Process to produce 2', 3'-Dideoxynucleosides

Claim 1

A process for producing a 2ʹ,3ʹ-dideoxynucleoside represented by the formula wherein B is a base selected from the group of purine and pyrimidine bases and R is a member selected from H and hydroxy-protecting groups, which comprises the steps of: (a) converting a member of the group consisting of L-­and D-γ-carboxy-γ-butyrolactone of the formula to a 5-O-hydroxy-protecting group-methyl-γ-butyrolactone of the formula wherein R is a hydroxy-protecting group, by reacting the compound of Formula 1 with a carboxy group reducing agent followed by reacting the resulting hydroxymethyl group with a hydroxy-protecting group reagent; (b) converting the intermediate from step (a), Formula 2, to the 5-O-hydroxy-protecting group-methyl-2,3-dideoxy-D-­or -L-pentofuranose of the formula wherein R is a hydroxy-protecting group, by reacting the compound of Formula 2 with a carbonyl group reducing agent; (c) converting the intermediate from step (b), Formula 3, to a 1-O-activating-group-5-O-hydroxy-protecting group-2,3-dideoxy-D- or -L-pentofuranose of the formula wherein R is a hydroxy-protecting group and A is an O-activating group selected from alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, arylthiocarbonyl, alkylsulfonyl, arylsulfonyl and carbonate groups, wherein the alkyl moiety may be an unsubstituted or substituted C₁-C₃ alkyl group and the aryl moiety may be an unsubstituted or substituted phenyl group and wherein the substituent on the alkyl and aryl moieties may be selected from 1 to 3 groups selected from halo and C₁-C₃ alkoxy groups, by reacting the compound of Formula 4 with an acylating or sulfonating or carbonylating agent corresponding to the group A above; (d) converting the intermediate from step (c), Formula 4, by reaction with a compound having one of the formulas HX and TMSX to the 1-leaving-group-5-O-protecting group-2,3-­dideoxy-D- or -L-pentofuranose of the formula wherein R is a hydroxy-protecting group and X is a leaving group selected from F, Cl, Br and I by reacting the compound of Formula 4 with a compound having one of the formulas HX and TMSX; (e) reacting the intermediate from step (d), Formula 5 with an activated base selected from purine and pyrimidine bases, wherein the base has been activated by means of reacting the pendant amino and hydroxy groups on the nucleus of the given base with an activating compound selected from silylating and acetylating and benzoylating agents, in the presence of one of a Bronsted acid and a Lewis acid and in the presence of a solvent selected from polar and non-polar solvents; and (f) recovering the dideoxynucleoside from step (e) above.