2-Aminoquinoline → 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylic acid quinolin-2-ylamide

HRID 1514938Notes

Reaction equation

HRID 1514938 reaction equation
C[Al](C)C.[NH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([C:33](OC)=[O:34])[CH:27]=2>C1(C)C=CC=CC=1>[N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[NH:5][C:33]([C:28]1[CH:27]=[C:26]2[C:31]([CH:32]=[C:24]([C:18]3[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=3[Cl:16])[NH:25]2)=[CH:30][CH:29]=1)=[O:34]

Participants

5

Reactant 3

HCID 113792-AminoquinolineHCID 16682925Trimethylaluminum2×HCID 66965661methyl 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylate

Product 1

HCID 669656772-(2,6-dichlorophenyl)-1H-indole-6-carboxylic acid quinolin-2-ylamide

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
100 °C

Procedure

To 10 mL of ice-cold toluene was added 844 μL of 2 M trimethylaluminum in toluene then 2-aminoquinoline (233 mg, 1.62 mmol) was added in one portion and the mixture was stirred for 25 min. To this was added a solution of methyl 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylate (470 mg, 1.47 mmol) (from Example 3-5) in toluene (7 mL) dropwise and the resulting solution was heated at 100° C. for 18 h. A second aliquot of trimethylaluminum was added and the mixture heated another 18 h, after which it was cooled to ambient temperature, quenched with 1N HCl, and basified by stirring with 8% NaHCO3. This mixture was filtered, and the filtrate separated. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were dried, filtered, and the solvent was removed under reduced pressure. The residue was chromatographed using a gradient of 20-50% heptane/ethyl acetate to give 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylic acid quinolin-2-ylamide. 1H NMR (DMSO-d6, 400 MHz) δ 11.85 (s, 1H), 11.06 (s, 1H), 8.40 (s, 2H), 8.22 (s, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.81 (dd, J=8.3, 1.5 Hz, 1H), 7.74 (td, J=6.8, 1.5 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.88 (s, 1H), 7.66 (s, 1H), 7.53 (m, 2H), 6.62 (s, 1H). MS (m/z) 432.0 (M+1); retention time=1.57 min (Method 10).

Workup

  1. temperaturethe mixture heated another 18 h
  2. temperatureafter which it was cooled to ambient temperature
  3. customquenched with 1N HCl
  4. stirringby stirring with 8% NaHCO3
  5. filtrationThis mixture was filtered
  6. customthe filtrate separated
  7. extractionThe aqueous layer was re-extracted with ethyl acetate
  8. customthe combined organic layers were dried
  9. filtrationfiltered
  10. customthe solvent was removed under reduced pressure
  11. customThe residue was chromatographed

Sources & evidence

ORD record
ord-119ac25d5c6349f0bace03590ff93454
Source dataset
uspto-grants-2012_07
Patent number
US08222248B2

Reaction notes

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