J. Yang et al. / European Journal of Medicinal Chemistry 101 (2015) 41e51
49
4
.1.20. N-(5-Carbamoyl-2-nitrophenyl)-3,4,5-
141.7, 140.4, 140.3, 138.8, 134.7, 130.7, 129.7, 129.4, 129.1, 128.6, 125.9,
124.8, 124.1, 119.7, 112.3, 105.1, 60.1, 55.8. HRMS (ESI-TOF): calcd for
trimethoxybenzamide (12)
þ
ꢂ1
Compound 12 was prepared from 11 (7.53 g, 20.0 mmol) and
C
29
H
27
N
4
O
7
[M þ H] 543.1874, found 543.1885. IR (KBr, cm ):
n
(
NH
preparation of 5. Yellow solid (7.22 g, 96%), m.p. 306e308 C. H
NMR (DMSO-d , 300 MHz): 10.81 (s, 1H), 8.51 (s, 1H), 8.24 (d,
J ¼ 6.5 Hz, 2H), 7.89 (d, J ¼ 8.5 Hz, 1H), 7.62 (br.s, 1H), 7.31 (s, 2H),
4
)
2
CO
3
(5.52 g, 57.4 mmol) according to the procedure for
3428, 3317, 3224, 1659, 1589, 1521, 1491, 1425, 1334, 1129.
ꢁ
1
6
d
4.1.25. N-(2-Amino-4-carbamoylphenyl)-3,4,5-
trimethoxybenzamide (16)
13
3
.88 (s, 6H), 3.76 (s, 3H). C NMR (DMSO-d
6
, 75 MHz):
d
165.4,
Compound 16 was prepared by using ethyl 4-amino
-3-nitrobenzoate (12.88 g, 61.3 mmol) and 3,4,5-
164.7,152.8,142.0,134.0,132.7,130.9,128.3,125.2,124.3,105.4, 60.2,
2
þ
5
6.1. HRMS (ESI-TOF): calcd for C17
H
18
N
3
O
7
[M þ H] 376.1139,
trimethoxybenzoic acid 8 (14.30 g, 67.4 mmol) as starting sub-
strates according to the synthesis route for compound 6. Yellow
solid (3.03 g, the overall yield of four steps was 14%), m.p.
ꢂ1
found 376.1144. IR (KBr, cm ):
1126.
n
3355, 1690, 1642, 1463, 1338, 1272,
ꢁ
1
2
37e238 C. H NMR (DMSO-d
6
, 300 MHz): d 9.68 (s, 1H), 7.76 (s,
4
.1.21. N-(2-Amino-5-carbamoylphenyl)-3,4,5-
1H), 7.32e7.33 (m, 3H), 7.24 (d, J ¼ 8.2Hz, 1H), 7.10e7.15 (m, 2H),
13
trimethoxybenzamide (13)
Compound 13 was prepared from 12 (3.75 g, 10.0 mmol) ac-
cording to the procedure for preparation of 6. Yellow solid (2.34 g,
5.05 (s, 2H), 3.87 (s, 6H), 3.74 (s, 3H). C NMR (DMSO-d
168.1, 164.8, 152.5, 142.6, 140.3, 132.5, 129.5, 125.9, 125.8, 115.7,
115.3, 105.4, 60.1, 56.1. HRMS (ESI-TOF): calcd for C17
6
, 75 MHz):
d
20 3 5
H N O
n 3462, 3373,
ꢁ
1
þ
ꢂ1
6
8%), m.p. 184e186 C. H NMR (DMSO-d
6
, 300 MHz):
d
9.68 (s, 1H),
[M þ H] 346.1397, found 346.1400. IR (KBr, cm ):
7.76 (s, 1H), 7.33 (s, 3H), 7.24 (d, J ¼ 8.2 Hz, 1H), 7.10e7.13 (m, 2H),
5
d
3240, 1642, 1583, 1492, 1336, 1236, 1123.
13
6
.05 (s, 2H), 3.87 (s, 6H), 3.74 (s, 3H). C NMR (DMSO-d , 75 MHz):
168.1, 164.7, 152.5, 142.6, 132.5, 129.5, 125.9, 125.8, 115.6, 115.3,
4.1.26. N-(4-Carbamoyl-2-(4-(2-oxopyridin-1(2H)-yl)benzamido)
phenyl)-3,4,5-trimethoxybenzamide (17)
þ
105.4, 60.1, 56.0. HRMS (ESI-TOF): calcd for C17
20
H N
3
O
5
[M þ H]
ꢂ1
3
46.1397, found 346.1400. IR (KBr, cm ):
n
3462, 3372, 3240, 1641,
Compound 17 was prepared from 16 (0.69 g, 2.0 mmol) and 4-
(2-oxopyridin-1(2H)-yl)benzoic acid 1 (0.65 g, 3.0 mmol) according
to the procedure for preparation of 7a. Yellow solid (0.62 g, 57%),
1584, 1492, 1336, 1236, 1123.
