JOURNAL OF CHEMICAL RESEARCH 2010 73
(d, J = 13.6 Hz, 1H), 8.46 (d, J = 13.6 Hz, 1H), 7.16 (t, J = 7.6 Hz,
2H), 6.96–6.87 (m, 5H), 4.34–4.22 (m, 8H), 2.65 (q, J = 7.6 Hz, 2H),
2.22 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H), 1.19
(t, J = 7.2 Hz, 3H); IR (KBr, cm-1) 3438, 2976, 2932, 1685, 1640,
1614, 1589, 1500, 1456, 1409, 1380, 1346, 1235, 1121, 1034, 993,
946, 881, 802, 755, 618, 584. HR-MS (ESI): Calcd for C25H32NO6
(MH+): 442.2224; Found: 442.2229.
Diethyl {3-methyl-4-[2-(4-methylphenoxy)ethoxy]phenyl}amino-
methylenemalonate (8e): Yellow solid; yield: 83%; m.p. 90–92 °C;
1H NMR spectrum (400 MHz; d6-CDCl3; TMS): δ (ppm) = 10.96
(d, J = 14.0 Hz, 1H), 8.44 (d, J = 14.0 Hz, 1H), 7.10 (d, J = 7.6 Hz,
2H), 6.94 (d, J = 12.0 Hz, 2H), 6.86 (d, J = 7.6 Hz, 3H), 4.33–4.22
(m, 8H), 2.30 (s, 3H), 2.24 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H), 1.33
(t, J = 7.2 Hz, 3H); IR (KBr, cm-1) 3444, 2925, 1683, 1638, 1611,
1586, 1510, 1445, 1404, 1383, 1346, 1276, 1231, 1120, 1030, 936,
801, 619, 509. HR-MS (ESI): Calcd for C24H30NO6 (MH+): 428.2068;
Found: 428.2069.
Ethyl 4-hydroxy-7-methyl-6-[2-(2-methylphenoxy)ethoxy]quinoline-
3-carboxylate (3c): Yellow solid; yield: 67%; m.p. 228–231 °C;
1H NMR spectrum (400 MHz; d6-DMSO; TMS): δ (ppm) = 12.20 (d,
J = 6.4 Hz, 1H), 8.44 (d, J = 6.4 Hz, 1H), 7.60 (s, 1H), 7.41 (s, 1H),
7.18–7.13 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H),
4.41 (d, J = 9.6 Hz, 4H), 4.20 (q, J = 7.2 Hz, 2H), 2.27 (s, 3H), 2.13
(s, 3H), 1.28 (t, J = 7.2 Hz, 3H); IR (KBr, cm−1) 3433, 3166, 3046,
2923, 1708, 1620, 1586, 1530, 1481, 1382, 1294, 1246, 1186, 1155,
1123, 1092, 1038, 900, 803, 747, 730, 623; HR-MS (ESI): Calcd for
C22H24NO5 (MH+): 382.1654; Found: 382.1654. HPLC: Rt = 6.0 min;
Purity: 100%
Ethyl 4-hydroxy-7-ethyl-6-[2-(2-methylphenoxy)ethoxy]quinoline-
3-carboxylate (3d): Ivory-white solid; yield: 65%; m.p. 224–225 °C;
1H NMR spectrum (400 MHz; d6-DMSO; TMS): δ (ppm) = 12.20 (d,
J = 6.8 Hz, 1H), 8.45 (d, J = 7.2 Hz, 1H), 7.61 (s, 1H), 7.41 (s, 1H),
7.18–7.13 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H),
4.41 (dd, J1 = 5.2 Hz, J2 = 4.8 Hz, 4H), 4.20 (q, J = 7.2 Hz, 2H), 2.68
(q, J = 7.2 Hz, 2H), 2.13 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.18 (t,
J = 7.6 Hz, 3H); IR (KBr, cm−1) 3430, 3061, 2967, 2919, 1699, 1620,
1587, 1535, 1475, 1384, 1291, 1248, 1188, 1150, 1245, 1087, 1038,
943, 886, 807, 749, 694; HR-MS (ESI): Calcd for C23H26NO5 (MH+):
396.1811; Found: 396.1807. HPLC: Rt = 5.9 min; Purity: 100%
Ethyl 4-hydroxy-7-methyl-6-[2-(4-methylphenoxy)ethoxy]quinoline-
Diethyl {3-ethyl-4-[2-(4-methylphenoxy)ethoxy]phenyl}amino-
methylenemalonate (8f): Brown solid; yield: 83%; m.p. 94–96 °C; 1H
NMR spectrum (400 MHz; d6-CDCl3; TMS): δ (ppm) = 10.99 (d,
J = 13.6 Hz, 1H), 8.46 (d, J = 13.6 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H),
6.94 (d, J = 6.0 Hz, 2H), 6.86 (d, J = 8.0 Hz, 3H), 4.33–4.22 (m, 8H),
2.64 (q, J = 7.6 Hz, 2H), 2.30 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H), 1.33
(t, J = 7.2 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H); IR (KBr, cm-1) 3433,
2975, 2933, 1684, 1643, 1613, 1586, 1509, 1456, 1407, 1383, 1262,
1229, 1114, 1034, 949, 874, 798, 619. HR-MS (ESI): Calcd for
C25H NO (MH+): 442.2224; Found: 442.2229.
