JPS588392B2 - Bronchodilators containing prostaglandin derivatives and derivatives thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel prostaglandin derivative having the general formula, a pharmaceutically acceptable salt thereof, and a bronchodilator containing the same as an active ingredient.

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 an alkyl group having 1 to 3 carbon atoms, and R3 and R4 represent a carbon number It represents an alkyl group having 1 to 3 atoms, and R5 represents a hydrogen atom or a hydroxyl group.

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

In the compounds shown in the present specification, including the above general formula (I), when the coordination of the substituent bonded to the cyclopenkune ring is at the α position, it is represented by a dotted line, and when it is at the β position, it is represented by a solid line. It is expressed as

Note that the wavy line indicates the case where any three-dimensional configuration can be adopted.

Among the compounds having the general formula (I) of the present invention, R2
Compounds in which is a hydrogen atom can also be in the form of pharmaceutically acceptable salts.

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

Glostaglandin derivatives having the structural formula represented by the general formula (I) are novel compounds that are completely unknown in the conventional literature, and the present inventors have found that these compounds have a remarkable effect compared to other compounds. The present invention was completed based on the discovery that it has a bronchodilating effect.

Pharmacological tests regarding the bronchodilator effect of the compound having the general formula (I) obtained by the present invention will be described below.

Test method 1 A specimen was administered intravenously to a guinea pig weighing 400 to 600 g that had been anesthetized with sodium bentobarbital, and then 2μ of histamine solution was added to it. /kg to 3μ
? /kg intravenously administered to the wrestler (competition wrestler).
Konzett-R6ssler method
le Pathologieund Pharmaco
Logie) 19 5th volume, 7l pages, 1940]
The increase suppression rate of airway resistance is determined by a modified method, and ■D5o
Test results for which the values were calculated: Table 1 illustrates the results of the bronchodilation effect of the tested grosstaglandin derivatives in guinea pigs.

Test method 2.
0 μ? A histamine solution having a concentration of 1.5 cm/ml was sprayed and inhaled, and a patient was selected to have difficulty breathing and roll over within 1 to 2 minutes in order to equalize the sensitivity, and that time is represented by C.

On the other hand, guinea pigs were sprayed with drug solutions having various concentrations and allowed to inhale for 1 minute, then exposed to the outside air for 1 minute, and further sprayed with a histamine solution having a concentration of 500 μf/rrtl, and then rolled over. The time taken to reach this point is measured, and the time is expressed as T.

From the action curve of drug concentration and T/C value, the drug concentration at which T/C=2, that is, the drug treatment allows the patient to withstand histamine spray for twice as long as in the case of no treatment, was calculated.

Test results: Table 2 illustrates the preventive effects of inhalation of the drug spray as a bronchodilator in guinea pigs.

Test method 3 Cats weighing 2 to 4 kg were anesthetized by intraperitoneal administration of urethane-chloralose, and then serotonin was administered at 15 to 50 μg/kg.
Continuous intravenous infusion at kg/min.

Artificial respiration is 20 to 25 rfLl/kg/mi
Inhalation of n is performed 25 times per minute, and the drug solution is atomized and inhaled along with the inhalation.

After inhalation, the decrease in airway pressure for up to 5 minutes is expressed in an area graph to determine the inhibition %, and from the effect concentration curve of the inhalation fluid concentration and inhibition %, the inhalation fluid concentration μ for 50% inhibition? /ml (
ID5o value) and further calculate the absolute inhalation amount μ? /k9
(I D, o value) was calculated from the inhalation volume, cat respiration volume, and drug solution concentration.

Test results: Table 3 illustrates the therapeutic effects of inhaled drug spray as a bronchodilator in cats.

Compound A: 9-oxo 11α・l5α-dihydroxy-17β-
Methyl-20-ingropyridium salt 13(trans)monenoic acid compound B: 9-oxo-1lα・15α-dihydroxy-17β-
Methyl-20-ingropylideneprost-5 (cis)
, l3(trans)-dienoic acid compound C: 9-oxo 15α-hydroxy-20-ingrohylidenprost-13(}lance)-enoic acid compound D: 9-oxo 15α-hydroxy-20-ingropylideneprost-5 (cis), 13(trans)-dienoic acid compound E: 9-oxo-11α・15α-dihydroxy-20-isopropyriteneprostole 5(cis), 13(trans)-monodienoic acid compound F: 9-oxo-11α・15α-dihydroxy-17-methyl-20-isopropylideneprostole x3 (trans) monoenoic acid methyl ester compound G: 9-oxo 11α・15α-dihydroxy-17-methyl-20-isopropylideneprostole 5 (cis),
13(trans)-dienoic acid methyl ester Furthermore, the bronchodilator effect of the compound having the general formula (I) of the present invention is characterized in that it is not suppressed by the β-adrenergic blocking agent; It has been found that the effects of isoproterenol and isoproterenol are suppressed by β-adrenergic blocking agents.

Acute toxicity test (a) Acute toxicity to mice (RFVL mouse) (b) Acute toxicity to rats (Wister Kondo strain rat) Therefore, the compound having the above general formula (I) can be used when bronchodilation is required. It is useful as a medicine.

The dosage form for that purpose is usually administered by an aerosol spray.

Here, the aerosol spray can be prepared according to a conventional method in the pharmaceutical field, but more specifically, the compound (I) of the present invention is mixed with ethanol, ethanol and propylene glycol, polyethylene glycol 200, 300, etc.
It is an inhalation liquid prepared by dissolving it in a mixed solvent with an alkylene glycol such as 400 or 400, and is applied to a patient using an inhaler at the time of use.

The amount used varies depending on symptoms, age, weight, etc., but it is usually around 20μ a day for adults. The amount ranges from 150 μg to 150 μg.

Among the compounds having the general formula (I) of the present invention, typical compounds are described below, but the compounds obtained by the present invention are not limited thereby.

■ 9-oxo 11α/15α-dihydroxy 20
-Ingropyriteneglost-13(trans)-enoic acid and its methyl, ethyl, n-probyl, isoprobyl esters 9-oxo 11α/15α-dihydroxy-20
-isopropyriteneprost = 5 (cis), 15 ( }
lance) monodienic acid and its methyl, ethyl, n-propyl, isopropyl esters 9-oquine-11α
・15α-dihydroxy=17-methyl-20-ingropyriteneprost-1 3 (trans)-enoic acid and its methyl, ethyl, n-probyl, isoprobyl ester ■ 9-oxo 11α・15α-dihydroxy-17
-Methyl-20-isopropylideneprostole 5(cis), 13(trans)-dienoic acid and its methyl, ethyl, n-propyl, isopropyl ester ■ 9-oxo 11α・15α-dihydroxy-17
-methyl-20(1'-methyl)-isopropylideneprost-13(trans)monoenoic acid and its methyl,
Ethyl, n-7” lopyl, isoprobyl ester ■ 9-oxo 11α・15α-dihydroxy-17
-Methyl-20(1'-methyl)-isoglopylideneprost-5(cis), 13(trans)-monodienoic acid and its methyl, ethyl, n-globil, isoprobil esters ■ 9-Oquine-11α/15α- dihydroxy-17
-Methyl-20 (1',3'-dimethyl)isopropyriteneprostol 13 (}lance) monoenoic acid and its methyl, ethyl, n-propyl, isopropyl esters 9-oxo 11α, 15α-dihydroxy-17
-Methyl-20 (1',3'-dimethyl)ingropyritenegrost-5 (cis), 13 (trans) monodienoic acid and its methyl, ethyl, n-provil, inglovir ester ■ 9-oxo-11α・15α-
Dihydroxy-20(1'-methyl)-isoglopylideneprost-13(trans)monoenoic acid and its methyl, ethyl, n-propyl, and isopropyl esters [phase] 9-oxo-11α・15α-dihydroxy-20(1 '-methyl)-isoglopylideneprost-5
(cis), 13(trans) monodienoic acid and its methyl, ethyl, n-provil, improvil esters 0 9-oxo 11α・15α-dihydroxy-20
(1',3'-dimethyl)isopropylideneprostol 13-(trans)-enoic acid and its methyl, ethyl, n-provil, inglovir esters 0 9-oxo■1α,15α-dihydroxy-20
(1',3'-dimethyl)ingropylideneprost-
5 (cis), 13 (trans) monodienoic acid and its methyl, ethyl, n-probyl, inglovir esters 0 9-oxo 15α-hydroxy-20-ingropylideneprost-13 (trans)-enoic acid and its methyl , ethyl, n-probyl and inglovir esters 0 9-oxo 15α-hydroxy-17-methyl-
20-Inpropylideneprost-13(trans)-
Enoic acid and its methyl, ethyl, n-probyl and inglobil esters ■ 9-oxo-15α-hydroxy-20-ingropyritenegrost-5 (cis),
13'(trans)monodienoic acid and its methyl, ethyl, n-propyl and isopropyl esters ■9-oxo-15α-hydroxy-17-methyl-2
0-inpropylidene gloss-5(cis), 13(+
-Rance)-Cyenoic acid, methyl, ethyl, n-
Provil and inglovir ester The compound having the general formula (I) of the present invention can be obtained by oxidizing the compound having the general formula to produce a compound having the general formula, and removing the hydroxyl protecting group of the thus obtained compound. obtained by.

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

R" represents a hydrogen atom or a substituent R60-.

R6 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 groups include 2-tetrahydrofuranyl, 2-tetrahydropyranyl, and 4-71 xytetrahydropyran-4-yl, which contain an oxygen atom or a sulfur atom in the ring with or without alkoxy as a substituent. 5- to 6-membered ring groups; linear or branched lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl; methoxymethyl, ethoxymethyl, n-propoxymethyl; Straight chain or branched lower alkyl group having alkoxy as a substituent; trimethylsilyl, triethylsilyl,
a linear or branched tri-lower alkylsilyl group such as tri-n-glopylsilyl; or a carbonate residue having the formula XOCO- (IV), where X is, for example, methyl, ethyl, n -Glovir, Inglovir, n
- Straight chain or branched lower alkyl group such as butyl: 1 to 3 halogen atoms at the β position such as 2,2,2-trichloroethyl, 2,2-dibromoethyl, 2-iodoethyl Ethyl group as a substituent: phenyl, 4-nitrophenyl, 2-chlorophenyl, 2,4-
A phenyl group with or without a substituent such as dichlorophenyl; an aromatic ring with or without a substituent such as benzyl, phenethyl, 4-nitrobenzyl, 4-chlorophenethyl, and an alkylene moiety having 1 to 2 carbon atoms; represents an aralkyl group.

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 (■) to produce the compound having the general formula (BE) 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-pyridine complex salt (Collins reagent), chromic anhydride, concentrated sulfuric acid monohydrate (Jones reagent), sodium dichromate, potassium dichromate, etc. Chromic acids: Organic active halogen compounds such as N-promacetamide, N-promuxuccinimide, N-promphthalimide, N-chlorop-toluenesulfonamide, N-I'olbenzenesulfonamide; aluminum tert-butoxide, aluminum inopropoxy Aluminum alkoxides such as dimethyl sulfoxide, dimethyl sulfoxide, dimethyl sulfoxide, 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, it may be an organic acid such as acetic acid or acetic monoanhydride, or an organic acid and an organic acid anhydride. Mixed solvent with; dichloromethane,
Halogenated hydrocarbons such as chlorophonohim and carbon tetrachloride are preferred.

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

When using anobenium alkoxides, aromatic hydrocarbons such as benzene, toluene, and xylene are suitable.

When dimethylsulfoxide dicyclohexyllupodiimide or dimethylsulfoxide acetic anhydride is used, other solvents are not particularly required as long as an excess of dimethylsulfoxide 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 dimethyl sulfoxide dihexylpodiimide 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 monopyridine complex salt (Collins reagent) and chromic anhydride-concentrated sulfuric acid-water (Jones reagent) are usually used as particularly suitable oxidizing agents.

There is no particular limitation on the reaction temperature, but in order to suppress side reactions, it is desirable to conduct the reaction at a relatively low temperature, usually from -20°C to room temperature, and particularly preferably from 0°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, thin layer chromatography, etc.

Next, the reaction for removing the hydroxyl protecting group from the compound having the general formula (II) thus obtained 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 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 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, and examples include dichloromethane, Halogenated hydrocarbons such as chloroform 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 hydroxides of alkali metals and alkali group metals such as potassium hydroxide and calcium hydroxide; acid groups such as alkali metal and alkali group metal carbonates such as potassium carbonate and calcium carbonate. may be used without particular limitation.

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

If other solvents are used, e.g. tetrahydrofuran,
Ethers such as dioxane; mixed solvents of water and organic solvents such as alcohols such as methanol and ethanol are 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.

Examples of acids or bases used include mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid; alkali metal and alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide; sodium carbonate; Carbonates of alkali metals and alkali metals 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 to be 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 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, thin layer chromatography, etc.

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 obtained in this way is obtained as a mixture of various geometric isomers and optical isomers, these can be separated and resolved in an appropriate synthetic step.

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

Method (1) A compound having the above general formula (II) in which A is an ethylene group and R is a protected hydroxyl group is synthesized by the following steps.

In the above formula, A in general formula (1) represents an ethylene group.

R1, R2, R3, R4, R5/and R6 have the same meanings as described above.

However, the hydroxyl group protecting group R6 is the hydroxyl group protecting group R7Co-
is a group that is not removed at the same time as is removed.

R7 is methyl, ethyl, n-propyl, isopropyl,
It represents a straight or branched alkyl group such as n-butyl, isobutyl, tert-butyl.

R8 and R'' represent a hydroxyl group-protecting group, and the hydroxyl group-protecting 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. There is no particular limitation as long as it is a protecting group, and examples of such a protecting group include the same protecting groups as R6 described above.

R9 represents a linear or branched alkyl protecting group such as methyl, ethyl, n-provil, improvil;
Here, the protecting group for the carboxyl 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. Such protecting groups include, for example, hydrocarbon groups such as methyl, ethyl, n-propyl, inglovil, n-butyl, isobutyl, phenyl, benzyl; halogenated alkyl groups such as 2,2,2-trichloroethyl; Examples include heterocyclic groups such as -tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, and 4-methoxytetrahydropyran-4-yl, but are particularly limited to these protecting groups. isn't it.

RI2 is a hydrogen atom or the same as the above-mentioned carboxyl group protecting group R10.

2 indicates a protecting group for the carbonyl group, and the protecting group for the carbonyl group is particularly limited as long as it does not affect other parts of the compound due to the removal reaction when the protecting group is removed later. For example, when an oxime is formed, a hydroxyimino group; a dialkoxy group such as dimethoxy and diethoxy; an alkylene dioxy group such as methylene dioxy and ethylene dioxy; and an alkylene dithio group such as ethylene dithio and trimethylene dithio. etc., but the protecting groups are not particularly limited to these.

Each step carried out using a known compound represented by the general formula (V) described in JP-A-4.8-57958 as a starting material will be described below.

The first step is a step of producing a compound having the general formula (Vf), and includes a reaction for protecting the carbonyl group of the compound having the general formula (V) and, if necessary, a reaction for converting the protecting group for the hydroxyl group. This is achieved by adding

The reaction for protecting the carbonyl group of the compound having the general formula (V) and, if necessary, the reaction for converting the protecting group for the hydroxyl group may be performed first.

The reaction for protecting the carbonyl group of the compound having the general formula (V) is carried out by contacting the compound with a compound that forms a protecting group for the carbonyl group in the presence or absence of a solvent.

