JPH025750B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a novel method for producing prostaglandin E ₁ derivatives useful as pharmaceuticals.

For more details, △ ⁷ - Prostaglandin E ₁ A prostaglandin useful as a pharmaceutical can be produced by reducing the double bonds at the 7 and 8 positions with an organotin hydride compound in the presence of a zero-valent palladium catalyst.
The present invention relates to a method for producing an E ₁ derivative.

<Prior Art> Prostaglandin E ₁ derivatives are compounds that have physiological effects such as platelet aggregation inhibition, vasodilatory, antiulcer, and immunosuppressive effects, and are being applied clinically. Conventionally, the method for obtaining the prostaglandin E ₁ derivative using the △ ⁷ -prostaglandin E ₁ derivative as a starting material involves converting the △ ⁷ -prostaglandin E ₁ derivative into α,α′-azobisisobutyronitrile. The purpose was accomplished by carrying out a reduction reaction via a radical reaction with an organotin hydride compound such as tributyltin hydride in the presence of a radical initiator such as or bis-t-butyl peroxide. . A particularly difficult point of this reaction is that a radical reduction reaction is carried out at high temperature on the △ ⁷ -prostaglandin E ₁ derivative, which is not very stable to heat. is a compound of sulfur atoms△
^7-5 -thiaprostaglandin E ₁ derivatives are easily decomposed to give undesirable by-products because their reaction intermediate becomes allyl sulfide radical. In addition, there were practical problems such as the need to use a large excess amount of the organic tin hydride compound in order to complete the reaction.

<Objective of the Invention> As a result of intensive research by the present inventors to find a more advantageous chemical synthesis method for producing prostaglandin E 1 derivatives from Δ ⁷ -prostaglandin E ₁ derivatives, △ ⁷ -prostaglandin E ₁ derivatives ₁ derivative to 0
The present invention has been made based on the discovery that a non-radical conjugate reduction reaction can proceed efficiently and in high yield at a lower temperature by using an organotin hydride compound in the presence of a valent palladium catalyst. has been reached.

Therefore, the object of the present invention is to selectively reduce the double bonds at positions 7 and 8 of △ ⁷ -prostaglandin E ₁ derivatives, and to produce prostaglandin E ₁ derivatives useful as pharmaceuticals in an industrially advantageous manner. And what's more, it's about getting it efficiently.

<Structure and effects of the invention> The manufacturing method of the present invention is based on the following formula [] [In the formula, R ¹ is a hydrogen atom, a C ₁ to C ₁₀ alkyl group,
Represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted _C3 - _C10 cycloalkyl group, or a substituted or unsubstituted phenyl ( _C1 - _C2 ) alkyl group, and ^R2 and ^R3 are the same or different. , represents a hydrogen atom, a tri(C ₁ - _{C 7} ) hydrocarbon silyl group, or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, and R ⁴ is a hydrogen atom, a methyl group,
or represents a vinyl group, R ⁵ is a linear or branched C ₃ -C ₈ alkyl group which may contain an oxygen atom; an optionally substituted phenyl group, phenoxy group or C ₃ -C ₁₀ cycloalkyl or a straight-chain or branched C1- _C5 alkyl group substituted with a _C1 -C6 alkoxy group, an optionally substituted phenyl group, a phenoxy group, or a _{C3 - C10 cycloalkyl} group , A represents a methylene group or a sulfur atom, and B represents a single bond or a methylene group. The display 〓〓 indicates that the 7Z body, the 7E body, or the 7Z body and the 7E body coexist in an arbitrary ratio. ] The following formula [] is characterized in that the △ ⁷ -prostaglandin E ₁ derivative represented by is reduced with an organotin hydride compound in the presence of a zero-valent palladium catalyst. [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A, and B
is the same as the above definition. ] This is a method for producing a prostaglandin E ₁ derivative represented by the following.

As described above, the production method of the present invention is directed to the production of △ ⁷ which is represented by the above formula [] and has a double bond at the 7th and 8th positions.
- Using a prostaglandin E ₁ derivative as a starting material, the double bond thereof is selectively reduced to produce a prostaglandin E ₁ derivative.

In the above formula [], R ¹ is a hydrogen atom, C ₁ to _{C 10}
Alkyl group, substituted or unsubstituted phenyl group,
substituted or unsubstituted _C3 - _C10 cycloalkyl group,
or substituted or unsubstituted phenyl (C ₁ -C ₂ )
Represents an alkyl group.

Examples of C ₁ to _{C 10} alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n
-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and other linear or branched ones.

Examples of substituents for directly substituted or unsubstituted phenyl groups include halogen atoms, hydroxy groups, and C _2
-C7 acyloxy group, C1-C4 alkyl group optionally substituted with a halogen atom, _C1 - _C4 alkoxy group optionally substituted with a halogen atom, nitrile group, carboxyl group, or (C1 _-C4 alkyl group _{optionally substituted} with a halogen atom) ₆ ) Alkoxycarbonyl group etc. are preferred. The halogen atom is preferably fluorine, chlorine or bromine, particularly fluorine or chlorine. As a _C2 - _C7 acyloxy group,
Mention may be made, for example, of acetoxy, propionyloxy, n-butyryloxy, iso-butyryloxy, n-valeryloxy, iso-valeryloxy, caproyloxy, enantyloxy or benzoyloxy.

Examples of the _C1 - _C4 alkyl group optionally substituted with halogen include methyl, ethyl, n-propyl, iso-propyl, n-butyl, chloromethyl,
Preferred examples include dichloromethyl and trifluoromethyl. Preferred examples of the _C1 - _C4 alkoxy group which may be substituted with halogen include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, chloromethoxy, dichloromethoxy, trifluoromethoxy, etc. be able to.
Examples of the ( _C1 - _C6 ) alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl,
Examples include butoxycarbonyl, hexyloxycarbonyl, and the like.

The substituted phenyl group has 1 to 3 substituents as described above.
, preferably one.

Substituted or unsubstituted _C3 - _C10 cycloalkyl groups include saturated or unsaturated _C3 substituted or unsubstituted with the same substituents as mentioned above;
_-C10 , preferably _C5 - _C6 , particularly preferably _C6 groups, such as cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclodecyl and the like.

Examples of the substituted or unsubstituted phenyl ( _C1 - _C2 ) alkyl group include benzyl, α-phenethyl, and β-phenethyl, in which the phenyl group is substituted with the same substituent as mentioned above or unsubstituted.

R ¹ is preferably a hydrogen atom or a C ₁ -C ₁₀ alkyl group.

R ² and R ³ are the same or different, a hydrogen atom,
It is a group that forms an acetal bond with the oxygen atom of a tri(C ₁ -C ₇ ) hydrocarbon silyl group or hydroxyl group.

As a tri(C ₁ - C ₇ ) hydrocarbon silyl group,
For example, trimethylsilyl, triethylsilyl, t
-tri(C ₁ -C ₄ ) such as butyldimethylsilyl group
alkylsilyl, diphenyl(C ₁ -C ₄ )alkylsilyl, such as t-butyldiphenylsilyl group;
Phenyl (C _1
-C4 ) Alkylsilyl or tribenzylsilyl groups are preferred.

Groups that form an acetal bond with the oxygen atom of a hydroxyl group include, for example, methoxymethyl, 1-ethoxyethyl, 2-methoxy-2-propyl, 2
-ethoxy-2-propyl, (2-methoxyethoxy)methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or 6,6-dimethyl-3-oxa-2-oxobicyclo[3.1.0]hex -4-yl group may be mentioned. Among these, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-ethoxyethyl, 2-methoxy-2-propyl, (2-
Particularly preferred are the methoxyethoxy)methyl or 6,6-dimethyl-3-oxa-2-oxobicyclo[3.1.0]hex-4-yl groups.

Among these, R ² or R ³ is a hydrogen atom,
Tri( _C1 - _C4 )alkylsilyl group, diphenyl( _C1 - _C4 )alkylsilyl group, phenyldi(C1 _-C4 )
_C4 ) alkylsilyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, 1-ethoxyethyl group, 2-ethoxy-2-propyl group,
(2-methoxyethoxy)methyl group, or 6,6
-dimethyl-3-oxa-2-oxo-bicyclo[3.1.0]hex-4-yl group is preferred.

