methyl (2S)-1-methyl-5-oxopyrrolidine-2-carboxylate

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The methyl ester compound from step 5a above (18.3 kg, 127.8 mol) and dimethyl sulfate (20.09 kg, 159.3 mol) were introduced into a reactor, and the mixture was heated to 60° C. under an N2 atmosphere. Heating was continued until the concentration of starting material dropped below 15%. An additional 6.25 kg (0.5 eq) of dimethyl sulfate was added with exothermic response. The thick reaction mixture was then cooled to 25° C., and a solution of triethylamine (16.12 kg) in diethyl ether (19.2 L) was added at such a rate that the temperature did not rise above 30° C. The emulsion was washed with two 50 L portions of water. The ether layer was separated, and the residue was extracted with ethyl acetate (60 l). The combined organic layers were dried over Na2SO4 and azeotroped with toluene until no more triethylamine remained in the residue. The residue was mixed with dimethyl sulfate (1.7 kg, 13.5 mol) and THF (70 L) and refluxed under nitrogen until the reaction was complete. The solvents were evaporated under vacuum, and the residue was-distilled under high vacuum to yield a colorless product. Heating dropped below 15% The thick reaction mixture was then cooled to 25° C. did not rise above 30° C The emulsion was washed with two 50 L portions of water The ether layer was separated the residue was extracted with ethyl acetate (60 l) The combined organic layers were dried over Na2SO4 azeotroped with toluene until no more triethylamine refluxed under nitrogen until the reaction The solvents were evaporated under vacuum the residue was-distilled under high vacuum to yield a colorless product

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

Procedure: Methyl 1-methyl-5-oxo-prolinate (0.308 g, 1.96 mmol) was dissolved in methanol (˜10 ml) and to this was added a solution of sodium hydroxide (0.157 g, 3.92 mmol) in water (˜10 ml). The mixture was heated at reflux for 3 hrs, then cooled and evaporated to leave a minimal amount of water. This was acidified to pH 1 using 2M aqueous hydrogen chloride. The aqueous layer was washed with dichloromethane and then separated and evaporated to give 1-methyl-5-oxo-proline as a white solid (0.300 g). The mixture was heated at reflux for 3 hrs cooled evaporated to leave a minimal amount of water The aqueous layer was washed with dichloromethane separated evaporated

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

Procedure: (L)-pyroglutamic acid methyl ester (1 g, 6.99 mmol) was dissolved/mixed with tetrahydrofuran (10 ml) and cooled to 0° C. using an ice-bath. Sodium hydride (0.201 g of a 60% suspension in oil, 8.38 mmol) was added to the mixture. After bubbling stopped, methyl iodide (0.522 ml, 8.38 mmol) was added and the mixture was allowed to warm to room temperature and then stirred for 1 hr. The solvent was evaporated and water was added (1 ml). The aqueous layer was then extracted with dichloromethane. Evaporation of the dichloromethane gave crude methyl 1-methyl-5-oxo-prolinate (0.308 g) which was used in the next step without further purification. After bubbling to warm to room temperature The solvent was evaporated water was added (1 ml) The aqueous layer was then extracted with dichloromethane Evaporation of the dichloromethane

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The methyl ester compound from step 5a above (18.3 kg, 127.8 mol) and dimethyl sulfate (20.09 kg, 159.3 mol) were introduced into a reactor, and the mixture was heated to 60° C. under an N2 atmosphere. Heating was continued until the concentration of starting material dropped below 15%. An additional 6.25 kg (0.5 eq) of dimethyl sulfate was added with exothermic response. The thick reaction mixture was then cooled to 25° C., and a solution of triethylamine (16.12 kg) in diethyl ether (19.2 L) was added at such a rate that the temperature did not rise above 30° C. The emulsion was washed with two 50 L portions of water. The ether layer was separated, and the residue was extracted with ethyl acetate (60 l). The combined organic layers were dried over Na2SO4 and azeotroped with toluene until no more triethylamine remained in the residue. The residue was mixed with dimethyl sulfate (1.7 kg, 13.5 mol) and THF (70 L) and refluxed under nitrogen until the reaction was complete. The solvents were evaporated under vacuum, and the residue was distilled under high vacuum to yield a colorless product. Heating dropped below 15% The thick reaction mixture was then cooled to 25° C. did not rise above 30° C The emulsion was washed with two 50 L portions of water The ether layer was separated the residue was extracted with ethyl acetate (60 l) The combined organic layers were dried over Na2SO4 azeotroped with toluene until no more triethylamine refluxed under nitrogen until the reaction The solvents were evaporated under vacuum the residue was distilled under high vacuum to yield a colorless product

