JP2999146B2 - 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 for reusing a racemic aminoketone derivative after racemizing an unnecessary optically active aminoketone derivative after optical resolution.

[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 body,
It is a compound effective 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 PIP is not racemized and reused, there arises a problem such as a decrease in the yield of the target product, which is not always industrially satisfactory. . As a method for obtaining 100% racemized PIP from optically active PIP, 3-phenyl-5- {2-ethyl-2-propenoyl) isoxazole [hereinafter referred to as PIE]
And a reaction with pyrrolidine to produce 100% racemized PIP. However, this method not only complicates the process for once isolating PIE but also complicates the process. This method is industrially unsatisfactory since a new equimolar amount of pyrrolidine is required. In addition, as a method for recovering the aminoketone derivative, 2
-Methyl-1- (4-trifluoromethylphenyl)-
A method in which 3-pyrrolidino-1-propanone (hereinafter abbreviated as MTP) is optically resolved with an optically active optical resolving agent, and pyrrolidine is added to the filtrate to recover MTP (JP-A-63-310878). There is M
There is no description or suggestion about the racemization rate of TP, and this recovery method is not a method of recovering an unnecessary optically active substance by racemizing it. In addition, this method is not industrially satisfactory because not only the production process becomes complicated because the recovered derivative is once isolated, but also expensive pyrrolidine is newly required.

[0003]

SUMMARY OF THE INVENTION According to the present invention, as described in the prior art, after an optical resolution of a racemic aminoketone derivative, an intermediate is once formed and isolated in order to racemize an unnecessary optically active aminoketone derivative. 100% of unnecessary optically active aminoketone derivatives by a simple and inexpensive method without reacting with pyrrolidine and causing racemization.
It is an object of the present invention to make the composition racem%.

[0004]

The present inventors have intensively studied a method for racemizing an optically active aminoketone derivative in order to achieve this object. As a result, surprisingly , the pair of the optically active aminoketone derivative and the reciprocal of the acid dissociation constant
It has been discovered that when a weak acid having a numerical value (pKa) of 2 or more is applied, the optically active aminoketone derivative is easily racemized. Furthermore, they have found that the optically active aminoketone derivative can be easily racemized without intentionally isolating the reaction intermediate by this racemization method, and have completed the present invention.

That is, the present invention provides a 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. The present invention provides a method of causing racemization by acting with a weak acid having a logarithmic value (pKa) of 2 or more of the reciprocal of the acid dissociation constant .

[0006] The method of the present invention is neither described or suggested in the above prior art, and is therefore a technique first discovered by the present inventors, and is an optically active aminoketone of high utility in the pharmaceutical field and industrially. This is a method for racemizing derivatives.

The specific embodiments of the present invention are as follows. Acid decomposition into organic solvent solution of optically active aminoketone derivative
A racemic aminoketone derivative is obtained by adding a weak acid having a logarithmic value (pKa) of 2 or more to the reciprocal of the separation constant and acting for several hours.

[0008] 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, (-) PIP having an aminoketone is specifically prepared by adding formalin to a solution of 3-phenyl-butylisoxazole and pyrrolidine in methanol to form PIP, and extracting the resultant with an organic solvent. Performed an optical resolution operation with addition of optically active D-10- mosquito <br/> Nfa over acid extraction after the organic solvent layer, after workup (-) isolating PIP as the hydrochloride salt. As a method for producing (+) MTP, first, 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 act on the optically active aminoketone derivative is an acid having an inverse logarithm of the acid dissociation constant (hereinafter abbreviated as pKa) 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 and succinic 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 concentration of the optically active aminoketone derivative in the organic solvent is not particularly limited, but may be from 1 to 50%
Range. 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 is 50% by weight or more, the reaction mixture becomes viscous and the reaction does not proceed sufficiently, so that the racemization ratio may decrease.

The logarithmic value (pKa) of the reciprocal of the acid dissociation constant is 2
The temperature at which the above-mentioned weak acid is allowed to act is allowed in the range of -10 to 80C, and preferably in the range of 0 to 60C. -10
If the temperature is lower than ℃, the reaction does not proceed sufficiently and the yield decreases. 8
When the temperature exceeds 0 ° C., the optically active aminoketone derivative is easily 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 completion of the racemization reaction, the solvent layer is neutralized and washed with an aqueous alkali solution such as sodium hydrogencarbonate or sodium carbonate, and if necessary, an intermediate by-produced by adding an equimolar amine such as pyrrolidine. It may be a racemized aminoketone derivative. Subsequently the solvent layer optically active after drying with water washed over anhydrous sodium sulfate or the like 10 cans <br/> files over acid may be optically resolved by adding an optical resolution agent such as acetyl phenylglycine.

