非布司他合成工艺改进

Improved Synthesis of Febuxostat

本研究对非布司他的合成工艺进行改进。邻羟基苯甲腈(2)与溴代异丁烷反应后,与N-溴代琥珀酰亚胺在室温条件下反应6 h得2-异丁氧基-5-溴苯甲腈(4),收率由文献的75.7%提升至95.3%。4与联硼酸频那醇酯经Miyaura硼基化反应得3-氰基-4-异丁氧基苯硼酸频那醇酯,与2-溴-4-甲基噻唑-5-甲酸乙酯在二噁烷/水的混合溶剂中经Suzuki反应得2-(3-氰基-4-异丁氧基苯基)-4-甲基噻唑-5-甲酸乙酯,避免了有毒溶剂甲苯的使用,收率也由文献的65.4%提高至72.6%。最后再经水解得目标产物,总收率58.7%(以2计)。

In this study, the synthetic process of febuxostat was improved. 5-Bromo-2-isobutoxybenzonitrile（4） was obtained via a substitution of 2-hydroxybenzonitrile（2） and bromoisobutan, followed by bromination with N-bromosuccinimide at room temperature, the yield was increased from 75.7% to 95.3%. Then compound 4 reacted with bis（pinacolato）diboron via Miyaura borylation to give 3-cyano-4-isobutoxyphenylboronic acid pinacol ester. Then the latter was subjected to Suzuki coupling with ethyl 2-bromo-4-methylthiazole-5-carboxylate in dioxane/H_2 O to afford ethyl 2-（3-cyano-4-isobutoxyphenyl）-4-methylthiazole-5-carboxylate with a yield of 72.6%, which was followed by a hydrolysis with sodium hydroxide to product the target compound with a total yield of 58.7%（based on 2）.