A kind of preparation method of memantine hydrochloride

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...

Examples

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...

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...

Examples

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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