Synthesis method of 3-oxo-1-cyclobutane carboxylic acid

Abstract

The invention discloses a synthetic method of 3-oxo-1-cyclobutane carboxylic acid, and belongs to the technical field of organic synthesis. The synthesis method comprises the following steps: S1, reacting chloroacetyl chloride with methyl acrylate in a solvent to generate 2, 2-dichloro-3-oxocyclobutane carboxylic acid methyl ester; s2, carrying out reductive dehalogenation on the 2-dichloro-3-oxocyclobutane carboxylic acid methyl ester, and converting the 2-dichloro-3-oxocyclobutane carboxylic acid methyl ester into 3-oxo-1-cyclobutane carboxylic acid methyl ester; and S3, carrying out a hydrolysis reaction on the 3-oxo-1-cyclobutane carboxylic acid methyl ester, so as to obtain the 3-oxo-1-cyclobutane carboxylic acid. The synthesis method of the 3-oxocyclobutane carboxylic acid is mild in reaction condition, high in yield and stable in product quality.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing 3-oxo-1-cyclobutane carboxylic acid. Background Technology

[0002] 3-Oxocyclobutane carboxylic acid and its derivatives represent a highly valuable, high-strength, rigid framework in modern medicinal chemistry. Its unique cyclobutanone structure effectively enhances molecular metabolic stability, adjusts the lipid-water partition coefficient, and endows the molecules with specific three-dimensional conformations, thereby enabling efficient binding to biological targets. This property makes it a key pharmacophore or structure-activity group, widely used in the synthesis of dozens of important active pharmaceutical ingredients. For example, in the molecular design of ACK1 antibodies, MDM2 antagonists, JAK inhibitors, CETP inhibitors, various kinase and PDE10 inhibitors, and thrombin inhibitors, the 3-oxocyclobutane structure is a core component for achieving their pharmacological activity. Therefore, this compound occupies a crucial strategic position in the development of cutting-edge autoimmune, chronic inflammation, and antitumor drugs.

[0003] In existing technologies, Stevens et al. reported the synthesis of 3-oxocyclobutane carboxylic acid from butadiene and acrylonitrile via a [2+2] cycloaddition reaction, followed by hydrolysis and oxidation. However, butadiene in this method is a gas, which is difficult to operate in industrial-scale production, posing safety risks and process control challenges. Tishkov et al. used 5-nitro-2-pentanone as a raw material, obtaining the target product through silylation, cyclization, and hydrolysis reactions, but this method involves expensive silanizing reagents, resulting in high raw material costs and poor economic efficiency. Furthermore, patent publication WO2012058187A1 discloses a method for synthesizing 3-methylenecyclobutylcarboxylate by reacting propadiene with acrylonitrile, followed by oxidation with ferric oxide and sodium periodate to prepare 3-oxocyclobutane carboxylic acid. However, propadiene is also a gas, making operation inconvenient, and sodium periodate is expensive, increasing production costs. The method reported by Paul et al. uses malonate and 1,3-dibromoacetone dimethyl condensate as raw materials to synthesize the target product through a [1+3] cyclization reaction and hydrolysis step. However, this method involves protection and deprotection processes and bromination reactions, which are lengthy, complex, and result in low yields.

[0004] In summary, existing synthetic methods generally suffer from problems such as harsh reaction conditions, high raw material costs, poor operational safety, cumbersome procedures, and low product yields, making it difficult to meet the needs of industrial production. Therefore, providing a method for synthesizing 3-oxocyclobutane carboxylic acid, which features simple operation, low cost, high yield, and suitability for industrial production, to solve the problems of harsh reaction conditions, low yields, and unsuitability for industrial production in existing technologies, has become a technical problem urgently needing to be solved by those skilled in the art. Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing 3-oxo-1-cyclobutane carboxylic acid, which is simple to operate, low in cost and high in yield, so as to solve the problem that the existing technology is difficult to industrialize.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: This invention discloses a method for synthesizing 3-oxo-1-cyclobutane carboxylic acid, which includes the following steps: S1. Chloroacetyl chloride reacts with methyl acrylate in a solvent to produce methyl 2,2-dichloro-3-oxocyclobutanecarboxylate; S2. 2,2-Dichloro-3-oxocyclobutane carboxylate is reduced and dehalogenated to methyl 3-oxo-1-cyclobutane carboxylate; S3. The hydrolysis of methyl 3-oxo-1-cyclobutanecarboxylate yields 3-oxo-1-cyclobutanecarboxylic acid.

