 & 2.4 Hz, 1H) 3.66 (s, 3H) 4.08 (br, 1H) 4.36 (q-like, J = 6.6 Hz, 1H) 5.58 (dd, J = 15.5 & 8.0 Hz, 1H) 5.77 (dd, J = 15.5 & 6.3 Hz, 1H) 7.10-7.19 (m, 4H)

[Reference Example 3](3S, 4R) -4- (tert-butyldimethylsiloxy
B) -1-butyryloxy-2- (5-methoxycarbo)
Nylhexyl) -3- (trans-2-tributylstani
Synthesis of ruvinyl) -1-cyclopentene

[0392]

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As raw materials and reagents, trans-1,2-
Bis (tributylstannyl) ethylene (1.92 g), methyllithium (1.25 mol / l, 4.93 ml), cuprous cyanide 250 mg, (4R) -tert-butyldimethylsiloxy-
The same operation as in Reference Example 1 was performed using 2- (5-methoxycarbonylhexyl) -2-cyclopenten-1-one (709 mg) and acetic anhydride (1.15 ml) to obtain (3S, 4R)-
4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylhexyl) -3
-(Trans-2-Tributylstannylvinyl) -1-cyclopentene (1.26 g) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.05 (s, 6H) 0.84 (s, 18H) 0.87 (t-like, J = 7 Hz, 3H) 1.2-2.5 (m, 34H) 2.8 -2.9 (m, 1H) 3.0-3.1 (m, 1H) 3.69 (s, 3H) 4.1-4.2 (m, 1H) 5.75 (dd, J = 18.8 & 8.6 Hz, 1H) 6.09 (d, J = 18.8 Hz , 1H)

[Reference Example 4](3S, 4R) -4- (tert-butyldimethylsiloxy
B) -1-butyryloxy-2- (5-methoxycarbo)
Nylhexyl) -3- (trans-2-iodovinyl)-
Synthesis of 1-cyclopentene

[0396]

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(3S, 4R)-
4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylhexyl) -3
Using-(trans-2-tributylstannylvinyl) -1-cyclopentene (1.10 g) and iodine (384 mg),
The same operation as in Reference Example 2 was performed, and (3S, 4R) -4-
(Tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylhexyl) -3-
(Trans-2-iodovinyl) -1-cyclopentene (2
74 mg).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s, 6H) 0.87 (s, 9H) 1.00 (t, J = 7.3 Hz, 3H) 1.15-1.8 (m, 10 H) 1.9- 2.1 (m, 1 H) 2.30 (t, J = 7.4 Hz, 2H) 2.38 (t, J = 7.4 Hz, 2H) 2.35-2.5 (m, 1H) 2.76 (dd, J = 15.5 & 6.6 Hz, 1H) 3.04 (dd, J = 9.4 & 4.4 Hz, 1H) 3.67 (s, 3H) 4.1-4.2 (m, 1H) 6.18 (d, J = 14.2 Hz, 1H) 6.36 (dd, J = 14.2 & 9.4 Hz, 1H )

Reference Example 5 (11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-16-phenyl-17,18,19,20-tetrano
Synthesis of methyl leuprostar-8,13-dienoate

[0400]

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As the raw materials and reagents, (3S, 4R)-
4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylhexyl) -3
-(Trans-2-iodovinyl) -1-cyclopentene
(193 mg), chromium (II) chloride (203 mg), nickel chloride
(0.1 mg) and phenylacetaldehyde (80 mg), and the same operation as in Example 37 was performed.
S, 13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16-phenyl-17,18,19,20-tetranor-prostar
Methyl 8,13-dienoate (135 mg, 71%) was obtained.

Incidentally, the obtained (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16-phenyl-
17, 18, 19, 20-tetranor-prostar-8,
Methyl 13-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.02 (s, 6H) 0.87 (s, 9H) 0.98 (t, J = 7.2 Hz, 3H) 1.1-1.8 (m, 10H) 1.9-2.05 (m, 1H) 2.28 (t, J = 7.4 Hz, 2H) 2.37 (t, J = 7.3 Hz, 2H) 2.35-2.45 (m, 1H) 2.7-2.9 (m, 3H) 2.95-3.05 (m, 1H ) 3.65 (s, 3H) 4.0-4.1 (m, 1H) 4.3-4.4 (m, 1H) 5.4-5.75 (m, 2H) 7.15-7.4 (m, 5H)

[Reference Example 6](11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-16-phenyl-17,1
8,19,20-tetranor-prostar-8,13-di
Synthesis of methyl enoate

[0405]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.25 ml), 11R, 12S, 13E) -9-butyryloxy-11-tert-butyldimethylsiloxy-
15-hydroxy-16-phenyl-17,18,1
The same operation as in Example 2 was performed using methyl 9,20-tetranor-prosta-8,13-dienoate (130 mg) to give (11R, 12S, 13E) -9-butyryloxy-11,15-diene. Dihydroxy-16-phenyl-1
7,18,19,20-tetranor-prostar-8,1
Two isomers for the configuration at the 15-position of methyl 3-dienoate were separately obtained (low-polarity compound: 43 mg, 41
%; Highly polar compound: 41 mg, 39%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.99 (t, J = 7.4 Hz, 3H) 1.15-1.4 (m, 4H) 1.5-1.88 (m, 8H) 1.90- 2.10 (m, 1H) 2.29 (t, J = 7.4 Hz, 2H) 2.39 (t, J = 7.3 Hz, 2H) 2.35-2.45 (m, 1H) 2.75-2.9 (m, 1H) 2.85 (d, J = 7.3 Hz, 2H) 2.03 (dd, J = 8.7 & 3.1 Hz, 1H) 3.66 (s, 3H) 3.95 (br, 1H) 4.3-4.4 (m, 1H) 5.41 (dd, J = 15.5 Hz, 8.9 Hz, 1H) 5.67 (dd, J = 15.5 & 6.3 Hz, 1H) 7.15-7.38 (m, 5H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.99 (t, J = 7.4 Hz, 3H) 1.15-1.4 (m, 5H) 1.5-1.78 (m, 5H) 1.82 ( br, 1H) 1.9-2.05 (m, 2H) 2.13 (br, 1H) 2.29 (t, J = 7.6 Hz, 2H) 2.39 (t, J = 7.3 Hz, 2H) 2.35-2.45 (m, 1H) 2.75- 2.9 (m, 1H) 2.83 (d, J = 6.6 Hz, 2H) 2.03 (dd, J = 8.9 & 2.7 Hz, 1H) 3.66 (s, 3H) 4.02 (br, 1H) 4.3-4.4 (m, 1H) 5.45 (dd, J = 15.5 & 8.9 Hz, 1H) 5.65 (dd, J = 15.5 & 6.4 Hz, 1H) 7.18-7.35 (m, 5H)

Example 73 (11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-16-phenoxy-17,18,19,20-tetra
Of methyl nor-7-thiaprosta-8,13-dienoate
Synthesis (R ¹ = Pr, R ² = H, R ³ = H, R ⁴ = Phenoxymethyl, W = ^t Bu
Me ₂ SiO, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0410]

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As the raw materials and reagents, (3S, 4R)-
4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio)
-3- (trans-2-iodovinyl) -1-cyclopentene (298 mg), chromium (II) chloride (307 mg), nickel chloride (0.3 mg) and phenoxyacetaldehyde (136 mg)
And the same operation as in Example 37 was performed using (11)
R, 12S, 13E) -9-butyryloxy-11-te
rt-butyldimethylsiloxy-15-hydroxy-16
-Phenoxy-17,18,19,20-tetranor-
Methyl 7-thiaprosta-8,13-dienoate (183 m
g, 60%).

