反应详情

To an ice-cold suspension of 0.61 g (1.39 mmol) (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanone (Example 8) in 3 mL dichloromethane were added 0.388 g (1.73 mmol) m-chloroperbenzoic acid (Aldrich, CAS RN 937-14-4). The cooling bath was removed, the reaction stirred at room temperature for 45 min., poured on a saturated solution of aqueous sodium bicarbonate and extracted three times with dichloromethane. The organic layers were washed with a saturated solution of aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate:methanol (100:0:0 to 0:100:0 to 0:0:100). From the resulting light brown foam (0.51 g; MS (ESI): m/z=456.087 [M+H]+), 0.20 g (0.44 mmol) were dissolved in 8 mL tetrahydrofuran and 0.09 mL (0.44 mmol) hexamethyldisilazane and 0.08 mL (1.1 mmol) methyl chloroformate were added. The resulting brown, turbid solution was stirred for 1.5 hours at room temperature, poured on saturated aqueous sodium bicarbonate solution and was extracted three times with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 25:75). The resulting orange solid (0.13 g) was dissolved in acetonitrile and a few drops N,N-dimethylformamide, filtered using a syringe micro filter and purified two times on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 65 mg (31%) of the title compound as a light brown foam. MS (ESI): m/z=474.054 [M+H]+.

1. customThe cooling bath was removed
2. additionpoured on a saturated solution of aqueous sodium bicarbonate
3. extractionextracted three times with dichloromethane
4. washThe organic layers were washed with a saturated solution of aqueous sodium bicarbonate and brine
5. dry with materialdried over magnesium sulfate
6. filtrationfiltered
7. additiontreated with silica gel
8. customevaporated
9. customThe resulting powder was purified by silica gel chromatography
10. dissolutionFrom the resulting light brown foam (0.51 g; MS (ESI): m/z=456.087 [M+H]+), 0.20 g (0.44 mmol) were dissolved in 8 mL tetrahydrofuran
11. stirringThe resulting brown, turbid solution was stirred for 1.5 hours at room temperature
12. extractionwas extracted three times with ethyl acetate
13. washThe organic layers were washed with brine
14. dry with materialdried over magnesium sulfate
15. filtrationfiltered
16. additiontreated with silica gel
17. customevaporated
18. customThe resulting powder was purified by silica gel chromatography
19. washeluting with a gradient of n-heptane:ethyl acetate (100:0 to 25:75)
20. dissolutionThe resulting orange solid (0.13 g) was dissolved in acetonitrile
21. filtrationa few drops N,N-dimethylformamide, filtered
22. filtrationmicro filter
23. custompurified two times on a preparative HPLC system (Phenomenex Gemini column)