A method for synthesizing a calone anhydride

Abstract

The application discloses a synthetic method of calone anhydride, and at least comprises the following steps: S1, methyl 3-tiglate is epoxidized to obtain methyl 3-methyl-3-(oxirane-2-yl)butanoate; S2, methyl 3-methyl-3-(oxirane-2-yl)butanoate is ring-opened to obtain 4-A-5-hydroxy-2,2-dimethyl-carboxylic acid methyl ester; S3, 4-A-5-hydroxy-2,2-dimethyl-carboxylic acid methyl ester is cyclized to obtain 3-(hydroxymethyl)-2,2-dimethylcyclopropane-1-carboxylic acid methyl ester; wherein A is one of chlorine, bromine and iodine; S4, 3-(hydroxymethyl)-2,2-dimethylcyclopropane-1-carboxylic acid methyl ester is oxidized to obtain 3-(methoxycarbonyl)-2,2-dimethylcyclopropane-1-carboxylic acid; S5, 3-(methoxycarbonyl)-2,2-dimethylcyclopropane-1-carboxylic acid is hydrolyzed to obtain 3,3-dimethylcyclopropane-1,2-dicarboxylic acid; and S6, 3,3-dimethylcyclopropane-1,2-dicarboxylic acid is cyclized to obtain calone anhydride. The synthetic route of the application avoids the use of dangerous materials such as ozone and potassium permanganate and environment-unfriendly reagents, and is more suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of chemical synthesis, more particularly, it relates to a synthesis method of carlonic anhydride. BACKGROUND

[0002] Carlonic anhydride is an important pharmaceutical intermediate, which can be used for the synthesis of oral hepatitis C protease inhibitor boceprevir and anti-coronavirus drug nirmatrelvir.

[0003] The common synthesis route for preparing carlonic anhydride is as follows:

[0004]

[0005] The starting material of this synthesis route is a chrysanthemum ester compound, which is relatively expensive. The oxidation reagent used in the first step is potassium permanganate, ozone and other oxidation reagents, which has heavy environmental pollution and high operation risk, and is not suitable for industrial production.

[0006] The Chinese patent document with publication number CN 102070575 A discloses a new synthesis method of carlonic anhydride, and the synthesis route is as follows:

[0007]

[0008] The first step of this route uses a sulfur reagent, which is relatively expensive. The byproduct dimethyl sulfide has a heavy odor and high toxicity, which is not suitable for industrial production.

[0009] The Chinese patent document with publication number CN 102952011 B discloses a synthesis method of calefarnic acid lactone and carlonic anhydride, and the synthesis route is as follows:

[0010]

[0011] The first step of this route uses a diazonium compound, which is relatively expensive and explosive, and has high risk in mass production, which is not suitable for industrial production.

[0012] The Chinese patent document with publication number CN 104151279 A discloses a synthesis method of carlonic anhydride, and the synthesis route is as follows:

[0013]

[0014] The reagent used for the oxidation ring-opening of the raw material cyclohexene in this route is potassium permanganate or ozone reagent, which is dangerous to operate and is not suitable for industrial production.

[0015] Therefore, it is of great significance to develop a method suitable for industrial production of carlonic anhydride. SUMMARY

[0016] In view of the deficiencies of the prior art, the present application aims to provide a synthetic method of calone anhydride, which has the advantage of being suitable for industrial production.

[0017] To achieve the above technical purpose, the present application provides the following technical scheme:

[0018] A synthetic method of calone anhydride, characterized in that it comprises at least the following steps:

[0019]

[0020] wherein A is one of chlorine, bromine and iodine;

[0021] S1: epoxidizing methyl chrysophanic acid to obtain methyl 3-methyl-3-(oxirane-2-yl)butanoate (KL-1);

[0022] S2: ring-opening methyl 3-methyl-3-(oxirane-2-yl)butanoate to obtain 4-A-5-hydroxy-2,2-dimethyl-carboxylic acid methyl ester (KL-2);

