T. Hasui et al. / Bioorg. Med. Chem. 22 (2014) 5428–5445
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4.53 (2H, s), 6.56 (1H, dd, J = 8.5, 2.0 Hz), 6.65 (1H, d, J = 2.0 Hz),
6.81 (1H, d, J = 8.5 Hz), 7.22–7.35 (4H, m), 10.60 (1H, br. s). Anal.
Calcd for C21H20N3O2F: C, 69.03; H, 5.52; N, 11.50. Found: C,
69.04; H, 5.51; N, 11.50.
6.83 (1H, d, J = 8.0 Hz), 6.96 (2H, d, J = 6.1 Hz), 7.20–7.25 (4H, m),
8.47 (2H, d, J = 6.1 Hz), 10.60 (1H, s). Anal. Calcd for C24H19N4O2F:
C, 69.55; H, 4.62; N, 13.52. Found: C, 69.38; H, 4.75; N, 13.25.
5.49. 6-[5-(4-Fluorophenyl)-1-(4-hydroxybutyl)-3-methyl-1H-
pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (16g)
5.42. 6-[1-Benzyl-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-
2H-1,4-benzoxazin-3(4H)-one (16c)
A mixture of 16f (0.49 g, 1.01 mmol) and 10 wt% palladium on
carbon (0.1 g) in EtOH (30 mL) was stirred at room temperature
for 5 h and at 50 °C for 18 h, under hydrogen atmosphere. The
insoluble material was removed by filtration, and the filtrate was
concentrated under reduced pressure. The residue was crystallized
from EtOAc/hexane to give 16g (0.35 g, 88%). 1H NMR (300 MHz,
DMSO-d6) d 1.10–1.37 (2H, m), 1.60–1.73 (2H, m), 2.18 (3H, s),
3.23–3.34 (2H, m), 3.88 (2H, t, J = 7.2 Hz), 4.34 (1H, t, J = 5.1 Hz),
4.52 (2H, s), 6.55 (1H, dd, J = 8.4, 1.8 Hz), 6.64 (1H, d, J = 1.8 Hz),
6.80 (1H, d, J = 8.4 Hz), 7.21–7.32 (4H, m), 10.58 (1H, s). Anal. Calcd
for C22H22N3O3F: C, 66.82; H, 5.61; N, 10.63. Found: C, 66.92; H,
5.71; N, 10.50.
Yield (38%). 1H NMR (300 MHz, DMSO-d6) d 2.21 (3H, s), 4.53
(2H, s), 5.15 (2H, s), 6.59 (1H, dd, J = 8.3, 2.1 Hz), 6.68 (2H, d,
J = 2.1 Hz), 6.82 (1H, d, J = 8.3 Hz), 6.97 (2H, dd, J = 7.9, 1.5 Hz),
7.19–7.32 (7H, m), 10.60 (1H, s). Anal. Calcd for C25H20N3O2F: C,
72.63; H, 4.88; N, 10.16. Found: C, 72.61; H, 4.94; N, 10.07.
5.43. 6-[5-(4-Fluorophenyl)-3-methyl-1-phenyl-1H-pyrazol-
4-yl]-2H-1,4-benzoxazin-3(4H)-one (16d)
Yield (16%). 1H NMR (300 MHz, DMSO-d6) d 2.26 (3H, s), 4.56
(2H, s), 6.59–6.75 (2H, m), 6.68 (1H, d, J = 8.3 Hz), 7.10–7.23 (6H,
m), 7.27–7.39 (3H, m), 10.65 (1H, s). Anal. Calcd for C24H18N3O2F:
C, 72.17; H, 4.54; N, 10.52. Found: C, 72.18; H, 4.58; N, 10.48.
5.50. 8-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
2H-1,4-benzoxazin-3(4H)-one (15b)
5.44. 6-[5-(4-Fluorophenyl)-1-(3-hydroxypropyl)-3-methyl-1H-
pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (16e)
A
mixture of 4-bromo-2-methyl-6-nitrophenol (9.4 g,
40.5 mmol), methyl bromoacetate (6.5 g, 42.5 mmol) and potas-
sium carbonate (8.4 g, 60.8 mmol) in DMSO (50 mL) was stirred
at room temperature for 48 h, diluted with water and 10% hydro-
chloric acid, and extracted with EtOAc. The organic layer was
washed with water and brine, dried over Na2SO4 and concentrated
in vacuo. The resulting solid was washed with hexane to give
methyl (4-bromo-2-methyl-6-nitrophenoxy)acetate (9.86 g, 80%).
A mixture of methyl (4-bromo-2-methyl-6-nitrophenoxy)acetate
(10.9 g, 35.8 mmol) and zinc dust (35 g, 535 mmol) in acetic acid
(100 mL) and THF (200 mL) was stirred at 45 °C for 30 min and at
reflux for 1 h, and filtered. The filtrate was concentrated in vacuo,
and the residue was diluted with EtOAc. The organic layer was
washed with aqueous NaHCO3 solution, water and brine, dried
over Na2SO4 and concentrated in vacuo. The residue was washed
with hexane, suspended in MeOH, and collected by filtration to
Yield (17%). 1H NMR (DMSO-d6) d 1.73–1.90 (2H, m), 2.18 (3H,
s), 3.27–3.40 (2H, m), 3.94 (2H, t, J = 7.2 Hz), 4.47 (1H, t,
J = 4.9 Hz), 4.53 (2H, s), 6.56 (1H, dd, J = 8.1, 2.1 Hz), 6.64 (1H, d,
J = 1.9 Hz), 6.81 (1H, d, J = 8.0 Hz), 7.17–7.41 (4H, m), 10.60 (1H,
s). Anal. Calcd for C21H20N3O3F: C, 66.13; H, 5.29; N, 11.02. Found:
C, 65.89; H, 5.16; N, 10.80.
