IMPROVED SYNTHESES AND PREPARATIONS OF INTERMEDIATES AND NEW POLYMORPHS THEREOF USEFUL FOR THE PREPARATION OF DONEPEZIL HYDROCHLORIDE

摘要

The invention relates to a process for preparing 2- (l-benzylpiperidin-4- ylmethyliden) -5, 6-dimethoxyindan-l-one (a key intermediate in the synthesis of donepezil hydrochloride), crystalline polymorph forms of this key intermediate and their use thereof for producing donepezil hydrochloride. In particular, the invention provides a method for producing the intermediate 2-(l -benzylpiperidin-4-ylmethyliden) -5, 6- dimethoxyindan-1-one. The process includes reacting 5, 6-dimethoxyindan-l-one with l-benzylpiperidine-4-carbaldehyde using potassium hydroxide in an aqueous solvent. The aqueous solvent can be a mixture of an organic solvent and water. Where the organic solvent is not miscible with water, the reaction may be performed in the presence of a phase transfer catalyst.