JPH08104686A - Racemic aliphatic heterocyclic carboxylic acid ester, and production of racemic aliphatic heterocyclic carboxylic acid - Google Patents

Abstract

PURPOSE: To obtain the subject compound in a short time and in a high yield under mild conditions by racemizing an optically active aliphatic heterocyclic carboxylic acid ester in the coexistence of as a base. CONSTITUTION: An optically active aliphatic heterocyclic carboxylic acid ester of the formula (R is 1-5C alkyl; n is 1,2) (e.g. optically active tetrahydrofuran-2- carboxylic acid ester) is racemized in the coexistence of a base (preferably an alkali metal alkoxide, alkali metal hydride, alkali metal amide) to obtain the objective compound. The catalyst is preferably used in an amount of 0.01-35mol% based on the compound of formula. The racemization reaction is preferably performed at 0-65 deg.C under an anhydrous condition. The reaction time is usually 0.1-30hr. A racemic aliphatic heterocyclic carboxylic acid is obtained by hydrolyzing the objective compound.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an optically active aliphatic heterocyclic carboxylic acid ester useful as an intermediate drug material or a liquid crystal raw material, and an optically active aliphatic heterocyclic carboxylic acid produced by enzymatic resolution or chemical resolution. (EN) It is intended to provide a racemic aliphatic heterocyclic carboxylic acid ester and a process for producing a racemic aliphatic heterocyclic carboxylic acid by racemizing an unnecessary optical antipode produced as a by-product.

[0002]

2. Description of the Related Art Conventionally, many optically active aliphatic heterocyclic carboxylic acid esters and optically active aliphatic heterocyclic carboxylic acids are useful as raw materials for medicines and agricultural chemicals, and as raw materials for liquid crystals. For example, optically active tetrahydrofuran carboxylic acid is known as a raw material for synthetic antibiotics and liquid crystal. Known methods for producing them include enzymatically reacting chemically synthesized racemic aliphatic heterocyclic carboxylic acid ester, for example, asymmetric hydrolysis with esterase or lipase. Further, a method of optically resolving racemic aliphatic heterocyclic carboxylic acid with brucine is known (Can. J. C.
hem. , 61. p1383 (1983)). However, in these methods, the yield of the desired optically active aliphatic heterocyclic carboxylic acid is theoretically 50% of the racemate,
It is insufficient as an industrial manufacturing method. Therefore, if an unnecessary enantiomer can be racemized and recycled as a raw material for enzymatic reaction or chemical resolution, racemic aliphatic heterocyclic carboxylic acid ester, racemic aliphatic heterocyclic carboxylic acid Heterocyclic carboxylic acid ester and optically active aliphatic heterocyclic carboxylic acid are theoretically 1
It can be produced with a yield close to 00%. Therefore, an optically active aliphatic heterocyclic carboxylic acid ester, a racemic aliphatic heterocyclic carboxylic acid ester by racemizing the optically active aliphatic heterocyclic carboxylic acid, a method for producing a racemic aliphatic heterocyclic carboxylic acid is an important technique. I can say. There is no known method for directly racemizing an optically active aliphatic heterocyclic carboxylic acid ester, for example, an optically active tetrahydrofuran-2-carboxylic acid ester, but a racemic reaction of an optically active tetrahydrofuran-2-carboxylic acid which is a hydrolysis product. The chemical method is known. For example, a method of heating to 100 ° C. or higher using a concentrated large excess aqueous sodium hydroxide solution (JP-A-2-124881) is only slightly known.

[0003]

The above-mentioned racemization method of optically active tetrahydrofuran-2-carboxylic acid requires a strong large amount of a strong base such as an aqueous solution of sodium hydroxide in a concentrated large amount, and thus a sufficient racemization rate is obtained. Requires severe heating conditions of 140 ° C. or higher. Therefore, in addition to being restricted by the reaction apparatus such as corrosion resistance and pressure resistance, the recovery rate is not always good. Therefore, an optically active aliphatic heterocyclic carboxylic acid ester and an optically active aliphatic heterocyclic carboxylic acid can be obtained in a short time under mild conditions and at high yield in a racemic aliphatic heterocyclic carboxylic acid ester and a racemic aliphatic heterocyclic carboxylic acid ester. An industrial production method for obtaining a cyclic carboxylic acid has been desired.

