Development of a Practical Manufacturing Process to Relebactam via Thorough Understanding of the Origin and Control of Oligomeric Impurities

The development of a robust manufacturing process to relebactam, a potent beta-lactamase inhibitor, is described. The origin and control strategy of oligomer impurities formed during hydrogenolysis of benzyl urea intermediate 9 and deprotection of Boc-sulfate intermediate 11 have been thoroughly studied and developed. The optimal manufacturing process has been successfully implemented for commercialization, preparing relebactam (1) in >99% purity with a non-detectable level of oligomers.