Title of Invention	PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE (S OR R)-α-AMINO ACID OR OPTICALLY ACTIVE (S OR R)-α-AMINO ACID ESTER
Abstract	The present invention discloses a process for preparing an optically active (S or R)-α-amino acid represented by the formula (II): wherein R represents an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aralkyl group, heteroarylalkyl group, aryl group or heteroaryl group, each of which may have a substituent(s), and * represents an asymmetric carbon atom, and an optically active (R or S)-α-amino acid ester represented by the formula (III): wherein R1 represents an alkyl group which may have a substituent(s), and * represents an asymmetric carbon atom, provided that it has an opposite absolute configuration to that of the compound of the formula (II), which comprises selectively reacting water with one of enantiomers of an α-amino acid ester which is a racemic mixture and represented by the formula (I): wherein R and R1 have the same meanings as defined above, in the presence of a lipase or a protease in an organic solvent.

Title of Invention

PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE (S OR R)-α-AMINO ACID OR OPTICALLY ACTIVE (S OR R)-α-AMINO ACID ESTER

Abstract

The present invention discloses a process for preparing an optically active (S or R)-α-amino acid represented by the formula (II): wherein R represents an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aralkyl group, heteroarylalkyl group, aryl group or heteroaryl group, each of which may have a substituent(s), and * represents an asymmetric carbon atom, and an optically active (R or S)-α-amino acid ester represented by the formula (III): wherein R1 represents an alkyl group which may have a substituent(s), and * represents an asymmetric carbon atom, provided that it has an opposite absolute configuration to that of the compound of the formula (II), which comprises selectively reacting water with one of enantiomers of an α-amino acid ester which is a racemic mixture and represented by the formula (I): wherein R and R1 have the same meanings as defined above, in the presence of a lipase or a protease in an organic solvent.

