JP2002348279A - Production method for optically active pyridylketone derivatives and optically active pyridylketone derivatives - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide optically active pyridylketone derivatives represented by general formula (2) which have neuron differentiation-promoting activity or neuroprotective activity. SOLUTION: The present invention is completed by finding that a diastereomer salt of the racemic body of a compound represented by general formula (1) and an optically active amine is separated, and the salt thus obtained is discomposed to give an optically active compound represented by general formula (1) as a free acid, and then the optically active compound thus obtained is subjected to a dehydration-and-condensation reaction with an amine, alcohol or phenol to give the optically active pyridylketone derivative represented by general formula (2).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active pyridyl ketone derivative which can be used as an agent for promoting neuronal differentiation or a neuroprotective agent, an optically active pyridyl ketone derivative and a salt thereof.

[0002]

2. Description of the Related Art Ketone derivatives having a high neuronal cell differentiation promoting action or a neuroprotective action have been reported (for example, PCT WO 99/05091;
-263770 and JP-A-11-263771).

[0003]

A racemic pyridyl ketone derivative represented by the following general formula (1) or (2) has already been filed (PCT / JP00 / 08090).
However, an optically active form of the compound represented by the formula (1) or (2) and a production method thereof have not been known.

[0004]

The present invention relates to a method for producing an optically active compound of the compound represented by the general formula (2) having an asymmetric carbon, the compound, a salt thereof, and an intermediate thereof. The present inventors have conducted intensive studies and found that the general formula (1)
The diastereomeric salt of the racemic compound of the compound represented by the formula and the optically active amine is separated, and the obtained salt is decomposed to obtain the optically active compound represented by the general formula (1). It has been found that an optically active pyridyl ketone derivative represented by the general formula (2) can be obtained by a dehydration condensation reaction with phenols or phenols, and completed the present invention. That is, the present invention

1) The following general formula (1)

Embedded image Wherein R1 is -C (= O) R4, -C (= O) OR
5, -C (= O) NR6R7 or -SO2R8 (R4,
R5, R6, R7 and R8 are the same or different and are a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group which may have a substituent, and an aryl which may have a substituent. R2 represents a hydrogen atom, an alkyl group or a cycloalkyl group, and represents an RS configuration at the position of the carbon atom marked with *.] Wherein one of the diastereomeric salts formed from is separated, then the diastereomeric salt is decomposed, and then an ester bond or an amide bond is formed with an amine, an alcohol or a phenol with a dehydrating condensing agent. Equation (2)

Embedded image [Wherein, R1 and R2 are the same as above. R3 is -OR9 (R
9 has an alkyl group, an aryl group which may have a substituent, an arylalkyl group which may have a substituent, a heterocyclic group which may have a substituent, and a substituent. Or a good heterocyclic alkyl group) or -NR10R11
(R10 and R11 are the same or different and represent a hydrogen atom, an alkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or R
10 and R11 together with the nitrogen atom form a heterocyclic ring which may have a substituent), and the R or S configuration is shown at the position of the carbon atom indicated by *. A method for producing an active pyridyl ketone derivative. 2) R1 in the general formulas (1) and (2) is -C (= O) R4
(R4 represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a cycloalkyl group). 3) R1 in the general formulas (1) and (2) represents an acetyl group;
The method for producing an optically active pyridyl ketone derivative according to the above 1), wherein R2 is a methyl group, a cyclohexyl group or a hydrogen atom.

4) The process for producing an optically active pyridyl ketone derivative according to the above 1), wherein the optically active amine that forms a diastereomer salt is an optically active 2-hydroxy-2-phenethylamine. 5) An optically active 2-hydroxy-2-phenethylamine is represented by the following general formula (3)

Embedded image [Wherein, Ar represents a phenyl group which may have a substituent, R12 represents a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent,
R13 and R14 are the same or different and each represent a hydrogen atom or an alkyl group, and when the carbon atom at the position of * is an asymmetric carbon atom, each represents an R configuration or an S configuration.] A method for producing a ketone derivative. 6) Ar in the general formula (3) represents a phenyl group, a p-nitrophenyl group or a 3,4-dihydroxyphenyl group;
12. The method for producing an optically active pyridyl ketone derivative according to the above 5), wherein 12 represents a hydrogen atom, a methyl group or a hydroxymethyl group, and R13 and R14 are both a hydrogen atom or a hydrogen atom and a methyl group.

7) Optically active 2-hydroxy-2-phenethylamines are represented by (1R, 2S)-(-)-2-amino-
1,2-diphenylethanol, (1S, 2R)-
(+)-2-amino-1,2-diphenylethanol,
(1R, 2S)-(−)-ephedrine, (1S, 2
R)-(+)-ephedrine, (1R, 2S)-(-)
-Norephedrine, (1S, 2R)-(+)-Norephedrine, (1R, 2R)-(-)-2-amino-1
-Phenyl-1,3-propanediol, (1S, 2
S)-(+)-2-Amino-1-phenyl-1,3-propanediol, (1R, 2R)-(-)-2-amino-1- (4-nitrophenyl) -1,3-propane Diol, (1S, 2S)-(+)-2-amino-1- (4
-Nitrophenyl) -1,3-propanediol,
(R)-(-)-norepinephrine or (S)-(+)
The method for producing an optically active pyridyl ketone derivative according to the above 4), which is -norepinephrine. 8) The process for producing an optically active pyridyl ketone derivative according to the above 1), wherein the amine bound by the dehydrating condensing agent is dimethylamine, diethylamine, piperidine or pyrrolidine. 9) The method for producing an optically active pyridyl ketone derivative according to 1) above, wherein the amine bound by the dehydrating condensing agent is piperidine.

10) An optically active pyridyl ketone derivative represented by the general formula (1) or a salt thereof according to any one of the above 1) to 3). 11) The optically active pyridyl ketone derivative represented by the general formula (1) according to any one of the above 1) to 3) and the optically active 2-hydroxy-2-phenethylamine according to any one of the above 5) to 7). Diastereomeric salts with the class. 12) An optically active pyridyl ketone derivative represented by the general formula (2) according to any one of the above 1) to 3) or a salt thereof.

