(4-methylmorpholin-3-yl)methanol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (4-Methyl-morpholin-3-yl)-methanol (387 mg, 2.95 mmol) in THF (7.5 mL) was added dropwise to a suspension of NaH (60% dispersion in oil, prewashed with hexane; 354 mg, 8.85 mmol) in anhydrous THF (7.5 mL) at 0° C. and stirred under nitrogen for 40 minutes. 4-(2,4-Difluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 12; 1.28 g, 3.54 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. The reaction mixture was stirred for 1 h and then the solvents were removed in vacuo. The residue was suspended between water and EtOAc. The aqueous phase was extracted with EtOAc (×3). The combined organic layers were washed with aqueous Na2CO3, 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 (4-methylmorpholin-3-yl)methyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate (197 mg, 19%) as a colourless oil. 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 The reaction mixture was stirred for 1 h the solvents were removed in vacuo The aqueous phase was extracted with EtOAc (×3) The combined organic layers were washed with aqueous Na2CO3 dried (MgSO4) the solvent removed in vacuo The residue was purified by column chromatography (normal phase, Apollo silica, 1% MeOH in DCM) the solvents were removed in vacuo

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: NaH (60% in oil, prewashed with hexane; 0.91 g, 22.9 mmol) was suspended in anhydrous THF (25 mL) under nitrogen and cooled to 0° C. with stirring. A solution of (4-methyl-morpholin-3-yl)-methanol (1.00 g, 2.62 mmol) in THF (25 mL) was added dropwise. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 3.16 g, 9.15 mmol) was added and the reaction mixture was stirred overnight at room temperature. A saturated aqueous solution of NaHCO3 (10 mL) was added and the solvents were removed in vacuo. The residue was partitioned between water and EtOAc and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with sat aq NaHCO3 (3×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash normal column chromatography (Apollo silica, 40-63 μm, 60 A) eluting with 1% MeOH in DCM to give (4-methylmorpholin-3-yl)methyl 4-(4-fluorophenyl)piperazine-1-carboxylate (2.15 g, 83%) as a white solid. the reaction mixture was stirred overnight at room temperature the solvents were removed in vacuo The residue was partitioned between water and EtOAc the aqueous phase was extracted with EtOAc The combined organic extracts were washed with sat aq NaHCO3 (3×100 mL) dried (MgSO4) the solvents were removed in vacuo The residue was purified by flash normal column chromatography (Apollo silica, 40-63 μm, 60 A) eluting with 1% MeOH in DCM

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: NaH (60% in oil, prewashed with hexane; 0.91 g, 22.9 mmol) was suspended in anhydrous THF (25 mL) under nitrogen and cooled to 0° C. with stirring. A solution of (4-methyl-morpholin-3-yl)-methanol (1.00 g, 2.62 mmol) in THF (25 mL) was added dropwise. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 3.16 g, 9.15 mmol) was added and the reaction mixture was stirred overnight at room temperature. A saturated aqueous solution of NaHCO3 (10 mL) was added and the solvents were removed in vacuo. The residue was partitioned between water and EtOAc and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with sat aq NaHCO3 (3×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash normal column chromatography (Apollo silica, 40-63 μm, 60 A) eluting with 1% MeOH in DCM to give (4-methylmorpholin-3-yl)methyl 4-(4-fluorophenyl)piperazine-1-carboxylate (2.15 g, 83%) as a white solid. the reaction mixture was stirred overnight at room temperature the solvents were removed in vacuo The residue was partitioned between water and EtOAc the aqueous phase was extracted with EtOAc The combined organic extracts were washed with sat aq NaHCO3 (3×100 mL) dried (MgSO4) the solvents were removed in vacuo The residue was purified by flash normal column chromatography (Apollo silica, 40-63 μm, 60 A) eluting with 1% MeOH in DCM

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: LiAlH4 (4.2 g, 110 mmol) was suspended in anhydrous THF (60 mL) under nitrogen, cooled to −10° C. with stirring and a solution of 3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Intermediate 7; 4.1 g, 18.4 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred for 20 minutes at 0° C., heated to reflux for 3 h and then stirred at room temperature overnight. The reaction mixture was cooled to −10° C. and quenched with the dropwise addition of 10% water in THF. The reaction mixture was diluted with THF (50 mL), stirred for 1 h at room temperature, filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DCM, dried (MgSO4) and the solvent removed in vacuo to give (4-methyl-morpholin-3-yl)-methanol (2.05 g, 85%) as a colourless liquid. The reaction mixture was stirred for 20 minutes at 0° C. heated to reflux for 3 h stirred at room temperature overnight The reaction mixture was cooled to −10° C. quenched with the dropwise addition of 10% water in THF The reaction mixture was diluted with THF (50 mL) stirred for 1 h at room temperature filtered the filtrate was concentrated in vacuo The residue was dissolved in DCM dried (MgSO4) the solvent removed in vacuo