Study On Synthesis Process Of Acotiamide Hydrochloride Hydrate

Acofide (acotiamide hydrochloride trihydrate) is the world’s first effective drug for the treatment of functional dyspepsia. This paper shows a more reasonable synthetic route of acofide based on the analysis of previous synthetic routes. Various factors of each step were investigated and the better process conditions were obtained.Firstly,2,4,5-Trimethoxybenzoic acid reacted with thionyl chloride and 2-aminothiazole-4-carboxylate to obtain 2-(2,4,5-trimethoxybenzamido)thiazole-4-carboxylate. The optimized conditions of acylchloride reaction were that:solvent DCM, the molar ratio of thionyl chloride and 2,4,5-trimethoxy benzoic acid was 1.4:1.0, reaction temperature 40℃, reaction time 1 hour. The optimized conditions of amidation reaction were that:solvent DCM, base 4-DMAP and TEA, reaction temperature 40℃, reaction time 7 hours, the molar ratio of 2,4,5-trimethoxy benzoyl chloride and 2-aminothiazole-4-carboxylate was 1.05:1.0. The reaction yield was 91.1%, and the product purity was 96.5%.Secondly, pyridine hydrochloride reacted with 2-(2,4,5-trimethoxy benzamido)thiazole-4-carboxylate to obtain 2-(2-hydroxy-4,5-dimethoxy benzamido)thiazole-4-carboxylate. The better conditions were that:solvent DMF, base pyridine, reaction temperature 150℃, reaction time 10 hours, the molar ratio was 5.0:1.0. Recrystallization from 25 times volumes of acetic acid gave 2-(2-hydroxy-4,5-dimethoxy benzamido)thiazole-4-carboxylate acetate and the product purity was 99.1%, the reaction yield was 81.4%.Thirdly,2-(2-hydroxy-4,5-dimethoxy benzamido)thiazole-4-carboxylateacetate and N,N-diisopropyl ethanediamine were used to synthesize N-((2-diisopropylamino)ethyl)-2-(2-hydroxyl-4,5-dimethoxy benzamido)thiazole-4-carboxamide hydrochloride trihydrate. The better conditions were that:solvent toluene, reaction temperature 110℃, reaction time 7 hours, the molar ratio of N,N-diisopropyl ethanediamine and 2-(2-hydroxy-4,5-dimethoxybenz amido)thiazole-4-carboxylate acetate was 3.0:1.0. Evaporation of the solvent and the residue was diluted with 5 times volumes of 80% isopropanol aqueous solution, and 3 equivalent of hydrochloric acid was added slowly to obtain the crude product. Recrystallization from 6 times volumes of 20% isopropanol aqueous solution gave crystals of acotiamide hydrochloride trihydrate. The reaction yield was 85.6% and the product purity was 99.2%.