Synthesis and anticoccidial activities of substituted ethyl 4-hydroxy-11-oxo-11H-chromeno[2,3-g]quinoline-3-carboxylates

Article abstract of DOI:10.3184/174751911X13090888724310

A series of substituted ethyl 4-hydroxy-11-oxo-11H-chromeno[2,3-g] quinoline-3-carboxylates were designed and synthesised as anticoccidial drugs, and the structures were characterised by ¹H NMR, MS, IR spectra and elementary analysis. The antic

Full text of DOI:10.3184/174751911X13090888724310

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 373
JUNE, 373–376
Synthesis and anticoccidial activities of substituted ethyl
4-hydroxy-11-oxo-11H-chromeno[2,3-g]quinoline-3-carboxylates
Zhi Wanga, Li-juan Zhoub, Yu-liang Wanga*, Ya-biao Wengc, Jun Hea and Kui Nieb
aDepartment of Chemistry, Sichuan University, Chengdu, Sichuan 610064, P. R. China
bCollege of Animal Science andTechnology, Southwest University, Chongqing 400715, P. R. China
cCollege of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong 510642, P. R. China
A series of substituted ethyl 4-hydroxy-11-oxo-11H-chromeno[2,3-g]quinoline-3-carboxylates were designed and
synthesised as anticoccidial drugs, and the structures were characterised by 1H NMR, MS, IR spectra and elementary
analysis. The anticocciadial activities of the new compounds were assessed according to the anticoccidial index
method. The results demonstrated that four of these compounds exihibited effective anticoccidial activities against
Eimeria tenella in chicken’s diet with a dose of 27 mg kg−1.
Keywords: anticoccidial activities, coccidiosis, Eimeria tenella
mass spectra were recorded with an Agilent 6210 (DOF-MAS) spec-
trometer (Agilent Inc., Santa Clara, CA, USA) using the electrospray
ionisation (ESI) method. The IR spectra were recorded with a
Perkin-Elmer 16PC-FT instrument (Perkin-Elmer Inc., Norwalk
Conn, CA, USA). Elemental analyses were carried out by a Euro
EA 3000 instrument (Euro Vector S.P.A., Italy). Analytical TLC was
carried out on precoated plates (silica gel GF254), and the spots were
visualised with UV light.
Coccidiosis, which is caused by protozoan parasites of the
genus Eimeria, causes morbidity and mortality of animals1 and
seriously hinders the development of the poultry industry.
Anticoccidial drugs were used to control this disease success-
fully in the past. However, when one drug was used for a period
of time, the coccidia inevitably developed resistance to it.2
Now the majority of the drugs used have lower activity
than before, and some, such as salinomycin, dinitolmide,
maduramicin and amprolium3, have completely lost their
anticoccidial activity.
Preparation of 1a–i;19 general procedure
A mixture of 2–chloro-5-nitrobenzoic acid (2.98 g, 14.8 mmol),
K2CO3 (2.91 g, 21.1 mmol) and DMF (N, N-dimethylformamide)
(50 mL) was stirred at 120–125 °C for 1–2 h, then the reaction
temperature was cooled down to 80–90 °C and substituted phenols
(16.3 mmol) were added. The mixture was stirred for 4–5 h and then
the temperature was raised to 120–125 °C and maintained for 7–9 h.
The pH of the mixture was adjusted to 1–2 with 36.5% hydrochloric
acid, and water (50 mL) was added to afford a yellow powder 1a–i by
filtration (81–85% yield following drying). The compounds 1a–i were
directly used for the next step without any further purification.
2-(2-Chloro-phenoxy)-5-nitro-benzoic acid (1a): Light yellow
In order to control coccidiosis successfully, many scientists
are trying to develop novel anticoccidial drugs with new
structures. In 1998, a new series of frenolicin B analogues
were synthesised and tested for activity against parasitic proto-
zoa of the genus Eimeria 4. Five years later, a set of 1-phenyl-
4-pyridyl-butadienes were found to exhibit in vitro activity
against Eimeria tenella in a cell-based assay.5 Since then,
a lot of new compounds with anticoccidial activity were
synthesised, such as 2-(4-fluorophenyl)-3-pyrimidine-4-
ylimidazo[1,2-a]piperidine derivatives,6 2-(4-fluorophenyl)-3-
(4-pyridinyl)-5-substituted pyrroles,7 diarylimidazo[1,2-a]
pyridine derivatives,8 imidazo[1,2-a]pyridine,9,10 and 5,6-
diarylimidazo[2,1-b][1,3]thiazoles.11 Since 2005, our group
have synthesised many novel compounds with anticoccidial
acitivity, such as ethyl 6-aryl-methoxy-7-alkoxy-4-hydroxy-3-
quinolinecarboxylates12, 4-(2-methoxyphenyl)-2-oxobutylqu-
inazolinone derivatives,13 3-(2-(2-methoxyphenyl)-2-oxoethyl)
quinazolinone derivatives,14 ethyl 6-substituted benzyloxy-
7-alkoxy-4-hydroxy-quinolinecarboxylates,15 ethyl 7-alkoxy-
6-(2-aryloxyethoxy)-4-hydroxy-quinolinecarboxylates,16 and
ethyl 6-alkoxy-7-phenyl-4-hydroxy-3-quinolinecarboxylates.17
In order to prepare more compounds with novel chemical
structures and aniticoccidial activity, a series of ethyl 4-
hydroxy-11-oxo-11H-chromeno[2,3-g]quinoline-3-carboxyl-
ates have been synthesised and are now reported for the
first time. Target compounds were prepared as shown in
Scheme 1.
