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

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.

Keywords

• Lenacapavir
• indazol-3-amine
• hydrazine
• regioselective cyclization
• process development