抗肿瘤候选新药intedanib的合成

Synthesis of Antitumor Drug-candidate Intedanib

3-硝基苯甲酸甲酯(2)经亲核取代、还原环合、N-乙酰化和缩合反应制得(E)-1-乙酰基-3-(甲氧基苯亚甲基)-2,3-二氢-1H-吲哚-2-氧代-6-甲酸甲酯(5)。另以N-甲基-4-硝基苯胺(6)经N-溴乙酰化、亲核取代和还原反应制得N-(4-氨基苯基)-N-甲基-2-(4-甲基哌嗪-1-基)乙酰胺(9)。5和9经缩合和脱乙酰化反应制得抗肿瘤药intedanib,总收率为28%(以2计),纯度99.5%。

Antitumor drug-candidate intedanib was synthesized from methyl 3-nitrobenzate （2） by nucleophilic substitution, reduction and ring closure, N-acetylation and condensation to give methyl （E）-l-acetyl-3- （methoxyphenylmethylene）-2,3-dihydro-lH-indol-2-oxo-6-carboxylate （5）, which was subjected to condensation with N- （4-aminophenyl） -N-methyl-2- （4-methylpiperazin- 1-yl） acetamide （9） and deacetylation with an overall yield of about 28 % （based on compound 2） and purity of 99.5 %. The intermediate 9 can be obtained from N-methy1-4-nitroaniline （6） by N-bromoactylation, nucleophilic substitution and reduction.