Full Text	1 SPECIFICATION PROCESS FOR PREPARING OPTICALLY ACTIVE (S OR R)-α-AMINO ACID AND OPTICALLY ACTIVE (R OR S)-α-AMINO ACID ESTER TECHNICAL FIELD [0001] The present invention relates to a process for simultaneously preparing an optically active (S or R)-α- amino acid and its antipode ester, an optically active (R or S) -α-amino acid ester, from an α-amino acid ester (racemic mixture). These optically active α-amino acid and an ester thereof are useful compounds as a starting materi- al or a synthetic intermediate of a natural substance having physiological activity or a medicine (for example, see Non-Patent Literature 1, and Patent Literatures 1 to 5) . BACKGROUND ART [0002] Heretofore, as a process for preparing an optically active α-amino acid and an ester thereof by an enantio- selective hydrolysis reaction using a lipase, there has been disclosed a method in which, for example, only one of enantiomers of various kinds of amino acid esters is selectively hydrolyzed in water in the presence of a porcine pancreatic lipase, a lipase originated from Burkholderia cepacia (Pseudomonas cepacia), or a lipase originated from Rhizopus to obtain an optically active (S)- amino acid and an optically active (R)-amino acid ester (for example, see Non-Patent Literature 2). [0003] However, according to this method, a large amount of an enzyme has been used, and there are problems that an E value which is an index of selectivity between enantiomers is generally low. When an optically active carboxylic acid 2 which is a product is water-soluble, it is difficult to recover 10 0% of the product from the aqueous solution after completion of the reaction, and yet, in the presence of a large amount of water, lowering in optical purity occurs due to self-hydrolysis reaction of the substrate. Inci- dentally, the E value has widely been utilized as an index of selectivity of kinetic optical resolution (for example, see Non-Patent Literature 3.). [0004] Also, as a conventional process for preparing an optically activeα-amino acid and an ester thereof by an enantio-selective hydrolysis reaction using a protease, there is disclosed, for example, a method in which one of the enantiomers of tyrosine ethyl ester is selectively hydrolyzed in acetonitrile in the presence of α-chymo- trypsin, subtilisin Carlsberg and subtilisin BPN' to obtain an optically active (S)-tyrosine and an optically active (R)-tyrosine ethyl ester (for example, see Non-Patent Literature 4). Here, various reactions were carried out by changing a content of water in acetonitrile, and the most preferable results can be obtained in an amount of 5 to 10% based on acetonitrile which is a solvent. [0005] However, no hydrolysis is carried out therein with a system in which a water content is extremely little as 10 equivalent or less based on an amount of the substrate. In the system used in this case, it is difficult to completely inhibit self-hydrolysis of the amino acid ester, and a substrate concentration based on the solvent is low so that it is not an industrially preferred method. [0006] Also, as a conventional process for preparing an optically activeα-amino acid and an ester thereof by an enantio-selective hydrolysis reaction using a protease, there is disclosed, for example, a method in which one of the enantiomers of tyrosine ethyl ester is selectively 3 hydrolyzed in an acetonitrile-water mixed solvent in the presence ofα-chymotrypsin, subtilisin Carlsberg and subtilisin BPN' to obtain an optically active (S)-tyrosine and an optically active (R)-tyrosine ethyl ester (for example, see Non-Patent Literature 4). Here, various reactions were carried out by changing a water content in acetonitrile, and the most preferred results can be obtained in an amount of 5 to 10% (v/v) of water based on acetonitrile which is a solvent. [0007] However, in the above-mentioned reaction systems, no hydrolysis is carried out with a system in which a water content is extremely little as 10 equivalent or less based on an amount of the substrate, nor referred to at all. In the system used in this case, an amount of water used as a substrate is still large, it is difficult to completely inhibit self-hydrolysis of the amino acid ester, and a substrate concentration based on the solvent is low so that it is not an industrially preferred method. Non-Patent Literature 1: J. Med. Chem., 46, 4533 (2003) Non-Patent Literature 2: Chirality, 8, 418 (1996) Non-Patent Literature 3: J. Am. Chem. Soc, 104, 72 94 (1982) Non-Patent Literature 4: Biotechnology Letters, 13, (5), 317 (1991) Non-Patent Literature 5: "Chemical Dictionary", published by Tokyo Kagaku Dojin Co., Ltd., p.94 8 (2000) Patent Literature 1: WO 9706162 Patent Literature 2: WO 2005063198 Patent Literature 3: WO 2004084812 Patent Literature 4: WO 9803473 Patent Literature 5: WO 2005051304 DISCLOSURE OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION 4 [0008] An object of the present invention is to solve the above-mentioned problems, and to provide a process for preparing an optically active (S or R)-α-amino acid and its antipode ester, an optically active (R or S)-α-amino acid ester, simultaneously from anα-amino acid ester (racemic mixture) according to hydrolysis using an enzyme with a simple and easy method, and a high E value. MEANS TO SOLVE THE PROBLEMS [0009] Heretofore, a preparation of an optically activeα- amino acid by enantio-selective hydrolysis of anα-amino acid ester (racemic mixture) is generally carried out by a method in which, a large amount of water and a racemic p- amino acid ester are reacted in a solvent mainly comprising water in the presence of a hydrolase. This is because, in hydrolysis of a racemicα-amino acid ester which is a substrate, it has been considered that a larger amount of water proceeds the reaction. The present inventors have earnestly studied to solve the problems as previously mentioned, and as a result, they have found out a novel reaction system, which can substantially and completely inhibit self-hydrolysis of a substrate (p-amino acid ester) which is easily hydrolyzed by water, which causes lowering in an optical purity, and can completely recover the optically activeα-amino acid which is generally considered to be difficult to obtain solely due to its water-solu- bility, which is improved in yield, selectivity, operat- ability, etc. as compared with the conventional techniques, and which is more advantageous as an industrial preparation method, which can be accomplished by reacting water and anα-amino acid ester (racemic mixture) in an organic solvent in the presence of a lipase or a protease. [0010] The present invention relates to a process for 5 preparing an optically active (S or R)-α-amino acid repre- sented by the formula (II): wherein R represents an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aralkyl group, a heteroarylalkyl group, an aryl group or a heteroaryl group, each of which may have a substituent(s), and * represents an asymmetric carbon atom, and an optically active (R or S)-α-amino acid ester repre- sented by the formula (III): 0 NH2 wherein R has the same meaning as defined above, R1 represents an alkyl group which may have a substi- tuent (s), and * represents an asymmetric carbon atom, provided that it has an opposite absolute con- figuration to that of the compound of the formula (ID, which comprises selectively reacting water with one of enantiomers of anα-amino acid ester which is a racemic mixture and represented by the formula (I): wherein R and R1 have the same meanings as defined above, 6 in the presence of a lipase or a protease in an organic solvent. [0011] The present invention also relates to a process for preparing an acid salt of an optically active (R or S) -ex- am i no acid ester, which comprises separating each of the optically active (S or R) -ot-amino acid represented by the above-mentioned formula (II): wherein R has the same meaning as defined above, and * represents an asymmetric carbon atom, and the optically active (R or S)-α-amino acid ester repre- sented by the above-mentioned formula (III): wherein R and R1 have the same meanings as defined above, and * represents an asymmetric carbon atom, provided that it has an opposite absolute configuration to that of the compound of the formula (ID, formed by the above-mentioned reaction from a mixture thereof, and reacting the resulting optically active (R or S)-α-amino acid ester with an acid. EFFECTS OF THE INVENTION [0012] According to the present invention, it can be provided a process for preparing an optically active (S or R)-α-amino acid and its antipode ester, an optically active 7 (R or S)-α-amino acid ester, simultaneously from anα- amino acid ester (racemic mixture) by a hydrolysis reaction using an enzyme according to a simple and easy method with a high E value. BEST MODE FOR CARRYING OUT THE INVENTION [0013] R in Compound (I) represents an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aralkyl group, heteroarylalkyl group, aryl group or heteroaryl group, each of which may have a substituent(s). [0014] The alkyl group of the alkyl group which may have a substituent(s) in the above-mentioned R is a linear or branched alkyl group having 1 to 10 carbon atoms, and there may be mentioned, for example, an alkyl group such as a methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group and decyl group, etc., preferably an alkyl group having 1 to 8 carbon atoms such as a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group and n-octyl group, etc., more preferably an alkyl group having 1 to 2 carbon atoms such as a methyl group and ethyl group, etc. Incidentally, these groups contain various kinds of isomers. [0015] The substituent(s) for the alkyl group which may have a substituent(s) may be mentioned, for example, a halogen atom such as a fluorine atom, chlorine atom, bromine atom, iodine atom, etc.; a hydroxyl group; an alkoxyl group having 1 to 4 carbon atoms such as a methoxyl group, ethoxyl group, propoxyl group, butoxyl group, etc.; an amino group; and a dialkylamino group which is disubstituted by alkyl groups having 1 to 6 carbon atoms such as a dimethylamino group, diethylamino group, etc.; a cyano group; and a nitro group, preferably a fluorine atom, 8 chlorine atom, hydroxy group, amino group and dialkylamino group. [0016] Such an alkyl group having the above-mentioned substituent(s) may be specifically mentioned, for example, a fluoromethyl group, chloromethyl group, hydroxymethyl group, methoxymethyl group, aminomethyl group, dimethyl- aminomethyl group, 2-chloroethyl group, 2,2-dichloroethyl group, 2-hydroxyethyl group and 2-cyanoethyl group, etc., preferably a fluoromethyl group, chloromethyl group, hydroxymethyl group, aminomethyl group, dimethylaminomethyl group, 2-chloroethyl group and 2-cyanoethyl group. [0017] The alkenyl group of the alkenyl group which may have a substituent(s) in the above-mentioned R is men- tioned, for example, an alkenyl group having 2 to 10 carbon atoms such as a vinyl group, propenyl group, butenyl group, pentenyl group, hexenyl group, heptenyl group, octenyl group, nonenyl group and decenyl group, etc., preferably an alkenyl group having 2 to 5 carbon atoms such as a vinyl group, propenyl group, butenyl group and pentenyl group, etc., more preferably an alkenyl group having 2 to 3 carbon atoms such as a vinyl group, 1-propenyl group and 2- propenyl group, etc. Incidentally, these groups contain various kinds of isomers. [0018] The substituent(s) for the alkenyl group which may have a substituent(s) may be mentioned, for example, a halogen atom such as a fluorine atom, chlorine atom, bromine atom, iodine atom, etc.; a hydroxyl group,- an alkoxyl group having 1 to 4 carbon atoms such as a methoxyl group, ethoxyl group, propoxyl group, butoxyl group, etc.; amino group; and a dialkylamino group which is disubstituted by alkyl groups having 1 to 6 carbon atoms such as a dimethylamino group, diethylamino group, etc.; a cyano group; and a nitro group, preferably a fluorine atom, 9 chlorine atom, hydroxy group, amino group and dialkylamino group. [0019] Such an alkenyl group having the above-mentioned substituent(s) may be specifically mentioned, for example, a 1-fluoroethenyl group, 1-chloroethenyl group, 1-hydroxy- ethenyl group, 1-methoxyethenyl group, 1-aminoethenyl group, 1-cyanoethenyl group, 2-fluoroethenyl group, 2- chloroethenyl group, 2-hydroxyethenyl group, 2-methoxy- ethenyl group, 2-aminoethenyl group, 2-cyanoethenyl group, 1,2-dimethylaminoethenyl group, 1-fluoro-2-propenyl group, l-chloro-2-propenyl group, 1-hydroxy-2-propenyl group, 1- methoxy-2-propenyl group, l-amino-2-propenyl group, 1- cyano-2-propenyl group, 3-fluoro-1-propenyl group, 3- chloro-1-propenyl group, 3-hydroxy-2-propenyl group, 3- methoxy-2-propenyl group, 3-amino-2-propenyl group, 2- cyano-2-propenyl group, 3,3-dimethylamino-2-propenyl group and 3,3-dichloro-2-propenyl group, etc., preferably a 1- fluoroethenyl group, 1-chloroethenyl group, 1-hydroxy- ethenyl group, 1-aminoethenyl group, 1-cyanoethenyl group, 1-fluoro-2-propenyl group, l-chloro-2-propenyl group and 1- cyano-2-propenyl group. [0020] The alkynyl group of the alkynyl group which may have a substituent(s) in the above-mentioned R may be mentioned, for example, an alkynyl group having 2 to 10 carbon atoms such as an ethynyl group, propynyl group, butynyl group, pentynyl group, hexynyl group, heptynyl group, octynyl group, nonynyl group and decynyl group, etc., preferably an alkynyl group having 2 to 5 carbon atoms such as an ethynyl group, propynyl group, butynyl group and pentynyl group, etc., more preferably an alkynyl group having 2 or 3 carbon atoms such as an ethynyl group, 1-propynyl group and 2-propynyl group, etc. Incidentally, these groups contain various kinds of isomers. [0021] 10 The substituent (s) for the alkynyl group which may- have a substituent(s) may be mentioned, for example, a halogen atom such as a fluorine atom, chlorine atom, bromine atom, iodine atom, etc.; a hydroxyl group; an alkoxyl group having 1 to 4 carbon atoms such as a methoxyl group, ethoxyl group, propoxyl group, butoxyl group, etc.; an amino group,- a dialkylamino group which is disubstituted by alkyl groups having 1 to 6 carbon atoms such as a di- methylamino group, diethylamino group, etc.; a cyano group; and a nitro group, preferably a fluorine atom, chlorine atom, hydroxy group, amino group and dialkylamino group. [0022] Such an alkynyl group which may have a substitu- ent (s) may be specifically mentioned, for example, a 2- fluoroethynyl group, 2-chloroethynyl group, 2-hydroxy- ethynyl group, 2-methoxyethynyl group, 2-aminoethynyl group, 2-cyanoethynyl group, 1-fluoro-2-propynyl group, 1- chloro-2-propynyl group, 1-hydroxy-2-propynyl group, 1- methoxy-2-propynyl group, 1-amino-2-propynyl group, 1- cyano-2-propynyl group, 1,1-dichloro-2-propynyl group and 1,l-diamino-2-propynyl group, etc., preferably a 2-fluoro- ethynyl group, 2-chloroethynyl group, 2-hydroxyethynyl group, 2-aminoethynyl group, 1-fluoro-2-propynyl group and 1,1-dichloro-2-propynyl group. [0023] The cycloalkyl group of the cycloalkyl group which may have a substituent(s) in the above-mentioned R may be mentioned a cycloalkyl group having 3 to 10 carbon atoms, and there may be mentioned, for example, a cycloalkyl group such as a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group and cyclodecyl group, etc. (Inci- dentally, these groups contain various kinds of isomers.), preferably a cycloalkyl group having 3 to 8 carbon atoms such as a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and cyclooctyl 11 group, etc., more preferably a cycloalkyl group having 3 to 6 carbon atoms such as a cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group, etc. [0024] The substituent(s) for the cycloalkyl group which may have a substituent(s) may be mentioned an alkyl group having 1 to 6 carbon chain atoms, a halogen atom such as a fluorine atom, chlorine atom, bromine atom, iodine atom, etc.; a hydroxyl group; an alkoxyl group having 1 to 4 carbon atoms such as a methoxyl group, ethoxyl group, propoxyl group, butoxyl group, etc.; an amino group; a dialkylamino group which is disubstituted by alkyl groups having 1 to 6 carbon atoms such as a dimethylamino group, diethylamino group, etc.; a cyano group; and a nitro group, preferably a fluorine atom, chlorine atom, hydroxy group, amino group and dialkylamino group. [0025] Such a cycloalkyl group which may have a substitu- ent (s) may be specifically mentioned, for example, a 1- fluorocyclopropyl group, 2-chlorocyclopropyl group, 3- fluorocyclobutyl group, methoxycyclopropyl group, amino- cyclopentyl group, dimethylaminocyclohexyl group, 2-chloro- cyclopropyl group, 2,2-dichlorocyclohexyl group, 2-hydroxy- cyclobutyl group and 2-cyanocyclohexyl group, etc., prefer- ably a fluorocyclopropyl group and chlorocyclobutyl group. [0026] The aralkyl group of the aralkyl group which may have a substituent(s) in the above-mentioned R may be mentioned, for example, an aralkyl group in which an alkyl group having 1 to 6 carbon atoms is substituted by an aryl group having 6 to 14 carbon atoms, such as a benzyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, phenethyl group, phenylpropyl group and phenylbutyl group, etc., preferably an aralkyl group in which an alkyl group having 1 to 4 carbon atoms is substituted by an aryl group, such as a benzyl group, 1-naphthylmethyl group, 2-naphthylmethyl 12 group, 1-phenethyl group, 2-phenethyl group, 3-phenylpropyl group and 3-phenylbutyl group, etc., particularly prefer- ably an aralkyl group in which a methyl group is substi- tuted by an aryl group, such as a benzyl group, 1-naphthyl- methyl group, 2-naphthylmethyl group, etc. Incidentally, these groups contain various kinds of isomers. [0027] The substituent(s) for the aralkyl group which may have a substituent(s) may be mentioned, for example, an alkyl group having 1 to 10 carbon atoms such as a methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, etc. (Incidentally, these groups contain various kinds of isomers.); a hydroxyl group; a nitro group,- a halogen atom such as a fluorine atom, chlorine atom, bromine atom, iodine atom, etc.; an alkoxyl group having 1 to 10 carbon atoms such as a methoxyl group, ethoxyl group, propoxyl group, butoxyl group, pentyloxyl group, hexyloxyl group, heptyloxyl group, octyloxyl group, nonyloxyl group, decyloxyl group, etc. (Incidentally, these groups contain various kinds of isomers.); an aralkyloxyl group having 7 to 10 carbon atoms such as a benzyloxyl group, phenethyloxyl group, phenylpropoxy group, etc. (Incidentally, these groups contain various kinds of isomers.); an aryloxyl group having 6 to 2 0 carbon atoms such as a phenyloxyl group, naphthyloxyl group, etc. (Incidentally, these groups contain various kinds of isomers.); an alkoxyalkoxyl group having 2 to 12 carbon atoms such as a methoxymethoxyl group, methoxyethoxyl group, etc. (Incidentally, these groups contain various kinds of isomers.); a monoalkylamino group such as a methylamino group, ethylamino group, etc. (Incidentally, these groups contain various kinds of isomers.); a dialkyl- amino group which is disubstituted by alkyl groups having 1 to 6 carbon atoms such as a dimethylamino group, diethyl- amino group, etc. (Incidentally, these groups contain 13 various kinds of isomers.); an acylaraino group having 1 to 12 carbon atoms such as a formylamino group, acetylamino group, benzoylamino group, etc. (Incidentally, these groups contain various kinds of isomers.); a nitro group; a cyano group; and a halogenated alkyl group having 1 to 12 carbon atoms such as a trifluoromethyl group, etc. [0028] As an aralkyl group having such a substituent(s), there may be specifically mentioned, for example, a 2- fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 3,4-difluorobenzyl group, 2,4-difluorobenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2,4-dichlorobenzyl group, 3,4-dichlorobenzyl group, 2-bromobenzyl group, 3-bromobenzyl group, 4-bromobenzyl group, 2,4-dibromobenzyl group, 3,4-dibromobenzyl group, 2- iodobenzyl group, 3-iodobenzyl group, 4-iodobenzyl group, 2,3-diiodobenzyl group, 3,4-diiodobenzyl group, 2-methyl- benzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 2-ethylbenzyl group, 3-ethylbenzyl group, 4-ethylbenzyl group, 2-hydroxybenzyl group, 3-hydroxybenzyl group, 4- hydroxybenzyl group, 2-methoxybenzyl group, 3-methoxybenzyl group, 4-methoxybenzyl group, 2,4-dimethoxybenzyl group, 3,4-dimethoxybenzyl group, 2-ethoxybenzyl group, 4-ethoxy- benzyl group, 2-trifluoromethylbenzyl group, 4-trifluoro- methylbenzyl group, 4-benzyloxybenzyl group, 2-nitrobenzyl group, 3-nitrobenzyl group, 4~nitrobenzyl group, 2-cyano- benzyl group, 3-cyanobenzyl group, 4-cyanobenzyl group, 4- dimethylaminobenzyl group, 4-formylaminobenzyl group, 2- acetylaminobenzyl group, 3-acetylaminobenzyl group, 4- acetylaminobenzyl group, 4-benzoylaminobenzyl group, 1- naphthylmethyl group, 2-naphthylmethyl group, 2-(2-fluoro- phenyl)ethyl group, 2-(3-fluorophenyl)ethyl group, 2-(4- fluorophenyl)ethyl group, 2-(3,4-difluorophenyl)ethyl group, 2-(2,4-difluorophenyl)ethyl group, 2-(2-chloro- phenyl)ethyl group, 2-(3-chlorophenyl)ethyl group, 2-(4- chlorophenyl)ethyl group, 2-(2,4-dichlorophenyl)ethyl 14 group, 2-(3,4-dichlorophenyl)ethyl group, 2-(2-bromo- phenyl)ethyl group, 2-(3-bromophenyl)ethyl group, 2-(4- bromopheny1)ethyl group, 2 -(2,4 -dibromophenyl)ethyl group, 2 -(3,4 -dibromophenyl)ethyl group, 2 -(2 -iodophenyl)ethyl group, 2 -(3 -iodophenyl)ethyl group, 2 -(4 -iodophenyl)ethyl group, 2-(2,3-diiodophenyl)ethyl group, 2-(3,4-diiodo- phenyl)ethyl group, 2-(2-tolyl)ethyl group, 2-(3-tolyl)- ethyl group, 2-(4-tolyl)ethyl group, 2-(2-ethylphenyl)ethyl group, 2-(3-ethylphenyl)ethyl group, 2-(4-ethylphenyl)ethyl group, 2-(2-hydroxyphenyl)ethyl group, 2-(4-hydroxyphenyl)- ethyl group, 2-(2-methoxyphenyl)ethyl group, 2-(3-methoxy- phenyl)ethyl group, 2-(4-methoxyphenyl)ethyl group, 2-(2,4- dimethoxyphenyl)ethyl group, 2-(3,4-dimethoxyphenyl)ethyl group, 2-(2-ethoxyphenyl)ethyl group, 2-(4-ethoxyphenyl)- ethyl group, 2-(2-trifluoromethylphenyl)ethyl group, 2-(4- trifluoromethylphenyl)ethyl group, 2-(4-benzyloxyphenyl)- ethyl group, 2-(2-nitrophenyl)ethyl group, 2-(3-nitro- phenyl)ethyl group, 2-(4-nitrophenyl)ethyl group, 2-(2- cyanophenyl)ethyl group, 2-(3-cyanophenyl)ethyl group, 2- (4-cyanopheny1)ethyl group, 2-(4-dimethylaminophenyl)ethyl group, 2 -(4 -formylaminophenyl)ethyl group, 2-(2 -acetyl- aminophenyl)ethyl group, 2-(3-acetylaminophenyl)ethyl group, 2-(4-acetylaminophenyl)ethyl group, 2-(4-benzoyl- aminophenyl)ethyl group, 3-(2-fluorophenyl)propyl group, 3- (4-fluorophenyl)propyl group, 3-(4-chlorophenyl)propyl group, 3-(4-bromophenyl)propyl group, 3-(4-iodophenyl)- propyl group, 3-(2-chlorophenyl)propyl group, 3-(2-methoxy- phenyl ) propyl group, 3-(4-methoxyphenyl)propyl group, 3- (3,4-dimethoxyphenyl)propyl group, 3-(4-trifluoromethyl- phenyl ) propyl group, 3-(2-trifluoromethylphenyl)propyl group, 3-(4-nitrophenyl)propyl group, 3-(4-cyanophenyl)- propyl group and 3-(4-acetylaminophenyl)propyl group, etc., preferably a 2-fluorobenzyl group, 3-fluorobenzyl group, 4- fluorobenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2-bromobenzyl group, 3-bromo- benzyl group, 4-bromobenzyl group, 2-iodobenzyl group, 3- 15 iodobenzyl group, 4-iodobenzyl group, 2-methylbenzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 2-hydroxybenzyl group, 4-hydroxybenzyl group, 2-methoxybenzyl group, 3- methoxybenzyl group, 4-methoxybenzyl group, 3,4-dimethoxy- benzyl group, 2-trifluoromethylbenzyl group, 4-trifluoro- methylbenzyl group, 4-benzyloxybenzyl group, 2-nitrobenzyl group, 3-nitrobenzyl group, 4-nitrobenzyl group, 2-cyano- benzyl group, 3-cyanobenzyl group, 4-cyanobenzyl group, 4- formylaminobenzyl group, 3-acetylaminobenzyl group, 4- acetylaminobenzyl group, 4-benzoylaminobenzyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, 2-(2- fluorophenyl)ethyl group, 2-(3-fluorophenyl)ethyl group, 2- (4 -fluorophenyl)ethyl group, 2 -(2-chlorophenyl)ethyl group, 2-(3-chlorophenyl)ethyl group, 2-(4-chlorophenyl)ethyl group, 2-(2-bromophenyl)ethyl group, 2-(3-bromophenyl)ethyl group, 2-(4-broraophenyl)ethyl group, 2-(2-iodophenyl)ethyl group, 2 -(3 -iodophenyl)ethyl group, 2-(4 -iodophenyl)ethyl group, 2-(2-tolyl)ethyl group, 2-(3-tolyl)ethyl group, 2- (4-tolyl)ethyl group, 2-(2-ethylphenyl)ethyl group, 2-(2- hydroxyphenyl)ethyl group, 2-(4-hydroxyphenyl)ethyl group, 2 -(2-methoxyphenyl)ethyl group, 2-(3-methoxyphenyl)ethyl group, 2-(4-methoxyphenyl)ethyl group, 2-(2,4-dimethoxy- phenyl)ethyl group, 2-(3,4-dimethoxyphenyl)ethyl group, 2- (2-trifluoromethylphenyl)ethyl group, 2-(4-trifluoromethyl- phenyl)ethyl group, 2-(4-benzyloxyphenyl)ethyl group, 2-(2- nitrophenyl)ethyl group, 2-(3-nitrophenyl)ethyl group, 2- (4-nitrophenyl)ethyl group, 2-(2-cyanopheny1)ethyl group, 2 -(3 -cyanopheny1)ethyl group, 2 -(4 -cyanopheny1)ethyl group, 2-(2-acetylaminophenyl)ethyl group, 2-(3-acetylamino- phenyl)ethyl group, 2-(4-acetylaminophenyl)ethyl group, 2- (4-benzoylaminophenyl)ethyl group, 3-(2-fluorophenyl)propyl group, 3-(4-fluorophenyl)propyl group, 3-(4-chlorophenyl)- propyl group, 3-(4-bromophenyl)propyl group, 3-(4-iodo- phenyl)propyl group, 3-(2-chlorophenyl)propyl group, 3-(2- methoxyphenyl)propyl group, 3-(4-methoxyphenyl)propyl group, 3-(3,4-dimethoxyphenyl)propyl group, 3-(4-trifluoro- 16 methylphenyDpropyl group, 3-(2-trifluoromethylphenyl)- propyl group, 3-(4-nitrophenyl)propyl group, 3-(4-cyano- phenyl)propyl group and 3-(4-acetylaminophenyl)propyl group, more preferably a 2-fluorobenzyl group, 4-fluoro- benzyl group, 2-chlorobenzyl group, 4-chlorobenzyl group, 2-bromobenzyl group, 4-bromobenzyl group, 2-iodobenzyl group, 4-iodobenzyl group, 2-methylbenzyl group, 4-methyl- benzyl group, 4-hydroxybenzyl group, 2-methoxybenzyl group, 4-methoxybenzyl group, 3,4-dimethoxybenzyl group, 2-tri- fluoromethylbenzyl group, 4-trifluoromethylbenzyl group, 4- benzyloxybenzyl group, 2-nitrobenzyl group, 4-nitrobenzyl group, 2-cyanobenzyl group, 3-cyanobenzyl group, 4-cyano- benzyl group, 3-acetylaminobenzyl group, 4-acetylamino- benzyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, 2-(2-fluorophenyl)ethyl group, 2-(4-fluorophenyl)- ethyl group, 2-(2-chlorophenyl)ethyl group, 2-(4-chloro- phenyl)ethyl group, 2-(2-bromophenyl)ethyl group, 2-(4- bromophenyl)ethyl group, 2-(2-iodophenyl)ethyl group, 2-(4- iodophenyl)ethyl group, 2-(2-tolyl)ethyl group, 2-(4- tolyDethyl group, 2-(4-hydroxyphenyl) ethyl group, 2-(2- methoxyphenyl)ethyl group, 2-(4-methoxyphenyl)ethyl group, 2-(3,4-dimethoxyphenyl)ethyl group, 2-(2-trifluoromethyl- phenyl) ethyl group, 2-(4-trifluoromethylphenyl)ethyl group, 2-(4-benzyloxyphenyl)ethyl group, 2-(2-nitrophenyl)ethyl group, 2-(4-nitrophenyl)ethyl group, 2-(2-cyanopheny1)ethyl group, 2-(4-cyanophenyl)ethyl group, 2-(2-acetylamino- phenyl) ethyl group and 2-(4-acetylaminophenyl)ethyl group), particularly preferably 2-fluorobenzyl group, 4-fluoro- benzyl group, 2-chlorobenzyl group, 4-chlorobenzyl group, 2-bromobenzyl group, 4-bromobenzyl group, 2-iodobenzyl group, 4-iodobenzyl group, 2-methylbenzyl group, 4-methyl- benzyl group, 4-hydroxybenzyl group, 2-methoxybenzyl group, 4-methoxybenzyl group, 3,4-dimethoxybenzyl group, 2-tri- fluoromethylbenzyl group, 4-trifluoromethylbenzyl group, 4- benzyloxybenzyl group, 2-nitrobenzyl group, 4-nitrobenzyl group, 2-cyanobenzyl group, 3-cyanobenzyl group, 4-cyano- 17 benzyl group, 3-acetylaminobenzyl group, 4-acetylamino- benzyl group, 1-naphthylmethyl group and 2-naphthylmethyl group. [0029] The heteroarylalkyl group of the heteroarylalkyl group which may have a substituent in the above-mentioned R may be mentioned, for example, a heteroarylalkyl group in which an alkyl group having 1 to 6 carbon atoms is substi- tuted by a heteroaryl group having 6 to 14 carbon atoms, such as a 2-pyridylmethyl group, 3-pyridylmethyl group, 3- pyridylmethyl group, 2-thienylmethyl group, 3-thienylmethyl group, 2-imidazolyl group, 4-imidazolyl group, 2-thienyl- methyl group, 3-indolylmethyl group, 2-pyridylethyl group, 2-thienylethyl group, 2-pyridylpropyl group, 2-pyridylbutyl group, etc., preferably a heteroarylalkyl group in which an alkyl group having 1 to 2 carbon atoms is substituted by a heteroaryl group, such as a 2-pyridylmethyl group, 2- thienylmethyl group, 3-indolylmethyl group, 2-pyridylethyl group, 2-thienylethyl group, etc., more preferably a heteroarylalkyl group in which a methyl group is substitut- ed by a heteroarylalkyl group, such as a 2-pyridylmethyl group, 2-thienylmethyl group, 3-indolylmethyl group, etc. Incidentally, these groups contain various kinds of isomers. [0030] The heteroaryl group of the heteroarylalkyl group which may have a substituent(s) in the above-mentioned R may be mentioned, for example, a 2-furyl group, 3-furyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-thienyl group, 3- thienyl group, 2-indolyl group, 3-indolyl group, 2-imid- azolyl group, 4-imidazolyl group, 3-pyrazolyl group, 2- pyrimidyl group, 4-pyrimidyl group, 2-quinolyl group and 3- quinolyl group. [0031] The substituent(s) for the heteroaryl group which 18 may have a substituent(s) may be mentioned an alkyl group having 1 to 4 carbon atoms such as a methyl group, ethyl group, propyl group, butyl group, etc. (Incidentally, these groups contain various kinds of isomers.); a hydroxyl group; a halogen atom such as a chlorine atom, bromine atom, iodine atom, fluorine atom, etc.; an alkoxyl group having 2 to 4 carbon atoms such as an ethoxyl group, etc. (Incidentally, these groups contain various kinds of isomers.); an amino group; a nitro group; a cyano group; and a halogenated alkyl group having 1 to 4 carbon atoms such as a trifluoromethyl group, etc. [0032] Such a heteroaryl group which may have a substi- tuent (s) may be specifically mentioned, for example, a 2- (3-methyl)furyl group, 2-(4Tmethyl)furyl group, 2-(3- ethyDfuryl group, 2-(4-ethyl) furyl group, 2-(3-fluoro)- furyl group, 2-(3-chloro)furyl group, 2-(3-hydroxy)furyl group, 2-(3-methoxy)furyl group, 2-(3-amino)furyl group, 2- (3-nitro)furyl group, 2-(3-cyano)fury1 group, 2-(3-methyl)- pyridyl group, 2-(4-methyl)pyridyl group, 2-(3-ethyl)- pyridyl group, 2-(4-ethyl)pyridyl group, 2-(3-fluoro)- pyridyl group, 2-(4-chloro)pyridyl group, 2-(3-hydroxy)- pyridyl group, 2-(3-methoxy)pyridyl group, 2-(3-amino)- pyridyl group, 2-(3-nitro)pyridyl group, 2-(3-cyano)pyridyl group, 2-(3,5-dichloro)pyridyl group, 3-(2-chloro)pyridyl group, 2-(3-methyl)pyrrolyl group and 2-(3-methyl)thienyl group, etc., preferably a 2-(3-methyl)furyl group, 2-(3- fluoro)furyl group, 2-(3-methyl)pyridyl group, 2-(3- fluoro)pyridyl group, 2-(3-nitro)pyridyl group, 2-(3- cyano)pyridyl group and 2-(3,5-dichloro)pyridyl group. [0033] Such a heteroarylalkyl group which may have a sub- stituent (s) may be specifically mentioned, for example, a 2 -(3-methyl)furylmethyl group, 2 -(4-methyl)furylmethyl group, 2-(3-ethyl)furylmethyl group, 2-(4-ethyl)furylmethyl group, 2-(3-fluoro)furylmethyl group, 2-(3-chloro)furyl- 19 methyl group, 2-(3-hydroxy)furylmethyl group, 2-(3- methoxy)furylmethy1 group, 2-(3-amino)furylmethyl group, 2- (3-nitro)furylmethyl group, 2-(3-cyano)furylmethyl group, 2-(3-methyl)pyridylmethyl group, 2-(4-methyl)pyridylmethyl group, 2-(3-ethyl)pyridylmethyl group, 2-(4-ethyDpyridyl- methyl group, 2-(3-fluoro)pyridylmethyl group, 2-(4- chloro)pyridylmethyl group, 2-(3-hydroxy)pyridylmethyl group, 2-(3-methoxy)pyridylmethyl group, 2-(3-amino)- pyridylmethyl group, 2-(3-nitro)pyridylmethyl group, 2-(3- cyano)pyridylmethyl group, 2-(3,5-dichloro)pyridylmethyl group, 3-(2-chloro)pyridylmethyl group, 2-(3-methyl)- pyrrolylmethyl group and 2-(3-methyl)thienylmethyl group, etc., preferably a 2-(3-methyl)furylmethyl group, 2-(3- fluoro)furylmethyl group, 2-(3-methyl)pyridylmethyl group, 2-(3-fluoro)pyridylmethyl group, 2-(3-nitro)pyridyl group, 2-(3-cyano)pyridylmethyl group and 2-(3 , 5-dichloro)pyridyl- methyl group. [0034] The aryl group of the aryl group which may have a substituent(s) in the above-mentioned R may be mentioned a phenyl group, naphthyl group, anthranyl group, phenanthryl group, biphenyl group and binaphthyl group. [0035] The substituent(s) for the aryl group which may have a substituent(s) may be mentioned an alkyl group having 1 to 4 carbon atoms such as a methyl group, ethyl group, propyl group, butyl group, etc. (Incidentally, these groups contain various kinds of isomers.); a hydroxyl group; a halogen atom such as a chlorine atom, bromine atom, iodine atom, fluorine atom, etc.; an alkoxyl group having 2 to 4 carbon atoms such as an ethoxyl group, etc. (Incidentally, these groups contain various kinds of isomers.); an alkyl- enedioxy group having 1 to 4 carbon atoms such as a methylenedioxy group, etc.; a nitro group; a cyano group; and a halogenated alkyl group having 1 to 4 carbon atoms such as a trifluoromethyl group, etc. 20 [0036] Such an aryl group which may have a substituent(s) may be specifically mentioned, for example, a 2-tolyl group, 3-tolyl group, 4-tolyl group, 2,3-xylyl group, 2,6- xylyl group, 2,4-xylyl group, 3,4-xylyl group, mesityl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4- hydroxyphenyl group, 2,3-dihydroxyphenyl group, 2,4- dihydroxyphenyl group, 3,4-dihydroxyphenyl group, 2-chloro- phenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 3,4- dichlorophenyl group, 3,5-dichlorophenyl group, 2-bromo- phenyl group, 3-bromophenyl group, 4-bromophenyl group, 2- iodophenyl group, 3-iodophenyl group, 4-iodophenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2,3-difluorophenyl group, 2,4-difluorophenyl group, 3,4-difluorophenyl group, 3-bromo-5-chloro-2-hydroxyphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4- methoxyphenyl group, 2,3-dimethoxyphenyl group, 2,4- dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 3,5- dimethoxyphenyl group, 3,4-methylenedioxyphenyl group, 4- ethoxyphenyl group, 4-butoxyphenyl group, 4-isopropoxy- phenyl group, 1-phenoxyphenyl group, 4-benzyloxyphenyl group, 4-trifluoromethylphenyl group, 2-nitrophenyl group, 3-nitrophenyl group, 4-nitrophenyl group, 4-cyanopheny1 group, 4-methoxycarbonylphenyl group, 1-naphthyl group and 2-naphthyl group, etc., preferably a phenyl group, 2-tolyl group, 3-tolyl group, 4-tolyl group, 2,3-xylyl group, 2- hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2,3-dihydroxyphenyl group, 2,4-dihydroxyphenyl group, 3,4-dihydroxyphenyl group, 2-chlorophenyl group, 3- chlorophenyl group, 4-chlorophenyl group, 2,3-dichloro- phenyl group, 2,4-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 2-bromophenyl group, 3- bromophenyl group, 4-bromophenyl group, 2-iodophenyl group, 3-iodophenyl group, 4-iodophenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 3,4- 21 difluorophenyl group, 3-bromo-5-chloro-2-hydroxyphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4- methoxyphenyl group, 2,3-dimethoxyphenyl group, 2,4- dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 3,5- dimethoxyphenyl group, 3,4-methylenedioxyphenyl group, 4- ethoxyphenyl group, 4-trifluoromethylphenyl group, 4- nitrophenyl group, 4-cyanophenyl group, 1-naphthyl group and 2-naphthyl group, more preferably phenyl group, 2-tolyl group, 3-tolyl group, 4-tolyl group, 2,3-xylyl group, 4- hydroxyphenyl group, 3,4-dihydroxyphenyl group, 2-chloro- phenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 3,4- dichlorophenyl group, 3,5-dichlorophenyl group, 2-bromo- phenyl group, 3-bromophenyl group, 4-bromophenyl group, 4- iodophenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 3,4-difluorophenyl group, 2- iodophenyl group, 3-iodophenyl group, 4-iodophenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxy- phenyl group, 2,3-dimethoxyphenyl group, 2,4-dimethoxy- phenyl group, 3,4-dimethoxyphenyl group, 3,5-dimethoxy- phenyl group, 3,4-methylenedioxyphenyl group, 4-trifluoro- methylphenyl group, 4-nitrophenyl group, 1-naphthyl group, 2-naphthyl group and 3-pyridyl group, particularly prefer- ably phenyl group, 2-tolyl group, 3-tolyl group, 4-tolyl group, 2,3-xylyl group, 2-chlorophenyl group, 3-chloro- phenyl group, 4-chlorophenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 2-bromophenyl group, 3-bromo- phenyl group, 4-bromophenyl group, 2-fluorophenyl group, 3- fluorophenyl group, 4-fluorophenyl group, 3,4-difluoro- phenyl group, 2-iodophenyl group, 3-iodophenyl group, 4- iodophenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2,3-dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl group or 3,4-methylenedioxyphenyl group. [0037] 22 The heteroaryl group of the heteroaryl group which may have a substituent(s) in the above-mentioned R may be mentioned, for example, a 2-furyl group, 3-furyl group, 2- pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-thienyl group, 3-thienyl group, 2-indolyl group, 3-indolyl group, 2-imidazolyl group, 4- imidazolyl group, 3-pyrazolyl group, 2-pyrimidyl group, 4- pyrimidyl group and quinolyl group. [0038] The substituent(s) for the heteroaryl group which may have a substituent(s) may be mentioned an alkyl group having 1 to 4 carbon atoms such as a methyl group, ethyl group, propyl group, butyl group, etc. (Incidentally, these groups contain various kinds of isomers.); a hydroxyl group; a halogen atom such as a chlorine atom, bromine atom, iodine atom, fluorine atom, etc.; an alkoxyl group having 2 to 4 carbon atoms such as an ethoxyl group, etc. (Incidentally, these groups contain various kinds of isomers.); an amino group; a nitro group; a cyano group; and a halogenated alkyl group having 1 to 4 carbon atoms such as a trifluoromethyl group, etc. [0039] Such a heteroaryl group which may have a substitu- ent(s) may be specifically mentioned, for example, a 2-(3- methyl)furyl group, 2-(4-methyl)furyl group, 2-(3-ethyl)- furyl group, 2-(4-ethyl)furyl group, 2-(3-fluoro)furyl group, 2-(3-chloro)furyl group, 2-(3-hydroxy)furyl group, 2-(3-methoxy)furyl group, 2-(3-amino)furyl group, 2-(3- nitro)furyl group, 2-(3-cyano)furyl group, 2-(3-methyl)- pyridyl group, 2-(4-methyl)pyridyl group, 2-(3-ethyl)- I pyridyl group, 2-(4-ethyl)pyridyl group, 2-(3-fluoro)- pyridyl group, 2-(4-chloro)pyridyl group, 2-(3-hydroxy)- pyridyl group, 2-(3-methoxy)pyridyl group, 2-(3-amino)- pyridyl group, 2-(3-nitro)pyridyl group, 2-(3-cyano)pyridyl group, 2-(3,5-dichloro)pyridyl group, 3-(2-chloro)pyridyl group, 2-(3-methyl)pyrrolyl group and 2-(3-methyl)thienyl 23 group, etc., preferably a 2-(3-methyl)fury1 group, 2-(3- fluoro)furyl group, 2-(3-methyl)pyridyl group, 2-(3- fluoro)pyridyl group, 2-(3-nitro)pyridyl group, 2-(3- cyano)pyridyl group and 2-(3,5-dichloro)pyridyl group. [0040] R1 in Compound (I) represents an alkyl group which may have a substituent(s). [0041] The alkyl group of the alkyl group which may have a substituent(s) in the above-mentioned R1 is a linear or branched alkyl group having 1 to 10 carbon atoms, and there may be mentioned, for example, an alkyl group such as a methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group and decyl group, preferably a linear or branched alkyl group having 1 to 6 carbon atoms such as a methyl group, ethyl group, n-propyl group, isopropyl group, n- butyl group, isobutyl group, sec-butyl group, n-pentyl group, n-hexyl group, etc., more preferably a linear or branched alkyl group having 1 to 4 carbon atoms such as a methyl group, ethyl group, n-propyl group, n-butyl group, isobutyl group, etc. Incidentally, these groups contain various kinds of isomers. [0042] The substituent(s) for the alkyl group which may have a substituent(s) may be mentioned a halogen atom such as a fluorine atom, chlorine atom, bromine atom, iodine atom, etc.; a hydroxyl group; an alkoxyl group having 1 to 4 carbon atoms such as a methoxyl group, ethoxyl group, propoxyl group, butoxyl group, etc.; a dialkylamino group which is di-substituted by an alkyl group having 1 to 6 carbon atoms such as a dimethylamino group, diethylamino group, etc.; and a cyano group, preferably a fluorine atom, chlorine atom, methoxyl group, ethoxyl group, hydroxyl group and cyano group, more preferably a fluorine atom, chlorine atom, methoxyl group and ethoxyl group. 24 [0043] Such an alkyl group which may have a substituent(s) may be specifically mentioned, for example, a 2-fluoroethyl group, 2-chloroethyl group, 2,2-difluoroethyl group, 2,2- dichloroethyl group, 2,2,2-trichloroethyl group, 2,2,2- trifluoroethyl group, 2-methoxyethyl group, 2-ethoxyethyl group, methoxymethyl group, 2-hydroxyethyl group, 2-cyano- ethyl group, 2-bromoethyl group, 2-dimethylamino group, 2- chloropropyl group, 3-chloropropyl group, etc., preferably a 2-chloroethyl group, 2,2,2-trichloroethyl group, 2,2,2- trifluoroethyl group, methoxymethyl group, 2-methoxyethyl group and 2-ethoxyethyl group. [0044] A lipase to be used in the reaction of the present invention is preferably a lipase derived from microorg- anisms which can be isolatable from an yeast or bacteria, more preferably a lipase originated from Burkholderia cepacia (Pseudomonas cepacia) (for example, AMANO PS (available from AMANO ENZYME CO.), etc.) can be used. Also, a protease to be used in the reaction of the present invention may be used, for example, a protease originated from pancreas of a vertebrate, Aspergillus Olyzae, Aspergillus Melleus, Bacillus subtilis, Bacillus stearothermophilus, etc. Incidentally, the lipase or protease may be used a commercially available product as such in a natural form or as an immobilized enzyme, and it may be used alone or in admixture of two or more kinds. Also, it may be used by previously removing an enzyme-immobilizing agent contained in the commercially available product. [0045] The above-mentioned lipase or protease may be used after subjecting a commercially available product in a natural form or an immobilized enzyme to chemical treatment or physical treatment. [0046] 25 As the above-mentioned chemical treatment or physical treatment method, there may be specifically men- tioned, for example, a method in which a lipase or protease is dissolved in a buffer (an organic solvent may exist therein depending on necessity), and freeze-dried as such or after stirring, etc. Incidentally, freeze-drying means a method in which an aqueous solution or a substance con- taining a water component is rapidly frozen at a tempera- ture of a freezing point or lower, and water is removed according to sublimation by reducing a pressure to a water vapor pressure of the frozen product or lower to dry the substance (for example, see Non-Patent Literature 3). Incidentally, according to the treatment, catalyst activity (reactivity or selectivity, etc.) can be improved. [0047] The above-mentioned buffer may be mentioned, for example, an aqueous solution of an inorganic acid salt such as an aqueous sodium phosphate solution, an aqueous potas- sium phosphate solution, etc.; an aqueous solution of an organic acid salt such as an aqueous sodium acetate solution, an aqueous ammonium acetate solution, an aqueous sodium citrate solution, etc., preferably an aqueous sodium phosphate solution, an aqueous potassium phosphate solution or an aqueous ammonium acetate solution is used. Incident- ally, these buffers may be used singly or in admixture of two or more kinds. [0048] A concentration of the above-mentioned buffer is preferably 0.01 to 2 mol/L, more preferably 0.05 to 0.5 mol/L, and a pH of the buffer is preferably 4 to 9, more preferably 7 to 8.5. [0049] An amount of the buffer to be used at the time of freeze-drying is not particularly limited so long as it is a concentration that the lipase or protease is completely dissolved, and it is preferably 10 ml to 1000 ml, more 26 preferably 10 ml to 100 ml based on 1 g of the lipase or protease. [0050] An amount of the above-mentioned lipase or protease to be used is preferably 0.1 to 1000 mg, more preferably 1 to 200 mg based on 1 g of Compound (I). [0051] The reaction of the present invention can be carried out in the presence of a lipase or a protease in an organic solvent. During the reaction of the present invention, the lipase or protease pertains to the reaction by presenting substantially in a suspended state in the reaction mixture, and it may be dissolved therein without any problem. Incidentally, the terms "in an organic solvent" in the present invention mean the state in which a reaction solvent to be used in hydrolysis is an organic solvent, and a liquid portion dissolved in the organic solvent, except for a lipase or protease (which may sometimes include an immobilizing agent) and a product precipitated as crystals, etc., does not cause phase separation from the reaction system (that is, a state in which water (it may contain an inorganic salt or organic salt mentioned hereinbelow), a substrate and an organic solvent comprises a single phase). [0052] As water to be used in the reaction of the present invention, purified water such as deionized water, distil- led water, etc. is generally used, and the water may con- tain an inorganic salt such as sodium phosphate, potassium phosphate, etc., or an organic salt such as sodium acetate, ammonium acetate, sodium citrate, etc. An amount of these inorganic salts and organic salts to be used is preferably in an amount of 0.01 to 10 mol/L, more preferably 0.1 to 1 mol/L based on the amount of water. Incidentally, the above-mentioned inorganic salt or organic salt is previous- ly dissolved in water to prepare a buffer and the buffer may be used in the reaction without any problem. 