Synthesis 2018; 50(16): 3177-3186
DOI: 10.1055/s-0037-1610155
special topic
© Georg Thieme Verlag Stuttgart · New York

Synthesis of HIV NNRTI Doravirine Analogues via Visible-Light Photoredox Decarboxylative Cross-Coupling

Linda M. Suen
Department of Discovery Chemistry, MRL, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA   Email: Abdellatif.el.marrouni@merck.com
,
Cheng Wang
Department of Discovery Chemistry, MRL, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA   Email: Abdellatif.el.marrouni@merck.com
,
David N. Hunter
Department of Discovery Chemistry, MRL, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA   Email: Abdellatif.el.marrouni@merck.com
,
Helen J. Mitchell
Department of Discovery Chemistry, MRL, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA   Email: Abdellatif.el.marrouni@merck.com
,
Antonella Converso
Department of Discovery Chemistry, MRL, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA   Email: Abdellatif.el.marrouni@merck.com
,
Department of Discovery Chemistry, MRL, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA   Email: Abdellatif.el.marrouni@merck.com
› Author Affiliations
Further Information

Publication History

Received: 12 March 2018

Accepted after revision: 23 April 2018

Publication Date:
30 May 2018 (eFirst)

Published as part of the Special Topic Modern Coupling Approaches and their Strategic Applications in Synthesis

Abstract

A C(sp2)–C(sp3) decarboxylative cross-coupling reaction utilizing dual nickel and photoredox catalysis for rapid parallel synthesis of diverse C-ring analogues of the HIV NNRTI clinical candidate doravirine is developed and described herein. This protocol features an alkylation with readily available and inexpensive methyl bromoacetate followed by hydrolysis to prepare an advanced doravirine intermediate, which undergoes decarboxylative cross-coupling with a variety of aryl and heteroaryl bromides. The mildness, broad applicability, and sustainability of the current methodology are improvements over previously reported procedures and allow for rapid parallel synthesis of analogues. The optimization and scope of this method are reported.

Supporting Information

 
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