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

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

Navanath Niphade, Anil Mali, Kunal Jagtap, Ramesh Chandra Ojha, Pravinchandra J. Vankawala and Vijayavitthal T. Mathad

 Department of Process Research and Development, Megafine Pharma (P) Ltd., 201, Lakhmapur, Dindori, Nashik 422 - 202, Maharashtra, India

 

Org. Process Res. Dev., 2008, 12 (4), pp 731–735

 

Publication Date (Web): May 30, 2008 (Article)

DOI: 10.1021/op800066m

 http://pubs.acs.org/doi/abs/10.1021/op800066m?prevSearch=donepezil&searchHistoryKey=

 

 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.