JPH10316607A - Method for producing optically active 2-hydroxy-1-indanone and derivatives thereof - Google Patents

Abstract

(57) [Summary] Optical activity 2 useful as a synthetic intermediate for pharmaceuticals and the like
-Hydroxy-1-indanone and its derivatives are produced in an industrial mass production process. An optically active 2-hydroxy-1-indanone and an optically active derivative thereof are obtained by allowing a hydrolase to act on an ester derivative of 2-hydroxy-1-indanone. Further, an ester derivative of optically active 2-hydroxy-1-indanone and an optically active 2-hydroxy-1-indanone are obtained by reacting a hydrolase and an esterifying agent on 2-hydroxy-1-indanone.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing optically active 2-hydroxy-1-indanone and derivatives thereof, which are useful as intermediates for the synthesis of pharmaceuticals and the like.

[0002]

2. Description of the Related Art As a method for producing optically active 2-hydroxy-1-indanone, a method for asymmetric oxidation of a silyl enol ether of 1-indanone (JP-A-7-22858) is known.
No. 6) is known, but there is a problem in implementing on an industrial scale, such as using an expensive catalyst.

An ester derivative of optically active 2-hydroxy-1-indanone can be obtained by esterifying the optically active 2-hydroxy-1-indanone produced by the above method. There is a problem in the method of manufacturing.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for producing optically active 2-hydroxy-1-indanone and a derivative thereof, which can be easily applied to an industrial mass production process.

[0005]

DISCLOSURE OF THE INVENTION The present inventors have searched a wide range of various enzymes in order to find an enzyme having a high discriminating ability of an optically active form of 2-hydroxy-1-indanone and a derivative thereof. Several types of hydrolases have the expected ability, and in hydrolysis and transesterification,
The present inventors have found that the desired compound can be obtained with high yield and optical purity, and have led to the present invention.

That is, the present invention provides the following general formula (1)

Embedded image (Wherein, R ¹ represents a hydrogen atom, an aryl group which may have a substituent, an alkyl group or an alkenyl group.) An enantiomer mixture of a carboxylic acid ester of 2-hydroxy-1-indanone represented by the following formula: A process for producing optically active 2-hydroxy-1-indanone and / or an optically active ester thereof, characterized in that the hydrolysis is carried out in the presence of a hydrolase.

Further, the present invention provides a method for preparing an enantiomeric mixture of 2-hydroxy-1-indanone in the presence of a hydrolase in the following general formula (2):

Embedded image ^{R 1 COR 3 ······ (2)} ( wherein, R ¹ represents a hydrogen atom, an optionally substituted aryl group, an alkyl group or alkenyl group, R ³ is halogen An optically active 2-hydroxy-1-indanone and / or an optically active ester thereof, characterized by esterification with an esterifying agent represented by an atom or an acyloxy group.

Further, the present invention provides a method for preparing an enantiomeric mixture of 2-hydroxy-1-indanone in the presence of a hydrolase, represented by the following general formula (3):

Embedded image ^{R 1 COOR 4 ······ (3)} ( wherein, R ^1, R ⁴ represents a hydrogen atom, an aryl group which may have a substituent, an alkyl group or an alkenyl radical, R ¹
And R ⁴ may be equal or different. ), Wherein the transesterification is carried out with an ester represented by the formula (1): (2) a method for producing optically active 2-hydroxy-1-indanone and / or an optically active ester thereof.

Hereinafter, the present invention will be described in detail.

The 2-hydroxy-1-indanone ester derivative represented by the general formula (1) used in the present invention can be easily produced, for example, by the following method.

That is, a method of reacting 1-indanone with a brominating agent such as bromine, dibromomeldrum acid or pyridinium bromide perbromide to synthesize 2-bromo1-indanone and reacting it with a carboxylate (B)
er. 23 (1924) 194). Alternatively, using phenylalanine as a starting material, the following general formula (4)

Embedded image (In the formula, R ¹ represents a hydrogen atom, an aryl group, an alkyl group or an alkenyl group which may have a substituent.) And the following general formula (5)

Embedded image (Wherein, R ¹ represents a hydrogen atom, an optionally substituted aryl group, an alkyl group or an alkenyl group, and X represents a chlorine or bromine atom). A method for producing the 2-hydroxy-1-indanone derivative represented by the formula (1) is also simple.

