JP2009263233A - Method for producing asymmetrically catalyzed michael reaction product, and method for producing pharmaceutical compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an asymmetrically catalyzed Michael reaction product capable of obtaining a corresponding Michael reaction product from an electron deficient alkene with acetaldehyde in a high asymmetric yield, and further, a method for producing a pharmaceutical compound by utilizing such the asymmetrically catalyzed Michael reaction product. <P>SOLUTION: This method for producing the asymmetrically catalyzed Michael reaction product is characterized by obtaining the Michael addition substance or its enantiomer by reacting the prescribed electron deficient alkene with acetaldehyde in the presence of an asymmetric catalyst or its enantiomer. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing an asymmetric catalyst Michael reaction product and a method for producing a pharmaceutical compound using the same.

  The Michael reaction is a carbon-carbon bond formation reaction that is important in organic chemistry. In particular, the asymmetric catalytic Michael reaction for obtaining a large amount of optically active substance from a small amount of asymmetric source is being actively studied all over the world. An example of the asymmetric catalytic Michael reaction is an addition reaction between an electron-deficient alkene and an aldehyde.

  For example, Non-Patent Document 1 reports an asymmetric catalytic Michael reaction between a nitroalkene and an aldehyde using water as a reaction solvent. Non-Patent Document 2 discloses an asymmetric catalytic Michael reaction between a nitroolefin and an aldehyde using a tripeptide as an organic catalyst. As seen in these reports, in recent years, many asymmetric catalytic Michael reactions using aldehydes as nucleophiles have been reported.

However, all the aldehydes generated in the reactants generated in these reports are α-substituted aldehydes, and no asymmetric catalytic Michael reaction that generates α-unsubstituted aldehydes has been reported. In order to carry out the asymmetric catalytic Michael reaction that generates an α-unsubstituted aldehyde, it is necessary to use acetaldehyde as an aldehyde that is a nucleophile, and acetaldehyde has high activity both as a nucleophile and as an electrophile. Therefore, it has been difficult to properly control the reaction.
S. Zhu, S .; Yu, D .; Ma, Angew. Chem. Int. Ed. 2008, 47, 545 M.M. Wiesner, J. et al. D. Revell, H .; Wennemers, Angew. Chem. Int. Ed. 2008, 47, 1871

  Accordingly, an object of the present invention is to provide a method for producing an asymmetric catalytic Michael reaction product capable of obtaining a corresponding Michael adduct with high asymmetric yield from an electron-deficient alkene and acetaldehyde. In addition, an object of the present invention is to provide a method for producing a pharmaceutical compound using such a method for producing an asymmetric catalytic Michael reaction product.

  In view of the above problems, the present inventors conducted extensive research. As a result, it was found that when an electron-deficient alkene and acetaldehyde were reacted with a specific asymmetric catalyst, the asymmetric catalytic Michael reaction proceeded with high enantioselectivity, and the present invention was completed. It came to do. Specifically, the present invention provides the following.

［式中、Ｘは、電子求引性基を示し、Ｙは、水素原子又は電子求引性基を示し、Ｒ^１は、一価の有機基を示し、Ｒ^２及びＲ^３は、それぞれ独立に、置換基を有していてもよいアリール基、ヘテロアリール基、シクロアルキル基、ヘテロシクロアルキル基、シクロアルケニル基、ヘテロシクロアルケニル基、アルキル基、アルケニル基、又はアルキニル基を示し、Ｒ^４は、シリル基、又はアルキル基を示し、Ｒ^５は、水酸基の保護基を示し、ｎは、０又は１を示す。］ (1) An electron-deficient alkene represented by the following general formula (1) and acetaldehyde are reacted in the presence of an asymmetric catalyst represented by the following general formula (2) or an enantiomer thereof, and the following general formula (3 ) Or an enantiomer thereof, and a method for producing an asymmetric catalytic Michael reaction product.

[Wherein, X represents an electron-withdrawing group, Y represents a hydrogen atom or an electron-withdrawing group, R ¹ represents a monovalent organic group, and R ² and R ³ are each independent. Represents an optionally substituted aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, alkyl group, alkenyl group, or alkynyl group, and R ⁴ Represents a silyl group or an alkyl group, R ⁵ represents a hydroxyl-protecting group, and n represents 0 or 1. ]

  According to the invention described in (1), since a predetermined organic catalyst is used for the asymmetric catalytic Michael reaction, the asymmetric catalytic Michael reaction between an electron-deficient alkene and acetaldehyde can be performed with high enantioselectivity, reaction efficiency, You can make progress. Moreover, since the acetaldehyde used in the invention described in (1) is easily available, the asymmetric catalytic Michael reaction can be performed at low cost.

(2) In the above general formula (2), R ² and R ³ are aryl groups optionally substituted by an electron donating group, and R ⁴ is a silyl group. A process for producing the described asymmetric catalyst Michael reaction product.

  (3) The electron donating group is an alkyl group, an alkoxy group, an alkylthio group, an aryloxy group, an arylthio group, a dialkylamino group, an alkylamino group, an amino group, a diarylamino group, an arylamino group, or an alkylarylamino group. The asymmetric catalyst Michael reaction product according to (2), which is at least one selected from the group consisting of:

  The inventions described in (2) and (3) limit the type of asymmetric catalyst in the asymmetric catalytic Michael reaction. By limiting the type of asymmetric catalyst, the enantioselectivity and reaction efficiency of the asymmetric catalyst Michael reaction can be further improved.

［式中、Ｒ^２及びＲ^３は、それぞれ独立に、置換基を有していてもよいアリール基、ヘテロアリール基、シクロアルキル基、ヘテロシクロアルキル基、シクロアルケニル基、ヘテロシクロアルケニル基、アルキル基、アルケニル基、又はアルキニル基を示し、Ｒ^４は、シリル基、又はアルキル基を示し、Ｒ^５は、水酸基の保護基を示し、ｎは、０又は１を示す。］ (4) A compound represented by the following structural formula (4) is reacted with acetaldehyde in the presence of an asymmetric catalyst represented by the following general formula (2). A compound represented by the following structural formula (6) is obtained by oxidizing the compound represented by the following structural formula (6), and then reduced by reducing the compound represented by the structural formula (6). A method for producing a pharmaceutical compound comprising obtaining a compound.

