Potassium Phosphate, Tribasic → 6-[2-Ethyl-5-fluoro-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carbonitrile

HRID 2038710Notes

Reaction equation

HRID 2038710 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.[CH2:19]([C:21]1[CH:26]=[C:25]([O:27][CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([F:36])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1)[CH3:20].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>[CH2:19]([C:21]1[CH:26]=[C:25]([O:27][CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[C:24]([F:36])=[CH:23][C:22]=1[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)[CH3:20]

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 712377736-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbonitrileHCID 86676270(2-((5-Ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane

Product 1

HCID 866762696-[2-Ethyl-5-fluoro-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carbonitrileYield 81.1%

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, 28.5 g, 93 mmol) and 2-[2-ethyl-5-fluoro-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Preparation 5, 73.8 g, 112 mmol) in dioxane (500 mL) was added a solution of potassium phosphate (59.2 g, 279 mmol) in water (120 mL). The mixture was degassed with nitrogen and then tetrakis(triphenylphosphine) palladium(0) (10.8 g, 9.3 mmol) was added. The reaction mixture was heated at 110° C. for 18 hours. The reaction mixture was concentrated in vacuo and the residue was redissolved in EtOAc (1 L) and filtered through Arbocel®, washing with EtOAc (2×500 mL). The combined organic phases were concentrated in vacuo to give a brown oil. The residue was purified by column chromatography on silica gel eluting with 10% EtOAc in heptane to give the title compound as a viscous oil (37.4 g) in an 81% yield.

Workup

  1. customThe mixture was degassed with nitrogen
  2. concentrationThe reaction mixture was concentrated in vacuo
  3. dissolutionthe residue was redissolved in EtOAc (1 L)
  4. filtrationfiltered through Arbocel®
  5. washwashing with EtOAc (2×500 mL)
  6. concentrationThe combined organic phases were concentrated in vacuo
  7. customto give a brown oil
  8. customThe residue was purified by column chromatography on silica gel eluting with 10% EtOAc in heptane

Sources & evidence

ORD record
ord-fde7f13ebfd948479d277ff4342a3418
Source dataset
uspto-grants-2013_11
Patent number
US08575336B2

Reaction notes

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