Synthesis of A-9758, an Inverse Agonist of Retinoic Acid-Related Orphan Receptor γt

Abstract

A-9758 is an inverse agonist of retinoic acid-related orphan receptor γt with well-characterized in vitro and in vivo antiinflammatory activity. A chromatography-free decagram-scale synthesis of this compound was developed to support pre-clinical research activities. This route was designed to enable late-stage structure−activity relationship studies of the amide moiety and convergently uses a reductive alkylation sequence between indole and benzaldehyde intermediates. A key advantage of this strategy is the fact that the indole precursor can be alkylated at C2, as required for A-9758, or at C3 to provide access to an isomeric chemical series. Access to the critical indole fragment was expedited via an underutilized SnAr/reductive cyclization cascade sequence, and the benzaldehyde fragment was prepared in two steps from inexpensive 2,4-dichlorobenzoic acid.