Zatosetron

Originator

Zatosetron maleate,Eli-Lilly

Uses

Antimigraine.

Manufacturing Process

A mixture of 5-chloromethyl salicylate, 3-chloro-2-methylpropene, potassium carbonate, and acetone was heated at reflux overnight. After cooling, the mixture was extracted with diethyl ether and ethyl acetate. The organic extracts were combined, washed twice with a 10% sodium chloride solution and water, dried over sodium sulfate, and concentrated in vacuum. The resulting liquid was vacuumed distilled. The fraction collected and the desired 5-chloro-2-(2-methyl-2-propenyloxy)benzoic acid, methyl ester was obtained. The 5-chloro-2-(2-methyl-2-propenyloxy)benzoic acid, methyl ester was heated at reflux for 6 h in 1-methyl-2-pyrrolidinone. The mixture was then vacuum distilled and the fraction collected and the desired 2-hydroxy-5- chloro-3-(2-methyl-2-propenyl)benzoic acid, methyl ester was obtained.
A mixture of the 2-hydroxy-5-chloro-3-(2-methyl-2-propenyl)benzoic acid, methyl ester and 1 L of methanol was saturated with 90% formic acid and then refluxed overnight. The solution was concentrated in vacuum, added to water, and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuum, providing the desired 2,2-dimethyl-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, methyl ester as an oil.
The 2,2-dimethyl-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, methyl ester were heated at reflux with sodium hydroxide and water for 2-3 h. After cooling, the mixture was extracted with diethyl ether and ethyl acetate. The aqueous layer was acidified with hydrochloric acid and again extracted with ethyl acetate and diethyl ether. These latter organic extracts were combined and washed with water, dried over sodium sulfate, and concentrated in vacuum. Crystallization of the resulting solid from ethyl acetate/hexane provided the desired 2,2-dimethyl-5-chloro-2,3-dihydrobenzofuran-7- carboxylic acid, 71% yield, melting point 158.5°-160°C.
A mixture of 2,2-dimethyl-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid and thionyl chloride was heated at reflux for 3 h. After the mixture was 3522 Zatosetron maleate concentrated in vacuum and azeotroped with toluene, dry toluene was added and the solution cooled to 5°C. A solution of N-methyl-tropamine in toluene was added in dropwise fashion and the reaction heated at reflux overnight. After cooling, the mixture was added to ice water, made basic, and extracted with diethyl ether/ethyl acetate. The organic layer was washed twice with 6 N hydrochloric acid. The combined aqueous extracts were cooled, made basic with sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate solution was washed twice with water, dried over sodium sulfate, and concentrated in vacuum providing of the endo-5-chloro-2,3-dihydro-2,2- dimethyl-N-(8-methyl-8-azabicyclo[3.2.1.]oct-3-yl-7-benzofurancarboxamide, free base, as an oil.
In practice it is usually used as maleate salt.

Therapeutic Function

Serotonin antagonist