Novel method for producing amantadine hydrochloride

Abstract

The invention provides a novel method for producing amantadine hydrochloride, which comprises the following steps of: adding ammonium salts such as ammonium bromide, ammonium chloride, ammonium fluoride, ammonium formate, ammonium nitrate, ammonium acetate, ammonium hydrogen phosphate and the like and acid into amination reaction materials for hydrolysis, dissolving amantadine materials into an aqueous solution, and separating insoluble substances to obtain hydrolysate; directly adding alkali liquor into hydrolysate for alkalization, extraction and back extraction to produce amantadine hydrochloride; or adding carbonate into the hydrolysate for precipitation, carrying out solid-liquid separation to obtain an intermediate amantadine carbonate precipitate, and directly adding hydrochloric acid or alkali liquor for alkalization, extraction and back extraction to produce amantadine hydrochloride. The method has the advantages of high hydrolysis yield, good impurity removal effect, no addition of acid or addition of a small amount of acid, less alkali consumption, less generated waste salt, environmental protection and low cost, and is a good method for industrial production of amantadine hydrochloride.

Description

Technical Field

[0001] The present invention relates to a method for producing an adamantane derivative, in particular to a method for producing adamantane hydrochloride. Background Art

[0002] Amantadine, also known as 1-adamantaneamine, has the chemical name 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 inhibits viral penetration into host cells, affects viral uncoating, and inhibits viral reproduction, thereby treating and preventing viral infections. It is suitable for preventing or treating respiratory infections caused by the Asian influenza A virus and is effective in treating Parkinson's disease. Amantadine and its salts are important chemical products and raw materials. They are also used as raw materials for the production of 3-amino-1-adamantanol, an intermediate in the production of vildeglucose; can be used to synthesize adamantyl quaternary ammonium bases, used in the manufacture of molecular sieves; and can also be used as a component of corrosion inhibitors, with a wide range of applications.

[0004] Because amantadine is alkaline, it can combine with acids to form salts. Amantadine can form salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, formic acid, acetic acid, and other acids. Most salts formed by amantadine combining with acids are soluble in water, but some, such as amantadine sulfate, are less water-soluble. Amantadine hydrochloride, formed by combining with hydrochloric acid, is highly water-soluble, facilitating absorption. Furthermore, hydrochloric acid is also present in gastric juice, minimizing its effect on the body. In pharmaceuticals, the hydrochloride salt of amantadine—amantadine hydrochloride—is used.

[0005] The industrial synthesis process for amantadine and its salts uses adamantane as the starting material, followed by bromine monosubstitution to produce 1-bromoadamantane. 1-Bromoadamantane then reacts with urea at high temperatures for an amination reaction. The final product of the amination reaction is a solid, often containing a large amount of urea decomposition products due to excessive urea dosage.

[0006] Hydrolyzing the amination reaction materials and separating and extracting the adamantane amine material from the mixed material at the end of the amination reaction are important steps to achieve the process purpose.

[0007] There are two existing hydrolysis processes: 1. Excess hydrochloric acid hydrolysis: The amination reaction product is hydrolyzed with excess hydrochloric acid, and the insoluble matter is filtered out. Excess hydrochloric acid hydrolysis involves adding at least 1 times the amount of hydrochloric acid in the reactants, sufficient to convert all of the adamantane groups into amantadine hydrochloride. This method is currently a commonly used hydrolysis process. While this hydrolysis method provides a relatively thorough hydrolysis, the addition of a large amount of hydrochloric acid requires subsequent neutralization with an alkali, which consumes a lot of alkali. The resulting salts are difficult to handle, increasing the salt concentration in the wastewater and requiring high energy consumption. The hydrolysis method disclosed in Chinese patent document CN101429129A is this method: excess hydrochloric acid is added to the product of the reaction of bromoadamantane and urea for hydrolysis. The hydrolysis method disclosed in Chinese patent document CN112479899A also follows this method: "S1: Take 15g of refined bromoamantadine and 10g of urea, stir and grind, and pass through a 200-mesh sieve; ... S5: Add 115ml of 2mol / L hydrogen chloride to a beaker, heat to dissolve, cool to 50°C, filter, and boil the filter cake with 45ml of mol / L hydrogen chloride for 20 minutes, cool to 50°C, filter a second time, and combine the two filtrates." 2. Direct hydrolysis with alkaline solution: The amination reaction product is reacted with water and alkaline solution, followed by direct steam distillation. This method simply adds water to the amination reactants to disperse them into a stirrable, fluid state. No solid-liquid separation is performed, and alkaline solution is directly added to the material to react and produce amantadine. The hydrolysis effect is unknown. This method is combined with steam distillation to gradually remove the material, allowing the remaining alkali to continue reacting with the unhydrolyzed material before distillation to improve the overall yield. This process results in a high yield due to the presence of residual material and impurities. The resulting amantadine is of low purity and has been eliminated.

[0008] Chinese patent document CN107325005A discloses a hydrolysis method: 2-3 times the amount of water and 5-10% concentrated hydrochloric acid by weight of the amination reaction product are added to the final amination reaction product. After soaking for 1-2 hours, the mixture is stirred and dispersed to produce a mixed aqueous phase. However, the subsequent operation involves stirring the mixed aqueous phase and simultaneously adding a strong base to raise the pH of the aqueous phase to 10-12. A small amount of acid is added to disperse the material, and then the insoluble matter is not separated. Instead, the entire mixture is added to the alkaline solution for reaction. This method is essentially the same as traditional water and alkaline hydrolysis. The addition of a small amount of acid enhances the dispersion effect, but consumes more base. The hydrolysis effect before the addition of the base is unknown and cannot be verified.

[0009] Chinese patent document CN101429129A also mentions another hydrolysis method: after bromoadamantane and urea react to form amantadine, the product is cooled and then added to drinking water to separate the amantadine from water-insoluble impurities. The document further states that bromoadamantane and urea are reacted to form water-insoluble amantadine. How can adding water to the water-insoluble amantadine produced by the reaction separate the water-insoluble impurities from the amantadine? This is inconsistent and incomprehensible. The detailed description of the method states that drinking water is added to the amination reaction, stirred thoroughly, to separate the amantadine from the impurities, and then concentrated hydrochloric acid is added until the solution reaches a pH of 1, generating amantadine hydrochloride that dissolves in the aqueous solution, followed by filtration to remove the water-insoluble impurities. It can be seen that adding drinking water to the amination reactants to separate adamantane amine and the impurities that are bound together is not for the purpose of hydrolysis, but simply to disperse the materials. The materials entrained in the insoluble matter are unknown, and the effect of adding only water for hydrolysis is unknown and cannot be verified.

[0010] Existing impurity removal and refining process: 1. Steam Distillation: A strong base (usually sodium hydroxide or potassium hydroxide) is added to the hydrolyzate for steam distillation, removing the amantadine via the steam. This method can directly yield a hydrous adamantane product, or it can react with an acid to yield an amantadine salt product.

[0011] 2. Organic Solvent Extraction: A strong base (usually sodium hydroxide or potassium hydroxide) is added to the hydrolyzate, followed by extraction with an organic solvent. The amantadine dissolves in the organic solvent and enters the organic phase. Water and acid are then added to the organic phase for back extraction, yielding a water-soluble, high-purity salt of amantadine and acid. This method is used to produce water-soluble amantadine salts.

[0012] The hydrolyzate can also be pretreated. There are two methods for pretreatment: 1. Precipitation method: Sulfate is added to the hydrolyzate to precipitate amantadine sulfate. The amantadine sulfate precipitate has a certain solubility, and the higher the acid concentration, the greater the solubility. This precipitation method has a low yield and poor impurity removal, with the content not significantly different from the hydrolyzate chromatographic analysis. Sulfate has low solubility and easily forms crystals, which can clog the bottom discharge port and pipes.

[0013] 2. Recrystallization: Concentrate and distill to obtain a crude amantadine salt. Dissolve the crude product in clean water at low temperature, and filter out insoluble impurities. Chinese patent document CN112479899A discloses an impurity removal method using recrystallization: "S7: Remove the lower aqueous phase, add activated carbon, boil for 20 minutes, filter while hot, and concentrate the filtrate under reduced pressure until a large amount of crystals precipitate. Filter, reconcentrate, freeze, crystallize, filter, and combine the two crystals to obtain the product. S8: Dissolve the product in water, decolorize with activated carbon, and filter. Concentrate the filtrate to near dryness, resulting in a large amount of crystals precipitating. S9: Add an appropriate amount of acetone to completely precipitate the crystals, filter, and thoroughly wash with acetone, drain, and dry to obtain purified, impurity-free amantadine hydrochloride." However, this document uses a reaction of bromoadamantane with urea followed by hydrolysis with excess hydrochloric acid. The hydrolyzed solution is then recrystallized to directly obtain amantadine hydrochloride. The resulting amantadine hydrochloride cannot be "impurity-free" as claimed in the document. During crystallization of the hydrolyzate, the free hydrogen and bromide ions in the solution combine to form amantadine hydrobromide crystals, which precipitate along with the amantadine hydrochloride crystals and cannot be removed by recrystallization. When analyzing its organic components using gas chromatography, the acid molecules are removed during sample preparation, making them undetectable and leading to a false impression of high purity. Quantitative titration to detect hydrogen and chloride ions in the product reveals insufficient purity.

