JPH07165734A - Production of (+)-3-phenyl-5-(2-(1-pyrrolidinylmethyl)-butyryl)isoxazole and its salt - Google Patents

Abstract

PURPOSE:To readily isolate the subject high optically purity compound having a central muscular relaxation effect in a high yield by optical resolution of a reaction solution itself of racemic 3-phenyl-5-{2-(1-pyrrolidinylmethyl) butyryl}isoxazole. CONSTITUTION:This compound is synthesized by reacting (A) 3-phenyl-5- butyrylisoxazole, (B) pyrrolidine and (C) formalin in an alcohol as a solvent, adding a water-immiscible organic solvent (preferably an alkyl acetate or a ketone) to the resultant reaction solution without isolating racemic 3- phenyl-5-{2-(1-pyrrolidinylmethyl)butyryl}isoxazole of the formula, extracting the compound of the formula, washing the organic solvent layer with water, subsequently adding an optically active sulfonic acid (especially preferably L-10-camphorsulfonic acid) thereto and carrying out optical resolution thereof. In addition, the optical resolution temperature is preferably -20 to 80 deg.C.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing (+)-3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole having a central muscle relaxant action and salts thereof. . More specifically, it is directly optically resolved without isolation from the compound from the reaction solution for forming racemic 3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole (+)-. 3-phenyl-
It relates to a method for producing 5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole and salts thereof.

[0002]

BACKGROUND OF THE INVENTION Racemic 3-phenyl-5- {2-
It is known that (1-pyrrolidinylmethyl) butyryl} isoxazole (hereinafter abbreviated as PIP) has 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 [abbreviated as (+)-PIP hereinafter] and salts thereof are Compared with PIP, it has a more prominent central muscle relaxing action and is an effective compound as a muscle tone improving agent.

By the way, as a method for producing this (+) PIP and a salt thereof, conventionally, 3-phenyl-5-butyrylisoxazole was reacted with pyrrolidine and formalin in methanol as disclosed in JP-A-5-51380. Then, the method of isolating the produced PIP from the reaction system in the form of a hydrochloride and optically resolving using the hydrochloride as a raw material is only known. Specifically, it is a method in which the hydrochloride of PIP is liberated with an alkali in water, PIP is extracted with an ester solvent such as ethyl acetate, and the obtained extract is dehydrated and then optically resolved with L-camphorsulfonic acid. is there. However, in this conventional method, the PIP produced in the reaction must be isolated once in the form of the hydrochloride, which not only complicates the process, but also causes a loss of yield in the process of isolating the hydrochloride. Occurring, it is not always industrially satisfactory.

[0004]

SUMMARY OF THE INVENTION The present invention aims to simplify the production process and improve the yield by efficiently optically resolving PIP produced in the reaction without isolating it in the form of hydrochloride or the like. To do.

[0005]

[Means for Solving the Problems] In order to achieve the above-mentioned objects, the present inventors diligently studied a (+) PIP production method from a PIP formation reaction mass. Especially, 3-phenyl-5-
It was found that the reaction of butyrylisoxazole, pyrrolidine and formalin in methanol proceeded almost quantitatively, and PIP was extracted from the reaction mass of PIP formation with an organic solvent immiscible with water and washed with water. After removing methanol as a reaction solvent, the extract is charged with L-camphorsulfonic acid and optically resolved, whereby (+) PIP having no problem in quality can be produced in a high resolution yield. I found it. The present invention was made based on these findings.

That is, according to the present invention, racemic 3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole represented by the formula (1) is optically resolved ((+)-3). -Phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole and its salt are produced by reacting 3-phenyl-5-butyrylisoxazole with pyrrolidine and formalin in an alcohol solvent. From the reaction mixture, the racemic 3
-Phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole or a salt thereof without isolation of water and a non-miscible organic solvent to extract the formula (1) (+)-3-Phenyl-5-, which is characterized in that the solvent solution is washed with water and, if necessary, dehydrated, and then an optically active sulfonic acid is added to the organic solvent layer for optical resolution.
This is a method for producing {2- (1-pyrrolidinylmethyl) butyryl} isoxazole and salts thereof.

