JPH11246501A - Production of optically active carboxylic acid amides - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject amides by a catalytic amount of an asymmetric source in a high catalytic efficiency by using a readily handleable reducing agent, by reacting a β-disubstituted-α,β-unsaturated carboxylic acid amides with a hydride reagent in the presence of an optically active metal compound. SOLUTION: Bate β-disubstituted-α, β-unsaturated carboxylic acid amides [e.g. a compounds of formula I (R<6> and R<7> are each a halogen or the like; R<8> to R<10> are each H, a halogen or the like), to be concrete, N-methyl-N- phenyl-3-phenyl-2-butanoic acid amide or the like] is reacted with a hydride reagent (a metal hydride or the like) in the presence of an optically active metal compound preferably an optically active cobalt (II) complex represented by a compound of formula II [R<1> and R<2> are mutually different and each H, a (substituted) alkyl or a (substituted) aryl; R<3> to R<5> are each H, an alkyl, an alkenyl or the liek] (e.g. a compound of formula III)} is reacted with a hydride reagent (a metal hydride or the like) preferably in the presence of an alcohol compound and a carboxylic acid compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing optically active carboxylic acid amides, and more particularly, to a synthetic intermediate of a physiologically active compound such as a pharmaceutical or an agricultural chemical, or a functional material such as a liquid crystal.
The present invention relates to a method for producing an optically active carboxylic acid amide useful as a raw material for synthesis in fine chemicals and the like.

[0002]

2. Description of the Related Art A general method for producing an optically active carboxylic acid derivative having an optically active site at the β-position includes, in addition to a general optical resolution method, various corresponding α, β- A method for producing optically active carboxylic acid amides having an asymmetric carbon at the β-position directly by an asymmetric reaction with an unsaturated carboxylic acid derivative has been proposed. For example, an organocopper reagent prepared in a system from a Grignard reagent, copper (I) bromide and dimethylsulfide to an α, β-unsaturated carboxylic acid amide prepared from an optically active oxazolidinone,
It has been reported that a stereoselective Michael addition can form an asymmetric carbon at the β-position (E. Nicols et al., J.O.
rg. Chem., 58 , 766 (1993)). Also reported is the reaction of stereoselectively adding a dialkyl copper reagent to α, β-unsaturated carboxylic acid amide prepared from optically active 2,2-dimethyloxazolidine to form asymmetric carbon at β position. (Koji Masakazu et al., J. Org. Chem., 59 , 6949)
(1994)). However, in these methods, for stereoselective expression, it is necessary to bind an optically active site to the substrate and remove it after the reaction, which requires complicated operations. Thus, a catalytic method for hydrogenating and reducing α, β-unsaturated carboxylic acids with a ruthenium (II) complex having an optically active binaphthol as a ligand has been proposed (Ryoji Noyori et al., J. Org. C.).
hem., 52 , 3174 (1987)). However, in this reaction, in order to reduce the α, β-unsaturated carboxylic acid having a substituent at the β-position while maintaining high stereoselectivity, high-pressure hydrogen at 80 to 110 atm is required, It is pointed out that such equipment must be prepared and that the preparation of the complex catalyst is not always simple.

[0003] Therefore, a catalytic asymmetric hydride reduction method which can be carried out with simple equipment and simple operation has been studied.
For example, there has been reported a method of constructing an asymmetric carbon at the β-position of an α, β-unsaturated carboxylic acid ester using a cobalt complex having optically active semicholine as a ligand and sodium borohydride as a reducing agent. (A. Pfaltz et al., An
gew. Chem. Int. Ed. Engl., 28 , 60 (1989)). However, in this reaction, a semi-choline ligand and cobalt chloride are mixed in a reaction solution to prepare a required catalyst, so that preparation of a homogeneous catalyst is not necessarily guaranteed, and there are not many types of applicable substrates. This is pointed out as a problem.

[0004]

DISCLOSURE OF THE INVENTION The present invention relates to an optically active carboxylic acid amide useful as a synthetic intermediate of a physiologically active compound such as a pharmaceutical or an agricultural chemical, a functional material such as a liquid crystal, or a raw material for synthesizing a fine chemical. It is an object of the present invention to provide a method capable of using a hydride reducing agent that is easy to handle and producing a catalyst with a high catalytic efficiency (turnover number) using an asymmetric source of a catalytic amount.

[0005]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have developed a method for reducing amides of α, β-unsaturated carboxylic acids by using a safe and easy-to-handle hydride reagent as a reducing agent. We have been diligently studying a method for synthesizing optically active carboxylic acid amides. As a result, they have found that the above problem can be solved by a reaction using an optically active metal compound as a catalyst, and have reached the present invention.

