In-flow synthesis of advanced precursors of Chiral APIs

In the field of APIs (Active Pharmaceutical Ingredients), the industry is gradually progressing towards enantiopure formulations. In this context, chiral amines are unanimously considered a class of paramount importance, due to their widespread diffusion in a plethora of compounds.1 The diastereoselective and metal free, trichlorosilane-mediate reduction of imines, bearing different and removable chiral auxiliaries, in combination either with achiral bases or catalytic amounts of chiral Lewis bases, represents a feasible approach to afford immediate precursors of chiral APIs.2 In the present work, the carbon-nitrogen double bond reduction was successfully performed in batch and in flow mode, in high yields and almost complete stereocontrol.3 By this metal-free approach, the formal synthesis of Rasagiline and Tamsulosin was successfully accomplished in micro(meso) flow reactors, under continuous flow conditions. Chiral primary amines were obtained, either by a continuous flow hydrogenolysis, or directly out from the flow reactor after an in-line aqueous work up, depending on the chiral auxiliary group at the amine nitrogen atom. References 1. Chiral Amine Synthesis: Methods, Developments and Applications (Ed.: T. C. Nugent), Wiley-VCH, Weinheim, 2010. 2. D. Brenna, M. Benaglia, R. Porta, S. D. Fernandes, A. J. Burke, Eur. J. Org. Chem, 2016, doi:10.1002/ejoc.201601268. 3. D. Brenna, M. Pirola, L. Raimondi, A.J. Burke, M. Benaglia, Bioorg. & Med. Chem., 2017, doi: http://dx.doi.org/10.1016/j.bmc.2017.01.02