[0023] S3: cyclizing 4-A-5-hydroxy-2,2-dimethyl-carboxylic acid methyl ester to obtain 3-(hydroxymethyl)-2,2-dimethylcyclopropane-1-carboxylic acid methyl ester (KL-3);

[0024] S4: oxidizing 3-(hydroxymethyl)-2,2-dimethylcyclopropane-1-carboxylic acid methyl ester to obtain 3-(methoxycarbonyl)-2,2-dimethylcyclopropane-1-carboxylic acid (KL-4);

[0025] S5: hydrolyzing 3-(methoxycarbonyl)-2,2-dimethylcyclopropane-1-carboxylic acid to obtain 3,3-dimethylcyclopropane-1,2-dicarboxylic acid (KL-5);

[0026] S6: cyclizing 3,3-dimethylcyclopropane-1,2-dicarboxylic acid to obtain calone anhydride.

[0027] Further preferably, in step S1, the oxidizing agent in the epoxidation process is one or a mixture of several of m-chloroperbenzoic acid, sodium hypochlorite and peroxoacetic acid; the solvent in the epoxidation process is one or a mixture of several of dichloromethane, dichloroethane, water and N-methylpyrrolidone; and the reaction temperature of the epoxidation is -5-20℃.

[0028] Further preferably, the oxidizing agent is preferably sodium hypochlorite, the solvent is preferably N-methylpyrrolidone, and the reaction temperature is preferably -5-0℃.

[0029] Further preferably, the specific operation steps of step S1 are as follows: drop sodium hypochlorite into NMP, control the temperature at-5-0℃, after dropping, stir for 1-2h, then drop methyl benzoate, control the temperature at-5-0℃, react for 2-5h, after the reaction is completed, add saturated sodium bisulfite solution and water to quench sodium hypochlorite, stand to separate layers, wash the organic layer with saturated brine, after separation, the organic layer is KL-1.

[0030] Further preferably, in step S2, the ring-opening reagent in the ring-opening process is one or a mixture of several of hydrochloric acid, hydrobromic acid and hydroiodic acid; the solvent in the ring-opening process is one or a mixture of several of dichloromethane, dichloroethane, water and N-methyl pyrrolidone; the reaction temperature of the ring-opening is 10-50℃.

[0031] Further preferably, the ring-opening reagent is preferably hydrochloric acid, the solvent is preferably water, and the reaction temperature is preferably 30-50℃.

[0032] Further preferably, the specific operation steps of step S2 are as follows: at room temperature, drop hydrochloric acid into the reaction liquid obtained in step S1, after dropping, warm up to 30-50℃, react for 3-5h, after the reaction is completed, add appropriate amount of water to the reaction liquid, then extract the product with ethyl acetate, stand to separate layers, then wash the organic layer with saturated brine, then concentrate to obtain KL-2.

[0033] Further preferably, in step S3, the cyclization agent in the cyclization process is one or a mixture of several of sodium tert-butoxide, potassium tert-butoxide and sodium tert-amylate; the solvent in the cyclization process is one or a mixture of several of tert-butanol, N,N-dimethylformamide, tetrahydrofuran and acetonitrile; the reaction temperature of the cyclization is-10-30℃.

[0034] Further preferably, the cyclization agent is preferably sodium tert-butoxide, the solvent is preferably tert-butanol, and the reaction temperature is preferably 25-30℃.

[0035] Further preferably, the specific operation steps of step S3 are as follows: add sodium tert-butoxide into tert-butanol, then slowly drop KL-2, after dropping, adjust the temperature to 25-30℃, react for 1-2h, after the reaction is completed, concentrate the tert-butanol under reduced pressure, add water, stand to separate layers, and the organic layer is KL-3.

[0036] Further preferably, in step S4, the oxidizing agent in the oxidation process is one or a mixture of two of sodium hypochlorite, a mixture of 2,2,6,6-tetramethylpiperidine-1-oxyl radical and potassium chloride, or Fe(NO3)3; the solvent in the oxidation process is one or a mixture of several of dichloromethane, dichloroethane, water and N-methyl pyrrolidone; the reaction temperature of the oxidation is-5-20℃.

