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Y. Isobe et al. / Bioorg. Med. Chem. 11 (2003) 4933–4940
tography. Monitoring of reaction was carried out by
using Merck 60 F254 silica gel, glass-supported TLC
plates, and visualization with UV light (254 and 365
nm).
s), 3.81 (3H, s), 3.74 (3H, s), 3.08 (3H, s). (4u) 6.78–6.98
(3H, m), 5.05 (1H, s), 4.76 (1H, tt, J=5.0, 5.0 Hz), 3.89
(3H, s), 3.33 (3H, s), 1.76–1.95 (6H, m), 1.60–1.67 (2H,
m). (4v) 7.79–7.82 (1H, m), 7.48–7.56 (2H, m), 6.43(2H,
s), 4.81 (1H, s), 3.09 (3H, s).
Chemistry
5,6-Diamino-3-ethyl-1-phenyluracil (5b). To a suspen-
sion of 4b (696 mg, 3mmol) and sodium nitrite (280 mg,
4 mmol) in water (20 mL) was added and 12 N HCl (0.3
mL). After 2 h of stirring, the reaction mixture was
neutralized to pH 7 with 10% NaOH solution, and the
resulting red-violet solid was collected (700 mg). To a
suspension of this solid (700 mg) in MeOH (30 mL) was
added 5% Pd/C (50 mg). After 1 h of stirring under a
H2 atmosphere, the catalyst was removed by filtration,
and the filtrate was concentrated. The residue was tri-
turated with ethyl acetate, and the resulting solid was
filtered to give 5b (652 mg, 88%) as a pale yellow solid.
1H NMR (DMSO-d6) d 7.50–7.56 (4H, m), 7.31–7.35
(3H, m), 5.34 (2H, s), 3.82 (2H, q, J=6.8 Hz), 1.08 (3H,
t, J=6.8 Hz); MS (TOF) m/z 247 (M+H)+.
6-Amino-3-ethyl-1-phenyluracil (4b). A suspension of N-
ethyl-N-phenylurea (820 mg, 5 mmol), cyanoacetic acid
(638 mg, 7.5 mmol) and acetic anhydride (1 mL) in ethyl
acetate (20 mL) was refluxed for 4 h, and was con-
centrated. Water (20 mL) was added to the residue, and
adjusted to pH 10 with 3N NaOH solution. After 6 h of
stirring, neutralized to pH 7 with 1N HCl solution, and
the resulting precipitate was collected to give 4b (950
mg, 78%) as a white solid. 1H NMR (DMSO-d6) d
7.49–7.57 (3H, m), 7.31–7.35 (2H, m), 6.09 (2H, brs),
4.80 (1H, s), 3.75 (2H, q, J=6.8 Hz), 1.06 (3H, t, J=6.8
Hz); MS (TOF) m/z 232 (M+H)+.
Compounds 4c–v were also prepared by using the same
1
procedure as for 4b. H NMR data (DMSO-d6: d) of
these compounds are shown below.
Compounds 5a–v and 10 were also prepared by using
1
the same procedure as for 5b. H NMR data (DMSO-
d6: d) of these compounds are shown below.
