A method for preparing 2-(hydroxymethylphosphinoyl)acetic acid and 2-(hydroxymethylphosphinoyl)acetic acid

Abstract

The present application relates to the technical field of phosphorus-containing flame-retardant polymer monomer, and particularly relates to a preparation method of 2-(hydroxymethyl phosphinyl) acetic acid, which comprises the following steps: S1, intermediate synthesis: an intermediate is synthesized through an Arbuzov rearrangement method, methyl phosphite di-R2 ester is reacted with a micro-excess of chloroacetic acid R4 ester to obtain an intermediate crude liquid; S2, intermediate hydrolysis: hydrochloric acid is added to the intermediate crude liquid or intermediate rectified product for hydrolysis reaction to obtain a final product crude liquid; S3, final product crude liquid post-treatment: the final product crude liquid is directly warmed and distilled to obtain the final product 2-(hydroxymethyl phosphinyl) acetic acid. The final product obtained through the preparation method has high purity and high yield, the post-treatment is extremely simple, the reaction condition is mild and controllable, the energy consumption is low, the cost is low, the economy is good, and the preparation method has market promotion prospects.

Description

Technical Field

[0001] This invention relates to the field of phosphorus-containing flame-retardant polymer monomer technology, and in particular to a method for preparing 2-(hydroxymethylphosphono)acetic acid and the 2-(hydroxymethylphosphono)acetic acid obtained by the method. Background Technology

[0002] The reactivity of the carboxyl and hydroxyl groups in carboxyphosphonate monomers allows them to be used as reactive flame retardants to modify various materials, compared to CEPPA. It has a significant advantage in phosphorus content and can be used in polyester flame retardancy; it can also be chelated with various metal ions to form flame retardants and used as an additive flame retardant. Based on the phosphorus-carbon bond introduced in methyl PA, when it is used as a flame retardant monomer in materials, it can significantly improve the compatibility and mechanical properties of materials compared with other similar metal complex flame retardants.

[0003] Chinese patent CN1396206A7 discloses 2-(hydroxymethylphosphono)acetic acid, whose structural formula is as follows: (Patent No.: CN1396206A7) Discloses phosphorus-containing flame-retardant polyethylene terephthalate / layered silicate nanocomposite material and its preparation method and uses. (NMR spectrum as shown) Figure 1 US Patent PHOSPHINYLALKANOYL PROLINES (Patent No.: US416826) also discloses a similar structure, the structural formula of which is as follows: However, there is currently no mature, efficient, and controllable synthetic route for this monomer, which prevents its large-scale promotion and use. Summary of the Invention

[0004] The purpose of this invention is to provide a simple, easy-to-implement, and economical method for preparing 2-(hydroxymethylphosphono)acetic acid, as well as the 2-(hydroxymethylphosphono)acetic acid obtained by this method.

[0005] To achieve the above objectives, the present invention adopts the following basic technical solution: a method for preparing 2-(hydroxymethylphosphono)acetic acid, comprising the following steps:

[0006] S1, Intermediate Synthesis:

[0007] The intermediate was synthesized by the Arbuzov rearrangement method. The di-R2 methylphosphite was heated to 60℃~100℃, and 1.02~1.09 times the molar amount of di-R2 methylphosphite R4 ester was slowly added dropwise to the di-R2 methylphosphite to start the reaction. The reaction temperature was maintained at 60℃~120℃. After the addition was completed, the temperature was kept for 1h~24h to obtain a crude intermediate liquid with the intermediate as the main component.

[0008] The main rearrangement reaction of the synthetic intermediate is as follows:

[0009]

[0010] S2, intermediate crude liquid hydrolysis:

[0011] Add 4.10 to 9.50 times the molar amount of hydrochloric acid to the crude intermediate obtained in step S1, and carry out a hydrolysis reaction at 102℃ to 125℃. The generated chloroalkane overflows and is recovered. After the addition is complete, keep warm at 102℃ to 125℃ for 1 h to 24 h to obtain the final product crude liquid.

[0012] The main hydrolysis reaction formulas are as follows:

[0013]

[0014] Wherein, R2 is an alkyl group, a hydrocarbon group with a benzene ring, a chloroalkyl group, or an allyl group, and R4 is hydrogen, an alkyl group, or a chloroalkyl group, and the alkyl group or chloroalkyl group in R2 or R4 has 1 to 4 carbon atoms;

[0015] S3. Post-treatment of the final product crude liquid:

[0016] The crude product obtained in step S2 is heated and distilled, with the distillation endpoint temperature not exceeding 160℃, to obtain the final product 2-(hydroxymethylphosphono)acetic acid.

[0017] Preferably, in step S1, the methyl phosphite diR2-based ester is selected from one of dimethyl phosphite, diethyl phosphite, diphenyl phosphite, diisopropanol methyl phosphite, and dichloroethanol methyl phosphite; the chloroacetic acid R4-based ester is selected from one of ethyl chloroacetate, methyl chloroacetate, propyl chloroacetate, and tert-butanol chloroacetate. When using the above-preferred reactants to prepare intermediates and final products, the raw material sources are abundant, the reaction conditions are mild, the reaction direction is strong, and the overall yield is high.

[0018] More preferably, the methylphosphite diR2 ester is selected from diethyl methylphosphite, and the chloroacetic acid R4 ester is selected from ethyl chloroacetate. The main component of the crude intermediate obtained in step S1 is the intermediate 2-(ethoxymethylphosphono)ethyl acetate.

[0019] Preferably, in step S1, the molar number of the added chloroacetic acid R4 ester is 1.02 to 1.08 times the molar number of the methyl phosphite diR2 ester.

[0020] More preferably, in step S1, after the addition is complete, the temperature is maintained at 60℃~120℃ for 1h~24h.

[0021] More preferably, in step S1, the dimethylphosphite R2-based ester is heated to 60°C–95°C, and 1.02–1.08 times the molar amount of chloroacetic acid R4-based ester is added dropwise to the dimethylphosphite R2-based ester to initiate the reaction. The reaction temperature is maintained at 60°C–115°C by controlling the dropwise addition rate. After the dropwise addition is completed, the temperature is kept at 60°C–115°C for 1 hour–24 hours.

[0022] More preferably, in step S1, under inert gas protection, the dimethylphosphite R2-based ester is heated to 60°C–95°C, and 1.02–1.08 times the molar amount of chloroacetic acid R4-based ester is added dropwise to the dimethylphosphite R2-based ester to initiate the reaction. The reaction temperature is maintained at 60°C–115°C by controlling the dropwise addition rate, and after the dropwise addition is completed, the temperature is maintained at 60°C–115°C for 1 hour–24 hours.

[0023] Preferably, the crude intermediate liquid obtained in step S1 is subjected to vacuum distillation, and then the refined intermediate product is hydrolyzed according to step S2.

[0024] Preferably, in step S2, the number of moles of hydrochloric acid is 4.10 to 9.30 times that of the intermediate obtained in step S1, and the concentration of the hydrochloric acid is 36%.

[0025] Further preferred, in step S2, the number of moles of hydrochloric acid is 4.10 to 6.70 times or 6.00 to 9.30 times that of the intermediate obtained in step S1.

[0026] More preferably, in step S1, the molar number of the chloroacetic acid R4-based ester added is 1.02 to 1.04 times the molar number of the methyl phosphite diR2-based ester.

[0027] Preferably, in step S2, hydrochloric acid is added dropwise to initiate the hydrolysis reaction at a temperature of 102℃~110℃. After the hydrochloric acid is added, the temperature is maintained at 102℃~110℃ for 1h~24h to obtain the final product crude liquid. More preferably, in step S2, after the addition is complete, the temperature is maintained at 102℃~110℃ for 6h~24h.

[0028] Preferably, in step S3, the final temperature of the heating distillation of the crude product is controlled between 151°C and 160°C.

[0029] Preferably, the gas chromatographic purity of the intermediate crude liquid obtained in step S1 is 75% to 99%.

[0030] Preferably, the intermediate synthesis in step S1 is carried out in a reaction vessel, and the intermediate crude liquid hydrolysis in step S2 is carried out in a second reaction vessel.

