Synthetic nucleosides and nucleotides. XI. Facile synthesis and antitumor activities of various 5-fluoropyrimidine nucleosides.

Abstract

Condensation of 2,4-bis-trimethylsilyloxy-5-fluoropyrimidine (2a) with 1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-D-ribofuranose (3a) by Friedel-Crafts catalysts was studied. When the reaction was run in acetonitrile at room temperature for 3 h with 1:1:1 molar ratio of the base, sugar and stannic chloride, 2'',3'',5''-tri-O-benzoyl-5-fluorouridine (4a) was obtained in an excellent yield (98%). As 1-O-acetyl sugars, 1,2,3,5-tetra-O-acetyl-.beta.-D-ribofuranose (3b), 1,2,3,4,6-penta-O-acetyl-.alpha.-D-glucopyranose (3c), and 1,2-di-O-acetyl-3-p-toluenesulfonyl-5-O-methoxycarbonyl-D-xylofuranose (3d) could also be used in place of 3a to give the corresponding 1-.beta.-D-glycosyl nucleosides highly stereoselectively. The same method of nucleoside synthesis was extended to the 5-fluorocytosine series to afford 5-fluorocytidine (7a) and 1-.beta.-D-arabinofuranosyl-5-fluorocytosine (7b) in good yields starting from trimethylsilylated N4-acetyl-5-fluorocytosine (6). Additionally, 2,4-dimethoxy-5-fluoropyrimidine (2b) could be coupled with 3a in similar conditions to give 1-(2,3,5-tri-O-benzoyl-.beta.-D-ribofuranosyl)-4-methoxy-5-fluoro-1,2-dihydropyrimidin-2-one (4e) in good yield. The antitumor activities of the various products obtained aganinst [mouse] ascites Sarcoma 180 were also described.