Synthesis 2020; 52(22): 3406-3414
DOI: 10.1055/s-0040-1707859
special topic
© Georg Thieme Verlag Stuttgart · New York

Practical Early Development Synthesis of Nav1.7 Inhibitor GDC-0310

Andreas Stumpf
Department of Small Molecule Process Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA   Email: Stumpf.andreas@gene.com   Email: Stjean.frederic@gene.com
,
Department of Small Molecule Process Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA   Email: Stumpf.andreas@gene.com   Email: Stjean.frederic@gene.com
,
David Lao
,
Zhigang Ken Cheng
,
Remy Angelaud
,
Francis Gosselin
› Author Affiliations
Further Information

Publication History

Received: 18 April 2020

Accepted after revision: 12 May 2020

Publication Date:
22 June 2020 (online)


Published as part of the Special Topic Synthesis in Industry

Abstract

The concise early development route to the Nav1.7 inhibitor GDC-0310 is described. The active pharmaceutical ingredient (API) contains one stereocenter, which was obtained with high enantiomeric excess (>99:1) by using an SN2 displacement approach to connect two intermediates: a chiral benzyl alcohol and a piperidine. The synthesis of the piperidine building block proceeded via a regioselective SNAr reaction on 1-chloro-2,4-difluorobenzene by N-Boc-4-piperidinemethanol, followed by installation of the methyl ester group by electrophilic aromatic bromination and a palladium-catalyzed alkoxycarbonylation. A subsequent Suzuki–Miyaura cross-coupling reaction was then telescoped directly into cleavage of the Boc group to provide the advanced piperidine intermediate. The key feature of the synthesis is the highly selective SN2 displacement of the chiral mesylate of (R)-1-(3,5-dichlorophenyl)ethan-1-ol with the piperidine intermediate, followed by a chiral purity upgrade via the corresponding (1S)-(+)-camphorsulfonic acid salt. After standard hydrolysis of the methyl ester and CDI mediated amidation to couple the resulting acid with methanesulfonamide, enantiomerically pure GDC-0310 was obtained in high overall yield (37%) on a 6.5 kilogram scale.

Supporting Information

 
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