JPS59101458A - Novel thiaprostaglandin derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [A is H, OH or protected OH; W is CH2CH2 or trans-CH=CH; M is H, metallic ion, 1-6C alkyl, etc.; R is 4-8C alkyl, adamantyl, R2-O-R3 (R2 and R3 are 1-7C alkyl), etc.; R1 is H or OH- protecting group; the wavy line is alpha-bond, beta-bond, etc.]. EXAMPLE:10,10-Dimethyl-11-deoxy-7-thiaprostaglandin E1-methyl ester. USE:Hypotensor, remedy for gastric ulcer, and antithrombic agent. PROCESS:The compound of formula I can be prepared by reacting the compound of formula II with the compound of formula III (M is 1-6C alkyl) in a solvent at -40 deg.C- room temperature for about 160min. The amount of the compound of formula II is preferably 1-3 times equivalent of the compound of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to thiaprostaglandin derivatives that have not been described in prior art publications and a method for producing the same, and particularly to 10,10-dimethyl-7-thiaprostaglandin derivatives having the following skeleton structure that has not been described in prior U.S. publications. -Regarding a prostaglandin derivative and its production method. The novel thiaprostaglandin derivatives are useful in the prevention or treatment of human diseases as antihypertensive agents, gastric ulcer therapeutic agents, antithrombotic agents, etc., and have extremely important medical and pharmaceutical value.

More specifically, the present invention relates to the following formula [■], where A represents a hydrogen atom, a hydroxyl group, or a protected hydroxyl group, and W represents a group -CH2CH2- or a group trans-CH=
CH- represents a hydrogen atom, a pharmaceutically acceptable metal ion, an ammonium ion, a quaternary ammonium ion derived from a primary to tertiary amine, a quaternary ammonium ion derived from a basic amino acid, and c.

- represents a member selected from the group consisting of C6 straight chain, branched or cyclic alkyl group, R is C4 to C8 straight chain, branched or cyclic alkyl group, adamantyl group, group -R2- 0-R, (where R2 and R5 are each 0
1 to C7 linear or branched alkyl group) and an aryloxy lower alkyl group in which the aryl group may have a substituent; R1 represents a hydrogen atom or a protecting group for a hydroxyl group in the aqueous formula; The wavy line (-vIA/VW) indicates an α-bond, a β-bond, or a mixture thereof, and relates to a thiaprostaglandin derivative represented by the following and its production method.

In the novel thiaprostaglandin derivative of the above formula [■], the formula (I) is the 8th, 11th, 12th,
Defined to include all optical isomers formed from asymmetric carbon atoms at positions 15, 16, 17, and 18, as well as mixtures and racemic compounds of these optical isomers in arbitrary proportions. be done. Glotaglandin (
PG) is a compound that is biosynthesized in vivo from arachidonic acid, and is known to be a physiologically active substance that exhibits various important physiological effects in minute amounts.

Officially, PG has brostanic acid as its basic skeleton, and the structure of its 5-membered ring portion is, for example, E, Fα.

It is also well known that it can be classified into various types such as A, B, C, D, H, and I [for example, [Monthly Pharmaceutical Affairs J Vo
l, 2. 31 (1980), ].

For example, prostaglandin El (PGEI) has the following structural formula and is named (11α, 13E, t5s)-tl, 15-dihydroxy-9-oxo-prost-13-en-1-oic acid. .

In the above structural formula, the bond indicated by the broken line -m-- is in the α-coordination, meaning that the substituent is bonded downward in this plane. Furthermore, the bond shown by the wedge line 1 is in the β-coordination, meaning that the substituent is bonded upward in this plane [see Nature, 212°38 (1960)].

Furthermore, the physiologically active effects of these PGs, for example, the circulatory system,
It has been reported that it affects almost all living tissues such as the respiratory, digestive, urinary, reproductive, and central nervous systems [e.g. Monthly Yakuji, J Vol. 2]
2.49 (1980)).

Conventionally, some of the natural PGs, such as PGF2α, PG
E, , PGE, etc. have already been put into practical use as pharmaceuticals.

However, natural PGs are generally rapidly metabolized and often physicochemically unstable, and have the disadvantage that they also suffer from side effects, and in addition, their physiologically active actions are not necessarily specific.

Recently, attempts have been made to develop non-natural PGs that have unique properties that are even better than the above-mentioned drawbacks of natural PGs.

The present inventors conducted development research on such non-natural PG. As a result, we succeeded in synthesizing a thiaprostaglandin derivative represented by the above formula [I], which has not been described in the literature, and compared to conventional PG, the compound [I] has superior selectivity. It was discovered that it has physiologically active effects.

Accordingly, an object of the present invention is to provide novel thiaprostaglandin derivatives. Another object of the present invention is to provide a method for producing the novel thiaprostaglandin derivatives.

The above objects and many other objects and advantages of the present invention will become more apparent from the following description.

In the compound of the formula [■] of the present invention, A represents a hydrogen atom, a hydroxyl group, or a protected hydroxyl group [-0R1'], where R(
represents a hydroxyl protecting group. In the formula [■], R1 represents a hydrogen atom or a hydroxyl group-protecting group. Examples of R1 and the above-mentioned R when indicating the protecting group include a tetrahydropyranyl group, a tetrahydrofuranyl group, a 1-alkoxyethyl group, a trimethylsilyl group, a triethylsilyl group, a 1-butyldimethylsilyl group, and a dimethyl-n- Protective groups such as propylsilyl group can be exemplified.

In the compound of the formula [■], W represents a -CH2CH, - group or a trans-CH=CH- group.

In the compound of formula CI,) of the present invention, M is a hydrogen atom, a pharmaceutically acceptable metal ion, an ammonium ion, a quaternary ammonium ion derived from a primary to tertiary amine, or a basic amino acid. Quaternary ammonium ion, C
Indicates a member selected from the group consisting of 1 to C6 straight chain, branched or cyclic alkyl groups.

Preferred examples of the metal ions include alkali metal ions such as Na ions and K ions. Examples of the quaternary ammonium ions include quaternary ammonium ions derived from primary amines such as methylamine, ethylamine, tris(hydroxymethyl)aminemethane, etc.; for example, dimethylamine, diethylamine, di-n-propylamine; Quaternary ammonium ions derived from tertiary amines such as , diisopropylamine, di-n-butylamine, etc.; e.g. trimethylamine, triethylamine, tri-n-propylamine,
Preferred examples include quaternary ammonium ions derived from tertiary amines such as tri-n-butylamine; and quaternary ammonium ions derived from basic amino acids such as arginine, lysine, and histidine.

Furthermore, examples of the straight chain, branched or cyclic alkyl groups of CI to C6 include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, inpropyl group. Examples include a 1-methyl-propyl group, a 2-methyl-propyl group, a t-butyl group, a cyclopentyl group, a cyclohexyl group, and the like.

Furthermore, in the compound of the present invention formula (Il), R is a C2-C8 linear, branched or cyclic alkyl group, an adamantyl group, a group -R2-0-R, (where R2 and R3 are each 08 to C7 straight-chain or branched alkyl group] and an aryloxy lower alkyl group in which the aryl group may have a substituent.

Examples of the C4 to C8 straight chain, branched or cyclic alkyl group include n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1-methylpentyl group, 2-methylpentyl group, 3-
Methylpentyl group, 4-methylpentyl group, 1-methylhexyl group, y-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group,
■, 1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 1,1-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 4, 4-dimethylpentyl group, 1.1-
Dimethylhexyl group, 2.2-dimethylhexyl group, 3
,3-dimethylhexyl:/A4.4) Preferred examples include 4-dimethylhexyl group, 5゜5-dimethylhexyl group, cyclobutyl group, cyclohentyl group, cyclohexyl &, 1-, 0-panopentyl group (isomers exist) (including individual isomers and mixtures of isomers).

Furthermore, examples of the group represented by the above group -R2-0-R, (where R2 and R3 are each a straight-chain or branched alkyl group of 01 to C7) include a 2-oxapentyl group, 4-methyl-2-oxapentyl group, 4,4-dimethyl-2-oxapentyl group, 2-oxahexyl group, 5-methyl-2-oxahexyl group, 5,5-dimethyl-2-oxahexyl group, 1-Methyl-2-oxapentyl group, 1.4-dimethyl-2-oxapentyl group, 1゜4.4-)1.1methyl-2-oxapentyl group, 1-methyl-2-oxahexyl group, 1,5-dimethyl-2-oxahexyl group, 1,5.5-1limethyl-2-oxahexyl group, 1,1-dimethyl-2-oxapentyl group, 1,1.4-1limethyl group -2-oxapentyl group, 1,1,4゜4-tetramethyl-2-oxapentyl group, 1゜1-dimethyl-2-oxahexyl group, 1,1゜5-trimethyl-2-oxahexyl group 1,1゜5.5-tetramethyl-2-oxahexyl group, 3-oxapentyl group, 4-methyl-3-oxapentyl group, 4.4-dimethyl-3-oxahentyl group, 3
-oxahexyl group, 5-methyl-3-oxahexyl group, 5,5-dimethyl-3-oxahexyl group, l-
Methyl-3-oxapentyl group, 1,4-dimethyl-3
-oxapentyl group, 1,4.4-)tumethyl-3-oxapentyl group, 1-methyl-3-oxahexyl group,
1゜5-dimethyl-3-oxahexyl group, 1,5゜5
-trimethyl-3-oxahexyl group, 2-methyl-3
-oxapentyl group, 2,4-dimethyl-3-oxapentyl group, 2-methyl-3-oxahexyl group, 2,5
-dimethyl-3-oxahexyl group, 2,5.5-1-limethyl-3-oxahexyl group, 1,1-dimethyl-3
-oxapentyl group, 1,1.4-trimethyl-3-oxapentyl group, 1,1,4.4-tetramethyl-3-
Oxapentyl group, 1,1-dimethyl-3-oxahexyl group, '1,1,5-toIJmethyl-3-oxahexyl group, 1,1,5.5-tetramethyl-3-oxahexyl group, 2 , 2-dimethyl-3-oxapentyl group, 2,2.4-1-limethyl-3-oxapentyl group, 2,2-dimethyl-3-oxahexyl group, 2,2.
5-trimethyl-3-oxahexyl group, 4-oxapentyl group, 4-oxahexyl group, 5-methyl-4-oxahexyl group, 5,5-dimethyl-4-oxahexyl group, 1-methyl-4- Oxapentyl group, 1-methyl-4-oxahexyl group, 1,5-dimethyl-4-oxahexyl group, 1,5.5-4limethyl-4-oxahexyl group, 2-methyl-4-oxapentyl group , 2-methyl-4-oxahexyl group, 2,5-dimethyl-4-
Oxahexyl group, 2,5.5-trimethyl-4-oxahexyl group, 3-methyl-4-oxapentyl group, 3
-Methyl-4-oxahexyl group, 3,5-dimethyl-
4-oxahexyl group, 3,5.5-1-dimethyl-4
-oxahexyl group, 1,1-dimethyl-4-oxapentyl group, 1,1-dimethyl-4-oxahexyl group,
1,1.5-1limethyl-4-oxahexyl group, 1,
1,5.5-tetramethyl-4-oxahexyl group, 2
, 2-dimethyl-4-oxapentyl group, 2,2-dimethyl-4-oxahexyl group, 2,2.5-trimethyl-4-oxahexyl group, 2,2,5.5-tetramethyl-4- Oxahexyl group, 3.3-dimethyl-4-oxahexyl group, 3,3-dimethyl-4-oxahexyl group, 3,3.5-1-limethyl-4-oxahexyl group, 3,3,5. 5-tetramethyl-4-oxahexyl group, 5-oxahexyl group, 5-oxaheptyl group,
1-methyl-5-oxahexyl group, 1-methyl-5-
Oxaheptyl group, 2-methyl-5-oxahexyl group, 2-methyl-5-oxaheptyl group, 3-methyl-5
-oxahexyl group, 3-methyl-5-oxaheptyl group, 4-methyl-5-oxahexyl group, 4-methyl-
5-oxaheptyl group, 1.1-dimethyl-5-oxahexyl group, 1゜1-dimethyl-5-oxaheptyl group, 2.2-dimethyl-5-oxahexyl group, 2,2-
Dimethyl-5-oxaheptyl group, 3,3-dimethyl-
5-oxahexyl group, 3,3-dimethyl-5-oxaheptyl group, 4,4-dimethyl-5-oxahexyl group, 4.4-dimethyl-5-oxaheptyl group, 6-oxaheptyl group, 1- Methyl-6-oxaheptyl group, 2
-Methyl-6-oxaheptyl group, 3-methyl-6-oxaheptyl group, 4-methyl-6-oxaheptyl group,
5-methyl-6-oxaheptyl group, 1,1-dimethyl-6-oxaheptyl group, 2,2-dimethyl-6-oxaheptyl group, 3,3-dimethyl-6-oxaheptyl group, 4,4- Dimethyl-6-oxaheptyl group, 5,5
-dimethyl-6-oxaheptyl group, etc. (if isomers exist, each isomer and a mixture of isomers are also included).

Furthermore, examples of substituents for the aryloxy lower alkyl group which the aryl group of R may have a substituent include halogen, trifluoromethyl, hydroxyl, nitro, lower alkyl, hydroxy lower alkyl and lower alkoxy. Examples include substituents selected from the group consisting of: An example of the aryl group is a phenyl group. Examples of such aryloxy lower alkyl groups include phenoxymethyl group, fluorophenoxymethyl group, metafluorophenoxymethyl group, parachlorophenoxymethyl group, metachlorophenoxymethyl group, metatrifluoromethylphenoxy-methyl group, and metafluorophenoxymethyl group. A phenyl group such as a hydroxyphenoxymethyl group, a varanitrophenoxymethyl group, a metanitrophenoxymethyl group, a varamethoxyphenoxymethyl group, a metamethoxyphenoxy-methyl group, a metamethylphenoxymethyl group, a metahydroxymethylphenoxymethyl group, etc. is a substituent. A preferred example is a phenyloxy lower alkyl group which may have the following.

The present invention formula [ID compound] is, for example, a compound represented by the following formula [■] (wherein A, WXR, R, and the wavy line □ have the same meanings as described for formula (1)). [■] (-ball., 7, /c o o M) 2 C■]
(In the formula, M is a linear, branched, or cyclic alkyl group of C□ to C6.) It can be produced from K by reacting it with a compound represented by the following in a reaction solvent.

Below, several aspects of the production of the formula [ID compound of the present invention] will be described in more detail. The above formula [■] compound and [■]
The compounds can also be produced from known compounds as described below.

According to one embodiment of the method of the present invention, the compound of the present invention represented by the formula [ID] can be produced, for example, as follows. In the following, the parts of the compound shown by the wavy line □ in the process diagram are omitted and shown by the solid line.

