帕瑞昔布杂质20

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: A solution of deoxybenzoin (407.4 g, 2.076 mol) in 2 L of absolute ethanol and 600 mL of water was treated with hydroxylamine hydrochloride (288 g, 4.15 mol) and sodium acetate trihydrate (564 g, 4.15 mol). The solution was then warmed to reflux for 2 hours. The reaction mixture was then diluted with 1000 mL of 30% aqueous ethanol and allowed to cool to room temperature whereupon crystals of pure oxime formed which were isolated by filtration and air dried to afford 415.4 g, 95%, mp 94°-96° C. of pure deoxybenzoin oxime. The solution was then warmed to reflux for 2 hours formed which were isolated by filtration and air dried

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

实验步骤: A suspension of the above oxime (5.0 g, 24 mmol), 1,2-dibromoethane (25 ml) and potassium carbonate (10.0 g, 72 mmol) in acetone (25 ml) was heated at reflux for 1 h, then stirred at ambient temperature for 72 h and finally heated at reflux for 4.5 h. Potassium iodide (0.5 g) was added and refluxing continued for an additional 16 h. Water (100 ml) was added and the resulting mixture extracted with dichloromethane (2×100 ml). The combined organic phases were washed with water (100 ml) and brine (10 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel (60 g, n-heptane/ethyl acetate 10/1) to give 3.6 g of 1,2-diphenylethanone O-(2-bromoethyl)oxime. was heated at reflux for 1 h finally heated at reflux for 4.5 h refluxing continued for an additional 16 h the resulting mixture extracted with dichloromethane (2×100 ml) The combined organic phases were washed with water (100 ml) and brine (10 ml) dried (MgSO4) The solvent was evaporated in vacuo the residue was purified by column chromatography on silica gel (60 g, n-heptane/ethyl acetate 10/1)

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

实验步骤: A suspension of the above oxime (5.0 g, 24 mmol), 1,2-dibromoethane (25 ml) and potassium carbonate (10.0 g, 72 mmol) in acetone (25 ml) was heated at reflux for 1 h, then stirred at ambient temperature for 72 h and finally heated at reflux for 4.5 h. Potassium iodide (0.5 g) was added and refluxing continued for an additional 16 h. Water (100 ml) was added and the resulting mixture extracted with dichloromethane (2×100 ml). The combined organic phases were washed with water (100 ml) and brine (10 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel (60 g, n-heptane/ethyl acetate 10/1) to give 3.6 g of 1,2-diphenylethanone O-(2-bromoethyl)oxime. was heated at reflux for 1 h finally heated at reflux for 4.5 h refluxing continued for an additional 16 h the resulting mixture extracted with dichloromethane (2×100 ml) The combined organic phases were washed with water (100 ml) and brine (10 ml) dried (MgSO4) The solvent was evaporated in vacuo the residue was purified by column chromatography on silica gel (60 g, n-heptane/ethyl acetate 10/1)

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

实验步骤: A mixture of 1,2-diphenylethanone (19.6 g, 100 mmol) and hydroxyl ammonium chloride (13.9 g, 200 mmol) in absolute ethanol (200 ml) was heated at reflux for 4 h. The solvent was evaporated in vacuo and the residue extracted with dichloromethane (2×100 ml). The combined organic phases were washed with water (2×50 ml) and brine (10 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the residue left for crystallisation. The crystallised product was suspended in n-heptane/diethylether 20/1 and the precipitate collected to give 5.1 g of 1,2-diphenylethanone oxime. was heated at reflux for 4 h The solvent was evaporated in vacuo the residue extracted with dichloromethane (2×100 ml) The combined organic phases were washed with water (2×50 ml) and brine (10 ml) dried (MgSO4) The solvent was evaporated in vacuo the residue left for crystallisation the precipitate collected

