JP2002363160A - Method for producing optically active 4-aryl-2-piperidinones - Google Patents

Abstract

(57) [Summary] [PROBLEMS] Optical activity 4 from the starting compound in a small number of reaction steps
-To provide a process capable of producing aryl-2-piperidinones. SOLUTION: Pyridinones (2) And arylboronic acids (3-1) Or arylboroxines (3-2) And the equation (4-1) Or an optically active form of the compound represented by the formula (4-2) Is reacted in the presence of a complex of an optically active compound of the formula (I) and rhodium to give an optically active 4-aryl-2-piperidinone (1) To manufacture. The catalyst is represented by the formula (4-1):
A complex of rhodium with an optically active compound of a compound in which both r ¹ and Ar ² are a phenyl group substituted by an alkyl group and an alkoxyl group is preferred.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing optically active 4-aryl-2-piperidinones.

[0002]

2. Description of the Related Art Optically active 4-aryl-2-piperidinones are compounds useful as intermediates of physiologically active substances such as baclofens, (-)-paroxetine and the like. A method is known in which an aldehyde is used as a starting compound and is produced through a four-step reaction process (Tetrahedron Lett., 2000 (41), 564).
7).

However, such a conventional production method requires a multi-step reaction process.

[0004]

Accordingly, the present inventors have developed an optically active 4-aryl-substituted compound from a starting compound in a small number of reaction steps.
As a result of intensive studies to develop a method capable of producing 2-piperidinones, it was found that when a pyridinone, a pyridinone and an arylboronic acid or an arylboroxine were reacted in the presence of a specific optically active ruthenium complex, one step was obtained. It has been found that optically active 4-aryl-2-piperidinones can be produced in the reaction step, and the present invention has been achieved.

[0005]

That is, the present invention provides a method of formula (2) [Wherein, R ² represents a hydrogen atom, an alkyl group, an aralkyl group,
It represents an alkoxycarbonyl group or an acyl group. And a pyridinone represented by the formula (3-1): [In the formula, R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ each independently represent a hydrogen atom, an alkyl group, an alkoxyl group, an aryl group or a halogen atom. Or an arylboronic acid represented by the formula (3-2): Wherein R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ have the same meaning as described above. Aryl boroxines represented by

Formula (4-1) [In the formula, Ar ¹ and Ar ² each independently represent a phenyl group which may have a substituent. Or an optically active form of the compound represented by the formula (4-2): [Wherein, Ar ¹ and Ar ² have the same meanings as described above. ]
In the presence of a complex of an optically active compound of the formula

Formula (1) characterized by reacting [Wherein, R ² , R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ have the same meanings as described above, and * indicates an asymmetric carbon atom. Optically active 4-aryl-2-
An object of the present invention is to provide a method for producing piperidinones.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION Pyridinones applied to the production method of the present invention are compounds represented by the formula (2). In formula (2), the substituent represented by R ² may be a hydrogen atom. The substituent R ² may be an alkyl group, an aralkyl group, an alkoxycarbonyl group, or an acyl group, and these substituents are usually substituents introduced into a nitrogen atom as a protecting group for protecting the nitrogen atom. is there. Here, as the alkyl group, for example, a methyl group, an ethyl group,
Alkyl groups having about 1 to 3 carbon atoms such as n-propyl group and isopropyl group, aralkyl groups such as benzyl group, alkoxycarbonyl groups such as t-butoxycarbonyl group, and acyl groups For example, an acetyl group, a benzoyl group and the like can be mentioned.

Such pyridinones include, for example, 5,
6-dihydro-2 (1H) -pyridinone, N-methyl-
5,6-dihydro-2 (1H) -pyridinone, N-ethyl-5,6-dihydro-2 (1H) -pyridinone, N-
n-propyl-5,6-dihydro-2 (1H) -pyridinone, Ni-propyl-5,6-dihydro-2 (1
H) -Pyridinone, Nt-butoxycarbonyl-5,
6-dihydro-2 (1H) -pyridinone, N-acetyl-5,6-dihydro-2 (1H) -pyridinone, N-benzyl-5,6-dihydro-2 (1H) -pyridinone and the like.

