Toluene → N-[2-({4-Chloro-6-[(4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl]-3-phenylquinolin-2-yl}oxy)ethyl]propanamide

HRID 1478521Notes

Reaction equation

HRID 1478521 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21](Cl)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]3[Cl:33])([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[OH:34][CH2:35][CH2:36][NH:37][C:38](=[O:41])[CH2:39][CH3:40].C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[Cl:33][C:19]1[C:18]2[C:23](=[CH:24][CH:25]=[C:16]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([OH:9])[C:10]3[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=3)[CH:17]=2)[N:22]=[C:21]([O:34][CH2:35][CH2:36][NH:37][C:38](=[O:41])[CH2:39][CH3:40])[C:20]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1

Participants

6

Reactant 4

HCID 1140TolueneHCID 24758Sodium hydrideHCID 87536PropionylaminoethanolHCID 90100965(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol

Product 1

HCID 118005506N-[2-({4-Chloro-6-[(4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl]-3-phenylquinolin-2-yl}oxy)ethyl]propanamide

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (100 mg, 0.202 mmol, Example 65), N-(2-hydroxylethyl)propionamide (34.2 μL, 0.303 mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineral oil, 32.3 mg, 0.808 mmol) were combined in a round bottom flask under an N2 atmosphere. The reaction solution was heated to reflux and refluxed overnight. The reaction solution was cooled to room temperature then transferred to a separatory funnel with EtOAc dilution, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/MeOH) then via reverse phase chromatography using acetonitrile with 0.05% trifluoroacetic acid in water as eluent. The fractions from the purification containing the desired product were transferred to a separatory funnel with EtOAc and extracted with a saturated, aqueous NaHCO3 solution. The aqueous layer was separated, extracted with EtOAc, then the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound. MS (ESI): mass calcd. for C31H28Cl2N4O3, 574.2; m/z found, 575.2 [M+H]+; 1H NMR (600 MHz, CD3OD) δ ppm 8.14 (s, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.78 (s, 1H), 7.68 (dd, J=8.8, 1.7 Hz, 1H), 7.47-7.41 (m, 2H), 7.41-7.37 (m, 1H), 7.38-7.34 (m, 4H), 7.34-7.30 (m, 2H), 6.32 (s, 1H), 4.52 (t, J=5.6 Hz, 2H), 3.53-3.44 (m, 5H), 2.11 (q, J=7.6 Hz, 2H), 1.04 (t, J=7.6 Hz, 3H).

Workup

  1. temperatureThe reaction solution was heated
  2. temperatureto reflux
  3. temperaturerefluxed overnight
  4. extractionextracted with saturated, aqueous NH4Cl
  5. customThe organic phase was separated
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe crude product was purified by flash column chromatography (silica gel, 0-10% DCM/MeOH)
  10. customThe fractions from the purification
  11. additioncontaining the desired product
  12. customwere transferred to a separatory funnel with EtOAc
  13. extractionextracted with a saturated, aqueous NaHCO3 solution
  14. customThe aqueous layer was separated
  15. extractionextracted with EtOAc
  16. dry with materialthe combined organic phases were dried over MgSO4
  17. filtrationfiltered
  18. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-7dd5a1babeb044b08f26f92dc07b7751
Source dataset
uspto-grants-2016_08
Patent number
US09403816B2

Reaction notes

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