In the above formula [], R ⁴ represents a hydrogen atom, a methyl group or a vinyl group.

In the above formula [], R ⁵ is a straight chain or branched C ₃ -C ₈ alkyl group which may contain an oxygen atom; an optionally substituted phenyl group, phenoxy group or C ₃ -C ₁₀ cycloalkyl group ;or
Straight chain or branched chain substituted with C ₁ - C ₆ alkoxy group, optionally substituted phenyl group, phenoxy group or C ₃ - C ₁₀ cycloalkyl group
Represents a _C1 - _C5 alkyl group.

Straight-chain or branched _C3 - _C8 alkyl groups which may contain an oxygen atom include 2-methoxyethyl, 2-ethoxyethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, 1-methylbutyl, - methylbutyl, 2-methylhexyl, 2-methyl-2-hexyl, 2-hexyl, 1,1-dimethylpentyl group, preferably 2
-methoxyethyl, butyl, pentyl, hexyl, (R)- or (S)-2-methyl-hexyl, 1-methylbutyl groups, particularly preferably butyl and pentyl groups.

The optionally substituted phenyl group and phenoxy group may be substituted with the substituents listed as the substituents for the substituted phenyl group of R ¹ . In addition, the optionally substituted C ₃ - C ₇ cycloalkyl group includes a saturated or unsaturated cycloalkyl group substituted with the same substituent as described above or unsubstituted.
_C3 to _C10 , preferably _C4 to _C7 , particularly preferably
C ₅ , C ₆ cycloalkyl groups, such as cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl,
Examples include cyclodecyl group.

Among straight _- chain or branched C1- _C5 alkyl groups substituted with _C1 -C6 alkoxy groups, optionally substituted phenyl groups, phenoxy groups or _C3 - _C10 cycloalkyl groups, _C Examples of _{the 1} to _C6 alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, and hexyloxy groups, and the optionally substituted phenyl and phenoxy groups include those mentioned above. It can be given as is. As the C ₃ -C ₁₀ cycloalkyl group, the above-mentioned ones can be mentioned as they are, and as the straight chain or branched chain C ₁ -C ₅ alkyl group, methyl,
ethyl, propyl, iso-propyl, butyl, iso
-butyl, sec-butyl, t-butyl, pentyl groups, etc., and the substituent may be bonded to any position thereof.

In the above formula [], A represents a methylene group or a sulfur atom. When A represents a methylene group, the above formula [] is replaced by the following formula [-1] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and B are the same as defined above. ] means a △ ⁷ -prostaglandin E ₁ derivative represented by, and when A represents a sulfur atom, the above formula [] is replaced by the following formula [-2] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and B are the same as defined above. ] means a 5-thia-Δ ⁷ -prostaglandin E ₁ derivative represented by:

In the above formula [], B represents a single bond or a methylene group. When B represents a single bond, the above formula [] becomes the following formula [-3] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and A are the same as defined above. ] means a △ ⁷ -prostaglandin E ₁ derivative represented by, and when B represents a methylene group, the above formula [ ] is replaced by the following formula [-4] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and A are the same as defined above. ] 15-deoxy-16-hydroxy-△ represented by
⁷ - means prostaglandin E ₁ derivative.

The above formula [] ([-1], [-2], [-3]
,
and [-4]), the double bond stereochemistry is 7Z, 7E, or 7Z.
This shows that the 7E body and the 7E body coexist in arbitrary proportions.

Also, the above formula [] ([-1], [-2], [-
3], and [-4]), the steric configuration of the substituent bonded to the cyclopentanone ring is the same as that of natural prostaglandin E ₁ . The following formula [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A and B are the same as defined above. ] The stereoisomer represented by and its mirror image, the following formula []ent [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A and B are the same as defined above. ] It also includes stereoisomers represented by these or mixtures of both in arbitrary proportions.

In addition, since the carbons substituted by OR ³ , R ⁴ and R ⁵ are asymmetric carbons, there are two types of optical isomers, but any of the optical isomers or a mixture of them in any proportion can be used. It includes.

