DD246764A5 - PROCESS FOR THE PREPARATION OF TIZANIDINE - Google Patents

Abstract

The invention relates to a process for the preparation of 5-chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole (tizanidine) for use as a medicament, in particular as myotonolytic. The aim of the invention is to provide an improved process by which tizanidine can be produced in high yield on an industrial scale. According to the invention, 5-chloro-4- (2-imidazolin-2-ylamino-2,1,3-benzothiadiazole is prepared by reacting 5-chloro-4-cyanamino-2,1,3-benzothiadiazole with ethylenediamine mono-p Toluenesulfonate in xylene.

Description

The compound is a centrally acting myotonolytic.

Characteristic of the known technical solutions

From DD-PS 106180 a process for the preparation of tizanidine is known by reacting S-methyl-N- (5-chloro-2,1,3-benzothiadiazol-4-yl) -isothiuronium iodide with ethylenediamine. However, this method is unsuitable as a production method because methylmercaptan is released.

According to another method of the same patent is 5-chloro-4-cyanamino-2,1,3-benzothiadiazole with

 Implemented ethylenediamine mono-p-toluenesulfonate. The reaction is carried out in n-pentanol at reflux temperature. This process is not very suitable for the industrial production of tizanidine, because solvents must be evaporated and a recrystallization of the product is required. The yield is low.

Object of the invention

The aim of the invention is to provide a novel process for the preparation of tizanidine, with which the compound can be obtained in a simple manner and in high yield.

Explanation of the essence of the invention

It is the object of the invention to find suitable starting compounds and reaction conditions for the preparation of tizanidine.

It has now been found that pure crystalline tizanidine in a simple manner and in very good yield by reacting 5-chloro-4-cyanamino-2,1,3-benzothiadiazole of the formula II,

NH

¹ CN

can be prepared with ethylenediamine mono-p-toluenesulfonate in xylene.

The process is conveniently carried out at temperatures 75-140 ° C, preferably between 80 and 110 ^c C,

in particular between 90 and 100 ° C, carried out.

The method according to the invention has several advantages. The reaction can be carried out as a one-pot process and the solvents need not be evaporated. Tizanidine crystallizes from the reaction mixture without additional

Procedural steps and is of particular purity. Furthermore, the process leads to a high yield. Another advantage is that the process can be conveniently carried out on an industrial scale because no polluting or difficult to handle solvents are used. The process is economical because the yield is high, the energy consumption is low and the solvents are inexpensive.

The 5-chloro-4-cyanamino-2,1,3-benzothiadiazole used as the starting compound may be prepared from 5-chloro-4-amino-2,1,3-

benzothiadizole be prepared.

embodiment

The invention is explained in more detail below with reference to some examples.

In the following examples, the temperatures, unless otherwise noted, refer to the internal temperature.

Example: 5-Chloro-4 (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole

125 kg of p-toluenesulfonic acid monohydrate are introduced into a mixture of 1301 xylene and 40 l of water with stirring and nitrogen purge. The mixture is heated to 50 ⁰ C, then allowed to run within 1 hour 44IÄthylendiamin. The mixture is heated to 95-96 ° C. Thereafter, 27.6kg of 5-chloro-4-cyanamino-2,1,3-benzothiadiazole are added during 2 hours and the mixture is stirred for 2 hours at 100 ° C (jacket temperature). Then allowed to flow 901 Waser within 10 minutes, at the same time the reaction mixture is cooled to 40 ⁰ C. Are then added over 30 minutes at 40 ⁰ 78130% Natrontauge C and the mixture cooled to 20-25 ° C. The suspension is centrifuged, the residue washed with 3Ol of water and dried in vacuo at about 20 Torr and 70 ⁰ C for 24 hours. 5-Chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole, m.p. 223-225X, is obtained.

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

51.5 kg of 5-chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole in 280I dimethylformamide are heated to 80 ⁰ C, treated with 1 kg of decolorizing carbon in 51 dimethylformamide and 15 minutes at 80 ° C stirred. The suspension is filtered, in the filtrate are introduced at 60 ⁰ C 8.3 kg of hydrogen chloride gas and the mixture stirred for 30 minutes. It is then cooled to 2O ⁰ C and stirred for 2 hours. The resulting suspension is centrifuged and the filter material washed first with dimethylformamide and then with ethanol. The resulting crude salt is boiled with 621 water and 240195% ethanol with stirring at reflux until everything is dissolved. Are then added 1137% hydrochloric acid to pH 2 and kühltauf to 0 ⁰ C from. After centrifugation, the crystals are washed with ethanol and dried under reduced pressure (60 Torr) at 70 ^° C. (jacket temperature). Mp of the hydrochloride 288-290 ° C.

The 5-chloro-4-cyanamino-2,1,3-benzothiadiazole used as starting compound is prepared as follows: 23 kg ammonium thiocyanate and 901 acetone are stirred at 20-25 ⁰ C for 30 minutes. Then allowed to run at 20-30 ⁰ C 271 benzoyl always within 30 minutes and stirred for 20 minutes at 20-25 ⁰ C. The suspension obtained is centrifuged and the filtrate is stored.

37.5 kg of 4-amino-5-chloro-2,1,3-benzothiadiazole and 9Ol of acetone are heated to reflux. Thereafter, the filtrate obtained above is allowed to flow in, and the mixture is heated to reflux for 2 hours. The reaction is monitored by thin-layer chromatography. The suspension is centrifuged after cooling to 20-25 ⁰ C centrifuged. The filtered material is introduced into 4751 of water, heated to 80 ⁰ C and treated at 8O ⁰ C within 15 minutes with 85130% of caustic soda. To the clear solution of lead acetate trihydrate are added within 40 minutes at 80 ⁰ C74kg and stirring the mixture for 30 minutes at 89 ⁰ C. It is then cooled to 5O ⁰ C, treated simultaneously with 21 phosphoric acid and about 51 30% sodium hydroxide solution and stirred at 50 ⁰ C for 1 hour. The resulting suspension is centrifuged and the filtrate is added with stirring 0.3 kg of ethylenediaminetetraacetic acid disodium salt dihydrate. The mixture is cooled to 20-25 ⁰ C and treated with about 31130% hydrochloric acid to pH 5.5. The mixture is stirred for 30 minutes at 20-25 °. The resulting suspension is centrifuged, the filter material is dried at about 6O ⁰ C and 20 Torr for 24 hours to give 5-chloro-4-cyanamino-2,1,3-benzothiadiazole, mp. 215-220 ⁰ C.

Claims (1)

Invention claim: Process for the preparation of 5-chloro-4- (2-imidolyn-2-ylamino) -2,1,3-benzothiadiazole, characterized in that Б-СЫоМ-суапатіпо-гл, 3-benzothiadiazole with ethylenediamine Mono-p-toluenesulfonate in xylene. Field of application of the invention The present invention relates to a process for the preparation of 5-chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole (tizanidine) of the formula I,