JPH04330053A - 5-thia-delta7-prostaglandin e compounds and its production - Google Patents

Abstract

PURPOSE:To provide a novel 5-thia-DELTA<7>-prostaglandin E compound expected to have an anti-cancer action, an antihypertensive action, an anti-ulcer action, etc. CONSTITUTION:A compound of formula I (R<1> is H, 1-10C alkyl; R<2> is 1-10C alkyl, 5-6C cycloalkyl; R<3>, R<4> are H, tri 1-6C hydrocarbon silyl; the group of formula II shows that the 7Z isomer and the 7E isomer or the 7Z isomer and the 7E isomer coexist in an arbitrary ratio) or a non-toxic acid adduct thereof when R<1> is H, e.g. 17,20-dimethyl-5-thia-DELTA<7>-prostaglandin E. The compound of formula I is obtained by reacting a 7-hydroxyprostaglandin compound of formula III (R<31>, R<41> are tri 1-6C hydrocarbon silyl) with an organic sulfonic acid-reactive derivative (e.g. methane sulfonyl chloride) in the presence of a basic carbonate, treating the obtained 7-organic sulfonyloxyprostaglandin compound with a basic compound, and subsequently, if necessary, subjecting the product to a protecting group-removing reaction, a hydrolysis reaction and/or a salt-forming reaction.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention provides a novel 5-thia-△7
-Regarding prostaglandin E and its production method.

0002

[Prior Art] Natural prostaglandins are autacoids with high biological and pharmacological activity. They have strong platelet aggregation inhibiting and vasodilatory effects, and like prostaglandin E1, Some have already been applied clinically. On the other hand, many studies have been conducted on various derivatives to overcome the pharmacological disadvantages of natural prostaglandins, namely their ability to simultaneously possess various physiological activities, their short duration of physiological activity, and their inability to take them. ing. Furthermore, prostaglandin types A and D are known to be cytotoxic to cancer cells. Since prostaglandins have a wide range of physiological activities, they have the potential to be developed into various pharmaceutical products by chemically modifying their skeletons.

0003

SUMMARY OF THE INVENTION An object of the present invention is to provide novel 5-thia-Δ7-prostaglandin E and a method for producing the same.

0004

[Means for Solving the Problems] The present inventor focused on the characteristics of prostaglandin, and as a result of intensive research to obtain new prostaglandin derivatives, the present inventors discovered a novel 5-thia-△7-prostaglandin E class. The present invention was achieved by discovering a method for producing the same.

5-Thia-Δ7 provided by the present invention
- Prostaglandin E has the following formula [I]

When 5-thia-Δ7-prostaglandin E represented by the following formula or R1 represents a hydrogen atom, it is a non-toxic salt of the acid.

In the above formula [I], R1 represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. Examples of such alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, etc. hydrogen atom, methyl group,
Ethyl group is preferred. R2 represents a linear or branched alkyl group having 1 to 10 carbon atoms or a 5- to 6-membered cycloalkyl group. The number of carbon atoms in such a straight chain or branched chain is 1 or more
Examples of the alkyl group 10 include methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, and decyl group. Examples of the 5- to 6-membered cycloalkyl group include a cyclopentyl group and a cyclohexyl group. Among these, R2
As such, pentyl group, 2-methylhexyl group, cyclopentyl group, and cyclohexyl group are preferable.

R3 and R4 in the above formula [I] represent a hydrogen atom or a tri(C1-C6) hydrocarbon silyl group. Such tri(C1-C6) hydrocarbon silyl groups include, for example, trimethylsilyl, triethylsilyl, t-
Examples include tri(C1-C4)alkylsilyl groups such as butyldimethylsilyl; diphenyl(C1-C4)alkylsilyl groups such as t-butyldiphenylsilyl group. Among these, R3 and R4 are preferably a hydrogen atom, a trimethylsilyl group, or a t-butyldimethylsilyl group, and particularly preferably a t-butyldimethylsilyl group. R3, R
These protecting groups used in 4 may be the same or different.

Representation of the above formula [I] (Chemical formula 5)

embedded image indicates that the 7Z form, the 7E form, or the 7Z form and the 7E form coexist in any proportion. 5-thia-△7- of the present invention
The carbon atoms at the 11th, 12th, and 15th positions of prostaglandin E are asymmetric carbon atoms, and the absolute configuration of these asymmetric carbon atoms may be either the R-configuration or the S-configuration, or any of both. It may be a mixture of the following proportions. Therefore, in the present invention, it is also possible to obtain 5-thia-Δ7-prostaglandin E having a steric configuration different from that of natural prostaglandins, and these compounds have the same steric configuration as natural prostaglandins. It is also expected that it will have different physiological activities than those that it has.

