JPH062708B2 - Process for producing 2-chloro-4-hydroxy-2-cyclopentenones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a novel method for producing 2-chloro-4-hydroxy-2-cyclopentenones.

More specifically, the present invention relates to a novel method for producing 2-chloro-4-hydroxy-2-cyclopentenones, which is useful as a synthetic intermediate for compounds having a cyclopentane skeleton such as prostaglandins.

4-hydroxy-2-cyclopentenones are compounds useful as synthetic intermediates for prostaglandins,
The 2-chloro-4-hydroxy-2-cyclopentenones having a chlorine atom of the present invention are useful as synthetic intermediates for novel prostaglandins.

<Prior Art and Its Problems> Conventionally, as a method for producing a compound having a 2-cyclopentenone skeleton having a halogen atom, US Pat. No. 3,755,426 is known.
In the specification, the following scheme [In the formula, X represents a halogen atom. ] The following scheme, which is filed by the present inventors or separately filed by the present inventors (JP-A-60-13755, JP-A-59-169200) [In the formula, X represents a halogen atom and R represents an alkyl group. A method for producing a compound having a 2-halo-2-cyclopentenone skeleton from a compound having a 2-cyclopentenone skeleton or a 2,3-epoxycyclopentanone skeleton is known by the route shown by

In addition to this, as a method for producing 2-halo-2-cyclopentenones, for example, a method of reacting 2-cyclopentenone with iodine azide, a method of obtaining from α-chloro-α-selenyl ketones, etc. Mitsuhashi
Chem. Pharm.Bul1., Chem. Pharm.Bul1., 13, 951 (1965); G. L. Dunn et al., Tetrahedron Lett. ), 3737 (1966); JMMcintosh, Canadayan
Journal of Chemistry (Can.J.Chem.), 49,
3045 (1971); Day J Butler (DJBuck
ley et al., Journal of Chemical Society Chemical Communication (J.Chem.Soc.Chem
m.Commun.), 506 (1980), etc.] is known.

However, none of these processes for producing 2-halo-2-cyclopentenones describes a process for producing 4-hydroxycyclopentenones having a hydroxyl group at the 4-position or a protected hydroxyl group.

2-Cyclopentenone having a hydroxyl group or a protected hydroxyl group at the 4-position, that is, 2-halo-4-hydroxy-2-cyclopentenones, is separately filed by the present inventors (Japanese Patent Application No. 59-244587). ) [In the formula, X represents a halogen atom, and R and R'represent a hydrogen atom or a protected hydroxyl-protecting group. ] It can manufacture from 2,3-epoxy-4-hydroxy cyclopentanone by the route shown by these. However, this production method has a drawback that 5-halo-4-hydroxy-2-cyclopentenones are produced together with 2-halo-4-hydroxy-2-cyclopentenones, and separation of these is difficult. .

On the other hand, conventionally, a method for obtaining a chlorohydrin compound by reacting an epoxy compound derived from an olefin compound with a metal chloride [eg, shear press (Sharpl
ess) et al., Journal of Organic Chemistry (J.Org.Chem.), 50,192 (1985)]. The present inventors have utilized the reaction between such an epoxy compound and a metal chloride, and have the following scheme. [In the formula, R represents an alkyl group. ] It was found that 2-chloro-3-hydroxycyclopentanones can be selectively obtained from 2,3-epoxycyclopentanones by the route shown by (JP-A-60-9226
2).

<Purpose of the Invention> The inventors of the present invention have paid attention to such a point, and as a result of diligent research on a method for producing 2-chloro-4-hydroxy-2-cyclopentenone, the following scheme [In the formula, R represents a protecting group for a protected hydroxyl group. ] 2,3-epoxy-4-hydroxycyclopentanones were obtained from 4-hydroxy-2-cyclopentenones by a route shown by Protected 2-chloro-3,4
The present invention has been accomplished by finding that 2-chloro-4-hydroxy-2-cyclopentenone can be selectively obtained by obtaining -dihydroxycyclopentanone and further dehydrating it.

Therefore, an object of the present invention is to provide a process for producing 2-chloro-4-hydroxy-2-cyclopentenones which is useful as a synthetic intermediate for compounds having a cyclopentane skeleton such as prostaglandins.

<Structure of Invention> The present invention has the following general formula [I]. [Wherein R ¹ represents a protective group for a protected hydroxyl group] is subjected to a dehydration reaction with 2-chloro-3,4-dihydroxycyclopentanone and, if necessary, a deprotection reaction or a protective group. Characterized by being attached to the conversion reaction of
The following formula [II] [In the formula, R ² represents a hydrogen atom or a protective group for a protected hydroxyl group. ] It is a manufacturing method of 2-chloro- 4-hydroxy- 2- cyclopentenone represented by these.

