JP2912570B2 - Racemization method for aminoketone derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing an optically active aminoketone derivative having a central muscle relaxing action. More specifically, the present invention provides a method of reusing an unnecessary optically active aminoketone derivative after racemizing the aminoketone derivative after optically resolving the aminoketone derivative.

[0002]

BACKGROUND OF THE INVENTION 3-Phenyl-5 with aminoketone
-{2- (Pyrrolidinylmethyl) butyryl} isoxazole (hereinafter abbreviated as PIP) is known to have a central muscle relaxing action (Japanese Patent Application Laid-Open No. 3-157375).
No.). In particular, one of the optically active PIPs has a more remarkable central muscle relaxing action than the racemic form, and is an effective compound as a muscle tone improving agent. The method for producing the optically active PIP, a method of optical resolution by forming diastereomeric salts with optically active L- camphorsulfonic scan <br/> sulfonic acid (JP-A-5-1380). In the optical resolution method, if the other unnecessary optically active substance is not recovered by any means, a problem such as a yield of less than 50% occurs, and it cannot be said that the method is industrially necessarily satisfactory. . However, there is no prior art about a method for recovering an unnecessary optically active substance. As a method for recovering the aminoketone derivative after the optical resolution, 2-methyl-1- (4-
(Trifluoromethylphenyl) -3-pyrrolidino-1-
There is a method of recovering MTP by adding pyrrolidine to the filtrate after optically resolving propanone (hereinafter abbreviated as MTP) with an optically active optical resolving agent (Japanese Patent Laid-Open No. 63-310878). There is no description or suggestion about the racemization rate of the MTP obtained in this way, and this recovery method is not a method of recovering unnecessary optically active substances by racemization. In the optical resolution method, if an unnecessary optically active substance is not recovered by racemization, 50% or more of the aminoketone derivative is discarded, which is not necessarily an industrially satisfactory method.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide an optically active aminoketone derivative which has been optically resolved with an optical resolving agent, as described above, and which is then subjected to 100% racemization and reused. It is assumed that.

[0004]

Means for Solving the Problems To achieve this object, the present inventors have intensively studied a method for racemizing an optically active aminoketone derivative by 100%. As a result, the optically active aminoketone derivative and the acid dissociation constant
An aqueous solution of a weak acid having a reciprocal logarithm (pKa) of 2 or more is applied to generate a propenone derivative, and subsequently an amine is added to the organic solvent layer to cause a reaction.
The inventors have found that a 0% racemized aminoketone derivative can be obtained, and have completed the present invention.

That is, in an organic solvent, the compound represented by the general formula (1)

Embedded image [Where R ¹ is

Embedded image (R ⁵ is a halogen atom: a lower alkyl group: a benzyl group: a benzoyl group: a pyridyl group: a furyl group optionally substituted with a lower alkyl group; a thienyl group optionally substituted with a lower alkyl group; a halogen atom A phenyl optionally substituted with a lower alkoxy group, a lower alkyl group, a trifluoromethyl group, a cyano group, a nitro group, an amino group, a dimethylamino group, an acetamido group, a methanesulfonylamide group, an acetyl group or a lower alkoxycarbonyl group R ⁶ represents a trifluoromethyl group or a phenyl group which may be substituted with a lower alkyl group; Z represents an oxygen atom or a sulfur atom; and R ² represents a lower alkyl group or a benzyl group. Methoxy, phenyl, allyl, trifluoromethyl or lower alkoxy, Represents a cyclopropylmethyl group. R ³ and R ⁴ each independently represent a saturated or unsaturated lower alkyl group, or R ³ and R ⁴ are cyclically bonded to form a group consisting of pyrrolidine, piperazine, hexamethyleneimine, morpholine and piperazine The optically active aminoketone derivative represented by the following formula may be formed in an organic solvent: a selected cyclic structure may be formed, and the cyclic structure may be substituted with a methyl group or a benzyl group. When the logarithm (pKa) of the reciprocal of the acid dissociation constant is 2 or more,
General formula (2) by acting with a certain weak acid aqueous solution

Embedded image (Wherein R ¹ and R ² are the same as described above), and after isolating the same, the compound of the general formula (3) is used in an organic solvent or without solvent.

Embedded image (Wherein R ³ and R ⁴ are the same as in the above formula (1)) to provide a method for producing a racemized aminoketone derivative by adding and reacting an amine represented by the formula (1).

