反应详情

To a mixture of 1-methyl-9-((3-methylazetidin-3-yl)amino)-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (Example #100, Step C, 0.120 g, 0.250 mmol) in MeOH (5 mL) and AcOH (0.5 mL) was added paraformaldehyde (neat, 0.060 g, 2 mmol). The reaction mixture was stirred at ambient temperature for 30 min then NaBH3CN (0.126 g, 2 mmol) was added and the reaction mixture was heated at 50° C. for 5 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by preparative HPLC (Table 3, Method 18) and further separated by chiral SFC (Table 2, Method 11) to give (S)-9-((1,3-dimethylazetidin-3-yl)amino)-1-methyl-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (Example #101-1, Enantiomer 1, SFC (Table 1, Method 16) Rt=5.21 min, 0.019 g, 12%) and (R)-9-((1,3-dimethylazetidin-3-yl)amino)-1-methyl-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (Example #101-2, Enantiomer 2, SFC (Table 1, Method 16) Rt=5.89 min, 0.020 g, 12%) as white solids.

1. temperaturethe reaction mixture was heated at 50° C. for 5 h
2. temperatureThe reaction mixture was cooled to ambient temperature
3. customthe solvent was removed in vacuo
4. customThe residue was purified by preparative HPLC (Table 3, Method 18)
5. customfurther separated by chiral SFC (Table 2, Method 11)