Development of a Novel Process for the Kilogram-Scale Synthesis of Spiro[1H-pyrido[2,3-d][1,3]oxazine-4,4′-piperidine]-2-one

Spiro[1H-pyrido[2,3-d][1,3]oxazine-4,4′-piperidine]-2-one (3) is a key building block in many biologically active compounds. The synthesis of this compound, as reported in the literature, is low-yielding. We have discovered and developed a robust, high-yielding process to generate 3 as a bis-HCl salt using alternative starting materials and reaction conditions. The developed process was successfully demonstrated on a kilogram scale. A two-batch kilo lab campaign generated the bis-HCl salt of 3 in >99 HPLC area percent purity and 77% overall yield.