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submitted on 17.08.2020 and posted on 19.08.2020by 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.