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

Abstract

The application provides a preparation method of 4-(hydroxymethyl phosphono)-2-carbonyl butyric acid, comprising the following steps: a) mixing methyl phosphonate diester, carboxylic acid and acryloyl cyanide to perform an addition reaction, and obtaining (3-cyano-3-carbonyl propyl) methyl phosphonate liquor after reduced pressure distillation; b) uniformly mixing the (3-cyano-3-carbonyl propyl) methyl phosphonate liquor obtained in step a) with water, cooling to 10-40 DEG C, then adding hydrochloric acid dropwise to perform acidification, continuing to stir for 0.1-1 h after the dropwise addition is completed, then performing a hydrolysis reaction, and finally performing purification treatment to obtain 4-(hydroxymethyl phosphono)-2-carbonyl butyric acid. Compared with the prior art, the preparation method provided by the application does not need to perform a cyanation reaction, avoids the use of high-cost, hard-to-obtain cyclic phosphonic anhydride and the highly toxic sodium cyanide; and the preparation method has short process steps, the raw materials are widely sourced and low in cost, the reaction conditions are mild, and the element comprehensive utilization rate is high.

Description

TECHNICAL FIELD

[0001] The present application relates to the chemical technology field, more particularly, to a preparation method of a pesticide intermediate 4-(hydroxymethyl phosphono)-2-carboxybutyric acid. BACKGROUND

[0002] 4-(hydroxymethyl phosphono)-2-carboxybutyric acid, abbreviated as PPO or ketonic acid, is an important intermediate in the synthesis process of glufosinate, and the compound can obtain glufosinate through steps such as amination reduction, and can obtain L-glufosinate through a biological enzyme method.

[0003] In 1980, FBC company first applied for a patent US4399287A for preparing ketonic acid intermediate, and 3-(ethoxymethyl phosphono) propionate was extended carbon chain through Claisen condensation to obtain ketonic acid intermediate 2-oxo-4-(hydroxymethyl acyl) butyric acid, and the reported separation yield of ketonic acid intermediate was about 30%. In 1991, Hoechst company reported a chemical synthesis method of 4-(hydroxymethyl phosphono)-2-carboxybutyric acid (J. Org. Chem. 1991, 56, 1783-1788): 3-(ethoxymethyl phosphono) propionate was first prepared by Michael addition of methyl phosphite monomethyl ester and ethyl acrylate under the action of sodium ethoxide, and then Claisen ester condensation was carried out with diethyl oxalate under the action of sodium ethoxide at-50℃, and then 4-(hydroxymethyl phosphono)-2-carboxybutyric acid was prepared by hydrolysis and decarboxylation with hydrochloric acid; but the method needs 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 48h; the reaction formula is shown in the following:

[0004]

[0005] Patent CN103665032A discloses a preparation method of glufosinate, and reports a method for preparing 4-(hydroxy-(methyl) phosphinyl)-2-oxobutyric acid which is an important intermediate of glufosinate prepared by a ketonic acid route, that is, 2,5-dioxo-1-oxa-2-phosphacyclopentane containing oxygen and phosphorus and cyanide are used as raw materials to generate ketonic cyanide compound in an organic solvent; then the ketonic cyanide compound is hydrolyzed in an acid solution to obtain ketonic acid material 4-(hydroxy-(methyl) phosphinyl)-2-oxobutyric acid; finally, glufosinate can be obtained through the processes of amination and hydrogenation reduction under the conditions of an alcohol solvent and a catalyst. However, the ring phosphonic anhydride used in the method is not easy to prepare, has high cost, and is difficult to purify.