[0031] More preferably, when the methyl phosphite diR2-based ester is selected from diethyl methyl phosphite and the chloroacetic acid R4-based ester is selected from methyl chloroacetate, the main component of the intermediate crude liquid obtained in step S1 is intermediate 2-(ethoxymethylphosphono)acetic acid methyl ester.

[0032] A 2-(hydroxymethylphosphono)acetic acid is prepared by the method described above.

[0033] This invention provides a method for preparing 2-(hydroxymethylphosphono)acetic acid based on a two-step reaction involving Arbuzov rearrangement and hydrolysis. This method is characterized by mild reaction conditions, ease of implementation, good economic efficiency, and the elimination of complex post-processing steps. The main steps include:

[0034] S1. Intermediate Synthesis: The intermediate was synthesized by the Arbuzov rearrangement method. A slight excess of chloroacetic acid R4 ester was added dropwise to methyl phosphite diR2 ester to react and obtain a crude intermediate solution with the intermediate as the main component.

[0035] S2, Hydrolysis of intermediate crude liquid: Hydrochloric acid is added to the intermediate crude liquid obtained in step S1 to carry out hydrolysis reaction, and the final product crude liquid is obtained.

[0036] S3. Post-treatment of crude final product: The crude final product obtained in step S2 is directly heated and distilled to obtain the final product 2-(hydroxymethylphosphono)acetic acid.

[0037] During the in-depth study of the above preparation method, the applicant unexpectedly discovered that in step S1, when a slightly excess R4-based chloroacetate is added dropwise to diR2-based methylphosphite for the rearrangement reaction, the excess R4-based chloroacetate, under suitable conditions (e.g., when the R4-based chloroacetate is in relatively large excess), reacts with the intermediate to generate very little or no byproducts. These byproducts can also react with hydrochloric acid in step S2 to generate the final product. The corresponding reaction equations are shown below.

[0038]

[0039] Furthermore, the formation of appropriate amounts of the aforementioned byproducts does not affect the yield or purity of the final product. Based on this, in step S1, the present invention selects a molar ratio of (1.02–1.09):1 between chloroacetic acid R4-based ester and methylphosphite diR2-based ester. This is because a low excess value would not significantly advance the reaction, while a high excess value might cause the chloroacetic acid R4-based ester to continue reacting with the intermediate, thus affecting the yield of the intermediate.

[0040] Meanwhile, the applicant discovered that when the heating temperature of diR2 methylphosphite is set to 60℃~100℃ in step S1, and the reaction temperature is controlled at 60℃~120℃ by adjusting the dropping rate and utilizing the self-exothermic reaction of the rearrangement reaction, comprehensive advantages in reaction rate, yield, energy saving, and other aspects can be obtained.

[0041] Based on the above understanding, the present invention provides an easy-to-implement method for preparing 2-(hydroxymethylphosphono)acetic acid and the 2-(hydroxymethylphosphono)acetic acid prepared by the method, wherein the preparation method includes the following steps:

[0042] S1, Intermediate Synthesis:

[0043] The intermediate was synthesized by the Arbuzov rearrangement method. The di-R2 methylphosphite was heated to 60℃~100℃, and 1.02~1.09 times the molar amount of di-R2 methylphosphite was slowly added dropwise to the di-R2 methylphosphite to start the reaction. The reaction temperature was maintained at 60℃~120℃. After the addition was completed, the temperature was kept at 60℃~120℃ for 1h~24h to obtain a crude intermediate liquid with the intermediate as the main component.

[0044] The main rearrangement reaction of the synthetic intermediate is as follows:

[0045]

[0046] S2, intermediate crude liquid hydrolysis:

[0047] Add 4.10 to 9.50 times the molar amount of hydrochloric acid to the crude intermediate obtained in step S1, and carry out a hydrolysis reaction at 102℃ to 125℃. The generated chloroalkane overflows and is recovered. After the addition is complete, keep warm at 102℃ to 125℃ for 1 h to 24 h to obtain the final product crude liquid.

[0048] The main hydrolysis reaction formulas are as follows:

[0049]

[0050] Wherein, R2 is an alkyl group, a hydrocarbon group with a benzene ring, a chloroalkyl group, or an allyl group, and R4 is hydrogen, an alkyl group, or a chloroalkyl group, and the alkyl group or chloroalkyl group in R2 or R4 has 1 to 4 carbon atoms.

[0051] S3. Post-treatment of the final product crude liquid:

[0052] The crude product obtained in step S2 is heated and distilled, with the distillation endpoint temperature not exceeding 160℃, to obtain the final product 2-(hydroxymethylphosphono)acetic acid.

[0053] To reduce the formation of byproducts, the preferred molar ratio of chloroacetic acid R4 ester to methyl phosphite diR2 ester is (1.02-1.08):1, and more preferably, the molar ratio of chloroacetic acid R4 ester to methyl phosphite diR2 ester is (1.02-1.04):1.

[0054] Based on the availability of reactants and to improve the directional selectivity of the rearrangement reaction, the dimethyl phosphite R2-based ester is selected from one of dimethyl phosphite, diethyl phosphite, diphenyl phosphite, diisopropanol methyl phosphite, and dichloroethanol methyl phosphite; the chloroacetic acid R4-based ester is selected from one of ethyl chloroacetate, methyl chloroacetate, propyl chloroacetate, and tert-butanol chloroacetate.

[0055] The above-mentioned reaction raw materials are abundant (all of which can be commercially available products), the reaction is highly directional, and the yield is high.

[0056] When the methylphosphite diR2-ester is selected from diethyl methylphosphite, and the chloroacetic acid R4-ester is selected from ethyl chloroacetate or methyl chloroacetate, the main components of the crude intermediate obtained in step S1 are intermediate ethyl 2-(ethoxymethylphosphono)acetate and intermediate methyl 2-(ethoxymethylphosphono)acetate, respectively. The obtained intermediates ethyl 2-(ethoxymethylphosphono)acetate and methyl 2-(ethoxymethylphosphono)acetate have a lower cost advantage compared to other intermediates.

[0057] Considering the controllability of the reaction temperature, in step S1, the dimethylphosphite R2 ester is heated to 60℃~95℃, and 1.02~1.08 times the molar amount of chloroacetic acid R4 ester is added dropwise to the dimethylphosphite R2 ester to initiate the reaction. By controlling the dropping rate, the reaction temperature is maintained at 60℃~115℃. After the dropping is completed, the temperature is kept at 60℃~115℃ for 1h~24h.

[0058] To reduce the interference of possible side reactions of dimethylphosphite R2 ester, in step S1, dimethylphosphite R2 ester is heated to 60℃~95℃ under inert gas protection, and 1.02~1.08 times the molar amount of dimethylphosphite R2 ester of chloroacetic acid R4 ester is added dropwise to dimethylphosphite R2 ester to start the reaction. The reaction temperature is maintained at 60℃~115℃ by controlling the dropwise addition rate. After the dropwise addition is completed, the temperature is maintained at 60℃~115℃ for 1h~24h.

[0059] In the crude intermediate obtained in step S1, the gas chromatographic purity of the intermediate is 75%–99%. To further improve the purity, the crude intermediate obtained in step S1 can be further subjected to vacuum distillation, and then the resulting intermediate distillate can be hydrolyzed according to step S2.

[0060] To ensure the hydrolysis reaction is adequate while also maximizing the utilization of byproducts and reducing post-processing pressure, in step S2, the molar amount of hydrochloric acid is 4.10 to 9.30 times that of the intermediate obtained in step S1, and the concentration of the hydrochloric acid is 36%. More preferably, the molar amount of hydrochloric acid is 4.10 to 6.70 times or 6.00 to 9.30 times that of the intermediate obtained in step S1.

[0061] To ensure the hydrolysis reaction proceeds fully, the heat preservation time after hydrolysis in step S2 is preferably 6h to 24h.

[0062] The rearrangement and hydrolysis two-step reactions of the present invention can be carried out in the same reaction vessel or in different reaction vessels. When carrying out industrial-scale production, it is preferable that the intermediate synthesis of step S1 is carried out in the reaction vessel, and the intermediate crude liquid hydrolysis of step S2 is carried out in the second reaction vessel. This can avoid mutual interference between the rearrangement reaction and the hydrolysis reaction, and can avoid the heavy cleaning work of the reaction vessel afterward, making it more suitable for industrial production.