[Wherein, R ² and R ³ each independently represents an aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, alkyl which may have a substituent. A group, an alkenyl group, or an alkynyl group; R ⁴ represents a silyl group or an alkyl group; R ⁵ represents a hydroxyl-protecting group; and n represents 0 or 1. ]

［式中、Ｒ^２及びＲ^３は、それぞれ独立に、置換基を有していてもよいアリール基、ヘテロアリール基、シクロアルキル基、ヘテロシクロアルキル基、シクロアルケニル基、ヘテロシクロアルケニル基、アルキル基、アルケニル基、又はアルキニル基を示し、Ｒ^４は、シリル基、又はアルキル基を示し、Ｒ^５は、水酸基の保護基を示し、ｎは、０又は１を示す。］ (5) A compound represented by the following structural formula (8) is reacted with acetaldehyde in the presence of an asymmetric catalyst represented by the following general formula (2 ′), and the following structural formula (9) is obtained. A compound represented by the following structural formula (10) is obtained by oxidizing the compound represented by the following formula, and then the compound represented by the structural formula (10) is reduced and represented by the following structural formula (11). A method for producing a pharmaceutical compound, comprising obtaining a pharmaceutical compound.

[Wherein, R ² and R ³ each independently represents an aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, alkyl which may have a substituent. A group, an alkenyl group, or an alkynyl group; R ⁴ represents a silyl group or an alkyl group; R ⁵ represents a hydroxyl-protecting group; and n represents 0 or 1. ]

  The invention described in (4) and (5) is a method for producing a pharmaceutical compound utilizing the method for producing an asymmetric catalyst Michael reaction product of the present invention. According to these inventions, important pharmaceutical compounds such as baclofen and pregabalin can be produced with high enantioselectivity and reaction efficiency.

  According to the present invention, since a predetermined organic catalyst is used for the asymmetric catalytic Michael reaction, the asymmetric catalytic Michael reaction between an electron-deficient alkene and acetaldehyde proceeds with high enantioselectivity and reaction efficiency. Can be made. In addition, since acetaldehyde used in the present invention is easily available, the asymmetric catalytic Michael reaction can be performed at a low cost.

  Hereinafter, embodiments of the present invention will be described. In addition, this invention is not limited to the following embodiment at all.

［式中、Ｘは、電子求引性基を示し、Ｙは、水素原子又は電子求引性基を示し、Ｒ^１は、一価の有機基を示し、Ｒ^２及びＲ^３は、それぞれ独立に、置換基を有していてもよいアリール基、ヘテロアリール基、シクロアルキル基、ヘテロシクロアルキル基、シクロアルケニル基、ヘテロシクロアルケニル基、アルキル基、アルケニル基、又はアルキニル基を示し、Ｒ^４は、シリル基、又はアルキル基を示し、Ｒ^５は、水酸基の保護基を示し、ｎは、０又は１を示す。］ <Method for producing asymmetric catalyst Michael reaction product>
The method for producing the asymmetric catalyst Michael reaction product of the present invention comprises an electron-deficient alkene represented by the following general formula (1) and an acetaldehyde, or an asymmetric catalyst represented by the following general formula (2) or an enantiomer thereof: To obtain a compound represented by the following general formula (3) or an enantiomer thereof.

[Wherein, X represents an electron-withdrawing group, Y represents a hydrogen atom or an electron-withdrawing group, R ¹ represents a monovalent organic group, and R ² and R ³ are each independent. Represents an optionally substituted aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, alkyl group, alkenyl group, or alkynyl group, and R ⁴ Represents a silyl group or an alkyl group, R ⁵ represents a hydroxyl-protecting group, and n represents 0 or 1. ]

[Electron-deficient alkene represented by general formula (1)]
In the method for producing an asymmetric catalyst Michael reaction product of the present invention, an electron-deficient alkene represented by the general formula (1) is used as an electrophilic reagent. In the electron-deficient alkene represented by the general formula (1), X represents an electron withdrawing group, and Y represents a hydrogen atom or an electron withdrawing group. The electron withdrawing group in X and Y is not particularly limited, and examples thereof include an acyl group, a nitro group, a cyano group, a carboxyl group, a thiocarboxyl group, a sulfo group, an alkoxycarbonyl group, and a carbamoyl group. it can. Of these electron withdrawing groups, a nitro group is particularly preferable. In the electron-deficient alkene represented by the general formula (1), X is preferably a nitro group and Y is a hydrogen atom.

  In the Michael reaction, the resonance between the double bond and the electron withdrawing group increases the reactivity of the double bond, and the carbon atom in the β position with respect to the electron withdrawing group attacks the nucleophilic attack. Reaction progresses by receiving. Therefore, the method for producing the asymmetric catalytic Michael reaction product of the present invention is basically carried out by using an electron-deficient alkene substituted with an electron-attracting group that causes resonance with a double bond. Is something that can be done.

In the electron-deficient alkene represented by the general formula (1), R ¹ represents a monovalent organic group. The monovalent organic group is not particularly limited, and may have an alkyl group, alkenyl group, alkynyl group, alkoxyalkyl group, alkoxyalkenyl group, alkoxyalkynyl group, alkoxycarbonyl group which may have a substituent. , Alkoxycarbonylalkyl group, alkoxycarbonylalkenyl group, alkoxycarbonylalkynyl group, acyl group, acylalkyl group, acylalkenyl group, acylalkynyl group, amide group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl Group, aryl group, heteroaryl group, cycloalkylalkyl group, cycloalkylalkenyl group, cycloalkylalkynyl group, heterocycloalkylalkyl group, heterocycloalkylalkenyl group, heterocyclo Alkyl alkynyl group, cycloalkenyl alkyl group, cycloalkenyl alkenyl group, cycloalkenyl alkynyl group, heterocycloalkenyl alkyl group, heterocycloalkenyl alkenyl group, heterocycloalkenyl alkynyl group, arylalkyl group, arylalkenyl group, arylalkynyl group, hetero An arylalkyl group, a heteroarylalkenyl group, or a heteroarylalkynyl group can be mentioned.

  In the present specification, the “alkyl group” used alone or as part of another group may be linear or branched. Although there is no restriction | limiting in particular in carbon number of an alkyl group, Preferably it is C1-C20, More preferably, it is C1-C6. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl. Group, n-pentyl group and the like.

  This alkyl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent. Examples of the substituent include an alkoxy group, an acyl group, a halogen atom, an amino group, a nitro group, a cyano group, a thiol group, and a hydroxyl group.

