WO2007026875A1

WO2007026875A1 - PROCESS FOR PRODUCING OPTICALLY ACTIVE (S OR R)-α-HYDROXY ACID AND OPTICALLY ACTIVE (R OR S)-α-HYDROXY ACID ESTER

Info

Publication number: WO2007026875A1
Application number: PCT/JP2006/317332
Authority: WO
Inventors: Yasuhito Yamamoto; Hiroyuki Miyata; Tadayoshi Konegawa
Original assignee: Ube Industries, Ltd.
Priority date: 2005-09-02
Filing date: 2006-09-01
Publication date: 2007-03-08
Also published as: JP5119923B2; JPWO2007026875A1

Abstract

A process for producing an optically active (S or R)-α-hydroxy acid represented by the general formula (II): (II) (wherein R represents optionally substituted aralkyl or heteroarylalkyl; and * indicates an asymmetric carbon atom) and an optically active (R or S)-α-hydroxy acid alkyl ester which is represented by the general formula (III): (III) (wherein R and * are the same as defined above; R1 represents optionally substituted alkyl; and the absolute configuration is opposite to that of the compound of the general formula (II)) and is obtained as an unreacted ingredient, the process being characterized by selectively hydrolyzing one enantiomer only of a racemic mixture of an α-hydroxy acid alkyl ester represented by the general formula (I): (I) (wherein R and R1 are the same as defined above) in the presence of a lipase in a mixed solvent comprising an organic solvent and water.

Description

Specification

Optically active (S or R) -a-hydroxy acid and optically active (R or S) _Hydroxy_Hydroxy acid ester production method

Technical field

[0001] The present invention relates to an optically active (R or S) ester which is an ester of an α-hydroxy acid ester (racemic mixture) and an optically active (S or R) -a-hydroxy acid and its enantiomer at the same time. The present invention relates to a method for obtaining a hydroxy acid ester. These optically active α-hydroxy acids and esters thereof are useful compounds as raw materials or synthetic intermediates for physiologically active substances (see, for example, Patent Documents 1-3).

Background art

[0002] Conventionally, optically active (S or R) from α-hydroxy acid ester (racemic mixture)

-Optically active (R or S) which is an ester of an a-hydroxy acid and its enantiomer.-a-Hydroxy acid ester can be obtained by using lipase to produce 3-aryl 2-hydroxypropionic acid ethyl ester (racemic). Mixture), or 3 heteroaryl-2 hydroxypropionic acid ethyl ester (racemic mixture) with only one enantiomer added in water to aqueous sodium hydroxide solution to pH 7.0 to 7.4 A method of hydrolyzing while preparing to obtain optically active 3 aryl 2 hydroxypropionic acid or optically active 3 heteroaryl 2 hydroxypropionic acid is disclosed. (See Non-Patent Document 1.)

[0003] However, this method has problems in terms of operation, for example, the E position, which is an index of selectivity between enantiomers by an enzyme, is low, and the pH in the system must always be controlled. The E value is widely used as an index of selectivity of kinetic optical resolution (see Non-Patent Document 2, for example).

Disclosure of the invention

Problems to be solved by the invention

[0004] An object of the present invention is to provide an optical activity (S or R) simultaneously with a high E value from a-hydroxy acid ester (racemic mixture) by enzymatic hydrolysis using a simple method. It is to provide a method for producing an optically active (R or S) -a-hydroxy acid ester which is an ester of -a-hydroxy acid and its enantiomer.

Non-Patent Document 1: Tetrahedron Letters, 35, (29), 5205 (1994)

Non-Patent Document 2: J. Am. Chem. Soc., 104, 7294 (1982)

Non-Patent Document 3: "Chemical Dictionary", Tokyo Chemical Doujinshi Publishing, 948 pages (2000)

Patent Document 1: WO2003 / 068235

Patent Document 2: WO2004Z056740

Patent Document 3: WO2005Z046734

Means for solving the problem

[0005] The present invention provides a compound represented by the general formula (I):

[0007] In the formula, R represents an aralkyl group or a heteroarylalkyl group which may have a substituent, and R ¹ represents an alkyl group which may have a substituent.

It is a general feature characterized in that only one enantiomer of an a-hydroxy acid alkyl ester (racemic mixture) represented by is selectively hydrolyzed in a mixed solvent of an organic solvent and water in the presence of lipase. Formula (Π):

In the formula, R is as defined above.

Optical activity (S or R) —a-hydroxy acid and general formula (III):

[0011] In the formula, R and R ¹ have the same meanings as described above. Having a paired arrangement,

It is related with the manufacturing method of unreacted optical activity (R or S)-a-hydroxy acid alkylester shown by these.

[0012] The present invention also provides a compound represented by the general formula (IV):

[0014] In the formula, R is as defined above.

A-hydroxy acid n-propyl ester represented by (racemic mixture).

[0015] The present invention further relates to a general formula (V):

[0017] In the formula, R is as defined above.

The optically active (R or S) -a-hydroxy acid n-propyl ester represented by The invention's effect

[0018] According to the present invention, an α-hydroxy acid ester (racemic mixture) is converted into an optically active (S or R) simultaneously by a hydrolysis reaction using an enzyme with a small amount of enzyme and a high threshold value by a simple method. It is possible to provide a method for producing an optically active (R or S) -a-hydroxy acid ester which is an ester of an a-hydroxy acid and its enantiomer.

BEST MODE FOR CARRYING OUT THE INVENTION

[0019] R in the compound (I) represents an aralkyl group or a heteroarylalkyl group which may have a substituent.

[0020] The aralkyl group of the aralkyl group which may have a substituent in R is, for example, a benzyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group, a phenethyl group, a phenylpropyl group, and a phenyl group. A force that includes an aralkyl group in which an alkyl group having 1 to 6 carbon atoms such as a rubutyl group is substituted with an aryl group having 6 to 14 carbon atoms, preferably a benzyl group , 1-naphthylmethyl group, 2-naphthylmethyl group, 1-phenethyl group, 2-phenethyl group, 3-phenylpropyl group, 3-phenylbutyl group, etc. substituted with an aryl group with 1 to 4 carbon atoms An aralkyl group, particularly preferably an aralkyl group in which an aryl group is substituted for a methyl group such as a benzyl group, a 1-naphthylmethyl group, or a 2-naphthylmethyl group. These groups include various isomers.

[0021] Examples of the substituent in the aralkyl group which may have a substituent include, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, 1 to C carbon atoms such as decyl group: L0 alkyl group (including these isomers); hydroxyl group; nitro group; halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom An alkoxyl group having 1 to 10 carbon atoms such as a methoxyl group, an ethoxyl group, a propoxyl group, a butoxyl group, a pentyloxyl group, a hexyloxyl group, a heptyloxyl group, an octyloxyl group, a nonyloxyl group and a decyloxyl group (in addition, these groups are Including various isomers)); C7-10 carbon atoms such as benzyloxyl group, phenethyloxyl group, and phenylpropoxyl group Alkyloxyl groups (including these isomers); aryloxyl groups such as phenyloxyl and neftyloxyl groups (these groups include various isomers); methoxymethoxyl group, methoxyxoxyl Alkoxyalkoxy groups such as groups (these groups include various isomers); monoalkylhydroxyl groups such as methylhydroxyl groups and ethylhydroxyl groups (note that these groups include various isomers). ); Dialkylhydroxyl groups such as dimethylhydroxyl group and jetylhydroxyl group (Note that these groups include various isomers.); Acylhydroxyl such as formylhydroxyl group, acetyl hydroxyl group, benzoylhydroxyl group, etc. Group (note that these groups include various isomers); a nitro group; a cyan group; And a halogenoalkyl group such as a trifluoromethyl group.

