molnupiravir synthesis
236865567
Evolving to an Ideal Synthesis of Molnupiravir, an Investigational Treatment for COVID 19
Tamas Benkovics John A McIntosh Samantha Silverman Peter E Maligres Taku Itoh Mark A Huffman Deeptak Verma Hsuan Ho Jonathan A Vroom Anthony R Knight Jessica A Hurtak William J Morris Neil A Strotman Grant S Murphy Kevin M Maloney Patrick S Fier
235080177
Progress Toward a Large Scale Synthesis of Molnupiravir (MK 4482, EIDD 2801) from Cytidine
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.
ACS omega
Grace P Ahlqvist Catherine P McGeough Chris Hugh Senanayake Joseph D Armstrong Ajay K Yadaw Sarabindu Roy Saeed Ahmad David R Snead Timothy F Jamison
233689828
A Convenient and Cost Efficient Route Suitable for "One Pot" Synthesis of Molnupiravir
Herein, we reported a convenient and cost efficient one pot synthesis of molnupiravir from cytidine. This method utilized N,N dimethylformamide dimethyl acetal (DMF DMA) as an extraordinary protecting agent to achieve site specific esterification at 5' hydroxyl group of the nucleoside easily, and afforded this promising drug candidate (purity up to 99% HPLC a/a) in 70% overall yield without chromatography purification, which is superior to the existing methods in aspect of the yield, the cost and the operation, and shows great potential value for commercial production. Furthermore, this excellent protecting agent was also successfully used in the synthesis of remdesivr from its parent nucleoside with a high total yield (76%
Tianwen Hu Yin Chih Liu Haitao Xue Haji A Aisa
234973454
A Biocatalytic Approach to a Key Intermediate for the Synthesis of the COVID 19 Experimental Drug Molnupiravir
Herein we report the conversion of cytidine 2 to N hydroxycytidine 7 catalysed by cytidine deaminase (CD) The wild type enzyme operates efficiently at high sustrate loadings and hydroxylamine concentrations to favor N hydroxy cytidine formation over uridine Although the wild type enzyme demonstrated good activity, we were able to further enhance the ratio of N hydroxycytidine to uridine produced through directed evolution of CD In particular, a T123G mutation close to the active site dramatically reduces cytidine hydrolysis activity whilst preserving desired amination activty The approach reported provides a new route to a key intermediate for the COVID 19 experimental drug Molnupiravir 1
Ashleigh J Burke William R Birmingham Yingying Zhuo Costa BZd Rebecca Crawshaw Thomas W Thorpe Ian Rowles James D Finnigan S Charnock Sarah L Lovelock Nicholas J Turner Anthony P Green
234211406
Chemists shorten synthesis of molnupiravir
Chemists have developed an environmentally friendly route for making the investigational antiviral compound molnupiravir from commodity chemicals in just three steps with 69% overall yield. They re.
234299359
Chemists shorten the synthesis of molnupiravir to prepare for scale up
230549813
A Short Synthesis of Molnupiravir
Philip J Kocienski
233808872
Synthesis of Molnupiravir from Uridine
Philip J Kocienski
234273488
Toward a Practical, Two Step Process for Molnupiravir from Cytidine
A two step synthesis of molnupiravir (1) is presented. This work focuses on the development of practical reaction and purification conditions toward a manufacturing route. The sequence commences from highly available cytidine (2) and molnupiravir is formed through direct hydroxamination of the cytosine ring and esterification of the sugar's primary alcohol without use of protecting or activating groups. A highly crystalline hydrate of N hydroxycytidine (3) resulted in an easily purified intermediate, and a practical, off the shelf enzyme was selected for the acylation. The yield was increased through a chemically promoted, selective ester cleavage which converted a by product, molnupiravir isobutyryl oxime ester (4) into the final API. Both reactions proceed in >90% assay yield and crystallization procedures are used to afford intermediate and active pharmaceutical ingredient in purities above 99% with an overall yield of 60% Excellent throughput and sustainability is achieved by limiting the total concentration to 7 volumes of solvent in the course of the two reactions with an overall PMI of 41 including work up and isolation. Environmentally friendly solvents, water and 2 methyl tetrahydrofuran, enhance sustainability of the operation.
Dinesh J Paymode Natarajan Vasudevan Saeed Ahmad Appasaheb L Kadam Flavio S P Cardoso Justina M Burns Rodger W Stringham David R Snead
235382135
Decoding molnupiravir induced mutagenesis in SARS CoV 2
Molnupiravir, a prodrug of the nucleoside derivative b D N 4 hydroxycytidine (NHC) is currently in clinical trials for COVID 19 therapy. However, the biochemical mechanisms involved in molnupiravir induced mutagenesis had not been explored. In a recent study, Gordon et al. demonstrated that NHC can be incorporated into viral RNA, and subsequently extended and used as template for RNA dependent RNA synthesis, proposing a mutagenesis model consistent with available virological evidence. Their study uncovers molecular mechanisms by which molnupiravir drives SARS CoV 2 into error catastrophe.
Journal of Biological Chemistry
Luis Menendez-Arias