In the arylboronic acid represented by the formula (3-1), examples of the alkyl group for R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ include a methyl group and an ethyl group. The group may be an alkyl group substituted with a halogen atom such as a fluorine atom, a chlorine atom, and a bromine atom, for example, a trifluoromethyl group. Examples of the alkoxyl group include a methoxy group and the like, examples of the aryl group include a phenyl group, and examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine atom.

Examples of the arylboronic acid (3-1) include phenylboronic acid, 2-fluorophenylboronic acid, 3-fluorophenylboronic acid, 4-fluorophenylboronic acid, 2-chlorophenylboronic acid,
Chlorophenylboronic acid, 4-chlorophenylboronic acid, 3,5-dichlorophenylboronic acid, 4-bromophenylboronic acid, 4-methylphenylboronic acid, 3,5
-Dimethylphenylboronic acid, 4-ethylphenylboronic acid, 3-methoxyphenylboronic acid, 4-methoxyphenylboronic acid, 3-trifluoromethylphenylboronic acid, 4-phenylphenylboronic acid, and the like,
The amount used is usually about 1 to 10 times, preferably about 3 to 8 times the mol of the pyridinone represented by the formula (2).

The arylboroxines represented by the formula (3-2) are compounds which can be produced by subjecting the arylboronic acid represented by the formula (3-1) to a dehydration reaction, such as benzene. It is a compound that can be produced by a method of heating an arylboronic acid represented by the formula (3-1) in a solvent that can azeotrope with water.

The arylboroxines (3-2) include, for example, phenylboroxine, 2-fluorophenylboroxine, 3-fluorophenylboroxine,
-Fluorophenylboroxine, 2-chlorophenylboroxine, 3-chlorophenylboroxine, 4-chlorophenylboroxine, 3,5-dichlorophenylboroxine, 4-bromophenylboroxine, 2-methylphenylboroxine, 3-methylphenyl Boroxine, 4-
Methylphenylboroxine, 3,5-dimethylphenylboroxine, 4-ethylphenylboroxine, 4-methoxyphenylboroxine, 3-trifluoromethylphenylboroxine, 4-phenylphenylboroxine, etc. The amount is usually about 0.33 to 3.33 mol times, preferably about 1 to 2.66 mol times, relative to the pyridinones represented by the formula (2).

The production method of the present invention relates to a method for preparing a pyridinone (2) represented by the formula (2) and an arylboronic acid represented by the formula (3-1) or an arylboroxine represented by the formula (3-2): In the presence of an optically active form of the compound represented by the formula (4-1) or a complex of the optically active form of the compound represented by the formula (4-2) and rhodium.

Ar ¹ and Ar ² in the formulas (4-1) and (4-2) each independently represent a phenyl group, but the phenyl group may have a substituent. Here, as the substituent, for example, a methyl group, an ethyl group, i-
Examples include an alkyl group such as a propyl group and an alkoxyl group such as a methoxy group. Each phenyl group is
It may have one or more such substituents, two or three or more such substituents.

The compound represented by the formula (4-1) is
Formula (4-1R) [Wherein, Ar ¹ and Ar ² each have the same meaning as described above. Or the formula (4-1S) [Wherein, Ar ¹ and Ar ² each have the same meaning as described above. ] Has an optically active isomer having a configuration shown by the formula:

The compound represented by the formula (4-2) is represented by the formula (4)
-2R) [Wherein, Ar ¹ and Ar ² each have the same meaning as described above. Or the formula (4-2S) [Wherein, Ar ¹ and Ar ² each have the same meaning as described above. ] Has an optically active isomer having a configuration shown by the formula:

Such a complex can be produced, for example, by a method of reacting acetylacetonatobis (ethylene) rhodium with a compound represented by the formula (4-1) or a compound represented by the formula (4-2).

