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A Concise Route to MK-4482 (EIDD-2801)

preprint
submitted on 17.08.2020 and posted on 19.08.2020 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.

Funding

The Bill and Melinda Gates Foundation (OPP1176590)

History

Email Address of Submitting Author

drsnead@vcu.edu

Institution

Virginia Commonwealth University

Country

USA

ORCID For Submitting Author

0000-0003-1239-533X

Declaration of Conflict of Interest

no conflict of interest

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