Industrial Scale-Up of Enantioselective Hydrogenation for the Asymmetric Synthesis of Rivastigmine

Abstract

Two efficient processes for the synthesis of rivastigmine, one of the most potent drugs for the treatment of mild-to-moderate dementia of the type presenting in Alzheimer's disease, has been developed. Of particular note is the processes used for the asymmetric hydrogenation by applying the highly efficient chiral spiro catalyst, Ir-SpiroPAP. The first route was easy to scale up in industry and provided the commercial intermediate (S)-3-(1-dimethylaminoethyl)phenol, 6, which is suitable for the manufacture of rivastigmine in active pharmaceutical ingredient (API) demand. The second route was convenient for operation and purification and completed the synthesis of rivastigmine (1) in four steps and 84% overall yield.

Lutidine‐Based Chiral Pincer Manganese Catalysts for Enantioselective Hydrogenation of Ketones

“…The amino ketones 6 ah – ak are also amenable to the procedure, giving the corresponding amino alcohols 7 ah – ak with 87–95 % ee . It is worth noting that chiral alcohols 7 j , 7 t , 7 aj , 7 ak , 7 al , and 7 am are the key intermediates for the synthesis of chiral drugs rivastigmine, phenylephrine, duloxetine, ezetimibe, and montelukast, respectively.…”

A Practical and Efficient Stereoselective Synthesis of (S)‐Rivastigmine and (R)‐Rivastigmine

“…Recent approaches have used chemoenzymatic synthesis with dynamic kinetic resolution,, ω‐transaminases,, and alcohol dehydrogenase from baker's yeast . Traditional metal catalysis has also been applied to the synthesis of rivastigmine via addition of diorganozinc to imines, iridium catalyzed enantioselective hydrogenation, and copper catalyzed hydroamination of alkynes . With the development and versatile application of total synthesis via organocatalysis, Hantzsch ester mediated reduction, and hydrosilylation catalyzed by chiral quaternary ammonium salts have also been successfully employed in the synthesis of this molecule.…”

Whole-Cell Biocatalyst for Chemoenzymatic Total Synthesis of Rivastigmine

“…Carbamate 2 was obtained from the commercially available 3-hydroxyacetophenone (1) in 91% yield according to reported procedures (Scheme 3) [43,44]. Then, it was subjected to an enantioselective biocatalytic reduction by Lactobacillus reuteri DSM 20016 whole cells into alcohol (R)-4, isolated in 90% yield and 98% ee.…”