Rapid Multikilogram Scale-Up of Di- and Trifluoromethoxy Proline Derivatives

This report describes the synthesis, development, and scale-up (up to 10 kg) of di- and trifluoromethoxy prolines, key fragments evaluated in the development of potential antiviral SARS-CoV2 Mpro inhibitors. We first demonstrate a scalable route to 1-tert-butyl 2-methyl (2S,4R)-4-(difluoromethoxy)­p...

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Bibliographic Details
Published in:Organic process research & development 2024-04, Vol.28 (4), p.1119-1128
Main Authors: Cabrera, Pablo J., Allais, Christophe, Arcari, Joel T., González-Esguevillas, María, McInturff, Emma L., Reese, Matthew R.
Format: Article
Language:English
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Summary:This report describes the synthesis, development, and scale-up (up to 10 kg) of di- and trifluoromethoxy prolines, key fragments evaluated in the development of potential antiviral SARS-CoV2 Mpro inhibitors. We first demonstrate a scalable route to 1-tert-butyl 2-methyl (2S,4R)-4-(difluoromethoxy)­pyrrolidine-1,2-dicarboxylate employing a Cu-catalyzed difluoromethylation of alcohols using 2,2-difluoro-2-(fluorosulfonyl)­acetic acid. We then demonstrate the optimization and scale-up of challenging 1-tert-butyl 2-methyl (2S,4R)-4-(trifluoromethoxy)­pyrrolidine-1,2-dicarboxylate through silver-mediated oxidative trifluoromethylation of the corresponding alcohol. Finally, we report on the oxidative fluoro-desulfurization of xanthates as a potentially scalable route to access chiral aliphatic trifluoromethoxy ethers.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.3c00493