[0007] In some embodiments of the present invention, the chloroacetyl chloride is dichloroacetyl chloride or trichloroacetyl chloride; Dichloroacetyl chloride reacts with methyl acrylate in a solvent under alkaline conditions to produce methyl 2,2-dichloro-3-oxocyclobutanecarboxylate. Alternatively, trichloroacetyl chloride reacts with methyl acrylate in a solvent in the presence of zinc reagent to produce methyl 2,2-dichloro-3-oxocyclobutanecarboxylate.

[0008] In some embodiments of the present invention, the base mentioned in step S1 is an organic base, preferably at least one of triethylamine, pyridine, diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), and 4-dimethylaminopyridine (DMAP); Preferably, the molar ratio of dichloroacetyl chloride, methyl acrylate, and organic base is 1–2:1:1.0–3.0.

[0009] In some embodiments of the present invention, the zinc reagent in step S1 is zinc powder, activated zinc powder, or a zinc-copper couple; Preferably, the molar ratio of trichloroacetyl chloride, methyl acrylate, zinc, and copper is 1–2:1:1.0–3.0:1.0–10.0.

[0010] In some embodiments of the present invention, the solvent used in step S1 is at least one selected from diethyl ether, n-hexane, toluene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, ethyl acetate, and methyl tert-butyl ether. Preferably, in step S1, the reaction temperature is -20 to 60°C and the reaction time is 10 to 15 hours.

[0011] In some embodiments of the present invention, in step S2, methyl 2,2-dichloro-3-oxocyclobutane carboxylate is dechlorinated in a solvent using zinc powder to obtain methyl 3-oxo-1-cyclobutane carboxylate.

[0012] In some embodiments of the present invention, the solvent used in step S2 is at least one of THF, ethanol, acetic acid, toluene, benzene, chlorobenzene, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and 1,4-dioxane; Preferably, the reaction temperature in step S2 is 20–120°C, and the reaction time is 10–30 h. Preferably, the molar ratio of methyl 2,2-dichloro-3-oxocyclobutane carboxylate to zinc powder is 1:2.0 to 4.0.

[0013] In some embodiments of the present invention, in step S3, methyl 3-oxo-1-cyclobutanecarboxylate undergoes a hydrolysis reaction under acidic or alkaline conditions; In some embodiments of the present invention, the acid is at least one selected from hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, and hydrobromic acid; The alkali is an inorganic alkali, preferably at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, and sodium carbonate.

[0014] In some embodiments of the present invention, in step S3, the molar ratio of methyl 3-oxo-1-cyclobutane carboxylate to acid or base is 1.0:1.5 to 3.0; Preferably, in step S3, the reaction temperature is 20–80°C and the reaction time is 4–10 h.

[0015] Compared with the prior art, the present invention has the following beneficial effects: The synthetic method for 3-oxocyclobutane carboxylic acid of the present invention features mild reaction conditions, high yield, and stable product quality. The synthetic route employed in this invention effectively overcomes the drawbacks of harsh reaction conditions in existing technologies, allowing for smooth operation under mild conditions. This not only significantly improves product yield but also ensures the stability and consistency of product quality.

[0016] The method of this invention has a simple process flow and easy operation steps, avoiding cumbersome purification and processing procedures, effectively reducing the uncertainty and safety risks introduced by complex operations, and is easy for production personnel to master and implement.

[0017] The method of this invention uses readily available and inexpensive raw materials: the raw materials required for synthesis are all common and easily obtainable chemicals in industry, with wide sources and low procurement costs, laying a solid material foundation for large-scale production and having a significant cost advantage.

[0018] The method of this invention has low equipment requirements, which is conducive to industrial scale-up. This method does not rely on special or expensive supporting equipment, and the requirements for production equipment are relatively simple, greatly reducing fixed asset investment and maintenance costs, and possessing excellent industrial scale-up potential and adaptability.

