JPS5942364A - Preparation of prostaglandin f - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a labor pain promotor or intestinal hyperkinetic agent, etc. from an easily available raw material in high yield in short step, by reducing a 7-sulfonyloxyprostaglandin F. CONSTITUTION:A 7-sulfonyloxyprostaglandin F of formula I (B is -CH2-CH2, -CH=CH- or -CidenticalC-,; R<1> is H, 1-10C alkyl, phenyl or cycloalkyl, etc.; R<2> is 1-14C alkyl, phenyl, etc.; R<3> and R<4> are H, OH, etc.; R<5> is unsubstituted 1- 8C alkyl, phenyl, etc.; R<6> is H, methyl, ethynyl, etc.; the dotted line part is a single or double bond) is reduced with a reducing reaction agent, e.g. sodium boron hydride, in a solvent, e.g. hexamethylphosphoric triamide or dimethyl sulfoxide, at 0-150 deg.C, preferably 30-100 deg.C, to give the aimed substance of formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing BuI:+7 taglandin F. More specifically, the present invention relates to a method for producing prostaglandin F by subjecting 7-sulfonyloxyprostaglandin F to a reduction reaction.

Prostaglandin F2α, a typical compound of the prostaglandin F class, has uterine smooth muscle contraction action and intestinal tract contraction action, and is a useful compound used as a pharmaceutical agent such as a labor stimulant and an intestinal motility promoter. .

Conventional production of these prostaglandin F-6= Many methods are known for this (J, B.

Bindra et al + Prostaglandln 5
ynthesis, Academic Press (1
977:1. (Reference), a typical method is (B, Samuelsson et al., 1Σ, Nagi, Tan, Ha, Shi, 410 (1965) ),)
e (11) A method via the important intermediate Corey lactone (E, J. Corey et al., J. Amer.
, Chem, Soc, +92, 397 (1970),
).

(lit) Method via 2-substituted-2-cyclobentenone, which is an important intermediate (C, J, Sih et al., Lito, Shima 3. Shini, 97, 865 (1975)
, ).

(lv) A method for selectively reducing s, 6-dihydroprostaglandin E2 or F, α (E, S).

Ferdinandi et al., Dan, J. Chem
,, 4f4, 1070'(1971);
C, T (, Lin et al. + Prosta 1andin
+ IL377 (1976), ).

etc. However, in these methods,
In the biosynthetic method (II), it is difficult to obtain polyunsaturated fatty acids as a raw material, and the yield from the polyunsaturated fatty acids is very low, making it difficult to purify and separate by-products. In addition, methods (n), (n+) and (lv) obtained by chemical synthesis involve many steps to obtain the starting materials,
Even if a starting material is easily obtained, there are drawbacks such as a very low yield of prostaglandin from such a starting material.

In recent years, in order to overcome these drawbacks, a three-component coupled Bousses method using a conjugate addition reaction to a 2-cyclobentenone system followed by a reaction/rate trapping process has been devised as a direct synthesis method for the boostaglandin skeleton. (G, 5tor
K et al., Yu, Amer, Chem.

Soc, 97.6260 (1975); K.
G., Untch et al., Niziebash, 44.3755
(1979)). However, these attempts require a multi-step process in which eruleto is captured using formaldehyde and trimethylsilyl chloride, which are low-molecular-weight compounds, and the resulting intermediate is used to synthesize the prostaglandin skeleton through chemical synthesis. However, the overall yield is low.

Furthermore, the reduction reaction of sulfonyloxyalkanes with sodium borohydride is known per se (R, 0,
Hutchin et al., J., O., Che., et al.

2259 (see IQ78)), but as far as the present inventors are aware, there is no example of its application to the prostaglandin system.

The present inventors focused on this point, and prostaglandin F.
Advantageous chemical synthesis methods include (1) use of easily obtained starting materials, (II) short reaction steps, (II
+) As a result of intensive research to find a synthetic method with advantages such as a high overall yield, we found that 7-hydroxy, which can be obtained in a higher yield than protected 4-hydroxy-2-cyclobentenones through a one-step reaction. The present invention was achieved by discovering that prostaglandins F can be obtained from prostaglandins E by selectively decentering the hydroxyl group at the 7-position and reducing the carbonyl group at the 9-position. .

