Continuous flow Aza-Michael reaction for preparing the fast-acting synthetic opioid drug Remifentanil

Abstract Remifentanil is a modern fentanyl analogue with ultrashort-action granted by an esterase-labile methyl propanoate chain. Here, we present the development of a continuous flow methodology for the key N-alkylation step of remifentanil preparation in a biphasic, “slug-flow” regime. We screened parameters under microwave-assisted reactions, translated conditions to flow settings, and obtained remifentanil under 15-min residence time in a 1-mL microreactor, with a space-time yield of 89 mg/mL·h and 94% yield.摘要 瑞芬太尼（Remifentanil）是一类新型超短效芬太尼（fentanyl）类似物，其分子中含有的酯酶不稳定的丙酸甲酯链赋予了其超短效的药理特性。本文报道了一种适用于瑞芬太尼制备关键N-烷基化步骤的连续流合成工艺，该工艺采用两相弹状流（slug-flow）反应体系。我们在微波辅助反应条件下对工艺参数进行了系统筛选，并将优化后的反应条件迁移至连续流反应装置中，最终在1 mL微反应器内仅需15分钟停留时间即可得到目标产物瑞芬太尼，时空产率可达89 mg/mL·h，反应收率达94%。