A method for synthesizing ethyl 2,4-dioxohexanoate

Abstract

This invention relates to the field of organic synthesis, and particularly to a method for synthesizing ethyl 2,4-dioxohexanoate. The steps are as follows: a mixture of diethyl oxalate and butanone is added dropwise to an organic solvent containing an alkali at 0-10°C; after the addition is complete, the temperature is raised to 35-45°C, and the reaction is carried out under essentially static or weakly stirred conditions for 6-16 hours; post-treatment yields the target product. This method, through the synergistic effect of "low-temperature dropwise addition" and "high-temperature static reaction," unexpectedly achieves effective suppression of regiomeric impurities, with the isomer content in the product being less than 0.5%. Simultaneously, since the purity of the crude product already meets the requirements of downstream reactions, the traditionally necessary vacuum distillation step can be omitted. This invention offers high yield, process safety, simple operation, and good reproducibility, possessing significant industrial application value.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and in particular to a method for synthesizing ethyl 2,4-dioxohexanoate. Background Technology

[0002] Acetaminophen is a highly effective and broad-spectrum pyrazole amide insecticide, exhibiting excellent control efficacy against various pests, including Lepidoptera, Hemiptera, and Thysanoptera. Ethyl 2,4-dioxohexanoate is a key β-dicarbonyl structural unit with important applications in pesticide synthesis, particularly as a core intermediate in the synthesis of acetamiprid. Its conventional preparation method involves the Claisen condensation reaction of butanone and diethyl oxalate under alkaline conditions. The reaction equation is as follows: .

[0003] However, because butanone (methyl ethyl ketone) is an asymmetric ketone, it possesses two distinct α-position reactive centers: the methyl group and the methylene group. In conventional processes (typically involving stirring at room temperature or low temperature for several hours), the reaction is kinetically controlled, inevitably resulting in the simultaneous formation of two regioisomers: the target product, ethyl 2,4-dioxohexanoate (Formula I), and its unwanted regioisomer (Formula II). .

[0004] The two isomers mentioned above have extremely similar physicochemical properties, making them difficult to separate effectively using conventional methods such as distillation and recrystallization. This makes it impossible to completely remove isomer impurities, severely affecting the purity of the final product and adversely impacting the quality of downstream products. In existing synthetic methods, the content of these regional isomers is at least 3%, and the yield of the Claisen condensation reaction is only about 75%. Purification is usually achieved using methods such as column chromatography, which are costly and inefficient. Furthermore, existing separation methods also suffer from unstable yields and a large number of byproducts.

[0005] Therefore, developing a synthetic method that can suppress the formation of the aforementioned regioisomer impurities from the reaction source, is simple to operate, and avoids complex purification steps has significant industrial value and practical significance. Summary of the Invention

[0006] This invention provides a method for synthesizing ethyl 2,4-dioxohexanoate, comprising the following steps: A mixture of diethyl oxalate and butanone is added dropwise to an organic solvent containing an alkali at 0-10°C; after the addition is complete, the temperature is raised to 35-45°C, and the reaction is carried out under essentially static or weakly stirred conditions for 6-16 hours; post-treatment yields the target product. This method, through the synergistic effect of "low-temperature dropwise addition" and "high-temperature static reaction," unexpectedly achieves effective suppression of regiomeric impurities, with the isomer content in the product potentially below 0.5%. Furthermore, since the purity of the crude product already meets the requirements of downstream reactions, the traditionally necessary vacuum distillation step can be omitted. This method offers high yield, process safety, simple operation, and good reproducibility, demonstrating significant industrial application value.

[0007] The specific technical solution of this application is as follows: A method for synthesizing ethyl 2,4-dioxohexanoate includes the following steps: under alkaline conditions, diethyl oxalate and butanone are reacted at 35-45°C under essentially static or slightly stirred conditions for 6-16 hours; after the reaction is completed, the target product is obtained through post-treatment.

[0008] The more specific steps are as follows: (1) At a temperature of 0-10℃, a mixture of diethyl oxalate and butanone is added dropwise to an organic solvent containing an alkali; (2) After the addition is complete, heat the reaction system to 35-45℃ and react for 6-16 hours under basically static or weak stirring conditions; (3) After the reaction is completed, the target product is obtained by quenching, extraction and concentration.

