tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate

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: Saturated aqueous NaHCO3 (15 mL) was added to a stirred solution of tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (1.09 g, 5.0 mmol) (Organic and Bio-Organic Chemistry (1972-1999); (1985); 2577-2580, WO 2006/114606 and US 2010/210640) in acetone (50 mL) at 0° C. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were added. Trichloroisocyanuric acid (2.32 g, 10.0 mmol) was then added for 20 min at 0° C. After addition, the reaction mixture was allowed to room temperature (RT) and further maintained overnight. 2-Propanol (3 mL) was added and the resulting solution was stirred at RT for 30 min, filtered through a pad of Celite, concentrated under vacuum, and treated with saturated aqueous Na2CO3 solution (15 mL) The aqueous solution was extracted with EtOAc (5 mL), acidified with 6N HCl and extracted with EtOAc (5×10 mL). The combined organic layers were dried over Na2SO4 and the solvent was concentrated to give title compound as a white solid (760 mg). (M−H)−229.9. After addition was allowed to room temperature (RT) further maintained overnight filtered through a pad of Celite concentrated under vacuum treated with saturated aqueous Na2CO3 solution (15 mL) The aqueous solution was extracted with EtOAc (5 mL) extracted with EtOAc (5×10 mL) The combined organic layers were dried over Na2SO4 the solvent was concentrated

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

実験手順: Saturated aqueous NaHCO3 (15 mL) was added to a stirred solution of tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (1.09 g, 5.0 mmol) (Organic and Bio-Organic Chemistry (1972-1999); (1985); 2577-2580, WO 2006/114606 and US 2010/210640) in acetone (50 mL) at 0° C. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were added. Trichloroisocyanuric acid (2.32 g, 10.0 mmol) was then added for 20 min at 0° C. After addition, the reaction mixture was allowed to room temperature (RT) and further maintained overnight. 2-Propanol (3 mL) was added and the resulting solution was stirred at RT for 30 min, filtered through a pad of Celite, concentrated under vacuum, and treated with saturated aqueous Na2CO3 solution (15 mL) The aqueous solution was extracted with EtOAc (5 mL), acidified with 6N HCl and extracted with EtOAc (5×10 mL). The combined organic layers were dried over Na2SO4 and the solvent was concentrated to give title compound as a white solid (760 mg). (M−H)−229.9. After addition was allowed to room temperature (RT) further maintained overnight filtered through a pad of Celite concentrated under vacuum treated with saturated aqueous Na2CO3 solution (15 mL) The aqueous solution was extracted with EtOAc (5 mL) extracted with EtOAc (5×10 mL) The combined organic layers were dried over Na2SO4 the solvent was concentrated

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

実験手順: Step L (1): tert-Butyl 3-(hydroxymethyl)morpholine-4-carboxylate. To a solution of 4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (4.7 g, 20.35 mmol) in THF (120 mL) were added Hunig's base (6.6 g, 50.875 mmol). Then chloroethylformate (2.65 g, 24.4 mmol) was added at 0° C. After stirring from 0° C. to rt over 1.5 h, NaBH4 (3.1 g, 81.4 mmol) was added and after 15 min, MeOH (20 mL) was added slowly at 0° C. After stirring at rt for 1 h, THF and MeOH was removed and ethyl acetate (600 mL) was added and the mixture was washed with NaHCO3, H2O, and dried (Na2SO4), and concentrated in vacuo. 3.56 g of product was obtained as the title compound (81% yield): 1H NMR (CDCl3, 500 MHz) δ 1.46 (9H, s), 2.03 (1H, brd s), 3.17 (1H, m), 3.46 (1H, m), 3.56 (1H, m), 3.72-3.86 (4H, m), 3.91 (1H, d, J=10 Hz), 3.99 (1H, brd s). After stirring at rt for 1 h THF and MeOH was removed ethyl acetate (600 mL) was added the mixture was washed with NaHCO3, H2O dried (Na2SO4) concentrated in vacuo

