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

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

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 activ...

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Veröffentlicht in:Journal of organic chemistry 2018-10, Vol.83 (19), p.11571-11576
Hauptverfasser: Savage, Scott, McClory, Andrew, Zhang, Haiming, Cravillion, Theresa, Lim, Ngiap-Kie, Masui, Colin, Robinson, Sarah J, Han, Chong, Ochs, Christoph, Rege, Pankaj D, Gosselin, Francis
Format: Artikel
Sprache:eng
Schlagworte:
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
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Zusammenfassung: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.
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.8b01551