Among the 5-thia-Δ7-prostaglandins E of the present invention, when R1 in the above formula [I] is a hydrogen atom, it can be used by utilizing the fact that it has a carboxylic acid moiety in the molecule. It can also be a non-toxic salt with a base. In this case, any base may be used as long as it is a pharmacologically acceptable non-toxic salt, such as sodium hydroxide, calcium hydroxide, sodium carbonate,
Inorganic bases such as potassium carbonate, sodium bicarbonate and potassium bicarbonate; organic bases such as ammonia, ethanolamine and diethanolamine are preferably used.

Specific examples of the 5-thia-Δ7-prostaglandin E of the present invention are as follows. (1) 5-thia-△7-prostaglandin E1 (
2) 17,20-dimethyl-5-thia-Δ7-prostaglandin E1 (3) 16,17,18,19,20-pentanoyl-
15-cyclohexyl-5-thia-Δ7-prostaglandin E1 (4) 16,17,18,19,20-pentanoyl-
15-Cyclopentyl-5-thia-△7-prostaglandin E1 (5) 20-methyl-5-thia-△7-prostaglandin E1 (6) Enantiomer of the compounds of (1) to (5) 15 The sodium salt, potassium salt, calcium salt, ammonium salt, ethanolammonium salt, or diethanolammonium salt (8
) (1) to (6) methyl ester (9) (1
) - Compounds (7) and (8) in which the hydroxyl group is protected by a t-butyldimethylsilyl group or a diphenylmethylsilyl group

The 5-thia-Δ7-prostaglandin E obtained in the present invention is a novel prostaglandin, and particularly has a double bond at the 7- and 8-positions and a sulfur atom at the 5-position. It has a new skeleton. On the other hand, prostaglandins are known to have various physiological activities, and research on the synthesis of various derivatives is currently being conducted. The 5-thia-△7-prostaglandin E of the present invention also has the potential for new medicinal effects in the sense that it has a new skeleton, and is expected to have anticancer, blood pressure lowering, antiulcer, or viral effects. be done. In addition, 5-thia-Δ7-prostaglandin E of the present invention is a novel compound 5 having platelet aggregation inhibitory activity.
It can also be an important synthetic intermediate for -thia-prostaglandin E1, and is useful in this sense as well.

Therefore, the 5-thia-Δ7-prostaglandin E of the present invention has the following formula [II]

The 7-hydroxy prostaglandins represented by the following formula are reacted with a reactive derivative of an organic sulfonic acid in the presence of a basic compound to form the corresponding 7-organosulfonyloxy prostaglandins, and then treated with basic compounds,
It is produced by subjecting it to deprotection and/or hydrolysis and/or salt-forming reaction as necessary.

The 7-hydroxyprostaglandins represented by the above formula [II], which are the raw material compounds in the production method of the present invention, are shown in Chart 1 below.

It is synthesized by a method similar to the method for producing 7-hydroxyprostaglandin E described in JP-A-57-7464, as shown in the example shown in [Image Omitted].

[0014] Furthermore, in the above formula [II], R1,
The definition of R2 is the same as in the above formula [I]. R3
1, R41 represents a tri(C1-C6) hydrocarbon silyl group, and examples of such protecting groups include the same ones as mentioned above.

As the basic compound used in reacting the 7-hydroxyprostaglandins of the above formula [II], amines are preferable, and examples of such amines include 4-dimethylaminopyridine, triethylamine, Examples include diisopropylcyclohexylamine, isopropyldimethylamine, diisopropylethylamine, and 4-dimethylaminopyridine is particularly preferred. Examples of reactive derivatives of organic sulfonic acids include organic sulfonic acids such as methanesulfonyl chloride, ethanesulfonyl chloride, n-butanesulfonyl chloride, t-butanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, and p-toluenesulfonyl chloride. Halides; organic sulfonic anhydrides such as methanesulfonic anhydride, ethanesulfonic anhydride, trifluoromethanesulfonic anhydride, benzenesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

The basic compound itself may be used as the solvent; for example, halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; ethers such as ether and tetrahydrofuran; benzene, toluene, pentane, Hydrocarbons such as hexane and cyclohexane are used, preferably dichloromethane.

