An alternative synthetic route to Nepicastat enabled by palladium catalyzed cyclization

Dopamine β-hydroxylase (DBH) inhibition represents a therapeutic strategy for cardiovascular and neuropsychiatric disorders. Nepicastat, a potent DBH inhibitor, has attracted considerable clinical interest, and several synthetic routes to this compound have been reported. Herein, we describe an alternative synthetic approach featuring Pd-catalyzed aromatic C H alkylation to construct the benzocyclohexane core. Multi-decagram synthesis of key intermediates was achieved, with a Hofmann rearrangement providing the 2-aminotetralin scaffold and (−)-mandelic acid enabling chiral resolution. Final cyclization furnished Nepicastat in high yield. This approach provides a practical route to Nepicastat and may offer opportunities for further structural diversification of this scaffold. • Practical and scalable Pd-catalyzed C H alkylation for benzocyclohexane synthesis. • Multi-decagram preparation of key intermediates under mild and safe conditions. • BTI-promoted Hofmann rearrangement enables safer amine synthesis without azides. • (−)-Mandelic acid provides efficient resolution of ( S )-5,7-difluoro-2-aminotetralin. • Final cyclization delivers Nepicastat in quantitative yield with improved safety.