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: Step L (1): tert-Butyl 3-(hydroxymethyl)morpholine-4-carboxylate. To a solution of 4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (4.7 g, 20.35 mmol) in THF (120 mL) were added Hunig's base (6.6 g, 50.875 mmol). Then chloroethylformate (2.65 g, 24.4 mmol) was added at 0° C. After stirring from 0° C. to rt over 1.5 h, NaBH4 (3.1 g, 81.4 mmol) was added and after 15 min, MeOH (20 mL) was added slowly at 0° C. After stirring at rt for 1 h, THF and MeOH was removed and ethyl acetate (600 mL) was added and the mixture was washed with NaHCO3, H2O, and dried (Na2SO4), and concentrated in vacuo. 3.56 g of product was obtained as the title compound (81% yield): 1H NMR (CDCl3, 500 MHz) δ 1.46 (9H, s), 2.03 (1H, brd s), 3.17 (1H, m), 3.46 (1H, m), 3.56 (1H, m), 3.72-3.86 (4H, m), 3.91 (1H, d, J=10 Hz), 3.99 (1H, brd s). After stirring at rt for 1 h THF and MeOH was removed ethyl acetate (600 mL) was added the mixture was washed with NaHCO3, H2O dried (Na2SO4) concentrated in vacuo

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

実験手順: 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%). 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 solvents removed in vacuo The aqueous phase was extracted with EtOAc (2×20 mL) The combined organic layers were washed with aq Na2CO3 (20 mL) 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; 1.23 g, 30.1 mmol) was suspended in anhydrous THF (50 mL) under nitrogen and cooled to 0° C. with stirring. A solution of 3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Intermediate 7; 2.23 g, 10.3 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred for 20 min at 0° C. 4-Nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 4.03 g, 12.3 mmol) was added and the reaction mixture was stirred for 48 h at room temperature. A sat aq NaHCO3 solution (10 mL) was added and the solvents were removed in vacuo. The residue was partitioned between water and EtOAc, the aqueous phase was extracted with EtOAc (2×100 mL). 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 3-(4-phenyl-piperazine-1-carbonyloxymethyl)-morpholine-4-carboxylic acid tert-butyl ester (3.35 g, 80%). The reaction mixture was stirred for 20 min at 0° C the reaction mixture was stirred for 48 h at room temperature the solvents were removed in vacuo The residue was partitioned between water and EtOAc the aqueous phase was extracted with EtOAc (2×100 mL) 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

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

実験手順: 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%). The reaction mixture was stirred for 20 min at 0° C 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 extracted with EtOAc The combined organic extracts were washed with sat aq NaHCO3 (3×100 mL) dried (MgSO4) 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

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

実験手順: 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%). The reaction mixture was stirred for 20 min at 0° C 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 extracted with EtOAc The combined organic extracts were washed with sat aq NaHCO3 (3×100 mL) dried (MgSO4) 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

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

実験手順: Morpholine-3,4-dicarboxylic acid 4-tert-butyl ester (9.50 g, 41 mmol) was dissolved in anhydrous THF (50 mL) under nitrogen and cooled to −10° C. A 1M solution of borane (82 mL, 82 mmol) was added dropwise whilst maintaining the temperature below 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to −5° C. and water (10 mL) was added cautiously followed by Na2CO3 (9.5 g) in water (20 mL). After stirring for 30 min at room temperature the THF was removed in vacuo, water was added and the reaction mixture was extracted with diethylether (×3). The combined organic extracts were dried (MgSO4) and the solvent was evaporated in vacuo to give 3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (8.9 g, 100%) as a colourless oil. whilst maintaining the temperature below 0° C to warm to room temperature The reaction mixture was cooled to −5° C. was removed in vacuo, water was added the reaction mixture was extracted with diethylether (×3) The combined organic extracts were dried (MgSO4) the solvent was evaporated in vacuo