JPS5835184B2 - prostaglandin - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a novel prostaglandin derivative having a prostaglandin having the general formula R3 and R4 described above.

In the general formula (I), A represents an ethylene group or a cis-vinylene group, R1 and R2 are the same or different and represent a hydrogen atom or a lower alkyl group, and R3 and R4 represent a lower alkyl group.

In the general formula (I), R1 and R2 are preferably the same or different, for example, a hydrogen atom; a carbon number of 1 to 3, such as methyl, ethyl, n-propyl, isopropyl.
represents a linear or branched alkyl group having
R3 and R4 represent a linear or branched alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, and isopropyl.

In the compound having the general formula (I) obtained by the method of the present invention, the arrangement of the substituent bonded to the cyclopentane ring, the arrangement of the double bond present in the substituent, and the hydroxyl group bonded to the substituent Various geometric and optical isomers exist depending on the arrangement of and the presence of asymmetric carbon atoms.

In the general formula (I), all of these isomers and mixtures of these isomers are represented by a single formula, but the scope of the description of the present invention is not limited thereby.

Among the compounds having the general formula (I) obtained by the method of the present invention, those in which R2 is a hydrogen atom can also be made into a pharmacologically acceptable salt form.

Examples of pharmacologically acceptable salt forms include salts of alkali metals or alkaline earth metals such as sodium, potassium, magnesium, and calcium; ammonium salts such as tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, and phenyltriethylammonium; Quaternary ammonium salts; methylamine, ethylamine, dimethylamine, diethylamine,
Salts of lower aliphatic, lower cycloaliphatic and lower araliphatic amines such as trimethylamine, triethylamine, N-methylhexylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, α-phenylethylamine, ethylenediamine: piperidine , morpholine, pyrrolidine, piperazine, pyridine, -methylpiperazine, salts of heterocyclic amines and their lower alkyl derivatives such as 4-ethylmorpholine: monoethanolamine, ethyljetanolamine, 2-amino-1-butanol Examples include amine salts containing hydrophilic groups such as.

Conventionally, 11-deoxyprostaglandin derivatives include, for example, 11-deoxyprostaglandin E1 or 11-deoxyglostaglandin E2 [F,
F, H, Lincoln et al.
tal, ): Journal Off-Organic
Chemistry (J, Org, Chem,) Volume 38, 9
51 (1973)], but the 11-deoxy-20-alkylidene prostaglandin derivative represented by the general formula (I) is a novel compound that is completely unknown in the literature. The present inventors believe that these compounds are known 11-deoxyprostaglandin E1.
They found that they have a more pronounced bronchodilatory effect than other drugs, and as a result of conducting research on a method for producing them, they completed the present invention.

The compound having the general formula (I) obtained by the method of the present invention showed significant drug-embedding effect, ie, bronchial muscle dilation effect, in animal tests.

That is, for example, 90 g was administered to a guinea pig weighing 400 to 600 g, which was anesthetized by administering bentoparbital sodium.
-Oxo-15α-hydroxy-20-isopropyritenefrost 13()lans)-enoic acid (11-thioxy-20-impropyritin prostaglandin E1)
was administered intravenously, followed by histamine 2 μP/9
Or 3μ? Konzett-Rossler 7 (Konzett-Rossler) by intravenously administering /kg
Land Pharmacology (Archive fffir)
Experimentelle Pathology
und Pharmakologie), vol. 195, p. 71 (1'940)], the increase suppression rate of airway resistance was determined, and the D5o value was calculated. As a result, this compound has an I D5o = 0.03 r/kti. and 11
■D5゜0.26 of deoxyprostaglandin E1
It showed about 8 times the activity compared to γ/kg.

Therefore, the compound having the general formula (I) is useful as a medicine for use in cases where bronchodilation is required.

The dosage form is usually as an aerosol spray.

The amount used varies depending on symptoms, age, body weight, etc., but is usually 30 μg to 150 μg per day for adults.

Among the compounds having the general formula (I) obtained by the method of the present invention, representative compounds are described below.

■ 9-oxo-15α-hydroxy-20-isopropylideneprost-13()lans)enoic acid and its methyl, ethyl, n-propyl and isopropyl esters ■ 9-oxo-15α-hydroxy-17-methyl-
20-Inpropylideneprost-13(trans)-
Enoic acid and its methyl, ethyl, n-propyl and isopropyl esters ■ 9-oxo-15α-hydroxy-20-impropylidenefrost-5 (cis),
13(trans)-dienoic acid and its methyl, ethyl, n-propyl and isopropyl esters ■ 9-oxo-15α-hydroxy-17-methyl-
20-inpropylideneprost-5(cis), 13(
)-dienoic acid, methyl, ethyl, n-
Propyl and isopropyl esters According to the method of the present invention, the compound having the general formula (I) is prepared by oxidizing the compound having the general formula to produce a compound having the general formula, and the hydroxyl protecting group of the thus obtained compound is removed. Obtained by removing.

However, in the above formula, A, R1, R2, R3 and R4 have the same meanings as described above.

R5 represents a hydroxyl protecting group.

Here, the protecting group for the hydroxyl group is not particularly limited as long as it does not affect other parts of the compound due to the removal reaction when the protecting group is later removed and replaced with a hydrogen atom; Examples of the group include rings with or without alkoxy as a substituent, such as 2-tetrahydrofuranyl, 2-tetrahydropyranyl, 2-tetrahydrochenyl, 2-tetrahydrothiopyranyl, and 4-methoxytetrahydropyran-4-yl. 5- to 6-membered ring group containing an oxygen atom or a sulfur atom; 1 carbon number such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, impentyl
A straight or branched alkyl group having 5 to 5 alkyl groups;
Methoxymethyl, ethoxymethyl, n-propoxymethyl, impropoxymethyl, n-butoxymethyl, isobutoxymethyl, n-pentoxymethyl, isopentoxymethyl, 1-ethoxyethyl, ■-ethoxypropyl, 2-ethoxybutyl, ■A linear or branched alkyl group having 1 to 5 carbon atoms and having alkoxy as a substituent such as ethoxypentyl; trimethylsilyl, triethylsilyl, tri-n-propylsilyl, tri-n-propylsilyl, tri- n-butylsilyl, triisobutylsilyl, )! A linear or branched trialkylsilyl group having 1 to 5 carbon atoms, such as J-n-pentylsilyl, or a carbonate residue having the formula, where R6 is, for example, methyl. , ethyl, n-propyl, isopropyl,
Straight chain or branched alkyl group having 1 to 5 carbon atoms such as n-butyl, isobutyl, n-pentyl; 2.2.2-)IJ, ? Ethyl groups having 1 to 3 halogen atoms as substituents at the β position, such as lorethyl, 2,2-dibromoethyl, 2-iodoethyl; phenyl, 4nitrophenyl, 2-chlorophenyl, 2,4 dichlorophenyl, etc. Phenyl group with or without substituents; alkylene moiety having an aromatic ring with or without substituents such as benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, 4-nitrobenzyl, 4-I'lorphenethyl; represents an aralkyl group having 1 to 5 carbon atoms.

However, it is not particularly limited to the above-mentioned protecting groups.

