N-叔丁氧羰基-顺式-4-氟-L-脯氨酸甲酯

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

实验步骤: To a stirred solution of compound obtained in step II (24.5 g, 0.1 mol) in 1,2-dichloroethane (300 mL) cooled to −10° C. was added diethylaminosulfur trifluoride (19.7 mL, 0.15 mol) over a period of 30 minutes. The reaction mixture was stirred at this temperature for 1 h then at room temperature for 16 h. The reaction mixture was quenched by adding mixture of crushed ice (300 g) and solid NaHCO3 (25.2 g, 0.3 mol). The two layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to obtain 1-tert-butyl 2-methyl (2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylate as a viscous liquid (24.7 g) in 100% yield. [α]D −53.3, (c, 1.0, CHCl3). m/z (M+1) 248; 1H NMR (CDCl3) 300 MHz δ 5.20 (ddd, J=3.8, 3.8, 49.1 Hz, 1H), 4.55 (d, J=9.5 Hz, ½H), 4.42 (d, J=8.9 Hz, ½H), 3.90-3.55 (m, 2H), 3.75 (s, 3H), 2.55-2.20 (m, 2H), 1.46 (s, 3H), 1.41 (s, 6H). at room temperature for 16 h The reaction mixture was quenched by adding The two layers were separated the aqueous layer was extracted with dichloromethane The combined organic layer was washed with brine dried over anhydrous Na2SO4 the solvent was removed under reduced pressure

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

实验步骤: The crude product of 1-tert-butyl 2-methyl (2S,4S)-4-fluoro-1,2-pyrrolidinedicarboxylate obtained in Example 7-6 (127.5 g) was dissolved in methanol (400 mL) and then 1N NaOH (800 mL) was added at room temperature.

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

实验步骤: To an aqueous solution of 2 mol/L NaOH (86 ml) was added dropwise under ice cooling a solution of 30.2 g of the compound obtained in Step 14-1 in MeOH (181 ml) under stirring over 60 minute, then the reaction mixture was stirred at room temperature for 16 hours. MeOH was evaporated under reduced pressure, to the solution was added toluene and stirred, then the aqueous layer was separated and the solution was stirred under ice cooling. To the solution was added dropwise 2 mol/L hydrochloric acid over 40 minutes, then extracted with EtOAc, the combined organic layer was washed with saturated brine, dried over Na2SO4, then, the drying agent was separated by filtration, and the solvent was evaporated under reduced pressure to obtain 25.1 g of a colorless solid. IPE (91 ml) was added, the suspension was stirred for 2 hours at room temperature, then, crystals were collected by filtration as 20.2 g of the title compound (colorless solid). The filtrate was concentrated under reduced pressure, IPE (9 ml) was added, stirred for 2 hours at room temperature, then, crystals were collected by filtration to 540 mg of the title compound (colorless solid). the reaction mixture was stirred at room temperature for 16 hours MeOH was evaporated under reduced pressure, to the solution was added toluene stirred the aqueous layer was separated the solution was stirred under ice cooling To the solution was added dropwise 2 mol/L hydrochloric acid over 40 minutes extracted with EtOAc the combined organic layer was washed with saturated brine dried over Na2SO4 the drying agent was separated by filtration the solvent was evaporated under reduced pressure

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

实验步骤: To a THF (20 mL) solution of 1-tert-butyl 2-methyl (2S,4S)-4-fluoro-1,2-pyrrolidinedicarboxylate (950 mg, 3.9 mmol) at 0° C., 5.8 mL 2M LiBH4 (11.6 mmol, 3 eq) was added slowly. The resulting mixture was left stirring overnight while allowing the temperature to warm up to room temperature. The resulting mixture was left

