JPS60149557A - Preparation of prostaglandin derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (Z<1> is carboxyl or protected carboxyl; Z<2> is OH or protected OH; Z<3> is hydroxymethyl or hydroxymethyl having protected OH; Z<4> is H, alkyl or substituted alkyl; Z<5> is H or alkyl; the bond extending from the 5-membered ring in the form of the dotted line is the alpha-configuration). EXAMPLE:(5Z, 9alpha, 11alpha, 13E, 15S)-9,15-Dihydroxy-11-hydroxymethyl-12-isoprosta- 5,13-dien-1-oic acid. USE:Medicines. PREPARATION:A compound expressed by formula II is treated with a carbonyl reducing agent, e.g. sodium boron nitride, or reacted with a Grignard reagent and if necessary deprotected to afford the aimed compound expressed by formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a novel prostaglandin derivative. More specifically, the present invention is based on the general formula [where zl is a carboxyl group or a protected carboxyl group, Z2 is a hydroxyl group or a protected hydroxyl group, and Z3
represents a hydroxymethyl group or a protected hydroxymethyl group, Z4 represents a hydrogen atom, an alkyl group or a substituted alkyl group. The bond extending from the 5-membered ring by the dotted line is 5
It shows a bond extending downward from the member ring surface, that is, the α coordination. The compound represented by the general formula [in the formula zl~ Z4 has the same meaning as above, Z
5 represents a hydrogen atom or an alkyl group. This invention relates to a method for producing a prostaglandin derivative represented by the following.

In addition, in the compounds of the present invention, in particular, z+ is a carboxyl group, Z2
is a hydroxyl group and Z3 is a hydroxymethyl group (I
II) holds the compound (IV) as shown below.
It can also be produced by using reaction G to remove 1M.

(n) Here, z',..., zS have the same meanings as described above, and Z6 represents a hydrogen atom or a hydroxyl group.

Prostaglandins and their analogs can be named as derivatives of brostanic acid with the following structure.

The method of counting the skeletal carbon atoms of brostanic acid is as shown in the above formula. The systematic name of brostanic acid is 7-[
β-octyl)-cyclobent-1α-yl]hebutanoic acid.

When the compound of the general formula (1) obtained by the present invention is named with brostanoic acid as the basic skeleton, (5Z, 9
α, 11α, 13E, 15S or l5R)-9
,15-dihydroxy-11-hydroxymethyl-12
-isoprosta-5゜13-diene-1-acid 15.1
It is a 5-disubstituted-ω-nor derivative. Regarding the nomenclature of prostaglandins and prostaglandin derivatives, see, for example, N. A. Nelson, Journal of Medicinal Chemistry, Vol. 17, pp. 911-918 (19
Please refer to 1974).

12-isobroscunic acid means a stereoisomer at the 12-position of brostanic acid as represented by the following formula.

The compound of the general formula (1) obtained by the present invention is 1
53 body and 15E body, and is not particularly limited to either of them. The compounds having the general formulas (1) and (II) obtained by the present invention are characterized in that all substituents attached to the five-membered ring of brostanoic acid have an α configuration, and in addition, the 11th-position substitution It is characterized in that the group is a hydroxymethyl group, and from these meanings, the above general formulas (1) and (
It) is a structurally novel compound,
Furthermore, as will be described later, the manufacturing method is also completely new. The general formula (1) obtained by the present invention
) and (II) also showed significant effects in pharmacological tests.

Among the compounds obtained by the present invention, those in which Zl is a carboxyl group can also be made into a pharmacologically acceptable salt form. Examples of pharmacologically acceptable salts include salts of alkali metals or alkaline earth metals such as sodium, potassium, magnesium, and calcium, ammonium salts, tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, and phenyltriethylammonium. Quaternary ammonium salts, such as methylamine, ethylamine, dimethylamine,
diethylamine trimethylamine, triethylamine,
Salts of lower aliphatic, lower cycloaliphatic and lower araliphatic amines such as N-methylhexylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, α-phenylethylamine, ethylenediamine piperidine, morpholine, pyrrolidine, salts of heterocyclic amines and their lower alkyl derivatives such as piperazine, pyridine, l-methylbiperazine, 4-ethylmorpholine, hydrophilic salts such as monoethanolamine, ethylgetanolamine, 2-amino-l-butanol; Examples include salts of amines containing groups.

In the general formula of the compounds of the present invention, 2+ represents a carboxyl group or a protected carboxyl group such as an ester, but specifically a free carboxyl group: methyl, ethyl, n-propyl, n-butyl, isobutyl, isopropenyl. , cyclohexylmethyl, benzyl and 2.2.2
- Substituted or unsubstituted alkyl esters such as trichloroethyl; heterocyclic esters such as 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrochenyl, and 4-methoxytetrahydropyran-4-yl; and the like.

Z2 is a hydroxyl group or a protected hydroxyl group such as an acyloxy group, and specifically a free hydroxyl group such as a water fII group protected with an alkyl group such as cetyl, chloroacetyl, or propionyl; such as benzoyl or p-phenylbenzoyl. Hydroxyl group protected by an aroyl group; 2.2. Hydroxyl group protected by a carbonic acid residue such as 2-trichloroethoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl; Hydroxyl group protected by a trialkylsilyl group such as trimethylsilyl ;2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrochenyl,
Hydroxyl group protected with a heterocyclic group such as 4-methoxytetrahydropyran-4-yl; protected with an alkoxyhydrocarbon group such as methoxymethyl, ethoxymethyl, 1-ethoxyethyl, 1-methoxycyclohexan-1-yl. Hydroxyl group: Examples include hydroxyl groups protected with hydrocarbon groups such as methyl, ethyl, and benzyl.

Z3 is a hydroxymethyl group or a hydroxymethyl group protected by a water group, specifically a free hydroxymethyl group or a hydroxymethyl group whose hydroxyl group is protected with the same protecting group as z2.

z4 is a hydrogen atom or an alkyl group, and the alkyl group is specifically preferably an alkyl group having 1 to 10 carbon atoms or a substituted alkyl group such as methyl, ethyl, pentyl, and owathyl.

ZS is hydrogen or an alkyl group, and the alkyl group preferably has 1 to 5 carbon atoms.

In the present invention, the protecting group for the carboxyl group included in general formula Z1 may be any group that does not substantially affect other parts of the compound when the protecting group is subsequently removed and replaced with a hydrogen atom. There are no particular limitations, and specific examples thereof are as described above.

The protecting group for the hydroxyl group contained in Z2 is particularly suitable if it does not affect other parts of the compound by the removal reaction when the protecting group is substantially removed later and replaced with a hydrogen atom. Without limitation, such protecting groups include those described above.

As the protecting group for the hydroxyl group contained in Z3, the compound of general formula (II) is preferably derived by cleaving the ether ring bond under acylation conditions and then undergoing several reaction steps, as described below. Acyl groups such as acetyl, propionyl, benzoyl, chloroacetyl, p-phenylbenzoyl are preferred, but are not particularly limited. There is no particular limitation as long as it does not affect other parts of the compound when the protecting group is substantially removed later and replaced with a hydrogen atom. Examples of such a protecting group include the hydroxyl group contained in Z2. The protecting group is arbitrarily selected from those listed above.

