反应详情

Scheme 3, step M, substep 2 (amidation): Dimethylformamide (10 μL, 0.14 mmol) and oxalyl chloride (119 μL, 1.38 mmol) is added to acetonitrile (3.7 mL) and stirred at room temperature for 10 minutes. 5-Cyano-3-fluoro-pyridine-2-carboxylic acid (213 mg, 1.28 mmol) is added and the mixture is stirred for another 10 minutes. This mixture is then added in a single portion to a solution of (4aR,7aS)-7a-(5-amino-2-fluoro-phenyl)-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]oxazin-2-amine (247 mg, 0.917 mmol) in ethanol (3.7 mL) and water (3.7 mL) heated to 55° C. The reaction mixture is stirred for 1.5 hours and then concentrated under reduced pressure. The residue is diluted with ethyl acetate, washed with ½ saturated sodium bicarbonate solution. The aqueous layer is extracted with ethyl acetate, and the combined organic layers are dried over sodium sulfate, filtered, and concentrated to give a residue, which is purified by silica gel flash chromatography eluting with a gradient of 7 M ammonia in methanol/dichloromethane (1/99) to 7 M ammonia in methanol/dichloromethane (10/90) to give the free base of the title compound (328 mg, 0.786 mmol). The free base is dissolved in dichloromethane (5 mL) and methanol (0.2 mL), and treated with hydrochloric acid (1 M in diethyl ether, 865 μL, 0.865 mmol), and concentrated under reduced pressure. Diethyl ether (3 mL) is added to the residue and concentrated and this is repeated a second time to give the title compound (349 mg, 0.769 mmol, 83.8%). ES/MS (m/z): 418.0 (M+1).

1. stirringthe mixture is stirred for another 10 minutes
2. temperatureheated to 55° C
3. stirringThe reaction mixture is stirred for 1.5 hours
4. concentrationconcentrated under reduced pressure
5. additionThe residue is diluted with ethyl acetate
6. washwashed with ½ saturated sodium bicarbonate solution
7. extractionThe aqueous layer is extracted with ethyl acetate
8. dry with materialthe combined organic layers are dried over sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated
11. customto give a residue, which
12. customis purified by silica gel flash chromatography
13. washeluting with a gradient of 7 M ammonia in methanol/dichloromethane (1/99) to 7 M ammonia in methanol/dichloromethane (10/90)