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A METHOD FOR PREPARING METHYL (Z)-3-4-METHYL2-(4-METHYL-1-PIPERAZINYL)ACETYL AMINOPHENYLAMINOPHENYLMETHYLENE)-OXINDOLE-6-CARBOXYLATE (INTEDANIB, NINTEDANIB)
A METHOD FOR PREPARING METHYL (Z)-3-4-METHYL2-(4-METHYL-1-PIPERAZINYL)ACETYL AMINOPHENYLAMINOPHENYLMETHYLENE)-OXINDOLE-6-CARBOXYLATE (INTEDANIB, NINTEDANIB)
The invention relates to a method of synthesizing methyl (Z)-3-[[4-[methyl[2-(4-methyl-1-piperazinyl)acetyl] amino]phenyl] amino]phenylmethylene)-oxindole-6-carboxylate of formula (1), known under the generic name of intedanib or nintedanib. The present method comprises a) a reaction of methyl oxindole-6-carboxylate with acetic anhydride at a temperature of 130 - 140°C, providing methyl 1-acetyl-oxindole-6-carboxylate; b) a reaction of methyl 1-acetyl-oxindole-6-carboxylate of with trimethyl orthobenzoate and acetic anhydride in the presence of toluene, providing methyl (E)-1-acetyl-3-(methoxyphenylmethylene)-oxindole-6-carboxylate; c) a reaction (E)-1-acetyl-3-(methoxyphenylmethylene)-oxindole-6-carboxylate with N-(4-aminophenyl)-N,4-dimethyl-1-piperazine acetamide and subsequently with an alkali hydroxide or alkali alkoxide in methanol or ethanol without isolation of the intermediate, providing methyl (Z)-3-[[4-[methyl[2-(4-methyl-1-piperazinyl)acetyl]amino]phenyl] amino]phenylmethylene)-oxindole-6-carboxylate, wherein the reaction is conducted at a temperature of 50 to 100°C. (1)
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机译:本发明涉及一种方法的合成(Z)-3-[[4- [甲基[2-(4-甲基-1-哌嗪基)乙酰基]氨基]苯基]氨基]苯基亚甲基)-氧吲哚-6-羧酸甲酯的方法式(1),以intedanib或nintedanib的通用名称已知。本方法包括:a)在130-140℃的温度下使6-羟吲哚甲基羧酸酯与乙酸酐反应,得到1-乙酰基-羟吲哚6-羧酸甲酯。 b)在甲苯存在下1-乙酰基-氧吲哚-6-羧酸甲酯与原苯甲酸三甲酯和乙酸酐的反应,得到甲基()乙酰基-1-乙酰基-3-(甲氧基苯基亚甲基) -羟吲哚-6-羧酸盐; c)( E I>)-1-乙酰基-3-(甲氧基苯基亚甲基)-羟吲哚-6-羧酸酯与 N I>-(4-氨基苯基)- N的反应 I>,4-二甲基-1-哌嗪乙酰胺,然后与碱金属氢氧化物或碱金属醇盐在甲醇或乙醇中的溶液分离,不分离中间体,得到甲基(Z)-3-[[4- [甲基[2-( 4-甲基-1-哌嗪基)乙酰基]氨基]苯基]氨基]苯基亚甲基)-氧吲哚-6-羧酸盐,其中反应在50至100℃的温度下进行。 (1)
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