JP2005102653A - Method for producing optically active piperazine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an optically active piperazine, e.g. capable of producing the optically active piperazine from a racemic piperazine under a mild condition in a good yield and optical purity and also improved in working property and economic property. <P>SOLUTION: This method for producing an optically active acyl piperazine and/or the optically active piperazine is characterized by performing the reaction of the piperazine having an asymmetric carbon in its molecule and being a mixture of its optical isomers with an acylating agent in the presence of a hydrolyzing enzyme to produce the optically active acylpiperazine and the optically active piperazine and collecting the optically active acylpiperazine and optically active piperazine. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for producing optically active piperazines useful as intermediates for agricultural chemicals, medicines and the like.

  Conventionally, as a method for producing optically active 2-methylpiperazine, which is useful as an intermediate for producing optically active piperazines, for example, quinolones useful as antibacterial substances, racemic 2-methylpiperazine is converted to 2 equivalents of optically active tartaric acid. A method of optical resolution (Patent Document 1 etc.), a method of optical resolution by inclusion of racemic 2-methylpiperazine with an optically active host compound (Non-Patent Document 1 etc.), a racemic 2-methylpiperazine 2- After reacting with phenoxypropionic acid to form a sparingly soluble diastereomer salt, a method of metathesis with alkali (Patent Documents 2, 3 etc.), and reacting 2-methylpiperazine such as racemate with optically active pantolactone A method of optical resolution after forming a pantoate (Patent Document 4, etc.) is known.

However, in the method described in Patent Document 1, although inexpensive racemic-2-methylpiperazine can be used, the yield of the target product is low, and there is a difficulty in recovering and reusing tartaric acid. When na (−)-tartaric acid is used, it is not an economical method. In the method described in Non-Patent Document 1, it is difficult to obtain a host compound, and the yield is low. In the methods described in Patent Documents 2 and 3, since sodium methoxide, which is a strong alkali, is used as an alkali used for metathesis, workability is not good. In addition, in the method described in Patent Document 3, the diastereomeric salt obtained from the reaction solution after the diastereomeric salt is used unless enantiomer 2-methylpiperazine is once converted into a mineral salt such as hydrochloride. Don't be. In the method described in Patent Document 4, expensive optically active pantolactone must be used in an amount of 1 to 2 moles with respect to the substrate, and when pantolactone is recycled to the optical resolution, it is lactonized from pantoic acid. The problem was that it could not be used without it. Furthermore, any of the above methods is a method for obtaining optically active 2-methylpiperazine by a chemical method, and is not a method for obtaining optically active 2-methylpiperazine that is closer to nature.
JP-A-3-279375 JP-A-9-268181 JP 2002-332277 A JP 2003-34683 A Chem. Lett. 513 (1988).

  The present invention has been made in view of the above problems, and has good workability and economical efficiency. For example, optically active piperazines can be produced from racemic piperazines under mild conditions with good yield and optical purity. An object of the present invention is to provide a method for producing optically active piperazines having improved properties and economy.

As a result of intensive studies to solve the above problems, the present inventors have found that racemic piperazines and acylating agents such as esters represented by the above general formula (4) are present in the presence of a hydrolase. R- or S-form optically active acylpiperazines and their enantiomers S-form or R-form optically active piperazines can be obtained in good yield and optical purity under the mild conditions. Further, it was found that R- or S-form optically active piperazines can be easily obtained by removing the acyl group from R-form or S-form optically active acylpiperazines, and further studies are repeated. The invention has been reached.
That is, the present invention is as follows.

1) A piperazine having an asymmetric carbon atom in the molecule and a mixture of optical isomers and an acylating agent are reacted in the presence of a hydrolase to produce an optically active acylpiperazine and an optically active piperazine. And producing an optically active acylpiperazine and / or an optically active piperazine, wherein an optically active acylpiperazine and an optically active piperazine are collected.

（式中、Ｒは置換基を有していてもよい炭化水素基を示す。）で表される化合物であり、光学活性アシルピペラジン類が、一般式（２）

（式中、Ｒ^１は水素原子、置換基を有していてもよい炭化水素基又はハロゲン原子を示し、Ａ^１はスペーサー又は結合手を示し、＊は不斉炭素を示し、Ｒは前記と同じ。）で表される化合物であり、光学活性ピペラジン類が、一般式（３）

（式中、Ｒは前記と同じ。）で表される化合物であることを特徴とする上記１）に記載の製造方法。 2) Piperazines, which are a mixture of optical isomers, are represented by the general formula (1)

(Wherein R represents a hydrocarbon group which may have a substituent), and the optically active acylpiperazine is represented by the general formula (2)

(Wherein R ¹ represents a hydrogen atom, an optionally substituted hydrocarbon group or a halogen atom, A ¹ represents a spacer or a bond, * represents an asymmetric carbon, and R represents The optically active piperazine is represented by the general formula (3).