[0007]

[Chemical 2]

In the method of the present invention, first, PIP is produced by reacting 3-phenyl-5-butyrylisoxazole with pyrrolidine and formalin. The reaction is carried out in an alcohol solvent. The alcohol solvent used is methanol, ethanol, n-propanol, iso-propanol, n-butanol, sec-
Butanol, iso-butanol, tert. A lower alcohol such as butanol, methyl cellosolve or ethyl cellosolve. Among these alcohol solvents, from the viewpoint of preventing a decrease in optical resolution yield in the subsequent optical resolution step, the partition coefficient between the water used in the optical resolution step and the immiscible organic solvent and water is the water side. Especially preferred is a solvent that favors methanol, ethanol,
Preference is given to alcohol solvents such as iso-propanol, methyl cellosolve and ethyl cellosolve, which are miscible with water at an arbitrary ratio.

3-Phenyl-5 for producing PIP
-There are various methods for the reaction of butyryl isoxazole with pyrrolidine and formalin, but usually, 3-phenyl-5-butyryl isoxazole and pyrrolidine are dissolved in an alcohol solvent, and the reaction is performed under a predetermined temperature condition. Then, a formalin aqueous solution may be dropped to react. If a large amount of the starting material 3-phenyl-5-butyrylisoxazole remains after the reaction, this may affect the quality of the (+) PIP obtained in the optical resolution step, the resolution yield, etc. Is the starting material 3-phenyl-5
It is preferred that little butyrylisoxazole remains. Therefore, the amounts of pyrrolidine and formalin to be used are preferably theoretical amounts or more with respect to 3-phenyl-5-butyrylisoxazole. The upper limit of the amount used is not particularly limited, but from the economical point of view, it is preferable to use all at 1.5 equivalents or less.

The reaction temperature is in the range of 0 ° C. or higher and the boiling point of the solvent or lower, preferably 20 to 100 ° C., from the viewpoint of suppressing the reaction rate and the by-product of impurities. The end point of the reaction can be easily known using a means such as gas chromatography or liquid chromatography.

In the method of the present invention, in order to shift the PIP from the reaction mass producing PIP to the optical resolution step without isolating the PIP, the reaction mass is mixed with an organic solvent immiscible with water and further with water. In addition, the organic solvent layer obtained by the liquid separation operation is further washed with water, and then subjected to an optical resolution operation through a dehydration operation if necessary.

The organic solvent immiscible with water added to the reaction solution is particularly preferably a solvent which can temporarily dissolve two optically active diastereomeric salts formed between optically active camphorsulfonic acid and PIP. Although not limited, specifically, ketones such as methyl propyl ketone and methyl isobutyl ketone, acetic acid alkyl esters such as propyl acetate, butyl acetate and amyl acetate, or benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene and the like. Aromatic hydrocarbons, and of these, butyl acetate is the most preferable solvent from the viewpoints of price, operability, recovery of organic solvent, and the like.

From the viewpoint of extraction efficiency, the amount of the organic solvent immiscible with water used for extracting the PIP produced from the reaction solution is 1% with respect to the PIP produced in the reaction. It is at least 2 times by weight, preferably at least 2 times by weight. The upper limit of the amount used is not particularly limited, but excessive use causes not only a decrease in optical resolution yield but also economically unfavorable. Therefore, it is usually used in an amount of 20 times by weight or less.

The alcohol solution used in the reaction is removed by washing the organic solvent layer from which PIP has been extracted with water. The amount and the number of times of water used for washing are not particularly limited, but the PI
It is good to carry out until the alcohol concentration in the P extract becomes 0.5% or less.

An optically active camphor sulfonic acid is used as the optical resolving agent. Specifically, the optically active camphor sulfonic acid means bromcamphor sulfonic acid, 3
-Camphorsulfonic acid, 8-camphorsulfonic acid,
Although it is 10-camphorsulfonic acid, L-10-camphorsulfonic acid is preferable from the viewpoint of the optical resolution yield of (+) PIP obtained in particular.

The amount of optically active camphor sulfonic acid used is not limited as long as it is 1 equivalent or more relative to 1 equivalent of PIP extracted with an organic solvent, but if it is 1.5 equivalents or less, the desired (+) PIP Since the optical resolution yield and isolation yield of the optically active camphor sulfonate are lowered, 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.degree. C. to 80.degree. C. As a specific operating method, a predetermined amount of optically active camphorsulfonic acid is added to the water-immiscible organic solvent, After melting once by an operation such as heating, cooling and crystallization may be performed. The crystallization temperature at this time is 0 to 20 ° C,
The crystallization time may be 1 to 5 hours.