[0006] A synthesis method of L-form glufosinate ammonium salt is disclosed in patent CN105218579A, wherein 4-(hydroxymethyl phosphinyl)-2-carbonyl butyric acid is prepared from 4-(ethoxy-(methyl)oxy phosphinyl)-2-acetoxy butyric acid as raw material. First, hydrochloric acid is used to hydrolyze 4-(hydroxymethyl phosphinyl)-2-carbonyl butyric acid to obtain 4-(hydroxymethyl phosphinyl)-2-carbonyl butyric acid, then sodium hydroxide is used to neutralize the salt, then sodium hypochlorite aqueous solution is used to oxidize 4-(hydroxymethyl phosphinyl)-2-carbonyl butyric acid under the catalysis of transition metal oxide to obtain sodium 4-(hydroxymethyl phosphinyl)-2-carbonyl butyric acid, and finally HCl gas is introduced to react to remove the salt to obtain 4-(hydroxymethyl phosphinyl)-2-carbonyl butyric acid. However, the method needs to use a large amount of acid and alkali to produce a large amount of by-product salt, and needs to use noble metal as a catalyst to increase the cost, and the by-product salt is difficult to handle. SUMMARY

[0007] Therefore, the present application aims to provide a preparation method of 4-(hydroxymethyl phosphinyl)-2-carbonyl butyric acid, which has short process steps, wide raw material sources and low cost, mild reaction conditions and high element comprehensive utilization rate.

[0008] The present application provides a preparation method of 4-(hydroxymethyl phosphinyl)-2-carbonyl butyric acid, which comprises the following steps:

[0009] a) mixing methyl phosphinate diester, carboxylic acid and acrylonitrile to perform addition reaction, and then performing vacuum distillation to obtain (3-cyano-3-carbonyl propyl) methyl phosphonate liquid;

[0010] b) uniformly mixing the (3-cyano-3-carbonyl propyl) methyl phosphonate liquid obtained in step a) with water, cooling to 10-40℃, then adding hydrochloric acid to perform acidification, continuing to stir for 0.1-1h after the addition is completed, then performing hydrolysis reaction, and finally performing purification treatment to obtain 4-(hydroxymethyl phosphinyl)-2-carbonyl butyric acid.

[0011] Preferably, the methyl phosphinate diester in step a) is selected from one or more of dimethyl phosphinate, diethyl phosphinate, dipropyl phosphinate and dibutyl phosphinate.

[0012] The carboxylic acid is selected from one or more of acetic acid, propionic acid, butyric acid, isobutyric acid, pentanoic acid and isopentanoic acid.

[0013] Preferably, the mass ratio of the methyl phosphinate diester and the carboxylic acid in step a) is 1:(1-20).

[0014] Preferably, the molar ratio of the acrylonitrile to the methyl phosphinate diester in step a) is (0.8-1.5):1.

[0015] Preferably, the mixing process in step a) is specifically as follows:

[0016] The methyl phosphonite is added into the carboxylic acid under stirring, and the temperature is controlled to 0-40℃, while the acryloyl cyanide is added dropwise, and the dropwise adding time is 0.1-5h.

[0017] Preferably, the temperature of the addition reaction in step a) is 0-90℃, and the time is 1-10h.

[0018] Preferably, the molar ratio of the hydrochloric acid to the methyl phosphonite in step b) is (1-5):1.

[0019] Preferably, the temperature of the acidification in step b) is 0-40℃.

[0020] Preferably, the temperature of the hydrolysis reaction in step b) is 60-130℃, and the time is 1-24h.

[0021] Preferably, the purification process in step b) is as follows:

[0022] The product obtained from the hydrolysis reaction is subjected to vacuum acid water removal, then is dissolved in acetone, and is filtered to remove insoluble salt, then methyl isobutyl ketone is added into the filtrate to crystallize, and 4-(hydroxymethyl phosphono)-2-carbonyl butyric acid is obtained.