Compounds that form protective groups for carbonyl groups that can be used include hydroxylamines such as hydroxylamine, methylhydroxylamine, and sodium hydroxylamine sulfonate that form oximes; methyl orthoformate that forms ketals, and orthoformic acid that forms ketals. Orthoformate esters such as ethyl esters: alkylene glycols such as methylene glycol and ethylene glycol that form cyclic ketals; alkylene dithioglycols such as ethylene dithioglycol and trimethylene dithioglycol that form cyclic thioketals are suitable. It can be mentioned as a chemical compound.

Next, if necessary, the reaction for converting the hydroxyl-protecting group R8 of the compound having the general formula (V) is carried out by converting the hydroxyl-protecting group R8
, followed by contact with a suitable protecting group-forming compound.

When the hydroxyl-protecting group is, for example, an acyl group such as acetinobepropionyl, benzoyl, or trifluoroacetyl, the hydroxyl-protecting group is also removed at the same time in the subsequent reduction reaction in the third step.

Therefore, when the protecting group for a hydroxyl group is, for example, an acyl group, it is necessary to remove the acyl group by contacting with an acid or a base, and then convert it with another suitable protecting group.

When the protecting group R8 for the hydroxyl group is, for example, a hydrocarbon group such as methyl or ethyl; or a carbonate residue of an ester such as benzyloxycarbonyl or ethoxycarbonyl, there is no particular need to convert the protecting group.

When the protecting group R10 of the hydroxyl group in the compound having the general formula (V) is an alkyl group such as methyl or ethyl, the reaction for removing the acyl group, which is the protecting group of the hydroxyl group, is carried out using methanol in the presence of a base. If the reaction is carried out using an alcohol such as ethanol as a solvent, the protecting group for the carboxyl group is converted by transesterification.

Next, a reaction in which the hydroxyl group formed in the above reaction is protected again with a protecting group that is not affected by subsequent reactions can be easily accomplished by contacting the hydroxyl group with a compound that forms a protecting group.

Compounds forming the protecting group used include, for example, heterocyclic compounds such as dihydropyran, dihydrothiopyran, dihydrothiophene, 4-methoxy5,6-dihydro-(2H)pyran; methoxymethyl chloride, ethoxyethyl chloride. Alkoxy halogenated hydrocarbon compounds such as: ethyl vinyl ether, unsaturated compounds such as methoxy-1-7 chlorohexene: halogenated hydrocarbon compounds such as methyl chloride, ethyl chloride: benzyloxy luponyl chloride, ethoxy chloride, etc. alkoxylponyl chloride compounds such as nyl chloride;
Suitable compounds include 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.

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

The second step is a step of producing a compound having the above general formula (■), and is a reaction in which the carboxyl group protecting group R10 of the compound having the above general formula (VI) is removed as necessary.

This reaction is a reaction that is performed as necessary, and when performing the reduction reaction in the next third step, the carboxyl group protecting group R1
The yield of the reduction reaction increases when 0 is removed.

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

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

The acid or base to be used is not particularly limited, and the acid or base used in ordinary hydrolysis can be used without particular limitation, but it is usually carried out suitably under basic conditions.

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

The third step is a step of producing a compound having the above general formula (■), in which the compound having the above general formula (■) is reduced, and then, when R12 is a hydrogen atom, the carboxyl group is protected as necessary. This is achieved by

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

Examples of reducing agents used include sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, lithium aluminum hydride, tri-tert-butoxylithium aluminum hydride, and trimethoxylithium aluminum hydride. Metal hydride compounds are preferably used.

The reaction is usually suitably carried out in the presence of a solvent.

Next, in the compound obtained, when R12 is a hydrogen atom, the carboxyl group is protected as necessary, so that when the isomers are later separated using column chromatography, etc., the carboxyl group is separated as it is. This is because the separation is more efficient than in the case where the

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

Compounds forming protective groups that can be used include, for example, diazo hydrocarbons such as diazomethane, diazoethane, diazo-n-propane, and diazo-n-butane: 2.2.2
-Halogenated alcohols such as trichloroethanol; dihydropyran, dihydrothiopyran, dihydrothiophene, 4-methoxy=5,6-dihydro (2H)
Examples include heterocyclic compounds such as pyran.

The fourth step is a step of producing a compound having the above general formula (K), and is carried out by removing the carbonyl group protecting group from the compound having the above general formula (■).

The reaction for removing a carbonyl protecting group from a protected carbonyl group differs depending on the type of protecting group.

If the protected carbonyl group is, for example, an oxime, a dialkoxy group such as dimethoxy, jetoxy, or an alkylene dioxy group such as methylenedioxy, ethylenedioxy, it may be removed by contacting with an acid.

When the protected carbonyl group is an alkylene dithio group such as ethylenedithio or trinotylene dithio, it is removed by contacting with mercuric chloride.

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

The fifth step is a step of producing a compound having the general formula (X), and is carried out by oxidizing the compound having the general formula (K).

The reaction is accomplished by contacting with peroxide in the presence or absence of a solvent.

Peroxides used include, for example, performic acid, peracetic acid, perpropionic acid, pertrifluoroacetic acid, perbenzoic acid, m-
Suitable peroxides include organic peracids such as chloroperbenzoic acid and monoperphthalic acid, and hydrogen peroxide.

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

The reaction is carried out in the presence of an oxidizing agent, and the type of oxidizing agent used and the reaction conditions are as described in the reaction for producing the compound having the general formula (III) by oxidizing the compound having the general formula (1). It is the same as when

The seventh step is a step of producing a compound having the general formula (X[I), in which the compound having the general formula (M) is prepared by the general formula (wherein R1, R3 and R4 have the same meanings as above). and H, 14 represents an alkyl group such as methyl or an aryl group such as phenyl.

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

) is achieved by reacting with Witzig's reagent.

The solvent to be used is not particularly limited, and may be any solvent commonly used in Witzig reactions.

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

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-boraperhydrophenalene hydride are preferably used.

The ninth step is a step of producing a compound having the general formula (xIV), by subjecting the compound having the general formula (xm) to a reaction for converting the protecting group R11 of the hydroxyl group and a reaction for protecting the hydroxyl group. achieved.

As a hydroxyl group-protecting group, the hydroxyl group-protecting group R7CO-
There is no particular limitation as long as the protecting group is not removed at the same time as is removed.

The reaction is carried out by removing the hydroxyl protecting group R11 and then contacting it with a suitable protecting group-forming compound.

The compound used to form a hydroxyl-protecting group and its reaction conditions are the same as those described in the first step.

The tenth step is a step for producing a compound having the general formula (II), which includes a reaction for removing the hydroxyl group protecting group R7CO- and the carboxyl group protecting group R13 of the compound having the general formula (XIV), and as necessary. This can be achieved by subjecting the carboxyl group to an esterification reaction.

In this step, after removing the hydroxyl-protecting group R7CO-, the carboxyl group is simultaneously protected when the hydroxyl-protecting group R7CO- is removed, without any special reaction to remove the carboxyl-protecting group Rl3. The group RI 3 may also be removed.

The reaction for removing the hydroxyl protecting group R7CO- is easily accomplished by contacting with an acid or base.

The reaction for removing the carboxyl protecting group R13 differs depending on the type of protecting group.

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

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 alkoxy carbonyl 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-propanol, and diisopropanol; and hydrochloric acid. , mineral acids such as hydrobromic acid or sulfuric acid, or organic acids such as methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid.

Method (2) A compound having the general formula (II) in which A is a cis-vinylene group and R is a protected hydroxyl group is synthesized by the following steps.

In the above formula, A represents a cis-vinylene group.

R1, R2, R3, R4, R' and R6 have the same meanings as described above.

R15 represents a hydroxyl-protecting group, and the hydroxyl-protecting group here 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 are no particular limitations, and examples of such protecting groups include the same protecting groups as R6 described above.

The following is [Journal of the American Chemical]
Nosaetei (J, Am.Chem.Soc.)9゛1
vol., page 5675 (1969)], each step carried out using a known compound represented by the general formula (X'W) as a starting material will be described.

The first step is a step of producing a compound having the general formula (XV[I), which is achieved by reacting a compound having the general formula (XM) with a Witzig reagent having the general formula (XV). .

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 (X■), and is achieved by reducing the compound having the general formula (X■).

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 subjecting the compound having the general formula (xm) to a reaction for converting the hydroxyl-protecting group RI5 and a reaction for protecting the hydroxyl group. be done.

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

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

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

Examples of reducing agents used include diisobutylaluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, and tri-t hydride.
Metal hydride compounds such as ert-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 fifth step is a step of producing a compound having the general formula (II), in which the compound having the general formula (XX) is manufactured by the general formula (where RI6 is an aryl group such as phenyl, an alkyl group such as n-butyl) Indicates a hydrocarbon group such as a group.

M2 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, if necessary, the carboxyl group of the resulting compound is esterified.

A compound having the general formula (XX) is represented by the general formula (X
The Wittzig reaction step of reacting with a compound having X [ is carried out using an excess of Witzig's reagent.

The product obtained by the above Wittzig reaction is a salt, which is easily converted into the free acid by treatment with an organic acid such as acetic acid, propionic acid, oxalic acid; or a mineral acid such as hydrochloric acid or hydrobromic acid. It can be converted to .

A subsequent, optional reaction to esterify the carboxyl groups of the compound thus obtained is accomplished by contacting the free acid with an esterifying agent.

The reaction conditions are the same as those described in the tenth step for producing an ester compound among the compounds having general formula (1).

Method (3) A compound having the general formula (1) above, in which A is an ethylene group and R is a hydrogen atom, is synthesized by the following steps.

In the above formula, R1, R2, R3, R4 and R6 have the same meanings as described above.

However, the hydroxyl-protecting group R6 is a group that is not removed at the same time when the hydroxyl-protecting groups R1 and 8 are removed.

R16 and R18 represent a hydroxyl group-protecting group, and the hydroxyl group-protecting 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 the above-mentioned R6 for R16.
Protecting groups similar to R ] 8 can be mentioned, such as acetyl, n-gropionyl, ingropionyl, n-butyryl, imbutyryl, benzoyl,
4-nitrobenzoyl, 2-chlorhensoyl, 2.4
Acyl groups such as -dichlorobenzoyl and phenylacetyl can be mentioned as suitable protecting groups.

R17 represents a protecting group for a carboxyl group, and the protecting group for a 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,
Hydrocarbon groups such as n-probyl, inglovir, n-butyl, isobutyl, phenyl, benzyl; 2.2.2
- halogenated alkyl group such as trichloroethyl; 2
Examples include heterocyclic groups such as -tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, and 4-methoxytetrahydropyran-4-yl, but are particularly limited to these protecting groups. It's not a thing.

Below, [Tetrahedron Letters (Tetrahedron Letters) 1]
972, p. 115], the general formula (
Each step carried out using a known compound represented by X]) as a starting material will be described.

The first step is a step of producing a compound having the general formula (xxm), and is a reaction to obtain a compound in which the hydroxyl group of the compound having the general formula (XXU) is protected.

The protecting group-forming compound used and its reaction conditions are the same as those described in the first step of method (1) above.

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

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

The reducing agent used and its reaction conditions are the same as those described in the fourth step of method (2) above.

The third step is a step of producing a compound having the general formula (XXV), in which the compound having the general formula (XXIV) is reacted with the Wissozzig reagent having the general formula (XN), and then this is reacted by a conventional method. This is achieved by converting it to the free acid by treatment with an acid and then protecting the carboxyl group of the resulting compound.

The reaction conditions for the Wittig reaction step are the same as those described in the fifth step of method (2) above.

The product obtained by the above Wittzig reaction is a salt, which is easily converted into the free acid by treatment with an organic acid such as acetic acid, propionic acid, oxalic acid; or a mineral acid such as hydrochloric acid or hydrobromic acid. It can be converted to .

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.

The reaction conditions are the same as those described in the third step of method (1) above.

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

Examples of the compound forming the protecting group used include acetyl chloride, n-gropionyl chloride, imbutyryl chloride, penzoyl chloride, 4-nitropenzoyl chloride, 4-chlorobenzoyl chloride, and phenylacetyl chloride. Acyl chloride compounds such as;
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.

The fifth step is a step of producing a compound having the above general formula (XXVI[), and is achieved by subjecting the compound having the above general formula (XXM) to a reaction for removing the hydroxyl protecting group R16.

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 general formula (III).

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

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. The catalytic reduction method used is preferably carried out.

The reaction is carried out in the presence of a solvent. The seventh step is a step of producing a compound having the general formula <xya<>, and is achieved by oxidizing the compound having the general formula (xx%l[).

The reaction is carried out in the presence of an oxidizing agent, and the type of oxidizing agent used and the reaction conditions are as described in the reaction for producing the compound having the general formula (III) by oxidizing the compound having the general formula (1). It is the same as when

The eighth step is a step of producing a compound having the general formula (XXX), and is achieved by reacting the compound having the general formula (XXK>) with the Witsch reagent having the general formula (XV).

The reaction conditions are the same as those described in the seventh step of method (1) above.

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

The reaction conditions are the same as those described in the eighth step of method (1) above.

The tenth step is a step of producing a compound having the general formula (xxn), and is achieved by subjecting the compound having the general formula (XXX[) 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 R18 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 for producing the compound having the general formula (xxm).

The eleventh step is a step of producing a compound having the general formula (II), which includes a reaction for removing the hydroxyl group-protecting group RI8 and the carboxyl group-protecting group R17 of the compound having the general formula (XXX[ ); This is achieved by subjecting a carboxyl group to an esterification reaction, if necessary.

In this step, after removing the hydroxyl-protecting groups R18, the carboxyl-protecting group R'7 is not particularly subjected to the reaction. Protecting group R17 may also be removed.

The reaction conditions are the same as those described in the tenth step of method (1) above.

Method (4) A compound having the general formula (1) above, in which A is a cis-vinylene group and R5' is a hydrogen atom, is synthesized by the following steps.

In the above formula, R1, R2, R3, R4, R6, R17 and RI8 have the same meanings as described above.

Each step carried out using the compound represented by the general formula (xx■) produced in the fifth step of the method (3) as a starting material will be described below.

The first step is a step of producing a compound having the general formula (xxXI[), and is achieved by oxidizing the compound having the general formula (XXV[I).

The reaction conditions of this step are the same as those described in the seventh step of the method (3) for producing the compound having the general formula (XXK).

The second step is a step of producing a compound having the above general formula (xxx■), and is achieved by reacting a compound having the above general formula (xxxv) with a Witzig reagent having the above general formula (XV).

The reaction conditions of this step are the same as those described in the seventh step of the method (1) for producing the compound having the general formula (X[l).

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

The reaction conditions of this step are the same as those described in the ninth step of method (3) for producing the compound having general formula (xx)a).

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

The reaction conditions of this step are the same as those described in the tenth step of the method (3) for producing the compound having the general formula (xxxu).

The fifth step is a step of producing a compound having the general formula (II), and includes a reaction for removing the hydroxyl group protecting group R18 and the carboxyl group protecting group R17 of the compound having the general formula (XXXW), and as necessary. This can be achieved by subjecting the carboxyl group to an esterification reaction.

The reaction conditions of this step are the same as those described in the tenth step of the method (1) for producing the compound having the general formula (II).

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, thin layer chromatography, etc.

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 present invention will be explained in more detail with reference to production examples and reference examples.

