methyl 1-benzyl-5-oxopyrrolidine-2-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a slurry of NaH (22 g of 60% NaH in mineral oil, 0.55 mol) in 400 mL benzene was added the product of Example 1A (0.387 mol) in 100 mL benzene dropwise via addition funnel. The mixture stirred for 30 minutes after the addition was complete, then was warmed to reflux and allowed to stir for 1.5 h. The reaction was cooled to 45° C. and stirred for 16 h. A portion of benzyl bromide (45 mL, 0.38 mol) was added, the mixture was warmed to reflux and an additional amount of benzyl bromide was added (45 mL, 0.38 mol). This solution stirred for 24 h at reflux, then was cooled to ambient temperature, filtered through Celite® diatomaceous earth and the residue was washed with CH2Cl2. The combined filtrates were concentrated under reduced pressure and excess benzyl bromide was removed via distillation. The distillation residue was purified via column chromatography (SiO2, 75% hexanes-EtOAc) to give 46.6 g of the title compound (0.2 mol, 52% yield). MS (DCl/NH3) m/z 234 (M+H)+. dropwise via addition funnel after the addition was warmed to reflux to stir for 1.5 h stirred for 16 h the mixture was warmed to reflux This solution stirred for 24 h at reflux was cooled to ambient temperature filtered through Celite® diatomaceous earth the residue was washed with CH2Cl2 The combined filtrates were concentrated under reduced pressure and excess benzyl bromide was removed via distillation The distillation residue was purified via column chromatography (SiO2, 75% hexanes-EtOAc)

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a slurry of NaH (22 g of 60% NaH in mineral oil, 0.55 mol) in 400 mL benzene was added the product of Example 1A (0.387 mol) in 100 mL benzene dropwise via addition funnel. The mixture stirred for 30 minutes after the addition was complete, then was warmed to reflux and allowed to stir for 1.5 h. The reaction was cooled to 45° C. and stirred for 16 h. A portion of benzyl bromide (45 mL, 0.38 mol) was added, the mixture was warmed to reflux and an additional amount of benzyl bromide was added (45 mL, 0.38 mol). This solution stirred for 24 h at reflux, then was cooled to ambient temperature, filtered through Celite® diatomaceous earth and the residue was washed with CH2Cl2. The combined filtrates were concentrated under reduced pressure and excess benzyl bromide was removed via distillation. The distillation residue was purified via column chromatography (SiO2, 75% hexanes-EtOAc) to give 46.6 g of the title compound (0.2 mol, 52% yield). MS (DCl/NH3) m/z 234 (M+H)+. dropwise via addition funnel after the addition was warmed to reflux to stir for 1.5 h stirred for 16 h the mixture was warmed to reflux This solution stirred for 24 h at reflux was cooled to ambient temperature filtered through Celite® diatomaceous earth the residue was washed with CH2Cl2 The combined filtrates were concentrated under reduced pressure and excess benzyl bromide was removed via distillation The distillation residue was purified via column chromatography (SiO2, 75% hexanes-EtOAc)

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a slurry of NaH (22 g of 60% NaH in mineral oil, 0.55 mol) in 400 mL benzene was added the product of Example 1A (0.387 mol) in 100 mL benzene dropwise via addition funnel. The mixture stirred for 30 minutes after the addition was complete, then was warmed to reflux and allowed to stir for 1.5 h. The reaction was cooled to 45° C. and stirred for 16 h. A portion of benzyl bromide (45 mL, 0.38 mol) was added, the mixture was warmed to reflux and an additional amount of benzyl bromide was added (45 mL, 0.38 mol). This solution stirred for 24 h at reflux, then was cooled to ambient temperature, filtered through Celite® diatomaceous earth and the residue was washed with CH2Cl2. The combined filtrates were concentrated under reduced pressure and excess benzyl bromide was removed via distillation. The distillation residue was purified via column chromatography (SiO2, 75% hexanes-EtOAc) to give 46.6 g of the title compound (0.2 mol, 52% yield). MS (DCl/NH3) m/z 234 (M+H)+. dropwise via addition funnel after the addition was warmed to reflux to stir for 1.5 h stirred for 16 h the mixture was warmed to reflux This solution stirred for 24 h at reflux was cooled to ambient temperature filtered through Celite® diatomaceous earth the residue was washed with CH2Cl2 The combined filtrates were concentrated under reduced pressure and excess benzyl bromide was removed via distillation The distillation residue was purified via column chromatography (SiO2, 75% hexanes-EtOAc)

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a slurry of NaH (22 g of 60% NaH in mineral oil, 0.55 mol) in 400 mL benzene was added the product of Example 1A (0.387 mol) in 100 mL benzene dropwise via addition funnel. The mixture stirred for 30 minutes after the addition was complete, then was warmed to reflux and allowed to stir for 1.5 h. The reaction was cooled to 45° C. and stirred for 16 h. A portion of benzyl bromide (45 mL, 0.38 mol) was added, the mixture was warmed to reflux and an additional amount of benzyl bromide was added (45 mL, 0.38 mol). This solution stirred for 24 h at reflux, then was cooled to ambient temperature, filtered through Celite® diatomaceous earth and the residue was washed with CH2Cl2. The combined filtrates were concentrated under reduced pressure and excess benzyl bromide was removed via distillation. The distillation residue was purified via column chromatography (SiO2, 75% hexanes-EtOAc) to give 46.6 g of the title compound (0.2 mol, 52% yield). MS (DCl/NH3) m/z 234 (M+H)+. dropwise via addition funnel after the addition was warmed to reflux to stir for 1.5 h stirred for 16 h the mixture was warmed to reflux This solution stirred for 24 h at reflux was cooled to ambient temperature filtered through Celite® diatomaceous earth the residue was washed with CH2Cl2 The combined filtrates were concentrated under reduced pressure and excess benzyl bromide was removed via distillation The distillation residue was purified via column chromatography (SiO2, 75% hexanes-EtOAc)

