High Yielding Continuous-Flow Synthesis of Norketamine

Hernando, Marcos Veguillas; Moore, Jonathan C.; Howie, Rowena A.; Castledine, Richard A.; Bourne, Samuel L.; Jenkins, Gareth N.; Licence, Peter; Poliakoff, Martyn; George, Michael W.

Abstract

A new continuous-flow process is presented for synthesis of the pharmaceutical intermediate norketamine (5). Our approach has been to take the well-established and industrially applied batch synthetic route to this promising antidepressant precursor and convert it to a telescoped multi-stage continuous-flow platform. This involves the α-bromination of a ketone, an imination/rearrangement sequence with liquid ammonia, and a thermally induced α-iminol rearrangement. Our approach is high yielding and provides several processing advantages including the reduction of many of the hazards conventionally associated with this route, particularly in the handling of liquid bromine, hydrogen bromide gas, and liquid ammonia. Each of these presents serious operational challenges in a batch process at scale.

Citation

Hernando, M. V., Moore, J. C., Howie, R. A., Castledine, R. A., Bourne, S. L., Jenkins, G. N., …George, M. W. (2022). High Yielding Continuous-Flow Synthesis of Norketamine. Organic Process Research and Development, 26(4), 1145-1151. https://doi.org/10.1021/acs.oprd.1c00407

• Journal Article Type: Article
• Acceptance Date: Mar 6, 2022
• Online Publication Date: Mar 26, 2022
• Publication Date: Apr 15, 2022
• Deposit Date: Jul 6, 2022
• Publicly Available Date: Jul 6, 2022
• Journal: Organic Process Research &Development
• Print ISSN: 1083-6160
• Electronic ISSN: 1520-586X
• Publisher: American Chemical Society (ACS)
• Peer Reviewed: Peer Reviewed
• Volume: 26
• Issue: 4
• Pages: 1145-1151
• DOI: https://doi.org/10.1021/acs.oprd.1c00407
• Keywords: Organic Chemistry; Physical and Theoretical Chemistry
• Public URL: https://nottingham-repository.worktribe.com/output/7655260
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.oprd.1c00407