[0412] The (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16-phenoxy-17,18,19,20-tetranor-7-thiaprosta-8,13-dienoic acid methyl is a hydroxyl group at the 15-position. Diastereomeric mixtures for configuration.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s, 3H) 0.05 (s, 1.5H) 0.06 (s, 1.5H) 0.88 (s, 4.5H) 0.89 (s, 4.5H) 1.00 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 8H) 2.29 (t, J = 6.5 Hz, 2H) 2.43 (t, J = 7.3 Hz, 2H) 2.4-2.7 (m, 1H) 2.80 -2.95 (m, 1H) 3.2 (br, 1H) 3.66 (s, 3H) 3.89 (dd, J = 9.4 & 7.5 Hz, 1H) 4.01 (dd, J = 9.4 & 3.4 Hz, 1H) 4.15-4.25 (m , 1H) 4.5-4.6 (m, 1H) 5.79 (d-like, J = 4.5 Hz, 2H) 6.85-7.00 (m, 3H) 7.25-7.33 (m, 2H)

Example 74 (11R, 12S, 13E) -9-Butyryloxy-1
1,15-dihydroxy-16-phenoxy-17,1
8,19,20-tetranor-7-thiaprosta-8,
Synthesis of methyl 13 -dienoate (R ¹ = Pr, R ² = H, R ³ = H, R
⁴ = Phenoxymethyl, W = OH, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, -
- = trans-CH = CH)

[0415]

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As raw materials and reagents, hydrogen fluoride pyridine solution (0.4 ml), (11R, 12S, 13E) -9-
Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16-phenoxy-17,18,
19,20-tetranor-7-thiaprosta-8,13
-Methyl-dienoate (172 mg) was used to carry out the same operation as in Example 2 to give (11R, 12S, 13E) -9-butyryloxy-11,15-dihydroxy-16-phenoxy-17,18,19. The two isomers for the configuration at position 15 of methyl 2,20-tetranor-7-thiaprosta-8,13-dienoate were obtained separately (low-polarity compound: 49 mg, 37%; high-polarity compound: 56 mg, 40%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 8H) 2.29 (t, J = 7.4 Hz, 2H ) 2.44 (t, J = 7.3 Hz, 2H) 2.5-2.75 (m, 3H) 2.97 (ddd, J = 16.5 & 6.6 & 1.3 Hz, 1H) 3.26 (m, 1H) 3.66 (s, 3H) 3.89 (dd , J = 9.6 & 7.3 Hz, 1H) 4.01 (dd, J = 9.6 & 3.6 Hz, 1H) 4.13-4.23 (m, 1H) 5.81 (d-like, J = 4.0 Hz, 2H) 6.88-7.00 (m, 3H) 7.22-7.35 (m, 2H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.00 (t, J = 7.6 Hz, 3H) 1.3-1.8 (m, 8H) 2.28 (t, J = 7.3 Hz, 2H ) 2.43 (t, J = 7.3 Hz, 2H) 2.45-2.72 (m, 3H) 2.7 (br-s, 1H) 2.94 (ddd, J = 16.5 & 6.9 & 1.3 Hz, 1H) 3.25 (m, 1H) 3.66 (s, 3H) 3.90 (dd, J = 9.6 & 7.2 Hz, 1H) 4.00 (dd, J = 9.6 & 3.6 Hz, 1H) 4.15-4.25 (m, 1H) 4.5-4.6 (m, 1H) 5.78-5.81 (m, 2H) 6.88-7.00 (m, 3H) 7.22-7.35 (m, 2H)

[Example 75](11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-19-phenyl-20-nor-7-thiaprostar
Synthesis of methyl 8,13-dienoate (R¹= Pr, R^Two= H, R^Three=
H, R^Four= 4-Phenylbutyl, W =^tBuMe_TwoSiO, X-Y = CH_Two-CH_Two, Z =
CO_TwoMe, n = 0,-= trans-CH = CH)

[0420]

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(3S, 4R)-
4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio)
-3- (trans-2-iodovinyl) -1-cyclopentene (298 mg), chromium (II) chloride (307 mg), nickel chloride (0.3 mg) and 5-phenylvaleraldehyde (162
mg), and the same operation as in Example 37 was performed, to obtain (11).
R, 12S, 13E) -9-butyryloxy-11-te
rt-butyldimethylsiloxy-15-hydroxy-19
-Phenyl-20-nor-7-thiaprosta-8,13
-Methyl dienoate (263 mg, 83%) was obtained.

Note that the (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-19-phenyl-
Methyl 20-nor-7-thiaprosta-8,13-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.03 (s, 3H) 0.04 (s, 3H) 0.87 (s, 9H) 1.00 (t, J = 7.3 Hz, 3H) 1.2-1.8 (m , 14H) 2.29 (t, J = 7.3 Hz, 2H) 2.42 (t, J = 7.5 Hz, 2H) 2.4-2.65 (m, 5H) 2.86 (dd, J = 16.0 & 7.1 Hz, 1H) 3.1-3.15 ( m, 1H) 3.66 (s, 3H) 4.02-4.15 (m, 2H) 5.52 (ddd, J = 15.5 & 8.6 & 2.6 Hz, 1H) 5.67 (dd, J = 15.5 & 6.1 Hz, 1H) 7.1-7.3 ( m, 5H) 7.25-7.33 (m, 2H)

[Example 76](11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-19-phenyl-20-nor
Synthesis of methyl 7-thiaprosta-8,13-dienoate
 (R¹= Pr, R^Two= H, R^Three= H, R^Four= 4-Phenylbutyl, W = OH, X-Y
= CH_Two-CH_Two, Z = CO _TwoMe, n = 0,-= trans-CH = CH)

[0425]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.5 ml), (11R, 12S, 13E) -9-
Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-19-phenyl-20-nor-7
-Methyl thiaprosta-8,13-dienoate (243 mg)
The same operation as in Example 2 was performed using (11R,
12S, 13E) -9-butyryloxy-11,15-
The two isomers for the configuration at position 15 of methyl dihydroxy-19-phenyl-20-nor-7-thiaprosta-8,13-dienoate were obtained separately (low polar compound: 70 mg, 36%; high). Polar compound: 73 mg, 37%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.3 Hz, 3H) 1.2-1.85 (m, 14H) 2.30 (t, J = 7.4 Hz, 2H ) 2.43 (t, J = 7.3 Hz, 2H) 2.45-2.75 (m, 5H) 2.94 (ddd, J = 16.0 & 6.2 & 1.3 Hz, 1H) 3.21 (d-like, J = 7.5 Hz, 1H) 3.66 ( s, 3H) 4.1-4.2 (m, 2H) 5.54 (dd, J = 15.5 & 7.8 Hz, 1H) 5.70 (dd, J = 15.5 & 6.6 Hz, 1H) 7.1-7.35 (m, 5H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 14H) 1.85 (br, 1H) 2.30 (t, J = 7.2 Hz, 2H) 2.43 (t, J = 7.4 Hz, 2H) 2.4-2.7 (m, 5H) 2.92 (ddd, J = 16.5 & 6.6 & 1.3 Hz, 1H) 3.20 (d-like, J = 7.5 Hz, 1H) 3.66 (s, 3H) 4.1-4.2 (m, 2H) 5.55 (dd, J = 15.5 & 7.9 Hz, 1H) 5.68 (dd, J = 15.5 & 6.4 Hz, 1H) 7.1-7.35 (m, 5H)

Example 77 (11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-17-Methyl-19,20-dinor-7-thiapros
Synthesis of Methyl 8,13-dienoate (R ¹ = Pr, R ² = H,
R ³ = H, R ⁴ = ⁱ Pr, W = ^t BuMe ₂ SiO, XY = CH ₂ -CH ₂ , Z = CO ₂ Me,
n = 0, - = trans-CH = CH)

[0430]

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As the raw materials and reagents, (3S, 4R)-
4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio)
Using -3- (trans-2-iodovinyl) -1-cyclopentene (239 mg), chromium (II) chloride (246 mg), nickel chloride (0.3 mg) and isovaleraldehyde (69 mg), By performing the same operation, (11R, 12
S, 13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-17-methyl-19,20-dinor-7-thiaprosta-8,13-
Methyl dienoate (127 mg, 57%) was obtained.

