(2R)-2-hydroxy-1-morpholin-4-ylpropan-1-one

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3,4-Dihydro-2H-pyran (90.5 ml, 1.2 eq) was added dropwise to a mixture of 4-[(R)-2-hydroxypropionyl]morpholine (132 g) and p-toluenesulfonic acid monohydrate (500 mg, 0.003 eq) in dry dichloromethane (500 ml) over a period of 15 min with stirring at 0° C. After being stirred for 30 min at 0° C., the mixture was washed with aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel chromatography, using n-hexane: ethyl acetate (8:1)˜ethyl acetate as an eluent, gave 4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (191.6 g, 95% yield) as a pale yellow oil. After being stirred for 30 min at 0° C. the mixture was washed with aqueous sodium bicarbonate dried over anhydrous magnesium sulfate concentrated under reduced pressure Purification of the residue by silica gel chromatography

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl (R)-lactate (175 g) and morpholine (440 ml, 3 eq) was heated at 85° C. for 40 h. The mixture was evaporated under reduced pressure. Purification of the residue by silica gel chromatography (using n-hexane:ethyl acetate=1:1 ˜ethyl acetate as an eluent) gave 4-[(R)-2-hydroxypropionyl]morpholine (232.4 g, 87% yield) as a pale yellow oil. The mixture was evaporated under reduced pressure Purification of the residue by silica gel chromatography (

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (R)-methyl lactate (24.42 g, 0.23 mol) were added morphline (21.46 g, 0.25 mol) and sodium methoxide in methanol (14%, 9.04 g, 0.02 mol) and the mixture was stirred for 3 hours at 50° C. After removal of the solvent in vacuo, the residue was subjected to azeotropic distillation three times with toluene to give the subject compound (quant.). After removal of the solvent in vacuo the residue was subjected to azeotropic distillation three times with toluene to give the subject compound (quant.)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (R)-methyl lactate (24.42 g, 0.23 mol) were added morphline (21.46 g, 0.25 mol) and sodium methoxide in methanol (14%, 9.04 g, 0.02 mol) and the mixture was stirred for 3 hours at 50° C. After removal of the solvent in vacuo, the residue was subjected to azeotropic distillation three times with toluene to give the subject compound (quant.). After removal of the solvent in vacuo the residue was subjected to azeotropic distillation three times with toluene to give the subject compound (quant.)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3,4-Dihydro-2H-pyran (90.5 ml, 1.2 eq) was added dropwise to a mixture of 4-[(R)-2-hydroxypropionyl]morpholine (132 g) and p-toluenesulfonic acid monohydrate (500 mg, 0.003 eq) in dry dichloromethane (500 ml) over a period of 15 min with stirring at 0° C. After being stirred for 30 min at 0° C., the mixture was washed with aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel chromatography, using n-hexane: ethyl acetate (8:1)˜ethyl acetate as an eluent, gave 4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (191.6 g, 95% yield) as a pale yellow oil. After being stirred for 30 min at 0° C. the mixture was washed with aqueous sodium bicarbonate dried over anhydrous magnesium sulfate concentrated under reduced pressure Purification of the residue by silica gel chromatography

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl (R)-lactate (175 g) and morpholine (440 ml, 3 eq) was heated at 85° C. for 40 h. The mixture was evaporated under reduced pressure. Purification of the residue by silica gel chromatography (using n-hexane:ethyl acetate=1:1 ˜ethyl acetate as an eluent) gave 4-[(R)-2-hydroxypropionyl]morpholine (232.4 g, 87% yield) as a pale yellow oil. The mixture was evaporated under reduced pressure Purification of the residue by silica gel chromatography (