-〇- That is, the present invention provides a compound of the following formula (T[
) A method for producing prostaglandin F represented by R.

The above formula CI) which is a raw material compound in the production method of the present invention
In 7-sulfonyloxybutyp-staglandin F represented by, B is -CH2-CH2-.

-CH=CH- or -〇=C-, -CH=CH
In the case of -, the double bond includes cis, trans, or a mixture thereof in any ratio, but cis is preferred.

In the above formula (0), R1 is a hydrogen atom, a C1-C7 alkyl group, or a substituted or unsubstituted phenyl group.

Represents a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted phenyl (c, to C2) alkyl group.

Examples of C1 to C1o alkyl groups include methyl,
Ethyl, n-propyl+ +so 7'lopyl.

n-butyl, Bee-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-
Mention may be made of linear or branched ones such as octyl, n-nonyl and n-decyl.

Examples of the substituent for a substituted or unsubstituted phenyl group include a hapgen atom and a hydroxy group.

A C7-C7 acyloxy group, a C1-C4 alkyl group optionally substituted with a halogen atom, and a C7-C4 alkyl group optionally substituted with a halogen atom.

A nitrile group, a carboxyl group, a (C5-C,)alkoxycarbonyl group, etc. are preferred. The halogen atom is preferably fluorine, chlorine or bromine, particularly fluorine or chlorine. Examples of the C2-C7 acyloxy group include acetoxy, propionyloxy, n-butyryloxy, ts
o-butyryloxy, n-valeryloxy+ 180
- Valeryloxy, caproyloxy, enantyloxy or benzoyloxy may be mentioned.

Examples of the C1-C4 furkyl group optionally substituted with halogen include methyl, n-propyl, and n-propyl+180
Preferred examples include -propyl, n-butyl, chloromethyl, dichloromethyl, and trifluoromethyl. C1 optionally substituted with
~C4 alkoxy groups include, for example, methoxy, ethoxy, n-p-boxy, 1so-p-poxy,
n-butoxy.

Preferred examples include chloromethoxy, dichlormethoxy, and trifluoropmethoxy. Examples of the (C8-C6) alfoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, and the like.

The substituted phenyl group can have 1 to 3, preferably 1 substituent as described above.

Substituted or unsubstituted cycloalkyl groups include saturated or unsaturated C6-C8, preferably C3-C6, particularly preferably C6 groups, substituted with the same substituents as mentioned above or unsubstituted, e.g. Examples include cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexyl, cyclooctyl, and the like.

Examples of the substituted or unsubstituted phenyl (C8-Ct) 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.

R1 is preferably a hydrogen atom or a C3-C5 alkyl group, particularly preferably a methyl group.

14- In the above formula CI), R2 is substituted with a halogen atom (), an optional C1-C4 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted phenyl group (
C, ~C2) is an alkyl group.

Examples of the C1-C4 alkyl group optionally substituted with halogen include methyl, ethyl, n-propyl + igo
-propyl, n-butyl, t-butyl.

Preferred examples include RI:II:I ethyl, dimethyl, trifluoromethyl, nonafluorobutyl, and the like.

Examples of the substituent for a substituted or unsubstituted phenyl group include a halogen atom and a hydroxyl group.

C7-C, acyloxy group, optionally substituted with a halogen atom (-C5-C4 alkyl group, C7-C4 alkyl group optionally substituted with a halogen atom).

Nitro group, nitrile group, carboxyl group or (C1-C
,) alfkhidicarbonyl group, etc. are preferred. The halogen atom is preferably fluorine, chlorine or bromine, particularly fluorine or chlorine. Examples of the C2-C acyloxy group include acetoxy, propionyloxy, n-butyryloxy, 1so-butyryloxy, n-valeryloxy+
! ! Mention may be made of 10-valeryloxyoxyloyloxy, enantyloxy or benzoyloxy. As the C1-C4 alkyl group which may be substituted with a halogen atom, the same substituents as mentioned above can be mentioned as preferred.

Examples of the C8-c4 alkoxy group which may be substituted with a halogen atom include methoxy, ethoxy, n-propoxy + 1so-propoxy In-butoxy, chloromethoxy, and dichloromethoxy.

