JPS5955868A - Preparation of prostaglandin e1 - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for the production of prostaglandin E. More specifically, when 1-prostaglandin E is selectively reduced, or the hydroxyl group is eliminated and removed from 7-hydroxyprostaglandin E, and then selectively reduced, 1-prostaglandin E is selectively reduced. , relates to a method of manufacturing the class.

Glotaglandin E1 is a type 1 prostaglandin and has an inhibitory effect on platelet aggregation.

It is a compound that has unique biological activities such as blood pressure-lowering effects, and is a useful natural product that has recently been used as a peripheral circulation treatment drug in the medical field.

Conventional methods for producing glosstaglandin 2+ include (1) a method for obtaining it by biosynthesis from dihomo-8-lylunic acid (D,
A, Dorp et all Biochem, Bi'o
phys.

Acta, 90, 204 (1964)) and chemically synthesized (11) method using intramolecular aldol condensation reaction of nitroalkane derivatives and optical resolution method (B, J,
Corey et al., J., Amer, Ohem,, Soc.
, 91, 535 (1969)), (iti)
A method of Michael addition of an organometallic compound to a 2-substituted-2-cyclobentenone derivative (C!, J, Sih
et al., J., Amer, Oflem.

5ac195, 1676 (1973) and A, F, Kl.
uge et al.

(1■) Protected prostaglandin ml, F1
A method of selectively reducing double bonds at positions 5 and 6 from a (E, J, Orey et al., J, Amer, Ohem, S
ac,,92.

2586 (1970)) are known (J, B.

Binclra et al., Proetagrandi
n 5ynthesis, Academic Pres.
s (1977), see). However, in these methods, the yield from the raw material dihomo-8-lyrinnic acid (obtained by biosynthesis) is very low, and it is difficult to purify and separate the by-products. The method obtained by 1v) requires many steps to obtain the starting material, and on the other hand, even if the starting material is easily obtained, the yield of Glostagrandein E from such starting material is very low. be.

The present invention focuses on this point, and the prostaglandin Fit
As a result of intensive research to find a synthetic method with advantages such as a short reaction step and a high total yield, we have found that the protected The hydroxyl group is removed from 7-hydroxyprostaglandin E obtained in high yield through a one-step reaction with 4-hydroxy-2-cyclobentenone to produce △7-gerostaglandin F2. and then selectively reducing the Glotaglandin E1
The present invention was achieved by discovering that these compounds can be obtained easily and in high yields.

That is, the method of the present invention selectively reduces a compound represented by the following formula [11s, its 15-form, its enantiomer, or a mixture of two-glostaglandin E in any proportion thereof, A Gloster method for obtaining a compound represented by the following formula, its 15-form, its enantiomer, or a mixture thereof in any proportion, which is then subjected to deretention and/or hydrolysis reactions as necessary. A method for producing grandins Ei, and a mixture of any proportion of the compound represented by the following formula [111], its 15-form, its enantiomer, or 7-hydroxyprostaglandins, as a basic compound. is reacted with a reactive derivative of an organic sulfonic acid in the presence of , and then subjected to deprotection and/or hydrolysis reaction as necessary to obtain a compound represented by the following formula, its 15-sulfonic form, its enantiomer, Alternatively, the following formula [ [1] A method for producing prostaglandin E1, which obtains the compound represented by the following, its 15-form, its enantiomer, or a mixture thereof in any proportion.

In the above reaction formula ['[[I], R1 is a hydrogen atom or tri(
CI-0) is a hydrocarbon-silyl group.

Examples of the tri(01-Cy) hydrocarbon silyl group include trimethylsilyl and triethylsilyl.

Tri(C,-C4) such as t-butyldimethylsilyl group
Preferred examples include alkylsilyl, diphenyl(C,-C,)alkylsilyl groups such as t-butyldiphenylsilyl groups, and tribenzylsilyl groups.

A hydrogen atom is particularly preferred as R1.

