filtered, and the filtrate was washed with water (150 mL).
The organic layer was separated and concentrated under
vacuum. The obtained residue was triturated with petroleum
ether (150 mL), and the obtained solid was filtered and dried
under vacuum: yield 60.0 g, 81%; mp 184-190 °C.
1H NMR (CDCl3): δ 8.9 (br s, 1H), 7.7-7.3 (m, 3H),
4.59 (s, 2H), 3.9 (s, 3H); 13C NMR: δ 179.2, 166.9,157.1,
132.6, 131.0, 130.5, 121.7, 55.8, 28.61. MS: m/e ) 245 M+.
Anal. Calcd for C9H9BrO3: C, 44.11; H, 3.70. Found: C,
44.08; H, 3.67.
3-Methoxy-4-(N-methyl-5-nitroindole-3-yl)benzoic Acid
(13). A mixture of N-methyl-5-nitroindole (12, 50.0 g,
0.284mol), 4-bromomethyl-3-methoxybenzoic acid (125.0 g,
0.510 mol), zinc bromide (37.5 g, 0.161 mol), and dioxane
(250 mL) was stirred at 60-65 °C for 14 h. Reaction mass
was filtered through hyflow and washed with dioxane (100
mL). The filtrate was evaporated and dissolved in dichlo-
romethane (150 mL), basified with sodium hydroxide (10.0
g, 0.25 mol) solution. The basic aqueous layer was acidified
with hydrochloric acid (12.5 mL) and was extracted with
dichloromethane (250 mL). The organic layer was washed
with water (250 mL) and concentrated, and a fine solid was
isolated in methanol (150 mL): yield 60.0 g, 62%; mp 234-
240 °C.
δ 164.6, 156.3, 140.2, 139.1, 136.8, 134.1, 131.7, 130.3,
129.1, 126.3, 125.4, 120.5, 115.7, 115.0, 109.0, 55.1, 32.5,
24.3, 19.5. MS: m/e ) 493 M+. Anal. Calcd for C25H23-
N3O6S: C, 60.84; H, 4.70; N, 8.51. Found: C, 60.72; H,
4.65; N, 8.46.
N1-{4-[(5-Amino-N-methyl-1H-3-indolyl)methyl]-3-
methylbenzoyl}-2-methyl-1-benzenesulfonamide (15). A
solution of N-{3-methyl-4-[(N-methyl-5-nitro-1H-3-indolyl)-
methylbenzoyl}-2-methyl-1-benzenesulfonamide (14, 40.0 g,
0.081 mol) tetrahydrofuran (120 mL), and Raney-nickel (8
mL) was placed under par hydrogenation apparatus under
hydrogen (3.0 kg) pressure at 25-35 °C for 2 h. The reaction
mass was filtered through a hyflow bed, and the catalyst was
washed with tetrahydrofuran (40 mL). The combined filtrates
were concentrated, and the obtained residue was triturated
with petroleum ether (150 mL) resulting in 33.2 g, 88% yield
of compound 15 as a fine solid.
1H NMR: δ 7.93 (d, 1H), 7.57-6.67 (m, 10H), 3.88 (s,
2H), 3.85 (s, 3H), 3.69 (s, 3H), 2.49 (s, 3H); 13C NMR: δ
164.6, 157.2, 144.7, 138.3, 138.0, 136.3, 135.2, 134.8, 134.6,
132.1, 129.5, 125.6, 125.0, 121.3, 114.7, 110.8, 108.0, 55.6,
32.5, 22.9, 20.3. MS: m/e ) 463 M+. Anal. Calcd for
C25H25N3O4S: C, 64.78; H, 5.44; N, 9.06. Found: C, 64.70;
H, 5.38; N, 8.99.