Here, acetylacetonatobis (ethylene) rhodium is represented by the formula (40) Is a complex compound represented by The amount of the compound represented by the formula (4-1) or the compound represented by the formula (4-2) is
It is usually about 1 to 1.3 times the mole of acetylacetonatobis (ethylene) rhodium.

The reaction is usually carried out by mixing acetylacetonatobis (ethylene) rhodium with the compound represented by the formula (4-1) or the compound represented by the formula (4-2) in a solvent. As the solvent, for example, 1,4-
Organic solvents such as dioxane, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, polar organic solvents such as methanol, ethanol, isopropanol and diglyme are used. As the solvent, such a polar organic solvent may be used alone, or two or more kinds may be used as a mixture. The solvent may include water, a non-polar solvent, and the like. The reaction temperature is usually from 10 ° C to 15 ° C.
The temperature is about 0 ° C, preferably about 20 ° C to 100 ° C.

In the reaction, the steric configuration of the compound represented by the formula (4-1) or the compound represented by the formula (4-2) is maintained as it is, and the rhodium complex of the compound represented by the formula (4-1) or Since the rhodium complex of the compound represented by the formula (4-2) is formed almost quantitatively, the compound represented by the formula (4-1)
Or a compound represented by the formula (4-2a), a compound represented by the formula (4-1R), the formula (4-1S),
An optically active complex can be obtained by using the optically active compound represented by 2R) or the formula (4-2S).

Such a complex is a complex in which an optically active form of the compound represented by the formula (4-1) or an optically active form of the compound represented by the formula (4-2) is coordinated with rhodium.
Usually, one optically active form of the compound represented by the formula (4-1) or the optically active form of the compound represented by the formula (4-2) is coordinated with rhodium. In such a complex, for example, bisacetylacetonate, ethylene, a solvent molecule, and the like constituting acetylacetonatobis (ethylene) rhodium may be coordinated with rhodium. During the reaction, a pyridinone represented by the formula (2), which is a starting compound, may be coordinated.

Among these complexes, the optically active 4-aryl-2-piperidinones (1) are represented by the formula (4-1) and are represented by Ar ¹ and A
A complex of rhodium with an optically active form of a compound in which r ² is a phenyl group substituted with an alkyl group and an alkoxyl group is preferable, and Ar ¹ and A 2 represented by the formula (4-1)
r ² is the equation (41) And a complex of rhodium with an optically active compound of a compound represented by the following formula:

The amount of the complex to be used in the production method of the present invention is usually about 0.01 to 0.1 mol, preferably about 0.0 mol, per mol of the pyridinone of the formula (2).
It is about 2 to 0.05 mole times.

The reaction is usually performed in a solvent. Examples of the solvent include 1,4-dioxane, tetrahydrofuran, dimethylformamide, dimethylacetamide, N
-Organic solvents such as polar organic solvents such as methylpyrrolidone, methanol, ethanol, isopropanol and diglyme can be used. The solvent may be such a polar organic solvent alone, or may be a mixed solvent obtained by mixing two or more polar organic solvents. The amount of the solvent to be used is generally 1 mol times to the pyridinones represented by the formula (2).
It is about 20 mole times, preferably about 3 mole times to 10 mole times.

The reaction may be carried out in the substantially absence of water or in the presence of water. It is preferable that the reaction is carried out in the presence of water in terms of the yield of the desired optically active 4-aryl-2-pyrreridinones (1), and an arylboroxine represented by the formula (3-2) is used. In this case, it is particularly preferable. When the reaction is carried out in the presence of water, the amount of water used is usually based on the amount of the boron atom contained in the arylboronic acid represented by the formula (3-1) or the arylboroxine represented by the formula (3-2). It is 0.3 mole times or more, preferably 0.6 mole times or more and 30 mole times or less, and more preferably 0.9 mole times or more.

For the reaction, for example, the compound of the formula (2)
May be mixed with an arylboronic acid represented by the formula (3-1) or an arylboroxine represented by the formula (3-2).

