V.K. Vyas et al. / European Journal of Medicinal Chemistry 82 (2014) 385e393
391
(Mþ2H)þ; 1H NMR (600 MHz, DMSO-d6)
d
11.29 (s, 1H, eOH), 10.41
AreH), 7.42 (m, 1H, AreH), 7.22 (d, 1H, J ¼ 8.4 Hz, AreH), 7.13 (t, 2H,
J ¼ 7.2 Hz, AreH), 6.83 (d,1H, J ¼ 8.4 Hz, AreH), 6.58 (d,1H, J ¼ 7.8 Hz,
AreH), 5.90 (s, 1H, AreH), 3.35 (d, 1H, J ¼ 6.9 Hz, eCH3), 3.11 (s, 3H,
(s, 1H, eNH), 7.79 (d, 1H, J ¼ 7.8 Hz, AreH), 7.42 (m, 1H, AreH), 7.22
(d, 1H, J ¼ 7.8 Hz, AreH), 7.15 (t, 2H, J ¼ 7.2 Hz, AreH), 7.09 (d, 1H,
J ¼ 7.8 Hz, AreH), 6.80 (m, 2H, AreH), 6.55 (d, J ¼ 7.8 Hz, 2H, AreH),
2.98 (s, 3H, CH3); 176.71 (2C), 171.29, 166.87, 163.35, 159.58, 157.17,
151.17,146.92,143.13,139.71,135.78 (2C),124.13 (2C),124.06,121.79,
121.71, 121.42, 121.17, 117.63, 108.75 (2C) 13.91, 11.24; Anal. Calcd for
eCH3); 13C NMR (100 MHz, DMSO)
d 211.38, 184.98, 162.2, 160.1,
159.7, 157.57, 151.38, 149.03, 136.36, 136.24 (2C), 131.1 (2C), 124.9
(2C), 121.56, 116.02, 115.97, 114.99, 111.91 (2C), 104.33, 13.93, 11.26;
Anal. Calcd for C25H17F3N2O3: C, 66.67; H, 3.80; F, 12.65; N, 6.22; O,
10.66 Found C, 66.62; H, 3.83; F, 12.63; N, 6.18; O, 10.62.
C
24H14F6N2O2: C, 60.51; H, 2.96; F, 23.93; N, 5.88; O, 6.72 Found C,
60.43; H, 2.92; F, 23.91; N, 5.82; O, 6.68.
4.1.4.2. 6-Ethyl-3-methyl-2-[(3,30,5-trifluorobiphenyl-4-yl)carba-
moyl]quinoline-4-carboxylic acid (19). Compound 19 was synthe-
sized according to the synthetic procedure given above as white
solid in yield of 40.32%, mp 230e232 ꢀC; FT-IR (cmꢁ1) 3348.23
(COOH); ESI-MS m/z 465.1 (MþH)þ, 466.9 (Mþ2H)þ; 1H NMR
4.1.3.8. N-biphenyl-4-yl-4-hydroxy-6-methoxy-3-methylquinoline-
2-carboxamide (14). Compound 14 was synthesized according to
the synthetic procedure given above as white solid in yield of
54.42%, mp 256e258 ꢀC; FT-IR (cmꢁ1) 3322.75 (NH), 1699.94 (C]
O); ESI-MS m/z 385.6 (MþH)þ, 386.5 (Mþ2H)þ; 1H NMR (400 MHz,
(400 MHz, DMSO-d6) d 10.97 (s,1H, eCOOH), 9.55 (s,1H, eNH), 7.21
DMSO-d6)
d
10.23 (s, 1H, eOH), 9.66 (s, 1H, eNH), 8.15 (d, 2H,
(m, 3H, AreH), 7.13 (m, 3H, AreH), 6.95 (m, 3H, AreH), 4.44 (q,
J ¼ 7.2 Hz, 3H, eC2H5) 2.22 (s, 3H, eCH3), 1.38 (t, 2H, J ¼ 6.8 Hz,
J ¼ 8.8 Hz, AreH), 8.07 (m, 2H, AreH), 7.61 (m, 2H, AreH), 7.43 (d,
2H, J ¼ 8.8 Hz, AreH), 7.29 (d, 1H, J ¼ 8.8 Hz, AreH), 6.89 (d, 3H,
J ¼ 8.8 Hz, AreH), 6.75 (t, J ¼ 8.8 Hz, 1H, AreH), 4.74 (d, 1H,
J ¼ 8.8 Hz, eOCH3), 2.50 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6)
eC2H5); 13C NMR (100 MHz, DMSO-d6)
d 211.4, 185.1, 179.1, 173.4,
172.7, 169.9(2C), 168.6, 153.6, 150.1, 138.1, 135.3, 132.0, 130.8,
123.5(2C), 119.5, 117.9, 117.3(2C), 112.5, 112.3, 111.4, 104.4, 32.12,
13.56; Anal. Calcd for C26H19F3N2O3: C, 67.24; H, 4.12; F, 12.27; N,
6.03; O, 10.33 Found C, 67.20; H, 4.09; F, 12.30; N, 6.01; O, 10.28.
