尼达尼布的合成工艺改进

Research on improvement on the synthesis process of nintedanib

文章以2-氧化吲哚-6-甲酸甲酯、原苯甲酸三乙酯和醋酐为起始原料反应得到关键中间体:(E)-1-乙酰基-3-(乙氧基-苯基-甲烯基)-2-氧-2,3-二氢-1H-吲哚-6-甲酸甲酯(4),再与另一起始原料N-(4-氨基苯基)-N-甲基-2-(4-甲基哌嗪-1-基)乙酰胺(3)缩合得尼达尼布,纯度99.8%,总收率62.7%。

In this paper,the key intermediate is prepared by the reaction of 2-oxidation of methyl-6-methyl formate,triethyl benzoate and vinegar as the starting material.(E)-1-acetylgroup-3-(ethoxy-phenyl-methenyl)-2-oxo-2,3-dihydro-1H-indole-6-methyl formate methyl ester(4),and then condensed with another starting material,N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide(3),forming nintedanid.The purity is 99.8%and the total yield is 62.7%.