反应条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The deoxybenzoin oxime (Step 1) was dissolved in anhydrous THF (565 mL) under a nitrogen atmosphere. The solution was cooled to −20° C. The solution was treated with lithium diisopropylamide (2 M, 800 mL, 1.60 mol) while allowing the reaction temperature to warm to 10-15° C. The reaction mixture to was cooled to −10° C. to −20° C. and anhydrous ethyl acetate (218 mL) was added to the solution while allowing the reaction temperature to rise to a maximum of 25° C. and held for 30 minutes at 25° C. The reaction mixture was cooled to about 0° C. Water was added to a quench flask and cooled to 0-5° C. The pre-cooled reaction mixture was transferred from the reaction flask to the quench flask while maintaining the temperature of the quench mixture below 25° C. The quenched mixture was cooled to 0-5° C. Hydrochloric acid (12 M) was added to the mixture, keeping the temperature below 25° C. during the addition by controlling the addition rate and stirred until all the solids dissolve (˜5 minutes). The pH of the stirred mixture was measured to be pH 3-4. The layers were separated and the organic layer was removed. Heptane was added to the organic layer with stirring. The organic layer was distilled until the pot temperature reached 90-91° C. The solution was cooled to 5° C. and filtered. The solid was washed with two 300 mL portions of ethyl acetate-heptane (20/80), cooled to 5° C. The solid product was dried on the funnel for several hours then dried at ambient under vacuum with a nitrogen sweep over the weekend to yield the isoxazoline (108.75 g, 57.7%). to warm to 10-15° C The reaction mixture to was cooled to −10° C. to −20° C. to rise to a maximum of 25° C. The reaction mixture was cooled to about 0° C cooled to 0-5° C The pre-cooled reaction mixture while maintaining the temperature of the quench mixture below 25° C The quenched mixture was cooled to 0-5° C the temperature below 25° C. during the addition dissolve (˜5 minutes) The layers were separated the organic layer was removed Heptane was added to the organic layer with stirring The organic layer was distilled until the pot temperature reached 90-91° C The solution was cooled to 5° C. filtered The solid was washed with two 300 mL portions of ethyl acetate-heptane (20/80) cooled to 5° C The solid product was dried on the funnel for several hours then dried at ambient under vacuum with a nitrogen sweep over the weekend

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

实验步骤: A solution of deoxybenzoin (407.4 g, 2.076 mol) in 2 L of absolute ethanol and 600 mL of water was treated with hydroxylamine hydrochloride (288 g, 4.15 mol) and sodium acetate trihydrate (564 g, 4.15 mol). The solution was then warmed to reflux for 2 hours. The reaction mixture was then diluted with 1000 mL of 30% aqueous ethanol and allowed to cool to room temperature whereupon crystals of pure oxime formed which were isolated by filtration and air dried to afford 415.4 g, 95%, mp 94°-96° C. of pure deoxybenzoin oxime. The solution was then warmed to reflux for 2 hours formed which were isolated by filtration and air dried

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: A suspension of the above oxime (5.0 g, 24 mmol), 1,2-dibromoethane (25 ml) and potassium carbonate (10.0 g, 72 mmol) in acetone (25 ml) was heated at reflux for 1 h, then stirred at ambient temperature for 72 h and finally heated at reflux for 4.5 h. Potassium iodide (0.5 g) was added and refluxing continued for an additional 16 h. Water (100 ml) was added and the resulting mixture extracted with dichloromethane (2×100 ml). The combined organic phases were washed with water (100 ml) and brine (10 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel (60 g, n-heptane/ethyl acetate 10/1) to give 3.6 g of 1,2-diphenylethanone O-(2-bromoethyl)oxime. was heated at reflux for 1 h finally heated at reflux for 4.5 h refluxing continued for an additional 16 h the resulting mixture extracted with dichloromethane (2×100 ml) The combined organic phases were washed with water (100 ml) and brine (10 ml) dried (MgSO4) The solvent was evaporated in vacuo the residue was purified by column chromatography on silica gel (60 g, n-heptane/ethyl acetate 10/1)

