反应详情

To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester (165.0 mg, 0.40 mmol) and O-ethylhydroxylamine hydrochloride (78.1 mg, 0.80 mmol, 2.0 eq) in anhydrous THF (9.4 mL) at 0° C. was added lithium hexamethyldisilazide (1M in THF, 1.2 mL, 1.2 mmol, 3.0 eq). After stirring at room temperature for 16 h, additional O-ethylhydroxylamine hydrochloride (234.3 mg, 2.40 mmol, 3.0 eq) and lithium hexamethyldisilazide (1M in THF, 3.6 mL, 3.6 mmol, 9.0 eq) were added at 0° C., and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate (5 mL) and diluted with ethyl acetate (50 mL). The organic layer was isolated and washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 45% to 100%, ethyl acetate in hexane, followed by gradient 0 to 15% methanol in ethyl acetate) to give an oil. Crystallization from DCM—ether—hexane afforded the title compound as a yellow solid (33.7 mg, 19.1%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 11.86 (s, 1H), 10.38 (s, 1H), 8.82 (s, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.73 (d, J=10.4 Hz, 1H), 7.44 (d, 8.4 Hz, 1H), 6.57 (t, J=8.4 Hz, 1H), 3.90 (q, J=7.2 Hz, 2H), 1.18 (t, J=6.8 Hz, 3H); LCMS (method D2): RT=1.24 min, [M+H]+=442.

1. stirringthe reaction mixture was stirred at room temperature for 3 days
2. customThe reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate (5 mL)
3. additiondiluted with ethyl acetate (50 mL)
4. customThe organic layer was isolated
5. washwashed with water and brine
6. dry with materialdried (Na2SO4)
7. filtrationfiltered
8. concentrationconcentrated in vacuo
9. customto give an oil
10. customCrystallization from DCM—ether—hexane