In carrying out the method of the present invention, the reaction of oxidizing the compound having the general formula (n) to produce the compound having the general formula (m) is carried out using an oxidizing agent in the presence or absence of a solvent. It is done by using

Examples of the oxidizing agent used include chromic acid, chromic anhydride, chromic anhydride-hydrolysine complex salt (Co11ins
reagent), chromic anhydride-concentrated sulfuric acid (Jones reagent)
, chromic acids such as sodium dichromate and potassium dichromate; N-bromoacetamide, N-bromsuccinimide, N-bromphthalimide, N-chloro-p-
Organic active halogen compounds such as toluenesulfonamide and N-chlorobenzenesulfonamide; aluminum alkoxides such as aluminum tertiary oxide and aluminum isopropoxide; dimethyl sulfoxide;
Dicyclohexylcarbodiimide, dimethyl sulfoxide-acetic anhydride, and the like are preferably used.

When using a solvent, there are no particular limitations on the solvent as long as it does not participate in this reaction, but for example, when using chromic acids, organic acids such as acetic acid, acetic acid anhydride, or organic acids and organic acid anhydrides can be used. Mixed solvents with dichloromethane, chloroform, carbon tetrachloride, etc., and logenated hydrocarbons are suitable.

When using an organic active halogen compound, aqueous organic solvents such as aqueous tertiary phthanol, aqueous acetone, and aqueous pyridine are suitable.

When aluminum alkoxides are used, aromatic hydrocarbons such as benzene, toluene, and xylene are preferred.

When dimethyl sulfoxide-dicyclohexylcarbodiimide or dimethyl sulfoxide-acetic anhydride is used, other solvents are not particularly required as long as an excess of dimethyl sulfoxide is used.

When aluminum alkoxides are used, it is preferable to use an excess of ketones such as acetone, methyl ethyl ketone, cyclohexanone, and benzoquinone as hydrogen acceptors in addition to the above-mentioned solvents.

In this reaction, it is necessary to completely remove water from the reaction system.

When dimethylsulfoxide-dicyclohexylcarbodiimide is used, a catalytic amount of an acid such as phosphoric acid or acetic acid is used in accordance with a conventional method.

In this reaction, chromic acids, particularly chromic anhydride-pyridine complex salt (Colins reagent) and chromic anhydride-concentrated sulfuric acid monohydrate (Jones reagent) are usually used as suitable oxidizing agents.

Although there is no particular limitation on the reaction temperature, it is desirable to carry out the reaction at a relatively low temperature in order to suppress side reactions, and the reaction is usually carried out at a temperature of -20°C to room temperature.

The reaction time varies mainly depending on the reaction temperature and the type of oxidizing agent used, but is about 5 minutes to 2 hours.

After the reaction is completed, the target compound of the oxidation reaction is collected from the reaction mixture according to a conventional method.

For example, after the reaction is completed, an organic solvent such as ether is added to the reaction mixture and then insoluble materials are removed.

After washing and drying the resulting organic solvent layer, the solvent is distilled off from the organic solvent layer.

The obtained target compound can be further purified, if necessary, using conventional methods such as column chromatography and thin layer chromatography.

Next, the reaction for removing the hydroxyl protecting group from the thus obtained compound having the general formula (In) differs depending on the type of the protecting group.

When the protecting group for a hydroxyl group is, for example, a heterocyclic group such as 2-tetrahydropyranyl or an alkyl group having an alkoxy substituent such as methoxymethyl, this protection can be 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 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 is not involved in the reaction, such as 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 particularly preferably carried out at room temperature.

When the protecting group for the hydroxyl group is an alkyl group such as methyl, this can be easily achieved by bringing it into contact 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 participate in the reaction, such as dichloromethane. , chloroform, and other halogenated hydrocarbons are preferably used.

The reaction temperature is not particularly limited, but in order to suppress side reactions, it is desirable to carry out the reaction at a relatively low temperature, and the reaction is preferably carried out at -30°C to room temperature.

When the hydroxyl protecting group is, for example, a trialkylsilyl group such as trimethylsilyl, this can be easily achieved by contacting it with water or water containing an acid or a base.

When water containing acids or bases is used, examples of the acids or bases contained include organic acids such as formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, and malonic acid; hydrochloric acid, hydrobromic acid, and sulfuric acid. Acids such as mineral acids or alkali metal and alkaline earth metal hydroxides such as potassium hydroxide, calcium hydroxide; bases such as alkali metal and alkaline earth metal carbonates such as potassium carbonate and calcium carbonate. Used without any particular restrictions.

In the reaction, if water is used as a solvent, no other solvent is particularly required.

When using other solvents, for example, tetrahydrofuran,
Ethers such as dioxane: A mixed solvent of water and an organic solvent such as alcohols such as methanol and ethanol is used.

The reaction temperature is not particularly limited, but it is usually suitably carried out at room temperature.

When the protecting group for the hydroxyl group is, for example, a carbonate residue of an ester such as ethoxycarbonyl, this can be easily achieved by contacting it with an acid or a base.

Acids or bases used include, for example, mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; hydroxides of alkali metals and alkaline earth metals such as potassium hydroxide, calcium hydroxide; Carbonates of alkali metals and alkaline earth metals, 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 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, such as 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 is carried out at room temperature to the reflux temperature of the solvent.

The reaction time depends mainly on the type of protecting group to be removed.

After completion of the reaction, the target compound of the reaction for removing the hydroxyl protecting group is collected from the reaction mixture according to a conventional method.

For example, after the reaction is completed, the reaction mixture is made neutral, then an appropriate organic solvent is added to perform extraction, and the solvent is distilled off from the extract.

The obtained target compound can be further purified, if necessary, using conventional methods such as column chromatography and thin layer chromatography.

Among the compounds having the general formula (I) thus obtained, those in which R2 is a hydrogen atom can be converted into a salt by a conventional method.

Furthermore, when the target compound thus obtained is a mixture of various geometric and optical isomers, these can be separated and resolved at an appropriate synthetic step.

The compound having the general formula (II) used as a raw material compound in carrying out the method of the present invention is a novel compound, and is produced, for example, by the following method.

First, in the compound having the general formula (II),
A compound in which A is an ethylene group is synthesized by the following steps.

In the above formula, R1, R2, R3, R4 and R5 have the same meanings as described above.

However, the hydroxyl-protecting group R5 is a group that is not removed at the same time when the hydroxyl-protecting group R9 is removed.

R7 and R9 represent a hydroxyl group-protecting group, and the hydroxyl group-protecting group may be one that does not affect other parts of the compound due to a removal reaction when the protecting group is later removed and replaced with a hydrogen atom. There is no particular limitation (such protecting groups include, for R7, the same protecting groups as the above-mentioned R5, and for R9, for example, acetyl, n-glopionyl, impropionyl, n-butyryl, imbutyryl). Suitable protecting groups include acyl groups such as , benzoyl, 4-nitrobenzoyl, 2-chlorobenzoyl, 2,4-dichlorobenzoyl, and phenylacetyl.

