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

Abstract

The application provides a preparation method of 4-(hydroxymethyl phosphinyl)-2-oxobutanoic acid, comprising the following steps: a) adding 4-halogen-2-oxobutanoate into dialkyl methyl phosphite dropwise and controlling the temperature to be-30-40 DEG C, and performing a reaction under vacuum to obtain an intermediate liquid; b) mixing the intermediate liquid obtained in the step a) with an acid, performing a hydrolysis reaction, and then performing a purification treatment to obtain 4-(hydroxymethyl phosphinyl)-2-oxobutanoic acid. Compared with the prior art, the preparation method provided by the application uses dialkyl methyl phosphite and 4-halogen-2-oxobutanoate as raw materials, utilizes the SN2 intramolecular rearrangement mechanism, can realize high-efficiency construction of a P-C bond, and the one-step yield of the Arbuzov reaction can be more than 95%, and the final target product 4-(hydroxymethyl phosphinyl)-2-oxobutanoic acid can be obtained through subsequent acidic hydrolysis of the skeleton structure, and the overall yield can be close to 90%; compared with other methods, the preparation method provided by the application is simple in steps, has few reaction by-products, and has a great improvement in 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 (PPO or keto acid) is an important intermediate in the synthesis of glufosinate. Racemic glufosinate can be obtained from this compound through steps such as ammoniation and reduction, while L-glufosinate can be obtained through asymmetric reduction or bio-enzyme catalysis.

[0003] In 1980, FBC reported a method for preparing keto acid intermediates in patent US4399287A, which extended the carbon chain of 3-(ethoxymethylphosphono)propionate via Claisen condensation to obtain the keto acid intermediate 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a separation yield of approximately 30%.

[0004] In 1991, Hoechst reported a chemical synthesis method for 4-(hydroxymethylphosphono)-2-carbonylbutyric acid (J. Org. Chem., 1991, 56, 1783-1788). This method utilizes the Michael addition reaction of 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:

[0005]

[0006] In addition, Chinese patent CN101641363A discloses a method for manufacturing phosphorus-containing α-keto acids. The method uses 3-(hydroxy(methyl)oxyphosphono)-propionic acid as a raw material and reacts it with an alcohol under acidic conditions to obtain 3-(hydroxy(methyl)oxyphosphono)-propionic acid ester. The ester is then further reacted with oxalate diester in the presence of sodium alkoxide to obtain a condensation product. After further hydrolysis, the keto acid product is obtained, with a total yield of about 50%.

[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 this invention is to provide a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, which has a short reaction step, high selectivity, few by-products, and a significantly improved yield compared to methods such as Claysen condensation.

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

[0010] a) Add 4-halo-2-carbonylbutyrate dropwise to methylphosphonic acid diester and control the temperature at -30 to 40 °C. React under vacuum to obtain intermediate solution.

[0011] b) The intermediate solution obtained in step a) is mixed with acid and subjected to hydrolysis reaction, followed by purification treatment to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0012] Preferably, the dialkyl methylphosphonite in step a) is selected from one or more of dimethyl methylphosphonite, diethyl methylphosphonite, dibutyl methylphosphonite, and diphenyl methylphosphonite.

[0013] Preferably, the molar ratio of methylphosphonite dialkyl ester and 4-halo-2-carbonylbutyrate in step a) is (0.9-2):1.

[0014] Preferably, the dripping time in step a) is 0.5h to 4h.

[0015] Preferably, the vacuum degree of the vacuum condition described in step a) is -0.01MPa to -0.1MPa.

[0016] Preferably, the reaction time in step a) is 0.5 h to 12 h.

[0017] Preferably, the acid in step b) is selected from one or more of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.

[0018] Preferably, the molar ratio of the acid in step b) to the methylphosphonic acid dialkyl ester in step a) is (1-10):1.

