Process and intermediates for preparing 1-[9'H-carbazol-4'-yloxy]-3-[ 2''-(2'''- methoxy -phenoxy)-ethyl)-amino]-propan-2-ol[carvedilol]
申请人:EGIS GYOGYSZERGYAR RT.
公开号:EP0918055A1
公开(公告)日:1999-05-26
A subject matter of the invention is a process for preparing 1-[9'H-carbazol-4'-yloxy]-3-[2''-(2'''--phenoxy)- ethyl}-amino]-propan-2-ol as well as the R or S enantiomer thereof and mixtures of the enantiomers and acid addition salts of these compounds, in which
a) 4-(oxiranylmethoxy)-9H-carbazole or the R or S enantiomer thereof is reacted with N-[2-(2'--phenoxy)-ethyl] -benzylamine in a protic organic solvent, and the thus formed 1-[N-benzyl}-2'-(2''--phenoxy)-ethyl}-amino]-3-[9'''H-carbazol-4'''-yloxy] -propan-2-ol [benzyl-carvedilol] is debenzylated by catalytic hydrogenation or
b) the N-[2-(2'--phenoxy) -ethyl]-benzylamine is reacted with epichlorohydrin, the thus formed 1-[N-benzyl}-2'-(2''--phenoxy)-ethyl}-amino]-3-[chloro] -propan-2-ol is reacted with 4-(hydroxy)-9H-carbazole and the thus formed 1-[N-benzyl}-2'-(2''--phenoxy)-ethyl}- amino]-3-[9'''H-carbazol-4'''-yloxy]-propan-2-ol is debenzylated by catalytic hydrogenation
本发明的一个主题是制备 1-[9'H-咔唑-4'-基氧基]-3-[2''-(2'''-苯氧基)-乙基}-氨基]-丙-2-醇及其 R 或 S 对映体和这些对映体的混合物以及这些化合物的酸加成盐的工艺,其中
a) 4-(环氧乙烷甲氧基)-9H-咔唑或其 R 或 S 对映体与 N-[2-(2'-苯氧基)-乙基]-苄胺在质子有机溶剂中反应、并通过催化氢化将由此形成的 1-[N-苄基}-2'-(2''-苯氧基)-乙基}-氨基]-3-[9'''H-咔唑-4'''-酰氧基]-丙-2-醇[苄基-卡维地洛]去苄基化或
b) N-[2-(2'-苯氧基)-乙基]-苄胺与环氧氯丙烷反应、将由此形成的 1-[N-苄基}-2'-(2''-苯氧基)-乙基}-氨基]-3-[氯]-丙-2-醇与 4-(羟基)-9H-咔唑反应,并将由此形成的 1-[N-苄基}-2'-(2''-苯氧基)-乙基}-氨基]-3-[9'''H-咔唑-4'''-氧基]-丙-2-醇催化加氢脱苄基。