Synthetic Process Research Of Febuxostat

Febuxostat is a urate lowering drug, an inhibitor of xanthine oxidase that is indicatedfor use in the treatment of hyperuricemia and gout. Febuxostat received marketingapproval by the European Medicines Agency on April21,2008and was approved by theU.S. Food and Drug Administration on February16,2009.Febuxostat is a non-purine selective inhibitor of xanthine oxidase. It works bynon-competitively blocking the molybdenum pterin center which is the active site onxanthine oxidase. Xanthine oxidase is needed to successively oxidize both hypoxanthineand xanthine to uric acid. Hence, febuxostat inhibits xanthine oxidase, therefore reducingproduction of uric acid. Febuxostat inhibits both, oxidized as well as reduced form ofxanthine oxidase because of which febuxostat cannot be easily displaced from themolybdenum pterin site.Based on consult enough literature, we confirmed a better synthetic method. Thesynthesis was started with4-hydroxythiobenzamide as reaction material, followed byformylation, alkylation, oximation, dehydrolysis, acidification, recrystallization,Febuxostat was synthesized.Through optimization of the experimental conditions obtained better proeessesconditions for each step of the synthesis.The optimum synthesis conditions of2-(4-hydroxyphenyl)-4-methyl-5-thiazole-Carboxylate was as follows: the molar ratio of4-hydroxybenzonitrile, chloroethylacetoacetate was1:1.4, with C2H5OH as solvent, the reaction temperature was70℃, andthe reaction time was2h, the yield was92%, the purity was99.5%.The optimum synthesis conditions of2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate was as follows: the molar ratio of2-(4-hydroxyphenyl)-4-methyl-5-thiazole-Carboxylate, HMTA was1:1.4, withTFA+C2H5COOH as solvent, thereaction temperature was reflux, and the reaction time was12h, the yield was50%, thepurity was95%.The optimum synthesis conditions of2-(3-formyl-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylate was as follows: the molar ratio of2-(3-formyl-4-hydroxyl phenyl)-4-methyl-5-thiazolecarboxylate, Isobutyl,bromide, KI, K2CO3, was1:5:2:2, with DMF assolvent, the reaction temperature was70℃, and the reaction time was3.5h, the yield was71%, the purity was95%. The optimum synthesis conditions of2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylate was as follows: the molar ratio of2-(3-formyl-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylate, NH2OH.HCl, HCOONa, was1:1.5:7, withHCOOH as solvent, the reaction temperature was reflux, and the reaction time was3h,the yield was95%, the purity was97.89%.The optimum synthesis conditions of2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid was as follows: the molar ratio of2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylate, NaOH was1:1.5, with C2H5OH as solvent,the reaction temperature was55℃, and the reaction time was1h, the yield was95%, thepurity was98.829%. through recrystallization the purity was up to99.77%.The synthetic route had the characteristic of mild reaction conditions, simpleoperation, high yield and good optical purity, was the most direct way to synthesizeFebuxostat, and had significant developing value and feasibility for industrial application.