Development of a Scalable Synthesis for the Spirocyclic Benzoxepane–Pyridine Core of FXR Agonist HEC96719

HEC96719 is a small-molecule farnesoid X receptor (FXR) agonist with potential for treating nonalcoholic steatohepatitis (NASH). Herein, we report a robust and scalable kilogram-scale synthesis of compound 9, the central and synthetically challenging spirocyclic benzoxepane–pyridine core of HEC96719. This optimized process features: (i) a protecting-group-enabled nucleophilic acylation, (ii) an industrially practical cyclopropanation using NaOH under phase-transfer conditions, (iii) an ortho-phenol-assisted deoxygenation protocol to access a highly strained methylene intermediate, (iv) a copper-mediated intramolecular Ullmann etherification, and (v) a palladium-catalyzed carbonylation employing a safe CO surrogate to avoid high-pressure carbon monoxide. Collectively, this process enhances operator safety, improves overall efficiency and yield, avoids chromatographic purification, and has been successfully demonstrated on a multikilogram scale, underscoring its potential for industrial application.