Water → 2-Chloro-1-[1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-yl]ethanone

HRID 644050Notes

Reaction equation

[Cl:1][CH2:2][C:3](Cl)=[O:4].N1C=CC=CC=1.[CH:12]1([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][CH3:29])[CH:21]=[CH:20]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>C1(C)C=CC=CC=1.CO>[Cl:1][CH2:2][C:3]([C:21]1[C:22]2[C:27](=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][CH:23]=2)[N:19]([CH2:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:20]=1)=[O:4]

Participants

Conditions

Temperature: 55 °C

Procedure

To a solution of 7-methoxyindole (5.00 g, 34.0 mmol) in dimethylformamide (50 ml) under nitrogen was added sodium hydride (60% dispersion in mineral oil; 1.50 g, 37.4 mmol). The mixture was stirred at room temperature for 10 minutes before the addition of bromomethylcyclohexane (5.20 ml, 37.4 mmol). The resulting mixture was stirred at room temperature for 42 hours and then partitioned between ethyl acetate (150 ml) and water (150 ml). The aqueous layer was extracted with ethyl acetate (150 ml) and the combined organic layers were washed with brine (150 ml), dried over sodium sulfate and concentrated in vacuo. The crude intermediate was purified by flash column chromatography eluting with 0-10% (v/v) ethyl acetate in n-heptane to afford 1-(cyclohexyl)methyl-7-methoxy-1H-indole (7.48 g, 30.7 mmol). Chloroacetyl chloride (8.66 ml, 109 mmol) was added dropwise over a period of 1.5 h, to a stirred solution of pyridine (2.20 ml, 27.2 mmol) and 1-(cyclohexyl)methyl-7-methoxy-1H-indole (6.60 g, 27.2 mmol) in toluene (50 ml) at 55° C. The resulting mixture was heated at 55° C. for a further 0.5 h then allowed to cool to room temperature. Water (60 ml) and methanol (10 ml) were added. The organic layer was separated and concentrated under reduced pressure to afford a dark brown residue. The residue was purified by column chromatography eluting with 5% (v/v) ethyl acetate in n-heptane. The solid obtained was repeatedly recrystallised from ether to give 2-chloro-1-[1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-yl]ethanone as a white solid (1.40 g).

Workup

temperatureto cool to room temperature
customThe organic layer was separated
concentrationconcentrated under reduced pressure
customto afford a dark brown residue
customThe residue was purified by column chromatography
washeluting with 5% (v/v) ethyl acetate in n-heptane
customThe solid obtained
customwas repeatedly recrystallised from ether

Sources & evidence

ORD record: ord-c1f4d04b132f4223a31fe0489562f2e8
Source dataset: uspto-grants-2010_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07700634B2

Reaction notes

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