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

[0021] The product obtained from the hydrolysis reaction was subjected to vacuum distillation at 50℃~150℃, then dissolved in an organic solvent and allowed to stand. The insoluble inorganic salts were removed by filtration, and the separated organic phase was dried by rotary evaporation. Methyl isobutyl ketone was added for recrystallization, and the product was filtered to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0022] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps: a) adding 4-halo-2-carbonylbutyrate dropwise to methylphosphonite dialkyl ester and controlling the temperature at -30 to 40°C, and reacting under vacuum to obtain an intermediate solution; b) mixing the intermediate solution obtained in step a) with acid, performing a hydrolysis reaction, and then purifying it to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. Compared with existing technologies, the preparation method provided by this invention uses methylphosphonite dialkyl ester and 4-halo-2-carbonylbutyrate as raw materials and utilizes the SN2 intramolecular rearrangement mechanism to achieve efficient construction of PC bonds. The single-step yield of the Arbuzov reaction can reach more than 95%. This skeletal structure can then be further subjected to acidic hydrolysis to obtain the final target product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with an overall yield approaching 90%. Compared with other methods, the preparation method provided by this invention has simple steps, fewer reaction byproducts, and a significantly improved yield. Attached Figure Description

[0023] Figure 1 The HPLC spectrum of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid obtained in Example 1 of this invention;

[0024] Figure 2 The HPLC chromatogram of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid standard is shown. Detailed Implementation

[0025] 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.

[0026] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps:

[0027] a) Add 4-halo-2-carbonylbutyrate dropwise to methylphosphonic acid diester and control the temperature at -30 to 40 °C. React under vacuum to obtain intermediate solution.

[0028] b) The intermediate solution obtained in step a) is mixed with acid and subjected to hydrolysis reaction, followed by purification treatment to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0029] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. Using methylphosphonite dialkyl ester (Formula I) and 4-halo-2-carbonylbutyrate (Formula II) as raw materials, and utilizing an SN2 intramolecular rearrangement mechanism, the PC bond can be efficiently constructed to obtain an intermediate (Formula III) solution. The single-step Arbuzov reaction yield can reach over 95%. This skeletal structure can then be further acidically hydrolyzed to obtain the final target product, 4-(hydroxymethylphosphono)-2-carbonylbutyric acid (Formula IV), with an overall yield approaching 90%. Compared to other methods, this method uses the arbuzov reaction of a haloester with a trivalent phosphonite ester, resulting in a shorter reaction step, higher selectivity, fewer byproducts, and a significantly improved yield compared to methods such as Claisen condensation.

[0030] The reaction formula for the preparation method of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid provided by this invention is as follows:

[0031]

[0032] This invention first involves dropwise addition of 4-halo-2-carbonylbutyrate to dialkyl methylphosphonite while controlling the temperature at -30 to 40°C, and then reacting under vacuum to obtain an intermediate solution; preferably, the reaction is as follows:

[0033] Dialkyl methylphosphonite was added to the reactor, followed by the gradual addition of 4-halo-2-carbonylbutyrate. During the reaction, the temperature was controlled to prevent it from becoming too high, and the vacuum was controlled to remove the haloalkane generated in the reaction. After the addition was completed, the reaction was continued at a certain temperature for a period of time to obtain the intermediate solution, thus completing the Arbuzov reaction.

[0034] In this invention, the dialkyl methylphosphonite is preferably selected from one or more of dimethyl methylphosphonite, diethyl methylphosphonite, dibutyl methylphosphonite, and diphenyl methylphosphonite, more preferably diethyl methylphosphonite or dimethyl methylphosphonite. This invention does not impose any special restrictions on the source of the dialkyl methylphosphonite; commercially available products well known to those skilled in the art can be used.

[0035] In this invention, the 4-halo-2-carbonylbutyrate has the structure shown in Formula II, wherein the halogen atom X can be one of Cl, Br, or I atoms, and the R3 group can be H or a C1-C10 alkyl group, preferably ethyl 4-bromo-2-carbonylbutyrate or ethyl 4-chloro-2-carbonylbutyrate. This invention does not impose any special restrictions on the source of the 4-halo-2-carbonylbutyrate; commercially available products well known to those skilled in the art can be used.

[0036] In this invention, the molar ratio of the methylphosphonite dialkyl ester and the 4-halo-2-carbonylbutyrate is preferably (0.9-2):1, more preferably (1-1.1):1.

