WO2005108341A1

WO2005108341A1 - Method for producing 3-oxocyclopentane-1-carboxylic acid or ester thereof

Info

Publication number: WO2005108341A1
Application number: PCT/JP2005/008828
Authority: WO
Inventors: Takashi Sugioka
Original assignee: Kuraray Co., Ltd.
Priority date: 2004-05-11
Filing date: 2005-05-10
Publication date: 2005-11-17

Abstract

Disclosed is a method for producing a compound represented by the general formula (II) below which is characterized in that a compound represented by the general formula (I) below is reacted with water without a catalyst or in the presence of an acid catalyst. (In the formula, R1, R6, X6, X7, X8, X9 and X10 respectively represent a hydrogen atom, an alkyl group or an aryl group; R2 and R3 respectively represent a hydrogen atom, an alkyl group, an aryl group or a group represented by the general formula: -CO2R4; at least one of X1, X2, X3, X4 and X5 represents a group represented by the general formula: -CO2R5 and the rest of them respectively represent a hydrogen atom, an alkyl group or an aryl group; R4 and R5 respectively represent an alkyl group or an aryl group; R7 and R8 respectively represent a hydrogen atom, an alkyl group, an aryl group or a group represented by the general formula: -CO2R9; and R9 represents a hydrogen atom, an alkyl group or an aryl group.)

Description

Specification

Method for producing 3-oxocyclopentane-1-1-rubric acid or its ester

TECHNICAL FIELD The present invention relates to a method for producing 3-oxocyclopentane-11-carboxylic acid or an ester thereof. The 3-oxocyclopentane-11-carboxylic acid or its ester obtained according to the present invention is useful as a synthetic intermediate of a xanthine derivative useful as an adenosine antagonist (see Japanese Patent Application Laid-Open No. 7-509492). Background art

Conventionally, as a method for producing 3-year-old oxocyclopentane_1-strength rubonic acid, (1) contacting trimethyl 3-oxo-1,2,4-cyclopentanetricarboxylate with a large amount of 8% aqueous sulfuric acid After heating, neutralize the excess sulfuric acid and extract with ethyl acetate.Wash the extract with water, extract with 2.5% aqueous sodium hydroxide, acidify the extract, and re-add ethyl acetate. (2) Triethyl 3-oxocyclopentane-1,1,1,2-tricarboxylate or triethyl 3 Method of hydrolyzing 1-year-old oxocyclopentane 1,1,1,4-tricarpoxylate with a mixture of 18% hydrochloric acid aqueous solution and glacial acetic acid, followed by decarboxylation (Pharmadi (Ph. a rma zie :), 1998, 53, 8, 8, 52 1—524. (3) A method of heat-treating cyclopentanone-2,3,5-tricarboxylic acid_3-monomethyl ester to decarboxylate it (Journalofthe American Chemical Society, Japan). Society), 197, Vol. 99, Vol. 16, No. 16, pp. 550 8—550 1 0 (pp. 55 09)), (4) 2-cyano 3-oxo-1 r-1-cyclo Ethyl pentanecarboxylate 1

Hydrolysis and decarboxylation by treatment with an 8% hydrochloric acid aqueous solution (Liebigs Anna 1 endder Chemie), 1979

(See p. 944-949, p. 947); (5) After the reaction of cyclopentenone with tert-butyldimethylsilyl peroxytriflate and formaldehyde dimethylhydrazone, Desilylation yields 3-year-old oxocyclopentane-one-pot strength lipoxaldehyde dimethylhydrazone, and then the 3-year-old oxocyclopentane-one-time lipoxaldehyde dimethyl hydrazone is reacted with Jones reagent or ozone. Oxidation method (see Journal of Organic Chemistry, 1997, Vol. 62, No. 15, pp. 5144-5155 (p. 5155)); (6) Cyclopentenone is converted to palladium A method of carbonylation in the presence of a catalyst and methanol to obtain dimethyl 3-oxocyclopentane-1,2-dicarboxylate, followed by hydrolysis under basic conditions to a dicarboxylic acid, followed by decarboxylation (Journal Journal of Organic Chemistry, 1997, Vol. 44, No. 20, pp. 3474-3482 (pp. 3481) It is. In the above method (1), since a strong acid such as sulfuric acid is used in an equimolar amount or more relative to the raw material, a large amount of waste is generated during the neutralization treatment, and the burden on the environment is large. Method (2) uses not only a strong acid such as hydrochloric acid but also glacial acetic acid in an equimolar amount or more with respect to the raw material. In method (3), the starting material, dimethoxytetrachlorocyclopentadiene, is difficult to obtain industrially, and it is necessary to use expensive metal reagents such as palladium and manganese. Method (4) requires the use of highly toxic sodium cyanide in the production of raw materials, and Method (5) requires the use of harmful and difficult-to-handle hydrazone derivatives and ozone. . In method (6), an expensive metal catalyst is used, and the diester is hydrolyzed and then decarboxylated, so that the reaction operation is complicated. Thus, all of the methods (1) to (6) are disadvantageous for industrial implementation.

