JPH07157475A - Method for resolving (+)-3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole and salts thereof - Google Patents

Abstract

(57) [Summary] [Purpose] High optical purity and high resolution (+)-
3-phenyl-5- {2- (1-pyrrolidinylmethyl)
Butyryl} isoxazole and its salts are obtained. [Structure] Racemic 3-phenyl-5- {2- (1-
In the method of optically resolving pyrrolidinylmethyl) butyryl} isoxazole using an optically active sulfonic acid as a resolving agent, the compound is optically resolved in an aromatic hydrocarbon solvent (+).
A method for resolving -3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole and salts thereof.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for resolving (+)-3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole and its salts having a central muscle relaxant action. Regarding

[Prior art]

Racemic 3-phenyl-5- {2- (1
-Pyrrolidinylmethyl) butyryl} isoxazole [hereinafter abbreviated as PIP] is known to have a central muscle relaxing action (JP-A-3-157375). In particular, one of the optically active substances (+)-3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl}
Isoxazole [hereinafter abbreviated as (+) PIP] has a more prominent central muscle relaxant action as compared with the racemate, and is an effective compound as a muscle tone improving agent. The conventional production method of this optically active (+) PIP is the optically active L-
This is a method of forming a diastereomeric salt with camphor-sulfonic acid and performing optical resolution (Japanese Patent Laid-Open No. 51380/1993).
issue). In the prior art, specifically, the hydrochloride of PIP produced through a synthetic process is dissolved in water, neutralized with an alkali such as sodium carbonate, PIP is converted into a free form, and then PIP is added with ethyl acetate. Is extracted and is optically resolved in a solvent of ethyl acetate using L-camphor-sulfonic acid as an optical resolving agent to produce an optically active camphor-sulfonate of (+) PIP.

By the way, (+) PIP L-camphor
The sulfonate has a high solubility in water, and therefore, if water is contained in the solvent used for optical resolution, the yield of optical resolution will be lowered. That is, a solvent such as ethyl acetate is compatible with water, and usually 100 parts of ethyl acetate is mixed with 3.6 parts of water.
It is known that water and a considerable amount of water dissolve. fact,
The ethyl acetate layer obtained by extracting free PIP from water with ethyl acetate brought in 2% or more of water, and kept a predetermined amount of L
-When camphor-sulfonic acid was charged and optical resolution was performed,
The optical resolution yield of (+) PIP is 50 based on (+) PIP.
It turns out that it is less than%. Therefore, the solution extracted with ethyl acetate must be dehydrated and filtered with a dehydrating agent such as anhydrous sodium sulfate in advance, and then subjected to optical resolution. However, even if such a dehydration operation is performed, the optical resolution yield in the ethyl acetate solvent is only about 80%, which is not necessarily high. In addition, when ethyl acetate is used as an optically resolving solvent, the dissolution of the solvent in the aqueous layer is large, and there are many problems in that the solvent recovery process is complicated from an industrial viewpoint.

[0004]

DISCLOSURE OF THE INVENTION In the present invention, as described above, PIP is optically resolved with an optically active sulfonic acid,
In a method for producing (+) PIP or a salt thereof, it is an object to solve the problems of the optical resolution solvent that the above-mentioned prior art has, and obtain (+) PIP or a salt thereof with a high optical resolution yield. Is.

[0005]

[Means for Solving the Problems] In order to achieve this object, the inventors of the present invention have made extensive studies on a solvent used for optical resolution. As a result, surprisingly, PIP camphor-sulfonate is not only capable of optical resolution in an aromatic hydrocarbon solvent such as toluene or xylene, but has a high optical purity, even though it is a highly polar compound. The inventors have found that the camphor-sulfonate of (+) PIP can be resolved with a high optical resolution yield, and have completed the present invention.

That is, according to the present invention, racemic 3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole represented by the formula (1) is optically resolved with an optically active sulfonic acid. In the method of optical resolution as an agent, (+)-3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole is characterized by performing optical resolution in an aromatic hydrocarbon solvent. And its salt resolution method.

[0007]

[Chemical 2]

According to the method of the present invention, not only the optical purity of optically resolved (+) PIP and the optical resolution yield are high, but the solubility of water in an aromatic hydrocarbon solvent is extremely small. The extract obtained after PIP extraction is an industrially valuable method because it does not require dehydration operation and can be directly subjected to optical resolution operation. For example,
L of (+) PIP when toluene is used as an optical resolution solvent
-The optical purity and the optical resolution yield of camphor-sulfonate are 98.5% ee and 96 mol% [(+) PIP, respectively].
It was a standard].

