(2R)-1-morpholin-4-yl-2-(oxan-2-yloxy)propan-1-one

Conditions: temp:52.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of magnesium (7.25 g, 0.298 mol) and iodine (catalytic amount) and 1-bromo-2,5-difluorobenzene (20.0 g, 0.178 mol) in THF (250 ml) was vigorously stirred. The color of iodine was disappeared and the inner temperature rose up to 65° C. To this mixture was added additional 1-bromo-2,5-difluorobenzene (30.0 g, 0.267 mol) dropwise to maintain the inner temperature from 50 to 55° C. over 45 min. The resulting mixture was stirred at 55° C. for 30 min. then at r.t. for 1 hr. The mixture was cooled down to −5° C. To this mixture was added a solution of 4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (52.5 g, 0.216 mol) in THF (150 ml) dropwise over 40 min. And the resulting mixture was stirred at r.t. for 4 hrs. The reaction mixture was cooled down to 5° C. and saturated NH4Cl aq. (100 ml) was added carefully. The whole was diluted with H2O (600 ml) and extracted with EtOAc (400 ml+200 ml×2). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (n-hexane:EtOAc=10:1˜5:1) to give (2R)-2′,5′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (47.3 g, 81%) as pale yellow syrup. rose up to 65° C The resulting mixture was stirred at 55° C. for 30 min. The mixture was cooled down to −5° C And the resulting mixture was stirred at r.t. for 4 hrs The reaction mixture was cooled down to 5° C. extracted with EtOAc (400 ml+200 ml×2) The combined organic layer was dried over Na2SO4 concentrated in vacuo The residue was chromatographed on silica gel (n-hexane:EtOAc=10:1˜5:1)

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:52.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of magnesium (7.25 g, 0.298 mol) and iodine (catalytic amount) and 1-bromo-2,5-difluorobenzene (20.0 g, 0.178 mol) in THF (250ml ) was vigously stirred. The color of iodine was disappeared and the inner temperature rose up to 65° C. To this mixture was added additional 1-bromo-2,5-difluorobenzene (30.0 g, 0.267 mol) dropwise to maintain the inner temperature from 50 to 55° C. over 45min. The resulting mixture was stirred at 55° C. for 30min. then at r.t. for 1 hr. The mixture was cooled down to −5° C. To this mixture was added a solution of 4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (52.5 g, 0.216 mol ) in THF (150ml) dropwise over 40min. And the resulting mixture was stirred at r.t. for 4hrs. The reaction mixture was cooled down to 5° C. and saturated NH4Cl aq. (100ml) was added carefully. The whole was diluted with H2O (600ml) and extracted with EtOAc (400 ml+200 ml×2). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (n-hexane: EtOAc=10:1˜5:1) to give (2R)-2′,5′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (47.3 g, 81% ) as pale yellow syrup. rose up to 65° C The resulting mixture was stirred at 55° C. for 30min. The mixture was cooled down to −5° C And the resulting mixture was stirred at r.t. for 4hrs The reaction mixture was cooled down to 5° C. extracted with EtOAc (400 ml+200 ml×2) The combined organic layer was dried over Na2SO4 concentrated in vacuo The residue was chromatographed on silica gel (n-hexane: EtOAc=10:1˜5:1)

Conditions: temp:52.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of magnesium (7.25 g, 0.298 mol) and iodine (catalytic amount) and 1-bromo-2,5-difluorobenzene (20.0 g, 0.178 mol) in THF (250 ml) was vigorously stirred. The color of iodine was disappeared and the inner temperature rose up to 65° C. To this mixture was added additional 1-bromo-2,5-difluorobenzene (30.0 g, 0.267 mol) dropwise to maintain the inner temperature from 50 to 55° C. over 45 min. The resulting mixture was stirred at 55° C. for 30 min. then at r.t. for 1 hr. The mixture was cooled down to −5° C. To this mixture was added a solution of 4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (52.5 g, 0.216 mol) in THF (150 ml) dropwise over 40 min. And the resulting mixture was stirred at r.t. for 4 hrs. The reaction mixture was cooled down to 5° C. and saturated NH4Cl aq. (100 ml) was added carefully. The whole was diluted with H2O (600 ml) and extracted with EtOAc (400 ml+200 ml×2). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (n-hexane:EtOAc=10:1˜5:1) to give (2R)-2′,5′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (47.3 g, 81%) as pale yellow syrup. rose up to 65° C The resulting mixture was stirred at 55° C. for 30 min. The mixture was cooled down to −5° C And the resulting mixture was stirred at r.t. for 4 hrs The reaction mixture was cooled down to 5° C. extracted with EtOAc (400 ml+200 ml×2) The combined organic layer was dried over Na2SO4 concentrated in vacuo The residue was chromatographed on silica gel (n-hexane:EtOAc=10:1˜5:1)