[0019] In summary, this invention successfully solves a series of key technical problems in the prior art, such as harsh reaction conditions, low yield, high cost, and difficulty in meeting the requirements of industrial production. It provides a simple, economical, efficient, environmentally friendly synthesis route suitable for large-scale industrial production, and has outstanding industrial application value and market prospects. Detailed Implementation

[0020] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0021] This invention discloses a method for synthesizing 3-oxo-1-cyclobutane carboxylic acid. First, dichloroacetyl chloride is reacted in situ with an organic base in a solvent to generate dichloroenone, or trichloroacetyl chloride is reacted with zinc-copper catalysis, to generate the intermediate methyl 2,2-dichloro-3-oxocyclobutane carboxylic acid. Then, methyl 2,2-dichloro-3-oxocyclobutane carboxylic acid is dechlorinated under the reducing action of zinc powder to obtain methyl 3-oxo-1-cyclobutane carboxylic acid. Finally, methyl 3-oxo-1-cyclobutane carboxylic acid is hydrolyzed to obtain 3-oxo-1-cyclobutane carboxylic acid. The synthetic route is as follows:

[0022] Specifically, the method for synthesizing 3-oxo-1-cyclobutane carboxylic acid of the present invention includes the following steps: S1. Dichloroacetyl chloride reacts with methyl acrylate in a solvent under alkaline conditions to produce methyl 2,2-dichloro-3-oxocyclobutanecarboxylate; Alternatively, trichloroacetyl chloride reacts with methyl acrylate in a solvent in the presence of zinc reagent to produce methyl 2,2-dichloro-3-oxocyclobutanecarboxylate.

[0023] The base mentioned in step S1 is an organic base, preferably at least one of triethylamine, pyridine, diisopropylethylamine, DABCO, and DMAP; The molar ratio of dichloroacetyl chloride, methyl acrylate, and organic base is 1–2:1:1.0–3.0.

[0024] The zinc reagent mentioned in step S1 is zinc powder, activated zinc powder, or a zinc-copper coupler; The molar ratio of trichloroacetyl chloride, methyl acrylate, zinc, and copper is 1–2:1:1.0–3.0:1.0–10.0.

[0025] The solvent used in step S1 is at least one of diethyl ether, n-hexane, toluene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, ethyl acetate, and methyl tert-butyl ether; The reaction temperature in step S1 is -20 to 60°C, and the reaction time is 10 to 15 hours.

[0026] S2. 2,2-Dichloro-3-oxocyclobutane carboxylate methyl ester was reacted in a solvent with zinc powder for reduction and dechlorination to obtain 3-oxo-1-cyclobutane carboxylate methyl ester.

[0027] The solvent used in step S2 is at least one of THF, ethanol, acetic acid, toluene, benzene, chlorobenzene, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and 1,4-dioxane; The reaction temperature in step S2 is 20–120°C, and the reaction time is 10–30 h. The molar ratio of methyl 2,2-dichloro-3-oxocyclobutane carboxylate to zinc powder is 1:2.0 to 4.0.

[0028] S3. The hydrolysis of methyl 3-oxo-1-cyclobutanecarboxylate yields 3-oxo-1-cyclobutanecarboxylic acid; In step S3, methyl 3-oxo-1-cyclobutanecarboxylate undergoes a hydrolysis reaction under acidic or alkaline conditions; The acid is at least one of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, and hydrobromic acid; The alkali is an inorganic alkali, preferably at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, and sodium carbonate.

[0029] The molar ratio of methyl 3-oxo-1-cyclobutane carboxylate to acid or base is 1.0:1.5 to 3.0; In step S3, the reaction temperature is 20–80°C and the reaction time is 4–10 h.

[0030] Example 1 This embodiment discloses the method for synthesizing 3-oxo-1-cyclobutane carboxylic acid of the present invention, as detailed below: Step 1: Preparation of methyl 2,2-dichloro-3-oxocyclobutanecarboxylate In a 500 mL three-necked flask, dichloroacetyl chloride (17.7 g, 0.12 mol), methyl acrylate (9.47 g, 0.11 mol), and n-hexane (150 mL) were added, and the mixture was stirred and cooled to 0 °C. Triethylamine (18.2 g, 0.18 mol) was slowly added dropwise. After the addition was complete, the temperature was raised to 40 °C, and the reaction was stirred for 20 h. After the reaction was complete, the triethylamine hydrochloride was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure to give 20.4 g of methyl 2,2-dichloro-3-oxocyclobutane carboxylate, a pale yellow oily liquid, with a yield of 94% (GC purity 98.5%).

