Synthesis of Donepezil Hydrochloride via Chemoselective Hydrogenation
Org. Process Res. Development
Ajay Singh Rawat, Sachin Pande, Nilay Bhatt, Raju Kharatkar, Chandrakant Belwal, and Anand Vardhan
Articles ASAP (As Soon As Publishable)
Publication Date (Web): April 9, 2013 (Article)
DOI: 10.1021/op400007p
A simple and highly chemoselective and cost-effective process for the synthesis of Donepezil 1
has been developed for commercial production. In the process, the
exocyclic double bond is mainly targeted for catalytic hydrogenation in
the presence of an N-benzyl group using sulfur, nitrogen, and
phosphorous catalyst modifiers. In some cases, catalytic hydrogenation
with Pd on charcoal also produced an undesired side product along with
the main product due to over reduction. Removal of these impurities by
crystallization, column chromatography, or other means of purification
makes the process tedious and lengthy, and sometimes it is difficult to
achieve the impurity limit as per International Conference on
Harmonisation (ICH) guidelines for active pharmaceutical ingredients. In
the present investigation we report the synthesis of Donepezil 1 in pure form wherein the debenzyl impurity is within the acceptable limits.
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