Preparation method of ethyl 4-chloroacetoacetate

Abstract

The invention discloses a preparation method of ethyl 4-chloroacetoacetate, and belongs to the technical field of compound synthesis. The method comprises the following steps: by taking diketene as a raw material, adding a polymethylsilsesquioxane polymerization inhibitor into a dichloromethane solvent, introducing chlorine at low temperature, carrying out chlorination reaction to generate 4-chloroacetoacetic acid, then esterifying the 4-chloroacetoacetic acid with absolute ethyl alcohol to obtain a crude product, and finally distilling and purifying to obtain the product. The preparation method is characterized in that a polymethylsilsesquioxane polymerization inhibitor is added before chlorination reaction, the polymerization inhibitor is prepared by grafting a functional monomer containing a 3, 5-di-tert-butyl-4-hydroxycinnamic acid structure onto surface-ethenylated polymethylsilsesquioxane microspheres, and the polymethylsilsesquioxane polymerization inhibitor has both steric hindrance and free radical capture capability. The method can effectively inhibit the self-polymerization and copolymerization tendency of diketene, intermediates and products in a reaction system, obviously reduces the generation of by-products such as dichloro and polychloro, enables the product to be high in yield and good in purity, and meets the quality requirements of high-end medical intermediates.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis technology, and particularly relates to a method for preparing ethyl 4-chloroacetoacetate. Background Technology

[0002] Ethyl 4-chloroacetoacetate is an important pharmaceutical and pesticide intermediate. It is a key raw material for the synthesis of ethyl aminothiazolate, an intermediate for the synthesis of cephalosporin drugs, and a crucial intermediate in the L-carnitine series of drugs and health foods, including the fourth-generation anti-inflammatory drug cefcaptin ester, the anti-cardiovascular drug piracetam, the anti-lipidemia drug atorvastatin, the anti-gout drug febuxostat, the antihypertensive drug amlodipine, and the anti-influenza virus arbidol. It is also a key intermediate in the latest AIDS treatment drug terbutaline.

[0003] Currently, there are two main routes for the industrial synthesis of ethyl 4-chloroacetoacetate:

[0004] The first method is the direct chlorination of ethyl acetoacetate. This method uses ethyl acetoacetate as a raw material and directly introduces chlorine gas to initiate the chlorination reaction under acidic or free radical initiation conditions. The advantage of this route is the readily available raw materials and relatively simple process. However, its prominent problem is poor chlorination selectivity. Ethyl acetoacetate molecules have two active sites that can be chlorinated, making it difficult to precisely control the reaction at the methylene group, easily generating various chlorination byproducts such as 2-chloro, 2,2-dichloro, and 2,4-dichloro. This not only leads to a reduced yield of the target product but also poses significant difficulties for subsequent separation and purification, resulting in generally low product purity, which is insufficient to meet the stringent quality requirements of high-end pharmaceutical intermediates.

[0005] The second method is the diketene chlorination-esterification method. This route first reacts diketene with chlorine to produce 4-chloroacetyl chloride, which is then esterified with ethanol to obtain the target product. Theoretically, this method has the potential for high atom economy and good selectivity because the hydrogen at the 4-position of diketene is more reactive than the hydrogen at the 2-position of ethyl acetoacetate, and theoretically can be preferentially chlorinated. However, diketene itself is extremely chemically reactive and readily undergoes dimerization or polymerization under heat, light, or in the presence of impurities; its chlorination product, 4-chloroacetyl chloride, and the final product, ethyl 4-chloroacetoacetate, also contain unsaturated bonds and electron-withdrawing groups, making them unstable in the reaction system and prone to self-polymerization or copolymerization with the raw materials.

[0006] In conclusion, developing a new method to effectively suppress side reactions and achieve high selectivity and high yield for the synthesis of high-purity ethyl 4-chloroacetoacetate has significant industrial application value. Summary of the Invention

[0007] In order to overcome the shortcomings of the prior art, the present invention introduces a polymethylsilsesquioxane polymerization inhibitor during the preparation process, which can significantly reduce the generation of by-products such as dichloro and polychlorinated compounds and improve the purity of the final product.

[0008] To achieve the above objectives, the following technical solution is adopted: This invention discloses a method for preparing ethyl 4-chloroacetoacetate, comprising the following steps:

[0009] S1. Add diketene to the reactor, slowly add dichloromethane, and stir at 300-400 r / min to completely dissolve the diketene. After the system temperature stabilizes at 20-25℃, add polymethylsilsesquioxane polymerization inhibitor and continue stirring for 10-15 min to disperse the polymerization inhibitor evenly.

