JPS6130570A - 7-thiaprostaglandin e1 and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R<1> is H, 1-10C alkyl, substituted or unsubstituted phenyl, etc.; R<2> and R<3> are H, tri 1-7C hydrocarbonsilyl, etc.; R<4> is H, methyl, or vinyl; R<5> is 3-6C alkyl which may contain O, phenyl, phenoxy, etc. which may be substituted; X is ethynylene, cis-vinylene, etc. n is 0 or 1) its epimer (n=1) or its enantiomer or its mixture. EXAMPLE:4,4,5,5-Dehydro-7-thiaprostaglandin E1. USE:Having an inhibitory action on blood platelet aggregation, vasodilating action, antihypertensive action, and useful as a preventive and a remedy for thrombosis, an inhibitor of blood platelet aggregation, a hypotensor, etc. PREPARATION:A compound shown by the formula II (R<11> is 1-10C alkyl, etc.; R<21> is tri 1-7C sivyl, etc.) a compound shown by the formula (III R<31> is tri 1-7C silyl, tc.), and an organocopper compound obtained from a copper compound shown by the formula CuQ (Q is halogen, etc.) are subjected to conjugated addition reaction, to give a compound shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to novel 7-thiabrostaglandins E1 and methods for producing the same. More specifically, an organocopper compound is conjugated to novel 7-thiabrostaglandin Els and 2-organothio-2-cyclobentenones useful as pharmaceuticals and their intermediates, and then as necessary A method for producing archabresta staglandin E by subjecting it to depolymerization and/or hydrolysis and/or salt-forming reaction, and a method for hydrogenating a 4,5 dehydro derivative of archiabreta staglandin E. 7
- A method for producing chia booster taglandins &amp;

BACKGROUND OF THE INVENTION Natural prostaglandins are known as local hormones with high biological and pharmacological activity, and therefore many studies have been conducted on their derivatives. Among natural prostaglandins, prostaglandin E has strong platelet aggregation inhibitory effects, vasodilatory effects, etc., and its clinical application is highly anticipated.

The biggest drawback of natural purustabrangins, especially PGE, is that they cannot be used orally because they are rapidly metabolized upon oral administration, and they usually have to be administered intravenously.

Hitherto, various studies have been conducted on human nibrostaglandins in which one or two of the carbon atoms forming the skeleton of natural prostaglandins are replaced with sulfur atoms.

For example, it has a skeleton in which the carbon atom at the 1st position is replaced with a sulfur atom (therefore, there is a sulfur atom at the 1st position, so it is displayed with the prefix IS.The same applies to structures in which other positions are substituted with sulfur). 1S-prostaglandin E or F;
Alphas (Journal Op Organic Chemistry)
Lee (J, Org, Chem,), 40
, 5 2 1 (I975) and JP-A-53-
34747).

3S-11-deoxyprostaglandin E.

(Tetrahedron Letters
etters), 1975, 765 and Journal of Medicinal Chemistry (J, Med.

Chem, ), 20, 1662 (I977))
, 7S-prostaglandin F1α (Journal of American Chemical Society (J.

Amer, Chem, Soc, ), 96.6757 (I
974)).

9S-Prostaglandin El (Tetrahedron LetteM) +
1974.4267 and 4459; Tetrahedron Letters
1976.4793 and Hete p Cycles
rocycles), 6 r 109
7 (I977)).

118-Prostaglandin E1 or F, α (Tetrahedron Letters)
rs), 1975, 1165), 13
S-prostaglandin E or F (USP).

4080.458 (I978)), and 15S-prostaglandin E, P (tetrahedron letters (Tc
trahedron Letters).

1977.1629) etc. are known.

Purpose of the Invention The present inventors previously succeeded in synthesizing derivatives of VC7-1000 apustadalandin E, which we reported separately.
- As a result of intensive research on new analogous compounds of thiabrostaglandin E and derivatives, we succeeded in synthesizing a novel 4,5-dehydro-7-thiabrostaglandin E1 class, and arrived at the present invention. It is.

Structure and Effects of the Invention The present invention provides compounds represented by the following formula [1] OR'OR'' and their 15 (when n = '0) or 16 (when n = 1) epimers, and their There is provided a novel 7-thiabrostaglandin E1 which is a casting body of or a mixture thereof in any proportion.

R1 is a hydrogen atom, CI""' cll+alkyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted 03-CIO cycloalkyl group, R-substituted or unsubstituted phenyl (C1-C3) alkyl group.

or - represents an equivalent cation.

Examples of the C1 to C8 alkyl group include methyl, ethyl, n-propyl, 1so-propyl, n-
Butyl, especially butyl, tert-butyl n-pentyl, n-hexyl, n-heptyl.

Straight or branched chains such as n-octyl, n-nonyl, and n-decyl can be used.

Substituents for substituted or unsubstituted phenyl groups include, for example, halogen atoms, hydroxy groups, C1-C, acyloxy groups, and C1-C4 which may be unsubstituted with halogen atoms.
Alkyl group, halogen atom f/! Preferred are C1-C4 alkoxy groups, nitrile groups, carboxyl groups, and (C1-C6) alkoxycarbonyl groups which may be substituted. The chlorine atom is preferably fluorine, chlorine or bromine, particularly fluorine or chlorine.

Examples of the C3-C, acyloxy group include acetoxy,
Propionyloxy, n-butyryloxy+ 180-
Mention may be made of butyryloxy, n-72leryloxy, jso-valeryloxy, caproyloxy, enantyloxy or benzoyloxy.

Examples of the C1-C4 alkyl group which may be substituted with halogen include methyl, ethyl, n-propyl, i@0-propyl, n-butyl, monomethyl, dichloromethyl,
Trif/rheo-methyl and the like may be mentioned as preferred. It may be substituted with halogen~s C
As the 1-C4 alkoxy group, for example, methoxy.

Ethoxy, n-propoxy + 1so-p-boxy, n
-butoxy, dichloromethoxy, methoxy, dichloromethoxy, trifluoromethoxy and the like are preferred. Examples of the (C, to C6) alkoxycarbonyl group include methoxycarbonyl and ethoxycarbonyl.

Butoxycarbonyl, hexyloxycarbonyl and the like can be mentioned.

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

The substituted or unsubstituted C3-C3° cycloalkyl group is substituted with the same substituents as mentioned above or unsubstituted, I- or unsaturated C1-C8°, preferably C, -C, , particularly preferably C6 groups, such as cyclopropyl-cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cycloμ
Examples of substituted or unsubstituted phenyl (Ct to Ct) alkyl groups capable of containing decyl, etc. include benzyl, α- Phenethyl and β-7 enethyl can be extracted.