Incidentally, the (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-17-methyl-1
Methyl 9,20-dinor-7-thiaprosta-8,13-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s, 6H) 0.88 (s, 9H) 0.7-1.0 (m, 9 H) 1.1-1.8 (m, 11 H) 2.30 (t, J = 7.3 Hz, 2H) 2.42 (t, J = 7.2 Hz, 2H) 2.3-2.7 (m, 3H) 2.84 (dd, J = 16.0 & 7.1 Hz, 1H) 3.05-3.15 (m, 1H) 3.65 (s , 3H) 4.0-4.2 (m, 2H) 5.57 (ddd, J = 16.0 & 8.6 & 2.6 Hz, 1H) 5.67 (dd, J = 16.0 & 6.5 Hz, 1H)

Example 78 (11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-17-methyl-19,20-
Methyl dinor-7-thiaprosta-8,13-dienoate
Synthesis ^{(R 1 = Pr, R 2} = H, R 3 = H, R 4 = i Pr, W = OH, XY = CH 2
-CH ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0435]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.4 ml), (11R, 12S, 13E) -9-
Methyl butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-17-methyl-19,20-dinor-7-thiaprosta-8,13-dienoate (12
(3 mg) and the same operation as in Example 2 was carried out to obtain (1
1R, 12S, 13E) -9-butyryloxy-11,
1-methyl 15-dihydroxy-17-methyl-19,20-dinor-7-thiaprosta-8,13-dienoate
Two isomers for configuration 5 were obtained separately
(Low polarity compound: 34 mg, 35%; High polarity compound: 37 mg,
38%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 0.92 (dd, J = 6.6 & 2.3 Hz, 6H) 1.01 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m , 11H) 2.31 (t, J = 7.4 Hz, 2H) 2.44 (t, J = 7.2 Hz, 2H) 2.5-2.75 (m, 3H) 2.97 (ddd, J = 16.5 & 6.5 & 1.3 Hz, 1H) 3.21 ( d-like, J = 7 Hz, 1H) 3.67 (s, 3H) 4.1-4.25 (m, 2H) 5.58 (dd, J = 15.6 & 7.9 Hz, 1H) 5.72 (dd, J = 15.6 & 6.1 Hz, 1H )

[Highly Polar Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 0.92 (dd, J = 6.6 & 2.3 Hz, 6H) 1.01 (t, J = 7.3 Hz, 3H) 1.2-1.8 (m , 11H) 2.31 (t, J = 7.4 Hz, 2H) 2.43 (t, J = 7.2 Hz, 2H) 2.5-2.75 (m, 3H) 2.94 (ddd, J = 16.6 & 6.9 & 1.3 Hz, 1H) 3.21 ( d-like, J = 7 Hz, 1H) 3.67 (s, 3H) 4.1-4.25 (m, 2H) 5.57 (dd, J = 15.6 & 7.7 Hz, 1H) 5.68 (dd, J = 15.6 & 6.3 Hz, 1H )

Example 79 (11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-16-cyclohexyl-17,18,19,20-te
Tolanol-7-thiaprosta-8,13-dienoic acid methyl ester
Synthesis (R ¹ = Pr, R ² = H, R ³ = H, R ⁴ = cyclohexylmethy
l, W = ^t BuMe ₂ SiO, XY = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = trans
-CH = CH)

[0440]

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(3S, 4R)-
4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio)
-3- (trans-2-iodovinyl) -1-cyclopentene (200 mg), chromium (II) chloride (246 mg), nickel chloride (0.3 mg) and cyclohexyl acetaldehyde (12 mg)
(6 mg), and the same operation as in Example 37 was carried out.
1R, 12S, 13E) -9-Butyryloxy-11-
tert-butyldimethylsiloxy-15-hydroxy-1
Methyl 6-cyclohexyl-17,18,19,20-tetranor-7-thiaprosta-8,13-dienoate
(145 mg, 71%).

Note that (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16-cyclohexyl-17,18,19,20-tetranor-7-thiaprosta-8,13-dienoic acid methyl is a hydroxyl group at position 15. Diastereomeric mixtures for configuration.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s, 6H) 0.87 (s, 9H) 0.8-1.0 (m, 2H) 1.00 (t, J = 7.4 Hz, 3H) 1.1-1.8 (m, 19 H) 2.30 (t, J = 7.4 Hz, 2H) 2.42 (t, J = 7.5 Hz, 2H) 2.4-2.7 (m, 3H) 2.8-2.95 (m, 1H) 3.1-3.2 (m, 1H) 3.66 (s, 3H) 4.2-4.25 (m, 2H) 5.53 (dd, J = 15.5 & 8.6 Hz, 1H) 5.66 (ddd, J = 15.5 & 6.3 & 2.0 Hz, 1H)

[Embodiment 80](11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-16-cyclohexyl-1
7,18,19,20-tetranor-7-thiaprosta
Synthesis of methyl -8,13-dienoate (R¹= Pr, R^Two= H, R
^Three= H, R^Four= cyclohexylmethyl, W = OH, X-Y = CH_Two-CH_Two, Z = CO_Two
Me, n = 0,-= trans-CH = CH)

[0445]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.4 ml), (11R, 12S, 13E) -9-
Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16-cyclohexyl-17,1
8,19,20-tetranor-7-thiaprosta-8,
The same operation as in Example 2 was performed using methyl 13-dienoate (140 mg) to give (11R, 12S, 13E) -9.
-Butyryloxy-11,15-dihydroxy-16-
15 of methyl cyclohexyl-17,18,19,20-tetranor-7-thiaprosta-8,13-dienoate
The two isomers for the configuration of the position were obtained separately.
(Low polarity compound: 44 mg, 40%; High polarity compound: 48 mg,
43%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.8-1.0 (m, 2H) 1.01 (t, J = 7.5 Hz, 3H) 1.1-1.85 (m, 19H) 2.31 ( t, J = 7.5 Hz, 2H) 2.44 (t, J = 7.3 Hz, 2H) 2.45-2.75 (m, 3H) 2.97 (ddd, J = 16.5 & 6.6 & 1.3 Hz, 1H) 3.22 (d-like, J = 7.9 Hz, 1H) 3.67 (s, 3H) 4.1-4.3 (m, 2H) 5.57 (dd, J = 15.5 & 8.0 Hz, 1H) 5.72 (dd, J = 15.5 & 6.3 Hz, 1H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.8-1.0 (m, 2H) 1.01 (t, J = 7.5 Hz, 3H) 1.0-1.8 (m, 19H) 2.31 ( t, J = 7.6 Hz, 2H) 2.43 (t, J = 7.3 Hz, 2H) 2.4-2.75 (m, 3H) 2.94 (ddd, J = 16.5 & 6.9 & 1.3 Hz, 1H) 3.21 (dd, J = 8.0 & 1.5 Hz, 1H) 3.67 (s, 3H) 4.15-4.3 (m, 2H) 5.55 (dd, J = 15.5 & 7.6 Hz, 1H) 5.68 (dd, J = 15.5 & 6.4 Hz, 1H)

[Example 81](13E, 15S, 17R) -9-butyryloxy-1
5- (tert-butyldimethylsiloxy) -17,20-
Dimethyl-7-thiaprosta-8,13-dienoic acid methyl ester
Synthesis (R¹= Pr, R^Two=^tBuMe_TwoSi, R^Three= H, R^Four= 2-Me-hexy
l, W = H, X-Y = CH _Two-CH_Two, Z = CO_TwoMe, n = 0,-= trans-CH = CH)

[0450]

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As raw materials and reagents, (1E, 3S, 5R)
-1-Iodo-3- (tert-butyldimethylsiloxy)
-5-methyl-1-nonene (785 mg), tert-butyllithium (1.54 mol / l, 2.57 ml), hexin copper 287 m
g, hexamethylphosphorus triamide (720 μl), 2
-(5-methoxycarbonylpentylthio) -2-cyclopenten-1-one (400 mg), butyric anhydride (729 μl)
The same operation as in Example 1 was performed using (13E, 1).
5S, 17R) -9-butyryloxy-15- (tert-
Butyldimethylsiloxy) -17,20-dimethyl-7
-Methyl thiaprosta-8,13-dienoate (367 mg)
I got

Note that (13E, 15S,
Methyl 17R) -9-butyryloxy-15- (tert-butyldimethylsiloxy) -17,20-dimethyl-7-thiaprosta-8,13-dienoate is a diastereomeric mixture for the configuration at the 12 position.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s, 6H) 0.84 (s, 9H) 0.8-0.9 (m, 6H) 0.96 (t, J = 7.4 Hz, 3H) 1.1-1.8 (m, 19H) 2.1-2.7 (m, 4H) 2.23 (t, J = 7.6 Hz, 2H) 2.38 (t, J = 7.4 Hz, 2H) 3.63 (s, 3H) 4.1 (br, 1H) 5.4-5.5 (m, 2H)

Example 82 (13E, 15S, 17R) -9-butyryloxy-1
5-hydroxy-17,20-dimethyl-7-thiapro
Synthesis of methyl star 8,13-dienoate (R ¹ = Pr, R ² =
H, R ³ = H, R ⁴ = 2-Me-hexyl, W = H, XY = CH ₂ -CH ₂ , Z = CO ₂ Me,
n = 0, - = trans-CH = CH)

[0455]