The retention of the hydroxyl group represented by Z6; the ili group itself does not undergo any change during other reactions, and when the retention group 8I, I is removed later, other parts of the compound There is no particular limitation as long as it does not have any influence, and such a protector 1ii1 can be arbitrarily selected from those mentioned above as the protecting group for the hydroxyl group contained in Z2, for example.

To explain the method of the present invention in more detail, compound (1) is obtained by reducing the compound having the general formula (II) with a carbonyl reducing agent or treating with a Grignard reagent, and then, if necessary, protecting the hydroxyl group. It can be obtained by carrying out a reaction for removing a protecting group from a carboxyl group or a carboxyl group in any order. In carrying out the process of the present invention, the reaction is carried out in the presence or absence of a solvent using a reducing agent or Z'
This is achieved by using a Grignard reagent designated as MgX, where Z' is an alkyl group, preferably a C5-C3 alkyl group, and X is a halogen. The reducing agent used is not particularly limited as long as it converts a carbonyl group into a hydroxyl group, and examples thereof include sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, and tert-hydride. Metal hydride compounds such as butoxylithium aluminum, trimethoxylithium aluminum hydride, and sodium cyanoborohydride are preferably used. The Grignard reagent (Z'Mgx) used is preferably an alkylmagnesium halide having 1 to 5 carbon atoms prepared by a reaction between metallic magnesium and an alkyl halide in ether or tetrahydrofuran.

The reaction is carried out in the presence or absence of a solvent, but in order for the reaction to proceed smoothly, it is preferable to use a solvent, and the solvent used is not particularly limited as long as it does not participate in this reaction. For example, in the case of a reduction reaction, alcohols such as methanol, ethanol, isopropanol,
Inert solvents such as ethers such as tetrahydrofuran and dioxane are used, and in the case of the Grignard reaction, inert solvents such as ethers and ethers such as tetrahydrofuran are preferably used. Although there are no particular limitations on the reaction temperature, a relatively low temperature is desirable in order to suppress side reactions, and the reaction is usually preferably carried out at -20°C to room temperature.

The reaction time varies mainly depending on the reaction temperature and the type of reaction reagent used, but is usually from 1 minute to 1 hour. After the reaction is completed, the target compound is collected from the reaction mixture according to a conventional method. For example, after the reaction is complete, an organic acid such as formic acid, acetic acid, oxalic acid, or tartaric acid is added to the reaction mixture to decompose the excess reducing agent or Grignard reagent, and then an organic solvent is added to perform extraction and the extract is washed with water. It is obtained by distilling off the solvent from the extract after drying. The obtained target compound may be processed by conventional methods, such as column chromatography, if necessary.
Further purification can be performed using thin layer chromatography or the like. Among the compounds having the general formula (1) thus obtained, those having hydroxyl or carboxyl protecting groups can be subjected to a reaction to remove those protecting groups, if necessary.

The reaction to remove the hydroxyl protecting group depends on the type of protecting group.
The conditions for removal are different. The retention of hydroxyl group 81M is, for example, A7
Cetyl, chloracetyl, 7”.

Acyl groups such as pionyl, benzoyl, and P-phenylbenzoyl 2. In the case of carbonic acid residues such as 2-trichloroethoxycarbonyl, nidoxycarbonyl, and benzyloxycarbonyl, this can be easily achieved by contacting with an acid or base. be done. Examples of acids or bases used include mineral acids such as hydrochloric acid, hydrochloric acid, and sulfuric acid; alkali metal and alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide; sodium carbonate; Alkali metal and alkaline earth metal carbonates such as potassium carbonate and calcium carbonate are preferably used. Usually, it is suitably carried out under basic conditions.

The reaction is carried out in the presence or absence of a solvent, but in order to carry out the reaction smoothly, it is preferable to use a solvent, and the solvent used is not particularly limited as long as it does not participate in the reaction, for example, Water; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and aqueous organic solvents such as mixtures of these fat"J agents and water are preferably used. There is no particular limitation on the reaction temperature. The reaction is carried out at room temperature to the reflux temperature of the solvent.When the hydroxyl protecting group is a trialkylsilyl group such as trimethylsilyl, it is easily achieved by contacting with water or water containing an acid.

When using water containing acids, the acids contained are particularly limited to organic acids such as formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, and malonic acid; mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid. can be used without .

The reaction is carried out in the presence or absence of a solvent.

Other solvents are usually not necessary if an excess of water is used. When using other solvents, organic solvents that are easily miscible with water, such as ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol, are preferably used.

There is no particular limitation on the reaction temperature, but it is usually suitably carried out at room temperature. The protecting group for the hydroxyl group is, for example, a heterocyclic group such as 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrochenyl, 4-methoxytetrahydropyran-4-yl; methoxymethyl, ethoxymethyl, 1
-ethoxyethyl, l-methoxycyclohexane-1-
In the case of an alkoxy hydrocarbon group such as yl, this is easily achieved by contacting with an acid. Preferred acids used include, for example, organic acids such as formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, and malonic acid; and mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid. The reaction is carried out in the presence or absence of a solvent, but in order to carry out the reaction smoothly, it is preferable to use a solvent, and the solvent to be used is not particularly limited as long as it does not participate in the reaction, for example, water; methanol,
Alcohols such as ethanol; tetrahydrofuran,
Ethers such as dioxane or aqueous organic solvents consisting of these organic solvents and water are preferably used. The reaction temperature is not particularly limited, and the reaction is carried out at room temperature to the reflux temperature of the solvent, and is particularly preferably carried out at room temperature. When the protecting group for the hydroxyl group is a hydrocarbon group such as methyl, ethyl, or benzyl, this can be easily achieved by contacting it with a boron halide compound such as boron trichloride or boron tribromide. The reaction is carried out in the presence or absence of a solvent, but it is preferable to use a solvent in order to carry out the reaction smoothly, and the solvent used is not particularly limited as long as it does not take part in the reaction, such as dichloride. , methane, chloroform and the like are preferably used.

There is no particular limitation on the reaction temperature, but in order to suppress side reactions, it is desirable to carry out the reaction at a relatively low temperature, and it is preferably carried out at -30□°C to room temperature. After the reaction is completed, the target compound of a certain reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an appropriate organic solvent to the reaction mixture after completion of the reaction, performing extraction, and distilling off the solvent from the extract.

