富马酸沃诺拉赞的合成工艺.pdfVIP

Chinese Journal of Pharmaceuticals 2016, 47 11 1348 1,2 1,2 1,2 1,2 1,2* 1. 201203 2. 201203 2- 2- -5- 2- -1H - -3- 5- 2- -3- -3- 5- 2- -1- -3- -1H - -3- 25.5 99.8 A 1001-8255 2016 11-1348-04 R975 .2 DOI 10.16522/ki.cjph.2016.11.001 Synthetic Process of Vonoprazan Fumarate YU Qianying1,2, LIU Yu1,2, YAO Kai1,2, LI Jianqi1,2, WANG Guan1,2* 1. Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203; 2. Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai 201203 ABSTRACT: 2-Bromo-1-2-fl uorophenylethan-1-one was synthesized from 2-fl uoroacetophenone by substitution with bromine, followed by substitution of malononitrile and cyclization under acid condition to give 2-chloro-5-2- fl uorophenyl-1H-pyrrole-3-carbonitrile, then the latter was converted to 5-2-fl uorophenyl-1H-pyrrole-3-carbaldehyde via dechlorination and hydrogenation, after substitution with pyridine-3-sulfonyl chloride, 5-2-fl uorophenyl-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 salifi cation with fumaric acid with an overall yield of 25.5 based on 2-fl uoroacetophenone and purity of 99.8 . Ke