Preparation method and application of amantadine carbonate

Abstract

The invention discloses a preparation method and application of amantadine carbonate. The amantadine carbonate compound is also called amantadine carbonate, is a white solid and has poor water solubility, and the steady-state structural formula of the amantadine carbonate compound is # imgabs0 #. Amantadine, a salt formed by combining the amantadine and an acid, a conjugate formed by the amantadine and an ammonium salt, amantadine amide, N-(1-amantadine)-urea, a hydrolysate obtained by hydrolyzing an amination reaction product and the like can be adopted as raw materials for preparation. The amantadine carbonate has good stability, is more environment-friendly, can replace amantadine and salts thereof, and is widely applied to the fields of medicines, organic synthesis, functional materials and the like. The invention also provides a few-acid hydrolysis method for hydrolyzing an amination reaction product, amantadine carbonate is prepared by using the few-acid hydrolysis method, and amantadine carbonate is used as an intermediate or a raw material for producing amantadine and salt thereof, so that the cost can be reduced, the generation of waste salt is reduced, and the method is environment-friendly and has remarkable beneficial effects.

Description

Technical Field

[0001] The present invention relates to a preparation method and application of an adamantane amine derivative, in particular to a preparation method and application of an adamantane amine carbonate. Background Art

[0002] Amantadine, also known as 1-adamantaneamine, has a chemical name of tricyclo[3,3,1,1(3,7)]decane-1-amine, also known as tricyclodecylamine, and has the following structure:

[0003] Amantadine is an antiviral drug that can inhibit viruses from penetrating into host cells, affect the uncoating of viruses, inhibit their reproduction, and play a role in treating and preventing viral infections. It is suitable for preventing or treating respiratory infections caused by Asian influenza A viruses and is effective in treating Parkinson's disease. Amantadine and its salts are important chemical products and raw materials. They can also be used as raw materials for the production of vildagliptin intermediates - 3-amino-1-adamantanol; they can be used to synthesize adamantyl quaternary ammonium bases and to manufacture SSZ-13 molecular sieves; they can also be used as corrosion inhibitor components, etc., and have a wide range of uses.

[0004] Since the amino group of adamantane is alkaline, it can combine with acid through hydrogen bonds to form salts. For example, it can form salts with acids such as hydrochloric acid, sulfuric acid, nitric acid, formic acid, and acetic acid. Most of the salts formed by adamantane and acid are soluble in water. The only known salt with poor water solubility is adamantane sulfate, also known as adamantane sulfate. The precipitation method is a classic purification method with simple operation and low cost. Amantadine sulfate has high water solubility, and its solubility increases with the increase of acidity. In the existing industrial production process of adamantane and its salts, strong acid is generally used for hydrolysis after the amination reaction, which limits its application as a precipitation intermediate for separation and purification; and the introduction of sulfate ions in the later wastewater treatment will produce mixed salts, which further limits the application of adamantane sulfate as a precipitation intermediate for separation.

[0005] In the existing industrial production process of amantadine and its salts, water distillation process and organic solvent extraction process are mostly used to purify amantadine. The water distillation process is to directly add alkali solution to the amination reaction materials or add alkali to the hydrolyzed materials, and perform high-temperature distillation under strong alkaline conditions. The sublimation of amantadine is utilized to distill it out through water vapor, and then condense and collect to obtain water-containing amantadine. The organic extraction process is also to react the amination reaction materials or the hydrolyzed materials with excess alkali to generate amantadine, and then use organic solvent extraction to dissolve amantadine in the organic solvent, separate it from the impurities insoluble in the organic solvent, and then use acidic solution and organic solvent dissolved with amantadine to perform back extraction, so that amantadine reacts with the acid in water to generate water-soluble salts that enter the water phase, thereby achieving the purpose of purifying amantadine.

[0006] The water distillation process has many disadvantages. First, a large amount of water needs to be distilled, which is inefficient and energy-intensive. In addition, during the water distillation process, adamantane easily aggregates into small balls with smooth surfaces, which are not easy to be distilled out, affecting the efficiency of water distillation and causing low yields. Second, an excessive amount of alkali is required and the side reactions consume alkali, resulting in a large amount of alkali consumption. The existing processes of directly adding alkali solution to the amination reaction product for water distillation and hydrolyzing with strong acid to generate adamantane salt and then reacting with alkali for water distillation require excessive alkali to achieve strong alkalinity. During the process of directly adding alkali solution to the amination reaction product for water distillation, the impurities generated by the amination reaction will consume alkali. Strong acid hydrolysis to generate adamantane salt will consume alkali and produce salt, increasing the cost of wastewater treatment. Third, the product obtained by water distillation has low purity and is difficult to control in terms of quality stability. 1-Bromoadamantane that is not completely reacted in the amination reaction is hydrolyzed to generate 1-adamantanol and 1,3-adamantanediamine, which are taken out together during water distillation, making the purity of adamantane low. Under strong alkali and high temperature conditions, the residual urea and biuret in the mixed material will hydrolyze and release ammonia, which will partially dissolve in the distilled water, causing the ammonia to be entrained in the amantadine product. In addition, the uncondensed amantadine and ammonia will be emitted into the production environment, resulting in a bad production environment that is difficult to manage.

[0007] The disadvantages of using organic solvent extraction technology are: the process is long, the introduction of organic solvents is dangerous, and the cost of organic solvent recycling is high. The purity of the hydrolyzate and the pretreated materials is not high, and the main content of adamantane in organic matter in chromatographic analysis is generally not higher than 98%. When organic solvents are used for extraction after alkalization, impurities will be dissolved in the organic solvent together, and then enter the aqueous phase when water and acid are added for back extraction, and the purity of the adamantane salt solution obtained is poor. There are many impurities remaining in the organic extractant, the energy consumption of recycling and treatment is large, and the impurity treatment is difficult. The introduction of organic solvents increases the safety risk of the production workshop, greatly increases the safety investment, and affects the health of the operators. . Summary of the invention

[0008] The present invention provides a preparation method of an amantadine derivative and application thereof, in particular to a preparation method of an amantadine carbonate and application thereof.

[0009] The inventors have found through research that a water-soluble salt of amantadine generates a white precipitate after adding a water-soluble carbonate. After washing the generated precipitate until the washing water is acidified and no bubbles are generated, acid is added to the precipitate, the precipitate dissolves and generates bubbles, and its properties are relatively stable, unlike amantadine, which is easy to sublime. After research, it was determined that it is a compound formed by the combination of amantadine and carbonic acid, which is the carbonate of amantadine. The molecular structure of amantadine carbonate is similar to that of amantadine sulfate, except that the sulfuric acid combined with amantadine is converted into carbonic acid. Its steady-state structure is also similar to that of amantadine sulfate. Amantadine and carbonic acid are combined in a ratio of 2:1 to form the steady-state structure of amantadine carbonate:

[0010] Just as amantadine hydrochloride is also called amantadine hydrochloride, amantadine carbonate is also called amantadine carbonate.

[0011] Excess sulfate solution is used to react with the hydrolyzate under acidic conditions to obtain amantadine sulfate precipitate. The filtrate after separation of the precipitate is added with carbonate to produce a precipitate. The precipitate has the same properties as amantadine carbonate, which confirms that the carbonate precipitate of amantadine is less water soluble than the sulfate precipitate. After mixing and stirring the amantadine sulfate and the water-soluble carbonate, a white solid material is filtered out, washed, and then acid is added. The precipitate is completely dissolved and bubbles are generated, indicating that the poorly water-soluble amantadine sulfate can also react with carbonate to produce amantadine carbonate.