ꢁ
1
4.1.22. N-(5-Carbamoyl-2-(4-(2-oxopyrrolidin-1-yl)benzamido)
m.p. 257e259 C. H NMR (DMSO-d , 300 MHz): d 10.32 (s, 1H),
6
phenyl)-3,4,5-trimethoxybenzamide (14a)
10.00 (s, 1H), 8.14 (s, 2H), 8.12 (s, 1H), 8.01 (br.s, 1H), 7.82e7.91 (m,
2H), 768 (d, J ¼ 6.6 Hz, 1H), 7.59 (d, J ¼ 8.4 Hz, 2H), 7.51e7.53 (m,
1H), 7.38 (br.s, 1H), 7.24 (s, 2H), 6.51 (d, J ¼ 9.0 Hz, 1H), 6.35 (t,
Compound 14a was prepared from 13 (1.04 g, 3.0 mmol) and 4-
(
2-oxopyrrolidin-1-yl)benzoic acid [28] (0.92 g, 4.5 mmol) ac-
13
cording to the procedure for preparation of 7a. Yellow solid (0.14 g,
J ¼ 6.6 Hz, 1H), 3.78 (s, 6H), 3.71 (s, 3H). C NMR (DMSO-d
6
,
ꢁ
1
9
%), m.p. 231e236 C. H NMR (DMSO-d
6
, 300 MHz):
d
10.18 (s, 1H),
75 MHz):
134.6, 133.5, 130.9, 130.2, 129.4, 128.5, 126.9, 126.0, 125.0, 124.3,
120.6, 105.8, 105.1, 60.1, 55.9. HRMS (ESI-TOF): calcd for C29
d 167.0, 164.90, 164.88, 161.0, 152.7, 143.5, 140.8, 138.6,
1
0.01 (s, 1H), 8.12 (s, 1H), 8.04 (d, J ¼ 8.7 Hz, 2H), 7.98 (br.s, 1H), 7.89
(
3
2
d, J ¼ 8.7 Hz, 1H), 7.82 (d, J ¼ 8.7 Hz, 3H), 7.34 (br.s, 1H), 7.23 (s, 2H),
27 4 7
H N O
n 3438, 3268,
þ
ꢂ1
.89 (t, J ¼ 6.9 Hz, 2H), 3.78 (s, 6H), 3.71 (s, 3H), 2.54 (t, J ¼ 8.1 Hz,
[M þ H] 543.1874, found 543.1878. IR (KBr, cm ):
13
H), 2.06e2.11 (m, 2H). C NMR (DMSO-d
65.0, 164.7, 152.6, 142.7, 134.4, 130.9, 130.2, 129.3, 128.4, 125.9,
24.8, 124.2, 118.3, 105.0, 60.1, 55.9, 17.2. HRMS (ESI-TOF): calcd for
6
, 75 MHz):
d
174.4, 167.0,
1684, 1651, 1586, 1535, 1502, 1338, 1122.
1
1
C
3
4.1.27. Ethyl 4-amino-3-(3,4,5-trimethoxybenzamido)benzoate
(18)
þ
ꢂ1
H
28 29
N
4
O
7
[M þ H] 533.2031, found 533.2040. IR (KBr, cm ):
n
354, 1653, 1586, 1503, 1414, 1389, 1336, 1126.
Compound 18 was prepared from 10 (4.04 g, 10.0 mmol) ac-
cording to the procedure for preparation of 6. Yellow solid (2.89 g,
ꢁ
1
4.1.23. N-(5-Carbamoyl-2-(4-(2-oxopiperidin-1-yl)benzamido)
77%), m.p. 148e150 C. H NMR (DMSO-d , 300 MHz): d 9.71 (s, 1H),
6
phenyl)-3,4,5-trimethoxybenzamide (14b)
7.46 (d, J ¼ 1.7 Hz, 1H), 7.33e7.37 (m, 3H), 7.22 (dd, J ¼ 1.7 Hz,
J ¼ 8.2 Hz, 1H), 5.23 (s, 2H), 4.28 (q, J ¼ 7.1 Hz, 2H), 3.86 (s, 6H), 3.74
Compound 14b was prepared from 13 (1.04 g, 3.0 mmol) and 4-
13
(
2-oxopiperidin-1-yl)benzoic acid [28] (0.99 g, 4.5 mmol) according
(s, 3H), 1.32 (t, J ¼ 7.1 Hz, 3H). C NMR (DMSO-d
6
, 75 MHz): d 165.8,
to the procedure for preparation of 7a. White powder (0.86 g, 52%),
164.8, 152.5, 142.8, 140.3, 129.4, 127.6, 127.5, 126.1, 117.1, 116.6, 105.5,
ꢁ
1
þ
m.p. 264e266 C. H NMR (DMSO-d
6
, 300 MHz):
d
10.23 (s, 1H),
60.3, 60.1. HRMS (ESI-TOF): calcd for C19
375.1551, found 375.1556. IR (KBr, cm ):
1583, 1491, 1336, 1231, 1127.
