WO2006120755A1

WO2006120755A1 - Process for producing cyclic acetal form of 3-oxocyclopentane-1-carboxylic acid

Info

Publication number: WO2006120755A1
Application number: PCT/JP2005/008831
Authority: WO
Inventors: Takashi Sugioka
Original assignee: Kuraray Co., Ltd.
Priority date: 2005-05-10
Filing date: 2005-05-10
Publication date: 2006-11-16

Abstract

Provided is a process for producing a cyclic acetal form of 3-oxocyclopentane-1-carboxylic acid more efficiently and industrially advantageously. The process for producing a cyclic acetal form of 3-oxocyclopentane-1-carboxylic acid represented by the general formula (V) is characterized by reacting 3-oxocyclopentane-1-carboxylic acid represented by the general formula (I) with a diol compound represented by the general formula (II) in the presence of an acid catalyst to obtain a mixture of a cyclic acetal monoester derivative and a cyclic acetal diester derivative, and then hydrolyzing the mixture under basic conditions. (I) (II) (V) (In the formulae, R1, R2, R3, R4, R5, R6 and R7 each represents a hydrogen atom, an alkyl group which may have a substituent or an aryl group which may have a substituent; R8, R9, R10, R11, R12 and R13 each represents a hydrogen atom, an alkyl group or an aryl group which may have a substituent, or arbitrary two of them may form a ring together with the carbon atom to which they are linked; and n represents 0 or 1.)

Description

Specification

3 Method for producing 1-year-old oxocyclopentane 1-carboxylic acid cyclic case Technical Field

The present invention relates to a method for producing a cyclic isomer of 3-oxocyclopentane and rubonic acid. The cyclic acetal form of 3-oxocyclopentane 1-carboxylic acid obtained by the present invention is, for example, an optically active 3-year-old xocyclopentane 1-one rubon which is an intermediate of a xanthine derivative useful as an adenosine antagonist. It is useful as an intermediate for the synthesis of acid derivatives (see Japanese Patent Publication No. 7-509492). Background art

Conventionally, as a method for producing a cyclic acetal form of 3-oxocyclopentane 1-1 rubonic acid, (1) 3-oxocyclopentane 1-1 rubonic acid was methyl esterified, and a diol derivative was used. A method is known in which the methyl ester group is hydrolyzed after the force sulfonyl group at the 3-position is converted to an alkyl group (see JP 7-509492, page 7).

In addition, as a method for producing 3-year-old oxocyclopentane rubonic acid, (2) trimethyl 3-oxo-1,2,4-cyclopentane tricarboxylate was converted into a large amount of 8% aqueous solution of sulfuric acid. After contact and heating, the excess sulfuric acid is neutralized and extracted with ethyl acetate, the extract is washed with water, extracted with 2.5% aqueous sodium hydroxide, the extract is acidified, and then acetic acid again. Extraction with ethyl acetate to obtain the desired product (see US Pat. No. 4,272,437, column 362); (3) triethyl 3-oxocyclopentane 1,1,2-tricarboxylate Alternatively, triethyl 3-year-old oxocyclopentane 1, 1, 4, 1 tricarboxylate can be hydrolyzed by treatment with a mixture of 18% aqueous hydrochloric acid and glacial acetic acid, followed by decarboxylation (Ph. rma zie :), 1998, 53, 8, 521-524)); (4) Cyclopentanone 1, 2, 5—Tricarboxylic acid—3—Demethylation by heat treatment of monomethyl ester (Journal of American Chemical Society, 1977, Vol. 99, No. 16, p. 5508—5510 (p. 5509) ); (5) 2-Cyanol 3-Oxo r 1 1-Ethyl cyclopentanecarboxylate 1

Hydrolysis and decarboxylation by treatment with an 8% aqueous hydrochloric acid solution (Lieb igs Anna len d er Ch emi e), 1979,

