A process for the preparation of 4-(hydroxymethylphosphono)-2-oxobutanoic acid

Abstract

The application provides a preparation method of 4-(hydroxymethyl phosphono)-2-carbonyl butyric acid, comprising the following steps: a) mixing methyl phosphite, a solvent, an initiator and acryloyl cyanide to perform an addition reaction, and then performing vacuum distillation to obtain a (3-cyano-3-carbonyl propyl) methyl phosphonate solution; b) uniformly mixing the (3-cyano-3-carbonyl propyl) methyl phosphonate solution obtained in the step a) with water, cooling to 10-40 DEG C, then adding hydrochloric acid dropwise to perform acidification, continuing to stir for 0.1-1 h after the dropwise addition is completed, then performing a hydrolysis reaction, and finally performing a purification treatment to obtain 4-(hydroxymethyl phosphono)-2-carbonyl butyric acid. Compared with the prior art, the preparation method provided by the application does not need to perform a cyanation reaction, avoids the use of high-cost, hard-to-obtain cyclic phosphonic anhydride and a highly toxic sodium cyanide, has short process steps, wide raw material sources and low cost, mild reaction conditions, less by-products and three wastes, and high comprehensive utilization rate of elements.

Description

Technical Field

[0001] This invention relates to the field of chemical technology, and more specifically, to a method for preparing the pesticide intermediate 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. Background Technology

[0002] 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, abbreviated as PPO or keto acid, is an important intermediate in the synthesis of glufosinate. This compound can be converted into glufosinate through steps such as ammoniation reduction, and L-glufosinate can be obtained through biological enzymatic conversion.

[0003] In 1980, FBC first applied for a patent US4399287A for the preparation of keto acid intermediates. 3-(ethoxymethylphosphono)propionate was extended by Claysen condensation to obtain the keto acid intermediate 2-oxo-4-(hydroxymethyl)butyric acid. The reported yield of the keto acid intermediate was about 30%. In 1991, Hoechst reported a chemical synthesis method for 4-(hydroxymethylphosphono)-2-carbonylbutyric acid (J. Org. Chem. 1991, 56, 1783-1788): ethyl 3-(ethoxymethylphosphono)-propionate was first prepared by Michael addition of methylphosphonite and ethyl acrylate in the presence of sodium ethoxide. Then, it underwent Claisen ester condensation with diethyl oxalate at -50°C in the presence of sodium ethoxide, followed by hydrolysis with hydrochloric acid to decarboxylate, yielding 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. However, this method required reaction at -50°C, had a low overall yield, generated a large amount of wastewater, and required a long crystallization time of up to 48 hours. The reaction formula is shown below:

[0004]

[0005] Patent CN103665032A discloses a method for preparing glufosinate, reporting a method for preparing 4-(hydroxy-(methyl)oxophosphono)-2-oxobutyric acid, an important intermediate of glufosinate, using a keto acid route. The method uses 2,5-dioxo-1-oxa-2-phosphocyclopentane, a five-membered heterocyclic compound containing oxygen and phosphorus, and cyanide as raw materials. A cyanidation reaction occurs in an organic solvent to generate a ketocyanide compound. Subsequently, hydrolysis in an acidic solution yields the keto acid 4-(hydroxy-(methyl)oxophosphono)-2-oxobutyric acid. Finally, under the conditions of an alcohol solvent and catalyst, amination and hydrogenation reduction processes yield glufosinate. However, the cyclic phosphonic anhydride used in this method is difficult to prepare, costly, and difficult to purify.

