JPH08208571A - Racemization of aminoketone derivative - Google Patents

Abstract

PURPOSE: To recover an aminoketone derivative by racemization from an unnecessary optically active aminoketone derivative prepared after optical resolution of an optically active aminoketone derivative having central muscle relaxation activity and to reuse the aminoketone derivative. CONSTITUTION: This derivative is shown by formula I (R<1> is a group of a formula II; R<2> is an alkyl, etc.; R<3> and R<4> are each pyrrolidine, etc.; R<5> is a halogen, etc.). The derivative, for example, is obtained by dissolving (-)-3- phenyl-5- 2(pyrrolidinylmethyl)butyryl}isoxazole hydrichloride in water and neutralizing the solution with an alkali such as sodium carbonate to give a solution of the subject liberated optically active derivative in an organic solvent such as ethyl acetate. The organic solvent layer of the solution is treated with an aqueous solution of a weak acid having preferably >=4 pKa value at 0-60 deg.C for several hours to form a propenone derivative of formula III. After the separation of the organic solvent solution, an amine of formula IV is added thereto and the propenone derivative is reacted with the amine to be racemized to give the objective derivative. The concentration of the subject derivative in the organic solvent is 10-30wt.% and that of the aqueous solution of the weak acid is preferably 1-50wt.%.

Description

Detailed Description of the Invention

[0001]

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

[0002]

2. Description of the Related Art 3-Phenyl-5 having aminoketone
-{2- (pyrrolidinylmethyl) butyryl} isoxazole [hereinafter abbreviated as PIP] is known to have a central muscle relaxant action (Japanese Patent Laid-Open No. 3-157375).
Issue). In particular, one of the optically active PIPs has a more prominent central muscle relaxant action than the racemic body, and is a compound effective as a muscle tone improving agent. A method for producing this optically active PIP is a method of forming a diastereomeric salt with optically active L-camphorsulfonic acid and optically resolving it (JP-A-5-1380). In the optical resolution method, if the other unnecessary optically active substance is not recovered by any means, problems such as a yield of less than 50% occur, and it cannot be said that the method is industrially satisfactory. . However, there is no prior art on a method of recovering an unnecessary optically active substance. As a method for recovering the aminoketone derivative after optical resolution, 2-methyl-1- (4-trifluoromethylphenyl) -3-pyrrolidino-1-propanone (hereinafter abbreviated as MTP) is used as an optically active There is a method of recovering MTP by adding pyrrolidine to the filtrate after optical resolution with a resolving agent (JP-A-63-310878), but there is no description or suggestion about the racemization rate of MTP obtained by recovery. Therefore, the recovery method is not a method for recovering unnecessary optically active substances by racemization. In the optical resolution method, a minimum of 50% of the aminoketone derivative is discarded unless the unnecessary optically active substance is racemized and recovered, which is not necessarily an industrially satisfactory method.

[0003]

DISCLOSURE OF THE INVENTION The present invention aims to recycle 100% racemization of unnecessary optically active aminoketone derivative after optically resolving the aminoketone derivative with an optical resolving agent as described above. It is what

[0004]

Means for Solving the Invention In order to achieve this object, the present inventors have made extensive studies on a method for racemizing an optically active aminoketone derivative to 100%. As a result, an optically active aminoketone derivative and a weak acid aqueous solution are allowed to act in an organic solvent to form a propenone derivative, and then amines are added to the organic solvent layer to react with each other to facilitate the reaction.
It was found that an aminoketone derivative having a racemization of 00% can be obtained, and the present invention has been completed.