(ID [■] [■] [ID] In the above embodiment, the compound of formula [I[) (the hole in the formula is a hydroxyl group) can be produced as follows. For example, the literature Te
trahedron Letters, 1925 (
1968), 5,5-dimethyl-2-cyclobentenone was first reacted with N-bromosuccinimide to produce 4-bromo-5,5-dimethyl-2-cyclobentenone. by treating with silver acetate 4
-Acetoxy-5°5-dimethyl-2-cyclobentenone can be produced.

Next, Tetrahedron Letters,
569 (1973), the above 4-acetoxy-5,5-dimethyl-2-cyclobentenone was subjected to a Michael addition reaction with nitromethane and a base to give 2,2-dimethyl-3-acetoxy-4- After producing nitromethylcyclopentanone, it is further prepared by adding ethylene glycol and a catalytic amount of nitromethylcyclopentanone in benzene, for example, and refluxing for about 8 hours. Ethylene acetal derivatives can be produced.

This is then reacted with, for example, potassium carbonate in a reaction solvent such as methanol for about 30 minutes to about 60 minutes at room temperature to obtain 2.2-dimethyl-3-.
After producing hydroxy-4-nitromethyl-cyclopentanone ethylene acetal, J. Org. Che
m,, 38. 4367 (1973), the compound of the formula [■] can be produced by subjecting it to a reduction reaction with, for example, titanium trichloride in a reaction solvent such as methanol water. Also, formula CII]
The compound (wherein A is hydrogen) can also be produced by the following method. For example, the literature Tetrahe-dr.
5,5-dimethyl-2-cyclobentenone was subjected to a Michael addition reaction with nitromethane and a base to form 2,2-dimethyl-4-nitromethyl-according to the method described in On Letters, 569 (1973). Cyclopentanone can be prepared and then refluxed, for example in benzene, with ethylene glycol and a catalyst Jt, for example para-toluenesulfonic acid, for about 8 hours, to produce its ethylene acetal derivative. This is then published in Document J, Org, Chem, 38.
According to the method described in 4367 (1973), the compound of the above formula [■] can be produced by subjecting it to a reduction reaction with, for example, titanium trichloride in methanol-water. The compound of formula [IV] (wherein the human is hydrogen or a hydroxyl group, and R is as defined above) is, for example, the compound of the formula CIH (wherein the human is hydrogen or a hydrogen group) which can be obtained as described above. is a hydroxyl group) in a compound of formula (Iff) (wherein R
using a phosphonate of the formula (as previously described) and a base such as sodium hydride, sodium methoxide, sodium methoxide, etc., according to the literature, J. Am.
, Chem.

Soc', 83.1733 (1961), and J.A.
m.

It can be produced by a reaction according to the method described in Chem, Soc, 90.3247 (1968).

As a reaction solvent, THF (tetrahydrofuran), D
Ethers such as ME (1,2-dimethoxyethane) dioxane, methylene chloride, etc. can be preferably used. The reaction is carried out at a temperature of, for example, about -20°C to about 70°C, and a temperature of about
It can be carried out with a reaction time of ~10 hours.

The ethylene groups at positions 13 and 14 produced in this reaction are preferentially trans-ethylene groups.

Further, the compound of formula CI) (wherein R has the same meaning as described for formula [■]) is described in the literature J-Am, Chem.

Soc, 90.3247 (1968), J. Am.

Chem, Soc, 88.5654' (1966)
, and J,Org,Chem,, 30.680 (19
It can be produced according to the method described in 65).

Compound of the above formula [v] (wherein, W is trans-CH=C
H- group, A is hydrogen or a hydroxyl group, and R is as defined above) is a compound of formula [jV] which can be obtained, for example, as described above (wherein human and R are as defined above). For example, it can be produced by subjecting the ketone group to a hydroxyl group by reacting with a reducing agent in a suitable reaction solvent.

Examples of the reducing agent include hydrides of metals such as boron and aluminum. Specific examples of such reducing agents include sodium borohydride, lithium borohydride, potassium borohydride, zinc borohydride, lithium cyanoborohydride, sodium trimethoxyborohydride, and triynepropoxyborohydride. Potassium, potassium tri-5eC-butylborohydride, lithium tri-5eC-butylborohydride, tetra-n-butyl-ammonium cyanoborohydride, lithium aluminum hydride, diisobutylaluminum hydride, lithium trimethoxyaluminum hydride, hydrogen Lithium triethoxyaluminum hydride, tri-t-butyloxyaluminum-lithium hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride. Other aluminum impropoxides, Reference J, Am, Chem, SOC, 94,
8616 (1972), J. Am. Chem. Soc.
,,101゜5843 (1979), J, Org, C
For example, there may be mentioned a ketone group reducing agent described in Hem., 44° 1363 (1979). In addition, all reducing agents capable of selectively converting only ketone groups into hydroxyl groups may be appropriately selected and used.

Examples of reaction solvents include water, methanol, ethanol, n
-Alcohols such as noropanol and impropanol,
Ethers such as dioxane, DME, THF, diglyme, DMF (N, N-dimethylformamide), DMSO
(dimethylphorphoquine), HMPA (hexamethylphosphoramide), and the like. The reaction is e.g.
It can be carried out at a temperature of about 80° to room temperature, for example, for about 1 to about 10 hours.

The above reduction of the ketone group of the compound of formula [■] to the hydroxyl group is
The formula obtained is usually not stereoselective [
Regarding the absolute coordination of the hydroxyl group of the compound V], R and S coordination isomers are formed, and a mixture of these isomers is usually obtained. Furthermore, when a stereoselective reducing agent is used, the production ratio of these isomers can be greatly biased toward one side.

In the compound of formula [V], W is a -CH2CH2- group, and A and R are as defined above, in the compound of formula [v],
It can be produced by subjecting a compound in which W is a -CH=CH- group and A and R are the above-mentioned general formulas to a catalytic hydrogenation reaction in a conventional manner.

Compound of the above formula [■] (wherein W is trans-CH=CH
- group or -CH2CH*- group, A and R are as defined above) is a compound of formula [v] which can be obtained, for example, as described above (wherein W is trans-CH=CH
- group or -CH, -CH2- group, A and R are as described above) can be produced by subjecting it to a deacetal reaction.

This deacetal reaction can be carried out by a conventional method, and the compound of formula [V] may be mixed with water-containing acetone, THF,
In an organic solvent such as an alcohol such as methanol or ethanol, suitable inorganic and organic acids such as hydrochloric acid,
Add sulfuric acid, acetic acid, monochloroacetic acid, etc. to
Seeding can be carried out by subjecting the reaction to a temperature of about 70° C. for about 1 to about 24 hours.

In addition, in the compound of formula CVD, W is -CI(2CE(, - group), and the compound in which A and R are the same as above is represented by the formula [■]
It can also be produced by subjecting a compound in which W is a -CH=CH- group and A and R are the same as above to a catalytic hydrogenation reaction in a conventional manner.

Furthermore, the compound of the above formula [■] (wherein A is a hydrogen atom or a protected hydroxyl group, !>, nt is a hydroxyl protecting group, and R and W are as defined above) is , for example, protecting the hydroxyl group of the compound of formula [■] (in the formula, human is a hydrogen atom or a hydroxyl group, and R and W are as defined above) which can be obtained as described above with a protecting group. It can be manufactured easily.

Examples of such hydroxyl protecting group R1 include tetrahydropyranyl group, tetrahydrofuranyl group, niemethoxyethyl group, l-ethoxyethyl group, 1-n-butoxyethyl group, 1-inbutyloxyethyl group, l- Preferred examples include 1-alkoxyethyl groups such as octyloxyethyl group and 1-yneoctyloxyethyl group, trimethylsilyl group, t-butyldimethylsilyl group, n-propyldimethylsilyl group, and triethylsilyl group.

A compound in which the hydroxyl group protecting group R1 in formula [■] is a tetrahydropyranyl group is, for example, a compound of formula [■] (wherein human is a hydrogen atom or a hydroxyl group, and W and R are the same as above). ) in methylene chloride with 2,3-dihydropyran and a catalytic amount of para-toluenesulfonic acid at, for example, about -20°C to about 50°C, for example, about 15 minutes to about 12 minutes.
It can be produced by subjecting it to a reaction for 0 minutes.

Protecting group R1 is a tetrahydrofuranyl group, a 1-alkoxyethyl group (e.g., 1-methoxyethyl group, 1-ethoxyethyl group, 1-n-butoxyethyl group, 1-isobutyloxyethyl group, 1-octyloxyethyl group) , 1-isooctyloxyethyl group, etc.), 2,3-dihydro-furan, vinyl alkyl ethers (examples ti, f vinyl methyl ether, vinyl ethyl ether, vinyl- n-butyl ether, vinyl isobutyl ether, vinyl octyl ether, vinyl isooctyl ether, etc.).

Also, in the formula [■], a protecting group R of a hydroxyl group protecting group.

Compounds in which is a t-butyldimethylsilyl group are described in Document J,
Am, Chem, Soc,, 94.6190 (1
972), a compound of the formula [VD (in the formula, human is a hydrogen atom or a hydroxyl group, and W and R are as defined above) was prepared using t-butyldimethylchlorosilane using DMF as a reaction solvent. It can be produced by a reaction using imidazole as a base.

Furthermore, a compound of formula [■] in which R1 is a trimethylsilyl group can also be produced by reacting with trimethylchlorosilane in the same manner.

In the compound of formula [■], W is a -CH2-CH,- group, and A, R, and R are as described above.
] In the compound, W is -CH=CH-= group, A, R1
and R can be produced by subjecting a compound in which R is as described above to a catalytic hydrogenation reaction in a conventional manner.

Thiaprostaglandin derivative 0 of the formula CD of the present invention, where the middle person is a hydrogen atom or a protected hydroxyl group, and W is -
CH2CHt- group or trans-CH=CH- group, RL is a hydroxyl group protecting group, M is 01 to C11
is a straight chain, branched or cyclic alkyl group, and R is as defined above. ) is a compound of formula [■] (wherein A, R
, R and W are as described above) with a compound of formula [■] (wherein M is a C1 to C6 straight chain, branched or cyclic alkyl group). can do.

For example, the compound of formula [■] is mixed with an inert solvent, such as THF,
I (by reacting with a base, e.g., lithium dialkylamide, for example, at about -40' to about -10°C for about 60 to about 90 minutes in a reaction solvent consisting of MPA or a mixed solvent thereof, to obtain the formula [■ ] produces the compound eruleto.

The lithium dialkylamide can be used with various dialkylamines such as diethylamine, diisopropylamine, piperidine, hexamethyldisilazane, di-n-butylamine, di-isobutylamine, di-n-propylamine, N-ethyl-n-propylamine, N-ethyl-isonorobylamine, N-S e C-butyl-n-propylamine, N-ethyl-n-butylamine or 1d N
-x Prepared from thyl-t-butylamine, etc. and various alkyllithium reagents, such as methyllithium or n-butyllithium, in an inert solvent, such as THF or 1,2-dimethoxyethane, by a conventional method at room temperature or below. be able to.

Next, the compound of formula 1] is added to the erulate solution of the compound of formula [■] which can be obtained as described above, and the mixture is subjected to a reaction for about 160 minutes, for example, at about -40°C to room temperature. C. The compound of the above formula [■] can be produced.

In this case, the compound of formula [■] is about 1 to 10% of the compound of formula [■]
It is preferable to use about 3 times the equivalent amount.

After the reaction is completed, the reaction is neutralized by adding IN-hydrochloric acid, diluted with a large amount of water, extracted with an organic solvent such as ethyl acetate, the solvent is distilled off, and the resulting residue is purified using silica gel, for example. It can be purified by column chromatography using ethyl acetate-n-hexane system.

The compound of formula 1] (wherein M is a C, -C, linear, branched or cyclic alkyl group) can be produced as follows. namely literature, Z.

Physiol, Chem, 281. 156 (194
4) or Gazz, Chim, 1ta1.89. 2
423 (1959).
An ester compound thereof can be produced by producing dithiocycaproic acid and then reacting it with an alcohol in a conventional manner. For example, dimethyl 6,6'-dithiocycaproic acid can be produced by reacting it with metasil. In the same manner, by using various alcohols, the corresponding ester compounds [■] can be produced.

Thiaprostaglandin derivatives of formula [I] of the present invention (wherein A is a hydrogen atom or a hydroxyl group, R1 is a hydrogen atom, and Kaede W is a -CH, CH2- group or a trans-C
H=CH- group, M is a C1-C6 straight chain, branched or cyclic alkyl group, and R is as described above. ) is a compound of formula [I], where A is a hydrogen atom or a protected hydroxyl group, R1 is a protecting group for the hydroxyl group, and W, M and R are the protecting groups of the compound as described above. It can be produced by eliminating it by a conventional method. For example, a compound of formula [I] (wherein the protecting group or R8 is a hydroxyl protecting group such as a tetrahydro-pyranyl group, a tetrahydrofuranyl group, a 1-alkoxyethyl group, a trimethylsilyl group, a triethylsilyl group),
A, W, M and R are as described above), for example, lower alcohols such as methanol, ethanol, etc., other water-containing organic solvents, such as TH
F-Adding acids such as hydrochloric acid, sulfuric acid, para-toluenesulfonic acid, acetic acid, oxalic acid, etc. in a solvent such as a water system,
For example, the protecting group can be removed by reaction at about 00 to about 40°C, for example, for about 1 to about 24 hours.

In the case of a compound of the formula CI] in which the protecting group or R1 is a 1-butyldimethylsilyl group and A, WXM and R are as previously described, reference J, Am, Chem.
, Soc, 94.6190 (1972), for example, by reaction with tetra-n-butylammonium fluoride in a reaction solvent such as THF. can be done.

A compound of formula [I] (where M is a hydrogen atom, A is a hydrogen atom or a hydroxyl group, R1 is a hydrogen atom, W
and R are as defined above) is a compound of formula [■] (wherein M is a C1 to C6 straight chain, branched or cyclic alkyl group, A, R, , W and R can be produced by subjecting the ester group of (as described above) to a chemical hydrolysis reaction in a conventional manner. Preferred examples of the solvent used in this hydrolysis reaction include alcohol-water systems such as methanol and ethanol, and examples of the base include ammonia, lithium hydroxide, sodium hydroxide, potassium hydroxide,
Caustic alkali such as calcium hydroxide, sodium carbonate, potassium carbonate, etc. can be used.

The reaction may be carried out, for example, at a temperature of about 0° to about 40°C, e.g.
Can be done subject to time conditions. After the reaction is completed, the residue is neutralized by adding dilute hydrochloric acid, for example, and the residue obtained by distilling off the organic solvent is subjected to purification by column chromatography, for example. It can be purified by

Furthermore, as another method, it can also be produced by subjecting it to a hydrolysis reaction using an enzyme. Generally, lipase is preferably used as the enzyme. This hydrolysis reaction is carried out in a buffer solution with a pH of around 4 to 8, but a pH around 7 is preferably employed.

For example, by mixing lipase and the above-mentioned ester compound in Mcl Ivaine's buffer at pH 7, e.g.
This can be carried out by subjecting it to a hydrolysis reaction at 0 to 50°C for, for example, 10 to 50 hours.

