Preparation method of key intermediate of gemfibrozil impurity A

Abstract

The invention provides a preparation method of a key intermediate of a gemfibrozil impurity A, and belongs to the technical field of chemical synthesis. According to the invention, a brand-new synthetic route of the gemfibrozil impurity A is designed firstly, and efficient preparation methods of three key intermediates are provided on the basis of the brand-new synthetic route. Specifically, the preparation method comprises the following steps: firstly, reacting with propionyl chloride in a 1, 2-dichloroethane environment under the catalysis of aluminum trichloride, and cooling, layering and drying a product to obtain a first intermediate; taking the first intermediate as a raw material, reacting with benzyl bromide in a DMF (Dimethyl Formamide) environment by taking potassium carbonate as an acid-binding agent, collecting an organic phase, dissolving with methanol, carrying out reduction reaction by using sodium borohydride under the catalysis of cerium chloride heptahydrate, and collecting to obtain a second intermediate; taking the second intermediate as a raw material, dissolving the second intermediate in methylbenzene, and performing dehydration reaction under the catalysis of TsOH.H2O to obtain a third intermediate; on the basis of the three intermediates, efficient synthesis of the gemfibrozil impurity A can be achieved, the synthesis route is short, and the process efficiency is high.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, specifically to a method for preparing the key intermediate of gemfibrozil impurity A. Background Technology

[0002] Gemfibrozil impurity A is a key impurity in the clofibrate derivative drug gemfibrozil, possessing definite antimalarial prodrug activity. As an antimalarial prodrug, it metabolizes into the active substance cyclic guanosine, which targets and inhibits dihydrofolate reductase (DHFR). Regarding preparation, although gemfibrozil impurity A can be extracted from the synthetic route of gemfibrozil, a direct synthetic method is essential for large-scale production. In existing technologies, conventional preparation processes for gemfibrozil impurity A are inefficient, lengthy, difficult to purify, and have low yields. Therefore, developing a more efficient synthetic method for gemfibrozil impurity A has been a long-standing technical challenge in this field; and intermediates in the synthetic route are key technical nodes for achieving a complete process. Summary of the Invention

[0003] The technical problem to be solved by this invention is: how to achieve efficient preparation of the key intermediate in the synthetic route of gemfibrozil impurity A.

[0004] To achieve the above technical objectives, the present invention adopts the following technical solution: The preparation method of the key intermediate of gemfibrozil impurity A includes: 1) adding aluminum trichloride to a 1,2-dichloroethane solution of gemfibrozil at -9~-7℃, stirring while maintaining the temperature; then adding propionyl chloride solution while maintaining the same temperature, and reacting while maintaining the temperature; pouring the reaction solution into an ice-water mixture, stirring to separate the layers; drying the organic layer with anhydrous sodium sulfate, and then concentrating under reduced pressure until dry.

[0005] Preferably, the process also includes: 2) adding potassium carbonate to the DMF solution of the product obtained in step 1) at 7~9℃, then adding benzyl bromide, reacting after the addition is complete, allowing the mixture to naturally rise to room temperature while stirring; cooling the reaction solution with ice water, then adding water, controlling the temperature at 20~25℃; after the addition is complete, adding ethyl acetate, stirring, separating the organic layer, drying with sodium sulfate, filtering, concentrating, dissolving the resulting concentrate in methanol, adding cerium trichloride heptahydrate and sodium borohydride when the internal temperature reaches 14~16℃, stirring after the addition is complete, controlling the reaction at 50~60℃, then cooling to room temperature; extracting with ethyl acetate and water while stirring, drying the organic phase with sodium sulfate, filtering, and concentrating.

[0006] Preferably, the method further includes: 3) placing the toluene solution of the product obtained in step 2) in an oil bath at 95~105°C and stirring, then adding TsOH·H2O to it, and heating the reaction solution under reflux after the addition is complete; cooling to room temperature, adding water and stirring; separating the aqueous layer, drying the organic phase with sodium sulfate, filtering, and concentrating.

