3,4-Diarylquinolinone to NoVel p38MAP Kinase Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6 1219
mL of H2O overnight. The product was filtered, washed with water,
was allowed to stir for 2 h. Water was added, and the reaction was
neutralized by NaOH. The mixture was extracted by ethyl acetate
(200 mL), and the organic phase was separated, dried over Na2-
SO4, and evaporated to yield 52% of 11 as a pale yellow oil: MS
+c Full ms (m/z) 164.2 (M+). 1H NMR (CDCl3, 200 MHz, ppm):
δ 1.0 (s, 3H, CH3), 1.1 (s, 3H, CH), 2.6-2.8 (m, 1H, CH), 3.8 (s,
2H, CH2), 7.1 (d, 2H, CHAr), 8.5 (d, 2H, CHAr). 13C NMR (CDCl3,
200 MHz, ppm): δ 18.0 (CH3), 40.1 (CH), 46.2 (CH2), 124.7 (CH),
143.2 (Cq), 149.7 (CH), 209.8 (CO).
4-Fluoro-N-hydroxybenzenecarboximidoyl Chloride (12). Com-
pound 12 was prepared according to the literature with an optimized
procedure in this study. (a) 4-Fluorobenzaldehyde (16 mmol) was
dissolved in 25 mL of ethanol, 25 mL of water, and 40 g of ice.
Hydroxylamine HCl (96 mmol) was added, followed by the
dropwise addition of 55 mL of 50% NaOH. When the addition of
NaOH was finished, the ice bath was removed, and the mixture
was allowed to stir at rt for 2 h, yielding 15.1 mmol of
4-fluorobenzaldehyde oxime (94%). (b) The oxime was dissolved
in 5 mL of DMF and stirred at rt, NCS (15.7 mmol) was added
slowly by spatula, and the reaction was stirred at rt for 2 h. The
reaction was quenched by adding water, and the mixture was
extracted with diethyl ether (200 mL). The organic phase was
washed with cold brine three times and separated, dried over Na2-
SO4, and evaporated. The residue was kept at 5 °C, where a white
solid precipitated to yield 95% of 12. 1H NMR (CDCl3, 200 MHz,
ppm): δ 7.1 (m, 2H, CHAr), 7.82 (m, 2H, CHAr), 7.9 (br s, 1H,
OH). Part of the compound was immediately used for the synthesis
of 13. It can be stored under argon at 7 °C.
4-[3-(4-Fluorophenyl)-5-isopropylisoxazol-4-yl]pyridine (13).
Compound 11 (2.5 mmol) and 4.3 mmol of 12 were stirred in 10
mL of ethanol at room temperature. By addition of 1 mL of
triethylamine, the color changed from yellow to deep orange then
to brown. The reaction mixture was stirred 4 h at rt and then
refluxed for 16 h. A saturated solution of NH4Cl (50 mL) was
added, and the mixture was extracted by ethyl acetate (200 mL).
The organic phase was separated, dried over Na2SO4, and evapo-
rated. The oily brown product was purified by column chromatog-
raphy using ethyl acetate 10/hexanes 1 to yield 45% of 13, which
precipitated from ethanol as clear white crystals: mp ) 144.0 °C.
1H NMR (CDCl3, 200 MHz, ppm): δ 1.3 (s, 3H, CH3), 1.4 (s, 3H,
CH3), 3.1-3.2 (m, 1H, CH), 7.1 (m, 4H, CHAr), 7.3 (m, 2H,
CHAr), 8.2 (d, 2H, CHAr). 13C NMR (CDCl3, 200 MHz, ppm): δ
20.9 (CH3), 26.4 (CH), 111.6 (Cq), 115.5 (CH), 116.0 (CH), 124.5
(CH), 130.2 (CH), 130.4 (CH), 138.8 (Cq), 150.1 (CH), 159.9 (Cq),
161.0 (Cq), 165.9 (Cq), 175.3 (Cq). Anal. (C17H15FN2O) C, H, N.
dried, and recrystallized from diethyl ether. Yield 79%; mp ) 212
1
°C; MS -c Full ms (m/z), 290.0 (M-). H NMR (DMSO-d6, 200
MHz, ppm): δ 2.3 (s, 3H, CH3), 7.1 (m, 1H, CHar), 7.3 (d, 2H,
CHar), 7.5 (s, 2H, CHar), 7.7 (d, 2H, CHar), 7.9 (d, 1H, CHar),
11.1 (br s, 1H, NH).
