Method for producing high-purity amantadine

Abstract

Hydrolyzing an amination reaction product, filtering out insoluble substances to obtain hydrolysate, reacting the hydrolysate with carbonate to generate an intermediate amantadine carbonate precipitate, carrying out solid-liquid separation, adding alkali liquor into the precipitate, carrying out steam distillation, and condensing and trapping fractions to obtain amantadine containing water. The method is high in impurity removal efficiency, inorganic ammonium and water-soluble organic impurities can be better removed, and amantadine distilled out by water is high in purity; the carbonate is recycled, the material loss is reduced, the distillation efficiency is improved, the energy consumption is reduced, and the method is green, environment-friendly and low in cost and is a good method for industrial production of amantadine.

Description

Technical Field

[0001] The present invention relates to a method for producing adamantane derivatives, in particular to a method for producing adamantane amine. 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 vildegrin intermediates—3-amino-1-adamantanol; they can be used to synthesize adamantyl quaternary ammonium bases and to manufacture molecular sieves; they can also be used as corrosion inhibitor components and have a wide range of uses.

[0004] The industrial synthesis process of adamantane is to use adamantane as raw material, generate 1-bromoadamantane through bromine substitution, and then react 1-bromoadamantane with urea at high temperature for amination. The end material of the amination reaction is solid, which usually contains a large amount of urea decomposition products due to excessive urea addition.

[0005] The amination reaction materials are hydrolyzed, and the adamantane material is separated and extracted from the amination reaction end point mixed material. A strong base (usually sodium hydroxide or potassium hydroxide) is added to the hydrolyzate for steam distillation, and the adamantane is taken out by the steam. This method can directly obtain a hydrous adamantane product, which reacts with an acid to obtain a salt product of adamantane.

[0006] The materials in the hydrolyzate can also be processed and then subjected to steam distillation. The commonly used treatment method is sulfate precipitation: sulfate is added to the hydrolyzate for precipitation to obtain adamantane sulfate precipitate. The adamantane 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 effect, which is not much different from the content of the hydrolyzate chromatographic analysis. The precipitate has a large water content, and some inorganic ammonium salts can be removed after washing. Sulfate has low solubility and is easy to form crystals, blocking the discharge port and pipeline at the bottom of the kettle.

[0007] The main disadvantages of steam distillation are: 1. High energy consumption, long time, large amount of wastewater generated and troublesome to handle. The steam distillation method requires the use of 8 to 10 times or more water-dispersible materials of the end material of the amination reaction and heating and distilling them out to achieve a sufficient separation and extraction effect. The distillation process takes a long time, usually eight or nine hours or more. It consumes a large amount of steam and consumes a lot of energy. The amount of water distilled is large, and the distillate water after mechanical separation of adamantane amine (filtration or centrifugation) still contains a lot of soluble ammonia and residual adamantane amine suspended particles, which makes the recovery and treatment of this part of the wastewater more troublesome.

[0008] 2. High alkali consumption. Due to the principle limitation of steam distillation, strong alkali (sodium hydroxide or potassium hydroxide) must be added in excess to allow adamantane amine to precipitate completely in a solid state so that it can be completely distilled out together with water vapor. Usually, more than 130% of the amount (molar amount) of adamantane amine in the reaction mixture needs to be added.

[0009] 3. Low purity. The incompletely reacted 1-bromoadamantane 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 urea and biuret remaining in the mixture will hydrolyze, releasing ammonia, which will partially dissolve in the distilled water, causing the ammonia to be entrained in the adamantane product, and the ammonia will be emitted into the production environment, resulting in ammonia pollution in the production environment. Summary of the invention

[0010] In view of the shortcomings of the existing process, the present invention provides a method for producing high-purity amantadine.

[0011] Amination reaction is carried out 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, etc. can also be added as a solvent to carry out the amination reaction to promote the reaction effect.

[0012] The amination product is hydrolyzed, and the insoluble matter is filtered out by controlling the temperature. The purpose of hydrolysis is to convert adamantane into a salt and dissolve it in water, thereby separating it from the insoluble impurities generated by the reaction to obtain a hydrolyzate. Different hydrolysis methods will result in different hydrolyzates of adamantane salts. The amination reaction product is hydrolyzed by adding water, or by adding acid, ammonium salt and other substances to water in a free combination, and the hydrolyzate is obtained by controlling the temperature and filtering out the insoluble matter. 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; the salt is ammonium bromide, ammonium chloride, ammonium fluoride, ammonium formate, ammonium nitrate, ammonium acetate, ammonium (hydrogen) phosphate and other ammonium salts, and one or more of them are used. Therefore, there can be a variety of adamantane salts in the hydrolyzate, and all of them are adamantane salts with good water solubility.

