CN116332890A - Preparation method of caronic anhydride - Google Patents
Preparation method of caronic anhydride Download PDFInfo
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- CN116332890A CN116332890A CN202310313982.9A CN202310313982A CN116332890A CN 116332890 A CN116332890 A CN 116332890A CN 202310313982 A CN202310313982 A CN 202310313982A CN 116332890 A CN116332890 A CN 116332890A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Abstract
The invention discloses a novel preparation method of caronic anhydride, which comprises the following steps: step S1: the method comprises the steps of carrying out dehydration condensation reaction on raw material 2-carbonyl-3-isopropylidene-1, 4-methyl succinate and hydrazine hydrate in a first organic solvent to generate 2-hydrazono-3-isopropylidene-1, 4-methyl succinate, and continuously carrying out intramolecular addition cyclization on the 2-hydrazono-3-isopropylidene-1, 4-methyl succinate to generate 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole; step S2: in the presence of alkali, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole is subjected to elimination reaction to generate 3, 3-dimethylcyclopropane-1, 2-dimethyl formate; step S3: acid hydrolyzing methyl 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid in an acidic environment to generate 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid; step S4: in the presence of a cyclization dehydrating agent, carrying out intramolecular dehydration cyclization on 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid to generate the caronic anhydride. The method reduces the generation of three wastes in the preparation process and reduces the harm to the environment.
Description
Technical Field
The invention belongs to the technical field of compound synthesis, and particularly relates to a novel preparation method of caronic anhydride.
Background
Carboxylic anhydride (KK) is also called 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane-2, 4-dione, is a key intermediate of an oral hepatitis C protease inhibitor Boceprevir, and can be used as a key intermediate of various medicines and fine chemicals.
The current preparation methods of the caronic anhydride mainly focus on the following routes:
(1) First route: starting from acetone or methyl isobutene ketone, preparing an intermediate 3, 3-dimethyl-2-methoxycarbonyl cyclopropane formate by a carbene-like cyclopropanation step with sulfur ylide, and preparing a target product by oxidation and intramolecular dehydration condensation, wherein the specific reaction route is as follows:
however, this route involves expensive sulfur ylides, and the associated sulfur-containing "three wastes" are large in quantity and difficult to handle, and are unsuitable for further scale-up.
(2) The second route: starting from isopentenol, preparing an intermediate 3, 3-dimethyl-2-hydroxymethyl cyclopropanecarboxylic acid from ethyl diazoacetate through a carbene-like cyclopropanation step, and preparing a target product through oxidation and intramolecular dehydration condensation, wherein the specific reaction route is as follows:
however, the route involves the isopentenol with a protecting group, ethyl diazoacetate and a special cuprous salt complex catalyst, so that hidden dangers exist in the aspects of raw material cost, production safety, pollution of three wastes and the like, and deeper optimization and improvement are needed.
(3) Third route: starting from ethyl chrysanthemate, the target product is obtained through oxidation, ester hydrolysis and intramolecular dehydration cyclization, and the specific reaction route is as follows:
however, the route has similar defects as the first route, the price of the raw material ethyl chrysanthemate is high, the market supply is unstable, the oxidant adopts permanganate, and the corresponding three wastes are difficult to treat.
Therefore, there is a need for an improved process for preparing caronic anhydride.
Disclosure of Invention
The present invention has been made in view of the above problems, and has as its object to provide a process for the preparation of a caronic anhydride which overcomes or at least partially solves the above problems.
The invention aims to provide a preparation method of a novel synthetic path of caronic anhydride.
A further object of the present invention is to reduce the generation of "three wastes" during the preparation process and to reduce the environmental hazard.
In particular, the invention provides a preparation method of a caronic anhydride, and the prepared reaction equation is shown as follows:
the preparation method comprises the following steps:
step S1: carrying out dehydration condensation reaction on raw material 2-carbonyl-3-isopropylidene-1, 4-methyl succinate and hydrazine hydrate in a first organic solvent to generate 2-hydrazono-3-isopropylidene-1, 4-methyl succinate (intermediate I), and continuously carrying out intramolecular addition cyclization on the 2-hydrazono-3-isopropylidene-1, 4-methyl succinate (intermediate I) to generate 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole (intermediate II);
step S2: in the presence of alkali, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole (intermediate II) is subjected to elimination reaction to generate 3, 3-dimethylcyclopropane-1, 2-dimethyl acid methyl ester (intermediate III);
step S3: acid hydrolysis of methyl 3, 3-dimethylcyclopropane-1, 2-dicarboxylate (intermediate III) in an acidic environment to form 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid; and
step S4: in the presence of a cyclization dehydrating agent, carrying out intramolecular dehydration cyclization on 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid to generate the caronic anhydride.
