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Development of heterogeneous catalyst systems for the continuous synthesis of chiral amines via asymmetric hydrogenation

Abstract

Continuous-flow synthesis of fine chemicals has several advantages over batch synthesis in terms of environmental compatibility, efficiency and safety. Nevertheless, most preparative methods still rely on conventional batch systems. For instance, chiral amines are ubiquitous functionalities in pharmaceutical compounds, but methods for their continuous synthesis with broad substrate generality remain very challenging. Here we show the development of heterogeneous iridium complexes combined with chiral phosphoric acids for the asymmetric hydrogenation of imines towards the continuous synthesis of chiral amines. Direct asymmetric reductive amination of ketones under a hydrogen atmosphere also proceeded smoothly using the same catalyst systems. Various chiral aromatic and aliphatic amines including pharmaceutical intermediates could be prepared in high yields with high enantioselectivities. It was found that continuous-flow reactions that use columns packed with the heterogeneous iridium complexes afforded chiral amines continuously for more than two days even at pressures lower than those in the corresponding batch reactions.

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Fig. 1: The substrate scope for asymmetric hydrogenation of aromatic imines.
Fig. 2: The substrate scope for DARA.
Fig. 3: The formal synthesis of tamsulosin.
Fig. 4: Asymmetric hydrogenation of an imine with a continuous-flow system.
Fig. 5: Direct asymmetric reductive amination of a ketone with a continuous-flow system.

Data availability

Other reaction procedures and characterization data of compounds are available in the Supplementary Information. All data is available from the authors on reasonable request.

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Acknowledgements

This work was supported in part by a Grant-in-Aid for Scientific Research from JSPS, the University of Tokyo, MEXT (Japan), AMED and JST. We thank T. Maki (The University of Tokyo) for scanning transmission electron microscopy and energy dispersive X-ray spectrometry analyses.

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Contributions

T.Y. and R.M. designed and performed the experiments. T.Y. conceived and designed the study. S.K. conceived, designed and directed the investigations and wrote the manuscript with revisions provided by T.Y and R.M.

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Correspondence to Shū Kobayashi.

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Supplementary Information

Supplementary Figs. 1–11, Tables 1–11, methods and references.

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Yasukawa, T., Masuda, R. & Kobayashi, S. Development of heterogeneous catalyst systems for the continuous synthesis of chiral amines via asymmetric hydrogenation. Nat Catal 2, 1088–1092 (2019). https://doi.org/10.1038/s41929-019-0371-y

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