Background and overview
Amantadine hydrochloride is a symmetrical tricyclic amine, which can inhibit the penetration of viruses into host cells, affect the uncoating of viruses, inhibit their reproduction, and have the effect of treating and preventing viral infections. Amantadine hydrochloride has antiviral properties and is administered orally for the treatment and prevention of influenza A and for the treatment of Parkinsonian neurological disorders, as well as for the treatment of shingles and post-shingles neuralgia.
At present, amantadine has been widely used in anti-influenza, and it is believed that administration of amantadine within 48 hours of onset can alleviate the symptoms of influenza A virus. In foreign countries, amantadine is used for the prevention and treatment of influenza, and the main dosage forms are single tablet, capsule and amantadine sulfate infusion. Domestic single amantadine tablets and capsules are mainly used for Parkinson’s disease, and compound amantadine hydrochloride is mainly used for the prevention and treatment of influenza, occupying a considerable market share. The mechanism of action of amantadine in the treatment of Parkinson’s disease is not clear, it may be related to amantadine promoting the release of dopamine (DA) from dopaminergic nerve endings in the striatum, strengthening the effects of dopamine and catecholamine in the central nervous system, and increasing dopamine in neurons. content related.
1) Patients with tremor paralysis who cannot tolerate levodopa treatment;
2) Prevention and treatment of respiratory tract infections and viral infections caused by Asian influenza A-II .
After this product enters the brain tissue, it can promote the release of dopamine from dopaminergic nerve endings in the striatum, or delay the metabolism of dopamine to produce anti-shock paralysis. Relieves tremors and stiffness. It has obvious curative effect on tremor paralysis, and is completely and rapidly absorbed in the gastrointestinal tract.
1) The more common adverse reactions are hallucinations and mental confusion, especially in elderly patients, which may be caused by anticholinergic effects; mood or other mental changes, generally due to stimulation or poisoning of the central nervous system.
2) The relatively rare adverse reactions are dysuria, which is caused by anticholinergic effect, mostly in the elderly; fainting, often secondary to orthostatic hypotension.
3) In long-term treatment, common adverse reactions include swelling of the feet or lower extremities, unexplained shortness of breath, and rapid weight gain. The latter may be due to congestive heart failure.
1. It is not advisable to drink alcoholic beverages during taking the medicine, as it may increase the adverse reactions of the nervous system, such as dizziness, light-headedness, orthostatic hypotension, etc.
2. Anticholinergic, antidepressant, anti-dyskinetic, antihistamine, antidiarrheal, opioid or phenothiazine-containing drugs may enhance anticholinergic adverse reactions, such as disturbance of consciousness, hallucinations, when combined with this product , nightmares, etc. Therefore, the dose of the above-mentioned drugs or this product should be reduced; at the same time, attention should be paid to the possibility of paralytic ileum.
3. This product should not be used in combination with central nervous system stimulants to avoid central nervous system excitation symptoms such as restlessness, irritability, insomnia, convulsions or heart rhythm disorders.
4. When diuretics such as hydrochlorothiazide and triamterene are used together with this product, the renal clearance of this product may be reduced, resulting in increased blood concentration and toxic reactions.
1. Using 1-bromoadamantane as raw material
1) Amination and salt-forming route with urea
In this route, adamantane is used as the initial raw material to react with liquid bromine to generate 1-bromoadamantane, and bromine is removed by distillation to obtain the crude 1-bromoadamantane with a yield of about 95%. 1-Bromoadamantane reacts with urea at 160°C using soybean oil as solvent, and the reaction is heated to 180-190°C to generate amantadine, and then extract, acidify and crystallize to obtain amantadine hydrochloride with a yield of about 80%. The preparation of 1-bromoadamantane by this route requires a large amount of bromine, which is seriously corroded to equipment, and has a large environmental pollution. During the amination reaction, the reaction temperature is higher and the reaction will suddenly heat up rapidly, there is a certain safety hazard, but This route has low cost of raw materials, simple operation and easy industrialization.
2) Reaction with formamide, hydrolysis, salt-forming route
In this route, adamantane is used as the initial raw material to react with liquid bromine to generate 1-bromoadamantane, and bromine is removed by distillation to obtain the crude 1-bromoadamantane with a yield of about 95%. 1-Bromoadamantane and formamide are catalyzed by manganese catalyst to react at 120°C for 3 hours to obtain amide. The amide is hydrolyzed by alkali, and then extracted, acidified and crystallized to obtain the salt.
Acid amantadine, the yield is about 85-90%. This route also uses liquid bromine to prepare 1-bromoadamantane, the amination is relatively mild with 1-bromoadamantane reacting with formamide and manganese catalyst, but a large amount of formamide and manganese catalyst is used, resulting in a higher total production cost, and the operation It is more complicated, the amount of “three wastes” is large and it is difficult to handle heavy metals.
2. Using adamantane as raw material
1) Reaction with acetonitrile through hydrolysis, salt-forming route
In this route, adamantane is used as the initial raw material, acetonitrile is added dropwise to sulfuric acid at -5–3°C , nickel catalyst and adamantane are added after the dropwise addition, and the reaction solution is reacted at 18°C for 6.5 hours. The crude 1-acetamidoadamantane is obtained by methane extraction and distillation, and the crude 1-acetamidoadamantane is dissolved in n-butanol to obtain amantadine hydrochloride through the steps of alkali reflux hydrolysis, dilution layering, salt formation and crystallization. The unit operation of this route is cumbersome, the total reaction period is long, a large amount of water is added in the reaction process, and a large amount of organic solvent is used for extraction, etc., so that a large amount of acidic and alkaline organic waste water is generated, which is easy to cause environmental pollution and industrial production costs are high.
2) Reaction with concentrated nitric acid to generate nitrate, through urea amination, free, salt-forming route
In this route, adamantane is used as the initial raw material to react with fuming nitric acid to generate adamantane nitrate, and then undergo urea ammonolysis to generate amantadine nitrate, and amantadine hydrochloride is obtained by freeing, extraction, salification and crystallization. The yield is about 90%. %. This route has low cost of raw materials, high yield, simple operation, mild conditions, and short reaction period, but a large amount of NO, NO2, HNO, HNO3, etc. will be generated during synthesis, which is difficult to handle effectively, and it is easy to cause environmental pollution, which is not conducive to industrialized production.
3) The route of reaction, hydrolysis and salt formation with nitrogen trichloride
In this route, adamantane is used as the initial raw material, and trichloroethane is used as a solvent to carry out amination reaction with nitrogen trichloride in the presence of aluminum trichloride, and hydrochloric acid is hydrolyzed into salt and purified to obtain amantadine hydrochloride. The yield is about 45- 50%. This route process is relatively simple, but the nitrogen trichloride used is a highly toxic drug, which is highly irritating, extremely unstable, and easy to explode, and should be avoided as much as possible in industrial production.