A preparation method of caronic anhydride

Abstract

The present invention discloses a novel method for preparing caronic anhydride, comprising: Step S1: Reacting methyl 2-oxo-3-isopropylidene-1,4-butanedioate with hydrazine hydrate in a first organic solvent to carry out a dehydration condensation reaction to generate methyl 2-hydrazono-3-isopropylidene-1,4-butanedioate, and allowing methyl 2-hydrazono-3-isopropylidene-1,4-butanedioate to continue to undergo intramolecular addition cyclization to form 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole; Step S2: Under the condition of the presence of a base, allowing 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole to undergo an elimination reaction to generate dimethyl 3,3-dimethylcyclopropane-1,2-dicarboxylate; Step S3: Under an acidic environment, subjecting dimethyl 3,3-dimethylcyclopropane-1,2-dicarboxylate to acid hydrolysis to generate 3,3-dimethylcyclopropane-1,2-dicarboxylic acid; and Step S4: In the presence of a cyclodehydrating agent, allowing 3,3-dimethylcyclopropane-1,2-dicarboxylic acid to undergo intramolecular dehydration cyclization to generate caronic anhydride. This method reduces the generation of "three wastes" during the preparation process and reduces the harm to the environment.

Description

Technical Field

[0001] The present invention belongs to the technical field of compound synthesis, and particularly relates to a novel preparation method of caronic anhydride. Background Art

[0002] Caronic anhydride (abbreviated as KK), also known as 6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione, is a key intermediate of the oral hepatitis C protease inhibitor Boceprevir, and can also be used as a key intermediate for a variety of pharmaceuticals and fine chemicals.

[0003] Currently, the preparation methods of caronic anhydride mainly focus on the following several routes:

[0004] (1) The first route: Starting from acetone or methyl isobutyl ketone, through a carbene cyclopropanation step with sulfur ylide to generate the intermediate 3,3-dimethyl-2-methoxycarbonylcyclopropanecarboxylate, and then through oxidation and intramolecular dehydration condensation to prepare the target product. The specific reaction route is as follows:

[0005]

[0006] However, this route involves expensive sulfur ylide, and there are a large amount of related sulfur-containing "three wastes" with great treatment difficulty, which is not suitable for further expanding the production scale.

[0007] (2) The second route: Starting from isoprenol, through a carbene cyclopropanation step with ethyl diazoacetate to generate the intermediate 3,3-dimethyl-2-hydroxymethylcyclopropanecarboxylic acid, and then through oxidation and intramolecular dehydration condensation to prepare the target product. The specific reaction route is as follows:

[0008]

[0009] However, this route involves isoprenol with a protecting group, ethyl diazoacetate and a special copper salt complex catalyst, and there are potential hazards in terms of raw material cost, production safety and "three wastes" pollution, which urgently need to be further optimized and improved.

[0010] (3) The third route: Starting from ethyl chrysanthemate, through oxidation, ester hydrolysis and intramolecular dehydration cyclization to obtain the target product. The specific reaction route is as follows:

[0011]

[0012] However, this route has similar defects to the first route. The price of the raw material ethyl chrysanthemate is relatively high and the market supply is unstable. The oxidant uses permanganate, and the corresponding "three wastes" treatment is difficult.

[0013] Therefore, it is urgent to improve the preparation process of caronic anhydride. Summary of the Invention

[0014] In view of the above problems, the present invention is proposed to provide a preparation method of caronic anhydride that overcomes the above problems or at least partially solves the above problems.

[0015] One object of the present invention is to provide a preparation method of caronic anhydride with a completely new synthetic route.

[0016] A further object of the present invention is to reduce the generation of "three wastes" during the preparation process and reduce the harm to the environment.

[0017] Specifically, the present invention provides a preparation method of caronic anhydride, and the reaction equation for its preparation is as follows:

[0018]

[0019] The preparation method includes the following steps:

[0020] Step S1: React methyl 2-oxo-3-isopropylidene-1,4-butanedioate with hydrazine hydrate in a first organic solvent to carry out a dehydration condensation reaction to form methyl 2-hydrazono-3-isopropylidene-1,4-butanedioate (Intermediate I), and make methyl 2-hydrazono-3-isopropylidene-1,4-butanedioate (Intermediate I) continue to carry out an intramolecular addition cyclization to form 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole (Intermediate II);

[0021] Step S2: Under the condition of the presence of a base, carry out an elimination reaction on 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole (Intermediate II) to form dimethyl 3,3-dimethylcyclopropane-1,2-dicarboxylate (Intermediate III);

[0022] Step S3: Carry out acid hydrolysis on dimethyl 3,3-dimethylcyclopropane-1,2-dicarboxylate (Intermediate III) in an acidic environment to form 3,3-dimethylcyclopropane-1,2-dicarboxylic acid; and

[0023] Step S4: In the presence of a cyclodehydrating agent, carry out intramolecular dehydration cyclization on 3,3-dimethylcyclopropane-1,2-dicarboxylic acid to form caronic anhydride.