[0006] Patent CN105218579A discloses a method for synthesizing L-type glufosinate-ammonium salts. The key intermediate, 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, is synthesized from 4-(ethoxy-(methyl)oxyphosphono)-2-acetoxybutyric acid. First, it is hydrolyzed with hydrochloric acid to obtain 4-(hydroxy-(methyl)oxyphosphono)-2-hydroxybutyric acid, which is then neutralized with sodium hydroxide to form a salt. Next, it is oxidized to sodium 4-(hydroxysodium-(methyl)oxyphosphono)-2-carbonylbutyrate sodium in the presence of a transition metal oxide catalysis using an aqueous sodium hypochlorite solution. Finally, HCl gas is introduced to desalinate the salt, yielding 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. However, this method requires large amounts of acid and alkali, generates significant amounts of byproduct salts, and necessitates the use of precious metal catalysts, increasing costs. Furthermore, the byproduct salts are difficult to handle. Summary of the Invention

[0007] In view of this, the purpose of the present invention is to provide a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, which has a short process step, widely available and low cost of raw materials, mild reaction conditions, low generation of by-products and waste, and high comprehensive utilization rate of elements.

[0008] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps:

[0009] a) Methylphosphonic acid monoester, solvent, initiator and acryloyl cyanide are mixed and subjected to addition reaction. After vacuum distillation, (3-cyano-3-carbonylpropyl)methylphosphonate solution is obtained;

[0010] b) Mix the (3-cyano-3-carbonylpropyl)methylphosphonate solution obtained in step a) with water, cool it to 10℃~40℃, and then add hydrochloric acid dropwise for acidification. After the addition is complete, continue stirring for 0.1h~1h, and then carry out hydrolysis reaction. Finally, after purification treatment, 4-(hydroxymethylphosphono)-2-carbonylbutyric acid is obtained.

[0011] Preferably, the methylphosphonite monoester in step a) is selected from one or more of methylphosphonite monomethyl ester, methylphosphonite monoethyl ester, methylphosphonite monopropyl ester and methylphosphonite monobutyl ester;

[0012] The solvent is selected from one or more of toluene, xylene, dichloroethane, dichloropropane, chlorobutane, and dichlorobutane;

[0013] The mass ratio of the methylphosphonic acid monoester to the solvent is 1:(0-20).

[0014] Preferably, the initiator in step a) is selected from one or more of diisopropyl peroxide dicarbonate, dicyclohexyl peroxide dicarbonate, di-p-tert-butylcyclohexyl peroxide dicarbonate, lauroyl peroxide, benzoyl peroxide, and 1,1,3,3-tetramethylbutyl peroxide neodecanoate.

[0015] The molar ratio of the initiator to methylphosphonic acid monoester is (0.005–0.2):1.

[0016] Preferably, the molar ratio of acryloyl cyanide to methylphosphonic acid monoester in step a) is (0.8 to 1.2):1.

[0017] Preferably, the mixing process in step a) specifically includes:

[0018] Under stirring conditions, methylphosphonic acid monoester is placed in a solvent, and 10wt% to 25wt% of initiator is added. The temperature is controlled at 40℃ to 50℃, and acryloyl cyanide and the remaining initiator are added dropwise over a period of 0.1h to 5h to complete the mixing process.

[0019] Preferably, the temperature of the addition reaction in step a) is 40℃~90℃ and the time is 1h~10h.

[0020] Preferably, the molar ratio of hydrochloric acid to methylphosphonic acid monoester in step b) is (1-5):1.

[0021] Preferably, the acidification temperature in step b) is 0°C to 40°C.

[0022] Preferably, the hydrolysis reaction in step b) is carried out at a temperature of 60°C to 130°C for 1 hour to 24 hours.

