Journal of Medicinal Chemistry
Article
NMR (40 MHz, DMSO-d6): δ 12.182 (s, 1H, SO2NH), 10.875 (s, 1H,
CONH), 8.206−7.755 (m, 4H, ArH), 7.224 (s, 1H, Prim-H), 4.343 (q,
J = 6.8 Hz, 2H, OCH2), 3.978 (s, 3H, OCH3), 1.287 (t, J = 6.8 Hz, 3H,
CH2CH3). 13C NMR (400 MHz, DMSO-d6): δ 168.555, 166.377,
155.468, 148.165, 135.846, 134.112, 132.075, 131.326, 130.935,
129.293, 129.014, 112.318, 61.983, 54.616, 13.836. HRMS (MALDI,
m/z): C15H16IN4O6S (M + H+) calcd 506.9830, found 506.9836.
Ethyl 2-(N-((4-Bromo-6-methoxypyrimidin-2-yl)carbamoyl)-
sulfamoyl)benzoate (10d). Yield: 0.85 g (64%), starting from 2.89
42.098. HRMS (MALDI, m/z): C15H15Cl2N4O6S (M + H+) calcd
449.0084, found 449.0082.
2-Iodoethyl 2-(N-((4-Chloro-6-methoxypyrimidin-2-yl)-
carbamoyl)sulfamoyl)benzoate (10j). Yield: 1.42 g (70%), starting
from 3.75 mmol of 5 and 3.75 mmol of 7. White solid. Mp: 148−150
°C. 1H NMR (400 MHz, DMSO-d6): δ 11.997 (s, 1H, SO2NH),
10.907 (s, 1H, CONH), 8.224−7.833 (m, 4H, ArH), 6.896 (s, 1H,
Pyrim-H), 4.528 (t, J = 6.4 Hz, 2H, COOCH2), 4.025 (s, 3H, OCH3),
3.474 (t, J = 6.4 Hz, 2H, CH2I). 13C NMR (400 MHz, DMSO-d6): δ
168.795, 164.081, 158.281, 154.509, 146.370, 134.411, 132.531,
129.823, 129.744, 129.483, 127.947, 99.609, 64.231, 53.410, 0.0000.
HRMS (ESI, m/z): C15H15ClIN4O6S (M + H+) calcd 540.9440, found
540.9439.
2-Chloroethyl 2-(N-((4-Iodo-6-methoxypyrimidin-2-yl)-
carbamoyl)sulfamoyl)benzoate (10k). Yield: 1.06 g (70%),
starting from 2.79 mmol of 3 and 2.79 mmol of 9. White solid. Mp:
165−167 °C. 1H NMR (400 MHz, DMSO-d6): δ 12.210 (s, 1H,
SO2NH), 10.843 (s, 1H, CONH), 8.221−7.806 (m, 4H, ArH), 7.228
(s, 1H, Pyrim-H), 4.554 (t, J = 4.2 Hz, 2H, COOCH2), 3.971 (s, 3H,
OCH3), 3.936 (t, J = 4.2 Hz, 2H, CH2Cl). 13C NMR (400 MHz,
DMSO-d6): δ 168.552, 165.982, 155.465, 148.211, 136.175, 134.154,
131.456, 131.348, 131.236, 129.522, 128.975, 112.283, 65.605, 54.630,
42.163. HRMS (ESI, m/z): C15H15IClN4O6S (M + H+) calcd
540.9440, found 540.9451.
2-Chloroethyl 2-(N-((4-Bromo-6-methoxypyrimidin-2-yl)-
carbamoyl)sulfamoyl)benzoate (10l). Yield: 0.66 g (67%), starting
from 2.00 mmol of 3 and 2.00 mmol of 8. White solid. Mp: 152−154
°C. 1H NMR (400 MHz, DMSO-d6): δ 12.031 (s, 1H, SO2NH),
10.933 (s, 1H, CONH), 8.221−7.804 (m, 4H, ArH), 7.042 (s, 1H,
Pyrim-H), 4.535 (t, J = 5.2 Hz, 2H, COOCH2), 4.006 (s, 3H, OCH3),
3.926 (t, J = 5.2 Hz, 2H, CH2Cl). 13C NMR (400 MHz, DMSO-d6): δ
169.770, 165.990, 155.909, 151.229, 148.051, 136.112, 134.216,
131.477, 131.416, 131.172, 129.608, 105.217, 65.597, 54.993, 42.126.
HRMS (ESI, m/z): C15H15BrClN4O6S (M + H+) calcd 492.9579,
found 492.9579.