One equivalent of a cation is 1, for example, S, +.

Tetramethylammonium, monomethylammonium,
Ammonium cations such as dimethylammonium, trimethylammonium, benzyl ammonium, phenethyl ammonium, morpholinium cation, monoethanol ammonium, piperidinium cation; Na
++ Alkali metal cation such as K+; 1/2Ca”
, 1/2Mg", 1/2Zn""1/3A
Examples include divalent or trivalent metal cations such as t''+.

For eight plates, a hydrogen atom + a C1-C1° alkyl group or a single cation is preferred.

R2 and R3 are the same or different, hydrogen atoms,)
! J (Cs-C?) A group that forms a 7-cetal bond with the oxygen atom of a hydrocarbon silyl group or hydroxyl group.

)! J (C, ~Ct) hydrocarbon silyl group,
Example Hatorimete Lucilil 8. Triethylsilyl.

Tri(C1-C4) such as t-butyldimerucilyl group
Preferred examples include alkylsilyl, t-butyldiphenylsilyl, diphenyl(00-4)alkylsilyl, and tribenzylsilyl.

An example of a group that forms an acetal bond with the lW elementary atom of a hydroxyl group is methoxymethyl.

1-ethoxyethyl, 2-methoxy-2-propyl, 2
-ethoxy-2-propyl, (2-methoxyethoxy)
Methyl, penzyloxymonodol, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or 6,6-dimethyl-3-oxa-2-oxobicyclo(3,1,0)hex-4-yl group are mentioned. be able to. Of these,
2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-ethoxyethyl, 2-methoxy-2-propyl,
(2-methoxyethoxy)methyl or 6,6-dimethyl-3-oxa-2-oxobicyclo (3,1,0)hex-4-yl group is preferred in %.

As Bl or R3, among these, a hydrogen atom, a tri(C1-C4) alkylsilyl group, diphenyl (C,"
Cm) alkylsilyl group, 2-f trahydrofuranyl group, 2-tetrahydrofuranyl group, 1-ethoxyethyl group, 2-ethoxy-2-propyl group, (2-methoxyethoxy)methyl group, or 6.6-dimethyl- 3-oxa-2-oxobicq [3,1,0)hekis-4-
The yl group is preferred.

In the above formula [1], R4 represents a hydrogen atom, a methyl group or a vinyl group.

In the above formula CI), R3 is a linear or branched C5-C, alkyl group which may contain an oxygen atom; a phenyl group which may be substituted.

Phenoxy group, or C1-CI6 cycloalkyl group; or C, -C, alkoxy group, optionally substituted phenyl group, phenoxy group, or C1-C11l
7. A straight chain substituted with a cycloalkyl group. Branched chain C1-C represents an alkyl group.

Straight chain or branched Cs that may contain oxygen atoms
~C, the alkyl group is 2-methoxyethyl, 2-ethoxyethyl, propyl.

Butyl, pentyl, hexyl, heptyl, octyl, 1
-Methyl-1-butyl, 2-methyl-1-butyl, 2-
Methylhexyl, 2-methyl-2-hexyl, 2-hexyl, 1,1-dimethylpentyl group, preferably 2-methoxyethyl, phthyl, pentyl, hexyl.

(R)- or (S)-2-methylhexyl.

2-hexyl, 1-methyl-1-butyl group, special K preferable t
Or butyl, pentyl, hexyl.

2-hexyl, 2-methino 1. One example is hexyl.

The substituted and stable phenyl group or phenoxy group may be substituted with the substituents listed as the substituents for the substituted phenyl group of R1. In addition, it is substituted with the same substituents as those mentioned above as the cycloalkyl group (S or unsubstituted 9-sum or unsaturated C1-C1). °, preferably 04
~C2, particularly preferably C, C, cycloalkyl groups, such as cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclodecyl groups, etc. can be used.

Among the C3-C6 alkoxy group, optionally substituted phenyl group, phenoxy group, C, ~C1゜cycloalkyl group, direct vertical a, Schiff is a branched m c, ~C, alkyl group. C1-C, alkoxy group 7,
For example, methoxy, ethoxy.

Examples include poxy, poxy, isopropoxy, butoxy, t-butoxy, hexyl, and oxy groups, and f! As the optionally substituted phenyl group and phenoxy group, the above-mentioned groups can be used as they are. As the C1-C dichloroalkyl group, the above-mentioned ones can be preferably mentioned as they are, and as the straight chain or branched chain C1-Cs alkyl group, methyl, ethyl, propyl, 1so-propyl, butyl* 1so-buty/ Examples include 171 degree-7'tyl, t-7'kit, pliers/I) group fx, and the substituent may be bonded to WItVc at any position thereof.

Further, in the compound IC represented by the above formula (I), the configuration of the substituent group bonded to VCIP5 on the cyclopentanone ring is natural prostaglandin E.

It is a particularly useful stereoisomer because it has the same steric configuration as, and "f" of the present invention is a stereoisomer of the following formula (I) ent where R', R", R ”, R', R'
, X, and length n are the same as the constant Mk described above.

It also includes stereoisomers represented by or mixtures thereof in arbitrary proportions. Also, since the carbons substituted by OR'', R' and Hs are asymmetric carbons, kC2
Although there are various types of optical isomers, any optical isomer or even the above formula (I) (I:I-a], [1-
The compound represented by the above formula El) (including (T-a), CI-h), and [■]) and its 15
(when n = 00) or 16 (when n = 1) refers to epimers and their enantiomers or mixtures thereof in arbitrary proportions.

In the above formula [1], X is an ethynylene group.

It represents a cis-vinylene group or a trans-vinylene group, and the above formula [13(a), when X is an ethynylene group, the following formula (I-a)-0Rs (b), where X is a cis-vinylene group] For groups, use the following formula % formula %
:] In the formula, R1, R1, R8, R4, R8, and n are the same as suggested above.

(When +j,

It is expressed as

The above formula [13((:I-a), CI-b), CI-c)
, and ('V)), n represents 0 or 1, and when n is 0, the following formula [131 where R', R'', R'', R', R6
, O and X are the same as the hole @.

When n is 1, the following formula [I] Om" oRs In the formula, RI, R2, Rs, R4, R1', and Oyohi X are the same as defined above.

It is expressed as

Preferred specific examples of the novel 7-thiabrostaglandin avian represented by the above formula [Natsu] provided by the present invention include the compounds shown below.

(I) 4,4.5.5-dehydro-7-thiabrostaglandin E.

(2) 4.4.5.5-dehydro-20-methyl-
Archabdistaglandin E0 (3) 4,4.5.5-dehyde 1=-20-ethyl-7-thiabrostaglandin E.

