A two-step route to MK-4482 (EIDD-2801, 1) was developed consisting of an esterification and hydroxamination of cytidine. The selective acylation and direct amination eliminate the need for protecting and activating...

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.

Bedaquiline is a crucial medicine in the global fight against tuberculosis, yet its high price places it out of reach for many patients. Herein, we describe improvements to the key industrial lithiation‐addition sequence that enable a higher yielding and therefore more economical synthesis of bedaquiline. Prioritization of mechanistic understanding and multi‐lab reproducibility led to optimized reaction conditions that feature an unusual base‐salt pairing and afford a doubling of the yield of racemic bedaquiline. We anticipate that implementation of these improvements on manufacturing scale will be facile, thereby substantially increasing the accessibility of this essential medication.

A two-step route to MK-4482 (EIDD-2801, <b>1</b>) was developed consisting of an esterification and hydroxamination of cytidine. The reactions can be conducted in either order with overall yields of 67% (first step—esterification) and 37% (first step—hydroxamination). Selective esterification of the nucleoside’s primary alcohol by enzymatic means eliminated the need for diol protection/deprotection, and direct transamination with hydroxylamine precluded the necessity of activating the nucleobase for amine coupling. This results in a significant advancement over the reported synthesis which is formed in at best 17% yield. The step count is reduced from five transformation to two, and the more expensive uridine is replaced with the more available cytidine.