| 摘要 |
A method for preparing gemcitabine and a method for preparing intermediates thereof are provided to facilitate the production of the gemcitabine, particularly on a commercial scale. A method for preparing gemcitabine comprises the steps of: (a) reducing a compound represented by a formula(16A) to produce a compound represented by a formula(19); (b) activating the hydroxyl group, for example, by conversion into a sulfonate(mesylate); (c) reacting the activated hydroxyl(mesylate) with a protected cytosine to produce a protected nucleoside; (d) optionally separating a beta anomer; (e) deprotecting the protected nucleoside; and (f) optionally separating the beta anomer, wherein R1 is unsubstituted or substituted C1-5 saturated or unsaturated alkyl, substituted phenyl, or C1-5 saturated or unsaturated aralkyl; R5 is unsubstituted or substituted phenyl, unsubstituted or substituted phenyl sulfonyl, or C1-5 alkylsulfonyl; and X is O or S. A method for preparing a compound represented by a formula(16) comprises the steps of: (a) hydrolyzing a mixture of erythro and threo isomers of a 3-substituted, alkyl 2,2-difluoro-3-hydroxy-3-(2,2-dialkyldioxolan-4-yl)-propionate in the presence of an acid to produce a 3-substituted-2-deoxy-2,2-difluoro-1-oxo-D-ribose; and (b) reacting the 3-substituted-2-deoxy-2,2-difluoro-1-oxo-D-ribose with a compound of R5NCX, optionally in presence of a base, wherein X is O or S, and R5 is unsubstituted or substituted phenyl, unsubstituted or substituted phenylsulfonyl, or C1-C5 alkylsulfonyl. A method for preparing the compound of the formula(16A) comprises the steps of: (a) dissolving a diastereomeric mixture of the formula(16) in a non-polar solvent: (b) cooling the mixture sufficiently to produce crystals of the compound of the formula(16A); (c) collecting a least a portion of the crystals; (d) optionally washing the crystals; and (e) optionally drying the crystals.
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