JPH02167A - 5-thia-delta7-prostaglandin e and production thereof - Google Patents

Abstract

NEW MATERIAL:5-Thia-DELTA<7>-prostaglandin Es expressed by formula I [R<1> is H or 1-10C alkyl; R<2> is (substituted) 1-10C alkyl or (substituted) cycloalkyl; R<3> and R<4> are H or protecting group; indication of formula II denotes 7Z, 7E isomer or coexistence of the 7Z and 7E isomers in an optional proportion] or innocuous salt of the acid thereof when R<1> is H. EXAMPLE:5-Thia-DELTA<7>-prostaglandin E1 methyl ester 11,15-bis-tert-butyldimethylsilyl ether. USE:A compound capable of exhibiting pharmacological action, such as anticancer, hypotensive, antiulcer action, etc. PREPARATION:7-Hydroxyprostaglandins expressed by formula III (R<31> and R<41> are protecting group) are reacted with a reactive derivative of an organic sulfonic acid in the presence of a basic compound to provide the corresponding 7-organic sulfonyloxyprostaglandins, which are then treated with a basic compound to afford the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 5-thia-Δ7-prostaglandin E
1 and its manufacturing method.

Natural prostaglandins are autacoids with high biological and pharmacological activity, and they have strong platelet aggregation inhibitory and vasodilatory effects, and like prostaglandin E, they have already been used clinically. Some applications are underway.

On the other hand, many studies have been conducted on various derivatives to overcome the pharmacological shortcomings 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.

Because prostaglandins have a wide range of physiological activities,
By chemically modifying its skeleton, it has the potential to be developed into various pharmaceutical products. The present inventor has focused on these characteristics of prostaglandins, and as a result of intensive research to obtain new prostaglandin derivatives, has discovered novel 5-thia-bar prostaglandins and a method for producing the same, and has arrived at the present invention. It is.

The 5-thiavar prostaglandins provided by the present invention have the following formula [! ] When 5-thia-bar prostaglandins represented by or R1 has a hydrogen atom, it is a non-toxic salt of the acid.

In the above formula (I), A is -CH-CH-(cig
) Furthermore, the 5-thia-N-purustabrandins of the present invention can be broadly classified into the following compounds.

OR' is the following formula (r) -1 R3 It is a so-called PGE type compound.

(When Ill A is -CH=CH-(cis), the compound of the present invention is represented by the following formula (I) -2 and is a so-called PGA type compound.

In the above formulas (1), (1)-1, and (1)-2, R1 represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. Examples of such a furkyl group include a methyl group, an ethyl group, a propyl group, and an inpropyl group.

Examples include butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, denyl group, etc. ((hydrogen atom, methyl group, and ethyl group are preferred. R2 is substituted or unsubstituted. is an alkyl group having 1 to 10 carbon atoms or a substituted or unsubstituted cycloalkyl group. Examples of substituents for the alkyl group or cycloalkyl group include halogen atoms such as fluorine, chlorine, and bromine; acetoxy group, propionyloxy group, butyryloxy group, inbutyryloxy group, valeryloxy group, invaleryloxy group.

7 siloxy groups such as valeryloxy group and caproyl group;
Furkyl groups such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, chloromethyl group, dichloromethyl group, trifluoromethyl group; alkoxy groups such as methoxy group, ethoxy group, propoxy group, inpropoxy group, butoxy group Examples include groups. Examples of such a substituent-substituted or unsubstituted alkyl group having 1 to 10 carbon atoms include a methyl group, an ethyl group, a propyl group, an inpropyl group, and a butyl group.

t-butyl group, pentyl group, hexyl group, heptyl group,
Examples include octyl group, nonyl group, and decyl group. Examples of the substituted or unsubstituted cycloalkyl group include a cyclopentyl group.

Examples include cyclohexyl group. Among these, R
2 is preferably a pentyl group, 2-methylhexyl group, cyclopentyl group, or cyclohexyl group.

The above formula (1), (I) -1, (t) -2K orlR''.