Conditions: temp:52.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of magnesium (7.25 g, 0.298 mol) and iodine (catalytic amount) and 1-bromo-2,5-difluorobenzene (20.0 g, 0.178 mol) in THF (250 ml) was vigorously stirred. The color of iodine was disappeared and the inner temperature rose up to 65° C. To this mixture was added additional 1-bromo-2,5-difluorobenzene (30.0 g, 0.267 mol) dropwise to maintain the inner temperature from 50 to 55° C. over 45 min. The resulting mixture was stirred at 55° C. for 30 min. then at r.t. for 1 hr. The mixture was cooled down to −5° C. To this mixture was added a solution of 4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (52.5 g, 0.216 mol) in THF (150 ml) dropwise over 40 min. And the resulting mixture was stirred at r.t. for 4 hrs. The reaction mixture was cooled down to 5° C. and saturated NH4Cl aq. (100 ml) was added carefully. The whole was diluted with H2O (600 ml) and extracted with EtOAc (400 ml+200 ml×2). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (n-hexane:EtOAc=10:1˜5:1) to give (2R)-2′,5′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (47.3 g, 81%) as pale yellow syrup. rose up to 65° C The resulting mixture was stirred at 55° C. for 30 min. The mixture was cooled down to −5° C And the resulting mixture was stirred at r.t. for 4 hrs The reaction mixture was cooled down to 5° C. extracted with EtOAc (400 ml+200 ml×2) The combined organic layer was dried over Na2SO4 concentrated in vacuo The residue was chromatographed on silica gel (n-hexane:EtOAc=10:1˜5:1)

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:52.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of magnesium (7.25 g, 0.298 mol) and iodine (catalytic amount) and 1-bromo-2,5-difluorobenzene (20.0 g, 0.178 mol) in THF (250ml ) was vigously stirred. The color of iodine was disappeared and the inner temperature rose up to 65° C. To this mixture was added additional 1-bromo-2,5-difluorobenzene (30.0 g, 0.267 mol) dropwise to maintain the inner temperature from 50 to 55° C. over 45min. The resulting mixture was stirred at 55° C. for 30min. then at r.t. for 1 hr. The mixture was cooled down to −5° C. To this mixture was added a solution of 4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (52.5 g, 0.216 mol ) in THF (150ml) dropwise over 40min. And the resulting mixture was stirred at r.t. for 4hrs. The reaction mixture was cooled down to 5° C. and saturated NH4Cl aq. (100ml) was added carefully. The whole was diluted with H2O (600ml) and extracted with EtOAc (400 ml+200 ml×2). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (n-hexane: EtOAc=10:1˜5:1) to give (2R)-2′,5′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (47.3 g, 81% ) as pale yellow syrup. rose up to 65° C The resulting mixture was stirred at 55° C. for 30min. The mixture was cooled down to −5° C And the resulting mixture was stirred at r.t. for 4hrs The reaction mixture was cooled down to 5° C. extracted with EtOAc (400 ml+200 ml×2) The combined organic layer was dried over Na2SO4 concentrated in vacuo The residue was chromatographed on silica gel (n-hexane: EtOAc=10:1˜5:1)

Conditions: temp:52.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of magnesium (7.25 g, 0.298 mol) and iodine (catalytic amount) and 1-bromo-2,5-difluorobenzene (20.0 g, 0.178 mol) in THF (250ml ) was vigously stirred. The color of iodine was disappeared and the inner temperature rose up to 65° C. To this mixture was added additional 1-bromo-2,5-difluorobenzene (30.0 g, 0.267 mol) dropwise to maintain the inner temperature from 50 to 55° C. over 45min. The resulting mixture was stirred at 55° C. for 30min. then at r.t. for 1 hr. The mixture was cooled down to −5° C. To this mixture was added a solution of 4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (52.5 g, 0.216 mol ) in THF (150ml) dropwise over 40min. And the resulting mixture was stirred at r.t. for 4hrs. The reaction mixture was cooled down to 5° C. and saturated NH4Cl aq. (100ml) was added carefully. The whole was diluted with H2O (600ml) and extracted with EtOAc (400 ml+200 ml×2). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (n-hexane: EtOAc=10:1˜5:1) to give (2R)-2′,5′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (47.3 g, 81% ) as pale yellow syrup. rose up to 65° C The resulting mixture was stirred at 55° C. for 30min. The mixture was cooled down to −5° C And the resulting mixture was stirred at r.t. for 4hrs The reaction mixture was cooled down to 5° C. extracted with EtOAc (400 ml+200 ml×2) The combined organic layer was dried over Na2SO4 concentrated in vacuo The residue was chromatographed on silica gel (n-hexane: EtOAc=10:1˜5:1)