  In the present specification, an “alkenyl group” used alone or as part of another group may be linear or branched. Although there is no restriction | limiting in particular in carbon number of an alkenyl group, Preferably it is C2-C20, More preferably, it is C2-C6. Examples of the alkenyl group include vinyl group, 1-propenyl group, allyl group, isopropenyl, 1-butenyl group and isobutenyl group.

  This alkenyl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent. Examples of the substituent include the groups described above as substituents for the alkyl group.

  In the present specification, an “alkynyl group” used alone or as part of another group may be linear or branched. Although there is no restriction | limiting in particular in carbon number of an alkynyl group, Preferably it is C2-C20, More preferably, it is C2-C6. Examples of the alkynyl group include ethynyl group, 1-propynyl group, 2-propynyl group, isopropynyl group, 1-butynyl group, isobutynyl group and the like.

  The alkynyl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent. Examples of the substituent include the groups described above as substituents for the alkyl group.

  In the present specification, the “alkoxy group” refers to a monovalent group in which an oxygen atom is bonded to the alkyl group, and includes a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, Examples include sec-butoxy group, t-butoxy group, n-pentoxy group, isopentoxy group, n-hexoxy group, n-heptoxy group and the like.

  In the present specification, an “acyl group” used alone or as part of another group refers to a group obtained by removing a hydroxyl group from a carboxylic acid. Although there is no restriction | limiting in particular in carbon number of an acyl group, Preferably it is C1-C20, More preferably, it is C1-C6. Examples of acyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, benzoyl, naphthoyl, furoyl and the like.

  This acyl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent. Examples of the substituent include an alkyl group, an alkoxy group, an alkoxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkylthio group, a halogen atom, an amino group, a nitro group, a cyano group, a thiol group, and a hydroxyl group.

  In the present specification, the “amide group” refers to a group in which one hydrogen atom of an amino group is substituted with the acyl group, and includes a formylamide group, an acetamide group, a propionamide group, a butyramide group, an isobutylamide group, and a barrelamide group. , Isovaleramide group, pivaloylamide group, benzamide group, naphthamide group, fullamide group and the like.

  In the present specification, a “cycloalkyl group” used alone or as part of another group refers to a non-aromatic saturated cyclic hydrocarbon group. Although there is no restriction | limiting in particular in carbon number of a cycloalkyl group, Preferably it is C3-C10, More preferably, it is C3-C6. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like.

  The cycloalkyl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent. Substituents include alkyl groups, alkoxy groups, alkoxyalkyl groups, alkoxycarbonyl groups, alkoxycarbonylalkyl groups, acyl groups, acylalkyl groups, alkylthio groups, halogen atoms, amino groups, nitro groups, cyano groups, thiol groups, hydroxyl groups Etc.

  In the present specification, a “heterocycloalkyl group” used alone or as part of another group refers to a group in which one or more carbon atoms on the ring of the cycloalkyl group are substituted with a heteroatom. Examples of the hetero atom include an oxygen atom, a nitrogen atom, and a sulfur atom. Examples of heterocycloalkyl groups include tetrahydrofuryl group, morpholinyl group, piperazinyl group, piperidyl group, pyrrolidinyl group and the like.

  The heterocycloalkyl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent. Examples of the substituent include the groups described above as substituents for the cycloalkyl group.

  In the present specification, a “cycloalkenyl group” used alone or as part of another group refers to a non-aromatic unsaturated cyclic hydrocarbon group. There may be one unsaturated bond on the ring, or two or more. Although there is no restriction | limiting in particular in carbon number of a cycloalkenyl group, Preferably it is C3-C10, More preferably, it is C3-C6. Examples of the cycloalkenyl group include a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, and the like.

  The cycloalkenyl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent. Examples of the substituent include the groups described above as substituents for the cycloalkyl group.

  In the present specification, a “heterocycloalkenyl group” used alone or as part of another group refers to a group in which one or more carbon atoms on the ring of the cycloalkenyl group are substituted with a heteroatom. Examples of the hetero atom include an oxygen atom, a nitrogen atom, and a sulfur atom. Examples of the heterocycloalkenyl group include a dihydrofuryl group, an imidazolyl group, a pyrrolinyl group, and a pyrazolinyl group.

  This heterocycloalkenyl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent. Examples of the substituent include the groups described above as substituents for the cycloalkyl group.

  In the present specification, the “aryl group” used alone or as part of another group represents an aromatic hydrocarbon group, and two or more rings may be condensed. Although there is no restriction | limiting in particular in carbon number of an aryl group, Preferably it is C5-C14, More preferably, it is C6-C10. Examples of the aryl group include a phenyl group, an indenyl group, a naphthyl group, a phenanthryl group, and an anthryl group.

  This aryl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent. Examples of the substituent include an alkyl group, an alkoxy group, an alkoxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an acyl group, an acylalkyl group, an alkylthio group, an alkylenedioxy group, a halogen atom, an amino group, a nitro group, and a cyano group. , A thiol group, a hydroxyl group and the like.

  In the present specification, a “heteroaryl group” used alone or as part of another group refers to a group in which one or more carbon atoms on the ring of the aryl group are substituted with a heteroatom. Examples of the hetero atom include an oxygen atom, a nitrogen atom, and a sulfur atom. Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, triazinyl, tetrazolyl, oxazolyl, indolizinyl, indolyl, isoindolyl, Indazolyl group, purinyl group, quinolidinyl group, isoquinolyl group, quinolyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, oxadiazolyl group, thiazolyl group, thiadiazolyl group, benzimidazolyl group, furyl group, thienyl group and the like can be mentioned.

  This heteroaryl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent. Examples of the substituent include the groups described above as substituents for the aryl group.

[Acetaldehyde]
In the method for producing the asymmetric catalyst Michael reaction product of the present invention, acetaldehyde is used as a nucleophile. Since acetaldehyde is easily available, a product can be obtained at low cost even when the asymmetric catalytic Michael reaction is performed on an industrial scale.

  Acetaldehyde is highly reactive both as a nucleophile and as an electrophile and is generally not suitable as a nucleophile for the asymmetric catalytic Michael reaction. In the present invention, a certain catalyst is used as the asymmetric catalyst. Therefore, even if acetaldehyde is used, only a desired reaction product can be produced with high enantioselectivity and reaction efficiency.