[0024] Optionally, in Step S1, the first organic solvent is one or more of dichloroethane, dichloropropane, toluene, sulfolane, and diethylene glycol monomethyl ether, and the volume dosage of the first organic solvent is 4 to 10 times the mass of methyl 2-oxo-3-isopropylidene-1,4-butanedioate;

[0025] The molar amount of hydrazine hydrate is 1.1 to 2.2 times the molar amount of methyl 2-oxo-3-isopropylidene-1,4-butanedioate.

[0026] Preferably, the volume of the first organic solvent used is 6 to 7 times the mass of methyl 2-oxo-3-isopropylidene-1,4-butanedioate, and the molar amount of hydrazine hydrate is 1.3 to 1.5 times the molar amount of methyl 2-oxo-3-isopropylidene-1,4-butanedioate.

[0027] Optionally, a reaction auxiliary reagent that enhances the positive charge of the carbonyl carbon is added to the reaction system in step S1, and step S1 specifically includes:

[0028] Add the raw materials methyl 2-oxo-3-isopropylidene-1,4-butanedioate, hydrazine hydrate, the first organic solvent and the reaction auxiliary reagent into a reaction vessel to form a reaction system, stir evenly, heat up to a first reaction temperature of 80 to 120 °C and react for 3 to 7 hours, so that methyl 2-oxo-3-isopropylidene-1,4-butanedioate and hydrazine hydrate undergo a dehydration condensation reaction to generate methyl 2-hydrazono-3-isopropylidene-1,4-butanedioate, and methyl 2-hydrazono-3-isopropylidene-1,4-butanedioate continues to undergo an intramolecular addition cyclization to form 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole;

[0029] Cool the reaction system to room temperature, add water to the reaction system, stir and then phase-separate to obtain a first organic phase containing the generated 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole.

[0030] Optionally, the reaction auxiliary reagent is one or more of acetic acid, propionic acid, benzoic acid, aluminum chloride and zinc chloride, and the molar amount of the reaction auxiliary reagent is 1.3 to 2.0 times the molar amount of hydrazine hydrate.

[0031] Preferably, the molar amount of the reaction auxiliary reagent is 1.4 to 1.7 times the molar amount of hydrazine hydrate, and the first reaction temperature is 90 to 100 °C.

[0032] Optionally, the 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole obtained in step S1 is contained in the first organic phase, and step S2 specifically includes:

[0033] Add a base to the first organic phase containing 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole, heat up to a second reaction temperature of 80 to 120 °C under stirring conditions and keep it warm for an elimination reaction for 2 to 5 hours, cool to room temperature, add water to the reaction system, stir and then phase-separate, dry the obtained organic phase and then remove the solvent to obtain methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate.

[0034] Optionally, the base is one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium methoxide, and sodium ethoxide, and the molar amount of the base is 0.2 to 0.6 times the molar amount of 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole.

[0035] Preferably, the molar amount of the base is 0.3 to 0.4 times the molar amount of 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole;

[0036] The second reaction temperature is 95 to 105 °C.

[0037] Optionally, step S3 specifically includes:

[0038] Charge the methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate obtained in step S2 and water into the reaction vessel, slowly add the acid solution to a pH value of 1.0 to 2.5 under stirring conditions, heat up to 40 to 70 °C, keep warm for acid hydrolysis reaction, cool to room temperature, and extract the reaction solution with a second organic solvent to obtain a second organic phase containing the generated 3,3-dimethylcyclopropane-1,2-dicarboxylic acid.

[0039] Optionally, the acid solution is an aqueous sulfuric acid solution, the mass fraction of the aqueous sulfuric acid solution is 30% to 70%, and the molar amount of sulfuric acid in the aqueous sulfuric acid solution is 0.5 to 2 times the molar amount of methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate.

[0040] Preferably, the mass fraction of the aqueous sulfuric acid solution is 40% to 50%, and the molar amount of sulfuric acid in the aqueous sulfuric acid solution is 0.8 to 1.2 times the molar amount of methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate.

[0041] Optionally, the second organic solvent is one or more of ethyl acetate, methyl acetate, chloroform, and 1,2-dichloroethane.