944-949 (see page 947)); (6) After reacting cyclopentenone with tert-butyldimethylsilyloxytriflate and formaldehyde dimethylhydrazone, desilylation followed by 3-year-old cyclocyclopentane 1 A method to oxidize olpoxaldehyde dimethyl hydrazone, and then oxidize the 3-year-old oxocyclopentane with Jones reagent or ozone (Journal of Organic Chemistry ( J ou rnalof Organic Chemistry), 1 997, 62, 15, 15144-5155 (page 5155)); (7) Carbonylation of cyclopentenone in the presence of palladium catalyst and methanol Dimethyl 3 1-year-old xocyclopentane-1,2-dicarboxylate is obtained and then hydrolyzed under basic conditions Method of decarboxylation after the formation of boric acid (see Journal of Organic Chemistry, 197 9 44, 20, 3474-3482 (3481)) It has been known. In the above method (1), since the 3-position carbonyl group is dimethylacetalized during the methyl esterification of 3-year-old xocyclopentane-1-carboxylic acid, the acetal group is removed with a strongly acidic aqueous solution. Since it is necessary to return to the carbonyl group and the process becomes complicated, there is a problem in industrial implementation.

In addition, the above method (2) uses a strong acid such as sulfuric acid in an equimolar amount or more with respect to the raw material, so there is a large amount of waste during the neutralization treatment, and the load on the environment is large. Method (3) uses not only a strong acid such as hydrochloric acid but also glacial acetic acid in an equimolar amount or more relative to the raw material, resulting in a large amount of wastewater during post-treatment and a large environmental burden. In method (4), the starting material dimethoxytetrachlorocyclopentagen is difficult to obtain industrially, and expensive metal reagents such as palladium and manganese must be used. Method (5) has the problem of having to use highly toxic sodium cyanide at the time of raw material production, and Method (6) has the problem of having to use hydrazone derivatives that are harmful and difficult to handle. . In the method (7), an expensive metal catalyst is used, and the diester is hydrolyzed and then decarboxylated, so that the reaction operation is complicated. Thus, the methods (1) to (7) are disadvantageous for industrial implementation. Accordingly, an object of the present invention is to provide a method for producing a cyclic acetal form of 3-oxocyclopentane and rubonic acid more efficiently and industrially advantageously.

Another object of the present invention is to provide a novel intermediate in producing a cyclic acetal product of 3-born oxocyclopentane-1 rubonic acid. Disclosure of the invention

According to the present invention, the above object is

[1] General formula (I) '

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ may each have a hydrogen atom, an alkyl group which may have a substituent, or a substituent. A 3-carboxycyclopentane-1-carboxylic acid (hereinafter referred to as 3-oxocyclopentane-1-1 mono-rubonic acid (I)) represented by the general formula in the presence of an acid catalyst. (II)

(Wherein R ⁸ , R ⁹ , R ^{1 Q} , R ¹¹ R ¹² and R ¹³ each represent a hydrogen atom, an alkyl group or an aryl group which may have a substituent, or Any two of these may combine with the carbon atom to which they are attached to form a ring, and n represents 0 or 1.)

By reacting with a diol compound represented by the following formula (hereinafter referred to as diol compound (I I)):

(In the formula, RR ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^{1 J} R ¹² , R ^{1 3} And n are as defined above. )

Cyclic acetal monoester derivatives [hereinafter referred to as cyclic acetal monoester derivatives (I I I)] and general formula (IV) '

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ RR ⁸ , R ⁹ .R 10 RRR 1 3 and n are as defined above.)

A mixture of a cyclic acetal derivate derivative represented by the formula [hereinafter referred to as a cyclic acetal diester derivative (IV)], and then the mixture is hydrolyzed under basic conditions. Formula (V)

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , RRR ⁹ , RRRR and n are as defined above.)

A method for producing a 3-oxocyclopentane-1-carboxylic acid cyclic acetal compound represented by the formula [hereinafter referred to as 3-oxocyclopentane-1-carboxylic acid cyclic acetal compound (V)];

[2] General formula (VI)

(Wherein R ⁶ and R ⁷ are as defined above; R ¹⁴ represents a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group; ^{^{^{1, X 2, X s X}}} 4 and X ^5, at least one formula of them - a group represented by C_〇 ₂ R ¹⁵ The other represents a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group, and R ¹⁵ represents a hydrogen atom, an optionally substituted alkyl group. Or an aryl group which may have a substituent. )

3-oxocyclopentane-1 1-carboxylic acid derivative [hereinafter referred to as 3-oxocyclopentane-1 1-carboxylic acid derivative (referred to as VD)] in the presence of a non-catalytic or catalytic amount of acid. By reacting with water, 3-oxocyclopentane and 1