[0004]

Therefore, the present inventors have obtained an optically active aliphatic heterocyclic carboxylic acid ester under mild conditions in a short time in a high yield with a high yield of racemic aliphatic heterocyclic carboxylic acid ester. As a result of diligent studies on the industrially feasible production method, it was found that this can be achieved by racemization in the presence of a base. Further, by hydrolyzing the obtained racemic aliphatic heterocyclic carboxylic acid ester, a racemic aliphatic heterocyclic carboxylic acid can be easily obtained. The present invention can be carried out under remarkably mild conditions as compared with the conditions for racemization of an optically active aliphatic heterocyclic carboxylic acid, and the recovery of the racemate is high.

That is, the present invention has the following general formula (I):

Embedded image (Wherein R represents a lower alkyl group having 1 to 5 carbon atoms, and n represents 1 or 2), and racemizing the optically active aliphatic heterocyclic carboxylic acid ester in the presence of a base. A method for producing a characteristic racemic aliphatic heterocyclic carboxylic acid ester.

The structure of the present invention will be described in detail below.

In the present invention, the optically active aliphatic heterocyclic carboxylic acid ester used as a starting material is an optically active substance in which the aliphatic heterocyclic skeleton is substituted with a carboxylic acid ester, and has a substituent other than the carboxylic acid ester. You can do it. Specifically, optically active tetrahydrofuran-
Examples thereof include 2-carboxylic acid ester, optically active tetrahydrofuran-3-carboxylic acid ester and optically active tetrahydropyran-2-carboxylic acid ester. Also,
An optically active aliphatic heterocyclic carboxylic acid ester obtained by esterifying an optically active aliphatic heterocyclic carboxylic acid can also be used as a raw material. Here, the optically active aliphatic heterocyclic carboxylic acid ester is represented by the general formula (I)
R represents a lower alkyl group having 1 to 5 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group and a neopentyl group. You can

When the optically active aliphatic heterocyclic carboxylic acid ester is esterified as the starting material of the present invention to obtain the optically active aliphatic heterocyclic carboxylic acid ester, a conventional method can be adopted. For example, by optically azeotropically dehydrating an optically active aliphatic heterocyclic carboxylic acid in an alcohol solvent without a catalyst, the presence of a mineral acid such as sulfuric acid or hydrochloric acid or an organic acid such as p-toluenesulfonic acid in the alcohol solvent. It can be easily converted to an ester below.

Here, the optically active aliphatic heterocyclic carboxylic acid ester and the optically active aliphatic heterocyclic carboxylic acid in the present invention are fats in which one optical isomer is contained more than the other optical isomer. Group heterocyclic carboxylic acid ester and aliphatic heterocyclic carboxylic acid, and substantially means an aliphatic heterocyclic carboxylic acid ester having an optical purity of 30% ee or more, and an aliphatic heterocyclic carboxylic acid.
The racemic aliphatic heterocyclic carboxylic acid ester and the racemic aliphatic heterocyclic carboxylic acid have an optical purity of 30%.
It means an aliphatic heterocyclic carboxylic acid ester having an ee of less than ee, and an aliphatic heterocyclic carboxylic acid.

The racemization of the present invention can be carried out in an inert solvent or without a solvent. Specifically, hydrocarbons such as benzene, toluene, xylene, octane, decane, and cyclohexane; methanol, ethanol,
Alcohols such as propanol, isopropanol, butanol, isobutanol, t-butanol; ethers such as ethyl ether, isopropyl ether, butyl ether, isobutyl ether, anisole; organic solvents such as dimethyl sulfoxide, hexamethylphosphoryl triamide, or their The mixed solvent can be used as a racemization solvent. From the economical viewpoint, the amount of the solvent used is preferably 0 to 5 times the volume of the substrate.

Further, in the racemization method of the present invention, even if a small amount of carboxylic acids coexist, racemization proceeds without any problem. Aliphatic carboxylic acids as carboxylic acids,
Examples thereof include aliphatic heterocyclic carboxylic acids. Since the activity of the base may be lost by the coexisting carboxylic acids, it is necessary to add an excess of the base, but it does not affect the racemization reaction at all. If there are many carboxylic acids, it is necessary to increase the amount of the base to be used. Therefore, in consideration of economical efficiency, the coexisting amount of carboxylic acids is preferably within 30 mol% with respect to the optically active aliphatic heterocyclic carboxylic acid ester. More preferably, it is within 20 mol%.

