Reaction Steps
A solution of 5-bromomethyl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (850 mg, 3.46 mmole) in DCM (30 mL) was sparged with N2 for 0.5 hr and then placed in a −20° C. bath. Thiophenol (384 μL, 1.0 equiv) and diisopropylethylamine (605 μL, 1.0 equiv) were added and the reaction was kept at −20° C. for 3 hr. After warming to RT, the reaction mixture was washed with water, dried (Na2SO4), and the solvent was removed. 1,2-Dichloroethane (10 mL), n-butanol (10 mL) and 1-(3-fluoro-benzyl)-1H-indazol-5-ylamine (750 mg, 0.9 equiv) were added to the residue and this mixture was heated at 85° C. for 2.5 hr. The solvents were removed and the residue was taken up in DCM, washed with sat. aq NaHCO3 solution and dried (Na2SO4). Removal of the solvent followed by chromatography on silica gel using DCM containing 0 to 2% MeOH as eluent afforded [1-(3-fluoro-benzyl)-1H-indazol-5-yl]-(5-phenylsulfanylmethyl-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-amine (957 mg, 58%) as a foam. 1H NMR (CDCl3) δ 4.48 (s, 2H), 5.59 (s, 2H), 6.53 (d, 1H, J=3 Hz), 6.8-7.0 (m, 3H), 7.2-7.6 (m, 9H), 7.95 (s, 1H), 8.06 (s, 1H), 8.15 (d, 1H, J=2 Hz), 8.88 (br s, 1H); MS: 481 (M+H)+; HPLC Ret Time: 1.87 min (YMC S7 C18, 3.0×50 mm column, 2 min gradient, 5 mL/min). This was dissolved in chloroform (25 mL), cooled in an ice bath and m-chloro-perbenzoic acid (500 mg, 57 to 80%, 1 equiv) was added in small portions over 15 min. After 1 hr., the reaction was washed with 10% aqueous NaHSO3 solution, sat. aq. NaHCO3 solution (three times) and dried (Na2SO4). Removal of the solvent left the product as a foam (957 mg, 95%). 1H NMR (CDCl3) δ 4.28 (d, 1H, J=14 Hz), 4.53 (d, 1H, J=14 Hz), 5.60 (s, 2H), 6.13 (d, 1H, J=3 Hz), 6.8-7.6 (m, 11H), 7.71 (dd, 1H, J=2, 9 Hz), 7.98 (s, 1H), 8.05 (s, 1H), 8.14 (d, 1H, J=2 Hz); MS: 497 (M+H)+; HPLC Ret Time: 1.67 min (YMC S7 C18, 3.0×50 mm column, 2 min gradient, 5 mL/min).
