Pyrazoles and Isoxazoles as Potent Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5425
potassium tert-butoxide (0.63 g, 7.20 mmol) in tert-butyl alcohol
(11 mL). The mixture was stirred vigorously for 45 min at room
temperature. To this mixture was then added 4′-n-butoxy-3-
(dimethylamino)acrylophenone 27 (0.5 g, 2.02 mmol) in tert-
butyl alcohol (11 mL). The reaction mixture was stirred for
16 h at 50 °C. The mixture was cooled, poured into ice water,
and extracted with ethyl acetate. The organic layer was dried
over magnesium sulfate and concentrated, and the residue was
purified by NH silica gel column chromatography (eluent:
hexane/ethyl acetate ) 8/1 to 1/1) to give a colorless solid.
Recrystallization of the solid from hexane gave 0.24 g (52%)
2′-n -Bu toxya cetop h en on e (36c). This compound was
prepared from 2′-hydroxyacetophenone (3 g, 22.0 mmol) as
described in the procedure for synthesizing 3a to yield 3.07 g
(73%) of a colorless oil: 1H NMR (200 MHz, CDCl3) δ 1.00 (t,
J ) 7.0 Hz, 3H), 1.42-1.63 (m, 2H), 1.76-1.94 (m, 2H), 2.64
(s, 3H), 4.08 (t, J ) 6.0 Hz, 2H), 6.90-7.04 (m, 2H), 7.38-7.51
(m, 1H), 7.70-7.79 (m, 1H).
3′-n -Bu toxya cetop h en on e (36d ). This compound was
prepared from 3′-hydroxyacetophenone (3 g, 22.0 mmol) as
described in the procedure for synthesizing 3a to yield 3.99 g
(94%) of a colorless oil: 1H NMR (200 MHz, CDCl3) δ 1.00 (t,
J ) 7.2 Hz, 3H), 1.40-1.63 (m, 2H), 1.70-1.89 (m, 2H), 2.60
(s, 3H), 4.03 (t, J ) 6.2 Hz, 2H), 7.06-7.16 (m, 1H), 7.37 (t, J
) 8.5 Hz, 1H), 7.46-7.59 (m, 2H).
5-(4-Meth oxyp h en yl)isoxa zole (37b). To a stirred mix-
ture of sodium hydride (60% in oil, 14.6 g, 385.4 mmol), ethyl
formate (43.8 g, 730.8 mmol), and tetrahydrofuran (300 mL)
was added 4′-methoxyacetophenone 36b (30 g, 182.7 mmol)
in tetrahydrofuran (100 mL) at 0 °C. The reaction mixture was
stirred for 2.5 h at room temperature, and then diluted with
water (200 mL) and washed with ethyl acetate. The aqueous
layer was separated and hydroxylamine hydrochloride (12.7
g, 182.7 mmol) was added. The mixture was stirred for 17 h
at room temperature, and then diluted with 1 M HCl and
extracted with ethyl acetate. The organic layer was dried over
magnesium sulfate and concentrated to give a yellow solid.
The crude solid was recrystallized from diethyl ether to give
15.8 g (49%) of 37b as a light yellow powder: mp 62-64 °C;
1H NMR (200 MHz, CDCl3) δ 3.87 (s, 3H), 6.40 (d, J ) 2.0 Hz,
1H), 6.99 (m, J AB ) 9.0 Hz, 2H), 7.74 (m, J AB ) 8.8 Hz, 2H),
8.25 (d, J ) 1.6 Hz, 1H); MS (ESI) m/z 198 (M + Na, 70%).
Anal. (C10H9NO2) C, H, N.
1
of 30 as a colorless powder: mp 81.5-82.5 °C; H NMR (200
MHz, CDCl3) δ 1.00 (t, J ) 7.4 Hz, 3H), 1.42-1.62 (m, 2H),
1.74-1.89 (m, 2H), 4.05 (t, J ) 6.5 Hz, 2H), 7.02 (m, J AB ) 8.8
Hz, 2H), 7.65 (m, J AB ) 5.4 Hz, 1H), 8.07 (m, J AB ) 8.8 Hz,
2H), 8.70 (m, J AB ) 5.4 Hz, 1H), 9.21 (d, J ) 1.0 Hz, 3H); MS
(ESI) m/z 251 (M + Na, 100%). Anal. (C14H16N2O) C, H, N.