The optically active camphorsulfonate of (+) PIP may be isolated from the above cooling mass by a solid-liquid separation operation such as suction filtration. The optical purity of the optically active sulfonate of (+) PIP isolated through such an operation is 9
It is 5% or more.

When it is necessary to produce free (+) PIP, specifically, the optically active camphorsulfonate of (+) PIP obtained by optical resolution as described above is dissolved in water, After liberating with an alkali such as sodium carbonate, extract into an organic solvent such as chloroform,
Concentrate to dryness.

As a method for producing (+) PIP hydrochloride, specifically, the above-mentioned optically active camphorsulfonate of (+) PIP is dissolved in water and liberated with an alkali such as sodium carbonate. After conversion, it is extracted with an organic solvent such as chloroform. After hydrochloric acid is added to the organic solvent layer to perform hydrochloric acid salification, an organic solvent such as ethyl acetate which reduces the solubility is added to the separated organic solvent layer for crystallization,
The crystallized mass may be isolated by a solid-liquid separation operation such as suction filtration.

[0021]

EXAMPLES The method of the present invention will be described in detail below with reference to examples. Reference Example [Synthesis of 3-phenyl-5-butyrylisoxazole] Benzaldoxime 100 g (0.82 mol) and 1-hexyne-3-ol 90 g (0.92mo)
1) was dissolved in 500 ml of dichloromethane. The reaction solution was ice-cooled, and 580 g of 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
(Prepared with 28 ml of hydrochloric acid and 13 ml of pyridine) was 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 the aqueous pyridine hydrochloride solution was prepared again (prepared with 14 ml of 6N hydrochloric acid and 6.7 ml of pyridine)
Was added dropwise over 10 minutes and stirred for 70 minutes. A 12% aqueous solution of sodium hypochlorite was added dropwise to this solution. The operation of cooling the internal temperature to 10 ° C. again and adding the pyridine hydrochloride aqueous solution and the 12% sodium hypochlorite aqueous solution was repeated. To the dichloromethane layer obtained by separating the reaction solution was added 1000 ml of a 5% aqueous sodium hydrogen sulfite solution, and the mixture was stirred for 30 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 give 3-
106 g of phenyl-5-butyrylisoxazole
(0.49 mol) was obtained. The yield based on benzaldoxime is 59.6 mol%. Melting point 89-90 ° C

EXAMPLES [Synthesis of (+) PIP Hydrochloride] 1) (+) PIP-L-10-camphorsulfonate 3-phenyl-5-butyrylisoxazole 100 g
(0.465 mol) and 39.7 g (0.
The reaction solution obtained by adding 555 mol) to 310 g of methanol was stirred, and 45.2 g (0.555 mol) of 37% aqueous formalin solution was added dropwise while maintaining 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 butyl acetate was added to the reaction solution, 150 g of water was added after extraction, and the layers were separated to obtain an organic layer. After washing the organic layer several times with 150 g of water, the organic layer was washed with 10 g of water.
-Camphorsulfonic acid ([α] 20D = 21 ° (C
= 2, water)) 218.5 g (0.87 mol) was added, and the mixture was kept warm at a temperature of 50 to 55 ° C for 30 minutes to be dissolved. Subsequently, the reaction solution was cooled at 0 to 5 ° C. for 2 hours, the precipitated crystals were collected by filtration, washed with butyl acetate and dried under reduced pressure to obtain the desired (+) PIP-L-10-camphorsulfonate. 166.7 g (0.22 mol) was obtained. The yield based on 3-phenyl-5-butyrylisoxazole was 47 m.
Melting point 115.8 to 116.3 ° C. [α] ²⁰ _D = -14.4 ° (C = 0.5, ethanol) Optical purity 98.5% ee

2) [(+) PIP hydrochloride] (+) PIP-L-10-camphorsulfonate 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 give the desired (+) PIP hydrochloride (44.2 g).
(0.13 mol) was obtained. (+) PIP-L-10-
Yield to camphor sulfonate is 60.3mo
1%. The yield based on 3-phenyl-5-butyrylisoxazole is 28.3 mol%. Melting point 158 to 159.5 ° C. [α] ²⁰ _D = + 29 ° (C = 0.5, water) Optical purity 99.9% ee or more

