Water → N-{1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-N-({2-[(cyclopentylmethyl)(ethyl)amino]-5-(trifluoromethyl)phenyl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine

HRID 1442515Notes

Reaction equation

HRID 1442515 reaction equation
[CH:1]1([CH2:6][N:7]([CH2:31][CH3:32])[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18][NH:19][C:20]2[N:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][S:29][CH3:30])=[CH:22][N:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:36]([C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:39]=1)[CH3:37].O>O1CCCC1.CN(C)C=O>[F:45][C:44]([F:46])([F:47])[C:42]1[CH:43]=[C:38]([CH:36]([N:19]([CH2:18][C:9]2[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=2[N:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:31][CH3:32])[C:20]2[N:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][S:29][CH3:30])=[CH:22][N:21]=2)[CH3:37])[CH:39]=[C:40]([C:48]([F:49])([F:50])[F:51])[CH:41]=1

Participants

7

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 129473971-(1-Bromoethyl)-3,5-bis(trifluoromethyl)benzeneHCID 68491507N-({2-[(cyclopentylmethyl)(ethyl)amino]-5-(trifluoromethyl)phenyl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine

Product 1

HCID 25056258N-{1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-N-({2-[(cyclopentylmethyl)(ethyl)amino]-5-(trifluoromethyl)phenyl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amineYield 91%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

To a stirred solution of N-({2-[(cyclopentylmethyl)(ethyl)amino]-5-(trifluoromethyl)phenyl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (4.39 g, 9.37 mmol) in tetrahydrofuran (40 mL) under ice cooling was added sodium hydride (50% in oil, 1.80 g, 37.5 mmol), and the mixture was stirred at 50° C. for 1 hour. After cooling to −78° C., to the reaction mixture was added a solution of 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (6.02 g, 18.7 mmol) obtained in Step 2 in N,N-dimethylformamide (40 mL), and the mixture was stirred for 2.5 hours with warming to room temperature. The reaction mixture was added with water and extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain the target compound, N-{1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-N-({2-[(cyclopentylmethyl)(ethyl)amino]-5-(trifluoromethyl)phenyl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (6.03 g, 91%), as a pale yellow oil.

Workup

  1. temperatureAfter cooling to −78° C., to the reaction mixture
  2. stirringthe mixture was stirred for 2.5 hours
  3. temperaturewith warming to room temperature
  4. extractionextracted with ethyl acetate
  5. washthe organic layer was washed with saturated brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationconcentrated under reduced pressure
  8. customthe resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1)

Sources & evidence

ORD record
ord-79c9ad82fa9241e3b971fe50ee91cca0
Source dataset
uspto-grants-2010_02
Patent number
US07659271B2

Reaction notes

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