Production example 1 9-oxo 11α・l5α-dihydroxy-17-methyl-20-inpropylideneprost-1 3 (
}trans) monoenoic acid 9β-hydroxy-11α・15α-di(2-tetrahydropyranyloxy)-17-methyl-20-isopropylideneprost-13(trans)monoenoic acid 766%
After dissolving in acetone 201rLl, -11 to -13
Jones reagent (chromic anhydride 2
6.725' was dissolved in 23 ml of concentrated sulfuric acid and water to make a total volume of 100 mA'.
Stir for 0 minutes.

After the reaction is complete, excess reagent is decomposed with inglobil alcohol, water is added, and the mixture is extracted with ethyl acetate.

After washing the extract with water and drying with anhydrous sodium sulfate, the solvent was distilled off from the extract to obtain an oily 9-oxo-11α・l5.
α-di(2-tetrahydropyranyloxy)-17-methyl-20-improbilitempros 1-1 3 (
trans) monoenoic acid 652~ is obtained.

Infrared absorption spectrum (liquid film) νmaxcIrL ”1
745, 17l2 Nuclear magnetic resonance spectrum (CC 1 4 ) δppm: 0
．． 90 (3H, doublet, J = 6Hz) 5.0 (IH, triplet, J = 6Hz) 5.55 (2H, multiplet) 9-Oxo-l1α・15α-di(2-tetrahydrodobilanyloxy) =17-Methyl-20=Isopropylidene Prostol 13 ( } lance) 652m9 of monoenoic acid was dissolved in acetic acid-water-tetrahydrofuran (15rrLl, 157
After dissolving in a mixed solvent of 7Il, 5rul), 35
Stir at ℃ for 4 hours and 30 minutes.

After the reaction is completed, water is added to the reaction mixture and extracted with ethyl acetate.

After washing the extract with water and drying over anhydrous sodium sulfate, the solvent is distilled off from the extract to obtain a residue of 640~.

When this was purified by column chromatography using silica gel, an oily 9-oxo-11α・l5α
-dihydroxy-l7-methyl-20-inpropyriteneprost-13(trans)monoenoic acid 210In
9 is obtained.

Infrared absorption spectrum L'maxCrn (liquid film)
3380, 1735, 1710 Nuclear magnetic resonance spectrum (CDCl3) δppm: 0.9
0 (3H, double line, J=6Hz) 1.58 (3H, - double line) 1. ．． 62 (3H, -multiplet) 4.10 (2H, multiplet) 5.57 (2H, multiplet) Potassium salt 408 mg of the above carboxylic acid was dissolved in 30% aqueous methanol 1-
After dissolving in 07711, 10 ul of a 30% aqueous methanol solution of 100 ml of potassium hydrogen carbonate was added, and the mixture was stirred at room temperature for 1 hour.

After the reaction is complete, the solvent is distilled off at low temperature, resulting in oily 9-oxo-l1α・15α-dihydroxy-17-methyl-2
0-Inglopylidenegrost-13 (trans)-
Potassium enoic acid salt 507 is obtained.

Infrared absorption spectrum (liquid film) νmaXCrrL-l:
l595 Production Example 2 9-oxo 1lα·15β-dihydroxy-17-methyl-20-ingropyriteneprost-13(trans)-enoic acid 9β-hydroxy-1lα·15β-di(2-tetrahydropyranyloxy) = 17 -Methyl-20-ingropylidenegrost-13(trans)-enoic acid 7641
When rl9 is used and reacted and treated in the same manner as in Production Example 1 (2), oily 9-oxo 11α, 15β-di(2-tetrahydropyranyloxy)-17-methyl-20-isopropylidene prostole 13 (trans) -enoic acid 750
1n9 is obtained.

Infrared absorption spectrum (liquid film) vmaxcrn 1
739, 1708 Nuclear magnetic resonance spectrum (CCI4) δppm: 0.90
(3H, doublet, J=6Hz) 5.03 (IH, triplet, J=6Hz) 5.50 (2H, multiplet) 9-oxo 11α・15β-di(2-tetrahydropyranyloxy)- 17-,Methyl-20-isoglopylideneprost-13(trans)-enoic acid 750 ~ was reacted and treated in the same manner as in Production Example 1 (2) to give an oily 9
-Oxo-11α·l5β-dihydroxy-17-methyl-20-ingropyritempest-13(trans)-enoic acid 163~ is obtained.

Infrared absorption spectrum (liquid film) vmaX sieve-1: 34
00, 1730, 968 Nuclear magnetic resonance spectrum (CDCl3) δppm: 0, 9
1 (3H, doublet, J=6Hz) 1.58 (3H, singlet) 1.64 (3H, singlet) 4.10 (2H, multiplet) 5.66 (2H, multiplet) Production example 3 9-oxo 11α・15α-dihydroxy-17-methyl-20-inpropylideneprost-13(trans)-enoic acid methyl ester 9β-hydroxy-1lα
・15α-di(2-tetrahydroviranyloxy)-1
7-methyl-20-ingropyriteneprost-13 (
When trans)-enoic acid methyl ester 3511n9 is reacted and treated in the same manner as in Production Example 1 Temprost-13(}lance)-enoic acid methyl ester 29
8′■ is obtained.

Infrared absorption spectrum (liquid film) vmaXcTL-1:l
746 Nuclear magnetic resonance spectrum (CCl4) δppm: 0.91
(3H, double line, J=6Hz) 3. ．． 6 8 (3H, singlet) 5.01 (IH, triplet, J=6Hz) 5.55 (2H, multiplet) 9-Oquine-11α·15α-di(2-tetrahydrode-biranyloxy) - 1. When 280 mg of 7-methyl-20-isopropylideneprost-13(trans)monoenoic acid methyl ester was reacted and treated in the same manner as in Production Example 1 (2), oily 9-oxo-11α·15α-dihydroxy-17-methyl was obtained. -20-Ingropylidenepros}-13(}lance)-enoic acid methyl ester 71
1n9 is obtained.

Infrared absorption spectrum (liquid film) νmaXCrrL-1:
3380, 1735 Nuclear magnetic resonance spectrum (CD3COCD3) δppm:
0.90 (3H, double line, J-=6Hz) 3.6 7
(3H, singlet) 5.57 (2H, multiplet) Production example 4 9-oxo-l1α・15α-dihydroxy-l7-methyl-20-ingropylideneprost-5 (cis),
13(trans)monodienoic acid 9α-hydroxyl1α
・15α-di(2-tetrahydroviranyloxy)-1
After dissolving 750 m9 of 7-methyl-20-inpropylideneprost-5(cis),13(}7ns) monodienoic acid in 201 rLl of acetone, 1 portion of Jones reagent was added at around -13°C and further Stir for 20 minutes.

After the reaction is complete, excess reagent is separated with isopropyl alcohol, water is added, and the mixture is extracted with ethyl acetate.

After washing the extract with water and drying with anhydrous sodium sulfate, the solvent was distilled off from the extract, and an oily 9-oxo 11α・15 was obtained.
α-di(2-tetrahydropyranyloxy)-17-methyl-20-ingropylideneprost-5 (cis),
13(trans)monodienoic acid 6311rI9 is obtained.

Infrared absorption spectrum (liquid film) νmaxcm-1:17
45, 1710 Nuclear magnetic resonance spectrum (CCI,) δppm: 0.91
(3H, doublet, J=6Hz) 9-oxo-1lα・15α-di(2-tetrahydropyranyloxy)-17-methyl-20-isopropylideneprost-5(cis),13(trans)-diene 625m9 of acid was converted into acetic acid-water-tetrahydrofuran (15
TrLl, 15mA, 5ml) and stirred at 35°C for 4 hours.

After the reaction is completed, water is added to the reaction mixture and extracted with ethyl acetate.

After washing the extract with water and drying over anhydrous sodium sulfate, the solvent was distilled off from the extract to obtain a residue of 610 cm.

When this was purified by column chromatography using silica gel, an oily 9-oxo-11α・l5α
203 mg of -dihydroxy-17-methyl-20-impropylidene starch-5(cis),l3(trans)monodienoic acid are obtained.

Furan) Infrared absorption spectrum (liquid film) νmax”21:338
0, 1740, l710 Nuclear magnetic resonance spectrum (CDs COCDs)
δppm: 0.91 (3H, doublet, J=6Hz) 1.59 (3H) 1.65 (3H) 4.11 (2H, multiplet) 5.38 (2H, multiplet) 5, 65 ( 2f{, multiplet) Production example 5 9-oxo-11α·l5β-dihydroxy-l7-methyl-20-ingropyritenegrost-5 (cis),
13(trans)monodienoic acid 9α-hydroxy-11α
・15α-di(2-tetrahydrodoviranyloxy)-1
7-Methyl-20-isopropyritenepros l-5 (
Production Example 4 using cis), 13(trans)-dienoic acid
When reacted and treated in the same manner as in (■), oily 9-oxo-1
1α・15β-di(2-tetrahydrodobilanyloxy)
-17-methyl-20-isopropylidene prostole 5
(cis), 13 (trans) monodienoic acid is obtained.

Infrared absorption spectrum (liquid film) vmaxcIrL-1:
1745, l710 Nuclear magnetic resonance spectrum (CCI4) δppm: 0.91
(.3H, double line, J = 6Hz) ■ 9-oxo-11α・15β-di(2-tetrahydrovilanyloxy)-17-methyl-20-impropylidene-5(cis), 13(trans) When reacted and treated in the same manner as in Production Example 4 (2) using monodienoic acid, oily 9-oxol l1α・15β-dihydroxy-17-
Methyl-20-ingropylideneprost-5 (cis)
, 13(trans)monodienoic acid is obtained.

Infrared absorption spectrum (liquid film) νmaxcfrL-I:
3380, 1730, l710 Nuclear magnetic resonance spectrum (CD3COCD3) δppm:
0.91 (3H, doublet, J=6Hz) 1.59 (3H, singlet) 1.63 (3H, singlet) 4. ．． 15 (2H, multiplet) 5.43 (2H, multiplet) 5.69 (2H, multiplet) Production example 6 9-oxo-11α・15α-dihydroxy-17-methyl-20-ingropylideneprost-5 (cis),
l3(trans) monodienoic acid methyl ester 9α-hydroxy-11α・l5α-di(2-tetrahydrobiranyloxy)=17-methyl-20-isopropyriteneprostole 5(cis),13(trans)-cyenoic acid methyl ester When 7511n9 is reacted and treated in the same manner as in Production Example 4 (2), oily 9-oxo-11 is produced.
α・15α-di(2-tetrahydropyranyloxy)-
17-methyl-20-ingropylideneprost-5 (
cis), 13(trans)-cienoic acid methyl ester 630~ is obtained.

Infrared absorption spectrum (liquid film) I/rnaxlZ'7
71”.1745 Nuclear magnetic resonance spectrum (cc 14) δppm:
0.90 (3H, doublet, J=6Hz) 3.6 7 (3H, - doublet) ■ 9-Oquine-1lα・15α-di(2-tetrahydropyranyloxy)-17-methyl-20- When reacting and treating inpropyriteneprost-5(cis), 13(trans)-dienoic acid methyl ester 610~ in the same manner as in Production Example 4 (■), oily 9-oxo 1lα・15α
-dihydroxy-17-methyl-20-inpropylideneprost-5(cis),13(trans)-genic acid methyl ester 1901n9 is obtained.

Infrared absorption spectrum (liquid film) νmaXCrrL-I:
3400, ■736 Nuclear magnetic resonance spectrum (CD3COCD3) δppm:
0.90 (3H, double line, 6Hz) 1,58 (3'f{, - double line) 1.60 (3H, - double line) 3.6 7 (3H, - double line) 5.38 ( 2H, multiplet) 5.65 (2H, multiplet) Production example 7 9-oxo 11α, 15α-dihydroxy-20-ingropylideneprost-13(trans)-enoic acid and 9-oxo 11α, 15β-dihydrolysis Kishi-20
-isozolopylideneprostol 13(trans)-enoic acid 9β-hydroxy-11α・15-di(2-tetrahydropyranyloxy)-20-isopropy') Te7 7
When reacting and treating ``Ross}-13(trans)-enoic acid i.oiy in the same manner as in Production Example 1 (■), an oily 9-
Oxo-11α・15-di(2-tetrahydropyranyloxy)-20-isopropylideneprost-13(trans)-enoic acid 9101rII? is obtained.

Infrared absorption spectrum (liquid film) νmaxcm-1:17
10, 1040, 1020 Nuclear magnetic resonance spectrum (CCI4) δppm: 5.5
4 (2H, multiplet) and 9-oxo 11α, 15-di(2-tetrahydrovilanyloxy)-20-inpropylitempest-13
Production example 1 using (trans)-enoic acid 910m9
The crude product obtained by the reaction and treatment in the same manner as in (2) was purified by preparative thin layer chromatography using benzene-dioxane-acetic acid (18:12:1) as a developing solvent, and an oily substance was separated from the more polar part. 9-oxo-11α・15α-dihydroxy-20-improhyritenglosst-13(}lance)-enoic acid was obtained,
9-oxo 11α and 15β from the less polar part
-dihydroxy-20-isopropyriteneprost-1
3(trans)-enoic acid is obtained.

15α-isomer: Ran) Infrared absorption spectrum (liquid film) νmaxσ-1: 33
60, 1735, l710, 970 Nuclear magnetic resonance spectrum (cD3cocD3) δppm:
1.58 (3H, -multiplet) 1.6 6 (3H, -multiplet) 5.58 (2H, multiplet) 15β-isomer: Infrared absorption spectrum (liquid film) vmaxσ21:33
70, l735, l710, 980 Nuclear magnetic resonance spectrum (CD3COCD3) δppm:
1. ．． 59 (3H, -multiplet) 1.66 (3H, -multiplet) 5.64 (2H, multiplet) Production example 8 9-Oxole l1α・15α-dihydroxy-20-inpropylideneprost-5 (cis) , 13(trans)-dienoic acid 9-α-hydroxy-11α·15α-di(2-tetrahydrovilanyloxy)-20-ingrohylitenprost-5(cis), 13(trans)-dienoic acid 12.
9P was dissolved in 300 μl of acetone, and 25 μl of Jones reagent was added dropwise while cooling to −20° C.

After the completion of the dropwise addition, the mixture was stirred at -20°C for 1 hour.

After the reaction is complete, the reaction mixture is poured into 2 liters of ice water and extracted with ether.

The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to give an oily product of 10. 3 g is obtained.

When this was purified by column chromatography using 100 g of silica gel, an oily 9-oxo-1lα·l5
α-di(2-tetrahydroheptaviranyloxy)-20-isopropylideneprost-5(cis), J. 8.41 P of 3(trans)-dienoic acid are obtained.

Infrared absorption spectrum (liquid film) νmaxcrrL”17
45, 1710, 1135, 1020, 970 Nuclear magnetic resonance spectrum/I/(CDC13) δppm: 4
．． 7 (2H, multiplet) 5.0-5.8 (5H, multiplet) ■ 9-oxo 11α・15α-di(2-tetrahydropyranyloxy)-20-isopropylideneprost-5
-(cis),13(trans)-di-r-7 acid 8.41
5' was dissolved in 100 ml of acetic acid, 10 ml of water, and 30 ml of tetrahydrofuran, heated at 40° C. for 1.5 hours, further added with 100 ml of water, and heated at 40° C. for another 1.5 hours.

