B. Mathew, P. Ruiz, S. Dutta et al.
European Journal of Medicinal Chemistry xxx (xxxx) xxx
4.6.65. 3-(2-((2,6-Difluorophenyl)amino)oxazol-5-yl)benzoic acid
(65) and methyl 3-(2-((2,6-difluorophenyl)amino)oxazol-5-yl)
benzoate (79)
4.6.68. 3-(2-((2,3-Difluorophenyl)amino)oxazol-5-yl)benzoic acid
(68) and methyl 3-(2-((2,3-difluorophenyl)amino)oxazol-5-yl)
benzoate (82)
By following procedure 4, the title compound 79 was obtained
from methyl 3-(2-bromoacetyl)benzoate and 1,3-difluoro-2-iso-
thiocyanatobenzene as a colorless solid in 56% yield (HPLC purity:
98.9%). TLC Rf ¼ 0.35 (30% EtOAc in Hexanes). M. P. ¼ 188e190 ꢀC.
By following procedure 4, the title compound 82 was obtained
from methyl 3-(2-bromoacetyl)benzoate and 2,3-difluoro-1-iso-
thiocyanatobenzene as a colorless solid in 58% yield (HPLC purity:
96.5%). TLC Rf ¼ 0.35 (30% EtOAc in Hexanes). M. P. ¼ 179e181 ꢀC.
ESI-MS m/z: 331.1. 1H NMR (400 MHz, DMSO‑d6):
d
9.80 (s, 1H), 8.03
ESI-MS m/z: 331.1. 1H NMR (400 MHz, DMSO‑d6):
d 10.44 (s, 1H),
(t, J ¼ 1.8 Hz, 1H), 7.84e7.73 (m, 2H), 7.59e7.50 (m, 1H), 7.47 (s, 1H),
7.31 (q, J ¼ 7.1, 6.5 Hz, 1H), 7.20 (t, J ¼ 8.0 Hz, 2H), 3.86 (s, 3H). HRMS
calcd for [C17H12F2N2O3þH]þ: 331.0884, Found: 331.0884.
8.14 (dt, J ¼ 1.8, 0.9 Hz, 1H), 8.03 (t, J ¼ 7.8 Hz, 1H), 7.86 (dddd,
J ¼ 13.7, 7.8, 1.8, 1.1 Hz, 2H), 7.63e7.57 (m, 2H), 7.18 (tdd, J ¼ 8.4, 6.0,
2.1 Hz, 1H), 7.04 (dddd, J ¼ 10.2, 8.6, 7.2, 1.5 Hz, 1H), 3.87 (s, 3H).
HRMS calcd for [C17H12F2N2O3þH]þ: 331.0884, Found: 331.0889.
Compound 82 was hydrolyzed by following procedure 2 to get
compound 68 as a colorless solid in 63% yield (HPLC purity: 99.7%).
TLC Rf ¼ 0.25 (40% EtOAc in Hexanes). M. P. ¼ 281e283 ꢀC. ESI-MS
Compound 79 was hydrolyzed by following procedure 2 to get
compound 65 as a colorless solid in 19% yield (HPLC purity: 95.1%).
TLC Rf ¼ 0.25 (40% EtOAc in Hexanes). M. P. ¼ 242e244 ꢀC. ESI-MS
m/z: 317.0. 1H NMR (400 MHz, DMSO‑d6):
d 9.78 (s, 1H), 8.02 (t,
J ¼ 1.7 Hz, 1H), 7.76 (ddt, J ¼ 22.6, 7.8, 1.5 Hz, 2H), 7.56e7.42 (m, 2H),
7.37e7.27 (m, 1H), 7.25e7.13 (m, 2H). HRMS calcd for
[C16H10F2N2O3þH]þ: 317.07323, Found: 317.07389.