27 [0053] An amount of the above-mentioned water is an amount equal to or less than the solubility (an amount capable of dissolving) of water in an organic solvent to be used (if the amount exceeds the solubility, phase separation of the liquid portion occurs), and an upper limit thereof may somewhat vary depending on the kind of Compound (I), and preferably 0.5 to 10 mol, more preferably 0.5 to 5.0 mol, further preferably 1.0 to 3.0 mol, particularly preferably 1.5 to 2.5 mol based on 1 mol of Compound (I). Incidental- ly, whereas it may vary deepening on the kind of Compound (I), when an amount of the water to be used exceeds 10 mol based on 1 mol of Compound (I), undesirable states occurs, for example, self-hydrolysis of Compound (I) which lowers an optical purity, elongation of the reaction time due to suspended state in which a slight amount of water does not dissolve in an organic solvent (a state in which phase separation occurs at the liquid portion), etc., so that the amount of the water to be used is preferably adjusted to an amount of the solubility of water in an organic solvent or less, preferably 10 mol or less. [0054] As the above-mentioned organic solvent, there may be mentioned, for example, an aliphatic hydrocarbon such as n- pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane and cyclopentane, etc.; an aromatic hydrocarbon such as benzene, toluene and xylene, etc.; an ether such as diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane, etc.; a ketone such as acetone and methyl ethyl ketone, etc., preferably n-hexane, n-heptane, cyclopentane, cyclo- hexane, toluene, diisopropyl ether, t-butyl methyl ether, cyclopentyl methyl ether and tetrahydrofuran, more prefer- ably n-hexane, cyclohexane, toluene, diisopropyl ether, t- butyl methyl ether and cyclopentyl methyl ether, particu- larly preferably cyclohexane, toluene and/or t-butyl methyl 28 ether is/are used. Incidentally, these organic solvents may be used singly or in admixture of two or more kinds. [0055] An amount of the above-mentioned organic solvent to be used is preferably 2 to 200 mL, more preferably 5 to 80 mL based on 1 g of Compound (I) . A ratio of the above- mentioned water and the organic solvent is not particularly limited, and an amount of water to be used may be an amount of the solubility of water in an organic solvent or less (that is, an amount which saturates in an organic solvent or less). [0056] The reaction of the present invention is desirably carried out in the presence of a surfactant. As the sur- factant to be used, there may be mentioned, for example, a nonionic surfactant such as polyethylene glycol, polyvinyl- pyrrolidone, polyethylene lauryl ether, polyethylene cetyl ether, polyoxyethylene octylphenyl ether, etc.; an ampho- teric surfactant such as 3-[(3-chloroamidopropyl)-dimethyl- ammonio]-2-hydroxy-l-propanesulfonate, 3-[(3-chloroamido- propyl) -dimethylammonio] -1-propanesulfonate, etc.; an anionic surfactant such as sodium dioctylsulfosuccinate, sodium dodecylsulfonate, tris(hydroxymethyl)aminomethane- dodecyl sulfate, etc.; a cationic surfactant such as cetyl trimethyl ammonium bromide or cetyl dimethylethyl ammonium bromide, etc., preferably a nonionic surfactant, more preferably polyethylene glycol, polyethylene cetyl ether, polyoxyethylene octylphenyl ether, particularly preferably polyoxyethylene octylphenyl ether is used. Incidentally, these surfactants may be used singly or in admixture of two or more kinds. [0057] An amount of the above-mentioned surfactant to be used is preferably 10 to 1000 mg, more preferably 50 to 200 mg based on 1 g of Compound (I). [0058] 29 The reaction of the present invention can be carried out by the method, for example, in which Compound (I), a lipase or a protease, water (if necessary, it may contain an inorganic salt or an organic salt) and an organic sol- vent are mixed and reacted with stirring, etc. A reaction temperature at that time is preferably 0 to 8 0°C, more preferably 10 to 50°C, particularly preferably 30 to 45°C, and a reaction pressure is not particularly limited. Incidentally, during the reaction, lipase or protease is substantially in a suspended state, and depending on a kind of Compound (I), Compound (I) is precipitated as a white solid in some cases with the progress of the reaction, but these suspension or precipitation does not cause any effect on the reaction. [0059] With regard to Compound (II) and Compound (III) obtained by the reaction of the present invention, when Compound (II) is precipitated after completion of the reaction, then, Compound (II) can be obtained, for example, by adding a suitable organic solvent (for example, aceto- nitrile, acetone, etc.) to the reaction mixture and filtered, and Compound (III) can be obtained by concentrat- ing the organic layer. Also, when Compound (II) is not precipitated after completion of the reaction, Compound (II) can be obtained, for example, by adjusting a pH of the mixture, extracting Compound (II) with water, further adjusting a pH of the extract again and extracting with an organic solvent, and concentrating the obtained organic layer. Compound (III) can be obtained by concentrating the organic layer which has been separated at the time of extracting Compound (II) with water. Incidentally, the obtained Compound (II) and Compound (III) may be further purified by the conventionally known method such as crystallization, recrystallization, distillation, column chromatography, etc. [0060] 30 In the present invention, each compound is separated from a mixture of an optically active (S or R)-α-amino acid represented by the above-mentioned formula (II) formed by the reaction with water and an optically active (R or S)-α- amino acid ester represented by the above-mentioned formula (III), and the obtained optically active (R or S)-α-amino acid ester is reacted with an acid to prepare an acid salt of the optically active (R or S)-α-amino acid ester. [0061] As the acid usable for the above-mentioned reaction, there may be mentioned, for example, hydrochloric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid, oxalic acid, formic acid and carbonic acid, preferably hydro- chloric acid is used. An amount of the above-mentioned acid to be used is preferably 0.5 to 2.0 mol, more preferably 0.9 to 1.5 mol based on 1 mol of Compound (III). [0062] Also, the above-mentioned reaction is preferably carried out in an organic solvent. Such an organic solvent may be mentioned, for example, at least one organic solvent selected from the group consisting of an ether, a ketone, an ester, an aliphatic hydrocarbon and an aromatic hydrocarbon. An amount of the above-mentioned organic solvent to be used is preferably 1 to 50 mL, more preferably 3 to 20 mL based on 1 g of Compound (III) . [0063] The above-mentioned reaction can be carried out, for example, by mixing Compound (III), an acid and an organic solvent, and reacting them with stirring, etc. A reaction temperature at that time is preferably -20 to 80°C, more preferably -10 to 50°C, particularly preferably -5 to 40°C, and a reaction pressure is not particularly limited. [0064] An acid salt of an optically active (R or S)-α-amino 31 acid ester obtained by the reaction of the present inven- tion can be further purified by a usual method such as crystallization, recrystallization, distillation, column chromatography, etc. EXAMPLES [0065] Next, the present invention is specifically explained by referring to Examples, but the scope of the present invention is not limited by these Examples. [0066] Reference example 1 (Synthesis of ethyl 2-amino-3-phenyl- propionate (racemic mixture)) To 10.0 mL (171 mmol) of ethanol were added 2.0 0 g (12.1 mmol) of 2-amino-3-phenylpropionic acid (racemic mixture) and 1.42 g (14.5 mmol) of cone, sulfuric acid, and they were reacted with stirring at 60°C for 4 hours. After completion of the reaction, the obtained reaction mixture was concentrated under reduced pressure, and then, 6 mol/L aqueous sodium hydroxide solution was added to the mixture to adjust a pH of the reaction mixture to 8.5* Then, 10 mL of t-butyl methyl ether and 4 mL of water were added to the mixture to extract the product, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2.34 g (Isolation yield based on 2-amino-3- phenylpropionic acid (racemic mixture): 89.0%) of ethyl 2- amino-3-phenylpropionate (racemic mixture) as colorless liquid. Incidentally, physical properties of the ethyl 2- amino-3-phenylpropionate (racemic mixture) were as follows. [0067] 'H-NMR (8 (ppm) , CDC13) : 1.22 (t, 3H, J=7.1Hz), 2.85 (dd, 1H, J=7.8, 13.5HZ), 3.06 (dd, 1H, J=5.4, 13.5Hz), 3.69 (dd, 1H, J=5.4, 7.8Hz), 4.14 (q, 2H, J=7.1Hz), 7.17-7.30 (m, 5H) 13C-NMR (5 (ppm), CDC13) : 14.2, 41.2, 55.9, 60.8, 126.7, 32 128.5, 129.3. 137.4, 175.0 MS (CI, i-C4H10) m/z: 194 (MH+) [0068] Example 1 (Synthesis of (S)-2-amino-3-phenylpropionic acid and ethyl (R)-2-amino-3-phenylpropionate) To 1.00 mL of t-butyl methyl ether saturated with water were added 100 mg (0.517 mmol) of ethyl 2-amino-3- phenylpropionate (racemic mixture) and 20.0 mg of a lipase (AMANO LIPASE PS (Trade name); available from Aldrich Corporation) originated from Burkholderia cepacia {Pseudo- monas cepacia), and the mixture was reacted at 30°C with stirring. After 156 hours, 0.5 mL of acetone was added to the reaction mixture and the resulting mixture was filtered to obtain 36.1 mg (Isolation yield based on ethyl 2-amino- 3-phenylpropionate (racemic mixture)=42.2%) of (S)-2-amino- 3-phenylpropionic acid as a mixture with the lipase. The (S)-2-amino-3-phenylpropionic acid was led to ethyl (S)-2-(2-furoylamino)-3-phenylpropionate according to the conventional manner, and when an optical purity thereof was measured by using high performance liquid chromato- graphy which uses an optically active column, it was 96.5% ee. The ethyl (R)-2-amino-3-phenylpropionate was led to ethyl (R)-2-(2-furoylamino)-3-phenylpropionate according to the conventional manner, and when an optical purity thereof was measured by using high performance liquid chromato- graphy which uses an optically active column, it was 89.5% ee. Incidentally, an E value in this reaction was 170. [0069] Analytical conditions of high performance liquid chromato- graphy; Optically active ethyl 2-(2-furoylamino)-3-phenylpropionate Column: CH.IRALCEL OJ-H (0.46 cmOx25 cm, available from DAICEL CHEMICAL INDUSTRIES, LTD.) Solvent: hexane/isopropyl alcohol (=8/2 (Volume ratio)) 33 Flow rate: 0.5 mL/min Temperature: 3 0°C Wavelength: 22 0 nm [0070] Also, physical properties of the (S)-2-amino-3- phenylpropionic acid were as follows. [0071] ^-NMR (8 (ppm) , CD3OD) : 3.12 (dd, 1H, J=8.0, 14.5Hz), 3.29 (dd, 1H, J=5.2, 14.5Hz), 3.99 (dd, 1H, J=5.2, 8.0Hz), 7.32- 7.45 (m, 5H) 13C-NMR (8 (ppm), CD3OD) : 39.2, 58.9, 130.5, 132.0, 132.2, 138.0, 176.8 MS (CI, i-C4H10) m/z: 166 (MH+) Specific Rotation: [a] 25D -26.5° (c 0.5, H20) Incidentally, a specific rotation of the obtained optically active 2-amino-3-phenylpropionic acid and a sign ([a]20D -33.4 to -35.0° (c2, H20) ) of the specific rotation of the (S)-2-amino-3-phenylpropionic acid mentioned in a brochure published by Wako Pure Chemical Industries, Ltd. are compared to each other so that the absolute configura- tion was determined. [0072] Physical properties of the ethyl (R)-2-amino-3- phenylpropionate were the same as those shown in Reference example 1. [0073] Analytical conditions of high performance liquid chromato- graphy; Optically active ethyl 2-(2-furoylamino)-3-phenylpropionate Column: CHIRALCEL OJ-H (0.46 cmOx25 cm, available from DAICEL CHEMICAL INDUSTRIES, LTD.) Solvent: hexane/isopropyl alcohol (=8/2 (Volume ratio)) Flow rate: 0.5 mL/min Temperature: 3 0°C Wavelength: 22 0 nm [0074] i 34 Also, physical properties of the (S)-2-amino-3- phenylpropionic acid were the same as those shown in Example 1. Physical properties of the ethyl (R)-2-amino-3- phenylpropionate were the same as those shown in Reference example 1. [0075] Reference example 2 (Synthesis of ethyl 2-amino-3-(3- fluorophenyDpropionate (racemic mixture)) To 10.0 mL (171 mmol) of ethanol were added 2.0 0 g (10.9 mmol) of 2-amino-3-(3-fluorophenyl)propionic acid (racemic mixture) and 1.29 g (13.1 mmol) of cone, sulfuric acid, and the mixture was reacted at 60°C for 4 hours with stirring. After completion of the reaction, the obtained reaction mixture was concentrated under reduced pressure, and then, 6 mol/L aqueous sodium hydroxide solution was added to the mixture to adjust a pH of the reaction mixture to 8.5. Then, 10 mL of ethyl acetate and 4 mL of water were added to the mixture to extract the desired product, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 1.97 g (Isolation yield based on 2-amino-3-(3-fluorophenyl)propionic acid (racemic mixture): 85.1%) of ethyl 2-amino-3-(3-fluorophenyl)- propionate (racemic mixture) as a colorless liquid. Incidentally, physical properties of the ethyl 2- amino-3-(3-fluorophenyl)propionate (racemic mixture) were as follows. [0076] "H-NMR (5 (ppm) , CDC13) : 1.25 (t, 3H, J=7.1Hz), 2.88 (dd, 1H, J=7.8, 13.6HZ), 3.07 (dd, 1H, J=5.5, 13.6Hz), 3.71 (dd, 1H, J=5.5, 7.8Hz), 4.17 (q, 2H, J=7.1Hz), 6.91-7.00 (m, 3H), 7.26 (m, 1H) 13C-NMR (8 (ppm), CDCl3) : 14.2, 40.8, 55.7, 61.1, 113.7, 113.8, 116.1, 116.3, 125.01, 125.02, 129.9, 130.0, 139.9, 140.0, 161.9, 163.9, 174.7 35 MS (CI, i-C4H10) m/z: 212 (MH+) [0077] Example 2 (Synthesis of (S)-2-amino-3-(3-fluorophenyl)- propionic acid and ethyl (R)-2-amino-3-(3-fluorophenyl)- propionate) To 1.0 mL of t-butyl methyl ether saturated with water were added 100 mg (0.473 mmol) of ethyl 2-amino-3-(3- fluorophenyl)propionate (racemic mixture) and 30.0 mg of a lipase (AMANO LIPASE PS (Trade name); available from ALDRICH CORPORATION) originated from Burkholderia cepacia (Pseudomonas cepacia), and reacted at 3 0°C. After 48 hours, 0.5 mL of acetone was added to the reaction mixture and the resulting mixture was filtered to obtain 31.1 mg (Isolation yield based on ethyl 2-amino-3-(3-fluorophenyl)- propionate (racemic mixture)=40.5%) of (S)-2-amino-3-(3- fluorophenyl)propionic acid as a mixture with the lipase. (S)-2-amino-3-(3-fluorophenyl)propionic acid was led to ethyl (S)-3- (3-fluorophenyl)-2-(2-furoylamino)propionate according to the conventional manner, and when its optical purity was measured by using high performance liquid chromatography which uses an optically active column, it was 98.0% ee. Ethyl (R)-2-amino-3-(3-fluorophenyl)propionate was led to ethyl (R)-3-(3-fluorophenyl)-2-(2-furoylamino)- propionate according to the conventional manner, and when its optical purity was measured by using high performance liquid chromatography which uses an optically active column, it was 82.8% ee. Incidentally, the E value in this reaction was 258. [0078] Analytical conditions of high performance liquid chromato- graphy; Optically active ethyl 3-(3-fluorophenyl)-2-(2-furoyl- amino) propionate Column: CHIRALCEL OJ-H (0.46 cmOx25 cm, available from DAICEL CHEMICAL INDUSTRIES, LTD.) 36 Solvent: hexane/isopropyl alcohol (=9/1 (Volume ratio)) Flow rate: 0.5 mL/min Temperature: 3 0°C Wavelength: 22 0 nm [0079] Also, physical properties of the (S)-2-amino-3-(3- fluorophenyDpropionic acid were as follows. [0080] XH-NMR (8 (ppm) , CD3OD) : 3.02 (dd, 1H, J=8.6, 14.6Hz), 3.31 (dd, 1H, J=4.5, 14.6Hz), 3.77 (dd, 1H, J=4.5, 8.6Hz), 7.00 (m, 1H) , 7.08 (m, 1H) , 7.12 (in, 1H) , 7.34 (m, 1H) 13C-NMR (8 (ppm), CD3OD) : 37.9, 57.3, 115.1, 115.2, 117.1, 117.3, 126.32, 126.34, 131.6, 131.7, 140.0, 140.1, 163.5, 165.5, 173.4 MS (CI, i-C4H10) m/z: 184 (MH+) Elemental analysis; Calcd: C, 59.01%; H, 5.50%; N, 7.65% Found: C, 57.86%; H, 5.46%; N, 7.90% [0081] Physical properties of the ethyl (R)-2-amino-3- (3- fluorophenyDpropionate were the same as those shown in Reference example 2. [0082] Reference example 3 (Synthesis of ethyl 2-amino-3-(4- fluorophenyDpropionate (racemic mixture)) To 10.0 mL (171 mmol) of ethanol were added 2.00 g (10.9 mmol) of 2-amino-3-(4-fluorophenyDpropionic acid (racemic mixture) and 1.2 9 g (13.1 mmol) of cone, sulfuric acid, and the mixture was reacted at 60°C for 4 hours with stirring. After completion of the reaction, the obtained reaction mixture was concentrated under reduced pressure, and then, 6 mol/L aqueous sodium hydroxide solution was added to the mixture to adjust a pH of the reaction mixture to 8.5. Then, 10 mL of t-butyl methyl ether and 4 mL of water were added to the mixture to extract the desired product, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was 37 concentrated under reduced pressure to obtain 1.95 g (Isolation yield based on 2-amino-3-(4-fluorophenyDpro- pionic acid (racemic mixture): 84.6%) of ethyl 2-amino-3- (4-fluorophenyDpropionate (racemic mixture) as a colorless liquid. Incidentally, physical properties of the ethyl 2- amino-3-(4-fluorophenyDpropionate (racemic mixture) were as follows. [0083] 'H-NMR (8 (ppm) , CDC13) : 1.23 (t, 3H, J=7.1Hz), 2.96 (dd, 1H, J=7.6, 13.7Hz), 3.04 (dd, 1H, J=5.5, 13.7Hz), 3.68 (dd, 1H, J=5.5, 7.6Hz), 4.16 (q, 2H, J=7.1Hz), 6.99 (m, 2H), 7.17 (m, 2H) 13C-NMR (8 (ppm), CDCI3) : 14.2, 40.2, 55.9, 61.0, 115.2, 115.4, 130.75, 130.81, 132.97, 133.00, 160.9, 162.9, 174.9 MS (CI, i-C4H10) m/z: 212 (MH+) Elemental analysis; Calcd: C, 62.55%; H, 6.68%; N, 6.63% Found: C, 61.19%; H, 6.54%; N, 6.51% [0084] Example 3 (Synthesis of (S)-2-amino-3-(4-fluorophenyl)- propionic acid and ethyl (R)-2-amino-3-(4-fluorophenyl)- propionate) To 1.0 mL of t-butyl methyl ether saturated with water were added 100 mg (0.473 mmol) of ethyl 2-amino-3-(4- fluorophenyl)propionate (racemic mixture) and 30.0 mg of a lipase (AMANO LIPASE PS (Trade name); available from Aldrich Corporation) originated from Burkholderia cepacia (Pseudomonas cepacia), and the mixture was reacted at 3 0°C with stirring. After 5 6 hours, 0.5 mL of acetone was added to the reaction mixture and the resulting mixture was filtered to obtain 36.7 mg (Isolation yield based on ethyl 2-amino-3-(4-fluorophenyDpropionate (racemic mixture)= 42.3%) of (S)-2-amino-3-(4-fluorophenyl)propionic acid as a mixture with the lipase. (S)-2-amino-3-(4-fluorophenyl)propionic acid was led to ethyl (S)-3-(4-fluorophenyl)-2-(2-furoylamino)propionate 38 according to the conventional manner, and when its optical purity was measured by using high performance liquid chromatography which uses an optically active column, it was 99.1% ee. Ethyl (R)-2-amino-3-(4-fluorophenyl)propionate was led to ethyl (R)-3-(4-fluorophenyl)-2-(2-furoylamino)- propionate according to the conventional manner, and when its optical purity was measured by using high performance liquid chromatography which uses an optically active column, it was 91.2% ee. Incidentally, the E value in this reaction was 698. [0085] Analytical conditions of high performance liquid chromato- graphy; Optically active ethyl 3-(4-fluorophenyl)-2-(2-furoyl- amino) propionate Column: CHIRALCEL OJ-H (0.46 cmOx25 cm, available from DAICEL CHEMICAL INDUSTRIES, LTD.) Solvent: hexane/isopropyl alcohol (=8/2 (Volume ratio)) Flow rate: 0.5 mL/min Temperature: 3 0°C Wavelength: 22 0 nm [0086] Also, physical properties of the (S)-2-amino-3-(4- fluorophenyl)propionic acid were as follows. [0087] XH-NMR (5 (ppm) , CD3OD) : 3.00 (dd, 1H, J=8.5, 14.7Hz), 3.27 (dd, 1H, J=4.5, 14.7HZ), 3.74 (dd, 1H, J=4.5, 8.5Hz), 7.05 (m, 2H), 7.31 (m, 2H) "C-NMR (8 (ppm), CD3OD) : 37.5, 57.6, 116.5, 116.6, 132.2, 132.3, 133.2, 133.3, 162.9, 164.6, 173.6 MS (CI, i-C4H10) m/z: 184 (MH+) Elemental analysis; Calcd: C, 59.01%; H, 5.50%; N, 7.65% Found: C, 58.73%; H, 5.49%; N, 7.68% [0088] Physical properties of the ethyl (R)-2-amino-3-(4- 39 fluorophenyDpropionate were the same as those shown in Reference example 3. [0089] Reference example 4 (Synthesis of ethyl 2-amino-3-(4-bromo- phenyDpropionate (racemic mixture)) To 5.00 mL (85.7 mmol) of ethanol were added 1.00 g (4.10 mmol) of 2-amino-3-(4-bromophenyl)propionic acid (racemic mixture) and 482 mg (4.92 mmol) of cone, sulfuric acid, and the mixture was reacted with stirring at 60°C for 4 hours. After completion of the reaction, the obtained reaction mixture was concentrated under reduced pressure, and then, 6 mol/L aqueous sodium hydroxide solution was added to the mixture to adjust a pH of the reaction mixture to 8.5. Then, 10 mL of t-butyl methyl ether and 4 mL of water were added to extract the desired product, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 916 mg (Isolation yield based on 2-amino-3-(4-bromophenyl)propionic acid (racemic mixture): 82.5%) of ethyl 2-amino-3-(4-bromophenyl)propionate (racemic mixture) as colorless liquid. Incidentally, physical properties of the ethyl 2- amino-3-(4-bromophenyl)propionate (racemic mixture) were as follows. [0090] 'H-NMR (6 (ppm) , CDC13) : 1.25 (t, 3H, J=7.1Hz), 2.83 (dd, 1H, J=7.7, 13.7Hz), 3.03 (dd, 1H, J=5.5, 13.7Hz), 3.68 (dd, 1H, J=5.5, 7.7Hz), 7.08 (m, 2H), 7.42 (m, 2H) 13C-NMR (8 (ppm) , CDCI3) : 14.2, 40.4, 55.7, 61.1, 120.8, 131.1, 131.7, 136.3, 174.7 MS (CI, i-C4H10) m/z: 272 (MH+) Elemental analysis; Calcd: C, 48.55%; H, 5.19%; N, 5.15% Found: C, 47.71%; H, 5.21%; N, 5.06% [0091] Example 4 (Synthesis of (S)-2-amino-3-(4-bromophenyl)- propionic acid and ethyl (R)-2-amino-3-(4-bromophenyl)- 40 propionate) To 1.0 mL of t-butyl methyl ether saturated with water were added 200 mg (0.367 mmol) of ethyl 2-amino-3-(4- bromophenyl)propionate (racemic mixture) and 3 0.0 mg of a lipase (AMANO LIPASE PS (Trade name); available from Aldrich Corporation) originated from Burkholderia cepacia {Pseudomonas cepacia), and the mixture was reacted with stirring at 30°C. After 56 hours, 0.5 mL of acetone was added to the reaction mixture and the resulting mixture was filtered to obtain 36.2 mg (Isolation yield based on ethyl 2-amino-3-(4-bromophenyl)propionate (racemic mixture)= 41.8%) of (S)-2-amino-3-phenylpropionic acid as a mixture with the lipase. (S)-2-amino-3-(4-bromophenyl)propionic acid was led to ethyl (S)-3-(4-bromophenyl)-2-(2-furoylamino)propionate according to the conventional manner, and when its optical purity was measured by using high performance liquid chromatography which uses an optically active column, it was 98.5% ee. Ethyl (R)-2-amino-3-(4-bromophenyl)propionate was led to ethyl (R)-3-(4-bromophenyl)-2-(2-furoylamino)pro- pionate according to the conventional manner, and when its optical purity was measured by using high performance liquid chromatography which uses an optically active column, it was 87.7% ee. Incidentally, the E value in this reaction was 388. [0092] Analytical conditions of high performance liquid chromato- graphy; Optically active ethyl 3-(4-bromophenyl)-2-(2-furoylamino)- propionate Column: CHIRALCEL OJ-H (0.46 cmOx25 cm, available from DAICEL CHEMICAL INDUSTRIES, LTD.) Solvent: hexane/isopropyl alcohol (=8/2 (Volume ratio)) Flow rate: 0.5 mL/min Temperature: 30°C 41 Wavelength: 22 0 run [0093] Also, physical properties of the (S)-2-amino-3-(4- bromophenyl)propionic acid were as follows. [0094] XH-NMR (6 (ppm) , CD3OD) : 2.99 (dd, 1H, J=8.4, 14.6Hz), 3.25 (dd, 1H, J=4.5, 14.6Hz), 3.74 (dd, 1H, J=4.5, 8.4Hz), 7.22 (m, 2H), 7.48 (m, 2H) 13C-NMR (5 (ppm) , CD3OD) : 37,7, 57.3, 122.2, 132.4, 133.0, 136.6, 173.5 MS (CI, i-C4H10) m/z: 244 (MH+) Elemental analysis,- Calcd: C, 44.29%; H, 4.13%; N, 5.74% Found: C, 43.95%; H, 4.06%; N, 5.66% [0095] Physical properties of the ethyl (R)-2-amino-3- (4- bromophenyDpropionate were the same as those shown in Reference example 4. [0096] Reference example 5 (Synthesis of ethyl 2-amino-3-(2- naphthyDpropionate (racemic mixture)) To 9.0 mL (154 mmol) of ethanol were added 1.80 g (8.36 mmol) of 2-amino-3-(naphthyl)propionic acid (racemic mixture) and 1.23 g (12.5 mmol) of cone, sulfuric acid, and the mixture was reacted with stirring at 60°C for 6 hours. After completion of the reaction, the obtained reaction mixture was concentrated under reduced pressure, and then, 6 mol/L aqueous sodium hydroxide solution was added to the mixture to adjust a pH of the reaction mixture to 8.5. Then, 18 mL of t-butyl methyl ether and 4 mL of water were added to extract the desired product, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 1.73 g (Isolation yield based on 2- amino-3-(2-naphthyl)propionic acid (racemic mixture): 85.0%) of ethyl 2-amino-3-(2-naphthyl)propionate (racemic mixture) as pale yellowish liquid. 42 Incidentally, physical properties of the ethyl 2- amino-3-(2-naphthyl)propionate (racemic mixture) were as follows. [0097] XH-NMR (5 (ppm) , CDC13) : 1.20 (t, 3H, J=7.lHz), 1.58 (s, 2H), 3.00 (dd, 1H, J=7.9, 13.5Hz), 3.23 (dd, 1H, J=5.3, 13.5HZ), 3.78 (dd, 1H, J=5.3, 7.9Hz), 4.15 (q, 2H, J=7.1Hz), 7.31 (dd, 1H, J=1.7, 8.4HZ), 7.39-7.45 (m, 2H), 7.64 (m, 1H), 7.76-7.79 (m, 3H) 13C-NMR (5 (ppm), CDC13) : 14.2, 40.2, 55.9, 61.0, 115.2, 115.4, 130.75, 130.81, 132.97, 133.00, 160.9, 162.9, 174.9 MS (El) m/z: 243 (M+) MS (CI, i-C4H10) m/z: 244 (MH+) Elemental analysis; Calcd: C, 74.05%; H, 7.04%; N, 5.76% Found: C, 72.89%; H, 6.72%; N, 5.58% [0098] Example 5 (Synthesis of (S)-2-amino-3-(2-naphthyl)propionic acid and ethyl (R)-2-amino-3-(2-naphthyl)propionate) To 2.0 mL of t-butyl methyl ether saturated with water were added 200 mg (0.822 mmol) of ethyl 2-amino-3-(2- naphthyDpropionate (racemic mixture) and 10.0 mg of a lipase (AMANO LIPASE PS (Trade name); available from Aldrich Corporation) originated from Burkholderia cepacia (Pseudomonas cepacia), and the mixture was reacted with stirring at 30°C. After 168 hours, the reaction mixture was filtered, and washed with 2.0 mL of t-butyl methyl ether to obtain 86.1 mg (Isolation yield based on ethyl 2- amino-3- (4-f luorophenyDpropionate (racemic mixture) =43 . 0%) of (S)-2-amino-3-(2-naphthyl)propionic acid as a mixture with the lipase. Also, after filtration, the filtrate was concen- trated under reduced pressure to obtain 110 mg (Isolation yield based on ethyl 2-amino-3-(2-naphthyl)propionate (racemic mixture)=55.0%) of ethyl (R)-2-amino-3-(2- naphthyDpropionate as pale yellowish liquid. (S)'-2-amino-3-(2-naphthyl) prop ionic acid was led to 43 ethyl (S)-2-(2-furoylamino)-3-(2-naphthyl)propionate according to the conventional manner, and when its optical purity was measured by using high performance liquid chromatography which uses an optically active column, it was 99.3% ee. Ethyl (R)-2-amino-3-(2-naphthyl)propionate was led to ethyl (R)-2-(2-furoylamino)-2-(2-naphthyl)propionate according to the conventional manner, and when its optical purity was measured by using high performance liquid chromatography which uses an optically active column, it was 7 9.3% ee. Incidentally, the E value in this reaction was 711. [0099] Analytical conditions of high performance liquid chromato- graphy; Optically active ethyl 3-(2-furoylamino)-3-(2-naphthyl)- propionate Column: CHIRALCEL OJ-H (0.46 cmx25 cm, available from DAICEL CHEMICAL INDUSTRIES, LTD.) Solvent: hexane/isopropyl alcohol (=8/2 (Volume ratio)) Flow rate: 0.5 mL/min Temperature -. 3 0 ° C Wavelength: 22 0 nm [0100] Also, physical properties of the (S)-2-amino-3-(2- naphthyDpropionic acid were as follows. [0101] 'H-NMR (8 (ppm), D2O) : 3.41 (dd, 1H, J=7.7, 14.6Hz), 3.53 (dd, 1H, J=5.7, 14.6HZ), 4.50 (dd, 1H, J=5.7, 7.7Hz), 7.46 (d, 1H, J=8.4Hz), 7.57-7.61 (m, 2H), 7.84 (s, 1H) 7.93-7.97 (m, 3H) 13C-NMR (6 (ppm), D2O) : 38.6, 56.8, 129.4, 129.67, 130.0, 130.6, 131.4, 131.8, 134.4, 135.4, 136.1, 174.0 MS (El) m/z: 215 (M+) MS (CI, i-C4H10) m/z: 216 (MH+) [0102] 44 Physical properties of the ethyl (R)-2-amino-3-(2- naphthyDpropionate were the same as those shown in Reference example 5. [0103] Reference example 6 (Synthesis of ethyl 2-amino-3-(3- indolyDpropionate (racemic mixture)) To 5.0 mL (85.6 mmol) of ethanol were added 1.00 g (4.90 mmol) of 2-amino-3-(3-indolyl)propionic acid (racemic mixture) and 0.96 g (9.79 mmol) of cone, sulfuric acid, and the mixture was reacted with stirring at 60°C for 4 hours. After completion of the reaction, the obtained reaction mixture was concentrated under reduced pressure, and then, 6 mol/L aqueous sodium hydroxide solution was added to the mixture to adjust a pH of the reaction mixture to 8.5. Then, 10 mL of t-butyl methyl ether and 4 mL of water were added to extract the desired product, and the organic layer was dried over anhydrous magnesium sulfate. After filtra- tion, the filtrate was concentrated under reduced pressure to obtain 0.97 g (Isolation yield based on 2-amino-3-(3- indolyl)propionic acid (racemic mixture): 85.0%) of ethyl 2-amino-3-(3-indolyl)propionate (racemic mixture) as colorless liquid. Incidentally, physical properties of the ethyl 2- amino-3-(3-indolyl)propionate (racemic mixture) were as follows. [0104] ' XH-NMR (8 (ppm) , D20) : 1.21 (t, 3H, J=7.0Hz), 1.63 (s, 2H) , 3.01 (dd, 1H, J=7.9, 14.4HZ), 3.25 (dd, 1H, J=4 . 8, 14.4Hz), 3.80 (dd, 1H, J=4.8, 7.9Hz), 4.14 (q, 2H, J=7.0Hz), 6.90 (s, 1H) 7.06-7.26 (m, 3H), 7.59 (d, 1H, J=7.9Hz), 9.07 (s, 1H) 13C-NMR (5 (ppm) , CDC13) : 14.1, 49.4, 55.0, 61.0, 110.6, 111.4, 118.6, 119.2, 121.8, 123.3, 127.5, 136.4, 175.4 MS (El) m/z: 232 (M+) MS (CI, i-C4H10) m/z: 233 (MH+) [0105] 45 Example 6 (Synthesis of (S)-2-amino-3-(3-indolyl)propionic acid and ethyl (R)-2-amino-3-(3-indolyl)propionate) To 4.0 mL of t-butyl methyl ether saturated with water were added 200 mg (0.822 mmol) of ethyl 2-amino-3-(3- indolyl)propionate (racemic mixture) and 10.0 mg of a lipase (AMANO LIPASE PS (Trade name); available from Aldrich Corporation) originated from Burkholderia cepacia (Pseudomonas cepacia) , and the mixture was reacted with stirring at 3 0°C. After 108 hours, the reaction mixture was filtered, and washed with 2.0 mL of t-butyl methyl ether to obtain 78.3 mg (Isolation yield based on ethyl 2- amino-3-(3-indolyl)propionate (racemic mixture)=44.5%) of (S)-2-amino-3-(3-indolyl)propionic acid as a mixture with the lipase. Also, after filtration, the filtrate was concen- trated under reduced pressure to obtain 106 mg (Isolation yield based on ethyl 2-amino-3-(3-indolyl)propionate (racemic mixture)=53.0%) of ethyl (R)-2-amino-3-(3- indolyl)propionate as colorless liquid. (S)-2-amino-3-(3-indolyl)propionic acid was led to ethyl (S)-2-(2-fluorophenyl)-3-(3-indolyl)propionate according to the conventional manner, and when its optical purity was measured by using high performance liquid chromatography which uses an optically active column, it was 98.7% ee. Ethyl (R)-2-amino-3-(3-indolyl)propionate was led to ethyl (R)-2-(2-fluorophenyl)-3-(3-indolyl)propionate according to the conventional manner, and when its optical purity was measured by using high performance liquid chromatography which uses an optically active column, it was 81.8% ee. Incidentally, the E value in this reaction was 392. [0106] Analytical conditions of high performance liquid chromato- graphy; Optically active ethyl 2-(2-furoylamino)-3-(3-indolyl)- 46 propionate Column: CHIRALCEL OJ-H (0.46 cmO>x25 cm, available from DAICEL CHEMICAL INDUSTRIES, LTD.) Solvent: hexane/isopropyl alcohol (=8/2 (Volume ratio)) Flow rate: 1.0 mL/min Temperature: 3 0°C Wavelength: 22 0 nm [0107] Also, physical properties of the (S)-2-amino-3-(3- indolyl)propionic acid were as follows. [0108] 'H-NMR (8 (ppm) , D2O) : 3.43 (dd, 1H, J=7.0, 15.4Hz), 3.50 (dd, 1H, J=5.5, 15.4HZ), 4.40 (dd, 1H, J=5.5, 7.0Hz), 7.21- 7.69 (m, 5H) 13C-NMR (8 (ppm), D2O) : 29.2, 56.8, 109.7, 115.6, 121.8, 123.1, 125.8, 129.0, 130.1, 139.9, 175.1 MS (El) m/z: 204 (M+) MS (CI, i-C4H10) m/z: 205 (MH+) [0109] Physical properties of the ethyl (R)-2-amino-3-(3- indolyl)propionate were the same as those shown in Reference example 6. [0110] Example 7 (Synthesis of (S)-2-amino-3-(4-fluorophenyl)- propionic acid and ethyl (R)-2-amino-3-(4-fluorophenyl)- propionate) : To 2.0 mL of t-butyl methyl ether saturated with water were added 200 trig (0.947 mmol) of ethyl 2-amino-3- (4- fluorophenyl)propionate (racemic mixture) and 1.0 mg ofα- chymotrypsin, and the mixture was reacted with stirring at 30°C. After 84 hours, the reaction mixture was filtered to obtain 70.8 mg (Isolation yield based on ethyl 2-amino-3- (4-fluorophenyl)propionate (racemic mixture)=4 0.8%) of (S) - 2-amino-3-(4-fluorophenyl)propionic acid. (S)-2-amino-3-(4-fluorophenyl)propionic acid was led to ethyl (S)-3-(4-fluorophenyl)-2-(2-furoylamino)propionate 47 according to the conventional manner, and when its optical purity was measured by using high performance liquid chromatography which uses an optically active column, it was 98.1% ee. Ethyl (R) -2-amino-3- (4-f luorophenyDpropionate was led to ethyl (R)-3-(4-fluorophenyl)-2-(2-furoylamino)- propionate according to the conventional manner, and when its optical purity was measured by using high performance liquid chromatography which uses an optically active column, it was 83.3% ee. Incidentally, the E value in this reaction was 271. [0111] Analytical conditions of high performance liquid chromato- graphy; Optically active ethyl 3-(4-fluorophenyl)-2-(2-furoyl- amino) propionate Column: CHIRALCEL OJ-H (0.46 cmOx25 cm, available from DAICEL CHEMICAL INDUSTRIES, LTD.) Solvent: hexane/isopropyl alcohol (=9/1 (Volume ratio)) Flow rate: 0.5 mL/min Temperature: 3 0°C Wavelength: 22 0 nm [0112] Also, physical properties of the (S)-2-amino-3-(4- fluorophenyl)propionic acid were the same as those shown in Example 3. [0113] Physical properties of the ethyl (R)-2-amino-3-(4- fluorophenyl)propionate were the same as those shown in Reference example 3. Reference example 7 (Synthesis of ethyl 2-amino-4-methyl- pentanoate (racemic mixture)) To 4 0 mL (69 mmol) of ethanol were added 4.0 0 g (8.36 mmol) of 2-amino-4-methylpentanoic acid (racemic mixture) and 4.4 9 g (61.0 mmol) of cone, sulfuric acid, and the mixture was reacted with stirring at 60°C for 6 hours. 48 After completion of the reaction, the obtained reaction mixture was concentrated under reduced pressure, and then, 6 mol/L aqueous sodium hydroxide solution was added to the mixture to adjust a pH of the reaction mixture to 8.5. Then, 40 mL of methylene chloride and 10 mL of water were added to the reaction mixture to extract the desired product, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 3.79 g (Isolation yield based on 2-amino-4-methylpentanoic acid (racemic mixture): 78.0%) of ethyl 2-amino-4-methylpentano- ate (racemic mixture) as colorless liquid. Incidentally, physical properties of the ethyl 2- amino-4-methylpentanoate (racemic mixture) were as follows. [0114] ^-NMR (5 (ppm) , CDC13) : 0.92-0.95 (m, 6H) , 1.28 (t, 3H, J=7.1Hz), 1.39-1.45 (m, 1H), 1.50 (s, 2H), 1.53-1.59 (m, 1H), 1.74-1.81 (m, 1H), 3.45 (dd, 1H, J=5.6, 8.7Hz) 4.17 (q, 2H, J=7.1Hz) 13C-NMR (8 (ppm), CDC13) : 14.2,21.9, 23.0, 24.8, 44.2, 52.9, 60.7, 176.7 MS (CI, i-C4H10) m/z: 160 (MH+) [0115] Example 8 (Synthesis of (S)-2-amino-4-methylpentanoic acid and ethyl (R)-2-amino-4-methyl-pentanoate) To 2.0 mL of t-butyl methyl ether saturated with water were added 100 mg (0.63 mmol) of ethyl 2-amino-4- methylpentanoate (racemic mixture) and 1.0 mg ofα-chymo- trypsin, and the mixture was reacted with stirring at 30°C. After 64 hours, the reaction mixture was filtered, and washed with 2.0 mL of t-butyl methyl ether to obtain 3 7.1 mg (Isolation yield based on ethyl 2-amino-3-(4-fluoro- phenyDpropionate (racemic mixture) =45.0%) of (S)-2-amino- 4-methylpentanoic acid. Also, after filtration, the filtrate was concen- trated under reduced pressure to obtain 50 mg (Isolation 49 yield based on ethyl 2-amino-4-methylpentanoate (racemic mixture)=50.0%) of ethyl (R)-2-amino-4-methylpentanoate as colorless liquid. (S)-2-amino-4-methylpentanoic acid was led to ethyl (S)-2-benzoylamino-4-methylpentanoate according to the conventional manner, and when its optical purity was measured by using high performance liquid chromatography which uses an optically active column, it was 98.2% ee. Ethyl (R)-2-amino-4-methylpentanoate was led to ethyl (R)-2-benzoylamino-4-methylpentanoate according to the conventional manner, and when its optical purity was measured by using high performance liquid chromatography which uses an optically active column, it was 88.8% ee. Incidentally, the E value in this reaction was 323. [0116] Analytical conditions of high performance liquid chromato- graphy; Optically active ethyl 2-benzoylamino-4-methylpentanoate Column: CHIRALCEL OD-H (0.46 cmOx25 cm, available from DAICEL CHEMICAL INDUSTRIES, LTD.) Solvent: hexane/isopropyl alcohol (=9/1 (Volume ratio)) Flow rate: 0.5 mL/min Temperature: 3 0°C Wavelength: 22 0 nm [0117] Also, physical properties of the (S)-2-amino-4- methylpentanoic acid were as follows. [0118] XH-NMR (8 (ppm) , D20) : 0.96-1.01 (m, 6H), 1.74-1.90 (m, 3H), 4.11 (m, 1H) 13C-NMR (8 (ppm) , CD3OD) : 23.9, 24.5, 26.8, 41.6, 54.3, 175.2 MS (CI, i-C4H10) m/z: 132 (MH+) Elemental analysis; Calcd: C, 54.94%; H, 9.99%; N, 10.68% Found: C, 54.42%; H, 9.83%; N, 10.73% [0119] 50 Physical properties of the ethyl (R)-2-amino-4- methylpentanoate were the same as those shown in Reference example 7. [0120] Reference example 8 (Synthesis of ethyl 2-amino-3-(4- methoxyphenyDpropionate (racemic mixture)) To 6.0 mL (103 mmol) of ethanol were added 600 mg (3.07 mmol) of 2-amino-3-(4-methoxyphenyl)propionic acid (racemic mixture) and 603 mg (6.15 mmol) of cone, sulfuric acid, and the mixture was reacted with stirring at 60°C for 4 hours. After completion of the reaction, the obtained reaction mixture was concentrated under reduced pressure, and then, 6 mol/L aqueous sodium hydroxide solution was added to the mixture to adjust a pH of the reaction mixture to 8.5. Then, 6 mL of t-butyl methyl ether and 2 mL of water were added to the reaction mixture to extract the desired product, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 618 mg (Isolation yield based on 2-amino-3-(4-methoxy- phenyl) propionic acid (racemic mixture): 90.0%) of ethyl 2- amino-3-(4-methoxyphenyl)propionate (racemic mixture) as colorless liquid. Incidentally, physical properties of the ethyl 2- amino-3-(4-methoxyphenyl)propionate (racemic mixture) were as follows. [0121] 'H-NMR (5 (ppm) , CDC13) : 1.25 (t, 3H, J=7.1Hz), 1.58 (s, 2H), 2.82 (dd, 1H, J=7.8, 13.7Hz), 3.02 (dd, 1H, J=5.4, 13.7HZ), 3.66 (dd, 1H, J=5.4, 7.8Hz), 3.79 (s, 3H), 1.17 (q, 2H, J=7.1Hz), 6.82-6.86 (m, 2H), 7.10-7.12 (m, 2H) 13C-NMR (5 (ppm), CDC13) : 14.2, 40.3, 55.3, 56.1, 60.9, 114.0, 129.3, 130.3, 158.6, 175.1 MS (CI, i-C4H10) m/z: 224 (MH+) Elemental analysis; Calcd: C, 64.55%; H, 7.67%; N, 6.27% Found: C, 64.27%; H, 7.27%; N, 6.17% 51 [0122] Example 9 (Synthesis of (S)-2-amino-3-(4-methoxyphenyl)- propionic acid and ethyl (R)-2-amino-3-(4-methoxyphenyl)- propionate) To 4.0 mL of t-butyl methyl ether saturated with water were added 200 mg (0.900 mmol) of ethyl 2-amino-3-(4- methoxyphenyl)propionate (racemic mixture) and 10.0 mg of a lipase (AMANO LIPASE PS (Trade name); available from ALDRICH CORPORATION) originated from Burkholderia cepacia (Pseudomonas cepacia), and the mixture was reacted with stirring at 3 0°C. After 96 hours, the reaction mixture was filtered, and washed with 2.0 mL of t-butyl methyl ether to obtain 90.0 mg (Isolation yield based on ethyl 2-amino-3- (4-fluorophenyl)propionate (racemic mixture)=4 8.6%) of (S) - 2-amino-3-(4-methoxyphenyl)propionic acid as a mixture with the lipase. Also, after filtration, the filtrate was concen- trated under reduced pressure to obtain 100 mg (Isolation yield based on ethyl 2-amino-3-(4-methoxyphenyl)propionate (racemic mixture)=50.0%) of ethyl (R)-2-amino-3-(4-methoxy- phenyl) propionate as pale yellowish liquid. (S)-2-amino-3-(4-methoxyphenyl)propionic acid was led to ethyl (S)-2-(2-furoylamino)-3-(4-methoxyphenyl)- propionate according to the conventional manner, and when its optical purity was measured by using high performance liquid chromatography which uses an optically active column, it was 99.0% ee. Ethyl (R)-2-amino-3-(4-methoxyphenyl)propionate was led to ethyl (R)-2-(2-furoylamino)-2-(4-methoxyphenyl)- propionate according to the conventional manner, and when its optical purity was measured by using high performance liquid chromatography which uses an optically active column, it was 98.8% ee. Incidentally, the E value in this reaction was 1042. [0123] Analytical conditions of high performance liquid chromato- 52 graphy; Optically active ethyl 3-(2-furoylamino)-3-(4-methoxy- phenyl)propionate Column: CHIRALCEL OJ-H (0.46 cmOx25 cm, available from DAICEL CHEMICAL INDUSTRIES, LTD.) Solvent: hexane/isopropyl alcohol (=8/2 (Volume ratio)) Flow rate: 0.5 mL/min Temperature: 3 0°C Wavelength: 22 0 nm [0124] Also, physical properties of the (S)-2-amino-3-(4- methoxyphenyl)propionic acid were as follows. [0125] 'H-NMR (5 (ppm) , CD3OD) : 3.20 (dd, 1H, J=7.4, 14.7Hz), 3.30 (dd, 1H, J=5.6, 14.7Hz), 4.36 (dd, 1H, J=5.6, 7.4Hz), 5.06 (s, 3H), 7.00-7.02 (m, 2H), 7.27-7.29 (m, 2H) 13C-NMR (8 (ppm), CD3OD) : 37.6, 57.0, 58.4, 117.6, 129.2, 133.7, 161.4, 174.1 MS (El) m/z: 195 (M+) MS (CI, i-C4H10) m/z: 196 (MH+) Elemental analysis; Calcd: C, 61.53%; H, 6.71%; N, 7.18% Found: C, 60.40%; H, 6.56%; N, 7.04% [0126] Physical properties of the ethyl (R)-2-amino-3- (4- methoxyphenyl)propionate were the same as those shown in Reference example 8. Example 10 (Synthesis of ethyl (R)-2-amino-3-phenyl- propionate hydrochloride) To 8 0 mL of t-butyl methyl ether saturated with water were added 4.00 g (20.7 mmol) of ethyl 2-amino-3- phenylpropionate (racemic mixture) and 800 mg of a lipase (AMANO LIPASE PS (Trade name); available from ALDRICH CORPORATION) originated from Burkholderia cepacia (Pseudomonas cepacia), and the mixture was reacted with stirring at 30°C. After 168 hours, the reaction mixture 53 was filtered, dried over magnesium sulfate, filtered, concentrated under reduced pressure and 12 mL of cyclo- hexane was added to the residue. To the resulting cyclo- hexane solution was added 1.52 g (10.1 mmol of hydrochloric acid) of a hydrochloric acid-ethanol solution (hydrochloric acid content: 24.3% by weight) at 0°C and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was filtered to obtain 1.90 g (Yield based on ethyl 2-amino-3-phenylpropionate (racemic mixture)=4 0.0%) of ethyl (R)-2-amino-3-phenylpropionate hydrochloride as white crystals. Ethyl (R)-2-amino-3-phenylpropionate hydrochloride was led to ethyl (R)-2-(2-furoylamino)-3-phenylpropionate according to the conventional manner, and when its optical purity was measured by using high performance liquid chromatography which uses an optically active column, it was 97.1% ee. [0127] Analytical conditions of high performance liquid chromato- graphy; Optically active ethyl 3-(2-furoylamino)-3-(4-methoxy- phenyl)propionate Column: CHIRALCEL OJ-H (0.46 cmOx25 cm, available from DAICEL CHEMICAL INDUSTRIES, LTD.) Solvent: hexane/isopropyl alcohol (=8/2 (Volume ratio)) Flow rate: 0.5 mL/min Temperature: 3 0°C Wavelength: 220 nm Also, physical properties of the ethyl (R)-2-amino- 3-phenylpropionate hydrochloride were as follows. [0128] "H-NMR (5 (ppm) , CD3OD) : 1.27 (t, 3H, J=7.2Hz), 3.26 (dd, 1H, J=7.3, 14.5Hz), 3.33 (dd, 1H, J=6.2, 14.5Hz), 4.30 (q, 4H, J=7.2Hz) 4.40 (dd, 1H, J=6.2, 7.3Hz), 7.30-7.47 (m, 5H) 13C-NMR (8 (ppm), CD3OD) : 16.0, 38.5, 57.0, 66.4, 130.9, 132.0, 132.2, 136.6, 172.4 54 MS (CI, i-C4H10) m/z: 194 (MH+) Elemental analysis; Calcd: C, 57.52%; H, 7.02%; N, 6.10% Found: C, 57.29%; H, 6.81%; N, 6.13% UTILIZABILITY IN INDUSTRY [0129] The present invention relates to a process for simultaneously preparing an optically active (S or R)-α- amino acid and an optically active (R or S) -ct-amino acid ester which is an antipode ester thereof from anα-amino acid ester (racemic mixture). The optically activeα-amino acid and an ester thereof are useful compounds as a start- ing material or a synthetic intermediate of a physiologic- ally active peptide or a lactam series antibiotics. 55 CLAIMS 1. A process for preparing an optically active (S or R)-oc- amino acid represented by the formula (II): wherein R represents an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aralkyl group, a heteroarylalkyl group, an aryl group or a heteroaryl group, each of which may have a substituent(s), and * represents an asymmetric carbon atom, and an optically active (R or S)-α-amino acid ester repre- sented by the formula (III): wherein R has the same meaning as defined above, R1 represents an alkyl group which may have a substi- tuent (s) , and * represents an asymmetric carbon atom, provided that it has an opposite absolute con- figuration to that of the compound of the formula (ID, which comprises selectively reacting water with one of enantiomers of anα-amino acid ester which is a racemic mixture and represented by the formula (I): 56 wherein R and R1 have the same meanings as defined above, in the presence of a lipase or a protease in an organic solvent. 2. The preparation process according to Claim 1, wherein an amount of water to be used is 0.5 to 10 mol based on 1 mol of theα-amino acid ester which is a racemic mixture. 3. The preparation process according to Claim 1 or 2, wherein the lipase is a lipase originated from Burkholderia cepacia (Pseudomonas cepacia). 4. The preparation process according to Claim 1, wherein a buffer is to be presented in a reaction system. 5. The preparation process according to Claim 4, wherein the buffer is an aqueous solution of at least one material selected from the group consisting of sodium phosphate, potassium phosphate, sodium acetate, ammonium acetate and sodium citrate. 6. The preparation process according to any one of Claims 1 to 5, wherein the lipase or protease is lyophilized or freeze-dried in the presence of a buffer. 7. The preparation process according to any one of Claims 1 to 6, wherein at least one surfactant selected from the group consisting of a nonionic surfactant, an amphoteric surfactant, an anionic surfactant and a cationic surfactant is present in the reaction. 8. The preparation process according to any one of Claims 1 to 7, wherein R is a benzyl group which may have a substituent(s). 9. The preparation process according to any one of Claims 57 1 to 8, wherein R1 is a methyl group or an ethyl group each of which may have a substituent(s). 10. The preparation process according to Claim 9, wherein the substituent (s) in R1 is/are a halogen atom(s) or an alkoxy group(s). 11. The preparation process according to any one of Claims 1 to 10, wherein the organic solvent to be used is at least one organic solvent selected from the group consisting of an ether, a ketone, an ester, an aliphatic hydrocarbon and an aromatic hydrocarbon. 12. The preparation process according to any one of Claims 1 to 10, wherein the organic solvent is t-butyl methyl ether. 13. The preparation process according to Claim 1, wherein each of the optically active (S or R)-α-amino acid repre- sented by the formula (II): wherein R has the same meaning as defined above, and * represents an asymmetric carbon atom, and the optically active (R or S)-α-amino acid ester represented by the formula (III): wherein R and R1 have the same meanings as defined above, and * represents an asymmetric carbon atom, 58 provided that it has an opposite absolute configura- tion to that of the compound of the formula (II), formed by the reaction according to Claim 1 is isolated from a mixture thereof. 14. A process for preparing an acid salt of an optically- active (R or S)-α-amino acid ester which comprises separating each of an optically active (S or R)-α-amino acid represented by the formula (II): wherein R represents an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aralkyl group, a heteroarylalkyl group, an aryl group or a heteroaryl cfroup, each of which may have a substituent(s), and * represents an asymmetric carbon atom, and an optically active (R or S)-α-amino acid ester repre- sented by the formula (III): wherein R has the same meaning as defined above, R1 represents an alkyl group which may have a substi- tuent (s), and * represents an asymmetric carbon atom, provided that it has an opposite absolute configura- tion to that of the compound of the formula (II), from a mixture of the above compounds, and reacting the resulting optically active (R or S)-α-amino acid ester with an acid. 59 15. The preparation process according to Claim 14, wherein the acid is at least one acid selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid, oxalic acid, formic acid and carbonic acid. , 16. The preparation process according to Claim 15, wherein the acid is hydrochloric acid. 17. The preparation process according to Claim 14, wherein the reaction is carried out in an organic solvent. 18. The preparation process according to Claim 17, wherein the organic solvent to be used is at least one organic solvent selected from the group consisting of an ether, a ketone, an ester, an aliphatic hydrocarbon and an aromatic hydrocarbon. The present invention discloses a process for preparing an optically active (S or R)-α-amino acid represented by the formula (II): wherein R represents an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aralkyl group, heteroarylalkyl group, aryl group or heteroaryl group, each of which may have a substituent(s), and * represents an asymmetric carbon atom, and an optically active (R or S)-α-amino acid ester represented by the formula (III): wherein R1 represents an alkyl group which may have a substituent(s), and * represents an asymmetric carbon atom, provided that it has an opposite absolute configuration to that of the compound of the formula (II), which comprises selectively reacting water with one of enantiomers of an α-amino acid ester which is a racemic mixture and represented by the formula (I): wherein R and R1 have the same meanings as defined above, in the presence of a lipase or a protease in an organic solvent.

