tert-butyl (3S,4S)-3-(bromomethyl)-4-fluoropyrrolidine-1-carboxylate

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (3S,4S)-3-Bromomethyl-1-tert-butoxycarbonyl-4-fluoropyrrolidine (1.91 g) was mixed with cyclopropylamine (23.6 mL). The mixture was stirred at 80° C. for 23 hours and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with saturated brine (2×20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane:ethyl acetate=2:1) to give (3S,4S)-1-tert-butoxycarbonyl-3-cyclopropylaminomethyl-4-fluoropyrrolidine as a pale brown oil (1.67 g). was concentrated under reduced pressure The residue was dissolved in ethyl acetate (100 mL) washed with saturated brine (2×20 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (eluant: hexane:ethyl acetate=2:1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (3S,4S)-3-Bromomethyl-1-tert-butoxycarbonyl-4-fluoropyrrolidine (1.91 g) was mixed with cyclopropylamine (23.6 mL). The mixture was stirred at 80° C. for 23 hours and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with saturated brine (2×20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane:ethyl acetate=2:1) to give (3S,4S)-1-tert-butoxycarbonyl-3-cyclopropylaminomethyl-4-fluoropyrrolidine as a pale brown oil (1.67 g). was concentrated under reduced pressure The residue was dissolved in ethyl acetate (100 mL) washed with saturated brine (2×20 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (eluant: hexane:ethyl acetate=2:1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (3S,4S)-3-Bromomethyl-1-tert-butoxycarbonyl-4-fluoropyrrolidine (1.91 g) was mixed with cyclopropylamine (23.6 mL). The mixture was stirred at 80° C. for 23 hours and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with saturated brine (2×20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3S,4S)-1-tert-butoxycarbonyl-3-cyclopropylaminomethyl-4-fluoropyrrolidine as a pale brown oil (1.67 g). was concentrated under reduced pressure The residue was dissolved in ethyl acetate (100 mL) washed with saturated brine (2×20 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1)

Conditions: temp:2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Process B: (3S,4R)-3-Bromomethyl-1-tert-butoxycarbonyl-4-hydroxypyrrolidine (561 mg) was dissolved in toluene (20 mL). To this solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.50 mL) was added and perfluoro-1-octanesulfonylfluoride (0.93 mL) was then added dropwise while the mixture was chilled in an ice water bath. After stirred at 2° C. for 1 hour, the reaction mixture was poured on a silica gel pad and was eluted with ethyl acetate (100 mL). The eluate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3S,4S)-3-bromomethyl-1-tert-butoxycarbonyl-4-fluoropyrrolidine as a yellow oil (447 mg). was chilled in an ice water bath the reaction mixture was poured on a silica gel pad was eluted with ethyl acetate (100 mL) The eluate was concentrated under reduced pressure the resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Process A: (3S,4R)-3-Bromomethyl-1-tert-butoxycarbonyl-4-hydroxypyrrolidine (1.97 g) was dissolved in dichloromethane (50 mL). While this solution was chilled in an ice water bath, diethylaminosulfur trifluoride (1.90 mL) was added dropwise and the mixture was stirred at room temperature for 19 hours. Subsequently, while the reaction mixture was chilled in an ice water bath, a saturated aqueous solution of sodium bicarbonate (40 mL) was added and the dichloromethane layer was separated. The dichloromethane layer was then washed sequentially with a saturated aqueous solution of sodium bicarbonate (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3S,4S)-3-bromomethyl-1-tert-butoxycarbonyl-4-fluoropyrrolidine as a yellow-brown tar (1.64 g). While this solution was chilled in an ice water bath Subsequently, while the reaction mixture was chilled in an ice water bath the dichloromethane layer was separated The dichloromethane layer was then washed sequentially with a saturated aqueous solution of sodium bicarbonate (20 mL) and saturated brine (20 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (3S,4S)-3-Bromomethyl-1-tert-butoxycarbonyl-4-fluoropyrrolidine (1.91 g) was mixed with cyclopropylamine (23.6 mL). The mixture was stirred at 80° C. for 23 hours and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with saturated brine (2×20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane:ethyl acetate=2:1) to give (3S,4S)-1-tert-butoxycarbonyl-3-cyclopropylaminomethyl-4-fluoropyrrolidine as a pale brown oil (1.67 g). was concentrated under reduced pressure The residue was dissolved in ethyl acetate (100 mL) washed with saturated brine (2×20 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (eluant: hexane:ethyl acetate=2:1)