526 JOURNAL OF CHEMICAL RESEARCH 2015
for 6 h at 55 °C. The product was obtained by filtration of palladium
dissolving tetrahydrofuran (20 mL). Sodium granules were the added
to the solution which was stirred overnight at 0 °C. Then the solution
(15 mL) was transferred to a dry flask and cooled to –20 °C. N-butyl
lithium (36 mL) was added dropwise at –20 °C in about 30 min with
stirring. A suspension of (10) (4.00 g, 9.83 mmol) in THF (60 mL) was
stirred under –20 °C. Then the above solution was added dropwise to
the suspension at –20 °C (monitored by TLC). The mixture was added
to buffer (NaHCO :Na CO = 1:1) under 5 °C with stirring and there
carbon, and solvent evaporation gave a pale yellow solid; yield 96%
1
(
24.47 g); m.p. 148.4–149.4 °C (lit. 148.5–151.5 °C); H NMR (600 MHz,
DMSO-d ): δ 7.18 (s, 1 H), 6.94 (d, J = 8.4 Hz, 1 H), 6.71 (d, J = 9.0 Hz, 1
6
13
H), 3.64 (s, 3 H). C NMR (151 MHz, DMSO-d ): δ 169.3, 148.9, 146.2,
6
–1
1
1
22.8, 117.9, 112.7, 109.2, 55.2. IR (KBr, νmax/cm ): 3458, 3351, 1673,
597, 1561, 1494, 1424, 1297, 1266, 1215, 1174, 1037, 910, 824.
-Cyanobenzoyl chloride (6): 4-Cyanobenzoic acid (5) (30.00 g,
03.90 mmol) was added to thionyl chloride (29.11 g, 244.68 mmol) in
4
3
2
3
2
was a precipitation. Betrixaban was obtained as a white solid after
1
batches with magnetic stirring. Then, three drops of DMF were added
to the solution. The reaction mixture was heated to reflux and stirred for
filtration; yield 68% (3.03 g). M.p. 214.5–215.5 °C; H NMR (600 MHz,
DMSO-d ): δ 8.73 (d, J = 9.0 Hz, 1 H), 8.51 (d, J = 7.8 Hz, 2 H), 8.35 (d,
6
1
.5 h (monitored by TLC). The solution was distilled at 235 °C to yield a
J = 9.0 Hz, 1 H), 8.17 (d, J = 8.4 Hz, 1 H), 7.77 (d, J = 3.6 Hz, 1 H), 7.61
(dd, J = 3.0, 9.0 Hz, 1 H), 7.41 (d, J = 8.4 Hz, 2 H), 6.94 (dd, J = 3.6, 9.0
1
white solid; yield 98% (5.50 g); m.p. 67.2–68.2 °C; H NMR (600 MHz,
DMSO-d ): δ 8.06 (d, J = 7.8 Hz, 2 H), 7.96 (d, J = 7.8 Hz, 2 H). C NMR
13
13
Hz, 1 H), 3.77 (s, 3 H), 2.84 (s, 6 H). C NMR (151 MHz, DMSO-d ): δ
6
6
(151 MHz, DMSO-d ): δ 165.9, 134.7, 132.6, 129.9, 118.1, 115.1. IR (KBr,
167.3, 165.8, 163.9, 154.3, 146.3, 137.5, 137.0, 128.1, 127.5, 126.6, 123.7,
6
–1
–1
νmax/cm ): 3101, 3051, 2229, 1772, 1739, 1597, 1401, 1287, 1211, 1167,
123.3, 117.3, 116.8, 113.7, 55.2. IR (KBr, νmax/cm ): 3310–2920, 1666,
+
+
896, 851, 634. HR-MS (ESI) m/z: [M+H] calcd for C H ClNO+H
1588, 1524, 1451, 1419, 1369, 1291, 1214, 1114, 1073, 931, 836, 768. HR-
8
4
+
+
1
66.0053; found 166.0054.
