Preparation method of edaravone

Abstract

The invention belongs to the field of preparation methods of medicines, and particularly relates to a preparation method of edaravone, which comprises the following steps: taking orthoester as a solvent, carrying out cyclization reaction on phenylhydrazine and ethyl acetoacetate under the catalytic action of acidic resin without reflux, and carrying out post-treatment to obtain the product edaravone. The preparation method disclosed by the invention is free of reflux, short in reaction time, high in yield, high in purity, simple in post-treatment, environment-friendly and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of drug preparation methods, and specifically relates to a method for preparing edaravone, a brain protective agent. Background Art

[0002]

[0003] Edaravone (3-methyl-1-phenyl-2-pyrazol-5-one) is a powerful free radical scavenger and antioxidant. It is a lipophilic compound that is easily absorbed through the blood-brain barrier. Edaravone is a brain protective agent developed by Mitsubishi Chemical Corporation of Japan and was launched in Japan on June 1, 2001. Its mechanism of action is to remove the increased free radicals after ischemia, inhibit lipid peroxidation, and protect tissues. In clinical practice, this product can be used to improve the neurological and daily life behavior symptoms of patients in the acute stage of cerebral infarction. It has mild side effects, significant therapeutic effects, and good prognostic effects.

[0004] At present, the synthesis of edaravone mainly includes two methods: the reaction of phenylhydrazine and ethyl acetoacetate, and the reaction of phenylhydrazine and butanone amide. Among them, ethyl acetoacetate and phenylhydrazine have higher reactivity, and ethyl acetoacetate is cheaper and more available than butanone amide, so method 1 is the reaction route reported more in the literature. According to current literature reports, this reaction is mostly carried out in ethanol, or directly with acetic acid or other acids as solvents, and the reaction needs to be carried out under the condition of solvent reflux, generally at a high temperature, the reaction is more violent, and the reaction time takes several hours. Excessive reaction temperature and long reaction time are not only not conducive to the operation of industrial large-scale production and production safety, but also affect the quality of the product, easily produce more impurities, and are not conducive to the control of drug quality.

[0005] Patent CN106117144A discloses an improved alkaline condensation method as follows:

[0006]

[0007] In this route, ethyl acetoacetate is dissolved in a lower alcohol, phenylhydrazine is added dropwise at 15-25°C, and after the addition is complete, the mixture is stirred at 15-25°C for 10 minutes, followed by the addition of a catalytic amount of a base, and the mixture is heated to reflux for reaction; after the reaction is completed, the mixture is cooled and stirred to precipitate, filtered, and the filter cake is washed with ethyl acetate until the filtrate is colorless, and then recrystallized with anhydrous ethanol to obtain the target product, edaravone. This route requires heating and reflux, and phenylhydrazine primary amine has a strong reaction activity. Under high temperature or excessive feeding conditions, it will simultaneously undergo Schiff base reaction and ester aminolysis reaction with ethyl acetoacetate, producing double condensation impurities, which affect the purity of the product.

[0008] Patent CN102285920A discloses a method using Na2S2O4 as a catalyst, as shown below:

[0009]

[0010] This route uses excessive phenylhydrazine or phenylhydrazine hydrochloride as feed material, and the generation of double condensation impurities is inevitable. In addition, a large amount of sodium dithionate is used as an oxygen consuming agent and catalyst in the process, which is highly dangerous and only suitable for small-scale laboratory synthesis, but not suitable for industrial production. The heating reflux operation causes a violent reaction, which affects the purity of the product. Patent US4857542 refluxes in ethanol for 3 hours, and the oxidation degradation of edaravone is obvious. The cost of refining and impurity removal is high, and the yield after refining is only 65%. Edaravone is a free radical scavenger and is easily oxidized and discolored. Increasing the reaction temperature or extending the reaction time will aggravate the generation of edaravone oxidation impurities, causing the finished product to be colored and the purity to be reduced.

[0011] The existing technology for synthesizing edaravone usually requires a high temperature (greater than 75°C) reaction in an organic acid or inorganic acid environment, or even under dangerous catalyst conditions, and the reaction time is not less than 2 hours. The product has a dark color and many impurities, and is only suitable for small-scale synthesis in the laboratory. Industrial production requires repeated refining to ensure that the product color and impurities meet the requirements for pharmaceutical use. The actual yield is low and the cost is high. Summary of the invention

[0012] The purpose of the present invention is to provide a method for preparing edaravone which does not require reflux, has a short reaction time, high yield, high purity, simple post-treatment, is environmentally friendly and suitable for industrial production, based on the prior art.

[0013] In order to achieve the above-mentioned object, the technical scheme adopted by the present invention is as follows: a method for preparing edaravone, comprising the following steps: using an orthoester as a solvent, under the catalytic action of an acidic resin, without reflux, phenylhydrazine and ethyl acetoacetate undergo a cyclization reaction, and obtaining the product edaravone through post-treatment;

[0014]

[0015] In a preferred embodiment, the resin is a macroporous strongly acidic styrene-based cation exchange resin, a macroporous medium acidic styrene-based cation exchange resin, or a macroporous weakly acidic styrene-based cation exchange resin.

