哌唑嗪(Prazosin)合成新工艺

An Improved Process of Preparation for Hypertension Agent Prazosin

由邻二甲氧基苯(Ⅰ)经硝化成4-硝基-1,2-二甲氧基苯(Ⅱ),还原成3,4-二甲氧基苯胺(Ⅲ),与光气反应得异氰酸-3,4-二甲氧基苯酯(Ⅳ)与氰胺缩合成N-3,4-二甲氧基苯基-N′-氰基代脲(Ⅴ)再用PCl_5/POCl_3闭环成2-氯-4-氨基-6,7-二甲氧基喹唑磷酸酰胺酯(Ⅵ)及水解成盐酸盐(Ⅶ)再碱化等八步反应合成哌唑嗪的药效关键结构2-氯-4-氨基-6,7-二甲氧基喹唑(Ⅷ),总产率按邻二甲氧基苯计为38.2％。其另一片段糠甲酰基哌嗪(Ⅸ)用哌嗪单盐酸盐代替单氢溴酸盐与糠甲酰氯反应获同样结果。

The key intermediate of prazosin, i. e. 2-chloro-4-amino-6, 7-dimethoxyquinazoline(Ⅷ) was prepared, in a total yield of 38.2％ with a cheaper raw material 1,2-dimethoxybenzene(Ⅰ) according to the following scheme: 1, 2-dimethoxybenzene(Ⅰ) was nitrated to give 3, 4-dimethoxynitrobenzene(Ⅱ), which was catalytically hydrogenated with Raney-Ni as catalyst to give 3,4-dimethoxyaniline(Ⅲ). (Ⅲ) was then subjected to react with phosgene to form 3,4-dimethoxyphenylisocyanate(Ⅳ), which was condensated with cyanoamine to give N-3,4-dimethoxyphenyl-N'-cyanourea (Ⅴ). Cyclization of (Ⅴ) with phosphorus pentachloride and phosphorus oxychloride to form 2-chloro-4-amino-6, 7-dimethoxyquinazoline phosphoramido ester(Ⅵ), which was subjected to hydrolysis to give 2-chloro-4-amino-6,7-dimethoxyquinazoline hydrochloride(Ⅶ). Finally(Ⅷ) was obtained after alkalinization of (Ⅶ). The fragment mono-α-furoyl piperazine was prepared by use of HCl, and its yield was as good as that by use of HBr.