In the method of the present invention, racemic PIP
Is produced by the method described in JP-A-3-157375. Specifically, PIP is produced by adding formalin to a solution prepared by dissolving 3-phenyl-5-butyrylisoxazole and pyrrolidine in methanol and reacting them. PIP undergoes a post-treatment operation and is usually isolated in the form of hydrochloride or the like.

Specific embodiments of the present invention are as follows.
PIP hydrochloride is dissolved in water and neutralized with an alkali such as sodium carbonate to give free PIP. Free PI
P is extracted with an aromatic hydrocarbon solvent to obtain a PIP aromatic hydrocarbon solution. By adding a predetermined amount of optically active camphor-sulfonic acid to the aromatic hydrocarbon solvent solution of PIP to dissolve it by heating, cooling (+) PI is performed.
The optically active sulfonate of P is optically resolved. At the time of this optical resolution, it is also possible to add a seed crystal of an optically active sulfonate of (+) PIP. Precipitated (+) PIP
The optically active sulfonate is isolated by a usual solid-liquid separation operation.

The aromatic hydrocarbon solvent used in the present invention is P
There is no particular limitation as long as IP can be optically divided. Specific examples include benzene, toluene, xylene, ethylbenzene, chlorobenzene, dichlorobenzene, and nitrobenzene. Among these, especially toluene,
Xylene is preferred.

The amount of the aromatic hydrocarbon solvent used varies depending on the kind of the solvent used, but if the amount is too small, the optical resolution will be insufficient. More than double. The upper limit is not particularly limited, but excessive use causes not only a decrease in optical resolution yield but also economically unfavorable. Therefore, it is usually preferable to use 20 times or less the weight of PIP.

In the present invention, the aromatic hydrocarbon solvent solution in which racemic PIP is dissolved is resolved with an optically active sulfonic acid. Specific examples of the optically active sulfonic acid include bromcamphorsulfonic acid, 3-camphorsulfonic acid, 8-camphorsulfonic acid, and 10-camphorsulfonic acid, and the optical purity of (+) PIP obtained in particular. From the viewpoints of the above, L-10-camphor sulfonic acid is preferable.

The amount of the optically active sulfonic acid used for the optical resolution is not limited as long as it is 1 equivalent or more with respect to 1 equivalent of the racemic PIP, but if it is 1.5 equivalents or less, the desired (+) PIP optical property is obtained. Since the optical resolution yield and isolation yield of the active camphor-sulfonate decrease, it is usually preferable to use 1.5 equivalents or more. The upper limit of the amount used is 3 equivalents or less from an economical point of view.

The optical resolution temperature is in the range of -20 to 80 ° C. As a specific operation method, a predetermined amount of optically active camphor-sulfonic acid is added to the aromatic hydrocarbon solvent layer and the mixture is heated. After once dissolved by such operations, cooling and crystallization may be performed. The crystallization temperature and time at this time are 0 to 20.
C, 1 to 5 hours may be sufficient.

The desired optically active camphor-sulfonate of (+) PIP may be isolated by a solid-liquid separation operation such as suction filtration after crystallization. The optical purity of the optically active sulfonate of (+) PIP isolated through such an operation is usually 95% or more.

When it is necessary to produce free (+) PIP, specifically, the optically active camphor-sulfonate of (+) PIP obtained by optical resolution as described above is dissolved in water. After liberation with an alkali such as sodium carbonate, extraction with an organic solvent such as chloroform and concentration to dryness may be performed.

As a method for producing (+) PIP hydrochloride, specifically, the optically active camphor-sulfonate of (+) PIP is liberated with an alkali in water and extracted into an organic solvent such as chloroform. To do. An aqueous hydrochloric acid solution is added to the organic solvent layer to perform hydrochloric acid salification, and the organic solvent layer obtained by liquid separation is crystallized by adding a poor solvent, for example, an organic solvent such as ethyl acetate, and then the crystallization mass is suction filtered. It may be isolated by a solid-liquid separation operation such as.

[0019]

