抗肿瘤药Lenvatinib相关杂质的合成

Synthesis of Related Impurities of Lenvatinib

为了控制原料药乐伐替尼质量,分别以化合物1和3为原料,经酰化、胺化,成脲得到2和5,然后这两个中间体发生亲核取代反应得到乐伐替尼杂质A:4-(3-氯-4-(3-环丙基脲)苯氧基)-7-甲氧基喹啉-6-甲酸甲酯。杂质A经碱水解,得到杂质B:4-(3-氯-4-(3-环丙基脲)苯氧基)-7-甲氧基喹啉-6-羧酸。两个杂质均为工艺杂质,其结构经核磁、质谱和元素分析确证。同时,对两个杂质产生的原因及机理进行了分析,为今后乐伐替尼的工业化生产提供指导。

To perform the quality control of lenvatinib, compounds 1 and 3 were used as the starting materials to obtain intermediate 2 and 5 via the reaction of acylation, amination and urea formation, then the two intermediates obtained the impurity A of levabrinib (4-(3-chloro-4-(3-cyclopropylurea)phenoxy)-7-methoxyquino line-6-methyl formate) by underwent nucleophilic substitution reaction. The impurity A was further subjected to alkali hydrolysis to obtain an impurity B (4-(3-chloro-4-(3-cyclopropylurea)phenoxy)-7-methoxyquinoline-6-carboxylic acid). These two impurities were process impurities and their structures were confirmed by NMR, MS and elemental analysis. At the same time, the causes and mechanisms of these impurities were analyzed to provide guidance for the industrial production of levartinib in the future.