[0014] Under the existing hydrolysis process, the impurity removal process also has its own obvious shortcomings.

[0015] The main disadvantages of steam distillation are: 1. High energy consumption, long processing time, and large volumes of wastewater generated, which are difficult to handle. Steam distillation requires using 8-10 times or more of the final amination reaction material in a water-dispersible form and heating it for adequate separation and extraction. The distillation process is lengthy, typically requiring eight to nine hours or more. It consumes large amounts of steam and energy. The large volume of water produced by distillation, even after mechanical separation of amantadine (filtration or centrifugation), still contains significant amounts of dissolved ammonia and residual amantadine suspended particulates, making the recovery and treatment of this wastewater complex.

[0016] 2. High alkali consumption. Due to the limitations of steam distillation, an excess of strong alkali (sodium hydroxide or potassium hydroxide) must be added to allow the amantadine to precipitate completely as a solid so that it can be distilled off along with the steam. Typically, the amount of alkali added should be at least 130% of the molar amount of amantadine in the reaction mixture.

[0017] 3. Low purity. Incompletely reacted 1-bromoadamantane hydrolyzes to form 1-adamantanol and 1,3-adamantanediamine, which are removed during distillation, resulting in low purity of the adamantane. Under strong alkaline and high temperature conditions, residual urea and biuret in the mixture hydrolyze, releasing ammonia, which partially dissolves in the distilled water. This causes ammonia to be carried over into the adamantane product and then released into the production environment, leading to ammonia contamination.

[0018] The major drawbacks of organic solvent extraction are: a long process, the risk of introducing organic solvents, and the high cost of organic solvent recovery. The purity of the hydrolyzate and pretreated materials is low, with chromatographic analysis showing the main amantadine content in organic matter generally below 98%. During organic solvent extraction after alkalization, impurities dissolve in the organic solvent and then enter the aqueous phase during back extraction with water and hydrochloric acid, resulting in a poorly purified amantadine hydrochloride solution. The organic extractant also contains a high number of residual impurities, resulting in high energy consumption and difficulty in impurity handling. Summary of the Invention

[0019] Aiming at the shortcomings of the existing process, the present invention provides a new method for producing amantadine hydrochloride.

[0020] An amination reaction is conducted using raw materials such as 1-bromoadamantane, and / or 1-chloroadamantane, and / or 1-fluoroadamantane, and / or 1-adamantanol, and / or 1-nitroadamantane, and / or 1-adamantanol nitrate to obtain an amination reaction product. The aminating agent is preferably urea. During the amination reaction, DMF, soybean oil, or the like may be added as a solvent to enhance the reaction efficiency.

[0021] The inventors have discovered that amantadine also forms hydrates with water and exhibits a small amount of solubility. Amantadine, when combined with ammonium salts such as ammonium bromide, ammonium chloride, ammonium fluoride, ammonium formate, ammonium nitrate, ammonium acetate, and ammonium (hydrogen) phosphate, can dissolve relatively quickly in water when provided with sufficient water and at a suitable temperature. Hydrolysis with the addition of ammonium salts is more effective than hydrolysis with water alone, and the amination reaction product is more adaptable. Further research has revealed that under alkaline conditions, amantadine can form solutions with these ammonium salts that dissolve in water, with the pH of the solution reaching approximately 9. This represents a significant technological advancement previously undiscovered by those skilled in the art. It is speculated that the hydrolysis of these ammonium salts in aqueous solution produces acid and ammonia. The amantadine combines with the acid to form an amantadine salt that dissolves in water, leaving the ammonia free in the solution or bound to it. Alternatively, the ammonium salts may bind to the amantadine through hydrogen bonds. Amantadine carbonate and amantadine sulfate, formed by the reaction of amantadine with ammonium carbonate (including ammonium bicarbonate) or ammonium sulfate (including ammonium bisulfate), are precipitated.

[0022] The key innovation of the new method for producing amantadine hydrochloride of the present invention is the adoption of a new hydrolysis process.

