Development and Kilogram-Scale Synthesis of a D2/5-HT2A Receptor Dual Antagonist (±)-SIPI 6360

The kilogram-scale synthesis of a D-2/5-HT2A receptor dual antagonist (+/-)-SIPI 6360 was developed as an alternative treatment for schizophrenia. Specifically, three conditions were modified and optimized, including the Vilsmeier conditions, to prepare quinoline 3. In addition, the palladium-catalyzed hydrogenation was modified to synthesize dihydroquinolin-2(1H)-one 5, and the reduction of beta-chloroamide was altered to form 3-chloropropanamine 8. Ultimately these improvements led to the preparation of a 1.5 kg of (+/-)-SIPI 6360 batch in eight steps with an overall yield of 34% and purity of 99.8%.