[0012] The structure of organic matter is complex, and so is the salt of organic matter. For example, the structure of amantadine hydrochloride is generally believed to be that the ratio of amantadine molecules to hydrogen chloride molecules is 1:1. In fact, the pH of aqueous solutions of the same concentration prepared by different amantadine hydrochlorides is different, which can be judged that the amantadine molecules and hydrochloric acid molecules are floating. In practice, it is also proved that the pH of aqueous solutions of the same concentration prepared by crystallization of amantadine hydrochloride solution can vary greatly when the amount of hydrochloric acid added is different. This shows that the number of hydrogen chloride molecules in the amantadine hydrochloride molecule combined with hydrogen chloride can be more than that of amantadine molecules. The same is true for amantadine carbonate. In theory, two amantadine molecules are combined with one carbonic acid molecule, but in the case of excess carbonic acid molecules, amantadine can also combine with more carbonic acid molecules just like combining with more hydrogen chloride molecules. Therefore, the reaction of amantadine with sufficient bicarbonate or the introduction of excess carbon dioxide does not rule out the possibility of generating amantadine bicarbonate. In addition, the hydrate of amantadine is alkaline and poorly soluble in water. The amantadine carbonate produced after the reaction with carbon dioxide may exist in the form of basic carbonate. In chemical nomenclature, the general term carbonate includes carbonate salts, acid carbonates (bicarbonates) and basic carbonates. Therefore, the compound amantadine carbonate described in the present invention includes amantadine carbonate salts formed by the combination of amantadine and carbonic acid, and also includes possible acid carbonates and basic carbonates of amantadine.

[0013] The preparation method of adamantane carbonate comprises the following multiple reaction methods, and then solid-liquid separation is performed to obtain adamantane carbonate.

[0014] 1. Using amantadine as a raw material, react with water and carbon dioxide, and / or bicarbonate to generate amantadine carbonate: .

[0015] Since carbonic acid is unstable and it is difficult to prepare a high-content carbonic acid solution, the common practice of using carbon dioxide to prepare carbonate is to pass carbon dioxide gas into an aqueous solution of an alkaline material. This method can also be used to produce amantadine carbonate: aqueous amantadine reacts with carbon dioxide to generate amantadine carbonate. This method is inefficient. Amantadine is a solid material, and the generated amantadine carbonate is also solid. Therefore, amantadine is not easy to fully contact with carbon dioxide and it is difficult to react completely. While steam distilling amantadine, passing carbon dioxide into the distilled gas phase to react with it is more complete. Amantadine can also react with bicarbonate to obtain amantadine carbonate. The bicarbonate is preferably a water-soluble bicarbonate, such as ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc., including but not limited to the use of one or more of them, and is prepared into an aqueous solution for use, the same below. When adding bicarbonate to react, an excess of bicarbonate is normally added, and the pH of the reaction solution is relatively high, reaching about 10~11.5; to ensure complete reaction, the pH of the reaction solution can be adjusted to 4~10.

[0016] Amantadine can also react with normal carbonate to generate a small amount of amantadine carbonate, but the product is a base, which will inhibit the reaction. Amantadine carbonate obtained by adding acid or strong acid weak base salt and other methods to consume hydroxide to adjust pH is classified into the following methods of preparing amantadine carbonate using salts formed by combining with amantadine acid and combinations formed by amantadine and ammonium salt as raw materials, and is also within the scope of protection of the present invention.

[0017] 2. The salt formed by the combination of amantadine and acid reacts with carbonate to form amantadine carbonate: .

[0018] The salt formed by combining amantadine with other acids except carbonic acid is added with carbonate, reacted to form amantadine carbonate, and solid-liquid separation can obtain amantadine carbonate solid with less water. The carbonate is a general carbonate, that is, it includes carbonate salt, acid carbonate (bicarbonate) and basic carbonate, the same below. Percarbonate is hydrolyzed to form carbonate, so the method of using percarbonate to indirectly react to form amantadine carbonate also belongs to the method of using carbonate reaction to form amantadine carbonate, and is also within the protection scope of the preparation method described in the present invention, the same below. The carbonate used is preferably a water-soluble carbonate, such as ammonium (bi) carbonate, sodium (bi) carbonate, potassium (bi) carbonate, etc., including but not limited to one or more thereof, and is prepared into an aqueous solution for use; the same below. The method of using percarbonate to dissolve in water to obtain a carbonate solution is also included therein, the same below. When adding carbonate to react, an excess of carbonate is normally added, and the pH of the reaction solution is relatively high, which can reach about 10~11.5; to ensure complete reaction, the pH of the reaction solution can be adjusted to 4~10.

[0019] The acid described in the salt formed by the combination of amantadine and acid includes but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, citric acid, etc., which can be one or more. Although amantadine sulfate has poor water solubility, it can also react with carbonate to generate amantadine carbonate. Using excess sulfate solution and aminated hydrolyzate to react under acidic conditions to obtain amantadine sulfate precipitation, adding carbonate to the filtrate after separation and precipitation will also produce precipitation, and the precipitation property is the same as that of amantadine carbonate, thus confirming that the carbonate precipitation of amantadine is less water-soluble than the sulfate precipitation. After the amantadine sulfate and water-soluble carbonate are mixed and stirred for reaction, the white solid material is filtered out, and acid is added after washing, and the precipitation is completely dissolved and bubbles are generated, proving that the water-poor amantadine sulfate can also react with carbonate to generate amantadine carbonate.

[0020] 3. The combination of adamantane and ammonium salt reacts with carbonate to form adamantane carbonate: .

[0021] The inventors have found that adamantane and ammonium salts can form a complex. It is speculated that the ammonium salt and adamantane are bonded by hydrogen bonds, or it may be a complex in other ways. The complex formed by adamantane and an ammonium salt includes a complex formed by adamantane and one or more of ammonium salts such as ammonium bromide, ammonium chloride, ammonium fluoride, ammonium formate, ammonium nitrate, ammonium acetate, ammonium (hydrogen) phosphate, and ammonium citrate. These complexes can be dissolved in water relatively quickly when there is sufficient water and temperature. Under alkaline conditions, the adamantane material can be dissolved in water with the above-mentioned solution, and the pH of the solution can be as high as about 9. The principle is that the complex formed by adamantane and an ammonium salt can be converted into a salt of adamantane combined with an acid: .

[0022] Heating is beneficial to the above reaction. Ammonium salts are hydrolyzed into acid and ammonia in aqueous solution. Amantadine combines with acid to form salts of amantadine. Ammonia is free in the solution, volatilizes or dissolves in water and combines again. Most of the amantadine salts are soluble in water. Except for ammonium sulfate (hydrogen) and ammonium carbonate (hydrogen) carbonate, amantadine and excess other ammonium salts slowly change from turbid to clear in a heated aqueous solution. Because ammonia is not completely volatilized, the reaction proceeds to the left after cooling. The combination of ammonia and amantadine salts is not as complete as the reaction of amantadine with acid. The intermolecular bonding is not strong enough, and some amantadine will precipitate. Therefore, the originally dissolved and transparent solution will become turbid again after cooling.

[0023] Adamantane amine and ammonium salt form a complex and are added to carbonate for reaction. Normally, an excess of carbonate is added and the pH of the reaction solution is relatively high, which may be around 10-12. To ensure a complete reaction, the pH of the reaction solution may be adjusted to 4-10.

[0024] The combination of amantadine and ammonium salt will hydrolyze to form ammonia in aqueous solution, and add bicarbonate to react to form amantadine carbonate, acid radical ions, carbon dioxide and ammonia; carbon dioxide and ammonia react to form ammonium carbonate. Therefore, the overall reaction of adding bicarbonate is: .