The base used in the present invention is preferably a base selected from the group consisting of alkali metal alkoxides, alkali metal hydrides and alkali metal amides.
Specific examples of the base used include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium-s-.
Examples thereof include alkali metal alkoxides such as butoxide and potassium-t-butoxide; alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal amides such as lithium amide, sodium amide and potassium amide. In the present invention, the amount of the base used is influenced by the temperature or time of racemization or the amount of carboxylic acids present together, but is preferably 0.01 mol% or more based on the optically active aliphatic heterocyclic carboxylic acid ester. Further, even if it is used in a large amount, it does not have any influence on the racemization reaction, but it is not necessarily advantageous in terms of chemical costs and isolation operation. In the presence of carboxylic acids, it is necessary to add more than the equivalent amount of carboxylic acid, but in consideration of reactivity and economical efficiency, it is preferably 0.01 to 40 mol% with respect to the optically active aliphatic heterocyclic carboxylic acid ester, and more preferably Is 0.01 to 35 mol%. If water is present in the reaction system, the base may be deactivated, so it is preferable to take sufficient care not to mix water.

The racemization reaction proceeds at 0 ° C. or higher, but it is preferably in the range of 0 ° C. to 100 ° C. in consideration of the reaction time. A particularly preferred temperature is 0 ° C or higher and lower than 65 ° C. The time required for racemization depends on the temperature or the type and amount of the base, but is usually 0.1 to 30 hours.

After the racemization reaction, the racemic aliphatic heterocyclic carboxylic acid ester can be recovered by a known method. For example, it can be distilled directly, or the base can be neutralized with a hydrogen halide gas such as hydrogen chloride and then distilled.
Alternatively, if the amount of the catalyst is small, the base of the racemization catalyst may be decomposed with water, extracted with an organic solvent immiscible with water, and then distilled. Further, in the case of obtaining a racemic aliphatic heterocyclic carboxylic acid, the aliphatic heterocyclic carboxylic acid ester may be hydrolyzed by a known method after the racemization reaction. For example, by adding water to the racemization reaction solution and heating,
It is hydrolyzed by treatment in an acidic aqueous solution of a mineral acid such as hydrochloric acid or sulfuric acid or an alkaline aqueous solution such as sodium hydroxide. Then, the solution is made into an acidic solution and then directly extracted with an organic solvent immiscible with water, or if necessary, concentrated and then extracted. Further, if necessary, the inorganic salt produced by neutralization is filtered off, concentrated, and directly distilled, whereby the racemic aliphatic heterocyclic carboxylic acid can be easily recovered.

The racemic aliphatic heterocyclic carboxylic acid ester thus obtained can be recycled as a starting material for an enzymatic reaction. The racemic aliphatic heterocyclic carboxylic acid can also be recycled as a starting material for diastereomeric salt resolution.

[0016]

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

The optical purity of the tetrahydrofuran carboxylic acid ester and the tetrahydrofuran carboxylic acid after the racemization reaction in the examples were determined by the following method. That is, when the optically active tetrahydrofuran carboxylic acid ester was racemized, water was added to the racemization reaction solution to deactivate the base, and then the ester was extracted with dichloromethane. The dichloromethane layer was dried over magnesium sulfate and then analyzed by HPLC. When tetrahydrofuran carboxylic acid coexists, sodium hydroxide aqueous solution is added so as to be equimolar with the base in terms of tetrahydrofuran carboxylic acid and refluxed for 1 hour to hydrolyze all to tetrahydrofuran carboxylic acid and then sulfuric acid. It was neutralized with and concentrated. Then, dichloromethane was added to filter inorganic salts, and the filtrate was concentrated to obtain tetrahydrofuran carboxylic acid. An excess of diethyl ether solution of diazomethane was added to 70 to 80 mg of the obtained crude tetrahydrofuran carboxylic acid, and the mixture was allowed to stand for about 15 minutes to synthesize tetrahydrofuran carboxylic acid methyl ester. The reaction mixture was concentrated to give a residue containing n-hexane / isopropanol = 995 /
5 (v / v) 0.8 ml was added to dissolve it, and if necessary, insoluble matter was filtered, and 1-2 μ was applied to HPLC as a sample solution.
1 was injected and analyzed. The column used for analysis is CHI
RALCEL OD (manufactured by Daicel), and n-hexane / isopropanol = 995/5 (v / v) was used as the mobile phase. Column temperature 25 ℃, flow rate 1.5ml / min,
Detection was carried out by UV (220 nm). Tetrahydrofuran-2-carboxylic acid methyl ester S form is 9.5 minutes,
R-form is 17.4 min, tetrahydrofuran-2-carboxylic acid isopropyl ester S-form is 7.8 min, R-form is 1
3.2 minutes, the S-form of tetrahydrofuran-2-carboxylic acid butyl ester was eluted at 8.0 minutes, and the R-form was eluted at 13.4 minutes. Further, the flow rate of tetrahydrofuran-3-carboxylic acid methyl ester was 0.5 ml / min, and the S-form was 23.
After 9 minutes, the R form was eluted at 26.4 minutes. The racemization rate was calculated by the following formula.

