(2S,4R)-2-(二甲基氨基甲酰基)-4-羟基吡咯烷-1-羧酸叔丁酯

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

实验步骤: 3.84 ml of triethylamine was added, at -15° to -20° C., to a solution of 5.8 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid dissolved in 85 ml of dry tetrahydrofuran, and then a solution of 2.63 ml of ethyl chloroformate in 25 ml of dry tetrahydrofuran was added to the resulting mixture at the same temperature. The reaction mixture was then stirred for 2 hours, after which 19.75 ml of 50% by volume aqueous dimethylamine was added to it at -20° to -25° C. The mixture was then stirred for 3 hours under ice cooling, after which it was allowed to stand overnight at room temperature. At the end of this time, the mixture was poured into a mixture of 30 ml of concentrated hydrochloric acid and ice and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluted with a 9:1 by volume mixture of ethyl acetate and methanol) to afford 429 mg of the title compound. The mixture was then stirred for 3 hours under ice cooling to stand overnight at room temperature extracted with ethyl acetate The extract was washed with an aqueous solution of sodium chloride dried The solvent was then removed by distillation under reduced pressure the residue was purified by column chromatography through silica gel ( eluted with a 9:1 by volume mixture of ethyl acetate and methanol)

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

实验步骤: 3.84 ml of triethylamine was added, at -15° to -20° C., to a solution of 5.8 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid dissolved in 85 ml of dry tetrahydrofuran, and then a solution of 2.63 ml of ethyl chloroformate in 25 ml of dry tetrahydrofuran was added to the resulting mixture at the same temperature. The reaction mixture was then stirred for 2 hours, after which 19.75 ml of 50% by volume aqueous dimethylamine was added to it at -20° to -25° C. The mixture was then stirred for 3 hours under ice cooling, after which it was allowed to stand overnight at room temperature. At the end of this time, the mixture was poured into a mixture of 30 ml of concentrated hydrochloric acid and ice and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluted with a 9:1 by volume mixture of ethyl acetate and methanol) to afford 429 mg of the title compound. The mixture was then stirred for 3 hours under ice cooling to stand overnight at room temperature extracted with ethyl acetate The extract was washed with an aqueous solution of sodium chloride dried The solvent was then removed by distillation under reduced pressure the residue was purified by column chromatography through silica gel ( eluted with a 9:1 by volume mixture of ethyl acetate and methanol)

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

实验步骤: 26.6 g of a mixture (approximately 3:1) of 1,1,2,3,3,3-hexafluoro-1-(diethylamino)propane and 1,2,3,3,3-pentafluoro-1-(diethylamino)-2-propene was added dropwise over a period of 10 minutes under ice cooling to a suspension of 25.7 g of the compound obtained in step 1-1a and 5.00 g of sodium fluoride in 260 mL of dichloromethane, after which the reaction mixture was stirred for 16 hours at room temperature. 100 mL of a 5% potassium carbonate aqueous solution was added under ice cooling to the reaction solution, and the reaction mixture was stirred for 30 minutes at the same temperature. After liquid separation, the aqueous layer thus obtained was extracted with chloroform, and the combined organic layer was washed with 50 mL of saturated brine and dried with magnesium sulfate, after which the drying agent was filtered off and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to column chromatography (silica gel 60, mobile phase: ethyl acetate/n-hexane=1/1 to 10/0; v/v) to obtain 12.2 g of the titled compound (pale yellow solid). the reaction mixture was stirred for 30 minutes at the same temperature After liquid separation the aqueous layer thus obtained was extracted with chloroform the combined organic layer was washed with 50 mL of saturated brine dried with magnesium sulfate after which the drying agent was filtered off the solvent was distilled off under reduced pressure The residue thus obtained

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

实验步骤: 26.6 g of a mixture (approximately 3:1) of 1,1,2,3,3,3-hexafluoro-1-(diethylamino)propane and 1,2,3,3,3-pentafluoro-1-(diethylamino)-2-propene was added dropwise over a period of 10 minutes under ice cooling to a suspension of 25.7 g of the compound obtained in step 1-1a and 5.00 g of sodium fluoride in 260 mL of dichloromethane, after which the reaction mixture was stirred for 16 hours at room temperature. 100 mL of a 5% potassium carbonate aqueous solution was added under ice cooling to the reaction solution, and the reaction mixture was stirred for 30 minutes at the same temperature. After liquid separation, the aqueous layer thus obtained was extracted with chloroform, and the combined organic layer was washed with 50 mL of saturated brine and dried with magnesium sulfate, after which the drying agent was filtered off and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to column chromatography (silica gel 60, mobile phase: ethyl acetate/n-hexane=1/1 to 10/0; v/v) to obtain 12.2 g of the titled compound (pale yellow solid). the reaction mixture was stirred for 30 minutes at the same temperature After liquid separation the aqueous layer thus obtained was extracted with chloroform the combined organic layer was washed with 50 mL of saturated brine dried with magnesium sulfate after which the drying agent was filtered off the solvent was distilled off under reduced pressure The residue thus obtained

