2-fluorophosphonooxyacetic acid triethyl ester and a process for its preparation

Abstract

This invention relates to triethyl 2-fluorophosphonoacetate and its preparation method. The preparation method includes mixing diethyl phosphite with a first solvent, then adding hyperbranched polyamine-modified resin and ethyl bromofluoroacetate for reaction; after the reaction, solid-liquid separation is performed, and the filtrate is treated to obtain triethyl 2-fluorophosphonoacetate. This invention uses hyperbranched polyamine-modified resin as a catalyst for diethyl phosphite and ethyl bromofluoroacetate, which can be removed by filtration after the reaction, simplifying post-treatment and significantly reducing the generation of waste salts and wastewater, thus reducing the cost of waste treatment. Simultaneously, the resin can be regenerated and reused during the reaction, reducing production costs. By optimizing the reaction conditions and resin dosage, the yield can reach over 91%, and the product has good color and high purity. The reaction conditions are mild, and the reaction rate is fast, showing good application prospects in industrial production.

Description

Technical Field

[0001] This invention relates to the field of phosphorus compound synthesis technology, specifically to a 2-fluorophosphonoacetic acid triethyl ester and its preparation method. Background Technology

[0002] Diethyl (ethoxyphosphinyl)fluoracetate is an important intermediate in the synthesis of fluorinated phosphonates and is widely used in pharmaceuticals, pesticides, and flame retardants. In the pharmaceutical field, it is used to construct fluorinated fragments of antiviral drugs (such as tenofovir analogs and oseltamivir analogs), synthesize lead compounds for antitumor / metabolic drugs containing monofluorovinyl pharmacophores such as HDAC inhibitors and DPP-4 inhibitors, and synthesize vitamins, insect pheromones, and chiral fluorinated natural products. In the pesticide field, it is mainly used to synthesize active ingredients in highly effective fluorinated pesticides / herbicides / insecticides; the introduction of fluorine atoms can improve the lipid solubility, metabolic stability, and target affinity of the agents. Furthermore, it can be used as a phosphorus-containing flame retardant additive in lithium-ion battery electrolytes (1%-10%, w / w). The phosphorus + fluorine dual flame retardant mechanism can effectively improve the thermal stability and flame retardant performance of the electrolyte and inhibit battery thermal runaway. Since 2-fluorophosphoryl acetate triethyl ester has a wide range of applications in pharmaceuticals, pesticides, materials and other fields, and its market prospects are broad, the efficient synthesis of 2-fluorophosphoryl acetate triethyl ester is particularly important.

[0003] Existing methods for synthesizing triethyl 2-fluorophosphonoacetate mostly involve the Michaelis-Arbuzov phosphonate synthesis reaction of triethyl phosphite and ethyl bromofluoroacetate. However, this method suffers from drawbacks such as high reaction temperatures (100-140℃), long reaction times (12-16 hours), direct emission of the byproduct bromoethane into the air causing significant environmental impact, and product deterioration and yellowing over long storage periods, making it unsuitable for industrial production. Furthermore, CN118772198A discloses a method for the efficient synthesis of triethyl phosphonoacetate using diethyl phosphite and ethyl chloroacetate as raw materials and an equivalent amount of sodium alkoxide as a base. This method is highly efficient and has a short reaction time, but it also generates large amounts of wastewater and waste salts during the post-processing.

[0004] Therefore, it is of great significance to develop a synthesis method that has high yield, simple operation, simple post-processing, reduces waste costs, and is environmentally friendly. Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing triethyl 2-fluorophosphorylacetate using modified resin catalysis. The product can be removed by filtration after the reaction. The operation is simple, greatly reducing the generation of waste salt and wastewater, and also reducing the cost of waste treatment.

[0006] To achieve the above-mentioned technical objectives, the present invention provides a method for preparing triethyl 2-fluorophosphonoacetate, comprising, After mixing diethyl phosphite with the first solvent, hyperbranched polyamine-modified resin and ethyl bromofluoroethylene were added to carry out the reaction. After the reaction was completed, the solid and liquid were separated, and the filtrate was treated to obtain triethyl 2-fluorophosphonoacetate.

[0007] Furthermore, the molar ratio of diethyl phosphite to ethyl bromofluoroacetate is 1:1.0-1.2; The amount of the hyperbranched polyamine modified resin is 10%-50% of the mass of diethyl phosphite.

[0008] Furthermore, the preparation method of the hyperbranched polyamine modified resin includes, A strong basic anion exchange resin, a second solvent, 1,4-butanediol diglycidyl ether and tetrabutylammonium bromide are mixed and reacted at elevated temperature to obtain an epoxy-modified resin. An epoxy-modified resin was mixed with an ethylenediamine solution and reacted at a higher temperature to obtain a first intermediate. The first intermediate, a second solvent, 1,4-butanediol diglycidyl ether, and tetrabutylammonium bromide were mixed and reacted at a higher temperature to obtain a second intermediate. The second intermediate was mixed with an ethylenediamine solution and reacted at a higher temperature to obtain a terminal amino hyperbranched resin. The terminal amine hyperbranched resin and trimethylamine solution were mixed, the pH was adjusted and the temperature was raised to react, and a third intermediate was obtained; the third intermediate was mixed with an alkaline solution to react and obtain hyperbranched polyamine modified resin.

