TICRYNAFEN

Originator

Diflurex,Anphar,France,1976

Uses

Selacryn (SmithKline Beecham).

Manufacturing Process

(a) To a solution of 55 g of 2,3-dichloroanisole (0.31 mol), 91 g of thiophene- 2-carboxylic acid chloride (0.62 mol) and 180 ml carbon disulfide; there was added little by little 82.7 g of anhydrous aluminum chloride, keeping the temperature at about 25°C. The reaction mixture was stirred at ambient temperature for five hours, left standing overnight and then heated for one hour at 55°C. The solution was cooled and hydrolyzed by 250 g of ice and 60 ml concentrated hydrochloric acid. The precipitate formed is treated with a 30% solution of caustic soda, then washed with water. After recrystallization in 95% ethanol, 88.6 g (yield 92%) of crystals are obtained melting at 108°C. The process can also be carried out without solvent keeping the same proportions of reactants, or in methylene chloride by adding a slight excess of aluminum chloride powder to a solution of one mol of dichloroanisole and one mol of acid chloride.
(b) 88.6 g of the ketone just obtained (0.308 mol) were dissolved in 300 ml of benzene, 123.5 g of aluminum chloride was added in small doses, and the mixture was boiled under reflux for two hours. The reaction mixture was hydrolyzed by 500 g ice; the precipitate extracted and taken up in a 10% aqueous caustic soda solution. The benzene phase obtained after hydrolysis is concentrated. The oil obtained is treated as above and the precipitate added to the other. The crystals were recrystallized in 50% ethanol, 60 g of product were obtained, melting at 142°C. The reaction may also be effected with excellent yields in methylene chloride. (c) A solution of sodium ethylate was prepared by dissolving 3.45 g of sodium (0.15 mol) in 300 ml absolute ethanol. There was then added 31 g of the preceding phenol (0.15 mol) then 25.8 g ethyl chloroacetate. The mixture was refluxed for 15 hours. Hot extraction was carried out to eliminate the sodium chloride.
The ester precipitated on cooling the filtrate. The product was recrystallized once in isopropanol to give 29.4 g of crystals melting at 58°C. The pure product melts at 63°C to 64°C. The ester was dissolved in a solution of 500 ml 95% ethanol and 9 ml of 10 N caustic soda.
The mixture was boiled under reflux for 30 minutes. The precipitate of the sodium salt of the acid which forms in the cold was extracted and taken up in warm water. The free acid was then precipitated in mineral acid medium. After recrystallization in 50% ethanol, it melted at 148°C to 149°C.

brand name

Tienilic Acid is INN and BAN.

Therapeutic Function

Diuretic, Hypertensive

Raw materials

Preparation Products