Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.
Procedure: To a solution of 4-[4-(2-methylquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]benzene-1,2-diamine (333 mg, 0.84 mmol) in THF (5 mL) at 0° C. was added ethyl isothiocyanate (74 uL, 0.84 mmol). After stirring for 2 h at 0° C., the reaction mixture was warmed to rt for 1 h and was then heated to 45° C. for 4 h. The mixture was then cooled back to rt and allowed to stir for 3 d. Addition of water was followed by extraction into ethyl acetate. The organic phase was then dried over magnesium sulfate, filtered, and concentrated. The residue obtained was then dissolved in acetonitrile (5 mL) and ethyl acetate (2 mL). To this solution was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (161 mg, 0.84 mmol). The mixture was heated to reflux for 1.5 h and was then cooled to rt. Water and ethyl acetate were then added. The biphasic mixture was filtered to remove solid materials, and the filtrate was then partitioned. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and then concentrated. The residue was purified by reverse-phase preparative HPLC to provide N-ethyl-6-[4-(2-methylquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1H-benzimidazol-2-amine as a diacetate salt (137 mg, 0.24 mmol, 29% yield). 1H NMR (400 MHz, dmso) δ 8.01 (d, 1H), 7.79-7.72 (m, 1H), 7.72-7.67 (m, 1H), 7.60 (d, 1H), 7.47-7.39 (m, 2H), 7.35 (s, 1H), 7.20-7.11 (m, 2H), 6.99 (d, 1H), 6.72 (br s, 1H), 5.02 (s, 2H), 4.47-4.38 (m, 2H), 4.22-4.13 (m, 2H), 3.37-3.27 (m, 2H), 2.48 (s, 3H), 1.89 (s, 7H), 1.18 (t, 3H); MS (EI) for C27H26N6O: 451 (MH+).
the reaction mixture was warmed to rt for 1 h
was then heated to 45° C. for 4 h
The mixture was then cooled back to rt
to stir for 3 d
was followed by extraction into ethyl acetate
The organic phase was then dried over magnesium sulfate
filtered
concentrated
The residue obtained
The mixture was heated
to reflux for 1.5 h
was then cooled to rt
The biphasic mixture was filtered
to remove solid materials
the filtrate was then partitioned
The aqueous phase was extracted with ethyl acetate
The combined organic extracts were dried over magnesium sulfate
filtered
concentrated
The residue was purified by reverse-phase preparative HPLC
Source ID: ord-0eea6c22188a4d428567a083732a78cf