(4c) 7.46–7.56 (3H, m), 7.31–7.34 (2H, m), 6.10 (2H,
brs), 4.80 (1H, s), 3.67 (2H, t, J=7.3Hz), 1.49 (2H, dq,
J=7.3, 7.6 Hz), 0.82 (3H, t, J=7.3Hz), ( 4d) 7.46–7.57
(3H, m), 7.30–7.34 (2H, m), 6.09 (2H, brs), 4.79 (1H, s),
3.71 (2H, t, J=7.0 Hz), 1.41–1.52 (2H, m), 1.24 (2H, tt,
J=7.0, 7.4 Hz), 0.87 (3H, t, J=7.0 Hz). (4e) 7.48–7.56
(3H, m), 7.29–7.33 (2H, m), 6.10 (2H, brs), 4.70 (1H, s),
3.77 (2H, t, J=6.8 Hz), 1.45–1.56 (2H, m), 1.20–1.33
(4H, m), 1.19–1.26 (2H, m), 0.85 (3H, t, J=6.8 Hz). (4f)
7.48–7.56 (3H, m), 7.29–7.32 (2H, m), 6.05 (2H, brs),
4.64 (1H, tt, J=8.6, 5.9 Hz), 2.18–2.31 (2H, m), 1.60–
1.76 (2H, m), 1.46–1.60 (3H, m), 0.96–1.26 (3H, m). (4g)
7.38–7.44 (1H, m), 7.29–732 (1H, m), 7.09–7.14 (2H, m),
6.09 (2H, brs), 4.80 (1H, s), 3.08 (3H, s), 2.35 (3H, s).
(4h) 7.42 (1H, t, J=8.0 Hz), 7.04–7.08 (1H, m), 6.87–
6.95 (2H, m), 6.13 (2H, brs), 4.80 (1H, s), 3.78 (3H, s),
3.08 (3H, s). (4i) 7.35–7.47 (2H, m), 7.22–7.24 (1H, m),
7.07–7.11 (1H, m), 6.17 (2H, brs), 4.80 (1H, s), 3.08 (3H,
s), 2.49 (3H, s). (4j) 7.51–7.59 (3H, m), 7.31–7.35 (1H,
m), 6.25 (2H, brs), 4.80 (1H, s), 3.08 (3H, s). (4k) 7.64–
7.72 (2H, m), 7.45–7.51 (1H, m), 7.37 (1H, d, J=8.4
Hz), 6.24 (2H, brs), 4.80 (1H, s), 3.08 (3H, s). (4l) 7.31–
7.49 (6H, m), 7.11–7.15 (1H, m), 6.91–6.94 (2H, m), 5.08
(2H, s), 5.03 (1H, s), 4.40 (2H, brs), 3.32 (3H, s). (4m)
7.23–7.35 (3H, m), 7.15 (1H, d, J=3.8 Hz), 6.04 (2H,
brs), 4.73 (1H, s), 3.01 (3H, s), 1.97 (3H, s). (4n) 7.45–
7.52 (1H, m), 7.18–7.27 (2H, m), 7.03–7.09 (1H, m), 6.10
(2H, brs), 4.78 (1H, s), 3.76 (3H, s), 3.07 (3H, s). (4o)
7.46–7.48 (1H, m), 7.21–7.29 (2H, m), 7.07–7.09 (1H,
m), 6.13(2H, brs), 4.80 (1H, s), 4.09 (2H, q, J=6.8 Hz),
3.10 (3H, s), 1.23 (3H, t, J=6.8 Hz). (4p) 7.45–7.54 (3H,
m), 7.30–7.36 (1H, m), 6.14 (2H, brs), 4.80 (1H, s), 3.09
(3H, s), 2.42 (3H, s). (4q) 7.65–7.69 (1H, m), 7.47–7.58
(3H, m), 6.30 (2H, brs), 4.82 (1H, s), 3.09 (3H, s). (4r)
7.81–7.83 (1H, m), 7.45–7.55 (3H, m), 6.30 (2H, brs),
4.82 (1H, s), 3.10 (3H, s). (4s) 7.14–7.24 (2H, m), 6.84–
6.88 (1H, m), 6.19 (2H, brs), 4.78 (1H, s), 3.87 (3H, s),
3.70 (3H, s), 3.08 (3H, s). (4t) 7.05 (1H, d, J=8.1 Hz),