R'' and R81 are the same or different, and are tri(C, ~
O? ) A hydrocarbon-silyl group, a group that forms an acetal bond with the oxygen atom of a hydroxyl group, or an acyl group of α to C. ) II (0,-Cy) Hydrocarbon silyl groups include those similar to those mentioned in (, l R1. Groups that form an acetal bond with the oxygen atom of the hydroxyl group include, for example, methoxymethyl, 1-ethoxy Ethyl, 2-methoxy-2-propyl, 2-ethoxy-2
-propyl, (2-methoxyethoxy)methyl.

benzyloxymethyl, 2-tetrahydropyranyl, 2
-tetrahydrofuranyl or halo,6-dimethyl-3-oxa-2-oxo-bicyclo[a,t,o]hex-4
-yl group may be mentioned. Among these, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-
Ethoxyethyl, 2-methoxy-2-propyl, (2-
methquinethoxy)methyl or 6,6-dimethyl-3-
Oxa-2-oxo-bicyclo[a, 1. o]hex-4-yl group is preferred. C7~C? Examples of the acyl group include acetyl and propionyl.

n-butyryl, 1sO-gtyryl, n-valeryl.

1s() -/<Leryl, caproyl, enantyl, benzoyl and the like. Among these, Ct
-Ce fatty acyl group e.g. acetyl, n- or 1eo
-Butyryl, caproyl or benzoyl are preferred.

These silyl groups, acyl groups, and groups forming acetal bonds are to be understood as film-retaining groups for hydroxyl groups. These silyl groups or groups forming acetal bonds are easily removed under acidic to neutral conditions.

Also, acyl groups are easily removed under basic conditions.

A 2-tetrahydropyranyl group or a t-butyldimethylsilyl group is particularly preferred as R1' and R''.

R4 is an unsubstituted 05-aS alkyl group; a substituted 01-C5 alkyl group substituted with an optionally substituted noenyl group, phenoxy group, C3-08 alkoxy group or 01-Os cycloalkyl group; or substituted Or it is an unsubstituted cycloalkyl group. The unsubstituted alkyl group of Cts-Cta may be linear or branched, such as n-pentyl, n-hexyl, 2
-methyl-1-hexyl, 2-methyl-2-hexyl,
n-heptyl, n-octyl, etc., n-pentyl, n-hexyl, 2-methyl-1-hexyl, 2
-Methyl-2-hexyl etc. can be mentioned. The substituted C1-C5 alkyl group may be linear or branched, and examples include t hamethyl, ethyl,
n-10 Hill, 1 day 0-propyl, n-butyl, 5e
Examples include c-butyl, 1-butyl, n-pentyl and the like.

These substituted alkyl groups include phenyl groups; phenoxy groups; ~
c6 alkoxy group is substituted with a C1-c6 cycloalkyl group such as dichloropentyl or cyclohexyl. These substituents further include halogen atoms, hydroxy groups,
at~C1 acyloxy group, optionally substituted with a halogen atom (:+-Oa alkyl group, 01~C4 alkoxy group optionally substituted with a halogen atom, nitrile group, carboxyl group, or (Ol-cs) It may be substituted with an alkoxycarbonyl group or the like.

Examples of halogen atoms include fluorine, chlorine or bromine, especially 7
Chlorine or chlorine is preferred. Examples of the ct-c1 acyloxy group include acetyloxy, propionyloxy, n
-butyryloxy, iso 7 butyryloxy, n-
Mention may be made of valeryloxy, fso-valeryloxy, n-hexanoyloxy, n-hexanoyloxy or benzoyloxy. Examples of the Cl-04 alkyl group which may be substituted with a norogen atom include methyl, ethyl, n-7'-ropyl, and 1FIo-7'-ropyl.

n-butyl, chloromethyl, dichloromethyl.