13) In the general formula (2), R1 is -C
(= O) R4 (R4 represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a cycloalkyl group), and R3 represents -NR10R11 (R10 and R11 are the same or different and represent a hydrogen atom or an alkyl group) Or R
10) and R11 together represent a 5- to 7-membered ring containing 0 to 1 nitrogen atom and 0 to 1 other heteroatom), or an optically active pyridyl ketone derivative or a salt thereof according to the above item 12). 14) In the general formula (2), R1 is -C (= O) R4
(R4 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms), R2 represents a methyl group, a cyclohexyl group or a hydrogen atom, and R3 represents a dimethylamino group, a diethylamino group, a 1-piperidyl group or a 1-pyrrolidinyl. 12. The optically active pyridyl ketone derivative or a salt thereof according to the above item 12), wherein

15) In the general formula (1), R1 is -C
(＝ O) The optically active pyridyl ketone derivative or a salt thereof according to the above 10), which is represented by R4 (R4 represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a cycloalkyl group). 16) In the general formula (1), R1 represents an acetyl group;
The optically active pyridyl ketone derivative or a salt thereof according to the above 10), wherein R2 is a hydrogen atom.

17) Ar in the general formula (3) represents an unsubstituted phenyl group substituted with a hydroxyl group or a nitro group;
12. The optically active salt according to the above 11), wherein 12 represents a hydrogen atom or an alkyl group which may be substituted with a hydroxyl group, and R13 and R14 are the same or different and are a hydrogen atom or an alkyl group. About.

[0012]

DESCRIPTION OF THE PREFERRED EMBODIMENTS A production scheme of a compound of the general formula (2) including the production method of the present invention is shown.

-Scheme-

The process for producing the optically active pyridyl ketone derivative represented by the above general formula (2) according to the present invention comprises the general formula (1)
Is separated from one of the diastereomeric salts formed from the racemic form of the pyridyl ketone derivative and the optically active amine, and then decomposes the diastereomer salt, and then amines, alcohols or It is characterized by forming an ester bond or an amide bond with phenols.

In the above general formulas (1) and (2), R1 is -C (= O) R4, -C (= O) OR5, -C (= O)
NR6R7 or -SO2R8 (R4, R5, R6, R7
And R8 are the same or different and represent a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group optionally having a substituent, or an arylalkyl group optionally having a substituent. And R2 is a hydrogen atom, an alkyl group or a cycloalkyl group. In the general formula (2), R3 is -OR9 (R9 is an alkyl group, an aryl group which may have a substituent, an arylalkyl group which may have a substituent, and a substituent. A heterocyclic group which may be substituted, a heterocyclic alkyl group which may have a substituent) or -NR10R11 (R10 and R10)
11 is the same or different and represents a hydrogen atom, an alkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or R10 and R11
Represents a heterocyclic ring which may have a substituent together with a nitrogen atom). In the above formula, the alkyl group is a straight-chain or branched-chain hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms and having no unsaturated bond, such as a methyl group, an ethyl group, and an n- Propyl group, n-
Butyl, n-pentyl, isopropyl, s-butyl, t-butyl and the like.

In the general formulas (1) and (2), the alkenyl group is a straight-chain or branched-chain hydrocarbon group having at least one double bond having 2 to 10 carbon atoms, preferably 2 to 5 carbon atoms. And preferably a double bond having 2 to 5 carbon atoms such as a vinyl group, a propenyl group, a 1-butenyl group, a 2-butenyl group, a 3-methyl-1-butenyl group and a 2-methyl-2-butenyl group. And a hydrocarbon group having one. In the above general formulas (1) and (2), the alkynyl group is a linear or branched hydrocarbon group having at least one triple bond having 2 to 10 carbon atoms, preferably 2 to 5 carbon atoms. Ethynyl group, propynyl group,
Examples thereof include a 1-butynyl group, a 2-butynyl group, and a 3-methyl-1-butynyl group. In the general formulas (1) and (2), the cycloalkyl group is a cyclic hydrocarbon group having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, And cyclohexyl group.

In the general formulas (1) and (2), the aryl group is an aromatic hydrocarbon group, such as a phenyl group and a naphthyl group. In the case of having a substituent, for example, a phenyl group may have 1 to 5 substituents, and for example, a naphthyl group may have 1 to 7 substituents. Represents an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, and 2 carbon atoms.
To 10 alkynyl groups, cycloalkyl groups having 3 to 8 carbon atoms, lower alkoxy groups having 1 to 5 carbon atoms, 1 carbon atoms
An acyl group having 1 to 5 carbon atoms, an acylamino group having 1 to 5 carbon atoms,
Examples thereof include a halogenoalkyl group having 1 to 3 carbon atoms, a hydroxyl group, a cyano group, and a halogen atom. When a compound has a plurality of substituents, the substituents may be the same or different, and when such positional isomers are present, all such isomers are also included in the present invention. Specific examples of the alkyl group having 1 to 5 carbon atoms, the alkenyl group having 2 to 10 carbon atoms, the alkynyl group having 2 to 10 carbon atoms, and the cycloalkyl group having 3 to 8 carbon atoms as the substituent include those described above. Groups. Also, the substituent has 1 to 5 carbon atoms.
Examples of the lower alkoxyl group include methoxy, ethoxy, n-propoxy, isopropoxy and n-
Butoxy group, s-butoxy group, t-butoxy group, n-pentyloxy group and the like. Examples of the acyl group having 1 to 5 carbon atoms include formyl group, acetyl group, propionyl group, butyryl group, valeryl group and the like. Examples of the acylamino group having 1 to 5 carbon atoms include formylamino group, acetylamino group, propionylamino group, and butyrylamino group. Examples of the halogenoalkyl group having 1 to 3 carbon atoms include fluoromethyl. Group, trifluoromethyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, bromomethyl group, dibromomethyl group, methyl iodide group, fluoroethyl group, trifluoroethyl group, trichloroethyl group, tetrachloroethyl group, pentachloro Ethyl group, tribromoethyl group, tetrabromoethyl group, Examples include a fluoropropyl group, a trichloropropyl group, a heptachloropropyl group, and a tetrabromopropyl group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the general formulas (1) and (2), the arylalkyl group is a group in which the above-mentioned aryl group is bonded to the above-mentioned alkyl group, for example, benzyl group, phenethyl group,
And a diphenylmethyl group. When the aryl group has a substituent, examples thereof include the same groups as the above-described aryl group. In the above general formulas (1) and (2), the heteroaryl group represents, for example, a 5- to 10-membered heteroaromatic ring containing at least one nitrogen atom, oxygen atom or sulfur atom as a hetero atom. Specific examples include a pyridyl group, a furyl group, a benzofuryl group, a thienyl group, a benzothienyl group, a quinolyl group, a pyrrolyl group, an indolyl group, an oxazolyl group, a pyrazolyl group, an isothiazolyl group, a pyridazinyl group, a pyrimidinyl group, and a pyrazinyl group. Can be When the aryl group has a substituent, examples thereof include the same groups as the above-described aryl group. In the above general formulas (1) and (2), the heterocyclic ring represents a monocyclic ring or a condensed ring containing 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom. . Specifically, for example, morpholinyl group, pyrrolidinyl group, piperidinyl group, hydantoyl group, oxiranyl group, oxetanyl group, tetrahydrofuryl group, tetrahydropyranyl group, tetrahydropyridyl group, tetrahydropyrimidinyl group, tetrahydrothienyl group, tetrahydrothiopyranyl group And the like. Further, when a substituent is present on the ring, the same groups as the above-mentioned substituents of the aryl group can be mentioned, and specific examples thereof are mentioned above. In the present invention, as a combination of the substituents of the general formula (1), R1 is an acetyl group, R2 is a hydrogen atom or an alkyl group is a methyl group, and a cycloalkyl group is a cyclohexyl group. Atoms are preferred. or,
As a combination of the substituents of the general formula (2), R1 is an acetyl group, R2 is a hydrogen atom or an alkyl group, a methyl group; a cycloalkyl group, a cyclohexyl group;
3 includes dimethylamino group, diethylamino group, 1
A -piperidyl group or 1-pyrrolidinyl group is preferred, and R2 is preferably a hydrogen atom and R3 is preferably a 1-piperidyl group.