Optionally, in the 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 4-10 times of the mass of the methyl 2-carbonyl-3-isopropylidene-1, 4-succinate;
the molar quantity of the hydrazine hydrate is 1.1 to 2.2 times of that of the methyl 2-carbonyl-3-isopropylidene-1, 4-succinate.
Preferably, the volume usage of the first organic solvent is 6-7 times of the mass of the methyl 2-carbonyl-3-isopropylidene-1, 4-succinate, and the molar quantity of the hydrazine hydrate is 1.3-1.5 times of the molar quantity of the methyl 2-carbonyl-3-isopropylidene-1, 4-succinate.
Optionally, a reaction auxiliary agent for enhancing the electropositivity of the carbonyl carbon is further added into the reaction system in the step S1, and the step S1 specifically comprises:
adding raw materials of 2-carbonyl-3-isopropylidene-1, 4-methyl succinate, hydrazine hydrate, a first organic solvent and a reaction auxiliary reagent into a reaction vessel to form a reaction system, uniformly stirring, heating to a first reaction temperature of 80-120 ℃ for reaction for 3-7 hours, so that the 2-carbonyl-3-isopropylidene-1, 4-methyl succinate and the hydrazine hydrate undergo a dehydration condensation reaction to generate 2-hydrazono-3-isopropylidene-1, 4-methyl succinate, and the 2-hydrazono-3-isopropylidene-1, 4-methyl succinate continuously undergoes intramolecular addition cyclization to generate 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole;
and cooling the reaction system to room temperature, adding water into the reaction system, stirring, and then carrying out phase separation to obtain a first organic phase containing the generated 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole.
Optionally, the reaction auxiliary reagent is one or more of acetic acid, propionic acid, benzoic acid, aluminum chloride and zinc chloride, and the molar quantity of the reaction auxiliary reagent is 1.3-2.0 times of that of hydrazine hydrate.
Preferably, the molar quantity of the reaction auxiliary reagent is 1.4-1.7 times of that of hydrazine hydrate, and the first reaction temperature is 90-100 ℃.
Optionally, the 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole obtained in step S1 is contained in a first organic phase, and step S2 specifically comprises:
adding alkali into a first organic phase containing 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole, heating to a second reaction temperature of 80-120 ℃ under stirring, preserving heat for elimination reaction for 2-5 hours, cooling to room temperature, adding water into a reaction system, stirring, separating phases, drying the obtained organic phase, and desolventizing to obtain the 3, 3-dimethylcyclopropane-1, 2-methyl diformate.
Optionally, the alkali is one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium methoxide and sodium ethoxide, and the molar amount of the alkali is 0.2-0.6 times of the molar amount of the 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole.
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;
the second reaction temperature is 95-105 ℃.
Optionally, step S3 specifically includes:
adding the methyl 3, 3-dimethylcyclopropane-1, 2-diformate obtained in the step S2 and water into a reaction vessel, slowly adding an acid solution to a pH value of 1.0-2.5 under stirring, heating to a temperature of 40-70 ℃, preserving heat for acid hydrolysis reaction, cooling to room temperature, and extracting the reaction solution with a second organic solvent to obtain a second organic phase containing the generated 3, 3-dimethylcyclopropane-1, 2-diformate.
Optionally, the acid solution is sulfuric acid aqueous solution, the mass fraction of the sulfuric acid aqueous solution is 30% -70%, and the molar quantity of sulfuric acid in the sulfuric acid aqueous solution is 0.5-2 times of the molar quantity of 3, 3-dimethylcyclopropane-1, 2-methyl diformate.
Preferably, the mass fraction of the sulfuric acid aqueous solution is 40% -50%, and the molar amount of sulfuric acid in the sulfuric acid aqueous solution is 0.8-1.2 times of the molar amount of 3, 3-dimethylcyclopropane-1, 2-dimethyl ester.
