反应详情

A suspension of 5-bromomethyl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (61 mg, 0.25 mmole), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 10 equiv) and NaHCO3 (42 mg, 2 equiv) in dry CH3CN (0.5 mL) under N2 was left stirring at RT for 3 days. 1-(3-Fluoro-benzyl)-1H-indazol-5-ylamine (54 mg, 0.9 equiv) and additional NaHCO3 (42 mg, 2 equiv) were added and the reaction was left stirring overnight. The reaction was diluted with DCM, washed with water, and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 0 to 3% MeOH) afforded 4-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethoxy}-piperidine-1-carboxylic acid tert-butyl ester as a foam (47 mg, 33%). This was treated with a mixture of DCM (1.5 mL) and TFA (1 mL) for 40 min and then the solvents were removed. The residue was taken up in DCM, washed with sat. aq. NaHCO3 solution, and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 0 to 5% MeOH) afforded the pure amine (11 mg, 29%) as an oil. 1H NMR (CDCl3) δ 1.1-1.3 (m, 2H), 1.7-1.9 (m, 4H), 2.5-2.6 (m, 2H), 3.0-3.1 (m, 2H), 3.44 (d, 2H, J=7 Hz), 4.85 (s, 2H), 5.59 (s, 2H), 6.55 (d, 1H, J=2 Hz), 6.8-7.0 (m, 3H), 7.2-7.5 (m, 4H), 7.97 (s, 1H), 8.05 (s, 1H), 8.20 (d, 1H, J=2 Hz), 9.70 (s, 1H); MS: 486 (M+H)+; HPLC Ret Time: 1.35 min (YMC S7 C18, 3.0×50 mm, 2 min gradient, 5 mL/min.

1. waitwas left
2. waitthe reaction was left
3. stirringstirring overnight
4. washwashed with water
5. dry with materialdried (Na2SO4)
6. customRemoval of the solvent
7. washfollowed by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 0 to 3% MeOH)