A method for synthesizing 4-(hydroxymethylphosphono)-2-oxobutanoic acid

Abstract

The application provides a synthesis method of 4-(hydroxymethyl phosphine) 2-carbonyl butyric acid, comprising the following steps: a) mixing acryloyl chloride, a first solvent, a polymerization inhibitor, a catalyst and sodium cyanide, performing a substitution reaction, and obtaining an acryloyl cyanide intermediate after reduced pressure distillation; b) mixing the acryloyl cyanide intermediate obtained in the step a) with hydrochloric acid and a polymerization inhibitor, performing a hydrolysis reaction, and obtaining 2-carbonyl-3-butenoic acid crude product after purification treatment; c) mixing the 2-carbonyl-3-butenoic acid crude product obtained in the step b) with a second solvent and methyl phosphinite, performing an addition reaction, recovering the solvent after water separation and extraction, and obtaining a ketonic acid ester solution; and d) adding hydrochloric acid to the ketonic acid ester solution obtained in the step c) to adjust the pH to be less than or equal to 3, performing a hydrolysis reaction, and obtaining 4-(hydroxymethyl phosphine) 2-carbonyl butyric acid after purification. The synthesis method selects inexpensive acryloyl chloride as a raw material, has mild reaction conditions, is simple to operate, has low production cost, is easy to realize industrialization, and has high yield.

Description

Technical Field

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

[0002] 4-(hydroxymethylphosphono)-2-carbonylbutyric acid (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 and reduction, and L-glufosinate can be obtained through enzymatic conversion. It has broad application prospects.

[0003] In 1980, FBC applied for a patent, US4399287A, for the preparation of keto acid intermediates, in which 3-(ethoxymethylphosphono)propionate was extended into carbon chains via Claisen condensation to obtain the keto acid intermediate 4-(hydroxymethylphosphono)-2-carbonylbutyric acid; however, the isolated yield of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid was only 30%. In 1991, Hoechst reported a chemical synthesis method for 4-(hydroxymethylphosphono)-2-carbonylbutyric acid (J. Org. Chem., 1991, 56, 1783-1788). This method utilizes a Michael addition reaction between monoethyl methylphosphonite and ethyl acrylate in the presence of sodium ethoxide to prepare ethyl 3-(ethoxymethylphosphono)-propionate. Then, it undergoes a Claisen ester condensation reaction with diethyl oxalate at -50°C in the presence of sodium ethoxide. Finally, it is decarboxylated by hydrochloric acid to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. However, this method requires the reaction to be carried out at -50°C, has a low overall yield, generates a large amount of wastewater, and the product crystallization time is as long as 48 hours. The reaction formula is shown below:

[0004]

[0005] Chinese patent CN103665032A discloses a method for synthesizing glufosinate. The patent uses oxygen- and phosphorus-containing five-membered heterocyclic phosphonic anhydride and cyanide as raw materials to undergo a cyanidation reaction in an organic solvent to generate a ketone nitrile compound. Then, the ketone acid 4-(hydroxymethylphosphono)-2-carbonylbutyric acid is obtained through a hydrolysis process in an acidic solution. However, the phosphonic anhydride used in this method is not easy to prepare, has high cost, and is difficult to purify.

[0006] In summary, providing a method for synthesizing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid with high yield, simple purification, and readily available raw materials has become a technical problem that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0007] In view of this, the purpose of this invention is to provide a method for synthesizing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, which uses inexpensive acryloyl chloride as a raw material, has mild reaction conditions, is easy to operate, has low production cost, is easy to industrialize, and has a high yield.

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

[0009] a) Acrylyl chloride, a first solvent, a polymerization inhibitor, a catalyst and sodium cyanide are mixed and subjected to a substitution reaction. After vacuum distillation, acrylyl cyanide intermediate is obtained.

[0010] b) The acryloyl cyanide intermediate obtained in step a) is mixed with hydrochloric acid and a polymerization inhibitor, and subjected to hydrolysis reaction. After purification, crude 2-carbonyl-3-butenoic acid is obtained.

[0011] c) The crude 2-carbonyl-3-butenoic acid obtained in step b) is mixed with the second solvent and methylphosphonate, and an addition reaction is carried out. After adding water for liquid-liquid extraction, the solvent is recovered to obtain a keto ester solution.

