反应详情

温度

25 °C

(+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 371)(10 mg, 0.021 mmol) was taken up in MeOH (0.5 mL) and THF (0.5 mL) and trimethyl orthoformate (0.173 mL, 1.566 mmol), AcOH (4.78 μl, 0.084 mmol), and oxetan-3-one (0.013 mL, 0.209 mmol) were added. The reaction was stirred at 25° C. for 2 hr, then NaCNBH4 (0.209 mL, 0.209 mmol) was added and the reaction stirred at 25° C. overnight. The reaction mixture was diluted with EtOAc and washed with sat'd NaHCO3, then brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm; 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 45-85% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. The material was further purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-1-(oxetan-3-yl)hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (2.4 mg).

1. additionNaCNBH4 (0.209 mL, 0.209 mmol) was added
2. stirringthe reaction stirred at 25° C. overnight
3. washwashed with sat'd NaHCO3
4. dry with materialThe organic layer was dried over Na2SO4
5. filtrationfiltered
6. concentrationconcentrated
7. customThe crude material was purified via preparative LC/MS with the following conditions
8. waitGradient: 45-85% B over 20 minutes
9. customa 5-minute hold
10. customThe material was further purified via preparative LC/MS with the following conditions
11. waitGradient: 40-80% B over 20 minutes
12. customa 5-minute hold
13. additionFractions containing the desired product
14. customdried via centrifugal evaporation