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Review
. 2021 Dec 17;25(12):2679-2685.
doi: 10.1021/acs.oprd.1c00219. Epub 2021 Dec 9.

Toward a Practical, Nonenzymatic Process for Investigational COVID-19 Antiviral Molnupiravir from Cytidine: Supply-Centered Synthesis

Vijayagopal Gopalsamuthiram  1 , Appasaheb L Kadam  1 , Jeffrey K Noble  1 , David R Snead  1 , Corshai Williams  2 , Timothy F Jamison  2 , Chris Senanayake  3 , Ajay K Yadaw  3 , Sarabindu Roy  3 , Gopal Sirasani  3 , B Frank Gupton  1 , Justina Burns  1 , Daniel W Cook  1 , Rodger W Stringham  1 , Saeed Ahmad  1 , Rudy Krack  1
Affiliations
Review

Toward a Practical, Nonenzymatic Process for Investigational COVID-19 Antiviral Molnupiravir from Cytidine: Supply-Centered Synthesis

Vijayagopal Gopalsamuthiram et al. Org Process Res Dev. .

Abstract

A scalable four-step synthesis of molnupiravir from cytidine is described herein. The attractiveness of this approach is its fully chemical nature involving inexpensive reagents and more environmentally friendly solvents such as water, isopropanol, acetonitrile, and acetone. Isolation and purification procedures are improved in comparison to our earlier study as all intermediates can be isolated via recrystallization. The key steps in the synthesis, namely, ester formation, hydroxyamination, and deprotection were carried out on a multigram scale to afford molnupiravir in 36-41% yield with an average purity of 98 wt % by qNMR and 99 area% by HPLC.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Discovery Route to Molnupiravir
Scheme 2
Scheme 2. Development Routes toward Molnupiravir
Scheme 3
Scheme 3. Our Initial Acetonide Approach to Molnupiravir (M4ALL Route II)
Figure 1
Figure 1
Side products in Step 2, Step 3, and Step 4.
Scheme 4
Scheme 4. Synthesis of Diacylated Side Product 11 and Its Subsequent Hydroxyamination Products
Scheme 5
Scheme 5. Hydroxyamination and Side Products Formed
See this image and copyright information in PMC

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