1
powder; yield: 85%; m.p. 173–174 °C; H NMR (400 MHz, CDCl3,
TMS): δ (ppm) = 9.21 (d, J = 2.8 Hz, 1H), 8.55 (dd, J1 = 2.8 Hz, J2 =
9.2 Hz, 1H), 8.36 (d, J = 9.2 Hz, 1H), 7.75 (m, 2H), 7.63 (m, 2H); IR
(KBr, cm−1) 3400, 1736, 1658, 1623, 1564, 14687, 1306; HR-MS
(ESI): Calcd for C13H9ClNO5 [M+H]+: 294.0170. Found: 294.0172.
2-(4-Methyl-phenoxy)-5-nitro-benzoic acid (1b): Light yellow
1
powder; m.p. 181–182 °C; yield: 81%; H NMR (400 MHz, CDCl3,
TMS): δ (ppm) = 9.05 (d, J = 2.8 Hz, 1H), 8.27 (dd, J1 = 2.8Hz, J2 =
9.0 Hz, 1H), 7.52 (s, 1H), 7.05 (d, J = 8.4 Hz, 2H), 7.00 (s, 1H), 7.39
(d, 1H), 2.59 (s, 3H); IR (KBr, cm−1) 3413, 2925, 1710, 1682, 1612,
1582, 1513, 1477, 1253, 1137, 836; HR-MS (ESI): Calcd for
C14H12NO5 [M+H]+: 274.0716. Found: 274.0685.
2-(4-Chloro-phenoxy)-5-nitro-benzoic acid (1c): Light yellow
1
powder; yield: 83%; m.p. 179–181 °C; H NMR (400 MHz, CDCl3,
TMS): δ (ppm) = 8.98 (d, J = 2.4 Hz, 1H), 8.32 (dd, J1 = 2.4 Hz, J2 =
8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 6.94
(d, J = 9.2 Hz, 1H); IR (KBr, cm−1) 3432, 3098, 1707, 1615, 1521,
1479, 1344, 747; HR-MS (ESI): Calcd for C13H9ClNO5 [M+H]+:
294.0170. Found: 294.0185.
2-(2-methyl-phenoxy)-5-nitro-benzoic acid (1d): Yellow powder;
1
yield: 84%; m.p. 165–167 °C; H NMR (400 MHz, CDCl3, TMS):
δ (ppm) = 9.23 (d, J = 2.8 Hz, 1H), 8.57 (dd, J1 = 2.6 Hz, J2 = 9.4 Hz,
1H), 8.20 (J = 9.2 Hz, 1H), 7.65–7.71 (m, 2H), 7.36–7.39 (m, 2H),
2.60 (s, 3H); IR (KBr, cm−1) 3400, 2936, 1715, 1645, 1603, 1598,
1436, 1265; HR-MS (ESI): Calcd for C14H12NO5 [M+H]+: 274.0716.
Found: 274.0711.
Experimental
The 2-chloro-5-nitro-benzoic acid sample was prepared by known
procedures.18 Other solvents and reagents were obtained from com-
mercial sources and used without further purification. The melting
points were recorded with a XRC-1 apparatus (Sichuan University
Instrument Inc., Chengdu, China), and the thermometer was uncor-
rected. Proton NMR spectra were recorded on a Varian unity Inova-
400spectrometer(VarianInc., PaloAlto, CA, USA)withd1-chloroform
and d6-DMSO as the solvents and TMS as the internal standard. The
2-(2-Methoxy-phenoxy)-5-nitro-benzoic acid (1e): Yellow powder;
1
yield: 85%; m.p. 175–176 °C; H NMR (400 MHz, CDCl3, TMS):
δ (ppm) = 9.03 (d, J = 3.2 Hz, 1H), 8.28 (dd, J1 = 2.8 Hz, J2 = 9.2 Hz,
1H), 7.09–7.11 (m, 2H), 6.99–7.01 (m, 2H), 6.90 (d, J = 9.2 Hz, 1H),
3.86 (s, 3H); IR (KBr, cm−1) 3072, 2974, 1688, 1615, 1580, 1507,
1454, 1351, 1298, 1175, 743; HR-MS (ESI): Calcd for
C14H12NO6[M+H]+: 290.0665. Found: 290.0643.
* Correspondent. E-mail: chemwang2000@163.com

374 JOURNAL OF CHEMICAL RESEARCH 2011
Scheme 1 General synthetic route. Reagents and conditions:(1):(a) DMF, K2CO3, 120–125 °C, 1h; (b) substituted phenol, 80–90 °C,
4h; (c) 120–125 °C, 7–9h; (2): PPA, 100–105 °C, 2h; (3) EtOAc, 5% Pd/C, 45 °C, 7–8h; (4) EtOAc, EMME, 7–8h; (5): diphenyl ether,
255 °C, 6–9min.
