August 2010
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2.54 (3H, s), 6.81 (1H, s), 7.06 (1H, s), 7.25 (1H, s), 9.15 (1H, s), 9.78 (1H, s).
1-Acetyl-2-butyl-4,6-dimethylindoline (15): To a suspension of allyltriphe-
nylphosphonium bromide (25.0 g, 65.3 mmol) in tetrahydrofuran (THF)
(200 ml) was added 1.6 M n-BuLi in hexane (65 ml, 65 mmol) dropwise
below 10 °C. The reaction mixture was stirred at the same temperature for
20 min. To the mixture was added 14 (5.66 g, 32.7 mmol) in THF (50 ml) at
the same temperature. After stirring for 20 min, water was added, and the
mixture was extracted with AcOEt. The organic layer was washed with
brine, dried over Na2SO4, and evaporated under reduced pressure. A solution
of the residue in MeOH (400 ml) was hydrogenated at 0.4 MPa in the pres-
ence of 10% Pd–C (2.70 g) at 35 °C for 16 h. After removal of the catalyst by
filtration, the filtrate was evaporated under reduced pressure. The residue
was purified by column chromatography (AcOEt : n-hexaneϭ1 : 3). To a so-
lution of the product in AcOH (38 ml) was added NaBH3CN (2.64 g,
37.8 mmol) portionwise at 10 °C, and then the mixture was stirred for
30 min at the same temperature. After addition of NaOH aqueous solution
(22 g/72 ml) at below 20 °C, the mixture was extracted with AcOEt. The or-
ganic layer was washed with saturated NaHCO3 solution and brine, dried
over Na2SO4, and evaporated under reduced pressure. To a solution of the
residue in CHCl3 (39 ml) were added Ac2O (2.7 ml, 29 mmol), and Et3N
(4.0 ml, 29 mmol). After stirring at room temperature for 30 min, the reac-
tion mixture was washed with 10% citric acid solution, saturated NaHCO3
solution and brine, dried over Na2SO4, and evaporated under reduced pres-
sure. The residue was purified by column chromatography (AcOEt : n-
Jϭ7.8 Hz), 6.30—7.20 (2H, br), 8.39 (1H, s), 9.05 (1H, s). MS m/z: 429
[MϩH]ϩ. Anal. Calcd for C19H32N4O3S2·HCl·H2O: C, 47.24; H, 7.30; N,
11.60; Cl, 7.34. Found: C, 47.08; H, 6.84; N, 11.61; Cl, 7.47.
Procedure for the Synthesis of 9a Compound 9a was synthesized from
10 via 11 and 12. To compound 12 was introduced a pivaloylamino moiety
at the 7-position according to the previous report11) and then the product was
converted to 9a according to the procedure for 1a. Compound 11 and 12
were prepared as follows:
2,4,6-Trimethylindole (11): To a mixture of 1014) (533 mg, 3.91 mmol)
and acetone (0.29 ml, 3.9 mmol) was added polyphosphoric acid (1.5 g), and
the mixture was heated gradually until 140 °C for 30 min. After addition of
water (10 ml), the mixture was extracted with Et2O. The organic layer was
washed with water, saturated NaHCO3 solution, and brine, dried over
Na2SO4, and evaporated under reduced pressure. The residue was purified by
column chromatography (AcOEt : n-hexaneϭ1 : 20) to give 11 as a crys-
1
talline solid (500 mg, 80% yield). H-NMR (CDCl3) d: 2.39 (6H, s), 2.45
(3H, s), 6.15 (1H, s), 6.70 (1H, s), 6.87 (1H, s).
1-Acetyl-2,4,6-trimethylindoline (12): To a solution of 11 (480 mg,
3.01 mmol) in AcOH (2 ml) in an ice bath was added NaBH3CN (378 mg,
6.02 mmol), and then the mixture was stirred for 2 h. After the mixture was
poured into cold water (8 ml), AcOEt (5 ml) was added, and then the mixture
was neutralized with NaOH. The organic layer was separated, washed with
water, dried over Na2SO4, and evaporated under reduced pressure. To a solu-
tion of the residue in benzene (2 ml) was added Ac2O (0.4 ml, 4 mmol), and
then the mixture was stirred for 1 h. After removal of the solvent under re-
duced pressure, a solution of the residue in CHCl3 (50 ml) was washed with
water, saturated NaHCO3 solution, and brine, dried over Na2SO4, and evapo-
rated under reduced pressure. The residue was purified by column chro-
matography (AcOEt : n-hexaneϭ1 : 1) to give 12 as a crystalline solid
(520 mg, 85% yield). 1H-NMR (CDCl3) d: 1.28 (3H, d, Jϭ6.4 Hz), 2.19
(3H, s), 2.30 (6H, s), 2.40—3.40 (2H, m), 4.47—4.57 (1H, m), 6.83 (1H, s),
7.81 (1H, s).