At this time, as a method of converting phenylalanine into a compound represented by the general formula (4), a known method can be used. 3-phenyllactic acid is produced by the action of nitrate (DE 3334739, J. Am.
Am. Chem. Soc. , 1987, 52, 4978.
-4984), a method in which an acyl halide or an acid anhydride is allowed to act thereon (Tetrahedron Le).
tt. , 1995, 36, 6449-52).

When acetic acid is used as the acidic solvent and sodium nitrite is used as the nitrite, in the 3-phenyllactic acid derivative represented by the above general formula (4), the compound in which R ¹ is a methyl group is converted from phenylalanine. Can be obtained directly (J. Org. Chem. 1987, 52, 49).
78-4984).

Further, 2-hydroxy-1-used in the present invention.
Indanone can be easily produced, for example, by the following method.

That is, a method in which a base is allowed to act on 1-indanone to generate an enol ether, followed by oxidation with various oxidizing agents (J. Org. Chem. 1994, 5).
9, 2358 and Tetrahedron Lett.
1981, 22, 607) or a method of hydrolyzing the 2-hydroxy-1-indanone ester derivative produced as described above (J. Pract. Chem. <
2>, 1924, 108, 197).

In the present invention, the reaction of an enzyme on an enantiomeric mixture of carboxylic acid esters of 2-hydroxy-1-indanone represented by the general formula (1) is carried out by reacting the enzyme with 2
An optically active form of 2-hydroxy-1-indanone is produced to selectively catalyze the hydrolysis of one of the optical isomers of the enantiomeric mixture of the carboxylic acid esters of -hydroxy-1-indanone. Together,
The generated optically active 2-hydroxy-1-indanone is a reaction in which a carboxylic acid ester of 2-hydroxy-1-indanone having an opposite absolute configuration with respect to the optical center remains.

Accordingly, for example, in producing an optically active substance of 2-hydroxy-1-indanone from an enantiomeric mixture of a carboxylic acid ester of 2-hydroxy-1-indanone represented by the general formula (1), If the compound to be used is an (R) -isomer, the enzyme may act on an enzyme having (R) -isomer selectivity. If the (S) -isomer is intended, an enzyme having (S) -isomer selectivity may be used. It should just work.

The carboxylic acid ester of 2-hydroxy-1-indanone as a raw material is preferably a racemic form (equivalent mixture of enantiomers) from the viewpoint of easy availability, but the enantiomer mixing ratio is limited. is not.

However, when the purpose is to produce the (R) form of alcohol using an enzyme having (R) selectivity, it is better to use an ester having a high content of the (R) form as the raw material to be used. This is advantageous because it is easy to obtain an alcohol having a high (R) ratio. Conversely, when the purpose is to produce the (S) form of alcohol using an enzyme having (S) selectivity, it is better to use a mixture having a high content of the (S) form as the starting material. (S) This is advantageous because it is easy to obtain alcohol having a high body ratio. On the other hand, when the purpose is to obtain the (R) form of the remaining ester, it is preferable to use an ester having a high (R) form content as a raw material using an enzyme having (S) form selectivity, Conversely, when the purpose is to obtain the (S) form of the remaining ester, it is preferable to use an ester having a high (S) form content as a raw material using an enzyme having (R) form selectivity. .

As R ¹ in the general formula (1), a hydrogen atom, an aryl group such as a phenyl group or a naphthyl group, an unsubstituted or substituted alkyl group or an alkenyl group can be used.
Examples of the unsubstituted alkyl group include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, t-
A butyl group and the like can be mentioned. Examples of the substituted alkyl group include a halogen atom such as fluorine, an alkoxyl group such as a methoxyl group, an ethoxyl group and a t-butoxyl group, an aryl group such as a phenyl group and a naphthyl group, an alkoxycarbonyl group such as a methoxycarbonyl group and an ethoxycarbonyl group. And an alkyl group substituted with an acyloxyl group, a nitro group, an amino group, a cyano group and the like. The aryl group may have a substituent, and examples of the substituent include an alkyl group.

