JP2006239608A - Separating method of optically active 3-substituted glycidic acid ester - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an efficient separating method of an optical isomer mixture of 3-saturated glycidic acid esters. <P>SOLUTION: The optical isomer mixture of the 3-saturated glycidic acid esters expressed by a general formula (1) is made into contact with a separating agent comprising an optially active polymaleimide derivative (specifically, optically active poly[(S)-N-α-methylbenzylmaleimide], optically active poly[(1S)-N-1-(1-cyclohexylethyl)maleimide], optically active polyäN-[(1S, 2S)-2-benzyloxycyclopentyl]maleimide} or the like), (in the general formula (1), R<SB>1</SB>is a methyl group or an ethyl group, n is 1 or 2 and * is an asymmetry carbon atom). <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for separating an optically active 3-substituted glycidic acid ester. Specifically, the present invention relates to a method for separating a mixture of optical isomers of a 3-substituted glycidic acid ester using a separating agent comprising an optically active polymaleimide derivative.

  In the fields of medicine, agricultural chemicals, foods, and biochemistry, it is very important to prepare optically pure compounds in order to prevent side effects, phytotoxicity, and improve drug efficacy per unit. The optically active 3-substituted glycidic acid ester, particularly (2R, 3S) -3- (4-methoxyphenyl) glycidic acid ester, contains diltiazem useful as a therapeutic agent for angina pectoris (2S, 3R) -1, This compound is useful as an intermediate for the synthesis of 5-benzothiazepine derivatives. Conventional production methods for obtaining optically active 3-substituted glycidic acid esters include asymmetric synthesis methods, chemical optical resolution methods such as diastereomeric salt formation, and biochemical resolution methods using enzymes and microorganisms. It has been.

  As a method for producing an optically active glycidic acid ester by asymmetric synthesis, a method in which a coupling reaction between a halogenoacetic acid ester and benzaldehyde is carried out in the presence of an optically active lithium amide compound and alkyl lithium (for example, see Patent Document 1), 2- A method for asymmetric reduction of a halogeno-3-oxo-3-phenylpropionic acid derivative (for example, see Patent Document 2) is known. However, these asymmetric synthesis methods are not suitable for industrialization from the viewpoint of cost because the reaction yield and optical purity are not high and expensive asymmetric sources are required.

  As the chemical optical resolution method, a method is used in which a racemic mixture of 3- (4-methoxyphenyl) glycidic acid is optically resolved using an optically active amine and then esterified (for example, see Patent Document 3), 3- ( A method in which an optically active organic amine is reacted with a racemic mixture of 4-methoxyphenyl) glycidic acid alkali metal salt for optical resolution and then esterified (for example, see Patent Document 4) is known. However, in these chemical optical resolution methods, the resulting diastereomeric salts must be separated and purified under specific conditions. Further, the optically active amine to be used is expensive, and usually requires an equimolar amount with respect to 3- (4-methoxyphenyl) glycidic acid to be separated. Therefore, it is necessary to perform a complicated operation such as recovery and reuse.

  Biochemical resolution methods include a method in which 3- (4-methoxyphenyl) glycidic acid ester is enzymatically asymmetrically hydrolyzed (see, for example, Patent Document 5), and 3- (4-methoxyphenyl) glycidic acid ester is used. Methods for enzymatically asymmetric transesterification (see, for example, Patent Document 6 and Patent Document 7) are known. However, these methods also have problems such as complicated post-processing operations and the necessity of using a special apparatus. Moreover, since the optical purity of the obtained optically active glycidic acid ester is low, an operation of crystallization to improve the optical purity is required.

  On the other hand, many optically active synthetic polymers that are used as optical isomer resolution agents for separating a mixture of optical isomers are known. For example, an optically active triphenylmethyl methacrylate polymer (for example, a patent) Reference 8), optically active acrylic acid amide polymer (for example, see Patent Document 9), polyacrylamide having an optically active substituent on the side chain chemically bonded to the silica gel surface (for example, see Patent Document 10), optically active norbornene Polymers (for example, see Patent Document 11) and the like are known, and the present inventors have filed patent applications for various optically active polymaleimide derivatives (for example, see Patent Documents 12 to 17).

Japanese Patent Laid-Open No. 1-226881 Japanese Patent Laid-Open No. 3-190865 JP 60-13776 A Japanese Patent Laid-Open No. 2-17168 Japanese Patent Laid-Open No. 2-109995 JP-A-4-222895 Japanese Patent Laid-Open No. 6-78790 JP-A-56-106907 JP 56-167708 A JP 63-1446 A Japanese Unexamined Patent Publication No. 7-118172 JP 2001-106729 A JP 2002-088121 A JP 2002-097227 A JP 2003-064054 A JP 2004-294219 A JP 2004-346011 A

  As described above, conventional asymmetric synthesis methods, chemical optical resolution methods using diastereomeric salt formation, and biochemical resolution methods using enzymes and microorganisms are the methods for producing optically active 3-substituted glycidic acid esters. It is insufficient.

  On the other hand, when the conventional optically active polymer is used as a separating agent for optically active compounds, it is known that there are many compounds that cannot be optically resolved because the target for optical resolution is limited. Therefore, in order to broaden the range of objects for optical resolution, it is desired to develop an optical resolution agent having a chemical structure different from that of the existing optical resolution agent and thereby exhibiting different optical resolution characteristics. .

  The present invention has been made in view of the above problems, and an object thereof is to provide a method for separating an optically active glycidic acid ester that can be carried out by an economical and efficient method and a method that can be applied industrially. It is in.

  As a result of intensive studies aimed at establishing a simpler method and a method exhibiting high resolution for the separation of an optical isomer mixture of optically active 3-substituted glycidic acid esters, the present inventors have determined that a specific optically active polymaleimide The present inventors have found that a separating agent composed of a derivative is extremely useful for separation of a mixture of optical isomers of an optically active 3-substituted glycidic acid ester, thereby completing the present invention.

  That is, the present invention is a method for separating an optically active 3-substituted glycidic acid ester as shown below.

1. The following general formula (1)
[In the general formula (1), R ₁ represents a methyl group or an ethyl group. n represents 1 or 2, and * represents an asymmetric carbon. ]

で示される３−置換グリシッド酸エステルの光学異性体混合物と、下記一般式（２）

A mixture of optical isomers of 3-substituted glycidic acid ester represented by the following general formula (2)

［上記一般式（２）中、Ｒ_１、Ｒ_２は、各々独立して、炭素数１〜１０の直鎖若しくは分岐したアルキル基、炭素数２〜１０の直鎖若しくは分岐したアルケニル基、炭素数２〜１０の直鎖若しくは分岐したアルキニル基、炭素数１〜１０の直鎖若しくは分岐したアルコキシ基で１又は複数置換された炭素数１〜１０の直鎖若しくは分岐したアルキル基、炭素数１〜１０の直鎖若しくは分岐したアルコキシ基で１又は複数置換された炭素数２〜１０の直鎖若しくは分岐したアルケニル基、炭素数１〜１０の直鎖若しくは分岐したアルコキシ基で１又は複数置換された炭素数２〜１０の直鎖若しくは分岐したアルキニル基、炭素数１〜１０の直鎖若しくは分岐したアルキルアミノ基で１又は複数置換された炭素数１〜１０の直鎖若しくは分岐したアルキル基、炭素数１〜１０の直鎖若しくは分岐したアルキルアミノ基で１又は複数置換された炭素数２〜１０の直鎖若しくは分岐したアルケニル基、炭素数１〜１０の直鎖若しくは分岐したアルキルアミノ基で１又は複数置換された炭素数２〜１０の直鎖若しくは分岐したアルキニル基、炭素数１〜１０の直鎖若しくは分岐したアルキル基で２置換されたアミノ基で１又は複数置換された炭素数１〜１０の直鎖若しくは分岐したアルキル基、炭素数１〜１０の直鎖若しくは分岐したアルキル基で２置換されたアミノ基で１又は複数置換された炭素数２〜１０の直鎖若しくは分岐したアルケニル基、炭素数１〜１０の直鎖若しくは分岐したアルキル基で２置換されたアミノ基で１又は複数置換された炭素数２〜１０の直鎖若しくは分岐したアルキニル基、炭素数１〜１０の直鎖若しくは分岐したアルキル基で３置換されたアンモニウム基で１又は複数置換された炭素数１〜１０の直鎖若しくは分岐したアルキル基、炭素数１〜１０の直鎖若しくは分岐したアルキル基で３置換されたアンモニウム基で１又は複数置換された炭素数２〜１０の直鎖若しくは分岐したアルケニル基、炭素数１〜１０の直鎖若しくは分岐したアルキル基で３置換されたアンモニウム基で１又は複数置換された炭素数２〜１０の直鎖若しくは分岐したアルキニル基、炭素数２〜１０の直鎖若しくは分岐したアルキルカルボニルオキシ基で１又は複数置換された炭素数１〜１０の直鎖若しくは分岐したアルキル基、炭素数２〜１０の直鎖若しくは分岐したアルキルカルボニルオキシ基で１又は複数置換された炭素数２〜１０の直鎖若しくは分岐したアルケニル基、炭素数２〜１０の直鎖若しくは分岐したアルキルカルボニルオキシ基で１又は複数置換された炭素数２〜１０の直鎖若しくは分岐したアルキニル基、炭素数３〜１０のシクロアルキル基、炭素数３〜１０のシクロアルケニル基、炭素又はヘテロ原子数５〜２０の芳香族基、炭素数１〜１０の直鎖若しくは分岐したアルキル基で核が１〜５置換された炭素又はヘテロ原子数５〜２０の芳香族基、炭素数２〜１０の直鎖若しくは分岐したアルケニル基で核が１〜５置換された炭素又はヘテロ原子数５〜２０の芳香族基、炭素数２〜１０の直鎖若しくは分岐したアルキニル基で核が１〜５置換された炭素又はヘテロ原子数５〜２０の芳香族基、炭素数１〜１０の直鎖若しくは分岐したアルコキシ基で核が１〜５置換された炭素又はヘテロ原子数５〜２０の芳香族基、ハロゲン原子で核が１〜５置換された炭素又はヘテロ原子数５〜２０の芳香族基を示す。但し、Ｒ_１、Ｒ_２は結合して環状構造を形成していてもよい。ｎは２〜１００００、＊印は不斉炭素を表す。］
で示される光学活性ポリマレイミド誘導体、下記一般式（３）

