盐酸尼非卡兰的合成新方法

A New Synthesis Method of Nifekalant Hydrochloride

以β-苯基丙酸为起始原料,依次经硝化、N-酰化和还原反应合成了盐酸尼非卡兰药物关键中间体——N-(2-羟乙基)-N-[3-(4-硝基苯基)]丙胺,三步总收率达66.5%.又以1,3-二甲基脲为原料,依次经氰基乙酸环合、乙醇胺脱胺、二氯亚砜氯化制得另一中间体——6-(2-氯乙基)氨基-1,3-二甲基-嘧啶二酮.上述二中间体反应形成1,3-二甲基-6-{2-[N-(2-羟乙基)-3-(4-硝基苯基)丙氨]乙氨基}-2,4-(1H,3H)-嘧啶二酮盐酸盐(盐酸尼非卡兰),总收率为54.5%(以β-苯基丙酸基准计算).

N- （2-Hydroxyethyl）-N- [3-（4-nitrophenyl）propyl] amine（3）, the key intermediate for the synthesis of Nifekalant hydrochloride, was prepared from β- phenylpropanoic acid as starting material in three-step by reaction of nitration, N- acylation and reduction in overall yield of about 66.5%. Additionally, 6-（2-chloroethyl）amino-l, 3- dimethylpyrimidinedione（7）, as another key intermediate, was synthesized by condensation of 1,3-dimethylurea successively with cyanoacetic acid and then treated with ethanolamine, followed by chlorination with thionyl chloride. Reaction of （3） with （7） afforded target compound 1,3-dimethyl-6-{2-[ N- （2-hydroxyethyl）-3-（4-nitrophenyl）propylamino] ethylaminol-2,4-（ 1 H, 3 H ）pyrimidinedione hydrochloride （Nifekalant hydrochloride）（ 1 ） in overall yield of about 54.5 % （based on β -phenylpropanoic acid）.