(3R)-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: To a stirred solution of (R)-tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (0.650 g, 2.99 mmol) in dichloromethane (10 mL) was added Et3N (1.25 mL, 8.98 mmol). MeSO2Cl (0.35 mL, 4.5 mmol) was added dropwise at 0° C. under N2 and the reaction mixture was stirred at 0° C. for 1 hour. The reaction was diluted with dichloromethane, washed with saturated aqueous NaHCO3 and brine, dried and concentrated. The residue was purified by silica gel chromatography (1:1 hexane/EtOAc) to give (S)-tert-butyl 3-((methylsulfonyloxy)methyl)morpholine-4-carboxylate (0.720 g, 81%) as a white solid. washed with saturated aqueous NaHCO3 and brine dried concentrated The residue was purified by silica gel chromatography (1:1 hexane/EtOAc)

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

实验步骤: To a stirred solution of (R)-tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (0.650 g, 2.99 mmol) in dichloromethane (10 mL) was added Et3N (1.25 mL, 8.98 mmol). MeSO2Cl (0.35 mL, 4.5 mmol) was added dropwise at 0° C. under N2 and the reaction mixture was stirred at 0° C. for 1 hour. The reaction was diluted with dichloromethane, washed with saturated aqueous NaHCO3 and brine, dried and concentrated. The residue was purified by silica gel chromatography (1:1 hexane/EtOAc) to give (S)-tert-butyl 3-((methylsulfonyloxy)methyl)morpholine-4-carboxylate (0.720 g, 81%) as a white solid. washed with saturated aqueous NaHCO3 and brine dried concentrated The residue was purified by silica gel chromatography (1:1 hexane/EtOAc)

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

实验步骤: The title product (2.0 g, yield: 95%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 102. (R)-tert-Butyl 3-(hydroxymethyl)morpholine-4-carboxylate (commercially available, 1.0 g, 4.60 mmol) and tert-butylchlorodiphenylsilane (1.4 ml, 5.52 mmol) were used as starting materials. The title product was purified by column chromatography (ISCO, eluting with 0→50% EtOAc/hexanes). The title product 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: The title product (2.0 g, yield: 95%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 102. (R)-tert-Butyl 3-(hydroxymethyl)morpholine-4-carboxylate (commercially available, 1.0 g, 4.60 mmol) and tert-butylchlorodiphenylsilane (1.4 ml, 5.52 mmol) were used as starting materials. The title product was purified by column chromatography (ISCO, eluting with 0→50% EtOAc/hexanes). The title product was purified by column chromatography (ISCO, eluting with 0→50% EtOAc/hexanes)

反应条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: NaH (60% in oil, prewashed with hexane; 1.38 g, 34.5 mmol) was suspended in anhydrous THF (50 mL) under nitrogen, the reaction mixture cooled to −5° C. with stirring and a solution of (R)-3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (2.50 g, 11.5 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred for 30 min at 0 to 3° C. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 5.01 g, 14.5 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was cooled with an ice bath and a 10% aq NaHCO3 solution (11 mL) was added. The solvents were removed in vacuo and the residue was partitioned between EtOAc (350 mL) and 10% aq NaHCO3 solution (100 mL)/water (200 mL). The EtOAc layer was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 70 g Isolute-Si column, gradient of EtOAc in hexane). The residue was dissolved in DCM and evaporated in vacuo and repeated once before drying in vacuo to give (3R)-3-[4-(4-fluorophenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (2.80 g) as a pale yellow gum. The reaction mixture was stirred for 30 min at 0 to 3° C the reaction mixture was stirred overnight at room temperature The reaction mixture was cooled with an ice bath The solvents were removed in vacuo the residue was partitioned between EtOAc (350 mL) and 10% aq NaHCO3 solution (100 mL)/water (200 mL) The EtOAc layer was dried (MgSO4) the solvent removed in vacuo The residue was purified by column chromatography (normal phase silica, 70 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:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: NaH (60% in oil, prewashed with hexane; 1.38 g, 34.5 mmol) was suspended in anhydrous THF (50 mL) under nitrogen, the reaction mixture cooled to −5° C. with stirring and a solution of (R)-3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (2.50 g, 11.5 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred for 30 min at 0 to 3° C. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 5.01 g, 14.5 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was cooled with an ice bath and a 10% aq NaHCO3 solution (11 mL) was added. The solvents were removed in vacuo and the residue was partitioned between EtOAc (350 mL) and 10% aq NaHCO3 solution (100 mL)/water (200 mL). The EtOAc layer was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 70 g Isolute-Si column, gradient of EtOAc in hexane). The residue was dissolved in DCM and evaporated in vacuo and repeated once before drying in vacuo to give (3R)-3-[4-(4-fluorophenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (2.80 g) as a pale yellow gum. The reaction mixture was stirred for 30 min at 0 to 3° C the reaction mixture was stirred overnight at room temperature The reaction mixture was cooled with an ice bath The solvents were removed in vacuo the residue was partitioned between EtOAc (350 mL) and 10% aq NaHCO3 solution (100 mL)/water (200 mL) The EtOAc layer was dried (MgSO4) the solvent removed in vacuo The residue was purified by column chromatography (normal phase silica, 70 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: To a stirred solution of (R)-tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (0.650 g, 2.99 mmol) in dichloromethane (10 mL) was added Et3N (1.25 mL, 8.98 mmol). MeSO2Cl (0.35 mL, 4.5 mmol) was added dropwise at 0° C. under N2 and the reaction mixture was stirred at 0° C. for 1 hour. The reaction was diluted with dichloromethane, washed with saturated aqueous NaHCO3 and brine, dried and concentrated. The residue was purified by silica gel chromatography (1:1 hexane/EtOAc) to give (S)-tert-butyl 3-((methylsulfonyloxy)methyl)morpholine-4-carboxylate (0.720 g, 81%) as a white solid. washed with saturated aqueous NaHCO3 and brine dried concentrated The residue was purified by silica gel chromatography (1:1 hexane/EtOAc)