Accordingly, it is an object of the present invention to provide a method for more efficiently and industrially advantageously producing 3-year-old oxocyclopentane-11-carboxylic acid or an ester thereof.

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have been able to convert a 3-oxocyclopentane-11-carponic acid derivative having a specific structure into water without a catalyst or in the presence of a catalytic amount of an acid. By conducting the reaction, it was found that 3-year-old oxocyclopentane-11-carboxylic acid or an ester thereof could be obtained in a good yield, and as a result, wastes could be significantly reduced, thereby completing the present invention. Disclosure of the invention

That is, the present invention provides a compound represented by the general formula (I):

(In the formula, R ¹ represents a hydrogen atom, an alkyl group which may have a substituent or a aryl group which may have a substituent, and R ² and R ³ represent a hydrogen atom and a substituent, respectively. Represents an alkyl group which may be substituted, an aryl group which may be substituted or a group represented by the general formula —C〇 ₂ R ⁴ , wherein X ¹ , X ² , X ³ , X ⁴ and X ⁵ at least one of them one general formula - C0 ₂ represents a group represented by R ^5, others have a hydrogen atom, which may have a substituent alkyl group or a substituted group And R ⁴ and R ⁵ each represent an alkyl group which may have a substituent or an aryl group which may have a substituent. 1-11 rubonic acid derivative [hereinafter referred to as 3-oxocyclopentane-1-carboxylic acid derivative (Referred to as (I)) with water in the absence of a catalyst or in the presence of a catalytic amount of an acid.

(In the formula, R ⁶ represents a hydrogen atom, an alkyl group which may have a substituent or a aryl group which may have a substituent, and R ⁷ and R ⁸ represent a hydrogen atom and a substituent, respectively. has optionally also an alkyl group, a group represented by the good Ariru group or the formula one C0 ₂ R ⁹ may have a substituent, R ⁹ may have a hydrogen atom, a substituent X ⁶ , X ⁷ , X ⁸ , X ⁹ and X ¹ ° represent a hydrogen atom, an alkyl group optionally substituted or a substituted alkyl group, respectively. Represents an aryl group which may have a group.)

The method for producing 3-oxocyclopentane-l-rubic acid or its ester [hereinafter sometimes referred to as 3-oxocyclopentane-l-lrubonic acid derivative (II)] is there.

ADVANTAGE OF THE INVENTION According to this invention, it is more efficient and industrially advantageous. Bonic acid or its esters can be produced. BEST MODE FOR CARRYING OUT THE INVENTION

In the above general formula, R ¹ R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , The alkyl group represented by each of X ⁷ , X ⁸ , 'X ⁹ and X ¹⁰ is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, and an isopropyl group. Group, butyl group, isobutyl group, tert-butyl group, 'hexyl group and the like. These alkyl groups may have a substituent. Examples of the substituent include a phenyl group, a tolyl group, a methoxyphenyl group, a chlorophenyl group, a bromophenyl group, a nitrophenyl group, and a naphthyl group. Aryl groups such as phenoxy, chlorophenoxy, bromophenoxy, nitrophenoxy and naphthyloxy; hydroxyl; methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert —Alkylthio groups such as butylthio, hexylthio, octylthio, cyclopentylthio, cyclohexylthio; phenylthio, tolylthio, methoxyphenylthio, chlorophenylthio, bromophenylthio, nitrophenyl. Niruchi Groups, such as § Li one thio group such as a naphthylthio group.

^{^{^{RR 2, R 3, R 4}}} , R 5, R 6, R 7, R 8, R 9, X 1, X 2, X 3, X 4, X 5, X 6, X 7, X 8, X 9 The aryl group represented by each of X ¹⁰ and X ¹⁰ is preferably an aryl group having 6 to 10 carbon atoms, and examples thereof include a phenyl group and a naphthyl group. These aryl groups may have a substituent, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a hexyl group, Alkyl groups such as octyl group, cyclopentyl group and cyclohexyl group; aryl groups such as phenyl group, tolyl group, methoxyphenyl group, chlorophenyl group, bromophenyl group, nitrophenyl group and naphthyl group; fluorine atom , Chlorine, bromine, iodine and other halogen atoms; methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, hexyloxy, octyloxy, cyclopentyloxy An alkoxyl group such as a cyclohexyloxy group; a phenoxy group; Aryloxy groups such as chlorophenoxy, bromophenoxy, nitrophenoxy, and naphthyloxy; hydroxyl; methylthio, ethylthio, propylthio, isopropylthio Alkylthio groups such as thiol, butylthio, isobutylthio, tert-butylthio, hexylthio, octylthio, cyclopentylthio, cyclohexylthio; phenylthio, tolylthio, methoxyphenylthio, chloro And arylthio groups such as a mouth phenylthio group, a promophenylthio group, a nitrophenylthio group and a naphthylthio group.