N-[2-(4-Fluorobenzoyl)phenyl]-4-methylbenzenesulfona-
mide (7). Compound 6 was reacted with fluorobenzene under
Friedel-Crafts conditions: 5.84 g of 6, 4.76 g of PCl5, and 20 mL
of fluorobenzene were refluxed until the solution became clear.
The mixture was cooled in an ice bath, and after addition of 11.6
g of AlCl3, the reaction was stirred for 1 h at 0 °C and then warmed
to rt. A sample was extracted by ethyl acetate, purified, and ana-
1
lyzed. MS +c Full ms (m/z), 370.0 (M+). H NMR (CDCl3, 200
MHz, ppm): δ 2.2 (s, 3H, CH3), 7.0 (m, 5H, CHar), 7.3-7.5 (m, 5H,
CHar), 7.53 (d, 1H, CHar), 7.8 (d, 1H, CHar), 9.80 (s, 1H, NH).
(2-Aminophenyl)(4-fluorophenyl)methanone (8). The crude
mixture of 7 was poured on ice/50 mL of HCl and stirred for 1 h
for complete deprotection. Ethyl acetate was added, and the organic
phase was separated and dried over Na2SO4. Evaporation under
vacuum gave a brown oil that was purified by column chromatog-
raphy (ethyl acetate/hexanes 1/5) to yield a yellow oil (67%) of
which bright yellow crystals were obtained by slow evaporation.
GC/MS rt ) 13.04 min; EI-MS (m/z) 215 (M+). 1H NMR (CDCl3,
200 MHz, ppm): δ 6.0 (br s, 2H, NH), 6.6 (t, 1H), 6.7 (d, 1H), 7.1
(t, 2H), 7.3 (m, 1H), 7.4 (dd, 1H), 7.7 (m, 2H).
4-(4-Fluorophenyl)-3-pyridin-4-ylquinoline-2(1H)-one (10).
Amounts equal to 175 mg (1 mmol) of pyridin-4-ylacetic acid
hydrochloride and 210 mg of PCl5 (1 mmol) were suspended in 4
mL of DCM and stirred overnight under a slight argon flow at rt.
After cooling at 0 °C, a solution of 215 mg (1 mmol) of 8 and 100
mg of pyridine in 4 mL of DCM were added via septum, and the
mixture was stirred for 12 h. Reaction progress was monitored as
decreasing of 8 by TLC until this material disappeared to form
compound 9, which was immediately used for ring closure: 2 mL
of ammonia was added, the mixture was stirred for 2 h, and the
organic phase was separated and extracted by DCM over a short
silica gel column. Evaporation gave a white solid, which was
washed with diethyl ether to yield 74% of compound 10; mp )
319 °C; MS +c Full ms (m/z) 317.0 (M+); GC/MS rt ) 45.73
1
min; EI-MS (m/z) 316 (M+). H NMR (CDCl3, 200 MHz, ppm):
δ 6.9-7.2 (m, 7H), 7.2 (m, 1H), 7.3 (d, 1H), 7.5 (m, 1H), 8.5 (ds,
2H), 12.0 (br s, 1H, NH). Anal. (C20H13FN2O) C, H, N.