[0023] The present application provides a preparation method of 4-(hydroxymethyl phosphono)-2-carbonyl butyric acid, comprising the following steps: a) mixing methyl phosphonite, carboxylic acid and acryloyl cyanide to perform addition reaction, and vacuum distillation to obtain (3-cyano-3-carbonyl propyl) methyl phosphonate solution; b) uniformly mixing the (3-cyano-3-carbonyl propyl) methyl phosphonate solution obtained from step a) with water, cooling to 10-40℃, then adding hydrochloric acid dropwise to perform acidification, continuing to stir for 0.1-1h after the dropwise adding is completed, then performing hydrolysis reaction, and finally performing purification treatment to obtain 4-(hydroxymethyl phosphono)-2-carbonyl butyric acid. Compared with the prior art, the preparation method provided by the present application uses methyl phosphonite and acryloyl cyanide as raw materials to perform addition reaction in a carboxylic acid system to obtain (3-cyano-3-carbonyl propyl) methyl phosphonate, and then hydrolyzes under acidic conditions to obtain the target product 4-(hydroxymethyl phosphono)-2-carbonyl butyric acid; the preparation method directly uses methyl phosphonite and acryloyl cyanide to perform addition reaction, without the need of cyanation reaction, thereby avoiding the use of high-cost, hard-to-obtain cyclic phosphonic anhydride and the highly toxic cyanide sodium; the acryloyl cyanide is directly introduced into the acryloyl cyanide through reaction, and then the target product is obtained through hydrolysis under acidic conditions, thereby avoiding the use of Claisen ester condensation and decarboxylation to introduce the carboxyl group, and also avoiding the use of noble metal catalytic oxidation after salification to produce the carbonyl group; and the preparation method has short process steps, the raw materials are widely available and low in cost, the reaction conditions are mild, and the element comprehensive utilization rate is high. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 HPLC profile of 4-(hydroxymethylphosphine)-2-carbonyl butyric acid sample;

[0025] Figure 2 HPLC profile of 4-(hydroxymethylphosphine)-2-carbonyl butyric acid sample obtained from Example 4 of the present application. DETAILED DESCRIPTION

[0026] The technical solutions of the present application will be described clearly and completely below in combination with the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by those skilled in the art without creative labor fall within the protection scope of the present application.

[0027] The present application provides a preparation method of 4-(hydroxymethylphosphine)-2-carbonyl butyric acid, comprising the following steps:

[0028] a) mixing dimethyl phosphonate, carboxylic acid and acrylonitrile to perform an addition reaction, and then performing vacuum distillation to obtain a (3-cyano-3-carbonyl propyl) methyl phosphonate solution;

[0029] b) uniformly mixing the (3-cyano-3-carbonyl propyl) methyl phosphonate solution obtained in step a) with water, cooling to 10-40℃, then adding hydrochloric acid dropwise to perform acidification, continuing to stir for 0.1-1h after the dropwise addition is completed, then performing a hydrolysis reaction, and finally performing purification treatment to obtain 4-(hydroxymethylphosphine)-2-carbonyl butyric acid.

[0030] The present application provides a preparation method of 4-(hydroxymethylphosphine)-2-carbonyl butyric acid. Dimethyl phosphonate (formula I; R1, R2 can represent C1-C4 alkyl) and acrylonitrile (formula II) are used as raw materials to perform a reaction in a carboxylic acid (formula III) system to obtain (3-cyano-3-carbonyl propyl) methyl phosphonate (formula IV), and then hydrolysis under acidic conditions to obtain the target product 4-(hydroxymethylphosphine)-2-carbonyl butyric acid (formula V).

[0031]

[0032] The preparation method of 4-(hydroxymethylphosphine)-2-carbonyl butyric acid provided by the present application has the following reaction formula:

[0033]

[0034] The preparation method directly uses methyl phosphonite and acryloyl cyanide for addition reaction, does not need cyanation reaction, avoids the use of high-cost, hard-to-obtain cyclic phosphonic anhydride and toxic sodium cyanide, directly introduces acyl cyanide by reacting with acryloyl cyanide, and obtains the target product by hydrolysis under acidic conditions, avoids the use of Claisen ester condensation and decarboxylation to add carboxyl, and avoids the production of carbonyl by salt formation and noble metal catalytic oxidation, and the preparation method has short process steps, wide raw material sources, low cost, mild reaction conditions and high element comprehensive utilization rate.

