Donepezil 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. 

N-Tfa- and iV-Fmoc-a-amino ketones have been synthesized56 by reaction of some N -heterocycles or benzene with chiral AM Tfa- and Fmoc-a-aminoacyl)benzotriazoles [e.g. (49)] in the presence of aluminium trichloride. Full preservation of chirality was reported. Aromatic side-chains in some of the (a-amineacyl)benzotriazole compounds gave a competitive intramolecular cyclization, again with retention of chirality [e.g. (49) to (50)]. A full report57 on the intramolecular acylation of aromatics with Meldrum s acid derivatives catalysed by metal trifluoromethanesulfonates under mild reaction conditions has appeared [e.g. (51) to (52)]. The method tolerates many functional groups and was extended to the synthesis of 1-tetralones, 1-benzosuberones and donepezil (53). 

Later it was described the synthesis of the donepezil HCI from 5,6-dimethoxy-2-(pyridin-4-yl)methylene-indan-l-one by the reaction with H2 over platinum dioxide at room temperature in acetic acid-methanol mixture to give 4-[(5,6-dimethoxy-l-indanon)-2-yl]methylpiperidine. The last one yielded donepesyl HCI by refluxing with benzyl bromide and triethylamine for 4 hours with the following addition of methanolic HCI (10%). 

Design, synthesis, and assessment of anticholinesterase activity of 2-(2-(4-Renzylpiperazin-l-yl)ethyl)isoindoline-l,3-dione derivatives showed that some of these compounds can function as potential acetylcholinesterase inhibitors with a potency comparable to that of donepezil [170]. 

Andreani A, Cavalli A, Granaiola M, Guardigli M, Leoni A, Locatelli A, Morigi R, Rambaldi M, Recanatini M, and Roda A. Synthesis and Screening for Antiacetylcholinesterase Activity of (l-Benzyl-4-oxopiperidin-3-ylidene)methylindoles and -pyrroles Related to DonepeziL/Mcd Chem. 2001 44 4011-4014. 

Pospisil, T., Veetil, A. T., Lovely Angel, P. A., Klan, P, Photochemical Synthesis of Substituted Indan 1 ones Related to Donepezil, Photochem. Photobiol. Sci. 2008, 7, 625 632. 

PospfSil T, Veetil AT, Antony LAP et al (2008) Photochemical synthesis of substituted indan-1-ones related to Donepezil. Photochem Photobiol Sci 7 625-632... 

A key step in the synthesis of donepezil (trade name Aricepl) is a directed aldol reaction that forms a,p-unsaturated carbonyl compound X. What carbonyl starting materials are needed to prepare X using a directed aldol reaction What reagents are needed to convert X to donepezil ... 

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