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A. Zlatkov et al. / European Journal of Medicinal Chemistry 35 (2000) 941–948
(0.35 g, 5 % of water amount) were added. The reaction
mixture was stirred under reflux for 70 h. The progress
of the reaction was followed on TLC (I). After cooling,
the two layers were separated by filtration. After drying
with anhydrous sodium sulfate and filtration, the or-
ganic layer was distilled. The residual solid was recrys-
tallised from ethanol. The product was dried at
90–95 °C. Yield: 85 %. M.p.: 149–151 [6].
3.1.7. 3,7-dimethyl-1-[2-(2-methyl-5-nitro-1H-
imidazol-1-yl)-ethyl]-2,3,6,7-tetrahydro-1H-2,6-
purinedione (2b)
3.1.7.1. Method A
Compound 2b was synthesised in the same manner in
methanol from 2-methyl-5-nitroimidazole sodium salt
and 1c for 20 h in yield 1.95 g (59 %).
3.1.7.2. Method B
3.1.4. General procedure for the preparation of sodium
salts of imidazole deri6ati6es
Sodium methoxide (0.012 mol, 1.94 g 33 % methano-
lic solution in 10 mL absolute methanol) was added to
3,7-dimethylxanthine (0.01 mol, 1.8 g) dissolved in 140
mL absolute methanol and the mixture was refluxed for
3 h. Then the volume of the solution was reduced to 60
mL and 1-(2-bromoethyl)-2-methyl-5-nitroimidazole (6)
(0.01 mol, 2.34 g) dissolved in 20 mL methanol was
added. The reaction mixture was heated under reflux for
15 h. The isolation of 2b was carried out as described in
General procedure. Yield: 2.25 g (68%). Rf=0.47 (I).
M.p.: \300 °C. IR (cm−1) Nujol: 1694 (wCꢀO), 1668
(wCꢀO); 1605, 1592, 1545, (wCꢀC, wCꢀN), 1345 (wNO2);
1H-NMR (DMSO-d6): 3.35 (s, 3H, CH3); 3.57 (s, 3H,
CH3); 4.11 (t, 2H, J=4.2 Hz, CH2); 4.35 (t, 2H, J=5.4
Hz, CH2); 7.95 (s, 1H, C88ꢁH), 8.20 (s, 1H, CꢁHꢁIm).
Anal. C13H15N7O40 (N).
Sodium methoxide (0.012 mol, 2.17 g 30 % methano-
lic solution in 10 mL absolute methanol) was added to
the corresponding imidazole derivative (0.01 mol) dis-
solved in 30 mL absolute methanol. The mixture was
heated under reflux for 1.5 h. Then this solution was
used for obtaining the novel compounds. If necessary
the solvent was removed and imidazole derivative
sodium salt was dissolved in an appropriate solvent to
prepare the novel products.
3.1.5. General procedure for the preparation of
compounds 2a–c and 3
To a solution of fresh prepared imidazole derivative
sodium salt in appropriate anhydrous solvent was added
1b (3.48 g, 0.01 mol) or 1c (2.42 g, 0.01 mol) dissolved
in 20 mL of the same solvent. The reaction mixture was
stirred under reflux. The reaction time was established
by TLC monitoring. Separated sodium halide was
filtered when hot, the filtrate was kept for 12 h at 4 °C.
The crude product was filtered and washed three fold
with methanol to give corresponding compound. If nec-
essary the product was recrystallised from methanol or
ethanol.
3.1.8. 3,7-dimethyl-1-[3-(4(5)-nitro-1H-imidazol-1-yl)-
propyl]-2,3,6,7-tetrahydro-1H-2,6-purinedione (2c)
2c was obtained as described in general method from
4(5)-nitroimidazole sodium salt and 1b for 21 h in
absolute methanol to give 2.0 g (56%). Rf=0.68 (I).
M.p.: 214–217, IR (cm−1) Nujol: 1698 (wCꢀO), 1685
(wCꢀO); 1600, 1590, 1543, (wCꢀC, wCꢀN), 1350 (wNO2);
1H-NMR (DMSO-d6): 2.04–2.15 (m, 2H, CH2); 3.33 (s,
3H, CH3); 3.41 (s, 3H, CH3); 3.91 (t, 2H, J=6.2 Hz,
CH2); 4.11 (t, 2H, J=7 Hz, CH2); 8.01 (s, 1H, C8ꢁH);
8.30 (s, 1H, CꢁH, Im); 8.43 (s, 1H, CꢁH, Im). Anal.
C13H15N7O4 (N).
3.1.6. 3,7-dimethyl-1-[3-(2-methyl-5-nitro-1H-
imidazol-1-yl)-propyl]-2,3,6,7-tetrahydro-
1H-2,6-purinedione (2a)
Compound 2a was prepared from 2-methyl-5-nitroim-
idazole sodium salt and 1b in anhydrous 2-
ethoxyethanol as described above for 6 h. Yield: 2.6 g
(75%). Rf=0.73 (I). M.p.: 230–233 (ethanol). IR
(cm−1) Nujol: 1710 (wCꢀO), 1695 (wCꢀO), 1651, 1610,
3.1.9. N-[1-[3-(3,7-dimethyl-2,6-dioxo-2,3,6,7-
tetrahydro-1H-1-purinyl)propyl]-2,5-dioxo-4-
imidazolidinyl]-urea (3)
Compound 3 was obtained as described above from
N-(2,5-dioxo-4-imidazolidinyl)-urea (allantoine) sodium
salt and 1b for 36 h in absolute methanol. After concen-
tration of the filtrate to minimal volume the separated
solid was filtered and the combined precipitate was
washed with cold methanol. Yield: 1.5 g (40%); Rf=
0.22 (I). M.p.: 194–196 (methanol). IR (cm−1) Nujol:
1
1550 (wCꢀC, wCꢀN), 1344 (wNO2); H-NMR (DMSO-
d6): 2.38 (s, 3H, ꢁCH3); 2.46–2.52 (m, 2H, CH2); 3.21 (s,
3H, CH3); 3.37 (s, 3H, CH3); 4.14 (t, 2H, J=6.5 Hz,
CH2); 4.62 (t, 2H, J=7 Hz, CH2); 7.59 (s, 1H, C8ꢁH);
8.29 (s, 1H, CꢁH, Im). Anal. C14H16N7O4 (N).