According to the method of the present invention, not only can a racemized aminoketone derivative be recovered from unnecessary optically active aminoketone derivatives in high yield, but also the organic solvent can be recovered without isolating the racemic aminoketone derivative once. There is also an advantage that the layer can be subjected to an optical resolution operation as it is, which is an industrially valuable method.

The specific embodiments of the present invention are as follows. The hydrochloride of the optically active aminoketone derivative is dissolved in water and neutralized with an alkali such as sodium carbonate to obtain a free optically active aminoketone derivative. The free aminoketone derivative is extracted with an organic solvent to obtain a solution of the optically active aminoketone derivative in an organic solvent. Acid dissociation determination in this organic solvent solution
A weak acid aqueous solution having a reciprocal logarithm (pKa) of 2 or more is added and allowed to act for several hours to produce a propenone derivative in the organic solvent layer. After liquid separation, amines are added to the organic solvent layer and reacted to obtain a racemized aminoketone derivative.

The optically active aminoketone derivative used in the method of the present invention can be produced by the method described in JP-A-5-51380. For example, (-)-3-phenyl-5- {2- (pyrrolidinylmethyl) butyryl} isoxazole having an aminoketone [hereinafter referred to as (-) PI
Specifically, formalin is added to a solution of 3-phenyl-butylisoxazole and pyrrolidine in methanol to form PIP, which is extracted with an organic solvent. Performed an optical resolution operation with addition of optically active D-10- Kan <br/> files over acid extraction after the organic solvent layer, after workup (-) isolating PIP as the hydrochloride salt. Also (+)
-2-Methyl-1- (4-trifluoromethylphenyl) -3-pyrrolidino-1-propanone [(+) MTP
Abbreviated as follows] is disclosed in JP-A-63-11 / 1988.
After generating MTP by the method described in Japanese Patent No. 9424, optical separation is performed by the method described in JP-A-63-225367 to produce (+) MTP. Specifically, 1-
(4-α , α , α-trifluoromethylphenyl) -1
-MTP is generated by adding concentrated hydrochloric acid to a mixed solution of propanone, paraformaldehyde, pyrrolidine hydrochloride and isopropyl alcohol and heating to reflux. MTP is L-
After optical resolution with acetylphenylglycine, it is isolated in the form of the (+) MTP hydrochloride.

Examples of the organic solvent used in the present invention include halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, ketones such as methyl propyl ketone and methyl isobutyl ketone, ethyl acetate and acetic acid. Alkyl acetates such as butyl, propyl acetate and amyl acetate, or aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene and nitrobenzene are preferred. Particularly preferred are alkyl acetates such as ethyl acetate and butyl acetate.

The weak acid to be reacted with the aminoketone derivative is an acid having a logarithmic value (hereinafter abbreviated as pKa) of the reciprocal of the acid dissociation constant of 2 or more . Preferred are inorganic acids such as hypochlorous acid and boric acid having a pKa of 4 or more, and organic acids such as acetic acid, butyric acid, glutaric acid, succinic acid, and benzoic acid.

The logarithm (pKa) of the reciprocal of the acid dissociation constant is 2
The amount of the above weak acid may be at least 0.1 times the mol of the aminoketone derivative, and preferably at least 1.0 times the mol. Especially preferably, it is 1.2 times or more. There is no particular upper limit to the amount used, but excessive use is not preferable from an economical point of view. Therefore, it is usually used in a molar amount of 10 times or less.

The logarithm (pKa) of the reciprocal of the acid dissociation constant is 2
More than it is not particularly limited, but is undesirably poor volumetric efficiency when too low a concentration as the concentration of the aqueous solution of a weak acid. On the other hand, when the concentration is increased, the production rate of the propenone derivative decreases, which is not preferable. Preferably 0.5 to 90% by weight
It is. More preferably, it is 1 to 50% by weight.

The concentration of the aminoketone derivative in the organic solvent is not particularly limited, but is in the range of 1 to 50% by weight. Preferably it is in the range of 10 to 30% by weight.
If the amount is less than 1% by weight, there is no particular problem in the reaction, but it is not preferable from the viewpoint of reduction in volumetric efficiency and economical viewpoint. On the other hand, if it exceeds 50% by weight, the reaction mixture becomes viscous, the reaction does not proceed sufficiently, and the yield of the propenone derivative may decrease.

