Synthesis And Characterization Of 2-(3-cyano-4-isobutyloxy Phenyl)-4-methyl-5-thiazolecarboxylic Acid

2-(3-cyano-4-isobutyloxyPhenyl)-4-methyl-5-thiazole carboxylic acid (Febuxost at), an antipodagrics, was synthesized by Teijin institute. It will have comprehensive applications in the future which were approved by the U.S. Food and Drug Administration (FDA) and on sale in America in March,2009. The purpose of this research was to improve and optimize the synthetic routes of Febuxostat. The main contents as follows:Synthesis of Febuxostat with ethylparaben as the starting material:The inter-mediate 3-cyano-4-isobutyloxythiobenzamide was synthesized from ethylparaben via Duff reaction, etherification, cyanidation, hydrolysis, ammoniation, thioformylation, which was subjected to cyclization with 2-chloroethyl acetoacetate, hydrolysis and then the desired compound Febuxostat was gained with an overall yield of 29.4%.Synthesis of Febuxostat with 4-hydroxybenzoic acid as the starting material:The target compounds was synthesized from 4-hydroxybenzoic acid through etherification (protection of phenolic hydroxyl), ammoniation, thioformylation, cyclization, deprotection, Duff reaction to get intermediate ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, followed by Williamson etherification, cyanidation, and hydrolysis and finally obtained Febuxostat with an overall yield of 26.5%. Another synthetic route was to use the same 4-hydroxybenzoic acid as raw material, reacted with isobutylbromide to obtain 4-isobutoxylbenzoic acid, followed by amination, thioformylation to receive 4-butoxythiobenzamide, and then cyclization with 2-chloroaletoacetate, Vilsmeier-Haack formylation, cyanidation, hydrolysis to give Febuxostat in 27.6%overall yield.Synthesis of Febuxostat with 4-hydroxybenzaldehyde as the starting material: The desired compound was synthesized from 4-hydroxybenzaldehyde firstly via four-steps reaction consisting of cyanidation, thioformylation, Hantzsch cyclization, Duff reaction to afford intermediate ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, then followed by etherification, cyanidation and hydrolysis. The total yield of Febuxostat was 30.1%. The structure of the target compound was confirmed by IR,1H NMR,13C NMR, MS and Elemental Analysis.