[0042] Optionally, the 3,3-dimethylcyclopropane-1,2-dicarboxylic acid obtained in step S3 is contained in the second organic phase, and step S4 specifically includes:

[0043] Add the second organic phase containing 3,3-dimethylcyclopropane-1,2-dicarboxylic acid and a cyclodehydrating agent into the reaction vessel, heat up to 75 to 80 °C under stirring to distill out the second organic solvent in the second organic phase, continue to heat to 130 to 140 °C for reflux, keep warm for intramolecular dehydration cyclization reaction for 3 to 4 hours, cool to below 70 °C, and separate through a packed column to obtain the finished product of caronic anhydride.

[0044] Optionally, the cyclodehydrating agent is acetic anhydride;

[0045] The step of separation through a packed column includes:

[0046] The cooled reaction solution is added to a packed column, and acetic acid and the remaining acetic anhydride in the reaction solution are distilled off by heating under reduced pressure. The fraction at 70-90 °C is collected to obtain the finished product of caronic anhydride.

[0047] The novel preparation method of caronic anhydride provided by the present invention uses methyl 2-oxo-3-isopropylidene-1,4-butanedioate as a raw material. First, it undergoes dehydration condensation with hydrazine to form methyl 2-hydrazono-3-isopropylidene-1,4-butanedioate (intermediate I), then undergoes intramolecular addition cyclization to form 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole (intermediate II), then undergoes an elimination reaction to form the key methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate (intermediate III), and finally this key intermediate III undergoes acid hydrolysis and intramolecular dehydration cyclization steps to obtain the target product caronic anhydride. The method of the present invention has an original synthesis route, and the "three wastes" generated during the preparation process are harmless nitrogen gas and a small amount of neutralization salts, significantly reducing the harm to the environment. This new process has the characteristics of smooth process, mild reaction conditions, easy industrialization and high product purity.

[0048] Furthermore, in the preparation method of caronic anhydride of the present invention, acid hydrolysis is used to hydrolyze the key intermediate III, which is more convenient than the post-treatment process of common base hydrolysis reactions, effectively reducing the amount of waste salts generated in the neutralization step.

[0049] The above description is only an overview of the technical solution of the present invention. In order to be able to understand the technical means of the present invention more clearly, it can be implemented according to the content of the specification. And in order to make the above and other purposes, features and advantages of the present invention more obvious and understandable, the specific embodiments of the present invention are specifically given below. Specific Embodiments

[0050] The following combines specific embodiments to further illustrate the technical solution of the present invention, but it should be understood that the present invention is not limited to these specific embodiments.

[0051] The embodiment of the present invention provides a preparation method of caronic anhydride, and the reaction equation for its preparation is as follows:

[0052]

[0053] This preparation method includes the following steps:

[0054] Step S1: React methyl 2-oxo-3-isopropylidene-1,4-butanedioate with hydrazine hydrate in a first organic solvent to carry out a dehydration condensation reaction to form methyl 2-hydrazono-3-isopropylidene-1,4-butanedioate (Intermediate I), and make methyl 2-hydrazono-3-isopropylidene-1,4-butanedioate (Intermediate I) continue to carry out an intramolecular addition cyclization to form 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole (Intermediate II);

[0055] Step S2: Under the condition of the presence of a base, make 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole (Intermediate II) undergo an elimination reaction to form dimethyl 3,3-dimethylcyclopropane-1,2-dicarboxylate (Intermediate III);

[0056] Step S3: Under an acidic environment, make dimethyl 3,3-dimethylcyclopropane-1,2-dicarboxylate (Intermediate III) undergo acid hydrolysis to form 3,3-dimethylcyclopropane-1,2-dicarboxylic acid; and

[0057] Step S4: In the presence of a cyclodehydrating agent, make 3,3-dimethylcyclopropane-1,2-dicarboxylic acid undergo an intramolecular dehydration cyclization to form caronic anhydride.

[0058] The novel method for preparing caronic anhydride provided by the embodiments of the present invention uses methyl 2-oxo-3-isopropylidene-1,4-butanedioate as a raw material. First, it undergoes a dehydration condensation reaction with hydrazine to form methyl 2-hydrazono-3-isopropylidene-1,4-butanedioate (Intermediate I), then undergoes an intramolecular addition cyclization to form 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole (Intermediate II), then undergoes an elimination reaction to form the key dimethyl 3,3-dimethylcyclopropane-1,2-dicarboxylate (Intermediate III), and finally this key Intermediate III is subjected to acid hydrolysis and intramolecular dehydration cyclization steps to obtain the target product caronic anhydride. The method of the present invention has an original synthesis route, and the "three wastes" generated during the preparation process are harmless nitrogen gas and a small amount of neutralization salts, significantly reducing the harm to the environment. This new process has the characteristics of a smooth process, mild reaction conditions, easy industrialization, and high product purity.