[0016] Furthermore, the orthoester is one or more of triethyl orthoformate, trimethyl orthoformate, triethyl orthoacetate, and trimethyl orthoacetate, preferably triethyl orthoacetate, and the ratio of the orthoester to phenylhydrazine is 1.5-4.5 mL / g, preferably 2.0 mL / g.

[0017] In a preferred embodiment, the mass ratio of the acidic resin to phenylhydrazine is 10%-50%, preferably 20%-40%.

[0018] Furthermore, the molar ratio of phenylhydrazine to ethyl acetoacetate is 0.9-1.1.

[0019] In a preferred embodiment, the cyclization reaction temperature is 20-50°C, preferably 30-40°C.

[0020] Furthermore, the cyclization reaction time is 1-1.5 h, preferably 1.5 h.

[0021] In a preferred embodiment, the post-treatment comprises the following steps: adding excess water to the reaction system (by adding water to precipitate edaravone), adjusting the pH to 8-9, filtering, slurrying twice with a mixed solvent, filtering with suction, and drying to obtain edaravone, the drying temperature being 60-90°C, preferably 60°C.

[0022] Furthermore, the mixed solvent comprises an organic solvent and water, wherein the organic solvent is n-hexane, methyl tert-butyl ether, ethyl acetate, petroleum ether, cyclohexane, preferably cyclohexane.

[0023] The mass fraction of the organic solvent in the mixed solvent is 70%-90%, preferably 80%.

[0024] The present invention is beneficial in that:

[0025] The acidic resin used in the present invention can not only provide an acidic environment for catalytic reaction, but also the resin can absorb impurities and pigments generated by the reaction.

[0026] The ethyl acetoacetate molecule contains two carbonyl structures: ketone carbonyl and ester carbonyl; the phenylhydrazine molecule also contains two amino structures: primary amine and secondary amine. Therefore, ethyl acetoacetate and phenylhydrazine can undergo two types of reactions: Schiff base reaction (condensation of primary amine and ketone) and ester aminolysis reaction, both of which react through nucleophilic addition-elimination mechanism. From the perspective of steric hindrance, the most likely reaction is the Schiff base reaction, followed by the ester aminolysis reaction: the Schiff base reaction generates water, while ethyl acetoacetate will hydrolyze, and anhydrous environment is more favorable for the reaction. The present invention creatively adds orthoesters (taking triethyl orthoacetate as an example), which can quickly react with the water generated by the Schiff base reaction under the catalysis of acidic resin, promote the Schiff base reaction, and the generated ethyl acetate can be further hydrolyzed into acetic acid and ethanol under acidic conditions. Acetic acid reacts in turn to catalyze the cyclization reaction. The triethyl orthoacetate and the acidic resin work together to shift the equilibrium to the right, forming a virtuous cycle. The reaction can be completed quickly at a lower temperature and the product has high purity and high yield.

[0027] Generally, the acidity of a catalyst significantly affects its catalytic performance. However, in the present invention, since the formed acetic acid reacts to catalyze the cyclization reaction, and triethyl orthoacetate and the acidic resin work together to shift the equilibrium to the right, the weakly acidic resin can also be used to prepare high-purity and high-yield edaravone. DETAILED DESCRIPTION

[0028] The present invention is described in detail below with reference to specific embodiments.

[0029] The yields in the following examples and comparative examples are calculated based on the molar number of the substrate fed in each specific step.

[0030] Example 1: Preparation of Edaravone

[0031] In a 500ml reaction bottle, add 100mL of triethyl orthoacetate, and add 10.2g of strong acid resin (D001 macroporous strong acid styrene cation exchange resin, Suzhou Ionway) in sequence under stirring at room temperature, 50.83g (0.47mol) of phenylhydrazine, and 62.47g (0.48mol) of ethyl acetoacetate, protect with nitrogen, gradually heat to 35°C, continue to react for 1.5h, filter to remove the resin; then add 200ml of water, adjust the pH to 8, filter, and beat twice with a mixed solvent of n-hexane and water (n-hexane mass fraction is 80%), and dry at 60°C to obtain 80.24g of edaravone, with a yield of 98%. The product purity is 99.5% by HPLC analysis.

[0032] Example 2: Preparation of Edaravone

[0033] In a 500ml reaction bottle, add 100mL of trimethyl orthoacetate, and add 10.2g of strong acid resin (D001 macroporous strong acid styrene cation exchange resin, Suzhou Ionway) in sequence under stirring at room temperature, 50.83g (0.47mol) of phenylhydrazine, and 62.47g (0.48mol) of ethyl acetoacetate, protect with nitrogen, gradually heat to 35°C, continue to react for 1.5h, filter to remove the resin; then add 200ml of water, adjust the pH to 9, filter, and beat twice with a mixed solvent of methyl tert-butyl ether and water (methyl tert-butyl ether mass fraction is 80%), and dry at 60°C to obtain 79.9g of edaravone, with a yield of 97.6%. The product purity is 99.2% by HPLC analysis.

