Sodium hydride → [(2R)-1,4-dimethylpiperazin-2-yl]methyl 4-(4-fluorophenyl)piperazine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

NaH (60% dispersion in mineral oil; 0.45 g, 11.3 mmol) was suspended in anhydrous THF (20 mL) under nitrogen and the reaction mixture was cooled to 0° C. with stirring. A solution of 1,4-dimethyl-(R)-2-hydroxymethyl piperazine (Intermediate 4; 0.50 g, 3.47 mmol) in THF (20 mL) was added dropwise. The reaction mixture was stirred for 10 minutes at 0° C. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 1.50 g, 4.34 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with sat. aq. NaHCO3 (40 mL) and the THF was removed in vacuo. The aqueous phase was extracted with EtOAc (100 mL). The organic layer was washed with sat. aq. NaHCO3 (5×100 mL), dried (MgSO4) and the solvent 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 [(2R)-1,4-dimethylpiperazin-2-yl]methyl 4-(4-fluorophenyl)piperazine-1-carboxylate (0.42 g, 35%) as a colourless gum.

Provenance & Evidence