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

Procedure: Methyl 1-benzyl-5-oxo-2-pyrrolidinecarboxylate (18.15 g, 77.8 mmol) and Lawesson's reagent (31.5 g, 77.9 mmol) were combined in dry tetrahydrofuran (100 mL) and stirred overnight at room temperature. The mixture was filtered, the filter cake was rinsed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (3:1, hexanes:ethyl acetate) to provide the title compound. MS (ESI) m/z: 250 (M+H)+; 1H NMR (CDCl3) δ 2.17 (m, 1H), 2.27 (m, 1H), 3.15 (m, 2H), 3.69 (s, 3H), 4.30 (dd, 1H), 4.37 (d, 1H), 5.73 (d, 1H), 7.32 (m, 5H). The mixture was filtered the filter cake was rinsed with tetrahydrofuran the filtrate was concentrated under reduced pressure The residue was dissolved in ethyl acetate washed with saturated sodium bicarbonate solution The organic phase was concentrated under reduced pressure the residue was purified by chromatography on silica gel (3:1, hexanes:ethyl acetate)

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

Procedure: 1-Benzyl-5-oxo-2-pyrrolidinecarboxylic acid (9.69 g, 44.2 mmol) in methanol (75 mL) was treated with sulfuric acid (0.5 mL) and refluxed for 2.5 hours. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The ethyl acetate phase was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification. refluxed for 2.5 hours concentrated under reduced pressure The residue was dissolved in ethyl acetate washed with saturated sodium bicarbonate solution The ethyl acetate phase was concentrated under reduced pressure

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

Procedure: Methyl 1-benzyl-5-oxo-2-pyrrolidinecarboxylate (18.15 g, 77.8 mmol) and Lawesson's reagent (31.5 g, 77.9 mmol) were combined in dry tetrahydrofuran (100 mL) and stirred overnight at room temperature. The mixture was filtered, the filter cake was rinsed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (3:1, hexanes:ethyl acetate) to provide the title compound. MS (ESI) m/z: 250 (M+H)+; 1H NMR (CDCl3) δ 2.17 (m, 1H), 2.27 (m, 1H), 3.15 (m, 2H), 3.69 (s, 3H), 4.30 (dd, 1H), 4.37 (d, 1H), 5.73 (d, 1H), 7.32 (m, 5H). The mixture was filtered the filter cake was rinsed with tetrahydrofuran the filtrate was concentrated under reduced pressure The residue was dissolved in ethyl acetate washed with saturated sodium bicarbonate solution The organic phase was concentrated under reduced pressure the residue was purified by chromatography on silica gel (3:1, hexanes:ethyl acetate)

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

Procedure: 1-Benzyl-5-oxo-2-pyrrolidinecarboxylic acid (9.69 g, 44.2 mmol) in methanol (75 mL) was treated with sulfuric acid (0.5 mL) and refluxed for 2.5 hours. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The ethyl acetate phase was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification. refluxed for 2.5 hours concentrated under reduced pressure The residue was dissolved in ethyl acetate washed with saturated sodium bicarbonate solution The ethyl acetate phase was concentrated under reduced pressure

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a slurry of NaH (22 g of 60% NaH in mineral oil, 0.55 mol) in 400 mL benzene was added the product of Example 1A (0.387 mol) in 100 mL benzene dropwise via addition funnel. The mixture stirred for 30 minutes after the addition was complete, then was warmed to reflux and allowed to stir for 1.5 h. The reaction was cooled to 45° C. and stirred for 16 h. A portion of benzyl bromide (45 mL, 0.38 mol) was added, the mixture was warmed to reflux and an additional amount of benzyl bromide was added (45 mL, 0.38 mol). This solution stirred for 24 h at reflux, then was cooled to ambient temperature, filtered through Celite® diatomaceous earth and the residue was washed with CH2Cl2. The combined filtrates were concentrated under reduced pressure and excess benzyl bromide was removed via distillation. The distillation residue was purified via column chromatography (SiO2, 75% hexanes-EtOAc) to give 46.6 g of the title compound (0.2 mol, 52% yield). MS (DCl/NH3) m/z 234 (M+H)+. dropwise via addition funnel after the addition was warmed to reflux to stir for 1.5 h stirred for 16 h the mixture was warmed to reflux This solution stirred for 24 h at reflux was cooled to ambient temperature filtered through Celite® diatomaceous earth the residue was washed with CH2Cl2 The combined filtrates were concentrated under reduced pressure and excess benzyl bromide was removed via distillation The distillation residue was purified via column chromatography (SiO2, 75% hexanes-EtOAc)