R4 in the above formula (1) -1VC represents a hydrogen atom or a protective group. The protecting group may be any protecting group as long as it can exist stably without being eliminated during the reactions and post-treatment steps carried out in the present invention, which will be described later. Examples of the protecting group include trimethylsilyl, triethyl, etc. Silyl, tri(C5-C4)furkylsilyl such as t-butyldimethylsilyl; diphenyl(C1-C4)furkylsilyl such as t-butyldiphenylsilyl)! J(C, ~Ca) hydrocarbon silyl group (silyl ether type protecting group), or methoxymethyl, l
-ethoxyethyl, 2-methoxy-2-propyl, 2-
Oxygen atoms such as ethoxy-2-propyl, (2-methoxyethoxy)methyl, benzyloxymethyl-2-tetrahydrofuranyl, 6,6-dimethyl-3-oxa-bicyclo(3.1.0)hex-4-yl group Examples include a group that forms a 7-cetal bond (acetal-protecting group). Among these, 13, R4 is a hydrogen atom, a trimethylsilyl group. t-
Butyldimethylsilyl group. A 2-tetrahydropyranyl group is preferred, and a t-butyldimethylsilyl group is particularly preferred.

The protecting groups used in R3 and R4 may be the same or different.

The above formula (2 people displaying 1'l is 72 bodies, 7E bodies, or 72 bodies)
This shows that the 7E body and the 7E body coexist in arbitrary proportions.

The carbon atoms at the 12th and 15th positions of the 5-thia-perprostaglandins of the present invention, and the carbon atoms at the 11th position of the 5-thia-perprostaglandins represented by formula (1)-1 are It is an asymmetric carbon atom, and the absolute configuration of the asymmetric carbon atom may be either the R-configuration or the S-configuration, or a mixture of both in any proportion.

Therefore, according to the present invention, 5-thia-perprostaglandins having a configuration different from that of natural prostaglandins can also be obtained, and these compounds are
It is also expected to have a different physiological activity from those having the same configuration as natural prostaglas/gins.

Among the 5-thia-N-boostaglandins of the present invention, when R1 in the above formula (13 K) is a hydrogen atom, it can be combined with a non-toxic base using the fact that it has a carboxylic acid moiety in the molecule. It can also be used as a salt. In this case, a pharmacologically acceptable non-toxic salt may be used as a base, such as sodium hydroxide.

Calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.] Inorganic bases; ammonia, ethanolamine.

Organic bases such as jetanolamine are preferably used.

Specific examples of the 5-thia-perprostaglandins of the present invention are as follows.

(:) 5-thia-bar prostaglandins represented by the above formula CI) -t (I) 5-thia-N-prostaglandin E.

(2) 17.20-dimethyl-5-thia-perprostaglandin E.

+31 1 6.1 7.1 8,1 9.2 0-
Pentatulu 15-cyclohexyl-5-thia-perprostaglandin E.

(4) 1 6,1 7.1 8,1 9.2 0-
Pentanol-15-sicqpentyl-5-17-a'-prostaglandin E1 (5120-methyl-5-thia-ni-prostaglandin E.

(6) Enantiomers of the compounds of (1) to (5) and epimers at the 15-position fil Sodium salts, potassium salts, calcium salts, ammonium salts, ethanolammonium salts, or jetanol ammonium of the compounds of (6) Salt f81 (methyl ester of the compound of 11 to (6) (
91 (compounds 11 to (7) and (8) are t-butyldimethylsilyl group, diphenylmethylsilyl group, methoxymethyl group, l-ethoxyethyl group, 2-ethoxy-2
- Compound (11) in which the hydroxyl group is protected by a protecting group of propyl group, methoxyethoxymethyl group, or tetrahydropyran-2-yl group 5-thia-N-purustabrandin represented by the above formula (1) -2 kind fi ($5-thia-〆-prostaglanodin A.

0111? , 20-dimethyl-5-thia-but-p-staglandin A1 α3 16. + 7.18,19.20-pentanol-15-cyclohexyl-5-thia-barboostaglandin A.

03] 6,17,18,19.20-Pentano-15-cyclobenzene-5-thia-prostaglandin A1 Q4120-Methyl-5-thia-N-prostaglandin A.