The reaction is a reaction between the hydroxyl group at the 7-position of the 7-hydroxyprostaglandins represented by the general formula [II] and a reactive derivative of an organic sulfonic acid, and stoichiometrically, the two compounds are Reacts in equimolar amounts. In order to carry out the actual reaction, the reactive derivative of organic sulfonic acid is usually used in a ratio of 1 mol to 10 mol per 1 mol of the 7-hydroxyprostaglandin of general formula [II]. Basic compounds are
1 per mole of the reactive derivative of the organic sulfonic acid used.
It is used in an amount of mol or more, preferably 2 mol or more. The amount of solvent used is usually 1 to 1000 times the volume, preferably 5 to 100 times the volume of the raw material compound represented by the above formula [I].
Double capacity is used. The reaction temperature varies depending on the raw material compound, basic compound, solvent, etc. used, but usually -
The temperature range is from 10°C to 50°C, preferably from 0°C to 3°C.
It is carried out in the range of 0°C. The reaction time varies depending on the conditions, but is about 0.1 to 10 hours. Progress of the reaction is monitored by methods such as thin layer chromatography.

[0018] Thus, according to the above reaction (hereinafter referred to as the first reaction), the corresponding 7-hydroxyprostaglandins of formula [II] have their 7-hydroxyl group converted to an organic sulfonyloxy group. -Organosulfonyloxyprostaglandins are produced. The 7-organosulfonyloxyprostaglandins are then treated with a basic compound (hereinafter referred to as the second reaction) to eliminate the corresponding organic sulfonic acid and form a bond between the carbon atom at the 7-position and the carbon atom at the 8-position. The heavy bond is converted into 5-thia-Δ7-prostaglandin E. This second reaction can be carried out using the same basic compound as the first reaction and at approximately the same temperature. Furthermore, the 7-organosulfonyloxyprostaglandins produced in the first reaction may be isolated and then subjected to the second reaction, or the first reaction and the second reaction may be performed in the same reaction system. You may go.

The 5-thia-Δ7-prostaglandin E thus obtained is further subjected to deprotection and/or hydrolysis and/or salt-forming reactions, if necessary. Deprotection of the tri(C1-C6) hydrocarbon silyl group is carried out, for example, in the presence of tetrabutylammonium fluoride or cesium fluoride (more preferably in the presence of a basic compound such as triethylamine),
A reaction solvent as described above (preferably a reaction solvent other than water)
The tests are carried out at approximately the same temperature and for approximately the same amount of time. Alternatively, using an acidic compound such as hydrofluoric acid or acetic acid,
Tri(C1-C
6) Hydrocarbon silyl groups can also be eliminated.

Hydrolysis of the ester group is carried out by treatment with lipase, esterase, etc. in water or a solvent containing water. The salt-forming reaction can be carried out by a neutralization reaction between 5-thia-Δ7-prostaglandins having a free carboxyl group and the above-mentioned inorganic base or organic base. The target compound thus obtained is isolated and purified by conventional means such as extraction and column chromatography.

[0021]

EXAMPLES The present invention will be explained in more detail with reference to Examples below. Reference Example 1 Synthesis of 7-hydroxy-5-thiaprostaglandin E1 methyl ester 11,15-bis-t-butyldimethylsilyl ether and its enantiomer 15-epi form 3
(s)-t-Butyldimethylsilyloxy-1-iodo-1-octene 6.07g (16.5mmol)
16.5 ml (2M solution) of t-butyllithium (33
mmol) was added thereto, and the mixture was stirred for 1 hour. Next, 2.15 g (16.5 mmol) of 1-pentynyl copper (I) and 5.4 g (33 mmol) of hexamethylphosphorus triamide were added.
mol) in 25 ml of anhydrous ether was added thereto, and the mixture was further stirred at -78°C for 1 hour. 4-tert-butyldimethylsilyloxy-2-cyclopentenone 3.18g (15m
mol) in anhydrous ether was added thereto, and the mixture was stirred at -78°C for 30 minutes and at -50°C for 10 minutes. 7-oxo-
5 Thiapentanoic acid methyl ester 2.0g (16.5m
mol) in 10 ml of anhydrous ether was added after cooling to -50°C, and the mixture was stirred at -50°C to -40°C for 40 minutes. p
The reaction solution was poured into an acetic acid-sodium acetate buffer adjusted to H4, and extracted with hexane. Dry over anhydrous magnesium sulfate, concentrate, and separate and purify using silica gel chromatography to obtain 7-hydroxy-5-thiaprostaglandin E1.
5.2 g (yield 55%) of a mixture of methyl ester 11,15-bis-t-butyldimethylsilyl ether and its enantiomer 15-epi isomer was obtained. TLC, Rf: 0.45 (solvent; hexane: ethyl acetate = 3:1) IR (cm-1, neat); 3500, 2950, 2
880, 1740, 1460, 1440, 1360, 1
250 NMR (δ ppm in CDCl3); 0.9 (
s, 18H), 0.9-1.7 (m, 11H), 1.7
~3.1 (m, 10H), 3.7 (s, 3H), 3.7
~4.4 (m, 3H), 5.65 (m, 2H)