[0018]

[Equation 1]

Example 1 In a 20 ml glass ampoule autoclave, (R)-
3.20 g of tetrahydrofuran-2-carboxylic acid isopropyl ester (hereinafter, (R) -tetrahydrofuran-2-carboxylic acid is abbreviated as "R-THFC".)
(0.0202 mol, 99% ee) and sodium hydride (60% purity) 0.021 g (0.0005 mol) were charged, while stirring with a stirrer in an argon atmosphere.
The reaction was carried out at 40 ° C for 2 hours. When the THFC isopropyl ester contained in the reaction solution was analyzed by GC, the recovery was 97.
%Met. Then, after adding 3.0 g of water to hydrolyze sodium hydride, 10 ml of dichloromethane was added to extract THFC isopropyl ester. The dichloromethane layer is dried over magnesium sulfate and HPL
It was injected into C and the optical purity was determined. The optical purity was 0% ee and the racemization rate was 100%.

Example 2 A 20 ml glass ampoule autoclave was charged with R-TH.
FC isopropyl ester 3.00 g (0.0190 mol, 99% ee) and potassium t-butoxide 0.10
g (0.0009 mol) and charged in an argon atmosphere,
The mixture was heated at 40 ° C. for 4 hours while stirring with a stirrer.
The THFC isopropyl ester contained in the reaction solution was
When analyzed, the recovery rate was 97%. When the optical purity was determined by treating in the same manner as in Example 1, the optical purity was 0%.
ee and the racemization rate was 100%.

Example 3 A 20 ml glass ampoule autoclave was charged with S-TH.
FC butyl ester 3.00 g (0.0174 mol, 6
3% ee) and sodium methoxide 0.07 g (0.0
(013 mol) was charged and heated at 70 ° C. for 4 hours while stirring with a stirrer under an argon atmosphere. When the THFC butyl ester contained in the reaction solution was analyzed by GC, the recovery was 94%. Then, the same treatment as in Example 1 was carried out to determine the optical purity. The optical purity was 0% ee and the racemization rate was 100%.

Example 4 A 20 ml glass ampoule autoclave was charged with S-TH.
FC methyl ester 3.10 g (0.0238 mol, 3
8% ee) and sodium methoxide 0.03 g (0.0
(006 mol) was charged, and the mixture was heated at 70 ° C. for 4 hours while stirring with a stirrer under an argon atmosphere. When the THFC methyl ester contained in the reaction solution was analyzed by GC, the recovery was 99%. Then, the same treatment as in Example 1 was carried out to determine the optical purity. The optical purity was 0% ee and the racemization rate was 100%.

Example 5 A 20 ml glass ampoule autoclave was charged with S-TH.
FC methyl ester 3.15 g (0.0242 mol, 3
8% ee) and sodium methoxide 0.06 g (0.0
(012 mol) was charged and heated at 50 ° C. for 1 hour while stirring with a stirrer under an argon atmosphere. When the THFC methyl ester contained in the reaction solution was analyzed by GC, the recovery was 96%. Then, the same treatment as in Example 1 was carried out to determine the optical purity. The optical purity was 0% ee and the racemization rate was 100%.

Example 6 A 20 ml glass ampoule autoclave was charged with S-TH.
FC methyl ester 3.05 g (0.0235 mol, 3
8% ee), sodium methoxide 0.10 g (0.0
019 mol), toluene 0.48 g, methanol 0.4
4 g was charged and heated at 70 ° C. for 2 hours while stirring with a stirrer under an argon atmosphere. TH contained in the reaction solution
GC analysis of FC methyl ester showed a recovery rate of 96.
%Met. Then, the same treatment as in Example 1 was carried out to determine the optical purity. The optical purity was 0% ee and the racemization rate was 100%.

