Potassium Carbonate → 3-(difluoromethyl)-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4(5H)-one

HRID 2209002Notes

Reaction equation

HRID 2209002 reaction equation
C([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)C1C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].C([O-])([O-])=O.[K+].[K+].B(O)O.C([O-])=O.[NH4+]>C1(C)C=CC=CC=1.O.CCOC(C)=O.CCO.CN(C=O)C.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.[OH-].[OH-].[Pd+2]>[F:20][CH:18]([F:19])[N:15]1[C:14]2[C:9](=[O:8])[NH:10][C:11]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[C:29]([O:30][CH3:31])[CH:28]=3)=[CH:12][C:13]=2[N:17]=[CH:16]1

Participants

13

Reactant 5

HCID 11430Potassium Carbonate2×HCID 61668Boronic AcidHCID 2723923Ammonium formateHCID 27347023,4-Dimethoxyphenylboronic acidHCID 1178440534-(benzyloxy)-6-chloro-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridine

Product 1

HCID 1178438163-(difluoromethyl)-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4(5H)-one

Reagents, catalysts & solvents 7

HCID 9942167Palladium hydroxideCatalystHCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 702EthanolSolventHCID 962WaterSolvent3×HCID 1140TolueneSolvent2×HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

4-(benzyloxy)-6-chloro-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridine 2.28 (113 mg, 0.365 mmol), 3,4-dimethoxyphenylboronic acid (107 mg, 0.588 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (14.5 mg, 0.0205 mmol) and K2CO3 (164 mg, 1.19 mmol) were taken up in toluene (3 mL) and water (0.6 mL) under Ar. The stirred mixture was heated to 90° C. After 3.5 h, additional boronic acid (35 mg, 0.19 mmol), catalyst (4.5 mg, 0.0064 mmol), and K2CO3 (53 mg, 0.38 mmol) were added as a suspension in toluene (1 mL) and water (0.3 mL). After an additional 1 h, the reaction mixture was cooled to r.t. and was diluted with EtOAc (20 mL) and water (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 (20% to 50% acetone in hexanes) provided a residue that was dissolved in EtOH (3 mL) and DMF (2 mL). Ammonium formate (260 mg, 4.1 mmol) and Pd(OH)2 on carbon (20 wt. % Pd, 40 mg) were added and the mixture was heated to 70° C. and stirred for 20 min. The mixture was diluted with DMF (5 mL) and filtered through Celite. The filtrate was concentrated in vacuo and the resulting crude solid was purified by silica gel chromatography (0% to 10% MeOH in DCM) to provide 3-(difluoromethyl)-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4(5H)-one 2.29.

Workup

  1. waitAfter an additional 1 h
  2. temperaturethe reaction mixture was cooled to r.t.
  3. customThe phases were separated
  4. extractionthe aqueous phase was extracted with EtOAc (20 mL)
  5. dry with materialThe organic phase was dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated onto silica gel
  8. customPurification by silica gel chromatography (20% to 50% acetone in hexanes)
  9. customprovided a residue that
  10. temperaturethe mixture was heated to 70° C.
  11. filtrationfiltered through Celite
  12. concentrationThe filtrate was concentrated in vacuo
  13. customthe resulting crude solid was purified by silica gel chromatography (0% to 10% MeOH in DCM)

Sources & evidence

ORD record
ord-448a3a01bc994e6eaf3b25defebcc074
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

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