Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 22 8147
to afford the title compound (0.271 g, yield 55%) as a light brown
oil. 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H, CHO), 9.59 (s,
1H, NH), 3.50 (t, J = 6.4 Hz, 2H, CH2), 3.31 (t, J = 6.4 Hz, 2H,
CH2), 2.81 (t, J = 7.2 Hz, 2H, CH2), 2.60-2.44 (m, 6H, 3 ꢀ CH2),
2.41 (s, 3H, CH3), 2.01-1.95 (m, 2H, CH2), 1.01 (t, J = 6.4 Hz,
6H, 2 ꢀ CH3). MS m/z (ESI): 292 [M þ H]þ.
5-(4-Bromobutyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic Acid
2-tert-Butyl Ester 4-Ethyl Ester (28). 5-(4-Bromobut-1-enyl)-3-
methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester
4-ethyl ester 27 (30 mg, 0.08 mmol) was dissolved in 3 mL of
ethanol. Then palladium on activated carbon (6 mg, 5%) was
added to the solution at room temperature. The reaction
mixture was stirred for 45 min under a hydrogen atmosphere.
After TLC showed the starting material had disappeared, the
reaction mixture was filtered and concentrated under reduced
pressure to give the title product (21 mg, 70%) as a colorless oil.
1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H, NH), 4.21 (q, J = 7.2
Hz, 2H, CH2), 3.45 (t, J = 6.8 Hz, 2H, CH2), 2.87 (t, J = 7.6 Hz,
2H, CH2), 2.46 (s, 3H, CH3), 1.85-1.80 (m, 2H, CH2),
1.76-1.70 (m, 2H, CH2), 1.51 (s, 9H, 3 ꢀ CH3), 1.27 (t, J =
7.2 Hz, 3H, CH3). MS m/z (ESI): 388 [M þ H]þ.
(Z)-5-(2-Diethylaminoethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-
indol-3-ylidenemethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo-
[3,2-c]azepin-4-one (23). Compound 22 and 5-fluoro-1,3-
dihydroindol-2-one (0.127 g, 0.84 mmol) were dissolved in 1.4 mL
of anhydrous ethanol. The resulting mixture was stirred for
10 min in the dark and treated with piperidine (0.15 mL, 1.49
mmol). The mixture was refluxed at 70 °C for about 1.5 h in an oil
bath under an argon atmosphere, and a large orange precipitate
formed. After TLC showed the starting material had disappeared,
the reaction mixture was allowed to cool to room temperature.
The precipitate was filtered and dried to give the title compound
(0.288 g, yield 80.76%) as an orange solid. 1H NMR (400 MHz,
DMSO-d6) δ 13.70 (s, 1H, NH), 10.90 (s, 1H, indole NH),
7.78-7.75 (m, 1H, ArH), 7.74 (s, 1H, CHdC), 6.96-6.91 (m,
1H, ArH), 6.86-6.83 (m, 1H, ArH), 3.51-3.48 (t, J = 6.8 Hz, 2H,
CH2), 3.36-3.28 (m, 4H, 2 ꢀ CH2), 2.92 (t, J = 7.2 Hz, 2H, CH2),
2.57-2.52 (m, 4H, 2 ꢀ CH2), 2.45 (s, 3H, CH3), 2.07-2.03 (m, 2H,
CH2), 0.97 (t, J = 6.8 Hz, 6H, 2 ꢀ CH3). MS m/z (ESI): 425 [M þ
H]þ. Elemental analysis (C24H29FN4O2) calcd: C, 67.90; H, 6.89;
N, 13.20; F, 4.48. Found: C, 67.81; H, 6.90; N, 13.11; F, 4.47.
HRMS calcd for C24H30FN4O2 [M þ H]þ: 425.234 73. Found:
425.234 17.
5-[4-(2-Diethylaminoethylamino)butyl]-3-methyl-1H-pyrrole-2,4-
dicarboxylic Acid 2-tert-Butyl Ester 4-Ethyl Ester (29). 5-(4-
Bromobutyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-
-butyl ester 4-ethyl ester 28 (220 mg, 0.57 mmol) was dissolved in
5 mL of dichloromethane. The mixture was treated with N,N-
diethylethylenediamine (164 μL, 1.13 mmol) and refluxed for 30
min in an oil bath. The reaction mixture was concentrated to
remove most of the solvent and refluxed for another 1 h. After
TLC showed the starting material had disappeared, the reaction
mixture was concentrated under reduced pressure and purified
by silica gel column chromatography to give the title compound
as a white solid (187 mg, 78%). 1H NMR (400 MHz, CDCl3) δ
4.21 (q, J = 7.2 Hz, 2H, CH2), 2.86 (t, J = 7.2 Hz, 2H, CH2),
2.63-2.58 (m, 4H, 2 ꢀ CH2), 2.52-2.47 (m, 2H, CH2), 2.45 (s,
3H, CH3), 2.45-2.44 (m, 4H, 2 ꢀ CH2), 1.64-1.61 (m, 2H,
CH2), 1.53-1.47 (m, 2H, CH2), 1.47 (s, 9H, 3 ꢀ CH3), 1.28 (t, J
= 7.2 Hz, 3H, CH3), 0.94 (t, J = 7.2 Hz, 6H, 2 ꢀ CH3). MS m/z
(ESI): 424 [M þ H]þ.
Compounds 23-25 were similarly prepared using the appro-
priate raw materials. In most cases, the products deposited as the
malate salts.