[0009] Furthermore, the temperature in step (1) is 0-5℃; the reaction temperature in step (2) is 38-42℃; and the reaction time is 8-12 hours.

[0010] Furthermore, the alkali mentioned in step (1) is selected from one or more of sodium ethoxide, sodium hydride, and potassium tert-butoxide; the organic solvent is selected from one or more of toluene, tetrahydrofuran, and diethyl ether.

[0011] Furthermore, the molar ratio of diethyl oxalate to butanone is (1.1-1.5):1; the molar ratio of the base to butanone is (1.0-1.2):1.

[0012] Furthermore, the weak stirring mentioned in step (2) refers to a stirring speed of less than 100 rpm, preferably not more than 50 rpm; the basically still refers to the complete cessation of mechanical stirring.

[0013] The above steps can achieve the following synergistic effect: (1) Safety and controllability of low-temperature dripping Dropwise addition at a low temperature of 0-10℃ effectively suppresses the intense exothermic reaction in the initial stage, avoids local overheating and side reactions, and ensures the stable generation of enol anions, laying the foundation for subsequent highly selective reactions. Lower temperatures also ensure that the isomer content meets the aforementioned standards. However, after verification, the inventors found that reaction conditions of -10-0℃ prolong the reaction time, while the isomer impurity content showed virtually no decreasing trend. Therefore, the aforementioned low-temperature reaction temperature was ultimately selected as the optimal choice.

[0014] (2) Thermodynamic control of the main reaction upon heating After the addition is complete, the temperature is raised to 35-45℃, providing sufficient energy to the reaction system and shifting the reaction from "kinetic control" to "thermodynamic control." Under these conditions, the initially generated unstable regiomeric impurities represented by Formula II can be continuously transformed into more stable target products through dynamic equilibrium.

[0015] (3) Equilibrium maintenance under static / weak stirring Unlike conventional chemical synthesis, which emphasizes vigorous stirring to enhance mass transfer, this invention employs a state of near-static or weak stirring, avoiding disturbances to the reaction equilibrium caused by vigorous stirring and providing a stable environment for the reversible reaction to reach thermodynamic equilibrium.

[0016] The synergistic effect of the above three technical elements enables the present invention to effectively suppress regioisomeric impurities at the source while ensuring process safety, and to obtain high yield and high purity products.

[0017] In addition, the quenching, extraction and concentration in step (3) are as follows: quench the reaction solution with dilute hydrochloric acid, separate the liquid, wash and concentrate under reduced pressure to remove the solvent.

[0018] The product prepared by the above steps was found by gas chromatography to have a normalized content of regiomeric impurities of less than 0.5%, and further less than 0.1%. Therefore, it can be used in downstream reactions without distillation purification.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. Excellent impurity control capability: The method of this invention can significantly suppress the formation of regioisomer impurities at the reaction source, resulting in a normalized content of regioisomer impurities in the product as low as below 0.5%, far lower than that of traditional methods. This effect is achieved through the synergistic effect of "low-temperature dropwise addition + high-temperature static reaction," which is the core feature that distinguishes this invention from existing technologies.

[0020] 2. Higher reaction yield: Under optimized reaction conditions, the reaction conversion is more complete, resulting in a stable yield of over 85%, which is significantly higher than that of traditional processes. This translates to lower production costs and higher economic benefits.

[0021] 3. High process safety: The low-temperature dropping stage in the production process effectively controls the exothermic reaction in the early stage, avoiding the risk of local overheating and overheating, making it more suitable for industrial-scale production.

[0022] 4. Simplified post-processing and significantly reduced costs: Since the crude product obtained has a purity of over 99%, it can be directly used in downstream reactions, eliminating the need for the vacuum distillation purification step required in traditional processes. This not only reduces equipment investment and energy consumption but also avoids product decomposition that may occur during high-temperature distillation, thereby improving the overall yield and production efficiency.