[In the general formula (2), R ₁ and R ₂ are each independently a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkenyl group having 2 to 10 carbon atoms, carbon A linear or branched alkynyl group having 2 to 10 carbon atoms, a linear or branched alkyl group having 1 to 10 carbon atoms substituted with one or more linear or branched alkoxy groups having 1 to 10 carbon atoms, 1 carbon atom 1 or more substituted with 1 to 10 linear or branched alkoxy groups having 1 to 10 carbon atoms or linear or branched alkenyl groups having 1 to 10 carbon atoms, or 1 or more substituted with linear or branched alkoxy groups having 1 to 10 carbon atoms A linear or branched alkynyl group having 2 to 10 carbon atoms, or a linear or branched group having 1 to 10 carbon atoms substituted with one or more linear or branched alkylamino groups having 1 to 10 carbon atoms. An alkyl group, a linear or branched alkenyl group having 2 to 10 carbon atoms, one or more substituted with a linear or branched alkylamino group having 1 to 10 carbon atoms, or a linear or branched alkyl group having 1 to 10 carbon atoms 1 or more substituted with an amino group that is 1 or more substituted with a linear or branched alkynyl group having 2 to 10 carbon atoms, or a disubstituted amino group with a linear or branched alkyl group having 1 to 10 carbon atoms A linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkyl group having 1 to 10 carbon atoms, or one or more substituted with an amino group disubstituted by a linear or branched alkyl group having 1 to 10 carbon atoms, or A branched alkenyl group, a straight chain or branched chain having 1 to 10 carbon atoms, one or more substituted with an amino group that is disubstituted by a straight chain or branched alkyl group having 1 to 10 carbon atoms A alkynyl group, a linear or branched alkyl group having 1 to 10 carbon atoms, one or more substituted with an ammonium group trisubstituted by a linear or branched alkyl group having 1 to 10 carbon atoms, A linear or branched alkenyl group having 2 to 10 carbon atoms, or a linear or branched alkyl group having 1 to 10 carbon atoms, which is substituted with one or more ammonium groups trisubstituted by linear or branched alkyl groups; 1 or more substituted linear or branched alkynyl groups having 1 or more substituted ammonium groups, or 1 or more substituted carbon atoms having 2 or 10 linear or branched alkylcarbonyloxy groups Charcoal substituted with 1 or 10 linear or branched alkyl groups or linear or branched alkylcarbonyloxy groups having 2 to 10 carbon atoms A linear or branched alkenyl group having 2 to 10 prime atoms, a linear or branched alkynyl group having 2 to 10 carbon atoms substituted with one or more linear or branched alkylcarbonyloxy groups having 2 to 10 carbon atoms, carbon A cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, carbon or an aromatic group having 5 to 20 hetero atoms, a linear or branched alkyl group having 1 to 10 carbon atoms, and a nucleus 1 to 5-substituted carbon or aromatic group having 5 to 20 hetero atoms, carbon having 1 to 5 carbon atoms substituted with a linear or branched alkenyl group having 2 to 10 carbon atoms, or aromatic having 5 to 20 hetero atoms Group, carbon having 1 to 5 carbon atoms substituted with a linear or branched alkynyl group having 2 to 10 carbon atoms, an aromatic group having 5 to 20 hetero atoms, and a linear or branched alkoxy group having 1 to 10 carbon atoms In showing the nucleus 1-5 substituted carbon or hetero atoms from 5 to 20 aromatic group, an aromatic group of carbon or hetero atoms from 5 to 20 in which nuclei are 1-5 substituted with a halogen atom. However, R ₁ and R ₂ may be bonded to form a cyclic structure. n represents 2 to 10000, and * represents an asymmetric carbon. ]
An optically active polymaleimide derivative represented by the following general formula (3)

［上記一般式（３）中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ_５、Ｒ_６、Ｒ_７、Ｒ_８、Ｒ_９、Ｒ_１０、Ｒ_１１は各々独立して、水素、メチル基、エチル基、炭素数３〜１０の直鎖若しくは分岐したアルキル基、メトキシ基、エトキシ基、炭素数３〜１０の直鎖若しくは分岐したアルコキシ基を示し、Ｒ_１２はメチル基、エチル基、ｎ−プロピル基、ｉ−プロピル基、ｎ―ブチル基、ｉ−ブチル基、ｔｅｒｔ−ブチル基、メトキシメチル基、エトキシメチル基又はエトキシエチル基を示す。ｎは２〜１００００、＊印は不斉炭素を表す。］
若しくは下記一般式（４）

[In the general formula (3), R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ are each independently hydrogen, methyl Group, an ethyl group, a linear or branched alkyl group having 3 to 10 carbon atoms, a methoxy group, an ethoxy group, a linear or branched alkoxy group having 3 to 10 carbon atoms, and R ₁₂ represents a methyl group, an ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, tert-butyl group, methoxymethyl group, ethoxymethyl group or ethoxyethyl group. n represents 2 to 10000, and * represents an asymmetric carbon. ]
Or the following general formula (4)

［上記一般式（４）中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ_５、Ｒ_６、Ｒ_７、Ｒ_８、Ｒ_９、Ｒ_１０、Ｒ_１１は各々独立して、水素、メチル基、エチル基、炭素数３〜１０の直鎖若しくは分岐したアルキル基、メトキシ基、エトキシ基、炭素数３〜１０の直鎖若しくは分岐したアルコキシ基を示し、Ｒ_１２はメチル基、エチル基、ｎ−プロピル基、ｉ−プロピル基、ｎ―ブチル基、ｉ−ブチル基、ｔｅｒｔ−ブチル基、メトキシメチル基、エトキシメチル基又はエトキシエチル基を示す。ｎは２〜１００００、＊印は不斉炭素を表す。］
で示される光学活性ポリマレイミド誘導体、及び下記一般式（５）

[In the general formula (4), R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ are each independently hydrogen, methyl Group, an ethyl group, a linear or branched alkyl group having 3 to 10 carbon atoms, a methoxy group, an ethoxy group, a linear or branched alkoxy group having 3 to 10 carbon atoms, and R ₁₂ represents a methyl group, an ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, tert-butyl group, methoxymethyl group, ethoxymethyl group or ethoxyethyl group. n represents 2 to 10000, and * represents an asymmetric carbon. ]
And an optically active polymaleimide derivative represented by the following general formula (5):

