Development of a Manufacturing Route to Avibactam, a β-Lactamase Inhibitor

Abstract

Process development work to provide an efficient, robust, and cost-effective manufacturing route to avibactam, a β-lactamase inhibitor is presented herewith. Aspects of this optimization work include the counterintuitive introduction of a protecting group to effect a difficult urea formation and the use of controlled feed hydrogenation conditions to facilitate an elegant one pot debenzylation and sulfation reaction. Overall, the commercial process delivers avibactam in much improved yield with significant reduction in the environmental footprint.

Synthesis of Avibactam Derivatives and Activity on β‐Lactamases and Peptidoglycan Biosynthesis Enzymes of Mycobacteria

“…Synthesis of avibactam was previously described using chiral piperidine derivatives, l ‐glutamic acid, or l ‐pyroglutamic acid as starting material. Recently, the process has been optimized starting from commercially available Boc‐benzylglutamate . Synthetic efforts devoted to the discovery of new DBOs have also been based on the olefin metathesis reaction or on a lipase catalytic resolution .…”

“…[13] Synthetic efforts devotedt ot he discoveryo fn ew DBOs have also been based on the olefin metathesis reaction [14] or on al ipase catalytic resolution. [13] Here, we report av ersatile route fort he functionalization of DBOs via the copper(I)-catalyzedH uisgen-Sharpless cycloaddition reaction ( Figure 1c). We show that the resulting triazole-containing DBOs retain the capacity to reach the periplasm of mycobacteria and to inhibit their b-lactamases.…”

Sulfation made simple: a strategy for synthesising sulfated molecules

“…20 However, the use of multiple steps and purification sequences is limiting. A process route to Avibactam 21 ( Fig. 1 and Chart 1(v) involved sulfation of the hydroxylamine intermediate using Me 3 NSO 3 , followed by cation exchange with tetrabutylammonium acetate, gave the organosulfate as its tetrabutylammonium salt.…”

“…This amine exchange has also been observed in the reaction of Et 3 N with PySO 3 . 21 We applied the optimal conditions to the synthesis of a range of sulfate esters (Chart 3). In all examples (Chart 3) we observed a near-quantitative conversion to the corresponding sulfate ester as the tributylammonium salt, independent of both electronic and steric factors.…”

Synthetic approaches towards avibactam and other diazabicyclooctane β-lactamase inhibitors

“…This allowed to isolate the (S/R) isomer of piperidine 22 with a 56% overall yield on a 300 kg scale. 32 Since only the trans isomer of 22 was isolated, the tedious selective saponification step could be avoided and amide 24 was directly obtained in 92% yield by treatment with a methanolic solution of ammonia (Scheme 5). A selective Fmocprotection of the amine was necessary before activating the hydroxylamine with carbonyldiimidazole to give intermediate 25.…”