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As a raw material and a reagent, a hydrogen fluoride pyridine solution (0.4 ml), (13E, 15S, 17R) -9-butyryloxy-15- (tert-butyldimethylsiloxy)
-17,20-dimethyl-7-thiaprosta-8,13
-Methyl dienoate (180 mg) was used to carry out the same operation as in Example 2 to give (13E, 15S, 17R) -9-butyryloxy-15-hydroxy-17,20-dimethyl-7-thiaprosta-8, 12 of methyl 13-dienoate
The two isomers for the configuration of the position were obtained separately.
(Low polarity compound: 80 mg, 50%, High polarity compound: 29 mg,
20%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.8-0.95 (m, 6H) 1.00 (t, J = 7.4 Hz, 3H) 1.1-1.8 (m, 19H) 2.15- 2.3 (m, 1 H) 2.30 (t, J = 7.2 Hz, 2H) 2.43 (t, J = 7.4 Hz, 2H) 2.45-2.75 (m, 4H) 3.3 (br, 1H) 3.67 (s, 3H) 4.2 (br, 1H) 5.5-6.9 (m, 2H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.8-0.95 (m, 6H) 1.00 (t, J = 7.3 Hz, 3H) 1.1-1.8 (m, 19H) 2.15- 2.3 (m, 1H) 2.30 (t, J = 7.3 Hz, 2H) 2.43 (t, J = 7.3 Hz, 2H) 2.45-2.75 (m, 4H) 3.3 (br, 1H) 3.67 (s, 3H) 4.2 ( br, 1H) 5.5-6.9 (m, 2H)

Example 83 (11R, 12S, 13E, 15S) -11,15-B
(Tert-butyldimethylsiloxy) -9- (2,2-
Dimethyl-6- (4-chlorophenoxy) -hexanoy
Loxy) -7-thiaprosta-8,13-dienoic acid
Synthesis of tyl (R ¹ = C (CH ₃ ) ₂ (CH ₂ ) ₄ OPh-p-Cl, R ² = ^t BuMe ₂ S
i, R ³ = H, R ⁴ = Pentyl, W = ^t BuMe ₂ SiO, XY = CH ₂ -CH ₂ , Z = CO
₂ Me, n = 0, - = trans-CH = CH)

[0460]

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As a raw material and a reagent, (1E, 3S) -1-
Iodo-3- (tert-butyldimethylsiloxy) -1-
Octene (442 mg), tert-butyllithium (1.50 mol
/ l, 1.60 ml), hexine copper 174 mg, hexamethylphosphorous triamide (436 μl), (4R) -tert-butyldimethylsiloxy-2- (5-methoxycarbonylpentylthio) -2-cyclopenten-1-one (373 mg,
1.0 mmol), 2,2-dimethyl-6- (4-chlorophenoxy) -hexanoic acid chloride (781 μl)
The same operation as in Example 1 was performed, and (11R, 12S, 13
E, 15S) -11,15-bis (tert-butyldimethylsiloxy) -9- (2,2-dimethyl-6- (4-chlorophenoxy) -hexanoyloxy) -7-thiaprosta-8,13-diene Methyl acid salt (520 mg, 60%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ )-0.05 (s, 6H)-0.01 (s, 6H) 0.83 (s, 9H) 0.84 (s, 9H) 1.21 (s, 6H) 1.1- 1.8 (m, 19H) 1.32 (t, J = 6.0 Hz, 2H) 2.27-2.47 (m, 2H) 2.5-2.65 (m, 2H) 2.82 (ddd, J = 16.1 & 6.9 & 1.3 Hz, 1H) 3.08 ( dd, J = 8.6 Hz, 1H) 3.61 (s, 3H) 3.87 (t, J = 16.3 Hz, 2H) 4.0-4.15 (m, 2H) 5.38 (dd, J = 15.5 & 8.6 Hz, 1H) 5.57 (dd , J = 15.5 & 6.0 Hz, 1H) 6.75 (d, J = 8.9 Hz, 2H) 7.16 (d, J = 8.9 Hz, 2H)

[Example 84] (11R, 12S, 13E, 15S) -9- (2,2-
Dimethyl-6- (4-chlorophenoxy) -hexanoy
Ruoxy) -11,15-dihydroxy-7-thiapro
Synthesis of methyl star 8,13-dienoate (R ¹ = C (CH ₃ ) ₂
(CH ₂ ) ₄ OPh-p-Cl, R ² = H, R ³ = H, R ⁴ = Pentyl, W = OH, XY = C
H ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0464]

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A pyridine solution of hydrogen fluoride (0.5 ml) was added as a raw material and a reagent, and (11R, 12S, 13E, 15E) was added.
S) -11,15-Bis (tert-butyldimethylsiloxy) -9- (2,2-dimethyl-6- (4-chlorophenoxy) -hexanoyloxy) -7-thiaprosta-
The same operation as in Example 2 was carried out using methyl 8,13-dienoate (538 mg), and (11R, 12S, 13E, 1
5S) -9- (2,2-Dimethyl-6- (4-chlorophenoxy) -hexanoyloxy) -11,15-dihydroxy-7-thiaprosta-8,13-dienoic acid methyl ester (240 mg, 75%) I got

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.88 (t, J = 6.5 Hz, 3H) 1.26 (s, 6H) 1.2-1.8 (m, 20H) 2.29 (t, J = 7.4 Hz, 2H) 2.35-2.7 (m, 3H) 2.90 (dd, J = 5.3 & 16.5 Hz, 1H) 3.22 (br-d, J = 7.9 Hz, 1H) 3.66 (s, 3H) 3.92 (t, J = 6.4 Hz , 2H) 4.05-4.2 (m, 2H) 5.55 (dd, J = 7.9 & 15.5 Hz, 1H) 5.70 (dd, J = 6.3 & 15.5 Hz, 1H) 6.80 (d, J = 8.9 Hz, 2H) 7.21 ( d, J = 8.9 Hz, 2H)

[Example 85](11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-16- (3-methoxyphenyl) -17,18,1
9,20-tetranor-7-thiaprosta-8,13-
Synthesis of methyl dienoate (R¹= Pr, R^Two= H, R^Three= H, R^Four= 3-M
eO-Benzyl, W =^tBuMe_TwoSiO, X-Y = CH_Two-CH_Two, Z = CO_TwoMe, n = 0,
-= trans-CH = CH)

[0468]

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As the raw materials and reagents, (3S, 4R)-
4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio)
Using -3- (trans-2-iodovinyl) -1-cyclopentene (415 mg), chromium (II) chloride (435 mg), nickel chloride (0.1 mg) and (3-methoxyphenyl) acetaldehyde (253 mg), By the same operation as in Example 37, (11R, 12S, 13E) -9-butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (3-methoxyphenyl) -17,1
8,19,20-tetranor-7-thiaprosta-8,
Methyl 13-dienoate (269 mg, 62%) was obtained.

Note that the (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (3-methoxyphenyl) -17,18,19,20-tetranor-7-thiaprosta-8,13-dienoic acid methyl is Fifteen
Is a mixture of diastereomers for the configuration of the hydroxyl group at the position.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s, 6H) 0.87 (s, 9H) 1.01 (t, J = 7.6 Hz, 3H) 1.3-1.8 (m, 8H) 2.30 (t , J = 7.3 Hz, 2H) 2.43 (t, J = 7.3 Hz, 2H) 2.4-2.9 (m, 6H) 3.14 (br-d, J = 7.3 Hz, 1H) 3.66 (s, 3H) 3.80 (s, 3H) 4.06-4.11 (m, 1H) 4.31-4.44 (m, 1H) 5.51-5.65 (m, 1H) 5.67-5.82 (m, 1H) 6.75-6.85 (m, 3H) 7.18-7.25 (m, 1H)

[Embodiment 86](11R, 12S, 13E) -9-butyryloxy-1
1,15-dihydroxy-16- (3-methoxyphenyl
Le) -17,18,19,20-tetranor-7-thia
Synthesis of methyl prostar-8,13-dienoate (R¹= Pr,
 R^Two= H, R^Three= H, R ^Four= 3-MeO-Benzyl, W = OH, X-Y = CH_Two-CH_Two, Z
= CO_TwoMe, n = 0,-= trans-CH = CH)

[0473]