[0025] The combination formed by adamantane amine and ammonium salt reacts with carbonate salt in aqueous solution, and the generated ammonia can also be dissolved in water to form ammonia water.

[0026] 4. The amide of adamantane reacts with carbonate to generate adamantane amine carbonate: , R is H or CH3(CH2) m , m is a natural number. Adding a small amount of alkali can accelerate the reaction. The alkali is preferably sodium hydroxide and / or potassium hydroxide, the same below.

[0027] The amide of adamantane is preferably 1-acetylaminoadamantane, and its main source is the reaction of adamantane with acetonitrile. Its preparation method is that adamantane and acetonitrile react under catalysis, and an organic solvent can be added to the reaction system. The catalyst is mainly a strong acid, an acidic ionic liquid, etc. The reaction product is subjected to steps such as removing the organic solvent and refining to obtain 1-acetylaminoadamantane, and then the above reaction is carried out to obtain adamantane carbonate. In order to improve the yield, more alkali can be added to make the hydrolysis complete, and the pH of the reaction solution is adjusted to 3-10 in the later stage to make the reaction conversion into adamantane carbonate more thorough.

[0028] The amide of amantadine can also be hydrolyzed with acid to form amantadine salt, which can then react with carbonate to form amantadine carbonate.

[0029] 5. Hydrolysis of N-(1-adamantane)-urea to generate adamantane carbonate: . Sufficient water will cause further reaction. The ammonia generated by the reaction can be dissolved in water to form ammonia water, and carbon dioxide can react with ammonia water to form ammonium carbonate.

[0030] 6. The hydrolyzate after the amination reaction product is hydrolyzed is reacted with carbonate to generate adamantane carbonate. The amination reaction product comprises 1-bromoadamantane, and / or 1-chloroadamantane, and / or 1-fluoroadamantane, and / or 1-adamantanol, and / or 1-nitroadamantane, and / or 1-adamantanol nitrate, and the aminating agent is preferably urea. DMF, soybean oil, etc. can also be added as a solvent for the amination reaction. In industry, 1-bromoadamantane is often used as a raw material, and the aminating agent is urea. The hydrolyzate is a hydrolyzate obtained by adding water to the amination reaction product, or adding acid, ammonium salt, etc. to water in a free combination, preferably a hydrolyzate obtained by filtering out insoluble matter after hydrolysis, and reacting with carbonate to generate adamantane carbonate. The acid is one or more commonly used acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, formic acid, acetic acid, citric acid, etc., and the ammonium salt is one or more ammonium salts such as ammonium bromide, ammonium chloride, ammonium fluoride, ammonium formate, ammonium nitrate, ammonium acetate, ammonium (hydrogen) phosphate, ammonium citrate, etc. The types of acids and ammonium salts added can be freely combined.

[0031] The traditional acid hydrolysis method is to add excess acid for hydrolysis to obtain a hydrolyzate with high acidity. It is easier and more stable for adamantane to combine with strong acid molecules. There is an excess of acid in this hydrolyzate, and adamantane substances mainly exist in the form of salts formed by the combination of adamantane and acid. This hydrolyzate can react with carbonate to form adamantane carbonate, but if excessive acid is added for hydrolysis, the salt content of the production wastewater after neutralization is very high, which will produce a large amount of waste salt and make wastewater treatment difficult.

[0032] The amination products of 1-bromoadamantane, and / or 1-chloroadamantane, and / or 1-fluoroadamantane, and / or 1-adamantanol, and / or 1-nitroadamantane, and / or 1-adamantanol nitrate with urea are complex, and the mechanism is rarely reported. There are also few existing research reports on the exact composition of the adamantane group. Public literature generally reports that adamantane amine is directly generated: , R is halogen, hydroxyl, nitro, nitrate ester, etc.

[0033] However, such public reaction equations do not explain the reaction products clearly. The inventors studied the amination reaction of 1-bromoadamantane with urea and found that the amination reaction product can dissolve the adamantane amine substances in the reaction materials in the aqueous solution by adding only water and combining with high temperature. The hydrolyzate at this time is weakly acidic with a pH of 4 to 7, and the insoluble matter is similar to the insoluble matter of acid hydrolysis; when the temperature of the hydrolyzate is lowered, the dissolved adamantane amine substances begin to precipitate again.

[0034] Continuing the study, the following uses the amination reaction of 1-bromoadamantane and urea as an example to illustrate the complex amination reaction.

[0035] 1-Bromoadamantane reacts with urea to form N-(1-adamantane)-urea: , The amino group in N-(1-adamantane)-urea can combine with hydrogen bromide to form a salt: , can also combine with ammonium bromide to form salts; The reaction material contains a small amount of water, and a small amount of 1-bromoadamantane is hydrolyzed to 1-adamantanol, causing urea to decompose at the same time: , Due to the excess of urea, the high temperature in the later stage of the reaction causes urea condensation: , biuret may continue to condense to form triuret, cyanuric acid, etc.; in addition, urea can also decompose at high temperature to form ammonia and cyanic acid (including isocyanic acid): , , further reaction can also generate cyanuric acid and isocyanuric acid, The generated cyanic acid can also form salts with amino groups, but hydrolysis decomposes cyanic acid into ammonia and carbon dioxide: In the later stage of the reaction of 1-bromoadamantane and urea at high temperature, adamantane and cyanic acid (including isocyanic acid) are generated. Part of the cyanic acid (including isocyanic acid) turns into gas and escapes, and part of it combines with adamantane. The ammonia generated in the reaction can react with the hydrogen bromide generated in the reaction: Part of the generated ammonium bromide combines with adamantane, and part of it escapes as exhaust gas in the form of white smoke.

[0036] The amination reaction product of 1-bromoadamantane and urea can be hydrolyzed by adding water, and it is speculated that the following reaction occurs: , , . The first two reactions are dominant. The amount of N-(1-adamantane)-urea that is not combined with ammonium salt or hydrogen bromide generated by the last reaction is very small. After hydrolysis, it will combine with ammonium bromide or hydrogen bromide to form the corresponding salt. The adamantane amine generated by hydrolysis in the second reaction can also combine with ammonium bromide: . When the hydrolyzate is heated, the aqueous solution gradually changes from turbid to clear, and the adamantane amine substances are dissolved: . Because ammonia does not evaporate completely, the reaction proceeds to the left after cooling. The combination of ammonia and ammonium salt with adamantane is not as complete as the reaction between adamantane and acid. The intermolecular bonding is not strong enough, and some adamantane will precipitate. Therefore, the originally transparent solution will become turbid after cooling.

[0037] The principle of the amination reaction of 1-chloroadamantane, and / or 1-fluoroadamantane, and / or 1-adamantanol, and / or 1-nitroadamantane, and / or 1-adamantanol nitrate with urea is similar. The amination reaction products of 1-bromoadamantane, and / or 1-chloroadamantane, and / or 1-fluoroadamantane, and / or 1-adamantanol, and / or 1-nitroadamantane, and / or 1-adamantanol nitrate with ammonium salts such as ammonium carbonate (bi) and ammonium chloride as aminating agents are also similar. Therefore, the known adamantane-type substances that may be present in the amination reaction product of 1-bromoadamantane, and / or 1-chloroadamantane, and / or 1-fluoroadamantane, and / or 1-adamantanol, and / or 1-nitroadamantane, and / or 1-adamantanol nitrate, the amination reaction product and the hydrolyzate after hydrolysis include: adamantane, a salt formed by the combination of adamantane and an acid, a combination of adamantane and an ammonium salt, N-(1-adamantanyl)-urea, and a salt formed by N-(1-adamantanyl)-urea and an acid, etc.