The logarithm (pKa) of the reciprocal of the acid dissociation constant is 2
The temperature at which the above-mentioned weak acid aqueous solution is allowed to act is -10 to 80.
° C, and is preferably in the range of 0-60 ° C.
If the temperature is lower than −10 ° C., the reaction does not proceed sufficiently, and the yield of the propenone derivative decreases. On the other hand, when the temperature exceeds 80 ° C., the aminoketone derivative is liable to be decomposed and the yield may be reduced.
The end point of the reaction can be easily known using a means such as gas chromatography or liquid chromatography.

After the formation of the propenone derivative is completed, the organic solvent layer may be separated and, if necessary, the unreacted aminoketone derivative may be removed by washing with a strong acid aqueous solution such as phosphoric acid or hydrochloric acid. The amount of amines added to the solvent layer to produce the racemic aminoketone derivative is theoretically equimolar to the propenone derivative, but more preferably 1.0 to 1.0.
It is 5 times mol.

The reaction temperature with the amines is -10 to 80.
C is acceptable, preferably 0-60C. -10
If the temperature is lower than ℃, the reaction does not proceed sufficiently and the yield decreases. 80
If the temperature exceeds ℃, by-products may be formed to lower the yield.

After completion of the reaction with amines, the resultant is washed with water and dried with anhydrous sodium sulfate or the like. Alternatively, in the case of a solvent azeotropic with water, water is removed by azeotropic distillation. It is possible to obtain an optically active aminoketone derivative thereof, required by optical resolution operation with addition of optical resolution agent such as optically active camphorsulfonic acid after drying. Further, if necessary, a method for producing a hydrochloride of a racemic aminoketone derivative includes, specifically, adding hydrochloric acid water after completion of the reaction, performing hydrochloric acid chloride, and reducing the solubility in the separated organic solvent layer such as ethyl acetate. After crystallization by adding the organic solvent described above, the crystallization mass may be isolated by a solid-liquid separation operation such as suction filtration.

[0018]

EXAMPLES The method of the present invention will be described below in detail with reference to examples. Reference Example 1 [3-Phenyl-5-butyrylisoxazole] 10 g (0.082 mol) of benzaldoxime and 9 g (0.092 mol) of 1-hexyn-3-ol were dissolved in 50 ml of dichloromethane. The reaction solution was ice-cooled, and 58 g (0.1 mol) of a 12% aqueous solution of sodium hypochlorite was added dropwise while maintaining the internal temperature at 15 to 25 ° C. After completion of the dropwise addition, the mixture was stirred for 3 hours while maintaining the internal temperature at 15 to 25 ° C. 49 g of a 12% aqueous sodium hypochlorite solution (0.07
9 mol) was added dropwise. Cool the internal temperature of the reaction solution to 10 ° C,
An aqueous solution of pyridine hydrochloride (prepared with 2.8 ml of 6N hydrochloric acid and 1.3 ml of pyridine) was added dropwise over 20 minutes. Thereafter, a 12% aqueous sodium hypochlorite solution and a pyridine hydrochloride aqueous solution were alternately and dropwisely added three times. 100 ml of a 5% aqueous sodium bisulfite solution was added to the dichloromethane layer obtained by separating the reaction solution, and the mixture was stirred for 30 minutes. The dichloromethane layer was washed with water and aqueous hydrochloric acid in that order, and then dichloromethane was distilled off. The residue was recrystallized from 40 ml of ethanol to obtain 10.6 g of the desired compound. 89-90 ° C

Reference Example 2 [3-phenyl-5- (2-pyrrolidinomethylbutyryl) isoxazole hydrochloride] (abbreviated as PIP hydrochloride) 20 g of 3-phenyl-5-butyrylisoxazole
(0.093 mol) and 7.93 g of pyrrolidine (0.1
11 mol) was added to 62 g of methanol. The reaction solution was stirred, and 9.04 g (0.111 mol) of a 37% aqueous solution of formalin was added dropwise while maintaining the internal temperature at 20 to 30 ° C. After completion of the dropwise addition, the mixture was kept at 20 to 30 ° C and stirred for 1 hour. 178 g of ethyl acetate was added to the reaction solution. Further, 150 g of water was added, and the mixture was separated and extracted to obtain an organic layer. The obtained organic layer was ice-cooled, and 178 g of a 2N hydrochloric acid aqueous solution was added thereto, followed by separation and extraction. The obtained aqueous layer was extracted with 180 g of chloroform. The aqueous layer was extracted again with chloroform, and the obtained chloroform layers were combined and dried over anhydrous sodium sulfate. Ethyl acetate 2 was added to the chloroform solution obtained by filtering off sodium sulfate.
94 g was added dropwise with stirring. The solution was cooled on ice, and the precipitated crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain 20.8 g of a colorless target compound. 151-153 ° C

