(1S,3aR,6aS)-八氢环戊二烯并[c]吡咯-1-羧酸叔丁酯草酸盐的合成

Synthesis of (1S,3aR,6aS)-t-Butyl Octahydrocyclopenta[c]pyrrole-1-carboxylate Oxalate

2-[N-(N'-苄基-L-脯氨酰)氨基]二苯甲酮的甘氨酸席夫碱Ni(Ⅱ)配合物,可立体选择性地与1-环戊烯甲醛发生Michael加成,并经酸性水解得(3aR,6aS)-1,3a,4,5,6,6a-六氢环戊二烯并[c]吡咯-1-羧酸,再经氢化还原、氨基保护和(S)-1,2,3,4-四氢-1-萘胺的手性拆分得(1S,3aR,6aS)-2-(叔丁氧羰基)八氢环戊二烯并[c]吡咯-1-羧酸,然后通过酯化、脱氨基保护基和成盐反应得特拉匹韦关键中间体(1S,3aR,6aS)-八氢环戊二烯并[c]吡咯-1-羧酸叔丁酯草酸盐,总收率约40%。

（1S,3aR,6aS）-t-Butyl octahydrocyclopenta[c]pyrrole-1-carboxylate oxalate,the key intermediate of telaprevir,was synthesized from （S）-glycine-nickel-（S）-2-[N-（N＇-benzyl-L-proplyl） amino] benzophenone via stereospecific Michael addition with cyclopent-l-enecarbaldehyde and acid hydrolysis to give （3aR,6aS）-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole-1-carboxylic acid,which was subjected to hydrogenation reduction,amino protection,chiral resolution in the presence of （S）-1,2,3,4-tetrahydro-1-naphthylammonium,esterification,amino deprotection and salinization with an overall yield of about 40％.