(Wherein R is the same as defined above), and the production method according to 1) above.

3) The production method according to 1) or 2) above, wherein optically active acylpiperazines and optically active piperazines produced by the reaction are further separated.

4) An optically active piperazine is generated by removing the acyl group from the optically active acylpiperazines produced by the reaction, and the optically active piperazines are in the relationship between the optically active piperazines represented by the general formula (3) and the enantiomers. The manufacturing method according to any one of 1) to 3) above, wherein

（式中、Ｒ^１は水素原子、置換基を有していてもよい炭化水素基又はハロゲン原子を示し、Ｒ^２は置換基を有していてもよい炭化水素基を示し、Ａ^１はスペーサー又は結合手を示す。但し、Ｒ^１がハロゲン原子のとき、Ａ^１はスペーサーである。）で表されるエステル類である、上記１）〜４）の何れかに記載の製造方法。 5) The acylating agent is represented by the general formula (4)

(In the formula, R ¹ represents a hydrogen atom, an optionally substituted hydrocarbon group or a halogen atom, R ² represents an optionally substituted hydrocarbon group, and A ¹ represents a spacer. Or a bond, provided that when R ¹ is a halogen atom, A ¹ is a spacer.) The production method according to any one of 1) to 4) above, which is an ester represented by:

6) The production method according to any one of 1) to 4) above, wherein the hydrolase is lipase.

7) The production method according to any one of 1) to 6) above, wherein the piperazine which is a mixture of optical isomers is a racemate.

8) The production method according to any one of 1) to 7) above, wherein the piperazine is 2-methylpiperazine.

  According to the production method of the present invention, it is possible to use an inexpensive racemic piperazine, and by reacting the racemic piperazine with an acylating agent in the presence of a hydrolase, The desired R-form and S-form optically active piperazines can be obtained under mild conditions without using various salts such as acid salts. In addition, since the production method of the present invention uses a hydrolase, it is less expensive than conventional chemical methods, and it is not necessary to remove by-products or impurities, so that workability is improved. Further, it is effective in that only the 4-position of piperazine can be selectively acylated.

（式中、Ｘは、置換基を示し、Ｑはアシル基を示す。）
Ｘで表される置換基は、特に制限されないが、上記反応により影響を受けない置換基であることが好ましい。Ｑで表されるアシル基は、特に制限されないが、上記反応により影響を受けないアシル基であることが好ましい。 The reaction involved in the preferred production method of the present invention is as follows.

(In the formula, X represents a substituent, and Q represents an acyl group.)
The substituent represented by X is not particularly limited, but is preferably a substituent that is not affected by the above reaction. The acyl group represented by Q is not particularly limited, but is preferably an acyl group that is not affected by the above reaction.

  The compound represented by the formula (1) is a preferred example of the compound represented by the formula (1 ′), and the compound represented by the formula (2) is preferably a compound represented by the formula (2 ′). The compound represented by the formula (3) is an example and a preferred example of the compound represented by the formula (3 ′) or (3 ″).

Each group in the above formula will be described.
Examples of the substituent represented by X include a hydrocarbon group that may have a substituent, a heterocyclic group that may have a substituent, a hydroxyl group that may have a substituent, and a substituent. A mercapto group which may have a group, an aldehyde group which may have a substituent, a carboxyl group which may have a substituent, an amino group which may have a substituent, a halogen atom, Examples thereof include a nitro group and a cyano group. Such a substituent may be any substituent as long as it is used in piperazines known as synthetic intermediates, and may be a hydrocarbon group which may have a substituent. Is particularly preferred.

  The hydrocarbon group optionally having a substituent represented by X or R is a hydrocarbon group or a substituted hydrocarbon group.

  Examples of the hydrocarbon group include an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, and the like.

  The alkyl group may be linear, branched or cyclic, and examples thereof include an alkyl group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, specifically a methyl group, an ethyl group, and n -Propyl group, 2-propyl group, n-butyl group, 2-butyl group, isobutyl group, tert-butyl group, n-pentyl group, 2-pentyl group, tert-pentyl group, 2-methylbutyl group, 3-methylbutyl Group, 2,2-dimethylpropyl group, n-hexyl group, 2-hexyl group, 3-hexyl group, tert-hexyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2- Examples include methylpentan-3-yl group, heptyl group, octyl group, nonyl group, decyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like. It is, or more preferably an alkyl group having 1 to 6 carbon atoms.

  The alkenyl group may be linear or branched, for example, an alkenyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, specifically an ethenyl group. , Propenyl group, 1-butenyl group, pentenyl group, hexenyl group and the like.

  The alkynyl group may be linear or branched, for example, an alkynyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, specifically an ethynyl group. 1-propynyl group, 2-propynyl group, 1-butynyl group, 3-butynyl group, pentynyl group, hexynyl group and the like.

  As an aryl group, a C6-C14 aryl group is mentioned, for example, Specifically, a phenyl group, a naphthyl group, an anthryl group, a biphenyl group etc. are mentioned.

