8-Hydroxyquinoline → tert-butyl 10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

HRID 474971Notes

Reaction equation

HRID 474971 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[N:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=2)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:22][N:7]1[C:8]2[CH2:9][CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][C:14]=2[C:5]2[CH:4]=[CH:3][C:2]([N:35]3[CH:36]=[CH:37][C:32]([C:29]4[CH:30]=[N:31][C:26]([C:25]([F:24])([F:39])[F:40])=[CH:27][CH:28]=4)=[CH:33][C:34]3=[O:38])=[N:23][C:6]1=2

Participants

7

Reactant 4

HCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 579504694-(6-(Trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-oneHCID 58093388tert-butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

Product 1

HCID 66874026tert-butyl 10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylateYield 19.6%

Reagents, catalysts & solvents 2

HCID 83717Copper iodideCatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
130 °C

Procedure

tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.20 g, 0.53 mmol), 4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (0.13 g, 0.55 mmol), and Cs2CO3 (0.19 g, 0.58 mmol) were suspended in DMSO (3.0 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (23 mg, 0.16 mmol) and copper iodide (0.13 g, 0.69 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (30 mL), and the resulting solution was stirred at ambient temperature for 6 h. The resulting solution was diluted with CH2Cl2, the resulting layers were separated, and the aqueous phase was extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(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, then increased to 0:100 over 20 column volumes and held for 4 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (56 mg, 19%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 9.20 (d, J=2.0 Hz, 1H), 8.50 (dd, J=8.0, 2.0 Hz, 1H), 8.06-8.03 (m, 3H), 7.36 (d, J=8.0 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.83 (dd, J=7.0, 2.0 Hz, 1H), 3.72-3.68 (m, 5H), 3.61-3.60 (m, 2H), 3.08-3.07 (m, 2H), 2.99-2.98 (m, 2H), 1.44 (s, 9H).

Workup

  1. customthe mixture was degassed 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 NH4Cl (aq.)/NH4OH/H2O (30 mL)
  6. additionThe resulting solution was diluted with CH2Cl2
  7. customthe resulting layers were separated
  8. extractionthe aqueous phase was extracted with CH2Cl2 (3×25 mL)
  9. dry with materialThe combined organic extracts were dried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated to dryness under reduced pressure
  12. temperatureFlash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes
  13. temperatureincreased to 0:100 over 20 column volumes

Sources & evidence

ORD record
ord-ecd80a452baa446db1ff9fe732f02a9b
Source dataset
uspto-grants-2014_01
Patent number
US08637501B2

Reaction notes

Loading…