Diethyl Ether → (3R,5S)-3-{Cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-[1,4]oxazin-6-yl]-carbamoyl}-5-phenylacetylamino-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester

Participants

Reaction Steps

To a solution of (3R,5S)-5-tert-Butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (338 mg, 0.73 mmol) in THF (5.0 mL), isobutyl chloroformate (0.1 mL, 0.79 mmol) and Et3N (0.1 mL, 0.79 mmol) are added at 0° C. After stirring for 1 h at the same temperature, the resulting precipitate is filtered off and the filtrate is concentrated. The evaporated residue is dissolved in THF (5 ml), 6-Cyclopropylamino-4-(3-methoxy-propyl)-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (200 mg, 0.66 mmol) and MgBr2.OEt2 (189 mg, 0.73 mmol) are added at room temperature. After stirring for 2 h, the reaction is quenched with H2O and resulting mixture is extracted with AcOEt, washed with 1N HCl solution, sat. NaHCO3aq and brine. The organic layer is dried (MgSO4), concentrated and purified by silica gel column chromatography to afford the title compound as a white amorphous solid. MS: 753 [M+H]+; tR (HPLC, CombiScreen ODS-AM 50×4.6 mm; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 2 min, flow 2.0 ml/min): 4.77 min.

Provenance & Evidence