The optically active amine used in the present invention is not particularly limited as long as it is an optically active amine which forms a diastereomer salt with the compound of the general formula (1). Phenethylamines. As the optically active 2-hydroxy-2-phenethylamines, Ar represents a phenyl group which may have a substituent, and R12 has a hydrogen atom, an alkyl group which may have a substituent, or a substituent. R13 and R14 are the same or different and each represent a hydrogen atom or an alkyl group, and when the carbon atom indicated by * is an asymmetric carbon atom, a general formula showing an R configuration or an S configuration, respectively. The amine represented by (3) is mentioned. In the general formula (3), Ar
Represents a phenyl group which may have a substituent, and examples of the substituent include the same groups as the above-described substituents of the aryl group, and specific examples thereof include the above examples. Preferred is an unsubstituted phenyl group, a phenyl group substituted with a hydroxyl group or a nitro group, and more preferred is an unsubstituted phenyl group, a p-nitrophenyl group or a 3,4-dihydroxyphenyl group. R12 represents a hydrogen atom, an alkyl group which may have a substituent, or an aryl group which may have a substituent, wherein an alkyl group which may have a substituent, Examples of the preferable aryl group include the above-mentioned alkyl group which may have a substituent and the same group as the above-mentioned aryl group which may have a substituent, and specific examples include the above examples. Preferably, an alkyl group which may be substituted with a hydrogen atom or a hydroxyl group, for example, a methyl group, a hydroxymethyl group and the like are exemplified. R13 and R14 are the same or different and each represent a hydrogen atom or an alkyl group, and the alkyl group includes the same groups as the above-mentioned alkyl groups, and specific examples include the above-described examples. The alkyl group is particularly preferably a lower alkyl group such as a methyl group.

As the optically active 2-hydroxy-2-phenethylamines represented by the general formula (3), generally available, for example, (1R, 2S)-(-)-2-amino-
1,2-diphenylethanol, (1S, 2R)-
(+)-2-amino-1,2-diphenylethanol,
(1R, 2S)-(−)-ephedrine, (1S, 2
R)-(+)-ephedrine, (1R, 2S)-(-)
-Norephedrine, (1S, 2R)-(+)-Norephedrine, (1R, 2R)-(-)-2-amino-1
-Phenyl-1,3-propanediol, (1S, 2
S)-(+)-2-Amino-1-phenyl-1,3-propanediol, (1R, 2R)-(-)-2-amino-1- (4-nitrophenyl) -1,3-propane Diol, (1S, 2S)-(+)-2-amino-1- (4
-Nitrophenyl) -1,3-propanediol,
(R)-(-)-epinephrine, (S)-(+)-epinephrine, (R)-(-)-norepinephrine, (S)
-(+)-Norepinephrine, among which (1
R, 2S)-(-)-2-amino-1,2-diphenylethanol and (1S, 2R)-(+)-2-amino-
1,2-Diphenylethanol is particularly preferred.

The production method of the present invention will be described in detail. The above-mentioned optically active amine and a solvent, and in some cases, an isomerization auxiliary are added to the racemic form of the compound represented by the general formula (1), and the temperature is from 40 ° C to a temperature of about the boiling point of the solvent used, preferably from 50 ° C to 70 ° C. C. for several hours to several tens of hours under heating and stirring, and after the racemate and the optically active amine, etc. are dissolved, -10
Cool to 40 ° C to 40 ° C and separate the diastereomeric salt that has precipitated out.

As the solvent, an organic solvent is usually preferable, and specific examples thereof include lower alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and 2-butanol, acetone, methyl ethyl ketone and methyl isobutyl ketone. , Diethyl ketone, di-
Ketones such as n-propyl ketone, di-iso-propyl ketone, methyl isopropyl ketone, aromatic hydrocarbons such as benzene, toluene, xylene, tetrahydrofuran, dioxane, isopropyl ether, 2-methoxyethyl ether, t-butoxymethyl Ethers such as ether and diethyl ether; hydrocarbons such as hexane, heptane and octane; halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane; esters such as methyl acetate, ethyl acetate and butyl acetate; Examples thereof include nitriles such as acetonitrile and propionitrile, and a mixed solvent composed of an appropriate combination of these organic solvents. More preferably, alcohols such as ethanol, 1-propanol, 2-propanol and 1-butanol are used. But There. The amount used varies depending on the solvent used, the racemate used and the optically active amine, but the amount of the solvent in which the racemate used and the optically active amine are dissolved is a guide. Approximately, about 1 to 200 mL, preferably about 2 to 80 mL, per 1 g of the diastereomer salt is good.

The molar ratio of the optically active amine used as a resolving agent to the compound of the formula (1) is preferably 0.8 to 1.2 equivalents from the viewpoint of the resolving efficiency. In addition, as the isomerization aid which may be used in the crystallization and causes isomerization between optical isomers, usually, amines which are more basic than the optically active amine are exemplified. Such amines include 1,
8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 6-dibutylamino-1,8-
Diazabicyclo [5.4.0] undec-7-ene, 1,
4-diazabicyclo [2.2.2] octane (DABC
Organic bases such as O), alkali metal alkoxides such as potassium t-butoxide and sodium methoxide, triethylamine, tri-n-butylamine, N, N-dimethylaminocyclohexylamine, N, N, N ′, N′-tetramethylenediamine Tertiary amines such as
BU, DBN and DABCO are preferred. The amount used is about 0.01 to 1 mol of the diastereomer salt.
About 0.3 mol is preferable, and preferably about 0.02 to 0.1 mol.
About 2 mol is good. Furthermore, isomerization between optical isomers also occurs by heating a salt solution of the optically active amine and the compound represented by the general formula (1).

