A process for the synthesis of 4-halo-2-oxobutanoate intermediates

Abstract

The application provides a synthesis method of a 4-halogen-2-carbonyl butyric acid ester intermediate, comprising the following steps: a) mixing cyanide, a phase transfer catalyst and 3-halogen propionyl halide to perform a substitution reaction, and filtering to obtain 3-halogen propionyl cyanide crude liquid; the phase transfer catalyst is selected from one or more of polyethylene glycol, crown ether compounds, polyaliphatic alcohol castor oil, quaternary ammonium salt and quaternary phosphonium salt; b) mixing the 3-halogen propionyl cyanide crude liquid obtained in step a) with an acid aqueous solution to perform a hydrolysis reaction, and purifying to obtain 4-halogen-2-carbonyl butyric acid crude liquid; c) mixing the 4-halogen-2-carbonyl butyric acid crude liquid obtained in step b) with alcohol to perform an esterification reaction, and then performing purification treatment to obtain the 4-halogen-2-carbonyl butyric acid ester intermediate. The synthesis method has the advantages of simple process, mild and easy-to-control conditions, and high yield.

Description

Technical Field

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

[0002] 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, abbreviated as PPO or keto acid, is an important intermediate in the synthesis of glufosinate, and this intermediate compound can be catalyzed by bio-enzymatic methods to obtain L-glufosinate.

[0003] There are several methods for synthesizing PPO. In 1980, FBC first applied for a patent (US4399287A) for the preparation of keto acid intermediates, which used 3-(ethoxymethylphosphono)propionate to obtain the keto acid intermediate 4-(hydroxymethylphosphono)-2-carbonylbutyric acid via Claisen condensation. The yield of the target product was only about 30%.

[0004] In 1991, Hoechest reported a chemical synthesis method for the intermediate of 4-halo-2-carbonylbutyrate (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, hydrolysis with hydrochloric acid decarboxylates yields the 4-halo-2-carbonylbutyrate intermediate. 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] As can be seen from the above, most of the reported PPO synthesis methods involve reaction steps such as Claisen condensation or ring-opening, requiring stringent synthesis conditions, complex control, and low yields. Therefore, it is necessary to start from the raw material intermediates to efficiently and conveniently construct the key skeletal components of PPO, thereby improving the synthesis yield. Summary of the Invention

[0007] In view of this, the purpose of the present invention is to provide a method for synthesizing 4-halo-2-carbonylbutyrate intermediate, which is simple, mild and easy to control, and has a high yield.

[0008] This invention provides a method for synthesizing a 4-halo-2-carbonylbutyrate intermediate, comprising the following steps:

[0009] a) A mixture of cyanide, a phase transfer catalyst and 3-halopropionyl halide is carried out to undergo a substitution reaction, and the mixture is filtered to obtain a crude 3-halopropionyl cyanide solution; the phase transfer catalyst is selected from one or more of polyethylene glycol, crown ether compounds, polyfatty alcohol castor oil, quaternary ammonium salts and quaternary phosphine salts.

[0010] b) Mix the crude 3-halopropionyl cyanide solution obtained in step a) with an acidic aqueous solution, carry out a hydrolysis reaction, and purify to obtain crude 4-halo-2-carbonylbutyric acid solution;

[0011] c) The crude 4-halo-2-carbonylbutyric acid solution obtained in step b) is mixed with an alcohol and subjected to esterification reaction, followed by purification treatment to obtain the 4-halo-2-carbonylbutyrate intermediate.

[0012] Preferably, the cyanide in step a) is selected from one or more of cuprous cyanide, sodium cyanide, and hydrocyanic acid;

[0013] The 3-halopropionyl halide is selected from one or more of 3-chloropropionyl chloride, 3-chloropropionyl bromide, 3-chloropropionyl iodide, 3-bromopropionyl chloride, 3-bromopropionyl bromide, 3-bromopropionyl iodide, 3-iodopropionyl chloride, 3-iodopropionyl bromide and 3-iodopropionyl iodide.