[0035] The application first mixes methyl phosphonite, carboxylic acid and acryloyl cyanide for addition reaction, and obtains (3-cyano-3-carbonylpropyl) methyl phosphonate liquid after reduced pressure distillation.

[0036] In the application, the methyl phosphonite is preferably one or more of dimethyl phosphite, diethyl phosphite, dipropyl phosphite and dibutyl phosphite, and is more preferably diethyl phosphite; the application does not have special limitations on the source of the methyl phosphonite, and commercially available goods known to those skilled in the art can be used.

[0037] In the application, the carboxylic acid is preferably one or more of acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid and isovaleric acid, and is more preferably acetic acid. The application does not have special limitations on the source of the carboxylic acid, and commercially available goods known to those skilled in the art can be used. In the application, the carboxylic acid has the functions of a reaction raw material and a solvent.

[0038] In the application, the mass ratio of the methyl phosphonite to the carboxylic acid is preferably 1:(1-20).

[0039] The application does not have special limitations on the source of the acryloyl cyanide, and commercially available goods known to those skilled in the art can be used.

[0040] In the application, the molar ratio of the acryloyl cyanide to the methyl phosphonite is preferably (0.8-1.5):1, and is more preferably (1-1.1):1.

[0041] In the application, the mixing process is preferably specifically as follows:

[0042] Under stirring, the methyl phosphonite is placed in the carboxylic acid, the temperature is controlled to 0-40℃, and the acryloyl cyanide is added dropwise at the same time, and the dropwise adding time is 0.1-5h.

[0043] More preferably, the temperature is controlled to 10-30℃, and the dropwise adding time is 1-3h.

[0044] Under stirring, the methyl phosphonite is placed in the carboxylic acid, the temperature is controlled to 10-30℃, and the acryloyl cyanide is added dropwise at the same time, and the dropwise adding time is 1-3h.

[0045] In this invention, the temperature of the addition reaction is preferably 0℃~90℃, more preferably 10℃~40℃; the time of the addition reaction is preferably 1h~10h, more preferably 2h~4h.

[0046] In this invention, the purpose of vacuum distillation is to remove the solvent; this invention does not impose any particular limitation on this.

[0047] After obtaining the (3-cyano-3-carbonylpropyl)methylphosphonate solution, the present invention mixes the obtained (3-cyano-3-carbonylpropyl)methylphosphonate solution with water evenly, cools it to 10℃~40℃, and then adds hydrochloric acid dropwise for acidification. After the addition is completed, stirring is continued for 0.1h~1h, followed by hydrolysis reaction. Finally, after purification treatment, 4-(hydroxymethylphosphono)-2-carbonylbutyric acid is obtained.

[0048] In this invention, the concentration of the hydrochloric acid is preferably 20% to 36%; commercially available products well known to those skilled in the art can be used.

[0049] In this invention, the molar ratio of hydrochloric acid (HCl) to methylphosphonic acid diester is preferably (1-5):1, more preferably (2-3):1.

[0050] In this invention, the acidification temperature is preferably 0°C to 40°C, and more preferably 30°C to 40°C.

[0051] In this invention, the temperature of the hydrolysis reaction is preferably 60℃~130℃, more preferably 90℃~120℃; the time of the hydrolysis reaction is preferably 1h~24h, more preferably 6h~12h.

[0052] In this invention, the hydrolysis reaction process is preferably as follows:

[0053] First, heat the material at normal pressure for about 1.5 to 2.5 hours to 105°C to 113°C, then hold it at that temperature and reflux for 2.5 to 3.5 hours, and then slowly heat it for another 2.5 to 3.5 hours to 114°C to 116°C.

