Toluene → HCID 118006184, compound

HRID 926600Notes

Reaction equation

HRID 926600 reaction equation
[N:1]1([C:6]2[CH:39]=[CH:38][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:40][O:41][CH2:42][CH2:43][OH:44].C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[Cl:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:22]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)[OH:23])[CH:18]=2)[N:13]=[C:12]([O:44][CH2:43][CH2:42][O:41][CH3:40])[C:11]=1[CH2:10][C:9]1[CH:38]=[CH:39][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1

Participants

6

Reactant 4

HCID 1140TolueneHCID 80192-MethoxyethanolHCID 24758Sodium hydrideHCID 74221327HCID 74221327, compound2×

Product 1

HCID 118006184HCID 118006184, compound

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

(3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloroquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol (100 mg, 0.174 mmol, Intermediate 64), 2-methoxyethanol (13.7 μL, 0.174 mmol), toluene (2 mL) and sodium hydride (60% dispersion in mineral oil, 17.4 mg, 0.435 mmol) were combined in a round bottom flask under an N2 atmosphere. The contents were heated to reflux and refluxed overnight. The reaction solution turned from a heterogeneous white mixture to slightly yellowish with a moderate amount of precipitate. The contents were cooled to 0° C. in an ice water bath then transferred to a separatory funnel with EtOAc dilution and extracted with saturated, aqueous NH4Cl and 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/(10% of a 2 M NH3 MeOH in DCM)) then further purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C33H29Cl2N5O3, 613.2. m/z found, 614.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ ppm 8.14 (d, J=2.5 Hz, 1H), 8.11 (d, J=2.1 Hz, 1H), 7.88 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.64 (dd, J=8.8, 2.1 Hz, 1H), 7.60 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.41-7.32 (m, 4H), 6.50-6.46 (m, 1H), 6.36 (s, 1H), 4.66-4.59 (m, 2H), 4.35 (s, 2H), 3.81-3.74 (m, 2H), 3.49 (s, 3H), 3.40 (s, 3H).

Workup

  1. temperatureThe contents were heated
  2. temperatureto reflux
  3. temperaturerefluxed overnight
  4. extractionextracted with saturated, aqueous NH4Cl
  5. customThe organic phase was separated
  6. dry with materialthen dried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe crude product was purified by flash column chromatography (silica gel, 0-10% DCM/(10% of a 2 M NH3 MeOH in DCM))
  10. customthen further purified via reverse phase chromatography

Sources & evidence

ORD record
ord-5814dbdd28a740ff82d93e519330d5d8
Source dataset
uspto-grants-2016_03
Patent number
US09284308B2

Reaction notes

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