Potassium Phosphate, Tribasic → 5-chloro-2-fluoro-4-(3-(1-methyl-1H-pyrazol-yl)pyridin-4-yloxy)benzenamine

HRID 1046012Notes

Reaction equation

HRID 1046012 reaction equation
Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([Cl: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.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:15][C:14]1[C:9]([O:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[C:21]2[CH:22]=[CH:23][N:19]([CH3:18])[N:20]=2)=[CH:10][C:11]([F:17])=[C:12]([NH2:16])[CH:13]=1

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 674657024-(3-Bromopyridin-4-yloxy)-5-chloro-2-fluorobenzenamine

Product 1

HCID 680094075-chloro-2-fluoro-4-(3-(1-methyl-1H-pyrazol-yl)pyridin-4-yloxy)benzenamineYield 49.1%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 2631-ButanolSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 4-(3-bromopyridin-4-yloxy)-5-chloro-2-fluorobenzenamine, (0.300 g, 0.945 mmol) in n-butanol (5 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.236 g, 1.134 mmol), S-Phos (0.078 g, 0.189 mmol), Pd2(dba)3 (0.087 g, 0.094 mmol) and potassium phosphate (0.602 g, 2.83 mmol). The resulting mixture was degassed and heated in a sealed tube at 100° C. for 20 h. The solvent from the reaction mixture was completely evaporated. The residue was stirred in a mixture of CH2Cl2-MeOH (1:1), filtered, rinsed, dried and subjected to chromatography (50-100% EtOAc-hexanes) to provide 5-chloro-2-fluoro-4-(3-(1-methyl-1H-pyrazol-yl)pyridin-4-yloxy)benzenamine, (0.148 g, 49.1% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.20 (m, 2H), 8.01 (s, 1H), 7.24 (d, J=8.5 Hz, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.51 (d, J=5.6 Hz, 1H), 5.51 (s, 2H), 3.88 (s, 3H); MS (ESI) m/z: 319.1 (M+H+).

Workup

  1. customThe resulting mixture was degassed
  2. customThe solvent from the reaction mixture was completely evaporated
  3. filtrationfiltered
  4. washrinsed
  5. customdried

Sources & evidence

ORD record
ord-d7c839514b6345349fbbba56cae74a12
Source dataset
uspto-grants-2013_10
Patent number
US08569319B2

Reaction notes

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