The complex may be prepared in advance. In the reaction of a pyridinone with an arylboronic acid or an arylboroxine, in the reaction system, acetylacetonatobis (ethylene) rhodium and an optically active compound of the compound represented by the formula (4-1) or a compound represented by the formula (4) It may be prepared by reacting the compound represented by -2) with an optically active compound. In this case, for example, acetylacetonate bis (ethylene) rhodium is mixed with an optically active form of the compound represented by the formula (4-1) or an optically active form of the compound represented by the formula (4-2) in a solvent. After that, pyridinones and arylboronic acids or arylboroxins may be added and mixed, or optically active forms of acetylacetonatobis (ethylene) rhodium and the compound represented by the formula (4-1) Alternatively, an optically active form of the compound represented by the formula (4-2) and an arylboronic acid or an arylboroxine may be mixed in a solvent, and then a pyridinone may be added. The reaction of the pyridinones with the arylboronic acids or arylboroxins is usually performed at 10 ° C to 1 ° C.
It is carried out at a temperature of about 50 ° C, preferably about 20 ° C to 100 ° C.

Thus, the optical activity 4- represented by the formula (1)
Aryl-2-piperidinones are formed. In order to obtain optically active 4-aryl-2-piperidinones from the reaction mixture after the reaction, for example, the solvent may be distilled off from the reaction mixture after the reaction. After the distillation, the obtained residue may be dissolved in, for example, ethyl acetate or the like to form a solution, and the solution may be washed with an aqueous sodium carbonate solution and dried with magnesium sulfate or the like. The dried solution may be purified by treating it with a column chromatograph.

The optically active 4-aryl- thus obtained
Examples of 2-piperidinones include 4- (phenyl)
-2-piperidinone, 4- (2-fluorophenyl)-
2-piperidinone, 4- (3-fluorophenyl) -2
-Piperidinone, 4- (4-fluorophenyl) -2-
Piperidinone, 4- (2-chlorophenyl) -2-piperidinone, 4- (3-chlorophenyl) -2-piperidinone, 4- (4-chlorophenyl) -2-piperidinone, 4- (3,5-dichlorophenyl) -2- Piperidinone, 4- (4-bromophenyl) -2-piperidinone, 4- (2-methylphenyl) -2-piperidinone,
4- (3-methylphenyl) -2-piperidinone, 4-
(4-methylphenyl) -2-piperidinone, 4-
(3,5-dimethylphenyl) -2-piperidinone, 4
-(4-ethylphenyl) -2-piperidinone, 4-
(3-methoxyphenyl) -2-piperidinone, 4-
(4-methoxyphenyl) -2-piperidinone, 4-
(3-trifluoromethylphenyl) -2-piperidinone, 4- (4-phenylphenyl) -2-piperidinone,

N-benzyl-4- (phenyl) -2-piperidinone, N-benzyl-4- (2-fluorophenyl) -2-piperidinone, N-benzyl-4- (3-fluorophenyl) -2-piperidinone , N-benzyl-
4- (4-fluorophenyl) -2-piperidinone, N
-Benzyl-4- (2-chlorophenyl) -2-piperidinone, N-benzyl-4- (3-chlorophenyl)-
2-piperidinone, N-benzyl-4- (4-chlorophenyl) -2-piperidinone, N-benzyl-4-
(3,5-dichlorophenyl) -2-piperidinone, N
-Benzyl-4- (4-bromophenyl) -2-piperidinone, N-benzyl-4- (2-methylphenyl)-
2-piperidinone, N-benzyl-4- (3-methylphenyl) -2-piperidinone, N-benzyl-4- (4
-Methylphenyl) -2-piperidinone, N-benzyl-4- (3,5-dimethylphenyl) -2-piperidinone, N-benzyl-4- (4-ethylphenyl) -2-
Piperidinone, N-benzyl-4- (3-methoxyphenyl) -2-piperidinone, N-benzyl-4- (4-
Methoxyphenyl) -2-piperidinone, N-benzyl-4- (3-trifluoromethylphenyl) -2-piperidinone, N-benzyl-4- (4-phenylphenyl) -2-piperidinone,