[0063] To effectively reduce or eliminate interference from the side reactions catalyzed by the generated chloroalkane in the formation of di-R2 alkyl methylphosphite, in step S1, the di-R2 methylphosphite is heated to 90°C–95°C, and 1.02–1.08 times the molar amount of chloroacetic acid R4 ester is added dropwise to initiate the reaction. The reaction temperature is maintained at 90°C–115°C by controlling the dropping rate. After the addition is complete, the temperature is maintained at 90°C–115°C for 1–24 hours. When the heating temperature of di-R2 methylphosphite is 90°C–95°C, and the reaction temperature is controlled at 90°C–115°C, the rearrangement reaction is promoted more efficiently.

[0064] To further reduce the occurrence of side reactions caused by the influence of the external environment on dimethyl phosphite R2-based ester, in step S1 of this invention, dimethyl phosphite R2-based ester is heated to 90℃~95℃ under inert gas protection, and 1.02~1.08 times the molar amount of dimethyl phosphite R2-based ester chloroacetic acid R4-based ester is added dropwise to dimethyl phosphite R2-based ester to initiate the reaction. By controlling the dropwise addition rate, the reaction temperature is maintained at 90℃~115℃, and after the dropwise addition is completed, the temperature is maintained at 90℃~115℃ for 1h~24h.

[0065] To reduce the formation of byproducts, in step S1, the present invention heats the di-R2 methyl phosphite to 60°C–70°C, and then adds 1.02–1.08 times the molar amount of chloroacetic acid R4 ester to the di-R2 methyl phosphite to initiate the reaction. The reaction temperature is maintained at 60°C–80°C by controlling the dropping rate. After the addition is complete, the temperature is maintained at 60°C–80°C for 1–24 hours. Thus, when the heating temperature of the di-R2 methyl phosphite is 60°C–70°C and the reaction temperature is controlled at 60°C–80°C, although the rearrangement reaction rate decreases slightly, the reaction between chloroacetic acid R4 ester and the intermediate is less likely to occur, and byproducts are less likely to form.

[0066] Furthermore, in order to protect the di-R2 methylphosphite from the influence of the external environment, in step S1 of this invention, the di-R2 methylphosphite is heated to 60°C to 70°C under the protection of an inert gas, and 1.02 to 1.08 times the molar amount of the di-R2 methylphosphite is added dropwise to the di-R2 methylphosphite to initiate the reaction. By controlling the dropwise addition rate, the reaction temperature is maintained at 60°C to 80°C, and after the dropwise addition is completed, the temperature is maintained at 60°C to 80°C for 1 hour to 24 hours.

[0067] As mentioned earlier, since this invention uses a slight excess of R4-based chloroacetic acid ester and diR2-based methylphosphite for a rearrangement reaction, a small amount of byproducts will be generated under suitable reaction conditions. When the crude liquid obtained in step S1 contains byproducts, during the hydrolysis reaction of the intermediate crude liquid in step S2, in addition to the main hydrolysis reaction between the intermediate and hydrochloric acid to obtain the final product, the byproducts also undergo hydrolysis with hydrochloric acid, generating a small or trace amount of the final product, as well as a small or very small amount of chloroacetic acid and chloroalkanes. Therefore, during the heating and distillation of the final product crude liquid in step S3, in addition to obtaining the final product and distilling off hydrochloric acid and water, chloroacetic acid will also be distilled off.

[0068] Although the presence of a small amount of byproducts has little impact on the yield and purity of the final product, it does objectively consume some of the intermediates. Therefore, the amount of byproducts should not be excessive. Preferably, in the crude intermediate liquid obtained in step S1, the weight ratio of a small or trace amount of byproducts to the crude intermediate liquid should not exceed 8.80%, and more preferably, not exceed 7.50%.

[0069] Furthermore, in the selection of the R2 or R4 group in the chloroacetic acid R4-based ester or methyl phosphite diR2-based ester, the present invention preferably uses an alkyl group, a hydrocarbon group with a benzene ring, a chloroalkyl group, or an allyl group, and an R4 group that is hydrogen, an alkyl group, or a chloroalkyl group, wherein the alkyl or chloroalkyl group in the R2 or R4 group has 1-4 carbon atoms. This facilitates the rapid departure of the R2 or R4 group from the system after generating the chloro derivative in the rearrangement or hydrolysis reaction, thereby promoting the reaction in a direction favorable to the product. R2 and R4 can be the same or different.

[0070] A 2-(hydroxymethylphosphono)acetic acid is prepared by the aforementioned preparation method.

[0071] The beneficial effects of this invention are:

[0072] This invention provides a simple, easy-to-implement, and economical method for preparing 2-(hydroxymethylphosphono)acetic acid. This method allows for the direct heating and distillation of the crude product liquid to obtain a high-purity final product. The post-processing is extremely simple, and the reaction conditions are mild and controllable with low energy consumption, making it easy to implement. The obtained final product has high purity (above 98%), high overall yield (above 95%), and low residual amounts of impurities such as water and hydrochloric acid. It is particularly suitable for the preparation of flame-retardant materials and has good market prospects.

[0073] The specific advantages are as follows:

[0074] 1. In the rearrangement reaction of step S1, this invention uses the dropwise addition of R4-based chloroacetic acid ester and R2-based methylphosphite ester, with R4-based chloroacetic acid ester added in a slightly excess molar ratio to R2-based methylphosphite ester. This ensures a more thorough reaction and, since R4-based chloroacetic acid ester is cheaper than R2-based methylphosphite ester, it reduces costs and is more economical. Even if R4-based chloroacetic acid ester is slightly in excess, causing further reaction between R4-based chloroacetic acid ester and intermediates to generate small or very small amounts of byproducts, these byproducts can generate the final product after hydrolysis in the second step and chloroacetic acid and chloroalkanes that can be directly distilled off in the third step of post-processing. Therefore, their impact on the overall yield, purity, and post-processing of the final product is negligible.

[0075] Therefore, the rearrangement reaction of R4-based chloroacetic acid ester with R2-based methylphosphite in a slight excess has obvious advantages such as thorough rearrangement reaction, good economy, and no impact on yield, purity, or post-processing.

[0076] 2. The Arbuzov rearrangement reaction in step S1 of this invention can be spontaneously promoted by the self-exothermic reaction after being started by heating at 60℃ to 100℃, with low energy consumption. Furthermore, the reaction temperature can be controlled within the range of 60℃ to 120℃ by adjusting the dropping rate, without the need for additional temperature control equipment. The reaction conditions are easy to achieve and simple to control.

[0077] 3. In step S1 of this invention, after the Arbuzov rearrangement reaction is started by heating, the reaction is controlled at a relatively high temperature of 90℃ to 115℃ based on the dropping rate adjustment. This helps to quickly remove the chloroalkanes generated during the reaction, thereby effectively reducing or eliminating the side reaction of the generated chloroalkanes "catalyzing" the formation of byproducts from the di-R2 alkyl methyl phosphite. The interference caused by (where R refers to R2) can lead to intermediate products with higher purity and yield.

[0078] 4. The hydrolysis reaction in step S2 of this invention also has the following significant advantages over the prior art:

[0079] First, the selection of hydrochloric acid addition in step S2 of the present invention, which is 4.10 to 9.50 times the molar number of the intermediate, and more preferably within the range of 4.10 to 9.50 times, 4.10 to 6.70 times, or 6.00 to 9.50 times, not only takes into account the requirements of the hydrolysis reaction of the intermediate, but also takes into account the comprehensive utilization of by-products, the reduction of post-processing separation difficulty, and economic factors.

[0080] Therefore, based on the actual number of moles of intermediates generated and the need for simplified post-processing and comprehensive utilization of by-products, this invention uses sufficient and appropriate amounts of hydrochloric acid. This satisfies the requirements of the hydrolysis reaction, ensures that alcohol by-products are fully converted into chloroalkanes and then overflowed for recovery, reduces the difficulty of separating the final product, and can also recover the more valuable chloroalkanes. This avoids the thorny problem of unreacted hydrochloric acid being difficult to handle due to its low recovery value, achieving multiple benefits and better economic efficiency. In addition, the selection of an appropriate concentration of hydrochloric acid (36%) is also more conducive to the advancement of hydrolysis and other reactions and reduces the pressure of post-processing.