(I), and then reacting the resulting reaction mixture containing 3-year-old oxocyclopentane-1-carboxylic acid (I) with the diol compound (II) in the presence of an acid catalyst, 3-oxocyclopentane-1—, characterized in that a mixture of a monoester derivative (III) and a cyclic acetal diester derivative (IV) is obtained, and then the mixture is hydrolyzed under basic conditions. Method for producing carboxylic acid cyclic acetal (V);

[3] Formula (III-1)

2- (2,2-dimethyl-3-hydroxypropyloxycarbonyl) -1,8-dimethyl-6,10-dioxaspiro [4.5] decane;

[4] Formula (IV-1)

1,2-Dipropane (1,8-Dimethyl-6,10-Dioxaspiro [4.5] Decane-2-Carboxylate) represented by the following formula: .

According to the present invention, the 3-year-old oxocyclopentane monorole rubonic acid cyclic acetal (V) can be produced more efficiently and advantageously industrially.

In addition, according to the present invention, there is provided a novel intermediate capable of producing a 3-year-old xocyclopentane — 1 strength rubonic acid cyclic acetal (V) more efficiently and industrially advantageously. 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 , R ¹⁰ R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , X ^The alkyl group represented by each of ¹ , X ² , X ³ , X ⁴ and X ⁵ is preferably a linear, branched or cyclic alkyl group having 1 to 12 carbon atoms, such as a methyl group, an ethyl group, a propyl group, Examples include isopropyl group, butyl group, hexyl group, octyl group, dodecyl group, cyclopentyl group, cyclohexyl group and the like. R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ R ¹² and R ¹³ may be any two of these together with the carbon atom to which they are bonded to form a ring. Examples thereof include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring. '

Also, have the ^{^{^{RR 2, R 3, R 4}}} , R 5, R 6, R 7, R 14, R 15, X 1, X 2, X 3, X 4 alkyl group the substituent represented our and X ⁵ Such substituents include, for example, phenyl groups, tolyl groups, methoxyphenyl groups, chlorophenyl groups, bromophenyl groups, ditrophenyl groups, naphthyl groups and the like; phenoxy groups, chlorophenyls, etc. An aryloxy group such as an enoxy group, a bromophenoxy group, a nitrophenoxy group, a naphthyloxy group; a hydroxyl group; a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isoptylthio group, a tert-butylthio group, a hexylthio group, Alkylthio groups such as octylthio group, cyclopentylthio group, cyclohexylthio group; phenylthio group, tolylthio group, metho Shifue two thio groups, black hole phenylene group, a heteroarylthio group, Buromofue two thio groups, Nitorofue two thio 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, R 10, R ", R 12, R 13, R 1 4, R 15, X 1, X 2, X ^The aryl group represented by each of ³ , X ⁴ and X ⁵ is preferably an aryl group having 6 to 10 carbon atoms, and examples thereof include a phenyl group and a naphthyl group, which have a substituent. Examples of such substituents include alkyl groups such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a tert-butyl group; a trifluoromethyl group; a chlorine atom, and a bromine atom A halogen atom such as methoxy group, ethoxy group, propoxy group, butoxy group, etc., nitro group, phenyl group, aryl group such as P-methoxyphenyl group, etc. 1-year-old oxocyclopentane The conductor (VI), non-catalytic or A process for obtaining 3-year-old oxocyclopentane 1-powered sulfonic acid (I) by reacting with water in the presence of a catalytic amount of acid will be described.

In this step, by reacting 3-oxocyclopentane-11 rubonic acid derivative (VI) with water, X ¹ in the 3-year-old oxocyclopentane 1-1 rubonic acid derivative (VI), The group represented by the general formula C0 ₂ R ¹⁵ represented by X ² , X ³ , X ⁴ and X ⁵ is hydrolyzed and then decarboxylated. The group represented by one C0 ₂ R ¹⁴ of the acid derivative (VI) may be hydrolyzed depending on the reaction temperature, but not decarboxylated. There is no particular limitation on the amount of water used, but it is usually in the range of 1 to 20 times the mass of 3-year-old oxocyclopentane and rubonic acid derivative (VI).

3-year-old oxocyclopentane _ 1 As one strength rubonic acid derivative (VI), for example, trimethyl 3-oxocyclopentane-1,1,4-tricarboxylate, trimethyl 3-oxocyclopentane-1, 2, 4-Tricarboxylate is used.