[0037] Further preferably, the oxidizing agent is preferably a mixture of sodium hypochlorite, 2,2,6,6-tetramethylpiperidine-1-oxyl radical, the solvent is preferably N-methylpyrrolidone, and the reaction temperature is preferably 0-10°C.

[0038] Further preferably, the specific operation steps of step S4 are as follows: 2,2,6,6-tetramethylpiperidine-1-oxyl radical is added in N-methylpyrrolidone, sodium hypochlorite is dropped, the temperature is controlled at 0-10°C, after dropping, stirring is conducted for 1-2 hours, then KL-3 is dropped, the temperature is controlled at 0-10°C, and reaction is conducted for 2-5 hours; after the reaction is completed, a saturated sodium bisulfite solution is added to quench the sodium hypochlorite, and a solution of KL-4 is obtained.

[0039] Further preferably, in step S5, the reagent in the hydrolysis process is one or a mixture of several of sodium hydroxide, potassium hydroxide, and lithium hydroxide; the solvent in the hydrolysis process is one or a mixture of several of tetrahydrofuran, water, methanol, and ethanol; and the reaction temperature of the hydrolysis is -5-20°C.

[0040] Further preferably, the hydrolysis reagent is preferably sodium hydroxide, and the reaction temperature is preferably -5-5°C.

[0041] Further preferably, the specific operation steps of step S5 are as follows: sodium hydroxide solution is dropped into the solution of KL-4, the temperature is controlled at -5-5°C, after dropping, stirring is conducted for 1-2 hours, the pH value of the solution is adjusted to 0-1 by using 10% hydrochloric acid, then ethyl acetate is added for extraction, saturated brine is used for washing, and then KL-5 is obtained by concentrating to remove solvent.

[0042] Further preferably, in step S6, the reagent in the cyclization process is one or a mixture of several of acetic anhydride, triphosgene, phosphorus pentoxide, and p-toluenesulfonic acid; the solvent in the cyclization process is one or a mixture of several of toluene, tetrahydrofuran, and 1,4-dioxane; and the reaction temperature of the cyclization is 7-100°C.

[0043] Further preferably, the cyclization reagent is preferably acetic anhydride, the solvent is preferably toluene, and the reaction temperature is preferably 100-110°C.

[0044] Further preferably, the specific operation steps of step S6 are as follows: toluene is added in KL-5, acetic anhydride is dropped, after dropping, the temperature is increased to 100-110°C, and reaction is conducted for 2-5 hours; toluene and acetic acid are recovered by reduced pressure distillation; and finally, carbenicillin anhydride is obtained by reduced pressure distillation.

[0045] In summary, the present application has the following beneficial effects: 1. The synthetic route of the present application is simple, the synthetic raw materials are low in price, and the operation of dangerous materials such as ozone and potassium permanganate is avoided, which is more suitable for industrial production, thereby reducing the pollution to the environment and the operation danger, and being more suitable for industrial production.

[0046] 2、The reaction of each step of the synthetic route of the present application is controllable, and all are common reaction unit operations, and the reaction raw materials, equipment and operation mode are more suitable for industrial production.

[0047] 3、The raw materials used in the present application are low in price, simple in acquisition route, stable in market supply, and green and environmentally friendly. DETAILED DESCRIPTION

[0048] The present application will be further described in conjunction with the following examples. Those skilled in the art can easily understand other advantages and effects of the present application from the disclosure of the present specification. The present application can also be implemented or applied by different specific embodiments, and various modifications or changes can be made to the details in the specification based on different views and applications without departing from the spirit of the present application.

[0049] Before further describing the specific embodiments of the present application, it should be understood that the scope of protection of the present application is not limited to the following specific embodiments; it should also be understood that the terms used in the embodiments of the present application are for the purpose of describing the specific embodiments, and are not intended to limit the scope of protection of the present application.

[0050] When the embodiments give numerical ranges, it should be understood that, unless otherwise specified by the present application, both endpoints of each numerical range and any number between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by those skilled in the art to which the present application belongs.

[0051] It is worth noting that the raw materials used in the present application are all ordinary commercially available products, and therefore their sources are not specifically limited. Preparation Example 1:

[0052] The preparation steps of 3-methyl-3-(oxetane-2-yl) butyric acid methyl ester (KL-1) are as follows: 300 mL of N-methyl pyrrolidone is added to a reactor, cooled to -5-0 ℃, and 700 g of sodium hypochlorite solution is added dropwise under the temperature condition of -5-0 ℃, and reacted for 2 h. After the reaction is completed, 142 g of methyl benzoate (KL-0) is added dropwise to the reaction solution, and the temperature is controlled at -5-0 ℃, and the reaction is kept for 2 h. Then 300 g of saturated sodium sulfite solution and 300 g of water are added, stirred for 1 h, and allowed to stand to separate the layers. The organic layer is washed once with 30 g of saturated brine, allowed to stand to separate the layers, and a light yellow liquid 150 g is obtained, with a yield of 94.94%.

[0053] Preparation Example 2:

[0054] 4-A-5-Hydroxy-2,2-dimethyl-carboxylic acid methyl ester (KL-2) was prepared as follows: 130 g of KL-1 and 200 g of water were added to a reactor and cooled to 0-5°C, and then 100 g of hydrochloric acid was added dropwise to the reaction solution. After the dropwise addition was completed, the temperature was raised to 35-40°C and the reaction was performed for 2 hours. After the reaction was completed, 200 mL of ethyl acetate was added to the reaction product, and the layers were separated by standing. The organic layer was washed with 50 mL of saturated brine, and concentrated under reduced pressure to obtain 152 g of a yellow liquid, with a yield of 95.24%.

[0055] Preparation Example 3:

[0056] 3-(Hydroxymethyl)-2,2-dimethylcyclopropane-1-carboxylic acid methyl ester (KL-3) was prepared as follows: 300 g of t-butyl alcohol and 95 g of sodium t-butoxide were added to a reactor and cooled to 5-10°C, and then 90 g of KL-2 was added dropwise to the mixture. After the dropwise addition was completed, the temperature was raised to 25-30°C and the reaction was performed for 2 hours. Then, the reaction product was concentrated to dryness, 10% hydrochloric acid was added to the reaction product, the pH was adjusted to 0-1, 50 mL of water was added, and stirring was performed for 30 minutes. The layers were separated by standing, and 68 g of a yellow liquid was obtained as the lower layer. The yield was 92.78%.

[0057] Preparation Example 4:

[0058] 3-(Methoxycarbonyl)-2,2-dimethylcyclopropane-1-carboxylic acid (KL-4) was prepared as follows: 200 g of N-methylpyrrolidone and 10 g of 2,2,6,6-tetramethylpiperidine-1-oxyl were added to a reactor and cooled to -5-0°C, and then 100 g of sodium hypochlorite was added dropwise to the mixture. After the dropwise addition was completed, the temperature was adjusted to -5-0°C, and the solution was maintained for 1-2 hours. Then, 60 g of KL-3 was added dropwise, the temperature was controlled to 0-5°C, and the reaction was performed for 2-5 hours. 50 g of a saturated sodium bisulfite solution was added to quench the sodium hypochlorite, and a solution of KL-4 was obtained.

[0059] Preparation Example 5:

[0060] 3,3-Dimethylcyclopropane-1,2-dicarboxylic acid (KL-5) was prepared as follows: The solution of KL-4 was cooled to 0-5°C, 40 g of a 30% sodium hydroxide solution was added dropwise, the temperature was controlled to 0-5°C, and after the dropwise addition was completed, stirring was performed for 1-2 hours. The pH of the solution was adjusted to 5-6 using 10% hydrochloric acid, 600 g of water was added, and extraction was performed twice using 600 g of ethyl acetate. After washing with 200 g of saturated brine, the solvent was distilled off under reduced pressure until no solvent remained, and 54 g of a white solid was obtained, with a yield of 90%.

