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) reacting acryloyl chloride with trimethylsilyl cyanide in the presence of iodide to obtain acryloyl cyanide; followed by acidification and hydrolysis to obtain a solution containing 2-carbonyl-3-butenoic acid; then subjecting it to esterification with an alcohol, and purifying it to obtain 2-carbonyl-3-butenoic acid ester; b) mixing a monoalkyl methylphosphonic acid ester compound with an organic solvent, and then adding an initiator and the 2-carbonyl-3-butenoic acid ester mixture obtained in step a) to perform a free radical addition reaction to obtain a ketoester compound; c) adding hydrochloric acid to the ketoester compound obtained in step b) to perform a hydrolysis reaction, and then purifying it to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. Compared with the prior art, the preparation method provided by this invention uses free radical addition to prepare ketoester compounds, which has a fast reaction rate, high yield, and low waste, and is suitable for industrial production.

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 1991, Hoechst reported the preparation of methyl 3-(ethoxymethylphosphono)-propionate by reacting diethyl methylphosphonite and methyl acrylate. This compound reacts with sodium methoxide to produce an anion, which, after being heated to room temperature, reacts with diethyl oxalate and then acidified to yield 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. The reaction formula is shown below:

[0004]

[0005] However, this method requires the reaction to be carried out at -50℃, and the overall yield is low, a large amount of wastewater is generated, and the product crystallization time is as long as 48 hours. In addition, a large amount of 4-(methylhydroxyphosphono)-2-carbonylbutyric acid in the crystallization mother liquor is not precipitated, resulting in a low yield of the entire process, which is not suitable for industrial production (J.Org.Chem.,1991,56,1783-1788).

[0006] Patent SU1583424A first reported a method for preparing ketone cyanide compounds by reacting 2,5-dioxo-1-oxa-2-phosphinecyclopentane and sodium cyanide as raw materials, followed by acid hydrolysis to obtain ketone acid compounds. The reaction formula is shown below:

[0007]

[0008] However, the raw material 2,5-dioxo-1-oxa-2-phosphocyclopentane used in this patent is not readily available, and the first step of the cyanidation reaction is difficult, resulting in a low overall yield and lacking industrial application value.

[0009] USSR1583424 reports a method for preparing these compounds by reacting sodium cyanide with a phosphorus-containing five-membered cyclic compound, followed by acidic hydrolysis. Although the process is short and yields high on a small scale, it requires highly toxic sodium cyanide and difficult-to-obtain intermediates, making it unsuitable for large-scale production.

[0010] Patent JP2008230992 reports a method for preparing this type of compound using benzenesulfonyl acetate, methyl vinyl phosphonate, and methanesulfonate. However, this method is lengthy and generates a large amount of sulfur-containing wastewater; moreover, the methyl vinyl phosphonate raw material mentioned in the method is difficult to obtain and is not suitable for industrial production.

[0011] 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

[0012] In view of this, the purpose of the present invention is to provide a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. This method uses free radical addition to prepare ketoester compounds, which has a fast reaction rate, high yield, and low waste, making it suitable for industrial production. At the same time, no inorganic salts are generated during the reaction. Therefore, after the hydrolysis reaction is completed, the acid solution in the system can be directly removed to obtain the target product without further extraction.

[0013] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps:

[0014] a) Acryloyl chloride was reacted with trimethylsilyl cyanide in the presence of iodide to obtain acryloyl cyanide; after acidification and hydrolysis, a solution containing 2-carbonyl-3-butenoic acid was obtained; then esterified with an alcohol and purified to obtain 2-carbonyl-3-butenoic acid ester.

[0015] b) After mixing the monoalkyl methylphosphonic acid ester compound with an organic solvent, an initiator and the 2-carbonyl-3-butenoate mixture obtained in step a) are added dropwise to carry out a free radical addition reaction to obtain keto ester compounds;

[0016] c) Add hydrochloric acid to the ketoester compound obtained in step b) to carry out hydrolysis reaction, and then purify it to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0017] Preferably, the alcohol in step a) is selected from one or more of ethanol, methanol, propanol, and n-butanol;

[0018] The molar ratio of the alcohol to 2-carbonyl-3-butenoic acid is (1-10):1.