The 2-chloro-3,4-dihydroxyclopentanones represented by the above formula [I] are represented by the following formula [IV] (In the formula, R ¹ is the same as the above definition.) A 4-hydroxy-2-cyclopentanone represented by the following formula is subjected to an epoxidation reaction, and the following formula [III] (Wherein R ¹ is the same as the above definition), and it can be obtained by subjecting the 2,3-epoxycyclopentanones to a chlorination reaction. it can.

In the above formulas [I], [III] and [IV], R represents a protecting group for a protected hydroxyl group. Examples of the protected hydroxyl-protecting group include a C ₂ -C ₇ acyl group, a tri (C ₁ -C ₇ ) hydrocarbon-silyl group, a group which forms an acetal bond together with an oxygen atom of the hydroxyl group, a habenzyl group and the like. Can be mentioned.

Examples of the C _{2 to} C ₇ acyl group include acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl,
Examples thereof include isovaleryl, caproyl, enanthyl, benzoyl and the like.

Examples of the tri (C ₁ -C ₇ ) hydrocarbon silyl group include tri (C ₁ -C ₄ ) alkylsilyl such as trimethylsilyl, triethylsilyl, and t-butyldimethylsilyl group, t
Diphenyl such as -butyldiphenylsilyl group (C _1-
C ₄ ) Alkylsilyl or tribenzylsilyl groups and the like can be mentioned.

Examples of the group that forms an acetal bond together with the oxygen atom of the hydroxyl group include methoxymethyl, 1-ethoxyethyl,
2-methoxy-2-propyl, 2-ethoxy-2-propyl, (2-methoxyethoxy) methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or 6,6-dimethyl-3-oxo-2 An -oxo-bicyclo [3,1,0] hex-4-yl group may be mentioned.

Of these protecting groups, a tri (C ₁ -C ₇ ) hydrocarbon silyl group is preferable, and among them, triethylsilyl and t
A -butyldimethylsilyl group is preferable, and a t-butyldimethylsilyl group is particularly preferable.

In the above formula [II], R ² represents a hydrogen atom or a protective group for a protected hydroxyl group. When R ² represents a protective group for a protected hydroxyl group, specific examples thereof are the same as those listed for R ¹ .

As a reagent for the epoxidation reaction of 4-hydroxy-2-cyclopentenones represented by the above formula [IV], alkylhydroperoxides such as t-butylhydroperoxide or hydrogen peroxide is used. t-Butyl hydroperoxide is preferred. When hydrogen peroxide is used as a reagent for the epoxidation reaction, anhydrous hydrogen peroxide may be used, but 90 to 5% aqueous hydrogen peroxide is usually used. The amount of hydrogen peroxide used is 1 to 50 equivalents, preferably 3 to 20 equivalents, relative to 4-hydroxy-2-cyclopentenone represented by the above formula [IV]. The epoxidation reaction is preferably carried out in the presence of a basic compound. Examples of the basic compound include quaternary ammonium hydroxides such as tetramethylammonium hydroxide and benzyltrimethylammonium hydroxide; lithium hydroxide, sodium hydroxide. And hydroxides such as potassium hydroxide; carbonates such as sodium carbonate and potassium carbonate, and the like, preferably alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; sodium carbonate, potassium carbonate and the like. Alkali metal carbonates such as are used, and particularly preferably sodium hydroxide is used. The amount of the basic compound used is 0.01 to 0.5 equivalents, preferably 0.05 to 0.2 equivalents, relative to 4-hydroxy-2-cyclopentenone represented by the above formula [IV]. As the reaction solvent, alcohols such as methanol, ethanol and t-butyl alcohol; ketones such as acetone and methyl ethyl ketone; ethers such as dioxane and dimethoxyethane; inert to hydrogen peroxide and miscible with water. Solvents may be mentioned, preferably alcohols such as methanol, ethanol, t-butyl alcohol and the like are used, and particularly preferably methanol and ethanol are used. The reaction temperature of the epoxidation reaction is preferably −20 to 50 ° C., particularly preferably −5.
It is in the range of ~ 30 ° C. The reaction time of the epoxidation reaction varies depending on the starting material compound, reagent, reaction solvent and reaction temperature used, but it is usually in the range of 5 minutes to 5 hours, preferably in the range of 10 minutes to 1 hour. After the completion of the epoxidation reaction, the 2,3-epoxy-4-hydroxycyclopentanones represented by the above formula [III] are purified by a conventional means such as extraction, washing with water, drying, concentration and chromatography. Can be taken, but the 2,3-epoxy-4
-Without isolating hydroxycyclopentanones
The crude reaction mixture can be directly used in the following reaction.