1
mmol of 2 and 2.89 mmol of 8. White solid. Mp: 167−169 °C. H
NMR (400 MHz, DMSO-d6): δ 11.996 (s, 1H, SO2NH), 10.932 (s,
1H, CONH), 8.206−7.766 (m, 4H, ArH), 7.048 (s, 1H, Prim-H),
4.333 (q, J = 6.8 Hz, 2H, OCH2), 4.024 (s, 3H, OCH3), 1.290 (t, J =
6.8 Hz, 3H,CH2CH3). 13C NMR (400 MHz, DMSO-d6): δ 169.776,
166.408, 155.925, 151.215, 148.067, 135.847, 134.136, 132.006,
131.327, 130.984, 129.361, 105.221, 61.978, 54.976, 13.778. HRMS
(MALDI, m/z): C15H16BrN4O6S (M + H+) calcd 458.9968, found
458.9963.
Methyl 2-(N-((4-Iodo-6-methoxypyrimidin-2-yl)carbamoyl)-
sulfamoyl)benzoate (10e). Yield: 0.30 g (52%), starting from 1.19
1
mmol of 1 and 1.19 mmol of 9. White solid. Mp: 150−152 °C. H
NMR (400 MHz, DMSO-d6): δ 12.178 (s, 1H, SO2NH), 10.846 (s,
1H, CONH), 8.190−7.768 (m, 4H, ArH), 7.220 (s, 1H, Pyrim-H),
3.965 (s, 3H, COOCH3), 3.857 (s, 3H, Pyrim-OCH3). 13C NMR (400
MHz, DMSO-d6): δ 168.597, 166.884, 155.483, 148.126, 135.810,
134.142, 131.787, 131.400, 131.008, 129.356, 128.962, 112.299,
54.642, 53.216. HRMS (MALDI, m/z): C14H14IN4O6S (M + H+)
calcd 492.9673, found 492.9665.
Methyl 2-(N-((4-Chloro-6-methoxypyrimidin-2-yl)-
carbamoyl)sulfamoyl)benzoate (10f). Yield: 0.44 g (58%), starting
from 1.88 mmol of 1 and 1.88 mmol of 7. White solid. Mp: 159−161
°C. 1H NMR (400 MHz, DMSO-d6): δ 11.983 (s, 1H, SO2NH),
10.914 (s, 1H, CONH), 8.200−7.760 (m, 4H, ArH), 6.895 (s, 1H,
Pyrim-H), 4.023 (s, 3H, COOCH3), 3.841 (s, 3H, Pyrim-OCH3). 13
C
NMR (400 MHz, DMSO-d6): δ 170.507, 166.918, 159.914, 156.206,
148.041, 135.815, 134.191, 131.722, 131.384, 131.080, 129.447,
101.295, 55.091, 53.090. HRMS (MALDI, m/z): C14H14ClN4O6S
(M + H+) calcd 401.0317, found 401.0311.
Methyl 2-(N-((4-Bromo-6-methoxypyrimidin-2-yl)-
carbamoyl)sulfamoyl)benzoate (10m). Yield: 1.26 g (84%),
starting from 3.28 mmol of 2 and 3.28 mmol of 8. White solid. Mp:
1
141−143 °C. H NMR (400 MHz, DMSO-d6): δ 12.008 (br, 1H,
2-Bromoethyl 2-(N-((4-Iodo-6-methoxypyrimidin-2-yl)-
carbamoyl)sulfamoyl)benzoate (10g). Yield: 1.0 g (54%), starting
from 3.17 mmol of 4 and 3.17 mmol of 9. White solid. Mp: 165−167
°C. 1H NMR (400 MHz, DMSO-d6): δ 12.201 (s, 1H, SO2NH),
10.843 (s, 1H, CONH), 8.212−7.807 (m, 4H, ArH), 7.222 (s, 1H,
Pyrim-H), 4.602 (t, J = 5.6 Hz, 2H, COOCH2), 3.959 (s, 3H, OCH3),
3.773 (t, J = 5.6 Hz, 2H,CH2Br). 13C NMR (400 MHz, CDCl3): δ
168.545, 165.844, 155.441, 148.143, 136.118, 134.185, 131.489,
131.383, 131.187, 129.561, 129.016, 112.287, 65.328, 54.632, 30.156.
HRMS (MALDI, m/z): C15H15IBrN4O6S (M + H+) calcd 584.8930,
found 584.8935.
2-Bromoethyl 2-(N-((4-Chloro-6-methoxypyrimidin-2-yl)-
carbamoyl)sulfamoyl)benzoate (10h). Yield: 0.7g (56%), starting
from 2.51 mmol of 4 and 2.51 mmol of 7. White solid. Mp: 170−172
°C. 1H NMR (400 MHz, DMSO-d6): δ 12.013 (s, 1H, SO2NH),
10.920 (s, 1H, CONH), 8.226−7.821 (m, 4H, ArH), 6.893 (s, 1H,
Pyrim-H), 4.594 (t, J = 5.6 Hz, 2H, COOCH2), 4.023 (s, 3H, OCH3),
3.775 (t, J = 5.6 Hz, 2H, CH2Br). 13C NMR (400 MHz, DMSO-d6): δ
170.430, 165.882, 159.998, 156.179, 148.054, 136.114, 134.219,
131.510, 131.445, 131.109, 129.646, 101.278, 65.309, 55.074, 30.079.
