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

September 10, 2018The Journal of Organic Chemistry

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

View at Publisher

Ask AI

Bookmark

Share

Key Points

Develop an efficient and stereocontrolled synthetic strategy to prepare the selective estrogen receptor degrader GDC-0810 by constructing a challenging tetrasubstituted all-carbon olefin.
Utilized a lithium tert-butoxide-mediated enolization-tosylation sequence to establish the key tetrasubstituted alkene framework.
Performed a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction as a core carbon-carbon bond forming step.
Completed the synthesis via global deprotection, pyrrolidine salt formation, and active pharmaceutical ingredient form control and isolation.
The lithium tert-butoxide-promoted enolization-tosylation delivered high stereoselectivity with an E:Z ratio of ≥95:5.
The synthetic sequence generated GDC-0810 free acid with a 40% overall yield.
Form control and isolation yielded the active pharmaceutical ingredient with >99.0% purity as determined by HPLC analysis.

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

Chemical synthesis study reports high-yield production of selective estrogen receptor degrader GDC-0810 in drug manufacturing, highlighting a stereocontrolled route to complex olefins.

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.

Discussion

No takes yet. Share an insight, caveat, or question.

Cite This Study

Savage et al. (2018) studied this question.

synapsesocial.com/papers/69d8afdf945c639271bedcad https://doi.org/10.1021/acs.joc.8b01551

View at Publisher

Ask AI

Bookmark

Share

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

Key Points

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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

Key Points

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Keep reading

Keep reading