反应详情

A sealed tube was charged with the intermediate from Example 1 Step E (230 mg, 0.52 mmol), (2,6-difluoropyridin-3-yl)boronic acid (580 mg, 3.6 mmol), and bis(triphenylphosphine)palladium(n) chloride (73 mg, 0.1 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed toluene (3.0 mL) and ethanol (3.0 mL) were added, followed by the addition of 2.0M aqueous sodium carbonate solution (2.6 mL, 5.2 mmol). The tube was sealed, placed in an oil bath at 90° C., and stirred for 3 hours. The reaction mixture was then cooled and poured into a mixture of ethyl acetate and brine. The aqueous layer was extracted twice with ethyl acetate and the combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo. Purification via flash chromatography (silica, 0-20% methanol/dichloromethane) was followed by purification via preparative chiral HPLC (AD column, 25% ethanol/heptane isocratic) to afford the title compound. 1H NMR (600 MHz, d6-DMSO) δ 11.75 (s, 1H), 10.57 (s, 1H), 8.49 (broad s, 1H), 8.43 (q, 1H), 7.92 (d, 1H), 7.72-7.69 (m, 1H), 7.62-7.61 (m, 2H), 7.58-7.52 (m, 1H), 7.37 (dd, 1H), 7.27 (broad s, 1H). Imidazole proton was not observed [M+H]+ 476. τR: 9.44 min (analytical chiral HPLC, AD column, 0.46 cm×25 cm, 25% ethanol/heptane, isocratic, flow rate=0.75 mL/min).

1. customThe tube was evacuated
2. additionFully degassed toluene (3.0 mL) and ethanol (3.0 mL) were added
3. customThe tube was sealed
4. customplaced in an oil bath at 90° C.
5. temperatureThe reaction mixture was then cooled
6. extractionThe aqueous layer was extracted twice with ethyl acetate
7. dry with materialthe combined organics were dried over magnesium sulfate
8. filtrationfiltered
9. concentrationconcentrated in vacuo
10. customPurification via flash chromatography (silica, 0-20% methanol/dichloromethane)
11. customwas followed by purification via preparative chiral HPLC (AD column, 25% ethanol/heptane isocratic)