Synthesis of Selective Estrogen Receptor Degrader GDC-0810 via Stereocontrolled Assembly of a Tetrasubstituted All-Carbon Olefin

Scott Savage; Andrew McClory; Haiming Zhang; Theresa Cravillion; Ngiap-Kie Lim; Colin Masui; Sarah J Robinson; Chong Han; Christoph Ochs; Pankaj D Rege; Francis Gosselin

doi:10.1021/acs.joc.8b01551

Synthesis of Selective Estrogen Receptor Degrader GDC-0810 via Stereocontrolled Assembly of a Tetrasubstituted All-Carbon Olefin

J Org Chem. 2018 Oct 5;83(19):11571-11576. doi: 10.1021/acs.joc.8b01551. Epub 2018 Sep 20.

Authors

Scott Savage, Andrew McClory, Haiming Zhang, Theresa Cravillion, Ngiap-Kie Lim, Colin Masui, Sarah J Robinson, Chong Han, Christoph Ochs¹, Pankaj D Rege¹, Francis Gosselin

Affiliation

¹ Department of Process Chemistry and Catalysis , F. Hoffmann-La Roche AG , Grenzacherstrasse 124 , CH-4070 Basel , Switzerland.

PMID: 30200756
DOI: 10.1021/acs.joc.8b01551

Abstract

We report an efficient synthesis of GDC-0810 on the basis of a sequence involving a highly stereoselective lithium tert-butoxide-mediated enolization-tosylation (≥95:5 E: Z) and a Pd-catalyzed Suzuki-Miyaura cross-coupling as key steps. Global deprotection, pyrrolidine salt formation, and final active pharmaceutical ingredient (API) form control/isolation produced GDC-0810 free acid in a 40% overall yield with >99.0% purity as ascertained by HPLC analysis.

MeSH terms

Alkenes / chemistry*
Carbon / chemistry*
Chemistry Techniques, Synthetic
Cinnamates / chemical synthesis*
Cinnamates / chemistry*
Cinnamates / pharmacology
Indazoles / chemical synthesis*
Indazoles / chemistry*
Indazoles / pharmacology
Ketones / chemistry
Receptors, Estrogen / metabolism*
Stereoisomerism

Substances

3-(4-(2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid
Alkenes
Cinnamates
Indazoles
Ketones
Receptors, Estrogen
Carbon