ethyl (2S)-1-benzylpyrrolidine-2-carboxylate

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

Procedure: N-Benzyl-L-proline ethyl ester (1.00 g, 4.3 mmol) was combined with aqueous 2N sodium hydroxide (5.0 mL, 10.0 mmol), tetrahydrofuran (2.0 mL) and MeOH (2.0 mL) and the mixture stirred at rt. until hydrolysis was complete. The mixture was then treated in a manner similar to preparation 104. Concentration of the filtrate netted 0.79 g (90%) of crude acid as a light yellowish solid. MS(ES): (M+1)+ 206.3, 207.3. until hydrolysis The mixture was then treated in a manner similar to preparation 104

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: First 6.91 mL (23.57 mmol) of titanium (IV) isopropoxide and then 14.3 mL (42.9 mmol, 3 M in diethyl ether) of ethylmagnesium bromide were slowly added dropwise to a solution of 5.0 g (21.43 mmol) of N-benzyl-L-proline ethyl ester in 80 mL of dry diethyl ether which had been cooled to −15° C. and the reaction mixture was stirred for 30 minutes at this temperature. Subsequently at approximately 10° C., 5.4 mL (42.9 mmol) of boron trifluoride-diethyl ether complex were added and the mixture was stirred for a further 75 hours at RT. While cooling, 50 mL of 1M NaOH was added, the mixture was stirred for 1 hours at RT, combined with 100 mL of diethyl ether, and the organic phase was separated off and dried over sodium sulfate. After the desiccant and solvent had been eliminated, the residue was purified by chromatography (silica gel, EtOAc). Yield: 0.745 g (16% of theoretical); C14H19NO (M=217.307); calc.: molpeak (M+H)+: 218; found: molpeak (M+H)+: 218; Rf value: 0.17 (silica gel, EtOAc). Subsequently at approximately 10° C., 5.4 mL (42.9 mmol) of boron trifluoride-diethyl ether complex were added the mixture was stirred for a further 75 hours at RT While cooling the mixture was stirred for 1 hours at RT the organic phase was separated off dried over sodium sulfate the residue was purified by chromatography (silica gel, EtOAc)

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

Procedure: N-Benzyl-L-proline ethyl ester (1.00 g, 4.3 mmol) was combined with aqueous 2N sodium hydroxide (5.0 mL, 10.0 mmol), tetrahydrofuran (2.0 mL) and MeOH (2.0 mL) and the mixture stirred at rt. until hydrolysis was complete. The mixture was then treated in a manner similar to preparation 104. Concentration of the filtrate netted 0.79 g (90%) of crude acid as a light yellowish solid. MS(ES): (M+1)+ 206.3, 207.3. until hydrolysis The mixture was then treated in a manner similar to preparation 104

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

Procedure: Ethyl 1-(phenylmethyl)-L-prolinate (13.20 g, 56.57 mmol) was dissolved in a mixture of THF (40 mL), EtOH (40 mL) and H2O (16 mL). To this solution was added solid sodium hydroxide (6.789 g, 169.73 mmol), and the mixture was stirred at room temperature overnight. The solution was adjusted to pH 2 with 1N aq. HCl and then extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo, and the resulting crude product was 1-(phenylmethyl)-L-proline hydrochloride (0.8 g). The aqueous layers were concentrated in vacuo, the residue was suspended in MeOH, and the resulting solid precipitate was collected by filtration and combined with the product from the organic extracts to provide 1-(phenylmethyl)-L-proline hydrochloride (13.30 g, 97%). LCMS: (M+H)+: 206.1 extracted with CH2Cl2 (3×50 mL) The combined organic layers were dried over Na2SO4 filtered concentrated in vacuo The aqueous layers were concentrated in vacuo the resulting solid precipitate was collected by filtration