[0014] Preferably, the amount of phase transfer catalyst added in step a) is 0.01% to 0.5% of the mass of 3-halopropionyl halide.

[0015] Preferably, the molar ratio of cyanide to 3-halopropionyl halide in step a) is (0.9 to 2.0): 1.

[0016] Preferably, the temperature of the substitution reaction in step a) is -10℃ to 110℃, and the time is 0.5h to 18h.

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

[0018] The molar ratio of acid to 3-halopropionyl cyanide in the aqueous solution 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 alcohol in step c) is selected from one or more of methanol, ethanol, isopropanol, and butanol;

[0021] The molar ratio of the alcohol to 4-halo-2-carbonylbutyric acid is (0.9–3):1.

[0022] Preferably, the esterification reaction in step c) is carried out at a temperature of 70°C to 105°C for a time of 1 hour to 24 hours.

[0023] Preferably, the purification process in step c) specifically includes:

[0024] Add 10wt%–30wt% sodium hydroxide aqueous solution to the product obtained from the esterification reaction, neutralize to pH 4–6, continuously desolvate under reduced pressure to 50℃–120℃, then cool to room temperature and filter to remove insoluble solids to obtain 4-halo-2-carbonylbutyric acid.

[0025] This invention provides a method for synthesizing a 4-halo-2-carbonylbutyrate intermediate, comprising the following steps: a) mixing cyanide, a phase transfer catalyst, and 3-halopropionyl halide to perform a substitution reaction, and filtering to obtain a crude 3-halopropionyl cyanide solution; wherein the phase transfer catalyst is selected from one or more of polyethylene glycol, crown ether compounds, polyfatty alcohol castor oil, quaternary ammonium salts, and quaternary phosphine salts; b) mixing the crude 3-halopropionyl cyanide solution obtained in step a) with an acidic aqueous solution to perform a hydrolysis reaction, and purifying to obtain a crude 4-halo-2-carbonylbutyrate solution; c) mixing the crude 4-halo-2-carbonylbutyrate solution obtained in step b) with an alcohol to perform an esterification reaction, and then purifying to obtain the 4-halo-2-carbonylbutyrate intermediate. Compared with the prior art, the synthesis method provided by the present invention uses 3-halopropionyl halide and cyanide as raw materials to obtain 3-halopropionyl cyanide through reaction. Under acidic conditions, the cyano group is hydrolyzed to generate 4-halo-2-carbonylbutyric acid, which is then further esterified with an alcohol to generate the final product 4-halo-2-carbonylbutyrate. The synthesis method is simple, mild, easy to control, and has a high yield. Attached Figure Description

[0026] Figure 1 The liquid phase spectrum of the 4-chloro-2-carbonylbutyric acid product in Example 1 of this invention;

[0027] Figure 2 The liquid phase spectrum of 4-chloro-2-carbonylbutyric acid standard;

[0028] Figure 3 This is a gas chromatogram of the ethyl 4-chloro-2-carbonylbutyrate product in Example 1 of the present invention. Detailed Implementation

[0029] 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.

[0030] This invention provides a method for synthesizing a 4-halo-2-carbonylbutyrate intermediate, comprising the following steps:

[0031] a) A mixture of cyanide, a phase transfer catalyst and 3-halopropionyl halide is carried out to undergo a substitution reaction, and the mixture is filtered to obtain a crude 3-halopropionyl cyanide solution; the phase transfer catalyst is selected from one or more of polyethylene glycol, crown ether compounds, polyfatty alcohol castor oil, quaternary ammonium salts and quaternary phosphine salts.

[0032] b) Mix the crude 3-halopropionyl cyanide solution obtained in step a) with an acidic aqueous solution, carry out a hydrolysis reaction, and purify to obtain crude 4-halo-2-carbonylbutyric acid solution;

[0033] c) The crude 4-halo-2-carbonylbutyric acid solution obtained in step b) is mixed with an alcohol and subjected to esterification reaction, followed by purification treatment to obtain the 4-halo-2-carbonylbutyrate intermediate.