(4) 4.4.5.5-dehydro-16-methyl-
7-Thiabrostaglandin Karasu (5) 4,4,5.5-dehyde G7-16.20-
Dimethyl-7-thiabrostaglandin E.

(6) 4,4,5,5-dehydro-17-methyl-archabdistaglandin E.

(7) 4.4,5.5-dehyde f' -17,20
-Dinotyl-7-thiabrostaglandin F4(a)4
．． 4.5.5-dehyde μm17(S), 20-dimethyl-archabdistaglandin also (9) 4.4,5.5-dehyde ρ-17@), 20-
Dimethyl-archabdistaglandin E.

01J 4.4.5.5-dehyde r'-20-3-f
Leu 1-6-methyl-archabstaglandin E.

(I1) 4,4,5,5-dehydro-20-ethyl-17-methyl-7-thiabrostaglandin E.

]2 4+4.5+Fl-dehyde, 1-16.17゜1
8.19.20-pentanol-15-cyclohexyl-
7-thiabrostaglandin E.

Q$ 4.4,5.5-dehydro-16,17°18
, ], 9, 20--pentanol-15-cyclopentyl-7-17 prostaglandin E1 ]4 4, 4.5, 5-dehydro-18-oxa-
7-Hand 7 ρ staglandin E.

(2) 4,4.5.5-dehydro-17,18°19
．． 20-tetratrue 16-cyclohexyl-7-thiabrostaglandin C104,4,s; s-dehydro-15-deoxy-16-hydroxy-57-thiabrostaglandin E
1 0 ~ 4.4,5.5-dehydro-15-deoxy-1
6-Hydroxy-18-oxa-7-17 prostaglandin E1 0 4.4,5.5-dehyde a-18,19゜20-
Trinor-15-thioxy-16-hydroxy-17-
Fetuxxi 7-thiabrostaglandin E1 (I) 4.4.5.5-dehydro-15-deoxy-
16-hydroxy-20-methyl-7-thiabrostaglandin E1 (I) 4,4,5.5-dehydro-15-deoxy-
16-hydroxy-17,20-dimethyl-archabμ stadalandin island (c) 4,4,5.5-dehydro-17,18°19
．． 20-tetratrue-15-thioki-16-hydroxy-16-cyclobenzene-7-thiabrostaglandin E.

) 4,4.5.5-dehydro-17,18°1.9
．． 20-tetratrue-15-deoxy-16-hydroxy-16-cyclohexyl-7-thiabrostaglandin E.

(To) 15-methyl derivative (2) of the compound near (I) to a
) 15-vinyl derivatives of the compounds of (I) to (2) (c) 16-methyl derivatives of the compounds of 06 to (b) -αe-
16-vinyl derivative of compound (2) @ (I) ~ (2)
(4E)-4,5-dihydro derivative (2) of the metal compound (4Z)-4 of the compound of (I) to (2),
5-dihydro derivative 4 (4Z)-4,5-dideuterio(deuterated) derivative of the compounds (I) to (c) ((4Z)-4,5- of the compounds 31(I) to (2) Methyl ester (2) of compound of ditrithio derivative (31(I)~)
I) Ethyl ester of the compound of ~ ■ @ Sodium salt of the compound of (I) ~ (A) −
Derivatives protected with a butyldimethylsilyl group and/or a 2-tetrahydropyranyl group (c) The compounds of (I) to (b) can be made into a halberd form, but are limited to these. isn't it. Also included are optical isomers at the 15th or 16th position of the compounds (]) to (2) and their Confucian isomers.

The novel 7-thiabrostaglandin E, 4 of the present invention represented by the above formula (I) represents a group of the following formula [■]OR'', and X is the same as the above-mentioned Uba.

A 2-year-old luganothio-2-cyclobentenone represented by the following formula (IVI CuQ... [■] It can be produced by carrying out a conjugate addition reaction with an organocopper compound obtained from the copper compound represented by [■] and subjecting it to deprotection and/or hydrolysis and/or salt-forming reaction as necessary.

The synthetic route of 7-thiabrostaglandinthia of the present invention, including the synthetic route of its raw material compounds, 2-organothio-2-cyclobentenones, is as follows:
C becomes.

oh... i... H8Vx\tri00R11 HU OH0H OH0)l R mouth, R"+ R", R' + R" r X r
n*ta and Q are the same as defined above.

One of the characteristics of the method of the present invention is that when the starting material and the intermediate are used, the intermediate intermediate progresses through the synthesis route in a steric OS as a mixture of the compound shown above and its isomer. If either the formula (m) or the formula (2) is optically active, each stereoisomer can be isolated as a pure product by separation at an appropriate step.

R31 in the tangential lithium compound of formula [1] is lp
This is the same machine as 1, but the hydrogen atom is removed from the definition of R1. Q in the copper compound of formula [IV) represents a halogen atom such as chlorine, fluorine, or bromine; a cyano group, a phenylthio group, or a l-pentynyl group.

In order to obtain an organic copper compound from a lithium compound of the formula [■] and a copper compound of the formula (IV), for example, documents G, H, P
o5ner+Organic Reaction, v
ol, 19, 1 (I972) I Tetraha
Dron L@tt, 2111247 (I980), etc. are considered as references.

In the method of the present invention, a trivalent organophosphorus compound such as a trialkylphosphine (eg, triethylphosphine) is used together with the organocopper compound.

tributylphosphine, etc.), trial-thylphosphite (e.g., trimethylphosphite, triethylphosphite, triisopropylphosphite, tri-n-
This conjugate addition reaction proceeds smoothly when using eg, hexamethylphosphorustriamide (butyl phosphite, etc.), hexamethylphosphorustriamide, or triphenylphosphine, but triphenylphosphine and hexamethylphosphorustriamide are particularly preferably used.

The method of the present invention combines 2-organo-2-cyclobentenones represented by the above formula [■] with an organocopper compound represented by the above formula (Ill), a trivalent organophosphorus compound, and an aprotic The reaction is carried out with K in the presence of an inert organic medium.

2-Organothio-2-cyclobentenones and the organocopper compound react in equimolar terms stoichiometrically, but usually, 0% per mole of 2-organothio-2-cyclobentenones is used. .5 to 5.0 times, preferably 0.8 to 2.0
The amount of the organic copper compound is preferably 1.0 to 1.5 times the amount by mole.

The reaction temperature is -100°C to 50°C, particularly preferably -80°C.
A temperature range of approximately 0°C to 0°C is employed. The reaction time varies depending on the reaction temperature, but is usually about 1 at -78°C to -20°C.
A time reaction is sufficient.