[0022] The aryl group of the aralkyl group which may have a substituent in R is a phenol group, a naphthyl group, an anthryl group, a phenanthryl group, a biphenyl group, and a binaphthyl group.

[0023] The substituent in the aryl group which may have a substituent is an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, or a butyl group. Including various isomers. ); Hydroxyl group; halogen atom such as chlorine atom, bromine atom, iodine atom, fluorine atom; alkoxyl group having 2 to 4 carbon atoms such as ethoxyl group (note that these groups include various isomers) C 1 -C 4 alkylenedioxy group such as methylenedioxy group; nitro group; cyano group; and halogenoalkyl group such as trifluoromethyl group.

Specific examples of the aryl group which may have such a substituent include, for example, 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 hydroxyphenol group, 4-hydroxyphenyl group, 2,3 dihydroxyphenyl group, 2,4 dihydroxyphenyl group 3, 4 Dihydroxyphenyl group, 2 Chlorophore group, 3 Chlorophore group, 4 Chlorophore group, 2, 3 Dichlorophenol group, 2,4 Dichlorophenol group, 3, 4 Dichlorophenol, 3, 5 Dichlorophenol, 2 Bromophenyl, 3— Bromophenyl, 4 Bromophenol, 2 Hydrophobe, 3 Feodophor, 4 Feodophor Group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluoroalkyl group, 2, 3 difluorophenyl group, 2, 4 difluorophenyl group, 3, 4 — difluorophenol group, 3 bromo 5 x 1 2-hydroxyphenol group, 2-methoxyphenyl group, 3-methoxyphenol group Groups, 4-methoxyphenyl groups, 2,3 dimethoxyphenyl groups, 2,4 dimethoxyphenyl groups, 3,4 dimethoxyphenyl groups, 3,5 dimethoxyphenyl groups, 3, 4 —Methylenedioxyphenyl group, 4-ethoxyphenyl group, 4-butoxyphenyl group, 4-isopropoxyphenyl group, 1-phenoxyphenyl group, 2-benzoxyphenyl group, 3-benzyloxyphenyl group Group, 4-benzyloxyphenyl group, 4 trifluoromethyl group, 2-trifluoro group, 3-trifluoro group, 4-trophenol group, 4 cyanophenol group, 4-methoxycarboro group -Lufuryl group, 1-naphthyl group and 2-naphthyl group Preferable is a phenyl group, a 2-tolyl group, a 3-tolyl group, a 4-tolyl group, a 2,3-xylyl group, a 2-hydroxyphenyl group, a 3-hydroxyphenyl group, a 4-hydroxyphenyl group, a 2,3 Dihydroxy phenol group, 2, 4 Dihydroxy phenol group, 3, 4 Dihydroxy phenol group, 2 Chlorophore group, 3 Chlorophore group, 4 Chlorophore group, 2, 3 Dichlorophenol group, 2, 4 Dichlorophenol Group, 3, 4 dichlorophenol group, 3,5 dichlorophenol group, 2 bromophenol group, 3 bromophenol group, 4 bromophenol group, 2 chlorophenol group, 3 chlorophenol group, 4 Fluorophore group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 3,4-difluorophenyl group, 3-bromo-5-chloro 2-hydroxyphenyl group, 2-methoxyphenyl group 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 Trifluoromethylphenol group, 2 Benzyloxyphenyl group, 3-Benzyloxyphenyl group, 4 —Benzyloxyphenyl group, 4—-Trophenyl group, 4 Cyanophenyl group, 1 naphthyl group and 2 naphthyl group, more preferably phenol group, 2 tolyl group, 3 tolyl group, 4 tolyl group, 2, 3 xylyl group, 4-hydroxyphenyl group, 3, 4 dihydroxyphenyl group, 2 Open mouth group, 3 Open mouth group, 4 Open mouth group, 2, 3 Dichlorophenol group, 2, 4 Dichlorophenol group, 3, 4-Diclonal mouth group 3, 5 Dichlorophenol, 2 Bromophenyl, 3 Bromophenyl, 4 Bromophenol, 4 Feodophor, 2 Fluorophenol, 3 Fluorophenol, 4 Fluorophenol Group, 3, 4 difluorophenol group, 2-pheophthalol group, 3 quadfarde group, 4 pheodophore group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group 2,3 dimethoxyphenyl group, 2,4-dimethoxyphenyl group, 3,4-dimethoxyphenyl group Group, 3,5-dimethoxyphenyl group, 3,4-methylenedioxyphenyl group, 4-trifluoromethylphenyl group, 2-benzyloxyphenyl group, 3-benzyloxyphenyl group 4 benzyloxyphenyl group, 4-trophenyl group, 1 naphthyl group and 2 naphthyl group, particularly preferably phenol group, 2 tolyl group, 3 tolyl group, 4 tolyl group, 2, 3 xylyl group, 2 Open mouth group, 3 Open mouth group, 4 Open mouth group, 2, 3 Dichlorophenol group, 2, 4 Dichlorophenol group, 3, 4 Dichlorophenol group, 3 , 5 Dichlorophenol group, 2 Bromophenyl group, 3 Bromophenyl group, 4 Bromophenyl group, 2 Fluorophenol group, 3 Fluorophenol group, 4 Fluorophenol group, 3, 4 Difluorophenol -Rhodo group, 2—Chodophenol group, 3 Codophenol group, 4 Codophenol group, 2-Methoxyphenol Le Groups, 3-methoxyphenyl, 4-methoxyphenyl, 4-benzyloxyphenyl, 2,3 dimethoxyphenyl, 3,4 dimethoxyphenyl, 3,5 dimethoxyphenyl, and 3, 4-Methylenedioxyphenyl group.

