Compound 4 (6 mmol) and potassium dihydrogenphosphate
(4.08 g, 30 mmol) were dissolved in acetonitrile (10 mL) and water
(10 mL), followed by the dropwise addition of sodium chlorite
(4.14 g, 60 mmol) dissolved in water (15 mL) at 0 °C. The reaction
mixture was stirred at room temperature and detected by TLC.
After completion, sodium hydroxide (1 mol/L) was added to adjust
pH to 10. The mixture was filtered and the filtrate was acidized by
hydrochloric acid (2 mol/L). Then the mixture was extracted with
ethyl acetate. The organic layer was washed with brine and
evaporated to obtain compounds 5a–f, directly used in the next
step without further purification.
N-(4-Chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1-(2-
chloro-5-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-
carboxamide (7d). White solid, yield 73.5%, m. p. 187-188 °C
(EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H, Ph-NH-
CO), 8.33 (d, J = 4.5 Hz, 1H, Ph-CO-NH), 7.69 (s, 1H, Ph-H), 7.50
– 7.54 (m, 2H, Ph-H and Pyrazole-H), 7.36 (d, J = 2.1 Hz, 1H, Ph-
H), 7.23 (d, J = 2.9 Hz, 1H, Ph-H), 7.12 (dd, J = 8.9, 2.9 Hz, 1H,
Ph-H), 3.80 (s, 3H, OCH3), 2.66 (d, J = 4.5 Hz, 3H, NHCH3), 2.18
(s, 3H, Ph-CH3). 13C NMR (101 MHz, DMSO-d6), δ 166.18,
158.29, 155.64, 141.18, 139.41, 138.71, 137.93, 135.80, 131.59,
131.17, 130.85, 129.97, 125.33, 121.36, 120.85, 117.03, 114.45,
106.43, 55.93, 26.03, 17.62. Elem. anal. calcd. for
C21H17Cl2F3N4O3 (%): C 50.32; H 3.42; N 11.18. Found (%): C
50.35; H 3.45; N 11.15.
4.1.3. General Synthetic Procedure for Compounds 7a-l.
Compound
5 (1.0 mmol) was dissolved in anhydrous
N-(4-Bromo-2-methyl-6-(methylcarbamoyl)phenyl)-1-(2-
chloro-5-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-
carboxamide (7e). White solid, yield 68.3%, m. p. 190-191 °C
(EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H, Ph-NH-
CO), 8.36 (d, J = 4.5 Hz, 1H, Ph-CO-NH), 7.71 (s, 1H, Ph-H), 7.62
(d, J = 1.4 Hz, 1H, Ph-H), 7.51 (m, 2H, Ph-H and Pyrazole-H),
7.24 (d, J = 2.9 Hz, 1H, Ph-H), 7.13 (dd, J = 8.9, 2.9 Hz, 1H, Ph-
H), 3.81 (s, 3H, OCH3), 2.67 (d, J = 4.5 Hz, 3H, NHCH3), 2.19 (s,
3H, Ph-CH3). 13C NMR (101 MHz, DMSO-d6) δ 166.13, 158.29,
155.60, 141.21, 139.39, 138.95, 137.95, 136.02, 134.11, 132.05,
129.97, 128.19, 121.37, 120.89, 119.25, 116.99, 114.43, 106.46,
55.88, 26.02, 17.56. Elem. anal. calcd. for C16H14N4O5S2 (%): C
47.28; H 3.47; N 13.78. Found (%): C 47.31; H 3.49; N 13.82.
N-(4-Chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1-(2-
cyano-5-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbox
amide (7f). White solid, yield 52.7%, m. p. 195-196 °C (EtOAc).