The compound of formula [■] of the present invention (wherein W is -CH, CH2-
group, M is a hydrogen atom or a C1-C0 linear, branched or cyclic alkyl group, A is a hydrogen atom, a hydroxyl group or a protected hydroxyl group, and RI is a hydrogen atom or a protecting group for the hydroxyl group. and R are as described above)
is a compound of formula [I] (wherein W is -Cf (=CH- group, M, A, R, and R are as defined above)
By subjecting it to a catalytic hydrogenation reaction in a conventional manner, its -
It can be produced by saturating a CH=CH- group and converting it into a -CH2CH,- group.

Furthermore, among the compounds of formula [I] of the present invention, compounds in which M is a metal ion, ammonium ion, or quaternary ammonium ion are compounds of formula [■] (wherein, M is a hydrogen atom, and A is a hydrogen atom). atom or hydroxyl group, R1 is a hydrogen atom, R and W are as described above), an equivalent amount of a metal hydroxide, ammonia, a primary amine, a tertiary amine, a tertiary amine, a base. It can be produced by neutralizing it in a conventional manner using a synthetic amino acid or the like.

Furthermore, the compound of formula [I] of the present invention (wherein M is C1-C
6 is a linear, branched or cyclic alkyl group, A is a hydrogen atom or a hydroxyl group, R7 is a hydrogen atom, R and W are as described above) is a formula [ ■〕
can be derived in a similar manner from a compound of formula CI] produced by the reaction of a compound of formula CI with a compound of formula (in which M is a C1-C6 straight-chain, branched or cyclic alkyl group) .

Each of these compounds of formula CII) can be purified, if desired, by subjecting it to a purification operation such as column chromatography, high performance liquid chromatography, thin layer chromatography, or the like. The compound of formula [■] is usually obtained as a racemic mixture. When obtaining an optically active form of the compound of formula [■], the intermediate obtained in each intermediate step is subjected to optical resolution, separated by chromatography, or the intermediate compound is produced by asymmetric synthesis. It can be produced by using an optically active intermediate obtained by.

For example, the formula [■] can be produced as described above.
In an animal experiment using rats, the thiaprostaglandin derivative of the present invention shown by has a blood pressure lowering effect due to a blood vessel wall dilation effect. Several of the compounds of the invention are useful as medicines, for example in the treatment of hypertension in humans.

Blood pressure lowering effect test: The blood pressure lowering effect is measured by fixing male Wistar rats weighing 250 to 350 g in a dorsal position under anesthesia with bentoparbital sodium. Blood pressure is recorded on a siborigraph using a pressure transducer by inserting a polyethylene catheter into the femoral artery.

The test drug is administered intravenously through a cannula inserted into the femoral vein, and intraarterially administered through a cannula inserted into the aortic arch from the right carotid artery.

The test drug is dissolved in 99% ethanol at a ratio of 5q/R1, and when used, it is further diluted with physiological saline so that the ethanol concentration is 6q or less.

Table 1 below shows some of the experimental results.

Furthermore, the thiaprostaglandin derivative of the present invention represented by formula (I) suppressed the occurrence of experimental ulcers in rats due to gastric mucosal damage caused by the administration of non-steroidal anti-inflammatory drugs such as indomethacin. It is useful as a preventive and therapeutic agent for gastric ulcers.

Ulcer development suppression effect test: ST D-Wi 5tar (ST) weighing approximately 180g
Experiments will be conducted using male rats.

The test drug was dissolved in 95'Ir (v/v) ethanol (5Tq/-j) L, KO15 C'M immediately before use.
With a solution containing C and 0.5% 'f'ween 80! I
! ! Prepare a cloudy solution and administer. 0.5% CMC for control group
A solution containing 0.5% Tween 80 and 0.5% Tween 80 is similarly administered.

After the rats were fasted for 24 hours (however, water intake was ad libitum), indomethacin was subcutaneously administered as a 5% sodium bicarbonate solution (40+v/2
m/~). The test drug is orally administered 10 minutes before indomethacin administration. The dose is 5yl/K9. Seven hours after administration of indomethacin, the rats are sacrificed by cervical dissection.

The stomach was removed, 10 d of physiological saline was injected into the cavity, and the stomach was immersed in 5% formalin solution for 15 minutes to fix it, then an incision was made along the large river side, and the tumor was found in the glandular stomach area. The length of each hemorrhagic layer (mm) was measured under a stereomicroscope,
The sum is the ulcer coefficient. In order to facilitate the measurement of the length of the ulcer, 20 minutes before sacrifice, the animal is anesthetized with urethane and 2% Pontamine Sky Blue 6B solution is injected into the tail vein. The ulcer incidence inhibition rate (correspondence) is calculated using the following formula.

Table 2 below shows some of the experimental results.

Table 2 Furthermore, since the thiaprostaglandin derivative of the present invention represented by the formula CD exhibited a platelet aggregation inhibitory effect using rabbit platelet-rich plasma, it is useful as a therapeutic agent for, for example, human thrombosis.

Platelet aggregation inhibitory effect test: 3.8q6 sodium citrate 1 was administered to the carotid artery via the carotid artery under anesthesia using male male rats weighing around 3 KSI.
Collect blood so that 9 volumes of blood were obtained.

r, p, m, I Centrifuge for 9 minutes and collect the supernatant to obtain platelet-rich plasma (PRP).

Agglutination tests were performed using a Payton agglomerator according to the method of Born, using PRP400 in siliconized cuvettes.
Add 50μI of the test drug dissolved in 0.1M phosphate buffer (PH7,4) and heat at 37°C, 1000r, p, m.
After 1 minute under constant stirring, add 0.2 μ/1 solution of collagen.
Platelet aggregation is induced by adding at and reacted for 5 minutes. The control group received 0.1 M I as a substitute for the test drug.
Add 50 μt of J acid buffer and proceed in the same manner.

The agglomeration suppression rate is calculated using the following formula.

(Maximum aggregation rate of control group) Table 3 below shows some of the experimental results.

Table 3 The formula [■] thiaprostaglandin derivatives of the present invention are useful for the prevention and treatment of these symptoms as agents for treating hypertension, thrombosis, and gastric ulcers, as shown in the above test results. It is.

The compound of trial formula [I] can be used in the form of a free acid or in the form of pharmaceutically acceptable metal salts, ammonium salts, quaternary ammonium salts, esters (see the definition of M in formula [I]), etc. It can be used as a treatment agent for the above treatment.

These compounds of formula CI) can be used alone or in any dosage form in admixture with other pharmaceuticals or any pharmaceutical carriers, diluents or other formulation auxiliaries.

Examples of oral dosage forms include tablets, granules, powders, hard capsules, soft capsules, suppositories, galenic preparations, and oral liquid preparations.

Tablets and capsules for oral administration may be in metered dosage form, with binders such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone, and lubricants such as magnesium stearate, talc, polyethylene glycol or Silica, excipients such as lactose, sugar 1. It may contain corn starch, calcium phosphate, sorbitol or glycine, disintegrants such as corn starch, calcium carboxymethyl cellulose, or acceptable wetting agents such as sodium lauryl sulfate. Tablets may be coated using conventional coating methods. A coloring agent, a flavoring agent, a flavoring agent, etc. can be added as necessary. As an injectable preparation, it can be packaged in ampoules containing a fixed dose, or in multi-dose, 4-dose containers with additives such as preservatives and solubilizing agents.

The formulations may be suspensions, solutions, oily or aqueous emulsions, and may contain additives such as suspending or dispersing agents. Examples of the liquid medium used in such dosage forms include organic solvents such as water, ethanol, glycerin, ethylene glycol, and polyethylene glycol.

Administration can be carried out by various injection methods such as intravenous injection, subcutaneous injection, intramuscular injection, or oral administration.

The effective dosage for humans of the compound of formula [I] is approximately 3,000 to 3,000 kg per day! 1llO1OO1
~1000~ can be given. These dosages can be determined as appropriate depending on the patient's medical condition, age, body weight, and administration method. Some of the preferred compounds included in this invention are described in the Examples below, and the Example O product is a mixture of all optical isomers produced by the process described in this invention. The present invention includes all optical isomers of the compounds shown in these Examples, mixtures of each optical isomer in arbitrary proportions, racemic compounds, 13.14-dihydro derivatives of these compounds, ester derivatives at the carboxyl group,
Also included are pharmaceutically acceptable salts and the like. These compounds included in the present invention, including optical isomers, include PGE,
It is named as a derivative of The reason why the absolute coordination of optical isomers is not specified is that the present invention includes all optical isomers and mixtures thereof in arbitrary proportions.

In addition, specific examples of A, W, M, R, and R1 in the formula CD shown in the following formula CI) compounds of the present invention and their production examples are shown by the example numbers in the table below.

Table A: Hydrogen atoms (Example, 5. 6. 7. 8. 9. 10. 1
1゜12, 13. 14. 15. 16. 17.
18°19, 20. 21. 22. 23. 2
4. 25°26, 27. 28. 29. 30.
31. 32°33, 34. 35. 36. 3
7. 38. 39°40, 41. 42. 43.
44. 45. 46°47, 48. 49. 5
0. 51. 52. 53゜54.55.112,1
13,114,115゜116.117,118,11
9,120°121.122,123,124,125
゜126.127, 128, 129, 130゜131.
144) Hydroxyl group (Example, 61762, 63, 64, 65°66, 6
7, 68. 69. 70. 71. 72°73,
74. 75. 76, '77, 78. 79°6
0, 61, 62. 63. 64. 65. 66°67, 68. 69. 70. 71. 72. 7
3゜74, 75. 76, 77, 78. 79.
80°81, 82. 83. 84. 85, 86
．． 87°88, 89. 90. 91. 92.
93. 94°95, 96. 97. 98. 99
．． 100°101, 102. 103. 104.
105°106, 107. 108. 109.
132°133, 134. 135. 136. 1
37°138, 139. 140. 141. 14
2゜145, 146. 147) Protected hydroxyl group (Example, 59 (b), 60 (b)) W:
CHzGHz-group (Example, 112. 113. 114. 115゜1
16.117,118,119,120°121.12
2,123,124,125°126.12'7,12
8,129,130゜131.132,133,134
．． 135°136.137,138,139,140
゜141.142,144,145,146゜147) -CH=CH- group (Example, 5. 6. 7. 8. 9. 10. 1
1゜12, 13. 14. 15. 16. 17.
18°19, 20. 21. 22. 23. 2
4. 25°26, 27. 28. 29. 30.
31. 32°33, 34. 35. 36. 3
7. 38. 39°40, 41. 42. 43.
44. 45. 46°47, 48. 49. 5
0. 51. 52. 53゜54, 55. 59(
b], 60(b), 61. 62°63, 6
4. 65. 66, 67, 68. 69°70,
71. 72. 73. 74. 75. 76°7
7, 78. 79. 80. 81. 82. 83
゜84, 85. 86. 87. 88. 89.
90°91, 92. 93. 94. 95. 96
．． 97°98.99,100,101,102,10
3.104,105,106,107.108°109
) M: Hydrogen atom (Example, 7. 18. 19. 20. 21. 2
2゜2.3, 26, 27, 28, 29, 30, 3L32
, 33. 34. 35. 36. 37. 38°39, 40. 41. 42. 43. 44. 4
5゜46, 47. 48. 49. 50. 51.
52゜53, 54. 55. 62. 68. 6
9. 70°71, 72.73.74. 75.76,
77°78, 79.80.81.82.83.84°8
5, 86.87.88.89.90.91゜92, 93
．． 94.95.96.97.99゜101.102,1
03,104,105゜106.107,108,10
9,114°116.117,118,119,120
゜121.123, 124, 126, 127゜128.
129,130,131,132゜133.134,1
35,136,138°139.140,141,14
2,144゜145.146,147) Pharmaceutically acceptable metal ions, ammonium ions
(Example, 15o) Quaternary ammonium ion derived from primary to tertiary amine (Example, 148) Quaternary ammonium ion derived from basic amino acid
(Example, 149) C1 to C6 linear, branched or cyclic alkyl group (Example, 5. 6. 8. 9. 10. 11.
12゜13, 14. 15, 16, 17, 24, 25
゜59(b), 60(b), 61, 63, 64, 65゜66.67.98. 100,112.1'13°11
5.122, 125, 137) R: C, ~C8 linear, branched or cyclic alkyl group (Examples, 5. 6. 7. 8. 9. 10. 1
8°1.9. '20. 21. 22. 23.
24. 25°26, 59(b), , 60(b)
, 61. 62. 63°64.65, 66.67
．． 68,69,70゜71.72,73,74,75,
76.77°115.116,117,118. 11
9゜120.132,133,134.13.5゜13
6.144) Adamantyl group (Example, 11, 27.78) Group -R20R3 (where R7 and R5 are C1-C1 straight chain or branched alkyl group) (Example, 15.16
．． 17. 34. :35°36, 37. 38
．． 39. 40. 41. 42°43, 44.
45. 46. 47. 48. , 49°50, 5
1. 52. 53. 54. 55. 85°86,
87. 88. 89. 90. 91. 92°9
3, 94. 95. 96. 97. 98. 99
゜100.101, 102, 103, 10.4゜105
．． 106,107,108,109゜123.124,
125. ．． 126,127゜128.129,130,
131,140°141.142,145,146,1
47) Aryloxy lower alkyl group in which the aryl group may have a substituent) (Example, 12. 13. 14. 28. 29.
30°31, 32. 33. 79. 80. 81
．． 82°83.84. 112,113,114,1
21°122.137,138,139) R1: Hydrogen atom (Example, 6. 7. 8. 9. 10. 11.
12゜13, 14. 15. 16. 17. 18
．． 19°20, 21. 22. 23. 24.
25. 26°27, 28. 29. 30. 31
．． 32. 33°34, 35. 36. 37.
38. 39. 40°41, 42. 43. 44
．． 45. 46. 47°48, 49. 50.
51. 52. 53. 54°55, 61. 62
．． 63. 64. 65. 66°67, 68.
69. 70. 71. 72. 73°74, 75
．． 76, 77, 78. 79. 80°81,
82. 83. 8'4. 85. 86. 87°8
8, 89. 90. 91. 92. 93. 94
゜95, 96. 97. 98. 99. 100°101, 102. 103. 104. 105゜1
06, 107. 108. 109. 113°11
4, 115. 116. 117. 118°119
．． 120. 121. 122. 123°124,
125. 126. 127. 128°129, 1
30. 131. 132. 133°134, 13
5. 136. 137. 138°139, 140
．． 141. 142. 144°145, 146.
147) Protecting group for hydroxyl group (Example, 5.59(b), 60(b), 11
2) Example 1 Dissolve 900 ~ of sodium in 360 d of ethanol to prepare nitromethane 142.2,9,5.5-dimethyl-2-
39.6 g of cyclobentenone was added and stirred at room temperature for 29 hours. The reaction solution was poured into 900ml of 10N hydrochloric acid and extracted with methine chloride/.