[0059] Furthermore, in the method for preparing caronic anhydride of the present invention, acid hydrolysis is used to hydrolyze the key Intermediate III, which is simpler than the post-treatment process of the common base hydrolysis reaction, effectively reducing the amount of waste salts generated in the neutralization step.

[0060] In some embodiments of the present invention, in step S1, the first organic solvent may be one or more of dichloroethane, dichloropropane, toluene, sulfolane, diethylene glycol monomethyl ether, etc. The volume dosage of the first organic solvent may be 4 to 10 times the mass of methyl 2-oxo-3-isopropylidene-1,4-butanedioate, such as 5 times, 6 times, 7 times, 8 times, 9 times; preferably, 6 to 7 times, so as to facilitate the smooth and complete progress of the dehydration condensation reaction.

[0061] In some embodiments, in step S1, the molar amount of hydrazine hydrate may be 1.1 to 2.2 times the molar amount of methyl 2-oxo-3-isopropylidene-1,4-butanedioate, such as 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2.0 times, 2.1 times; preferably, 1.3 to 1.5 times, so as to more facilitate the complete reaction of methyl 2-oxo-3-isopropylidene-1,4-butanedioate and improve the conversion rate of methyl 2-oxo-3-isopropylidene-1,4-butanedioate.

[0062] In some further embodiments, a reaction auxiliary reagent that strengthens the positive charge of the carbonyl carbon is added to the reaction system of step S1. This reaction auxiliary reagent can significantly promote the dehydration condensation reaction of methyl 2-oxo-3-isopropylidene-1,4-butanedioate and hydrazine, and also has a certain promoting effect on the subsequent intramolecular addition cyclization reaction, thereby further improving the conversion rate of methyl 2-oxo-3-isopropylidene-1,4-butanedioate.

[0063] Optionally, the reaction auxiliary reagent may be one or more of acetic acid, propionic acid, benzoic acid, aluminum chloride, zinc chloride, etc. The molar amount of the reaction auxiliary reagent may be 1.3 to 2.0 times the molar amount of hydrazine hydrate, such as 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, preferably 1.4 to 1.7 times.

[0064] In some embodiments, step S1 may specifically include:

[0065] Into a reaction vessel, raw materials methyl 2-oxo-3-isopropylidene-1,4-butanedioate, hydrazine hydrate, a first organic solvent and a reaction auxiliary reagent are added to form a reaction system, which is stirred evenly and heated to a first reaction temperature of 80-120 °C for 3-7 hours to cause dehydration condensation reaction between methyl 2-oxo-3-isopropylidene-1,4-butanedioate and hydrazine hydrate to generate methyl 2-hydrazono-3-isopropylidene-1,4-butanedioate, and cause methyl 2-hydrazono-3-isopropylidene-1,4-butanedioate to continue to carry out intramolecular addition cyclization to generate 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole; the reaction system is cooled to room temperature, water is added to the reaction system, and after stirring, phase separation is carried out to obtain a first organic phase containing the generated 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole.

[0066] In actual operation, methyl 2-oxo-3-isopropylidene-1,4-butanedioate, hydrazine hydrate, a first organic solvent and a reaction auxiliary reagent can be sequentially added to a reaction vessel (such as a reaction flask). The phase separation operation is completed by standing. The first organic phase obtained by phase separation can be directly used for the next reaction after drying.

[0067] The first reaction temperature can be, for example, about 85 °C, 90 °C, 95 °C, 100 °C, 105 °C, 110 °C, or 115 °C. In a preferred embodiment, the first reaction temperature can be controlled at 90-100 °C to further improve the precise control of the dehydration condensation reaction and the subsequent intramolecular addition cyclization reaction.

[0068] As described above, the 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole obtained in step S1 is contained in the first organic phase. Correspondingly, in some embodiments of the present invention, step S2 may specifically include:

[0069] To the first organic phase containing 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole, a base is added, and the mixture is heated to a second reaction temperature of 80-120 °C under stirring conditions and kept warm for an elimination reaction for 2-5 hours, cooled to room temperature, water is added to the reaction system, and after stirring, phase separation is carried out. The obtained organic phase is dried and then stripped to obtain a crude product of methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate.

[0070] In some embodiments, the base can be one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium methoxide, sodium ethoxide, etc. Preferably, the base can be potassium hydroxide and / or sodium methoxide.

[0071] The molar amount of the base can be 0.2 to 0.6 times the molar amount of 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole, such as 0.3 times, 0.4 times, 0.5 times. Preferably, it is 0.3 to 0.4 times, so as to promote the smooth and complete progress of the elimination reaction.