The △ ⁷ -prostaglandin E ₁ derivative, which is the starting material of the present invention, is prepared by the following reaction formula by a method separately proposed by the present inventors (see, for example, Japanese Patent Application Laid-Open No. 58-83670). As shown, the 7-hydroxyprostaglandin E ₁ derivative is an aldol condensate of an enolate intermediate obtained by conjugate addition of an organocopper compound to a protected (optically active) 4-hydroxy-2-cyclopentenone. It can be easily obtained by subjecting it to a dehydration reaction.

[In the above reaction formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A,
and B are the same as defined above. Also R ¹¹ ,
R ²¹ and R ³¹ are the same as the definitions of R ¹ , R ² , and ^{R 3} except that they are hydrogen atoms. ] Preferred specific examples of the Δ ⁷ -prostaglandin E ₁ derivative represented by the above formula [ ], which is the starting material of the present invention, include the compounds shown below. Note that prostaglandin E ₁ is PGE ₁
It is abbreviated as . In addition, both compounds and 7Z
Although there are geometric isomers such as isomer and 7E isomer, both can be similarly used as starting materials of the present invention, so it should be understood that both isomers are included, although they are not specifically expressed.

(1) △ ⁷ -PGE ₁ (2) 15-methyl - △ ⁷ -PGE ₁ (3) 15-vinyl - ⁷ -PGE ₁ (4) 20-methyl - ⁷ -PGE ₁ (5) 20-ethyl -△ ⁷ -PGE ₁ (6) 17(S),20-dimethyl-△ ⁷ -PGE ₁ (7) 17(R),20-dimethyl-△ ⁷ -PGE ₁ (8) 16-methyl-△ ⁷ - PGE ₁ (9) 16,16-dimethyl-△ ⁷ -PGE ₁ (10) 16, 17, 18, 19, 20-pentanol-15-cyclopentyl-△ ⁷ -PGE ₁ (11) 16, 17, 18, 19 ,20-pentanol-15-cyclohexyl-△ ⁷ -PGE ₁ (12) 17,18,19,20-tetranol-16-cyclohexyl-△ ⁷ -PGE ₁ (13) 18-oxa-△ ⁷ -PGE ₁ (14 ) 17,18,19,20-tetranol-16-phenyl-△ ⁷ -PGE ₁ (15) 17,18,19,20-tetranol-16-phenoxy-△ ⁷ -PGE ₁ (16) 15-deoxy-16 -Hydroxy-△ ⁷ -
PGE ₁ (17) 15-deoxy-16-hydroxy-16-methyl-△ ⁷ -PGE ₁ (18) 15-deoxy-16-hydroxy-16-vinyl-△ ⁷ -PGE ₁ (19) 15-deoxy-16 -hydroxy-20-methyl-△ ⁷ -PGE ₁ (20) 15-deoxy-16-hydroxy-17, 18,
19,20-tetranol-16-cyclohexyl-△
⁷ -PGE ₁ (21) 15-deoxy-16-hydroxy-17, 18,
19,20-tetranor-16-phenyl-△ ⁷ −
PGE ₁ (22) 15-deoxy-16-hydroxy-17,20-
Dimethyl-△ ⁷ -PGE ₁ (23) 5-thia-△ ⁷ -PGE ₁ derivative (24) of (1) to (22) Enantiomer (25) of the compound (1) to (23) (1) to Methyl ester of (24) (26) Ethyl ester of (1) to (24) (27) The hydroxyl groups (11th and 15th or 16th positions) of the compounds of (1) to (26) are 2-tetrahydropyranyl groups. Examples include, but are not limited to, compounds protected with and/or t-butyldimethylsilyl groups. Also included are the 15-epi forms (or 16-epi forms) of the compounds (1) to (27) and their mirror images.

The method of the present invention is to selectively reduce the double bonds at positions 7 and 8 of the above formula [] to lead to the prostaglandin E ₁ derivative represented by the above formula [].
That is, the Δ ⁷ -prostaglandin E ₁ derivative represented by the above formula [] is reacted with an organotin hydride compound in the presence of a zero-valent palladium catalyst to produce the corresponding prostaglandin E represented by the above formula []. ₁ derivative can be easily obtained.

