Synthesis Of Anti-gout Drug Febuxostat

Gout is a chronic inflammatory arthritis characterized by the deposition of urate crystals in joints and other connective tissues,secondary to prolonged hyperuricemia.Defined as serum uric acid（s UA）concentration exceeding the solubility of uric acid in extracellular fluid（6.8 mg/dl）.Increased levels of hyperuricemia increase the risk of gouty arthritis and uric acid urolithiasis.Currently,there are three main methods for reducing urate in gout,namely reducing urate production by using xanthine oxidase inhibitors（XOI）,using uricosuric agents to promote uric acid excretion,or using uricase to reduce urate uric acid.Febuxostat is a non-purine xanthine oxidoreductase inhibitor,which can reduce the formation of uric acid by inhibiting xanthine oxidase to treat gout.Developed by Japan’s Teijin Company,it was launched in the EU and the United States in April 2008 and February 2009.In 2013,the domestic generic febuxostat was launched in China.In September 2018,the original manufacturer’s febuxostat tablets were also launched in China.Listed for clinical treatment of long-term gout and hyperuricemia.It has great development value in the drug market for the treatment of gout.This thesis mainly studies the synthesis and crystal preparation of febuxostat,and improves and optimizes the process.Using 4-hydroxybenzonitrile as the starting material,through thiolation reaction,cyclization reaction,Duff reaction,etherification reaction,cyanation reaction,ester hydrolysis reaction,and finally through recrystallization and crystal form research to obtain febuxostat crystal Type A.The specific research contents are as follows:（1）Synthesis of 2-（3-formyl-4-hydroxyphenyl）-4-methylthiazole-5-carboxylic acid ethyl ester:using 4-cyanobenzonitrile as starting material,under acidic conditions 4-hydroxybenzylthioamide was synthesized by electrophilic addition reaction with the thioreagent thioacetamide,and the yield was 96.79%.Then,2-2-hydroxybenzylthioamide was synthesized by Hantzsch cyclization reaction with ethyl 2-chloroacetoacetate using ethanol as solvent and ethyl2-chloroacetoacetate.（4-hydroxyphenyl）-4-methylthiazole-5-carboxylic acid ethyl ester,the yield was 98.46%;finally reacted with hexamethylenetetramine by Duff,electrophilic aromatic substitution occurred to obtain 2-（3-formyl-4-hydroxyphenyl）-4-methylthiazole-5-carboxylate,85.53%yield.（2）Synthesis of Febuxostat:2-（3-formyl-4-hydroxyphenyl）-4-methylthiazole-5-carboxylate ethyl ester with DMAC as solvent and bromoisobutane through etherification reaction nucleophilic substitution of SN2 occurred to generate ethyl 2-（3-formyl-4-isobutoxyphenyl）-4-methylthiazole-5-carboxylate with a yield of 99.12%;The process of nuclear addition elimination reaction gave2-（3-cyano-4-isobutoxyphenyl）-4-methylthiazole-5-carboxylate ethyl ester with a yield of 96.55%;finally,under basic conditions the crude febuxostat was obtained by ester hydrolysis with a yield of 98.70%;the finished febuxostat was obtained by recrystallization from ethyl acetate with a yield of 99.20%and a HPLC purity of 99.96%.（3）Febuxostat crystal form research:By improving and optimizing the crystal form preparation process,the best process conditions for the preparation of febuxostat crystal form A were obtained:at 75℃,febuxostat was dissolved in 8 times the amount（W/V）in anhydrous ethanol,after dissolving for 10 min,slowly（0.5°C/min～1°C/min）cooled to 10°C,stirred at low speed（within 100 r/min）for crystallization for 4 h,the yield was 96%.（4）Scale-up experiment:The optimal process conditions were obtained by small-scale selection,and three batches of pilot scale-up experiments were carried out to synthesize the target compound febuxostat.The total yield was above 68%,and the HPLC purity was above 99.9%.The quality is basically the same as the test results.The intermediates and final products studied in this thesis were characterized by IR,¹HNMR,¹³CNMR,MS and PXRD.