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

Embedded image [Wherein R ¹ is

[Chemical 6]Represents (R^FiveIs a halogen atom: lower alkyl group: benz
Group: benzoyl group: pyridyl group: lower alkyl group
Optionally substituted furyl group; substituted with a lower alkyl group
Optionally substituted thienyl group; halogen atom, lower alcohol
Xy group, lower alkyl group, trifluoromethyl group, sia
Group, nitro group, amino group, dimethylamino group, aceto group
Amide group, methanesulfonylamide group, acetyl group or
May be substituted with a lower alkoxycarbonyl group
A phenyl group or a naphthyl group, R ⁶Is trifluorome
A phenyl group which may be substituted with a tyl group or a lower alkyl group.
Group, Z represents an oxygen atom or a sulfur atom. ),
R²Is a lower alkyl group, a benzyl group, a methoxy group, a group
Phenyl group, allyl group, trifluoromethyl group or low
Of primary alkoxy group or cyclopropylmethyl group
You. R³And R^FourAre independently saturated or unsaturated
Represents a lower alkyl group of R³And R^FourAre connected in a ring
Pyrrolidine, piperazine, hexamethyleneimine, mol
A kind selected from the group consisting of holin and piperazine
It may have a ring structure, and the ring structure
The structure may be substituted with a methyl group or a benzyl group.
An optically active aminoketone derivative represented by
General formula (2)

[Chemical 7] After forming a propenone derivative represented by the formula (R ¹ and R ² are the same as the above) and isolating the derivative, the compound represented by the general formula (3) in an organic solvent or without a solvent is used.

Embedded image (In the formula, R ³ and R ⁴ are the same as those in the above formula (1)], and a method for producing a racemized aminoketone derivative by adding and reacting an amine represented by the formula is provided.

According to the method of the present invention, not only is it possible to recover a racemized aminoketone derivative from unnecessary optically active aminoketone derivative in a high yield, but also the once racemized aminoketone derivative can be isolated from the organic solvent without isolation operation. It is an industrially valuable method because it has the advantage that it can be directly subjected to the optical resolution operation in layers.

Specific embodiments of the present invention are as follows. The optically active aminoketone derivative hydrochloride is dissolved in water and neutralized with an alkali such as sodium carbonate to give 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. A weak acid aqueous solution is added to this organic solvent solution and allowed to act for several hours to form 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, (−) PI
Abbreviated as P] specifically, formalin is added to a solution of 3-phenyl-butylisoxazole and pyrrolidine dissolved in methanol to generate PIP, which is extracted with an organic solvent. After the extraction, an optically active D-10-camphorsulfonic acid is added to the organic solvent layer to perform an optical resolution operation, and after the post treatment, (-) PIP is isolated as a hydrochloride. Also (+)-
2-methyl-1- (4-trifluoromethylphenyl)
As a method for producing -3-pyrrolidino-1-propanone [abbreviated as (+) MTP], first, JP-A-63-1194 is used.
After producing MTP by the method described in JP-A No. 24, the optical division is carried out by the method described in JP-A-63-225367 to produce (+) MTP. Specifically, 1- (4-
MTP is produced by adding concentrated hydrochloric acid to a mixed solution of α, α, α-trifluoromethylphenyl) -1-propanone, paraformaldehyde, pyrrolidine hydrochloride and isopropyl alcohol and heating under reflux. MTP is (+) after performing optical resolution with L-acetylphenylglycine.
Isolated in the form of the hydrochloride salt of MTP.

Specific 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. Acetic acid alkyl esters such as butyl, propyl acetate and amyl acetate, or aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene and nitrobenzene are preferable. Particularly preferred are alkyl acetates such as ethyl acetate and butyl acetate.

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

The amount of the weak acid used may be 0.1 times or more the molar amount of the aminoketone derivative, but is preferably 1.0.
It may be at least twice the mole. Particularly preferably, it is 1.2 times or more mol. There is no particular upper limit on the amount used,
It is not preferable from an economical point of view to use too much.
Therefore, it is usually used in a molar amount of 10 times or less.

