Azasetron hydrochloride

Chemical Properties

White to Off-White Solid

Originator

Azasetron,Pharm Chemical

Uses

As a 5-HT3 receptor antagonist, Azasetron hydrochloride can be used as an antiemetic.

Definition

ChEBI: Azasetron hydrochloride is a benzoxazine.

Manufacturing Process

To a solution of 2-(2-carboxy-4-chlorophenoxy)acetic acid in concentrated sulfuric acid is added dropwise a mixed liquid of fuming nitric acid and concentrated sulfuric acid under stirring with keeping at a temperature below 10°C. After the addition, the reaction mixture is stirred and poured into 10 L of ice-cold water. The precipitated crystals are collected by filtration, washed with 2 L of water four times and them dried to give 2-(2-carboxy-4-chloro-6- nitrophenoxy)acetic acid.
To a solution of ferrous sulfate heptahydrate in of hot water is added a solution of 2-(2-carboxy-4-chloro-6-nitrophenoxy)acetic acid and aqueous concentrated ammonia solution in water under stirring. After stirring, to the reaction mixture is twice added aqueous concentrated ammonia solution. While the reaction mixture becomes exothermic, stirring is continued. The resultant mixture is filtered through a celite layer under reduced pressure and washed with hot water twice. The filtrate is cooled and made acid with concentrated hydrochloric acid. The precipitated crystals are washed with water and dried to give 6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8- carboxylic acid.
A mixture of 6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid, methanol and concentrated sulfuric acid is refluxed under heating with stirring, and then cooled. The precipitated crystals are collected by filtration, washed with methanol and dried to give methyl 6-chloro-3,4-dihydro-3-oxo- 2H-1,4-benzoxazine-8-carboxylate, melting point 239°-241°C.
To a solution of methyl 6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylate in dimethylformamide is added potassium t-butoxide and solution stirred at room temperature. To the resultant solution is added dropwise a solution of methyl iodide in dimethylformainide under stirring. After the reaction solution is stirred, water is added thereto. The insoluble substance is collected by filtration, washed with water and dried to give methyl 6-chloro- 3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylate. A mixture of methyl 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4- benzoxazine-8-carboxylate, ethanol and 4% aqueous potassium hydroxide solution is refluxed with heating. The resultant solution is cooled and water is added thereto followed by filtration. The filtrate is made acid with concentrated hydrochloric acid. The precipitated crystals are collected by filtration, washed with water and dried, and then recrystallized from ethanol to give 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid, melting point 241°-243°C.
A solution of 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8- carboxylic acid in tetrahydrofuran and dimethylformamide is cooled to below 0°C and triethylamine is added under stirring thereto. Further, ethyl chlorocarbonate is added and the mixture is stirred at room temperature. To the resultant mixture is added 3-amino-8-azabicyclo[3.2.1]octane and the mixture stirred. After completion of the reaction, aqueous sodium hydrogen carbonate and ethyl acetate are added. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is distilled off to give 6-chloro-3,4-dihydro-4-methyl-N-(8-azabicyclo[3.2.1]oct-3-yl)-3- oxo-2H-1,4-benzoxazine-8-carboxamide. In practice it is usually used as hydrochloride.

Therapeutic Function

Antiemetic