阿替美唑盐酸盐合成工艺的改进  

Improved Synthesis of Atipamzole Hydrochloride

作　　者：李斌[1] 薛峰[1] 居沈贵[1] 

机构地区：[1]南京工业大学化工学院,江苏南京211816

出　　处：《精细化工》2016年第3期342-345,共4页Fine Chemicals

基　　金：国家自然科学基金(21176118)~~

摘　　要：以2-(2-溴乙酰基)-2-乙基茚酮为原料经过咪唑成环,羰基还原,最后盐酸化合成盐酸阿替美唑,总收率58%。其各步中间体结构经1HNMR、MS分析测试技术确证。改进了咪唑成环过程工艺条件,并考察了反应温度对收率的影响,确定了最佳反应条件:反应温度140℃,通氨气,反应时间4 h,将咪唑成环反应的收率由50%提高至72%。对于羰基还原过程采用黄鸣龙还原法替代原有的钯碳还原法,采用正交实验法优化了反应条件,确定了最优的工艺条件:反应溶剂为二甘醇,反应温度190℃,n(氢氧化钾)∶n〔4-(2-乙基-2-茚酮)咪唑〕=2∶1,n(水合肼)∶n〔4-(2-乙基-2-茚酮咪唑〕=7∶1,收率为81%。Atipamzole hydrochloride was synthesized from 2-（ 2-bromine acetyl）-2- ethylindanone through reactions includingthe imidazole ring formation,carbonyl reduction and hydrochlorination. The total product yield was 58%. The structure of intermediate of each reaction were confirmed by1 HNMR and MS. The technological conditions of imidazole ring formation were improved,and the effect of reaction temperature on the yield was investigated. The optimum reaction conditions were as follow：Reaction temperature 140 ℃,under the condition of ammonia,reaction for 4 hours. The yield of the reaction was increased to 72% from 50%. In the process of reduction of the carbonyl group,the method of Huang Minglong reduction was used to replace the original palladium carbon reduction method,and the optimum reaction conditions were optimized by orthogonal experiment. The optimum reaction were as follows： the solvent for the reaction was diethylene glycol,reaction temperature 190 ℃,n（ potassium hydroxide） ∶ n〔4-（ 2-ethyl-2-indanone） imidazole 〕= 2 ∶ 1,n（ hydrazine） ∶ n〔4-（ 2-ethyl-2-indanone）imidazole〕= 7∶1,and the yield was 81%.

关 键 词：咪唑成环 黄鸣龙还原法 盐酸阿替美唑 正交实验法 医药原料 

分 类 号：TQ469[化学工程—制药化工]