KR960001725B1 - Process for the production of tizanidine - Google Patents

Abstract

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Description

How to prepare tizanidine

The present invention relates to a process for preparing 5-chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole (tizanidine) of the general formula (I) :

The compound has a central action muscular rigidity.

Pure crystalline tizanidine is simple by reacting 5-chloro-4-cyanamino-2,1,3-benzothiadiazole of formula (II) with ethylenediamine mono-p-toluene sulfonate in xylene. It has also been found that it can be produced with very good yields:

The method is preferably carried out at a temperature of 75 to 140 ℃, preferably 80 to 110 ℃, and more preferably 90 to 100 ℃.

The method according to the invention provides several advantages. In other words, the process according to the invention can be carried out in a one-step reaction and does not require evaporation of the solvent. Tizanidine can be crystallized from the reaction mixture without carrying out additional processing steps and has a very high purity. In addition, the method of the present invention is characterized by a high yield. Another advantage is that the process of the present invention can be easily performed on an industrial scale because it uses solvents that do not adversely affect the surrounding environment or are easy to handle. That is, the method of the present invention is economical because of low energy consumption and low solvent.

5-chloro-4-cyanoamino-2,1,3-benzothiadiazole used as starting material can be prepared from 5-chloro-4-amino-2,1,3-benzothiadiazole.

In the examples below all temperatures are in degrees Celsius and are not accurate. Unless otherwise specified, the temperature is the internal temperature.

Example 1

5-chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole

Under a nitrogen atmosphere, 125 kg of p-toluene-sulfonic acid monohydrate was added to the mixture of 130 liters of xylene and 40 liters of water with stirring. The mixture was heated to 50 ° C. and treated with 44 liters of ethylenediamine in 1 hour. After heating the mixture to 95-96 ° C., 27.6 kg of 5-clo-4-cyananimo-2,1,3-benzothiadiazole was added within 2 hours, and the mixture was 100 ° C. (surface temperature). Stirred for 2 h. Thereafter, 90 liters of water was added over 10 minutes and the mixture was cooled to 40 ° C. during the addition. Then 78 L of 40 ° C. 30% sodium hydroxide solution was added for 30 minutes and the mixture was cooled to 20-25 ° C. The suspension was centrifuged and the residue was washed with 30 L of water and then dried at a temperature of 70 ° C. under vacuum of about 20 mm Hg for 24 hours to give 30 kg of the title compound (melting point: 223 to 225 ° C.). (98% purity).

Example 2

5-chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole hydrochloride

51.5 kg of 5-chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole in 280 L of dimethylformamide was heated at 80 DEG C and decolorized carbon in 5 L of dimethylformamide. After treatment with 1 kg, the mixture was stirred at 80 ° C. for 15 minutes. The suspension was filtered, HCl gas was injected into 8.3 kg of the filtrate at 60 ° C., and the mixture was stirred for another 30 minutes. After cooling to 20 ° C., the mixture was stirred for 2 hours. The resulting suspension was centrifuged and the solid was first washed with dimethylformamide and then with ethanol. The resulting crude salt was refluxed with stirring in 62 liters of water and 240 liters of 95% ethanol until it all dissolved. The mixture was treated with 1 L of 37% hydrochloric acid to adjust the pH to 2, and then cooled to 0 ° C. After centrifugation, the crystalline precipitate was washed with ethanol and then dried under 70 ° C. (surface temperature) and vacuum (60 mm Hg). Melting point of hydrochloride was 288-290 degreeC.

5-Chloro-4-cyanoamino-2,1,3-benzothiadiazole used as starting material was prepared as follows:

23 kg of ammonium rhodenide and 90 L of acetone were stirred at 20-25 DEG C for 30 minutes. Then 27 L of benzoyl chloride was added at 20-30 DEG C over 30 minutes and the mixture was added at 20-25 DEG C for 20 minutes. Stirred. The resulting suspension was centrifuged and the filtrate was collected.

시간 동안 환류시켰다. 이어서, 박막 크로마토그래피로 반응을 수행하였다. 20 내지 25℃로 냉각시킨 후, 현탁액을 원심 분리시켰다. 고체를 물 475ℓ에 혼합시킨 후, 80℃로 가열하고, 그 온도에서 30% 수산화나트륨 용액 85ℓ로 15분 동안 처리하였다. 상기 맑은 용액을 80℃에서 아세트산납트리하이드레이트 74㎏으로 40동안 처리하고, 그 혼합물을 80℃에서 30분 동안 교반하였다. 그 후, 상기 혼합물을 50℃로 냉각시키고, 동시에 인산 2ℓ 및 30% 수산화나트륨 용액 약 5ℓ로 처리하였다. 혼합물을 50℃에서 다시 1시간 동안 교반하였다. 생성된 현탁액을 원심 분리시키고, 여액을 에틸렌디아민 테트라아세트산 이나트륨염-디하이드레이트 0.3㎏으로 교반하면서 처리하였다. 혼합물을 20 내지 25℃로 냉각시키고, 30% 염산 약 31ℓ로 pH를 5.5로 조정하였다. 혼합물을 20 내지25℃에서 30분 동안 교반하였다. 생성된 현탁액을 원심 분리시키고, 고체를 약 60℃ 및 20㎜Hg에서 24시간 동안 건조시켜 5-클로로-4-시안아미노-2,1,3-벤조티아디아졸을 수득하였다.(융점 : 215 내지 220℃).37.5 kg of 4-amino-5-chloro-2,1,3-benzothiadiazole and 90 L of acetone were refluxed and then treated with the filtrate. The mixture

It was refluxed for hours. Subsequently, the reaction was performed by thin layer chromatography. After cooling to 20-25 ° C., the suspension was centrifuged. The solid was mixed in 475 L of water and then heated to 80 ° C. and treated with 85 L of 30% sodium hydroxide solution at that temperature for 15 minutes. The clear solution was treated with 74 kg of lead acetate trihydrate at 80 ° C. for 40 minutes and the mixture was stirred at 80 ° C. for 30 minutes. The mixture was then cooled to 50 ° C. and treated simultaneously with 2 L phosphoric acid and about 5 L 30% sodium hydroxide solution. The mixture was stirred again at 50 ° C. for 1 h. The resulting suspension was centrifuged and the filtrate was treated with 0.3 kg of ethylenediamine tetraacetic acid disodium salt-dihydrate. The mixture was cooled to 20-25 [deg.] C. and the pH adjusted to 5.5 with about 31 liters of 30% hydrochloric acid. The mixture was stirred at 20-25 ° C. for 30 minutes. The resulting suspension was centrifuged and the solid was dried at about 60 ° C. and 20 mm Hg for 24 hours to afford 5-chloro-4-cyanamino-2,1,3-benzothiadiazole. (Melting point: 215 To 220 ° C.).

Claims (2)

5-Chloro-, characterized by reacting 5-chloro-4-cyanoamino-2,1,3-benzothiadiazole with ethylenediamine mono-p-toluene sulfonate in xylene under a temperature of 80 to 100 ° C. Process for preparing 4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole. The method of claim 1 wherein the reaction is carried out at a temperature of 90 to 100 ℃.