Acetic Acid → (2S)-3-[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanamide

HRID 595294Notes

Reaction equation

HRID 595294 reaction equation
Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C(O)(=O)C.[NH2:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:24]=[N:25][N:26]([CH2:28][C@H:29]([OH:33])[C:30]([NH2:32])=[O:31])[CH:27]=2)[CH:19]=[C:20]([CH3:22])[CH:21]=1>O1CCOCC1.O>[F:9][CH:8]([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:15][C:16]2[CH:17]=[C:18]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][C@H:29]([OH:33])[C:30]([NH2:32])=[O:31])[CH:27]=3)[CH:19]=[C:20]([CH3:22])[CH:21]=2)[N:7]=1

Participants

6

Reactant 3

HCID 176Acetic AcidHCID 717429242-Chloro-4-(difluoromethyl)pyrimidineHCID 118208773(2S)-3-[4-(3-amino-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanamide

Product 1

HCID 118208546(2S)-3-[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

2-Chloro-4-(difluoromethyl)pyrimidine (24.8 mg, 0.12 mmol) and acetic acid (0.0074 mL, 0.130 mmol) were added to an oven-dried flask containing (2S)-3-[4-(3-amino-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanamide (46.2 mg, 0.12 mmol) dissolved in dioxane (0.41 mL). The mixture was stirred for 3 hours at 120° C. The mixture was then cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (2 to 100% EtOAc/hexanes) to afford (2S)-3-[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanamide. MS ESI calcd. for C18H19F2N6O2 [M+H]+ 389. found 389. 1H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.68 (d, J=4.9 Hz, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 7.37 (s, 1H), 7.34 (s, 1H), 7.32 (s, 1H), 7.04 (d, J=4.9 Hz, 1H), 7.01 (s, 1H), 6.87 (t, J=54.4 Hz, 1H), 5.86 (d, J=5.9 Hz, 1H), 4.41-4.33 (m, 1H), 4.24-4.18 (m, 1H), 4.17-4.13 (m, 1H), 2.28 (s, 3H).

Workup

  1. temperatureThe mixture was then cooled to room temperature
  2. extractionextracted with EtOAc (3×)
  3. dry with materialThe combined organic layers were dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by column chromatography on silica gel (2 to 100% EtOAc/hexanes)

Sources & evidence

ORD record
ord-3076b087993e490786a95d9ab321901a
Source dataset
uspto-grants-2016_01
Patent number
US09242984B2

Reaction notes

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