[0031] Step 2: Preparation of methyl 3-oxo-1-cyclobutanecarboxylate In a 250 mL three-necked flask, methyl 2,2-dichloro-3-oxocyclobutane carboxylate (17.73 g, 0.09 mol), zinc powder (11.8 g, 0.18 mol), and ethanol (100 mL) prepared in step 1 were added. The mixture was heated to 60 °C and stirred for 15 h. After the reaction was completed, excess zinc powder was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain 10.15 g of light brown oily liquid methyl 3-oxo-1-cyclobutane carboxylate, with a yield of 88% (GC purity 97.8%).

[0032] Step 3: Preparation of 3-oxo-1-cyclobutanecarboxylic acid In a 150 mL three-necked flask, methyl 3-oxo-1-cyclobutanecarboxylate (9.0 g, 0.07 mol) obtained in step 2 and 18% hydrochloric acid (40 mL, 0.24 mol) were added, and the mixture was heated to 80 °C and stirred for 8 h. After standing and separating into layers, the organic phase was concentrated to dryness under reduced pressure, and ethyl acetate (50 mL) was added and stirred. The mixture was filtered and dried under vacuum to obtain 6.88 g of white solid 3-oxo-1-cyclobutanecarboxylic acid, with a yield of 86% (GC purity 99.2%).

[0033] The overall yield of this embodiment is: 94% × 88% × 86% = 71.1%.

[0034] Example 2 This embodiment discloses the method for synthesizing 3-oxo-1-cyclobutane carboxylic acid of the present invention, as detailed below: Step 1: Preparation of methyl 2,2-dichloro-3-oxocyclobutanecarboxylate In a 1L three-necked flask, dichloroacetyl chloride (44.2 g, 0.30 mol), methyl acrylate (24.1 g, 0.28 mol), and diethyl ether (300 mL) were added, and the mixture was stirred and heated to 40°C. Triethylamine (54.6 g, 0.54 mol) was added dropwise, and the mixture was refluxed for 15 h after the addition was complete. The mixture was filtered to remove salt, and the filtrate was concentrated to give 51.3 g of methyl 2,2-dichloro-3-oxocyclobutanecarboxylate, with a yield of 93% (HPLC purity 98.2%).

[0035] Step 2: Preparation of methyl 3-oxo-1-cyclobutanecarboxylate In a 500 mL three-necked flask, methyl 2,2-dichloro-3-oxocyclobutane carboxylate (43.4 g, 0.22 mol), zinc powder (36.0 g, 0.55 mol), and acetic acid (200 mL) prepared in step 1 were added, and the mixture was heated to 80 °C and reacted for 12 h. The mixture was filtered, and the filtrate was concentrated to give 24.5 g of methyl 3-oxo-1-cyclobutane carboxylate, with a yield of 87% (HPLC purity 98.0%).

[0036] Step 3: Preparation of 3-oxo-1-cyclobutanecarboxylic acid In a 150 mL three-necked flask, methyl 3-oxo-1-cyclobutane carboxylate (21.8 g, 0.17 mol) prepared in step 2 and 50% sulfuric acid (50 mL, 0.26 mol) were added, and the mixture was heated to 80 °C and reacted for 6 h. After separation, the organic phase was concentrated, slurried with n-hexane (100 mL), and dried to give 17.5 g of white solid, yield 90% (HPLC purity 99.5%).

[0037] The overall yield in this embodiment is: 93% × 87% × 90% = 72.5% Example 3 This embodiment discloses the method for synthesizing 3-oxo-1-cyclobutane carboxylic acid of the present invention, as detailed below: Step 1: Preparation of methyl 2,2-dichloro-3-oxocyclobutanecarboxylate In a 250 mL three-necked flask, dichloroacetyl chloride (13.3 g, 0.09 mol), methyl acrylate (7.3 g, 0.085 mol), and tetrahydrofuran (100 mL) were added, and the mixture was cooled to -10 °C. Triethylamine (13.6 g, 0.135 mol) was added dropwise, and after the addition was complete, the temperature was slowly raised to 20 °C and the reaction was carried out for 25 h. The mixture was filtered to remove salt, and the filtrate was concentrated to give 15.2 g of methyl 2,2-dichloro-3-oxocyclobutane carboxylate, with a yield of 91% (GC purity 98.0%).

[0038] Step 2: Preparation of methyl 3-oxo-1-cyclobutanecarboxylate In a 250 mL three-necked flask, methyl 2,2-dichloro-3-oxocyclobutane carboxylate (13.2 g, 0.067 mol), zinc powder (10.6 g, 0.16 mol), and tetrahydrofuran (120 mL) were added, and the mixture was stirred at room temperature (25 °C) for 24 h. The mixture was filtered, and the filtrate was concentrated to give 7.1 g of methyl 3-oxo-1-cyclobutane carboxylate, with a yield of 83% (HPLC purity 97.5%).

