An Improved and Efficient Process for the Production of Donepezil Hydrochloride: Substitution of Sodium Hydroxide for n-Butyl Lithium via Phase Transfer Catalysis

Abstract

A simple, efficient and highly economic process for the production of donepezil hydrochloride (1), an anti-Alzheimer drug is reported. The process relies upon improved and large-scale synthesis of a key intermediate: 1-benzylpiperidine-4-carboxaldehyde (2), and the introduction of operationally simple chemistry at the penultimate stage wherein 2 is reacted with 5,6-dimethoxy indanone (3) in the presence of sodium hydroxide and a phase transfer catalyst (PTC) in a biphasic solvent to furnish the intermediate 4, which is reduced and directly treated with hydrochloric acid to furnish highly pure donepezil hydrochloride with desired polymorphic form. The improved process provides donepezil hydrochloride at considerably lower cost and allows the omission of hazardous chemicals.

Design, Synthesis, and Evaluation of Donepezil-Like Compounds as AChE and BACE-1 Inhibitors

“…Even though the yield was comparable with that reported in literature, 26 this method allowed us to obtain the desired product in good yields avoiding the use of dichloromethane or toluene, both during the reaction and the purification steps, and to simplify the workup procedure into a filtration/recrystallization protocol. The registered yields ranged from moderate to good depending on the position of the methoxyl group on the indanone moiety.…”

“…Letter methanol; nor was formation of the hydroxyl impurity observed 26 or were other purification steps required. Even though the yield was comparable with that reported in literature, 26 this method allowed us to obtain the desired product in good yields avoiding the use of dichloromethane or toluene, both during the reaction and the purification steps, and to simplify the workup procedure into a filtration/recrystallization protocol.…”

“…Furthermore, at the best of our knowledge only a report exists for the synthesis of compounds 17 under heterogeneous conditions in a biphasic system H 2 O/dichlomethane, using NaOH as base in the presence of a phase transfer catalyst. 26 Thus, starting from that report, we developed a sustainable US-assisted method to obtain a new class of indanonylidenyl precursors of donepezil by substituting the homogeneous base catalyst with a commercial basic resin Amberlyst A-26 27 as efficient and recyclable heterogeneous catalyst to realize a regioselective aldol condensation between the indanones 5−9 and 1-benzyl-piperidine moieties 10−12.…”

Analysis of acetylcholinesterase inhibitors: bioanalysis, degradation and metabolism

“…Soon, it was tested against AChE and found to be a highly selective inhibitor of the enzyme. Recently, a more economic process has been reported for a large‐scale synthesis (Niphade et al ., 2008). Details for the most relevant methods developed for the analysis of 3 are given in Table 3.…”

reKinetics and Mass Transfer in the Hydrogenation of 2-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methylene)-5,6-dimethoxy- -2,3-dihydroinden-1-one hydrochloride over Pt/C Catalyst

“…In particular, it is useful for prevention and treatment of Alzheimer's disease by virtue of its acetyl cholinesterase inhibitory action 22 . There are many processes described mainly in patent literature [23][24][25][26][27][28][29][30][31][32] for producing (4) and its pharmaceutically acceptable salts. Complete chemo-selectivity is unlikely, because the starting compound (1) has more than one functionality susceptible to hydrogenation.…”