Specific examples of the aralkyl group having such a substituent include, for example, 2 fluoro-orbityl benzyl group, 3-fluo-oral benzylyl group, 4 fluo-oral benzylyl group, 3,4-difluorobenzyl group, 2 , 4 Difluorobenzyl group, 2 Dichlorodiethyl benzyl group, 3 Diclonal benzyl group, 4 Diclonal benzyl group, 2, 4 Dicyclodiethyl benzyl group, 3, 4 Dicyclodiethyl benzyl group, 2 Bromobenzyl Group, 3 bromobenzyl group, 4 bromobenzyl group, 2, 4 dibromobenzyl group, 3, 4 dibromobenzyl group, 2 rdodobenzyl group, 3 rdodobenzyl group, 4 rdodobenzyl group, 2, 3 rdodobenzyl group, 3,4 rdodo Benzyl group, 2-methylbenzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 2-ethylbenzyl group, 3-ethylbenzyl group, 4-ethylbenzyl group, 2-hydroxybenzyl group, 3-hydride Roxybenzyl 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 trifluoromethylbenzyl group, 2 benzyloxybenzyl group, 3 benzyloxybenzyl group, 4 monobenzyloxybenzyl group, 2-to-benzyl group, 3-trobenzyl group, 4-trobenzyl group, 2-cyanobenzyl group, 3-cyanobenzyl group, 4-cyanobenzyl group, 4-dimethylhydroxybenzyl group, 4-formylhydroxybenzyl group, 2-acetylhydroxybenzyl group, 3-acetylhydroxybenzyl group Group, 4-acetylhydroxybenzyl group, 4-benzoylhydro Cybenyl group, 2- (2 fluorophenyl) 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 chlorophenyl) ethyl group, 2— (3 chlorophenyl) ethyl group, 2— (4 chlorophenyl) ) Ethyl group, 2- (2,4 dicyclophenyl) ethyl group, 2- (3,4-dichlorophenyl) ethyl group, 2- (2 bromophenyl) ethyl group, 2- (3 Bromophenyl) ethyl group, 2— (4 Bromophenyl) ethyl group, 2— (2,4 Dibromophenyl) ethyl group, 2— (3,4 Dibromophenyl) Ethyl group, 2— (2 tert-phenyl) ethyl group, 2— (3 tert-phenyl) ethyl group, 2 (4- tert-phenyl) ethyl group, 2— (2, 3 jorde) ethyl group, 2 — (3,4-jodophenyl) ethyl group, 2- (2 tolyl) ethyl group, 2- (3 tolyl) ethyl group, 2- (4 tolyl) ethyl group, 2— (2 ethyl phenyl) 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-methoxyphenyl) 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-trifluorophenyl) ethyl group 2-, (3-diphenyl) ethyl group, 2- (4-trifluoro) ethyl group, 2- (2-cyanophenyl) ethyl group, 2- (3-cyanophenyl) ethyl group, 2 — (4 cyanophyl) ethyl group, 2- (4-dimethylhydroxyphenyl) ethyl group, 2— (4-formylhydroxyphenyl) ethyl group, 2- (2 acetylhydroxyphenyl) Ethyl group, 2- (3-acetylhydroxyphenyl) ethyl group, 2- (4-acetylethylphenyl) ethyl group,

2— (4 Benzylhydroxyphenyl) ethyl group, 3— (2 Fluorophenyl) propyl group, 3— (4 Fluorophenyl) propyl group, 3— (4 Chlorophenyl) propyl group ,

3— (4 Bromophenyl) propyl group, 3— (4 Phodophenol) propyl group, 3— (2—Black-Fuel) propyl group, 3— (2—Methoxyphenol) propyl group, 3— (4-methoxyphenyl) propyl group, 3- (3,4-dimethoxyphenyl) propyl group, 3- (4-trifluoromethylphenol) propyl group, 3-((2-trifluoromethylphenyl)) Forces such as propyl group, 3 mono (4-trophenyl) propyl group, 3- (4-cyanophenol) propyl group and 3- (4-acetylhydroxyphenol) propyl group, etc., preferably 2-fluoro Benzyl group, 3 Fluorobenzyl group, 4 Fluorobenzyl group, 2 Chloro benzyl group, 3 Chloro benzyl group, 4 Chloro benzyl group, 2 bromobenzyl group, 3 bromo benzyl group, 4 bromobenzyl group, 22 odor benzyl group , 3 Jill group, 4 Yodobenjiru group, 2-methylbenzyl group, 3-methylbenzyl group, 4 Mechiruben Zyl group, 2-hydroxybenzyl group, 4-hydroxybenzyl group, 2-methoxybenzyl group, 3-methoxybenzyl group, 4-methoxybenzyl group, 3,4 dimethoxybenzyl group, 2-trifluoromethylbenzyl group, 4 trifluoride Romethylbenzyl group, 2 benzyloxybenzyl group, 3 benzyloxybenzyl group, 4 monobenzyloxybenzyl group, 2-nitrobenzyl group, 3-trobenzyl group, 4-trobenzyl group, 2 cyanobenzyl group, 3 —Cyanobenzyl group, 4-Cyanobenzyl group, 4-Formylhydroxybenzyl group, 3-Acetylhydroxybenzyl group, 4-Acetylhydroxybenzyl group, 4-Benzylhydroxybenzyl group, 2- (2 Fluorophenyl) ethyl 2— (3 fluorophenyl) ethyl group, 2— (4 fluorophenyl) ethyl group, 2 (2-clonal phenyl) ethyl group, 2- (3 black-phlorophenyl) ethyl group, 2- (4-crophyl-phenyl) ethyl group, 2- (2 bromophenyl) ethyl group, 2- (3 Bromophenyl) ethyl group, 2— (4 Bromophenyl) ethyl group, 2— (2 Chordphenol) ethyl group, 2— (3 Chordphenol) ethyl group, 2— (4 Chordphenol) ) Ethyl group, 2- (2 tolyl) ethyl group, 2- (3 tolyl) ethyl group, 2- (4 tolyl) ethyl group, 2- (2 ethyl phenyl) ethyl group, 2 (2-hydroxyphenyl) L) 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 dimethoxyphenyl) ethyl group, 2— (3,4 dimethoxyphenyl) ethyl group, 2— (2 trifluoromethylphenol) 2- (4-trifluorophenyl) ethyl group, 2- (4-trifluorophenyl) ethyl group, 2- (4-trifluorophenyl) ethyl group, 2- (3-trifluorophenyl) ethyl group Group, 2- (4-trophenyl) ethyl group, 2- (2 cyanophyl) ethyl group, 2- (3 cyanophyl) ethyl group, 2- (4 cyanophyl) ethyl group, 2- ( 2-acetyl-phenyl) ethyl group, 2- (3-acetyl-phenyl) phenyl group, 2- (4-acetyl-hydroxyphenyl) ethyl group, 2- (4-benzoyl) Hydroxyphenyl) ethyl group, 3— (2 Fluorophenyl) propyl group, 3— (4 Fluorophenyl) propyl group, 3— (4 Chlorophenyl) propyl group, 3— (4 Bromophenol) -Lu) propyl group, 3— (4 odors) pill group, 3— (2 chlorophene) propyl group, 3— (2-methoxyphenyl) propyl, 3- (4-methoxyphenyl) propyl, 3- (3,4-dimethoxyphenyl) propyl 3— (4 trifluoromethylphenol) propyl group, 3— (2 trifluoromethylphenol) propyl group, 3— (4-trifluorophenyl) propyl group, 3— (4 cyanophane— ) Propyl group and 3- (4-acetylhydroxyphenyl) propyl group, more preferably 2-fluorobenzyl group, 4-fluorobenzyl group, 2-chlorobenzyl group, 4-chlorobenzene group Group, 2 bromobenzyl group, 4 bromobenzyl group, 2 rdodobenzyl group, 4-benzyl group, 2 methylbenzyl group, 4 methylbenzyl group, 4-hydroxybenzyl group, 2 -methoxybenzyl group, 4 -methoxybenzyl group, 3 , 4 Dimethoxybenzyl group, 2 trifluoromethylbenzyl group, 4 trifluoromethylbenzyl group, 4 benzyloxybenzyl group, 2-trobenzyl group, 4-trobenzyl group, 2 Nobenzyl group, 3-Cyanobenzyl group, 4-Cyanobenzyl group, 3-Acetylhydroxybenzyl group, 4-Acetylhydroxybenzyl group, 2- (2 Fluorophenyl) ethyl group, 2- (4 Fluorophenyl) ethyl group , 2— (2 Chlorophenyl) ethyl group, 2— (4 Chlorophenyl) ethyl group, 2— (2 Bromophenyl) ethyl group, 2— (4 Bromophenyl) ethyl group , 2- (2 pseudophenyl) ethyl group, 2- (4 pseudophenyl) ethyl group, 2- (2 tolyl) ethyl group, 2- (4 tolyl) ethyl group, 2- (4-hydroxyphenyl) ethyl group Group, 2- (2-methoxyphenyl) ethyl group, 2- (4-methoxyphenyl) ethyl group, 2- (3,4-dimethoxyphenyl) ethyl group, 2- (2 trifluoromethylphenol) Ethyl group, 2 (4-trifluoromethylphenol) ethyl group, 2— 4-Benzyloxyphenyl) ethyl group, 2- (2-trophenyl) ethyl group, 2— (4-trophenyl) ethyl group, 2 -— (2 cyanophyl) ethyl group, 2 -— (4 A cyanophenyl) ethyl group, a 2- (2-acetylhydroxyphenyl) ethyl group and a 2- (4-acetylhydroxyphenyl) ethyl group.