Trifluoromethoxy is preferred. (C7-C6) Alkoxycarponino! Examples of the group include methoxycarbonyl, hydroxycarbonyl, and butoxycarbonyl.

Hexyloxycarbonyl, etc. can be expressed.

Examples of the substituted or unsubstituted phenyl (C, to 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.

R2 is preferably a methyl, trifluoromethyl or p-tolyl group, with a methyl group being particularly preferred.

In the above formula (IIT), R3 and R4 are the same or different and represent a hydrogen atom, a hydroxyl group, or a protected hydroxyl group. Here as a protecting group)! J(C.

~C1) A hydrocarbon-silyl group, a group that forms a 7-cetal bond with the oxygen atom of a hydroxyl group, or a C2-C1 7-syl group is preferably mentioned.

) ') (C1-C1) hydrocarbon silyl group,
For example, trimethylsilyl, triethylsilyl.

(such as t-butyldimethylsilyl group)! j (C, ~
Preferred examples include diphenyl (C1-C4) ylkylsilyl or tribenzylsilyl groups such as C4) furkylsilyl and t-butyldiphenylsilyl groups.

Examples of groups that form a 7-cetal bond with the oxygen atom of a hydroxyl group include methoxymethyl, 117-ethoxyethyl, 2-methoxy-propan-2-yl, and 2-ethoxypropan-2-yl.

(2-methoxyethoxy)methyl, benzyloxymethyl, trihydropyran-2-yl.

Tetrahydrofuran-2-yl, 4-methoxytetrahydropyran-4-yl or 6,6-dimethyl-3-oxa-2-oxobicicρ[3°1.0]hexa-4-
Examples include the yl group. Among these, 1-ethoxyethyl, 2-methoxypropan-2-yl, (2-
methoxyethoxy)methyl, tetrahydrobilane-2-
yl, 4-methoxytetrahydropyran-4-yl or 6,6-dimethyl-3-oxa-2-oquine-bicyclo(3,1,0)hex-4-yl group is preferred.

Ct%C, as an acyl group, for example, acetyl.

Propionyl, n-butyryl + 1so-butyryl.

n-valeryl + 1so-valeryl, caproyl.

Enantyl, benzoyl, etc. can be mentioned. Among these, c, to c6 aliphatic acyl groups such as 18-acetyl, n- or 1so-butyryl, caproyl or benzoyl are preferred.

R3 and R4 are t-butyldimethylsilyl group,
Tetrahydrobilan-2-yl group, 4-methoxytetrahydrobilan-4-yl group, 6゜6-dimethyl-3-oxa-2-oxo-bicyclo(3,1,0)hex-4
A hydroxyl group protected with a -yl group is particularly preferred.

In the above formula (I), R5 is an unsubstituted C1-C8 alkyl group; an optionally substituted phenyl group.

Phenoxy group, C1-C6 alkoxy group or C3
~C, substituted C1-C substituted with dichlorofurkyl group
, an alkyl group; or a substituted or unsubstituted cycloalkyl group. C5~C1! The unsubstituted alkyl group may be linear or branched, such as methyl, ethyl + n-propyl, igo-propyl, n-butyl + n-pentyl, n-hexyl, 2 -Methyl-1-hexyl, 2,2-dimethyl-1
-hexyl, 2-hexyl, 2-methyl-2-hexyl, n-heptyl, n-octyl, etc.

The substituted C3-C, alkyl group may be linear or branched, for example methyl, ethyl, n
-propyl, 1so-7'lopyl.

Examples include n-butyl, 8ec-butyl, t-butyl+1-pentyl, and the like. These substituted alkyl groups include phenyl group; phenoxy group; methoxy, ethoxy, n-propoxy, 1po-pboxy, n-butoxy+1so-butoxy.

01-C6 alkoxy groups such as t-butoxy, n-pentoxy, n-hexoxy; or substituted with C6-C6 cycloalkyl groups such as cyclopentyl and cyclohexyl. may be substituted with the substituents listed as substituents.