That is, the present invention includes the following inventions. (1) A method for producing an optically active carboxylic acid amide, comprising a step of reacting a β-disubstituted-α, β-unsaturated carboxylic acid amide with a hydride reagent in the presence of an optically active metal compound. (2) The method according to the above (1), wherein the reaction between the β-disubstituted-α, β-unsaturated carboxylic acid amide and a hydride reagent is carried out in the presence of an optically active metal compound and an alcohol compound. (3) The method according to the above (1), wherein the reaction of the β-disubstituted-α, β-unsaturated carboxylic acid amide with a hydride reagent is carried out in the presence of an optically active metal compound and a carboxylic acid compound. (4) The method according to (1) above, wherein the reaction of the β-disubstituted-α, β-unsaturated carboxylic acid amide with a hydride reagent is carried out in the presence of an optically active metal compound, an alcohol compound and a carboxylic acid compound. (5) The optically active metal compound is an optically active cobalt (II)
The method according to any one of the above (1) to (4), which is a complex. (6) The optically active cobalt (II) complex has the following formula (a):

[0007]

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(Wherein R ¹ and R ² are different groups, each being a hydrogen atom, a linear or branched alkyl group or an aryl group, and the alkyl group and the aryl group each have a substituent. And two R ^{1 s} or two R ^{2 s} may be mutually bonded to form a ring,
R ³ , R ⁴ and R ⁵ may be the same or different and each represents a hydrogen atom, a linear or branched alkyl group, a linear or branched alkenyl group, an aryl group, an acyl group, an alkoxycarbonyl group. An aryloxycarbonyl group or an aralkyloxycarbonyl group, wherein the alkyl group, alkenyl group, aryl group, acyl group, alkoxycarbonyl group, aryloxycarbonyl group and aralkyloxycarbonyl group may have a substituent, R ⁴ and R ⁵ may be mutually connected to form a ring in cooperation with the carbon atom to which R ⁴ and R ⁵ are respectively bonded. The method according to the above (5), which is a compound represented by the formula: (7) The optically active metal compound is an optically active cobalt (II)
I) The method according to any one of the above (1) to (4), which is a complex. (8) The method according to any one of (1) to (7), wherein the hydride reagent is a metal hydride.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, a method for producing an optically active carboxylic amide of the present invention (hereinafter, referred to as “method of the present invention”) will be described in detail. In the method of the present invention, the α, β-unsaturated carboxylic acid amide used as a starting material is a prochiral compound having an appropriate substituent having a carbon-carbon double bond conjugated to a carbonyl group in the molecule. There is no particular limitation as long as it is present, and it can be appropriately selected according to the desired optically active carboxylic acid amide.
The method according to the invention particularly relates to the following formula (b):

[0010]

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(Wherein R ⁶ and R ⁷ are different from each other and are a halogen atom, a nitro group, a nitroso group, a cyano group,
Alkoxy group, aryloxy group, aralkyloxy group, silyl group, alkoxycarbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, alkylthiocarbonyl group, alkoxythiocarbonyl group,
Arylthiocarbonyl group, aralkylthiocarbonyl group, amino group, amine oxide group, hydrazine group (-N
HNH-R; R = hydrogen, C _1-10 - alkyl, aryl,
Aralkyl etc.), hydrazone group (-C (= N-NH-
R) —R ′; R, R ′ = hydrogen, C _1-10 -alkyl, aryl, aralkyl, etc.), acylhydrazone group (—C (=
N—NH—CO—R) —R ′; R, R ′ = hydrogen, C _1-10
-Alkyl, aryl, aralkyl, etc.), a sulfide group, a sulfinyl group, a sulfonyl group, a phosphino group, a phosphinyl group, a phosphorous group, an acyl group, a linear or branched alkyl group, a cycloalkyl group or an aryl group. The group may have a substituent;
R ⁸ , R ⁹ and R ¹⁰ may be the same or different,
Hydrogen atom, halogen atom, nitro group, nitroso group, cyano group, alkoxy group, aryloxy group, aralkyloxy group, silyl group, alkoxycarbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group,
Alkyl thio group, an alkoxycarbonyl thiocarbonyl group, arylthio group, aralkylthio group, an amino group, an amine oxide group, a hydrazine group (-NHNH-R; R = hydrogen, C _1-10 - alkyl, aryl, aralkyl, etc.) , A hydrazone group (-C (= N-N
R—R ′; R, R ′ = hydrogen, C _1-10 -alkyl,
Aryl, aralkyl, etc.), acylhydrazone group (-C
(= N-NH-CO-R) -R '; R, R' = hydrogen, C
_1-10 -alkyl, aryl, aralkyl, etc.), sulfide group, sulfinyl group, sulfonyl group, phosphino group,
It is a phosphinyl group, a phosphorous group, an acyl group, a linear or branched alkyl group, a cycloalkyl group or an aryl group, and these groups may have a substituent. )
It is suitable for producing a corresponding optically active carboxylic acid amide using a β-disubstituted-α, β-unsaturated carboxylic acid amide represented by the following formula as a starting material. Among the α, β-unsaturated carboxylic acid amides, the method of the present invention provides, as a starting material, α, β-unsaturated carboxylic acid amides,
It is effective when a corresponding optically active carboxylic acid amide is produced by using a β-disubstituted-α, β-unsaturated carboxylic acid amide in which R ⁸ is a hydrogen atom in the formula (b).

In the above formula (b), R ⁶ , R ⁷ , R ⁸ ,
Representative examples of the halogen atom represented by R ⁹ or R ¹⁰ include fluorine, chlorine, and bromine. Representative examples of the alkoxy group include C _1-10- such as a methoxy group and an ethoxy group.
Alkoxy groups are typical examples of aryloxy groups,
Representative examples of the phenoxy group and the naphthyloxy group and the aralkyloxy group include a benzyloxy group and a phenethyloxy group.