[0023] Preferably, the purification process in step b) specifically includes:

[0024] The product obtained from the hydrolysis reaction was subjected to reduced pressure to remove acid water, then dissolved in acetone, filtered to remove insoluble salts, and methyl isobutyl ketone was added to the filtrate for crystallization to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0025] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps: a) mixing methylphosphonic acid monoester, solvent, initiator and acryloyl cyanide, performing an addition reaction, and distilling under reduced pressure to obtain (3-cyano-3-carbonylpropyl)methylphosphonate solution; b) mixing the (3-cyano-3-carbonylpropyl)methylphosphonate solution obtained in step a) with water, cooling to 10℃~40℃, then adding hydrochloric acid dropwise for acidification, continuing stirring for 0.1h~1h after the addition is complete, then performing a hydrolysis reaction, and finally purifying to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. Compared with existing technologies, the preparation method provided by this invention uses methylphosphonite monoester and acryloyl cyanide as raw materials to carry out a free radical addition reaction to obtain (3-cyano-3-carbonylpropyl)methylphosphonate, and then hydrolyzes it under acidic conditions to obtain the target product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. This preparation method directly uses methylphosphonite monoester and acryloyl cyanide for addition reaction, without the need for cyanidation reaction, thus avoiding the use of high-cost and hard-to-obtain cyclic phosphonic anhydride and highly toxic sodium cyanide. At the same time, the reaction with acryloyl cyanide directly introduces the acryloyl cyanide group, and then hydrolyzes it under acidic conditions to obtain the target product, avoiding the use of Claisen ester condensation and decarboxylation to add the carboxyl group, and also avoiding the production of carbonyl group by noble metal catalytic oxidation after salt formation. In addition, this preparation method has short process steps, widely available and low-cost raw materials, mild reaction conditions, less by-products and waste generation, and high comprehensive utilization rate of elements. Attached Figure Description

[0026] Figure 1 The HPLC chromatogram of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid standard is shown below.

[0027] Figure 2 This is the HPLC spectrum of the 4-(hydroxymethylphosphono)-2-carbonylbutyric acid sample obtained in Example 3 of the present invention. Detailed Implementation

[0028] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0029] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps:

[0030] a) Methylphosphonic acid monoester, solvent, initiator and acryloyl cyanide are mixed and subjected to addition reaction. After vacuum distillation, (3-cyano-3-carbonylpropyl)methylphosphonate solution is obtained;

[0031] b) Mix the (3-cyano-3-carbonylpropyl)methylphosphonate solution obtained in step a) with water, cool it to 10℃~40℃, and then add hydrochloric acid dropwise for acidification. After the addition is complete, continue stirring for 0.1h~1h, and then carry out hydrolysis reaction. Finally, after purification treatment, 4-(hydroxymethylphosphono)-2-carbonylbutyric acid is obtained.

[0032] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, using methylphosphonite monoester (Formula I; R1 can be represented as a C1-C4 alkyl group) and acryloyl cyanide (Formula II) as raw materials. First, a free radical addition reaction is carried out to obtain (3-cyano-3-carbonylpropyl)methylphosphonate (Formula III), and then hydrolyzed under acidic conditions to obtain the target product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid (Formula IV).

[0033]

[0034] The reaction formula for the preparation method of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid provided by this invention is as follows:

[0035]

[0036] The preparation method provided by this invention directly uses methylphosphonite monoester and acryloyl cyanide for an addition reaction, eliminating the need for cyanation and avoiding the use of high-cost and difficult-to-obtain cyclic phosphonic anhydride and highly toxic sodium cyanide. Simultaneously, the reaction with acryloyl cyanide directly introduces an acrylic acid group, followed by hydrolysis under acidic conditions to obtain the target product. This avoids the use of Claisen ester condensation and decarboxylation to add a carboxyl group, and also avoids the production of a carbonyl group through precious metal catalytic oxidation after salt formation. Furthermore, this preparation method has short process steps, widely available and low-cost raw materials, mild reaction conditions, minimal byproducts and waste generation, and high element utilization rate.

[0037] The present invention first mixes methylphosphonic acid monoester, solvent, initiator and acryloyl cyanide, performs addition reaction, and obtains (3-cyano-3-carbonylpropyl)methylphosphonate solution after vacuum distillation.