[0012] d) After adjusting the pH of the ketoester solution obtained in step c) to ≤3 with hydrochloric acid, hydrolysis reaction was carried out, and 4-(hydroxymethylphosphono)-2-carbonylbutyric acid was obtained after purification.

[0013] Preferably, in step a), the first solvent is selected from one or more of acetonitrile, ethyl acetate, tetrahydrofuran, and phenylacetonitrile.

[0014] Preferably, the polymerization inhibitor in step a) is selected from one or more of p-hydroxyanisole, 2,6-di-tert-butyl-p-cresol, tert-butylhydroquinone, and methylhydroquinone; the mass ratio of the polymerization inhibitor to acryloyl chloride is (0.001-0.05):1.

[0015] Preferably, the catalyst in step a) is cuprous cyanide; the molar ratio of the catalyst, sodium cyanide and acryloyl chloride is (0.01-0.1):(0.8-2):1.

[0016] Preferably, the temperature of the substitution reaction in step a) is 0℃~100℃ and the time is 0.5h~24h.

[0017] Preferably, the temperature of vacuum distillation in step a) is 10°C to 60°C.

[0018] Preferably, the hydrolysis reaction in step b) is carried out at a temperature of 50°C to 130°C for 1 hour to 24 hours.

[0019] Preferably, in step c), the second solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, ethyl acetate, n-hexane, tetrahydrofuran, and toluene;

[0020] The methyl phosphonite is selected from one or more of dimethyl methyl phosphonite, diethyl methyl phosphonite, dipropyl methyl phosphonite, and dibutyl methyl phosphonite.

[0021] Preferably, the temperature of the addition reaction in step c) is -10℃ to 80℃, and the time is 0.1h to 24h.

[0022] Preferably, the hydrolysis reaction in step d) is carried out at a temperature of 80°C to 130°C for a time of 0.1 h to 24 h.

[0023] This invention provides a method for synthesizing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps: a) mixing acryloyl chloride, a first solvent, a polymerization inhibitor, a catalyst, and sodium cyanide, performing a substitution reaction, and obtaining an acryloyl cyanide intermediate after vacuum distillation; b) mixing the acryloyl cyanide intermediate obtained in step a) with hydrochloric acid and a polymerization inhibitor, performing a hydrolysis reaction, and then purifying to obtain crude 2-carbonyl-3-butenoic acid; c) mixing the crude 2-carbonyl-3-butenoic acid obtained in step b) with a second solvent and methylphosphonite, performing an addition reaction, adding water for liquid-liquid extraction, and recovering the solvent to obtain a ketoester solution; d) adjusting the pH of the ketoester solution obtained in step c) to ≤3 with hydrochloric acid, performing a hydrolysis reaction, and purifying to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. Compared with existing technologies, the synthesis method provided by this invention uses acryloyl chloride as a raw material, adds a polymerization inhibitor, and reacts with sodium cyanide in the presence of a catalyst to obtain acryloyl cyanide. Then, it is hydrolyzed under acidic conditions to obtain 2-carbonyl-3-butenoic acid. 2-carbonyl-3-butenoic acid undergoes an addition reaction with methylphosphonite to obtain a keto ester, which is further hydrolyzed and purified to obtain the target product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. This synthesis method uses inexpensive acryloyl chloride as a raw material, has mild reaction conditions, is simple to operate, has low production costs, is easy to industrialize, and has a high yield. Attached Figure Description

[0024] Figure 1 This is the GC spectrum of acryloyl cyanide in Example 1 of the present invention;

[0025] Figure 2 The HPLC spectrum of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid obtained in Example 1 of this invention;

[0026] Figure 3 The HPLC chromatogram of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid standard is shown. Detailed Implementation

[0027] 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.

[0028] This invention provides a method for synthesizing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps:

[0029] a) Acrylyl chloride, a first solvent, a polymerization inhibitor, a catalyst and sodium cyanide are mixed and subjected to a substitution reaction. After vacuum distillation, acrylyl cyanide intermediate is obtained.

[0030] b) The acryloyl cyanide intermediate obtained in step a) is mixed with hydrochloric acid and a polymerization inhibitor, and subjected to hydrolysis reaction. After purification, crude 2-carbonyl-3-butenoic acid is obtained.

[0031] c) The crude 2-carbonyl-3-butenoic acid obtained in step b) is mixed with the second solvent and methylphosphonate, and an addition reaction is carried out. After adding water for liquid-liquid extraction, the solvent is recovered to obtain a keto ester solution.