Example 1 Synthesis of 5-thia-Δ7-prostaglandin E1 methyl ester 11,15-bis-t-butyldimethylsilyl ether and its enantiomer 15-epi form Reference Example 1
Add 1.25 g (1.98 mmol) of the mixture of 7-hydroxy-5-thiaprostaglandin E1 methyl ester 11,15-bis-t-butyldimethylsilyl ether and its enantiomer 15-epi form to 10 ml.
was dissolved in anhydrous dichloromethane, 1.65 g (13.5 mmol) of 4-dimethylaminopyridine was added, and 0.5 ml (6.7 mmol) of methanesulfonyl chloride was dissolved at 0°C.
1) was added, and the mixture was stirred at 0°C for 5 hours, and further stirred at room temperature for 1 hour. Water was added and extracted with dichloromethane. It was dried over anhydrous magnesium sulfate, concentrated, and then separated and purified using silica gel chromatography to obtain 5-thia-Δ7-prostaglandin E1 methyl ester 11,15-bis-t-butyldimethylsilyl ether and its enantiomer 15- A mixture of epiforms was obtained. Of these, 59 are 7E bodies.
0 mg (yield 49%), 7Z form 150 mg (yield 12
%)Met.

TLC, 7E form, Rf: 0.65 (solvent;
Hexane: ethyl acetate = 3:1) 7Z form, Rf: 0.68 (solvent; hexane: ethyl acetate = 3:1) 7E form IR (cm-1, neat); 2980, 2870, 1
740, 1640, 1460, 1360, 1255NM
R(δ ppm in CDCl3); 0.9(s,
18H), 0.7-2.1 (m, 13H), 2.1-2
．． 8 (m, 6H), 3.0-3.5 (m, 3H), 3.
70 (s, 3H), 3.9-4.3 (m, 2H), 5.
55 (m, 2H), 6.8 (dt, 1H, J=7.5,
2.0) 7Z body IR (cm-1, neat); 2980, 2870, 1
740, 1450, 1255 NMR (δ ppm in CDCl3); 0.9 (
s, 18H), 0.7-2.1 (m, 13H), 2.1
~2.7 (m, 6H), 3.0 ~ 3.6 (m, 3H),
3.7 (s, 3H), 3.7-4.35 (m, 2H),
5.3-5.9 (m, 2H), 5.55 (m, 2H)

Example 2 16,17,18,19,20-pentanoyl-15-
Synthesis of cyclohexyl-5-thia-Δ7-prostaglandin E1 methyl ester 11,15-bis-t-butyldimethylsilyl ether 16,17,18,19,20-pentanoyl-15-
Cyclohexyl-7-hydroxy-5-thia-△7 -
Prostaglandin E1 methyl ester 11,15-
Bis-t-butyldimethylsilyl ether 560mg (
0.87 mmol) was dissolved in 5 ml of anhydrous dichloromethane, and 530 mg of 4-dimethylaminopyridine (4.3
5 mmol), then added 170 μl (2.2 mmol) of methanesulfonyl chloride at 0°C, and then
The mixture was stirred for 1 hour and further stirred at room temperature for 3 hours. Water was added and extracted with dichloromethane. Dry over anhydrous magnesium sulfate, concentrate and separate and purify using silica gel chromatography to obtain 16,17,18,19,20-pentanoyl-15-cyclohexyl-5-thia-Δ7-prostaglandin E1 methyl ester 11,15 -bis-t
-butyldimethylsilyl ether 315 mg (yield 58
%, mixture of 7E and 7Z forms, 7E:7Z=4:1)
I got it.