[Asymmetric catalyst represented by general formula (2)]
In the method for producing the asymmetric catalyst Michael reaction product of the present invention, a catalyst represented by the general formula (2) is used as the catalyst. In the general formula (2), R ² and R ³ are each independently an aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group which may have a substituent. A group, an alkyl group, an alkenyl group, or an alkynyl group;

The substituent that R ² and R ³ may have is not particularly limited, and may be an electron withdrawing group or an electron donating group.

The electron donating group which is a substituent that R ² and R ³ may have is not particularly limited, but is an alkyl group, an alkoxy group, an alkylthio group, an aryloxy group, an arylthio group, a dialkyl. Mention may be made of amino groups, alkylamino groups, amino groups, diarylamino groups, arylamino groups and alkylarylamino groups.

Further, the electron withdrawing group which is a substituent which R ² and R ³ may have is not particularly limited, but is an acyl group, a nitro group, a cyano group, a carboxyl group, a thiocarboxyl. A group, a sulfo group, an alkoxycarbonyl group, and a carbamoyl group.

In the general formula (2), R ⁴ represents a silyl group or an alkyl group.

In the present specification, the “silyl group” refers to a group represented by H ₃ Si— or a group in which one or more hydrogen atoms of this group are substituted with an alkyl group, an aryl group, or the like. Examples of the silyl group include trimethylsilyl (TMS) group, triethylsilyl (TES) group, t-butyldimethylsilyl (TBS) group, triisopropylsilyl (TIPS) group, t-butyldiphenylsilyl (TBDPS) group, and the like. It is done.

In the general formula (2), R ⁵ represents a hydroxyl-protecting group, and n represents 0 or 1.

  As the hydroxyl-protecting group, commonly used protecting groups such as an alkyl group, an acetyl group, and a silyl group can be used.

When n = 1, the substitution position of the OR ⁵ group may be either the 3-position or the 4-position.

As this asymmetric catalyst, those in which R ² and R ³ are aryl groups optionally substituted by an electron donating group and R ⁶ is a silyl group are preferable.

As such a compound, specifically, a compound represented by the following chemical formula (2-1) in which R ² and R ³ are phenyl groups, R ⁴ is TMS, and n is 0, or an enantiomer (2-2) thereof Can be mentioned.

  The asymmetric catalyst represented by the general formula (2) can be produced using proline or a derivative thereof (3-hydroxyproline, 4-hydroxyproline, etc.) as a starting material ((a) H. Gotoh, R. et al. Masui, H. Ogino, M. Shoji, Y. Hayashi, Angew. Chem. Int. Ed. 2006, 45, p. 6853, (b) Y. Hayashi, T. Okano, S. Arakeke, D. Hazelard, Angew. Chem. Int. Ed. 2007, 46, p. 4922, (c) H. Gotoh, Y. Hayashi, Org. Lett. 2007, 9, p. 2859, etc.).

[Reaction conditions]
As described above, in the method for producing an asymmetric catalytic Michael reaction product according to the present invention, the electron-deficient alkene represented by the general formula (1) and acetaldehyde are represented by the general formula (2). The reaction is carried out in the presence of an asymmetric catalyst or an enantiomer thereof to obtain a compound represented by the above general formula (3) or an enantiomer thereof.

  In addition, when the compound represented by the above general formula (2) is used as an asymmetric catalyst, the compound represented by the above general formula (3) is obtained, and the compound represented by the above general formula (2) When the enantiomer of is used as an asymmetric catalyst, the enantiomer of the compound represented by the general formula (3) is obtained.

  The amount of acetaldehyde used is preferably 1 equivalent to 50 equivalents and more preferably 3 equivalents to 20 equivalents with respect to the electron-deficient alkene represented by the general formula (1). The amount of the asymmetric catalyst used is preferably 0.01 equivalents or more and 1 equivalents or less, and 0.05 equivalents or more and 0.3 equivalents or less with respect to the electron-deficient alkene represented by the general formula (1). More preferably.

  This reaction may be performed in an organic solvent or in water. Examples of the organic solvent include 1,4-dioxane, hexane, methanol, dichloromethane, chloroform, diethyl ether, ethyl acetate, dimethoxyethane (DME), acetone, acetonitrile, benzene, toluene, tetrahydrofuran (THF), dimethylformamide (DMF), and the like. Is mentioned. Among these, 1,4-dioxane is particularly preferable.

  The reaction temperature is preferably from −10 ° C. to 40 ° C., more preferably from 5 ° C. to 30 ° C. If the reaction temperature is too high, side reactions are liable to occur and the yield may be reduced. On the other hand, when the reaction temperature is too low, the reaction rate decreases.

  The reaction time depends on conditions such as the electron-deficient alkene, acetaldehyde, and asymmetric catalyst used, but is usually 10 to 80 hours.

<Method for producing pharmaceutical compound>
The method for producing a pharmaceutical compound of the present invention utilizes the above-described method for producing an asymmetric catalyst Michael reaction product.

  For example, a compound represented by the following structural formula (4) and acetaldehyde are reacted in the presence of an asymmetric catalyst represented by the following general formula (2), and the resulting structural formula (5) is obtained. A compound represented by the following structural formula (7) is obtained by oxidizing the compound obtained to obtain a compound represented by the following structural formula (6) and then reducing the compound represented by the structural formula (6). A compound can be obtained.

［式中、Ｒ^２及びＲ^３は、それぞれ独立に、置換基を有していてもよいアリール基、ヘテロアリール基、シクロアルキル基、ヘテロシクロアルキル基、シクロアルケニル基、ヘテロシクロアルケニル基、アルキル基、アルケニル基、又はアルキニル基を示し、Ｒ^４は、シリル基、又はアルキル基を示し、Ｒ^５は、水酸基の保護基を示し、ｎは、０又は１を示す。］

[Wherein, R ² and R ³ each independently represents an aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, alkyl which may have a substituent. A group, an alkenyl group, or an alkynyl group; R ⁴ represents a silyl group or an alkyl group; R ⁵ represents a hydroxyl-protecting group; and n represents 0 or 1. ]

The compound represented by the structural formula (4) is an electron-deficient alkene represented by the general formula (1), wherein X is a nitro group, Y is a hydrogen atom, and R ¹ is a p-chlorophenyl group. . By reacting the electron-deficient alkene and acetaldehyde in the presence of the asymmetric catalyst represented by the general formula (2), a compound represented by the structural formula (5) can be obtained. Then, after oxidizing the aldehyde group of the compound represented by the structural formula (5) to obtain the compound represented by the structural formula (6), the nitro group of the compound represented by the structural formula (6) is obtained. Is reduced to an amino group to obtain a pharmaceutical compound represented by the structural formula (7).