R8 represents a protecting group for the carboxyl group, and the protecting group for the carboxyl group is one that does not affect other parts of the compound due to a removal reaction when the protecting group is later removed and replaced with a hydrogen atom. If so, there is no particular limitation, and examples of such protecting groups include methyl, ethyl, n
-propyl, inpropyl, n-butyl, isobutyl,
Hydrocarbon groups such as phenyl and benzyl: 2, 2, 2-
halogenated alkyl group such as trichloroethyl; 2-
Examples include heterocyclic groups such as tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofucinyl, and 4-methoxytetrahydropyran-4-yl, but are particularly limited to these protective groups. isn't it.

Below is [Tetrahedron Letters 19]
Each step carried out using a known compound represented by the general formula (V) described in 1972, p. 115 as a starting material will be described.

The first step is a step of producing a compound having the general formula (Vl), and is a reaction to obtain a compound having the hydroxyl group of the compound having the general formula (V) protected.

Compounds forming the protecting group used include, for example, heterocyclic compounds such as dihydropyran, dihydrothiopyran, dihydrothiophene, 4-methoxy-5,6-hydro(2H)pyran; methoxymethylene chloride, ethoxyethylene chloride; Alkoxy halogenated hydrocarbon compounds such as ethyl vinyl ether, methoxy-1-
Unsaturated compounds such as cyclohexene: halogenated hydrocarbon compounds such as methyl chloride, ethyl chloride;
Suitable compounds include alkoxycarbonyl chloride compounds such as benzyloxycarbonyl chloride and ethoxycarbonyl chloride; hexamethyldisilazane and the like.

When heterocyclic or unsaturated compounds are used, the reaction is carried out with a small amount of acid, e.g. mineral acids such as hydrochloric acid, hydrobromic acid or organic acids such as picric acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid. Performed in the presence of acid.

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

It is preferable to use a solvent to facilitate the reaction.
The solvent to be used is not particularly limited as long as it does not participate in this reaction, and for example, inert organic solvents such as chloroform, halogenated hydrocarbons such as dichloromethane, and nitrites such as niacetonitrile are preferably used.

Next, when an alkoxyhalogenated hydrocarbon compound, a halogenated hydrocarbon compound, an alkoxycarbonyl chloride compound or hexamethyldisilazane is used, the reaction is carried out in the presence of a base.

The base to be used is an alkoxy halogenated hydrocarbon compound; in the case of a halogenated hydrocarbon compound, an alkali metal hydride such as sodium hydride, potassium hydride, lithium hydride; an alkali such as sodium amide or potassium amide; Examples include metal amides; alkali metal alkoxides such as sodium methoxide and potassium ethoxide; and metal salts of dialkyl sulfoxide such as sodium and potassium salts of dimethyl sulfoxide.

When an alkoxycarbonyl chloride compound or hexamethyldisilazane is used, tertiary amines such as trimethylamine, triethylamine, and pyridine can be used.

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

It is preferable to use a solvent to facilitate the reaction.
The solvent to be used is not particularly limited as long as it does not participate in this reaction, and examples include ethers such as tetrahydrofuran, dioxane, and diethyl ether; hydrocarbons such as benzene, toluene, and cyclohexane, and dialkylformamides such as dimethylformamide. ; Inert organic solvents such as dialkyl sulfoxides such as dimethyl sulfoxide are preferably used.

Although the reaction temperature is not particularly limited in any case, it is usually suitably carried out at about 0°C to room temperature.

The reaction time varies mainly depending on the reaction temperature and the type of compound forming the protecting group used, but is about 1 hour to 24 hours.

The second step is a step of producing a compound having the general formula (■), and is achieved by reducing the compound having the general formula (VI).

The reaction is carried out in the presence of a reducing agent.

Examples of the reducing agent used include diisobutylaluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, and tritetrahydride.
Metal hydride compounds such as rt-butoxylithium aluminum and trimethoxylithium aluminum hydride are preferably used.

In particular, diisobutylaluminum hydride is preferably used because the reaction progresses at relatively low temperatures and side reactions are less likely to occur.

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 to be used is not particularly limited as long as it does not participate in the reaction, and examples include methanol, Alcohols such as ethanol; ethers such as tetrahydrofuran and dioxane;
Inert organic solvents such as hydrocarbons such as benzene and toluene are preferably used.

The reaction temperature is desirably carried out at a relatively low temperature in order to suppress side reactions, and is usually suitably carried out at a temperature of -75°C to room temperature.

The third step is a step of producing a compound having the general formula (■), and converting the compound having the general formula (■) into a compound having the general formula (where R10 is an aryl group such as phenyl or an alkyl group such as n-butyl). Indicates a hydrocarbon group such as a group.

M represents an alkali metal such as sodium or potassium.

), which is then converted to the free acid by treatment with an acid in a conventional manner, and then the carboxyl group of the resulting compound is protected.

A compound having the above general formula (■) is converted into a compound having the above general formula (XVI
) is usually carried out in the Wittzig reaction step in which the compound 1 having the general formula (■) is reacted with the compound 1 having the general formula (■) in the presence of a solvent.
This is carried out using about 1 to 20 moles of the compound having the general formula (XVI) per mole, preferably an excess amount of Witzig's reagent.

The solvents used are those commonly used in Witschich reactions without particular limitation, such as diethyl ether, tetrahydrofuran, dioxannat ethers; hydrocarbons such as benzene, toluene, and hexane; dialkyl sulfoxides such as dimethyl sulfoxide; Examples include inert organic solvents such as dialkylformamides such as dimethylformamide and halogenated hydrocarbons such as dichloromethane and chloroform.

The reaction is also preferably carried out in an inert gas such as nitrogen, argon, or helium.

There is no particular limitation on the reaction temperature, and the reaction is carried out at 0°C to the reflux temperature of the solvent, and is usually suitably carried out at room temperature.

The products obtained by the above Wittzig reaction are salts, which can be easily converted to the free acid by treatment with organic acids such as acetic acid, propionic acid, oxalic acid; mineral acids such as hydrochloric acid, hydrobromic acid, etc. Can be converted.

Next, the reaction for protecting the carboxyl group is carried out by contacting the compound with a compound that forms a protecting group for the carboxyl group in the presence or absence of a solvent.

Compounds forming the protecting group used include, for example, diazomethane, diazoethane, diazo-p-propane, diazo-n-butane, diazoisobutane, diazo-n-octane, 1-diazo-2ethylhexane, 1-cyaso-2- Diazo hydrocarbons such as flopene, cyclohexyldiazomethane, phenylcyatomethane; 2.2.2
-Halogenated alcohols such as trichloroethanol; dihydropyran, dihydrothiopyran, dihydrothiophene, 4-methoxy-5,6-sihydro (2H)
Examples include heterocyclic compounds such as pyran.

The solvent used when using diazo hydrocarbons is not particularly limited as long as it does not participate in this reaction, and ethers such as diethyl ether and dioxane are suitable.

There is no particular limitation on the reaction temperature, but in order to suppress side reactions and prevent decomposition of diazo hydrocarbons, it is desirable to carry out the reaction at a relatively low temperature, and it is usually preferably carried out under water cooling.

When a halogenated alcohol such as 2.2.2-trichloroethanol is used, the reaction is preferably carried out in the presence of a dehydrating agent such as sulfuric acid or dicyclohexylcarbodiimide.

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 to be used is not particularly limited as long as it does not participate in the reaction, and examples include diethyl ether, Ethers such as dioxane are preferably used.