The extract was washed with brine, dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography (silica gel, n-hexane: ethyl acetate - 6:1). , 33.36 g of 2-dimethyl-4-ditromethylcyclopentanone were obtained. mp56°-58°C (methylene chloride-〇-hexane recrystallization).

Next, this 2,2-dimethyl-4-ditromethylcyclopentanone 30.65 L ethylene glycol 1B, 6
7g, paratoluenesulfonic acid monohydrate 0.68. A solution of 170 m7 of benzea was refluxed for 13 hours using a DeanStark apparatus. The reaction solution was washed with water, the washings were extracted again with benzene, all the benzene layers were combined, washed with an aqueous sodium bicarbonate solution and brine in that order, dried over anhydrous magnesium sulfate, and concentrated to give 2.2- 38.817 ml of dimethyl-4-ditromethylcyclobentanone ethylene acetal was obtained.

Next, 270 my of sodium methoxide was added to a solution of 1.076 g of this 2,2-dimethyl-4-ditromethylcyclopentanone ethylene acetal and a 10-proof methanol solution, and the mixture was cooled on ice to form a 25.54 titanium trichloride aqueous solution 12 ．．
1 Ml and 9.2 g of ammonium acetate, water”, J, Q
ml of the mixture was added and stirred at -2° to 10°C. Next, it was extracted with ethyl acetate, and the extract was washed with a 5-carbon aqueous solution and brine in that order, and dried over anhydrous magnesium sulfate. 776 square meters of non-ethylene acetal was obtained.

2720.1?30,1480°139G, 1370,1160°1075.1020°NMR (cDrl, -TMS) a: 0.95.
t, o2(3E(X2.S) CE(,X21.
60 2.27 (4H, m) Cs
H, Cs H2,47-3,13 (I H, m)
c4-H3,93(4E(,S)
-〇CH,CI(to -9,67(IH,d,J
==1.6H2) CHO Example 2 60 Sodium hydride 0.90g, methylene chloride 23
Cool m to 8°C, add 5.50 g of dimethyl 2-oxo-3,3-dimethylheptylphosphonate, 1 methylene chloride
2 m of the solution was added dropwise at 8° to 20° C. over 4 minutes. 2 more
Stirred at 2-27°C for 1 hour. Cool the reaction solution and add 2,2
-Dimethyl-4-formylcyclopentanone ethylene acetal 3.37y1 A solution of 124 methylene chloride was added at 5°
It was added dropwise at ~10°C, and further stirred at 14° to 19°C for 90 minutes.

The residue obtained by concentrating the reaction solution was subjected to column chromatography (silica gel, n-hexane: ethyl acetate - 12:1).
2,2-dimethyl-4-(3-oxo-
4.75 g of 4,4-dimethyl-1-octenyl)-cyclopentanone ethylene acetal was obtained. mp27-2
9℃1470.1385,1365゜1155.1080,1045 NMR1045N 3-TMS) δ: 0.40-2.45 (13H, m) 1.00 (6H,,,S) 1.10 (6H,S) 2.50 3.10 (IH, m) C4H
3.90 (4H,s) -0C
HICH20-6,43 (IH, d, J=15Hz
) 27th CH=6.92 (IF(,d,dJ
=15,7H2) 1'-position CH=Example 3 Lithium aluminum hydride 584Tng, ether 4
0m was cooled to -70°C and 2,2-dimethyl-4-(3
A solution of 4.75 ji of -oxo-4,4-dimethyl-1-octenyl)-cyclopentanone ethylene acetal and ether 33a was added dropwise at -70° to -66°C, and the mixture was further stirred at -70°C for 90 minutes.

Then, methanol was added dropwise and water was further added.

The reaction solution was filtered, and the filtered residue was washed with ether and combined with the previous filtrate to separate the layers. The aqueous layer was extracted again with ether, all ether layers were combined, washed with brine, dried over anhydrous magnesium sulfate, concentrated and 2,2-dimethyl-4-
(3-Hydroxy-4°4-dimethyl-1-octenyl)-cyclopentanone ethylene acetal 4.48. @
I got it.

1385.1365, 1160゜1080.975 NMR (CDCI 3-TMS) δ: 0.50-2.17 (14H, m) 0.80, 0.83 (3Hx2, s) 0.9
7 (6H, s) 2.30-2.97 (I H, m) C
,-H3,90(4H-s) 0CHzC
HzD-3,20-4,17(IH,m)
3' position CH5,34-5,67 (2H, m)
CH=CH Example 4 (a) 2,2-dimethyl-4-(3-hydroxy-4,
4-dimethyl-1-octenyl)-cyclopentanone ethylene acetal 4.48 g, acetone 120 g, IN
- A solution of 10.81f of hydrochloric acid was refluxed for 80 minutes. The reaction solution was concentrated, and the resulting residue was diluted with brine and extracted with ether. The ether layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated to obtain 3.91 g of 2,2-dimethyl-4-(3-hydroxy-4,4-dimethyl-1-octenyl)cyclopentanone. Ta.

(b) 2,2-dimethyl-4-(3-hydroxy-4,
4-dimethyl-1-octenyl)-cyclopentanone 3
．． In a solution of 84 g, 43 g of methylene chloride, and 114 g of para-toluenesulfonic acid monohydrate, 1.
82.9', a solution of 1 g of methylene chloride at 27° to 28.
The mixture was added dropwise at 5° C. and further stirred for 40 minutes.

Next, 5ml aqueous sodium bicarbonate solution was added to separate the layers, and the aqueous layer was further extracted with methylene chloride. All methylene chloride layers were combined, dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography (silica gel 1, n-hexane: c-tyl acetate-10:1). Then 2.2-
Dimethyl-4-(3-tetrahydropyranyloxy-4
, 4-dimethyl-1-octenyl)-cyclopentanone 4.17 g was obtained.

ax 1.380, 1360, 1115° 1020.975 NM[CDCCDCl5-Tδ: 0.85, 0.90 (3HX2, s) 1.0
3, 1.08 (3HX2, s) 0.50-3
．． 10 (20FT,, m) 3.20-4.1.3 (
3H,m)4.47-4.73 (IH,m)5
．． 23-5.67 ('2H, m) CH=C
H Example 5 Diisopropylamine 1.025g, THF 9.9
ml solution of n-butyllithium hexane solution 6.33
m1 (1,6M solution) was added dropwise at -40° to -15°C,
The mixture was further stirred at -40° to -30°C for 40 minutes.

Next, 1.48 g of 2,2-dimethyl-4-(3-tetrahydropyranyloxy-4,4-dimethyl-1-octenyl)-cyclopentanone, 7.4 m of HMPA, and THFl
,? / solution was added dropwise at -30° to -40°C, and then
Stir for 5 minutes.

Next, dimethyl 6.6'-dithiodihexanoate 3.
27 g was added dropwise at -60 to -28°C and further stirred for 2 hours.

IN-hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium bicarbonate solution and a saline solution, dried over anhydrous magnesium sulfate, and the residue obtained by distilling off the solvent was subjected to column chromatography (silica gel, n-hexane:ethyl acetate-8=1). Well purified 10,10,16,16-tetramethyl-11-deoxy-7-thia-PGE,
An oil of 15-tetrahydropyranyl ether methyl ester 1.14.9 was obtained.

Example 6 10.10,16.16-tetramethyl-11-deoxy-7-thia-PGE, 15-tetrahydropyranyl ether methyl ester 1.10,9°methanol 1
A solution of 4d1 para-toluenesulfonic acid monohydrate 257~ was allowed to stand at 1°C for 16 hours. The reaction solution was poured into sodium bicarbonate solution and extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue obtained was purified by column chromatography (silica gel, n-hexane: ethyl acetate-5-1) to obtain an oily 10 , 10
゜16.16-Tetramethyl-11-deoxy-7-thia-PGE, methyl ester 0.92.9% was obtained.

NMR (CDCl2-TMS) δ: 0.30-3.50 (36F(,m)3.65-4.
10 (LH, m) C,5-H3,67(
3f(,S) C00CR.

5.50-5.93 (2H, m) C'
H=CH Example 7゜10.10,16.16-titramethel-11-theoxy-7-thia PGE, methyl ester 670 ~, methanol 14,4 7. IN-Caustic soda aqueous solution 3.21
The mixture of
The mixture was further left at 0° C. for 16 hours.

Water and IN-hydrochloric acid were added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the residue obtained by distilling off the solution was subjected to column chromatography (silica gel, n-hexane:ethyl acetate-2).
:1) to produce oily 10.10,16.16-
Citramethyl-11-deoxy-7-thea-PGE, 5
I got 22■.

NMR (CDC13-TMS) δ: 0.30-3.50 (35H:m >3.65 4.
10 (IH, m) C15H5, '50-
5.93 (2H, m) Cf(=CH6,
16(2H, bs) OH,, C0OH 2,2-dimethyl-4-formyrunclopentanone ethylene acetal shown in Example 1, formula CII and Example 2 to Examples using the compound shown in Formula CII and Niharu] Various compounds shown up to Example 55 below were produced by subjecting to the same reactions, extraction, purification operations, etc. as shown up to Section 7.

Example 8 10.10-dimethyl-11-deoxy-7-thia-P
GE1-methyl ester NMR (CDCI, -TMS) δ: 0.50-3.30 (32F(,m)3.66
(3H,s) C00CHs3.85-4
．． 40 (IH,'m) c,, -H5,
50-5,90(2H, m) CH=CH
Example 9 10.10.16-drimethyl-11'-deoxy-7
-Thia-PGE1-methyl ester NMR (CDCI,
-TMS') δ: 0.50-3.30 (34H, m) 3.65 (3F(,s) COOC
Hs3.75-4.20 (tH, m) c
15 H5,45-5,90 (2H, m)
CH=CH Example 10 10.10-dimethyl-11-deoxy-15-cyclohexyl-7-thia-16,17,18°19.20-
Pentanol-PGE, methyl ester NMR (CDC1,-TMS) δ: 0.30-3.40 (32H, m) 3.66
(3H,s) C00CH33,60
4,10(IH,m) Cps H5,
40-5,90(2H,m) CH=CH
Example 11 10.10-dimethyl-11-deoxy-15-adamantyl-16,17,18,19,20-pentanol-PGE1 methyl ester NMR (CD(1,-TMS
) δ: 0.50-4.10 (37H, m) 3.66 (3H, s') C00C
Hs5.40-5.90 (2H, m) C
H=CH Example 12 10.10-dimethyl-11-deoxy-16-phuninoxy 7-thia 17.18,19°20-tetratrue PGE, -methyl ester NMR (CDC13-TM
S) δ: 0.80-3゜40 (21H, m) 3.63 (3Hs s) C00CH
s3,. 80 4.25 (2 Hym) c
,6 H4,254,80(IH,m)C
sy, H5,50-6,10(2H,m)
CH=CH6,50-7,50(5H,m)
Aromatic iH Example 13 10.10-dimethyl-11-deoxy-16-, (P
-fluorophenoxy)-7-thia-17°18.19
．． 20-tetratrue PGE1-methyl ester NMR (CDCI, -TMS) δ: 0.50-3.50 (21H, m) 3.65
(3H, s) C00CHs3.70 4
．． 20 (2H, m) c16 H4,2
0-4,85 (IH, m) Cps H5
,50-6,20(2E(,m) CH
=CH6,50-7,35(4H,m) Aromatic 3JH Example 14 10.10-dimethyl-11-deoxy-16-(m-
Chlorophenoxy)-7-thia-17゜18.19,2
0-tetratrue PGE, -methyl ester NMR (CDCI3-TMS') δ: 0.50-3.
50 (2iH, m) 3.65 (3FI, S)
C00CI(.

3.60 4.30 C2t(,m) C+
e H4,30-4,90(IH,m>
C,, -FT5.50-6.20 (2H, m)
CH=CH(6,25-7,70(4H,m)
Aromatic iH Example 15 10,10,16,16-tetramethyl-11-deoxy-17-oxa-7-thia-PGE.

Methyl ester NMR (CDCI, -LTMS) 0.50-3.70 (34[(,m)3.65
(3H, s) C00CHs3.80 4
．． 20 (1[(,m) Cxi H5,
50-5,90(2H,m) CH=CH Example 16 10.10,16.16-tetramethyl-11-deoxy-18-oxa-7-thia-PGE.

-Methyl ester NMR (CDCI3-TMS) δ: 0.50-4.30 (35H, m) 3.66
(3H,s) C00CH35,50-
6,0(21(,m) CH=CH Example 1
7 10.10,16,16-tetramethyl-11-deoxy-19-oxa-7-thia-PGE.

-Methyl ester NMR (CDCI, -TMS) δ: 0.30-4.00 (32H, m) 3.30 (3H, s) C0CHs
3.64 (3F(,S) C00C
H35,40-5,90(2F(,m)
CH=CH Example 18 10.10-dimethyl-11-deoxy-7-thia-P
G.E.

NMR (CDCI, -TMS) δ: 0.40-3.
40 (31H, m) 3.90 4.40 (1,H, m) C+
5 H5,50-5,83(2H,m)
CF(=C1(6,0(2H, bs), O
H,C00Ff Example 19 10.10-dimethyl-11-deoxy-7-thia-2
0-True PGE.

NMR (CDCI, -TMS) δ: 0.40-3.40 (29H, m) 3.90 4.40 (IH, m)' CI
! I H5,50-5,84 (2H, m)
CH=CH6,02(2H,bs) OH,C
0OH Example 20 10.10-dimethyl-11-deoxy-7-thia-2
1,22-dihomo-PGE.

NMR (CDCI, -TMS) δ: 0.30-3.45 (35H, m) 3.90-4.40 (IH, m) C15
H5,50-5,82(2H,m)', CH=C
H6,0(2H,bs) OH,C0OHExample 21 10.10.16-drimethyl-11-deoxy-7-
Chia-PGE1 NMR (CDCI3-TMS) 23: 0.30-3.50 (33H, m) 3.80-4.20 CIH, m) c,,
H5,50-5,85(2H,m)C
H=CF(6,05(2Lbs) OH,C0
OH Example 22 10.10,16.16-Tetramethyl-11-deoxy-7-thia-21-homo-PGE.

NMR (CDCI, -TMS) δ: 0.30-3
．． 50 (37H, m) 3.64 4.09 (IH, m) C+5
H5,50-5,92 (2H, m)
CF(=CH6,20(2H2bs) OH,
C0OH Example 23 10.10.17-drimethyl-11-deoxy-7-
Thea-PGE.

