Liu Z,
*,
Klapars A,
Simmons B,
Bellomo A,
Kalinin A,
Weisel M,
Hill J,
Silverman SM.
*
Merck & Co., Inc., Rahway, USA
Development and Implementation of an Aluminum-Promoted Phosphorylation in the Uprifosbuvir
Manufacturing Route.
Org. Process Res. Dev. 2021;
25: 661-667
DOI:
10.1021/acs.oprd.0c00487
Key words
uprifosbuvir - hepatitis C - MK-3682 - phosphorylation - prodrug - nucleotides
Significance
The hepatitis C virus (HCV) has infected 170 million people worldwide. Over 70 million
have succumbed to chronic hepatitis C that can lead to a spectrum of conditions affecting
the liver, ranging from inflammation to cirrhosis and cancer. Uprifosbuvir (MK-3682)
is an NS5B RNA polymerase inhibitor that was of interest as a combination therapy
for the treatment of HCV infections. It is a nucleoside-based prodrug that utilizes
the 5′-aryloxyphosphoramidate or ProTide moiety A to enhance cellular permeability and phosphorylation rates. Over 20 forms of uprifosbuvir
have been identified, some showing dramatically reduced bioavailability.
Comment
A major improvement in the multikilogram-scale synthesis of C entailed the reaction of phosphoramidate A (1.0 equiv) with nucleoside B (1.2 equiv) promoted by dimethylaluminum chloride (0.5 equiv) and 2,6-lutidine (1.25
equiv) in THF at 35 °C. Under these precisely defined conditions, uprifosbuvir was
isolated in 81% yield with >100:1 diastereoselectivity at the phosphorus stereocenter
and >100:1 selectivity for the 5′-mono phosphorylation product C over the undesired bisphosphorylation side products D. A small increase in the reaction temperature led to a significant increase in the
formation of cyclic phosphoramidate impurity E. Techniques and apparatus are described to safely handle neat pyrophoric dimethylaluminum
chloride.