[0039] Step 3: Preparation of 3-oxo-1-cyclobutanecarboxylic acid In a 150 mL three-necked flask, methyl 3-oxo-1-cyclobutane carboxylate (7.0 g, 0.055 mol) prepared in step 2 and 50% phosphoric acid (30 mL, 0.22 mol) were added, and the mixture was heated to 70 °C and reacted for 10 h. After separation, the organic phase was concentrated, slurried with ethanol (30 mL), and dried to give 5.4 g of white solid, yield 86% (HPLC purity 99.1%).

[0040] The overall yield in this embodiment is 91% × 83% × 86% = 65.8%.

[0041] Example 4 This embodiment discloses the method for synthesizing 3-oxo-1-cyclobutane carboxylic acid of the present invention, as detailed below: Step 1: Preparation of methyl 2,2-dichloro-3-oxocyclobutanecarboxylate Activated zinc powder (13.1 g, 0.2 mol, containing a small amount of copper) was added to a 500 mL three-necked flask, followed by anhydrous THF (200 mL). The mixture was heated to 50 °C for 30 min with stirring. The temperature was then lowered to 30 °C, and trichloroacetyl chloride (36.3 g, 0.2 mol) was slowly added dropwise. After the addition was complete, the mixture was kept warm and stirred for 1 h. Methyl acrylate (17.2 g, 0.2 mol) was then added dropwise, with the temperature controlled at 20-30 °C during the addition process. After the addition was complete, the mixture was heated to 80 °C and refluxed for 20 h. After the reaction was complete, the mixture was cooled to room temperature, and unreacted zinc and copper powder was removed by filtration. The filtrate was concentrated under reduced pressure (40 °C, -0.09 MPa) using a rotary evaporator until no fraction remained, yielding 36.3 g of a pale yellow oily liquid, methyl 2,2-dichloro-3-oxocyclobutanecarboxylate, with an HPLC purity of 98.2% and a yield of 92.3%. Step 2: Preparation of methyl 3-oxo-1-cyclobutanecarboxylate To a 250 mL three-necked flask, add methyl 2,2-dichloro-3-oxocyclobutane carboxylate (19.7 g, 0.1 mol) and zinc powder (13.1 g, 0.2 mol) obtained in step 1, along with 100 mL of ethanol. The mixture was stirred and heated to 60 °C for 15 h. After the reaction was complete, excess zinc powder was removed by filtration. The filtrate was concentrated under reduced pressure (45 °C, -0.09 MPa) to dryness, yielding 11.5 g of a light brown oily liquid, methyl 3-oxo-1-cyclobutane carboxylate, with an HPLC purity of 97.5% and a yield of 89.8%. Step 3: Preparation of 3-oxo-1-cyclobutanecarboxylic acid 11.3 g (0.088 mol) of methyl 3-oxo-1-cyclobutane carboxylate obtained in step 2 was added to a 250 mL three-necked flask, followed by 20 mL (0.15 mol) of 30% sodium hydroxide solution. The mixture was stirred and heated to 90 °C for 8 h. After the reaction was complete, the mixture was cooled to room temperature, the pH was adjusted to 2-3 with hydrochloric acid, and ethyl acetate (50 mL × 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate for 2 h, filtered, and concentrated under reduced pressure (40 °C, -0.09 MPa) to dryness. Hexane (30 mL) was added and stirred for 1 h, filtered, and dried under vacuum (50 °C, -0.09 MPa) for 4 h to obtain 9.05 g of white solid 3-oxo-1-cyclobutane carboxylic acid with an HPLC purity of 99.3% and a yield of 90.1%. The overall yield of this embodiment is 92.3% × 97.5% × 90.1% = 81.1%.

[0042] Example 5 This embodiment uses dichloroacetyl chloride as a raw material and systematically investigates the effects of molar ratio, solvent type, reaction time, and reaction temperature on the overall product yield. The synthesis steps are the same as in Example 1, only the reaction conditions are adjusted. Specific results are shown in Table 1. The results indicate that using the method of this invention, the overall yield of 3-oxo-1-cyclobutanecarboxylic acid is 55-82%.