N-methyl-4- (phenyl) -2-piperidinone, N-methyl-4- (2-fluorophenyl)
-2-piperidinone, N-methyl-4- (3-fluorophenyl) -2-piperidinone, N-methyl-4- (4
-Fluorophenyl) -2-piperidinone, N-methyl-4- (2-chlorophenyl) -2-piperidinone, N
-Methyl-4- (3-chlorophenyl) -2-piperidinone, N-methyl-4- (4-chlorophenyl) -2-
Piperidinone, N-methyl-4- (3,5-dichlorophenyl) -2-piperidinone, N-methyl-4- (4-
Bromophenyl) -2-piperidinone, N-methyl-4
-(2-methylphenyl) -2-piperidinone, N-methyl-4- (3-methylphenyl) -2-piperidinone, N-methyl-4- (4-methylphenyl) -2-piperidinone, N-methyl- 4- (3,5-dimethylphenyl) -2-piperidinone, N-methyl-4- (4-ethylphenyl) -2-piperidinone, N-methyl-4-
(3-methoxyphenyl) -2-piperidinone, N-methyl-4- (4-methoxyphenyl) -2-piperidinone, N-methyl-4- (3-trifluoromethylphenyl) -2-piperidinone, N-methyl -4- (4-phenylphenyl) -2-piperidinone,

N-ethyl-4- (phenyl) -2-piperidinone, N-ethyl-4- (2-fluorophenyl)
-2-piperidinone, N-ethyl-4- (3-fluorophenyl) -2-piperidinone, N-ethyl-4- (4
-Fluorophenyl) -2-piperidinone, N-ethyl-4- (2-chlorophenyl) -2-piperidinone,
-(3-chlorophenyl) -2-piperidinone, N-ethyl-4- (4-chlorophenyl) -2-piperidinone, N-ethyl-4- (3,5-dichlorophenyl)-
2-piperidinone, N-ethyl-4- (4-bromophenyl) -2-piperidinone, N-ethyl-4- (2-methylphenyl) -2-piperidinone, N-ethyl-4-
(3-methylphenyl) -2-piperidinone, N-ethyl-4- (4-methylphenyl) -2-piperidinone,
N-ethyl-4- (3,5-dimethylphenyl) -2-
Piperidinone, N-ethyl-4- (4-ethylphenyl) -2-piperidinone, N-ethyl-4- (3-methoxyphenyl) -2-piperidinone, N-ethyl-4-
(4-methoxyphenyl) -2-piperidinone, N-ethyl-4- (3-trifluoromethylphenyl) -2-
Piperidinone, N-ethyl-4- (4-phenylphenyl) -2-piperidinone,

Nn-propyl-4- (phenyl) -2
-Piperidinone, N-n-propyl-4- (2-fluorophenyl) -2-piperidinone, N-n-propyl-
4- (3-fluorophenyl) -2-piperidinone, N
-N-propyl-4- (4-fluorophenyl) -2-
Piperidinone, Nn-propyl-4- (2-chlorophenyl) -2-piperidinone, Nn-propyl-4-
(3-chlorophenyl) -2-piperidinone, Nn-
Propyl-4- (4-chlorophenyl) -2-piperidinone, Nn-propyl-4- (3,5-dichlorophenyl) -2-piperidinone, Nn-propyl-4-
(4-bromophenyl) -2-piperidinone, Nn-
Propyl-4- (2-methylphenyl) -2-piperidinone, Nn-propyl-4- (3-methylphenyl)
-2-piperidinone, N-n-propyl-4- (4-methylphenyl) -2-piperidinone, N-n-propyl-4- (3,5-dimethylphenyl) -2-piperidinone, N-n-propyl -4- (4-ethylphenyl)-
2-piperidinone, N-n-propyl-4- (3-methoxyphenyl) -2-piperidinone, N-n-propyl-4- (4-methoxyphenyl) -2-piperidinone,
Nn-propyl-4- (3-trifluoromethylphenyl) -2-piperidinone, Nn-propyl-4-
(4-phenylphenyl) -2-piperidinone,