After the reaction is completed, the reaction mixture is diluted with 500 ml of saturated brine and extracted with a mixed solvent of ethyl acetate and benzene (1:1).

After washing with saturated brine, the solvent is distilled off to obtain an oily product with a compound size of 6.91.

This was subjected to column chromatography using 1002 silica gel to obtain the desired product of 2.81.

When recrystallized from ethyl acetate-hexane, the melting point is 64.
9-oxo 11α 15 as a crystal with -66℃
α-dihydroxy-20-isopropylidene prostole 5(cis),13(trans)-dienoic acid 2,11 is obtained.

Specific optical rotation (ct)',,'-5 7. 5°(C-1,
Tetrahydrofuran) Infrared absorption spectrum (Nujol) νmax 21
:3380, 1730, 1705, 1160, 970 Nuclear magnetic resonance spectrum (CD3COCD3) δppm:
4.08 (2H, multiplet) 5.17 (IH, triplet) 5.42 (2H, multiplet) 5.68 (2H, multiplet) Mass spectrum m/e: 392 Sodium salt, dicarvone Acid 4 0 81rI9 ( 1.0 4
mmol) in 30% aqueous methanol lorul, then sodium bicarbonate 100771&(
1. ] 9 mmol) of 30% aqueous methanol solution (10 rIll) was added, and the mixture was stirred at room temperature for 1 hour.

After the reaction is complete, the solvent is distilled off at a low temperature, resulting in 9-okine-1
500 m9 of 1α.15α-dihydroxy-20-ingropylideneglost-5(cis),13(trans)-dienoic acid sodium salt are obtained as a waxy powder.

Production Example 9 9-oxo-11α・15β-dihydroxy-20-isoprohyriteneprostole 5(cis),13(trans)-dienoic acid 9-α-hydroxy-11α・15β-di(2-tetrahydropyranyloxy) -20-isopropylidenest-5(cis),13(}lance)-dienoic acid 6.5
1 and treated in the same manner as in the case of 15α integrally, an oily 9-oxine-11α-5β-di(2-tetrahydrobyranyloxy)-20-inpropylidene starch was obtained.
4.12 of 5(cis),13(trans)-dienoic acid are obtained.

Infrared absorption spectrum (liquid film) Published by vmaX'': 1
745, 1710, 1135, 1020, 970 Nuclear magnetic resonance spectrum (CDCl3) δppm: 4.7
(2H, multiplet) 5.0 to 5.8 (5H, multiplet) ■ 9-oxo 11α・l5β-di(2-tetrahydropyranyloxy)-20-isopropylideneprost-5
When 4.2 g of (cis)-13(4-lance) monodienic acid was treated in the same manner as in the case of monolithic 15α, an oily 9-
1.2 g of Okin-1lα·15β-dihydroxy-20-isopropylideneprostol 5(cis),13(trans)monodienoic acid is obtained.

Infrared absorption spectrum (liquid film) νmaXcfrL-1:
3380, 1730, 1160, 970 Nuclear magnetic resonance spectrum (CD3COCD3) δppm:
4.07 (2H, multiplet) 5.15 (IH, triplet) 5.4 (2H, multiplet) 5.68 (2H, multiplet) Mass spectrum m/e: 3 9 2 Production example 10 9- Oxo 15-(2-tetrahydropyranyloxy)-20-ingropylidenegrost-13(}lance)monoenoic acid 9α-hydroxy-15-(2-tetrahydropyranyloxy)=20-ingropylidenepros}- 13 (4
Lance)-enoic acid (2.6) was dissolved in 80rrLl of 1-acetone and mixed with John's (Jone) under stirring at -20~-lθ°C.
s) Add 5rrLl of oxidizing reagent.

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

The reaction solution was diluted with 200 ml of ice water, extracted with ether, the extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an oily target compound 2.
61 is obtained.

Infrared absorption spectrum (liquid film) CrIL': 320
0,2750, 1740, 1710:1200, 1l3
0, 111O, 1020, 970 Nuclear magnetic resonance spectrum (CDCl3) δppm: 5'.
55 (2H, multiplet) 5.10 (IH, multiplet) 4.70 (IH, multiplet) Production example l1 (1) 9-oxo-l5α-hydroxy-20-yne 7' D
HiIJ Temprost-13 (trans) monoenoic acid methyl ester and 9-oxo-15β-hydroxy-
50% of 26 g of 20-inpropyriteneprost-13(trans)monoenoic acid methyl ester and 9-oxo-15-(2-tetrahydrovilanyloxy)-20-inpropyriteneprost-13(trans)monoenoic acid Dissolved in acetic acid aqueous solution and heated to 50℃
The reaction was completed by stirring for 1.5 hours at .

The reaction solution was diluted with 2001 rL 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 of 2.21.

An ether solution of diazomethane was added to this residue until the yellow color of diazomethane no longer disappeared, and the ether was distilled off to obtain 2.23 g of an oily residue.

By separating and purifying this residue using silica gel column chromatography and thin layer chromatography,
Target 15α-hydroxy body 730 in oil form, respectively
~ and 15β-hydroxy form 680 ~ are obtained.

15α-hydroxy infrared absorption spectrum (liquid film) cfrL-1: 3480
, 1740, 1200, 1170, 970 Nuclear magnetic resonance spectrum (CDC13) δppm: 3.6
5 (3H, singlet) 4.10 (IH, multiplet) 5.10 (IH, multiplet) 5.60 (2H, multiplet) Mass spectrometry (molecular weight 392): Molecular ion peak 392 15β-hydroxy body red External absorption spectrum (liquid film) cm-1: 3480, 1
740, 1200, 1170, 970 Nuclear magnetic resonance spectrum (CDC13) δppm: 3.6
5 (3H, singlet) 4.10 (IH, multiplet) 5.1.3 (IH, multiplet) 5.60 (2H, multiplet) Mass spectrometry (molecular weight 392): Molecular ion peak 392 Production example 11 (2)a 9-oxo-15α-hydroxy-20-isoprohyriteneprost-13(trans)monoenoic acid 9-oxo-15α-hydroxy-20-isoprohyriteneprost-13(trans)-enoic acid methyl ester 7301n9 was dissolved in 15 ml of methanol, 10 ml of a 5% aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours.

After the reaction is complete, dilute the reaction solution with 150ml of ice water to 7%
After neutralization with an aqueous hydrochloric acid solution, the mixture is extracted with ethyl acetate, the extract is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain an oily residue 7301II9.

By crystallizing this residue from ether and n-hexane, the target compound 52 having a melting point of 40-45°C was obtained.
41n9 is obtained as a crystal.

Infrared absorption spectrum (liquid film) cIrL-1: 3400
, 2670, 1740, 1720, 1460, 1410
, 1280, 1220, 1160, 970゛Nuclear magnetic resonance spectrum (CD3COCD3) δppm:
4.08 (IH, multiplet) 5. 1. 6 (1'H, triplet) 5.64 (2H, multiplet) 6.50 (2}I, multiplet) Mass spectrometry (molecular weight 378): Molecular ion peak 378 9-oxo-15α-hydroxy-20- After dissolving 150 mg of Improhylitemprost-13 (trans) monoenoic acid potassium salt 9-oxo-15α-hydroxy-20-Inglohylitemprost-15(trans)-enoic acid in a mixed solvent of 8 ml of methanol and 2 ml of water, Add 28 mg of potassium carbonate and stir 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 170 mg of the target compound in powder form.

Infrared absorption spectrum (liquid paraffin) 3400,1
735, 1580-1560cm-1 Production Example 11(2)b 9-oxo-15β-hydroxy-20-infurohiritenglost-13(trans)-enoic acid 9-oxo-15β-hydroxy-20-infurohiriten Prost-13(trans)-enoic acid methyl ester 6801n9 was reacted in the same manner as in (2)a of Production Example 11,
By treatment, the oily target compound 650rrI9
is obtained.

Infrared absorption spectrum (liquid film) CIrL': 3400
, 2680, 1740, 1720, 1270, 1160
, 970 Nuclear magnetic resonance spectrum (CD3COCD3) δppm:
4.08 (LH, multiplet) 5.12 (IH, triplet) 5.60 (2H, multiplet) Mass spectrometry (molecular weight 378): Molecular ion peak 378 Production example 12 9-oxo-15-(2- Tetrahydrodobilanyloxy) -2 0-isopropylideneprost-5(cis),13(trans)-dienoic acid 9α-hydroxy-1
5 = (2-tetrahydropyranyloxy)-20-isopropylidenebrost 5 (cis), 13 (trans)
By reacting and treating 2.51 g of -dienoic acid simultaneously with Production Example 10, 235 g of the target compound in the form of an oil is obtained.

Infrared absorption spectrum (liquid film) cIrL': 320
0, 2650, 1740, 1710, 1130, 101
5,970 Production Example 13) 9-Oquine-15α-hydroxy-20-impropylideneprost-5(cis),13(trans)-cienoic acid methyl ester and 9-oxo-15β-hydroxy-20-isopropyritene Pros l--5 (cis),
13(trans)-dienoic acid methyl ester 9-oxo 15-(2-tetrahydrovilanyloxy)-20-impropylidenest = 5(cis), 1
2.34 g of 3(trans)-dienoic acid was prepared from Production Example 11 (
By reacting and treating in the same manner as in 1), the target compound in oil form, 0.70 g of 15α-hydroxy form, and 15
0.771 of the β-hydroxy form is obtained.

l5α-hydroxy substance infrared absorption spectrum (liquid film) cm-1: 3450, 1
740, 1435, 1200, 1l55, 1010, 9
70 Nuclear magnetic resonance spectrum (CDCIs) δppm: 3.6
5 (3H, -multiplet) 4.08 (IH, multiplet) 5.08 (IH, triplet) 5.33 (2H, multiplet) 5.56 (2H, multiplet) l5β-hydroxy body infrared Absorption spectrum (liquid film) cm-1: 3480, 1
740, 1430, 1240, 1215, l155, 9
70 Nuclear magnetic resonance spectrum (CDCl3) δppm: 3.6
5 (3H, - multiplet) 4.08 (IH, multiplet) 5.10 (IH, multiplet) 5.35 (2H, multiplet) 5.56 (2H, multiplet) Production example 13 (2 )a 9-oxo 15α-hydroxy-20-impropylidene-5(cis), 13(}lance)-dienoic acid 9-oxo 15α-hydroxy-20-impropylidene-5(cis), 13 After dissolving 690 mg of (trans)-cienoic acid methyl ester in 15 ml of methanol and adding 15 ml of a 5% aqueous sodium hydroxide solution, the mixture was stirred at room temperature for 1 hour.

After the reaction is complete, dilute the reaction solution with 100 ml of ice water and add 7
% aqueous hydrochloric acid solution, extracted with ethyl acetate, washed the extract with water, dried over anhydrous sodium sulfate, and removed 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) cm-1: 3400, 2
650, 1740, 1710, 1400, 1230, 1
150,1060,960 Nuclear magnetic resonance spectrum (CDs COCDs)
δppm: 4.04 (LH, multiplet) 5.12 (1.H, multiplet) 5.32 (2H, multiplet) 5.57 (2H, multiplet) Mass spectrometry (molecular weight 376): Molecular ion peak 376 Production Example 13(2)b 9-oxo-15β-hydroxy-20-inpropylideneprost-5 (cis), 13(trans)-dienoic acid 9-oxo-15β-hydroxy-20-inpropylideneprost-5 (cis), 13(}7ance)-Cyenoic acid methyl ester 7 6 5 ynywo By reacting and treating in the same manner as in (2)a of Production Example 13, 667m9 of the target compound in the form of an oil is obtained.

Infrared absorption spectrum (liquid film) CrfL': 340
0, 2650, l740, 1710.1400, 123
0, 1150, iooo, 960 Nuclear magnetic resonance spectrum (CD3COCD3) δppm:
4.03 (IH, multiplet) 5.10 (LH, multiplet) 5.36 (2H, multiplet) 5.60 (2H, multiplet) Mass spectrometry (molecular weight 376): Molecular Iole Peak 376 Formulation Example 9- 3 mg of oxo-1lα·l5α-dihydroxy-20-impropylidene-5(cis),13(trans)-dienoic acid (above compound E) was dissolved in 30 ml of ethanol-propylene glycol (2:1 volume ratio) mixture. ,
Use as an inhalation liquid.

Usually, this solution is administered once for adults using an inhaler at a dose of 0.3 to 0.
．． Administer 5 rul.

Reference example 1 1α-acetoxy 2β-methoxy carbonyl-3α-
(6-ethoxycarbonylhexyl)-4α-(1・1
'-ethylenedithioethyl)cyclopenkunelα-acetoxy2β-methoxycarbonyl=3α-
(6-ethoxylponylhexyl)-4α-acetylpentane 22.14P dichloromethane 501r
After dissolving in Ll, 80 ml of ethylene dithioglycol and boron trifluoride ethyl ether complex compound L under ice cooling.
Add 6 ml and stir for 1 hour.

After the reaction is complete, ice water is added to the reaction mixture and then ether is added for extraction.

The extract is washed successively with water, an aqueous potassium bicarbonate solution, and water, and dried over anhydrous sodium sulfate.

After drying, the solvent is distilled off, and the resulting gummy residue is purified by column chromatography using silica gel. The portion eluted with benzene containing 5% ethyl acetate is collected and collected from the eluate. When the solvent was distilled off, 23.0 g of the target compound was obtained as an oil.

Infrared absorption spectrum (liquid film) vmaxcm-1:17
38 Nuclear magnetic resonance spectrum (CDCl3) δppm: 1.2
3 (3H, triplet) 1.78 (3H, -double) 2.0 2 (3H, -double) 3.70 (3H, -double) Reference example 2 lα-hydroxy-2β-methoxycarbonyl 3α−
(6-methoxylponylhexyl)-4α-( 1
- t'-ethylenedithioethyl)cyclopentane 1α-acetoxy 2β-methoxycarbonyl-3α-
(6-ethoxylponylhexyl)-4α-(1・1
'-ethylenedithioethyl)cyclopentane23. (l
After dissolving 10 g of potassium carbonate in 250 ml of methanol, the solution was stirred at room temperature for 2.5 hours.

After the reaction is complete, an acetic acid aqueous solution is added to the reaction mixture, followed by ethyl acetate for extraction.

After washing the extract with water, it is dried over anhydrous sodium sulfate.

After drying, the solvent is distilled off, and the resulting gummy residue is purified by column chromatography using 200 g of silica gel. The portion eluted with benzene to benzene containing 30% ethyl acetate is collected, and the eluate is collected. When the solvent is distilled off, the target compound 20.42 is obtained as an oil.

Infrared absorption spectrum (liquid film) νmaccm-1:17
30, 3450 Nuclear magnetic resonance spectrum (CDCl3) δppm: 3.6
6 (3H, -double line) 3.70 (3H, -double line) Reference example 3 lα-(2-tetrahydrobilanyloxy)-2β-methoxycarbonyl-3α-(6-methoxyluponylhexyl)- 4α-(lt'-ethylenecythioethyl)
Cyclopentane lα-hydroxy-2β-methoxycarbonyl-3α
-(6-methoxycarbonylhexyl)-4α-( 1
- t'-ethylenedithioethyl)cyclopentane 2
After dissolving 0.4P in 120 ml of benzene, 70 rul of dihydropyran and a catalytic amount of picric acid were added under water cooling, and the mixture was stirred for 15 hours.