[0019] Preferably, the esterification reaction in step a) is carried out at a temperature of 40°C to 110°C for 2 hours to 8 hours.

[0020] Preferably, the organic solvent in step b) is selected from one or more of toluene, xylene, n-octane, and isooctane;

[0021] The mass ratio of the organic solvent to the monoalkyl methylphosphonic acid ester compound is (0-10):1.

[0022] Preferably, the molar ratio of the methylphosphonic acid monoalkyl ester and the 2-carbonyl-3-butenoate in step b) is (1-5):1.

[0023] Preferably, the initiator in step b) is selected from one or more of tert-butyl peroxyoctanoate, tert-butyl pervalerate, tert-butyl peroxydecanoate, tert-butyl peroxybenzoate, and benzoyl peroxide;

[0024] The mass ratio of the initiator to 2-carbonyl-3-butenoate is (0.04–0.2):1.

[0025] Preferably, the temperature of the free radical addition reaction in step b) is 80°C to 140°C.

[0026] Preferably, the mass concentration of hydrochloric acid in step c) is 10% to 36%;

[0027] The molar ratio of hydrochloric acid to ketoester compounds is (2-10):1.

[0028] Preferably, the hydrolysis reaction in step c) is carried out at a temperature of 50°C to 100°C for a time of 1 hour to 24 hours.

[0029] Preferably, the purification process in step c) specifically includes:

[0030] The product obtained from the hydrolysis reaction was dehydrated under reduced pressure and excess hydrogen chloride was removed, and then dried under vacuum to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0031] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps: a) reacting acryloyl chloride with trimethylsilyl cyanide in the presence of iodide to obtain acryloyl cyanide; after acidification and hydrolysis, obtaining a solution containing 2-carbonyl-3-butenoic acid; then performing an esterification reaction with an alcohol, and purifying to obtain 2-carbonyl-3-butenoic acid ester; b) mixing a monoalkyl methylphosphonic acid ester compound with an organic solvent, and then adding an initiator and the 2-carbonyl-3-butenoic acid ester mixture obtained in step a) to perform a free radical addition reaction to obtain a ketoester compound; c) adding hydrochloric acid to the ketoester compound obtained in step b) to perform a hydrolysis reaction, and then purifying to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. Compared with existing technologies, the preparation method provided by this invention uses acryloyl chloride as a raw material, which undergoes a substitution reaction with trimethylsilyl cyanide in the presence of iodide to obtain acryloyl cyanide. After acidification and hydrolysis, it reacts with a lower alcohol to obtain 2-carbonyl-3-butenoate, which is then reacted with a monoalkyl methylphosphonic acid ester compound and, under the action of an initiator, undergoes Michael radical addition to obtain ketoester compounds. Finally, it is further hydrolyzed under acidic conditions to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. This preparation method uses free radical addition to prepare ketoester compounds, which has a fast reaction rate, high yield, and low waste, making it suitable for industrial production. At the same time, no inorganic salts are generated during the reaction, so after the hydrolysis reaction, the acid solution in the system can be directly removed to obtain the target product without further extraction. Attached Figure Description

[0032] Figure 1 The gas chromatogram of ethyl 2-carbonyl-3-butenoate, the intermediate obtained in Example 1 of this invention (retention time 6.292 min);

[0033] Figure 2 The liquid chromatogram of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid obtained in Example 1 of this invention (retention time 14.591 min);

[0034] Figure 3 The liquid chromatogram of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid standard (retention time 14.608 min). Detailed Implementation

[0035] 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.

[0036] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps:

[0037] a) Acryloyl chloride was reacted with trimethylsilyl cyanide in the presence of iodide to obtain acryloyl cyanide; after acidification and hydrolysis, a solution containing 2-carbonyl-3-butenoic acid was obtained; then esterified with an alcohol and purified to obtain 2-carbonyl-3-butenoic acid ester.