H
23
N
2
O
6
[M þ H]
ꢂ1
9
.99 (s,1H), 8.13 (s, 1H), 8.01 (s, 3H), 7.87 (d, J ¼ 12.3 Hz, 2H), 7.46 (d,
n 3424, 3337, 1711, 1631,
J ¼ 7.2 Hz, 2H), 7.38 (s, 1H), 7.23 (s, 2H), 3.77 (s, 6H), 3.72 (s, 3H),
1
3
3
7
1
.67 (s, 2H), 2.43 (s, 2H), 1.87 (br.s, 4H). C NMR (DMSO-d
5 MHz): 169.1, 167.1, 165.2, 164.8, 152.7, 146.8, 134.5, 131.0, 130.3,
29.4, 128.2, 125.9, 125.6, 124.9, 124.3, 105.1, 60.1, 55.9, 50.4, 32.7,
6
,
d
4.1.28. Ethyl-(4-(2-oxopyridin-1(2H)-yl)benzamido)-3-(3,4,5-
trimethoxybenzamido)benzoate (19)
þ
2
5
2.9, 20.8. HRMS (ESI-TOF): calcd for C29
47.2187, found 547.2197. IR (KBr, cm ):
H
31
N
4
O
7
[M þ H]
Compound 19 was prepared from 18 (2.25 g, 6.0 mmol) and 4-
(2-oxopyridin-1(2H)-yl)benzoic acid 1 (1.94 g, 9.0 mmol) according
to the procedure for preparation of 7a. Pale-white solid (2.33 g,
ꢂ1
n 3486, 3275, 2941, 1685,
1644, 1593, 1502, 1337, 1136.
ꢁ
1
6
8%), m.p. 166e168 C. H NMR (DMSO-d , 300 MHz): d 10.36 (s,
6
4
.1.24. N-(4-Carbamoyl-2-(3,4,5-trimethoxybenzamido)phenyl)-2-
1H),10.06 (s,1H), 8.26 (d, J ¼ 1.5 Hz,1H), 8.14 (d, J ¼ 8.4 Hz, 2H), 8.02
(d, J ¼ 8.4 Hz, 1H), 7.91 (dd, J ¼ 1.6 Hz, J ¼ 8.5 Hz, 1H), 7.68 (dd,
J ¼ 1.3 Hz, J ¼ 6.2 Hz, 1H), 7.56e7.61 (m, 2H), 7.51e7.54 (m, 1H), 7.26
(s, 2H), 6.51 (d, J ¼ 9.2 Hz, 1H), 6.36 (t, J ¼ 6.7 Hz, 1H), 4.36 (q,
oxo-1-phenyl-1,2-di- hydropyridine-4-carboxamide (15)
Compound 15 was prepared from 13 (0.35 g, 1.0 mmol) and 2-
oxo-1-phenyl-1,2-dihydropyridine-4-carboxylic acid (0.32 g,
13
1.5 mmol) according to the procedure for preparation of 7a. Yellow
J ¼ 7.0 Hz, 2H), 3.78 (s, 6H), 3.72 (s, 3H), 1.35 (t, J ¼ 7.0 Hz, 3H).
C
ꢁ
1
solid (0.26 g, 49%), m.p. 265e269 C. H NMR (DMSO-d
10.12 (s, 1H), 9.89 (s,1H), 8.53 (d, J ¼ 1.5 Hz,1H), 8.01e8.03 (m, 3H),
.94 (d, J ¼ 8.4 Hz, 1H), 7.82 (d, J ¼ 8.4 Hz, 1H), 7.46e7.55 (m, 5H),
6
, 300 MHz):
6
NMR (DMSO-d , 75 MHz): d 165.1, 165.02, 164.99, 161.0, 152.7, 143.6,
140.8, 138.6, 136.2, 133.5, 130.3, 129.3, 128.6, 127.1, 126.8, 126.6,
d
7
126.2, 124.7, 120.6, 105.8, 105.2, 60.8, 60.1, 56.0, 14.2. HRMS (ESI-
þ
7
3
.37 (br.s,1H), 7.21 (s, 2H), 6.60 (d, J ¼ 9.6 Hz,1H), 3.76 (s, 6H), 3.73 (s,
TOF): calcd for C31
30
H N
3
O
8
[M þ H] 572.2027, found 572.2034. IR
13
ꢂ1
H). C NMR (DMSO-d
6
, 75 MHz):
d
166.9, 164.6, 163.0, 160.9, 152.6,
(KBr, cm ):
n
3227, 1720, 1653, 1590, 1535, 1505, 1475, 1340, 1126.