The reaction temperature is not particularly limited, but it is usually suitably carried out at room temperature.

When using heterocyclic compounds, a small amount of acid, such as hydrochloric acid,
It is carried out in the presence of a mineral acid such as hydrobromic acid or an organic acid such as picric acid, trifluoroacetic acid, benzenesulfonic acid, p-)luenesulfonic acid.

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

It is preferable to use a solvent to facilitate the reaction.
The solvent used is not particularly limited as long as it does not participate in this reaction, and inert organic solvents such as halogenated hydrocarbons such as chloroform and dichloromethane; nitriles such as acetonitrile 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.

The fourth step is a step of producing a compound having the general formula (IX), and is achieved by subjecting the compound having the general formula (■) to a reaction that protects the hydroxyl group.

Compounds forming protective groups used include, for example, acyl chlorides such as acetyl chloride, n-propionyl chloride, inbutyryl chloride, benzoyl chloride, 4-nitrobenzoyl chloride, 4-chlorobenzoyl chloride, phenylacetyl chloride. Compounds: Suitable compounds include acid anhydrides such as acetic anhydride, propionic anhydride, and benzoic anhydride.

The reaction is usually suitably carried out in the presence of a base, and the bases used include trimethylamine, triethylamine,
Examples include tertiary amines such as pyridine.

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

It is preferable to use a solvent to facilitate the reaction.
The solvent used is not particularly limited as long as it does not participate in this reaction (for example, ethers such as tetrahydrofuran, dioxane, and diethyl ether; hydrocarbons such as benzene, toluene, and cyclohexane; dialkylformamides such as dimethylformamide). Inert organic solvents such as the following are preferably used.

Although the reaction temperature is not particularly limited, it is usually carried out at around 0°C to 70°C.

The reaction time varies mainly depending on the reaction temperature and the type of compound forming the protecting group used, but is about 1 hour to 24 hours.

The fifth step is a step of producing a compound having the general formula (X), and is achieved by subjecting the compound having the general formula (IX) to a reaction for removing the hydroxyl protecting group R7.

The type of acid or base used and the reaction conditions are the same as those described in the reaction for removing the hydroxyl protecting group from the compound having the general formula (I[[).

The sixth step is a step of producing a compound having the general formula (XI), and is achieved by reducing the compound having the general formula (X).

The reaction is carried out using a reducing agent in the presence of a solvent.

The reducing agent used is not particularly limited as long as it converts only double bonds into ethylene bonds without reducing carbonyl groups; for example, hydrogen is used in the presence of a catalyst such as palladium on carbon or platinum oxide. A catalytic reduction method is preferably carried out.

The reaction is carried out in the presence of a solvent, but the solvent to be used is not particularly limited as long as it does not participate in the reaction; for example, alcohols such as methanol, ethanol, and isopropanol; ethers such as tetrahydrofuran and dioxane. Inert organic solvents such as the following are preferably used.

There is no particular limitation on the reaction temperature, but it is usually suitably carried out around room temperature.

When the catalytic reduction method is used, the reaction is carried out until the calculated amount of hydrogen gas is absorbed.

The seventh step is a step of producing a compound having the above general formula (■), and is achieved by oxidizing the compound having the above general formula (XI).

The reaction is carried out in the presence of an oxidizing agent, and the type of oxidizing agent used and the reaction conditions are such that the compound having the general formula (I[) is oxidized to produce the compound having the general formula (III). This is the same as in the case described above.

The eighth step is a step of producing a compound having the above general formula (xm), in which a compound having the above general formula (■) is produced by the general formula (wherein R1, R3 and R4 have the same meanings as described above). , R11 represents an alkyl group such as methyl or an aryl group such as phenyl.

M■ represents a metal ion such as sodium, potassium, or lithium.

) is achieved by reacting with Witzig's reagent.

The solvent used is not particularly limited to those used in general Winchch reactions, such as ethers such as diethyl ether, tetrahydrofuran, and dioxane; hydrocarbons such as benzene, toluene, and hexane;
Examples include inert organic solvents such as dialkyl sulfoxides such as dimethyl sulfoxide; dialkyl formamides such as dimethylformamide; and halogenated hydrocarbons such as dichloromethane and chloroform.

The reaction is also preferably carried out in an inert gas such as nitrogen, argon, or helium.

There is no particular limitation on the reaction temperature, and the reaction is carried out at 0°C to the reflux temperature of the solvent, and is usually suitably carried out at room temperature.

The ninth step is a step of producing a compound having the general formula (X[V), and is achieved by reducing the compound having the general formula (xm).

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

The reducing agent used is not particularly limited as long as it converts a carbonyl group into a hydroxyl group without reducing double bonds, such as sodium borohydride, potassium borohydride, lithium borohydride, Metal hydride compounds such as zinc boron, tri-tert-butoxylithium aluminum hydride, trimethoxylithium aluminum hydride, sodium cyanoborohydride, and lithium-9b-poraperhydrophenalene hydride 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, Alcohols such as methanol, ethanol and isopropanol; inert organic solvents such as ethers such as tetrahydrone and dioxane 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 the reaction temperature is usually suitably carried out at -10°C to room temperature.

The disciple process is a process for producing a compound having the general formula (XV), and is achieved by subjecting the compound having the general formula (xrv) to a reaction that protects the hydroxyl group.

The hydroxyl-protecting group is not particularly limited as long as it is not removed simultaneously when the hydroxyl-protecting group R9 is removed later.

The compound forming the protecting group used in the reaction and the reaction conditions thereof are the same as those described in the first step above.

The first step is a step for producing a compound having the general formula (II), in which the hydroxyl-protecting group R9 and the carboxyl-protecting group R8 of the compound having the general formula (XV) are
This is achieved by subjecting the carboxyl group to a reaction that removes the carboxyl group and, if necessary, esterifies the carboxyl group.

In this step, after removing the hydroxyl protecting group R9,
Even if the reaction for removing the carboxyl group-protecting group R8 is not particularly performed, the carboxyl group-protecting group R8 may also be removed at the same time when the hydroxyl group-protecting group R9 is removed.

The reaction for removing the hydroxyl protecting group R9 is easily accomplished by contacting with an acid or base.

Examples of acids or bases used include mineral acids such as hydrochloric acid, hydrobromic 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 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. Water: Alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; 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.

The reaction for removing the carboxyl protecting group R8 differs depending on the type of protecting group.

Protecting groups for carboxyl groups are, for example, methyl, ethyl, n-
In the case of hydrocarbon groups such as propyl, n-butyl, isobutyl, benzyl, this is achieved by contacting with acids or bases.

The acids or bases used are those commonly used in hydrolysis 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 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, such as water. Alternatively, a mixed solvent of water and any alcohol such as methanol or ethanol or an ether such as tetrahydrofuran or dioxane is preferably used.

The reaction temperature is not particularly limited and is carried out at room temperature to the reflux temperature of the solvent.

When the carboxyl group protecting group is a halogenated alkyl group such as 2,2,2-trichloroethyl, zinc-
This is achieved by contacting with acetic acid.

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

The solvent to be used is not particularly limited as long as it does not participate in this reaction, and suitable examples include water; ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol; or a mixed solvent of these organic solvents and water. used.

