Process for recovery of the desired cis-1,3-oxathiolane nucleosides from their undesired trans-isomers

The present invention relates to commercial processes for the production of antiviral cis-1,3-oxathiolane and 1,3-dioxolane nucleoside analogues, some of which include, but are not limited to cis-(−)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone (1, Lamivudine, 3TC, BCH-189) and its 5-fluoro analogue, cis-(−)-4-amino-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone (2, Emtricitabine, (−)-FTC)). In particular, the present invention relates to a new and efficient process for converting the undesired trans-1,3-oxathiolane and 1,3-dioxolane nucleoside isomers to the desired cis-1,3-oxathiolane and 1,3-dioxolane nucleoside isomers by a method of anomerization/transglycosylation, and a highly efficient method of separating the anomeric mixture of 1,3-oxathiolane nucleoside analogues to their single anomers. A process for the preparation of 1,3-oxathiolane nucleoside analogues in predominantly the cis-form, from mixture of cis-/trans-1,3-oxathiolane nucleosides or their protected derivatives thereof, comprising:(i) treatment of the cis-/trans-1,3-oxathiolane nucleosides (or protected derivatives thereof) with a pyrimidine base (or it derivatives thereof) and an acid,(ii) adding a suitable acid to the obtained cis-/trans-mixture of isomers,(iii) selective crystallization of the desired cis-isomer salt from a solvent or combination of solvents, and(iv) treatment of the predominantly cis-isomer salt with a suitable base to offer the free 1,3-oxathiolane nucleosides, and thereafter optionally repeating steps (i) to (iv) inclusive.