When t-butyl hydroperoxide is used as a reagent for the epoxidation reaction of 4-hydroxy-2-cyclopentenones, anhydrous t-butyl hydroperoxide may be used, but usually a 90% or less solution is used. , Preferably a 50 to 5% solution is used. As the solvent for the solution of t-butyl hydroperoxide, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane; aromatic hydrocarbons such as benzene and toluene are used. The amount of t-butyl hydroperoxide used is 4-hydroxy-type represented by the above formula [IV].
1 to 20 equivalents, preferably 1 to 5 equivalents, relative to 2-cyclopentenone are used. The epoxidation reaction is preferably carried out in the presence of a basic compound, and examples of such a basic compound include quaternary ammonium hydroxides such as tetramethylammonium hydroxide, tetraethylammonium hydroxide and benzyltrimethylammonium hydroxide. It is used, and benzyltrimethylammonium hydroxide is particularly preferably used. The amount of the basic compound used is 0.01 with respect to 4-hydroxy-2-cyclopentenone represented by the above formula [IV].
~ 0.5 equivalents, preferably 0.05-0.2 equivalents are used. As the reaction solvent, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane and the like;
Aromatic hydrocarbons such as benzene, toluene, xylene, etc .; Ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc .; Hexane,
Saturated hydrocarbons such as cyclohexane and petroleum ether are used, preferably halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane are used, and particularly preferably dichloromethane is used. The reaction temperature of the epoxidation reaction is preferably -20 to 50 ° C, particularly preferably -5 to 30 ° C. The reaction time of the epoxidation reaction depends on the starting material compound, reagent, reaction solvent,
The reaction time varies depending on the reaction temperature, but is usually 5 minutes to 5 hours, preferably 10 minutes to 1 hour. After completion of the epoxidation reaction, the 2,3-epoxy-4-hydroxycyclopentanones represented by the above formula [III] are purified by a conventional means such as extraction, washing with water, drying, concentration, chromatography and the like. The crude reaction mixture can be directly subjected to the following reaction without isolating the 2,3-epoxy-4-hydroxycyclopentanones.

2,3 represented by the above formula [III] obtained by the above reaction
-As the metal chloride used as a reagent for the chlorination reaction of epoxy-4-hydroxycyclopentanones,
Examples thereof include titanium tetrachloride, tin tetrachloride, aluminum trichloride, iron trichloride, zinc chloride, etc., preferably titanium tetrachloride and tin tetrachloride, and particularly titanium tetrachloride.

The amount of the chlorination reagent and metal chloride used is such that the chlorine ion generated from the metal chloride is 1 to 200 equivalents with respect to the 2,3-epoxy 4-hydroxycyclopentanone represented by the above formula [III]. , Preferably 2 to 50 equivalents are used. Examples of the reaction solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and tetrachloroethane; aromatic hydrocarbons such as benzene and toluene; saturated hydrocarbons such as hexane and cyclohexane; methanol and ethanol. Alcohols such as etc .; Ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane etc .; Ketones such as acetone, methyl ethyl ketone etc .;
Examples thereof include aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc., preferably halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether and tetrahydrofuran. It is used, and particularly preferably dichloromethane and diethyl ether are used.

The chlorination reaction temperature is preferably -100 to 100 ° C,
Particularly preferably, it is in the range of -80 to 50 ° C.

The reaction time of the chlorination reaction depends on the raw material compounds, reagents,
It depends on the reaction solvent and the reaction temperature, but usually 5 minutes to 50 minutes.
It is carried out in the range of time, preferably in the range of 10 minutes to 24 hours.

After the completion of the halogenation reaction, 2-chloro-3,4-dihydroxycyclopentanones represented by the above formula [I] are purified and fractionated by a conventional means such as extraction, washing with water, drying and chromatography. However, the reaction mixture can be directly subjected to the following dehydration reaction without isolation of the 2-chloro-3,4-dihydroxycyclopentanones.

Examples of the dehydration reaction reagent used in the dehydration reaction of 2-chloro-3,4-hydroxycyclopentanones obtained by the above reaction include, for example, alumina, silica gel, dicyclohexylcarbodiimide, or phosphoryl chloride in the presence of a basic compound. , A thionyl chloride halogenating reagent; a reactive derivative of an organic sulfonic acid such as an organic sulfonic acid halide or an organic sulfonic acid anhydride is used in the presence of a basic compound, preferably alumina, silica gel, dicyclohexycarbodiimide. , A reactive derivative of an organic sulfonic acid is used in the presence of a basic compound.