[0038] In this invention, the methylphosphonite monoester is preferably selected from one or more of monomethyl methylphosphonite, monoethyl methylphosphonite, monopropyl methylphosphonite, and monobutyl methylphosphonite, more preferably monoethyl methylphosphonite or monobutyl methylphosphonite. This invention does not impose any special restrictions on the source of the methylphosphonite monoester; commercially available products well known to those skilled in the art can be used.

[0039] In this invention, the solvent is preferably selected from one or more of toluene, xylene, dichloroethane, dichloropropane, chlorobutane, and dichlorobutane, and more preferably toluene, xylene, or dichloroethane. This invention does not impose any special restrictions on the source of the solvent; commercially available products well-known to those skilled in the art can be used.

[0040] In this invention, the preferred mass ratio of the methylphosphonic acid monoester to the solvent is 1:(0-20); wherein, when the solvent is 0, the methylphosphonic acid monoester is used as a solvent, and this invention does not impose any special restrictions on this.

[0041] In this invention, the initiator is preferably selected from one or more of diisopropyl peroxide dicarbonate, dicyclohexyl peroxide dicarbonate, di-p-tert-butylcyclohexyl peroxide dicarbonate, lauroyl peroxide, benzoyl peroxide, and 1,1,3,3-tetramethylbutyl peroxyneodecanoate. This invention does not impose any particular limitation on the source of the initiator; commercially available products well known to those skilled in the art can be used.

[0042] In this invention, the molar ratio of the initiator to methylphosphonic acid monoester is preferably (0.005-0.2):1, more preferably (0.02-0.05):1.

[0043] The present invention does not impose any special restrictions on the source of the acryloyl cyanide, and commercially available products well known to those skilled in the art can be used.

[0044] In this invention, the molar ratio of acryloyl cyanide to methylphosphonic acid monoester is preferably (0.8-1.2):1, more preferably (0.9-1):1.

[0045] In this invention, the mixing process is preferably specifically as follows:

[0046] Under stirring conditions, methylphosphonic acid monoester was placed in a solvent, and 10wt% to 25wt% of initiator was added. The temperature was controlled at 40℃ to 50℃, and acryloyl cyanide and the remaining initiator were added dropwise over a period of 0.1h to 5h to complete the mixing process.

[0047] More preferably:

[0048] Under stirring conditions, methylphosphonic acid monoester is placed in a solvent, and 10wt%–20wt% of initiator is added. The temperature is controlled at 45°C, and acryloyl cyanide and the remaining 90wt%–80wt% of initiator are added dropwise over a period of 1–3 hours to complete the mixing process.

[0049] In this invention, the temperature of the addition reaction is preferably 40°C to 90°C; the time of the addition reaction is preferably 1h to 10h, more preferably 3h to 6h.

[0050] In this invention, the purpose of vacuum distillation is to remove the solvent; this invention does not impose any particular limitation on this.

[0051] After obtaining the (3-cyano-3-carbonylpropyl)methylphosphonate solution, the present invention mixes the obtained (3-cyano-3-carbonylpropyl)methylphosphonate solution with water evenly, cools it to 10℃~40℃, and then adds hydrochloric acid dropwise for acidification. After the addition is completed, stirring is continued for 0.1h~1h, followed by hydrolysis reaction. Finally, after purification treatment, 4-(hydroxymethylphosphono)-2-carbonylbutyric acid is obtained.

[0052] In this invention, the concentration of the hydrochloric acid is preferably 20% to 36%; commercially available products well known to those skilled in the art can be used.

[0053] In this invention, the molar ratio of hydrochloric acid (HCl) to methylphosphonic acid monoester is preferably (1-5):1, more preferably (2-3):1.

[0054] In this invention, the acidification temperature is preferably 0°C to 40°C, and more preferably 30°C to 40°C.

[0055] In this invention, the temperature of the hydrolysis reaction is preferably 60℃~130℃, more preferably 90℃~120℃; the time of the hydrolysis reaction is preferably 1h~24h, more preferably 6h~12h.