Next, the obtained crystals of the diastereomer salt are recrystallized, if necessary, and then a weakly basic aqueous solution such as an aqueous solution of sodium hydrogencarbonate is added at -5 ° C to 20 ° C, preferably -5 ° C to 5 ° C. The salt is decomposed without causing racemization by acting at a low temperature of ℃, and the liberated optically active amine is immiscible with water, such as an organic solvent such as ethyl acetate, diethyl ether, chloroform, toluene, and tetrahydrofuran. By extracting and separating the mixture with the mixed organic solvent, an aqueous solution of the compound of the general formula (1) having high optical purity and chemical purity can be obtained. If necessary, the pyridyl ketone derivative of the general formula (1) can be isolated by neutralizing the aqueous solution and applying a commonly used purification method of an organic compound as necessary.

Further, the optically active pyridyl ketone derivative represented by the general formula (1) or a solution thereof is converted into benzene,
Toluene, aromatic hydrocarbons such as xylene, chloroform, dichloromethane, halogenated hydrocarbons such as 1,2-dichloroethane, tetrahydrofuran, dioxane,
Isopropyl ether, 2-methoxyethyl ether,
A solvent selected from ethers such as diethyl ether,
Or in a mixed solvent thereof at -5 ° C to 20 ° C, preferably-
At a low temperature of 5 ° C to 5 ° C, 1- [3- (dimethylamino)
Propyl] -3-ethylcarbodiimide hydrochloride,
By reacting with a dehydrating condensing agent such as 1'-carbonyldiimidazole and 1,3-dicyclohexylcarbodiimide and an appropriate alcohol, amine or phenol, an ester bond or an amide bond is formed by a dehydrating condensation reaction without racemization. The pyridyl ketone derivative represented by the general formula (2) is obtained. Suitable alcohols, amines or phenols include the compounds corresponding to R3 in general formula (2).
The compounds corresponding to R3 are preferably amines, among which dimethylamine, diethylamine, piperidine and pyrrolidine are preferable, and pyrrolidine is particularly preferable. The optically active pyridyl ketone derivative of the general formula (2) is
Isolation can be performed by applying a commonly used purification method of an organic compound.

The racemic compound represented by the general formula (1), which is a raw material of this production method, is prepared, for example, according to the above-mentioned scheme.
Compound (5) described in JP-A No. 11-263770 was used to prepare alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and 2-butanol, tetrahydrofuran, dioxane, isopropyl ether and 2-methoxyethyl ether. , An ether such as diethyl ether, water and an appropriate combination of these solvents, an aminomethylation reaction using formalin and an appropriate primary or secondary amine, for example, piperidine, followed by the same solvent It can also be produced by reacting an appropriate aminoethanethiol derivative at 50 ° C. to the boiling point of the solvent, preferably 60 ° C. to 90 ° C. In addition, the compound (5) is commercially available and can be easily obtained from the compound (4) according to the above publication.
It can also be synthesized by reacting sodium cyanate and an acrylate and then hydrolyzing the ester.

The present invention further includes an optically active pyridyl ketone derivative represented by the above general formula (1) or a salt thereof. As the ion when the salt of the optically active pyridyl ketone derivative represented by the general formula (1) is a salt with a base,
Alkali metal ion such as sodium ion, potassium ion, lithium ion, etc., alkaline earth metal ion such as magnesium ion, calcium ion, etc., ammonium ion, organic ammonium ion such as trimethylammonium ion, dimethylammonium ion, tris (hydroxyethyl) Ammonium ion and the like. Examples of the organic ammonium ion include an ammonium ion based on an optically active amine which can be used in the method for producing the optically active pyridyl ketone derivative of the present invention. Examples of the acid used in the case of the acid addition salt include the acids described below. Furthermore, the present invention also includes an optically active pyridyl ketone derivative represented by the above general formula (2) or a salt thereof. Examples of the acid used when the salt of the optically active pyridyl ketone derivative represented by the general formula (2) is an acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and acetic acid, propionic acid, oxalic acid, and the like. Cinnamic acid, benzoic acid,
Organic acids such as p-nitrobenzoic acid, trifluoroacetic acid, methanesulfonic acid, and paratoluenesulfonic acid are exemplified.

Examples of the compound represented by the general formula (1) or (2) in the present invention include the following compounds. The symbols used as abbreviations are as follows, and also indicate optical isomers. (Ac: acetyl group, Me: methyl group, Et: ethyl group, Bu: butyl group, Ph: phenyl group, Bn: benzyl group)

[Table 1]

[Table 2]

The optically active compound of the general formula (1) or (2) is produced by the above-mentioned production method of the present invention, and is subjected to high-performance liquid chromatography using a commercially available optically active column under appropriate conditions. It is also possible to separate and produce isomers.

[0032]

EXAMPLES The present invention will now be described specifically with reference to examples, but the present invention is not limited to these examples. The NMR values in Examples are δ values (ppm) measured using a 200 MHz nuclear magnetic resonance apparatus and tetramethylsilane as an internal standard.

Example 1 (+)-N- {2- [4-oxo-4-piperidino-2- (3-pyridylcarbonyl)
Synthesis of butylthio] ethyl {acetamide (1) (±) -3-{[2- (acetylamino) ethylthio] methyl} -4-oxo-4- (3-pyridyl)
Synthesis of butyric acid 4-oxo- described in JP-A-11-263770
7.00 g (39.1 mmol) of 4- (3-pyridyl) butyric acid
l) in ethanol (25 mL) in piperidine 3.6
5 g (42.9 mmol) and 3.50 g (43.1 mmol) of a 37% aqueous formaldehyde solution were added, and the mixture was heated at 80 ° C. for 3 hours. Thereafter, 4.65 g (39.0 mmol) of n-acetylcysteamine in ethanol (3
0 mL) solution and heated at 80 ° C. for 3 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (chloroform: methanol: acetic acid = 20: 1: 0.5) to give (±) -3-{[2- (acetylamino) ethylthio] methyl} -4-oxo. 7.30 g (23.5 mmol, 60%) of -4- (3-pyridyl) butyric acid was obtained. ¹ H-NMR (200 MHz FT, TMS, DMSO-
_{d 6) 1.77 (3H, s} ) 2.40-3.30 (8H) 4.02-4.20 (1H, m) 7.55-7.63 (1H, m) 7.87-8 .03 (1H, m) 8.31-8.38 (1H, m) 8.81 (1H, dd, J = 4.8, 1.7 Hz) 9.15 (1H)

