Potassium Fluoride → 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

HRID 1253460Notes

Reaction equation

HRID 1253460 reaction equation
Br[C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1.[CH3:15][N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[N:17]1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[K+]>CN(C=O)C.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]>[CH3:14][O:13][C:4]1[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=[C:2]([C:19]2[CH:18]=[N:17][N:16]([CH3:15])[CH:20]=2)[CH:3]=1

Participants

7

Reactant 4

HCID 522689Potassium FluorideHCID 2734635Tri-tert-butylphosphine tetrafluoroborateHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 584048986-Bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile

Product 1

HCID 672075884-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (50.0 mg, 0.198 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (61.9 mg, 0.298 mmol), tri-t-butylphosphonium tetrafluoroborate (5.8 mg, 0.02 mmol), tris(dibenzylideneacetone)dipalladium (0) (9.1 mg, 9.9 μmol), and potassium fluoride (38.0 mg, 0.655 mmol) were suspended in DMF (2 ml) and sparged with argon for 10 minutes. The mixture was heated to 100° C. for 2 h. The reaction mixture was cooled to ambient temperature, diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05%. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to give an off-white solid. The residue was further purified by column chromatography on silica gel (methanol/dichloromethane gradient) to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.86 (s, 1H); 8.53 (s, 1H); 8.36 (s, 1H); 8.08 (s, 1H); 7.26 (s, 1H); 4.05 (s, 3H); 3.87 (s, 3H). LRMS (ESI) calculated for C13H12N5O [M+H]+, 254.1; found 254.1.

Workup

  1. customsparged with argon for 10 minutes
  2. temperatureThe reaction mixture was cooled to ambient temperature
  3. additiondiluted in ethyl acetate
  4. washwashed with saturated aqueous sodium hydrogen carbonate and brine
  5. dry with materialthen dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by preparative HPLC Reverse phase (C-18)
  9. washeluting with Acetonitrile/Water+0.05%
  10. additionThe fractions containing product
  11. additiondiluted in ethyl acetate
  12. washwashed with aqueous sodium bicarbonate
  13. dry with materialdried over sodium sulfate
  14. filtrationThe solution was filtered
  15. concentrationconcentrated under reduced pressure
  16. customto give an off-white solid
  17. customThe residue was further purified by column chromatography on silica gel (methanol/dichloromethane gradient)

Sources & evidence

ORD record
ord-8ec4c51387164d07971ece2734496953
Source dataset
uspto-grants-2013_06
Patent number
US08455477B2

Reaction notes

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