The reaction is carried out in the presence of an organic medium. An inert aprotic organic medium is used that is liquid at the reaction temperature and does not react with the reaction reagents.

Examples of such aprotic inert living medium include:
Pentane, hexane, heptane.

Saturated hydrocarbons such as cyclohexane, aromatic hydrocarbons such as benzene, toluene, xylene, ether solvents such as diethyl ether, tetrahydro-7, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and other hexamethylphosphoric tri-7
(HMP), N,N-dimethylformamide (D
MF), N,N-dimethyl 7cetamide (DMAC),
Examples include so-called aprotic polar solvents such as dimethyl sulfoxide, sulfolane, and N-methylpyridone, and it is also possible to use them as a mixed solvent of two or more solvents. Furthermore, as the aptonically active inert organic medium, the inert medium used for producing the organocopper compound may be used as it is. That is, the reaction may be carried out by adding the 2-organo-2-cyclobentenone to the reaction system in which the organocopper compound was produced. The amount of organic medium used is sufficient as long as it allows the reaction to proceed smoothly, and is usually 1 to 100 times the volume of the raw materials, preferably 2 to 20 times the volume of the raw materials.

The trivalent organic phosphorus compound can be present during the preparation of the organic copper compound as described above, and the reaction can also be carried out by adding 2-organothio-2-schiff-pentynon into the system.

In this way, the hydroxyl group of the compound represented by formula (I) is protected, and an ester of the carboxylic acid at the 1-position is obtained.

The invention? l! Since the I production method uses a reaction that proceeds stereospecifically, a compound having the configuration represented by (I) above can be obtained by %9 from a starting material having the configuration represented by K and the formula [IT]. Therefore, from the bronze statue body of the above formula (I), a mirror body of the above formula (expressed as lean) of the above formula [1] is obtained.

After the reaction, the resulting product is separated from the reaction solution and purified by conventional means. For example, extraction and washing, chromatography, or a combination thereof may be used.

Furthermore, the compound obtained here, in which the hydroxyl group is protected and the carphone group at the 1-position is an ester, can then be subjected to deprotection, hydrolysis, or salt-forming reaction, if necessary.

Removal of the protecting group (R11 and/or R31) of the hydroxyl group can be performed using vinegar, for example, when the protecting group forms an acetal bond with the oxygen atom of the hydroxyl group. The reaction is preferably carried out using a pyridinylam salt of p-)luenesulfonic acid or a cation exchange resin as a catalyst and water, tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile, etc. as a reaction solvent. The reaction is usually -78
It is carried out for about 10 minutes to 3 days at a temperature range of .degree. C. to +50.degree. In addition, when the protecting group is an IJ ('C1~Ct) hydrocarbon silyl group, for example, acetic acid, tetrabutylammonium fluoride, cesium fluorand, hydrofluoric acid, heptadhydro-opyridine, etc. are used as a catalyst, The reaction is carried out in the reaction solvent described above at the same temperature and for the same period of time.

The removal of the carboxyl group (Rst), that is, the hydrolysis reaction, uses an enzyme such as lipase or esterase, and water It will be done for about an hour.

According to the present invention, the carboxyl group-containing compound produced by the above hydrolysis reaction is then subjected to a salt-forming reaction, if necessary, to yield the corresponding carboxylate.

The salt-forming reaction is known per se, and is carried out by a conventional method using a carboxylic acid and an equivalent amount of a cyclic compound such as potassium hydroxide, sodium hydroxide, or sodium sulfate, or ammonia, trimethylamine, monoethanolamine, or morpholine. Is it possible to cause a neutralization reaction by K? The novel 7-thiabrostaglandin E, represented by the above formula CI), produced by the above method, is produced by the 2-organothio-2-cyclobentate represented by the above formula [11], which is used as a starting material. Depending on the type of X in the non-class, the following formula [1-a) (when X is a group), the following formula [1-a]
b) (when X is a cis-vinylene group), the following formula [1-c
) (when X is a trans-binine group).

That is, 4,4,5,5-dehyde a-7-thiabrostaglandin E8 represented by the following formula [1-a).

(4Z)-4,5-dehydro-7-thiabrostaglandin represented by turtle, and thiaprostaglandin E of the following formula (I-c).

(4Z)-4,5-dehydro- represented by the above formula [1-b) obtained by the method of the present invention
7-thiabrostaglandin E□ is the above formula [I-a]
It is obtained by catalytic reduction of 4,4,5,5-dehydro=7-thousand abdistaglandin E1 represented by the above formula (I-b) in the presence of a hydrogenation catalyst. By catalytically reducing (4Z) -4,5-dehyde R-7-thiabrostaglandin E□ in the presence of a hydrogenation catalyst, 7-thiabrostaglandin represented by the following formula [■] Gin E1 type is produced. That is, this process is illustrated as follows.

Formula (Tb) Formula [V] Below, step 1. The culm 2 will be explained one after another. .

81 is 4, 4, 5°5 represented by the above formula (I-a)
-Dehydro-7-thiabrostaglandin E, n is contacted with (4Z)-4,5-dehydro-7-thiabrostaglandin E1 represented by the above formula (I-b:) The catalytic ring reaction is carried out in the presence of a hydrogenation catalyst.The hydrogenation catalyst used is a commonly used palladium-based catalyst, platinum catalyst, or rhodium catalyst.Palladium Examples of the system catalyst include palladium-activated carbon, palladium-calcium carbonate, and barium-barium sulfate, among which palladium-activated carbon is preferable. will be (4Z')-4,5
-dehyde cy-,7-thousandbrostagmondin E, etc., is obtained by using Lindlar's compound 1% or quinoline-treated barium palladium Mate compound.

Shirokane M! Platinum oxide, platinum black, etc. are used as a medium, but since the starting material for the method of the present invention contains sulfur atoms forming sulfide bonds, this sulfur atom tends to poison the catalyst. , not selected as a preferred hydrogenation medium. Examples of the rhodium catalyst include chlorotris(triphenylphosphine)0dium(I). Other examples include ruthenium-based catalysts, and details regarding these hydrogenation catalysts, including reaction conditions for various catalyst pressures, can be found in Nippon Kagaku Kinsen's New Experimental Chemistry Course 15. Co., Ltd.) 333
Pages 448 (I97, 7) VC described.

An example of the reaction conditions is when palladium-activated carbon is mixed with water and mixed with water. Two bottles of acetic acid, ethanol, and methanol are used as the reaction solvent, and the reaction is usually carried out for 1110 to several days at room temperature under normal pressure. It's enough to make you bald.