[0032] d) After adjusting the pH of the ketoester solution obtained in step c) to ≤3 with hydrochloric acid, hydrolysis reaction was carried out, and 4-(hydroxymethylphosphono)-2-carbonylbutyric acid was obtained after purification.

[0033] This invention provides a method for synthesizing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, using acryloyl chloride (Formula I) as a raw material, with the addition of a small amount of polymerization inhibitor, and undergoing a substitution reaction with sodium cyanide in the presence of a catalyst to obtain acryloyl cyanide (Formula II), which is then hydrolyzed under acidic conditions to obtain 2-carbonyl-3-butenoic acid (Formula III). 2-carbonyl-3-butenoic acid undergoes an addition reaction with diethyl methylphosphonite to obtain a ketoester (Formula IV), which is further hydrolyzed and purified to obtain the target product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid (Formula V).

[0034]

[0035] The reaction formula for the synthesis method of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid provided by this invention is as follows:

[0036]

[0037] This invention first involves mixing acryloyl chloride, a first solvent, a polymerization inhibitor, a catalyst, and sodium cyanide to carry out a substitution reaction, followed by vacuum distillation to obtain an acryloyl cyanide intermediate. This invention does not impose any special restrictions on the source of the acryloyl chloride and sodium cyanide; commercially available products well-known to those skilled in the art can be used.

[0038] In this invention, the first solvent is preferably selected from one or more of acetonitrile, ethyl acetate, tetrahydrofuran, and phenylacetonitrile, more preferably acetonitrile or ethyl acetate. This invention does not impose any special restrictions on the source of the first solvent; commercially available products well-known to those skilled in the art can be used.

[0039] In this invention, the polymerization inhibitor is preferably selected from one or more of p-hydroxyanisole (MEHQ), 2,6-di-tert-butyl-p-cresol (BHT), tert-butylhydroquinone (MTBHQ), and methylhydroquinone (THQ), more preferably p-hydroxyanisole (MEHQ) or 2,6-di-tert-butyl-p-cresol (BHT). This invention does not impose any particular limitation on the source of the polymerization inhibitor; commercially available products well known to those skilled in the art can be used.

[0040] In this invention, the mass ratio of the polymerization inhibitor to acryloyl chloride is preferably (0.001-0.05):1, more preferably (0.002-0.02):1.

[0041] In this invention, the catalyst is preferably cuprous cyanide. This invention does not impose any special restrictions on the source of the catalyst; commercially available products well-known to those skilled in the art can be used.

[0042] In this invention, the molar ratio of the catalyst, sodium cyanide and acryloyl chloride is (0.01-0.1):(0.8-2):1, more preferably (0.02-0.05):(1-1.5):1.

[0043] In this invention, the process of mixing acryloyl chloride, the first solvent, the polymerization inhibitor, the catalyst, and sodium cyanide is preferably specifically as follows:

[0044] Acryloyl chloride is placed in the first solvent, and then a polymerization inhibitor, a catalyst, and sodium cyanide are added.

[0045] Afterwards, the mixture is heated and reacted for a period of time. After cooling, a liquid containing acryloyl cyanide is obtained. Then, the acryloyl cyanide intermediate is obtained by vacuum distillation at a certain temperature.

[0046] In this invention, the temperature of the substitution reaction is preferably 0℃~100℃, more preferably 40℃~70℃; the time of the substitution reaction is preferably 0.5h~24h, more preferably 3h~10h.

[0047] In this invention, the temperature of the vacuum distillation is preferably 10°C to 60°C, and more preferably 30°C to 50°C.

[0048] After obtaining the acryloyl cyanide intermediate, the present invention mixes the obtained acryloyl cyanide intermediate with hydrochloric acid and a polymerization inhibitor, performs a hydrolysis reaction, and then purifies it to obtain crude 2-carbonyl-3-butenoic acid.

[0049] In this invention, the mass concentration of the hydrochloric acid is preferably 20% to 36%; this invention does not have any special restrictions on the source of the hydrochloric acid, and commercially available products well known to those skilled in the art can be used.

[0050] In this invention, the molar ratio of hydrochloric acid to acryloyl cyanide is preferably (1-15):1, more preferably (2-5):1.

