tert-butyl (2S,4S)-2-carbamoyl-4-fluoropyrrolidine-1-carboxylate

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

Procedure: tert-Butyl (2S,4S)-2-aminocarbonyl-4-fluoro-1-pyrrolidinecarboxylate obtained in Example 7-8 (46 g) was dissolved in 4N HCl in dioxane (200 mL) and the resulting mixture was stirred for 10 minutes at room temperature. After removal of the solvent, the resulting residue was triturated with ethyl acetate to give the target compound as a white powder (34 g). After removal of the solvent the resulting residue was triturated with ethyl acetate

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

Procedure: tert-Butyl (2S,4S)-2-aminocarbonyl-4-fluoro-1-pyrrolidinecarboxylate obtained in Example 7-8 (46 g) was dissolved in 4N HCl in dioxane (200 mL) and the resulting mixture was stirred for 10 minutes at room temperature. After removal of the solvent, the resulting residue was triturated with ethyl acetate to give the target compound as a white powder (34 g). After removal of the solvent the resulting residue was triturated with ethyl acetate

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The reactor was charged with (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide (116 g, 1 wt, 1 eq.), isopropyl acetate (578 mL, 5 vol), and pyridine (88 mL, 0.8 vol, 2.2 eq). The resulting slurry was stirred at approx. 20° C. Trifluoroacetic anhydride (77 mL, 1.0 wt, 1.1 eq.) was added over at least 30 minutes, maintaining the temperature at approx. 20° C. The reaction solution was stirred an additonal 1 hour at approx. 20° C. Water (578 mL, 5 vol) was added slowly, and the reaction mixture was stirred for 15 minutes. The stirring was stopped, the layers were allowed to separate, and the aqueous (lower) layer was discarded. The organic layer was concentrated under vacuum at a jacket temperature of approximately 50° C. to half volume. The reaction was diluted back up to 5 volumes with isopropyl acetate. The reactor contents were cooled to 20° C., and the reactor was charged with p-toluenesulfonic acid (94 g, 0.8 wt, 1 eq). The reaction was stirred for 2 hours, and GC analysis at this point should show complete consumption of (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide. The reaction was concentrated to 3 volumes under full vacuum at a jacket temperature of approximately 50° C. and 2 volumes of isopropyl alcohol were added. The reaction was concentrated to a final volume of 4 volumes. The reaction was cooled to 0° C. and held for 30 minutes. The solids were collected by filtration, washed with isopropyl alcohol (1 vol), and then dried under vacuum at approx. 50° C. to constant weight. Yield: 68-71%. maintaining the temperature at approx. 20° C The reaction solution was stirred an additonal 1 hour at approx. 20° C the reaction mixture was stirred for 15 minutes to separate The organic layer was concentrated under vacuum at a jacket temperature of approximately 50° C. to half volume The reaction was diluted back up to 5 volumes with isopropyl acetate The reactor contents were cooled to 20° C. The reaction was stirred for 2 hours consumption of (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide The reaction was concentrated to 3 volumes under full vacuum at a jacket temperature of approximately 50° C. and 2 volumes of isopropyl alcohol were added The reaction was concentrated to a final volume of 4 volumes The reaction was cooled to 0° C. The solids were collected by filtration washed with isopropyl alcohol (1 vol) dried under vacuum at approx. 50° C. to constant weight

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A reactor was charged with (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-proline (130 g, 1 wt, 1 eq.), dichloromethane (520 mL, 4 vol), pyridine (55 mL, 0.4 vol, 1.2 eq), and Boc-anhydride (145 g, 1.1 wt, 1.2 eq.). The reaction solution was stirred at approximately 20° C. for 2 hours. The reactor was charged with ammonium bicarbonate (62 g, 0.5 wt, 1.44 eq), and was stirred at approximately 20° C. overnight. The reaction was filtered over a bed of celite (130 g, 1 wt), and the filter cake was washed with dichloromethane (260 mL, 2 vol). The filtrate was concentrated to a volume of 3 volumes, heptane (520 mL, 4 vol) was added, and again concentrated to a final volume of 3 volumes. Heptane (390 mL, 3 vol) was added, and the reaction was cooled to approx. 5° C. for 30 min. was stirred at approximately 20° C. overnight The reaction was filtered over a bed of celite (130 g, 1 wt) the filter cake was washed with dichloromethane (260 mL, 2 vol) The filtrate was concentrated to a volume of 3 volumes, heptane (520 mL, 4 vol) was added again concentrated to a final volume of 3 volumes Heptane (390 mL, 3 vol) was added the reaction was cooled to approx. 5° C. for 30 min.