[0013] The hydrolyzate can be extracted with an organic solvent with poor water solubility 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 one of them or a mixture of multiple types in any proportion is used.

[0014] The hydrolyzate is filtered to remove insoluble matter during or after the hydrolysis process, and decolorized using a decolorizing agent, preferably activated carbon or activated carbon fiber. The hydrolyzate can also be decolorized using a decolorizing agent recovered by decolorizing with an aqueous solution of amantadine hydrochloride. The filtered insoluble matter and the decolorizing agent can be washed with water to recover the entrained material, and a small amount of material entrained in the insoluble matter can be recovered by secondary hydrolysis.

[0015] The aminated hydrolyzate or the washed hydrolyzate is directly added with alkali solution, and the conventional water distillation process is used. The incompletely reacted 1-bromoadamantane is hydrolyzed to generate 1-adamantanol and impurities such as 1,3-adamantanediamine, which are taken out together during water distillation, making the purity of adamantane low. Therefore, the hydrolyzate can be 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., one of which is used, or a plurality of them are mixed in any proportion. The organic solvent is concentrated and distilled to recover substances such as 1-adamantanol and 1,3-adamantanediamine.

[0016] Even after extraction and washing with an organic solvent with poor water solubility, most of the water-soluble impurities still remain in the hydrolyzate, and the purity of the amantadine produced by the traditional water distillation process will not be significantly improved. During water distillation, under strong alkali and high temperature conditions, the urea, biuret, etc. remaining in the mixed material will be hydrolyzed, releasing ammonia, which is partially dissolved in the distilled water, causing the amantadine product to carry ammonia, and the ammonia is emitted into the production environment, resulting in ammonia pollution in the production environment. In this regard, the present invention also provides a new impurity removal process.

[0017] The amantadine salt reacts with the carbonate to generate an intermediate amantadine carbonate precipitate. The solid-liquid separation is performed, and the water-soluble inorganic salts and organic impurities are separated with the liquid, and the content of the intermediate amantadine carbonate precipitate is increased. Then, an alkali is added for alkalization, and the alkalized material is subjected to steam distillation. The condensed fraction is captured to obtain water-containing high-purity amantadine. One of the main sources of the amantadine salt is the hydrolyzate obtained by hydrolyzing the amination reaction product and filtering out the insoluble matter, or the hydrolyzate is further treated to obtain it.

[0018] The hydrolyzate is subjected to a precipitation reaction with a carbonate, and solid-liquid separation is performed to obtain an intermediate amantadine carbonate precipitate. The amantadine salt contained in the hydrolyzate reacts with the carbonate to generate an amantadine carbonate precipitate. The carbonate used is a carbonate other than amantadine carbonate in a broad sense, that is, it includes carbonates and bicarbonates. Preferably, it is a water-soluble carbonate and / or bicarbonate, such as ammonium carbonate (bicarbonate), sodium carbonate (bicarbonate), potassium carbonate (bicarbonate), etc., including but not limited to one or more thereof, which is prepared into an aqueous solution for use. Amantadine carbonate can also be generated by using carbonates or bicarbonates with poor water solubility. For example, calcium carbonate can also be reacted with an amantadine hydrochloride solution to obtain amantadine carbonate, but because calcium carbonate is a solid and the product is also a solid, mass transfer is difficult, and it is very difficult to react completely, and the purity of the obtained amantadine carbonate is not high. In addition, if calcium carbonate is to be reacted completely, the hydrogen chloride molecules in the amantadine hydrochloride must be excessive, and the amantadine will also be excessive, which is not worth the loss.

