Process for Preparing Gemcitabine and Associated Intermediates

A process for preparing 2-deoxy-2,2-difluoro-D-erythro-pentofuranose-1-ulose of the structural formula 4:

• the process comprising:
• heating a mixture of the D-erythro isomer of formula 15A:
• in a water-miscible solvent, water and an acid for a sufficient time period to allow substantial completion of the reaction;
• optionally reducing the solution volume by distillation;
• adding a water immiscible solvent and removing water from the mixture;
• and
• further distilling the solvent mixture, to obtain a compound of formula 4.

A process for isolating the D-threo isomers (3S)-3-hydroxy-2,2-difluoro-3-(2,2-dimethyldioxolan-4-yl)propionic acid dicyclohexylammonium salts having the structural fonnula 15B:

• from the filtrate solution obtained after selective precipitation of the D-erythro isomer, the process comprising:
• optionally reducing the volume of the filtrate solution by evaporation;
• allowing the crystals of the D-threo isomer to precipitate;
• collecting the crystals by filtration;
• optionally washing the crystals;
• and
• optionally drying the crystals.

A process for preparing the 3,5-disubstituted-2-deoxy-2,2-difluoro-D-erythro-pentofuranos-1-uloses, having the structural formula 11A, and 3,5-disubstituted-2-deoxy-2,2-difluoro-D-threo-pentofuranos-1-uloses, having the formula 11B:

• wherein R is acetyl, phenyl, 2-phenylethenyl, phenyl acetyl, 1-naphthylmethyl, benzyl, 2-methylbenzyl, 4-methylbenzyl, 2-chlorobenzyl, or 4-chlorobenzyl, the process comprising:
• dissolving the corresponding 2-deoxy-2,2-difluoro pentofuranos-1-ulose in an organic solvent, optionally under inert atmosphere;
• adding at least one base and an acid chloride;
• refluxing the mixture for sufficient time period to allow substantial completion of the esterification reaction;
• removing the ammonium salt by-product;
• cooling the filtrate to obtain a second portion;
• evaporating the solvent to obtain a solid;
• and
• optionally purifying the product.