(3R,7AS)-四氢-3-苯基-3H,5H-吡咯并[1,2-C]噁唑-5-酮

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

实验步骤: A suspension of 148.5 g of (S)-5-hydroxymethyl-pyrrolidin-2-one in 891 mL of toluene is treated with 172.1 mL of benzaldehyde at room temperature. p-Toluenesulphonic acid (2.94 g) is added and the reaction mixture stirred at reflux for 20 hours with azeotropic removal of water. The reaction mixture is treated with 500 mL of a 5% solution of sodium hydrogen carbonate in water. The organic layer is separated and washed once with 500 mL of a 40% solution of sodium bisulphite solution followed by 2×250 mL of water. The organic layer is dried with sodium sulphate, filtered and the solvent removed to give an oil. Fractional distillation in vacuum produces pure (3R,7aS)-3-phenyl-tetrahydro-pyrrolo[1,2-c]oxazol-5-one. The organic layer is separated washed once with 500 mL of a 40% solution of sodium bisulphite solution The organic layer is dried with sodium sulphate filtered the solvent removed to give an oil Fractional distillation in vacuum

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

实验步骤: A suspension of 148.5 g of (S)-5-hydroxymethyl-pyrrolidin-2-one in 891 mL of toluene is treated with 172.1 mL of benzaldehyde at room temperature. p-Toluenesulphonic acid (2.94 g) is added and the reaction mixture stirred at reflux for 20 hours with azeotropic removal of water. The reaction mixture is treated with 500 mL of a 5% solution of sodium hydrogen carbonate in water. The organic layer is separated and washed once with 500 mL of a 40% solution of sodium bisulphite solution followed by 2×250 mL of water. The organic layer is dried with sodium sulphate, filtered and the solvent removed to give an oil. Fractional distillation in vacuum produces pure (3R,7aS)-3-phenyl-tetrahydro-pyrrolo[1,2-c]oxazol-5-one. The organic layer is separated washed once with 500 mL of a 40% solution of sodium bisulphite solution The organic layer is dried with sodium sulphate filtered the solvent removed to give an oil Fractional distillation in vacuum

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

实验步骤: To a solution of (2R, 5S)-8-oxo-2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane (50 g, 246 mmol, J. Org. Chem., 51, 3140 (1986)) in tetrahydrofuran (1500 ml), lithium diisopropylamide (2M tetrahydrofuran-heptane solution, 147.6 ml, 295.2 mmol) was dropwise added at -78° C., and the reaction solution was stirred at the same temperature for 30 minutes. A solution of (2S, 4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxyprolinal (61.0 g, 245.9 mmol) in tetrahydrofuran (400 ml) was dropwise added thereto, and the reaction solution was stirred at the same temperature for 30 minutes. Acetic acid (17.6 ml, 307.5 mmol) was dropwise added to the reaction solution. Then, the dry ice bath was removed and the reaction mixture solution was stirred for 30 minutes. To the reaction solution, ethyl acetate and 5% sodium hydrogen carbonate aqueous solution were added and the solution mixture was subjected to liquid separation and the aqueous layer was extracted with ethyl acetate. The organic layers were put together and washed with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ethyl acetate and n-hexane were added to the residue and the precipitated crystal was collected by filtration to obtain (2R, 5S)-7-[[(2S, 4R)-N-tert-butoxycarbonyl-4-(tert-butyldimethylsiloxy)pyrrolidin-2-yl](hydroxy)methyl]-8-oxo-2-phenyl-3-oxa-1azabicyclo[3.3.01octane diastereomer A (14.0 g, yield: 11.3%). The filtrate was concentrated to obtain an oily diastereomer mixture (114.7 g, yield: 87.5%). the reaction solution was stirred at the same temperature for 30 minutes Then, the dry ice bath was removed the reaction mixture solution was stirred for 30 minutes To the reaction solution, ethyl acetate and 5% sodium hydrogen carbonate aqueous solution were added the solution mixture was subjected to liquid separation the aqueous layer was extracted with ethyl acetate washed with a saturated sodium chloride aqueous solution dried over anhydrous sodium sulfate concentrated under reduced pressure Ethyl acetate and n-hexane were added to the residue the precipitated crystal was collected by filtration

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

实验步骤: Toluene (36 L, 6 vol), L-pyroglutaminol (6.0 Kg, 1.0 eq), benzaldehyde (8.3 Kg, 1.5 eq) and p-toluenesulfonic acid (134 g, 1.5% mol) were charged to a reactor. The resulting mixture was heated to reflux and the water formed during the reaction was separated out by using Dean-Stark condenser. The completion of the reaction was monitored by HPLC until L-pyroglutaminol was ≦0.1%. It was cooled to 15˜20° C., added aqueous 5% NaHCO3 (3 vol), agitated for 15 min and separated the layers. 20% aqueous NaHSO3 (6 vol) was charged to the organic phase, upon stirring for 30 min, filtered through Celite and washed the cake with toluene. Separated the organic phase (this step could be skipped if there was no solid), and filtered the organic phase through a thin pad of silica gel (1.0 wt/wt) and washed the silica gel with toluene three times. Combined the organic phase and monitored by HPLC. If impurity (RRT=1.5)>1.5%, repeated the silica gel filtration procedures until the impurity (RRT=1.5)≦1.5%. Dried the filtrate with anhydrous Na2SO4 for at least 2 hrs, filtered and washed the cake with toluene for twice. Concentrated below 55° C. (bath temp) under vacuum to afford 8.30 kg (78.6% yield) of the title compound with 94.6% HPLC purity. ESI MS m/z (M+H)+ 204.11. The resulting mixture was heated to reflux was separated out It was cooled to 15˜20° C. added aqueous 5% NaHCO3 (3 vol) separated the layers 20% aqueous NaHSO3 (6 vol) was charged to the organic phase upon stirring for 30 min filtered through Celite washed the cake with toluene Separated the organic phase (this step filtered the organic phase through a thin pad of silica gel (1.0 wt/wt) washed the silica gel with toluene three times the silica gel filtration procedures until the impurity (RRT=1.5)≦1.5% Dried the filtrate with anhydrous Na2SO4 for at least 2 hrs filtered washed the cake with toluene for twice Concentrated below 55° C. (bath temp) under vacuum