-(4-Cyanobenzamido)-5-methoxybenzoic acid (7): 2-Amino-5-
methoxybenzoic acid (4) (27.73 g, 165.88 mmol) was dissolved in THF
550 mL). The solution was stirred at –5–0 °C for 20 min and Et N
MS (ESI) m/z: [M+H] calcd for C H ClN O +H 452.1493; found
23 22 5 3
2
452.1484.
(
Published online: 1 September 2015
3
(17.92 g, 177.09 mmol ) was added to the solution. Then, 4-cyanobenzoyl
chloride (27.46 g, 165.88 mmol) in THF (50 mL) was added dropwise
to the above mixture at –5–0 °C. Subsequently, the mixture was stirred
at room temperature for 1 h (monitored by TLC). Then the mixture was
References
evaporated to yield a white solid; yield 94% (46.13 g); m.p. 222.5–223.5
1
1
°
1
C; H NMR (600 MHz, DMSO-d ): δ 11.85 (s, 1 H), 8.46 (d, J = 6.0 Hz,
6
13
2
P. Zhang, W. Huang, L. Wang, L. Bao, Z. J. Jia, S. M. Bauer, E. A. Goldman,
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H), 8.06 (s, 4 H), 7.49 (s, 1 H), 7.27 (s, 1 H), 3.79 (s, 3 H). C NMR (151
MHz, DMSO-d ): δ 169.3, 162.8, 154.8, 138.6, 133.5, 132.9, 127.8, 122.4,
6
–1
120.0, 119.2, 118.2, 114.9, 114.1, 55.4. IR (KBr, νmax/cm ): 3141, 2230,
1705, 1666, 1612, 1539, 1508, 1387, 1315, 1203, 1037, 853, 822, 790, 732.
3
4
5
+
+
HR-MS (ESI) m/z: [M+Na] calcd for C H N O +Na 319.0711; found
16
12
2
4
319.0689.
M. Palladino, G. Merli and L. Thomson, Expert Opin. Investig. Drugs, 2013,
2
2, 1465.
2-(4-Cyanobenzamido)-5-methoxybenzoyl chloride (8): 2-(4-Cyano-
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benzamido)-5-methoxybenzoic acid (7) (24.01 g, 81.04 mmol) was
added to THF (480 mL) in a three-neck round-bottom flask with magnetic
stirring. Then, three drops of DMF and thionyl chloride (11.55 g, 97.08
mmol) were added to the solution. After that it was heated to 66 °C and
stirred for 3 h (monitored by TLC). Then the solution was evaporated to
6
7
8
1
9
10
G. Denas and V. Pengo, Expert Opin. Investig. Drugs, 2013, 22, 1281.
S. J. Connolly, J. Eikelboom, P. Dorian, S. H. Hohnloser, D. D. Gretler, U.
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yield a yellow solid; yield 94% (24.03 g); m.p. 234.7–235.7 °C; H NMR
(
7
600 MHz, CDCl ): δ 8.39 (d, J = 7.8 Hz, 2 H), 7.80 (d, J = 7.8 Hz, 2 H),
3
13
.65 (t, 2 H), 7.44 (d, J = 9.0 Hz, 1 H), 3.94 (s, 3 H). C NMR (151 MHz,
11
CDCl ): δ 160.0, 159.2, 153.3, 140.5, 134.4, 132.5, 129.2, 128.4, 126.2,
3
12 J. P. Kanter, K. Suizno and S. S. Zuberi, WO Patent 2008057972, 2008.
13 A. Pandey, E. P. T. Leitao, J. Rato and Z. J. Song, WO Patent 2011084519,
2011.
–1
1
1
18.2, 118.0, 115.4, 108.9, 56.1. IR (KBr, νmax/cm ): 2224, 1759, 1623,
572, 1489, 1349, 1292, 1251, 1064, 1027, 836, 779. HR-MS (ESI) m/z:
+
+
14 H. Zhao, Q. Q. Chun, H. Wang and Z. H. Shang, Zhongguo Xinyao Zazhi,
[M+H] calcd for C H ClN O +H 315.0545; found 315.0531.
16 11 2 3
2
014, 23, 2902.
N - (5 - Chloropyr idi n-2-yl) -2- (4 - c ya nobenza m id o) -5 -
15
D. F. Chen, S. Hui, Z. P. Hu, B. K. Gao, R. Cheng, X. M. Jia, X. F. Liu, J. Luo
and Z. X. Xiang, CN Patent 104693114 A, 2015.
methoxybenzamide (10): 5-Chloropyridin-2-amine (9) (10.02 g, 77.79
mmol) in anhydrous (150 mL) acetonitrile was stirred at –5–0 °C for
2
16
Y. R. Babu, M. Bhagavanraju, G. D. Reddy, G. J. Peters and V. V. S. R.
0 min, then sodium hydride (3.20 g, 133.38 mmol) was added to the
solution. After that, compound 8 (18.00 g, 57.19 mmol) dissolved in
acetonitrile was added dropwise to the mixture, and the temperature
remained unchanged. The solution was stirred at room temperature for
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18
2
19
P. K. S. Sarma, V. P. Acharya, S. R. Kasibhatla, A. Tiwari, V. N. Reddy and
A. Bischoff, WO Patent 2010127208, 2010
1
h (monitored by TLC). The mixture was evaporated to a third and
filtered to give a yellow-green solid. The solid was recrystallised in
acetonitrile to give N-(5-chloropyridin-2-yl)-2-(4-cyanobenzamido)-5-
2
0
A. Kudelko and M. Wróblowska, Tetrahedron. Lett. 2014, 55, 3252.
21 R. Zhang, L. Lei, Y. G. Xu, W. Y. Hua and G. Q. Gong, Bioorg. Med. Chem.
Lett., 2007, 17, 2430.
1
methoxybenzamide; yield 81% (19.21 g); m.p. 210.4–211.4 °C; H NMR
2
2
2
3
J. H. Lee, S. Kang, J. Y. Lee and J. H. Jung, Soft. Matter., 2012, 8, 6557.
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(
8
600 MHz, DMSO-d ): δ 11.14 (s, 1 H), 10.99 (s, 1 H), 8.42 (s, 1 H),
6
.13 (d, J = 9.0 Hz, 1 H), 8.02 (s, 4 H), 7.94 (d, J = 8.4 Hz, 2 H), 7.39
13
(s, 1 H), 7.17 (d, J = 8.4 Hz, 1 H), 3.85 (s, 3 H). C NMR (151 MHz,
DMSO-d ): δ 167.0, 163.5, 155.6, 150.6, 146.3, 138.6, 137.8, 132.7, 129.9,
6
24 M.J. Ashton, D.C. Cook, G. Fenton, J.A. Karlsson, M.N. Palfreyman, D.
Raeburn, A.J. Ratcliffe, J.E. Souness, S. Thurairatnam and N. Vicker, J.
Med. Chem., 1994 37, 1696.
1
28.1, 127.0, 125.7, 124.9, 118.3, 117.9, 116.1, 113.9, 113.8, 55.4. IR (KBr,
–1
νmax/cm ): 3229, 2228, 1679, 1513, 1460, 1418, 1370, 1298, 1280, 1218,
+
25 B. Kohl, B. Mueller and W. Palosch, WO Patent 2004080967, 2004.
1118, 1070, 931, 827, 751, 674. HR-MS (ESI) m/z: [M+Na] calcd for
2
6
G. Y. Chen, Y. W. Zhou, C. L. Cai, J. Lu and X. Zhang, Molecules, 2014,
+
C H ClN O +Na 429.0742; found 429.0725.
21
15
4
3
Betrixaban (1): Dimethylamine aqueous solution was added dropwise
to sodium hydroxide in a three-neck round-bottom flask with magnetic
stirring. Dimethylamine (4.43 g, 98.26 mmol) gas was accurate achieved
2
2
7
8
P. Vitale, L. D. Nunno and A. Scilimati, Tetrahedron, 2011, 67, 6944.
29 A. Morrison and T. P. C. Mulholland, J. Chem. Soc., 1958, 1702.