4-氯-7-甲氧基喹啉-6-甲酰胺的简便合成

Facile Synthesis of 4-Chloro-7-methoxyquinoline-6-carboxamide

摘要:

研究了一种合成抗癌药Lenvatinib关键中间体4-氯-7-甲氧基喹啉-6-甲酰胺的新方法。以BF3?Et2O作为催化剂和溶剂，在微波促进下3-甲氧基苯胺与Vilsmeier试剂和3,3-二乙氧基丙酸乙酯发生串联的甲酰化/加成环化/氯化反应一锅合成4-氯-7-甲氧基喹啉-6-甲醛，90 ℃下反应20 min，收率72.2%；然后在CuI和TBHP的作用下，直接与碳酸氢铵发生氧化酰胺化得到目标产物，在CuI 5 mol%、80 ℃反应4 h的条件下，收率84.5%。该方法合成路线短，原料价廉易得，原子经济性好，产物收率高，反应条件温和，操作简便。

Abstract:

A simple and efficient method was developed for the synthesis of 4-chloro-7-methoxyquinoline-6-carnoxamide as the key intermediate of the anticancer drug Lenvatinib. Using BF3?Et2O as catalyst and solvent, the cascade formylation/addition-cyclization/chloration of 3-methoxyaniline with Vilsmeier reagent and ethyl 3,3-dimethoxypropionate at 90 ℃ for 20 min under microwave irradiation gave 4-chloro-7-methoxyquinoline-6-carboxaldehyde with 72.2% yield. After that, 4-chloro-7-methoxyquinoline-6-carboxamide was synthesized in 84.5% yield via direct oxidative amidation of 4-chloro-7-methoxyquinoline-6-carboxaldehyde with ammonium bicarbonate in the presence of CuI and TBHP under the conditions of CuI 5 mol%, reaction temperature 80 ℃ and reaction time 4 h. The procedure has the advantages of short synthetic route, cheap and easily obtained raw materials, high atomic efficiency, high yield, mild reaction condition, easy operation.