When alumina is used as a reagent for the dehydration reaction, any of acidic alumina, neutral alumina and basic alumina may be used. The amount of alumina used varies depending on the dehydrating ability of the alumina used, but is 0.5 to 50 times, preferably 0.5 to 50 times the weight of 2-chloro-3,4-dihydroxycyclopentanone represented by the above formula [I]. Is used in a range of 2 to 20 times. The dehydration reaction proceeds even without using a reaction solvent, but normally, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, etc .; saturated hydrocarbons such as hexane, cyclohexane, petroleum ether, etc .; benzene, toluene. , Aromatic hydrocarbons such as xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like, preferably halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane and the like are used. And particularly preferably dichloromethane is used. The reaction temperature for the dehydration reaction is preferably −20.
C. to 100.degree. C., particularly preferably 0.degree. C. to 50.degree. The reaction time of the dehydration reaction is the raw material compound used,
It depends on the reagent, reaction solvent and reaction temperature, but usually 10
Minutes to 50 hours, preferably 30 minutes to 2
It is in the range of 0 hours. The dehydration reaction with alumina described above can also be carried out by filling the column with alumina and subjecting it to ordinary column chromatography using the same solvent as the reaction solvent described above as a developing solution.
After completion of the dehydration reaction, 2- represented by the above formula [II]
Chloro-4-hydroxy-2-cyclopentenones can be purified and fractionated by ordinary means, for example, after passing the residue and extracting the residue, followed by purification by chromatography, distillation, recrystallization or the like, but if necessary. A deprotection reaction of a hydroxyl protecting group or a conversion reaction of a hydroxyl protecting group may be carried out. A known method can be adopted for the deprotection reaction of the protective group for the hydroxyl group. That is, when the protective group is an acyl group such as an acetyl group or a propionyl group, it can be easily deprotected by hydrolyzing it with a hydrolase such as pig liver esterase. When the protective group is a trihydrocarbon silyl group such as a trimethylsilyl group or a t-butyldimethylsilyl group, for example, tetrabutylammonium fluoride, cesium fluoride, potassium fluoride,
In the presence of fluoride ion such as hydrogen fluoride, acetic acid,
It can be deprotected by hydrolysis under acidic conditions such as hydrochloric acid. The protective group is a 2-tetrahydropyranyl group, 2-
In the case of a group forming an acetal bond with an oxygen atom of a hydroxyl group such as a tetrahydrofuranyl group or 1-ethoxyethyl group, it can be deprotected by hydrolyzing it under an acidic condition such as acetic acid or hydrochloric acid. When the protecting group is a benzyl group, it can be deprotected by a reduction reaction known per se.
The conversion reaction of the hydroxyl-protecting group may be carried out by protecting the hydroxyl group of 2-chloro-4-hydroxy-2-cyclopentenone obtained by the deprotection reaction of the hydroxyl-protecting group. A 2-chloro-4-hydroxy-cyclopentenone protecting group protected with a hydroxyl protecting group,
It may be directly converted into a different protecting group without passing through chloro-4-hydroxy-2-cyclopentenone.
A known method can be adopted for the reaction for protecting the hydroxyl group. That is, when the protective group is an acyl group such as an acetyl group, a propionyl group or a benzoyl group, the protective group can be easily introduced by reacting an acid halide or an acid anhydride with pyridine. When the protecting group is a trihydrocarbon silyl group such as a trimethylsilyl group or a t-butyldimethylsilyl group, the protecting group can be obtained by reacting a trihydrocarbyl silyl halide in the presence of triethylamine and dimethylaminopyridine. Can be introduced. 2 protecting groups
In the case of a tetrahydropyranyl group, a 2-tetrahydrofuranyl group, a 1-ethoxyethyl group, etc., the corresponding vinyl ether compound, dihydropyran, dihydrofuran,
The protecting group can be introduced by contacting ethyl vinyl ether in the presence of an acidic catalyst such as paratoluenesulfonic acid. Converting a protective group of 2-chloro-4-hydroxy-2-cyclopentenone protected with a protective group of hydroxyl group into a different protective group directly without passing through 2-chloro-4-hydroxy-2-cyclopentenone For example, in the case of converting a silyl group into an acetyl group, it can be converted by reacting with acetic anhydride in the presence of a Lewis acid such as iron trichloride or tin chloride.