[0019] In addition to using the hydrolyzate directly, the hydrolyzate can also be used to further process the obtained amantadine salt and react with carbonate to form an amantadine carbonate precipitate. For example, the hydrolyzate is used to prepare amantadine sulfate, which is then reacted with carbonate to form an amantadine carbonate precipitate. Amantadine sulfate is a precipitate, so sulfuric acid and sulfuric acid (hydrogen) salt are generally not used during hydrolysis. For another example, the crude and unqualified products of amantadine salt produced by the hydrolyzate, or the amantadine salt whose product quality is not enough to meet customer needs is directly prepared by alkalization and water distillation, and reacted with carbonate to form an amantadine carbonate precipitate.

[0020] The method of the present invention is used to generate adamantane carbonate precipitate, and the temperature for separating the intermediate adamantane carbonate precipitate is preferably between room temperature and 80°C. Controlling the temperature for filtering out the adamantane carbonate precipitate to be the same as or higher than that for filtering out the insoluble matter can make the obtained adamantane carbonate precipitate carry less impurities. The content of adamantane carbonate chromatographic detection can usually reach more than 98%. The separated adamantane carbonate is bound to carry impurities and other salts due to its entrained water, which can be washed and removed. Washing can be carried out with clean water or weakly alkaline water, and a surfactant can be added to the water. Solvents such as methanol, ethanol, N-methylpyrrolidone, ethyl acetate, methyl acetate, acetone, ethylene glycol and their aqueous solutions can also be used, using one of them, or a mixture of multiple solvents in any proportion. 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 effect of washing and removing impurities is better at a high temperature. The impurities of the adamantane carbonate after washing are even lower.

[0021] The aqueous solution after separation of adamantane carbonate can also be extracted with an organic solvent with poor water solubility 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 one of them or a mixture of multiple of them in any proportion is used.

[0022] The intermediate amantadine carbonate precipitate obtained above is added with a base to react and generate amantadine, the pH of the alkalized liquid is controlled to be greater than 10, and steam distillation is performed. The condensed fraction is captured to obtain hydrous amantadine, and a part of the water can be removed to produce an amantadine product with less water content. In order to make the steam distillation complete, it is preferred that the pH of the alkalized liquid is controlled to be greater than 12. The base is preferably sodium hydroxide and / or potassium hydroxide, the same below.

[0023] After the amantadine is distilled out by steam, the remaining carbonate is reused to react with the hydrolyzate to generate amantadine carbonate. In the later stage of water distillation, due to the small amount of amantadine material, a large amount of water is distilled, and the amount of amantadine is very small, so the distillation efficiency is low; if the distillation is not continued, the material will be lost and the yield will be low. The small amount of amantadine and the remaining carbonate left in the later stage of water distillation are reused to react with the hydrolyzate to generate amantadine carbonate. The material is circulated and almost no material is lost, which can greatly shorten the water distillation time, improve efficiency and reduce energy consumption. The remaining carbonate aqueous solution and the crystalline solid mixed material that may be formed contain excess alkali, which can be neutralized by adding acid or bicarbonate, or absorb carbon dioxide to convert the excess alkali into carbonate, or directly reused to react with the hydrolyzate to generate amantadine carbonate. It can also be used to react with substances that react with acid or alkali. For example, it can be used as tail gas absorption water to absorb hydrogen chloride, hydrogen bromide, bromine, chlorine, etc. to produce tail gas.

[0024] Carbonates have high solubility and are prepared into solutions to react with hydrolyzates to generate adamantane carbonate, which can greatly reduce the generation of wastewater compared to sulfates. For complete precipitation, sulfates or carbonates need to be excessive. Excessive sulfate precipitation will remain in the wastewater, generating new salts and forming mixed salts; while excessive carbonates will decompose after neutralization in the later stage, without generating new salts, and the salt components are single, making them easy to handle.

[0025] Compared with the prior art, the present invention has high impurity removal efficiency, can better remove inorganic ammonium and water-soluble organic impurities, and the distilled adamantane has high purity; carbonate and excess alkali solution are recycled, which reduces material loss, improves distillation efficiency, reduces energy consumption, is green and environmentally friendly, and has low cost. It is a good method for industrial production of adamantane. DETAILED DESCRIPTION The following describes the embodiments of the present invention in detail in combination with the main technical content of the invention. The embodiments described below are only exemplary and are only used to explain the present invention, rather than to limit the present invention.

[0027] Example: 30 g of the product after the amination reaction of 1-bromoadamantane and urea was taken, heated to hydrolyze, then cooled to filter, to obtain a hydrolyzate. Samples were taken for chromatographic analysis, and the content of adamantane was 97.62%.