[0009] Furthermore, the mass ratio of the strongly basic anion exchange resin, the second solvent, 1,4-butanediol diglycidyl ether, and tetrabutylammonium bromide is 1:10-20:2-5:0.5; The mass ratio of the epoxy-modified resin to the ethylenediamine solution is 1:5-8, the mass ratio of the second intermediate to the ethylenediamine solution is 1:5-8, and the mass concentration of the ethylenediamine solution is 30%-40%. The mass ratio of the first intermediate, the second solvent, 1,4-butanediol diglycidyl ether, and tetrabutylammonium bromide is 1:10-20:2-5:0.5; The mass concentration of the trimethylamine solution is 25%-35%; The pH is adjusted to 7.5-9.5; The concentration of hydroxide ions in the alkaline solution is 0.2-1.0 mol / L.

[0010] Furthermore, the heating reaction is carried out at 40-50°C for 2-10 hours; The second solvent includes at least one of water, N,N-dimethylformamide, acetone, diethyl ether, ethanol, and cyclohexane.

[0011] Furthermore, the strongly basic anion exchange resin is activated by soaking in acid and / or alkali and swelling before use.

[0012] Further, the first solvent includes at least one selected from 1,2-dichloroethane, acetonitrile, toluene, cyclohexane, ethyl acetate, tetrahydrofuran, and dimethyl sulfoxide.

[0013] Furthermore, the reaction is carried out at a temperature of 20-30°C for 0.5-4 hours.

[0014] Furthermore, the process includes atmospheric distillation to recover the first solvent and vacuum distillation to collect the 120-122℃ / 5mm Hg fraction.

[0015] The present invention also provides a 2-fluorophosphonoacetic acid triethyl ester, which is obtained by the above preparation method.

[0016] Compared with the prior art, the beneficial effects of the present invention include: This invention uses hyperbranched polyamine-modified resin as a catalyst for diethyl phosphite and ethyl bromofluoroethylene. The catalyst can be removed by filtration after the reaction, simplifying post-treatment and significantly reducing the generation of waste salts and wastewater, thus lowering waste treatment costs. Simultaneously, the resin can be recycled and reused during the reaction, reducing production costs. By optimizing reaction conditions and resin dosage, the yield can reach over 91%, and the product has good color and high purity. The reaction conditions are mild, and the reaction rate is fast, showing promising application prospects in industrial production.

[0017] The above description is only an overview of the technical solution of this application. In order to better understand the technical means of this application and to implement it in accordance with the contents of the specification, and to make the above and other objects, features and advantages of this application more obvious and understandable, the following are specific embodiments of this application. Attached Figure Description

[0018] To more clearly illustrate the technical solutions of this application, the accompanying drawings used in this application will be briefly described below. Obviously, the drawings described below are merely some embodiments of this application. For those skilled in the art, other drawings can be obtained from these drawings without any creative effort.

[0019] Figure 1 The 1H NMR spectrum of triethyl 2-fluorophosphorylacetate prepared in Example 4 is shown. Figure 2 The carbon NMR spectrum of 2-fluorophosphorylacetic acid triethyl ester prepared in Example 4 is shown. Detailed Implementation

[0020] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains; the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the invention; the terms “comprising” and “having”, and any variations thereof, in the specification, claims, and foregoing description of the invention, are intended to cover non-exclusive inclusion.

[0022] In this document, the term "embodiment" means that a particular feature, structure, or characteristic described in connection with an embodiment may be included in at least one embodiment of the invention. The appearance of this phrase in various places throughout the specification does not necessarily refer to the same embodiment, nor is it a separate or alternative embodiment mutually exclusive with other embodiments. It will be explicitly and implicitly understood by those skilled in the art that the embodiments described herein can be combined with other embodiments.

[0023] The synthesis of 2-fluorophosphoacetic acid triethyl ester from triethyl phosphite and ethyl bromofluoroacetate via the Michaelis-Arbuzov reaction (a type of nucleophilic substitution reaction) is a conventional method reported in the literature. It is mainly divided into solvent-free heating, fractional heating, and solvent-catalyzed methods. The solvent-free heating method is relatively simple, involving direct heating of the mixed raw materials, followed by purification of the product via vacuum distillation after the reaction. The fractional heating method uses a fractionating column to continuously remove the byproduct bromoethane, shifting the reaction equilibrium towards the product, which is then collected by vacuum distillation. The solvent-catalyzed method generally uses crown ethers as phase transfer catalysts, allowing the reaction to proceed at relatively low temperatures (105°C). These traditional methods suffer from high reaction temperatures (100-140°C), long reaction times (12-16 hours), and difficulties in handling the byproduct bromoethane. Using diethyl phosphite and ethyl chlorophosphite as raw materials, and employing an equivalent amount of sodium alkoxide as a base, offers advantages such as room temperature reaction capability, high efficiency, and short reaction time, but generates an equivalent amount of waste salt, resulting in higher treatment costs.

