Study On The Synthesis Of Febuxostat And Its Practical Process Research

Febuxostat is the first new class of highly potent selective xanthine oxidase inhibitors and is a new drug for the treatment of gout.Febuxostat was developed by Teijin Corporation of Japan and approved for markeing in early 2004 in Japan.This drug was also launched in Europe in 2008;and approved for marketing in the United States in 2009by FDA.The original research patent had expired in 2018.A process route was studied in this thesis which is expected to realize the industrial production of febuxostat.First,febuxostat was synthesized from hydroxy thiobenzamide as starting materials,condensed with ethyl 2-chloroacetoacetate to construct thiazole structure,to produce ethyl 2-（4-hydroxyphenyl）-4-methylthiazoleb-5-carboxylic ester in 98.5%yield and its purity arrived at 98.7%by HPLC.Second,the compound from above step reacted with hexamethylenetetramine to introduce a formyl group in the aromatic ring to obtain ethyl2-（4-hydroxy-3-formylphenyl）-4-methylthiazole-5-carboxylic ester in 40.8%yield and97.7%purity with HPLC.Third,the formylated derivative was transformed into ethyl2-（3-cyano-4-hydroxyphenyl）-4-methylthiazole-5-carboxylic ester in two steps,aldehyde oxime as an intermediate,which completed the key structure of cyano group,and the yield of two steps reached at 60.33%with 87.75%purity.Fifth,O-alkylation was performed with isobutyl bromide in the presence of nanometer-sized potassium carbonate to give ethyl 2-（3-cyano-4-isobutoxyphenyl）-4-methylthiazole-5-carboxylic ester,the yield arrived at 91.2%and with 86.49%purity.Sixth,the hydrolysis was smoothly completed to produce the target compound with 89.24%yield and 97.6%purity under alkaline conditions.In this process study,the process conditions were optimalized by examining the effects of material ratio,reaction temperature and reaction time on the reaction,and the crystallization conditions of the six intermediates was investigated.The total yield of six-step reaction reached at 19.7%.In the synthesis of 2-（3-cyanophenyl）-4-methylthiazole-5-carboxylic ester,not only the formylation of aryl ring was studied,but also its corresponding aldehyde oximes and oxime ethers derivatives have been investigated.And all synthetic intermediates were characterized by ¹HNMR and ¹³CNMR.The process route used in this article has no special reagents and harsh operating conditions,the raw materials are easy to obtain,the conditions are mild,the operation are stable,the yield is high.It provides a convenient route for the industrial production of febuxostat.