Month 2016
Synthesis of thiophene-2-carboxamide derivatives
13C-NMR (100MHz, DMSO-d6) δ: δ: 25.26 (C-24, C-26),
25.60 (C-25), 32.57 (C-23, C-27), 49.07 (C-22), 57.0-
57.03 (C-19, C-20), 100.97 (C-15), 103.08 (C-12), 107.86
(C-16), 125.60 (C-3), 128.74 (C-2), 138.14 (C-4), 149.69
(C-5), 150.89 (C-11), 151.2 (C-14), 155.2 (C-13), 156.91
(C-9), 157.38 (C-17), and 161.87(C-7). LC-MS (ESI, m/z):
413.5 (M+H). Anal. Calcd. for C21H24N4O3S (412.51): C,
61.15; H, 5.86; N, 13.58. Found: C, 61.23; H, 5.76; N, 13.44.
3-(6,7-Dimethoxy-quinazolin-4-ylamino)-thiophene-2-carboxylic
obtained as a pale brown solid (380mg, 53%). mp: 249.6–
252.1°C. IR (ATR, cmꢀ1) ʋ: 3310.42 (N-H), 3102.8 (amide
N-H), 3078.64 (Ar-CH), 1635.68 (C¼O), 1541.39 (Ar-
1
C¼C), 1277.37 (C–O). H-NMR (300 MHz, DMSO-d6) δ
(ppm): 3.99 (s, 3H, –OCH3), 4.01 (s, 3H, –OCH3), 7.34 (s,
1H, Ar-H), 7.79 (s, 1H, Ar-H), 7.84 (d, J=5.4Hz, 1H,
thiophene-H), 7.87 (d, J= 8.7 Hz, 2H, Ar-H), 7.90 (d,
J=5.1Hz, 1H, thiophene-H), 8.0 (d, J= 8.4 Hz, 2H, Ar-H),
8.89 (s, 1H, Ar-H), 11.37 (bs, 1H, -NH). 13C-NMR
(100MHz, DMSO-d6) δ: 56.98 (C-19), 57.30 (C-20),
102.36 (C-15), 104.21 (C-12), 108.93 (C-16), 119.93
(C-28), 123.93 (C-23. C-27), 124.12 (C-24, C-26), 128.1
(C-25), 129.98 (C-3), 137.32 (C-2), 138.13 (C-4), 140.73
(C-22), 146.90 (C-11), 146.98 (C-5), 149.73 (C-14), 151.18
(C-13), 153.97 (C-9), 156.99 (C-17), and 162.13(C-7).
LC-MS (ESI, m/z): 475.4 (M+ H). Anal. Calcd. for
C22H17F3N4O3S (474.46): C, 55.69; H, 3.61; N, 11.81.
Found: C, 55.78; H 3.64; N, 11.70.
acid (4-fluoro-phenyl)-amide (7d).
This compound was
prepared by coupling of compound 6 with 4-fluoroaniline in
the presence of EDC.HCl. It was obtained as an off-white
solid (460 mg, 72%). mp: 233.6–235.8°C. IR (ATR, cmꢀ1) ʋ:
3190.34 (N-H), 3024.46 (amide N-H), 1620.72 (C¼O),
1520.46 (Ar-C¼C), 1268.26 (C–O). 1H-NMR (300MHz,
DMSO-d6) δ (ppm): 3.96 (s, 3H, –OCH3), 4.01 (s, 3H,
–OCH3), 7.32 (s, 1H, Ar-H), 7.66 (d, J= 9.0 Hz, 2H, Ar-H),
7.8 (s, 1H, Ar-H), 7.87 (d, J= 5.4 Hz, 1H, thiophene-1H),
7.97 (d, J= 8.7 Hz, 2H, Ar-H), 7.95 (d, J= 5.1 Hz, 1H,
thiophene-H), 8.85 (s, 1H, –N¼CH), 10.3 (bs, -NH), 11.8
(bs, 1H, -NH). 13C-NMR (100MHz, DMSO-d6) δ: 57.08–
57.22 (C-19, C-20), 100.93 (C-15), 103.72 (C-12), 107.93
(C-16), 115.87 (C-24, C-26), 120.10 (C-23, C-27), 129.83 (C-
3), 136.72 (C-2), 138.1 (C-4), 136.89 (C-22), 147.1 (C-5),
147.36 (C-11), 150.01 (C-14), 150.93 (C-13), 154.60 (C-9),
158.32 (C-25), 161.33 (C-17), and 164.12 (C-7). LC-MS
(ESI, m/z): 425.4 (M+ H). Anal. Calcd. for C21H17FN4O3S
(424.46): C, 59.43; H, 4.04; N, 13.20. Found: C, 59.32; H,
3.96; N, 13.26.
