Water → racemic 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)-2-methylbutane-1,2-diol

HRID 595307Notes

Reaction equation

HRID 595307 reaction equation
[F:1][CH:2]([F:27])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([C:23]([CH3:25])=[CH2:24])[CH3:22])[CH:20]=3)[CH:13]=[C:12]([CH3:26])[CH:11]=2)[N:4]=1.C[N+]1([O-])CC[O:32]CC1.C1COCC1.[OH2:41]>[Cl-].[Na+].O.[Os](=O)(=O)(=O)=O>[F:27][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH3:22])[C:23]([CH3:25])([OH:32])[CH2:24][OH:41])[CH:20]=3)[CH:13]=[C:12]([CH3:26])[CH:11]=2)[N:4]=1

Participants

7

Reactant 4

HCID 962WaterHCID 8028TetrahydrofuranHCID 82029Methyl morpholine oxideHCID 1182088554-(difluoromethyl)-N-(3-methyl-5-(1-(3-methylbut-3-en-2-yl)-1H-pyrazol-4-yl)phenyl)pyrimidin-2-amine

Product 1

HCID 118208635racemic 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)-2-methylbutane-1,2-diol

Reagents, catalysts & solvents 2

HCID 30318Osmium TetroxideCatalystHCID 57417360Sodium chloride; waterSolvent

Procedure

Osmium tetroxide (4% solution in water, 1.06 ml, 0.14 mmol) was added to a flask containing 4-(difluoromethyl)-N-(3-methyl-5-(1-(3-methylbut-3-en-2-yl)-1H-pyrazol-4-yl)phenyl)pyrimidin-2-amine (200 mg, 0.54 mmol), N-methylmorpholine N-oxide (127 mg, 1.08 mmol), THF (2.5 ml) and water (1.25 ml) was. The reaction mixture was allowed to stir at room temperature for 3 hrs. The reaction was diluted with brine and reaction product extracted with ethyl acetate (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (20-100% ethyl acetate/hexanes) to afford racemic 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)-2-methylbutane-1,2-diol. The racemic mixture was purified by chiral SFC (Phenomenex Lux-4, 21×250 mm, 70 mL/min, 20% Methanol/CO2) to afford 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)-2-methylbutane-1,2-diol. (Example 22.1, Isomer 1, first eluting): MS ESI calcd. for C20H24F2N5O2 [M+H]+ 404. found 404. 1H NMR (500 MHz, DMSOd-6) δ 9.87 (s, 1H), 8.68 (d, J=5.0 Hz, 1H), 7.99 (s, 1H), 7.85 (s, 1H), 7.75 (s, 1H), 7.35 (s, 1H), 7.04 (m, 2H), 6.86 (t, J=54.5 Hz, 1H), 4.65 (t, J=4.5 Hz, 1H), 4.62 (s, 1H), 4.43 (q, J=6.5 Hz, 1H), 3.08 (m, 2H), 2.28 (s, 3H), 1.43 (d, J=6.5 Hz, 3H), 1.03 (s, 3H); and 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)-2-methylbutane-1,2-diol. (Example 22.2, Isomer 2, second eluting): MS ESI calcd. for C20H24F2N5O2 [M+H]+ 404. found 404. 1H NMR (500 MHz, DMSOd-6) δ 9.85 (s, 1H), 8.66 (d, J=4.0 Hz, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.32 (s, 1H), 7.06-7.02 (m, 2H), 6.84 (t, J=45.5 Hz, 1H), 4.62 (t, J=4.5 Hz, 1H), 4.53 (s, 1H), 4.39 (q, J=6.5 Hz, 1H), 3.10-3.06 (m, 2H), 2.26 (s, 3H), 1.41 (d, J=6.5 Hz, 3H), 1.00 (s, 3H).

Workup

  1. extractionextracted with ethyl acetate (2×20 mL)
  2. dry with materialdried over anhydrous sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was purified by column chromatography on silica (20-100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-f642a07c0f234fab8e5d40a386b049d3
Source dataset
uspto-grants-2016_01
Patent number
US09242984B2

Reaction notes

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