In this step, it is preferable to add a catalytic amount of acid to improve the reaction rate.

Examples of acids that can be added in this step include mineral acids such as sulfuric acid, hydrochloric acid, and nitric acid; organic acids such as acetic acid, benzoic acid, methanesulfonic acid, and: -toluenesulfonic acid, camphorsulfonic acid, and the like. . Among these, it is preferable to use hydrochloric acid, sulfuric acid or p-toluenesulfonic acid in view of the reaction temperature, operability and economy. When the acid is added, the amount used is in the range of 0.001 to 50 mol% with respect to the 3-year-old cyclocyclopentane-1-carboxylic acid derivative (VI) from the viewpoint of production efficiency and economy. The range of 0.001 to 30 mol% is more preferable.

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. For example, hydrocarbons such as pentane, hexane, heptane, octane, petroleum ether, and benzene; jetyl ether, tetrahydrofuran, diisopropyl ether, dioxane, Ethers such as dimethoxyethane and dibutyl ether; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethane, trichloroethane, and chloroform benzene; Or a mixture of these is used.

In this process, alcohol is produced as the reaction proceeds, so the reaction product is 3-year-old oxocyclopentane and rubonic acid (I) or a mixture of its esters. By controlling the concentration of alcohol in the system, the ratio of the product 3-year-old oxocyclopentane 1-power rubonic acid (I) and its ester can be controlled. That is, the produced alcohol is removed from the reaction system by a method such as distillation, or water is added to the reaction system to lower the alcohol concentration in the system, thereby reducing the amount of 3-oxocyclopentane-1-carbon. Acid (I) can be the main product. For this purpose, the above-described operation is usually carried out so that the relative concentration of alcohol with respect to water is 10% by mass or less during the reaction.

The reaction temperature and reaction time are as follows: 3-oxocyclopentane and rubonic acid derivative (VI), the amount of water used, the type and amount of acid when further acid is added, and the solvent when coexisting with the solvent It depends on the type and amount used. Therefore, these reaction conditions can be appropriately selected from the viewpoint of achieving an industrially advantageous reaction rate and a high yield of 3-year-old xoxocyclopentane-1-carboxylic acid (I). Usually, the reaction temperature is A range of 20 to 100 hours and a reaction time of 1 to 20 hours are preferable from the viewpoint of reaction control, production efficiency, and the like.

The 3-oxocyclopentane mononuclear rubonic acid (I) obtained in this way is separated and purified according to the usual method used for separation and purification of organic compounds, and then subjected to the next step reaction. However, the reaction mixture can be left untreated for the next step reaction, or the water can be removed by a method such as adding water to an azeotrope and azeotropically dehydrating the water for the next step. It can also be attached. From the viewpoint of operability, the separation and purification step of 3-year-old cyclocyclopentane-1-carboxylic acid (I) can be omitted by subjecting the obtained reaction mixture to the next step as it is. Next, the step of reacting 3-oxocyclopentane-1-carboxylic acid (I) with diol compound (I I) in the presence of an acid catalyst will be described.

Examples of the diol compound (II) include ethylene glycol, 2,3-butanediol, 1,2-propanediol, 1,2-butanediol, 1,2-pentanediol, hydrobenzoin, 3, 3— Dimethyl-1,2-butanediol, cis-1,2,2-cyclohexanediol, cis-l, 2-cyclopentanediol, 1-phenyl-1,1,1 ethanediol, neopentyl diol, 1, Examples include 3-propanediol, 2-methyl-1,3-propanediol, 2,4-monopentanediol, 1,3-butanediol, and 2-phenyl-1,3-propanediol. The amount of the diol compound (II) is selected from the viewpoint of increasing the conversion rate of the raw material. It is preferably in the range of 0.5 to 5 equivalents relative to (I).

The acid medium is not particularly limited as long as it is an acid used for ordinary acetalization, for example, mineral acids such as sulfuric acid, hydrochloric acid, and nitric acid; organic acids such as methanesulfonic acid, P-toluenesulfonic acid, and camphorsulfonic acid; Examples include acid type ion exchange resins such as Amberlist 15 (trade name, manufactured by Tokyo Organic Chemical Industry Co., Ltd.) and Amberlite IR— 1 1 8 (trade name, manufactured by Tokyo Organic Chemical Industry Co., Ltd.). The amount of the acid catalyst to be used is preferably in the range of 1 to 50 mol% with respect to 3-oxocyclopentane / monophosphorus acid (I). When the reaction solution using the acid used in the previous step is directly applied to this step, the reaction may be performed without adding the above-described acid, or an acid may be added as necessary.

The reaction is preferably carried out in the presence of a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction. For example, aliphatic hydrocarbons such as hexane, heptane, octane and cyclohexane; aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene and mesitylene Ethers such as tetrahydrofuran, jetyl ether, diisopropyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, and diethylene glycol dimethyl ether. These solvents may be used alone or in combination of two or more. From the viewpoint of production efficiency, the amount of the solvent used is preferably in the range of 0.5 to 20 times the mass of 3-oxocyclopentane-1 rubonic acid (I).

Water is generated as the reaction progresses. By removing the water, it is possible to obtain a mixture of cyclic acetal monoester derivative (III) and cyclic acetal diester derivative (IV) in high yield. it can. The method for removing water is not particularly limited, but a method of distilling out of the reaction system by azeotropy using a solvent azeotropic with water, a dehydrating agent that does not adversely affect the reaction such as molecular sieves in the system The method of making it coexist is mentioned.

In the case of distilling water out of the system by azeotropic distillation, among the solvents described above, the larger the proportion of water in the azeotropic composition, the more advantageous from the viewpoint of reaction efficiency. Examples thereof include toluene, xylene, mesitylene, cyclohexane, diisopropyl ether, and tetrahydrofuran. When using a dehydrating agent, it is preferable to use a sufficient amount of the dehydrating agent to absorb the theoretical amount of water produced.

The reaction temperature and reaction time are as follows: 3-year-old oxocyclopentane 1-carboxylic acid (I), acid It depends on the type and amount used, the type and amount of solvent used, and the dehydration method, and can be selected as appropriate in order to achieve an industrially advantageous reaction rate and selectivity.

1 50 ° C range, reaction time; A range of ~ 10 hours is preferred.

The mixture of the cyclic acetal monoester derivative (I I I) and the cyclic acetal diester derivative (IV) thus obtained can be subjected to the next step described later after purification as it is or as a mixture. The purification method is not particularly limited, and methods usually used for separation and purification of organic compounds such as recrystallization and column chromatography can be applied. Next, a process of hydrolyzing a mixture of the cyclic acetal monoester derivative (I I I) and the cyclic acetal gestester derivative (IV) under basic conditions will be described.

The base is not particularly limited as long as it is a base used for normal ester hydrolysis. For example, alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide; calcium hydroxide, magnesium hydroxide, Examples include alkaline earth metal hydroxides such as barium hydroxide. From the viewpoint of production efficiency, the amount of the base used is preferably in the range of 0.8 to 5 equivalents relative to the mixture of the cyclic acetal monoester derivative (I I I) and the cyclic acetal monoester derivative (IV).

For the purpose of making the reaction system a homogeneous solution and allowing the hydrolysis reaction to proceed rapidly, a solvent that dissolves in both water and the cyclic acetyl monoester derivative (III) and the cyclic acetyl monoester derivative (IV) may be added. As such a solvent, alcohol is preferable. There are no particular restrictions on the type of alcohol, but for example, saturated aliphatic primary alcohols such as methanol, ethanol, 1-propanol, 1-butanol, 1-hexanol, 1-octanol, .2-ethyl, and 1-hexanol. And saturated aliphatic secondary alcohols such as 2-propanol, 2-butanol, and cyclohexanol. When alcohol is added to the reaction system, the amount of addition varies depending on the mixing ratio of the mixture of the cyclic acetal monoester derivative (III) and the cyclic acetal monoester derivative (IV). There is no particular limitation as long as it is present, but it is usually in the range of 0.5 to 5 times the mass of the reaction mixture. The reaction temperature and reaction time vary depending on the type and amount of base used, the cyclic acetal monoester derivative (III) and the cyclic acetellugester derivative (IV), the amount of water, and the amount of alcohol used. As 50 ~ 1 20 ° C range, reaction time as 3 It ranges from 0 minutes to 5 hours.