The enzyme used in the reaction is represented by the general formula (1)
An enzyme having the ability to preferentially hydrolyze either the (R) -form or the (S) -form of the enantiomer mixture of the carboxylic acid ester of 2-hydroxy-1-indanone represented by Mobactor (Acro
genus, Alcaligenes
genes), Aspergillus (Aspergill)
us) genus, Burkholderi
a) genus, Candida genus, Chromobacterium genus, Humicola genus, Mucor (Muco)
r) genus, Pseudomonas
Genus, Rhizomucor, Rhizopus, Thermus
s) Microorganisms belonging to the genus and lipase derived from pig pancreas, or microorganisms belonging to the genus Aspergillus and aminoacylase derived from pig kidney, or Aspergillus, Bacillus (B
acillus, Tritiraquium
microorganisms belonging to the genus Cium and a protease derived from pig pancreas or an esterase derived from pig liver.

Further, in view of its high activity, Achromobacter sp.
Alcaligenes SP
sp. ), Aspergils niger
rus niger) and Aspergillus oryzae (A
spargillus oryzae), Burkholderia sp.,
Candida antarctica
narctica), Candida cylindracea, Candida utilis
s), Chromobacterium biscosum (Chromo)
bacterium viscosum), Humicola
Huginola langinos
a), Mucor miehe
i), Pseudomon cepacia
as cepacia), Pseudomonas sp., Rhizomucor.
Rhizomucor miehei, Rhizopus arhizu
s), Rhizopus s
p. ), Thermus aquaticus (Thermus a
quatics, Thermus Flavas (Therm)
us fluvus), Thermus thermophilus (T
hermus thermophilus, lipase from pig pancreas, or Aspergillus meleus (Asp)
ergillus melleus, aminoacylase from pig kidney, or Aspergillus meleus (Asp)
ergillus melleus, Aspergillus niger, Aspergillus oryzae (Aspergillus o)
ryzae), Aspergillus sp.
gillus sp. ), Bacillus licheniformis,
Tritirachium album
album), a protease derived from pig pancreas, an esterase derived from pig liver, and the like can be preferably used.

The amount of these enzymes used is usually from 0.01% to 100% by weight, preferably from 0.1% by weight to the 2-hydroxy-1-indanone derivative represented by the general formula (1). 50% by weight. When the amount is small, the reaction speed is slow. When a large excess is used, the reaction results are not significantly improved and are not economical.

As the enzyme, a powder or solution of the enzyme itself may be used as it is, or it may be used after immobilization. Examples of the method of immobilization include an adsorption method, a simple bonding method, a cross-linking method, an inclusive method, and the like. In addition, as a carrier for immobilization at the time of immobilization, inorganic substances such as silica gel, alumina, activated carbon, acid clay, bleached clay, kaolinite, bentonite, hydroxyapatite, calcium phosphate, porous glass, metal oxide, etc. , Polyethylene, polypropylene, polystyrene, acrylic resin, acrylate resin,
Examples include phenol-formalin resin, anion exchange resin, cation exchange resin, starch, and organic polymers such as gluten. Further, other than these, any other immobilized carrier may be used as long as it does not inhibit the expression of the active function of the enzyme and is insoluble in the solvent used.

As a method for immobilizing the enzyme on the carrier, a known method which has been conventionally used when the enzyme is carried on the carrier can be used. At this time, the weight of the enzyme to be immobilized is preferably 0.1 to 700 mg of the protein containing 1 to 100% of the enzyme per 1 g of the carrier.

The reaction may be a batch type or a continuous type, but in the case of industrial scale, it is preferable to carry out the continuous reaction using a bioreactor filled with immobilized enzyme.

The reaction is usually performed in a solvent, and water or a buffer can be used as the solvent. As the buffer solution, commonly used well-known inorganic phosphate buffers such as sodium phosphate and potassium phosphate, sodium acetate, potassium acetate,
A buffer solution of an organic acid salt such as sodium citrate can be used, and its pH is preferably 5 to 12 for alkali-resistant enzymes and 1.5 to 7 for acid-resistant enzymes.

In addition, at the time of hydrolysis, alcohols such as methanol, ethylene glycol and 2-propanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, acetone,
Ketones such as cyclohexanone, halogenated hydrocarbons such as dichloromethane and chlorobenzene, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and hexamethylphosphoramide So-called polar aprotic solvents such as 1,3-dimethyl-2-imidazolidinone, nitrated hydrocarbons such as nitromethane and nitrobenzene, and nitriles such as acetonitrile and benzonitrile may be added to the solvent.

As the solvent to be added to water or alcohols, one of the above-mentioned solvents may be used, or a mixture of two or more thereof may be used. Alcohols, ethers, nitriles, halogenated hydrocarbons, and aromatic hydrocarbons are preferred in view of high solubility of raw materials and products. When the above-mentioned solvent is mixed and used in addition to water or buffer, it is preferable to contain 5% or more by volume of water or buffer and 10% or more in terms of a high reaction rate.

The concentration of the ester derivative of 2-hydroxy-1-indanone used as a substrate is usually 0.1 to 60% by weight, preferably 1 to 50% by weight. The reaction temperature is usually -20C to 120C, preferably 0C to 90C.
It is. The reaction time is generally 15 minutes to 40 days, preferably 30 minutes to 20 days.

When the reaction is carried out for a long time, the yield of the obtained alcohol is improved, but the optical purity is lowered. Conversely, the yield of the remaining ester decreases, but the optical purity increases. Therefore, the reaction may be stopped according to the optical purity or yield of the target compound, that is, the optical purity of the target compound is measured using ordinary analytical means such as high performance liquid chromatography, and the required optical purity is measured. It may be stopped when the purity or yield is shown.

After completion of the reaction, the enzyme can be recovered by filtration or centrifugal precipitation, and the recovered enzyme can be reused. The reaction product and unreacted raw materials can be easily recovered by extracting the reaction mixture or a solution from which the enzyme has been removed from the reaction mixture with an organic solvent and removing the organic solvent. The mixture of the reaction product and unreacted raw materials can be separated and purified by using a conventional purification method such as distillation or column chromatography to obtain an optically active substance.

In the present invention, the reaction in which an enzyme and an esterifying agent are allowed to act on an enantiomer mixture of 2-hydroxy-1-indanone is performed when the enzyme is either one of the optical isomers of the enantiomer mixture of 2-hydroxy-1-indanone. To selectively catalyze the esterification of the isomers or to selectively catalyze the hydrolysis of the resulting ester,
An optically active form of an ester derivative of -hydroxy-1-indanone is produced, and the produced ester derivative of optically active 2-hydroxy-1-indanone is 2-hydroxy-1 having an opposite absolute configuration with respect to the optical center. −
This is a reaction in which indanone remains.

The starting material, 2-hydroxy-1-indanone, is racemic (equivalent mixture of enantiomers) in that it is easily available.
Is preferred, but the enantiomer mixing ratio is not limited, and any mixing ratio may be used.

However, when the purpose is to produce the (R) form of the ester using an enzyme having (R) selectivity with respect to the formation of the ester, the starting material used is an alcohol having a high content of the (R) form. Use is advantageous because an ester having a high (R) form ratio is easily obtained. Conversely, when the purpose is to produce an (S) form of an ester using an enzyme having (S) selectivity, it is better to use a mixture having a high content of the (S) form as a raw material. This is advantageous because an ester having a high (S) -ratio is easily obtained. On the other hand, when the purpose is to obtain the (R) form of the remaining alcohol, it is preferable to use an alcohol having a high (R) form content as a raw material using an enzyme having (S) form selectivity, Conversely, if the purpose is to obtain the (S) form of the remaining alcohol,
It is preferable to use an alcohol having a high (S) body content as a raw material using an enzyme having (R) body selectivity.