When silica gel is used as a reagent for dehydration reaction of 2-chloro-3,4-dihydroxycyclopentanones, the amount of silica gel used varies depending on the dehydration ability of the silica gel used, but is represented by the above formula [I]. -Chloro-
It is used in the range of 1 to 100 times, preferably 5 to 50 times, the weight of 3,4-dihydroxycyclopentanone. The dehydration reaction proceeds even without using a reaction solvent, but usually aromatic hydrocarbons such as benzene, toluene, xylene, etc .; saturated hydrocarbons such as hexanecyclohexane, petroleum ether, etc .; dichloromethane, chloroform, carbon tetrachloride. , Halogenated hydrocarbons such as dichloroethane; ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane; esters such as ethyl acetate, butyl acetate, etc., preferably benzene, toluene, xylene, etc. Such aromatic hydrocarbons are used. The reaction temperature for the dehydration reaction is preferably 0 ° C to 200 ° C, particularly preferably 30 ° C to 15 ° C.
It is carried out in the range of 0 ° C. The reaction time of the dehydration reaction varies depending on the starting compound used, the reaction solvent and the reaction temperature, but is usually in the range of 30 minutes to 100 hours, and preferably in the range of 1 hour to 50 hours. The dehydration reaction with silica gel described above can also be carried out by filling the column with silica gel and subjecting it to ordinary column chromatography using the same solvent as the reaction solvent described above as a developing solvent. After the completion of the dehydration reaction, the 2-chloro-4-hydroxy-2-cyclopentenones represented by the above formula [II] can be chromatographed or distilled and re-extracted by a conventional means such as passing and extracting the residue. Although it can be purified and fractionated by a crystal or the like, if necessary, a deprotection reaction of a hydroxyl-protecting group or a conversion reaction of a hydroxyl-protecting group may be carried out in the same manner as in the above method. 2-chloro-3,4
-When dicyclohexylcarbodiimide is used as a reagent for dehydration reaction of dihydroxycyclopentanones,
It is preferable to use cupric chloride or a basic compound together with dicyclohexylcarbodiimide, and cupric chloride is particularly preferably used. As the basic compound used together with dicyclohexylcarbodiimide, amines are preferable, and as such amines, pyridine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, triethylamine, isopropyldimethylamine, diisopropylcyclohexylamine, quinuclidine, triethylenediamine, etc. Is mentioned. When dicyclohexylcarbodiimide and cupric chloride are used as reagents for the dehydration reaction, dicyclohexylcarbodiimide is used in an amount of 1 to 50 mol, preferably 1 to 10 mol, per 1 mol of 2-chloro-3,4-dihydroxycyclopentanones. Used in
Cupric chloride is used in the range of 0.1 to 10 mol, preferably 0.5 to 5 mol.

The reaction solvent is, for example, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride or dichloroethane;
Ethers such as ether and tetrahydrofuran; hydrocarbons such as benzene, toluene, pentane, hexane and cyclohexane are used, preferably dichloromethane,
Dichloroethane and ether are used.

The temperature of the dehydration reaction is performed in the range of 0 ° C to 150 ° C, preferably 15 ° C to 100 ° C. The reaction time of the dehydration reaction varies depending on the starting material compound, the reagent, the reaction solvent, and the reaction temperature used, but is usually in the range of 1 hour to 100 hours, and preferably in the range of 2 to 24 hours. After the completion of the dehydration reaction, the 2-chloro-4-hydroxy-2-cyclopentenones represented by the above formula [II] are purified by a conventional method such as extraction, drying, concentration, chromatography or distillation. Can be collected. The thus-obtained 2-chloro-4-hydroxy-2-cyclopentenones were subjected to the deprotection reaction of the hydroxyl-protecting group or the conversion reaction of the hydroxyl-protecting group in the same manner as in the above method. Is also good.

When a basic compound and a reactive derivative of an organic sulfonic acid are used as reagents for dehydration reaction, amines are preferable as the basic compound used here, and examples of such amines include pyridine and 4-dimethylamino. Pyridine, triethylamine, diisopropylcyclohexylamine, isopropyldimethylamine, diisopropylethylamine and the like can be mentioned, and among them, pyridine and 4-dimethylaminopyridine are particularly preferable. Examples of the reactive derivative of organic sulfonic acid include shrimp methanesulfonyl chloride, trifluoromethanesulfonyl chloride,
Organic sulfonic acid halides such as p-toluenesulfonyl chloride; organic sulfonic acid anhydrides such as methanesulfonic acid anhydride and trifluoromethanesulfonic acid anhydride, and the like, and preferably methanesulfonyl chloride p
-Toluenesulfonyl chloride is used. The reactive derivative of the organic sulfonic acid used is 2-chloro-3,4.
-0.5 mol / mol of dihydroxycyclopentanones
It is used in the range of 10 to 10 times mol, preferably 1 to 3 times mol, and the basic compound is 1 to 20 times mol, preferably 2 times.
It is used in the range of up to 6 times by mole. Although the basic compound itself may be used as the solvent used at this time, for example, halogenated hydrocarbon tails such as dichloromethane, chloroform and carbon tetrachloride; ethers such as ether and tetrahydrofuran; aromatics such as benzene and toluene. Hydrocarbons;
Hydrocarbons such as pentane, hexane, cyclohexane, etc. are used, preferably dichloromethane. The amount of the solvent used may be an amount sufficient for promptly proceeding the reaction, and is usually 1 to 10 with respect to the raw material compound.
A 00-fold volume, preferably 5-100-fold volume is used.
The reaction temperature of the dehydration reaction varies depending on the starting materials and reagents used, but is in the range of 0 ° C to 50 ° C, preferably 10 ° C to 3 ° C.
It is carried out in the range of 0 ° C. The reaction time of the dehydration reaction varies depending on the raw material compound used, the reagent, the reaction solvent, and the reaction temperature, but is usually in the range of 20 minutes to 24 hours, and preferably in the range of 1 hour to 10 hours. After completion of the dehydration reaction, the 2-chloro-4-hydroxy-2-cyclopentenones represented by the above formula [II] can be prepared by conventional means such as extraction, drying, concentration, chromatography or distillation, recrystallization and the like. Although it can be purified and fractionated, if necessary, the deprotection reaction of the protective group for the hydroxyl group or the conversion reaction of the hydroxyl group may be carried out in the same manner as in the above method.