[0023] 5. The process is simple and has good reproducibility: This invention achieves efficient purification simply by controlling the dropping temperature, reaction temperature, and stirring state, without requiring special equipment. The reaction conditions are mild and well-defined, the process is stable, and it is easy to scale up industrially. Attached Figure Description

[0024] Figure 1 The gas chromatogram of the product obtained in Example 1, The regional isomer impurity peaks shown at a retention time of approximately 12.8 min in the figure have essentially disappeared (less than 0.1%). Figure 2 The gas chromatogram of the product obtained in Comparative Example 3 is shown below. A distinct regional isomer impurity peak (approximately 5.6%) is visible at a retention time of approximately 12.8 min in the figure. Detailed Implementation

[0025] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions in the embodiments of this invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this invention.

[0026] Unless otherwise specified, the methods described in the following examples are conventional methods, and the reagents and materials used are all commercially available.

[0027] Example 1 A method for synthesizing ethyl 2,4-dioxohexanoate, comprising the following steps: Add 182.05g toluene and 34.36g sodium ethoxide to a dry 500mL four-necked flask and cool to 0-5℃. Mix 36.41g butanone and 73.78g diethyl oxalate evenly and slowly add them dropwise to the four-necked flask through a constant pressure dropping funnel over a period of 1-1.5 hours, keeping the internal temperature below 10℃ during the addition process. After the addition is complete, take a sample to check if the reaction is complete, then remove the ice-water bath, stop the stirring, and allow the system to stand still. Allow it to warm naturally to room temperature (20-25℃), then place the four-necked flask in a 40℃ constant temperature water bath and react for 12 hours. After the reaction is complete, cool to 0-5℃ and slowly add 10% dilute hydrochloric acid solution to adjust the pH to 6-7. Allow the mixture to stand and separate into layers.

[0028] The aqueous phase was extracted with 72.82 g of toluene, and the organic phases were combined. The organic phase was washed with 72.82 g of water for 20 min, allowed to stand, and separated. The organic phase was concentrated under reduced pressure to remove the solvent, yielding 79.39 g of a pale yellow oily liquid. The product yield was 91.5% (based on methyl ethyl ketone), and the product purity was 99.2%. The gas chromatogram of the obtained product is shown below. Figure 1 As shown, the regioisomer impurity peak at 12.8 min has essentially disappeared, indicating that the normalized content of the regioisomer impurity is <0.1%. This purity meets the requirements for downstream chlorination reactions, and no further vacuum distillation purification is necessary.

[0029] Example 2 A method for synthesizing ethyl 2,4-dioxohexanoate, comprising the following steps: Add 182.05g anhydrous tetrahydrofuran and 13.33g sodium hydride to a dry 500mL four-necked flask and cool to 0-5℃. Mix 36.41g butanone and 73.78g diethyl oxalate evenly and slowly add them dropwise to the four-necked flask through a constant pressure dropping funnel over a period of 1-1.5 hours, keeping the internal temperature below 10℃ during the addition process. After the addition is complete, take a sample to check if the reaction is complete. Remove the ice-water bath and allow the system to naturally warm to room temperature (20-25℃). Then place the four-necked flask in a 40℃ constant temperature water bath and adjust the stirring speed to 50 rpm. React under these conditions for 12 hours. After the reaction is complete, cool to 0-5℃ and slowly add 10% dilute hydrochloric acid solution to adjust the pH to 6-7. Allow the mixture to stand and separate into layers.

[0030] After extraction of the aqueous phase with 72.82 g of tetrahydrofuran, the organic phases were combined, and then washed with 72.82 g of water for 20 min. The mixture was allowed to stand and separated. The organic phase was then concentrated under reduced pressure to remove the solvent, yielding 78.57 g of a pale yellow oily liquid. The product yield was 90.2% (based on butanone), the product purity was 98.8%, and the regiomeric impurity content was <0.4%. This purity meets the requirements for downstream chlorination reactions, and no further purification under reduced pressure distillation is necessary.

[0031] Example 3 A method for synthesizing ethyl 2,4-dioxohexanoate, comprising the following steps: Add 182.05g toluene and 34.36g sodium ethoxide to a dry 500mL four-necked flask and cool to 0-5℃. Mix 36.41g butanone and 73.78g diethyl oxalate thoroughly and slowly add them dropwise to the four-necked flask through a constant pressure dropping funnel over a period of 1-1.5 hours, keeping the internal temperature below 10℃ during the addition process. After the addition is complete, take a sample to check if the reaction is complete. Remove the ice-water bath and allow the system to naturally warm to room temperature (20-25℃). Then place the four-necked flask in a 38℃ constant temperature water bath and adjust the stirring speed to 50 rpm. React under these conditions for 12 hours. After the reaction is complete, cool to 0-5℃ and slowly add 10% dilute hydrochloric acid solution to adjust the pH to 6-7. Allow the mixture to stand and separate into layers.