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As raw materials and reagents, a solution of hydrogen fluoride in pyridine (0.5 ml), (11R, 12S, 13E) -9-
Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (3-methoxyphenyl)
Using methyl -17,18,19,20-tetranor-7-thiaprosta-8,13-dienoate (262 mg),
By performing the same operation as in Example 2, (11R, 12S, 1
3E) -9-Butyryloxy-11,15-dihydroxy-16- (3-methoxyphenyl) -17,18,1
9,20-tetranor-7-thiaprosta-8,13-
The two isomers for the configuration at position 15 of methyl dienoate were obtained separately (low polarity compound: 74 mg, 35%; high polarity compound: 92 mg, 43%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.00 (t, J = 7.6 Hz, 3H) 1.3-1.8 (m, 8H) 1.88 (br, 1H) 2.17 (br, 1H) 2.31 (t, J = 7.3 Hz, 2H) 2.43 (t, J = 7.3 Hz, 2H) 2.40-2.72 (m, 3H) 2.82 (d, J = 6.6 Hz, 2H) 2.90 (ddd, J = 16.5 & 6.6 & 1.3 Hz, 1H) 3.19 (dd, J = 8.6 & 2.3 Hz, 1H) 3.74 (s, 3H) 3.80 (s, 3H) 3.95-4.05 (br, 1H) 4.30-4.42 (m, 1H) 5.50 (ddd, J = 15.5 & 8.6 & 1.0 Hz, 1H) 5.75 (dd, J = 15.5 & 6.3 Hz, 1H) 6.74-6.83 (m, 3H) 7.15-7.25 (m, 1H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.6 Hz, 3H) 1.3-1.8 (m, 8H) 1.88 (br, 1H) 2.30 (t, J = 7.3 Hz, 2H) 2.36 (br, 1H) 2.44 (t, J = 7.3 Hz, 2H) 2.35-2.97 (m, 6H) 3.20 (dd, J = 8.3 & 2.4 Hz, 1H) 3.66 (s, 3H) ) 3.80 (s, 3H) 4.04-4.12 (br, 1H) 4.31-4.43 (m, 1H) 5.58 (dd, J = 15.5 & 8.2 Hz, 1H) 5.75 (dd, J = 15.5 & 5.9 Hz, 1H) 6.73 -6.85 (m, 3H) 7.15-7.25 (m, 1H)

[Example 87](11R, 12S, 13E) -9-butyryloxy-1
1-tert-butyldimethylsiloxy-15-hydroxy
-16- (3-methoxycarbonylphenyl) -17,
18,19,20-tetranor-7-thiaprostar
Synthesis of methyl 8,13-dienoate (R¹= Pr, R^Two= H, R^Three=
H, R^Four= 3-MeO_TwoC-Benzyl, W =^tBuMe_TwoSiO, X-Y = CH_Two-CH_Two, Z
= CO_TwoMe, n = 0,-= trans-CH = CH)

[0478]

Embedded image

(3S, 4R)-
4- (tert-butyldimethylsiloxy) -1-butyryloxy-2- (5-methoxycarbonylpentylthio)
-3- (trans-2-iodovinyl) -1-cyclopentene (360 mg), chromium (II) chloride (433 mg), nickel chloride (0.1 mg) and methyl 3- (formylmethyl) benzoate (251 mg) Using the same procedure as in Example 37, (11R, 12S, 13E) -9-butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (3-methoxycarbonylphenyl) -1
Methyl 7,18,19,20-tetranor-7-thiaprosta-8,13-dienoate (141 mg, 36%) was obtained.

Incidentally, the obtained (11R, 12S,
13E) -9-Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (3-methoxycarbonylphenyl) -17,18,19,20-
Methyl tetranor-7-thiaprosta-8,13-dienoate is a mixture of diastereomers for the configuration of the hydroxyl group at position 15.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.02 (s, 3H) 0.03 (s, 3H) 0.87 (s, 9H) 1.01 (t, J = 7.6 Hz, 3H) 1.3-1.8 (m , 8H) 2.30 (t, J = 7.3 Hz, 2H) 2.43 (t, J = 7.3 Hz, 2H) 2.37-2.70 (m, 3H) 2.80-2.92 (m, 3H) 3.13 (br-d, J = 7.9 Hz, 1H) 3.91 (s, 3H) 3.80 (s, 3H) 4.02-4.10 (m, 1H) 4.34-4.45 (m, 1H) 5.57 (dd, J = 15.5 & 8.3 Hz, 1H) 5.68-5.80 (m , 1H) 7.33-6.48 (m, 2H) 7.89-7.93 (m, 2H)

Example 88 (11R, 12S, 13E) -9-Butyryloxy-1
1,15-dihydroxy-16- (3-methoxycarbo
Nylphenyl) -17,18,19,20-tetranor
Synthesis of methyl -7-thiaprosta-8,13-dienoate (R ¹ = Pr, R ² = H, R ³ = H, R ⁴ = 3-MeO ₂ C-Benzyl, W = OH, X-
Y = CH ₂ -CH ₂ , Z = CO ₂ Me, n = 0, - = trans-CH = CH)

[0483]

Embedded image

As raw materials and reagents, a pyridine solution of hydrogen fluoride (0.3 ml), (11R, 12S, 13E) -9-
Butyryloxy-11-tert-butyldimethylsiloxy-15-hydroxy-16- (3-methoxycarbonylphenyl) -17,18,19,20-tetranor-7
-Methyl thiaprosta-8,13-dienoate (137 mg)
The same operation as in Example 2 was performed using (11R,
12S, 13E) -9-butyryloxy-11,15-
The two isomers for the configuration at position 15 of methyl dihydroxy-16- (3-methoxycarbonylphenyl) -17,18,19,20-tetranor-7-thiaprosta-8,13-dienoate were obtained separately. (Low polarity compound: 31 mg, 28%; High polarity compound: 52 mg, 46%).

[Low Polarity Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.00 (t, J = 7.6 Hz, 3H) 1.3-1.8 (m, 8H) 1.92 (br-d, J = 4.0 Hz) , 1H) 2.31 (t, J = 7.3 Hz, 2H) 2.42 (t, J = 7.3 Hz, 2H) 2.44 (br, 1H) 2.45-2.72 (m, 3H) 2.80-3.00 (m, 3H) 3.21 (dd , J = 8.6 & 3.3 Hz, 1H) 3.66 (s, 3H) 3.92 (s, 3H) 3.95-4.05 (m, 1H) 4.30-4.41 (m, 1H) 5.45 (dd, J = 15.5 & 8.6 Hz, 1H ) 5.75 (dd, J = 15.5 & 6.9 Hz, 1H) 7.32-7.47 (m, 2H) 7.86-7.92 (m, 2H)

[Highly Polar Compound] ¹ H-NMR (270 MHz, δ ppm, CDCl ₃ ) 1.01 (t, J = 7.3 Hz, 3H) 1.3-1.8 (m, 8H) 1.87 (br, 1H) 2.30 (t, J = 7.3 Hz, 2H) 2.40-2.70 (m, 3H) 2.43 (t, J = 7.3 Hz, 2H) 2.48 (br, 1H) 2.81-2.98 (m, 3H) 3.20 (dd, J = 8.3 & 2.0 Hz , 1H) 3.66 (s, 3H) 3.91 (s, 3H) 4.02-4.10 (br, 1H) 4.35-4.47 (m, 1H) 5.55 (ddd, J = 15.5 & 8.3 & 1.0 Hz, 1H) 5.76 (dd, J = 15.5 & 5.9 Hz, 1H) 7.32-7.47 (m, 2H) 7.85-7.93 (m, 2H)

[Example 89](11R, 12S, 13E, 15S) -9-butyryl
Xy-11,15-bis (tert-butyldimethylsiloxy
B) of 7-thiaprosta-8,13-dienoic acid amide
Synthesis (R¹= Pr, R^Two=^tBuMe_TwoSi, R^Three= H, R^Four= Pentyl, W =^tBu
Me_TwoSiO, X-Y = CH _Two-CH_Two, Z = CONH_Two, n = 0,-= trans-CH = CH)

[0488]

Embedded image

(11R, 12S, 13E, 15S) -9
A solution of -butyryloxy-11,15-bis (tert-butyldimethylsiloxy) -7-thiaprosta-8,13-dienoic acid (201 mg) in methylene chloride (3 ml) was prepared at -40 ° C.
After cooling to the solution, add isobutyl chloroformate (47 μl) to the solution.
And triethylamine (63 μl) and leave at -40 ° C.
Stirred for minutes. Further, 1 ml of 30% aqueous ammonia was added, and the mixture was stirred overnight while warming to room temperature. The reaction was diluted with ethyl acetate and neutralized with dilute hydrochloric acid. The desired product was extracted from the mixture with ethyl acetate, and the extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution.
The solution was concentrated under reduced pressure, and purified by silica gel column chromatography (45% ethyl acetate / hexane).
1R, 12S, 13E, 15S) -9-butyryloxy-11,15-bis (tert-butyldimethylsiloxy)
-7-Thiaprosta-8,13-dienoic acid amide (169
mg, 84%).

