8-Hydroxyquinoline → tert-butyl 6-methyl-8-(6-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-1(6H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

HRID 474955Notes

Reaction equation

HRID 474955 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:24][C:25]([F:42])([F:41])[C:26]1[N:31]=[CH:30][C:29]([CH2:32][O:33][C:34]2[CH:39]=[N:38][NH:37][C:36](=[O:40])[CH:35]=2)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:37]3[C:36](=[O:40])[CH:35]=[C:34]([O:33][CH2:32][C:29]4[CH:30]=[N:31][C:26]([C:25]([F:24])([F:41])[F:42])=[CH:27][CH:28]=4)[CH:39]=[N:38]3)[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]1=2

Participants

7

Reactant 4

HCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 668688325-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-oneHCID 66874851tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

Product 1

HCID 66873698tert-butyl 6-methyl-8-(6-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-1(6H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylateYield 24%

Reagents, catalysts & solvents 2

HCID 83717Copper iodideCatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
110 °C

Procedure

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.13 g, 0.34 mmol), 5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-one (0.10 g, 0.67 mmol), and Cs2CO3 (0.14 g, 0.44 mmol) were suspended in DMSO (2.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (15 mg, 0.10 mmol) and copper iodide (0.16 g, 0.84 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 110° C. for 48 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4C1(aq.)/NH4OH/H2O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2 (30 mL) and washed with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (40 mL) (2×20 mL). The resulting organic solution was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes) gave the title compound (46 mg, 24%) as an orange film: 1H NMR (500 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.23 (d, J=8.5 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.99 (d, J=3.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.05 (dd, J=8.5, 1.5 Hz, 1H), 6.56 (d, J=2.5 Hz, 1H), 5.41 (s, 2H), 4.59-4.57 (m, 2H), 3.68-3.64 (m, 5H), 3.01-2.98 (m, 2H), 1.97-1.90 (m, 2H), 1.36-1.27 (m, 9H).

Workup

  1. customthe air was removed under vacuum for 15 min
  2. additionwere added to the suspension
  3. customThe evacuation/Ar flushing process
  4. temperatureThe mixture was cooled
  5. additiondiluted with 5.0:3.5:1.5 NH4C1(aq.)/NH4OH/H2O (30 mL)
  6. filtrationThe resulting solids were collected by filtration
  7. dissolutiondissolved in CH2Cl2 (30 mL)
  8. washwashed with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (40 mL) (2×20 mL)
  9. dry with materialThe resulting organic solution was dried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated to dryness under reduced pressure
  12. temperatureFlash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes)

Sources & evidence

ORD record
ord-a6a5dfd218844db2acc55c3010b1bb6e
Source dataset
uspto-grants-2014_01
Patent number
US08637501B2

Reaction notes

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