Manufacturing process for memantine

Abstract

This method for manufacturing 3,5-dimethyl-1-adamantanamine includes the following steps (i) through (iii). (i) A step for reacting 3,5-dimethyl-1-adamantanol with oxygen and nitrile in an organic solvent to obtain a reaction solution. (ii) A step for adding water to the reaction solution obtained in step (i) to obtain 1-amido-3,5-dimethyladamantane. (iii) A step for hydrolyzing the 1-amido-3,5-dimethyladamantane obtained in step (ii) in the presence of an alcohol-containing solvent and an inorganic base.

Description

technical field

[0001] The invention relates to a production method of 3,5-dimethyl-1-adamantanamine. Background technique

[0002] 3,5-Dimethyl-1-adamantanamine (hereinafter also referred to as "memantine") is N-methyl-D-aspartic acid (hereinafter also referred to as "NMDA".) The antagonist is used as a therapeutic agent for Alzheimer's disease. This agent acts as a low-affinity anti-competitive electrical-dependent antagonist for NMDA receptors. Specifically, this agent will not affect normal neurotransmission or long-term potentiation (LTP) formation, but Protective effects on neuroexcitotoxicity against sustained low-concentration glutamate stimulation. In addition, this agent has a different mechanism of action from acetylcholinesterase inhibitors, so it can also be used in combination with donepezil. Therefore, this agent has the potential to expand the scope of Alzheimer's disease treatment.

[0003] As a method for synthesizing this agent, for example, various m...

Examples

Embodiment 1

[0103] 3,5-Dimethyl-1-adamantanol: 10.00 g (55.5 mmol), acetonitrile: 4.55 g (110.9 mmol), and toluene: 25.00 g were added to a 300 mL round bottom flask to obtain a mixed solution. In addition, 3,5-dimethyl-1-adamantanol was produced according to the method described in p.7390-7391 of Journal of the American Chemical Society (vol. 122, 30, 2000). Next, 97% concentrated sulfuric acid: 11.00 g (108.8 mmol) was added dropwise to the mixed solution in the flask over 23 minutes, and the resulting reaction solution was stirred at 21° C. for 2 hours to continue the reaction. In the reaction solution, after confirming the disappearance of 3,5-dimethyl-1-adamantanol by gas chromatography (GC), water: 33.66 g was added to the reaction solution to stop the reaction, and 1-acetamide-3, 5-Dimethyladamantane in toluene (2-phase solution). 1-hexanol: 25.01g was added to this two-phase solution, and liquid separation operation was performed twice, and the water phase was removed from the tw...

Embodiment 2

[0105] 3,5-Dimethyl-1-adamantanol: 1.00 g (5.50 mmol), acetonitrile: 0.46 g (11.1 mmol), and mesitylene: 9.61 g were added to a test tube with an outer diameter of 30 mm to obtain a mixed liquid. Then, 97% concentrated sulfuric acid: 1.12 g (11.1 mmol) was added dropwise to the mixed solution in the test tube, and the resulting reaction solution was stirred at 30° C. for 3 hours to continue the reaction. Then, in the reaction solution, add water: 6.09g to stop the reaction, wash and remove the water phase from the reaction solution, thereby obtaining a mesitylene solution containing 1-acetamide-3,5-dimethyladamantane (reaction yield : 80.4%). Then, sodium hydroxide (NaOH): 0.71 g and 1-hexanol: 9.61 g were added to the obtained solution, and the obtained reaction solution was stirred at 130° C. for 18 hours to perform 1-acetamide-3,5 - Hydrolysis of dimethyladamantane. Then, in this reaction solution, formation of memantine was confirmed by GC (reaction yield: 96.2%).

Embodiment 3

[0107] 3,5-Dimethyl-1-adamantanol: 0.09 g (0.50 mmol), acetonitrile: 0.25 g (6.0 mmol), and toluene: 0.87 g were added to a test tube with an outer diameter of 15 mm to obtain a mixed liquid. Then, p-toluenesulfonic acid: 0.19 g (1.00 mmol) was added to the mixed solution in the test tube, and the obtained reaction solution was stirred at 70° C. for 24 hours to continue the reaction. Then, add water: 1.00g to stop the reaction in the reaction solution, wash and remove the water phase from the reaction solution, thus obtaining a toluene solution containing 1-acetamide-3,5-dimethyladamantane (reaction yield: 64 %). Then, sodium hydroxide (NaOH): 0.052 g and 1-hexanol: 0.82 g were added to the obtained solution, and the obtained reaction solution was stirred at 126° C. for 18 hours to perform 1-acetamide-3,5 - Hydrolysis of dimethyladamantane. Then, in this reaction solution, formation of memantine was confirmed by GC (reaction yield: 96%).

