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

Abstract

This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps: a) mixing methylphosphonite diester, carboxylic acid, and acryloyl chloride, performing an addition reaction, and distilling under reduced pressure to obtain a (3-chloro-3-carbonylpropyl)methylphosphonate solution; b) mixing the (3-chloro-3-carbonylpropyl)methylphosphonate solution obtained in step a) with sodium cyanide, solvent, and catalyst, performing a substitution reaction, and purifying to obtain a (3-cyano-3-carbonylpropyl)methylphosphonate solution; c) mixing the (3-cyano-3-carbonylpropyl)methylphosphonate solution obtained in step b) with water, cooling to 10℃~40℃, adding hydrochloric acid dropwise for acidification, 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 has simple process steps, mild reaction conditions, 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, mild reaction conditions, 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 diester, carboxylic acid and acryloyl chloride were mixed and subjected to an addition reaction. After vacuum distillation, (3-chloro-3-carbonylpropyl)methylphosphonate solution was obtained.

[0010] b) The (3-chloro-3-carbonylpropyl)methylphosphonate solution obtained in step a) is mixed with sodium cyanide, solvent and catalyst to carry out a substitution reaction, and after purification, (3-cyano-3-carbonylpropyl)methylphosphonate solution is obtained.

[0011] c) Mix the (3-cyano-3-carbonylpropyl)methylphosphonate solution obtained in step b) with water until homogeneous, cool to 10℃~40℃, then add hydrochloric acid dropwise for acidification. After the addition is complete, continue stirring for 0.1h~1h, then carry out hydrolysis reaction, and finally purify to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0012] Preferably, the methylphosphonite diester in step a) is selected from one or more of dimethylphosphonite, diethyl methylphosphonite, dipropyl methylphosphonite, and dibutyl methylphosphonite;

[0013] The carboxylic acid is selected from one or more of acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid;

[0014] The mass ratio of the methylphosphonic acid diester to the carboxylic acid is 1:(1-20);

[0015] The molar ratio of acryloyl chloride to methylphosphonic acid diester is (0.8–1.5):1.

[0016] Preferably, the mixing process in step a) specifically includes:

[0017] Under stirring conditions, methylphosphonic acid diester is placed in carboxylic acid and the temperature is controlled at 0℃~40℃. Acryloyl chloride is added dropwise over a period of 0.1h~5h to complete the mixing process.

[0018] Preferably, the temperature of the addition reaction in step a) is 0℃~90℃ and the time is 1h~10h.

[0019] Preferably, the solvent in step b) is acetonitrile or butyronitrile;

[0020] The catalyst is selected from one or more of cuprous chloride, cuprous bromide, cuprous iodide, ferric chloride, ferrous bromide, ferrous iodide, zinc chloride, zinc bromide, and zinc iodide;

[0021] The mass ratio of the solvent to methylphosphonic acid diester is (1-20):1; the molar ratio of sodium cyanide, catalyst to methylphosphonic acid diester is (0.8-1.5):(0.002-0.02):1.

[0022] Preferably, the temperature of the substitution reaction in step b) is 80°C to 120°C and the time is 1h to 12h.

[0023] Preferably, the molar ratio of hydrochloric acid to methylphosphonic acid diester in step c) is (1-5):1.

[0024] Preferably, the acidification temperature in step c) is 0°C to 40°C.

[0025] Preferably, the hydrolysis reaction in step c) is carried out at a temperature of 60°C to 130°C for a time of 1 hour to 24 hours.

[0026] Preferably, the purification process in step c) specifically includes:

[0027] 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.