Preferred examples include trifluoromethyl. C7-C which may be substituted with
Examples of the 4-alkoxy group include methoxy, ethoxy,
n-propoxy, 1θO-propoquine, n-butoxy7.
Chloromethoxy7. Jikuro mouth metki 7. Preferred examples include trifluoromethoxy. (C
, ~aS) Examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, and the like. Examples of the substituted C1-0s alkyl group include, for example, a C1-at alkyl group substituted with a phenoxy group or a phenyl group, which may be substituted with a fluorine atom, a chlorine atom, a methyl, ethyl or trifluoromethyl group, or Propoxymethyl, ethoxyethyl, propoxyethyl, butoxymethyl, methoxyglobil, 2
-Ethoxy-1,1-dimethylethyl, propoxydimethylmethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexyldimethylmethyl, 2-cyclohexyl-1,1-dimethylethyl, and the like are preferred. As the substituted or unsubstituted cycloalkyl group, the above substituted C
1-08 Substituted with the same substituent as the substituent listed for the alkyl group or unsubstituted saturated or unsaturated 06-Os
, preferably aS to C6 groups, such as t hacyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, etc.R', l! :l, n-hentyl, n-hexyl,
2-methyl, 1-hexyl, 2-methyl-2-hexyl, cyclohexylmethyl, cyclopentyl or cyclohexyl groups are preferred.

R1 is a hydrogen atom, a methyl group, an ethynyl group (-〇3CH)
or a protected ethynyl group. Preferred examples of the protected ethynyl group include trimethyl/lylethynyl and t-butyldimethylsilylethynyl groups. Among these, a hydrogen atom or a methyl group is preferred, and a hydrogen atom is particularly preferred.

Since the 7-hydroxyprostaglandins represented by the above formula [■] have asymmetric carbon atoms at the 7th and 8th positions, various stereoisomers exist. That is, the above formula [1
11] are exemplified by the following formula [ma], ll:
1Ilb), [l1lc'l, 14[al[111
a] [mb) [mc]-[111a] A compound represented by the following is exemplified. In the present invention,
It includes the 15-shrimp forms, their enantiomers, and mixtures of their isomers in arbitrary proportions.

Sea urchin Unexamined Patent Publication No. 153725/1983 and Japanese Patent Application No. 1983-
Protected 4-hydroxy-2-cyclopentenone can be easily obtained in high yield by a method such as that described in No. 81306.

The method of the present invention starts by removing and removing the hydroxyl group at the 7-position of 7-hydroxyprostaglandin E of the above formula [■], leading to Δ7-prostaglandin E of the above formula ['l]. Ru. That is, the compound of formula [1] can be easily obtained by reacting the compound of formula [1] with a reactive derivative of an organic sulfonic acid in the presence of a basic compound. At this time, the reaction passes through 7-sulfonyloxyprostaglandin E as an intermediate, as shown in the reaction formula below, and after isolating this intermediate, by reacting with a basic compound, the formula [l
] can be obtained.

7-Sulfonyloxyprostaglandin E 〇-Retention group As the basic compound used here, amines are preferable, and examples of such amines include 4-dimethylaminopyridine, triethylamine, diisopropylcyclohexylamine, isopropyl dimethylamine,
Examples include diisoglobylethylamine, and among these, 4-dimethylaminopyridine is particularly preferred.

Examples of reactive derivatives of organic sulfonic acids include organic sulfonic acid/S chlorides such as hamethanesulfonylchloride (IJ)'' and p-)luenesulfonyl chloride; organic sulfonic anhydrides such as methanesulfonic anhydride;

The reactive derivative of the organic sulfonic acid used has the formula [[[]
]7-hydroxyprostaglandin E, 0.
The amount of the basic compound used is 5 to 10 times the mole, preferably 2 to 3 times the mole, and the basic compound is used in the range of 1 to 20 times the mole, preferably 4 to 6 times the mole. As the solvent used at this time, the basic compound itself may be used, but for example, halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; ethers such as ether and tetrahydrofuran; benzene, toluene, pentane, hexane, Hydrocarbons such as cyclohexane are used, preferably dichloromethane. The amount of solvent used is sufficient as long as it allows the reaction to proceed quickly, and is usually 1 to 1000 times the volume of the raw material compound, preferably 5 to 1000 times the volume of the starting material compound.
100 times the volume is used. The reaction temperature depends on the raw materials used,
Although it varies depending on the reagent, it is carried out at a temperature in the range of 0°C to 50°C, preferably in the range of 10°C to 30°C. The reaction time varies depending on the conditions, but is preferably about 0.1 to 10 hours, more preferably 0.5 to 5 hours.