Examples of the substituted C1-C alkyl group include a phenoxy group which may be substituted with a fluorine atom, a chlorine atom, a methyl, ethyl or trifluoromethyl group, or a C1-C2 furkyl group substituted with a phenyl group; or bupoxymethyl, ethoxyethyl, propoxyethyl.

Butoxymethyl, methoxypropyl, 2-ethoxy-1
, 1-dimethylethyl, propoxydimethylmethyl, or cyclohexylmethyl, cyclohexylethyl, cyclohexyldimethylmethyl, 2-cyclohexyl-1,
1-dimethylethyl and the like are preferred.

As the substituted or unsubstituted cycloalkyl group, the same ones listed for R1 can be mentioned.

R5 is n-pentyl, n-hexyl.

2-methyl-1-hexyl, 2-methyl-2-hexyl, 2,2-dimethyl-1-hexyl, cyclohexylmethyl, cyclopentyl, cyclohexyl group, or methyl group is preferred.

In the above formula (1), R6 is a hydrogen atom or a methyl group.

It is an ethynyl group (-CmiCH) or a protected ethynyl group. Preferred examples of the protected ethynyl group include trimethylsilylethynyl and t-butyldimethylsilylethynyl. Among these 21- , a hydrogen atom or a methyl group is preferred. A hydrogen atom is particularly preferred as R6.

The symbol / in the above formula (1) represents a single bond or a double bond. Double bonds are particularly preferred.

7-sulfonyloxyprostaglandin F represented by the above formula CI) has the 7th and 8th positions.

Since it has asymmetric carbon atoms at positions 9, 11, 12, and 15, various stereoisomers exist, and 7-sulfonyloxyprostaglandin F used in the present invention has all these stereoisomers. It includes isomers, optical isomers, and mixtures thereof in arbitrary proportions.

Among these, especially the following formula [■'] 22- [- has a β-configuration. 7-sulfonyloxyprostaglandin F represented by ``7c'', ie, those in which the substituents at the 11th and 12th positions have a trans configuration with respect to each other, and / is a double bond are preferred.

Further, the 7-sulfonyloxyprostaglandins F of the above formula [1'] can be exemplified by the arrangement around the carbon atoms at the 7th, 8th, and 9th positions, as shown in the following formulas (I'a) to (I'
h) (I'a), (I'b) (I
'c) (l'a)CI'e
) (r・,](I'g)
Examples include compounds represented by (I'h). In the present invention, mixtures of the 15-:r-pi form, the bell-shaped form thereof, and the isomers thereof in arbitrary proportions are included.

In the present invention, prostaglandin F represented by the following formula [π] R is obtained by subjecting 7-sulfonyloxy prostaglandin F of the above formula (I) to a reduction reaction.

In the present invention, the reducing reactant is preferably a borohydride metal compound. Examples of the borohydride metal compound include lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, and particularly preferably sodium borohydride.

As the reduction reaction solvent, aprotic polar solvents such as N,N-dimethylformamide, hexamethylphosphoric triamide, dimethyl sulfoxide are used, and hexamethylphosphoric triamide or dimethyl sulfoxide is particularly preferred.

The conditions for producing prostaglandin F by reducing the 7-sulfonyloxy prostaglandin F of the above formula (1) of the present invention are as follows.

The borohydride metal compound used in the reduction reaction is preferably 0.5 to 50 times the mole of 7-sulfonyloxyprostaglandin F represented by the above formula (I),
Particularly preferably, 0.6 to 10 times the mole is used. The amount of solvent to be used is sufficient as long as it allows the reaction to proceed quickly, and is usually 1 to 1000 times the volume, preferably 5 to 100 times the volume of the starting compound CI). The reaction temperature varies depending on the raw materials, reagents, and solvents used, but it is carried out in the range of 0°C to 150°C, preferably in the range of 30°C to 100°C. The reaction time varies depending on the conditions, but is 0.
About 1 to 48 hours is preferable, and more preferably 0.1 hours.
~24 hours. The progress of the reaction is monitored by methods such as thin layer chromatography, and the disappearance of the raw materials is considered to be the end. After the reaction, prostaglandin F represented by the above formula [■] -26= is separated and purified by treating the reaction solution in a conventional manner. That is, they are separated and purified by a combination of extraction, washing, drying, concentration, chromatography, and the like.