1
3-carboxylate (3e): Yellow solid; yield: 63%; m.p. 226–228 °C; H
NMR spectrum (400 MHz; d -DMSO; TMS): δ (ppm) = 12.20 (s,
1H), 8.44 (s, 1H), 7.58 (s, 1H),67.41 (s, 1H), 7.10 (d, J = 8.4 Hz, 2H),
6.90 (d, J = 8.4 Hz, 2H), 4.36 (dd, J1 = J2 = 5.2 Hz, 4H), 4.20 (q,
J = 7.2 Hz, 2H), 2.27 (s, 3H), 2.24 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); IR
(KBr, cm−1) 3427, 3167, 3043, 2922, 1708, 1619, 1586, 1531, 1481,
1450, 1382, 1294, 1245, 1184, 1154, 1092, 1039, 945, 900, 802, 745,
701, 622; HR-MS (ESI): Calcd for C22H NO5 (MH+): 382.1654;
Found: 382.1646. HPLC: Rt = 6.0 min; Puri2ty4 : 100%
Ethyl 4-hydroxy-7-ethyl-6-[2-(4-methylphenoxy)ethoxy]quinoline-
3-carboxylate (3f): Buff solid; yield: 70%; m.p. 225–227 °C; 1H NMR
spectrum (400 MHz; d6-DMSO; TMS): δ (ppm) = 12.20 (d, J = 6.8
Hz, 1H), 8.45 (d, J = 6.4 Hz, 1H), 7.58 (s, 1H), 7.41 (s, 1H), 7.09
(d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 4.37 (dd, J1 = 4.8 Hz,
J2 = 4.4 Hz, 4H), 4.20 (q, J = 7.2 Hz, 2H), 2.67 (q, J = 7.2 Hz, 2H),
2.33 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H); IR
(KBr, cm−1) 3419, 2921, 2852, 1712, 1621, 1584, 1532, 1477, 1390,
1295, 1245, 1182, 1151, 1093, 1042, 939, 902, 804, 620; HR-MS
(ESI): Calcd for C H NO5 (MH+): 396.1811; Found: 396.1804.
HPLC: Rt = 6.0 min;23Pu2r6ity: 100%
Di3e2thyl6{3-methyl-4-[2-(4-fluorophenoxy)ethoxy]phenyl}amino-
1
methylenemalonate (8g): Buff solid; yield: 82%; m.p. 87–88 °C; H
NMR spectrum (400 MHz; d -CDCl ; TMS): δ (ppm) = 10.96 (d,
J = 14.0 Hz, 1H), 8.44 (d, J = 164.0 Hz,31H), 7.01–6.84 (m, 7H), 4.33–
4.22 (m, 8H), 2.23 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H), 1.33 (t, J = 7.2 Hz,
3H); IR (KBr, cm−1) 3436, 2984, 2924, 1682, 1637, 1612, 1586, 1509,
1448, 1402, 1381, 1346, 1228, 1122, 1032, 849, 826, 800, 748, 619,
512. HR-MS (ESI): Calcd for C23H27FNO6 (MH+): 432.1817; Found:
432.1820.
Diethyl {3-ethyl-4-[2-(4-fluoro-phenoxy)ethoxy]phenyl}amino-
1
methylenemalonate (8h): Buff solid; yield: 81%; m.p. 92–94 °C; H
NMR spectrum (400 MHz; d -CDCl ; TMS): δ (ppm) = 10.98 (d,
J = 14.0 Hz, 1H), 8.45 (d, J = 164.0 Hz,31H), 7.01–6.85 (m, 7H), 4.33–
4.22 (m, 8H), 2.63 (q, J = 7.6 Hz, 2H), 1.38 (t, J = 7.6 Hz, 3H), 1.33
(t, J = 7.6 Hz, 3H), 1.18 (t, J = 7.6 Hz, 3H); IR (KBr, cm−1) 3436,
2979, 2931, 2866, 1692, 1655, 1615, 1508, 1456, 1410, 1384, 1347,
1269, 1235, 1111, 946, 834, 799, 748, 619. HR-MS (ESI): Calcd for
C24H29FNO6 (MH+): 446.1973; Found: 446.1975.