In the present invention, the 3-oxocyclopentane-11-carboxylic acid derivative (I) is reacted with water to form X ¹ , X ¹ ^The general formula represented by ² , X ³ , X ⁴ and X ⁵ — The group represented by C 0 ₂ R ⁵ undergoes hydrolysis and then is decarboxylated. groups of the formula one C0 ₂ R ⁴ represented by R ² and R ³ in one COSR ¹ and the 3-O Kiso cyclopentane one 1 Ichiriki carboxylic acid derivative having acid derivative (I) is (I), the reaction Depending on the temperature, it may be hydrolyzed but not decarboxylated. The amount of water used is not particularly limited, but is usually in the range of 1 to 20 times the mass of the 3-oxocyclopentane-1-carboxylic acid derivative (I).

In the present invention, it is preferable to add a catalytic amount of an acid to improve the reaction rate.

Examples of the acid that can be added in the present invention include mineral acids such as sulfuric acid, hydrochloric acid, and nitric acid; and organic acids such as acetic acid, benzoic acid, methanesulfonic acid, and the like: —toluenesulfonic acid, camphorsulfonic acid, and the like. You. Among these, hydrochloric acid, sulfuric acid or P-toluenesulfonic acid is preferably used in consideration of the reaction temperature, operability, catalyst economy, and the like. When an acid is added, the amount of the acid to be added is preferably in the range of 0.001 to 50 mol% with respect to the 3-oxocyclopentane-1-carboxylic acid derivative (I) from the viewpoint of production efficiency and economy. Preferably, the content is 0.001 to 30 mol%.

The reaction may be performed in the presence of an organic solvent. The organic solvent is not particularly limited as long as it does not adversely affect the reaction. Examples of the organic solvent include hydrocarbons such as pentane, hexane, heptane, octane, petroleum ether, and benzene; Ethers such as dimethoxyethane and dibutyl ether; halogenated hydrocarbons such as methylene chloride, chloroform-form, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethane, trichloroethane, and cyclobenzene; or These mixtures are used. Since alcohol is generated as the reaction proceeds, the reaction product, namely 3-oxocyclopentane-1-carboxylic acid derivative (II), is a mixture of 3-oxocyclopentane-11-carboxylic acid or an ester thereof, By controlling the alcohol concentration in the reaction system, the ratio of the product 3-oxocyclopentane-1-carboxylic acid and its ester can be controlled. That is, if alcohol is removed outside the reaction system or water is added to the reaction system, 3-oxocyclopentane-11-carboxylic acid becomes a main product, and water is removed outside the reaction system or the reaction proceeds. If the corresponding alcohol is added to the system, the main product is 3-ester oxocyclopentane, an ester of rubonic acid.

The reaction temperature and reaction time are determined based on the amount of the 3-oxocyclopentane-l-carboxylic acid derivative (I), the amount of water used, the type and amount of the acid when the acid is further added, and the amount of the solvent when the solvent is present. Depends on type and amount used. Therefore, in order to achieve an industrially advantageous reaction rate and selectivity, it is also necessary to select whether the main component of the desired 3-oxocyclopentane-1-carboxylic acid derivative (II) is a carboxylic acid, a carboxylic acid ester, Alternatively, depending on whether a mixture may be used, these reaction conditions can be appropriately selected together with the above-mentioned operations such as addition of water or alcohol to the reaction system or removal of water or alcohol from the reaction system, but usually, The reaction temperature is preferably in the range of 20 to 100 ° C., and the reaction time is preferably in the range of 1 to 20 hours, from the viewpoints of control of the reaction and production efficiency.

The thus obtained 3-oxocyclopentane-1 strong rubonic acid derivative (II) can be isolated and purified by a method generally used in the isolation and purification of organic compounds. For example, an organic solvent such as toluene, xylene, diisopropyl ether, methyl acetate, or ethyl acetate is added to the reaction mixture to separate an organic layer, and the organic layer is dried over anhydrous sodium sulfate or the like and then concentrated. The obtained crude product is purified by recrystallization, distillation, column chromatography, etc. as necessary. Also, after adding an organic solvent that azeotropes with water and dehydrating the water in the reaction system by azeotropic distillation, the crude product obtained by concentrating the organic layer is recrystallized, distilled, It may be purified by column chromatography or the like. Example