Step 2 is (4z)- represented by the upper %+7 formula (I-b)
This is a step of catalytically reducing 4,5-dehydro-7-thiabrostaglandin E1 with 7-thiabrostaglandin Ei represented by the above formula [■]. 8, the above formula C
4,4,5,5-dehydro-7- represented by I-a)
Using thiabrostaglandin El as a starting material, along the way,
Steps 1 and 2 can be carried out without isolating the (4Z)-4,5-dehydro-7-17 prostadalandin E represented by the above formula (T-b). 7-Thiabrostaglandin E represented by V) may be obtained, and this method is usually adopted except in the case of Lindlar catalyst or palladium-barium sulfate catalyst poisoned with quinoline. Therefore, the same conditions as in step 1 are applied for the hydrogenation catalyst, reaction solvent, reaction temperature, and reaction time.

The thus obtained compounds of formula [1-b) and formula [V] can be isolated by a commonly used method,
This is achieved through operations such as washing, extraction, and chromatography.

Formula (I-a) and formula C1-b obtained by washing with water according to the present invention
), formula (I-e), and various 7-17 prostaglandin E represented by formula [■], derivatives in which Hm and R1 are free hydroxyl groups have platelet aggregation inhibitory effects and blood vessel aggregation inhibitory effects. It has prostaglandin-like effects when dilating and lowering blood pressure, and is useful as a drug expected to have these physiological effects, such as a thrombosis treatment or prevention drug, a platelet collection inhibitor, and an antihypertensive drug. .

In addition, gastrointestinal diseases such as duodenal ulcers and ulcers, hepatitis,
Fulminant hepatitis, fatty liver, hepatic coma.

Hepatofibular diseases such as hepatorenal hypertrophy and cirrhosis, pancreatic diseases such as pancreatitis, diabetic nephropathy, acute renal failure, cystitis, urinary diseases such as retrourethral disease, respiratory diseases such as pneumonia and tracheitis, endocrine diseases,
It can be used for the prevention and/or treatment of various diseases such as immune diseases, alcoholism, carbon tetrachloride poisoning, and lowered blood pressure.

Furthermore, in the production method of the present invention, catalytic reduction is carried out in deuterium,
or (4Z)-4,5-dehyde q-7-thiabrostaglandin compounds represented by formula [1-b) with deuterium or tritium by conducting in tritium, or It has a noteworthy feature of being able to obtain a 7-thiabrostaglandin EI structure represented by the formula [■]. Such deuterium- or tritium-labeled compounds are useful compounds for quantifying or studying the in vivo dynamics of 7-thiabrostaglandin E□, which is useful as a corresponding pharmaceutical, and from this point of view, the method of the present invention is also useful. This can be said to show its usefulness.

Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 (E)-(38)-t-butyldimethylsilyloxy-
1-Iodo-1-octene (4,39F, 11.94
rrvnoL) was dissolved in ether (20 mg) and cooled to -78°C, and then t-butyllithium (I,9M
, 12.9m.

23,9rrrnoL) was added thereto, and the mixture was stirred at -78°C for 2 hours.

Phenylthio @ (2,06f, 11.94 mm
rlt) and hexamethylphosphorustriamide (5,8
4y, 35.8nynal') of ether (20
td) solution was added to the reaction mixture and stirred at -78°C for 1 hour. Then (R)-4-t-butyldimethylsilyloxy-2-(5-methoxycarbonyl-2-pentynylthio)-2-cyclobentenone (3,95t
.

10,7 mmol) of tetrahydro7rane (50
mg) solution was added and stirred at -78°C for 15 minutes and at -40°C for 3θ minutes.

Add 2M acetate buffer to the reaction mixture and add hexane (
I50m/! After extracting with X3), each organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated after removing P to obtain a crude product of 6.8f. This product was coated with silica gel (hexane: ethyl acetate = 4.:]) K-attached 17 to obtain the desired 11.15-bis(t-butyldimethylsilyl)-4,4,5,5- Dehyde a-7-thiabroscugrandin E, methyl ester (6,83ft 11.2 mrnoZ + 9
4%).

Nuclear magnetic resonance absorption (cDct, , δ(pr+m)); 0
．． 06 (I2H, 8), 0.87 (21H),
1.0~1.8 (8H, m), 2.3~3.6 (L
OT(,11'',)+3.67(3H,s-).

3.80-4.40 (2H, m), 5.50-5.
75 (2H, m).

Infrared absorption spectrum (liquid film, 7m”); 1745, 1
250, 1165, 1110, 1075, 96
5°885, 835, 805 +'775° Mass spectrometry (FD-MS); 610 (M").

Example 2 11.15-bis(I-butyldimethylsilyl)-4,4,s,s-dehydro-7-1,07 obtained in Example 1
Prostaglandin EI methyl ester (I, 22f,
2.0 mmot) was dissolved in acetonitrile (50 d)K, pyridine (I,0++ff1) and then hydrogen heptathide-pyridine (2,0 rnl) were added, and the mixture was stirred at air temperature for 3 hours. The reaction solution was neutralized by adding an aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate (I50mj 780 ml of wholesale product was obtained. This material was subjected to silica gel column chromatography (hexane:ethyl acetate = 3) to obtain the desired 4,4
．． 5.5-dehydro-7-thiabrostaglandin methyl ester (710■, 1.86 mmot+ 93
h) was obtained.

Nuclear magnetic resonance absorption (CDCts, δ(pam)); 0.
7-1.0 (3H, m), 1.0-1.8 (8H
, m).

2.3-3.5 (I2H, m), 3.67 (3H
,s).

3.8~4.4 (2H, m), 5.6~5.8 (
2H,', m).

Infrared absorption spectrum (liquid film*); 3400
, 1740, 1260, 845, 730° mass spectrometry (FD-MS): 382 (M+).

'gL Example 3 In Example I, (E) -(as) -t-buq-lucime+lucilyloxy-1-iodo-1-octene K (E) -(33,5R) -3-t -butyldimethylsilyloxy-5-meryl-iodo-1-
Using 1-pentynyl steel instead of nonene and phenylthio steel,! By the same operating procedure as in Example 1, 11.15-bis(t-butyldimethylsilyloxy)-4,4,5,5-dehydro-17(R), 20
-Dimethyl-7-thiabrostaglandin methyl ester was obtained in a yield of 89%.

Nuclear magnetic resonance absorption (CDC4, δ (ppm)); 0
．． 06 (I2H,s), 0.87 (24H),
1.0~1.8 (9)1m), 2.3~3.6 (
I(H(, m), 3.67 (3H, s) 3.85~
4.35 (2H, m), 5.50-5.75 (2
H, m).