[0037] In this invention, the dripping time is preferably 0.5h to 4h, more preferably 1h to 2h; the temperature is controlled at -30 to 40°C during the dripping process to prevent the temperature from being too high, preferably -5°C to 10°C; the reaction is also carried out during the dripping process.

[0038] In this invention, the vacuum degree of the vacuum condition is preferably -0.01MPa to -0.1MPa, more preferably -0.05MPa to -0.09MPa; the haloalkane generated by the reaction is removed under the above vacuum conditions.

[0039] In this invention, the reaction time is preferably 0.5h to 12h, more preferably 1h to 3h.

[0040] After obtaining the intermediate solution, the present invention mixes the obtained intermediate solution with acid, performs hydrolysis reaction, and then purifies it to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0041] In this invention, the acid is preferably selected from one or more of hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and more preferably hydrochloric acid. This invention does not impose any special restrictions on the source of the acid; commercially available products well-known to those skilled in the art can be used.

[0042] In this invention, the molar ratio of the acid to the methylphosphonic acid dialkyl ester is preferably (1-10):1, more preferably (2-4):1.

[0043] In this invention, the temperature of the hydrolysis reaction is preferably 50℃~130℃, more preferably 70℃~100℃; the time of the hydrolysis reaction is preferably 1h~24h, more preferably 3h~10h.

[0044] In this invention, the purification process is preferably as follows:

[0045] The product obtained from the hydrolysis reaction was subjected to vacuum distillation at 50℃~150℃, then dissolved in an organic solvent and allowed to stand. The insoluble inorganic salts were removed by filtration, the separated organic phase was dried by rotary evaporation, and methyl isobutyl ketone was added for recrystallization. The product was then filtered to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0046] More preferably:

[0047] The product obtained from the hydrolysis reaction was subjected to vacuum distillation at 80℃~100℃ to remove excess acid and alcohol water, and a liquid was obtained. After being fully dissolved in an organic solvent, the liquid was allowed to stand, filtered to remove insoluble inorganic salts, and the separated organic phase was dried by rotary evaporation. Methyl isobutyl ketone was added for recrystallization, and the liquid was filtered to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0048] In this invention, the organic solvent is preferably selected from one or more of toluene, acetone, acetonitrile, and tetrahydrofuran, more preferably toluene. This invention does not impose any particular limitation on the source of the organic solvent; commercially available products well known to those skilled in the art can be used.

[0049] In this invention, the volume ratio of the organic solvent to the excess acid and alcohol-water mixture is preferably (1-10):1, more preferably (2-6):1.

[0050] This invention provides a method for preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, comprising the following steps: a) adding 4-halo-2-carbonylbutyrate dropwise to methylphosphonite dialkyl ester and controlling the temperature at -30 to 40°C, and reacting under vacuum to obtain an intermediate solution; b) mixing the intermediate solution obtained in step a) with acid, performing a hydrolysis reaction, and then purifying it to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid. Compared with existing technologies, the preparation method provided by this invention uses methylphosphonite dialkyl ester and 4-halo-2-carbonylbutyrate as raw materials and utilizes the SN2 intramolecular rearrangement mechanism to achieve efficient construction of PC bonds. The single-step yield of the Arbuzov reaction can reach more than 95%. This skeletal structure can then be further subjected to acidic hydrolysis to obtain the final target product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with an overall yield approaching 90%. Compared with other methods, the preparation method provided by this invention has simple steps, fewer reaction byproducts, and a significantly improved yield.

[0051] 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.

[0052] Example 1

[0053] 71.6 g (95%, 0.5 mol) of diethyl methylphosphonite was added to a 500 ml four-necked flask, and then pre-stirred and cooled to 0 °C. Subsequently, 80.3 g (95%, 0.5 mol) of ethyl 4-chloro-2-carbonylbutyrate was slowly added dropwise, maintaining the reaction temperature between -5 and 5 °C throughout the addition process, which was completed in approximately 2 hours. Simultaneously, a vacuum of -0.05 MPa was maintained during the reaction to remove components such as chloroethane generated during the reaction. After the addition was complete, the reaction was continued at this temperature for 3 hours to obtain 112.8 g of crude ethyl 4-(ethoxymethylphosphono)-2-carbonylbutyrate solution.