2-(4-Methoxy-phenoxy)-5-nitro-benzoic acid (1f): Light yellow
(d, J = 2.8 Hz, 1H), 8.27 (dd, J1 = 2.8 Hz, J2 = 9.2 Hz, 1H), 7.29–7.38
(m, 3H), 7.08 (m, 1H), 6.76 (d, J = 9.6 Hz, 1H), 2.21 (s, 3H); IR
(KBr, cm−1) 3106, 2919, 1658, 1620, 1527, 1468, 1341, 1299, 1135,
828; HR-MS (ESI): Calcd for C14H10NO4[M+H]+: 256.0611. Found:
256.0603.
1
powder; yield: 85%; m.p. 173–175 °C; H NMR (400 MHz, CDCl3,
TMS): δ (ppm) = 9.05 (d, J = 3.2 Hz, 1H), 8.26 (dd, J1 = 2.8 Hz, J2 =
9.2 Hz, 1H), 7.34–7.38 (m, 2H), 7.07–7.10 (m, 2H), 6.84 (d, J = 9.2
Hz, 1H), 3.80 (s, 3H); IR (KBr, cm−1) 3443, 2963, 1706, 1613, 1508,
1477, 1344, 1239, 1182, 1033, 918, 838, 803; HR-MS (ESI): Calcd
for C14H12NO6 [M+H]+: 290.0665. Found: 290.0652.
2-Chloro-7-nitro-xanthen-9-one (2c): Grey powder; yield: 92%;
m.p. 213–215 °C ; 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) = 9.28
(d, J = 2.8 Hz, 1H), 8.65 (dd, J1 = 2.8 Hz, J2 = 9.2 Hz, 1H), 8.35 (d,
J = 2.8 Hz, 1H), 7.89 (m, 2H), 7.56 (d, J = 9.2 Hz, 1H); IR (KBr,
cm−1) 3013, 2934, 1687, 1676, 1488, 1456, 1330; HR-MS (ESI):
Calcd for C13H7ClNO4 [M+H]+: 276.0064. Found: 276.0051.
5-Methyl-2-nitro-xanthen-9-one (2d): Grey powder; yield: 92%;
m.p. 214–216 °C; 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) = 9.23
(d, J = 2.8 Hz, 1H), 8.57(dd, J1 = 2.4 Hz, J2 = 9.4 Hz, 1H), 8.37 (d,
J = 9.2 Hz, 1H), 7.80–7.84 (m, 1H), 7.57 (d, J = 9.6 Hz, 1H), 7.47–
7.50 (m, 1H), 2.10 (s, 3H); IR (KBr, cm−1) 3030, 2998, 1670, 1611,
1535, 1469, 1428, 1306; HR-MS (ESI): Calcd for C14H10NO4[M+H]+:
256.0611. Found: 256.0601.
5-Methoxy-2-nitro-xanthen-9-one (2e): Grey powder; yield: 92%;
m.p. 220–221 °C; 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) = 9.23
(d, J = 3.2 Hz, 1H), 8.57 (dd, J1 = 2.8 Hz, J2 = 9.2 Hz, 1H), 7.92 (d,
J = 9.2 Hz, 1H), 7.76 (d, J = 9.6 Hz, 1H), 7.48–7.42 (m, 2H), 4.06
(s, 3H); IR (KBr, cm−1) 3103, 2924, 1667, 1608, 1491, 1446, 1339,
756; HR-MS (ESI): Calcd for C14H10NO5 [M+H]+: 272.0560. Found:
272.0567.
2-Methoxy-7-nitro-xanthen-9-one (2f): Grey powder; yield: 92%;
m.p. 223–224 °C; 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) = 9.24
(d, J = 2.8 Hz, 1H), 8.55 (dd, J1 = 2.8 Hz, J2 = 9.0 Hz, 1H), 7.71 (d,
J = 3.2 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H),
7.41 (dd, J1 = 3.0 Hz, J2 = 9.0 Hz, 1H), 3.95 (s, 3H); IR (KBr, cm−1)
3039, 2997, 1660, 1621, 1525, 1471, 1430, 1346, 1294, 1146; HR-MS
(ESI): Calcd for C14H10NO5 [M+H]+: 272.0560. Found: 272.0554.
2-Tert-butyl-7-nitro-xanthen-9-one (2g): Grey powder; yield: 94%;
m.p. 218–220 °C; 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) = 9.05
(J = 2.8 Hz, 1H), 8.21 (dd, J1 = 2.8 Hz, J2 = 9.2 Hz, 1H), 7.80 (d, J =
8.8 Hz, 1H), 7.23 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 3.2 Hz, 1H), 1.26
(s, 9H); IR (KBr, cm−1) 3049, 1689, 1615, 1589, 1545, 1424, 1305;
HR-MS (ESI): Calcd for C17H16NO4 [M+H]+: 298.1080. Found:
298.1042.
2-(4-Tert-butyl-phenoxy)-5-nitro-benzoic acid (1g): Light yellow
1
powder; yield: 85%; m.p. 160–162 °C; H NMR (400 MHz, CDCl3,
TMS): δ (ppm) = 9.06 (d, J = 2.8 Hz, 1H), 8.29 (dd, J1 = 2.8 Hz, J2 =
9.2 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 6.94
(d, J = 8.8 Hz, 2H), 1.273 (s, 9H); IR (KBr, cm−1) 3437, 3076, 2965,
1710, 1611, 1582, 1515, 1478, 1426, 1374, 1259, 1204, 803; HR-MS
(ESI): Calcd for C17H18NO5 [M+H]+: 316.1186. Found: 316.1192.