EXAMPLES The method of the present invention will be described in detail below with reference to examples. Reference Example 1 [Synthesis of 3-phenyl-5-butyrylisoxazole] 100 g (0.82 mol) of benzaldoxime and 90 g (0.92 mol) of 1-hexyne-3-ol were dissolved in 500 ml of dichloromethane. The reaction solution was ice-cooled, and 580 g of a 12% sodium hypochlorite aqueous solution (1.
(0 mol) 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 solution, 490 g (0.79 mol) of a 12% sodium hypochlorite aqueous solution was added dropwise. The internal temperature of the reaction solution was cooled to 10 ° C, and a pyridine hydrochloride aqueous solution (6N hydrochloric acid 2
8 ml and pyridine 13 ml) were added dropwise over 20 minutes. After stirring the reaction solution for 70 minutes, 490 g (0.79 mol) of 12% sodium hypochlorite was added dropwise.
The internal temperature was cooled to 10 ° C., and pyridine hydrochloride aqueous solution (prepared with 6N hydrochloric acid 14 ml and pyridine 6.7 ml) was added to 1 again.
The mixture was added dropwise over 0 minutes and stirred for 70 minutes. 1 in this solution
A 2% aqueous solution of sodium hypochlorite was added dropwise. Once again, the internal temperature was cooled to 10 ° C. and pyridine hydrochloride aqueous solution and 12%
The operation of adding an aqueous solution of sodium hypochlorite was repeated. 5% of the dichloromethane layer was obtained by separating the reaction mixture.
Add 30 ml of aqueous sodium hydrogen sulfite solution to 30
Stir for minutes. The reaction mixture was separated, and the obtained dichloromethane layer was washed with 1000 ml of water and 1000 ml of 1N hydrochloric acid in this order. The obtained dichloromethane layer was heated and concentrated, and the obtained residue was recrystallized from 400 ml of ethanol to obtain 106 g (yield 59.6 mol%) of the desired compound. Melting point 89
~ 90 ° C

Reference Example 2 [Synthesis of Racemic PIP Hydrochloride] 100 g of 3-phenyl-5-butyrylisoxazole
(0.465 mol) and 39.7 g (0.
555 mol) was added to 310 g of methanol. The reaction solution was stirred, and 45.2 g (0.555 mol) of 37% aqueous formalin solution was added dropwise while keeping the internal temperature at 20 to 30 ° C. After the completion of dropping, the mixture was stirred for 1 hour while maintaining the internal temperature at 20 to 30 ° C. 890 g of ethyl acetate was added to the reaction solution. Further, 750 g of water was added and liquid separation extraction was performed to obtain an organic layer. The obtained organic layer was ice-cooled, and 890 g of a 2N aqueous hydrochloric acid solution was added for liquid separation and extraction. The obtained aqueous layer was extracted with 900 g of chloroform. The aqueous layer was extracted again with 120 g of chloroform,
The obtained chloroform was combined and dried over anhydrous sodium sulfate. To the chloroform solution obtained by filtering off sodium sulfate, 1470 g of ethyl acetate 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 104.0 g of the colorless target compound.
(Yield 67 mol%) was obtained. Melting point 151-153 ° C

Example 1 [(+) PIP-L-10-camphor-sulfonate]
Racemic PIP hydrochloride 91.5 g (0.272 mo
l) a mixed solution of 550 ml of water and 640 ml of toluene
Dissolved in. 6% aqueous sodium hydrogen carbonate solution
660 ml of the liquid was added dropwise. The reaction was stirred for 10 minutes
After that, liquid separation was performed to obtain an organic layer. In the organic solvent layer obtained by liquid separation
L-10-camphor sulfonic acid [[α]²⁰ _D= 21 °
(C = 2, water)] 126.4 g (0.544 mol)
In addition, the mixture was stirred for 30 minutes to dissolve it. Reaction mixture under ice cooling, 2
After stirring for an hour, the precipitated crystals are collected by filtration and washed with toluene,
The desired (+) PIP-L-10-car is dried under reduced pressure.
99.2 g (0.130 mol)
Got For the (+) form in the racemic PIP hydrochloride
The yield was 96 mol%. Melting point 115.8-116.3 ° C [α]²⁰ _D= -14.4 ° (C = 0.5, ethanol) Optical purity 98.5% ee

Example 2 [(+) PIP-L-10-camphor-sulfonate]
Racemic PIP hydrochloride 91.5 g (0.272 mo
l) was dissolved in a mixed solution of 550 ml of water and 640 ml of nitrobenzene. 660 ml of a 6% sodium hydrogen carbonate aqueous solution was added dropwise to this solution. The reaction solution was stirred for 10 minutes and then separated to obtain an organic layer. L-10-camphor-sulfonic acid [[α] ²⁰ _D = 2 was added to the organic solvent layer obtained by liquid separation.
1 ° (C = 2, water)] 126.4 g (0.544 mo
1) was added and stirred for 30 minutes to dissolve. The reaction solution was stirred under ice cooling for 2 hours, and the precipitated crystals were collected by filtration, washed with nitrobenzene, and dried under reduced pressure to obtain the desired (+) PIP.
95.3 g of -L-10-camphor sulfonate
(0.125 mol) was obtained. The yield of racemic PIP hydrochloride based on the (+) isomer was 92 mol%. Mp _{^{115.8~116.3 ℃ [α] 20 D =}} -14.4 ° (C = 0.5, ethanol - Le) Optical purity 98.5% ee

Comparative Example 1 [(+) PIP-L-10-camphor-sulfonate]
Racemic PIP hydrochloride 91.5 g (0.274 mo
l) is a mixed solution of 550 ml of water and 640 ml of ethyl acetate.
It dissolved in the liquid. 6% aqueous sodium hydrogen carbonate solution
660 ml of solution was added dropwise. The reaction was stirred for 10 minutes
After that, liquid separation was performed to obtain an organic layer. In the organic solvent layer obtained by liquid separation
L-10-camphor-sulfonic acid ([α] ²⁰ _D= 21 °
(C = 2, water)] 14.2 g (0.06 mo) was added
It was dissolved by stirring for 30 minutes. Stir the reaction mixture under ice cooling for 2 hours.
Crystals precipitated by stirring are collected by filtration, washed with toluene and then under reduced pressure.
Desired (+) PIP-L-10-camphor after drying
-22.4 g (0.029 mol) of sulfonate were obtained.
The yield of racemic PIP hydrochloride based on the (+) form is 2
It was 1.1 mol%. Melting point 115.8-116.3 ° C [α]²⁰ _D= -14.4 ° (C = 0.5, ethanol) Optical purity 98.5% ee

Comparative Example 2 [(+) PIP-L-10-camphor-sulfonate]
Racemic PIP hydrochloride 91.5 g (0.274 mo
l) was dissolved in a mixed solution of 550 ml of water and 640 ml of ethyl acetate. 660 ml of a 6% sodium hydrogen carbonate aqueous solution was added dropwise to this solution. The reaction solution was stirred for 10 minutes and then separated to obtain an organic layer. The aqueous layer is again washed with ethyl acetate 55
The organic layer obtained by extraction with 0 ml was combined with the organic layer obtained above, and dried over 400 g of anhydrous sodium sulfate. The filtrate obtained by filtering out sodium sulfate was L-10-camphor.
Sulfonic acid ([α] ²⁰ _D = 21 ° (C = 2, water)] 1
4.2 g (0.06 mol) was added and dissolved by stirring for 30 minutes. The reaction solution was stirred under ice cooling for 6 hours, and the precipitated crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the desired (+) PIP-L-10-camphor-sulfonate 87. 0 g (0.113 mol) was obtained. Racemic P
The yield based on the (+) form in IP hydrochloride was 82.4 mol.
%Met. Mp _{^{115.8~116.3 ℃ [α] 20 D =}} -14.4 ° (C = 0.5, ethanol - Le) Optical purity 98.5% ee

Reference Example 3 [(+) PIP Hydrochloride] (+) PIP-L-10-camphor-sulfonate 16
6.7 g (0.218 mol) was dissolved in a mixed liquid of 950 ml of water and 950 ml of ethyl acetate, and 530 ml of a 10% sodium carbonate aqueous solution was added dropwise. The reaction solution was stirred for 10 minutes and then separated to obtain an organic layer. The obtained organic layer is 1
It was washed with 260 ml of 0% aqueous sodium carbonate solution and further with 260 ml of water. Add 2N hydrochloric acid to the organic layer 5
00 ml was added and liquid separation extraction was carried out to obtain an aqueous layer. The organic layer was extracted again with 260 ml of 2N hydrochloric acid, and the obtained aqueous layer was combined with the previously obtained aqueous layer. Chloroform 3 in the obtained aqueous solution
20 ml was added and extracted to obtain a chloroform layer. The chloroform layer obtained by extracting the aqueous layer again with 320 ml of chloroform was combined with the previously obtained chloroform layer. The obtained chloroform solution was dried over anhydrous sodium sulfate.
1800 ml of ethyl acetate was added dropwise to the chloroform solution obtained by filtering off sodium sulfate. This solution was cooled on ice for 3
Stir for hours. The precipitated crystals were collected by filtration and washed with ethyl acetate to obtain 31.5 g of the target (+) PIP hydrochloride. The yield based on (+) PIP-L-10-camphor-sulfonate is 60.3 mol%. Melting point 158 to 159.5 ° C. [α] ²⁰ _D = + 29 ° (C = 0.5, water) Optical purity 99.9% ee or more

[0026]

According to the method of the present invention, (+) PIP or a salt thereof can be obtained with high optical purity and high optical resolution yield.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Ryuichi Mita 30 Asamuta-cho, Omuta-shi, Fukuoka Mitsui Toatsu Chemical Co., Ltd.

Claims (2)

[Claims] 1. Optical resolution of racemic 3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole represented by formula (1) using an optically active sulfonic acid as a resolving agent. Of (+)-3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole and a salt thereof, which is characterized by performing optical resolution in an aromatic hydrocarbon solvent. Division method. [Chemical 1] 2. The method according to claim 1, wherein the optical resolution temperature is −20 to 80 ° C.