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

实验步骤: A mixture of 1,2-diphenylethanone (19.6 g, 100 mmol) and hydroxyl ammonium chloride (13.9 g, 200 mmol) in absolute ethanol (200 ml) was heated at reflux for 4 h. The solvent was evaporated in vacuo and the residue extracted with dichloromethane (2×100 ml). The combined organic phases were washed with water (2×50 ml) and brine (10 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the residue left for crystallisation. The crystallised product was suspended in n-heptane/diethylether 20/1 and the precipitate collected to give 5.1 g of 1,2-diphenylethanone oxime. was heated at reflux for 4 h The solvent was evaporated in vacuo the residue extracted with dichloromethane (2×100 ml) The combined organic phases were washed with water (2×50 ml) and brine (10 ml) dried (MgSO4) The solvent was evaporated in vacuo the residue left for crystallisation the precipitate collected

反应条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The deoxybenzoin oxime (Step 1) was dissolved in anhydrous THF (565 mL) under a nitrogen atmosphere. The solution was cooled to −20° C. The solution was treated with lithium diisopropylamide (2 M, 800 mL, 1.60 mol) while allowing the reaction temperature to warm to 10-15° C. The reaction mixture to was cooled to −10° C. to −20° C. and anhydrous ethyl acetate (218 mL) was added to the solution while allowing the reaction temperature to rise to a maximum of 25° C. and held for 30 minutes at 25° C. The reaction mixture was cooled to about 0° C. Water was added to a quench flask and cooled to 0-5° C. The pre-cooled reaction mixture was transferred from the reaction flask to the quench flask while maintaining the temperature of the quench mixture below 25° C. The quenched mixture was cooled to 0-5° C. Hydrochloric acid (12 M) was added to the mixture, keeping the temperature below 25° C. during the addition by controlling the addition rate and stirred until all the solids dissolve (˜5 minutes). The pH of the stirred mixture was measured to be pH 3-4. The layers were separated and the organic layer was removed. Heptane was added to the organic layer with stirring. The organic layer was distilled until the pot temperature reached 90-91° C. The solution was cooled to 5° C. and filtered. The solid was washed with two 300 mL portions of ethyl acetate-heptane (20/80), cooled to 5° C. The solid product was dried on the funnel for several hours then dried at ambient under vacuum with a nitrogen sweep over the weekend to yield the isoxazoline (108.75 g, 57.7%). to warm to 10-15° C The reaction mixture to was cooled to −10° C. to −20° C. to rise to a maximum of 25° C. The reaction mixture was cooled to about 0° C cooled to 0-5° C The pre-cooled reaction mixture while maintaining the temperature of the quench mixture below 25° C The quenched mixture was cooled to 0-5° C the temperature below 25° C. during the addition dissolve (˜5 minutes) The layers were separated the organic layer was removed Heptane was added to the organic layer with stirring The organic layer was distilled until the pot temperature reached 90-91° C The solution was cooled to 5° C. filtered The solid was washed with two 300 mL portions of ethyl acetate-heptane (20/80) cooled to 5° C The solid product was dried on the funnel for several hours then dried at ambient under vacuum with a nitrogen sweep over the weekend

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

实验步骤: A solution of deoxybenzoin (407.4 g, 2.076 mol) in 2 L of absolute ethanol and 600 mL of water was treated with hydroxylamine hydrochloride (288 g, 4.15 mol) and sodium acetate trihydrate (564 g, 4.15 mol). The solution was then warmed to reflux for 2 hours. The reaction mixture was then diluted with 1000 mL of 30% aqueous ethanol and allowed to cool to room temperature whereupon crystals of pure oxime formed which were isolated by filtration and air dried to afford 415.4 g, 95%, mp 94°-96° C. of pure deoxybenzoin oxime. The solution was then warmed to reflux for 2 hours formed which were isolated by filtration and air dried