The obtained target compound can be further purified, if necessary, using conventional methods such as column chromatography, thin layer chromatography, etc. Next, in the reaction for removing the protecting group of the carboxyl group, the removal conditions differ depending on the type of protecting group. When the protecting group for a carboxyl group is a hydrocarbon group such as methyl, ethyl, n-propyl, n-butyl, isobutyl, isopropyl, n-octyl, 2-ethylhexyl, 2-propenyl, cyclohexylmethyl, benzyl, acid or by contacting with a base. The acids or bases used are those commonly used for hydrolyzing esters without particular limitation, such as mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, or sodium hydroxide, potassium hydroxide, and water. Alkali metal and alkaline earth metal hydroxides such as barium oxide; alkali metal and alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, and calcium carbonate are preferably used. Usually, it is suitably carried out under basic conditions. The reaction is carried out in the presence or absence of a solvent, but in order to make the reaction proceed smoothly, it is preferable to use a solvent, and the solvent to be used is not particularly limited as long as it does not participate in the reaction. For example, water or a mixed solvent of water and an alcohol such as methanol or ethanol or an ether such as tetrahydrofuran or dioxane is preferably used. There is no particular limitation on the reaction temperature, and the reaction is carried out at room temperature or the reflux temperature of the solvent. When the carboxyl protecting group is an alkyl halide such as 2.2.2-1-lichloroethyl, this is achieved by contacting with zinc and acetic acid. The reaction is carried out in the presence or absence of a solvent, but in order to make the reaction proceed smoothly, it is preferable to use a solvent, and the solvent used is not particularly limited as long as it does not take part in the reaction, such as Water; ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol; or a mixed solvent of these organic solvents and water are preferably used.

The reaction temperature is not particularly limited and is usually suitably carried out at room temperature. Protecting groups for carboxyl groups include, for example, 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrochenyl, 4-methoxytetrahydropyran-4
In the case of complex bag serialization such as -il, this is achieved by contacting with an acid.

Examples of acids used include formic acid, acetic acid pro- and onic acid,
Organic acids such as acetic acid, oxalic acid and malonic acid; mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid are preferably used. The reaction is carried out in the presence or absence of a solvent, but it is preferable to use a solvent in order to carry out the reaction smoothly, and the solvent used is not particularly limited as long as it does not participate in the reaction. For example, water; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and mixed solvents of these organic solvents and water are preferably used. The reaction temperature is not particularly limited, and the reaction is carried out at room temperature to the reflux temperature of the solvent, and is preferably carried out at room temperature. After the reaction is completed, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, a suitable organic solvent is added to the reaction mixture, extraction is performed, and the solvent is distilled off from the extract. The obtained target compound can be further purified, if necessary, by conventional methods such as column chromatography and thin layer chromatography.

The compound having the general formula (II) used as a raw material in carrying out the method of the present invention is a new compound, and can be produced, for example, by the following method, but is of course not limited to these. It's not something you can do.

(V) (VT) (■) (XI) (XI[) (XI[[) In the compound having the general formula (IV) used as a raw material compound in implementing the method of the present invention, z6 represents a hydrogen atom. When z6 represents a protecting group for water #I group, it is a novel compound.

The method for deriving compound <m> from compound (IV) is a reaction that removes the MW-holding group, and the method is to
The method is exactly the same as that described in the method for deriving compound (1) from.

Further, the starting material (IV) is a new compound, and can be produced, for example, from the compound having the general formula (IX) as follows.

(IX) (XV) (XVI) (XLX) (X■) (X■) (IV) In the above formula, the meanings of 21 to 21' are the same as described above. The protecting group for the carbonyl group is not particularly limited as long as it does not undergo any change in the seventh step, that is, the step of oxidizing alcohol to aldehyde. Examples of groups include alkylenedioxy groups such as methylenedioxy and ethylenedioxy; dialkoxy groups such as dimethoxy and jetoxy;
Examples include alkydine dithio group nioximes such as ethylene dithio and trimethylene dithio, but the protecting group is not particularly limited to these.

Z7 represents a hydroxyl protecting group. 2? The protecting group for the hydroxyl group represented by is one that does not undergo °ζ change in the subsequent 4th, 5th, and 12th steps, and that does not affect other parts of the compound in the step of removing the protecting group. Although there is no particular limitation as long as it does not give the following, it is desirable to select a protecting group that can be preferentially removed in distinction from the hydroxyl group-protecting groups contained in Z2 and Z. Such protecting groups include, for example, chloroacetyl group, 2.2.
Examples include ditrichloroethoxycarbonyl group, but are not limited to these.

Here, A also represents an oxygen atom only when 24 represents an alkyl group. When A represents an oxygen atom, the fifth
and the first O step, that is, the step of protecting the carbonyl group,
The step of removing the protective group for the carbonyl group can be omitted.

In this case, both aldehyde and ketone will be present in the eighth step, ie, the Wittig reaction described below.
Since the Uiteisohi reaction occurs preferentially to aldehydes, compounds represented by the general formula (XII[) are mainly produced.

The compound having the general formula (V) used here as a raw material compound is a known compound, and its synthesis method is, for example,
Fujise, Kazan, Uda, Koya, Kurosawa, Nippon Kagaku Zasshi Vol. 82, pp. 367-372 (1961).

The steps from the first step to the 16th step will be briefly explained below.

The first step is a reaction to protect the alcohol, and the protecting group contained in Z2 is selected from one that does not change during the subsequent steps.

The second step is an aldol condensation-like reaction, which is achieved by using a compound having the general formula and a Lewis acid such as titanium tetrachloride, tin tetrachloride, aluminum trichloride, or boron trifluoride etherate as a reaction reagent. Here, 25 represents an acyl group such as acetyl or propionyl; an alkyl group such as methyl or ethyl; or a trialkylsilyl group such as nitrimethylsilyl. The reaction using titanium tetrachloride is described, for example, in Kinide, Izawa, and Saigo, Chemistry Letters, (1974), pp. 323-326.

The third step is a reaction to protect the hydroxyl group.
As IW, a protecting group as described above for Z7 is chosen.

This is easily achieved by heating with the indicated carboxylic acid anhydride.

Therefore, in this case Z3 represents a hydroxymethyl group protected by forming an ester with a carboxylic acid RCOOH. In common practice, heating in acetic anhydride in the presence of P-toluenesulfonic acid is sufficient to accomplish the purpose.

The fifth step is a reaction for protecting the carbonyl group, and the protecting itI group of the carbonyl group is selected from those mentioned above for A, and the objective is achieved by the reaction 7' known as -i.

The sixth step is a reaction for removing the hydroxyl protecting group Z7.

When Z7 represents a chloroacetyl group, it can be removed by gentle heating with thiourea or 2-amino-thioethanol. Z7 is 2
．． When it represents a 2.2-trichloroethoxycarbonyl group, it can be removed by treatment with zinc powder.

The seventh step is a reaction in which a hydroxyl group is oxidized to an aldehyde, and the oxidizing agent is not particularly limited as long as it does not affect other parts of the compound, and known oxidizing agents are preferably used.

A compound having the general formula (XII) can be obtained by reacting the phosphonium ylide shown with the compound having the general formula (X■).

The ninth step is a reaction for protecting the carboxyl group, and any protecting group for the carboxyl group may be used without particular limitation as long as it does not change in the subsequent steps.

The 10th step is a reaction for removing the protecting group of the carbonyl group, and known removal conditions depending on the protecting group represented by 8 are preferably used.

