Morpholine → 1-(2,4-difluoro-phenyl)-5-(4-fluoro-3-morpholin-4-yl-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole

HRID 2207999Notes

Reaction equation

HRID 2207999 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[N:12]=[C:11]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[N:13]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:3]=2)[CH2:10][C:11]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])=[N:12]1

Participants

7

Reactant 4

HCID 8083MorpholineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 1184317545-(3-bromo-4-fluoro-phenyl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole

Product 1

HCID 1184317201-(2,4-difluoro-phenyl)-5-(4-fluoro-3-morpholin-4-yl-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazoleYield 52.2%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

5-(3-Bromo-4-fluoro-phenyl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (30.0 mg, 0.06 mmol) prepared in Step 5 of Preparation 7, morpholine (7.0 uL, 0.08 mmol), Pd2(dba)3 (3.0 mg, cat.), BINAP (4.0 mg, cat.) and sodium t-butoxide (9.0 mg, 0.10 mmol) were added to toluene (1.0 mL). The reaction mixture was stirred at 100° C. for 7 hours and then filtered through celite pad. Ethyl acetate was added to the filtrate, which was washed with a saturated solution of sodium hydrogen carbonate and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/8) to give 15.0 mg of the titled compound as a yellow liquid.

Workup

  1. filtrationfiltered through celite pad
  2. additionEthyl acetate was added to the filtrate, which
  3. washwas washed with a saturated solution of sodium hydrogen carbonate and brine
  4. dry with materialdried on anhydrous magnesium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customto give a yellow liquid residue
  7. customThe resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/8)

Sources & evidence

ORD record
ord-4f9ba42c4d6a4e779a986109e74c0437
Source dataset
uspto-grants-2016_06
Patent number
US09376420B2

Reaction notes

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