Examples of the zero-valent palladium catalyst used in the above reaction include zero-valent palladium itself, or those that form a complex with an appropriate ligand, but considering the catalyst efficiency, Improved solubility in organic matter0
Preferred are valent palladium complexes. Examples of the ligand for such a zero-valent palladium catalyst include 1,2-diphenylphosphine, methyldiphenylphosphine, triphenylphosphine, and dibenzylideneacetone, but triphenylphosphine is particularly preferred. As the zero-valent palladium complex coordinated with the ligand, tetrakis(triphenylphosphine)palladium(0) can be mentioned.

Furthermore, even if the catalyst is reduced in the reaction system to produce a zero-valent palladium catalyst, the reaction will proceed, and the present invention can be carried out preferably.

The amount of the zero-valent palladium catalyst used is related to its catalytic ability, but it is usually 10 mol% to 0.01 mol%, preferably 3 mol%, based on the raw material compound [].
It is sufficient to use an amount of ~0.1 mol%.

Examples of the organic tin hydride compound include dibutyltin dihydride, tributyltin hydride, tributyltin deuteride, and triphenyltin hydride, and tributyltin hydride is particularly preferred since it is easily available.

The amount of the organic tin hydride compound used varies depending on its reactivity, but is usually 1 equivalent to 1000 equivalents, preferably 1 equivalent to 1,000 equivalents relative to the raw material compound.
100 equivalents are used, particularly preferably 2 to 10 equivalents. A reaction solvent may be used as necessary, and benzene, tetrahydrofuran, chloroform, dioxane, etc. are usually used, but the reaction proceeds even without a solvent, and if the reaction system is homogeneous, a solvent-free reaction is preferable.

The reaction temperature is in the range of 0°C to 100°C, preferably 20°C to 60°C, and the reaction time is in the range of 1 to 48 hours, but the reaction temperature and reaction time may vary depending on the catalyst used and the reaction time. It usually varies depending on the reducing agent, and it is effective to carry out the reaction while monitoring it using analytical means such as gas chromatography, liquid chromatography, and thin layer chromatography.

After completion of the reaction, the prostaglandin E ₁ derivative represented by the above formula [] can be obtained by a conventional method.
For example, separation and purification can be carried out using separation means such as addition of water, extraction, washing, drying, D separation, and chromatography after concentration.

Thus, the prostaglandin E 1 derivative represented by the above formula [] is isolated, but the prostaglandin E ₁ derivative represented by the above formula []
From nat and the above formula []eat, the following formula []nat and the following formula []ent, which are the corresponding prostaglandin E ₁ derivatives, respectively. [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A, and B
is the same as the above definition. ] A prostaglandin E ₁ derivative having the configuration represented by the following will be obtained as the main product.

A specific example of the prostaglandin E ₁ derivative represented by the above formula [] is the above formula []
Compounds corresponding to specific examples of the Δ ⁷ -prostaglandin E ₁ derivative represented by the formula are listed as such.

Thus, according to the present invention, a useful synthetic method that avoids radical reactions and can obtain Δ ⁷ -prostaglandin E ₁ derivatives in high yield under mild conditions has been completed.

The present invention will be explained below with reference to Examples.

Example 1 Prostaglandin E ₁ methyl ester 11,15
-Synthesis of bis(t-butyldimethylsilyl)ether △ ⁷ -Prostaglandin E ₁ methyl ester 11,
Tetrakis(triphenylphosphine)palladium(0) (538 mg,
Tributyltin hydride (81.5 g,
280 mmol) was gradually added dropwise over 12 hours. After the dropwise addition was completed, 100 ml of a saturated ammonium chloride aqueous solution was added, and after stirring for 15 minutes, extraction was performed with hexane (300 ml x 3), and the resulting organic layer was washed with brine. The separated organic layer was dried over anhydrous magnesium sulfate,
After filtering and concentrating, 165 g of crude product was obtained. This was subjected to silica gel column chromatography (silica gel 1 kg; hexane → hexane: ethyl acetate =
9:1) to separate prostaglandins.
E ₁ methyl ester 11,15-bis(t-butyldimethylsilyl)ether (49.5g, 83.0mmol89
I got %.