technical field

[0001] The invention relates to a production method of 3,5-dimethyl-1-adamantanamine. Background technique

[0002] 3,5-Dimethyl-1-adamantanamine (hereinafter also referred to as "memantine") is N-methyl-D-aspartic acid (hereinafter also referred to as "NMDA".) The antagonist is used as a therapeutic agent for Alzheimer's disease. This agent acts as a low-affinity anti-competitive electrical-dependent antagonist for NMDA receptors. Specifically, this agent will not affect normal neurotransmission or long-term potentiation (LTP) formation, but Protective effects on neuroexcitotoxicity against sustained low-concentration glutamate stimulation. In addition, this agent has a different mechanism of action from acetylcholinesterase inhibitors, so it can also be used in combination with donepezil. Therefore, this agent has the potential to expand the scope of Alzheimer's disease treatment.

[0003] As a method for synthesizing this agent, for example, various m...

Examples

Embodiment 1

[0103] 3,5-Dimethyl-1-adamantanol: 10.00 g (55.5 mmol), acetonitrile: 4.55 g (110.9 mmol), and toluene: 25.00 g were added to a 300 mL round bottom flask to obtain a mixed solution. In addition, 3,5-dimethyl-1-adamantanol was produced according to the method described in p.7390-7391 of Journal of the American Chemical Society (vol. 122, 30, 2000). Next, 97% concentrated sulfuric acid: 11.00 g (108.8 mmol) was added dropwise to the mixed solution in the flask over 23 minutes, and the resulting reaction solution was stirred at 21° C. for 2 hours to continue the reaction. In the reaction solution, after confirming the disappearance of 3,5-dimethyl-1-adamantanol by gas chromatography (GC), water: 33.66 g was added to the reaction solution to stop the reaction, and 1-acetamide-3, 5-Dimethyladamantane in toluene (2-phase solution). 1-hexanol: 25.01g was added to this two-phase solution, and liquid separation operation was performed twice, and the water phase was removed from the tw...

Embodiment 2

[0105] 3,5-Dimethyl-1-adamantanol: 1.00 g (5.50 mmol), acetonitrile: 0.46 g (11.1 mmol), and mesitylene: 9.61 g were added to a test tube with an outer diameter of 30 mm to obtain a mixed liquid. Then, 97% concentrated sulfuric acid: 1.12 g (11.1 mmol) was added dropwise to the mixed solution in the test tube, and the resulting reaction solution was stirred at 30° C. for 3 hours to continue the reaction. Then, in the reaction solution, add water: 6.09g to stop the reaction, wash and remove the water phase from the reaction solution, thereby obtaining a mesitylene solution containing 1-acetamide-3,5-dimethyladamantane (reaction yield : 80.4%). Then, sodium hydroxide (NaOH): 0.71 g and 1-hexanol: 9.61 g were added to the obtained solution, and the obtained reaction solution was stirred at 130° C. for 18 hours to perform 1-acetamide-3,5 - Hydrolysis of dimethyladamantane. Then, in this reaction solution, formation of memantine was confirmed by GC (reaction yield: 96.2%).

Embodiment 3

[0107] 3,5-Dimethyl-1-adamantanol: 0.09 g (0.50 mmol), acetonitrile: 0.25 g (6.0 mmol), and toluene: 0.87 g were added to a test tube with an outer diameter of 15 mm to obtain a mixed liquid. Then, p-toluenesulfonic acid: 0.19 g (1.00 mmol) was added to the mixed solution in the test tube, and the obtained reaction solution was stirred at 70° C. for 24 hours to continue the reaction. Then, add water: 1.00g to stop the reaction in the reaction solution, wash and remove the water phase from the reaction solution, thus obtaining a toluene solution containing 1-acetamide-3,5-dimethyladamantane (reaction yield: 64 %). Then, sodium hydroxide (NaOH): 0.052 g and 1-hexanol: 0.82 g were added to the obtained solution, and the obtained reaction solution was stirred at 126° C. for 18 hours to perform 1-acetamide-3,5 - Hydrolysis of dimethyladamantane. Then, in this reaction solution, formation of memantine was confirmed by GC (reaction yield: 96%).

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