General procedure for the synthesis of N-Boc-azetidine-3-carboxamide from 1-Boc-azetidine-3-carboxylic acid: 1-[(tert-butoxy)carbonyl]azetidine-3-carboxylic acid (4.96 g, 24.65 mmol) and triethylamine (TEA, 5.84 mL, 42.0 mmol) were dissolved in tetrahydrofuran (THF, 60 mL) and the the mixture was cooled to -20 °C. Isobutyl chloroformate (4.8 mL, 37.0 mmol) was added slowly with stirring, followed by stirring the reaction mixture at -10 °C for 15 min. 28% ammonia (7.46 mL, 394 mmol) was added, then the mixture was gradually warmed to room temperature and stirring was continued for 1 hour. Upon completion of the reaction, the reaction was quenched with saturated sodium bicarbonate (NaHCO?) solution, the reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by fast column chromatography using 20-100% ethyl acetate (EtOAc)/heptane gradient elution and 1-4% methanol (MeOH)/ethyl acetate (EtOAc) elution sequentially to afford N-Boc-azetidine-3-carboxamide (3.99 g, 81% yield) as a white solid. The product was confirmed by 1H-NMR (CDCl?, 250 MHz) and HPLC-MS (Method A): 1H-NMR δ [ppm] = 5.47 (s, 2H), 4.22-4.01 (m, 4H), 3.34-3.15 (m, 1H), 1.46 (s, 9H); HPLC-MS [m/z]: 222.95 [M + Na ]+.
