反应详情

温度

0 °C

A 25 mL round bottom flask was charged with copper (I) iodide (8.16 mg, 0.043 mmol) in THF (1 mL), and cooled to 0° C. A solution of methylmagnesium bromide (1.53 mL, 2.142 mmol, 1.4 M in THF) was added dropwise to the stirred solution and stirred for 20 min. To solution of methyl cuprate was added 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 (100 mg, 0.214 mmol, from example 137) in THF (1 mL) and the reaction was stirred at 0° C. for an additional 2 h. The resulting mixture was quenched slowly with saturated ammonium chloride, and the aqueous layer was washed with EtOAc (×3). The combined organic layers were then washed with brine (100 mL), 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 (21.6 mg, 17% yield) as a TFA salt. LC-MS (M+H)+ 483.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 10.36 (1 H, br. s.), 9.30 (1 H, br. s.), 8.05 (1 H, s), 7.22-7.33 (2 H, m), 7.08-7.20 (6 H, m), 4.62-4.76 (2 H, m), 4.34-4.46 (1 H, m), 3.82-3.92 (3 H, m), 2.16-2.34 (2 H, m), 2.04-2.14 (1 H, m), 1.92-2.04 (1 H, m), 1.43-1.53 (3 H, m).

1. stirringthe reaction was stirred at 0° C. for an additional 2 h
2. customThe resulting mixture was quenched slowly with saturated ammonium chloride
3. washthe aqueous layer was washed with EtOAc (×3)
4. washThe combined organic layers were then washed with brine (100 mL)
5. dry with materialdried over sodium sulfate
6. concentrationconcentrated in vacuo
7. customThe crude product was purified