［上記一般式（５）中、Ｘ_１〜Ｘ_８は各々独立して、メチレン基、酸素原子、カルボニル基、カルボニルオキシ基、カルボニルアミノ基、アミノカルボニル基、アミノカルボニルオキシ基又は単結合を表し、Ｒ_１〜Ｒ_８は各々独立して水素原子、メチル基、エチル基、炭素数３〜１０の直鎖状，分岐状若しくは環式のアルキル基、メトキシ基、エトキシ基、炭素数３〜１０の直鎖状，分岐状若しくは環式のアルコキシ基、炭素数５〜１０の芳香族基、メチル基で芳香環上の水素が１〜４置換された炭素数５〜１０の芳香族基、エチル基で芳香環上の水素が１〜４置換された炭素数５〜１０の芳香族基、炭素数３〜６の直鎖状，分岐状若しくは環式のアルキル基で芳香環上の水素が１〜４置換された炭素数５〜１０の芳香族基、メトキシ基で芳香環上の水素が１〜４置換された炭素数５〜１０の芳香族基、エトキシ基で芳香環上の水素が１〜４置換された炭素数５〜１０の芳香族基、炭素数３〜６の直鎖状，分岐状若しくは環式のアルコキシ基で芳香環上の水素が１〜４置換された炭素数５〜１０の芳香族基、ベンジル基、メチル基で芳香環上の水素が１〜４置換されたベンジル基、エチル基で芳香環上の水素が１〜４置換されたベンジル基、炭素数３〜６の直鎖状，分岐状若しくは環式のアルキル基で芳香環上の水素が１〜４置換されたベンジル基、メトキシ基で芳香環上の水素が１〜４置換されたベンジル基、エトキシ基で芳香環上の水素が１〜４置換されたベンジル基、炭素数３〜６の直鎖状，分岐状若しくは環式のアルコキシ基で芳香環上の水素が１〜４置換されたベンジル基、２−フェニルエチル基、メチル基で芳香環上の水素が１〜４置換された２−フェニルエチル基、エチル基で芳香環上の水素が１〜４置換された２−フェニルエチル基、炭素数３〜６の直鎖状，分岐状若しくは環式のアルキル基で芳香環上の水素が１〜４置換された２−フェニルエチル基、メトキシ基で芳香環上の水素が１〜４置換された２−フェニルエチル基、エトキシ基で芳香環上の水素が１〜４置換された２−フェニルエチル基、炭素数３〜６の直鎖状，分岐状若しくは環式のアルコキシ基で芳香環上の水素が１〜４置換された２−フェニルエチル基、原子数５〜１０からなるヘテロ環芳香族基を示す。ただし、Ｒ_１−Ｘ_１、Ｒ_２−Ｘ_２、Ｒ_３−Ｘ_３、Ｒ_４−Ｘ_４、Ｒ_５−Ｘ_５、Ｒ_６−Ｘ_６、Ｒ_７−Ｘ_７、Ｒ_８−Ｘ_８が全て同じ置換基となることはない。ｎは２〜１００００、＊印は不斉炭素を表す。］
で示される光学活性ポリマレイミド誘導体からなる群より選ばれる光学活性ポリマレイミド誘導体からなる分離剤とを接触させることを特徴とする光学活性３−置換グリシッド酸エステルの分離方法。

[In General Formula (5), X _{1 to} X ₈ each independently represents a methylene group, an oxygen atom, a carbonyl group, a carbonyloxy group, a carbonylamino group, an aminocarbonyl group, an aminocarbonyloxy group, or a single bond. , R _{1 to} R ₈ are each independently a hydrogen atom, a methyl group, an ethyl group, a linear, branched or cyclic alkyl group having 3 to 10 carbon atoms, a methoxy group, an ethoxy group, or a carbon number of 3 to 10 A linear, branched or cyclic alkoxy group, an aromatic group having 5 to 10 carbon atoms, an aromatic group having 5 to 10 carbon atoms in which hydrogen on an aromatic ring is substituted with a methyl group by 1 to 4 carbon atoms, ethyl Group having 1 to 4 hydrogen atoms on the aromatic ring substituted with 1 to 4 carbon atoms, a straight chain, branched or cyclic alkyl group having 3 to 6 carbon atoms with 1 hydrogen atom on the aromatic ring ˜4 substituted aromatic group having 5 to 10 carbon atoms, methoxy group An aromatic group having 5 to 10 carbon atoms substituted with 1 to 4 hydrogen atoms on the aromatic ring, an aromatic group having 5 to 10 carbon atoms substituted with 1 to 4 hydrogen atoms on the aromatic ring with an ethoxy group, and 3 carbon atoms The hydrogen on the aromatic ring is substituted with an aromatic group having 5 to 10 carbon atoms, a benzyl group, or a methyl group in which the hydrogen on the aromatic ring is substituted with 1 to 4 linear, branched or cyclic alkoxy groups. 1 to 4 substituted benzyl groups, 1 to 4 hydrogen atoms on the aromatic ring with an ethyl group, 3 to 6 linear, branched or cyclic alkyl groups on the aromatic ring Benzyl group substituted with 1 to 4 hydrogen atoms, benzyl group substituted with 1 to 4 hydrogen atoms on the aromatic ring with methoxy group, benzyl group substituted with 1 to 4 hydrogen atoms on the aromatic ring with ethoxy group, 3 carbon atoms A benzene in which hydrogen on the aromatic ring is substituted with 1 to 4 linear, branched or cyclic alkoxy groups Group, 2-phenylethyl group, 2-phenylethyl group in which hydrogen on the aromatic ring is substituted by 1 to 4 by methyl group, 2-phenylethyl group in which hydrogen on the aromatic ring is substituted by 1 to 4 by ethyl group 2-phenylethyl group having 1 to 4 hydrogen atoms on the aromatic ring substituted with a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms, 1 to 4 hydrogen atoms on the aromatic ring with a methoxy group Aromatic with a substituted 2-phenylethyl group, a 2-phenylethyl group substituted with 1 to 4 hydrogens on the aromatic ring with an ethoxy group, a linear, branched or cyclic alkoxy group with 3 to 6 carbon atoms A 2-phenylethyl group substituted with 1 to 4 hydrogen atoms on the ring and a heterocyclic aromatic group having 5 to 10 atoms. _{However, R 1 -X 1, R 2} -X 2, R 3 -X 3, R 4 -X 4, R 5 -X 5, R 6 -X 6, R 7 -X 7, R 8 -X 8 is They are not all the same substituents. n represents 2 to 10000, and * represents an asymmetric carbon. ]
A separation method of an optically active 3-substituted glycidic acid ester comprising contacting with a separating agent comprising an optically active polymaleimide derivative selected from the group consisting of optically active polymaleimide derivatives represented by the formula:

  2. 1. The separating agent comprising an optically active polymaleimide derivative, wherein the separating agent comprises an optically active polymaleimide derivative supported on a carrier. The separation method of the optically active 3-substituted glycidic acid ester described in 1.

  3. The separation agent comprising an optically active polymaleimide derivative is a column packed with a separation agent comprising an optically active polymaleimide derivative supported on a carrier, and an optical isomer of a 3-substituted glycidic acid ester under high-performance liquid chromatography separation conditions The above-mentioned 1. characterized in that the mixture is separated. Or 2. The separation method of the optically active 3-substituted glycidic acid ester described in 1.

  ADVANTAGE OF THE INVENTION According to this invention, the method of isolate | separating the optical isomer mixture of 3-substituted glycidic acid ester easily and efficiently can be provided using the separating agent which consists of an optically active polymaleimide derivative. The optically active 3-substituted glycidic acid ester obtained by separation is extremely useful as a pharmaceutical and agrochemical intermediate.

  Specific examples of the 3-substituted glycidic acid ester represented by the general formula (1) of the present invention include 3- (2-methoxyphenyl) glycidic acid methyl ester and 3- (3-methoxyphenyl) glycidic acid methyl ester. Ester, 3- (4-methoxyphenyl) glycidic acid methyl ester, 3- (2,3-dimethoxyphenyl) glycidic acid methyl ester, 3- (2,4-dimethoxyphenyl) glycidic acid methyl ester, 3- (2, 5-Dimethoxyphenyl) glycidic acid methyl ester, 3- (2,6-dimethoxyphenyl) glycidic acid methyl ester, 3- (3,4-dimethoxyphenyl) glycidic acid methyl ester, 3- (3,5-dimethoxyphenyl) Glycidic acid methyl ester, 3- (3,6-dimethoxyphenyl) glycidyl Acid methyl ester, 3- (2-methoxyphenyl) glycidic acid ethyl ester, 3- (3-methoxyphenyl) glycidic acid ethyl ester, 3- (4-methoxyphenyl) glycidic acid ethyl ester, 3- (2,3- Dimethoxyphenyl) glycidic acid ethyl ester, 3- (2,4-dimethoxyphenyl) glycidic acid ethyl ester, 3- (2,5-dimethoxyphenyl) glycidic acid ethyl ester, 3- (2,6-dimethoxyphenyl) glycidic acid Examples include ethyl ester, 3- (3,4-dimethoxyphenyl) glycidic acid ethyl ester, 3- (3,5-dimethoxyphenyl) glycidic acid ethyl ester, and 3- (3,6-dimethoxyphenyl) glycidic acid ethyl ester. It is done.

