Practical Synthesis of 7-Bromo-4-chloro-1H-indazol-3-amine: An Important Intermediate to Lenacapavir

Author:

Asad Naeem1,Lyons Michael1,Muniz Machado Rodrigues Shirley1,Burns Justina1,Roper Thomas1ORCID,Laidlaw G.1,Ahmad Saeed1,Gupton B.1,Klumpp Douglas1,Jin Limei1ORCID

Affiliation:

1. Medicines for All Institute, Virginia Commonwealth University, Richmond, VA 23284-3068, USA

Abstract

7-Bromo-4-chloro-1H-indazol-3-amine is a heterocyclic fragment used in the synthesis of Lenacapavir, a potent capsid inhibitor for the treatment of HIV-1 infections. In this manuscript, we describe a new approach to synthesizing 7-bromo-4-chloro-1H-indazol-3-amine from inexpensive 2,6-dichlorobenzonitrile. This synthetic method utilizes a two-step sequence including regioselective bromination and heterocycle formation with hydrazine to give the desired product in an overall isolated yield of 38–45%. The new protocol has been successfully demonstrated on hundred-gram scales without the need for column chromatography purification. This new synthesis provides a potential economical route to the large-scale production of this heterocyclic fragment of Lenacapavir.

Funder

Bill & Melinda Gates Foundation

Publisher

MDPI AG

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