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

Procedure: In tetrahydrofuran (100 ml) were dissolved 1-bromo-2-fluorobenzene (5.6 ml), ethyl bromide (0.37 ml) and 4-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (11.3 g). To the mixture was added magnesium (turnings, 1.33 g). The mixture was stirred for 2 hours at room temperature. To the reaction mixture were added a saturated aqueous ammonium chloride solution (40 ml) and water (40 ml). The mixture was extracted with ethyl acetate (200 ml). The organic layer was washed with water, dried over magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10:1→8:1) to give (2R)-2'-fluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (8.7 g) as a pale yellow oily substance. The mixture was extracted with ethyl acetate (200 ml) The organic layer was washed with water dried over magnesium sulfate distilled under reduced pressure The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10:1→8:1)

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

Procedure: In tetrahydrofuran (100 ml) were dissolved 1-bromo-2-fluorobenzene (5.6 ml), ethyl bromide (0.37 ml) and 4-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (11.3 g). To the mixture was added magnesium (turnings, 1.33 g). The mixture was stirred for 2 hours at room temperature. To the reaction mixture were added a saturated aqueous ammonium chloride solution (40 ml) and water (40 ml). The mixture was extracted with ethyl acetate (200 ml). The organic layer was washed with water, dried over magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10:1→8:1) to give (2R)-2'-fluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (8.7 g) as a pale yellow oily substance. The mixture was extracted with ethyl acetate (200 ml) The organic layer was washed with water dried over magnesium sulfate distilled under reduced pressure The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10:1→8:1)

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

Procedure: In tetrahydrofuran (100 ml) were dissolved 1-bromo-2-fluorobenzene (5.6 ml), ethyl bromide (0.37 ml) and 4-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (11.3 g). To the mixture was added magnesium (turnings, 1.33 g). The mixture was stirred for 2 hours at room temperature. To the reaction mixture were added a saturated aqueous ammonium chloride solution (40 ml) and water (40 ml). The mixture was extracted with ethyl acetate (200 ml). The organic layer was washed with water, dried over magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10:1→8:1) to give (2R)-2'-fluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (8.7 g) as a pale yellow oily substance. The mixture was extracted with ethyl acetate (200 ml) The organic layer was washed with water dried over magnesium sulfate distilled under reduced pressure The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10:1→8:1)

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

Procedure: To a solution of 1-bromo-4-chlorobenzene (20 g) in tetrahydrofuran (260 ml) was added magnesium (turnings, 7.47 g). The mixture was vigorously stirred at room temperature. When the temperature of the mixture reached 40° C., the reaction vessel was cooled in a water bath. A solution of 1-bromo-4-chlorobenzene (38.9 g) in tetrahydrofuran (90 ml), was added dropwise to the mixture at 34°-40° C., followed by stirring for an hour at 30° C. To the mixture was added dropwise a solution of 4-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (60 g) in tetrahydrofuran (60 ml) over the period of 15 minutes at 0° C. The mixture was stirred for 3 hours at room temperature. To the reaction mixture were added a saturated aqueous ammonium chloride solution (120 ml) and water (100 ml). The mixture was extracted with ethyl acetate (500 ml). The organic layer was washed with water, dried over magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 900 g, eluent: hexane/ethyl acetate=30:1→10:1) to give (2R)-4'-chloro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (66 g) as a pale yellow oily substance. reached 40° C. the reaction vessel was cooled in a water bath by stirring for an hour at 30° C The mixture was stirred for 3 hours at room temperature The mixture was extracted with ethyl acetate (500 ml) The organic layer was washed with water dried over magnesium sulfate distilled under reduced pressure The residue was purified by silica gel column chromatography (silica gel 900 g, eluent: hexane/ethyl acetate=30:1→10:1)