[0038] Based on the above research, the present invention also provides a method for hydrolyzing the above-mentioned amination reaction product with a small amount of acid: only water is added to the amination reaction product, or a small amount of acid and / or ammonium salt is added to the water for hydrolysis, the amount of hydrogen ion substance corresponding to the added acid is within 0.7 times the amount of adamantane substance contained in the amination reaction product, the amount of ammonium ion added is within 0.9 times the amount of adamantane substance contained in the amination reaction product, and the amount of acid and ammonium salt added can be freely adjusted to meet the requirement that the sum of the amount of hydrogen and ammonium ion substance in the cation corresponding to the acid ion in the hydrolyzate is greater than or equal to the amount of adamantane substance contained; the acid is one or more commonly used acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, formic acid, acetic acid, citric acid, etc., the ammonium salt is one or more ammonium salts such as ammonium bromide, ammonium chloride, ammonium fluoride, ammonium formate, ammonium nitrate, ammonium acetate, ammonium (hydrogen) phosphate, ammonium citrate, etc., and the types of acid and ammonium salt added can be freely combined; preferably, only water is added for hydrolysis and then insoluble matter is filtered out to obtain the hydrolyzate. The total amount of water added during the hydrolysis process is generally 2 to 10 of the weight of the amination reaction product. The more water is added, the better the hydrolysis effect is, but the material concentration is low and the wastewater produced in the later stage increases. Like traditional hydrolysis, the hydrolysis process needs to be heated, generally to above 50°C. Maintaining a higher temperature will have a better hydrolysis effect, preferably 50 to 100°C, and the hydrolysis time is preferably 0.5 to 5h. If pressurization and other means are used, the temperature can also be raised to a higher level, but the required heat and energy consumption will increase. By adjusting the amount of water added and the hydrolysis temperature according to actual needs, the optimal cost conditions can be found.

[0039] There will be impurities of amination reaction in the hydrolyzate, some of which are insoluble in the hydrolyzate, and the content of some impurities in the hydrolyzate varies with the temperature of the hydrolyzate, such as urea condensation products. It is preferred to cool down after hydrolysis to allow the water-soluble impurities to be partially precipitated and filtered out together with the water-insoluble impurities. However, the temperature of the hydrolyzate obtained by the less-acid hydrolysis method cannot be lowered too low to prevent the material from precipitating and being filtered out. Generally, the temperature is controlled at 30°C to 85°C to filter out insoluble matter. The actual temperature for filtering out insoluble matter needs to be adjusted in combination with the amount of water added. If the amount of water added for hydrolysis is large, the temperature can be lower, and if the amount of water added is small, the temperature needs to be higher. Excess acid is added to the insoluble matter filtered out after hydrolysis for secondary hydrolysis. The added acid is one or more of commonly used acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, formic acid, acetic acid, citric acid, etc.; the secondary hydrolyzate is reused for the initial hydrolysis of the amination reaction product.

[0040] When halogenated adamantane and adamantane-type substances substituted with functional groups such as nitro and nitrate groups that produce acid radicals after hydrolysis are used to react with urea, urea is usually in excess, and most of the acid radicals in the reactants remain in the materials after the reaction. When water and ammonium salts are added for hydrolysis, adamantane can be dissolved in water by combining with them; when non-halogenated adamantane and adamantane-type substances substituted with functional groups such as nitro and nitrate groups that produce acid radicals after hydrolysis are used to react with urea, such as the product of the reaction of adamantane alcohol and urea, a relatively large amount of ammonium salt and / or acid needs to be added to combine with adamantane in the reaction product and dissolve in water. In short, in order to ensure a good hydrolysis effect, the sum of the amount of hydrogen and ammonium radical substances in the cations corresponding to the acid radical ions in the hydrolyzate must be greater than or equal to the amount of adamantane contained.

[0041] Compared with the traditional acid hydrolysis, the addition of ammonium salt for hydrolysis can also obtain a yield equivalent to that of acid hydrolysis. The addition of acid hydrolysis can make the adamantane group-containing substance generated by the reaction form adamantane salt more quickly. Most of the salts of adamantane are soluble in water, thereby achieving the purpose of hydrolysis. Therefore, the addition of acid can increase the material dispersion speed, facilitate the stirring of bulk materials, and save the dispersion time of the foam material. In order to better protect the present invention, it is limited to add an acid within 0.7 times the amount of the adamantane group substance in the reactant. The addition of an acid more than 0.7 times the amount of the adamantane group substance in the reactant can also hydrolyze, but compared with the traditional excessive acid hydrolysis, the amount of acid is not much reduced and is not very meaningful. In the case of sufficient water and sufficient temperature, the same solubility can be achieved without adding acid, so that the reaction material is fully hydrolyzed and dissolved in the aqueous solution more quickly. Without adding acid, only water and ammonium salt are added for hydrolysis, and the pH of the hydrolyzate is generally 3~9. After the bulk material is dispersed, it is stirred and hydrolyzed, which can save hydrolysis time and make the material hydrolyzed more completely. Generally, it needs to be heated and stirred for more than half an hour. After the hydrolysis is completed, the material is dissolved in the aqueous solution, and the residue is filtered out by cooling to obtain a hydrolyzate containing the adamantane material. The chromatographic analysis content can generally be higher than 97.5%, which is higher than the traditional excessive acid hydrolysis method; the residue that cannot be hydrolyzed in the residue is very small, which is equivalent to the residue of the traditional excessive acid hydrolysis method.

[0042] In order to better protect the present invention, the amount of ammonium radical added to the ammonium salt is limited to within 0.9 times the amount of the adamantane amine substance contained in the amination reaction product. The ammonium salt can be added directly or by adding a precursor to generate the ammonium salt through reaction. For example, the ammonium chloride can be added by directly adding ammonium chloride and its solution, or by adding a precursor such as ammonia water, ammonium bicarbonate, ammonium carbonate, and then adding hydrochloric acid to generate the ammonium chloride through reaction.

[0043] By using this low-acid hydrolysis process, a hydrolysis yield equivalent to that of the traditional excess acid hydrolysis method can be obtained without adding acid, adding less acid, adding less ammonium salt, etc., and the purity of the material in the hydrolyzate is higher than that of the traditional excess acid hydrolysis method.

[0044] The hydrolyzate obtained by the above-mentioned less-acid hydrolysis method is hydrolyzed, reacted with carbonate to generate amantadine carbonate, and solid-liquid separation is performed to collect solids to obtain amantadine carbonate. The hydrolyzate obtained by traditional excessive acid hydrolysis can also be successfully prepared to obtain amantadine carbonate, but the amount of acid added is large and a large amount of carbonate is required. It can be first neutralized with an alkali to a weak acidity, and then reacted with carbonate to prepare amantadine carbonate. Regardless of whether an alkali or carbonate is used, the neutralization reaction will produce a large amount of waste salt, and wastewater treatment is also difficult.

[0045] The product after amination reaction of 1-bromoadamantane, and / or 1-chloroadamantane, and / or 1-fluoroadamantane, and / or 1-adamantanol, and / or 1-nitroadamantane, and / or 1-adamantanol nitrate is hydrolyzed by a little acid hydrolysis method or a lot acid hydrolysis method to obtain a hydrolyzate, or it can be first prepared into adamantane sulfate, and then reacted with carbonate to generate adamantane carbonate. The lot acid hydrolysis method is based on the little acid hydrolysis method, and the amount of acid added is increased for hydrolysis, and the amount of hydrogen ion substance corresponding to the added acid is more than 0.7 times the amount of adamantane substance contained in the amination reaction product. The amount of hydrogen ion substance corresponding to the added acid is more than 1 times the amount of adamantane substance contained in the amination reaction product, which is a traditional excessive acid hydrolysis method. The acid is one or more of common acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, formic acid, acetic acid, citric acid, etc. Compared with the preferred hydrolysis temperature of 50-100°C, the hydrolysis time of 0.5-5h, and the temperature of the insoluble matter filtered out after hydrolysis of 30-85°C in the less-acid hydrolysis method, the temperature of the more-acid hydrolysis method and the temperature of filtering out the insoluble matter can be lower.

