Reaction Steps
A mixture of methyl (±)-4-isopropyl-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (275.1 mg, 0.61 mmol), 1.0 N LiOH (0.73 mL, 0.73 mmol), THF (3 mL), and H2O (2.3 mL) was stirred at 35° C. for 45 min, and the resulting solution was stirred at RT. After 17.5 h, the solution was filtered, and the filtrate was neutralized with 1.0 N HCl (0.73 mL). Since the product did not precipitate, the solution was acidified with TFA (0.2 mL) and concentrated. The resulting solid was triturated with H2O to leave a nearly colorless solid, which was dissolved with warming in 1:1 CH3CN/H2O. The solution was cooled to RT and diluted with several volumes of H2O/0.1% TFA. ODS chromatography (20% CH3CN/H2O-0.1% TFA), concentration, and lyophilization gave the title compound (293.4 mg, 80%) as a colorless powder: HPLC (PRP-1®, 20% CH3CN/H2O-0.1% TFA) K'=2.5; 1H NMR (400 MHz, CD3OD) δ 7.70-7.76 (m, 2H), 7.65 (d, J=2.2 Hz, 1H), 7.61 (dd, J=8.5, 2.2 Hz, 1H), 7.53-7.60 (m, 2H), 6.62 (d, J=8.5 Hz, 1H), 5.33 (d, J=16.9 Hz, 1H), 5.21 (dd, J=8.9, 5.2 Hz, 1H), 4.97 (d, J=1.9 Hz, 2H), 4.72-4.85 (m, 1H), 4.10 (d, J=16.9 Hz, 1H), 2.96 (dd, J=16.8, 8.9 Hz, 1H), 2.65 (dd, J=16.8, 5.2 Hz, 1H), 1.21 (d, J=6.7 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H); MS (ES) m/e 436.2 (M+H)+. Anal. Calcd for C23H25N5O4.1.25 CF3CO2H.1.25 H2O: C, 51.00; H, 4.83; N, 11.66. Found: C, 51.12; H, 4.91; N, 11.37.