[0056] In this invention, the hydrolysis reaction process is preferably as follows:

[0057] First, heat the material at normal pressure for about 1.5 to 2.5 hours to 105°C to 113°C, then hold it at that temperature and reflux for 2.5 to 3.5 hours, and then slowly heat it for another 2.5 to 3.5 hours to 114°C to 116°C.

[0058] or,

[0059] After a slow heating process of 7 to 9 hours, the temperature reaches 115℃ to 125℃.

[0060] In this invention, the purification process is preferably as follows:

[0061] The product obtained from the hydrolysis reaction was subjected to reduced pressure to remove acid water, then dissolved in acetone, filtered to remove insoluble salts, and methyl isobutyl ketone was added to the filtrate for crystallization to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0062] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps: a) mixing methylphosphonic acid monoester, solvent, initiator and acryloyl cyanide, performing an addition reaction, and distilling under reduced pressure to obtain (3-cyano-3-carbonylpropyl)methylphosphonate solution; b) mixing the (3-cyano-3-carbonylpropyl)methylphosphonate solution obtained in step a) with water, cooling to 10℃~40℃, then adding hydrochloric acid dropwise for acidification, continuing stirring for 0.1h~1h after the addition is complete, then performing a hydrolysis reaction, and finally purifying to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. Compared with existing technologies, the preparation method provided by this invention uses methylphosphonite monoester and acryloyl cyanide as raw materials to carry out a free radical addition reaction to obtain (3-cyano-3-carbonylpropyl)methylphosphonate, and then hydrolyzes it under acidic conditions to obtain the target product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. This preparation method directly uses methylphosphonite monoester and acryloyl cyanide for addition reaction, without the need for cyanidation reaction, thus avoiding the use of high-cost and hard-to-obtain cyclic phosphonic anhydride and highly toxic sodium cyanide. At the same time, the reaction with acryloyl cyanide directly introduces the acryloyl cyanide group, and then hydrolyzes it under acidic conditions to obtain the target product, avoiding the use of Claisen ester condensation and decarboxylation to add the carboxyl group, and also avoiding the production of carbonyl group by noble metal catalytic oxidation after salt formation. In addition, this preparation method has short process steps, widely available and low-cost raw materials, mild reaction conditions, less by-products and waste generation, and high comprehensive utilization rate of elements.

[0063] To further illustrate the present invention, the following embodiments are provided for detailed description. All raw materials used in the following embodiments of the present invention are commercially available products.

[0064] Example 1

[0065] 1) Add 55.1 g (0.5 mol) of 98% monoethyl methylphosphonate to 300 g of dichloroethane solvent, and add 0.3 g of dicyclohexyl peroxide. Heat to 45 °C, and simultaneously add 37.2 g (0.45 mol) of 98% acryloyl cyanide and 2.7 g of dicyclohexyl peroxide dropwise. Control the temperature at 45-50 °C and the dropwise addition time is 1 h. After the dropwise addition is completed, continue to keep the reaction at the temperature for 6 h to obtain a solution containing (3-cyano-3-carbonylpropyl)methylphosphonate. Remove the solvent from the solution by vacuum distillation to obtain the (3-cyano-3-carbonylpropyl)methylphosphonate solution.

[0066] 2) The (3-cyano-3-carbonylpropyl)methylphosphonate solution obtained above was added to 50g of deionized water and stirred until homogeneous. The mixture was cooled to below 40℃, and then 121.7g (1.0mol) of 30% hydrochloric acid was added dropwise for acidification, with the acidification temperature controlled below 40℃. After the addition was complete, the mixture was stirred for 0.5h, and then the hydrolysis reaction was carried out by heating. First, the temperature was raised to 110℃ at normal pressure for about 2h, then refluxed at 110℃ for 3h, and then slowly raised to 115℃ for 3h. Finally, the acid was removed under reduced pressure for 1h under a vacuum of -0.095Mpa, with an endpoint temperature of 65℃. 150g of acetone was added and refluxed to dissolve the acid. The insoluble salts were removed by filtration, and 400g of methyl isobutyl ketone was added to the filtrate for crystallization to obtain 59.2g of white solid product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a content of 97.8% and a yield of 64.3%.

