A kind of preparation method of D, L-naproxen

Abstract

The present invention relates to a method for preparing D, L-naproxen, and belongs to the technical field of drug synthesis. In order to solve the existing problem of large pollution and the need to add an additional rearrangement catalyst, a method for preparing D, L-naproxen is provided, comprising adding 6-methoxy-2-propionylnaphthalene, diol and copper halide to a water-insoluble organic solvent with a boiling point higher than 100°C and performing a reflux reaction under reflux conditions, separating the water produced by the reaction during the reflux reaction, reacting until no water is produced, cooling to 80°C to 100°C for insulation reaction, and obtaining a rearrangement reaction intermediate esterification product; hydrolyzing reaction is performed under the action of an aqueous solution of an alkali metal hydroxide, and then acidifying to obtain a product D, L-naproxen. The present invention does not need to add an additional rearrangement catalyst, reduces pollution to the environment, has the advantages of being environmentally friendly, and is more convenient to operate, and has the advantages of a high product yield.

Description

Technical Field

[0001] The invention relates to a preparation method of D, L-naproxen and belongs to the technical field of drug synthesis. Background Art

[0002] D, L-naproxen, chemical name D, L-6-methoxy-α-methyl-2-naphthylacetic acid, has the following structural formula:

[0003]

[0004] Naproxen is a non-steroidal anti-inflammatory analgesic with good anti-inflammatory, antipyretic and analgesic effects, low toxicity, small and mild side effects, and good tolerance. It has been widely used in the world and has become one of the world's major antipyretic analgesics and best-selling over-the-counter drugs. It is also included in the national basic medical insurance drug catalog.

[0005] The synthetic routes reported so far for the synthesis of naproxen using 6-methoxy-2-propionylnaphthalene as the starting material are:

[0006] 6-methoxy-2-propionylnaphthalene is used as a raw material, after being brominated with tribromotrimethylaniline, it is ketalized with neopentyl glycol under the catalysis of p-toluenesulfonic acid, and then rearranged by zinc oxide catalysis to obtain a rearranged product, which is hydrolyzed with a strong base and then acidified to obtain a crude product, and finally recrystallized with methanol to obtain D, L-naproxen. In the rearrangement process, zinc oxide is used as a rearrangement catalyst, which is prone to the presence of many three wastes, and the various types of catalysts used are not conducive to the reaction operation.

[0007] 6-methoxy-2-propionylnaphthalene is used as a raw material, reacted with a diol and copper chloride to obtain 2-chloro-1-(6-methoxy-2-naphthyl)propan-1-one acetal, the acetal is washed with water after layering, and then refluxed for dehydration, and then zinc acetate is added for catalytic rearrangement to obtain an ester, the ester is hydrolyzed under strong alkaline conditions, and then acidified to obtain DL-naproxen crude product. Another example is the Chinese patent application (publication number: CN109485561 A) 6-methoxy-2-propionylnaphthalene is used as a raw material, reacted with diol A and copper chloride to obtain 2-chloro-1-(6-methoxy-2-naphthyl)propan-1-one ketal A (hereinafter referred to as ketal A), and the purified or unpurified ketal A is subjected to rearrangement reaction to obtain ester A; ketal A or acid hydrolysis is performed to obtain 2-chloro-1-(6-methoxy-2-naphthyl)propan-1-one (hereinafter referred to as 2-chloro-propan-1-one), and the purified or unpurified 2-chloro-propan-1-one is subjected to ketal reaction with diol B to obtain 2-chloro-1-(6-methoxy-2-naphthyl)propan-1-one ketal B (hereinafter referred to as ketal B), and ketal B is further subjected to rearrangement reaction to obtain ester B, and the ester A or B is hydrolyzed under strong alkaline conditions, and zinc acetate is used as a rearrangement catalyst in the rearrangement process to perform reflux reaction, and then acidification is performed to obtain DL-naproxen. However, the main problems of the above synthesis are: the synthesis process and production cycle are long, the separation operation is cumbersome, and the ketal reaction and rearrangement reaction processes need to be treated separately. The rearrangement process also requires the addition of a rearrangement catalyst for the reaction, and there is a large amount of three wastes generated, which is not conducive to industrial production. Summary of the invention

[0008] The present invention aims at the above problems existing in the prior art and provides a method for preparing D,L-naproxen, which solves the problem of how to reduce wastewater pollution and has a high product yield.

