Cesium carbonate → benzyl 2-oxo-5-phenyl-1-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate

Participants

Reaction Conditions

Reaction Steps

To a stirred mixture of benzyl 2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate (1.20 g, 3.11 mmol, prepared according to J. Med. Chem., 49:2311-2319 (2006), compound #4a), 2-iodopyridine (1.00 g, 4.88 mmol), cuprous iodide (0.15 g, 0.788 mmol) and Cs2CO3 (3.05 g, 9.36 mmol) in dioxane (25 mL) was added (+/−)-trans-1,2-diaminocyclohexane (0.19 mL, 1.58 mmol) under nitrogen. The reaction mixture was then heated to 120° C. and gently refluxed for 10 min. It was then cooled to room temperature under nitrogen. This mixture was diluted with 100 mL of EtOAc, 40 mL of pH 4 phosphate buffer and 40 mL of saturated NaHCO3 solution. The insoluble material was removed by filtration through a 2 inch pad of CELITE®, and rinsed with EtOAc (2×30 mL). The aqueous phase was separated and extracted with 160 mL of EtOAc. The combined EtOAc extracts were washed with saturated NaHCO3 solution (1×30 mL) and brine (1×20 mL), then dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane/EtOAc) to afford Intermediate 1A (0.88 g, 61%): 1H NMR (400 MHz, DMSO-d6) δ 8.61 (1 H, d, J=8.14 Hz), 8.47 (1 H, dd, J=4.73, 1.21 Hz), 7.94-8.03 (1 H, m), 7.64 (2 H, d, J=7.92 Hz), 7.47-7.60 (4 H, m), 7.27-7.44 (9 H, m), 6.97 (1 H, d, J=8.14 Hz), 5.39 (1 H, d, J=8.36 Hz), 5.10 (2 H, s); HPLC: RT=2.930 min (CHROMOLITH® ODS 4.6×50 mm (4 min grad) eluting with 10-90% aqueous MeOH over 4 minutes containing 0.% TFA, 4 mL/min, monitoring at 220 nm); MS(ES): m/z=463.3 [M+H]+.

Provenance & Evidence