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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。
Aim To improve the synthetic technology of Dababuvir Methods The o-tert-butylphenol was used as a starting material to obtain the key intermediate 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) pyrimidine-2 by halogenation, methylation and Ullmann coupling reaction (5). Using methyl 6-bromo-2-naphthalenecarboxylate as starting material, hydrolysis and Curtis rearrangement and sulfonylation were carried out to obtain the intermediate N- ( (9,5); Intermediate 5 is reacted with an intermediate (6,5-tetramethyl-1,3,2-dioxaborolan-2- Dababepir was obtained via Suzuki coupling reaction. The structure was confirmed by 1H-NMR, 13C-NMR, IR and MS spectra. RESULTS AND CONCLUSIONS The synthesis route of dabanibabil was established and the process was optimized with an overall yield of 29.0% based on o-tert-butylphenol. The raw materials used in the process are cheap, easy to operate and mild to the conditions, which lays the foundation for the industrialized production of Dababevirine.