L-Proline, 4-hydroxy-1-methyl-, methyl ester, trans- (9CI)

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

Procedure: Methyl (2S,4R)-4-hydroxy-1-methyl-pyrrolidine-2-carboxylate 3b (6 g, 37 mmol) was dissolved in 100 mL of dichloromethane, followed by addition of imidazole (7.70 g, 113 mmol) and tert-butyl dimethylchlorosilane (6.80 g, 45 mmol) successively. After stirring for 12 hours, the reaction mixture was diluted with 100 mL of dichloromethane, washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound methyl (2S,4R)-4-(tert-butyl(dimethyl)silyl)oxy-1-methyl-pyrrolidine-2-carboxylate 3c crude product as a colourless oil, which was directly used in the next step without purification. washed with water (50 mL) and saturated brine (50 mL) successively dried over anhydrous sodium sulfate filtered concentrated under reduced pressure the resulting residue was purified by silica gel column chromatography with elution system

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

Procedure: Methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate 3a (5.53 g, 38 mmol) was dissolved in 80 mL of methanol in an ice-water bath, followed by addition of 40% formaldehyde solution (31 mL, 380 mmol) and sodium cyanoborohydride (12 g, 190 mmol) in batches. The reaction mixture was stirred for 0.5 hours, then warmed up to room temperature and stirred for 3 hours. The mixture was quenched with 40 mL of water, concentrated under reduced pressure and extracted with dichloromethane (80 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound methyl (2S,4R)-4-hydroxy-1-methyl-pyrrolidine-2-carboxylate 3b crude product as a colourless oil, which was directly used in the next step. stirred for 3 hours The mixture was quenched with 40 mL of water concentrated under reduced pressure extracted with dichloromethane (80 mL×3) The combined organic extracts were washed with saturated brine (30 mL×2) dried over anhydrous sodium sulfate filtered The filtrate was concentrated under reduced pressure

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

Procedure: Methyl (2S,4R)-4-hydroxy-1-methyl-pyrrolidine-2-carboxylate 3b (6 g, 37 mmol) was dissolved in 100 mL of dichloromethane, followed by addition of imidazole (7.70 g, 113 mmol) and tert-butyl dimethylchlorosilane (6.80 g, 45 mmol) successively. After stirring for 12 hours, the reaction mixture was diluted with 100 mL of dichloromethane, washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound methyl (2S,4R)-4-(tert-butyl(dimethyl)silyl)oxy-1-methyl-pyrrolidine-2-carboxylate 3c crude product as a colourless oi, which was directly used in the next step without purification. washed with water (50 mL) and saturated brine (50 mL) successively dried over anhydrous sodium sulfate filtered concentrated under reduced pressure the resulting residue was purified by silica gel column chromatography with elution system

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

Procedure: Methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate 3a (5.53 g, 38 mmol) was dissolved in 80 mL of methanol in an ice-water bath, followed by addition of 40% formaldehyde solution (31 mL, 380 mmol) and sodium cyanoborohydride (12 g, 190 mmol) in batches. The reaction mixture was stirred for 0.5 hours, then warmed up to room temperature and stirred for 3 hours. The mixture was quenched with 40 mL of water, concentrated under reduced pressure and extracted with dichloromethane (80 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound methyl (2S,4R)-4-hydroxy-1-methyl-pyrrolidine-2-carboxylate 3b crude product as a colourless oil, which was directly used in the next step. stirred for 3 hours The mixture was quenched with 40 mL of water concentrated under reduced pressure extracted with dichloromethane (80 mL×3) The combined organic extracts were washed with saturated brine (30 mL×2) dried over anhydrous sodium sulfate filtered The filtrate was concentrated under reduced pressure