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s), 0.05 (s) ... 12 H 0.8-0.9 (m, 3H) 0.88 (s, 9H) 0.89 (s, 9H) 1.00 (t, J = 7.4 Hz, 3H) 1.2-1.8 (m, 16H) 2.20 (t, J = 7.4 Hz, 2H) 2.4-2.7 (m, 3H) 2.42 (t, J = 7.4 Hz, 2H) 2.89 ( dd, J = 6.9 & 16.2 Hz, 1H) 3.13 (d, J = 5.8 Hz, 1H) 4.0-4.2 (m, 2H) 5.43 (dd, J = 8.7 & 15.3 Hz, 1H) 5.5-5.7 (m, 2H ) 5.62 (dd, J = 5.8 & 15.3 Hz, 1H)

[Embodiment 90](11R, 12S, 13E, 15S) -9-butyryl
Xy-11,15-dihydroxy-7-thiaprostar
Synthesis of 8,13-dienoic acid amide (R¹= Pr, R ^Two= H, R^Three=
H, R^Four= Pentyl, W = OH, X-Y = CH_Two-CH_Two, Z = CONH_Two, n = 0,-= t
rans-CH = CH)

[0492]

Embedded image

As raw materials and reagents, a hydrogen fluoride pyridine solution (0.2 ml), (11R, 12S, 13E, 15
S) -9-Butyryloxy-11,15-bis (tert-
Butyldimethylsiloxy) -7-thiaprosta-8,1
The same operation as in Example 2 was performed using 3-dienoic acid amide (169 mg) to obtain (11R, 12S, 13E, 15E).
S) -9-Butyryloxy-11,15-dihydroxy-7-thiaprosta-8,13-dienoic acid amide (101
mg, 91%).

[0494] ^{1 H-NMR (270 MHz,} δppm, CDCl 3) 0.88 (t, J = 6.6 Hz, 3H) 1.01 (t, J = 7.4 Hz, 3H) 1.2 - 1.8 (m, 16H) 2.22 (t, J = 7.3 Hz, 2H) 2.4-2.8 (m, 3H) 2.44 (t, J = 7.4 Hz, 2H) 2.90 (ddd, J = 1.2 & 6.1 & 10.9 Hz, 1H) 3.23 (dd, J = 2.8 & 8.1 Hz, 1H) 4.09 (dt, J = 6.6 & 6.6 Hz, 1H) 4.1-4.2 (m, 1H) 5.54 (dd, J = 7.9 & 15.5 Hz, 1H) 5.68 (dd, J = 6.6 & 15.5 Hz, 1H ) 5.80 (br.s, 1H) 5.92 (br.s, 1H)

[Example 91]N, N-diethyl (11R, 12S, 13E, 15S) -9
-Butyryloxy-11,15-bis (tert-butyldi
Methylsiloxy) -7-thiaprosta-8,13-die
Synthesis of acid amide (R¹= Pr, R^Two=^tBuMe_TwoSi, R^Three= H, R^Four= P
entyl, W =^tBuMe _TwoSiO, X-Y = CH_Two-CH_Two, Z = CONEt_Two, n = 0,-=
trans-CH = CH)

[0496]

Embedded image

As raw materials and reagents, (11R, 12
S, 13E, 15S) -9-Butyryloxy-11,1
Example 89 was prepared using 5-bis (tert-butyldimethylsiloxy) -7-thiaprosta-8,13-dienoic acid (201 mg), isobutyl chloroformate (47 μl), triethylamine (63 μl), and diethylamine (37 μl). By performing the same operation, N, N-diethyl (11R, 12S, 13E, 1
5S) -9-butyryloxy-11,15-bis (tert
-Butyldimethylsiloxy) -7-thiaprosta-8,
13-dienoic acid amide (189 mg, 87%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s), 0.05 (s) 12 H 0.8-0.9 (m, 3H) 0.87 (s, 9H) 0.89 (s, 9H) 1.00 (t , J = 7.4 Hz, 3H) 1.10 (t, J = 7.1 Hz, 3H) 1.17 (t, J = 7.3 Hz, 3H) 1.2-1.8 (m, 16H) 2.28 (t, J = 7.6 Hz, 2H) 2.4 -2.7 (m, 3H) 2.42 (t, J = 7.3 Hz, 2H) 2.91 (ddd, J = 1.6 & 6.9 & 16.2 Hz, 1H) 3.13 (dd, J = 2.6 & 8.6 Hz, 1H) 3.29 (q, J = 7.3 Hz, 2H) 3.32 (q, J = 6.9 Hz, 2H) 4.0-4.2 (m, 2H) 5.43 (ddd, J = 0.7 & 8.6 & 15.2 Hz, 1H) 5.62 (dd, J = 5.9 & 15.5 (Hz, 1H)

Example 92 N, N-Diethyl (11R, 12S, 13E, 15S) -9
-Butyryloxy-11,15-dihydroxy-7-thio
Synthesis of Aprostar-8,13-dienoic acid amide (R ¹ = Pr,
R ² = H, R ³ = H, R ⁴ = Pentyl, W = OH, XY = CH ₂ -CH ₂ , Z = COE
t ₂ , n = 0, - = trans-CH = CH)

[0500]

Embedded image

As raw materials and reagents, a pyridine solution of hydrogen fluoride (0.2 ml), N, N-diethyl (11R, 12S, 1
The same operation as in Example 2 was performed using (3E, 15S) -9-butyryloxy-11,15-bis (tert-butyldimethylsiloxy) -7-thiaprosta-8,13-dienoic acid amide (169 mg). And N, N-diethyl (11R,
12S, 13E, 15S) -9-butyryloxy-1
1,15-dihydroxy-7-thiaprosta-8,13
-Dienoic amide (101 mg, 78%) was obtained.

¹ H-NMR (270 MHz, δppm, CDCl ₃ ) 0.88 (t, J = 6.8 Hz, 3H) 1.00 (t, J = 7.3 Hz, 3H) 1.11 (t, J = 7.1 Hz, 3H) 1.17 (t, J = 7.1 Hz, 3H) 1.2-1.8 (m, 16H) 2.28 (t, J = 7.6 Hz, 2H) 2.4-2.7 (m, 3H) 2.43 (t, J = 7.3 Hz, 2H) 2.91 ( ddd, J = 1.0 & 6.8 & 16.3 Hz, 1H) 3.2-3.4 (m, 5H) 4.08 (dt, J = 6.6 & 6.6 Hz, 1H) 4.0-4.2 (m, 1H) 5.56 (dd, J = 8.1 & 15.3 Hz, 1H) 5.68 (dd, J = 6.4 & 15.3 Hz, 1H)

Example 93 Measurement of MCP-1-Induced Cell Migration Inhibitory Activity In order to examine the cell migration inhibitory activities of the test compounds described in Table 1, cell migration induced by the monocytic migration factor MCP-1 / MCAF Was measured using the human promonocyte-derived leukemia cell THP-1 (ATCC TIB203) as a migrating cell using the method of FALK et al. (J. Immunol.
Methods 33, 239-247 (198
0)) was carried out as follows. That is, a 96-well microchemotaxis chamber (Neuroprobe)
THP-1 in the upper chamber (200 μl)
Cells were cultured in 2 × 10 ⁶ / ml (10% fetal calf serum (FCS) supplemented RPMI-1640 medium (Flow Laborat).
recombinants human MCP-1 (Peprotech) in the lower chamber (35 μl).
Was diluted to a final concentration of 20 ng / ml, and a polycarbonate filter (pore size 5 μm, PVP-free, Neuroprobe) was placed between the two chambers.
Was fixed and incubated at 37 ° C. under 5% CO ₂ for 2 hours. Take out the filter, Diff
The cells that migrated to the lower surface of the filter were fixed and stained with Quick solution (manufactured by Kokusai Reagent Co., Ltd.).
(Molecular Device) at a measurement wavelength of 550 nm, and the average value of the three wells was obtained as an index of the number of migrated cells. At this time, a test compound was added to the upper chamber at various concentrations together with the THP-1 cells, and the cell migration inhibitory activity was determined. The percentage of cell migration inhibition was Δ (the number of migrating cells by MCP-1 added to the lower chamber when the test compound was added to the upper chamber)-(the absence of the test compound in the upper chamber and the MCP in the lower chamber).
-1 (number of migrating cells without addition of test compound)} to {(number of migrated cells by MCP-1 added to lower chamber without addition of test compound in upper chamber)-(no test compound added to upper chamber, lower chamber) MCP
-1) (the number of migrating cells without addition). The concentration of the compound showing 50% inhibition was defined as the degree of inhibition: IC ₅₀ . The results are shown in Tables 1 to 9.