[0024] Based on this, the present invention is proposed.

[0025] A method for preparing triethyl 2-fluorophosphonoacetate, comprising, After mixing diethyl phosphite with the first solvent, hyperbranched polyamine-modified resin and ethyl bromofluoroethylene were added to carry out the reaction. After the reaction was completed, the solid and liquid were separated, and the filtrate was treated to obtain triethyl 2-fluorophosphonoacetate.

[0026] In this invention, hyperbranched polyamine-modified resin is used as a catalyst for the esterification reaction of diethyl phosphite and ethyl bromofluoroethylene. Compared to using organic or inorganic bases, the resin can be removed by filtration after the reaction, simplifying post-treatment and significantly reducing the generation of waste salts and wastewater, thus lowering the cost of waste treatment. Simultaneously, the resin can be recycled and reused during the reaction, reducing production costs. By optimizing the reaction conditions and resin dosage, the yield can reach over 91%, and the product has good color and high purity. The reaction conditions are mild, and the reaction rate is fast.

[0027] The overall reaction formula of this invention, using diethyl phosphite and ethyl bromofluoroethylene as raw materials and hyperbranched polyamine modified resin as a catalyst, is as follows: .

[0028] The reaction mechanism is an SN2 nucleophilic substitution reaction, as shown below: .

[0029] The specific process of this reaction mechanism is that, in the presence of hyperbranched polyamine modified resin, diethyl phosphite is deprotonated to generate a phosphoanion intermediate, which then attacks ethyl bromofluoroacetate to generate the target product, triethyl 2-fluorophosphorylacetate.

[0030] Hyperbranched polyamine-modified resin is obtained by activating anion exchange resin, followed by epoxy functionalization, alternating layer-by-layer grafting growth of hyperbranched polyamine with epoxy and amine groups, and quaternization to enhance basicity. This allows for the superposition of multiple functional sites: the original quaternary ammonium groups, hyperbranched terminal amines, and deep quaternization. The integration of alternating layer-by-layer epoxy-amine growth with deep quaternization systematically combines the two stages of in-situ hyperbranching and deep quaternization. First, a high-density hyperbranched structure with terminal amine groups is constructed in situ within the resin channels through multiple rounds of alternating epoxy-amine reactions. Then, deep quaternization with trimethylamine is performed, potentially achieving ultra-high exchange capacity. The hyperbranched structure provides numerous terminal amine sites, and deep quaternization converts all these sites into strongly basic quaternary ammonium groups, significantly improving the exchange capacity and basicity per unit mass of resin.

[0031] In some preferred embodiments, the molar ratio of diethyl phosphite to ethyl bromofluoroacetate is 1:1.0-1.2; The amount of the hyperbranched polyamine modified resin is 10%-50% of the mass of diethyl phosphite.

[0032] In some preferred embodiments, the method for preparing the hyperbranched polyamine modified resin includes, A strong basic anion exchange resin, a second solvent, 1,4-butanediol diglycidyl ether and tetrabutylammonium bromide are mixed and reacted at elevated temperature to obtain an epoxy-modified resin. An epoxy-modified resin was mixed with an ethylenediamine solution and reacted at a higher temperature to obtain a first intermediate. The first intermediate, a second solvent, 1,4-butanediol diglycidyl ether, and tetrabutylammonium bromide were mixed and reacted at a higher temperature to obtain a second intermediate. The second intermediate was mixed with an ethylenediamine solution and reacted at a higher temperature to obtain a terminal amino hyperbranched resin. The terminal amine hyperbranched resin and trimethylamine solution were mixed, the pH was adjusted and the temperature was raised to react, and a third intermediate was obtained; the third intermediate was mixed with an alkaline solution to react and obtain hyperbranched polyamine modified resin.

[0033] In some preferred embodiments, the mass ratio of the strongly basic anion exchange resin, the second solvent, 1,4-butanediol diglycidyl ether, and tetrabutylammonium bromide is 1:10-20:2-5:0.5. The mass ratio of the epoxy-modified resin to the ethylenediamine solution is 1:5-8, the mass ratio of the second intermediate to the ethylenediamine solution is 1:5-8, and the mass concentration of the ethylenediamine solution is 30%-40%. The mass ratio of the first intermediate, the second solvent, 1,4-butanediol diglycidyl ether, and tetrabutylammonium bromide is 1:10-20:2-5:0.5; The mass concentration of the trimethylamine solution is 25%-35%; The pH is adjusted to 7.5-9.5; The concentration of hydroxide ions in the alkaline solution is 0.2-1.0 mol / L.

[0034] In some preferred embodiments, the heating reaction is carried out at 40-50°C for 2-10 hours; The second solvent includes at least one of water, N,N-dimethylformamide, acetone, diethyl ether, ethanol, and cyclohexane.

