反应详情

A mixture of phosphorus pentoxide (300 mg, 1.057 mmol) and 85% phosphoric acid (0.3 mL, 0.021 mmol) was stirred at 100° C. under nitrogen for 1 hr before 2-amino-2-methyl-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butan-1-ol (Example 50, 10 mg, 0.021 mmol) was added. The clear solution was stirred at the same temperature for 2 hr before ice (˜2 gram) was added. The reaction mixture was stirred at room temperature for 3 hour and dissolved in a minimum amount of methanol and dichloromethane. Purification using reverse phase HPLC (PHENOMENEX® Luna Axia 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration, and lyophilization gave 2-amino-2-methyl-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butyl dihydrogen phosphate, 0.4 TFA (8 mg, 0.012 mmol, 60.3% yield) as a white solid. The compound had an HPLC retention time=3.16 min (condition C); LC/MS M+1=563.4; 1H NMR (400 MHz, MeOD+CDCl3) δ ppm 8.07 (1H, s), 7.86 (1H, d, J=7.7 Hz), 7.52-7.63 (5H, m), 7.24-7.33 (2H, m), 3.98 (1H, dd, J=11.5, 5.5 Hz), 3.89 (1H, dd, J=11.5, 5.5 Hz), 3.04 (2H, t, J=6.9 Hz), 2.90 (2H, t, J=6.9 Hz), 2.65-2.85 (2H, m), 2.08 (1H, td, J=13.1, 4.7 Hz), 1.94 (1H, td, J=13.1, 4.7 Hz), 1.41 (3H, s).

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3. customPurification
4. concentrationphase HPLC (PHENOMENEX® Luna Axia 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration, and lyophilization