Pilot-Plant Preparation of 3,4-Dihydropyridin-2-one Derivatives, the Core Structures of P2X7 Receptor Antagonists

The pilot-plant syntheses of 3 and 4, the core structures of a series of P2X7 antagonists are described. The sole stereogenic center in the dihydropyridinone ring was generated by catalytic desymmetrization. Selective formylation, followed by a tandem imination/lactamization sequence, produced the 3,4-dihydropyridin-2-one ring. The compounds 3 and 4 were produced at multikilogram scale in good overall yield (∼22% over six steps) and excellent stereochemical purity (97% ee for 3, 100% ee for 4).