Large-Scale Enantioselective Reduction of 2,3-Disubstituted Indenopyridine Enables a Practical Manufacturing Process for an 11β-HSD-1 Inhibitor

An economical and practical manufacturing process for an 11β-HSD-1 inhibitor is reported. The key feature of the synthesis is the identification of a unique and effective MeO-BoQPhos ligand for the Ir-catalyzed asymmetric hydrogenation of a fused tricyclic indenopyridinium salt. It is the first highly reactive chiral P,N ligand system to be utilized in asymmetric pyridine reduction. The enantioenriched indanopiperidine was produced with a low catalyst loading of 1000 ppm [Ir(COD)Cl]2. The challenges and solutions for final active pharmaceutical ingredient (API) physicochemical properties are also described. This asymmetric synthesis of the API was accomplished in 38% overall yield with >99.8% ee and >99.5 area % purity. This overall process results in a much shorter production cycle and significant waste reduction on the manufacturing scale.