Process Optimization for the Large-Scale Preparation of (2S,3aR,7aS)-tert-Butyl Hexahydro-2,5-methanopyrrolo[3,2-c]pyridine-1(4H)-carboxylate, an Intermediate for Nicotinic Acetylcholine Receptor Agonists

An optimized large-scale synthesis of (2S,3aR,7aS)-tert-butyl hexahydro-2,5-methanopyrrolo[3,2-c]pyridine-1(4H)-carboxylate (1A), an important intermediate for nicotinic acetylcholine receptor agonists, is described. The key feature of the synthesis involves three transformations in a one-pot process, including debenzylation and ring hydrogenation of two fused bicyclic rings. Multihundred gram quantities of 1A were prepared.