[0032] The aqueous phase was extracted with 72.82 g of toluene, and the organic phases were combined. 72.82 g of water was added to wash the organic phase for 20 min. After standing and separation, the organic phase was concentrated under reduced pressure to remove the solvent, yielding 78.67 g of a pale yellow oily liquid. The product yield was 90.5% (based on butanone), the product purity was 99%, and the regiomeric impurity content was <0.3%. This purity meets the requirements for downstream chlorination reactions, and no further purification under reduced pressure distillation is necessary.

[0033] Example 4 A method for synthesizing ethyl 2,4-dioxohexanoate, comprising the following steps: Add 182.05g toluene and 34.36g sodium ethoxide to a dry 500mL four-necked flask and cool to 0-5℃. Mix 36.41g butanone and 73.78g diethyl oxalate thoroughly and slowly add them dropwise to the four-necked flask through a constant pressure dropping funnel over a period of 1-1.5 hours, keeping the internal temperature below 10℃ during the addition process. After the addition is complete, take a sample to check if the reaction is complete. Remove the ice-water bath and allow the system to naturally warm to room temperature (20-25℃). Then place the four-necked flask in a 42℃ constant temperature water bath and adjust the stirring speed to 50 rpm. React under these conditions for 12 hours. After the reaction is complete, cool to 0-5℃ and slowly add 10% dilute hydrochloric acid solution to adjust the pH to 6-7. Allow the mixture to stand and separate into layers.

[0034] The aqueous phase was extracted with 72.82 g of toluene, and the organic phases were combined. The organic phase was washed with 72.82 g of water for 20 min, allowed to stand, and separated. The organic phase was concentrated under reduced pressure to remove the solvent, yielding 79.03 g of a pale yellow oily liquid. The product yield was 91% (based on butanone), the product purity was 99.1%, and the regiomeric impurity content was <0.2%. This purity meets the requirements for downstream chlorination reactions, and no further purification under reduced pressure distillation is necessary.

[0035] Example 5 A method for synthesizing ethyl 2,4-dioxohexanoate, comprising the following steps: Add 182.05g toluene and 34.36g sodium ethoxide to a dry 500mL four-necked flask and cool to 0-5℃. Mix 36.41g butanone and 73.78g diethyl oxalate thoroughly and slowly add them dropwise to the four-necked flask through a constant pressure dropping funnel over a period of 1-1.5 hours, keeping the internal temperature below 10℃ during the addition process. After the addition is complete, take a sample to check if the reaction is complete. Remove the ice-water bath and allow the system to naturally warm to room temperature (20-25℃). Then place the four-necked flask in a 40℃ constant temperature water bath and adjust the stirring speed to 50 rpm. React under these conditions for 8 hours. After the reaction is complete, cool to 0-5℃ and slowly add 10% dilute hydrochloric acid solution to adjust the pH to 6-7. Allow the mixture to stand and separate into layers.

[0036] After extraction of the aqueous phase with 72.82 g of toluene, the organic phases were combined, and 77.32 g of water was added to wash the organic phase for 20 min. The mixture was allowed to stand and separated. The organic phase was then concentrated under reduced pressure to remove the solvent, yielding 79.39 g of a pale yellow oily liquid. The product yield was 88.5% (based on butanone), the product purity was 98.5%, and the regiomeric impurity content was <0.5%. This purity meets the requirements for downstream chlorination reactions, and no further purification under reduced pressure distillation is necessary.