There is no particular limitation on the concentration of the aqueous solution of the weak acid, but if the concentration is too low, the volumetric efficiency becomes poor, which is not preferable. Further, if the concentration is increased, the production rate of the propenone derivative is lowered, which is not preferable. It is preferably 0.5 to 90% by weight. It is more preferably 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. It is preferably in the range of 10 to 30% by weight.
If it is less than 1% by weight, there is no particular problem in terms of reaction, but it is not preferable from the viewpoint of reduction in volumetric efficiency and economy. 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 temperature at which the weak acid aqueous solution is allowed to act is -10 to 8
It is allowed up to 0 ° C, preferably in the range of 0 to 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, if the temperature exceeds 80 ° C., the decomposition of the aminoketone derivative is likely to occur, and the yield may decrease. 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 form the racemic aminoketone derivative is theoretically equimolar to the propenone derivative, but more preferably 1.0.
It is 5 times the molar amount.

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

After the reaction with amines is completed, the product is washed with water and dried with anhydrous sodium sulfate or the like. Alternatively, if the solvent is an azeotrope with water, the water is removed by azeotropic distillation. After drying, an optically active aminoketone derivative required can be obtained by an optical resolution operation by adding an optically active optical resolving agent such as 10-camphorsulfonic acid. In addition, as a method for producing a hydrochloride of a racemic aminoketone derivative, if necessary, specifically, after completion of the reaction, hydrochloric acid is added to perform hydrochloric acid salification, and chloroform or the like, which reduces solubility in a separated organic solvent layer, is used. After adding an organic solvent for crystallization, 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 in detail below with reference to examples. Reference Example 1 10 g (0.082 mol) of [3-phenyl-5-butyrylisoxazole] benzaldoxime and 9 g (0.092 mol) of 1-hexyne-3-ol were dissolved in 50 ml of dichloromethane. The reaction solution was ice-cooled, and 58 g (0.1 mol) of a 12% sodium hypochlorite aqueous solution was added dropwise while keeping the internal temperature at 15 to 25 ° C. After completion of dropping, the mixture was stirred for 3 hours while maintaining the internal temperature at 15 to 25 ° C. To this reaction liquid, 49 g (0.07%) of a 12% sodium hypochlorite aqueous solution was added.
9 mol) was added dropwise. The internal temperature of the reaction solution was cooled to 10 ° C,
An aqueous pyridine hydrochloride solution (prepared with 2.8 ml of 6N hydrochloric acid and 1.3 ml of pyridine) was added dropwise over 20 minutes. Then, a 12% sodium hypochlorite aqueous solution and a pyridine hydrochloride aqueous solution were alternately dropped into the reaction solution three times each. To the dichloromethane layer obtained by separating the reaction solution was added 100 ml of a 5% aqueous sodium hydrogen sulfite solution, and the mixture was stirred for 30 minutes. The dichloromethane layer was washed with water and hydrochloric acid in this order, and then dichloromethane was distilled off. The residue was recrystallized from 40 ml of ethanol to obtain 10.6 g of the target compound. Melting point 89-90 ° C

Reference Example 2 [3-Phenyl-5- (2-pyrrolidinomethylbutyryl) isoxazole hydrochloride] (abbreviated as PIP hydrochloride) 3-phenyl-5-butyrylisoxazole 20 g
(0.093 mol) and pyrrolidine 7.93 g (0.1
11 mol) was added to 62 g of methanol. The reaction solution was stirred, and 9.04 g (0.111 mol) of 37% aqueous formalin solution was added dropwise while maintaining the internal temperature at 20 to 30 ° C. After completion of the dropping, the temperature was maintained at 20 to 30 ° C. and the mixture was stirred for 1 hour. 178 g of ethyl acetate was added to the reaction solution. Further, 150 g of water was added and liquid separation extraction was performed to obtain an organic layer. The obtained organic layer was ice-cooled, and 178 g of a 2N hydrochloric acid aqueous solution was added for liquid 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 ice-cooled and the precipitated crystals were collected by filtration, washed with ethyl acetate and dried under reduced pressure to give 20.8 g of the colorless target compound. Melting point 151-153 ° C