IR (neat): 1743, 1253, 835, 774 cm ^-1 NMR (δppm in CDCl ₃ ): 0 ~ 0.2 (m, 12H), 0.89 (s, 18H), 0.7 ~
1.1 (m, 3H), 1.1~3.0 (m, 24H), 3.70 (s,
3H), 3.7-4.4 (m, 2H), 5.4-5.7 (m, 2H) Example 2 17(R), 20-dimethyl-5-thiaprostaglandin E ₁ Methyl ester 11, 15-bis(t-
Synthesis of butyldimethylsilyl) ether 17(R),20-dimethyl-5-thia-△ ⁷ -prostaglandin E ₁ methyl ester 11,15-bis(t-butyldimethylsilyl)ether 29.7g,
tributyltin hydride (53.9 g,
185 mmol) was added dropwise at room temperature for 8 hours.
After the same post-treatment and separation and purification as in Example 1, 17
(R), 20-dimethyl-5-thiaprostaglandin E ₁ methyl ester 11,15-bis(t-butyldimethylsilyl) ether (27.0 g, 42.0 mmol,
91%).

NMR (δppm in CDCl ₃ ): 0~0.2 (m, 12H), 0.87 (s, 18H), 0.7~
1.1 (m, 6H), 1.1~3.0 (m, 27H), 3.62 (s,
3H), 3.8-4.3 (m, 2H), 5.4-5.6 (m, 2H) Example 3 17(S),20-dimethyl-5-thiaprostaglandin E ₁ Methyl ester 11,15-bis(t-
Synthesis of butyldimethylsilyl) ether 17(S),20-dimethyl-5-thia-△ ⁷ -prostaglandin E ₁ methyl ester 11,15-bis(t-butyldimethylsilyl)ether (7.1g,
tributyltin hydride (19.4 g,
66.5 mmol) was added dropwise at room temperature over 6 hours.
After the same post-treatment and separation and purification as in Example 1, 17
(S),20-dimethyl-5-thiaprostaglandin E ₁ methyl ester 11,15-bis(t-butyldimethylsilyl)ether (6.35g, 9.9mmol,
89%).

NMR (δppm in CDCl ₃ ): 0~0.2 (m, 12H), 0.87 (s, 18H), 0.7~
1.1 (m, 6H), 1.1~3.0 (m, 27H), 3.63 (s,
3H), 3.8-4.3 (m, 2H), 5.4-5.6 (m, 2H) Example 4 Synthesis of 17(S),20-dimethyl-5-thiaprostaglandin E ₁ methyl ester 17(S), 20 -dimethyl-5-thia-△ ⁷ -prostaglandin E ₁ methyl ester (1.20g,
Tributyltin hydride (2.50 g, 8.6 mmol) was added dropwise over 48 hours to a solution of tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol) in tetrahydrofuran (3 ml). Extract with ethyl acetate as in Example 1, and separate and purify in the same manner (20 g of silica gel; hexane: ethyl acetate = 1:3) to obtain 17(S),20-dimethyl-5-thiaprostaglandin E ₁ methyl. Ester (1.00 g, 2.42 mmol, 83%) was obtained.

NMR (δppm in CDCl ₃ ): 0.9 (m, 6H), 1.2-1.6 (m, 15H), 1.8-2.8
(m, 10H), 3.67 (s, 3H), 4.2~4.2 (m,
2H), 5.7 (m, 2H) Example 5 15-deoxy-16-hydroxy-16-methyl prostaglandin E ₁ methyl ester 11,16-
Synthesis of bis(t-butyldimethylsilyl)ether 15-deoxy-16-hydroxy-16-methyl-
△ ⁷ - Prostaglandin E ₁ methyl ester 11,
16-bis(t-butyldimethylsilyl)ether (3.72 g, 5.85 mmol) and tetrakis(triphenylphosphine)palladium(0) (68 mg,
Tributyltin hydride (6.81 g, 23.4 mmol) was added dropwise to a mixed solution of 0.059 mmol) over 5 hours at room temperature. After post-treatment, separation and purification in the same manner as in Example 1, 15
-deoxy-16-hydroxy-16-methyl prostaglandin E ₁ methyl ester 11,16-bis(t-butyldimethylsilyl) ether (3.13 g,
4.91 mmol, 84%).

