US EPA

7424812 

Journal Article 

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

Gao, G; Du, S; Yang, Y; Lei, X; Huang, H; Chang, M; , 

2018 

1 

Molecules
ISSN: 1420-3049 

MDPI 

BASEL 

23 

9 

2207 

English 

30200331 

10.3390/molecules23092207 

WOS:000447365100118 

http://www.mdpi.com/1420-3049/23/9/2207
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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. 

Alzheimer’s syndrome; Asymmetric catalysis; Asymmetric reductive amination; Phosphoramidite ligands; Rivastigmine; ligand; rivastigmine; amination; chemistry; oxidation reduction reaction; preclinical study; synthesis; Amination; Drug Evaluation, Preclinical; Ligands; Oxidation-Reduction; Rivastigmine