α49 Enantiomer of the compound of 01 to α4, epimer at the 15-position Sodium salt, potassium salt of the compound of α1 to α$,
Calcium salt, ammonium salt, ethanol ammonium salt or jetanol ammonium salt + methyl ester α orange of compound of 171 H ~ α9
The compounds αl to αG and αη are a t-butyldimethylsilyl group, a diphenylmethylsilyl group, a methoxymethyl group, a l-ethoxyethyl group, and a 2-ethoxy-2-propyl group.

A compound whose hydroxyl group is protected by a methoxyethoxymethyl group or a tetrahydropyran-2-yl group.

The 5-thia-perprostaglandins obtained in the present invention are novel prostaglandins, particularly those having a new skeleton having double bonds at the 7- and 8-positions and a sulfur atom at the 5-position. It is.

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-perprostaglandins of the present invention also have a new skeleton, so they have the potential to exhibit new medicinal effects, such as anti-cancer effects.

It is expected to have antihypertensive, antiulcer, and antiviral effects.

Furthermore, among the compounds obtained in the present invention, 5-thia-perprostaglandins represented by the above formula It can also serve as a synthetic intermediate and is useful in this sense.

Therefore, among the 5-thia-perprostaglandins of the present invention, the 5-thia-perprostaglandins represented by the above formula (1)-1 are the 7-hydroxyprostaglandins represented by the following formula, reacting with a reactive derivative of an organic sulfonic acid in the presence of a basic compound to form the corresponding 7-organosulfonyloxyprostaglandins;
The compound is then treated with a basic compound and, if necessary, subjected to deprotection and/or hydrolysis and/or salt-forming reaction.

The above formula [■] which is a raw material compound in the production method of the present invention
7-hydroxyprostaglandins represented by
As shown in the example in Chart 1 below, JP-A-57-746
It is synthesized by a method similar to the method for producing 7-hydroxyprostaglandins described in Publication No. 4.

Chart 1 Furthermore, in the above formula [■], the definitions of R1 and 12 are the same as in the case of the above formula (I). R31 and R41 represent a protecting group, and the same protecting groups as mentioned above can be mentioned.

As the basic compound used when reacting the 7-hydroxyprostaglandins of the above formula [■], amines are preferable, and such amines include, for example,
Examples include 4-dimethylaminepyridine, triethylamine, diimpropylcyclohexylamine, isopropyldimethylamine, and diisopropylethylamine, with 4-dimethylaminepyridine being particularly preferred.

Examples of reactive derivatives of organic sulfonic acids include methanesulfonyl chloride, ethanesulfonyl chloride, n-
Phantasulfonyl chloride.

t-7'' Tansulfonyl chloride Organic sulfonic acid halides such as methanesulfonyl chloride, benzenesulfonyl chloride, p-) toluenesulfonyl chloride; methanesulfonic anhydride, ethanesulfonic anhydride, m-water) trifluoromethanesulfonic acid, Examples include organic sulfonic anhydrides such as benzenesulfonic anhydride and p-)toluenesulfonic anhydride.

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

The reaction is a reaction between the hydroxyl group at the 7-position of 7-hydroxyprostaglandins represented by the general formula [■] and a reactive derivative of an organic sulfonic acid, and stoichiometrically, the two compounds react in equimolar amounts. do.

In order to actually carry out the 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 the general formula [■].

The basic compound is used in an amount of 1 mol or more, preferably 2 mol or more, per 1 mol of the reactive derivative of the organic sulfonic acid used.

The amount of the solvent used is usually 1 to 1000 times the volume, preferably 5 times the volume of the raw material compound represented by the above formula (1).
~100 times the volume is used.

The reaction temperature depends on the raw material compounds and basic compounds used.

Although it differs depending on the solvent etc., it is usually carried out in the range of -10°C to 50°C, preferably in the range of O'C to 30°C.The reaction time varies depending on the conditions, but it is 0.1 to 1.
It takes about 0 hours. The progress of the reaction may be followed by methods such as thin layer p-mography.

Thus, according to the above reaction (hereinafter referred to as the first reaction), the hydroxyl group at the 7-position of the 7-hydroxy prostaglandin of the above formula [■] is converted to an organic sulfonyloxy group, and the corresponding 7-organosulfonyloxy Prostaglandins 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 reaction between the 8-position carbon atom and the 8-position carbon atom. The double bond is converted into 5-thia-do-prostaglandins. This second reaction can be carried out using the same basic compound as the first reaction and at a similar 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 can do it (・.