Examples of the heteroarylalkyl group that may have a substituent in R include, for example, a 2-pyridylmethyl group, a 3-pyridylmethyl group, a 3-pyridylmethyl group, a 2-phenylmethyl group, Carbon atoms such as -rumethyl group, 2 imidazolyl group, 4 imidazolyl group, 2 acetylmethyl group, 3 indolylmethyl group, 2 pyridylethyl group, 2-chelylethyl group, 2-pyridylpropyl group, 2-pyridylbutyl group Heteroaryl in which an alkyl group having 1 to 6 carbon atoms is substituted with a heteroaryl group having 6 to 14 carbon atoms Forces that can be incorporated into alkyl groups, preferably 2-alkylidyl groups such as 2-pyridylmethyl group, 2-phenylmethyl group, 3-indolylmethyl group, 2-pyridylethyl group, and 2-chelethyl group. A heteroaryl alkyl group substituted by a heteroaryl group, more preferably a heteroaryl alkyl group in which a heteroaryl alkyl group is substituted for a methyl group such as a 2-pyridylmethyl group, a 2-cellmethyl group, or a 3-indolylmethyl group . These groups include various isomers.

[0027] The heteroaryl group of the heteroarylalkyl group which may have a substituent in R is, for example, a 2-furyl group, a 3-furyl group, a 2-pyridyl group, a 3-pyridyl group, 4 Pyridyl group, 2 pyrrolyl group, 3 pyrrolyl group, 2 chayl group, 3 chael group, 2—indolyl group, 3 —indolyl group, 2 —imidazolyl group, 4 —imidazolyl group, 3 pyrazolyl group, 2 pyrimidyl group Group, 4 pyrimidyl group and quinolyl group.

[0028] Examples of the substituent of the heteroaryl group which may have a substituent include an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, and a butyl group. ); Hydroxyl group; halogen atom such as chlorine atom, bromine atom, iodine atom and fluorine atom; alkoxyl group having 2 to 4 carbon atoms such as ethoxyl group (note that these groups are And various isomers)); hydroxyl group; nitro group; cyano group; and halogenoalkyl groups such as trifluoromethyl group.

[0029] Specific examples of the heteroaryl group which may have such a substituent include, for example, 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 hydroxy) furyl group, 2- (3 ditro) furyl group, 2- (3 cyano) furyl group, 2- (3-methyl) pyridyl group, 2 mono (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 hydroxy) pyridyl group, 2— (3 double) 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) cell group are preferable. 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 It is a group.

[0030] Specific examples of the heteroarylalkyl group which may have such a substituent include 2- (3-methyl) furylmethyl group and 2- (4-methyl) furylmethyl group. 2- (3-Ethyl) furylmethyl group, 2- (4-Ethyl) furylmethyl group, 2- (3-Fluoro) furylmethyl group, 2- (3-Chloro) furylmethyl group, 2- ( 3-hydroxy) furylmethyl group, 2- (3-methoxy) furylmethyl group, 2- (3-amino) furylmethyl group, 2- (3-nitro) furylmethyl group, 2- (3-ciano) furyl Methyl group, 2- (3-methyl) pyridylmethyl group, 2- (4-methyl) pyridylmethyl group, 2- (3-ethyl) pyridylmethyl group, 2- (4-ethyl) pyridylmethyl group, 2- (3- Fluoro) pyridylmethyl group, 2— (4-chloro) pyridylmethyl group, 2 -— (3-hydroxy) pyrid Rumethyl 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, 2- (3-methyl) chelmethyl group, etc. Preferably, 2- (3-methyl) furylmethyl group, 2- (3-fluoro) furylmethyl group, 2- (3-methyl) pyridylmethyl group, 2- (3-fluoro) pyridylmethyl group, 2- ( A 3-nitro) pyridyl group, a 2- (3-cyano) pyridylmethyl group and a 2- (3,5-dichloro) pyridylmethyl group.

[0031] R ¹ in the compound (I) represents an alkyl group which may have a substituent.

[0032] The alkyl group of the alkyl group which may have a substituent in R ¹ is a linear or branched alkyl group having 1 to LO carbon atoms, such as a methyl group or an ethyl group. A group, an alkyl group such as a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group and a decyl group, preferably an ethyl group, an n-propyl group, an isopropyl group, _n -butyl group, isobutyl group, _sec -butyl group, n-pentyl group, n-hexyl group and the like, which are linear or branched alkyl groups having 1 to 6 carbon atoms, more preferably n-propyl A linear or branched alkyl group having 1 to 4 carbon atoms such as a group, n-butyl group and isobutyl group. These groups include various isomers.

[0033] Examples of the substituent in the alkyl group which may have a substituent include a fluorine atom, chlorine Halogen atoms such as atoms, bromine atoms and iodine atoms; hydroxyl groups; carbon chain 1-4 alkoxy groups such as methoxyl groups, ethoxyl groups, propoxyl groups and butoxyl groups; dimethyl hydroxyl groups and jetyl hydroxyl groups A dialkylhydroxyl group; and a force including a cyano group, preferably a fluorine atom, a chlorine atom, a methoxyl group, an ethoxyl group, a hydroxyl group and a cyano group, and more preferably a fluorine atom, a chlorine atom, a methoxyl group and an ethoxyl group.