Reference Example 3 [(-)-3-phenyl-5- (2-pyrrolidinomethylbutyryl) isoxazole hydrochloride] PIP 10 g
(0.0333 mol) was dissolved in 200 ml of ethyl acetate. 11.5 g of D-10 camphorsulfonic acid was added to this solution.
Was added and stirred for 30 minutes to dissolve. The solution was stirred under ice cooling for 2 hours and the precipitated crystals were collected by filtration. The obtained crystals are washed with ethyl acetate and then dried to obtain (-) PIP.D-1.
11.8 g of 0-camphorsulfonic acid was obtained. (-) PI
7.0 g of P-D-10-camphorsulfonic acid was added to 40 m of water.
It was dissolved in a mixed solution of 1 and 40 ml of ethyl acetate, 22 ml of a 10% sodium carbonate aqueous solution was added, and the mixture was stirred for 10 minutes.
The reaction solution was separated, and the obtained organic layer was washed with 11 ml of a 10% sodium carbonate aqueous solution. Then, add this organic layer to 2
It was extracted twice with 17 ml of N hydrochloric acid water, and the aqueous layers were combined. This aqueous solution was extracted twice with 12 ml of chloroform and the chloroform layers were combined. The obtained chloroform solution was dried over anhydrous sodium sulfate. 72 ml of ethyl acetate was added dropwise to the chloroform solution obtained by filtering off sodium sulfate, and the mixture was stirred for 1 hour at room temperature and then for 1 hour under ice cooling.
The precipitated crystals were collected by filtration to obtain 2.5 g of (-) PIP hydrochloride. Melting point 145 to 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% sodium carbonate aqueous solution 74
1.9 g (0.350 mol) was added for desalting, the solvent layer was separated, and washed with 500 g of water. After cleaning, pure water 500
An aqueous acetic acid solution in which 40 g (0.670 mol) of acetic acid was dissolved was added to g, and the mixture was stirred at a temperature of 20 to 30 ° C. for 15 hours for reaction. After completion of the reaction, the organic solvent layer was separated and washed with 250 g of a 5% phosphoric acid aqueous solution and 250 g of water. Pyrrolidine (26.2 g, 0.368 mol) was added to the organic solvent layer to give 20
The reaction was allowed to stir at ~ 30 ° C for 1 hour. After completion of the reaction, the organic solvent layer was washed with water and dried over anhydrous sodium sulfate. After removing the desiccant, the organic solvent layer was concentrated under reduced pressure to obtain 95.0 g (0.318 mol) of racemic PIP. The yield with respect to (−) PIP was 95%, and as a result of analysis by liquid chromatography using a chiral column, the ratio of the (+) form and the (−) form of PIP was 50:50.

Example 2 (-) PIP hydrochloride (112.2 g) was added to butyl acetate (500 g).
(0.335 mol) and 5% sodium carbonate aqueous solution 74
1.9 g (0.350 mol) was added for desalting, the solvent layer was separated, and washed with 500 g of water. After cleaning, pure water 500
An aqueous acetic acid solution in which 40 g (0.670 mol) of acetic acid was dissolved was added to g, and the mixture was reacted by stirring 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% phosphoric acid aqueous solution and 250 g of water. Pyrrolidine (26.2 g, 0.368 mol) was added to the organic solvent layer to give 20
The reaction was allowed to stir at ~ 30 ° C for 1 hour. After completion of the reaction, the organic solvent layer was washed with water and dried over anhydrous sodium sulfate. After removing the desiccant, L-10-camphorsulfonic acid 15
5 g (0.67 mol) was added to form two kinds of diastereomeric salts, which were then crystallized to separate the hardly soluble diastereomeric salts. Drying gave (+) PIP camphorsulfonate. Yield 112.1 g (0.147 mol) Yield 43.9 mol% Optical purity 99.5% ee