The raw material compound 7-sulfonyloxyprostaglandin F of the above formula CI) is produced by reducing 7-sulfonyloxyprostaglandin E represented by the following formula (). This method is a novel method, and therefore, the present invention also provides the following manufacturing method.

That is, 7-sulfonyloxyprostaglandin E represented by the following formula (m) is subjected to a reduction reaction to obtain 7-sulfonyloxyprostaglandin E represented by the following formula (I).
This is a method for producing prostaglandin F represented by the following formula (II), which is characterized in that sulfonyloxy prostaglandin F is obtained and then subjected to a reduction reaction.

The above formula [■] Nioite, B, R', R", R3,
R', R'.

R6 and the symbol 7 are the same as described in the above formula (0).

The 7-sulfonyloxyprostaglandin E of the above formula (m) can be obtained from JP-A-55-1 as shown in the reaction formula below.
It is produced by obtaining 7-hydromaxip p-staglandin E from cyclobentenones by the method described in Japanese Patent No. 53725, followed by sulfonylation, and optionally subjecting to deprotection or hydrolysis reaction.

29- The reduction reaction of the 7-sulfonyloxyprostaglandin E of the above formula [■] can be carried out in the same manner as the reduction reaction of the 7-sulfonyloxyprostaglandin F of the above formula [%].

That is, the reducing reactant is preferably a borohydride metal compound. Examples of the borohydride metal compound include lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, and particularly preferably sodium borohydride.

As the reduction reaction solvent, aprotic polar solvents such as N,N-dimethylformamide, hexamethylphosphoric triamide, and dimethyl sulfoxide are used, with hexamethylphosphoric triamide or dimethyl sulfoxide being particularly preferred.

The conditions for producing prostaglandin F by reduction of 7-sulfonyloxyprostaglandin E of the above formula CII+) are as follows.

The borohydride metal compound used in the reduction reaction is preferably 0.5 to 50 times mole, particularly preferably 0.6 to 10 times the mole of 7-sulfonyloxyprostaglandin E represented by the above formula (m). Use moles. The amount of solvent to be used is sufficient as long as it is sufficient for the reaction to proceed quickly, and usually 1 to 1000 times the volume, preferably 5 to 100 times the volume of the starting compound (m) is used.The reaction temperature is Although it varies depending on the raw materials, reagents, and solvents used, it is carried out in the range of 0°C to 150°C, preferably in the range of 30°C to 100°C.The reaction time varies depending on the case, but
．． It is preferably about 1 to 48 hours, more preferably 0.
1 to 24 hours. The progress of the reaction is monitored by methods such as thin layer chromatography, and the disappearance of the raw materials is considered to be the end. After the reaction, prostaglandin F represented by the above formula (1) is separated and purified by treating the reaction solution in a conventional manner. i.e. for example extraction, washing,
It is separated and purified by a combination of methods such as drying, concentration, and chromatography.

In the present invention, 7-sulfonyloxyprostaglandin E of the above formula (m) is reduced, and then the obtained 7-sulfonyloxyprostaglandin E of the above formula (I) is isolated. The desired prostaglandin F of the formula (II) can also be obtained by continuing the reduction reaction without further processing.

Prostaglandin F class (II) obtained by subjecting to the reduction reaction of the present invention is represented by the following formula % () () ), for example, based on the arrangement around the carbon atoms at the 8th and 9th positions. Compounds that can be mentioned include: The present invention includes mixtures of these isomers in arbitrary proportions.

Thus, by the method of the present invention, prostaglandin F represented by the above formula (II) can be obtained from 7-sulfonyloxyprostaglandin E (,1) or 7-sulfonyloxyprostaglandin E, which is an easily available raw material compound. It can be easily obtained from Grandin E (Dir).

Prostaglandin F obtained by the present invention is a compound that is expected to have physiological effects similar to prostaglandin F and α, such as uterine smooth muscle contraction and Wk duct contraction, and is expected to be useful as a pharmaceutical. It can also serve as a useful intermediate that can lead to other useful prostaglandins, such as pstaglandin E and pstaglandin I.

The production method of the present invention provides useful compounds more easily than readily available raw material compounds, and is therefore extremely significant.