The progress of the reaction is monitored by a method such as thin layer chromatography. After the reaction is completed, the Δ7-prostaglandins represented by the above formula ['I] are separated and purified by treating the reaction solution in a conventional manner. i.e. extraction, washing, drying, for example.

It is separated and purified by a combination of methods such as concentration and chromatography. The product obtained is optionally 11
The protecting group for the hydroxyl group at the position and the 15th position may be removed. Removal of K is accomplished by known methods, for example by treating the product in acetic acid-water-tetrahydrofuran mixture (3:1:1 to 3:2:2) at room temperature (197
2)).

The thus obtained 8-prostaglandin E represented by the above formula [I] has stereoisomers with respect to the double bond at the 7th and 8th positions. That is, examples of the compound of the above formula [■] include compounds represented by the following formulas [■a] and [■b] [1a]['lb]. In the present invention,
It includes its 15-shrimp form, its enantiomer 1 and mixtures of their isomers in any proportion.

Mape prostaglandin E is then subjected to selective reduction. Preferred methods for selective reduction include reduction using zinc-based reducing agents such as zinc dust, zinc-silver, and zinc-copper; or catalytic reduction using Raney nickel.

When using a zinc reducing agent, the reaction is carried out in the presence of glacial acetic acid. The amount of the zinc-based reducing agent used is 1 to 500 times the mole of the raw material compound [1], preferably 5 to 100 times the mole.
The amount of glacial acetic acid is 1 to 2000 times the mole, preferably 10 to 1000 times the mole. Examples of the solvent used at this time include methanol and ethanol.

Alcohols such as isoglobil alcohol; dimethoxyethane, dimethylformamide, dimethyl sulfoxide, acetic acid, or a mixed solvent thereof are preferred, and methanol, inglobil alcohol, and acetic acid are particularly preferred. The amount of solvent used is sufficient as long as it allows the reaction to proceed quickly, and is usually 1 to 2000 times the volume, preferably 5 to 1000 times the volume of the starting compound [■]. The reaction temperature varies depending on the raw materials, reagents, and solvents used, but is in the range of 0°C to 115°C, preferably 1
The temperature is 0°C to 80°C. The reaction time varies depending on the conditions, but is preferably about 1 to 48 hours, and more preferably 3 to 24 hours. The progress of the reaction is monitored by methods such as thin layer chromatography. After completion of the reaction, the glosstaglandin Ei represented by the above formula [■]
The substances can be separated and refined by treating the reaction solution in a conventional manner, such as extraction, washing, drying, concentration, etc.
It is separated and purified by a combination of methods such as chromatography.

Catalytic reduction using Raney nickel is carried out selectively under a hydrogen atmosphere. The Raney nickel used in this case is usually 2 to 30 wt%, preferably 5 to 20 wt% based on the raw material.
It is used in the wt% range. The pressure of the hydrogenation reaction is usually in the range of normal pressure to 5 atm, preferably in the range of normal pressure to 3 atm. As the solvent used at this time, for example, alcohols such as methanol, ethanol, and butanol; ethers such as dioxane and tetrahydrofuran; esters such as ethyl acetate; acetic acid; dimethylformamide; or a mixed solvent thereof are preferably used. Particularly preferably methanol is used. The amount of solvent used is sufficient as long as it allows the reaction to proceed quickly, and is usually 1 to 200 times the volume of the starting compound [■], preferably 5 to 100 times the volume. The reaction temperature varies depending on the raw materials, reagents, solvents, etc. used, but is carried out in the range of 0°C to 60°C, preferably in the range of 10°C to 40°C. The progress of the reaction is monitored by methods such as thin layer chromatography. After completion of the reaction, the Glotaglandin h group represented by the above formula (13) is separated and purified by treating the reaction solution in a conventional manner. That is, for example, by a combination of filtration concentration, chromatography, etc. It is separated and purified by this method.