2-Phenoxy-5-nitro-benzoic acid (1h): Bright yellow powder; yield:
83%; m.p. 155–156 °C; 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) =
9.03 (d, J = 2.8 Hz, 1H), 8.29 (dd, J1 = 3.2 Hz, J2 = 9.2 Hz, 1H),
7.48–7.52 (m, 2H), 7.33–7.37 (m, 1H), 7.15–7.17 (m, 2H), 6.92 (d,
J = 9.6 Hz, 1H); IR (KBr, cm−1)= 3399, 2986, 1705, 1655, 1613, 1588,
1454, 1155; HR-MS (ESI): Calcd for C13H10NO5[M+H]+: 260.0560.
Found: 260.0557.
2-(4-Fluoro-phenoxy)-5-nitro-benzoic acid (1i): Light yellow
1
powder; yield: 82%; m.p. 170–171 °C; H NMR (400 MHz, CDCl3,
TMS): δ (ppm) = 9.06 (d, J = 2.8 Hz, 1H), 8.29 (dd, J1 = 2.8 Hz, J2 =
9.2 Hz, 1H), 7.50 (t, J = 8.8 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.94
(d, J = 8.8 Hz, 1H); IR (KBr, cm−1) 3431, 3080, 1707, 1615, 1584,
1502, 1478, 1348, 1267, 1183, 835; HR-MS (ESI):Calcd for
C13H9FNO5[M+H]+: 278.0466. Found: 278.0470.
Preparation of 2a–i;20 general procedure
PPA (polyphosphoric acid) (10.58 g) was stirred and heated to
100–105 °C in a three-necked flask, then 1a–i (7.9 mmol) was added,
the mixture was kept 2–3h at this temperature, then water (50 mL) was
poured off. After filtration, the obtained solid was washed with satu-
rated sodium bicarbonate (3×20 mL), water (20 mL) and was dried.
The yields of the products were 92–94%. The obtained intermediates
2a–i were directly used for the next step without further purification.
5-Chloro-2-nitro-xanthen-9-one (2a): Grey powder; yield: 93%;
m.p. 215–217 °C; 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) = 9.25
(d, J = 2.8 Hz, 1H), 8.54 (dd, J1 = 2.8 Hz, J2 = 9.2 Hz, 1H), 8.14
(d, J = 2.8 Hz, 1H), 7.63 (m, 2H), 7.47 (d, J = 9.2 Hz, 1H); IR
(KBr, cm−1) 3100, 2969, 1678, 1635, 1534, 1458, 1304; HR-MS (ESI):
Calcd for C13H7ClNO4 [M+H]+: 276.0064. Found: 276.0095.
2-Nitro-xanthen-9-one (2h): Grey powder; yield: 93%; m.p. 200–
1
202 °C; H NMR (400 MHz, CDCl3, TMS): δ (ppm) = 9.00 (d, J =
2.8 Hz, 1H), 8.31 (dd, J1 = 2.8 Hz, J2 = 9.2 Hz, 1H), 7.11–7.21 (m,
4H), 6.90 (d, J = 9.2 Hz, 1H); IR (KBr, cm−1) 3079, 1669, 1605, 1574,
1532, 1464, 1314, 770; HR-MS (ESI): Calcd for C13H8NO4[M+H]+:
242.0454. Found: 242.0470.
2-Methyl-7-nitro-xanthen-9-one (2b): Grey powder; yield: 94%;
m.p. 209–210 °C; 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) = 9.06

JOURNAL OF CHEMICAL RESEARCH 2011 375
2-Fluoro-7-nitro-xanthen-9-one (2i): Grey powder; yield: 93%;
m.p. 238–239 °C; 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) = 9.22
(d, J = 2.8 Hz, 1H), 8.59 (dd, J1 = 3.2 Hz, J2 = 9.2 Hz, 1H), 7.99–8.01
(m, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.52–7.61 (m, 1H), 6.56 (d, J =
9.6 Hz, 1H); IR (KBr, cm−1) 3089, 1662, 1624, 1527, 1470, 1342,
1291, 839; HR-MS (ESI): Calcd for C13H7FNO4 [M+H]+: 260.0360.
Found: 260.0350.
CDCl3, TMS): δ (ppm) = 10.78 (d, J = 14.0 Hz, 1H), 8.43 (d, J =
14.0 Hz, 1H), 8.21 (d, J = 7.2 Hz, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.93
(m, 2H), 7.70 (m, 2H), 7.50 (t, J = 7.2 Hz, 1H), 4.22 (q, J = 7.6 Hz,
2H), 4.14(q, J = 7.6 Hz, 2H), 1.26 (m, 6H); HR-MS (ESI): IR (KBr,
cm−1) 3149, 2989, 1680, 1620, 1460, 1403, 1272, 1076; Calcd for
C21H20NO6 [M+H]+: 382.1291. Found: 382.1290.