[0081] Secondly, the hydrolysis reaction in step S2 of this invention is carried out at a relatively high temperature of 102℃ to 125℃ after the hydrochloric acid is added, which makes the hydrolysis reaction more complete and is conducive to further improving the yield and purity of the final product.

[0082] Finally, since the carboxyl group of the final product obtained by this invention is stable and not easily decarboxylated during hydrolysis, it can withstand hydrolysis at high temperatures. Therefore, this invention can be hydrolyzed at higher temperatures to ensure the full progress of the hydrolysis reaction, which is beneficial to improving the yield and purity of the final product.

[0083] 5. In step S3, this invention only requires heating and distilling the crude product to remove unreacted hydrochloric acid and water (and chloroacetic acid if the crude product contains trace amounts or small amounts of byproducts). This yields a high-purity final product. The post-processing is extremely simple, and the residual amounts of impurities such as water and hydrochloric acid are extremely low (e.g., water content not exceeding 1.0%, and virtually no hydrochloric acid odor). The product grade is higher and fully meets the stringent requirements for the preparation of flame-retardant materials.

[0084] 6. The two-step reaction of the present invention has a high overall yield (at least 96%) and the final product has a higher phosphorus content, which means that it can be used in smaller quantities and is more economical when used in flame retardant materials. Attached Figure Description

[0085] Figure 1 The ¹H-NMR spectra of the final product 2-(hydroxymethylphosphono)acetic acid obtained in Examples 1-10 are shown.

[0086] Figure 2 Mass spectra of the intermediate 2-(ethoxymethylphosphono)ethyl acetate obtained in Examples 1-4, 6-8, and 10.

[0087] Figure 3 The 1H-NMR spectrum of methyl 2-(ethoxymethylphosphono)acetate, another intermediate obtained in Examples 5 and 9.

[0088] Figure 4 The mass spectrum of a small amount of byproduct A included in the crude intermediate liquid of Examples 2, 4, and 10. Detailed Implementation

[0089] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0090] Example 1:

[0091] A method for preparing 2-(hydroxymethylphosphono)acetic acid includes the following steps:

[0092] S1, Intermediate Synthesis:

[0093] The intermediate was synthesized via the Arbuzov rearrangement method. Under nitrogen protection, 136.28 g of 99.8% pure diethyl methyl phosphite (calculated as 1.000 mol) was added to a 500 mL flask and heated to 95 °C. Then, 126.21 g of 99% pure ethyl chlorophosphite (calculated as 1.020 mol, therefore the molar ratio of ethyl chlorophosphite to diethyl methyl phosphite was 1.02:1) was slowly added dropwise. As ethyl chlorophosphite was added, the temperature of the material slowly rose to 115 °C. Ethyl chloroethane overflowed and was recovered. The dropping rate was controlled, and the reaction temperature was maintained between 105 °C and 115 °C. After the addition was complete, the mixture was kept at 110 °C (a certain degree of fluctuation was allowed, maintaining it within the range of 105 °C to 115 °C) for 8 hours, yielding 194.2 g of crude intermediate liquid.

[0094] The main component of the crude intermediate was ethyl 2-(ethoxymethylphosphinyl)acetate with a gas chromatographic purity of 98.5%, and a rearrangement yield of 98.6% based on diethyl methylphosphite. The mass spectrum of ethyl 2-(ethoxymethylphosphinyl)acetate is shown below. Figure 2 ;

[0095] The rearrangement reaction formula for the synthesis of intermediate 2-(ethoxymethylphosphono)ethyl acetate in step S1 of this embodiment is as follows:

[0096]

[0097] S2, intermediate crude liquid hydrolysis:

[0098] The 194.2 g of crude intermediate solution in the reaction vessel (500 ml flask) of step S1 above was heated to 102 °C (the purity of the intermediate in the crude intermediate solution was 98.5%). 611 g of 36% hydrochloric acid (calculated as 6.026 mol, with a molar ratio of hydrochloric acid to intermediate of 6.11:1) was slowly added dropwise to the above crude solution to carry out the reaction. The generated chloroethane overflowed and was recovered. After the addition was completed, the temperature was kept in the range of 102 °C to 110 °C for 15 hours to obtain the final product crude solution.

[0099] The main hydrolysis reaction formula of the intermediate in step S2 of this embodiment is as follows:

[0100]

[0101] S3. Post-treatment of the final product crude liquid

[0102] The crude product obtained in step S2 was directly heated and distilled to remove unreacted hydrochloric acid and water. The distillation temperature was raised to a maximum of 155°C until no more liquid was distilled off, yielding 138.4 g of the final product 2-(hydroxymethylphosphono)acetic acid with an HCl-NMR purity of 98%. Its water content was less than 0.3%, and it had no hydrochloric acid odor. The overall yield was 98.3%. The HCl-NMR spectrum of the final product 2-(hydroxymethylphosphono)acetic acid is shown below. Figure 1 .

[0103] Example 2:

[0104] A method for preparing 2-(hydroxymethylphosphono)acetic acid includes the following steps:

[0105] S1, Intermediate Synthesis:

[0106] The intermediate was synthesized via the Arbuzov rearrangement method. Under nitrogen protection, 136.28 g of 99.8% diethyl methyl phosphite (1 mol) was added to a 500 mL flask and heated to 95 °C. Then, 128.74 g of 99% ethyl chloroacetate (1.04 mol, molar ratio of ethyl chloroacetate to diethyl methyl phosphite 1.04:1) was slowly added dropwise. As ethyl chloroacetate was added, the temperature of the material slowly rose to 115 °C. Ethyl chloroacetate was recovered from the overflow. The dropping rate was controlled, and the reaction temperature was maintained at 105 °C–115 °C. After the addition was complete, the mixture was kept at 110 °C (or maintained within the range of 105 °C–115 °C) for 8 hours to obtain 198.45 g of crude intermediate solution.

[0108] In step S1 of Example 2, the 198.45 g crude intermediate solution mainly consisted of ethyl 2-(ethoxymethylphosphono)acetate with a gas chromatographic purity of 96.25%. The calculated mass of the intermediate was 191 g, with a molar number of 0.985. Based on diethyl methylphosphite, the rearrangement yield was 98.5%. The mass spectrum of ethyl 2-(ethoxymethylphosphono)acetate is shown below. Figure 2 ;

[0109] The rearrangement reaction formula for the synthesis of intermediate 2-(ethoxymethylphosphono)ethyl acetate in step S1 of Example 2 is as follows:

[0110]

[0111] The crude intermediate solution obtained in step S1 of Example 2 also includes a very small amount of byproduct A (2.75 g) generated from the reaction of ethyl chloroacetate with intermediate 2-(ethoxymethylphosphono)ethyl acetate, as well as unreacted ethyl chloroacetate, monoethyl methylphosphite, and other impurities. The mass spectrum of byproduct A is attached. Figure 4The English and Chinese names of byproduct A are as follows: 2-((2-ethoxy-2-ethoxycarbonyl)(methyl)phosphinyl)acetate.

[0112] The reaction formula for the reaction of ethyl chloroacetate with intermediate 2-(ethoxymethylphosphono)ethyl acetate in step S1 of Example 2 to produce a small amount of byproduct A is as follows:

[0113]

[0114] S2, intermediate crude liquid hydrolysis:

[0115] The crude intermediate solution (198.45 g / mL obtained in step S1 above, with a combined gas chromatographic purity of 97.6% for intermediate 2-(ethoxymethylphosphono)ethyl acetate and a small amount of byproduct A) was poured into a second reaction vessel (specifically a 1000 mL flask). The temperature was raised to 102 °C, and 611 g of 36% hydrochloric acid was slowly added dropwise (calculated to be 6.026 mol of hydrochloric acid, with a molar ratio of hydrochloric acid to intermediate of 6.12:1). The generated chloroethane was recovered. After the addition was complete, the mixture was kept at 102 °C to 110 °C for 15 hours to obtain the final crude product solution.