[0072] The second reaction temperature can be, for example, about 85 °C, 90 °C, 95 °C, 100 °C, 105 °C, 110 °C, or 115 °C. In a preferred embodiment, the second reaction temperature can be controlled at 95 - 105 °C to further improve the precise control of the elimination reaction.

[0073] In some embodiments of the present invention, step S3 may specifically include:

[0074] Put the methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate obtained in step S2 and water into the reaction vessel, slowly add the acid solution to a pH value of 1.0 - 2.5 under stirring conditions, heat up to 40 - 70 °C, keep the temperature for acid hydrolysis reaction, cool to room temperature, and extract the reaction solution with a second organic solvent to obtain a second organic phase containing the generated 3,3-dimethylcyclopropane-1,2-dicarboxylic acid.

[0075] Specifically, the extraction process can be carried out multiple times (such as 2 - 3 times), the organic phases obtained each time are combined, the combined organic phase is dried and then filtered to obtain a second organic phase containing the generated 3,3-dimethylcyclopropane-1,2-dicarboxylic acid, which is directly used for the next step of the reaction. The second organic solvent can be selected from organic solvents with a suitable polarity to extract the product from the reaction solution, such as one or more of ethyl acetate, methyl acetate, chloroform, and 1,2-dichloroethane.

[0076] The pH value of the acidic environment is in the range of 1.0 - 2.5, such as 1.2, 1.4, 1.5, 1.7, 1.9, 2.0, 2.2, 2.3, 2.4.

[0077] The acid solution can be any suitable strong acid solution, such as sulfuric acid solution, hydrochloric acid solution, benzenesulfonic acid solution, p-toluenesulfonic acid solution, etc.

[0078] In a specific embodiment, the acid solution is an aqueous sulfuric acid solution, which can not only ensure the required pH value but also reduce the raw material cost.

[0079] Further, the mass fraction of the sulfuric acid aqueous solution can be 30% to 70%, such as 40%, 50%, 60%; the molar amount of sulfuric acid in the sulfuric acid aqueous solution can be 0.5 to 2 times the molar amount of methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate, such as 0.6 times, 0.7 times, 0.8 times, 0.9 times, 1.0 times, 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, so as to ensure the complete acid hydrolysis reaction.

[0080] More preferably, the mass fraction of the sulfuric acid aqueous solution is 40% to 50%, and the molar amount of sulfuric acid in the sulfuric acid aqueous solution is 0.8 to 1.2 times the molar amount of methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate.

[0081] In actual operation, the conversion rate of intermediate III (methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate) can be monitored to determine whether the acid hydrolysis reaction has been completed.

[0082] As described above, the 3,3-dimethylcyclopropane-1,2-dicarboxylic acid obtained in step S3 is contained in the second organic phase. Correspondingly, in some embodiments of the present invention, step S4 may specifically include:

[0083] Adding the second organic phase containing 3,3-dimethylcyclopropane-1,2-dicarboxylic acid and a cyclodehydrating agent into the reaction vessel, heating and raising the temperature to 75 - 80°C with stirring to distill out the second organic solvent in the second organic phase, continuing to heat to 130 - 140°C for reflux, maintaining the temperature for intramolecular dehydration cyclization reaction for 3 - 4 hours, cooling to below 70°C, and separating through a packed column to obtain the finished product of caronic anhydride.

[0084] The cyclodehydrating agent can be any reagent suitable for promoting the dehydration cyclization reaction. In a specific embodiment, the cyclodehydrating agent can be acetic anhydride.

[0085] In some further embodiments, the step of separation through a packed column may specifically include:

[0086] Adding the cooled reaction solution to the packed column, heating and evaporating acetic acid and the remaining acetic anhydride in the reaction solution under reduced pressure, and collecting the fraction at 70 - 90°C to obtain the finished product of caronic anhydride. The reduced pressure condition can be, for example, -0.095 MPa. The packed column generally can use glass packing or Dixon stainless steel packing, etc.

[0087] The following describes the implementation modes of the present invention through specific non-limiting embodiments. Those skilled in the art can easily understand the other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific implementation modes. Various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0088] Example 1

[0089] Step 1: Preparation of 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole

[0090] Methyl 2-oxo-3-isopropylidene-1,4-butanedioate (40.0 g / 0.20 mol), hydrazine hydrate with a mass fraction of wt 40% (20.8 g / 0.26 mol), 280 ml of 1,2-dichloroethane, and glacial acetic acid (21.8 g / 0.36 mol) were successively added to a 500 ml single-necked flask, stirred and mixed evenly, heated to reflux for 4 h, sampled and monitored until the content of the raw material methyl 2-oxo-3-isopropylidene-1,4-butanedioate < 1.0% (HPLC-Area%), stopped heating, the reaction solution was cooled to room temperature, 80 ml of water was added to the reaction flask, stirred for 10 min and then left to stand for phase separation. The organic phase was dried with anhydrous sodium sulfate, filtered and used for the next reaction.

