Water → HCID 178464361, compound

HRID 1442522Notes

Reaction equation

HRID 1442522 reaction equation
[CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[N:24]([CH2:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:30][CH2:29]2)[CH2:25][CH3:26])=[N:10][CH:11]=1.[H-].[Na+].Br[CH:43]([C:45]1[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[C:47]([C:55]([F:58])([F:57])[F:56])[CH:46]=1)[CH3:44].O>O1CCCC1.CN(C)C=O>[F:52][C:51]([F:53])([F:54])[C:49]1[CH:50]=[C:45]([CH:43]([N:12]([CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:22])([F:21])[F:23])[CH:17]=[CH:16][C:15]=2[N:24]([CH2:27][C@H:28]2[CH2:29][CH2:30][C@H:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32][CH2:33]2)[CH2:25][CH3:26])[C:9]2[N:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][S:2][CH3:1])=[CH:11][N:10]=2)[CH3:44])[CH:46]=[C:47]([C:55]([F:56])([F:57])[F:58])[CH:48]=1.[F:56][C:55]([F:58])([F:57])[C:47]1[CH:46]=[C:45]([CH:43]([N:12]([CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:15]=2[N:24]([CH2:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:30][CH2:29]2)[CH2:25][CH3:26])[C:9]2[N:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][S:2][CH3:1])=[CH:11][N:10]=2)[CH3:44])[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=1

Participants

8

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 129473971-(1-Bromoethyl)-3,5-bis(trifluoromethyl)benzeneHCID 178471776HCID 178471776, compound

Product 2

HCID 178464361HCID 178464361, compoundYield 23%HCID 178471777HCID 178471777, compoundYield 12%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of ethyl trans-{4-[({2-[({5-[2-(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetate (10.2 mg, 0.018 mmol) in tetrahydrofuran (0.3 mL) under ice cooling was added sodium hydride (50% in oil, 3.4 mg, 0.072 mmol), and the mixture was stirred at room temperature for 30 minutes. After cooling to −78° C., to the reaction mixture was added a solution of 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (6.9 mg, 0.021 mmol) in N,N-dimethylformamide (0.3 mL), and the mixture was stirred for 14 hours with warming to room temperature. The reaction mixture was added with water, and extracted with ethyl acetate, and the organic layer was washed twice with water. 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→chloroform:methanol=20:1) to obtain ethyl trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetate (compound of Example 43, 1.8 mg, 12%) as a pale yellow oil, and trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid (compound of Example 44, 3.2 mg, 23%) as a pale yellow oil.

Workup

  1. temperatureAfter cooling to −78° C., to the reaction mixture
  2. stirringthe mixture was stirred for 14 hours
  3. temperaturewith warming to room temperature
  4. extractionextracted with ethyl acetate
  5. washthe organic layer was washed twice with water
  6. washThe organic layer was washed with saturated brine
  7. dry with materialdried over anhydrous sodium sulfate
  8. concentrationconcentrated under reduced pressure
  9. customthe resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1→chloroform:methanol=20:1)

Sources & evidence

ORD record
ord-890fcdd20e6740bfa8dd554dd84b74e3
Source dataset
uspto-grants-2010_02
Patent number
US07659271B2

Reaction notes

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