Further, the results obtained by examining the cell migration inhibitory activity of the test compound using the same method as described above using human blood monosites instead of THP-1 cells are shown in Table 10.

Here, human blood monosites are as follows:
And got. The same amount of physiological saline in 50 ml of human peripheral blood
And Ficoll-paq previously returned to room temperature.
ue (Pharmacia). Per tube
Ficoll-paqu was added to 25 ml of the peripheral blood dilution.
e was 17 ml. After centrifugation at 400 g for 30 minutes at room temperature,
Slowly suck the middle layer with a pipette,
Physiological saline was added, centrifuged at 200 g for 10 minutes, and then cel
I pellet was obtained. The obtained cell pell
10 ml of physiological saline was added to the mixture, and 200 g of the suspension was added.
After centrifugal washing at 0 minutes, RPMI-
10 ml of 1640 medium was added and well suspended. 10cm
And incubate at 37 ° C for 1 hour.
After removing adherent cells, 5 ml of RP supplemented with 10% FCS
Washed three times with MI-1640 medium. Then violently
Peel off the attached cells by petting
And the resulting cell suspension was centrifuged at 200 g for 5 minutes.
Get cell pellet, RPM with 10% FCS
2 × 10 in I-1640 medium ⁶/ Ml
Manufactured as human blood monosites to evaluate cell migration inhibitory activity
It was used for.

[0506]

[Table 1]

[0507]

[Table 2]

[0508]

[Table 3]

[0509]

[Table 4]

[0510]

[Table 5]

[0511]

[Table 6]

[0512]

[Table 7]

[0513]

[Table 8]

[0514]

[Table 9]

[0515]

[Table 10]

Example 94 After Carotid Artery Endothelial Injury in Rats Using a Balloon Catheter
Test compound inhibiting action on membrane thickening : (11R, 12S, 13E, 15S, 17
R) -9-Butyryloxy-11,15-dihydroxy
-17,20-dimethyl-7-thiaprosta-8,13
-. Methyl dienoic acid Crows et al. Method (Lab.Invest, 49 vol.
206, 1983) according to the following method.
Male Wistar rats weighing 300-350 g were used. The rat was incised in the neck under anesthesia with pentobarbital sodium, and a balloon catheter (fogarty, 2F) was inserted from the right external carotid artery to the origin of the common carotid artery. After inflating the balloon with physiological saline to such an extent that resistance was slightly generated, the intima was injured by pulling the catheter to the external carotid artery in this state. This operation 3
After repetition, the catheter was removed and the external carotid artery was ligated. 14 days later, the chest was opened under diethyl ether anesthesia,
After perfusion and fixation from the aortic arch with Carnoy's solution (methanol: chloroform: acetic acid = 6: 3: 1), the right common carotid artery was excised and fixed with neutral formalin solution. After the fixed carotid artery was stained with Elasticavan Gieson, the media and the intimal thickening (Intim) were stained.
The area of a) was measured with an image analyzer (LUZEX2D).

The test compound was administered subcutaneously 3 days before the operation using a miniosmotic pump implanted in the back of the rat, and was 3.2 μg / rat until 11 days after the operation.
/ Hr continuously.

The intimal thickening inhibitory activity of the test compound was determined by the following formula.

Inhibition rate of intimal hyperplasia (%) = (1−T / C) × 100 (where T represents the test compound-administered group and C represents the control group (solvent-administered) rat. The ratio of the area of the membrane thickened part to the area of the media part [Intima / Media] is shown.) Table 11 shows the test results.

[0520]

[Table 11]

As is clear from the test results, the test compound inhibits the intimal thickening of blood vessels.

Example 95 After Injury of Rat Carotid Artery Endothelium by Balloon Catheter
Inhibitory effect on membrane thickening Test compound: (11R, 12S, 13E, 15S) -9
-Butyryloxy-11,15-dihydroxy-15-
Cyclohexyl-16,17,18,19,20-pen
An experiment was conducted in the same manner as in Example 94. Methyl tanol-7-thiaprosta-8,13-dienoate Table 12 shows the test results.

[0523]

[Table 12]

As is clear from the test results, the test compound inhibits the intimal thickening of blood vessels.

Example 96 After Carotid Endothelial Injury in Rabbits Using a Balloon Catheter
Test compound inhibiting action on membrane thickening : (11R, 12S, 13E, 15S, 17
R) -9-Butyryloxy-11,15-dihydroxy
-17,20-dimethyl-7-thiaprosta-8,13
-. Methyl dienoic acid Crows et al. Method (Lab.Invest, 49 vol.
206, 1983) according to the following method. A New Zealand white rabbit (male) weighing about 4 kg was used. The rabbit was incised in the neck under anesthesia with sodium pentobarbital, and a balloon catheter (fogarty, 3F) was inserted from the right external carotid artery to the origin of the common carotid artery. After inflating the balloon with physiological saline to such an extent that resistance was slightly generated, the intima was injured by pulling the catheter to the external carotid artery in this state. After performing this operation once, the catheter was removed and the external carotid artery was ligated. Ten days later, the chest was opened under pentobarbital anesthesia, and the right common carotid artery was excised and fixed with neutral formalin solution. Fix the carotid artery fixed to Elastica van Gi
After eson staining, the areas of the media (Media) and the intimal thickening (Intima) were measured using an image analyzer (LUZE).
X2D).

The test compound was administered subcutaneously 3 days prior to the operation using a miniosmotic pump implanted in the back of the rabbit, and until day 10 after the operation, 32 μg / rabbit /
It was administered continuously at the rate of hr every day.

The intimal thickening inhibitory activity of the test compound was determined by the following formula.

Inhibition rate of intimal hyperplasia (%) = (1−T / C) × 100 (where T represents the test compound-administered group and C represents the control group (solvent-administered) rabbit. The ratio [Intima / Media] between the area of the membrane thickened part and the area of the medial part is shown.) Table 13 shows the test results.

[0529]

[Table 13]

Example 97 Measurement of Platelet Aggregation Inhibitory Activity (1) Measurement of Rat Platelet Aggregation Inhibitory Activity Wistar rats (male, about 400 g) were fasted for one day and then whole blood was injected from the abdominal aorta under ether anesthesia. Collect blood, 3.
1/10 volume of 8% sodium citrate aqueous solution was added and mixed immediately. The upper layer was centrifuged at 1000 rpm for 10 minutes to obtain platelet-rich plasma, and the lower layer was centrifuged at 3000 rpm for 10 minutes to obtain the upper layer as platelet-poor plasma. Platelet-rich plasma diluted with platelet-poor plasma so that the platelet count became 3.5 × 10 ⁸ / mm ³ was used for measurement. The platelet was measured using an automatic blood cell counter MEK-4500 (Nihon Kohden). Platelet aggregation is measured by NBS HEMA TRACER 801 (MC Medical)
The measurement was performed by measuring the turbidity using. Fill a cuvette with 90 μl of platelet fluid and add 5 μl of each test compound.
After adjusting the final concentration to the desired final concentration and heating at 37 ° C for 1 minute, add 5 μl of 100 μM adenosine diphosphate aqueous solution (MC Medical) to induce platelet aggregation. I let it. Aggregation inhibitory activity was determined by the following equation.

Aggregation inhibition rate (%) = {1- (maximum turbidity change when test compound is added) / (maximum turbidity change when test compound is not added)} × 100 And compound showing 50% inhibition Was determined as IC ₅₀ . Tables 14 and 15 show the results.

