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

HRID 474939

Reaction equation

HRID 474939 reaction equation
[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+].[ClH:58]>CS(C)=O.CCOCC.C(Cl)Cl.[Cu]I>[ClH:58].[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]([C:19]2[CH:20]=[CH:21][C:22]3[C:23]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29][C:24]=4[N:25]([CH3:28])[C:26]=3[CH:27]=2)[C:8](=[O:12])[CH:7]=1

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 220503904-(2,4-difluorobenzyloxy)-1H-pyridin-2-oneHCID 58093439tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

Product 1

HCID 668737074-(2,4-Difluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochlorideYield 48%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 679Dimethyl SulfoxideSolventHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
135 °C

Procedure

A suspension of 4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (114 mg, 0.479 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (165 mg, 0.435 mmol), CuI (99 mg, 0.52 mmol), 8-hydroxyquinoline (13 mg, 0.087 mmol) and Cs2CO3 (156 mg, 0.479 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N2 and stirred at 135° C. for 2 d. 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 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (Et2O/(8:1.9:0.1 Et2O/MeOH/NH4OH) afforded a yellow residue. 2 N HCl in Et2O (100 mL) was added to a solution of the yellow residue in CH2Cl2 (5 mL) under N2, and the resulting suspension was stirred at 25° C. for 2 d. The suspension was filtered, and the solid was washed with Et2O and put in a vacuum oven at 45° C. for 2 h to afford 98 mg (48%) of the title compound as a white powder: 1H NMR (500 MHz, DMSO-d6) δ 9.02 (br s, 2H), 7.67 (dd, J=15.0, 9.0 Hz, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.44 (d, J=1.5 Hz, 1H), 7.35 (ddd, J=10.5, 10.5, 2.0 Hz, 1H), 7.18 (ddd, J=8.5, 8.5, 2.5 Hz, 1H), 6.95 (dd, J=8.5, 2.0 Hz, 1H), 6.07 (dd, J=7.5, 3.0 Hz, 1H), 6.04 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 3.69 (s, 3H), 3.41-3.31 (m, 4H), 3.26-3.22 (m, 2H), 3.14-3.10 (m, 2H); ESI MS m/z 436 [M+H]+.

Workup

  1. customwas degassed under reduced pressure for 45 min
  2. temperatureThe suspension was cooled
  3. addition9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added
  4. stirringthe resulting suspension was stirred at 25° C. for 30 min
  5. washthe filtrate was washed with brine
  6. additionActivated carbon was added to the resulting solution
  7. filtrationthe resulting suspension was filtered
  8. dry with materialThe filtrate was dried over Na2SO4
  9. concentrationconcentrated under reduced pressure
  10. customFlash chromatography on silica gel (Et2O/(8:1.9:0.1 Et2O/MeOH/NH4OH) afforded a yellow residue
  11. stirringthe resulting suspension was stirred at 25° C. for 2 d
  12. filtrationThe suspension was filtered
  13. washthe solid was washed with Et2O
  14. waitput in a vacuum oven at 45° C. for 2 h

Sources & evidence

ORD record
ord-915d4efc5cf2478da5e790ddefc06cbb
Source dataset
uspto-grants-2014_01
Patent number
US08637501B2

Linked notes

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