[0010] S2. Control the system temperature at 0-5℃, slowly introduce chlorine gas at a rate of 20-30 mL / min, and stop introducing chlorine when the residual amount of diketene is ≤0.5% by gas chromatography. Stir the reaction for 2.5-3 hours to obtain a dichloromethane solution of 4-chloroacetoacetic acid.

[0011] S3. Keep the system temperature at 15-20℃, and add anhydrous ethanol dropwise to the above dichloromethane solution of 4-chloroacetoacetic acid through a constant pressure dropping funnel. After the addition is complete, raise the temperature to 30-35℃ and keep the reaction at this temperature for 1.5-2 hours. Stop the reaction when the conversion rate of 4-chloroacetoacetic acid is ≥99% as monitored by gas chromatography to obtain crude ethyl 4-chloroacetoacetate.

[0012] S4. Distillation and solvent removal: The crude product is distilled under normal pressure to remove dichloromethane and excess ethanol. The first fraction is collected until the distillation temperature stabilizes above 80°C to obtain the solvent-removed crude product. Then, a vacuum distillation apparatus is used with a vacuum degree set to 0.095-0.098 MPa, and the temperature is slowly raised to 100-110°C. The fraction with a distillation temperature of 85-90°C is collected to obtain ethyl 4-chloroacetoacetate product.

[0013] Furthermore, the preparation method of the polymethylsilsesquioxane polymerization inhibitor includes the following steps:

[0014] (1) Synthesis of functional monomers: 3,5-di-tert-butyl-4-hydroxycinnamic acid and α-vinylbenzyl alcohol were added to the reaction apparatus, followed by toluene and p-toluenesulfonic acid. The mixture was heated to reflux for 4-6 hours, and the water produced by the reaction was collected through a water separator. After the reaction was completed, the reaction solution was cooled to room temperature, washed twice with 5% sodium carbonate solution, and then washed with deionized water until neutral. The organic phase was dried with anhydrous magnesium sulfate and toluene was removed by vacuum distillation to obtain the functional monomers.

[0015] (2) Grafting modification of polymethylsilsesquioxane microspheres: Deionized water and sodium lauryl ether sulfate were added to the reaction apparatus and stirred to dissolve. Then, surface-ethylene-modified polymethylsilsesquioxane microspheres were added and ultrasonically dispersed for 30 min to make the microspheres uniformly suspended. Then, styrene and functional monomers were added in sequence, stirred evenly, and heated to 70°C. 0.5 g of potassium persulfate was added and reacted for 4 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, centrifuged, and the precipitate was washed three times with deionized water and ethanol in sequence. The precipitate was then dried under vacuum to obtain polymethylsilsesquioxane polymerization inhibitor.

[0016] Furthermore, the preparation method of the surface-ethylene-modified polymethyl silsesquioxane microspheres includes the following steps: adding methyltrimethoxysilane, vinyltrimethoxysilane and ultrapure water into a reaction apparatus, stirring at room temperature for 2 hours, then adding ammonia water, continuing to stir for 20 minutes, washing the obtained microspheres with ethanol, then washing with distilled water until neutral, and vacuum drying to obtain surface-ethylene-modified polymethyl silsesquioxane microspheres.

[0017] Further, in step S1, the amount of dichloromethane added is 2.0-3.5 times the mass of diketene; the amount of polymethylsilsesquioxane polymerization inhibitor added is 0.05%-0.2% of the mass of diketene.

[0018] Further, in step S2, the total amount of chlorine introduced is in a molar ratio of 1.02-1.10:1 to diketene.

[0019] Further, in step S3, the molar ratio of the amount of anhydrous ethanol added to diketene is 1.5-2.5:1.

[0020] Further, in step (1), the molar ratio of 3,5-di-tert-butyl-4-hydroxycinnamic acid to α-vinylbenzyl alcohol is 1:1.05-1.25; the amount of toluene added is 3-6 times the total mass of 3,5-di-tert-butyl-4-hydroxycinnamic acid and α-vinylbenzyl alcohol; and the amount of p-toluenesulfonic acid added is 1%-3% of the mass of 3,5-di-tert-butyl-4-hydroxycinnamic acid.

[0021] Further, in step (2), the mass ratio of the surface-ethylene-modified polymethylsilsesquioxane microspheres, styrene, and functional monomers is 1:0.8-1.5:0.2-0.6; the amount of deionized water added is 8-15 times the total mass of the three reactants in step (2); and the amount of sodium lauryl ether sulfate added is 0.5%-2.0% of the mass of deionized water.

