Stereoselective Metal-Free Reduction of Chiral Imines in Batch and Flow Mode: A Convenient Strategy for the Synthesis of Chiral Active Pharmaceutical Ingredients

Abstract

he convenient, metal-free reduction of imines that contain an inexpensive and removable chiral auxiliary allowed for the synthesis of the immediate precursors of chiral active pharmaceutical ingredients (APIs). This protocol was carried out under batch and flow conditions to give the correspoding prod- ucts in high yields with almost complete stereocontrol. In the presence of trichlorosilane, an inexpensive and nontoxic reduc- ing agent, and an achiral Lewis base such as N,N-dimethyl- Introduction The pharmaceutical industry is gradually progressing towards enantiopure formulations. Most newly introduced drugs are chiral, and it is expected that approximately 95 % of pharma- ceutical drugs will be chiral by 2020. [1] In this context, chiral amines are considered a class of paramount importance, be- cause they are found in a plethora of compounds such as those of pharmaceutical interest as well as those developed for agro- chemicals, fragrances, and fine chemicals. [2] The reduction of the C=N group is one of the most widely used approaches to synthesize chiral amines, and over the last ten years, successful catalytic enantioselective methods based on both metal-pro- moted [3] and organocatalyzed [4] strategies have been devel- oped. When an industrial synthesis of a chiral pharmaceutical prod- uct must be planned, however, issues such as the chemical effi- ciency and robustness of the procedure, its general applicabil- ity, and economic considerations become crucially important. For these reasons, the applications of many chiral catalytic sys- tems are often not feasible, and the use of inexpensive and readily available chiral auxiliaries becomes an attractive and economic alternative. This also holds true for the synthesis of [a] Dipartimento di Chimica, Università degli Studi di Milano, via Golgi 19, 20133 Milano, Italy E-mail: maurizio.benaglia@unimi.it http://users2.unimi.it/Benagliagroup [b] Istituto di Scienze e Tecnologie Molecolari ISTM-CNR, Via Golgi 19, 20133 Milano, Italy [c] Department of Chemistry and Chemistry Center of Évora, University of Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal Supporting information and ORCID(s) from the author(s) for this article are available on the WWW under http://dx.doi.org/10.1002/ejoc.201601268. Eur. J. Org. Chem. 2017, 39–44 © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim39 formamide, the formal syntheses of Rivastgmine, calcimimetic NPS R-568, and a Rho kinases inhibitor were successfully accom- plished. For the first time, both the diastereoselective imine re- duction and the auxiliary removal were efficiently performed in a micro- or mesoreactor under continuous-flow conditions, which paved the way towards the development of a practical process for the syntheses of industrially relevant, biologically active, enantiopure N-alkylamines