3-(7-Fluoro-9-oxo-9H-xanthen-2-ylamino)-acrylic acid ethyl ester
(4i): Yellow powder; yield: 83%; m.p. 220–221 °C; 1H NMR
(400 MHz, CDCl3, TMS): δ (ppm) = 11.21 (d, J = 13.2 Hz, 1H), 8.58
(d, J = 13.2 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.99 (dd, J1 = 2.8 Hz,
J2 = 8.0 Hz, 1H), 7.53 (m, 4H), 4.31–4.35 (m, 4H), 1.35–1.40 (m, 6H);
IR (KBr, cm−1) 3139, 2979, 1690, 1644, 1480, 1403, 1272, 1223,
1066, 803; Calcd for C21H19FNO6 [M+H]+: 400.1197. Found:
400.1182.
Preparation of 3a–i and 4a–i; general procedure
The compounds 2a–i (6.7 mmol) were reduced by 5% Pd/C (0.46 g)
in a catalysed hydrogenation in EtOAc (ethyl acetate) (18.6 mL) at
atmospheric pressure for 7–9 h. Then EMME (ethoxymethylene
diethyl malonate) (1.45 g, 6.7 mmol) was added, and the mixture was
refluxed for another 7–8 h and filtered at a lower temperature. The
filtrate was evaporated under reduced pressure condition to afford the
crudeproducts,whichwererecrystallisedwithethanol/dichloromethane
(50–80 mL) (1:1) and dried to obtain 4a–i in 81–83% yield.
4-(5-Chloro-9-oxo-9H-xanthen-2-ylamino)-acrylic acid ethyl ester
(4a): Yellow powder; yield: 81%; m.p. 217–218 °C; 1H NMR
(400 MHz, CDCl3, TMS): δ (ppm) = 11.01 (d, J = 13.2 Hz, 1H), 8.89
(d, J = 13.2 Hz, 1H), 8.37 (d, J = 3.2 Hz, 1H), 8.02 (m, 3H), 7.93
(dd, J1 = 2.8 Hz, J2 = 8.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 4.36 (m,
4H), 1.36 (m, 6H); IR (KBr, cm−1) 3137, 1639, 1404, 1279, 1224,
1064, 807; HR-MS (ESI): Calcd for C21H19ClNO6 [M+H]+: 416.0902.
Found: 416.0891.
3-(7-Methyl-9-oxo-9H-xanthen-2-ylamino)-acrylic acid ethyl ester
(4b): Yellow powder; yield: 82%; m.p. 205–206°C ; 1H NMR
(400 MHz, CDCl3, TMS): δ (ppm) = 11.16 (d, J = 13.2 Hz, 1H), 8.69
(d, J = 13.2 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.89 (dd, J1 = 2.4 Hz,
J2 = 8.8 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.13 (m, 2H), 6.56 (d, J =
3.2 Hz, 1H), 4.36 (m, 4H), 2.63 (s, 3H), 1.39(m, 6H); IR (KBr, cm−1)
3999, 3066, 2982, 1720, 1663, 1619, 1473, 1412, 1377, 1292, 1079,
802; HR-MS (ESI): Calcd for C22H22NO6[M+H]+: 396.1448. Found:
396.1434.
Preparation of 5a–i; general procedure
Diphenyl ether (13 mL) was heated to 120–130 °C for 0.5–1 h to
evaporate a trace of water, and then the temperature was increased
to 255 °C, compounds 4a–i (6.03 mmol) were added and stirred for
7–9 min. Then petroleum ether (50 mL) was added to the mixture at
the temperature of 100–110 °C to obtain crude products by filtration.
The products were washed with ethyl acetate (3×20 mL) and dried,
and the yields of the products were 63–70%.
Ethyl 7-chloro-4-hydroxy-11-oxo-11H-chromeno[2,3-g]quinoline-
3-carboxylate (5a): Orange solid; yield: 63%; m.p. 244–246 °C;
1H NMR (400 MHz; DMSO-d6; TMS): δ (ppm) = 12.42 (s, 1H), 8.55
(s, 1H), 8.05 (s, 1H), 7.91–7.97 (m, 3H), 7.76 (s, 1H), 4.26 (q, J =
6.4 Hz, 2H), 1.31 (t, J = 6.4 Hz, 3H); IR (KBr, cm−1) 3433, 3089,
2925, 1716, 1667, 1598, 1534, 1473, 1443, 768; HR-MS (ESI): Calcd
for C19H13ClNO5 [M+H]+: 370.0479. Found: 370.0473; Anal. Calcd
for C19H12ClNO5: C, 61.72; H, 3.27; N, 3.79. Found: C, 61.71;
H, 3.24; N, 3.81%.
Ethyl 9-methyl-4-hydroxy-11-oxo-11H-chromeno[2,3-g]quinoline-
3-carboxylate (5b): Yellow solid; yield: 63%; m.p. 221–222 °C;
1H NMR (400 MHz, DMSO-d6, TMS): δ (ppm) =12.38 (s, 1H), 8.54
(s, 1H), 8.06 (s, 1H), 7.90–7.96 (m, 2H), 7.74 (s, 1H), 7.60 (s, 1H),
4.25 (q, J = 7.2 Hz, 2H), 1.24 (s, 3H), 1.06 (t, 3H, J = 7.2 Hz); IR
(KBr, cm−1) 3435, 3078, 2923, 1716, 1618, 1566, 1509, 1470, 758;
HR-MS (ESI): Calcd for C20H16NO5 [M+H]+: 350.1079. Found:
350.1021; Anal. Calcd for C20H15NO5: C, 68.76; H, 4.33; N, 4.01.