The 11th step is the step of reducing the α, β unsaturated carbonyl group to convert it into allyl alcohol, and the reducing agent can be used without any particular restrictions as long as it does not change other parts of the compound. As such a reducing agent, for example, a known zinc borohydride is preferably used.

The twelfth step is a reaction to protect the hydroxyl group, and the protecting group for the hydroxyl group is one that does not undergo any change during the subsequent reaction steps, and is used to protect other parts of the compound during the subsequent reaction to remove the protecting group. No impact.

Any suitable material may be used.

The 13th step is a reaction in which the hydroxyl groups i1i &z' are removed and replaced with hydrogen atoms, and is the same reaction as described above for the 6th step.

The 14th step is a step of oxidizing the hydroxyl group and converting it into an aldehyde, and is similar to the above-mentioned 7th step.

The 15th step is the Uiteisohi reaction, which is the 8th step mentioned above.
It is the same as the process.

The 16th step is a step of protecting the carboxyl group,
Although it is similar to the ninth step described above, if the reaction is subsequently performed to remove each protecting group by the method described in claim 2, the 16th step can be omitted. In that case, as is clear from the mortar, in the compound having the general formula (IV), zl means a carboxyl group.

After the completion of the reaction, the target compound of each step is collected from the reaction mixture by a conventional method, and if necessary, the target compound obtained is subjected to a conventional method such as column chromatography, thin layer chromatography, or preparative high performance liquid chromatography. It can be further purified by means.

Next, the method of the present invention will be explained in more detail with reference to Examples and Reference Examples, but the scope of the present invention is of course not limited by these.

The following abbreviations were used.

mp: Touch point (uncorrected) TLC: Thin layer talamatography (unless otherwise specified, Merck's thin silica gel plate ART 5715 is used) IR: Infrared absorption spectrum mass: Mass spectrum n1Ilr: Nuclear magnetic resonance absorption spectrum (Proton, 1
00MIIZ Te measurement)” C-nmr: Carbon-13
Nuclear magnetic resonance absorption spectrum [α]D: Only the main peaks are shown in the data of the optical intensity ir.

For Fass data, only the parent peak or the peak corresponding to it is described.

So-1-acid Ul+ (5Z, 9α, 11α, 13E)-11-acetyl oxymethyl-9-hydroxy-15-oxo-12-isoprosta-5,13-diene-1-es, 150 mg of methyl ester in 8 ml of methanol The solution was cooled in an ice-water bath, and 40 mg of sodium borohydride was added while stirring. After 1 hour, 6 mA of IN aqueous potassium hydroxide solution is added, and the mixture is stirred at room temperature for 1 hour. A saturated aqueous solution of oxalic acid was added dropwise to bring the reaction solution to pH-3, and most of the methanol was distilled off under reduced pressure using a water jet pump, and the remaining aqueous layer was divided into several portions using 100 ml of ethyl acetate. Extract.

After combining the ethyl acetate layers and washing with a small amount of brine,
By drying over magnesium sulfate and distilling off the solvent, 157 mg of an oil was obtained. This was subjected to column chromatography using 9 g of silica gel-60 manufactured by Merck & Co., and eluted with chloroform containing 3 to 15% methanol. A fraction of 25 rrt Il was purified using 23 Honkishiki.

From N018 to NO, 12 fractions ttl km
Pure (5Z, 9α) as an oil by

11α, 13E, 15R)-9,15-dihydro, waxy 11-hydroxymethyl-12-isoprosta-5,
76.6 mg of 13-diene-1 acid was obtained. No.1
Pure (5Z, 9α, ll
α, 13B, 153) -9,15-dihydroxy-11-hydroxymethyl-12-isoprosta-5,
38.6 mg of 13-diene-1-acid was obtained. No,
Fractions No. 13 and No. 155 were collected and concentrated to obtain 25.7 mg of a mixture of the above two compounds as an oily substance. This was confirmed by the following analytical means.

(However, for 15S and 15R, the one with the smaller Rf value in tlc was assumed to be the 15S form.) tlc (Ethyl acetate expansion twice) 153 form Rf = 0.20 15E form Rf = 0.29 tic (benzene: dioxane : Acetic acid 20 : 10
: 1) 15S form Rf = 0.35 15E form Rf = 0.45 tic (ethyl acetate:acetic acid 100:1) 153 form
Rf = 0.14 15E body Rf = 0.24 ir (liquid film) c, m-' 15S body: 34oo, 2920,28 50.1710.970 15E body: 3400,2920.28 50, j710,970 [ α]23: 153 bodies: +17.1'(C=1.11 CI(C1,
)15 R body: → -47.5° (C=1.07 CHC
13) nmr (CD Cl 3) σPPm (TM
from S) 153 bodies 0.87 (t, 3H) 1.05-2.5 (C, 20H) 2.6-2.9 (m, IH) 3.59 (d, 211) 4.0-4 .3 (m, 2H) 4.96 (S, 4H) 5.2-6.1 (m 4H) 15E body 0.87 (t, 3H) 1.0-2.5 (C, 20H) 2. 5-2.9 (m, L H) 3.56 (d, 2H) 4.0-4.3 (m, 2H) 4.96 (S, 4H) 5.2-6.0 (rn 4 H ) -5,13-diene-1-diene-1-2-nintenka-kazui-tensui methyloxy-11-acetyloxymethyl-15-oxo-12-isobroster5. 21.0 mg of 13-diene-1-acid methyl ester is dissolved in 10 mβ alcohol, and 60 mg of sodium borohydride is added little by little while stirring at room temperature. After stirring for 30 minutes,
Remove alcohol under reduced pressure and leave 20mj! Add saturated aqueous sodium hydrogen tartrate solution and add 40 r of ethyl acetate.
Extract 5 times with nn. The ethyl acetate extracts were combined, washed with a small amount of aqueous sodium bicarbonate and a small amount of brine, dried over sodium sulfate, and then ethyl acetate was distilled off to obtain 205 mg of an oily substance. This product was found to be (5Z, 9α) as indicated based on the following analysis data and the results of Example 3 shown below.

11α, 13E)-9-acetyloxy-11-acetyloxymethyl-15-hydroxy-12-isobroster 5,13-diene-1-acid methyl ester.

tic (cyclohexane:ethyl acetate l:1)Rf
=0.25 0.3 iv (liquid film) cm-' 3450.2930,2850°1735.970 3-diene-1-acid 0)1 Oily substance obtained in Example 2, namely (5Z, 9α).

11α, 13B)-9-acetyloxy-11-acetyloxymethyl-15-hydroxy-12-isoprosta-5,13-diene-1-acid-methyl ester 15
3.15B mixture 205mg 20mj! of methanol, 20 ml of 1N aqueous potassium hydroxide solution was added thereto, and the mixture was stirred at room temperature for 1.5 hours.