[0067] Example 2

[0068] 1) Add 55.1 g (0.5 mol) of 98% methylphosphonic acid monoethyl ester to 300 g of dichloroethane solvent, and add 0.3 g of benzoyl peroxide. Heat to 45 °C, and simultaneously add 37.2 g (0.45 mol) of 98% acryloyl cyanide and 2.2 g of benzoyl peroxide dropwise. Control the temperature at 65-70 °C and the dropwise addition time is 2 h. After the dropwise addition is completed, continue to keep the reaction at the temperature for 4 h to obtain a solution containing (3-cyano-3-carbonylpropyl) methylphosphonate. Remove the solvent from the solution by vacuum distillation to obtain the (3-cyano-3-carbonylpropyl) methylphosphonate solution.

[0069] 2) The (3-cyano-3-carbonylpropyl)methylphosphonate solution obtained above was added to 50g of deionized water and stirred until homogeneous. The mixture was cooled to below 40℃, and then 121.7g (1.0mol) of 30% hydrochloric acid was added dropwise for acidification, with the acidification temperature controlled below 40℃. After the addition was complete, stirring and mixing continued for 0.5h. Then, a hydrolysis reaction was carried out under normal pressure with a slow increase in temperature. After a slow increase in temperature for 8h, the temperature reached 120℃. The steam was turned off, and the acid was removed under reduced pressure under a vacuum of -0.03Mpa until the temperature dropped to about 100℃. The vacuum was then released. 150g of acetone was added and refluxed to dissolve the acid. The insoluble salts were removed by filtration. 400g of methyl isobutyl ketone was added to the filtrate for crystallization to obtain 53.4g of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a purity of 95.6% and a yield of 56.7%.

[0070] Example 3

[0071] 1) Add 55.1 g (0.5 mol) of 98% monoethyl methylphosphonate to 300 g of dichloroethane solvent, and add 1.5 g of dicyclohexyl peroxide. Heat to 45 °C, and simultaneously add 41.3 g (0.5 mol) of 98% acryloyl cyanide and 5.9 g of dicyclohexyl peroxide dropwise. Control the temperature at 45-50 °C and the dropwise addition time is 1 h. After the dropwise addition is completed, continue to keep the reaction at the temperature for 6 h to obtain a solution containing (3-cyano-3-carbonylpropyl)methylphosphonate. Remove the solvent from the solution by vacuum distillation to obtain the (3-cyano-3-carbonylpropyl)methylphosphonate solution.

[0072] 2) The obtained (3-cyano-3-carbonylpropyl)methylphosphonate solution was added to 50g of deionized water and stirred until homogeneous. The mixture was cooled to below 40℃, and then 182.5g (1.5mol) of 30% hydrochloric acid was added dropwise for acidification, maintaining the acidification temperature below 40℃. After the addition was complete, stirring and mixing continued for 0.5h. Then, a hydrolysis reaction was carried out by heating. First, the temperature was raised to 110℃ under normal pressure for about 2h, then refluxed at 110℃ for 3h, followed by a slow increase to 115℃ for another 3h. Finally, the acid was removed under reduced pressure for 1h under a vacuum of -0.095Mpa, with an endpoint temperature of 65℃. 150g of acetone was added and refluxed to dissolve the acid. The insoluble salts were removed by filtration. 400g of methyl isobutyl ketone was added to the filtrate for crystallization, yielding 59.8g of the white solid product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. The product was quantified by HPLC using a standard as an external standard (standard sample: Figure 1 ,sample: Figure 2 The content is 98.5%, and the yield is 65.4%.