34- Example 1 (1) 7-hydroxy-5,6-dihydro-15-deoxy-13,14-:)hydro-17,18°19.2
Mixture of 7-8 and 7-1 bodies of 0-tetranorprostaglandin E2 methyl ester 1l-t-butyldimethylsilyl ether and 61 bodies of Sonera 41 W (
0,097nynoJ) in anhydrous dichloromethane, 5m
1 of anhydrous triethylamine and cooled to 40°C.
After adding 5 μl (0.11 mmol), methanesulfonyl chloride (0.11 mmol) was added.

After stirring at -40°C for 1.5 hours, the mixture was poured onto ice water and extracted with ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. Concentrate by filtration to obtain 7-methanesulfonyloxy-
5,6-dihydro-15-deoxy-13,14-dihydro-17,18,19,20-tetranorprostaglandin E2 methyl ester 1-t-butyldimethylsilyl ether 7-8 and 7-1 bodies and 42 ml of oil containing a mixture of these dJ forms was obtained.

spectral data NMR: δCDCl; 3.04 and 3.08 (s, 3H).

3.67 (s + 3H) + 3.9-4.4 (m, IH).

5.4-5.8 (m, IH) (11) 7-Methanesulfonyloxy-5,6-dihydro-15-deoxy-13゜14- obtained in the above reaction
Dihydro-17,18,19,20-tetranorprostaglandin E2 methyl ester 9-8 and 9-1 bodies of 1l-t-butyldimethylsilyl ether, their 7-8 and 7-1 bodies, and their 61 bodies 31.8 ml of oil containing a mixture of bodies were obtained.

Spectrum data NMR: δCDIJ; 3.10 (s, 3H), 3.67 (s, 3H
).

4.0-4.2 (m, IH) 1 4.2-4.5 (m, 11().

52-5.6 (m, 1) () dl di (lit) 7-methanesulfonyloxy-5,6-dihydro-15-deoxy-1 obtained by the method of (1)
3,14-dihydro-17,18,1!1.20-tetranorprostaglandin E2 methyl ester 1l-t
-butyldimethylsilyl ether 9-8 and 9-1
The oily substance 261A9 containing a mixture of the 7-8, 37- and 7-1 isomers, and their di isomers was dissolved in 0.3 ml of anhydrous hexamethylphosphoric triamide, and sodium borohydride 7 was dissolved ( o, 1 s mmoJ) and stirred at room temperature for 50 minutes and then at 60°C for 1.5 hours. Water was added and extracted with ether, and the organic layer □ was washed with water and dried over anhydrous magnesium sulfate.

f After overconcentration, it was separated and purified using silica gel thin layer chromatography to obtain 5,6-dihydro-15-deoxy-13,
14-dihydro-+ 7.18゜19.20-tetranorprostaglandin F2 methyl ester 9-8 and 9-1 bodies of 1l-t-butyldimethylsilyl ether, and a mixture of 67 bodies thereof5. 3■ (Yield 24%
) was obtained.

Example 2 38- (1) (7R) -7-hydroxy-5,6-dihydroprostaglandin E2 methyl ester 1]115
-bis-t-butyldimethylsilyl ether 200 inches (
328 μmat ) to anhydrous pyridine 2 m7! Methanesulfonyl chloride 76μ71 while cooling with water and stirring
(985 μmol) was added and stirred at 0°C for 1.5 hours. The mixture was poured onto ice water, extracted with pentane, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. rConcentrated M(7R)-7-methanesulfonyloxy-5,6-
Dihydroprostaglandin E2 methyl ester11.
210 ml of an oil containing 15-bis-t-butyldimethylsilyl ether was obtained.

spectral data NMR: δcDct; 3.04(8,3H), s, 6s(s, 3T().

3.8-4.4 ('m, 2H).