IR (cm-1, neat); 2970,
2860, 1740, 1640, 1455, 1355,
1260NMR (δ ppm in CDCl3); 0
．． 9 (s, 18H), 0.9-2.2 (m, 13H),
2.2-2.7 (m, 6H), 3.0-3.65 (m,
3H), 3.65 (s, 3H), 3.7-4.4 (m,
2H), 5.2-5.9 (m, 0.2H, 7Z body), 5
．． 5 (m, 2H), 6.9 (t, 0.8H, J=8,7
E body)

Example 3 Synthesis of 17(s),20-dimethyl-5-thia-Δ7-prostaglandin E1 methyl ester 11,15-bis-t-butyldimethylsilyl ether 7-hydroxy-17(s) ,20-dimethyl-5-thia-△7
-Prostaglandin E1 methyl ester 11,15
-bis-t-butyldimethylsilyl ether 120mg
(0.18 mmol) was dissolved in 2 ml of anhydrous dichloromethane, and 110 mg of 4-dimethylaminopyridine (0.18 mmol) was dissolved in 2 ml of anhydrous dichloromethane.
9 mmol) was added thereto, and 30 μl (0.4 mmol) of methanesulfonyl chloride was added at 0° C., and the mixture was stirred for 1 hour. Next, the mixture was returned to room temperature and stirred for 5 hours. Water was added and extraction was performed with dichloromethane. Dry over anhydrous magnesium sulfate, concentrate, and separate and purify by thin layer chromatography to obtain 1
7(s),20-dimethyl-5-thia-Δ7-prostaglandin E1 methyl ester 11,15-bis-
76 mg t-butyldimethylsilyl ether (yield 66
%, mixture of 7E and 7Z forms, 7E:7Z=4:1)

IR (cm-1, neat); 2980,
2860, 1740, 1640, 1460, 1360,
1255 NMR (δ ppm in CDCl3); 0.9 (
s, 18H), 0.7-2.0 (m, 17H), 2.0
~2.7 (m, 6H), 3.0 ~ 3.7 (m, 3H),
3.70 (s, 3H), 3.7-4.5 (m, 2H),
5.2-5.9 (m, 0.2H, 7Z body), 5.6 (m
, 2H), 6.9 (t, 0.8H, J=8,7E body)

Example 4 Synthesis of 15-epi form of (7E)-7,8-dehydro-5-thiaprostaglandin E1 methyl ester and its enantiomer (7E)-7,8-dehydro-5-thiaprosta Grandin E1 methyl ester 11,15-bis-t-butyldimethylsilyl ether and its enantiomer 15-epi form 213 mg (0.35 mmol) were dissolved in 10 ml of acetonitrile, and 40% aqueous hydrogen fluoride solution was added to 0.0 ml of acetonitrile.
Add 5 ml and stir at room temperature for 30 minutes. After 40 minutes, an aqueous sodium bicarbonate solution was added to terminate the reaction, followed by extraction with ethyl acetate. After drying, the solvent was distilled off and purified by thin layer chromatography to obtain 100 mg of a mixture of (7E)-7,8-dehydro-5-thiaprostaglandin E1 methyl ester and its enantiomer 15-epi form ( A yield of 75% was obtained.

TLC, Rf: 0.45 (solvent; hexane: ethyl acetate = 1:4) IR (cm-1, neat); 3400, 2770, 2
750, 2670, 1720, 1640, 1440, 1
240 NMR (δ ppm in CDCl3); 0.9 (
s, 3H), 0.7-2.0 (m, 8H), 1.9 (d
d, 2H, J=7), 2.2 to 3.0 (m, 8H), 3
．． 25 (d, 2H, J=8), 3.5 (m, 1H), 3
．． 7 (s, 3H), 4.2 (m, 2H), 5.65 (m
, 2H), 6.8 (dd, J=8.0, 1.5) Other compounds can be similarly deprotected.