[0009] The object of the present invention is achieved by the following technical scheme: a method for preparing D,L-naproxen, characterized in that the method comprises the following steps:

[0010] A. adding 6-methoxy-2-propionylnaphthalene, diol and copper halide to a water-insoluble organic solvent having a boiling point higher than 100° C. and performing a reflux reaction under reflux conditions, separating the water produced by the reaction during the reflux reaction, reacting until no water is produced, cooling to 80° C. to 100° C. and performing a heat-insulating reaction to obtain a rearrangement reaction intermediate esterification product;

[0011] B. The obtained rearrangement reaction intermediate ester is subjected to a hydrolysis reaction under the action of an aqueous solution of an alkali metal hydroxide, and then acidified to obtain the product D,L-naproxen.

[0012] By putting 6-methoxy-2-propionylnaphthalene, diol and copper halide into the reaction system at the same time, and carrying out reflux reaction in a water-insoluble organic solvent with a boiling point higher than 100°C, the water generated during the reaction is refluxed and separated and removed, so that the halogenation and ketal reaction can be completed directly under the reflux condition in a "one-pot method" without using a low-boiling point alcohol solvent for the halogenation reaction. After the reaction is carried out until no water is generated, that is, after no water can be separated (equivalent to separating and removing all the water), it is indicated that the early halogenation and ketal reaction are basically completed, and it is only necessary to reduce the temperature of the reaction system to 80°C to 100°C, without separating the ketal, and directly adopt the "one-pot method" The continuous downward reaction avoids the complicated operation of the separation process. At the same time, in the subsequent heat preservation reaction process, the reaction is not carried out in a reflux state, and no separation operation and temperature reduction treatment are performed. The small amount of acid generated in the system during the previous reaction process can be better kept in the heat preservation reaction system to avoid the small amount of acid generated from being lost too quickly in the subsequent reaction. The subsequent reaction can be effectively heat-insulated under weakly acidic conditions without adding rearrangement catalysts such as zinc oxide and zinc acetate, that is, the rearrangement can be effectively achieved to form a rearrangement intermediate esterification product, so that the intermediate ketal (2-chloro-1-(6-methoxy-2-naphthyl) The propan-1-one ketal) is fully converted into a rearrangement product, which is equivalent to reducing the separation link of halogenation and ketal, and avoiding the generation of biochemical difficult-to-treat wastewater such as p-toluenesulfonic acid and zinc ion wastewater in the ketal rearrangement link, and no additional rearrangement catalyst is required, which reduces pollution to the environment, has the advantages of being environmentally friendly, and is more convenient to operate. Without adding a rearrangement catalyst, the reaction system is kept warm at a lower temperature, and the reaction system can be kept under weak acid conditions, so that the reaction can be fully and effectively carried out, and the product yield is high, the yield is more than 79%, and the purity quality can reach more than 99%. It is best to carry out the insulation reaction under the condition of cooling to 80°C to 95°C in the above step A.

[0013] The intermediate esterification product of the above rearrangement reaction is the corresponding esterification product obtained, and its structural formula is as follows:

[0014]

[0015] Where R corresponds to the R group in the diol (HOROH), and X corresponds to the halogen atom in the copper halide.

[0016] In the above-mentioned preparation method of D, L-naproxen, since a small amount of acid will be generated during the reflux reaction, the present invention is used to treat in one pot, and the insulation of the reflux reaction and the insulation reaction is improved, so that the reaction system can be carried out in a weak acid environment, and the copper ions of the copper halide will produce cuprous ions during the previous reaction, which can promote the subsequent rearrangement reaction, so that there is no need to add a rearrangement catalyst such as zinc acetate to ensure that the reaction proceeds in the positive direction, and it also has the advantage of high product yield. Preferably, the pH value of the reaction system is controlled to be 6.0-7.0 during the insulation reaction described in step A. It is best to be more conducive to promoting the rearrangement reaction in a weak acid system with a pH value of less than 7, and because there is a small amount of acid in the reaction system, the weak acidity of the reaction system can be effectively maintained. In order to better maintain the pH value in the insulation reaction system, a small amount of acid can be added as needed to adjust, such as adding hydrochloric acid or hydrobromic acid, etc., and the pH value of the reaction system is preferably 6.0-6.8.