N-(2,4,6-Trimethyl-1-propyl-5-sulfamoylaminoindolin-7-yl)-2,2-di-
methylpropanamide Hydrochloride (9a): A crystalline solid. mp 156—
160 °C. IR (Nujol) cmϪ1: 1666. 1H-NMR (DMSO-d6) d: 0.83 (3H, t,
Jϭ7.1 Hz), 1.29 (9H, s), 1.39 (3H, d, Jϭ6.1 Hz), 1.50—1.85 (2H, m), 2.12
(3H, s), 2.26 (3H, s), 2.68—2.80 (1H, m), 2.95—3.05 (1H, m), 3.20—3.30
(1H, m), 3.35—4.00 (2H, m), 4.15—4.40 (1H, m), 6.50—7.50 (2H, br), 8.49
(1H, s), 9.30—9.70 (1H, br). MS m/z: 397 [MϩH]ϩ. Anal. Calcd for
C19H32N4O4S·HCl·H2O·0.1Et2O: C, 49.11; H, 7.65; N, 11.81; Cl, 7.47.
Found: C, 48.95; H, 7.35; N, 11.93; Cl, 7.24.
1
hexaneϭ1 : 2) to give 15 (3.48 g, 42% yield). H-NMR (CDCl3) d: 0.80—
1.00 (3H, m), 1.20—1.80 (6H, m), 2.20 (3H, s), 2.26 (3H, s), 2.31 (3H, s),
2.50—2.74 (1H, m), 2.95—3.20 (1H, m), 4.20—4.40 (0.7H, m), 4.70—4.85
(0.3H, m), 6.68 (1H, s), 6.74 (0.3H, s), 7.82 (0.7H, s).
N-(2-Butyl-1,4,6-trimethyl-5-sulfamoylaminoindolin-7-yl)-2,2-dimethyl-
propanamide Hydrochloride (9d): A crystalline solid. mp 180—183 °C. IR
(Nujol) cmϪ1: 1672. 1H-NMR (DMSO-d6) d: 0.85—0.95 (3H, m), 1.26 (9H,
s), 1.30—1.40 (4H, m), 1.50—1.65 (1H, m), 1.85—2.00 (1H, m), 2.10 (3H,
s), 2.25 (3H, s), 2.70—2.90 (1H, m), 2.83 (3H, s), 3.27 (1H, dd, Jϭ15.6,
7.1 Hz), 3.40—4.00 (1H, m), 6.40—7.20 (2H, br), 8.44 (1H, s), 9.24 (1H, s).
MS m/z: 409 [MϪH]Ϫ. Anal. Calcd for C20H34N4O3S·HCl·0.7H2O: C,
52.26; H, 7.98; N, 12.19; Cl, 7.71. Found: C, 52.02; H, 7.60; N, 12.07; Cl,
7.59.
Procedure for the Synthesis of 18a Compound 18a was synthesized
from 13 via 19, 20, and 22a. Compound 20 was converted to 22a according
to the procedure for 1a. Compound 20 was prepared as follows:
2-Acetoxymethyl-1-acetyl-4,6-dimethylindoline (19): To a suspension of
LiAlH4 (2.10 g, 55.3 mmol) in Et2O (160 ml) in an ice bath was added 13
(8.0 g, 37 mmol) portionwise, and then the mixture was stirred at the same
temperature for 1 h. After addition of water and AcOEt (300 ml), the mixture
was filtrated. The two layers of the filtrate were separated, and the organic
layer was dried over Na2SO4, and evaporated under reduced pressure to give
2-hydroxymethyl-4,6-dimethylindole (36) as a crystalline solid. To a solu-
tion of 36 in AcOH (60 ml) was added NaBH3CN (5.14 g, 73.6 mmol) por-
tionwise at 10 °C, and then the mixture was stirred for 30 min at the same
temperature. After addition of NaOH aqueous solution (40 g/140 ml) below
20 °C, the mixture was extracted with AcOEt. The organic layer was washed
with saturated NaHCO3 solution and brine, dried over Na2SO4, and evapo-
rated under reduced pressure. To a solution of the residue in CHCl3 (70 ml)
were added Ac2O (10.4 ml, 110 mmol), and Et3N (15.4 ml, 110 mmol). After
stirring at room temperature for 16 h, the reaction mixture was washed with
10% citric acid solution, saturated NaHCO3 solution and brine, dried over
Na2SO4, and evaporated under reduced pressure. The crystalline residue was
Procedure for the Synthesis of 9b and 9c Compounds 9b and 9c were
synthesized from 12 according to the procedure for 9a.