[0116] The hydrolysis reaction formula of intermediate 2-(ethoxymethylphosphono)ethyl acetate in step S2 of this embodiment is as follows:

[0117]

[0118] The hydrolysis reaction formula for the small amount of byproduct A in step S2 of this embodiment is as follows:

[0119]

[0120] S3. Post-treatment of the final product crude liquid:

[0121] The crude product obtained in step S2 was heated and distilled to remove unreacted hydrochloric acid, water, and chloroacetic acid (chloroacetic acid is produced by the hydrolysis of a small amount of byproduct A). The distillation temperature was raised to a maximum of 155°C until no more liquid was distilled off, yielding 138.55 g of the final product 2-(hydroxymethylphosphono)acetic acid with an HCl-NMR purity of over 99%. Its moisture content was less than 0.4%, and it had no hydrochloric acid odor. The overall yield was 99.4%. The HCl-NMR spectrum of the final product 2-(hydroxymethylphosphono)acetic acid is shown below. Figure 1 .

[0122] This second example is carried out under nitrogen protection, which helps to prevent diethyl methyl phosphite from undergoing side reactions that could affect the purity and yield of the intermediate and the final product; inert gas protection can also be used; of course, inert gas protection is not required.

[0123] In Example 2, the rearrangement and hydrolysis reactions are carried out in two different reaction vessels, which avoids the mutual influence between the two steps of rearrangement and hydrolysis (this influence is more obvious during industrial scale-up). In particular, it avoids the side reaction between the hydrochloric acid added in the hydrolysis reaction and the diethyl methyl phosphite in the rearrangement reaction, making it more suitable for large-scale production.

[0124] Example 3:

[0125] A method for preparing 2-(hydroxymethylphosphono)acetic acid includes the following steps:

[0126] S1, Intermediate Synthesis:

[0127] The intermediate was synthesized via the Arbuzov rearrangement method. 136.28 g of 99.8% pure diethyl methyl phosphite (calculated as 1 mol) was added to a 500 mL flask and heated to 95 °C. Then, 126.21 g of 99% pure ethyl chloroacetate (calculated as 1.020 mol, with a molar ratio of ethyl chloroacetate to diethyl methyl phosphite of 1.02:1) was slowly added dropwise. As ethyl chloroacetate was added, the temperature of the material slowly increased to 115 °C. Ethyl chloroacetate was recovered from the overflow. The dropping rate was controlled, and the reaction temperature was maintained between 100 °C and 115 °C. After the addition was complete, the mixture was kept at 105 °C (or maintained within the range of 100 °C to 115 °C) for 12 hours to obtain 196.8 g of crude 2-(ethoxymethylphosphono)ethyl acetate intermediate.

[0128] The main component of the crude intermediate was ethyl 2-(ethoxymethylphosphono)acetate with a gas chromatographic purity of 98.3%, and the rearrangement yield was 98.7% based on diethyl methylphosphite.

[0129] The mass spectrum of intermediate 2-(ethoxymethylphosphono)ethyl acetate is shown in [reference needed]. Figure 2 ;

[0130] The rearrangement reaction formula for the synthesis of intermediate 2-(ethoxymethylphosphono)ethyl acetate in step S1 of this embodiment is as follows:

[0131]

[0132] S2, intermediate crude liquid hydrolysis; and S3, final product crude liquid post-processing:

[0133] The 196.8 g of crude intermediate solution (with a gas chromatographic purity of 98.3%) was poured into a 1000 ml flask and heated to 102 °C. 921 g of 36% hydrochloric acid (calculated as 9.084 mol, resulting in a molar ratio of 9.11:1 for hydrochloric acid to the intermediate) was slowly added dropwise. The generated chloroethane was recovered. After the addition was complete, the mixture was kept at 102 °C–110 °C for 15 hours, and then distilled to remove unreacted hydrochloric acid and water. The distillation temperature was raised to a maximum of 155 °C until no more liquid was distilled off, yielding 139 g of the final product, 2-(hydroxymethylphosphono)acetic acid, with an H-NMR purity of 98.0%. Its water content was less than 0.4%, and it had no hydrochloric acid odor. The overall yield was 98.7%. The H-NMR spectrum of the final product, 2-(hydroxymethylphosphono)acetic acid, is shown below. Figure 1 ;

[0134] The main hydrolysis reaction formula of the intermediate in step S2 of this embodiment is as follows:

[0135]

[0136] Example 4:

[0137] A method for preparing 2-(hydroxymethylphosphono)acetic acid includes the following steps:

[0138] S1, Intermediate Synthesis:

[0139] The intermediate was synthesized via the Arbuzov rearrangement method. Under no inert gas protection, 136.28 g of 99.8% diethyl methyl phosphite (1 mol) was added to a 500 mL flask and heated to 95 °C. Then, 133.69 g of 99% ethyl chlorophosphite (1.08 mol) was slowly added dropwise, with a molar ratio of ethyl chlorophosphite to diethyl methyl phosphite of 1.08:1. As ethyl chlorophosphite was added, the temperature of the material slowly increased to 115 °C. The dropping rate was controlled to maintain the reaction temperature between 105 °C and 115 °C. Ethyl chloroethane was recovered from the overflow. After the addition was complete, the mixture was kept at 105 °C to 115 °C for 5 hours, yielding 216.1 g of crude intermediate solution.

[0140] The main components of the crude intermediate liquid include ethyl 2-(ethoxymethylphosphono)acetate with a gas chromatographic purity of 81.87%; the calculated molar amount of the intermediate is 0.912 mol, and the rearrangement yield is 91% based on diethyl methylphosphite.

[0141] The mass spectrum of intermediate 2-(ethoxymethylphosphono)ethyl acetate is shown in [reference needed]. Figure 2 ;

[0142] The rearrangement reaction formula for the synthesis of intermediate 2-(ethoxymethylphosphono)ethyl acetate in step S1 of this embodiment is as follows:

[0143] ;

[0145] The crude intermediate solution obtained in step S1 of this embodiment also includes a small amount of byproduct A (15.12 g, calculated to be 0.06 mol), generated from the reaction of ethyl chloroacetate with intermediate 2-(ethoxymethylphosphono)ethyl acetate, as well as unreacted ethyl chloroacetate and methylphosphite monoethyl ester, among other impurities. The small amount of byproduct A generated can react with hydrochloric acid in the next step to form the final product; the mass spectrum of the small amount of byproduct A is shown in the appendix. Figure 4 .

[0146] The English and Chinese names of byproduct A are: 2-((2-ethoxy-2-ethoxycarbonyl)(methyl)phosphinyl)acetate.

[0147] The reaction formula for the reaction of ethyl chloroacetate with intermediate 2-(ethoxymethylphosphono)ethyl acetate in step S1 of this embodiment to produce a small amount of byproduct A is as follows:

[0148]

[0149] S2, intermediate crude liquid hydrolysis; and S3, final product crude liquid post-processing:

[0150] The 216.1 g crude intermediate solution obtained in step S1 above (containing an intermediate with a purity of 81.87% and a small amount of substance A15.12 g) was poured into the second reaction vessel (specifically a 1000 ml flask) and heated to 102 °C. 611 g of 36% hydrochloric acid (calculated as 6.026 mol, with a molar ratio of hydrochloric acid to intermediate of 6.61:1) was slowly added dropwise. The generated chloroethane overflowed and was recovered. After the addition was completed, the temperature was kept at 102 °C to 110 °C for 23 hours to obtain the final product crude solution.

[0151] Next, the crude product was heated and distilled to remove unreacted hydrochloric acid, water, and chloroacetic acid (chloroacetic acid is produced by the hydrolysis of a small amount of byproduct A). The distillation temperature was raised to a maximum of 155°C until no more liquid was distilled off, yielding 136.87 g of the final product 2-(hydroxymethylphosphono)acetic acid with an H-NMR purity of 98%, a water content of 0.3%, and no residual hydrochloric acid odor. (The calculated final product was 0.972 mol). The overall yield was 97.2%. The H-NMR spectrum of the final product 2-(hydroxymethylphosphono)acetic acid is shown below. Figure 1 .