NMR (CDCI, -TMS) δ: 0.30-3.49 (33H, m) 3.90 4.
40 (IH, m) C+a H5,
50-5,90(2H,m) CH=CH
6,02(2F(,bs) OH,C0OH
Example 24 1-0, 10-dimethyl-11-deoxy-16°1
6-propano-7-thia-PGE, ethyl ester NMR (CDCI, -TMS) δ: 0.30-3.50 (39H, m) 3.80 4.
40 (3H, m) C10FT, C00C
H2C5,50-5,93(2H,m) CH
=CH (Example 25 10,10-dimethyl-11-deoxy-15-cyclopentyl-7-thia-16,17,18°19.20
-Pentanol-PGE, ethyl ester NMR (CDcI, -TMS) δ: 0.30-3.50 (33H, m) 3.7Q 4.40 (3H, m) c', f
l H, C00CH2C5,50-5,90(2H,
rn) CH=CH Example 26 10.10-dimethyl-11-deoxy-15-cyclohexyl-7-thia 16,17,18°19.20-
Pentanoru PGE.

NMR (CDCI, -TMS) δ: 0.30-3.
5 (31H, m) 3.6 4.1 (LH, m) c,,
H5,40-5,90 (2H, m)
CH=CH6,30(2H,bs) OH,C
0OH Example 27 10.10-dimethyl-11-deoxy-eradamantyl-16,17.1 g, 19.20-pentanol-PGE.

NMR (CDCI3-TMS') δ: 0.30-3.50 (35H, m) 3.40 3.90 (IH, m) Cu
H5,45-5,85(2H,m) CH
=CH4,75(2H,bs) OH,C0O
H Example 28 10.10-Dimethyl-11-deoxy-16-funinoxy7-thia 17,18,19°20-tetratrue PGE1 NMR (CDCI, -TMS) δ: 0.70-3.
50 (20H,m) 3.68-4.32 (2f(,m) C,6-
H4,40-4,73(IH,m) c,, -
H5,60-6,10(2H,m) CH=CH
6,40-7,60(7H,m) OH,C0OH
, Aromatic 3WH Example 29 10.10-dimethyl-11-deoxy-16-(p-
:yfluorophenoxy)-7-thia-17゜18.19
．． 20-Tetra True PGE.

NMR (CDCI, -TMS) δ: 0.5 0-
3.5 0 (20H, m) 3.70 4.20
(2H=m) C+a H4,204,80(
IH, m) C+s H5,60-6,10(
2H, m) CH=CH6,50-7,35
(6H, m) OH, C0OH, aromatic ring Example 30 10.10-dimethyl-11-deoxy-1-6-(m
-chlorophenoxy)-7-thia-17°18.19.
20-Tetra True PGE.

NMR (C'DC13-TMS) δ: 0.50-3.
50 (20H, m) 3.60 4.30 (2,
H, m) c, 6 H4.30 4.90
(IH', m) C15H5,50-6,20
(2H, m) CH=CH6,25-7,70
(6H, m) OH, C0OH, aromatic ring H Example 3
1 10.10-dimethyl-11-deoxy-16-(m
-)lifluoromethylphenoxy)-7-thia-17,
18,19,20-tetratrue NMR (CDCI, -
TMS) δ: 0, 50-3.5・0 (20H, m) 3, 62 4
．． 31 (2H,m) c,a H4,3
0 4.75 (IF(,m) C,s
H5, 23-6.10 (2H, m)
CH=CH6, 40 (2H,l)S)
OH, COOH6, 90-7.87 (4H, m)
Aromatic ring H Example 32 10,10-dimethyl-11-deoxy-16-(m
-hydroxyphenoxy)-7-thia-17,18,1
9.20-Tetra True PC)E.

NMR (cDc I, -TMS) δ: 0, 50-
3.50 (20H, m) 3,60 4.20 (2H, m) C+
a H4, 29-4.89 (IH, m)
C,, -H5, 5 0-6.2 0 (2 H
, m) CH=CH6, 25-7.60
(7H, m) OH, COOH, aroma 3Ji
I (Example 33 10,10-dimethyl-11-deoxy-16-(m-
methoxyphenoxy)-7-thia-17.

18, 19.20-Tetra True PGE.

NMR (CDCI3-TMS) δ: 0, 50-3.50 (20H, rn) 3, 79
(3H,,5) OCH33,70 4
．． 20 (2H, m) C10 H4,
2 8 4.8 8 (L H, rn)
C 1y H5, 51-6.19 (2
H, m) CH=CH6, 26-7, 65 (
6H, m) OH, COOH, aroma 3JH Example 3
4 10,10-dimethyl-11-deoxy-17-oxa-7-thia-PGE1 NMR (CDCI, -TMS) δ: 0,3 0-4.52 (30H, m)5,5
0-5.90 (2H, m) CH=CH6
, 60 (2H, bs) OH, COOH
Example 35 10,10-dimethyl-11-deoxy-17-oxa-7-thia-21-homo-PGE.

NMR (CDCI3-TMS') δ: 0, 30-4, 51 (32H, m) 5, 51-5.95 (2H, m) CH=
CH6, 80 (2H, bs) OH, C
OOH Example 36 10,10.16-drimethyl-11-deoxy-17
-Oxa-7-thia-PGE.

NMR (CDCI, -TMS) δ; 0, 30
'-4.35 (32H, m)5, 45-5.90 (
2H,m) CH=CH6,80 (2
H, bs) OH, COOH Example 37 10,10,16.19-tetramethyl-11-deoxy-17-oxa-7-thia-PGE.

NMR (CDCI, -TMS') δ: 0, 34-4.35 (34H, m) 5, 46-5.95 (2H, m) CH=
CH6, 60 (2t(, bs)
OH, COOH Example 38 10,10,16,16-tetramethyl-11-deoxy-17-oxa-7-thia-PGE1NMR (C
DCI3-TMS') δ: 0.30-3.65 (33H', m) 4.00
(LH, d, J=6Hz) c15 H5,5
0-5,90(2H,m) CH=CH
6,70 (2H, bs) OH, C0OH
Example 39 10.10-Dimethyl-11-deoxy-18-oxa-7-thia-PGE.

NMR (CDC13-TMS) δ: 0.30-4.40 (30H, m) 5.46-5.95 (2H, m) CH=
CH6,5Q (2H, bs) OFT,
C0OH Example 40 10.10-Dimethyl-11-deoxy-18-oxerf-thia-21-homo-, P()E.

NMR (CDCI, -TMS) δ: 0.30-3.
70 (31H, m) 3.94 4.45, (IH, m) CI
! l H5,50-5,94 (2H+m)
cF(=cE(6,65(2H,bS)
OH,C0C)H Example 41 10.10.16-1limethyl-11-deoxy-18
-Oxa-7-thia-PGE1NMR (cDc 13-
TMS) δ: 0.35-3.80 (31H, m) 3.85 4.30 (IH, m) C10
85,47-5,90(2H,m) CH=
CH6,75 (2H, bs) OH, C0OH
Example 42 10.10.16-4limethyl-11-deoxy-18
-Oxa-7-thia-21-homo-PGE1NMR (C
DCI3-T"MS) δ: 0.30-3.70 (3
3H,'m) 3.80 4.30 (LH,m)
C+s H5,45-5,90 (2H', m)
CH=CH6,0(2H,bs) O
H,COOH Example 43 10.10,16.16-tetramethyl-11-deoxy-18-ogycer 7-thia PGE1NMR (CDC
I, -TMS) a: 0.30-3.80 (33
H, m) 3.80-4.20 (IH, m) C,,
-H5,50-6,0(2H,m) CH=
CH6,60(2H,bs) OH,C0OH
Example 44 10.10,16.16-tetramethyl-11-deoxy-18-oxa-7-thia-21-homo-PGE.

NMR (CDCI, -THE) δ: 0.30-&80 (35H, m) &8l-416 (LH, m) 011-H5,4
7-5,96(2B', m) CH=CH6
,70(2H,ba) OH,COOHExample 45 10.10-dumethyl-11-deoxy-19-oxa-7-thia-PGE1 NMR (CDCI, -TM,S) δ: 0, 35-170 (26B , m) 3.37
(3H, a) OCR.

3.9O-440(IR, tyt) C,, -H5
, 49-5, 84 (2B, sold) CH=CH6.
60 (2H+ bs) 0H1COOH Example 46 10.10-dumethyl-11-deoxy-19-oxa-7-thia-21-homo-PGE1NMR (cix:
l, -Tus) δ: 0, 35-3.70 (31H
, m ) 3, 91-4.39 (I H, rn )
G'l! -H5, 41-5,94 (2H, m)
CH=CH6,10(2H,bs) 0H=CO
OH Example 47 10.10.16-drimethyl-11-deoxy-19
-Oxa-7-thia-PGE1 NMR (CDCI, -TMS) δ: o, as-a, 7o (2sH, m) 3.36 C3H, s) OCH.

3.80-4.20(1,if,tx) C8,-
Hs, 45-5.90. (2H, m) CH=CH
7,0(2H,b s )OH,C0OHExample 48 10.10.16-1limethyl-11-deoxy-19
-Oxa-7-thia-21-homo-PGE.

NMR (CDC1, -TMS) δ: 0,30-:l(,70(33H,m)3,80-
420 (I H, ML) Css-'5, 5
0-5.90 (2H, m) CH=CH6,9
0(2H,b s ) OH,C0OHExample 49 10.10,16.16-tetramethyl-11-deoxy-19-oxa-7-thia-PGE1NMR (CDC
1,-TMS) δ: 0,4-170 (30H, tn) &37 (3ff, s) 0CHs3.7O-
410 (IH, m) C15-H5, 45-5,9
5(2H, rn) CH=CH6,90(2H,
ba) OH-COOH Example 50 10.10,16,16-tetramethyl-11-deoxy-19-oxa-7-thia-21-homo-PGE.

NMR (CDCL, -TMS) δ: 0, 30-4.30 (36B, rn) 5.50
-6.0 (2H, m) CH=CH6, 90(
2Hr b') OH-C00H---'-1=
Disintegration = -, Example 51 10.10-Dimethyl-11-deoxy-20-oxa-7-thea-21-homo-PGE.

NM, R(CDCl, -TMS) δ80, 4-3.7
0 (H, m) 3.36 (]#, s) 0CR83,9
0-4,40(111,m) C1,-H2SO-
s, 90(2H,rn') CH=CH6,02(
2H, b s ) OH, COOH Example 52 10.10-Dimethyl-11-deoxy-20-oxa-7-thia-21,22-sohomo PGE.

NMR (CDC1, -TMS) δ: 0.35-3.70 (33H, m) 3, 9.0-440 (L H, m) C,, -
H5, 45-5,86 (2B, m) CH=
CH6.65 (2H, b s ) 0LCOO
H Example 53 to, 1o, to-drimethyl-11-deoxy-20
-Oxa-7-thia-21-homo-PGE1NMR (C
DCI, -TMS) δ: 0.4-3.70 (30B', information) 3.36
(3H, s) OCH.

&80-4.20 (IH, Shu) C1a ”5,
48-5.86 (2H, ra) CH=CH6
,60(2H, bs)0LCOOHExample 54 10.10,16.16-tetramethyl-11-deoxy-20-oxa-7-thia-homo-PGE.

NMR (CDCI, -TMS) δ: 0, 35-3.70 (32H, rn) 3.35
(3H, g) 0CH33,70-4,10(I
H, m) C1s ”5, 40-5.95 (
2H, m, ) CH=CH6,90(2,#,
b s ) OR, COOH Example 55 10.10,16.16-tetramethyl-11-deoxy-20-oxa-7-thia-21,22-dihomo-P
G.B.

NMR (CDCI, -TMS) δ; 0.30-3. ．． 70(37,H,m)3,70-41
5 (L H, m, ) Cs2-H5, 50-
5,85 (2Hr m) CH-CH7,0 (2
H, b s ) OH, C0OH Example 56 Dissolve 0.45.9 i of sodium in 180 d of ethanol, then dissolve in nitromethane 7143.9,4-acetoxy-
5,5-Tmethylcyclopent-2-en-1-one 3
0.34 F was added, and the mixture was stirred at 28° C. for 3 hours under an argon stream. The reaction solution was poured into 1ON hydrochloric acid at 20° C. or below, and extracted using methylene chloride. The extract was washed with brine, dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography (silica gel, methylene chloride: ethyl acetate-2011) to 2°2
-Tmethyl-3-acetoxy-4-nitromethylcyclopentanone 27.60,! I got i'.

Then 2,2-dumethyl-3-acetoxy-4-nitromethylcyclopentanone27. OL benzene 150m,
Ethylene glycol 15, o, ii+, para-toluene sulfone enemy 1 Mizugaki 0.45 & Dean 5ta
An RLC device was attached and the mixture was refluxed for 8 hours.

Water and benzene were added to the reaction solution to separate the layers, and the benzene layer was washed with Sgt. , methylene chloride:ethyl acetate-50
11) to produce 2,2-methyl-3-acetoxy-4-nitromethylcyclopentanone ethylene acecool.

15.16 g of trans isomer, 7.32 Ii of cis isomer
Obtained.

Next, 2,2-dimethyl-3-acetoxy-4-nitromethylcyclopentanone ethylene acecool (trans form), 5,211. 50 g of methanol, 4 g of potassium carbonate
．． 0 g of the mixture was stirred at 25-30°C for 5 hours. 5Bmi of IN-hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the residue obtained by condensation was subjected to column chromatography (silica gel, methylene chloride-ethyl acetate-20+).
1) 2,2-dimethyl-3-hydroxy-4-ditromethylcyclopentanone ethylene acetal (trans isomer) was prepared by J) IF 272. ! I got i+.

Next, a solution of 1.00 g of this 2,2-dimethyl-3-hydroxy-4-nitromethylcyclopentanone ethylene acecool (trans isomer) and 8 me methanol was cooled to 5°C, and 0.288 g of sodium methoxide was added. Ta. Next, ammonium acetate & 421, water 32g, 25.5
A 10.6M titanium trichloride aqueous solution was added at 0°C or lower under an argon stream, and the mixture was further stirred at -5°C for 90 minutes. The reaction solution was extracted with ethyl acetate, and the extract was diluted with sodium bicarbonate solution. The aqueous layer was extracted again with ethyl acetate,
All ethyl acetate solutions were combined, washed with brine, dried over anhydrous (tit magnesium), and the solvent was evaporated to 2.
-dimethyl-3-hydroxy-4-formylcyclopentanone ethylene acetal (trans form) so o
I got a by.

1475.1310, 1225, 1070°, 95
5,735 NMR (CDCL, = TMS) δ: 0.92.0.98 (3HX2.8) 1.93-2.28 (2ff, I) 2.40-3.00 (1#, I) C ,H3,4
2 (I If s bs ) OH3,93C4H
,s) OCR,CH,03,8O-410(1
#, ff1) C, -H9,77CIH,ci,
, J=IHz) CHO Example 57 Somethyl 2-oxo-3-methyl-heptylphosphonate) 5.32. Sodium methoxide L16J9e was added to a solution of 50 mJ of SJ and TliF and stirred at 13°C for 40 minutes.Next, 2,2-dimethyl-3-hydroxy-4
-Formylcyclopentanone ethylene acecool (trans form) 3. 30 L THF heart fluid was added and stirred at 59-10°C for 2 hours.

