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

• Published in: Collection of Czechoslovak chemical communications Vol. 69; no. 4; pp. 905 - 917
• Main Authors: Pískala, Alois, Hanna, Naeem B., Masojídková, Milena, Fiedler, Pavel, Votruba, Ivan
• Format: Journal Article
• Language: English
• Published: 2004
• ISSN: 0010-0765; 1212-6950
• DOI: 10.1135/cccc20040905

Treatment of methoxyribosyltriazinone
4
with hydrazine in methanol afforded crude 4-hydrazino-1-β-D-ribofuranosyl-1,3,5-triazin-2(
1H
)-one (
N
4
-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 (
N
4
-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(1
H
)-one (
N
4
-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.