Methyl chloroformate → (6-Chloro-4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanone

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Reaction Steps

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]+.

Provenance & Evidence