3-(6,7-Dimethoxy-quinazolin-4-ylamino)-thiophene-2-carboxylic
acid (3-fluoro-phenyl)-amide (7e). This compound was prepared
by coupling of compound 6 with 3-fluoroaniline in the presence
of EDC.HCl. It was obtained as an off-white solid (520 mg,
81%). mp: 248.2–250.1°C. IR (ATR, cmꢀ1) ʋ: 3298.42 (N-H),
3090.22 (amide N-H), 3010.77 (Ar-CH), 1626.68 (C¼O),
1533.27 (Ar-C¼C), 1276.17(C–O). 1H-NMR (300MHz,
DMSO-d6) δ (ppm): 3.96 (s, 3H, –OCH3), 4.0 (s, 3H,
–OCH3), 7.3 (s, 1H, Ar-H), 7.32–7.47 (m, 3H, Ar-H), 7.61–
7.65 (m, 1H, Ar-H), 7.8 (s, 1H, Ar-H), 7.87 (d, J= 5.4Hz, 1H,
thiophene-1H), 7.97 (d, J= 5.1 Hz, 1H, thiophene-H), 8.85 (s,
1H, –N¼CH), 10.45 (bs, 1H, –NH), 11.79 (bs, 1H, -NH). 13C-
NMR (100 MHz, DMSO-d6) δ: 57.01–57.11 (C-19, C-20),
100.86 (C-15), 103.53 (C-12), 107.64-107.90 (C-16), 116.76
(C-23), 110.85-111.06 (C-25), 126.80 (C-27), 129.79 (C-3),
130.68-130.77 (C-26), 136.68 (C-2), 137.23 (C-4), 140.69-
140.80 (C-22), 146.1 (C-5), 146.72 (C-11), 149.53 (C-14),
150.89 (C-13), 153.82 (C-9), 160.97 (C-24), 161.21 (C-17),
and 163.60 (C-7). LC-MS (ESI, m/z): 425.4 (M+ H). Anal.
Calcd. for C21H17FN4O3S (424.46): C, 59.43; H, 4.04; N,
13.20. Found: C, 59.28; H, 3.92; N, 13.0.
3-(6,7-Dimethoxy-quinazolin-4-ylamino)-thiophene-2-
carboxylicacid cyclopropylamide (7g). This compound was
prepared by coupling of compound 6 with cyclopropylamine
in the presence of EDC.HCl. It was obtained as a yellow
solid (335mg, 60%). mp: 243.8–249.2°C. IR (ATR, cmꢀ1) ʋ:
3198.67 (N-H), 3082.41 (amide N-H), 2891.64 (Ar-CH),
1
1624.05 (C¼O), 1512.50 (Ar-C¼C), 1275.23 (C–O). H-
NMR (300 MHz, DMSO-d6) δ (ppm): 0.53–0.6 (m, 2H,
cyclopropane), 0.65–0.68 (m, 2H, cyclopropane), 2.83–2.89
(m, 1H, cyclopropane), 3.98 (s, 3H, –OCH3), 4.01 (s, 3H,
–OCH3), 7.39 (s, 1H, Ar-H), 7.79 (s, 1H, Ar-H), 7.84 (d,
J=5.4Hz, 1H, thiophene-H), 7.87(d, J= 5.1 Hz, 1H,
thiophene-H), 8.90 (s, 1H, Ar-H), 12.45 (bs, 1H, -NH). 13C-
NMR (100MHz, DMSO-d6) δ: 8.47 (C-23, C-24), 28.29 (C-
22), 57.0-57.03 (C-19, C-20), 105.51 (C-15), 107.72 (C-12),
112.59 (C-16), 127.79 (C-3), 130.21 (C-2), 133.76 (C-4),
141.41 (C-5), 143.25 (C-11), 154.35 (C-14), 155.72 (C-13),
161.73 (C-9), 162.00 (C-17), and 168.98 (C-7). LC-MS (ESI,
m/z): 371.4 (M+ H). Anal. Calcd. for C18H18N4O3S (370.43):
C, 58.36; H, 4.90; N, 15.21. Found: C, 58.24; H 4.84; N, 14.98.
Acknowledgments. We are thankful to the Anthem Biosciences
management, Anthem Biosciences, Bangalore, India, for their
invaluable support and allocation of resources for this work. We
would like to thank the Analytical Chemistry team, Department
of Analytical Chemistry, Anthem Biosciences, Bangalore, India,
for having carried out all the analytical work. Also, we would
like to thank the Molecular Biology team of Anthem
Biosciences for executing the VEGFR-2 activity studies.
REFERENCES AND NOTES
[1] Carmeliet, P. Nature 2006, 438, 932.
[2] Folkman, J. N Engl J Med 1971, 285, 1182.
[3] Klagsbrun, M.; Moses, M. A. Chem Biol 1999, 6, R217.
3-(6,7-Dimethoxy-quinazolin-4-ylamino)-thiophene-2-carboxyli
cacid (4-trifluoromethyl-phenyl)-amide (7f). This compound
was prepared by coupling of compound 6 with 4-
trifluoromethylaniline in the presence of EDC.HCl. It was
[4] Cross, M. J.; Dixelius, J.; Matsumoto, T.; Claesson-Welsh, L.
Trends Biochem Sci 2003, 28, 488.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet