非布司他的合成研究

Study on Synthesis of Febuxostat

非布司他是由日本Teijin公司研发的黄嘌呤氧化酶抑制剂,用于具有痛风症状的高尿酸血症的长期治疗。以4-羟基苯甲醛为起始原料,经过亲核加成-消除-脱水、硫解、Hantzsch环合、Duff甲酰化、醚化、亲核加成-消除、脱水和水解反应制得标题化合物,并对合成工艺进行优化,反应总收率为55.1%（以4-羟基苯甲醛计）。通过＂一锅法＂分别合成了中间体4-羟基硫代苯甲酰胺和2-（3-氰基-4-异丁氧基苯基）-4-甲基噻唑-5-甲酸乙酯。改进后的工艺路线操作步骤更简单,总收率更高,更加适用于工业生产。

Febuxostat is used for long-term treatment of hyperuricemia with gout symptoms,which was developed by Teijin company as a xanthine oxidase inhibitor.In this paper,using 4-hydroxybenzaldehyde as starting material,febuxostat was synthesized via nucleophilic addition-elimination-dehydration,thiolysis,Hantzsch cyclization,Duff formylation,etherification,nucleophilic addition-elimination,dehydration and hydrolysis reaction.Meanwhile,the synthetic process of febuxostat was optimized.The overall yield of febxostat was 55.1%（calculated by 4-hydroxybenzaldehyde）.The intermediates 4-hydroxybenzothioamide and ethyl 2-（3-cyano-4-isobutoxyphenyl）-4-methylthiazole-5-carboxylate were prepared by one-pot method,respectively.After optimization,the synthetic process is simple,the total yield is higher.It is more suitable for industrial production.