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.
Highlights
Molnupiravir (MK-4482, EIDD-2801) is in development byMerck after licensing from Ridgeback Biopharmaceuticals as an orally dosed antiviral for the treatment of COVID-19.1 Animal studies have shown successful inhibition of SARS-CoV-22 as well as prevention of viral transmission.[3]
If shown to be safe and effective in ongoing clinical trials, this compound would be an important tool in the toolbox of physicians working to counter the effects of the SARS-CoV-2 virus pandemic
We previously demonstrated the potential of a two-step route from cytidine (8) to molnupiravir (7), which has many advantages over the previously patented route including cost and the overall yield (Figure 1).[5]
Summary
Merck after licensing from Ridgeback Biopharmaceuticals as an orally dosed antiviral for the treatment of COVID-19.1 Animal studies have shown successful inhibition of SARS-CoV-22 as well as prevention of viral transmission.[3]. Since the yield for the final two steps is not reported, this route has a 17% maximum overall yield (Scheme 1). We previously demonstrated the potential of a two-step route from cytidine (8) to molnupiravir (7), which has many advantages over the previously patented route including cost and the overall yield (Figure 1).[5]. Several challenges prevent the previously reported route from being implemented at the manufacturing scale. Most notably, both the intermediate and the final active pharmaceutical ingredient (API) were purified by column chromatography, so we sought to develop alternate workup and crystallization procedures to provide a pure material without chromatographic purification. We set out to re-examine this route to enable this process to be run at an increased scale
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