凡德他尼的合成工艺研究

报道了凡德他尼(1)的合成工艺研究。以香草酸甲酯(2)为起始原料,依次经烷基化、硝化、还原、环合得到7-苄氧基-6-甲氧基-3,4-二氢喹唑啉-4-酮,然后经氯化与2-氟-4-溴苯胺缩合、脱苄得到4-(4-溴-2-氟苯胺基)-7-羟基-6-甲氧基喹唑啉,最后经缩合、脱保护、还原胺化得到抗肿瘤药凡德他尼(1),总收率约43%。所研制的合成工艺路线各步收率均较高,而且操作简便,无需特殊试剂和条件,预期适合工业化生产的要求。

Study on the synthesis of Vandetanib

This paper deals with the development of a practical process for Vandetanib(1).Methyl vanillate was subjected to alkylation,nitration,reduction,cyclization to give 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one,and then chlorination,condensation with 4-bromo-2-fluorobenzenamine,debenzylation to give 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxy quinazoline,finally,an antitumor drug Vandetanib was obtained via condensation,de-protection,reductive amination with an overall yield of about 43%.In conclusion,this streamlined synthetic process of Vandetanib(1) highlights excellent yield in almost every procedure,ease of operation,robustness,and thus should be amenable to large-scale production.