[0017] In the above-mentioned preparation method of D, L-naproxen, preferably, the water content of the reaction system is controlled to be ≤0.5% during the insulation reaction process in step A. The subsequent insulation reaction system is carried out under substantially anhydrous conditions, which can promote the rearrangement reaction. If there is too much water in the reaction system, the rearrangement reaction cannot be carried out effectively, which is not conducive to ensuring the yield and quality of the product. Carrying out the insulation reaction under substantially anhydrous conditions is conducive to further ensuring the yield and quality of the product.

[0018] In the above-mentioned preparation method of D, L-naproxen, the purpose of the non-water-soluble organic solvent with a boiling point higher than 100°C is to make the temperature of the reflux reaction above 100°C, so that the reaction can be promoted so that the chlorination and ketal reactions can be completed under the "one-pot method" conditions, and the water generated in the reaction system can be more effectively taken out and separated under the reflux state. The above-mentioned non-water-soluble organic solvent can be used. The water is separated out under the reflux state through a water separator, which better guarantees the effective progress, and has the advantages of high product yield and less by-products. The above-mentioned non-water-soluble organic solvent is preferably selected from aromatic hydrocarbon solvents, which can better realize that the reaction can be effectively carried out from chlorination, ketal and subsequent rearrangement, and better realize that the three steps can be completed under the "one-pot method" conditions without separation. As preferably, the non-water-soluble organic solvent in step A is selected from toluene or xylene.

[0019] In the above-mentioned preparation method of D,L-naproxen, preferably, the copper halide in step A is selected from copper chloride or copper bromide. The reaction can be effectively carried out, and a small amount of acid such as hydrogen chloride or hydrogen bromide can be produced during the reaction. In this way, the subsequent rearrangement reaction does not need to add a rearrangement catalyst such as zinc oxide or zinc acetate, etc., and can effectively promote the rearrangement reaction, and also has the advantage of high yield.

[0020] In the above-mentioned preparation method of D, L-naproxen, the amount of raw materials can be fed according to the amount of each raw material, and the raw materials can be fed according to the molar equivalent of the reaction, which can more effectively ensure that the raw materials are fully reacted, reduce the waste of raw materials, reduce by-products, and further improve the product yield. Preferably, the molar ratio of 6-methoxy-2-propionyl naphthalene, diol and copper halide in step A is: 1: 1.0 ~ 1.3: 2.0 ~ 2.3. The diol here can be a diol raw material such as ethylene glycol, neopentyl glycol or propylene glycol. The more preferred molar ratio is 1: 1.1 ~ 1.2: 2.1 ~ 2.2.

[0021] In the above-mentioned preparation method of D,L-naproxen, preferably, the alkali metal hydroxide in step B is selected from sodium hydroxide or potassium hydroxide.

[0022] In the above-mentioned preparation method of D,L-naproxen, preferably, the hydrolysis reaction in step B is carried out under reflux conditions, which is conducive to the full progress of the hydrolysis reaction and better conversion into the corresponding product.

[0023] In the above-mentioned preparation method of D, L-naproxen, preferably, the acidification in step B uses hydrochloric acid or an acidic adjustment system with a pH value of 4 to 5. The acidification treatment is performed so that the product is finally converted from a sodium salt of a carboxylic acid to a carboxylic acid-based product D, L-naproxen.

[0024] In the above-mentioned preparation method of D, L-naproxen, after the heat preservation reaction in step A is completed, general post-treatment can be performed. For example, water can be added to the reaction solution for washing treatment, then the reaction solution can be allowed to stand, the water layer can be separated, and the collected organic layer can be distilled to remove the solvent. The obtained residue is the rearranged intermediate esterification product, which is used for the next hydrolysis reaction. Adding the washing treatment here is beneficial to dissolving the copper halide in water, which can be recycled.

[0025] In the above-mentioned preparation method of D, L-naproxen, activated carbon can be added for decolorization before the acidification treatment in step B and after the hydrolysis treatment, which is beneficial to improve the color quality of the product. The amount of activated carbon added can be based on the general decolorization requirements and is not too limited. It is best to select the weight of activated carbon to be within the range of 3% to 12% of the weight of the material to be decolorized.

[0026] In the above-mentioned preparation method of D,L-naproxen, after acidification, the obtained product is subjected to recrystallization treatment, and the recrystallization can be carried out using an alcohol solvent, such as methanol, ethanol, propanol or isopropanol, which is beneficial to improve the quality and purity requirements of the product. It is best to use methanol or ethanol.

