8-Hydroxyquinoline → HCID 68657859, compound

HRID 930783Notes

Reaction equation

HRID 930783 reaction equation
Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][N:35]([C:2]2[C:3]([F:23])=[CH:4][C:5]3[C:6]4[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=4[N:8]([CH3:11])[C:9]=3[CH:10]=2)[C:34](=[O:38])[CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1

Participants

7

Reactant 4

HCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 36077244-Benzyloxy-2(1H)-pyridoneHCID 86635686HCID 86635686, compound

Product 1

HCID 68657859HCID 68657859, compoundYield 29.6%

Reagents, catalysts & solvents 2

HCID 83717Copper iodideCatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
133 °C

Procedure

tert-Butyl 7-bromo-8-fluoro-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (720 mg, 1.88 mmol), 4-benzyloxypyridone (380 mg, 1.9 mmol) and Cs2CO3 (680 mg, 2.1 mmol) were suspended in DMSO (8.0 mL) and the resulting suspension was degassed for 15 min. The system was flushed with Ar. Then 8-hydroxyquinoline (87 mg, 0.60 mmol) and copper iodide (114 mg, 0.599 mmol) were added. The degassing/Ar flushing process was repeated twice more, and the reaction mixture was heated at 133° C. for 18 h under argon. The reaction mixture was cooled, diluted with 15% solution of concentrated ammonium hydroxide in methanol (25 mL) and stirred at ambient temperature for 30 min. The reaction was further diluted with dichloromethane (75 mL). The solution was filtered through silica gel and concentrated under reduced pressure. The residue was diluted with CH2Cl2 and washed with H2O (25 mL) and brine (3×50 mL). The combined organics were dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, (1:1 hexanes/EtOAc)/(10:1:0.1 dichloromethane/methanol/concentrated ammonium hydroxide), 1:0 to 0:1) to afford crude tert-butyl 7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-8-fluoro-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (280 mg) as a yellow oil. This oil was dissolved in dichloromethane (3 mL) and TFA (1 mL) was added. The reaction mixture was stirred at ambient temperature for 1 h, concentrated and dried under vacuum overnight to provide the title compound (200 mg), which was used in the next step without further purification: ESI MS m/z 404 [M+H]+.

Workup

  1. customthe resulting suspension was degassed for 15 min
  2. customThe system was flushed with Ar
  3. customThe degassing/Ar flushing process
  4. temperatureThe reaction mixture was cooled
  5. additiondiluted with 15% solution of concentrated ammonium hydroxide in methanol (25 mL)
  6. additionThe reaction was further diluted with dichloromethane (75 mL)
  7. filtrationThe solution was filtered through silica gel
  8. concentrationconcentrated under reduced pressure
  9. additionThe residue was diluted with CH2Cl2
  10. washwashed with H2O (25 mL) and brine (3×50 mL)
  11. dry with materialThe combined organics were dried over Na2SO4
  12. concentrationconcentrated to dryness
  13. customThe crude material was purified by flash chromatography (silica gel, (1:1 hexanes/EtOAc)/(10:1:0.1 dichloromethane/methanol/concentrated ammonium hydroxide), 1:0 to 0:1)

Sources & evidence

ORD record
ord-27a0ca81a2494abd8b1431e779b09837
Source dataset
uspto-grants-2016_03
Patent number
US09296743B2

Reaction notes

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