5128 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Sun et al.
ylid en em eth yl]-4-m eth yl-1H-p yr r ol-3-yl}p r op ion ic Acid
(11f). This compound was prepared using the same procedure
as for preparation of 11c with a yield of 97%: H NMR (360
indolin-2-one, and 0.05 g (0.6 mmol) of piperidine were refluxed
in 5 mL of ethanol overnight. The mixture was concentrated
to dryness and chromatographed on a silica gel column eluting
with ethyl acetate-hexane-acetic acid to give 80 mg (23%
yield) of 3-[2,4-dimethyl-5-(2-oxo-1,2-dihydroindol-3-ylidenem-
ethyl)-1H-pyrrol-3-yl]propionic acid (16a ) as a mustard yellow
solid: 1H NMR (360 MHz, DMSO-d6) δ 13.38 (s, br, 1H, NH-
1′), 12.05 (s, br, 1H, CH2CH2COOH-4′), 10.70 (s, br, 1H, NH-
1), 7.69 (d, J ) 7.39 Hz, 1H, H-4), 7.53 (s, 1H, H-vinyl), 7.06
(t, J ) 7.39 Hz, 1H, H-6), 6.95 (t, J ) 7.39 Hz, 1H, H-5), 6.85
(d, J ) 7.39 Hz, 1H, H-7), 2.63 (t, J ) 7.45 Hz, 2H, CH2CH2-
COOH-4′), 2.34 (t, J ) 7.45 Hz, 2H, CH2CH2COOH-4′), 2.28
(s, 3H, CH3), 2.24 (s, 3H, CH3); MS m/z (relative intensity, %)
311 ([M + 1]+, 100). Anal. (C18H18N2O3) C, H, N.
3-[5-(5-Br om o-2-oxo-1,2-dih ydr oin dol-3-yliden em eth yl)-
2,4-d im eth yl-1H-p yr r ol-3-yl]p r op ion ic Acid (16b). The
reaction mixture of 106.0 mg (0.5 mmol) of 5-bromo-indolin-
2-one, 97.5 mg (0.5 mmol) of 15, and 75 µL (0.75 mmol) of
piperidine in 2.0 mL of ethanol was heated at 95 °C for 5 h
and cooled to room temperature. The precipitate was filtered,
washed with cold ethanol, 2 N hydrogen chloride, and water,
and dried to give 171 mg (88%) of 3-[5-(5-bromo-2-oxo-1,2-
dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrol-3-yl]-
propionic acid as a dark yellow solid: 1H NMR (360 MHz,
DMSO-d6) δ 12.04 (s, br, 1H, CH2CH2COOH-4′), 10.80 (s, br,
1H, NH-1), 8.00 (d, J ) 2.06 Hz, 1H, H-4), 7.67 (s, 1H, H-vinyl),
7.19 (dd, J ) 2.06, 8.50 Hz, 1H, H-6), 6.79 (d, J ) 8.50 Hz,
1H, H-7), 2.64 (t, J ) 7.63 Hz, 2H, CH2CH2COOH-4′), 2.35 (t,
J ) 7.63 Hz, 2H, CH2CH2COOH-4′), 2.29 (s, 3H, CH3), 2.27
(s, 3H, CH3); MS m/z (relative intensity, %) 389 (M+, 100).
Anal. (C18H17BrN2O3) C, H, N.
3-[4-(2-C a r b o xye t h yl)-3,5-d im e t h yl-1H -p y r r o l-2-y l
m eth ylen e]-2-oxo-2,3-dih ydr o-1H-in dole-5-car boxylic Acid
(16c). This compound was prepared using the same procedure
as for preparation of 16b with a yield of 65%: 1H NMR (300
MHz, DMSO-d6) δ 13.39 (s, 1H, NH-1′), 12.31 (s, br, 2H,
COOH-5 and CH2CH2COOH-4′), 11.07 (s, 1H, NH-1), 8.04 (s,
1H, H-4), 7.72 (d, J ) 8.07 Hz, 1H, H-6), 7.70 (s, 1H, H-vinyl),
6.93 (d, J ) 8.07 Hz, 1H, H-7), 2.64 (t, J ) 7.37 Hz, 2H, CH2-
CH2COOH-4′), 2.34 (t, J ) 7.37 Hz, 2H, CH2CH2COOH-4′),
2.30 (s, 3H, CH3), 2.28 (s, 3H, CH3); MS m/z (relative intensity,
%) 354 (M+, 100). Anal. (C19H18N2O5‚0.5H2O) C, H, N.
3-[2,4-Dim eth yl-5-(2-oxo-5-su lfa m oyl-1,2-d ih yd r oin d ol-
3-ylid en em et h yl)-1H -p yr r ol-3-yl]p r op ion ic Acid (16d ).