The reaction temperature is not particularly limited and is usually suitably carried out at room temperature.

When the protecting group for the carboxyl group is a heterocyclic group such as 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrochenyl, 4-methoxytetrahydropyran-4-yl, by contacting with an acid. achieved.

Preferred acids used include 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 preferably carried out in the presence of a solvent.

The solvent to be used is not particularly limited as long as it does not participate in this reaction, and suitable examples include water; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and mixed solvents of these organic solvents and water. 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.

The reaction time mainly depends on the type of protecting group to be removed and the reaction conditions for its removal.

Next, if necessary, the reaction of esterifying the carboxyl group is carried out by contacting it with an esterifying agent in the presence or absence of a solvent.

The esterifying agent to be used is not particularly limited, and may be an esterifying agent that is commonly used for converting a carboxyl group into an alkoxycarbonyl group.

Esterifying agents used include, for example, diazoalkanes such as diazomethane, diazoethane, diazo-n-propane, and diazoisopropane; alcohols that form ester groups such as methanol, ethanol, n-propatool, and isopropane; and mineral acids such as hydrochloric acid, hydrobromic acid or sulfuric acid, or organic acids such as methanesulfonic acid, benzenesulfonic acid or p-)luenesulfonic acid.

When diazoalkanes are used, the reaction is preferably carried out in the presence of a solvent.

The solvent to be used is not particularly limited as long as it does not participate in this reaction, and ethers such as diethyl ether and dioxane are suitable.

There is no particular limitation on the reaction temperature, but in order to suppress side reactions and prevent decomposition of diazoalkanes, it is desirable to carry out the reaction at a relatively low temperature, and it is usually preferably carried out under water cooling.

When using an alcohol in the presence of an acid, an excess of the alcohol is usually preferably used as a solvent.

The reaction temperature is not particularly limited, but it is preferably carried out at room temperature or around the reflux temperature of the alcohol used.

The reaction time varies mainly depending on the reaction temperature and the type of alcohol used, but is about 1 hour to 2 days.

Next, in the compound having the general formula (I[),
A compound in which A is a cis-vinylene group is synthesized by the following steps.

In the above formula, R1, R2, R3, R4, R5, R8 and R9 have the same meanings as described above.

Hereinafter, the general formula (X) produced in the fifth step described above
Each step carried out using the compound represented by as a starting material will be explained.

The first step is a step of producing a compound having the general formula (xvm), and is achieved by oxidizing the compound having the general formula (X).

The reaction conditions of this step are the same as those described in the seventh step for producing the compound having the general formula (■).

The second step is a step of producing a compound having the general formula (XIX), and is achieved by reacting the compound having the general formula (XVI[) with the Witzig reagent having the general formula (xvn).

The reaction conditions in this step are the same as those described in the eighth step for producing the compound having general formula (xm).

The third step is a step of producing a compound having the general formula (XX), and is achieved by reducing the compound having the general formula (XIX).

The reaction conditions of this step are the same as those described in the ninth step for producing the compound having the general formula (xrv).

The fourth step is a step of producing a compound having the general formula (XXI), and is achieved by subjecting the compound having the general formula (XX) to a reaction that protects the hydroxyl group.

The reaction conditions of this step are the same as those described in the disciple step for producing the compound having the general formula (XV).

The fifth step is a step of producing a compound having the above general formula (n), in which the hydroxyl group protecting group R9 and the carboxyl group protecting group R8 of the compound having the above general formula (XXt)
This is achieved by subjecting the carboxyl group to a reaction that removes the carboxyl group and, if necessary, esterifies the carboxyl group.

The reaction conditions of this step are the same as those described in the first step of producing the compound having the general formula (n).

In each of the above steps, each target compound can be obtained by treating the reaction mixture in a conventional manner after the reaction is completed.

The obtained target compound can be further purified, if necessary, using conventional methods such as column chromatography and thin layer chromatography.

Further, when the target compound of each step obtained in this way is obtained as a mixture of various geometric isomers and optical isomers, these can be separated and resolved at an appropriate synthetic step.

Next, the method of the present invention will be explained in more detail with reference to Examples and Reference Examples.

Example 1 9-oxo-15-(2-tetrahydropyranyloxy)-20-isopropylideneprost-13()lance)-enoic acid 9α-hydroxy-16(2-tetrahydropyranyloxy)-20-isopropylideneprost )−
13() lance)-enoic acid 2.6? acetone 80rr
John's (
Jones) Add 5 ml of oxidizing reagent.

Thereafter, the reaction is completed by stirring at -20 to -10°C for 30 minutes.

The reaction solution is diluted with ice water 2007711, extracted with ether, the extract is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain the target compound 2.61 in the form of an oil.

Infrared absorption spectrum (liquid film) CrfL-1: 3200
．． 2750-11740.1710.1200.113
0.1110.1020, 70 Nuclear magnetic resonance spectrum (CDC13) δppm: 5.5
5 (2H1 multiplet) 5.10 (IH1 multiplet) 4.70 (IH1 multiplet) Example 2 (1) 9-oxo-15α-hydroxy-20-isopropylidenepros)-13()lance)- Enoic acid methyl ester and 9-oxo-15β-hydroxy-20-impropylideneprost)-13()7ns)-enoic acid methyl ester oxo-15(2tetrahydropyranyloxy)-20-isopropylideneprost 13(trans )-enoic acid (2.62%) was dissolved in a 50% acetic acid aqueous solution and stirred at 50°C for 1.5 hours to complete the reaction.

The reaction solution was diluted with 200 ml of ice water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an oily residue (2.21).

An ether solution of diazomethane is added to this residue until the yellow color of diazomethane no longer disappears, and then the ether is distilled off to obtain an oily residue of 2.23S'.

By separating and purifying this residue using silica gel column chromatography and thin layer chromatography,
Target 15α-hydroxy body 730 in oil form, respectively
ml9 and 15β-hydroxy form 6801n9 are obtained.

15α-hydroxy infrared absorption spectrum (liquid film) cIrL-1: 3480
．． 1740.120011170, 70 Nuclear magnetic resonance spectrum (CDC13) δppm: 3.6
5 (3H, singlet) 4.10 (IH1 multiplet) 5.10 (IH, multiplet) 5.60 (2H1 multiplet) Mass spectrometry (molecular weight 392): Molecular ion peak 392 15β-hydroxy body infrared Absorption spectrum (liquid film) CrfL-1:3480
．． 1740.1200, 1170°70 Nuclear magnetic resonance spectrum (CDC13) δppm: 3.6
5 (3H1 multiplet) 4.10 (LH1 multiplet) 5.13 (IH, multiplet) 5.60 (2H1 multiplet) Mass spectrometry (molecular weight 392): Molecular ion peak 392 Example 2 (2) a 9-oxo-15α-hydroxy-20-isopropylideneprost-13()lance)-enoic acid 9-oxo-15α-hydroxy-20-isopropylideneprost-13()lance)-enoic acid methyl ester 730 μm in methanol After dissolving in 13rnl and adding 10TLl of a 5% aqueous sodium hydroxide solution, the mixture was stirred at room temperature for 2 hours.

After the reaction is complete, dilute the reaction solution with 150 TLl of ice water.
% aqueous hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an oily residue 730W19.