[0054] 121.7 g (1.0 mol) of 30% hydrochloric acid was added dropwise to the above-mentioned solution. The mixture was then stirred and heated to 95 °C for 8 hours to fully hydrolyze the solution. Excess acid and alcohol-water were removed by vacuum distillation, with the endpoint temperature controlled at 90 °C, yielding 106.2 g of the solution. 250.0 g of toluene was then added, and the solution was thoroughly dissolved by shaking. After standing for 1 hour, insoluble inorganic salts were removed by filtration. The separated organic phase was further evaporated to dryness by rotary evaporation. 100.0 g of methyl isobutyl ketone was added for recrystallization. Finally, filtration yielded 82.7 g of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a purity of 97.5% and a yield of 89.6% (0.447 mol). See the liquid chromatography results for details. Figure 1 As shown.

[0055] Example 2

[0056] 56.8 g (95%, 0.5 mol) of dimethyl methylphosphonite was added to a 500 ml four-necked flask, and the mixture was pre-stirred and cooled to 0 °C. Then, 80.3 g (95%, 0.5 mol) of ethyl 4-chloro-2-carbonylbutyrate was slowly added dropwise, maintaining the reaction temperature between -5 and 5 °C throughout the addition process, which was completed in approximately 2 hours. Simultaneously, a vacuum of -0.05 MPa was maintained during the reaction to remove chloromethane and other components generated during the reaction. After the addition was complete, the reaction was continued at this temperature for 3 hours to obtain 108.6 g of crude ethyl 4-(methoxymethylphosphono)-2-carbonylbutyrate.

[0057] 121.7 g (1.0 mol) of 30% hydrochloric acid was added dropwise to the above-mentioned solution. The mixture was then stirred and heated to 95 °C for 8 hours to fully hydrolyze the solution. Excess acid and alcohol-water were removed by vacuum distillation, with the final temperature controlled at 90 °C, yielding 105.4 g of the solution. 250.0 g of toluene was then added, and the solution was thoroughly dissolved by shaking. After standing for 1 hour, insoluble inorganic salts were removed by filtration. The separated organic phase was further evaporated to dryness by rotary evaporation. 100.0 g of methyl isobutyl ketone was added for recrystallization. Finally, filtration yielded 79.5 g of the product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a purity of 97.6% and a yield of 86.2% (0.431 mol).

[0058] Example 3

[0059] 71.6 g (95%, 0.5 mol) of diethyl methylphosphonite was added to a 500 ml four-necked flask, and then pre-stirred and cooled to 0 °C. Subsequently, 110 g (95%, 0.5 mol) of ethyl 4-bromo-2-carbonylbutyrate was slowly added dropwise, maintaining the reaction temperature between -5 and 5 °C throughout the addition process, which was completed in approximately 2 hours. Simultaneously, a vacuum of -0.05 MPa was maintained during the reaction to remove components such as bromoethane generated during the reaction. After the addition was complete, the reaction was continued at this temperature for 3 hours to obtain 112.1 g of crude ethyl 4-(ethoxymethylphosphono)-2-carbonylbutyrate solution.

[0060] 121.7 g (1.0 mol) of 30% hydrochloric acid was added dropwise to the above solution, and then the mixture was stirred and heated to 95 °C for 8 h to fully hydrolyze the solution. Excess acid and alcohol-water were then removed by vacuum distillation, with the endpoint temperature controlled at 90 °C, yielding 108.5 g of the solution. 250.0 g of toluene was then added, and the solution was thoroughly shaken to dissolve. After standing for 1 h, insoluble inorganic salts were removed by filtration. The separated organic phase was further evaporated to dryness by rotary evaporation, and 100.0 g of methyl isobutyl ketone was added for recrystallization. Finally, filtration yielded 83.1 g of the product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a purity of 97.3% and a yield of 89.8% (0.449 mol).

