8-Hydroxyquinoline → tert-Butyl 10-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate

HRID 474903Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 474903
Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=2)=[N:30][CH:31]=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[C:5](=[CH:4][CH:3]=[C:2]([N:35]3[CH:36]=[CH:37][C:32]([C:29]4[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:39])[F:40])=[CH:31][N:30]=4)=[CH:33][C:34]3=[O:38])[CH:10]=2)[C:6]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:7]1=2

Komponenten

7

Edukt 4

HCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 576255234-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-oneHCID 58093410tert-Butyl 8-bromo-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate

Produkt 1

HCID 66873731tert-Butyl 10-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylateAusbeute 29,5 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 83717Copper iodideKatalysatorHCID 679Dimethyl SulfoxideLösungsmittel

Reaktionsbedingungen

Temperatur
130 °C

Versuchsvorschrift

tert-Butyl 8-bromo-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate (0.15 g, 0.39 mmol), 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (0.13 g, 0.54 mmol), and Cs2CO3 (0.19 g, 0.60 mmol) were suspended in DMSO (3.3 mL), and the air was removed 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, 0.59 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 5:1 MeOH/NH4OH (15 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH2Cl2 (75 mL). The resulting solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 and washed with brine (3×25 mL). The organic solution was dried over Na2SO4, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 5 column volumes; increased to 0:100 over 20 column volumes and held for 5 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 (62 mg, 20%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.91 (d, J=7.5 Hz, 1H), 7.60-7.57 (m, 2H), 7.35-7.32 (m, 1H), 7.28-7.26 (s, 1H), 7.08-7.02 (m, 2H), 4.68-4.64 (m, 2H), 3.78-3.74 (m, 4H), 3.71-3.69 (m, 1H), 2.95-2.94 (m, 2H), 1.96-1.91 (m, 2H), 1.43 (s, 9H); ESI MS m/z 539 [M+H]+.

Aufarbeitung

  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 5:1 MeOH/NH4OH (15 mL)
  6. additionThe reaction was further diluted with CH2Cl2 (75 mL)
  7. filtrationThe resulting solution was filtered through silica gel
  8. concentrationthe filtrate was concentrated under reduced pressure
  9. additionThe residue was diluted with CH2Cl2
  10. washwashed with brine (3×25 mL)
  11. dry with materialThe organic solution was dried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated to dryness
  14. temperatureFlash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 5 column volumes; increased to 0:100 over 20 column volumes and held for 5 column volumes)

Quellen und Nachweise

ORD-Eintrag
ord-9b7bea22bdff44da8bfc4ea9030846f8
Quelldatensatz
uspto-grants-2014_01
Patentnummer
US08637501B2

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