Infrared absorption spectrum (liquid film r Crn7”); 17
45, 1250.1165.1110.1075.96
5.885°835, 805. 775゜Quality Jl) Analysis ()'D-MS); 638 (M+)
, 581 (M-57), 57゜Example 4 11.15-bis(t-butyldimersilyloxy)-4,4,5,5-dehydro-17 obtained in Example 3
(R), 20-dimethyl-7-thiabrostaglandin methyl ester was subjected to the same deprotection reaction, post-treatment, and purification as in Example 2 to obtain 4.4.5.5-dimethyl with a yield of 79%.
Dehydro-17(R), 20-dimethyl-7-thiabrostaglandin E1 methyl ester was obtained.

Nuclear magnetic resonance absorption (CDC4, δ (ppm)); 0.
7-1.0 (6H, m), 1.0-1.9 (9H,
m).

2,: 3-3.5 (I2H, m), 3.67 (3
H, s.).

3.8~4.4 (2H, m), 5.6~5.8 (2
H, m).

Infrared absorption spectrum (liquid film * 5711-”); 3
400, 1740. 1240. 1200. 11
65. 1075°1040, 965.735°, mass spectrometry (FD-MS); 410 (M+).

Example 5 In the same manner as in Example 1, (E), -(38) -t-butyldimethylsilyloxy-3-cyclohexyl-1-
From iodo-1-propene and (R)-4-t-butyldimethylsilyloxy-2-((E)-5-methoxycarbonyl-2-pentenylthio)-2-cyclobentenone in a yield of 87% ( 4E)-11,X5-bis(t-7
'Tyldimethylsilyl)-4,5-dehydro-16,1
7.1 g of 19.20-pentanol-15-cyclohexyl-7-thiabrostaglandin methyl ester was obtained.

Nuclear magnetic resonance absorption (CDC4, δ (ppm)); 0.0
6 (I28,s), 0.87 (I8H,s),
0.8-1.9 (IIH, m), 1.9-3.1 (
IOH, m), 3.7-4.3 (2mm), 3.
63 (3L s), 5.2-5.8 (4H, m)
.

Infrared absorption spectrum (9m, Crn”); 30B
0. 1740. 1270. 1200. 1080
．． 975. 885°835, 805. 775° mass spectrometry (FD-MS>; 624 (M”).

Example 6 (4E)-11,15-bis(t
-butyldimethylsilyl) -4,5-dehydro-16
, 17,1,8,19,20-pentanol-15-cyclohexyl-7-thiabrostaglandin methyl ester was deprotected in exactly the same manner as in Example 2.

Work-up and purification yielded (4E)-4,5-dehydro-16,17,18,19',20-pentanol-15-cyclohexyl-7-thiabrostadalandin E, methyl ester with a yield of 86%. the law of nature.

Nuclear magnetic resonance absorption (CDC4, δ (ppm)); 0.8-
1. "9 (IIH, m), 1.9-3.2 (I2H
, m).

3.7-4.3 (2H, m), 3.63 (3H,
s).

5.2-5.8 (4H, m).

Infrared absorption spectrum (liquid film, 6n-')'.

3420, 3080. 1740. 1270. 1
200. 1080. 975°910, 730° Mass spectrometry (FD-MS): 396 (M-'
).

Example 7 Using the same machine as Example 1, dt-(E)-4-)riftylsilyloxy-1-iodo-1-octene (R)-4
-t-butyldimethylsilyloxy-2- ((Z)
-5-methoxycarbonyl-2-pentenyl)-
From 2-cyclobentenone with a yield of 79% (4Z) -(
I6R8) -1l-t-buF-rudimethylsilyl)
-4,5-dehydro-15-thioxy-16-methyl-16-)! J methylsilyloxy-7-thiabrostaglandin E0 methyl ester was obtained.

Nuclear magnetic resonance absorption (CDC4, δ (ppm)); 0.
0-0.2 (I5H, m), 0.87 (9H,
s), 0.7-1.0 (3H, m), 1.18
(3H, s), 1.1-2.0 (6H, m).

2, (I-3,1(I2H,m), 3.61 (
3H,s), 1.1-2.0(6H,'m),
2.0~3.1 (I2H,m)+3.61
(3H1s).

3.8-4.2 (IH, rn), 5.2-6.0
(4H, m).

Infrared absorption spectrum (liquid film r cJn-”); 30
80, 1740. 1250. 835. 775° mass spectrometry (FD-MS); 584 (M”).

Example 8 (4Z) -(I6R8) -11 obtained in Example 7
-t-7'Tyldimethylsilyl)-4,5-dehydro-
15-deoxy-16-methyl-16-drimethylsilyloxy-7-thiabrostaglandin E, methyl ester was released in exactly the same manner as in Example 2, post-treatment +'
me L Te yield s3s Te(4Z) -(I6R8
)-4,5-de-15-deoxy-16-hydro p
xy-16-methyl-7-thiabrostaglandin E,
A methyl ester was obtained.

Nuclear magnetic resonance absorption (CDC4, δ (ppm)); 0.
88 (3H, tl 1.14 (3H, s), 1.
1-2.0 (6H.

m), 2.0-3.4 (I4H, m), 3.61
(3H,s), 3.6-4. s (2H, m),
5.2-6.0 (4H, m).

Infrared absorption spectrum (liquid film/m”) e.

3420, 1?40.1260.845.730°Mass spectrometry (FD-MS); 398 (M+).

Example 9 11.15-bis(t-butyldimethylsilyl)-4,4,5,5-dehydro-7-thiabrostaglandin methyl ester obtained in Example 1 (610rig
. The product was obtained and subjected to VC on a silica gel column 70 (hexane:ethyl acetate = 4:1) to obtain the desired (4Z)-11°15-bis(I-butyldimethylsilyl)-4,5-dehydro-arch. Abrostaglandin Island Methyl Ester (Cape 428, 0.7
0 mmoL + 70%).

Nuclear magnetic resonance absorption ('CDCm, δ (ppm)): 0.0
6 (I, 2H, S), 0.87' (3H, s),
1.0-1.8 (8H, m), 2. :3-3.6
(IOH, m), 3.67 (3H, 8).

3.8-4.4 (2H, m), 5.2-5.8
(4H, m).

Infrared collection spectrum (liquid film + CI'1-'); 1
745, 1250.1, 165.1110.1075.
965.885°, 835,805,775° Mass spectrometry (FD-MS); 612 (M”).

Example 10 (4z)-11,15-bis(t-butyldimethylsilyl)-415-tehydro 7-17 prostaglandin F4 methyl ester (306F7p+) obtained in Example 9
0.5rnmot) was subjected to disengagement-1 post-treatment in exactly the same manner as in Example 2. 'l! ' L Te (4Z) -4,5-
Dehydro-7-thiabrostaglandin E1 methyl ester (I77+η* 0.46 nzmot, 92 t
6) was obtained.

