JP5234901B2 - Method for producing asymmetric catalyst Michael reaction product - Google Patents

Description

  The present invention relates to a method for producing an asymmetric catalytic Michael reaction product, and more specifically, a method for producing an asymmetric catalytic Michael reaction product for obtaining a corresponding Michael adduct from an α, β-unsaturated aldehyde and a nitroalkane. About. The present invention also relates to a method for producing a pharmaceutical compound in which such asymmetric catalytic Michael reaction is involved.

  The Michael reaction is an important carbon-carbon bond formation reaction in organic synthesis. In particular, the asymmetric catalytic Michael reaction for obtaining a large amount of an optically active substance from a small amount of an asymmetric source is being actively studied all over the world. Among these, the Michael adduct obtained by the asymmetric catalytic Michael reaction between an electron-deficient alkene and a nitroalkane is important in terms of synthetic chemistry because it can be an intermediate of compounds such as pharmaceuticals and agricultural chemicals.

  Until now, most electron-deficient alkenes use α, β-unsaturated ketones and α, β-unsaturated esters, and few use α, β-unsaturated aldehydes. This is probably because the reactivity of aldehyde is high and the 1,2-addition reaction occurs competitively, making the target Michael reaction difficult.

  In recent years, synthetic reactions using organic catalysts have been actively developed, and Michael reactions using α, β-unsaturated aldehydes have been reported (Non-patent Document 1). To 4).

  For example, Non-Patent Documents 1 to 3 disclose a technique in which a nitroalkane is once converted to a corresponding silylnitronate and then reacted with an α, β-unsaturated aldehyde in the presence of a phase transfer catalyst. However, in the techniques described in Non-Patent Documents 1 to 3, it is necessary to induce nitroalkane to the corresponding silyl nitronate, and it is impossible to use simple and versatile nitromethane.

Non-Patent Document 4 discloses a technique of reacting an α, β-unsaturated aldehyde with a nitroalkane using an organic catalyst having an imidazole skeleton. However, in the technique described in Non-Patent Document 4, when nitromethane was used, the asymmetric yield was as low as 47% ee.
Ooi, T .; Doda, K .; Maruoka, K .; J .; Am. Chem. Soc. 2003, 125, p. 9022 Ooi, T .; Morimoto, K .; Doda, K .; Maruoka, K .; Chem. Lett. 2004, 33, p. 824 Ooi, T .; Doda, K .; Takeda, S .; Maruoka, K .; Tetrahedron Lett. 2006, 47, p. 145 Hojabri, L.H. Hartikka, A .; Mohghdam, F .; M.M. Arvidsson, P .; I. Adv. Synth. Catal. 2007, 349, p. 740

  Therefore, the present invention provides a method for producing an asymmetric catalytic Michael reaction product capable of obtaining a corresponding Michael adduct with a high asymmetric yield from an α, β-unsaturated aldehyde and a nitroalkane such as nitromethane. The purpose is to provide. In addition, an object of the present invention is to provide a method for producing a pharmaceutical compound in which such asymmetric catalytic Michael reaction is involved.

  This inventor repeated earnest research in order to solve the said subject. As a result, it has been found that the above problems can be solved by using a specific catalyst, and the present invention has been completed. More specifically, the present invention provides the following.

［式中、Ｒ^１は、置換基を有していてもよいアルキル基、アルケニル基、アルキニル基、アルコキシアルキル基、アルコキシアルケニル基、アルコキシアルキニル基、アルコキシカルボニル基、アルコキシカルボニルアルキル基、アルコキシカルボニルアルケニル基、アルコキシカルボニルアルキニル基、アシル基、アシルアルキル基、アシルアルケニル基、アシルアルキニル基、アミド基、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、アリール基、ヘテロアリール基、シクロアルキルアルキル基、シクロアルキルアルケニル基、シクロアルキルアルキニル基、ヘテロシクロアルキルアルキル基、ヘテロシクロアルキルアルケニル基、ヘテロシクロアルキルアルキニル基、シクロアルケニルアルキル基、シクロアルケニルアルケニル基、シクロアルケニルアルキニル基、ヘテロシクロアルケニルアルキル基、ヘテロシクロアルケニルアルケニル基、ヘテロシクロアルケニルアルキニル基、アリールアルキル基、アリールアルケニル基、アリールアルキニル基、ヘテロアリールアルキル基、ヘテロアリールアルケニル基、又はヘテロアリールアルキニル基を示し、Ｒ^２，Ｒ^３は、それぞれ独立に水素原子又はアルキル基を示し、Ｒ^４，Ｒ^５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^６は、水素原子、Ｈ _３ Ｓｉ−、Ｈ _３ Ｓｉ−の１以上の水素原子がアルキル基又はアリール基によって置換された基、又はアルキル基を示し、Ｒ^７は、水酸基の保護基を示し、ｎは０又は１を示す。］ (1) An asymmetric catalyst represented by the following general formula (3) comprising an α, β-unsaturated aldehyde represented by the following general formula (1) and a nitroalkane represented by the following general formula (2): Alternatively, the reaction is carried out in the presence of an enantiomer thereof to obtain a compound represented by the following general formula (4) or an enantiomer thereof, and a method for producing an asymmetric catalytic Michael reaction product.

[Wherein, R ¹ represents an alkyl group, alkenyl group, alkynyl group, alkoxyalkyl group, alkoxyalkenyl group, alkoxyalkynyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkenyl group which may have a substituent. 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, heterocycloalkylalkynyl group, cycloalkenyl group Rualkyl group, cycloalkenylalkenyl group, cycloalkenylalkynyl group, heterocycloalkenylalkyl group, heterocycloalkenylalkenyl group, heterocycloalkenylalkynyl group, arylalkyl group, arylalkenyl group, arylalkynyl group, heteroarylalkyl group, heteroaryl An alkenyl group or a heteroarylalkynyl group; R ² and R ³ each independently represents a hydrogen atom or an alkyl group; and R ⁴ and R ⁵ each independently represents an aryl group optionally having a substituent. , A heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, a cycloalkenyl group, a heterocycloalkenyl group, an alkyl group, an alkenyl group, or an alkynyl group, R ⁶ represents a hydrogen atom, H ₃ Si—, H ₃ Si -1 Group hydrogen atom of the above is substituted by an alkyl group or an aryl group, or an alkyl group, R ⁷ represents a protecting group for a hydroxyl group, n represents 0 or 1. ]

(2) In the above general formula (3), R ⁴ and R ⁵ are aryl groups which may have a substituent, and R ⁶ is a silyl group. A method for producing a catalytic Michael reaction product.

  (3) The method for producing an asymmetric catalyst Michael reaction product according to (1) or (2), wherein the nitroalkane represented by the general formula (2) is nitromethane.

［式中、Ｒ^４，Ｒ^５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^６は、水素原子、Ｈ _３ Ｓｉ−、Ｈ _３ Ｓｉ−の１以上の水素原子がアルキル基又はアリール基によって置換された基、又はアルキル基を示し、Ｒ^７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 (5) and nitromethane are reacted in the presence of an asymmetric catalyst represented by the following general formula (3). A compound represented by the following structural formula (7) is obtained by oxidizing the compound represented by the following structural formula (7) and then reduced to a pharmaceutical compound represented by the following structural formula (8). A process for producing a pharmaceutical compound, characterized in that

[Wherein R ⁴ and R ⁵ are each independently an aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, alkyl group which may have a substituent. , An alkenyl group, or an alkynyl group, R ⁶ represents a hydrogen atom, a group in which one or more hydrogen atoms of H ₃ Si—, H ₃ Si— are substituted with an alkyl group or an aryl group , or an alkyl group, R ⁷ represents a hydroxyl-protecting group, and n represents 0 or 1. ]

［式中、Ｒ^４，Ｒ^５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^６は、水素原子、Ｈ _３ Ｓｉ−、Ｈ _３ Ｓｉ−の１以上の水素原子がアルキル基又はアリール基によって置換された基、又はアルキル基を示し、Ｒ^７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 (9) is reacted with nitromethane in the presence of an asymmetric catalyst represented by the following general formula (3 ′). A compound represented by the following structural formula (11) is obtained by oxidizing the compound represented by the following structural formula (11), and then the pharmaceutical represented by the following structural formula (12) by reducing the compound represented by the structural formula (11). A method for producing a pharmaceutical compound comprising obtaining a compound.

[Wherein R ⁴ and R ⁵ are each independently an aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, alkyl group which may have a substituent. , An alkenyl group, or an alkynyl group, R ⁶ represents a hydrogen atom, a group in which one or more hydrogen atoms of H ₃ Si—, H ₃ Si— are substituted with an alkyl group or an aryl group , or an alkyl group, R ⁷ represents a hydroxyl-protecting group, and n represents 0 or 1. ]

(6) A method for producing a pharmaceutical compound, comprising reducing a compound represented by the following structural formula (11) to obtain a pharmaceutical compound represented by the following structural formula (12).

  According to the method for producing an asymmetric catalytic Michael reaction product according to the present invention, a corresponding Michael adduct can be obtained in high asymmetric yield from an α, β-unsaturated aldehyde and a nitroalkane such as nitromethane. It is. Moreover, it is possible to produce a pharmaceutical compound efficiently by utilizing such an asymmetric catalytic Michael reaction.

[Method for producing asymmetric catalyst Michael reaction product]
The method for producing an asymmetric catalytic Michael reaction product according to the present invention comprises an α, β-unsaturated aldehyde represented by the following general formula (1) and a nitroalkane represented by the following general formula (2): The reaction is carried out in the presence of an asymmetric catalyst represented by the following general formula (3) or its enantiomer to obtain a compound represented by the following general formula (4) or its enantiomer.

<Α, β-unsaturated aldehyde represented by general formula (1)>
In the general formula (1), R ¹ is an alkyl group, alkenyl group, alkynyl group, alkoxyalkyl group, alkoxyalkenyl group, alkoxyalkynyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group which may have a substituent. , 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, heterocycloalkylalkynyl group, Chloroalkenylalkyl group, cycloalkenylalkenyl group, cycloalkenylalkynyl group, heterocycloalkenylalkyl group, heterocycloalkenylalkenyl group, heterocycloalkenylalkynyl group, arylalkyl group, arylalkenyl group, arylalkynyl group, heteroarylalkyl group, A heteroarylalkenyl group or a heteroarylalkynyl group;

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-heptyl 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 alkenyl groups include vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, isobutenyl and the like.
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.

<Nitroalkane represented by general formula (2)>
In the general formula (2), R ² and R ³ each independently represent a hydrogen atom or an alkyl group. The alkyl group is as defined above.
As this nitroalkane, those in which R ² and R ³ are both hydrogen atoms, that is, nitromethane are preferred because of their high versatility. According to the method for producing an asymmetric catalytic Michael reaction product according to the present invention, even when nitromethane is used in this way, a Michael adduct can be obtained with a high asymmetric yield.

