Acetic Acid → Carbamic acid, N-(9-fluoro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-, phenylmethyl ester

Participants

Reaction Conditions

Reaction Steps

To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-(benzyloxycarbonylamino)acetic acid (6.06 g, 18.59 mmol) in THF (40 mL) cooled at 0° C. was added oxalyl chloride (1.627 mL, 18.59 mmol), followed by DMF (0.05 mL). The mixture was stirred at 0° C. for 1.5 h. A solution of Intermediate A11 (2 g, 9.29 mmol) and 4-methylmorpholine (3.06 mL, 27.9 mmol) in THF (15 mL) was added slowly. After the addition, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was filtered through CELITE® and washed with 40 ml THF. The filtrate was treated with 7N NH3/MeOH (40 mL). The mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated, the residue was taken into EtOAc (150 mL), washed with 1N NaOH (150 mL), the aqueous layer was extracted with EtOAc (2×125 mL). The combined extracts were washed with brine, dried (MgSO4), filtered and concentrated. The residue was dissolved in acetic acid (13 mL, 227 mmol) and treated with ammonium acetate (3.58 g, 46.5 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and suspended in saturated NaHCO3, extracted thrice with DCM. The combined extracts were washed with brine, dried and concentrated. The residue was purified by silica gel chromatography (hexane/EtOAc) to give Intermediate B1A (3.0 g, 79%): HPLC: RT=2.780 min (H2O/MeOH with TFA, CHROMOLITH® SpeedROD, 4.6×50 mm, gradient=4 min, wavelength=220 nm); MS(ES): m/z=404 [M+H+]; 1H NMR (400 MHz, CDCl3) δ 7.92 (1H, br. s.), 7.57 (2H, d, J=7.04 Hz), 7.46-7.53 (1H, m), 7.30-7.46 (8H, m), 7.15-7.23 (2H, m), 6.61 (1H, d, J=8.14 Hz), 5.42 (1H, d, J=8.36 Hz), 5.20 (2H, s).

Provenance & Evidence