Pyridine → Isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

Add 3,5-bis(trifluoromethyl)benzylamine (5.47 g, 22.5 mmol) followed by titanium isopropoxide (5.98 mL, 20.1 mmol) to a solution of isopropyl 8-bromo-5-oxo-2,3,4,5-tetrahydro benzo[b]azepine-1-carboxylate (5.24 g, 16.1 mmol) in tetrahydrofuran (20 mL) at room temperature under nitrogen was and stir the solution for 4 h. Dilute the reaction with methanol (40 mL) and slowly add sodium borohydride (0.912 g, 24.1 mmol) over 15 min to the reaction and stir at room temperature for 3.5 h. Quench the reaction with addition of 2 N NaOH (56 mL) and water (50 mL) and stir for 0.5 h. Filter the mixture and wash the solids with ethyl acetate/ethanol (4:1, 3×100 mL). Separate the filtrate and wash the organic layer with 2 N NaOH, 2 N HCl, and brine (50 mL each), then dry the solution over sodium sulfate, filter and remove the solvent under reduced pressure to afford isopropyl-5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate as a white solid. Add acetic anhydride (22.6 mL, 241 mmol) dropwise to a suspension of isopropyl 5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (8.89 g, 16.1 mmol) and pyridine (19.6 mL g, 241 mmol) in dichloromethane (64 mL) under nitrogen cooled to 0° C. After the addition is complete, remove the cooling bath and warm the reaction to room temperature and stir for 12 h. Dilute the mixture with dichloromethane (100 mL) and wash with 2 N hydrochloric acid (2×50 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to afford the title compound as a white solid (7.60 g, 79%, 2 steps): ESI MS 595 (M+H).

Provenance & Evidence