The 5-thia-N-prostaglandins thus obtained are further subjected to deprotection and/or hydrolysis and/or treatment as necessary.
Or subjected to a salt-forming reaction.

Deprotection of the hydroxyl protecting group can be carried out using K as follows.

When the protecting group is a group that forms a 7-cetal bond with the oxygen atom of the hydroxyl group, for example, acetic acid, a pyridinium salt of p-toluenesulfonic acid, or a cation exchange resin is used as a catalyst, and water, tetrahydrofuran, ethyl ether, etc. are used as a catalyst. , dioxane.

This reaction is more preferably carried out by using acetone, 7-cetonitrile, etc. as the reaction solvent. The reaction is usually carried out at a temperature range of -20°C to +80°C for about 1 minute to 3 days. Also, protecting groups)! In the case of J(C,-C,) hydrocarbon silyl group, for example, K in the presence of tetrabutylammonium fluoride or cesium fluoride (more preferably in the coexistence of a basic compound such as triethylamine), as described above. The reaction is carried out in a reaction solvent (preferably a water-flooded reaction solvent) at about the same temperature and for about the same time. Alternatively, by subjecting it to a normal deprotection reaction using an acidic compound such as hydrofluoric acid or acetic acid)! J(C1~C,
) 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-thiago 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.

Among the 5-thia-go prostaglandins of the present invention, the compound represented by the above formula (1)-2 is represented by the following formula (1).
5-17-N-prostaglandins coated with -1' R3 are treated with an acidic compound, and then deprotected and/or
Alternatively, it can be produced by subjecting it to hydrolysis and/or salt-forming reactions.

The compound of the above formula (t)-s' is a compound of the formula (t)-1 in which the group R4 is a hydrogen atom, and such a compound is a compound of the above-mentioned reactive derivative of an organic sulfonic acid. After the reaction, it is obtained by subjecting it to a deprotection reaction.

Acidic compounds used when treating the compound of formula (1)-1' above include mineral acids such as hydrofluoric acid, hydrochloric acid, and sulfuric acid, and organic acids such as acetic acid, citric acid, and p-toluenesulfonic acid. is preferably used. (The amount of acidic compound used is 1 to 2 o for starting compound (I)-1'.
o times the mole, preferably in the range of 1 to 10 times the mole.

Examples of solvents used at this time include alcohols such as metazol, ethanol, and inglobil alcohol; water;
Dioxane, tetrahydrofuran (THF), acetonitrile, dimethyl sulfoxide (DMSO), or a mixed solvent thereof are preferred, and particularly preferred are water,
methanol, THF, 7-cetonitrile, and a mixed solvent thereof. The amount of solvent used is sufficient as long as the reaction proceeds quickly, and usually the amount of solvent used is
I) -1' to 1 to 1000 times the capacity, preferably 5
~400 times the volume is used. The reaction temperature depends on the raw material compounds and reagents used.

Although it varies depending on the solvent, the temperature is θ°C to 120°C, preferably 103 to 80°C.

The reaction time varies depending on the conditions, but is preferably about 30 minutes to 48 hours, more preferably 1 hour to 24 hours. The progress of the reaction is monitored by methods such as thin layer chromatography.

The above reaction can also be carried out as follows. That is, after the reaction of the 7-hydroxyprostaglandins of the general formula (II) described above with a reactive derivative of an organic sulfonic acid, hydrofluoric acid is added.

When a debinding reaction is performed using an acidic compound such as acetic acid, the above reaction can be performed in the same reaction system following the deprotection reaction.

In this way, a PGA type compound of the above formula (I)-2 is obtained, and if necessary, this compound can be further subjected to deprotection reaction, hydrolysis reaction, and salt formation reaction in the same manner as described above.

The target compound 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.

According to the present invention, 5-
Thia-perprostaglandins are obtained, and such compounds are expected to have pharmacological effects such as anticancer, blood pressure lowering, and antiulcer effects.