[0023] The obtained amination reaction product is hydrolyzed by adding water and ammonium salt, or water, ammonium salt and acid, wherein the amount of water added is 2.5 to 10 times the weight of the amination reaction product, the total amount of ammonium salt added is greater than 0 kg, and the amount of acid added is within 0.7 times the amount of the adamantane group substance in the reactant. Insoluble matter is filtered out to obtain a hydrolyzate.

[0024] The ammonium salt can be one or more of ammonium bromide, ammonium chloride, ammonium fluoride, ammonium formate, ammonium nitrate, ammonium acetate, or ammonium (hydrogen) phosphate. The acid can be one or more of common acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, formic acid, and acetic acid, preferably hydrochloric acid or hydrobromic acid. The ammonium salt can be added directly or by reacting a precursor. For example, ammonium chloride can be added directly or by adding a precursor such as ammonia water, ammonium bicarbonate, or ammonium carbonate, followed by hydrochloric acid to react and generate ammonium chloride.

[0025] To accelerate material dispersion and facilitate stirring of bulk materials, a small amount of acid can be added, or it can be omitted. Instead of adding acid, only water and an ammonium salt are added for hydrolysis, with the pH of the hydrolyzate generally being between 3 and 9. Adding acid for hydrolysis allows the adamantane-containing substance generated by the reaction to rapidly form a salt of adamantane. Most adamantane salts are readily soluble in water, thus achieving the hydrolysis goal. Therefore, adding an acid greater than 0.7 times the amount of adamantane-containing substance in the reactants can also hydrolyze the product. However, compared to conventional hydrolysis with excessive acid, the amount of acid is reduced only slightly, making it less meaningful. To better protect the present invention, the acid added is limited to less than 0.7 times the amount of adamantane-containing substance in the reactants.

[0026] The amount of acid added can be zero, meaning that hydrolysis can be performed with water and ammonium salts without acid, achieving yields comparable to those achieved with acid hydrolysis. Adding a small amount of acid can increase the dispersion rate, facilitate stirring of bulk materials, and save time in dispersing the foam. However, with sufficient water and temperature, the same solubility can be achieved without the addition of acid, allowing the reaction materials to be fully hydrolyzed and dissolved more quickly in the aqueous solution.

[0027] When halogenated adamantane or adamantane substituted with functional groups such as nitro or nitrate groups that generate acid groups upon hydrolysis reacts with urea, an excess of urea is typically used, leaving most of the acid groups in the reactants remaining in the reaction mixture. When water and ammonium salts are added for hydrolysis, the adamantane binds with them and dissolves in water. When non-halogenated adamantane or adamantane substituted with functional groups such as nitro or nitrate groups that generate acid groups upon hydrolysis reacts with urea, such as the product of the reaction of adamantane alcohol with urea, a relatively large amount of ammonium salt and / or acid must be added to bind with the adamantane in the reaction product and dissolve it in water. To ensure complete hydrolysis, the total amount of ammonium salt and acid in the hydrolyzate must not be less than the amount of adamantane groups in the reaction product. The total amount of water added for hydrolysis is generally at least 2.5 times and less than 10 times the weight of the amination reaction product. The hydrolysis process is generally heated to 60°C to 100°C, with higher temperatures providing optimal results to ensure complete hydrolysis. Adding more water will result in better hydrolysis effect, but the material concentration will be low and the wastewater in the later stage of production will increase.

[0028] Dispersing bulk material and then stirring it for hydrolysis can save time and ensure more complete hydrolysis. Generally, the hydrolysis process requires at least half an hour of stirring and heat preservation. After the hydrolysis is complete, the material is dissolved in an aqueous solution, cooled, and filtered to remove the residue. This yields a hydrolyzed solution containing the amantadine material, which can be analyzed by chromatography to yield a content exceeding 97.5%. Residues of unhydrolyzed material in the residue are minimal, comparable to those observed in conventional excess acid hydrolysis methods. This hydrolysis effect is unexpected for those skilled in the art and differs from the results reported in the literature. The hydrolyzed solution may contain impurities from the amination reaction, some of which are insoluble, while the content of some impurities, such as urea condensates, varies with the temperature of the hydrolyzed solution. It is preferred to cool the solution after hydrolysis to allow water-soluble impurities to precipitate, allowing them to be removed along with the insoluble impurities by filtration. However, the hydrolyzed solution temperature should not be lowered too low to prevent precipitation. The temperature is generally maintained between 20°C and 80°C, adjusted based on the amount of water added. When hydrolysis is performed with a high amount of water, the temperature can be lowered; with a low amount of water, the temperature may be higher.