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of 0.68 g (4.33 mmole) (S)-Methyl 1-methyl-5-oxopyrrolidine-2-carboxylate in 15 ml dry tetrahydrofuran was cooled to −78° C. and under argon atmosphere, 2.2 ml (2.2 mmole) of 1M lithium aluminum hydride solution in tetrahydrofuran was added drop by drop during 20 minutes, stirred at −78° C. for 1 hour and removing the cooling bath left to warm up to 0° C. at stirring. While ice cooling, 0.22 ml 10% of sodium hydroxide aqueous solution was added, stirred for 10 minutes, then 0.22 ml of water was added and the reaction mixture stirred for 1.5 hours allowing it to warm to room temperature. The precipitate was filtered and washed with 5×2 ml of ethyl acetate. The combined filtrates were dried over magnesium sulfate and evaporated at 35° C. in good vacuum, giving 0.52 g (93%) product which was pure enough for the next step. removing the cooling bath left to warm up to 0° C. at stirring While ice cooling, 0.22 ml 10% of sodium hydroxide aqueous solution was added stirred for 10 minutes 0.22 ml of water was added the reaction mixture stirred for 1.5 hours to warm to room temperature The precipitate was filtered washed with 5×2 ml of ethyl acetate The combined filtrates were dried over magnesium sulfate evaporated at 35° C. in good vacuum

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The methyl ester compound from step 5a above (18.3 kg, 127.8 mol) and dimethyl sulfate (20.09 kg, 159.3 mol) were introduced into a reactor, and the mixture was heated to 60° C. under an N2 atmosphere. Heating was continued until the concentration of starting material dropped below 15%. An additional 6.25 kg (0.5 eq) of dimethyl sulfate was added with exothermic response. The thick reaction mixture was then cooled to 25° C., and a solution of triethylamine (16.12 kg) in diethyl ether (19.2 L) was added at such a rate that the temperature did not rise above 30° C. The emulsion was washed with two 50 L portions of water. The ether layer was separated, and the residue was extracted with ethyl acetate (60 l). The combined organic layers were dried over Na2SO4 and azeotroped with toluene until no more triethylamine remained in the residue. The residue was mixed with dimethyl sulfate (1.7 kg, 13.5 mol) and THF (70 L) and refluxed under nitrogen until the reaction was complete. The solvents were evaporated under vacuum, and the residue was distilled under high vacuum to yield a colorless product. Heating dropped below 15% The thick reaction mixture was then cooled to 25° C. did not rise above 30° C The emulsion was washed with two 50 L portions of water The ether layer was separated the residue was extracted with ethyl acetate (60 l) The combined organic layers were dried over Na2SO4 azeotroped with toluene until no more triethylamine refluxed under nitrogen until the reaction The solvents were evaporated under vacuum the residue was distilled under high vacuum to yield a colorless product

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of 0.68 g (4.33 mmole) (S)-Methyl 1-methyl-5-oxopyrrolidine-2-carboxylate in 15 ml dry tetrahydrofuran was cooled to −78° C. and under argon atmosphere, 2.2 ml (2.2 mmole) of 1M lithium aluminum hydride solution in tetrahydrofuran was added drop by drop during 20 minutes, stirred at −78° C. for 1 hour and removing the cooling bath left to warm up to 0° C. at stirring. While ice cooling, 0.22 ml 10% of sodium hydroxide aqueous solution was added, stirred for 10 minutes, then 0.22 ml of water was added and the reaction mixture stirred for 1.5 hours allowing it to warm to room temperature. The precipitate was filtered and washed with 5×2 ml of ethyl acetate. The combined filtrates were dried over magnesium sulfate and evaporated at 35° C. in good vacuum, giving 0.52 g (93%) product which was pure enough for the next step. removing the cooling bath left to warm up to 0° C. at stirring While ice cooling, 0.22 ml 10% of sodium hydroxide aqueous solution was added stirred for 10 minutes 0.22 ml of water was added the reaction mixture stirred for 1.5 hours to warm to room temperature The precipitate was filtered washed with 5×2 ml of ethyl acetate The combined filtrates were dried over magnesium sulfate evaporated at 35° C. in good vacuum