Representative examples of the silyl group include a silyl group substituted with a C _1-10 -alkyl group such as a trimethylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group and / or an aryl group. Can be Representative examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, an n-butoxycarbonyl group, a C _1-10 -alkoxy-carbonyl group such as an n-octyloxycarbonyl group, and a representative example of the aryloxycarbonyl group. Is a phenoxycarbonyl group or a naphthyloxycarbonyl group, and representative examples of an aralkyloxycarbonyl group include a benzyloxycarbonyl group and a phenethyloxycarbonyl group.

[0014] Representative examples of alkylthio group, a methyl thio group, ethyl thio group, n- butyl thio group, C _1-10, such as n- octyl thio group - alkyl - thio group, Arukokishichio Representative examples of the carbonyl group include a methoxythiocarbonyl group, an ethoxythiocarbonyl group,
n- butoxy thiocarbonyl group, C _1-10, such as n- octyloxy thiocarbonyl group - alkoxy - thiocarbonyl group, as a representative example of arylthiocarbonyl group,
A phenylthiocarbonyl group, a naphthylthiocarbonyl group is a representative example of an aralkylthiocarbonyl group, a benzylthiocarbonyl group, a phenethylthiocarbonyl group is a representative example of an aryloxythiocarbonyl group, a phenoxythiocarbonyl group, a naphthyloxy Representative examples of the aralkyloxythiocarbonyl group as the thiocarbonyl group include a benzyloxythiocarbonyl group and a phenethyloxythiocarbonyl group.

A typical example of the amino group is dimethylamido.
Di (C) such as _1-10-Alkyl) a
And a representative example of an amine oxide group.
Is a dimethylamino oxide group, diethylaminooxy
Di (C)_1-10-Alkyl) amino oxide groups
I can do it. Typical examples of hydrazine groups include hydrazino
C, methylhydrazino, ethylhydrazino, etc.
_1-10A hydrazone group;
Is a typical example of -C (= N-NH_Two) -R '(R'
Is as defined above), a methylhydrazone group (-C (= N-N
H-CH_Three) -R '; R' is as defined above), ethyl hydride
Razone group (-C (= N-NH-C_TwoH_Five) -R '; R'
Is the same as defined above), and is a representative of an acylhydrazone group.
As an example, an acetylhydrazone group (-C (= N-NH
-CO-CH_Three) -R '; R' is as defined above), propyl
Onylhydrazone group (-C (= N-NH-CO-C_TwoH
_Five) -R '; R' is as defined above.

Representative examples of the sulfide group include a C _1-10 -alkyl sulfide group such as a methyl sulfide group, an aralkyl sulfide group such as a benzyl sulfide group, and an aryl sulfide group such as a phenyl sulfide group. examples, C _1-10 such as methylsulfinyl group - alkylsulfinyl group, an aralkyl sulfinyl group and benzyl sulfinyl group, representative examples of the sulfonyl group, C _1-10, such as methylsulfonyl group - alkylsulfonyl Groups, aralkylsulfonyl groups such as benzylsulfonyl group, and arylsulfonyl groups such as phenylsulfonyl group.

Representative examples of the phosphino group include di (C _1-10 -alkyl) phosphino groups such as a dimethylphosphino group, diaralkylphosphino groups such as a dibenzylphosphino group, and diaryl groups such as a diphenylphosphino group. A phosphino group is mentioned, and as a typical example of the phosphinyl group,
Di (C _1-10 -alkyl) phosphinyl group such as dimethylphosphinyl group, diaralkylphosphinyl group such as dibenzylphosphinyl group, and diarylphosphinyl group such as diphenylphosphinyl group; Representative examples of the phosphorous group include di (C) such as a dimethylphosphorus group.
_1-10 -alkyl) Phosphorus group, diarylphosphorus group such as dibenzylphosphorus group, and diarylphosphorus group such as diphenylphosphorus group.

Representative examples of the acyl group include an acetyl group,
And C _1-10 -acyl groups such as propionyl group. Representative examples of the linear or branched alkyl group include methyl, ethyl, isopropyl, t-butyl, sec.
And C _1-10 -alkyl groups such as -butyl group and n-butyl group. Representative examples of cycloalkyl groups include C _1-10 -alkyl groups such as cyclopentyl, cyclohexyl and cycloheptyl.
_{And 3-10} -cycloalkyl groups.

Representative examples of the aryl group include a phenyl group, a p-methoxyphenyl group, a p-chlorophenyl group,
substituted or unsubstituted aromatic hydrocarbon groups such as p-fluorophenyl group, α-naphthyl group, β-naphthyl group; furyl group, thienyl group, pyridyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl And substituted or unsubstituted aromatic heterocyclic groups such as a group, imidazolyl group, pyrazolyl group, pyrimidinyl group, pyridazinyl group, pyraridinyl group, quinolyl group and isoquinolyl group.

In the above formula (b), R ⁶ , R ⁷ , R ⁸ ,
The aforementioned group represented by R ⁹ or R ¹⁰ may be substituted with a suitable substituent such as the aforementioned C _1-10 -alkyl group, C _1-10 -alkoxy group, halogen atom and the like. Also,
R ⁹ and R ¹⁰ are mutually bonded to form, for example,-(C
_{H 2) 4 -, - (} CH 2) 5 -, - CH 2 CH 2 OCH
_A bivalent group such as ₂ CH ₂ — may be formed to form a 5-membered ring, 6-membered ring, or other ring structure with an adjacent nitrogen atom.