  Examples of the aralkyl group include a group in which at least one hydrogen atom of the alkyl group is substituted with the aryl group. For example, an aralkyl group having 7 to 12 carbon atoms is preferable, specifically, a benzyl group, 2-phenyl An ethyl group, 1-phenylpropyl group, 3-naphthylpropyl group, etc. are mentioned.

The substituted hydrocarbon group is a hydrocarbon group in which at least one hydrogen atom of the hydrocarbon group is substituted with a substituent (abbreviated as a substituent).
Examples of the substituent in the substituted hydrocarbon group include a hydrocarbon group, a substituted hydrocarbon group, an aliphatic heterocyclic group, a substituted aliphatic heterocyclic group, an aromatic heterocyclic group, a substituted aromatic heterocyclic group, an alkoxyl group, and a substituted group. Alkoxyl group, aryloxy group, substituted aryloxy group, aralkyloxy group, substituted aralkyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, alkylthio group, aralkylthio group, arylthio group, halogen atom, halogenated Examples include a hydrocarbon group, an alkylenedioxy group, an amino group, a substituted amino group, a cyano group, a nitro group, a hydroxyl group, a carboxyl group, and a sulfo group.

Hereinafter, the substitution in the substituted hydrocarbon group will be described more specifically.
The hydrocarbon group and the substituted hydrocarbon group as a substituent are the same as the hydrocarbon group and the substituted hydrocarbon group in the hydrocarbon group which may have the above substituent.

The aliphatic heterocyclic group as a substituent includes, for example, 2 to 14 carbon atoms and at least one hetero atom, preferably 1 to 3 hetero atoms such as a nitrogen atom, an oxygen atom, and a sulfur atom. And a 5- to 8-membered, preferably 5- or 6-membered monocyclic aliphatic heterocyclic group, a polycyclic or a condensed aliphatic heterocyclic group. Specific examples of the aliphatic heterocyclic group include pyrrolidyl-2-one group, piperidino group, piperazinyl group, morpholino group, morpholinyl group, tetrahydrofuryl group, tetrahydropyranyl group and the like.
The substituted aliphatic heterocyclic group as a substituent is exemplified by an aliphatic heterocyclic group in which one or two or more hydrogen atoms of the aliphatic heterocyclic group are replaced with a further substituent. Examples include a substituent in the substituted hydrocarbon group represented by the above X or R.

The aromatic heterocyclic group as a substituent has, for example, 2 to 15 carbon atoms and contains at least one, preferably 1 to 3 hetero atoms such as nitrogen, oxygen and sulfur atoms as hetero atoms. , 5 to 8 membered, preferably 5 or 6 membered monocyclic heteroaryl group, polycyclic or condensed ring heteroaryl group, and examples thereof include furyl group and thienyl. Group, pyridyl group, pyrimidyl group, pyrazyl group, pyridazyl group, pyrazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, benzofuryl group, benzothienyl group, quinolyl group, isoquinolyl group, quinoxalyl group, phthalazyl group, quinazolyl group, naphthyridyl group Cinnolyl group, benzimidazolyl group, benzoxazolyl group, benzothiazolyl group and the like.
The substituted aromatic heterocyclic group as a substituent is exemplified by an aromatic heterocyclic group in which one or two or more hydrogen atoms of the aromatic heterocyclic group are replaced by a further substituent. Examples include a substituent in the substituted hydrocarbon group represented by the above X or R.

The alkoxyl group as a substituent may be linear, branched or cyclic, and is exemplified by, for example, an alkoxy group having 1 to 6 carbon atoms. Specific examples thereof include a methoxy group, an ethoxy group, n-propoxy group, 2-propoxy group, n-butoxy group, 2-butoxy group, isobutoxy group, tert-butoxy group, n-pentyloxy group, 2-methylbutoxy group, 3-methylbutoxy group, 2,2- Examples include dimethylpropyloxy group, n-hexyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 4-methylpentyloxy group, 5-methylpentyloxy group, cyclohexyloxy group and the like.
The substituted alkoxyl group as a substituent is an alkoxyl group in which one or more hydrogen atoms of the alkoxyl group are replaced with a further substituent, and the further substituent is a substituted carbon atom represented by the above X or R. Examples include a substituent in a hydrogen group.

The aryloxy group as a substituent is exemplified by an aryloxy group having 6 to 14 carbon atoms, and specific examples thereof include a phenyloxy group, a naphthyloxy group, an anthryloxy group, and the like. .
The substituted aryloxy group as a substituent is an aryloxy group in which one or more hydrogen atoms of the aryloxy group are replaced with a further substituent, and the further substituent is represented by the above X or R. And the like in the substituted hydrocarbon group.