m/z: 317.0. 1H NMR (400 MHz, DMSO‑d6):
d 10.44 (s, 1H), 8.16 (td,
J ¼ 1.8, 0.5 Hz, 1H), 8.03 (ddt, J ¼ 8.7, 7.3, 1.6 Hz, 1H), 7.85e7.75 (m
2H), 7.60 (s, 1H), 7.54 (t, J ¼ 8.4 Hz, 1H), 7.21e7.13 (m, 1H), 7.07e6.99
(m, 1H). 13C NMR (100 MHz, DMSO‑d6):
d 167.0, 156.3, 150.1 (dd, JC-
¼ 244.2, 10.5 Hz), 143.6, 140.3 (dd, JC-F ¼ 247.2, 15.0 Hz), 131.7,
F
4.6.66. 3-(2-((2,4-Difluorophenyl)amino)oxazol-5-yl)benzoic acid
(66) and methyl 3-(2-((2,4-difluorophenyl)amino)oxazol-5-yl)
benzoate (80)
129.4, 129.1 (dd, JC-F ¼ 8.2, 2.3 Hz), 128.2, 127.9, 126.8, 124.4 (dd, JC-
¼ 8.6, 4.8 Hz), 123.3, 123.2, 115.1 (d, JC-F ¼ 2.9 Hz), 110.0 (d, JC-
F
¼ 17.1 Hz). HRMS calcd for [C16H10F2N2O3þH]þ: 317.07323, Found:
F
By following procedure 4, the title compound 80 was obtained
from methyl 3-(2-bromoacetyl)benzoate and 2,4-difluoro-1-iso-
thiocyanatobenzene as a colorless solid in 52% yield (HPLC purity:
100%). TLC Rf ¼ 0.35 (30% EtOAc in Hexanes). M. P. ¼ 193e195 ꢀC.
317.07346.
4.6.69. 4-(2-((2-Fluorophenyl)amino)oxazol-5-yl)benzoic acid (69)
and methyl 4-(2-((2-fluorophenyl)amino)oxazol-5-yl)benzoate (83)
By following procedure 4, the title compound 83 was obtained
from methyl 4-(2-bromoacetyl)benzoate and 1-fluoro-2-iso-
thiocyanatobenzene as a colorless solid in 36% yield (HPLC purity:
95%). TLC Rf ¼ 0.35 (30% EtOAc in Hexanes). M. P. ¼ 217e219 ꢀC. ESI-
ESI-MS m/z: 331.1. 1H NMR (400 MHz, DMSO‑d6):
d 10.14 (s, 1H),
8.22e8.06 (m, 2H), 7.84 (dddd, J ¼ 10.6, 7.8, 1.8, 1.2 Hz, 2H),
7.65e7.51 (m, 2H), 7.32 (ddd, J ¼ 11.6, 8.9, 2.9 Hz, 1H), 7.15e7.00 (m,
1H), 3.87 (s, 3H). HRMS calcd for [C17H12F2N2O3þH]þ: 331.0884,
Found: 331.0883.
MS m/z: 313.1. 1H NMR (400 MHz, DMSO‑d6):
d 10.23 (s, 1H), 8.15
Compound 80 was hydrolyzed by following procedure 2 to get
compound 66 as a colorless solid in 33% yield (HPLC purity: 95.4%).
TLC Rf ¼ 0.25 (40% EtOAc in Hexanes). M. P. ¼ 262e264 ꢀC. ESI-MS
(td, J ¼ 8.4, 1.7 Hz, 1H), 8.04e7.98 (m, 2H), 7.73e7.67 (m, 3H),
7.30e7.17 (m, 2H), 7.09e7.02 (m, 1H), 3.86 (s, 3H). HRMS calcd for
[C17H13FN2O3þH]þ: 313.0983, Found: 313.0992.
m/z: 317.0. 1H NMR (400 MHz, DMSO‑d6):
d
10.12 (s, 1H), 8.21e8.08
Compound 83 was hydrolyzed by following procedure 2 to get
compound 69 as a colorless solid in 17% yield (HPLC purity: 96.3%).
TLC Rf ¼ 0.25 (40% EtOAc in Hexanes). M. P. ¼ 267e269 ꢀC. ESI-MS
(m, 2H), 7.81 (dd, J ¼ 7.7, 1.8 Hz, 2H), 7.59e7.47 (m, 2H), 7.32 (ddd,
J ¼ 11.6, 8.9, 2.9 Hz, 1H), 7.12e7.05 (m, 1H). HRMS calcd for
[C16H10F2N2O3þH]þ: 317.07323, Found: 317.07366.
m/z: 299.1. 1H NMR (400 MHz, DMSO‑d6):
d 10.20 (s, 1H), 8.15 (td,
J ¼ 8.3, 1.7 Hz, 1H), 8.03e7.96 (m, 2H), 7.71e7.64 (m, 3H), 7.30e7.17
(m, 2H), 7.10e7.03 (m, 1H). HRMS calcd for [C16H11FN2O3þH]þ:
299.08265, Found: 299.0827.