Comparative Example [Synthesis of (+) PIP Hydrochloride] 1) PIP Hydrochloride 3-Phenyl-5-butyrylisoxazole 100 g
(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 colorless PIP hydrochloride (104.0).
g (0.31 mol) was obtained. The yield based on 3-phenyl-5-butyrylisoxazole is 67 mol%. Melting point 151-153 ° C

2) [Synthesis of (+) PIP-L-10-camphorsulfonate] 91.5 g (0.274 mol) of PIP hydrochloride was added to water 55.
It was dissolved in a mixed solution of 0 ml and 640 ml of ethyl acetate. A 6% aqueous solution of sodium hydrogencarbonate 660 was added to this solution.
ml was added dropwise. The reaction solution was stirred for 10 minutes and then separated to obtain an organic layer. The aqueous layer was extracted again with 550 ml of ethyl acetate, and the obtained organic layer was combined with the previously obtained organic layer and dried over anhydrous sodium sulfate. To the filtrate obtained by filtering off sodium sulfate, L-10-camphorsulfonic acid ([α] ²⁰
_D = 21 ° (C = 2, water)] 127.7 g (0.55 m
ol) was added and stirred for 30 minutes to dissolve. 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 obtain the desired (+) PIP-.
87.0 g of L-10-camphor sulfonate (0.
114 mol) was obtained. The yield based on 3-phenyl-5-butyrylisoxazole is 24.5 mol%. Melting point 115.8-116.3 ° C [α] ²⁰ _D = -14.4 ° (C = 0.5, ethanol) Optical purity 98.5% ee

3) [Synthesis of (+) PIP hydrochloride] (+) PIP-L-10-camphorsulfonate 8
7.0 g (0.114 mol) was dissolved in a mixed solution of 496 ml of water and 496 ml of ethyl acetate, and 276 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 136 ml of 0% sodium carbonate aqueous solution and further with 136 ml of water. Add 2N hydrochloric acid water to this organic layer.
60 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 1 in the obtained aqueous solution
67 ml was added and extracted to obtain a chloroform layer. The chloroform layer obtained by extracting the aqueous layer with 167 ml of chloroform again was combined with the previously obtained chloroform layer. The obtained chloroform solution was dried over anhydrous sodium sulfate.
To the chloroform solution obtained by filtering off sodium sulfate, 940 ml of ethyl acetate was added dropwise. This solution was stirred under ice cooling for 3 hours. The precipitated crystals were collected by filtration and washed with ethyl acetate to obtain 60.3 g (0.
18 mol) was obtained. The yield based on (+) PIP-L-10-camphorsulfonate is 60.3 mol%. The yield based on 3-phenyl-5-butyrylisoxazole is 14.7 mol%. Melting point 158 to 159.5 ° C. [α] ²⁰ _D = + 29 ° (C = 0.5, water) Optical purity 99.9% ee or more

[0027]

The production process simplified by the method of the present invention provides a high optical purity and a high optical resolution yield (+).
It has become possible to produce PIP and its salts.

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

Claims (3)

[Claims] 1. An optically active 3-phenyl-5 by optically resolving racemic 3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} isoxazole represented by the formula (1). In the method for producing-{2- (1-pyrrolidinylmethyl) butyryl} isoxazole, from a reaction solution obtained by reacting 3-phenyl-5-butyrylisoxazole, pyrrolidine and formalin in an alcohol solvent, Racemic 3-phenyl-5- {2- (1
-Pyrrolidinylmethyl) butyryl} isoxazole or a salt thereof is necessary after isolation of a compound of formula (1) by adding an immiscible organic solvent with water and isolating the organic solvent layer with water without isolation. (+)-3-phenyl-5- {2- (1-pyrrolidinylmethyl) butyryl} iso, which is characterized in that optically active sulfonic acid is added to the organic solvent layer for optical resolution after dehydration according to Process for producing oxazole and salts thereof. [Chemical 1] 2. The method according to claim 1, wherein the organic solvent immiscible with water is an alkyl acetate, a ketone, or an aromatic hydrocarbon. 3. The method according to claim 1, wherein the optical resolution temperature is −20 to 80 ° C.