1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 2.3 Hz, 1H, Ph-H),
8.54 (d, J = 4.3 Hz, 1H), 8.22 (dd, J = 9.2, 2.4 Hz, 1H, Ph-H), 7.96
(s, 1H, Ph-H), 7.85 (s, 1H, Pyrazole-H), 7.76 (d, J = 1.8 Hz, 1H,
Ph-H), 6.84 (d, J = 9.2 Hz, 1H, Ph-H), 2.45 (d, J = 4.4 Hz, 3H,
NHCH3), 2.10 (s, 3H, Ph-CH3). 13C NMR (101 MHz, DMSO-d6)
δ 164.87, 153.27, 143.96, 143.29, 141.09, 135.94, 135.76, 134.85,
134.26, 133.50, 131.38, 127.58, 123.86, 123.74, 121.11, 118.35,
111.83, 107.70, 26.50, 17.14. Elem. anal. calcd. for
C21H14ClF3N6O4 (%): C 49.77; H 2.78; N 16.58; Found (%): C
49.79; H 2.75; N 16.63.
dichloromethane (10 mL), followed by the dropwise addition of
oxalyl chloride (0.140 g, 1.1 mmol) and dimethyl formamide (0.1
mL), and the reaction was stirred at room temperature for 1 h. Then
the reaction mixture was evaporated to obtain the corresponding
acyl chloride, and the acyl chloride dissolved in anhydrous
tetrahydrofuran (10 mL) was dropwise added to the stirred mixture
of compound 6 (1 mmol) and N,N-diisopropylethylamine (0.142
g, 1.1 mmol) in anhydrous tetrahydrofuran at 0 °C. Then the
reaction was stirred at room temperature and detected by TLC.
After completion, the mixture was extracted with ethyl acetate, and
washed with saturated sodium bicarbonate, hydrochloric acid (2
mol/L) and brine successively. The organic layer was evaporated
and purified on silica gel with ethyl acetate/petroleum to afford
compounds 7a−l.
N-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1-(2,4-
dichloro-3-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbo
xamide (7a). Yellow solid, yield 68.5%, m. p. 198-199 °C (EtOAc).
1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H, Ph-NH-CO), 8.32
(d, J = 4.5 Hz, 1H, Ph-CO-NH), 8.04 (s, 2H, 2Ph-H), 7.83 (s, 1H,
Pyrazole-H), 7.50 (d, J = 1.9 Hz, 1H, Ph-H), 7.35 (d, J = 2.1 Hz,
1H, Ph-H), 2.63 (d, J = 4.5 Hz, 3H, NHCH3), 2.19 (s, 3H, Ph-CH3).
13C NMR (400 MHz, DMSO-d6) δ 166.58, 155.92, 147.85, 142.80,
139.97, 139.14, 138.37, 136.56, 132.35, 131.73, 131.69, 131.54,
130.60, 126.63, 125.91, 124.36, 121.12, 107.35, 26.48, 18.07.
Elem. anal. calcd. for C20H13Cl3F3N5O4 (%): C 43.62; H 2.38; N,
12.72. Found (%): C 43.58; H 2.35; N 12.70.
N-(4-chloro-2-(isopropylcarbamoyl)-6-methylphenyl)-1-(2,4-
dichloro-3-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-
carboxamide (7b). Yellow solid, yield 71.4%, m. p. 204-205 °C
(EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H, Ph-NH-
CO), 8.17 (d, J = 7.6 Hz, 1H, Ph-CO-NH), 8.03 (s, 2H, 2Ph-H),
7.83 (s, 1H, Pyrazole-H), 7.49 (d, J = 1.9 Hz, 1H, Ph-H), 7.30 (d,
J = 2.1 Hz, 1H, Ph-H), 3.89 – 3.82 (m, 1H, CH(CH3)2), 2.20 (s,
3H, Ph-CH3), 1.01 (d, J = 6.6 Hz, 6H, CH(CH3)2). 13C NMR (400
MHz, DMSO-d6) δ 165.24, 155.73, 147.82, 142.82, 139.89,
138.94, 138.34, 137.00, 132.42, 131.54, 131.48, 131.43, 130.56,
126.65, 125.99, 124.40, 120.48, 107.34, 41.27, 22.49, 18.08.
