P. Crepaldi et al. / Bioorg. Med. Chem. 17 (2009) 4612–4621
4619
7.49 (m, 1H); /.57-/.60 (m, 2H); 8.08–8.12 (m, 1H); IR (KBr): 3398,
1720, 1360, 1180 cmꢀ1. Anal. Calcd for C12H12ClN3O4S2: C, 39.83;
H, 3.34; N, 11.61; S, 17.72. Found: C, 39.85; H, 3.32; N, 11.61; S, 17.71.
(s, 1H); 7.33 (d, 2H, J = 8 Hz); 7.88 (d, 2H, J = 8 Hz); IR (KBr): 3450,
3215, 1350, 1172 cmꢀ1. Anal. Calcd for C16H21N3O3S2: C, 52.29; H,
5.76; N, 11.43; S, 17.45. Found: C, 52.30; H, 5.76; N, 11.42; S, 17.43.
5.4.6. 5-Dimethylamino-naphtalene-1-sulfonic 6-amino-2-(2-
hydroxy-ethylsulfanyl)-pyrimidin-4-yl ester (5f)
5.4.14. 2-Chloro-benzensulfonic acid 6-amino-2-pentylpyrimidin-
4-yl ester (5n)
Yellow oil, 77% yield; 1H NMR (CDCl3) d: 2.83 (br s, 1H); 2.73 (t,
2H, J = 6 Hz); 2.85 (s, 6H); 3.48 (t, 2H, J = 6 Hz), 5.49 (br s, 2H); 5.81
(s, 1H); 7.18 (d, 2H, J = 8 Hz); 7.48–7.63 (m, 4H); 8.24–8.30 (m,
4H); 8.60 (d, 2H, J = 8 Hz); IR (KBr): 3456, 3230, 1720, 1356,
1180 cmꢀ1. Anal. Calcd for C18H20N4O4S2: C, 51.41; H, 4.79; N,
13.32; S, 15.25. Found: C, 51.44; H, 4.76; N, 13.32; S, 15.26.
Yield: 67%, foam: ; 1H NMR (DMSO-d6)d:0.84(t, 3H, J = 6 Hz); 1.18–
1.38 (m, 6H); 2.87–2-89 (m, 2H); 5.87 (s, 1H), 7.37 (br s, 2H); 7.7.58–
7.63 (m, 2H); 7.80–7.82 (m, 2H); 8.15–8.17 (m, 1H); IR (KBr): 3432,
3278, 1358, 1180 cmꢀ1. Anal. Calcd for C15H18ClN3O3S2: C, 46.44; H,
4.68; N, 10.83; S, 16.53. Found: C, 46.42; H, 4.70; N, 10.83; S, 16.53.
5.5. General procedure for the synthesis of 6b,c
5.4.7. Toluene-4-sulfonic acid 6-amino-2-(2,2,2-trifluoro-
ethylsulfanyl)-pyrimidin-4-yl ester (5g)
A solution of compounds 5b,c (1.25 mmol) in CF3COOH (3 mL)
was stirred at room temperature for 40 min. Then, the solvent
was removed and the residue was dissolved in water (5 mL) neu-
tralized with saturated NaHCO3 solution, and extracted with ethyl
acetate (10 mL ꢁ 3). The organic layer, dried with Na2SO4, was
evaporated to furnish the compounds 6b,c.
Yield: 71%, mp: 133–136 °C; 1H NMR (CDCl3) d: 2.45 (s, 3H);
3.57 (q, 2H, J = 10 Hz); 5.23 (br s, 2H); 5.95 (s, 1H); 7.35 (d, 2H,
J = 8 Hz); 7.87 (d, 2H, J = 8 Hz); IR (KBr): 3450, 3220, 1360,
1170 cmꢀ1. Anal. Calcd for C13H12F3N3O3S2: C, 41.16; H, 3.19; N,
11.08; S, 16.90. Found: C, 41.15; H, 3.20; N, 11.08; S, 16.87.
