Synthesis of Diastereomerically Pure Nucleotide Phosphoramidates

Abstract

Prodrugs of therapeutic nucleoside monophosphates masked as phosphoramidate derivatives have become an increasingly important class of antiviral drugs in pharmaceutical research for delivering nucleotides in vitro and in vivo. Conventionally, phosphoramidate derivatives are prepared as a mixture of two diastereomers. We report a class of stable phosphoramidating reagents containing an amino acid ester and two phenolic groups, one unsubstituted and the other with electron-withdrawing substituents. The reagents can be isolated as single diastereomers and reacted with the 5'-hydroxyl group of nucleosides through selective nucleophilic displacement of the substituted phenol to prepare single diastereomer phosphoramidate products. This method has been used to prepare the HCV clinical candidate PSI-7977 in high yield and high diastereomeric purity.

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

“…Ross et al 221 also prepared several chiral phosphoramidate reagent bearing substituted phenols that would act as leaving groups during the phosphorylation step. p -Nitrophenyl phosphoramidate reagent 441 was prepared from the commercially available p -nitrophenyl dichlorophosphate by reaction with phenol and amino acid hydrochloride (Scheme 130).…”

Sofosbuvir: The Discovery of a Curative Therapy for the Treatment of Hepatitis C Virus

“…The first test of this concept utilised a p-nitrophenolate phosphate ester 18 (Figure 8.10) of the phosphoramidating reagent. When 18 was reacted with the uridine nucleoside in the presence of a strong base, good yields of the nucleoside phosphoramidate was achieved, although as a mixture of isomers (Figure 8.10) [45]. However, we were able to selectively crystallise the p-nitrophenolate phosphoramidating reagent and obtain the reagent with the desired Sp configuration at the phosphorus atom.…”

“…Further optimisation of the reaction yield, diastereoselectivity, reagent reactivity and reaction duration were achieved using the pentafluorophenolate phosphate ester phosphoramidating reagent 19 (Figure 8.10). Reagent 19 could be easily isolated in a diastereomeric excess of 99% by direct crystallisation and was stable over extended periods of time [45]. With this reagent in hand sofosbuvir was accessible by direct diastereoselective synthesis in high yield and > 99.7% isomeric purity after direct crystallisation from the crude reaction mixture.…”

Fabrication of a highly sensitive amperometric sensor using 1,4-phenylene-N,N′-bis (O,O-diphenylphoramidate)/CdS quantum dots/multi-walled carbon nanotubes for nanomolar detection of captopril

“…These types of compounds are potential bidentate ligands for the coordination to the metal cations [36,37]. In addition, due to the presence of the two phosphorus atoms in their structures, they will show more anticancer, antibacterial, antiviral drugs and enzyme inhibitory properties than phosphoramidates [38][39][40].…”