[0051] In this invention, the polymerization inhibitor is preferably selected from one or more of p-hydroxyanisole (MEHQ), 2,6-di-tert-butyl-p-cresol (BHT), tert-butylhydroquinone (MTBHQ), and methylhydroquinone (THQ), more preferably p-hydroxyanisole (MEHQ) or 2,6-di-tert-butyl-p-cresol (BHT). This invention does not impose any particular limitation on the source of the polymerization inhibitor; commercially available products well known to those skilled in the art can be used.

[0052] In this invention, the mass ratio of the polymerization inhibitor to acryloyl cyanide is preferably (0.001-0.05):1, more preferably (0.005-0.02):1.

[0053] In this invention, the process of mixing the obtained acryloyl cyanide intermediate with hydrochloric acid and a polymerization inhibitor is preferably as follows:

[0054] Acryloyl cyanide intermediate is added to a certain amount of hydrochloric acid, and then a small amount of polymerization inhibitor is added.

[0055] Afterwards, the mixture was heated and hydrolyzed for a period of time, and then purified to obtain crude 2-carbonyl-3-butenoic acid.

[0056] In this invention, the temperature of the hydrolysis reaction is preferably 50℃~130℃, more preferably 80℃~110℃; the time of the hydrolysis reaction is preferably 1h~24h, more preferably 3h~6h.

[0057] In this invention, the purification process is preferably as follows:

[0058] After the hydrolysis reaction, the acid water was removed under reduced pressure to obtain crude 2-carbonyl-3-butenoic acid, which was directly used in the next reaction.

[0059] After obtaining the crude 2-carbonyl-3-butenoic acid, the present invention mixes the crude 2-carbonyl-3-butenoic acid with a second solvent and methylphosphonate, performs an addition reaction, adds water for liquid-liquid extraction, and recovers the solvent to obtain a keto ester solution.

[0060] In this invention, the second solvent is preferably selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, ethyl acetate, n-hexane, tetrahydrofuran, and toluene, and more preferably ethyl acetate, methanol, or ethanol. This invention does not impose any particular limitation on the source of the second solvent; commercially available products well known to those skilled in the art can be used. In this invention, the second solvent is preferably subjected to anhydrous treatment to obtain an anhydrous solvent.

[0061] In this invention, the methylphosphonite is preferably selected from one or more of dimethyl methylphosphonite, diethyl methylphosphonite, dipropyl methylphosphonite, and dibutyl methylphosphonite, more preferably dimethyl methylphosphonite or diethyl methylphosphonite. This invention does not impose any special restrictions on the source of the methylphosphonite; commercially available products well known to those skilled in the art can be used.

[0062] In this invention, the molar ratio of methylphosphonite to acryloyl cyanide is preferably (0.95-1.2):1, more preferably (1-1.05):1.

[0063] In this invention, the process of mixing the obtained crude 2-carbonyl-3-butenoic acid with the second solvent and methylphosphonite is preferably as follows:

[0064] The crude 2-carbonyl-3-butenoic acid was dispersed in a second solvent, and methylphosphonite was slowly added dropwise under nitrogen protection.

[0065] Afterward, the reaction was kept at a certain temperature for a certain period of time, water was added for liquid extraction, and the solvent was recovered to obtain a keto ester solution.

[0066] In this invention, the temperature of the addition reaction is preferably -10℃ to 80℃, more preferably 10℃ to 50℃; the time of the addition reaction is preferably 0.1h to 24h, more preferably 0.5h to 5h.

[0067] In this invention, the preferred mass ratio of water to acryloyl cyanide is (2-10):1, more preferably (3-5):1.

[0068] After obtaining the ketoester solution, the present invention adjusts the pH of the obtained ketoester solution to ≤3 with hydrochloric acid, performs a hydrolysis reaction, and purifies it to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0069] In this invention, the mass concentration of the hydrochloric acid is preferably 20% to 36%; this invention does not have any special restrictions on the source of the hydrochloric acid, and commercially available products well known to those skilled in the art can be used.

[0070] In this invention, the temperature of the hydrolysis reaction is preferably 80℃~130℃, more preferably 100℃~120℃; the time of the hydrolysis reaction is preferably 0.1h~24h, more preferably 3h~5h.