[0022] Further, the molar ratio of methyltrimethoxysilane to vinyltrimethoxysilane is 2.5-4:1; the amount of ultrapure water added is 5-10 times the total mass of methyltrimethoxysilane and vinyltrimethoxysilane; and the amount of ammonia added is 0.05%-0.15% of the total mass of methyltrimethoxysilane and vinyltrimethoxysilane.

[0023] The beneficial effects of this invention are:

[0024] The method for preparing ethyl 4-chloroacetoacetate disclosed in this invention can significantly reduce the generation of byproducts such as dichloro and polychlorinated compounds and improve the purity of the final product.

[0025] This invention first prepares vinyl-rich polymethylsilsesquioxane microspheres by hydrolytic condensation of methyltrimethoxysilane and vinyltrimethoxysilane. Using these microspheres as a carrier, a functional monomer containing a 3,5-di-tert-butyl-4-hydroxycinnamic acid structure is grafted onto their surface through a copolymerization reaction, thereby preparing a composite polymerization inhibitor. The polymethylsilsesquioxane microspheres themselves have a stable three-dimensional network structure and a large specific surface area. Grafting modification further enriches their pore structure and increases their specific surface area. The grafted 3,5-di-tert-butyl-4-hydroxycinnamic acid structure is a typical hindered phenolic free radical scavenger. The hydrogen atoms on its phenolic hydroxyl groups can quickly and efficiently provide active free radicals, causing them to transform into stable molecules. This chemically terminates the polymerization reaction and inhibits the self-polymerization and copolymerization tendencies of the raw material diketene, the intermediate 4-chloroacetoacetic acid, and the product ethyl 4-chloroacetoacetate in chlorination and subsequent processes, fundamentally reducing the generation of impurities such as high molecular weight polymers.

[0026] The polymethylsilsesquioxane backbone itself has excellent chemical and thermal stability, which enables the polymerization inhibitor to maintain structural integrity and long-lasting activity under acidic and alkaline environments and temperature conditions during the reaction, and it is not easy to deactivate, thus providing a continuous and stable protective effect throughout the entire reaction cycle. Attached Figure Description

[0027] Figure 1 The diagram shows the preparation equation for the polymethylsilsesquioxane polymerization inhibitor of this invention.

[0028] Figure 2 The image shows the FTIR spectrum of the polymethylsilsesquioxane polymerization inhibitor in Example 3 of this invention.

[0029] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used together with the embodiments of the invention to explain the invention and do not constitute a limitation thereof. Detailed Implementation

[0030] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to this invention. The preferred embodiments and materials described herein are for illustrative purposes only and do not limit the scope of this application.

[0032] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, and the experimental materials used in the following examples are all purchased from commercial channels.

[0033] Example 1:

[0034] A method for preparing ethyl 4-chloroacetoacetate includes the following steps:

[0035] S1. Add diketene to the reactor, slowly add dichloromethane, and stir at 300 r / min to completely dissolve the diketene. After the system temperature stabilizes at 20℃, add polymethylsilsesquioxane polymerization inhibitor and continue stirring for 10 min to ensure uniform dispersion of the polymerization inhibitor.

[0036] S2. Control the system temperature at 0℃, slowly introduce chlorine gas at a rate of 20 mL / min, and stop introducing chlorine when the residual amount of diketene is ≤0.5% by gas chromatography. Stir the reaction for 2.5 h to obtain a dichloromethane solution of 4-chloroacetoacetic acid.

[0037] S3. Keep the system temperature at 15℃, add anhydrous ethanol dropwise to the above dichloromethane solution of 4-chloroacetoacetic acid through a constant pressure dropping funnel. After the addition is complete, raise the temperature to 30℃ and keep the reaction at this temperature for 1.5h. Stop the reaction when the conversion rate of 4-chloroacetoacetic acid is ≥99% by gas chromatography to obtain crude ethyl 4-chloroacetoacetate.

[0038] S4. Distillation and desolventization: Distill the crude product under normal pressure to remove dichloromethane and excess ethanol. Collect the first fraction until the distillation temperature stabilizes above 80°C to obtain the desolventized crude product. Then, use a vacuum distillation apparatus, set the vacuum degree to 0.095 MPa, and slowly raise the temperature to 100°C. Collect the fraction with a distillation temperature of 85°C to obtain ethyl 4-chloroacetoacetate product.

