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Toward Secure Supply of Remdesivir via a 2-Pot Triazine Synthesis: Supply Centered Synthesis

preprint
submitted on 01.08.2020 and posted on 10.08.2020 by Dinesh J. Paymode, Flavio S. P. Cardoso, Joshua D. Sieber, John W. Tomlin, Daniel W. Cook, Justina Burns, Rodger W. Stringham, B. Frank Gupton, David Snead, Toolika Agrawal
Pyrrolotriazine 1 is an important precursor to Remdesivir, and an efficient synthesis is disclosed. This route features atom economy and reduced derivatization of starting materials, by making use of highly abundant, commoditized raw material inputs. The yield of triazine was doubled from 31% to 59%, and the synthetic step count was reduced from 4 to 2. A one-pot cascade sequence was developed for direct cyanation of pyrrole. Amination and cyclization with formamidine acetate complete the synthesis. The problematic nature of typically dilute electrophilic aminations was solved with semi-continuous processing. Moreover, development of a continuous platform afforded access to the ideal yet non-commercial aminating reagent, monochloramine. These efforts help to secure the Remdesivir supply chain.

Funding

Bill and Melinda Gates Foundation (BMGF) OPP1176590

History

Email Address of Submitting Author

drsnead@vcu.edu

Institution

Medicines for All Institute, Virginia Commonwealth University

Country

United States of America

ORCID For Submitting Author

0000-0003-1239-533X

Declaration of Conflict of Interest

The authors declare no competing financial interests.

Version Notes

Joshua D. Sieber added to list of authors and email address corrected with figshare.

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