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of lithium diisopropylamide (110 mmol, 100 ml of THF, prepared from diisopropylamine (15.6 ml, 110 mmol) and n-butyl lithium (70.1 ml, 1.57M, 110 mmol)) was added (2R,5S)-2-phenyl-3-oxa-1-azabicyclo(3.3.0)octan-8-one (10.2 g, 50 mmol) under stirring at −78° C. After stirring at the same temperature for 1 hour, a solution of chloromethyl methyl ether (5.7 ml, 75 mmol) in THF (50 ml) was added to the reaction mixture and stirring was conducted further at −78° C. for 90 minutes. The reaction mixture was poured in a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (middle pressure Yamazen, linear gradient of n-hexane/ethyl acetate from 9:1 to 7:3, 30 ml/min, φ 80 mm×300 mm, range 0.08) to give (2R,5S,7S)-7-methoxymethyl-2-phenyl-3-oxa-1-azabicyclo(3.3.0)octan-8-one (1.06 g, 9%) as a colorless oil. After stirring at the same temperature for 1 hour stirring followed by extraction with ethyl acetate The extract was washed with saturated brine dried over anhydrous magnesium sulfate distilled under reduced pressure to remove the solvent The residue was purified by silica gel column chromatography (middle pressure Yamazen, linear gradient of n-hexane/ethyl acetate from 9:1 to 7:3, 30 ml/min, φ 80 mm×300 mm, range 0.08)

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

实验步骤: To a solution of (2R,5S)-2-phenyl-3-oxa-1-azabicyclo(3.3.0)octan-8-one (5.08 g, 25 mmol) in THF (30 ml), lithium diisopropylamide (a 2.0M solution in THF, 13.1 ml, 26.3 mmol) was added dropwise at −78° C. under stirring. After the reaction mixture was stirred at the same temperature for 15 minutes, methyl iodide (7.78 ml, 125 mmol) was added thereto and stirring was conducted further for 30 minutes at −40° C. The reaction mixture was poured in an ice-saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (middle pressure Yamazen, linear gradient of n-hexane/ethyl acetate form 4:1 to 1:1, 30 ml/min, φ 50 mm×300 mm, range 0.32) to give (2R,5S,7S)-7-methyl-2-phenyl-3-oxa-1-azabicyclo(3.3.0)octan-8-one (3.8 g, 70%) as a colorless oil. After the reaction mixture was stirred at the same temperature for 15 minutes stirring followed by extraction with ethyl acetate The extract was washed with saturated brine dried over anhydrous magnesium sulfate distilled under reduced pressure to remove the solvent The residue was purified by silica gel column chromatography (middle pressure Yamazen, linear gradient of n-hexane/ethyl acetate form 4:1 to 1:1, 30 ml/min, φ 50 mm×300 mm, range 0.32)

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

实验步骤: A suspension of 148.5 g of (S)-5-hydroxymethyl-pyrrolidin-2-one in 891 mL of toluene is treated with 172.1 mL of benzaldehyde at room temperature. p-Toluenesulphonic acid (2.94 g) is added and the reaction mixture stirred at reflux for 20 hours with azeotropic removal of water. The reaction mixture is treated with 500 mL of a 5% solution of sodium hydrogen carbonate in water. The organic layer is separated and washed once with 500 mL of a 40% solution of sodium bisulphite solution followed by 2×250 mL of water. The organic layer is dried with sodium sulphate, filtered and the solvent removed to give an oil. Fractional distillation in vacuum produces pure (3R,7aS)-3-phenyl-tetrahydro-pyrrolo[1,2-c]oxazol-5-one. The organic layer is separated washed once with 500 mL of a 40% solution of sodium bisulphite solution The organic layer is dried with sodium sulphate filtered the solvent removed to give an oil Fractional distillation in vacuum

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

实验步骤: A suspension of 148.5 g of (S)-5-hydroxymethyl-pyrrolidin-2-one in 891 mL of toluene is treated with 172.1 mL of benzaldehyde at room temperature. p-Toluenesulphonic acid (2.94 g) is added and the reaction mixture stirred at reflux for 20 hours with azeotropic removal of water. The reaction mixture is treated with 500 mL of a 5% solution of sodium hydrogen carbonate in water. The organic layer is separated and washed once with 500 mL of a 40% solution of sodium bisulphite solution followed by 2×250 mL of water. The organic layer is dried with sodium sulphate, filtered and the solvent removed to give an oil. Fractional distillation in vacuum produces pure (3R,7aS)-3-phenyl-tetrahydro-pyrrolo[1,2-c]oxazol-5-one. The organic layer is separated washed once with 500 mL of a 40% solution of sodium bisulphite solution The organic layer is dried with sodium sulphate filtered the solvent removed to give an oil Fractional distillation in vacuum