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

Reference example 1 3(s)-t-butyldimethylsilyloxy-1-iodo-1-octene 6.07 g (16.5 mmoA')
Dissolved in 30 ml of anhydrous ether under argon atmosphere -78
16.5 rnl (2M solution) (33 mmoJ) of t-butyllithium was added at °C, and the mixture was stirred for 1 hour.

Next, 1-pentynyl copper (I) 2.1 s 9 (16
, 5 mmoJ) and 25 m/anhydrous -r-- of hexamethylphosphorustriamide 5-49 (33 mmoJ).
The solution was added to the flask, and the mixture was further stirred at -78°C for 1 hour.

A solution of 3.18 g (15 mrr+ol) of 4-t-butyldimethylsilyloxy-2-cyclobentenone in 20 ml of anhydrous ether was added and the mixture was heated at -78°C for 30 minutes.

The mixture was stirred at -50°C for 10 minutes. 7-oxo-5-thiapentanoic acid methyl ester 2.0 g (16.5 mmo/
) 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. PH4
The reaction solution was poured into an acetic acid-sodium acetate buffer solution adjusted to 20% and extracted with hexane.

Dry over anhydrous magnesium sulfate, concentrate, and separate and purify using silica gel chromatography to obtain 7-adoloxy 5-
Thiab p-staglandin E111.5.29 (yield 55%) of a mixture of 15-bis-t-butyldimethylsilyl erthyl and its enantiomer 15-shrimp form was obtained.

TLc, Rt: 0.4 s (solvent; hexane:ethyl acetate-3:1)
IR (m, naat) r 3500.2950.2B80,1740,1460°+440. 1360. 1250°NMR (δ ppm in CDC7!3); 0.
9 (8,1sH), 0.9-1.7 (m,
t+H).

C7~3.1 (m, 10H), 3.7 (8,3)1
).

3.7-4.4 (m, 3H), 5.65 (m, 2H).

Synthesis of Example 1 7-Hydoxy-5-thiaprostaglandin E1 methyl ester 11゜15-bis-t- obtained in Reference Example 1
Butyldimethylsilyl ether and its enantiomer 15-
Shrimp body mixture 1,25.9 (t, 98 mmoJ)
was dissolved in 10 mJ of anhydrous dichloromethane, 1.659 (13.5 mmoJ) of 4-dimethyl-7minopyridine was added, and 0.0 m of methanesulfonyl chloride was added at o'c. s
ml (6.7 mmol) was added, stirred at 0°C for 5 hours, and further stirred at room temperature for 1 hour. Water was added and extracted with dichloromethane.

Dry over anhydrous magnesium sulfate, #condensate, and separate and purify using silica gel chromatography to obtain 5-thia-△7-prostaglandin E, methyl ester 11.15-bis-
t-Gyldimethylsilyl ether and its enantiomer 1
A mixture of 5-shrimp bodies was obtained. Of these, 590 are 7E bodies.
my (yield 49%), 72 bodies is 150■ (yield 12%)
)Met.

TLC,? E form, Rf: 0.6', 5 (solvent; hexane: ethyl acetate = 3:1) 72 form, Rt: o, 6s (i medium; H*S7
: ethyl acetate = 3:1) LL doctor IR (cm-', neat): 2980,
2870. 1740. 1640. 1460°13
60, 1255 NMR (δppm in CDCl, ): (h9(
s, 18H), 0.7-2.1 (m, 13H).

2.1-2.8 (m, a) I), 3. o ~3. s
(m, 3H).

3.70 (s, 3H), 3.9~4.3 (m, 2H
).

5.55 (m, 2H), 6.8 (dt, I
H, J = 7.5, 2.0) 72 bodies IR (cm, neat): 2980.2870.1?40. 1450, 1255
NMR (δppm in CDCl3): 0.9
(8,18H), 0.7-2.1 (m, 1
3H).

2; 1-2.7 (m, 6H), 3.0-3.6 (m, 3
H).

