盐酸阿夫唑嗪的改进合成方法

A Modified Synthesis of Alfuzosin Hydrochloride

摘要:

提出了一种盐酸阿夫唑嗪（1）的改进合成方法。以2-氨基-4,5-二甲氧基苯甲腈为原料，与DMF缩合得6,7-二甲氧基喹唑啉二酮（2），再经氯化、胺化得到2-氯-4氨基-6,7-二甲氧基喹唑啉（4），最后与N-3-甲氨基丙基-2-四氢呋喃甲酰胺（5）缩合，再酸化得到目标产物1，总产率41.3%。该方法避免了剧毒物质的使用，缩短了合成路线。探讨了关键中间体2合成过程中催化剂、反应温度和反应时间对收率的影响，结果表明在氯化锌催化时盐酸存在下于170℃反应5小时，2的产率可高达98%。化合物的结构经IR、1HNMR 和MS 等进行了表征。

Abstract:

A modified synthesis of alfuzosin hydrochloride (1) is proposed. The 2-chloro-4-amino-6,7 -dimethoxyquinazolin(4) was prepared from 6,7-dimethoxyquinazolindione (2) through chlorination and amination, and the synthesis of 2 was cyclocondensed by 2-amino- 4,5-dimethoxybenzonitrile with DMF in the catalyst of ZnCl2 in sealed tube. Compound 4 was condensed with tetrahydro-N-[3-(methylamino)-propyl]-2-furancarboxamide (5) and then treated with hydrogen chloride to give the target compound 1. The total yield is 41.3%. This method avoids highly toxic sodium cyanate, and shortens the synthetic route. The effects of catalyst, temperature and time to the yield of key intermediate 2 were investigated. The results show that the optimal yield of 2 reaches 98% with the catalyst of zinc chloride in the presence of hydrochloric acid at 170℃ for 5 h. The target products were characterized with IR, ESI-MS and 1HNMR.