Preparation method of donepezil

Abstract

The invention provides a preparation method of donepezil. The method comprises the following steps: using hydride (4) and substituted benzyl ester of substituted sulfuric acid to perform the condensation reaction, and then collecting donepezil (1) from the reaction product. The method of the invention can not generate impurities, the purity of the obtained product is greatly increased, the yield is up to 85%, the reaction time is as short as 2-5 hours, the operation is simple, the stability is good, the equipment investment is small and the method is applicable to industrial production. The reaction formula is shown below.

Description

technical field [0001] The invention relates to a production process of donepezil. technical background [0002] Donepezil hydrochloride (1) is an acetylcholinesterase inhibitor (AchEI) developed by Japan's Eisai Pharmaceutical Company, which was first launched in the United States in 1997. This product is highly selective for neuronal acetylcholinesterase, has no liver toxicity, and is clinically used for the treatment of Alzheimer's disease. Donepezil is the raw material of donepezil hydrochloride, and donepezil hydrochloride can be obtained by making donepezil hydrochloride. Bibliographical information synthetic donepezil method mainly contains two big classes: [0003] Method 1: EP0711756A1 reacts 5,6-dimethoxy-2-(4-pyridyl)methylene]-1-indanone (2) with benzyl bromide to generate quaternary ammonium salt (3), and then use Platinum oxide catalytic hydrogenation obtains donepezil (1), and the general reaction formula is as follows: [0004] [0005] Method 2, US200...

AI Technical Summary

Problems solved by technology

[0007] The inventor has found through tests that the reduction stability of the last step of the process of the method is very poor, and there are mainly the following problems: (1) because the benzyl group is easy to take off during the reduction process to generate more impurities, it needs repeated refining to remove , leading to low and unstable hydrogenation yields

(2) Use platinum dioxide as a catalyst, which is expensive and difficult to recycle;

[0008] And method two, the technology that provides, its shortcoming is that the product donepezil that generates when the last step of this process reacts with benzyl bromide to connect benzyl can further react with benzyl bromide to produce a certain amount of impurity (5), resulting in a sharp drop in product purity, It needs two or more refinements to remove, resulting in low yield, only 70-75%, see the following general reaction formula:

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