3.7 (s, 3H), 3.7-4.3s (m, 2H)
.

s, a ~5.9 (m, IH), s, ss (m, 2H)
Example 2 16.17.18,19.20-pentanol-15-cyclohexyl-7-hydroxy-5-thiaprostaglandin E, methyl ester 11,15-bis-t-butyldimethylsilyl ether 560119 (0,87m
4-dimethylaminopyridine 530 (4,35 mmol) was dissolved in 5 rnl of anhydrous dichloromethane and
Methanesulfo=7+ and 170 pl of chloride (2,2rnmo7I) were added at 0°C, and the mixture was stirred for 2 hours, 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 coomadography to give a solution of 16°17.18.1
9.20-Pentanol-15-cyclohexyl-5-thia-prostaglandin E1 methyl ester 11.
15-bis-t-7/Tyldimethylsilyl ether 3t
sms+ (yield 858%.

Mixture of 7E body and 7E body, 7E near Z = 4:1R ((
X, neat): 2970.2860, 1740, 1640, 1455°1355.126O NMR (δppm in CDCj!3): 0.9
(s, t 8H), 0.9~2.2 (m, t
3H).

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, 0.2 H, 72 bodies), 5
．． 5 (m, 2H).

6.9 (t, 0.8H, J=8.7E body) Example 3 'L 7-Hydroxy-17(, ), 20-dimethyl-5-1,7 Prostaglandin E1 methyl ester 11.15-
Bis-t-butyldimethylsilyl ether 120N
(0.18 mmoj) was dissolved in 2 ml of anhydrous methane, 4-dimethylaminopyridine was added with 30 μl of methanesulfonyl chloride (0.4 rrm
ol) and stir 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. It was dried over anhydrous magnesium sulfate, concentrated, and then separated and purified using thin layer p-mudography.
), 20-dimethyl-5-thia-N-prostaglandin E1 methyl ester ++l+s-histo-t-butyldimethylsilyl ether 71/76 # (yield 66%
,? Mixture of E form and 7z form, 7E near Z=4:I) l IR (m, neat): 2980.2860,1740. +640.1460°1360.1255 NMR (δppm in CD(J,): 0.9 (
a, 18H), 0.7-2.0 (m, 17H)
.

2.0-2.7 (m, 6H), 3.0-3.7
(m, 3H).

3, F O(s, 3H), 3.7~4.5(m
, 2H).

5.2-5.9 (m, 0.2H, 72 bodies), 5
．． 6 (m-2H)+6.9 (t, o, s)I,
J=8.7E) Example 4 (7E) -7,8-dehydro-5-thiaprostaglandin E, methyl ester + 1.15-bis-t-
Butyldimethylsilyl ether and the enantiomer of 7-15-
Dissolve z-isomer 213# (0.35 mmol) in +om/ acetonitrile and add 40 tiohydrogen fluoride aqueous solution.
, sml and stirred at room temperature for 30 minutes. After 40 minutes, a reconstituted aqueous sodium hydrogen oxide solution was added to terminate the reaction, followed by extraction with ethyl acetate. After drying, the solvent was distilled off and separated and purified by thin layer coomadography to obtain (7E) -7,8
A mixture of -dehydro-5-thiaprostaglandin E, methyl ester, and its enantiomer 15-shrimp form was obtained in an amount of 100 da (yield: 75 da).

TLC, Rf: 0.45 (solvent; hexane: ethyl acetate = 1:4) I
R(cYIL-', neat): 3400.
2770, 2750, 2670.1?20°1640,
1440. 124O NMR (δppm in CDCj3): 0.9
(m, 31(), O, 7~2.0 (m, 8H)
.

1.9 (dd, 2H, J-7), 2.2-3.0
(m, 8H).

3.2s (a, 2H, J-a), 3. s(m,tH).

3.7 (s, 3H), 4.2 (m, 2H).

s, 6s (m, 2H), 6.8 (dd, J
-8,0,1,5) Other compounds can be similarly deprotected.

Grandin A, methyl ester (old = 0.5) 23
9 (yield 32%) and its 12-shrimp body (Rf=0.5
7) 24# (yield 33%) was obtained.