[0035] In some preferred embodiments, the strongly basic anion exchange resin is activated by soaking in acid and / or alkali and swelling before use. This activation treatment opens the resin's pores, allowing hyperbranched polyamines to grow in situ within the resin macropores, rather than simply being coated on the surface. This enables the hyperbranched polymer to extend beyond the resin's outer surface and penetrate deep into the pores, forming a three-dimensional functional layer distribution. Combined with the resin's inherent porous structure, this promises to achieve high-density functionalization while maintaining good mass transfer performance.

[0036] Acid and / or alkali soaking and swelling to activate resins are conventional treatment methods in the art and are not strictly limited. As a typical implementation method, the following steps can be taken: rinsing the strongly basic anion exchange resin with deionized water until the effluent is clear; then soaking it in 3%-8% hydrochloric acid for 2 hours, followed by washing with water until neutral; then soaking it in 5% sodium hydroxide solution for 2 hours, followed by washing with water until neutral; repeating the acid and alkali washing twice; then soaking the treated resin in ethanol for 0.5-2 hours; finally, soaking it in N,N-dimethylformamide for 10-18 hours to swell and fully open the pores; filtering and keeping it moist but not dry.

[0037] In some preferred embodiments, the first solvent includes at least one selected from 1,2-dichloroethane, acetonitrile, toluene, cyclohexane, ethyl acetate, tetrahydrofuran, and dimethyl sulfoxide. Preferably, the first solvent is 1,2-dichloroethane because it is an aprotic polar solvent, lacking active hydrogen, and therefore cannot solvate phosphine anions via hydrogen bonding. This results in a higher degree of exposure of the "naked" electron cloud of the phosphine anion, significantly enhancing its nucleophilicity and improving the yield. Furthermore, 1,2-dichloroethane exhibits good solubility for most organic substrates and many inorganic salts, ensuring sufficient contact of reactants in a homogeneous phase and increasing the effective collision frequency.

[0038] In some preferred embodiments, the reaction is carried out at a temperature of 20-30°C for 0.5-4 hours.

[0039] In some preferred embodiments, the process includes atmospheric distillation to recover the first solvent and vacuum distillation to collect the 120-122°C / 5 mm Hg fraction.

[0040] This invention does not limit the type of strongly basic anion exchange resin, and those skilled in the art can select it according to the actual situation. For example, it can be a D201 type strongly basic anion exchange resin.

[0041] This invention does not strictly limit the source of the raw materials diethyl phosphite and ethyl bromofluoroethylene; they can be prepared in-house or be commercially available products, provided their purity meets or exceeds the requirements in this field. As a typical implementation method, the preparation of diethyl phosphite includes mixing phosphorus trichloride and anhydrous ethanol at a molar ratio of 1:2-2.5, reacting at a temperature of -10 to 10°C, collecting the unreacted ethanol by atmospheric distillation, and then performing vacuum distillation to collect the fraction at 75-78°C / 15 mm Hg to obtain diethyl phosphite.

[0042] The present invention does not strictly limit the solvents of the raw materials used in the preparation of strongly basic anion exchange resins, such as ethylenediamine solution, trimethylamine solution, and alkali solution. Exemplarily, these solvents can be at least one of water, N,N-dimethylformamide, acetone, diethyl ether, ethanol, cyclohexane, etc., preferably water. The ratio of the third intermediate to the alkali solution in the final step is not strictly limited; however, to conserve alkali solution, the mass ratio of the third intermediate to the alkali solution is 1:10-15.

[0043] The present invention will be further described in detail below through specific embodiments. It should be noted that the embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application. Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in this field or in accordance with the product instructions. Reagents or instruments used that do not specify the manufacturer are all conventional products that can be obtained commercially.

[0044] Preparation Example 1 A method for preparing diethyl phosphite includes the following steps: Under nitrogen protection, 149.7 g (1.09 mol) of phosphorus trichloride was added dropwise to 250.1 g (5.43 mol, 4.98 equivalents) of anhydrous ethanol, with the internal temperature controlled to not exceed 10 °C. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 1 h. The reaction solution was distilled at atmospheric pressure to recover excess ethanol 141.8 g (3.08 mol, 2.83 equivalents), followed by vacuum distillation. The fraction collected at 75-78 °C / 15 mm Hg yielded 140.0 g of diethyl phosphite, with a yield of 93% and a purity of 99.5%.

[0045] Preparation Example 2 A method for preparing diethyl phosphite includes the following steps: Under nitrogen protection, 164.8 g (1.20 mol) of phosphorus trichloride was added dropwise to 129.9 g (2.82 mol, 2.35 equivalents) of anhydrous ethanol, with the internal temperature controlled to not exceed 10 °C. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 1 hour. The reaction solution was distilled at atmospheric pressure to recover excess ethanol (6.63 g, 0.14 mol, 0.12 equivalents), followed by vacuum distillation. The fraction collected at 75-78 °C / 15 mm Hg yielded 140.9 g of diethyl phosphite, with a yield of 85% and a purity of 99.1%.

