Study On The Synthetic Process Of Febuxostat

Febuxostat is widely used by the majority of patients with gout for their long-term treatment of hyperuricemia.Because of its less side-effect and inhibition of synthesis uric acid,it plays an increasingly important role in the treatment of gout.In this thesis,a synthetic route for Febuxostat was designed,experimentally verified and optimized.The main details are described as follows:In the first chapter,the pathogenesis of gout and the characteristics and classification of drugs for the treatment of gout were introduced.Besides,the structure,pharmacological mechanism,pharmacokinetics and the synthetic methods were also described.which provided theoretical support for our work.In the second chapter,based on the retrosynthesis analysis,a synthetic route of Febuxostat starting from 4-hydroxythiobenzamide 6was designed.Firstly,thiobenzamide 6 was cyclized by Hantazsch reaction to obtain a thiazole 5,followed by formylation at the ortho position of the phenolic hydroxyl group to form an intermediate 4 via Duff reaction.Next,the formyl group was converted to cyano by treatment with NH₄OAc/NaClO₂.After etherification of hydroxyl group with brominated isobutane,the phenolic ether 2 was obtained.Finally,the final product was prepared via hydrolysis of ester under the basic conditions and then acidified.The experimental results showed that the presented five-step route gave Febuxostat with a total yield of 32%.NH₄OAc/NaClO₂ was applied successfully in transforming aromatic aldehydes into the aromatic nitriles in synthetic route of Febuxostat in last chapter.In this chapter,NH₄OAc/NaClO₂ was tried to extending to a series of normal aromatic aldehydes to achieve the preparation of aromatic nitriles from aldehydes,while the experiment results showed that N-chloro aldimines or aromatic nitriles were synthesized employing this reaction system.In summary,a optimal synthetic route for Febuxostat was described as follows:Initially,4-hydroxythiobenzamide 6 was cyclized with ethyl2-chloroacetoacetate in ethanol under reflux giving ethyl 2-?4-hydroxyphenyl?-4-methyl-5-thiazolecarboxylate 5 in 93.2%yield.The intermediate 5 was then reacted with HMTA in the presence of concentrated sulfuric acid to give formyl compound 4 in 65.3%yield.Subsequently,the formyl group of 4 was converted to cyano by treatment with NH₄OAc/NaClO₂,affording intermediate 3 in 69.4%yield.Then S_N2 nucleophilic substitution reaction was occured between phenolic compounds 3 and bromoisobutane,affording the phenolic ether 2 in81.4%yield.Finally,Febuxostat 1 was obtained in 91.8%yield by hydrolysis using sodium hydroxide and then acidification with concentrated hydrochloric acid.The advantages of this synthetic process including mild reaction conditions,cheap and readily available raw materials,easy operation and high-purity products,which made this route own a good prospect of industrial production.Besides,expaning the NH₄OAc/NaClO₂ system to ordinary aryl aldehyde substrates led to the synthesis of a series of aryl nitriles or N-chloro aldimines.