[0037] Example 6 A method for synthesizing ethyl 2,4-dioxohexanoate, comprising the following steps: Add 182.05g toluene and 34.36g sodium ethoxide to a dry 500mL four-necked flask and cool to 0-5℃. Mix 36.41g butanone and 73.78g diethyl oxalate thoroughly and slowly add them dropwise to the four-necked flask through a constant pressure dropping funnel over a period of 1-1.5 hours, keeping the internal temperature below 10℃ during the addition process. After the addition is complete, take a sample to check if the reaction is complete. Remove the ice-water bath and allow the system to naturally warm to room temperature (20-25℃). Then place the four-necked flask in a 40℃ constant temperature water bath and adjust the stirring speed to 50 rpm. React under these conditions for 10 hours. After the reaction is complete, cool to 0-5℃ and slowly add 10% dilute hydrochloric acid solution to adjust the pH to 6-7. Allow the mixture to stand and separate into layers.

[0038] After extraction of the aqueous phase with 72.82 g of toluene, the organic phases were combined, and 77.32 g of water was added to wash the organic phase for 20 min. The mixture was allowed to stand and separated. The organic phase was then concentrated under reduced pressure to remove the solvent, yielding 78.24 g of a pale yellow oily liquid. The product yield was 90% (based on butanone), the product purity was 99%, and the regiomeric impurity content was <0.5%. This purity meets the requirements for downstream chlorination reactions, and no further purification under reduced pressure distillation is necessary.

[0039] Comparative Example 1: A method for synthesizing ethyl 2,4-dioxohexanoate, comprising the following steps: Add 182.05g toluene and 34.36g sodium ethoxide to a dry 500mL four-necked flask and cool to 0-5℃. Mix 36.41g butanone and 73.78g diethyl oxalate evenly and slowly add them dropwise to the four-necked flask through a constant pressure dropping funnel over a period of 1-1.5 hours, keeping the internal temperature below 10℃ during the addition process. After the addition is complete and the reaction is confirmed to be complete, remove the ice-water bath, turn off the stirring, and allow the system to stand still. Allow it to naturally warm to room temperature (20-25℃) and react for 12 hours. After the reaction is complete, cool to 0-5℃ and slowly add 10% dilute hydrochloric acid solution to adjust the pH to 6-7. Allow the mixture to stand and separate into layers.

[0040] After extraction of the aqueous phase with 72.82 g of toluene, the organic phases were combined, and then washed with 72.82 g of water for 20 min. The mixture was allowed to stand and separated. The organic phase was then concentrated under reduced pressure to remove the solvent, yielding 74.17 g of a pale yellow oily liquid. The product yield was 78% (based on butanone), with a purity of 90.5% and a regiomeric impurity content of <4.3%. This purity was insufficient for downstream chlorination reactions, requiring further purification by reduced-pressure distillation.

[0041] Compared to Example 1, under the same low-temperature dropping conditions as Comparative Example 1, if the main reaction is not continued at 40°C, the isomer impurity content is as high as 4.3%, and the yield is only 78%. This demonstrates that an appropriate high-temperature main reaction is one of the key conditions for achieving high purity and high yield. However, excessively high temperatures will lead to more side reactions and the generation of more impurities. Therefore, the reaction temperature range of this application is preferred.

[0042] Comparative Example 2: A method for synthesizing ethyl 2,4-dioxohexanoate, comprising the following steps: Add 182.05g toluene and 34.36g sodium ethoxide to a dry 500mL four-necked flask. Mix 36.41g butanone and 73.78g diethyl oxalate thoroughly and slowly add the mixture dropwise through a constant pressure dropping funnel to the four-necked flask over a period of 1-1.5 hours, maintaining an internal temperature of 35-40℃ during the addition process. After the addition is complete and the reaction is confirmed to be complete, place the four-necked flask in a constant temperature water bath at 35-40℃, turn off the stirring, and allow the system to stand completely still for 12 hours. After the reaction is complete, cool the flask to 0-5℃ and slowly add 10% dilute hydrochloric acid solution to adjust the pH to 6-7. Allow the mixture to stand and separate into layers.

[0043] After extraction of the aqueous phase with 72.82 g of toluene, the organic phases were combined, and then washed with 72.82 g of water for 20 min. The mixture was allowed to stand and separated. The organic phase was then concentrated under reduced pressure to remove the solvent, yielding 79.47 g of a pale yellow oily liquid. The product yield was 88% (based on butanone), with a purity of 95.3% and a regiomeric impurity content of <2.5%. This purity was insufficient for downstream chlorination reactions, requiring further purification by reduced-pressure distillation.