[0152] The hydrolysis reaction formula of the intermediate in step S2 of this embodiment is as follows:

[0153]

[0154] The hydrolysis reaction formula for the small amount of byproduct A in step S2 of this embodiment is as follows:

[0155]

[0156] Example 5:

[0157] A method for preparing 2-(hydroxymethylphosphono)acetic acid includes the following steps:

[0158] S1, Intermediate Synthesis:

[0159] The intermediate was synthesized via the Arbuzov rearrangement method. 136.28 g of 99.8% diethyl methyl phosphite (1 mol) was added to a 500 mL flask and heated to 90 °C. Then, 111.79 g of 99% methyl chloroacetate (1.02 mol) was slowly added dropwise. The molar ratio of methyl chloroacetate to diethyl methyl phosphite was 1.02:1. As methyl chloroacetate was added, the temperature of the material slowly increased to 115 °C. Ethyl chloroacetate was recovered from the overflow. The dropping rate was controlled, and the reaction temperature was maintained at 105 °C–115 °C. After the addition was complete, the mixture was kept at 105 °C–115 °C for 8 hours to obtain 182.28 g of crude intermediate solution.

[0160] The main component of the crude intermediate was methyl 2-(ethoxymethylphosphinyl)acetate with a gas chromatography purity of 98.6%. The calculated molar amount of methyl 2-(ethoxymethylphosphinyl)acetate was 0.998 mol, and the rearrangement yield was 99.8% based on diethyl methyl phosphite.

[0161] The 1H NMR (nuclear magnetic resonance) spectrum of the intermediate methyl 2-(ethoxymethylphosphono)acetate is shown below. Figure 3 ;

[0162] The rearrangement reaction formula for the synthesis of intermediate 2-(ethoxymethylphosphono)acetate in step S1 of Example 5 is as follows:

[0163]

[0164] S2, intermediate crude liquid hydrolysis; and S3, final product crude liquid post-treatment:

[0165] The above 182.28 g of crude intermediate solution (containing 98.6% purity intermediate (methyl 2-(ethoxymethylphosphono)acetate)) was poured into a second reaction vessel (specifically a 1000 ml flask). The temperature was raised to 102 °C, and 414.88 g of 36% hydrochloric acid (calculated as 4.092 mol, with a molar ratio of hydrochloric acid to intermediate of 4.10:1) was slowly added dropwise. The generated chloroethane and chloromethane overflowed and were recovered. After the addition was complete, the solution was collected at 10 °C. After holding the solution at 2℃~110℃ for 23 hours, distillation was initiated to remove unreacted hydrochloric acid and water. The distillation temperature was raised to a maximum of 150℃ until no more liquid droplets were distilled off, yielding 138.3 g of the final product 2-(hydroxymethylphosphono)acetic acid with an HCl-NMR purity of 98%. The water content was less than 0.5%, and the calculated final product was 0.982 mol, with an overall yield of 98.2%. The HCl-NMR spectrum of the final product 2-(hydroxymethylphosphono)acetic acid is shown below. Figure 1 ;

[0166] The hydrolysis reaction formula of the intermediate in step S2 of this embodiment is as follows:

[0167]

[0168] Example 6:

[0169] A method for preparing 2-(hydroxymethylphosphono)acetic acid includes the following steps:

[0170] S1, Intermediate Synthesis:

[0171] The intermediate was synthesized via the Arbuzov rearrangement method. Under nitrogen protection, 136.28 g of 99.8% diethyl methyl phosphite (1 mol) was added to a 500 mL flask and heated to 60 °C. Then, 126.21 g of 99% ethyl chloroacetate (1.02 mol) was slowly added dropwise. The molar ratio of ethyl chloroacetate to diethyl methyl phosphite was 1.02:1. As ethyl chloroacetate was added, the dropping rate was controlled, and the reaction temperature was maintained at 60 °C–65 °C. Ethyl chloroacetate was recovered. After the addition was complete, the mixture was kept at 60 °C–65 °C for 18 hours to obtain 198 g of crude intermediate solution.

[0172] The main component of the crude intermediate obtained in step S1 of this embodiment is ethyl 2-(ethoxymethylphosphinyl)acetate, with a gas chromatography purity of 97.88%; the rearrangement yield is 99% based on diethyl methylphosphite.

[0173] The mass spectrum of intermediate 2-(ethoxymethylphosphono)ethyl acetate is shown in [reference needed]. Figure 2 ;

[0174] The rearrangement reaction formula for the synthesis of intermediate 2-(ethoxymethylphosphono)ethyl acetate in step S1 of this embodiment is as follows:

[0175]

[0176] S2, intermediate crude liquid hydrolysis:

[0177] The 198 g of crude intermediate solution in the reaction vessel (500 ml flask) of step S1 above was heated to 102 °C (the purity of ethyl 2-(ethoxymethylphosphono)acetate in the crude intermediate solution was 97.88%). 611 g (calculated as 6.026 mol) of 36% hydrochloric acid was slowly added dropwise to the above crude solution to carry out the hydrolysis reaction. The molar ratio of hydrochloric acid to intermediate was 6.09:1. The generated chloroethane overflowed and was recovered. After the addition was completed, the temperature was kept in the range of 102 °C to 125 °C for 15 hours to obtain the final product crude solution.

[0178] The main hydrolysis reaction formula of the intermediate crude liquid in step S2 of this embodiment is as follows:

[0179]

[0180] S3. Post-treatment of the final product crude liquid

[0181] The crude product obtained in step S2 was directly heated and distilled to remove unreacted hydrochloric acid and water. The distillation temperature was raised to a maximum of 155°C until no more liquid was distilled off, yielding 138 grams of the final product 2-(hydroxymethylphosphono)acetic acid with an HCl-NMR purity of 98%. Its water content was less than 0.3%, and it had no hydrochloric acid odor. The overall yield was 98%. The HCl-NMR spectrum of the final product 2-(hydroxymethylphosphono)acetic acid is shown below. Figure 1 .

[0182] It is understood that in some other embodiments, steps S1, S2 and S3 are basically the same as in this embodiment six. The only difference is that in step S1, the reaction temperature in step S1 is controlled at 60℃~70℃ by adjusting the dropping rate, the overflowing chloroethane is recovered, and after the dropping is completed, the temperature is kept at 60℃~80℃ for 12h~24h before hydrolysis in step S2. This can also yield relatively ideal results.

[0183] Example 7:

[0184] A method for preparing 2-(hydroxymethylphosphono)acetic acid includes the following steps:

[0185] S1, Intermediate Synthesis:

[0186] The intermediate was synthesized via the Arbuzov rearrangement method. Under nitrogen protection, 136.28 g of 99.8% diethyl methyl phosphite (calculated as 1 mol) was added to a 500 mL flask and heated to 100 °C. Then, 126.21 g of 99% ethyl chloroacetate (calculated as 1.020 mol, with a molar ratio of ethyl chloroacetate to diethyl methyl phosphite of 1.02:1) was slowly added dropwise. As ethyl chloroacetate was added, the temperature of the material slowly increased to 115 °C. Ethyl chloroacetate was recovered from the overflow. The dropping rate was controlled, and the reaction temperature was maintained at 100 °C–120 °C. After the addition was complete, the temperature was kept within the range of 100 °C–120 °C for 8 hours, yielding 193.9 g of crude intermediate solution.

[0187] The main component of the crude intermediate was ethyl 2-(ethoxymethylphosphinyl)acetate with a gas chromatography purity of 98.5%, and the rearrangement yield was 98.4% based on diethyl methylphosphite.

[0188] The mass spectrum of intermediate 2-(ethoxymethylphosphono)ethyl acetate is shown in [reference needed]. Figure 2 ;

[0189] The rearrangement reaction formula for the synthesis of intermediate 2-(ethoxymethylphosphono)ethyl acetate in step S1 of this embodiment is as follows:

[0190]

[0191] S2, intermediate crude liquid hydrolysis:

[0192] The 193.9 g of crude intermediate solution in the reaction vessel (500 ml flask) of step S1 above was heated to 102 °C (the purity of the intermediate in the crude intermediate solution was 98.5%). 409.1 g of 36% hydrochloric acid (calculated as 4.035 mol, with a molar ratio of hydrochloric acid to intermediate of 4.10:1) was slowly added dropwise to the above crude solution to carry out the reaction. The generated chloroethane overflowed and was recovered. After the addition was completed, the temperature was kept in the range of 102 °C to 110 °C for 15 hours to obtain the final product crude solution.