[0038] b) After mixing the monoalkyl methylphosphonic acid ester compound with an organic solvent, an initiator and the 2-carbonyl-3-butenoate mixture obtained in step a) are added dropwise to carry out a free radical addition reaction to obtain keto ester compounds;

[0039] c) Add hydrochloric acid to the ketoester compound obtained in step b) to carry out hydrolysis reaction, and then purify it to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0040] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid (Formula VI). Acryloyl chloride (Formula I) is used as a raw material, and a substitution reaction is carried out with trimethylsilyl cyanide in the presence of iodide to obtain acryloyl cyanide (Formula II). After acidification and hydrolysis, a solution containing 2-carbonyl-3-butenoic acid (Formula III) is obtained. This solution is then reacted with a lower alcohol to obtain 2-carbonyl-3-butenoic acid ester (Formula IV). This ester is then reacted with a monoalkyl methylphosphonic acid ester compound, and under the action of an initiator, undergoes Michael radical addition to obtain a ketoester compound (Formula V). Further hydrolysis under acidic conditions yields 4-(hydroxymethylphosphono)-2-carbonylbutyric acid (Formula VI).

[0041]

[0042] The reaction formula for the preparation method of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid provided by this invention is as follows:

[0043]

[0044] This method uses free radical addition to prepare ketoester compounds (Formula V), which is fast, has high yield, and produces little waste, making it suitable for industrial production. Furthermore, no inorganic salts are generated during the reaction; therefore, after the hydrolysis reaction, the target compound can be obtained simply by removing the acid solution without further extraction. Moreover, the starting material, acryloyl chloride, is a readily available commercial raw material. Although the yield of the intermediate 2-carbonyl-3-butenoate is relatively low, the cost is not high. The reaction raw materials for the subsequent 2-carbonyl-3-butenoate and methylphosphonite reactions have higher economic value; therefore, improving the yield of this part and reducing raw material loss has a significant impact on the overall cost.

[0045] This invention first reacts acryloyl chloride with trimethylsilane cyanide in the presence of iodide to obtain acryloyl cyanide; after acidification and hydrolysis, a solution containing 2-carbonyl-3-butenoic acid is obtained; then, an esterification reaction is carried out with an alcohol, and after purification, 2-carbonyl-3-butenoic acid ester is obtained. This invention does not have any particular restrictions on the sources of the acryloyl chloride, iodide, trimethylsilane cyanide, and alcohol; commercially available products well known to those skilled in the art can be used.

[0046] In this invention, the process of reacting acryloyl chloride with trimethylsilyl cyanide in the presence of iodide is preferably as follows:

[0047] Acryloyl chloride was placed in a reaction flask, and trimethylsilyl cyanide and iodide were added. After the addition was complete, the mixture was heated under nitrogen protection and reacted for a period of time. The by-product chlorosilane and unreacted raw materials were removed by distillation to obtain acryloyl cyanide.

[0048] In this invention, the iodide is preferably selected from one or more of zinc iodide, sodium iodide and potassium iodide, and more preferably zinc iodide.

[0049] In this invention, the reaction temperature is preferably 50℃~150℃, more preferably 100℃; the reaction time is preferably 1h~3h, more preferably 2h.

[0050] In this invention, the acidification and hydrolysis process is preferably as follows:

[0051] The obtained acryloyl cyanide was cooled to room temperature and added to hydrochloric acid with a mass concentration of 10% to 36%. The temperature was raised to 50°C to 150°C, and the hydrolysis reaction was carried out for 4 to 6 hours. The acid water was removed under reduced pressure to obtain a solution containing 2-carbonyl-3-butenoic acid.

[0052] More preferably:

[0053] The obtained acryloyl cyanide was cooled to room temperature and added to 30% hydrochloric acid. The mixture was heated to 100°C and hydrolyzed for 5 hours. The acid water was then removed under reduced pressure to obtain a solution containing 2-carbonyl-3-butenoic acid.

[0054] In this invention, the alcohol is preferably selected from one or more of ethanol, methanol, propanol, and n-butanol, more preferably ethanol. This invention uses the aforementioned C1-C4 lower alcohols for subsequent esterification reactions; the molar ratio of the alcohol to 2-carbonyl-3-butenoic acid is preferably (1-10):1, more preferably (3-5):1.

[0055] In this invention, the temperature of the esterification reaction is preferably 40°C to 110°C, and the specific temperature is determined according to the type of lower alcohol selected above; the time of the esterification reaction is preferably 2h to 8h, more preferably 3h to 4h.

[0056] In this invention, the purification process is preferably specifically as follows:

[0057] After the esterification reaction was completed, the mixture was cooled to room temperature, neutralized with alkali, and the solvent was removed under reduced pressure. Acetone was then added to dissolve the solvent, and the insoluble salt was removed by filtration. The filtrate was then distilled under reduced pressure to obtain the intermediate 2-carbonyl-3-butenoate.

[0058] After obtaining the 2-carbonyl-3-butenoate, the present invention mixes a monoalkyl methylphosphonic acid ester compound with an organic solvent, and then adds an initiator and the 2-carbonyl-3-butenoate mixture obtained in step a) to carry out a free radical addition reaction to obtain a keto ester compound.

[0059] In this invention, the monoalkyl methylphosphonite esters are preferably monoethyl methylphosphonite and / or monobutyl methylphosphonite. This invention does not impose any special restrictions on the source of the monoalkyl methylphosphonite esters; commercially available products well-known to those skilled in the art can be used. This invention eliminates the need for expensive and highly reactive Grignard reagents, effectively avoiding safety issues caused by intense exothermic reactions. The 2-carbonyl-3-butenoate ester obtained from acryloyl chloride has high purity, which is beneficial for subsequent radical addition reactions with monomethylphosphonite esters. Simultaneously, the reaction exhibits high selectivity and a short reaction time; the resulting ketoester intermediate requires no further post-processing after hydrolysis, and the purity of the obtained 4-(hydroxymethylphosphono)-2-carbonylbutyric acid product meets the requirements for subsequent use.

[0060] In this invention, the organic solvent is preferably selected from one or more of toluene, xylene, n-octane and isooctane, more preferably toluene or n-octane; this invention does not have any special restrictions on the source of the organic solvent, and commercially available products well known to those skilled in the art can be used.

[0061] In this invention, the preferred mass ratio of the organic solvent to the monoalkyl methylphosphonic acid ester compound is (0-10):1, more preferably (0-3):1; wherein, when the organic solvent is 0, the raw material monoalkyl methylphosphonic acid ester compound is used as the organic solvent, and this invention does not have any special limitations on this.

[0062] In this invention, the molar ratio of the methylphosphonic acid monoalkyl ester and the 2-carbonyl-3-butenoate is preferably (1-5):1, more preferably (1-3):1.

[0063] In this invention, the initiator is preferably selected from one or more of tert-butyl peroxysoctoate, tert-butyl peroxypentanoate, tert-butyl peroxyneodecanate, tert-butyl peroxyneodecanate, and benzoyl peroxide, more preferably tert-butyl peroxysoctoate, tert-butyl peroxypentanoate, tert-butyl peroxyneodecanate, tert-butyl peroxyneodecanate, or benzoyl peroxide; this invention does not have any special restrictions on the source of the initiator, and commercially available organic peroxide initiators known to those skilled in the art can be used.

[0064] In this invention, the mass ratio of the initiator to 2-carbonyl-3-butenoate is preferably (0.04-0.2):1, more preferably (0.07-0.1):1.

[0065] In this invention, the process of mixing the monoalkyl methylphosphonic acid ester compound, the organic solvent, the initiator, and the obtained 2-carbonyl-3-butenoate is preferably as follows:

[0066] A monoalkyl ester of methylphosphonic acid and an organic solvent were added to a reaction flask, heated to a certain temperature, and under nitrogen protection, a mixture containing an initiator and 2-carbonyl-3-butenoate was added dropwise with vigorous stirring.