  Conventionally known methods can be used for oxidation of the aldehyde group and reduction of the nitro group.

  The pharmaceutical compound represented by the structural formula (8) thus obtained is called baclofen and is known as an antispasmodic agent.

  Conventionally, several methods for producing baclofen have been known, but each of them requires a multi-step reaction, and a more efficient production method has been desired ((a) P. Camps, D. Munoz-Torrero). , L. Sanchez, Tetrahedron: Asymmetry 2004, 15, p. 2039, (b) F. Feluga, V. Gombac, G. Pitaco, E. Valentin, Tetrahedron: Asymmetry 2005, 16, p. NJ Convine, M.E. Popkin, Synlett 2006, p. 1589, etc.).

  On the other hand, according to the method described above, after obtaining the compound represented by the structural formula (5) by the asymmetric catalytic Michael reaction, baclofen can be obtained by a reaction of only two steps.

  Further, a compound represented by the following structural formula (8) and acetaldehyde are reacted in the presence of an asymmetric catalyst represented by the following general formula (2 ′), and the obtained structural formula (9) represents The compound represented by the following structural formula (10) is obtained by oxidizing the compound represented by the following structural formula (10), and then reduced by the compound represented by the structural formula (10). Pharmaceutical compounds can be obtained.

［式中、Ｒ^２及びＲ^３は、それぞれ独立に、置換基を有していてもよいアリール基、ヘテロアリール基、シクロアルキル基、ヘテロシクロアルキル基、シクロアルケニル基、ヘテロシクロアルケニル基、アルキル基、アルケニル基、又はアルキニル基を示し、Ｒ^４は、シリル基、又はアルキル基を示し、Ｒ^５は、水酸基の保護基を示し、ｎは、０又は１を示す。］

[Wherein, R ² and R ³ each independently represents an aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, alkyl which may have a substituent. A group, an alkenyl group, or an alkynyl group; R ⁴ represents a silyl group or an alkyl group; R ⁵ represents a hydroxyl-protecting group; and n represents 0 or 1. ]

The compound represented by the structural formula (8) is an electron-deficient alkene represented by the general formula (1), wherein X is a nitro group, Y is a hydrogen atom, and R ¹ is an isobutyl group. By reacting the electron-deficient alkene and acetaldehyde in the presence of the asymmetric catalyst represented by the general formula (2 ′), the compound represented by the structural formula (9) can be obtained. Then, after oxidizing the aldehyde group of the compound represented by the structural formula (9) to obtain the compound represented by the structural formula (10), the nitro group of the compound represented by the structural formula (10) is obtained. Is reduced to an amino group to obtain a pharmaceutical compound represented by the structural formula (11).

  Conventionally known methods can be used for oxidation of the aldehyde group and reduction of the nitro group.

  The pharmaceutical compound represented by the above structural formula (11) thus obtained is called pregabalin and is known as an antiepileptic agent.

  Conventionally, several methods for producing pregabalin are known, but each of them requires a multi-step reaction, and a more efficient production method has been desired (T. Mita, K. Sasaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2005, 127, p. 514, etc.).

  On the other hand, according to the method described above, after obtaining the compound represented by the structural formula (9) by the asymmetric catalytic Michael reaction, pregabalin can be obtained by a reaction of only two steps.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples at all.

<Catalyst used in this example>
In this example, proline and the following two types of catalysts were used.

  These catalysts were purchased from Aldrich (Product Nos. 677183 and 368199 in order from Catalyst 1). The enantiomers of catalysts 1 and 2 are also commercially available from Aldrich (product numbers 677191 and 382337 in order from the enantiomer of catalyst 1).

<Test Example 1>
As shown in the following reaction formula, β-nitrostyrene and acetaldehyde were reacted in the presence of proline and the above catalysts 1 and 2 to obtain a Michael adduct.

  Unless otherwise specified, the above reaction is performed by reacting β-nitrostyrene (0.75 mmol) and acetaldehyde (7.5 mmol) at room temperature in a solvent (150 μl) containing a catalyst (0.075 mmol) for 18 hours. Was done. The results are shown in Table 1.

  As can be seen from Table 1, the yield and enantioselectivity are higher when the Michael reaction is performed using catalyst 1 (entries 2 and 4 to 7). It can also be seen that 1,4-dioxane is most preferred as the solvent.

<Test Example 2>
As shown in the following reaction formula, various nitroalkenes and acetaldehyde were reacted in the presence of the catalyst 1 to obtain a Michael adduct.

  Unless otherwise specified, the above reaction was performed by reacting nitroalkene (0.75 mmol) and acetaldehyde (7.5 mmol) in 1,4-dioxane (150 μl) containing catalyst 1 (0.075 mmol) at room temperature. It was done by letting. The results are shown in Table 2.

  As can be seen from Table 2, good results were obtained not only when R was a phenyl group (entry 1) but also when it was a naphthyl group (entry 2). Further, when R is an aromatic group substituted with an electron donating group (entry 3), when R is an aromatic group substituted with an electron withdrawing group (entries 4, 5, 6, And 7) also show that the yield and enantioselectivity are both high. Also, good results were obtained both when R is a heteroaryl group (entry 8) and when R is an alkyl group (entries 9 and 10).

  Hereinafter, the manufacturing method and identification result of the Michael adduct in entries 1 to 10 in Table 2 are shown.

[Production Method of (S) -4-Nitro-3-phenylbutanal (Entry 1)]
In a test tube cooled to 4 ° C. and sealed (ACE GLASS, product number 5027-05), catalyst 1 (24.4 mg, 0.075 mmol) and β-nitrostyrene (111.8 mg, 0.75 mmol). ) Was dissolved in 1,4-dioxane (150 μl) and to this was added acetaldehyde (420 μl, 7.5 mmol). After stirring the reaction mixture at room temperature for 18 hours, the reaction mixture was cooled with 1N hydrochloric acid. Extraction was performed three times with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. After filtration, concentration was performed under vacuum. Purification was performed using column chromatography with an ethyl acetate: hexane gradient of 1:20 to 1: 6.

¹ H NMR (CDCl ₃ ) δ 2.94 (1H, dd, J = 1.2, 2.0 Hz), 2.96 (1H, dd, J = 1.2, 2.0 Hz), 4.08 (1H , Quint, J = 7.2 Hz), 4.62 (1H, dd, J = 7.6, 12.4 Hz), 4.68 (1H, dd, J = 7.6, 12.4 Hz), 7. 20-7.40 (5H, m), 9.70 (1H, s);
¹³ C NMR (CDCl ₃ ) δ 37.9, 46.4, 79.4, 127.4 (2C), 128.1, 129.2 (2C), 138.1, 199.1;
IR (neat) ν 3032, 1723, 1548, 1380, 765, 702 cm ⁻¹ ;
_{^{HRMS (ESI): [M +}} Na] + calculated for C 10 H 11 NO 3 Na: 216.0631, found: 216.0645;
[Α] _D ^22-23 (c 0.71, CHCl ₃ ).
Enantiomeric excess was determined by GLC (Bodman Chiraldex Γ-TA column, 40 ° C., 10 ° C./min gradient, 60 kPa), T _R 1 = 43.1 (minor), T _R 2 = 44.7 (major) min.

[Production method of (S) -3- (2-naphthyl) -4-nitrobutanal (entry 2)]
(S) -3- (2-naphthyl) -4-nitrobutanal was produced in the same manner as in entry 1 except that 2- (β-nitrovinyl) naphthalene was used instead of β-nitrostyrene.

¹ H NMR (CDCl ₃ ) δ 2.99 (1H, dd, J = 7.6, 18.0 Hz), 3.06 (1H, dd, J = 7.2, 18.0 Hz), 4.25 (1H , Quint, J = 6.8 Hz), 4.70 (1H, dd, J = 7.6, 13.6 Hz), 4.75 (1H, dd, J = 7.6, 13.2 Hz), 7. 34 (1H, dd, J = 2.8, 9.2 Hz), 7.43-7.54 (2H, m), 7.69 (1H, s), 7.89-7.89 (3H, m ), 9.72 (1H, s);
¹³ C NMR (CDCl ₃ ) δ 38.1, 46.4, 55.2, 79.7, 114.5, 128.4 (2C), 128.4 (2C), 126.6, 126.7, 127 .8, 129.2, 132.9, 133.3, 135.4, 198.8;
IR (neat) ν 1722, 1550, 1379, 821, 751 cm ⁻¹ ;
_{^{HRMS (ESI): [M +}} Na] + calculated for C 14 H 13 NO 3 Na: 266.0788, found: 266.0770;
^{_{[Α] D 20 -34.3 (c1.6}} , CHCl 3).
The product was converted to the corresponding alcohol with NaBH 4 and enantiomeric excess was determined by HPLC using a Chiralpak AS-H column (10/1 hexane / i-PrOH; flow rate 1.0ml / min, T R 1 = 11.2 (Major), T _R 2 = 11.9 (minor) min).

[Method for producing (S) -3- (4-methoxyphenyl) -4-nitrobutanal (entry 3)]
(S) -3- (4-methoxyphenyl) -4-nitrobutanal was produced in the same manner as in entry 1 except that 4-methoxy-β-nitrostyrene was used instead of β-nitrostyrene.

¹ H NMR (CDCl ₃ ) δ 2.90 (2H, d, J = 7.6 Hz), 3.78 (3H, s), 4.02 (1H, quint, J = 7.2 Hz), 4.57 ( 1H, dd, J = 7.6, 12.4 Hz), 4.64 (1H, dd, J = 7.6, 12.4 Hz), 6.86 (2H, d, J = 8.8 Hz), 7 .14 (2H, d, J = 8.4 Hz), 9.69 (1H, s);
¹³ C NMR (CDCl ₃ ) δ 37.3, 46.5, 55.2, 79.7, 114.5 (2C), 128.4 (2C), 129.9, 159.2, 199.0;
IR (neat) ν2921, 2839, 1716, 1556, 1515, 1252, 1031, 833 cm ⁻¹ ;
_{^{HRMS (ESI): [M +}} Na] + calculated for C 11 H 13 NO 4 Na: 246.0733, found: 246.0737;
^{_{[Α] D 28 -22 (c1.5}} , CHCl 3).
The product was converted to the corresponding alcohol with NaBH 4 and enantiomeric excess was determined by HPLC using a Chiralpak AS-H column (10/1 hexane / i-PrOH; flow rate 1.0ml / min, T R 1 = 17.6 (Major), T _R 2 = 22.3 (minor) min).

[Method for producing (S) -3- (4-bromophenyl) -4-nitrobutanal (entry 4)]
(S) -3- (4-Bromophenyl) -4-nitrobutanal was produced in the same manner as in entry 1 except that 4-bromo-β-nitrostyrene was used instead of β-nitrostyrene.

¹ H NMR (CDCl ₃ ) δ 2.94 (2H, d, J = 6.8 Hz), 4.05 (1H, quint, J = 7.2 Hz), 4.59 (1H, dd, J = 7.6) , 12.4 Hz), 4.67 (1H, dd, J = 6.8, 12.4 Hz), 7.11 (2H, d, J = 8.4 Hz), 7.47 (2H, d, J = 8.4 Hz), 9.70 (1 H, s);
¹³ C NMR (CDCl ₃ ) δ 37.3, 46.3, 79.0, 122.1, 129.1 (2C), 132.3 (2C), 137.2, 198.3;
IR (neat) ν2922, 2847, 2736, 1715, 1556, 1488, 1378, 1074, 1011, 1113, 727, 532 cm ⁻¹ ;
HRMS (ESI): [M + Na] ⁺ calculated for C ₁₀ H ₁₀ BrNO ₃ Na: 293.9736, found: 293.9717;
^{_{[Α] D 28 -34 (c0.93}} , CHCl 3).
The product was converted to the corresponding alcohol with NaBH 4 and enantiomers were separated by HPLC using a Chiralpak IC column (10/1 hexane / i-PrOH; flow rate 1.0ml / min, T R 1 = 11.1 (minor) , T _R 2 = 11.7 (major) min).

[Method for producing (S) -3- (4-chlorophenyl) -4-nitrobutanal (entry 5)]
(S) -3- (4-Chlorophenyl) -4-nitrobutanal was produced in the same manner as in entry 1 except that 4-chloro-β-nitrostyrene was used instead of β-nitrostyrene.

¹ H NMR (CDCl ₃ ) δ 2.94 (2H, d, J = 6.8 Hz), 4.06 (1H, quint, J = 6.8 Hz), 4.59 (1H, dd, J = 7.2) , 12.0 Hz), 4.67 (1H, dd, J = 7.2, 12.0 Hz), 7.18 (2H, d, J = 8.4 Hz), 7.32 (2H, d, J = 9.2 Hz), 9.71 (1H, s);
¹³ C NMR (CDCl ₃ ) δ 37.3, 46.3, 79.1, 128.8 (2C), 129.4 (2C), 134.0, 136.7, 198.3;
IR (neat) ν 1723, 1551, 1494, 1379, 1094, 1014, 829 cm ⁻¹ ;
_{^{HRMS (ESI): [M +}} Na] + calculated for C 10 H 10 ClNO 3 Na: 250.0241, found: 250.0229;
^{_{[Α] D 28 -24 (c0.83}} , CHCl 3).
The product was converted to the corresponding alcohol with NaBH 4 and enantiomeric excess was determined by HPLC using a Chiralpak IC column (10/1 hexane / i-PrOH; flow rate 1.0ml / min, T R 1 = 11.4 (minor ), T _R 2 = 12.1 (major) min).

This (S) -3- (4-chlorophenyl) -4-nitrobutanal corresponds to a compound represented by the following structural formula (5), and this compound is described in the literature (P. Camps, D. Munoz-Torrero). , L. Sanchez, Tetrahedron: Asymmetry 2004, 15, 2039), which is represented by the following structural formula (7) by oxidation with sodium chlorite and then reduction using a Raney nickel catalyst. Baclofen can be obtained.

[Method for producing (S) -4-nitro-3- (4-nitrophenyl) butanal (entry 6)]
(S) -4-nitro-3- (4-nitrophenyl) butanal was produced in the same manner as in entry 1 except that 4-nitro-β-nitrostyrene was used instead of β-nitrostyrene.

¹ H NMR (CDCl ₃ ) δ 3.03 (2H, d, J = 6.8 Hz), 4.21 (1H, quint, J = 7.2 Hz), 4.67 (1H, dd, J = 8.4) , 12.8 Hz), 4.75 (1H, dd, J = 13.2 Hz), 7.42 (2H, d, J = 8.8 Hz), 8.20 (2H, d, J = 8.8 Hz) , 9.73 (1H, s);
¹³ C NMR (CDCl ₃ ) δ 37.4, 46.1, 78.4, 124.3 (2C), 128.6 (2C), 145.7, 147.6, 197.6;
IR (neat) ν3081, 2922, 2851, 1719, 1556, 1519 cm ⁻¹ ;
HRMS (ESI): [M + Na] ⁺ calculated for C ₁₀ H ₁₀ N ₂ O ₅ Na: 261.0482, found: 261.0489;
^{_{[Α] D 28 -19 (c1.9}} , CHCl 3).
The product was converted to the corresponding alcohol with NaBH 4 and enantiomeric excess was determined by HPLC using a Chiralcel OJ-H column (10/1 hexane / i-PrOH; flow rate 1.0ml / min, T R 1 = 78.0 (Major), T _R 2 = 97.8 (minor) min).

[Method for producing (S) -4-nitro-3- (4-trifluoromethylphenyl) butanal (entry 7)]
(S) -4-nitro-3- (4-trifluoromethylphenyl) butanal was prepared in the same manner as in entry 1 except that β-nitro-4-trifluoromethylstyrene was used instead of β-nitrostyrene. Manufactured.

¹ H NMR (CDCl ₃ ): δ 2.99 (2H, d, J = 6.8 Hz), 4.16 (1 H, quint, J = 7.2 Hz), 4.65 (1H, dd, J = 4. 8, 8.0 Hz), 4.72 (1H, dd, J = 5.6, 7.2 Hz), 7.38 (2H, d, J = 8.4 Hz), 7.61 (2H, d, J = 8.4 Hz), 9.73 (1 H, s);
¹³ C NMR (CDCl ₃ ): δ 37.6, 46.2, 78.8, 125.1, 126.1 (2C), 127.9 (2C), 130.3, 142.4, 197.9;
IR (neat): ν 2385, 2311, 1724, 1554, 1379, 1326, 1165, 1117, 1068, 840 cm ⁻¹ ; HRMS (ESI): [M−H] calculated for C ₁₁ H ₉ F ₃ NO ₃ : 260. 0529, found: 260.0527;
[Α] _D ²¹ = −6.9 (c0.79, MeOH).
The product was converted to the corresponding alcohol with NaBH 4 and enantiomeric excess was determined by HPLC using a Chiralcel OJ-H column (10/1 hexane / i-PrOH; flow rate 1.0ml / min, T R 1 = 13.6 (Major), T _R 2 = 15.2 (minor) min).

[Method for producing (S) -3- (2-furyl) -4-nitrobutanal (entry 8)]
(S) -3- (2-furyl) -4-nitrobutanal was produced in the same manner as in entry 1 except that 2- (β-nitrovinyl) furan was used instead of β-nitrostyrene.

¹ H NMR (CDCl ₃ ) δ 2.93 (1H, dd, J = 7.2, 18.0 Hz), 3.01 (1H, ddd, J = 1.2, 7.2, 18.4 Hz), 4 .18 (1H, quint, J = 6.8 Hz), 4.66 (1H, dd, J = 6.4, 12.4 Hz), 4.71 (1H, dd, J = 7.2, 12.8 Hz) ), 6.18 (1H, d, J = 2.8 Hz), 6.31 (1H, dd, J = 2.0, 3.2 Hz), 7.35 (1H, d, J = 1.2 Hz) , 9.76 (1H, s);
¹³ C NMR (CDCl ₃ ) δ 31.7, 43.8, 76.9, 107.4, 110.5, 142.5, 151.0, 198.5;
IR (neat) ν 1724, 1555, 1376, 748 cm ⁻¹ ;
HRMS (ESI): [M + Na] ⁺ calculated for C ₈ H ₉ NO ₄ Na: 206.0424, found: 206.0422;
^{_{[Α] D 28 -23 (c0.27}} , CHCl 3).
Enantiomeric excision determined by GLC (Bodman Chiraldex Γ-TA column, 40 ° C., 10 ° C./min gradient, 60 kPa, T _R 1 = 20.2 (minor), T _R 2 = 20.7 (major) min).