[0034] Specific examples of the alkyl group which may have such a substituent include, for example, 2 fluoroethyl group, 2-chlorodiethyl group, 2,2-difluoroethyl group, 2,2-dichloro Oral ethyl group, 2, 2, 2-trichlorodiethyl group, 2, 2, 2-trifluoroethyl group, 2-methoxy cetyl group, 2-ethoxyethyl group, methoxymethyl group, 2-hydroxyethyl group, 2 —Chainoethyl group, 2-bromoethyl group, 2-dimethylhydroxyl group, 2-chloropropyl group, 3-chloropropyl group and the like, preferably 2-chloroethyl group, 2,2,2-trichloroethyl group A 2, 2, 2-trifluoroethyl group, a methoxymethyl group, a 2-methoxycetyl group, and a 2-ethoxyethyl group.

[0035] The compound (I) used in the reaction of the present invention can be easily produced, for example, by reacting a-hydroxy acid with an alcohol in the presence of sulfuric acid (see later reference examples). Listed).

[0036] The compound (IV) used in the reaction of the present invention can be easily produced by, for example, reacting a-hydroxy acid with 1-propanol in the presence of sulfuric acid (afterwards). Described in the reference example).

[0037] The lipase used in the hydrolysis reaction of the present invention is preferably a lipase of a microorganism that can be isolated from yeast or bacteria, more preferably a lipase derived from Bartahorderia 'sepashia (Syudumonas' sepasia) (for example, Amano PS (manufactured by Amano Enzyme) etc. is used. As the lipase, a commercially available product can be used as it is in its natural form or as a fixed enzyme, and it may be used alone or in combination of two or more. In addition, the enzyme immobilizing agent contained in the commercially available product can be removed before use.

[0038] The above-mentioned lipase is commercially available in its natural form or as an immobilized enzyme! It may be used after chemical treatment or physical treatment. [0039] As the chemical treatment or physical treatment method, specifically, for example, lipase is dissolved in a buffer solution (an organic solvent may be present if necessary) and frozen as it is or with stirring. The method of drying etc. is mentioned. Freeze-drying is a method in which a substance containing an aqueous solution and water is rapidly frozen at a temperature below the freezing point, depressurized below the water vapor pressure of the frozen material, sublimated and removed, and the substance is dried. (For example, see Non-Patent Document 3). Note that catalytic treatment (reactivity, selectivity, etc.) can be improved by this treatment.

[0040] The amount of the lipase to be used is preferably 0.1 to LOOOmg, more preferably l200mg, relative to compound (I) lg.

[0041] The hydrolysis reaction of the present invention is preferably carried out in a two-phase solvent of water and an organic solvent, in a two-phase solvent of a buffer solution and an organic solvent, in a two-phase solvent of an aqueous inorganic base solution and an organic solvent. It is carried out in a two-phase solvent consisting of a buffer solution containing an inorganic base and an organic solvent.

[0042] As the water, purified water such as ion-exchanged water or distilled water is preferably used.

[0043] Examples of the organic solvent include aliphatic hydrocarbons such as n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, and cyclopentane; benzene, toluene And aromatic hydrocarbons such as xylene; etherols such as jetyl ether, t-butylmethylenoateol, diisopropinoleetenore, cyclopentinolemethinoleetenole; and esters such as ethyl acetate and butyl acetate Preferably n-xane, n-heptane, cyclopentane, cyclohexane, tonolene, diisopropyl ether, t-butyl methyl ether and Z or cyclopentyl methyl ether, more preferably n-xane, cyclohexane, toluene, diisopropyl ether T-butyl methyl ether and / or cyclopent Methyl ether, Yellow Sun, toluene and Z or t- butyl methyl ether is used particularly preferably cyclohexylene. These organic solvents may be used alone or in combination of two or more.

[0044] As the inorganic base, for example, a weakly basic inorganic base, more preferably an alkali metal hydrogen carbonate, particularly preferably potassium hydrogen carbonate or sodium hydrogen carbonate is used.

[0045] The amount of the inorganic base to be used is preferably 0.1 2.0 mol per 1 mol of compound (I). More preferably, it is 0.5 to 1.0 mol.

[0046] Examples of the buffer include an aqueous solution of an organic acid salt such as an aqueous solution of sodium phosphate and an aqueous solution of potassium phosphate; an aqueous solution of an organic acid salt such as an aqueous solution of sodium acetate and an aqueous solution of sodium citrate; Preferably, an aqueous solution of an inorganic acid salt, more preferably an aqueous sodium phosphate solution and an aqueous Z or potassium phosphate solution is used. These buffers may be used alone or in combination of two or more.

[0047] The concentration of the buffer is preferably 0.01 to 2 mol ZL, more preferably 0.05 to 0.5 mol 1 ZL, and the pH of the buffer is preferably 4 to 9, more preferably 6 to 8. It is.

[0048] Solvent in the hydrolysis reaction of the present invention (two-phase solvent of water and organic solvent, two-phase solvent of buffer and organic solvent, two-phase solvent of aqueous inorganic base solution and organic solvent, or The use amount of a buffer solution containing an inorganic base and a two-phase solvent (organic solvent) is preferably 2 to 200 mL, more preferably 5 to 80 mL, relative to compound (I) lg.

[0049] In the hydrolysis reaction of the present invention, the amount of the organic solvent used in the case of using a mixed solvent of an organic solvent and a buffer as a solvent is preferably 0. 1 to: LOmL, more preferably 0.5 to 5 mL.

[0050] The hydrolysis reaction of the present invention includes, for example, a compound (1), a lipase and a solvent (in a two-phase solvent of water and an organic solvent, a two-phase solvent of a buffer solution and an organic solvent, an aqueous inorganic base solution) A two-phase solvent with an organic solvent, or a two-phase solvent with a buffer solution containing an inorganic base and an organic solvent) is mixed and reacted with stirring. The reaction temperature at that time is preferably 0 to 80 ° C, more preferably 10 to 50 ° C, and the reaction pressure is not particularly limited. In conducting the reaction, in order to neutralize the compound (II) produced with the progress of the reaction, a base such as sodium hydroxide or potassium hydroxide (or an aqueous solution thereof) may be appropriately added. You may do it.

[0051] The compound (II) obtained by the hydrolysis of the present invention can be used, for example, after the completion of the reaction, in an appropriate organic solvent (for example, t-butyl methyl ether, toluene, hexane, heptane, cyclohexane). It can be obtained by adding compound (III) and extracting compound (III) to the organic layer, followed by filtration. Further, it can be obtained by a method of adding an acid to the obtained filtrate (including the compound (III)) and acidifying it, and then separating and concentrating the organic layer. The These can be further purified by general methods such as crystallization, recrystallization, distillation, column chromatography and the like.

Example

Next, the ability to specifically describe the present invention with reference to examples The scope of the present invention is not limited to these.

[0053] Reference Example 1 (Synthesis of 2-hydroxy-3-phenolpropionic acid methyl ester (racemic mixture))

Methanol 15. Add 3.0 g (18. lmmol) of 2-hydroxy-3-phenolpropionic acid (racemic mixture) and 88.5 mg (0.90 mmol) of concentrated sulfuric acid to OmL (370 mmol) and mix with stirring. The reaction was performed at ° C for 2 hours. After completion of the reaction, 1 mL of a saturated aqueous sodium hydrogen carbonate solution was concentrated in vacuo to the resulting reaction solution. Next, 20 mL of ethyl acetate and 5 mL of water were added for liquid separation, and the organic phase was washed with 2 mL of saturated sodium chloride and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2.98 g of 2-hydroxy-3-phenylpropionic acid methyl ester (racemic mixture) as a colorless liquid (2 hydroxy 3-phenylpropionic acid (racemic mixture) standard) Isolated yield: 91.7%).