Examples of the aralkyloxy group as a substituent include, for example, an aralkyloxy group having 7 to 12 carbon atoms. Specific examples thereof include benzyloxy group, 2-phenylethoxy group, 1-phenylpropoxy group, 2 -Phenylpropoxy group, 3-phenylpropoxy group, 1-phenylbutoxy group, 2-phenylbutoxy group, 3-phenylbutoxy group, 4-phenylbutoxy group, 1-phenylpentyloxy group, 2-phenylpentyloxy group, 3 -Phenylpentyloxy group, 4-phenylpentyloxy group, 5-phenylpentyloxy group, 1-phenylhexyloxy group, 2-phenylhexyloxy group, 3-phenylhexyloxy group, 4-phenylhexyloxy group, 5- Phenylhexyloxy group, 6-phenylhexyloxy group, etc. It is below.
The substituted aralkyloxy group as a substituent is an aralkyloxy group in which one or more hydrogen atoms of the aralkyloxy group are replaced by a further substituent, and the further substituent is represented by the above X or R. And the like in the substituted hydrocarbon group.

  The alkoxycarbonyl group as a substituent may be linear, branched or cyclic, and is exemplified by, for example, an alkoxycarbonyl group having 2 to 19 carbon atoms. Specific examples thereof include a methoxycarbonyl group, Ethoxycarbonyl group, n-propoxycarbonyl group, 2-propoxycarbonyl group, n-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group, 2-ethylhexyloxycarbonyl group, lauryloxycarbonyl group, Examples include stearyloxycarbonyl group and cyclohexyloxycarbonyl group.

  The aryloxycarbonyl group as a substituent is, for example, an aryloxycarbonyl group having 7 to 20 carbon atoms, and specific examples thereof include a phenoxycarbonyl group and a naphthyloxycarbonyl group.

  The aralkyloxycarbonyl group as a substituent is exemplified by, for example, an aralkyloxycarbonyl group having 8 to 15 carbon atoms. Specific examples thereof include benzyloxycarbonyl group, phenylethoxycarbonyl group, 9-fluorene group. Nylmethyloxycarbonyl and the like.

  The alkylthio group as a substituent may be linear, branched or cyclic, and is exemplified by, for example, an alkylthio group having 1 to 6 carbon atoms. Specific examples thereof include a methylthio group, an ethylthio group, Examples include n-propylthio group, 2-propylthio group, n-butylthio group, 2-butylthio group, isobutylthio group, tert-butylthio group, pentylthio group, hexylthio group, cyclohexylthio group and the like.

  The aralkylthio group as a substituent is exemplified by an aralkylthio group having 7 to 12 carbon atoms, and specific examples thereof include a benzylthio group and a 2-phenethylthio group.

  The arylthio group as a substituent is exemplified by, for example, an arylthio group having 6 to 14 carbon atoms, and specific examples thereof include a phenylthio group and a naphthylthio group.

  Examples of the halogen atom as a substituent include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

  Examples of the halogenated hydrocarbon group as a substituent include a hydrocarbon group in which at least one hydrogen atom of the hydrocarbon group is halogenated (for example, fluorinated, chlorinated, brominated, iodinated, etc.). Examples of the halogenated hydrocarbon group include a halogenated alkyl group. Examples of the halogenated alkyl group include a halogenated alkyl group having 1 to 10 carbon atoms. Specific examples thereof include a chloromethyl group, a bromomethyl group, a 2-chloroethyl group, and 3-bromopropyl. Group, fluoromethyl group, fluoroethyl group, fluoropropyl group, fluorobutyl group, fluoropentyl group, fluorohexyl group, fluoroheptyl group, fluorooctyl group, fluorononyl group, fluorodecyl group, difluoromethyl group, difluoroethyl group, Fluorocyclohexyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, 3,3,3-trifluoropropyl group, pentafluoroethyl group, 3,3,4,4,4-pentafluorobutyl group Perfluoro-n-propyl group, perfluoroisopropyl group, Rufluoro-n-butyl group, perfluoroisobutyl group, perfluoro-tert-butyl group, perfluoro-sec-butyl group, perfluoropentyl group, perfluoroisopentyl group, perfluoro-tert-pentyl group, perfluoro-n-hexyl group, perfluoroiso Examples include hexyl group, perfluoroheptyl group, perfluorooctyl group, perfluorononyl group, perfluorodecyl group, 2-perfluorooctylethyl group, perfluorocyclopropyl group, perfluorocyclopentyl group, perfluorocyclohexyl group and the like.

  The alkylenedioxy group as a substituent is, for example, an alkylenedioxy group having 1 to 3 carbon atoms. Specific examples thereof include a methylenedioxy group, an ethylenedioxy group, and a propylenedioxy group. And trimethylenedioxy group.

  The substituted amino group as a substituent is an amino group in which one or two hydrogen atoms of the amino group are replaced with a substituent in the substituted hydrocarbon group represented by the above X or R.

