Quinol-4-ones as Steroid A-Ring Mimetics
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26 7893
8H), 1.30 (s, 3H), 1.14 (s, 3H), 0.8 (br s, 6H). MS (ESI): m/e 408
(MH+). HPLC purity: method A 99%, tR 2.76 min; method B 99%,
tR 6.96 min.
layer was washed with water and dried (MgSO4). Removal of the
volatiles provided a residue which was purified with silica gel
chromatography using 80% ethyl acetate in petroleum ether as the
eluent. The product-rich fractions were collected and the volatiles
removed in vacuo. The residue was recrystallized from petroleum
1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(tri-
fluoromethyl)pentyl]-3,5-dimethyl-1H-pyridin-4-one (21). Mp:
1
1
ether to provide 0.051 g of product. Mp: 180-182 °C. H NMR
246-247 °C. H NMR (400 MHz, DMSO-d6): δ 7.29 (s, 2H),
(400 MHz, CDCl3): δ 7.65 (m, 2H), 7.12 (m, 5H), 6.79 (m, 1H),
6.82 (m, 1H), 4.11 (s, 2H), 3.71 (s, 3H), 2.62 (d, 1H), 2.39 (d,
1H), 1.58 (s, 3H), 1.36 (s, 3H). MS (ESI): m/e 411 (MH+). HPLC
purity: method A 94%, tR 2.90 min; method B 96%, tR 7.67 min.
1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(tri-
fluoromethyl)pentyl]-1H-quinazolin-4-one (27). (a) A solution of
2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-(trifluoromethyl)-
oxirane (500 mg, 1.71 mmol) and 2-aminobenzamide (1.17 g, 8.56
mmol) in DMF (2.5 mL) was heated at 140 °C for 20 h. The
reaction mixture was diluted with ether and washed with water and
brine. The organic layer was dried (Na2SO4), filtered, and concen-
trated. Purification of the residue by column chromatography (15-
30% ethyl acetate in hexanes) afforded 447 mg (61%) of 2-[[4-
(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoro-
methyl)pentyl]amino]benzamide as a white foam: 1H NMR (400
MHz, DMSO-d6): δ 8.19 (m, 1H, NH), 7.72 (s, 1H, NH), 7.51 (d,
1H, J ) 7.9 Hz), 7.08 (m, 1H), 7.06 (m, 1H, NH), 6.98 (dd, 1H,
J ) 10.8, 3.0 Hz), 6.85 (m, 2H), 6.46 (m, 1H), 5.91 (d, 1H, J )
8.2 Hz), 5.87 (s, 1H, OH), 3.72 (s, 3H), 2.88 (m, 2H), 2.68 (m,
1H), 1.94 (d, 1H, J ) 15.0 Hz), 1.49 (s, 3H), 1.33 (s, 3H). MS
(ES): m/e 429 ([M + H]+). (b) To a solution of 2-[[4-(5-fluoro-
2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]-
amino]benzamide (106 mg, 0.247 mmol) in 6.0 mL of trimethyl
orthoformate was added 0.1 mL of trifluoroacetic acid. After 1.5 h
at room temperature, the reaction mixture was concentrated.
Purification by column chromatography (70% EtOAc/hexanes)
afforded 82.1 mg (76%) of the title compound as a white solid.
7.05 (m, 3H), 6.27 (s, 1H, OH), 3.80 (s, 3H), 3.61 (d, 1H, J )
15.0 Hz), 3.37 (d, 1H, J ) 15.0 Hz), 2.80 (d, 1H, J ) 15.6 Hz),
2.00 (d, 1H, J ) 15.6 Hz), 1.75 (s, 6H), 1.53 (s, 3H), 1.31 (s, 3H).
FTIR (neat): 1649 cm-1. MS (ES): m/e 416 ([M + H]+). HPLC
purity: method A 99%, tR 2.95 min; method B 94%, tR 7.69 min.
2-[(2,4-Dimethylimidazol-1-yl)methyl]-1,1,1-trifluoro-4-(5-
fluoro-2-methoxyphenyl)-4-methylpentan-2-ol (22). Mp: 185-
1
186 °C. H NMR (400 MHz, CDCl3): δ 7.04 (m, 1H), 6.87 (m,
1H), 6.78 (m, 1H), 6.40 (s, 1H), 3.80 (s, 3H), 3.70 (m, 2H), 2.45
(m, 2H), 2.22 (s, 3H), 2.15 (s, 3H), 1.47 (s, 3H), 1.36 (s, 3H). MS
(ESI): m/e 389 (MH+). HPLC purity: method A 99%, tR 2.75 min;
method C 96%, tR 7.04 min.
