Study On The Synthesis Process Of Acotiamide Hydrochloride And Its Important Intermediates

This topic includes two parts:the study of the synthesis of acotiamide hydrochloride which is used in the treatment of functional dyspepsia,and the synthesis of the important intermediates 2-amino-1,3-thiazole and-4-carboxylic acid methyl ester.First of all,after the screening of the existing process of acotiamide hydrochloride,the selection of 2,4,5-trimethoxybenzoic acid as the starting material,the halogenation reaction,the acylation reaction and the amine reactiongave N-[2-(diisopropylamino)ethyl]-2-[(2-hydroxy-4,5-dimetho-xybenzoyl)amino]-1,3-thiazolecarboxamide,then,methanol refining,the sodium salt is produced in a solution of 0.5 mol/L of sodium hydroxide,and finally salt formation reaction in 20%is opropanolwater solution to obtain N-[2-(diisopropylamino)ethyl]-2-[(2 Hydroxy-4,5-dimethoxyb-enzoyl)amino]-1,3-thiazole-4-carboxamide trihydrate hydro-chloride with a total yield greater than 50%,a single product less than 0.1%,HPLC purity greater than 99%.Through the optimization of the synthetic conditions and the final products,the production process with mild reaction conditions and stable product quality yield has been obtained.Secondly,through the summary to the existing screening process,the choice of pyruvate as the starting material,through the esterification reaction to obtained pyruvate methyl ester,and then in the role of NBS and mutagens DES reaction to produce methyl-2-amino-1,3-thiazole-4-car-boxylate.The synthetic reaction conditions were optimized,the steps of synthesis and the production of "three wastes" were reduced,and the quality and yield of the product were greatly improved,which satisfied the requirement of the quality of the production of acotiamide hydrochloride.