[3[[2-Methoxy-4-[[[(2-methyl phenyl)sulfonyl]amino]-
carbonyl]phenyl]methyl]-N-methyl-1H-indole-5-yl]car-
bamicacid Cyclopentylester (10). To a solution of N1-{4-
[(5-amino-N-methyl-1H-3-indolyl)methyl]-3-methylbenzoyl}-
2-methyl-1-benzenesulfonamide (15, 25.0 g, 0.053 mol) was
added dichloromethane (125 mL), N-methylmorpholine (25
mL, 0.227 mol), and cyclopentylchloroformate (11.25 mL,
0.087 mol) at 25-35 °C under nitrogen atmosphere, and the
solution was stirred for 30 min. The reaction mixture was
quenched slowly with a solution of hydrochloric acid (12.5
mL) and water (112.5 mL). The separated organic layer was
washed with water (125 mL), and the solvent was completely
removed under vacuum: yield as a solid 27.5 g, 89%.
1H NMR (CDCl3): δ 9.67 (s, 1H), 8.23 (d, 1H), 7.01-
7.51 (m, 9H), 6.73 (s, 1H), 6.58 (s, 1H), 5.08-5.23 (m, 1H),
3.98 (s, 2H), 3.79 (s, 3H), 3.73 (q, 4H), 3.67 (s, 3H), 2.66
(s, 3H), 1.45-1.87 (m, 8H), 1.22 (t, 3H). 13C NMR: δ 164.6,
156.3, 135, 127, 109, 77, 55, 32.4, 23.3. MS: m/e ) 575
M+. Anal. Calcd for C31H33N3O6S: C, 64.68; H, 5.78; N,
7.30. Found: C, 64.61; H, 5.68; N, 7.28.
1H NMR (CDCl3): δ 8.5 (s, 1H), 8.05 (d, 1H), 7.6-7.2
(m, 4H), 6.9 (s, 1H), 4.2 (s, 2H), 3.9 (s, 3H), 3.85 (s, 3H);
13C NMR: δ 171.0, 156.6, 140.2, 139.4, 134.0, 130.2, 129.7,
125.9, 121.7, 118.7, 115.3, 110.8, 55.4, 32.7, 24.4. MS: m/e
) 341 M+. Anal. Calcd for C18H16N2O5: C, 63.52; H, 4.74;
N, 8.23. Found: C, 63.40; H, 4.68; N, 8.19.
N1-{3-Methyl-4-[(N-methyl-5-nitro-1H-3-indolyl)meth-
ylbenzoyl}-2-methyl-1-benzenesulfonamide (14). A mix-
ture of 3-methoxy-4-(N-methyl-5-nitroindole-3-yl)benzoic
acid (13, 50.0 g, 0.147 mol), 4-(dimethylamino)pyridine (5.0
g, 0.040 mol), 1,3-dicyclohexylcarbodiimide (30.0 g, 0.145
mol), and o-toluenesulfonamide (25.0 g, 0.146 mol) in
dichloromethane (250 mL) was stirred under reflux for 5 h.
After the reaction was cooled to 25-35 °C, the solid was
filtered, the filtrate was washed with a solution of hydro-
chloric acid (25 mL) and water (225 mL) followed by rinsing
with water, and the organic layer was concentrated under
vacuum. The resulting crude material was dissolved in
methanol (150 mL), cooled to 0 °C for 30 min; the byproduct
(dicyclohexylurea) was filtered, and the solid was washed
with cool methanol (25 mL), and the filtrate was concentrated
under vacuum: yield 45.5 g, 63%.
1H NMR (CDCl3): δ 9.05 (br s, 1H), 8.51 (d, 1H), 8.25
(d, 1H), 8.11 (d, 1H), 7.5-7.1 (m, 7H), 6.92 (s, 1H), 4.10
(s, 2H), 3.88 (s, 3H), 3.78 (s, 3H), 2.68 (s, 3H). 13C NMR:
Received for review July 2, 2004.
OP049869I
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Vol. 8, No. 6, 2004 / Organic Process Research & Development