  The separating agent used in the present invention contains an effective amount of an optically active polymaleimide derivative for separating a mixture of optical isomers of 3-substituted glycidic acid ester. The optically active polymaleimide derivative is a compound represented by the above general formulas (2) to (5).

  The optically active polymaleimide derivative represented by the general formula (2) is not particularly limited. Specifically, poly [(2S) -N-2-butylmaleimide], poly [(2S)- N-2-pentylmaleimide], poly [(2S) -N-2-hexylmaleimide], poly [(3S) -N-3-hexylmaleimide], poly [(2S) -N-2-heptylmaleimide] , Poly [(3S) -N-3-heptylmaleimide], poly [(2S) -N-2-octylmaleimide], poly [(3S) -N-3-octylmaleimide], poly [(4S)- N-4-octylmaleimide], poly [(2S) -N-2-nonylmaleimide], poly [(3S) -N-3-nonylmaleimide], poly [(4S) -N-4-nonylmaleimide], Poly [(2S) -N 2-decylmaleimide], poly [(3S) -N-3-decylmaleimide], poly [(4S) -N-4-decylmaleimide], poly [(5S) -N-5-decylmaleimide], poly [ (2S) -N-2-octadecylmaleimide], poly [(2S) -N-2- (3-methylbutyl) maleimide], poly [(2S) -N-2- (3-methylpentyl) maleimide], poly [(2S) -N-2- (4-methylpentyl) maleimide], poly [(2S) -N-2- (3,3-dimethylbutyl) maleimide], poly [(3S) -N-3- ( 2,2-dimethylpentyl) maleimide], poly [(2S) -N-2- (3-pentenyl) maleimide], poly [(3S) -N-3- (4-methyl-1-hexenyl) maleimide], Poly [(2S) -N-2- ( -Pentynyl) maleimide], poly [(3S) -N-3- (4,4-dimethyl-1-hexynyl) maleimide], poly [(2S) -N-2- (1-methoxypropyl) maleimide], poly [(2S) -N-2- (1-methoxy-3-methylbutyl) maleimide], poly [(2S) -N-2- (1-methoxy-3,3-dimethylbutyl) maleimide], poly [(2S ) -N-2- (1-methoxyethoxy-3,3-dimethylbutyl) maleimide], poly [(2S) -N-2- (1-methoxyethoxy-3,3-dimethylbutyl) maleimide], poly [ (1S) -N-1- (1-cyclopropylethyl) maleimide], poly {(1S) -N-1- [1- (1-decahydronaphthyl) ethyl] maleimide}, poly [(S) -N -Α-methylbenzyl Reimide], poly {(1S) -N-1- [1- (1-naphthyl) ethyl] maleimide}, poly [(1S) -N- (2,3-dihydro-1H-inden-1-yl) maleimide ], Poly {(1S) -N-1- [1- (2-methylphenyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (3-methylphenyl) ethyl] maleimide}, Poly {(1S) -N-1- [1- (4-methylphenyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (2-ethylphenyl) ethyl] maleimide}, poly { (1S) -N-1- [1- (3-ethylphenyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (4-ethylphenyl) ethyl] maleimide}, poly {(1S ) -N-1- [1- (2-methoxyphenyl) ethyl Maleimide}, poly {(1S) -N-1- [1- (3-methoxyphenyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (4-methoxyphenyl) ethyl] maleimide} , Poly {(1S) -N-1- [1- (2-chlorophenyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (3-chlorophenyl) ethyl] maleimide}, poly {( 1S) -N-1- [1- (4-chlorophenyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (2-fluorophenyl) ethyl] maleimide}, poly {(1S)- N-1- [1- (3-fluorophenyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (4-fluorophenyl) ethyl] maleimide}, poly {(1S) -N— 1- [1- (2,6-dimethylphenol Enyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (2,6-diethylphenyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (2,4 , 6-trifluorophenyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (pentafluorophenyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (2 -Pyridyl) ethyl] maleimide} and the like, and polymers obtained by asymmetric anion polymerization using these (S) and enantiomer (R) monomers are also included. Of these, optically active poly [(S) -N-α-methylbenzylmaleimide] is particularly preferable in the method of the present invention.

  In addition, specific examples of the optically active maleimide derivative represented by the general formula (3) or the general formula (4) include poly [(1S) -N-1- (1-cyclohexylethyl) maleimide], poly { (1S) -N-1- [1- (2-methylcyclohexyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (2,6-dimethylcyclohexyl) ethyl] maleimide}, poly { (1S) -N-1- [1- (3,5-dimethylcyclohexyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (2-ethylcyclohexyl) ethyl] maleimide}, poly { (1S) -N-1- [1- (2,6-diethylcyclohexyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (3,5-diethylcyclohexyl) ethyl] maleimide}, Po {(1S) -N-1- [1- (2-i-propylcyclohexyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (2,6-di-i-propylcyclohexyl) Ethyl] maleimide}, poly {(1S) -N-1- [1- (3,5-di-i-propylmethylcyclohexyl) ethyl] maleimide}, poly {(1S) -N-1- [1- ( 2-n-butylcyclohexyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (2,6-di-n-butylcyclohexyl) ethyl] maleimide}, poly {(1S) -N- 1- [1- (3,5-di-n-butylcyclohexyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (2-t-butylcyclohexyl) ethyl] maleimide}, poly { (1S) -N-1- [1- (2, -Di-t-butylcyclohexyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (3,5-di-t-butylcyclohexyl) ethyl] maleimide}, poly [(1S) -N -1- (1-cyclohexylpropyl) maleimide], poly {(1S) -N-1- [1- (2-methylcyclohexyl) propyl] maleimide}, poly {(1S) -N-1- [1- ( 2,6-dimethylcyclohexyl) propyl] maleimide}, poly {(1S) -N-1- [1- (3,5-dimethylcyclohexyl) propyl] maleimide}, poly {(1S) -N-1- [1 -(2-ethylcyclohexyl) propyl] maleimide}, poly {(1S) -N-1- [1- (2,6-diethylcyclohexyl) propyl] maleimide}, poly {(1S) -N-1- [1- (3,5-diethylcyclohexyl) propyl] maleimide}, poly {(1S) -N-1- [1- (2-i-propylcyclohexyl) propyl] maleimide}, poly {(1S) -N— 1- [1- (2,6-di-i-propylcyclohexyl) propyl] maleimide}, poly {(1S) -N-1- [1- (3,5-di-i-propylmethylcyclohexyl) propyl] Maleimide}, poly {(1S) -N-1- [1- (2-n-butylcyclohexyl) propyl] maleimide}, poly {(1S) -N-1- [1- (2,6-di-n) -Butylcyclohexyl) propyl] maleimide}, poly {(1S) -N-1- [1- (3,5-di-n-butylcyclohexyl) propyl] maleimide}, poly {(1S) -N-1- [ 1- (2-t-bu Lucyclohexyl) propyl] maleimide}, poly {(1S) -N-1- [1- (2,6-di-t-butylcyclohexyl) propyl] maleimide}, poly {(1S) -N-1- [1 -(3,5-di-t-butylcyclohexyl) propyl] maleimide}, poly {(1S) -N-1- [1- (2-methoxycyclohexyl) ethyl] maleimide}, poly {(1S) -N- 1- [1- (2,6-dimethoxycyclohexyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (3,5-dimethoxycyclohexyl) ethyl] maleimide}, poly {(1S)- N-1- [1- (2-t-butoxycyclohexyl) ethyl] maleimide}, poly {(1S) -N-1- [1- (2,6-di-t-butoxycyclohexyl) ethyl] maleimide , Poly {(1S) -N-1- [1- (3,5-di-t-butoxycyclohexyl) ethyl] maleimide} and the like. These (S) and enantiomer (R) monomers Also included are polymers obtained by asymmetric anion polymerization using Of these, optically active poly [(1S) -N-1- (1-cyclohexylethyl) maleimide] is particularly preferred in the method of the present invention.