The product thus obtained is optionally added to the 11th position.

The protecting group for the hydroxyl group at position 15 may be removed. Removal is accomplished, for example, by treating the product in an acetic acid-water-tetrahydroalan mixture at room temperature. In this way, the desired prostaglandins and the like are produced.

The feature of the method of the present invention is that the starting material (9[-J
The advantage is that prostaglandins B1 can be easily obtained from 4-hydroxy-2-cyclobentenone) in only three steps with a high overall yield.

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

Reference Example 1 "SiO' x O81" x The reaction was carried out under an argon atmosphere. (1ias;-3
-1-butyldimethylsilyloxy-1-youbi-1-
10 mg (2.2 mmol) of octene s was dissolved in 10 ml of anhydrous ether and cooled to -78<0>C. 1-Butyllithium solution (2,24M pentane solution) 1,9
6 (4.4 mmol) was added, and the mixture was stirred at -78°C for 80 minutes to obtain an alkenyllithium solution. 1-Pentynyl copper ([) 287 Atsushi 9 (2,2 mmol) to hexamethylphosphorustriamide 1,0 d (4,6 mmol)
) and stirred at room temperature for 1 hour. Anhydrous ether 10m/
was added, cooled to -78°C, processed into the above alkenyllithium solution, and stirred at -78°C for 15 minutes. 4-t-butyldimethylsilyloxy-2-cyclobentenone 425
mg (2.0 mmol) of anhydrous ether 10-solution was cooled to -78°C and added for 10 minutes at -78°C.

The mixture was stirred at -50°C for 10 minutes. t-butyldimethylsilyl 7-oginobutanoate 620 kg (2.4 mmol)
A solution of anhydrous ether 10117 was added after cooling to -50°C, and the mixture was stirred at -50°C to -40°C for 1.5 hours. pH4
The reaction solution was poured into an acetic acid-sodium acetate buffer solution containing 1 m of Klu, and extracted with hexane. Dry over anhydrous magnesium sulfate, filtrate and concentrate, add + to 7-hydroxyprostaglandin -butyldimethylsilyl ester 11.1
An oily substance containing 5-bis-t-butyldimethylsilyl ether was obtained.

7-hydroxyprostaglandin B, t-butyldimethylsilyl ester 11.15-bis-t-butyldimethylsilyl ether thin layer chromatography Rt: 0.39 (Developing solvent: hexane: acetone = 4: 1) In the above reaction Obtained 7-hydroxyprostaglandin E-
+t-butyldimethylsilyl ester 11. Oil B containing 15-bis-t-butyldimethylsilyl ether
Dissolve 50119 in ether 3 omj, pH 1 hydrochloric acid 5
After adding 0 ml of the mixture and stirring for 20 minutes, the mixture was extracted with ether. Wash with saturated saline and dry with anhydrous magnesium sulfate.
After overconcentration, 7-hydroxyprostaglandin F411,1 was separated and purified by silica gel column chromatography.
5-bis-t-butyldimethylsilyl ether 5241
9 (yield: 44 cm).

7-Hydroxyprostaglandin K11l, 15-pis-t-butyldimethylsilyl ether Thin layer chromatography Rf: 0.42 (Developing solvent: hexane/acetone = 2:1) Engineering R (liquid film): 3450, 1726, 1708
゜1252.831111”-1 CDCtl.

NMR (δ), o ~ o, z (m, t2111)
.

o, 57 (s, tsH), o, 7-1.1 (m, 3H), 1.0-3.0 (m
, 22H), 3.5-3.9 (m.

IH), 3.8-4.4(m, 2I().