Example 7 A 20 ml glass ampoule autoclave was charged with S-TH.
FC methyl ester 3.10 g (0.0238 mol, 3
8% ee) and sodium amide 0.05 g (0.001
(3 mol) was charged and heated at 70 ° C. for 4 hours while stirring with a stirrer under an argon atmosphere. When the THFC methyl ester contained in the reaction solution was analyzed by GC, the recovery was 92%. Then, the same treatment as in Example 1 was carried out to determine the optical purity. The optical purity was 0% ee and the racemization rate was 100%.

Example 8 A 20 ml glass ampoule autoclave was charged with S-TH.
FC methyl ester 2.40 g (0.0184 mol, 3
8% ee), S-THFC 0.39 g (0.0034 mol, 46% ee) and sodium methoxide 0.27 g
(0.0049 mol) was charged and heated at 85 ° C. for 6 hours while stirring with a stirrer under an argon atmosphere. The THFC methyl ester and THFC contained in the reaction solution are
When analyzed, the recovery rate was 94%. Sampling a small amount to determine the optical purity of THFC methyl ester by HPLC
Was 0% ee, and the racemization rate was 10
It was 0%. Then, 6.8 g of a 10% sodium hydroxide aqueous solution was added, and the mixture was heated at 70 ° C. for 1 hour to obtain S-THFC.
The methyl ester was hydrolyzed. After cooling 60% sulfuric acid 1.
It was neutralized with 8 g and concentrated. 20 ml of dichloromethane was added and the precipitated sodium sulfate was filtered and then concentrated. The obtained concentrated THFC was converted to methyl ester with diazomethane to determine the optical purity. Optical purity is 7% ee
Met.

Example 9 A 20 ml glass ampoule autoclave was charged with S-TH.
FC methyl ester 4.00 g (0.0307 mol, 3
8% ee), sodium methoxide 0.05 g (0.0
009 mol) and dimethylsulfoxide (5.2 g) were charged, and while stirring with a stirrer under an argon atmosphere, 9
Heated at 0 ° C. for 1 hour. When the THFC methyl ester contained in the reaction solution was analyzed by GC, the recovery was 94%. Next, 5.0 g of water was added to deactivate sodium methoxide, and then 20 ml of ethyl acetate was added to add TH.
The FC methyl ester was extracted. The ethyl acetate layer was dried over magnesium sulfate and injected into HPLC to determine the optical purity. Optical purity is 0% ee and racemization rate is 1
00%.

Example 10 56.1 g of S-THFC (0.483 mol 46% e)
e), 120.0 g of methanol and 0.24 g of concentrated sulfuric acid
300 ml 4 equipped with a thermometer, condenser and stirrer
The mixture was placed in a one-necked flask and heated under reflux for 3.5 hours. After the reaction, 5 mol% of THFC remained. 0.5 g of 50% aqueous sodium hydroxide solution was added to neutralize the sulfuric acid, and the precipitated sodium sulfate was filtered. Toluene 120g in the filtrate
Was added thereto and the mixture was concentrated while being azeotropically dehydrated to obtain 70.2 g of an S-THFCC methylelter concentrate. The water content is 0.
It was less than 04%.

The above S-THFC methyl ester concentrate and 5.32 g (0.098 mol) of sodium methoxide were placed in a 200 ml four-necked flask equipped with a thermometer, a condenser and a stirrer, and the mixture was heated at 60 ° C. under an argon stream to 3 ° C. Heated for hours. The optical purity was determined by sampling a portion of the racemization reaction solution and found to be 0% ee, with a racemization rate of 1
00%. Then, 60.0 g of water and 38.5 g of 40% sodium hydroxide aqueous solution are added, and the mixture is refluxed for 1 hour.
The HFC methyl ester was hydrolyzed. While keeping the temperature at 20 to 30 ° C., 39.4 g of 60% sulfuric acid was added dropwise to neutralize,
Concentrated. After 150 g of toluene was added and the mixture was azeotropically dehydrated and concentrated to 120 g, the precipitated sodium sulfate was filtered off. Further, the filtrate was concentrated to 60 g and distilled under reduced pressure to obtain 101 ° C / 532 Pa racemic THFC47.6.
g was obtained. The overall yield of THFC was 85%, and the obtained THFC had an optical purity of 2% ee.

Example 11 In a 100 ml flask equipped with a thermometer, 30.0 g (0.190 mol, 99% e) of R-THFC isopropyl ester was added.
e, water 0.017% by weight), 2-propanol 3.0
g and sodium methoxide 0.20 g (0.003
(7 mol) and charged with a stirrer at 30 ° C. for 2 hours. When the THFC isopropyl ester contained in the reaction solution was analyzed by GC, the recovery was 97%. When the optical purity was obtained by sampling a part of the reaction solution, it was found to be 0% e.
and the racemization rate was 100%.

