Large-Scale Amide Coupling in Aqueous Media: Process for the Production of Diazabicyclooctane β‑Lactamase Inhibitors

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 β-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.