After most of the methanol is distilled off under reduced pressure, a saturated aqueous solution of oxalic acid is added to the remaining aqueous solution, the pH is adjusted to 2-3, and the mixture is extracted five times with 50 ml of ethyl acetate. The ethyl acetate extracts were combined and washed once with a small amount of brine, dried over magnesium sulfate, and concentrated under reduced pressure.
170 mg of oil was obtained. A thin silica gel plate (20cm x 20cm) prepared from this with a thickness of 2mm 2
The sample was subjected to preparative thin layer chromatography using a thin film and developed with ethyl acetate containing 1% acetic acid. Rf is 0.15
The silica gel layer ranging from 0.25 to 0.25 is scraped off and extracted with methanol, the silica gel is removed by filtration, and then concentrated. The concentrate was dissolved in 60 mJ of ethyl acetate and washed three times with water containing acetic acid to remove impurities derived from silica gel.
After further washing once with brine and drying with magnesium sulfate, the desired (5
Z, 9α, llα, 13B, 15S)-9,15-dihydroxy-11-hydroxymethyl-12-isoprosta-5,13-diene-1-acid at 65 mg fI.

This was confirmed by the following analytical data.

tlc (ethyl acetate containing 1% acetic acid) Rf = 0.1
4 Weighing (liquid film) νcm”' 3400.2920.2B50°1710.970 nmr (CDCIs) δPPm (from TMS) 0
．． 87 (t, 3H) 1.05-2.5 (C, 20H) 2.6-2.9 (m, IH) 3.59 (d, 2H) 4.0-4.3 (m, 2 H) 4.96 (S, 4H) 5.2-6.1 (m 4 H) Rf in the preparative thin layer chromatography of Example 3
After scraping off the silica gel layer with a range of 0.25 to 0.3, extracting with methanol and removing the silica gel by mouth, ? Ii shrink.

60 mj of ethyl acetate from the concentrate! After washing three times with aqueous solution containing acetic acid and once with a small amount of brine, drying with magnesium sulfate and distilling off ethyl acetate, the desired (5Z, 9α, 11α, 13E,
15R)-9,15-dihydroxy-11-hydroxymethyl-12-isoproster 5゜13-diene-1-
35+ng of #1 was obtained.

This was confirmed using the following analytical data.

tic (ethyl acetate containing 1% acetic acid) Rf = 0.24 ir (liquid film) cm-' 3400.2920.2B50°1710.970 -5.13-diene-1- (5Z, 9α, 11α, '13B )-9-7-1=Tyloxy-11-acetyloxymethyl-15-oxo-
164 mg of 12-isoprosta-5,13-dien-1-acid methyl ester are dissolved in 16 ml of ether and stirred in a dry ice-acetone bath. To this was added an ether solution of methylmagnesium iodite (0.75
Add 2 ml (excess) of M) and gradually lower the temperature while continuing to stir. 1 more after reaching room temperature
After continued stirring for an hour, while cooling and stirring in an ice-water bath, add a small amount of saturated solution of sodium hydrogen tartrate to decompose the excess Grignard reagent, and then distill off the ether under reduced pressure. . To the remaining reaction mixture, 10 ml of methanol was added, followed by 10 mβ of 1N potassium hydroxide solution, and after stirring at room temperature for 2 hours, most of the methanol was distilled off under gentle reduced pressure, and hydrogen tartrate was added to the remaining aqueous solution. Carefully add sodium saturated solution to pH 3,5-4,0.
Make it. This aqueous layer was extracted five times with 50 ml of ethyl acetate, the extracts were combined, washed once with a small amount of brine, dried over sodium sulfate, and the solvent was distilled off to produce an oily crude product. 140 mg of the product was obtained. this thing 1
Silcagel'FB layer plate (20cm
The mixture was subjected to preparative thin layer chromatography using a 20cm x 20 cm) and developed twice with ethyl acetate containing 1% vinegar #I.

The silica gel layer with Rf from 0.25 to 0.32 was scraped off, extracted with methanol, and treated in the same manner as described above in Examples 3 and 4 to obtain the target compound containing mainly the 15S form (5Z , 9α, 11α, 13E)-9
゜15-dihydroxy-11-hydroxymethyl-15
-Methyl-12-isoprosta-5,13-diene-1
-Acid 54 cod was obtained.

The silica gel layer with an Rf of 0.32 to 0.4 was scraped off, extracted with methanol, and subjected to the same treatment to obtain the target compound (5Z, 9α,
11α, 13E)-9,15-dihydroxy-11-hydroxymethyl-15-methyl-12-isoprosta-
36 mg of 5,13-diene-I-acid were obtained.

(However, in determining the 1.5S and 15E bodies, it was assumed that the smaller Rf value in TLC was the 153 body.) This was confirmed by the following analytical data.

tfc (ethyl acetate:acetic acid 99:1) 153 body R
f = 0.25 15E body Rf = 0.27 ir (liquid film) cm-' 3450.2930, 2850°1710.970 nmr (CDC13) δPPm (TMS) 0.8
El (t3H) 1.05-2.8 (C21H) (1,275311
) 1', 27 (S 3H) 3.57 (m 2H) 4.0 to 4.3 (ml H) 4.9 (S, 4H) 5.2 ・6.1 (m 4I() (ir, nmr are the same for 153 body and 15E body)
Oxo-12-isoproster 5.13-diene-1-
115 mg of acid methyl ester are dissolved in 10 ml of alcohol, and while stirring in an ice-water bath, 50 mg of sodium borohydride is added in portions and stirring is continued for 2 hours. After removing the alcohol under reduced pressure, 10 mβ of methanol and 1N aqueous potassium hydroxide solution IQmn were added to the residue, and the mixture was stirred at room temperature for 1.5 hours. After distilling off most of the methanol under gentle vacuum, a saturated aqueous solution of oxalic acid is carefully added to the remaining aqueous solution to bring it to pH3. Extracted 6 times with ethyl acetate 4 Q tn It, combined the extracts, washed once with a small amount of brine, dried over magnesium sulfate, and distilled off the solvent to obtain 105 m of an oily crude product.
I got g.

This was subjected to column chromatography using 7 g of silica gel and eluted with chloroform containing 5 to 10% methanol to obtain 20 horns of 25 mβ.

By collecting and concentrating 14 fractions, the target compound (5Z, 9α, 11α) was obtained as an oil.

13E)-20-ethyl-9,15-dihydroxy-1
1-Hydroxymethyl-12-isoproster 5.13
-diene-1-acid (mixture of 153,15R) 72 mg
was gotten. This was confirmed from the following analysis data.

tlc (benzene:dioxane:acetic acid 20:10
: l) Rf = 0.4 (155, 15B mixture) Rf = 0.47 ir (liquid film) Sican-' 3450.2920, 2850°1710.970 nmr (CDCl2) δPPm (from TMS) 0.8
7 (tm 3H) 1.0-2.9 (m 25 H) 3.57 (m 2H) 4.0-4.3 (m 2 H) 5.0 (S 4H) 5.2-6.1 (m 4 H) -5,13-diene-1-acid methyl ester 1Ac The crude product obtained in Reference Example 3, namely (5Z, 9α.