[0046] Preparation Example 3 A method for preparing a hyperbranched polyamine modified resin includes the following steps: S1. Resin pretreatment and activation Take D201 strong basic anion exchange resin, rinse with deionized water until the effluent is clear; soak in 5% hydrochloric acid for 2 hours, wash with water until neutral; then soak in 5% NaOH solution for 2 hours, wash with water until neutral; repeat the cycle twice; soak in ethanol for 1 hour, then soak in N,N-dimethylformamide to swell for 12 hours to fully open the pores; filter to obtain activated resin for later use, keeping it moist and not drying.

[0047] S2, epoxy functionalization of resin skeleton The activated resin was transferred to a three-necked flask, and N,N-dimethylformamide, 1,4-butanediol diglycidyl ether, and tetrabutylammonium bromide were added. The mass ratio of the activated resin, N,N-dimethylformamide, 1,4-butanediol diglycidyl ether, and tetrabutylammonium bromide was 1:10:4:0.5. The mixture was then heated to 50°C and stirred for 4 hours to introduce epoxy groups into the surface and pores of the activated resin. After filtration, the resin was washed with N,N-dimethylformamide, ethanol, and deionized water, respectively, to obtain the epoxy-modified resin.

[0048] S3, hyperbranched polyamine graft growth Epoxy-modified resin was mixed with a 35% ethylenediamine aqueous solution at a mass ratio of 1:5, and then the mixture was heated to 50°C and reacted for 4 hours. A large amount of primary amine was generated at the end. After filtration and washing with water, a first intermediate was obtained. The first intermediate was mixed with N,N-dimethylformamide, 1,4-butanediol diglycidyl ether, and tetrabutylammonium bromide, wherein the mass ratio of the first intermediate, N,N-dimethylformamide, 1,4-butanediol diglycidyl ether, and tetrabutylammonium bromide was 1:10:4:0.5. The mixture was heated to 45°C and reacted for 3 hours. Epoxy was regenerated at the end. After filtration and washing with water, a second intermediate was obtained. The second intermediate was mixed with a 35% ethylenediamine aqueous solution at a mass ratio of 1:8, and the mixture was heated to 55°C and reacted for 4 hours. After filtration and washing with water, a terminal amine hyperbranched resin was obtained.

[0049] S4, quaternization enhances alkalinity. The terminal amine hyperbranched resin was mixed with a 30% triethylamine ethanol solution at a mass ratio of 1:10, and the pH was adjusted to 8.5 with sodium carbonate. The mixture was then heated to 50°C and reacted for 6 hours to deeply quaternize the terminal amine and stabilize the strongly basic sites. After filtration, the resin was washed with ethanol and water, and finally soaked in a 0.5 mol / L NaOH solution for 4 hours. After filtration, the resin was washed with ethanol and water to obtain the hyperbranched polyamine modified resin.

[0050] The hyperbranched polyamine modified resins used in the following examples were all obtained according to Preparation Example 3, and the specific preparation methods will not be described again.

[0051] Example 1 A method for preparing triethyl 2-fluorophosphonoacetate includes the following steps: In a 500 mL three-necked flask, 138.1 g (1.0 mol) of diethyl phosphite obtained in Preparation Example 1 and 200 mL of acetonitrile were added. After stirring until homogeneous, 20.7 g of hyperbranched polyamine-modified resin was added. Subsequently, 194.2 g (1.05 mol, 1.05 equivalent) of ethyl bromofluoroethylene was added dropwise, controlling the dropping rate to maintain the system temperature at 25-30 °C. After the addition was complete, the reaction was continued to be stirred at room temperature (25 °C) for 1 h.

[0052] After the reaction was monitored by TLC until complete, the resin was removed by filtration, and the filter cake was washed with a small amount of acetonitrile. The filtrates were combined, the solvent was recovered by atmospheric distillation, and then the fraction was collected by vacuum distillation at 120-122℃ / 5mm Hg to obtain 220.9 g of colorless and transparent liquid triethyl 2-fluorophosphorylacetate, with a yield of 91.2%.

[0053] Example 2 A method for preparing triethyl 2-fluorophosphonoacetate includes the following steps: In a 500 mL three-necked flask, 138.1 g (1.0 mol) of diethyl phosphite obtained in Preparation Example 2 and 200 mL of acetonitrile were added. After stirring until homogeneous, 20.7 g of hyperbranched polyamine-modified resin was added. Subsequently, 194.2 g (1.05 mol, 1.05 equivalent) of ethyl bromofluoroethylene was added dropwise, controlling the dropping rate to maintain the system temperature at 25-30 °C. After the addition was complete, the reaction was continued to be stirred at room temperature (25 °C) for 1 h.

[0054] After the reaction was monitored by TLC until complete, the resin was removed by filtration, and the filter cake was washed with a small amount of acetonitrile. The filtrates were combined, the solvent was recovered by atmospheric distillation, and then the fraction was collected by vacuum distillation at 120-122℃ / 5mm Hg to obtain 220.4 g of colorless and transparent liquid triethyl 2-fluorophosphorylacetate, with a yield of 91.0%.