Example 3 (2.2) g of (-) PIP hydrochloride in 500 g of butyl acetate
(0.335 mol) and 5% sodium carbonate aqueous solution 74
1.9 g (0.350 mol) was added for desalting, the solvent layer was separated, and washed with 500 g of water. After cleaning, pure water 500
An aqueous solution of butyric acid in which 59 g (0.670 mol) of butyric acid was dissolved was added to g and stirred at a temperature of 20 to 30 ° C. for 10 hours to cause a reaction. After completion of the reaction, the organic solvent layer was separated and washed with 250 g of a 5% phosphoric acid aqueous solution and 250 g of water. Pyrrolidine (26.2 g, 0.368 mol) was added to the organic solvent layer to give 20
The reaction was allowed to stir at ~ 30 ° C for 1 hour. After completion of the reaction, the organic solvent layer was washed with water and dried over anhydrous sodium sulfate. After removing the desiccant, L-10-camphorsulfonic acid 15
5 g (0.67 mol) was added to form two kinds of diastereomeric salts, which were then crystallized to separate the hardly soluble diastereomeric salts. Drying gave (+) PIP camphorsulfonate. Yield 111.5 g (0.146 mol) Yield 43.6 mol% Optical purity 99.5% ee

Example 4 To 500 g of toluene, 100 g of (-) PIP (0.335)
Mol), and boric acid 41.
A boric acid aqueous solution in which 4 g (0.670 mol) was dissolved was added, and the mixture was stirred at a temperature of 20 to 30 ° C. for 10 hours to be reacted.
After completion of the reaction, the organic solvent layer is separated, and a 5% phosphoric acid aqueous solution 25
It was washed with 0 g and 250 g of water. Pyrrolidine (26.2 g, 0.368 mol) was added to the organic solvent layer, and the temperature was 20 to 30 ° C.
And reacted for 1 hour under stirring. After completion of the reaction, the organic solvent layer was washed with water and dried over anhydrous sodium sulfate. After removing the desiccant, L-10-camphorsulfonic acid 155 g
(0.67 mol) was added to form two kinds of diastereomeric salts, which were then crystallized to separate the hardly soluble diastereomeric salts. Drying gave (+) PIP camphorsulfonate. 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)
-1-propanone 2.5 g, paraformaldehyde 1.
To a mixed solution of 11 g, pyrrolidine hydrochloride (1.6 g) and isopropyl alcohol (20 ml) was added concentrated hydrochloric acid (0.1 ml), and the mixture was heated under reflux 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 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, the drying agent was removed, and the mixture was concentrated to obtain 1.58 g of the objective compound as an oily substance.

Reference Example 5 (+)-2-methyl-1- (4-trifluoromethylphenyl)
Phenyl) -3-pyrrolidino-1-propanone hydrochloride MTP 306 g (1.07 mol) and d-acetylphene
Nylglycine ([α] ²⁰ _D−212.8 °, c = 1.
(0, methanol) 210 g (1.08 mol) of ethyl acetate
It was dissolved in 1400 ml of water to form a salt, and then dissolved at room temperature.
Let stand overnight and stir at about 5 ° C. for 3 hours. The precipitated crystals
After filtering and drying under reduced pressure, MTP.L-acetylphenyl
219 g of glycine salt are obtained. 175g secondary from the filtrate
A crystal was obtained. 394 g of crystals, 630 ml of 10% saline, vinegar
950 ml of ethyl acidate and 60 ml of 28% ammonia water
After adding and dissolving, the organic layer was washed with brine, and anhydrous sodium sulfate was added.
Dry with gnesium. Then cool in ethyl acetate solution.
After gradually introducing 29 g of rejected hydrogen chloride gas, at an internal temperature of about 5 ° C
Stir for 2 hours. The precipitated crystals were 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 5% ammonia water 119.0 g
(0.350 mol) was added for desalting. After desalting, the solution was separated, the solvent layer was washed with 500 g of water, and 500 g of pure water was added to 4 g of acetic acid.
An acetic acid aqueous 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 completion of stirring, the organic solvent layer was separated, and 250 g of a 5% phosphoric acid aqueous solution and water 25
It was washed with 0 g. 26.2 g of pyrrolidine in the organic solvent layer
(0.368 mol) was added and the mixture was reacted at 20 to 30 ° C. for 1 hour with stirring. After the reaction was completed, the organic solvent layer was washed with 400 g of a 5% sodium carbonate aqueous solution. After washing, it was dried with 20 g of anhydrous magnesium sulfate for 20 hours. After removing the desiccant, it is concentrated under reduced pressure to give an oily MTP.
93.67 g (0.318 mol) was obtained. Yield is (+)
It was 98 mol% with respect to MTP hydrochloride. The analysis of the oily MTP by liquid chromatography using a chiral column revealed that the ratio of the (+) form to the (-) form was 5
It was 0:50 and the racemization rate was 100%.

