抗肿瘤药物 linifanib 的合成

目的 合成抗肿瘤药物 linifanib 并优化其工艺。方法 以 2,6-二氟苯甲腈为原料经取代、重氮化、环合等 4 步反应制得关键中间体3-氨基-4-碘吲唑（5）；以对氟硝基苯为原料经 Suzuki 偶联、还原、缩合反应得到关键中间体1-(2-氟-5-甲基苯基)-3-4-(4,4,5,5-四甲基-1,3,2-二氧杂环硼乙烷-2-基)苯基]脲（10）；中间体 5 与 10 经 Suzuki 偶联反应制得抗肿瘤药 linifanib。结果 目标化合物的结构经¹H-NMR 谱和质谱确证，总收率为39.4%。结论 与文献报道的工艺比较, 新工艺成本低廉，操作简单，反应时间缩短，有利于工业化生产。

Synthesis of antineoplastic agent linifanib

Linifanib(ABT-869),a novel potent and selective inhibitor of the VEGF and PDGF platelet-derived growth factor families of RTKs,was designed to inhibit angiogenesis,tumor growth,and metastasis.In order to improve the synthesis of linifanib and to optimize its procedure,a confluent synthetic route was designed.The key intermediate 4-iodo-1H-indazol-3-amine(5) was synthesized from 2,6-difluorobenzonitrile via ammonolysis,diazo-reaction,cyclization with hydrazine hydrate.Another key intermediate 1-(2-fluoro-5-methylphenyl)-3-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea(10) was prepared from 1-fluoro-4-nitrobenzene via Suzuki cross coupling reaction,reduction and condensation with 1-fluoro-2-isocyanato-4-methylbenzene.Finally,5 reacted with 10 via Suzuki cross coupling reaction to afford target compound linifanib.The overall yield of the target compound was 39.4%,and its structure was confirmed by 1H-NMR and MS.In comparison with the reported procedure,the improved process has the advantage of low cost,simple operation,short reaction time and it is also suitable for industrial production.