Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Apr 8;6(15):10396-10402.
doi: 10.1021/acsomega.1c00772. eCollection 2021 Apr 20.

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

Grace P Ahlqvist  1 , Catherine P McGeough  1 , Chris Senanayake  2 , Joseph D Armstrong  2 , Ajay Yadaw  2 , Sarabindu Roy  2 , Saeed Ahmad  3 , David R Snead  3 , Timothy F Jamison  1
Affiliations

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

Grace P Ahlqvist et al. ACS Omega. .

Abstract

Molnupiravir (MK-4482, EIDD-2801) is a promising orally bioavailable drug candidate for the 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 a 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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Synthetic Route of Molnupiravir Disclosed by Emory University in 2019
Figure 1
Figure 1
This work (green) compared to the previous work (blue).
Scheme 2
Scheme 2. (a) Synthesis of Acetone Oxime (11); (b) Synthesis of Acylating Agent 9 Using Acetone Oxime (11) and Isobutyryl Chloride (13)
Figure 2
Figure 2
Various solvents screened for the enzymatic acylation of cytidine (MeCN = acetonitrile, CPME = cyclopentyl methyl ether, 2-MeTHF = 2-methyl tetrahydrofuran).
Figure 3
Figure 3
Assessment of solvent volume versus enzyme loading. See SI, Section 2.7, for additional details.
See this image and copyright information in PMC

References

    1. Cross R. Merck & Co. Joins Race for COVID-19 Vaccines and Therapies. Chem. Eng. News 2020, 98, 12.10.47287/cen-09844-buscon1. - DOI
    1. Sheahan T. P.; Sims A. C.; Zhou S.; Graham R. L.; Pruijssers A. J.; Agostini M. L.; Leist S. R.; Schäfer A.; Dinnon K. H.; Stevens L. J.; Chappell J. D.; Lu X.; Hughes T. M.; George A. S.; Hill C. S.; Montgomery S. A.; Brown A. J.; Bluemling G. R.; Natchus M. G.; Saindane M.; Kolykhalov A. A.; Painter G.; Harcourt J.; Tamin A.; Thornburg N. J.; Swanstrom R.; Denison M. R.; Baric R. S. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci. Transl. Med. 2020, 12, eabb588310.1126/scitranslmed.abb5883. - DOI - PMC - PubMed
    1. Cox R. M.; Wolf J. D.; Plemper R. K. Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets. Nat. Microbiol. 2021, 6, 11–18. 10.1038/s41564-020-00835-2. - DOI - PMC - PubMed
    1. Painter G. R.; Bluemling G. R.; Natchus M. G.; Guthrie D.. N4-Hydroxycytidine and Derivatives and Anti-Viral Uses Related Thereto. WO2019113462A12019
    1. Vasudevan N.; Ahlqvist G. P.; McGeough C. P.; Paymode D. J.; Cardoso F. S. P.; Lucas T.; Dietz J.-P.; Opatz T.; Jamison T. F.; Gupton F. B.; Snead D. R. A concise route to MK-4482 (EIDD-2801) from cytidine. Chem. Commun. 2020, 56, 13363–13364. 10.1039/D0CC05944G. - DOI - PubMed