Reference Example 3 [(-)-3-Phenyl-5- (2-pyrrolidinomethylbutyryl) isoxazole hydrochloride] 10 g (0.0333 mol) of PIP was added to 200 ml of ethyl acetate.
Dissolved in ml. This solution was added to D-10 camphor <br/> phosphate 11.5g was stirred for 30 minutes to dissolve.
The solution was stirred for 2 hours under ice cooling, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethyl acetate and then dried (-).
To obtain a PIP · D-10- camphorsulfonic acid 11.8g. (-) PIP · D-10- camphorsulfonic acid 7.0
g was dissolved in a mixture of 40 ml of water and 40 ml of ethyl acetate, and 22 ml of a 10% aqueous sodium carbonate solution was added.
Stirred for minutes. The reaction solution was separated, and the obtained organic layer was separated into 10
Washed with 11 ml of a 10% aqueous sodium carbonate solution. Then
The organic layer was extracted twice with 17 ml of 2N aqueous hydrochloric acid, and the aqueous layers were combined. From this aqueous solution, add 2 ml of chloroform
It was extracted twice and the chloroform layers were combined. The obtained chloroform solution was dried over anhydrous sodium sulfate. Ethyl acetate 7 was added to the chloroform solution obtained by filtering off sodium sulfate.
2 ml was added dropwise, and the mixture was stirred at room temperature for 1 hour.
Stirred for hours. The precipitated crystals were collected by filtration to obtain 2.5 g of (-) PIP hydrochloride. Melting point 145-146 ° C Optical purity 99.85% or more

Example 1 112.2 g of (-) PIP hydrochloride was added to 500 g of butyl acetate.
(0.335 mol) and 5% aqueous solution of sodium carbonate 74
1.9 g (0.350 mol) was added for desalting, and the solvent layer was separated and washed with 500 g of water. After washing, pure water 500
An aqueous solution of acetic acid in which 40 g (0.670 mol) of acetic acid was dissolved was added to the resulting mixture, and the mixture was stirred and reacted at a temperature of 20 to 30 ° C. for 15 hours. After completion of the reaction, the organic solvent layer was separated and washed with 250 g of a 5% aqueous phosphoric acid solution and 250 g of water. To the organic solvent layer was added 26.2 g (0.368 mol) of pyrrolidine to give 20
The reaction was carried out under stirring at ℃ 30 ° C. for 1 hour. After the reaction was completed, the organic solvent layer was washed with water and dried over anhydrous sodium sulfate. After removing the drying agent, the organic solvent layer was concentrated under reduced pressure to obtain 95.0 g (0.318 mol) of racemic PIP. The yield based on (−) PIP was 95%, and as a result of analysis by liquid chromatography using a chiral column, the ratio of (+) form to (−) form of PIP was 50:50.

EXAMPLE 2 112.2 g of (-) PIP hydrochloride was added to 500 g of butyl acetate.
(0.335 mol) and 5% aqueous solution of sodium carbonate 74
1.9 g (0.350 mol) was added for desalting, and the solvent layer was separated and washed with 500 g of water. After washing, pure water 500
An aqueous solution of acetic acid in which 40 g (0.670 mol) of acetic acid was dissolved was added thereto, and the mixture was stirred and reacted at a temperature of 20 to 30 ° C. for 10 hours. After completion of the reaction, the organic solvent layer was separated and washed with 250 g of a 5% aqueous phosphoric acid solution and 250 g of water. To the organic solvent layer was added 26.2 g (0.368 mol) of pyrrolidine to give 20
The reaction was carried out under stirring at ℃ 30 ° C. for 1 hour. After the reaction was completed, the organic solvent layer was washed with water and dried over anhydrous sodium sulfate. After drying agent removing L-10- camphorsulfonic acid 1
55 g (0.67 mol) were added to form two kinds of diastereomeric salts, and the crystals were crystallized to separate poorly soluble diastereomeric salts. Dried (+) to obtain a camphor scan <br/> sulfonic acid salt of PIP. Yield 112.1 g (0.147 mol) Yield 43.9 mol% Optical purity 99.5% ee