Found: C, 68.71; H, 4.25; N, 4.02%.
Ethyl 9-chloro-4-hydroxy-11-oxo-11H-chromeno[2,3-g]quinoline-
3-carboxylate (5c): Yellow solid; yield: 64%; m.p. 242–244 °C;
1H NMR (400 MHz, DMSO-d6, TMS): δ (ppm) =12.42 (s, 1H), 8.55
(s, 1H), 8.05 (s, 1H), 7.97 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.77 (s,
1H), 4.26 (q, 2H, J = 6.4 Hz), 1.32 (t, 3H, J = 6.4 Hz); IR (KBr, cm−1)
3431, 3084, 2956, 1717, 1666, 1601, 1533, 1461, 787; HR-MS (ESI):
Calcd for C19H13ClNO5 [M+H]+: 370.0479. Found: 370.0476; Anal.
Calcd for C19H12ClNO5: C, 61.72; H, 3.27; N, 3.79. Found: C, 61.70;
H, 3.20; N, 3.75%.
Ethyl 7-methyl-4-hydroxy-11-oxo-11H-chromeno[2,3-g]quinoline-
3-carboxylate (5d): Yellow solid; yield: 66%; m.p. 221–222 °C;
1H NMR (400 MHz, DMSO-d6, TMS): δ (ppm) =12.40 (s, 1H), 8.54
(s, 1H), 8.23 (s, 1H), 7.88–8.02 (m, 2H), 7.70 (s, 2H), 4.27 (q, J =
6.4 Hz, 2H), 1.32 (s, 3H), 1.06 (t, J = 6.4 Hz, 3H); IR (KBr, cm−1)
3428, 3085, 2977, 1716, 1665, 1596, 1533, 1467, 1420, 809; HR-MS
(ESI): Calcd for C20H16NO5 [M+H]+: 350.1079. Found: 350.1020;
Anal. Calcd for C20H15NO5: C, 68.76; H, 4.33; N, 4.01. Found:
C, 68.74; H, 4.30; N, 4.05%.
3-(7-Chloro-9-oxo-9H-xanthen-2-ylamino)-acrylic acid ethyl ester
(4c): Yellow powder; yield: 83%; m.p. 225–226 °C; 1H NMR
(400 MHz, CDCl3, TMS): δ (ppm) = 11.22 (d, J = 13.2 Hz, 1H), 8.56
(d, J = 13.2 Hz, 1H), 7.60–7.95 (m, 1H), 7.46–7.60 (m, 3H), 4.21–
4.37 (m, 4H), 1.31–1.40 (m, 6H); IR (KBr, cm−1) 3400, 1678, 1615,
1245, 1164; HR-MS (ESI): Calcd for C21H19ClNO6[M+H]+: 416.0902.
Found: 416.0901.
3-(5-Methyl-9-oxo-9H-xanthen-2-ylamino)-acrylic acid ethyl ester
(4d): Yellow powder; yield: 83%; m.p. 181–192 °C; 1H NMR
(400 MHz, CDCl3, TMS): δ (ppm) = 11.22 (d, J = 13.2 Hz, 1H), 8.59
(d, J = 13.2 Hz, 1H), 8.21 (d, J = 2.8 Hz, 1H), 8.08 (m, 2H), 7.99
(dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H), 7.54 (J = 3.2 Hz, 1H), 7.08 (d, J =
8.8 Hz, 1H), 4.56 (m, 4H), 2.35 (s, 3H), 1.45(m, 6H); IR (KBr, cm−1)
3400, 2981, 1636, 1486, 1407, 1381, 1278, 1222, 1064, 807; HR-MS
(ESI): Calcd for C22H22NO6[M+H]+: 396.1448. Found: 396.1443.
3-(5-Methoxy-9-oxo-9H-xanthen-2-ylamino)-acrylic acid ethyl
1
ester (4e): Yellow powder; yield: 83%; m.p. 223–224 °C; H NMR
(400 MHz, CDCl3, TMS): δ (ppm) = 11.01 (d, J = 13.6 Hz, 1H),
8.58(d, J = 13.6 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 8.8 Hz,
1H), 7.66 (d, J = 8.8 Hz, 1H), 7.49–7.51 (m, 1H), 7.27–7.35 (m, 2H),
4.25–4.35 (m, 4H), 4.05 (s, 3H), 1.33–1.41 (m, 6H); IR (KBr, cm−1)
3430, 3154, 2979, 1692, 1662, 1640, 1495, 1420, 1312, 1267, 1220,
798; HR-MS (ESI): Calcd for C22H22NO7[M+H]+: 412.1397. Found:
412.1390.