The physical properties of 2-hydroxy-3-phenylpropionic acid methyl ester (racemic mixture) were as follows.

[0054] — NMR (S (ppm), CDC1): 2.95 (dd, 1H, −T = 6.9, 13.9Ηζ), 3. ll (dd,

Three

1Η, J = 4.4, 13.9Hz), 3.74 (s, 3Η), 4.43 (dd, 1Η, J = 4.4, 6.9Hz), 7. 19-7.30 (m, 5Η)

¹³ C-NMR (δ (ppm), CDC1): 40.6, 52.4, 71.3, 126.9, 128.4, 129.5

Three

, 136.4, 174.6

MS (El) m / z: 180 (M ⁺ )

MS (CI, i—CH) m / z: 181 (MH +)

4 10

[0055] Reference Example 2 (Synthesis of 2-hydroxy-3 phenylpropionic acid ethyl ester (racemic mixture))

Ethanol 5. Add 1.0 g (6. Ommol) of 2-hydroxy-l-propylpropionic acid (racemic mixture) and 29.5 mg (0.3 mmol) of concentrated sulfuric acid to OmL (85.6 mmol) and stir. The reaction was carried out at 50 ° C for 4 hours. After completion of the reaction, 2 mL of a saturated aqueous sodium hydrogen carbonate solution was added to the resulting reaction solution and concentrated under reduced pressure. Subsequently, 15 mL of ethyl acetate and 3 mL of water were added to separate the solution, and the organic phase was washed with 2 mL of saturated sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 935 mg of 2-hydroxy-3-phenylpropionic acid ethyl ester (racemic mixture) as a colorless liquid (isolated on the basis of 2-hydroxy-3 phenylpropionic acid (racemic mixture)). Rate: 80.0%). The physical properties of 2-hydroxy-3phenylpropionic acid ethyl ester (racemic mixture) were as follows.

[0056] NMR (δ (ppm), CDC1): 1.27 (t, 3H, J = 7.2 Hz), 2.96 (dd, 1H, J =

Three

6.8, 13.9Hz), 3.l l (dd, 1H, J = 4.5, 13.9Hz), 4.21 (q, 2H, J = 7.2Hz

), 4.42 (dd, 1H, J = 4.5, 6.8Hz), 7.21—7.30 (m, 5H)

¹³ C—NMR (δ (ppm), CDC1): 14. 2, 40.6, 61.7, 71.3, 126.9, 128.4,

Three

129.5, 136.4, 174.2

MS (CI, i— CH) m / z: 195 (MH ⁺ )

4 10

Elemental analysis; Calcd: C, 68. 02%; H, 7. 27%

Found: C, 67. 55%; H, 7. 26%

[0057] Reference Example 3 (Synthesis of 2-hydroxy-3-phenolpropionic acid n-propyl ester (racemic mixture))

To 1-propanol 7.5 mL (100 mmol), add 1.5 g (9. Ommol) of 2-hydroxyl-3-phenolpropionic acid (racemic mixture) and 44 mg (0.5 mmol) of concentrated sulfuric acid. C was allowed to react for 6 hours. After completion of the reaction, 3 mL of a saturated aqueous sodium hydrogen carbonate solution was added to the resulting reaction solution and concentrated under reduced pressure. Next, 20 mL of ethyl acetate and 3 mL of water were added for liquid separation, and the organic phase was washed with 2 mL of saturated sodium chloride and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 1.69 g of 2-hydroxy-3-phenylpropionic acid n-propyl ester (racemic mixture) as a colorless liquid (2-hydroxy-3-phenylpropionic acid (racemic) Mixture) Base isolated yield: 90.0%).

Incidentally, 2-hydroxy-3-phenolpropionic acid n-propyl ester (racemic mixture) is a novel compound represented by the following physical property values. [0058] H-NMR (δ (ppm), CDC1): 0.91 (t, 3H, J = 7.4Hz), 1.63 (tq, 2H, J = 6

Three

.8, 7.4Hz), 2.95 (dd, 1H, J = 6.9, 13.9Hz), 3.09 (dd, 1H, J = 4.6, 13.9Hz), 4.08 (t, 2H, J = 6.8Hz) 4.41 (dd , 1H, J = 4.6, 6.9Hz), 7.19-7.28 (m, 5H)

¹³ C-NMR (δ (ppm), CDC1): 10.3, 21.9, 40.6, 67.2, 71.3, 126.8, 1

Three

28.3.129.5, 136.5, 174.3

MS (CI, i—CH) m / z: 209 (MH ⁺ )

4 10

Elemental analysis; Calcd: C, 69.21%; H, 7.74%

Found: C, 68.42%; H, 7.36%

[0059] Reference Example 4 (Synthesis of 2-hydroxy-3phenolpropionic acid isobutyl ester (racemic mixture))

To 15.0 mL (163 mmol) of 2-methyl 1-propanol, add 3.0 g (18. Immol) of 2-hydroxy-3-phenolpropionic acid (racemic mixture) and 177 mg (l.8 mmol) of concentrated sulfuric acid while stirring. The reaction was carried out at 50 ° C for 8 hours. After completion of the reaction, 1 mL of water was added to the resulting reaction solution, and the pH was adjusted to 7.0 with an ImolZL aqueous solution of sodium hydroxide and concentrated under reduced pressure. Subsequently, 15 mL of cyclohexane and 3 mL of water were added and separated, and the organic phase was washed with 2 mL of saturated sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 3.81 g of 2-hydroxy-3-phenolpropionic acid isobutyl ester (racemic mixture) as a colorless liquid (2-hydroxy-3 phenolpropionic acid (racemic mixture) standard) Isolated yield: 95.0%).

The physical properties of 2-hydroxy-3-phenolpropionic acid isobutyl ester (racemic mixture) were as follows.