Ethyl 4-hydroxy-7-methyl-6-[2-(4-fluoro-phenoxy)ethoxy]quinoline-
1
3-carboxylate (3g): Yellow solid; yield: 68%; m.p. 239–240 °C; H
NMR spectrum (400 MHz; d -DMSO; TMS): δ (ppm) = 12.20 (d,
J = 6.4 Hz, 1H), 8.44 (d, J = 66.4 Hz, 1H), 7.58 (s, 1H), 7.41 (s, 1H),
7.13 (t, J = 8.8 Hz, 2H), 7.03 (t, J = 8.4 Hz, 2H), 4.38 (s, 4H), 4.20 (q,
J = 6.8 Hz, 2H), 2.26 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H); IR (KBr, cm−1)
3425, 3162, 2922, 2854, 1701, 1620, 1584, 1531, 1508, 1481, 1450,
1383, 1295, 1253, 1208, 1186, 1155, 1095, 1038, 900, 827, 803, 750,
700, 620; HR-MS (ESI): Calcd for C H21FNO5 (MH+): 386.1404;
Found: 386.1402. HPLC: Rt = 5.9 min; 2P1urity: 100%
General procedure for preparation of 3a–h
Diphenyl ether (10 ml) was heated to 260 °C and compounds 5a–h
(3 g) were added. The reaction mixture was stirred at 255 °C for 6–9
minutes, and then cooled to room temperature. Petroleum ether
(50 mL) was added to the mixture and the obtained solid was filtrated,
washed with petroleum ether and dried. The yields of the products
3a–h were 60–75 %. The physical and spectra data of the compounds
3a–h are as follows.
Ethyl 4-hydroxy-7-ethyl-6-[2-(4-fluoro-phenoxy)ethoxy]quinoline-
3-carboxylate (3h): Ivory-white solid; yield: 72%; m.p. 232–235 °C;
1H NMR spectrum (400 MHz; d6-DMSO; TMS): δ (ppm) = 12.20
(d, J = 6.8 Hz, 1H), 8.45 (d, J = 6.8 Hz, 1H), 7.59 (s, 1H), 7.41
(s, 1H), 7.15–7.11 (m, 2H), 7.04–7.00 (m, 2H), 4.38 (s, 4H), 4.20
(q, J = 7.2 Hz, 2H), 2.66 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H),
1.17 (t, J = 7.2 Hz, 3H); IR (KBr, cm−1) 3430, 3166, 2966, 2877, 1694,
1617, 1584, 1552, 1531, 1507, 1477, 1389, 1335, 1292, 1249, 1183,
1148, 1093, 1038, 936, 901, 807, 755, 695, 625; HR-MS (ESI): Calcd
for C22H FNO (MH+): 400.1560; Found: 400.1556. HPLC: Rt = 5.9
min; Pur2i3ty: 1050%
Ethyl4-hydroxy-7-methyl-6-(2-phenoxyethoxy)quinoline-3-carboxy-
late (3a): Yellow solid; yield: 62%; m.p. 230–232 °C; 1H NMR
spectrum (400 MHz; d6-DMSO; TMS): δ (ppm) = 12.20 (d, J = 6.8
Hz, 1H), 8.44 (d, J = 6.8 Hz, 1H), 7.59 (s, 1H), 7.41 (s, 1H),
7.33–7.29 (m, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.95 (t, J = 7.2 Hz, 1H),
4.41–4.39 (m, 4H), 4.20 (q, J = 7.2 Hz, 2H), 2.26 (s, 3H), 1.28
(t, J = 7.2 Hz, 3H); IR (KBr, cm−1) 3432, 3035, 2921, 2846, 1705,
1621, 1586, 1529, 1481, 1383, 1295, 1247, 1184, 1154, 1091, 1038,
939, 897, 803, 751, 694, 620; HR-MS (ESI): Calcd for C21H22NO5
(MH+): 368.1498; Found: 368.1508. HPLC: Rt = 6.0 min; Purity:
100%
Ethyl 4-hydroxy-7-ethyl-6-(2-phenoxyethoxy)quinoline-3-carboxy-
late (3b): Buff solid; yield: 65%; m.p. 226–228 °C; 1H NMR spectrum
(400 MHz; d6-DMSO; TMS): δ (ppm) = 12.20 (d, J = 6.4 Hz, 1H),
8.45 (d, J = 6.4 Hz, 1H), 7.59 (s, 1H), 7.41 (s, 1H), 7.30
(t, J = 7.6 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 6.94 (t, J = 7.2 Hz, 1H),
4.40 (s, 4H), 4.20 (q, J = 7.2 Hz, 2H), 2.66 (q, J = 7.2 Hz, 2H), 1.28
(t, J = 6.8 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H); IR (KBr, cm−1) 3432,
3168, 3051, 2967, 2924, 1712, 1619, 1584, 1530, 1478, 1388, 1294,
1246, 1182, 1149, 1090, 1043, 937, 900, 802, 749, 691, 621; HR-MS
(ESI): Calcd for C H NO5 (MH+): 382.1654; Found: 382.1650.
HPLC: Rt = 6.0 min;22Pu2r4ity: 100%
Biological assay
The anticoccidial activities of the compounds 3a–h were evaluated
according to the anticoccidial index method,15–17 using decoquinate
and diclazuril as reference drug. Briefly, the chickens used to test the
anticoccidial activity of compounds were fed to 12-days of age by the
feedstuff without using any anticoccidial drugs.
Groups of the chickens were randomly housed, with 10 in each
cage, 12 cages were randomly assigned by tier. Groups 1–10 of
13-day-old chickens were fed the basal starter diet with the com-
pounds 3a–h or decoquinate in 27 mg kg−1, or diclazuril in 1 mg kg−1