RU2102394C1 - Method for production of hydrochloride of ethyl ester of 10-(3-morpholyl propyonyl)phenothiazine carbamine-2 acid - Google Patents

Abstract

FIELD: organic synthesis; medicine, namely, treatment of myocardial infarction and arrhythmia. SUBSTANCE: 3-aminodiphenyl amine is treated by ethyl ester of chlorocarbonic acid, the process is carried out in two-phase system comprising toluene and aqueous solution of sodium hydrocarbonate. When reaction is completed then water and excess of toluene are removed of reaction mass and iodine and sulfur are added into thus prepared mass. When reaction is completed then reaction product as suspension is directed for acylation with 3-chloropropyonyl chloride. Product which is prepared by acylation is crystallized and is fed for treatment with the help of morpholine. Then treatment with hydrogen chloride is carried out and desired product is isolated. Yield of hydrochloride of ethyl ester of 10-(3-morpholyl propyonyl)phenothiazine carbamine-2-acid is 36.7 %. Its melting point is 190 C. EFFECT: simplified technology; improved efficiency.

Description

 The present invention relates to basic organic synthesis, and in particular to a method for producing 10- (3-morpholylpropionyl) phenothiazinecarbamic-2 acid (I) hydrochloride used to treat myocardial infarction and arrhythmia.

A known method of obtaining I, comprising several technological stages. According to this method, diphenylaminocarbamic acid-3 acid (II) ethyl ester is obtained from 3-aminodiphenylamine and chlorocarbonate ethyl ester in an alcoholic solution of sodium hydroxide at a temperature of 5-7 ^° C, which is isolated by diluting the reaction mass with water, filtered, dried, and then subjected to thionation sulfur in toluene at 110-114 ^o C in the presence of iodine. The resulting phenothiazine carbamic acid-2 ethyl ester ethyl ester (II) is filtered, dried, then acylated with 3-chloropropionyl chloride at a temperature of 110-114 ^° C. for 4 hours in toluene.

 The obtained ethyl ester of 10- (3-chloropropionyl) phenothiazinecarbamic-2 acid (IV) is boiled with morpholine in toluene, the precipitated morphine hydrochloride precipitate is filtered off, the base I is extracted from the filtrate with dilute hydrochloric acid solution, then the base is again made alkaline. The base is dried and dissolved in toluene, an ethereal solution of hydrogen chloride is added. The precipitate of the target product I is filtered and dried. The yield of the target product is 27.6% based on the starting 3-aminodiphenylamine.

 In the known method for producing I, due to the use of an alcoholic solution of sodium hydroxide at the stage of interaction of 3-aminodiphenylamine with ethyl ester of chlorocarbonic acid, the latter is hydrolyzed, which entails a large consumption of it.

 The disadvantage of this method is also the relatively low yield of the target product and a large number of technological stages.

 The task of the invention is to increase the yield of the target product, simplifying the process.

 The problem is solved in that in the known method, the interaction of 3-aminodiphenylamine with ethyl ester of chlorocarbonic acid is carried out in a two-phase system: toluene, an aqueous solution of sodium hydrogencarbonate; water and excess toluene are removed from the reaction mass, sulfur and iodine are added to the resulting mass; then the suspension of the thionation reaction product is sent for acylation; the product from the acylation step is crystallized and sent to the step of reacting with morpholine, followed by treatment of the product of this step with hydrogen chloride.

 The proposed method is illustrated by the following example.

 Example.

 a). Obtaining ethyl ester of 10- (3-chloropropionyl) phenothiazinecarbamic-2 acid (product IV).

A toluene solution of 3-aminodiphenylamine (0.92 kg in 10 l) is added to an aqueous solution of sodium hydrogencarbonate (0.63 kg in 6.25 l of water), then 0.65 kg of chlorocarbonate ethyl ester is gradually added with stirring at a temperature of 10 -20 ^o C, stir the mass. At the end of the reaction, the organic layer is separated from the aqueous layer, washed with water.

 Azeotropic water and an excess of toluene are distilled off from the toluene solution. 0.32 kg of sulfur and 0.02 kg of crystalline iodine are added to the remaining toluene solution of diphenylaminocarbamic-3 ethyl ethyl ester and stirred at boiling.

At the end of the reaction, a thick mass of the obtained product III was diluted with 0.85 L of toluene to obtain a suspension, 0.61 kg of 3-chloropropionyl chloride was added and the reaction was carried out at the boil. 0.1 kg of activated carbon is added to the reaction product, filtered hot from coal. The filtrate is cooled to 5-10 ^o C, the precipitated product IV is filtered, washed with toluene. 0.98 kg of product IV is obtained.

The washed precipitate is recrystallized from toluene to give 0.78 kg of product IV with a melting point of 16865-169.5 ^° C. (literary _mp 169-170 ^° C.). Yield 52% (calculated on the starting 3-aminodiphenylamine).

 b) Obtaining 10- (3-morpholylpropionyl) phenothiazinecarbamic-2 acid ethyl ester hydrochloride.

 A mixture of 0.98 kg (0.0026 mol) of product IV, 0.5 kg (0.0057 mol) of morpholine and 4.9 L of toluene is boiled for 3 hours. The precipitate of morpholine hydrochloride is filtered off, washed with water until neutral, then base I is extracted with a dilute hydrochloric acid solution. The acidic aqueous extract is treated with activated carbon and a solution of sodium hydroxide is added to the filtrate until an alkaline reaction.

The precipitated precipitate of the base is filtered, dried, and then dissolved in toluene and an ethereal solution of hydrogen chloride is added. The precipitated hydrochloride precipitate is filtered and dried to obtain 0.87 kg of the target product. Yield 36.7% (calculated on the starting 3-aminodiphenylamine), t _pl. 190 ^o C (literary t _pl. 190 ^o C).

 The proposed method allows to increase the yield of the target product by 9.1% compared with the prototype, as well as significantly simplify the process by reducing the number of process steps compared to the known method; Avoid contact of dust-containing intermediate products II, III and IV that cause allergies; reduce the consumption of ethyl ester of chlorocarbonic acid, as the use of an aqueous solution of acidic sodium carbonate, which is not miscible with a toluene solution of ethyl ester of chlorocarbonic acid, prevents its hydrolysis.

Claims (1)

 A method for producing 10- (3-morpholylpropionyl) phenothiazinecarbamic-2 acid ethyl ester hydrochloride from 3-aminodiphenylamine, the process comprising the following main steps: reacting 3-aminodiphenylamine with chlorocarbonyl ethyl ester to produce diphenylamino carbamino-3 acid ethyl ester, treating ethyl diphenylamino carbamino-3 acid -3 sulfuric acid in the presence of iodine to obtain phenothiazine carbamic-2 acid ethyl ester, subsequent acylation of the above ethyl ester with 3-chloropropionyl chloride with obtaining ethyl ester of 10- (3-chloropropionyl) phenothiazinecarbamic-2 acid, treating this ester with morpholine, then with hydrogen chloride, followed by isolation of the target product, characterized in that the reaction of 3-aminodiphenylamine with ethyl ether of chlorocarbonic acid is carried out in a two-phase system: toluene aqueous solution acidic sodium carbonate, at the end of the reaction, water and excess toluene are removed from the reaction mass and sulfur and iodine are added to the resulting mass, a suspension of the reaction product is sent for acylation, t from the acylation step is crystallized and sent to the treatment step with morpholine.