METHODS TO MANUFACTURE 1,3-DIOXOLANE NUCLEOSIDES

This application provides a process for preparing enantiomerically pure -D-dioxolane nucleosides. In particular, a new synthesis of (−)-DAPD, suitable for large scale development, is described. In one embodiment the invention provides a process for preparing a substantially pure -D- or -L-1,3-dioxolane nucleosides comprising a) preparing or obtaining an esterified 2,2-dialkoxy ethanol; b) cyclizing the esterified 2,2-dialkoxy ethanol with glycolic acid to obtain a 1,3-dioxolane lactone; c) resolving the 1,3-dioxolane lactone to obtain a substantially pure D- or L-lactone; d) selectively reducing and activating the D- or L-chiral lactone to obtain a substantially pure D- or L-1,3-dioxolane; e) coupling the D- or L-1,3-dioxolane to an activated and/or protected purine or pyrimidine base; and f) optionally purifying the nucleoside to obtain a substantially pure protected -D- or -L-1,3-dioxolane nucleoside.