773092-05-0

Acotiamide HCl is the hydrochloride salt form of acotiamide, a prokinetic agent with gastrointestinal (GI) motility-enhancing activity, which belongs to a class of drugs called 'gastroprokinetics' primarily used in the treatment of functional dyspepsia (indigestion). A synthetic route to acotiamide that employs pyridine hydrochloride to selectively cleave a 2-substituted methyl ether from a 2,4,5-trimethoxy benzamide intermediate, as a key step, has been reported. Acofide Trihydrate is a gastrointestinal prokinectic agent used in the treatment of functional malnutrition. A tablet for the treatment of functional dyspepsia.

Brand name

Acofide

Synthesis

Commercial 3,4,5-trimethoxybenzoic acid was first converted to the corresponding acid chloride, which was isolated by co-distillation with hexane. In refluxing dichloroethane (DCE), the acid chloride was coupled with the commercially available thiazole amine to give the desired amidothiazole in 89% yield. From this intermediate, amide linkage, selective demethylation of the 2-methoxy group, salt formation, and recrystallization were accomplished in the following sequence: the thiazole ester was reacted with N,N-diisopropyl ethylenediamine in DMA at elevated temperatures. Upon cooling, the mixture was dissolved in n-butanol and washed with aqueous sodium hydroxide. Subsequent treatment with HCl gas in isopropanol gave the corresponding HCl salt as crystals that could be collected by filtration. The product obtained was further crystallized from 4:1 isopropanol and water to give the desired product acotimide (I) as the hydrochloride trihydrate in 71% yield.