[0091] Step 2: Preparation of methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate

[0092] The organic phase obtained in Step 1 and potassium hydroxide (3.4 g / 0.06 mol) were successively added to a 500 ml single-necked flask, heated to reflux with stirring for 3 h, sampled and monitored until the content of Intermediate II (3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole) < 1.0% (HPLC-Area%), stopped heating, the reaction solution was cooled to room temperature, 100 ml of water was added to the reaction flask, stirred for 10 min and then left to stand for phase separation. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to obtain 29.6 g of solid crude product of Intermediate III (methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate) with a content of 95.35%.

[0093] The overall yield of Steps 1 and 2 was 75.9%.

[0094] Step 3: Preparation of 3,3-dimethylcyclopropane-1,2-dicarboxylic acid

[0095] Into a 250 ml single-necked flask, add the crude product of Intermediate III (29.6 g / 0.15 mol) and 30 g of water in sequence. While stirring, slowly add dropwise an aqueous sulfuric acid solution (mass fraction wt 40%) (29.4 g / 0.12 mol). After the addition is complete, heat up to 50 - 55 °C and keep the temperature for reaction for 2 h. Take a sample for monitoring until the content of Intermediate III (methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate) < 2.0% (HPLC-Area%). Stop heating. When the reaction solution cools to room temperature, extract it 3 times with 50 ml of ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate and then filter. The filtrate is directly used for the next step of the reaction.

[0096] Step 4: Preparation of caronic anhydride

[0097] Into a 250 ml single-necked flask, add the organic phase obtained in Step 3 and acetic anhydride (61.2 g / 0.60 mol) in sequence. While stirring, heat up to 75 - 80 °C to distill out the solvent ethyl acetate. Continue to heat up to 130 - 140 °C for reflux, keep the temperature for reaction for 3 h. Stop heating and cool down to below 70 °C. Add a 10 cm packing column, evacuate with an oil pump (-0.095 Mpa), heat up to distill out acetic acid and the remaining acetic anhydride in the reaction system, and collect the fraction with a top temperature of 70 - 90 °C. After cooling, 9.7 g of caronic anhydride product with a content of 99.01% is obtained.

[0098] The overall yield of the two steps of Step 3 and Step 4 is 45.8%.

[0099] The overall yield of the four-step reaction is 34.4%.

[0100] Example 2

[0101] Step 1: Preparation of 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole

[0102] Into a 500 ml single-necked flask, add methyl 2-oxo-3-isopropylidene-1,4-butanedioate (40.0 g / 0.20 mol), hydrazine hydrate with a mass fraction of wt 40% (24.0 g / 0.30 mol), 240 ml of 1,2-dichloroethane and glacial acetic acid (28.8 g / 0.48 mol) in sequence. Stir and mix evenly, heat to reflux for reaction for 5 h. Take a sample for monitoring until the content of the raw material methyl 2-oxo-3-isopropylidene-1,4-butanedioate < 0.7% (HPLC-Area%). Stop heating. When the reaction solution cools to room temperature, add 80 ml of water to the reaction flask, stir for 10 min and then let it stand for phase separation. The organic phase is dried over anhydrous sodium sulfate and filtered for use in the next step of the reaction.

[0103] Step 2: Preparation of methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate

[0104] To a 500 ml single-necked flask, add successively the organic phase obtained in Step 1 and sodium methoxide (4.4 g / 0.08 mol). Heat with stirring to reflux for 3 h. Sample and monitor until the content of Intermediate II (3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole) < 1.0% (HPLC-Area%). Stop heating. When the reaction solution cools to room temperature, add 90 ml of water to the reaction flask. Stir for 10 min and then let it stand for phase separation. The organic phase is dried over anhydrous sodium sulfate, filtered, and then concentrated by evaporation to obtain 28.0 g of crude solid of Intermediate III (dimethyl cyclopropane-1,2-dicarboxylate), with a content of 96.13%.

[0105] The overall yield of the two steps of Step 1 and Step 2 is 72.4%.