After the reaction, the solvent was distilled off from the reaction mixture, and the resulting gummy residue was purified by column chromatography using 350 g of neutral alumina (grade ■).
The fraction eluted with hexane containing 0% benzene to benzene containing 5% ethyl acetate is collected, and the solvent is distilled off from the eluate to obtain the target compound 21.44P in the form of an oil.

Infrared absorption spectrum (liquid film) νmaxcm-1:10
30, 1730 Nuclear magnetic resonance spectrum (CCI4) δppm: 3.60
(3H, - heavy line) 3.6 5 (3H, - heavy line) Reference example 4 1α-(2-tetrahydropyranyloxy)-2β-methoxycarbonyl-3α-(6-h ruboxyhexyl)
-4α-(1,1'-ethylenedithioethyl)cyclopenkune1α-(2-tetrahydropyranyloxy)-2β-methoxycarbonyl-3α-(6-methoxyluponylhexyl)-4α-(1-1' -Ethylenedithioethyl)cyclobentane (3.4S') was dissolved in 200rrLl of 30% water-containing methanol containing 5% potassium carbonate, and then stirred at room temperature for 4 hours and 40 minutes.

After the reaction is completed, water is added to the reaction mixture, followed by hexane for extraction.

After adding acetic acid to the aqueous layer to make it acidic, ether is added for extraction.

After washing the extract with water, it is dried over anhydrous sodium sulfate.

After drying, the solvent is distilled off from the extract to obtain the target compound 2.41 in the form of an oil.

Infrared absorption spectrum (liquid film) νmaXcrrL-1:
1710, l730 Nuclear magnetic resonance spectrum (CCI4) δppm: 3.70
(3H, singlet) Reference example 5 1α-(2-tetrahydrodobilanyloxy)-2β-hydroxymethyl-3α-(6-methoxycarbonylhexyl)-4α-(1·1′-ethylenedithioethyl)cyclopentane 1α- (2-tetrahydropyranyloxy)-2β-methoxycarbonyl-3α-(6-carboxyhexyl)
-4α-(1,1′-ethylenedithioethyl)cyclopentane 2.71 and potassium hydrogen carbonate L3f After dissolving the potassium salt of the raw material compound in 2001rLl of anhydrous tetrahydrofuran, lithium borohydride was prepared at room temperature. Add 3.2 g dropwise.

After the addition is complete, the reaction mixture is stirred for 15 hours at room temperature and then for 5.5 hours at reflux temperature.

After the reaction is complete, the reaction mixture is poured into ice water, acidified with dilute hydrochloric acid and acetic acid, and extracted with ether.

After washing the extract with water, it is dried over anhydrous sodium sulfate.

Next, diazomethane is added to the extract to perform esterification.

After the reaction is complete, the solvent is distilled off from the reaction mixture and the resulting residue is treated with neutral alumina (grade L) 41? Purification was performed by column chromatography using benzene ~ 3
% ethyl acetate was collected, and the solvent was distilled off from the eluate to obtain 158 g of the target compound in the form of an oil.

Infrared absorption spectrum (liquid film) vmaxcm-1:17
35, 3460 Nuclear magnetic resonance spectrum (CCl4) δppm: 1.75
(3H, singlet) 3.59 (3H, singlet) Reference example 6 1α-(2-tetrahydrobiranyloxy)-2β-hydroxymethyl-3α-(6-methoxycarbonylhexyl)-4α-acetylcyclopentane oxidation Dimercury 5.4. O? After suspending 92 g of boron trifluoride ethyl ether complex compound in 300 ml of 15% tetrahydrofuran aqueous solution, 1α
-(2-tetrahydropyranyloxy)-2β-hydroxymethyl-3α-(6-methoxycarbonylhexyl)-4α-(1·1′-ethylenedithioethyl)cyclopenkune5. Add OS' and stir for 25 minutes.

After the reaction is complete, ether is added to the reaction mixture and filtered thoroughly.

After washing the P solution with an aqueous sodium bicarbonate solution and water, it is dried over anhydrous sodium sulfate.

Next, the solvent was distilled off from the filtrate, and the resulting residue was purified by column chromatography using 100 g of alumina, and the portion eluted with benzene to benzene containing 1 to 40% ethyl acetate was collected and eluted. When the solvent is distilled off from the liquid, the target compound 3.4 2 1 'y' is obtained as an oil.

Infrared absorption spectrum (liquid film) 'rnaXcrrL'
: l705, l738, 3450 Nuclear magnetic resonance spectrum (CCI4) δppm: 1.12
(3H, singlet) 3.62 (3H, singlet) Reference example 7 1α-(2-tetrahydropyranyloxy)-2β-hydroxymethyl-3α-(6-methoxycarbonylhexyl)-4β-acetyl pentane reference 300 ml of a 50% aqueous methanol solution containing 25% potassium carbonate containing 3.4211 1α-(2-tetrahydobilanyloxy)-2β-hydroxymethyl-3α-(6-methoxycarbonylhexyl)-4α=acetyl pentane obtained in Example 6 2, at 50℃ after dissolving in
Stir for 5 hours.

After the reaction, methanol is distilled off from the reaction mixture, acetic acid is added to make it acidic, and ethyl acetate is added to perform extraction.

After drying the extract over anhydrous sodium sulfate, the solvent was distilled off from the extract and the resulting residue was treated with alumina (grade L) 30.
Purification was performed by column chromatography using g, and the part eluted with benzene ~ l ~ benzene containing 40% ethyl acetate was collected. When the solvent was distilled off from the eluate, the target compound 3.40S' was obtained as an oil. can get.

Infrared absorption spectrum (liquid film) vmaXC'rIt-1
:l705, 1738, 3460 Nuclear magnetic resonance spectrum (CDCl3) δppm: tl4
(3K, singlet) 3.6 2 (3H, singlet) Reference example 8 1α-(2-tetrahydrobilanyloxy)-2β-hydroxymethyl-3α-(6-methoxylponylhexyl)-4β=acetoxy Cyclopentane lα-(2-tetrahydrobilanyloxy)-2β-hydroxymethyl-3α-(6-methoxycarbonylhexyl)-4β-acetylcyclopentane 3.2L? After dissolving in 70 Tll of dichloromethane, 5.31 ml of solid sodium bicarbonate and 5.31 ml of m-chloroperbenzoic acid were dissolved. :
Add l' and stir at room temperature for 15 hours.

After the reaction is completed, the reaction mixture is treated in the same manner as in Example 2 to obtain 1.658P of the target compound in the form of an oil.

Infrared absorption spectrum (liquid film) νmaXcIrL-1:
l740, 3470 Nuclear magnetic resonance spectrum (CCI4) δppm: 1.98
(3H, single line) 3.

62 (3H, singlet) Reference example 9 1α-(2-tetrahydrobilanyloxy)-2β-formyl-3α-(6-methoxycarbonylhexyl)-
4β-a7toxycyclopentane 1α-(2-tetrahydrobilanyloxy)=2β-hydroxymethyl-3α-(6-methoxylponylhexyl)-4β-acetoxycyclopentane 1.753P
After dissolving in 300 ml of dichloromethane, chromic anhydride monopyridine complex salt 17P was added and stirred for 15 minutes under water cooling.

After the reaction is complete, ether is added to the reaction mixture, followed by a cold dilute aqueous hydrochloric acid solution, and the ether layer is washed with an aqueous sodium bicarbonate solution and then dried over anhydrous sodium sulfate.

After drying, the solvent is distilled off from the reaction mixture to obtain the target compound 1.63f in the form of an oil.

Infrared absorption spectrum (liquid film) νmaxcm-1:17
40, 2700 Nuclear magnetic resonance spectrum (CDCl3) δppm: 1.9
3 (3H, singlet) 3.58 (3H, singlet) 9.6 9 (IH, br / doublet) Reference example 1
0 dimethyl 2-oxo 4,8-dimethyl-7-nonenylphosphonate dimethyl methylphosphoone}10.25' in a tetrahydrofuran solution (80 ml) in an argon stream at -60
15.1% n-butyllithium-hexane solution 4 at °C
A solution of 3,7-dimethyl-6-octenoic acid methyl ester 7.227P in tetrahydrofuran (30 ml) was added dropwise to dimethyl phosphonate synthesized by dropping 1TrLl under stirring while keeping the temperature below -50°C.
) was added dropwise, and the mixture was further stirred at -50 to -60°C for 3 hours and 10 minutes, then the cooling bath was removed and stirring was continued at room temperature until the internal temperature reached 0°C.

After the reaction is completed, acetic acid and water are sequentially added to the reaction mixture, and the mixture is extracted with ether.

After washing the extract with water and drying over anhydrous sodium sulfate, the solvent is distilled off from the extract.

When the obtained residue is distilled under reduced pressure, it has a boiling point of 124-127
°C/0. The target compound 4.858f is obtained as an oil with 1 mvrtHg.

Infrared absorption spectrum (liquid film) νm, 1 drift-1:1
7l 5 Nuclear magnetic resonance spectrum (CCI4) δppm: 0.90
(3H, double line, J=6Hz) 1.5 7 (3H, singlet) 1.64 (3H, singlet) 2.89 (2H, double line, J=23Hz) 3.66 (6
H, double line, J=LIHz) 4.96 (IH, triple line,
J=7i{z) Reference example 11 9β-acetoxyl1α-(2-tetrahydrobilanyloxy)=15-oxo 17-methyl-20-ingropylideneprostol l3(trans)monoenoic acid methyl ester 52.9% Oily sodium hydride 29211l9 was washed with dry petroleum ether to remove oil, and then suspended in 2 orul of dimethoxyethane, cooled with water in an argon stream, and dimethyl 2-oxo4,8-dimethyl-
A dimethoxyethane solution (20 ml) containing 1.85 g of 7-nonenylphosphonate was added dropwise, and after further stirring for 3 hours and 30 minutes, 10 rrLl of dimethoxyethane was added.

2.1α-(2-tetrahydrobilanyloxy)-2β-formyl-3α-(6-methoxylponylhexyl)-4β-acetoxycyclopentane was added to this solution under water cooling.
35? A dimethoxyethane solution (30 TrLl) of was added dropwise and stirred for an additional 25 minutes.

After the reaction is complete, acetic acid and then excess ether are added to the reaction mixture, the organic solvent layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain a 4.08P residue.

When this is purified by column chromatography using alumina, the target compound 2.0181 is obtained as an oil.

Infrared absorption spectrum (liquid film) νmaXCrrL-l:
l740, l695, 1670, l630, l035,
1025 Nuclear magnetic resonance spectrum (CCI4) δppm: 0.90
(3H, doublet, J=6Hz) 1.60 (3H1 singlet) 1.64 (3H, singlet) 1.98 (3H, singlet) 3.5 9 C 3H, singlet) 4.90 (2H, multiplet) 6.31 (2H, multiplet) Reference example l2 9β-acetoxy-11α-(2-tetrahydropyranyloxy)=15-hydroxy-17-methyl-20-
(Ingropylideneprost-13 (trans)
-9β-acetoxy 1 under water cooling with enoic acid methyl ester
1α-(2-tetrahydropyranyloxy) -1 5
-Oxo-17-methyl-20-ingropylidenepro♂t-13(trans)-enoic acid methyl ester 2.0
To a solution of 251 in anhydrous methanol (50 ml) was added 1.52 ml of sodium borohydride little by little, and the mixture was stirred for 20 minutes.

After the reaction is complete, acetic acid is added to decompose excess sodium borohydride, water is added, and the mixture is extracted with ethyl acetate.

After washing the extract with water and drying over anhydrous sodium sulfate, the solvent is distilled off from the extract to obtain a residue of 2.2'if.

The residue is purified by column chromatography using silica gel to obtain the target compound 1.989f as an oil.

Infrared absorption spectrum (liquid film) νmaxcm-1:34
80, l740, nuclear magnetic resonance spectrum (CCl4) δppm: 0.91
(3H, doublet, 6Hz) 1.5 7 (3H, singlet) 1.64 (3H, singlet) 1.9 5 (3H, singlet) 3.60 (3H, singlet) 5.49 (2H, multiplet) Reference example 13 9β-acetoxy 11α・15α-dihydroxy-1
7-Methyl-20-isopropylidenepros}-13
(trans)=enoic acid methyl ester and 9β-acetoxy-11α·15β=dihydroxy-l7-methyl-20-inpropylideneprost-1. 3 (trans) monoenoic acid methyl ester 9β-acetoxy 11α-(2-tetrahydropyranyloxy)-45-hydroxy-17-methyl-20-
Isopropylideneprostol 13(trans)monoic acid methyl ester 1.981' was mixed with acetic acid, water, tetrahydrofuran (40ml-17rnl-8 rul
) and then stirred at around 35°C for 4 hours and 30 minutes.

After the reaction is completed, water is added to the reaction mixture and extracted with ethyl acetate.

After washing the extract with water and drying over anhydrous sodium sulfate, the solvent was distilled off from the extract to obtain 2.11 g of a residue.

This is purified by column chromatography using silica gel.

The 15β-isomer of the target compound, 418~, was obtained from the 15~20% ethyl acetate-benzene outflow, and then 20~
A mixture of 15-position isomers 419P is obtained from the benzene outflow portion containing 30% ethyl acetate, and the l5α monoisomer 3261n9 of the target compound is obtained from the benzene outflow portion containing 30 to 80% ethyl acetate.

l5α-isomer: Infrared absorption spectrum (liquid film) vmaXcrrL-1:
3380, 1735 Nuclear magnetic resonance spectrum (CDCI3) δppm: 0
．． 91 (3H, doublet, J=6Hz) 1.57 (3H, singlet) 1.64 (3H, singlet) 3.60 (3H, singlet) 4.95 (2H, multiplet) 5. 45 (2H, multiplet) 15β-isomer: Infrared absorption spectrum (liquid film) vrnaxcfrL-1
:3430, 1735 Nuclear magnetic resonance spectrum (CDCI3) δppm: 1.5
7 (3H, singlet) 1.68 (3H, singlet) 1.98 (3H, singlet) 3,63 (3H, singlet) 4.92 (2H, multiplet) 5.58 (2H, multiplet) Reference example 14 9β-acetoxy iiα・15α-di(2-tetrahydrovilanyloxy)-17-methyl-20-inpropylideneprost-13(trans)monoic acid methyl ester 9β-acetoxyllα・15α-dihydroxy- 1
7-Methyl-20-inpropylidenepros}-13(
Add 5 ml of dihydropyran to a solution of 510 ml of trans)-enoic acid methyl ester in 5 ml of benzene at room temperature.
Then, a catalytic amount of bicric acid was added under water cooling, and the mixture was left to stand for 2 hours and 30 minutes.

After the reaction is completed, the reaction mixture is directly purified by alumina chromatography to obtain an oily crude product of the target compound. ．． 4911 is obtained.

Infrared absorption spectrum (liquid film) vmaXcIrL-1:
1735, 1030, 1020 Nuclear magnetic resonance spectrum (CCI4.) δppm: 0.9
1 (3H, doublet, J=6Hz) 1.93 (3H, singlet) 3.57 (3H, singlet) 5.4.3 (2H, multiplet) Reference example 15 9β-acetoxy 11α/15β -di(2-tetrahydrocyranyloxy)-17-methyl-20--inpropyriteneprost-1 3 (trans)monoic acid methyl ester 9β-acetoxy11α・15β-dihyto7x-1
7-Methyl-20-ingropylidenepros l--13
By reacting and treating in the same manner as in Reference Example 14 using 555~ of (trans)monodenoic acid methyl esters, 1.30 g of a crude product of the target compound is obtained.