[0034] Example 3: Preparation of Edaravone

[0035] In a 500ml reaction bottle, add 100mL of trimethyl orthoformate, and add 20.3g of weakly acidic resin (D113 macroporous weakly acidic acrylic acid cation exchange resin, Suzhou Ionway) in sequence under stirring at room temperature, 50.83g (0.47mol) of phenylhydrazine, and 62.47g (0.48mol) of ethyl acetoacetate, protect with nitrogen, gradually heat to 40°C, continue to react for 1.5h, filter to remove the resin; then add 200ml of water, adjust the pH to 8.5, filter, beat twice with a mixed solvent of ethyl acetate and water (ethyl acetate mass fraction is 80%), and dry at 60°C to obtain 79.8g of edaravone, with a yield of 97.5%. The product purity is 99.3% by HPLC analysis.

[0036] Comparative Example 1: Preparation of Edaravone

[0037] In a 500ml reaction bottle, 100mL of ethanol was added, and 20.3g of strong acid resin (D001 macroporous strong acid styrene cation exchange resin, Suzhou Ionway) was added in sequence under stirring at room temperature, 50.83g (0.47mol) of phenylhydrazine, and 62.47g (0.48mol) of ethyl acetoacetate were added, and nitrogen was protected, and the temperature was gradually raised to 35°C. The reaction was continued for 1.5h, and the resin was removed by filtration; 200ml of water was added, the pH was adjusted to 8, filtered, and slurried twice with a mixed solvent of n-hexane and water (n-hexane mass fraction was 80%), and dried at 60°C to obtain 74.5g of edaravone, with a yield of 91%. The product purity was 99.3% by HPLC analysis.

[0038] Comparative Example 2: Preparation of Edaravone

[0039] In a 500ml reaction bottle, 100mL of ethanol was added, and 10.2g of weakly acidic resin (D113 macroporous weakly acidic acrylic acid cation exchange resin, Suzhou Ionway) was added in sequence under stirring at room temperature, 50.83g (0.47mol) of phenylhydrazine, and 62.47g (0.48mol) of ethyl acetoacetate were added, and nitrogen was protected, and the temperature was gradually raised to 35°C. The reaction was continued for 1.5h, and the resin was removed by filtration; 200ml of water was added, the pH was adjusted to 8, filtered, and slurried twice with a mixed solvent of n-hexane and water (n-hexane mass fraction was 80%), and dried at 60°C to obtain 65.5g of edaravone, with a yield of 80%. The product purity was 99.2% by HPLC analysis.

[0040] In the description of the present invention, reference to terms such as "embodiment", "specific example" or "practical application" means that the specific features, structures, materials or characteristics described in combination with the embodiment are included in at least one embodiment or example of the present invention; the schematic expressions of the above terms do not necessarily refer to the same embodiment or example, and the specific features, structures, materials or characteristics described may be combined in an appropriate manner in any one or more embodiments or examples.

[0041] The above embodiments are only used to illustrate the technical solutions of the present invention. Those skilled in the art should understand that the above embodiments do not limit the present invention in any form, and any technical solutions obtained by equivalent replacement or equivalent transformation shall fall within the protection scope of the present invention.

Claims

1. A method for preparing edaravone, It is characterized in that The method comprises the following steps: using orthoester as solvent, under the catalysis of acidic resin, without reflux, phenylhydrazine and ethyl acetoacetate undergo cyclization reaction, and obtaining the product edaravone through post-treatment; 2. A method for preparing edaravone according to claim 1, Features: The resin is a macroporous strongly acidic styrene-based cation exchange resin or a macroporous weakly acidic styrene-based cation exchange resin.

3. A method for preparing edaravone according to claim 1, Features: The orthoester is one or more of triethyl orthoformate, trimethyl orthoformate, triethyl orthoacetate, and trimethyl orthoacetate, preferably triethyl orthoacetate. The ratio of the orthoester to phenylhydrazine is 1.5-4.5 mL / g, preferably 2.0 mL / g.

4. A method for preparing edaravone according to claim 2, Features: The mass ratio of the acidic resin to phenylhydrazine is 10%-50%, preferably 20%-40%.

5. A method for preparing edaravone according to claim 1, Features: The molar ratio of the phenylhydrazine to the ethyl acetoacetate is 0.9-1.

1.

6. A method for preparing edaravone according to claim 1, Features: The cyclization reaction temperature is 20-50°C, preferably 30-40°C.

7. A method for preparing edaravone according to claim 1, Features: The cyclization reaction time is 1-1.5h, preferably 1.5h.

8. A method for preparing edaravone according to claim 1, Features: The post-treatment comprises the following steps: adding excess water to the reaction system, adjusting the pH to 8-9, filtering, beating with a mixed solvent twice, filtering, and drying at a drying temperature of 60-90°C, preferably 60°C.

9. A method for preparing edaravone according to claim 8, Features: The mixed solvent comprises an organic solvent and water, wherein the organic solvent is n-hexane, methyl tert-butyl ether, ethyl acetate, petroleum ether, cyclohexane, and preferably cyclohexane.

10. A method for preparing edaravone according to claim 9, Features: The mass fraction of the organic solvent in the mixed solvent is 70%-90%, preferably 80%.

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