Tetrahydrofuran → 2-Chloro-6-fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile

HRID 1409310Notes

Reaction equation

HRID 1409310 reaction equation
[Cl:1][C:2]1[CH:9]=[C:8](I)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].C1COCC1.[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[N:23]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[N:24]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:9]=[C:8]([C:27]2[N:23]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[N:24]=[CH:25][CH:26]=2)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 10340Sodium CarbonateHCID 115872081-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 671681832-Chloro-6-fluoro-4-iodobenzonitrile

Product 1

HCID 671718412-Chloro-6-fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrileYield 102.5%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
60 °C

Procedure

2-Chloro-6-fluoro-4-iodobenzonitrile (291 mmol, 82 g), THF (800 ml) and 1-(tetra-hydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (350 mmol, 97 g) were added into a flask and stirred. Bis(triphenylphosphine)palladium(II) chloride (14.57 mmol, 10.22 g), sodium carbonate (699 mmol, 74.1 g) and water (350 ml) were added. The resulting mixture was heated to 60° C. and stirred for 2 h. The solvents were evaporated. Water was added and the mixture was left to stir overnight. EtOAc and water were added and the insoluble precipitates were removed by filtration. The organic phase was separated from the filtrate and the water phase was extracted with more EtOAc. The combined organics were evaporated and the residue was combined with previously filtrated solid. The collected solids were suspended in EtOH and water. The mixture was heated to boiling point, allowed to cool to RT and stirred for an hour at ambient temperature. The mixture was cooled to 0° C. and stirred for another hour. The precipitate was washed with a small amount of cold 1:1 water/EtOH. The filtered solids were dried under vacuum. 91.2 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.50-1.70 (m, 3H), 1.79-1.89 (m, 1H), 1.92-2.03 (m, 1H), 2.30-2.44 (m, 1H), 3.56-3.67 (m, 1H), 3.93-4.02 (m, 1H), 5.36 (dd, 1H), 6.78 (d, 1H), 7.66 (d, 1H), 7.73 (dd, 1H), 7.80-7.83 (m, 1H).

Workup

  1. stirringstirred for 2 h
  2. customThe solvents were evaporated
  3. additionWater was added
  4. waitthe mixture was left
  5. stirringto stir overnight
  6. additionEtOAc and water were added
  7. customthe insoluble precipitates
  8. customwere removed by filtration
  9. customThe organic phase was separated from the filtrate
  10. extractionthe water phase was extracted with more EtOAc
  11. customThe combined organics were evaporated
  12. temperatureThe mixture was heated
  13. temperatureto cool to RT
  14. stirringstirred for an hour at ambient temperature
  15. temperatureThe mixture was cooled to 0° C.
  16. stirringstirred for another hour
  17. washThe precipitate was washed with a small amount of cold 1:1 water/EtOH
  18. customThe filtered solids were dried under vacuum

Sources & evidence

ORD record
ord-1738f6db354147cc857724acae09ccdd
Source dataset
uspto-grants-2014_12
Patent number
US08921378B2

Reaction notes

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