By crystallizing this residue from ether and n-hexane, the target compound 524 having a melting point of 40-45°C was obtained.
(2) is obtained as a crystal.

Infrared absorption spectrum (liquid film) crfL-1: 3400
．． 2670.1740.1720.1460.1410
, 1280.1220.113Q, 97Q Nuclear magnetic resonance spectrum # (CD3COCD3) δpp
m: 4.08 (IH1 multiplet) 5.16 (LH, triplet) 5.64 (2H1 multiplet) 6.50 (2H1 multiplet) Mass spectrometry (molecular weight 378): Molecular ion peak 378 9-oxo -15α-Hydroxy-20-isopropylideneprost-13()lance)-enoic acid potassium salt 9-oxo15α Hydroxy0 Isopropylideneprost-13()lance)-enoic acid 15
After dissolving 0■ in a mixed solvent of 8a of methanol and 2mA of water, 281v of potassium carbonate was added and stirred at room temperature for 1 hour.

After the reaction is completed, the solvent is distilled off from the reaction solution under reduced pressure to obtain the target compound 1701v in powder form.

Infrared absorption spectrum (liquid paraffin) 3400.1
735.1580-1560crfL-1 Example 2(2)b 9-oxo-15β-hydroxy-20-impropylideneprost-13()lans)-enoic acid 9-oxo-15β-hydroxy-20-impropylidene By reacting and treating Denprost-13()lance)-enoic acid methyl ester 6807Q in the same manner as in Example 2 (2)a, 650m9 of the target compound in the form of an oil is obtained.

Infrared absorption spectrum (liquid film) c7n': 3400.2
680.1740.1720゜1270.1160.9
70 Nuclear magnetic resonance spectrum (CD3COCD3) δppm:
4.08 (LH, multiplet) 5.12 (LH, triplet) 5.60 (2H1 multiplet) Mass spectrometry (molecular weight 378): Molecular ion peak 378 Example 3 9-oxy-15-(2- Tetrahydropyranyloxy)-20-isopropylideneprost 5(cis), 13
(trans)-dienoic acid 9α-hydroxy-15-(2
-Tetrahydropyranyloxy)-20-isopropylideneprost-5(cis),13(trans)-dienoic acid 2.51 was reacted and treated in the same manner as in Example 1 to obtain the oily target compound 2.35f. can get.

Infrared absorption spectrum (liquid film) crfLl: 3200.
2650.1740.1710.1130.1015.
970 Example 4 (1) 9-oxo-15α-hydroxy-20-isofuroylideneprost-5(cis), 13()lans)-dienoic acid methyl ester and 9-oxo-15β-hydroxy-20-improst Viritemprost-5 (cis), 1
3(trans)-dienoic acid methyl ester oxo-15-(2 tetrahydropyranyloxy)-20-improvilitenprost 5(cis),13(trans)-dienoic acid 2.342 Example 2
By reacting and treating in the same manner as in (1), the desired oily compounds, 0.70P of 15α-hydroxy compound and 0.771 P of 15β-hydroxy compound, are obtained.

15α-hydroxy substance infrared absorption spectrum (liquid film) crfL”: 3450.
1740.1435.1200゜1155.1010.
970 Nuclear magnetic resonance spectrum (CDC13) δppm: 3.6
5 (3H, singlet) 4.08 (IH1 multiplet) 5.08 (LH, triplet) 5.33 (2H1 multiplet) 5.56 (2H1 multiplet) 15β-hydroxy body infrared absorption spectrum (liquid film) CrrL": 348
0.1740.1430, 1240°1215.115
5.970 Nuclear magnetic resonance spectrum (CDC13) δppm: 3.6
5 (3H, singlet) 4.08 (IH1 multiplet) 5.10 (IH1 multiplet) 5.35 (2H1 multiplet) 5.56 (2H1 multiplet) Example 4 (2) a 9- Oxo-15α-hydroxy-20-improbilitenprost-5(cis),13()lance)-dienoic acid 9-oxo-15α-hydroxy-20-improvilitenprost-5(cis),13()7 ) −−)
Enoic acid methyl ester 6901n9 to methanol 151
(dissolved in rLl and 5% hydroxide) IJium aqueous solution 157
After adding 1 u, stir at room temperature for 1 hour.

After the reaction is complete, dilute the reaction solution with 100 ml of ice water and add 7
After neutralizing with % hydrochloric acid aqueous solution, extracting with ethyl acetate, washing the extract with water, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure.The resulting oily residue was purified by column chromatography. Oily target compound 51
1■ is obtained.

Infrared absorption spectrum (liquid film) crrL-1: 3400
．． 2650,1710.1400.1230.1150
．． 1060,960 Nuclear magnetic resonance spectrum (CD3COCD3) δppm:
4.04 (IH1 multiplet) 5.12 (IH1 multiplet) 5.32 (2H1 multiplet) 5.57 (2H1 multiplet) Mass spectrometry (molecular weight 376): Molecular ion peak 376 Example 4 (2) b 9-oxo-15β-hydroxy-20-improbilitenprost-5(cis), 13(trans)-dienoic acid 9-oxo-15β-hydroxy-20-isoprobilitenprost)-5(cis), 13 ()-Lance)-dienoic acid methyl ester 763■ By reacting and treating in the same manner as in (2)a of Example 4, the target compound 667 in the form of an oil was obtained.
■ is obtained.

Infrared absorption spectrum (liquid film) cm': 3400.2650, 1740, 1710°1400.
1230.1150,1000°60 Nuclear magnetic resonance spectrum (CD3COCD3) δppm:
4.03 (IH1 multiplet) 5.10 (IH, multiplet) 5.36 (2H1 multiplet) 5.60 (2H1 multiplet) Mass spectrometry (molecular weight 376): Molecular ion peak 376 Reference example 1 3-oxo -6-syn(2-tetrahydropyranyloxymethyl)-2-oxabicyclo[3.3.O]-octane 3-oxo-6-syn-hydroxymethyl-2oxabicyclo[3.3.0)-octane 3.351 anhydrous 2.
3-dihydropyran (dissolved in 51 rLl, 15μ p
-) Add luenesulfonic acid and stir at room temperature for 20 minutes.

After the reaction is complete, dilute with 2007d ethyl acetate and
By washing three times with saturated brine of OmA', drying with anhydrous sodium sulfate, and evaporating the solvent, an oily target compound 5.95f is obtained.

Infrared absorption spectrum (liquid film) cIIL-1:1780
．． 1165.1125.1035 Reference Example 2 3-Hydroxy-6-syn(2-tetrahydropyranyloxymethyl)-2-oxabicyclo[3.3.0]-
3-oxo-6-syn(2tetrahydropyranyloxymethyl)-2-oxabicyclo[3.
3.0)-octane 5.9i to anhydrous toluene 1OO77
11 and stirred at -70°C under an argon gas stream.

Add diisobutylaluminum hydride (
21 ml of 25P/1ooyn-hexane solution was gradually added and stirred at -70°C for 30 minutes.

After the reaction is complete, a 2:1 solution of tetrahydrofuran and water 18
After gradually adding 07711 dropwise, the mixture was returned to room temperature.

After removing the precipitated insoluble matter using Celite, diluting with saturated brine and extracting with ethyl acetate, the organic layer was washed with water and dried over anhydrous sodium sulfate to remove the solvent, yielding the target compound 5.89S in the form of an oil. ' is obtained.

Infrared absorption spectrum (liquid film) crIL”: 3450
．． 1125.1065.1025 Nuclear magnetic resonance spectrum (CDC13) δppm: 4.6 to 4.8 (2H, multiplet) 5.58 (LH1 multiplet) Reference example 3 1α-hydroxy-2α-(6-medoxycarpo= /
1/-2-cis-hexenyl)-3β-(2tetrahydropyranyloxymethyl)-cyclopentane 7.10S' and 2
When (4-carboxybutyl)trinoenylphosphonium furomide 321 is added to the sodium methylsulfinyl carbanion solution obtained from dimethylsulfoxide of 007d in an argon gas stream at 20° C. or below, a red ylide solution is obtained.

Add 3-hydroxy-6-syn(2-tetrahydropyranyloxymethyl)-2oxabicyclo[3.3
・201 rL of a dimethyl sulfoxide solution containing 5.81 l of 0]-octane is added, and the mixture is stirred at room temperature for 30 minutes.

After the reaction is complete, add 500ml of 1.5% cold (0°C) hydrochloric acid aqueous solution.
After diluting the reaction solution in Step 1, extraction with ether is performed, and the extract is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain an oily residue of the carboxylic acid.

After treating this residue with an ether solution of diazomethane, the ether was distilled off to obtain an ester residue 14.
? was obtained, and the residue was treated with silica gel 140'? By column chromatography using 6.57f? is obtained.

Infrared absorption spectrum (liquid film) crrL-1:3480
．． 1740.1200.1■40.1120.1030 Nuclear magnetic resonance spectrum (CDC13) δppm: 3.6
7 (3H1 multiplet) 4.23 (IH1 multiplet) 4.80 (IH1 multiplet) 5.50 (2H1 multiplet) Reference example 4 1α-acetoxy-2α-(6-medoxycarbonyl-2- cis-hexenyl/1/) -3β-(2-tetrahydropyranyloxymethyl)-cyclopenkune 1α-hydroxy-2α-(6-medoxycarbonyl-2-cis-hexenyl)-3β-(2-tetrahydropyranyloxymethyl)- 6.49 P of cyclopentane is dissolved in a mixed solution of 201 rLl of pyridine and 10T/Ll of acetic anhydride and stirred at 40°C for 2 hours.

After the reaction is completed, the reaction solution is diluted with 1501 flL of water and extracted with a mixed solvent of benzene and ethyl acetate.

The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the target compound 7.2 in the form of an oil.
69 is obtained.

Infrared absorption spectrum (liquid film) CrrL”: 1740.
1245.1030 Nuclear magnetic resonance spectrum (CDC13) δppm: 2.0
3 (3H1 multiplet) 3.67 (3H1 multiplet) 4.62 (IH, multiplet) 5.23 (IH1 multiplet) 5.42 (2H1 multiplet) Reference example 5 1α-acetoxy-2α- (6-Medoxycarbonyl-2-cis-hexenyl)-3β-hydroxymethylcyclopentane 1α-acetoxy-2α-(6-medoxycarbonyl-2-cis-hexenyl, 11/)-3β-(2tetrahydropyranyloxymethyl )-cyclopentane 7.2
0f was dissolved in 1501 rLl of methanol containing 10% water, and 4z p-)luenesulfonic acid was added to give 40
Stir at ℃ for 1 hour.

After the reaction was completed, the solution was diluted with 400 ml of ether, washed with saturated brine, washed with anhydrous sulfuric acid, and dried over IJum, and the solvent was distilled off under reduced pressure. An oily residue is obtained.

This residue was subjected to column chromatography using s,oy silica gel to obtain the oily target compound 5.
．． 053f is obtained.

Infrared absorption spectrum (liquid film) CfIL-1: 3500
．． 1740.1380, 1250.1170.1025 Nuclear magnetic resonance spectrum (CDC13) δppm: 2.0
3 (3H1-double line) 3.65. (2H1 multiplet) 3.68 (3H1-multiplet) 5.25 (LH1 multiplet) 5.45 (2H1 multiplet) Reference example 6 1α-acetoxy-2α-(6-medoxycarbonylhexyl)-3β- Hydroxymethylcyclopentane 1α Acetoxy 2α (6-methoxycarbonyl-2-cis-hexenyl)-3β-Hydroxymethyl-cyclopentane 3.0P was dissolved in 50ml of methanol, and 5% palladium-carbon 2.0P was dissolved. Conventional hydrogenation is carried out using Of as a catalyst.

After removing the catalyst, the solvent is distilled off under reduced pressure to obtain the target compound 2.81 in the form of an oil.

Infrared absorption spectrum (liquid film) cm': 350
0.1740.1380.1250°1175.102
0 Nuclear magnetic resonance spectrum (CDC13) δppm: 2.0
3 (3H, - multiplet) 3.63 (2H1 multiplet) 3.70 (3H1 - multiplet) 5.28 (LH, multiplet) Reference example 7 1α-acetoxy to 2α-(6-medoxycarbonylhexyl )-3β-formyl-cyclopenkun Anhydrous dichloromethane 2001rLl to pyridine 11.7
1 was added, and chromic anhydride 7.361 was added while stirring at 15° C. under an argon stream to prepare a Collins oxidation reagent.

After cooling the solution to 3-5°C, 1α-acetoxy-2α
Add 2.76 P of -(6-medoxycarbonylhexyl)-3β-hydroxymethyl-cyclopenkune and stir for 20 minutes.

After completion of the reaction, dilute the reaction solution with 1 liter of ether and 3% hydroxide) Wash with IJium aqueous solution, 3% hydrochloric acid aqueous solution, 5% sodium bicarbonate aqueous solution, water, and anhydrous sulfuric acid)
By sequentially carrying out IJum drying and distilling off the solvent, an oily target compound 2.56y' is obtained.

Reference Example 8 9α-acetoxy-1-5-oxo-20-infrobiliteneprost-13()lance)-enoic acid methyl ester 50% oily sodium hydride 0.495S' was washed with dry petroleum ether to remove oil. After removal, the suspension was suspended in 150 TrL of anhydrous dimethoxyethane, and then 2.7 liters of dimethyl-2oxo-8-methyl-7-ranenylphosphonate was added dropwise under water cooling and stirring in an argon gas stream, and the mixture was stirred at room temperature for 4 hours. Stir for an hour.

To this solution was added 2.50 f of 1α-acetoxy-2α-(6-medoxycarbonylhexyl)-3β-formyl-cyclopentane under water cooling, and the mixture was stirred for 2 hours.

After the reaction was completed, 200 mL of ether was added, and the organic layer was washed with a dilute aqueous hydrochloric acid solution and water.

After drying the organic layer over anhydrous sodium sulfate, the organic solvent was distilled off under reduced pressure to obtain a 4.58P oily residue.

This residue is purified by alumina column chromatography to obtain oily target compound 2.451.

