Phosphoramidate pronucleotides have proven to be an effective strategy for the intracellular delivery of nucleoside 5'-monophosphates. This review will summarize our efforts to understand the in vitro and in vivo behavior of phosphoramidate monoesters of 3'-azido-3'-deoxythymidine (AZT), 3'-fluoro-3'-deoxythymidine (FLT) and 5-fluoro-2'-deoxyuridine (FUdR). Insights drawn from these studies have proved valuable for the future design of phosphoramidate-based pronucleotides.
This unit describes a method for generating nucleoside phosphoramidate monoesters (S.3 and S.4; Fig. 15.1.1) from H-phosphonate intermediates (S.2). Two different methods are outlined for generating H-phosphonate monoesters. Both methods are simple and utilize readily available phosphitylating reagents. The nucleoside H-phosphonate monoesters are subsequently oxidized to the nucleoside phosphoramidates in the presence of iodine and the appropriate amino acid methyl ester.Phosphitylation. The Basic Protocol utilizes diphenyl phosphite as the phosphitylating agent. Diphenyl phosphite is inexpensive, is easy to handle, and produces high yields of the H-phosphonate monoester (S.2). This method involves reaction of diphenyl phosphite with a nucleoside followed by a basic work-up to yield the nucleoside H-phosphonate monoester.The Alternate Protocol utilizes bis(N,N-diisopropylamino)chlorophosphine as the phosphitylating agent. Bis(N,N-diisopropylamino)chlorophosphine is more reactive than diphenyl phosphite, is relatively inexpensive and easy to handle, and produces high yields of the H-phosphonate. Nucleosides are reacted with bis(N,N-diisopropylamino)chlorophosphine to generate a nucleoside bis(N,N-diisopropylamino)phosphine intermediate, followed by an acidic work-up to yield the nucleoside H-phosphonate monoesters.
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