3,5-Bis(trifluoromethyl)benzylamine → Tert-butyl 4-[2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-yloxy]-butyrate

HRID 604165Notes

Reaction equation

HRID 604165 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:65][C:66]([F:80])([F:79])[C:67]1[CH:68]=[C:69]([CH:72]=[C:73]([C:75]([F:78])([F:77])[F:76])[CH:74]=1)[CH2:70][NH2:71].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C>[F:65][C:66]([F:79])([F:80])[C:67]1[CH:68]=[C:69]([CH:72]=[C:73]([C:75]([F:78])([F:76])[F:77])[CH:74]=1)[CH2:70][NH:71][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][N:3]=1

Participants

9

Reactant 4

HCID 5210993,5-Bis(trifluoromethyl)benzylamineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 57556051Tert-butyl 4-(2-chloro-pyrimidin-5-yloxy)-butyrate

Product 1

HCID 86626523Tert-butyl 4-[2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-yloxy]-butyrateYield 63.6%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

Tert-butyl 4-(2-chloropyrimidin-5-yloxy)-butyrate (5.0 g) is dissolved in toluene (100 ml) and thereto are added palladium acetate (412 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.26 g), and the mixture is stirred under nitrogen atmosphere at 50° C. for 1 hour. The reaction solution is cooled to room temperature, and thereto are added 3,5-bis-trifluoromethyl-benzylamine (5.35 g) and sodium tert-butoxide (3.88 g) and the mixture is stirred at 35° C. for 2 hours. Thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) and NH-silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to give tert-butyl 4-[2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-yloxy]-butyrate (5.59 g). MS (m/z): 480 [M+H]+

Workup

  1. temperatureThe reaction solution is cooled to room temperature
  2. stirringthe mixture is stirred at 35° C. for 2 hours
  3. customthe mixture is separated
  4. washthe organic layer is washed with a saturated brine
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) and NH-silica gel column chromatography (hexane:ethyl acetate=4:1→2:1)

Sources & evidence

ORD record
ord-e61f63c0e5bc45de9dfaee8a73f6c869
Source dataset
uspto-grants-2011_03
Patent number
US07906517B2

Reaction notes

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