[0034] This invention provides a method for synthesizing a 4-halo-2-carbonylbutyrate intermediate, using 3-halopropionyl halide (Formula I) and cyanide (Formula II) as raw materials, to obtain 3-halopropionyl cyanide (Formula III) through reaction, and then hydrolyzing the cyano group under acidic conditions to generate 4-halo-2-carbonylbutyric acid (Formula IV), which is then further esterified with an alcohol (Formula V) to generate the final product 4-halo-2-carbonylbutyrate (Formula VI).

[0035] The innovation of this invention lies in the construction of a carbon chain skeleton through the carbon-enrichment reaction of 3-halopropionyl cyanide with sodium cyanide. The halogen atom at the top of the carbon chain can be further bridged to compounds such as alkyl phosphonates, thereby efficiently and conveniently preparing 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, an important intermediate of glufosinate. The substitution reaction is carried out in a solvent-free manner, and the reaction is fully realized through a specific phase transfer catalyst. The residual solid raw materials and the salt generated in the reaction can be directly filtered out, effectively reducing the solvent separation and recovery steps. After the 3-halopropionyl cyanide is hydrolyzed in acid to generate 4-halo-2-carbonylbutyric acid, excess water can be removed from the system and the remaining acid can be used to further catalyze the esterification reaction.

[0036] The synthetic method for the 4-halo-2-carbonylbutyrate intermediate provided by this invention has the following reaction formula:

[0037]

[0038] The present invention first mixes cyanide, phase transfer catalyst and 3-halopropionyl halide to carry out substitution reaction, and then filters to obtain crude 3-halopropionyl cyanide solution.

[0039] In this invention, the cyanide is preferably selected from one or more of cuprous cyanide, sodium cyanide, and hydrogen cyanide, more preferably cuprous cyanide; the phase transfer catalyst is selected from one or more of polyethylene glycol, crown ether compounds, polyfatty alcohol castor oil, quaternary ammonium salts, and quaternary phosphine salts, preferably polyethylene glycol, crown ether compounds, polyfatty alcohol castor oil, quaternary ammonium salts, or quaternary phosphine salts, more preferably polyethylene glycol or crown ether compounds; the 3-halopropionyl halide is preferably selected from one or more of 3-chloropropionyl chloride, 3-chloropropionyl bromide, 3-chloropropionyl iodide, 3-bromopropionyl chloride, 3-bromopropionyl bromide, 3-bromopropionyl iodide, 3-iodopropionyl chloride, 3-iodopropionyl bromide, and 3-iodopropionyl iodide, more preferably 3-chloropropionyl chloride or 3-chloropropionyl bromide. This invention does not impose any special restrictions on the source of the above-mentioned cyanide, phase transfer catalyst, and 3-halopropionyl halide; commercially available products well known to those skilled in the art can be used.

[0040] In this invention, the amount of phase transfer catalyst added is preferably 0.01% to 0.5% of the mass of 3-halopropionyl halide, more preferably 0.07% to 0.1%.

[0041] In this invention, the molar ratio of the cyanide to the 3-halopropionyl halide is preferably (0.9 to 2.0):1, more preferably (1 to 1.1):1.

[0042] In this invention, the process of mixing cyanide, phase transfer catalyst, and 3-halopropionyl halide is preferably specifically as follows:

[0043] Cyanide (solid) and a phase transfer catalyst were added to the reactor, followed by the gradual addition of 3-halopropionyl halide (liquid); the temperature was then increased and the reaction was stirred.

[0044] In this invention, the temperature of the substitution reaction is preferably -10℃ to 110℃, more preferably 50℃ to 70℃; the time of the substitution reaction is preferably 0.5h to 18h, more preferably 3h to 6h.

[0045] In this invention, the preferred filtration method is vacuum filtration, the purpose of which is to remove insoluble solids and obtain crude 3-halopropionyl cyanide solution.