[0055] Example 3 A method for preparing triethyl 2-fluorophosphonoacetate includes the following steps: In a 500 mL three-necked flask, 138.1 g (1.0 mol) of diethyl phosphite obtained in Preparation Example 1 and 200 mL of cyclohexane were added. After stirring until homogeneous, 20.7 g of hyperbranched polyamine-modified resin was added. Subsequently, 194.2 g (1.05 mol, 1.05 equivalent) of ethyl bromofluoroethylene was added dropwise, controlling the dropping rate to maintain the system temperature at 25-30 °C. After the addition was complete, the reaction was continued to be stirred at room temperature (25 °C) for 1 h.

[0056] After the reaction was monitored by TLC until complete, the resin was removed by filtration, and the filter cake was washed with a small amount of cyclohexane. The filtrates were combined, the solvent was recovered by atmospheric distillation, and then the fraction was collected by vacuum distillation at 122℃ / 5mm Hg to obtain 109.5 g of colorless and transparent liquid triethyl 2-fluorophosphorylacetate, with a yield of 45.2%.

[0057] Example 4 A method for preparing triethyl 2-fluorophosphonoacetate includes the following steps: In a 500 mL three-necked flask, 138.1 g (1.0 mol) of diethyl phosphite obtained in Preparation Example 1 and 200 mL of 1,2-dichloroethane were added. After stirring until homogeneous, 20.7 g of hyperbranched polyamine-modified resin was added. Subsequently, 194.2 g (1.05 mol, 1.05 equivalent) of ethyl bromofluoroacetate was added dropwise, controlling the dropping rate to maintain the system temperature at 25-30 °C. After the addition was complete, the reaction was continued to be stirred at room temperature (25 °C) for 1 h.

[0058] After the reaction was monitored by TLC until complete, the resin was removed by filtration, and the filter cake was washed with a small amount of 1,2-dichloroethane. The filtrates were combined, the solvent was recovered by atmospheric distillation, and then the fraction was collected by vacuum distillation at 120-122℃ / 5mm Hg to give 228.4 g of colorless and transparent liquid triethyl 2-fluorophosphorylacetate, with a yield of 94.3%.

[0059] The product yield in this embodiment is significantly higher than that in Examples 1-3. Because 1,2-dichloroethane is an aprotic polar solvent and does not contain active hydrogen, it cannot solvate phosphine anions through hydrogen bonding. This results in a higher degree of exposure of the "bare" electron cloud of the phosphine anion, significantly enhancing its nucleophilicity and increasing the yield. Furthermore, 1,2-dichloroethane has good solubility for most organic substrates and many inorganic salts, ensuring sufficient contact of reactants in a homogeneous phase and increasing the effective collision frequency.

[0060] Comparative Example 1 A method for preparing triethyl 2-fluorophosphonoacetate includes the following steps: In a 500 mL three-necked flask, 138.1 g (1.0 mol) of diethyl phosphite obtained in Preparation Example 1 and 200 mL of 1,2-dichloroethane were added. After stirring until homogeneous, 20.7 g of hyperbranched polyamine-modified resin was added. Subsequently, 194.2 g (1.05 mol, 1.05 equivalent) of ethyl bromofluoroacetate was added dropwise, controlling the dropping rate to maintain the system temperature at 25-30 °C. After the addition was complete, the temperature was raised to 45 °C and the reaction was stirred for 1 h.

[0061] After the reaction was monitored by TLC until complete, the resin was removed by filtration, and the filter cake was washed with a small amount of 1,2-dichloroethane. The filtrates were combined, the solvent was recovered by atmospheric distillation, and then the fraction was collected by vacuum distillation at 120-122℃ / 5mm Hg to obtain 228.9 g of colorless and transparent liquid triethyl 2-fluorophosphorylacetate, with a yield of 94.5%.

[0062] Compared to Example 4, Comparative Example 1 increased the reaction temperature from room temperature (25°C) to 45°C, indicating that the increased temperature was beneficial to the reaction. However, the yield improvement was not significant, and for energy-saving purposes, the reaction was preferably carried out at room temperature.

[0063] Example 5 A method for preparing triethyl 2-fluorophosphonoacetate includes the following steps: In a 500 mL three-necked flask, 138.1 g (1.0 mol) of diethyl phosphite obtained in Preparation Example 1 and 200 mL of tetrahydrofuran were added. After stirring until homogeneous, 20.7 g of hyperbranched polyamine-modified resin was added. Subsequently, 194.2 g (1.05 mol, 1.05 equivalent) of ethyl bromofluoroacetate was added dropwise, controlling the dropping rate to maintain the system temperature at 25-30 °C. After the addition was complete, the reaction was continued to be stirred at room temperature (25 °C) for 1 h.

[0064] After the reaction was monitored by TLC until complete, the resin was removed by filtration, and the filter cake was washed with a small amount of tetrahydrofuran. The filtrates were combined, the solvent was recovered by atmospheric distillation, and then the fraction was collected by vacuum distillation at 120-122℃ / 5mm Hg to give 224.0 g of colorless and transparent liquid triethyl 2-fluorophosphorylacetate, with a yield of 92.5%.