  Furthermore, as the optically active polymaleimide derivative represented by the general formula (5), for example, as a compound having one substituent at any of the 2, 3, 4, and 5 positions of the cyclopentyl group, specifically, Poly {N-[(1S, 2S) -2-methylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-ethylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2 -N-propylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-i-propylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-n-butylcyclopentyl] maleimide} , Poly {N-[(1S, 2S) -2-i-butylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-t-butylcyclopentyl] maleimi }, Poly {N-[(1S, 2S) -2-phenylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-benzylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2- (2-phenylethyl) cyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-methoxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-ethoxycyclopentyl] maleimide }, Poly {N-[(1S, 2S) -2-n-propoxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-i-propoxycyclopentyl] maleimide}, poly {N-[( 1S, 2S) -2-n-butoxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-i-butoxycyclopentyl] maleimide , Poly {N-[(1S, 2S) -2-t-butoxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-phenoxycyclopentyl] maleimide}, poly {N-[(1S, 2S ) -2-benzyloxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2- (2-phenylethoxy) cyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-acetylcyclopentyl] ] Maleimide}, poly {N-[(1S, 2S) -2-propionylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-n-butyrylcyclopentyl] maleimide}, poly {N- [ (1S, 2S) -2-i-butyrylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-n-valerylcyclopentyl] male Imido}, poly {N-[(1S, 2S) -2-i-valerylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-pivaloylcyclopentyl] maleimide}, poly {N- [(1S, 2S) -2-benzoylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-phenylacetylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2- (3 -Phenylpropionyl) cyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-acetoxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-propionyloxycyclopentyl] maleimide}, poly { N-[(1S, 2S) -2-n-butyryloxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-i-butyl Ryloxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-n-valeryloxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-i-valeryloxycyclopentyl] Maleimide}, poly {N-[(1S, 2S) -2-pivaloyloxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-benzoyloxycyclopentyl] maleimide}, poly {N- [ (1S, 2S) -2-phenylacetoxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2- (3-phenylpropionyloxy) cyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-methoxycarbonylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-ethoxycarbonylsilane Lopentyl] maleimide}, poly {N-[(1S, 2S) -2-n-propoxycarbonylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-i-propoxycarbonylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-n-butoxycarbonylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-i-butoxycarbonylcyclopentyl] maleimide}, poly {N-[(1S , 2S) -2-t-butoxycarbonylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-phenoxycarbonylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-benzyloxy Carbonylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2- (2-phenyl ester) Toxicarbonyl) cyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-N-acetylaminocyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-N-propionylaminocyclopentyl] maleimide }, Poly {N-[(1S, 2S) -2-Nn-butyrylaminocyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-Ni-butyrylaminocyclopentyl] maleimide }, Poly {N-[(1S, 2S) -2-Nn-valerylaminocyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-Ni-valerylaminocyclopentyl] maleimide }, Poly {N-[(1S, 2S) -2-N-pivaloylaminocyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-N- Nzoylaminocyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-N-phenylacetylaminocyclopentyl] maleimide}, poly {N-[(1S, 2S) -2- (N-3-phenyl) Propionylamino) cyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-N-methylcarbamoylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-N-ethylcarbamoylcyclopentyl] maleimide }, Poly {N-[(1S, 2S) -2-Nn-propylcarbamoylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-Ni-propylcarbamoylcyclopentyl] maleimide}, Poly {N-[(1S, 2S) -2-Nn-butylcarbamoylcyclopentyl] maleimide , Poly {N-[(1S, 2S) -2-Ni-butylcarbamoylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-Nt-butylcarbamoylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-N-phenylcarbamoylcyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-N-benzylcarbamoylcyclopentyl] maleimide}, poly {N-[(1S , 2S) -2- (N-2-phenylethylcarbamoyl) cyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-N-methylcarbamoyloxycyclopentyl] maleimide}, poly {N-[(1S , 2S) -2-N-ethylcarbamoyloxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-N- n-propylcarbamoyloxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-Ni-propylcarbamoyloxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-N- n-butylcarbamoyloxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-Ni-butylcarbamoyloxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-N- t-butylcarbamoyloxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-N-phenylcarbamoyloxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2-N-benzylcarbamoyl] Oxycyclopentyl] maleimide}, poly {N-[(1S, 2S) -2- (N-2-phenyl) Cycloalkenyl ethylcarbamoyloxy) cyclopentyl] maleimide}, and the like.

  Further, among the optically active polymaleimide derivatives represented by the general formula (5), as a compound having two substituents at any of the 2, 3, 4, and 5 positions of the cyclopentyl group, specifically, poly { N-[(1S, 2S, 3S) -2,3-dimethylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S) -2,3-diethylcyclopentyl] maleimide}, poly {N-[( 1S, 2S, 3S) -2,3-di-n-propylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S) -2,3-di-i-propylcyclopentyl] maleimide}, poly { N-[(1S, 2S, 3S) -2,3-di-n-butylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S) -2,3-di-i-butylcyclopentyl] maleimide } Poly {N-[(1S, 2S, 3S) -2,3-di-t-butylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S) -2,3-dimethoxycyclopentyl] maleimide}, Poly {N-[(1S, 2S, 3S) -2,3-diethoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S) -2,3-di-n-propoxycyclopentyl] maleimide} , Poly {N-[(1S, 2S, 3S) -2,3-di-i-propoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S) -2,3-di-n-butoxy Cyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S) -2,3-di-i-butoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S) -2,3-di -T-Butoxy Clopentyl] maleimide}, poly {N-[(1S, 2S, 4S) -2,3-dimethylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 4S) -2,3-diethylcyclopentyl] maleimide} , Poly {N-[(1S, 2S, 4S) -2,3-di-n-propylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 4S) -2,3-di-i-propyl Cyclopentyl] maleimide}, poly {N-[(1S, 2S, 4S) -2,3-di-n-butylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 4S) -2,3-di -I-butylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 4S) -2,3-di-t-butylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 4S) -2 , 3-Di Methoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 4S) -2,3-diethoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 4S) -2,3-di-n -Propoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 4S) -2,3-di-i-propoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 4S) -2,3 -Di-n-butoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 4S) -2,3-di-i-butoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 4S) -2,3-di-t-butoxycyclopentyl] maleimide} and the like.

  Further, among the optically active polymaleimide derivatives represented by the general formula (5), as a compound having three substituents at any of the 2, 3, 4, and 5 positions of the cyclopentyl group, specifically, poly { N-[(1S, 2S, 3S, 4S) -2,3,4-trimethylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S) -2,3,4-triethylcyclopentyl] maleimide }, Poly {N-[(1S, 2S, 3S, 4S) -2,3,4-tri-n-propylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S) -2, 3,4-tri-i-propylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S) -2,3,4-tri-n-butylcyclopentyl] maleimide}, poly {N- [ (1S, 2S 3S, 4S) -2,3,4-tri-i-butylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S) -2,3,4-tri-t-butylcyclopentyl] maleimide }, Poly {N-[(1S, 2S, 3S, 4S) -2,3,4-trimethoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S) -2,3,4 -Triethoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S) -2,3,4-tri-n-propoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S , 4S) -2,3,4-tri-i-propoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S) -2,3,4-tri-n-butoxycyclopentyl] maleimide} The {N-[(1S, 2S, 3S, 4S) -2,3,4-tri-i-butoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S) -2,3,4 -Tri-t-butoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 5S) -2,3,4-trimethylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 5S) -2,3,4-triethylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 5S) -2,3,4-tri-n-propylcyclopentyl] maleimide}, poly {N- [(1S, 2S, 3S, 5S) -2,3,4-tri-i-propylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 5S) -2,3,4-tri- n-butylcyclopentyl] ma Reimide}, poly {N-[(1S, 2S, 3S, 5S) -2,3,4-tri-i-butylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 5S) -2 , 3,4-tri-t-butylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 5S) -2,3,4-trimethoxycyclopentyl] maleimide}, poly {N-[(1S , 2S, 3S, 5S) -2,3,4-triethoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 5S) -2,3,4-tri-n-propoxycyclopentyl] maleimide }, Poly {N-[(1S, 2S, 3S, 5S) -2,3,4-tri-i-propoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 5S) -2, 3,4-tri-n-but Cycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 5S) -2,3,4-tri-i-butoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 5S ) -2,3,4-tri-t-butoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S, 5R) -2,3,4,5-tetramethylcyclopentyl] maleimide}, Poly {N-[(1S, 2S, 3S, 4S, 5S) -2,3,4,5-tetraethylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S, 5S) -2, 3,4,5-tetra-n-propylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S, 5S) -2,3,4,5-tetra-i-propylcyclopentyl] maleimide} , {N-[(1S, 2S, 3S, 4S, 5S) -2,3,4,5-tetra-n-butylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S, 5S ) -2,3,4,5-tetra-i-butylcyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S, 5S) -2,3,4,5-tetra-t-butyl Cyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S, 5S) -2,3,4,5-tetramethoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S , 5S) -2,3,4,5-tetra-ethoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S, 5S) -2,3,4,5-tetra-n-propoxy Cyclopentyl] maleimide}, poly {N- [(1S, 2S, 3S, 4S, 5S) -2,3,4,5-tetra-i-propoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S, 5S) -2, 3,4,5-tetra-n-butoxycyclopentyl] maleimide}, poly {N-[(1S, 2S, 3S, 4S, 5S) -2,3,4,5-tetra-i-butoxycyclopentyl] maleimide} , Poly {N-[(1S, 2S, 3S, 4S, 5S) -2,3,4,5-tetra-t-butoxycyclopentyl] maleimide} and the like. In the present invention, not only these optically active substances but also polymers obtained by asymmetric anionic polymerization using their enantiomeric monomers are included as optically active polymaleimide derivatives represented by the above general formula (5). Of these, optically active poly {N-[(1S, 2S) -2-benzyloxycyclopentyl] maleimide} is particularly preferable in the method of the present invention.