3-(7-Methoxy-9-oxo-9H-xanthen-2-ylamino)-acrylic acid ethyl
Ethyl 4-hydroxy-7-methoxy-11-oxo-11H-chromeno[2,3-g]quinoline-
1
1
ester (4f): Yellow powder; yield: 82%; m.p. 226–228 °C; H NMR
3-carboxylate (5e): Yellow; yield: 68%; m.p. 214–216 °C; H NMR
(400 MHz, CDCl3, TMS): δ (ppm) = 11.23 (d, J = 13.6 Hz, 1H), 8.61
(d, J = 13.6 Hz, 1H), 8.11 (s, 1H), 7.71 (s, 1H), 7.46–7.54 (m, 3H),
7.38 (s, 1H), 4.29–4.34 (m, 4H), 3.95 (s, 3H), 1.37–1.41 (m, 6H); IR
(KBr, cm−1) 3411, 3188, 2983, 1724, 1659, 1620, 1482, 1413, 1300,
1077, 815; HR-MS (ESI): Calcd for C22H22NO7[M+H]+: 412.1397.
Found: 412.1396.
(400 MHz, DMSO-d6, TMS): δ (ppm) =12.43 (s, 1H), 8.60 (s, 1H),
8.03 (s, 1H), 7.96 (s, 1H), 7.71 (s, 1H), 7.51–7.61 (m, 2H), 3.85 (s,
3H), 3.41 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H); IR (KBr, cm−1)
3436, 3075, 2983, 1688, 1615, 1594, 1568, 1486, 785; HR-MS (ESI):
Calcd for C20H16NO6 [M+H]+: 366.0979. Found: 366.0971; Anal.
Calcd for C20H15NO6: C, 65.75; H, 4.14; N, 3.83. Found: C, 65.79;
H, 4.19; N, 3.81%.
Ethyl 4-hydroxy-9-methoxy-11-oxo-11H-chromeno[2,3-g]quinoline-
3-carboxylate (5f): Yellow solid; yield: 70%; m.p. 242–243 °C;
1H NMR (400 MHz, DMSO-d6, TMS): δ (ppm) =12.61 (s, 1H), 8.65
(s, 1H), 8.06 (s, 1H), 7.74 (s, 1H), 7.54 (s, 1H), 7.40–7.51 (m, 2H),
4.29 (q, J = 7.2 Hz, 2H), 4.02 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); IR
(KBr, cm−1) 3446, 3085, 2982, 1698, 1616, 1597, 1569, 1597, 1569,
1499, 1445, 778; HR-MS (ESI): Calcd for C20H16NO6 [M+H]+:
366.0979. Found: 366.0965; Anal. Calcd for C20H15NO6: C, 65.75;
H, 4.14; N, 3.83. Found: C, 65.76; H, 4.11; N, 3.78%.
3-(7-Tert-butyl-9-oxo-9H-xanthen-2-ylamino)-acrylic acid ethyl
1
ester (4g): Yellow powder; yield: 82%; m.p. 208–210 °C; H NMR
(400 MHz, CDCl3, TMS): δ (ppm) = 10.89 (d, J = 14.0 Hz, 1H), 8.35
(d, J = 14.0 Hz, 1H), 8.25 (d, J = 3.2 Hz, 1H), 8.01 (dd, J1 = 2.8 Hz,
J2 = 8.2 Hz, 1H), 7.83–7.90 (m, 2H), 7.50 (d, J = 3.2 Hz, 1H), 7.21
(d, J = 3.2 Hz, 1H), 4.22 (m, 4H), 1.28 (m, 15H); IR (KBr, cm−1) 3401,
3198, 2993, 1734, 1669, 1660, 1452, 1433, 1296; HR-MS (ESI):
Calcd for C25H28NO6 [M+H]+: 438.1917. Found: 438.1910.
3-(9-Oxo-9H-xanthen-2-ylamino)-acrylic acid ethyl ester (4h):
1
Yellow powder; yield: 83%; m.p. 190–192 °C; H NMR (400 MHz,

376 JOURNAL OF CHEMICAL RESEARCH 2011
Ethyl 9-tert-butyl-4-hydroxy-11-oxo-11H-chromeno[2,3-g]quinoline-
3-carboxylates (5g): Yellow solid; yield: 69%; m.p. 226–228 °C; H
used for the next step without further purification. Pure and well dried
intermediates 4a–i were necessary. Otherwise, many by-products
would form and the purification process of 5a–i would become very
difficult in the next step.
The last ring-closing reaction was carried out by heating the inter-
mediates 4a–i in diphenyl ether above 255 °C for 6–9 minutes. Time
and temperature of the reaction must be strictly controlled to improve
the purity of crude products because the products of this step could not
dissolve in any solvent and were very difficult to purify.
1
NMR (400 MHz, DMSO-d6, TMS): δ (ppm) =12.40 (s, 1H), 8.54 (s,
1H), 7.90–7.96 (m, 3H), 7.63 (s, 1H), 7.61 (s, 1H), 4.25 (q, J = 7.2 Hz,
2H), 1.31 (t, J = 7.2 Hz, 3H), 1.25 (s, 9H); IR (KBr, cm−1) 3435, 3082,
2960, 1716, 1663, 1602, 1530, 1492, 1466, 787; HR-MS (ESI): Calcd
for C23H22NO5 [M+H]+: 392.1479. Found: 392.1489; Anal. Calcd
for C23H21NO5: C, 70.58; H, 5.41; N, 3.58. Found: C, 70.55; H, 5.31;
N, 3.59%.
