Synfacts 2021; 17(06): 0599
DOI: 10.1055/s-0040-1719729
Synthesis of Natural Products and Potential Drugs

A Refined ProTide Route to Uprifosbuvir

Contributor(s):
Philip Kocienski
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.
 

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.


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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.


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Publication History

Publication Date:
18 May 2021 (online)

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