反应详情

A solution of 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (84 mg, 0.180 mmol, from example 137) in benzene (1 mL) was treated with ethylene glycol (0.011 mL, 0.198 mmol), and 4-methylbenzenesulfonic acid, hydrate (34.2 mg, 0.180 mmol). The mixture was heated to reflux using a Dean-Stark trap for 6 h, the mixture was cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The aqueous phase was extracted twice more with ethyl acetate and the combined organic layers were combined and washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (39.4 mg, 34% yield) as a TFA salt. LC-MS (M+H)+ 511.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.75 (1 H, br. s.), 7.30-7.33 (1 H, m), 7.25-7.29 (2 H, m), 7.09-7.17 (3 H, m), 7.06 (1 H, br. s.), 7.02 (1 H, dd, J=8.5, 2.4 Hz), 4.45-4.54 (1 H, m), 4.32-4.42 (2 H, m), 4.02-4.11 (4 H, m), 3.83 (3 H, s), 2.32-2.40 (1 H, m), 2.23 (1 H, d, J=13.7 Hz), 2.08-2.19 (2 H, m).

1. temperatureThe mixture was heated
2. temperatureto reflux
3. customfor 6 h
4. customquenched with saturated sodium bicarbonate
5. extractionextracted with ethyl acetate
6. extractionThe aqueous phase was extracted twice more with ethyl acetate
7. washwashed with brine
8. dry with materialdried over sodium sulfate
9. concentrationconcentrated in vacuo
10. customThe crude product was purified