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a dichloromethane (500 ml) solution of N-[(2R)-2-hydroxypropionyl]morpholine (141 g) was added p-toluenesulfonic acid mono hydrate (1.67 g). To the mixture was added dropwise (30 minutes) 3,4-dihydro-2H-pyran (89.3 g) under ice-cooling, which was stirred for 30 minutes at room temperature. The reaction mixture was washed with a 5% aqueous solution of sodium hydrogen carbonate (150 ml×2), which was dried (magnesium sulfate), then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel chromatography [silica gel 800 g, eluent: hexane-ethyl acetate=8:1→ethyl acetate] to give N-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (184 g) as a pale yellow oily product. cooling The reaction mixture was washed with a 5% aqueous solution of sodium hydrogen carbonate (150 ml×2), which was dried (magnesium sulfate) the solvent was distilled off under reduced pressure The residue was purified by means of a silica gel chromatography [silica gel 800 g, eluent: hexane-ethyl acetate=8:1→ethyl acetate]

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl (R)-lactate (104 g) and morpholine (260 ml) was heated for 60 hours at 85° C. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by means of a silica gel chromatography (silica gel 800 g, eluent: hexane-ethyl acetate=1:1→etyl acetate) to give N-[(2R)-2-hydroxypropionyl]morpholine (141 g) as a pale yellow oily product. The reaction mixture was concentrated under reduced pressure the concentrate was purified by means of a silica gel chromatography (silica gel 800 g, eluent: hexane-ethyl acetate=1:1→etyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of sodium hydride (60% in paraffin liquid) (8.41 g, 210 mmol) in tetrahydrofuran (120 ml was dropped (2R)-1-morpholin-4-yl-1-oxopropane-2-ol (32.1 g) in tetrahydrofuran (150 ml) under stirring, ice cooling and an atmosphere of nitrogen. The mixture was then stirred for 30 minutes at 50° C. After being ice-cooled, thereto was dropped a solution of p-toluenesulfonyl chloride (45.8 g, 234 mmol) in tetrahydrofuran (180 ml), and the mixture was stirred for 4 hours at room temperature. Thereto was added 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to give the oily residue. Thereto was added diethyl ether and the resulting precipitate was taken by filtration, washed with diethyl ether and dried under reduced pressure to give the subject compound as a white solid (36.1 g, 115 mmol, 58%). The mixture was then stirred for 30 minutes at 50° C cooled the mixture was stirred for 4 hours at room temperature the mixture was extracted with ethyl acetate The organic layer was washed with water an aqueous saturated sodium chloride solution and dried over magnesium sulfate The solvent was removed under reduced pressure to give the oily residue the resulting precipitate was taken by filtration washed with diethyl ether dried under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (R)-methyl lactate (24.42 g, 0.23 mol) were added morphline (21.46 g, 0.25 mol) and sodium methoxide in methanol (14%, 9.04 g, 0.02 mol) and the mixture was stirred for 3 hours at 50° C. After removal of the solvent in vacuo, the residue was subjected to azeotropic distillation three times with toluene to give the subject compound (quant.). After removal of the solvent in vacuo the residue was subjected to azeotropic distillation three times with toluene to give the subject compound (quant.)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3,4-Dihydro-2H-pyran (90.5 ml, 1.2 eq) was added dropwise to a mixture of 4-[(R)-2-hydroxypropionyl]morpholine (132 g) and p-toluenesulfonic acid monohydrate (500 mg, 0.003 eq) in dry dichloromethane (500 ml) over a period of 15 min with stirring at 0° C. After being stirred for 30 min at 0° C., the mixture was washed with aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel chromatography, using n-hexane: ethyl acetate (8:1)˜ethyl acetate as an eluent, gave 4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (191.6 g, 95% yield) as a pale yellow oil. After being stirred for 30 min at 0° C. the mixture was washed with aqueous sodium bicarbonate dried over anhydrous magnesium sulfate concentrated under reduced pressure Purification of the residue by silica gel chromatography

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl (R)-lactate (175 g) and morpholine (440 ml, 3 eq) was heated at 85° C. for 40 h. The mixture was evaporated under reduced pressure. Purification of the residue by silica gel chromatography (using n-hexane:ethyl acetate=1:1 ˜ethyl acetate as an eluent) gave 4-[(R)-2-hydroxypropionyl]morpholine (232.4 g, 87% yield) as a pale yellow oil. The mixture was evaporated under reduced pressure Purification of the residue by silica gel chromatography (