(2) Optically active 3-{[2- (acetylamino) ethylthio] methyl} -4-oxo-4- (3
-Pyridyl) butyric acid (1R, 2S) -2-amino-1,
Synthesis of 2-diphenylethanol salt 7.27 g of (±) -3-{[2- (acetylamino) ethylthio] methyl} -4-oxo-4- (3-pyridyl) butyric acid obtained in (1) (23 .4 mmol) to (1
5.00 g (23.4 mmol) of (R, 2S)-(-)-2-amino-1,2-diphenylethanol and 135 mL of isopropanol were added, and the mixture was heated to a bath temperature of 70 ° C.
After confirming dissolution, the bath temperature was set to 55 ° C., and the mixture was stirred for 6 hours. After stirring at room temperature overnight, the precipitated crystals were collected by filtration, washed with a small amount of isopropanol, and dried to give an optically active compound.
{[2- (acetylamino) ethylthio] methyl} -4
-Oxo-4- (3-pyridyl) butyric acid (1R, 2S)
-2-amino-1,2-diphenylethanol salt 8.1
5 g (66.4% yield) was obtained. ¹ H-NMR (200 MHz FT, TMS, CD ₃ O
D) 1.90 (3H, s) 2.48-2.95 (6H) 3.18-3.38 (2H, m) 4.04-4.24 (1H, m) 4.42 (1H, d, J = 4.2 Hz) 5.17 (1H, d, J = 4.2 Hz) 6.95-7.37 (10H) 7.53-7.63 (1H, m) 8.45 (1H, td, J = 9.1, 1.9 Hz) 8.71 (1H, dd, J = 5.9, 1.6 Hz) 9.12-9.18 (1H, m)

Using an optically active column (CHIRALCEL OB manufactured by Daicel Chemical Industries, Ltd.), a mobile phase;
Hexane / ethanol (0.1% acetic acid) = 87/13,
When analyzed by high performance liquid chromatography at a flow rate of 1.2 mL / min, the optical isomers were separated, and the retention times were shorter, 14.5 to 15.8 minutes, and longer, 22.5 to 24.7 minutes. The analysis result of the above salt was determined by optical purity (ee: enantiomer exces).
s)> 99%. On the other hand, the salt recovered by evaporating the filtrate and the washing solution is 3-{[2- (acetylamino) ethylthio] having the opposite absolute configuration to the salt obtained as crystals.
It had a large amount of methyl {-4-oxo-4- (3-pyridyl) butyric acid, and had an optical purity (ee) of 39%.

(3) Optically active 3-{[2- (acetylamino) ethylthio] methyl} -4-oxo-4- (3
-Pyridyl) butyric acid (1R, 2S) -2-amino-1,
Optical purification of 2-diphenylethanol salt 3-{[2- (acetylamino) ethylthio] methyl} -4-oxo-4- obtained by distilling off the solvent from the filtrate and washings from which crystals have been removed in (2). (3-Pyridyl) butyric acid To 4.12 g (7.6 mmol) of (1R, 2S) -2-amino-1,2-diphenylethanol salt, 30 mL of isopropanol was added, and the mixture was heated to a bath temperature of 65 ° C. After confirming dissolution, the bath temperature was adjusted to 50 ° C., and seed crystals prepared separately in advance were inoculated and stirred for 4 hours. After further stirring at room temperature overnight, the precipitated crystals were collected by filtration, washed with a small amount of isopropanol, and dried to obtain an optically active 3-{[2- (acetylamino) having the same absolute configuration as the salt crystals of (2). ) Ethylthio] methyl} -4-oxo-4- (3-pyridyl) butyric acid (1R, 2S) -2-amino-1,2-
2.08 g of diphenylethanol salt (50.6% yield)
I got

This salt was subjected to an optically active column (CHIRALCEL O manufactured by Daicel Chemical Industries, Ltd.) in the same manner as in (2).
When analyzed by high performance liquid chromatography using B), the optical purity (ee) was> 99%. on the other hand,
The salt recovered by distilling off the filtrate and the washing solution from the solvent gave 3-{[2- (acetylamino) ethylthio] methyl} -4-oxo-4- having the opposite absolute configuration to the salt obtained as crystals.
High in (3-pyridyl) butyric acid, optical purity (ee) 2
6%.

(4) Synthesis of (+)-N- {2- [4-oxo-4-piperidino-2- (3-pyridylcarbonyl) butylthio] ethyl} acetamide Optical activity 3 obtained as a crystal by (2) -{[2- (acetylamino) ethylthio] methyl} -4-oxo-4-
(3-pyridyl) butyric acid (1R, 2S) -2-amino-
4.00 g of 1,2-diphenylethanol salt (7.6 m
mol) was dissolved in 10 mL of water under ice cooling, and 15 mL of a 7% aqueous sodium hydrogen carbonate solution was added for neutralization. (1R, 2S)-with tetrahydrofuran-ethyl acetate (1: 1)
After extracting and separating (-)-2-amino-1,2-diphenylethanol, the aqueous layer was treated with 35% tetrahydrofuran.
0 mL was added. Then, 1N hydrochloric acid 11.5m under ice cooling
L, further 0.83 mL (8.4 mmol) of piperidine,
1.61 g (8.4 mmol) of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride,
1.14 g of 1-hydroxybenzotriazole (8.4
mmol) and stirred for 5 hours under ice cooling. After evaporating the solvent under reduced pressure under ice-cooling, an aqueous sodium hydrogen carbonate solution previously cooled with ice was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution previously cooled on ice, dried over magnesium sulfate, and the solvent was distilled off to obtain (+)-N- {2- [4-oxo-4-piperidino-2.
2.23 g (5.9 mmol, 77% yield) of-(3-pyridylcarbonyl) butylthio] ethyl} -acetamide
I got [Α] _D = + 73.5 (C = 1.0, MeOH, 25
℃)

Using an optically active column (CHIRALCEL OD manufactured by Daicel Chemical Industries, Ltd.), a mobile phase;
Hexane / ethanol (1% diethylamine) = 91.
When analyzed by high performance liquid chromatography at 5 / 8.5, flow rate: 1.0 mL / min, the optical isomers were separated,
Retention time is (+) 32.1-36.7 minutes, (-) 25.7-29.0
Minutes. The analysis result of this compound showed that the optical purity (e
e) 99%.