[0060] 'H-NMRC δ (ppm), CDC1): 0.92 (d, 3H, J = 6.7 Hz), 0.93 (d, 3H, J = 6

Three

.7Hz), 1.94 (ddqq, 1H, J = 6.7, 6.7, 6.7, 6.7Hz), 2.97 (dd, 1H, J = 6.8, 14.0Hz), 3.13 (dd, 1H, J = 4.6, 14.0Hz), 3.91 (dd, 1H, J = 6.7, 10.6Hz), 3.96 (dd, 1H, J = 6.7, 10.6Hz), 4.45 (dd, 1H, J = 4.6, 6.8Hz), 7.21-7.30 (m, 5H)

¹³ C-NMR (δ (ppm), CDC1): 19.00, 19.02, 27.7, 40.7, 71.3, 71.7, 126. 9. 128.4, 129.5, 136.4, 174.3

MS (CI, i— CH) m / z: 223 (MH ⁺ )

4 10

Elemental analysis; Calcd: C, 70. 24%; H, 8. 16%

Found: C, 69. 12%; H, 8. 13%

[0061] Example 1 ((S) -2 hydroxy-3 phenolpropionic acid and (R) -2 hydroxy

3 Synthesis of methyl propionic acid methyl ester)

50 mmol ZL potassium phosphate aqueous solution with pH 8.2 1. OmL and cyclohexane 1. Methyl ester of 2-hydroxy-3-phenylpropionate synthesized in Reference Example 1 (racemic mixture) 100 mg (0 55 mmol) was kept at 30 ° C. At the same temperature, add 23.3 mg (0.28 mmol) of sodium hydrogen carbonate and lmg of lipase (Amano Lipase PS (trade name); Aldrich) from Burkholderia cepacia (Pseudomonas cepacia) at the same temperature and stir. The reaction was carried out at 30 ° C. After 18 hours, hexane, saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture for liquid separation. The aqueous layer was washed with cyclohexane, and then the ethyl acetate was adjusted to pH 1-2 with 2 mol ZL hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (S) -2-hydroxy-3-phenylpropionic acid 43.3 mg (2-hydroxy-3-phenylpropionic acid methyl ester (racemic mixture). ) Base isolated yield = 47.0%).

When (S) -2 hydroxy 3 -phenol propionic acid was derived to n-propyl ester by a conventional method, the optical purity was measured using high performance liquid chromatography using an optically active column. 87. 2% ee Met. (S) -2 Hydroxy-13-propylpropionic acid n-propyl ester is a novel compound.

When the optical purity of (R) -2-hydroxy-3phenylpropionic acid methyl ester was measured using high performance liquid chromatography using an optically active column, it was 93.7% ee.

The E value in this reaction was 51.

[0062] Analysis conditions for high performance liquid chromatography;

Column: Chiralcel OB— H (0.46 cm Φ X 25 cm, manufactured by Daicel Chemical Industries)

Solvent: hexane Z isopropyl alcohol (= 98/2 (volume ratio)) Flow rate: 0.5ml / min

Temperature: 30 ° C

Wavelength: 220nm

[0063] The physical properties of (S) 3 hydroxy-3 phenolpropionic acid were as follows.

— NMR (δ (ppm), CDC1): 3.00 (dd, 1H, J = 7.2, 14.0Hz), 3.21 (dd,

Three

1H, J = 4.3, 14.0Hz), 4.52 (dd, 1H, J = 4.3, 7.2Hz), 7.25-7.34 (m,

5H)

¹³ C-NMR (δ (ppm), CDC1): 40.2, 71.0, 127.2, 128.6, 129.5, 135.

Three

8, 177.7

MS (El) m / z: 167 (M ⁺ )

MS (CI, i—CH) m / z: 166 (MH +)

4 10

Elemental analysis; Calcd: C, 65.05%; H, 6.07%

Found: C, 64.77%; H, 5.87%

Specific rotation: [a] ²⁶ —19.1 ° (c 1.00, HO)

D 2

[0064] The specific optical rotation of the obtained optically active 2-hydroxy-3-phenolpropionic acid and the specific rotation of (S) -3-hydroxy-3-phenolpropionic acid described in the Aldrich catalog. The absolute configuration was determined by comparing with the sign ([hi] ²⁴ —20.8 ° (c 2, HO))

D 2

[0065] Example 2 ((S) -2 hydroxy-l-3 proppropionic acid and (R) -2 hydroxy

3 Synthesis of ethyl propylpropionate)

pH8.2 50mmol ZL potassium phosphate aqueous solution 1. OmL and cyclohexane 1. In a mixture of OmL, 2-hydroxy-3-phenolpropionate ester mixed in race example 2 (racemic mixture) 100mg (0.51mmol) Was kept at 30 ° C. At the same temperature, 21.6 mg (0.26 mmol) of sodium bicarbonate and lmg of lipase (Amano Lipase PS (trade name); manufactured by Aldrich) originating from Burkholderia cepacia (Pseudomonas cepacia) were added to the resulting mixture while stirring. The reaction was performed at 30 ° C. After 5.5 hours, cyclohexane, a saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture to separate the layers. After washing the aqueous layer with cyclohexane, adjust the pH to 1-2 with 2 mol ZL hydrochloric acid. Liquid separation was performed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. (S) -2-Hydroxy-3-phenolpropionic acid 35.9 mg (2 hydroxy-3-phenolpropionic acid ethyl ester (racemic mixture) Base isolation yield = 42.0%).

When (S) -2 hydroxy 3 -phenol propionic acid was derived into n-propyl ester by a conventional method and optical purity was measured using high performance liquid chromatography using an optically active column, 98.0% ee Met.

When the optical purity of (R) -2-hydroxy-3-phenylpropionic acid ethyl ester was measured using high performance liquid chromatography using an optically active column, it was 83. l% ee.

The E value in this reaction was 262.

[0066] Analytical conditions for high performance liquid chromatography;

(S) — 3-Hydroxy 3-phenolpropionic acid n-propyl ester

Column: Chiralcel OB—H (0.46 cm Φ X 25 cm, manufactured by Daicel Chemical Industries) Solvent: hexane Z isopropyl alcohol (= 98/2 (volume ratio))

Flow rate: 0.5m min

Temperature: 30 ° C

Wavelength: 220nm

[0067] (R) —3 Hydroxy-3 phenylpropionic acid ethyl ester

Column: Chiralcel OJ—H (0.46cm Φ X 25cm, manufactured by Daicel Chemical Industries)

Solvent: hexane Z isopropyl alcohol (= 98/2 (volume ratio))

Flow rate: 1. Om mm

Temperature: 30 ° C

Wavelength: 220nm

The physical properties of (S) -2 hydroxy-3 phenolpropionic acid were the same as those shown in Example 1.

[0068] Example 3 ((S) -2 hydroxy-3 phenolpropionic acid and (R) -2 hydroxy

3 Synthesis of propylpropionic acid n-propyl ester)

50 mmol ZL potassium phosphate aqueous solution with pH 8.2 1. OmL and cyclohexane 1. OmL 100 mg (0.48 mmol) of 2-hydroxy-3 phenolpropionic acid n-propyl ester (racemic mixture) synthesized in Reference Example 3 was added to the mixed solution and kept at 30 ° C. Sodium bicarbonate 20.2 mg (0.24 mmol) and Burkholderia c epacia (Pseudomonas cepacia) origin Rino, ~~ ce (Amano Lipase PS (trade name) manufactured by Zoldrich) lmg at the same temperature And reacted at 30 ° C. with stirring. After 7 hours, cyclohexane, a saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture for liquid separation. The obtained mixed solution was allowed to stand, followed by liquid separation, and the organic phase was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give (R) 2-hydroxy-3-phenylpropionic acid n-propyl ester 44. Omg (2-hydroxy-3-phenolpropionic acid n-propyl ester (racemic mixture) ) Base isolated yield = 44.0%). In addition, the aqueous layer was washed with cyclohexane, and then the ethyl acetate was adjusted to pH 12 with 2 mol ZL hydrochloric acid. The organic layer was separated from the resulting mixture, dried over magnesium sulfate, and concentrated under reduced pressure to give (S) 2 hydroxy 3 phenol propionic acid 34.3 mg (2 hydroxy 3 phenol propionic acid The isolated yield based on n-propyl ester (racemic mixture) = 43.0%) was obtained.

