Improved gemfibrozil intermediate preparation method

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to an improved gemfibrozil intermediate preparation method which comprises the following steps: S1, adding metal lithium and diisopropylamine into an organic solvent, cooling to 0-5 DEG C, adding a catalyst, carrying out ultrasonic-assisted reaction, heating to 8 DEG C, and continuing ultrasonic treatment; and S2, after the reaction of the metal lithium in the step S1 is finished, controlling the system temperature, then slowly dropwise adding isobutyl isobutyrate, carrying out heat-preservation stirring, dropwise adding 1, 3-bromochloropropane or 1, 3-dibromopropane, carrying out a heat-preservation reaction after the dropwise adding is finished, carrying out a quenching reaction after the reaction is finished, carrying out liquid separation, washing with water, carrying out reduced pressure distillation on an organic phase, and collecting fractions, thereby obtaining the product. According to the preparation method provided by the invention, by optimizing reaction conditions and a post-treatment process, the process flow is simplified, the generation of byproducts and impurities is effectively reduced, the final product is ensured to be high in purity and few in impurities, and the yield is high and can reach 95% or above.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to an improved preparation method of a gemfibrozil intermediate. 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] Gemfibrozil is a clofibric acid lipid regulating drug, mainly used as a lipid regulating drug. It mainly activates peroxisome proliferator-activated receptor α (PPARα) and PPARγ, reduces the synthesis of very low-density lipoprotein cholesterol (VLDL-C), increases lipoprotein esterase activity, promotes the decomposition of VLDL-C, inhibits the decomposition of high-density lipoprotein cholesterol (HDL-C), and increases the synthesis of apolipoprotein Al and apolipoprotein A2, thereby increasing the HDL-C content, thereby reducing triglyceride and low-density lipoprotein cholesterol (LDL-C) levels.

[0005] The existing preparation method of Gemfibrozil mainly comprises the following steps: synthesizing Gemfibrozil from halovaleric acid and its derivative fragments with dimethylphenol; this method is widely used in industry. The synthesis of Gemfibrozil's important intermediates 5-chloro-2,2-dimethyl-isobutyl valerate and 5-bromo-2,2-dimethyl-isobutyl valerate mainly uses lithium diisopropylamide as a raw material, reacts with isobutyl isobutyrate, and then reacts with 1,3-bromochloropropane or 1,3-dibromopropane to obtain the obtained products.

[0006] U.S. Patent No. 5,654,476 discloses the catalytic reaction of lithium diisopropylamide with styrene to obtain 5-bromo-2,2-dimethylvalerate. However, the reaction produces by-products such as ethylbenzene, 1,3-diphenylbutane and 1,4-diphenylbutane. These impurities will be introduced into the crude product during the synthesis of gemfibrozil, causing certain difficulties for the subsequent refined production.

[0007] Chinese patent application CN112592275A discloses a method for preparing 5-chloro-2,2-dimethylisobutyl valerate, which includes heat exchange treatment and reaction between phase A and phase B, successively adding isobutyl isobutyrate phase C, 1,3-bromochloropropane phase D, and dilute hydrochloric acid phase E for reaction, quenching in a quenching module, and post-processing to obtain 5-chloro-2,2-dimethylisobutyl valerate. It is mentioned that n-butyl lithium is used instead of metallic lithium. Although microchannel reaction can be achieved, n-butyl lithium will not react completely when n-butyl lithium reacts with isobutyl isobutyrate. The impurity chlorooctane (with a boiling point of 181.5°C) produced by the reaction of n-butyl lithium and 1,3-bromochloropropane requires higher distillation conditions to completely remove it.

[0008] Therefore, it is necessary to provide a method for preparing a gemfibrozil intermediate with a simple process to obtain a product with less impurities, high purity and high yield. Summary of the invention

[0009] 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 a gemfibrozil intermediate. The technical solution of the present invention is:

[0010] An improved method for preparing a gemfibrozil intermediate, wherein the gemfibrozil intermediate is 5-chloro-2,2-dimethylvaleric acid isobutyl ester or 5-bromo-2,2-dimethylvaleric acid isobutyl ester, specifically comprising the following preparation steps:

[0011] S1. Add metallic lithium and diisopropylamine to an organic solvent, then cool to 0-5°C, add a catalyst, perform an ultrasonic-assisted reaction, heat to 8°C, and continue ultrasonic treatment;

[0012] S2. After the reaction of the metallic lithium in step S1 is completed, the system temperature is controlled, and then isobutyl isobutyrate is slowly added dropwise. After the addition is completed, the mixture is kept warm and stirred. Then, 1,3-bromochloropropane or 1,3-dibromopropane is added dropwise. After the addition is completed, the mixture is kept warm for reaction. After the reaction is completed, the reaction is quenched, the mixture is filtered, separated, and washed with water. The organic phase is distilled under reduced pressure, and the fractions are collected to obtain the gemfibrozil intermediate 5-chloro-2,2-dimethylvaleric acid isobutyl ester or 5-bromo-2,2-dimethylvaleric acid isobutyl ester.

