Bromide ion → [(S)-1-(4-Chloro-3-methyl-phenyl)-2,2,2-trifluoro-ethyl]-(3-[1,3]dioxolan-2-yl-4-methyl-phenyl)-amine

HRID 1629724Notes

Reaction equation

HRID 1629724 reaction equation
Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH2:14])[C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[CH3:15].[Br-].Br[C:18]1[CH:19]=[CH:20][C:21]([CH3:29])=[C:22]([CH:24]2[O:28][CH2:27][CH2:26][O:25]2)[CH:23]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>CCOC(C)=O.C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:14][C:18]2[CH:19]=[CH:20][C:21]([CH3:29])=[C:22]([CH:24]3[O:25][CH2:26][CH2:27][O:28]3)[CH:23]=2)[C:10]([F:12])([F:13])[F:11])=[CH:5][C:4]=1[CH3:15]

Participants

10

Reactant 5

HCID 259Bromide ionHCID 10796Cesium carbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 57517340(S)-1-(4-chloro-3-methyl-phenyl)-2,2,2-trifluoro-ethylamine hydrochlorideHCID 583744502-(5-Bromo-2-methylphenyl)-1,3-dioxolane

Product 1

HCID 68258686[(S)-1-(4-Chloro-3-methyl-phenyl)-2,2,2-trifluoro-ethyl]-(3-[1,3]dioxolan-2-yl-4-methyl-phenyl)-amine

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolventHCID 6386tert-ButanolSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
100 °C

Procedure

(S)-1-(4-Chloro-3-methyl-phenyl)-2,2,2-trifluoro-ethylamine hydrochloride (5.00 g, 19.22 mmol) was taken up in EtOAc and washed with saturated aqueous NaHCO3, water (3×) and brine (2×). The organic layer was dried over MgSO4, filtered and concentrated. To a solution of the residue and bromide INT 31 (6.08 g, 24.99 mmol) in toluene (83 mL) and tert-butanol (33 mL) was added XPhos (1.83 g, 3.84 mmol) followed by Cs2CO3 (18.79 g, 57.67 mmol). The mixture was degassed for 10 minutes and Pd(OAc)2 (0.43 g, 1.92 mmol) was added. The reaction mixture was stirred at 100° C. for 4 hours. The mixture was diluted with EtOAc and washed with H2O (3×). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine (2×), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (heptane/EtOAc) to afford INT 32.

Workup

  1. washwashed with saturated aqueous NaHCO3, water (3×) and brine (2×)
  2. dry with materialThe organic layer was dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe mixture was degassed for 10 minutes
  6. washwashed with H2O (3×)
  7. extractionThe aqueous layer was extracted with EtOAc
  8. washThe combined organic layers were washed with brine (2×)
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe residue was purified by chromatography on silica gel (heptane/EtOAc)
  13. customto afford INT 32

Sources & evidence

ORD record
ord-74a3ba2666124bf99eca54a2ebb33ed4
Source dataset
uspto-grants-2014_07
Patent number
US08791100B2

Reaction notes

Loading…