Here we describe an efficient and cost-effective chemoenzymatic synthesis of the β-lactamase inhibitor avibactam starting from commercially available ethyl 5-hydroxy­picolinate hydro­chloride. Avibactam was synthesized in 10 steps with an overall yield of 23.9%. The synthetic route features a novel lipase-catalyzed resolution step during the preparation of (2S,5S)-ethyl 5-hydroxy­piperidine-2-carboxylate, a valuable precursor of the key intermediate ethyl (2S,5R)-5-((benzyloxy)­amino)­piperidine-2-carboxylate. Our synthetic route was used to produce 400 g of avibactam sodium salt.

An efficient synthesis of avibactam starting from commercially available ethyl-5-hydroxypicolinate was completed in 10 steps and 23.9% overall yield. The synthesis features a novel lipase-catalyzed resolution, in the preparation of (2S,5S)-5hydroxypiperidine-2-carboxylate acid, which is a valuable precusor of the key intermediate ethyl (2S,5R)-5-((benzyloxy)amino)piperidine-2-carboxylate. An optimized one-pot debenzylation/sulfation reaction, followed by cation exchange, gave the avibactam sodium salt on a 400.0 g scale.

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