[0054] or,

[0055] After a slow heating process of 7 to 9 hours, the temperature reaches 115℃ to 125℃.

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

[0057] The product obtained from the hydrolysis reaction was subjected to reduced pressure to remove acid water, then dissolved in acetone, filtered to remove insoluble salts, and methyl isobutyl ketone was added to the filtrate for crystallization to obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.

[0058] The application provides a preparation method of 4-(hydroxymethyl phosphinyl)-2-carbonyl butyric acid, which comprises the following steps: a) mixing methyl phosphonate diester, carboxylic acid and acryloyl cyanide to perform an addition reaction, and performing vacuum distillation to obtain (3-cyano-3-carbonyl propyl) methyl phosphonate solution; b) uniformly mixing the (3-cyano-3-carbonyl propyl) methyl phosphonate solution obtained in the step a) with water, cooling to 10-40 DEG C, then adding hydrochloric acid dropwise to perform acidification, continuing to stir for 0.1-1 h after the dropwise addition is completed, then performing a hydrolysis reaction, and finally performing purification treatment to obtain 4-(hydroxymethyl phosphinyl)-2-carbonyl butyric acid. Compared with the prior art, the preparation method provided by the application uses methyl phosphonate diester and acryloyl cyanide as raw materials to perform an addition reaction in a carboxylic acid system to obtain (3-cyano-3-carbonyl propyl) methyl phosphonate, and then hydrolysis is performed under an acidic condition to obtain the target product 4-(hydroxymethyl phosphinyl)-2-carbonyl butyric acid; the preparation method directly uses methyl phosphonate diester and acryloyl cyanide to perform an addition reaction, and does not need to perform a cyanation reaction, thereby avoiding the use of high-cost, hard-to-obtain cyclic phosphonic anhydride and the highly toxic cyanide sodium; meanwhile, the acryloyl cyanide is directly introduced by reacting with acryloyl cyanide, and then hydrolysis is performed under an acidic condition to obtain the target product, thereby avoiding the use of the Klesse ester condensation and decarboxylation mode to introduce a carboxyl group, and avoiding the use of a noble metal catalytic oxidation after salification to produce a carbonyl group; and the preparation method has short process steps, the raw materials are widely sourced and low in cost, the reaction condition is mild, and the element comprehensive utilization rate is high.

[0059] In order to further illustrate the application, the following examples are used to make a detailed description. The raw materials used in the following examples of the application are all commercially available.

[0060] Example 1

[0061] 1) 69.4g (0.5mol) of 98% diethyl methyl phosphonate is added into 250g of acetic acid, and the mixture is stirred and uniformly mixed, and then cooled to 10 DEG C, 41.3g (0.5mol) of 98% acryloyl cyanide is slowly added dropwise, and the temperature is controlled at 10 DEG C, the dropwise addition is completed in 2h, and after the addition is completed, the solution is continuously incubated at 10 DEG C for 3h to obtain a solution containing (3-cyano-3-carbonyl propyl) methyl phosphonate, and the solution is subjected to vacuum distillation to remove the solvent acetic acid and the by-product ethyl acetate, thereby obtaining (3-cyano-3-carbonyl propyl) methyl phosphonate solution.

[0062] 2) The obtained (3-cyano-3-carbonylpropyl) methylphosphonate solution was added to 50 g of deionized water and stirred to mix uniformly, and then cooled to below 40°C. Then 121.7 g (1.0 mol) of 30% hydrochloric acid was added dropwise for acidification, and the acidification temperature was controlled to be below 40°C. After the dropwise addition was completed, stirring and mixing was continued for 0.5 h, and then a temperature rising hydrolysis reaction was performed. First, the temperature was raised to 110°C under normal pressure for about 2 h, then kept at 110°C for 3 h, then slowly raised to 115°C for 3 h, and finally, deacidification was performed under reduced pressure at -0.095 Mpa for 1 h, with the terminal temperature being 65°C. Then 150 g of acetone was added to reflux and dissolve, the insoluble salt was removed by filtration, and 400 g of methyl isobutyl ketone was added to the filtrate for crystallization, to obtain white solid product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid 48.6 g, with a content of 95.3% and a yield of 51.5%.