[0061] Example 4

[0062] 78.8 g (95%, 0.55 mol) of diethyl methylphosphonite was added to a 500 ml four-necked flask. The mixture was then pre-stirred, cooled, and kept at 0 °C. Subsequently, 80.3 g (95%, 0.5 mol) of ethyl 4-chloro-2-carbonylbutyrate was slowly added dropwise, maintaining the reaction temperature between -5 and 5 °C throughout the addition process, which was completed in approximately 2 hours. Simultaneously, a vacuum of -0.05 MPa was maintained during the reaction to remove components such as chloroethane generated during the reaction. After the addition was complete, the temperature was slowly raised to 5 °C and the reaction was maintained at this temperature for 3 hours, yielding 118.5 g of crude ethyl 4-(ethoxymethylphosphono)-2-carbonylbutyrate solution.

[0063] 121.7 g (1.0 mol) of 30% hydrochloric acid was added dropwise to the above-mentioned solution, and then the mixture was stirred and heated to 95 °C for 8 hours to fully hydrolyze the solution. Excess acid and alcohol-water were then removed by vacuum distillation, with the endpoint temperature controlled at 90 °C, yielding 106.8 g of the solution. 250.0 g of toluene was then added, and the solution was thoroughly dissolved by shaking. After standing for 1 hour, insoluble inorganic salts were removed by filtration. The separated organic phase was further evaporated to dryness by rotary evaporation, and 100.0 g of methyl isobutyl ketone was added for recrystallization. Finally, filtration yielded 84.0 g of the product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a purity of 96.9% and a yield of 90.4% (0.452 mol).

[0064] Example 5

[0065] 71.6 g (95%, 0.5 mol) of diethyl methylphosphonite was added to a 500 ml four-necked flask. The mixture was then pre-stirred and cooled to 0 °C. Subsequently, 80.3 g (95%, 0.5 mol) of ethyl 4-chloro-2-carbonylbutyrate was slowly added dropwise, maintaining the reaction temperature between -30 and -20 °C throughout the addition process, which was completed in approximately 2 hours. After the addition was complete, the temperature was slowly raised to 5 °C and maintained for 3 hours, with the vacuum level controlled at -0.05 MPa to remove chloroethane and other components. 110.0 g of crude ethyl 4-(ethoxymethylphosphono)-2-carbonylbutyrate solution was obtained.

[0066] 121.7 g (1.0 mol) of 30% hydrochloric acid was added dropwise to the above solution, and then the mixture was stirred and heated to 95 °C for 8 h to fully hydrolyze the solution. Excess acid and alcohol-water were then removed by vacuum distillation, with the endpoint temperature controlled at 90 °C, yielding 106.2 g of the solution. 250.0 g of toluene was then added, and the solution was thoroughly dissolved by shaking. After standing for 1 h, insoluble inorganic salts were removed by filtration. The separated organic phase was further evaporated to dryness by rotary evaporation, and 100.0 g of methyl isobutyl ketone was added for recrystallization. Finally, filtration yielded 82.4 g of the product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a purity of 97.5% and a yield of 89.3% (0.446 mol).

[0067] Example 6

[0068] 71.6 g (95%, 0.5 mol) of diethyl methylphosphonite was added to a 500 ml four-necked flask, and then pre-stirred and cooled to 0 °C. Subsequently, 80.3 g (95%, 0.5 mol) of ethyl 4-chloro-2-carbonylbutyrate was slowly added dropwise, maintaining the reaction temperature between -5 and 5 °C throughout the addition process, which was completed in approximately 2 hours. Simultaneously, a vacuum of -0.1 MPa was maintained during the reaction to remove components such as chloroethane generated during the reaction. After the addition was complete, the reaction was continued at this temperature for 3 hours to obtain 105.9 g of crude ethyl 4-(ethoxymethylphosphono)-2-carbonylbutyrate solution.

[0069] 121.7 g (1.0 mol) of 30% hydrochloric acid was added dropwise to the above solution, and then the mixture was stirred and heated to 95 °C for 8 h to fully hydrolyze the solution. Excess acid and alcohol-water were then removed by vacuum distillation, with the endpoint temperature controlled at 90 °C, yielding 102.1 g of the solution. 250.0 g of toluene was then added, and the solution was thoroughly dissolved by shaking. After standing for 1 h, insoluble inorganic salts were removed by filtration. The separated organic phase was further evaporated to dryness by rotary evaporation, and 100.0 g of methyl isobutyl ketone was added for recrystallization. Finally, filtration yielded 80.1 g of the product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a purity of 98.0% and a yield of 87.3% (0.436 mol).