5.3-5.7 (m, 2H), 5.5-7.
0 (m, 2H) Example 1 0H Length 810081° Dissolve in 4-dimethylaminopyridine 3
Add 67μt (3,0 mmol) of methanesulfonyl chloride while stirring while cooling with water.
o1') was added and stirred at 0°C for 20 minutes and at room temperature for 16 hours. Saturated brine was added, the pH was adjusted to 2 with oxalic acid, and the mixture was extracted with dichloromethane. After drying over anhydrous magnesium sulfate, filtration and concentration, the product was separated and purified using silica gel column chromatography to obtain (7K)-7,8-dehydroprostaglandin B+11.15-bis-t-butyldimethylsilyl ether zt6mg (yield 4s%) and (7Z)−
+11.15- to 7,8-dehydroglostaglandin
Bis-1-butyldimethylsilyl ether 51 (yield: 12) was obtained.

(7K)-7,8-7'+ to hydroprostaglandin
Bis-t-butyldimethylsilyl ether thin layer chromatography Rf: 0.50 (developing solvent; hexane: acetone = 2+
1) Engineering R (liquid film): 3600-2400.1713.

1650.1461, 1255゜1073, 833.772゜729C version-1 NMR (δ0D"'): O ~ 0.2 (m, 12H)
, 0.84 (El, 9H), 0.87 (El
19. HLO, 7-1.1 (m, 3H),
1.0-3.0 (m, 20H), 3.2-3.7 (
ml IH), 3.8-4.3 (m.

2H), 5.3-5.7 (m, 21()
.

6.66 (dt, IH, J=7.5.

2.0), 9.0~9+8 (m, IH)
(7Z)-7,8-f hydroprostaglandin E, bis-t-butyldimethylsilyl ether thin layer chromatography Rf: 0.53 (developing solvent; hexane: acetone = 2:
1) Engineering R (liquid film); 31) 00-2400.1740.

1648.1460.1254.

1077, 836. 773°1 757α NMR (δ0D0t'); O~0.2 (m, 12H)
, 0.88 (Sun, 9H), 0°90 (s, 9H).

(1,7~1.1 (m, 3H), 1.0~3
．． 0 (m', 20H), 3.3-3.5 (m.

IH), 3.8-4.3 (m, 2H).

4.8-6.0 (m, IH), 5.4-5
．． 8(m,2H)"' Example 2 (7K)-7,8-dehydroglostaglandin E, 1
1.15-bis-t-butyldimethylsilyl ether 4
7+I+9 (81 mmol) was dissolved in 2-acetic acid, 400 mg (6.1 mmol) of zinc powder was added, and the mixture was stirred at room temperature for 22 hours. The mixture was poured onto ice water, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration and concentration, it was separated and purified using silica gel column chromatography to give Glotaglandin +11.
15-bis-monobutyldimethylsilyl ether 21
mg (yield: 45 cm).

Prostaglandin F! +11.15-bis-monobutyldimethylsilyl ether thin layer chromatography Rf: 0.58 (hexane: ethyl acetate = 1:1
)ER (liquid film): 3600-2400, 1743°17
10. 1460. 1253.

1098, 834. 774cm’ CDCt.

NMR (δ), 0-0.2 (m, 12H),
0.88 (e, 9H), 0.90 (s, 9H).

0.7-1.1 (m, 3H), 1.0-2.9
(m, 24H), 3.9-4.4(m,
2H), 4.8-5.8 (m.

IH), 5.4-5.7 (m, 2H) Example 3 By almost the same operation as in Example 3, (7Z)-7,8-dehydroprostaglandin Fi+11.15-bis-t
-butyldimethylsilyl ether 30μm to prostaglandin, 111.15-bis-t-butyldimethylsilyl ether 1 note Example 4 Glostaglandin EI bis-t-butyldimethylsilyl ether 10m9 (17μm01) to hydrogen fluoride- Acetonitrile solution (47 typhnohydric acid 0.5ml + 7
Dissolve in 7tonitrile 10m/) 1.0+m and dilute at room temperature.
Stirred for 0 minutes. After adding a 10% hydrogen carbonate solution, the pH was adjusted to 3 with oxalic acid, extracted with ethyl acetate,
The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. After overconcentration, separation was performed using silica gel thin layer chromatography, and prostaglandin
3.9 tn9 (69% yield) was obtained.

