Azasetron hydrochloride Chemical Properties

Melting point:

281° (dec); mp 305° (dec) (Kawakita)

storage temp. 

Sealed in dry,Room Temperature

solubility 

Methanol (Slightly), Water (Slightly)

form 

White solid.

color 

White

CAS DataBase Reference

123040-16-4(CAS DataBase Reference)

Safety Information

Toxicity

LD50 in male, female rats (mg/kg): 135, 132 i.v. (Takagi)

Azasetron hydrochloride Usage And Synthesis

Description

Nazasetron (azasetron) hydrochloride is the fourth in the class of highly potent 5- HT₃ receptor antagonists to reach the market for prophylaxis of severe nausea and vomiting induced by cytotoxic chemotherapy and by total body X-radiation. In a study with 146 cancer patients suffering from emesis induced by cisplatin, nazasetron was reported to be markedly effective in 72% of subjects. Nazasetron is devoid of dopamine D₂ receptor blocking activity and therefore is free of the extrapyrimidal side effects associated with other commonly used antiemetics such as metoclopramide and domperidone. Nazasetron has been reported to be potentially useful for the treatment of gastrointestinal motility dysfunction, such as gastric stasis, vomiting and irritable bowel syndrome.

Chemical Properties

White to Off-White Solid

Originator

Yoshitomi (Japan)

Uses

A 5-HT3 receptor antagonist. Used as an antiemetic.

Uses

Azasetron HCl is a selective 5-HT3 receptor antagonist with IC50 of 0.33 nM used in the management of nausea and vomiting induced by cancer chemotherapy.

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.

brand name

Serotone

Therapeutic Function

Antiemetic

Biological Activity

A selective and potent 5-HT 3 antagonist (K i = 2.9 nM).

storage

Desiccate at -20°C

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