[0007] Preferably, in step 1), the amounts of each material are in the following proportions: gemfibrozil 10g; 1,2-dichloroethane 60mL; aluminum trichloride 12.8g; propionyl chloride 8.10g; ice-water mixture 100mL.

[0008] Preferably, in step 2), the amounts of each material are in the following proportions: 10g of the product obtained in step 1); 50g of DMF; 8g of potassium carbonate; 15g of benzyl bromide; 100g of water added after cooling the reaction solution with ice water; 15g of the concentrated solution; 75g of methanol; 26g of cerium trichloride heptahydrate; 5g of sodium borohydride; 100g of ethyl acetate used in both steps; and 200g of water mixed with ethyl acetate.

[0009] Preferably, in step 3), the amounts of each material are in the following proportions: 10g of the product obtained in step 2); 500g of toluene; 0.072g of TsOH·H2O; and 30mL of water.

[0010] Preferably, in step 1), aluminum trichloride is added to the 1,2-dichloroethane solution of gemfibrozil at -8°C.

[0011] Preferably, the duration of heat preservation and stirring in step 1) is 50 minutes.

[0012] Preferably, the duration of the heat preservation reaction in step 1) is 10 minutes.

[0013] Preferably, in step 2), potassium carbonate is added to the DMF solution of the product obtained in step 1) at 8°C.

[0014] Preferably, potassium carbonate in step 2) is added all at once.

[0015] Preferably, in step 2), the stirring time after the temperature naturally rises to room temperature is 1 hour.

[0016] As a preferred option, in step 2), when the internal temperature reaches 15°C, cerium trichloride heptahydrate is added.

[0017] Preferably, the stirring time at 50~60℃ in step 2) is 5h.

[0018] Preferably, the temperature of the oil bath in step 3) is 100°C.

[0019] Preferably, the stirring time in the oil bath in step 3) is 10 minutes.

[0020] Preferably, TsOH·H2O is added all at once in step 3).

[0021] Preferably, the heating and reflux time in step 3) is 12 hours.

[0022] Preferably, the stirring time after adding water in step 3) is 2 hours.

[0023] This invention provides a method for preparing key intermediates of gemfibrozil impurity A. The technical solution first designs a novel synthetic route for gemfibrozil impurity A, and then provides efficient preparation methods for three key intermediates. Specifically, this invention first reacts propionyl chloride with aluminum trichloride in a 1,2-dichloroethane environment under the catalysis of aluminum trichloride. The product is cooled, separated into layers, and dried to obtain the first intermediate. Using the first intermediate as a raw material, it reacts with benzyl bromide in a DMF environment using potassium carbonate as an acid-binding agent. The collected organic phase is dissolved in methanol, and then reduced with sodium borohydride under the catalysis of cerium trichloride heptahydrate to obtain the second intermediate. Using the second intermediate as a raw material, it is dissolved in toluene and undergoes a dehydration reaction under the catalysis of TsOH·H2O to obtain the third intermediate. Based on the three intermediates of this invention, efficient synthesis of gemfibrozil impurity A can be achieved. This invention features a short synthetic route, high process efficiency, convenient purification, and high yield and purity. Attached Figure Description

[0024] Figure 1 This is a high-performance liquid chromatogram of gemfibrozil impurity A synthesized based on the three intermediates of this invention.

[0025] Figure 2 This is the overall synthetic reaction route diagram for synthesizing gemfibrozil impurity A based on the three intermediates of this invention. Detailed Implementation

[0026] The specific embodiments of the present invention will be described in detail below. To avoid excessive and unnecessary detail, well-known structures or functions will not be described in detail in the following embodiments. The approximate language used in the following embodiments is for quantitative purposes, indicating that a certain degree of variation in quantity is permissible without changing the basic function. Unless otherwise defined, the technical and scientific terms used in the following embodiments have the same meaning as commonly understood by those skilled in the art to which this invention pertains.

[0027] The synthetic method and route for gemfibrozil impurity A are as follows: Figure 2 As shown.

