Reaction Steps
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).