[0046] Sulfate precipitation is also a method for removing impurities. It is quite unexpected that sulfate precipitation can also be converted into carbonate precipitation. Sulfate (hydrogen) salts and / or sulfuric acid are added to the hydrolyzate, and the pH of the reaction solution is controlled to be less than 8 at the end of the reaction, and the precipitate is filtered out to obtain adamantane sulfate; preferably, water-soluble sulfates and / or hydrogen sulfates are used, such as ammonium (hydrogen) sulfate, sodium (hydrogen) sulfate, potassium (hydrogen) sulfate, etc., and / or sulfuric acid, including but not limited to one or more thereof, preferably prepared into an aqueous solution for use. The higher the acidity of the reaction solution, the greater the solubility of adamantane sulfate in it, so the pH of the reaction solution should not be too low. During solid-liquid separation, the temperature of filtering out the adamantane sulfate precipitate is controlled to be the same as or higher than the temperature of filtering out the insoluble matter from the hydrolyzate, so that the adamantane sulfate precipitate obtained can carry fewer impurities.

[0047] The obtained amantadine sulfate is then reacted with carbonate to generate amantadine carbonate, thereby preparing amantadine carbonate: .

[0048] There may be undiscovered forms of adamantane substances in the hydrolyzate. The present invention can treat 1-bromoadamantane, and / or 1-chloroadamantane, and / or 1-fluoroadamantane, and / or 1-adamantanol, and / or 1-nitroadamantane, and / or 1-adamantanol nitrate as a product of amination reaction, and the hydrolyzate after hydrolysis by adding only water, adding acid, and / or ammonium salt to water, etc., reacts with carbonate to obtain adamantane carbonate; or reacts with sulfate (hydrogen) salt, and / or sulfuric acid to generate adamantane sulfate, and then reacts with carbonate to generate adamantane carbonate; if subsequent research finds that other adamantane substances exist in the hydrolyzate obtained by the above hydrolysis method, and can react with carbonate to generate adamantane carbonate, or can react with sulfate (hydrogen) salt, and / or sulfuric acid to generate adamantane sulfate, and then reacts with carbonate to generate adamantane carbonate, then the method of preparing adamantane carbonate by reacting the adamantane substance with carbonate is also within the protection scope of the preparation method described in the present invention.

[0049] Regardless of the hydrolysis method used, in order to obtain high-purity adamantane amine carbonate, the hydrolyzate can be pretreated. During or after the hydrolysis, the hydrolyzate from which insoluble matter is filtered out is decolorized using a decolorizer, and the decolorizer is preferably activated carbon or activated carbon fiber. The filtered insoluble matter and the decolorizer can be washed with water to recover the entrained material, and the entrained material in the insoluble matter is recovered by secondary hydrolysis. The secondary hydrolysis method can use the method of the low-acid hydrolysis of the present invention, or the traditional excessive acid hydrolysis method, and can also use the alkali solution water steaming method to recover the entrained material in the insoluble matter. The acid added in the acid-added secondary hydrolysis is one or more commonly used acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, formic acid, acetic acid, citric acid, etc.; the secondary hydrolyzate is reused for the primary hydrolysis of the amination reaction product.

[0050] After hydrolysis and decolorization, the temperature is controlled and filtered to remove insoluble matter to obtain a hydrolyzate, which can be extracted with a poorly water-soluble solvent to remove some impurities, and the solvent is concentrated and distilled to recover 1-adamantanol; the organic solvent used is preferably benzene, toluene, xylene, heptane, octane, trimethylpentane, methylhexane, cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane, ethylcyclohexane, methyl tert-butyl ether, carbonates, non-water-soluble silicone oil and other commonly used poorly water-soluble solvents, one of which is used, or a mixture of multiple solvents in any proportion.

[0051] The adamantane carbonate produced by the above reaction can be filtered out at the same temperature or higher than the temperature at which the reaction solution containing adamantane amine is purified (e.g., the insoluble matter is filtered out from the hydrolyzate) during solid-liquid separation, so that the adamantane carbonate precipitate obtained contains fewer impurities. The temperature for separating the adamantane carbonate precipitate is preferably 20° C. to 85° C. After solid-liquid separation, salt and other impurities are bound to be entrained due to the entrained water, which can be washed and removed to prepare adamantane carbonate with higher purity. Clean water or weakly alkaline water can be used for washing, and a detergent such as a surfactant can be added to the water, and a solvent can also be used for washing. The solvent preferably uses a commonly used solvent, including but not limited to: alcohols (methanol, ethanol, ethylene glycol, isopropanol, etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (pentane, hexane, heptane, octane, etc.), alicyclic hydrocarbons (cyclopentane, methylcyclopentane, cyclohexane, cyclohexanone, toluene cyclohexanone, etc.), halogenated hydrocarbons (chlorobenzene, dichlorobenzene, dichloromethane, chloroform, etc.), ethers (ethyl ether, methyl tert-butyl ether, etc.), esters (methyl formate, methyl acetate, ethyl acetate, propyl acetate, etc.), ketones (acetone, methyl butyl ketone, methyl isobutyl ketone, etc.), glycol derivatives (ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, etc.), N-methylpyrrolidone, acetonitrile, carbonates, silicone oil and other solvents, and possible aqueous solutions thereof, one of which is used, or a mixture of multiple solvents in any proportion. The detergent and solvent are preferably substances that are easy to remove later. The impurities of the washed adamantane carbonate are lower and the purity is higher. The washing can be repeated multiple times as required. The temperature range for washing the intermediate adamantane carbonate precipitate is any temperature between room temperature and the boiling point of the washing liquid. The adamantane carbonate can also be steamed to remove volatile impurities such as 1-adamantanamine, 1-adamantanol, ammonia and solvent.

[0052] The hydrolyzate reacts with carbonate to generate adamantane carbonate. The filtrate after filtering out the adamantane carbonate contains bromide ions and excess carbonate and bicarbonate, and can be reused in production. During the reuse in production, acid can be directly added, and the pH can be adjusted to acidic, and then the bromine element can be recovered; preferably, it can be reused to remove excess bromine in the reaction product of adamantane and bromine, and / or used to absorb bromine and hydrogen bromide generated in the reaction, and after adjusting the pH to acidic, chlorine gas displacement is used to recover the bromine element.

[0053] Due to its special physical and chemical properties, adamantane carbonate compounds are widely used, including the following uses.

[0054] 1. Application in medicine. Amantadine carbonate has poor water solubility and has little impact on the environment after being spilled; it is not bitter and has a good taste; it is weaker in alkalinity than amantadine and is gentler on the human body; it reacts with hydrochloric acid in gastric juice after entering the stomach to produce amantadine hydrochloride, which does not affect human absorption and does not increase acid; it has little effect on organisms that do not produce gastric acid. The above advantages make it possible to be used as an amantadine-type drug and is also suitable as a sustained-release drug.