[0028] The product after amination reaction with 1-chloroadamantane, and / or 1-fluoroadamantane, and / or 1-adamantanol, and / or 1-nitroadamantane, and / or 1-adamantanol nitrate can also be used, and the aminating agent is preferably urea; the hydrolysis method is to add water to the substance, or add acid, ammonium salt and other substances to the water in a free combination to hydrolyze the obtained hydrolyzate, preferably the hydrolyzate obtained by controlling the temperature and filtering out the insoluble matter after hydrolysis and decolorization. The hydrolyzate in which the insoluble matter is filtered out during or after the hydrolysis is 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 for extraction is preferably benzene, toluene, xylene, heptane, octane, trimethylpentane, methylhexane, cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane, ethylcyclohexane, methyl tert-butyl ether, etc., one of which is used, or a plurality of them are mixed in any proportion.

[0029] The hydrolyzate is added with an excess of sodium bicarbonate solution and heated to 70°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. Sampling chromatographic analysis 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. The temperature for separating the intermediate adamantane carbonate precipitate is preferably room temperature to 80°C.

[0030] 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.

[0031] The intermediate amantadine carbonate precipitate can be washed to remove inorganic salts and other organic impurities. Clean water or weak alkaline water can be used for washing. Surfactants can be added to the water. Solvents such as methanol, ethanol, N-methylpyrrolidone, ethyl acetate, methyl acetate, acetone, ethylene glycol and their aqueous solutions can also be used. One of them can be used, or multiple of them can be mixed in any proportion. The temperature range for washing the intermediate amantadine carbonate precipitate is any temperature between room temperature and the boiling point of the washing liquid.

[0032] 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%.

[0033] 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.

Claims

1. A method for producing high-purity amantadine, comprising the following steps and features: The amantadine salt reacts with the carbonate to generate an intermediate amantadine carbonate precipitate, and the solid-liquid separation is performed. The intermediate amantadine carbonate precipitate is alkalized by adding alkali, the alkalized material is subjected to steam distillation, and the condensed fraction is captured to obtain the water-containing amantadine.

2. The method for producing high-purity amantadine according to claim 1, characterized in that: One of the sources of the adamantane amine salt is hydrolyzing the amination reaction product and filtering out the insoluble matter to obtain a hydrolyzate, or further treating the hydrolyzate to obtain the adamantane amine salt.

3. The method for producing high-purity amantadine according to claim 2, characterized in that: The hydrolyzate 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, etc., and one of them or a mixture of multiple types in any proportion can be used.

4. The method for producing high-purity amantadine according to claim 2, characterized in that: The amination reaction product includes 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; the hydrolyzate is a hydrolyzate obtained by hydrolyzing the amination reaction product by adding water, or adding acid, ammonium salt and other substances to water in a free combination, and is preferably a hydrolyzate obtained by hydrolyzing and decolorizing and then controlling the temperature to filter out insoluble matter.

5. The method for producing high-purity amantadine according to claim 1, characterized in that: The carbonate is other broad carbonates other than adamantane carbonate, i.e., includes carbonates and bicarbonates; 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, prepared into an aqueous solution for use.

6. The method for producing high-purity amantadine according to claim 1, characterized in that: The temperature for separating the intermediate amantadine carbonate precipitate is preferably between room temperature and 80°C.

7. The method for producing high-purity amantadine according to claim 1, characterized in that: The intermediate adamantane carbonate precipitate obtained after solid-liquid separation is washed to prepare adamantane amine.

8. The method for producing high-purity amantadine according to claim 7, characterized in that: The washing liquid used for washing the intermediate adamantane carbonate precipitate is preferably clean water or weakly alkaline water. A surfactant may be added to the water. Solvents such as methanol, ethanol, N-methylpyrrolidone, ethyl acetate, methyl acetate, acetone, ethylene glycol and their aqueous solutions may also be used. One of them may be used, or a mixture of multiple solvents in any proportion.

9. The method for producing high-purity amantadine according to claim 1, characterized in that: The alkali is preferably sodium hydroxide and / or potassium hydroxide.

10. The method for producing high-purity amantadine according to claim 1, characterized in that: The carbonate remaining after distilling out the adamantane amine with steam is recycled to the hydrolyzate to react and generate the adamantane amine carbonate.

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