Method for preparing donepezil hydrochloride

Abstract

The invention provides a method for preparing donepezil hydrochloride, which comprises the steps as follows: (1) 5,6-dimethoxy-2-(4-pyridyl)methylene-1-idenone (II) is taken as a starting material, and is processed through catalytic hydrogenation under the action of platinum dioxides, so as to generate compounds that are 5,6-dimethoxy-2-(4-piperidyl)methylene-2,3-dihydro-1-idenone (III); (2) the obtained compounds (III) and benzaldehyde are processed through condensation, so as to generate 1-benzyl-4-[(5,6-dimethoxy-1-idenone)-2-methylene]piperidine (IV); and (3) the obtained compounds (IV) and hydrogen chloride are processed through salifying, so as to generate 1-benzyl-4-[(5,6-dimethoxy-1-idenone)-2-methylene]piperidine hydrochloride that is donepezil hydrochloride (I). In the method for preparing donepezil hydrochloride, 5,6-dimethoxy-2-(4-pyridyl)methylene-1-idenone is taken as the starting material, and three-step reaction comprising catalytic hydrogenation, condensation and salifying are adopted to prepare donepezil hydrochloride. The method is simple and efficient to operate, has the advantages of mild reaction conditions, high safety and higher yield coefficient, is easy to control, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of donepezil hydrochloride, which belongs to the technical field of pharmaceutical production. Background technique [0002] Donepezil hydrochloride (I) is a second-generation reversible acetylcholinesterase inhibitor (AchEI) developed by Japan's Eisai Pharmaceutical Company in the late 1980s. It was approved by the U.S. FDA in 1996 and launched in the U.S. in 1997. It has been listed in more than 40 countries and regions around the world. Donepezil hydrochloride is a highly selective, long-acting, and reversible acetylcholinesterase inhibitor, which increases the concentration of an important neurotransmitter, acetylcholine, mainly by specifically inhibiting the activity of acetylcholinesterase in the brain. It can treat mild to moderate Alzheimer's disease (AD), delay the memory decline of AD patients, improve their cognitive function, and improve the self-care ability of patients. [0003] Alzheimer'...

AI Technical Summary

Problems solved by technology

[0011] This method mainly has the following problems: (1) The stability of the final reduction step is very poor, because the benzyl group is easy to remove during the reduction process, and more impurities are generated, which requires It can only be removed after repeated refining, resulting in very unstable hydrogenation yield

(2) Benzyl bromide has high toxicity, serious environmental pollution, and bad influence on the health of workers, so it is not suitable for industrial production

Because benzyl chloride is highly toxic, it has caused great harm to the environment and staff; in addition, benzyl chloride has the danger of combustion and explosion, which brings hidden dangers to safe production, so this route is not advisable

(2) Each step of the synthetic route requires cumbersome post-processing, which increases the cost and labor intensity of the staff, and reduces work efficiency

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