(3S)-3-(羟甲基)吗啉-4-羧酸叔丁酯

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: NaH (60% in oil, prewashed with hexane; 2.76 g, 69.0 mmol) was suspended in anhydrous THF (100 mL) under nitrogen and the reaction mixture was cooled to 0° C. with stirring. A solution of (S)-3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (5.00 g, 23.0 mmol) in THF (100 mL) was added dropwise. The reaction mixture was stirred for 30 minutes at 0° C. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 10.0 g, 29.0 mmol) was added and the reaction mixture was stirred overnight at room temperature before standing for 24 h. The reaction mixture was cooled to 5-10° C. A 10% aqueous solution of NaHCO3 (22 mL) was added and the solvents were removed in vacuo. The residue was partitioned between EtOAc (700 mL) and 10% aqueous solution of NaHCO3 (200 mL)/water (400 mL). The EtOAc layer was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 100 g Isolute-Si column, gradient of EtOAc in hexane). The residue was dissolved in DCM and evaporated in vacuo and repeated before drying in vacuo to give (3S)-3-[4-(4-fluorophenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (8.19 g, 84%) as an orange gum. The reaction mixture was stirred for 30 minutes at 0° C the reaction mixture was stirred overnight at room temperature The reaction mixture was cooled to 5-10° C the solvents were removed in vacuo The residue was partitioned between EtOAc (700 mL) and 10% aqueous solution of NaHCO3 (200 mL)/water (400 mL) The EtOAc layer was dried (MgSO4) the solvent removed in vacuo The residue was purified by column chromatography (normal phase silica, 100 g Isolute-Si column, gradient of EtOAc in hexane) The residue was dissolved in DCM evaporated in vacuo before drying in vacuo

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: NaH (60% in oil, prewashed with hexane; 2.76 g, 69.0 mmol) was suspended in anhydrous THF (100 mL) under nitrogen and the reaction mixture was cooled to 0° C. with stirring. A solution of (S)-3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (5.00 g, 23.0 mmol) in THF (100 mL) was added dropwise. The reaction mixture was stirred for 30 minutes at 0° C. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 10.0 g, 29.0 mmol) was added and the reaction mixture was stirred overnight at room temperature before standing for 24 h. The reaction mixture was cooled to 5-10° C. A 10% aqueous solution of NaHCO3 (22 mL) was added and the solvents were removed in vacuo. The residue was partitioned between EtOAc (700 mL) and 10% aqueous solution of NaHCO3 (200 mL)/water (400 mL). The EtOAc layer was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 100 g Isolute-Si column, gradient of EtOAc in hexane). The residue was dissolved in DCM and evaporated in vacuo and repeated before drying in vacuo to give (3S)-3-[4-(4-fluorophenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (8.19 g, 84%) as an orange gum. The reaction mixture was stirred for 30 minutes at 0° C the reaction mixture was stirred overnight at room temperature The reaction mixture was cooled to 5-10° C the solvents were removed in vacuo The residue was partitioned between EtOAc (700 mL) and 10% aqueous solution of NaHCO3 (200 mL)/water (400 mL) The EtOAc layer was dried (MgSO4) the solvent removed in vacuo The residue was purified by column chromatography (normal phase silica, 100 g Isolute-Si column, gradient of EtOAc in hexane) The residue was dissolved in DCM evaporated in vacuo before drying in vacuo

反应条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 4C (150 mg, 0.35 mmol), DPPA (0.11 ml, 0.53 mmol) and Et3N (0.12 ml, 0.88 mmol) in toluene (3.5 ml) was heated at 55° C. for 3 h. Additional DPPA (0.02 ml, 0.10 mmol) was added, and the mixture was stirred at this temperature for another 1 h. (S)-3-Hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (115 mg, 0.53 mmol) was added, and the resulting mixture was heated at 80° C. overnight. The mixture was cooled to rt, diluted with EtOAc (80 ml), washed with H2O (1×30 ml), saturated Na2CO3 (2×30 ml) and brine (1×30 ml). The mixture was dried (MgSO4), filtered and concentrated. The residue was triturated in MTBE (20 ml) and filtered to give 4D (124 mg, 55%) which was used in the next step without further purification. was added the resulting mixture was heated at 80° C. overnight The mixture was cooled to rt washed with H2O (1×30 ml), saturated Na2CO3 (2×30 ml) and brine (1×30 ml) The mixture was dried (MgSO4) filtered concentrated The residue was triturated in MTBE (20 ml) filtered

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)-tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (1.00 g, 4.60 mmol) in DCM (10 ml) were added sequentially triethylamine (1.3 ml, 9.21 mmol), tert-butylchlorodiphenylsilane (1.414 ml, 5.52 mmol) and DMAP (0.56 g, 4.60 mmol) and the resulting mixture was stirred overnight at ambient temperature. The mixture was diluted with water and the aqueous phase was extracted with DCM. The organic layer was separated and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, eluting with 0→50% EtOAc/hexanes) to afford the title product (1.0 g, yield: 48%). the aqueous phase was extracted with DCM The organic layer was separated concentrated under reduced pressure The concentrate was purified by column chromatography (ISCO, eluting with 0→50% EtOAc/hexanes)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)-tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (1.00 g, 4.60 mmol) in DCM (10 ml) were added sequentially triethylamine (1.3 ml, 9.21 mmol), tert-butylchlorodiphenylsilane (1.414 ml, 5.52 mmol) and DMAP (0.56 g, 4.60 mmol) and the resulting mixture was stirred overnight at ambient temperature. The mixture was diluted with water and the aqueous phase was extracted with DCM. The organic layer was separated and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, eluting with 0→50% EtOAc/hexanes) to afford the title product (1.0 g, yield: 48%). the aqueous phase was extracted with DCM The organic layer was separated concentrated under reduced pressure The concentrate was purified by column chromatography (ISCO, eluting with 0→50% EtOAc/hexanes)