[0070] Example 7

[0071] 71.6 g (95%, 0.5 mol) of diethyl methylphosphonite was added to a 500 ml four-necked flask, and then pre-stirred and cooled to 0 °C. Subsequently, 80.3 g (95%, 0.5 mol) of ethyl 4-chloro-2-carbonylbutyrate was slowly added dropwise, maintaining the reaction temperature between -5 and 5 °C throughout the addition process, which was completed in approximately 4 hours. Simultaneously, a vacuum of -0.05 MPa was maintained during the reaction to remove components such as chloroethane generated during the reaction. After the addition was complete, the reaction was continued at this temperature for 3 hours to obtain 112.2 g of crude ethyl 4-(ethoxymethylphosphono)-2-carbonylbutyrate solution.

[0072] 121.7 g (1.0 mol) of 30% hydrochloric acid was added dropwise to the above solution, and then the mixture was stirred and heated to 95 °C for 8 h to fully hydrolyze the solution. Excess acid and alcohol-water were then removed by vacuum distillation, with the endpoint temperature controlled at 90 °C, yielding 106.2 g of the solution. 250.0 g of toluene was then added, and the solution was thoroughly dissolved by shaking. After standing for 1 h, insoluble inorganic salts were removed by filtration. The separated organic phase was further evaporated to dryness by rotary evaporation, and 100.0 g of methyl isobutyl ketone was added for recrystallization. Finally, filtration yielded 82.5 g of the product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a purity of 97.5% and a yield of 89.4% (0.447 mol).

[0073] Example 8

[0074] 71.6 g (95%, 0.5 mol) of diethyl methylphosphonite was added to a 500 ml four-necked flask, and then pre-stirred and cooled to 0 °C. Subsequently, 80.3 g (95%, 0.5 mol) of ethyl 4-chloro-2-carbonylbutyrate was slowly added dropwise, maintaining the reaction temperature between -5 and 5 °C throughout the addition process, which was completed in approximately 2 hours. Simultaneously, a vacuum of -0.05 MPa was maintained during the reaction to remove components such as chloroethane generated during the reaction. After the addition was complete, the reaction was continued at this temperature for 12 hours to obtain 112.2 g of crude ethyl 4-(ethoxymethylphosphono)-2-carbonylbutyrate solution.

[0075] 121.7 g (1.0 mol) of 30% hydrochloric acid was added dropwise to the above solution, and then the mixture was stirred and heated to 95 °C for 8 h to fully hydrolyze the solution. Excess acid and alcohol-water were then removed by vacuum distillation, with the endpoint temperature controlled at 90 °C, yielding 106.2 g of the solution. 250.0 g of toluene was then added, and the solution was thoroughly dissolved by shaking. After standing for 1 h, insoluble inorganic salts were removed by filtration. The separated organic phase was further evaporated to dryness by rotary evaporation, and 100.0 g of methyl isobutyl ketone was added for recrystallization. Finally, filtration yielded 82.5 g of the product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a purity of 97.5% and a yield of 89.4% (0.447 mol).

[0076] Example 9

[0077] 71.6 g (95%, 0.5 mol) of diethyl methylphosphonite was added to a 500 ml four-necked flask, and then pre-stirred and cooled to 0 °C. Subsequently, 80.3 g (95%, 0.5 mol) of ethyl 4-chloro-2-carbonylbutyrate was slowly added dropwise, maintaining the reaction temperature between -5 and 5 °C throughout the addition process, which was completed in approximately 2 hours. Simultaneously, a vacuum of -0.05 MPa was maintained during the reaction to remove components such as chloroethane generated during the reaction. After the addition was complete, the reaction was continued at this temperature for 3 hours to obtain 112.8 g of crude ethyl 4-(ethoxymethylphosphono)-2-carbonylbutyrate solution.