5-(Cyclopropylhydroxymethyl)-3-methyl-1H-pyrrole-2,4-dicar-
boxylic Acid 2-tert-Butyl Ester 4-Ethyl Ester (26). To a stirred
solution of cyclopropylmagnesium bromide (15 mL, 0.5 mol/L)
cooled to -10 °C in an ice-salt bath under an argon atmosphere
was slowly added a solution of 5-formyl-3-methyl-1H-pyrrole-
2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 17 (1.26 g,
4.5 mmol) in tetrahydrofuran (10 mL) . Upon completion of the
addition, the ice-salt bath was removed. The mixture was
stirred for 1 h at room temperature until TLC indicated that
all starting materials had been consumed. The reaction mixture
was quenched with water, diluted with 10% sulfuric acid solu-
tion (20 mL), and stirred for a further 30 min. The residue was
extracted with ethyl acetate (50 mL ꢀ 3). The combined organic
layers were washed with water and brine (50 mL each), dried
over anhydrous magnesium sulfate, and evaporated to give a
yellow solid. The resulting solid was purified by silica gel column
chromatography to give the title compound (0.576 g, 39.6%) as
a white solid. 1H NMR (400 MHz, CDCl3) δ 9.47 (s, 1H, NH),
4.56 (d, J = 7.6 Hz, 1H, CH), 4.29 (q, J = 7.2 Hz, 2H, CH2), 2.51
(s, 3H, CH3), 1.53 (s, 9H, 3 ꢀ CH3), 1.35 (t, J = 6.8 Hz, 3H,
CH3), 0.62-0.61 (m, 1H, CH), 0.61-0.58 (m, 2H, CH2),
0.55-0.30 (m, 2H, CH2). MS m/z (ESI): 322 [M - H]-.
5-(4-Bromobut-1-enyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic
Acid 2-tert-Butyl Ester 4-Ethyl Ester (27). 5-(Cyclopropylhydroxy-
methyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester
4-ethyl ester 26 (323 mg, 1 mmol) was dissolved in 4 mL of ethanol.
To the mixture was added 40% hydrobromic acid (2.8 mL), and the
solution was stirred for 30 min at room temperature. After TLC
showed the starting material disappeared, the reaction mixture was
extracted with ethyl acetate (10 mL ꢀ 5). The combined organic
extracts were washed with saturated brine (15 mL), dried over
anhydrous magnesium sulfate, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography to give the title compound (345 mg, yield 89.5%) as
a white solid. 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H, NH), 7.14
(d, J= 16.4 Hz, 1H, CHdC), 6.05 (td, J=16.4Hz, J=6.8Hz, 1H,
CdCH), 4.31 (q, J = 7.2 Hz, 2H, CH2), 3.47 (t, J = 6.8 Hz, 2H,
CH2), 2.83-2.78 (m, 2H, CH2), 2.52 (s, 3H, CH3), 1.58 (s, 9H, 3 ꢀ
CH3), 1.37 (t, J = 7.2 Hz, 3H, CH3). MS m/z (ESI): 329 [M þ H]þ.
5-(2-Diethylaminoethyl)-3-methyl-6,7,8,9-tetrahydro-1H,5H-
1,5-diazacyclopentacycloocten-4-one (30). Trimethylaluminum
(489 μL, 2 mol/L) was dissolved in 3 mL of toluene. Then a
solution of 5-(4-diethylaminobutyl)-3-methyl-1H-pyrrole-2,4-
dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 29 (345 mg,
0.82 mmol) in 6 mL of toluene was added at room temperature.
Upon completion of the addition, the reaction mixture was
stirred for 30 min at room temperature and heated to reflux for 2
h in an oil bath. After TLC showed the starting material had
disappeared, the reaction mixture was quenched with water,
diluted with hydrochloric acid solution (1 mL, 2 mol/L), and
stirred for 30 min at room temperature. The mixture was
adjusted to pH 10 with 10% aqueous sodium hydroxide solution
and extracted with ethyl acetate (25 mL ꢀ 3). The combined
organic extracts were washed with saturated brine (25 mL),
dried over anhydrous magnesium sulfate, filtered, and concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography to give the title compound as a
white solid (60 mg, 26.7%). 1H NMR (400 MHz, CDCl3) δ 8.35
(s, 1H, NH), 6.25 (s, 1H, pyrrole ArH), 2.68-2.64 (m, 4H, 2 ꢀ
CH2), 2.51 (q, J = 7.2 Hz, 4H, 2 ꢀ CH2), 2.04 (s, 3H, CH3), 1.66
(br s, 4H, 2 ꢀ CH2), 1.24-1.18 (m, 4H, 2 ꢀ CH2), 0.96 (t, J = 7.2
Hz, 6H, 2 ꢀ CH3). MS m/z (ESI): 278 [M þ H]þ.
5-(2-Diethylaminoethyl)-3-methyl-4-oxo-4,5,6,7,8,9-hexa-
hydro-1H-1,5-diazacyclopentacyclooctene-2-carbaldehyde (31).
To a stirred solution of N,N-dimethylformamide (88 μL) in
dichloromethane was slowly added 35 μL of phosphorus oxy-
chloride under an argon atmosphere while maintaining the
temperature at 0 °C. Upon completion of the addition, the
mixture was stirred for 15 min at room temperature and cooled
to 0-5 °C in an ice-water bath. A mixture of 30 (70 mg, 0.25
mmol) in 2 mL of N,N-dimethylformamide was added dropwise
to the above solution. Upon completion of the addition, the
mixture was stirred for 2 h at 0 °C and diluted with cold water
(5 mL). The resulting mixture was adjusted to pH 12 with 10%
aqueous sodium hydroxide solution and extracted with dichloro-
methane (15 mL ꢀ 3). The combined organic layers were washed