Example 12 In a 100 ml flask equipped with a thermometer, 30.0 g of S-THFC methyl ester (0.231 mol, 50% ee, water content 0.027% by weight), 5.0 g of cyclohexane and 0.30 g of sodium methoxide. (0.0055 mol)
Was charged and stirred at 25 ° C. for 3 hours with a stirrer. A methanol solution containing 0.20 g of hydrogen chloride gas in the reaction solution.
After neutralization with 0 g, concentration and distillation under reduced pressure were performed at 61 to 63 ° C./1.
27.5 g of a racemic THFC methyl ester fraction of 3 kPa was obtained. The yield is 92% and the racemization rate is 100.
%Met.

Example 13 In a 20 ml glass ampoule autoclave, (S)-
Tetrahydrofuran-3-carboxylic acid methyl ester 2.0 g (0.015 mol, 52% ee) and sodium methoxide 0.04 g (0.0007 mol) were charged,
Stirred at 20 ° C. for 3 hours. When the tetrahydrofuran-3-methyl carboxylic acid methyl ester contained in the reaction solution was analyzed by GC, the recovery was 97%. When a part of the reaction solution was sampled to determine the optical purity, the optical purity was 0% ee and the racemization rate was 100%.

Comparative Example 1 A 20 ml glass ampoule autoclave was charged with R-TH.
FC2.52 g (0.0217 mol, 99% ee), sodium methoxide 1.23 g (0.0228 mol) and toluene 1.50 g were charged and heated at 115 ° C. for 6 hours while stirring with a stirrer under an argon atmosphere. .
When the THFC contained in the reaction liquid was analyzed by GC, the recovery was 77%. Then, the mixture was neutralized with 1.86 g of 60% sulfuric acid and treated in the same manner as in Example 8 to determine the optical purity. The optical purity was 98.7% ee and the racemization rate was 0.3%.

[0034]

INDUSTRIAL APPLICABILITY According to the present invention, an optically active aliphatic heterocyclic carboxylic acid ester can be racemized in a short time under mild conditions, and a high yield of the racemic aliphatic heterocyclic carboxylic acid ester can be obtained. Moreover, if the obtained racemic aliphatic heterocyclic carboxylic acid ester is hydrolyzed, the racemic aliphatic heterocyclic carboxylic acid can be easily obtained.

Claims (8)

[Claims] 1. The following general formula (I): (Wherein R represents a lower alkyl group having 1 to 5 carbon atoms, and n represents 1 or 2), and racemizing the optically active aliphatic heterocyclic carboxylic acid ester in the presence of a base. A method for producing a racemic aliphatic heterocyclic carboxylic acid ester, which is characterized. 2. The method for producing a racemic aliphatic heterocyclic carboxylic acid ester according to claim 1, wherein the optically active aliphatic heterocyclic carboxylic acid ester is an optically active tetrahydrofuran carboxylic acid ester. 3. The production method according to claim 1 or 2, wherein the base is at least one selected from the group consisting of alkali metal alkoxides, alkali metal hydrides and alkali metal amides. 4. The racemic aliphatic compound according to claim 1, wherein the base is allowed to coexist in an amount of 0.01 mol% to 40 mol% with respect to the optically active aliphatic heterocyclic carboxylic acid ester. Process for producing heterocyclic carboxylic acid ester. 5. The method for producing a racemic aliphatic heterocyclic carboxylic acid ester according to any one of claims 1 to 4, wherein the racemization is performed at a temperature of 0 ° C or higher and lower than 100 ° C. 6. The method for producing a racemic aliphatic heterocyclic carboxylic acid ester according to claim 1, wherein racemization is performed at a temperature of 0 ° C. or higher and lower than 65 ° C. 7. A method for producing a racemic aliphatic heterocyclic carboxylic acid, which comprises hydrolyzing a racemic aliphatic heterocyclic carboxylic acid ester obtained by the method according to any one of claims 1 to 6. 8. An optically active aliphatic heterocyclic carboxylic acid ester produced by esterifying an optically active aliphatic heterocyclic carboxylic acid is used as a starting material.
7. The method for producing the racemic aliphatic heterocyclic carboxylic acid ester according to any one of 6 above.