2-Acetyl-4′-n -bu toxya cetop h en on e (31). A mixture of two
drops of dry ethanol, 4′-n-butoxyacetophenone 19 (2 g, 10.4
mmol), and dibenzo-18-crown-6 (0.062 g, 0.166 mmol) in
tetrahydrofuran (13 mL) was added to a stirred mixture of
sodium hydride (60% in oil, 0.853 g, 21.8 mmol) and ethyl
acetate (1.83 g, 20.8 mmol) in tetrahydrofuran (13 mL) at room
temperature. The mixture was stirred for 3 h at 80 °C and
then cooled to room temperature and diluted with 1 M HCl.
The mixture was extracted with ethyl acetate and the extract
was dried over magnesium sulfate and concentrated, and the
residue was purified by silica gel column chromatography
(eluent: hexane/ethyl acetate ) 8/1) to give 2.17 g (89%) of 31
as yellow crystals:1H NMR (200 MHz, CDCl3) δ 0.99 (t, J )
7.4 Hz, 3H), 1.40-1.60 (m, 2H), 1.72-1.84 (m, 2H), 2.17 (s,
3H), 4.03 (t, J ) 6.5 Hz, 2H), 6.11 (s, 1H), 6.93 (m, J AB ) 9.0
Hz, 2H), 7.86 (m, J AB ) 9.0 Hz, 2H).
5-P h en ylisoxa zole (37a ). This compound was prepared
from acetophenone (2.47 g, 20.5 mmol) as described in the
procedure for synthesizing 37b to yield 1.70 g (57%) of a yellow
oil: 1H NMR (300 MHz, CDCl3) δ 6.52 (d, J ) 1.2 Hz, 1H),
7.43-7.52 (m, 3H), 7.76-7.83 (m, 2H), 8.29 (d, J ) 1.2 Hz,
1H); MS (EI) m/z 145 (M+, 100%). Anal. (C9H7NO) C, H, N.
5-(2-n -Bu toxyp h en yl)isoxa zole (37c). This compound
was prepared from 2′-n-butoxyacetophenone 36c (1.75 g, 9.10
mmol) as described in the procedure for synthesizing 37b to
yield 0.930 g (35%) of a colorless powder: mp 33-34.5 °C; 1H
NMR (200 MHz, CDCl3) δ 1.01 (t, J ) 7.2 Hz, 3H), 1.43-1.63
(m, 2H), 1.82-1.94 (m, 2H), 4.12 (t, J ) 6.3 Hz, 2H), 6.82 (d,
J ) 1.8 Hz, 1H), 6.97-7.12 (m, 2H), 7.34-7.44 (m, 1H), 8.01
(dd, J ) 1.8 Hz, 7.8 Hz, 1H), 8.31 (d, J ) 1.8 Hz, 1H); MS
(ESI) m/z 240 (M + Na, 100%). Anal. (C13H15NO2) C, H, N.
5-(3-n -Bu toxyp h en yl)isoxa zole (37d ). This compound
was prepared from 3′-n-butoxyacetophenone 36d (3 g, 15.6
mmol) as described in the procedure for synthesizing 37b to
yield 0.910 g (27%) of a colorless oil: 1H NMR (200 MHz,
CDCl3) δ 1.00 (t, J ) 7.4 Hz, 3H), 1.45-1.62 (m, 2H), 1.73-
1.85 (m, 2H), 4.03 (t, J ) 6.3 Hz, 2H), 6.51 (d, J ) 2.0 Hz,
1H), 6.94-7.02 (m, 1H), 7.30-7.42 (m, 3H), 8.29 (d, J ) 2.0
Hz, 1H); MS (EI) m/z 217 (M+, 36%). Anal. (C13H15NO2) C, H,
N.
4′-n -Bu toxyp r op iop h en on e (38). This compound was
prepared from 4′-hydroxypropiophenone (3.3 g, 22.0 mmol) as
described in the procedure for synthesizing 3a to yield 4.20 g
(93%) of a colorless oil: 1H NMR (200 MHz, CDCl3) δ 0.99 (t,
J ) 7.2 Hz, 3H), 1.21 (t, J ) 7.2 Hz, 3H), 1.40-1.62 (m, 2H),
1.70-1.90 (m, 2H), 2.96 (q, J ) 7.2 Hz, 2H), 4.03 (t, J ) 5.6
Hz, 2H), 6.91 (m, J AB ) 8.8 Hz, 2H), 7.95 (m, J AB ) 8.8 Hz,
2H).
