Water → 3-chloro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine

HRID 2279032Notes

Reaction equation

HRID 2279032 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](Cl)[CH:10]=1.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C([O-])([O-])=O.[K+].[K+].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>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:21]2[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=2)[CH:10]=1)[NH2:16]

Participants

7

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 866416833-Chloro-4-(2-chloropyridin-4-yloxy)benzenamine

Product 1

HCID 673982863-chloro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamineYield 104.8%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
90 °C

Procedure

3-Chloro-4-(2-chloropyridin-4-yloxy)benzenamine (0.89 g, 3.49 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole (0.871 g, 4.19 mmol) and K2CO3 (1.302 g, 9.42 mmol) were combined in DME (6 mL)/H2O (7.5 mL) and the headspace was flushed with Ar for 10 min. Pd(Ph3P)4 (0.202 g, 0.174 mmol) was then added and the biphasic reaction was heated at 90° C. overnight. The mixture was cooled to RT and filtered to remove insoluble material. The filtrate was diluted with THF, washed with brine (3×) and the combined aqueous phases were back-extracted with THF (2×). The combined organics were washed with brine (1×), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (MeOH/CHCl3) to afford 3-chloro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (1.10 g, 83%). 1H NMR (400 MHz, DMSO-d6): δ 8.30-8.29 (m, 1 H), 8.22 (s, 1 H), 7.92 (s, 1 H), 7.12 (m, 1 H), 7.00-6.98 (m, 1 H), 6.72 (br s, 1 H), 6.58-6.54 (m, 1 H), 6.47-6.44 (m, 1 H), 5.44 (s, 2 H), 3.84 (s, 3H); MS (ESI) m/z: 301.1 (M+H+): 303.0 (M+2+H+).

Workup

  1. customthe headspace was flushed with Ar for 10 min
  2. customthe biphasic reaction
  3. temperatureThe mixture was cooled to RT
  4. filtrationfiltered
  5. customto remove insoluble material
  6. additionThe filtrate was diluted with THF
  7. washwashed with brine (3×)
  8. extractionthe combined aqueous phases were back-extracted with THF (2×)
  9. washThe combined organics were washed with brine (1×)
  10. dry with materialdried over MgSO4
  11. concentrationconcentrated in vacuo
  12. custompurified by silica gel chromatography (MeOH/CHCl3)

Sources & evidence

ORD record
ord-f1d5532a93294184ac5fd5dee67513a3
Source dataset
uspto-grants-2015_09
Patent number
US09133183B2

Reaction notes

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