<Asymmetric catalyst represented by general formula (3)>
In the general formula (3), R ⁴ and R ⁵ 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; These groups are as defined above.
These groups may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent. Examples of the substituent include electron-withdrawing groups such as a halogen atom and a halogenated alkyl group, but unsubstituted one is preferable.

In the general formula (3), R ⁶ represents a hydrogen atom, 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 (3), R ⁷ 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 ⁷ group may be either the 3-position or the 4-position.

As this asymmetric catalyst, those in which R ⁴ and R ⁵ are aryl groups which may have a substituent and R ⁶ is a silyl group are preferred from the viewpoint of the high asymmetric yield.

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

<Reaction conditions, etc.>
As described above, the method for producing an asymmetric catalytic Michael reaction product according to the present invention is represented by the α, β-unsaturated aldehyde represented by the general formula (1) and the general formula (2). Nitroalkane is reacted in the presence of the asymmetric catalyst represented by the above general formula (3) or its enantiomer to obtain the compound represented by the above general formula (4) or its enantiomer.
In addition, when the compound represented by the general formula (3) is used as an asymmetric catalyst, the compound represented by the general formula (4) is obtained, and the compound represented by the general formula (3) is obtained. When the enantiomer of is used as an asymmetric catalyst, the enantiomer of the compound represented by the general formula (4) is obtained.

  The amount of nitroalkane used is preferably 1 to 30 equivalents, more preferably 1 to 5 equivalents, relative to the α, β-unsaturated aldehyde. Moreover, it is preferable that it is 0.01-1 equivalent with respect to (alpha), (beta) -unsaturated aldehyde, and, as for the usage-amount of an asymmetric catalyst, it is more preferable that it is 0.05-0.3 equivalent.

  This reaction may be performed in an organic solvent or without a solvent. Examples of the organic solvent include methanol, dichloromethane, chloroform, diethyl ether, ethyl acetate, dimethoxyethane (DME), acetone, acetonitrile, benzene, toluene, tetrahydrofuran (THF), dimethylformamide (DMF), and the like. Among these, methanol is particularly preferable.

The reaction temperature is preferably -20 to 100 ° C, more preferably 0 to 40 ° 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 the conditions such as α, β-unsaturated aldehyde, nitroalkane, asymmetric catalyst, etc. to be used, but is usually 2 to 120 hours.
The reaction atmosphere is not particularly limited, but an inert gas atmosphere is preferable. Nitrogen, helium, argon, etc. can be used as the inert gas.

In the reaction, in addition to the α, β-unsaturated aldehyde, the nitroalkane, and the asymmetric catalyst, an additive that is a weak acid or a weak base may be added. The reaction rate can be increased by adding such an additive. Examples of the additive include benzoic acid, p-nitrophenol, trifluoroacetic acid, sodium bicarbonate, sodium acetate and the like.
In the α, β-unsaturated aldehyde represented by the general formula (1), when R ¹ is an alkyl group, an arylalkyl group or the like, the reaction may proceed excessively, so the additive may be added. It is preferable not to add.

[Method for producing pharmaceutical compound]
Various pharmaceutical compounds can be produced by using the method for producing the asymmetric catalyst Michael reaction product described above.

  For example, a compound represented by the following structural formula (5) and nitromethane are reacted in the presence of an asymmetric catalyst represented by the following general formula (3), and the resulting structural formula (6) is obtained. The compound represented by the following structural formula (7) is obtained by oxidizing the compound represented by the following structural formula (7), and then the compound represented by the following structural formula (7) is reduced. A compound can be obtained.

The compound represented by the structural formula (5) is ^{one in} which R ¹ is a p-chlorophenyl group in the α, β-unsaturated aldehyde represented by the general formula (1). By reacting the α, β-unsaturated aldehyde and nitromethane in the presence of the asymmetric catalyst represented by the general formula (3), the compound represented by the structural formula (6) is obtained. Then, after oxidizing the aldehyde group of the compound represented by the structural formula (6) to obtain the compound represented by the structural formula (7), the nitro group of the compound represented by the structural formula (7) is obtained. Is reduced to an amino group to obtain a pharmaceutical compound represented by the structural formula (8).
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 all of them require a multi-step reaction, and a more efficient production method has been desired ((a) Camps, P .; Munoz-Torrero, Sanchez, L .; Tetrahedron: Asymmetry; 2004, 15, p.2039, (b) Feluga, F .; Gombac, V .; Pitacco, G .; Valentin, E .; 134, (c) Armstrong, A .; See Convine, NJ; Popkin, M. E .; Synlett; 2006, p. 1589, etc.).
On the other hand, according to the method described above, after obtaining the compound represented by the structural formula (6) 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 (9) and nitromethane are reacted in the presence of an asymmetric catalyst represented by the following general formula (3 ′), and the resulting structural formula (10) is obtained. The compound represented by the following structural formula (11) is obtained by oxidizing the compound represented by the following structural formula (11), and then the compound represented by the structural formula (11) is reduced. Can be obtained.

The compound represented by the structural formula (9) is an α, β-unsaturated aldehyde represented by the general formula (1) in which R ¹ is an isobutyl group. By reacting the α, β-unsaturated aldehyde and nitromethane in the presence of the asymmetric catalyst represented by the general formula (3 ′), a compound represented by the structural formula (10) is obtained. . Then, after oxidizing the aldehyde group of the compound represented by the structural formula (10) to obtain the compound represented by the structural formula (11), the nitro group of the compound represented by the structural formula (11) is obtained. Is reduced to an amino group to obtain a pharmaceutical compound represented by the structural formula (12).
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 (12) thus obtained is called pregabalin and is known as an antiepileptic agent.