In the method of the present invention, representative examples of α, β-unsaturated carboxylic acid amides used as starting materials include N-methyl-N-phenyl-3-phenyl-2-butenoic acid amide and N-phenyl 3-Phenyl-2-butenoic acid amide and N-methyl-N-phenyl-3-cyclohexyl-2-butenoic acid amide, N-methyl-N-phenyl-3- (p-fluorophenyl) -2-butenoic acid Amides and the like.

The process of the present invention comprises the steps of starting α, β-
As unsaturated carboxylic acid amides, α, β-unsaturated carboxylic acid amides represented by the above formula (b), particularly β-disubstituted-α, wherein R ⁸ is a hydrogen atom in the above formula (b)
Using β-unsaturated carboxylic acid amides, the corresponding formula (c):

[0023]

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Wherein R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰
Is as defined above. This is useful as a method for obtaining an optically active carboxylic acid amide represented by the formula (c), particularly, a β-disubstituted-optically active carboxylic acid amide wherein R ⁸ is a hydrogen atom in the formula (c). As the β-disubstituted-optically active carboxylic acid amides, N-methyl-N-phenyl-3-phenylbutanoic acid amide, N-phenyl-3-phenylbutanoic acid amide, N-methyl-N-phenyl-3-acid Cyclohexylbutanoic acid amide and N-methyl-N-phenyl-3- (p-fluorophenyl) butanoic acid amide are exemplified.

In the method of the present invention, the optically active metal compound used as a catalyst is not particularly limited.
Titanium, vanadium, manganese, iron, cobalt, zinc,
A typical example is a complex of at least one transition metal selected from nickel, ruthenium, rhodium, hafnium, zirconium and the like. Among them, as a complex of at least one transition metal selected from titanium, vanadium, manganese, iron, cobalt, nickel and ruthenium, for example, an optically active titanium (IV) complex, an optically active iron (III) complex, an optically active Ruthenium (III)
Complexes, optically active oxovanadium (IV) complexes, optically active manganese (III) complexes, optically active cobalt (II) complexes, optically active cobalt (III) complexes and the like. In the method of the present invention, in particular, the following formula (a):

[0026]

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(In the formula, R ¹ and R ² are different groups, each being a hydrogen atom, a linear or branched alkyl group or an aryl group, and the alkyl group and the aryl group each have a substituent. And two R ^{1 s} or two R ^{2 s} may be mutually bonded to form a ring,
R ³ , R ⁴ and R ⁵ may be the same or different and each represents a hydrogen atom, a linear or branched alkyl group, a linear or branched alkenyl group, an aryl group, an acyl group, an alkoxycarbonyl group. An aryloxycarbonyl group or an aralkyloxycarbonyl group, wherein the alkyl group, alkenyl group, aryl group, acyl group, alkoxycarbonyl group, aryloxycarbonyl group and aralkyloxycarbonyl group may have a substituent, R ⁴ and R ⁵ may be mutually connected to form a ring in cooperation with the carbon atom to which R ⁴ and R ⁵ are respectively bonded. The use of the optically active cobalt (II) complex represented by the formula (1) is preferable because an optically active carboxylic acid amide can be obtained with a high optical yield.

In the above formula (a) representing this optically active cobalt (II) complex, R ¹ and R ² are different groups, each being a hydrogen atom, a linear or branched alkyl group or an aryl group; The alkyl group and the aryl group may have a substituent. Examples of the linear or branched alkyl group include a methyl group, an ethyl group, an isopropyl group,
t-butyl group, sec-butyl group, n-propyl group, n
A C _1-10 -alkyl group such as a -butyl group is typical. Examples of the aryl group include a substituted or unsubstituted aromatic hydrocarbon group such as a phenyl group, a p-methoxyphenyl group, a p-chlorophenyl group, a p-fluorophenyl group, an α-naphthyl group, a β-naphthyl group; Group, thienyl group, pyridyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, pyrimidinyl group, pyridazinyl group, pyraridinyl group, quinolyl group, isoquinolyl group, etc. Aromatic heterocyclic groups are typical.

Further, two R ^{1 s} or two R ^{2 s} may be mutually bonded to form a ring.
_They may be mutually bonded via a group such as — (CH ₂ ) ₄ — to form a ring such as a 6-membered ring. Further, R ³ , R ⁴ and R
⁵ may be the same or different, a hydrogen atom, a linear or branched alkyl group, a linear or branched alkenyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group or an aralkyloxycarbonyl Group, the alkyl group, alkenyl group, aryl group, acyl group, alkoxycarbonyl group,
The aryloxycarbonyl group and the aralkyloxycarbonyl group may have a substituent.

Examples of the linear or branched alkyl group include a methyl group, an ethyl group, an isopropyl group, a t-butyl group and a se
C _1-10 such as c-butyl group, n-propyl group, n-butyl group, etc.
-Alkyl groups are typical. Examples of the linear or branched alkenyl group include a vinyl group, an allyl group, and crotyl (2-
A C _2-10 -alkenyl group such as a butenyl) group and an isopropenyl (1-methylvinyl) group is typical. Examples of the aryl group include a phenyl group, a p-methoxyphenyl group,
5-dimethoxyphenyl group, p-chlorophenyl group, p
-Fluorophenyl group, 3,5-dimethylphenyl group,
Substituted or unsubstituted aromatic hydrocarbon groups such as 2,4,6-trimethylphenyl group and naphthyl group; furyl group, thienyl group, pyridyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl Representative examples are a substituted or unsubstituted aromatic heterocyclic group such as a group, a pyrazolyl group, a pyrimidinyl group, a pyridazinyl group, a pyraridinyl group, a quinolyl group, and an isoquinolyl group.
Examples of the acyl group include C _1-10 -aliphatic acyl groups such as acetyl, trifluoroacetyl, propionyl, butyryl, isobutyryl, and pivaloyl; benzoyl, 3,5-dimethylbenzoyl, 2,4 2,6-trimethylbenzoyl group, 2,6-dimethoxybenzoyl group, 2,4,6-trimethoxybenzoyl group, 2,6-
A diisopropoxybenzoyl group, a naphthylcarbonyl group, an aromatic acyl group such as an anthrylcarbonyl group are typical, and as a representative example of the alkoxycarbonyl group,
Methoxycarbonyl group, an ethoxycarbonyl group, n- butoxycarbonyl group, n- octyloxy group, cyclopentyloxy group, cyclohexyloxy group, cyclooctyloxy carbonyl group, C _1-10, such as isobornyl oxycarbonyl group - alkoxy A typical example of a carbonyl group as an aryloxycarbonyl group is a phenoxycarbonyl group and a naphthyloxycarbonyl group, and a typical example of an aralkyloxycarbonyl group is a benzyloxycarbonyl group and a phenethyloxycarbonyl group.

R ⁴ and R ⁵ may be mutually connected to form a ring in cooperation with the carbon atom to which R ⁴ and R ⁵ are bonded. For example, R ⁴ and R ⁵ are linked to each other, - (CH _{2) 4} - or -CH = CH-C
When H = CH-, a cyclohexane ring or a benzene ring is formed, respectively, and the thus formed cyclohexane ring, benzene ring, or the like ring includes, for example, a methyl group, an ethyl group, an isopropyl group, a t-butyl group, It may be substituted with one or more substituents selected from C _1-10 -alkyl groups such as sec-butyl group, n-propyl group and n-butyl group; and aryl groups such as phenyl group and naphthyl group. The benzene ring may be condensed to form a condensed polycyclic ring such as a naphthalene ring. Specific examples of the optically active cobalt (II) complex represented by the formula (a) include the following formulas (a-1) to (a-1).
And those represented by (a-18).

[0032]

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[0033]

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[0034]

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[0035]

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[0036]

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[0037]

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[0038]

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[0039]

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[0040]

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[0041]

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[0042]

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[0043]

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[0044]

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[0045]

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[0046]

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[0047]

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[0048]

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[0049]

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Optically active cobalt represented by the above formula (a)
The (II) complex and the optically active cobalt (III) complex can be prepared according to a known method. For example, Y. Nishid
a, etal., Inorg. Chim. Acta, 38, 213 (1980); L. Cla
isen, Ann. Chem., 297 , 57 (1897); EG Jager, Z. C
hem., 8, 30, 392, and 475 (1968). For example, an optically active cobalt (II) complex is obtained by formylating a 1,3-diketone derivative and reacting it with a 1,2-diphenyldiamine derivative serving as an asymmetric source to form a ligand, and subsequently, in the presence of sodium hydroxide. It can be prepared by adding an aqueous cobalt (II) chloride solution and heating. For example, the optically active cobalt (II) complex represented by the formula (a-7) is represented by the following formula (d-1)
And (d-2).

[0051]

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In the production of the optically active cobalt (II) complex, the formylation of 1,3-diketone is carried out, for example, by reacting
The reaction can be carried out by adding 5 molar equivalents of trimethyl orthoformate and heating and refluxing in an acetic anhydride solvent.
The dehydration-condensation reaction with an optically active diamine can be performed by adding 2 equivalents of the above-mentioned formylation compound in an alcohol solvent, stirring the mixture at room temperature for 1 to 2 hours, and then heating the mixture to 50 ° C. The crude product obtained by concentration can be purified by a conventional purification method such as silica gel column chromatography, reprecipitation, and recrystallization.

The amount of sodium hydroxide used in the complex formation reaction between the ligand and cobalt (II) chloride is 2.0 mol equivalent or more, preferably 2.0 to 2.0 mol equivalent to the ligand.
3.0 molar equivalents. Further, the aqueous solution of cobalt (II) chloride is used in such an amount that the amount of cobalt (II) chloride is at least 1.0 molar equivalent, preferably 1.0 to 1.5 molar equivalents to the ligand. The reaction is carried out under a flow of nitrogen or argon gas, and the solvent and water to be added are degassed. The reaction proceeds at a reaction temperature of 0 ° C. or higher,
By heating to about 30 to 80 ° C., the reaction time can be shortened, and more preferably 40 to 60 ° C. As the solvent, alcohol solvents such as methanol, ethanol, and 2-propanol are preferable. In the production of the optically active cobalt (II) complex, the precipitation of the optically active cobalt (II) complex starts about 1 to 10 minutes after the addition of the aqueous cobalt (II) chloride solution.
Performed continuously for 0 minutes to 2 hours. Thereafter, the reaction mixture is cooled to room temperature, and water is added as necessary to sufficiently precipitate the reaction product. Next, after filtration and washing with water under nitrogen gas, the desired product can be obtained by vacuum drying.