[0061] Preparation Example 6:

[0062] The preparation steps of the caronic anhydride are as follows: 30 g of KL-5 and 100 g of toluene are added to a reactor, 30 g of acetic anhydride is added dropwise at 25-30, and then the temperature is raised to 100-105, and the reaction is kept for 2 h, and toluene and acetic acid are recovered by concentration under reduced pressure to obtain 24 g of white solid, with a yield of 90.29%.

[0063] Embodiment: a synthesis method of caronic anhydride, at least comprising the following steps:

[0064] S1: KL-0 is epoxidized to obtain KL-1; the oxidizing agent in the epoxidation process is a mixture of one or more of m-chloroperoxybenzoic acid, sodium hypochlorite and peroxyacetic acid; the solvent in the epoxidation process is a mixture of one or more of dichloromethane, dichloroethane, water and N-methyl pyrrolidone; the reaction temperature of epoxidation is -5-20;

[0065] S2: KL-1 is ring-opened to obtain KL-2; the ring-opening reagent in the ring-opening process is a mixture of one or more of hydrochloric acid, hydrobromic acid and hydroiodic acid; the solvent in the ring-opening process is a mixture of one or more of dichloromethane, dichloroethane, water and N-methyl pyrrolidone; the reaction temperature of ring-opening is 10-50;

[0066] S3: KL-2 is cyclized to obtain KL-3; the cyclization agent in the cyclization process is a mixture of one or more of sodium tert-butoxide, potassium tert-butoxide and sodium tert-amylate; the solvent in the cyclization process is a mixture of one or more of tert-butanol, N,N-dimethylformamide, tetrahydrofuran and acetonitrile; the reaction temperature of cyclization is -10-30;

[0067] S4: KL-3 is oxidized to obtain KL-4; the oxidizing agent in the oxidation process is a mixture of sodium hypochlorite and 2,2,6,6-tetramethylpiperidine-1-oxyl radical or Fe(NO3)3 or a mixture of one or two of sodium hypochlorite, 2,2,6,6-tetramethylpiperidine-1-oxyl radical and potassium chloride; the solvent in the oxidation process is a mixture of one or more of dichloromethane, dichloroethane, water and N-methyl pyrrolidone; the reaction temperature of oxidation is -5-20;

[0068] S5: KL-4 is hydrolyzed to obtain KL-5; the reagent in the hydrolysis process is a mixture of one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; the solvent in the hydrolysis process is a mixture of one or more of tetrahydrofuran, water, methanol and ethanol; the reaction temperature of hydrolysis is -5-20;

[0069] S6: cyclization of compound KL-5 to obtain carboxylic anhydride; reagent in cyclization process is a mixture of one or several of acetic anhydride, triphosgene, phosphorus pentoxide, p-toluene sulfonic acid; solvent in cyclization process is a mixture of one or several of toluene, tetrahydrofuran, 1,4-dioxane; reaction temperature of cyclization is 7-100°C.

[0070] Performance test

[0071] 1. NMR test method: BRUKER 400MHz, solvent is DMSO.

[0072] 2. GC method for determining purity:

[0073] (1) Instruments and tools

[0074] ① Gas chromatograph: Agilent 7890 equipped with FID detector or equivalent instrument.

[0075] ② Column: SE-5430 m x 0.32 mm x 1 m.

[0076] ③ Data processing system: chromatographic workstation.

[0077] (2) Chromatographic conditions

[0078] Injection port temperature: 250°C

[0079] Detector temperature: 280°C

[0080] Carrier gas (constant pressure mode):

[0081] Nitrogen: total pressure 0.2 MPa, pre-column pressure 0.1 MPa

[0082] Hydrogen: 0.1 MPa

[0083] Air: 0.1 MPa

[0084] Temperature program: 80 program (2 min), 20 in: a mode, 250: (5 min)

[0085] (3) Preparation of test sample:

[0086] Direct injection 0.2 L or dilution with solvent 5 times 0.5 L.

[0087] (4) Injection sequence:

[0088] After the instrument is stable, inject the system blank, then inject the test sample solution and record the chromatogram.

[0089] (5) Result calculation:

[0090] Purity or related substances % = A / (substance injected into system blank, positive

[0091] A: The area of ​​the main peak or each impurity peak.

[0092] ∑_{i=1}^{n} (sum of peak areas of all components).

[0093] The yellow liquid from Preparation Example 1 was subjected to NMR analysis. The 1H-NMR (400MHz, DMSO) results were: 3.62–3.64 (s, 3H), 2.60–2.62 (m, 1H), 2.40–2.42 (m, 1H), 2.24–2.26 (m, 2H), 1.98–2.00 (m, 1H), 0.96–0.98 (s, 2H). NMR confirmed Preparation Example 1 as KL-1. GC analysis determined the purity to be 98.9%.

[0094] The yellow liquid from Preparation Example 2 was subjected to NMR analysis. The 1H-NMR (400MHz, DMSO) results were: 6.10–6.12 (s, 1H), 4.05–4.07 (m, 2H), 3.62–3.64 (s, 3H), 3.50–3.52 (m, 1H), 2.24–2.26 (m, 2H), 1.98–2.00 (m, 1H), 0.96–0.98 (s, 2H). NMR confirmed Preparation Example 2 as KL-2. GC analysis determined the purity to be 98.0%.

[0095] The yellow liquid from Preparation Example 3 was subjected to NMR analysis. The 1H-NMR (400MHz, DMSO) results were: 6.10–6.12 (s, 1H), 4.05–4.07 (m, 2H), 3.62–3.64 (s, 3H), 3.50–3.52 (m, 1H), 2.24–2.26 (m, 2H), 1.98–2.00 (m, 1H), 0.96–0.98 (s, 2H). NMR confirmed Preparation Example 3 as KL-3. GC analysis determined the purity to be 98.0%.

[0096] The white solid from Preparation Example 4 was subjected to NMR analysis. The 1H-NMR (400 MHz, DMSO) results were: Rs 12.75–12.77 (s, 2H), 2.25–2.27 (d, 2H), 0.96–0.98 (s, 2H). NMR confirmed Preparation Example 4 as KL-5. GC analysis determined the purity to be 98.8%.

[0097] The white solid prepared in Example 5 was subjected to NMR analysis. ¹H-NMR (400 MHz, DMSO) ¹⁹ R⁻¹ (d, 2H), 0.97-0.99 (s, 2H) confirmed that the white solid was carbolic acid. GC analysis determined the purity to be 99.2%.

[0098] The carlonic anhydride obtained in Example 6 was subjected to nuclear magnetic test, 1H-NMR (400MHz, DMSO) R: 2.27-2.29 (d, 2H), 0.97-0.99 (s, 2H), the white solid was identified as carlonic anhydride by nuclear magnetic. The purity was determined by GC to be 99.2%.

[0099] The synthetic route of the embodiment, the purity of the final product is 99.2%, the total yield is 67.7% (product yield = S1 yield * S2 yield * S3 yield * S4 yield * S5 yield * S6 yield), the raw material cost is controlled within 150,000 yuan / ton, which fully meets the benefit effect of the application.

[0100] Comparative example:

[0101] Common synthetic route for preparing carlonic anhydride:

[0102]

[0103] Using ethyl chrysanthemate as raw material, first oxidized by acetone and potassium permanganate, then hydrolyzed by liquid alkali, and then obtained carlonic acid after adjusting the acid with hydrochloric acid, and finally ring-closing by acetic anhydride and sodium acetate. The ethyl chrysanthemate raw material of this route is relatively expensive, and the production manufacturer is less. A large amount of potassium permanganate is used in the oxidation process, which is easy to catch fire and pollutes the environment. The solvent acetone cannot be reused after recovery, which greatly increases the production cost. The total yield of this route is 50%, and the raw material cost reaches 250,000 yuan / ton.

[0104] Therefore, compared with the synthetic route of the comparative example, the route of the application has great advantages in raw material cost, and the unit operation is simple and safe, and the controllability is strong, which is more suitable for industrial production.

[0105] The specific embodiments of the application are only an explanation of the application, and are not a limitation of the application, and those skilled in the art can make non-creative contribution modifications to the embodiments according to the needs after reading the specification, but as long as it is within the scope of the claims of the application, it is protected by the patent law.