[0027] The preparation method of D,L-naproxen of the present invention can be represented by the following chemical reaction formula (the alkaline hydroxide is taken as NaOH as an example):

[0028]

[0029] In summary, compared with the prior art, the present invention has the following advantages:

[0030] 1. The present invention does not require the addition of an additional rearrangement catalyst, reduces environmental pollution, has the advantage of being environmentally friendly, and is more convenient to operate. Without the need to add a rearrangement catalyst, the heat preservation reaction system is reacted at a lowered temperature, and a "one-pot method" is used for the reaction. The reaction system can be kept under weak acid conditions, and has the advantage of a high product yield of more than 79%, and a purity quality of more than 99%.

[0031] 2. The present invention allows the subsequent heat preservation reaction system to be carried out under substantially anhydrous conditions, which can better promote the rearrangement reaction and is beneficial to further ensure the yield and quality of the product. DETAILED DESCRIPTION

[0032] The technical solution of the present invention is further specifically described below through specific embodiments, but the present invention is not limited to these embodiments. Example 1

[0033] In a 500ml clean three-necked flask, add 33g of 6-methoxy-2-propionylnaphthalene, 12g of ethylene glycol, 43.7g of copper chloride and 200ml of toluene, raise the temperature to reflux reaction, and control the temperature at 112℃±3℃ during the reflux reaction. Separate the water generated by the reaction during the reaction. When no more water is generated, continue the reflux reaction for 2 hours. Confirm that the water content of the system is ≤0.5% without separation. Cool the system directly to 90℃~95℃ and keep the temperature for 1 hour. Confirm that the pH value of the heat preservation reaction system is 6.0~6.5 under weak acid conditions, so that the reaction is fully rearranged to obtain the rearrangement intermediate esterification product. The HPLC control of 6-methoxy-2-propionylnaphthalene residue is 0.34%, and the acetal (2-chloro-1-(6-methoxy-2-naphthyl) Propan-1-ketal) basically disappears. After the reaction is completed, 100 ml of water is added for water washing and separation. The copper chloride recovered in the water layer can be used. The collected organic layer is subjected to reduced pressure distillation to remove toluene. 45 g of a 30% by mass sodium hydroxide aqueous solution is added to the residue, and the temperature is raised to reflux conditions for reflux hydrolysis reaction for 3 hours. Then 3 g of activated carbon is added for decolorization treatment for 0.5 hours. The filtrate is filtered and the filtrate is collected. The pH value of the filtrate is adjusted to 4-5 with hydrochloric acid, and then the temperature is raised to 80°C for suction filtration. The filter cake is recrystallized with methanol, filtered, and the filter cake is dried to obtain a product D, L-naproxen with a weight of 28.5 g, a purity of 99.7% detected by HPLC, and a molar yield of 80.2%. The obtained D, L-naproxen product is compared with the standard product of D, L-naproxen to confirm that the method obtains the D, L-naproxen product. Example 2

[0034] In a 500ml clean three-necked flask, add 33g of 6-methoxy-2-propionylnaphthalene, 12.4g of ethylene glycol, 72.5g of copper bromide and 200ml of toluene, raise the temperature to reflux, and reflux reaction at 112℃±3℃. Separate the water generated by the reaction during the reaction. When no more water is generated, continue the reflux reaction for 1 hour. Confirm that the water content of the system is ≤0.5% by the central control. No separation is required. Directly cool the system temperature to 95℃~100℃ and keep the temperature for 2 hours. Confirm that the pH value of the incubation reaction system is 6.0~6.5 under weak acid conditions, so that the reaction is fully rearranged to obtain the rearrangement intermediate esterification product. The HPLC central control 6-methoxy-2-propionylnaphthalene residue is 0.25%, and the acetal (2-chloro-1-(6-methoxy-2-naphthyl) The mixture was washed with 100 ml of water, and copper bromide was recovered from the water layer and used as a separator. The collected organic layer was distilled under reduced pressure to remove toluene. 45 g of a 30% by mass sodium hydroxide aqueous solution was added to the residue, and the mixture was heated to reflux for hydrolysis for 3 h. 3 g of activated carbon was added and the mixture was heated for decolorization for 0.5 h. The mixture was filtered and the filtrate was collected. The pH of the filtrate was adjusted to 4-5 with hydrochloric acid. The filter cake was recrystallized with methanol and filtered. The filter cake was dried to obtain 28.8 g of the dry product D,L-naproxen. The purity was 99.8% and the molar yield was 81.2% according to HPLC. The obtained D,L-naproxen product was compared with the standard product of D,L-naproxen to confirm that the product obtained by this method was D,L-naproxen. Example 3