[0063] Example 2

[0064] 1) 69.4 g (0.5 mol) of 98% diethyl methylphosphonite was added to 250 g of acetic acid, and stirred to mix uniformly, with the temperature being controlled to be 30°C. Then 41.3 g (0.5 mol) of 98% acryloyl cyanide was added dropwise for reaction, with the temperature being controlled to be 30°C. The dropwise addition was completed in 1 h, and after the addition was completed, the reaction was continued at 30°C for 2 h, to obtain a solution containing (3-cyano-3-carbonylpropyl) methylphosphonate. The solution was subjected to reduced pressure distillation to remove the solvent acetic acid and the byproduct ethyl acetate, to obtain a (3-cyano-3-carbonylpropyl) methylphosphonate solution.

[0065] 2) The obtained (3-cyano-3-carbonylpropyl) methylphosphonate solution was added to 50 g of deionized water and stirred to mix uniformly, and then cooled to below 40°C. Then 121.7 g (1.0 mol) of 30% hydrochloric acid was added dropwise for acidification, and the acidification temperature was controlled to be below 40°C. After the dropwise addition was completed, stirring and mixing was continued for 0.5 h, and then a temperature rising hydrolysis reaction was performed. First, the temperature was raised to 110°C under normal pressure for about 2 h, then kept at 110°C for 3 h, then slowly raised to 115°C for 3 h, and finally, deacidification was performed under reduced pressure at -0.095 Mpa for 1 h, with the terminal temperature being 65°C. Then 150 g of acetone was added to reflux and dissolve, the insoluble salt was removed by filtration, and 400 g of methyl isobutyl ketone was added to the filtrate for crystallization, to obtain white solid product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid 48.6 g, with a content of 95.3% and a yield of 51.5%.

[0066] Example 3

[0067] 1) 69.4 g (0.5 mol) of 98% diethyl methylphosphonite was added to 250 g of acetic acid, and the mixture was stirred and mixed uniformly while controlling the temperature at 30°C. 41.3 g (0.5 mol) of 98% acryloyl cyanide was added dropwise slowly, and the temperature was controlled at 30°C. The dropwise addition was completed in 1 h, and the reaction was continued at 30°C for 2 h after the completion of the addition. A solution containing (3-cyano-3-carbonylpropyl) methylphosphonate was obtained, and the solution was subjected to distillation under reduced pressure to remove the solvent acetic acid and the by-product ethyl acetate, thereby obtaining a (3-cyano-3-carbonylpropyl) methylphosphonate solution.

[0068] 2) The (3-cyano-3-carbonylpropyl) methylphosphonate solution obtained above was added to 50 g of deionized water, and the mixture was stirred and mixed uniformly while being cooled to below 40°C. Then, 182.5 g (1.5 mol) of 30% hydrochloric acid was added dropwise to perform acidification while controlling the acidification temperature at below 40°C. After the completion of the dropwise addition, the mixture was stirred and mixed for 0.5 h, and then a slow warming normal pressure hydrolysis reaction was performed. After 8 h of slow warming, the temperature reached 120°C, and the steam was turned off. The acid was removed under reduced pressure under a vacuum of -0.03 Mpa until the temperature decreased to about 100°C. Then, 150 g of acetone was added to reflux and dissolve, and the insoluble salt was removed by filtration. The filtrate was subjected to crystallization by adding 400 g of methyl isobutyl ketone, thereby obtaining white solid product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid 44.2 g, which had a content of 92.6% and a yield of 45.5%.

