Centre for Intelligent Microprocess of Pharmaceutical Synthesis, Department of Chemical Engineering, POSTECH (Pohang University of Science and Technology), Pohang, 790-784, South Korea.
Department of Chemistry, College of Science, Korea University, Seoul, 02841, South Korea.
Chemistry. 2019 Sep 6;25(50):11641-11645. doi: 10.1002/chem.201903267. Epub 2019 Aug 20.
Ibuprofen was prepared from an inactive and inexpensive p-xylene by three-step flow functionalizations through chemoselective metalations of benzyl positions in sequence using an in situ generated LICKOR-type superbase. The flow approach in the microreactor facilitated the comprehensive exploration of over 100 conditions in the first-step reaction by varying concentrations, temperatures, solvents, and equivalents of reagents, enabling optimal conditions to be found with 95 % yield by significantly suppressing the formation of byproducts, followed by the second C-H metalation step in 95 % yield. Moreover, gram-scale synthesis of ibuprofen in the final step was achieved by biphasic flow reaction of solution-phase intermediate with CO , isolating 2.3 g for 10 min of operation time.
布洛芬由一种非活性且廉价的对二甲苯通过三步流动功能化反应制备而成，该反应通过原位生成的 LICKOR 型超强碱依次对苄基位置进行选择性金属化。在微反应器中的流动方法有助于通过改变浓度、温度、溶剂和试剂当量等条件，全面探索第一步反应中的 100 多种条件，从而找到最佳条件，使副产物的生成得到显著抑制，产率达到 95%，然后以 95%的产率进行第二步 C-H 金属化。此外，通过溶液相中间体与 CO 的两相流反应实现了布洛芬的克级规模合成，在 10 分钟的操作时间内分离出 2.3 克布洛芬。
