Water → 2,3-difluoro-4-[2-(1-methyl-1H-pyrazol-4-yl)-pyridin-4-yloxy]-phenylamine

HRID 450417Notes

Reaction equation

HRID 450417 reaction equation
Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:16])[C:10]=2[F:17])[CH:5]=[CH:4][N:3]=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.[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:11]1[C:10]([F:17])=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[CH:7]=2)[CH:14]=[CH:13][C:12]=1[NH2:15]

Participants

7

Reactant 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 866238534-(2-Chloro-pyridin-4-yloxy)-2,3-difluorophenylamine

Product 1

HCID 668104662,3-difluoro-4-[2-(1-methyl-1H-pyrazol-4-yl)-pyridin-4-yloxy]-phenylamineYield 55.1%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
70 °C

Procedure

Nitrogen was bubbled though a solution of 4-(2-chloro-pyridin-4-yloxy)-2,3-difluoro-phenylamine (2 g, 7.8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.6 g, 7.8 mmol) and Na2CO3 (1.65 g, 15.6 mmol) in DME (12 mL)/H2O (4 mL) for 20 min. Pd(PPh3)4 (450 mg, 0.4 mmol), was added and then resulting mixture was degassed in vacuo, blanketed with nitrogen and heated to 70° C. for 16 h. The reaction was concentrated to dryness under reduced pressure. The crude product was suspended in water and extracted with EtOAc (3×10 mL). The organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography to give 2,3-difluoro-4-[2-(1-methyl-1H-pyrazol-4-yl)-pyridin-4-yloxy]-phenylamine (1.3 g, 55% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.40 (d, J=6.0 Hz, 1H), 8.32 (s, 1H), 8.02 (s, 1H), 7.26 (s, 1H), 6.96 (t, J=8.8 Hz, 1H), 6.71-6.68 (m, 2H), 5.62 (s, 2H), 3.92 (s, 3H); MS (ESI) m/z: 303.2 [M+14]+.

Workup

  1. customresulting mixture
  2. customwas degassed in vacuo
  3. concentrationThe reaction was concentrated to dryness under reduced pressure
  4. extractionextracted with EtOAc (3×10 mL)
  5. washThe organic layer was washed with brine
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated in vacuo
  8. custompurified by silica gel chromatography

Sources & evidence

ORD record
ord-936caf719e204b26860f0a3c63657eed
Source dataset
uspto-grants-2013_07
Patent number
US08486951B2

Reaction notes

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