JPH0649017A - Method for purifying chlorphenesin carbamate - Google Patents

Abstract

PURPOSE:To purify the objective CPC extremely efficiently and in high purity without causing decomposed products of CPC or by-products resulting from transfer of carbamoyl group by using a specific stabilizer. CONSTITUTION:In a method for purifying chlorphenesin carbamate (CPC), water contained in the chlorophenecine carbamate is azeotropically dehydrated together with an organic solvent in the presence of at least one selected from the group consisting of iron, nickel, cobalt, copper and zinc salts and ammonium salt of mineral acid as a stabilizer.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for purifying chlorphenesin carbamate.

[0002]

BACKGROUND OF THE INVENTION Chlorphenesin carbamate (hereinafter abbreviated as CPC) is a compound useful as a muscle relaxant, and is disclosed in US Pat. No. 3,161,5.
Nos. 67 and 3,214,336 disclose the synthetic method and pharmaceutical use. As an example of the synthesis, 3-
A method has been adopted in which p-chlorophenoxy-2-hydroxypropyl chlorocarbonate is synthesized and ammonium hydroxide is allowed to act on it to synthesize CPC. When CPC is synthesized by these methods, it is necessary to perform purification in order to finally remove water and by-products contained in the target product. As this purification method, conventionally, a method is used in which water contained in CPC is first dried by azeotropic dehydration with an organic solvent such as toluene, and then dried, and then recrystallized by adding an alcohol such as methanol. . However, during azeotropic dehydration with an organic solvent to remove water, a decomposition product (CP
D) or a by-product (CE of carbamoyl group transfer)
The problem that C) occurs is pointed out. Therefore, high-purity CPC can be obtained by repeating purification by recrystallization several times.
Is obtained, and it is quite complicated industrially.

[0003]

[Chemical 1]

The present inventors examined the cause of the formation of these decomposition products and by-products. As a result, the crude CPC crystals obtained by the above-described synthesis method usually contain about 10 to 30% by weight of water, but when CPC is heated in the presence of water, it becomes unstable in its chemical structure. , It became clear that decomposition products and by-products are produced. Therefore, the present inventors have diligently studied these problems in the refining stage in order to improve the yield of the target compound and advantageously perform industrial production. As a result, they have found that by using a specific stabilizer in the purification stage, it is possible to obtain high-purity CPC without producing degradation products and byproducts such as CPD and CEC, and completed the present invention. This is industrially advantageous as compared with the conventional one.

[0005]

The summary of the present invention is as follows.
In the method for purifying chlorphenesin carbamate, the water contained in the chlorphenesin carbamate is selected from the group consisting of salts of iron, nickel, cobalt, copper or zinc as a stabilizer and ammonium salt of mineral acid. The present invention relates to a method for purifying chlorphenesin carbamate, which comprises azeotropic dehydration with an organic solvent in the presence of at least one of

The stabilizers used in the present invention include salts of iron, nickel, cobalt, copper, or zinc, and ammonium salts of mineral acids. Specifically, iron,
Examples include nickel, cobalt, copper, or zinc mineral salts (hydrochlorides, sulfates, phosphates), acetates, and ammonium salts of various mineral acids. In particular, ferric sulfate, ammonium sulfate, and ammonium chloride are available. It is preferable because it is easy and inexpensive. These stabilizers can be used alone or in admixture of two or more. The amount of the stabilizer added is usually 0.01% by weight or more, preferably 0.1 to 0.5% by weight, based on CPC. If the added amount is less than 0.01% by weight, the stability of CPC cannot be achieved and the decomposition products and by-products such as CPD and CEC described above are likely to occur. It's not economical because you can't get what you want.

