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Molecules 2018, 23(9), 2207; https://doi.org/10.3390/molecules23092207

Direct Asymmetric Reductive Amination for the Synthesis of (S)-Rivastigmine

1
College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging, Shandong Normal University, 88 Wenhuadong Road, Jinan 250014, China
2
Shanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 22 Xinong Road, Yangling, Shanxi 712100, China
These authors contributed equally to this research.
*
Authors to whom correspondence should be addressed.
Received: 20 July 2018 / Revised: 25 August 2018 / Accepted: 28 August 2018 / Published: 31 August 2018
(This article belongs to the Special Issue Stereogenic Centers)
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Abstract

In this article we demonstrate how asymmetric total synthesis of (S)-rivastigmine has been achieved using direct asymmetric reductive amination as the key transformation in four steps. The route started with readily available and cheap m-hydroxyacetophenone, through esterification, asymmetric reductive amination, N-diphenylmethyl deprotection and reductive amination, to provide the final (S)-rivastigmine in 82% overall yield and 96% enantioselectivity. In the asymmetric reductive amination, catalysed by the iridium–phosphoramidite ligand complex and helped by some additives, the readily prepared 3-acetylphenyl ethyl(methyl)carbamate directly reductively coupled with diphenylmethanamine to yield the chiral amine product in 96% ee and 93% yield. View Full-Text
Keywords: Alzheimer’s syndrome; rivastigmine; asymmetric reductive amination; asymmetric catalysis; phosphoramidite ligands Alzheimer’s syndrome; rivastigmine; asymmetric reductive amination; asymmetric catalysis; phosphoramidite ligands
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Gao, G.; Du, S.; Yang, Y.; Lei, X.; Huang, H.; Chang, M. Direct Asymmetric Reductive Amination for the Synthesis of (S)-Rivastigmine. Molecules 2018, 23, 2207.

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