Since the optically active cobalt (II) complex thus obtained is very susceptible to oxidation in the air, iodine is added in advance and the iodine is stable in the air and easy to handle. Structural analysis can be performed on a cobalt (III) halide complex. That is, in a dichloromethane solvent, iodine (I ₂ ) 0.5 was added to the optically active cobalt (II) complex.
A molar equivalent was added, the mixture was stirred and reacted at room temperature, and the product obtained by concentration was treated with dichloromethane-diethyl ether-
Cobalt recrystallized with hexane and capable of X-ray analysis
(III) A complex crystal is obtained and can be subjected to analysis. For example, the optically active cobalt (II) complex represented by the formula (a-10) is iodinated by the above method, and is changed to an optically active cobalt (III) complex represented by the following formula (a-19). Structural analysis by X-ray diffraction can be performed. The optically active cobalt (I) represented by the formula (a-19)
II) Complexes are also effective as catalysts for use in the method of the present invention.

[0055]

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In the method of the present invention, when the optically active cobalt (II) complex represented by the formula (a) is used as a catalyst, optically active carboxylic amides can be obtained with a high optical yield and a high chemical yield. To achieve this, 0.001 to 50 mol% of the α, β-unsaturated carboxylic acid amide is used,
Preferably, it is used in a proportion of 0.01 to 50 mol%, more preferably in a proportion of 0.05 to 10 mol%.

The method of the present invention comprises the steps of: converting a β-disubstituted-α, β-unsaturated carboxylic acid amide into an optically active metal represented by the aforementioned optically active cobalt (II) complex represented by the formula (a). This is a method in which a compound is used as a catalyst to react with a hydride reagent, and the reaction is preferably performed in the coexistence of an alcohol compound and / or a carboxylic acid compound. As a typical example of this alcohol compound, the following formula (e):

[0058]

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The compound represented by the following formula: In the above formula (e), R ¹¹ , R ¹² and R ¹³ may be the same or different and each may be a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group, or an oxygen atom in a carbon chain. A straight-chain, branched or cyclic hydrocarbon group containing a hetero atom such as an atom, a nitrogen atom and a sulfur atom, which may have a substituent such as a hydroxyl group, an amino group, an ester group or a carbonyl group. Good. Examples of the linear or branched alkyl group in the formula (e) include C _1- such as methyl group, ethyl group, n-propyl group, isopropyl group, t-butyl group, sec-butyl group and n-butyl group. _{A 10} -alkyl group is typical. Representative examples of the cycloalkyl group include a C _3-10 -cycloalkyl group such as a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
Representative examples of the aryl group include a phenyl group, a p-methoxyphenyl group, a p-chlorophenyl group, a p-fluorophenyl group, and a naphthyl group. A straight chain containing a hetero atom such as an oxygen atom, a nitrogen atom, or a sulfur atom in a carbon chain,
Representative examples of the branched or cyclic hydrocarbon group include a methoxyethyl group, a methoxypropyl group, a 2-furyl group, a 3-furyl group, and a 2-tetrahydropyranyl group.
R ¹² and R ¹³ may be mutually bonded to form a ring, for example, — (CH ₂ ) ₄ —, — (CH ₂ ) ₅
And the like, they may be mutually bonded via a group such as-to form a ring such as a 5-membered ring or a 6-membered ring.

Specific examples of the alcohol compound include aliphatic or alicyclic alcohols such as methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, t-butanol, cyclopentanol, cyclohexanol and cycloheptanol, and phenol. , Resorcinol, aromatic alcohols such as 2-hydroxypyridine, polyalcohols such as ethylene glycol and propylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, propylene glycol monomethyl ether, tetrahydrofurfuryl alcohol, tetrahydropyrene-2-methanol , Furfuryl alcohol, tetrahydro-3-furanmethanol, 2,2-dimethyl-1,3-dioxolan-4-methanol Chain or cyclic ether alcohols and the like, dihydro-5- (hydroxymethyl) -2 (3
H) -lactone alcohol such as furanone, 2- (methylamino) ethanol, 2- (ethylamino) ethanol, 2-pyridinemethanol, 2-pyridineethanol, 2-pyridinepropanol, 2-piperidinemethanol, 1-methyl-2 Linear or cyclic amino alcohols such as -piperidinemethanol and 1-methyl-2-pyrrolidinemethanol; and thioether alcohols such as 2- (methylthio) ethanol and 2-thiophenmethanol. Among them, in that optically active carboxylic acid amides can be obtained with high optical yield and high chemical yield,
Aliphatic alcohols are preferred.