4′-n -Bu toxy-2-h yd r oxy-1-m eth yla cr ylop h en on e (39). To
a stirred suspension of sodium hydride (60% in oil, 1.94 g, 48.4
mmol) in ethyl formate (19.26 g, 260 mmol) was added 4′-n-
butoxypropiophenone 38 (3.8 g, 18.4 mmol) in tetrahydrofuran
(24 mL). The reaction mixture was stirred for 20 min at room
temperature, and then diluted with 0.5 M HCl and extracted
with ethyl acetate. The organic layer was dried over magne-
sium sulfate and concentrated, and the residue was purified
by silica gel column chromatography (eluent: hexane/ethyl
acetate ) 9/ 1) to give 1.12 g (26%) of 39 as a colorless
5-(4-n -Bu toxyp h en yl)-3-m eth ylisoxa zole (32). To a solu-
tion of 2-acetyl-4′-n-butoxyacetophenone 31 (0.3 g, 1.28 mmol)
in pyridine (3 mL) was added hydroxylamine hydrochloride
(0.098 g, 1.41 mmol). The mixture was stirred for 30 min at
room temperature. To this mixture was then added 6 M HCl
(7 mL), and the result was extracted with ethyl acetate. The
organic layer was washed with brine, dried over magnesium
sulfate, and concentrated to give a light yellow solid. The crude
solid was recrystallized from hexane/ethyl acetate to give 0.100
g (34%) of 32 as a colorless powder: mp 77.5-79 °C; 1H NMR
(200 MHz, CDCl3) δ 0.99 (t, J ) 7.3 Hz, 3H), 1.40-1.61 (m,
2H), 1.72-1.84 (m, 2H), 2.33 (s, 3H), 4.01 (t, J ) 6.4 Hz, 2H),
6.23 (s, 1H), 6.95 (m, J AB ) 8.8 Hz, 2H), 7.68 (m, J AB ) 8.8
Hz, 2H); MS (ESI) m/z 254 (M + Na, 73%). Anal. (C14H17NO2)
C, H, N.
3-(4-n -Bu toxyp h en yl)-5-m eth ylp yr a zole (33). To a solu-
tion of 2-acetyl-4′-n-butoxyacetophenone 31 (0.2 g, 0.85 mmol)
in methanol (5 mL) was added hydrazine monohydrate (0.047
g, 0.94 mmol). The mixture was stirred for 1 h at room
temperature. This mixture was then concentrated and the
residue was purified by silica gel column chromatography
(eluent: hexane/ethyl acetate ) 3/1) to give 0.175 g (89%) of
33 as a colorless powder: mp 100-101 °C; 1H NMR (200 MHz,
CDCl3) δ 0.98 (t, J ) 7.4 Hz, 3H), 1.41-1.61 (m, 2H), 1.70-
1.83 (m, 2H), 2.35 (s, 3H), 4.00 (t, J ) 6.5 Hz, 2H), 6.28 (s,
1H), 6.93 (m, J AB ) 8.7 Hz, 2H), 7.61 (m, J AB ) 8.7 Hz, 2H);
MS (ESI) m/z 231 (M + H, 100%). Anal. (C14H18N2O) C, H, N.
5-(4-n -Bu toxyp h en yl)tetr a zole (35). To a mixture of 4-n-
butoxybenzonitrile 34 (5 g, 28.5 mmol) and ammonium chloride
(1.68 g, 31.4 mmol) in N,N-dimethylformamide (57 mL) was
added sodium azide (2.04 g, 31.4 mmol). The reaction mixture
was stirred for 30 h at 120 °C. After stirring, the mixture was
cooled to room temperature and the solvent was removed
under reduced pressure. The mixture was diluted with 1 M
HCl and a colorless solid precipitate was filtered and recrys-
tallized from water/ethanol to give 4.60 g (74%) of 35 as
colorless crystals: mp 198.5-200 °C; 1H NMR (200 MHz,
DMSO-d6) δ 0.95 (t, J ) 7.3 Hz, 3H), 1.36-1.57 (m, 2H), 1.66-
1.81 (m, 2H), 4.07 (t, J ) 6.3 Hz, 2H), 7.15 (m, J AB ) 8.9 Hz,
2H), 7.97 (m, J AB ) 8.9 Hz, 2H); MS (ESI) m/z 217 (M - H,
100%). Anal. (C11H14N4O) C, H, N.