The enzyme used in the reaction is the aforementioned lipase,
Esterases, aminoacylases and proteases can be used.

The amount of these enzymes to be used is usually 0.01 to 100% by weight, preferably 0.1 to 50% by weight, based on the 2-hydroxy-1-indanone derivative. When the amount is small, the reaction speed is slow. When a large excess is used, the reaction results are not significantly improved and are not economical.

As the enzyme, a powder or a solution of the enzyme itself may be used as it is, or it may be used after immobilization. Examples of the method of immobilization include an adsorption method, a simple bonding method, a cross-linking method, an inclusive method, and the like. The immobilization carrier and the method of immobilization when immobilizing are the same as described above.

The reaction may be a batch system or a continuous system, but in an industrial scale, it is preferable to carry out the continuous reaction using a bioreactor filled with immobilized enzymes.

When the esterifying agent represented by the general formula (2) is allowed to act as the esterifying agent, R ¹ in the general formula (2) is the same as R ^{1 in the} general formula (1). Things. R ³ is a halogen atom such as chlorine or bromine or an acyloxy group represented by R ² OCO—. Incidentally, R ² may include the same as the R ^1, R ¹ and R ² may be the same. Specific examples include acetic anhydride.

When the esterifying agent represented by the general formula (2) is allowed to act as the esterifying agent, the amount of the esterifying agent used is 1.0 to 1.0% based on 2-hydroxy-1-indanone as a substrate. The molar amount is twice to 100 times, preferably 1.2 to 60 times. In the case of a small amount, the reaction is incomplete, and the use of a large excess does not significantly improve the reaction results, and is not economical.

When the ester represented by the general formula (3) is subjected to transesterification by acting, the ester represented by the general formula (3)
As R ^{4 in} the formula, an aryl group such as a phenyl group or a naphthyl group, an unsubstituted or substituted alkyl group or an alkenyl group can be used. Examples of the unsubstituted alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group and an isopropyl group. Group, isobutyl group, t-butyl group and the like. Examples of the substituted alkyl group include a halogen atom such as fluorine, an alkoxyl group such as a methoxyl group, an ethoxyl group and a t-butoxyl group, an aryl group such as a phenyl group and a naphthyl group, an alkoxycarbonyl group such as a methoxycarbonyl group and an ethoxycarbonyl group. , Acyloxyl group, nitro group, amino group,
An alkyl group substituted by a cyano group or the like can be given.

When the ester represented by the general formula (3) is allowed to act as the esterifying agent, the amount of the ester used is preferably at least 1.0 times the molar amount of 2-hydroxy-1-indanone as the substrate. Is at least 1.2 times mol. The reaction may be performed using an ester as a solvent.

When an ester represented by the general formula (3) is allowed to act as an esterifying agent, the ester is represented by R
The structure of ⁴ is preferably a structure having a double bond between the α carbon and the β carbon of the oxygen atom. This produces alcohol as a by-product of the enzyme-catalyzed esterification reaction,
As a result, alcoholysis of the ester derivative of 2-hydroxy-1-indanone generated by the esterification occurs as a side reaction, which is caused by the esterifying agent having a structure having a double bond between the α carbon and the β carbon. Alcohol is quickly isomerized to a carbonyl compound, so that a side reaction of alcoholysis does not occur.

The esterifying agents represented by the general formulas (2) and (3)
In any of the methods using any of the above, the reaction is usually performed in a solvent, and an organic solvent is used as the solvent, but the organic solvent is not particularly limited as long as it does not deactivate the enzyme.

