4-Nitrophenyl chloroformate (5.17 g, 25.7 mmol) was dissolved in DCM (200 mL) at room temperature and the reaction mixture was cooled to 0° C. and DIPEA (6.94 g, 9.38 mL, 53.9 mmol) and 1,4-dimethyl-(S)-2-hydroxymethyl piperazine (Intermediate 3; 3.70 g, 25.7 mmol) were added. The reaction mixture was stirred at room temperature for 2 h and then split into three equal volumes. To one portion was added 1-(2,4-difluoro-phenyl)-piperazine (1.68 g, 8.5 mmol) and stirred for 48 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc (500 mL) and 1.0M aq NaOH solution (200 mL). The organic layer was washed with 1.0M aq NaOH solution (5×125 mL), brine (100 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was dissolved in DCM (100 mL) and isocyanate resin (3 g) was added, the reaction mixture was shaken for 14 h, filtered and the solvents were removed in vacuo. The residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×26 mm (100 g), 30 mL/min, gradient 0% to 30% (over 75 min) to 100% (over 13 min) MeOH in water with 1% formic acid). The residue was de-salted using K2CO3 in DCM to give [(2S)-1,4-dimethylpiperazin-2-yl]methyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate (1.23 g, 39.4%) as a light yellow gum.
