General procedure for the synthesis of tert-butyl (R)-2-carbamoylpyrrolidine-1-carboxylate from Boc-D-proline:
Example 1; Synthesis of tert-butyl (R)-2-carbamoylpyrrolidine-1-carboxylate.
N-Methylmorpholine (9.85 g, 97.5 mmol) and isobutyl chloroformate (13.3 g, 97.5 mmol) were added to a THF solution (98 mL) of (R)-pyrrolidine-1,2-dicarboxylic acid 1- tert-butyl ester (20.0 g, 92.9 mmol) at -78 °C and stirred for 1 hour. Ammonium hydroxide (58 mL) was slowly added while the reaction system was warmed to room temperature and stirring was continued for 2 hours. Upon completion of the reaction, the reaction mixture was partitioned between dichloromethane and water. The organic phase was washed with 1 M HCl, dried over anhydrous sodium sulfate, filtered and concentrated to give the title product (10.8 g, 54%) as a colorless semi-solid.1H NMR (300 MHz, CDCl3): δ (ppm) 5.91-6.13 (m, 1H), 4.17-4.30 (m, 2H), 3.37-3.48 (m, 2H), 2.10- 2.18 (m, 2H), 1.84-1.96 (m, 2H), 1.45 (s, 9H).