The 3-year-old oxocyclopentane monoacetate rubonic acid cyclic acetal (V) thus obtained is very preferably treated with an acid first in the isolation and purification. . Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; and organic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, acetic acid, and benzoic acid. The amount of acid used depends on the progress of the reaction in the reaction mixture, but from the viewpoint of the stability of the 3-oxocyclopentane-1-carboxylic acid cyclic acetal (V), If it is the quantity made into 3-5, there will be no restriction | limiting in particular.

Subsequent to the above operation, the 3-year-old oxocyclopentane 1-1_carboxylic acid cyclic acetal compound (V) can be separated and purified by applying a method commonly used for separation and purification of organic compounds. . For example, extraction with an organic solvent such as toluene, the extract is concentrated, and the residue is purified by column chromatography, recrystallization, or the like. Example

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

Reference Example 1 (Example of production of 3-year-old xocyclopentane-1-carboxylic acid)

Into a 100 ml reactor equipped with a thermometer, magnetic rotor, dropping funnel and Y-tube, water 50 ml and p-toluenesulfonic acid monohydrate (0.19, 1 mm o 1) was charged. This solution was heated until water was refluxed, and trimethyl 3-oxocyclopentane-1, 2, 4-tricarboxylate (25.8 g, 10 O mm o 1) was added dropwise over 1 hour. . After completion of the dropwise addition, the methanol produced in the reaction was withdrawn as a mixture with water under reflux conditions, and an amount of water corresponding to the withdrawn amount was added to maintain the reaction mixture volume in the reactor. Reacted for hours. The obtained reaction mixture was analyzed by gas chromatography. The conversion of trimethyl 3-oxocyclopentane-1,2,4-tricarboxylate was 99%, and the product was 3-year-old xo. It was a mixture of cyclopentane 1-strength rubonic acid and 3-year-old oxocyclopentane 1-strength methyl boronate [former Z latter = 99.7 / 0.3 (area ratio)]. Toluene 5 O m 1 was added to the resulting 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.

1 By drying, 3-years-old cyclocyclopentane 1-carboxylic acid (12.2 g, yield 95%) was obtained. Example 1

A 200mI reactor equipped with a thermometer, magnetic rotor, Dean-Stark moisture meter and condenser, toluene 10 Om 1, 3-oxocyclopentanecarboxylic acid obtained by the method of Reference Example (6 4 g, 5 Ommo 1), neopentyldaricol (10.9 g, 105 mmo 1) and p-toluenesulfonic acid monohydrate (0.095 g, 0.55 mm o 1). The resulting solution was reacted for 2 hours under reflux, and water formed was removed by azeotropic distillation. The reaction mixture was cooled to 2 or less and 5 Oml of saturated aqueous sodium hydrogen carbonate solution was added. The reaction mixture was allowed to stand for liquid separation, and after confirming that the pH of the aqueous layer was 7 or more, the organic layer was separated. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. 2_ (2,2-Dimethyl-3-hydroxypropyloxycarbonyl) —8, 8-Dimethyl-6, 10— Dioxaspiro [4.5] decane 10.8 g (72% yield) and 2, 2-dimethylpropane 1, 3-di-rouge (8,8-dimethyl-6,10-dioxaspiro [4.5] decane 2-Carboxylate) 5.96 g (yield 24%) was obtained.

2- (2,2-Dimethyl-3-hydroxypropyloxycarbonyl) 1,8-dimethyl-6,10-dioxaspiro [4.5] Decane:

iH—NMR spectrum (270 MHz, CDC 1 ₃ , TMS) δ 3.95 (s, 2 H), 3.52-3. 41 (m, 4H), 3.29 (d, 2 H, J = 7. 3 H z)., 3. 00-2. 85 (m, 1 H) 2.41 -1.90 (m, 7 H), 0.98 (s, 3 H), 0.96 (s, 3H ), 0.93 (s, 6 H)

1,2-Dimethylpropane 1,3-di-rouge (8,8-dimethyl-6,10-dioxy saspiro [4.5] decane-2-carboxylate):

. ijH- NMR spectrum _{(270MHz, CDC 1 3, TMS} ) δ 3. 90 (s, 4 H), 3. 51 -3 40 (m, 8H), 2. 95 - 2. 85 (m, 2H), 2. 35— 1.92 (m, 12H), 0.98 (s, 6H), 0.96 (s, 6H), 0.95 (s, 6H) Example 2

