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Althuis, T.H., Hess, H.J., et al. (1977) Synthesis and identification of the major metabolites of prazosin formed in dog and rat. Journal of Medicinal Chemistry, 20, 146-149.

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  • 标题: 凡德他尼的合成工艺研究Study on Synthetic Process of Vandetanib

    作者: 张志鹏, 周艳红, 李冬冬, 石伟, 王亚楼

    关键字: 凡德他尼, VEGFR抑制剂, 喹唑啉, 合成, 抗肿瘤Vandetanib, VEGFR Inhibitor, Quinazoline, Synthesis, Anticancer

    期刊名称: 《Studies in Synthetic Chemistry》, Vol.3 No.2, 2015-08-17

    摘要: 目的:提供一条合成凡德他尼新工艺路线。方法:以香兰素为起始原料,经过酚羟基苄基保护、氧化、硝化、还原、环合和氯代反应得到7-苄氧基-4-氯-6-甲氧基喹唑啉,再与2-氟-4-溴苯胺发生取代反应,然后脱苄基生成4-(2-氟-4-溴苯胺基)-6-甲氧基-7-羟基喹唑啉(10),收率33.1%;以4-哌啶甲酸乙酯为原料,经Leuckart N-甲基化反应、酯基还原反应,然后和对甲苯磺酰氯反应生成磺酸酯(14),收率35.1%。最后将(10)和(14)在碱性条件下缩合得到目标产物凡德他尼(1)。(1)的总收率11.6% (以化合物(2)和(11)计)。结果:目标化合物及其中间体的化学结构都经过IR、1H-NMR和HR-MS图谱确证。结论:本方法缩短了反应步骤,反应条件温和、操作简便。 Objective: To develop a new synthetic route for Vandetanib. Methods: 4-(2-fluoro-4-bromo-ami- no)-6-methoxy-7-hydroxy-quinazoline (10) was prepared from vanillin (2) via phenolic hydroxyl protection, oxidation, nitration, reduction, cyclization and chlorination to afford 7-benzyloxy-4- chloro-6-methoxy-quinazoline (7), and then (7) coupled with 2-fluoro-4-bromoaniline, followed by debenzylation, yield 33.1%. (1-methylpiperidin-4-yl)methyl 4-methylbenzenesulfonate (14) was prepared from ethyl piperidine-4-carboxylate(11) by Leuckart reaction, reduction and then reacted with p-toluenesulfonyl chloride, yielding 35.1%. In addition, 10 was reacted with 14 to yield the antitumor drug vandetanib (1) with an overall yield of 11.6% (based on compound 2 and 11). Results: The structure of all products was confirmed by IR, 1H-NMR and HR-MS. Conclusion: The improved process has several advantages over those reported procedures, such as brief reac-tion steps, mild conditions, and simple operations.