Next, vinegar vLso* was added, and water and methylene chloride were added to separate the layers. The aqueous layer was further extracted with methylene chloride, all the methylene chloride layers were combined, dried over anhydrous magnesium, concentrated, and the resulting residue was subjected to column chromatography (
Oily product of 2,2-dimethyl-3-hydroxy-4-(3-oxo-4-methyl-1-octenyl)-cyclopentanone ethylene acetal prepared from silica dal, n-hexane-ethyl acetate) K. 2.74.9 was obtained.

NME (CDC13-TMS) δ: 0.6q-:3. oc23u, m) 3.67 (IH, d, J='1Hz) C, -H3, 93
(4H,s) OCR',CH,06
,23(IM, d”, J=l 6Hz) 2
' position CH = 6.8TCIH, dd, J = 16.7H2)
L' position CH-Example 58 (a) Lithium aluminum hydride 0.33 P,
Cool 20 ml of ether and add 2.72 g of 2,2-dimethyl-3-hydroxy-4-(3-oxo-4-methyl-1-octenyl)-cyclopentanone ethylene acetal.
, a solution of ether 15- was added dropwise at -659°C to -50°C, and the mixture was further stirred at -709°C to -40°C for 210 minutes. Next, 45 meters of methanol and 40 meters of ether! were added in this order and filtered. Water was added to solution F to separate the layers, and the aqueous layer was further extracted with ether.

All the ethers I@ were combined, washed with brine, dried over anhydrous sodium chloride, and the solvent was distilled off to give 2.2-methyl-3-hydroxy-4-(3-hydroxy-4-methyl- An oily substance zs2y of 1-octenyl)-cyclopentanone ethylene acecool was obtained.

(6) 2,2-dimethyl-3-hydroxy-4-(3-
Hydroxy-4-methyl-1-octenyl)-cyclopentanone ethylene acetal 2.62.9°Acetone 6
A solution of 6 ml of hydrochloric acid was allowed to stand at 0° C. for 16 hours. Next, the solvent was distilled off and the mixture was extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give 2゜2-dimethyl-3-hydroxy-4-
(3-Hydroxy-4-methyl-1-octenyl)-cyclopentanone oil 237I was obtained.

NME (CDC1, -TMS) δ: 0, 30-4.20 (2611, m) 5.40-5
．． 90 (2H, ff1) Example 59 (α) 2,2-dimethyl-3-dimethyl-4-(3
-hydroxy-4-methyl-1-octenyl)-cyclopentanone 848η% DM'F 4ml, imidazole 5
71 of trimethyl-t-butylchlorosilane in a solution of 40q
0 +l1ii' was added and stirred at 5°C for 8 hours. After cooling, water was added and extracted with ethyl acetate. Wash the extract with sodium bicarbonate solution and then water.

The residue obtained by drying with anhydrous magnesium sulfate and condensation was purified by column chromatography (silical% n-hexane-ethyl acetate) to give 2,2-dimethyl-3-(
dimethyl-t-butylsilyloxy)-4-(3-(dimethyl-t-butylsilyloxy)-4-methyl-1-
octenyl)-cyclopentanone oil L48811
I got it.

(b) Diisopropylamine 908■, THF8.
The solution of 4d was cooled to -30°C, 5.44 ml of n-glylithium hexane solution (1.65 mol solution) was added, and the mixture was further stirred at -40°C for 30 minutes. Next, 2,2-dumethyl-
3-(dimethyl-t-butylsilyloxy)'-4-(
3-(dimethyl-8-butylsilyloxy)-4-methyl-1-octenyl)-cyclopentano 7L4701%
HMPA6.5nl.

A solution of THFL1 was added dropwise and heated at -389°C to -32°C.
Stirred for 0 minutes. Then dimethyl 6.6'-sothiodihexanoate) 2.89I! Reduced at -a 2L-2a℃,
The mixture was further stirred at -26L8°C for 200 minutes.

Then IN-salt 1216.7d was added and extracted with methylene chloride. The extract was dried with anhydrous magnesium sulfate, and S
The residue obtained by +M+'i was subjected to column chromatography (
10,10.16-4limethyl-7-thia PGE purified by silica gel, n-hexane-ethyl acetate),
11.692η of an oily product of 15-bis(dimethyl+t-f methylsilyl ether) methyl ester was obtained.

NMR (CDCl2-TMS) δ: o, 08 (12R, g) 5i (CHs).

0,9 (18Hrs) SiC(CHs
) 30.3-4.3 (33ff, m) 3.66 (3fi, s) C00CHs5, 4-
6.0 (2H* rn ) CH=CH Example 6° (α) 2,2-dimethyl-3-hydroxy-4-(3
-Hydroxy-4-methyl-1-octenyl)-cyclopentanone Z 3 sy, methylene chloride 25, tsukura doluene sulfonic acid 1 water fA 9 my TRF
Combine 15 mil of O and cool, and add 2,3-sohydrobirane 1.82.1? It is! '--90 at 2℃
Three parties agitated. Next, aqueous sodium bicarbonate solution was added to loosen the mixture, and the aqueous layer was further extracted with methylene chloride. All the methylene chloride layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
,2-methyl-3-tetrahydropyranyloxy-4
-(3-tetrahydropyranyloxy-4-methyl-1
-octenyl)-cyclopentanone oil 3.92&
I got it.

(b) Diisopropyl/l/humin 2-721. T.H.
Cool the F25 solution to −35°C under a stream of argon,
tL-Butyllithium hexane solution wx6. smHLes
The mixture was stirred at -40'C for 30 minutes. Next, 2,2-dimethyl-3-tetrahydropyranyloxy-4-(3-tetrahydropyranyloxy-4-
Methyl-1-octenyl)-cyclopentanone 3.92
A solution of 19.6 mJ of HMPA and 3.3 ml of THF was added dropwise and stirred at -40°C to -30°C for 80 minutes. Next, trimethyl 6.6'-dithiosohexanoate & 67g
was added dropwise at -309--22°C and then -259-10
The mixture was stirred at ℃ for 200 minutes. Next, IN-Salt 950mA! was added and extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated, and the resulting residue was purified by column chromatography (silica gel% n-hexane-ethyl acetate) to obtain 10.10.16-)limethyl-7-thia-PGE111. .15-Bis(tetrahydropyranyl ether) methyl ester oil! 84.9 was obtained.

NMR (CDC13-TM'S) δ: 0, 3-43 (49H, rn) 3.67 (3H, s) C00CH35
,4-6,0(2H,m)CH
=CH Example 61 10.10.16-drimethyl-7-thia PGE11
1,15-bis(tetrahydropyranyl ether) methyl ester zso, p% vinegar W-Water-THFC3+ 1) Add a solution of 28 to 45? It was left at -47°C for 7 hours.

Next, water was poured into a knife and extracted with ethyl vinegar. The extract was dried over anhydrous magnesium sulfate and concentrated, and the resulting residue was purified by column chromatography (silica gel, n-hexane-ethyl acetate) to obtain 10°10, , 16-)limethyl-7-thia PGE. , methyl ester oil L
42g was obtained.

Nu R(CDC1,-TME)δ! 0.3O-43 (35B, normal) 3.67 (3H, s) C00C Crow 5-5
0-6-0 (2Hp trb ) CH=CH Example 62 Water bath obtained by stirring 5 g of lipase powder produced by culturing NR400, a new strain similar to the Rhizopus genus, and 50 g of water at 0° C. for 1 hour. Liquid 38WLe,McLlvai
ng buffer (p#7) 2a4 solution, 10°10.16-1
-Limethyl-7-thia PGE ethyl ester 500
The mixed solution (2) was stirred at 34-37°C for 27 hours.

After cooling, saline and ethyl acetate were added and the mixture was filtered and separated. The aqueous layer was further extracted with ethyl acetate, all ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was subjected to thin layer chromatography (silica gel, methylene chloride!ethyl acetate-1+2). Purified by 10,1
0.16-)su)f Roux? - Cheer PGE, I) Oil 17011v was obtained.

nMR (CDCt, -TMS) δ: 0.30-4.60 (33#, m) 5.0-6.50 (sff, m) CH=CH,O
K, C0OH 2,2-dimethyl- shown in Example 56
Using 3-hydroxy-4-formylcyclopentanone ethylene acetal, a compound represented by formula [1111 and formula [v]], the same reaction, removal and purification operations as shown in Example 57 to Example 62 were carried out. Accordingly, various compounds shown in Examples 1o9t below were prepared.

Example 63 10.10.16-trimethyl-fu-thia-PGE1 ethyl ester NMR (CDCI, -TMs) δ: 0, 30-460 (40H, rn) 5, 40-6.
0 (2H, rn) CH=CH Example 64 10.10.16-) Limethyl-7-thia PGE1 isopropyl ester NMR (CDCL, -TMs) δ=0.30-
4.60 (41H, m) 4.60-5.40 (IH', m) C00CH5, '4
0-6.0 (2H, m) CH=CH Example 65
-10.10.16-)limethyl-7-thiaPGE
, s g c-butyl ester NMR (CDCL
, -TMS) δ: 0.30-4.5 (43H, m) 4, 55-5-25 (IHe rrb) C
00CH5, 39-6,02 (2H, rn) C
H=CH Example 66 10.10.16-1-limethyl-7-thia PGE, n
-Hexyl ester NMR (CDCI3-TMS) δ; 0,30-4.60 (48H, m)5,38-a
O3 (2E, s) CH=CH Example 67 10.10.16-trimethyl-fu-thia-PGE1 cyclohexyl ester NMR (CDC13-TMS) δ: 0, 30-4.60 (45H, rn) 460-5.
40 (if, m) s, 40-6.10 (2H, m) CH=C
H Example 68 10.10-tumethyl-7-thia-PGE.

NMR (CDCl, -TMS) δ: 0.30-3.50 (29ff, bath) 3.50-4.50 (2H, m) C,, -LC8
, -H5゜o -6,40c5hfSatoru) OH,C00
LCH=CH Example 69 10.10-Tmethyl-7-thia-20-true GE1 NM' R (CDCl, -TMS') δ: 0, 30
-3.50 (27H, m) C50-4,50 (2H, m) C11-H, C1, -
H5,0-6,39(sff',yn)OLCOOLC
B=CH Example 70 10.10-tumethyl-7-thia-21t22-dihomo-paEI NMR (CDCI, -TMS) δ: 0.30-3.50 (33H, normal) 3.50-4.48 ( 2H,m) C,1-H%C
1,-H5,0-6,38(5H,m') OH,C0
OH,CH=CH Example 71 10.10.16-drimethyl-7-thia21-homo-PGEl NMR (CDC1,-TMS) 2g 0, 30-460 (35H, m) 5.0-6.45 (5H ,m)OHlCOOIi%
CH=CH Example 72 10, Lo, 17-4limethyl-7-thia-21-homo-PGEI NuR (CDCl, -TMS) δ: 6.3o-tso (3sff, s) 5,o -6,50 (5H, m) 0LCOOH,CH
=CH Example 73 10.10.16.16-titramethyl-7-thiaP
G.E.

NMR (CDC1,-TMS) δ: 0.30-C45 (33ff, Satoru) 3.45-440 (2H, nL) to HH,01
m-H5,23(3H, b s ) 0LCOOH5,
40-6,O(2H,rn) CH=CH Example 7
4 10=10+'i6,16-tetramethyl-thia-
21-Homo-PGE1 NMR (CDCI3-TMS') δ: 0.30-3.45 (35H%rrL) 3.45-4.
40C2Hr'rrL)C11-LC1!1"5.25
(3H, bs) 0LCOOH5, 40-6,02
(2H, rrL) CH=CH Example 75 10.10-Tmethyl-15-cyclobutyl-7-thea-16,17,18,19,20-pentanol-PGE
1 N /It R (CDC13-TMS) δ: 0.50
-3.45 (25H, m) 3, 45-4.40C2H, barbarian) C8, -LC
,,-Hs,04 (3H,ba) OH,C0
0E5.45-6-0 (2Ht LI'rL)
CH-CH Example 76 10.10-dimethyl-15-cyclopentyl-7-thea-16,17,18,19120-pentanol-PG
E1 NMR (CDCl, -TMS) δ: 0.40-3
．． 45 (27H, m) 3.45-440 (2H, yyt) C11H, C
,, -C5,03(3H,b s ) 0LCOOH
5,45-6,0(2H,m) CH=CH Example 77 10.10-dimethyl-15-cyclohexyl-7-thia-16,17,1g, 19.20-pentanol-P'
G.E.

NMR (CDCIs-TMS) δ: o, 4o-3.5 (29H, yx) 3.5'-4,3Czli, m)C,, -H-C1,-
C5,05(ah,ba) OH,C00H5-45
-5-95(2H+rn) CH=CH Example 78 10.10-Tmethyl-15-adamantyl-7-thia-16,17,18,19,20-pentanol-PGE
1 NMR (CDCI3-TMS') δ: 0, 50-3.40 (33H, rn) 3.40-3
．． 90 (2B, m) C,, -H,C,ll-C
5,01 (311r bs) OB, Coon5
, 40-5.90 (2H,rn) CH=CH
Example 79 10.10-tumethyl-16-funinoxy7-thia 17,18.19',20-tetratrue PGE.

NA (R (CDC1s-TMS) δ: 0.50-3.40 (18H, m) 3.40-4.30 (3H, Satoru) C,1-LC
Yu. -H4, 40-4,73 (L H, m)
C15-C5, 60-6,10 (2H, m)
CH=CH6,40-7,45(8Hyrn)O
H, COOH, aromatic mH Example 80 10.10-dimethyl-16-(P-fluorophenoxy)-7-thia-17,18,19,20-tetratrue PGE1 NMR (CDCI, -TMS") δ-o, 5o-a4o(1sH, m) 3.40-4.20 (3H, rrt) C11
-LC,6-H4,20-4,80(IH', 7
71. ) C1, -C5, 50-a 10 (2
H, m) CH=CH6,50-7,40(7B
, sound, ) Oli, C0OH, aromatic ring H Example 8
1 10.10-dimethyl-16-(m-riC11lfphenoxy)-7-thia-17,18,19,20-tetratrue PGE.

0.50-3.40 (18Bgrn) 3.50-4.30 (3H,rn) C11-
H%Cto-H4, 30-490 (IH,m)
C11-H.

s, 5o-6,2o(zH,yx) CH=CH6
,25-7,70('?H,m) 0LCOOL Aromatic iH Example 82 10.10-dumethyl/l/-15-(rn-=trophenoxy)-7-thia-17,18119,20-tetratrue PGE .

NMR (CDCL, -TMSJδ: 0.50-3.40 (18H, fn,) 140-4.3
,0 (3H,m,) Cu-LCt6H4,28
−4,76(I H, yn ) Cts −Hs,
56-6.14 (2#, regular) CH=CH6,40 (3H
, bs) 0LCOOH6,7s-s,os(4B*
m) Aromatic Ring H Example 83 10.10-Tmethyl-16-(tn-hydroxymethylphenoxy)-7-thia-i7,18.