4.6.67. 3-(2-((2,5-Difluorophenyl)amino)oxazol-5-yl)benzoic acid
(67) and methyl 3-(2-((2,5-difluorophenyl)amino)oxazol-5-yl)
benzoate (81)
4.6.70. 4-(2-((3-Fluorophenyl)amino)oxazol-5-yl)benzoic acid (70)
and methyl 4-(2-((3-fluorophenyl)amino)oxazol-5-yl)benzoate (84)
By following procedure 4, the title compound 84 was obtained
from methyl 4-(2-bromoacetyl)benzoate and 1-fluoro-3-iso-
thiocyanatobenzene as an off-white solid in 39% yield (HPLC purity:
99%). TLC Rf ¼ 0.35 (30% EtOAc in Hexanes). M. P. ¼ 216e218 ꢀC. ESI-
By following procedure 4, the title compound 81 was obtained
from methyl 3-(2-bromoacetyl)benzoate and 2,5-difluoro-1-iso-
thiocyanatobenzene as a colorless solid in 51% yield (HPLC purity:
99.1%). TLC Rf ¼ 0.35 (30% EtOAc in Hexanes). M. P. ¼ 175e177 ꢀC.
ESI-MS m/z: 331.1. 1H NMR (400 MHz, DMSO‑d6):
d 10.51 (s, 1H),
8.25e8.10 (m, 2H), 7.87 (dddd, J ¼ 16.0, 7.8, 1.8, 1.2 Hz, 2H),
7.68e7.63 (m, 1H), 7.63e7.56 (m, 1H), 7.29 (ddd, J ¼ 10.9, 9.0, 5.1 Hz,
1H), 6.87e6.75 (m, 1H), 3.88 (s, 3H). HRMS calcd for
[C17H12F2N2O3þH]þ: 331.0884, Found: 331.0882.
MS m/z: 313.1. 1H NMR (400 MHz, DMSO‑d6):
d 10.77 (s, 1H),
8.04e7.99 (m, 2H), 7.74e7.69 (m, 3H), 7.66e7.60 (m, 1H), 7.38e7.32
(m, 2H), 6.82e6.75 (m, 1H), 3.86 (s, 3H). HRMS calcd for
[C17H13FN2O3þH]þ: 313.0983, Found: 313.0990.
Compound 81 was hydrolyzed by following procedure 2 to get
compound 67 as a colorless solid in 39% yield (HPLC purity: 99.6%).
TLC Rf ¼ 0.25 (40% EtOAc in Hexanes). M. P. ¼ 290e292 ꢀC. ESI-MS
Compound 84 was hydrolyzed by following procedure 2 to get
compound 70 as a colorless solid in 16% yield (HPLC purity: 96.2%).
TLC Rf ¼ 0.25 (40% EtOAc in Hexanes). M. P. ¼ 282e284 ꢀC. ESI-MS
m/z: 317.1. 1H NMR (400 MHz, DMSO‑d6):
d
10.49 (s, 1H), 8.24e8.12
m/z: 299.0. 1H NMR (400 MHz, DMSO‑d6):
d 10.75 (s, 1H), 8.01e7.97
(m, 2H), 7.84 (tt, J ¼ 7.8, 1.4 Hz, 2H), 7.64 (s, 1H), 7.55 (t, J ¼ 7.8 Hz,
(m, 2H), 7.71e7.61 (m, 4H), 7.39e7.31 (m, 2H), 6.79 (ddt, J ¼ 8.8, 5.6,
2.8 Hz, 1H). HRMS calcd for [C16H11FN2O3þH]þ: 299.08265, Found:
299.0829.
1H), 7.28 (ddd, J ¼ 11.0, 9.0, 5.2 Hz, 1H), 6.85e6.77 (m, 1H). 13C NMR
(100 MHz, DMSO‑d6):
d
167.0, 158.1 (dd, JC-F ¼ 238.4, 2.1 Hz), 156.0,
147.8 (dd, JC-F ¼ 240.4, 2.5 Hz), 143.6, 131.7, 129.4, 128.3 (dd, JC-
¼ 26.1, 13.0 Hz), 128.1, 128.0, 126.8, 123.3, 123.2, 116.1 (dd, JC-
4.6.71. 4-(2-((4-Fluorophenyl)amino)oxazol-5-yl)benzoic acid (71)
and methyl 4-(2-((4-fluorophenyl)amino)oxazol-5-yl)benzoate (85)
By following procedure 4, the title compound 85 was obtained
from methyl 4-(2-bromoacetyl)benzoate and 1-fluoro-4-
F
¼ 21.3, 10.2 Hz), 107.8 (dd, JC-F ¼ 24.5, 7.5 Hz), 105.9 (d, JC-
F
¼ 30.3 Hz). HRMS calcd for [C16H10F2N2O3þH]þ: 317.07323,
F
Found: 317.07387.
17