公开(公告)号：US20230028651A1

公开(公告)日：2023-01-26

申请号：US17852227

申请日：2022-06-28

申请人： Genentech, Inc. ,  Hoffmann-La Roche Inc.

发明人： Francis GOSSELIN ,  Stefan G. KOENIG ,  Eduardo V. MERCADO-MARIN ,  Andreas STUMPF ,  Daniel ZELL ,  Haiming ZHANG ,  Stephan BACHMANN ,  Diane E. CARRERA ,  Michael E. DALZIEL ,  Yonghui GE ,  Jie ZHANG ,  Raphael BIGLER ,  Laure Elizabeth Simone FINET ,  Regis Jean Georges MONDIERE ,  Yuki NAKAGAWA

IPC分类号： C07D495/04

摘要： A manufacturing process to a bis-mesylate salt 1b of the pan-RAF inhibitor 4-amino-n-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide. The process features a number of efficient key reactions, including a robust and scalable Pd-catalyzed carbonylation reaction to generate thienopyrimidine 2 and a highly chemoselective PtN/C-catalyzed nitro group reduction to access penultimate intermediate 7. The final amide coupling of 7 and 2 was accomplished by a mild and safe protocol employing N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate (TCFH) as the coupling reagent, to produce a 1:1 adduct of the freebase and THF. The adduct afforded compound 1b with excellent yield, purity, and form stability on a multikilogram production scale after reaction with MsOH and recrystallization. The methods are able to produce a compound having upwards of 95% purity.