2-[(2,3-Dihydrobenzo[1,4]oxazin-4-yl)methyl]-1,1,1-trifluoro-
4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol (23). Mp: 98-
1
99 °C. H NMR (400 MHz, CDCl3): δ 7.13 (dd, 1H), 6.88 (m,
1H), 6.72 (m, 1H), 6.65 (m, 1H), 6.56 (m, 2H), 5.85 (d, 1H), 4.03
(m, 2H), 3.73 (s, 3H), 3.20 (d, 1H), 3.05 (m, 2H), 2.98 (d, 1H)
2.52 (d, 1H), 2.10 (d, 1H) 1.58 (s, 3H), 1.35 (s, 3H). MS (ESI):
m/e 428 (MH+). HPLC purity: method A 98%, tR 5.25 min; method
B 99%, tR 11.83 min.
1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(tri-
fluoromethyl)pentyl]-2,3-dihydro-1H-quinolin-4-one (24). To a
mixture of LAH (0.003 g) in anhydrous THF (0.8 mL) at 0-5 °C
was added 11 (0.031 g). The mixture was stirred for 1 h and an
additional 3-4 mg of LAH added. After 2 h the reaction was
quenched with acetic acid, water, and ether. The organic layer was
washed with water, saturated NaHCO3, and brine and dried
(MgSO4). Removal of the volatiles in vacuo provided a residue
which was purified with flash silica gel chromatography using 33%
ethyl acetate in hexanes as the eluent. The product-rich fractions
were collected and the volatiles removed in vacuo to provide 0.015
g of 1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(tri-
fluoromethyl)pentyl]-1,2,3,4-tetrahydroquinolin-4-ol. A mixture of
this alcohol (0.015 g) and MnO2 (0.2 g) in 2 mL of CH2Cl2 was
stirred overnight, applied to a column of flash silica gel, and eluted
with 25% ethyl acetate in hexanes. The product-rich fractions were
collected and the volatiles removed in vacuo. Mass: 0.010 g. Mp:
1
Mp: 118-121 °C. H NMR (400 MHz, MeOH-d4): δ 8.20 (s,
1H), 8.16 (d, 1H, J ) 8.0 Hz), 7.69 (m, 1H), 7.49 (m, 1H), 7.27
(d, 1H, J ) 9.8 Hz), 7.08 (d, 1H, J ) 8.6 Hz), 7.03 (m, 2H), 4.14
(m, 2H), 3.93 (s, 3H), 3.01 (d, 1H, J ) 15.2 Hz), 2.16 (d, 1H, J )
15.2 Hz), 1.69 (s, 3H), 1.47 (s, 3H). MS (ES): m/e 439 ([M +
H]+). HPLC purity: method A 99%, tR 3.21 min; method B 98%,
tR 7.97 min.
1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(tri-
fluoromethyl)pentyl]-1H-[1,5]naphthyridin-4-one (28). Mp: 193-
195 °C. 1H NMR (400 MHz, MeOH-d4): δ 8.64 (m, 1H), 7.78 (d,
1H, J ) 7.9 Hz), 7.54 (m, 2H), 7.28 (d, 1H, J ) 9.8 Hz), 7.02 (m,
2H), 6.37 (d, 1H, J ) 7.9 Hz), 4.23 (d, 1H, J ) 16.0 Hz), 4.11 (d,
1H, J ) 16.0 Hz), 3.91 (s, 3H), 2.95 (d, 1H, J ) 15.2 Hz), 2.15 (d,
1H, J ) 15.2 Hz), 1.68 (s, 3H), 1.47 (s, 3H). FTIR (neat): 1625,
1584 cm-1. MS (ES): m/e 440 ([M + H]+).
1
132-134 °C. H NMR (400 MHz, CDCl3): δ 7.80 (d, 1H), 7.13
(m, 3H), 6.88 (m, 1H), 6.77 (m, 1H), 6.67 (m, 1H), 5.91 (d, 1H),
3.78 (s, 3H), 3.52 (d, 1H), 3.28 (m, 2H), 3.02 (d, 1H), 2.55 (m,
4H) 2.18 (d, 1H), 1.56 (s, 3H), 1.38 (s, 3H). IR (cm-1): 1672,
1603. MS (ESI): m/e 440 (MH+). HPLC purity: method A 96%,
tR 4.74 min; method B 98%, tR 10.82 min.