[0028] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps: a) mixing methylphosphonite diester, carboxylic acid, and acryloyl chloride, performing an addition reaction, and distilling under reduced pressure to obtain a (3-chloro-3-carbonylpropyl)methylphosphonate solution; b) mixing the (3-chloro-3-carbonylpropyl)methylphosphonate solution obtained in step a) with sodium cyanide, solvent, and catalyst, performing a substitution reaction, and purifying to obtain a (3-cyano-3-carbonylpropyl)methylphosphonate solution; c) mixing the (3-cyano-3-carbonylpropyl)methylphosphonate solution obtained in step b) with water, cooling to 10℃~40℃, adding hydrochloric acid dropwise for acidification, 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 diester and acryloyl chloride as raw materials. First, they react in a carboxylic acid system to obtain (3-chloro-3-carbonylpropyl)methylphosphonate, then undergo a substitution reaction with sodium cyanide to obtain (3-cyano-3-carbonylpropyl)methylphosphonate, and finally hydrolyze under acidic conditions to obtain the target product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. The raw materials methylphosphonite diester and acryloyl chloride are readily available, avoiding the use of high-cost and difficult-to-obtain cyclic phosphonic anhydrides. The cyanidation reaction introduces the acrylic acid cyanide group, and then hydrolyzes under acidic conditions to obtain the target product, avoiding the use of Claisen ester condensation and decarboxylation to add the carboxyl group. It also avoids the production of carbonyl groups by noble metal catalytic oxidation after salt formation. Furthermore, the process steps are simple, the reaction conditions are mild, and the comprehensive utilization rate of elements is high. Attached Figure Description

[0029] Figure 1 The HPLC chromatogram of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid standard is shown below.

[0030] Figure 2 This is the HPLC spectrum of the 4-(hydroxymethylphosphono)-2-carbonylbutyric acid sample obtained in Example 4 of the present invention. Detailed Implementation

[0031] 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.

[0032] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps:

[0033] a) Methylphosphonic acid diester, carboxylic acid and acryloyl chloride were mixed and subjected to an addition reaction. After vacuum distillation, (3-chloro-3-carbonylpropyl)methylphosphonate solution was obtained.

[0034] b) The (3-chloro-3-carbonylpropyl)methylphosphonate solution obtained in step a) is mixed with sodium cyanide, solvent and catalyst to carry out a substitution reaction, and after purification, (3-cyano-3-carbonylpropyl)methylphosphonate solution is obtained.

[0035] c) Mix the (3-cyano-3-carbonylpropyl)methylphosphonate solution obtained in step b) with water until homogeneous, cool to 10℃~40℃, then add hydrochloric acid dropwise for acidification. After the addition is complete, continue stirring for 0.1h~1h, then carry out hydrolysis reaction, and finally purify to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0036] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, using methylphosphonite diester (Formula I; R1 and R2 can be represented as C1-C4 alkyl groups) and acryloyl chloride (Formula II) as raw materials. First, the reaction is carried out in a carboxylic acid (Formula III) system to obtain (3-chloro-3-carbonylpropyl)methylphosphonate (Formula IV), then a substitution reaction is carried out with sodium cyanide to obtain (3-cyano-3-carbonylpropyl)methylphosphonate (Formula V), and finally hydrolyzed under acidic conditions to obtain the target product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid (Formula VI).

[0037]

[0038] The reaction formula for the preparation method of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid provided by this invention is as follows:

[0039]

[0040] The preparation method provided by this invention uses readily available raw materials, methylphosphonite diester and acryloyl chloride, avoiding the use of high-cost and difficult-to-obtain cyclic phosphonic anhydrides; it introduces acrylic acid cyanide groups through cyanidation reaction, and then hydrolyzes the target product under acidic conditions, avoiding the use of Claisen ester condensation and decarboxylation to add carboxyl groups; it also avoids the use of noble metal catalytic oxidation to produce carbonyl groups after salt formation; and the process steps are simple, the reaction conditions are mild, and the comprehensive utilization rate of elements is high.

[0041] The present invention first mixes methylphosphonite diester, carboxylic acid and acryloyl chloride, performs an addition reaction, and obtains (3-chloro-3-carbonylpropyl)methylphosphonate solution after vacuum distillation.

[0042] In this invention, the methylphosphonite diester is preferably selected from one or more of dimethyl methylphosphonite, diethyl methylphosphonite, dipropyl methylphosphonite, and dibutyl methylphosphonite, and more preferably diethyl methylphosphonite. This invention does not impose any special restrictions on the source of the methylphosphonite diester, and commercially available products well known to those skilled in the art can be used.

[0043] In this invention, the carboxylic acid is preferably selected from one or more of acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid, more preferably acetic acid. The invention does not impose any particular limitation on the source of the carboxylic acid; commercially available products well known to those skilled in the art can be used. In this invention, the carboxylic acid serves as both a reactant and a solvent.

