富马酸沃诺拉赞的合成工艺  

Synthetic Process of Vonoprazan Fumarate

作　　者：余倩盈 刘育[1,2] 姚凯[1,2] 李建其[1,2] 王冠[1,2] 

机构地区：[1]中国医药工业研究总院上海医药工业研究院化学制药新技术中心,上海201203 [2]上海药物合成工艺过程工程技术研究中心,上海201203

出　　处：《中国医药工业杂志》2016年第11期1348-1351,共4页Chinese Journal of Pharmaceuticals

摘　　要：邻氟苯乙酮经溴取代得2-溴代邻氟苯乙酮,经丙二腈取代、酸化闭环得2-氯-5-(2-氟苯基)-1H-吡咯-3-腈,经脱氯、镍催化氢化得5-(2-氟苯基)吡咯-3-甲醛,与吡啶-3-磺酰氯发生亲核取代反应生成5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛,与甲胺盐酸盐经还原氨化后与富马酸成盐得可逆性质子泵抑制剂富马酸沃诺拉赞,总收率25.5%(以邻氟苯乙酮计),纯度99.8%。2-Bromo-1-（2-fluorophenyl）ethan-l-one was synthesized from 2-fluoroacetophenone by substitution with bromine, followed by substitution of malononitrile and cyclization under acid condition to give 2-chloro-5- （2- fluorophenyl）-1H-pyrrole-3-carbonitrile, then the latter was converted to 5-（2-fluorophenyl）-1H-pyrrole-3-carbaldehyde via dechlorination and hydrogenation, after substitution with pyridine-3-sulfonyl chloride, 5-（2-fluorophenyl）-1-（pyrdin- 3-ylsulfonyl） -1H-pyrrole-3-carbaldehyde was obtained. Finally, vonoprazan fumarate, a reversible proton pump inhibitor, was prepared through reductive amination with methylamine hydrochloride and salification with fumaric acid with an overall yield of 25.5 % （based on 2-fluoroacetophenone） and purity of 99.8 %.

关 键 词：沃诺拉赞 可逆性质子泵抑制剂 合成工艺 

分 类 号：R975.2[医药卫生—药品]