N-Methylmorpholine (0.072 mL) and isobutyl chloroformate (0.039 mL) were added to a stirred solution of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (95 mg) in dichloromethane (5 mL) at −20° C. and the resultant mixture was stirred for 30 min. Hexahydro-3-[4-(trifluoromethoxy)benzyl]-2H-1,4-diazepin-2-one hydrochloride obtained in Step D (91 mg) and IV-methylmorpholine (0.036 mL) were added. The reaction mixture was stirred for 30 min at −20° C. and 2 h at ambient temperature and then evaporated. The residue was purified by preparative TLC (silica gel, methanol/saturated aqueous ammonium hydroxide/dichloromethane 4.4:0.1:95.5), and the isomers were subsequently resolved by HPLC (ChiralPAK OD, 7% ethanol/hexane) to provide the slower eluting (R,R)-isomer.