This compound was prepared using the same procedure as for
preparation of 16b with a yield of 60%: 1H NMR (300 MHz,
DMSO-d6) δ 13.40 (s, 1H, NH-1′), 12.09 (s, br, 1H, CH2CH2-
COOH-4′), 11.10 (s, 1H, NH-1), 8.16 (s, 1H, H-4), 7.65 (s, 1H,
H-vinyl), 7.55 (d, J ) 8.21 Hz, 1H, H-6), 7.10 (s, br, 2H, H2-
NSO2-5), 6.98 (d, J ) 8.21 Hz, 1H, H-7), 2.64 (t, J ) 7.22 Hz,
2H, CH2CH2COOH-4′), 2.38 (t, J ) 7.22 Hz, 2H, CH2CH2-
COOH-4′), 2.31 (s, 3H, CH3), 2.28 (s, 3H, CH3); MS m/z
(relative intensity, %) 389 (M+, 100). Anal. (C18H19N3O5S‚
0.8H2O) C, H, N.
1
MHz, DMSO-d6) δ 13.29 (s, br, 1H, NH-1′), 12.07 (s, br, 1H,
CH2CH2COOH-4′), 10.88 (s, br, 1H, NH-1), 7.82 (d, J ) 7.77,
1H, H-4), 7.65 (s, 1H, H-vinyl), 7.36 (t, J ) 8.06 Hz, 1H, H-5′′),
7.29 (dd, J ) 1.40, 7.77 Hz, 1H, H-5), 7.20 (d, J ) 8.06 Hz,
1H, H-6′′), 7.16 (d, J ) 2.23 Hz, 1H, H-2′′), 7.14-7.15 (m, br,
1H, H-5′), 7.09 (d, J ) 1.40 Hz, 1H, H-7), 6.91 (dd, J ) 2.23,
8.06 Hz, 1H, H-4′′), 3.82 (s, 3H, OCH3-3′′), 2.65 (t, J ) 7.55
Hz, 2H, CH2CH2COOH-4′), 2.57 (t, J ) 7.55 Hz, 2H, CH2CH2-
COOH-4′), 2.27 (s, 3H, CH3-3′); MS m/z (relative intensity, %)
401 (M+, 7). Anal. (C24H22N2O4‚0.75H2O) C, H, N.
3-{5-[6-(2-Met h oxy-p h en yl)-2-oxo-1,2-d ih yd r oin d ol-3-
ylid en em eth yl]-4-m eth yl-1H-p yr r ol-3-yl}p r op ion ic Acid
(11g). This compound was prepared using the same procedure
as for preparation of 11c with a yield of 86%: 1H NMR (360
MHz, DMSO-d6) δ 13.29 (s, br, 1H, NH-1′), 11.59 (s, br, 1H,
CH2CH2COOH-4′), 10.78 (s, br, 1H, NH-1), 7.76 (d, J ) 8.13
Hz, 1H, H-4), 7.62 (s, 1H, H-vinyl), 7.29-7.34 (m, 2H), 6.99-
7.15 (m, 6H), 3.76 (s, 3H, OCH3-2′′), 2.66 (t, J ) 7.46 Hz, 2H,
CH2CH2COOH-4′), 2.45 (t, J ) 7.46 Hz, 2H, CH2CH2COOH-
4′), 2.27 (s, 3H, CH3-3′); MS m/z (relative intensity, %) 401
([M - 1]+, 100). Anal. (C24H22N2O4‚H2O) C, H, N.
3-{5-[6-(4-Met h oxyp h en yl)-2-oxo-1,2-d ih yd r oin d ol-3-
ylid en em eth yl]-4-m eth yl-1H-p yr r ol-3-yl}p r op ion ic Acid
(11h ). This compound was prepared using the same procedure
as for preparation of 11c with a yield of 59%: 1H NMR (360
MHz, DMSO-d6) δ 13.26 (s, br, 1H, NH-1′), 10.83 (s, br, 1H,
NH-1), 7.78 (d, J ) 8.07 Hz, 1H, H-4), 7.61 (s, 1H, H-vinyl),
7.57 (d, J ) 8.95 Hz, 2H, H-2′′,6′′), 7.22 (dd, J ) 1.44, 8.07 Hz,
1H, H-5), 7.13 (d, J ) 3.09 Hz, 1H, H-5′), 7.04 (d, J ) 1.44 Hz,
1H, H-7), 7.00 (d, J ) 8.95 Hz, 2H, H-3′′,5′′), 3.79 (s, 3H, OCH3-
4′′), 2.65 (t, J ) 7.65 Hz, 2H, CH2CH2COOH-4′), 2.44 (t, J )
7.65 Hz, 2H, CH2CH2COOH-4′), 2.27 (s, 3H, CH3-3′); MS m/z
(relative intensity, %) 403 ([M + 1]+, 100). Anal. (C24H22N2O4‚
0.5H2O) C, H, N.
