(5R)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-one

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

Procedure: Under atmosphere of argon, a solution of (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolidine-2-one (2 g) in benzene (20 mL) was added by p-toluene sulfonic acid monohydrate (166 mg) and paraformic aldehyde (290 mg) and stirred for an hour at the room temperature. The mixture was added by ethyl 5-mercaptopentanoate (1.41 g) and stirred heating using Dean-Stark apparatus for three hours at the temperature of 125° C. The mixture was diluted with tert-butylmethylether solution, washed with water and saturated brine, dried over an sodium sulfate, concentrated and purified by column chromatography on silica gel (ethyl acetate:hexane=1:6). Under atmosphere of argon, the purified compound (1.9 g) in tetrahyrdorfuran solution (1.5 mL) was added by 1M tetrabutylammonium fluoride in tetrahydrofuran (4.7 mL) and stirred for an hour at room temperature. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to give the title compound (1.05 mg) having the following physical data. stirred heating for three hours at the temperature of 125° C washed with water and saturated brine dried over an sodium sulfate concentrated purified by column chromatography on silica gel (ethyl acetate:hexane=1:6) Under atmosphere of argon, the purified compound (1.9 g) in tetrahyrdorfuran solution (1.5 mL) was added by 1M tetrabutylammonium fluoride in tetrahydrofuran (4.7 mL) stirred for an hour at room temperature The mixture was diluted with ethyl acetate washed with water and saturated brine The organic layer was dried over sodium sulfate concentrated purified by column chromatography on silica gel (ethyl acetate:hexane=1:2)

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

Procedure: A THF (20 ml) solution of the (5R)-5-[(tert-butyldimethylsilyloxy)methyl]pyrrolidin-2-one (5.73 g, 25 mmols) was added dropwise, during cooling with ice, to a THF (100 ml) suspension of NaH (60% oil disp. 1.20 g, 30 mmols), whereafter the mixture was stirred for 30 minutes at room temperature. To the mixture, MeI (7.8 ml, 125 mmols) was added during cooling with ice, and the mixture was stirred for 15 hours at room temperature. During cooling with ice, a saturated aqueous solution (50 ml) of NH4Cl was added, and the solvent was distilled off under reduced pressure. The residue was diluted with water, whereafter the dilution was extracted with AcOEt (50 ml×3), and the organic layer was dried over MgSO4. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 250 g, MeOH—CHCl3 3:97 v/v) to obtain (5R)-5-[(tert-butyldimethylsilyloxy)methyl]-1-methylpyrrolidin-2-one (6.00 g, 98.8%). during cooling with ice the mixture was stirred for 15 hours at room temperature During cooling with ice the solvent was distilled off under reduced pressure The residue was diluted with water, whereafter the dilution was extracted with AcOEt (50 ml×3) the organic layer was dried over MgSO4 The solvent was distilled off under reduced pressure

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

Procedure: Imidazole (5.24 g, 77 mmols) was added to a CH2Cl2 (85 ml) solution of (5R)-5-(hydroxymethyl)-2-pyrrolidinone (4.03 g, 35 mmols). Then, during cooling with ice, a CH2Cl2 (15 ml) solution of tert-butyldimethylsilyl chloride (4.53 g, 30 mmols) was added, and the mixture was stirred for 15 hours at room temperature. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 300 g, MeOH—CHCl3 5:95 v/v) to obtain (5R)-5-[(tert-butyldimethylsilyloxy)methyl]pyrrolidin-2-one (7.92 g, 98.7%): Then, during cooling with ice The solvent was distilled off under reduced pressure

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

Procedure: Under atmosphere of argon, a solution of (5R)-5-hydroxymethylpyrollidin-2-one (10 g) and imidazole (8.8 g) in dry dimethylformamide (50 mL) was added by a solution of t-butyldimethylsilyl chloride (15.6 g) in dry dimethylformamide (50 mL) at room temperature, and the mixture was stirred for 5 hours. To the mixture, a mixed solvent of ethyl acetate and hexane was added. The diluted solution was washed with water and brine successively, dried over an anhydrous sodium sulfate, concentrated under reduced pressure to give the title compound (21.41 g) having the following physical data. The diluted solution was washed with water and brine successively dried over an anhydrous sodium sulfate concentrated under reduced pressure

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

Procedure: Under atmosphere of argon, a solution of (5R)-5-hydroxymethylpyrollidin-2-one (10 g) and imidazole (8.8 g) in dry dimethylformamide (50 mL) was added by a solution of t-butyldimethylsilyl chloride (15.6 g) in dry dimethylformamide (50 mL) at room temperature, and the mixture was stirred for 5 hours. To the mixture, a mixed solvent of ethyl acetate and hexane was added. The diluted solution was washed with water and brine successively, dried over an anhydrous sodium sulfate, concentrated under reduced pressure to give the title compound (21.41 g) having the following physical data. The diluted solution was washed with water and brine successively dried over an anhydrous sodium sulfate concentrated under reduced pressure

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

Procedure: To a solution of (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-pyrrolidinone (11.2 g) in tetrahydrofuran (97 mL) were potassium tert-butoxide (6.27 g) and methyl bromoacetate (8.11 g) at 0° C. and the solution was stirred for 2 Hours. To the reaction solution were added water, ethyl acetate and hexane and the reaction solution was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (14.3 g) having the following physical data. at 0° C. the reaction solution was separated The aqueous layer was extracted with ethyl acetate The combined organic layer was washed with water and brine dried over anhydrous sodium sulfate concentrated

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

Procedure: Under atmosphere of argon, a solution of (5R)-5-hydroxymethylpyrollidin-2-one (10 g) and imidazole (8.8 g) in dry dimethylformamide (50 mL) was added by a solution of t-butyldimethylsilyl chloride (15.6 g) in dry dimethylformamide (50 mL) at room temperature, and the mixture was stirred for 5 hours. To the mixture, a mixed solvent of ethyl acetate and hexane was added. The diluted solution was washed with water and brine successively, dried over an anhydrous sodium sulfate, concentrated under reduced pressure to give the title compound (21.41 g) having the following physical data. The diluted solution was washed with water and brine successively dried over an anhydrous sodium sulfate concentrated under reduced pressure

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

Procedure: To a solution of (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-pyrrolidinone (11.2 g) in tetrahydrofuran (97 mL) were potassium tert-butoxide (6.27 g) and methyl bromoacetate (8.11 g) at 0° C. and the solution was stirred for 2 hours. To the reaction solution were added water, ethyl acetate and hexane and the reaction solution was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (14.3 g) having the following physical data. at 0° C. the reaction solution was separated The aqueous layer was extracted with ethyl acetate The combined organic layer was washed with water and brine dried over anhydrous sodium sulfate concentrated

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

Procedure: Under atmosphere of argon, a solution of (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolidine-2-one (2 g) in benzene (20 mL) was added by p-toluene sulfonic acid monohydrate (166 mg) and paraformic aldehyde (290 mg) and stirred for an hour at the room temperature. The mixture was added by ethyl 5-mercaptopentanoate (1.41 g) and stirred heating using Dean-Stark apparatus for three hours at the temperature of 125° C. The mixture was diluted with tert-butylmethylether solution, washed with water and saturated brine, dried over an sodium sulfate, concentrated and purified by column chromatography on silica gel (ethyl acetate:hexane=1:6). Under atmosphere of argon, the purified compound (1.9 g) in tetrahyrdorfuran solution (1.5 mL) was added by 1M tetrabutylammonium fluoride in tetrahydrofuran (4.7 mL) and stirred for an hour at room temperature. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to give the title compound (1.05 mg) having the following physical data. stirred heating for three hours at the temperature of 125° C washed with water and saturated brine dried over an sodium sulfate concentrated purified by column chromatography on silica gel (ethyl acetate:hexane=1:6) Under atmosphere of argon, the purified compound (1.9 g) in tetrahyrdorfuran solution (1.5 mL) was added by 1M tetrabutylammonium fluoride in tetrahydrofuran (4.7 mL) stirred for an hour at room temperature The mixture was diluted with ethyl acetate washed with water and saturated brine The organic layer was dried over sodium sulfate concentrated purified by column chromatography on silica gel (ethyl acetate:hexane=1:2)

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

Procedure: A THF (20 ml) solution of the (5R)-5-[(tert-butyldimethylsilyloxy)methyl]pyrrolidin-2-one (5.73 g, 25 mmols) was added dropwise, during cooling with ice, to a THF (100 ml) suspension of NaH (60% oil disp. 1.20 g, 30 mmols), whereafter the mixture was stirred for 30 minutes at room temperature. To the mixture, MeI (7.8 ml, 125 mmols) was added during cooling with ice, and the mixture was stirred for 15 hours at room temperature. During cooling with ice, a saturated aqueous solution (50 ml) of NH4Cl was added, and the solvent was distilled off under reduced pressure. The residue was diluted with water, whereafter the dilution was extracted with AcOEt (50 ml×3), and the organic layer was dried over MgSO4. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 250 g, MeOH—CHCl3 3:97 v/v) to obtain (5R)-5-[(tert-butyldimethylsilyloxy)methyl]-1-methylpyrrolidin-2-one (6.00 g, 98.8%). during cooling with ice the mixture was stirred for 15 hours at room temperature During cooling with ice the solvent was distilled off under reduced pressure The residue was diluted with water, whereafter the dilution was extracted with AcOEt (50 ml×3) the organic layer was dried over MgSO4 The solvent was distilled off under reduced pressure

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

Procedure: Imidazole (5.24 g, 77 mmols) was added to a CH2Cl2 (85 ml) solution of (5R)-5-(hydroxymethyl)-2-pyrrolidinone (4.03 g, 35 mmols). Then, during cooling with ice, a CH2Cl2 (15 ml) solution of tert-butyldimethylsilyl chloride (4.53 g, 30 mmols) was added, and the mixture was stirred for 15 hours at room temperature. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 300 g, MeOH—CHCl3 5:95 v/v) to obtain (5R)-5-[(tert-butyldimethylsilyloxy)methyl]pyrrolidin-2-one (7.92 g, 98.7%): Then, during cooling with ice The solvent was distilled off under reduced pressure

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

Procedure: Under atmosphere of argon, a solution of (5R)-5-hydroxymethylpyrollidin-2-one (10 g) and imidazole (8.8 g) in dry dimethylformamide (50 mL) was added by a solution of t-butyldimethylsilyl chloride (15.6 g) in dry dimethylformamide (50 mL) at room temperature, and the mixture was stirred for 5 hours. To the mixture, a mixed solvent of ethyl acetate and hexane was added. The diluted solution was washed with water and brine successively, dried over an anhydrous sodium sulfate, concentrated under reduced pressure to give the title compound (21.41 g) having the following physical data. The diluted solution was washed with water and brine successively dried over an anhydrous sodium sulfate concentrated under reduced pressure