Potassium Phosphate, Tribasic → 6-[5-Fluoro-4-methoxy-2-(2,2,2-trifluoro-ethyl)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carbonitrile

HRID 340083Notes

Reaction equation

HRID 340083 reaction equation
Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]#[N:18])=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][CH:3]=1.[F:19][C:20]1[C:21]([O:40][CH3:41])=[CH:22][C:23]([CH2:35][C:36]([F:39])([F:38])[F:37])=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][C:20]1[C:21]([O:40][CH3:41])=[CH:22][C:23]([CH2:35][C:36]([F:39])([F:38])[F:37])=[C:24]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([C:17]#[N:18])=[N:7][N:8]3[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)=[CH:4][CH:3]=2)[CH:25]=1

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 712377736-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbonitrileHCID 712382822-[5-Fluoro-4-methoxy-2-(2,2,2-trifluoro-ethyl)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

Product 1

HCID 712380616-[5-Fluoro-4-methoxy-2-(2,2,2-trifluoro-ethyl)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carbonitrileYield 31%

Reagents, catalysts & solvents 3

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of 6-bromo-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carbonitrile (Preparation 2, 3.99 g, 13.03 mmol) and 2-[5-fluoro-4-methoxy-2-(2,2,2-trifluoro-ethyl)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Preparation 36, 7.46 g, 15.63 mmol) in dioxane (60 mL) was added a solution of potassium phosphate (18.8 g, 39.09 mmol) in water (12 mL). The mixture was degassed with nitrogen, treated with tetrakis (triphenylphosphine) palladium(0) (3.01 g, 2.6 mmol) and heated at 110° C. for 18 hours. The reaction mixture was concentrated in vacuo and the residue was redissolved in EtOAc (500 mL) and filtered through Arbocel®, washing with EtOAc (2×500 mL). The combined organic phases were washed with water (300 mL), dried over MgSO4 and concentrated in vacuo to give a brown oil. The residue was purified by column chromatography on silica gel, eluting with 25% EtOAc in heptanes, to give the title compound (1.737 g) in a 31% yield.

Workup

  1. customThe mixture was degassed with nitrogen
  2. concentrationThe reaction mixture was concentrated in vacuo
  3. dissolutionthe residue was redissolved in EtOAc (500 mL)
  4. filtrationfiltered through Arbocel®
  5. washwashing with EtOAc (2×500 mL)
  6. washThe combined organic phases were washed with water (300 mL)
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated in vacuo
  9. customto give a brown oil
  10. customThe residue was purified by column chromatography on silica gel
  11. washeluting with 25% EtOAc in heptanes

Sources & evidence

ORD record
ord-e2162dec3ec44e568378b1f742c7f184
Source dataset
uspto-grants-2014_11
Patent number
US08895544B2

Reaction notes

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