Efficient Manufacturing Process for the Selective
Estrogen Receptor Degrader GDC-9545 (Giredestrant) via a Crystallization-Driven
Diastereoselective Pictet–Spengler Condensation
posted on 2021-11-09, 15:05authored byJie Xu, Cheol K. Chung, Andrew McClory, Kyle A. Mack, Michael E. Dalziel, Alec Fettes, Kyle Clagg, Ngiap-Kie Lim, Georg Wuitschik, Christian Jenny, Laure Finet, Michael Kammerer, Haiming Zhang, Rémy Angelaud, Francis Gosselin
GDC-9545 is a selective estrogen
receptor degrader that is being
developed as a treatment for ER+/HER2– breast cancer. A robust,
convergent manufacturing process for GDC-9545 was developed. The process
features a Wenker aziridine synthesis to produce the key starting
material tryptamine 11, a highly efficient C–N
coupling between aminoazetidine 9 and 2,6-difluoro-4-bromobenzaldehyde
diethyl acetal (33) to construct key intermediate 10, and a crystallization-driven diastereoselective Pictet–Spengler
reaction to furnish the active pharmaceutical ingredient GDC-9545·tartrate.