Development of a Robust Manufacturing Route for Molnupiravir, an Antiviral for the Treatment of COVID-19

Abstract

Herein is described the development of a large-scale manufacturing process for molnupiravir, an orally dosed antiviral that was recently demonstrated to be efficacious for the treatment of patients with COVID-19. The yield, robustness, and efficiency of each of the five steps were improved, ultimately culminating in a 1.6-fold improvement in overall yield and a dramatic increase in the overall throughput compared to the baseline process.

Development of a Manufacturing Process toward the Convergent Synthesis of the COVID-19 Antiviral Ensitrelvir

“…COVID-19 has been recognized as a palpable threat that demands efficacious treatment. Until now, two novel oral antiviral drugs, Molnupiravir − (MK-4482 from Merck, formerly EIDD-2801 from Drug Innovations at Emory, LLC) and Nirmatrelvir (PF-07321332 from Pfizer), have been available and have helped reduce the risk of hospitalization or death. , These breakthrough drugs based on small molecules can be supplied affordably, thus offering a remedy for a broad range of patients including those in developing countries.…”

Early Clinical Development of Lufotrelvir as a Potential Therapy for COVID-19

“…Because of the rapid spread of SARS-CoV-2, a global pandemic emerged with health agencies seeking therapeutic options . A number of approaches to treating patients infected with the SARS-CoV-2 have been in clinical development (Figure ), including remdesivir and molnupiravir . One treatment strategy is to target the 3CL protease to selectively inhibit replication of the coronavirus.…”

“… 2 A number of approaches to treating patients infected with the SARS-CoV-2 have been in clinical development ( Figure 1 ), including remdesivir and molnupiravir. 3 One treatment strategy is to target the 3CL protease to selectively inhibit replication of the coronavirus. Toward this approach, PF-00835231 ( 1 ) was designed as a potent and first in class 3CL protease inhibitor which would be administered by intravenous infusion.…”

Concise two-step chemical synthesis of molnupiravir

“…They were able to improve 1.6-fold the overall yield, optimizing each step and this protocol has been adopted to produce tons per year of molnupiravir (2). 9 For extra details, see also Section 3 on ESI. † Given the importance of all those mentioned chemical syntheses and some inherent limitations of the reported approaches to molnupiravir (2), it is evident that more efficient and inexpensive routes from uridine (1) still need to be developed.…”

“…They were able to improve 1.6-fold the overall yield, optimizing each step and this protocol has been adopted to produce tons per year of molnupiravir (2). 9 For extra details, see also Section 3 on ESI. †…”