11α, 13E)-11-acetyloxymethyl-15
,15-ethylenedioxy-59-hydroxy-12-
About 0.7 g of a mixture of isoproster 5.13-diene-1 acid methyl ester and its 9-acetylated product was added to 50 ml
P-)luenesulfonic acid-
Add 50+*g of hydrate and stir at room temperature for 2 hours.

After removing the acetone under reduced pressure, the residue was dissolved in 250 mβ of ethyl acetate, the ethyl acetate solution was poured into a small amount of saturated sodium bicarbonate solution, washed with a small amount of brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. By evaporation, 0.7 g of oily crude product was obtained. This was subjected to column chromatography using 35 g of silica gel, developed and eluted with cyclohexane containing ethyl acetate (20-30%), and
5 fractions of RNZ followed by 24 30ml fractions. The desired compound (5
Z, 9α, 11α, 13B)-9-acetyloxy-1
0.235 g of 1-acetyloxymethyl-15-oxo-12-isoprosta-5,13-diene-1-acid methyl ester was obtained as an oily substance. This was confirmed by the following analysis data.

tlc (benzene: ethyl acetate 6:4) Rf = 0
．． 24th C (cyclohexane: ethyl acetate 8: developed 23 times) R
f =0.24 [α]24=+14 @ (C=0.86/'oo bottom Lzum)ir (liquid film) Vcm-' 2925.2850.1740°1670, 1620 r++5r(CDCl2) δPP+n( TMS)
0.89 (L 3H) 1.1~2.7 (C20H) (2,015,2,0
(excluding 9S) 2.01 (S 3H) 2.09 (S 3H) 2.7" 3.1 (rn I H) 3.65 (S 3H) 3.8 ~ 4.1 (m 2H) 5. 1 to 5.5' (m 314) 6.1 (d IH) 6.89 (dd IH) 13-diene-1-acid methyl ester H No. 1 in column chromatography of Reference Example 1
By collecting and concentrating the fractions from 2 to NO, 29, the indicated target compounds (5'Z, 9α, 11α,
13B) -11-acetyloxymethyl-9-hydroxy-15-oxo-12-isoprosta-5,13-diene-1-acid methyl ester as an oil at 0.28
2g was obtained.

This was confirmed by the following analytical data.

tic (benzene:ethyl acetate 6:4)Rf =0
．． 57 tlc (cyclohexane; ethyl acetate 8: 23 times development) Rf = 0.24 [α] O' = +20° (C = 2.14 chloroform)
ir (liquid film) νcm-' 3500.2925, 2850°1740.1660.1620 nmr (CDCl2) δPPm (from TMS) 0.8
9 (t 3H) 1.1-2.7 (C21H) (excluding 2,015311) 2.01 (S 3H) 2.7-3.0 (m I H) 3.65 (S 3H) 4. 0 (m 2H) 4.36 (m IH) 5.4 (m 2H) 6.01 (d IH) 7.5 (dd IH) Star 5.13-Dien-1-acid methyl ester H Tubulo Star 5.13 -Dien-1-acid methyl ester Crude product obtained in Reference Example 4 (5Z, 9α.

11α, 13 B)-15,15-ethylenedioxy-
9-Hydroxy-11-hydroxymethyl-12-isoprosta-5,13-diene-1-acid methyl ester 0
．． 7 g is dissolved in 6 m It of acetic anhydride, and 2 ml of pyridine is added to this while stirring in an ice-water bath. 1
After continued stirring for an hour, acetic anhydride and pyridine were removed under reduced pressure to obtain 0.7 g of an oily substance. This product was immediately used as a raw material for Reference Example 1.

tic (benzene:ethyl acetate 6:4)Rr =0
．． 38 (9-hydroxy form) Rf = 0.56 (9
-acetyloxy form)ir (n(gHg,) I'C
m-'3400. 2925. 2850. 1730
ter5.13-diene-1-acid methyl ester H (5Z, 9α, 11α, 13 E) -15,15-ethylenedioxy-9-hydroxy-11-hydroxymethyl-12-isoprosta-5°13-diene -1-acid 0.70g to diethyl ether 79mI! To? understand,
To this is added an excess of diethyl ether solution of diazomethane. The desired (5Z) was immediately obtained by removing excess diazomethane and diethyl ether under reduced pressure.

9α, 11α, 13 E)-15,15-ethylenedioxy-9-hydroxy-11-hydroxymethyl-12
0.71 g of -isoprosta-5,13-diene-1-acid methyl ester was obtained as an oil. This product was immediately used as a raw material for Reference Example 3.

tlc (ethyl acetate) Rf =0.47 ir (liquid film) cm-' 3400.2930,2850,1740ter5,13
-diene-1-acid H to oH8U 4.43 g of 4-carbohydroxybutyltriphenylphosphonium bromide dried at 90°C under reduced pressure for 1 hour (
1 Om mo #) is dissolved in dry dimethyl sulfoxide 9 m It. While stirring this at room temperature,
Add 9 ml of a solution of sodium methylsulfinyl carbanide in dimethylsulfoxide (2.09M) to obtain a red-orange phosphorane solution. In addition to this, obtained in Reference Example 6 (
3 a S, 4 S, 5 R, 6a S) -heki・su.

Hydro-4-'((E)-3,3-ethylenedioxy-
1-Octenylgo 2-hydroxymethyl-2H-cyclopenda (b) Furan 0°66 g (2 m m o
Add a solution of dimethyl sulfoxide (10ml) and stir at room temperature for 1.5 hours.

Dimethyl sulfoxide was removed in a high vacuum to a residue of 60%
Add ml cold water. After extracting the aqueous layer four times with 50 tnl of ethyl acetate:ether (1:1) mixed solvent, about 4 g of sodium hydrogen tartrate was added to the aqueous layer to adjust the pH.
It should be about 4. Perform extraction operation 6 times with ether 60mβ,
The ether extracts were combined, washed with a small amount of brine, dried over sodium sulfate, and the desired crude products (5Z, 9 a, 11 a, I 3.
E) 15.15-x ethylenedioxy-9-hydroxy-11-hydroxymethyl-12-isoprosta-5,
0.7 g of 13-diene-1-acid was obtained as an oil. This product was used as the raw material for Reference Example 4 without any particular purification.

tlc (acetic acid) Rf = 0.15 9bego” (Is, 2R, 3R, 4R)-4-acetyloxymethyl-1-benzoyloxy-3-((E
)-3,3-ethylenedioxy-1-octenyl]-2
-Pormylmethyl-cyclopenkune 0.95g and methanol 50ml! , and 1N potassium hydroxide aqueous solution 5
Stir the mixture of 0rn 12 at room temperature. After 3.5 hours, most of the methanol was distilled off under gentle reduced pressure, and the remaining aqueous layer was saturated with sodium chloride and then extracted with 100 ml of ethyl acetate.

