Abstract

Enantiomerically pure secondary alcohols are useful in the synthesis of several natural products and as active pharmaceutical intermediates (API). Due to the high demand for these chiral compounds, much progress has been made in the areas of asymmetric synthesis and catalysis. In this context, biocatalysis together with continuous flow technology can be a valuable tool for more versatile and sustainable methods, with lower cost, greater stereoselectivity and less environmental impact. This work aims to obtain an enantiomerically pure alcohol of industrial interest, (4 Fluorophenyl) (furan-2-yl) methanol (3), by performing a kinetic resolution using immobilized Candida antarctica lipase B (Novozyme 435, N435) under continuous-flow conditions. Initial study was carried out to optimize batch reaction conditions. The best results were obtained using isooctane as solvent, 37.7 mg of N435 and three equivalents of isopropenyl acetate as acyl donor at 60 °C for 24 h. Under these conditions, a conversion of 49% and 91 of enantiomeric ratio was obtained. Optimized batch conditions were translated to the continuous flow reactor leading to the desired product in 30 min of residence time, 47% conversion and an enantiomeric ratio of 61.

摘要

对映体纯的仲醇可用于合成多种天然产物和作为活性药物中间体 (API)。由于对这些手性化合物的高需求，在不对称合成和催化领域取得了很大进展。在这种情况下，生物催化与连续流技术一起可以成为一种有价值的工具，可以实现更通用和可持续的方法，并且成本更低，立体选择性更强，对环境的影响更小。本工作旨在通过使用固定化南极念珠菌进行动力学拆分，获得具有工业价值的对映体纯醇，(4 氟苯基) (呋喃-2-基) 甲醇 ( 3 )连续流动条件下的脂肪酶 B（Novozyme 435、N435）。进行了初步研究以优化间歇反应条件。使用异辛烷作为溶剂，37.7 mg N435 和三当量乙酸异丙烯酯作为酰基供体，在 60 °C 下反应 24 小时，获得了最佳结果。在此条件下，获得了49%的转化率和91的对映体比率。优化的间歇条件被转化为连续流动反应器，在 30 分钟的停留时间内产生所需的产物，转化率为 47%，对映体比率为 61。