[0193] The main hydrolysis reaction formula of the intermediate in step S2 of this embodiment is as follows:

[0194]

[0195] S3. Post-treatment of the final product crude liquid

[0196] The crude product obtained in step S2 was directly heated and distilled to remove unreacted hydrochloric acid and water. The distillation temperature was raised to a maximum of 155°C until no more liquid was distilled off, yielding 138.2 g of the final product 2-(hydroxymethylphosphono)acetic acid with an HCl-NMR purity of 98%. Its water content was less than 0.3%, and it had no hydrochloric acid odor. The overall yield was 98.1%. The HCl-NMR spectrum of the final product 2-(hydroxymethylphosphono)acetic acid is shown below. Figure 1 .

[0197] Example 8:

[0198] A method for preparing 2-(hydroxymethylphosphono)acetic acid includes the following steps:

[0199] S1, Intermediate Synthesis:

[0200] The intermediate was synthesized via the Arbuzov rearrangement method. 136.28 g of 99.8% pure diethyl methyl phosphite (calculated as 1 mol) was added to a 500 mL flask and heated to 90 °C. Then, 126.21 g of 99% pure ethyl chloroacetate (calculated as 1.020 mol, with a molar ratio of ethyl chloroacetate to diethyl methyl phosphite of 1.02:1) was slowly added dropwise. As ethyl chloroacetate was added, the temperature of the material slowly increased to 115 °C. Ethyl chloroacetate was recovered from the overflow. The dropping rate was controlled, and the reaction temperature was maintained at 90 °C–120 °C. After the addition was complete, the temperature was maintained at 90 °C–120 °C for 13 hours, yielding 194.6 g of crude 2-(ethoxymethylphosphono)ethyl acetate intermediate.

[0201] The main component of the crude intermediate was ethyl acetate 2-(ethoxymethylphosphono)acetate with a gas chromatographic purity of 98.4%; the rearrangement yield was 98.7% based on diethyl methylphosphite.

[0202] The mass spectrum of the ethyl acetate intermediate (2-(ethoxymethylphosphono)ethyl acetate) is shown in [reference needed]. Figure 2 ;

[0203] The rearrangement reaction formula for the synthesis of the 2-(ethoxymethylphosphono)ethyl acetate intermediate in step 8S1 of this embodiment is as follows:

[0204]

[0205] S2, intermediate crude liquid hydrolysis and S3 final product crude liquid post-treatment:

[0206] The 194.6 g of crude intermediate solution (with a gas chromatographic purity of 98.4%) was poured into a 1000 mL flask and heated to 102 °C. 930.72 g (calculated as 9.180 mol, molar ratio of hydrochloric acid to intermediate of 9.30:1) of 36% hydrochloric acid was slowly added dropwise. The generated chloroethane was recovered. After the addition was complete, the mixture was kept at 102 °C–110 °C for 15 hours, and then distilled to remove unreacted hydrochloric acid and water. The distillation temperature was raised to a maximum of 155 °C until no more liquid was distilled off, yielding 138.70 g of the final product, 2-(hydroxymethylphosphono)acetic acid, with an H-NMR purity of 98%. Its water content was less than 0.4%, and it had no hydrochloric acid odor. The overall yield was 98.5%. The H-NMR spectrum of the final product, 2-(hydroxymethylphosphono)acetic acid, is shown below. Figure 1 ;

[0207] The main hydrolysis reaction formula of the intermediate in step S2 of this embodiment is as follows:

[0208]

[0209] Example 9:

[0210] A method for preparing 2-(hydroxymethylphosphono)acetic acid includes the following steps:

[0211] S1, Intermediate Synthesis:

[0212] The intermediate was synthesized via the Arbuzov rearrangement method. 136.28 g of 99.8% diethyl methyl phosphite (1 mol) was added to a 500 mL flask and heated to 90 °C. Then, 111.79 g of 99% methyl chloroacetate (1.02 mol) was slowly added dropwise. The molar ratio of methyl chloroacetate to diethyl methyl phosphite was 1.02:1. As methyl chloroacetate was added, the temperature of the material slowly increased to 115 °C. The dropping rate was controlled, and the reaction temperature was maintained at 90 °C–120 °C. Ethyl chloroacetate was recovered from the overflow. After the addition was complete, the mixture was kept at 90 °C–120 °C for 12 hours to obtain 181.89 g of crude intermediate solution.

[0213] The main component of the crude intermediate was methyl 2-(ethoxymethylphosphinyl)acetate with a gas chromatographic purity of 98.6%. The calculated molar amount of methyl 2-(ethoxymethylphosphinyl)acetate was 0.996 mol, and the rearrangement yield was 99.6% based on diethyl methyl phosphite.

[0214] The 1H NMR (nuclear magnetic resonance) spectrum of the intermediate methyl 2-(ethoxymethylphosphono)acetate is shown below. Figure 3 ;

[0215] The rearrangement reaction formula for the synthesis of intermediate 2-(ethoxymethylphosphono)acetate in step S1 of Example 9 is as follows:

[0216]

[0217] S2, intermediate crude liquid hydrolysis; and S3, final product crude liquid post-treatment:

[0218] The above 181.89 g of crude intermediate solution (containing 98.6% purity intermediate methyl 2-(ethoxymethylphosphono)acetate) was poured into a second reaction vessel (specifically a 1000 ml flask). The temperature was raised to 102 °C, and 959.35 g of 36% hydrochloric acid (calculated as 9.462 mol, with a molar ratio of hydrochloric acid to intermediate of 9.50:1) was slowly added dropwise. The generated chloroethane and chloromethane overflowed and were recovered. After the addition was complete, the solution was collected at 10 °C. After holding the solution at 2℃~110℃ for 23 hours, distillation was initiated to remove unreacted hydrochloric acid and water. The distillation temperature was raised to a maximum of 150℃ until no more liquid droplets were distilled off, yielding 138.5 g of the final product 2-(hydroxymethylphosphono)acetic acid with an HCl-NMR purity of 98%. The water content was less than 0.5%, and the calculated final product was 0.984 mol, with an overall yield of 98.4%. The HCl-NMR spectrum of the final product 2-(hydroxymethylphosphono)acetic acid is shown below. Figure 1 ;

[0219] The hydrolysis reaction formula of the intermediate in step S2 of this embodiment is as follows:

[0220]

[0221] Example 10:

[0222] A method for preparing 2-(hydroxymethylphosphono)acetic acid includes the following steps:

[0223] S1, Intermediate Synthesis:

[0224] The intermediate was synthesized via the Arbuzov rearrangement method. 136.28 g of 99.8% diethyl methyl phosphite (1.000 mol) was added to a 500 mL flask under no inert gas protection. The flask was heated to 95 °C, and then 134.87 g of 99% ethyl chlorophosphite (1.090 mol) was slowly added dropwise. The molar ratio of ethyl chlorophosphite to diethyl methyl phosphite was 1.09:1. As ethyl chlorophosphite was added, the temperature of the material slowly increased to 115 °C. The dropping rate was controlled to maintain the reaction temperature between 105 °C and 115 °C. Ethyl chloroethane was recovered from the overflow. After the addition was complete, the mixture was kept at 105 °C to 115 °C for 5 hours, yielding 216.3 g of crude intermediate solution.

[0225] The main components of the crude intermediate liquid include ethyl 2-(ethoxymethylphosphono)acetate with a gas chromatographic purity of 81.44%; the calculated molar amount of the intermediate is 0.908 mol, and the rearrangement yield is 91% based on diethyl methylphosphite.

[0226] The mass spectrum of intermediate 2-(ethoxymethylphosphono)ethyl acetate is shown in [reference needed]. Figure 2 ;

[0227] The rearrangement reaction formula for the synthesis of intermediate 2-(ethoxymethylphosphono)ethyl acetate in step S1 of this embodiment is as follows:

[0228]

[0229] The crude intermediate solution obtained in step S1 of this embodiment also includes a small amount of byproduct A (15.89 g, calculated to be 0.063 mol), generated from the reaction of ethyl chloroacetate with intermediate 2-(ethoxymethylphosphono)ethyl acetate, unreacted ethyl chloroacetate, and methylphosphite monoethyl ester, among other impurities. The small amount of byproduct A generated can react with hydrochloric acid in the next step to form the final product; the mass spectrum of the small amount of byproduct A is shown in the appendix. Figure 4 .

[0230] The English and Chinese names of byproduct A are: 2-((2-ethoxy-2-ethoxycarbonyl)(methyl)phosphinyl)acetate.

