Sodium hydride → 2-(4-Phenylpiperazine-1-carbonyloxymethyl)-morpholine-4-carboxylic acid tert-butyl ester

Participants

Reaction Conditions

Reaction Steps

2-Hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (4.13 g, 19.0 mmol) was dissolved in anhydrous THF (20 mL) and the solution cooled to 0° C. NaH (60% wt dispersion in oil; 2.28 g, 57.0 mmol) was added and the grey suspension stirred for 10 minutes before 4-nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 7.46 g, 22.8 mmol) was added. The reaction was stirred at room temperature over the weekend. A further 1.5 equivalents of NaH (60% wt dispersion in oil) (1.14 g, 28.5 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was cooled to 0° C. and quenched with sat aq NaHCO3 solution (50 mL) before the THF was removed in vacuo. The organic product was extracted with EtOAc (3×50 mL) and the organic layers combined, washed with sat aq NaHCO3 solution (3×50 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×36 mm (200 g), 30 mL/min, gradient 0% to 80% (over 120 mins) MeOH in water with 1% formic acid) to afford 2-(4-phenylpiperazine-1-carbonyloxymethyl)-morpholine-4-carboxylic acid tert-butyl ester (6.67 g, 87% yield) as a dark brown oil.

Provenance & Evidence