[0055] 2. Application in organic synthesis. Amantadine carbonate is used as raw material and synthetic intermediate, and is used to prepare or purify adamantane derivatives such as 1-adamantanamine and other adamantane salts. It can be widely used in organic synthesis, preparation of APIs and organic basic chemical raw materials. As we all know, precipitates are important substances for purification. Amantadine sulfate can be used to purify adamantane salt compounds, and amantadine carbonate is used to purify adamantane salt compounds, which has better effects than amantadine sulfate. As mentioned above, the product of amination reaction has many impurities. After the insoluble matter is filtered out of the hydrolyzate, sulfate precipitation is added, and the temperature is controlled for solid-liquid separation. Most of the water-soluble impurities are taken away with the liquid, and a small amount remains in the precipitate, but the content of the precipitate is generally not higher than 98.5%. When carbonate is used to generate adamantane carbonate precipitate, the temperature is also controlled for solid-liquid separation. The chromatographic analysis of the precipitate shows that the adamantane content is generally higher than 99.5%, and the impurity removal efficiency is much higher than that of the adamantane sulfate precipitation process. In some amination reactions, solvents such as DMF and soybean oil are added to promote the reaction, making the amination reaction product more complex. Using carbonate for precipitation separation can also achieve good results, and a large number of impurities are carried away by the aqueous solution during solid-liquid separation. Amantadine carbonate is less soluble in water than sulfate, and washing can further remove the entrained water-soluble impurities, resulting in less material loss. In addition, the aqueous solution after washing can easily remove carbonate ions and can be reused, reducing the generation of process wastewater and water treatment waste salt; while the sulfate ions entrained in the washing water of amantadine sulfate precipitation cannot be removed and cannot be reused, and washing will increase process wastewater. Amantadine carbonate is less soluble in water than amantadine sulfate, and the reaction solution is alkaline, more environmentally friendly, with better application prospects, and more in line with the requirements of environmental protection and clean production. Therefore, amantadine carbonate has very significant advantages in the production of amantadine and other salts of amantadine. When industrially producing amantadine and its salts, carbonate is added to the hydrolyzate to react to generate amantadine carbonate precipitate, and solid-liquid separation is performed. The amantadine carbonate precipitate can also be refined by the aforementioned washing, water distillation and other methods; then alkali is added to react with the amantadine carbonate, and the conventional water distillation process or organic matter extraction process is used to produce amantadine and its salts. The carbonate after extracting amantadine can be reused to react with the hydrolyzate to generate amantadine carbonate precipitate, which is recycled to reduce alkali consumption, reduce waste salt generation, and reduce production costs; through the precipitation of amantadine carbonate and the purification treatment of the precipitate, impurities such as ammonia and 1-adamantanol can be removed, greatly improving the purity of subsequent products, and the impurity removal efficiency and yield are greatly improved. Therefore, the use of amantadine carbonate for the purification of amantadine and its salts greatly reduces the shortcomings of existing industrial production. Amantadine carbonate can also directly react with other acids to produce other salts of amantadine. It can also be used to recover amantadine materials from wastewater and slag containing amantadine and its salts.The conversion of amantadine into amantadine carbonate has good stability, is not easy to sublimate, and is easy to dry, which solves the shortcomings of amantadine that it is easy to sublimate, difficult to dry, and difficult to store. Amantadine carbonate can also replace amantadine and other amantadine salts and directly serve as a raw material for synthesizing other adamantane derivatives. For example, amantadine carbonate replaces hydrous amantadine as a raw material for the production of amantadine hydrochloride, and its purity is higher than that of hydrous amantadine and it is more stable and controllable; it is more convenient to store and transport than hydrous amantadine, and the measurement is more accurate, which has obvious advantages in the production of amantadine hydrochloride raw materials. For another example, when amantadine hydrochloride is used as a raw material for the production of 3-amino-1-adamantanol, it will produce hydrochloric acid fumes after mixing with sulfuric acid and nitric acid, which affects the environment. Using amantadine carbonate will not produce gases that affect the environment, but water and carbon dioxide. For another example, adamantane carbonate is used as a raw material to synthesize N,N,N-trimethyl-1-adamantyl ammonium hydroxide, which is used as a molecular sieve template. Downstream products include CHA-structured mobile source denitration molecular sieves, which are used for mobile source (automobile) exhaust denitration treatment. There are many downstream products of adamantane, and the applications of adamantane carbonate in organic synthesis cannot be listed one by one. Similar applications are all within the scope of protection of the present invention.

[0056] 3. Application in functional materials. Amantadine carbonate is a white solid at room temperature and pressure, with poor water solubility and good thermal stability. It can be made into very fine solid powder with low density, large specific surface area, and poor affinity between dry product and water. Therefore, amantadine carbonate can be used as a functional material, used to make porous materials, used as a molecular sieve template to synthesize molecular sieves, used as a hydrophobic material and to prepare hydrophobic materials, used as a raw material for corrosive agents, and to replace the components of amantadine and its salts in traditional corrosion inhibitors. In addition, amantadine can also be used to absorb carbon dioxide to generate amantadine carbonate for carbon fixation, and amantadine carbonate can be decarbonized by reacting with acid. The application of amantadine carbonate in functional materials is very numerous and cannot be listed one by one. Similar applications are all within the scope of protection of the present invention. DETAILED DESCRIPTION The main technical contents of the present invention have been described in detail above, and those skilled in the art can understand them. The following examples are briefly described to help understanding. The following examples are merely exemplary and are only used to illustrate the present invention, rather than to limit the present invention.

[0057] Embodiment 1: Take 5.0g of 54.0% water-containing adamantane, place it in a three-necked flask, add 20g water, stir evenly, insert a catheter to the liquid, slowly introduce air, continue stirring for 60 minutes, the material in the bottle is still white, and a small amount is attached to the wall of the upper part of the flask. Remove stirring, close the container, set a catheter to draw out the carbon dioxide gas produced by the subsequent reaction and collect it, use a connected feeder to add an excessive amount of dilute sulfuric acid solution, and rotate to wash all the white materials attached to the upper part to react completely. React until no more gas is produced, and white precipitation materials are still residual in the bottle. The amount of gas produced by the drainage method is 155.2mL. Calculated according to standard conditions, the yield of adamantane carbonate is 91.1%. Filter out white solid material and collect for standby use. Add 50% potassium carbonate solution to the clarified filtrate, produce gas immediately, and generate precipitate, indicating that the water solubility of adamantane sulfate precipitation is better than that of adamantane carbonate. Neutralize until no gas is generated in the liquid, then age for 10 minutes, filter out the precipitate, combine it with the previously filtered white solid material and put it into a three-necked flask again, add 10g of water and 4g of 50% potassium carbonate solution, continue stirring for 20 minutes, filter out the white precipitate, add potassium carbonate to the filtrate, no solid is generated, and then wash the white precipitate with clean water several times until the filtrate is acidified and no bubbles are generated. Then transfer the washed white precipitate solid material to a closed container, add an excess of dilute sulfuric acid solution according to the above method, collect the released carbon dioxide gas, and measure the amount of carbon dioxide gas generated to be 165.1mL. It can be determined that this white solid is the carbonate of adamantane; through the detection and calculation of carbonate ions, it can be concluded that the ratio of adamantane to carbonic acid in the carbonate of adamantane is 2:1; calculated under standard conditions, the yield of adamantane carbonate is 96.9%.

[0058] Embodiment 2: Take 30.0g of the product of the amination reaction of 1-bromoadamantane and urea under the condition of DMF as solvent, add 60g of water and 0.1g of activated carbon, heat to 100℃, stir and hydrolyze for half an hour, then cool to 85℃ and filter. The filtrate is sampled and analyzed by chromatography, and the content of adamantane is 98.12%. 100g of 13% sodium bicarbonate solution at 70℃ is added to the filtrate and the temperature is raised to 70℃ and stirred to react for 10 minutes. Gas is generated and a white adamantane carbonate precipitate is generated. After heating to 85℃, filter while hot to obtain a filter residue containing adamantane carbonate. Add 50g of clean water, stir and heat to 70℃ and wash for half an hour, filter while hot to obtain a filter residue containing adamantane carbonate after washing 43.1g, containing 58% water. Sample chromatographic analysis, the content of adamantane is 99.88%. Dry to constant weight to obtain 17.8g of adamantane carbonate white solid. Apply white powder on the clay board, pour water on it, and the water will slide down the surface, which can keep the clay board from being soaked by water.

