A kind of preparation method of amantadine

Abstract

The invention provides a method for preparing adamantane, and relates to the technical field of chemical production. The method comprises the following steps: mixing 1-bromoadamantane, an organic solvent and an aminating agent and heating at 160-250° C. to obtain adamantane; the organic solvent comprises one or more of diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether and tetraethylene glycol dimethyl ether, and the aminating agent is a mixture of urea and sodium bicarbonate; the method solves the technical problems that the current preparation of adamantane has a large risk, high cost and is difficult to use for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of chemical production, and in particular to a method for preparing amantadine. Background Art

[0002] Amantadine is used as a preventive drug for influenza and later for the treatment of influenza virus in adults. Later, the drug was found to alleviate the symptoms of Parkinson's disease and drug-induced extrapyramidal syndrome. Amantadine is a weak antagonist of NMDA-type glutamate receptors that can increase the release of dopamine and block the reuptake of dopamine. It also has an anticholinergic effect similar to benzhexol. This drug may also promote the release of norepinephrine from nerve endings in the brain. It can treat the motor disorders of Parkinson's disease and improve the dyskinesia that occurs after long-term treatment with dopaminergic drugs for Parkinson's disease.

[0003] At present, the preparation of adamantane is obtained by brominating adamantane and then reacting it with urea. The key step is the amination reaction of bromoadamantane and urea. The method is divided into the following four types: 1. Mix bromoadamantane and urea evenly, heat to 180°C, start the reaction, and the internal temperature rises sharply to 230-240°C. After the reaction is completed, cool naturally, add concentrated hydrochloric acid to dissolve, move into a distillation tank, add sodium hydroxide to alkalize, and then steam distill to obtain adamantane (CN12479896). 2. Bromoadamantane and ammonium carbonate are mixed and heated to 135°C in an autoclave and react for several hours. After the reaction is completed, cool naturally, add water layer, and obtain adamantane (CN109516920). 3. Bromoadamantane is converted with a Grignard reagent and then reacted with 3,3-di-tert-butyloxyaziridine to obtain adamantane amine; (OL, 2018, 8064) 4. Bromoadamantane is reacted with sodium amide, ammonia and diphenylphosphine under pressure to produce adamantane amine (JOC, 1984, 4609).

[0004] Among the above technologies, the method for preparing adamantane amine has the following main defects: 1. The production cost is relatively high; 2. The temperature rises sharply during the reaction and gas is released, which places high demands on factory equipment and also poses great safety risks; 3. Expensive reagents and format reagents with safety risks are used, making it difficult to achieve industrial production. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing amantadine, which solves the technical problems that the current preparation of amantadine has high risks, high costs and is difficult to use for industrial production.

[0006] The present invention solves the technical problem by adopting the following technical solutions.

[0007] The present application provides a method for preparing adamantane, comprising the following steps: mixing 1-bromoadamantane, an organic solvent and an aminating agent and heating the mixture at 160-250° C. to obtain adamantane; the organic solvent comprises one or more of diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether and tetraethylene glycol dimethyl ether; and the aminating agent is a mixture of urea and sodium bicarbonate. The boiling point of diethylene glycol dimethyl ether is about 162° C., the boiling point of diethylene glycol diethyl ether is about 180-190° C., the boiling point of triethylene glycol dimethyl ether is about 216° C., and the boiling point of tetraethylene glycol dimethyl ether is about 275-276° C. Since the organic solvent used is several or one of the above solvents, when heating, it is necessary to adjust the heating temperature according to the composition of the organic solvent actually used. When the organic solvent used contains diethylene glycol dimethyl ether, the heating temperature is controlled at 160-162° C. When the organic solvent used does not contain diethylene glycol dimethyl ether but contains diethylene glycol diethyl ether, the heating temperature is about 160-180° C., and so on.

[0008] Furthermore, the above reaction equation is shown in Formula I:

[0009]

[0010] Furthermore, the volume ratio of the 1-bromoadamantane to the organic solvent is 1:(3-10). This volume ratio can ensure that the reaction system is evenly mixed and easy to stir, thereby ensuring the smooth progress of the reaction.