1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(tri-
fluoromethyl)pentyl]-1H-[1,6]naphthyridin-4-one (29). Mp: 229-
2-[(3,4-Dihydro-2H-quinolin-1-yl)methyl]-1,1,1-trifluoro-4-(5-
fluoro-2-methoxyphenyl)-4-methylpentan-2-ol (25). To a mixture
of 9 (0.21 g, 0.72 mmol) and 1,2,3,4-tetrahydoquinoline (0.096 g;
0.72 mmol) in methylene chloride (5 mL) was added flash silica
gel (0.5 g). The volatiles were removed in vacuo. The residue was
heated in a microwave at 150 °C for 4 min, applied to a column of
flash silica gel, and eluted with 5% ethyl acetate in hexanes. The
product-rich fractions were concentrated in vacuo. The residue was
treated with ethereal HCl and the volatiles removed in vacuo.
Trituration with hexanes and neutralization provided 0.06 g of the
1
230 °C. H NMR (400 MHz, MeOH-d4): δ 9.28 (s, 1H), 8.43 (d,
1H, J ) 6.4 Hz), 7.77 (d, 1H, J ) 8.0 Hz), 7.29 (m, 1H), 7.03 (m,
2H), 6.94 (d, 1H, J ) 6.4 Hz), 6.27 (d, 1H, J ) 8.0 Hz), 4.13 (d,
1H, J ) 15.9 Hz), 4.05 (d, 1H, J ) 15.9 Hz), 3.92 (s, 3H), 2.98 (d,
1H, J ) 15.2 Hz), 2.14 (d, 1H, J ) 15.2 Hz), 1.69 (s, 3H), 1.47 (s,
3H). FTIR (neat): 1642, 1587 cm-1. MS (ES): m/e 439 ([M +
H]+). HPLC purity: method A 99%, tR 2.59 min; method B 99%,
tR 6.91 min.
1-(2-Hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentyl)-
1
1
oily product. H NMR (400 MHz, CDCl3): δ 7.11 (dd, 1H), 6.87
1H-quinolin-4-one (30). Mp: 80-82 °C. H NMR (400 MHz,
(m, 3H), 6.73 (m, 2H), 6.60 (m, 1H), 5.97 (d, 1H), 3.73 (s, 3H),
3.27 (d, 1H), 3.15-2.90 (m, 3H), 2.67 (m, 2H), 2.55 (d, 1H) 2.12
(d, 1H), 1.57 (s, 3H), 1.40 (s, 3H). MS (ESI): m/e 426 (MH+).
HPLC purity: method A 99%, tR 4.21 min; method B 98%, tR 13.07
min.
2-(Benzoimidazol-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-
methoxyphenyl)-4-methylpentan-2-ol (26). A mixture of 9 (0.12
g, 0.41 mmol), benzimidazole (0.048 g; 0.41 mmol), and potassium
tert-butoxide (0.1 mL of a 1 M solution in THF, 0.1 mmol) in
DMSO (3 mL) was heated at 130 °C for 2 h, cooled to room
temperature, and diluted with ethyl acetate and water. The organic
CDCl3): δ 8.30 (d, 1H, J ) 7.3 Hz), 7.53 (m, 1H), 7.39 (m, 5H),
7.26 (m, 2H), 7.18 (d, 1H, J ) 8.7 Hz), 6.09 (d, 1H, J ) 7.9 Hz),
4.08 (d, 1H, J ) 15.8 Hz), 3.91 (d, 1H, J ) 15.8 Hz), 3.71 (s, 1H,
OH), 2.39 (d, 1H, J ) 15.4 Hz), 2.25 (d, 1H, J ) 15.4 Hz), 1.61
(s, 3H), 1.37 (s, 3H). MS (ES): m/e 390 ([M + H]+). HPLC
purity: method A 99%, tR 3.25 min; method B 99%, tR 7.60 min.
1-[2-Hydroxy-4-(2-hydroxyphenyl)-4-methyl-2-(trifluorometh-
1
yl)pentyl]-1H-quinolin-4-one (31). Mp: 157 °C. H NMR (400
MHz, MeOH-d4): δ 8.6 (d, 1H), 8.45 (d, 1H), 7.9 (t, 1H), 7.75 (t,
1H), 7.55 (d, 1H), 7.5 (d, 1H), 7.18 (t, 1H), 7.05, (d, 1H), 6.98 (t,
1H), 6.85(d, 1H), 3.25 (m, 2H), 4.6 (s, 2H), 2.2 (d, 1H), 1.73 (s,