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

实验步骤: Methyl(2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylate (5.00 g) was dissolved in methanol (30 mL). While stirring this solution under ice cooling, 5 mol/L aqueous sodium hydroxide (12 mL) was gradually added dropwise. After stirring at room temperature for 2 hours, the reaction mixture was evaporated under reduced pressure to remove methanol. The resulting residue was washed with diethyl ether, diluted with 10% aqueous potassium bisulfate (70 mL), and then extracted with ethyl acetate. The extracted solution was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Diisopropyl ether (20 mL) was added to the resulting residue and the precipitated crystal was collected by filtration to give the titled compound (3.91 g, white powder). After stirring at room temperature for 2 hours the reaction mixture was evaporated under reduced pressure to remove methanol The resulting residue was washed with diethyl ether diluted with 10% aqueous potassium bisulfate (70 mL) extracted with ethyl acetate The extracted solution was washed with water and saturated aqueous sodium chloride dried over anhydrous sodium sulfate concentrated under reduced pressure Diisopropyl ether (20 mL) was added to the resulting 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: Methyl(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylate (4.91 g, 0.020 mol) and sodium fluoride (1.01 g, 0.024 mol) were suspended in dichloromethane (50 mL), followed by addition of Ishikawa reagent (4.35 mL, 0.024 mol) under ice cooling. The reaction mixture was slowly warmed to room temperature and then stirred for 20 hours. After the reaction, the reaction mixture was poured into ice-cold saturated aqueous sodium bicarbonate (70 mL) and then separated into organic and aqueous layers. The aqueous layer was extracted with ethyl acetate. This extracted solution was combined with the organic layer obtained above, washed sequentially with 10% aqueous potassium bisulfate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. After drying, the solvent and the decomposition product of Ishikawa reagent (N,N-diethyl-2,3,3,3-tetrafluoropropionamide) were distilled off under reduced pressure, and the residue was applied to silica gel column chromatography (developing solvent; hexane:ethyl acetate=5:1 to 0:1) to give the titled compound (4.61 g, colorless oil). After the reaction separated into organic and aqueous layers The aqueous layer was extracted with ethyl acetate obtained above, washed sequentially with 10% aqueous potassium bisulfate and saturated aqueous sodium chloride dried over anhydrous sodium sulfate After drying the solvent and the decomposition product of Ishikawa reagent (N,N-diethyl-2,3,3,3-tetrafluoropropionamide) were distilled off under reduced pressure

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

实验步骤: To a stirred solution of compound obtained in step II (24.5 g, 0.1 mol) in 1,2-dichloroethane (300 mL) cooled to −10° C. was added diethylaminosulfur trifluoride (19.7 mL, 0.15 mol) over a period of 30 minutes. The reaction mixture was stirred at this temperature for 1 h then at room temperature for 16 h. The reaction mixture was quenched by adding mixture of crushed ice (300 g) and solid NaHCO3 (25.2 g, 0.3 mol). The two layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to obtain 1-tert-butyl 2-methyl (2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylate as a viscous liquid (24.7 g) in 100% yield. [α]D −53.3, (c, 1.0, CHCl3). m/z (M+1) 248; 1H NMR (CDCl3) 300 MHz δ 5.20 (ddd, J=3.8, 3.8, 49.1 Hz, 1H), 4.55 (d, J=9.5 Hz, ½H), 4.42 (d, J=8.9 Hz, ½H), 3.90-3.55 (m, 2H), 3.75 (s, 3H), 2.55-2.20 (m, 2H), 1.46 (s, 3H), 1.41 (s, 6H). at room temperature for 16 h The reaction mixture was quenched by adding The two layers were separated the aqueous layer was extracted with dichloromethane The combined organic layer was washed with brine dried over anhydrous Na2SO4 the solvent was removed under reduced pressure

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

实验步骤: The crude product of 1-tert-butyl 2-methyl (2S,4S)-4-fluoro-1,2-pyrrolidinedicarboxylate obtained in Example 7-6 (127.5 g) was dissolved in methanol (400 mL) and then 1N NaOH (800 mL) was added at room temperature.