[0035] In a 500ml clean three-necked flask, add 33g of 6-methoxy-2-propionylnaphthalene, 12g of ethylene glycol, 45.7g of cupric chloride and 200ml of xylene, and heat to reflux reaction. During the reflux reaction, remove the water generated by the reaction; when no more water is generated, continue to reflux for 1 hour. The central control confirms that the water content of the system is ≤0.5%. No separation is required. The system temperature is directly cooled to 90℃~95℃ and kept warm for 1.5 hours. Under the weak acid condition of confirming that the pH value of the warm reaction system is 6.0~6.8, the reaction is fully rearranged to obtain the rearrangement intermediate esterification product. The HPLC central control 6-methoxy-2-propionylnaphthalene residue is 0.22%, and the acetal (2-chloro-1-(6-methoxy-2-naphthyl) The product was washed with 100 ml of water, and the copper chloride was recovered from the water layer and used. The collected organic layer was distilled under reduced pressure to remove toluene. Then, 50 g of a 30% by mass potassium hydroxide aqueous solution was added to the residue, and the temperature was raised to reflux for reflux hydrolysis for 3 h. Then, 3 g of activated carbon was added and the temperature was raised for decolorization for 0.5 h. The filtrate was collected and the pH of the filtrate was adjusted to 4-5 with hydrochloric acid. The filter cake was recrystallized with ethanol, filtered, and dried to obtain 28.2 g of D,L-naproxen. The purity was 99.6% and the molar yield was 79.5% according to HPLC. The obtained D,L-naproxen product was compared with the standard product of D,L-naproxen to confirm that the product obtained by this method was D,L-naproxen. Example 4

[0036] In a 500ml clean three-necked flask, 33g of 6-methoxy-2-propionylnaphthalene, 15.2g of propylene glycol, 47.8g of cupric chloride and 200ml of toluene were added, and the temperature was raised to reflux reaction. The water generated by the reaction was separated during the reaction. When no more water was generated, the reflux reaction was continued for 1 hour. The central control confirmed that the water content of the system was ≤0.5%. No separation was required. The system was directly cooled to 85℃~90℃ for insulation reaction for 1 hour. Under the weak acid condition of confirming that the pH value of the insulation reaction system was 6.0~6.5, the reaction was fully rearranged to obtain the rearrangement intermediate esterification product. The HPLC central control 6-methoxy-2-propionylnaphthalene residue was 0.31%, and the acetal (2-chloro-1-(6-methoxy-2-naphthyl) Propan-1-ketal) basically disappears. After the reaction is completed, 100 ml of water is added for water washing and separation. The copper chloride recovered from the water layer can be used. The collected organic layer is subjected to reduced pressure distillation to remove toluene. 45 g of a 30% by mass sodium hydroxide aqueous solution is added to the residue, and then the temperature is raised to reflux conditions for reflux hydrolysis reaction for 3 hours. Then 3 g of activated carbon is added for decolorization treatment for 0.5 hours. The filtrate is filtered and the filtrate is collected. The pH value of the filtrate is adjusted to 4-5 with hydrochloric acid, and then the temperature is raised to 80°C for suction filtration. The filter cake is recrystallized with methanol and filtered. The filter cake is dried to obtain a product D, L-naproxen with a weight of 28.4 g, a purity of 99.6% detected by HPLC, and a molar yield of 80.2%. The obtained D, L-naproxen product is compared with the standard product of D, L-naproxen to confirm that the method obtains the D, L-naproxen product. Example 5