Crystal structure of 10 has been proven by X-ray analysis: CAD4
Enraf Nonius, Cu KR, SIR-92, SHELXL-97. Further details of the
crystal structure analysis are available in references.21
Crystal structure of 13 has been proven by X-ray analysis: CAD4
Enraf Nonius, Cu KR, SIR-92, SHELXL-97. Further details of the
crystal structure analysis are available in the references.22
3-Methyl-1-pyridin-4-ylbutan-2-one (11). (a) Diisopropylamine
(12.0 mmol) in 20 mL of THF was cooled to -78 °C, butyllithium
(1.6 M, 1.1 equiv) was added dropwise, and the reaction mixture
was stirred for 1 h at -78 °C. Picoline (11.0 mmol) in THF was
added dropwise, and the color changed to yellow then became
brown. The reaction was stirred for 1 h at -78, followed by addition
of isobutyraldehyde (11.1 mmol) in THF and again stirred for 3 h
at -78 °C, then allowed to stir to reach rt. Water (50 mL) was
added carefully, and the mixture was extracted by ethyl acetate
(200 mL). The organic phase was separated, dried over Na2SO4,
and evaporated. The oily yellow product was purified by column
chromatography using ethyl acetate 10/hexanes 1 to yield 3-methyl-
1-(pyridine-4-yl)butan-2-ol. A sample was analyzed: MS +c Full
ms (m/z) 166.2 (M+1). 1H NMR (CDCl3, 200 MHz, ppm): δ 0.88
(s, 3H, CH3), 0.92 (s, 3H, CH3), 1.62 (m, 1H, CH), 2.5-2.65 (m,
2H, CH2), 3.48 (m, 1H, CH), 4.44 (br s, 1H, OH), 7.0 (d, 2H,
CHAr), 8.1 (d, 2H, CHAr). 13C NMR (CDCl3, 200 MHz, ppm): δ
17.3 (CH3), 18.8 (CH3), 33.7 (CH), 40.1 (CH2), 77.1 (CH), 124.9
(CH), 148.7 (CH), 149.7 (Cq).
1-(4-Fluorophenyl)-2-(4-pyridin) Ethanone (14). Diisopropy-
lamine (138 mmol) in THF (150 mL) was cooled to -78 °C under
argon, n-butyl lithium (1.6 M, 50 mL) was added, and the mixture
was stirred for 1 h (preparation of LDA). Picoline (92 mmol) in
THF was added dropwise, and after 1 h, 4-fluoro-N-methoxy-N-
methylbenzamide (92 mmol) in THF was added and the reaction
was then warmed to 0 °C over a period of 2 h. Brine (50 mL) was
added, and the mixture was extracted by diethyl ether (200 mL).
The organic phase was separated, dried over Na2SO4, and evapo-
rated. The oily orange-brown product was purified by column
chromatography using DCM 95/ethanol 5 to yield 39% of com-
1
pound 14: mp ) 91.4 °C. H NMR (CDCl3, 200 MHz, ppm): δ
4.27 (s, 2H, CH2), 7.1-7.2 (m, 4H, CHAr), 8.0 (m, 2H, CHAr),
8.6 (d, 2H, CHAr).
4-[3-(4-Fluorophenyl)-5-phenylisoxazol-4-yl]pyridine (15). (a)
Amounts equal to 21.5 g (100 mmol) of compound 14, sodium
acetate (36.1 g, 440 mmol), hydroxylamine HCl (22.0 g, 320 mmol),
and 250 mL 50% methanol/water were refluxed for 1.5 h. By
cooling in an ice bath, the product precipitated as a solid, which
was filtered, washed with water, and dried over P2O5 (yield 90%).
A sample of 1-(4-fluorophenyl)-2-(4-pyridin) ethanone oxime was
(b) Jone’s Oxidation: 3-methyl-1-(pyridine-4-yl)butan-2-ol (1.2
mmol) was dissolved in 5 mL of acetone, the freshly prepared
Jone’s reagent (2 mL of concentrated sulfuric acid were added to
2 g of sodium dichromate dihydrate dissolved in 6 mL of water to
form a carrot-orange solution) was dropped in intervals until the
color changed from yellow to red brown, and the reaction mixture
1
analyzed: mp ) 137.6 °C; MS +c Full ms (m/z) 230 (M+). H