[0028]

INDUSTRIAL APPLICABILITY According to the method of the present invention, not only is it possible to recover a racemized aminoketone derivative from an unnecessary optically active aminoketone derivative in a high yield, but also a racemized aminoketone derivative can be obtained without isolation operation. It is an industrially valuable method because it has the advantage that it can be directly subjected to the optical resolution operation in the organic solvent layer.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/425 C07B 55/00 A 7419-4H (72) Inventor Ryuichi Mita Asmuta, Omuta City, Fukuoka Prefecture 30-cho Mitsui Toatsu Chemical Co., Ltd.

Claims (6)

[Claims] 1. A compound represented by the general formula (1):[R in this formula¹IsRepresents (R^FiveIs a halogen atom: lower alkyl group: benz
Group: benzoyl group: pyridyl group: lower alkyl group
Optionally substituted furyl group; substituted with a lower alkyl group
Optionally substituted thienyl group; halogen atom, lower alcohol
Xy group, lower alkyl group, trifluoromethyl group, sia
Group, nitro group, amino group, dimethylamino group, aceto group
Amide group, methanesulfonylamide group, acetyl group or
May be substituted with a lower alkoxycarbonyl group
A phenyl group or a naphthyl group, R ⁶Is trifluorome
A phenyl group which may be substituted with a tyl group or a lower alkyl group.
Group, Z represents an oxygen atom or a sulfur atom. ),
R²Is a lower alkyl group, a benzyl group, a methoxy group, a group
Phenyl group, allyl group, trifluoromethyl group or low
Of primary alkoxy group or cyclopropylmethyl group
You. R³And R^FourAre independently saturated or unsaturated
Represents a lower alkyl group of R³And R^FourAre connected in a ring
Pyrrolidine, piperazine, hexamethyleneimine, mol
A kind selected from the group consisting of holin and piperazine
It may have a ring structure, and the ring structure
The structure may be substituted with a methyl group or a benzyl group.
An optically active aminoketone derivative represented by
By reacting with a weak acid aqueous solution in the general formula (2)(R in the formula¹, R²Is the same as above)
After forming a conductor and isolating it,
In a solvent, the compound represented by the general formula (3):(R in the formula³, R^FourIs the same as the above formula (1)]
Induced racemic aminoketone
How to make a body. 2. The method according to claim 1, wherein the organic solvent is a halogenated hydrocarbon, an acetic acid alkyl ester, a ketone, or an aromatic hydrocarbon. 3. The logarithmic value (pK) of the reciprocal of the acid dissociation constant of a weak acid.
The method according to claim 1, wherein a) is 2 or more. 4. The temperature at which the weak acid aqueous solution is allowed to act is -10 to 10.
The method according to claim 1, which is 70 ° C. 5. The method according to claim 1, wherein the amount of the weak acid used is 0.1 to 10 times that of the aminoketone derivative. 6. The reaction temperature for reacting with amines is -10.
The method of claim 1, wherein the temperature is ˜70 ° C.