[0069] Example 4

[0070] 1) 69.4 g (0.5 mol) of 98% diethyl methylphosphonite was added to 300 g of acetic acid, and the mixture was stirred and mixed uniformly while being cooled and cooled to 10°C. 45.5 g (0.55 mol) of 98% acryloyl cyanide was added dropwise slowly, and the temperature was controlled at 10°C. The dropwise addition was completed in 2 h, and the reaction was continued at 10°C for 3 h after the completion of the addition. A solution containing (3-cyano-3-carbonylpropyl) methylphosphonate was obtained, and the solution was subjected to distillation under reduced pressure to remove the solvent acetic acid and the by-product ethyl acetate, thereby obtaining a (3-cyano-3-carbonylpropyl) methylphosphonate solution.

[0071] 2) The (3-cyano-3-carbonylpropyl) methylphosphonate solution obtained above was added to 50 g of deionized water and stirred to mix uniformly, and then cooled to below 40°C, followed by dropwise addition of 182.5 g (1.5 mol) of 30% hydrochloric acid for acidification, with the acidification temperature controlled to be below 40°C, and after the dropwise addition was completed, stirring and mixing was continued for 0.5 h, and then a temperature- raising hydrolysis reaction was performed; first, normal pressure temperature raising for about 2 h to 110°C, then 3 h of refluxing at 110°C, then slow temperature raising for 3 h to 115°C, and finally 1 h of reduced pressure deacidification under vacuum at -0.095 Mpa, with the terminal temperature being 65°C; 150 g of acetone was added to reflux and dissolve, and insoluble salts were removed by filtration, and 400 g of methyl isobutyl ketone was added to the filtrate for crystallization, to obtain 50.5 g of white solid product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with the content being 98.5% by HPLC quantification using a standard as an external standard (standard: Figure 1 , sample: Figure 2 ), and the yield being 55.3%.

[0072] Example 5

[0073] 1) 69.4 g (0.5 mol) of 98% diethyl methylphosphonite was added to 300 g of acetic acid, and stirred to mix uniformly, with the temperature controlled to be 30°C, and 45.5 g (0.55 mol) of 98% acryloyl cyanide was slowly added dropwise for reaction, with the temperature controlled to be 30°C, and after 1 h of dropwise addition was completed, 30°C temperature raising was continued for 2 h, to obtain a solution containing (3-cyano-3-carbonylpropyl) methylphosphonate, and the solution was subjected to reduced pressure distillation to remove the solvent acetic acid and the byproduct ethyl acetate, to obtain a (3-cyano-3-carbonylpropyl) methylphosphonate solution.

[0074] 2) The (3-cyano-3-carbonylpropyl) methylphosphonate solution obtained above was added to 50 g of deionized water and stirred to mix uniformly, and then cooled to below 40°C, followed by dropwise addition of 121.7 g (1.0 mol) of 30% hydrochloric acid for acidification, with the acidification temperature controlled to be below 40°C, and after the dropwise addition was completed, stirring and mixing was continued for 0.5 h, and then a slow temperature- raising normal pressure hydrolysis reaction was performed; after slow temperature raising for 8 h, 120°C was reached, steam was turned off, and reduced pressure deacidification was performed under vacuum at -0.03 Mpa until the temperature was reduced to about 100°C, at which point the vacuum was released; 150 g of acetone was added to reflux and dissolve, and insoluble salts were removed by filtration, and 400 g of methyl isobutyl ketone was added to the filtrate for crystallization, to obtain 46.5 g of white solid product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, with the content being 95.1%, and the yield being 49.1%.

[0075] Example 6

[0076] 1) 69.4 g (0.5 mol) of 98% diethyl methyl phosphonite was added into 300 g of acetic acid, the mixture was stirred and mixed uniformly, and cooled to 10°C, 45.5 g (0.55 mol) of 98% acryloyl cyanide was added dropwise slowly, and the temperature was controlled at 10°C, the dropping was completed in 2 h, and the reaction was continued for 3 h at 10°C after the dropping was completed, to obtain a solution containing (3-cyano-3-carbonylpropyl) methyl phosphonate, the solution was distilled under reduced pressure to remove the solvent acetic acid and by-product ethyl acetate, to obtain (3-cyano-3-carbonylpropyl) methyl phosphonate solution.

[0077] 2) The (3-cyano-3-carbonylpropyl) methyl phosphonate solution obtained above was added into 50 g of deionized water, stirred and mixed uniformly, and cooled to below 40°C, then 121.7 g (1.0 mol) of 30% hydrochloric acid was added dropwise for acidification, and the acidification temperature was controlled below 40°C, the dropping was completed, and the stirring and mixing was continued for 0.5 h, then the hydrolysis reaction was carried out under slow warming and normal pressure; the temperature reached 120°C after slow warming for 8 h, the steam was turned off, and the acid was removed under reduced pressure under vacuum condition of -0.03 Mpa until the temperature was reduced to about 100°C, then the vacuum was released; 150 g of acetone was added to reflux and dissolve, the insoluble salt was removed by filtration, 400 g of methyl isobutyl ketone was added into the filtrate for crystallization, to obtain white solid product 4-(hydroxymethyl phosphono)-2-carbonyl butyric acid 49.0 g, content 97.8%, yield 53.2%.

[0078] The above description of disclosed embodiments enables one skilled in the art to make or use the application. Numerous modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein can be applied to other embodiments without departing from the spirit or scope of the application. Therefore, the present application is not intended 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-oxobutanoic acid, comprising the following steps: a) mixing dimethyl phosphite, carboxylic acid and acryloyl cyanide to perform an addition reaction, and then distilling under reduced pressure to obtain a (3-cyano-3-oxopropyl) methyl phosphonate solution; b) mixing the (3-cyano-3-oxopropyl) methyl phosphonate solution obtained in step a) with water, cooling to 10-40°C, then adding hydrochloric acid dropwise to perform acidification, continuing to stir for 0.1-1 h after the dropwise addition is completed, then performing a hydrolysis reaction, and finally performing purification treatment to obtain 4-(hydroxymethylphosphono)-2-oxobutanoic acid.

2. The production method according to claim 1, characterized by, The dimethyl phosphite in step a) is selected from one or more of dimethyl phosphite, diethyl phosphite, dipropyl phosphite and dibutyl phosphite. The carboxylic acid is selected from one or more of acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid and isovaleric acid.

3. The production method according to claim 1, characterized by, The mass ratio of the dimethyl phosphite to the carboxylic acid in step a) is 1:(1-20).

4. The method of claim 1, wherein, The molar ratio of the acryloyl cyanide to the dimethyl phosphite in step a) is (0.8-1.5):

1.

5. The preparation method according to claim 1, characterized in that, The mixing process in step a) is specifically as follows: The dimethyl phosphite is placed in the carboxylic acid under stirring, and the temperature is controlled to 0-40°C, while the acryloyl cyanide is added dropwise, and the dropwise addition time is 0.1-5 h.

6. The method of claim 1, wherein, The temperature of the addition reaction in step a) is 0-90°C, and the time is 1-10 h.

7. The preparation method according to claim 1, characterized in that, The molar ratio of the hydrochloric acid to the dimethyl phosphite in step b) is (1-5):

1.

8. The method of claim 1, wherein, The temperature of the acidification in step b) is 0-40°C.

9. The method of claim 1, wherein, The temperature of the hydrolysis reaction in step b) is 60-130°C, and the time is 1-24 h.

10. The method of claim 1, wherein, The purification treatment process in step b) is specifically as follows: The product obtained from the hydrolysis reaction is subjected to removal of acid water under reduced pressure, then is dissolved in acetone, insoluble salts are removed by filtration, methyl isobutyl ketone is added to the filtrate to perform crystallization, and 4-(hydroxymethylphosphono)-2-oxobutanoic acid is obtained.

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