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Method for preparing memantine hydrochloride

A technology for memantine hydrochloride and a compound, which is applied in the fields of medicine and chemistry to achieve the effects of controlling neuron dysfunction, reducing residual solvent with high boiling point, and avoiding solvent azeotrope effect

Active Publication Date: 2015-04-29
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In the method for preparing memantine hydrochloride disclosed above, all due to some insufficient factors, it is not suitable for industrialized production; and most of the processes adopt alcohol solvents to crystallize memantine hydrochloride To obtain medicinal memantine hydrochloride, which may cause the product to contain trace amounts of halogenated hydrocarbon genotoxic impurities such as ethyl chloride and methyl chloride

Method used

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  • Method for preparing memantine hydrochloride
  • Method for preparing memantine hydrochloride
  • Method for preparing memantine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] 1.1 Preparation of 1-acetylamino-3,5-dimethyladamantane (III)

[0039] Compound (IV) (100g, 0.411mol) and acetamide (121.5g, 2.057mol) were stirred and mixed, heated in an oil bath to 130°C and kept for 4~5h, then the reaction was stopped. After cooling, add 1000ml of dichloromethane and 500ml of drinking water, stir evenly, let stand, separate the liquids, extract the water phase with 500ml of dichloromethane again, and combine the organic phases. 1000ml of drinking water was washed twice, the organic phase was concentrated to dryness under reduced pressure, recrystallized with water, and dried under reduced pressure to obtain compound (III) as a white solid (GC>99.0%, yield 92%).

[0040]

[0041] 1.2 Preparation of 1-amino-3,5-dimethyladamantane (II)

[0042] Compound (III) (80g, 0.361mol) was dissolved in 400ml of n-butanol under the protection of nitrogen, 85% KOH (95.4g, 1.45mol) was added with stirring, heated to 120°C for 10~11h, and the reaction was stopp...

Embodiment 2

[0050] 2.1 Preparation of 1-acetylamino-3,5-dimethyladamantane (III)

[0051] Compound (IV) (100g, 0.411mol) and acetamide (97.2g, 1.646mol) were stirred and mixed, heated in an oil bath to 120°C and kept for 4~5h, then the reaction was stopped. After cooling, add 1000ml of dichloromethane and 500ml of drinking water, stir evenly, let stand, separate the liquids, extract the water phase with 500ml of dichloromethane again, and combine the organic phases. 1000ml of drinking water was washed twice, the organic phase was concentrated to dryness under reduced pressure, recrystallized with water, and dried under reduced pressure to obtain compound (III) as a white solid (GC>99.0%, yield 91%).

[0052]

[0053] 2.2 Preparation of 1-amino-3,5-dimethyladamantane (II)

[0054] Dissolve compound (III) (80g, 0.361mol) in 400ml of n-butanol under the protection of nitrogen, add 85% KOH (119.3g, 1.807mol) under stirring, heat the oil bath to 130°C for 10~11h, stop reaction. Cool, a...

Embodiment 3

[0058] 3.1 Preparation of 1-acetylamino-3,5-dimethyladamantane (III)

[0059] Compound (IV) (60g, 0.247mol) and acetamide (29.2g, 0.494mol) were stirred and mixed, heated in an oil bath to 125°C and kept for 6~7h, then the reaction was stopped. After cooling, add 600ml of dichloromethane and 300ml of drinking water, stir evenly, let stand, separate the liquids, extract the water phase with 300ml of dichloromethane again, and combine the organic phases. 600ml of drinking water was washed twice, the organic phase was concentrated to dryness under reduced pressure, recrystallized with water, and dried under reduced pressure to obtain compound (III) as a white solid (GC>99.0%, yield 87%).

[0060]

[0061] 3.2 Preparation of 1-amino-3,5-dimethyladamantane (II)

[0062] Dissolve compound (III) (40g, 0.181mol) in 240ml n-butanol under nitrogen protection, add 85% KOH (119.3g, 1.807mol) under stirring, heat the oil bath to 125°C for 8~9h, stop reaction. Cool, add 240ml drinki...

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Abstract

The invention discloses a method for preparing memantine hydrochloride. The method is characterized in that the method provided by the invention uses 1-bromo-3,5-dimethyladamantane (represented by a general formula IV in the description) as a starting material which is subjected to an amination reaction with acetamine to obtain a key intermediate 1-actamido-3,5-dimethyladmantane (represented by a general formula III in the description); the compound represented by the general formula III is subjected to alcoholysis in a mixture system of inorganic base and n-butyl alcohol for deacetylated to obtain memantine; memantine is treated using hydrochloric acid in a ketone solvent to obtain memantine hydrochloride. The method provided by the invention overcomes deficiencies in the prior art and has the advantages that the raw materials are simple and readily available, the reaction steps are simple and short, and the operations are convenient and fast, therefore, the method is suitable for industrial production.

Description

Technical field: [0001] The invention belongs to the technical field of medicine and chemistry, and in particular relates to a preparation method of memantine hydrochloride, an anti-senile dementia drug. Background technique: [0002] The anti-Alzheimer's drug memantine hydrochloride (Memantine hydrochloride), the chemical name is 1-amino-3,5-dimethylamantadine hydrochloride, and the English name is 3,5-Dimethyl-1-aminoadamantane hydrochloride (formula I ), is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, mainly used for the treatment of moderate to severe Alzheimer's disease. The drug was first developed by the German company Merz and was launched in Germany under the trade name Akatinol in 1982 for the treatment of Parkinson's disease. In 2002, H. Lundbeck was listed in the European Union under the trade name Ebixa for the treatment of moderate to severe Alzheimer's disease ( Alzheimer Disease, AD), imported into China under the trade name Ebishen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/38C07C209/62C07C231/08C07C233/06
Inventor 蔡中文邹益品韩公超叶文润邓杰
Owner CHONGQING PHARMA RES INST
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