EXAMPLE 3 112.2 g of (-) PIP hydrochloride was added to 500 g of butyl acetate.
(0.335 mol) and 5% aqueous solution of sodium carbonate 74
1.9 g (0.350 mol) was added for desalting, and the solvent layer was separated and washed with 500 g of water. After washing, pure water 500
A solution of butyric acid in which 59 g (0.670 mol) of butyric acid was dissolved was added to the resulting mixture, and the mixture was stirred at a temperature of 20 to 30 ° C. for 10 hours to react. After completion of the reaction, the organic solvent layer was separated and washed with 250 g of a 5% aqueous phosphoric acid solution and 250 g of water. To the organic solvent layer was added 26.2 g (0.368 mol) of pyrrolidine to give 20
The reaction was carried out under stirring at ℃ 30 ° C. for 1 hour. After the reaction was completed, the organic solvent layer was washed with water and dried over anhydrous sodium sulfate. After drying agent removing L-10- camphorsulfonic acid 1
55 g (0.67 mol) were added to form two kinds of diastereomeric salts, and the crystals were crystallized to separate poorly soluble diastereomeric salts. Dried (+) to obtain a camphor scan <br/> sulfonic acid salt of PIP. Yield 111.5 g (0.146 mol) Yield 43.6 mol% Optical purity 99.5% ee

Example 4 100 g of (-) PIP (0.335) was added to 500 g of toluene.
Mol) was dissolved, and boric acid was added to 500 g of pure water.
A boric acid aqueous solution in which 4 g (0.670 mol) was dissolved was added, and the mixture was stirred and reacted at a temperature of 20 to 30 ° C. for 10 hours.
After the reaction is completed, the organic solvent layer is separated, and a 5% aqueous solution of phosphoric acid 25
Washed with 0 g and 250 g of water. To the organic solvent layer was added 26.2 g (0.368 mol) of pyrrolidine, and the mixture was added at 20 to 30 ° C.
For 1 hour under stirring. After the reaction was completed, the organic solvent layer was washed with water and dried over anhydrous sodium sulfate. L-10- camphorsulfonic acid 155g after drying agents removed
(0.67 mol) to form two diastereomeric salts, which were crystallized to separate the hardly soluble diastereomeric salts. Dried (+) was obtained camphorsulfonate of PIP. Yield 109.8 g (0.144 mol) Yield 43.0 mol% Optical purity 99.2% ee

Reference Example 4 2-methyl-1- (4-trifluoromethylphenyl)
-3-Pyrrolidino-1-propanone 1- (4-α, α, α-trifluoromethylphenyl)
2.5 g of -1-propanone, paraformaldehyde 1.
0.1 ml of concentrated hydrochloric acid is added to a mixture of 11 g, 1.6 g of pyrrolidine hydrochloride and 20 ml of isopropyl alcohol, and the mixture is refluxed for 16 hours. After completion of the reaction, the reaction solution is concentrated under reduced pressure, and isopropyl alcohol is distilled off. Water is added to the obtained residue, and the mixture is washed with ethyl acetate. The aqueous layer is made alkaline with aqueous ammonia and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated after removing the desiccant to give 1.58 g of the target compound as an oil.

Reference Example 5 (+)-2-Methyl-1- (4-trifluoromethylf
Enyl) -3-pyrrolidino-1-propanone hydrochloride MTP (306 g, 1.07 mol) and d-acetylphene
Nylglycine ([α] ²⁰ _D−212.8 °, c = 1.
210 g (1.08 mol) of ethyl acetate
Dissolved in 1400 ml of water to form a salt,
Stir overnight then stir at about 5 ° C. for 3 hours. The precipitated crystals
After filtration and drying under reduced pressure, MTP ・ L-acetylphenyl
219 g of the glycine salt are obtained. 175g secondary from filtrate
A crystal was obtained. 394 g of crystals, 630 ml of 10% saline, vinegar
Ethyl acid 950ml and 28% ammonia water 60ml
The organic layer was washed with brine and dried over anhydrous
Dry with gnesium. Then cool in ethyl acetate solution
After gradually introducing 29 g of hydrogen chloride gas at an internal temperature of about 5 ° C
Stir for 2 hours. The precipitated crystals are filtered and washed with ethyl acetate.
After washing and drying under reduced pressure, 217 g of (+) MTP hydrochloride was obtained.
Was.