[0532]

[Table 14]

[0533]

[Table 15]

(2) Measurement of Human Platelet Aggregation Inhibitory Activity From 50 ml of venous blood provided by healthy volunteers,
Platelet-rich and platelet-poor plasma were prepared as described above.
The measurement of platelet aggregation was performed in the same manner as described above. However, unlike the measurement of rat platelet aggregation inhibitory activity,
A test drug is added to platelet-poor plasma, and the mixture is heated at 37 ° C. for 5 minutes. Then, platelet-rich plasma is added so that the blood count becomes 3.5 × 10 ⁸ / mm ^3, and a 100 μM adenosine diphosphate aqueous solution (M Platelet aggregation was induced by adding 5 μl of C. Medical. Aggregation inhibition activity was calculated in the same manner as above. Table 16 shows the results.

[0535]

[Table 16]

[0536]

In the 7-thiaprostaglandins of the present invention, a compound wherein R ² is a hydrogen atom and W is a hydroxyl group, an enantiomer thereof, or a mixture thereof at an arbitrary ratio;
Or a drug containing a pharmaceutically acceptable salt thereof as an active ingredient is a chemokine such as MCP-1 / MC
It has the activity of inhibiting cell migration induced by AF. Thus, for example, vascular restenosis or vascular reocclusion that occurs after intimal injury in angioplasty,
It is useful as a preventive or therapeutic agent for diseases characterized by accumulation of monosites in blood, such as vascular stenosis or vascular occlusion, mainly due to atherosclerotic lesion formation in the coronary artery or cervical aorta. is there.

Alternatively, the 7-thiaprostaglandins of the present invention have a platelet aggregation inhibitory activity, which is a typical physiological action of prostaglandins, and the prostaglandins have been conventionally useful. It is useful as an agent for preventing and treating thrombosis, myocardial infarction, angina and the like.

Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/557 ADS A61K 31/557 ADS (72) Inventor Takashi Ishii 4-3-1 Asahigaoka, Hino-shi, Tokyo Teijin Limited Tokyo Research Center (72) Inventor Noriaki Endo 4-2-2 Asahigaoka, Hino-shi, Tokyo Teijin Limited Tokyo Research Center (58) Field surveyed (Int. Cl. ⁶ , DB name) C07C 405/00 CA (STN ) CAOLD (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] 1. A compound represented by the following formula (I): [Wherein, R ¹ is a C1-C10 linear or branched alkyl group, a C2-C10 linear or branched alkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C3-C10 A substituted or unsubstituted amino acid residue including a cycloalkyl group, a substituted or unsubstituted phenyl (C1 to C2) alkyl group, a substituted or unsubstituted phenoxy (C1 to C7) alkyl group, or a carbonyl group of an enol ester; Represents a group represented by R ²
Represents a hydrogen atom, a tri (C1 to C7 hydrocarbon) silyl group, or a group that forms an acetal bond with an oxygen atom of a hydroxyl group. R ³ represents a hydrogen atom, a methyl group, or a vinyl group. R ⁴ is C1~C8 straight or branched alkyl group, a linear or branched alkenyl group of C2-C8, linear or branched alkynyl group C2-C8, a substituted or unsubstituted phenyl group, A substituted or unsubstituted C3-C10 cycloalkyl group,
A C1-C5 alkoxy group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted C3-C10 cycloalkyl group,
A linear or branched C1-C5 alkyl group substituted with a substituted or unsubstituted heterocyclic group,
Represents an alkenyl group of C5 and an alkynyl group of C2 to C5. W is a hydrogen atom, a hydroxyl group, a tri (C1-C7
(Hydrocarbon) represents a siloxy group or a group that forms an acetal bond. XY represents an ethylene group, a vinylene group, or an ether bond in which X is an oxygen atom and Y is methylene. Z represents CO ₂ R ⁵ or CONR ⁶ R ⁷ . R
⁵ is a hydrogen atom, a C1-C10 linear or branched alkyl group, a C2-C10 linear or branched alkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C3-C10 cycloalkyl. Groups, substituted or unsubstituted phenyl (C1-C2) alkyl groups,
Alternatively, it represents one equivalent of a cation. R ⁶ and R ⁷ are the same or different and represent a hydrogen atom, a C1 to C5 linear or branched alkyl group, or a group that forms a C4 to C6 heterocycle together with the amide nitrogen atom. n represents 0 or 1. Signage - represents a double bond or a single bond. 7-thiaprostaglandins which are compounds represented by the formula: or their enantiomers, or mixtures thereof in any proportion. 2. A group in which R ¹ is a substituted or unsubstituted amino acid residue including a C1 to C5 linear or branched alkyl group, a substituted or unsubstituted phenyl group, or a carbonyl group of an enol ester. , R ² is a hydrogen atom, a trimethylsilyl group, a tert-butyldimethylsilyl group, or a 2-tetrahydropyranyl group, R ³ is a hydrogen atom or a methyl group, and R ⁴ is a C1 to C8 linear or branched. Alkyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted C3 to C10 cycloalkyl group, or C1 to C5 alkoxy group, substituted or unsubstituted aromatic group, and substituted or unsubstituted phenoxy Linear or substituted with a group, a substituted or unsubstituted C3-C10 cycloalkyl group, or a substituted or unsubstituted heterocyclic group; Branched C1~C5 alkyl group, W is hydrogen atom, a hydroxyl group or,, tert
-Butyldimethylsiloxy group, XY is an ethylene group, a vinylene group, or a group that is an ether bond in which X is an oxygen atom and Y is methylene, Z is CO ₂ R ⁵ or CONR
⁶ R ⁷ , wherein R ⁵ is a C1 to C5 linear or branched alkyl group or an allyl group, R ⁶ and R ⁷ are the same or different, a hydrogen atom, or a C1 to C5 linear or branched The 7-thiaprostaglandins according to claim 1, wherein the alkyl group, n is 0 or 1, and- is a double bond or a single bond. 3. R ¹ is a C1-C5 linear or branched alkyl group or a phenyl group, R ² is a hydrogen atom,
Trimethylsilyl group, tert-butyldimethylsilyl group,
Or a 2-tetrahydropyranyl group, R ³ is a hydrogen atom or a methyl group, R ⁴ is a C1 to C8 linear or branched alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C3 to A cycloalkyl group of C10, or a linear or branched C1-C5 alkyl group substituted with a substituted or unsubstituted phenyl group, W is a hydroxyl group, or a tert-butyldimethylsiloxy group, XY is an ethylene group, a vinylene group or,, X is an oxygen atom, Y is an ether bond methylene group, Z is in CO ₂ R ^5, R ⁵ is a methyl group, butyl group or an allyl group,, n is 0, signage - - is 7-thia-prostaglandins of claim 1 is a double bond. 4. R ¹ is a propyl group, R ² and R ³ are a hydrogen atom, R ⁴ is a 2-methylhexyl group or a substituted or unsubstituted benzyl group, XY is an ethylene group, or
X is an oxygen atom, Y is a methylene ether bond,
Z is in CO ₂ R ^5, R ⁵ is a methyl radical, n is 0, signage - is 7-thia-prostaglandins of claim 1 is a double bond. 5. A compound represented by the following formula (II): [Wherein, R ³ , R ⁴ , n, and the notation — are the same as defined above, and R ²¹ is a tri (C1 to C7 hydrocarbon) silyl group or a group that forms an acetal bond with a hydroxyl group oxygen atom. Represents M is a lithium atom, or tri (C
1-C6 hydrocarbon) represents a stannyl group. ] And an organic tin compound and an organic tin compound represented by CuQ [wherein Q represents a halogen atom, a cyano group, a phenylthio group, a 1-pentynyl group, or a 1-hexynyl group. And an organocopper compound prepared from the following formula (III): [Wherein, XY is the same as defined above. W ′ represents a hydrogen atom, a tri (C1 to C7 hydrocarbon) siloxy group, or a group that forms an acetal bond. Z ′ represents CO ₂ R ⁵¹ , where R ⁵¹ is a C1-C10 linear or branched alkyl group, a C2-C10 linear or branched alkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl group. Represents a substituted C3-C10 cycloalkyl group or a substituted or unsubstituted phenyl (C1-C2) alkyl group. After reacting with represented by 2-organothio-2-cyclopentenone or its enantiomeric or mixtures of them at any ratio in], further, (R ¹ CO) in ₂ O [wherein, R ¹ is the Same as definition. Or R ¹ COCl wherein R ¹ is as defined above. Or the following formula (IV): [Wherein, R ¹ is the same as defined above. And subjecting it to at least one of deprotection, hydrolysis, amidation, and salt formation as required.