[0037] In a 500ml clean three-necked flask, 33g of 6-methoxy-2-propionylnaphthalene, 19g of neopentyl glycol, 45.7g of cupric chloride and 200ml of toluene were added, and the temperature was raised to reflux reaction. The water generated by the reaction was separated during the reflux reaction. When no more water was generated, the reflux reaction was continued for 1 hour. The central control confirmed that the water content of the system was ≤0.5%. No separation was required. The system was directly cooled to 80℃~85℃ for insulation reaction for 2 hours. Under the weak acid condition of confirming that the pH value of the insulation reaction system was 6.0~6.5, the reaction was fully rearranged to obtain the rearrangement intermediate esterification product. The HPLC central control 6-methoxy-2-propionylnaphthalene residue was 0.28%, and the acetal (2-chloro-1-(6-methoxy-2-naphthyl) Propan-1-ketone acetal) basically disappears. After the reaction is completed, 150 ml of water is added for water washing and separation. The copper chloride recovered in the water layer can be used. The collected organic layer is subjected to reduced pressure distillation to remove toluene. 45 g of a 30% by mass sodium hydroxide aqueous solution is added to the residue, and then the temperature is raised to reflux conditions for reflux hydrolysis reaction for 3 hours. Then 3 g of activated carbon is added for decolorization treatment for 0.5 hours. The filtrate is filtered and the filtrate is collected. The pH value of the filtrate is adjusted to 4-5 with hydrochloric acid, and then the temperature is raised to 80°C for suction filtration. The filter cake is recrystallized with methanol and filtered. The filter cake is dried to obtain a product D, L-naproxen with a weight of 28.7 g, a purity of 99.7% detected by HPLC, and a molar yield of 80.8%. The obtained D, L-naproxen product is compared with the standard product of D, L-naproxen to confirm that the method obtains the D, L-naproxen product.

[0038] Comparative Example 1

[0039] In order to illustrate the effect of lowering the temperature of the reaction system on the rearrangement reaction after no water is generated during the reflux reaction of the present invention, this comparative example directly adopts the method of controlling the reflux temperature for confirmation.

[0040] In a 500ml clean three-necked flask, 33g of 6-methoxy-2-propionylnaphthalene, 12g of ethylene glycol, 43.7g of cupric chloride and 200ml of toluene were added. The temperature was raised to reflux reaction. During the reflux reaction, the temperature was controlled at 112℃±3℃ for reflux reaction. The water generated by the reaction was separated during the reaction. When no more water was generated, the reflux reaction could be continued for 2 hours. The central control confirmed that the water content of the system was ≤0.5%. The temperature was not lowered and the reaction was continued under reflux for 1 hour to obtain a rearrangement intermediate. However, the residual 6-methoxy-2-propionylnaphthalene was 0.37% according to the central control of HPLC, but the content of ketal (2-chloro-1-(6-methoxy-2-naphthyl) propan-1-one ketal) was as high as 20.6%. The reaction was continued under reflux for another hour. The central control of HPLC found that the ketal had basically no change, indicating that the rearrangement reaction here was basically no longer proceeding. The reaction was terminated and no subsequent treatment was performed. This also shows that if the reflux state is used throughout the reaction, it is not conducive to the rearrangement reaction.

[0041] The specific embodiments described in the present invention are merely examples of the spirit of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the attached claims.

[0042] Although the present invention has been described in detail and some specific embodiments have been cited, it is obvious to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention.

Claims

1. A method for preparing D,L-naproxen, characterized in that: The method comprises the following steps: A. Adding 6-methoxy-2-propionylnaphthalene, diol and copper halide to a water-insoluble organic solvent having a boiling point higher than 100° C. and performing a reflux reaction under reflux conditions, separating the water produced by the reaction during the reflux reaction, reacting until no water is produced, cooling to 80° C. to 100° C. for heat preservation reaction to obtain a rearrangement reaction intermediate esterification product; during the heat preservation reaction, controlling the pH value of the reaction system to be 6.0 to 7.0; during the heat preservation reaction, controlling the water content of the reaction system to be ≤0.5%; the water-insoluble organic solvent is selected from toluene or xylene; and the copper halide is selected from copper chloride or copper bromide; B. The obtained rearrangement reaction intermediate ester is subjected to a hydrolysis reaction under the action of an aqueous solution of an alkali metal hydroxide, and then acidified to obtain the product D, L-naproxen; the alkali metal hydroxide is selected from sodium hydroxide or potassium hydroxide; the hydrolysis reaction is carried out under reflux conditions; the acidification uses hydrochloric acid or sulfuric acid to adjust the pH value of the system to 4-5.

2. The method for preparing D,L-naproxen according to claim 1, characterized in that: The molar ratio of 6-methoxy-2-propionylnaphthalene, diol and copper halide in step A is 1:1.0-1.3:2.0-2.3.

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