Example 5 (+) MTP hydrochloride 107.96 in 500 g of butyl acetate
g (0.335 mol) and 119.0 g of 5% aqueous ammonia
(0.350 mol) and desalted. After desalting, liquid separation was performed, and the solvent layer was washed with 500 g of water.
An aqueous acetic acid solution in which 0 g (0.670 mol) was dissolved was added, and the mixture was stirred at a temperature of 20 to 30 ° C. for 10 hours. After the stirring, the organic solvent layer was separated, and 250 g of a 5% aqueous phosphoric acid solution and 25 g of water were added.
Washed 0 g. 26.2 g of pyrrolidine was added to the organic solvent layer.
(0.368 mol) was added and reacted at 20-30 ° C. for 1 hour with stirring. After the completion of the reaction, the organic solvent layer was washed with 400 g of a 5% aqueous sodium carbonate solution. After washing, it was dried with 20 g of anhydrous magnesium sulfate for 20 hours. After removing the desiccant, the mixture is concentrated under reduced pressure to give an oily MTP.
93.67 g (0.318 mol) were obtained. Yield is (+)
It was 98 mol% based on MTP hydrochloride. The oil MTP was analyzed by liquid chromatography using a chiral column. As a result, the ratio between the (+) form and the (−) form was 5%.
0:50 and the racemization rate was 100%.

[0028]

According to the method of the present invention, not only the racemized aminoketone derivative can be recovered from the unnecessary optically active aminoketone derivative in high yield, but also the aminoketone derivative once racemized can be recovered without the isolation operation. There is also an advantage that the organic solvent layer can be directly subjected to an optical resolution operation, which is an industrially valuable method.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/42 A61K 31/42 31/425 31/425 C07B 55/00 C07B 55/00 A (56) -208556 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07C 225/16 C07C 221/00 C07D 261/08 C07D 275/02 C07B 55/00 CA (STN) REGISTRY (STN )

Claims (5)

(57) [Claims] 1. A compound of the general formula (1) in an organic solvent: [Wherein R ¹ is (R ⁵ is a halogen atom: a lower alkyl group: a benzyl group: a benzoyl group: a pyridyl group: a furyl group optionally substituted with a lower alkyl group; a thienyl group optionally substituted with a lower alkyl group; a halogen atom A phenyl optionally substituted with a lower alkoxy group, a lower alkyl group, a trifluoromethyl group, a cyano group, a nitro group, an amino group, a dimethylamino group, an acetamido group, a methanesulfonylamide group, an acetyl group or a lower alkoxycarbonyl group R ⁶ represents a trifluoromethyl group or a phenyl group which may be substituted with a lower alkyl group; Z represents an oxygen atom or a sulfur atom; and R ² represents a lower alkyl group or a benzyl group. Methoxy, phenyl, allyl, trifluoromethyl or lower alkoxy, Represents a cyclopropylmethyl group. R ³ and R ⁴ each independently represent a saturated or unsaturated lower alkyl group, or R ³ and R ⁴ are cyclically bonded to form a group consisting of pyrrolidine, piperazine, hexamethyleneimine, morpholine and piperazine The optically active aminoketone derivative represented by the following formula may be formed in an organic solvent: a selected cyclic structure may be formed, and the cyclic structure may be substituted with a methyl group or a benzyl group. When the logarithm (pKa) of the reciprocal of the acid dissociation constant is 2 or more,
By reacting with a certain weak acid aqueous solution, general formula (2) (Wherein R ¹ and R ² are the same as described above), and after isolating this, the compound is represented by the general formula (3) in an organic solvent or without solvent. (Wherein R ³ and R ⁴ are the same as those in the above formula (1)) to produce a racemized aminoketone derivative by adding and reacting an amine represented by the formula (1). 2. The method according to claim 1, wherein the organic solvent is a halogenated hydrocarbon, an alkyl acetate, a ketone, or an aromatic hydrocarbon. 3. The logarithmic value (pKa) of the reciprocal of the acid dissociation constant is
The temperature at which the reaction with a weak acid aqueous solution of 2 or more is -10 to 7
The method of claim 1, wherein the temperature is 0 ° C. 4. The logarithmic value (pKa) of the reciprocal of the acid dissociation constant is
The method according to claim 1, wherein the amount of the weak acid that is 2 or more is 0.1 to 10 times the amount of the aminoketone derivative. 5. The reaction temperature for reacting with amines is -10.
The method according to claim 1, wherein the temperature is -70 ° C.