Infrared absorption spectrum (liquid film) cIfL-1: 1740
．． 1700.1670, 1625.1370.1240
．． 117011020 nuclear magnetic resonance spectrum (CDC1
3) δppm: 2.03 (3H, singlet) 3.64 (3H11t) 5.00-5.35 (2H, multiplet) 6.10 (IH12t) 6.52 (LH14t) ) Reference Example 9 9α-acetoxy-15-hydroxy-20ingropylideneprost-13()lance)enoic acid methyl ester 9α-acetoxy-15-oxo-20-isopropylideneprost-13()7nprost-enoic acid Dissolve 2.41 methyl ester in 5 Qrul of anhydrous methanol and
Cool to 5°C and stir.

After adding 210 μ of sodium borohydride to the solution, the mixture was stirred at 3-5° C. for 1 hour.

After the reaction is completed, the mixture is diluted with a cold 3% aqueous hydrochloric acid solution, extracted with a mixed solution of benzene and ethyl acetate, and the extract is washed with water and dried over anhydrous sodium sulfate.

By distilling off the solvent, an oily residue is obtained.

Further, this residue was purified by silica gel column chromatography to obtain the target compound 2.3 in the form of an oil.
1' is obtained.

Infrared absorption spectrum (liquid film) crIL-1: 3500
．． 1740.1245.1020 Nuclear Magnetic Resonance Spectrum (CDC1,) δppm: 2.0 (3HJ singlet) 3.65 (3H11 multiplet) 4.07 (IH1 multiplet) 5.0~5.4 (2H1 multiplet) ) 5.50 (2'H, multiplet) Reference example 10 9α-acetoxy-15-(2-tetrahydropyranyloxy)-20-isopropylideneprost-13(trans)-enoic acid methyl ester 9α-acetoxy-15 -Hydroxy-20isopropylideneprost-13()lance)-enoic acid methyl ester 2.3? was dissolved in 5M of 2,3-dihydropyran and 1
Add 0 ml of p-toluenesulfonic acid and stir at room temperature for 30 minutes.

After the reaction was completed, ether 2007711 was added and washed with water (1
After drying with anhydrous sodium sulfate and distilling off the solvent, the desired oily compound 2.
81 is obtained.

Infrared absorption spectrum (liquid film) cIIL': 1740.
1375.1240.1200゜10201965 Reference example 11 9α-hydroxy-15-(2-tetrahydropyranyloxy)-20-isopropylideneprost-13(trans)-enoic acid 9α-acetoxy 15-(2-tetrahydropyranyloxy) )-20-Impropylidenepros)-13(trans)-enoic acid methyl ester (3.01) was dissolved in 90 TL of methanol, and 3.0 l of 5% aqueous sodium hydroxide solution was added.
After adding rfLl, the mixture was stirred at 40°C for 3 hours.

After completion of the reaction, dilute with ice water, neutralize with 7% aqueous hydrochloric acid solution, extract with ethyl acetate, wash the organic layer with water, and remove anhydrous sulfuric acid.) After drying with IJum, the solvent is distilled off under reduced pressure to obtain an oil. The target compound 2.61 is obtained.

Infrared absorption spectrum (liquid film) CIr1. -1:342
0.2750,1710.120011110.102
0,970 Nuclear magnetic resonance spectrum (CDC13) δppm: 4.7
(IH1 multiplet) 5.0 to 5.5 (3H1 multiplet) 6.0 (2H1 multiplet) Reference example 12 1α-acetoxy-2α-(6-medoxycarbonyl-2-cis-hexenyl)-3β- By reacting and treating 2.01 of formyl-cyclopentane lα-acetoxy-2α-(6-medoxycarponyl-2-cis-hexenyl)-3β-hydroxymethyl-cyclopentane in the same manner as in Reference Example 7, an oily 1.952 of the target compound is obtained.

Reference example 13 9α-acetoxy-15-oxo-20-isopropylideneprostole 5(cis), 13(J lance)-dienoic acid methyl ester 1α-acetoxy-2α-(6-medoxycarbonyl-2-cis-hexenyl )-3β-formyl-cyclopentane 1.95f is reacted and treated in the same manner as in Reference Example 8 to obtain an oily target compound 2.53f.

Infrared absorption spectrum (liquid film) CIrL': 173
5.1695.1670.1630°1370.124
0.1160.1030 nuclear magnetic resonance spectrum (CDC
13) δppm: 2.02 (3H, singlet) 3.65 (3H, singlet) 5.0 to 5.5 (3H1 multiplet) 6.10 (IH, doublet) 5.72 (IH, Reference example 14 9α-acetoxy-15-hydroxy-20-impropylideneprost-5(cis), 13(trans)-dienoic acid methyl ester 9α-acetoxy-15-oxo-20-impropylideneprost- 5 (cis), 13
(trans)-dienoic acid methyl ester 2.58? By reacting and treating in the same manner as in Reference Example 9, an oily target compound 2.24P is obtained.

Infrared absorption spectrum (liquid film) Crn-1: 3500.
1740.1370, 1240.1160.1020,
965 Nuclear magnetic resonance spectrum (CDC13) δppm: 2.0
1 (3-H, 1 weight line) 3.67 (3H, singlet) 4.08 (LH1 multiplet) 5.0-5.6 (5H, multiplet) Reference example 15 9α-acetoxy-15- (2-Tetrahydropyranyloxy)-20-inpropylideneprost-5(cis), 13(trans)-dienoic acid methyl ester 9-acetoxy-15-hydroxy-20-isopropylideneprost-5(cis), 13 By reacting and treating 2.20f of (h-lance)-dienoic acid methyl ester in the same manner as in Reference Example 10, an oily target compound of 2.9 (l
is obtained.

Infrared absorption spectrum (liquid film) crIl": 1740.
1370.1240.1200゜1015.970 Reference example 16 9α-hydroxy-15-(2-tetrahydropyranyloxy)-20-inpropylideneprost-5(cis),13(trans)-dienoic acid 9α-acetoxy- 15-(2-tetrahydropyranyloxy)-20-isopropylideneprost-5(cis),13(trans)-dienoic acid methyl ester 2.9
IP was dissolved in 80 TL of methanol, 50 rr of 5% sodium hydroxide aqueous solution was added, and the mixture was stirred at 40°C for 3 hours.

After the reaction was completed, the reaction solution was diluted with 2007711 ice water, neutralized with 7% hydrochloric acid aqueous solution, and extracted with ethyl acetate.
By sequentially washing the extract with water, drying over anhydrous sodium sulfate, and distilling off the solvent under reduced pressure, an oily target compound 2.
51S' is obtained.

Infrared absorption spectrum (liquid film) (17711:3450
．． 3150, 2650.1710.1200.1130
, 1110, 1015, 65 Nuclear magnetic resonance spectrum (CDCl2) δppm: 4.7
0 (II (, multiplet) 4.95-5.60 (5H1 multiplet) 5.9Q (2H1 multiplet)

Claims (1)

[Claims] (In the formula, A represents an ethylene group or a cis-vinylene group, R1 and R2 are the same or different and represent a hydrogen atom or a lower alkyl group, R3 and R4 represent a lower alkyl group, R5 represents a hydroxyl group protecting group) to produce a compound having the formula (wherein A, R1, R2, R3, R4 and R5 have the same meanings as described above) , and then subjecting the obtained compound to a reaction for removing a hydroxyl protecting group.