Synthesis Of Febuxostat

Owing to better living levels and the concomitant increasement of sorghum and protein diets,uric acid level show a rising trend and the prevalence of hyperuricemia has been growing in recent years.Allopurinol had been the only medicine for gout disease in the past years.Due to its pharmacological mechanism,it has the disadvantages of poor efficacy and more adverse reactions.The new anti-gout drug,febuxostat,was applied in Japan in early 2004 by Teijin Corporation.The EU has approved febuxostat in May 2008 and US FDA has approved it in February 2009.Febuxostat is a selective xanthine oxidase inhibitor.Due to its high selectivity,febuxostat has the advantages of rapid onset,good efficacy,fewer side effects and high safety.Based on reviewing a large amount of literatures,this paper carefully summarizes the synthesis process of febuxostat that reported in domestic and foreign literatures.A synthetic route suitable for industrial research with high yield,cheap raw materials,less toxicity,less environmental pollution and simple operation was designed and improved.In this route,using p-hydroxy phenol as a starting material,p-hydroxy benzonitrile was synthesized with hydroxylamine instead of potassium ketamine with a yield of 90.4%.2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester was then obtained by one-pot method using thioacetamide and ethyl 2-chloroacetoacetate,and the reaction yield was 95.4%.Subsequently,2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-carboxylic acid ethyl ester was formed by a Duff-Bill reaction with a yield of 83.2%.This ester was then reacted with bromoisobutane to give ethyl2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-carboxylate,and the reaction yield was76.5%.Afterwards,cyanation reaction gave ethyl2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-carboxylate with a yield of 97.1%.Finally,the hydrolysis reaction of the ester was carried out under basic conditions to obtain febuxostat,and the reaction yield was 85.2%.The total yield was 45.6%.The structures of the target molecule and intermediates in the process were confirmed by IR,~1H-NMR and EI-MS.