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Progress Towards a Large-Scale Synthesis of Molnupiravir (MK-4482, EIDD-2801) from Cytidine

preprint
submitted on 09.02.2021, 16:57 and posted on 16.02.2021, 05:24 by Grace P. Ahlqvist, Catherine P. McGeough, Chris Senanayake, Joseph D. Armstrong, Ajay Yadaw, Sarabindu Roy, Saeed Ahmad, David R. Snead, Tim Jamison

Molnupiravir (MK-4482, EIDD-2801) is a promising orally bioavailable drug candidate for treatment of COVID-19. Herein we describe a supply-centered and chromatography-free synthesis of molnupiravir from cytidine, consisting of two steps: a selective enzymatic acylation followed by transamination to yield the final drug product. Both steps have been successfully performed on decagram scale: the first step at 200 g, and the second step at 80 g. Overall, molnupiravir has been obtained in a 41% overall isolated yield compared to a maximum 17% isolated yield in the patented route. This route provides many advantages to the initial route described in the patent literature and would decrease the cost of this pharmaceutical should it prove safe and efficacious in ongoing clinical trials.

Funding

Bill and Melinda Gates Foundation (OPP1176590)

National Science Foundation Graduate Research Fellowship under Grant No. 1745302

History

Email Address of Submitting Author

tfj@mit.edu

Institution

Massachusetts Institute of Technology

Country

United States

ORCID For Submitting Author

0000-0002-8601-7799

Declaration of Conflict of Interest

No conflicts to declare