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Preparation method of memantine hydrochloride

A technology of memantine hydrochloride and hydrochloric acid, which is applied in the field of dementia therapeutic drugs, can solve the problems of low boiling point of ether, difficulty in condensing steam, strong volatility, etc., and achieve safe operation, good product purity and crystal form, and cost reduction Effect

Inactive Publication Date: 2003-03-05
GUANGZHOU INST OF GEOCHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The post-treatment of the two steps of acetylamidation and alcoholysis in the above method all adopts benzene, which is harmful to the environment and human body, as the extraction solvent; in the alcoholysis process, diethylene glycol, which is relatively expensive, is used as the proton donor; The crystallization process uses a mixed solvent of ethanol / ether. Due to the low boiling point of ether, strong volatility, and difficulty in condensing the vapor, a large amount of ether is volatilized during the process of adding ether to the ethanol in the reflux state, resulting in a great loss and easily causing combustion and explosion. accidents, so the method in the above literature has shortcomings

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Add 1-bromo-3,5-dimethyladamantane (20g) and urea (30g) into the reaction flask, add 160ml of ethylene glycol, heat the oil bath to 70-80°C, react for 30 hours, and cool to room temperature. Add 27g of sodium hydroxide and 100ml of ethylene glycol, heat the oil bath to 80°C, react for 20 hours, cool, add 30ml of water, extract 2-3 times with chloroform, combine the chloroform layers, dry with anhydrous magnesium sulfate, pump filtered, and concentrated by rotary evaporation to obtain a yellow oil, which is the crude product of 1-amino-3,5-dimethyladamantane, to which a 37% hydrochloric acid solution by weight was added to obtain a white solid, which was drained, washed with a small amount of water, and washed with Chloroform was recrystallized 2-3 times to obtain 1-amino-3,5-dimethyladamantane hydrochloride (i.e. memantine hydrochloride) fine product, weighing 12.4 grams, melting point 290-295°C (sublimation), total Yield 70%.

Embodiment 2

[0017] Add 1-bromo-3,5-dimethyladamantane (20g) and urea (12.5g) into the reaction flask, add 160ml of diethylene glycol, heat the oil bath to 170-180°C, react for 5 hours, and cool to room temperature , add 20g of sodium hydroxide, 100ml of diethylene glycol, heat the oil bath to 160°C, reflux for 12 hours, cool, add 30ml of water, extract 2-3 times with chloroform, combine the chloroform layers, and dry with anhydrous magnesium sulfate , filtered by suction, and concentrated by rotary evaporation to obtain a yellow oil, which is a crude product of 1-amino-3,5-dimethyladamantane, to which a 14% hydrochloric acid solution by weight was added to obtain a white solid, which was drained and washed with a small amount of water , recrystallized 2-3 times with chloroform to obtain 1-amino-3,5-dimethyladamantane hydrochloride (i.e. memantine hydrochloride) fine product, weighing 13.8 grams, melting point 290-295°C (sublimation) , a total yield of 78%.

Embodiment 3

[0019] Add 1-bromo-3,5-dimethyladamantane (20g) and urea (5g) into the reaction flask, add 160ml of glycerol, heat the oil bath to 120-130°C, react for 10 hours, and cool to room temperature. Add 3.5g of sodium hydroxide and 100ml of glycerol, heat the oil bath to 120°C, reflux for 15 hours, cool, add 30ml of water, extract 2-3 times with chloroform, combine the chloroform layers, and dry with anhydrous magnesium sulfate , filtered by suction, and concentrated by rotary evaporation to obtain a yellow oil, which is a crude product of 1-amino-3,5-dimethyladamantane, to which a 5% hydrochloric acid solution by weight was added to obtain a white solid, which was drained and washed with a small amount of water , recrystallized 2-3 times with chloroform to obtain the refined product of 1-amino-3,5-dimethyladamantane hydrochloride (i.e. memantine hydrochloride), weighing 13.3 grams, melting point 290-295°C (sublimation) , The total yield is 75%.

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PUM

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Abstract

The preparation method of medicine for curing dementia, N-methyl-D-aspartic acid (NMDA) receptor antagonist memantine hydrochloride includes the following steps: using polybasic alcohol as solvent; making 1-bromo-3,5-dimethyl adamantane and urea according to the mole ratio of 1:0.25-10 react for 0.5-48 hr. at 20-200 deg.C; after the reaction is completed, adding sodium hydroxide into the reactionsolution according to that the mole ratio of 1-bromo-3,5-dimethyl adamantane and sodium hydroxide is 1:0.1-10, making alcoholysis at 50-200 deg.C, chloroform extraction, concentration, acidification with hydrochloric acid and salt-forming so as to obtain the invented menantine hydrochloride. It features safe and simple operation and low cost, etc.

Description

technical field [0001] The invention relates to a preparation method of memantine hydrochloride, which is a drug for treating dementia and an N-methyl-D-aspartic acid (NMDA) receptor antagonist. technical background [0002] Memantine is an excellent drug for the treatment of dementia developed by German company Merz. It has been launched in Germany, and it has also completed phase III clinical research in the United States and other countries in the European Union and will be launched soon. Its chemical name is: 1-amino-3,5-dimethyladamantane hydrochloride, which is a non-competitive, moderately strong and fast voltage-gated NMDA receptor antagonist, which can prevent the overloading of intracellular calcium And inhibit the excitotoxicity of excitatory amino acids, clinical studies have confirmed that it has good curative effect on both vascular dementia and Alzheimer's dementia, which is an advantage that other types of dementia drugs currently under ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P25/28C07C209/00C07C211/38
Inventor 邹永朱杰熊晓云魏文
Owner GUANGZHOU INST OF GEOCHEMISTRY - CHINESE ACAD OF SCI
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