6.94 (1H, s), 6.82–6.86 (1H, m), 6.14 (2H, brs), 4.80 (1H,
(5a) 7.25–7.55 (7H, m), 5.34 (2H, s), (5c) 7.49–7.56 (3H,
m), 7.31–7.34 (2H, m), 5.35 (2H, brs), 3.74 (2H, t,
J=7.3Hz), 1.53(2H, m), 0.84 (3H, t, J=7.3Hz). ( 5d)
7.46–7.56 (2H, m), 7.30–7.38 (3H, m), 5.34 (2H, brs),
3.77 (2H, t, J=7.3Hz), 1.37–1.58 (2H, m), 1.19–1.27
(2H, m), 0.88 (3H, t, J=7.3Hz). ( 5e) 7.49-7.57 (3H, m),
7.30–7.34 (2H, m), 5.34 (2H, brs), 3.77 (2H, t, J=6.8
Hz), 1.46–1.56 (2H, m), 1.21–1.33 (4H, m), 1.19–1.27
(2H, m), 0.85 (3H, t, J=6.8 Hz). (5f) 7.24–7.77 (7H, m),
6.56 (2H, brs), 4.65 (1H, m), 2.25 (2H, m), 1.51–1.80
(5H, m), 1.15–1.28 (3H, m). (5g) 7.32–7.42 (4H, m), 7.14
(2H, m), 5.34 (2H, brs), 3.19 (3H, s), 2.36 (3H, s). (5h)
9.51 (2H, brs), 7.46 (1H, t, J=8.4 Hz), 7.08–7.12 (1H,
m), 6.92–7.01 (4H, m), 3.78 (3H, s), 3.17 (3H, s). (5i)
9.35 (2H, brs), 7.39–7.51 (2H, m), 7.29–7.30 (1H, m),
7.12–7.18 (1H, m), 6.89 (2H, brs), 3.14 (3H, s), 2.50 (3H,
s). (5j) 9.46 (2H, brs), 7.55–7.63 (3H, m), 7.36–7.39 (1H,
m), 7.05 (2H, s), 3.17 (3H, s). (5k) 7.69–7.71 (2H, m),
7.47–7.51 (1H, m), 7.37–7.39 (1H, m), 5.54 (2H, s), 3.17
(3H, s). (5l) 7.36–7.49 (6H, m), 6.90–7.06 (3H, m), 5.42
(2H, s), 5.11 (2H, s), 3.16 (3H, s). (5m) 9.52 (2H, s),
7.29–7.47 (4H, m), 6.99 (2H, s), 3.19 (3H, s), 2.08 (3H,
s). (5n) 9.50 (2H, s), 7.50–7.53 (1H, m), 7.23–7.33 (2H,
m), 7.08–7.12 (1H, m), 7.03 (2H, s), 3.77 (3H, s), 3.17
(3H, s). (5o) 9.49 (2H, s), 7.47–7.50 (1H, m), 7.22–7.32
(2H, m), 7.08–7.10 (1H, m), 7.00 (2H, s), 4.09 (2H, q,
J=7.0 Hz), 3.18 (3H, s), 1.22 (3H, t, J=7.0 Hz). (5p)
9.58 (2H, s), 7.48–7.57 (2H, m), 7.32–7.38 (2H, m), 7.10
(2H, s), 3.18 (3H, s), 2.44 (3H, s). (5q) 9.58 (2H, s), 7.85–
7.89 (1H, m), 7.46–7.58 (2H, m), 7.13 (2H, s), 3.17 (3H,
s). (5r) 9.59 (2H, s), 7.84–7.87 (1H, m), 7.49–7.62 (3H,
m), 7.27 (2H, s), 3.20 (3H, s). (5s) 7.11–7.23(3H, m),
6.79–6.87 (2H, m), 5.44 (2H, brs), 3.87 (3H, s), 3.66
(3H, s), 3.15 (3H, s). (5t) 6.81–6.98 (3H, m), 3.80 (3H,
s), 3.72 (3H, s), 3.32 (3H, s). (5u) 9.46 (2H, s), 7.09
(2H, s), 6.78–6.98 (3H, m), 5.05 (1H, s), 4.76 (1H, tt,
J=5.0, 5.0 Hz), 3.89 (3H, s), 3.33 (3H, s), 1.76–1.95