[0046] After obtaining the crude 3-halopropionyl cyanide solution, the present invention mixes the obtained crude 3-halopropionyl cyanide solution with an acidic aqueous solution, performs a hydrolysis reaction, and after purification, obtains crude 4-halo-2-carbonylbutyric acid solution.

[0047] In this invention, the acidic aqueous solution 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 acidic aqueous solution; commercially available products well-known to those skilled in the art can be used.

[0048] In this invention, the molar ratio of acid to 3-halopropionyl cyanide in the acidic aqueous solution is preferably (1-10):1, more preferably (3-4):1.

[0049] In this invention, the temperature of the hydrolysis reaction is preferably 50℃~130℃, more preferably 90℃~110℃; the time of the hydrolysis reaction is preferably 1h~24h, more preferably 3h~10h.

[0050] In this invention, the purification process is preferably specifically as follows:

[0051] The product obtained from the hydrolysis reaction was dehydrated under reduced pressure to remove excess water, cooled to room temperature, and the insoluble salt solid was filtered off to obtain crude 4-halo-2-carbonylbutyric acid solution.

[0052] In this invention, the temperature at which excess water is removed by decompression is preferably 50°C to 150°C, more preferably 90°C to 100°C.

[0053] After obtaining the crude 4-halo-2-carbonylbutyric acid solution, the present invention mixes the obtained crude 4-halo-2-carbonylbutyric acid solution with an alcohol, performs an esterification reaction, and then purifies it to obtain a 4-halo-2-carbonylbutyrate intermediate.

[0054] In this invention, the alcohol is preferably selected from one or more of methanol, ethanol, isopropanol, and butanol, and more preferably ethanol. This invention does not impose any special restrictions on the source of the alcohol; commercially available products well known to those skilled in the art can be used.

[0055] In this invention, the molar ratio of the alcohol to 4-halo-2-carbonylbutyric acid is preferably (0.9-3):1, more preferably (1.1-1.5):1.

[0056] In this invention, the temperature of the esterification reaction is preferably 70℃~105℃, more preferably 75℃~90℃; the time of the esterification reaction is preferably 1h~24h, more preferably 4h~8h; the heating reflux reaction technique known to those skilled in the art can be used.

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

[0058] Add 10wt% to 30wt% sodium hydroxide aqueous solution to the product obtained by esterification reaction, neutralize to pH 4 to 6, continuously desolvent under reduced pressure to 50℃ to 120℃, then cool to room temperature and filter to remove insoluble solids to obtain ethyl 4-halo-2-carbonylbutyrate.

[0059] More preferably:

[0060] Add 20 wt% sodium hydroxide aqueous solution to the product obtained from the esterification reaction to neutralize to pH 5, continue desolvation under reduced pressure to 105℃~110℃, then cool to room temperature and filter to remove insoluble solids to obtain ethyl 4-halo-2-carbonylbutyrate.

[0061] This invention provides a method for synthesizing a 4-halo-2-carbonylbutyrate intermediate, comprising the following steps: a) mixing cyanide, a phase transfer catalyst, and 3-halopropionyl halide to perform a substitution reaction, and filtering to obtain a crude 3-halopropionyl cyanide solution; wherein the phase transfer catalyst is selected from one or more of polyethylene glycol, crown ether compounds, polyfatty alcohol castor oil, quaternary ammonium salts, and quaternary phosphine salts; b) mixing the crude 3-halopropionyl cyanide solution obtained in step a) with an acidic aqueous solution to perform a hydrolysis reaction, and purifying to obtain a crude 4-halo-2-carbonylbutyrate solution; c) mixing the crude 4-halo-2-carbonylbutyrate solution obtained in step b) with an alcohol to perform an esterification reaction, and then purifying to obtain the 4-halo-2-carbonylbutyrate intermediate. Compared with the prior art, the synthesis method provided by the present invention uses 3-halopropionyl halide and cyanide as raw materials to obtain 3-halopropionyl cyanide through reaction. Under acidic conditions, the cyano group is hydrolyzed to generate 4-halo-2-carbonylbutyric acid, which is then further esterified with an alcohol to generate the final product 4-halo-2-carbonylbutyrate. The synthesis method is simple, mild, easy to control, and has a high yield.

