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Fine purification method for key intermediate of Donepezil Hydrochloride

A technology of donepezil hydrochloride and a purification method, applied in directions such as organic chemistry, can solve problems such as being unfavorable to industrialized operation, complicated and difficult to operate, and difficult to treat three wastes, achieving production cost and environmental protection advantages, simplifying industrial operation, and reducing impurity content. Effect

Active Publication Date: 2009-01-14
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method uses mixed solvents methanesulfonyl chloride and triethylamine in the reaction process, and methanesulfonyl chloride has strong tear gas and irritation, high toxicity, not only harmful to the environment, but also increases the difficulty of the treatment of three wastes, and does not It is beneficial to industrial operation. In addition, this method adjusts the pH value, separates liquid, concentrates under reduced pressure and then washes with solvent during the post-treatment process of salt formation in a certain solvent. The whole process is complicated and difficult to operate.

Method used

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  • Fine purification method for key intermediate of Donepezil Hydrochloride
  • Fine purification method for key intermediate of Donepezil Hydrochloride
  • Fine purification method for key intermediate of Donepezil Hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Add 300ml of toluene and 15g of crude compound (I) to a 500ml reaction flask, add 2.3g of potassium hydroxide under stirring, heat to reflux at 110°C, react for 20 minutes, cool and filter the precipitated solid, then add the solid to 150ml of methanol and stir well , filtered to obtain a white solid, dried at 50°C to obtain 11.3g of a white solid, purity: 96.28%, yield: 75.3%.

Embodiment 2

[0031] Add 150ml of toluene and 15g of crude compound (I) to a 250ml reaction flask, add 2.3g of potassium hydroxide under stirring, heat at 60°C for 3 hours, cool and filter the precipitated solid, then add the solid to 150ml of methanol and stir evenly, and filter to obtain White solid was dried at 50°C to obtain 12.3g of white solid, purity: 97.13%, yield: 82%.

Embodiment 3

[0033] Add 200ml of toluene and 20g of crude compound (I) to a 250ml reaction flask, add 5.0g of potassium carbonate under stirring, heat to reflux at 110°C, react for 18 hours, cool and filter the precipitated solid, add the solid to 200ml of dichloromethane and stir for 5 Minutes, 100ml of water was added to separate layers, and the lower layer was concentrated to obtain a light yellow solid, then the solid was added to 50ml of methanol and stirred evenly, filtered to obtain a white solid, dried at 50°C to obtain 16.7g of a white solid, purity: 97.44%, yield: 83.5% .

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Abstract

The invention discloses a refining method of a key intermediate of 2-(1-benzyl-piperidine-4-methyl alkenyl)-5, 6 dimethoxy-indanone of Donepezil, namely, a compound (I), and the method is to obtain the high purity compound (I) by agitating a crude product of the compound (I) in the presence of inorganic base in a benzenoid aromatic hydrocarbon-containing organic solvent of C6 to C12 at a certain temperature. The method has advantages of simple operation, short reaction time, single solvent and low cost, and is suitable for the industrialized production.

Description

technical field [0001] The present invention relates to a key intermediate 2-(1-benzyl-piperidin-4-ylmethylenyl)-5,6 dihydrochloride of donepezil hydrochloride with high quality, high yield and low cost under industrial production scale The method for refining methoxy-indanone belongs to the field of chemical industry and chemical medicine. Background technique [0002] Donepezil hydrochloride is an acetylcholinesterase inhibitor developed by Japan's Eisai Company for the treatment of Alzheimer's dementia (AD). It has the advantages of high selectivity, small dose, long half-life, small adverse reactions, and no liver toxicity. The chemical name is: 1-benzyl-4-[(5,6-dimethoxyindanon-2-yl)methyl]piperidine hydrochloride. The structural formula of donepezil is as follows: [0003] [0004] At present, there are multiple synthetic routes for donepezil and its salts, wherein the key intermediate of the present invention relates to 5,6-dimethoxy-1-indanone (III) and 1-benzy...

Claims

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Application Information

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IPC IPC(8): C07D211/32
Inventor 何凯敏蹇锋甘立新
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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