Infrared absorption spectrum (liquid film) vrllaXCrr
L”.1735, 1030, 1015 Nuclear magnetic resonance spectrum (CC■4) δppm: 0.89
(3H, doublet, J-6Hz) 1.98 (3H, singlet) 3.58 (3H, singlet) 5.41 (2H, multiplet) Reference example l6 9β-hydroxy-11α・15α-di (2-tetrahydrobiranyloxy)-17-methyl-20-impropyriteneprost-13(}lance) monoenoic acid crude 9β-acetoxy-11α・15α-di(2-tetrahydropyranyloxy)-17-methyl- 20-isopropyriteneprostol 13(}lance) monoenoic acid methyl ester 1. 4 9 1? WotJ potassium 1.5
g in 15 ml of water and 35 rnl of methanol, and then stirred vigorously at room temperature with occasional heating.

After 17 hours and 45 minutes, water is added to the reaction mixture and extracted with a 50% ether-containing hexane solution to remove the neutral portion, then the aqueous layer is acidified with acetic acid and extracted with ethyl acetate.

After washing the extract with water and drying with anhydrous sodium sulfate, the solvent was distilled off from the extract, and 766 m9 of the target compound was obtained as an oil.
is obtained.

Infrared absorption spectrum (liquid film) vmaXCTL-1:3
400, 17lO Nuclear magnetic resonance spectrum (eel4) δppm: 0.9
1 (3H, doublet, 6Hz) 5.03 (1.H, triplet, 6Hz) 5.47 (2H, multiplet) Reference example 1-7 9β-hydroxy-l1α・l5β-di(2-tetrahydride Biranyloxy)-17-methyl-20-isopropylideneprost-13(1-lance) monoenoic acid crude 9β-acetoxy 11α・15β-di(2-tetrahydrovilanyloxy)-17-methyl-20-ingropylidene When 1.3 g of st-13(}lance)-enoic acid methyl ester is reacted and treated in the same manner as in Reference Example 16, an oily target compound 764m9 is obtained.

Infrared absorption spectrum (liquid film) νmaXCIrL-1:
3400, 1710 Nuclear magnetic resonance spectrum (CCI4) δppm: 0.84
(3H, doublet, 6Hz) 4.98 (IH, triplet, 6Hz) 5.38 (2H, multiplet) Reference example 18 9β-hydroxy-11α・l5α-di(2-tetrahydrobiranyloxy)-17 -Methyl-20-ingropylideneprost-13 (trans) monoenoic acid methyl ester 9β-hydroxy-1lα・15α-di(2-tetrahydropyranyloxy)-17-methyl-20-isopropylidene prostole 13 (trans) Monoenoic acid 125m
An ethereal solution of diazomethane is added to a solution of 9 in 5 rrL of ether until the reaction mixture takes on a pale yellow color.

After the reaction is completed, the solvent is distilled off under reduced pressure to obtain the target compound 127 in the form of an oil.

Infrared absorption spectrum (liquid film) νmaXCrrL-1:
3400,1730 Reference example 19 3-oxo-6-syn(3-oxo-5,9-dimethyl-1,8-dienyl)-7-antiacetoxy 2
-Oxabicyclo[3.3.0]-Octane 52.9% Oily sodium hydride 3211n9 was washed with dry petroleum ether to remove oil, and then suspended in 2 oml of dimethoxyethane and cooled with water in an argon stream. , dimethyl 2-oxo 4 obtained in Reference Example 10 under stirring
・8-dimethyl-7-nonenylphosphonate 2.03
Add 5P dimethoxyethane solution (20yul) dropwise,
After stirring for an additional 3 hours, 10rrL of dimethoxyethane was added.
Add l.

Add 3-oxo-6-synformyl = 7- to this solution under water cooling.
Antiacetoxy 2-oxabicyclo[3.3.O
]-octane 1.35S' dimethoxyethane solution (3
0 ml) was added dropwise, and the mixture was further stirred for 2 hours.

After the reaction is completed, acetic acid and then ether are added to the reaction mixture, and the organic solvent layer is washed with water, dried over anhydrous sodium sulfate, and then the solvent is distilled off.

The obtained residue was purified by column chromatography using silica gel, and the target compound 1.6 was obtained as an oil.
91 is obtained.

Infrared absorption spectrum (liquid film) νmaxcfrL publication: l
770, l740, 1695, 1670, l630 Nuclear magnetic resonance spectrum (CDCl3) δppm: 0.9
0 (3H, doublet, J=6Hz) 1.6 1 (3H, singlet) 1.65 (3H, singlet) 2.0 3 (3H. singlet) Reference example 20 3-okine-6-syn (3α-hydroxy-5,9-dimethyl-1,8-dienyl)-7-antiacetoxy-2-oxabisic[3,3,0]-octane and 3-oxo-6-syn(3β-hydroxy- 5.9-
Dimethyldesulfonate-1,8-dienyl)-7-antiacetoxy2-oxabicyclo[3,3,0]-octane 3-oxo-6-syn(3-oxo-5,9-dimethyldesynyl-1,8- (dienyl)-7-antiacetoxy 2
-Oxabishiku [3.3.0] -Octane 270mg
was dissolved in 4 ml of dimethoxyethane under water cooling.
．． 55M zinc borohydride-dimethoxyethane solution
．． s ml and stir for an additional hour.

After the reaction is complete, excess reagent is decomposed with dilute acetic acid, water is added, and the mixture is extracted with ethyl acetate.

After washing the extract with water and drying with anhydrous sodium sulfate, the solvent was distilled off from the extract and the resulting residue was subjected to preparative thin layer chromatography and purified using ether as a developing solvent. The smaller portion yields 89 mg of the 3α monoisomer of the target compound, and the more polar portion yields ~80 ~ of the 3β monoisomer of the target compound.

3α monoisomer: Infrared absorption spectrum (liquid film) νmaxCrrL-1:
3500, 1780 Nuclear magnetic resonance spectrum (CDC 1 3) δppm: 0
．． 91 (3H, doublet, J=6Hz) 1.58 (3H, singlet) 1.65 (3H, singlet) 5.51 (2H, multiplet) 3β-isomer: Infrared absorption spectrum (liquid membranous) νmaxcIft-1:
3500, 1780 Nuclear magnetic resonance spectrum (CDCl3) δppm: 0.9
0 (3H, doublet, J=6Hz) 1.5 7 (3H, singlet) 1.6 4 (3H, singlet) 5.51 (2H, multiplet) Reference example 21 3-oxo-6-syn (3α-hydroxy-5,9-dimethyltecar 1,8-dienyl)-7-antihydroxy-2-oxabicyclo[3,3,0]-octane 3-oxo-6-syn(3α-hydroxy-59-dimethylteca- 1.8-dienyl)-7-antiacel.xy-2-oxabicyclo[3.3.0]-octane 1.
After dissolving 201rL9 in 2 ml of anhydrous methanol, 65 mg of anhydrous potassium carbonate was added and stirred for 20 minutes.

After the reaction is complete, acetic acid and then water are added, followed by extraction with ethyl acetate.

After washing the extract with water and drying over anhydrous sodium sulfate, the solvent was distilled off from the extract to obtain the target compound 9. in the form of an oil. 3 m9
is obtained.

Infrared absorption spectrum (liquid film) νmaXcm-1:17
70 Nuclear magnetic resonance spectrum (CDC13) δppm: 0.9
1 (3H, doublet, J=6Hz) 1.58 (3H, singlet) 1.68 (3H, singlet) 5.54 (2H, multiplet) Reference example 22 3-oxo-6-syn (3β -Hydroxy-5,9-dimethyldecar-1,8-dienyl)-7-antihydroxy-2-oxabicyclo[3,3-O]-octane 3-oxo-6-syn(3β-hydroxy-5,9-dimethyldec- When the reaction and treatment are performed in the same manner as in Reference Example 21 using 1,8-genyl)-7-antiacetoxy2-oxabicyclo[-3,3,0]-octane, an oily target compound is obtained.

Infrared absorption spectrum (liquid film) νrrlaXcIrL-
1:l 770 Nuclear magnetic resonance spectrum (CDCl3) δppm: 0.9
0 (3H, doublet, J=6Hz) 1.5 7 (3H, singlet) 1.68 (3H, singlet) 5.54 (2H, multiplet) Reference example 23 3-oxo-6-syn [ 3α-(2-tetrahydrobilanyloxy)-5,9-dimethyldeoxy-1,8-dienyl]-7-anti(2-tetrahydropyranyloxy)-2-oxabicyclo[3,3,0]-octane 3-oxo-6-syn(3α-hydroxy-5,9-dimethylteca-1,8-dienyl)-7-7-thihydroxy-2-oxabicyclo[3.3.0]-octane 15
By reacting and treating in the same manner as in Reference Example 14 using 0m9, crude target compounds 301 to 301 are obtained.

Infrared absorption spectrum (liquid film) L/maxCfrL-1
:1770, l030 Nuclear magnetic resonance spectrum (CDCl3) δppm: 0.9
1 (3H, doublet, J=6Hz) Reference example 24 3-oxo-6-syn[3β-(2-tetrahydrobilanyloxy)-5,9-dimethyldec-1,8-dienyl]-7-anti( 2-tetrahydrobilanyloxy)-2-oxabicyclo[3.3.0]-octane 3-oxo-6-syn(3β-hydroxy-5.9-dimethyldeca=1.8-dienyl)-7-antihydroxy By reacting and treating in the same manner as in Reference Example 14 using -2-oxabicyclo[3.3.0]-octane, the crude target compound is obtained.

Infrared absorption spectrum (liquid film) vmaXcrI'L-1
:1770, ■025 Nuclear magnetic resonance spectrum (CDCI3) δppm: 0.9
0 (3H, doublet, J=6Hz) Reference example 25 3-hydroxy-6-syn[3α-(2-tetrahydrobilanyloxy)-5,9-dimethyldeoxy-1,8-dienyl]-7- Anti(2-tetrahydrobilanyloxy)-2-oxabicyclo[3.3.0]-octane 3-oxo-6-syn[3α-(2-tetrahydrobilanyloxy)-5.9-dimethyldec-1. 8-dienyl]-7-anti(2-tetrahydropyranyloxy)-2-oxabicyclo[3.3.0]-octane 19
After cooling a solution of 0 to 5771 liters of toluene to -60°C, a toluene solution (1 ml) of 190 mg of diisobutylaluminum hydride was added dropwise with stirring,
Stir for an additional 30 minutes.

After the reaction is completed, 1 ml of methanol and water are added, and the mixture is extracted with ethyl acetate.

After washing the extract with water and drying over anhydrous sodium sulfate, the solvent is distilled off from the extract to obtain 170 mg of the target compound in the form of an oil.

Infrared absorption spectrum (liquid film) Vmax(:FIL
”.34201 1030 Nuclear magnetic resonance spectrum (CDCl3) δppm: 0.9
1 (3H, double line, J = 6Hz) Reference example 26 3-hydroxy-6-syn[3β-(2-tetrahydropyranyloxy)-5,9-dimethyldeoxy-1,8-dienyl]-7- Anti(2-tetrahydropyranyloxy)-2-oxabicyclo[3.3.0]-octane 3-oxine-6-syn[3β-(2-tetrahydrobyranyloxy)-5.9-dimethyldeoxy-1・When reacting and treating in the same manner as in Reference Example 25 using 8-dienyl]-7-anti-(2-tetrahydrobilanyloxy)-2-oxabicyclo[3.3.0]-octane, an oily target compound was obtained. is obtained.

Infrared absorption spectrum (liquid film) νmaxcm-1:34
10,1030 Nuclear magnetic resonance spectrum (CDCI3) δppm: 0.9
0 (3H, doublet, J=6Hz) Reference example 27 9α-hydroxy-l1α・15α-di(2-tetrahydropyranyloxy)-17-methyl-20-inpropylideneprost-5(cis)l3(trans )-dienoic acid 2M-sodium methylsulfinyl carbanion in 1.3 ml of a dimethyl sulfoxide solution at 20° C. or below in an argon atmosphere, add triphenylcarpoquine butylphosphonium bromide 6241n9 to 2 ml of a dimethyl sulfoxide solution. is added dropwise under stirring to obtain a red ylide solution.

Add this solution to 3-hydroxy-6-syn Oxabicyclo [3.3.0]
- 220 mg of octane in 5 ml of dimethyl sulfoxide solution
1 and stirred at room temperature for 20 hours.

After the reaction is complete, dimethyl sulfoxide is distilled off under reduced pressure.
An aqueous sodium/lium hydrogen carbonate solution is added to the resulting residue, and the mixture is washed with ethyl acetate to remove neutral substances.

The aqueous layer was then acidified with oxalic acid to a pH of around 3, extracted with a hexane-ether mixed solvent (1:1), the extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off from the extract, leaving an oily target. Compound 1981ft9 was obtained.

Infrared absorption spectrum (liquid film) νmaXCIrL=1:
3400, l708 Nuclear magnetic resonance spectrometer (CC■4) δppm: 0.9
1 (3H, doublet, 6Hz) 5.01 (IH, triplet, 6Hz) Reference example 28 9α-hydroxy=l1α・15β-di(2-tetrahydropyranyloxy)-17-methyl-20-impro Pyrideneprost-5(cis),13(trans)-1-dienoic acid 3-hydroxy-6-syn[3β-(2-tetrahydropyranyloxy)-5,9-dimethyldec-1,8-dienyl]-7 -Anti(2-tetrahydropyranyloxy)-2-oxabicyclo[3.3.0]-octane is reacted and treated in the same manner as in Reference Example 27 to obtain an oily target compound.

Infrared absorption novel vector (liquid film) vmaXcIrL-1:
3400, l710 Nuclear magnetic resonance spectrum (CCI4) δppm: 0.91
．． (3H, doublet, J=6Hz) 5.02 (IH, triplet, J=6Hz) Reference example 29 9α-hydroxy-11α・15α-di(2-tetrahydropyranyloxy)-17-methyl-20 -isopropylideneprost-5 (cis), 1. 3 (} lance) monodienoic acid methyl ester 9α-hydroxy-1
1α・15α-di(2-tetrahydropyranyloxy)
-17-methyl-20-isopropylideneprost-5
An ethereal solution of diazomethane is added to a solution of 730 m9 of (cis),13(trans) monodienoic acid dissolved in 5 rrLl of ether until the reaction mixture takes on a pale yellow color.

After the reaction is completed, the solvent is distilled off under reduced pressure to obtain 728m9 of the target compound in the form of an oil.

Infrared absorption spectrum (liquid film) vmaxcrrl]:
3400, 1730 nuclear magnetic resonance spectrum (cc l4) δppm:
0.91 (3H, double line, J=6Hz) 5. Oi (LH, triplet, J=6Hz) Reference example 30 9β-acetoxy 11α-(2-tetrahydrobylanyloxy)-15-oxo-20-ingropylidenepros l=1.3(}lance) monoenoic acid 52.9% oily sodium hydride 117.4 dimethyl 2-oxo-8-mer prepared according to Reference Example IO
11'-7-nonenylphosphonate 1g and 1
α-(2-tetrahydrobilanyloxy)-2β-formyl-3α-(6-methoxycarbonylhexyl)-4
By reacting and treating 68,077 g of β-acetoxycyclopentane in the same manner as in Reference Example 11, 898 m9 of the target compound in the form of an oil is obtained.