[0078] 196.0 g (1.0 mol) of 50% sulfuric acid was added dropwise to the above-mentioned solution, and then the mixture was stirred and heated to 95 °C for 8 hours to fully hydrolyze the solution. The solution was then neutralized to pH 7.0 with 30% sodium hydroxide solution. Excess alcohol and water were removed by vacuum distillation, with the final temperature controlled at 90 °C, yielding 186.5 g of the solution. 250.0 g of acetone was added, and the solution was thoroughly shaken to dissolve. The solution was then filtered to remove insoluble inorganic salts. After the filtrate stood for 1 hour, the insoluble inorganic salts were removed again by filtration. The resulting organic phase was further dried by rotary evaporation, and then recrystallized with 100 g of methyl isobutyl ketone. The final product, 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, was obtained by filtration, with a purity of 83.5% and a yield of 84.1% (0.420 mol).

[0079] Example 10

[0080] 71.6 g (95%, 0.5 mol) of diethyl methylphosphonite was added to a 500 ml four-necked flask, and then pre-stirred and cooled to 0 °C. Subsequently, 80.3 g (95%, 0.5 mol) of ethyl 4-chloro-2-carbonylbutyrate was slowly added dropwise, maintaining the reaction temperature between -5 and 5 °C throughout the addition process, which was completed in approximately 2 hours. Simultaneously, a vacuum of -0.05 MPa was maintained during the reaction to remove components such as chloroethane generated during the reaction. After the addition was complete, the reaction was continued at this temperature for 3 hours to obtain 112.8 g of crude ethyl 4-(ethoxymethylphosphono)-2-carbonylbutyrate solution.

[0081] 243.4 g (2.0 mol) of 30% hydrochloric acid was added dropwise to the above solution, and then the mixture was stirred and heated to 95 °C for 8 h to fully hydrolyze the solution. Excess acid and alcohol-water were then removed by vacuum distillation, with the endpoint temperature controlled at 90 °C, yielding 126.8 g of the solution. 250.0 g of toluene was then added, and the solution was thoroughly dissolved by shaking. After standing for 1 h, insoluble inorganic salts were removed by filtration. The separated organic phase was further evaporated to dryness by rotary evaporation, and 100.0 g of methyl isobutyl ketone was added for recrystallization. Finally, filtration yielded 91.8 g of the product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a purity of 87.8% and a yield of 89.6% (0.448 mol).

[0082] Example 11

[0083] 71.6 g (95%, 0.5 mol) of diethyl methylphosphonite was added to a 500 ml four-necked flask, and then pre-stirred and cooled to 0 °C. Subsequently, 80.3 g (95%, 0.5 mol) of ethyl 4-chloro-2-carbonylbutyrate was slowly added dropwise, maintaining the reaction temperature between -5 and 5 °C throughout the addition process, which was completed in approximately 2 hours. Simultaneously, a vacuum of -0.05 MPa was maintained during the reaction to remove components such as chloroethane generated during the reaction. After the addition was complete, the reaction was continued at this temperature for 3 hours to obtain 112.8 g of crude ethyl 4-(ethoxymethylphosphono)-2-carbonylbutyrate solution.

[0084] 121.7 g (1.0 mol) of 30% hydrochloric acid was added dropwise to the above solution, and then the mixture was stirred and heated to 95 °C for 12 h to fully hydrolyze the solution. Excess acid and alcohol-water were then removed by vacuum distillation, with the endpoint temperature controlled at 90 °C, yielding 106.2 g of the solution. 250.0 g of toluene was then added, and the solution was thoroughly dissolved by shaking. After standing for 1 h, insoluble inorganic salts were removed by filtration. The separated organic phase was further evaporated to dryness by rotary evaporation, and 100.0 g of methyl isobutyl ketone was added for recrystallization. Finally, filtration yielded 82.8 g of the product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a purity of 97.4% and a yield of 89.6% (0.448 mol).

