Study On Synthesis Of Febuxostat

ObjectiveFebuxostat is used for treatment of hyperuricemia and gout,which was developed by Teijin company as non-purine xanthine oxidase inhibitor.It is of great social and economic significance to search for better synthetic method of febuxostat which is more moderate,simpler,cheaper and more efficient,because of its the higher price and no patent protection in China.MethodsBased on literatures and experimental attempts,the synthetic route of febuxostat was determined:using 4-hydroxybenzaldehyde as the starting material,the target compound was synthesized via eight steps,which were nucleophilic addition elimination dehydration,sulfidation,Hantzsch cyclization,formylation,etherification,nucleophilic addition elimination,dehydration and hydrolysis reaction.Moreover,the synthetic route was improved:the two steps reaction of nucleophilic addition,elimination,dehydration and sulfidation were combined into one pot;The three steps etherification,nucleophilic addition,elimination and dehydration reaction were combined into one pot.ResultsThe overall yield of febxostat was 55.9%and the purity was 99.29%,an increase of 12.9%over the literature.The chemical structure of febuxostat and its intermediates were confirmed by MS and~1H NMR.Optimization of process conditions:(1)In the process of synthesis of the compound(2),the nucleophilic addition elimination dehydration reaction occurred in formic acid at reflux,in which the optimal mole ratio of 4-hydroxybenzaldehyde and hydroxylamine hydrochloride as well as sodium hydroxide was 1?1.2?1.2.Subsequently,sulfidation reaction occurred in a mixture of formic acid and concentrated hydrochloric acid(v/v=1?1)at 60?,in which the optimal mole ratio of4-hydroxybenzaldehyde and thioacetamide was 1?1.6.(2)In the process of synthesis of compound(4),the cyclization reaction occurred in absolute ethanol at reflux,in which the optimal mole ratio of compound(2)and ethyl 2-chloroacetoacetate was 1?1.05.(3)In the process of synthesis of compound(5),the formylation reaction occurred in a mixture of polyphosphoric acid and absolute ethanol(v/v=3?1)at90?in 10 h,in which the optimal mole ratio of compound(4)and HMTA was 1?1.(4)In the process of synthesis of compound(6),the etherification reaction occurred in DMF at 90?,in which the optimal molar ratio of compound(6)and iso-butyl bromide as well as potassium carbonate was 1?3?3.The nucleophilic addition elimination reaction occurred in DMF at 50?.The dehydration reaction occurred in DMF at 100?,in which the optimal mole ratio of compound(5)and thionyl chloride was 1?2.5.(5)In the process of synthesis of febuxostat,the hydrolysis reaction occurred in a mixture of ethanol and water(v/v=3?1)at reflux,in which the optimal molar ratio of compound(6)and sodium hydroxide was 1?1.3.ConclusionsIn this paper,the synthesis method and the reaction conditions of febuxostat was optimized.The intermediates of 4-hydroxythiobenzamide and ethyl2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylatewere synthesized by one pot reaction.The improved synthesis method is more streamlined,relatively low cost,simpler and higher yield,which is suitable for industrial production.