Nuclear magnetic resonance absorption (CDC/4.δ (ppm)): 0.8
8 (3H, t), i, o-1, 8 (8H, m),
2.2-3.6 (I2H, m), 3.63 (3H,
s), 3.8-4.4 (2H, m).

5.2-5.8 (4H, m).

Infrared absorption spectrum (liquid film + rrq-”); 34
00, 1740.1260.845.730° Mass spectrometry (FD-MS); 384 (M”).

Example 11 4,4,5,5-dehydrostaglandin E obtained in Example 2, methyl ester (I91+I9.0.5mm
After dissolving ot) in a7ton (2n=/) and adding a pH 8 phosphate buffer (20πt), the liver esterase (Sigma Co., Ltd. 1fl, No E-3128, p.
H8.0.2m) was added and stirred at room temperature for 24 hours. After the reaction is completed, 0. The aqueous layer was acidified to pH 4 with IN salt solution, concentrated with ammonium acid, extracted with IC ethyl acetate, and washed with brine. The organic layer was dried over magnesium and concentrated under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography (hexane:ethyl acetate=1:
4, 0.1% acetic acid) for purification, 4,4.5.
5-dehydeq-7-thiabrostaglandin E1(]
62W, 0.44 mmot, 88%) was obtained.

Nuclear magnetic co-+4 absorption (CDC14, δ (ppm));
0.7-1.0 (37 (, m), 1.0-1.8
(8H, m), 2.3-3.5 (I0) (, m>,
3.8-4.4 (2)I, m), 5.6-5.8
(2H.

m), 6.30 (3H, bs).

Infrared absorption spectrum (liquid film + ctI+-'); 3
400, x74”o, 1710°, fff & analysis (
FD-', 4S); 368 (M+).

Example 12 (4Z)-4,5-dehydro- obtained in Example 10
7-Thiabrostaglandin E, methyl ester was prepared by the same hydrolysis method as in Example 11 (4Z
) -4,5-dehydro-7-thiabrostaglandin E□ was obtained in a yield of 87 cm.

Nuclear magnetic resonance absorption (CDC4, δ (ppm)): 0.
88 (3H, t), i, o-i, s (8H, m)
, 2.2-3.6 (IOH, m), 3.8-4.4
(2H, m), 5.2-5.8 (4H.

m), 6.50 (3H, bs).

Infrared absorption spectrum (liquid ffet * cm-”)
; 3400, 1740.1710° Mass spectrometry (FD-MS); 370 (M+).

Example 13 11.15-bis(t-butyldimethylsilyl)-4,4,5,5-dehydro 17(R) obtained in Example 3
, 20-dimethyl-7-thiabrostaglandin isomer methyl ester (I28, 0.20 mmot) was dissolved in ethyl acetate (ay), 50 μ of 10% palladium-activated carbon was added, and the mixture was stirred at room temperature for 24 hours. Using the catalyst, washing with ethyl acetate and concentrating to obtain a crude product, which was directly subjected to the same desilylation reaction as in Example 2, yielding 17(It), 2G, which corresponds to the standard product. -Jime thousand ru 7-
Thiabrostaglandin E1 methyl ester yield 62
obtained in chi.

Example 14 In Example 13, chlorotris(triphenylphosphine) μdium (
I), and e-product K matches 17(R),
20-dimethyl-7-thousand p-staglandin E, methyl ester was obtained.

Example 15 In the same manner as in Example 13, ii, ts-bis(t-butyldimethylsilyl)-4,4,5,5-dehydro-
17(R,), 20-dimethyl-7-thiabrostaglandin methyl ester was used as a starting material and catalytically reduced with deuterium using 10-thipalladium-activated carbon as a hydrogenation catalyst. 17(R), which is deprotected like 1dl and matches the standard product.
, 20-dimethyl-archabdistaglandin E
, -4,4,5,5-d4 methyl ester was obtained.

Example 16 11.15-bis(t-butyldimethylsilyl)-4,4,5,5-dehydro-17(
R), 20-dimethyl-7-thiabrostaglandin E, starting with methyl ester, 10-group palladium as a raw material, and tritium using activated carbon as a hydrogenation catalyst. 17 (
R), 20-dimethyl-archiabrostaglandin E□-4+4+5+5 L4 methyl ester was obtained.

Patent application Teidai Co., Ltd. Ne±,,':, J Agent Patent Attorney Mae 1) Jun #'-,i.

