Process research and scale-up of the κ-opioid receptor agonist CJ-15,161 drug candidate

This account depicts strategies adopted during the development of the K-opioid receptor agonist CJ-15,161. While the original discovery synthesis was enabled for scale-up, concomitant process research aimed at identifying a novel and more efficient route was undertaken. In the former case, an efficient four-step sequence has been developed, where the process features four consecutive regioselective and stereospecific inversions at a single aziridinium stereogenic center, which leads to overall retention of stereochemistry in a single operation. The search for novel routes has also resulted in two converging methods involving efficient intermolecular N-arylation strategies. The first approach involves Pd-catalyzed intermolecular N-arylation of an appropriately functionalized diamine, obtained from the precursor alpha-amino acids or, more conveniently, from the corresponding 1,2-amino alcohols. The second approach exploits efficient intermolecular N-arylation of oxazolidinones using catalytic copper in the presence of a bidentate ligand leading to a straightforward and practical synthesis of CJ-15,161.