  The optically active polymaleimide derivatives represented by the general formulas (2) to (5) used in the present invention can be prepared by methods described in the literature (for example, JP 2002-088121 A, JP 2002-097227 A, JP It can be easily prepared by asymmetric anionic polymerization of the corresponding optically active maleimide derivative as a raw material according to the method described in JP 2003-064054 A, JP 2004-346011 A, and the like. As a polymerization method of the optically active maleimide derivative, for example, an asymmetric ligand and an anionic polymerization catalyst are added and dissolved in a reaction solvent, and then an optically active maleimide derivative as a raw material is added thereto and reacted. As the asymmetric ligand, (−)-sparteine or an optically active bisoxazoline derivative is preferable. Examples of the anionic polymerization catalyst include organometallic catalysts such as n-butyl lithium, fluorenyl lithium, diethyl zinc, and dimethyl zinc.

  As the separating agent comprising the optically active polymaleimide derivative represented by the general formulas (2) to (5) used in the present invention, the optically active polymaleimide derivative itself or the optically active polymaleimide derivative supported on a carrier. Can be mentioned as suitable.

  In the case where the optically active polymaleimide derivative represented by the general formulas (2) to (5) is supported on a carrier, specifically, as the carrier, silica gel, alumina, crosslinked polystyrene, polyacrylic acid derivative, polysiloxane, and The thing surface-treated with these alkylsilanes etc. is mentioned. A carrier having a particle diameter of 1 μm to 200 μm and an average pore diameter of 10 to 3000 Å are preferable as a carrier for a separating agent in high performance liquid chromatography or gas chromatography.

  The supporting method is not particularly limited, but the optically active polymaleimide derivative used in the present invention and the porous carrier may be brought into physical contact with each other, or the polymer may be used during the production of the optically active polymaleimide derivative. A functional group may be imparted to the end of the substrate and chemically bonded to the porous carrier.

  The amount of the optically active polymaleimide derivative represented by the general formulas (2) to (5) supported on the carrier varies depending on the type and physical properties of the carrier used, and is not particularly limited. On the other hand, it can be supported in the range of 1 to 50% by weight.

  The method for separating the optical isomer mixture of the 3-substituted glycidic acid ester using the separating agent comprising the optically active polymaleimide derivative represented by the general formulas (2) to (5) is not particularly limited. However, the optical isomer mixture of 3-substituted glycidic acid esters can be easily separated by various chromatographic methods such as high performance liquid chromatography and gas chromatography.

  When the separation agent in which the optically active polymaleimide derivative represented by the above general formulas (2) to (5) is supported on a porous carrier is used as a packing in a column for high performance liquid chromatography, as an eluent The present invention can be widely applied to both normal phase systems using hexane-isopropanol and reverse phase systems using alcohol-water.

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

The liquid chromatography column used in the following examples is a stainless steel column of 4.6 mm ID × 250 mm L. The column was packed with a packing made of silica gel carrying an optically active polymaleimide derivative.
For separation of optical isomer mixture of 3-substituted glycidic acid ester by separating agent comprising optically active polymaleimide derivative and detection of separated optically active 3-substituted glycidic acid ester, Tosoh multi-pump CCPM, UV-visible detector UV-8020, refractive index detector RI-8020 was used.

Reference Example 1 Preparation of (S) -N-α-methylbenzylmaleimide In a 500 ml round bottom three-necked flask equipped with a cooling condenser, a dropping funnel and a stirrer, 4.00 g (40.8 mmol) of maleic anhydride and dried After 240 ml of benzene was added and dissolved by stirring, it was cooled to 0 ° C. on an ice bath.

  Next, a solution prepared by dissolving 5.2 ml (40.8 mmol) of (S) -1-phenethylamine in 100 ml of dry benzene was added thereto using a dropping funnel, and then returned to room temperature and stirred for 1 hour.

  Further, while vigorously stirring the reaction solution, 5.56 g (40.8 mmol) of zinc chloride was added thereto, heated to 80 ° C. on an oil bath, and 11.5 ml (54.5 mmol) of hexamethyldisilazane was added to 80 ml of dry benzene. The solution dissolved in was added dropwise using a dropping funnel, and further reacted for 5 hours under reflux with heating.

After completion of the reaction, the reaction mixture was cooled to room temperature, washed with 2N hydrochloric acid, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crude (S) -N- α-methylbenzylmaleimide was obtained. The obtained (S) -N-α-methylbenzylmaleimide was subsequently purified by column chromatography (n-hexane / ethyl acetate = 9/1, vol / vol), followed by distillation purification (114 ° C./8.3×10 -3 mmHg) to obtain 6.90 g of a white solid [yield 84%, specific rotation [α] ₄₃₅ ²⁵ = −98.1 ° (C = 1.0, THF, l = 10 cm)].

Reference Example 2 Preparation of (1S) -N-1- (1-cyclohexylethyl) maleimide In a 500 ml round bottom three-necked flask equipped with a cooling condenser, a dropping funnel and a stirring bar, 2.94 g (30. 0 mmol) and 155 ml of dry benzene were added and dissolved by stirring, and then cooled to 0 ° C. on an ice bath.

  Next, a solution obtained by dissolving 3.82 g (30.0 mmol) of (S)-(+)-1-cyclohexylethylamine in 65 ml of dry benzene was added thereto using a dropping funnel, and then returned to room temperature and stirred for 1 hour. went.

  Further, while stirring the reaction solution vigorously, 4.09 g (30.0 mmol) of zinc chloride was added thereto, and heated to 80 ° C. on an oil bath, and 9.68 g (60.0 mmol) of hexamethyldisilazane was added to 78 ml of dry benzene. The solution dissolved in was added dropwise using a dropping funnel, and further reacted for 5 hours under reflux with heating.

After completion of the reaction, the reaction mixture is cooled to room temperature, washed with 2N hydrochloric acid, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crude (1S) -N- 1- (1-cyclohexylethyl) maleimide was obtained. The obtained (1S) -N-1- (1-cyclohexylethyl) maleimide was subsequently purified by column chromatography (n-hexane / ethyl acetate = 4/1, vol / vol) to give 5.50 g of a pale yellow oil. [Yield 89%, specific rotation [α] _D ²⁵ = −6.5 ° (C = 1.0, THF, l = 10 cm)].

Reference Example 3 Preparation of N-[(1S, 2S) -2-benzyloxycyclopentyl] maleimide In a 500 ml round bottom three-necked flask equipped with a cooling condenser, a dropping funnel and a stir bar, 2.55 g (26 0.0 mmol) and 140 ml of dry benzene were added and dissolved by stirring, and then cooled to 0 ° C. on an ice bath.

  Next, a solution obtained by dissolving 4.97 g (26.0 mmol) of (1S, 2S) -2-benzyloxycyclopentylamine in 80 ml of dry benzene was added thereto using a dropping funnel, and then returned to room temperature and stirred for 1 hour. went.

  Further, while vigorously stirring the reaction solution, 3.54 g (26.0 mmol) of zinc chloride was added thereto, heated to 80 ° C. on an oil bath, and 8.39 g (52.0 mmol) of hexamethyldisilazane was added to 70 ml of dry benzene. The solution dissolved in was added dropwise using a dropping funnel, and further reacted for 5 hours under reflux with heating.

After completion of the reaction, the reaction mixture was cooled to room temperature, washed with 2N hydrochloric acid, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crude N-[(1S, 2S) -2-Benzyloxycyclopentyl] maleimide was obtained. The obtained N-[(1S, 2S) -2-benzyloxycyclopentyl] maleimide was subsequently purified by column chromatography (n-hexane / ethyl acetate = 9/1, vol / vol) to give a pale yellow oil. 40 g were obtained [yield 91%, specific rotation [α] _D ²⁵ = + 36.6 ° (C = 1.0, THF, l = 10 cm)].

Reference Example 4 Preparation of optically active poly [(S) -N-α-methylbenzylmaleimide] In a 25 ml eggplant-shaped flask containing a magnetic stirrer, 30.9 mg (0.25 mmol) of diethylzinc, (−)-spa 70.3 mg (0.30 mmol) of lutein and 5 ml of dry toluene were charged, and the mixture was stirred at 0 ° C. for 30 minutes with stirring, and then (S) -N-α-methylbenzyl obtained in Reference Example 1 was added to this solution. 503 mg (2.50 mmol) of maleimide was added, and the reaction was further carried out at the same temperature for 72 hours.

After completion of the reaction, the reaction solution was poured into 50 ml of methanol, and then the precipitate was collected by filtration. The obtained red solid was washed with 1N hydrochloric acid, then washed with water, and then dried under reduced pressure at room temperature to obtain 0.5 g of the objective optically active poly [(S) -N-α-methylbenzylmaleimide] as white. Obtained as a solid [yield 100%, number average molecular weight (Mn) = 12.7 × 10 ³ , Mw / Mn = 10.0, specific rotation [α] ₄₃₅ ²⁵ = 242.2 ° (C = 1. 0, CHCl ₃ )].

Reference Example 5 Preparation of optically active poly [(1S) -N-1- (1-cyclohexylethyl) maleimide] In a 50 ml eggplant-shaped flask containing a magnetic stirrer, 100 mg (0.83 mmol) of diethyl zinc, (-) -After charging 230 mg (1.00 mmol) of sparteine and 17.5 ml of dry toluene and stirring at -11 ° C for 30 minutes while stirring, (1S) -N-1 obtained in Reference Example 2 was added to this solution. 2.07 g (10.0 mmol) of-(1-cyclohexylethyl) maleimide was added, and the reaction was further performed at the same temperature for 96 hours.

After completion of the reaction, the reaction solution was poured into 200 ml of methanol, and then the precipitate was collected by filtration. The obtained red solid was washed with 1N hydrochloric acid, then with water, and then dried under reduced pressure at room temperature to obtain the target optically active poly [(1S) -N-1- (1-cyclohexylethyl) maleimide] 1. .12 g was obtained as a white solid [yield 63%, number average molecular weight (Mn) = 16.7 × 10 ³ , Mw / Mn = 10.2, specific rotation [α] ₄₃₅ ²⁵ = 378.1 ° ( C = 1.0, CHCl ₃ )].

Reference Example 6 Preparation of optically active poly {N-[(1S, 2S) -2-benzyloxycyclopentyl] maleimide} In a 50 ml eggplant-shaped flask containing a magnetic stirrer, 0.12 g (1.0 mmol) of diethylzinc, (-)-Sparteine (0.28 g, 1.2 mmol) and dry toluene (2 ml) were charged, and the mixture was stirred at -10 ° C. for 30 minutes with stirring. Then, this solution was mixed with N-[(( [1S, 2S) -2-Benzyloxycyclopentyl] maleimide (2.71 g, 10.0 mmol) was added to a dry toluene 18 ml solution, and the reaction was further carried out at the same temperature for 168 hours.

After completion of the reaction, the reaction solution was poured into 200 ml of methanol, and then the precipitate was collected by filtration. The obtained red solid was washed with 1N hydrochloric acid and then with water, and then dried under reduced pressure at room temperature to obtain the target optically active poly {N-[(1S, 2S) -2-benzyloxycyclopentyl] maleimide}. 2.23 g was obtained as a white solid [yield 82%, number average molecular weight (Mn) = 20.2 × 10 ³ , Mw / Mn = 7.0, specific rotation [α] ₄₃₅ ²⁵ = 209.6 ° (C = 1.0, CHCl ₃ )].

Preparation Example 1 Preparation of silica gel supporting 10% optically active poly [(S) -N-α-methylbenzylmaleimide] and its packed column Optically active poly [(S) obtained in Reference Example 4 in a 50 ml eggplant type flask -N-α-methylbenzylmaleimide] 500 mg and chloroform 10 ml were charged and dissolved, and then 4.5 g of silica gel (average particle size 5 μm, average pore size 1000 angstroms) was added, and then chloroform was distilled off under reduced pressure using a rotary evaporator. 5 g of silica gel carrying 10% of optically active poly [(S) -N-α-methylbenzylmaleimide] as the target product was obtained.

  The obtained optically active poly [(S) -N-α-methylbenzylmaleimide] 10% -supported silica gel was dispersed in isopropanol, and then a stainless steel 4.6 mm ID × 250 mmL column was used with a high pressure pump and a pressure of 300 kg / Filled with cm2. The obtained column had 8600 theoretical plates.

  In the measurement of the number of theoretical plates, n-hexane / isopropanol = 90/10 (vol / vol) was used as an eluent, and measurement was performed by elution of toluene. The number of theoretical plates was calculated by the following formula.

Theoretical plate number (N) = 5.54 × [Tr / (W1 / 2)] ²
Tr = retention time (sec)
W1 / 2 = half-value width (mm).

Preparation Example 2 Preparation of optically active poly [(1S) -N-1- (1-cyclohexylethyl) maleimide] 10% silica gel and its packed column Optically active poly obtained in Reference Example 5 was placed in a 50 ml eggplant-shaped flask. After 500 mg of [(1S) -N-1- (1-cyclohexylethyl) maleimide] and 10 ml of chloroform were charged and dissolved, 4.5 g of silica gel (average particle size 5 μm, average pore size 1000 angstrom) was added, and then with a rotary evaporator. Chloroform was distilled off under reduced pressure to obtain 5 g of silica gel carrying 10% of the target optically active poly [(1S) -N-1- (1-cyclohexylethyl) maleimide].

The obtained optically active poly [(1S) -N-1- (1-cyclohexylethyl) maleimide] 10% supported silica gel was dispersed in isopropanol, and then a high pressure pump was used on a stainless steel 4.6 mm ID × 250 mmL column. At a pressure of 300 kg / cm ² . The obtained column had 8900 theoretical plates.

  In the measurement of the number of theoretical plates, n-hexane / isopropanol = 90/10 (vol / vol) was used as an eluent, and measurement was performed by elution of toluene. The number of theoretical plates was calculated by the following formula.

Theoretical plate number (N) = 5.54 × [Tr / (W1 / 2)] ²
Tr = retention time (sec)
W1 / 2 = Half width (mm)
Preparation Example 3 Preparation of silica gel supporting 10% optically active poly {N-[(1S, 2S) -2-benzyloxycyclopentyl] maleimide} and its packed column Optical activity obtained in Reference Example 6 in a 50 ml eggplant type flask After adding and dissolving 500 mg of poly {N-[(1S, 2S) -2-benzyloxycyclopentyl] maleimide} and 10 ml of chloroform, 4.5 g of silica gel (average particle size 5 μm, average pore size 1000 Å) was added, and then rotary Chloroform was distilled off under reduced pressure with an evaporator to obtain 5 g of silica gel carrying 10% of the target optically active poly {N-[(1S, 2S) -2-benzyloxycyclopentyl] maleimide}.

  The obtained optically active poly {N-[(1S, 2S) -2-benzyloxycyclopentyl] maleimide} 10% supported silica gel was dispersed in isopropanol, and a high pressure pump was applied to a stainless steel 4.6 mm ID × 250 mm L column. Used and filled at a pressure of 300 kg / cm 2. The obtained column had 8500 theoretical plates.

  In the measurement of the number of theoretical plates, n-hexane / isopropanol = 90/10 (vol / vol) was used as an eluent, and measurement was performed by elution of toluene. The number of theoretical plates was calculated by the following formula.

Theoretical plate number (N) = 5.54 × [Tr / (W1 / 2)] ²
Tr = retention time (sec)
W1 / 2 = Half width (mm)
Examples 1 to 3
3- (4-methoxyphenyl) glycidic acid using the column prepared in Preparation Examples 1 to 3, using a flow rate of 1.0 ml / min and hexane / isopropanol = 9/1 (v / v) as an eluent. Separation of the methyl ester was performed. The results are also shown in Table 1.

Claims (3)

The following general formula (1)

[In the above general formula (1), R ₁ represents a methyl group or an ethyl group. n represents 1 or 2, and * represents an asymmetric carbon. ]
A mixture of optical isomers of 3-substituted glycidic acid ester represented by the following general formula (2)
The following general formula (2)

[In the general formula (2), R ₁ and R ₂ are each independently a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkenyl group having 2 to 10 carbon atoms, carbon A linear or branched alkynyl group having 2 to 10 carbon atoms, a linear or branched alkyl group having 1 to 10 carbon atoms substituted with one or more linear or branched alkoxy groups having 1 to 10 carbon atoms, 1 carbon atom 1 or more substituted with 1 to 10 linear or branched alkoxy groups having 1 to 10 carbon atoms or linear or branched alkenyl groups having 1 to 10 carbon atoms, or 1 or more substituted with linear or branched alkoxy groups having 1 to 10 carbon atoms A linear or branched alkynyl group having 2 to 10 carbon atoms, or a linear or branched group having 1 to 10 carbon atoms substituted with one or more linear or branched alkylamino groups having 1 to 10 carbon atoms. An alkyl group, a linear or branched alkenyl group having 2 to 10 carbon atoms, one or more substituted with a linear or branched alkylamino group having 1 to 10 carbon atoms, or a linear or branched alkyl group having 1 to 10 carbon atoms 1 or more substituted with an amino group that is 1 or more substituted with a linear or branched alkynyl group having 2 to 10 carbon atoms, or a disubstituted amino group with a linear or branched alkyl group having 1 to 10 carbon atoms A linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkyl group having 1 to 10 carbon atoms, or one or more substituted with an amino group disubstituted by a linear or branched alkyl group having 1 to 10 carbon atoms, or A branched alkenyl group, a straight chain or branched chain having 1 to 10 carbon atoms, one or more substituted with an amino group that is disubstituted by a straight chain or branched alkyl group having 1 to 10 carbon atoms A alkynyl group, a linear or branched alkyl group having 1 to 10 carbon atoms, one or more substituted with an ammonium group trisubstituted by a linear or branched alkyl group having 1 to 10 carbon atoms, A linear or branched alkenyl group having 2 to 10 carbon atoms, or a linear or branched alkyl group having 1 to 10 carbon atoms, which is substituted with one or more ammonium groups trisubstituted by linear or branched alkyl groups; 1 or more substituted linear or branched alkynyl groups having 1 or more substituted ammonium groups, or 1 or more substituted carbon atoms having 2 or 10 linear or branched alkylcarbonyloxy groups Charcoal substituted with 1 or 10 linear or branched alkyl group or linear or branched alkylcarbonyloxy group having 2 to 10 carbon atoms A linear or branched alkenyl group having 2 to 10 prime atoms, a linear or branched alkynyl group having 2 to 10 carbon atoms substituted with one or more linear or branched alkylcarbonyloxy groups having 2 to 10 carbon atoms, carbon A cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, carbon or an aromatic group having 5 to 20 hetero atoms, a linear or branched alkyl group having 1 to 10 carbon atoms, and a nucleus 1 to 5-substituted carbon or aromatic group having 5 to 20 hetero atoms, carbon having 1 to 5 carbon atoms substituted with a linear or branched alkenyl group having 2 to 10 carbon atoms, or aromatic having 5 to 20 hetero atoms Group, carbon having 1 to 5 carbon atoms substituted with a linear or branched alkynyl group having 2 to 10 carbon atoms, an aromatic group having 5 to 20 hetero atoms, and a linear or branched alkoxy group having 1 to 10 carbon atoms In showing the nucleus 1-5 substituted carbon or hetero atoms from 5 to 20 aromatic group, an aromatic group of carbon or hetero atoms from 5 to 20 in which nuclei are 1-5 substituted with a halogen atom. However, R ₁ and R ₂ may be bonded to form a cyclic structure. n represents 2 to 10000, and * represents an asymmetric carbon. ]
An optically active polymaleimide derivative represented by the following general formula (3)

[In the general formula (3), R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ are each independently hydrogen, methyl Group, an ethyl group, a linear or branched alkyl group having 3 to 10 carbon atoms, a methoxy group, an ethoxy group, a linear or branched alkoxy group having 3 to 10 carbon atoms, and R ₁₂ represents a methyl group, an ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, tert-butyl group, methoxymethyl group, ethoxymethyl group or ethoxyethyl group. n represents 2 to 10000, and * represents an asymmetric carbon. ]
Or the following general formula (4)

[In the general formula (4), R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ are each independently hydrogen, methyl Group, an ethyl group, a linear or branched alkyl group having 3 to 10 carbon atoms, a methoxy group, an ethoxy group, a linear or branched alkoxy group having 3 to 10 carbon atoms, and R ₁₂ represents a methyl group, an ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, tert-butyl group, methoxymethyl group, ethoxymethyl group or ethoxyethyl group. n represents 2 to 10000, and * represents an asymmetric carbon. ]
And an optically active polymaleimide derivative represented by the following general formula (5):

[In General Formula (5), X _{1 to} X ₈ each independently represents a methylene group, an oxygen atom, a carbonyl group, a carbonyloxy group, a carbonylamino group, an aminocarbonyl group, an aminocarbonyloxy group, or a single bond. , R _{1 to} R ₈ are each independently a hydrogen atom, a methyl group, an ethyl group, a linear, branched or cyclic alkyl group having 3 to 10 carbon atoms, a methoxy group, an ethoxy group, or a carbon number of 3 to 10 A linear, branched or cyclic alkoxy group, an aromatic group having 5 to 10 carbon atoms, an aromatic group having 5 to 10 carbon atoms in which hydrogen on an aromatic ring is substituted with a methyl group by 1 to 4 carbon atoms, ethyl Group having 1 to 4 hydrogen atoms on the aromatic ring substituted with 1 to 4 carbon atoms, a straight chain, branched or cyclic alkyl group having 3 to 6 carbon atoms with 1 hydrogen atom on the aromatic ring ˜4 substituted aromatic group having 5 to 10 carbon atoms, methoxy group An aromatic group having 5 to 10 carbon atoms substituted with 1 to 4 hydrogen atoms on the aromatic ring, an aromatic group having 5 to 10 carbon atoms substituted with 1 to 4 hydrogen atoms on the aromatic ring with an ethoxy group, and 3 carbon atoms The hydrogen on the aromatic ring is substituted with an aromatic group having 5 to 10 carbon atoms, a benzyl group, or a methyl group in which the hydrogen on the aromatic ring is substituted with 1 to 4 linear, branched or cyclic alkoxy groups. 1 to 4 substituted benzyl groups, 1 to 4 hydrogen atoms on the aromatic ring with an ethyl group, 3 to 6 linear, branched or cyclic alkyl groups on the aromatic ring Benzyl group substituted with 1 to 4 hydrogen atoms, benzyl group substituted with 1 to 4 hydrogen atoms on the aromatic ring with methoxy group, benzyl group substituted with 1 to 4 hydrogen atoms on the aromatic ring with ethoxy group, 3 carbon atoms A benzene in which hydrogen on the aromatic ring is substituted with 1 to 4 linear, branched or cyclic alkoxy groups Group, 2-phenylethyl group, 2-phenylethyl group in which hydrogen on the aromatic ring is substituted by 1 to 4 by methyl group, 2-phenylethyl group in which hydrogen on the aromatic ring is substituted by 1 to 4 by ethyl group 2-phenylethyl group having 1 to 4 hydrogen atoms on the aromatic ring substituted with a linear, branched or cyclic alkyl group having 3 to 6 carbon atoms, 1 to 4 hydrogen atoms on the aromatic ring with a methoxy group Aromatic with a substituted 2-phenylethyl group, a 2-phenylethyl group substituted with 1 to 4 hydrogens on the aromatic ring with an ethoxy group, a linear, branched or cyclic alkoxy group with 3 to 6 carbon atoms A 2-phenylethyl group substituted with 1 to 4 hydrogen atoms on the ring and a heterocyclic aromatic group having 5 to 10 atoms. _{However, R 1 -X 1, R 2} -X 2, R 3 -X 3, R 4 -X 4, R 5 -X 5, R 6 -X 6, R 7 -X 7, R 8 -X 8 is They are not all the same substituents. n represents 2 to 10000, and * represents an asymmetric carbon. ]
A separation method of an optically active 3-substituted glycidic acid ester comprising contacting with a separating agent comprising an optically active polymaleimide derivative selected from the group consisting of optically active polymaleimide derivatives represented by the formula:   2. The method for separating an optically active 3-substituted glycidic acid ester according to claim 1, wherein the separating agent comprising an optically active polymaleimide derivative is a separating agent comprising an optically active polymaleimide derivative supported on a carrier. The separation agent comprising an optically active polymaleimide derivative is a column packed with a separation agent comprising an optically active polymaleimide derivative supported on a carrier, and an optical isomer of a 3-substituted glycidic acid ester under high-performance liquid chromatography separation conditions The method for separating an optically active 3-substituted glycidic acid ester according to claim 1, wherein the mixture is separated.