[0073] Example 4

[0074] 1) Add 69.4 g (0.5 mol) of 98% methylphosphonic acid monobutyl ester to 300 g of dichloroethane solvent, and add 0.3 g of benzoyl peroxide. Heat to 45 °C, and simultaneously add 41.3 g (0.5 mol) of 98% acryloyl cyanide and 2.2 g of benzoyl peroxide dropwise. Control the temperature at 65-70 °C and the dropwise addition time is 2 h. After the dropwise addition is completed, continue to keep the temperature for 4 h to obtain a solution containing (3-cyano-3-carbonylpropyl) methylphosphonate. Remove the solvent from the solution by vacuum distillation to obtain the (3-cyano-3-carbonylpropyl) methylphosphonate solution.

[0075] 2) The (3-cyano-3-carbonylpropyl)methylphosphonate solution obtained above was added to 50g of deionized water and stirred until homogeneous. The mixture was cooled to below 40℃, and then 182.5g (1.5mol) of 30% hydrochloric acid was added dropwise for acidification, with the acidification temperature controlled below 40℃. After the addition was complete, stirring and mixing continued for 0.5h. Then, a hydrolysis reaction was carried out under normal pressure with a slow increase in temperature. After a slow increase in temperature for 8h, the temperature reached 120℃. The steam was turned off, and the acid was removed under reduced pressure under a vacuum of -0.03Mpa until the temperature dropped to about 100℃. The vacuum was then released. 150g of acetone was added and refluxed to dissolve the acid. The insoluble salts were removed by filtration. 400g of methyl isobutyl ketone was added to the filtrate for crystallization to obtain 51.8g of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, a white solid product with a content of 96.3% and a yield of 55.4%.

[0076] Example 5

[0077] 1) Add 69.4 g (0.5 mol) of 98% methylphosphonic acid monobutyl ester to 300 g of dichloroethane solvent, and add 1.2 g of benzoyl peroxide. Heat to 45 °C, and simultaneously add 41.3 g (0.5 mol) of 98% acryloyl cyanide and 4.9 g of benzoyl peroxide dropwise. Control the temperature at 65-70 °C and the dropwise addition time is 3 h. After the dropwise addition is completed, continue to keep the temperature for 3 h to obtain a solution containing (3-cyano-3-carbonylpropyl) methylphosphonate. Remove the solvent from the solution by vacuum distillation to obtain the (3-cyano-3-carbonylpropyl) methylphosphonate solution.

[0078] 2) The (3-cyano-3-carbonylpropyl)methylphosphonate solution obtained above was added to 50g of deionized water and stirred until homogeneous. The mixture was cooled to below 40℃, and then 121.7g (1.0mol) of 30% hydrochloric acid was added dropwise for acidification, with the acidification temperature controlled below 40℃. After the addition was complete, stirring and mixing continued for 0.5h, followed by a slow heating and atmospheric pressure hydrolysis reaction. After slowly heating for 8h to reach 120℃, the steam was turned off, and the acid was removed under reduced pressure under a vacuum of -0.03Mpa until the temperature dropped to about 100℃. The vacuum was then released. 150g of acetone was added and refluxed to dissolve the acid. The insoluble salts were removed by filtration, and 400g of methyl isobutyl ketone was added to the filtrate for crystallization to obtain 43.6g of the white solid product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a purity of 95.1% and a yield of 46.1%.

[0079] Example 6

[0080] 1) Add 69.4 g (0.5 mol) of 98% monobutyl methylphosphonate to 300 g of dichloroethane solvent, and add 1.5 g of dicyclohexyl peroxide. Heat to 45 °C, and simultaneously add 37.2 g (0.45 mol) of 98% acryloyl cyanide and 5.9 g of dicyclohexyl peroxide dropwise. Control the temperature at 45-50 °C and the dropwise addition time is 2 h. After the dropwise addition is completed, continue to keep the reaction at the temperature for 4 h to obtain a solution containing (3-cyano-3-carbonylpropyl)methylphosphonate. Remove the solvent from the solution by vacuum distillation to obtain the (3-cyano-3-carbonylpropyl)methylphosphonate solution.