Contents equipped with thermometer, magnetic rotator, Dean-Stark moisture meter and condenser tube Toluene 1.5 L, 3-liter xocyclopentane obtained by the method of Reference Example 1 1 _Carboxylic acid (128 g, lmol), neopentyl glycol (218. 8 g, 2.1 mo 1) and p-toluenesulfonic acid (9.5 g, 5 Ommo 1) were charged. The resulting solution was reacted for 2 hours under reflux, and water formed was removed azeotropically. The reaction mixture was cooled to 20 below and saturated aqueous sodium bicarbonate solution 5 Om 1 was added. The reaction mixture was allowed to stand for liquid separation, and after confirming that the pH of the aqueous layer was 7 or more, the organic layer was separated. By concentrating the organic layer under reduced pressure, 2_ (2,2-dimethyl-3-hydroxypropyloxycarbonyl) -1,8-dimethyl-6,10-dioxaspiro [4.5] decane and 2, 350 g of a mixture of 2-dimethylpropane-1,3-di-rouge (8,8-dimethyl-6,10-dioxaspiro [4.5] decane-2-force loxylate) was obtained.

The mixture obtained above was then transferred to a 2 L reactor equipped with a thermometer, magnetic rotor and condenser, methanol (500 ml) and water (500 ml) were added, and sodium hydroxide ( 60 g, 1.5mo 1) was gradually added, and the mixture was heated to an internal temperature of 50 ° C and stirred for 2 hours. The reaction mixture is then concentrated under reduced pressure to remove methanol,

The aqueous layer was adjusted with 20% aqueous sulfuric acid so that the pH of the aqueous layer was in the range of 4.0 to 4.5. 1 L of toluene was added to this solution and stirred at room temperature for 30 minutes, and then the organic layer was separated. The organic layer was washed with 200 ml of water, concentrated under reduced pressure, and the residue was recrystallized from cyclohexane to give 8,8-dimethyl-6,10-dioxaspiro [4.5] decane. Rubonic acid 173.

3 g (99% purity, yield of 81% from 3-oxocyclopentane monosulfuric acid) was obtained. Example 3

A reactor with a 10 Oml capacity equipped with a thermometer, magnetic rotor, dropping funnel and Y-tube, water 5 Om 1 and! ) Monotoluenesulfonic acid monohydrate (0.19 g, lmmol) was charged. The solution was heated until water was refluxed, and trimethyl 3-year-old oxocyclopentane-1,2,4-tricarboxylate (25.8 g, 10 Ommo 1) was added dropwise over 1 hour. After completion of the dropwise addition, the methanol produced in the reaction was withdrawn as a mixture with water under reflux conditions, and an amount of water corresponding to the withdrawn amount was added to maintain the reaction mixture volume in the reactor. Reacted for hours. The obtained reaction mixture was analyzed by gas chromatography. As a result, the conversion of trimethyl 3-year-old oxocyclopentane-1,2,4-tricarboxylate was 99%, and the product was 3-oxocyclo It was a mixture of pentane 1-strength rubonic acid and 3-year-old oxocyclopentane 1-1-carboxylate [former Z latter = 99. 7 / 0.3 (area ratio)]. To this reaction mixture, 50 ml of toluene was added, and water contained therein was removed by azeotropic distillation, followed by addition of neopentyldaricol (21.9 g 21 Ommo 1). The mixture was reacted for 2 hours under reflux, and the water formed was removed azeotropically. The reaction mixture was cooled below 20 ° C. and saturated aqueous sodium hydrogen carbonate solution 5 Om 1 was added. The reaction mixture was allowed to stand for liquid separation, and after confirming that the pH of the aqueous layer was 7 or more, the organic layer was separated. This organic layer was concentrated under reduced pressure to give 2- (2,2-dimethyl-3-hydroxypropyloxycarbonyl) 1,8,8-dimethyl-1,6,10-dioxaspiro [4.5] decane and 2, 2 -38.9 g of a mixture of dimethylpropane-1,3-diyldisulfate (8,8-dimethyl-6,10-dioxaspiro [4.5] decane-2-carboxylate) was obtained.