[0044] In this invention, the mass ratio of the methylphosphonic acid diester to the carboxylic acid is preferably 1:(1-20).

[0045] The present invention does not impose any special restrictions on the source of the acryloyl chloride; commercially available products well known to those skilled in the art can be used.

[0046] In this invention, the molar ratio of acryloyl chloride to methylphosphonic acid diester is preferably (0.8-1.5):1, more preferably (1-1.1):1.

[0047] In this invention, the mixing process is preferably specifically as follows:

[0048] Under stirring conditions, methylphosphonic acid diester is placed in carboxylic acid and the temperature is controlled at 0℃~40℃. Acryloyl chloride is added dropwise over a period of 0.1h~5h to complete the mixing process.

[0049] More preferably:

[0050] Under stirring conditions, methylphosphonic acid diester is placed in carboxylic acid and the temperature is controlled at 10℃~30℃. Acryloyl chloride is added dropwise over a period of 1h~3h to complete the mixing process.

[0051] In this invention, the temperature of the addition reaction is preferably 0℃~90℃, more preferably 10℃~40℃; the time of the addition reaction is preferably 1h~10h, more preferably 2h~4h.

[0052] In this invention, the purpose of the vacuum distillation is to remove the solvent and by-product carboxylic acid esters; this invention does not have any particular limitations in this regard.

[0053] After obtaining the (3-chloro-3-carbonylpropyl)methylphosphonate solution, the present invention mixes the obtained (3-chloro-3-carbonylpropyl)methylphosphonate solution with sodium cyanide, solvent and catalyst to carry out a substitution reaction, and after purification, obtains the (3-cyano-3-carbonylpropyl)methylphosphonate solution.

[0054] The present invention does not impose any special restrictions on the source of the sodium cyanide, solvent, and catalyst; commercially available products well known to those skilled in the art can be used.

[0055] In this invention, the molar ratio of sodium cyanide to methylphosphonic acid diester is preferably (0.8-1.5):1, more preferably (1-1.1):1.

[0056] In this invention, the solvent is preferably acetonitrile or butyronitrile; the mass ratio of the solvent to methylphosphonic acid diester is (1-20):1.

[0057] In this invention, the catalyst is preferably selected from one or more of cuprous chloride, cuprous bromide, cuprous iodide, ferric chloride, ferrous bromide, ferrous iodide, zinc chloride, zinc bromide, and zinc iodide, and more preferably from cuprous chloride, ferric chloride, zinc chloride, or zinc iodide.

[0058] In this invention, the molar ratio of the catalyst to methylphosphonic acid diester is preferably (0.002-0.02):1, more preferably (0.005-0.01):1.

[0059] In this invention, the substitution reaction is preferably a reflux reaction; the temperature of the substitution reaction is preferably 80℃~120℃; and the time of the substitution reaction is preferably 1h~12h, more preferably 4h~8h.

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

[0061] After the substitution reaction was complete, the temperature was lowered to below 40°C, and the mixture was washed with water to separate the layers, remove the by-product salts and catalyst, and the organic phase was distilled under reduced pressure to obtain (3-cyano-3-carbonylpropyl)methylphosphonate.

[0062] In this invention, the molar ratio of water used for washing to methylphosphonic acid diester is preferably (5-11):1, more preferably (8-10):1.

[0063] 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.

[0064] 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.

[0065] In this invention, the molar ratio of hydrochloric acid (HCl) to methylphosphonic acid diester is preferably (1-5):1, more preferably (2-3):1.

[0066] In this invention, the acidification temperature is preferably 0°C to 40°C, and more preferably 30°C to 40°C.

[0067] 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.

[0068] In this invention, the hydrolysis reaction process is preferably as follows:

[0069] 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.

[0070] or,

[0071] After a slow heating process of 7 to 9 hours, the temperature reaches 115℃ to 125℃.

[0072] In this invention, the purification process is preferably as follows:

[0073] 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.