[0039] According to the appendix Figure 1 The preparation method of the polymethylsilsesquioxane polymerization inhibitor includes the following steps:

[0040] (1) Synthesis of functional monomers: 3,5-di-tert-butyl-4-hydroxycinnamic acid and α-vinylbenzyl alcohol were added to the reaction apparatus, along with toluene and p-toluenesulfonic acid. The mixture was heated to reflux for 4 hours, and the water produced during the reaction was collected through a water separator. After the reaction was completed, the reaction solution was cooled to room temperature, washed twice with 5% sodium carbonate solution, and then washed with deionized water until neutral. The organic phase was dried over anhydrous magnesium sulfate and toluene was removed by vacuum distillation to obtain the functional monomers.

[0041] (2) Grafting modification of polymethylsilsesquioxane microspheres: Deionized water and sodium lauryl ether sulfate were added to the reaction apparatus and stirred to dissolve. Then, surface-ethylene-modified polymethylsilsesquioxane microspheres were added and ultrasonically dispersed for 30 min to make the microspheres uniformly suspended. Then, styrene and functional monomers were added in sequence, stirred evenly, and heated to 70°C. 0.5 g of potassium persulfate was added and reacted for 4 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, centrifuged, and the precipitate was washed three times with deionized water and ethanol in sequence. The precipitate was then dried under vacuum to obtain polymethylsilsesquioxane polymerization inhibitor.

[0042] The preparation method of the surface-ethylene-modified polymethyl silsesquioxane microspheres includes the following steps: adding methyltrimethoxysilane, vinyltrimethoxysilane and ultrapure water into a reaction apparatus, stirring at room temperature for 2 hours, then adding ammonia water, continuing to stir for 20 minutes, washing the obtained microspheres with ethanol, then washing with distilled water until neutral, and drying under vacuum to obtain surface-ethylene-modified polymethyl silsesquioxane microspheres.

[0043] In step S1, the amount of dichloromethane added is 2.0 times the mass of diketene; the amount of polymethylsilsesquioxane polymerization inhibitor added is 0.05% of the mass of diketene.

[0044] In step S2, the total amount of chlorine introduced is in a molar ratio of 1.02:1 to diketene.

[0045] In step S3, the molar ratio of anhydrous ethanol to diketene is 1.5:1.

[0046] In step (1), the molar ratio of 3,5-di-tert-butyl-4-hydroxycinnamic acid to α-vinylbenzyl alcohol is 1:1.05; the amount of toluene added is 3 times the total mass of 3,5-di-tert-butyl-4-hydroxycinnamic acid and α-vinylbenzyl alcohol; and the amount of p-toluenesulfonic acid added is 1% of the mass of 3,5-di-tert-butyl-4-hydroxycinnamic acid.

[0047] In step (2), the mass ratio of the surface-ethylene-modified polymethyl silsesquioxane microspheres, styrene, and functional monomers is 1:0.8:0.2; the amount of deionized water added is 8 times the total mass of the three reactants in step (2); and the amount of sodium lauryl ether sulfate added is 0.5% of the mass of deionized water.

[0048] The molar ratio of methyltrimethoxysilane to vinyltrimethoxysilane is 2.5:1; the amount of ultrapure water added is 5 times the total mass of methyltrimethoxysilane and vinyltrimethoxysilane; the amount of ammonia added is 0.05% of the total mass of methyltrimethoxysilane and vinyltrimethoxysilane.

[0049] Example 2:

[0050] A method for preparing ethyl 4-chloroacetoacetate includes the following steps:

[0051] S1. Add diketene to the reactor, slowly add dichloromethane, and stir at 400 r / min to completely dissolve the diketene. After the system temperature stabilizes at 25℃, add polymethylsilsesquioxane polymerization inhibitor and continue stirring for 15 min to ensure uniform dispersion of the polymerization inhibitor.

[0052] S2. Control the system temperature at 5℃, slowly introduce chlorine gas at a rate of 30 mL / min, and stop introducing chlorine when the residual amount of diketene is ≤0.5% by gas chromatography. Stir the reaction for 3 hours to obtain a dichloromethane solution of 4-chloroacetoacetic acid.

[0053] S3. Keep the system temperature at 20℃, add anhydrous ethanol dropwise to the above dichloromethane solution of 4-chloroacetoacetic acid through a constant pressure dropping funnel. After the addition is complete, raise the temperature to 35℃ and keep the reaction at this temperature for 2 hours. Stop the reaction when the conversion rate of 4-chloroacetoacetic acid is ≥99% by gas chromatography to obtain crude ethyl 4-chloroacetoacetate.