Example 2 (-)-N- {2- [4-oxo-4-piperidino-2- (3-pyridylcarbonyl)
Synthesis of butylthio] ethyl {acetamide (1) Optically active 3-{[2- (acetylamino) ethylthio] methyl} -4-oxo-4- (3-pyridyl)
Synthesis of (1S, 2R) -2-amino-1,2-diphenylethanol salt of butyric acid (±) -3-{[2- (acetylamino) ethylthio] methyl}-obtained in (1) of Example 1. 4-oxo-4
-(3-pyridyl) butyric acid 3.63 g (11.7 mmol
l) is (1S, 2R)-(+)-2-amino-1,2-
2.50 g (11.7 mmol) of diphenylethanol
And 70 mL of isopropanol were added, and the mixture was heated to a bath temperature of 70 ° C. After confirming dissolution, the bath temperature was set to 55 ° C., and the mixture was stirred for 6 hours. After further stirring at room temperature overnight, the precipitated crystals were collected by filtration,
After washing with a small amount of isopropanol and drying, optically active 3-{[2- (acetylamino) ethylthio] methyl} -4-oxo-4- (3-pyridyl) butyric acid (1
4.35 g (70.9% yield) of (S, 2R) -2-amino-1,2-diphenylethanol salt was obtained.

This salt was used in the same manner as in Example 1 (2), using an optically active column (CHIRA manufactured by Daicel Chemical Industries, Ltd.).
When analyzed by high performance liquid chromatography using LCEL OB), the optical purity (ee) was> 99%. On the other hand, the salt recovered by distilling off the solvent from the filtrate and the washing solution has a 3-position in the absolute configuration opposite to that of the salt obtained as crystals.
{[2- (acetylamino) ethylthio] methyl} -4
-Oxo-4- (3-pyridyl) butyric acid was present in a large amount, and the optical purity (ee) was 38%.

(2) Synthesis of (−)-N- {2- [4-oxo-4-piperidino-2- (3-pyridylcarbonyl) butylthio] ethyl} acetamide Optical activity 3 obtained as a crystal by (1) -{[2- (acetylamino) ethylthio] methyl} -4-oxo-4-
(3-pyridyl) butyric acid (1S, 2R) -2-amino-
4.00 g of 1,2-diphenylethanol salt (7.6 m
mol) was dissolved in 10 mL of water under ice cooling, and 15 mL of a 7% aqueous sodium hydrogen carbonate solution was added for neutralization. (1S, 2R)-with tetrahydrofuran-ethyl acetate (1: 1)
After (+)-2-amino-1,2-diphenylethanol was extracted and separated, the aqueous layer was treated with 35% tetrahydrofuran.
0 mL was added. Then, 1N hydrochloric acid 11.5m under ice cooling
L, further 0.83 mL (8.3 mmol) of piperidine,
1.61 g (8.4 mmol) of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride,
1.14 g of 1-hydroxybenzotriazole (8.4
mmol) and stirred for 5 hours under ice cooling. After evaporating the solvent under reduced pressure under ice-cooling, an aqueous sodium hydrogen carbonate solution previously cooled with ice was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution previously cooled on ice, dried over magnesium sulfate, and the solvent was distilled off to give (-)-N- {2- [4-oxo-4-piperidino-2.
-(3-pyridylcarbonyl) butylthio] ethyl} -acetamide 2.24 g (5.9 mmol, 77% yield)
I got [Α] _D = −73.6 (C = 1.0, MeOH, 25
℃)

This compound was prepared in the same manner as in Example 1, (4)
Optically active column (CHI manufactured by Daicel Chemical Industries, Ltd.)
RALCEL OD), and the optical purity (ee) was> 99% when analyzed by high performance liquid chromatography.
Met.

Example 3-1 Optically active 3-{[2- (N
-Cyclohexylacetylamino) ethylthio] methyl} -4-oxo-4- (3-pyridyl) butyric acid (1
Synthesis of (S, 2R) -2-amino-1,2-diphenylethanol salt (±) -3-{[2- (N-cyclohexylacetylamino) ethylthio] methyl} -4-oxo-4- (3-
Pyridyl) butyric acid (194 mg, 0.50 mmol)
106 mg (0.50 mmol) of (S, 2R)-(+)-2-amino-1,2-diphenylethanol and 2 mL of t-butyl methyl ether were added and left at room temperature for 10 days. After confirming the precipitation of crystals, 3 mL of t-butyl methyl ether was added, and the mixture was stirred at room temperature overnight. The crystals are collected by filtration, washed with a small amount of isopropanol, and dried to obtain optically active 3-{[2- (N-cyclohexylacetylamino) ethylthio] methyl} -4-oxo-4- (3-pyridyl) butyric acid ( 190 mg (yield 63.3%) of 1S, 2R) -2-amino-1,2-diphenylethanol salt was obtained. ¹ H-NMR (200 MHz FT, TMS, CD ₃ O
D) 0.97-1.95 (10H) 2.07 (3H) 2.40-3.01 (6H) 3.15-3.45 (2H, m) 3.47-3.77 (1H, m) 4.01-4.25 (1H, m) 4.40 (1H, d, J = 4.3 Hz) 5.14 (1H, d, J = 4.3 Hz) 7.03-7.33 ( 10H) 7.50-7.64 (1H, m) 8.41-8.52 (1H, m) 8.66-8.77 (1H, m) 9.12-9.21 (1H, m)

Using an optically active column (CHIRALCEL AS manufactured by Daicel Chemical Industries, Ltd.), a mobile phase;
Hexane / ethanol (0.1% acetic acid) = 87/13,
When analyzed by high performance liquid chromatography at a flow rate of 1.2 mL / min, the optical isomers were separated. The analysis result of the salt showed that the optical purity (ee) was 28%. On the other hand, the salt recovered by distilling off the solvent of the filtrate and the washing solution is 3-{[2- (N-cyclohexylacetylamino) ethylthio] methyl} -4 having the opposite absolute configuration to the salt obtained as crystals.
-Oxo-4- (3-pyridyl) butyric acid was abundant, and the optical purity (ee) was 10%.

Example 3-2 Optically active 3-{[2- (N
-Cyclohexylacetylamino) ethylthio] methyl} -4-oxo-4- (3-pyridyl) butyric acid (1
Synthesis of (S, 2R) -2-amino-1,2-diphenylethanol salt (±) -3-{[2- (N-cyclohexylacetylamino) ethylthio] methyl} -4-oxo-4- (3-
To 645 mg (1.64 mmol) of pyridyl) butyric acid
350 mg (1.64 mmol) of (S, 2R)-(+)-2-amino-1,2-diphenylethanol, 0.7 mL of ethanol and 7 mL of t-butyl methyl ether were added, and the mixture was heated to reflux. After confirming dissolution, heating was stopped and the mixture was stirred at room temperature overnight. The precipitated crystals are collected by filtration, washed with a small amount of t-butyl methyl ether, and dried to obtain an optical activity of 3%.
-{[2- (N-cyclohexylacetylamino) ethylthio] methyl} -4-oxo-4- (3-pyridyl)
268 mg (yield 27.0%) of butyric acid (1S, 2R) -2-amino-1,2-diphenylethanol salt was obtained.