[0013] Furthermore, the weight ratio of the organic solvent in step S1 to the isobutyl isobutyrate in step S2 is 1-5:1, preferably 2-3:1; the organic solvent is one of 1,3-dioxane, toluene, xylene, tetrahydrofuran or 2-methyltetrahydrofuran, preferably tetrahydrofuran or 2-methyltetrahydrofuran.

[0014] Furthermore, the amount of the catalyst added in step S1 is 3-10%, preferably 3-6%, of the weight of isobutyl isobutyrate in step S1; the catalyst is ultrafine molybdenum dioxide; the particle size of the ultrafine molybdenum dioxide is 20nm-10μm, preferably 50nm-1μm.

[0015] Furthermore, in the ultrasonic reaction in step S1, the ultrasonic power is 20-100 W, preferably 60-80 W, and the ultrasonic treatment is continued for 30-50 min after heating.

[0016] Furthermore, the added amounts of metallic lithium and diisopropylamine in step S1 are both 1.0-1.6 times the molar amount of isobutyl isobutyrate in step S2, preferably 1.0-1.3.

[0017] Furthermore, in step S2, the temperature of the entire reaction system is controlled to be 0-5°C.

[0018] Furthermore, in step S2, the added amount of 1,3-bromochloropropane or 1,3-dibromopropane is 1-1.5 times the molar amount of isobutyl isobutyrate, preferably 1.0-1.3.

[0019] Furthermore, in step S2, after the isobutyl isobutyrate is added dropwise, the mixture is stirred at room temperature for 30-50 minutes, and after the 1,3-bromochloropropane or 1,3-dibromopropane is added dropwise, the mixture is reacted at room temperature for 30-50 minutes.

[0020] Furthermore, the quenching reaction in step S2 is performed by adding a 5% dilute hydrochloric acid solution into the reaction system.

[0021] Furthermore, in step S2, the organic phase is subjected to conventional reduced pressure distillation to remove the solvent to obtain the product.

[0022] The traditional preparation process of gemfibrozil intermediates is not only cumbersome, but also faces the severe challenge of purity and yield being difficult to guarantee. This status quo not only increases production costs, but also limits the large-scale production and application of gemfibrozil drugs. In the preparation method of the gemfibrozil intermediate provided by the present invention, diisopropylamine first reacts with metallic lithium to generate metallic lithium amide, and lithium amide reacts with isobutyl isobutyrate to generate isobutyl isobutyrate lithium, and diisopropylamine is freed again; at the same time, in the reaction process of metallic lithium and diisopropylamine, a catalyst molybdenum dioxide of a specific particle size is added, and combined with ultrasonic-assisted technology, the propagation and vibration of ultrasonic waves in the reaction system not only accelerate the molecular motion of the reactants, but also promote the effective collision between the reactants, thereby significantly improving the reaction rate. More importantly, by accurately controlling the ultrasonic conditions and the action time, the yield and purity of the finally obtained gemfibrozil intermediate can be effectively improved, and the generation of impurities can be greatly reduced.

[0023] In addition, another notable feature of the present invention is the significant shortening of the reaction time. In the traditional process, each step of the reaction often takes several hours or even longer to complete. In the preparation process of the present invention, by optimizing the reaction conditions and process parameters, the reaction time is effectively shortened. This change not only improves production efficiency, but also reduces byproducts and impurities that may be generated due to long-term reactions.

[0024] Finally, the preparation method of the present invention has achieved remarkable results in reducing the generation of impurities. In the traditional preparation process, the presence of impurities such as ethylbenzene, 1,3-diphenylbutane and 1,4-diphenylbutane has always been a problem affecting the purity and quality of the product. In the preparation process of the present invention, by precisely controlling the reaction conditions and post-treatment process, after the reaction is completed, only a simple distillation operation is required to obtain a Gemfibrozil intermediate with a purity of more than 98%, successfully reducing the generation of these impurities. In the final Gemfibrozil intermediate, the presence of the above three impurities was not detected.

[0025] Compared with the prior art, the improved method for preparing gemfibrozil intermediate provided by the present invention has the following advantages:

[0026] The improved preparation method of gemfibrozil intermediate provided by the present invention can reduce reaction steps and cumbersome operations, and by optimizing reaction conditions and post-processing process, not only simplifies the process flow, effectively reduces the generation of by-products and impurities, ensures high purity and few impurities of the final product, does not produce impurities such as chlorooctane, ethylbenzene, 1,3-diphenylbutane and 1,4-diphenylbutane, and has a high yield, which can reach more than 95%, improves the utilization rate of raw materials and the yield of products, reduces production costs and increases economic benefits, and is very suitable for industrial-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The HPLC spectrum of the gemfibrozil intermediate 5-chloro-2,2-dimethyl-isobutyl valerate prepared in Example 1 of the present invention;

[0028] Figure 2 HPLC spectrum of 5-bromo-2,2-dimethyl-isobutyl valerate, an intermediate of gemfibrozil, prepared in Example 2 of the present invention;

[0029] Figure 3 The HPLC spectrum of the gemfibrozil intermediate 5-chloro-2,2-dimethyl-isobutyl valerate prepared in Comparative Example 1 of the present invention. DETAILED DESCRIPTION

[0030] 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.

[0031] 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.

[0032] Example 1 Synthesis of Gemfibrozil Intermediate 5-Chloro-2,2-dimethyl-Isobutyl Valerate

[0033] The preparation method of the gemfibrozil intermediate 5-chloro-2,2-dimethyl-isobutyl valerate comprises the following steps:

[0034] S1. Add 300 g of tetrahydrofuran, 6.26 g of metallic lithium (1.3 times the molar amount of isobutyl isobutyrate), and 91.2 g of diisopropylamine (1.3 times the molar amount of isobutyl isobutyrate) to a reaction bottle, cool the mixture to 0-5°C, add 6.0 g of molybdenum dioxide with a particle size of 50 nm (6% of the weight of isobutyl isobutyrate), and perform ultrasonic-assisted reaction. The power of the ultrasonic reaction is 70 W, and the reaction system is heated to 8°C. Continue ultrasonic treatment for 40 min until the metallic lithium disappears.

[0035] S2. After the reaction of the metallic lithium in step S1 is completed, the system temperature is controlled at 0-5°C, 100 g of isobutyl isobutyrate is slowly added dropwise, and after the addition is completed, the mixture is stirred at a temperature of 0-5°C for 40 minutes. The temperature is then controlled at 0-5°C, and then 141.92 g of 1,3-bromochloropropane (1.3 times the molar amount of isobutyl isobutyrate) is added dropwise. After the addition is completed, the mixture is reacted at a temperature of 40 minutes. After the heat preservation is terminated, 50 mL of 5% dilute hydrochloric acid is added to quench the reaction, the mixture is filtered and separated, and the mixture is washed once with 100 mL of water. The organic phase is then subjected to conventional reduced pressure distillation to remove the solvent to obtain 5-chloro-2,2-dimethylvaleric acid isobutyl ester, an intermediate of gemfibrozil, to obtain 148.65 g of the mixture, with a yield of 97.12% and a purity of 99.40977%.

[0036] The specific process synthesis steps are as follows:

[0037]

[0038] Example 2 Synthesis of Gemfibrozil Intermediate 5-Bromo-2,2-Dimethyl-Isobutyl Valerate

[0039] The preparation method of the gemfibrozil intermediate 5-bromo-2,2-dimethyl-isobutyl valerate comprises the following steps:

[0040] S1. Add 200 g of tetrahydrofuran, 6.26 g of metallic lithium (1.3 times the molar amount of isobutyl isobutyrate), and 91.2 g of diisopropylamine (1.3 times the molar amount of isobutyl isobutyrate) to a reaction flask, cool the mixture to 0-5°C, add 6.0 g of molybdenum dioxide with a particle size of 50 nm (6% of the weight of isobutyl isobutyrate), and perform ultrasonic-assisted reaction. The power of the ultrasonic reaction is 70 W, and the reaction system is heated to 8°C, and ultrasonic stirring is continued for 45 min;

[0041] S2. After the reaction of the metallic lithium in step S1 is completed, the system temperature is controlled at 0-5°C, 100 g of isobutyl isobutyrate is slowly added dropwise, and after the addition is completed, the mixture is stirred at this temperature for 45 min. The temperature is controlled at 0-5°C, and 181.99 g of 1,3-dibromopropane (1.3 times the molar amount of isobutyl isobutyrate) is added dropwise. After the addition is completed, the mixture is reacted at this temperature for 45 min. After the insulation is terminated, 50 mL of 5% dilute hydrochloric acid is added to quench the reaction. After separation, the mixture is washed once with 100 mL of water, and the organic phase is subjected to conventional reduced pressure distillation to remove the solvent to obtain 5-bromo-2,2-dimethylvaleric acid isobutyl ester, an intermediate of gemfibrozil, with an amount of 177.61 g, a yield of 96.58%, and a purity of 99.57428%.

[0042] The specific process synthesis steps are as follows:

[0043]

[0044] Example 3

[0045] The preparation method of the gemfibrozil intermediate 5-chloro-2,2-dimethyl-isobutyl valerate comprises the following steps:

[0046] S1. Add 300 g of tetrahydrofuran, 4.81 g of metallic lithium (1.0 times the molar amount of isobutyl isobutyrate), and 70.16 g of diisopropylamine (1.0 times the molar amount of isobutyl isobutyrate) to a reaction bottle, cool the mixture to 0-5°C, add 3.0 g of molybdenum dioxide with a particle size of 1 μm (3% of the weight of isobutyl isobutyrate), and perform ultrasonic-assisted reaction. The power of the ultrasonic reaction is 60 W, and the reaction system is heated to 8°C. Continue ultrasonic treatment for 30 min until the metallic lithium disappears.

[0047] S2. After the reaction of the metallic lithium in step S1 is completed, the system temperature is controlled at 0-5°C, 100 g of isobutyl isobutyrate is slowly added dropwise, and after the addition is completed, the mixture is stirred at a temperature of 0-5°C for 30 minutes. The temperature is then controlled at 0-5°C, and then 109.17 g of 1,3-bromochloropropane (1.0 times the molar amount of isobutyl isobutyrate) is added dropwise. After the addition is completed, the mixture is reacted at a temperature of 30 minutes. After the heat preservation is terminated, 50 mL of 5% dilute hydrochloric acid is added to quench the reaction, the mixture is filtered and separated, and the mixture is washed once with 100 mL of water. The organic phase is then subjected to conventional reduced pressure distillation to remove the solvent to obtain 5-chloro-2,2-dimethylvaleric acid isobutyl ester, an intermediate of gemfibrozil, to obtain 145.60 g of the mixture, with a yield of 95.12% and a purity of 99.25063%.

[0048] Example 4

[0049] The preparation method of the gemfibrozil intermediate 5-chloro-2,2-dimethyl-isobutyl valerate comprises the following steps:

[0050] S1. Add 250 g of tetrahydrofuran, 5.78 g of metallic lithium (1.2 times the molar amount of isobutyl isobutyrate), and 84.20 g of diisopropylamine (1.2 times the molar amount of isobutyl isobutyrate) to a reaction flask, cool the mixture to 0-5°C, add 5.0 g of molybdenum dioxide with a particle size of 60 nm (5% of the weight of isobutyl isobutyrate), and perform ultrasonic-assisted reaction. The power of the ultrasonic reaction is 80 W, and the reaction system is heated to 8°C. Continue ultrasonic treatment for 50 min until the metallic lithium disappears.

[0051] S2. After the reaction of the metallic lithium in step S1 is completed, the system temperature is controlled at 0-5°C, 100 g of isobutyl isobutyrate is slowly added dropwise, and after the addition is completed, the mixture is stirred at room temperature for 50 min, the temperature is controlled at 0-5°C, and then 131.0 g of 1,3-bromochloropropane (1.2 times the molar amount of isobutyl isobutyrate) is added dropwise. After the addition is completed, the mixture is reacted at room temperature for 50 min. After the insulation is terminated, 50 mL of 5% dilute hydrochloric acid is added to quench the reaction, the mixture is filtered and separated, and the mixture is washed once with 100 mL of water. The organic phase is then subjected to conventional reduced pressure distillation to remove the solvent to obtain 5-chloro-2,2-dimethylvaleric acid isobutyl ester, an intermediate of gemfibrozil, to obtain 147.85 g of the mixture, with a yield of 96.59% and a purity of 98.79743%.

[0052] Comparative Example 1

[0053] Compared with Example 1, the difference is that styrene is used for catalysis in step S1, and no ultrasonic-assisted treatment is performed during the catalytic reaction. Other parameters and operations are the same as those in Example 1.

[0054] Specifically, the preparation method of the gemfibrozil intermediate 5-chloro-2,2-dimethyl-isobutyl valerate comprises the following steps:

[0055] S1. Add 300 g of tetrahydrofuran, 6.26 g of metallic lithium (1.3 times the molar amount of isobutyl isobutyrate), and 91.2 g of diisopropylamine (1.3 times the molar amount of isobutyl isobutyrate) into a reaction flask, cool the mixture to 0-5 ° C, add 72.2 g of styrene (1.0 times the molar amount of isobutyl isobutyrate) dropwise, stir, and heat the reaction system to 8 ° C. Continue stirring for 40 min. If the metallic lithium does not disappear, continue to keep it at 10-20 ° C and stir. After about 2 hours, the metallic lithium disappears, the reaction is completed, and the reaction solution is brown-red.

[0056] S2. After the reaction of the metal lithium in step S1 is completed, the system temperature is controlled at 0-5°C, 100g of isobutyl isobutyrate is slowly added dropwise, after the addition is completed, the mixture is stirred at a temperature of 0-5°C for 40 minutes, and then 141.92g of 1,3-bromochloropropane (1.3 times the molar amount of isobutyl isobutyrate) is added dropwise, after the addition is completed, the mixture is reacted at a temperature of 40 minutes, and after the insulation is completed, 50mL of 5% dilute hydrochloric acid is added to quench the reaction, and then the mixture is separated and washed once with 100mL of water, and then the organic phase is subjected to conventional vacuum distillation to remove the solvent, and the intermediate of gemfibrozil, 5-chloro-2,2-dimethylvaleric acid isobutyl ester, is obtained, and 128.65g of brown oil is obtained, and a colorless liquid is obtained after rectification, and 118.68g is obtained, with a yield of 77.54%. The purity is 92.43132%.

[0057] Comparative Example 2

[0058] Compared with Example 4, the difference is that ultrasonic-assisted treatment is not performed in step S1, and other parameters and operations are the same as those in Example 4.

[0059] Specifically, the preparation method of the gemfibrozil intermediate 5-chloro-2,2-dimethyl-isobutyl valerate comprises the following steps:

[0060] S1. Add 250 g of tetrahydrofuran, 5.78 g of metallic lithium (1.2 times the molar amount of isobutyl isobutyrate), and 84.20 g of diisopropylamine (1.2 times the molar amount of isobutyl isobutyrate) to a reaction flask, cool the mixture to 0-5°C, add 5.0 g of 60 nm molybdenum dioxide (5% of the weight of isobutyl isobutyrate), stir, and heat the reaction system to 8°C, and continue stirring for 3-4 hours until the metallic lithium disappears;

[0061] S2. After the reaction of the metallic lithium in step S1 is completed, the system temperature is controlled at 0-5°C, 100 g of isobutyl isobutyrate is slowly added dropwise, and after the addition is completed, the mixture is stirred at a temperature of 0-5°C for 50 minutes. The temperature is then controlled at 0-5°C, and 131.0 g of 1,3-bromochloropropane (1.2 times the molar amount of isobutyl isobutyrate) is then added dropwise. After the addition is completed, the mixture is reacted at a temperature of 50 minutes. After the heat preservation is terminated, 50 mL of 5% dilute hydrochloric acid is added to quench the reaction, the mixture is filtered and separated, and the mixture is washed once with 100 mL of water. The organic phase is then subjected to conventional reduced pressure distillation to remove the solvent to obtain 5-chloro-2,2-dimethylvaleric acid isobutyl ester, an intermediate of gemfibrozil, to obtain 130.55 g of the mixture, with a yield of 85.29% and a purity of 98.25275%.

[0062] Comparative Example 3

[0063] Compared with Example 1, the difference is that the ultrasonic power in step S1 is set to 120 W, and other parameters and operations are the same as those in Example 1.

[0064] In Comparative Example 3, 140.6 g of 5-chloro-2,2-dimethylvaleric acid isobutyl ester, an intermediate of gemfibrozil, was obtained with a yield of 91.86% and a purity of 98.25292%.

[0065] Test Example 1. Detection of Yield, Purity and Impurities of Gemfibrozil Intermediate Prepared by the Present Invention

[0066] The gemfibrozil intermediates prepared in Examples 1-4 and Comparative Examples 1-3 of the present invention were tested for purity and the contents of impurities ethylbenzene, 1,3-diphenylbutane and 1,4-diphenylbutane using high performance liquid chromatography (HPLC). The specific results are shown in Table 1.

[0067] Table 1

[0068]

[0069]

[0070] As shown in Table 1, the gemfibrozil intermediates obtained in Examples 1-4 effectively reduce the generation of by-products and impurities, and the final product has high purity and few impurities, and no impurities such as ethylbenzene, 1,3-diphenylbutane and 1,4-diphenylbutane are detected, and the yield can reach more than 95%, and the purity can reach more than 98%, indicating that the method of the present invention can improve the utilization rate of raw materials and the yield of products, reduce production costs and increase economic benefits, and is very suitable for industrial-scale production. When some conditions in the reaction process are changed in Comparative Examples 1 to 3, the yield and purity of the obtained gemfibrozil intermediates have decreased to varying degrees.

[0071] 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 a gemfibrozil intermediate, characterized in that: The gemfibrozil intermediate is 5-chloro-2,2-dimethylvaleric acid isobutyl ester or 5-bromo-2,2-dimethylvaleric acid isobutyl ester, and specifically comprises the following preparation steps: S1. Add metallic lithium and diisopropylamine to an organic solvent, then cool to 0-5°C, add a catalyst, perform an ultrasonic-assisted reaction, heat to 8°C, and continue ultrasonic treatment; S2. After the reaction of the metallic lithium in step S1 is completed, the system temperature is controlled, and then isobutyl isobutyrate is added dropwise. After the addition is completed, the mixture is stirred at the temperature maintained. Then, 1,3-bromochloropropane or 1,3-dibromopropane is added dropwise. After the addition is completed, the mixture is heated and reacted. After the reaction is completed, the reaction is quenched, the liquids are separated, the mixture is washed with water, and the organic phase is distilled under reduced pressure. The fractions are collected to obtain a gemfibrozil intermediate.

2. The improved method for preparing gemfibrozil intermediate according to claim 1, characterized in that: The weight ratio of the organic solvent in step S1 to the isobutyl isobutyrate in step S2 is 1-5:1; the organic solvent is one of 1,3-dioxane, toluene, xylene, tetrahydrofuran or 2-methyltetrahydrofuran.

3. The improved method for preparing gemfibrozil intermediate according to claim 2, characterized in that: The amount of the catalyst added in step S1 is 3-10% of the weight of the isobutyl isobutyrate in step S1; the catalyst is ultrafine molybdenum dioxide; the particle size of the ultrafine molybdenum dioxide is 20nm-10μm.

4. The improved method for preparing gemfibrozil intermediate according to claim 3, characterized in that: The ultrasonic power during the ultrasonic reaction in step S1 is 20-100 W, and the ultrasonic treatment is continued for 30-50 minutes after the temperature is raised.

5. The improved method for preparing gemfibrozil intermediate according to claim 1, characterized in that: The amounts of metallic lithium and diisopropylamine added in step S1 are both 1.0-1.6 times the molar amount of isobutyl isobutyrate in step S2.

6. The improved method for preparing gemfibrozil intermediate according to claim 1, characterized in that: In step S2, the temperature of the entire reaction system is controlled to be 0-5°C.

7. The improved method for preparing gemfibrozil intermediate according to claim 1, characterized in that: In the step S2, the added amount of 1,3-bromochloropropane or 1,3-dibromopropane is 1.0-1.5 times the molar amount of isobutyl isobutyrate.

8. The improved method for preparing gemfibrozil intermediate according to claim 1, characterized in that: In the step S2, after the isobutyl isobutyrate is added dropwise, the mixture is stirred at room temperature for 30-50 minutes, and after the 1,3-bromochloropropane or 1,3-dibromopropane is added dropwise, the mixture is reacted at room temperature for 30-50 minutes.

9. The improved method for preparing gemfibrozil intermediate according to claim 1, characterized in that: The quenching reaction in step S2 is performed by adding a 5% dilute hydrochloric acid solution into the reaction system.

10. The improved method for preparing gemfibrozil intermediate according to claim 1, characterized in that: In step S2, the organic phase is subjected to conventional reduced pressure distillation to remove the solvent to obtain the product.

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