d
178.8, 174.0, 170.0, 165.0, 161.6, 159.6, 152.7, 150.5, 142.5, 136.5,
135.6, 133.7, 130.1, 129.6, 128.4, 122.5, 122.3, 118.8, 116.01, 111.04,
109.39, 21.13; Anal. Calcd for C24H20N2O3 C, 74.98; H, 5.24; N, 7.29;
O, 12.49 Found: C, 74.94; H, 5.22; N, 7.22; O, 12.44.
4.1.4.3. 6-Fluoro-3-methyl-2-[(3,30,5-trifluorobiphenyl-4-yl)carba-
moyl]quinoline-4-carboxylic acid (20). Compound 20 was synthe-
sized according to the synthetic procedure given above as
yellowish-white solid in yield of 43.81%, mp 241e243 ꢀC; FT-IR
4.1.3.9. N-biphenyl-4-yl-4-hydroxy-3-methylquinoline-2-
carboxamide (15). Compound 15 was synthesized according to the
synthetic procedure given above as white solid in yield of 58.18%,
mp 246e248 ꢀC; FT-IR (cmꢁ1) 3325.64 (OH), 1647.88 (C]O); ESI-
MS m/z 355.1 (MþH)þ, 356.1 (Mþ2H)þ; 1H NMR (400 MHz,
(cmꢁ1
)
3384.23 (COOH); ESI-MS m/z 456.1 (MþH)þ, 457.2
(Mþ2H)þ; 1H NMR (600 MHz, DMSO-d6)
d 11.52 (s, 1H, eCOOH),
9.11 (s, 1H, eNH), 8.31 (d, 1H, J ¼ 7.2 Hz, AreH), 7.75 (d, 1H,
J ¼ 7.8 Hz, AreH), 7.41 (d, 2H, J ¼ 4.2 Hz, AreH), 7.22 (d, 1H,
J ¼ 16.8 Hz, CH), 7.13 (t, 2H, J ¼ 5.4 Hz, AreH), 6.95 (d, 1H, J ¼ 3.0 Hz,
CH), 6.65 (d, 1H, J ¼ 3.0 Hz, CH), 3.64 (s, 3H, CH3); 13C NMR
DMSO-d6)
d 10.107 (s, 1H, eOH), 8.37 (s, 1H, eNH), 8.25 (d, 1H,
J ¼ 7.5 Hz, AreH), 7.94 (m, 3H, AreH), 7.53 (t, 2H, J ¼ 8 Hz, AreH),
7.46 (t, 3H, J ¼ 7.5 Hz, AreH), 7.32 (m, AreH), 3.37 (s, 3H, CH3); 13
C
NMR (100 MHz, DMSO-d6):
d
163.6, 160.2, 151.5, 142.8, 137.1 (2C),
(100 MHz, DMSO-d6): d 211.56, 176.83 (2C) 171.09, 167.87, 163.24,
136.8, 132.9, 129.8, 128.6, 128.5, 128.3, 127.3, 125.7, 125.3, 125.1,
122.9, 119.7, 115.0, 114.7 (2C), 110.3, 14.4; Anal. Calcd for
157.30, 151.89, 148.89, 144.07, 137.68, 136.15, 131.07, 125.97, 123.47
(2C), 121.71, 118.58, 115.77, 108.77(2C), 13.92; Anal. Calcd for
C
23H18N2O2: C, 77.95; H, 5.12; N, 7.90; O, 9.03 Found C, 77.91; H,
C24H14F4N2O : C, 63.44; H, 3.11; F, 16.72; N, 6.17; O, 10.56 Found C,
5.13; N, 7.85; O, 9.01.
63.41; H, 3.12; F, 16.98; N, 6.19; O, 10.55.
4.1.4. General procedure for the synthesis of 6-substituted-4-
carboxylicacidquinoline-2-carboxamide derivatives (18e26)
4.1.4.4. 6-Ethoxy-3-methyl-2-[(3,30,5-trifluorobiphenyl-4-yl)carba-
moyl]quinoline-4-carboxylic acid (21). Compound 21 was synthe-
sized according to the synthetic procedure given above as
yellowish-white solid in yield of 47.56%, mp 215e217 ꢀC; FT-IR
In a cooled (0e5 ꢀC) solution of 7e15 (0.0047 mol) and trie-
thylamine (TEA) (0.014 mol) in toluene under inert environment
triflic anhydride (Tf2O) (0.009 mol) was added drop wise, stirred at
room temperature for 36e42 h. Reaction mixture was treated with
NaHCO3 solution and extracted with chloroform, which afforded
(cmꢁ1
)
3362.12 (COOH); ESI-MS m/z 480.0 (MþH)þ, 481.0
(Mþ2H)þ; 1H NMR (400 MHz, DMSO-d6)
d 12.03 (s, 1H, eCOOH),
10.40 (s, 1H, eNH) 7.40 (m, 3H, AreH), 7.39 (t, J ¼ 7.2 Hz, 2H, AreH),
7.37 (m, 2H, AreH), 7.28 (m, 2H, AreH), 4.45 (q, J ¼ 7.2 Hz, 3H,
eC2H5) 2.23 (s, 3H, eCH3), 1.38 (t, 2H, J ¼ 8 Hz, eC2H5); 13C NMR
quinoline triflates (16aei).
A mixture of quinoline triflate
(0.002 mol), Zn(CN)2 (0.004 mol), Pde(Ph3P)4 (0.00016 mol), in
DMF was stirred at 150 ꢀC for 20e24 h. After cooling, saturated
sodium carbonate and water were added, and mixture was
extracted with ethylacetate, washed with brine and dried over
anhydrous sodium sulfate, which afforded 17aei. In 4-cyano
quinoline derivatives (17aei) (0.0011 mol), 10% solution of NaOH
was added and reflux gently for 1e2 h. After cooling, 6 M HCl with
stirring was added until the solution become acidic and precipita-
tion of residue was complete. The residues were collected by vac-
uum filtration and washed with cold water. Finally, the compounds
(18e26) were subjected to silica column chromatography.
(100 MHz, DMSO-d6)
d 211.4, 185.1, 180.4, 172.7, 169.1, 165.4, 163.2,
158.1, 155.3, 153.2, 140.0, 138.6, 132.1, 130.0 (2C), 121.7 (2C), 113.4,
113.1, 108.3,105.2,103.5,102.9,102.5, 26.12, 32.12, 13.41; Anal. Calcd
for C26H19F3N2O4 C, 65.00; H, 3.99; F, 11.86; N, 5.83; O, 13.32 Found
C, 65.04; H, 3.96; F, 11.84; N, 5.80; O, 13.28.
4.1.4.5. 6-Methoxy-3-methyl-2-[(3,30,5-trifluorobiphenyl-4-yl)carba-
moyl]quinoline-4-carboxylic acid (22). Compound 22 was synthe-
sized according to the synthetic procedure given above as
yellowish-white solid in yield of 45.86%, mp 210e212 ꢀC; FT-IR
(cmꢁ1
)
3321.80 (COOH); ESI-MS m/z 466.0 (MþH)þ, 466.9
4.1.4.1. 3,6-Dimethyl-2-[(3,30,5-trifluorobiphenyl-4-yl)carbamoyl]
quinoline-4-carboxylic acid (18). Compound 18 was synthesized
according to the synthetic procedure given above as white solid, in
yield of 42.61%, mp 213e215 ꢀC; FT-IR (cmꢁ1) 3340.13 (COOH); ESI-
MS m/z 450.1 (MþH)þ, 451.9 (Mþ2H)þ; 1H NMR (600 MHz, DMSO-
(Mþ2H)þ; 1H NMR (600 MHz, DMSO-d6)
d 11.01 (s, 1H, eCOOH),
9.39 (s, 1H, eNH), 8.30 (d, 1H, J ¼ 7.8 Hz, AreH), 7.79 (d, 1H,
J ¼ 7.8 Hz, AreH), 7.42 (m,1H, AreH), 7.22 (d,1H, J ¼ 10.8 Hz, AreH),
7.12 (t, 1H, J ¼ 7.2 Hz, AreH), 7.01 (d, 1H, J ¼ 3.6 Hz, AreH), 6.82 (d,
1H, J ¼ 7.8 Hz, CH), 3.54 (d, 3H, J ¼ 7.2 Hz, eOCH3), 2.91 (s, 3H,
d6)
d
11.31 (s, 1H, eCOOH), 10.13 (s, 1H, eNH), 7.75 (d, 1H, J ¼ 7.8 Hz,
eCH3); 13C NMR (100 MHz, DMSO-d6)
d 211.56, 176.75(2C), 163.36,