This salt was prepared in the same manner as in Example 3-1 by using an optically active column (CHIRALC manufactured by Daicel Chemical Industries, Ltd.).
Analysis by high performance liquid chromatography using EL AS) revealed an optical purity (ee) of 55%.

Example 4 (1) Optically active 3-{[2- (t-butoxycarbonylamino) ethylthio] methyl} -4-oxo-4-
(3-pyridyl) butyric acid (1S, 2R) -2-amino-
Synthesis of 1,2-diphenylethanol salt To (±) -3-{[2- (t-butoxycarbonylamino) ethylthio] methyl} -4-oxo-4- (3-pyridyl) butyric acid (624 mg, 1.76 mmol) (1
376 mg (1.76 mmol) of (S, 2R)-(+)-2-amino-1,2-diphenylethanol, 2 mL of ethanol and 16 mL of t-butyl methyl ether were added, and the mixture was heated to reflux. After confirming dissolution, heating was stopped and the mixture was stirred at room temperature overnight. The precipitated crystals are collected by filtration, washed with a small amount of t-butyl methyl ether, and dried to obtain optically active 3-{[2- (N-cyclohexylacetylamino) ethylthio] methyl} -4-oxo-4- ( 235 mg (yield 23.5%) of (3-pyridyl) butyric acid (1S, 2R) -2-amino-1,2-diphenylethanol salt were obtained. ¹ H-NMR (200 MHz FT, TMS, CD ₃ O
D) 1.41 (9H, s) 2.40-3.00 (6H) 3.16 (2H, t, J = 7.0 Hz) 4.04-4.25 (1H, m) 4.38 ( 1H, d, J = 4.4 Hz) 5.12 (1H, d, J = 4.4 Hz) 6.97-7.38 (10H) 7.51-7.63 (1H, m) 8.46 ( 1H, td, J = 8.1, 1.9 Hz) 8.70 (1H, dd, J = 4.9, 1.6 Hz) 9.16 (1H, d, J = 1.6 Hz)

Using an optically active column (CHIRALCEL OB manufactured by Daicel Chemical Industries, Ltd.), a mobile phase;
Hexane / ethanol (0.1% acetic acid) = 88/12,
When analyzed by high performance liquid chromatography at a flow rate of 1.0 mL / min, the optical isomers were separated, and the retention time was 11.0 to 12.5 minutes for the shorter one and 13.8 to 15.4 minutes for the longer one. The analysis result of the salt showed that the optical purity (ee) was 52%.

(2) Optically active 3-{[2- (t-butoxycarbonylamino) ethylthio] methyl} -4-oxo-4- (3-pyridyl) butyric acid (1S, 2R) -2
Optical purification of -amino-1,2-diphenylethanol salt Optically active 3-{[2
-(T-Butoxycarbonylamino) ethylthio] methyl} -4-oxo-4- (3-pyridyl) butyric acid (1S,
1.3 g of ethanol was added to 235 mg (0.41 mmol) of 2R) -2-amino-1,2-diphenylethanol salt.
L and 2 mL of t-butyl methyl ether were added, and the mixture was heated to reflux. After confirming dissolution, heating was stopped, 5 mL of t-butyl methyl ether was added, and the mixture was stirred at room temperature overnight. The precipitated crystals are collected by filtration, washed with a small amount of t-butyl methyl ether, and dried to give optically active 3-{[2- (N-cyclohexylacetylamino) ethylthio] methyl} -4-.
Oxo-4- (3-pyridyl) butyric acid (1S, 2R)-
2-amino-1,2-diphenylethanol salt 110 m
g (46.0% yield).

This salt was prepared in the same manner as in Example 4 (1) by using an optically active column (CHIRA manufactured by Daicel Chemical Industries, Ltd.).
When analyzed by high performance liquid chromatography using LCEL OB), the optical purity (ee) was 89%.

[0052]

[Test Example] The evaluation results of the racemic pyridyl ketone derivative represented by the general formula (2) are shown as test examples.

Test Example 1 Cytoprotective Effect on Taxol [Method] Differentiated PC12 cells (rat pheochromocytoma) were used as a model for taxol-induced neurons. Damage to PC12 cells was measured by the amount of lactate dehydrogenase (LDH) released with cell death. PC12
NGF (Nerve Growth Factor: 100 ng / m)
L) Differentiated in the presence for 29 hours. After pretreatment with a racemic pyridyl ketone derivative (test substance) represented by the general formula (2) or a control drug for 19 hours, taxol (0.24
μM) was added. Surviving cells were measured from the amount of LDH released 3 days (72 hours) after the addition of taxol.
NK5805 [(1R, 2S) -2-
[(2R)-(2-acetylamino-2-carboxy)
[Ethylthio] methyl-3-oxo-1-cyclopentanecarboxylic acid] was used. NK5805 is a compound discovered by Nippon Kayaku and described in PCT WO99 / 05091. The protective effect of NK5805 at 30 μM administration was defined as 100%, and the survival rate of PC12 cells was calculated from the following formula based on the amount of LDH released at that time. 100 × {(LDH release amount of taxol group) − (LDH release amount of taxol and test substance administration group)} / {(LDH release amount of taxol group) − (taxol and NK58
05 30 μM administration group LDH release amount)｝ NK5805 30 μM protective effect (100%)
It was equivalent to the cell viability without the addition of taxol. [Results] (±) -N- {2- [4-oxo-4-piperidino-2- (3-pyridylcarbonyl) butylthio] ethyl} acetamide and (±) -3-{[2- (cyclohexylacetylamino) Ethylthio] methyl} -N,
N-dimethyl-4-oxo-4- (3-pyridyl) butyric amide showed a protective effect of 50% or more when 10 μM was added.