NMR (δppm in CDCl ₃ ): 0 to 0.2 (m, 12H), 0.86 (s, 18H), 0.7 to
1.1 (m, 3H), 1.13 (s, 3H), 1.1~3.3 (m,
24H), 3.67 (s, 3H), 3.9~4.1 (m, 1H),
5.4-5.7 (m, 2H)

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ¹ is a hydrogen atom, a C ₁ to C ₁₀ alkyl group,
Represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted _C3 - _C10 cycloalkyl group, or a substituted or unsubstituted phenyl ( _C1 - _C2 ) alkyl group, and ^R2 and ^R3 are the same or different. , represents a hydrogen atom, a tri(C ₁ - _{C 7} ) hydrocarbon silyl group, or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, and R ⁴ is a hydrogen atom, a methyl group,
or represents a vinyl group, R ⁵ is a linear or branched C ₃ -C ₈ alkyl group which may contain an oxygen atom; an optionally substituted phenyl group, phenoxy group or C ₃ -C ₁₀ cycloalkyl or a straight-chain or branched C1- _C5 alkyl group substituted with a _C1 -C6 alkoxy group, an optionally substituted phenyl group, a phenoxy group, or a _{C3 - C10 cycloalkyl} group , A represents a methylene group or a sulfur atom, and B represents a single bond or a methylene group. The display 〓〓 indicates that the 7Z body, the 7E body, or the 7Z body and the 7E body coexist in an arbitrary ratio. ] The following formula [] is characterized in that the △ ⁷ -prostaglandin E ₁ derivative represented by is reduced with an organotin hydride compound in the presence of a zero-valent palladium catalyst. [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A, and B
is the same as the above definition. ] A method for producing a prostaglandin E ₁ derivative represented by: 2. The method for producing a prostaglandin E ₁ derivative according to claim 1, wherein the organotin hydride compound is tributyltin hydride. 3. The method for producing a prostaglandin E ₁ derivative according to claim 1 or 2, wherein the 0-valent palladium catalyst is tetrakis(triphenylphosphine)palladium(0). 4 Any one of claims 1 to 3, wherein R ¹ is a hydrogen atom or a C ₁ to C ₁₀ alkyl group
A method for producing the prostaglandin E ₁ derivative described in Section 1. 5 R ² and R ³ are the same or different and are hydrogen atom, tri(C ₁ -C ₄ )alkylsilyl group, diphenyl(C ₁ -C ₄ )alkylsilyl group, phenyldi(C ₁ -
_C4 ) alkylsilyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, 1-ethoxyethyl group, 2-ethoxy-2-propyl group,
(2-methoxyethoxy)methyl group, or 6,
Prostaglandin E ₁ according to any one of claims 1 to 4, which is a 6-dimethyl-3-oxa-2-oxobicyclo[3,1,0]hex-4-yl group. Method for producing derivatives. 6. The method for producing a prostaglandin E ₁ derivative according to any one of claims 1 to 5, wherein R ⁴ is a hydrogen atom. 7. The method for producing a prostaglandin E ₁ derivative according to any one of claims 1 to 5, wherein R ⁴ is a methyl group. 8. The method for producing a prostaglandin E ₁ derivative according to any one of claims 1 to 5, wherein R ⁴ is a vinyl group. 9 ^R5 is a butyl group, a pentyl group, a hexyl group,
1-methylbutyl group, 1-methylpentyl group, 1
-Methylhexyl group, 2-methylpentyl group, 2
-Methylhexyl group, cyclopentyl group, cyclohexyl group, cyclohexylmethyl group, or phenyl group. The method for producing a prostaglandin E ₁ derivative according to any one of claims 1 to 8. 10 Claim 1 in which A is a methylene group
10. A method for producing a prostaglandin E ₁ derivative according to any one of items 9 to 9. 11. The method for producing a prostaglandin E ₁ derivative according to any one of claims 1 to 9, wherein A is a sulfur atom. 12 Claims 1 to 12 in which B is a single bond
12. A method for producing a prostaglandin E ₁ derivative according to any one of Item 11. 13 Claim 1 in which B is a methylene group
12. A method for producing a prostaglandin E ₁ derivative according to any one of Items 1 to 11.