Glotaglandin B+ Melting point 1 1 4.8 - 1 1 5.7°C
Optical rotation [α sum -53.3° (CO.6 3 THE
') Procedural Amendment Document January 1980/J' Japan Patent Office Commissioner 1, Indication of Case Patent Application No. 57-166481 No. 28 Title of Invention Prostaglanshift E, Manufacturing Process of Class 3 Case of Person Who Makes Amendment Relationship with Patent Applicant 1-11 Minamihonmachi, Higashi-ku, Osaka (300) Teijin Limited Representative Tomoo Tokusue 5 Column 6 of Detailed Description of the Invention J of the specification subject to amendment, Contents of Amendment (1) ) "Dihomo-8-lylunic acid" on page 8, line 17 of the specification is corrected to "dihomo-γ-lylunic acid."

(2) “Dihomo-8-lylunic acid” on page 9, line 15
The text has been corrected to read "dihomo-gamma-lylunic acid."

(3) In the 17th page, lines 14 to 15, "n-pentyl" is corrected to "?L-pen'til".

that's all

Claims (1)

[Claims] 1. Selective reduction of a compound represented by the following formula [I], its 15-form, its enantiomer, or a mixture of these Δ7-prostaglandin E in any proportion. 1. Then, if necessary, the compound represented by the following formula [■], its enantiomer, or a mixture thereof in any proportion, is subjected to deprotection and/or hydrolysis reaction. A method for producing prostaglandin E1 to obtain. 2. A method for producing prostaglandin E1 according to claim 1, which selectively reduces the prostaglandin E1 by catalytic reduction using a zinc-based reducing agent or Raney nickel. 3. The method for producing glostaglandin &e. 4. The method for producing Glostaglandin Fits according to any one of claims 1 to 3, wherein R1 in the above formula [1'] is a hydrogen atom. 5. In the above formula [1], R4 is an n-pentyl group. 2-methyl-1-hexyl group, cyclopentyl group or 7
A method for producing prostaglandin E1 according to any one of claims 1 to 4, which is a chlorohexyl group. 6. The compound according to any one of claims 1 to 5, wherein in the above formula [1'l, R'' and R' are a tetrahydrobilan-2-yl group or a 1-butyldimethylsilyl group. A method for producing prostaglandin E+. 7. A compound represented by the following formula [■], its 15-form, its enantiomer, or a mixture of these 7-hydroxyprostaglandins in any proportion, is added to a base. A compound represented by the following formula [1], its 15-sulfonic form, It is characterized by obtaining a mixture of their enantiomers or their 1-prostaglandin E types in arbitrary proportions, then selectively reducing them, and further subjecting them to deprotection and/or hydrolysis reactions as necessary. A prostaglandin & analogue R production method for obtaining a compound represented by the following formula [11], its 15-form, its enantiomer, or a mixture of any ratio thereof. 8. Zinc-based reduction 9. A method for producing grosstaglandin EI according to claim 7, wherein the reactive derivative of the organic sulfonic acid is methanesulfonyl chloride, p-toluenesulfonyl chloride or p-toluenesulfonyl chloride. A method for producing prostaglandin Ei according to claim 7 or 8, which is methanesulfonic anhydride, and claims 7 to 9, wherein the basic compound is an amine. The method for producing grosstaglandin Fit according to any one of claims 7 to 10, wherein in the above formula [[11], R1 is a hydrogen atom. 12. A method for producing prostaglandin E according to any one of claims 7 to 11, wherein in the above formula [■], R5 is a hydrogen atom. 13. , the prostaglandin according to any one of claims 7 to 12, wherein R4 in the above formula ['1lll is n-pentyl, 2-methyl-1-hexyl group, nclopentyl group, or cyclohexyl group. Method for producing Fits. 14. Any one of claims 7 to 13, which is the above formula [■] K-iteR5llR4+catetrahytropyran-2-yl group or !-butyldimethylsilyl group. The method for producing prostaglandin E1 described above.