Collect. Czech. Chem. Commun. 2004, 69, 905-917

Synthesis of N4-Amino and N4-Hydroxy Derivatives of 5-Azacytidine. A Facile Rearrangement of the N4-Amino Derivative to 5-(3-β-D-Ribofuranosylureido)-1H-1,2,4-triazole

Alois Pískala*, Naeem B. Hanna, Milena Masojídková, Pavel Fiedler and Ivan Votruba

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic


Treatment of methoxyribosyltriazinone 4 with hydrazine in methanol afforded crude 4-hydrazino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one (N4-amino-5-azacytidine) (2), which rearranged rapidly to isomeric 5-ribosylureidotriazole 6. The rearrangement proceeds easily also in water solutions of 2. Alkaline hydrolysis of 6 gave a mixture of 5-ureidotriazole 7 and 5-aminotriazole 8. Acid hydrolysis of 6 afforded only 7. This compound was also prepared by thermal rearrangement of 5-amino-1-carbamoyltriazole 9 or on reaction of cyano(formyl)guanidine 10 with hydrazine hydrochloride. Treatment of benzoylated methoxyribosyltriazinone 4a with hydrazine in methanol gave only the rearranged product 6a. Reaction of tribenzoylribosyl isocyanate 12 with aminotriazole 8 gave 1-triazolecarboxamidotribenzoylribose 13, which afforded by methanolysis oxazoloribofuranose 14 and aminotriazole 8. Compound 14 was also obtained by methanolysis of blocked ribosylcarbamate 16. Reaction of methoxyribosyltriazinone 4 with hydroxylamine in methanol afforded 4-hydroxylamino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one (N4-hydroxy-5-azacytidine) (3), which on the action of excess hydroxylamine yielded 1-cyano-1-hydroxy-5-β-D-ribofuranosylisobiuret (19). Treatment of methoxy-1,3,5-triazinone 18 with a solution of hydroxylamine in methanol gave 4-hydroxylamino-1-methyl-1,3,5-triazin-2(1H)-one (N4-hydroxy-1-methyl-5-azacytosine) (17). Heating of cyano(formyl)guanidine 10 with hydroxylamine hydrochloride in water lead to the formation of triuret (21). The mechanisms of the reactions of methoxyribosyltriazinone 4 with hydrazine and hydroxylamine are discussed. Compounds 2, 6 and 19 exhibited no significant antibacterial or cytostatic activity.

Keywords: 1,3,5-Triazines; 1,2,4-Triazoles; Nucleosides; Ureas; Hydrazones; Cleavage; Antibacterial activity.

References: 19 live references.