[0074] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps: a) mixing methylphosphonite diester, carboxylic acid, and acryloyl chloride, performing an addition reaction, and distilling under reduced pressure to obtain a (3-chloro-3-carbonylpropyl)methylphosphonate solution; b) mixing the (3-chloro-3-carbonylpropyl)methylphosphonate solution obtained in step a) with sodium cyanide, solvent, and catalyst, performing a substitution reaction, and purifying to obtain a (3-cyano-3-carbonylpropyl)methylphosphonate solution; c) mixing the (3-cyano-3-carbonylpropyl)methylphosphonate solution obtained in step b) with water, cooling to 10℃~40℃, adding hydrochloric acid dropwise for acidification, 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 diester and acryloyl chloride as raw materials. First, they react in a carboxylic acid system to obtain (3-chloro-3-carbonylpropyl)methylphosphonate, then undergo a substitution reaction with sodium cyanide to obtain (3-cyano-3-carbonylpropyl)methylphosphonate, and finally hydrolyze under acidic conditions to obtain the target product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. The raw materials methylphosphonite diester and acryloyl chloride are readily available, avoiding the use of high-cost and difficult-to-obtain cyclic phosphonic anhydrides. The cyanidation reaction introduces the acrylic acid cyanide group, and then hydrolyzes under acidic conditions to obtain the target product, avoiding the use of Claisen ester condensation and decarboxylation to add the carboxyl group. It also avoids the production of carbonyl groups by noble metal catalytic oxidation after salt formation. Furthermore, the process steps are simple, the reaction conditions are mild, and the comprehensive utilization rate of elements is high.

[0075] 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.

[0076] Example 1

[0077] 1) Add 69.4 g (0.5 mol) of 98% diethyl methylphosphonate to 250 g of acetic acid, stir and mix evenly, cool to 10 °C, slowly add 46.2 g (0.5 mol) of 98% acryloyl chloride dropwise, and control the temperature at 10 °C. The addition is completed in 2 h. After the addition is completed, continue to keep the reaction at 10 °C for 3 h to obtain a solution containing (3-chloro-3-carbonylpropyl)methylphosphonate. Remove the solvent acetic acid and the by-product ethyl acetate by vacuum distillation to obtain the (3-chloro-3-carbonylpropyl)methylphosphonate solution.

[0078] 2) The (3-chloro-3-carbonylpropyl)methylphosphonate solution obtained from the above addition reaction and 25.0 g (0.5 mol) of 98% sodium cyanide were added to 250 g of acetonitrile and stirred to dissolve. 0.84 g of ferric chloride catalyst was added, and the mixture was refluxed at 80-85 °C for 8 h. After the reaction was completed, the temperature was lowered to below 40 °C. 18 g of deionized water was added for washing, and the mixture was allowed to stand to separate into layers. The lower layer of saturated salt solution was removed, and the organic phase was distilled under reduced pressure to obtain the (3-cyano-3-carbonylpropyl)methylphosphonate solution.

[0079] 3) 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 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 47.6g of white solid product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a content of 93.5% and a yield of 49.5%.

[0080] Example 2

[0081] 1) Add 69.4 g (0.5 mol) of 98% diethyl methylphosphonate to 250 g of acetic acid, stir and mix evenly, cool to 30 °C, and slowly add 46.2 g (0.5 mol) of 98% acryloyl chloride dropwise while controlling the temperature at 30 °C. The addition is completed in 1 hour. After the addition is completed, continue to keep the reaction at 30 °C for 2 hours to obtain a solution containing (3-chloro-3-carbonylpropyl)methylphosphonate. Remove the solvent acetic acid and the by-product ethyl acetate by vacuum distillation to obtain the (3-chloro-3-carbonylpropyl)methylphosphonate solution.

[0082] 2) The (3-chloro-3-carbonylpropyl)methylphosphonate solution obtained from the above addition reaction and 25.0 g (0.5 mol) of 98% sodium cyanide were added to 250 g of acetonitrile and stirred to dissolve. 0.35 g of zinc chloride catalyst was added, and the mixture was refluxed at 80-85 °C for 8 h. After the reaction was completed, the temperature was lowered to below 40 °C. 18 g of deionized water was added for washing, and the mixture was allowed to stand and separate into layers. The lower saturated salt solution was removed, and the organic phase was distilled under reduced pressure to obtain the (3-cyano-3-carbonylpropyl)methylphosphonate solution.