゛1ζ41. ．． −

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [I] [In the formula, R^1 is a hydrogen atom, C_1 to C_1_0 alkyl group, substituted or unsubstituted represents a phenyl group, a substituted or unsubstituted C_3-C_1_0 cycloalkyl group, a substituted or unsubstituted phenyl (C_1-C_2) alkyl group, or a monoequivalent cation, R^2 and R^3 are the same or different, Hydrogen atom, tri(C_1~C_7
) represents a hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, R^4 represents a hydrogen atom, a methyl group, or a vinyl group, and R^5 represents a straight group that may contain an oxygen atom. Chain or branched chain C_3~C
_8 alkyl group; optionally substituted phenyl group, phenoxy group, or C_3 to C_1_0 cycloalkyl group; or C_1 to C_6 alkoxy group, optionally substituted phenyl group, phenoxy group, or C_3 to C_1_0
It represents a straight chain or branched C_1 to C_5 alkyl group substituted with a cycloalkyl group, X represents an ethynylene group, a cis-vinylene group, or a trans-vinylene group, and n represents 0 or 1. ] 7-thiabrostaglandin E_1 which is a compound represented by the above and its 15 (when n = 1) epimer and its enantiomer or a mixture thereof in any proportion
kind. 2. 7-thiabrostaglandin E_1 according to claim 1, wherein n is 0. 3. 7-thiabrostaglandin E_1 according to claim 1, wherein n is 1. 7-thiabrostaglandin E_1 according to any one of claims 1 to 3, wherein 4 and X are ethynylene groups. 7-thiabrostaglandin E_1 according to any one of claims 1 to 3, wherein 5 and X are cis-vinylene groups. 6. 7-Thiabrostaglandin E_1 according to any one of claims 1 to 5, wherein R^1 is a hydrogen atom, an alkyl group of C_1 to C_1_0, or a cation of one equivalent. 7. R^2 and R^3 are the same or different; hydrogen atom, tri(C_1-C_4)alkylsilyl group, diphenyl(
C_1 to C_4) Alkylsilyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, 1-ethoxyethyl group, 2-ethoxy-2-propyl group, (2-methoxyethoxy)methyl group, or 6,6- dimethyl-
7-thiabrostaglandin E_1 according to any one of claims 1 to 6, which is a 3-oxa-2-oxobicyclo[3.1.0]hex-4-yl group. . 8. 7-Thiabrostaglandin E_1 according to any one of claims 1 to 7, wherein R^4 is a hydrogen atom. 9. 7-thiabrostaglandin E_1 according to any one of claims 1 to 7, wherein R^4 is a methyl group. 10. Claims 1 to 10 in which R^4 is a vinyl group
7-Thiabrostaglandin E_1 according to any one of Item 7. 11, R^5 is a butyl group, a pentyl group, a hexyl group, 1
-methyl-1-butyl group, 2-methyl-1-butyl group,
Any one of claims 1 to 10 which is a 2-hexyl group, 2-methylhexyl group, 2-ethoxyethyl group, cyclopentyl group, cyclohexyl group, cyclopentylmethyl group, cyclohexylmethyl group, or phenyl group 7-thiabrostaglandin E_1 according to item 1. 12. The following formula [II] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼... [II] [In the formula, R^1^1 is a C_1 to C_1_0 alkyl group,
Represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted C_3-C_1_0 cycloalkyl group, a substituted or unsubstituted phenyl (C_1-C_2) alkyl group, and R^2^1 is a tri(C_1-C_7) hydrocarbon It represents a silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, and X is as defined above. ]
2-organothio-2-cyclopentenones, their enantiomers, or mixtures of them in arbitrary proportions represented by the following formula [III] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[III] [In the formula , R^3^1 represents a group that forms an acetal bond with the oxygen atom of a tri(C_1 to C_7) hydrogencarbonate silyl group or hydroxyl group, and R^4, R^5, and n are the same as defined above. ] An organic lithium compound represented by the following formula [IV] CuQ...[IV] [wherein Q represents a halogen atom, a cyano group, a phenylthio group, or a 1-pentynyl group. ] The following formula [I] ▲ Formula, which is characterized by subjecting it to a conjugate addition reaction with an organocopper compound obtained from a copper compound represented by the formula, and subjecting it to deprotection and/or hydrolysis and/or salt production reaction as necessary. , chemical formulas, tables, etc. ▼...[I] Naka, R^1, R^2, R^3, R^4, R^5, X and n are the same as defined above. Production of 7-thiabrostaglandin E_1, which is a compound represented by and its 15 (when n = 0) or 16 (when n = 1) epimer and its enantiomer or a mixture thereof in any proportion Law. 13. The method for producing 7-thiabrostaglandin E_1 according to claim 12, wherein the conjugate addition reaction is carried out in the presence of a trivalent organic phosphorus compound. 14. The following formula [I -a] ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [I -a] [In the formula, R^1, R^2, R^3, R^4, R^5 , and n are the same as defined above. ] The following formula [I-b] is characterized by catalytic reduction of 4,4,5,5-dehydro-7-thiabrostaglandin E^1 represented by [I-b] ▲Formula , chemical formulas, tables, etc.▼...[I-b] [In the formula, R^1, R^2, R^3, R^4, R^5, and n are the same as defined above. ] A method for producing 4,5-dehydro-7-thiabrostaglandin E_1 represented by: 15. 7 according to claim 14, wherein the hydrogenation catalyst is a palladium-based catalyst, a platinum catalyst, or a rhodium catalyst.
- A method for producing thiabrostaglandin E_1. 16. The method for producing 7-thiabrostaglandin E_1 according to claim 15, wherein the palladium-based catalyst is a Lindlar catalyst or a palladium-barium sulfate catalyst poisoned with quinoline. 17. The method for producing 7-thiabrostaglandin E_1 according to claim 15, wherein the platinum catalyst is platinum oxide or platinum black. 18. Claim 15, wherein the rhodium catalyst is chlorotris(triphenylphosphine)rhodium(I)
A method for producing 7-thiabrostaglandin E_1 as described in Section 1. 19. The following formula [I -b] ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [I -b] In the formula, R^1, R^2, R^3, R^4, R^5, and n are the same as defined above. The following formula [V] is characterized by catalytic reduction of 4,5-didehydro-7-thiabrostaglandin E_1 expressed by the following in the presence of a hydrogenation catalyst. ▲There are mathematical formulas, chemical formulas, tables, etc.▼・...[V] [In the formula, R^1, R^2, R^3, R^4, R^5, and n are the same as defined above. ] A method for producing 7-thiabrostaglandin E_1 represented by: 20. The method for producing 7-thiabrostaglandin E_1 according to claim 19, wherein the hydrogenation catalyst is a palladium-based catalyst, a platinum catalyst, or a rhodium catalyst. 21. The method for producing 7-thiabrostaglandin E_1 according to claim 20, wherein the palladium-based catalyst is palladium-activated carbon, palladium-calcium carbonate, or palladium-barium sulfate. 22. The method for producing 7-thiabrostaglandin E_1 according to claim 20, wherein the palladium-based catalyst is a Lindlar catalyst or a palladium-barium sulfate catalyst poisoned with quinoline. 23. The method for producing 7-thiabrostaglandin E_1 according to claim 20, wherein the platinum catalyst is platinum oxide or platinum black. 24. Claim 20, wherein the rhodium catalyst is chlorotris(triphenylphosphine)rhodium(I)
A method for producing 7-thiabrostaglandin E_1 as described in Section 1. 25, The following formula [I -a] ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [I -a] [In the formula, R^1, R^2, R^3, R^4, R^5 , and n are the same as defined above. ] The following formula is characterized by catalytic reduction of 4,5-tetradehydro-7-thiabrostaglandin E_1 represented by <V> in the presence of a hydrogenation catalyst. ▲There are mathematical formulas, chemical formulas, tables, etc. ▼...[V] In the formula, R^1, R^2, R^3, R^4, R^5, and n are the same as defined above. A method for producing 7-thiabrostaglandin E_1 represented by 26. The method for producing 7-thiabrostaglandin E_1 according to claim 25, wherein the hydrogenation catalyst is a palladium catalyst, a platinum catalyst, or a rhodium catalyst. 27. The method for producing 7-thiabrostaglandin E_1 according to claim 26, wherein the palladium-based catalyst is palladium-activated carbon, palladium-calcium carbonate, or palladium-barium sulfate. 28. The method for producing 7-thiabrostaglandin E_1 according to claim 26, wherein the platinum catalyst is platinum oxide or platinum black. 29. Claim 26, wherein the rhodium catalyst is chlorotris(triphenylphosphine)rhodium(I)
A method for producing 7-thiabrostaglandin E_1 as described in Section 1.