[0071] In this invention, the purification process is preferably specifically as follows:

[0072] The product obtained from the hydrolysis reaction was subjected to vacuum distillation at 90℃~110℃ to remove the solvent, then dissolved in acetone, filtered to remove insoluble salts, and the filtrate was concentrated under vacuum to half volume. Methyl isobutyl ketone was added to crystallize the product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0073] The synthesis method provided by this invention has the following beneficial effects:

[0074] (1) Using inexpensive acryloyl chloride as raw material, the reaction conditions are mild, the operation is simple, the production cost is low, and it is easy to industrialize; (2) The crude 2-carbonyl-3-butenoic acid obtained by substitution, hydrolysis and concentration does not need to be separated and can be directly used for subsequent addition reactions. The process steps are simple and mild; (3) In the presence of ammonium chloride in the crude product, the hydrolysis temperature is higher and the reaction is more thorough, which can efficiently obtain the final product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0075] This invention provides a method for synthesizing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps: a) mixing acryloyl chloride, a first solvent, a polymerization inhibitor, a catalyst, and sodium cyanide, performing a substitution reaction, and obtaining an acryloyl cyanide intermediate after vacuum distillation; b) mixing the acryloyl cyanide intermediate obtained in step a) with hydrochloric acid and a polymerization inhibitor, performing a hydrolysis reaction, and then purifying to obtain crude 2-carbonyl-3-butenoic acid; c) mixing the crude 2-carbonyl-3-butenoic acid obtained in step b) with a second solvent and methylphosphonite, performing an addition reaction, adding water for liquid-liquid extraction, and recovering the solvent to obtain a ketoester solution; d) adjusting the pH of the ketoester solution obtained in step c) to ≤3 with hydrochloric acid, performing a hydrolysis reaction, and purifying to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. Compared with existing technologies, the synthesis method provided by this invention uses acryloyl chloride as a raw material, adds a polymerization inhibitor, and reacts with sodium cyanide in the presence of a catalyst to obtain acryloyl cyanide. Then, it is hydrolyzed under acidic conditions to obtain 2-carbonyl-3-butenoic acid. 2-carbonyl-3-butenoic acid undergoes an addition reaction with methylphosphonite to obtain a keto ester, which is further hydrolyzed and purified to obtain the target product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. This synthesis method uses inexpensive acryloyl chloride as a raw material, has mild reaction conditions, is simple to operate, has low production costs, is easy to industrialize, and has a high yield.

[0076] 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.

[0077] Example 1

[0078] (1) Add 94.3 g of 96% acryloyl chloride and 280 mL of acetonitrile to a 1000 mL four-necked flask, then add 0.2 g of p-hydroxyanisole, 1.8 g of 99% cuprous cyanide and 52.5 g of sodium cyanide. Heat to 50-60 °C and react for 6 h. After cooling, a liquid containing acryloyl cyanide is obtained. Distill under reduced pressure at 40-50 °C to separate 73.5 g of 96% acryloyl cyanide intermediate (GC spectrum see [reference]). Figure 1 (As shown), the yield was 87%.

[0079] (2) The acryloyl cyanide obtained above was added to a 500 mL four-necked flask containing 215 g of 30% hydrochloric acid, and 0.2 g of p-hydroxyanisole was added. The mixture was heated to 100-110 °C for hydrolysis. After 3 h, the acid water was removed under reduced pressure to obtain crude 2-carbonyl-3-butenoic acid.

[0080] (3) The crude 2-carbonyl-3-butenoic acid obtained above was dispersed in 200g of anhydrous ethyl acetate. 98g of 96% dimethyl methylphosphonate was slowly added dropwise under nitrogen protection. The temperature was controlled at 20-30℃ and the reaction was kept at this temperature for 3h. 210g of water was added for separation and extraction. The solvent was recovered to obtain a keto ester solution.

[0081] (4) In the ketoester solution obtained above, hydrochloric acid was added to adjust the pH to 2.5-3.0, the temperature was raised to 110-120℃ and kept at this temperature for 3 hours. After removing the solvent by vacuum distillation at 100℃, 300 mL of acetone was added to dissolve the solvent, and the insoluble salt was removed by filtration. The filtrate was concentrated under reduced pressure to half its volume, and 500 mL of methyl isobutyl ketone was added to crystallize the solution, yielding 119.1 g of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid (HPLC chromatogram can be found in [reference]). Figure 2 As shown, the standard sample is Figure 3 The purity was 96%, and the yield was 73%.