5.45. 6-{1-[4-(Benzyloxy)butyl]-5-(4-fluorophenyl)-3-methyl-
1H-pyrazol-4-yl}-2H-1,4-benzoxazin-3(4H)-one (16f)
Yield (44%). 1H NMR (300 MHz, CDCl3) d 1.47–1.59 (2H, m),
1.81–1.92 (2H, m), 2.30 (3H, s), 3.38 (2H, t, J = 6.3 Hz), 3.99 (2H,
t, J = 7.5 Hz), 4.22 (2H, s), 4.57 (2H, s), 6.43 (1H, d, J = 2.1 Hz),
6.65 (1H, dd, J = 8.4, 2.1 Hz), 6.84 (1H, d, J = 8.4 Hz), 6.98–7.08
(2H, m), 7.11–7.18 (2H, m), 7.22–7.36 (5H, m), 7.97 (1H, s).
give
6-bromo-8-methyl-2H-l,4-benzoxazin-3(4H)-one
(5.8 g,
70%). 1H NMR (300 MHz, DMSO-d6) d 2.14 (s, 3H), 4.60 (s, 2H),
6.87 (d, J = 2.3 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 10.72 (s, 1H). A mix-
ture of 6-bromo-8-methyl-2H-1,4-benzoxazin-3(4H)- one (2.0 g,
8.3 mmol), bis(pinacolato)diboron (2.3 g, 9.1 mmol), potassium
acetate (2.9 g, 29.5 mmol) [1,1-bis(diphenylphosphino)ferro-
cene]dichloropalladium(II) dichloromethane complex (0.34 g,
0.42 mmol) in 1,4-dioxane (50 mL) was stirred at 90 °C for 12 h
under argon atmosphere, diluted with water and extracted with
EtOAc. The organic layer was dried over Na2SO4 and concentrated
in vacuo. The residue was suspended in IPE, and collected by
filtration to give 15b (2.36 g, 98%) as a solid. 1H NMR (300 MHz,
DMSO-d6) d 1.27 (s, 12H), 2.15 (s, 3H), 4.61 (s, 2H), 7.06 (s, 1H),
7.13 (s, 1H), 10.61 (s, 1H).
5.46. 6-[5-(4-Fluorophenyl)-3-methyl-1-(pyridin-2-ylmethyl)-
1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (16h)
Yield (52%). 1H NMR (300 MHz, DMSO-d6) d 2.20 (3H, s), 4.54
(2H, s), 5.22 (2H, s), 6.61 (1H, d, J = 8.1 Hz), 6.69 (1H, s), 6.83 (1H,
d, J = 8.1 Hz), 7.02 (1H, d, J = 7.7 Hz), 7.16–7.37 (5H, m), 7.68–
7.82 (1H, m), 8.49 (1H, d, J = 4.5 Hz), 10.60 (1H, s). Anal. Calcd for
C24H19N4O2F: C, 69.55; H, 4.62; N, 13.52. Found: C, 69.28; H,
4.66; N, 13.13.
5.47. 6-[5-(4-Fluorophenyl)-3-methyl-1-(pyridin-3-ylmethyl)-
1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (16i)
Yield (21%). 1H NMR (300 MHz, DMSO-d6) d 2.21 (3H, s), 4.53
(2H, s), 5.20 (2H, s), 6.60 (1H, dd, J = 8.3, 1.9 Hz), 6.68 (1H, d,
J = 1.9 Hz), 6.82 (1H, d, J = 8.3 Hz), 7.21–7.35 (5H, m), 7.37–7.44
(1H, m), 8.19 (1H, s), 8.45 (1H, d, J = 3.8 Hz), 10.60 (1H, s). Anal.
Calcd for C24H19N4O2F 0.1(EtOAc): C, 69.24; H, 4.72; N, 13.24.
Found: C, 68.92; H, 4.69; N, 13.16.
5.51. tert-Butyl-2-(pyridin-2-ylmethylene)hydrazinecarboxylate
(18a)
A mixture of pyridine-2-carbaldehyde (5.0 g, 46.7 mmol) and
tert-butyl carbazate (7.4 g, 56.0 mmol) in EtOH (50 mL) was stirred
at room temperature for 3 h, and then concentrated under reduced
pressure. The residue was suspended in IPE and collected by filtra-
tion to give 18a (5.6 g, 55%). 1H NMR (300 MHz, CDCl3) d 1.55 (9H,
s), 7.21–7.28 (1H, m), 7.65–7.73 (1H, m), 7.94 (1H, s), 8.07 (1H, d,
J = 8.1 Hz), 8.36 (1H, s), 8.53–8.59 (1H, m).
5.48. 6-[5-(4-Fluorophenyl)-3-methyl-1-(pyridin-4-ylmethyl)-
1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (16j)
Yield (5%). 1H NMR (300 MHz, DMSO-d6) d 2.22 (3H, s), 4.54 (2H,
s), 5.20 (2H, s), 6.62 (1H, dd, J = 8.3, 2.3 H), 6.69 (1H, d, J = 1.9 Hz),
The compound 18b,c were prepared in a manner similar to that
described for 18a.