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A Concise Route to MK-4482 (EIDD-2801)
preprintsubmitted on 17.08.2020, 21:18 and posted on 19.08.2020, 05:12 by Natarajan Vasudevan, Grace P. Ahlqvist, Catherine P. McGeough, Dinesh J. Paymode, Flavio S. P. Cardoso, Tobias Lucas, Jule-Phillip Dietz, Till Opatz, Timothy F. Jamison, B. Frank Gupton, David Snead
A two-step route to MK-4482 (EIDD-2801, 1) 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.