Full Text

1
SPECIFICATION
PROCESS FOR PREPARING OPTICALLY ACTIVE (S OR R)-α-AMINO
ACID AND OPTICALLY ACTIVE (R OR S)-α-AMINO ACID ESTER
TECHNICAL FIELD
[0001]
The present invention relates to a process for
simultaneously preparing an optically active (S or R)-α-
amino acid and its antipode ester, an optically active (R
or S) -α-amino acid ester, from an α-amino acid ester
(racemic mixture). These optically active α-amino acid and
an ester thereof are useful compounds as a starting materi-
al or a synthetic intermediate of a natural substance
having physiological activity or a medicine (for example,
see Non-Patent Literature 1, and Patent Literatures 1 to
5) .
BACKGROUND ART
[0002]
Heretofore, as a process for preparing an optically
active α-amino acid and an ester thereof by an enantio-
selective hydrolysis reaction using a lipase, there has
been disclosed a method in which, for example, only one of
enantiomers of various kinds of amino acid esters is
selectively hydrolyzed in water in the presence of a
porcine pancreatic lipase, a lipase originated from
Burkholderia cepacia (Pseudomonas cepacia), or a lipase
originated from Rhizopus to obtain an optically active (S)-
amino acid and an optically active (R)-amino acid ester
(for example, see Non-Patent Literature 2).
[0003]
However, according to this method, a large amount of
an enzyme has been used, and there are problems that an E
value which is an index of selectivity between enantiomers
is generally low. When an optically active carboxylic acid

2
which is a product is water-soluble, it is difficult to
recover 10 0% of the product from the aqueous solution after
completion of the reaction, and yet, in the presence of a
large amount of water, lowering in optical purity occurs
due to self-hydrolysis reaction of the substrate. Inci-
dentally, the E value has widely been utilized as an index
of selectivity of kinetic optical resolution (for example,
see Non-Patent Literature 3.).
[0004]
Also, as a conventional process for preparing an
optically activeα-amino acid and an ester thereof by an
enantio-selective hydrolysis reaction using a protease,
there is disclosed, for example, a method in which one of
the enantiomers of tyrosine ethyl ester is selectively
hydrolyzed in acetonitrile in the presence of α-chymo-
trypsin, subtilisin Carlsberg and subtilisin BPN' to obtain
an optically active (S)-tyrosine and an optically active
(R)-tyrosine ethyl ester (for example, see Non-Patent
Literature 4). Here, various reactions were carried out by
changing a content of water in acetonitrile, and the most
preferable results can be obtained in an amount of 5 to 10%
based on acetonitrile which is a solvent.
[0005]
However, no hydrolysis is carried out therein with a
system in which a water content is extremely little as 10
equivalent or less based on an amount of the substrate. In
the system used in this case, it is difficult to completely
inhibit self-hydrolysis of the amino acid ester, and a
substrate concentration based on the solvent is low so that
it is not an industrially preferred method.
[0006]
Also, as a conventional process for preparing an
optically activeα-amino acid and an ester thereof by an
enantio-selective hydrolysis reaction using a protease,
there is disclosed, for example, a method in which one of
the enantiomers of tyrosine ethyl ester is selectively

