Hydrochloric Acid → racemic 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)-1,1,1-trifluoro-2-methylpropan-2-ol

HRID 595310Notes

Reaction equation

HRID 595310 reaction equation
[F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[F:9][CH:10]([F:34])[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[CH:19]=[C:20]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][C:31](=[O:33])[CH3:32])[CH:29]=3)[CH:21]=[C:22]([CH3:24])[CH:23]=2)[N:12]=1.[F-].[Cs+].Cl>C1COCC1.CS(C)=O.O>[F:34][CH:10]([F:9])[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[CH:19]=[C:20]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][C:31]([CH3:32])([OH:33])[C:2]([F:4])([F:3])[F:1])[CH:29]=3)[CH:21]=[C:22]([CH3:24])[CH:23]=2)[N:12]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 25953Cesium fluoride2×HCID 552549(Trifluoromethyl)trimethylsilane2×HCID 1182087981-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)propan-2-one

Product 1

HCID 118208528racemic 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)-1,1,1-trifluoro-2-methylpropan-2-ol

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 23503278(Methanesulfinyl)methane--water (1/1)Solvent

Procedure

(Trifluoromethyl)trimethylsilane (0.103 ml, 0.70 mmol) was added to a 20° C. solution of 1-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)propan-2-one (100 mg, 0.28 mmol) and cesium fluoride (4.3 mg, 0.028 mmol) in THF (1 mL). The reaction was allowed to stir for 60 minutes at room temperature and additional cesium fluoride (4.25 mg, 0.03 mmol) and (trifluoromethyl)trimethylsilane (0.103 ml, 0.70 mmol) were then added. The reaction was stirred for 18 hours and filtered through a plug of glass wool. The filtrate was treated with hydrochloric acid (6N, 1 mL, 6 mmol) and stirred for 30 minutes. The reaction was concentrated under reduced pressure to afford the crude product residue. The crude product residue was dissolved in DMSO/water and purified by mass triggered reverse phase HPLC (ACN/water+0.1% TFA) to afford racemic 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)-1,1,1-trifluoro-2-methylpropan-2-ol. MS ESI calcd. for C19H19F5N5O [M+H]+ 428. found 428. The racemic mixture was purified by chiral SFC (Chiralpak, IA, 21×250 (mm), 70 mL/min, 25% Methanol/CO2) to afford (S or R)-3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)-1,1,1-trifluoro-2-methylpropan-2-ol

Workup

  1. stirringThe reaction was stirred for 18 hours
  2. filtrationfiltered through a plug of glass wool
  3. stirringstirred for 30 minutes
  4. concentrationThe reaction was concentrated under reduced pressure
  5. customto afford the crude product residue
  6. custompurified by mass triggered reverse phase HPLC (ACN/water+0.1% TFA)

Sources & evidence

ORD record
ord-c4ae4961c74e438f8928be6802e13afd
Source dataset
uspto-grants-2016_01
Patent number
US09242984B2

Reaction notes

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