A 25-mL RB-flask was charged with 3-[4-(3,4-difluorophenoxy)phenyl]propanoic acid (180 mg, 0.650 mmol), tert-butyl-4-(3-amino-4-fluorophenyl)-1-piperidine carboxylate (180 mg, 0.610 mmol), 1-[3-(Dimethylamino) propyl]-3-ethylcarbodimide hydrochloride (1.22 mmol, 190 mg), 4-dimethylaminopyridine (20 mg) in DMF:DCM (0.4:4.0 mL) at room temperature. The reaction mixture was stirred for 12 h and water (10.0 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with CHCl3 (3×10 mL) The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by chromatography (silica gel, hexanes:EtOAc 6:1) to afford tert-butyl 4-[3-({3-[4-(3,4-difluorophenoxy)phenyl]propanoyl}amino)-4-fluorophenyl]-1-piperidinecarboxylate (85.0 mg, 25.0%): 1H NMR (400 MHz, CDCl3) δ 8.32-8.15 (m, 1H), 7.47-6.45 (m, 10H), 4.41-4.07 (br, 2H), 3.17-2.96 (m, 2H), 2.90-2.67 (m, 4H), 2.67-2.56 (m, 1H), 1.91-1.69 (m, 2H), 1.68-1.48 (m, 2H), 1.47 (s, 9H); ESMS m/e 553.3 (M−H+).