[0044] Compared to Example 1, in Comparative Example 2, under the same high-temperature main reaction conditions, if the dropping temperature was not controlled within 0-10°C, the isomer impurity content reached 2.5%, and the yield also decreased. This demonstrates that low-temperature dropping is another key condition for achieving high purity and high yield.

[0045] Comparative Example 3: A method for synthesizing ethyl 2,4-dioxohexanoate, comprising the following steps: Add 182.05g toluene and 34.36g sodium ethoxide to a dry 500mL four-necked flask at room temperature (20-25℃). Mix 36.41g butanone and 73.78g diethyl oxalate thoroughly and slowly add the mixture dropwise through a constant pressure dropping funnel over a period of 1-1.5 hours. Maintain the temperature at 20-25℃ during the addition process. After the addition is complete, take a sample to check if the reaction is complete. Once the reaction is complete, stop stirring and allow the system to stand still for 12 hours. After the reaction is complete, cool the system to 0-5℃ and slowly add 10% dilute hydrochloric acid solution to adjust the pH to 6-7. Allow the mixture to stand and separate into layers.

[0046] The aqueous phase was extracted with 72.82 g of toluene, and the organic phases were combined. The organic phase was washed with 72.82 g of water for 20 min, allowed to stand, and separated. The organic phase was concentrated under reduced pressure to remove the solvent, yielding 69.16 g of a pale yellow oily liquid. The product yield was 72% (based on methyl ethyl ketone), and the product purity was 89.6%. The gas chromatogram of the obtained product is shown below. Figure 2 As shown, a distinct regioisomer impurity peak is visible at 12.8 min, with a normalized content of approximately 5.6%. This purity is insufficient for downstream chlorination reactions, necessitating vacuum distillation purification.

[0047] Compared to Example 1, Comparative Example 3, which simultaneously employed room temperature dropwise addition and room temperature reaction, had an isomer impurity content as high as 5.6% and a yield of only 72%. This demonstrates that low-temperature dropwise addition and high-temperature main reaction must be used in synergy; using them alone or lacking both simultaneously will not achieve the superior effects of this invention.

[0048] The crude product obtained above (containing 5.6% isomer impurities) was subjected to conventional vacuum distillation. After distillation, the product purity was 96.5%, and the regioisomer impurity content decreased to 1.1%. However, due to losses during the distillation process, the yield decreased from 72% to 68%. Even after distillation, its purity of 96.5% was still significantly lower than the product purity obtained in the above examples. This further demonstrates that the synthesis method of the present invention, due to its high product purity, can omit the traditionally necessary vacuum distillation step, thus simplifying the process.

[0049] Comparative Example 4: A method for synthesizing ethyl 2,4-dioxohexanoate, comprising the following steps: Add 182.05g toluene and 34.36g sodium ethoxide to a dry 500mL four-necked flask and cool to 0-5℃. Mix 36.41g butanone and 73.78g diethyl oxalate thoroughly and slowly add them dropwise to the four-necked flask through a constant pressure dropping funnel over a period of 1-1.5 hours, keeping the internal temperature below 10℃ during the addition process. After the addition is complete, remove the ice-water bath and allow the system to naturally warm to room temperature (20-25℃). Then place the four-necked flask in a 40℃ constant temperature water bath and adjust the stirring speed to 500 rpm. React under these conditions for 12 hours. After the reaction is complete, cool to 0-5℃ and slowly add 10% dilute hydrochloric acid solution to adjust the pH to 6-7. Allow the mixture to stand and separate into layers.

[0050] After extraction of the aqueous phase with 72.82 g of toluene, the organic phases were combined, and 77.16 g of water was added to wash the organic phase for 20 min. The mixture was allowed to stand and separated. The organic phase was then concentrated under reduced pressure to remove the solvent, yielding 79.39 g of a pale yellow oily liquid. The product yield was 85% (based on butanone), with a purity of 94.80% and a regiomeric impurity content of <3.8%. This purity was insufficient for downstream chlorination reactions, requiring further purification by reduced-pressure distillation.