Claims

1. A method for synthesizing a calone anhydride, characterized by, At least comprising the following steps: Wherein A is one of chlorine, bromine, iodine; S1: epoxidizing the compound methyl 3-oxobutanoate to obtain methyl 3-methyl-3-(oxetan-2-yl)butanoate; S2: ring-opening methyl 3-methyl-3-(oxetan-2-yl)butanoate to obtain 4-A-5-hydroxy-3,3-dimethyl-carboxylic acid methyl ester; S3: cyclizing 4-A-5-hydroxy-3,3-dimethyl-carboxylic acid methyl ester to obtain 3-(hydroxymethyl)-2,2-dimethylcyclopropane-1-carboxylic acid methyl ester; S4: oxidizing 3-(hydroxymethyl)-2,2-dimethylcyclopropane-1-carboxylic acid methyl ester to obtain 3-(methoxycarbonyl)-2,2-dimethylcyclopropane-1-carboxylic acid; S5: hydrolyzing 3-(methoxycarbonyl)-2,2-dimethylcyclopropane-1-carboxylic acid to obtain 3,3-dimethylcyclopropane-1,2-dicarboxylic acid; S6: cyclizing 3,3-dimethylcyclopropane-1,2-dicarboxylic acid to obtain chalcone anhydride; In the step S1, the oxidant in the epoxidation process is one or a mixture of several of m-chloroperoxybenzoic acid, sodium hypochlorite, peracetic acid; the solvent in the epoxidation process is one or a mixture of several of dichloromethane, dichloroethane, water, N-methyl pyrrolidone; the reaction temperature of the epoxidation is -5-20℃.

2. The method of claim 1, wherein the carboxylic anhydride is synthesized by the reaction of a carboxylic acid with acetic anhydride. In the step S2, the ring-opening reagent in the ring-opening process is one or a mixture of several of hydrochloric acid, hydrobromic acid, hydroiodic acid; the solvent in the ring-opening process is one or a mixture of several of dichloromethane, dichloroethane, water, N-methyl pyrrolidone; the reaction temperature of the ring-opening is 10-50℃.

3. The method of claim 1, wherein the carboxylic anhydride is synthesized by the reaction of a carboxylic acid with acetic anhydride. In the step S3, the cyclization agent in the cyclization process is one or a mixture of several of sodium tert-butoxide, potassium tert-butoxide, sodium tert-amylate; the solvent in the cyclization process is one or a mixture of several of tert-butanol, N,N-dimethylformamide, tetrahydrofuran, acetonitrile; the reaction temperature of the cyclization is -10-30℃.

4. The method of claim 1, wherein the carboxylic anhydride is synthesized by the reaction of a carboxylic acid with acetic anhydride. In the step S4, the oxidant in the oxidation process is a mixture of sodium hypochlorite and 2,2,6,6-tetramethylpiperidine-1-oxyl radical or a mixture of Fe(NO3)3·H2O and 2,2,6,6-tetramethylpiperidine-1-oxyl radical; the solvent in the oxidation process is one or a mixture of several of dichloromethane, dichloroethane, water, N-methyl pyrrolidone; the reaction temperature of the oxidation is -5-20℃.

5. The method of claim 1, wherein the carboxylic anhydride is synthesized by the reaction of a carboxylic acid with acetic anhydride. In the step S5, the reagent in the hydrolysis process is one or a mixture of several of sodium hydroxide, potassium hydroxide, lithium hydroxide; the solvent in the hydrolysis process is one or a mixture of several of tetrahydrofuran, water, methanol, ethanol; the reaction temperature of the hydrolysis is -5-20℃.

6. The method of claim 1, wherein the carboxylic anhydride is synthesized by the reaction of a carboxylic acid with acetic anhydride. In the step S6, the reagent in the cyclization process is one or a mixture of several of acetic anhydride, triphosgene, phosphorus pentoxide, p-toluenesulfonic acid; the solvent in the cyclization process is one or a mixture of several of toluene, tetrahydrofuran, 1,4-dioxane; the reaction temperature of the cyclization is 7-100℃.

Images