[0062] 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.

[0063] Example 1

[0064] (1) Add 50.3g of cuprous cyanide (0.55mol) powder and 0.07g of polyethylene glycol to a 500ml four-necked flask, then gradually add 66.85g of 95% 3-chloropropionyl chloride (0.5mol), and heat to 60℃ and continue the reaction for 6h; filter to remove insoluble solids from the system and obtain 55.1g of filtrate.

[0065] (2) Add 180g (1.5mol) of 30% hydrochloric acid to the above solution, stir and heat to 100℃ for 6 hours to fully hydrolyze the solution, then further reduce the pressure and heat to 95℃ to remove the acid water. Cool to room temperature and filter out the insoluble salt solids to obtain 67.74g of crude 4-chloro-2-carbonylbutyric acid solution, of which the purity of 4-chloro-2-carbonylbutyric acid is 87.5% and the yield is 86.84% (0.434mol). See the liquid phase spectrum for details. Figure 1 Additionally, the HPLC chromatogram of the 4-chloro-2-carbonylbutyric acid standard can be found here. Figure 2 .

[0066] (3) After the above solution cooled, 50.6 g (1.1 mol) of anhydrous ethanol was added, and the mixture was heated to 75 °C and refluxed for 6 h. After the reaction was complete, 75.0 g of 20% sodium hydroxide aqueous solution was slowly added until the pH reached 5.0. The solution was continuously removed under reduced pressure until 105 °C, then cooled to room temperature and filtered to remove insoluble solids, yielding 70.4 g of the final product. Gas chromatography analysis showed that the purity of ethyl 4-chloro-2-carbonylbutyrate was 93.4%, and the overall yield was 79.94% (0.400 mol). See the gas chromatogram for details. Figure 3 .

[0067] Example 2

[0068] (1) Add 50.3g of cuprous cyanide (0.55mol) powder and 0.07g of polyethylene glycol to a 500ml four-necked flask, then gradually add 90.26g of 95% 3-chloropropionyl bromide (0.5mol), and heat to 60℃ and continue the reaction for 6h; filter to remove insoluble solids from the system and obtain 56.1g of filtrate.

[0069] (2) Add 180g (1.5mol) of 30% hydrochloric acid to the above solution, stir and heat to 100℃ for 6h to fully hydrolyze the solution, then further reduce the pressure and heat to 95℃ to remove the acid water, cool to room temperature and filter out the insoluble salt solids to obtain 70.45g of crude 4-chloro-2-carbonylbutyric acid solution, of which the purity of 4-chloro-2-carbonylbutyric acid is 85.9% and the yield is 88.67% (0.443mol).

[0070] (3) After the above liquid has cooled, 50.6 g (1.1 mol) of anhydrous ethanol is added, the temperature is raised to 75 °C and stirred under reflux for 6 h. After the reaction is complete, 74.3 g of 20% sodium hydroxide aqueous solution is slowly added until the pH is 5.0. The solution is continuously desoluble under reduced pressure to 105 °C, then cooled to room temperature and filtered to remove insoluble solids, yielding 70.7 g of the final product. Gas phase analysis showed that the purity of ethyl 4-chloro-2-carbonylbutyrate was 93.6%, and the overall yield was 80.46% (0.402 mol).

[0071] Examples 3-9

[0072] The preparation method provided in Example 1 was used, with the difference being the change in the type and amount of phase transfer catalyst, the specific reaction conditions and experimental results, as shown in Table 1.

[0073] Reaction conditions and experimental results in Examples 3-9

[0074]

[0075] Example 10

[0076] (1) Add 27.0g sodium cyanide (0.55mol) powder and 0.07g polyethylene glycol to a 500ml four-necked flask, then gradually add 66.85g 95% 3-chloropropionyl chloride (0.5mol), and heat to 60℃ and continue the reaction for 6h; filter to remove insoluble solids from the system and obtain 54.3g of filtrate.