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

Procedure: Into a 5,000 ml 3-necked roundbottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of lithium aluminum hydride (54.0 g, 1.42 mol) in tetrahydrofuran (3,500 ml) at 0° C. This was followed by the dropwise addition of a solution of ethyl 1-benzylprolinate (330 g, 1.42 mol) in tetrahydrofuran (500 ml), maintaining an internal temperature of 0° C. (2 hours total addition time). The resulting solution was allowed to stir for 2 hours while the temperature was maintained at 0° C. The reaction mixture was then quenched by the addition of water. The solution was filtered, and the filtration residue was washed once with 500 ml of tetrahydrofuran. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The residue was dissolved in 3,000 ml of ethyl acetate, dried over sodium sulfate, filtered and concentrated to afford 1-benzylpyrrolidin-2-yl)methanol, which was used without further purification. Into a 5,000 ml 3-necked roundbottom flask purged maintained with an inert atmosphere of nitrogen at 0° C was maintained at 0° C The reaction mixture was then quenched by the addition of water The solution was filtered the filtration residue was washed once with 500 ml of tetrahydrofuran The filtrate was concentrated by evaporation under vacuum a rotary evaporator The residue was dissolved in 3,000 ml of ethyl acetate dried over sodium sulfate filtered concentrated to afford 1-benzylpyrrolidin-2-yl)methanol, which was used without further purification

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

Procedure: Into a 500 ml 3-necked roundbottom flask, was placed ethyl prolinate (20.0 g, 140. mmol). This was followed by the addition of a solution of benzaldehyde (14.8 g, 140. mmol) in dichloromethane (100 ml). This was followed by the addition of a solution of sodium triacetoxyborohydride (60.0 g, 280. mmol) in acetic acid (20 ml). The resulting solution was allowed to stirring for 12 hours at room temperature. Adjustment of the pH to 7 was accomplished by the addition of solid potassium carbonate. The resulting solution was extracted one time with 500 ml of EtOAc and concentrated by evaporation to afford ethyl 1-benzylprolinate that was used without further purification. Into a 500 ml 3-necked roundbottom flask, was placed The resulting solution was extracted one time with 500 ml of EtOAc concentrated by evaporation

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: First 6.91 mL (23.57 mmol) of titanium (IV) isopropoxide and then 14.3 mL (42.9 mmol, 3 M in diethyl ether) of ethylmagnesium bromide were slowly added dropwise to a solution of 5.0 g (21.43 mmol) of N-benzyl-L-proline ethyl ester in 80 mL of dry diethyl ether which had been cooled to −15° C. and the reaction mixture was stirred for 30 minutes at this temperature. Subsequently at approximately 10° C., 5.4 mL (42.9 mmol) of boron trifluoride-diethyl ether complex were added and the mixture was stirred for a further 75 hours at RT. While cooling, 50 mL of 1M NaOH was added, the mixture was stirred for 1 hours at RT, combined with 100 mL of diethyl ether, and the organic phase was separated off and dried over sodium sulfate. After the desiccant and solvent had been eliminated, the residue was purified by chromatography (silica gel, EtOAc). Yield: 0.745 g (16% of theoretical); C14H19NO (M=217.307); calc.: molpeak (M+H)+: 218; found: molpeak (M+H)+: 218; Rf value: 0.17 (silica gel, EtOAc). Subsequently at approximately 10° C., 5.4 mL (42.9 mmol) of boron trifluoride-diethyl ether complex were added the mixture was stirred for a further 75 hours at RT While cooling the mixture was stirred for 1 hours at RT the organic phase was separated off dried over sodium sulfate the residue was purified by chromatography (silica gel, EtOAc)

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

Procedure: N-Benzyl-L-proline ethyl ester (1.00 g, 4.3 mmol) was combined with aqueous 2N sodium hydroxide (5.0 mL, 10.0 mmol), tetrahydrofuran (2.0 mL) and MeOH (2.0 mL) and the mixture stirred at rt. until hydrolysis was complete. The mixture was then treated in a manner similar to preparation 104. Concentration of the filtrate netted 0.79 g (90%) of crude acid as a light yellowish solid. MS(ES): (M+1)+ 206.3, 207.3. until hydrolysis The mixture was then treated in a manner similar to preparation 104