8-Hydroxyquinoline → 4-(4-Chlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

HRID 474998Notes

Reaction equation

HRID 474998 reaction equation
[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28][C:23]=3[N:24]([CH3:27])[C:25]=2[CH:26]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[ClH:1].[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]4[C:22]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28][C:23]=5[N:24]([CH3:27])[C:25]=4[CH:26]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 574978644-[(4-Chlorophenyl)methoxy]pyridin-2(1H)-oneHCID 58093439tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

Product 1

HCID 668734014-(4-Chlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochlorideYield 45.9%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
135 °C

Procedure

A suspension of 4-(4-chlorobenzyloxy)pyridin-2(1H)-one (91.0 mg, 0.38 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H) carboxylate (160 mg, 0.42 mmol), 8-hydroxyquinoline (11 mg, 0.072 mmol) and Cs2CO3 (137 mg, 0.42 mmol) in DMSO (10.0 mL) was degassed under reduced pressure for 40 min. CuI (87 mg, 0.46 mmol) was added to the above solution, and the reaction mixture was degassed under reduced pressure for 2×5 min. The reaction mixture was heated at 135° C. under nitrogen overnight. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 5 min. Celite was added, and the suspension was stirred for 5 min. The suspension was filtered through Celite, and the filtrate was washed with brine. The resulting solution was dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in dichloromethane (1.0 mL), and HCl (2M in diethyl ether, 5.0 mL) was added. The resulting slurry was stirred at room temperature overnight and concentrated under reduced pressure. Purification by preparative HPLC followed by preparative TLC (DCM/MeOH/concentrated ammonia 96:3.6:0.4) and preparative HPCL afforded the title compound (41 mg, 23%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.58 (d, J=8.5 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.39 (d, J=1.5 Hz, 1H), 7.01 (dd, J=8.5, 2.0 Hz, 1H), 6.28 (dd, J=8.0, 3.0 Hz, 1H), 6.11 (d, J=2.5 Hz, 1H), 5.17 (s, 2H), 3.74 (s, 3H), 3.54 (t, J=5.5 Hz, 2H), 3.48 (t, J=5.5 Hz, 2H), 3.35-3.33 (m, 2H), 3.23 (t, J=5.5 Hz, 2H); ESI MS m/z 434 [M+H]+.

Workup

  1. customwas degassed under reduced pressure for 40 min
  2. customthe reaction mixture was degassed under reduced pressure for 2×5 min
  3. temperatureThe suspension was cooled
  4. addition9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added
  5. additionCelite was added
  6. stirringthe suspension was stirred for 5 min
  7. filtrationThe suspension was filtered through Celite
  8. washthe filtrate was washed with brine
  9. dry with materialThe resulting solution was dried over Na2SO4
  10. concentrationconcentrated under reduced pressure
  11. dissolutionThe residue was dissolved in dichloromethane (1.0 mL)
  12. additionHCl (2M in diethyl ether, 5.0 mL) was added
  13. stirringThe resulting slurry was stirred at room temperature overnight
  14. concentrationconcentrated under reduced pressure
  15. customPurification by preparative HPLC

Sources & evidence

ORD record
ord-00258289fcff4c24956ce036ecd0d571
Source dataset
uspto-grants-2014_01
Patent number
US08637501B2

Reaction notes

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