Water → HCID 66729575, compound

HRID 516636Notes

Reaction equation

HRID 516636 reaction equation
Br[C:2]1[C:3]([F:23])=[C:4]([N:8]([CH2:20][O:21][CH3:22])[S:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=[N:31]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[S:9]([N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:34]2[N:30]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)[N:31]=[CH:32][CH:33]=2)[C:3]=1[F:23])[CH2:20][O:21][CH3:22])(=[O:11])=[O:10]

Participants

7

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 115872081-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole2×HCID 66729400HCID 66729400, compound

Product 1

HCID 66729575HCID 66729575, compoundYield 127.8%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

N-(3-Bromo-2-fluoro-phenyl)-2,5-difluoro-N-methoxymethyl-benzenesulfonamide (12 g, 29.25 mmol) was dissolved in 1,4-dioxane (156 mL) and argon was bubbled through the solution for 10 minutes. 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (prepared as described in WO2010/010154) (10.6 g, 38.03 mmol, 1.3 eq) was then added, followed by cesium carbonate (9.5 g, 29.25 mmol, 2 eq), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (Pd(dppf)Cl2.CH2Cl2) (1.2 g, 1.46 mmol, 0.05 eq) and water (0.9 mL) and the reaction mixture was heated to 100° C. and stirred at this temperature for 2 h. A further addition of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4 g, 0.5 eq) was made and heating was continued for 2 h. The mixture was then concentrated under reduced pressure, taken up with AcOEt (200 mL) and filtered over a Celite pad. The filtrate was washed with water and brine, dried over Na2SO4 and evaporated to dryness. The crude was purified by chromatography on silica gel (cyclohexane/AcOEt 7:3) to give 18 g of 2,5-difluoro-N-{2-fluoro-3-[2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenyl}-N-methoxymethyl-benzene-sulfonamide contaminated by N-tetrahydropyranylpyrazole.

Workup

  1. customargon was bubbled through the solution for 10 minutes
  2. temperatureheating
  3. waitwas continued for 2 h
  4. concentrationThe mixture was then concentrated under reduced pressure
  5. filtrationfiltered over a Celite pad
  6. washThe filtrate was washed with water and brine
  7. dry with materialdried over Na2SO4
  8. customevaporated to dryness
  9. customThe crude was purified by chromatography on silica gel (cyclohexane/AcOEt 7:3)

Sources & evidence

ORD record
ord-cdb86e55fb4b41dea1d76dca19a3bab7
Source dataset
uspto-grants-2015_08
Patent number
US09114137B2

Reaction notes

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