Infrared absorption spectrum (liquid film) νmaXcIrL-1:
1735, 1695, 1670, 1625, l035 Nuclear magnetic resonance spectrum (CCl4) δppm: 1.48
(3H, singlet) 1.58 (3H, singlet) 1.8 7 (3H1 singlet) 3.48 (3H, singlet) 6.22 (2H, multiplet) Reference example 31 9β-acetoxy 11α- (2-tetrahydropyranyloxy)-1 5-hydroxy-20-impropylideneprostol 13(trans)monoic acid methyl ester 9β-acetoxy 11α-1(2-tetrahydropyranyloxy)-15-oxo20-ing Rohiritenprost-13 (trans)=enoic acid methyl ester 89
8■ is reacted and treated in the same manner as in Reference Example 12 to obtain the target compound 851Tn9 in the form of an oil.

Infrared absorption spectrum (liquid film) νmaXCrrL-1:
3420, l735 Reference Example 32 9β-acetoxy-11α-15-di(2-tetrahydrobilanyloxy)-20-inpropylideneprost-13(trans)monoenoic acid methyl ester 9β-acetoxy-11α-(2-tetrahydro When the reaction and treatment were carried out in the same manner as in Reference Example 14 using 851 m9 of villanyloxy)-1 5-hydroxy-20-ingropyritempros l-13(}lance)-enoic acid methyl ester, the crude target compound 1. ．． 55 g' are obtained.

Reference example 33 9β-hydroxy-11α-5-di(2-tetrahydropyranyloxy)-20-improhylitenprost-
1.3(}lance) monoenoic acid crude 9β-acetoxy-11
α-15-di(2-tetrahydropyranyloxy)-2
0-Ingropylidenepros}-13(trans)-enoic acid methyl ester 1.55S' was reacted and treated in the same manner as in Reference Example 6, yielding the target compound 1-01f in the form of an oil.
is obtained.

Infrared absorption spectrum (liquid film) νmaXCrrL-1:
3380, 1710, 1035, 1020 nuclear magnetic resonance spectrum 5.44 (2H, multiplet) Reference example 34 3-Oquino-6-syn (3-oxo-9-methylteca-
1,8-dienyl)-7-7-thi(p-phenylbenzoyloxy)-2-oxa-cis-bicyclo[3.3.
0]-Octane 52.9% oily sodium hydride 3 4
After washing 61rI9 with dry petroleum ether to remove oil, it was suspended in 20 ml of dimethoxyethane, and dimethyl 2-oxo-8-methyl-7-nonenyl phosphor obtained in Reference Example 30 was suspended in 20 ml of dimethoxyethane and cooled with water in an argon stream. Nate 2.0
A dimethoxyethane solution (20 ml) of 751 was added dropwise,
After stirring for a further 3 hours, 10 ml of dimethoxyethane are added.

Add 3-oxo-6-synformyl-7- to this solution under water cooling.
Anti(p-phenylbenzoyloxy)-2-oxasis-bicyclo[3.3.0]-octane 1.2
A dimethoxyethane solution (39 ml) of 2P is added dropwise, and the mixture is further stirred for 2 hours.

After the reaction is completed, the same treatment as in Reference Example 19 is carried out, and the obtained product is purified by column chromatography using silica to obtain the target compound 1.37g as an oil.

Infrared absorption spectrum (liquid film) νmaxcm-1:
l783, 1723, 1680, l635, l280,
1l85, 1120, 755 Nuclear magnetic resonance spectrum (CDCl3) δppm: 5.0
~5.5 (3H, multiplet) 6.28 (IH, doublet) 6.8 (LH, quartet) 7.3 ~ 8.2 (9H, multiplet) Reference example 35 3-oxo- 6-syn(3α-hydroxy-9-methyl-1,8-dienyl)-7-anti(p-phenylbenzoyloxy)-2-oxasis-bicyclo[3,3
・0]-octane and 3-oxo6-syn(3β-
Hydroxy-9-methyldec(1,8-dienyl)-7
-Anti(p-phenylbenzoyloxy)-2-oxasis-bicyclo[3.3.0]-octane 3-oxo-6-syn(3-oxo9-methyldec-
1,8-dienyl)-7-anti(p-phenylbenzoyloxy)-2-oxa-cis-bicyclo[3.3.
0]-octane 290m9 dimethoxyethane 5771
1 ml of 0.55M zinc borohydride dimethoxyethane solution was added to the solution dissolved in
Stir for an hour.

After the reaction was completed, it was treated in the same manner as in Reference Example 20, and the obtained product was subjected to preparative thin layer chromatography.
Purification using ether as a developing solvent yielded 95m9 of the 3α monoisomer of the target compound from the less polar fraction, and 77m of the 3β-isomer from the more polar fraction.
9 is obtained.

3α monoisomer infrared absorption spectrum (liquid film) vrnaX sieve-l: 3
500, 1780, 1720, 1615, 1280, l
185, 1120, 975, 750 Nuclear magnetic resonance spectrum (CDCl3) δppm: 4.1
3 (IH, multiplet) 4.9-5.4 (3H, multiplet) 5.64 (2H, multiplet) 7.3-8.2 (9H, multiplet) 3β monoisomer infrared absorption spectrum (liquid film) νmaxcm-1:35
00, l780, 1720, l615, 1280, 11
85, 1 ■ 20, 975, 750 Nuclear magnetic resonance spectrum (CDC13) δppm: 4.1
3 (IH, multiplet) 4.9-5.4 (3H, multiplet) 5.64 (2H, multiplet) 7.3-8.2 (9H, multiplet) Reference example 36 3-oxo-6 -Syn(3α-hydroxy-9-meldeca-1,8-genyl)-7-antihydroxy-2
-Ox-cis-bicyclo[3.3.0]-octane 3-oxo-6-syn(3α-hydroxy-9-methyldec-1.8-dienyl)-7-anti(p-phenylbenzoyloxy)-2 -oxa-cis-bicyclo[3
・3.0] - After dissolving 1.401 n9 of octane in 3 rnl of anhydrous methanol, 75 m9 of anhydrous potassium carbonate is added and stirred for 35 minutes.

After the reaction was completed, the same post-treatment as in Reference Example 21 was carried out to obtain 99 lbs. of the target compound in the form of an oil.

Infrared absorption spectrum (liquid film) vmaxC: IrL-1
:3400, 1760, 1175, 1080, 970 Nuclear magnetic resonance spectrum (CDC13) δppm: 1.6
0 (6H, doublet) 3,8-4.2 (2H, multiplet) 4.8-5.3 (2H, multiplet) 5.55 (2H, multiplet) Reference example 37 3-oxo- 6-syn(3β-hydroxy-9-methyldecar-1,8-dienyl)-7-antihydroxy-2
-Ox-cis-bicyclo[3.3.0]-octane 3-okino-6-syn(3β-hydroxy-9-methyldec-1.8-dienyl)-7-anti(p-phenylbenzoyloxy)- 2-oxa-cis-bicyclo[3
・3.0]-Octane (91 mg) is reacted and treated in the same manner as in Reference Example 36 to obtain the target compound in the form of an oil.

Infrared absorption spectrum (liquid film) νmaxCrrL-1:
3400, l760, 1175, 1080, 970 Nuclear magnetic resonance spectrum (CDCI3) δppm: 1.6
(6H, doublet) 38-4.2 (2H, multiplet) 48-5.3 (2H. multiplet) 5.55 (2H, multiplet) Reference example 38 3-oxo=6-syn [3α -(2-tetrahydrobilanyloxy)-9-methyldecar-1,8-dienyl]-
7-Anti(2-tetrahydrobilanyloxy)-2-
Oxa-cis-bicyclo[3,3,0]-octane 3-oxo-6-syn(3α-hydroxy-9-methyldecar-1,8-dienyl)-7-antihydroxy-2
-Oxase bicyclo [3.3.0] -Octane 3
1.85 P of dihydrohyrin was added to a solution of 0.8 g dissolved in 15 ml of benzene at room temperature, and then a catalytic amount of picric acid was added to the solution under water cooling, and the mixture was left to stand for 3 hours.

After the reaction was completed, 200 ml of ether was added to the reaction solution, and the
% sodium bicarbonate, then washed with water until clear and dried over anhydrous sodium sulfate.

The solvent is distilled off, and the residue is purified by column chromatography on silica gel to obtain 43 g of the target compound as an oil.

Infrared absorption spectrum (liquid film) vmaxcr/L-1:
1175, 1130, 1070, 1015, 970 Nuclear magnetic resonance spectrum (CDC■3) δppm: 4.7
(2H, multiplet) 4.8-5.2 (2H, multiplet) 5.0 (2H, multiplet) Reference example 39 3-oxo-6-syn[3β-(2-tetrahydropyranyloxy)-9 -Methylteca-1,8-dienyl]-
7-Anti(2-tetrahydrohyranyloxy)-2-
Oxasis-bicyclo[3.3.0]-octane 3-oxo-6-syn(3β-hydroxy-9-methyldecar-1.8-dienyl)-7-antihydroxy-2
-Oxacysubicyclo[3.3.O]-Octane 2
．． By subjecting 71 to the same reaction treatment as in Reference Example 38, oily target compound 351 is obtained.

Infrared absorption spectrum (liquid film) νmaXcrn-1:1
775, 1130, 1070, 1015, 970 Nuclear magnetic resonance spectrum (CDCl3) δppm: 4.7
(2H, multiplet) 48-5.2 (2H, multiplet) 5.0 (2H, multiplet) Reference example 40 3-hydroxy-6-syn[3α-(2-tetrahydropyranyloxy)-9- Methyldecar 1,8-dienyl]-7-anti(2-tetrahydrobilanyloxy)-
2-oxa-cis-bicyclo[3.3.0]-octane 3-oxo-6-syn[3α-(2-tetrahydropyranyloxy)-9-methyldeca-1.8-dienyl]-
7-Anti(2-tetrahydropyranyloxy)-2-
Oxa-cis-bicyclo[3.3.0]-octane4.
When 3 g is used and treated in the same manner as in Reference Example 25, oily target compound 4.11 is obtained.

Infrared absorption spectrum (liquid film) vmaXcrIl-1:
3400, 1130, 1070, 1015, 970 Nuclear magnetic resonance spectrum (CDCl3) δppm: 4. ．．
7 (2H, multiplet) 5.15 (IH, triplet) 5.6 (2H, multiplet) Reference example 41 3-hydroxy-6-syn[3β-(2-tetrahydropyranyloxy)-9-methyldeca -■・8-dienyl]-7-anti(2-tetrahydrobilanyloxy)-
2-Oxase-bicyclo[3.3.0]-octane 3-oxo-6-syn[3β-(2-tetrahydropyranyloxy)-9-methyldecal 1.8-dienyl]-
7-Anti(2-tetrahydropyranyloxy)-2-
oxa-cis-bicyclo[3.3.0]-octane 35
When the mixture is treated in the same manner as in Reference Example 25, 33 g of the target compound in the form of an oil is obtained.

Infrared absorption spectrum (liquid film) vmaXcrfL-1:
3400, l130, 1070, l015, 970 Nuclear magnetic resonance spectrum (CDCl3) δppm: 4. ．．
7 (2H, multiplet) 5.15 (LH, triplet) 5.6 (2H, multiplet) Reference example 42 9α-hydroxy-l1α・15α-di(2-tetrahydrobyranyloxy)-20-ingropyriten Rost-5(cis),13(trans)monodienoic acid 3-hydroxy-6-syn[3α-(2-tetrahydropyranyloxy)-9-methyldecar-1,8-dienyl]-7-anti(2-tetrahydro hyranyloxy)-
When treated in the same manner as in Reference Example 27 using 4.1 g of 2-oxasis-bicyclo[3.3.0]-octane, the target compound 362 is obtained as an oil.

Infrared absorption spectrum (liquid film) νmaxCIrL-1:
3450, 3200, 2750, 171.5, l160
, l105, 1020 Nuclear magnetic resonance spectrum (CDCI3) δppm: 4. ．．
73 (2H, multiplet) 5.17 (IH, triplet) 5.5 (4-H, multiplet) Reference example 43 9α-hydroxy-l1α・l5β-di(2-tel・lahydrobilanyloxy )-20-Isopropyriteneprostole 5(cis),13(trans)-dienoic acid 3-hydroxy-6-syn[3β-(2-tetrahydropyranyloxy)-9-methyldeca-1,8-dienyl]- 7-Anti(2-tetrahydrobilanyloxy)-
When treated in the same manner as in Reference Example 27 using 2-oxercis-bicyclo[3.3.0]-octane 3.31, the oily target compound 3.01 is obtained.

Infrared absorption spectrum (liquid film) νmaxCm':
3450, 3200, 2750, 17I5, 1160,
1105, 1020 Nuclear magnetic resonance spectrum (CDCl3) δppm: 4, 7
3 (2I{, multiplet) 5.17 (4H, multiplet) 5.5 (4H, multiplet) Reference example 44 3-oxo6-syn(2-tetrahydrobyranyloxymethyl)-2-oxabicyclo[ 3.3.0]-octane 3-okino-6-syn-hydroxymethyl-2-oxabicyclo[3.3.0]-octane 3.35'? was dissolved in 715 ml of anhydrous 2-3-dihydropyra, and 15 g of p.
-} Add toluenesulfonic acid and stir at room temperature for 20 minutes.

After the reaction is complete, dilute with 200ml of acetate to 100ml.
By washing three times with 1 ml of saturated saline, drying with anhydrous sodium sulfate, and evaporating the solvent, an oily target compound 5.952 is obtained.

Infrared absorption spectrum (liquid film) cm-1: 1780
, 1165, 1125, 1035 Reference example 45 3-Hydroquine-6-syn(2-tetrahydrobyranyloxymethyl)-2-oxabicyclo[3.3.O]-
3-oxo-6-syn(2-tetrahydrobylanyloxymethyl)-2-oxabicyclo obtained from Octane Reference Example 44 [
3.3.0] - 5.9 g of octane to 100 g of anhydrous toluene
ml and stirred at -70°C under an argon gas stream.

Add diisobutylaluminum hydride (
2El/100rul H-hexane solution) 21rnl 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 0 ml dropwise, the mixture was returned to room temperature.

After removing the precipitated insoluble matter by filtration using Celite, diluting with saturated brine and extracting with ethyl acetate, the organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the oily target compound 5. 89 g is obtained.

Infrared absorption spectrum (liquid film) cm': 345
0,1125, 1065, 1025 Nuclear magnetic resonance spectrum (CDCl3) δppm: 4.6 to 4.8 (2H, multiplet) 5.58 (IH, multiplet) Reference example 46 1α-hydroxy-2α-(6- Methoxy carbonyl
2-7suhexenyl)-3β-(2-tetrahydrobylanyloxymethyl)-cyclopentane 7.10P and 20
A red ylide solution is obtained by adding 32 g of (4-carpoxybutyl)triphenylphosphonium bromide to a sodium methylsulfinyl carbanion solution obtained from 0 ml of dimethyl sulfoxide in an argon gas stream at a temperature below 20°C.

Add 3-hydroxy-6-syn-(2-tetrahydrobyranyloxymethyl)-2-oxabicyclo[3
・20 ml of a dimethyl sulfoxide solution containing 5.82% of 3.0]-octane was added, and the mixture was stirred at room temperature for 30 minutes.