[0065] Example 6 A method for preparing triethyl 2-fluorophosphonoacetate includes the following steps: In a 500 mL three-necked flask, 138.1 g (1.0 mol) of diethyl phosphite obtained in Preparation Example 1 and 200 mL of 1,2-dichloroethane were added. After stirring until homogeneous, 20.7 g of hyperbranched polyamine-modified resin was added. Subsequently, 212.7 g (1.15 mol, 1.15 equivalents) of ethyl bromofluoroacetate was added dropwise, controlling the dropping rate to maintain the system temperature at 25-30 °C. After the addition was complete, the reaction was continued to be stirred at room temperature (25 °C) for 1 h.

[0066] After the reaction was monitored by TLC until complete, the resin was removed by filtration, and the filter cake was washed with a small amount of 1,2-dichloroethane. The filtrates were combined, the solvent was recovered by atmospheric distillation, and then the fraction was collected by vacuum distillation at 120-122℃ / 5mm Hg to give 227.6 g of colorless and transparent liquid triethyl 2-fluorophosphorylacetate, with a yield of 94.0%.

[0067] Example 7 A method for preparing triethyl 2-fluorophosphonoacetate includes the following steps: In a 500 mL three-necked flask, 138.1 g (1.0 mol) of diethyl phosphite obtained in Preparation Example 1 and 200 mL of 1,2-dichloroethane were added. After stirring until homogeneous, 13.8 g of hyperbranched polyamine-modified resin was added. Subsequently, 194.2 g (1.05 mol, 1.05 equivalent) of ethyl bromofluoroacetate was added dropwise, controlling the dropping rate to maintain the system temperature at 25-30 °C. After the addition was complete, the reaction was continued to be stirred at room temperature (25 °C) for 1 h.

[0068] After the reaction was monitored by TLC until complete, the resin was removed by filtration, and the filter cake was washed with a small amount of 1,2-dichloroethane. The filtrates were combined, the solvent was recovered by atmospheric distillation, and then the fraction was collected by vacuum distillation at 120-122℃ / 5mm Hg to obtain 220.6 g of colorless and transparent triethyl 2-fluorophosphorylacetate, with a yield of 91.1%.

[0069] Example 8 Based on Example 7, the hyperbranched polyamine modified resin was recovered after the reaction. The recovered hyperbranched polyamine modified resin was used for the next batch preparation, and so on for ten batches. After the tenth filtrate was combined, the solvent was recovered by atmospheric distillation, followed by vacuum distillation. The fraction collected at 120-122℃ / 5mm Hg yielded 227.2g of colorless and transparent liquid 2-fluorophosphoryl acetate, with a yield of 93.8%.

[0070] This demonstrates that the hyperbranched polyamine modified resin of the present invention has very stable catalytic performance and can be used for multiple batches of production.

[0071] Comparative Example 2 A method for preparing triethyl 2-fluorophosphonoacetate includes the following steps: In a 500 mL three-necked flask, 138.1 g (1.0 mol) of diethyl phosphite obtained in Preparation Example 1 and 200 mL of 1,2-dichloroethane were added. After stirring until homogeneous, 138.1 g (1.0 mol) of sodium ethoxide was added; subsequently, 194.2 g (1.05 mol, 1.05 equivalent) of ethyl bromofluoroacetate was added dropwise, controlling the dropping rate to maintain the system temperature at 25-30 °C. After the addition was complete, the reaction was stirred at room temperature (25 °C) for 1 h.

[0072] After the reaction was monitored to be complete by TLC, sodium bromide was washed away by adding water, and the aqueous phase was washed with a small amount of 1,2-dichloroethane. After the organic phases were combined, the solvent was recovered by atmospheric distillation, followed by vacuum distillation. The fraction collected at 120-122℃ / 5mm Hg was used to obtain 228.4 g of colorless and transparent triethyl 2-fluorophosphorylacetate, with a yield of 82.7%.

[0073] This comparative example uses sodium ethoxide as the catalyst for the esterification reaction. Compared to Example 8, the mass of sodium ethoxide added (138.1 g) is significantly higher than that of the hyperbranched polyamine modified resin (13.8 g), and the yield is significantly lower than that of Example 8 (91.1%). Furthermore, it generates sodium ethoxide equivalent waste salt and a large amount of phosphorus-containing wastewater, resulting in high treatment costs.

[0074] Comparative Example 3 A method for preparing triethyl 2-fluorophosphonoacetate without the use of any catalyst includes the following steps: In a 500 mL three-necked flask, 138.1 g (1.0 mol) of diethyl phosphite and 200 mL of 1,2-dichloroethane were added and stirred until homogeneous. Then, 194.2 g (1.05 mol, 1.05 equivalent) of ethyl bromofluoroacetate was added dropwise, controlling the dropping rate to maintain the system temperature at 25-30 °C. After the addition was complete, the reaction was continued at room temperature (25 °C) with stirring for 1 h. After 1 h of reaction, the solvent was recovered by atmospheric distillation, followed by vacuum distillation, collecting the fraction at 120-122 °C / 5 mm Hg to obtain 3.6 g of colorless, transparent liquid triethyl 2-fluorophosphorylacetate, with a yield of 1.5%.