Ethyl 4-hydroxy-11-oxo-11H-chromeno[2,3-g]quinoline-3-carbox-
ylate (5h) : Yellow solid; yield: 65%; m.p. 190–192 °C; H NMR
The data for anticoccidial activities of the tested compounds 5a–i
are shown in Table 1. In the positive control group, the ACI was
obviously 69 and 94. In the negative control group, no coccidiosis
happened in the chickens and the ACI was 200. So the control was
set up. Compounds 5a, 5b, 5c and 5d showed anticoccidial activities
against the Eimeria tenella with the ACI 147, 123, 133, 148 respec-
tively.
1
(400 MHz, DMSO-d6, TMS): δ (ppm) =12.42 (s, 1H), 8.64 (s, 1H),
8.11–8.18 (m, 1H), 8.04 (s, 1H), 7.90–7.97 (m, 2H), 7.67–7.75 (m,
1H), 7.50 (s, 1H), 4.30 (q, J = 7.2 Hz, 3H), 1.33 (t, J = 7.2 Hz, 2H);
IR (KBr, cm−1) 3427, 3080, 2976, 1716, 1664, 1603, 1532, 1461, 757;
HR-MS (ESI): Calcd for C19H14NO5 [M+H]+: 336.0879. Found:
336.0869; Anal. Calcd for C19H13NO5: C, 68.06; H, 3.91; N, 4.18.
Found: C, 68.01; H, 3.89; N, 4.15%.
Conclusion
Ethyl 9-fluoro-4-hydroxy-11-oxo-11H-chromeno[2,3-g]quinoline-
1
In summary, for the first time nine substituted ethyl 4-hydroxy-
11-oxo-11H-chromeno[2,3-g]-quinoline-3-carboxylates were
designed and synthesised as new anticoccidial drugs. The
results indicate that the compounds 5a, 5b, 5c and 5d have
anticoccidial activities against Eemeria tenella at a dose of
27 mg kg−1 and they might be developed as available anticoc-
cidial drugs. Further research work is still in progress.
3-carboxylate (5i): Yellow solid; yield: 64%; m.p. 238–239 °C; H
NMR (400 MHz, DMSO-d6, TMS): δ (ppm) =12.41 (s, 1H), 8.16 (s,
1H), 7.61 (s, 1H), 7.51 (s, 1H), 7.30–7.45 (m, 3H), 3.83 (q, J = 7.2 Hz,
2H), 0.87 (t, J = 7.2 Hz, 3H); IR (KBr, cm−1) 3428, 3081, 2925, 1718,
1666, 1605, 1533, 1466, 815; HR-MS (ESI): Calcd for C19H13FNO5
[M+H]+: 354.0779. Found: 354.0770; Anal. Calcd for C19H12FNO5:
C, 64.59; H, 3.42; N, 3.96. Found: C, 64.54; H, 3.41; N, 3.92%.
Biological asssay
The anticoccidial activities of the compounds 5a–d and 5e–i were
evaluated according to the anticoccidial index (ACI) method21, using
decoquinate as reference drug. The chickens used to test anticoccidial
activities of the compounds were 12-day old broilers, which were fed
normally without any anticoccidial drug and drank clean water.
Groups of the chickens were randomly housed, with 15 in each cage,
and 15 cages were randomly assigned by tier. Groups 1–5 and 8–13 of
13–days chicken were fed starter diet with the compounds 5a–i and
decoquinate in 27mg kg–1. Groups 1–6 and 8–14 of 14–days chicken
were artificially infected with the Eimeria tenell spores with 100 000
oocysts. On observing the chicken after infection for 7 days, we
recorded the weight gain, mortality, dropping scores, lesion scores
and oocyst scores of the chicken and calculated the ACI. The results of
test are given in Table 1.
The authors are grateful for financial support from the National
Science Foundation of China (No.21072135).
Received 14 February 2011; accepted 29 May 2011
Paper 1100572 doi: 10.3184/174751911X13090888724310
Published online: 11 July 2011
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Results and discussion
The nucleophilic substitution reaction in the first step was finished at
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used for the next step. The compounds 2a–i were easily synthesised
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Table 1 Data for anticocciadial activity of the compounds 5a–i
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Group Test com-
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Rate of Survival Lesion Oocyst ACI
relative rate/% value value
/mg kg−1
weight
gain /%
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1
2
3
4
5
6
5a
9
83
91
87
76
64
93
100
100
100
93
21
19
18
19
19
28
20
40
40
40
20
40
147
123
133
148
130
69
5b
5c
5d
Decoquinate
Infected-
untreated
Uninfected-
untreated
5e
97
7
100
100
0
0
200
8
9
10
11
12
13
14
20
62
69
50
49
76
64
75
80
34
18
28
32
24
19
30
40
40
30
40
40
20
40
21
84
5f
5g
90
100
73
5h
95
5i
75
60
Decoquinate
Infected-
untreated
Uninfected-
untreated
93
130
95
100
19 K.Q. Wu, Y.L. Wang, H. Zheng, CN 1597657.
20 C. Wright, G.V. Ullas, J. Label Compd Radiopharm. 2002, 45, 1267.
21 S.D. Folz, B.L. Lee, L.H. Nowakowski, D.L. Rector and B.M. Folz, J.
Parasitol. 1989, 75, 696.
15
100
100
0
0
200

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