Sodium hydride → (4S,5S)-4-methyl-5-((4-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)methyl)oxazolidin-2-one

HRID 595308Notes

Reaction equation

HRID 595308 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.ClCC(O)[C@@H:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])(C)C)[CH3:30]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:30][C@H:29]1[C@H:34]([CH2:37][N:12]2[CH:11]=[C:10]([C:8]3[CH:7]=[C:6]([NH:15][C:16]4[N:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][N:17]=4)[CH:5]=[C:4]([CH3:3])[CH:9]=3)[CH:14]=[N:13]2)[O:33][C:32](=[O:38])[NH:31]1

Participants

7

Reactant 3

HCID 24758Sodium hydrideHCID 118208677N-(3-methyl-5-(1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amineHCID 118216459tert-butyl ((2S)-4-chloro-3-hydroxybutan-2-yl)carbamate

Product 1

HCID 118208550(4S,5S)-4-methyl-5-((4-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)methyl)oxazolidin-2-one

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
40 °C

Procedure

Sodium hydride (60% dispersion in mineral oil, 28 mg, 0.71 mmol) was added to a mixture of N-(3-methyl-5-(1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (150 mg, 0.47 mmol) in DMF (3 mL), and the mixture was stirred for 5 minutes. A mixture of tert-butyl ((2S)-4-chloro-3-hydroxybutan-2-yl)carbamate (110 mg, 0.49 mmol) in DMF (2 mL) was added and the mixture was heated to 40° C. for 4 hours. The mixture was then allowed to cool to room temperature and diluted with ethyl acetate and water. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was then purified by column chromatography on silica gel. The purified diasteromeric mixture was separated by chiral SFC (Chiralpak ID, 21×250 (mm), 25% CO2 with methanol as the diluent) to afford (4S,5S)-4-methyl-5-((4-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)methyl)oxazolidin-2-one (Isomer 1, early eluting): MS ESI calc'd. for C20H20F3N6O2 [M+H]+ 433. found 433. 1H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.80 (d, J=4.3 Hz, 1H), 8.06 (s, 1H), 7.85-7.76 (m, 2H), 7.73 (s, 1H), 7.35 (s, 1H), 7.24 (d, J=4.6 Hz, 1H), 7.06 (s, 1H), 4.47-4.35 (m, 3H), 3.75-3.59 (m, 1H), 2.29 (s, 3H), 1.10 (d, J=5.8 Hz, 3H).

Workup

  1. additionwas added
  2. temperatureto cool to room temperature
  3. customThe organic layer was separated
  4. dry with materialdried over anhydrous magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe crude residue was then purified by column chromatography on silica gel
  8. customThe purified diasteromeric mixture was separated by chiral SFC (Chiralpak ID, 21×250 (mm), 25% CO2 with methanol as the diluent)

Sources & evidence

ORD record
ord-9f5420c65f614952ac3b1b87867a1cdf
Source dataset
uspto-grants-2016_01
Patent number
US09242984B2

Reaction notes

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