Synthetic nucleosides and nucleotides. XVIII. Synthesis and cytostatic activity of 5-fluoropyrimidine nucleosides of 3-amino-3-deoxy-.BETA.-D-ribofuranose and related compounds.

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Abstract
Treatment of 1,2:5,6-di-O-isopropylidene-3-amino-3-deoxy-.alpha.-D-allofuranose (1) with trifluoroacetic anhydride afforded a crystalline 3-trifluoroacetamido derivative (2)in good yield. Selective removal of the 5,6-O-isopropylidene group of 2 by treatment with 70% acetic acid followed by oxidation with periodate and subsequent reduction with sodium borohydride gave crystalline 1,2-O-isopropylidene-3-deoxy-3-trifluoroacetamido-.alpha.-D-ribofuranose (3) in good yield. p-Nitrobenzoylation of 3 followed by acetolysis afforded crystalline 1,2-di-O-acetyl-3-deoxy-3-trifluoroacetamido-5-O-p-nitrobenzoyl-.beta.-D-ribofuranose (5). Coupling of the resulting 1-O-acetyl sugar with bis-trimethylsilylated derivatives of N4-acyl-5-fluorocytosines, N4-acylcytosines, 5-fluorouracil and N4-acetyl-5-methylcytosine using SnCl4 afforded the corresponding fully acylated nucleosides (7). Saponification of 7 gave 3-amino-3-deoxy-.beta.-D-ribonucleosides (8a-8d). Alternatively, 2,4-dimethoxy-5-methylpyrimidine was also coupled with 5 followed by treatment with ammonia to give 8d. The nucleosides (8a-8d) thus obtained were examined for cytostatic effect on mouse leukemic L5178Y cells. The compounds tested were active against this system and their ED50 values were 0.7 .mu.g/ml, 7 .mu.g/ml, 16 .mu.g/ml and 60 .mu.g/ml, respectively.