Development of a Practical Manufacturing Process to Relebactam via Thorough Understanding of the Origin and Control of Oligomeric Impurities

Kim, Jung‐Chul; Itoh, Tetsuji; Xu, Feng; Dance, Zachary E. X.; Waldman, Jacob H.; Wallace, Debra J.; Feiyue, Wu; Kats-Kagan, Roman; Ekkati, Anil R.; Brunskill, Andrew P. J.; Peng, Feng; Fier, Patrick S.; Obligacion, Jennifer V.; Sherry, Benjamin D.; Liu, Zhijian; Emerson, Khateeta M.; Fine, Adam J.; Jenks, Anna; Armenante, Marco Euclide

doi:10.1021/acs.oprd.1c00149

Cited by 3 publications

(2 citation statements)

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“…The optimum reaction conditions required the use of isopropylacetate (IPA) in addition to AcOH and water to This process, although run on a pilot-scale multiple times, encountered a few shortcomings: (1) oligomer formation was observed in the hydroxy intermediate and in the crude relebactam product, (2) heavy slurry formation at the sulfation step made batch agitation cumbersome, and (3) there were difficulties using TMSI on a pilot scale. Therefore, the Merck team underwent the reinvestigation of these problems and published the outcomes in recent results [60]. It was established that the oligomer formation results from the hydroxy product 6 and is activated by the presence of a base during the reaction and by water in the crystalized form of hydroxy urea product.…”

Section: Introductionmentioning

confidence: 99%

“…The optimum reaction conditions required the use of isopropylacetate (IPA) in addition to AcOH and water to suppress oligomer formation during the reaction process. The thickness of the batch during the sulfation reaction was avoided by replacing the SO 3 -pyridine complex with a SO 3 -Et 3 N complex, and TMSI was replaced with bromotrimethylsilane (TMSBr) for the deprotection of Boc in the final step [60].…”

Section: Introductionmentioning

confidence: 99%

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Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

et al. 2022

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Antibacterial resistance towards the β-lactam (BL) drugs is now ubiquitous, and there is a major global health concern associated with the emergence of new β-lactamases (BLAs) as the primary cause of resistance. In addition to the development of new antibacterial drugs, β-lactamase inhibition is an alternative modality that can be implemented to tackle this resistance channel. This strategy has successfully revitalized the efficacy of a number of otherwise obsolete BLs since the discovery of the first β-lactamase inhibitor (BLI), clavulanic acid. Over the years, β-lactamase inhibition research has grown, leading to the introduction of new synthetic inhibitors, and a few are currently in clinical trials. Of note, the 1, 6-diazabicyclo [3,2,1]octan-7-one (DBO) scaffold gained the attention of researchers around the world, which finally culminated in the approval of two BLIs, avibactam and relebactam, which can successfully inhibit Ambler class A, C, and D β-lactamases. Boronic acids have shown promise in coping with Ambler class B β-lactamases in recent research, in addition to classes A, C, and D with the clinical use of vaborbactam. This review focuses on the further developments in the synthetic strategies using DBO as well as boronic acid derivatives. In addition, various other potential serine- and metallo- β-lactamases inhibitors that have been developed in last few years are discussed briefly as well. Furthermore, binding interactions of the representative inhibitors have been discussed based on the crystal structure data of inhibitor-enzyme complex, published in the literature.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%