[0028] In this synthetic method, three key intermediates (i.e. Figure 2 The synthesis methods of compounds 2, 4 and 5 in the above are as follows.

[0029] 1. Synthesis of Compound 2 Aluminum trichloride (12.8 g) was added to a solution of gemfibrozil (10 g) in 1,2-dichloroethane (60 ml) at -8 °C, and the mixture was stirred at this temperature for 50 minutes. Then, propionyl chloride (8.10 g) solution was added while maintaining the same temperature, and the reaction was continued for 10 minutes. The reaction mixture was poured into a prepared ice-water solution (100 ml ice water) and stirred to separate the layers. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 2 (10.8 g).

[0030] 2. Synthesis of Compound 4 At 8°C, 8g of potassium carbonate was added at once to a 50g DMF solution of 10g of compound 2, followed by the slow addition of 15g of benzyl bromide. After the addition was complete, the reaction mixture was allowed to cool to room temperature and stirred for 1 hour. The reaction solution was then cooled with ice water, and 100g of water was slowly added while maintaining the temperature at 20-25°C. After the addition was complete, 100g of ethyl acetate was added, and the mixture was stirred. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The concentrated solution (15g) was used directly in the following reaction.

[0031] The above concentrated solution (15g) was dissolved in 75g methanol. When the internal temperature reached 15℃, 26g of cerium trichloride heptahydrate and 5g of borohydride were added. After the addition was complete, the reaction was stirred at 50-60℃ for 5 hours and then cooled to room temperature. Extraction was performed by adding 100g of ethyl acetate to 200g of water and stirring. The organic phase was dried over sodium sulfate, filtered, and concentrated to obtain an oily liquid compound 4 (10.5g).

[0032] 3. Synthesis of Compound 5 A 10 g solution of compound 4 in toluene (500 g) was stirred in an oil bath at 100 °C for 10 minutes. Then, 0.072 g (0.38 mmol) of TsOH·H₂O was added in a single addition. Immediately after the addition, the reaction mixture was refluxed for 12 hours. After cooling to room temperature, 30 mL of water was added and the mixture was stirred for 2 hours. The aqueous layer was separated, the organic phase was dried over sodium sulfate, filtered, and concentrated to give an oily liquid compound 5 (6.2 g).

[0033] Based on the three key intermediates mentioned above, the following method was used to synthesize and purify gemfibrozil impurity A: At room temperature, 3 g of NaOH in 27 mL of water was added to a 50 g solution of isopropanol containing 6 g of compound 5. After the addition was complete, the reaction mixture was placed in a water bath at 35°C and stirred for 28 hours. The mixture was cooled to room temperature, diluted with 100 mL of water, and the isopropanol was evaporated under reduced pressure. The pH was then adjusted to 4-5 with 2NHCl, followed by extraction with 100 g of ethyl acetate, drying with sodium sulfate, filtering, and concentrating to obtain 4.2 g of a white solid.

[0034] The white solid was added to a mixed solvent of 400g n-heptane and 50g acetonitrile, sonicated at 20-30℃ for 5-6 hours, cooled to -10℃, stirred for 1-2 hours, filtered, and the filter cake was washed with a small amount of n-heptane and dried. The final product (3.8g) was obtained with a purity of 99.5%.

[0035] Analysis method: The method used was high performance liquid chromatography (General Chapter 0512, Part IV, Chinese Pharmacopoeia 2020 Edition).

[0036] Test solution: Accurately weigh approximately 250 mg of gemfibrozil impurity A into a 25 mL volumetric flask, dissolve it in solvent, dilute to the mark, and shake well.

[0037] Chromatographic conditions: Agilent 1100, Agilent 1260 or equivalent liquid chromatograph; Elite, Hypersil ODS2, 5μm, 4.0×250mm or equivalent column; methanol-water (75:24) as mobile phase; flow rate 1.0 mL / min; detection wavelength 276 nm; column temperature 35℃; injection volume 100µL.

[0038] Assay: Accurately measure the test solution and standard solution, inject them separately into the liquid chromatograph, and record the chromatograms. The chromatograms are shown below. Figure 1 As shown, the specific parameters are shown in Table 1 below.