3-[2,4-Dim et h yl-5-(2-oxo-1,2-d ih yd r oin d ol-3-ylid en e-
m eth yl)-1H-p yr r ol-3-yl]p r op ion ic Acid (16a ). 4-(2-Meth-
oxycarbonylethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid
benzyl ester (2.0 g, 6.3 mmol) was hydrogenated over 0.2 g of
10% palladium on carbon in 40 mL of methanol for 2 h at room
temperature. The catalyst was removed by filtration and
washed with 40 mL of methanol. The filtrate was evaporated
to dryness and dried overnight in a vacuum oven to give 1.3 g
(92% yield) of 4-(2-methoxycarbonylethyl)-3,5-dimethyl-1H-
pyrrole-2-carboxylic acid (12).
Compound 12 (1.3 g, 5.8 mmol) was ground with 0.5 g of
anhydrous sodium acetate and then heated at 100 °C for 3
days. The mixture was dissolved in water, extracted with ethyl
acetate, and chromatographed on a column of silica gel in ethyl
acetate-hexane to give 0.4 g (38% yield) of 3-(2,4-dimethyl-
1H-pyrrol-3-yl)propionic acid methyl ester (13) as a thick, pale
yellow oil.
Compound 13 (0.35 g, 1.9 mmol) and 0.5 g (3.9 mmol) of
chloromethylenedimethylammonium chloride in 10 mL of
dichloroethane were stirred at room temperature under ni-
trogen for 2 h. The reaction mixture was concentrated and
treated with 10 mL of 6 M sodium hydroxide solution and then
extracted three times with 10 mL of ethyl acetate. The ethyl
acetate extracts were combined, dried over anhydrous sodium
sulfate, and evaporated to dryness to give 0.24 g (60% yield)
of 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)propionic acid meth-
yl ester (14) as a brown oil.
Compound 14 (0.23 g, 1.1 mmol) in 6 N sodium hydroxide
(10 mL) was heated at 100 °C for 2 h. The reaction mixture
was cooled to room temperature, acidified with 6 N hydro-
chloric acid, and extracted three times with 10 mL of ethyl
acetate. The combined organic layers were washed with 10 mL
of water and 5 mL of brine, dried over anhydrous sodium
sulfate, and evaporated to dryness to give 230 mg (100%) of
crude 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)propionic acid
(15) as a brown oil.
3-[5-(6-Met h oxy-2-oxo-1,2-d ih yd r oin d ol-3-ylid en em e-
th yl)-2,4-d im eth yl-1H-p yr r ol-3-yl]p r op ion ic Acid (16e).
This compound was prepared using the same procedure as for
preparation of 16b with a yield of 76%: 1H NMR (360 MHz,
DMSO-d6) δ 13.15 (s, br, 1H, NH-1′), 11.70 (s, br, 1H, CH2-
CH2COOH-4′), 10.65 (s, br, 1H, NH-1), 7.58 (d, J ) 8.27 Hz,
1H, H-4), 7.39 (s, 1H, H-vinyl), 6.54 (dd, J ) 2.26, 8.27 Hz,
1H, H-5), 6.43 (d, J ) 2.26 Hz, 1H, H-7), 3.74 (s, 3H, OCH3-6),
2.62 (t, J ) 7.67 Hz, 2H, CH2CH2COOH-4′), 2.30 (t, J ) 7.67
Hz, 2H, CH2CH2COOH-4′), 2.26 (s, 3H, CH3), and 2.22 (s, 3H,
CH3); MS m/z (relative intensity, %) 341 (M+, 100). Anal.
(C19H20N2O4‚0.5H2O) C, H, N.
3-[2,4-Dim eth yl-5-(2-oxo-6-p h en yl-1,2-d ih yd r oin d ol-3-
ylid en em eth yl)-1H-p yr r ol-3-yl]p r op ion ic Acid (16f). This
compound was prepared using the same procedure as for
1
preparation of 16b with a yield of 71%: H NMR (360 MHz,
DMSO-d6) δ 13.38 (s, br, 1H, NH-1′), 12.05 (s, br, 1H, CH2-
CH2COOH-4′), 10.81 (s, br, 1H, NH-1), 7.79 (d, J ) 7.84 Hz,
1H, H-4), 7.62 (d, J ) 7.51 Hz, 2H, H-2′′,6′′), 7.58 (s, 1H,
H-vinyl), 7.44 (t, J ) 7.51 Hz, 2H, H-3′′,5′′), 7.32 (t, br, J )
Compound 15 (0.22 g, 1.1 mmol), 0.15 g (1.1 mmol) of