<Effect of the Invention> Thus, according to the present invention, 2-chloro-4 of the formula [II] is used.
-Hydroxy-2-cyclpentenones were obtained in high yield, and the obtained 2-chloro-4-hydroxy-2-cyclopentenones represented by the formula [II] are prostaglandin compounds useful as pharmaceuticals. It is extremely useful as a synthetic intermediate for compounds having a cyclopentane skeleton such as, and the industrial significance of the present invention is immeasurable.

<Examples> Hereinafter, the present invention will be described in more detail with reference to Examples.

Reference Example 1 Production of 4-t-butyldimethylsilyloxy-2,3-epoxycyclopentanone 10 g of 4-t-butyldimethylsilyloxy-2-cyclopentenone was dissolved in 50 ml of methanol, and 10 ml of 30% hydrogen peroxide solution was added. 0.5 ml of a 1N aqueous sodium hydroxide solution was added while stirring with ice cooling, and the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous ammonium chloride was added, the mixture was concentrated, extracted with water and hexane, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate and over-concentrating, it was subjected to silica gel column chromatography, and 8.22 g of 4-t-butyldimethylsilyloxy-2,3-epoxycyclopentanone low polar isomer (yield 76%) and high polarity were obtained. Isomer 0.98
g (yield 9%) was obtained.

Spectral data Low polarity isomer NMR: δCDCl ₃ 0.12 (S, 6H), 0.88 (4,9H), 0.93 (d, 1H, J = 18.0Hz), 2.53 (dd, 1H, J = 18.0,6,0 Hz ), 3.36 (d, 1H, J = 2.4Hz), 3.75 (d1H, J = 2.4Hz), 4.57 (d, 1H, J = 6.0Hz) NMR: δCDCl ₃ 0.13 (S, 3H), 0.16 (S, 3H), 0.90 (S, 9H), 2.30 (d, 2H, J = 8.0Hz), 3.36 (d, 1H, J = 3.0Hz), 3.83 (dd, 1H, J = 3.0,1.5Hz), 4.37 ( td, 1H, J = 8.0,1.5 Hz) Reference Example 2 4-t using titanium tetrachloride as a chlorination reaction reagent
-Butyldimethylsilyloxy-2-chloro-3-hydroxycyclopentanone 970 mg of 4-t-butyldimethylsilyloxy-2,3-epoxycyclopentanone obtained according to Reference Example 1
(4.25 mmol) was dissolved in 25 ml of dichloromethane and -78
10 ml of 0.53 M titanium tetrachloride-dichloromethane solution was added to the mixture while cooling and stirring at 0 ° C, and the mixture was stirred at -78 ° C → -40 ° C for 4 hours. The reaction solution was poured onto a saturated aqueous solution of sodium hydrogen carbonate and stirred for 5 minutes. After passing through Celite, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated saline. The extract was dried over anhydrous sodium sulfate, overconcentrated and then subjected to silica gel column chromatography to obtain 508 mg of 4-t-butyldimethylsilyloxy-2-chloro-3-hydroxycyclopentanone (yield 45%).

Spectral data NMR: δCDCl ₃₀ 0 to 0.3 (m6H), 0.89 (S, 9H), 1.8 to 3.3 (m, 3H) 3.9 to 4.8 (m, 3H) Reference Example 3 Tin tetrachloride was used as a chlorination reaction reagent. , 4-t-
Production of butyldimethylsilyloxy-2-chloro-3-hydroxycyclopentanone 91 mg of 4-t-butyldimethylsilyloxy-2,3-epoxycyclopentanone obtained according to Reference Example 1
(0.4 mmol) was dissolved in 5 ml of diethyl ether, 521 mg (2 mmol) of tin tetrachloride was added, and the mixture was refluxed for 5 hours. Saturated saline was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with brine. The extract was dried over anhydrous magnesium sulfate, overconcentrated, and subjected to silica gel column chromatography to obtain 40 mg (yield 38%) of 4-t-butyldimethylsilyloxy-2-chloro-3-hydroxycyclopentanone.

