Sodium hydride → racemic 2-hydroxy-2-methyl-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoic acid

HRID 595282Notes

Reaction equation

HRID 595282 reaction equation
[H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[CH:9]=1.[CH3:26][C:27]1([C:30]([O:32]C)=[O:31])[O:29][CH2:28]1>CN(C=O)C.CCOC(C)=O>[OH:29][C:27]([CH3:28])([CH2:26][N:12]1[CH:11]=[C:10]([C:8]2[CH:7]=[C:6]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][N:17]=3)[CH:5]=[C:4]([CH3:3])[CH:9]=2)[CH:14]=[N:13]1)[C:30]([OH:32])=[O:31]

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 3525005Methyl 2-methylglycidateHCID 118208677N-(3-methyl-5-(1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine

Product 1

HCID 118208615racemic 2-hydroxy-2-methyl-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoic acid

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

Sodium hydride (23.5 mg, 0.59 mmol) at 0° C. was added to an oven-dried vial containing N-[3-methyl-5-(1H-pyrazol-4-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (75 mg, 0.24 mmol) in DMF (0.8 mL). The mixture was stirred for 10 minutes, and then methyl 2-methylglycidate (0.03 mL, 0.24 mmol) was added. The reaction was warmed to room temperature and stirred overnight, followed by subsequent heating to 70° C. overnight. The mixture was cooled to room temperature, diluted with EtOAc, washed with water (3×), then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (45 to 85% ACN/water with 0.1% TFA modifier) to afford racemic 2-hydroxy-2-methyl-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoic acid. MS ESI calcd. for C19H18F3N5O3 [M+H]+ 422. found 422.

Workup

  1. stirringstirred overnight
  2. temperatureby subsequent heating to 70° C. overnight
  3. temperatureThe mixture was cooled to room temperature
  4. washwashed with water (3×)
  5. dry with materialbrine, dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by reverse phase HPLC (45 to 85% ACN/water with 0.1% TFA modifier)

Sources & evidence

ORD record
ord-890fe01c30c4427e86acca0470f6eed2
Source dataset
uspto-grants-2016_01
Patent number
US09242984B2

Reaction notes

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