反应详情

To a homogeneous solution of 3-fluoro-4-(5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (52 mg, 0.20 mmol, Compound B of Example 28) and 3-(4-fluorophenylamino)-3-oxopropanoic acid (39 mg, 0.20 mmol, Compound A of Example 25) in anhydrous DMF (2 mL), at room temperature under nitrogen atmosphere, was added diisopropylethylamine (52 μL, 0.30 mmol). The mixture was stirred for 5 minutes before o-benzotriazol-l-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (96 mg, 0.30 mmol) was added in one portion. The mixture was stirred for 17.5 h before the reaction was concentrated in vacuo to remove volatiles. The resultant residue was diluted with ethyl acetate and washed twice with 10% aqueous lithium chloride before being concentrated in vacuo. Purification by silica gel (Merck KGaA, 230-400 mesh particle size) flash chromatography, eluting with 1% methanol in chloroform, afforded an off-white solid that was triturated and sonicated in the presence of anhydrous ethyl ether (3 mL). The title compound (66 mg, 75%) was isolated by filtration as a white solid. 1H NMR (CDCl3) δ 9.28 (s, 1H), 8.67 (s, 1H), 7.83 (s, 1H), 7.80-7.73 (m, 1H), 7.67 (d, 1H, J=2.5 Hz), 7.54-7.49 (m, 2H), 7.28-7.26 (m, 2H), 7.10-7.02 (m, 2H), 6.64 (d, 1H, J=2.3 Hz), 3.56 (s, 2H), 2.60 (s, 3H); HRMS(ESI), 436.1221 (M+H)+ calc, 436.1230 (M+H)+ found.

1. additionwas added in one portion
2. concentrationwas concentrated in vacuo
3. customto remove volatiles
4. additionThe resultant residue was diluted with ethyl acetate
5. washwashed twice with 10% aqueous lithium chloride
6. concentrationbefore being concentrated in vacuo
7. customPurification by silica gel (Merck KGaA, 230-400 mesh particle size) flash chromatography
8. washeluting with 1% methanol in chloroform
9. customafforded an off-white solid
10. customthat was triturated
11. customsonicated in the presence of anhydrous ethyl ether (3 mL)