After the reaction is complete, add 500ml of 1.5% cold (O℃) hydrochloric acid aqueous solution.
After diluting the reaction solution with 1 liter, ether extraction is performed, 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.
The residue is subjected to column chromatography using 140 g of silica gel to obtain the target compound 6.57P in the form of an oil.

Infrared absorption spectrum (liquid film m'1; 3480
, 1740, 1200, 1140, 1120, 1030 Nuclear magnetic resonance spectrum (CDC13) δppm: 3.6
7 (3H, singlet) 4.23 (LH, multiplet) 4.80 (LH, multiplet) 5.50 (2H, multiplet) Reference example 47 1α-acetoxy 2α-(6-methoxycarbonyl-
2-hexenyl)-3β-(2-tetrahydropyranyloxymethyl)-cyclopentane lα-hydroxy-2α-(6-methoxycarbonyl-
6.49 g of 2-cis-hexenyl)-3β-(2-tetrahydropyranyloxymethyl)-cyclopentane,
Dissolve in a mixed solution of 20 ml of pyridine and 1.0 ml of acetic anhydride and stir at 40°C for 2 hours.

After the reaction is completed, the reaction solution is diluted with 150 ml 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.
6? is obtained.

Infrared absorption spectrum (liquid film) cm-1: l740, 1
245, 1030 Nuclear magnetic resonance spectrum (CDC■3) δppm: 2.
0 3 (3H, singlet) 3.6 7 (3H, singlet) 4. ．． 62 (IH, multiplet) 5.23 (IH, multiplet) 5.4.2 (2H, multiplet) Reference example 48 1α-ace1・xy-2α-(6-me1・xycarbonyl-2 7.20 Dissolve @ in 150 ml of methanol containing 10% water, 1.
Add p-toluenesulfonic acid No. 42 and stir at 40° C. for 1 hour.

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

This residue was subjected to column chromatography using 8.02 silica gel to obtain the target compound 5 in the form of an oil.
．． 053P is obtained.

Infrared absorption spectrum (liquid film) crrl-1:3500
, 1740, 1380, 1250, 1170, 1025 Nuclear magnetic resonance spectrum (CDCl3) δppm: 2
．． 03 (3H, singlet) 3.65 (2H, multiplet) 3.6 8 (3H, singlet) 5.25 (IH, multiplet) 5.45 (2H, multiplet) Reference example 49 1α-acetoxy 2α-(6-methoxycarbonylhexyl)-3β-hydroxymeth)I/-cyclopentane 1α-acetoxy 2α-(6-methoxycarbonyl-
3.01 of 2-cis-hexenyl)-3β-hydroxymethyl-cyclopentane was dissolved in 50 ml of methanol,
Conventional hydrogenation is carried out using 2.0 g of 5% palladium on carbon 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-1: 3500, 1
740, l380, 1250, 1175, 102l Nuclear magnetic resonance spectrum (CDCl3) δppm: 2.
03 (3H, singlet) 3.63 (2H, multiplet) 3.70 (3H, singlet) 5.28 (IH, multiplet) Reference example 50 1α-acetoxy 2α-(6-methoxycarbonylhexyl)-3β - Formyl-cyclopentane Add 11.72 ml of pyridine to 200 ml of anhydrous dichloromethane, and add 7.362 ml of chromic anhydride while stirring at 15° C. under an argon stream to prepare a Collins oxidation reagent.

After cooling the solution to 3-5'C, 276 g of 1α-acetoxy-2α-(6-methoxycarbonylhexyl)-3β-hydroxymethyl-cyclopentane was added and stirred for 20 minutes.

After the reaction is complete, dilute the reaction solution with 1 t of ether, wash with 3% aqueous sodium hydroxide solution, 3% aqueous hydrochloric acid solution, 5% aqueous sodium bicarbonate solution, water, and dry with anhydrous sodium sulfate in order to distill off the solvent. Thus, the oily target compound 2.56P is obtained.

Reference Example 51 9α-acetoxy 15-oxo 20-ingropyriteneprost-13 (trans) monoenoic acid methyl ester 0.495 g of 50% oily sodium hydride was washed with dry petroleum ether to remove oil, and anhydrous dimethoxy After suspending in 150 ml of ethane, dimethyl-2-oxo-8-methyl-7 was cooled with water in an argon gas stream and stirred.
Add 2.77 g of monononenylphosphonate dropwise and stir at room temperature for 4 hours.

To this solution was added 2.50 P of 1α-acetoxy-2α-(6-methoxycarbonylhexyl 9-3β-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 4.58? An oily residue is obtained.

By purifying this residue by subjecting it to alumina cadmium chromatography, the oily target compound 2.451 is obtained.

Infrared absorption spectrum (liquid film) cm': 1740, 1700, 1670, 1625, 1370,
124G, 1170, 1020 nuclear magnetic resonance spectrum (
CDCI,,) δppm: 103 (3H, singlet) 3.64 (3H, singlet) 5.00 to 5.35 (2H, multiplet) 6.1. 0 (IH, double line) 6.52 (LH, quadruple line) Reference example 52 9α-acetoxy-15-hydroxy-20-isopropylidene prostole 13 (}7 ence) to enoic acid methyl ester 9α-acetoxy 15 - Okino 20-Inglohylitenprost-13 (trans) monoenoic acid methyl ester 2-41 was dissolved in 50 ml of anhydrous methanol to give 3 to 5
Cool to ℃ and stir.

After adding sodium borohydride 2101rI9 to the solution, it is 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 solvent of benzene and ethyl acetate, and the extract is washed with water and dried over anhydrous sodium sulfate.

By distilling off the solvent, 2.5 g of an oily residue is obtained.

Furthermore, this residue was purified by silica gel column chromatography to obtain the target compound 2.3 in the form of an oil.
6P is obtained.

Infrared absorption spectrum (liquid "A'J= shape") cm'
:3500, 1740, 1245, 1020 nuclear magnetic resonance spectrum (CDCI3) δppm: 2.0 (3H,
Singlet) 3.65 (3H, singlet) 4.07 (LH, multiplet) 5.0-5.4 (2H, multiplet) 5-50 (2H, multiplet) Reference example 53 9α- Acetoxyl 1,5-(2-tetrahydrobilanyloxy)-20-ingropylideneprost-13(
}Trans) monoenoic acid methyl ester 9α-acetoxy-15-hydroxy-20-isoglopylideneprost-13 (trans) monoenoic acid methyl ester 2.3P was dissolved in 5 ml of 2,3-dihydropyran to give a p of 10~ Add mono-toluenesulfonic acid for 30 minutes at room temperature.
Stir for a minute.

After the reaction was completed, 200 ml of noether was added and washed with water (
After drying with anhydrous sodium sulfate (100 ml x 3) and distilling off the solvent, an oily target compound (2.8'?) was obtained. is obtained.

Infrared absorption spectrum (liquid film) cm': 1740, 1375, I240, 1200, 1020,
965 Reference example 54 9α-hydroxy-15-(2-te}・lahydrobilanyloxy)-2 0-ingropylideneprost-1
3(trans)monoenoic acid 9α-acetoxyl 1 5-(2-tetrahydrobilanyloxy)-20-ingropylidenegrost-13
Dissolve 3.0 g of (J Lance)-enoic acid methyl ester in 90 ml of methanol, and dissolve 3.0 g of 5% aqueous sodium hydroxide solution.
After adding 0ml, stir at 40°C for 3 hours.

After completion of the reaction, diluted with ice water, neutralized with 7% aqueous hydrochloric acid solution, extracted with ethyl acetate, washed the organic layer with water, dried over anhydrous sodium sulfate, and distilled off the solvent under reduced pressure to obtain the target compound 2 in the form of an oil. .62 is obtained.

Infrared absorption spectrum (liquid film) cm': 3420, 2750, 1710, l 2 0 0, 11
10, 1020, 970 Nuclear magnetic resonance spectrum (CDCI3) δppm: 4.
7 (IH, multiplet) 5.0-5.5 (3H, multiplet) 6.0 (2H, multiplet) Reference example 55 1α-acetoxy 2α-(6-methoxycarbonyl-
2-cis-hexyl(1=nyl)-3β-formyl-cyclopenotane 1α-acetoxy-2α-(6-methoxycarbonyl-
By reacting and treating 2.07 of 2-cis-hexenyl)-3β-hydroxymethyl-cyclopentane in the same manner as in Reference Example 50, an oily target compound 1.95f is obtained.

Reference example 56 9α-acetoxy-15-oxo20-ingropylidenepros}-5(cis),13(trans)-dienoic acid methyl ester 1α-acetoxy2α-(6-methoxycarbonyl-
By reacting and treating 1.95 P of 2-cis-hexenyl)-3β-formyl-cyclopencune in the same manner as in Reference Example 51, 2.53 g of the target compound in the form of an oil is obtained.

Infrared absorption spectrum (liquid film) cm. ' :1735
, 1695, 1670, 630, 1370, l24
0, 1160, 1030 nuclear magnetic resonance spectrum (CDC
l3) δppm: 2.02 (3H, singlet) 3.65 (3H, singlet) 5.0 to 5.5 (3H, multiplet) 6.10 (IH, doublet) 6.72 (LH, quadruple line) Reference example 57 9α-acetoxy15-hydroxy-20-ingropylideneglost-5(cis),13(trans)-cyenic acid methyl ester 9α-acetoxy15-oxo-20-isopropylidenepro Sto 5 (cis), l3 (trans)-cienoic acid methyl ester2. 5sg was reacted and treated in the same manner as in Reference Example 52 to obtain the target compound 224y in the form of an oil.
is obtained.

Infrared absorption spectrum (liquid film) cm': 350
0, l740, 1370, 1240, 1160, IQ2
0,965 Nuclear magnetic resonance spectrum (CDCl3) δppm: 2.0
1 (3H, singlet) 3.67 (3H, singlet) 4.08 (LH, multiplet) 5.0~5.6 (5H, multiplet) Reference example 58 9α~acetoxy-15-( 2-tetrahydropyranyloxy)-20-isopropylideneprost-5(cis),l3(trans)-dienoic acid methyl ester 9-acetoxy15-hydroxy-20-1sopropylideneprost-5(cis),13( By reacting and treating 2.20 g of trans) monodienoic acid methyl ester in the same manner as in Reference Example 53, 2.91' of the oily target compound was obtained.
is obtained.

Infrared absorption spectrum (liquid film) cm-1: 1740, 1
370,1240, l200, 1015, 970 Reference example 59 9α-hydroxy-15-(2-tetrahydropyranyloxy)-20-ingropyriteneprost-5(cis),13(trans)monodienoic acid 9α-acetoxy 1
291 g of 5-(2-tetrahydropyranyloxy)-20-inpropylidene glost-5(cis),13(trans)-dienoic acid methyl ester was mixed with 80 g of methanol.
After adding 50 ml of 5% aqueous sodium hydroxide solution, the mixture was stirred at 40°C for 3 hours.

After the reaction is complete, dilute the reaction solution with 200ml of ice water to 7%
After neutralization with an aqueous hydrochloric acid solution, extraction was performed 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 target compound 2.51?
is obtained.

Infrared absorption spectrum (liquid film) cm': 3450, 3150, 2650, 1710, 1200,
1130, 1110, 1015, 965 Nuclear magnetic resonance spectrum (CDCl3) δppm: 4.
70 (IH, multiplet) 4.95 to 5.60 (5H, multiplet) 5.90 (2H, multiplet)

Claims (1)

[Scope of Claims] 1 General formula (wherein A represents an ethylene group or a cis-vinylene group, R1 and R2 are the same or different and represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R ″
and R4 represents an alkyl group having 4 to 3 carbon atoms, and R5 represents a hydrogen atom or a hydroxyl group. ) and a pharmacologically acceptable salt thereof. 2 9-Oxo-11α・15α(Arashi・Haβ)-dihydroxy-20-isopropyriteneprost-13(
A compound according to claim 1, which is represented by trans)-enoic acid. 3. The compound according to claim 1, which is represented by 9-oxo-11α·15α (or β)-dihydroxy-20-inpropylideneprost-5(cis),13(trans)-dienoic acid. 4. The compound according to claim 1, which is represented by 9-oxo-11α·15α (or β)-dihydroxy-20-inpropylideneprost-5(cis),13(trans)monodienoic acid methyl ester. 5 9-oxo 11α・15α (or β)-dihydroxy-20-inpropylidenepros 1--5 (
The compound according to claim 1, which is represented by the sodium salt of cis), l3(trans)-dienoic acid. 6 9-oxo-11α・15α (or β)-dihydroxy-17β-methyl-20-improhylitempest-1. 3. The compound according to claim 1, which is represented by (trans)monoenoic acid. 7 9-oxo-11α・15α (at a certain degree C. is β)-dihydroxy-17β-methyl-20-ingurohyritenglosst-13(trans)-enoic acid methyl ester according to claim 1 Compound. 8. The compound according to claim 1, which is represented by 9-oxo-11α·15α (or β)-dihydroxy-17β-methyl-20-ingropylideneprost-13(trans)-enoic acid potassium salt. 9 9-Oxo-l1α・15α (or β)-dihydroxy-17β-methyl-20-improhylitenprost-5(cis),1.3(}lance)-dienoic acid Claim 1 Compounds described in Section. 10 9-okine-11α・{5α (or β) monodihydroxy-17β-methyl-20-isoprohylitempros}-5 (cis), 13 (trans) monodienoic acid methyl ester Claim 1 Compounds described in Section. 11 9-oxo-l5α (or β) ~ hydroxy-20-inpropylidenegrost-13 (trans)
- The compound according to claim 1, which is represented by enoic acid. 12 9-Oxole 5α (or β)-hydroxy-20 = ingropylideneprost-13 (trans)
Claim 1 indicated by monoenoic acid methyl ester
Compounds described in Section. 13 9-oxo-15α (or β) monohydroxy-20-ingropylideneprost-13 (trans)
The compound according to claim 1, which is represented by the monoenoic acid potassium salt. 14 9-oxo-15α (or β) monohydroxy-20-ingropyriteneprost-5 (cis), 13
Claim 1 indicated by (trans)-dienoic acid
Compounds described in Section. 15 9-oxol 5α (or β) = hydroxy-20-ingropylideneprost-5 (cis), 13
The compound according to claim 1, which is represented by (trans)-dienoic acid methyl ester. 16 General formula (wherein A represents an ethylene group or a cis-vinylene group, R1 and R2 are the same or different and represent a philic atom or an alkyl group having 1 to 3 carbon atoms, R3
and R4 represents an alkyl group having 1 to 3 carbon atoms, and R5 represents a hydrogen atom or a hydroxyl group. ) and a pharmacologically acceptable salt thereof. 17 Prostaglandin derivatives are 9-oxo-11
The bronchodilator according to claim 16, which is represented by α·15α-dihydroxy-20-improhylitempest-5(cis),13(trans)-dienoic acid. 18 Prostaglandin derivatives are 9-oxo-11
The bronchodilator according to claim 16, which is represented by α·15α-dihydroxy-20-inpropylideneprost-5(cis),13(trans)-dienoic acid sodium salt. 19 Prostaglandin derivatives are 9-oxo-11
The bronchodilator according to claim 16, which is α·15α-dihydroxy-17β-methyl-20-ingropylideneprost-5(cis),13(trans)monodienoic acid.