Use of Lipase Catalytic Resolution in the Preparation of Ethyl (2S,5R)-5-((Benzyloxy)amino)piperidine-2-carboxylate, a Key Intermediate of the β-Lactamase Inhibitor Avibactam

Abstract

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.

Scale-Up Synthesis of IID572: A New β-Lactamase Inhibitor

“…(c) Pyridine hydrogenation from known 11 (Scheme c): although this was a promising approach, the synthesis of 11 starting from expensive methyl 3-methylpyridine-2-carboxylate ( 10 ) was not reproduced in a satisfactory yield; in addition, the ammonolysis also did not work well. A similar approach was later successfully applied in an alternative avibactam synthesis . All three initial approaches were abandoned.…”

“…A similar approach was later successfully applied in an alternative avibactam synthesis. 9 All three initial approaches were abandoned.…”

Synthetic approaches towards avibactam and other diazabicyclooctane β-lactamase inhibitors

“…In 2018, the teams of Chen and Wu, described an alternative approach to avibactam, starting from ethyl 5-hydroxypicolinate hydrochloride 27 (Scheme 6). 33 This aromatic starting material is first fully reduced, thus avoiding lengthy multistep protocols, to directly obtained piperidine 28 with an excellent 97:3 diasteromeric ratio in favor of the cis isomer. Using a lipase, the (S,S) ester 29 can be easily separated from the (R,R) acid 29' after a protection step with a Boc group.…”

From Waste to Value—Direct Utilization of α-Angelica Lactone as a Nonconventional Irreversible Acylating Agent in a Chromatography-Free Lipase-Catalyzed KR Approach toward sec-Alcohols

“…Classical enzymatic kinetic resolution (EKR) relies on a simple and well-known phenomenon that due to the chirality of the active site of the enzyme, one enantiomer fits better into the active site than its counterpart and is therefore converted at a higher rate . The EKR methodology has become one of the most prevalent approaches used nowadays in the synthesis of optically active compounds (especially chiral sec -alcohols/esters, − carboxylic acids/esters, − and primary amines/amides − ) mostly because of the possibility of obtaining both enantiomeric forms of the respective racemic substrates in a single run at relatively mild temperatures. However, the applicability of the EKR process on an industrial scale is strongly limited as this method is not attractive from the practical point of view due to several drawbacks mainly associated with low reaction yields (in the best-case scenario, only one substrate enantiomer reacts for a theoretical maximum yield of 50%) and high cost of isolation and purification operations of the desired products.…”