Hereinafter, the present invention will be described specifically with reference to examples, but the present invention is not limited to these examples. Example 1

A 100 m I reactor equipped with a thermometer, a magnetic rotor, a dropping funnel and a condenser, 5 Om 1 of water and! ) —Toluenesulfonic acid monohydrate (0.19 g, lmmol) was charged. The solution was heated until the water was refluxed, and cyclopentanone-1,2,3,5-tricarboxylate trimethylate (25.8 g, lOmmol) was added dropwise over 1 hour. After completion of the dropwise addition, the mixture was reacted for 3 hours under reflux conditions. When the reaction mixture was analyzed by gas chromatography, the conversion of the starting material was 98%, and the product was 3-oxocyclopentane-1-carboxylic acid 3-hydroxycyclopentane-1-methyl carboxylate. = 90Z 10 (area ratio). The reaction mixture was cooled to below 2 Ot: and extracted three times with 5 mL of ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 3-oxocyclopentane-1 monorubic acid (11.64 g, yield 82%) and 3-oxocyclopentane. Methyl pentane-1-carboxylate (1.54 g, yield 12%) was obtained. Example 2

5 Oml of water was charged into a 100 ml reactor equipped with a thermometer, a magnetic rotor, a dropping funnel and a condenser. The mixture was heated until the water was reduced, and cyclopentanone-1,2,3,5-trimethyl tricarboxylate (25.8 g, 10 Ommo 1) was added dropwise over 1 hour. After completion of the dropwise addition, the mixture was reacted for 5 hours under reflux conditions. When the reaction mixture was analyzed by gas chromatography, the conversion of the starting material was 99%, and the product was 3-oxocyclopentane-1-butane rubonic acid 3-oxocyclopentane-1-methyl carboxylate = 86/14 (area ratio). Example 3

5 Om1 water and p-toluenesulfonic acid monohydrate (0.19 g, lmmol) in a 10 Om1 reactor equipped with thermometer, magnetic rotor, dropping funnel, and Y-tube Was charged. The solution was heated until the water was refluxed, and cyclopentanone-2,3,5-trimethyl tricarboxylate (25.8 g, 10 Ommo 1) was added dropwise over 1 hour. After dropping, remove the methanol and water generated in the reaction as a mixture under reflux conditions. The reaction mixture was reacted for 3 hours while maintaining the volume of the reaction mixture in the reactor by adding water corresponding to the volume of the reaction mixture. When the reaction mixture was analyzed by gas chromatography, the conversion of the starting material was 99%, and the product was 3-hydroxycyclopentane-1-1 rubonic acid / 3-oxocyclopentane-1-1. Methyl carboxylate was 99.7 / 0.3 (area ratio). 50 ml of toluene was added to the obtained reaction mixture, and the remaining water was removed by azeotropic dehydration. Thereafter, the residue was cooled to 0 ° C, and the precipitated crystals were collected by filtration and dried under reduced pressure to give 3-hydroxycyclopentene-1 rubric acid (12.2 g, yield 9%). 5%). Industrial applicability

The 3-oxocyclopentane-11-carboxylic acid derivative (II) obtained according to the present invention is useful as a synthetic intermediate of a xanthine derivative which is useful as an adenosine antagonist.

Claims

Scope of claim

1. General formula (I)

(Wherein, R ¹ represents a hydrogen atom, an alkyl group which may have a substituent, or a T-reel group which may have a substituent, and R ² and R ³ represent a hydrogen atom and a substituent, respectively. X ¹ , X ² , X ³ , X ^4, and X. ⁵ represent an alkyl group which may have, an aryl group which may have a substituent or a group represented by the general formula: C 0 ₂ R ⁴ . at least one of them one general formula - C0 ₂ represents a group represented by R ^5, others have a hydrogen atom, which may have a substituent alkyl group or a substituted group And R ⁴ and R ⁵ each represent an alkyl group which may have a substituent or an aryl group which may have a substituent. Reacting carboxylic acid derivatives with water in the presence or absence of a catalytic amount of acid Formula, wherein (II)

(In the formula, R ⁶ represents a hydrogen atom, an alkyl group which may have a substituent or a aryl group which may have a substituent, and R ⁷ and R ⁸ represent a hydrogen atom and a substituent, respectively. Represents an alkyl group which may be substituted, an aryl group which may be substituted or a group represented by the general formula —CO 2 R ⁹ , wherein R ⁹ may be a hydrogen atom or may have a substituent X ⁶ , X ⁷ , X ⁸ , X ⁹ and X ¹⁰ each represent a hydrogen atom, an alkyl group or a substituent which may have a substituent, Represents an aryl group which may have

A method for producing 3-year-old oxocyclopentane-1-carboxylic acid or an ester thereof represented by the formula: