Improved gemfibrozil preparation method

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to an improved gemfibrozil preparation method which comprises the following preparation steps: S1, preparing 2, 5-xylenol sodium salt; s2, preparing a gemfibrozil crude product; according to the improved gemfibrozil preparation method provided by the invention, the use of a harmful solvent, a phase transfer catalyst and the like is avoided, and the process flow and the reaction conditions are optimized, so that the reaction efficiency is remarkably improved, and the yield and the purity of the prepared gemfibrozil are improved. The operation is simple, and industrial production is facilitated.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to an improved preparation method of gemfibrozil. Background Art

[0002] Gemfibrozil, chemical name is 2,2-dimethyl-5-(2,5-dimethylphenyloxy)-pentanoic acid, English name is 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, the structural formula is as follows:

[0003]

[0004] There are two main methods for preparing Gemfibrozil:

[0005] One is to react xylenol with bromochloropropane or dibromopropane and then synthesize gemfibrozil with butyric acid fragment. This route is costly, causes serious environmental pollution, is dangerous to operate, and is not easy to industrialize.

[0006] The other is halobaleric acid and its derivative fragments, which are then combined with xylenol to synthesize gemfibrozil;

[0007] This method is widely used in industry, and literature reports that it needs to use highly toxic solvent toluene or DMF which is not easy to recycle and causes pollution for synthesis, which is easy to cause environmental pollution. After the reaction is completed, there is likely to be residual 2,5-dimethylphenol, about 1.0%. The post-treatment process mostly requires high-temperature distillation to remove the remaining dimethylphenol and a small amount of colored impurities derived from it, and gemfibrozil dimethylphenol ester impurities are easily produced at high temperatures.

[0008] Among them, U.S. Patent No. 4665226A discloses that 2,5-dimethylphenol is first prepared into sodium phenolate in a mixture of toluene and DMSO, and then condensed with 2,2-dimethyl-5-chloro-valeric acid isobutyl ester under the catalysis of sodium iodide, and then directly added with alkali for hydrolysis to obtain gemfibrozil. The reaction process uses toluene and DMSO as solvents, and azeotropic dehydration is required in the preparation of sodium phenolate, which is complicated to operate, and toluene and DMSO are not easy to recover, which is easy to cause environmental pollution.

[0009] U.S. Patent No. 5654476A discloses that 5-bromo-2,2-dimethyl methyl pentanoate and 2,5-dimethylphenol are condensed in the presence of potassium carbonate and under the action of a phase transfer catalyst, and the condensation product is extracted with methanol, and then hydrolyzed in methanol to obtain gemfibrozil sodium salt, and then acidified with hydrochloric acid to obtain the target product. In the reaction process, 5-bromo-2,2-dimethyl methyl pentanoate needs to be added in batches at high temperature, which is not easy to operate. The reaction temperature is high, 103-115°C, and after the reaction is completed, the reaction liquid is dark in color, and the color of the final product is difficult to remove. Moreover, the reaction effect is poor and the yield is low, only 69.1%.

[0010] European Patent EP0575303 also adopts a similar method to prepare Gemfibrozil. The reaction is carried out in toluene under the catalysis of tetrabutylammonium bromide. Tetrabutylammonium bromide is not easy to recover, and toluene is easy to cause environmental pollution. Summary of the invention

[0011] In order to solve the problems existing in the prior art, the object of the present invention is to provide an improved method for preparing gemfibrozil. The technical solution of the present invention is:

[0012] An improved method for preparing gemfibrozil comprises the following steps:

[0013] S1. Preparation of 2,5-dimethylphenol sodium salt:

[0014] Mix 2,5-xylenol and a solvent, add solid sodium hydroxide under stirring, stir until solid precipitates, then cool, filter, and dry to obtain 2,5-xylenol sodium salt;

[0015] S2. Preparation of Gemfibrozil crude product:

[0016] The 2,5-dimethylphenol sodium salt obtained in step S1 is crushed and sieved, 5-chloro-2,2-dimethylvaleric acid isobutyl ester is added, and the mixture is heated and stirred for reaction. After the reaction is completed, the mixture is cooled to room temperature, filtered, and unreacted 5-chloro-2,2-dimethylvaleric acid isobutyl ester is distilled out under vacuum; after no fraction flows out, sodium hydroxide solution is added to the reaction system, and the mixture is heated to reflux. After the reaction is completed, extraction is performed, and then the pH value is adjusted, and the mixture is separated after stirring. The organic phase is cooled, crystallized, and filtered to obtain a crude product of gemfibrozil;

[0017] S3. Refining of Gemfibrozil:

[0018] A methanol aqueous solution is added to the crude gemfibrozil obtained in step S2, and the mixture is heated until dissolved, and then cooled for crystallization, filtered, and dried to obtain the refined gemfibrozil.

[0019] Furthermore, the solvent in step S1 is one or a combination of methanol, ethanol or isopropanol, preferably methanol, and the amount of the solvent added is 3-8 times the weight of 2,5-dimethylphenol, preferably 5 times.

[0020] Furthermore, in step S1, the molar ratio of 2,5-dimethylphenol to sodium hydroxide solid is 1:1-1.5, preferably 1:1.2-1.3.

[0021] Furthermore, in the step S1, after adding sodium hydroxide solid, stirring is carried out for 30-40 minutes, and solid is gradually precipitated during the stirring process, and then the temperature is cooled to 0-5°C, filtered, and the filter cake is vacuum dried at 40°C for 4-5 hours.

[0022] Furthermore, the 2,5-dimethylphenol sodium salt in step S2 is crushed and then passed through a 100-200 mesh sieve, preferably a 150-200 mesh sieve.

[0023] Furthermore, in step S2, the amount of 5-chloro-2,2-dimethylvalerate isobutyl ester added is 3-8 times, preferably 5 times, the weight of 2,5-dimethylphenol sodium salt.

[0024] Furthermore, after adding 5-chloro-2,2-dimethylvalerate isobutyl ester in step S2, the stirring speed is 70-90 r / min, preferably 80 r / min, the reaction temperature is 80-100° C., preferably 80-90° C., and the reaction time is 4-8 h.

[0025] Furthermore, the unreacted 5-chloro-2,2-dimethylvaleric acid isobutyl ester distilled out by vacuum decompression in step S2 can be reused after being tested and found to meet the standards.

[0026] Furthermore, the concentration of the sodium hydroxide solution added in step S2 is 20-30%, and the amount of the sodium hydroxide solution added is 3-5 times the weight of 2,5-dimethylphenol sodium salt, preferably 3 times.

[0027] Furthermore, the reaction time of heating under reflux in step S2 is 4-5 hours, then n-butane is added for extraction, followed by adjusting the pH to 2-3 with hydrochloric acid, cooling to 0-5°C for crystallization for 1-2 hours, and filtering to obtain a crude product of Gemfibrozil.

[0028] Furthermore, the mass concentration of the methanol aqueous solution in step S3 is 45-55%, preferably 50%, and the amount of the methanol aqueous solution added is 5 times the weight of the crude gemfibrozil. The crude gemfibrozil is heated to 60°C until it is completely dissolved, then cooled to 0-5°C for crystallization for 1-2h, filtered, and dried to obtain refined gemfibrozil.

[0029] The improved preparation method of Gemfibrozil provided by the present invention avoids the use of harmful organic solvents such as toluene or DMSO, as well as phase transfer catalysts (such as tetrabutylammonium bromide) and other catalysts (such as sodium iodide) that may cause environmental problems, and instead adopts a more environmentally friendly and efficient new approach. The present invention adopts a 2,5-dimethylphenol sodium solid with a particle size of 100-200 mesh and a chloride to react, so that the two-phase reaction is more efficient and thorough. The use of 2,5-dimethylphenol sodium salt with a special particle size and an excess of chloride to react significantly improves the contact frequency and reaction rate between the reactants, ensures that the 2,5-dimethylphenol sodium solid is completely reacted, reduces the unreacted raw material residue, improves the yield and purity of the product, and effectively reduces the emission of harmful substances. After the reaction is completed, there is almost no 2,5-dimethylphenol remaining in the Gemfibrozil product finally obtained (the content is less than 0.05%), which is greatly reduced compared to the approximately 0.5% residue in the traditional process.

[0030] In addition, the use of other solvents and catalysts is avoided in the reaction, which not only simplifies the reaction system and reduces production costs, but also avoids side reactions and impurity generation that may be caused by the catalyst.

[0031] Secondly, this technology controls the reaction temperature within a more moderate range of 80-90°C by finely regulating the reaction conditions. Compared with high-temperature reactions, it can effectively reduce energy consumption, improve reaction efficiency, and improve the yield and purity of the product. In addition, the 5-chloro-2,2-dimethylvaleric acid isobutyl ester in the reaction can be recovered and reused by vacuum distillation, which not only reduces production costs but also conforms to the concept of sustainable development. Finally, in the product refining process, the present invention uses methanol aqueous solution for recrystallization refining, which can make the purity of the obtained product reach more than 99.9%.

[0032] Compared with the prior art, the improved method for preparing gemfibrozil provided by the present invention has the following advantages:

[0033] The improved preparation method of Gemfibrozil provided by the present invention avoids the use of harmful solvents, phase transfer catalysts, etc., and significantly improves the reaction efficiency by optimizing the process flow and reaction conditions, thereby improving the yield and purity of the prepared Gemfibrozil. The operation is simple and convenient, and it is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The HPLC spectrum of Gemfibrozil prepared in Example 1 of the present invention;

[0035] Figure 2 The HPLC spectrum of Gemfibrozil prepared in Comparative Example 3 of the present invention. DETAILED DESCRIPTION

[0036] The present invention is further illustrated below through the description of specific implementation methods, but this is not a limitation of the present invention. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not deviate from the basic idea of ​​the present invention, they are all within the protection scope of the present invention.

[0037] In the following examples and comparative examples, reagents not otherwise specified are conventional reagents and can be purchased from conventional reagent production and sales companies. The methods used are all prior art unless otherwise specified.

[0038] Example 1

[0039] An improved method for preparing gemfibrozil comprises the following steps:

[0040] S1. Preparation of 2,5-dimethylphenol sodium salt:

[0041] In a three-necked flask, add 100g 2,5-dimethylphenol and 300g ethanol, add 32.7g (1 times the molar amount of 2,5-dimethylphenol) of sodium hydroxide solid under stirring, stir for 30min, solid gradually precipitates during stirring, cool to 0-5°C, filter, and dry the filter cake under vacuum at 40°C for 4h to obtain 117.6g, with a yield of 99.66%;

[0042] S2. Preparation of Gemfibrozil Crude Product

[0043] In a three-necked flask, add 100g of 2,5-dimethylphenol sodium salt that has been crushed and passed through a 100-mesh screen, add 300g of 5-chloro-2,2-dimethylvaleric acid isobutyl ester, stir, heat to 90°C, react for 6h, and monitor the reaction progress by TLC. After the reaction is completed, cool to room temperature and filter, open vacuum and reduce pressure to distill out the unreacted 5-chloro-2,2-dimethylvaleric acid isobutyl ester, after the distillation is completed, add 400g of 30% sodium hydroxide solution to the reaction solution, heat to 100°C, reflux for 5h, monitor the reaction progress by TLC, after the reaction is completed, add 300g of n-hexane to the reaction solution, adjust the pH value to 2-3 with hydrochloric acid, stir and separate, cool the organic phase to 0-5°C, crystallize for 2h, filter and dry to obtain 171.75g ​​of crude gemfibrozil with a yield of 98.90%;

[0044] S3. Refining of Gemfibrozil:

[0045] Add 170g of crude gemfibrozil into a three-necked reaction flask, add 850g of 45% methanol aqueous solution, heat to 60°C until all the solids are dissolved, cool to 0-5°C for crystallization for 2h, filter and dry to obtain 164.85g of gemfibrozil, with a refined yield of 96.97%, a total yield of 95.57% and a purity of 99.971%.

[0046] Example 2

[0047] An improved method for preparing gemfibrozil comprises the following steps:

[0048] S1. Preparation of 2,5-dimethylphenol sodium salt:

[0049] In a three-necked flask, add 100g 2,5-dimethylphenol and 500g methanol, add 39.3g (1.2 times the molar amount of 2,5-dimethylphenol) of sodium hydroxide solid under stirring, stir for 35min, solid gradually precipitates during stirring, cool to 0-5℃, filter, and dry the filter cake in vacuum at 40℃ for 4.5h to obtain 117.8g, with a yield of 99.83%;

[0050] S2. Preparation of Gemfibrozil crude product:

[0051] In a three-necked flask, add 100g of 2,5-dimethylphenol sodium salt that has been crushed and passed through a 150-mesh screen, add 500g of 5-chloro-2,2-dimethylvaleric acid isobutyl ester, stir, heat to 80°C, react for 7h, and monitor the reaction progress by TLC. After the reaction is completed, cool to room temperature and filter, and distill out the unreacted 5-chloro-2,2-dimethylvaleric acid isobutyl ester by vacuum decompression. After the distillation is completed, add 300g of 20% sodium hydroxide solution to the reaction solution, heat to 100°C, reflux for 5h, and monitor the reaction progress by TLC. After the reaction is completed, adjust the pH value to 2-3 with hydrochloric acid, stir and separate the liquids, cool the organic phase to 0-5°C, and crystallize for 2h.

[0052] Filter and dry to obtain 171.85 g of crude gemfibrozil with a yield of 98.96%;

[0053] S3. Refining of Gemfibrozil:

[0054] Add 170g of crude gemfibrozil into a three-necked reaction flask, add 850g of 50% methanol aqueous solution, heat to 60°C until all the solids are dissolved, cool to 0-5°C for crystallization for 2h, filter and dry to obtain 165.21g of gemfibrozil, with a refined yield of 97.18%, a total yield of 96.01% and a purity of 99.972%.

[0055] Example 3

[0056] An improved method for preparing gemfibrozil comprises the following steps:

[0057] S1. Preparation of 2,5-dimethylphenol sodium salt,

[0058] In a three-necked flask, add 100g of 2,5-dimethylphenol and 800g of isopropanol, add 49.1g (1.5 times the molar amount of 2,5-dimethylphenol) of sodium hydroxide solid while stirring, stir for 30min, solid gradually precipitates during the stirring process, cool to 0-5°C, filter, and dry the filter cake in vacuum at 40°C for 5h to obtain 117.3g, with a yield of 99.41%;

[0059] S2. Preparation of Gemfibrozil crude product:

[0060] In a three-necked flask, add 100g of 2,5-dimethylphenol sodium salt that has been crushed and passed through a 200-mesh screen, add 800g of 5-chloro-2,2-dimethylvaleric acid isobutyl ester, stir, heat to 100°C, react for 4h, monitor the reaction progress by TLC, after the reaction is completed, cool to room temperature and filter, open vacuum and reduce pressure to distill out the unreacted 5-chloro-2,2-dimethylvaleric acid isobutyl ester, after the distillation is completed, add 500g of 20% sodium hydroxide solution to the reaction solution, heat to 100°C, reflux for 4h, monitor the reaction progress by TLC, after the reaction is completed, add 300g of n-hexane to the reaction solution, adjust the pH value to 2-3 with hydrochloric acid, stir and separate, cool the organic phase to 0-5°C, crystallize for 1h, filter and dry to obtain 171.73g of crude gemfibrozil with a yield of 98.89%;

[0061] S3. Refining of Gemfibrozil:

[0062] Add 170g of crude gemfibrozil into a three-necked reaction flask, add 850g of 55% methanol aqueous solution, heat to 60°C until all the solids are dissolved, cool to 0-5°C for crystallization for 1h, filter and dry to obtain 165.18g of gemfibrozil, with a refined yield of 97.16%, a total yield of 95.92% and a purity of 99.974%.

[0063] Comparative Example 1

[0064] Compared with Example 2, the difference is that the 2,5-dimethylphenol sodium salt added in step S2 is not crushed, and other parameters and operations are the same as those in Example 2.

[0065] The specific preparation method of Gemfibrozil comprises the following preparation steps:

[0066] S1. Preparation of 2,5-dimethylphenol sodium salt:

[0067] In a three-necked flask, add 100g 2,5-dimethylphenol and 500g methanol, add 39.3g (1.2 times the molar amount of 2,5-dimethylphenol) of sodium hydroxide solid under stirring, stir for 35min, solid gradually precipitates during stirring, cool to 0-5℃, filter, and dry the filter cake under vacuum at 40℃ for 4.5h to obtain 117.7g, with a yield of 99.75%;

[0068] S2. Preparation of Gemfibrozil crude product:

[0069] In a three-necked flask, add 100g of uncrushed 2,5-dimethylphenol sodium salt, add 500g of 5-chloro-2,2-dimethylvaleric acid isobutyl ester, stir, heat to 80°C, react for 7h, and monitor the reaction progress by TLC. After the reaction is completed, cool to room temperature and filter, open vacuum and reduce pressure to distill out the unreacted 5-chloro-2,2-dimethylvaleric acid isobutyl ester. After the distillation is completed, add 300g of 20% sodium hydroxide solution to the reaction solution, heat to 100°C, reflux for 5h, monitor the reaction progress by TLC, and after the reaction is completed, adjust the pH value to 2-3 with hydrochloric acid, stir and separate, cool the organic phase to 0-5°C, crystallize for 2h, filter and dry to obtain 160.75g of crude gemfibrozil with a yield of 92.57%;

[0070] S3. Refining of Gemfibrozil:

[0071] Add 160g of crude gemfibrozil into a three-necked reaction flask, add 800g of 50% methanol aqueous solution, heat to 60°C until all the solids are dissolved, cool to 0-5°C for crystallization for 2h, filter and dry to obtain 156.24g of gemfibrozil, with a refined yield of 97.65%, a total yield of 90.17% and a purity of 99.956%.

[0072] Comparative Example 2

[0073] Compared with Example 2, the difference is that the 2,5-dimethylphenol sodium salt used in step S2 is crushed and passed through a 250-mesh sieve, and other parameters and operations are the same as those in Example 2.

[0074] The specific preparation method of Gemfibrozil comprises the following preparation steps:

[0075] S1. Preparation of 2,5-dimethylphenol sodium salt,

[0076] In a three-necked flask, add 100g 2,5-dimethylphenol and 500g methanol, add 39.3g (1.2 times the molar amount of 2,5-dimethylphenol) of sodium hydroxide solid under stirring, stir for 35min, solid gradually precipitates during stirring, cool to 0-5℃, filter, and dry the filter cake in vacuum at 40℃ for 4.5h to obtain 117.5g, with a yield of 99.56%;

[0077] S2. Preparation of Gemfibrozil crude product:

[0078] In a three-necked flask, add 100g of 2,5-dimethylphenol sodium salt that has been crushed and passed through a 250-mesh screen, add 500g of 5-chloro-2,2-dimethylvaleric acid isobutyl ester, stir, heat to 80°C, react for 7h, and monitor the reaction progress by TLC. After the reaction is completed, cool to room temperature and filter, open vacuum and reduce pressure to distill out the unreacted 5-chloro-2,2-dimethylvaleric acid isobutyl ester, after the distillation is completed, add 300g of 20% sodium hydroxide solution to the reaction solution, heat to 100°C, reflux for 5h, monitor the reaction progress by TLC, after the reaction is completed, adjust the pH value to 2-3 with hydrochloric acid, stir and separate, cool the organic phase to 0-5°C, crystallize for 2h, filter and dry to obtain 171.52g of crude gemfibrozil with a yield of 98.77%;

[0079] S3. Refining of Gemfibrozil:

[0080] Add 170g of crude gemfibrozil into a three-necked reaction flask, add 850g of 50% methanol aqueous solution, heat to 60°C until all the solids are dissolved, cool to 0-5°C for crystallization for 1-2h, filter and dry to obtain 164.88g of gemfibrozil, with a refined yield of 96.99%, a total yield of 95.56% and a purity of 99.952%.

[0081] Comparative Example 3

[0082] Compared with Example 2, the difference is that the reaction temperature of 2,5-dimethylphenol sodium salt and 5-chloro-2,2-dimethylvaleric acid isobutyl ester in step S2 is 110° C., and other parameters and operations are the same as those in Example 2.

[0083] The specific preparation method of Gemfibrozil comprises the following preparation steps:

[0084] S1. Preparation of 2,5-dimethylphenol sodium salt:

[0085] In a three-necked flask, add 100g 2,5-dimethylphenol and 500g methanol, add 39.3g (1.2 times the molar amount of 2,5-dimethylphenol) of sodium hydroxide solid under stirring, stir for 35min, solid gradually precipitates during stirring, cool to 0-5℃, filter, and dry the filter cake in vacuum at 40℃ for 4.5h to obtain 117.4g, with a yield of 99.49%;

[0086] S2. Preparation of Gemfibrozil crude product:

[0087] In a three-necked flask, add 100g of 2,5-dimethylphenol sodium salt that has been crushed and passed through a 150-mesh screen, add 500g of 5-chloro-2,2-dimethylvaleric acid isobutyl ester, stir, heat to 110°C, react for 7h, and monitor the reaction progress by TLC. After the reaction is completed, cool to room temperature and filter, open vacuum and reduce pressure to distill out the unreacted 5-chloro-2,2-dimethylvaleric acid isobutyl ester. After the distillation is completed, add 300g of 20% sodium hydroxide solution to the reaction solution, heat to 100°C, reflux for 5h, and monitor the reaction progress by TLC. After the reaction is completed, adjust the pH value to 2-3 with hydrochloric acid, stir and separate, cool the organic phase to 0-5°C, crystallize for 2h, filter and dry to obtain 169.84g of crude gemfibrozil with a yield of 97.8%;

[0088] S3. Refining of Gemfibrozil:

[0089] Add 169 g of crude gemfibrozil into a three-necked reaction flask, add 845 g of 50% methanol aqueous solution, heat to 60°C until all the solids are dissolved, cool to 0-5°C for crystallization for 2 h, filter and dry to obtain 163.9 g of gemfibrozil, with a refined yield of 96.98%, a total yield of 94.36% and a purity of 99.971%.

[0090] Comparative Example 4

[0091] Comparative Example 4 adopts the preparation method of Gemfibrozil disclosed in U.S. Pat. No. 4,665,226A, and the specific preparation steps are as follows:

[0092] Add 22.0g 2,5-dimethylphenol to a three-necked reaction bottle, add 135ml toluene, add 18ml dimethyl sulfoxide, add 7.8g sodium hydroxide, reflux the mixture to react, reflux to remove water until no water is produced, add 2.8g sodium iodide, add 41.3g chloride, reflux for 13 hours, then add 14.0g sodium hydroxide, continue heating for 4 hours, distill toluene, then add 90mL water and 30mL n-hexane, separate the liquids, discard the organic layer, acidify the aqueous layer with hydrochloric acid to a pH of 2-3, crystallize at 0-5℃ for 1-2 hours, filter and dry to obtain 42.5g of crude gemfibrozil, then refine with 212.5g 50% methanol water, and dry to obtain 41.5g of gemfibrozil, with a total yield of 92.05% and a purity of 99.225%.

[0093] Test Example 1. Detection of the total yield, refined yield and purity of Gemfibrozil prepared by the present invention

[0094] The gemfibrozil prepared in Examples 1-4 of the present invention and Comparative Examples 1-4 was tested by high performance liquid chromatography (HPLC), and the purity (%) and the residual content (%) of 2,5-dimethylphenol were recorded.

[0095] Table 1

[0096] Group Total yield (%) 2,5-Dimethylphenol Residue (%) purity(%) Example 1 95.57 Not detected 99.971 Example 2 96.01 Not detected 99.972 Example 3 95.92 Not detected 99.974 Comparative Example 1 90.17 Not detected 99.956 Comparative Example 2 95.56 Not detected 99.952 Comparative Example 3 94.36 Not detected 99.971 Comparative Example 4 92.05 0.451 99.225

[0097] As shown in Table 1, the total yield of gemfibrozil prepared by the methods of Examples 1-4 of the present invention is above 95%, which can effectively improve the utilization rate of raw materials and the yield of products, and the purity can reach above 99.9%, and no 2,5-dimethylphenol remains.

[0098] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. An improved method for preparing gemfibrozil, characterized in that: The method comprises the following preparation steps: S1. Preparation of 2,5-dimethylphenol sodium salt: Mix 2,5-xylenol and a solvent, add solid sodium hydroxide under stirring, stir until solid precipitates, then cool, filter, and dry to obtain 2,5-xylenol sodium salt; S2. Preparation of Gemfibrozil crude product: The 2,5-dimethylphenol sodium salt obtained in step S1 is crushed and sieved, 5-chloro-2,2-dimethylvaleric acid isobutyl ester is added, and the mixture is heated and stirred for reaction. After the reaction is completed, the mixture is cooled to room temperature, filtered, and unreacted 5-chloro-2,2-dimethylvaleric acid isobutyl ester is distilled out under vacuum; after no fraction flows out, sodium hydroxide solution is added to the reaction system, and the mixture is heated to reflux. After the reaction is completed, extraction is performed, and then the pH value is adjusted, and the mixture is separated after stirring. The organic phase is cooled, crystallized, and filtered to obtain a crude product of gemfibrozil; S3, Gemfibrozil Refining: A methanol aqueous solution is added to the crude gemfibrozil obtained in step S2, and the mixture is heated until dissolved, and then cooled for crystallization, filtered, and dried to obtain the refined gemfibrozil.

2. The improved method for preparing gemfibrozil according to claim 1, wherein The solvent in step S1 is methanol, ethanol or isopropanol or a combination of the two, and the amount of the solvent added is 3-8 times the weight of 2,5-dimethylphenol.

3. The improved method for preparing gemfibrozil according to claim 1, characterized in that: In the step S1, the molar ratio of 2,5-dimethylphenol to sodium hydroxide solid is 1:1-1.

5.

4. The improved method for preparing Gemfibrozil according to claim 1, characterized in that: In the step S1, after adding sodium hydroxide solid, stirring is carried out for 30-40 minutes, and solid is gradually precipitated during the stirring process, and then the temperature is lowered to 0-5° C., filtered, and the filter cake is vacuum dried at 40° C. for 4-5 hours.

5. The improved method for preparing Gemfibrozil according to claim 1, characterized in that: In the step S2, the 2,5-dimethylphenol sodium salt is crushed and then passed through a 100-200 mesh sieve.

6. The improved method for preparing Gemfibrozil according to claim 1, characterized in that: In the step S2, the amount of 5-chloro-2,2-dimethylvalerate isobutyl ester added is 3-8 times the weight of 2,5-dimethylphenol sodium salt.

7. The improved method for preparing Gemfibrozil according to claim 1, characterized in that: In the step S2, after adding 5-chloro-2,2-dimethylvaleric acid isobutyl ester, the stirring speed is 70-90 r / min, the reaction temperature is 80-100° C., and the reaction time is 4-8 h.

8. The improved method for preparing Gemfibrozil according to claim 1, characterized in that: The concentration of the sodium hydroxide solution added in step S2 is 20-30%, and the amount of the sodium hydroxide solution added is 3-5 times the weight of 2,5-dimethylphenol sodium salt.

9. The improved method for preparing Gemfibrozil according to claim 1, characterized in that: The reaction time of heating under reflux in step S2 is 4-5 hours, then n-butane is added for extraction, followed by adjusting the pH to 2-3 with hydrochloric acid, cooling to 0-5° C. for crystallization for 1-2 hours, and filtering to obtain a crude product of Gemfibrozil.

10. The improved method for preparing Gemfibrozil according to claim 1, characterized in that: The methanol aqueous solution in step S3 has a mass concentration of 45-55%, is heated to 60° C. until the crude gemfibrozil is completely dissolved, then cooled to 0-5° C. for crystallization for 1-2 hours, filtered, and dried to obtain refined gemfibrozil.

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