[0029] This hydrolysis process can achieve a hydrolysis yield comparable to that of conventional methods using excess acid without the addition of acid, and the purity of the hydrolyzed liquid is also high. The hydrolyzed liquid can be extracted with a poorly water-soluble organic solvent to remove some impurities, and the organic solvent can be 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, or the like, and any one of these or a mixture of multiple solvents in any proportion can be used.

[0030] During or after the hydrolysis process, the hydrolyzate from which insoluble matter is filtered out may be decolorized by the addition of a decolorizing agent. Common decolorizing agents include activated carbon and activated carbon fiber. The hydrolyzate may also be decolorized using a decolorizing agent recovered from decolorization of an aqueous solution of amantadine hydrochloride. The filtered insoluble matter and decolorizing agent may be washed with water to recover entrained material. A small amount of material entrained in the insoluble matter may be recovered by secondary hydrolysis. If a small amount of water is intentionally added during the primary hydrolysis to perform a preliminary hydrolysis, followed by a secondary or multiple hydrolysis, to circumvent the limitations of the present invention, the total amount of water is 2.5 to 10 times the weight of the amination reaction product as defined herein, the total amount of ammonium salt added is greater than 0 kg, and the amount of acid added is no more than 0.7 times the amount of adamantane group in the reactants, and this also falls within the scope of the present invention.

[0031] The amination hydrolyzate, or the washed hydrolyzate, can be directly added to alkaline solution to produce amantadine hydrochloride using an alkaline extraction method. Because no acid is added to the hydrolyzate, even if acid is added, the amount is less than in traditional methods, resulting in less base consumption and salt production. Even after extraction and washing with poorly water-soluble organic solvents, most water-soluble impurities remain in the hydrolyzate. Traditional methods such as steam distillation and alkaline extraction do not significantly improve the purity of amantadine hydrochloride, and the amount of impurities carried by the organic solvent remains comparable.

[0032] The present invention also provides a novel impurity removal process: a hydrolyzed solution is subjected to a precipitation reaction with a carbonate, followed by solid-liquid separation, to obtain an intermediate, amantadine carbonate. The carbonate used is a carbonate other than amantadine carbonate, broadly defined as carbonates and bicarbonates. Preferably, the carbonate and / or bicarbonate are water-soluble, such as ammonium (bi)carbonate, sodium (bi)carbonate, potassium (bi)carbonate, and the like, including but not limited to one or more thereof, and are prepared as an aqueous solution for use. Amantadine carbonate can also be produced using poorly water-insoluble carbonates or bicarbonates. For example, amantadine carbonate can be produced by reacting calcium carbonate with an amantadine hydrochloride solution. However, because calcium carbonate is a solid and the product is also solid, mass transfer is difficult, achieving complete reaction, and the resulting amantadine carbonate is of low purity. Furthermore, to achieve complete reaction of calcium carbonate, an excess of hydrogen chloride molecules in the amantadine hydrochloride is required, which in turn results in an excess of amantadine, which is not worth the effort.

[0033] By using the method of the present invention to generate an amantadine carbonate precipitate, controlling the temperature at which the amantadine carbonate precipitate is filtered out to be the same as or higher than that at which the insoluble matter is removed, the resulting amantadine carbonate precipitate can be reduced in impurities. Chromatographic analysis of amantadine carbonate typically reveals levels exceeding 98%. The separated amantadine carbonate, due to its entrained moisture, is bound to contain impurities and other salts, which can be removed by washing. Washing can be performed with clean water or weakly alkaline water, with the addition of a surfactant. Alternatively, solvents such as methanol, ethanol, N-methylpyrrolidone, ethyl acetate, methyl acetate, acetone, and ethylene glycol, and their aqueous solutions, can be used alone or in any combination of various solvents. The washed amantadine carbonate contains even fewer impurities.

[0034] The aqueous solution after separation of the amantadine carbonate can also be extracted with a poorly water-soluble organic solvent to remove some impurities for ease of subsequent processing. 1-adamantanol can be recovered by concentrated distillation of the organic solvent. The organic solvent used is preferably benzene, toluene, xylene, heptane, octane, trimethylpentane, methylhexane, cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane, ethylcyclohexane, methyl tert-butyl ether, or the like, and one or more of these can be used in any proportion.

