(S)-3-(Boc-amino)pyrrolidine

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131852-53-4

122536-76-9

1. In a 500 mL four-necked flask fitted with a stirrer, thermometer, Dimroth condenser and titration funnel, 17.6 g (0.1 mol, optical purity 99.5% ee) of (S)-3-amino-1-benzylpyrrolidine was added. Subsequently, 158.7 g of water and 0.2 g of cationic DS (produced by Sanyo Chemical Industries, Ltd.) were added and the pH of the mixture was adjusted to 11 ± 0.5 using 48% aqueous sodium hydroxide solution. 2. The mixture was stirred at 50 to 60 °C while 26.2 g (0.12 mol) of di-tert-butyl dicarbonate (DiBoc) was added dropwise for about 2 hours. During the dropwise addition, the pH of the reaction solution was maintained at 11 ± 0.5 using 48% aqueous sodium hydroxide. 3. After completion of the dropwise addition, stirring was continued for 1 hour, after which the reaction solution was cooled to room temperature and the precipitated crystals were separated by filtration. 4. The resulting crystals were dried under vacuum at 50 °C to afford 26.0 g of (S)-1 -benzyl-3-tert-butoxycarbonylaminopyrrolidine in 94.1% yield, 99.1% chemical purity and 99.5% optical purity ee. 5. Using the same apparatus as in Step 1 , 26.0 g (optical purity 99.5% ee) of (S)-1 -benzyl-3-tert-butoxycarbonylaminopyrrolidine, 120 g of water, and 2.6 g of 5% Pd/C (PE-type, 55.27% water content, manufactured by NE Chemcat Corp.) were added. The reaction was stirred at 40°C reaction temperature for 10 hours under hydrogen atmosphere. 6. After confirming the completion of the reaction by GC analysis, the Pd/C was removed by filtration and the filtrate was concentrated to 30 g using an evaporator. 7. The concentrated product was mixed with toluene and concentrated again to 20 g to remove water by azeotropy. 8. 25 g of hexane was slowly added to the concentrated solution with stirring to precipitate crystals, followed by continued stirring in an ice bath for 2 hours. 9. The precipitated crystals were separated by filtration and dried under vacuum to afford 15.4 g of (S)-3-tert-butoxycarbonylaminopyrrolidine in 87.4% yield, 99.5% chemical purity, 99.5% optical purity ee, and 0.4% water content.