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A kind of preparation method of memantine hydrochloride

A technology for memantine hydrochloride and hydrochloric acid, applied in the fields of medicine and chemistry, can solve the problems of unsuitable industrialized production, poor safety and operability, and high production cost, and achieve the effects of reducing high-boiling-point solvent residue, good product quality, and simplifying operating procedures and steps.

Active Publication Date: 2018-02-23
CHONGQING PHARMA RES INST
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  • Description
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Problems solved by technology

[0009] (3) Urea method: patent WO2005023753 (same family patent CN1594277) discloses a preparation method of memantine hydrochloride, the reaction formula is as follows, starting with 1-bromo-3,5-dimethyladamantane, and urea in formic acid carry out acylation reaction in medium, then add mineral acids such as hydrochloric acid to carry out acid hydrolysis, alkalization, salt formation, recrystallization to prepare memantine hydrochloride, the reaction time of this method is short, but because it also needs further refining to obtain qualified products, the total yield is higher Low, and the use of irritating and corrosive formic acid high-temperature reaction, the equipment loss is large, and the safety operability is poor
[0011] (4) Thiourea method: patents WO2008040560 and WO2007096124 disclose a preparation method of memantine hydrochloride (the reaction formula is as follows), using 1-bromo-3,5-dimethyladamantane or 3,5-dimethyladamantanol As the starting material, carry out Ritter reaction under acidic conditions through halogenated acetonitrile, then condense with urea or thiourea, alkali hydrolyze, and form salt to prepare memantine hydrochloride. Due to the long route, some raw materials are relatively expensive in this method, resulting in relatively high production costs
[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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  • A kind of preparation method of memantine hydrochloride
  • A kind of preparation method of memantine hydrochloride
  • A kind of preparation method of memantine hydrochloride

Examples

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Effect test

Embodiment 1

[0035] 1.1 Preparation of 1-acetylamino-3,5-dimethyladamantane (III)

[0036] 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%).

[0037] 1.2 Preparation of 1-amino-3,5-dimethyladamantane (II)

[0038] 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 stopped. Cool, add 4...

Embodiment 2

[0045] 2.1 Preparation of 1-acetylamino-3,5-dimethyladamantane (III)

[0046] 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%).

[0047] 2.2 Preparation of 1-amino-3,5-dimethyladamantane (II)

[0048] 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, add 400ml drink...

Embodiment 3

[0052] 3.1 Preparation of 1-acetylamino-3,5-dimethyladamantane (III)

[0053] 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%).

[0054] 3.2 Preparation of 1-amino-3,5-dimethyladamantane (II)

[0055] 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 drinking water, cont...

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Abstract

The invention discloses a method for preparing memantine hydrochloride, which is characterized in that: the method of the invention uses 1-bromo-3,5-dimethyladamantane (formula IV) as a starting material, and performs amination reaction with acetamide , to obtain the key intermediate 1-acetylamino-3,5-dimethyladamantane (formula III), alcoholysis of the compound of formula III in the mixed system of inorganic base and n-butanol, deacetylation to obtain memantine, memantine Memantine hydrochloride can be obtained by treating with hydrochloric acid in a ketone solvent. The method of the invention overcomes the disadvantages of the prior art, and has the advantages of simple and easy-to-obtain raw materials, short reaction steps, convenient operation, and 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 medicine. 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), was imported into China under the trade name Ebi...

Claims

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Application Information

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Patent Type & Authority Patents(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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