Synthesis of the antitumoral nucleoside capecitabine through a chemo-enzymatic approach

Capecitabine is a 50-deoxynucleoside endowed with antitumoral activity. We planned a new approach to its synthesis: a cross linked enzyme aggregate subtilisin (Alcalase CLEA)-catalyzed alcoholysis allowed the selective deprotection of primary acetyl ester of the N1-(20,30,50-tri-O-acetyl-b-D-ribofuranosyl)-5-fluoro- N4-(n-pentyloxycarbonyl)cytosine affording the corresponding 50-hydroxyderivative; the 50-alcohol was transformed into the methyl group of capecitabine after a careful investigation about the best reducing agent and reaction conditions.