Example 5 (7 g) -7,8-dehydro-5-thiab ρ staglandin E, methyl ester 11.15-bis-t-butyldimethylsilyl ether and 15-shrimp form 121 N (0,2 mmoA ') 10m/7
Dissolve in setonitrile, add 0.54 qb of hydrogen fluoride aqueous solution, heat to 40°C and stir for 4 hours. After the reaction, return to the room source, add an aqueous sodium bicarbonate solution to terminate the reaction, and extract with ethyl acetate. After drying, the solvent was distilled off and a thin layer was applied using p-mography (solvent; hexane:
Separation and purification with ethyl acetate = 1:3) resulted in (7E) -
7,8-dehydro-5-thiaprosta IR (crIL
-', neat): 3450, 2950.
2870. 1?35. +700°1645, 1
580. 1435 NMR (δ ppm in CDCl3): 0.
8-2.2 (m, 14H), 2.2-2.8 (m,
4H).

3.3 (d −2HIJ =8−0) + 3.
7 (6, 3H).

4.0 to 4.35 (m, 2H).

5.5 (dd, I H, J -15,0,6,0
).

5.9 (aa, I H, J snow 15.0. 6.0
).

6.4 (dd, IH, J -6,0,2,0)
.

6.7 (t, IH, J Tomi S, O).

7.5 (dd, IH, J -6,0,3,0)
Mass (20eV, m/e): 366 (M+), 348, 215, 134, 120゜l
Ol (100chi) 2-shrimp body IR (cm, neat): 3450.2950, 2870.1735.1700°1645.1580.1435 NMR (δppm in CDCJ3): 0.8~
2.2 (m, 14H), 2.2~2.8 (m
, 4H).

3.35 (d, 2H, J = 8.0), 3.7 (8, 3H
).

3.9-4.4 (m, 2H) + 5.4 (dd, I H, J = 16.0. 6.
0).

5, s s (dd, I H, J= 16.0.
6.0).

6.4 (dd, I H, J= 6.0. 2.0
).

6.7 (t, IH, J=8.0).

7.4 (dd, I H, J-6,0,3,0)M
ass has the same pattern as (7E)-7,8-dedraw 5-thiaprostaglandin A1 methyl ester.

Example 6 Synthesis of 16.17.18,19.20-penta/-15-cyclohexyl-7(E)-7,s-dehydro-5-thi7 prostaglandin A, methyl ester 16.17.18, 19.20-Pentanol-15-cyclohexyl-7(E)-7,8-dehydro-5-thiaprostaglandin E1 methyl ester 102 w
(0.26 mmo/) is dissolved in 21 R/hydrofuran, 0.5 N hydrochloric acid aqueous solution is added, and the mixture is heated at 40"G K and stirred for 3 hours. The reaction is terminated by adding sodium bicarbonate aqueous solution, and ethyl acetate is added. After extraction and drying, the solvent was distilled off and purified by thin layer chromatography to obtain 16.17°18.19.20-pentanol-15-
Cyclohexyl-7(E)-7,8-dehydro-5-
Thiaprostaglandin A1 methyl ester 55m9 (
Yield 856 cm) was obtained.

TLC: Rf-o,s (solvent; hexane: ethyl acetate = 1:3) IR (cm'''', nellj): 2960.2
860.1?40. +700.1645゜l 575 NMR (δppm in CDc/3): 0.8~
2.2 (rn, 14H), 2.2~2.7 (m
, 4H).

3.3 (d, 2H, J=8.0), 3.65 (s, 3H
).

3.9-4.3 (m, 2H).

5.5 (dd, l H, J= 15.0.6.0
).

5.9 (dd, I H, J= 15.0.6.0
).

6.4 (dd, IH, J=6.0.2.0).

6.7 (t, IH, J = 8.0).

7.5 (dd, IH, J -6,0,3,0)
The target product was obtained.

NMR (δppm in CDC13): 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, IH), 4.2 (m, 2H).

5.6 (m, 2H), 6.8 (dd, J=8
．． 0.1.5) Example 7

Claims (13)