5.4.8. 2-Chloro-benzensulfonic acid 6-amino-2-(2,2,2-trifluoro-
ethylsulfanyl)-pyrimidin-4-yl ester (5h)
5.5.1. Toluene-4-sulfonic acid 6-amino-2-(2-amino-
ethylsulfanyl)-pyrimidin-4-yl ester (6b)
Yield: 62%, mp: 119–121 °C; 1H NMR (CDCl3) d: 3.42 (q, 2H,
J = 10 Hz); 5.26 (br s, 2H); 5.98 (s, 1H); 7.54–7.57 (m, 1H); 7.60–
7.62 (m, 2H); 8.09–8.13 (m, 1H); IR (KBr): 3400, 3230, 1360,
1180 cmꢀ1. Anal. Calcd for C12H9ClF3N3O3S2: C, 36.05; H, 2.27; N,
10.51; S, 16.04. Found: C, 36.02; H, 2.30; N, 10.51; S, 16.05.
Yield: 87%, mp: 104–106 °C 1H NMR (DMSO-d6) d: 2.43 (s, 3H);
2.63 (t, 2H, J = 8 Hz); 2.78 (t, 2H, J = 8 Hz); 3.35 (br s,2H); 5.82
(s,1H); 7.31 (br s,2H); 7.50 (d, 2H,J = 8 Hz); 7.86 (d, 2H, J = 8 Hz);
IR (KBr): 3560, 3450, 3220, 1360, 1183 cmꢀ1. Anal. Calcd for
C13H16N4O3S2: C, 45.87; H, 4.74; N, 16.46; S, 18.84. Found: C,
45.86; H, 4.74; N, 16.47; S, 18.81.
5.4.9. 5-Dimethylamino-naphtalene-1-sulfonic acid 6-amino-2-
(2,2,2-trifluoro-ethylsulfanyl)-pyrimidin-4-yl ester (5i)
Yield: 65%, mp: 163–165 °C; 1H NMR (CDCl3) d: 2.90 (s, 6H);
3.34 (q, 2H, J = 10 Hz); 5.10 (br s, 2H); 5.96 (s, 1H); 7.24 (d, 1H,
J = 7 Hz); 7.52–7.67 (m, 2H); 8.28–8.35 (m, 2H); 8.66 (d, 1H, J =
7 Hz); IR (KBr): 3450, 3225, 1350, 1170 cmꢀ1. Anal. Calcd for
C18H17F3N4O3S2: C, 47.15; H, 3.74; N, 12.22; S, 13.99. Found: C,
47.15; H, 3.75; N, 12.24; S, 13.99.
5.5.2. 5-Dimethylamino-naphtalene-1-sulfonic acid 6-amino-2-
(2-amino-ethylsulfanyl)-pyrimidin-4-yl ester (6c)
Yield: 86%, mp: 144–146 °C; 1H NMR (CDCl3) d: 2.80 (s, 6H);
2.81–2.98 (m, 4H); 5.18 (br s, 2H); 5.69 (s, 1H); 5.85 (br s, 2H);
7.12 (d, 1H, J = 8 Hz); 7.42–7.57 (m, 2H); 8.21 (d, 2H, J = 8 Hz);
8.54 (d, 2H, J = 8 Hz); IR (KBr): 3564, 3449, 3220, 1365,
1178 cmꢀ1. Anal. Calcd for C18H21N5O3S2: C, 51.53; H, 5.05; N,
16.69; S, 15.29. Found: C, 51.52; H, 5.06; N, 16.69; S, 15.27.
5.4.10. Toluene-4-sulfonic acid 6-amino-2-(2-chloro
benzylsulfanyl)-pyrimidin-4-yl ester (5j)
5.6. Synthesis of 6-hydroxy-2-mercapto-3H-pyrimidin-4-one (8)
Yield: 68%, foam; 1H NMR (DMSO-d6) d: 2.35 (s, 3H); 4,10 (s,
2H); 5.87 (s, 1H); 7.25–7.30 (m, 2H); 7.42–7.49 (m, 6H); 7.86 (d,
2H, J = 8 Hz); IR (KBr): 3430, 3280, 1358, 1180 cmꢀ1. Anal. Calcd
for C18H16ClN3O3S2: C, 51.24; H, 3.82; N, 9.96; S, 15.20. Found: C,
51.25; H, 3.81; N, 9.98; S, 15.20.
