P. Reigan et al. / European Journal of Medicinal Chemistry 43 (2008) 1248e1260
1257
and POCl3 (15 ml, 160.9 mmol, 16 eq) was stirred for 1 h with
heating at reflux. Excess POCl3 was removed under vacuum
then dichloromethane (200 ml) and iced water (100 ml) were
added and the mixture stirred until the black solid dissolved.
The organic layer was separated, washed with bicarbonate so-
lution, dried over MgSO4 and then evaporated to dryness in
vacuo. The yellow residue was recrystallized (1:1, v/v, tolu-
ene/hexane) to give pure 30 as fine colourless needles
(1.02 g, 65.6%). TLC Rf 0.68 (4:1, EtOAc/hexane); m.pt.
NH2), 10.42 (1H, s, N1eH); 13C NMR (DMSO-d6) d: 14.8
(CH3), 63.1 (CH2), 85.1 (C20eH), 99.8 (C-5), 145.2 (C10e
H), 145.4 (C-6) 160.7 (C-2), 163.7 (C-4); MS: (APCIþ) 182
(M þ H, 100%), (APCIꢃ) 180 (M ꢃ H, 100%).
4.2.8. 7H-Pyrrolo[2,3-d]pyrimidin-2(1H )-one (16)
A solution of (Z )-6-amino-5-(2-ethoxyethenyl)-1H-pyrimi-
din-2-one (0.50 g, 2.76 mmol, 1 eq) and concentrated HCl
(3.0 ml) in water (20 ml) was heated at reflux for 30 min.
The solution was evaporated and the residue was made alka-
line (pH w 9) with aqueous 20% K2CO3 and extracted with
EtOAc (2 ꢂ 75 ml). The solvent was removed by distillation
under reduced pressure and the resulting precipitate was col-
lected by filtration, washed serially with water and ethanol,
and vacuum-dried to provide the title compound 16 as a beige
powder (0.37 g, 85.0%). TLC Rf 0.54 (4:1, EtOAc/MeOH);
m.pt. 159e160 ꢀC; 1H NMR (DMSO-d6) d: 6.46 (1H, d,
1
186e188 ꢀC, m.pt. [31] 188e190 ꢀC; H NMR (DMSO-d6)
3
d: 6.62 (1H, d, JHH ¼ 3.2 Hz, C5eH), 7.71 (1H, d,
3JHH ¼ 3.2 Hz, C6eH), 8.60 (1H, s, C2eH), 12.58 (1H, s,
N7eH); 13C NMR (DMSO-d6) d: 98.7 (C-5), 116.5 (C-9),
128.3 (C-6), 150.2 (C-8), 150.4, (C-2), 151.7 (C-4); MS:
(APCIþ) 154 (35Cl Mþ, 20%), (APCIꢃ) 152 (35Cl Mꢃ,
100%). Elemental analysis: C6H4ClN3, calculated (%): C
46.93, H 2.63, N 27.36, Cl 23.09. Found (%): C 47.39, H
2.32, N 26.41, Cl 23.54.
3
3JHH ¼ 3.3 Hz, C5eH), 7.04 (1H, d, JHH ¼ 3.3 Hz, C6eH),
8.47 (1H, s, C4eH), 11.80 (1H, s, N1eH), 11.85 (1H, s,
N7eH); 13C NMR (DMSO-d6) d: 101.7 (C-5), 107.6 (C-9),
120.3 (C-6), 143.1 (C-8), 148.0 (C-2), 158.4 (C-4); IR:
1710 cmꢃ1 (C]O), 3450 cmꢃ1 (NeH); MS: (APCIþ) 136
(M þ H, 100%), (APCIꢃ) 134 (M ꢃ H, 100%). Elemental
analysis: C6H5N3O, calculated (%): C 53.33, H 3.73, N
31.10. Found (%): C 53.08, H 3.56, N 30.51.
4.2.6. 7H-Pyrrolo[2,3-d]pyrimidine (17)
7H-Pyrrolo[2,3-d]pyrimidine was prepared by an adapta-
tion of a known procedure [31]. A solution of 4-chloro-7H-
pyrrolo[2,3-d]pyrimidine (0.12 g, 0.8 mmol, 1 eq) in ethanol
(20 ml) and concentrated aqueous NH3 (0.5 ml, 6.6 mmol,
8.25 eq) and 10% Pd/C (0.04 g) was stirred in a H2 atmosphere
for 6 h at room temperature. The catalyst was removed by fil-
tration and the solvent was evaporated. The residue was
washed with H2O, filtered and dried under high vacuum giving
the title compound 17 as a fine colourless powder (0.08 g,
83.7%). TLC Rf 0.62 (4:1, EtOAc/MeOH); m.pt. 129e
130 ꢀC, m.pt. [31] 131e133 ꢀC; 1H NMR (DMSO-d6) d:
4.2.9. 6H-Imidazo[1,2-c]pyrimidin-5-one (24)
Chloroacetaldehyde (50%, v/v, solution in water, 1.4 ml,
10.8 mmol, 1.2 eq) was added dropwise to a stirred mixture
of 6-amino-1H-pyrimidin-2-one (1.0 g, 9.0 mmol, 1 eq) in
DMF (6.0 ml) at 50 ꢀC. A colour change of white to pink
was observed after the addition of chloroacetaldehyde. The re-
action mixture was heated at 50 ꢀC for 12 h. The solvent was
removed by distillation under reduced pressure and the result-
ing precipitate was collected by filtration, washed serially with
ethanol and ether, and dried to provide the title compound 24
as a beige powder (0.91 g, 74.7%). TLC Rf 0.45 (4:1, EtOAc/
3
6.61 (1H, d, JHH ¼ 3.5 Hz, C5eH), 7.59 (1H, d,
3JHH ¼ 3.5 Hz, C6eH), 8.77 (1H, s, C4eH), 9.02 (1H, s,
C2eH), 12.26 (1H, s, N7eH); 13C NMR (DMSO-d6) d: 99.3
(C-5), 118.1 (C-9), 127.2 (C-6), 148.7 (C-8), 150.7, (C-2),
151.0 (C-4); IR: 3450 cmꢃ1 (NeH); MS: (APCIþ) 120
(M þ H, 100%). Elemental analysis: C6H5N3, calculated
(%): C 60.50, H 4.23, N 35.27. Found (%): C 59.26, H 5.29,
N 34.16.
1
MeOH); m.pt. 278.0e278.5 ꢀC, m.pt. [29] 272e274 ꢀC; H
3
NMR (DMSO-d6) d: 6.87 (1H, d, JHH ¼ 7.4 Hz, C8eH),
3
7.79 (1H, d, JHH ¼ 7.4 Hz, C7eH), 7.92 (1H, d,
3
4.2.7. (Z )-6-Amino-5-(2-ethoxyethenyl)-1H-pyrimidin-
2-one (32)
3JHH ¼ 2.2 Hz, C3eH), 8.10 (1H, d, JHH ¼ 2.2 Hz, C2eH),
12.72 (1H, br s, N6eH); 13C NMR (DMSO-d6) d: 93.7 (C-3),
115.0 (C-7), 123.8 (C-2), 138.8 (C-8), 145.6 (C-9), 145.9
(C-5); IR: 1720 cmꢃ1 (C]O), 3340 cmꢃ1 (NeH); MS:
(ESþ) 136 (M þ H, 60%), (ESꢃ) 134 (M ꢃ H, 100%). Ele-
mental analysis: C6H5N3O, calculated (%): C 53.33, H 3.73,
N 31.10. Found (%): C 53.15, H 3.67, N 30.96.
A
mixture of 6-amino-5-bromo-1H-pyrimidin-2-one
(0.95 g, 5.0 mmol, 1 eq), (Z )-1-ethoxy-2-(tributylstannyl)e-
thene (2.17 g, 6.0 mmol, 1.2 eq), tetraethylammonium chlo-
ride (0.92 g, 5.0 mmol, 1 eq) and PdCl2(PPh3)2 (140 mg,
0.2 mmol, 0.04 eq) in DMF (20 ml) was heated at reflux for
5 h. The reaction mixture was reduced to dryness in vacuo,
giving a brown coloured residue and purified by fractionation
through a short silica gel column (4:1, v/v, EtOAc/hexane), the
required fractions were pooled and evaporated, recrystalliza-
tion from ethanol gave compound 32 as a beige powder
(0.58 g, 64.0%). TLC Rf 0.49 (4:1, EtOAc/MeOH); m.pt.
89.5e90 ꢀC; 1H NMR (DMSO-d6) d: 1.27 (3H, t,
J ¼ 7.2 Hz, eCH2eCH3), 4.07 (2H, q, J ¼ 7.2 Hz, CH2e
4.2.10. 5-Chloro-6-methyl-3H-pyrimidin-4-one (35)
A
mixture of 6-methyl-3H-pyrimidin-4-one (5.0 g,
45.4 mmol, 1 eq) in glacial AcOH (100 ml) was heated to
80 ꢀC until the solid dissolved. The mixture was cooled to
60 ꢀC and NCS (6.67 g, 49.9 mmol, 1.1 eq) was added. The re-
action mixture was heated at reflux for 5 h. The reaction mix-
ture was evaporated to dryness in vacuo, the residue was
treated with a minimum amount of water and placed in the re-
frigerator at 5 ꢀC overnight. A colourless precipitate formed
3
CH3), 5.28 (1H, d, JHH ¼ 7.0 Hz, C10eH), 6.42 (1H, d,
3JHH ¼ 7.0 Hz, C20eH), 7.50 (1H, s, C4eH), 6.48 (2H, s,