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Vol. 61, No. 2
monitored using TLC sheets precoated with UV fluorescent mp 164–165°C; IR (KBr) cm−1: 3398–2360 (O–H and NH2),
1
silica gel Merck 60F 254 using acetone–benzene (1:9) and 1716, 1681 (2C=O); H-NMR (DMSO-d6, 300MHz) δ (ppm):
were visualized using UV lamp.
6.82–6.88 (m, 1H, Ar-H), 7.36–7.50 (m, 1H, Ar-H), 7.52–7.55
The starting material 2-chloronicotinic acid and other (m, 1H, Ar-H), 7.82–7.90 (m, 1H, H5, pyr.), 8.22 (dd, 1H, J=
chemicals were obtained from Aldrich, Fluka, or Merck 5.4, 1.8Hz, H4, pyr.), 8.40 (s, 2H, NH2, D2O exchangeable),
Chemicals.
8.54 (dd, 1H, J=4.5, 1.8Hz, H6, pyr.), 13.79 (br, 1H, O–H,
+
·
General Procedure for 1a–e, 2a,b A mixture of 2-chlo- D2O exchangeable); MS (EI) m/z (% rel. int.): 258 (M , 0.17).
ronicotinic acid (0.157g, 0.01mol), anhydrous K2CO3 (2.76g, Anal. Calcd for C13H10N2O4 (258.23): C, 60.47; H, 3.90; N,
0.02mol) and an appropriate substituted amino compound 10.85; Found: C, 60.33; H, 4.05; N, 10.78.
(0.01mol) in isopropanol (30mL) was heated under reflux for
2-(2-Carbamoylphenylamino)nicotinic Acid (2b): Yield
4h. The reaction mixture was concentrated under reduced 80%; mp 150–151°C; IR (KBr) cm−1: 3429–2400 (O–H and
1
pressure to half its volume then cooled. The separated solid NH2), 1716, 1680 (2C=O); H-NMR (DMSO-d6, 300MHz) δ
was filtered, dried and crystallized from isopropanol.
(ppm): 7.51–7.55 (m, 3H, 2Ar-H, H5, pyr.), 8.13–8.28 (m, 2H,
2-[(2-Bromophenyl)amino]nicotinic Acid (1a): Yield 75%; Ar-H and H4, pyr.), 8.53–8.55 (m, 2H, Ar-H, H6, pyr.), 13.70
mp 187–188°C; IR (KBr) cm−1: 3200–2200 (O–H and NH), (br, 1H, O–H, D2O exchangeable); MS (EI) m/z (% rel. int.):
3097 (C–H aromatic), 1720 (C=O); 1H-NMR (DMSO-d6, 256 (M−H, 67.86), 213 (15.48). Anal. Calcd for C13H11N3O3
300MHz) δ (ppm): 5.54 (s, 1H, NH, D2O exchangeable), (257.24): C, 60.70; H, 4.31; N, 16.33; Found: C, 60.53; H, 4.25;
7.51–7.55 (m, 5H, 4H arom. and H5, pyr.), 8.23 (dd, 1H, J=6.0, N, 16.57.
1.8Hz, H4, pyr.), 8.55 (dd, 1H, J= 4.8, 1.8Hz, H6, pyr.), 13.75
General Procedure for 3a,b A mixture of 3,6-dichlo-
(br, 1H, OH, D2O exchangeable); MS (electron ionization (EI)) ropyridazine (1.49g, 0.01mol), anhydrous K2CO3 (2.76g,
m/z (% rel. int.): 294 (M+2, 0.20), 293 (M+H), 171 (9.30), 0.02mol) and the appropriate substituted amino benzoic acid
157 (100), 122 (5.78), 78 (23.63). Anal. Calcd for C12H9BrN2O2 (1.37g, 0.01mol) in isopropanol (30mL) was heated under
(293.12): C, 49.17; H, 3.09; N, 9.56; Found: C, 49.34 H, 3.25; reflux for 4h. The reaction mixture was concentrated under
N, 9.23.
reduced pressure to half its volume then cooled. The separated
2-[(2,4-Dichlorophenyl)amino]nicotinic Acid (1b): Yield solid was filtered, dried and crystallized from isopropanol.
70%; mp 51–52°C; IR (KBr) cm−1: 3417–2580 (O–H and NH),
3 - [ ( 6 - C h l o r o p y r i d a z i n - 3 - y l ) a m i n o ] b e n z o i c A c i d ( 3a): Yield
3190 (C–H aromatic), 1700 (C=O); 1H-NMR (DMSO-d6, 80%; mp 189–190°C; IR (KBr) cm−1: 3298–2553 (O–H and
1
300MHz) δ (ppm): 5.52 (s, 1H, NH, D2O exchangeable), 6.78 NH), 1685 (C=O); H-NMR (DMSO-d6, 300MHz) δ (ppm):
(d, 1H, Ar-H), 7.08 (d, 1H, Ar-H), 7.26 (s, 1H, Ar-H), 7.51–7.55 6.43 (d, 1H, Ar-H), 6.77–6.81 (m, 2H, Ar-H), 7.06 (d, 1H,
(m, 1H, H5, pyr.), 8.22 (d, 1H, H4, pyr.), 8.55 (d, 1H, H6, pyr.); Ar-H), 7.96 (d, 1H, pyridazine H-4), 8.37 (d, 1H, pyridazine
+
·
MS (EI) m/z (% rel. int.): 286 (M+4, 58.74), 282 (M , 3.72). H-5), 9.80 (s, 1H, NH, D2O exchangeable); MS (EI) m/z (% rel.
+
·
Anal. Calcd for C12H8Cl2N2O2 (283.11): C, 50.91; H, 2.85; N, int.): 251 (M+2, 10.51), 249 (M , 32.00), 248 (M−H, 100).
9.89; Found: C, 50.86; H, 2.98; N, 10.08. Anal. Calcd for C11H8ClN3O2 (249.65): C, 52.92; H, 3.23; N,
2-[(2-Chloropyridin-3-yl)amino]nicotinic Acid (1c): Yield 16.83; Found: C, 52.75; H, 3.45; N, 16.66.
65%; mp 174–175°C; IR (KBr) cm−1: 3452–2360 (O–H and
4 - [ ( 6 - C h l o r o p y r i d a z i n - 3 - y l ) a m i n o ] b e n z o i c A c i d ( 3b): Yield
1
NH), 1720 (C=O); H-NMR (DMSO-d6, 300MHz) δ (ppm): 70%; mp 244–245°C; IR (KBr) cm−1: 3294–2549 (O–H and
1
5.55 (s, 1H, NH, D2O exchangeable), 7.10 (d, 1H, H4, pyr.), NH), 1666 (C=O); H-NMR (DMSO-d6, 300MHz) δ (ppm):
7.51–7.57 (m, 2H, Ar-H), 8.22 (d, 1H, H4, pyr.), 8.53–8.56 (m, 7.27 (d, 2H, Ar-H), 7.64 (d, 2H, Ar-H), 7.81 (d, 1H, pyridazine
2H, H6, pyr.), 13.79 (br, 1H, OH, D2O exchangeable); MS (EI) H-4), 7.92 (d, 1H, pyridazine H-5), 9.91 (s, 1H, NH, D2O ex-
m/z (% rel. int.): 249 (M, 0.19), 251 (M+2, 0.18). Anal. Calcd changeable); MS (EI) m/z (% rel. int.): 251 (M+2, 1.11), 249
+
·
for C11H8ClN3O2 (249.65): C, 52.92; H, 3.23; N, 16.83; Found: (M , 0.92), 248 (M–H, 0.92). Anal. Calcd for C11H8ClN3O2
C, 52.68; H, 3.42; N, 16.98.
(249.65): C, 52.92; H, 3.23; N, 16.83; Found: C, 52.65; H, 3.18;
2-[(4,5-Dihydrothiazol-2-yl)amino]nicotinic Acid (1d): Yield N, 16.78.
50%; mp 110–111°C; IR (KBr) cm−1: 3400–2353 (O–H and
General Procedure for 4a,b A mixture of an appropri-
NH), 1643 (C=O); H-NMR (DMSO-d6, 300MHz) δ (ppm): ate 3a,b (0.5g, 0.002mol) and thiourea (0.23g, 0.003mol) in
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3.45 (t, 2H, J=7.5Hz, CH2), 3.86 (t, 2H, J=7.5Hz, CH2), 5.55 absolute ethanol (20mL) was heated under reflux for 3h. The
(s, 1H, NH, D2O exchangeable), 7.33–7.37 (m, 1H, H5, pyr.), reaction mixture was allowed to cool to room temperature and
7.89 (d, 1H, H4, pyr.), 8.31 (d, 1H, H6, pyr.); MS (EI) m/z (% the excess solvent was removed under diminished pressure.
+
·
rel. int.): 223 (M , 3.86), 224 (M+H, 7.26). Anal. Calcd for The crude isothiouronium salt was combined with sodium
C9H9N3O2S (223.25): C, 48.42; H, 4.06; N, 18.82; Found: C, hydroxide solution (10%, 20mL) and the mixture was heated
48.16; H, 4.25; N, 18.79.
under reflux for 2h. After cooling, the mixture was acidified
2-[(1H-Benzo[d]imidazol-2-yl)amino]nicotinic Acid (1e): with glacial acetic acid, the precipitated orange solid product
Yield 65%; mp 189–190°C; IR (KBr) cm−1: 3290–2588 (O–H was filtered, washed with water and crystallized from ethanol.
and NH), 1681 (C=O); 1H-NMR (DMSO-d6, 300MHz) δ
3-[(6-Sulphanylpyridazin-3-yl)amino]benzoic Acid (4a):
(ppm): 7.07–7.10 (m, 2H, Ar-H), 7.25–7.28 (m, 2H, Ar-H), Yield 50%; mp 149–150°C; IR (KBr) cm−1: 3444–2650 (O–H
7.39–7.43 (m, 1H, H5, pyr), 8.24 (s, 2H, 2NH, D2O exchange- and NH), 1681 (C=O), ; 1H-NMR (DMSO-d6, 300MHz) δ
able), 8.01 (dd, 1H, J=6.0, 1.8Hz, H4, pyr.), 8.37 (dd, 1H, J= (ppm): 7.05–7.91 (m, 4H, Ar-H), 7.99 (d, 1H, pyridazine H-4),
+
·
4.8, 1.8Hz, H6, pyr.); MS (EI) m/z (% rel. int.): 254 (M , 8.10 (d, 1H, pyridazine H-5), 8.98 (s, 1H, NH or SH, D2O ex-
0.92). Anal. Calcd for C13H10N4O2 (254.24): C, 61.41; H, 3.96; changeable), 9.55 (s, 1H, NH or SH, D2O exchangeable); MS
+
·
N, 22.04; Found: C, 61.25; H, 3.77; N, 21.96.
(EI) m/z (% rel. int.): 247 (M , 20.97), 246 (M−H, 20.14).
2-(2-Carbamoylphenoxy)nicotinic Acid (2a): Yield 85%; Anal. Calcd for C11H9N3O2S (247.27): C, 53.43; H, 3.67; N,