[0039]

[0040] The embodiments of the present invention have been described in detail above, but the content described is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the scope of the present invention should be included within the protection scope of the present invention.

Claims

1. A process for the preparation of a key intermediate of gemfibrozil impurity A, characterized by, Comprising: 1) adding aluminum chloride to a 1,2-dichloroethane solution of gemfibrozil under the condition of -9~ -7℃, and after completion of the addition, keeping the temperature and stirring; Then adding a propionyl chloride solution under the same temperature, keeping the reaction; pouring the reaction liquid into an ice water mixture, stirring and separating the layers; Drying the organic layer with anhydrous sodium sulfate, and then concentrating to dryness under reduced pressure.

2. A process for the preparation of Gemfibrozil impurity A key intermediate as claimed in claim 1, wherein, Also comprising: 2) adding potassium carbonate to a DMF solution of the product obtained in step 1), then adding benzyl bromide, after completion of the addition, reacting, and naturally rising to room temperature, stirring; cooling the reaction liquid with ice water, then adding water, controlling the temperature at 20~25℃; after completion of the addition, adding ethyl acetate, stirring, and then separating the organic layer, drying with sodium sulfate, filtering, and concentrating; dissolving the concentrated liquid obtained with methanol, when the internal temperature reaches 14~16℃, adding cerium chloride heptahydrate, adding sodium borohydride, after completion of the addition, controlling the reaction at 50~60℃ and stirring, and then cooling to room temperature; stirring and extracting with ethyl acetate and water, drying the organic phase with sodium sulfate, filtering, and concentrating.

3. A process for the preparation of Gemfibrozil impurity A key intermediate as claimed in claim 2, wherein, Also comprising: 3) placing a toluene solution of the product obtained in step 2) in an oil bath at 95~105℃ and stirring, then adding TsOH·H2O to it, after completion of the addition, heating the reaction liquid to reflux; cooling to room temperature, adding water and stirring; separating the water layer, drying the organic phase with sodium sulfate, filtering, and concentrating.

4. A process for the preparation of Gemfibrozil impurity A key intermediate as claimed in claim 1, wherein, In step 1), the amounts of the materials meet the following proportions: gemfibrozil 10g; 1,2-dichloroethane 60mL; aluminum chloride 12.8g; propionyl chloride 8.10g; ice water mixture 100mL.

5. A process for the preparation of Gemfibrozil impurity A key intermediate as claimed in claim 2, wherein, In step 2), the amounts of the materials meet the following proportions: the product obtained in step 1) 10g; DMF 50g; potassium carbonate 8g; benzyl bromide 15g; the amount of water added after cooling the reaction liquid with ice water 100g; the concentrated liquid 15g; methanol 75g; cerium chloride heptahydrate 26g; sodium borohydride 5g; the amount of ethyl acetate used twice is 100g; the amount of water mixed with ethyl acetate is 200g. In step 3), the amounts of the materials meet the following proportions: the product obtained in step 2) 10g; toluene 500g; TsOH·H2O 0.072g; the amount of water added 30mL.

6. A process for the preparation of Gemfibrozil impurity A key intermediate as claimed in claim 3, wherein, In step 1), aluminum chloride is added to a 1,2-dichloroethane solution of gemfibrozil under the condition of -8℃.

7. A process for the preparation of Gemfibrozil impurity A key intermediate according to claim 1, characterized in that, The duration of the said keeping stirring in step 1) is 50 minutes.

8. A process for the preparation of Gemfibrozil impurity A key intermediate according to claim 1, characterized in that, The duration of the said keeping reaction in step 1) is 10 minutes.

9. A process for the preparation of Gemfibrozil impurity A key intermediate according to claim 1, characterized in that, In step 2), potassium carbonate is added to a DMF solution of the product obtained in step 1) under the condition of 8℃.

10. A process for the preparation of Gemfibrozil impurity A key intermediate as claimed in claim 2, wherein, ​

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