[0011] Furthermore, the molar ratio of the above-mentioned 1-bromoadamantane to urea and sodium bicarbonate is 1:(5-15):(1-3). This molar ratio can ensure that the 1-bromoadamantane is fully aminated, thereby generating a sufficient amount of adamantane amine and improving the yield. When the amount of the aminating agent used is higher than this interval, it will lead to waste of the aminating agent, and when the amount of the aminating agent used is lower than this interval, it will lead to insufficient amination, and it will be difficult to generate adamantane amine, which will lead to waste of raw materials.

[0012] Furthermore, the above-mentioned heating further includes post-treatment, which includes the following steps: mixing 1-bromoadamantane, an organic solvent and an aminating agent, heating the mixture at 160-250° C. to obtain a mixture, recovering the mixture under reduced pressure, cooling the mixture, and then adding water, stirring and dispersing the mixture to obtain adamantane. The reduced pressure recovery and stirring and dispersing can further remove impurities and a small amount of residual organic solvent, thereby further purifying the mixture to obtain adamantane with higher purity.

[0013] Furthermore, the above post-treatment further includes recrystallization purification or salt purification. Recrystallization purification or salt purification can further remove inorganic impurities therein to further obtain adamantane amine with higher purity.

[0014] Compared with the prior art, the present invention has at least the following advantages or beneficial effects:

[0015] The invention provides a method for preparing adamantane. The method can prepare adamantane by a simple mixing and heating method, wherein the organic solvent used can be recycled and reused, the production temperature is not too high, and the method has advantages in the link of safe production. In addition, almost no gas is generated during the preparation process, and the requirements on equipment are easier to achieve, the risk is lower, the method is more friendly to the employees on the production line, and the method can be more conveniently used for large-scale preparation such as industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments are briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without creative work.

[0017] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of adamantane amine in Experimental Example 1 of the present invention;

[0018] Figure 2 It is the hydrogen nuclear magnetic resonance spectrum of adamantane hydrochloride in Experimental Example 2 of the present invention. DETAILED DESCRIPTION

[0019] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0020] It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of the present application can be combined with each other. The present invention will be described in detail below with reference to specific embodiments.

[0021] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0022] Example 1

[0023] This embodiment provides a method for preparing adamantane: add 80g of bromoadamantane, 500ml of diethylene glycol dimethyl ether, 223g of urea and 62.5g of sodium bicarbonate to a 1L three-necked flask, heat to 170°C with mechanical stirring, reflux the system, and gas escapes during the process. React for 3 hours, end the reaction, cool down, evaporate most of the solvent under reduced pressure, cool down to near room temperature, add 400ml of water, stir and disperse for 1 hour, filter, drain the water, and dry in a reduced pressure oven to obtain 51.7g of off-white solid, with a yield of 92%.

[0024] Example 2

[0025] This embodiment provides a method for preparing adamantane: add 120g of bromoadamantane, 1000ml of diethylene glycol diethyl ether, 334g of urea and 140g of sodium bicarbonate to a 2L three-necked flask, heat to 190°C with mechanical stirring, reflux the system, and gas escapes during the process. React for 2 hours, end the reaction, cool down, evaporate most of the solvent under reduced pressure, cool down to near room temperature, add 600ml of water, stir and disperse for 1 hour, filter, drain the water, and dry in a reduced pressure oven to obtain 76.8g of light yellow solid with a yield of 90.5%.

[0026] Example 3

[0027] This embodiment provides a method for preparing adamantane: add 130g of bromoadamantane, 1000ml of triethylene glycol dimethyl ether, 362.8g of urea and 47.5g of sodium bicarbonate to a 2L three-necked flask, heat to 210°C with mechanical stirring, and reflux the system slightly, with gas escaping during the process. React for 3 hours, end the reaction, cool down, evaporate most of the solvent under reduced pressure, cool down to near room temperature, add 500ml of water, stir and disperse for 1 hour, filter, drain the water, and dry in a reduced pressure oven to obtain 75.6g of light yellow solid with a yield of 89.6%.