19.20-Tetratrue PGE1 NMR (CDCI, -TMS) a: 0.50-&40 (18B, m) 140-430 (3H, m) c, -H, c,,H
4,40-4,90C3H,rn) c,,LCH,
05,61-6,08(6H,m)□H,c00Lc
H=cH6,72-7,56(4H,m) Aromatic Ring H Example 84 10.10-trimethyl-16-(m-methylfuunoxy)-7-thi7-17.18,19.20-tetratrue PGB.

NMR (CDCI3-TMS') a: 0.50-3.40 (18H, m) 3,40-490 (7H, ym) '1□-i
f, ni',, -HlCl. -H, CM.

5,50-a20(2H,rn)CH
=CH6,50-7,45(7If,rn) 0
LCOOH, aromatic ring H Example 85 10.10-tumethyl-17-oxa-7-thia PGE NMR (CDC1, -TMS) δ: 0, 30-4, s o (29Hs rn') 5.0
-6.40 (sH, 7)? , ) OH%C0OH,
CH=CH Example 8G 10.10.19-1 Limethyl-17-oxa-7-thia-PGE□ NAi R (CDC13-TMS) δ: 0.30-4
．． 50 (31H, m) 5, 0-6.40 (5Hyrn) 0LGOO
R,CH=CH Example 87 10.10-dimethyl-17-oxa-7-thia-21
-Homo-PGE.

NuR (CDC1s-TMS) δ1 0.30-4.50 (31H, ff1) 5.0-6.5
0 (5H, m) 0LCOOLCH=CH Example 8
8 10.10.16-1 Limethyl-17-oxa-7-thia-PGE1 NMR (CDCI, -TMS) lj: 0.30-4.50 (31H, m) 5.0-6.50 (5H, m) 0LCOOH,C
H=CH Example 89 10.10.16-1 Limethyl-17-oxa-7-thia-21-homo-PGE.

NMR (CDCL, -TMS) δ: 0.3O-440 (33B, m) 5,00-6.50 (5E, m) 0LCOO
LCB=CH Example 9°10.10,16.16-titramethyl-17-oxa-7-thia-PGE.

NMR (CDC!, -TMS) δ: 0, 20-4.40 (33H, m) 5°25
(3H,bg) OH,C00H5,50-6,0(
2H, rn) CH=CH Example 91 10110.16.16-tetramethyl-1 fuoxerfuthier 21-homo-PGE.

NMR (CDC13-TMS) δ: 0.20-4.40 (35H, tyt) 5.22
C3H, bs) OH, C00H5-50-6-0(
2HT rn ) CH=CH Example 92 10 , . 10-dimethyl-18-oxa-7-thia-
P.G.E.

NMR (CDCL, -TMS) 6fold 0, 30-4.40 (291-1, m) 5.20
(aH, bg) 0LCOOH5, 50-5
,85(2H,m) CH=CH Example 93 10.10-Tmethyl-18-oxa-7-thia-21
-Homo-PGE1 N MR (CDC1s TM S) δ: 0, 30-4
．． 42 (31H, m)5.25 (3H, bs
) 5,50-5.86 (2H,rn) CH=C
H Example 94 10.10.16-)dimethyl-18-oxurf-thia-PGE NMR (CDC1,-TMS) δ; 0.30-4.40 (314, m) 5.20 (3H, bs) 5,50-aO(2H,m)CH=CH Example 95 10.10.16-)dimethyl-18-oxaaf-thia-21-homo-PGE.

NMR (CDCl, -TMS) δ: 0, 30-4.
4.0 (33B', m) 5.2! o (3
H, b1+) 011. C00H5,50-6,0(
2Hr m) CH-CH Example 96 10.10,16.16-titramethyl-is-oxa-7-thia-PGE□ NMR (CDCl, -TMS) δ; o, 3o-t
4o (3aH, m) 5.40 (3H, b s ) 0LCOOH5
-50-6,0(2Bsrn) CH=CH Example 97 10.10,16,16-tetramethyl-18-oxaaf-thia-21-homo-PGE.

NMR (CDC13-TMS) δ: 0, 30-4.40 (35H, m) 5.4g
(3H, bs) 0LCOOH5,50-6,0(2
Hr rn ) CH=CH Example 98 10.10-Tmethyl-19-oxa-7-thia PG
E, ethyl ester NMR (CDC13-TMS) δ: 0, 50-440 (33Hp'In) 140
(3H, s) 0CfIss, s o -s,
98 (2H, rn) CH=”Example 99 10.10-Tmethyl-19-oxa-7-thia-21
-Homo-PGB.

NMR (CDC1, -TMS) δ: 0, ao-4,4o (axH, rrL) 5.22
(3H, b s ) OL”OR5, 50-6,02
(2H,rn) "'=CH Example 100 10,10.16-)dimethyl-19-oxerf-thia-PGE, ethyl ester NMR (CDCl, -TMS) δ: 0,50-4.40 (35H, m ) 3.36
(3H, s) OCH.

5, 48-6.0 (2H, m) CH=CH
Example 101 10.10.16-Dolimethyl-19-oxa-7-thia-21-homo-PGE1 NMR (CDC13-TMS) δ2 0,30-4.40 (33H, m, )5.10
(3H, ba) 0LCOOH5, 50-6,02
(2H, rn) CH=CH Example 102 10.10,16.16-tetramethyl-19-oxurf-thia-PGE.

NMR (CDC13-TMS) δr 0.50-4.40 (3(lH, m): 11.40 (3Hts) OC
H470 (3H, bs) OH, C00H5,
40-6,0 (2ff, m) CH=CH Example 103 10.10,16.16-tetramethyl-19-oxaaf-thia-21-homo-PGB.

NMR' (CDC1, -TMS)a: 0.30-4.40 (35H, m) 4.60 (3H, bs) OR', C00
H5,40-6,0(2H,m) CH=CH
Example 104 10.10-tmethyl-20-oxa-7-thia-21
-Homo-PGE.

NMR (CDC1, -TMS) δ2 0.50-4.40 (28H, yyz)"A, 40
(3H,s) OCR.

5.10 (3H, bs) 0H-COO
H5,45-6,0(2H,fn) CH=
CH Example 105 10.10-dimethyl-20-oxa-7-thia-21
,22-dihomo-PGB.

NMR (CDC13-TMS) δ: 0.30-4.40 (33H, m) 5.0'-6,40C511, m,') OH,C
0OH,CH=CH Example 106 10.10.16-drimethyl-20-oxa-7-thia-21-homo-PGE1 N'MR (CDCl, -TMS) δ: 0, 40-4
．． 40 (30H, m) 3.38 (3H, S)
OCR.

5.0-6.5O(5H,m,)OH,C0OH,CH
=CH Example 107 10.10.16-Dorimethyl-20-oxa-7-thia-21,22-duhomo PGEINbfR (CDCl
, -TMS) δ: 0.30-4.40 (3s#, y
x) 5.0-6.50 (5#, m) 0LCOOLCH
=CH Example 108 10.10,16.16-tetramethyl-20-oxurf-thia-21-homo-PGE.

NMR (CDC13-TMS) δ: 0.5O-440(32H, m) 3.40 C3H,s) 0CR4,65(
3B, ba) OH,C00H5,40-6,0
(2H, rn) CH=CH Example 109 10.10,16.16-tetramethyl-20-oxaaf-thia-21,22-dihomo-PGE.

NMR (CDCl, -TMS'l a +0.3O
-440 (37H, m) 4.70 (3Hj+g) OR', C0
0H5,40-6゜OO(2H,m) CH
=CH Example 110 As shown in Examples 2 to 4 using 2,2-methyl-4-formyl-cyclopentanone-ethylene acetal and dimethyl 2-oxo-3-phenoxypropylphosphonate as starting materials. 2,2-dimethyl-4-(4
-phenoxy-3-tetrahydropyranyloxy-1-
butenyl)-cyclopentanone was produced.

NMR (, CDC1, -TMS) δ: 0.58-3.16 (114, m) L03.1.08 (6H, a) 3.22-4.08 (4H, ya) 4, 08-5. 00 (2H, m) 5.43-5.87 (2H, rn) CH=C
H6, 71-7,47 (5H, m) aromatic ring H
Example 111 2.2-methyl-4-(4-phenoxy-3-tetrahydropyranyloxy-1-guthynyl)-cyclopentanone 1.14 (1, methanol 30%, 10%) F radium carbon powder 620mm A catalytic hydrogenation reaction was carried out at room temperature using hydrogen gas in a conventional manner. Reaction 0. The solvent of the p liquid obtained by filtration was distilled off to give 2,2-methyl-4-(4-phenoxy-3-tetrahydropyranyloxybutyl)-
Cyclopentanone 965~ was obtained.

NMR (CDCI, -TMS) δ: 0, 60-2.90 (21H, rn) 3, 10-4
．． 40 (511, rn) 4, 50-5.00 (I
Iit' m ) 6.65-7.50 (in 5,
77Z) Aromatic fpH Example 112 Duinprobylamine 660~. Add n-butyllithium hexane to 5 ml of THFL bath solution under an argon stream.
4. , I Id (1,6 molar solution) from −28° to
temperature at -26°C, and further at -329°C for 30°C.
Stir for 1 minute. Then 2,2-tmethyl-4-(4-phenoxy-3-tetrahydropyranyloxybutyl)-cyclopentanone 965 m? , HMPA5-1TBF
The bath solution of 30% was added dropwise and stirred at -499°C to -45°C for 14 minutes, and then for 60 minutes at -419°C. Then, 208.9% of dimethyl 6.6'-dithioduhexanoate was added.
Add a solution of Ti1Fl to -4O! 120 at -3O℃
The mixture was stirred for a minute. Next, 71 g of IN-soap and 20 g of water were added in this order, and the mixture was extracted with ethyl acetate. Extraction W- + water washing, anhydrous W
The iron content obtained by drying and concentrating with tm magnesium was purified by column chromatography (silica dal, n-hexane:ethyl acetate-4:1) to obtain 10.10-methyl-
II-deoxy-13,14-dihydro-16-funinoxyfuthia 17,18,19°20-tetratrue PGE115-tetrahytone.

628 g of pyranyl ether methyl ester oil was administered.

NMR (CDC13-TMS) δ: 0.60-3.0 (29H, m) 3.0O-440 (6H, m) 3.67 C3H, s) C00CHs4.
60-4.97 (14pm) 6,65-7.60 (5B, m) Aromatic destruction H Example 113 10.10-Tmethyl-13,14-dihydro-16-
Fuetsukishifuchia 17 , 18 .

19. A solution of 20-tetratrue PGE, 15-tetrahydropyranyl ether methyl ester, 4609° of methanol, 53 mf of paratoluenesulfonic acid and 1 water was allowed to stand at 0°C for 16 hours.

Next, water was added to the mixture, and the mixture was extracted with methylene chloride.

The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The resulting residue was purified by column chromatography (silica gel, n-hexane: ethyl acetate - 2:1) to obtain 10.10- Dumethyl-j3, 14-dihydro-16-funinoxyfuthia 17.18,19.
20-tetratrue PGE1 methyl ester 264m?
I got it.

NMR (CDC1s-TMS) δ: 0.70-3.40 (25H, ff1) 3.40-4.
50 (3H, rn) C1, -H-C1, -H3,6
4(3R,s) C00CR.

6.60-7.50 (5H, m) Aromatic ring H Example 114 10.10-dimethyl-11-deoxy-13°14-
dihydro-16-funinoxy 7-thia 17.18,
19.20-Tetratrue PGE1 methyl ester 26
4η, methanol 6g, IN-caustic soda 1.25r
The solution of rLl was left at 09-5°C for 110 hours. Next, IN-Shioba 26m1. 7 ml of water was added in this order, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was subjected to thin layer chromatography (silica gel, chloroform:acetone-2:
1) to give 10.10-methyl-11-deoxy-13,14-dihydro-16-funinoxyfuthia 17,18. -19.20-Tetra True PGE
1134■ was obtained.

NMR (CDC13-TMS) δ: 0.6-3.0 (23H, m) 3, 17 (IH, d, J=6Hz) C, -
H3,60-4,40(3H,m) C,, -LC,,
-H6,34(2H,b s ) OH,COOH
6,60-7,70(5H,rn) Aromatic ring H 2,2-methyl-4-formyl-cyclopentanone-ethylene acetal shown in Example 1, formula [■] and formula [
Example 2 to Example 4 using the compound represented by
(b) '! Various compounds shown in Examples 111 to 114 or Example 61 were subjected to the same reactions, extraction, purification operations, etc. as shown in Examples 111 to 131 below.

Example 115 10.10-tmethyl-11-deoxy-13°14-
Dihydro-7-thia PGE, methyl ester NMR (CDCt, -TMS) δ; 0.4-10 (35H, m) 3.16 CIH, d, J = 611z) C, -H3,
67 (3H, s) C00CH.

&3-3.9 (1#, m) Cl1l −
H Example 116 10.10-tmethyl-11-deoxy-13°14-
Dihydro-7-thia-21,22-dihomo PGE1 NMR (CIX:l, -TMS) δ: 0.4-3. o(3L&,yy+,,)3.16C
IH, d, J = 6Hz)C,, -H3,3-3,9(I
H, m) C,, -H6,3(2H, bs
) 0H1COOH Example 117 10.1θ, 16-)rifthyl-11-deoxy-13
, 14-dihydro-7-thia-PGE.

NMR (CDCt, -TMS) δ: 0.4-3.0 (36R, m) 3.16 (IH, d, J = 6Hz) Ca-H3.2
-3.7(LH,m) C,, -H6,3(
2B*ba) OR, COOH Example 118 10.10,16.16-tetramethyl-11-deoxy-13,14-sohydro-7-thia GEI NMR (CDC1,-TMS) δ: 0.4-3.0 (3811, m) 3,o -3,6(2B', rrb)C, -HlCl
, -H6,2(211, b s ) OH',
C0OH Example 119 10;10-dimethyl-11-deoxy-13°14-
dihydro-15-cyclopentyl-7-thia-16,1
7,18,19,20-pentanol-PGE.

NMR (CDCI, -TAfS)) δ: 0.5-3.0
(32H, m) 3.0-3.6 (2H, m) C8-H,, C1,-
H6,3(2Q b s) OR, C0OIi Example 120 10.10-Tmethyl-11-deoxy-13°14-
Dihydro-15-cyclohexyl-7-thia-1617
18,19,,20 pentanol) GE NMR (CDCI, -1'Ms) δ20.5-&O
(34HXm) &0-3.6 (2B, m) C3-LC,, -H6
,3(,2J bs)OHXCOOHExample 121 10.10-dimethyl-11-deoxy-13°14-
Dihydro-16-(P-fluorophenoxy)-7-thia-17,'18,19,20-tetratrueP
G.E.