In the method of the present invention, the alcohol compound represented by the formula (e) may be used alone or in combination of two or more. Specific examples of two or more combinations include ethanol / ethylene glycol, ethanol / propylene glycol, ethanol / ethylene glycol monomethyl ether, ethanol / propylene glycol monomethyl ether, ethanol / tetrahydrofurfuryl alcohol, and ethanol / tetrahydropyrene-2-methanol. , Ethanol / furfuryl alcohol, ethanol / tetrahydro-3-furanmethanol, ethanol / 5-methyltetrahydrofuran-2
Methanol, propanol, butanol, 2-propanol, 2,2-dimethylethanol, 2,2,2-trifluoroethanol, cyclopentanol, cyclohexanol, etc. Are typical combinations. As a typical example of the carboxylic acid compound, the following formula (f):

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The compound represented by the following formula: In the formula (f), R ¹⁴ represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, an aryl group, or a straight chain containing a hetero atom such as an oxygen atom, a nitrogen atom, or a sulfur atom in a carbon chain. A chain, branched or cyclic hydrocarbon group,
These may have a substituent such as a hydroxyl group, an amino group, an ester group or a carbonyl group. As the linear or branched alkyl group in the formula (f), a methyl group,
Substituted or unsubstituted C _1- such as ethyl group, isopropyl group, t-butyl group, sec-butyl group, n-propyl group, n-butyl group, trifluoromethyl group and 2,2,2-trifluoroethyl. _{A 10} -alkyl group is typical. Representative examples of the cycloalkyl group include a C _3-10 -cycloalkyl group such as a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. As the aryl group, a phenyl group, a p-methoxyphenyl group, a p-chlorophenyl group,
Representative examples include a p-fluorophenyl group and a naphthyl group. Examples of a linear, branched or cyclic hydrocarbon group containing a hetero atom such as an oxygen atom, a nitrogen atom, and a sulfur atom in a carbon chain include a methoxyethyl group, a methoxypropyl group, and a methoxyethyl group.
-Furyl, 3-furyl, 2-tetrahydropyranyl and the like are representative.

Specific examples of the carboxylic acid compound include aliphatic or alicyclic carboxylic acids such as formic acid, acetic acid, propionic acid, isobutanoic acid, trifluoroacetic acid, pentafluoroethanecarboxylic acid, methoxyacetic acid, cyclohexanecarboxylic acid and malonic acid. Acids and dicarboxylic acids, and aromatic carboxylic acids and dicarboxylic acids such as benzoic acid, phenylacetic acid, 3,3,3-triphenylacetic acid, methoxyphenylacetic acid, pyran-2-carboxylic acid, and 2-thiophenecarboxylic acid; No. Among them, aliphatic carboxylic acids and aromatic carboxylic acids are preferred in that optically active carboxylic acid amides can be obtained with high optical yield and high chemical yield.

In the method of the present invention, the carboxylic acid compound represented by the formula (f) may be used alone or in combination of two or more. In the method of the present invention, when the alcohol compound represented by the formula (e) and / or the carboxylic acid compound represented by the formula (f) are used, the amount of these compounds used is high optical yield and high chemical yield. In order to obtain optically active carboxylic amides in a yield, α, β-
0.01 to 1 mol of the unsaturated carboxylic acid amides.
It is preferably used in a proportion of 50 mol, more preferably in a proportion of 1 to 30 mol.

The metal hydride used as the hydride reagent in the method of the present invention is not particularly limited, and examples thereof include lithium aluminum hydride, lithium tri (t-butoxy) aluminum hydride, lithium borohydride, and borohydride. Sodium, potassium borohydride,
Calcium borohydride, ammonium borohydride,
Representative is sodium cyanoborohydride and the like.

These hydride reagents may be metal chlorides such as titanium chloride, rubidium chloride, and cerium chloride, and hydride reagents involving metal exchange in the presence of quaternary ammonium salts such as tetramethylammonium chloride and tetrabutylammonium bromide. . Also, sodium tri (methoxy) borohydride, sodium tri (ethoxy) borohydride, sodium tri (isopropoxy) borohydride, sodium tri (t-butoxy) borohydride, potassium tri (isopropoxy) borohydride When a trialkoxy metal hydrogen complex such as potassium tri (t-butoxy) borohydride is used, the optical compound can be obtained with high chemical yield and high optical yield without using the alcohol compound represented by the formula (e). Active carboxylic amides can be obtained.

When using a metal hydrogen complex of tricarboxylic acid such as sodium tri (acetic acid) borohydride, sodium tri (propionic acid) borohydride, sodium tri (tetrahydro-2-furancarboxylic acid) borohydride, the above formula is used. An optically active carboxylic amide can be obtained with a high chemical yield and a high optical yield without using the carboxylic acid compound represented by (f).

In the method of the present invention, the reaction is preferably performed in a liquid phase. At this time, a solvent can be used if necessary. As the solvent used, an aliphatic hydrocarbon solvent, an aromatic hydrocarbon solvent, an alicyclic hydrocarbon solvent, an ester solvent, an ether solvent, and a halogen solvent are effective. In particular, a halogen-based solvent such as carbon tetrachloride, chloroform and Freon 113, or an aromatic hydrocarbon-based solvent such as toluene is preferable. When a solvent is used, the amount of the solvent used is usually α,
For 1 mmol of β-unsaturated carboxylic acid amides, 1
The ratio is about 1 ml to about 1 L, and the use amount of about 5 to 100 ml is effective because optically active carboxylic acid amides can be obtained with high optical yield and high chemical yield.