[0054] S4. Distillation and solvent removal: Distill the crude product under normal pressure to remove dichloromethane and excess ethanol. Collect the first fraction until the distillation temperature stabilizes above 80°C to obtain the solvent-removed crude product. Then, use a vacuum distillation apparatus, set the vacuum degree to 0.098 MPa, and slowly raise the temperature to 110°C. Collect the fraction at 90°C to obtain ethyl 4-chloroacetoacetate product.

[0055] The preparation method of the polymethylsilsesquioxane polymerization inhibitor includes the following steps:

[0056] (1) Synthesis of functional monomers: 3,5-di-tert-butyl-4-hydroxycinnamic acid and α-vinylbenzyl alcohol were added to the reaction apparatus, along with toluene and p-toluenesulfonic acid. The mixture was heated to reflux for 6 hours, and the water produced during the reaction was collected through a water separator. After the reaction was completed, the reaction solution was cooled to room temperature, washed twice with 5% sodium carbonate solution, and then washed with deionized water until neutral. The organic phase was dried over anhydrous magnesium sulfate and toluene was removed by vacuum distillation to obtain the functional monomers.

[0057] (2) Grafting modification of polymethylsilsesquioxane microspheres: Deionized water and sodium lauryl ether sulfate were added to the reaction apparatus and stirred to dissolve. Then, surface-ethylene-modified polymethylsilsesquioxane microspheres were added and ultrasonically dispersed for 30 min to make the microspheres uniformly suspended. Then, styrene and functional monomers were added in sequence, stirred evenly, and heated to 70°C. 0.5 g of potassium persulfate was added and reacted for 4 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, centrifuged, and the precipitate was washed three times with deionized water and ethanol in sequence. The precipitate was then dried under vacuum to obtain polymethylsilsesquioxane polymerization inhibitor.

[0058] The preparation method of the surface-ethylene-modified polymethyl silsesquioxane microspheres includes the following steps: adding methyltrimethoxysilane, vinyltrimethoxysilane and ultrapure water into a reaction apparatus, stirring at room temperature for 2 hours, then adding ammonia water, continuing to stir for 20 minutes, washing the obtained microspheres with ethanol, then washing with distilled water until neutral, and drying under vacuum to obtain surface-ethylene-modified polymethyl silsesquioxane microspheres.

[0059] In step S1, the amount of dichloromethane added is 3.5 times the mass of diketene; the amount of polymethylsilsesquioxane polymerization inhibitor added is 0.2% of the mass of diketene.

[0060] In step S2, the total amount of chlorine introduced is in a molar ratio of 1.10:1 to diketene.

[0061] In step S3, the molar ratio of anhydrous ethanol to diketene is 2.5:1.

[0062] In step (1), the molar ratio of 3,5-di-tert-butyl-4-hydroxycinnamic acid to α-vinylbenzyl alcohol is 1:1.25; the amount of toluene added is 6 times the total mass of 3,5-di-tert-butyl-4-hydroxycinnamic acid and α-vinylbenzyl alcohol; and the amount of p-toluenesulfonic acid added is 3% of the mass of 3,5-di-tert-butyl-4-hydroxycinnamic acid.

[0063] In step (2), the mass ratio of the surface-ethylene-modified polymethylsilsesquioxane microspheres, styrene, and functional monomers is 1:1.5:0.6; the amount of deionized water added is 15 times the total mass of the three reactants in step (2); and the amount of sodium lauryl ether sulfate added is 2.0% of the mass of deionized water.

[0064] The molar ratio of methyltrimethoxysilane to vinyltrimethoxysilane is 4:1; the amount of ultrapure water added is 10 times the total mass of methyltrimethoxysilane and vinyltrimethoxysilane; the amount of ammonia added is 0.15% of the total mass of methyltrimethoxysilane and vinyltrimethoxysilane.

[0065] Example 3:

[0066] A method for preparing ethyl 4-chloroacetoacetate includes the following steps:

[0067] S1. Add diketene to the reactor, slowly add dichloromethane, and stir at 350 r / min to completely dissolve the diketene. After the system temperature stabilizes at 22.5℃, add polymethylsilsesquioxane polymerization inhibitor and continue stirring for 12.5 min to ensure uniform dispersion of the polymerization inhibitor.