HRMS (MALDI, m/z): C15H15ClBrN4O6S (M + H+) calcd 492.9579,
found 492.9573.
2-Chloroethyl 2-(N-((4-Chloro-6-methoxypyrimidin-2-yl)-
carbamoyl)sulfamoyl)benzoate (10i). Yield: 1.07 g (85%), starting
from 2.80 mmol of 3 and 2.80 mmol of 7. White solid. Mp: 167−169
°C. 1H NMR (400 MHz, DMSO-d6): δ 12.019 (br, 1H,
SO2NH),10.927 (s, 1H, CONH), 8.240−7.832 (m, 4H, ArH), 6.870
(s, 1H, Pyrim-H), 4.545 (t, J = 5.2 Hz, 2H, COOCH2), 4.028 (s, 3H,
OCH3), 3.930 (t, J = 5.2 Hz, 2H, CH2Cl). 13C NMR (400 MHz,
DMSO-d6): δ 170.410, 165.986, 160.008, 156.175, 148.057, 136.099,
134.211, 131.489, 131.417, 131.138, 129.622, 101.271, 65.579, 55.063,
SO2NH), 10.926 (s, 1H, CONH), 8.219−7.765 (m, 4H, ArH), 7.032
(s, 1H, Pyrim-H), 4.017 (s, 3H, COOCH3), 3.858(s, 1H, Pyrim-
OCH3). 13C NMR (400 MHz, DMSO-d6): δ 168.703, 165.778,
154.802, 150.017, 146.890, 134.667, 133.063, 130.610, 130.274,
129.939, 128.305, 104.100, 53.884,52.003. HRMS (ESI, m/z):
C14H14BrN4O6S (M + H+) calcd 444.9812, found 444.9820.
2-Bromoethyl 2-(N-((4-Bromo-6-methoxypyrimidin-2-yl)-
carbamoyl)sulfamoyl)benzoate (10n). Yield: 0.87 g (60%),
starting from 2.69 mmol of 4 and 2.69 mmol of 8. White solid. Mp:
154−156 °C. 1H NMR (400 MHz, DMSO-d6): δ 12.031 (s, 1H,
SO2NH), 10.899 (s, 1H, CONH), 8.226−7.817 (m, 4H, ArH), 7.026
(s, 1H, Pyrim-H), 4.602 (t, J = 5.6 Hz, 2H, COOCH2), 4.008 (s, 3H,
OCH3), 3.780 (t, J = 5.6 Hz, 2H, CH2Br). 13C NMR (400 MHz,
DMSO-d6): δ 169.766, 165.894, 155.926, 151.211, 148.110, 136.191,
134.163, 131.477, 131.409, 131.130, 129.595, 105.176, 65.309, 54.984,
30.107. HRMS (ESI, m/z): C15H15Br2N4O6S (M + H+) calcd
536.9074, found 536.9066.
2-((tert-Butyldimethylsilyl)oxy)ethyl 2-(N-((4-Chloro-6-me-
thoxypyrimidin-2-yl)carbamoyl)sulfamoyl)benzoate (10o).
Yield: 0.99 g (48%), starting from 3.80 mmol of 6 and 3.80 mmol
of 7. White solid. Mp: 154−156 °C. 1H NMR (400 MHz, DMSO-d6):
δ 12.019 (s, 1H, SO2NH), 10.945 (s, 1H, CONH), 8.236−7.772 (m,
4H, ArH), 6.916 (s, 1H, Pyrim-H), 4.343 (t, J = 4.4 Hz, 2H,
COOCH2), 4.044 (s, 3H, OCH3), 3.867 (t, J = 4.4 Hz, 2H, CH2OSi),
0.805 (s, 9H, C(CH3)3), 0.000 (s, 6H, Si(CH3)2). 13C NMR (400
MHz, DMSO-d6): δ 170.445, 166.222, 159.991, 156.206, 148.059,
136.063, 134.127, 131.593, 131.564, 131.257, 129.464, 101.247,
66.935, 60.594, 55.052, 25.594, 17.806, −5.476. HRMS (ESI, m/z):
C21H30ClN4O7SSi (M + H+) calcd 545.1288, found 545.1289.
2-((tert-Butyldimethylsilyl)oxy)ethyl 2-(N-((4-Bromo-6-me-
thoxypyrimidin-2-yl)carbamoyl)sulfamoyl)benzoate (10p).
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dx.doi.org/10.1021/jm301501k | J. Med. Chem. 2013, 56, 210−219