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The methyl ester compound from step 5a above (18.3 kg, 127.8 mol) and dimethyl sulfate (20.09 kg, 159.3 mol) were introduced into a reactor, and the mixture was heated to 60° C. under an N2 atmosphere. Heating was continued until the concentration of starting material dropped below 15%. An additional 6.25 kg (0.5 eq) of dimethyl sulfate was added with exothermic response. The thick reaction mixture was then cooled to 25° C., and a solution of triethylamine (16.12 kg) in diethyl ether (19.2 L) was added at such a rate that the temperature did not rise above 30° C. The emulsion was washed with two 50 L portions of water. The ether layer was separated, and the residue was extracted with ethyl acetate (60 l). The combined organic layers were dried over Na2SO4 and azeotroped with toluene until no more triethylamine remained in the residue. The residue was mixed with dimethyl sulfate (1.7 kg, 13.5 mol) and THF (70 L) and refluxed under nitrogen until the reaction was complete. The solvents were evaporated under vacuum, and the residue was distilled under high vacuum to yield a colorless product. Heating dropped below 15% The thick reaction mixture was then cooled to 25° C. did not rise above 30° C The emulsion was washed with two 50 L portions of water The ether layer was separated the residue was extracted with ethyl acetate (60 l) The combined organic layers were dried over Na2SO4 azeotroped with toluene until no more triethylamine refluxed under nitrogen until the reaction The solvents were evaporated under vacuum the residue was distilled under high vacuum to yield a colorless product

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

Procedure: Methyl 1-methyl-5-oxo-prolinate (0.308 g, 1.96 mmol) was dissolved in methanol (˜10 ml) and to this was added a solution of sodium hydroxide (0.157 g, 3.92 mmol) in water (˜10 ml). The mixture was heated at reflux for 3 hrs, then cooled and evaporated to leave a minimal amount of water. This was acidified to pH 1 using 2M aqueous hydrogen chloride. The aqueous layer was washed with dichloromethane and then separated and evaporated to give 1-methyl-5-oxo-proline as a white solid (0.300 g). The mixture was heated at reflux for 3 hrs cooled evaporated to leave a minimal amount of water The aqueous layer was washed with dichloromethane separated evaporated

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

Procedure: (L)-pyroglutamic acid methyl ester (1 g, 6.99 mmol) was dissolved/mixed with tetrahydrofuran (10 ml) and cooled to 0° C. using an ice-bath. Sodium hydride (0.201 g of a 60% suspension in oil, 8.38 mmol) was added to the mixture. After bubbling stopped, methyl iodide (0.522 ml, 8.38 mmol) was added and the mixture was allowed to warm to room temperature and then stirred for 1 hr. The solvent was evaporated and water was added (1 ml). The aqueous layer was then extracted with dichloromethane. Evaporation of the dichloromethane gave crude methyl 1-methyl-5-oxo-prolinate (0.308 g) which was used in the next step without further purification. After bubbling to warm to room temperature The solvent was evaporated water was added (1 ml) The aqueous layer was then extracted with dichloromethane Evaporation of the dichloromethane

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

Procedure: (L)-pyroglutamic acid methyl ester (1 g, 6.99 mmol) was dissolved/mixed with tetrahydrofuran (10 ml) and cooled to 0° C. using an ice-bath. Sodium hydride (0.201 g of a 60% suspension in oil, 8.38 mmol) was added to the mixture. After bubbling stopped, methyl iodide (0.522 ml, 8.38 mmol) was added and the mixture was allowed to warm to room temperature and then stirred for 1 hr. The solvent was evaporated and water was added (1 ml). The aqueous layer was then extracted with dichloromethane. Evaporation of the dichloromethane gave crude methyl 1-methyl-5-oxo-prolinate (0.308 g) which was used in the next step without further purification. After bubbling to warm to room temperature The solvent was evaporated water was added (1 ml) The aqueous layer was then extracted with dichloromethane Evaporation of the dichloromethane

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The methyl ester compound from step 5a above (18.3 kg, 127.8 mol) and dimethyl sulfate (20.09 kg, 159.3 mol) were introduced into a reactor, and the mixture was heated to 60° C. under an N2 atmosphere. Heating was continued until the concentration of starting material dropped below 15%. An additional 6.25 kg (0.5 eq) of dimethyl sulfate was added with exothermic response. The thick reaction mixture was then cooled to 25° C., and a solution of triethylamine (16.12 kg) in diethyl ether (19.2 L) was added at such a rate that the temperature did not rise above 30° C. The emulsion was washed with two 50 L portions of water. The ether layer was separated, and the residue was extracted with ethyl acetate (60 l). The combined organic layers were dried over Na2SO4 and azeotroped with toluene until no more triethylamine remained in the residue. The residue was mixed with dimethyl sulfate (1.7 kg, 13.5 mol) and THF (70 L) and refluxed under nitrogen until the reaction was complete. The solvents were evaporated under vacuum, and the residue was distilled under high vacuum to yield a colorless product. Heating dropped below 15% The thick reaction mixture was then cooled to 25° C. did not rise above 30° C The emulsion was washed with two 50 L portions of water The ether layer was separated the residue was extracted with ethyl acetate (60 l) The combined organic layers were dried over Na2SO4 azeotroped with toluene until no more triethylamine refluxed under nitrogen until the reaction The solvents were evaporated under vacuum the residue was distilled under high vacuum to yield a colorless product