3
hydrolyzed in an acetonitrile-water mixed solvent in the
presence ofα-chymotrypsin, subtilisin Carlsberg and
subtilisin BPN' to obtain an optically active (S)-tyrosine
and an optically active (R)-tyrosine ethyl ester (for
example, see Non-Patent Literature 4). Here, various
reactions were carried out by changing a water content in
acetonitrile, and the most preferred results can be
obtained in an amount of 5 to 10% (v/v) of water based on
acetonitrile which is a solvent.
[0007]
However, in the above-mentioned reaction systems, no
hydrolysis is carried out with a system in which a water
content is extremely little as 10 equivalent or less based
on an amount of the substrate, nor referred to at all. In
the system used in this case, an amount of water used as a
substrate is still large, it is difficult to completely
inhibit self-hydrolysis of the amino acid ester, and a
substrate concentration based on the solvent is low so that
it is not an industrially preferred method.
Non-Patent Literature 1: J. Med. Chem., 46, 4533 (2003)
Non-Patent Literature 2: Chirality, 8, 418 (1996)
Non-Patent Literature 3: J. Am. Chem. Soc, 104, 72 94
(1982)
Non-Patent Literature 4: Biotechnology Letters, 13, (5),
317 (1991)
Non-Patent Literature 5: "Chemical Dictionary", published
by Tokyo Kagaku Dojin Co., Ltd., p.94 8 (2000)
Patent Literature 1: WO 9706162
Patent Literature 2: WO 2005063198
Patent Literature 3: WO 2004084812
Patent Literature 4: WO 9803473
Patent Literature 5: WO 2005051304
DISCLOSURE OF THE INVENTION
PROBLEMS TO BE SOLVED BY THE INVENTION

4
[0008]
An object of the present invention is to solve the
above-mentioned problems, and to provide a process for
preparing an optically active (S or R)-α-amino acid and its
antipode ester, an optically active (R or S)-α-amino acid
ester, simultaneously from anα-amino acid ester (racemic
mixture) according to hydrolysis using an enzyme with a
simple and easy method, and a high E value.
MEANS TO SOLVE THE PROBLEMS
[0009]
Heretofore, a preparation of an optically activeα-
amino acid by enantio-selective hydrolysis of anα-amino
acid ester (racemic mixture) is generally carried out by a
method in which, a large amount of water and a racemic p-
amino acid ester are reacted in a solvent mainly comprising
water in the presence of a hydrolase. This is because, in
hydrolysis of a racemicα-amino acid ester which is a
substrate, it has been considered that a larger amount of
water proceeds the reaction. The present inventors have
earnestly studied to solve the problems as previously
mentioned, and as a result, they have found out a novel
reaction system, which can substantially and completely
inhibit self-hydrolysis of a substrate (p-amino acid ester)
which is easily hydrolyzed by water, which causes lowering
in an optical purity, and can completely recover the
optically activeα-amino acid which is generally considered
to be difficult to obtain solely due to its water-solu-
bility, which is improved in yield, selectivity, operat-
ability, etc. as compared with the conventional techniques,
and which is more advantageous as an industrial preparation
method, which can be accomplished by reacting water and anα-amino acid ester (racemic mixture) in an organic solvent
in the presence of a lipase or a protease.
[0010]
The present invention relates to a process for

5
preparing an optically active (S or R)-α-amino acid repre-
sented by the formula (II):

wherein R represents an alkyl group, an alkenyl
group, an alkynyl group, a cycloalkyl group, an
aralkyl group, a heteroarylalkyl group, an aryl
group or a heteroaryl group, each of which may have
a substituent(s), and * represents an asymmetric
carbon atom,
and an optically active (R or S)-α-amino acid ester repre-
sented by the formula (III):
0
NH2
wherein R has the same meaning as defined above, R1
represents an alkyl group which may have a substi-
tuent (s), and * represents an asymmetric carbon
atom, provided that it has an opposite absolute con-
figuration to that of the compound of the formula
(ID,
which comprises selectively reacting water with one of
enantiomers of anα-amino acid ester which is a racemic
mixture and represented by the formula (I):

wherein R and R1 have the same meanings as defined
above,

6
in the presence of a lipase or a protease in an organic
solvent.
[0011]
The present invention also relates to a process for
preparing an acid salt of an optically active (R or S) -ex-
am i no acid ester, which comprises separating each of the
optically active (S or R) -ot-amino acid represented by the
above-mentioned formula (II):

wherein R has the same meaning as defined above, and *
represents an asymmetric carbon atom,
and the optically active (R or S)-α-amino acid ester repre-
sented by the above-mentioned formula (III):

wherein R and R1 have the same meanings as defined
above, and * represents an asymmetric carbon atom,
provided that it has an opposite absolute
configuration to that of the compound of the formula
(ID,
formed by the above-mentioned reaction from a mixture
thereof, and reacting the resulting optically active (R or
S)-α-amino acid ester with an acid.
EFFECTS OF THE INVENTION
[0012]
According to the present invention, it can be
provided a process for preparing an optically active (S or
R)-α-amino acid and its antipode ester, an optically active

7
(R or S)-α-amino acid ester, simultaneously from anα-
amino acid ester (racemic mixture) by a hydrolysis reaction
using an enzyme according to a simple and easy method with
a high E value.
BEST MODE FOR CARRYING OUT THE INVENTION
[0013]
R in Compound (I) represents an alkyl group, alkenyl
group, alkynyl group, cycloalkyl group, aralkyl group,
heteroarylalkyl group, aryl group or heteroaryl group, each
of which may have a substituent(s).
[0014]
The alkyl group of the alkyl group which may have a
substituent(s) in the above-mentioned R is a linear or
branched alkyl group having 1 to 10 carbon atoms, and there
may be mentioned, for example, an alkyl group such as a
methyl group, ethyl group, propyl group, butyl group,
pentyl group, hexyl group, heptyl group, octyl group, nonyl
group and decyl group, etc., preferably an alkyl group
having 1 to 8 carbon atoms such as a methyl group, ethyl
group, n-propyl group, isopropyl group, n-butyl group and
n-octyl group, etc., more preferably an alkyl group having
1 to 2 carbon atoms such as a methyl group and ethyl group,
etc. Incidentally, these groups contain various kinds of
isomers.
[0015]
The substituent(s) for the alkyl group which may
have a substituent(s) may be mentioned, for example, a
halogen atom such as a fluorine atom, chlorine atom,
bromine atom, iodine atom, etc.; a hydroxyl group; an
alkoxyl group having 1 to 4 carbon atoms such as a methoxyl
group, ethoxyl group, propoxyl group, butoxyl group, etc.;
an amino group; and a dialkylamino group which is
disubstituted by alkyl groups having 1 to 6 carbon atoms
such as a dimethylamino group, diethylamino group, etc.; a
cyano group; and a nitro group, preferably a fluorine atom,

8
chlorine atom, hydroxy group, amino group and dialkylamino
group.
[0016]
Such an alkyl group having the above-mentioned
substituent(s) may be specifically mentioned, for example,
a fluoromethyl group, chloromethyl group, hydroxymethyl
group, methoxymethyl group, aminomethyl group, dimethyl-
aminomethyl group, 2-chloroethyl group, 2,2-dichloroethyl
group, 2-hydroxyethyl group and 2-cyanoethyl group, etc.,
preferably a fluoromethyl group, chloromethyl group,
hydroxymethyl group, aminomethyl group, dimethylaminomethyl
group, 2-chloroethyl group and 2-cyanoethyl group.
[0017]
The alkenyl group of the alkenyl group which may
have a substituent(s) in the above-mentioned R is men-
tioned, for example, an alkenyl group having 2 to 10 carbon
atoms such as a vinyl group, propenyl group, butenyl group,
pentenyl group, hexenyl group, heptenyl group, octenyl
group, nonenyl group and decenyl group, etc., preferably an
alkenyl group having 2 to 5 carbon atoms such as a vinyl
group, propenyl group, butenyl group and pentenyl group,
etc., more preferably an alkenyl group having 2 to 3 carbon
atoms such as a vinyl group, 1-propenyl group and 2-
propenyl group, etc. Incidentally, these groups contain
various kinds of isomers.
[0018]
The substituent(s) for the alkenyl group which may
have a substituent(s) may be mentioned, for example, a
halogen atom such as a fluorine atom, chlorine atom,
bromine atom, iodine atom, etc.; a hydroxyl group,- an
alkoxyl group having 1 to 4 carbon atoms such as a methoxyl
group, ethoxyl group, propoxyl group, butoxyl group, etc.;
amino group; and a dialkylamino group which is
disubstituted by alkyl groups having 1 to 6 carbon atoms
such as a dimethylamino group, diethylamino group, etc.; a
cyano group; and a nitro group, preferably a fluorine atom,

9
chlorine atom, hydroxy group, amino group and dialkylamino
group.
[0019]
Such an alkenyl group having the above-mentioned
substituent(s) may be specifically mentioned, for example,
a 1-fluoroethenyl group, 1-chloroethenyl group, 1-hydroxy-
ethenyl group, 1-methoxyethenyl group, 1-aminoethenyl
group, 1-cyanoethenyl group, 2-fluoroethenyl group, 2-
chloroethenyl group, 2-hydroxyethenyl group, 2-methoxy-
ethenyl group, 2-aminoethenyl group, 2-cyanoethenyl group,
1,2-dimethylaminoethenyl group, 1-fluoro-2-propenyl group,
l-chloro-2-propenyl group, 1-hydroxy-2-propenyl group, 1-
methoxy-2-propenyl group, l-amino-2-propenyl group, 1-
cyano-2-propenyl group, 3-fluoro-1-propenyl group, 3-
chloro-1-propenyl group, 3-hydroxy-2-propenyl group, 3-
methoxy-2-propenyl group, 3-amino-2-propenyl group, 2-
cyano-2-propenyl group, 3,3-dimethylamino-2-propenyl group
and 3,3-dichloro-2-propenyl group, etc., preferably a 1-
fluoroethenyl group, 1-chloroethenyl group, 1-hydroxy-
ethenyl group, 1-aminoethenyl group, 1-cyanoethenyl group,
1-fluoro-2-propenyl group, l-chloro-2-propenyl group and 1-
cyano-2-propenyl group.
[0020]
The alkynyl group of the alkynyl group which may
have a substituent(s) in the above-mentioned R may be
mentioned, for example, an alkynyl group having 2 to 10
carbon atoms such as an ethynyl group, propynyl group,
butynyl group, pentynyl group, hexynyl group, heptynyl
group, octynyl group, nonynyl group and decynyl group,
etc., preferably an alkynyl group having 2 to 5 carbon
atoms such as an ethynyl group, propynyl group, butynyl
group and pentynyl group, etc., more preferably an alkynyl
group having 2 or 3 carbon atoms such as an ethynyl group,
1-propynyl group and 2-propynyl group, etc. Incidentally,
these groups contain various kinds of isomers.
[0021]

10
The substituent (s) for the alkynyl group which may-
have a substituent(s) may be mentioned, for example, a
halogen atom such as a fluorine atom, chlorine atom,
bromine atom, iodine atom, etc.; a hydroxyl group; an
alkoxyl group having 1 to 4 carbon atoms such as a methoxyl
group, ethoxyl group, propoxyl group, butoxyl group, etc.;
an amino group,- a dialkylamino group which is disubstituted
by alkyl groups having 1 to 6 carbon atoms such as a di-
methylamino group, diethylamino group, etc.; a cyano group;
and a nitro group, preferably a fluorine atom, chlorine
atom, hydroxy group, amino group and dialkylamino group.
[0022]
Such an alkynyl group which may have a substitu-
ent (s) may be specifically mentioned, for example, a 2-
fluoroethynyl group, 2-chloroethynyl group, 2-hydroxy-
ethynyl group, 2-methoxyethynyl group, 2-aminoethynyl
group, 2-cyanoethynyl group, 1-fluoro-2-propynyl group, 1-
chloro-2-propynyl group, 1-hydroxy-2-propynyl group, 1-
methoxy-2-propynyl group, 1-amino-2-propynyl group, 1-
cyano-2-propynyl group, 1,1-dichloro-2-propynyl group and
1,l-diamino-2-propynyl group, etc., preferably a 2-fluoro-
ethynyl group, 2-chloroethynyl group, 2-hydroxyethynyl
group, 2-aminoethynyl group, 1-fluoro-2-propynyl group and
1,1-dichloro-2-propynyl group.
[0023]
The cycloalkyl group of the cycloalkyl group which
may have a substituent(s) in the above-mentioned R may be
mentioned a cycloalkyl group having 3 to 10 carbon atoms,
and there may be mentioned, for example, a cycloalkyl group
such as a cyclopropyl group, cyclobutyl group, cyclopentyl
group, cyclohexyl group, cycloheptyl group, cyclooctyl
group, cyclononyl group and cyclodecyl group, etc. (Inci-
dentally, these groups contain various kinds of isomers.),
preferably a cycloalkyl group having 3 to 8 carbon atoms
such as a cyclopropyl group, cyclobutyl group, cyclopentyl
group, cyclohexyl group, cycloheptyl group and cyclooctyl

11
group, etc., more preferably a cycloalkyl group having 3 to
6 carbon atoms such as a cyclopropyl group, cyclobutyl
group, cyclopentyl group and cyclohexyl group, etc.
[0024]
The substituent(s) for the cycloalkyl group which
may have a substituent(s) may be mentioned an alkyl group
having 1 to 6 carbon chain atoms, a halogen atom such as a
fluorine atom, chlorine atom, bromine atom, iodine atom,
etc.; a hydroxyl group; an alkoxyl group having 1 to 4
carbon atoms such as a methoxyl group, ethoxyl group,
propoxyl group, butoxyl group, etc.; an amino group; a
dialkylamino group which is disubstituted by alkyl groups
having 1 to 6 carbon atoms such as a dimethylamino group,
diethylamino group, etc.; a cyano group; and a nitro group,
preferably a fluorine atom, chlorine atom, hydroxy group,
amino group and dialkylamino group.
[0025]
Such a cycloalkyl group which may have a substitu-
ent (s) may be specifically mentioned, for example, a 1-
fluorocyclopropyl group, 2-chlorocyclopropyl group, 3-
fluorocyclobutyl group, methoxycyclopropyl group, amino-
cyclopentyl group, dimethylaminocyclohexyl group, 2-chloro-
cyclopropyl group, 2,2-dichlorocyclohexyl group, 2-hydroxy-
cyclobutyl group and 2-cyanocyclohexyl group, etc., prefer-
ably a fluorocyclopropyl group and chlorocyclobutyl group.
[0026]
The aralkyl group of the aralkyl group which may
have a substituent(s) in the above-mentioned R may be
mentioned, for example, an aralkyl group in which an alkyl
group having 1 to 6 carbon atoms is substituted by an aryl
group having 6 to 14 carbon atoms, such as a benzyl group,
1-naphthylmethyl group, 2-naphthylmethyl group, phenethyl
group, phenylpropyl group and phenylbutyl group, etc.,
preferably an aralkyl group in which an alkyl group having
1 to 4 carbon atoms is substituted by an aryl group, such
as a benzyl group, 1-naphthylmethyl group, 2-naphthylmethyl

12
group, 1-phenethyl group, 2-phenethyl group, 3-phenylpropyl
group and 3-phenylbutyl group, etc., particularly prefer-
ably an aralkyl group in which a methyl group is substi-
tuted by an aryl group, such as a benzyl group, 1-naphthyl-
methyl group, 2-naphthylmethyl group, etc. Incidentally,
these groups contain various kinds of isomers.
[0027]
The substituent(s) for the aralkyl group which may
have a substituent(s) may be mentioned, for example, an
alkyl group having 1 to 10 carbon atoms such as a methyl
group, ethyl group, propyl group, butyl group, pentyl
group, hexyl group, heptyl group, octyl group, nonyl group,
decyl group, etc. (Incidentally, these groups contain
various kinds of isomers.); a hydroxyl group; a nitro
group,- a halogen atom such as a fluorine atom, chlorine
atom, bromine atom, iodine atom, etc.; an alkoxyl group
having 1 to 10 carbon atoms such as a methoxyl group,
ethoxyl group, propoxyl group, butoxyl group, pentyloxyl
group, hexyloxyl group, heptyloxyl group, octyloxyl group,
nonyloxyl group, decyloxyl group, etc. (Incidentally, these
groups contain various kinds of isomers.); an aralkyloxyl
group having 7 to 10 carbon atoms such as a benzyloxyl
group, phenethyloxyl group, phenylpropoxy group, etc.
(Incidentally, these groups contain various kinds of
isomers.); an aryloxyl group having 6 to 2 0 carbon atoms
such as a phenyloxyl group, naphthyloxyl group, etc.
(Incidentally, these groups contain various kinds of
isomers.); an alkoxyalkoxyl group having 2 to 12 carbon
atoms such as a methoxymethoxyl group, methoxyethoxyl
group, etc. (Incidentally, these groups contain various
kinds of isomers.); a monoalkylamino group such as a
methylamino group, ethylamino group, etc. (Incidentally,
these groups contain various kinds of isomers.); a dialkyl-
amino group which is disubstituted by alkyl groups having 1
to 6 carbon atoms such as a dimethylamino group, diethyl-
amino group, etc. (Incidentally, these groups contain

13
various kinds of isomers.); an acylaraino group having 1 to
12 carbon atoms such as a formylamino group, acetylamino
group, benzoylamino group, etc. (Incidentally, these groups
contain various kinds of isomers.); a nitro group; a cyano
group; and a halogenated alkyl group having 1 to 12 carbon
atoms such as a trifluoromethyl group, etc.
[0028]
As an aralkyl group having such a substituent(s),
there may be specifically mentioned, for example, a 2-
fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl
group, 3,4-difluorobenzyl group, 2,4-difluorobenzyl group,
2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl
group, 2,4-dichlorobenzyl group, 3,4-dichlorobenzyl group,
2-bromobenzyl group, 3-bromobenzyl group, 4-bromobenzyl
group, 2,4-dibromobenzyl group, 3,4-dibromobenzyl group, 2-
iodobenzyl group, 3-iodobenzyl group, 4-iodobenzyl group,
2,3-diiodobenzyl group, 3,4-diiodobenzyl group, 2-methyl-
benzyl group, 3-methylbenzyl group, 4-methylbenzyl group,
2-ethylbenzyl group, 3-ethylbenzyl group, 4-ethylbenzyl
group, 2-hydroxybenzyl group, 3-hydroxybenzyl group, 4-
hydroxybenzyl group, 2-methoxybenzyl group, 3-methoxybenzyl
group, 4-methoxybenzyl group, 2,4-dimethoxybenzyl group,
3,4-dimethoxybenzyl group, 2-ethoxybenzyl group, 4-ethoxy-
benzyl group, 2-trifluoromethylbenzyl group, 4-trifluoro-
methylbenzyl group, 4-benzyloxybenzyl group, 2-nitrobenzyl
group, 3-nitrobenzyl group, 4~nitrobenzyl group, 2-cyano-
benzyl group, 3-cyanobenzyl group, 4-cyanobenzyl group, 4-
dimethylaminobenzyl group, 4-formylaminobenzyl group, 2-
acetylaminobenzyl group, 3-acetylaminobenzyl group, 4-
acetylaminobenzyl group, 4-benzoylaminobenzyl group, 1-
naphthylmethyl group, 2-naphthylmethyl group, 2-(2-fluoro-
phenyl)ethyl group, 2-(3-fluorophenyl)ethyl group, 2-(4-
fluorophenyl)ethyl group, 2-(3,4-difluorophenyl)ethyl
group, 2-(2,4-difluorophenyl)ethyl group, 2-(2-chloro-
phenyl)ethyl group, 2-(3-chlorophenyl)ethyl group, 2-(4-
chlorophenyl)ethyl group, 2-(2,4-dichlorophenyl)ethyl

14
group, 2-(3,4-dichlorophenyl)ethyl group, 2-(2-bromo-
phenyl)ethyl group, 2-(3-bromophenyl)ethyl group, 2-(4-
bromopheny1)ethyl group, 2 -(2,4 -dibromophenyl)ethyl group,
2 -(3,4 -dibromophenyl)ethyl group, 2 -(2 -iodophenyl)ethyl
group, 2 -(3 -iodophenyl)ethyl group, 2 -(4 -iodophenyl)ethyl
group, 2-(2,3-diiodophenyl)ethyl group, 2-(3,4-diiodo-
phenyl)ethyl group, 2-(2-tolyl)ethyl group, 2-(3-tolyl)-
ethyl group, 2-(4-tolyl)ethyl group, 2-(2-ethylphenyl)ethyl
group, 2-(3-ethylphenyl)ethyl group, 2-(4-ethylphenyl)ethyl
group, 2-(2-hydroxyphenyl)ethyl group, 2-(4-hydroxyphenyl)-
ethyl group, 2-(2-methoxyphenyl)ethyl group, 2-(3-methoxy-
phenyl)ethyl group, 2-(4-methoxyphenyl)ethyl group, 2-(2,4-
dimethoxyphenyl)ethyl group, 2-(3,4-dimethoxyphenyl)ethyl
group, 2-(2-ethoxyphenyl)ethyl group, 2-(4-ethoxyphenyl)-
ethyl group, 2-(2-trifluoromethylphenyl)ethyl group, 2-(4-
trifluoromethylphenyl)ethyl group, 2-(4-benzyloxyphenyl)-
ethyl group, 2-(2-nitrophenyl)ethyl group, 2-(3-nitro-
phenyl)ethyl group, 2-(4-nitrophenyl)ethyl group, 2-(2-
cyanophenyl)ethyl group, 2-(3-cyanophenyl)ethyl group, 2-
(4-cyanopheny1)ethyl group, 2-(4-dimethylaminophenyl)ethyl
group, 2 -(4 -formylaminophenyl)ethyl group, 2-(2 -acetyl-
aminophenyl)ethyl group, 2-(3-acetylaminophenyl)ethyl
group, 2-(4-acetylaminophenyl)ethyl group, 2-(4-benzoyl-
aminophenyl)ethyl group, 3-(2-fluorophenyl)propyl group, 3-
(4-fluorophenyl)propyl group, 3-(4-chlorophenyl)propyl
group, 3-(4-bromophenyl)propyl group, 3-(4-iodophenyl)-
propyl group, 3-(2-chlorophenyl)propyl group, 3-(2-methoxy-
phenyl ) propyl group, 3-(4-methoxyphenyl)propyl group, 3-
(3,4-dimethoxyphenyl)propyl group, 3-(4-trifluoromethyl-
phenyl ) propyl group, 3-(2-trifluoromethylphenyl)propyl
group, 3-(4-nitrophenyl)propyl group, 3-(4-cyanophenyl)-
propyl group and 3-(4-acetylaminophenyl)propyl group, etc.,
preferably a 2-fluorobenzyl group, 3-fluorobenzyl group, 4-
fluorobenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl
group, 4-chlorobenzyl group, 2-bromobenzyl group, 3-bromo-
benzyl group, 4-bromobenzyl group, 2-iodobenzyl group, 3-

15
iodobenzyl group, 4-iodobenzyl group, 2-methylbenzyl group,
3-methylbenzyl group, 4-methylbenzyl group, 2-hydroxybenzyl
group, 4-hydroxybenzyl group, 2-methoxybenzyl group, 3-
methoxybenzyl group, 4-methoxybenzyl group, 3,4-dimethoxy-
benzyl group, 2-trifluoromethylbenzyl group, 4-trifluoro-
methylbenzyl group, 4-benzyloxybenzyl group, 2-nitrobenzyl
group, 3-nitrobenzyl group, 4-nitrobenzyl group, 2-cyano-
benzyl group, 3-cyanobenzyl group, 4-cyanobenzyl group, 4-
formylaminobenzyl group, 3-acetylaminobenzyl group, 4-
acetylaminobenzyl group, 4-benzoylaminobenzyl group,
1-naphthylmethyl group, 2-naphthylmethyl group, 2-(2-
fluorophenyl)ethyl group, 2-(3-fluorophenyl)ethyl group, 2-
(4 -fluorophenyl)ethyl group, 2 -(2-chlorophenyl)ethyl group,
2-(3-chlorophenyl)ethyl group, 2-(4-chlorophenyl)ethyl
group, 2-(2-bromophenyl)ethyl group, 2-(3-bromophenyl)ethyl
group, 2-(4-broraophenyl)ethyl group, 2-(2-iodophenyl)ethyl
group, 2 -(3 -iodophenyl)ethyl group, 2-(4 -iodophenyl)ethyl
group, 2-(2-tolyl)ethyl group, 2-(3-tolyl)ethyl group, 2-
(4-tolyl)ethyl group, 2-(2-ethylphenyl)ethyl group, 2-(2-
hydroxyphenyl)ethyl group, 2-(4-hydroxyphenyl)ethyl group,
2 -(2-methoxyphenyl)ethyl group, 2-(3-methoxyphenyl)ethyl
group, 2-(4-methoxyphenyl)ethyl group, 2-(2,4-dimethoxy-
phenyl)ethyl group, 2-(3,4-dimethoxyphenyl)ethyl group, 2-
(2-trifluoromethylphenyl)ethyl group, 2-(4-trifluoromethyl-
phenyl)ethyl group, 2-(4-benzyloxyphenyl)ethyl group, 2-(2-
nitrophenyl)ethyl group, 2-(3-nitrophenyl)ethyl group, 2-
(4-nitrophenyl)ethyl group, 2-(2-cyanopheny1)ethyl group,
2 -(3 -cyanopheny1)ethyl group, 2 -(4 -cyanopheny1)ethyl group,
2-(2-acetylaminophenyl)ethyl group, 2-(3-acetylamino-
phenyl)ethyl group, 2-(4-acetylaminophenyl)ethyl group, 2-
(4-benzoylaminophenyl)ethyl group, 3-(2-fluorophenyl)propyl
group, 3-(4-fluorophenyl)propyl group, 3-(4-chlorophenyl)-
propyl group, 3-(4-bromophenyl)propyl group, 3-(4-iodo-
phenyl)propyl group, 3-(2-chlorophenyl)propyl group, 3-(2-
methoxyphenyl)propyl group, 3-(4-methoxyphenyl)propyl
group, 3-(3,4-dimethoxyphenyl)propyl group, 3-(4-trifluoro-

16
methylphenyDpropyl group, 3-(2-trifluoromethylphenyl)-
propyl group, 3-(4-nitrophenyl)propyl group, 3-(4-cyano-
phenyl)propyl group and 3-(4-acetylaminophenyl)propyl
group, more preferably a 2-fluorobenzyl group, 4-fluoro-
benzyl group, 2-chlorobenzyl group, 4-chlorobenzyl group,
2-bromobenzyl group, 4-bromobenzyl group, 2-iodobenzyl
group, 4-iodobenzyl group, 2-methylbenzyl group, 4-methyl-
benzyl group, 4-hydroxybenzyl group, 2-methoxybenzyl group,
4-methoxybenzyl group, 3,4-dimethoxybenzyl group, 2-tri-
fluoromethylbenzyl group, 4-trifluoromethylbenzyl group, 4-
benzyloxybenzyl group, 2-nitrobenzyl group, 4-nitrobenzyl
group, 2-cyanobenzyl group, 3-cyanobenzyl group, 4-cyano-
benzyl group, 3-acetylaminobenzyl group, 4-acetylamino-
benzyl group, 1-naphthylmethyl group, 2-naphthylmethyl
group, 2-(2-fluorophenyl)ethyl group, 2-(4-fluorophenyl)-
ethyl group, 2-(2-chlorophenyl)ethyl group, 2-(4-chloro-
phenyl)ethyl group, 2-(2-bromophenyl)ethyl group, 2-(4-
bromophenyl)ethyl group, 2-(2-iodophenyl)ethyl group, 2-(4-
iodophenyl)ethyl group, 2-(2-tolyl)ethyl group, 2-(4-
tolyDethyl group, 2-(4-hydroxyphenyl) ethyl group, 2-(2-
methoxyphenyl)ethyl group, 2-(4-methoxyphenyl)ethyl group,
2-(3,4-dimethoxyphenyl)ethyl group, 2-(2-trifluoromethyl-
phenyl) ethyl group, 2-(4-trifluoromethylphenyl)ethyl group,
2-(4-benzyloxyphenyl)ethyl group, 2-(2-nitrophenyl)ethyl
group, 2-(4-nitrophenyl)ethyl group, 2-(2-cyanopheny1)ethyl
group, 2-(4-cyanophenyl)ethyl group, 2-(2-acetylamino-
phenyl) ethyl group and 2-(4-acetylaminophenyl)ethyl group),
particularly preferably 2-fluorobenzyl group, 4-fluoro-
benzyl group, 2-chlorobenzyl group, 4-chlorobenzyl group,
2-bromobenzyl group, 4-bromobenzyl group, 2-iodobenzyl
group, 4-iodobenzyl group, 2-methylbenzyl group, 4-methyl-
benzyl group, 4-hydroxybenzyl group, 2-methoxybenzyl group,
4-methoxybenzyl group, 3,4-dimethoxybenzyl group, 2-tri-
fluoromethylbenzyl group, 4-trifluoromethylbenzyl group, 4-
benzyloxybenzyl group, 2-nitrobenzyl group, 4-nitrobenzyl
group, 2-cyanobenzyl group, 3-cyanobenzyl group, 4-cyano-