Conventionally, several methods for producing pregabalin are known, but all of them require a multi-step reaction, and a more efficient production method has been desired (Mita, T .; Sasaki, K .; Kanai, Shibasaki, M .; 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 (10) by the asymmetric catalytic Michael reaction, pregabalin can be obtained by a reaction of only two steps.

  Examples of the present invention will be described below, but the scope of the present invention is not limited to these examples.

  In this example, the following four types of asymmetric catalysts were used.

  Of these, catalyst 3 and its enantiomer ((S)-(−)-diphenyl-2-pyrrolidinemethanol) were purchased from Aldrich (product numbers 382337, 368199). In addition, catalyst 2 can be prepared according to literature (Li, K .; Zhou, Z .; Wang, L .; Chen, Q .; Zhao, G .; Zhou, Q .; Tang, C .; Tetrahedron: Asymmetry; 2003, 14 , P. 95). Catalyst 1 was produced using (S)-(−)-diphenyl-2-pyrrolidinemethanol as a starting material according to the following reaction formula. Catalyst 1 'was produced in the same manner as Catalyst 1 using Catalyst 3 as a starting material.

<Manufacture of catalyst 1>

  TMSCl (5.1 ml) in DMF (13.9 ml) containing (S)-(−)-diphenyl-2-pyrrolidinemethanol (3.5 g, 13.9 mmol) and imidazole (3.8 g, 55.5 mmol). 41.7 mmol) at 0 ° C. After the reaction solution was stirred at room temperature for 17 hours, a phosphate buffer solution at pH 7.0 at 0 ° C. was added to stop the reaction. And after extracting organic substance 3 times with ethyl acetate, the organic layer (ethyl acetate layer) was dried with anhydrous sodium sulfate. Thereafter, the organic layer was filtered and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate: hexane = 1: 7 to 1: 3) to obtain Catalyst 1 in a yield of 93%.

¹ H NMR (CDCl ₃ ): δ-0.13 (9H, s), 1.28-1.41 (1H, m), 1.47-1.61 (3H, m), 2.71-2 .88 (2H, m), 4.01 (1H, d, J = 7.0 Hz), 7.14-7.28 (6H, m), 7.29-7.35 (2H, d), 7 .39-7.45 (2H, m);
¹³ C NMR (CDCl ₃ ): δ 2.1, 25.0, 27.4, 47.1, 65.3, 83.1, 126.7, 126.9, 127.5, 128.4, 145. 7, 146.7;
IR (neat): ν2954, 1491, 1446, 1250, 1072, 879, 839 cm ⁻¹ ;
HRMS (FAB): [M + H] ⁺ calculated value C ₂₀ H ₂₈ ONSi: 326.1940, found: 326.1967;
^{_{[Α] D 33 -52.4 (c}} = 1.04, CHCl 3).

<Test Example 1>
As shown in the following reaction formula, cinnamaldehyde and nitromethane were reacted in the presence of the catalysts 1 to 3 to obtain a Michael adduct.

  Unless otherwise specified, the above reaction was carried out using cinnamaldehyde (0.6 mmol) and nitromethane (1.8 mmol) at room temperature (25 ° C.) with catalyst (0.06 mmol, 10 mol%) and benzoic acid (0.12 mmol). , 20 mol%). The reaction atmosphere was argon. The results are shown in Table 1.

  As can be seen from Table 1, a Michael adduct can be obtained with a high asymmetric yield by using the catalysts 1 to 3, and the asymmetric yield was particularly high when the catalyst 1 was used (entries 1 to 5). ). As the solvent, methanol was most preferred (entries 5 to 7).

<Test Example 2>
As shown in the following reaction formula, various α, β-unsaturated aldehydes and nitromethane were reacted in the presence of the catalyst 1 to obtain a Michael adduct.

  Unless otherwise specified, the above reaction is carried out by using α, β-unsaturated aldehyde (0.6 mmol) and nitromethane (1.8 mmol) at room temperature (25 ° C.) and catalyst 1 (0.06 mmol, 10 mol%) and The reaction was carried out in a solvent containing benzoic acid (0.12 mmol, 20 mol%). The reaction atmosphere was argon. 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). In addition, when R is an electron-rich group such as 3,4-methylenedioxyphenyl group or p-methoxyphenyl group (entries 3 and 4), p-bromophenyl group, p-chlorophenyl group, p Even in the case of electron-deficient groups such as -nitrophenyl groups (entries 5, 6, 8), a high asymmetric yield was obtained. Good results were also obtained when R was a heteroaryl group (entry 9). When R is an alkyl group, a high asymmetric yield was obtained without adding benzoic acid (entries 11 to 13). The amount of catalyst 1 added could be reduced to 2 mol% with respect to the α, β-unsaturated aldehyde (entry 7).

  Hereinafter, the manufacturing method and identification result (NMR, IR, HRMS) of the Michael adduct in entries 1 to 13 in Table 2 are shown.

<Production of (S) -4-nitro-3-phenylbutanal (entry 1)>
Benzoic acid (14.7 mg, 0.12 mmol, 10 mol%) in methanol (1.2 ml) containing catalyst 1 (19.5 mg, 0.06 mmol, 10 mol%) and cinnamaldehyde (79.2 mg, 0.6 mmol). ) And nitromethane (96 μl, 1.8 mmol) were added at room temperature. The reaction was stirred at room temperature for 18 hours and then quenched with a saturated aqueous solution of NaHCO ₃ . And after extracting organic substance with ethyl acetate, the organic layer (ethyl acetate layer) was dried with anhydrous sodium sulfate. Thereafter, the organic layer was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 20-1: 6) to obtain 4-nitro-3-phenylbutanal (104.3 mg, 0.54 mmol) in a yield of 90%. .