[0059] Embodiment 3: Take 30.0g of the product after the amination reaction of 1-bromoadamantane and urea, add 100g of water, 2g of ammonium acetate and 0.1g of activated carbon, heat to 90℃, stir and hydrolyze for 1 hour, then cool to 60℃ and filter. The filtrate is sampled and chromatographically analyzed, and the content of adamantane is 97.62%. Add 100g of 13% sodium bicarbonate solution at 20℃ to the filtrate and heat to 30℃ and stir to react for 10 minutes. Gas is generated and white adamantane carbonate precipitate is generated. Cool to 20℃ and filter. Add 50g of clean water to the filter residue, stir and heat to 60℃ and wash for half an hour, and filter while hot to obtain 43.0g of filter residue containing adamantane carbonate after washing, with a water content of 58%. The filter residue was put into a three-necked flask, concentrated hydrochloric acid was added dropwise and the temperature was raised until the solid material was completely dissolved, and the solution pH was adjusted to 1.51. The solution was concentrated and crystallized, filtered and dried to constant weight to obtain 12.2 g of adamantane hydrochloride crystals. Sampling was performed and the chromatographic analysis showed that the adamantane content was 99.89%, and the other indicators also met the pharmacopoeia standards.

[0060] Embodiment 4: Take 30g of the product after the amination reaction of 1-bromoadamantane and urea, add 300g of water, raise the temperature to 50°C, hydrolyze for 5h, then cool to 30°C, filter the insoluble matter to obtain the hydrolyzate. Sample chromatographic analysis shows that the content of adamantane is 97.62%.

[0061] The product after amination reaction can also be carried out using 1-chloroadamantane, and / or 1-fluoroadamantane, and / or 1-adamantanol, and / or 1-nitroadamantane, and / or 1-adamantanol nitrate, and the aminating agent is preferably urea. Hydrolysis can be carried out in a free combination of substances such as acid and ammonium salt in the hydrolysis water. The hydrolyzate of insoluble matter is filtered out during or after the hydrolysis, and decolorized using a decolorizing agent, and the decolorizing agent is preferably activated carbon or activated carbon fiber. The hydrolyzate can be extracted with a poorly water-soluble organic solvent to remove some impurities, and the organic solvent used is preferably benzene, toluene, xylene, heptane, octane, trimethylpentane, methylhexane, cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane, ethylcyclohexane, methyl tert-butyl ether, carbonates, non-water-soluble silicone oil and other commonly used poorly water-soluble solvents, using one of them, or a plurality of arbitrary proportions.

[0062] The hydrolyzate is added with an excess of sodium bicarbonate solution and heated to 50°C for 10 minutes under stirring to generate an intermediate adamantane carbonate precipitate, which is filtered while hot to obtain 44 g of intermediate adamantane carbonate precipitate residue containing 60% water. Chromatographic analysis of the sample shows that the adamantane content is 99.78%. The added sodium bicarbonate is a type of carbonate, and other carbonates and bicarbonates may also be added; preferably, water-soluble carbonates and / or bicarbonates, such as ammonium (bi) carbonate, sodium (bi) carbonate, potassium (bi) carbonate, etc., including but not limited to one or more thereof, are prepared into an aqueous solution for use.

[0063] Half of the intermediate adamantane carbonate residue was put into a three-necked flask, 20 g of water was added and stirred, sodium hydroxide solution was added to adjust the pH to 12.78, steam distillation was performed, the distillate was collected and filtered to obtain 12.3 g of solid, containing 46% water. Sample chromatographic analysis showed that the adamantane content was 99.89%. The sodium hydroxide solution added can be replaced by potassium hydroxide solution, the same below.

[0064] The salt and other impurities carried by the intermediate adamantane carbonate precipitate can be washed and removed to prepare adamantane carbonate with higher purity. Clean water or weakly alkaline water can be used for washing, and a detergent such as a surfactant can be added to the water. Solvent washing can also be used. The solvent preferably uses a commonly used solvent, including but not limited to: alcohols (methanol, ethanol, ethylene glycol, isopropanol, etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (pentane, hexane, heptane, octane, etc.), alicyclic hydrocarbons (cyclopentane, methylcyclopentane, cyclohexane, cyclohexanone, toluene cyclohexanone, etc.), halogenated hydrocarbons (chlorobenzene, dichlorobenzene, dichloromethane, chloroform, etc.), ethers (ethyl ether, methyl tert-butyl ether, etc.), esters (methyl formate, methyl acetate, ethyl acetate, propyl acetate, etc.), ketones (acetone, methyl butyl ketone, methyl isobutyl ketone, etc.), glycol derivatives (ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, etc.), N-methylpyrrolidone, acetonitrile, carbonates, silicone oil and other solvents, and possible aqueous solutions thereof, one of which is used, or a mixture of multiple solvents in any proportion. The detergent and solvent are preferably substances that are easy to remove later. The impurities of the washed adamantane carbonate are lower and the purity is higher. The washing can be repeated multiple times as required. The temperature range for washing the intermediate adamantane carbonate precipitate is any temperature between room temperature and the boiling point of the washing liquid. The adamantane carbonate can also be steamed to remove volatile impurities such as 1-adamantanamine, 1-adamantanol, ammonia and solvent.

[0065] The other half of the intermediate adamantane carbonate residue was put into a three-necked flask, 30 g of water was added, and the mixture was stirred and washed at 50°C for 30 minutes. The residue was filtered while hot, and the residue was 20 g, with a water content of 56%. Sample chromatographic analysis showed that the adamantane content was 99.83%. After washing, 20 g of water was added to the intermediate adamantane carbonate, and the pH was adjusted to 13.34 by adding sodium hydroxide lye. The mixture was steam distilled, and the distillate was collected and filtered to obtain 12.2 g of solid, with a water content of 47%. Sample chromatographic analysis showed that the adamantane content was 99.91%.

[0066] The residual material after water distillation contains a small amount of adamantane amine materials, and the remaining excess alkali and a large amount of carbonate can be reused in the hydrolyzate to react and generate adamantane carbonate. Excess alkali is neutralized by adding acid or bicarbonate, or by absorbing carbon dioxide to convert the excess alkali into carbonate. The acid contained in the hydrolyzate can also be directly reused to react with the hydrolyzate to generate adamantane carbonate.

[0067] Embodiment 5: Take 30g of the product after the amination reaction of 1-bromoadamantane and urea, add excess hydrochloric acid for hydrolysis, control the temperature at 35°C to filter out insoluble matter to obtain a hydrolyzate, add excess sodium sulfate solution to the hydrolyzate, control the pH of the reaction solution to <8, heat to 50°C to filter out the precipitate to obtain adamantane sulfate. Other water-soluble sulfates and / or bisulfates, such as ammonium sulfate (hydrogen), sodium bisulfate, potassium sulfate (hydrogen), etc., and / or sulfuric acid, including but not limited to one or more thereof, are also used, preferably prepared as an aqueous solution for use. Filter out the obtained adamantane sulfate, add excess potassium carbonate solution to react, generate adamantane carbonate, heat to 50°C to filter out the solid, and obtain adamantane carbonate. Wash the adamantane carbonate with ethanol and then dry it to obtain refined adamantane carbonate, with a chromatographic purity of 99.91%. The refined amantadine carbonate was then added with hydrochloric acid to adjust the pH to 2.11, concentrated and crystallized, filtered and dried to constant weight to obtain 10.2 g of amantadine hydrochloride crystals. Samples were taken for analysis. Chromatographic analysis showed that the amantadine content was 99.90%, and the other indicators also met the pharmacopoeia standards.