For example, ethers such as diethyl ether, tetrahydrofuran and dioxane, ketones such as acetone and cyclohexanone, halogenated hydrocarbons such as dichloromethane and chlorobenzene, benzene, toluene,
Aromatic hydrocarbons such as xylene, aliphatic hydrocarbons such as hexane, dimethylformamide, dimethylacetamide,
Dimethyl sulfoxide, hexamethylphosphoramide,
Examples include so-called polar aprotic solvents such as 1,3-dimethyl-2-imidazolidinone, nitrated hydrocarbons such as nitromethane and nitrobenzene, and nitriles such as acetonitrile and benzonitrile.

In the esterification reaction, as described above, alcohol is produced as a by-product, and the alcoholysis of the ester due to these may occur as a by-product. It is effective to add molecular sieves to the reaction solution. The amount of 2-hydroxy-1 as a substrate
-0.01% to 20%, preferably 0.1% to 10% by weight of indanone.

The concentration of 2-hydroxy-1-indanone as a substrate is generally 0.1 to 60% by weight, preferably 1 to 50% by weight. The reaction temperature is usually −20 ° C.
The temperature is 120C, preferably 0C to 90C. The reaction time is generally 15 minutes to 40 days, preferably 30 minutes to 20 days.

When the reaction is carried out for a long time, the yield of the obtained ester is improved, but the optical purity is lowered. Conversely, the yield of the remaining alcohol is reduced, but the optical purity is improved. Therefore, the reaction may be stopped according to the optical purity or yield of the target compound, that is, the optical purity of the target compound is measured using ordinary analytical means such as high performance liquid chromatography, and the required optical purity is measured. It may be stopped when the purity or yield is shown.

After completion of the reaction, the enzyme can be recovered by filtration or centrifugal precipitation, and the recovered enzyme can be reused. The reaction products and unreacted raw materials can be easily recovered by removing the organic solvent from the reaction mixture or a solution from which the enzyme has been removed from the reaction mixture. The mixture of the reaction product and the unreacted raw material can be separated and purified by a conventional purification method such as distillation or column chromatography to obtain an optically active substance.

[0051]

【Example】

Examples 1-47 (±) -2-acetoxy-1-indanone (14.3 m
g, 75.2 μmol) in phosphate buffer (pH 7,
3.62 ml) and methanol (1.21 ml), and the mixture was dissolved in enzyme (14.3 mg).
Shake for hours. A part of the solution was extracted and analyzed by high performance liquid chromatography (daicel OB column, ethanol: hexane = 1: 4, flow rate = 0.5 ml / min,
Retention time: 2-hydroxy-1-indanone = 11.6
Min (R form) and 16.1 min (S form), 2-acetoxy-
1-Indanone = 20.1 minutes (R form) and 22.2 minutes (S form)). Enzyme trade name, manufacturer, genus and analysis results of high performance liquid chromatography (2-hydroxy-1-
Table 1 shows the optical purity (ee%), yield (%), and absolute configuration of indanone (alcohol) and the optical purity (ee%) and yield (%) of 2-acetoxy-1-indanone (ester). It is shown in FIG. Table 1 is for Examples 1-31 and Table 2 is for Examples 32-47.

Examples 48 to 53 (±) -2-hydroxy-1-indanone (37.0 m
g, 250 μmol) with diisopropyl ether (5
ml) and toluene (3.33 ml), vinyl acetate (69.1 μl, 750 μmol) and enzyme (30.0 mg) were added, and the mixture was shaken at room temperature for 60 hours.
A part of the solution was withdrawn and analyzed by high performance liquid chromatography (daicel OB column, ethanol: hexane = 1: 4, flow rate = 0.5 ml / min, retention time: 2-
Hydroxy-1-indanone = 11.6 minutes (R form) and 16.1 minutes (S form), 2-acetoxy-1-indanone = 20.1 minutes (R form) and 22.2 minutes (S form)) . Origin of enzyme, trade name, manufacturer and analysis results of high performance liquid chromatography (optical purity (ee%), yield (%), absolute configuration, and 2-acetoxy-1 of 2-hydroxy-1-indanone (alcohol)) -Indanone (ester)
Table 3 shows the optical purity (ee%) and the yield (%) of the above.

