4-羟基-2-(4-异丙基噻唑-2-基)-7-甲氧基-8-甲基喹啉的合成

Synthesis of 2-(4-Isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-ol

2-甲基-3-硝基苯酚经甲基化、傅-克酰化和硝基还原反应得2-甲基-3-氨基-4-乙酰基苯甲醚(2)。3-甲基-2-丁酮经溴代、环合、Sandmeyer反应、氰基取代和碱性水解反应得4-异丙基噻唑-2-甲酸(3),3氯化后,与2经N-酰化反应得N-(2-甲基-3-甲氧基-6-乙酰基苯基)-4-异丙基噻唑-2-甲酰胺,最后在叔丁醇钾作用下环合得抗丙型肝炎病毒药物simeprevir关键中间体4-羟基-2-(4-异丙基噻唑-2-基)-7-甲氧基-8-甲基喹啉,总收率约9%(以3-甲基-2-丁酮计)。

2-Methyl-3-amino-4-acethylanisole （2） was prepared from 2-methyl-3-nitrophenol via methylation, Friedel-Crafts reaction and reduction. 2- （4-Isopropylthiazol-2-yl） -7-methoxy-8-methylquinolin-4-ol, the key intermediate of anti-HCV drug simeprevir, was synthesized from 3-methyl-2-butanone by bromination, cyclization, Sandmeyer reaction, cyano-substitution, and hydrolysis to give 4-isopropylthiazole-2-formic acid （3）, which was subjected to chlorination, N-acylation with 2, and cyclization in the presence of t-BuOK. The overall yield was about 9% （based on 3-methyl-2-butanone）.