[0077] (2) Add 180g (1.5mol) of 30% hydrochloric acid to the above solution, stir and heat to 100℃ for 6h of complete hydrolysis reaction, then further reduce the pressure and heat to 95℃ to remove acid water, cool to room temperature and filter out insoluble salt solids to obtain 65.70g of crude 4-chloro-2-carbonylbutyric acid solution, of which the purity of 4-chloro-2-carbonylbutyric acid is 86.80% and the yield is 83.56% (0.418mol).

[0078] (3) After the above liquid has cooled, 50.6 g (1.1 mol) of anhydrous ethanol is added, the temperature is raised to 75 °C and stirred under reflux for 6 h. After the reaction is complete, 75.0 g of 20% sodium hydroxide aqueous solution is slowly added until the pH is 5.0. The solution is continuously desoluble under reduced pressure to 105 °C, then cooled to room temperature and filtered to remove insoluble solids, yielding 69.2 g of the final product. Gas phase analysis showed that the purity of ethyl 4-chloro-2-carbonylbutyrate was 91.2%, and the overall yield was 76.73% (0.384 mol).

[0079] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for synthesizing 4-halo-2-carbonylbutyrate, comprising the following steps: a) A mixture of cyanide, a phase transfer catalyst, and 3-halopropionyl halide is carried out to undergo a substitution reaction. After filtration, a crude 3-halopropionyl cyanide solution is obtained. The substitution reaction is carried out in a solvent-free manner. The phase transfer catalyst is selected from one or more of polyethylene glycol, crown ether compounds, polyfatty alcohol castor oil, quaternary ammonium salts, and quaternary phosphine salts. The amount of phase transfer catalyst added is 0.01% to 0.5% of the mass of 3-halopropionyl halide. The cyanide in step a) is selected from one or more of cuprous cyanide, sodium cyanide, and hydrogen cyanide. The 3-halopropionyl halide is selected from one or more of 3-chloropropionyl chloride, 3-chloropropionyl bromide, 3-chloropropionyl iodide, 3-bromopropionyl chloride, 3-bromopropionyl bromide, 3-bromopropionyl iodide, 3-iodopropionyl chloride, 3-iodopropionyl bromide, and 3-iodopropionyl iodide. The substitution reaction described in step a) is carried out at a temperature of 50℃~70℃ for a time of 0.5h~18h. b) The crude 3-halopropionyl cyanide solution obtained in step a) is mixed with an acidic aqueous solution and subjected to hydrolysis reaction. After purification, a crude 4-halo-2-carbonylbutyric acid solution is obtained. The acidic aqueous solution is selected from one or more of hydrochloric acid and sulfuric acid. c) The crude 4-halo-2-carbonylbutyric acid solution obtained in step b) is mixed with an alcohol and subjected to esterification reaction, followed by purification to obtain 4-halo-2-carbonylbutyrate ester; wherein the alcohol is selected from one or more of methanol, ethanol, isopropanol and butanol; The purification process is specifically as follows: Add 10wt%~30wt% sodium hydroxide aqueous solution to the product obtained from the esterification reaction, neutralize to pH 4~6, continuously desolvent under reduced pressure to 50℃~120℃, then cool to room temperature and filter to remove insoluble solids to obtain 4-halo-2-carbonylbutyrate.

2. The synthesis method according to claim 1, characterized in that, The molar ratio of cyanide and 3-halopropionyl halide in step a) is (0.9~2.0):

1.

3. The synthesis method according to claim 1, characterized in that, The molar ratio of acid to 3-halopropionyl cyanide in the acidic aqueous solution described in step b) is (1~10):

1.

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

5. The synthesis method according to claim 1, characterized in that, The molar ratio of the alcohol to 4-halo-2-carbonylbutyric acid in step c) is (0.9~3):

1.

6. The synthesis method according to claim 1, characterized in that, The esterification reaction in step c) is carried out at a temperature of 70℃~105℃ for 1h~24h.

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