Example 1 Production of 4-t-butyldimethylsilyloxy-2-chloro-2-cyclopentenone using alumina as a dehydration reaction reagent 8 g of 4-t-butyldimethylsilyloxy-3-hydroxy-2-chlorocyclopentanone obtained according to Reference Example 2 or 3 was dissolved in 50 ml of dichloromethane, 20 g of neutral alumina was added, and the mixture was stirred for 50 minutes. 10 g of neutral alumina was added and stirred for 4 hours, and 10 g of neutral alumina was further added. Stir for 2 hours, pass, and remove the residue to 50
It was washed with 0 ml of ethyl acetate. Combine the eluates and concentrate,
Silica gel column chromatography, 4-t-
5.27 g (yield 71%) of butyldimethylsilyloxy-2-chloro-2-cyclopentenone was obtained.

Spectral data NMR: δCDCl ₃ 0.13 (S, 6H), 0.89 (S, 9H), 2.40 (dd, 1H, J = 18.6Hz, 2.2Hz), 2.81 (dd, 1H, J = 18.6Hz, 6.0Hz), 4.95 (dt, 1H, J = 6.0Hz, 2.5Hz), 7.31 (d, 1H, J = 2.5Hz) Example 2 4-t-butyldimethylsilyloxy-2-cyclo using silica gel as a dehydration reaction reagent. Manufacture of pentenone 110 mg of 4-t-butyldimethylsilyloxy-2-chloro-3-hydroxycyclopentanone obtained according to Reference Example 2 or 3 was dissolved in 15 ml of benzene, 1 g of silica gel was added, and the mixture was refluxed for 60 hours. After concentration, the residue was subjected to silica gel column chromatography to obtain 54 mg (yield 52%) of 4-t-butyldimethylsilyloxy-2-chloro-2-cyclopentenone.

Example 3 Production of 4-t-butyldimethylsilyloxy-2-chloro-2-cyclopentenone using dicyclopexylcarbodiimide as a dehydration reaction reagent 500 mg of 4-t-butyldimethylsilyloxy-2-chloro-3-hydroxycyclopentanone obtained according to Reference Example 2 or 3 was dissolved in 10 ml of diethyl ether to obtain 1.5 g of dicyclohexylcarbodiimide and 300 mg of copper (II) chloride. In addition, the mixture was refluxed for 15 hours. Saturated saline was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After over-concentration, use for silica gel column chromatography, 4-t-
261 mg (yield 56%) of butyldimethylsilyloxy-2-chloro-2-cyclopentenone was obtained.

Example 4 4-t-butyldimethylsilyloxy-2-using methanesulfonyl chloride pyridine as a dehydration reaction reagent
Production of chloro-2-cyclopentenone 2.65 g (10 mmol) of 4-t-butyldimethylsilyloxy-2-chloro-3-hydroxycyclopentanone obtained according to Reference Example 2 or 3 was dissolved in 30 ml of dichloromethane, and 2.4 ml (30 mmol) of pyridine was added. It was 1.01 ml (13 mmol) of methanesulfonyl chloride while stirring with ice cooling
Was added, and the mixture was stirred at room temperature for 15 hours. Add saturated saline,
It was extracted with ethyl acetate. The aqueous layer was extracted twice more, and the organic layers were combined and washed with saturated brine. It was dried over anhydrous sodium sulfate, over-concentrated and then subjected to silica gel column chromatography, 4-t-butyldimethylsilyloxy-2.
-Chloro-2-cyclopentenone 2.12 g (yield 86%)
Got

Example 5 p-toluenesulfonyl chloride-as a dehydration reaction reagent
Production of 4-t-butyldimethylsilyloxy-2-chloro-2-cyclopentenone using dimethylaminopyrizone 1.32 g (5 mmol) of 4-t-butyldimethylsilyloxy-2-chloro-3-hydroxycyclopentanone obtained according to Reference Example 2 or 3 was dissolved in 15 ml of dichloromethane, and 1.83 g (15 mmol) of dimethylaminopyridine was added. added. P-Toluenesulfonyl chloride with stirring under ice cooling
1.24 g (6.5 mmol) was added, and the mixture was stirred at room temperature for 20 hours. Saturated saline was added and extracted with ethyl acetate, and the aqueous layer was further added to 2
Extracted once. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After overconcentration, it was subjected to silica gel column chromatography, and 4-t-butyldimethylsilyloxy-2-chloro-2-cyclopentenone 97 was used.
2 mg (79% yield) was obtained.

Reference Example 4 Production of 4-t-butyl dimethylsilyloxy-2-chloro-2-cyclopentenone from 4-t-butyldimethylsilyloxy-2,3-epoxycyclopentanone 21.7 g of 4-t-butyldimethylsilyloxy-2,3-epoxycyclopentanone obtained according to Reference Example 1 (9
5 mmol) is dissolved in 350 ml of dichloromethane, and the temperature is -78 ° C.
1M titanium tetrachloride-dichloromethane solution 1 cooled to room temperature
40 ml (140 mmol) was added and the mixture was stirred at -78 ° C for 5 hours. The reaction solution was poured onto saturated saline and extracted with ethyl acetate. The aqueous layer was further extracted twice with ethyl acetate, the organic layers were combined, and washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order. The extract was dried over anhydrous sodium sulfate, overconcentrated, and subjected to alumina column chromatography to obtain 15.5 g (yield 66%) of 4-t-butyldimethylsilyloxy-2-chloro-2-cyclopentenone.