[0085] Example 12

[0086] 71.6 g (95%, 0.5 mol) of diethyl methylphosphonite was added to a 500 ml four-necked flask, and then pre-stirred and cooled to 0 °C. Subsequently, 80.3 g (95%, 0.5 mol) of ethyl 4-chloro-2-carbonylbutyrate was slowly added dropwise, maintaining the reaction temperature between -5 and 5 °C throughout the addition process, which was completed in approximately 2 hours. Simultaneously, a vacuum of -0.05 MPa was maintained during the reaction to remove components such as chloroethane generated during the reaction. After the addition was complete, the reaction was continued at this temperature for 3 hours to obtain 112.8 g of crude ethyl 4-(ethoxymethylphosphono)-2-carbonylbutyrate solution.

[0087] 121.7 g (1.0 mol) of 30% hydrochloric acid was added dropwise to the above solution, and then the mixture was stirred and heated to 105 °C for 8 h to fully hydrolyze the solution. Excess acid and alcohol-water were then removed by vacuum distillation, with the endpoint temperature controlled at 90 °C, yielding 105.3 g of the solution. 250.0 g of toluene was then added, and the solution was thoroughly dissolved by shaking. After standing for 1 h, insoluble inorganic salts were removed by filtration. The separated organic phase was further evaporated to dryness by rotary evaporation, and 100.0 g of methyl isobutyl ketone was added for recrystallization. Finally, filtration yielded 83.0 g of the product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a purity of 97.0% and a yield of 89.5% (0.447 mol).

[0088] Example 13

[0089] 71.6 g (95%, 0.5 mol) of diethyl methylphosphonite was added to a 500 ml four-necked flask, and then pre-stirred and cooled to 0 °C. Subsequently, 80.3 g (95%, 0.5 mol) of ethyl 4-chloro-2-carbonylbutyrate was slowly added dropwise, maintaining the reaction temperature between -5 and 5 °C throughout the addition process, which was completed in approximately 2 hours. Simultaneously, a vacuum of -0.05 MPa was maintained during the reaction to remove components such as chloroethane generated during the reaction. After the addition was complete, the reaction was continued at this temperature for 3 hours to obtain 112.8 g of crude ethyl 4-(ethoxymethylphosphono)-2-carbonylbutyrate solution.

[0090] 121.7 g (1.0 mol) of 30% hydrochloric acid was added dropwise to the above solution, and then the mixture was stirred and heated to 95 °C for 8 h to fully hydrolyze the solution. Excess acid and alcohol-water were then removed by vacuum distillation, with the endpoint temperature controlled at 100 °C, yielding 100.4 g of the solution. 250.0 g of toluene was then added, and the solution was thoroughly dissolved by shaking. After standing for 1 h, insoluble inorganic salts were removed by filtration. The separated organic phase was further evaporated to dryness by rotary evaporation, and 100.0 g of methyl isobutyl ketone was added for recrystallization. Finally, filtration yielded 77.5 g of the product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with a purity of 97.9% and a yield of 84.3% (0.422 mol).

[0091] 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) 4-Halo-2-carbonylbutyrate is added dropwise to dialkyl methylphosphonite while the temperature is controlled at -30~10℃, and the reaction is carried out under vacuum to obtain an intermediate solution; the dialkyl methylphosphonite is diethyl methylphosphonite; the molar ratio of dialkyl methylphosphonite to 4-halo-2-carbonylbutyrate is (1~1.1):1; the dropwise addition time is 0.5h~4h; the vacuum degree is -0.01MPa~-0.1MPa; the reaction time is 0.5h~12h; b) The intermediate solution obtained in step a) is mixed with acid and subjected to hydrolysis reaction, followed by purification treatment to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid; The acid is hydrochloric acid, and the molar ratio of the acid to the methylphosphonic acid dialkyl ester in step a) is (1~10):

1. The hydrolysis reaction is carried out at a temperature of 50℃~130℃ for 1h~24h. The purification process is as follows: The product obtained from the hydrolysis reaction was subjected to vacuum distillation at 50℃~150℃, then dissolved in an organic solvent and allowed to stand. The insoluble inorganic salts were removed by filtration, and the separated organic phase was dried by rotary evaporation. Methyl isobutyl ketone was added for recrystallization, and the product was filtered to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

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