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A reactor was charged with (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-proline (130 g, 1 wt, 1 eq.), dichloromethane (520 mL, 4 vol), pyridine (55 mL, 0.4 vol, 1.2 eq), and Boc-anhydride (145 g, 1.1 wt, 1.2 eq.). The reaction solution was stirred at approximately 20° C. for 2 hours. The reactor was charged with ammonium bicarbonate (62 g, 0.5 wt, 1.44 eq), and was stirred at approximately 20° C. overnight. The reaction was filtered over a bed of celite (130 g, 1 wt), and the filter cake was washed with dichloromethane (260 mL, 2 vol). The filtrate was concentrated to a volume of 3 volumes, heptane (520 mL, 4 vol) was added, and again concentrated to a final volume of 3 volumes. Heptane (390 mL, 3 vol) was added, and the reaction was cooled to approx. 5° C. for 30 min. was stirred at approximately 20° C. overnight The reaction was filtered over a bed of celite (130 g, 1 wt) the filter cake was washed with dichloromethane (260 mL, 2 vol) The filtrate was concentrated to a volume of 3 volumes, heptane (520 mL, 4 vol) was added again concentrated to a final volume of 3 volumes Heptane (390 mL, 3 vol) was added the reaction was cooled to approx. 5° C. for 30 min.

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (2S,4S)-2-carbamoyl-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g), conc. HCl (0.6 ml) and 1-butanol (10 ml) was heated for 48 h at 50° C. The RM was evaporated and partitioned DCM and aqueous NaHCO3, the DCM layers were dried over Na2SO4 and evaporated. A solution of 7 M ammonia in methanol (10 ml) was added to the residue and the mixture was stood for 60 h at it in a sealed vessel. Evaporation and trituration with EtOH gave the title compound as a white solid. The RM was evaporated partitioned DCM and aqueous NaHCO3 the DCM layers were dried over Na2SO4 evaporated A solution of 7 M ammonia in methanol (10 ml) was added to the residue Evaporation and trituration with EtOH

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (2S,4S)-2-carbamoyl-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g), conc. Hydrochoric acid (0.6 ml) and 1-butanol (10 ml) is heated for 48 hours at 50° C. The reaction mixture is evaporated and partitioned dichloromethane and aqueous sodium bicarbonate, the dichloromethane layers are dried over sodium sulphate and evaporated. A solution of 7M ammonia in methanol (10 ml) is added to the residue and the mixture is stood for 60 hours at room temperature in a sealed vessel. Evaporation and trituration with ethanol gives the title compound as a white solid. The reaction mixture is evaporated partitioned dichloromethane and aqueous sodium bicarbonate the dichloromethane layers are dried over sodium sulphate evaporated A solution of 7M ammonia in methanol (10 ml) is added to the residue Evaporation and trituration with ethanol

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

Procedure: In a 5.0 L 4-necked RB flask, fitted with a mechanical stirrer and reflux condenser, were added tert-butyl 2-(aminocarbonyl)-4-[(methylsulfonyl)oxy]pyrrolidine-1-carboxylate (100 gm, 0.32 M), THF (500 ml), a tetrabutylammonium fluoride solution (153.4 gm, 0.48 mol in 500 ml THF) and water (35 ml) at 25-35° C. while stirring. The reaction mixture was brought to 55-60° C. and maintained for 48-60 hrs while stirring. The progress of the reaction was monitored by HPLC and after ascertaining completion, the reaction mixture was poured slowly into an ice cold water (1.5 L) and dichloromethane (0.72 L) mixture. The aqueous layer was washed with additional MDC (210 ml×3). The organic layers were combined and washed with a saturated brine solution (0.5 L). The dichloromethane layer was distilled below 40° C. under vacuum and hexane (500 ml) was added to the resulting mass. The trace dichloromethane was distilled off. The resulting mass was taken as such to the next stage. In a 5.0 L 4-necked RB flask, fitted with a mechanical stirrer reflux condenser was brought to 55-60° C. maintained for 48-60 hrs The aqueous layer was washed with additional MDC (210 ml×3) washed with a saturated brine solution (0.5 L) The dichloromethane layer was distilled below 40° C. under vacuum and hexane (500 ml) was added to the resulting mass The trace dichloromethane was distilled off