  Examples of the heterocyclic group optionally having a substituent represented by X include an aliphatic heterocyclic group, a substituted aliphatic heterocyclic group, an aromatic heterocyclic group, and a substituted aromatic heterocyclic group, and these Each of these groups may have the same meaning as the group in the above substituted hydrocarbon group.

  Examples of the hydroxyl group which may have a substituent represented by X include a hydroxyl group or a hydroxyl group substituted with the above-described hydrocarbon group.

  Examples of the mercapto group optionally having a substituent represented by X include a mercapto group or a mercapto group substituted with, for example, the above-described hydrocarbon group.

  Examples of the aldehyde group optionally having a substituent represented by X include an aldehyde group or an aldehyde group substituted with, for example, the above-described hydrocarbon group.

  Examples of the carboxyl group optionally having a substituent represented by X include a carboxyl group or a carboxyl group substituted with, for example, the above-described hydrocarbon group.

  Examples of the amino group optionally having a substituent represented by X include an amino group or an amino group substituted with, for example, the above-described hydrocarbon group.

  The acyl group represented by Q may be linear or branched, for example, an acyl group having 1 to 18 carbon atoms derived from a carboxylic acid such as an aliphatic carboxylic acid or an aromatic carboxylic acid, or an acyl derived from a sulfonic acid. Group, an acyl group derived from phosphonic acid, and specific examples are described below.

  As an acylating agent used by this invention, ester represented by the said General formula (4) is preferable, for example. Specific examples of the ester represented by the general formula (4) include, for example, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate, isopropyl propionate, methyl chloroacetate, chloroacetic acid Examples include ethyl and isopropyl chloroacetate.

The hydrocarbon group which may have a substituent represented by R ¹ represented by the general formula (2) has the same meaning as the hydrocarbon group which may have a substituent represented by X or R. It may be.

Examples of the halogen atom represented by R ¹ in the general formula (2) include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The spacer represented by ^{A 1} in the general formula (2), an alkylene group, a divalent divalent organic group such as an aromatic _{group, - [(CH 2) n1} -CO- (CH 2) n2] n3 _{-, - [(CH 2)} n4 -CONH- (CH 2) n5] n6 -, - [(CH 2) n7 -O- (CH 2) n8] n9 - , and the like.

The alkylene group represented by A ^1, also include alkylene groups branched or number may also be a carbon cyclic 1-6 linear, and specific examples thereof include a methylene group, an ethylene group, a propylene group, Examples include butylene, 2-methylpropylene, pentylene, 2,2-dimethylpropylene, 2-ethylpropylene, hexylene, and cyclohexylene.

Examples of the divalent aromatic group represented by A ¹ include an alkylene group having 1 to 12 carbon atoms, and specific examples thereof include a phenylene group, a biphenyldiyl group, —CH ₂ C ₆ H ₅ —, _{-CH 2 C 6 H 4 CH 2} - and the like.

N1 to n9 each independently represent a natural number, preferably 1 to 6, and more preferably 1 to 3. Incidentally, the _{- (CH 2) n1 -,} - (CH 2) n2 -, - (CH 2) n4 -, - (CH 2) n5 -, - (CH 2) n7 - and - _{(CH 2) n8} - Each may be linear or branched. That is, the — (CH ₂ ) — unit is not a simple repeating unit, but a unit used for convenience to represent the number of carbon atoms and the number of hydrogen. Therefore, for example, when — (CH ₂ ) _n1 — is branched and the natural number represented by n1 is 3, such — (CH ₂ ) _n1 — is —CH (CH ₃ ) —CH ₂ —. _{, -CH 2 -CH (CH 3)} -, - CH (CH 2 CH 3) - or -C _{(CH 3) 2} - a. In the case of a branched form having 2 carbon atoms, it is —CH (CH ₃ ) —.

A ¹ represents a spacer or a bond, but is preferably a spacer.

  The piperazine represented by the general formula (1) used in the present invention is preferably a racemate. Specific examples thereof include 2-methylpiperazine, 2-ethylpiperazine, 2-propylpiperazine, Examples include 2-butylpiperazine, 2-pentylpiperazine, 2-hexylpiperazine and the like, and 2-methylpiperazine is preferable.

  As the piperazines represented by the general formula (1), racemic compounds are preferably used. In addition to the racemic compounds, piperazines having higher optical purity than the raw piperazines can be used according to the present invention. Since it can be produced, low optical purity piperazines and high optical purity piperazines can also be used.

  In the production method of the present invention, when the piperazine represented by the general formula (1) and the ester represented by the general formula (4) are used as the acylating agent, the amount used is the same as that of the raw piperazine. On the other hand, esters are appropriately selected from the range of 0.3 to 10 equivalents, preferably 0.5 to 1 equivalents.