[0068] S2. Control the system temperature at 2.5℃, slowly introduce chlorine gas at a rate of 25 mL / min, and stop introducing chlorine when the residual amount of diketene is ≤0.5% by gas chromatography. Stir the reaction for 2.75 h to obtain a dichloromethane solution of 4-chloroacetoacetic acid.

[0069] S3. Keep the system temperature at 17.5℃, add anhydrous ethanol dropwise to the dichloromethane solution of the above 4-chloroacetoacetic acid through a constant pressure dropping funnel. After the addition is complete, raise the temperature to 32.5℃ and keep the reaction at this temperature for 1.75h. Stop the reaction when the conversion rate of 4-chloroacetoacetic acid is ≥99% by gas chromatography to obtain crude ethyl 4-chloroacetoacetate.

[0070] S4. Distillation and solvent removal: The crude product is distilled at atmospheric pressure to remove dichloromethane and excess ethanol. The first fraction is collected until the distillation temperature stabilizes above 80°C to obtain the solvent-removed crude product. Then, a vacuum distillation apparatus is used with a vacuum degree of 0.0965 MPa and the temperature is slowly raised to 105°C. The fraction with a distillation temperature of 87.5°C is collected to obtain ethyl 4-chloroacetoacetate product.

[0071] The preparation method of the polymethylsilsesquioxane polymerization inhibitor includes the following steps:

[0072] (1) Synthesis of functional monomers: 3,5-di-tert-butyl-4-hydroxycinnamic acid and α-vinylbenzyl alcohol were added to the reaction apparatus, along with toluene and p-toluenesulfonic acid. The mixture was heated to reflux for 5 hours, and the water produced during the reaction was collected through a water separator. After the reaction was completed, the reaction solution was cooled to room temperature, washed twice with 5% sodium carbonate solution, and then washed with deionized water until neutral. The organic phase was dried over anhydrous magnesium sulfate and toluene was removed by vacuum distillation to obtain the functional monomers.

[0073] (2) Grafting modification of polymethylsilsesquioxane microspheres: Deionized water and sodium lauryl ether sulfate were added to the reaction apparatus and stirred to dissolve. Then, surface-ethylene-modified polymethylsilsesquioxane microspheres were added and ultrasonically dispersed for 30 min to make the microspheres uniformly suspended. Then, styrene and functional monomers were added in sequence, stirred evenly, and heated to 70°C. 0.5 g of potassium persulfate was added and reacted for 4 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, centrifuged, and the precipitate was washed three times with deionized water and ethanol in sequence. The precipitate was then dried under vacuum to obtain polymethylsilsesquioxane polymerization inhibitor.

[0074] The preparation method of the surface-ethylene-modified polymethyl silsesquioxane microspheres includes the following steps: adding methyltrimethoxysilane, vinyltrimethoxysilane and ultrapure water into a reaction apparatus, stirring at room temperature for 2 hours, then adding ammonia water, continuing to stir for 20 minutes, washing the obtained microspheres with ethanol, then washing with distilled water until neutral, and drying under vacuum to obtain surface-ethylene-modified polymethyl silsesquioxane microspheres.

[0075] In step S1, the amount of dichloromethane added is 2.75 times the mass of diketene; the amount of polymethylsilsesquioxane polymerization inhibitor added is 0.12% of the mass of diketene.

[0076] In step S2, the total amount of chlorine introduced is in a molar ratio of 1.06:1 to diketene.

[0077] In step S3, the molar ratio of anhydrous ethanol to diketene is 2.0:1.

[0078] In step (1), the molar ratio of 3,5-di-tert-butyl-4-hydroxycinnamic acid to α-vinylbenzyl alcohol is 1:1.15; the amount of toluene added is 4.5 times the total mass of 3,5-di-tert-butyl-4-hydroxycinnamic acid and α-vinylbenzyl alcohol; and the amount of p-toluenesulfonic acid added is 2% of the mass of 3,5-di-tert-butyl-4-hydroxycinnamic acid.

[0079] In step (2), the mass ratio of the surface-ethylene-modified polymethylsilsesquioxane microspheres, styrene, and functional monomers is 1:1.15:0.4; the amount of deionized water added is 11.5 times the total mass of the three reactants in step (2); and the amount of sodium lauryl ether sulfate added is 1.25% of the mass of deionized water.

[0080] The molar ratio of methyltrimethoxysilane to vinyltrimethoxysilane is 3.25:1; the amount of ultrapure water added is 7.5 times the total mass of methyltrimethoxysilane and vinyltrimethoxysilane; the amount of ammonia added is 0.10% of the total mass of methyltrimethoxysilane and vinyltrimethoxysilane.

[0081] Comparative Example 1:

[0082] A method for preparing ethyl 4-chloroacetoacetate. The difference between this comparative example and Example 3 is that no polymerization inhibitor is added, while the rest is the same as Example 3.

[0083] Comparative Example 2:

[0084] A method for preparing ethyl 4-chloroacetoacetate. The difference between this comparative example and Example 3 is that hydroquinone, a conventional polymerization inhibitor, is used instead of polymethylsilsesquioxane polymerization inhibitor. All other aspects are the same as in Example 3.

[0085] Results Analysis

[0086] The polymethylsilsesquioxane polymerization inhibitor prepared in Example 3 was characterized by FTIR spectroscopy, and the image is shown below. Figure 2 .from Figure 2 It can be seen from the image that it is 1732.8 cm. -1 The peak at 3425.7 cm⁻¹ corresponds to the C=O stretching vibration in the ester group, indicating that 3,5-di-tert-butyl-4-hydroxycinnamic acid successfully reacted with α-vinylbenzyl alcohol to form an ester group. -1 The peak at 1367.1 cm⁻¹ corresponds to the stretching vibration of the phenolic hydroxyl group (OH). -1 The peak at 1028.9 cm⁻¹ corresponds to the C-CH₃ bending vibration in the tert-butyl group, indicating that the hindered phenolic structure was successfully introduced into the functional monomer. -1 1135.2cm -1 The peak at 1601.4 cm⁻¹ represents the Si-O-Si stretching vibration, a characteristic peak of the polymethylsilsesquioxane framework, indicating that the surface-ethylene-modified polymethylsilsesquioxane microspheres were successfully retained in the final product. -1 The peak at position C=C represents the stretching vibration of the benzene ring and originates from the functional monomer and the comonomer styrene. Therefore, this invention successfully synthesizes a polymethylsilsesquioxane polymerization inhibitor.

[0087] The product yield, product purity, and product appearance of each embodiment and comparative example of the present invention were compared, and the results are shown in Table 1.

[0088] Table 1 Comparison of the effects of the embodiments and comparative examples

[0089] project Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Product yield / % 96.5 95.8 96.2 78.5 92.2 Product purity / % 99.5 99.3 99.4 92.3 95.1 Product Appearance Colorless and transparent Colorless and transparent Colorless and transparent pale yellow Colorless and transparent

[0090] As shown in Table 1, the polymethylsilsesquioxane polymerization inhibitor prepared using this invention effectively inhibits the polymerization reaction of diketene, intermediates, and products, with significantly higher product yield and purity than the comparative example. The polymerization inhibitor of this invention exhibits high stability and long-lasting polymerization inhibition effect, significantly reducing side reactions and ensuring high product quality.

[0091] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

[0092] The present invention and its embodiments have been described above. This description is not restrictive, and the embodiments shown are only one of the embodiments of the present invention. The actual application is not limited to this. In conclusion, if those skilled in the art are inspired by this description and design similar methods and embodiments without departing from the spirit of the present invention, they should all fall within the protection scope of the present invention.

Claims

1. A process for the preparation of ethyl 4-chloroacetoacetate, characterized in that: Comprising the following steps: S1. Add double vinyl ketone to the reactor, slowly add dichloromethane, and fully dissolve the double vinyl ketone at a stirring speed of 300-400 r / min. After the system temperature is stabilized to 20-25℃, add the polysiloxane polymerization inhibitor, and continue stirring for 10-15 min to uniformly disperse the polymerization inhibitor; S2. Control the system temperature at 0-5℃, slowly introduce chlorine gas at a rate of 20-30 mL / min, stop the chlorine gas introduction when the residual amount of double vinyl ketone is less than or equal to 0.5% by gas chromatography, and stir for 2.5-3 h to obtain a dichloromethane solution of 4-chloroacetoacetic acid; S3. Keep the system temperature at 15-20℃, and add anhydrous ethanol to the above-mentioned dichloromethane solution of 4-chloroacetoacetic acid through a constant pressure dropping funnel. After the addition is completed, warm to 30-35℃, and keep the temperature for 1.5-2 h. Stop the reaction when the conversion rate of 4-chloroacetoacetic acid is greater than or equal to 99% by gas chromatography, and obtain a crude 4-chloroacetoacetic acid ethyl ester product; S4. Distill the solvent: distill dichloromethane and excess ethanol from the crude product at normal pressure, collect the front fraction until the distillation temperature is stabilized above 80℃, obtain a desolventized crude product, and then use a vacuum rectification device, set the vacuum degree to 0.095-0.098 MPa, slowly warm to a kettle temperature of 100-110℃, and collect components with a distillation temperature of 85-90℃ to obtain a 4-chloroacetoacetic acid ethyl ester product.

