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以3-甲氧基苯胺和3,3-二乙氧基丙酸乙酯为原料,通过串联的甲酰化-加成环化-氯化反应和氧化酰胺化反应,制备得到了抗癌药Lenvatinib(乐伐替尼)关键中间体4-氯-7-甲氧基喹啉-6-甲酰胺。用1HNMR、13CNMR和EA对产物进行了结构表征,并考察了最佳反应条件。结果表明:以BF_3·Et_2O作为催化剂和溶剂,在微波辅助下,n(3-甲氧基苯胺)∶n(3,3-二乙氧基丙酸乙酯)∶n(DMF)∶n(POCl_3)=1.0∶1.0∶1.0∶2.5,90℃反应20 min,一锅法合成得到了4-氯-7-甲氧基喹啉-6-甲醛,收率72.2%;然后,以CuI为催化剂,在n(CuI)∶n(4-氯-7-甲氧基喹啉-6-甲醛)∶n(NH_4HCO_3)∶n(TBHP)=1∶20∶60∶30,80℃反应4 h的条件下,制备得到了4-氯-7-甲氧基喹啉-6-甲酰胺,收率84.5%。
Using 3-methoxyaniline and ethyl 3,3-diethoxypropionate as starting materials, anti-cancer drugs were prepared by formylation-addition cyclization-chlorination and oxidative amidation in series 4-Chloro-7-methoxyquinoline-6-carboxamide, the key intermediate of Lenvatinib (Levignine). The products were characterized by 1HNMR, 13CNMR and EA, and the best reaction conditions were investigated. The results showed that n (3-methoxyaniline): n (ethyl 3,3-diethoxypropionate): n (DMF): n POCl_3) = 1.0:1.0:1.0:2.5 at 90 ℃ for 20 min. The 4-chloro-7-methoxyquinoline-6-carboxaldehyde was obtained in one pot. The yield was 72.2% The reaction was performed at 80 ℃ for 4 h with n (NH4HCO3): n (NH4HCO3): n (NH4HCO3): n Under the conditions of preparation 4-chloro-7-methoxyquinoline-6-carboxamide, yield 84.5%.