In the present invention, the method for synthesizing the crude CPC crystal is not particularly limited and may be a known method. For example, the purification method of the present invention comprises 3-p-chlorophenoxy-
It is applied to the purification of crude CPC obtained by synthesizing 2-hydroxypropyl chlorocarbonate and reacting it with ammonium hydroxide. As described above, the crude CPC crystal usually contains about 10 to 30% by weight of water,
This water is removed by azeotropically adding to the crude CPC an organic solvent such as toluene, benzene, xylene, monochlorobenzene and nitrobenzene together with a stabilizer. The azeotropic temperature at this time is naturally limited depending on the organic solvent used, but is 80 to 100 ° C, preferably 80 to 85 ° C. By adding a stabilizer and performing azeotropic dehydration in the presence of the stabilizer, CPC becomes 100 in the presence of water.
It is stable even when heated to ~ 120 ° C. However, since the melting point of CPC is 89 to 91 ° C., it is better to avoid heating to a temperature higher than this.

Since the dehydrated crude CPC crystals contain not only a stabilizer but also a small amount of decomposition products and by-products generated in the synthesis process, an alcohol such as methanol and an adsorbent such as activated carbon and celite are then added. In addition, it is purified and crystallized. The CPC thus purified has a high purity in which a decomposed product of CPC or a by-product resulting from the transfer of a carbamoyl group is not detected and is useful as a muscle relaxant or the like in pharmaceutical applications.

[0009]

EXAMPLES The present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples. Example 1 40 g of CPC, 10 g of water, 200 g of toluene and 0.04 g of ferric sulfate were charged into a four-necked flask, water was distilled off by azeotropic dehydration, and 6 g of methanol was added to 60-65.
After dissolving at 0 ° C, 1 g of activated carbon and 1.5 g of celite were charged, stirred at 80 to 85 ° C for 30 minutes, and hot filtered. Then, the filtrate was cooled, CPC was crystallized, filtered and dried to obtain 38 g of CPC. When the obtained CPC was analyzed by liquid chromatography, degradation products and by-products CPD and CEC were not detected, and the CPC content was 9
It was 9.98%.

Example 2 Ammonium sulphate was added in place of 0.04 g of ferric sulphate.
Example 1 was repeated except that 08 g was used. As a result, when 38.5 g of CPC was obtained and analyzed by liquid chromatography, it was found that decomposed products and by-products CPD and CE were obtained.
C was not detected and the CPC content was 99.97%.

Example 3 Ammonium chloride was added in place of 0.04 g of ferric sulfate.
The same procedure as in Example 1 was carried out except that 05 g was used. As a result, 37.8 g of CPC was obtained and analyzed by liquid chromatography to find that degradation products and by-products CPD and CE
No C was detected and the CPC content was 99.95%.

COMPARATIVE EXAMPLE 1 40 g of CPC, 10 g of water and 200 g of toluene were charged into a four-necked flask, water was distilled off by azeotropic dehydration, 6 g of methanol was added and dissolved at 60 to 65 ° C., and then 1 g of activated carbon and Celite were added. 1.5 g was charged, the mixture was stirred at 80 to 85 ° C. for 30 minutes, and hot filtered. Then, the filtrate was cooled, CPC was crystallized, filtered and dried to obtain 38 g of CPC. The obtained CPC was analyzed by liquid chromatography to find that decomposed products and by-products CPD1%, CE
C5% formation was observed and the CPC content was 94%.

Example 4 40 g of CPC, 10 g of water, 80 g of toluene and 0.04 g of ferric sulfate were charged into a four-necked flask, and the mixture was heated to 85 ° C. for 4 hours.
The mixture was heated under reflux for 0 hours. After that, when analyzed by liquid chromatography, it was found that decomposed products and by-products CPD and C
No EC was detected.

Example 5 40 g of CPC, 10 g of water, 80 g of toluene and 0.10 g of ammonium sulfate were charged into a four-necked flask, and 85
The mixture was heated to reflux for 20 hours at 0 ° C. After that, when analyzed by liquid chromatography, CP which is a decomposition product and a by-product
D and CEC were not detected.

Example 6 40 g of CPC, 10 g of water, 80 g of toluene and 0.05 g of ammonium chloride were charged into a four-necked flask, and 85
The mixture was heated to reflux for 20 hours at 0 ° C. After that, when analyzed by liquid chromatography, CP which is a decomposition product and a by-product
D and CEC were not detected.