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 C ₁₀ H ₁₁ NO ₃ Na: 216.0631, found: 216.0645;
[Α] _D ^22-23 (c = 0.71, CHCl ₃ ).

The asymmetric yield was determined from the result of GLC (Bodman Chiraldex Γ-TA column, 40 ° C., 10 ° C./min gradient, 60 kPa). T _R 1 = 43.1 min (minor), T _R 2 = 44.7 min (major).

<Production of (S) -3- (2-naphthyl) -4-nitrobutanal (entry 2)>
3- (2-Naphtyl) -4-nitrobutanal was obtained in 94% yield in the same manner as in Entry 1 except that 3- (2-naphthyl) propenal was used instead of cinnamaldehyde.

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): ν1722, 1550, 1379, 821, 751 cm ⁻¹ ;
HRMS (ESI): [M + Na] ⁺ calculated C ₁₄ H ₁₃ NO ₃ Na: 266.0788, found: 266.0770;
^{_{[Α] D 20 -34.3 (c}} = 1.6, CHCl 3).

The asymmetric yield is the result of HPLC (hexane / isopropyl alcohol = 10/1, flow rate 1.0 ml / min) using a Chiralpac AS-H column after converting the obtained compound to the corresponding alcohol with NaBH _4. I asked for it. T _R 1 = 111.2 min (major), T _R 2 = 11.9 min (minor).

<Production of (S) -3- (3,4-methylenedioxyphenyl) -4-nitrobutanal (entry 3)>
The 3- (3,4-methylenedioxyphenyl) -4-nitrobutanal was collected in the same manner as in entry 1 except that 3- (3,4-methylenedioxyphenyl) propenal was used instead of cinnamaldehyde. Obtained at a rate of 80%.

¹ H NMR (CDCl ₃ ): δ2.85-2.91 (2H, m), 3.99 (1H, quint, J = 7.2 Hz), 4.55 (1H, dd, J = 7.6) 12.4 Hz), 4.62 (1H, dd, J = 7.2, 12.4 Hz), 5.94 (2H, s), 6.65-6.71 (2H, m), 6.75 ( 1H, d, J = 7.6 Hz), 9.68 (1H, d, J = 0.8 Hz)
¹³ C NMR (CDCl ₃ ): δ 37.8, 46.5, 79.7, 101.3, 107.5, 108.8, 120.8, 131.7, 147.3, 148.2, 199. 1;
IR (neat): ν 2904, 1722, 1555, 1505, 1489, 1444, 1380, 1249, 1038, 933, 815 cm ⁻¹ ;
HRMS (ESI): [M + Na] ⁺ calculated C ₁₁ H ₁₁ NO ₅ Na: 260.0529, found: 260.0544;
^{_{[Α] D 28 -22 (c}} = 0.37, CHCl 3).

The asymmetric yield is the result of HPLC (hexane / isopropyl alcohol = 10/1, flow rate 1.0 ml / min) using a Chiralpac AS-H column after converting the obtained compound to the corresponding alcohol with NaBH _4. I asked for it. T _R 1 = 24.2 minutes (major), T _R 2 = 45.8 minutes (minor).

<Production of (S) -3- (4-methoxyphenyl) -4-nitrobutanal (entry 4)>
3- (4-methoxyphenyl) -4-nitrobutanal was obtained in a yield of 88% in the same manner as in entry 1, except that 3- (4-methoxyphenyl) propenal was used instead of cinnamaldehyde.

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 C ₁₁ H ₁₃ NO ₄ Na: 246.0733, found: 246.0737;
^{_{[Α] D 28 -22 (c}} = 1.5, CHCl 3).

The asymmetric yield is the result of HPLC (hexane / isopropyl alcohol = 10/1, flow rate 1.0 ml / min) using a Chiralpac AS-H column after converting the obtained compound to the corresponding alcohol with NaBH _4. I asked for it. T _R 1 = 17.6 minutes (major), T _R 2 = 22.3 minutes (minor).

<Production of (S) -3- (4-bromophenyl) -4-nitrobutanal (entry 5)>
3- (4-Bromophenyl) -4-nitrobutanal was obtained in a yield of 87% in the same manner as in entry 1, except that 3- (4-bromophenyl) propenal was used instead of cinnamaldehyde.

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 (1H, 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 C ₁₀ H ₁₀ BrNO ₃ Na: 293.9736, found: 293.9717;
[Α] _D ²⁸ -34 (c = 0.93, CHCl ₃ ).

The asymmetric yield is obtained from the results of HPLC (hexane / isopropyl alcohol = 10/1, flow rate 1.0 ml / min) using a Chiralpac IC column after the obtained compound is converted to the corresponding alcohol by NaBH _4. It was. T _R 1 = 11.1 minutes (minor), T _R 2 = 11.7 minutes (major).

<Production of (S) -3- (4-chlorophenyl) -4-nitrobutanal (entries 6, 7)>
In entry 6, 3- (4-chlorophenyl) -4-nitrobutanal was obtained in a yield of 83% in the same manner as in entry 1, except that 3- (4-chlorophenyl) propenal was used instead of cinnamaldehyde. .
In entry 7, benzoic acid (18.2 mg, 4 mol%) in methanol (1.85 ml) containing catalyst 1 (24.3 mg, 2 mol%) and 3- (4-chlorophenyl) propenal (622 mg, 3.73 mmol). ) And nitromethane (0.60 ml, 3 eq) were added at room temperature. The reaction was stirred at room temperature for 40 hours and then quenched with a saturated aqueous solution of NaHCO ₃ . And after extracting organic substance with ethyl acetate, the organic layer (ethyl acetate layer) was dried with anhydrous sodium sulfate. Thereafter, the organic layer was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 20-1: 6) to give 3- (4-chlorophenyl) -4-nitrobutanal (680 mg, 2.99 mmol) in 80% yield. Obtained.