Reference Example 5 Production of 4-t-butyldimethylsilyloxy-2-chloro-2-cyclopentenone from 4-t-butyldimethylsilyl-2-cyclopentenone 425 mg (2. mmol) of 4-t-butyldimethylsilyloxy-2-cyclopentenone was dissolved in dry dichloromethane and 1.06 ml of a 2.27 M solution of t-butyl hydroperoxide in dichloroethane was added. Add 40 ml of 40% benzyltrimethylammonium hydroxide in methanol and add 3
Stir for 0 minutes. Further, 40 μ of a benzyltrimethylammonium hydroxide solution was added and stirred for 40 minutes. The mixture was cooled to −78 ° C., 3 ml of 1M titanium tetrachloride in dichloromethane was added, and the mixture was stirred at −78 ° C. to −40 ° C. for 1.5 hours. Furthermore, add 3 ml of titanium tetrachloride solution, and -40 ℃
The mixture was stirred at -30 ° C for 3 hours. The mixture was poured onto saturated brine, extracted with ethyl acetate, and the aqueous layer was extracted twice more. The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and after overconcentration, the obtained oily substance was dissolved in 5 ml of dichloromethane, and 6 g of neutral alumina was added thereto.
Stir for hours. The residue was washed with ethyl acetate, and the eluates were combined and concentrated. This was subjected to silica gel column chromatography, and 2-chloro-4-t-butyldimethylsilyloxy-2-cyclopentenone 205 mg
(Yield 41%) was obtained.

Example 6 Preparation of 4-acetoxy-2-chloro-2-cyclopentenone 382 mg (1.41 mmol) of iron trichloride / hexahydrate was dried by heating under reduced pressure, and 2 ml of acetic anhydride was added to give a suspension. Examples 4-9
4-t-butyldimethylsilyloxy-2-chloro-2-cyclopentenone 3 g (12.2 mmo
(1) was dissolved in 4.65 ml of acetic anhydride, an iron chloride solution was added while stirring with ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was poured little by little on saturated aqueous sodium hydrogen carbonate, and ethyl acetate was added for extraction. After separation and separation, the aqueous layer was extracted twice more with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After over-concentration, it was subjected to silica gel column chromatography to obtain 2.11 g of 4-acetoxy-2-chloro-2-cyclopentenone (yield 9
9%) was obtained.

Spectral data NMR: δCDCl ₃ 2.04 (3H, S), 2.43 (1H, dd, J = 18.6,2.0Hz), 2.89 (1H, dd, J = 18.6,6.0Hz), 5.66 (1H, dt, J = 6.0) , 2.5Hz), 7.43 (1H, d, J = 2.5Hz)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location B01J 31/02 103 X 7821-4G C07B 61/00 300

Claims (7)

[Claims] 1. The following formula [I] [In the formula, R ¹ represents a protective group for a protected hydroxyl group. ] 2-chloro-3,4-dihydroxycyclopentanone represented by the following is subjected to a dehydration reaction, and if necessary, subjected to a deprotection reaction or a protective group conversion reaction,
The following formula [II] [In the formula, R ² represents a hydrogen atom or a protective group for a protected hydroxyl group. ] The manufacturing method of 2-chloro- 4-hydroxy- 2- cyclopentenone represented by these. 2. The method for producing 2-chloro-4-hydroxy-2-cyclopentenones according to claim 1, wherein alumina is used as a dehydration reaction reagent. 3. The method for producing 2-chloro-4-hydroxy-2-cyclopentenones according to claim 1, wherein silica gel is used as a dehydration reaction reagent. 4. The method according to claim 1, wherein dicyclohexylcarbodiimide is used as the dehydration reaction reagent.
Process for producing chloro-4-hydroxy-2-cyclopentenones. 5. The method for producing 2-chloro-4-hydroxy-2-cyclopentenones according to claim 1, wherein a basic compound and a reactive derivative of an organic sulfonic acid are used as a dehydration reaction reagent. 6. A process for producing 2-chloro-4-hydroxy-2-cyclopentenones according to claim 5, wherein methanesulfonyl chloride or p-toluenesulfonyl chloride is used as the reactive derivative of the organic sulfonic acid. . 7. The method for producing 2-chloro-4-hydroxy-2-cyclopentenones according to claim 5 or 6, wherein amines are used as the basic compound.