  Specific examples of the optically active acylpiperazine represented by the general formula (2) obtained by the preferred production method of the present invention, particularly optically active 4-acylpiperazines, include 2R-methyl-4-acetylpiperazine, 2S-methyl. -4-acetylpiperazine, 2R-methyl-4-propionylpiperazine, 2S-methyl-4-propionylpiperazine, 2R-methyl-4-butyrylpiperazine, 2S-methyl-4-butyrylpiperazine, 2R-methyl-4- Benzoylpiperazine, 2S-methyl-4-benzoylpiperazine, 2R-ethyl-4-acetylpiperazine, 2S-ethyl-4-acetylpiperazine, 2R-propyl-4-acetylpiperazine, 2S-propyl-4-acetylpiperazine, 2R- Butyl-4-acetylpiperazine, 2S-butyl- - acetyl piperazine, 2S-pentyl-4-acetyl piperazine, 2R- pentyl-4-acetyl piperazine, 2R- hexyl-4-acetyl piperazine, 2S-hexyl-4-acetyl piperazine.

  Specific examples of the optically active piperazines represented by the above general formula (3) and the optically active piperazines represented by the above general formula (3) obtained by the production method of the present invention are in an enantiomeric relationship. Examples include 2R-methylpiperazine, 2S-methylpiperazine, 2R-ethylpiperazine, 2S-ethylpiperazine, 2R-propylpiperazine, 2S-propylpiperazine, 2R-butylpiperazine, 2S-butylpiperazine, 2S-pentylpiperazine, 2R -Pentylpiperazine, 2R-hexylpiperazine, 2S-hexylpiperazine and the like.

  Examples of the hydrolase used in the present invention include carboxyesterase, allyl esterase, cholinesterase, lipase and the like. Specifically, lipase originating from Aspergillus niger, lipase originating from Mucor javanicus, porcine pancreas, etc. Lipases originating from, lipases originating from Pseudomonas aeruginosa, lipases originating from Pseudomonas cepasia, lipases originating from Pseudomonas fluorescens, Rhizopus sp. Lipases originating from Rhizomucor miehei, lipases originating from Candida rugosa, lipases originating from Candida antarctica, esterases originating from pig liver, and the like. These hydrolases are preferably lipases, and more preferably lipases derived from bacteria such as Pseudomonas spp. And Alcigenes spp., Lipases originating from Candida antarctica, and the like. Moreover, a commercial item can also be used for the hydrolase used by this invention. For example, PS, PS-D, PS-C (derived from Pseudomonas spp.) Manufactured by Amano Enzyme Co., Ltd., AK-20 (derived from Pseudomonas spp.) Manufactured by Amano Enzyme Co., Ltd., AH (derived from Pseudomonas spp.) Manufactured by Amano Enzyme, For example, Lipase QL, QLC, QLG (derived from the genus Algigenes), Novozym 435 manufactured by Novozymes, etc. are preferably used. As these hydrolases, commercially available products can be used as they are. Moreover, the hydrolase used in the present invention may be used alone or in appropriate combination of two or more.

The enzyme may be added directly to the reaction solution at once, or may be divided and added intermittently to the reaction solution.
The amount of the enzyme used is usually in the range of 0.1 to 100% by mass (w / w), preferably 10 to 50% by mass (w / w) based on the piperazine represented by the general formula (1). Is appropriately selected.

  The reaction of the piperazine represented by the general formula (1) and the ester represented by the general formula (4) can be carried out in the presence of a solvent depending on the type of ester used. .

Examples of the solvent include aliphatic hydrocarbons such as pentane, hexane, heptane, octane, decane, and cyclohexane, aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, 1,2-dichloroethane, chloroform, and tetrachloride. Halogenated hydrocarbons such as carbon and o-dichlorobenzene, ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, ethylene glycol diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,3-dioxolane Alcohols such as methanol, ethanol, 2-propanol, n-butanol, 2-ethoxyethanol, benzyl alcohol, ethylene glycol, propylene glycol, 1,2-propanediol, glycerin Polyhydric alcohols and the like, N- dimethylformamide, N, amides such as N- dimethylacetamide, sulfoxides such as dimethyl sulfoxide, cyano-containing organic compounds such as acetonitrile, N- methylpyrrolidone, water and the like. These solvents may be used alone or in appropriate combination of two or more.
The usage-amount of a solvent is suitably selected from the range of 0-100 times volume normally with respect to piperazine (1), Preferably it is 5-20 times volume.
The reaction temperature is appropriately selected from the range of usually 0 to 100 ° C, preferably 20 to 50 ° C.
The reaction time is appropriately selected from the range of usually 1 to 48 hours, preferably 5 to 18 hours.

