Study On Synthesis Of Febuxostat And Its Intermediates

Febuxostat is the first novel non purine XO (xanthine oxidase) highly efficient selective suppressant. The Uloric was produced by Japan WuTian pharmaceutical co., LTD., And approved by the FDA (Food and Drug Administration) in February13,2009. This paper choosed p-hydroxy benzaldehyde as starting material, which yield to the desired product via cyanation, acetylation, cyclization, acylation, cyanation, etherification and hydrolysis. This strategy provides a safe, mild, simple, efficient access to a mass of Febuxostat.In the first step, p-hydroxybenzaldehyde was treated with hydroxylamine hydrochloride to give a intermediate oxime, which undergo a hydrolysis to produce the desired product4-cyanophenol. The optimal condition was got after several attempts.In the second step, p-hydroxy thiobenzamide was synthesized by4-cyanophenol and thio-formylating reagents. Compared three different methods, and selected the standard condition after several experiments.The third step was the cyclization of the above product with2-chloro acetoacetic acid ethyl ester. After reaction completed, we could get the2-(4-hydroxyphenyl)-4-methyl thiazole-5-carboxylic acid ethyl ester. The optimal condition was got after several attempts.In the forth step, the formylation of the intermediate with hexamethylenetetramine or paraformaldehyde was happened. Compared these two different methods, andwe could obtain the optimal condition.In the fifth step, the intermediate2-(3-Formyl-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester was synthesized by the substitution reaction between1-bromo-2-methylpropane and the phenolic hydroxyl of the intermediate. The optimal condition was got after several attempts.The sixth step was similar to the first step. The production was received through the cyanation of the fifth production. The optimal condition was got after several experiments.The seventh step was hydrolysis of the ester. After hydrolysised in the lye, Febuxostat was obtained by separating out from the mixture. Then, the pure production was got after recrystallization.The perfect and established route was got by several experiments. There are seven steps, and the yield of each step was high. The total yield was about forty-three percent.