Efficient Manufacturing Process for the Selective
Estrogen Receptor Degrader GDC-9545 (Giredestrant) via a Crystallization-Driven
Diastereoselective Pictet–Spengler Condensation

Xu, Jie; Chung, Cheol K.; McClory, Andrew; Mack, Kyle A.; Dalziel, Michael E.; Fettes, Alec; Clagg, Kyle; Lim, Ngiap-Kie; Wuitschik, Georg; Jenny, Christian; Finet, Laure; Kammerer, Michael; Zhang, Haiming; Angelaud, Rémy; Gosselin, Francis

doi:10.1021/acs.oprd.1c00263.s001

op1c00263_si_001.pdf (507.04 kB)

Efficient Manufacturing Process for the Selective Estrogen Receptor Degrader GDC-9545 (Giredestrant) via a Crystallization-Driven Diastereoselective Pictet–Spengler Condensation

journal contribution

posted on 2021-11-09, 15:05 authored by Jie 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.