（式中、Ｒ、Ｒ^１及びＡ^１は前記と同じ。）で表される２Ｒ−４−アシルピペラジン類）が得られる。一方、該ラセミ体のピペラジン類中の２Ｓ−ピペラジン類は、アシル化剤（例えば上記エステル類）とは実質的に反応せずに、上記一般式（３）で表される光学活性ピペラジン類として一般式（３−２）

（式中、Ｒは前記と同じ。）で表される２Ｓ−ピペラジン類が得られる。 A preferable production method of the present invention uses, for example, a racemate as the piperazine represented by the general formula (1), and an acylating agent (for example, an ester represented by the general formula (4)). By reacting in the presence of the hydrolase, only the 2R-piperazine in the racemic piperazine substantially reacts to produce an optically active acylpiperazine represented by the general formula (2). (For example, general formula (2-1)

(Wherein R, R ¹ and A ¹ are the same as described above) 2R-4-acylpiperazines). On the other hand, 2S-piperazines in the racemic piperazines do not substantially react with acylating agents (for example, the above esters), and as optically active piperazines represented by the above general formula (3) Formula (3-2)

(Wherein, R is the same as above) 2S-piperazines are obtained.

（式中、Ｒ、Ｒ^１及びＡ^１は前記と同じ。）で表される２Ｓ−４−アシルピペラジン類が得られる。一方、該ラセミ体のピペラジン類中の２Ｒ−ピペラジン類は、実質的にアシル化剤（例えばエステル類）とは反応せずに、上記一般式（３）で表される光学活性ピペラジン類として前記一般式（３−２）で表される２Ｓ−ピペラジン類とはエナンチオマーの関係にある、一般式（３−１）

（式中、Ｒは前記と同じ。）で表される２Ｓ−ピペラジン類が得られる。
このようにして得られた光学活性アシルピペラジン類は、必要に応じて脱アシル化反応させることにより、光学活性アシルピペラジン類からアシル基を脱離させて光学活性ピペラジンを生成させることによって、上記一般式（３）で表される光学活性ピペラジン類とはエナンチオマーの関係にある光学活性ピペラジン類を得ることができる。 Here, by changing the hydrolase used, it is also possible to react 2S-piperazines in the racemic piperazines with acylating agents (eg, esters). That is, only the 2S-piperazines in the racemic piperazine substantially react with an acylating agent (for example, esters), and the optically active acylpiperazines represented by the general formula (2) The 2S-4-acylpiperazines represented by the formula (2-2) are in an enantiomeric relationship and are represented by the general formula (2-2)

(Wherein, R, R ¹ and A ¹ are the same as described above) 2S-4-acylpiperazines are obtained. On the other hand, the 2R-piperazines in the racemic piperazines do not substantially react with acylating agents (for example, esters), and the optically active piperazines represented by the general formula (3) are The 2S-piperazines represented by the general formula (3-2) are in an enantiomeric relationship and are represented by the general formula (3-1)

(Wherein, R is the same as above) 2S-piperazines are obtained.
The optically active acylpiperazines thus obtained are subjected to a deacylation reaction as necessary to remove the acyl group from the optically active acylpiperazines to produce optically active piperazine. An optically active piperazine having an enantiomeric relationship with the optically active piperazine represented by the formula (3) can be obtained.

The deacylation reaction can be performed by a conventional method. For example, the method etc. which perform a deacylation in presence of an acid or a base in a solvent are mentioned. More specifically, the target piperazine can be obtained by mixing an acid or base and an optically active acyl piperazine and heating to reflux. In the present invention, the deacylation reaction may be performed using a catalytic amount of the hydrolase in a solvent.
Examples of the solvent include hydrocarbon solvents (eg, hexane, pentane, cyclohexane, etc.), amide solvents (eg, N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone, etc.), Aromatic hydrocarbon solvents (eg, toluene, benzene, chlorobenzene, etc.), aliphatic ester solvents (eg, ethyl acetate, propyl acetate, butyl acetate, etc.), ether solvents (eg, diisopropyl ether, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogenated hydrocarbon solvents (eg, chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride, etc.), alcohol solvents (eg, methanol, ethanol isopropanol) , Ter - butanol), ketone solvents (e.g., acetone, methyl ethyl ketone, etc.), sulfoxide solvents (e.g., dimethyl sulfoxide), nitrile solvents (e.g., acetonitrile, propionitrile) and the like.
Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrogen bromide, perchloric acid, and phosphoric acid; organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid. Etc.
Examples of the base include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; sodium methoxide, sodium Metal alkoxides such as ethoxide, magnesium ethoxide, sodium isopropoxide, lithium tert-butoxide; ammonia, methylamine, diisopropylamine, trimethylamine, triethylamine, tributylamine, triphenylamine, diisopropylethylamine, N-methylmorpholine, N- Methylpiperidine, imidazole, pyridine, p-chloropyridine, 3-picoline, 2-picoline, 4-N, N-dimethylaminopyridine, 1,7-diazabicyclo- [ , 4,0] - undec-7-amines such as ene and the like.
As the acid, 1 to 2N hydrochloric acid is preferable.
The amount of the acid or base used is 0.01 to 10-fold mol amount, more preferably 0.01 to 1-fold mol amount based on the optically active acylpiperazine.

