tert-Butyl piperazine-1-carboxylate → 5-(2-chloro-phenyl)-1-[4-(4-BOC-piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole

HRID 2208101Notes

Reaction equation

HRID 2208101 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH2:11][C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])=[N:9]2)=[CH:4][CH:3]=1.[C:30]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].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>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([N:40]3[CH2:39][CH2:38][N:37]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:42][CH2:41]3)=[CH:7][CH:6]=2)[N:9]=[C:10]([C:20]([C:26]([F:27])([F:29])[F:28])([C:22]([F:25])([F:24])[F:23])[OH:21])[CH2:11]1

Participants

7

Reactant 4

HCID 143452tert-Butyl piperazine-1-carboxylateHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 1184316661-(4-Bromo-phenyl)-5-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole

Product 1

HCID 1184319155-(2-chloro-phenyl)-1-[4-(4-BOC-piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazoleYield 46.1%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

1-(4-Bromo-phenyl)-5-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (500.0 mg, 1.00 mmol) prepared in Step 5 of Preparation 24, 1-BOC-piperazine (241.0 mg, 1.30 mmol), Pd2(dba)3 (45.0 mg, 0.05 mmol), BINAP (62.0 mg, 0.10 mmol) and sodium t-butoxide (144.0 mg, 1.50 mmol) were added to toluene (10.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with 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=1/2) to give 280.0 mg of the titled compound as a yellow liquid.

Workup

  1. filtrationfiltered through celite pad
  2. additionA saturated solution of ammonium chloride was added to the filtrate, which
  3. extractionwas then extracted with ethyl acetate three times
  4. extractionThe combined extract
  5. washwas washed with brine
  6. dry with materialdried on anhydrous magnesium sulfate
  7. concentrationconcentrated under reduced pressure
  8. customto give a yellow liquid residue
  9. customThe resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2)

Sources & evidence

ORD record
ord-da7b847a4cfb4a33999618eb948fbec7
Source dataset
uspto-grants-2016_06
Patent number
US09376420B2

Reaction notes

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