Large-Scale Tandem Cyclization Applied to Potentially High-Volume SSTR4 Agonists

Somatostatin receptor subtype 4 (SSTR4) antagonists are potential clinical targets for pain. We describe the efforts toward a robust large-scale synthesis of certain small-molecule SSTR4 agonist compounds. Previous routes used metal-mediated reactions and produced stereochemical mixtures. The molecule has a 3-azabicyclo[3.1.0]hexane ring system with cis-stereochemistry. A unique tandem cyclization at the multi-kilogram scale was employed to generate the fused ring system with exclusive cis-stereochemistry observed. The potential commercial synthesis is an efficient, economical process with good control points. This novel tandem cyclization was implemented to swiftly scale up a similar compound for early-phase studies.