The reaction temperature is usually preferably in the range of -100 to 50 ° C, more preferably in the range of -80 to 30 ° C.
Particularly preferably, it is −60 to 25 ° C. The reaction can be carried out at normal pressure as long as the solvent does not evaporate. The reaction time is usually about 1 minute to 10 days, and a sample of the reaction mixture is sequentially collected, and is subjected to thin-layer chromatography (TLC) and gas chromatography (GC).
And the like to confirm the progress of the reaction.

In the method of the present invention, the target optically active carboxylic acid amides can be recovered and purified from the reaction mixture obtained by the above reaction by a known method, for example, distillation,
It can be carried out by combining methods such as adsorption, extraction, and recrystallization.

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EXAMPLES Hereinafter, the present invention will be described in a shell form with reference to examples, but the scope of the present invention is not limited to these examples. Example 1 A first reactor was charged with 275 mg (7.5 mmo) of sodium borohydride.
l), cool to 0 ° C under nitrogen atmosphere, and add chloroform
25 ml was added. Further, 10.1 ml (104 mmol) of tetrahydrofurfuryl alcohol was added dropwise thereto, and
Stirred for hours.

Next, 3.5 mg (1 mol%) of the optically active cobalt (II) complex represented by the above formula (a-7) was placed in the second reactor, and 5 ml of chloroform was added at room temperature under a nitrogen atmosphere. After stirring, N-methyl-N-phenyl-3-phenyl-2-butenoic acid amide 126 mg (0.5 mmol) in chloroform 5
ml was added. To the second reactor, 4.8 ml of the reducing reagent prepared in the first reactor was added dropwise, followed by stirring at room temperature for 24 hours.

After treatment with 1 M hydrochloric acid, the reaction mixture was extracted with chloroform. The resulting reaction mixture was separated and purified by silica gel column chromatography, and N-methyl-N-phenyl-3-, which is a 1,4-reduced product, was obtained. Phenylbutanoic acid amide
Obtained in 46% yield. The optical purity of this product was analyzed by high performance liquid chromatography (optically active column: CHIRALPAK AD, manufactured by Daicel Chemical Industries, Ltd.).
Met.

Examples 2 to 6 In each of the examples, the optically active cobalt (II) complex shown in Table 1 was replaced with 1 mol% of the optically active cobalt (II) complex represented by the formula (a-7). The reaction was carried out in the same manner as in Example 1 except that it was used. Table 1 shows the chemical yield and optical purity of the obtained 1,4-reductant.

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[Table 1]

Examples 7 to 13 In each example, N-methyl-N-phenyl-3-phenyl
The reaction was carried out in the same manner as in Example 1, except that the amide compounds shown in Table 2 were used instead of -2-butenoic acid amide. Table 2 shows the chemical yield and optical purity of the obtained 1,4-reduced product.

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[Table 2]

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According to the method of the present invention, a safe and inexpensive sodium borohydride or the like is used as a hydride reagent.
Optically active carboxylic amides can be produced from α, β-unsaturated carboxylic amides. The optically active carboxylic acid amides are useful as synthetic intermediates of physiologically active compounds such as pharmaceuticals and agricultural chemicals, functional materials such as liquid crystals, and raw materials for synthesizing fine chemicals.

Claims (8)

[Claims] 1. A process for producing an optically active carboxylic acid amide, comprising a step of reacting a β-disubstituted-α, β-unsaturated carboxylic acid amide with a hydride reagent in the presence of an optically active metal compound. 2. The method according to claim 1, wherein the reaction between the β-disubstituted-α, β-unsaturated carboxylic acid amide and the hydride reagent is carried out in the presence of an optically active metal compound and an alcohol compound. 3. The method according to claim 1, wherein the reaction of the β-disubstituted-α, β-unsaturated carboxylic acid amide with a hydride reagent is carried out in the presence of an optically active metal compound and a carboxylic acid compound. 4. The method according to claim 1, wherein the reaction of the β-disubstituted-α, β-unsaturated carboxylic acid amide with a hydride reagent is carried out in the presence of an optically active metal compound, an alcohol compound and a carboxylic acid compound. 5. The method according to claim 1, wherein the optically active metal compound is an optically active cobalt (II) complex. 6. The optically active cobalt (II) complex has the following formula (a): (Wherein, R ¹ and R ² are different groups, each being a hydrogen atom, a linear or branched alkyl group or an aryl group, and the alkyl group and the aryl group may have a substituent. Two R ^{1 s} or two R ^{2 s}
R ³ and R ³ may be bonded to each other to form a ring.
R ⁴ and R ⁵ may be the same or different, and represent a hydrogen atom, a linear or branched alkyl group, a linear or branched alkenyl group, an aryl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group. Or an aralkyloxycarbonyl group, wherein the alkyl group, alkenyl group, aryl group, acyl group, alkoxycarbonyl group, aryloxycarbonyl group and aralkyloxycarbonyl group may have a substituent;
⁴ and R ⁵ may be linked together to form a ring in cooperation with the carbon atom to which R ⁴ and R ⁵ are each attached. The method according to claim 5, which is a compound represented by the formula: 7. The method according to claim 1, wherein the optically active metal compound is an optically active cobalt (III) complex. 8. The method according to claim 1, wherein the hydride reagent is a metal hydride.