Abstract
Herein, the amide coupling of six primary amines with the sodium salt of diazabicyclooctane acid in an aqueous medium without an additional base/surfactant or organic solvent is described. The product was efficiently isolated from the reaction through simple filtration and recrystallized using hot water treatment as a swift and cost-effective process. The methodology was implemented on a kilogram scale to produce penultimate intermediates for synthesizing fi-lactamase inhibitors such as zidebactam, relebactam, and nacubactam. The comparison of green metrics for several previously reported amide coupling methods was discussed. The developed procedure avoids using hazardous organic solvents and provides a simple isolation method at the operational level with high purity and efficiency.