Ni-propyl-4- (phenyl) -2
-Piperidinone, Ni-propyl-4- (2-fluorophenyl) -2-piperidinone, Ni-propyl-
4- (3-fluorophenyl) -2-piperidinone, N
-I-propyl-4- (4-fluorophenyl) -2-
Piperidinone, Ni-propyl-4- (2-chlorophenyl) -2-piperidinone, Ni-propyl-4-
(3-chlorophenyl) -2-piperidinone, Ni-
Propyl-4- (4-chlorophenyl) -2-piperidinone, Ni-propyl-4- (3,5-dichlorophenyl) -2-piperidinone, Ni-propyl-4-
(4-bromophenyl) -2-piperidinone, Ni-
Propyl-4- (2-methylphenyl) -2-piperidinone, Ni-propyl-4- (3-methylphenyl)
-2-piperidinone, Ni-propyl-4- (4-methylphenyl) -2-piperidinone, Ni-propyl-4- (3,5-dimethylphenyl) -2-piperidinone, Ni-propyl -4- (4-ethylphenyl)-
2-piperidinone, Ni-propyl-4- (3-methoxyphenyl) -2-piperidinone, Ni-propyl-4- (4-methoxyphenyl) -2-piperidinone,
Ni-propyl-4- (3-trifluoromethylphenyl) -2-piperidinone, Ni-propyl-4-
(4-phenylphenyl) -2-piperidinone,

Nt-butoxycarbonyl-4- (phenyl) -2-piperidinone, Nt-butoxycarbonyl-4- (2-fluorophenyl) -2-piperidinone, Nt-butoxycarbonyl-4- ( 3-fluorophenyl) -2-piperidinone, Nt-butoxycarbonyl-4- (4-fluorophenyl) -2-piperidinone, Nt-butoxycarbonyl-4- (2-chlorophenyl) -2-piperidinone, N -T-butoxycarbonyl-4- (3-chlorophenyl) -2-piperidinone, Nt-butoxycarbonyl-4- (4-chlorophenyl) -2-piperidinone, Nt-butoxycarbonyl-4- (3,5 -Dichlorophenyl) -2-piperidinone, Nt-butoxycarbonyl-4- (4-bromophenyl) -2- Peridinone, Nt-butoxycarbonyl-4- (2-methylphenyl) -2-piperidinone, Nt-butoxycarbonyl-4- (3-methylphenyl) -2-piperidinone, Nt-butoxycarbonyl-4 -(4-methylphenyl) -2-piperidinone, Nt-butoxycarbonyl-4- (3,5-dimethylphenyl) -2-piperidinone, Nt-butoxycarbonyl-4- (4-ethylphenyl)- 2-piperidinone, Nt-butoxycarbonyl-4- (3-methoxyphenyl) -2-piperidinone, Nt-butoxycarbonyl-4- (4-methoxyphenyl) -2-piperidinone, Nt-butoxycarbonyl -4- (3-trifluoromethylphenyl) -2-piperidinone, N-
t-butoxycarbonyl-4- (4-phenylphenyl) -2-piperidinone,

