The discovery and development of new antibacterial agents active against important MDR Gram-negative pathogens has become of increasing importance in recent years, as the incidence of infections with these resistant bacteria has become more problematic. The promising molecule Monobactam A  is totally synthetic monocyclic �-lactam containing a sulfonic acid activating group at the N1-position of the azetidinone ring and a hydroxypyridone siderophore tethered at the C4-position. The current work describes the continuous efforts to develop an efficient and scalable chemical process capable to kilograms of the complicated API for toxicological and early clinical development . This 11 step synthesis starts from the formation of the �-lactam core through [2+2] cycloaddition of the readily available starting material N-Boc-glycine (3  ) and imine 2  , which was generated from another commodity of acetal 1 . Other key transformations in the synthetic sequence involve classical resolution of amine 4  , efficient asymmetric formation of urea 5  with CDI treatment, amide coupling and purification, global deprotection with BBr3and unique API purification protocol.

Early process development of Monobactam A: Access to kilograms of the complicated API through continuous improvement

246th National Meeting (2013)

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