达萨布韦的合成工艺研究  

Improved synthesis of dasabuvir

作　　者：钱萍[1] 夏娟娟[1] 杜鑫明 张晔[1] 张晓菁[1] 赵燕芳[1] 

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016

出　　处：《中国药物化学杂志》2016年第5期375-379,共5页Chinese Journal of Medicinal Chemistry

基　　金：教育部创新团队发展计划和辽宁省高校创新团队支持计划资助(IRT1073).

摘　　要：目的改进达萨布韦的合成工艺。方法以邻叔丁基苯酚为原料,经卤代、甲基化、Ullmann偶联反应得到关键中间体1-(3-叔丁基-5-碘-4-甲氧基苯基)嘧啶-2,4-(1H,3H)-二酮(5);以6-溴-2-萘甲酸甲酯为起始原料,经水解、Curtis重排、磺酰化、取代反应得到中间体N-(6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)萘-2-基)甲烷磺胺(9);中间体5与中间体9经Suzuki偶联反应得到达萨布韦,其结构经1H-NM R、13C-NM R、IR和MS谱确证。结果与结论确定了达萨布韦的合成路线并进行工艺优化,总收率达29.0%(以邻叔丁基苯酚计)。该工艺路线所用原料价廉易得、操作简便、条件温和,为达萨布韦的工业化生产奠定了基础。Dasabuvir,an orally active specific NS5 B RdRp inhibitor,was researched by Abb Vie laboratories.It is effective for the treatment of hepatitis C. An optimal process has been developed after summarizing all the synthetic methods reported for dasabuvir. Taking 2-tert-butylphenol as the starting material,1-（ 3-tert-butyl-5-iodo-4-methoxyphenyl） uracil（ 5） was synthesized though incorporated reaction of halogenation,methylation and condensation. Another key intermediate,pinacol 6-（ methylsulfonamido）-2-naphthylboronate（ 9）was prepared from methyl 6-bromo-2-naphthoate via hydrolysis,rearrangement,acylation and substitution.The intermediate 5 was condensed with intermediate 9,followed by Suzuki reaction to give dasabuvir. The total yield of dasabuvir was 29. 0%（ calculated from 2-tert-butylphenol） and its purity was 99. 7%（ HPLC）. The structure of dasabuvir was confirmed by MS,IR,1H-NMR and13C-NMR,and the structures of some intermediates were confirmed by MS and1H-NMR.

关 键 词：达萨布韦 NS5B RdRp抑制剂 工艺改进 

分 类 号：R914.5[医药卫生—药物化学]