[0083] 3) 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 42.3g of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, a white solid product with a content of 91.8% and a yield of 43.1%.

[0084] Example 3

[0085] 1) Add 69.4 g (0.5 mol) of 98% diethyl methylphosphonate to 250 g of acetic acid, stir and mix evenly, cool to 10 °C, slowly add 50.8 g (0.55 mol) of 98% acryloyl chloride dropwise, and control the temperature at 10 °C. The addition is completed in 2 h. After the addition is completed, continue to keep the reaction at 10 °C for 3 h to obtain a solution containing (3-chloro-3-carbonylpropyl)methylphosphonate. Remove the solvent acetic acid and the by-product ethyl acetate by vacuum distillation to obtain the (3-chloro-3-carbonylpropyl)methylphosphonate solution.

[0086] 2) The (3-chloro-3-carbonylpropyl)methylphosphonate solution obtained from the above addition reaction and 27.5 g (0.55 mol) of 98% sodium cyanide were added to 250 g of butadiene nitrile and stirred to dissolve. 0.35 g of zinc chloride catalyst was added, and the mixture was refluxed at 115-120 °C for 4 h. After the reaction was completed, the temperature was lowered to below 40 °C. 36 g of deionized water was added for washing, and the mixture was allowed to stand and separate into layers. The lower layer of saturated salt solution was removed, and the organic phase was distilled under reduced pressure to obtain the (3-cyano-3-carbonylpropyl)methylphosphonate solution.

[0087] 3) 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 46.7g of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a purity of 97.6% and a yield of 50.6%.

[0088] Example 4

[0089] 1) Add 69.4 g (0.5 mol) of 98% diethyl methylphosphonate to 300 g of acetic acid, stir and mix evenly, cool to 10 °C, slowly add 50.8 g (0.55 mol) of 98% acryloyl chloride dropwise, and control the temperature at 10 °C. The addition is completed in 2 h. After the addition is completed, continue to keep the reaction at 10 °C for 3 h to obtain a solution containing (3-chloro-3-carbonylpropyl)methylphosphonate. Remove the solvent acetic acid and the by-product ethyl acetate by vacuum distillation to obtain the (3-chloro-3-carbonylpropyl)methylphosphonate solution.

[0090] 2) The (3-chloro-3-carbonylpropyl)methylphosphonate solution obtained from the above addition reaction and 27.5 g (0.55 mol) of 98% sodium cyanide were added to 250 g of butadiene nitrile and stirred to dissolve. 0.35 g of zinc chloride catalyst was added, and the mixture was refluxed at 115-120 °C for 4 h. After the reaction was completed, the temperature was lowered to below 40 °C. 36 g of deionized water was added for washing, and the mixture was allowed to stand and separate into layers. The lower layer of saturated salt solution was removed, and the organic phase was distilled under reduced pressure to obtain the (3-cyano-3-carbonylpropyl)methylphosphonate solution.

[0091] 3) 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 47.2g of a 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 was 97.5%, and the yield was 51.1%.

[0092] Example 5

[0093] 1) Add 69.4 g (0.5 mol) of 98% diethyl methylphosphonate to 300 g of acetic acid, stir and mix evenly, cool to 30 °C, and slowly add 50.8 g (0.55 mol) of 98% acryloyl chloride dropwise while controlling the temperature at 30 °C. The addition is completed in 1 hour. After the addition is completed, continue to keep the reaction at 30 °C for 2 hours to obtain a solution containing (3-chloro-3-carbonylpropyl)methylphosphonate. Remove the solvent acetic acid and the by-product ethyl acetate by vacuum distillation to obtain the (3-chloro-3-carbonylpropyl)methylphosphonate solution.

[0094] 2) The (3-chloro-3-carbonylpropyl)methylphosphonate solution obtained from the above addition reaction and 27.5 g (0.55 mol) of 98% sodium cyanide were added to 250 g of butadiene nitrile and stirred to dissolve. 0.84 g of ferric chloride catalyst was added, and the mixture was refluxed at 115-120 °C for 4 h. After the reaction was completed, the temperature was lowered to below 40 °C. 36 g of deionized water was added for washing, and the mixture was allowed to stand to separate into layers. The lower saturated salt solution was removed, and the organic phase was distilled under reduced pressure to obtain the (3-cyano-3-carbonylpropyl)methylphosphonate solution.