The ethyl acetate extracts were combined, washed with a small amount of brine, dried over sodium sulfate, and the solvent was distilled off to give a colorless semicircular product (3a S, 4 S, 5 R, 6a
S) -hexahydro-4-((E)i,3-ethylenedioxy-1-octenyl]-2-hydroxy-5-
0.66 g of hydroζtramethyl-2H-cyclopenda(b) furan was obtained.

tlc (acetic acid) Rf =0.25 ir (KBr) vcm-' 3400, 2950. 2924゜2850, 1020 Clopenkun Celite thoroughly dried at 150℃ under reduced pressure - 54518g
and 9 g of chromic acid 2-pyridine complex (Collins' reagent) and 90+ nIl of dry purified methylene chloride were stirred at -5'' to 0°C in an argon atmosphere to obtain Reference Example 8. (Is, 2R, 3R, 4R) )-4-acetyloxymethyl-1-benzoyloni-1-cy3- ((E)
-3,3-ethylenedioxy-1-octenyl)-2-
(2-hydroxyethyl)-cyclopenkune 1.08g
of methylene chloride (15 mj) was added to the solution at once,
Stir for a minute. Thereafter, 18 g of finely ground sodium hydrogen sulfate was added and stirred for an additional 10 minutes.

Pass the reaction mixture through a glass filter lined with Celite-545, and wash thoroughly with methylene chloride. After combining the oral performance with the washing liquid and concentrating it, 300 mj of ether! to remove most of the chromium compound precipitate (IS, 2R) by concentrating the ether solution.
.

tic (benzene:ethyl acetate 8:2) Rf =0.
33 ir (liquid film) cm-' 2930, 2850. 2720. 17351?2
0. 1600. 715 (Is, 2R, 3R, 4R)-4-acetyloxymethyl-1-benzoyloxy-2-(2-chloroacetyloxyethyl)-3-((E)-3,3-ethylenedioxy-1- Dissolve 1.183 g of octenylcocyclobencune in 120 mj of alcohol, add 167 mg of thiourea and 185+ ng of sodium hydrogen carbonate, and dissolve 7
Stir in an oil bath at 0°C. After 24 hours, the alcohol was removed from the mixture and the remainder was dissolved in 400 m# of ether.
This ether solution was washed twice with a small amount of saturated sodium bicarbonate solution and three times with a small amount of saturated saline solution, dried over sodium sulfate, and the ether was distilled off to obtain a crude product (IS).

2R,3R,4R)-4-acetyloxymethyl-1-
1.08 g of benzoyloxy-3-((E)-3,3-ethylenedioxy-1-octenyl]-2-(2-hydroxyethyl)-cyclopencune was obtained as an oil.

tie (benzene:conityl acetate 8:2) Rf =0
．． 17 ir (liquid film) cm-' 3500.2940.2860.17401?20,1
600.715 -2- (2-chloroacetyloxyethyl)-3-(
(E)-3,3-ethylenedioxy-(13,2R,3
R,4R)-4-acetyloxymethyl-1-benzoyloxy-2-(2-chloroacetyloxyethyl)-
A mixture of 1.804 g of 3-((E)-3-oxo-1-octenyl]-cyclopencune, benzene Looml, 6 mJ of ethylene glycol, and 2 (1+ g) of P-toluenesulfonic acid monohydrate was heated and placed in a water separator. The benzene solution is refluxed while being dehydrated using a thread attached. After 24 hours, the benzene solution is washed three times each with a small amount of sodium bicarbonate solution and a small amount of saline solution, and after drying with sodium sulfate, the benzene is distilled off to obtain an oily crude product. 1.96 g was obtained.By column chromatography using 70 g of silica gel, the pure target product ( Is, 2R, 3R, 4R)-4-acetyloxymethyl-1-benzoyloxy-2-(2-chloroacedeloxyethyl)-3-((E)-3,3-ethylenedioxy-1-octenyl )-Cyclopenkune 1.2g
was obtained as an oil. This was confirmed by the following analytical data.

tic (benzene:ethyl acetate 8:2) Rf =0.
44 ir (liquid film) cm-' 2940.2B50.1760, 17401720.1
600.715 [α), :6=+24' (C=2.34 methanol) nmr (CCJ4) δPPm-(TMs empty) 0.87 (t, 3H) 1.1-3.0 (C15H) ( (excluding 1,955311) 1.95 (S 3H) 3.6-4.0 (m 2 H) (3,93S21+
) 3.93 (S 2H) 4.14 (t 211) 5.42 (d IH) 5.55 (m IH) 6.0 (dd IH) 7.3 ~ 1.6 (m 3 H) 7.9-8.1 (m2■1) ',,,,/ (IR, 3aR, 5S, 6R, 6aR) -hexahydro-5-benzoyloxy-6-(2-chloroacetyloxyethyl)- 1=(2-oxo-hebutyl 1-IH
-Cyclopenc (5.98 C3 furan and 1 g of P-toluenesulfonic acid monohydrate are dissolved in 120 m+2 of acetic anhydride, and the solution is stirred in a 70° C. oil bath.

After 2.5 hours, acetic anhydride is distilled off under reduced pressure, and the residue is dissolved in 500 mβ of ethyl acetate, washed twice with a small amount of sodium bicarbonate solution and three times with a small amount of brine, dried over magnesium sulfate, and concentrated. This gave 48 g of crude product Ei. This was subjected to column chromatography using 300 g of silica gel, and cyclohexane containing ethyl acetate (20%) was used. For customer use, 2 fractions of 200 mjl each
0 wood stones. The pure target compound (1
3,2R,3R,4R)-4-acetyloxymethyl-
1-Benzoyloxy-2-(2-chloroacetyloxyethyl)-3-((E)-3-meno-quino-1-octenyl)-cyclopenkune 4.179+J< Obtained as an oily substance. The following analytical data G I confirmed this.

tic (Hensen:Ethyl acetate 8:2) Rf =0.
37 ir (liquid film) CII+-1 2950.2925,2850,1760°1740.
1720, 1670, 1625° 1600.715 [α) zs = +17° (C = 1.06 chloro 5 to J rem) 0.87 (t 3H) 1.1~3.1 (C13H) (1,995311 and 2.54t211 excluded)1
．． 99 (S 3H) 2.54 (t 2H) 3.8-4.3 (m 2 H) (excluding 3,99S2H and 4.18t2+1)3.
99 (S 2H) 4.18 (t 2 H) 5.57 (m IH) 6.19 (d IH) 7.03 (d d IH) 7.3 to 7.7' (m 3H) 7. 9 to 8.2 (m 2 H) (Is, 2R, 3R, 4R)-4-acetyloxymethyl-1-benzoyloxy-2-(2-
chloroacetyloxyethyl)-3-((E)-3,3
-A mixture of 5 mg of ethylenedioxy-1-octenyl-cyclopenkune, 1 mff of acetone, and 1 mg of P-1-luenesulfonic acid hydrate was stirred at room temperature for 2 hours, the acetone was removed under reduced pressure, and the residue was diluted with 10 m7 of ethyl acetate. !
The title compound (
IS, 2R, 3R, 4R)-4-acetyloxymethyl-1-benzoyloxy-2-(2-chloroacetyloxyethyl)-3-((E)-3-oxo-1-octenyl-cyclopenkune 4 mg was obtained.