2. The process for the preparation of ethyl 4-chloroacetoacetate according to claim 1, characterized in that: The preparation method of the polysiloxane polymerization inhibitor comprises the following steps: (1) Synthesis of functional monomer: add 3,5-di-tert-butyl-4-hydroxycinnamic acid and α-vinylbenzyl alcohol to a reaction device, add toluene and p-toluenesulfonic acid, heat to reflux for 4-6 h, collect the water produced during the reaction through a water trap, cool the reaction liquid to room temperature after the reaction is completed, wash twice with 5% sodium carbonate solution, and then wash with deionized water until neutral. Dry the organic phase with anhydrous magnesium sulfate, and then remove toluene by vacuum distillation to obtain the functional monomer; (2) Graft modification of polysiloxane microspheres: add deionized water and sodium lauryl polyether sulfate to a reaction device, stir and dissolve, then add surface ethyleneated polysiloxane microspheres, ultrasonic dispersion for 30 min to uniformly suspend the microspheres, and then sequentially add styrene and the functional monomer. After uniform stirring, warm to 70℃, add 0.5 g of potassium persulfate, and react for 4 h under nitrogen protection. After the reaction is completed, cool to room temperature, centrifugal separation, wash the precipitate with deionized water and ethanol for 3 times, and vacuum dry to obtain the polysiloxane polymerization inhibitor.

3. The process for the preparation of ethyl 4-chloroacetoacetate according to claim 2, characterized in that: The preparation method of the surface ethyleneated polysiloxane microspheres comprises the following steps: add methyltrimethoxysilane, vinyltrimethoxysilane and ultrapure water to a reaction device, stir for 2 h at room temperature, then add 3 mol / L ammonia water, continue to stir for 20 min, wash the obtained microspheres with ethanol, then wash with distilled water until neutral, and vacuum dry to obtain the surface ethyleneated polysiloxane microspheres.

4. The process for the preparation of ethyl 4-chloroacetoacetate according to claim 1, characterized in that: The amount of dichloromethane added in step S1 is 2.0-3.5 times the mass of the ketene; the amount of poly-methylsilsesquioxane polymerization inhibitor added is 0.05%-0.2% of the mass of the ketene.

5. The process for the preparation of ethyl 4-chloroacetoacetate according to claim 1, characterized in that: In step S2, the total amount of chlorine gas introduced is in a molar ratio of 1.02-1.10:1 to the ketene.

6. The process for the preparation of ethyl 4-chloroacetoacetate according to claim 1, characterized in that: In step S3, the amount of anhydrous ethanol added is in a molar ratio of 1.5-2.5:1 to the ketene.

7. The process for the preparation of ethyl 4-chloroacetoacetate according to claim 2, characterized in that: In step (1), the molar ratio of 3,5-di-tert-butyl-4-hydroxycinnamic acid to α-vinylbenzyl alcohol is 1:1.05-1.25; the amount of toluene added is 3-6 times the total mass of 3,5-di-tert-butyl-4-hydroxycinnamic acid and α-vinylbenzyl alcohol; the amount of p-toluenesulfonic acid added is 1%-3% of the mass of 3,5-di-tert-butyl-4-hydroxycinnamic acid.

8. The process for the preparation of ethyl 4-chloroacetoacetate according to claim 2, characterized in that: In step (2), the mass ratio of surface-vinylated poly-methylsilsesquioxane microspheres, styrene, and functional monomer is 1:0.8-1.5:0.2-0.6; the amount of deionized water added is 8-15 times the total mass of the three reactants in step (2); the amount of sodium lauryl polyether sulfate added is 0.5%-2.0% of the mass of the deionized water.

9. The process for the preparation of ethyl 4-chloroacetoacetate according to claim 3, characterized in that: The molar ratio of methyltrimethoxysilane to vinyltrimethoxysilane is 2.5-4:1; the amount of ultrapure water added is 5-10 times the total mass of methyltrimethoxysilane and vinyltrimethoxysilane; the amount of ammonia water added is 0.05%-0.15% of the total mass of methyltrimethoxysilane and vinyltrimethoxysilane.

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