[0068] Embodiment 6: Adamantane and acetonitrile were reacted under the catalysis of concentrated sulfuric acid, and the organic solvent was removed and refined to obtain 20g of crude 1-acetylaminoadamantane, containing 76% of 1-acetylaminoadamantane. 40g of 45% sodium carbonate and 2g of sodium hydroxide were added, and the temperature was raised to 90℃ for hydrolysis for 2h. The temperature was then lowered to room temperature and hydrochloric acid was added to adjust the pH of the reaction solution to 8.21. The temperature was then raised to 50℃ for solid-liquid separation to obtain 28g of adamantane carbonate, containing 55% water. It was then washed and dried with ethanol to obtain 10.5g of refined adamantane carbonate dry product, with a chromatographic purity of 99.86%. Dilute acetic acid was added to react until no more gas was generated, and then a few drops of dilute acetic acid were added. The end point pH was 1.78. The solid-liquid separation and washing of the precipitate were performed, and then dried to obtain 11.2g of adamantane acetate solid, with a chromatographic content of 99.88%.

Claims

1. A method for preparing adamantane carbonate, comprising the following methods: ① Using amantadine as a raw material, reacting with water and carbon dioxide, and / or bicarbonate to generate amantadine carbonate: ； ② The combination of adamantane and ammonium salt reacts with carbonate to generate adamantane carbonate: ； ③ The amide of adamantane reacts with carbonate to generate adamantane amine carbonate: , R is H or CH3(CH2) m , m is a natural number; ④N-(1-adamantane)-urea is hydrolyzed to generate adamantane carbonate: ； ⑤ The product of amination reaction of 1-bromoadamantane, and / or 1-chloroadamantane, and / or 1-fluoroadamantane, and / or 1-adamantanol, and / or 1-nitroadamantane, and / or 1-adamantanol nitrate with urea is hydrolyzed by a little acid hydrolysis method to obtain a hydrolyzate, which is reacted with carbonate to generate adamantane carbonate; ⑥ The product of amination reaction of 1-bromoadamantane, and / or 1-chloroadamantane, and / or 1-fluoroadamantane, and / or 1-adamantanol, and / or 1-nitroadamantane, and / or 1-adamantanol nitrate with urea is hydrolyzed by a little acid hydrolysis method or a lot acid hydrolysis method to obtain a hydrolyzate, which is first prepared into adamantane sulfate, and then reacted with carbonate to generate adamantane carbonate: 。 2. The method for preparing an amantadine carbonate compound according to claim 1, wherein: The bicarbonate refers only to bicarbonate, and the carbonate is other broad carbonates other than adamantane carbonate, including normal carbonate, acid carbonate (bicarbonate) and basic carbonate; preferably water-soluble carbonate and / or bicarbonate, such as ammonium (bi) carbonate, sodium (bi) carbonate, potassium (bi) carbonate, etc., including but not limited to one or more thereof; preferably prepared as an aqueous solution for use.

3. The method for preparing an amantadine carbonate compound according to claim 1, wherein: The combination of adamantane and an ammonium salt comprises a combination of adamantane and one or more ammonium salts selected from the group consisting of ammonium bromide, ammonium chloride, ammonium fluoride, ammonium formate, ammonium nitrate, ammonium acetate, ammonium (hydrogen) phosphate, and ammonium citrate.

4. The method for preparing an amantadine carbonate compound according to claim 1, wherein: The amination reaction product is hydrolyzed by a low-acid hydrolysis method to obtain a hydrolyzate, preferably a hydrolyzate obtained by filtering out insoluble matter after hydrolysis; the low-acid hydrolysis method is to add only water to the amination reaction product, or to add a small amount of acid and / or ammonium salt to the water for hydrolysis; the amount of water added is preferably 2 to 10 times the weight of the amination reaction product, the amount of hydrogen ions corresponding to the added acid is within 0.7 times the amount of the adamantane substance contained in the amination reaction product, the amount of ammonium ions added is within 0.9 times the amount of the adamantane substance contained in the amination reaction product, and the acid and ammonium salt are preferably within 0.5 to 1.0 times the amount of the adamantane substance contained in the amination reaction product. The amount of salt added can be freely adjusted to meet the requirement that the sum of the amount of hydrogen and ammonium radical substances in the cations corresponding to the acid radical ions in the hydrolyzate is greater than or equal to the amount of the substance of the contained adamantane; the acid is one or more commonly used acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, formic acid, acetic acid, citric acid, etc., the ammonium salt is one or more ammonium salts such as ammonium bromide, ammonium chloride, ammonium fluoride, ammonium formate, ammonium nitrate, ammonium acetate, ammonium (hydrogen) phosphate, ammonium citrate, etc., and the types of acids and ammonium salts added can be freely combined; preferably, only water is added for hydrolysis and then insoluble matter is filtered out to obtain the hydrolyzate.

5. The method for preparing an amantadine carbonate compound according to claim 1, wherein: The amination reaction product is hydrolyzed by a low-acid hydrolysis method or a high-acid hydrolysis method to obtain a hydrolyzate, and amantadine sulfate is first prepared. The high-acid hydrolysis method is based on the low-acid hydrolysis method described in claim 4, and the amount of acid added is increased for hydrolysis. The amount of hydrogen ion substance corresponding to the added acid is more than 0.7 times the amount of amantadine substance contained in the amination reaction product. The acid is one or more commonly used acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, formic acid, acetic acid, citric acid, etc.; the method for preparing amantadine sulfate is to add sulfate (hydrogen) salt and / or sulfuric acid to the hydrolyzate, control the pH of the reaction solution at the reaction end point to be less than 8, and filter out the precipitate to obtain amantadine sulfate; preferably, water-soluble sulfate and / or hydrogen sulfate, such as ammonium (hydrogen) sulfate, sodium (hydrogen) sulfate, potassium (hydrogen) sulfate, etc., and / or sulfuric acid are used, and one or more of them are used, preferably prepared into an aqueous solution for use.

6. The method for preparing an amantadine carbonate compound according to any one of claims 1, 4 and 5, characterized in that: The hydrolysis temperature of the amination reaction product is preferably 50-100° C., the hydrolysis time is preferably 0.5-5 h, and the temperature of the insoluble matter filtered out after hydrolysis is preferably 30-85° C.; the insoluble matter filtered out after hydrolysis is subjected to secondary hydrolysis, and the secondary hydrolyzate is reused for the primary hydrolysis of the amination reaction product.

7. The method for preparing an amantadine carbonate compound according to claim 1, wherein: The amide of adamantane is preferably 1-acetylaminoadamantane; the preferred source of 1-acetylaminoadamantane is obtained by reacting adamantane with acetonitrile.

8. The method for preparing an amantadine carbonate compound according to claim 1, wherein: The adamantane carbonate generated by the reaction is subjected to solid-liquid separation, and the temperature for separating the adamantane carbonate precipitate is preferably 20° C. to 85° C.; after the solid-liquid separation, the adamantane carbonate product with higher purity is obtained by washing, water distillation and other methods.

9. An amantadine carbonate product prepared by the method for preparing an amantadine carbonate compound according to claim 1 or 8.

10. The adamantane carbonate prepared according to claim 1 or 8 is used as an intermediate or raw material in organic synthesis, in the preparation of drugs, as a functional material, and in the preparation of functional materials.

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