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Improved Preparation of a Key Hydroxylamine Intermediate for Relebactam: Rate Enhancement of Benzyl Ether Hydrogenolysis with DABCO

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journal contribution
posted on 01.02.2018, 00:00 authored by Jianguo Yin, Mark Weisel, Yining Ji, Zhijian Liu, Jinchu Liu, Debra J. Wallace, Feng Xu, Benjamin D. Sherry, Nobuyoshi Yasuda
Previous methods to prepare a bicyclic N-hydroxyl urea intermediate in the synthesis of the potent β-lactamase inhibitor relebactam were effective, but deemed unsuitable for long-term use. Therefore, we developed an in situ protection protocol during hydrogenolysis and a robust deprotection/isolation sequence of this unstable intermediate employing a reactive crystallization. During the hydrogenation studies, we discovered a significant rate enhancement of O-benzyl ether hydrogenolysis in the presence of organic amine bases, especially DABCO. The broader utility of the application of organic bases on the hydrogenolysis of a range of O- and N-benzyl-containing substrates was demonstrated.