N-acetyl-4- (phenyl) -2-piperidinone, N-acetyl-4- (2-fluorophenyl) -2-piperidinone, N-acetyl-4- (3-fluorophenyl) -2-piperidinone , N-acetyl-
4- (4-fluorophenyl) -2-piperidinone, N
-Acetyl-4- (2-chlorophenyl) -2-piperidinone, N-acetyl-4- (3-chlorophenyl)-
2-piperidinone, N-acetyl-4- (4-chlorophenyl) -2-piperidinone, N-acetyl-4-
(3,5-dichlorophenyl) -2-piperidinone, N
-Acetyl-4- (4-bromophenyl) -2-piperidinone, N-acetyl-4- (2-methylphenyl)-
2-piperidinone, N-acetyl-4- (3-methylphenyl) -2-piperidinone, N-acetyl-4- (4
-Methylphenyl) -2-piperidinone, N-acetyl-4- (3,5-dimethylphenyl) -2-piperidinone, N-acetyl-4- (4-ethylphenyl) -2-
Piperidinone, N-acetyl-4- (3-methoxyphenyl) -2-piperidinone, N-acetyl-4- (4-
Methoxyphenyl) -2-piperidinone, N-acetyl-4- (3-trifluoromethylphenyl) -2-piperidinone, N-acetyl-4- (4-phenylphenyl) -2-piperidinone and the like.

[0038]

According to the production method of the present invention, the pyridinone and the arylboronic acid or the arylboroxine are used as the raw materials in one step to produce the optically active 4-aryl-2-aryl.
Piperidinones can be produced.

[0039]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 Under a nitrogen atmosphere, acetylacetonatobis (ethylene) rhodium (1.6 mg) was added to a reaction vessel under the formula (51). (5.6 mg) and 122 mg of 4-fluorophenylboroxine were added, 1 cm ³ of 1,4-dioxane was added, and the mixture was stirred at room temperature for 3 minutes and mixed. Then, N-benzyl-5,6-dihydro-2 (1
37.4 mg of H) -pyridinone and 18 mm ³ of water were added, and the mixture was stirred and reacted at 40 ° C. for 12 hours.

The reaction mixture after the reaction was concentrated under reduced pressure, and ethyl acetate was added to the obtained residue to form a solution. The solution was washed with a saturated aqueous solution of sodium carbonate, and dried by adding magnesium sulfate. After drying, magnesium sulfate was removed and purified by column chromatography to give N-benzyl-4-.
41.9 mg of (4-fluorophenyl) -2-piperidine [R-isomer, enantiomeric excess was 96% ee] was obtained (yield 74%).

Example 2 Instead of the compound represented by the formula (51), a compound represented by the formula (52) Except for using 4.1 mg of a compound (R-form) represented by
By operating in the same manner as in Example 1, N-benzyl-4- (4-
Fluorophenyl) -2-piperidine [R-isomer, enantiomeric excess 97% ee] was obtained in a yield of 63%.

Example 3 Instead of the compound represented by the formula (51), the compound represented by the formula (53) Except for using 4.2 mg of the compound (R-form) represented by
By operating in the same manner as in Example 1, N-benzyl-4- (4-
Fluorophenyl) -2-piperidine [R-isomer, enantiomeric excess 96% ee] was obtained in a yield of 53%.

Example 4 Instead of the compound represented by the formula (51), the compound represented by the formula (54) Except that 4.9 mg of the compound (R-isomer) represented by
By operating in the same manner as in Example 1, N-benzyl-4- (4-
Fluorophenyl) -2-piperidine [R-isomer, enantiomeric excess 96% ee] was obtained in a yield of 54%.

Example 5 N-benzyl-4- (4-fluorophenyl) -2-piperidine [R-form] was prepared in the same manner as in Example 2 except that the reaction was carried out at 100 ° C. without adding water. Obtained. The yield was less than 5%.

Example 6 The procedure of Example 2 was repeated, except that 103 mg of phenylboroxine was used instead of 4-fluorophenylboroxine, the reaction temperature was 100 ° C., and the reaction time was 3 hours. -Benzyl-4- (phenyl) -2-piperidinone [R-isomer, enantiomeric excess is 94% ee] with a yield of 75
%.

Example 7 Phenylboronic acid 122m in place of phenylboroxine
g and 1,4 dioxane 1 cm ³ instead of 1,4
- a mixed solvent 1 cm ³ of dioxane 0.9 cm ³ and water 0.1 cm ^3, except that the reaction without the addition of water 18 mm ³ are in the same manner as in Example 6, N-benzyl -
4- (Phenyl) -2-piperidinone [R-form, enantiomeric excess 93% ee] was obtained in a yield of 70%.

