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Potassium Carbonate → 2,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine

HRID 1046002
Notes
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Reaction equation

HRID 1046002 reaction equation
Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH2:16])=[C:11]([F:17])[CH:10]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[F:17][C:11]1[CH:10]=[C:9]([O:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH2:16]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 673992554-(3-Bromopyridin-4-yloxy)-2,5-difluorobenzenamine

Product 1

HCID 673981442,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamineYield 65%

Reagents, catalysts & solvents 2

HCID 962
Water
Solvent
HCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

In a sealed tube, 4-(3-bromopyridin-4-yloxy)-2,5-difluorobenzenamine (0.42 g, 1.395 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.363 g, 1.744 mmol), potassium carbonate (0.578 g, 4.18 mmol), and tetrakistriphenylphosphine palladium (0) (0.081 g, 0.070 mmol) were suspended in dioxane (8 mL) and water (1.333 mL). The mixture was degassed with Ar and heated at 90° C. overnight. The reaction mixture was cooled and partitioned between EtOAc and saturated aqueous NaHCO3. The mixture was extracted with EtOAc (3×). The combined organic extracts were dried, evaporated and purified by silica gel chromatography (hexanes/EtOAc) to yield 2,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine (272 mg, 65% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.80 (s, 1H) 8.22-8.20 (m, 2H), 8.00 (s, 1H), 7.24-7.19 (tri, 1H), 6.76-6.71 (m, 1H), 6.62 (d, 1H), 5.50 (br s, 2H), 3.78 (s, 3H); MS (ESI) m/z: 301.0 (M+H+).

Workup

  1. customThe mixture was degassed with Ar
  2. temperatureThe reaction mixture was cooled
  3. custompartitioned between EtOAc and saturated aqueous NaHCO3
  4. extractionThe mixture was extracted with EtOAc (3×)
  5. customThe combined organic extracts were dried
  6. customevaporated
  7. custompurified by silica gel chromatography (hexanes/EtOAc)

Sources & evidence

ORD record
ord-ffb70b69f02c4a6d95dfb3548881e5ff
Source dataset
uspto-grants-2013_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08569319B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes