Abstract

6-Amino-1, 3-dimethyl-1H-pyrimidine-2, 4-dione 2 was prepared by alkylation of 6-amino- 1H-pyrimidine-2, 4-dione 1 with methyl iodide. Formylation of 2 with formic acid afforded N-(1, 3- dimethyl-dioxo-tetrahydropyrimidin-4-yl)-formamide 3. The nitration of 3 gave N - (1,3-dimethyl-5- nitro-dioxo-tetrahydropyrimidin-4-yl) formamide 4. Reduction of 4 by zinc dust in glacial acetic acid yielded dimethyl-dihydro-purine-2, 6-dione 5. Addition of bromine to 2 leads to the formation of 6- amino-5-bromo-dimethyl-pyrimidine-2, 4-dione 7, cycloaddition of 7 with formamide afford the same product (theophylline 5), alkylated of 5 with methyl iodide to give caffeine 6. Reaction of 7 with glycine gave 2-(6-amino-dimethyl-dioxo-tetrahydropyrimidin-5-ylamino) acetic acid 8, refluxing of 8 with acetic acid /methanol gave dimethyl-dihydropyrimidopyrazine-trione 9, alkylation of 9 with alkyliodide afforded tetra-alkyldihydropyrimidopyrazine- trione 10a and 10b. The Cytotoxicity screen of the synthesized compounds was evaluated and the result showed that 10a, 10b, 9, 8, 7 and 6 exhibited highly potential antitumor activity.

Keywords: Alkylation, antitumor, caffeine, cytotoxicity, pyrimidine, reduction.

Graphical Abstract