[0035] The resulting intermediate amantadine carbonate precipitate is reacted with hydrochloric acid to obtain amantadine hydrochloride. The resulting amantadine hydrochloride aqueous solution can be extracted with a poorly water-soluble organic solvent to remove some impurities. The organic solvent used for extraction is preferably benzene, toluene, xylene, heptane, octane, trimethylpentane, methylhexane, cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane, ethylcyclohexane, methyl tert-butyl ether, or the like, and any one of these or a mixture of multiple solvents in any proportion can be used.

[0036] The hydrolyzed solution or intermediate amantadine carbonate precipitate is added with a base to react and generate amantadine. The pH of the alkalized solution is controlled to be greater than 10, and a poorly water-soluble organic solvent is added for extraction. Oil-water separation can obtain an organic phase containing amantadine. Water and hydrochloric acid are added to the organic phase, and the mixture is stirred and extracted to obtain an amantadine hydrochloride aqueous solution. The poorly water-soluble organic solvent used is preferably benzene, toluene, xylene, heptane, octane, trimethylpentane, methylhexane, cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane, ethylcyclohexane, methyl tert-butyl ether, or the like, and any one of these or a mixture of multiple solvents in any proportion can be used.

[0037] In the above method, after the amantadine produced by the reaction of amantadine carbonate with a base is separated by extraction using an organic solvent, the remaining carbonate is recycled to the hydrolyzed liquid to react with amantadine carbonate. The remaining carbonate aqueous solution and crystalline solid contain excess base, which can be neutralized by adding acid or bicarbonate, or by absorbing carbon dioxide to convert the excess base into carbonate, or directly recycled to react with the hydrolyzed liquid to produce amantadine carbonate. Alternatively, the carbonate can be used to react with acid- or base-reactive substances. For example, it can be used as tail gas absorption water to absorb hydrogen chloride, hydrogen bromide, bromine, chlorine, and other gases to produce tail gas.

[0038] The aqueous amantadine hydrochloride solution obtained by the above method can be decolorized with activated carbon, the activated carbon separated, the decolorized solution concentrated and crystallized, the crystals separated, and then dried to obtain the amantadine hydrochloride product. The separated activated carbon can be reused for decolorizing the hydrolyzed solution. After solid-liquid separation, the amantadine hydrochloride crystals can be washed with an organic solvent to remove impurities and then dried to improve product quality. The organic solvent used is preferably N-methylpyrrolidone, ethyl acetate, acetone, toluene, xylene, etc., and can be used alone or in combination in any proportion.

[0039] Compared with the prior art, the present invention has the following characteristics and advantages: 1. No acid is added or less acid is added for hydrolysis, resulting in high yield and less slag. Carbonate precipitation is used, which has weak alkalinity, less decomposition of ammonium salt, and ammonium is retained in the aqueous solution, resulting in less escaping ammonia gas. Less salt is generated in the entire system, making wastewater treatment easier. 2. The amantadine carbonate precipitation method has low energy consumption, high yield, high impurity removal efficiency, and higher product purity. The organic solvent extraction method has low residual impurities in the organic solvent; 3. The carbonate converted from the reaction of amantadine carbonate and alkali can be recycled, which reduces material consumption and production wastewater; 4. No acid is added to the hydrolyzate, and the production of amantadine carbonate uses an alkaline medium. The production system equipment has low corrosion, low-cost equipment can be selected, and the service life is improved. The production process is also more environmentally friendly. DETAILED DESCRIPTION The following embodiments of the present invention are described in detail in conjunction with the main technical content of the invention. The embodiments described below are merely exemplary and are only used to explain the present invention, rather than to limit the present invention.

[0041] Example: S1 Hydrolysis: Take 20 g of the product from the amination reaction of 1-bromoadamantane with urea, add 60 g of water, 2 g of ammonium bicarbonate, 2 g of acetic acid, and 0.1 g of activated carbon, heat to 80°C, and stir to hydrolyze for 1 hour. Then cool to 70°C and filter. Chromatographic analysis of the filtrate reveals an amantadine content of 97.56%.

[0042] The amination reaction product can be the product of an amination reaction between 1-bromoadamantane, and / or 1-chloroadamantane, and / or 1-fluoroadamantane, and / or 1-adamantanol, and / or 1-nitroadamantane, and / or 1-adamantanol nitrate and urea. Water and an ammonium salt, or water, an ammonium salt, and an acid are added for hydrolysis. The amount of water added is 2.5 to 10 times the weight of the amination reaction product, the total amount of ammonium salt added is greater than 0 kg, and the amount of acid added is no more than 0.7 times the amount of adamantane groups in the reactants. Insoluble matter is filtered off to obtain a hydrolyzate. The ammonium salt is preferably one or more of ammonium bromide, ammonium chloride, ammonium fluoride, ammonium formate, ammonium nitrate, ammonium acetate, and ammonium (hydrogen) phosphate. The acid is one or more of commonly used acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, formic acid, and acetic acid, preferably hydrochloric acid or hydrobromic acid. The ammonium salt can be added directly or generated by reaction by adding a precursor. After hydrolysis, the insoluble matter is filtered out to obtain a hydrolyzed solution, and the filtration temperature is 20°C to 80°C. The hydrolyzed solution can also be extracted with a poorly water-soluble organic solvent to remove some impurities, and the organic 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, etc., and any one of them or a mixture of multiple types in any proportion can be used.

[0043] S2 Preparation of amantadine hydrochloride aqueous solution: The filtrate was then added with an excess of sodium bicarbonate solution for complete precipitation. The mixture was then heated to 60°C and stirred for 10 minutes to form an intermediate amantadine carbonate precipitate. The residue was filtered while hot to yield 29.6 g of the intermediate amantadine carbonate residue, containing 60% water. Chromatographic analysis of the sample revealed an amantadine content of 99.68%. The added sodium bicarbonate is a carbonate salt; other carbonates and bicarbonates may also be added. Water-soluble carbonates and / or bicarbonates, such as ammonium (bi)carbonate, sodium (bi)carbonate, and potassium (bi)carbonate, are preferred, and may be prepared as an aqueous solution. The intermediate amantadine carbonate precipitate can be washed to remove inorganic salts and other organic impurities. Washing can be performed with clean water or weakly alkaline water, optionally with a surfactant. Alternatively, solvents such as methanol, ethanol, N-methylpyrrolidone, ethyl acetate, methyl acetate, acetone, and ethylene glycol, and their aqueous solutions, may be used alone or in combination in any proportion.

[0044] Place half of the intermediate amantadine carbonate residue into a three-necked flask, add 20g of water, and stir to disperse. Alkaline solution is added and heated to 80°C to alkalize the residue to produce amantadine. After the wastewater is alkalized to a pH of 13.15, 30g of toluene is added for extraction, and the toluene and aqueous phases are separated. The alkali solution can be sodium hydroxide and / or potassium hydroxide solution. The amantadine is extracted into the organic phase, leaving a small amount of amantadine-based materials and alkali solution in the aqueous phase, along with a large amount of carbonate. This can be recycled and reacted with the hydrolyzate to produce amantadine carbonate. Excess base can be neutralized by adding acid or bicarbonate, or by absorbing carbon dioxide to convert the excess base into carbonate.

[0045] 30 g of water is added to the toluene phase, and hydrochloric acid is added to adjust the pH of the aqueous solution to 2.01. The aqueous phase is separated to obtain an aqueous solution of amantadine hydrochloride. The extraction organic solvent can also be benzene, xylene, heptane, octane, trimethylpentane, methylhexane, cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane, ethylcyclohexane, methyl tert-butyl ether, etc., and any one of these or a mixture of multiples thereof in any proportion can be used.

[0046] Alternatively, the hydrolyzate obtained in S1 may be directly alkalized, extracted, and stripped to obtain an aqueous solution of amantadine hydrochloride.

[0047] The remaining half of the intermediate amantadine carbonate residue is placed in a three-necked flask, 10 g of water is added with stirring, and hydrochloric acid is added to react. The pH of the aqueous solution is adjusted to 1.91 to obtain an amantadine hydrochloride solution. This amantadine hydrochloride aqueous solution can be extracted with a poorly water-soluble organic solvent to remove some impurities. The organic solvent used for extraction is preferably benzene, toluene, xylene, heptane, octane, trimethylpentane, methylhexane, cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane, ethylcyclohexane, or methyl tert-butyl ether, and any one of these solvents or a combination of any two or more solvents can be used.

[0048] S3: Preparation of finished amantadine hydrochloride from an aqueous amantadine hydrochloride solution: Combine the above aqueous amantadine hydrochloride solutions and add 0.1 g of activated carbon for decolorization. Remove the activated carbon, concentrate, and crystallize. Filter and dry to constant weight to obtain 9.2 g of amantadine hydrochloride crystals. Samples were collected and analyzed by chromatography. The amantadine content was 99.93%. All other parameters met pharmacopoeial standards.