This was confirmed by the following analysis data.

tic (benzene:ethyl acetate 8:2) Rf =0.
37 ir (liquid film) cm-' 2950.2925.2B50, 1760°1740.
1720.1670,1625゜1600.715 0 Pen [C Hoon 0-CPh G O (IR, 3aR, 5S, 6R, 6aR)-hexahydro-5-benzoyloxy-6-(2-hydroxyethyl)-1-( 0.30 g (0.77 m mol) of 2-oxo-hebutyl)-1H-cyclopenta[C]furan and 0.102 g (0.9 m mol) of chloroacedel chloride
l) in 10 mj+ of dry ether, cooled in an ice-water bath and mixed with 0.071 g of pyridine (0.9 mj+) while stirring.
Add ol).

After 1 hour, the ether solution was diluted by adding 70 ml of ether, and the ether solution was sequentially washed with water, aqueous sodium bicarbonate, 1N hydrochloric acid, and aqueous sodium bicarbonate, and then dried over magnesium sulfate. By distilling off the ether, a colorless oily product was obtained. 0.312g was obtained.

This is determined by the following analysis data: (IR, 3aR,
5S, 6R, 6aR)-hexahydro-5-benzoyloxy-6-(2-chloroacetyloxyethyl)-1
-(2-oxo-hebutyl)-1H-cyclopenta(C
) confirmed that it was a franc.

tic (cyclohexane:ethyl acetate 684)Rf
=0.35 [α) ”= +51.7 @(C=1.16 methanol)ir (liquid film) can-' 2950.2860.1?60,1710°1600.
1270.713 nmr (CCJ4) δPPm (from TMS) 0.9
1 (t 3H) 1.1-3.1 (Cl7H) 3.3-3.7 (m I H) 3.94 (S 2H) 3.9-4.3 (m I H) 4.19 ( t 2H) 4.58 (m IH) 5.50 (m IH) 7.3 - 7.6 (m 3 fl) 7.9 - 8.1 (m 2 H) (C) Furan 1 2-acetoxy- 1-heptene 6.357 g (40,7
m mol) purified methylene chloride 8Q rn Il
This solution was cooled to 0°C to 5°C in an argon atmosphere while stirring, and a solution of titanium tetrachloride in methylene chloride (0.64M) was added to the solution (63.8 m j!). (40.7mm
Add 10.15 g of 6-nipytetrahydroanhydroaucubigenin benzoate (
A methylene chloride solution (5 mmol) containing 37.05 mmol)
Add 0 mj slowly dropwise. 0 more after dripping
After stirring for 30 minutes at ℃~5℃, 200 mj of saturated sodium bicarbonate solution was obtained and cooled to a colored reaction solution! was added to decompose the titanium complex. After separating the methylene chloride layer, the aqueous layer was mixed with 400 mj of ethyl acetate! After extracting 5 times with
After washing twice, drying with magnesium sulfate, and concentrating, 15.27 g of an oily crude product was obtained. Subjected to column chromatography using 300 g of silica gel, ethyl acetate
Develop and elute with methylene chloride containing ~20% 500mj
Collect 21 + fractions.

8.82 g of pure product as a colorless oil was obtained by collecting and concentrating the fractions N017 to NO,13.
(22.7 mmol) was obtained. By collecting and concentrating the N006 fraction and the NO,14 to NO21 fractions, a product containing a small amount of impurities is obtained.
．． 96g was obtained. This product is expressed as (IR, 3aR, 5S, 6R, 6aR) according to the analytical data shown below.
-hexahydro-5-benzoyloxy-6-(2-hydroxyethyl)-1-(2-oxo-hebutyl)-1
It was confirmed that it was H-cyclopentaCC)furan.

tlc (cyclohexane:ethyl acetate 6:4)Rf
=0.1 tic (methylene chloride:ethyl acetate 10:1)Rf
=0.2 [α) 2S= +68.6° (C=1.101 methanol)ir (liquid film) cm-' 3450.2940.2B50.17131600.1
275,1110,10701025.712 mass M” = 388 nmr (CDCI2:+) δPPm (from TMS)
0.88 (t3H) 1.1 ~ 3.1, (C18H) 3.4 ~ 4.4 (C4H) 4.64 (m IH) 5.57 (ml1l) 7.3 ~ 7.6 ( m 3 H) 7.9 ~ 8.2 (m 2 H) "C-nmr (CDCj, +) δPPm (downfield from TMS) 209.538 16 (i, 333 133.1291
30.270 129.687 (2C) 128.64
8 (2C) 79.008 77°188 74.719
61.465 52.953 48.66543.59
7 43.402 42.94737.425 31.
381 28.65323.195 22.415 1
3.904-cph 6-nipytetrahydroanhydroaucubigenin7.
27 g (42.8 mmol) was dissolved in 20 m# of pyridine, and 7.6 g (54 mmol) of benzoyl chloride was added dropwise to the solution while stirring and cooling in an ice-water bath.

After completion of the dropwise addition, the mixture was returned to room temperature and stirred with IW for another 2 hours, and then washed with 500 ml of ether, water, 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate, and saturated brine in this order. The crude product 1 was obtained by drying the ether solution over sodium sulfate and then concentrating it.
Obtained 2.46 g as an oil. 500g of silica gel
The product was purified by column chromatography using a mixed solvent of benzene and ethyl acetate, and 10.18 g of colorless crystals were obtained. The following analytical data confirmed that it was 6-nipytetrahydroanhydroaucubigenin benzoate.

mP 60-61 °C tic (methylene chloride) Rf = 0.75 [α) ” = +32.76 (C = 1.04 methanol) ir (KBr) vcm-' 2940.2850, 1710.12B51120.1
055.710 mass M” = 274 nmr (CDC#s) δPPm (from TMS) 1.
6-3.0 (C7H) 3.3-3.6 (m l H) 3.6-4.2 (C3II) 5.27 (d IH5CPS) 5.45 (m IH) 7.3-7. 7 (m 3 H) 7.9-8.2 (m 2 H) I″C-nmr (CDCI!, 3) δPPm (
from TMS) 166.073 133.067 130
．． 337129.620 (2G) 128.518 (2
C) 100.77179.202 71.731 5
9.64641.648 40.088 36.125
(2C) '21.831 Patent applicant Toshi Co., Ltd.

Claims (1)

[Claims] General formula [In the formula, 21 is a carboxyl group or a protected carboxyl group, Z2 is a hydroxyl group or a protected hydroxyl group, Z3 is a hydroxymethyl group or a hydroxymethyl group protected from a hydroxyl group, and Z4 is a hydrogen atom , represents an alkyl group or a substituted alkyl group. The dotted line extending from the five-membered ring indicates a bond extending downward from the plane of the five-membered ring, that is, the α-coordination. [In the formula, Zl, Z4 has the same meaning as above, zS
represents a hydrogen atom or an alkyl group. ] A method for producing a prostaglandin derivative represented by