[0081] 2) The (3-cyano-3-carbonylpropyl)methylphosphonate solution obtained above was added to 50g of deionized water and stirred until homogeneous. The mixture was cooled to below 40℃, and then 121.7g (1.0mol) of 30% hydrochloric acid was added dropwise for acidification, with the acidification temperature controlled below 40℃. After the addition was complete, the mixture was stirred for 0.5h, and then the hydrolysis reaction was carried out by heating. First, the temperature was raised to 110℃ at normal pressure for about 2h, then refluxed at 110℃ for 3h, and then slowly raised to 115℃ for 3h. Finally, the acid was removed under reduced pressure for 1h under a vacuum of -0.095Mpa, with an endpoint temperature of 65℃. 150g of acetone was added and refluxed to dissolve the acid. The insoluble salts were removed by filtration, and 400g of methyl isobutyl ketone was added to the filtrate for crystallization to obtain 57.5g of white solid product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a content of 96.5% and a yield of 61.7%.

[0082] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, characterized in that, Includes the following steps: a) Methylphosphonic acid monoester, solvent, initiator and acryloyl cyanide are mixed and subjected to addition reaction. After vacuum distillation, (3-cyano-3-carbonylpropyl)methylphosphonate solution is obtained; b) Mix the (3-cyano-3-carbonylpropyl)methylphosphonate solution obtained in step a) with water, cool it to 10℃~40℃, add hydrochloric acid dropwise for acidification, continue stirring for 0.1h~1h after the addition is complete, then carry out hydrolysis reaction, and finally purify to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid; The initiator is selected from one or more of diisopropyl peroxide, dicyclohexyl peroxide, di-p-tert-butylcyclohexyl peroxide, lauroyl peroxide, benzoyl peroxide, and 1,1,3,3-tetramethylbutyl peroxide. The methylphosphonite monoester is selected from one or more of methylphosphonite monomethyl ester, methylphosphonite monoethyl ester, methylphosphonite monopropyl ester, and methylphosphonite monobutyl ester; The molar ratio of the initiator to methylphosphonic acid monoester in step a) is (0.02-0.05):1; The mixing process described in step a) is as follows: Under stirring conditions, methylphosphonic acid monoester is placed in a solvent, and 10wt%~25wt% of initiator is added. The temperature is controlled at 40℃~50℃, and acryloyl cyanide and the remaining initiator are added dropwise over a period of 0.1h~5h to complete the mixing process.

2. The preparation method according to claim 1, characterized in that, The solvent mentioned in step a) is selected from one or more of toluene, xylene, dichloroethane, dichloropropane, chlorobutane, and dichlorobutane; The mass ratio of the methylphosphonic acid monoester to the solvent is 1:(0~20).

3. The preparation method according to claim 1, characterized in that, The molar ratio of acryloyl cyanide to methylphosphonic acid monoester in step a) is (0.8~1.2):

1.

4. The preparation method according to claim 1, characterized in that, The addition reaction in step a) takes 1 h to 10 h.

5. The preparation method according to claim 1, characterized in that, The molar ratio of hydrochloric acid to methylphosphonic acid monoester in step b) is (1~5):

1.

6. The preparation method according to claim 1, characterized in that, The acidification temperature described in step b) is 0℃~40℃.

7. The preparation method according to claim 1, characterized in that, The hydrolysis reaction described in step b) is carried out at a temperature of 60℃ to 130℃ for a time of 1h to 24h.

8. The preparation method according to claim 1, characterized in that, The purification process described in step b) is as follows: The product obtained from the hydrolysis reaction was subjected to reduced pressure to remove acid water, then dissolved in acetone, filtered to remove insoluble salts, and methyl isobutyl ketone was added to the filtrate for crystallization to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

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