Example 5 Synthesis of (7E)-7,8-dehydro-5-thiaprostaglandin E1 (7E)-7,8-dehydro-5-thiaprostaglandin E1 methyl ester 54 mg (0.14 mmol)
) to 8 ml of pH 8 phosphate buffer, and then add 0.8 ml of acetone solution of
Add 80 μl of Rase and stir at room temperature for 4 hours. The pH was adjusted to 3.5 with hydrochloric acid at 0°C and extracted with ethyl acetate. After drying, the product was purified by thin layer chromatography to obtain the desired product. NMR (δ ppm in CDCl3); 0.7~
2.0 (m, 11H), 1.9 (dd, 2H, J=7)
, 2.2-3.0 (m, 9H), 3.25 (d, 2H,
J=8), 3.5 (m, 1H), 4.2 (m, 2H),
5.6 (m, 2H), 6.8 (dd, J=8.0, 1.
5)

[0031]

According to the present invention, 5-thia-Δ7-prostaglandin E is obtained, and such compounds are expected to have pharmacological effects such as anticancer, hypotensive, and antiulcer effects.

Claims (12)

[Claims] 1. A nontoxic salt of 5-thia-Δ7-prostaglandin E represented by the following formula [I] or an acid thereof when R1 is a hydrogen atom. 2. The compound according to claim 1, wherein in the above formula [I], R1 is a hydrogen atom, a methyl group, or an ethyl group.
-Thia-△7 -Prostaglandin E or R1
A non-toxic salt of an acid when is a hydrogen atom. 3. The 5-thia-Δ7 according to claim 1, wherein in the above formula [I], R2 is a pentyl group, 2-methylhexyl group, cyclopentyl group or cyclohexyl group.
- Non-toxic salts of prostaglandin E or its acid when R1 is a hydrogen atom. 4. The 5-thia-Δ according to claim 1, wherein in the above formula [I], R3 and R4 are a hydrogen atom, a trimethylsilyl group or a t-butyldimethylsilyl group.
7-Prostaglandin E or a non-toxic salt of the acid when R1 is a hydrogen atom. 5. A 7-hydroxy prostaglandin represented by the following formula [II] [Chemical 2] is reacted with a reactive derivative of an organic sulfonic acid in the presence of a basic compound to form the corresponding 7-hydroxyprostaglandin. organic sulfonyloxyprostaglandins, then treated with a basic compound,
The following formula [I], which is subjected to deprotection and/or hydrolysis and/or salt production reaction as necessary.
A method for producing a non-toxic salt of 5-thia-Δ7-prostaglandin E represented by the following formula or an acid when R1 is a hydrogen atom. 6. 5-thia-Δ7-prostaglandin E according to claim 5, wherein the reactive derivative of the organic sulfonic acid is an organic sulfonic acid halide or an organic sulfonic anhydride, or when R1 is a hydrogen atom. A method for producing non-toxic salts of the acid. 7. The organic sulfonic acid halide is methanesulfonyl chloride, ethanesulfonyl chloride, n-
The process for producing a non-toxic salt of 5-thia-Δ7-prostaglandin E or the acid according to claim 6, which is butanesulfonyl chloride, t-butanesulfonyl chloride or trifluoromethanesulfonyl chloride, or when R1 is a hydrogen atom. . 8. The organic sulfonic anhydride is methanesulfonic anhydride, ethanesulfonic anhydride, trifluoromethanesulfonic anhydride, benzenesulfonic anhydride or p-
5-thia-Δ according to claim 6, which is toluenesulfonic acid.
7 - A method for producing a nontoxic salt of prostaglandin E or its acid when R1 is a hydrogen atom. 9. 5-Thia-Δ7-prostaglandin E according to any one of claims 5 to 8, wherein the basic compound is an amine, or when R1 is a hydrogen atom, the acid is non-toxic. Salt manufacturing method. 10. In the above formula [II], R1
is a hydrogen atom, a methyl group or an ethyl group.
9. A method for producing a nontoxic salt of 5-thia-Δ7-prostaglandin E according to any one of Items 9 or 9, when R1 is a hydrogen atom. 11. The 5-thia-Δ7-prosta according to any one of claims 5 to 10, wherein in the above formula [II], R2 is a pentyl group, a 2-methylhexyl group, a cyclopentyl group, or a cyclohexyl group. Grandin E
A method for producing a non-toxic salt of an acid when R1 or R1 is a hydrogen atom. 12. In the above formula [II], R31,
Any one of claims 5 to 11, wherein R41 is a hydrogen atom, a trimethylsilyl group or a t-butyldimethylsilyl group.
A method for producing a nontoxic salt of 5-thia-Δ7-prostaglandin E or the acid described in Section 1, when R1 is a hydrogen atom.