tert-butyl (2S,4R)-2-cyano-4-hydroxypyrrolidine-1-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 6.40 g (30 mmol) of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-pyrrolidine-2-carbonitrile was dissolved in 100 ml of acetonitrile and 8.56 g (45 mmol) of 4-methylbenzenesulphonic acid monohydrate was added to the solution. The mixture was stirred at room temperature for 24 hours and was evaporated under reduced pressure. 500 ml of diethyl ether was added to the resulting brown oil. It was stirred 10 minutes and kept in the refrigerator for a night. The resulting white crystalline material was filtered off and washed with diethyl ether. 6.31 g (73%) of the above product are obtained. M.p.: 110-113° C. was evaporated under reduced pressure 500 ml of diethyl ether was added to the resulting brown oil It was stirred 10 minutes kept in the refrigerator for a night The resulting white crystalline material was filtered off washed with diethyl ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 6.40 g (30 mmol) of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-pyrrolidine-2-carbonitrile was dissolved in 100 ml of acetonitrile and 8.56 g (45 mmol) of 4-methylbenzenesulphonic acid monohydrate was added to the solution. The mixture was stirred at room temperature for 24 hours and was evaporated under reduced pressure. 500 ml of diethyl ether was added to the resulting brown oil. It was stirred 10 minutes and kept in the refrigerator for a night. The resulting white crystalline material was filtered off and washed with diethyl ether. 6.31 g (73%) of the above product are obtained. M.p.: 110-113° C. was evaporated under reduced pressure 500 ml of diethyl ether was added to the resulting brown oil It was stirred 10 minutes kept in the refrigerator for a night The resulting white crystalline material was filtered off washed with diethyl ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 7.82 g (34 mmol) of tert-butyl (2S,4R)-2-(aminocarbonyl)-4-hydroxypyrrolidine-1-carboxylate was dissolved in 80 ml of pyridine and 12 ml (84 mmol) of trifluoroacetic anhydride was added to the solution dropwise, at −20 C□. The mixture was stirred at room temperature for a day. The excess of anhydride was hydrolised by addition of some drops of water. To this mixture 200 ml of ethyl acetate was added and it was washed with 10% aqueous hydrogen chloride (to pH 3-5), 50 ml 2 N solution of sodium hydroxide and 50 ml brine. The organic solution was dried over sodium sulphate and evaporated to result in an oil. Yield: 5.35 g (74%). (MH30)=213, (MH+)2=426. it was washed with 10% aqueous hydrogen chloride (to pH 3-5), 50 ml 2 N solution of sodium hydroxide and 50 ml brine The organic solution was dried over sodium sulphate evaporated to result in an oil

反応条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (2S,4R)-tert-Butyl 2-cyano-4-hydroxypyrrolidine-1-carboxylate 13d (49.7 g, 0.2344 mol) was dissolved in 1130 mL of dichloromethane with stirring under argon atmosphere. The mixture was cooled to −30° C. followed by addition of diethylaminosulfur trifluoride (56.7 g, 0.3516 mol). After stirred for 45 minutes, the reaction mixture was warmed up to −5° C. Then the mixture was reacted overnight at room temperature. The reaction was monitored by TLC until the disappearance of the starting materials. The reaction mixture was neutralized with saturated aqueous sodium carbonate solution to pH>7 at such a rate that the reaction temperature was kept below 20° C. Then ice water and 500 mL of dichloromethane were added. The separated organic phase was washed with 500 mL of saturated aqueous sodium hydrogen sulfate and 500 mL of saturated brine successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure in which the concentration temperature was kept below 38° C. to obtain the title compound (2S,4S)-tert-butyl 2-cyano-4-fluoropyrrolidine-1-carboxylate 13e (50 g, yield 100%) as a light yellow solid. After stirred for 45 minutes the reaction mixture was warmed up to −5° C Then the mixture was reacted overnight at room temperature was kept below 20° C The separated organic phase was washed with 500 mL of saturated aqueous sodium hydrogen sulfate and 500 mL of saturated brine successively dried over anhydrous sodium sulfate filtered concentrated under reduced pressure in which the concentration temperature was kept below 38° C.

反応条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (2S,4R)-tert-Butyl 2-carbamoyl-4-hydroxypyrrolidine-1-carboxylate 13c (74 g, 0.3217 mol) was dissolved in 740 mL of pyridine with stirring under argon atmosphere. The mixture was cooled to −20° C. followed by dropwise addition of trifluoroacetic anhydride (169 g, 0.804 mol). Upon completion of the addition, the reaction mixture was warmed up to room temperature. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was quenched with water and diluted with 0.8 L of ethyl acetate. The separated organic phase was washed with 500 mL of saturated brine and neutralized with 400 mL of concentrated hydrochloric acid to slight acidity. The resulting mixture was washed with 300 mL of aqueous sodium hydroxide solution (2 M) and 500 mL saturated brine successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (2S,4R)-tert-butyl 2-cyano-4-hydroxypyrrolidine-1-carboxylate 13d (49.7 g, yield 73%) as a brown oil. Upon completion of the addition the reaction mixture was warmed up to room temperature The mixture was quenched with water diluted with 0.8 L of ethyl acetate The separated organic phase was washed with 500 mL of saturated brine and neutralized with 400 mL of concentrated hydrochloric acid to slight acidity The resulting mixture was washed with 300 mL of aqueous sodium hydroxide solution (2 M) and 500 mL saturated brine successively dried over anhydrous sodium sulfate filtered concentrated under reduced pressure