5+3~L8 (m, 3 T() ru (liquid film); 1744, +365. 1252. 1175°8
34σ−1 0SiX
08iX(11) Obtained in the above reaction ( 7 R)
-7-methanesulfonyloxy-5,6-dihydroprustabrandin F2 methyl ester +3+5-bis-t
-210 parts of butyldimethylsilyl ether and 1 part of ethanol. Dissolved in sm/, 13 da of sodium borohydride (
It was added to a 0.5 ml ethanol solution of 334 μmo/ ) while being stirred while being cooled with water. After stirring at 0°C for 1 hour, saturated brine was added and extracted with ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. r superconcentrated, (7R)-
7-methanesulfonyloxy-5,6-dihydroprustabrandin F2 methyl ester 11.15-bis-t
-7-R and 7-8 of butyldimethylsilyl ether
180 ml of oil containing a mixture of .

Spectrum data NMR: δCD(J, ; 3.09(a, 31(), 3.65(n, 3H)
.

3.7-4.5 (m, 3H).

5.2-5.7 (m, 31N IR (liquid film); 350 (1,1737,1358,1252°1173
．． (?R)-7-sulfonyl-yl-xy-5,6-dihydroprostaglandin F obtained by the method of 832 (110(1))
An oil containing a mixture of 9-8 and 9-R forms of 2-methyl ester 11.15-bis-t-butyldimethylsilyl ether was dissolved in anhydrous hexamethylphosphoric triamide 1.5- and hydrogenated. Boron F 37
(2) 41- (0.9s mmo71) was added and stirred at 50°C for 1.5 hours. Saturated brine was added and extracted with hexane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, overconcentrated, and separated and purified using silica gel column chromatography to obtain 5.6-dihydroprustabrandine F2 methyl ester 11.15-bis-t-butyldimethylsilyl. Mixture of 9-8 and 9-R forms of ether 77~ (yield 4
9%).

Example 3 (1) (7n) -7-Hydroxyprostaglandin E1 methyl ester 11.15-bis-t-butyldimethylsilyl ether 30~(49μmat) was dissolved in 0.51+1/ of anhydrous pyridine and stirred at room temperature. While stirring, 42-11.4 μJ (+47 μmol) of methanesulfonyl chloride was added, and the mixture was stirred for 2 hours. The reaction solution was poured onto ice water and extracted with pentane, and the organic layer was washed with water and dried over anhydrous sodium sulfate. r superconcentrated, (7R)-7-methanesulfonyloxyprostaglandin E.

31 m9 of an oil containing methyl ester 11.15-bis-t-butyldimethylsilyl ether was obtained.

Spectrum data NMR: δCDC4; 3.08 (St 3H) + 3.65CB + 3
H) +3.8~4.4 (m, 2H) +5.3~
5.8 (m, 3H) IR (liquid film); 1729.1363,1253,1175°1 833 (m CII) (7R)-7-sulfonyloxyprostaglandin E obtained by the method of (1) Methyl ester 11
．． Oily substance 33119 containing 15-bis-t-butyl dinotylsilyl ether was dissolved in 3 mJ of anhydrous hexamethylphosphoric triamide, sodium borohydride g my (240 μmol) was added, and the mixture was stirred at 80° C. for 5 hours. Saturated brine was added, extracted with hexane, and the organic layer was washed with water and dried over anhydrous sodium sulfate. f After overconcentration, it was separated and purified by silica gel column chromatography to obtain p-staglandin F, α-methyl ester 11.
15-bis-t-butyldimethylsilyl ether 9 da(
(yield 31%) and prostaglandin F, β methyl ester 11.15-bis-t-butyldimethylsilyl ether 5■ (yield 17%).

Example 4 7-methanesulfonyloxy-5,6-dihydro-16°17.1 obtained by the same method as Example 2(1)
B, 19.20-pentanol-15-cyclopentyl prostaglandin F, methyl ester 11.15-bis-t-butyldimethylsilyl ether 9-8 and 9-
Oil containing a mixture of R, 7-8 and 7-R bodies 73■
5 by processing almost in the same manner as in Example 2 (nD).
．． 6-dihydro-16,17,1B, 19.20-pentanol-15-cyclopentyl prostaglandin F,
Methyl ester 11. Mixture of 9-8 and 9-'R forms of 15-bis-t-butyldimethylsilyl ether 27
(yield 42 cm) was obtained.

