Toluene → HCID 118005597, compound

HRID 1478523Notes

Reaction equation

HRID 1478523 reaction equation
Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:31]3[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=3)([C:21]3[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=1.[F:37][C:38]([F:42])([F:41])[CH2:39][OH:40].C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[Cl:18][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:31]3[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=3)([C:21]3[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=[C:2]([O:40][CH2:39][C:38]([F:42])([F:41])[F:37])[C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1

Participants

6

Reactant 4

HCID 1140TolueneHCID 64092,2,2-Trifluoroethanol2×HCID 24758Sodium hydride2×HCID 117868534HCID 117868534, compound

Product 1

HCID 118005597HCID 118005597, compound

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl) [6-(trifluoromethyl) pyridin-3-yl]methanol (200 mg, 0.378 mmol, Example 66), 2,2,2-trifluoroethanol (14.0 μL, 0.19 mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineral oil, 19 mg, 0.47 mmol) were combined in a round bottom flask under an N2 atmosphere. The reaction solution was heated to reflux and refluxed overnight. Analysis showed the reaction had only progressed a moderate amount, so additional reagents were added, 2,2,2-trifluoroethanol (14.0 μL, 0.19 mmol) and sodium hydride (60% dispersion in mineral oil, 6 mg, 0.19 mmol) and contents were heated at reflux for an additional 48 hours. The contents were 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 material was purified 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 afford the title compound. MS (ESI): mass calcd. for C28H19ClF6N4O2, 592.1; m/z found, 593.2 [M+H]+; 1H NMR (600 MHz, CD3OD) δ ppm 8.80 (d, J=2.1 Hz, 1H), 8.28 (d, J=1.9 Hz, 1H), 8.17 (s, 1H), 8.05 (dd, J=8.2, 2.0 Hz, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.86 (dd, J=8.3, 0.4 Hz, 1H), 7.75 (dd, J=8.8, 2.2 Hz, 1H), 7.51-7.42 (m, 3H), 7.37-7.34 (m, 2H), 6.60 (s, 1H), 5.00 (q, J=8.6 Hz, 2H), 3.56 (s, 3H).

Workup

  1. temperatureThe reaction solution was heated
  2. temperatureto reflux
  3. temperaturerefluxed overnight
  4. additionwere added
  5. temperatureat reflux for an additional 48 hours
  6. extractionextracted with saturated, aqueous NH4Cl
  7. customThe organic phase was separated
  8. dry with materialthen dried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe crude material was purified via reverse phase chromatography
  12. customThe fractions from the purification
  13. additioncontaining the desired product
  14. customwere transferred to a separatory funnel with EtOAc
  15. extractionextracted with a saturated, aqueous NaHCO3 solution
  16. customThe aqueous layer was separated
  17. extractionextracted with EtOAc
  18. dry with materialthe combined organic phases were dried over MgSO4
  19. filtrationfiltered
  20. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-e96dc235e7344383a5af98b70e8dbde7
Source dataset
uspto-grants-2016_08
Patent number
US09403816B2

Reaction notes

Loading…