兰索拉唑关键中间体2,3-二甲基-4-(2,2,2-三氟乙氧基)吡啶-N-氧化物合成工艺改进  

Synthesis Improvement of the Key Intermediate of Lansoprazole 2,3-Dimethyl-4-(2,2,2-trifluoroethoxy)pyridine-N-oxide

作　　者：高学智 王庆河[1] 仝巧林 杨建文 程卯生[1] GAO Xuezhi;WANG Qinghe;TONG Qiaolin;YANG Jianwen;CHENG Maosheng(Key Lab.of Structure-based Drug Design ＆ Diseovery,Shenyang Pharmaceutical University,Shenyang 110016)

机构地区：[1]沈阳药科大学,基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016

出　　处：《中国医药工业杂志》2018年第9期1252-1254,共3页Chinese Journal of Pharmaceuticals

摘　　要：2,3-二甲基-4-(2,2,2-三氟乙氧基)吡啶-N-氧化物是合成兰索拉唑的关键中间体,本研究对其合成工艺进行改进。用钨酸钠/过氧化氢代替冰乙酸/过氧化氢在水中将2,3-二甲基吡啶氧化成2,3-二甲基吡啶-N-氧化物(3),收率由85%提高到91%。然后以价廉的溴化钠/溴酸钠作为溴源直接和3发生氧化溴代反应合成4-溴-2,3-二甲基吡啶-N-氧化物(4),避免了原路线中混酸硝化反应时大量废酸的产生。最后4在叔丁醇钾作用下与三氟乙醇在DMF中反应合成目标化合物,收率由80%提高至89%。改进后的路线反应条件温和,操作简便,绿色环保,总收率56.7%。The synthesis for 2,3-dimethyl-4-（2,2,2-trifluoroethoxy）pyridine-N-oxide, the key intermediate of lansoprazole was developed. At first, sodium tungstate/hydrogen peroxide was used instead of acetic acid/hydrogen peroxide to oxidize 2,3-dimethylpyridine in water to 2,3-dimethylpyridine-N-oxide（3）, the yield was increased from 85% to 91%. Subsequently, 4-bromo-2,3-dimethylpyridine-N-oxide（4） was obtained via an oxidative bromination of 3 under Na Br/Na Br O3 and H2 SO4, which could avoid the formation of a large amount of waste acid during the nitration with the mixed acid. Finally, 4 reacted with trifluoroethanol in DMF in the presence of potassium tert-butoxide to afford the target compound with a yield of 89%. This improved synthetic route had some advantages, such as mild reaction conditions, simple operation and environmental protection, and the total yield was up to 56.7%.

关 键 词：兰索拉唑 抗消化性溃疡药 关键中间体 催化氧化 氧化溴代 

分 类 号：R975.6[医药卫生—药品] R914.5[医药卫生—药学]