1,3-Dimethyl-5-aminoadamantane hydrochloride
Menantine Hydrochloride
CAS: 41100-52-1
Molecular Formula: C12H22ClN
1,3-Dimethyl-5-aminoadamantane hydrochloride - Names and Identifiers
1,3-Dimethyl-5-aminoadamantane hydrochloride - Physico-chemical Properties
| Molecular Formula | C12H22ClN |
| Molar Mass | 215.76 |
| Melting Point | 292 °C |
| Boling Point | 239.8°C at 760 mmHg |
| Flash Point | 92.3°C |
| Solubility | Soluble in Water (up to 20 mg/ml) |
| Vapor Presure | 0.0393mmHg at 25°C |
| Appearance | Crystalline powder |
| Color | White |
| Merck | 14,5806 |
| Storage Condition | Inert atmosphere,2-8°C |
| Stability | Stable for 1 year from date of purchase as supplied. Solutions in distilled water may be stored at -20°C for up to 2 months. |
| MDL | MFCD00214336 |
| Physical and Chemical Properties | White or off-white crystalline powder |
| Use | Anti-dementia drugs |
1,3-Dimethyl-5-aminoadamantane hydrochloride - Risk and Safety
| Safety Description | 24/25 - Avoid contact with skin and eyes. |
| WGK Germany | 3 |
| HS Code | 29213000 |
| Hazard Class | IRRITANT |
1,3-Dimethyl-5-aminoadamantane hydrochloride - Reference Information
| overview | memantine hydrochloride is a dementia treatment drug developed by Merz company of Germany. it is a new type of low-moderate affinity, voltage-dependent, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, which can block NMDA receptors non-competitively, reduce NMDA receptor overexcitement caused by glutamate, and prevent cell apoptosis, improving memory is a new generation of drugs to improve cognitive function. In February 2002, the European Patent and Drug Commission (CPMP) approved it for the treatment of patients with moderate and severe Alzheimer's disease. It was listed in Germany in August of the same year and was approved by the US Food and Drug Administration (FDA) on October 17, 2003 for the treatment of patients with moderate and severe Alzheimer's disease. Further studies have shown that memantine hydrochloride is also effective in patients with mild to moderate Alzheimer's disease. Alzheimer's disease (Alzheimer disease,AD), also known as senile dementia, is one of the common diseases of the elderly. It is mainly manifested as memory loss and recognition impairment. It is a progressive degenerative neurological disease. Currently, cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and memantine hydrochloride are approved for the treatment of Alzheimer's disease. |
| traits | memantine hydrochloride is white crystal or powder. The molecular weight is 215.81. |
| Synthesis method | 1. Grignard method 1-bromo -3, 5-dimethyl fund gangane reacts with methyl lithium under ultrasonic conditions to obtain 1-Lithium -3, 5-dimethyl fund gangane. Then, it is reacted with NH4Cl to give memantine. Finally, it is acidified into salt, which is memantine hydrochloride. This method needs to be carried out under anhydrous and oxygen-free conditions, and requires ultrasonic equipment. The operating conditions are relatively harsh, which requires high operators and is not suitable for industrial production. Fig. 1 is the synthetic route of memantine hydrochloride 2. acetonitrile method 1, 3-dimethyl fund rigid alkane is substituted under the action of bromine to obtain 1-bromo-3, 5-dimethyl fund rigid alkane, and then 1-acetamido -3, 5-dimethyl fund rigid alkane is obtained by acetamylation. Then, it is hydrolyzed under alkaline conditions. Finally, acidify into salt, which is memantine hydrochloride. Figure 2 is the synthetic route of memantine hydrochloride 3. Urea method 1, 3-dimethyl fund rigid alkane is brominated to obtain 1-bromo-3, 5-dimethyl fund rigid alkane. This intermediate undergoes a substitution reaction with urea to obtain N-3, 5-dimethyl fund rigid alkan-1-yl urea, which is hydrolyzed by ethylene glycol to obtain memantine, and then acidified to form a salt, which is memantine hydrochloride. The advantage of this method is that the raw material urea is easy to obtain, and the required reagents are less toxic to the environment, especially the intermediate products obtained by the amidation and alcoholysis reaction of 1-bromo-3, 5-dimethylfund rigid alkane do not need to be separated, and the direct "one-pot" reaction can be done, simplifying the experimental steps. However, in the reaction process of 1-bromo -3, 5-dimethyl fund and urea amidation, due to the large steric hindrance, when bromine replaces hydrogen in urea, the reaction is more difficult, resulting in a longer reaction time, lower reaction yield, and higher industrial production costs. At the same time, in the alcoholysis process, the carbon atom in the amide group of the urea compound has poor activity to form C, which leads to a decrease in the alcoholysis efficiency. Therefore, the required reaction temperature is higher and the reaction conditions are harsh. The total yield is only 31%, which is not suitable for large-scale production. Figure 3 shows the synthetic route of memantine hydrochloride. 4. The chlorination method uses anhydrous AlCl3 as a catalyst, and 1,3-dimethyl-based rigid alkanes are chlorinated by tert-butyl chloride to 1-chloro-3, 5-dimethyl-based rigid alkanes, and then acetamides to obtain 1-acetamido -3, 5-dimethyl-based rigid alkanes, which are then hydrolyzed to memantine, and then acidified to salt to obtain memantine hydrochloride. The total yield of this method reaches 76.1% and is suitable for industrial production. However, this method needs to be carried out under anhydrous conditions, and AlCl3 needs to be continuously added during the chlorination process. At the same time, because the tert-butyl chlorine itself is prone to elimination reaction, it needs to be prepared on site and is not easy to operate, and the chlorinated 1-chloro-3, 5-dimethylfund has low activity, resulting in low reaction conversion rate. In the whole reaction process, the requirements for reaction temperature are relatively strict and the energy consumption is relatively high. Figure 4 shows the synthetic route of memantine hydrochloride. 