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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%。
Starting from 2- (2-bromoacetyl) -2-ethyl-indanone via imidazole ring, carbonyl reduction and finally hydrochloric acid synthesis of atipamezole hydrochloride, the total yield of 58%. The structure of each step intermediates by 1HNMR, MS analysis test confirmed. The process conditions of imidazole ring formation were improved, and the influence of reaction temperature on the yield was investigated. The optimal reaction conditions were determined: the reaction temperature was 140 ℃, ammonia was passed and the reaction time was 4 h. 50% increase to 72%. For the carbonyl reduction process Huangmenglong reduction method instead of the original palladium carbon reduction method, the orthogonal experimental method to optimize the reaction conditions, to determine the optimal process conditions: the reaction solvent is diethylene glycol, the reaction temperature is 190 ℃, n (hydrogen (2-ethyl-2-indanone) imidazole] = 2: 1, n : 1, yield 81%.