Next, the mixture obtained above was transferred to a 2 L reactor equipped with a thermometer, magnetic rotor and condenser, methanol (500 ml) and water (500 ml) were added, and sodium hydroxide ( 60 g, 1.5mo 1) was gradually added, and the mixture was heated to an internal temperature of 50 and stirred for 2 hours. Thereafter, the reaction mixture was concentrated under reduced pressure to remove methanol, and the pH of the aqueous layer was adjusted to a range of 4.0 to 4.5 with a 20% aqueous sulfuric acid solution. 1 L of toluene was added to this solution and stirred at room temperature for 30 minutes, and then the organic layer was separated. The organic layer was washed with 20 Oml of water, concentrated under reduced pressure, and the residue was recrystallized from cyclohexane to give 8,8-dimethyl-6,10-dioxaspiro [4.5] decane _ 2 _carboxylic acid 16.05 g (99% purity, 75% yield from trimethyl 3-year-old oxocyclopentane-1,2,4,4-tricarboxylate) was obtained. Industrial applicability

The 3-year-old oxocyclopentane monocycle (V) obtained according to the present invention is an optically active 3-odium intermediate that is useful as an adenosine antagonist. It is useful as an intermediate for synthesizing rubonic acid derivatives.

Four

Claims

Scope of request

1. General formula (I)

(In the formula, each of RR ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ represents a hydrogen atom, an alkyl group which may have a substituent, or an aryl group which may have a substituent. 3-year-old oxocyclopentane represented by the general formula (II) in the presence of an acid catalyst.

(Wherein R ⁸ , R ⁹ , R ^{1 Q} , R ¹¹ , R ¹² and R ¹³ each represents a hydrogen atom, an alkyl group or an aryl group which may have a substituent, or these Any two of them may be joined together with the carbon atom to which they are attached to form a ring, and n represents 0 or 1.)

By reacting with a diol compound represented by general formula (I I I)

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and n are as defined above )

Cyclic acetal monoester derivatives represented by general formula (IV)

^{^{(Wherein, RR 2, R 3, R}} 4, R 5, R 6, R 7, R 8, R 9, R 10, R ", R 12, R 13 and n are as defined above.)

A mixture of the cyclic acetal gestester derivatives represented by formula (V), and then hydrolyzing the mixture under basic conditions:

A method for producing a cyclic acetal product of 3-year-old oxocyclopentane-1-carboxylic acid represented by the formula:

2. General formula (VI)

(Wherein R ⁶ , R ⁷ and R ¹⁴ each represent a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group, X ¹ , X ² , X ³ , X ⁴ and X ^{5 each} represents at least one of the groups represented by the general formula 1 C0 ₂ R ¹⁵ , and the other represents a hydrogen atom, an alkyl group which may have a substituent or a substituted group. R ¹⁵ represents a hydrogen atom, an alkyl group that may have a substituent, or an aryl group that may have a substituent.

Is reacted with water in the presence of an uncatalyzed or catalytic amount of acid to produce a general formula (I)

(Wherein R ⁶ and R ⁷ are as defined above, and RR ² , R ³ , R ⁴ and R ⁵ are each a hydrogen atom, an optionally substituted alkyl group or a substituent. Represents an aryl S that may have 3-year-old oxocyclopentane-1 obtained with 1-strength rubonic acid, and then obtained 3-oxocyclopentane_ 1 reaction mixture containing 1-strength rubonic acid in the presence of an acid catalyst (II)

By reacting with a diol compound represented by general formula (I I I)

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and n are as defined above. It is as follows.)

And cyclic formula monoester derivatives of general formula (IV)

(Wherein RR ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^{1 1} R ^{1 2} , R ^{1 3} and n are as defined above. )

A mixture of cyclic gestester derivatives represented by the following general formula (V), characterized in that the mixture is hydrolyzed under basic conditions:

(Wherein R ¹ R ² , R ³ , R ⁴ , R ⁵ , R ⁶ R ⁷ , RRRRR 1 2 R 1 3 and n are as defined above.)

The manufacturing method of the cyclic acetal body of 3-oxo cyclopentane 1 carboxylic acid shown by these.

3. Formula (III_1)

2 (2,2-dimethyl-3-hydroxypropyloxyluronyl) 8, 8-dimethyl 6,10-dioxaspiro [4.5] decane.

4. Formula (IV 1)

(IV-1)

2,2-Dimethylpropane-1,3-diyldi (8,8-dimethyl-60-dioxaspiro [4.5] decane-2-carboxylate).