A method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid

Abstract

This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps: a) mixing acryloyl chloride, a first solvent, a polymerization inhibitor, a catalyst, and potassium ferrocyanide, and carrying out a substitution reaction, followed by vacuum distillation to obtain an acryloyl cyanide intermediate; b) mixing the acryloyl cyanide intermediate obtained in step a) with hydrochloric acid and a polymerization inhibitor, carrying out 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 methylphosphine dichloride, and carrying out an addition reaction to obtain a solution containing diacryl chloride; d) mixing the solution containing diacryl chloride obtained in step c) with water, carrying out a hydrolysis reaction, and purifying to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. The preparation method provided by this invention is simple, with mild and easily controllable conditions, low cost, and high yield.

Description

Technical Field

[0001] This invention relates to the field of fine 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 into carbon chain via Claisen condensation to obtain the keto acid intermediate 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. The isolated yield of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid was approximately 30%.

[0004] In 1991, Hoechst reported a chemical synthesis of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. The method involved the Michael addition reaction of methylphosphonite monoethyl ester and ethyl acrylate in the presence of sodium ethoxide to prepare ethyl 3-(ethoxymethylphosphono)-propionate. This ethyl ester was then reacted with diethyl oxalate at -50°C in the presence of sodium ethoxide to undergo a Claisen ester condensation reaction. Finally, hydrolysis with hydrochloric acid decarboxylation yielded 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 resulted in a long crystallization time of up to 48 hours (J. Org. Chem., 1991, 56, 1783-1788). The reaction formula is shown below:

[0005]

[0006] Chinese patent CN103665032A discloses a method for preparing glufosinate. This patent uses oxygen- and phosphorus-containing five-membered heterocyclic phosphonic anhydride and cyanide as raw materials, undergoing a cyanidation reaction in an organic solvent to generate a ketone nitrile compound; then, through hydrolysis in an acidic solution, it yields the ketonic acid 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. The cyclic phosphonic anhydride used in this method is difficult to prepare, costly, and difficult to purify.

[0007] Therefore, how to provide a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid with high yield, simple purification, and readily available raw materials has become an urgent problem to be solved. Summary of the Invention

[0008] In view of this, the purpose of the present invention is to provide a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, which is simple, mild and easy to control, low in cost, and has a high yield.

[0009] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps:

[0010] a) Acryloyl chloride, first solvent, polymerization inhibitor, catalyst and potassium ferrocyanide are mixed and subjected to substitution reaction. After vacuum distillation, acryloyl cyanide intermediate is obtained.

[0011] 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.

[0012] c) The crude 2-carbonyl-3-butenoic acid obtained in step b) is mixed with the second solvent and methylphosphine dichloride to carry out an addition reaction to obtain a solution containing diacyl chloride;

[0013] d) The solution containing diacyl chloride obtained in step c) was mixed with water and subjected to hydrolysis reaction. After purification, 4-(hydroxymethylphosphono)-2-carbonylbutyric acid was obtained.

[0014] Preferably, in step a), the first solvent is selected from one or more of acetonitrile, ethyl acetate, tetrahydrofuran, and phenylacetonitrile.

[0015] 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.

[0016] Preferably, the catalyst in step a) is cuprous cyanide; the molar ratio of the catalyst, potassium ferrocyanide and acryloyl chloride is (0.01-0.1):(0.3-3):1.

[0017] Preferably, the temperature of the substitution reaction in step a) is 0℃~100℃ and the time is 0.5h~48h.

[0018] Preferably, the temperature of vacuum distillation in step a) is 10°C to 60°C.

[0019] 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.

[0020] Preferably, in step c), the second solvent is selected from one or more of dichloromethane, dichloroethane, chloroform, hexane, heptane, benzene, toluene, and xylene.

[0021] Preferably, the temperature of the addition reaction in step c) is 0℃~100℃ and the time is 1h~24h.

[0022] Preferably, the hydrolysis reaction in step d) is carried out at a temperature of 0°C to 100°C for a time of 0.1 h to 24 h.

[0023] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps: a) mixing acryloyl chloride, a first solvent, a polymerization inhibitor, a catalyst, and potassium ferrocyanide, 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 methylphosphine dichloride, performing an addition reaction to obtain a solution containing diacryl chloride; d) mixing the solution containing diacryl chloride obtained in step c) with water, performing a hydrolysis reaction, and purifying to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. Compared with existing technologies, the preparation method provided by this invention uses acryloyl chloride as raw material, and adds a polymerization inhibitor. In the presence of a catalyst, it undergoes a substitution reaction with potassium ferrocyanide to obtain acryloyl cyanide, which is then hydrolyzed under acidic conditions to obtain 2-carbonyl-3-butenoic acid. 2-carbonyl-3-butenoic acid undergoes an addition reaction with methylphosphine dichloride to obtain diacyl chloride, which is further hydrolyzed and purified to obtain the target product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. This preparation method is simple, has mild and easy-to-control conditions, low cost, and 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 preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps:

[0029] a) Acryloyl chloride, first solvent, polymerization inhibitor, catalyst and potassium ferrocyanide are mixed and subjected to substitution reaction. After vacuum distillation, acryloyl 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 methylphosphine dichloride to carry out an addition reaction to obtain a solution containing diacyl chloride;

[0032] d) The solution containing diacyl chloride obtained in step c) was mixed with water and subjected to hydrolysis reaction. After purification, 4-(hydroxymethylphosphono)-2-carbonylbutyric acid was obtained.

[0033] This invention provides a method for preparing 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 potassium ferrocyanide 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 methylphosphine dichloride to obtain diacyl chloride (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 preparation 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 potassium ferrocyanide, and then carrying out a substitution reaction. The resulting product is obtained by vacuum distillation. This invention does not impose any special restrictions on the sources of the acryloyl chloride and potassium ferrocyanide; 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). 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 preferred molar ratio of the catalyst, potassium ferrocyanide, and acryloyl chloride is (0.01-0.1):(0.3-3):1, and more preferably (0.02-0.05):(0.5-1.5):1.

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

[0044] Acryloyl chloride is placed in the first solvent, and then a polymerization inhibitor, a catalyst, and potassium ferrocyanide 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 50℃~80℃; the time of the substitution reaction is preferably 0.5h~48h, more preferably 6h~12h.

[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). 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] The acryloyl cyanide intermediate was added to a certain amount of hydrochloric acid, and then a small amount of polymerization inhibitor was 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 a mixture containing 2-carbonyl-3-butenoic acid and ammonium chloride. Acetone was then added to dissolve the mixture, and the insoluble salts were removed by filtration. The filtrate was then distilled 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 methylphosphine dichloride to carry out an addition reaction to obtain a solution containing diacyl chloride.

[0060] In this invention, the second solvent is preferably selected from one or more of dichloromethane, dichloroethane, chloroform, hexane, heptane, benzene, toluene, and xylene, more preferably dichloromethane, hexane, or toluene. 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] The present invention does not impose any special restrictions on the source of the methyl dichloride; commercially available products well known to those skilled in the art can be used.

[0062] In this invention, the molar ratio of methylphosphine dichloride 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 methylphosphine dichloride is preferably as follows:

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

[0065] Afterward, the reaction was kept at a certain temperature for a certain period of time, and then cooled to obtain a solution containing diacyl chloride.

[0066] In this invention, the temperature of the addition reaction is preferably 0℃~100℃, more preferably 30℃~70℃; the time of the addition reaction is preferably 1h~24h, more preferably 3h~8h.

[0067] After obtaining the solution containing diacyl chloride, the present invention mixes the obtained solution containing diacyl chloride with water, performs a hydrolysis reaction, and after purification, obtains 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0068] In this invention, the mass ratio of water to the second solvent is preferably (0.1-5):1, more preferably (0.5-2):1; and the water is added slowly for the reaction.

[0069] In this invention, the temperature of the hydrolysis reaction is preferably 0℃~100℃, more preferably 10℃~40℃; the time of the hydrolysis reaction is preferably 0.1h~24h, more preferably 0.5h~3h.

[0070] In this invention, the purification process is preferably specifically as follows:

[0071] After the hydrolysis reaction was completed, the second solvent was removed by separation of the aqueous layer by vacuum distillation to obtain the product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0072] The preparation method provided by this invention has the following beneficial effects:

[0073] (1) Inexpensive acryloyl chloride is selected as the raw material. The reaction conditions are mild, the operation is simple, the production cost is low, and it is easy to industrialize. (2) The final product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid is obtained efficiently through simple process steps such as substitution, hydrolysis, and addition under relatively mild conditions.

[0074] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps: a) mixing acryloyl chloride, a first solvent, a polymerization inhibitor, a catalyst, and potassium ferrocyanide, 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 methylphosphine dichloride, performing an addition reaction to obtain a solution containing diacryl chloride; d) mixing the solution containing diacryl chloride obtained in step c) with water, performing a hydrolysis reaction, and purifying to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. Compared with existing technologies, the preparation method provided by this invention uses acryloyl chloride as raw material, and adds a polymerization inhibitor. In the presence of a catalyst, it undergoes a substitution reaction with potassium ferrocyanide to obtain acryloyl cyanide, which is then hydrolyzed under acidic conditions to obtain 2-carbonyl-3-butenoic acid. 2-carbonyl-3-butenoic acid undergoes an addition reaction with methylphosphine dichloride to obtain diacyl chloride, which is further hydrolyzed and purified to obtain the target product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. This preparation method is simple, has mild and easy-to-control conditions, low cost, and high yield.

[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 94.3g of 96% acryloyl chloride and 300mL of acetonitrile to a 1000mL four-necked flask, then add 0.2g of p-hydroxyanisole, 4.5g of 99% cuprous cyanide and 376g of potassium ferrocyanide. Heat to 70-80℃ and reflux for 12h. After cooling, a solution containing acryloyl cyanide is obtained. Distill under reduced pressure at 40-50℃ to separate 71.2g of 97% acryloyl cyanide intermediate (GC spectrum see [reference]). Figure 1 (As shown), the yield was 85%.

[0078] (2) The acryloyl cyanide obtained above was added to a 500 mL four-necked flask containing 210 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 a mixture containing 2-carbonyl-3-butenoic acid and ammonium chloride. 100 mL of acetone was added to dissolve the mixture. The insoluble salt was removed by filtration. The filtrate was distilled under reduced pressure to obtain crude 2-carbonyl-3-butenoic acid.

[0079] (3) The crude 2-carbonyl-3-butenoic acid obtained above was dispersed in 200g of anhydrous dichloromethane, and 102g of 97% methylphosphine chloride was slowly added dropwise under nitrogen protection. The temperature was controlled at 40-50℃ and the reaction was kept at this temperature for 5h. The solution containing diacyl chloride was obtained by cooling.

[0080] (4) To the solution containing diacyl chloride obtained above, 100g of water was slowly added, and the reaction was carried out at a temperature of 20-30℃ for 1 hour. After the reaction was completed, the solvent was removed by separating the layers, and the aqueous layer was separated by vacuum distillation to obtain 156.4g of the product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid (HPLC chromatogram can be found in [reference]). Figure 2 As shown, the standard sample is Figure 3 The purity is 92%, and the yield is 94%.

[0081] Example 2

[0082] (1) Add 94.3g of 96% acryloyl chloride and 300mL of acetonitrile to a 1000mL four-necked flask, then add 1.0g of 2,6-di-tert-butyl-p-cresol, 1.8g of 99% cuprous cyanide and 113g of potassium ferrocyanide. Heat to 50-60℃ and keep the reaction at this temperature for 6h. After cooling, a liquid containing acryloyl cyanide is obtained. Distill under reduced pressure at 30-40℃ to separate 61.6g of 96% acryloyl cyanide intermediate, with a yield of 73%.

[0083] (2) The acryloyl cyanide obtained above was added to a 1000 mL four-necked flask containing 440 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 a mixture containing 2-carbonyl-3-butenoic acid and ammonium chloride. 100 mL of acetone was added to dissolve the mixture. The insoluble salt was removed by filtration. The filtrate was distilled under reduced pressure to obtain crude 2-carbonyl-3-butenoic acid.

[0084] (3) The crude 2-carbonyl-3-butenoic acid obtained above was dispersed in 200g of anhydrous dichloromethane, and 93g of 97% methylphosphine chloride was slowly added dropwise under nitrogen protection. The temperature was controlled at 30-40℃ and the reaction was kept at this temperature for 8h. The solution containing diacyl chloride was obtained by cooling.

[0085] (4) 200g of water was slowly added to the solution containing diacyl chloride obtained above, and the reaction was carried out at a temperature of 10-20℃ for 3h. After the reaction was completed, the solvent was removed by separation of the aqueous layer by vacuum distillation to obtain 132.9g of product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid with a purity of 91% and a yield of 92%.

[0086] Example 3

[0087] (1) Add 94.3g of 96% acryloyl chloride and 300mL of acetonitrile to a 1000mL four-necked flask, then add 1.0g of methylhydroquinone, 4.5g of 99% cuprous cyanide and 188g of potassium ferrocyanide. Heat to 70-80℃ and reflux for 10h. After cooling, a liquid containing acryloyl cyanide is obtained. Distill under reduced pressure at 40-50℃ to separate 68.1g of 94% acryloyl cyanide intermediate, with a yield of 79%.

[0088] (2) The acryloyl cyanide obtained above was added to a 500 mL four-necked flask containing 290 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 a mixture containing 2-carbonyl-3-butenoic acid and ammonium chloride. 100 mL of acetone was added to dissolve the mixture. The insoluble salt was removed by filtration. The filtrate was distilled under reduced pressure to obtain crude 2-carbonyl-3-butenoic acid.

[0089] (3) The crude 2-carbonyl-3-butenoic acid obtained above was dispersed in 150g of anhydrous dichloromethane, and 95g of 97% methylphosphine chloride was slowly added dropwise under nitrogen protection. The temperature was controlled at 60-70℃ and the reaction was kept at this temperature for 3h. The solution containing diacyl chloride was obtained by cooling.

[0090] (4) 300g of water was slowly added to the solution containing diacyl chloride obtained above, and the reaction was carried out at a temperature of 30-40℃ for 0.5h. After the reaction was completed, the solvent was removed by separation of the layers, and the aqueous layer was separated by vacuum distillation to obtain 143.9g of product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid with a purity of 90% and a yield of 91%.

[0091] Example 4

[0092] (1) Add 94.3g of 96% acryloyl chloride and 250mL of acetonitrile to a 1000mL four-necked flask, then add 0.2g of p-hydroxyanisole, 4.5g of 99% cuprous cyanide and 188g of potassium ferrocyanide. Heat to 70-80℃ and reflux for 10h. After cooling, a liquid containing acryloyl cyanide is obtained. Distill under reduced pressure at 40-50℃ to separate 68.4g of 96% acryloyl cyanide intermediate, with a yield of 81%.

[0093] (2) The acryloyl cyanide obtained above was added to a 500 mL four-necked flask containing 295 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 a mixture containing 2-carbonyl-3-butenoic acid and ammonium chloride. 100 mL of acetone was added to dissolve the mixture. The insoluble salt was removed by filtration. The filtrate was distilled under reduced pressure to obtain crude 2-carbonyl-3-butenoic acid.

[0094] (3) The crude 2-carbonyl-3-butenoic acid obtained above was dispersed in 200g of anhydrous dichloromethane, and 100g of 97% methylphosphine chloride was slowly added dropwise under nitrogen protection. The temperature was controlled at 40-50℃ and the reaction was kept at this temperature for 5h. The solution containing diacyl chloride was obtained by cooling.

[0095] (4) 100g of water was slowly added to the solution containing diacyl chloride obtained above, and the reaction was carried out at a temperature of 20-30℃ for 2h. After the reaction was completed, the solvent was removed by separation of the aqueous layer by vacuum distillation to obtain 150.7g of product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid with a purity of 90% and a yield of 93%.

[0096] Example 5

[0097] The preparation method provided in Example 1 was used, except that the polymerization inhibitor p-hydroxyanisole was not added in the substitution reaction stage, and the solvent in the addition step was hexane (replacing dichloromethane). Other steps were the same as in Example 1. 49.5 g of 95% acryloyl cyanide intermediate was obtained, with a yield of 58%; 103.3 g of product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid was obtained, with a purity of 88% and a yield of 87%.

[0098] Example 6

[0099] The preparation method provided in Example 1 was used, except that the solvent in the substitution reaction stage was ethyl acetate (replacing acetonitrile), and the solvent in the addition step was toluene (replacing dichloromethane). Other steps were the same as in Example 1. 68.3 g of 95% acryloyl cyanide intermediate was obtained, with a yield of 80%; 142.5 g of product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid was obtained, with a purity of 89% and a yield of 88%.

[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) Acryloyl chloride, a first solvent, a polymerization inhibitor, cuprous cyanide and potassium ferrocyanide are mixed and subjected to a substitution reaction. After vacuum distillation, acryloyl cyanide intermediate is obtained. 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 methylphosphine dichloride to carry out an addition reaction to obtain a solution containing the diacyl chloride shown in Formula IV; d) The solution containing diacyl chloride obtained in step c) was mixed with water and subjected to hydrolysis reaction. After purification, 4-(hydroxymethylphosphono)-2-carbonylbutyric acid was obtained. The polymerization inhibitor is selected from p-hydroxyanisole, 2,6-di-tert-butyl-p-cresol, or methylhydroquinone; 。 2. The preparation method according to claim 1, characterized in that, In step a), the first solvent is selected from one or more of acetonitrile, ethyl acetate, tetrahydrofuran, and phenylacetonitrile.

3. The preparation 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.

4. The preparation method according to claim 1, characterized in that, The molar ratio of cuprous cyanide, potassium ferrocyanide and acryloyl chloride in step a) is (0.01~0.1):(0.3~3):

1.

5. The preparation 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~48h.

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

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 50℃ to 130℃ for a time of 1h to 24h.

8. The preparation method according to claim 1, characterized in that, In step c), the second solvent is selected from one or more of dichloromethane, dichloroethane, chloroform, hexane, heptane, benzene, toluene, and xylene.

9. The preparation method according to claim 1, characterized in that, The addition reaction in step c) is carried out at a temperature of 0°C to 100°C for a time of 1 h to 24 h.

10. The preparation method according to claim 1, characterized in that, The hydrolysis reaction in step d) is carried out at a temperature of 0℃ to 100℃ for a time of 0.1h to 24h.

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