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Synthesizing technology of donepezil hydrochloride

A technology of donepezil hydrochloride and synthesis process, applied in directions such as organic chemistry, can solve problems such as low total yield and many steps, and achieve the effects of high yield and low production cost

Inactive Publication Date: 2012-03-07
陕西方舟制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The published patent (CN100436416) "Donepezil Hydrochloride Synthesis Technology" takes diethyl malonate as starting material, and prepares donepezil hydrochloride through five-step reactions such as condensation, reduction, substitution, and final ring-closing decarboxylation. There are many steps, and the total The yield is not high

Method used

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  • Synthesizing technology of donepezil hydrochloride
  • Synthesizing technology of donepezil hydrochloride
  • Synthesizing technology of donepezil hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Preparation of 2,3-dihydro-5,6-dimethoxy-2-(4-piperidinyl)methyl-1-indanone (II):

[0031] In a 1L hydrogenation reactor, add 10g (0.035mol) of substituted indanone, 300ml of glacial acetic acid, 1g of 10% palladium charcoal, feed hydrogen at 75°C, pressurize at 0.35MPa for 1 hour, cool to 30°C, and filter out Palladium charcoal to obtain a hydrogenation solution, evaporate the solvent to glacial acetic acid at -0.08MPa and 95°C, add 10% sodium bicarbonate aqueous solution to neutralize the reaction product until the pH value is 7, add 200ml dichloromethane to extract three times, and the organic layer is extracted with 20g sodium bicarbonate Dry over sodium sulfate for 24 hours, remove sodium sulfate, and concentrate the filtrate to obtain 8.5 g of yellow oil (II), with a yield of 84%. The feed ratio (molar ratio) of the above reaction is: 5,6-dimethoxy-2-(pyridin-4-yl)methylmethylene-1-indanone:hydrogen=1:(3~5), Here the ratio hydrogen=(3~5) refers to any value betwe...

Embodiment 2

[0033] Preparation of 2,3-dihydro-5,6-dimethoxy-2-(4-piperidinyl)methyl-1-indanone (II):

[0034] In a 1L hydrogenation reactor, add 10g (0.035mol) of substituted indanone, 300ml of glacial acetic acid, 1g of 10% palladium on carbon, pass hydrogen gas at 75°C, pressurize at 0.35MPa for 2 hours, cool to 30°C, and filter out Palladium charcoal to obtain a hydrogenation solution, evaporate the solvent to glacial acetic acid at -0.08MPa and 95°C, add 10% sodium bicarbonate aqueous solution to neutralize the reaction product until the pH value is 7, add 200ml dichloromethane to extract four times, and use 20g After drying over anhydrous sodium sulfate for 20 hours, the sodium sulfate was removed, and the filtrate was concentrated to obtain 7.8 g of yellow oil (II), with a yield of 77%. The feed ratio (molar ratio) of the above reaction is: 5,6-dimethoxy-2-(pyridin-4-yl)methylmethylene-1-indanone:hydrogen=1:(3~5), The ratio hydrogen=(3~5) here refers to any value between 3~5, such ...

Embodiment 3

[0036] The preparation of donepezil hydrochloride (I):

[0037] Add 30g (0.104mol) hydride and 500ml dichloromethane into a dry 1L three-necked flask, stir, dissolve at 35°C, add dropwise 45ml (0.325mol) of triethylamine, continue stirring for 10 minutes, and add dropwise 40ml ( 0.345 mol) of benzyl chloride, maintained at 35°C and continued to react for 4 hours, cooled to 20-25°C, filtered with suction, discarded the filter residue, concentrated the filtrate, dissolved the concentrate in 300ml of methanol, added dropwise 10% methanolic hydrogen chloride solution to form a salt, Cool and crystallize at 4°C, filter, wash the filter cake with 50ml of methanol, and dry at 58-60°C to obtain 24g of crude donepezil hydrochloride. After filtration, the solid was dried at 58-60° C. to obtain 15 g of donepezil hydrochloride (I), with a yield of 61%. The feed ratio (molar ratio) of the above reaction is: compound II: benzyl chloride: 10% methanolic hydrogen chloride solution=1: (3~5): ...

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Abstract

The invention relates to the synthesis of donepezil hydrochloride. According to a published patent CN100436416 which relates to a synthesizing technology of donepezil hydrochloride, diethyl malonate is adopted as an initial material, and 5 steps of condensation, reduction, substitution, ring-closing, and decarboxylation are adopted, such that donepezil hydrochloride is obtained. The steps are complicated, and the total yield is not high. The invention aims at providing a donepezil hydrochloride synthesizing technology employing 5,6-dimethoxy-2-(4-pyridyl)methylene-indan-1-one as an initial material. The technical scheme of the invention comprises steps that: the raw material is processed through hydrogenation, cooling, and filtration; a solvent glacial acetic acid is removed by reduced-pressure distillation; the obtained solution is processed through neutralization and extraction; a filtrate is condensed, and is dissolved in dichloromethane; the mixture is stirred, and triethylamine and benzyl chloride are dropped into the solution; the solution is cooled, the filtrate is condensed, and the obtained material is dissolved in methanol; a methanol solution of hydrogen chloride is dropped into the solution, such that a salt is formed; and the solution is cooled, crystallized, filtered, and dried, such that donepezil hydrochloride is obtained. The synthesizing technology provided by the invention is advantaged in short synthetic route and improved total yield. With the technology, the donepezil hydrochloride content is higher than 99%. The technology is suitable for industrialized productions.

Description

technical field [0001] The invention relates to a synthesis process of donepezil hydrochloride, which specifically refers to the synthesis of donepezil hydrochloride by using 5,6-dimethoxy-2-(4-pyridyl)methylene-1-indanone as a starting material. Background technique [0002] Donepezil Hydrochloride (Donepezil Hydrochloride) chemical name (±) 2,3-dihydro-5,6-dimethoxy-2{[(1-benzyl)-4-piperidinyl]methyl}-1H- Inden-1-one hydrochloride, an anti-acetylcholinesterase inhibitor, has strong and highly selective anti-acetylcholinesterase activity, and has a long-lasting effect and high safety. It is developed by Eisai Co., Ltd. and is an American food and drug The second drug approved by the FDA to treat Alzheimer's disease. It has been approved for import in China, and the trade name is "Aricept", which is used for the treatment of mild or moderate Alzheimer's dementia symptoms. At present, there are many synthetic routes for preparing donepezil hydrochloride, and according to re...

Claims

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Application Information

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IPC IPC(8): C07D211/32
Inventor 王宇杜小英
Owner 陕西方舟制药有限公司
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