[Test Example 2] Effect on taxol-induced neuritis model [Method] Using SD female rats (weighing 215 to 225 g), the values before the electrophysiological test were taken one week before the start of the administration of the test substance. . On the day of initiation of test substance administration, animals were
Animals were randomly divided into groups and weighed.
On days 2 and 5 after the start of test substance administration, taxol (A.
G. FIG. Scientific 6 mg / mL (50
% Saline / 25% Cremophore / 25% ethanol) solution at a dose of 15 mg / kg,
Administration was via the tail vein. That is, the total dose of taxol is 3
It was 0 mg / kg. The test substance was administered intraperitoneally (ip) or orally (po) once a day for 45 days. The test substance was prepared by adding 15% PEG400 immediately before administration every day, mixing with an orbital shaker for 40 minutes, and diluting with physiological saline. A group that received only taxol served as a control. Afferent and efferent nerve conduction velocities (NCV) were determined by De Koning and Gisp.
measurements were performed in a double-blind fashion using the method reported by En. Animals are anesthetized with isoflurane and Deltaphase I
The temperature was kept in thermal pads and the rectal temperature was monitored. The stimulating needle electrode was inserted near the sciatic nerve of the notch of the greater sciatic and near the cervical nerve at the heel, and the recording electrode was inserted into the worm muscle of the plantar. Stimulation was performed with a 0.1 msec rectangular wave from a Grass S88 stimulator via an isolator. Bioelectric amplifier (ETH-260, manufactured by CB science Inc.) for recording of evoked potential
And computer (Maclab1200, Macint
oshIIci) was used. Afferent and efferent NCV
Gives the distance between the two stimulation electrodes through each electrode, H
It was measured by dividing the difference in latency between the wave and the M wave. Electrophysiological evaluations were performed two weeks after taxol administration.
Statistical processing includes Student's t-test or S
Assay was performed by ANOVA using tatview. The significance level of the evaluation was 5%. [Results] (±) -N- {2- [4-oxo-4-piperidino-2- (3-pyridylcarbonyl) butylthio] ethyl} acetamide had a concentration of 2.5 mg / kg i. p. But 20mg / kg p. o. However, the effect was improved as compared with the control group.

[0055]

Industrial Applicability The present invention provides a method for producing an optically active substance of a pyridyl ketone derivative having an excellent neuronal cell protecting action and a neuronal cell differentiation promoting action, enabling its supply, and studying the metabolism of the derivative in vivo. It is also useful.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Ichiro Koga 2-336 Kitabukuro-cho, Saitama-shi, Saitama F-term (reference) 4C055 AA01 BA01 CA02 CA18 DA01 FA03 FA42 GA01 4H006 AA02 AC83 AD15 BB14 BC51

Claims (12)

[Claims] (1) The following general formula (1): Wherein R1 is -C (= O) R4, -C (= O) OR
5, -C (= O) NR6R7 or -SO2R8 (R4,
R5, R6, R7 and R8 are the same or different and are a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group which may have a substituent, and an aryl which may have a substituent. R2 represents a hydrogen atom, an alkyl group or a cycloalkyl group, and represents an RS configuration at the position of the carbon atom marked with *.] Wherein one of the diastereomeric salts formed from is separated, then the diastereomeric salt is decomposed, and then an ester bond or an amide bond is formed with an amine, an alcohol or a phenol with a dehydrating condensing agent. Formula (2) [Wherein, R1 and R2 are the same as above. R3 is -OR9 (R
9 has an alkyl group, an aryl group which may have a substituent, an arylalkyl group which may have a substituent, a heterocyclic group which may have a substituent, and a substituent. Or a good heterocyclic alkyl group) or -NR10R11
(R10 and R11 are the same or different and represent a hydrogen atom, an alkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or R
10 and R11 together with the nitrogen atom form a heterocyclic ring which may have a substituent), and the R or S configuration is shown at the position of the carbon atom indicated by *. A method for producing an active pyridyl ketone derivative. 2. In the general formulas (1) and (2), R1 is -C (=
O) The method for producing an optically active pyridyl ketone derivative according to claim 1, wherein R4 is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a cycloalkyl group. 3. The method for producing an optically active pyridyl ketone derivative according to claim 1, wherein R1 in the general formulas (1) and (2) represents an acetyl group, and R2 is a methyl group, a cyclohexyl group or a hydrogen atom. 4. The method for producing an optically active pyridyl ketone derivative according to claim 1, wherein the optically active amine which forms a diastereomer salt is an optically active 2-hydroxy-2-phenethylamine. 5. An optically active 2-hydroxy-2-phenethylamine having the following general formula (3): ## STR3 ## [Wherein, Ar represents a phenyl group which may have a substituent, R12 represents a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent,
R13 and R14 are the same or different and each represent a hydrogen atom or an alkyl group, and when the carbon atom at the position of * is an asymmetric carbon atom, each represents an R configuration or an S configuration]. A method for producing a ketone derivative. 6. In the general formula (3), Ar represents a phenyl group, p-nitrophenyl group or 3,4-dihydroxyphenyl group, R12 represents a hydrogen atom, methyl group or hydroxymethyl group, and R13 and R14 represent The method for producing an optically active pyridyl ketone derivative according to claim 5, wherein both are a hydrogen atom or a hydrogen atom and a methyl group. 7. An optically active 2-hydroxy-2-phenethylamine comprising (1R, 2S)-(−)-2-amino-1,
2-diphenylethanol, (1S, 2R)-(+)-
2-amino-1,2-diphenylethanol, (1R,
2S)-(-)-ephedrine, (1S, 2R)-
(+)-Ephedrine, (1R, 2S)-(−)-norephedrine, (1S, 2R)-(+)-norephedrine, (1R, 2R)-(−)-2-amino-1-phenyl- 1,3-propanediol, (1S, 2S)-
(+)-2-amino-1-phenyl-1,3-propanediol, (1R, 2R)-(-)-2-amino-1-
(4-nitrophenyl) -1,3-propanediol,
(1S, 2S)-(+)-2-amino-1- (4-nitrophenyl) -1,3-propanediol, (R)-
The method for producing an optically active pyridyl ketone derivative according to claim 4, which is (-)-norepinephrine or (S)-(+)-norepinephrine. 8. The process for producing an optically active pyridyl ketone derivative according to claim 1, wherein the amine bound by the dehydrating condensing agent is dimethylamine, diethylamine, piperidine or pyrrolidine. 9. The method for producing an optically active pyridyl ketone derivative according to claim 1, wherein the amine bound by the dehydrating condensing agent is piperidine. 10. An optically active pyridyl ketone derivative represented by the general formula (1) according to claim 1, or a salt thereof. 11. An optically active pyridyl ketone derivative represented by the general formula (1) according to any one of claims 1 to 3, and an optically active 2-hydroxy-2-hydroxyl according to any one of claims 5 to 7. Diastereomeric salts with phenethylamines. 12. An optically active pyridyl ketone derivative represented by the general formula (2) according to claim 1 or a salt thereof.