[Method for producing (R) -3- (nitromethyl) heptanal (entry 9)]
(R) -3- (nitromethyl) heptanal was produced in the same manner as in entry 1 except that 1-nitro-1-hexene was used instead of β-nitrostyrene.

¹ H NMR (CDCl ₃ ) δ 0.90 (3H, t, J = 6.8 Hz), 1.25-1.38 (4H, m), 1.38-1.47 (2H, m), 2. 54-2.67 (2H, m), 2.72 (1H, quint, J = 6.0 Hz), 4.42-4.47 (2H, m), 9.79 (1H, s);
¹³ C NMR (CDCl ₃ ) δ 13.8, 22.5, 28.7, 31.2, 32.0, 45.3, 78.4, 199.9;
IR (neat) ν2931, 1725, 1551, 1382 cm ⁻¹ ;
_{^{HRMS (ESI): [M +}} Na] + calculated for C 8 H 15 NO 3 Na: 196.0944, found: 196.0942;
[Α] _D ²⁸ -5.5 (c0.27, CHCl ₃ ).
Enantiomeric excision determined by GLC (Bodman Chiraldex Γ-TA column, 40 ° C., 10 ° C./min gradient, 60 kPa, T _R 1 = 14.3 (minor), T _R 2 = 14.9 (major) min.)

[Method for producing (R) -5-methyl-3- (nitromethyl) hexanal (entry 10)]
(R) -5-methyl-3- (nitromethyl) hexanal was produced in the same manner as in entry 1 except that 4-methyl-1-nitro-1-pentene was used instead of β-nitrostyrene.

¹ H NMR (CDCl ₃ ) δ 0.90 (3H, d, J = 6.8 Hz), 0.93 (3H, d, J = 6.8 Hz), 1.23-1.31 (2H, m), 1.63 (1H, septet, J = 6.8 Hz), 2.56 (1H, dd, J = 5.6, 18.4 Hz), 2.66 (1H, dd, J = 6.8, 18. 4 Hz), 2.77 (1 H, quint, J = 6.4 Hz), 4.41 (1 H, dd, J = 6.4, 12.4 Hz), 4.45 (1 H, dd, J = 7.6) , 12.0 Hz), 9.78 (1H, s);
¹³ C NMR (CDCl ₃ ) δ 22.3 (2C), 25.1, 29.9, 40.6, 45.5, 78.5, 200.0;
IR (neat) ν 2959, 1725, 1551, 1384 cm ⁻¹ ;
HRMS (ESI): [M + Na] ⁺ calculated for C ₈ H ₁₅ NO ₃ Na: 196.0944, found: 196.0934;
^{_{[Α] D 28 -3.7 (c1.3}} , CHCl 3).
Enantiomeric excess was determined by GLC (Bodman Chiraldex Γ-TA column, 40 ° C., 10 ° C./min gradient, 60 kPa, T _R 1 = 12.2 (minor), T _R 2 = 12.4 (major) min).

This (R) -5-methyl-3- (nitromethyl) hexanal corresponds to the enantiomer of the compound represented by the following structural formula (9), but is represented by the following structural formula (9) using the enantiomer of the catalyst 1. After obtaining the compound, the compound represented by the structural formula (9) is described in the literature (H. Goto, H. Ishikawa, Y. Hayashi, Org. Lett. 2007, 9, 5307). Pregabalin represented by the following structural formula (11) can be obtained by oxidizing with sodium chlorite and then reducing with a palladium catalyst.

Claims (5)

An electron-deficient alkene represented by the following general formula (1) and acetaldehyde are reacted in the presence of an asymmetric catalyst represented by the following general formula (2) or an enantiomer thereof, and represented by the following general formula (3). A process for producing an asymmetric catalytic Michael reaction product, characterized in that the compound or enantiomer thereof is obtained.

[Wherein, X represents an electron-withdrawing group, Y represents a hydrogen atom or an electron-withdrawing group, R ¹ represents a monovalent organic group, and R ² and R ³ are each independent. Represents an optionally substituted aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, alkyl group, alkenyl group, or alkynyl group, and R ⁴ Represents a silyl group or an alkyl group, R ⁵ represents a hydroxyl-protecting group, and n represents 0 or 1. ] 2. The non-reactive compound according to claim 1, wherein in the general formula (2), R ² and R ³ are aryl groups optionally substituted by an electron donating group, and R ⁴ is a silyl group. A method for producing a simultaneous catalytic Michael reaction product.   The electron-donating group is a group consisting of an alkyl group, an alkoxy group, an alkylthio group, an aryloxy group, an arylthio group, a dialkylamino group, an alkylamino group, an amino group, a diarylamino group, an arylamino group, and an alkylarylamino group. The asymmetric catalyst Michael reaction product according to claim 2, which is at least one selected from the group consisting of: The compound represented by the following structural formula (4) is reacted with acetaldehyde in the presence of the asymmetric catalyst represented by the following general formula (2), and the resulting structural formula (5) is obtained. The compound is oxidized to obtain a compound represented by the following structural formula (6), and then the compound represented by the structural formula (6) is reduced to obtain a pharmaceutical compound represented by the following structural formula (7). A method for producing a pharmaceutical compound, comprising:

[Wherein, R ² and R ³ each independently represents an aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, alkyl which may have a substituent. A group, an alkenyl group, or an alkynyl group; R ⁴ represents a silyl group or an alkyl group; R ⁵ represents a hydroxyl-protecting group; and n represents 0 or 1. ] A compound represented by the following structural formula (8) is reacted with acetaldehyde in the presence of an asymmetric catalyst represented by the following general formula (2 ′), and the resulting structural formula (9) is obtained. To obtain a compound represented by the following structural formula (10), and then reduce the compound represented by the structural formula (10) to obtain a pharmaceutical compound represented by the following structural formula (11). A process for producing a pharmaceutical compound, characterized in that it is obtained.

[Wherein, R ² and R ³ each independently represents an aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, alkyl which may have a substituent. A group, an alkenyl group, or an alkynyl group; R ⁴ represents a silyl group or an alkyl group; R ⁵ represents a hydroxyl-protecting group; and n represents 0 or 1. ]