Sodium hydride → 3-[4-(4-Fluorophenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester

温度

-10 °C

NaH (60% in oil, prewashed with hexane; 1.30 g, 31.7 mmol) was suspended in anhydrous THF (50 mL) under nitrogen and the reaction mixture was cooled to −10° C. with stirring. A solution of 3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Intermediate 7; 2.30 g, 10.6 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred for 20 min at 0° C. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 4.38 g, 12.7 mmol) was added and the reaction mixture was stirred overnight at room temperature. Sat aq NaHCO3 solution (10 mL) was added and the solvents were removed in vacuo. The residue was partitioned between water and EtOAc and the aqueous phase extracted with EtOAc. The combined organic extracts were washed with sat aq NaHCO3 (3×100 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash normal column chromatography (Apollo silica, 40-63 μm, 60 A) eluting with EtOAc/hexane. Impure material was further purified by flash normal phase chromatography using 1% MeOH in DCM to give 3-[4-(4-fluorophenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (3.05 g, 68%).

1. stirringThe reaction mixture was stirred for 20 min at 0° C
2. stirringthe reaction mixture was stirred overnight at room temperature
3. customthe solvents were removed in vacuo
4. customThe residue was partitioned between water and EtOAc
5. extractionthe aqueous phase extracted with EtOAc
6. washThe combined organic extracts were washed with sat aq NaHCO3 (3×100 mL)
7. dry with materialdried (MgSO4)
8. customthe solvent removed in vacuo
9. customThe residue was purified by flash normal column chromatography (Apollo silica, 40-63 μm, 60 A)
10. washeluting with EtOAc/hexane
11. customImpure material was further purified by flash normal phase chromatography

ORDレコード

ord-35137145ffa84acda50a26dc0e0a0145

出典データセット

uspto-grants-2010_12

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07851471B2