Rivastigmine syntheses

Figure 5. Cartoon of a cholinergic synapse showing major steps in the synthesis of acetylcholine. The two major receptor types, the ionotropic nicotinic receptor and the metabotropic muscarinic receptor, are shown (see also Chapter 1). Presynaptic muscarinic (M2) and nicotinic receptors are also depicted. Drugs which have been widely used to manipulate the cholinergic systems, and which are mentioned in the text, include the muscarinic receptor antagonists scopolamine and atropine and the nicotinic receptor agonist nicotine. Anticholinesterases (discussed elsewhere in this volume) include drugs such as physostigmine, rivastigmine, donepezil, and galanthamine.

Wolfson, C., Oremus, M., Shukla, V., et al. Donepezil and rivastigmine in the treatment of Alzheimer s disease a best-evidence synthesis of the published data on their efficacy and cost-effectiveness. Clm. Ther. 24, 862-886, 2002. 

In addition to the discovery route,21 52 several alternate syntheses of rivastigmine have been reported. The discovery route involved synthesis of key intermediate phenol 39 by following Stedman s procedure,53 as shown in Scheme 7. This was then treated with N-ethyl-jV-methyl carbamoyl chloride (40) to afford racemic rivastigmine ( 2), which was resolved using di-p-toluoyl-D-tartrate (DTTA) to give (. -rivastigmine (2). 

An interesting approach to the generation of l4C-labeled rivastigmine needed for in vivo studies was published by Novartis (Scheme 11).57 The synthesis of 14C-labeled 2 was initiated by l4C-labeled cyanation of iodide 48 to provide 3-methoxybenzo-14C-nitrile (49) in 80% yield. Copper-mediated addition of methyl magnesium bromide to nitrile 49 formed an imine that was hydrolyzed with aqueous HC1 to the corresponding... 

Two efficient processes for the synthesis of rivastigmine, one of the potent drugs for the treatment of Alzheimer s disease, have been developed for industrial applications with Ir-(5)-28a-catalyzed asymmetric hydrogenation as the key step [70]. Additionally, the Ir-28a-catalyzed asymmetric hydrogenation of ketones was also used as a key step in the synthesis of natural products of (-)-mesembrine [71] and (-)-centrolobine [72]. 

In 2009, Backvall s catalyst was also employed at a low catalyst loading (0.5 mol%) by these authors in combination with CALB to perform the DKR of l-(6-chloropyridin-3-yl)ethanol by using similar conditions. The corresponding acetate was achieved in 91% yield and enantioselectivity of >99% ee, as shown in Scheme 8.37. This reaction constituted the key step of a synthesis of a neonicotinoide pesticide derivative depicted in Scheme 8.37. These conditions were also applied by Gotor et al. to the total synthesis of (5)-rivastigmine, employed as a drug for the treatment of dementia of the Alzheimer s type. " As shown in Scheme 8.37, the key step of this synthesis... 

The use of a glucose/ GDH system for the regeneration of the NADH cofactor also allowed the development of a pH-based screening method for the identification and characterization of novel co-TAs. This three-enzyme cascade found application, for example, in the synthesis of the pharmaceutical intermediate 4-phenylpyrrolidin-2-one [33] and the anti-Alzheimer s disease drug (S)-rivastigmine [34]. As an... 

Fuchs, M Koszelewski, D., Tauber, K, Kroutil, W and Faber, K (2010) Chemoenzymatic asymmetric total synthesis of (S)-rivastigmine using (o-transaminases. Chem. Commun.,... 

Figure 13.35 Multienzymatic synthesis of S)-3-(l-aminoethyl)phenyl ethyl(methyl)carbamate, an intermediate of (S)-rivastigmine employing LDH for coproduct removal.

Indian researchers investigated the chemoenzymatic route to rivastigmine 41. Rivastigmine is pharmaceutically active compound that inhibits acetylcholinase enzymes. The key step in the synthesis was the bioreduction of the ketone 39 moiety as shown in Scheme 6.15 [25]. 

M.K. Sethi, S.R. Bhandya, N. Maddur, R. Shukla, A. Kumar, V.S.N. Jayalakshmi Mittapalli, Asymmetric synthesis of an enantiomerically pure rivastigmine intermediate using ketoreduc-... 

Three-step chemoenzymatic synthesis of the anticholinergic drug (S)-rivastigmine. 

Our group achieved the synthesis of (S)-rivastigmine (26), a drug for the treatment of Alzheimer s and Parkinson s diseases, emplo5ung the DKR of secondary alcohol as the key step (Scheme 5.43) [34]. In this s mthesis, chiral alcohol (R)-24 as a key intermediate was obtained from its racemate via the DKR catalyzed by CAL-B (Novozym 435) and a pol)mier-bound Ru catalyst 10. The conversion of (R)-24 to the target molecule (S)-26 (97% ee) was accomplished via two steps. The overall yield was 57% from the starting material. 

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