[0095] 3) 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 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 41.0g of white solid product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a content of 97.0% and a yield of 44.2%.

[0096] Example 6

[0097] 1) Add 69.4 g (0.5 mol) of 98% diethyl methylphosphonate to 300 g of acetic acid, stir and mix evenly, cool to 30 °C, and slowly add 46.2 g (0.5 mol) of 98% acryloyl chloride dropwise while controlling the temperature at 30 °C. The addition is completed in 1 hour. After the addition is completed, continue to keep the reaction at 30 °C for 2 hours to obtain a solution containing (3-chloro-3-carbonylpropyl)methylphosphonate. Remove the solvent acetic acid and the by-product ethyl acetate by vacuum distillation to obtain the (3-chloro-3-carbonylpropyl)methylphosphonate solution.

[0098] 2) The (3-chloro-3-carbonylpropyl)methylphosphonate solution obtained from the above addition reaction and 25.0 g (0.5 mol) of 98% sodium cyanide were added to 250 g of acetonitrile and stirred to dissolve. 0.84 g of ferric chloride catalyst was added, and the mixture was refluxed at 80-85 °C for 4 h. After the reaction was completed, the temperature was lowered to below 40 °C. 18 g of deionized water was added for washing, and the mixture was allowed to stand and separate into layers. The lower layer of saturated salt solution was removed, and the organic phase was distilled under reduced pressure to obtain the (3-cyano-3-carbonylpropyl)methylphosphonate solution.

[0099] 3) 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 at -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 40.2g of white solid product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a content of 92.1% and a yield of 41.1%.

[0100] 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, comprising the following steps: a) Methylphosphonic acid diester, carboxylic acid and acryloyl chloride are mixed and subjected to an addition reaction. After vacuum distillation, (3-chloro-3-carbonylpropyl)methylphosphonate solution is obtained. b) The (3-chloro-3-carbonylpropyl)methylphosphonate solution obtained in step a) is mixed with sodium cyanide, solvent, and catalyst to carry out a substitution reaction. After purification, the (3-cyano-3-carbonylpropyl)methylphosphonate solution is obtained. The catalyst is selected from one or more of cuprous chloride, cuprous bromide, cuprous iodide, ferric chloride, ferrous bromide, ferrous iodide, zinc chloride, zinc bromide, and zinc iodide. c) Mix the (3-cyano-3-carbonylpropyl)methylphosphonate solution obtained in step b) with water until homogeneous, cool 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.

2. The preparation method according to claim 1, characterized in that, The methylphosphonite diester mentioned in step a) is selected from one or more of dimethyl methylphosphonite, diethyl methylphosphonite, dipropyl methylphosphonite, and dibutyl methylphosphonite; The carboxylic acid is selected from one or more of acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid; The mass ratio of the methylphosphonic acid diester to the carboxylic acid is 1:(1~20). The molar ratio of acryloyl chloride to methylphosphonic acid diester is (0.8~1.5):

1.

3. The preparation method according to claim 1, characterized in that, The mixing process described in step a) is as follows: Under stirring conditions, methylphosphonic acid diester is placed in carboxylic acid and the temperature is controlled at 0℃~40℃. Acryloyl chloride is added dropwise over a period of 0.1h~5h to complete the mixing process.

4. The preparation method according to claim 1, characterized in that, The addition reaction in step a) is carried out at a temperature of 0°C to 90°C for 1 hour to 10 hours.

5. The preparation method according to claim 1, characterized in that, The solvent mentioned in step b) is acetonitrile or butyronitrile; The mass ratio of the solvent to methylphosphonic acid diester is (1~20):1; the molar ratio of sodium cyanide, catalyst to methylphosphonic acid diester is (0.8~1.5):(0.002~0.02):

1.

6. The preparation method according to claim 1, characterized in that, The substitution reaction described in step b) is carried out at a temperature of 80℃~120℃ for 1h~12h.

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

1.

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

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

10. The preparation method according to claim 1, characterized in that, The purification process described in step c) 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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