The optically active piperazines and optically active acylpiperazines obtained in this way, especially optically active 4-acylpiperazines, are obtained under mild conditions using a hydrolase, so it is necessary to remove by-products and impurities. However, a higher optical purity can be obtained by performing a post-treatment if necessary.
In the present invention, the optically active piperazines, their optically active optically active piperazines and optically active acylpiperazines are known per se, for example, solvent extraction, liquid conversion, phase transfer, salting out, crystallization, recrystallization, It can be easily separated and purified by crystallization, chromatography or the like.
Further, the obtained optically active piperazine, its optically active optically active piperazine and optically active acylpiperazine, particularly optically active 4-acylpiperazine are useful as intermediates for pharmaceuticals, agricultural chemicals and the like.

  Hereinafter, the present invention will be described in detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto. In the following examples, the apparatus used for measuring physical properties and the like is as follows.

Analysis conditions GLC: HP5890 (manufactured by Hewlett Packard)
Chemical purity of amidation and deamidation GC: Neutrabond-1, 0.25 mm × 30 m
Amide optical purity NMR: DRX500 (manufactured by Bruker)
Shift reagent: 2,2,2-Trifluoro-1- (9-anthryl) -ethanol

Example 1.
Racemic 2-methylpiperazine (10.0 g, 99.8 mmol) and butyl acetate (6.38 g, 54.9 mmol) were added to Novozym 435 (Novozym, 50 wt%) in diisopropyl ether (IPE, 200 ml). The reaction was carried out at 0 ° C. for 16 hours. After completion of the reaction, by NMR analysis, (S) -4-acetyl 2-methylpiperazine having a conversion of 44.5% and an optical purity of 33.2% ee and (R)-having an optical purity of 7.7% ee 2-methylpiperazine was obtained.

Example 2
Racemic 2-methylpiperazine (10.0 g, 99.8 mmol) and ethyl acetate (4.84 g, 54.9 mmol) were added to Novozym 435 (manufactured by Novozyme, 50 wt%) in tetrahydrofuran (THF, 200 ml) at 30 ° C. For 16 hours. After completion of the reaction, by NMR analysis, (S) -4-acetyl 2-methylpiperazine having a conversion rate of 28.4% and an optical purity of 50.9% ee and (R)-having an optical purity of 15.8% ee 2-methylpiperazine was obtained.

Example 3
Racemic 2-methylpiperazine (10.0 g, 99.8 mmol) and ethyl acetate (4.84 g, 54.9 mmol) were combined with Lipase PS-C (Amano Enzyme, 50 wt.) In diisopropyl ether (IPE, 200 ml). %) Was reacted at 30 ° C. for 16 hours. After completion of the reaction, by NMR analysis, (R) -4-acetyl 2-methylpiperazine having a conversion of 16.7% and an optical purity of 31.9% ee and (S)-having an optical purity of 6.1% ee 2-methylpiperazine was obtained.

INDUSTRIAL APPLICABILITY The present invention is used for the production of optically active piperazines useful as intermediates for pharmaceuticals, agricultural chemicals, and the like, and optically active piperazines and optically active acylpiperazines that are enantiomers thereof.

Claims (8)

  An optically active acylpiperazine and an optically active piperazine are produced by reacting a piperazine, which is a mixture of optical isomers with an asymmetric carbon atom in the molecule, and an acylating agent in the presence of a hydrolase. And producing an optically active acylpiperazine and / or an optically active piperazine, wherein the optically active acylpiperazine and the optically active piperazine are collected. Piperazines, which are mixtures of optical isomers, are represented by the general formula (1)

(Wherein R represents a hydrocarbon group which may have a substituent), and the optically active acylpiperazine is represented by the general formula (2)

(Wherein R ¹ represents a hydrogen atom, an optionally substituted hydrocarbon group or a halogen atom, A ¹ represents a spacer or a bond, * represents an asymmetric carbon, and R represents The optically active piperazine is represented by the general formula (3).

The production method according to claim 1, wherein R is the same as defined above.   The production method according to claim 1 or 2, wherein the optically active acylpiperazines and the optically active piperazines produced by the reaction are further separated.   An optically active piperazine is generated by removing an acyl group from the optically active acylpiperazines produced by the reaction, and the optically active piperazines are in an enantiomer relationship with the optically active piperazines represented by the general formula (3). The manufacturing method in any one of Claims 1-3 characterized by these. The acylating agent has the general formula (4)

(In the formula, R ¹ represents a hydrogen atom, an optionally substituted hydrocarbon group or a halogen atom, R ² represents an optionally substituted hydrocarbon group, and A ¹ represents a spacer. Or a bond, wherein when R ¹ is a halogen atom, A ¹ is a spacer.) The production method according to claim 1.   The method according to any one of claims 1 to 4, wherein the hydrolase is a lipase.   The method according to any one of claims 1 to 6, wherein the piperazine which is a mixture of optical isomers is a racemate. The manufacturing method according to claim 1, wherein the piperazine is 2-methylpiperazine.