Example 7 40 g of CPC, 10 g of water and 0.04 g of ferric sulfate were placed in a four-necked flask and heated to 85 ° C. for 40 hours under reflux. Then, when analyzed by liquid chromatography, degradation products and by-products CPD and CEC were not detected.

Comparative Example 2 CPC (40 g), water (10 g) and toluene (80 g) were charged in a four-necked flask and heated to 85 ° C. for 8 hours under reflux. afterwards,
When analyzed by liquid chromatography,
By-products CPD 7.5% and CEC 16.5% were produced, and the CPC content was 76%.

Example 8 40 g of chlorphenesin (CPD) was suspended in 200 g of benzene, and phosgene 23 was added at 20 to 30 ° C.
A solution of g of cold benzene (100 g) was added dropwise over 1 hour, and the temperature was kept at 30 ° C. until the crystals were dissolved. After that, 24 g of triethylamine was added dropwise at the same temperature and kept warm for 1 hour. Furthermore, 100 ml of cold water extracted 3 times, and the hydrochloride of triethylamine was removed. To the benzene solution of 3-p-chlorophenoxy-2-hydroxypropyl chlorocarbonate thus obtained, 50 g of 28% ammonia water was added dropwise at 20 to 25 ° C over 2 hours, and at the same temperature. It was kept warm for 24 hours. After that, the mixture was neutralized with 10% sulfuric acid to pH 8.0 to 8.5, and the obtained crystals were separated by filtration and washed with 100 ml of water three times.
As a result, 50 g of crude CPC (10 g of which was water) was obtained.
50 g of the obtained crude CPC, 200 g of toluene, and 0.04 g of ferric sulfate were charged into a four-necked flask, water was distilled off by azeotropic dehydration, and 6 g of methanol was added to 60-
After melting at 65 ° C, activated carbon 1g and Celite 1.5
g was charged, the mixture was stirred at 80 to 85 ° C. for 30 minutes, and hot filtration was performed. After that, the filtrate was cooled, CPC was crystallized, filtered and dried to obtain 38 g of CPC. The obtained CPC
Was analyzed by liquid chromatography, no degradation products and by-products CPD and CEC were detected, and CPC
The content was 99.96%.

Comparative Example 3 50 g of crude CPC (10 g of which was water) was obtained in the same manner as in Example 8. 50 g of the obtained crude CPC and 200 g of toluene were charged into a four-necked flask, water was distilled off by azeotropic dehydration, 6 g of methanol was added and dissolved at 60 to 65 ° C., and then 1 g of activated carbon and 1.5 g of celite were added. The mixture was charged, stirred at 80 to 85 ° C. for 30 minutes, and hot filtered. Then, the filtrate was cooled, CPC was crystallized, filtered and dried to obtain 37.5 g of CPC. When the obtained CPC was analyzed by liquid chromatography, it was found that decomposed products and by-products CPD1% and CEC5.5% were produced, and the CPC content was 93.5%.

[0020]

The use of the stabilizer according to the present invention does not cause decomposition products of CPC or byproducts due to the transfer of carbamoyl groups, and the desired CP
C can be highly efficiently purified to high purity.

Claims (4)

[Claims] 1. A method for purifying chlorphenesin carbamate, wherein water contained in the chlorphenesin carbamate is used as a stabilizer for iron, nickel, cobalt,
A method for purifying chlorphenesin carbamate, which comprises performing azeotropic dehydration with an organic solvent in the presence of at least one selected from the group consisting of salts of copper or zinc, and ammonium salts of mineral acids. 2. The purification method according to claim 1, wherein the stabilizer is ferric sulfate, ammonium sulfate or ammonium chloride. 3. The purification method according to claim 1, wherein the amount of the stabilizer added is 0.01% by weight or more based on chlorphenesin carbamate. 4. The purification method according to claim 1, wherein the organic solvent is toluene, benzene, xylene, monochlorobenzene, or nitrobenzene.