[0231] The reaction formula for the reaction of ethyl chloroacetate with intermediate 2-(ethoxymethylphosphono)ethyl acetate in step S1 of this embodiment to produce a small amount of byproduct A is as follows:

[0232]

[0233] S2, intermediate crude liquid hydrolysis; and S3, final product crude liquid post-processing:

[0234] The 216.3 g crude intermediate solution obtained in step S1 above (containing an intermediate with a purity of 81.44% and a small amount of substance A15.89 g) was poured into the second reaction vessel (specifically a 1000 ml flask) and heated to 102 °C. 611 g of 36% hydrochloric acid (calculated as 6.026 mol, with a molar ratio of hydrochloric acid to intermediate of 6.64:1) was slowly added dropwise. The generated chloroethane overflowed and was recovered. After the addition was completed, the temperature was maintained at 102 °C to 110 °C for 23 hours to obtain the final product crude solution.

[0235] Next, the crude product was heated and distilled to remove unreacted hydrochloric acid, water, and chloroacetic acid (chloroacetic acid is produced by the hydrolysis of a small amount of byproduct A). The distillation temperature was raised to a maximum of 155°C until no more liquid was distilled off, yielding 136.56 g of the final product 2-(hydroxymethylphosphono)acetic acid with an H-NMR purity of 98%, a water content of 0.4%, and no residual hydrochloric acid odor. (The calculated final product was 0.970 mol). The overall yield was 97.0%. The H-NMR spectrum of the final product 2-(hydroxymethylphosphono)acetic acid is shown below. Figure 1 .

[0236] The hydrolysis reaction formula of the intermediate in step S2 of this embodiment is as follows:

[0237]

[0238] The hydrolysis reaction formula of the small amount of byproduct A in step S2 of this embodiment is as follows:

[0239]

[0240] In some other embodiments, to ensure the hydrolysis reaction proceeds fully, it is preferable to set the heat preservation time after hydrolysis in step S2 to 6h to 24h.

[0241] The insulation temperature, insulation temperature range, and insulation time used in the above embodiments can be appropriately adjusted when using larger volume reaction vessels (such as 50-liter reaction kettles) or industrial mass production.

[0242] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing 2-(hydroxymethylphosphono)acetic acid, characterized in that, Includes the following steps: S1, Intermediate Synthesis: The intermediate was synthesized by the Arbuzov rearrangement method. The di-R2 methylphosphite was heated to 60℃~100℃, and 1.02~1.09 times the molar amount of di-R2 methylphosphite R4 ester was slowly added dropwise to the di-R2 methylphosphite to start the reaction. The reaction temperature was maintained at 60℃~120℃. After the addition was completed, the temperature was kept for 1h~24h to obtain a crude intermediate liquid with the intermediate as the main component. The main rearrangement reaction of the synthetic intermediate is as follows: S2, intermediate crude liquid hydrolysis: Add 4.10 to 9.50 times the molar amount of hydrochloric acid to the crude intermediate obtained in step S1, and carry out a hydrolysis reaction at 102℃ to 125℃. The generated chloroalkane overflows and is recovered. After the addition is complete, keep warm at 102℃ to 125℃ for 1 h to 24 h to obtain the final product crude liquid. The main hydrolysis reaction formulas are as follows: Wherein, R2 is an alkyl group, a hydrocarbon group with a benzene ring, a chloroalkyl group, or an allyl group, and R4 is hydrogen, an alkyl group, or a chloroalkyl group, and the alkyl or chloroalkyl group in R2 or R4 has 1 to 4 carbon atoms; S3. Post-treatment of the final product crude liquid: The crude product obtained in step S2 is heated and distilled, with the distillation endpoint temperature not exceeding 160℃, to obtain the final product 2-(hydroxymethylphosphono)acetic acid.

2. The method for preparing 2-(hydroxymethylphosphono)acetic acid according to claim 1, characterized in that, In step S1, the methyl phosphite diR2 ester is selected from one of dimethyl phosphite, diethyl phosphite, diphenyl phosphite, diisopropanol methyl phosphite, and dichloroethanol methyl phosphite; the chloroacetic acid R4 ester is selected from one of ethyl chloroacetate, methyl chloroacetate, propyl chloroacetate, and tert-butanol chloroacetate.

3. The method for preparing 2-(hydroxymethylphosphono)acetic acid according to claim 2, characterized in that, When the methylphosphite diR2-based ester is selected from diethyl methylphosphite and the chloroacetic acid R4-based ester is selected from ethyl chloroacetate, the main component of the intermediate crude liquid obtained in step S1 is the intermediate 2-(ethoxymethylphosphono)ethyl acetate.

4. The method for preparing 2-(hydroxymethylphosphono)acetic acid according to claim 1, characterized in that, In step S1, the molar number of the R4-based chloroacetic acid ester added is 1.02 to 1.08 times the molar number of the R2-based methylphosphite ester.

5. The method for preparing 2-(hydroxymethylphosphono)acetic acid according to claim 4, characterized in that, In step S1, the dimethylphosphite R2 ester is heated to 60℃~95℃, and 1.02~1.08 times the molar amount of chloroacetic acid R4 ester is added dropwise to the dimethylphosphite R2 ester to initiate the reaction. The reaction temperature is maintained at 60℃~115℃ by controlling the dropwise addition rate. After the dropwise addition is completed, the temperature is maintained at 60℃~115℃ for 1h~24h.

6. The method for preparing 2-(hydroxymethylphosphono)acetic acid according to claim 4, characterized in that, In step S1, under inert gas protection, the dimethylphosphite R2 ester is heated to 60℃~95℃, and 1.02~1.08 times the molar amount of chloroacetic acid R4 ester is added dropwise to the dimethylphosphite R2 ester to initiate the reaction. The reaction temperature is maintained at 60℃~115℃ by controlling the dropping rate. After the dropping is completed, the temperature is maintained at 60℃~115℃ for 1h~24h.

7. The method for preparing 2-(hydroxymethylphosphono)acetic acid according to claim 1, characterized in that, The crude intermediate liquid obtained in step S1 is subjected to vacuum distillation, and then the refined intermediate product is hydrolyzed according to step S2.

8. The method for preparing 2-(hydroxymethylphosphono)acetic acid according to claim 1, characterized in that, In step S2, the number of moles of hydrochloric acid is 4.10 to 9.30 times that of the intermediate obtained in step S1, and the concentration of the hydrochloric acid is 36%.

9. The method for preparing 2-(hydroxymethylphosphono)acetic acid according to claim 4, characterized in that, In step S1, the molar number of the R4-based chloroacetic acid ester added is 1.02 to 1.04 times the molar number of the R2-based methylphosphite ester.

10. The method for preparing 2-(hydroxymethylphosphono)acetic acid according to claim 1, characterized in that, In step S2, the temperature is raised to 102℃~110℃ and hydrochloric acid is added dropwise to carry out the hydrolysis reaction. After the hydrochloric acid is added, the temperature is maintained at 102℃~110℃ for 1h~24h to obtain the final product crude liquid.

11. The method for preparing 2-(hydroxymethylphosphono)acetic acid according to claim 1, characterized in that, In step S3, the final temperature of the heating distillation of the crude product is controlled between 151℃ and 160℃.

12. The method for preparing 2-(hydroxymethylphosphono)acetic acid according to claim 1, characterized in that, The intermediate crude liquid obtained in step S1 has a gas chromatographic purity of 75% to 99%.

13. The method for preparing 2-(hydroxymethylphosphono)acetic acid according to claim 1, characterized in that, The intermediate synthesis in step S1 is carried out in a reaction vessel, while the crude intermediate hydrolysis in step S2 is carried out in a second reaction vessel.

14. The method for preparing 2-(hydroxymethylphosphono)acetic acid according to claim 2, characterized in that, When the methyl phosphite diR2-based ester is selected from diethyl methyl phosphite, and the chloroacetic acid R4-based ester is selected from methyl chloroacetate, the main component of the intermediate crude liquid obtained in step S1 is intermediate 2-(ethoxymethylphosphono)acetic acid methyl ester.

15. A 2-(hydroxymethylphosphono)acetic acid, characterized in that, It is prepared by the method for preparing 2-(hydroxymethylphosphono)acetic acid as described in any one of claims 1 to 14.

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