Development of Scalable Synthesis of Chiral Sultam via a Chiral Phosphoric Acid-Promoted tert-Butyl Carbamate Deprotection–Resolution Sequence or Diastereoselective Hydrogenation

The discovery and process development for the synthesis of diastereopure sultam (1), a key chiral intermediate in route to a clinical candidate, are disclosed. Continuous route development to access (1) was required to satisfy both time and dynamic material needs during successive campaigns. Three distinct methods were developed to obtain diastereopure material. The first-generation process invoked time-intensive supercritical fluid chromatography (SFC) to access the diastereopure (2). Subsequent route development enabled a scalable, time-effective classical resolution approach that provided >20 kg of (1). Lastly, a Ruthenium-catalyzed diastereoselective hydrogenation approach was demonstrated on a hundred-gram scale and then coupled to the resolution technology to access (1), both reducing step count and improving overall yield relative to the resolution approach.