[0067] In this invention, the preferred temperature for the free radical addition reaction is 80°C to 140°C, and the specific reaction temperature depends on the selection of the initiator.

[0068] In this invention, the free radical addition reaction time is preferably 10 min to 20 min, more preferably 15 min.

[0069] In this invention, after the free radical addition reaction, the reactants can be directly used in subsequent experiments; preferably, it also includes:

[0070] The material is introduced into a thin-film evaporator to separate excess monoalkyl methylphosphonite compounds, byproducts, etc., to obtain ketoester compounds; the temperature of the thin-film evaporator is preferably set to 120℃~180℃, and the specific distillation temperature depends on the type of monoalkyl methylphosphonite selected; the pressure of the thin-film evaporator is preferably controlled at -0.09Mpa~-0.1Mpa.

[0071] After obtaining the ketoester compound, the present invention adds hydrochloric acid to the obtained ketoester compound to carry out a hydrolysis reaction, and then purifies it to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0072] In this invention, the mass concentration of the hydrochloric acid is preferably 10% to 36%, more preferably 20% to 30%; 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.

[0073] In this invention, the molar ratio of hydrochloric acid (HCl) to ketoester compounds is preferably (2-10):1, more preferably (3-5):1.

[0074] In this invention, the temperature of the hydrolysis reaction is preferably 50℃~100℃, more preferably 90℃~100℃; the time of the hydrolysis reaction is preferably 1h~24h, more preferably 5h~10h.

[0075] In this invention, the purification process is preferably as follows:

[0076] The product obtained from the hydrolysis reaction was dehydrated under reduced pressure and excess hydrogen chloride was removed, and then dried under vacuum to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0077] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps: a) reacting acryloyl chloride with trimethylsilyl cyanide in the presence of iodide to obtain acryloyl cyanide; after acidification and hydrolysis, obtaining a solution containing 2-carbonyl-3-butenoic acid; then performing an esterification reaction with an alcohol, and purifying to obtain 2-carbonyl-3-butenoic acid ester; b) mixing a monoalkyl methylphosphonic acid ester compound with an organic solvent, and then adding an initiator and the 2-carbonyl-3-butenoic acid ester mixture obtained in step a) to perform a free radical addition reaction to obtain a ketoester compound; c) adding hydrochloric acid to the ketoester compound obtained in step b) to perform a hydrolysis reaction, and then purifying to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. Compared with existing technologies, the preparation method provided by this invention uses acryloyl chloride as a raw material, which undergoes a substitution reaction with trimethylsilyl cyanide in the presence of iodide to obtain acryloyl cyanide. After acidification and hydrolysis, it reacts with a lower alcohol to obtain 2-carbonyl-3-butenoate, which is then reacted with a monoalkyl methylphosphonic acid ester compound and, under the action of an initiator, undergoes Michael radical addition to obtain ketoester compounds. Finally, it is further hydrolyzed under acidic conditions to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. This preparation method uses free radical addition to prepare ketoester compounds, which has a fast reaction rate, high yield, and low waste, making it suitable for industrial production. At the same time, no inorganic salts are generated during the reaction, so after the hydrolysis reaction, the acid solution in the system can be directly removed to obtain the target product without further extraction.

[0078] 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.

[0079] Example 1

[0080] (1) Place 90.6 g of acryloyl chloride in a reaction flask, add 99 g of trimethylsilyl cyanide and 9.6 g of zinc iodide. After the addition is complete, under nitrogen protection, heat to 100 °C and react for 2 h. Distill to remove byproduct chlorosilane and unreacted trimethylsilyl cyanide. Cool to room temperature and add 600 g of 30% hydrochloric acid. Heat to 100 °C and hydrolyze for 5 h. Continue to remove acid water under reduced pressure to obtain a solution containing 2-carbonyl-3-butenoic acid. Add 140 g of ethanol and carry out esterification reaction at 70 °C for 3 h. Cool to room temperature, neutralize with ammonium bicarbonate, remove solvent under reduced pressure, add acetone to dissolve, filter to remove insoluble salts, and distill the filtrate under reduced pressure to obtain 113.0 g of 96.3% intermediate ethyl 2-carbonyl-3-butenoic acid (see gas chromatogram). Figure 1 As shown), the yield was 85% (based on acryloyl chloride).

[0081] (2) 68g of mono-n-butyl methylphosphonite and 204g of toluene were added to a four-necked flask and heated to 90°C under nitrogen protection. A mixture containing 3.84g of tert-amyl peroxypentanoate and 64g of ethyl 2-carbonyl-3-butenoate was added dropwise with vigorous stirring. The temperature was maintained at 90°C, and stirring was continued for 15 minutes. Subsequently, the solution was introduced into a thin-film evaporator, and 135g of crude ketoester was obtained.

[0082] (3) Add 304g of 30% hydrochloric acid to the ketoester material obtained in step (2) for acidification and hydrolysis. After the addition is complete, raise the temperature to 100℃ and maintain it for 7h. After hydrolysis is completed, remove water and excess hydrogen chloride under reduced pressure at this temperature, and dry under vacuum to obtain 76.2g of 92% pure 4-(hydroxymethylphosphono)-2-carbonylbutyric acid (see liquid chromatogram). Figure 2 As shown; additionally: see the liquid chromatogram of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid standard. Figure 3 As shown), the yield was 92% (based on ethyl 2-carbonyl-3-butenoate).

[0083] Example 2

[0084] (1) Based on the process conditions adjusted in step (1) of Example 1: a feed solution containing 2-carbonyl-3-butenoic acid was obtained, 130g of methanol was added, and the esterification reaction was carried out at 60°C for 3.5h. The temperature was then lowered to room temperature, sodium bicarbonate was added to neutralize the solvent, and acetone was added to dissolve the solvent. The insoluble salt was removed by filtration, and the filtrate was distilled under reduced pressure to obtain 97.3g of 96.1% intermediate methyl 2-carbonyl-3-butenoic acid, with a yield of 82% (based on acryloyl chloride).

[0085] (2) 108g of monoethyl methylphosphonite was added to a four-necked flask, heated to 80°C, and under nitrogen protection, a mixture containing 2.56g of tert-butyl peroxypentanoate and 57g of methyl 2-carbonyl-3-butenoate was added dropwise with vigorous stirring. The temperature was maintained at 80°C, and stirring was continued for 15 minutes. Subsequently, the solution was introduced into a thin-film evaporator, and 125g of crude ketoester was obtained.

[0086] (3) Add 182.5g of 30% hydrochloric acid to the keto ester material obtained in step (2) for acidification and hydrolysis. After the addition is complete, raise the temperature to 90°C and maintain it for 12h. After the hydrolysis is completed, raise the temperature, remove water and excess hydrogen chloride under reduced pressure, and dry under vacuum to obtain 73.7g of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid with a purity of 91% and a yield of 90% (based on methyl 2-carbonyl-3-butenoate).

[0087] Example 3

[0088] (1) Based on the process conditions adjusted in step (1) of Example 1: a feed solution containing 2-carbonyl-3-butenoic acid was obtained, and 270g of n-butanol was added. After esterification reaction at 115°C for 4 hours, the temperature was lowered to room temperature. Sodium carbonate was added to neutralize the solvent and the solvent was removed under reduced pressure. Acetone was added to dissolve the solvent, and the insoluble salt was removed by filtration. The filtrate was distilled under reduced pressure to obtain 132.1g of 94.5% intermediate 2-carbonyl-3-butenoic acid n-butyl ester, with a yield of 80% (based on acryloyl chloride).

[0089] (2) 204 g of monoisobutyl methylphosphonite was added to a four-necked flask, heated to 100 °C, and under nitrogen protection, a mixture containing 3.20 g of tert-butyl peroxypentanoate and 78 g of n-butyl 2-carbonyl-3-butenoate was added dropwise with vigorous stirring. The temperature was maintained at 100 °C, and stirring was continued for 15 min. Subsequently, the solution was introduced into a thin-film evaporator, and 162 g of crude ketoester was obtained.

[0090] (3) Add 219g of 25% hydrochloric acid to the keto ester material obtained in step (2) for acidification and hydrolysis. After the addition is complete, raise the temperature to 95°C and maintain it for 10h. After the hydrolysis is completed, raise the temperature, remove water and excess hydrogen chloride under reduced pressure, and dry under vacuum to obtain 70.5g of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid with a purity of 88% and a yield of 89% (based on 2-carbonyl-3-butenoic acid n-butyl ester).

[0091] Example 4

[0092] (1) Based on the process conditions adjusted in step (1) of Example 1: a feed solution containing 2-carbonyl-3-butenoic acid was obtained, 140g of ethanol was added, and the esterification reaction was carried out at 75°C for 4h. After cooling to room temperature, ammonium bicarbonate was added to neutralize and the solvent was removed under reduced pressure. Acetone was added to dissolve the solvent, and the insoluble salt was removed by filtration. The filtrate was distilled under reduced pressure to obtain 110.9g of 95.8% intermediate ethyl 2-carbonyl-3-butenoic acid, with a yield of 83% (based on acryloyl chloride).

[0093] (2) 204 g of methylphosphonite n-butyl ester was added to a four-necked flask, heated to 140 °C, and under nitrogen protection, a mixture containing 12.8 g of tert-butyl benzoate peroxide and 64 g of ethyl 2-carbonyl-3-butenoate was added dropwise with vigorous stirring. The temperature was maintained at 140 °C, and stirring was continued for 15 min. Subsequently, the solution was introduced into a thin-film evaporator, and 138 g of crude ketoester was obtained.

[0094] (3) Add 365g of 10% hydrochloric acid to the ketoester material obtained in step (2) for acidification and hydrolysis. After the addition is complete, raise the temperature to 100℃ and maintain it for 8h. After the hydrolysis is completed, raise the temperature, remove water and excess hydrogen chloride under reduced pressure, and dry under vacuum to obtain 76.1g of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid with a purity of 90% and a yield of 94% (based on ethyl 2-carbonyl-3-butenoate).

[0095] Example 5

[0096] (1) Based on the process conditions adjusted in step (1) of Example 1: a feed solution containing 2-carbonyl-3-butenoic acid was obtained, 230g of ethanol was added, and the esterification reaction was carried out at 80°C for 3.6h. After cooling to room temperature, ammonium bicarbonate was added to neutralize and the solvent was removed under reduced pressure. Acetone was added to dissolve the solvent, and the insoluble salt was removed by filtration. The filtrate was distilled under reduced pressure to obtain 112.0g of 96% intermediate ethyl 2-carbonyl-3-butenoic acid, with a yield of 84% (based on acryloyl chloride).

[0097] (2) Add 68g of monobutyl methylphosphonite and 136g of n-octane to a four-necked flask, heat to 90°C, under nitrogen protection, and dropwise add a mixture containing 3.84g of tert-amyl peroxypentanoate and 64g of ethyl 2-carbonyl-3-butenoate while stirring vigorously. Maintain the temperature at 90°C and continue stirring for 15 minutes to obtain a ketoester solution, which can be used directly for subsequent experiments without separation.

[0098] (3) Add 608g of 30% hydrochloric acid to the ketoester material obtained in step (2) for acidification and hydrolysis. After the addition is complete, raise the temperature to 95°C and maintain it for 7h. After the hydrolysis is completed, cool down and let it stand to separate into layers. Raise the temperature of the water layer, remove water and excess hydrogen chloride under reduced pressure, and dry it under vacuum to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid with a purity of 89% and a yield of 91% (based on ethyl 2-carbonyl-3-butenoate).

[0099] Example 6

[0100] (1) Based on the process conditions adjusted in step (1) of Example 1: a feed solution containing 2-carbonyl-3-butenoic acid was obtained, 180g of propanol was added, and the esterification reaction was carried out at 98°C for 3.7h. After cooling to room temperature, ammonium bicarbonate was added to neutralize and the solvent was removed under reduced pressure. Acetone was added to dissolve the solvent, and the insoluble salt was removed by filtration. The filtrate was distilled under reduced pressure to obtain 120.8g of 95.2% intermediate propyl 2-carbonyl-3-butenoic acid, with a yield of 81% (based on acryloyl chloride).

[0101] (2) 270 g of ethyl methylphosphonite was added to a four-necked flask and heated to 140 °C under nitrogen protection. A mixture containing 1.92 g of tert-amyl peroxypentanoate, 3.20 g of tert-butyl peroxybenzoate, and 71 g of propyl 2-carbonyl-3-butenoate was added dropwise with vigorous stirring. The temperature was maintained at 140 °C, and stirring continued for 15 min. Subsequently, the solution was introduced into a thin-film evaporator, and 132 g of crude ketoester was obtained.

[0102] (3) Add 304g of 30% hydrochloric acid to the ketoester material obtained in step (2) for acidification and hydrolysis. After the addition is complete, raise the temperature to 50°C and maintain it for 24h. After the hydrolysis is completed, raise the temperature, remove water and excess hydrogen chloride under reduced pressure, and dry under vacuum to obtain 73.7g of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid with a purity of 91% and a yield of 90% (based on propyl 2-carbonyl-3-butenoate).

[0103] 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 is reacted with trimethylsilyl cyanide in the presence of iodide to obtain acryloyl cyanide; after acidification and hydrolysis, a solution containing 2-carbonyl-3-butenoic acid is obtained; then, it is esterified with an alcohol, and after purification, ethyl 2-carbonyl-3-butenoic acid is obtained; wherein the alcohol is selected from ethanol; The iodide is selected from one or more of zinc iodide, sodium iodide, and potassium iodide; b) After mixing the monoalkyl methylphosphonic acid ester compound and the organic solvent, an initiator and the 2-carbonyl-3-butenoate mixture obtained in step a) are added dropwise to carry out a free radical addition reaction to obtain a keto ester compound; the mass ratio of the organic solvent to the monoalkyl methylphosphonic acid ester compound is (0~10):1, and when the amount of organic solvent is 0, the monoalkyl methylphosphonic acid ester compound acts as an organic solvent. The keto ester compounds have the structure shown in Formula V: Formula V R is ethyl or n-butyl; The monoalkyl methylphosphonite esters are monoethyl methylphosphonite and / or monobutyl methylphosphonite; c) Add hydrochloric acid to the ketoester compound obtained in step b) to carry out hydrolysis reaction, and then purify it to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

2. The production method according to claim 1, characterized by, The molar ratio of the alcohol to 2-carbonyl-3-butenoic acid in step a) is (1~10):

1.

3. The method of claim 1, wherein, The esterification reaction in step a) is carried out at a temperature of 40℃ to 110℃ for 2 hours to 8 hours.

4. The method of claim 1, wherein, The organic solvent mentioned in step b) is selected from one or more of toluene, xylene, n-octane and isooctane.

5. The preparation method according to claim 1, characterized in that, The molar ratio of the monoalkyl methylphosphonic acid ester and the 2-carbonyl-3-butenoate in step b) is (1~5):

1.

6. The method of claim 1, wherein, The initiator mentioned in step b) is selected from one or more of the following: tert-butyl peroxyoctanoate, tert-butyl pervalerate, tert-butyl peroxyneodecanate, tert-butyl peroxybenzoate, and benzoyl peroxide. The mass ratio of the initiator to 2-carbonyl-3-butenoate is (0.04~0.2):

1.

7. The preparation method according to claim 1, characterized in that, The temperature for the free radical addition reaction described in step b) is 80℃~140℃.

8. The method of claim 1, wherein, The hydrochloric acid concentration in step c) is 10%~36% by mass; The molar ratio of hydrochloric acid to keto ester compounds is (2~10):

1.

9. The preparation method according to claim 1, characterized in that, The hydrolysis reaction in step c) is carried out at a temperature of 50℃ to 100℃ 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 dehydrated under reduced pressure and excess hydrogen chloride was removed, and then dried under vacuum to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

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