反応条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (2S,4R)-tert-Butyl 2-cyano-4-hydroxypyrrolidine-1-carboxylate 13d (49.7 g, 0.2344 mol) was dissolved in 1130 mL of dichloromethane with stirring under argon atmosphere. The mixture was cooled to −30° C. followed by addition of diethylaminosulfur trifluoride (56.7 g, 0.3516 mol). After stirred for 45 minutes, the reaction mixture was warmed up to −5° C. Then the mixture was reacted overnight at room temperature. The reaction was monitored by TLC until the disappearance of the starting materials. The reaction mixture was neutralized with saturated aqueous sodium carbonate solution to pH >7 at such a rate that the reaction temperature was kept below 20° C. Then ice water and 500 mL of dichloromethane were added. The separated organic phase was washed with 500 mL of saturated aqueous sodium hydrogen sulfate and 500 mL of saturated brine successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure in which the concentration temperature was kept below 38° C. to obtain the title compound (2S,4S)-tent-butyl 2-cyano-4-fluoropyrrolidine-1-carboxylate 13e (50 g, yield 100%) as a light yellow solid. After stirred for 45 minutes the reaction mixture was warmed up to −5° C Then the mixture was reacted overnight at room temperature was kept below 20° C The separated organic phase was washed with 500 mL of saturated aqueous sodium hydrogen sulfate and 500 mL of saturated brine successively dried over anhydrous sodium sulfate filtered concentrated under reduced pressure in which the concentration temperature was kept below 38° C.

反応条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (2S,4R)-tert-Butyl 2-carbamoyl-4-hydroxypyrrolidine-1-carboxylate 13c (74 g, 0.3217 mol) was dissolved in 740 mL of pyridine with stirring under argon atmosphere. The mixture was cooled to −20° C. followed by dropwise addition of trifluoroacetic anhydride (169 g, 0.804 mol). Upon completion of the addition, the reaction mixture was warmed up to room temperature. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was quenched with water and diluted with 0.8 L of ethyl acetate. The separated organic phase was washed with 500 mL of saturated brine and neutralized with 400 mL of concentrated hydrochloric acid to slight acidity. The resulting mixture was washed with 300 mL of aqueous sodium hydroxide solution (2 M) and 500 mL saturated brine successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (2S,4R)-tert-butyl 2-cyano-4-hydroxypyrrolidine-1-carboxylate 13d (49.7 g, yield 73%) as a brown oil. Upon completion of the addition the reaction mixture was warmed up to room temperature The mixture was quenched with water diluted with 0.8 L of ethyl acetate The separated organic phase was washed with 500 mL of saturated brine and neutralized with 400 mL of concentrated hydrochloric acid to slight acidity The resulting mixture was washed with 300 mL of aqueous sodium hydroxide solution (2 M) and 500 mL saturated brine successively dried over anhydrous sodium sulfate filtered concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 6.40 g (30 mmol) of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-pyrrolidine-2-carbonitrile was dissolved in 100 ml of acetonitrile and 8.56 g (45 mmol) of 4-methylbenzenesulphonic acid monohydrate was added to the solution. The mixture was stirred at room temperature for 24 hours and was evaporated under reduced pressure. 500 ml of diethyl ether was added to the resulting brown oil. It was stirred 10 minutes and kept in the refrigerator for a night. The resulting white crystalline material was filtered off and washed with diethyl ether. 6.31 g (73%) of the above product are obtained. M.p.: 110-113° C. was evaporated under reduced pressure 500 ml of diethyl ether was added to the resulting brown oil It was stirred 10 minutes kept in the refrigerator for a night The resulting white crystalline material was filtered off washed with diethyl ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 7.82 g (34 mmol) of tert-butyl (2S,4R)-2-(aminocarbonyl)-4-hydroxypyrrolidine-1-carboxylate was dissolved in 80 ml of pyridine and 12 ml (84 mmol) of trifluoroacetic anhydride was added to the solution dropwise, at −20 C□. The mixture was stirred at room temperature for a day. The excess of anhydride was hydrolised by addition of some drops of water. To this mixture 200 ml of ethyl acetate was added and it was washed with 10% aqueous hydrogen chloride (to pH 3-5), 50 ml 2 N solution of sodium hydroxide and 50 ml brine. The organic solution was dried over sodium sulphate and evaporated to result in an oil. Yield: 5.35 g (74%). (MH30)=213, (MH+)2=426. it was washed with 10% aqueous hydrogen chloride (to pH 3-5), 50 ml 2 N solution of sodium hydroxide and 50 ml brine The organic solution was dried over sodium sulphate evaporated to result in an oil