Elem. anal. calcd. for C22H17Cl3F3N5O4 (%): C 45.66; H 2.96; N
12.10. Found (%): C 45.69; H 2.98; N 12.09.
Methyl 3-(5-((4-bromo-2-methyl-6-(methylcarbamoyl)phenyl)
carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-4-chlorobenzoa
1
te (7g). White solid, yield 65.8%, m. p. 211-212 °C (EtOAc). H
NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H, Ph-NH-CO), 8.24 (d,
J = 7.7 Hz, 1H, Ph-CO-NH), 8.09 (dd, J = 8.4, 1.7 Hz, 1H), 8.05
(s, 1H, Ph-H), 7.90 (s, 1H, Pyrazole-H), 7.81 (d, J = 8.4 Hz, 1H,
Ph-H), 7.47 (d, J = 1.7 Hz, 1H, Ph-H), 7.30 (d, J = 1.7 Hz, 1H, Ph-
H), 3.97 – 3.80 (m, 4H, OCH3 and NHCH), 2.19 (s, 3H, Ph-CH3),
1.02 (d, J = 6.3 Hz, 6H, CH(CH3)2). 13C NMR (101 MHz, DMSO-
d6) δ 164.70, 164.51, 155.42, 141.67, 139.15, 138.59, 137.92,
136.64, 135.60, 131.45, 131.11, 130.93, 130.28, 129.25, 125.55,
120.78, 117.11, 106.75, 52.61, 40.84, 21.96, 17.61. Elem. anal.
calcd. for C24H21Cl2F3N4O4 (%): C 51.72; H 3.80; N 10.05; Found
(%): C 51.69; H 3.84; N 10.08.
N-(4-Bromo-2-methyl-6-(methylcarbamoyl)phenyl)-1-(2,4-
dichloro-3-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbo
xamide (7c). Yellow solid, yield 69.0%, m. p. 210-211 °C
(EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H, Ph-NH-
CO), 8.34 (d, J = 4.5 Hz, 1H, Ph-CO-NH), 8.04 (s, 2H, 2Ph-H),
7.83 (s, 1H, Pyrazole-H), 7.64 (d, J = 1.4 Hz, 1H, Ph-H), 7.48 (d,
J = 1.8 Hz, 1H, Ph-H), 2.63 (d, J = 4.5 Hz, 3H, NHCH3), 2.18 (s,
3H, Ph-CH3). 13C NMR (400 MHz, DMSO-d6) δ 165.97, 155.35,
147.33, 142.29, 139.45, 138.89, 137.87, 136.29, 134.14, 131.85,
131.68, 130.11, 128.26, 126.12, 123.85, 120.60, 119.46, 106.86,
25.98, 17.48. Elem. anal. calcd. for C20H13BrCl2F3N5O4 (%): C
40.36; H 2.20; N, 11.77. Found (%): C 40.32; H 2.23; N 11.70.
Methyl 3-(5-((4-bromo-2-methyl-6-(methylcarbamoyl)phenyl)
carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-4-chlorobenzoa
te (7h). White solid, yield 60.9%, m. p. 216-217 °C (EtOAc). 1H
NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H, Ph-NH-CO), 8.32 (d,
J = 4.1 Hz, 1H, Ph-CO-NH), 8.11 – 8.06 (m, 2H, 2Ph-H), 7.82 (d,
J = 8.9 Hz, 1H, 1H, Ph-H), 7.77 (s, 1H, Pyrazole-H), 7.62 (d, J =
1.5 Hz, 1H, Ph-H), 7.47 (d, J = 1.5 Hz, 1H, Ph-H), 3.88 (s, 3H,
OCH3), 2.64 (d, J = 4.4 Hz, 3H, NHCH3), 2.18 (s, 3H, Ph-CH3).13C
NMR (101 MHz, DMSO-d6) δ 165.99, 164.53, 155.57, 141.65,
139.37, 138.94, 137.82, 136.18, 135.47, 134.10, 131.92, 131.46,
130.33, 129.32, 129.28, 128.21, 120.78, 119.32, 106.52, 52.59,