17
benzyl group, 3-acetylaminobenzyl group, 4-acetylamino-
benzyl group, 1-naphthylmethyl group and 2-naphthylmethyl
group.
[0029]
The heteroarylalkyl group of the heteroarylalkyl
group which may have a substituent in the above-mentioned R
may be mentioned, for example, a heteroarylalkyl group in
which an alkyl group having 1 to 6 carbon atoms is substi-
tuted by a heteroaryl group having 6 to 14 carbon atoms,
such as a 2-pyridylmethyl group, 3-pyridylmethyl group, 3-
pyridylmethyl group, 2-thienylmethyl group, 3-thienylmethyl
group, 2-imidazolyl group, 4-imidazolyl group, 2-thienyl-
methyl group, 3-indolylmethyl group, 2-pyridylethyl group,
2-thienylethyl group, 2-pyridylpropyl group, 2-pyridylbutyl
group, etc., preferably a heteroarylalkyl group in which an
alkyl group having 1 to 2 carbon atoms is substituted by a
heteroaryl group, such as a 2-pyridylmethyl group, 2-
thienylmethyl group, 3-indolylmethyl group, 2-pyridylethyl
group, 2-thienylethyl group, etc., more preferably a
heteroarylalkyl group in which a methyl group is substitut-
ed by a heteroarylalkyl group, such as a 2-pyridylmethyl
group, 2-thienylmethyl group, 3-indolylmethyl group, etc.
Incidentally, these groups contain various kinds of
isomers.
[0030]
The heteroaryl group of the heteroarylalkyl group
which may have a substituent(s) in the above-mentioned R
may be mentioned, for example, a 2-furyl group, 3-furyl
group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group,
2-pyrrolyl group, 3-pyrrolyl group, 2-thienyl group, 3-
thienyl group, 2-indolyl group, 3-indolyl group, 2-imid-
azolyl group, 4-imidazolyl group, 3-pyrazolyl group, 2-
pyrimidyl group, 4-pyrimidyl group, 2-quinolyl group and 3-
quinolyl group.
[0031]
The substituent(s) for the heteroaryl group which

18
may have a substituent(s) may be mentioned an alkyl group
having 1 to 4 carbon atoms such as a methyl group, ethyl
group, propyl group, butyl group, etc. (Incidentally, these
groups contain various kinds of isomers.); a hydroxyl
group; a halogen atom such as a chlorine atom, bromine
atom, iodine atom, fluorine atom, etc.; an alkoxyl group
having 2 to 4 carbon atoms such as an ethoxyl group, etc.
(Incidentally, these groups contain various kinds of
isomers.); an amino group; a nitro group; a cyano group;
and a halogenated alkyl group having 1 to 4 carbon atoms
such as a trifluoromethyl group, etc.
[0032]
Such a heteroaryl group which may have a substi-
tuent (s) may be specifically mentioned, for example, a 2-
(3-methyl)furyl group, 2-(4Tmethyl)furyl group, 2-(3-
ethyDfuryl group, 2-(4-ethyl) furyl group, 2-(3-fluoro)-
furyl group, 2-(3-chloro)furyl group, 2-(3-hydroxy)furyl
group, 2-(3-methoxy)furyl group, 2-(3-amino)furyl group, 2-
(3-nitro)furyl group, 2-(3-cyano)fury1 group, 2-(3-methyl)-
pyridyl group, 2-(4-methyl)pyridyl group, 2-(3-ethyl)-
pyridyl group, 2-(4-ethyl)pyridyl group, 2-(3-fluoro)-
pyridyl group, 2-(4-chloro)pyridyl group, 2-(3-hydroxy)-
pyridyl group, 2-(3-methoxy)pyridyl group, 2-(3-amino)-
pyridyl group, 2-(3-nitro)pyridyl group, 2-(3-cyano)pyridyl
group, 2-(3,5-dichloro)pyridyl group, 3-(2-chloro)pyridyl
group, 2-(3-methyl)pyrrolyl group and 2-(3-methyl)thienyl
group, etc., preferably a 2-(3-methyl)furyl group, 2-(3-
fluoro)furyl group, 2-(3-methyl)pyridyl group, 2-(3-
fluoro)pyridyl group, 2-(3-nitro)pyridyl group, 2-(3-
cyano)pyridyl group and 2-(3,5-dichloro)pyridyl group.
[0033]
Such a heteroarylalkyl group which may have a sub-
stituent (s) may be specifically mentioned, for example, a
2 -(3-methyl)furylmethyl group, 2 -(4-methyl)furylmethyl
group, 2-(3-ethyl)furylmethyl group, 2-(4-ethyl)furylmethyl
group, 2-(3-fluoro)furylmethyl group, 2-(3-chloro)furyl-

19
methyl group, 2-(3-hydroxy)furylmethyl group, 2-(3-
methoxy)furylmethy1 group, 2-(3-amino)furylmethyl group, 2-
(3-nitro)furylmethyl group, 2-(3-cyano)furylmethyl group,
2-(3-methyl)pyridylmethyl group, 2-(4-methyl)pyridylmethyl
group, 2-(3-ethyl)pyridylmethyl group, 2-(4-ethyDpyridyl-
methyl group, 2-(3-fluoro)pyridylmethyl group, 2-(4-
chloro)pyridylmethyl group, 2-(3-hydroxy)pyridylmethyl
group, 2-(3-methoxy)pyridylmethyl group, 2-(3-amino)-
pyridylmethyl group, 2-(3-nitro)pyridylmethyl group, 2-(3-
cyano)pyridylmethyl group, 2-(3,5-dichloro)pyridylmethyl
group, 3-(2-chloro)pyridylmethyl group, 2-(3-methyl)-
pyrrolylmethyl group and 2-(3-methyl)thienylmethyl group,
etc., preferably a 2-(3-methyl)furylmethyl group, 2-(3-
fluoro)furylmethyl group, 2-(3-methyl)pyridylmethyl group,
2-(3-fluoro)pyridylmethyl group, 2-(3-nitro)pyridyl group,
2-(3-cyano)pyridylmethyl group and 2-(3 , 5-dichloro)pyridyl-
methyl group.
[0034]
The aryl group of the aryl group which may have a
substituent(s) in the above-mentioned R may be mentioned a
phenyl group, naphthyl group, anthranyl group, phenanthryl
group, biphenyl group and binaphthyl group.
[0035]
The substituent(s) for the aryl group which may have
a substituent(s) may be mentioned an alkyl group having 1
to 4 carbon atoms such as a methyl group, ethyl group,
propyl group, butyl group, etc. (Incidentally, these groups
contain various kinds of isomers.); a hydroxyl group; a
halogen atom such as a chlorine atom, bromine atom, iodine
atom, fluorine atom, etc.; an alkoxyl group having 2 to 4
carbon atoms such as an ethoxyl group, etc. (Incidentally,
these groups contain various kinds of isomers.); an alkyl-
enedioxy group having 1 to 4 carbon atoms such as a
methylenedioxy group, etc.; a nitro group; a cyano group;
and a halogenated alkyl group having 1 to 4 carbon atoms
such as a trifluoromethyl group, etc.

20
[0036]
Such an aryl group which may have a substituent(s)
may be specifically mentioned, for example, a 2-tolyl
group, 3-tolyl group, 4-tolyl group, 2,3-xylyl group, 2,6-
xylyl group, 2,4-xylyl group, 3,4-xylyl group, mesityl
group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-
hydroxyphenyl group, 2,3-dihydroxyphenyl group, 2,4-
dihydroxyphenyl group, 3,4-dihydroxyphenyl group, 2-chloro-
phenyl group, 3-chlorophenyl group, 4-chlorophenyl group,
2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 3,4-
dichlorophenyl group, 3,5-dichlorophenyl group, 2-bromo-
phenyl group, 3-bromophenyl group, 4-bromophenyl group, 2-
iodophenyl group, 3-iodophenyl group, 4-iodophenyl group,
2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl
group, 2,3-difluorophenyl group, 2,4-difluorophenyl group,
3,4-difluorophenyl group, 3-bromo-5-chloro-2-hydroxyphenyl
group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-
methoxyphenyl group, 2,3-dimethoxyphenyl group, 2,4-
dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 3,5-
dimethoxyphenyl group, 3,4-methylenedioxyphenyl group, 4-
ethoxyphenyl group, 4-butoxyphenyl group, 4-isopropoxy-
phenyl group, 1-phenoxyphenyl group, 4-benzyloxyphenyl
group, 4-trifluoromethylphenyl group, 2-nitrophenyl group,
3-nitrophenyl group, 4-nitrophenyl group, 4-cyanopheny1
group, 4-methoxycarbonylphenyl group, 1-naphthyl group and
2-naphthyl group, etc., preferably a phenyl group, 2-tolyl
group, 3-tolyl group, 4-tolyl group, 2,3-xylyl group, 2-
hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl
group, 2,3-dihydroxyphenyl group, 2,4-dihydroxyphenyl
group, 3,4-dihydroxyphenyl group, 2-chlorophenyl group, 3-
chlorophenyl group, 4-chlorophenyl group, 2,3-dichloro-
phenyl group, 2,4-dichlorophenyl group, 3,4-dichlorophenyl
group, 3,5-dichlorophenyl group, 2-bromophenyl group, 3-
bromophenyl group, 4-bromophenyl group, 2-iodophenyl group,
3-iodophenyl group, 4-iodophenyl group, 2-fluorophenyl
group, 3-fluorophenyl group, 4-fluorophenyl group, 3,4-

21
difluorophenyl group, 3-bromo-5-chloro-2-hydroxyphenyl
group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-
methoxyphenyl group, 2,3-dimethoxyphenyl group, 2,4-
dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 3,5-
dimethoxyphenyl group, 3,4-methylenedioxyphenyl group, 4-
ethoxyphenyl group, 4-trifluoromethylphenyl group, 4-
nitrophenyl group, 4-cyanophenyl group, 1-naphthyl group
and 2-naphthyl group, more preferably phenyl group, 2-tolyl
group, 3-tolyl group, 4-tolyl group, 2,3-xylyl group, 4-
hydroxyphenyl group, 3,4-dihydroxyphenyl group, 2-chloro-
phenyl group, 3-chlorophenyl group, 4-chlorophenyl group,
2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 3,4-
dichlorophenyl group, 3,5-dichlorophenyl group, 2-bromo-
phenyl group, 3-bromophenyl group, 4-bromophenyl group, 4-
iodophenyl group, 2-fluorophenyl group, 3-fluorophenyl
group, 4-fluorophenyl group, 3,4-difluorophenyl group, 2-
iodophenyl group, 3-iodophenyl group, 4-iodophenyl group,
2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxy-
phenyl group, 2,3-dimethoxyphenyl group, 2,4-dimethoxy-
phenyl group, 3,4-dimethoxyphenyl group, 3,5-dimethoxy-
phenyl group, 3,4-methylenedioxyphenyl group, 4-trifluoro-
methylphenyl group, 4-nitrophenyl group, 1-naphthyl group,
2-naphthyl group and 3-pyridyl group, particularly prefer-
ably phenyl group, 2-tolyl group, 3-tolyl group, 4-tolyl
group, 2,3-xylyl group, 2-chlorophenyl group, 3-chloro-
phenyl group, 4-chlorophenyl group, 2,3-dichlorophenyl
group, 2,4-dichlorophenyl group, 3,4-dichlorophenyl group,
3,5-dichlorophenyl group, 2-bromophenyl group, 3-bromo-
phenyl group, 4-bromophenyl group, 2-fluorophenyl group, 3-
fluorophenyl group, 4-fluorophenyl group, 3,4-difluoro-
phenyl group, 2-iodophenyl group, 3-iodophenyl group, 4-
iodophenyl group, 2-methoxyphenyl group, 3-methoxyphenyl
group, 4-methoxyphenyl group, 2,3-dimethoxyphenyl group,
3,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl group or
3,4-methylenedioxyphenyl group.
[0037]

22
The heteroaryl group of the heteroaryl group which
may have a substituent(s) in the above-mentioned R may be
mentioned, for example, a 2-furyl group, 3-furyl group, 2-
pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrrolyl
group, 3-pyrrolyl group, 2-thienyl group, 3-thienyl group,
2-indolyl group, 3-indolyl group, 2-imidazolyl group, 4-
imidazolyl group, 3-pyrazolyl group, 2-pyrimidyl group, 4-
pyrimidyl group and quinolyl group.
[0038]
The substituent(s) for the heteroaryl group which
may have a substituent(s) may be mentioned an alkyl group
having 1 to 4 carbon atoms such as a methyl group, ethyl
group, propyl group, butyl group, etc. (Incidentally, these
groups contain various kinds of isomers.); a hydroxyl
group; a halogen atom such as a chlorine atom, bromine
atom, iodine atom, fluorine atom, etc.; an alkoxyl group
having 2 to 4 carbon atoms such as an ethoxyl group, etc.
(Incidentally, these groups contain various kinds of
isomers.); an amino group; a nitro group; a cyano group;
and a halogenated alkyl group having 1 to 4 carbon atoms
such as a trifluoromethyl group, etc.
[0039]
Such a heteroaryl group which may have a substitu-
ent(s) may be specifically mentioned, for example, a 2-(3-
methyl)furyl group, 2-(4-methyl)furyl group, 2-(3-ethyl)-
furyl group, 2-(4-ethyl)furyl group, 2-(3-fluoro)furyl
group, 2-(3-chloro)furyl group, 2-(3-hydroxy)furyl group,
2-(3-methoxy)furyl group, 2-(3-amino)furyl group, 2-(3-
nitro)furyl group, 2-(3-cyano)furyl group, 2-(3-methyl)-
pyridyl group, 2-(4-methyl)pyridyl group, 2-(3-ethyl)-
I
pyridyl group, 2-(4-ethyl)pyridyl group, 2-(3-fluoro)-
pyridyl group, 2-(4-chloro)pyridyl group, 2-(3-hydroxy)-
pyridyl group, 2-(3-methoxy)pyridyl group, 2-(3-amino)-
pyridyl group, 2-(3-nitro)pyridyl group, 2-(3-cyano)pyridyl
group, 2-(3,5-dichloro)pyridyl group, 3-(2-chloro)pyridyl
group, 2-(3-methyl)pyrrolyl group and 2-(3-methyl)thienyl

23
group, etc., preferably a 2-(3-methyl)fury1 group, 2-(3-
fluoro)furyl group, 2-(3-methyl)pyridyl group, 2-(3-
fluoro)pyridyl group, 2-(3-nitro)pyridyl group, 2-(3-
cyano)pyridyl group and 2-(3,5-dichloro)pyridyl group.
[0040]
R1 in Compound (I) represents an alkyl group which
may have a substituent(s).
[0041]
The alkyl group of the alkyl group which may have a
substituent(s) in the above-mentioned R1 is a linear or
branched alkyl group having 1 to 10 carbon atoms, and there
may be mentioned, for example, an alkyl group such as a
methyl group, ethyl group, propyl group, butyl group,
pentyl group, hexyl group, heptyl group, octyl group, nonyl
group and decyl group, preferably a linear or branched
alkyl group having 1 to 6 carbon atoms such as a methyl
group, ethyl group, n-propyl group, isopropyl group, n-
butyl group, isobutyl group, sec-butyl group, n-pentyl
group, n-hexyl group, etc., more preferably a linear or
branched alkyl group having 1 to 4 carbon atoms such as a
methyl group, ethyl group, n-propyl group, n-butyl group,
isobutyl group, etc. Incidentally, these groups contain
various kinds of isomers.
[0042]
The substituent(s) for the alkyl group which may
have a substituent(s) may be mentioned a halogen atom such
as a fluorine atom, chlorine atom, bromine atom, iodine
atom, etc.; a hydroxyl group; an alkoxyl group having 1 to
4 carbon atoms such as a methoxyl group, ethoxyl group,
propoxyl group, butoxyl group, etc.; a dialkylamino group
which is di-substituted by an alkyl group having 1 to 6
carbon atoms such as a dimethylamino group, diethylamino
group, etc.; and a cyano group, preferably a fluorine atom,
chlorine atom, methoxyl group, ethoxyl group, hydroxyl
group and cyano group, more preferably a fluorine atom,
chlorine atom, methoxyl group and ethoxyl group.

24
[0043]
Such an alkyl group which may have a substituent(s)
may be specifically mentioned, for example, a 2-fluoroethyl
group, 2-chloroethyl group, 2,2-difluoroethyl group, 2,2-
dichloroethyl group, 2,2,2-trichloroethyl group, 2,2,2-
trifluoroethyl group, 2-methoxyethyl group, 2-ethoxyethyl
group, methoxymethyl group, 2-hydroxyethyl group, 2-cyano-
ethyl group, 2-bromoethyl group, 2-dimethylamino group, 2-
chloropropyl group, 3-chloropropyl group, etc., preferably
a 2-chloroethyl group, 2,2,2-trichloroethyl group, 2,2,2-
trifluoroethyl group, methoxymethyl group, 2-methoxyethyl
group and 2-ethoxyethyl group.
[0044]
A lipase to be used in the reaction of the present
invention is preferably a lipase derived from microorg-
anisms which can be isolatable from an yeast or bacteria,
more preferably a lipase originated from Burkholderia
cepacia (Pseudomonas cepacia) (for example, AMANO PS
(available from AMANO ENZYME CO.), etc.) can be used.
Also, a protease to be used in the reaction of the present
invention may be used, for example, a protease originated
from pancreas of a vertebrate, Aspergillus Olyzae,
Aspergillus Melleus, Bacillus subtilis, Bacillus
stearothermophilus, etc.
Incidentally, the lipase or protease may be used a
commercially available product as such in a natural form or
as an immobilized enzyme, and it may be used alone or in
admixture of two or more kinds. Also, it may be used by
previously removing an enzyme-immobilizing agent contained
in the commercially available product.
[0045]
The above-mentioned lipase or protease may be used
after subjecting a commercially available product in a
natural form or an immobilized enzyme to chemical treatment
or physical treatment.
[0046]

25
As the above-mentioned chemical treatment or
physical treatment method, there may be specifically men-
tioned, for example, a method in which a lipase or protease
is dissolved in a buffer (an organic solvent may exist
therein depending on necessity), and freeze-dried as such
or after stirring, etc. Incidentally, freeze-drying means
a method in which an aqueous solution or a substance con-
taining a water component is rapidly frozen at a tempera-
ture of a freezing point or lower, and water is removed
according to sublimation by reducing a pressure to a water
vapor pressure of the frozen product or lower to dry the
substance (for example, see Non-Patent Literature 3).
Incidentally, according to the treatment, catalyst activity
(reactivity or selectivity, etc.) can be improved.
[0047]
The above-mentioned buffer may be mentioned, for
example, an aqueous solution of an inorganic acid salt such
as an aqueous sodium phosphate solution, an aqueous potas-
sium phosphate solution, etc.; an aqueous solution of an
organic acid salt such as an aqueous sodium acetate
solution, an aqueous ammonium acetate solution, an aqueous
sodium citrate solution, etc., preferably an aqueous sodium
phosphate solution, an aqueous potassium phosphate solution
or an aqueous ammonium acetate solution is used. Incident-
ally, these buffers may be used singly or in admixture of
two or more kinds.
[0048]
A concentration of the above-mentioned buffer is
preferably 0.01 to 2 mol/L, more preferably 0.05 to 0.5
mol/L, and a pH of the buffer is preferably 4 to 9, more
preferably 7 to 8.5.
[0049]
An amount of the buffer to be used at the time of
freeze-drying is not particularly limited so long as it is
a concentration that the lipase or protease is completely
dissolved, and it is preferably 10 ml to 1000 ml, more

26
preferably 10 ml to 100 ml based on 1 g of the lipase or
protease.
[0050]
An amount of the above-mentioned lipase or protease
to be used is preferably 0.1 to 1000 mg, more preferably 1
to 200 mg based on 1 g of Compound (I).
[0051]
The reaction of the present invention can be carried
out in the presence of a lipase or a protease in an organic
solvent. During the reaction of the present invention, the
lipase or protease pertains to the reaction by presenting
substantially in a suspended state in the reaction mixture,
and it may be dissolved therein without any problem.
Incidentally, the terms "in an organic solvent" in the
present invention mean the state in which a reaction
solvent to be used in hydrolysis is an organic solvent, and
a liquid portion dissolved in the organic solvent, except
for a lipase or protease (which may sometimes include an
immobilizing agent) and a product precipitated as crystals,
etc., does not cause phase separation from the reaction
system (that is, a state in which water (it may contain an
inorganic salt or organic salt mentioned hereinbelow), a
substrate and an organic solvent comprises a single phase).
[0052]
As water to be used in the reaction of the present
invention, purified water such as deionized water, distil-
led water, etc. is generally used, and the water may con-
tain an inorganic salt such as sodium phosphate, potassium
phosphate, etc., or an organic salt such as sodium acetate,
ammonium acetate, sodium citrate, etc. An amount of these
inorganic salts and organic salts to be used is preferably
in an amount of 0.01 to 10 mol/L, more preferably 0.1 to 1
mol/L based on the amount of water. Incidentally, the
above-mentioned inorganic salt or organic salt is previous-
ly dissolved in water to prepare a buffer and the buffer
may be used in the reaction without any problem.

27
[0053]
An amount of the above-mentioned water is an amount
equal to or less than the solubility (an amount capable of
dissolving) of water in an organic solvent to be used (if
the amount exceeds the solubility, phase separation of the
liquid portion occurs), and an upper limit thereof may
somewhat vary depending on the kind of Compound (I), and
preferably 0.5 to 10 mol, more preferably 0.5 to 5.0 mol,
further preferably 1.0 to 3.0 mol, particularly preferably
1.5 to 2.5 mol based on 1 mol of Compound (I). Incidental-
ly, whereas it may vary deepening on the kind of Compound
(I), when an amount of the water to be used exceeds 10 mol
based on 1 mol of Compound (I), undesirable states occurs,
for example, self-hydrolysis of Compound (I) which lowers
an optical purity, elongation of the reaction time due to
suspended state in which a slight amount of water does not
dissolve in an organic solvent (a state in which phase
separation occurs at the liquid portion), etc., so that the
amount of the water to be used is preferably adjusted to an
amount of the solubility of water in an organic solvent or
less, preferably 10 mol or less.
[0054]
As the above-mentioned organic solvent, there may be
mentioned, for example, an aliphatic hydrocarbon such as n-
pentane, n-hexane, n-heptane, n-octane, cyclopentane,
cyclohexane and cyclopentane, etc.; an aromatic hydrocarbon
such as benzene, toluene and xylene, etc.; an ether such as
diethyl ether, t-butyl methyl ether, diisopropyl ether,
cyclopentyl methyl ether, tetrahydrofuran and 1,4-dioxane,
etc.; a ketone such as acetone and methyl ethyl ketone,
etc., preferably n-hexane, n-heptane, cyclopentane, cyclo-
hexane, toluene, diisopropyl ether, t-butyl methyl ether,
cyclopentyl methyl ether and tetrahydrofuran, more prefer-
ably n-hexane, cyclohexane, toluene, diisopropyl ether, t-
butyl methyl ether and cyclopentyl methyl ether, particu-
larly preferably cyclohexane, toluene and/or t-butyl methyl

28
ether is/are used. Incidentally, these organic solvents
may be used singly or in admixture of two or more kinds.
[0055]
An amount of the above-mentioned organic solvent to
be used is preferably 2 to 200 mL, more preferably 5 to 80
mL based on 1 g of Compound (I) . A ratio of the above-
mentioned water and the organic solvent is not particularly
limited, and an amount of water to be used may be an amount
of the solubility of water in an organic solvent or less
(that is, an amount which saturates in an organic solvent
or less).
[0056]
The reaction of the present invention is desirably
carried out in the presence of a surfactant. As the sur-
factant to be used, there may be mentioned, for example, a
nonionic surfactant such as polyethylene glycol, polyvinyl-
pyrrolidone, polyethylene lauryl ether, polyethylene cetyl
ether, polyoxyethylene octylphenyl ether, etc.; an ampho-
teric surfactant such as 3-[(3-chloroamidopropyl)-dimethyl-
ammonio]-2-hydroxy-l-propanesulfonate, 3-[(3-chloroamido-
propyl) -dimethylammonio] -1-propanesulfonate, etc.; an
anionic surfactant such as sodium dioctylsulfosuccinate,
sodium dodecylsulfonate, tris(hydroxymethyl)aminomethane-
dodecyl sulfate, etc.; a cationic surfactant such as cetyl
trimethyl ammonium bromide or cetyl dimethylethyl ammonium
bromide, etc., preferably a nonionic surfactant, more
preferably polyethylene glycol, polyethylene cetyl ether,
polyoxyethylene octylphenyl ether, particularly preferably
polyoxyethylene octylphenyl ether is used. Incidentally,
these surfactants may be used singly or in admixture of two
or more kinds.
[0057]
An amount of the above-mentioned surfactant to be
used is preferably 10 to 1000 mg, more preferably 50 to 200
mg based on 1 g of Compound (I).
[0058]

29
The reaction of the present invention can be carried
out by the method, for example, in which Compound (I), a
lipase or a protease, water (if necessary, it may contain
an inorganic salt or an organic salt) and an organic sol-
vent are mixed and reacted with stirring, etc. A reaction
temperature at that time is preferably 0 to 8 0°C, more
preferably 10 to 50°C, particularly preferably 30 to 45°C,
and a reaction pressure is not particularly limited.
Incidentally, during the reaction, lipase or protease is
substantially in a suspended state, and depending on a kind
of Compound (I), Compound (I) is precipitated as a white
solid in some cases with the progress of the reaction, but
these suspension or precipitation does not cause any effect
on the reaction.
[0059]
With regard to Compound (II) and Compound (III)
obtained by the reaction of the present invention, when
Compound (II) is precipitated after completion of the
reaction, then, Compound (II) can be obtained, for example,
by adding a suitable organic solvent (for example, aceto-
nitrile, acetone, etc.) to the reaction mixture and
filtered, and Compound (III) can be obtained by concentrat-
ing the organic layer. Also, when Compound (II) is not
precipitated after completion of the reaction, Compound
(II) can be obtained, for example, by adjusting a pH of the
mixture, extracting Compound (II) with water, further
adjusting a pH of the extract again and extracting with an
organic solvent, and concentrating the obtained organic
layer. Compound (III) can be obtained by concentrating the
organic layer which has been separated at the time of
extracting Compound (II) with water. Incidentally, the
obtained Compound (II) and Compound (III) may be further
purified by the conventionally known method such as
crystallization, recrystallization, distillation, column
chromatography, etc.
[0060]

30
In the present invention, each compound is separated
from a mixture of an optically active (S or R)-α-amino acid
represented by the above-mentioned formula (II) formed by
the reaction with water and an optically active (R or S)-α-
amino acid ester represented by the above-mentioned formula
(III), and the obtained optically active (R or S)-α-amino
acid ester is reacted with an acid to prepare an acid salt
of the optically active (R or S)-α-amino acid ester.
[0061]
As the acid usable for the above-mentioned reaction,
there may be mentioned, for example, hydrochloric acid,
sulfuric acid, acetic acid, p-toluenesulfonic acid, oxalic
acid, formic acid and carbonic acid, preferably hydro-
chloric acid is used.
An amount of the above-mentioned acid to be used is
preferably 0.5 to 2.0 mol, more preferably 0.9 to 1.5 mol
based on 1 mol of Compound (III).
[0062]
Also, the above-mentioned reaction is preferably
carried out in an organic solvent. Such an organic solvent
may be mentioned, for example, at least one organic solvent
selected from the group consisting of an ether, a ketone,
an ester, an aliphatic hydrocarbon and an aromatic
hydrocarbon.
An amount of the above-mentioned organic solvent to
be used is preferably 1 to 50 mL, more preferably 3 to 20
mL based on 1 g of Compound (III) .
[0063]
The above-mentioned reaction can be carried out, for
example, by mixing Compound (III), an acid and an organic
solvent, and reacting them with stirring, etc. A reaction
temperature at that time is preferably -20 to 80°C, more
preferably -10 to 50°C, particularly preferably -5 to 40°C,
and a reaction pressure is not particularly limited.
[0064]
An acid salt of an optically active (R or S)-α-amino

31
acid ester obtained by the reaction of the present inven-
tion can be further purified by a usual method such as
crystallization, recrystallization, distillation, column
chromatography, etc.
EXAMPLES
[0065]
Next, the present invention is specifically
explained by referring to Examples, but the scope of the
present invention is not limited by these Examples.
[0066]
Reference example 1 (Synthesis of ethyl 2-amino-3-phenyl-
propionate (racemic mixture))
To 10.0 mL (171 mmol) of ethanol were added 2.0 0 g
(12.1 mmol) of 2-amino-3-phenylpropionic acid (racemic
mixture) and 1.42 g (14.5 mmol) of cone, sulfuric acid, and
they were reacted with stirring at 60°C for 4 hours. After
completion of the reaction, the obtained reaction mixture
was concentrated under reduced pressure, and then, 6 mol/L
aqueous sodium hydroxide solution was added to the mixture
to adjust a pH of the reaction mixture to 8.5* Then, 10 mL
of t-butyl methyl ether and 4 mL of water were added to the
mixture to extract the product, and the organic layer was
dried over anhydrous magnesium sulfate. After filtration,
the filtrate was concentrated under reduced pressure to
obtain 2.34 g (Isolation yield based on 2-amino-3-
phenylpropionic acid (racemic mixture): 89.0%) of ethyl 2-
amino-3-phenylpropionate (racemic mixture) as colorless
liquid.
Incidentally, physical properties of the ethyl 2-
amino-3-phenylpropionate (racemic mixture) were as follows.
[0067]
'H-NMR (8 (ppm) , CDC13) : 1.22 (t, 3H, J=7.1Hz), 2.85 (dd,
1H, J=7.8, 13.5HZ), 3.06 (dd, 1H, J=5.4, 13.5Hz), 3.69 (dd,
1H, J=5.4, 7.8Hz), 4.14 (q, 2H, J=7.1Hz), 7.17-7.30 (m, 5H)
13C-NMR (5 (ppm), CDC13) : 14.2, 41.2, 55.9, 60.8, 126.7,

32
128.5, 129.3. 137.4, 175.0
MS (CI, i-C4H10) m/z: 194 (MH+)
[0068]
Example 1 (Synthesis of (S)-2-amino-3-phenylpropionic acid
and ethyl (R)-2-amino-3-phenylpropionate)
To 1.00 mL of t-butyl methyl ether saturated with
water were added 100 mg (0.517 mmol) of ethyl 2-amino-3-
phenylpropionate (racemic mixture) and 20.0 mg of a lipase
(AMANO LIPASE PS (Trade name); available from Aldrich
Corporation) originated from Burkholderia cepacia {Pseudo-
monas cepacia), and the mixture was reacted at 30°C with
stirring. After 156 hours, 0.5 mL of acetone was added to
the reaction mixture and the resulting mixture was filtered
to obtain 36.1 mg (Isolation yield based on ethyl 2-amino-
3-phenylpropionate (racemic mixture)=42.2%) of (S)-2-amino-
3-phenylpropionic acid as a mixture with the lipase.
The (S)-2-amino-3-phenylpropionic acid was led to
ethyl (S)-2-(2-furoylamino)-3-phenylpropionate according to
the conventional manner, and when an optical purity thereof
was measured by using high performance liquid chromato-
graphy which uses an optically active column, it was 96.5%
ee.
The ethyl (R)-2-amino-3-phenylpropionate was led to
ethyl (R)-2-(2-furoylamino)-3-phenylpropionate according to
the conventional manner, and when an optical purity thereof
was measured by using high performance liquid chromato-
graphy which uses an optically active column, it was 89.5%
ee.
Incidentally, an E value in this reaction was 170.
[0069]
Analytical conditions of high performance liquid chromato-
graphy;
Optically active ethyl 2-(2-furoylamino)-3-phenylpropionate
Column: CH.IRALCEL OJ-H (0.46 cmOx25 cm, available from
DAICEL CHEMICAL INDUSTRIES, LTD.)
Solvent: hexane/isopropyl alcohol (=8/2 (Volume ratio))

33
Flow rate: 0.5 mL/min
Temperature: 3 0°C
Wavelength: 22 0 nm
[0070]
Also, physical properties of the (S)-2-amino-3-
phenylpropionic acid were as follows.
[0071]
^-NMR (8 (ppm) , CD3OD) : 3.12 (dd, 1H, J=8.0, 14.5Hz), 3.29
(dd, 1H, J=5.2, 14.5Hz), 3.99 (dd, 1H, J=5.2, 8.0Hz), 7.32-
7.45 (m, 5H)
13C-NMR (8 (ppm), CD3OD) : 39.2, 58.9, 130.5, 132.0, 132.2,
138.0, 176.8
MS (CI, i-C4H10) m/z: 166 (MH+)
Specific Rotation: [a] 25D -26.5° (c 0.5, H20)
Incidentally, a specific rotation of the obtained
optically active 2-amino-3-phenylpropionic acid and a sign
([a]20D -33.4 to -35.0° (c2, H20) ) of the specific rotation
of the (S)-2-amino-3-phenylpropionic acid mentioned in a
brochure published by Wako Pure Chemical Industries, Ltd.
are compared to each other so that the absolute configura-
tion was determined.
[0072]
Physical properties of the ethyl (R)-2-amino-3-
phenylpropionate were the same as those shown in Reference
example 1.
[0073]
Analytical conditions of high performance liquid chromato-
graphy;
Optically active ethyl 2-(2-furoylamino)-3-phenylpropionate
Column: CHIRALCEL OJ-H (0.46 cmOx25 cm, available from
DAICEL CHEMICAL INDUSTRIES, LTD.)
Solvent: hexane/isopropyl alcohol (=8/2 (Volume ratio))
Flow rate: 0.5 mL/min
Temperature: 3 0°C
Wavelength: 22 0 nm
[0074]

i 34
Also, physical properties of the (S)-2-amino-3-
phenylpropionic acid were the same as those shown in
Example 1.
Physical properties of the ethyl (R)-2-amino-3-
phenylpropionate were the same as those shown in Reference
example 1.
[0075]
Reference example 2 (Synthesis of ethyl 2-amino-3-(3-
fluorophenyDpropionate (racemic mixture))
To 10.0 mL (171 mmol) of ethanol were added 2.0 0 g
(10.9 mmol) of 2-amino-3-(3-fluorophenyl)propionic acid
(racemic mixture) and 1.29 g (13.1 mmol) of cone, sulfuric
acid, and the mixture was reacted at 60°C for 4 hours with
stirring. After completion of the reaction, the obtained
reaction mixture was concentrated under reduced pressure,
and then, 6 mol/L aqueous sodium hydroxide solution was
added to the mixture to adjust a pH of the reaction mixture
to 8.5. Then, 10 mL of ethyl acetate and 4 mL of water
were added to the mixture to extract the desired product,
and the organic layer was dried over anhydrous magnesium
sulfate. After filtration, the filtrate was concentrated
under reduced pressure to obtain 1.97 g (Isolation yield
based on 2-amino-3-(3-fluorophenyl)propionic acid (racemic
mixture): 85.1%) of ethyl 2-amino-3-(3-fluorophenyl)-
propionate (racemic mixture) as a colorless liquid.
Incidentally, physical properties of the ethyl 2-
amino-3-(3-fluorophenyl)propionate (racemic mixture) were
as follows.
[0076]
"H-NMR (5 (ppm) , CDC13) : 1.25 (t, 3H, J=7.1Hz), 2.88 (dd,
1H, J=7.8, 13.6HZ), 3.07 (dd, 1H, J=5.5, 13.6Hz), 3.71 (dd,
1H, J=5.5, 7.8Hz), 4.17 (q, 2H, J=7.1Hz), 6.91-7.00 (m,
3H), 7.26 (m, 1H)
13C-NMR (8 (ppm), CDCl3) : 14.2, 40.8, 55.7, 61.1, 113.7,
113.8, 116.1, 116.3, 125.01, 125.02, 129.9, 130.0, 139.9,
140.0, 161.9, 163.9, 174.7

35
MS (CI, i-C4H10) m/z: 212 (MH+)
[0077]
Example 2 (Synthesis of (S)-2-amino-3-(3-fluorophenyl)-
propionic acid and ethyl (R)-2-amino-3-(3-fluorophenyl)-
propionate)
To 1.0 mL of t-butyl methyl ether saturated with
water were added 100 mg (0.473 mmol) of ethyl 2-amino-3-(3-
fluorophenyl)propionate (racemic mixture) and 30.0 mg of a
lipase (AMANO LIPASE PS (Trade name); available from
ALDRICH CORPORATION) originated from Burkholderia cepacia
(Pseudomonas cepacia), and reacted at 3 0°C. After 48
hours, 0.5 mL of acetone was added to the reaction mixture
and the resulting mixture was filtered to obtain 31.1 mg
(Isolation yield based on ethyl 2-amino-3-(3-fluorophenyl)-
propionate (racemic mixture)=40.5%) of (S)-2-amino-3-(3-
fluorophenyl)propionic acid as a mixture with the lipase.
(S)-2-amino-3-(3-fluorophenyl)propionic acid was led
to ethyl (S)-3- (3-fluorophenyl)-2-(2-furoylamino)propionate
according to the conventional manner, and when its optical
purity was measured by using high performance liquid
chromatography which uses an optically active column, it
was 98.0% ee.
Ethyl (R)-2-amino-3-(3-fluorophenyl)propionate was
led to ethyl (R)-3-(3-fluorophenyl)-2-(2-furoylamino)-
propionate according to the conventional manner, and when
its optical purity was measured by using high performance
liquid chromatography which uses an optically active
column, it was 82.8% ee.
Incidentally, the E value in this reaction was 258.
[0078]
Analytical conditions of high performance liquid chromato-
graphy;
Optically active ethyl 3-(3-fluorophenyl)-2-(2-furoyl-
amino) propionate
Column: CHIRALCEL OJ-H (0.46 cmOx25 cm, available from
DAICEL CHEMICAL INDUSTRIES, LTD.)

36
Solvent: hexane/isopropyl alcohol (=9/1 (Volume ratio))
Flow rate: 0.5 mL/min
Temperature: 3 0°C
Wavelength: 22 0 nm
[0079]
Also, physical properties of the (S)-2-amino-3-(3-
fluorophenyDpropionic acid were as follows.
[0080]
XH-NMR (8 (ppm) , CD3OD) : 3.02 (dd, 1H, J=8.6, 14.6Hz), 3.31
(dd, 1H, J=4.5, 14.6Hz), 3.77 (dd, 1H, J=4.5, 8.6Hz), 7.00
(m, 1H) , 7.08 (m, 1H) , 7.12 (in, 1H) , 7.34 (m, 1H)
13C-NMR (8 (ppm), CD3OD) : 37.9, 57.3, 115.1, 115.2, 117.1,
117.3, 126.32, 126.34, 131.6, 131.7, 140.0, 140.1, 163.5,
165.5, 173.4
MS (CI, i-C4H10) m/z: 184 (MH+)
Elemental analysis; Calcd: C, 59.01%; H, 5.50%; N, 7.65%
Found: C, 57.86%; H, 5.46%; N, 7.90%
[0081]
Physical properties of the ethyl (R)-2-amino-3- (3-
fluorophenyDpropionate were the same as those shown in
Reference example 2.
[0082]
Reference example 3 (Synthesis of ethyl 2-amino-3-(4-
fluorophenyDpropionate (racemic mixture))
To 10.0 mL (171 mmol) of ethanol were added 2.00 g
(10.9 mmol) of 2-amino-3-(4-fluorophenyDpropionic acid
(racemic mixture) and 1.2 9 g (13.1 mmol) of cone, sulfuric
acid, and the mixture was reacted at 60°C for 4 hours with
stirring. After completion of the reaction, the obtained
reaction mixture was concentrated under reduced pressure,
and then, 6 mol/L aqueous sodium hydroxide solution was
added to the mixture to adjust a pH of the reaction mixture
to 8.5. Then, 10 mL of t-butyl methyl ether and 4 mL of
water were added to the mixture to extract the desired
product, and the organic layer was dried over anhydrous
magnesium sulfate. After filtration, the filtrate was

37
concentrated under reduced pressure to obtain 1.95 g
(Isolation yield based on 2-amino-3-(4-fluorophenyDpro-
pionic acid (racemic mixture): 84.6%) of ethyl 2-amino-3-
(4-fluorophenyDpropionate (racemic mixture) as a colorless
liquid.
Incidentally, physical properties of the ethyl 2-
amino-3-(4-fluorophenyDpropionate (racemic mixture) were
as follows.
[0083]
'H-NMR (8 (ppm) , CDC13) : 1.23 (t, 3H, J=7.1Hz), 2.96 (dd,
1H, J=7.6, 13.7Hz), 3.04 (dd, 1H, J=5.5, 13.7Hz), 3.68 (dd,
1H, J=5.5, 7.6Hz), 4.16 (q, 2H, J=7.1Hz), 6.99 (m, 2H),
7.17 (m, 2H)
13C-NMR (8 (ppm), CDCI3) : 14.2, 40.2, 55.9, 61.0, 115.2,
115.4, 130.75, 130.81, 132.97, 133.00, 160.9, 162.9, 174.9
MS (CI, i-C4H10) m/z: 212 (MH+)
Elemental analysis; Calcd: C, 62.55%; H, 6.68%; N, 6.63%
Found: C, 61.19%; H, 6.54%; N, 6.51%
[0084]
Example 3 (Synthesis of (S)-2-amino-3-(4-fluorophenyl)-
propionic acid and ethyl (R)-2-amino-3-(4-fluorophenyl)-
propionate)
To 1.0 mL of t-butyl methyl ether saturated with
water were added 100 mg (0.473 mmol) of ethyl 2-amino-3-(4-
fluorophenyl)propionate (racemic mixture) and 30.0 mg of a
lipase (AMANO LIPASE PS (Trade name); available from
Aldrich Corporation) originated from Burkholderia cepacia
(Pseudomonas cepacia), and the mixture was reacted at 3 0°C
with stirring. After 5 6 hours, 0.5 mL of acetone was added
to the reaction mixture and the resulting mixture was
filtered to obtain 36.7 mg (Isolation yield based on ethyl
2-amino-3-(4-fluorophenyDpropionate (racemic mixture)=
42.3%) of (S)-2-amino-3-(4-fluorophenyl)propionic acid as a
mixture with the lipase.
(S)-2-amino-3-(4-fluorophenyl)propionic acid was led
to ethyl (S)-3-(4-fluorophenyl)-2-(2-furoylamino)propionate

38
according to the conventional manner, and when its optical
purity was measured by using high performance liquid
chromatography which uses an optically active column, it
was 99.1% ee.
Ethyl (R)-2-amino-3-(4-fluorophenyl)propionate was
led to ethyl (R)-3-(4-fluorophenyl)-2-(2-furoylamino)-
propionate according to the conventional manner, and when
its optical purity was measured by using high performance
liquid chromatography which uses an optically active
column, it was 91.2% ee.
Incidentally, the E value in this reaction was 698.
[0085]
Analytical conditions of high performance liquid chromato-
graphy;
Optically active ethyl 3-(4-fluorophenyl)-2-(2-furoyl-
amino) propionate
Column: CHIRALCEL OJ-H (0.46 cmOx25 cm, available from
DAICEL CHEMICAL INDUSTRIES, LTD.)
Solvent: hexane/isopropyl alcohol (=8/2 (Volume ratio))
Flow rate: 0.5 mL/min
Temperature: 3 0°C
Wavelength: 22 0 nm
[0086]
Also, physical properties of the (S)-2-amino-3-(4-
fluorophenyl)propionic acid were as follows.
[0087]
XH-NMR (5 (ppm) , CD3OD) : 3.00 (dd, 1H, J=8.5, 14.7Hz), 3.27
(dd, 1H, J=4.5, 14.7HZ), 3.74 (dd, 1H, J=4.5, 8.5Hz), 7.05
(m, 2H), 7.31 (m, 2H)
"C-NMR (8 (ppm), CD3OD) : 37.5, 57.6, 116.5, 116.6, 132.2,
132.3, 133.2, 133.3, 162.9, 164.6, 173.6
MS (CI, i-C4H10) m/z: 184 (MH+)
Elemental analysis; Calcd: C, 59.01%; H, 5.50%; N, 7.65%
Found: C, 58.73%; H, 5.49%; N, 7.68%
[0088]
Physical properties of the ethyl (R)-2-amino-3-(4-

39
fluorophenyDpropionate were the same as those shown in
Reference example 3.
[0089]
Reference example 4 (Synthesis of ethyl 2-amino-3-(4-bromo-
phenyDpropionate (racemic mixture))
To 5.00 mL (85.7 mmol) of ethanol were added 1.00 g
(4.10 mmol) of 2-amino-3-(4-bromophenyl)propionic acid
(racemic mixture) and 482 mg (4.92 mmol) of cone, sulfuric
acid, and the mixture was reacted with stirring at 60°C for
4 hours. After completion of the reaction, the obtained
reaction mixture was concentrated under reduced pressure,
and then, 6 mol/L aqueous sodium hydroxide solution was
added to the mixture to adjust a pH of the reaction mixture
to 8.5. Then, 10 mL of t-butyl methyl ether and 4 mL of
water were added to extract the desired product, and the
organic layer was dried over anhydrous magnesium sulfate.
After filtration, the filtrate was concentrated under
reduced pressure to obtain 916 mg (Isolation yield based on
2-amino-3-(4-bromophenyl)propionic acid (racemic mixture):
82.5%) of ethyl 2-amino-3-(4-bromophenyl)propionate
(racemic mixture) as colorless liquid.
Incidentally, physical properties of the ethyl 2-
amino-3-(4-bromophenyl)propionate (racemic mixture) were as
follows.
[0090]
'H-NMR (6 (ppm) , CDC13) : 1.25 (t, 3H, J=7.1Hz), 2.83 (dd,
1H, J=7.7, 13.7Hz), 3.03 (dd, 1H, J=5.5, 13.7Hz), 3.68 (dd,
1H, J=5.5, 7.7Hz), 7.08 (m, 2H), 7.42 (m, 2H)
13C-NMR (8 (ppm) , CDCI3) : 14.2, 40.4, 55.7, 61.1, 120.8,
131.1, 131.7, 136.3, 174.7
MS (CI, i-C4H10) m/z: 272 (MH+)
Elemental analysis; Calcd: C, 48.55%; H, 5.19%; N, 5.15%
Found: C, 47.71%; H, 5.21%; N, 5.06%
[0091]
Example 4 (Synthesis of (S)-2-amino-3-(4-bromophenyl)-
propionic acid and ethyl (R)-2-amino-3-(4-bromophenyl)-

40
propionate)
To 1.0 mL of t-butyl methyl ether saturated with
water were added 200 mg (0.367 mmol) of ethyl 2-amino-3-(4-
bromophenyl)propionate (racemic mixture) and 3 0.0 mg of a
lipase (AMANO LIPASE PS (Trade name); available from
Aldrich Corporation) originated from Burkholderia cepacia
{Pseudomonas cepacia), and the mixture was reacted with
stirring at 30°C. After 56 hours, 0.5 mL of acetone was
added to the reaction mixture and the resulting mixture was
filtered to obtain 36.2 mg (Isolation yield based on ethyl
2-amino-3-(4-bromophenyl)propionate (racemic mixture)=
41.8%) of (S)-2-amino-3-phenylpropionic acid as a mixture
with the lipase.
(S)-2-amino-3-(4-bromophenyl)propionic acid was led
to ethyl (S)-3-(4-bromophenyl)-2-(2-furoylamino)propionate
according to the conventional manner, and when its optical
purity was measured by using high performance liquid
chromatography which uses an optically active column, it
was 98.5% ee.
Ethyl (R)-2-amino-3-(4-bromophenyl)propionate was
led to ethyl (R)-3-(4-bromophenyl)-2-(2-furoylamino)pro-
pionate according to the conventional manner, and when its
optical purity was measured by using high performance
liquid chromatography which uses an optically active
column, it was 87.7% ee.
Incidentally, the E value in this reaction was 388.
[0092]
Analytical conditions of high performance liquid chromato-
graphy;
Optically active ethyl 3-(4-bromophenyl)-2-(2-furoylamino)-
propionate
Column: CHIRALCEL OJ-H (0.46 cmOx25 cm, available from
DAICEL CHEMICAL INDUSTRIES, LTD.)
Solvent: hexane/isopropyl alcohol (=8/2 (Volume ratio))
Flow rate: 0.5 mL/min
Temperature: 30°C

41
Wavelength: 22 0 run
[0093]
Also, physical properties of the (S)-2-amino-3-(4-
bromophenyl)propionic acid were as follows.
[0094]
XH-NMR (6 (ppm) , CD3OD) : 2.99 (dd, 1H, J=8.4, 14.6Hz), 3.25
(dd, 1H, J=4.5, 14.6Hz), 3.74 (dd, 1H, J=4.5, 8.4Hz), 7.22
(m, 2H), 7.48 (m, 2H)
13C-NMR (5 (ppm) , CD3OD) : 37,7, 57.3, 122.2, 132.4, 133.0,
136.6, 173.5
MS (CI, i-C4H10) m/z: 244 (MH+)
Elemental analysis,- Calcd: C, 44.29%; H, 4.13%; N, 5.74%
Found: C, 43.95%; H, 4.06%; N, 5.66%
[0095]
Physical properties of the ethyl (R)-2-amino-3- (4-
bromophenyDpropionate were the same as those shown in
Reference example 4.
[0096]
Reference example 5 (Synthesis of ethyl 2-amino-3-(2-
naphthyDpropionate (racemic mixture))
To 9.0 mL (154 mmol) of ethanol were added 1.80 g
(8.36 mmol) of 2-amino-3-(naphthyl)propionic acid (racemic
mixture) and 1.23 g (12.5 mmol) of cone, sulfuric acid, and
the mixture was reacted with stirring at 60°C for 6 hours.
After completion of the reaction, the obtained reaction
mixture was concentrated under reduced pressure, and then,
6 mol/L aqueous sodium hydroxide solution was added to the
mixture to adjust a pH of the reaction mixture to 8.5.
Then, 18 mL of t-butyl methyl ether and 4 mL of water were
added to extract the desired product, and the organic layer
was dried over anhydrous magnesium sulfate. After
filtration, the filtrate was concentrated under reduced
pressure to obtain 1.73 g (Isolation yield based on 2-
amino-3-(2-naphthyl)propionic acid (racemic mixture):
85.0%) of ethyl 2-amino-3-(2-naphthyl)propionate (racemic
mixture) as pale yellowish liquid.

42
Incidentally, physical properties of the ethyl 2-
amino-3-(2-naphthyl)propionate (racemic mixture) were as
follows.
[0097]
XH-NMR (5 (ppm) , CDC13) : 1.20 (t, 3H, J=7.lHz), 1.58 (s,
2H), 3.00 (dd, 1H, J=7.9, 13.5Hz), 3.23 (dd, 1H, J=5.3,
13.5HZ), 3.78 (dd, 1H, J=5.3, 7.9Hz), 4.15 (q, 2H,
J=7.1Hz), 7.31 (dd, 1H, J=1.7, 8.4HZ), 7.39-7.45 (m, 2H),
7.64 (m, 1H), 7.76-7.79 (m, 3H)
13C-NMR (5 (ppm), CDC13) : 14.2, 40.2, 55.9, 61.0, 115.2,
115.4, 130.75, 130.81, 132.97, 133.00, 160.9, 162.9, 174.9
MS (El) m/z: 243 (M+)
MS (CI, i-C4H10) m/z: 244 (MH+)
Elemental analysis; Calcd: C, 74.05%; H, 7.04%; N, 5.76%
Found: C, 72.89%; H, 6.72%; N, 5.58%
[0098]
Example 5 (Synthesis of (S)-2-amino-3-(2-naphthyl)propionic
acid and ethyl (R)-2-amino-3-(2-naphthyl)propionate)
To 2.0 mL of t-butyl methyl ether saturated with
water were added 200 mg (0.822 mmol) of ethyl 2-amino-3-(2-
naphthyDpropionate (racemic mixture) and 10.0 mg of a
lipase (AMANO LIPASE PS (Trade name); available from
Aldrich Corporation) originated from Burkholderia cepacia
(Pseudomonas cepacia), and the mixture was reacted with
stirring at 30°C. After 168 hours, the reaction mixture
was filtered, and washed with 2.0 mL of t-butyl methyl
ether to obtain 86.1 mg (Isolation yield based on ethyl 2-
amino-3- (4-f luorophenyDpropionate (racemic mixture) =43 . 0%)
of (S)-2-amino-3-(2-naphthyl)propionic acid as a mixture
with the lipase.
Also, after filtration, the filtrate was concen-
trated under reduced pressure to obtain 110 mg (Isolation
yield based on ethyl 2-amino-3-(2-naphthyl)propionate
(racemic mixture)=55.0%) of ethyl (R)-2-amino-3-(2-
naphthyDpropionate as pale yellowish liquid.
(S)'-2-amino-3-(2-naphthyl) prop ionic acid was led to

43
ethyl (S)-2-(2-furoylamino)-3-(2-naphthyl)propionate
according to the conventional manner, and when its optical
purity was measured by using high performance liquid
chromatography which uses an optically active column, it
was 99.3% ee.
Ethyl (R)-2-amino-3-(2-naphthyl)propionate was led
to ethyl (R)-2-(2-furoylamino)-2-(2-naphthyl)propionate
according to the conventional manner, and when its optical
purity was measured by using high performance liquid
chromatography which uses an optically active column, it
was 7 9.3% ee.
Incidentally, the E value in this reaction was 711.
[0099]
Analytical conditions of high performance liquid chromato-
graphy;
Optically active ethyl 3-(2-furoylamino)-3-(2-naphthyl)-
propionate
Column: CHIRALCEL OJ-H (0.46 cmx25 cm, available from
DAICEL CHEMICAL INDUSTRIES, LTD.)
Solvent: hexane/isopropyl alcohol (=8/2 (Volume ratio))
Flow rate: 0.5 mL/min
Temperature -. 3 0 ° C
Wavelength: 22 0 nm
[0100]
Also, physical properties of the (S)-2-amino-3-(2-
naphthyDpropionic acid were as follows.
[0101]
'H-NMR (8 (ppm), D2O) : 3.41 (dd, 1H, J=7.7, 14.6Hz), 3.53
(dd, 1H, J=5.7, 14.6HZ), 4.50 (dd, 1H, J=5.7, 7.7Hz), 7.46
(d, 1H, J=8.4Hz), 7.57-7.61 (m, 2H), 7.84 (s, 1H)
7.93-7.97 (m, 3H)
13C-NMR (6 (ppm), D2O) : 38.6, 56.8, 129.4, 129.67, 130.0,
130.6, 131.4, 131.8, 134.4, 135.4, 136.1, 174.0
MS (El) m/z: 215 (M+)
MS (CI, i-C4H10) m/z: 216 (MH+)
[0102]

44
Physical properties of the ethyl (R)-2-amino-3-(2-
naphthyDpropionate were the same as those shown in
Reference example 5.
[0103]
Reference example 6 (Synthesis of ethyl 2-amino-3-(3-
indolyDpropionate (racemic mixture))
To 5.0 mL (85.6 mmol) of ethanol were added 1.00 g
(4.90 mmol) of 2-amino-3-(3-indolyl)propionic acid (racemic
mixture) and 0.96 g (9.79 mmol) of cone, sulfuric acid, and
the mixture was reacted with stirring at 60°C for 4 hours.
After completion of the reaction, the obtained reaction
mixture was concentrated under reduced pressure, and then,
6 mol/L aqueous sodium hydroxide solution was added to the
mixture to adjust a pH of the reaction mixture to 8.5.
Then, 10 mL of t-butyl methyl ether and 4 mL of water were
added to extract the desired product, and the organic layer
was dried over anhydrous magnesium sulfate. After filtra-
tion, the filtrate was concentrated under reduced pressure
to obtain 0.97 g (Isolation yield based on 2-amino-3-(3-
indolyl)propionic acid (racemic mixture): 85.0%) of ethyl
2-amino-3-(3-indolyl)propionate (racemic mixture) as
colorless liquid.
Incidentally, physical properties of the ethyl 2-
amino-3-(3-indolyl)propionate (racemic mixture) were as
follows.
[0104] '
XH-NMR (8 (ppm) , D20) : 1.21 (t, 3H, J=7.0Hz), 1.63 (s, 2H) ,
3.01 (dd, 1H, J=7.9, 14.4HZ), 3.25 (dd, 1H, J=4 . 8, 14.4Hz),
3.80 (dd, 1H, J=4.8, 7.9Hz), 4.14 (q, 2H, J=7.0Hz), 6.90
(s, 1H) 7.06-7.26 (m, 3H), 7.59 (d, 1H, J=7.9Hz), 9.07 (s,
1H)
13C-NMR (5 (ppm) , CDC13) : 14.1, 49.4, 55.0, 61.0, 110.6,
111.4, 118.6, 119.2, 121.8, 123.3, 127.5, 136.4, 175.4
MS (El) m/z: 232 (M+)
MS (CI, i-C4H10) m/z: 233 (MH+)
[0105]

45
Example 6 (Synthesis of (S)-2-amino-3-(3-indolyl)propionic
acid and ethyl (R)-2-amino-3-(3-indolyl)propionate)
To 4.0 mL of t-butyl methyl ether saturated with
water were added 200 mg (0.822 mmol) of ethyl 2-amino-3-(3-
indolyl)propionate (racemic mixture) and 10.0 mg of a
lipase (AMANO LIPASE PS (Trade name); available from
Aldrich Corporation) originated from Burkholderia cepacia
(Pseudomonas cepacia) , and the mixture was reacted with
stirring at 3 0°C. After 108 hours, the reaction mixture
was filtered, and washed with 2.0 mL of t-butyl methyl
ether to obtain 78.3 mg (Isolation yield based on ethyl 2-
amino-3-(3-indolyl)propionate (racemic mixture)=44.5%) of
(S)-2-amino-3-(3-indolyl)propionic acid as a mixture with
the lipase.
Also, after filtration, the filtrate was concen-
trated under reduced pressure to obtain 106 mg (Isolation
yield based on ethyl 2-amino-3-(3-indolyl)propionate
(racemic mixture)=53.0%) of ethyl (R)-2-amino-3-(3-
indolyl)propionate as colorless liquid.
(S)-2-amino-3-(3-indolyl)propionic acid was led to
ethyl (S)-2-(2-fluorophenyl)-3-(3-indolyl)propionate
according to the conventional manner, and when its optical
purity was measured by using high performance liquid
chromatography which uses an optically active column, it
was 98.7% ee.
Ethyl (R)-2-amino-3-(3-indolyl)propionate was led to
ethyl (R)-2-(2-fluorophenyl)-3-(3-indolyl)propionate
according to the conventional manner, and when its optical
purity was measured by using high performance liquid
chromatography which uses an optically active column, it
was 81.8% ee.
Incidentally, the E value in this reaction was 392.
[0106]
Analytical conditions of high performance liquid chromato-
graphy;
Optically active ethyl 2-(2-furoylamino)-3-(3-indolyl)-

46
propionate
Column: CHIRALCEL OJ-H (0.46 cmO>x25 cm, available from
DAICEL CHEMICAL INDUSTRIES, LTD.)
Solvent: hexane/isopropyl alcohol (=8/2 (Volume ratio))
Flow rate: 1.0 mL/min
Temperature: 3 0°C
Wavelength: 22 0 nm
[0107]
Also, physical properties of the (S)-2-amino-3-(3-
indolyl)propionic acid were as follows.
[0108]
'H-NMR (8 (ppm) , D2O) : 3.43 (dd, 1H, J=7.0, 15.4Hz), 3.50
(dd, 1H, J=5.5, 15.4HZ), 4.40 (dd, 1H, J=5.5, 7.0Hz), 7.21-
7.69 (m, 5H)
13C-NMR (8 (ppm), D2O) : 29.2, 56.8, 109.7, 115.6, 121.8,
123.1, 125.8, 129.0, 130.1, 139.9, 175.1
MS (El) m/z: 204 (M+)
MS (CI, i-C4H10) m/z: 205 (MH+)
[0109]
Physical properties of the ethyl (R)-2-amino-3-(3-
indolyl)propionate were the same as those shown in
Reference example 6.
[0110]
Example 7 (Synthesis of (S)-2-amino-3-(4-fluorophenyl)-
propionic acid and ethyl (R)-2-amino-3-(4-fluorophenyl)-
propionate) :
To 2.0 mL of t-butyl methyl ether saturated with
water were added 200 trig (0.947 mmol) of ethyl 2-amino-3- (4-
fluorophenyl)propionate (racemic mixture) and 1.0 mg ofα-
chymotrypsin, and the mixture was reacted with stirring at
30°C. After 84 hours, the reaction mixture was filtered to
obtain 70.8 mg (Isolation yield based on ethyl 2-amino-3-
(4-fluorophenyl)propionate (racemic mixture)=4 0.8%) of (S) -
2-amino-3-(4-fluorophenyl)propionic acid.
(S)-2-amino-3-(4-fluorophenyl)propionic acid was led
to ethyl (S)-3-(4-fluorophenyl)-2-(2-furoylamino)propionate

47
according to the conventional manner, and when its optical
purity was measured by using high performance liquid
chromatography which uses an optically active column, it
was 98.1% ee.
Ethyl (R) -2-amino-3- (4-f luorophenyDpropionate was
led to ethyl (R)-3-(4-fluorophenyl)-2-(2-furoylamino)-
propionate according to the conventional manner, and when
its optical purity was measured by using high performance
liquid chromatography which uses an optically active
column, it was 83.3% ee.
Incidentally, the E value in this reaction was 271.
[0111]
Analytical conditions of high performance liquid chromato-
graphy;
Optically active ethyl 3-(4-fluorophenyl)-2-(2-furoyl-
amino) propionate
Column: CHIRALCEL OJ-H (0.46 cmOx25 cm, available from
DAICEL CHEMICAL INDUSTRIES, LTD.)
Solvent: hexane/isopropyl alcohol (=9/1 (Volume ratio))
Flow rate: 0.5 mL/min
Temperature: 3 0°C
Wavelength: 22 0 nm
[0112]
Also, physical properties of the (S)-2-amino-3-(4-
fluorophenyl)propionic acid were the same as those shown in
Example 3.
[0113]
Physical properties of the ethyl (R)-2-amino-3-(4-
fluorophenyl)propionate were the same as those shown in
Reference example 3.
Reference example 7 (Synthesis of ethyl 2-amino-4-methyl-
pentanoate (racemic mixture))
To 4 0 mL (69 mmol) of ethanol were added 4.0 0 g
(8.36 mmol) of 2-amino-4-methylpentanoic acid (racemic
mixture) and 4.4 9 g (61.0 mmol) of cone, sulfuric acid, and
the mixture was reacted with stirring at 60°C for 6 hours.

48
After completion of the reaction, the obtained reaction
mixture was concentrated under reduced pressure, and then,
6 mol/L aqueous sodium hydroxide solution was added to the
mixture to adjust a pH of the reaction mixture to 8.5.
Then, 40 mL of methylene chloride and 10 mL of water were
added to the reaction mixture to extract the desired
product, and the organic layer was dried over anhydrous
magnesium sulfate. After filtration, the filtrate was
concentrated under reduced pressure to obtain 3.79 g
(Isolation yield based on 2-amino-4-methylpentanoic acid
(racemic mixture): 78.0%) of ethyl 2-amino-4-methylpentano-
ate (racemic mixture) as colorless liquid.
Incidentally, physical properties of the ethyl 2-
amino-4-methylpentanoate (racemic mixture) were as follows.
[0114]
^-NMR (5 (ppm) , CDC13) : 0.92-0.95 (m, 6H) , 1.28 (t, 3H,
J=7.1Hz), 1.39-1.45 (m, 1H), 1.50 (s, 2H), 1.53-1.59 (m,
1H), 1.74-1.81 (m, 1H), 3.45 (dd, 1H, J=5.6, 8.7Hz)
4.17 (q, 2H, J=7.1Hz)
13C-NMR (8 (ppm), CDC13) : 14.2,21.9, 23.0, 24.8, 44.2, 52.9,
60.7, 176.7
MS (CI, i-C4H10) m/z: 160 (MH+)
[0115]
Example 8 (Synthesis of (S)-2-amino-4-methylpentanoic acid
and ethyl (R)-2-amino-4-methyl-pentanoate)
To 2.0 mL of t-butyl methyl ether saturated with
water were added 100 mg (0.63 mmol) of ethyl 2-amino-4-
methylpentanoate (racemic mixture) and 1.0 mg ofα-chymo-
trypsin, and the mixture was reacted with stirring at 30°C.
After 64 hours, the reaction mixture was filtered, and
washed with 2.0 mL of t-butyl methyl ether to obtain 3 7.1
mg (Isolation yield based on ethyl 2-amino-3-(4-fluoro-
phenyDpropionate (racemic mixture) =45.0%) of (S)-2-amino-
4-methylpentanoic acid.
Also, after filtration, the filtrate was concen-
trated under reduced pressure to obtain 50 mg (Isolation

49
yield based on ethyl 2-amino-4-methylpentanoate (racemic
mixture)=50.0%) of ethyl (R)-2-amino-4-methylpentanoate as
colorless liquid.
(S)-2-amino-4-methylpentanoic acid was led to ethyl
(S)-2-benzoylamino-4-methylpentanoate according to the
conventional manner, and when its optical purity was
measured by using high performance liquid chromatography
which uses an optically active column, it was 98.2% ee.
Ethyl (R)-2-amino-4-methylpentanoate was led to
ethyl (R)-2-benzoylamino-4-methylpentanoate according to
the conventional manner, and when its optical purity was
measured by using high performance liquid chromatography
which uses an optically active column, it was 88.8% ee.
Incidentally, the E value in this reaction was 323.
[0116]
Analytical conditions of high performance liquid chromato-
graphy;
Optically active ethyl 2-benzoylamino-4-methylpentanoate
Column: CHIRALCEL OD-H (0.46 cmOx25 cm, available from
DAICEL CHEMICAL INDUSTRIES, LTD.)
Solvent: hexane/isopropyl alcohol (=9/1 (Volume ratio))
Flow rate: 0.5 mL/min
Temperature: 3 0°C
Wavelength: 22 0 nm
[0117]
Also, physical properties of the (S)-2-amino-4-
methylpentanoic acid were as follows.
[0118]
XH-NMR (8 (ppm) , D20) :
0.96-1.01 (m, 6H), 1.74-1.90 (m, 3H), 4.11 (m, 1H)
13C-NMR (8 (ppm) , CD3OD) : 23.9, 24.5, 26.8, 41.6, 54.3,
175.2
MS (CI, i-C4H10) m/z: 132 (MH+)
Elemental analysis; Calcd: C, 54.94%; H, 9.99%; N, 10.68%
Found: C, 54.42%; H, 9.83%; N, 10.73%
[0119]

50
Physical properties of the ethyl (R)-2-amino-4-
methylpentanoate were the same as those shown in Reference
example 7.
[0120]
Reference example 8 (Synthesis of ethyl 2-amino-3-(4-
methoxyphenyDpropionate (racemic mixture))
To 6.0 mL (103 mmol) of ethanol were added 600 mg
(3.07 mmol) of 2-amino-3-(4-methoxyphenyl)propionic acid
(racemic mixture) and 603 mg (6.15 mmol) of cone, sulfuric
acid, and the mixture was reacted with stirring at 60°C for
4 hours. After completion of the reaction, the obtained
reaction mixture was concentrated under reduced pressure,
and then, 6 mol/L aqueous sodium hydroxide solution was
added to the mixture to adjust a pH of the reaction mixture
to 8.5. Then, 6 mL of t-butyl methyl ether and 2 mL of
water were added to the reaction mixture to extract the
desired product, and the organic layer was dried over
anhydrous magnesium sulfate. After filtration, the
filtrate was concentrated under reduced pressure to obtain
618 mg (Isolation yield based on 2-amino-3-(4-methoxy-
phenyl) propionic acid (racemic mixture): 90.0%) of ethyl 2-
amino-3-(4-methoxyphenyl)propionate (racemic mixture) as
colorless liquid.
Incidentally, physical properties of the ethyl 2-
amino-3-(4-methoxyphenyl)propionate (racemic mixture) were
as follows.
[0121]
'H-NMR (5 (ppm) , CDC13) : 1.25 (t, 3H, J=7.1Hz), 1.58 (s,
2H), 2.82 (dd, 1H, J=7.8, 13.7Hz), 3.02 (dd, 1H, J=5.4,
13.7HZ), 3.66 (dd, 1H, J=5.4, 7.8Hz), 3.79 (s, 3H), 1.17
(q, 2H, J=7.1Hz), 6.82-6.86 (m, 2H), 7.10-7.12 (m, 2H)
13C-NMR (5 (ppm), CDC13) : 14.2, 40.3, 55.3, 56.1, 60.9,
114.0, 129.3, 130.3, 158.6, 175.1
MS (CI, i-C4H10) m/z: 224 (MH+)
Elemental analysis; Calcd: C, 64.55%; H, 7.67%; N, 6.27%
Found: C, 64.27%; H, 7.27%; N, 6.17%

51
[0122]
Example 9 (Synthesis of (S)-2-amino-3-(4-methoxyphenyl)-
propionic acid and ethyl (R)-2-amino-3-(4-methoxyphenyl)-
propionate)
To 4.0 mL of t-butyl methyl ether saturated with
water were added 200 mg (0.900 mmol) of ethyl 2-amino-3-(4-
methoxyphenyl)propionate (racemic mixture) and 10.0 mg of a
lipase (AMANO LIPASE PS (Trade name); available from
ALDRICH CORPORATION) originated from Burkholderia cepacia
(Pseudomonas cepacia), and the mixture was reacted with
stirring at 3 0°C. After 96 hours, the reaction mixture was
filtered, and washed with 2.0 mL of t-butyl methyl ether to
obtain 90.0 mg (Isolation yield based on ethyl 2-amino-3-
(4-fluorophenyl)propionate (racemic mixture)=4 8.6%) of (S) -
2-amino-3-(4-methoxyphenyl)propionic acid as a mixture with
the lipase.
Also, after filtration, the filtrate was concen-
trated under reduced pressure to obtain 100 mg (Isolation
yield based on ethyl 2-amino-3-(4-methoxyphenyl)propionate
(racemic mixture)=50.0%) of ethyl (R)-2-amino-3-(4-methoxy-
phenyl) propionate as pale yellowish liquid.
(S)-2-amino-3-(4-methoxyphenyl)propionic acid was
led to ethyl (S)-2-(2-furoylamino)-3-(4-methoxyphenyl)-
propionate according to the conventional manner, and when
its optical purity was measured by using high performance
liquid chromatography which uses an optically active
column, it was 99.0% ee.
Ethyl (R)-2-amino-3-(4-methoxyphenyl)propionate was
led to ethyl (R)-2-(2-furoylamino)-2-(4-methoxyphenyl)-
propionate according to the conventional manner, and when
its optical purity was measured by using high performance
liquid chromatography which uses an optically active
column, it was 98.8% ee.
Incidentally, the E value in this reaction was 1042.
[0123]
Analytical conditions of high performance liquid chromato-

52
graphy;
Optically active ethyl 3-(2-furoylamino)-3-(4-methoxy-
phenyl)propionate
Column: CHIRALCEL OJ-H (0.46 cmOx25 cm, available from
DAICEL CHEMICAL INDUSTRIES, LTD.)
Solvent: hexane/isopropyl alcohol (=8/2 (Volume ratio))
Flow rate: 0.5 mL/min
Temperature: 3 0°C
Wavelength: 22 0 nm
[0124]
Also, physical properties of the (S)-2-amino-3-(4-
methoxyphenyl)propionic acid were as follows.
[0125]
'H-NMR (5 (ppm) , CD3OD) :
3.20 (dd, 1H, J=7.4, 14.7Hz), 3.30 (dd, 1H, J=5.6, 14.7Hz),
4.36 (dd, 1H, J=5.6, 7.4Hz), 5.06 (s, 3H), 7.00-7.02 (m,
2H), 7.27-7.29 (m, 2H)
13C-NMR (8 (ppm), CD3OD) : 37.6, 57.0, 58.4, 117.6, 129.2,
133.7, 161.4, 174.1
MS (El) m/z: 195 (M+)
MS (CI, i-C4H10) m/z: 196 (MH+)
Elemental analysis; Calcd: C, 61.53%; H, 6.71%; N, 7.18%
Found: C, 60.40%; H, 6.56%; N, 7.04%
[0126]
Physical properties of the ethyl (R)-2-amino-3- (4-
methoxyphenyl)propionate were the same as those shown in
Reference example 8.
Example 10 (Synthesis of ethyl (R)-2-amino-3-phenyl-
propionate hydrochloride)
To 8 0 mL of t-butyl methyl ether saturated with
water were added 4.00 g (20.7 mmol) of ethyl 2-amino-3-
phenylpropionate (racemic mixture) and 800 mg of a lipase
(AMANO LIPASE PS (Trade name); available from ALDRICH
CORPORATION) originated from Burkholderia cepacia
(Pseudomonas cepacia), and the mixture was reacted with
stirring at 30°C. After 168 hours, the reaction mixture

53
was filtered, dried over magnesium sulfate, filtered,
concentrated under reduced pressure and 12 mL of cyclo-
hexane was added to the residue. To the resulting cyclo-
hexane solution was added 1.52 g (10.1 mmol of hydrochloric
acid) of a hydrochloric acid-ethanol solution (hydrochloric
acid content: 24.3% by weight) at 0°C and the mixture was
stirred at the same temperature for 1 hour. The reaction
mixture was filtered to obtain 1.90 g (Yield based on ethyl
2-amino-3-phenylpropionate (racemic mixture)=4 0.0%) of
ethyl (R)-2-amino-3-phenylpropionate hydrochloride as white
crystals.
Ethyl (R)-2-amino-3-phenylpropionate hydrochloride
was led to ethyl (R)-2-(2-furoylamino)-3-phenylpropionate
according to the conventional manner, and when its optical
purity was measured by using high performance liquid
chromatography which uses an optically active column, it
was 97.1% ee.
[0127]
Analytical conditions of high performance liquid chromato-
graphy;
Optically active ethyl 3-(2-furoylamino)-3-(4-methoxy-
phenyl)propionate
Column: CHIRALCEL OJ-H (0.46 cmOx25 cm, available from
DAICEL CHEMICAL INDUSTRIES, LTD.)
Solvent: hexane/isopropyl alcohol (=8/2 (Volume ratio))
Flow rate: 0.5 mL/min
Temperature: 3 0°C
Wavelength: 220 nm
Also, physical properties of the ethyl (R)-2-amino-
3-phenylpropionate hydrochloride were as follows.
[0128]
"H-NMR (5 (ppm) , CD3OD) : 1.27 (t, 3H, J=7.2Hz), 3.26 (dd,
1H, J=7.3, 14.5Hz), 3.33 (dd, 1H, J=6.2, 14.5Hz), 4.30 (q,
4H, J=7.2Hz) 4.40 (dd, 1H, J=6.2, 7.3Hz), 7.30-7.47 (m, 5H)
13C-NMR (8 (ppm), CD3OD) : 16.0, 38.5, 57.0, 66.4, 130.9,
132.0, 132.2, 136.6, 172.4

54
MS (CI, i-C4H10) m/z: 194 (MH+)
Elemental analysis; Calcd: C, 57.52%; H, 7.02%; N, 6.10%
Found: C, 57.29%; H, 6.81%; N, 6.13%
UTILIZABILITY IN INDUSTRY
[0129]
The present invention relates to a process for
simultaneously preparing an optically active (S or R)-α-
amino acid and an optically active (R or S) -ct-amino acid
ester which is an antipode ester thereof from anα-amino
acid ester (racemic mixture). The optically activeα-amino
acid and an ester thereof are useful compounds as a start-
ing material or a synthetic intermediate of a physiologic-
ally active peptide or a lactam series antibiotics.

55
CLAIMS
1. A process for preparing an optically active (S or R)-oc-
amino acid represented by the formula (II):

wherein R represents an alkyl group, an alkenyl
group, an alkynyl group, a cycloalkyl group, an
aralkyl group, a heteroarylalkyl group, an aryl
group or a heteroaryl group, each of which may have
a substituent(s), and * represents an asymmetric
carbon atom,
and an optically active (R or S)-α-amino acid ester repre-
sented by the formula (III):

wherein R has the same meaning as defined above, R1
represents an alkyl group which may have a substi-
tuent (s) , and * represents an asymmetric carbon
atom, provided that it has an opposite absolute con-
figuration to that of the compound of the formula
(ID,
which comprises selectively reacting water with one of
enantiomers of anα-amino acid ester which is a racemic
mixture and represented by the formula (I):

56
wherein R and R1 have the same meanings as defined
above,
in the presence of a lipase or a protease in an organic
solvent.
2. The preparation process according to Claim 1, wherein
an amount of water to be used is 0.5 to 10 mol based on 1
mol of theα-amino acid ester which is a racemic mixture.
3. The preparation process according to Claim 1 or 2,
wherein the lipase is a lipase originated from Burkholderia
cepacia (Pseudomonas cepacia).
4. The preparation process according to Claim 1, wherein a
buffer is to be presented in a reaction system.
5. The preparation process according to Claim 4, wherein
the buffer is an aqueous solution of at least one material
selected from the group consisting of sodium phosphate,
potassium phosphate, sodium acetate, ammonium acetate and
sodium citrate.

6. The preparation process according to any one of Claims
1 to 5, wherein the lipase or protease is lyophilized or
freeze-dried in the presence of a buffer.
7. The preparation process according to any one of Claims
1 to 6, wherein at least one surfactant selected from the
group consisting of a nonionic surfactant, an amphoteric
surfactant, an anionic surfactant and a cationic surfactant
is present in the reaction.
8. The preparation process according to any one of Claims
1 to 7, wherein R is a benzyl group which may have a
substituent(s).
9. The preparation process according to any one of Claims

57
1 to 8, wherein R1 is a methyl group or an ethyl group each
of which may have a substituent(s).
10. The preparation process according to Claim 9, wherein
the substituent (s) in R1 is/are a halogen atom(s) or an
alkoxy group(s).
11. The preparation process according to any one of Claims
1 to 10, wherein the organic solvent to be used is at least
one organic solvent selected from the group consisting of
an ether, a ketone, an ester, an aliphatic hydrocarbon and
an aromatic hydrocarbon.
12. The preparation process according to any one of Claims
1 to 10, wherein the organic solvent is t-butyl methyl
ether.
13. The preparation process according to Claim 1, wherein
each of the optically active (S or R)-α-amino acid repre-
sented by the formula (II):

wherein R has the same meaning as defined above, and
* represents an asymmetric carbon atom,
and the optically active (R or S)-α-amino acid ester
represented by the formula (III):

wherein R and R1 have the same meanings as defined
above, and * represents an asymmetric carbon atom,

58
provided that it has an opposite absolute configura-
tion to that of the compound of the formula (II),
formed by the reaction according to Claim 1 is isolated
from a mixture thereof.
14. A process for preparing an acid salt of an optically-
active (R or S)-α-amino acid ester which comprises
separating each of an optically active (S or R)-α-amino
acid represented by the formula (II):

wherein R represents an alkyl group, an alkenyl
group, an alkynyl group, a cycloalkyl group, an
aralkyl group, a heteroarylalkyl group, an aryl
group or a heteroaryl cfroup, each of which may have
a substituent(s), and * represents an asymmetric
carbon atom,
and an optically active (R or S)-α-amino acid ester repre-
sented by the formula (III):

wherein R has the same meaning as defined above, R1
represents an alkyl group which may have a substi-
tuent (s), and * represents an asymmetric carbon atom,
provided that it has an opposite absolute configura-
tion to that of the compound of the formula (II),
from a mixture of the above compounds, and reacting the
resulting optically active (R or S)-α-amino acid ester with
an acid.

59
15. The preparation process according to Claim 14, wherein
the acid is at least one acid selected from the group
consisting of hydrochloric acid, sulfuric acid, acetic
acid, p-toluenesulfonic acid, oxalic acid, formic acid and
carbonic acid. ,
16. The preparation process according to Claim 15, wherein
the acid is hydrochloric acid.
17. The preparation process according to Claim 14, wherein
the reaction is carried out in an organic solvent.
18. The preparation process according to Claim 17, wherein
the organic solvent to be used is at least one organic
solvent selected from the group consisting of an ether, a
ketone, an ester, an aliphatic hydrocarbon and an aromatic
hydrocarbon.

The present invention discloses a process for
preparing an optically active (S or R)-α-amino acid
represented by the formula (II):
wherein R represents an alkyl group, alkenyl group,
alkynyl group, cycloalkyl group, aralkyl group,
heteroarylalkyl group, aryl group or heteroaryl
group, each of which may have a substituent(s), and
* represents an asymmetric carbon atom,
and an optically active (R or S)-α-amino acid ester
represented by the formula (III):
wherein R1 represents an alkyl group which may have
a substituent(s), and * represents an asymmetric
carbon atom, provided that it has an opposite
absolute configuration to that of the compound of
the formula (II),
which comprises selectively reacting water with one of
enantiomers of an α-amino acid ester which is a racemic
mixture and represented by the formula (I):
wherein R and R1 have the same meanings as defined
above,
in the presence of a lipase or a protease in an organic
solvent.

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Patent Number

259357

Indian Patent Application Number

843/KOLNP/2008

PG Journal Number

11/2014

Publication Date

14-Mar-2014

Grant Date

10-Mar-2014

Date of Filing

26-Feb-2008

Name of Patentee

UBE INDUSTRIES, LTD.

Applicant Address

1978-96, OAZA KOGUSHI UBE-SHI, YAMAGUCHI

Inventors:

#	Inventor's Name	Inventor's Address
1	YAMAMOTO YASUHITO	C/O UBE RESEARCH LABORATORY, UBE INDUSTRIES, LTD., 1978-5, OAZA KOGUSHI, UBE-SHI, YAMAGUCHI 755-8633
2	KONEGAWA TADAYOSHI	C/O UBE RESEARCH LABORATORY, UBE INDUSTRIES, LTD., 1978-5, OAZA KOGUSHI, UBE-SHI, YAMAGUCHI 755-8633
3	MIYATA HIROYUKI	C/O UBE RESEARCH LABORATORY, UBE INDUSTRIES, LTD., 1978-5, OAZA KOGUSHI, UBE-SHI, YAMAGUCHI 755-8633

PCT International Classification Number

C12P 41/00

PCT International Application Number

PCT/JP2006/316735

PCT International Filing date

2006-08-25

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2005-243730	2005-08-25	Japan