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 C ₁₀ H ₁₀ ClNO ₃ Na: 250.0241, found: 250.0229;
^{_{[Α] D 28 -24 (c}} = 0.83, CHCl 3).

The asymmetric yield is obtained from the results of HPLC (hexane / isopropyl alcohol = 10/1, flow rate 1.0 ml / min) using a Chiralpac IC column after the obtained compound is converted to the corresponding alcohol by NaBH _4. It was. T _R 1 = 11.4 minutes (minor), T _R 2 = 12.1 minutes (major).

<Production of (S) -4-nitro-3- (4-nitrophenyl) butanal (entry 8)>
4-Nitro-3- (4-nitrophenyl) butanal was obtained in the same manner as in entry 1 except that 3- (4-nitrophenyl) propenal was used instead of cinnamaldehyde and the reaction temperature was 4 ° C. %.

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): ν 3081, 2922, 2851, 1719, 1556, 1519 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{C 10 H 10 N 2 O 5} Na: 261.0482, Found: 261.0489;
^{_{[Α] D 28 -19 (c}} = 1.9, CHCl 3).

The asymmetric yield is the result of HPLC (hexane / isopropyl alcohol = 10/1, flow rate 1.0 ml / min) using a Chiralcel OJ-H column after converting the obtained compound to the corresponding alcohol with NaBH _4. I asked for it. T _R 1 = 78.0 minutes (major), T _R 2 = 97.8 minutes (minor).

<Production of (S) -3- (2-furyl) 4-nitrobutanal (entry 9)>
3- (2-Furyl) 4-nitrobutanal was obtained in a yield of 82% in the same manner as in entry 1, except that 3-furylpropenal was used instead of cinnamaldehyde.

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 (1 H, d, J = 2.8 Hz), 6.31 (1 H, dd, J = 2.0, 3.2 Hz), 7.35 (1 H, 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] + calcd _{C 8 H 9 NO 4 Na:} 206.0424, Found: 206.0422;
^{_{[Α] D 28 -23 (c}} = 0.27, CHCl 3).

The asymmetric yield was determined from the result of GLC (Bodman Chiraldex Γ-TA column, 40 ° C., 10 ° C./min gradient, 60 kPa). T _R 1 = 20.2 min (minor), T _R 2 = 20.7 min (major).

<Production of (R) -3- (nitromethyl) heptanal (entries 10 and 11)>
In entry 10, 3- (nitromethyl) heptanal was obtained in a yield of 53% in the same manner as in entry 1, except that 2-heptenal was used instead of cinnamaldehyde.
In entry 11, 3- (nitromethyl) heptanal was obtained in a yield of 77% in the same manner as in entry 10, except that benzoic acid was not added.

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] + calcd _{C 8 H 15 NO 3 Na:} 196.0944, Found: 196.0942;
[Α] _D ²⁸ -5.5 (c = 0.27, CHCl ₃ ).

The asymmetric yield was determined from the result of GLC (Bodman Chiraldex Γ-TA column, 40 ° C., 10 ° C./min gradient, 60 kPa). T _R 1 = 14.3 min (minor), T _R 2 = 14.9 min (major).

<Production of (R) -5-methyl-3- (nitromethyl) hexanal (entry 12)>
5-methyl-3- (nitromethyl) hexanal was obtained in a yield of 68% in the same manner as in entry 1, except that 5-methyl-2-hexenal was used in place of cinnamaldehyde and benzoic acid was not added.

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 (1H, quint, J = 6.4 Hz), 4.41 (1H, dd, J = 6.4, 12.4 Hz), 4.45 (1H, 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] + calcd _{C 8 H 15 NO 3 Na:} 196.0944, Found: 196.0934;
[Α] _D ²⁸ -3.7 (c = 1.3, CHCl ₃ ).

The asymmetric yield was determined from the result of GLC (Bodman Chiraldex Γ-TA column, 40 ° C., 10 ° C./min gradient, 60 kPa). T _R 1 = 20.2 min (minor), T _R 2 = 20.7 min (major).

<Production of (R) -3- (nitromethyl) -5-phenylpentanal (entry 13)>
3- (Nitromethyl) -5-phenylpentanal was obtained in a yield of 76% in the same manner as in entry 1 except that 5-phenyl-2-pentenal was used instead of cinnamaldehyde and benzoic acid was not added. .

¹ H NMR (CDCl ₃ ): δ 1.77-1.88 (2H, m), 2.65-2.86 (5H, m), 4.56 (2H, d, J = 5.6 Hz), 7 .23 (2H, d, J = 7.6 Hz), 7.24-7.32 (1H, m), 7.37 (2H, t, J = 7.2 Hz), 9.83 (1H, s) ;
¹³ C NMR (CDCl ₃ ): δ 31.5, 32.8, 33.1, 45.2, 78.1, 126.3, 128.2 (2C), 128.6 (2C), 140.4, 199.7;
IR (neat): ν 2938, 1723, 1550, 1384, 750.2, 701.0 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{C 12 H 15 NO 3 Na:} 244.0944, Found: 244.0935;
[Α] _D ²⁸ -1.3 (c = 2.3, CHCl ₃ ).

