Water → 4-(benzyloxy)-6-(1-tert-butyl-1H-pyrazol-4-yl)-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridine

HRID 2209004Notes

Reaction equation

HRID 2209004 reaction equation
[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH:18]([F:20])[F:19])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([N:26]1[CH:30]=[C:29](C2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1)([CH3:25])([CH3:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.CCOC(C)=O.[Cl-].[Na+].O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH:18]([F:20])[F:19])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([C:29]2[CH:28]=[N:27][N:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:30]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

9

Reactant 4

HCID 962WaterHCID 62657Potassium Phosphate, TribasicHCID 1178431521-tert-butyl-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazoleHCID 1178440534-(benzyloxy)-6-chloro-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridine

Product 1

HCID 1178437304-(benzyloxy)-6-(1-tert-butyl-1H-pyrazol-4-yl)-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridine

Reagents, catalysts & solvents 4

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
100 °C

Procedure

4-(benzyloxy)-6-chloro-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridine 2.28 (109 mg, 0.352 mmol), 1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazole (177 mg, 0.708 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (17 mg, 0.024 mmol) and K3PO4 (235 mg, 1.11 mmol) were taken up in dioxane (3 mL) under Ar. Water (0.45 mL) was added and the stirred mixture was heated to 100° C. After 1.25 h, the reaction mixture was cooled to r.t. and was diluted with EtOAc (20 mL) and half-saturated brine (20 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (20 mL). The organic phase was dried over Na2SO4, filtered, and concentrated onto silica gel. Purification by silica gel chromatography (15% to 50% EtOAc in hexanes) provided 4-(benzyloxy)-6-(1-tert-butyl-1H-pyrazol-4-yl)-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridine 2.31.

Workup

  1. temperaturethe reaction mixture was cooled to r.t.
  2. customThe phases were separated
  3. extractionthe aqueous phase was extracted with EtOAc (20 mL)
  4. dry with materialThe organic phase was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated onto silica gel
  7. customPurification by silica gel chromatography (15% to 50% EtOAc in hexanes)

Sources & evidence

ORD record
ord-23f12a24a81645a294a8c1ea0425e76d
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

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