N-[1-(2-Methoxyethyl)-2,4,6-trimethyl-5-sulfamoylaminoindolin-7-yl]-
2,2-dimethylpropanamide Hydrochloride (9b): A crystalline solid. mp
164—167 °C. IR (Nujol) cmϪ1: 1653. 1H-NMR (DMSO-d6) d: 1.25 (9H, s),
1.34 (3H, d, Jϭ6.1 Hz), 2.10 (3H, s), 2.22 (3H, s), 2.45—2.70 (1H, m),
3.15—3.45 (1H, m), 3.26 (3H, s), 3.40—3.70 (4H, m), 3.90 (1H, s), 4.00—
4.30 (1H, br), 6.20—7.20 (2H, br), 8.37 (1H, s), 9.22 (1H, s). MS m/z: 411
[MϪH]Ϫ. Anal. Calcd for C19H32N4O4S·HCl·H2O: C, 50.42; H, 7.44; N,
12.38; Cl, 7.83. Found: C, 50.45; H, 7.35; N, 12.29; Cl, 7.60.
N-[1-(2-Ethoxyethyl)-2,4,6-trimethyl-5-sulfamoylaminoindolin-7-yl]-2,2-
dimethylpropanamide Hydrochloride (9c): A crystalline solid. mp 165—
168 °C. IR (Nujol) cmϪ1: 1654. 1H-NMR (DMSO-d6) d: 1.12 (3H, t,
Jϭ7.1 Hz), 1.26 (9H, s), 1.34 (3H, d, Jϭ5.9 Hz), 2.10 (3H, s), 2.22 (3H, s),
2.50—2.70 (1H, m), 3.15—3.55 (7H, m), 4.00—4.40 (2H, br), 6.40—7.20
(2H, br), 8.37 (1H, s), 9.15—9.40 (1H, br). MS m/z: 427 [MϩH]ϩ. Anal.
Calcd for C20H34N4O4S·HCl·0.5H2O: C, 50.89; H, 7.69; N, 11.87; Cl, 7.51.
Found: C, 50.66; H, 7.41; N, 11.84; Cl, 7.48.
1
rinsed with i-Pr2O to obtain 19 (7.43 g, 77% yield). H-NMR (CDCl3) d:
2.00 (3H, s), 2.19 (3H, s), 2.31 (3H, s), 2.36 (3H, s), 2.70 (1H, d,
Jϭ16.0 Hz), 3.15 (1H, dd, Jϭ16.0, 8.6 Hz), 3.80—4.30 (2H, m), 4.50—5.20
(1H, m), 6.69 (1H, s), 7.40—8.00 (1H, br).
Procedure for the Synthesis of 9d Compound 9d was synthesized from
13 via 14 and 15. Compound 15 was converted to 9d according to the proce-
dure for 9a. Compound 15 was prepared as follows:
1-Acetyl-2-hydroxymethyl-4,6-dimethylindoline (37): To a solution of 19
(17.4 g, 66.6 mmol) in MeOH (175 ml) in an ice bath was added 1.0 M LiOH
aqueous solution (80 ml, 80 mmol), and then the mixture was stirred at the
same temperature for 0.5 h. After addition of 5% citric acid solution
(100 ml), the solvent was removed under reduced pressure. The precipitate
formed was collected by filtration to obtain 37 as a crystalline solid (14.0 g,
4,6-Dimethylindole-2-carbaldehyde (14): To a suspension of LiAlH4
(4.11 g, 108 mmol) in Et2O (320 ml) in an ice bath was added 1312) (15.7 g,
72.2 mmol) portionwise, and then the mixture was stirred at the same tem-
perature for 1 h. After addition of water and AcOEt (300 ml), the mixture
was filtrated. The two layers of the filtrate were separated, and the organic
layer was dried over Na2SO4, and evaporated under reduced pressure. To a
solution of the residue in CH2Cl2 (540 ml) was added activated MnO2
(43.9 g, 505 mmol). After stirring at room temperature for 15 h, activated
MnO2 (10.0 g, 115 mmol) was added, and stirred for 6 h. The mixture was
filtrated, and the filtrate was evaporated under reduced pressure. The residue
was purified by column chromatography (AcOEt : n-hexaneϭ1 : 1) to give 14
as a crystalline solid (7.78 g, 62% yield). 1H-NMR (CDCl3) d: 2.43 (3H, s),
1
96% yield). H-NMR (CDCl3) d: 1.50—2.20 (1H, br), 2.19 (3H, s), 2.31
(3H, s), 2.40 (3H, s), 2.30—2.80 (1H, m), 3.00—3.40 (1H, m), 3.65 (2H, d,
Jϭ6.4 Hz), 4.50—5.20 (1H, m), 6.20—8.00 (2H, m).
1-Acetyl-2-methoxymethyl-4,6-dimethylindoline (20): To a solution of 37
(8.34 g, 38.0 mmol) in DMF (83 ml) in an ice bath was added 60% suspen-
sion of NaH in mineral oil (1.37 g, 34 mmol). After stirring for 10 min at the
same temperature, MeI (11.8 ml, 190 mmol) was added, and stirred for 1.5 h