[0028] Example 4

[0029] This embodiment provides a method for preparing adamantane: add 130g of bromoadamantane, 1300ml of tetraethylene glycol dimethyl ether, 170g of urea and 150g of sodium bicarbonate to a 2L three-necked flask, and heat to 245°C with mechanical stirring, with gas escaping during the process. React for 1 hour, and when the reaction is finished, cool down, evaporate most of the solvent under reduced pressure, cool down to near room temperature, add 700ml of water, stir and disperse for 1 hour, filter, drain the water, and dry in a reduced pressure oven to obtain 80.6g of a khaki solid with a yield of 88.2%.

[0030] Example 5

[0031] The present embodiment provides a method for preparing adamantane hydrochloride: 100 g of the adamantane solid obtained in the above embodiments 1 to 4 is taken into a 1L three-necked flask, 280 mL of ethanol is added, and the solution is dissolved by heating at 50°C, the temperature is slightly lowered, 5 g of activated carbon is heated, and the temperature is kept at 55°C for about 30 min, decolorized and filtered, 81 g of concentrated hydrochloric acid is added dropwise to the filtrate, and 200 mL of 95% ethanol is added after the addition, the solution is heated to reflux and kept warm for 30 min, the heating is removed, the solution is cooled naturally to precipitate a solid, the solution is kept warm in an ice-water bath for 1.5 hours, the solution is filtered, and the solution is dried under reduced pressure to obtain 114.3 g of adamantane hydrochloride as a white solid with a yield of 92.3%.

[0032] Experimental Example 1

[0033] The amantadine prepared in Example 3 of the present invention was subjected to a nuclear magnetic resonance hydrogen spectrum experiment, and the results obtained were as follows: Figure 1 As shown, according to Figure 1 As shown in the results, the structural formula of the adamantane amine prepared in Example 3 of the present invention is as shown in the structural formula of the adamantane amine in formula (I). It can be seen that the present invention successfully obtains structurally stable adamantane amine with a higher yield using this method.

[0034] Experimental Example 2

[0035] The amantadine hydrochloride prepared in Example 5 of the present invention was subjected to a nuclear magnetic resonance spectroscopy experiment, and the results obtained were as follows: Figure 2 As shown, according to Figure 2 As shown in the results, the structural formula of the adamantane hydrochloride prepared in Example 5 of the present invention is obtained by compounding the structural formula of adamantane with HCl in formula (I). It can be seen that the present invention successfully obtains adamantane hydrochloride with a stable structure by this method with a higher yield.

[0036] In summary, the embodiments of the present invention provide a method for preparing adamantane, which can prepare adamantane by a simple mixing and heating method, wherein the organic solvent used can be recycled and reused, and the production temperature is not too high, which has advantages in the safe production link, and almost no gas is generated during the preparation process, and the requirements for equipment are easier to achieve, the risk is lower, and it is more friendly to the front-line production staff, and can be more conveniently used for large-scale preparation such as industrial production.

[0037] The embodiments described above are part of the embodiments of the present invention, rather than all of the embodiments. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention claimed for protection, but merely represents selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

Claims

1. A method for preparing amantadine, characterized in that: The method comprises the following steps: mixing 1-bromoadamantane, an organic solvent and an aminating agent and heating the mixture at 160-250° C. to obtain adamantane; the organic solvent is one or more of diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether and tetraethylene glycol dimethyl ether; and the aminating agent is a mixture of urea and sodium bicarbonate; The reaction equation is shown in Formula I: （I）； The molar ratio of the 1-bromoadamantane to the urea and the sodium bicarbonate is 1:(5-15):(1-3).

2. The method for preparing amantadine according to claim 1, characterized in that: The volume ratio of the 1-bromoadamantane to the organic solvent is 1:(3-10).

3. The method for preparing amantadine according to claim 1, characterized in that: The method further comprises post-treatment after the heating, comprising the following steps: mixing 1-bromoadamantane, an organic solvent and an aminating agent and heating the mixture at 160-250° C. to obtain a mixture, recovering the mixture under reduced pressure and cooling the mixture, adding water in turn, stirring and dispersing the mixture to obtain the adamantane amine.

4. The method for preparing amantadine according to claim 3, characterized in that: The post-treatment also includes recrystallization purification or salt purification.

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