[1-benzyl-5-(hydroxymethyl)pyrrolidin-2-yl]methanol

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

Procedure: To a solution of 1-benzyl-2,5-bis(hydroxymethyl)-pyrrolidine (30 g) and imidazole (27.8 g) in dimethylformamide (300 ml) was added portionwise t-butyldimethylsilyl chloride (20.4 g) at room temperature. After stirring for 1 hour at room temperature, water (0.9 l) and ethyl acetate (1.4 l) was added to the mixture. After shaking, aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layer was washed with water (3 times) and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (eluent:nexane/ethyl acetate, 8:2-7:3 V/V) to give 1-benzyl-5-t-butyldimethylsilyloxymethyl-2-hydroxymethylpyrrolidine (16.8 g). After shaking aqueous layer was separated extracted twice with ethyl acetate The combined organic layer was washed with water (3 times) and brine dried over magnesium sulfate evaporated under reduced pressure chromatographed on silica gel (eluent:nexane/ethyl acetate, 8:2-7:3 V/V)

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

Procedure: To a solution of 1-benzyl-2,5-bis(hydroxymethyl)-pyrrolidine (30 g) and imidazole (27.8 g) in dimethylformamide (300 ml) was added portionwise t-butyldimethylsilyl chloride (20.4 g) at room temperature. After stirring for 1 hour at room temperature, water (0.9 l) and ethyl acetate (1.4 l) was added to the mixture. After shaking, aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layer was washed with water (3 times) and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (eluent:nexane/ethyl acetate, 8:2-7:3 V/V) to give 1-benzyl-5-t-butyldimethylsilyloxymethyl-2-hydroxymethylpyrrolidine (16.8 g). After shaking aqueous layer was separated extracted twice with ethyl acetate The combined organic layer was washed with water (3 times) and brine dried over magnesium sulfate evaporated under reduced pressure chromatographed on silica gel (eluent:nexane/ethyl acetate, 8:2-7:3 V/V)

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

Procedure: To a suspension of lithium aluminum hydride 10.25 g) in tetrahydrofuran (550 ml) was added dropwise a solution of 1-benzyl-2,5-bis(ethoxycarbonyl)pyrrolidine (55 g) in tetrahydrofuran (100 ml). The reaction mixture was stirred for 30 minutes at 0° C., allowed to warm to room temperature and then stirred at the same temperature for 1 hour. And then water was added carefully until excess lithium aluminum hydride was decomposed. After the precipitate was filtered off, the filtrate was evaporated under reduced pressure to give crude 1-benzyl-2,5-bis(hydroxymethyl)pyrrolidine (38.52 g). to warm to room temperature stirred at the same temperature for 1 hour After the precipitate was filtered off the filtrate was evaporated under reduced pressure

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

Procedure: A solution of 96.4 grams of 1-benzyl-pyrrolidine-2,5-dicarboxylic acid, 2-ethyl ester, 5-methyl ester in 380 ml of anhydrous tetrahydrofuran is dripped rapidly into a solution of lithium aluminum hydride (437 mmol) in tetrahydrofuran (1.4 liter) at 0° C. After complete addition, the mixture is stirred for 3 hours at ambient temperature and then carefully quenched with 57.8 ml of water followed by 38.6 ml of 10% sodium hydroxide. The mixture is stirred overnight, filtered through Celite, the Celite washed with CH2Cl2 and the combined filtrate evaporated to provide 67.11 grams of crude (1-benzyl-5-hydroxymethyl-pyrrolidine-2-yl)-methanol. After complete addition carefully quenched with 57.8 ml of water The mixture is stirred overnight filtered through Celite the Celite washed with CH2Cl2 the combined filtrate evaporated

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

Procedure: To a solution of 1-benzyl-2,5-bis(hydroxymethyl)pyrrolidine (30 g) and imidazole (27.8 g) in dimethylformamide (300 ml) was added portionwise t-butyldimethylsilyl chloride (20.4 g) at room temperature. After stirring for 1 hour at room temperature, water (0.9 l) and ethyl acetate (1.4 l) was added to the mixture. After shaking, aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layer was washed with water (3 times) and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (eluent:nexane/ethyl acetate, 8:2-7:3 V/V) to give 1-benzyl-5-t-butyldimethylsilyloxymethyl-2-hydroxymethylpyrrolidine (16.8 g). After shaking aqueous layer was separated extracted twice with ethyl acetate The combined organic layer was washed with water (3 times) and brine dried over magnesium sulfate evaporated under reduced pressure chromatographed on silica gel (eluent:nexane/ethyl acetate, 8:2-7:3 V/V)

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

Procedure: To a suspension of lithium aluminum hydride (10.25 g) in tetrahydrofuran (550 ml) was added dropwise a solution of 1-benzyl-2,5-bis(ethoxycarbonyl)pyrrolidine (55 g) in tetrahydrofuran (100 ml). The reaction mixture was stirred for 30 minutes at 0° C., allowed to warm to room temperature and then stirred at the same temperature for 1 hour. And then water was added carefully until excess lithium aluminum hydride was decomposed. After the precipitate was filtered off, the filtrate was evaporated under reduced pressure to give crude 1-benzyl-2,5-bis(hydroxymethyl)pyrrolidine (38.52 g). to warm to room temperature stirred at the same temperature for 1 hour After the precipitate was filtered off the filtrate was evaporated under reduced pressure

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

Procedure: To a solution of 1-benzyl-2,5-bis(hydroxymethyl)-pyrrolidine (30 g) and imidazole (27.8 g) in dimethylformamide (300 ml) was added portionwise t-butyldimethylsilyl chloride (20.4 g) at room temperature. After stirring for 1 hour at room temperature, water (0.9 l) and ethyl acetate (1.4 l) was added to the mixture. After shaking, aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layer was washed with water (3 times) and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (eluent:nexane/ethyl acetate, 8:2-7:3 V/V) to give 1-benzyl-5-t-butyldimethylsilyloxymethyl-2-hydroxymethylpyrrolidine (16.8 g). After shaking aqueous layer was separated extracted twice with ethyl acetate The combined organic layer was washed with water (3 times) and brine dried over magnesium sulfate evaporated under reduced pressure chromatographed on silica gel (eluent:nexane/ethyl acetate, 8:2-7:3 V/V)

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

Procedure: To a suspension of lithium aluminum hydride 10.25 g) in tetrahydrofuran (550 ml) was added dropwise a solution of 1-benzyl-2,5-bis(ethoxycarbonyl)pyrrolidine (55 g) in tetrahydrofuran (100 ml). The reaction mixture was stirred for 30 minutes at 0° C., allowed to warm to room temperature and then stirred at the same temperature for 1 hour. And then water was added carefully until excess lithium aluminum hydride was decomposed. After the precipitate was filtered off, the filtrate was evaporated under reduced pressure to give crude 1-benzyl-2,5-bis(hydroxymethyl)pyrrolidine (38.52 g). to warm to room temperature stirred at the same temperature for 1 hour After the precipitate was filtered off the filtrate was evaporated under reduced pressure