5. Nitration method uses N-hydroxyphthalimide (NHPI) as catalyst, and 1,3-dimethyl-based rigid alkanes are nitrated to obtain 1-nitro -3,5-dimethyl-based rigid alkanes. Then, it is hydrogenated and reduced to memantine by Pd/C catalysis. Finally, it is acidified into salt by hydrochloric acid to obtain memantine hydrochloride. This method uses NHPI as the catalyst in the nitration reaction. The reaction conditions are mild, the conversion rate is high, bromine is not required, and the equipment requirements are not high. At the same time, it avoids the use of more toxic reagents. The intermediate does not need to be purified. The impurities can be removed at the end. However, this method has great danger in catalytic hydrogenation and has a long reduction time (24h ~ 72h). Figure 5 is the synthetic route of memantine hydrochloride 6. The amidation reaction of 1, 3-dimethyl fund and formamide is obtained by the amidation reaction of 1-formamide -3, 5-dimethyl fund, which is then acidified into salt, which is memantine hydrochloride. This method will produce a large amount of NO2 gas during the reaction process, resulting in the need for a large amount of alkali for neutralization in the post-treatment process. Figure 6 shows the synthetic route of memantine hydrochloride 7. Direct ammoniation 1,3-dimethyl-based rigid alkanes complete the substitution reaction and Ritter reaction of bromine in one step under the action of bromine and acetonitrile. The intermediate product is directly alcoholized and hydrolyzed into memantine without separation, and then acidified into salt to obtain memantine hydrochloride. The raw material utilization rate of this method is not high, and this "one-pot method" enables multi-step reactions to be carried out in the same container, which will produce more by-products and is not easy to separate and control. Fig. 7 shows the synthetic route of memantine hydrochloride |
| Combined use with other drugs | 1. Combined use with huperzine A: Huperzine A is a drug extracted from the traditional Chinese medicine Huperzia serrata and is a reversible competitive cholinesterase inhibitor. Memantine has different binding ability to different glutamate receptor subtypes or its ion channels, reducing glutamate excitotoxicity, thus treating AD. AD patients not only have a variety of neurotransmitter changes, but also have postsynaptic receptor abnormalities, so the use of cholinesterase inhibitors and glutamate receptor inhibitors can play a synergistic effect. 2. Combined use with donepezil: Donepezil is the second generation cholinesterase inhibitor, which has high selectivity to cholinesterase in the central nervous system, long half-life, and lower toxicity than huperzine A. Donepezil and huperzine A act on different nerve conduction systems. When the two are used in combination, they can produce a synergistic effect, thereby enhancing the efficacy. Although the special mechanism of action has not been discovered, it has been proved that patients with moderate and severe AD will produce better therapeutic effects when treated with memantine hydrochloride combined with other drugs. 3. Combined use with nimodipine: Nimodipine is a dihydropyridine Ca2 antagonist, which can act on nerve cells, cerebrovascular cells and glial cells of the central nervous system, and can significantly expand the cerebral blood vessels and meninges The diameter of blood vessels can delay the cognitive decline of patients to a certain extent. When nimodipine is used in combination with memantine hydrochloride, its different pharmacological action links and mechanisms of action can complement each other, thus producing better curative effect. 4. Combined use with Ginkgo biloba: The main components of Ginkgo biloba are flavonoids and solanoids, which have antithrombotic, anticoagulant, anti-platelet aggregation, antioxidant and lipid-regulating effects, improve vascular wall permeability and reduce brain damage, It has a protective effect on brain microvascular smooth muscle cells, and has a significant protective effect on "vascular damage" [14]. The role of vascular factors in the pathogenesis of AD is gradually being paid attention to. A large number of epidemiological, clinical and basic studies have shown that many risk factors related to vascular factors or hemodynamics can increase the risk of AD. Therefore, the combination of memantine hydrochloride acting on NMDA receptor and ginkgo biloba can play a synergistic role. (2015-11-02) |
| pharmacokinetics | memantine hydrochloride is well absorbed by oral administration and is not affected by food. the therapeutic dose range shows linear pharmacokinetic characteristics, and age and gender do not affect its pharmacokinetic properties. Oral administration reached the peak blood concentration for 3-7h, t1/2 was 60-80h, the average distribution volume was 9-11L-kg -1, the plasma protein binding rate was 45%, 57%-82% was excreted in urine in the form of prototype and the rest in the form of metabolites N -3, 5-dimethyl-glucuronide, 6-hydroxyl dollar and 1-nitroso-deaminememepantine. Metabolites have certain NMDA receptor antagonistic activity. Renal clearance rate is affected by urine pH. When urine pH is 8, renal clearance rate decreases by 80%. |
| use | anti-Alzheimer's drug |
Last Update：2024-04-09 20:48:19
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