Preparing gemcitabine comprises reducing a dihydro-furan-2-one compound to give a furan compound, activating the hydroxyl group and reacting with a protected cytosine to give a protected nucleoside and terminal protection of the nucleoside

摘要

Preparation of gemcitabine comprises reducing a dihydro-furan-2-one compound (16A) to give a furan compound (19), activating the hydroxyl group by converting into a sulfonate (mesylate), reacting the activated hydroxyl (mesylate) with a protected cytosine to produce a protected nucleoside, optionally removing the beta -anomers, terminal protection of the protected nucleoside and again optionally removing the beta -anomer. Preparation of gemcitabine comprises reducing a dihydro-furan-2-one compound of formula (16A) to give a furan compound of formula (19), activating the hydroxyl group by converting into a sulfonate (mesylate), reacting the activated hydroxyl (mesylate) with a protected cytosine to produce a protected nucleoside, optionally removing the beta -anomers, terminal protection of the protected nucleoside and again optionally removing the beta -anomer. R 1optionally substituted and -saturated 1-5C alkyl, substituted phenyl or optionally saturated aralkyl; R 5optionally substituted phenyl, -phenylsulfonyl or 1-5C alkylsulfonyl; and X : O or S. Independent claims are included for: (1) 3-substituted alkyl-2,2-difluoro-3-hydroxy-3-(2,2-dialkyldioxolan-4-yl)-propionate compound of formula (15); (2) 3,5-disubstituted 2-desoxy-2,2-difluoro-1-oxo-D-ribose compound of formula (16); (3) the preparation of (16) comprising hydrolysis of a mixture of erythro- and threo-isomer of 3-alkyl-2,2-difluoro-3-hydroxy 3-(2,2-dialkyldioxolan-4-yl)-propionate in the presence of an acid to give 3-substituted 2-desoxy-2,2-difluoro-1-oxo-D-ribose and reaction of 3-substituted 2-desoxy-2,2-difluoro-1-oxo-D-ribose with a cyanide compound of formula (R 5NCX), optionally in the presence of a base; and (4) the preparation of (16A), with a purity of at least 95%, comprising dissolving a diastereomeric mixture of (D-erythro- and D-threo)-(16) in a non-polar solvent, cooling the mixture to give (16A), collecting the separated crystals, washing and optionally drying. R 2, R 31-3C alkyl; and R 41-4C alkyl. [Image] [Image] .