反应详情

3-Hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Intermediate 7; 250 mg, 0.76 mmol) in THF (5 mL) was added dropwise to a suspension of NaH (60% dispersion in oil, prewashed with hexane; 138 mg, 3.45 mmol) in anhydrous THF (5 mL) at 0° C. and stirred under nitrogen for 35 minutes. 4-(2,4-Difluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 12; 501 mg, 1.38 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with the addition of aqueous NaHCO3 (0.5 mL) at 0° C. and the solvents removed in vacuo. The residue was suspended between aq Na2CO3 (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic layers were washed with aq Na2CO3 (20 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase, Apollo silica, 1% MeOH in DCM) and the solvents were removed in vacuo to give 3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (170 mg, 34%).

1. stirringthe reaction mixture was stirred at room temperature overnight
2. customThe reaction mixture was quenched with the addition of aqueous NaHCO3 (0.5 mL) at 0° C.
3. customthe solvents removed in vacuo
4. extractionThe aqueous phase was extracted with EtOAc (2×20 mL)
5. washThe combined organic layers were washed with aq Na2CO3 (20 mL)
6. dry with materialdried (MgSO4)
7. customthe solvent removed in vacuo
8. customThe residue was purified by column chromatography (normal phase, Apollo silica, 1% MeOH in DCM)
9. customthe solvents were removed in vacuo