Benzene, 1-bromo-4-(trifluoromethyl)- → 4-Methyl-2-{4'-trifluoromethyl-5-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-biphenyl-3-yl}-pentanoic acid ethyl ester

HRID 889754Notes

Reaction equation

HRID 889754 reaction equation
[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.Br[C:63]1[CH:68]=[CH:67][C:66]([C:69]([F:72])([F:71])[F:70])=[CH:65][CH:64]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:17][CH2:18][N:19]([C:63]3[CH:68]=[CH:67][C:66]([C:69]([F:72])([F:71])[F:70])=[CH:65][CH:64]=3)[CH2:20][CH2:21]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]

Participants

7

Reactant 4

HCID 67872Benzene, 1-bromo-4-(trifluoromethyl)-HCID 2734941(1,1'-Binaphthalen)-2-yldi-tert-butylphosphineHCID 23676156Sodium t-butoxideHCID 576660434-Methyl-2-(5-piperidin-4-yl-4'-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester

Product 1

HCID 576659164-Methyl-2-{4'-trifluoromethyl-5-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-biphenyl-3-yl}-pentanoic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

To a solution of a mixture of 4-methyl-2-(5-piperidin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester and methyl ester (68b) (75 mg, 0.17 mmol) in toluene (1.0 mL) was added Pd2(dba)3 (1.6 mg, 0.0017 mmol), racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (0.7 mg, 0.0017 mmol), 1-bromo-4-trifluoromethyl-benzene (38 mg, 0.17 mmol) and sodium tert-butoxide (22 mg, 0.23 mmol). The mixture was heated, in a sealed-tube, to reflux for 3.5 h. The reaction was quenched with H2O at room temperature and extracted with EtOAc (3×10 mL). The organic was washed with brine (2×10 mL), dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 4-methyl-2-{4′-trifluoromethyl-5-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-biphenyl-3-yl}-pentanoic acid ethyl ester and methyl ester. Calcd for C32H33F6NO2 (M+H) 578.60, Found 578.4 (methyl ester) and Calcd for C33H35F6NO2 (M+H) 592.63, Found 592.31 (ethyl ester).

Workup

  1. temperatureThe mixture was heated, in a sealed-tube
  2. temperatureto reflux for 3.5 h
  3. customThe reaction was quenched with H2O at room temperature
  4. extractionextracted with EtOAc (3×10 mL)
  5. washThe organic was washed with brine (2×10 mL)
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated in vacuo
  8. customThe crude mixture was purified by ISCO column chromatography

Sources & evidence

ORD record
ord-4b8448efccb9473fbb8a537037982084
Source dataset
uspto-grants-2012_08
Patent number
US08252935B2

Reaction notes

Loading…