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of tert-butyl (2S,4S)-2-carbamoyl-4-fluoropyrrolidine-1-carboxylate (50 g, 0.2155 mmol) in dry dichloromethane (500 ml) was added triethylamine (87.06 g, 0.862 mmol) and the mixture was cooled to 0° C. Trifluoroacetic anhydride (58.83 g, 0.2801 mmol) was added over period of 10 min and the mixture was stirred for 30 min at same temperature under nitrogen atmosphere. The mixture was diluted with water (300 ml) and the layers were separated. The aqueous layer was extracted with dichloromethane (100 ml). The combined organic phase was washed with 1N HCl (200 ml), 5% aqueous NaHCO3 (100 ml) and water (2×300 ml). The solution was dried over anhydrous Na2SO4 and then evaporated under reduced pressure to give 45 g of the product as a pale yellow solid; 1H NMR (CDCl3, 300 MHz) δ 1.49-1.53 (d, 9H, rotomer), 2.25-2.47 (m, 1H), 2.64 (t, J=14.7 Hz, 1H), 3.52 (dd, J=9.6, 3.6 Hz, 0.5H, rotomer), 3.64 (dd, J=9.3, 3.3 Hz, 0.5H, rotomer), 3.73-3.94 (m, 1H), 4.64 (d, J=8.7 Hz, 0.6H, rotomer), 4.76 (d, J=8.7 Hz, 0.4H, rotomer), 5.31 (br d, J=51.3 Hz, 1H). the layers were separated The aqueous layer was extracted with dichloromethane (100 ml) The combined organic phase was washed with 1N HCl (200 ml), 5% aqueous NaHCO3 (100 ml) and water (2×300 ml) The solution was dried over anhydrous Na2SO4 evaporated under reduced pressure

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a well stirred solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (50 g, 0.2145 mmol) in dry THF (1000 ml) was added TEA (32.49 g, 0.3217 mmol) at room temperature. The mixture was cooled to −10° C. and ethyl chloroformate (34.93 g, 0.3217 mmol) was added over period of 20 min. The mixture was stirred for 30 min at the same temperature under nitrogen atmosphere and aqueous ammonium hydroxide (500 ml) was added. The aqueous mixture was stirred at room temperature for 18 h and THF in the mixture was evaporated under reduced pressure. The aqueous mixture was further diluted with water (100 ml) and extracted with chloroform (3×100 ml). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was stirred in petroleum ether (250 ml) for 20 min to give a white filterable solid. The product was collected by filtration and dried to give 44.7 g of the product as a white solid. 1H NMR (CDCl3, 300 MHz) δ 1.48 (s, 9H), 2.20-2.80 (m, 2H), 3.51-3.85 (m, 2H), 4.38 (br s, 1H), 5.21 (d, J=52.2 Hz, 1H), 5.50 (br s, 1H), 6.16 (br s, 0.5H, rotomer), 6.59 (br s, 0.5H, rotomer) The aqueous mixture was stirred at room temperature for 18 h THF in the mixture was evaporated under reduced pressure The aqueous mixture was further diluted with water (100 ml) extracted with chloroform (3×100 ml) The combined organic extracts were dried over Na2SO4 concentrated under reduced pressure The residue was stirred in petroleum ether (250 ml) for 20 min to give a white filterable solid The product was collected by filtration dried

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

Procedure: (2S,4S)-1-(tert-Butoxycarbonyl)-2-carbamoyl-4-fluoropyrrolidine (122 g) was suspended in ethyl acetate (400 mL). While stirring this suspension under ice cooling, 4 mol/L hydrochloric acid-ethyl acetate (525 mL) was slowly added dropwise. After stirring at ice-cold temperature for 30 minutes and at room temperature for 3 hours, the precipitated crystal was collected by filtration to give the titled compound (85.9 g, white powder). After stirring at ice-cold temperature for 30 minutes and at room temperature for 3 hours the precipitated crystal was collected by filtration

Conditions: temp:-11.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2S,4S)-1-(tert-Butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (70.0 g) was dissolved in tetrahydrofuran (700 mL) and then cooled to −11° C. To this solution, triethylamine (33.4 g) and ethyl chlorocarbonate (35.8 g) were slowly added and stirred at −15° C. for 30 minutes. Subsequently, 28% aqueous ammonia (73 mL) was added to the reaction mixture. After stirring at −10° C. for 40 minutes, a mixture of ethyl acetate and tetrahydrofuran (4:1, 1400 mL) and water (230 mL) were added and stirred. The reaction mixture was separated into organic and aqueous layers, and the aqueous layer was further extracted with a mixture of ethyl acetate and tetrahydrofuran (4:1, 350 mL). The combined organic layers were washed sequentially with 10% aqueous potassium bisulfate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude crystal was recrystallized from a mixed solvent of acetonitrile and diisopropyl ether to give the titled compound (57.7 g, white powder). After stirring at −10° C. for 40 minutes were added stirred The reaction mixture was separated into organic and aqueous layers the aqueous layer was further extracted with a mixture of ethyl acetate and tetrahydrofuran (4:1, 350 mL) The combined organic layers were washed sequentially with 10% aqueous potassium bisulfate and saturated aqueous sodium chloride dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting crude crystal was recrystallized from a mixed solvent of acetonitrile and diisopropyl ether