Example 8 In place of 4-fluorophenylboroxine, 137 mg of 4-chlorophenylboroxine was used.
Except that the reaction time was 6 hours, the procedure was as in Example 2, except that N-benzyl-4- (4-chlorophenyl) was used.
-2-piperidinone [R-isomer, enantiomeric excess is 95%
ee] in a yield of 68%.

Example 9 Example 9 was repeated except that 19.4 mg of 5,6-dihydro-2 (1H) -pyridinone was used instead of N-benzyl-5,6-dihydro-2 (1H) -pyridinone. By the same operation, 4- (4-fluorophenyl) -2-piperidinone [R-isomer, enantiomeric excess 98.3% ee] was obtained in a yield of 82%.

Example 10 The procedure of Example 9 was repeated, except that 4.1 mg of the compound represented by the formula (52) was used instead of the compound represented by the formula (51). Phenyl) -2-piperidinone [R-isomer, enantiomeric excess is 97.8% e
e] was obtained with a yield of 73%.

Example 11 The procedure of Example 9 was repeated, except that 4.2 mg of the compound represented by the formula (53) was used instead of the compound represented by the formula (51). Phenyl) -2-piperidinone [R-isomer, enantiomeric excess is 98.4% e
e] was obtained with a yield of 84%.

Example 12 The procedure of Example 9 was repeated, except that 4.9 mg of the compound of the formula (54) was used instead of the compound of the formula (51), to give 4- (4-fluoro Phenyl) -2-piperidinone [R-isomer, enantiomeric excess is 98.5% e
e] was obtained with a yield of 76%.

Claims (9)

[Claims] 1. Equation (2) [Wherein, R ² represents a hydrogen atom, an alkyl group, an aralkyl group,
It represents an alkoxycarbonyl group or an acyl group. And a pyridinone represented by the formula (3-1): [In the formula, R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ each independently represent a hydrogen atom, an alkyl group, an alkoxyl group, an aryl group or a halogen atom. Or an arylboronic acid represented by the formula (3-2): Wherein R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ have the same meaning as described above. With an arylboroxine of the formula (4-1) [In the formula, Ar ¹ and Ar ² each independently represent a phenyl group which may have a substituent. Or an optically active form of the compound represented by the formula (4-2): [Wherein, Ar ¹ and Ar ² have the same meanings as described above. ]
Wherein the reaction is carried out in the presence of a complex of an optically active form of the compound represented by the formula and rhodium. [Wherein, R ² , R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ have the same meanings as described above, and * indicates an asymmetric carbon atom. Optically active 4-aryl-2-
A method for producing piperidinone. 2. The method according to claim 1, wherein Ar ¹ and Ar ² in the formula (4-1) are each a phenyl group substituted with an alkyl group and an alkoxyl group. 3. Ar ¹ and Ar ² are of the formula (41) The production method according to claim 2, wherein the substituent is represented by the formula: 4. The production method according to claim 1, wherein the reaction is carried out in an organic solvent. 5. The method according to claim 4, wherein the organic solvent is a polar organic solvent, and the reaction is carried out in the presence of water. 6. The amount of water used is 0.3 mole times the boron atom contained in the arylboronic acids represented by the formula (3-1) or the arylboroxins represented by the formula (3-2). The manufacturing method according to claim 5, which is the above. 7. A complex of rhodium with a compound represented by the formula (4-1), wherein Ar ¹ and Ar ² are both phenyl groups substituted by an alkyl group and an alkoxyl group. 8. The complex according to claim 7, wherein Ar ¹ and Ar ² are both substituents represented by the formula (41). 9. An acetylacetonatobis (ethylene) rhodium compound of the formula (4-1a) [Wherein, Ar ¹ and Ar ² each have the same meaning as described above. The method for producing a complex according to claim 7, wherein the compound is reacted with a compound represented by the formula: