Intermediate and process for preparing of beta- anomer enriched 21-deoxy,21,21-difluoro-D-ribofuranosyl nucleosides

A process for preparing a compound of formula (I):

• wherein,
• P is hydrogen or a hydroxy protective group;
• the method comprising:
• contacting a compound of formula (IV):
• wherein P is as defined hereinbefore, with trichloroacetonitrile, in an inert organic solvent and in the presence of a base.

A stereoselective glycosylation process for the preparation of greater than about 99% β-enriched anomer of gemcitabine hydrochloride formula (IIb):

• comprising the steps of:
• a) glycosylating a compound of formula (I),
• wherein P is as defined hereinbefore, with cytosine of formula (Va) or (Vb),
• wherein R4 is a nitrogen protective group, and R5 is a hydroxy protective group, in the presence of an inert organic solvent and optionally in the presence of a Lewis acid catalyst to protected gemcitabine free base of formula (IIa),
• wherein P and R4 are as defined hereinbefore;
• b) removing the protective groups by treating the compound of formula (IIa) with aqueous ammonia in the presence of a C1-3 alcohol or with hydroxy ion exchanged anion exchange resins, to give the β-enriched anomer of gemcitabine free base of formula (IIc);
• c) contacting the gemcitabine free base of formula (IIc) with hydrogen chloride in a C1-3 alcohol to give the β-enriched anomer of gemcitabine hydrochloride of formula (IIb) in a yield of at least about 95% and optionally a purity of at least about 95%;
• and
• d) optionally further enriching the β-anomer content of gemcitabine hydrochloride of formula (IIb) to greater than about 99% through crystallization from a mixture of a C2-3 aliphatic organic acid and water.