<Test Example 3>
As shown in the following reaction formula, cinnamaldehyde and nitroethane were reacted in the presence of the catalyst 1 to obtain a Michael adduct.

  The above reaction was carried out in the same manner as in entry 1 of Test Example 2, except that nitroethane was used instead of nitromethane, and the literature ((a) T. Ooi, K. Doda, K. Maruoka .; J. Am. Chem. Soc., 2003, 125, p.9022, (b) L. Hojabri, A. Hartikka, F. M. Moghdamdam, P. I. Arvidsson .; Adv. Synth. Cata .; 2007, 349, p. ).

For the anti-isomer, the asymmetric yield was determined from the results of GLC (Bodman Chiraldex Γ-TA column, 40 ° C., 10 ° C./min gradient, 60 kPa). T _R 1 = 33.3 minutes (major), T _R 2 = 37.0 minutes (minor). ^{_{[Α] D 21 -25 (c}} = 0.39, CHCl 3), literature values ^{_{[α] D 24 -21.4 (c}} = 0.66, CHCl 3).
For the syn isomer, the asymmetric yield was determined from the results of GLC (Bodman Chiraldex Γ-TA column, 40 ° C., 10 ° C./min gradient, 60 kPa). T _R 1 = 33.3 minutes (major), T _R 2 = 37.0 minutes (minor).

  As can be seen from the above results, when nitroethane was used instead of nitromethane, the diastereoselectivity was 1: 1, but a Michael adduct could be obtained with high enantioselectivity.

<Test Example 4>
As shown in the following reaction formula, cinnamaldehyde and 2-nitropropane were reacted in the presence of the catalyst 1 to obtain a Michael adduct.

  The above reaction was carried out in the same manner as in entry 1 of Test Example 2 except that 2-nitropropane was used instead of nitromethane and no solvent was used, and literature (C. E. T. Mitchell, S. E. Brenner) was used. , J. Garcia-Fortanet, S. V. Ley .; Org. Biomol. Chem .; 2006, 4, p.

The asymmetric yield was determined from the result of GLC (Bodman Chiraldex Γ-TA column, 40 ° C., 10 ° C./min gradient, 60 kPa). T _R 1 = 35.8 minutes (major), T _R 2 = 36.7 minutes (minor).

  As can be seen from the above results, even when 2-nitropropane was used instead of nitromethane, a Michael adduct could be obtained with a high asymmetric yield.

<Test Example 5>
As shown in the following reaction formula, a compound represented by the following structural formula (5) and nitromethane are reacted in the presence of the catalyst 1, and the resulting compound represented by the following structural formula (6) is oxidized. Thus, a compound represented by the following structural formula (7) was obtained. By reducing the compound represented by the structural formula (7), a pharmaceutical compound (baclofen) represented by the following structural formula (8) can be obtained.

Specifically, the compound represented by the structural formula (6) was obtained in the same manner as in entry 7 of Test Example 2. The compound represented by the structural formula (6) (52.4 mg, 0.23 mmol), NaH ₂ PO ₃ .2H ₂ O (103.9 mg, 0.69 mmol), and 2-methyl-2-butene (0.13 ml) 1.15 mmol) was dissolved in a mixed solvent of t-butanol (0.35 ml) and water (0.12 ml), and further NaClO ₂ (41.6 mg, 0.46 mmol) was added. The reaction solution was stirred at room temperature for 10 minutes, and then the pH 7.0 phosphate buffer solution was added to stop the reaction. And after extracting organic substance 3 times with ethyl acetate, the organic layer (ethyl acetate layer) was dried with anhydrous sodium sulfate. Thereafter, the organic layer was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain the compound represented by the structural formula (7) (53.8 mg) at a yield of 96%. The spectroscopic data was consistent with the literature (P. Camps, D. Munoz-Torrero, L. Sanchez .; Tetrahedron Asymmetry; 2004, 15, p. 2039).

  The compound represented by the structural formula (7) is converted into Raney nickel as described in, for example, the literature (P. Camps, D. Munoz-Torrero, L. Sanchez .; Tetrahedron Asymmetry; 2004, 15, p. 2039). Baclofen represented by the structural formula (8) can be obtained by reduction using a catalyst.

  Thus, after obtaining the compound represented by the structural formula (6) by the asymmetric catalytic Michael reaction, baclofen can be obtained by a reaction of only two steps.

<Test Example 6>
As shown in the following reaction formula, the compound represented by the following structural formula (9) is reacted with nitromethane in the presence of the catalyst 1 ′, and the resulting compound represented by the following structural formula (10) is oxidized. Then, after obtaining the compound represented by the following structural formula (11), the compound represented by the following structural formula (12) is reduced by reducing the compound represented by the structural formula (11) (pregabalin). Got.

  Specifically, the compound represented by the structural formula (10) was obtained in the same manner as in the entry 12 of Test Example 2 except that the catalyst 1 'was used instead of the catalyst 1. Then, in the same manner as in Test Example 5, the compound represented by the structural formula (11) (662.6 mg) was obtained with a yield of 79%. The identification results (NMR, IR, HRMS) of the compound represented by the structural formula (11) are shown below.

