Development and Practical Synthesis of a Triple Reuptake Inhibitor, (1R,2S)-SIPI 5357

A new chromatography-free synthetic route to triple reuptake inhibitor (1R,2S)-SIPI 5357 was developed and demonstrated on a 300-g scale. The key feature of this route is an asymmetric induction reaction, where the (2S,3S)-aminoketone 6 was highly stereoselectively reduced to (1R,2S,3S)-amino alcohol 7. After hydrogenation, chlorination, and cyclization, (1R,2S)-SIPI 5357 was prepared in 33% overall yield via seven steps from α-bromo ketone 3.