NMR (CDCI, -This)) δ: 0.6-3.0
(231iXm) 3.17 (1#, d, J=6Hz) C8=H&6-4
．． 4 (374' m) Crs -H, Cts -H
6,32C2H(b s) OH, Coon6.50-
7.35 (4H,m) Aromatic'iJH Example 122 10.10-Tmethyl-11-deoxy-13°14-
Dihydro-16-(m-chlorophenoxy)-7-thia-17,18,19,20-tetratrue PGE, ethyl ester NMR (CDC et al.-TMS) δ: 0.6-3.4 (2sBXm) 3.6 -4.5 (5A m) C,, -H,C,6-
11, C00CR.

6.25-7.70 (4B, m) Aromatic ring H Example 1
23 10.10-tmethyl-11-deoxy-13゜14-
Dihydro-17-oxa-7-thia-PG1 1JMR (CDC13-TMS) δ: 0.40-3.90 (34bem) 6.32 (2H, b s) OR, C'OOE Example 124 10. 10.16-)dimethyl-11-deoxy-13
, 14-dihydro-17-oxa-7-thia-PGE.

NMR (CDC13-TMS) δ: 0.35-&80 (36HXm) 6.30 (2H, b s) 0HXCOOE Example 1
25 10.10,16.16-titramethel-11-deoxy-13,14-dihydro-17-oxa-7-thia PGE, methyl ester NMR (CDC13-TMS)
δ: 0.40-3.70 (39#, m) 3.67 (3
11Xs) C00CR.

Example 126 10.10-dimethyl-11-deoxy-13°14-
Dihydro-18-oxurf-thea-PGE1 NMR (C1) lIl-TMS) δ: 0.4
-3.9 (34IiXm) 6.30 (24b s) OB, C00B decoration example 1
27 10.10.16-1-dimethyl-11-deokine-1
3.14-dihydro-18-oxa-7-thia-PGE
.

NMR (CDCI, -TMS)) δ20.4-3.8 (36H, m) 6.20 (2 bg) OH, COOH Example 128 10.10,16.16-tetramethyl-11-deoxy -13,14-dihydro-18-oxerf-thia-
P.G.E.

NOR (CDC1, -TMS) δ: 0.30-3.70 (384m) 6.20 (2BXb s) 0HXCOOH Example 1
29 10, No-dimethyl-11-deoxy-13°14-
Dihydro-19-oxurf-thia-PGE1 NMR (CDCI, -TM; S) δ: 0.5-3.9 (31#, m) 3.36 (3HXs) 0CHs 6.30 (2 or 8) OI C0OH Example 130 10,10,16-trimethyl-11-deoxy-13,14-dihydro-19-oxurf-thia-P
G.E.

NMR (CDC13-TMS) δ: 0.5-3.8 (33bem) 3.35 (34s) 0CH3 6,26 (211,b s) OE, C00E Example 131 10.10,16.16- Chitramethel-11-deoxy-13,14-dihydro-19-oxa-7-thia-
21-Homo-PGE.

NMR (CDCI, -TMS) δ: 0.3-3.8 (40 beads) 6.30 (2B, bs) Oli, 2,2-methyl-3-hydroxy shown in C00B Example 56 4-
Polmyl-cyclopentanone ethylene acetal, formula [
111) and Example 57 to Example 59(a)-1-'c', Example 60 using the compound represented by the formula [vm]
((Z), Examples 114 to 114 from Example 11i, or the following Example 142 with the same reaction, extraction, and input operations as shown in Examples 61 and 62.
Various compounds shown above were produced.

Example 132 10.10-tumethyl-13,14-sohydro-7-thia PGE.

N1vill (CDC2, -TlvfS) δ: 0.3
-3.9 (35B, m) 5.20 (3#, Xb s) 01iXCOOE Example 133 10.10.16-1 Limethyl-13,14-dihydro-7-thea-PGE.

NMR (CDCI, -TMS) δ: 0.3-3.85 (371i, helmet) 5.2 (3#,, b s) Off, CO'OR
Example 134 10, lo, 16.16-titramethyl-13°14-
Dihydro-7-thia-PGE.

i′vMR(0°DCI3-TMS)δ:0.4-
3.0 (3611, m) 3.0-3.8 (3H, m) C3-HXC,, -B
, C,, -H5,15(3#Xb,9) 0IiX
COOH Example 135 10.10-dimethyl-13,14-dihydro-15-
Cyclopentyl-7-thia-i6,17°18.19.
20-pentanol-PGE.

8MR((,DCL, -TMS)δ:0.5-:A,
0 (30H, m) 3.0-3.8 <31iX Fufu Z, N C, -1
1,C,, -11,C,, -H5,2(3H,b s)
Osho C00B Example 136 10.10-dimethyl-13,14-dihydro-15-
Cyclohexyl-7-thia-16,17°18.19.
20-Pentanolu PGB.

NMR (CDCI3-TMS) δ: 0.5-3.0 (32-Fi, m) 3.0-3.8
(3fi, m) C8-1i, C,, -BXC,
, -H5,2(3fi, bs) OH,C0OHExample 137 10.10-Tmethyl-13,14-dihydro-16-
Fetxy 7-thia 17,18°19-20-tetratrue PGE, ether ester IJMR (CDCI, -'2''MS) δ: 0.6-3.
4 (2THXm) 3.6-4.50 (6H1)n) CB -t
i, C,, -g, C164, COOC; H2 6,60-7,70 (5#Xm) Aromatic fjJR Example 1
38 10.10-dimethyl-13,14-dihydro-16-
(μm fluorophenoxy)-7-thia-17,18,
19,20-tetratrue PGE.

NMR ((, LrC1, -TMS) a: 0°6-1
(211 people ηL) 3.17 (IJ d, J=6Hz,) C3-Ha
fi-4,4(411,m) C,,-11,C,,-
11,, C1, -115,3 (311Xbs) OH,
C00B6.50-7.35 (4HXm) Aromatic 7m Example 139 10.10-dimethy/1=-13,14-sohydro n-1
6-('n-chlorophenoxy)-7-thia-1r,x
g, x9.2o-ter-y, t-rou PGE.

NMR (CDCI3-TMS) a: 0.6-3.0 (2lli, m) 3.16 (L#, d, J-6Hz) C, -IJ
3.6-4.4 (4J4 m) C,, -1i, C
,,-1i, C,,-H5,2(3H,bs)OH,
COOH 6,20-7,7o (4Q rn) Aromatic ring B Example 1
40 10.10-dimethyl-13,14-dihydro-17-
Oxa-7-thia-PGE NMR (C:DC13-TMS) δ: 0.4-3.9 (33B, m) 5.3 (3J bs) OR, C00B Example 141 10.10-Tmethyl-13, 14-dihydro-18-
Oxa-7-thia-jaE.

NMR (CDCI, -TMS) δ: 0.4-3.9 (33H, m) 5.2 (3IiSb s) 01iXCOOH Example 142 10.10.16-)dimethyl-13,14-dihydro 18oxa-7 -Chia-PGE.

NMR (CDCI, -Th1S) δ: 0.4-3J
(35Q m) 5.2 (3B, b s) 0HXCOOH Example 1
43 A catalytic hydrogenation reaction was carried out at room temperature according to a conventional method using 178 ml of the compound of Example 8, 15 ml of acetic acid, 1300 ml of tipalladium carbon powder, and hydrogen gas.

The residue obtained by filtering the reaction solution and removing the solvent from the tear fluid was purified by column chromatography (silica gel, n-hexane: ethyl acetate - 2:1) to obtain the product shown in Example 115. The same compound was obtained as an oil from 102.

Example 144 100 m9 of the compound of Example 115 was subjected to the same reaction, suspension and purification operations as shown in Example 7 to obtain 10.10-dimethyl-11-deoxy-13,14-
Dihydro-7-thia-PGE.

6Q got 1+9.

NMR (CDCI, -TMS) δ: 0.4-10 (34#Xm) 3.16' (lH, dXJ=6Hz) C3-B3.
3-3.9 (1#, m) C, -H6,3 (2H,
b s) OH, COOH Example 145 The compound shown in Example 96 was subjected to the same reaction, extraction and purification operations as shown in Example 143, and 10,
10,16.16-tetramethyl-13,14-dihydro-18-oxa-7-thia-PGE was obtained.

NMR (CDCl, -TA4S) δ: 0.3-3.8 (37H, m) 5.2 (311, b s) 0HSCoon Example 1
46 Using the compound shown in Example 98, the same reaction as shown in Example 143 was carried out, and 10.
10-dimethyl-13,14-dihydro-19-oxa-7-thia-PGE was obtained.

NAiR(C1)C13-TMS')J 20.5-3
．． 9 (30H, m) 3.37 (3H, 5) OCR.

5.3 (3HSb s) Oli, C0OH performance matrix 147 Using the compound shown in Example 102, the same reaction, extraction and purification operations as shown in Example 143 were performed to obtain 10
, 10,16.16-tetramethyl-13,14-dihydro-19-oxa-7-thia-PGI,'' was obtained.

NMR (CDCIs-TMS) δ: 0.5-3.8 (34J m) λ36 (3B, s, OCR,) 5.3 (3B, bs, 0HXCOOE) Example 14
8 Compounds 104~ of Example 22, tris(hydroxymethyl)aminomethane 30.4 m9, and methanol 3d bath solution was fanned and each section was distilled off to obtain tris(hydroxymethyl)aminomethane salt of the compound of Example 22. 132~ was obtained.

NM-R (CD30D-TMS) δ: 0.3-3.4 (35H, m1 3.65 (6B, 8, (-CB20) s) 3
．． 4-4.0 (iHX\C3s -B)5.15 (
7#, s) 5.50-5.90 (2B, 8CH=CIi) Example 149 Product 116 of Example 62 in an aqueous solution of L~lysine 41~
After dissolving m9, it was subjected to freeze-drying according to a conventional method to obtain 157 da of the L-rigid salt of the product of Example 62.

NMR (CD, OD-TMS)) δ: 0.30-3.50 (40HXrn,) 5.15 C
8H, S) 3.5-+, t (zM % Cx+ -H, C15-
H) 5.50-5.84 (2BXm, CH=CH)
Example 150 An aqueous solution of Compound 104 of Example 21 was washed and neutralized with dilute aqueous sodium hydroxide solution under cooling, and then freeze-dried in a conventional manner to obtain sodium salt 109m9 of Compound of Example 21.

NMR (D, O-3-()rimethersilyl)-sodium propionate (-44) J O,3θ-3,50 (33H, rn) 3.80-4°20 (to 1μd"+s-#)4 .7
7 (1be8) 5.50-5.90 (2sho-CH=CH) Example 15
1 A solution of 22.0y of 6'-dithiodihexanoic acid, 200y of methanol, and 1z92y of acetyl chloride was refluxed for 2 hours.

After cooling, water was added and extracted with methylene chloride. The extract was washed with aqueous sodium bicarbonate and then with brine, dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography (silica gel, n-hexane-ethyl acetate) to obtain trimethyl 6. 6'-dithiodihexanoate 18.23
Get y fc.

NMR (CDCl2-TMS) δ: 1.20-2. ．． 0(12B, m) -(CH2)
, CCOO2,07-2,9<8B,? lZ) -
3CE, -1-C1i2COO3,67 (61i', S
) C00CR.

IRvFinnom-l.

a□z, 2950.2860. 1740.1440.1365.1260,1200.
1170゜212-6 Mizuhashidate-cho, Toyama City 4 202 0 Inventor Hiroki Nogami 418 Shinbo, Toyama City 0 Inventor Masahiro Togashi 17 Yuueno, Nakashinyo Gujoichi-cho, Toyama Prefecture 0 Inventor Katsumasa Nagai Mizuochi, Toyama City 92-6 0 Inventor Yutaka Kato - 115-3 Shinjo Ginza, Toyama City ・[Co., Ltd.] Inventor Tetsuo Kakuzaki Toyama Kata Dechi 868 ■) Inventor 1897-0 Asahi-cho Sakai, Shimoshinyo-gun, Taihei Layer, Toyama Prefecture Inventor Hiroshi Bisou 2-34 Tatemachi, Shinminato City 0 Inventor Kumamoto Katsumi 1 531 Nishinakano, Toyama City 0 Inventor Hiroko Murakami 334 Mizuhashi Shinbori, Toyama City 0 Inventor Yoko Kabubu 297-3 Hongo-cho, Toyama City 7

Claims (1)

[Claims] 1. The following formula [■] In the formula, A represents a hydrogen atom, a hydroxyl group, or a protected hydroxyl group, and W represents a group -CH2C)I2- or a group trans-CH
=CH-, M is a hydrogen atom, a pharmaceutically acceptable metal ion, an ammonium ion, a quaternary ammonium ion derived from a primary to tertiary amine, a quaternary ammonium ion derived from a basic amino acid and a C1 to C6 straight chain, branched or cyclic alkyl group, R is a C4 to C8 straight chain, branched or cyclic alkyl group, an adamantyl group, a group R20Rs (Here, R2 and R3 each represent a linear or branched alkyl group of 01 to C7) and an aryloxy lower alkyl group in which the aryl group may have a substituent, and R2 is A thiaprostaglandin derivative represented by the following formula, which represents a protecting group for a hydrogen atom or a hydroxyl group, and the wavy line (-1) in the formula represents an α bond, a β bond, or a mixture thereof. 2. The phenyl group has a substituent selected from the group consisting of aryloxy lower alkyl group in formula [■] OR, halogen, trifluoromethyl, hydroxyl, nitro, lower alkyl, hydroxy lower alkyl and lower alkoxy. The thiaprostaglandin derivative according to claim 1, which is an optionally phenyloxy lower alkyl group. 3. The following formula [■] 1 However, in the formula, A, W, R,, R1 and the wavy line (~) have the same meaning as described for the following formula [I], and the compound represented by the following formula [■] +S\/\ /\/COOM)2... [■] However, in the formula, M represents a C1 to C0 linear, branched or cyclic alkyl group. Characterized by the following formula [I], where A represents a hydrogen atom, a hydroxyl group, or a protected hydroxyl group, and W represents a group -CH2CH2- or a group trans-CH=
CH- represents a hydrogen atom, a pharmaceutically acceptable metal ion, an ammonium ion, a quaternary ammonium ion derived from a primary to tertiary amine, a quaternary ammonium ion derived from a basic amino acid, and Represents a member selected from the group consisting of C1 to C6 straight chain, branched or cyclic alkyl groups, R is a C4 to C8 straight chain, branched or cyclic alkyl group, adamantyl group, group -R20Rs (Here, R6 and R5 are each C1
~ C7 linear or branched alkyl group) and an aryloxy lower alkyl group in which the aryl group may have a substituent, R1 represents a hydrogen atom or a hydroxyl group protecting group, in the formula The wavy line (□) indicates an α bond, a β bond, or a mixture thereof. A method for producing a thiaprostaglandin derivative represented by: 4. In the formula [I], the aryloxy lower alkyl group of OR has a phenyl group carrying a substituent selected from the group consisting of halogen, trifluoromethyl, hydroxyl, nitro, lower alkyl, hydroxy lower alkyl and lower alkoxy. 4. The method according to claim 3, wherein the phenyloxy lower alkyl group is an optionally substituted phenyloxy lower alkyl group.