[0015]

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] 3-phenyl-5-butyrylisoxazole 20 g (0.093 mol) and pyrrolidine 7.93 g ( 0.111 mol) in methanol 6
2 g. The reaction solution was stirred, and 9.04 g (0.1%) of a 37% aqueous formalin solution was maintained while maintaining the internal temperature at 20 to 30 ° C.
11 mol) was added dropwise. 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 obtained.
Was added for liquid separation and extraction. The resulting aqueous layer was washed with chloroform 1
Extracted with 80 g. The aqueous layer was extracted again with chloroform,
The obtained chloroform layers were combined and dried over anhydrous sodium sulfate. 294 g of ethyl acetate was added dropwise to a chloroform solution obtained by filtering off sodium sulfate while 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 camphorsulfonate 11.8g. (-) PIP · D- camphorsulfonate 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 and desalted. The organic solvent layer was separated, washed with 500 g of water, and dried with 15 g of anhydrous sodium sulfate. Acetic acid 10g after desiccant removal
(0.168 mol) and stirred at a temperature of 20 to 30 ° C. for 15 hours to cause a racemization reaction. After completion of the reaction, the organic solvent layer was washed with 400 g of a 5% aqueous sodium carbonate solution and dried with 20 g of anhydrous sodium sulfate. After the desiccant was removed, the ratio of the (+) form and the (-) form of PIP in the organic solvent layer was determined by liquid chromatography analysis using a chiral column, and the result was 50:50. 155 g (0.67 mol) of L-10-camphorsulfonic acid was added to the organic solvent layer to give 2
Different diastereomeric salts were formed, the poorly soluble diastereomer salt was crystallized, and the solid was separated and dried to obtain (+) PIP · L-10-camphorsulfonate. Yield 115.0 g (0.151 mol) Yield 45.1 mol% [vs. (-) PIP hydrochloride] Optical purity 99.5% ee

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 and desalted. The organic solvent layer was separated, washed with 500 g of water, and dried with 15 g of anhydrous sodium sulfate. After drying, 20 g of acetic acid (0.3 g
33 mol) and stirred at a temperature of 20 to 30 ° C. for 15 hours to cause a racemization reaction. After the reaction, 5% of organic solvent layer
It was washed with 400 g of an aqueous sodium carbonate solution and dried with 20 g of anhydrous sodium sulfate. After removing the desiccant, P in the reaction solution was determined by liquid chromatography analysis using a chiral column.
The result of examining the ratio of the (+) form and the (-) form of IP was 50: 5.
It was 0. 155 g (0.67 mol) of L-10-camphorsulfonic acid was added to the organic solvent layer to form two kinds of diastereomeric salts, and a hardly soluble diastereomer salt was crystallized to separate a solid. Dry (+) PIP ・
L-10-Camphorsulfonate was obtained. Yield 109.9 g (0.144 mol) Yield 43.0 mol% [vs. (-) PIP hydrochloride] Optical purity 99.5% 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-trifluoromethylphenyl)
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 toluene 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
Obtain crystals. 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. After removing the desiccant, in ethyl acetate solution
After gradually introducing 29 g of hydrogen chloride gas under cooling, the internal temperature was reduced to approx.
Stir for 2 hours at ° C. The precipitated crystals are filtered, and ethyl acetate is added.
After washing with water and drying under reduced pressure, (+) MTP hydrochloride 217 g
Get.

EXAMPLE 3 (+) 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 and 10 g of acetic acid (0.16 g).
8 mol) and stirred at a temperature of 20 to 30 ° C. for 25 hours to cause a racemization reaction. 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 MT.
93.67 g (0.318 mol) of P were obtained. The yield was 98 mol% based on (+) MTP hydrochloride. Further, as a result of performing liquid chromatography analysis of MTP using a chiral column, the ratio of (+)-form: (-)-form was 50:50.
Met.

[0023]

According to the method of the present invention, in order to racemize an unnecessary optically active aminoketone derivative, an intermediate is once generated, isolated, and reacted with an amine such as pyrrolidine to be newly racemized. In addition, it is possible to racemize an unnecessary optically active aminoketone derivative by 100% by a simple and inexpensive method, which is an industrially valuable method.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/42 A61K 31/42 31/425 31/425 C07B 55/00 C07B 55/00 A (58) Fields surveyed (Int. Cl. ^7, DB name) C07C 221/00 C07C 225/06 C07D 261/08 C07D 275/02 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A compound of the general formula (1) [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. A method of causing a logarithmic value ( pKa) of the reciprocal of the acid dissociation constant to act on a weak acid having 2 or more to cause racemization. 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 method according to claim 1, wherein the weak acid having a logarithm (pKa) of the reciprocal of the acid dissociation constant of 2 or more is an organic acid. 4. The logarithmic value (pKa) of the reciprocal of the acid dissociation constant is
The method according to claim 1, wherein the temperature at which the reaction with two or more weak acids is carried out is -5 to 80C.