Potassium Carbonate → N-(4-(3-(1-(cyanomethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-1-(4-Fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

HRID 1046027Notes

Reaction equation

HRID 1046027 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]([NH:16][C:17]([C:19]2[C:20](=[O:32])[N:21]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=[CH:23][CH:24]=2)=[O:18])=[C:11]([F:33])[CH:10]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[N:44][N:45]([CH2:47][C:48]#[N:49])[CH:46]=2)O1.C(=O)([O-])[O-].[K+].[K+].C([O-])(O)=O.[Na+]>O1CCOCC1.O.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>[C:48]([CH2:47][N:45]1[CH:46]=[C:42]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[C:11]([F:33])[CH:10]=2)[CH:43]=[N:44]1)#[N:49]

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 516892Sodium BicarbonateHCID 674680952-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrileHCID 68009215N-(4-(3-Bromopyridin-4-yloxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Product 1

HCID 54596485N-(4-(3-(1-(cyanomethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-1-(4-Fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamideYield 24%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
85 °C

Procedure

N-(4-(3-Bromopyridin-4-yloxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.119 g, 0.231 mmol) was combined with 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrile (0.054 g, 0.231 mmol) and potassium carbonate (0.096 g, 0.692 mmol) in dioxane (4 mL) and water (0.667 mL), sparged with argon for several minutes, treated with tetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.012 mmol) and heated to 85° C. overnight. The mixture was cooled to room temperature, treated with saturated NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with brine, dried over MgSO4 and concentrated to dryness. The crude material was purified over silica gel (40-100% EtOAc/Hex) to afford N-(4-(3-(1-(cyanomethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-1-(4-Fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (30 mg, 24% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H); 8.91 (s, 1H); 8.61 (dd, J=7.4, 2.1 Hz, 1H); 8.55 (m, 1H); 8.44 (s, 1H); 8.29 (d, J=5.7 Hz, 1H); 8.24 (s, 1H); 8.16 (dd, J=6.6, 2.2 Hz, 1H); 7.67 (dd, J=11.0, 7.3 Hz, 1H); 7.60 (dd, J=8.7, 4.9 Hz, 2H); 7.42 (t, J=8.7 Hz, 2H); 6.75 (m, 2H); 5.54 (s, 2H); MS (ESI) m/z: 543.1 (M+H+).

Workup

  1. customsparged with argon for several minutes
  2. temperatureThe mixture was cooled to room temperature
  3. extractionextracted with EtOAc (2×)
  4. washThe combined organics were washed with brine
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated to dryness
  7. customThe crude material was purified over silica gel (40-100% EtOAc/Hex)

Sources & evidence

ORD record
ord-4ba2631ab75a45cc97013670e4928e29
Source dataset
uspto-grants-2013_10
Patent number
US08569319B2

Reaction notes

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