(a) Synthesis of (3S)-4-benzyl-3-(chloromethyl)morpholine: [(3R)-4-benzylmorpholin-3-yl]methanol (1.83 g, 8.8 mmol) was dissolved in anhydrous dichloromethane (15 mL) under argon protection. To this solution thionyl chloride (3.15 g, 26.5 mmol) and N,N-dimethylformamide (DMF, 2 drops) were added sequentially. The reaction mixture was heated to reflux with continuous stirring for 2 h 30 min. After completion of the reaction, the solvent was removed by rotary evaporator. The residue was neutralized with saturated aqueous sodium bicarbonate and subsequently extracted with ethyl acetate (3 × 15 mL). The organic phases were combined, dried with anhydrous sodium sulfate, filtered and concentrated to afford the oily product (3S)-4-benzyl-3-(chloromethyl)morpholine (1.88 g, 94% yield). The product was characterized by 1H NMR (500 MHz, CDCl3) and LCMS: 1H NMR (500 MHz, CDCl3) δ 2.3-2.4 (m, 1H), 2.7 (m, 1H), 2.8 (m, 1H), 3.5 (d, 1H), 3.6-3.9 (m, 5H), 4.0 (d, 1H), 7.3 (m, 1H) , 7.4 (m, 4H); LCMS: m/z 226 [M + H]+.