[0082] Example 2

[0083] (1) Add 94.3g of 96% acryloyl chloride and 280mL of acetonitrile to a 1000mL four-necked flask, then add 0.5g of 2,6-di-tert-butyl-p-cresol, 4.5g of 99% cuprous cyanide and 50.0g of sodium cyanide. Heat to 50-60℃ and react for 6h. After cooling, a liquid containing acryloyl cyanide is obtained. Distill under reduced pressure at 30-40℃ to separate 70.1g of 96% acryloyl cyanide intermediate, with a yield of 83%.

[0084] (2) The acryloyl cyanide obtained above was added to a 500 mL four-necked flask containing 500 g of 30% hydrochloric acid, and 0.2 g of p-hydroxyanisole was added. The mixture was heated to 80-90 °C for hydrolysis. After 6 h, the acid water was removed under reduced pressure to obtain crude 2-carbonyl-3-butenoic acid.

[0085] (3) The crude 2-carbonyl-3-butenoic acid obtained above was dispersed in 200g of anhydrous ethyl acetate. 122g of 97% diethyl methylphosphonate was slowly added dropwise under nitrogen protection. The temperature was controlled at 40-50℃ and the reaction was kept at this temperature for 1h. 210g of water was added for separation and extraction. The solvent was recovered to obtain a keto ester solution.

[0086] (4) In the ketoester solution obtained above, hydrochloric acid was added to adjust the pH to 2.5-3.0, the temperature was raised to 110-120℃ and kept at the temperature for 3h, the solvent was removed by vacuum distillation at 100℃, 300mL of acetone was added to dissolve, the insoluble salt was removed by filtration, the filtrate was concentrated under vacuum to half volume, 500mL of methyl isobutyl ketone was added to crystallize, and 118.0g of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid with a purity of 95% and a yield of 75% was obtained.

[0087] Example 3

[0088] (1) Add 94.3g of 96% acryloyl chloride and 300mL of acetonitrile to a 1000mL four-necked flask, then add 2.0g of methylhydroquinone, 1.8g of 99% cuprous cyanide and 75.0g of sodium cyanide. Heat to 40-50℃ and react for 10h. After cooling, a liquid containing acryloyl cyanide is obtained. Distill under reduced pressure at 40-50℃ to separate 73.5g of 97% acryloyl cyanide intermediate, with a yield of 88%.

[0089] (2) The acryloyl cyanide obtained above was added to a 500 mL four-necked flask containing 325 g of 20% hydrochloric acid, and 0.2 g of p-hydroxyanisole was added. The mixture was heated to 90-100 °C for hydrolysis. After 5 h, the acid water was removed under reduced pressure to obtain crude 2-carbonyl-3-butenoic acid.

[0090] (3) The crude 2-carbonyl-3-butenoic acid obtained above was dispersed in 150g of anhydrous ethyl acetate. 123.5g of 97% diethyl methylphosphonate was slowly added dropwise under nitrogen protection. The temperature was controlled at 40-50℃ and the reaction was maintained for 0.5h. 300g of water was added for separation and extraction. The solvent was recovered to obtain a keto ester solution.

[0091] (4) In the ketoester solution obtained above, hydrochloric acid was added to adjust the pH to 2.0-2.5, the temperature was raised to 100-110℃ and kept at the temperature for 4 hours. After removing the solvent by vacuum distillation at 100℃, 300 mL of acetone was added to dissolve it, and the insoluble salt was removed by filtration. The filtrate was concentrated under vacuum to half volume, and 500 mL of methyl isobutyl ketone was added to crystallize, yielding 117.2 g of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid with a purity of 96% and a yield of 71%.

[0092] Example 4

[0093] (1) Add 94.3g of 96% acryloyl chloride and 300mL of acetonitrile to a 1000mL four-necked flask, then add 0.2g of p-hydroxyanisole, 1.8g of 99% cuprous cyanide and 50.0g of sodium cyanide. Heat to 60-70℃ and react for 3h. After cooling, a liquid containing acryloyl cyanide is obtained. Distill under reduced pressure at 40-50℃ to separate 69.2g of 96% acryloyl cyanide intermediate, with a yield of 82%.

[0094] (2) The acryloyl cyanide obtained above was added to a 500 mL four-necked flask containing 300 g of 30% hydrochloric acid, and 0.2 g of p-hydroxyanisole was added. The mixture was heated to 100-110 °C for hydrolysis. After 3 h, the acid water was removed under reduced pressure to obtain crude 2-carbonyl-3-butenoic acid.