[Claims] (1) The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
[I] [In the formula, R^1 represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, and R^2 is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms.
~10 alkyl groups or substituted or unsubstituted cycloalkyl groups, R^3 and R^4 are the same or different and represent a hydrogen atom or a protective group. Display▲There are mathematical formulas, chemical formulas, tables, etc.▼ is 7Z body, 7E body, or 7Z body and 7
It shows that the E form coexists in any proportion. ] A non-toxic salt of 5-thia-Δ^7-prostaglandin E represented by the following or an acid thereof when R^1 is a hydrogen atom. (2) 5-thia-Δ^7-prostaglandin E or R according to claim 1, wherein in the above formula [I], R^1 is a hydrogen atom, a methyl group, or an ethyl group.
When ^1 represents a hydrogen atom, it is a non-toxic salt of the acid. (3) In the above formula [I], R^2 is a pentyl group,
5-thia-Δ^7-prostaglandin E according to claim 1 or 2, which is a 2-methylhexyl group, a cyclopentyl group or a cyclohexyl group, or when R^1 represents a hydrogen atom; Non-toxic salts of acids. (4) In the above formula [I], R^3 and R^4 are a hydrogen atom, a tri(C_1 to C_6) hydrocarbon silyl group, or a group that forms an acetal bond with an oxygen atom, Claim 1 ~5- as described in any one of paragraphs 3 to 5-
Thia-Δ^7-prostaglandin E or a non-toxic salt of the acid when R^1 represents a hydrogen atom. (5) Claims 1 to 4, wherein in the above formula [I], R^3 and R^4 are a hydrogen atom, a trimethylsilyl group, a t-butyldimethylsilyl group, or a 2-tetrahydropyranyl group. 5- as described in any one of the above
Thia-Δ^7-prostaglandin E or a non-toxic salt of the acid when R^1 represents a hydrogen atom. (6) The following formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
[II] [In the formula, R^1 and R^2 are the same as defined above, and R^
3^1 and R^4^1 represent a protecting group. ] 7-
hydroxyprostaglandins are reacted with a reactive derivative of an organic sulfonic acid in the presence of a basic compound,
The following formula [I] is characterized in that the corresponding 7-organosulfonyloxyprostaglandins are prepared, then treated with a basic compound, and optionally subjected to deprotection and/or hydrolysis and/or salt formation reaction. ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
[I] [In the formula, R^1, R^2, R^3, R^4, indication ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is the same as the above definition. ] A non-toxic salt of 5-thia-Δ^7-prostaglandin E represented by the following or an acid thereof when R^1 represents a hydrogen atom. (7) 5-thia-Δ^7-prostaglandin E or R^1 according to claim 6, wherein the reactive derivative of organic sulfonic acid is an organic sulfonic acid halide or an organic sulfonic anhydride; A process for producing non-toxic salts of acids when hydrogen atoms are represented. (8) 5-thia-Δ^ according to claim 7, wherein the organic sulfonic acid halide is methanesulfonyl chloride, ethanesulfonyl chloride, n-butanesulfonyl chloride, t-butanesulfonyl chloride, or trifluoromethanesulfonyl chloride. A method for producing a non-toxic salt of 7-prostaglandin E or its acid when R^1 represents a hydrogen atom. (9) 5-thia- as defined in claim 7, wherein the organic sulfonic anhydride is methanesulfonic anhydride, ethanesulfonic anhydride, trifluoromethanesulfonic anhydride, benzenesulfonic anhydride or P-toluenesulfonic anhydride.
A method for producing a nontoxic salt of Δ^7-prostaglandin E or an acid thereof when R^1 represents a hydrogen atom. (10) 5-thia-Δ^7 according to any one of claims 6 to 9, wherein the basic compound is an amine.
- A method for producing a non-toxic salt of prostaglandin E or its acid when R^1 represents a hydrogen atom. (11) 5-thia-Δ^7- according to any one of claims 6 to 10, wherein in the above formula [II], R^1 is a hydrogen atom, a methyl group, or an ethyl group. A method for producing a non-toxic salt of prostaglandin E or its acid when R^1 represents a hydrogen atom. (12) In the above formula [II], R^2 is a pentyl group,
5-thia-Δ^7-prostaglandin E according to any one of claims 6 to 11, which is a 2-methylhexyl group, a cyclopentyl group, or a cyclohexyl group, or R^1 is hydrogen When representing an atom, the non-toxic salt of the acid. (13) Claims 6 to 12, wherein in the above formula [II], R^3 and R^4 are a hydrogen atom, a trimethylsilyl group, an L-butyldimethylsilyl group, or a 2-tetrahydropyranyl group. 5-thia- according to any one of
A method for producing a nontoxic salt of Δ^7-prostaglandin E or an acid thereof when R^1 represents a hydrogen atom.