[0051] Compared to Example 1, in Comparative Example 4, under the same low-temperature dropwise addition and 40°C main reaction conditions, vigorous stirring at 500 rpm resulted in an isomer impurity content as high as 3.8%, and the yield was also reduced. This demonstrates that weak stirring is a necessary condition for achieving high purity and high yield, while vigorous stirring disrupts the reaction equilibrium and is detrimental to impurity elimination.

[0052] Experimental Example 1 The product obtained in Example 5 (purity 98.5%, isomer impurities <0.5%) was subjected to chlorination and compared with the product obtained in Comparative Example 3 by conventional vacuum distillation (purity 96.5%, isomer impurities 1.1%).

[0053] Following the synthesis method described in paragraphs 0038-0042 of the prior art CN103102307A, ethyl 2,4-dioxohexanoate was cyclized with hydrazine hydrate, methylated with dimethyl sulfate, and chlorinated with sulfonyl chloride to obtain a chlorinated intermediate, as shown below: It is evident that the product obtained by the method of this invention can be directly applied to downstream reactions without distillation, and the reaction effect is superior to that of the product obtained by distillation in traditional methods.

[0054] The above embodiments and comparative data demonstrate that the combination of a temperature range of 35-45°C and a static / weak stirring state used in this invention is key to achieving high selectivity, low impurity content, and simplified post-processing. Too low a temperature results in incomplete reaction and fails to effectively suppress impurities, while too high a temperature leads to increased side reactions. Furthermore, while vigorous mechanical stirring is traditionally considered beneficial for mass transfer, it is actually detrimental to obtaining high-purity products in this reaction. The purity of the product obtained by the method of this invention surpasses that of products obtained through distillation using traditional methods, thus achieving a simplified process by "omitting distillation."

[0055] The present invention has been described in detail with reference to the preferred embodiments described above, but the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, those skilled in the art can make various equivalent modifications or substitutions to the embodiments of the present invention, and such modifications or substitutions should all be within the scope of the present invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should also be covered within the protection scope of the present invention.

Claims

1. A method for the synthesis of ethyl 2,4-dioxohexanoate, characterized in that, Includes the following steps: Under alkaline conditions, diethyl oxalate and butanone are reacted at 35-45°C for 6-16 hours under essentially static or slightly stirred conditions; after the reaction is completed, the target product is obtained through post-treatment.

2. The method for synthesizing ethyl 2,4-dioxohexanoate according to claim 1, characterized in that, The specific steps are as follows: (1) At a temperature of 0-10℃, a mixture of diethyl oxalate and butanone is added dropwise to an organic solvent containing an alkali; (2) After the addition is complete, heat the reaction system to 35-45℃ and react for 6-16 hours under basically static or weak stirring conditions; (3) After the reaction is completed, the target product is obtained by quenching, extraction and concentration.

3. The method for synthesizing ethyl 2,4-dioxohexanoate according to claim 2, characterized in that, The temperature in step (1) is 0-5℃; the reaction temperature in step (2) is 38-42℃; and the reaction time is 8-12 hours.

4. The method for synthesizing ethyl 2,4-dioxohexanoate according to claim 2 or 3, characterized in that, The base mentioned in step (1) is selected from one or more of sodium ethoxide, sodium hydride, and potassium tert-butoxide; the organic solvent is selected from one or more of toluene, tetrahydrofuran, and diethyl ether.

5. The method for synthesizing ethyl 2,4-dioxohexanoate according to claim 2 or 3, characterized in that, The molar ratio of diethyl oxalate to butanone is (1.1-1.5):1; the molar ratio of the base to butanone is (1.0-1.2):

1.

6. The method for synthesizing ethyl 2,4-dioxohexanoate according to claim 2 or 3, characterized in that, The weak stirring mentioned in step (2) refers to a stirring speed of less than 100 revolutions per minute, and the basically still refers to the complete cessation of mechanical stirring.

7. The method for synthesizing ethyl 2,4-dioxohexanoate according to claim 6, characterized in that, The term "weak stirring" refers to a stirring speed of no more than 50 revolutions per minute.

8. The method for synthesizing ethyl 2,4-dioxohexanoate according to claim 2, characterized in that, The quenching, extraction, and concentration in step (3) are as follows: quenching with hydrochloric acid, extraction of the aqueous phase with toluene, and removal of the solvent by vacuum distillation after combining the organic phases.

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