(S) —When 2-hydroxy-3-phenolpropionic acid was derived into n-propyl ester by a conventional method and optical purity was measured using high performance liquid chromatography using an optically active column, 98.5% ee Met.

When the optical purity of (R) -2-hydroxy-3phenolpropionic acid n-propyl ester was measured using high performance liquid chromatography using an optically active column, it was 85. l% ee. In addition, (R) -2-hydroxyl-3-phenolpropionic acid n-propyl ester is a novel compound.

The E value in this reaction was 363.

Analytical conditions for high performance liquid chromatography;

Solvent: hexane Z isopropyl alcohol (= 98/2 (volume ratio))

Flow rate: 0.5m min

Temperature: 30 ° C Wavelength: 220nm

The specific rotation of (R) -2 hydroxy-3 phenolpropionic acid n-propyl ester was as follows.

Specific rotation: [α] ²⁵ + 15. 8 ° (c O. 80, CHC1) or (R) -2 Hydroxy 1 3 Hue

D 3

-The other physical properties of lupropionic acid n-propyl ester were the same as those shown in Reference Example 3.

Example 4 (Synthesis of (S) -2 hydroxy-3-phenolpropionic acid and (R) -2 hydroxy-3-phenolpropionic acid isobutyl ester)

2-Hydroxy-3-phenolpropionic acid isobutyrate ester synthesized in Reference Example 4 (racemic mixture) 3. 25 g (mixture of 8. 1 mL of 50 mmol ZL potassium phosphate pH 8.2 and 8. 1 mL of cyclohexane 14. 6 mmol) was kept at 30 ° C. At the same temperature, add 614 mg (7.3 mmol) of sodium bicarbonate and 32.5 mg of lipase (Amano Lipase PS (trade name); manufactured by Aldrich) originating from Burkholderia cepacia (Pseudomonas cepacia) at the same temperature and stirring. The reaction was carried out at 30 ° C. After 21 hours, cyclohexane, saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture to separate the layers. After the aqueous layer was washed with cyclohexane, ethyl acetate was added, and the pH was adjusted to 12 with 2 mol ZL hydrochloric acid, followed by liquid separation. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (S) -2-hydroxy-3-phenylpropionic acid 1.14 g (2-hydroxy-3-phenolpropionic acid isobutyl ester (racemic mixture) ) Base isolated yield = 46.9%).

(S) —When 2-hydroxy-3-phenolpropionic acid was derived into n-propyl ester by a conventional method and the optical purity was measured using high performance liquid chromatography using an optically active column, 96.5% ee Met.

When the optical purity of (R) -2-hydroxy-3 phenolpropionic acid n-propyl ester was measured using high performance liquid chromatography using an optically active column, it was 90.0% ee.

The E value in this reaction was 174. [0071] Analysis conditions for high performance liquid chromatography;

Column: Chiralcel OJ—H (0.46 cm Φ X 25 cm, manufactured by Daicel Chemical Industries) Solvent: hexane Z isopropyl alcohol (= 98/2 (volume ratio))

Flow rate: 0.5m min

Temperature: 30 ° C

Wavelength: 220nm

The physical properties of (S) -2-hydroxy-3-phenolpropionic acid were the same as those shown in Example 1.

Industrial applicability

[0072] The present invention relates to an optically active (R or S) -a which is an ester of an α-hydroxy acid alkyl ester (racemic mixture) and an optically active (S or R) -a-hydroxy acid and its enantiomer at the same time. -It relates to a method for obtaining hydroxy acid alkyl esters.

These optically active α-hydroxy acids and esters thereof are useful as raw materials or synthetic intermediates for physiologically active substances such as pharmaceuticals.

Claims

The scope of the claims

[1]-General formula (I)

In the formula, R represents an aralkyl group or a heteroarylalkyl group which may have a substituent, and R ¹ represents an alkyl group which may have a substituent.

It is a general feature characterized in that only one enantiomer of a racemic mixture of a-hydroxy acid alkyl ester represented by the above is selectively hydrolyzed in a mixed solvent of an organic solvent and water in the presence of lipase. Formula (Π):

In the formula, R is as defined above, * represents an asymmetric carbon atom,

An optically active (S or R) a-hydroxy acid represented by general formula (III)

In the formula, R and R ¹ have the same steric absolute configuration as that of the compound of the general formula (II) as defined above,

A method for producing an unreacted optically active (R or S) —a-hydroxy acid alkyl ester represented by

[2] The production method according to claim 1, which is a renose derived from Burkholderia cepacia (Pseudomonas cepacia).

[3] The production method according to claim 1 or 2, wherein R may have a substituent and may be a benzyl group.

[4] R ¹ may have a substituent, and may be an n-propyl group, an isobutyl group, or an n-butyl group. The manufacturing method according to any one of claims 1 to 3, wherein:

[5] The production method according to any one of claims 1 to 4, wherein the mixed solvent of the organic solvent and water forms two phases.

[6] The reaction includes a two-phase solvent of water and an organic solvent, a two-phase solvent of a buffer solution and an organic solvent, a two-phase solvent of an aqueous inorganic base solution and an organic solvent, or an inorganic base. The production method according to any one of claims 1 to 5, which is carried out in a two-phase solvent comprising a buffer solution and an organic solvent.

[7] The buffer solution is at least one selected from the group consisting of an aqueous solution of sodium phosphate, an aqueous solution of potassium phosphate, an aqueous solution of sodium acetate, an aqueous solution of sodium citrate and an aqueous solution of ammonium acetate. The manufacturing method according to Item 6.

8. The production method according to claim 6, wherein the inorganic base is sodium hydrogen carbonate or potassium hydrogen carbonate.

[9] The production method according to claim 6, wherein the organic solvent is an aliphatic hydrocarbon, an aromatic hydrocarbon or an ether.

[10] The production method according to claim 6, wherein the organic solvent is toluene, cyclohexane, or t-butyl methyl ether.

[11] General formula (II) generated by hydrolysis reaction:

In the formula, R is as defined above, * represents an asymmetric carbon atom,

(S or R) — a-hydroxy acid and general formula (III)

In the formula, R, R ¹ and * have the same steric absolute configuration as defined above, which is opposite to the compound of the general formula (II).

Unreacted optical activity represented by (R or S) — mixed with a-hydroxy acid alkyl ester The production method according to claim 1, wherein each is isolated from the compound.

[12] General formula (IV):

In the formula, R represents an aralkyl group or a heteroarylalkyl group which may have a substituent,

A racemic mixture of a-hydroxy acid n-propyl ester represented by

[13] General formula (V):

In the formula, R represents an aralkyl group or a heteroarylalkyl group which may have a substituent, * represents an asymmetric carbon atom,

An optically active (R or S) -a-hydroxy acid n-propyl ester represented by