[0043] Table 1 shows the effect of reaction conditions on the overall product yield using dichloroacetyl chloride as a starting material.

[0044] Example 6 This example uses trichloroacetyl chloride as a raw material and systematically investigates the effects of molar ratio, solvent type, reaction time, and reaction temperature on the overall product yield. The synthesis steps are the same as in Example 4, with only the reaction conditions adjusted. Specific results are shown in Table 2. The results indicate that using the method of this invention, the overall yield of 3-oxo-1-cyclobutanecarboxylic acid is 50-83%.

[0045] Table 2 shows the effect of reaction conditions on the overall product yield using trichloroacetyl chloride as a starting material.

[0046] The above description is merely a preferred embodiment of the invention and does not constitute any limitation on the invention. Any simple modifications, equivalent substitutions, and improvements made to the above embodiments based on the technical essence of the invention and within the spirit and principles of the invention shall still fall within the protection scope of the invention's technical solution.

Claims

1. A method for synthesizing 3-oxo-1-cyclobutane carboxylic acid, characterized in that, Includes the following steps: S1. Chloroacetyl chloride reacts with methyl acrylate in a solvent to produce methyl 2,2-dichloro-3-oxocyclobutanecarboxylate; S2. 2,2-Dichloro-3-oxocyclobutane carboxylate is reduced and dehalogenated to methyl 3-oxo-1-cyclobutane carboxylate; S3. The hydrolysis of methyl 3-oxo-1-cyclobutanecarboxylate yields 3-oxo-1-cyclobutanecarboxylic acid.

2. The synthesis method according to claim 1, characterized in that, The chloroacetyl chloride is dichloroacetyl chloride or trichloroacetyl chloride; Dichloroacetyl chloride reacts with methyl acrylate in a solvent under alkaline conditions to produce methyl 2,2-dichloro-3-oxocyclobutanecarboxylate. Alternatively, trichloroacetyl chloride reacts with methyl acrylate in a solvent in the presence of zinc reagent to produce methyl 2,2-dichloro-3-oxocyclobutanecarboxylate.

3. The synthesis method according to claim 2, characterized in that, The base mentioned in step S1 is an organic base, preferably at least one of triethylamine, pyridine, diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, and 4-dimethylaminopyridine; Preferably, the molar ratio of dichloroacetyl chloride, methyl acrylate, and organic base is 1–2:1:1.0–3.

0.

4. The synthesis method according to claim 2, characterized in that, The zinc reagent mentioned in step S1 is zinc powder, activated zinc powder, or a zinc-copper coupler; Preferably, the molar ratio of trichloroacetyl chloride, methyl acrylate, zinc, and copper is 1–2:1:1.0–3.0:1.0–10.

0.

5. The synthesis method according to any one of claims 1 to 4, characterized in that, The solvent used in step S1 is at least one of diethyl ether, n-hexane, toluene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, ethyl acetate, and methyl tert-butyl ether; Preferably, in step S1, the reaction temperature is -20 to 60°C and the reaction time is 10 to 15 hours.

6. The synthesis method according to claim 1, characterized in that, In step S2, methyl 2,2-dichloro-3-oxocyclobutane carboxylate is dechlorinated in a solvent using zinc powder to obtain methyl 3-oxo-1-cyclobutane carboxylate.

7. The synthesis method according to claim 6, characterized in that, The solvent used in step S2 is at least one of THF, ethanol, acetic acid, toluene, benzene, chlorobenzene, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and 1,4-dioxane; Preferably, the reaction temperature in step S2 is 20–120°C, and the reaction time is 10–30 h. Preferably, the molar ratio of methyl 2,2-dichloro-3-oxocyclobutane carboxylate to zinc powder is 1:2.0 to 4.

0.

8. The synthesis method according to claim 1, characterized in that, In step S3, methyl 3-oxo-1-cyclobutanecarboxylate undergoes hydrolysis under acidic or alkaline conditions.

9. The synthesis method according to claim 8, characterized in that, The acid is at least one of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, and hydrobromic acid; The alkali is an inorganic alkali, preferably at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, and sodium carbonate.

10. The synthesis method according to claim 8, characterized in that, In step S3, the molar ratio of methyl 3-oxo-1-cyclobutane carboxylate to acid or base is 1.0:1.5-3.0; Preferably, in step S3, the reaction temperature is 20–80°C and the reaction time is 4–10 h.

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