Progress Toward a Large-Scale Synthesis of Molnupiravir (MK-4482, EIDD-2801) from Cytidine
Grace P Ahlqvist1, Catherine P McGeough1, Chris Senanayake2
1Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
ACS Omega
|May 31, 2021
Summary
A new synthesis of molnupiravir (MK-4482) offers a more efficient and cost-effective production method. This chromatography-free process yields significantly higher molnupiravir quantities compared to patented routes.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Biocatalysis
Background:
- Molnupiravir (MK-4482, EIDD-2801) is an orally bioavailable antiviral drug candidate for COVID-19 treatment.
- Existing synthesis routes for molnupiravir have limitations in yield and scalability.
Purpose of the Study:
- To develop a supply-centered, chromatography-free synthesis of molnupiravir.
- To improve the overall yield and reduce the production cost of molnupiravir.
Main Methods:
- A two-step synthesis starting from cytidine.
- Involves selective enzymatic acylation followed by transamination.
- Successfully scaled to decagram quantities (200 g and 80 g).
Main Results:
- Achieved a 41% overall isolated yield of molnupiravir.
- This yield is substantially higher than the 17% yield from the patented route.
- Demonstrated feasibility on a decagram scale.
Conclusions:
- The developed synthesis route is more efficient and scalable than previous methods.
- This improved process could decrease the cost of molnupiravir.
- Offers a viable alternative for large-scale production if clinical efficacy is confirmed.
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