Phenol → HCID 89784031, compound

HRID 1055858Notes

Reaction equation

HRID 1055858 reaction equation
[H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH:27]([CH2:30][CH3:31])[CH2:26][NH:25][C:24](=[O:32])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.CS(C)=O>[CH2:30]([CH:27]1[CH2:26][NH:25][C:24](=[O:32])[C:23]2[CH:22]=[C:21]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:13]=3[N:12]=[C:11]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:20]=[CH:19]4)[NH:29][C:28]1=2)[CH3:31]

Participants

7

Reactant 4

HCID 996PhenolHCID 6422Trifluoroacetic acidHCID 24758Sodium hydrideHCID 89783190HCID 89783190, compound

Product 1

HCID 89784031HCID 89784031, compoundYield 40%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

To a slurry of NaH (60% in mineral oil; 0.064 g, 1.611 mmol) in 1 mL DMF was added phenol (0.152 g, 1.611 mmol). After 10 min, rac-2-(2-chloroquinolin-8-yl)-7-ethyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 22; 0.075 g, 0.230 mmol) was added, and the reaction was heated to 70° C. After 2 h, the reaction was cooled and treated with TFA (0.124 ml, 1.611 mmol) and 1 mL DMSO, and the solution was filtered and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 15-100% ACN/H2O with 0.1% TFA); product-containing fraction was treated with saturated aq. NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted 3×DCM. The combined organic layers were then dried over Na2SO4, filtered, and concentrated in vacuo to give rac-7-ethyl-2-(2-phenoxyquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.035 g, 0.091 mmol, 40% yield) as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.12 (1H, br. s), 8.50 (1H, d, J=8.8 Hz), 8.14 (1H, dt, J=7.5, 0.7 Hz), 7.80 (1H, dt, J=8.0, 0.7 Hz), 7.35-7.64 (7H, m), 6.90-7.00 (1H, m), 6.82-6.91 (1H, m), 3.38-3.45 (1H, m), 3.12-3.20 (1H, m), 2.24-2.34 (1H, m), 1.13-1.34 (2H, m), 0.82 (3H, t, J=7.3 Hz). m/z (ESI, +ve) 384.0 (M+H)+.

Workup

  1. waitAfter 2 h
  2. temperaturethe reaction was cooled
  3. filtrationthe solution was filtered
  4. custompurified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 15-100% ACN/H2O with 0.1% TFA)
  5. additionproduct-containing fraction
  6. additionwas treated with saturated aq. NaHCO3 and DCM
  7. customThe organic layer was separated
  8. extractionthe aq. layer was extracted 3×DCM
  9. dry with materialThe combined organic layers were then dried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-0719f4b5245a471194ccaae439b5412d
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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