¹ H NMR (CDCl ₃ ): δ 0.90 (6H, t, J = 7.2 Hz), 1.30 (2H, dt, J = 2.8, 7.2 Hz), 1.61-1.72 ( 1H, m), 2.51 (2H, d, J = 6.4 Hz), 2.68 (1H, quint, J = 6.8 Hz), 4.45 (1H, dd, J = 6.0, 12 .0Hz), 4.51 (1H, dd, J = 6.4, 12.0 Hz);
¹³ C NMR (CDCl ₃ ): δ 22.2, 22.5, 25.0, 31.8, 35.6, 40.4, 78.5, 177.1;
IR (neat): ν 3159, 2960, 1712, 1553, 1383 cm ⁻¹ ;
HRMS (ESI): [M−H] calculated C ₈ H ₁₄ NO ₄ : 188.0917, found: 188.0919;
[Α] _D ²² +6.3 (c = 0.69, MeOH).

  Subsequently, the compound (68.1 mg, 0.36 mmol) represented by the structural formula (11) was dissolved in methanol (0.36 ml), and 10% PD / C (20.4 mg) was further added. The reaction mixture was stirred at room temperature for 48 hours under a hydrogen atmosphere, filtered through celite, and the solvent was distilled off under reduced pressure. The white residue was washed with hexane to obtain pregabalin (53.5 mg) represented by the structural formula (12) in a yield of 93%. The identification of the compounds is described in the literature ((a) R. Andruszkiewicz and R. B. Silverman; Synthesis; 1989, 12, p. 953, (b) M. J. Burk, P. D. De Koning, T.M. Grote, M. S. Hoekstra, G. Hoge, R. A. Jennings, W. S. Kissel, T. V. Le, I. C. Lennon, T. A. Mulhen, J. A. Ramsden J. Org.Chem .; 2003, 68, p.5731, (c) MS Hoekstra, DM Sobielay, M. A. Schwindt, T. A. Muther, T. M. M. A. Wade; Grot , B. K. Huckbee, V. S. Hendrickson, L. C. Franklin, E. J. Granger, G. L. Karlick, Org. Proc. Res. Dev., 1997, 1, p.26). I went.

  Thus, after obtaining the compound represented by the structural formula (10) by the asymmetric catalytic Michael reaction, pregabalin could be obtained by a reaction of only two steps.

Claims (5)

An α, β-unsaturated aldehyde represented by the following general formula (1) and a nitroalkane represented by the following general formula (2) are converted into an asymmetric catalyst represented by the following general formula (3) or an enantiomer thereof. To obtain a compound represented by the following general formula (4) or an enantiomer thereof, and a method for producing an asymmetric catalytic Michael reaction product:

[Wherein, R ¹ represents an alkyl group, alkenyl group, alkynyl group, alkoxyalkyl group, alkoxyalkenyl group, alkoxyalkynyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkenyl group which may have a substituent. 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, heterocycloalkylalkynyl group, cycloalkenyl group Rualkyl group, cycloalkenylalkenyl group, cycloalkenylalkynyl group, heterocycloalkenylalkyl group, heterocycloalkenylalkenyl group, heterocycloalkenylalkynyl group, arylalkyl group, arylalkenyl group, arylalkynyl group, heteroarylalkyl group, heteroaryl An alkenyl group or a heteroarylalkynyl group; R ² and R ³ each independently represents a hydrogen atom or an alkyl group; and R ⁴ and R ⁵ each independently represents an aryl group optionally having a substituent. , A heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, a cycloalkenyl group, a heterocycloalkenyl group, an alkyl group, an alkenyl group, or an alkynyl group, R ⁶ represents a hydrogen atom, H ₃ Si—, H ₃ Si -1 Group hydrogen atom of the above is substituted by an alkyl group or an aryl group, or an alkyl group, R ⁷ represents a protecting group for a hydroxyl group, n represents 0 or 1. ] In the general formula (3), R ⁴ and R ⁵ are aryl groups which may have a substituent, and R ⁶ is an alkyl group or one or more hydrogen atoms of H ₃ Si— or H ₃ Si— The method for producing an asymmetric catalytic Michael reaction product according to claim 1, wherein the product is a group substituted by an aryl group .   The method for producing an asymmetric catalytic Michael reaction product according to claim 1 or 2, wherein the nitroalkane represented by the general formula (2) is nitromethane. A compound represented by the following structural formula (6) obtained by reacting a compound represented by the following structural formula (5) with nitromethane in the presence of an asymmetric catalyst represented by the following general formula (3). To obtain a compound represented by the following structural formula (7), and then reduce the compound represented by the structural formula (7) to obtain a pharmaceutical compound represented by the following structural formula (8). A method for producing a pharmaceutical compound characterized by the above.

[Wherein R ⁴ and R ⁵ are each independently an aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, alkyl group which may have a substituent. , An alkenyl group, or an alkynyl group, R ⁶ represents a hydrogen atom, a group in which one or more hydrogen atoms of H ₃ Si—, H ₃ Si— are substituted with an alkyl group or an aryl group , or an alkyl group, R ⁷ represents a hydroxyl-protecting group, and n represents 0 or 1. ] A compound represented by the following structural formula (9) is reacted with nitromethane in the presence of an asymmetric catalyst represented by the following general formula (3 ′), and the resulting structural formula (10) is obtained. The compound is oxidized to obtain a compound represented by the following structural formula (11), and then the compound represented by the structural formula (11) is reduced to obtain a pharmaceutical compound represented by the following structural formula (12). A method for producing a pharmaceutical compound, comprising:

[Wherein R ⁴ and R ⁵ are each independently an aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, alkyl group which may have a substituent. , An alkenyl group, or an alkynyl group, R ⁶ represents a hydrogen atom, a group in which one or more hydrogen atoms of H ₃ Si—, H ₃ Si— are substituted with an alkyl group or an aryl group , or an alkyl group, R ⁷ represents a hydroxyl-protecting group, and n represents 0 or 1. ]