Continuous-flow stereoselective catalytic synthesis of Active pharmaceutical Ingredients in micro- and (3D-printed) meso- reactors

In the last few years, continuous-flow systems1 have become very popular as a powerful tool for performing synthesis of organic molecules. In this context, we explored the use of different micro- and mesoreactors to develop stereoselective catalytic reactions under continuous flow conditions aimed to the synthesis of chiral Active Pharmaceutical Ingredients.2 In this field we reported the in-flow synthesis of chiral 1,2-amino alcohols displaying biological activities (norephedrine, metaraminol, and methoxamine) using 3D-printed reactors (Scheme 1).3 These devices were designed, fabricated from different materials (PLA, HIPS, NYLON), and used in a catalytic stereoselective Henry reaction. The use of readily prepared and tuneable 3D-printed reactors allowed for a rapid screening of devices with different sizes, shapes and channel dimensions, aimed at the identification of the best performing reactor set up. The optimized process afforded products in high yields, moderate diasteroselectivity and up to 90% e.e. through two-steps, all-in-flow sequence that involves, after the nitroaldol reaction, a continuous flow hydrogenation. To highlight the potential industrial application of this methodology, a multistep continuous synthesis of norephedrine has been realized: the product was isolated without any intermediates purification or solvent switching operation.