45-Example 5 7-methanesulfonyloxy-5,6-dihydro-16°17.1 obtained by the same method as Example 2 (1)
B, 19.20-pentanol-15-cyclohexyl prostaglandin F2 methyl ester 11.15-bis-t-butyldimethylsilyl ether 9-8 and 9-
Oil containing a mixture of R, 7-8 and 7-R bodies 56■
By treating in the same manner as Example 2 (Ill), 5,6-dehyde q -16,17,1B, 19.20
-Pentanol-15-cyclohexyl prostaglandin F, methyl ester 11. A mixture of 9-8 and 9-R isomers of 11.15-bis-t-butyl dinotylsilyl ether 23η (yield: 47 h) was obtained.

46- Example 6 (7R)-7-sulfonyloxybrostaglandin E, methyl ester obtained by the method of Example 3 (1) 11.1
Dissolve 31 μmol of an oil containing 5-bis-t-butyldimethylsilyl ether in 0.5 μmol of anhydrous dimethyl sulfoxide, and add 15 # (39 μmol) of sodium borohydride.
was added and stirred at 50°C for 20 hours. Saturated brine was added, extracted with hexane, and the organic layer was washed with water and dried over anhydrous sodium sulfate. After concentrating VX*, it was separated and purified by silica gel column chromatography to produce 10 μg of p-staglandin F, α-methyl ester 11,15-bis-1-butyldimethylsilyl ether (yield: 34 cm) and prostaglandin F, β-methyl Ester 11.15-bis-t-butyldiethylsilyl ether 5■ (lts11
7'%).

Example 7 (17S)- obtained by the same method as Example 3 (1)
7-Methanesulfonyloxy-17,20-dimethyl prostaglandin E1 methyl ester 11.15-bis(tetrahydropyran-2-yl)ether of 7-8 and ? By treating 80 da of oil containing a mixture of -R isomers in substantially the same manner as in Example 3, (178)-17,2
0-diethyl prostaglandin F, methyl ester 1
1. A mixture of 9-8 and 9-8 bodies of 15-bis(tetrahydropyran-2-yl) ether 36■ (yield 53
%) was obtained.

Examples 1 to 7 The main values of the spectrum data of prostaglandin F obtained in i8 Examples 1 to 7 above are shown below.

49-

Claims (1)

[Claims] 1. A method for producing prostaglandins F represented by the following formula [Ir) u, which comprises subjecting a two-sulfonyloxy prostaglandin F represented by the following formula CI) to a reduction reaction. . 2. A method for producing prostaglandin F according to claim 1, which uses a metal borohydride compound as a reducing reagent. 3. The method for producing prostaglandin F according to claim 2, wherein the borohydride metal compound is sodium borohydride. 4. The method for producing prostaglandin F according to any one of claims 1 to 3, in which hexamethylospolittriamide or dimethyl sulfoxide is used as the reduction reaction solvent. 5. The method for producing prostaglandin F according to any one of claims 1 to 4, wherein R1 in the above formula [■] is a methyl group. 6. The i-4 system of prostaglandin F according to any one of claims 1 to 7, wherein R6 in the above formula (1) is a hydrogen atom. 7. In the above formula (1), R11 is an n-pentyl group. n-hexyl group, 2-methyl-1-hexyl group, 2-methyl-2-hexyl group, 2,2-dimethyl-1-hexyl group, cyclopentyl group. Cyclohexylmethyl group, cyclohexyl group. or a methyl group, the method for producing prostaglandin F according to any one of claims 1 to 6. 8. In the above formula [T), R'' and R' are t-butyldimethylsilyl group, tetrahydrobilan-2-yl group, 4-
methoxytetrahydropyraf-4-yl group, or 6.6
-cymethyl-3-o7-2-oxobicyclo(3,
1,0) A method for producing prostaglandin F according to any one of claims 1 to 7, which is a hydroxyl group protected with a hex-4-yl group. 9. The method for producing prostaglandin F according to claims 1 to 8, wherein R2 in the above formula [■] is a methyl group. 10. 7-sulfonyloxyprostaglandin E represented by the following formula (m) is subjected to a reduction reaction to obtain 7-sulfonyloxyprostaglandin E represented by the following formula (1).
A method for producing prostaglandin F represented by the following formula (II) 5-, which comprises obtaining sulfonyloxy prostaglandin E and then subjecting it to a reduction reaction.