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

实验步骤: 24.9 g of 1-hydroxybenzotriazole monohydrate and 24.9 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added under ice cooling to a 250 mL tetrahydrofuran solution of 25.1 g of (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline and stirred for 15 minutes. 10.7 g of a 50% dimethylamine aqueous solution was added dropwise over a period of 10 minutes to the reaction mixture, and the reaction mixture was stirred for 15 hours at room temperature. The solvent was distilled off under reduced pressure, after which 100 mL of a saturated sodium hydrogencarbonate aqueous solution was added and extraction was performed with chloroform (50 mL×2). The extract was dried with anhydrous sodium sulfate, the drying agent was filtered off, and the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60N, mobile phase: chloroform/methanol=20/1 to 9/1; v/v) to obtain 26.2 g of the titled compound (colorless solid). the reaction mixture was stirred for 15 hours at room temperature The solvent was distilled off under reduced pressure after which 100 mL of a saturated sodium hydrogencarbonate aqueous solution was added extraction The extract was dried with anhydrous sodium sulfate the drying agent was filtered off the reaction mixture was concentrated under reduced pressure The residue was purified by column chromatography (silica gel 60N, mobile phase: chloroform/methanol=20/1 to 9/1; v/v)

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

实验步骤: 3.84 ml of triethylamine was added, at -15° to -20° C., to a solution of 5.8 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid dissolved in 85 ml of dry tetrahydrofuran, and then a solution of 2.63 ml of ethyl chloroformate in 25 ml of dry tetrahydrofuran was added to the resulting mixture at the same temperature. The reaction mixture was then stirred for 2 hours, after which 19.75 ml of 50% by volume aqueous dimethylamine was added to it at -20° to -25° C. The mixture was then stirred for 3 hours under ice cooling, after which is was allowed to stand overnight at room temperature. At the end of this time, the mixture was poured into a mixture of 30 ml of concentrated hydrochloric acid and ice and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluted with a 9:1 by volume mixture of ethyl acetate and methanol) to afford 429 mg of the title compound. The mixture was then stirred for 3 hours under ice cooling to stand overnight at room temperature extracted with ethyl acetate The extract was washed with an aqueous solution of sodium chloride dried The solvent was then removed by distillation under reduced pressure the residue was purified by column chromatography through silica gel ( eluted with a 9:1 by volume mixture of ethyl acetate and methanol)

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

实验步骤: 3.84 ml of triethylamine was added, at -15° to -20° C., to a solution of 5.8 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid dissolved in 85 ml of dry tetrahydrofuran, and then a solution of 2.63 ml of ethyl chloroformate in 25 ml of dry tetrahydrofuran was added to the resulting mixture at the same temperature. The reaction mixture was then stirred for 2 hours, after which 19.75 ml of 50% by volume aqueous dimethylamine was added to it at -20° to -25° C. The mixture was then stirred for 3 hours under ice cooling, after which is was allowed to stand overnight at room temperature. At the end of this time, the mixture was poured into a mixture of 30 ml of concentrated hydrochloric acid and ice and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluted with a 9:1 by volume mixture of ethyl acetate and methanol) to afford 429 mg of the title compound. The mixture was then stirred for 3 hours under ice cooling to stand overnight at room temperature extracted with ethyl acetate The extract was washed with an aqueous solution of sodium chloride dried The solvent was then removed by distillation under reduced pressure the residue was purified by column chromatography through silica gel ( eluted with a 9:1 by volume mixture of ethyl acetate and methanol)

反应条件: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-Nitrobenzenesulfonyl chloride (0.895 g) was added to a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-(N,N-dimethylcarbamoyl)pyrrolidine (0.993 g) and pyridine (0.6 g) in methylene chloride (10 ml) and stirred at 4° C. for 16 hours under an atmosphere of nitrogen. The reaction mixture was washed with aqueous citric acid (1.0 M), saturated sodium bicarbonate and dried over magnesium sulfate. The product was then purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the required product were combined and evaporated under vacuum to give (2S,4R)-1-(tert-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)-4-[(4-nitrophenyl)sulfonyloxy]pyrrolidine as a yellow gum (0.685 g); 1H NMR Spectrum: (DMSO d6) 1.30-1.36 (s, 9H), 1.98-2.07 (m, 1H); 2.37-2.48 (m, 1H); 2.83 (s, 3H), 3.00 (s, 3H), 3.45-3.55 (m, 2H), 4.70 (m, 1H), 5.23 (m, 1H), 8.21 (d, 2H), 8.47 (d, 2H). The reaction mixture was washed with aqueous citric acid (1.0 M), saturated sodium bicarbonate dried over magnesium sulfate The product was then purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5) The fractions containing the required product evaporated under vacuum