[0075] In summary, this invention utilizes hyperbranched polyamine-modified resin as a catalyst for diethyl phosphite and ethyl bromofluoroethylene. The catalyst can be removed by filtration after the reaction, simplifying post-treatment and significantly reducing the generation of waste salts and wastewater, thus lowering waste treatment costs. Furthermore, the resin can be recycled and reused during the reaction, reducing production costs. By optimizing reaction conditions and resin dosage, a yield of over 91% can be achieved, with the product exhibiting good color and high purity. The reaction conditions are mild, and the reaction rate is fast, demonstrating promising application prospects in industrial production.

[0076] The specific embodiments of the present invention described above do not constitute a limitation on the scope of protection of the present invention. Any other corresponding changes and modifications made in accordance with the technical concept of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing triethyl 2-fluorophosphonoacetate, characterized in that, include, After mixing diethyl phosphite with the first solvent, hyperbranched polyamine-modified resin and ethyl bromofluoroethylene were added to carry out the reaction. After the reaction was completed, the solid and liquid were separated, and the filtrate was treated to obtain triethyl 2-fluorophosphonoacetate.

2. The method for preparing triethyl 2-fluorophosphonoacetate according to claim 1, characterized in that, The molar ratio of diethyl phosphite to ethyl bromofluoroacetate is 1:1.0-1.2; The amount of the hyperbranched polyamine modified resin is 10%-50% of the mass of diethyl phosphite.

3. The method for preparing triethyl 2-fluorophosphonoacetate according to claim 1, characterized in that, The preparation method of the hyperbranched polyamine modified resin includes, A strong basic anion exchange resin, a second solvent, 1,4-butanediol diglycidyl ether and tetrabutylammonium bromide are mixed and reacted at elevated temperature to obtain an epoxy-modified resin. An epoxy-modified resin was mixed with an ethylenediamine solution and reacted at a higher temperature to obtain a first intermediate. The first intermediate, a second solvent, 1,4-butanediol diglycidyl ether, and tetrabutylammonium bromide were mixed and reacted at a higher temperature to obtain a second intermediate. The second intermediate was mixed with an ethylenediamine solution and reacted at a higher temperature to obtain a terminal amino hyperbranched resin. The terminal amine hyperbranched resin and trimethylamine solution were mixed, the pH was adjusted and the temperature was raised to react, and a third intermediate was obtained; the third intermediate was mixed with an alkaline solution to react and obtain hyperbranched polyamine modified resin.

4. The method for preparing triethyl 2-fluorophosphonoacetate according to claim 3, characterized in that, The mass ratio of the strongly basic anion exchange resin, the second solvent, 1,4-butanediol diglycidyl ether, and tetrabutylammonium bromide is 1:10-20:2-5:0.

5. The mass ratio of the epoxy-modified resin to the ethylenediamine solution is 1:5-8, the mass ratio of the second intermediate to the ethylenediamine solution is 1:5-8, and the mass concentration of the ethylenediamine solution is 30%-40%. The mass ratio of the first intermediate, the second solvent, 1,4-butanediol diglycidyl ether, and tetrabutylammonium bromide is 1:10-20:2-5:0.5; The mass concentration of the trimethylamine solution is 25%-35%; The pH is adjusted to 7.5-9.5; The concentration of hydroxide ions in the alkaline solution is 0.2-1.0 mol / L.

5. The method for preparing triethyl 2-fluorophosphonoacetate according to claim 3, characterized in that, The heating reaction is carried out at 40-50℃ for 2-10 hours; The second solvent includes at least one of water, N,N-dimethylformamide, acetone, diethyl ether, ethanol, and cyclohexane.

6. The method for preparing triethyl 2-fluorophosphonoacetate according to claim 3, characterized in that, The strongly basic anion exchange resin is activated by soaking in acid and / or alkali and swelling before use.

7. The method for preparing triethyl 2-fluorophosphonoacetate according to claim 1, characterized in that, The first solvent includes at least one of 1,2-dichloroethane, acetonitrile, toluene, cyclohexane, ethyl acetate, tetrahydrofuran, and dimethyl sulfoxide.

8. The method for preparing triethyl 2-fluorophosphonoacetate according to claim 1, characterized in that, The reaction was carried out at a temperature of 20-30℃ for 0.5-4 hours.

9. The method for preparing triethyl 2-fluorophosphonoacetate according to claim 1, characterized in that, The process includes atmospheric distillation to recover the first solvent and vacuum distillation to collect the 120-122℃ / 5mm Hg fraction.

10. A 2-fluorophosphonoacetic acid triethyl ester, characterized in that, It is obtained by the preparation method according to any one of claims 1-9.

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