[Table 1]

[Table 2]

[Table 3]

Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // C07M 7:00 (72) Inventor Tanijiro Hiyama 4-29-3-101 Kamizuruma, Sagamihara City, Kanagawa Prefecture

Claims (5)

[Claims] (1) The following general formula (1): (Wherein, R ¹ represents a hydrogen atom, an aryl group which may have a substituent, an alkyl group or an alkenyl group.) An enantiomer mixture of a carboxylic acid ester of 2-hydroxy-1-indanone represented by the following formula: A method for producing optically active 2-hydroxy-1-indanone and / or an optically active ester thereof, characterized in that the hydrolysis is carried out in the presence of a hydrolase. 2. An enantiomeric mixture of 2-hydroxy-1-indanone is prepared by reacting an enantiomeric mixture of 2-hydroxy-1-indanone with the following general formula (2): R ¹ COR ³ (2) In the formula, R ¹ represents a hydrogen atom, an aryl group, an alkyl group or an alkenyl group which may have a substituent, and R ³ represents a halogen atom or an acyloxy group.) A process for producing an optically active 2-hydroxy-1-indanone and / or an optically active ester thereof. 3. An enantiomeric mixture of 2-hydroxy-1-indanone is prepared by reacting an enantiomeric mixture of 2-hydroxy-1-indanone with the following general formula (3): R ¹ COOR ⁴ (3) among, R ^1, R ⁴ represents a hydrogen atom, an aryl group which may have a substituent, an alkyl group or alkenyl group, R ¹
And R ⁴ may be equal or different. ). A method for producing optically active 2-hydroxy-1-indanone and / or an optically active ester thereof, wherein the esterification is carried out with an ester represented by the following formula: 4. The method according to claim 1, wherein the enzyme is Achromobacter.
genus, Alcaligene
nes), Aspergillus (Aspergillus)
s) Genus, Burkholderia
Genus, genus Candida, genus Chromobacterium, genus Humicola, mucor
Genus, Pseudomonas, Rhizomucor, Rhizopus (R)
A microorganism belonging to the genus hizopus, the genus Thermus and a lipase derived from pig pancreas, or a microorganism belonging to the genus Aspergillus and an aminoacylase derived from pig kidney or Aspergillus, or Bacillus (Baci)
lulus), Tritirachi
um) a microorganism belonging to the genus and a protease derived from pig pancreas or an esterase derived from pig liver, and represented by the following general formula (1): (Wherein, R ¹ represents a hydrogen atom, an aryl group, an alkyl group or an alkenyl group which may have a substituent.) In the enantiomer mixture of a carboxylic acid ester of 2-hydroxy-1-indanone represented by the formula: The production method according to claim 1, 2 or 3, wherein the enzyme has an ability to preferentially hydrolyze one of the (R) form and the (S) form. 5. The method according to claim 1, wherein the enzyme is Achromobacter sp.
chromobacter sp. ), Alkaligenes
SP (Alcaligenes sp.), Aspergillus niger
r), Aspergillus oryzae
us oryzae), Brucordelia sp. (B
urkholderia sp. ), Candida Antarctic
a), Candida Sylindrasse
cylindracea, Candida utilis, Chromobacterium chromobacterium
viscosum), Humicola Langinosa (Hu)
michola langinosa), Mucor miehei, Pseudomonas
Sepacia (Pseudomonas cepaci)
a), Pseudomon sp.
as sp. ), Rhizomucor My High (Rhizo)
mucor miehei), Rhizopus alitus (R
hizopus arhizus, Rhizopus sp., Thermus aquaticus, Thermus flubus, Thermus thermophils (Thermus thermo)
philus), lipase derived from pig pancreas or Aspergillus meleus (Aspergillus mel)
leus), an aminoacylase derived from pig kidney, Aspergillus meleus
eus), Aspergillus niger (Aspergil)
rus niger) and Aspergillus oryzae (A
spergillus oryzae), Aspergillus sp., Bacillus lic.
4. The method according to claim 1, 2 or 3, wherein the method is a protease derived from pig pancreas or an esterase derived from pig liver.