[0049] After solid-liquid separation, the obtained amantadine hydrochloride salt crystals can be washed with an organic solvent to remove impurities and then dried to improve product quality. The organic solvent used is preferably N-methylpyrrolidone, ethyl acetate, acetone, toluene, xylene, etc., and one of them or a mixture of multiple types in any proportion can be used.

Claims

1. A novel method for producing amantadine hydrochloride, comprising the following steps and features: S1: 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, adding water and ammonium salt, or water, ammonium salt and acid for hydrolysis, the amount of water added is 2.5 to 10 times the weight of the amination reaction product, the total amount of ammonium salt added is greater than 0 kg, the amount of acid added is within 0.7 times the amount of the adamantane group substance in the reactants, and filtering out insoluble matter to obtain a hydrolyzate; S2: adding carbonate to the hydrolyzate obtained in S1 to precipitate and perform solid-liquid separation to obtain an intermediate amantadine carbonate precipitate, and reacting the intermediate amantadine carbonate precipitate with hydrochloric acid to obtain an amantadine hydrochloride aqueous solution; adding a base to the hydrolyzate or the intermediate amantadine carbonate precipitate obtained in S1 to react to generate amantadine, adding an organic solvent with poor water solubility to extract, and separating oil from water to obtain an organic phase containing amantadine, and adding water and hydrochloric acid to the organic phase for stirring and extraction to obtain an amantadine hydrochloride aqueous solution; S3: The aqueous solution of amantadine hydrochloride is concentrated and crystallized to obtain amantadine hydrochloride, which is then dried to obtain a finished product.

2. The novel method for producing amantadine hydrochloride according to claim 1, characterized in that: The ammonium salt described in S1 hydrolysis is preferably one or more of ammonium bromide, ammonium chloride, ammonium fluoride, ammonium formate, ammonium nitrate, ammonium acetate, ammonium (hydrogen) phosphate and the like, and the acid is one or more of commonly used acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, formic acid, acetic acid, etc., preferably hydrochloric acid and hydrobromic acid.

3. The novel method for producing amantadine hydrochloride according to claim 1, characterized in that: The ammonium salt can be added directly or generated by reaction by adding a precursor.

4. The novel method for producing amantadine hydrochloride according to claim 1, characterized in that: The alkali is preferably sodium hydroxide and / or potassium hydroxide.

5. The novel method for producing amantadine hydrochloride according to claim 1, characterized in that: The carbonate added to the hydrolyzate is other broad carbonates other than adamantane carbonate, i.e., includes carbonates and bicarbonates; preferably, it is a 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, and is prepared into an aqueous solution for use.

6. The novel method for producing amantadine hydrochloride according to claim 1, characterized in that: The poorly water-soluble organic solvent for extracting adamantane amine is preferably benzene, toluene, xylene, heptane, octane, trimethylpentane, methylhexane, cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane, ethylcyclohexane, methyl tert-butyl ether, etc., one of which or a mixture of multiple thereof in any proportion.

7. The novel method for producing amantadine hydrochloride according to claim 1, characterized in that: The intermediate amantadine carbonate precipitate obtained after the hydrolyzate reacts with the carbonate and the solid-liquid separation is washed to prepare amantadine hydrochloride.

8. The novel method for producing amantadine hydrochloride according to claim 1, characterized in that: After the amantadine generated by the reaction of amantadine carbonate and alkali is separated by organic solvent extraction, the remaining carbonate is recycled to the hydrolyzate to react and generate amantadine carbonate.

9. The novel method for producing amantadine hydrochloride according to claim 1, characterized in that: The aqueous solution of amantadine hydrochloride is extracted with an organic solvent with poor water solubility to remove some impurities. The organic solvent used for extraction is preferably benzene, toluene, xylene, heptane, octane, trimethylpentane, methylhexane, cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane, ethylcyclohexane, methyl tert-butyl ether, etc., and one of them or a mixture of multiple ones in any proportion is used.

10. The novel method for producing amantadine hydrochloride according to claim 1, characterized in that: After solid-liquid separation of the obtained adamantane hydrochloride salt crystals, they can be washed with an organic solvent to remove impurities and then dried to improve product quality; the organic solvent used is preferably N-methylpyrrolidone, ethyl acetate, acetone, toluene, xylene, etc., one of which can be used, or a mixture of multiple types in any proportion.

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