[0095] (3) The crude 2-carbonyl-3-butenoic acid obtained above was dispersed in 200g of anhydrous ethyl acetate. 117g of 97% diethyl methylphosphonate was slowly added dropwise under nitrogen protection. The reaction was carried out at 10-20℃ for 5h. 350g of water was added for separation and extraction. The solvent was recovered to obtain a keto ester solution.

[0096] (4) In the ketoester solution obtained above, hydrochloric acid was added to adjust the pH to 2.5-3.0, the temperature was raised to 100-110℃ and kept at the temperature for 5 hours. After removing the solvent by vacuum distillation at 100℃, 300 mL of acetone was added to dissolve it, and the insoluble salt was removed by filtration. The filtrate was concentrated under vacuum to half volume, and 500 mL of methyl isobutyl ketone was added to crystallize it to obtain 113.1 g of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid with a purity of 94% and a yield of 72%.

[0097] Example 5

[0098] The synthesis method provided in Example 2 was used, except that the polymerization inhibitor 2,6-di-tert-butyl-p-cresol was not added in the substitution reaction stage, and methanol (replacing ethyl acetate) was used as the solvent in the addition step. Other steps were the same as in Example 2. 46.9 g of 95% acryloyl cyanide intermediate was obtained, with a yield of 55%; 70.9 g of product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid was obtained, with a purity of 95% and a yield of 68%.

[0099] Example 6

[0100] The synthesis method provided in Example 2 was used, except that the solvent in the substitution reaction stage was ethyl acetate (replacing acetonitrile), and the solvent in the addition step was ethanol (replacing ethyl acetate). Other steps were the same as in Example 2. 66.7 g of 96% acryloyl cyanide intermediate was obtained, with a yield of 79%; 93.4 g of product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid was obtained, with a purity of 96% and a yield of 63%.

[0101] 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 synthesizing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps: a) Acryloyl chloride, a first solvent, a polymerization inhibitor, a catalyst, and sodium cyanide are mixed and subjected to a substitution reaction. The intermediate acryloyl cyanide is obtained by vacuum distillation. The catalyst is cuprous cyanide. The polymerization inhibitor is selected from one or more of p-hydroxyanisole, 2,6-di-tert-butyl-p-cresol, tert-butylhydroquinone, and methylhydroquinone. The first solvent is acetonitrile. b) The acryloyl cyanide intermediate obtained in step a) is mixed with hydrochloric acid and a polymerization inhibitor, and subjected to hydrolysis reaction. After purification, crude 2-carbonyl-3-butenoic acid is obtained. c) The crude 2-carbonyl-3-butenoic acid obtained in step b) is mixed with the second solvent and methylphosphonite, and an addition reaction is carried out. After adding water for liquid-liquid extraction, the solvent is recovered to obtain a keto ester solution. The second solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, ethyl acetate, n-hexane, tetrahydrofuran, and toluene. d) After adjusting the pH of the ketoester solution obtained in step c) to ≤3 with hydrochloric acid, hydrolysis reaction was carried out, and 4-(hydroxymethylphosphono)-2-carbonylbutyric acid was obtained after purification.

2. The synthesis method according to claim 1, characterized in that, The mass ratio of the polymerization inhibitor to acryloyl chloride in step a) is (0.001~0.05):

1.

3. The synthesis method according to claim 1, characterized in that, The molar ratio of the catalyst, sodium cyanide and acryloyl chloride in step a) is (0.01~0.1):(0.8~2):

1.

4. The synthesis method according to claim 1, characterized in that, The temperature of the substitution reaction in step a) is 0℃~100℃ and the time is 0.5h~24h.

5. The synthesis method according to claim 1, characterized in that, The temperature for vacuum distillation in step a) is 10℃~60℃.

6. The synthesis method according to claim 1, characterized in that, The hydrolysis reaction described in step b) is carried out at a temperature of 50℃ to 130℃ for a time of 1h to 24h.

7. The synthesis method according to claim 1, characterized in that, The methylphosphonite ester mentioned in step c) is selected from one or more of dimethyl methylphosphonite, diethyl methylphosphonite, dipropyl methylphosphonite and dibutyl methylphosphonite.

8. The synthesis method according to claim 1, characterized in that, The addition reaction in step c) is carried out at a temperature of -10℃ to 80℃ for a time of 0.1h to 24h.

9. The synthesis method according to claim 1, characterized in that, The hydrolysis reaction described in step d) is carried out at a temperature of 80℃~130℃ for a time of 0.1h~24h.

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