posted on 2021-09-11, 06:29authored byDaniel Zell, Michael E. Dalziel, Diane E. Carrera, Andreas Stumpf, Stephan Bachmann, Eduardo Mercado-Marin, Stefan G. Koenig, Haiming Zhang, Francis Gosselin
Herein, the development of a streamlined
manufacturing process
for the pan-RAF inhibitor belvarafenib (GDC-5573) is reported. The
process to belvarafenib features a number of efficient key reactions,
including a robust and scalable Pd-catalyzed carbonylation reaction
to generate thienopyrimidine 2 and a highly chemoselective
Pt/V/C-catalyzed nitro group reduction to access the penultimate intermediate 3. The final amide coupling was accomplished by a mild and
safe protocol employing N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate as the
coupling reagent, which afforded belvarafenib on a multikilogram production
scale after recrystallization.