[0106] Step 3: Preparation of 3,3-dimethylcyclopropane-1,2-dicarboxylic acid

[0107] Charge successively the crude product of Intermediate III (28.0 g / 0.14 mol) and 30 g of water into a 250 ml single-necked flask. Slowly add dropwise the sulfuric acid aqueous solution (mass fraction wt 50%) (27.4 g / 0.14 mol) with stirring. After the addition is complete, heat up to 65 - 70 °C and hold for 1.5 h. Sample and monitor until the content of Intermediate III (dimethyl cyclopropane-1,2-dicarboxylate) < 2.0% (HPLC-Area%). Stop heating. When the reaction solution cools to room temperature, extract with 50 ml of ethyl acetate three times. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and the filtrate is directly used for the next step of the reaction.

[0108] Step 4: Preparation of caronic anhydride

[0109] To a 250 ml single-necked flask, add successively the organic phase obtained in Step 3 and acetic anhydride (61.2 g / 0.60 mol). Heat with stirring to distill out the solvent ethyl acetate at 75 - 80 °C. Continue to heat up to 130 - 140 °C for reflux. Hold for 3 h. Stop heating and cool to below 70 °C. Add a 10 cm packing column. Evacuate with an oil pump (-0.095 Mpa). Heat up to distill out acetic acid and the remaining acetic anhydride in the reaction system. Collect the fraction with a top temperature of 70 - 90 °C. After cooling, 8.8 g of caronic anhydride product is obtained, with a content of 99.18%.

[0110] The overall yield of the two steps of Step 3 and Step 4 is 44.7%.

[0111] The overall yield of the four-step reaction is 31.3%.

[0112] The preparation method of caronic anhydride of the present invention adopts a brand-new synthetic route design. Using methyl 2-oxo-3-isopropylidene-1,4-butanedioate and hydrazine hydrate as basic raw materials, the key intermediate dimethyl caronate is obtained through steps such as dehydration condensation, intramolecular addition cyclization, and elimination in sequence, and then the target product is obtained through steps of ester hydrolysis and intramolecular dehydration cyclization. This synthetic route is innovative, and the reaction conditions for each step are relatively mild, the post-treatment is simple and smooth, the amount of "three wastes" is small, and it is easy to industrialize, etc., and has considerable practical potential.

[0113] In the specification provided here, a large number of specific details are described. However, it can be understood that the embodiments of the present invention can be practiced without these specific details. In some instances, well-known methods, structures, and technologies are not shown in detail so as not to obscure the understanding of this specification.

[0114] At this point, those skilled in the art should recognize that although multiple exemplary embodiments of the present invention have been shown and described in detail herein, many other variations or modifications that conform to the principles of the present invention can still be directly determined or derived from the content disclosed in the present invention without departing from the spirit and scope of the present invention. Therefore, the scope of the present invention should be understood and determined to cover all these other variations or modifications.

Claims

1. A method for preparing caronic anhydride, comprising the following steps: Step S1: Reacting methyl 2-oxo-3-isopropylidene-1,4-butanedioate with hydrazine hydrate in a first organic solvent to perform a dehydration condensation reaction to form methyl 2-hydrazono-3-isopropylidene-1,4-butanedioate, and then subjecting methyl 2-hydrazono-3-isopropylidene-1,4-butanedioate to an intramolecular addition cyclization reaction to form 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole; Step S2: Under the condition of the presence of a base, subjecting 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole to an elimination reaction to form dimethyl 3,3-dimethylcyclopropane-1,2-dicarboxylate; Step S3: Subjecting dimethyl 3,3-dimethylcyclopropane-1,2-dicarboxylate to acid hydrolysis in an acidic environment to form 3,3-dimethylcyclopropane-1,2-dicarboxylic acid; And Step S4: In the presence of a cyclodehydrating agent, subjecting 3,3-dimethylcyclopropane-1,2-dicarboxylic acid to an intramolecular dehydration cyclization reaction to form caronic anhydride.

2. The method for preparing caronic anhydride according to claim 1, wherein, In the said Step S1, the first organic solvent is one or more of dichloroethane, dichloropropane, toluene, sulfolane and diethylene glycol monomethyl ether; The molar amount of hydrazine hydrate is 1.1 - 2.2 times the molar amount of methyl 2-oxo-3-isopropylidene-1,4-butanedioate.

3. The preparation method of caronic anhydride according to claim 2, wherein, The molar amount of hydrazine hydrate is 1.3 - 1.5 times the molar amount of methyl 2-oxo-3-isopropylidene-1,4-butanedioate.

4. The method for preparing caronic anhydride according to any one of claims 1-3, wherein A reaction auxiliary reagent for strengthening the positive charge of the carbonyl carbon is further added to the reaction system of the said Step S1, and the said Step S1 specifically comprises: Adding methyl 2-oxo-3-isopropylidene-1,4-butanedioate, hydrazine hydrate, the first organic solvent and the reaction auxiliary reagent into a reaction vessel to form the reaction system, stirring evenly, heating up to a first reaction temperature of 80 - 120 °C and reacting for 3 - 7 hours, so that methyl 2-oxo-3-isopropylidene-1,4-butanedioate reacts with hydrazine hydrate to perform a dehydration condensation reaction to form methyl 2-hydrazono-3-isopropylidene-1,4-butanedioate, and then subjecting methyl 2-hydrazono-3-isopropylidene-1,4-butanedioate to an intramolecular addition cyclization reaction to form 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole; Lowering the temperature of the reaction system to room temperature, adding water to the reaction system, stirring and then performing phase separation to obtain a first organic phase containing the generated 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole; Wherein, the reaction auxiliary reagent is one or more of acetic acid, propionic acid, benzoic acid, aluminum chloride and zinc chloride.

5. The preparation method of caronic anhydride according to claim 4, wherein, The molar amount of the reaction auxiliary reagent is 1.3 - 2.0 times the molar amount of hydrazine hydrate.

6. The method for preparing caronic anhydride according to claim 5, wherein, The molar amount of the reaction auxiliary reagent is 1.4 - 1.7 times the molar amount of hydrazine hydrate, and the first reaction temperature is 90 - 100 °C.

7. The preparation method of caronic anhydride according to claim 1, wherein, The 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole obtained in the said Step S1 is contained in the first organic phase, and the said Step S2 specifically comprises: The base is added to the first organic phase containing 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole, and the mixture is heated to a second reaction temperature of 80 - 120 °C under stirring conditions and kept at this temperature for 2 - 5 hours for an elimination reaction. Then it is cooled to room temperature, water is added to the reaction system, and after stirring, the phases are separated. The obtained organic phase is dried and then stripped to obtain methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate.

8. The method for preparing caronic anhydride according to claim 7, wherein, The base is one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium methoxide, and sodium ethoxide, and the molar amount of the base is 0.2 - 0.6 times the molar amount of 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole; The second reaction temperature is 95 - 105 °C.

9. The method for preparing caronic anhydride according to claim 8, wherein, The molar amount of the base is 0.3 - 0.4 times the molar amount of 3,3-dimethyl-4,5-dimethoxycarbonyl-2,4-dihydropyrazole.

10. The preparation method of caronic anhydride according to claim 1, wherein, The specific steps of step S3 include: Methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate obtained in step S2 and water are put into a reaction vessel, and an acid solution is slowly added under stirring conditions until the pH value is 1.0 - 2.

5. Then it is heated to 40 - 70 °C and kept at this temperature for an acid hydrolysis reaction. After cooling to room temperature, the reaction solution is extracted with a second organic solvent to obtain a second organic phase containing the generated 3,3-dimethylcyclopropane-1,2-dicarboxylic acid.

11. The preparation method of caronic anhydride according to claim 10, wherein, The acid solution is an aqueous sulfuric acid solution, the mass fraction of the aqueous sulfuric acid solution is 30% - 70%, and the molar amount of sulfuric acid in the aqueous sulfuric acid solution is 0.5 - 2 times the molar amount of methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate; The second organic solvent is one or more of ethyl acetate, methyl acetate, chloroform, and 1,2-dichloroethane.

12. The preparation method of caronic anhydride according to claim 11, wherein, The mass fraction of the aqueous sulfuric acid solution is 40% - 50%, and the molar amount of sulfuric acid in the aqueous sulfuric acid solution is 0.8 - 1.2 times the molar amount of methyl 3,3-dimethylcyclopropane-1,2-dicarboxylate.

13. The preparation method of caronic anhydride according to claim 1, wherein, The 3,3-dimethylcyclopropane-1,2-dicarboxylic acid obtained in step S3 is contained in the second organic phase, and the specific steps of step S4 include: The second organic phase containing 3,3-dimethylcyclopropane-1,2-dicarboxylic acid and the cyclodehydrating agent are added into a reaction vessel, and the second organic solvent in the second organic phase is distilled out by heating to 75 - 80 °C under stirring. Then it is continuously heated to 130 - 140 °C for reflux, and kept at this temperature for an intramolecular dehydration cyclization reaction for 3 - 4 hours. After cooling to below 70 °C, the product of caronic anhydride is obtained by separation through a packed column.

14. The preparation method of caronic anhydride according to claim 13, wherein, The cyclodehydrating agent is acetic anhydride; The steps of separation through a packed column include: The cooled reaction solution is added to the packed column, and acetic acid and the remaining acetic anhydride in the reaction solution are distilled off by heating under reduced pressure conditions. The fraction at 70 - 90 °C is collected to obtain the product of caronic anhydride.

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