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

实验步骤: 1-[3-(Dimethylamino)propyl]-3-ethylearbodiimide hydrochloride (2.48 g) was added to a stirred suspension of N-tert-butoxycarbonyl-L-hydroxyproline (2.0 g), 4-(dimethylamino)pyridine (5.28 g) and dimethylamine hydrochloride (1.4 g) in methylene chloride (100 ml) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with citric acid (1.0 M), saturated sodium bicarbonate and saturated brine before drying over magnesium sulfate. The product was then purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10). The fractions containing the expected product were combined and evaporated under vacuum to give (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-(N,N-dimethylcarbamoyl)pyrrolidine as a colourless gum (1.01 g); 1H NMR Spectrum: (DMSO d6) 1.29-1.40 (m, 9H), 1.74-1.83 (m, 1H), 2.04-2.15 (m, 1H), 2.80-2.87 (m, 3H), 3.03 (s, 3H), 3.26 (m, 1H), 3.40 (m, 1H), 4.28 (m, 1H), 4.64 (m, 1H), 4.95 (d, 1H). The reaction mixture was washed with citric acid (1.0 M), saturated sodium bicarbonate and saturated brine before drying over magnesium sulfate The product was then purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10) The fractions containing the expected product evaporated under vacuum

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 9.6 g of tert-butyl (2S,4R)-2-[(dimethylamino)carbonyl]-4-hydroxypyrrolidine-1-carboxylate in THF (100 ml) was added 937 mg of NaH and the reaction mixture was stirred at 60° C. for one hour. After returning to room temperature, 12.5 g of allyl iodide was added to the reaction solution, and the reaction mixture was refluxed for one hour. To the reaction solution was added water and the resulting mixture was extracted with EtOAc, then was washed with saturated brine. The organic layer was dried over Na2SO4, then the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: CHCl3/MeOH=18/1 to 9/1; v/v) to obtain 6.70 g of the title compound (light brown oil). After returning to room temperature the reaction mixture was refluxed for one hour the resulting mixture was extracted with EtOAc was washed with saturated brine The organic layer was dried over Na2SO4 the drying agent was separated by filtration the solvent was evaporated under reduced pressure The obtained residue was purified by column chromatography (silicagel 60; mobile phase: CHCl3/MeOH=18/1 to 9/1; v/v)

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

实验步骤: To a solution of 11.0 g of the compound obtained in Step 88-1 in EtOAc (100 ml) was added dropwise a solution of 4 mol/l hydrochloric acid in EtOAc (100 ml) over 20 minutes. The solution was stirred at room temperature for two hours and then the solvent was evaporated under reduced pressure. EtOAc was added, and the solution was stirred for 30 minutes. Thereafter, the precipitated solid was filtered and then dried to obtain 8.21 g of the title compound (colorless solid). the solvent was evaporated under reduced pressure EtOAc was added the solution was stirred for 30 minutes Thereafter, the precipitated solid was filtered dried

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

实验步骤: 3.84 ml of triethylamine was added, at -15° to -20° C., to a solution of 5.8 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid dissolved in 85 ml of dry tetrahydrofuran, and then a solution of 2.63 ml of ethyl chloroformate in 25 ml of dry tetrahydrofuran was added to the resulting mixture at the same temperature. The reaction mixture was then stirred for 2 hours, after which 19.75 ml of 50% by volume aqueous dimethylamine was added to it at -20° to -25° C. The mixture was then stirred for 3 hours under ice cooling, after which is was allowed to stand overnight at room temperature. At the end of this time, the mixture was poured into a mixture of 30 ml of concentrated hydrochloric acid and ice and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluted with a 9:1 by volume mixture of ethyl acetate and methanol) to afford 429 mg of the title compound. The mixture was then stirred for 3 hours under ice cooling to stand overnight at room temperature extracted with ethyl acetate The extract was washed with an aqueous solution of sodium chloride dried The solvent was then removed by distillation under reduced pressure the residue was purified by column chromatography through silica gel ( eluted with a 9:1 by volume mixture of ethyl acetate and methanol)