The thiourea (1) (1 g, 0.013 mol) and diethyl malonate (7)
(1.97 mL, 0.013 mol) were added to a freshly prepared solution of
sodium ethylate (Na 0.3 g, 0.013 mol, in EtOH, 20 mL).
The mixture was refluxed for 3 h, then the precipitate was fil-
tered off. The solid was dissolved in water (10 mL), the pH adjusted
around 7–8, and the resulted precipitate was filtered.
5.4.11. 2-Chloro-benzensulfonic acid 6-amino-2-(2-chloro
benzylsulfanyl)-pyrimidin-4-yl ester (5k)
White solid (67% yield, mp >300 °C); 1H NMR (DMSO-d6) d: 3.34
(s, 1H); 4.10 (s, 1H); 10.46 (br s, 2H); IR (KBr): 3390, 3334, 1690,
1320 cmꢀ1. Anal. Calcd for C4H4N2O2S: C, 33.33; H, 2.80; N,
19.43; S, 22.24. Found: C, 33.36; H, 2.80; N, 19.40; S, 22.23.
Yield: 43%, foam; 1H NMR (DMSO-d6) d: 3.92 (s, 2H); 5.91 (s,
1H); 7.23–7.81 (m, 8H); 8.08–8.12 (m, 2H); IR (KBr): 3435, 3282,
1358, 1180 cmꢀ1. Anal. Calcd for C17H13Cl2N3O3S2: C, 46.16; H,
2.96; N, 9.50; S, 14.50. Found: C, 46.15; H, 2.97; N, 9.50; S, 14.47.
5.7. Synthesis of 6-hydroxy-2-(2-chloro benzylsulfanyl)-3H-
pyrimidin-4-one (9)
5.4.12. 5-Dimethylamino-naphtalene-1-sulfonic acid 6-amino-
2-(2-chloro benzylsulfanyl)-pyrimidin-4-yl ester (5l)
Yield: 51%, foam; 1H NMR (CDCl3) d: 2.76 (s, 6H); 3.75 (s, 2H);
5.09 (br s, 2H); 5.89 (s, 1H); 6.90–6.92 (m, 2H); 7.03–7.27 (m,
3H); 7.48–7.62 (m, 2H); 8.27–8.34 (m, 2H); 8.56–8.59 (m, 1H); IR
To a solution of compound 8 (0.3 g, 2 mmol) in 20 mL of NaOH
0.1 M in CH3OH, the 2-chlorobenzyl chloride (0.66 mL, 5 mmol)
was added, and the solution was stirred for 2.5 h at room temper-
ature. Then the solvent was removed and the residue was washed
with water (10–15 mL) and filtered to furnish the right compound.
Yield: 68% mp >300 °C; 1H NMR (DMSO-d6) d: 3.35 (br s, 2H);
4.21 (s, 1H); 4.32 (s, 2H); 7.25–7.27 (m, 2H); 7.41–7.43 (m, 1H);
7.46–7.60 (m, 1H); IR (KBr): 3390, 3334, 1690, 1320 cmꢀ1. Anal.
Calcd for C11H9ClN2O2S: C, 49.17; H, 3.38; N, 10.42; S, 11.93.
Found: C, 49.15; H, 3.40; N, 10.42; S, 11.93.
(KBr): 3445, 3220, 1350, 1170 cmꢀ1
.
Anal. Calcd for
C23H21ClN4O3S2: C, 55.14; H, 4.22; N, 11.18; S, 12.80. Found: C,
55.13; H, 4.23; N, 11.18; S, 12.80.
5.4.13. Toluene-4-sulfonic acid 6-amino-2-pentyl-pyrimidin-4-
yl ester (5m)
Yield: 71%, foam; 1H NMR (CDCl3) d: 0.87 (t, 3H, J = 6 Hz); 1.19–
1.42 (m, 6H); 2.44 (s, 3H); 2.82 (t, 2H, J = 8 Hz)); 5.09 (br s, 2H); 5.87