Chemistry

A stereoselective method for synthesizing phosphoramidate-containing nucleosides could enable efficient synthesis of pronucleotide (ProTide) nucleoside prodrugs. The ProTide synthesis method involves adding a phosphoramidate functional group to the 5' position of a nucleoside, but lacks selectivity for the biologically relevant (R)-enantiomer at the phosphorus stereocenter, yielding unwanted analogs. The stereoselective method utilizes a lutidine analog to catalyze the reaction between phosphoramidate chloride and uridine to produce the prodrug MK-3682 in a single step with a combined yield of 92% for the phosphorus (R)- and (S)-enantiomers of the 5' analog and 99:1 selectivity for the (R)-enantiomer over the (S)-enantiomer. When applied to a range of other nucleoside analogs, the method produced the corresponding phosphoramidate-containing compound with combined yields of up to 96% for the 5' analogs and up to 98:2 selectivity for the phosphorus (R)-enantiomers. Next steps by Merck & Co. Inc. could include applying the method to other nucleoside-based therapies in its pipeline...