Optionally, the second organic solvent is one or more of ethyl acetate, methyl acetate, chloroform and 1, 2-dichloroethane.
Optionally, the 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid obtained in step S3 is contained in a second organic phase, and step S4 specifically comprises:
adding a second organic phase containing 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid and a cyclization dehydrating agent into a reaction container, heating to 75-80 ℃ under stirring to extract a second organic solvent in the second organic phase, continuously heating to 130-140 ℃ for reflux, carrying out intramolecular dehydration cyclization reaction for 3-4 hours under heat preservation, cooling to below 70 ℃, and separating by a filler column to obtain a finished product of the caronic anhydride.
Optionally, the cyclized dehydrating agent is acetic anhydride;
the step of separating by a packed column comprises:
adding the cooled reaction liquid into a filling column, heating and steaming to remove acetic acid and residual acetic anhydride in the reaction liquid under the condition of reduced pressure, and collecting fractions at 70-90 ℃ to obtain a finished product of the caronic anhydride.
According to the brand-new preparation method of the caronic anhydride, 2-carbonyl-3-isopropylidene-1, 4-methyl succinate is used as a raw material, firstly, the raw material is dehydrated and condensed with hydrazine to generate 2-hydrazono-3-isopropylidene-1, 4-methyl succinate (intermediate I), then, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole (intermediate II) is generated through intramolecular addition cyclization, then, the elimination reaction is performed to generate key 3, 3-dimethylcyclopropane-1, 2-methyl succinate (intermediate III), and finally, the key intermediate III is subjected to acid hydrolysis and intramolecular dehydration cyclization to obtain the target product caronic anhydride. The method has an original synthesis path, and three wastes generated in the preparation process are harmless nitrogen and a small amount of neutral salt, so that the harm to the environment is obviously reduced. The new process has the characteristics of smooth process, mild reaction condition, easy industrialization, high product purity and the like.
Furthermore, the key intermediate III is hydrolyzed in an acid hydrolysis mode in the preparation method of the caronic anhydride, so that the method is simpler and more convenient than the common post-treatment flow of alkaline hydrolysis reaction, and the waste salt amount generated in the neutralization step is effectively reduced.
The foregoing description is only an overview of the present invention, and is intended to be implemented in accordance with the teachings of the present invention in order that the same may be more clearly understood and to make the same and other objects, features and advantages of the present invention more readily apparent.
Detailed Description
The technical scheme of the present invention will be further described with reference to specific examples, but it should be understood that the present invention is not limited to these specific examples.
The embodiment of the invention provides a preparation method of caronic anhydride, and the prepared reaction equation is shown as follows:
the preparation method comprises the following steps:
step S1: carrying out dehydration condensation reaction on raw material 2-carbonyl-3-isopropylidene-1, 4-methyl succinate and hydrazine hydrate in a first organic solvent to generate 2-hydrazono-3-isopropylidene-1, 4-methyl succinate (intermediate I), and continuously carrying out intramolecular addition cyclization on the 2-hydrazono-3-isopropylidene-1, 4-methyl succinate (intermediate I) to generate 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole (intermediate II);
step S2: in the presence of alkali, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole (intermediate II) is subjected to elimination reaction to generate 3, 3-dimethylcyclopropane-1, 2-dimethyl acid methyl ester (intermediate III);
step S3: acid hydrolysis of methyl 3, 3-dimethylcyclopropane-1, 2-dicarboxylate (intermediate III) in an acidic environment to form 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid; and
step S4: in the presence of a cyclization dehydrating agent, carrying out intramolecular dehydration cyclization on 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid to generate the caronic anhydride.
According to the brand-new preparation method of the caronic anhydride, 2-carbonyl-3-isopropylidene-1, 4-methyl succinate is used as a raw material, firstly, the raw material is dehydrated and condensed with hydrazine to generate 2-hydrazono-3-isopropylidene-1, 4-methyl succinate (intermediate I), then 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole (intermediate II) is generated through intramolecular addition cyclization, then key 3, 3-dimethylcyclopropane-1, 2-methyl benzoate (intermediate III) is generated through elimination reaction, and finally, the key intermediate III is subjected to acid hydrolysis and intramolecular dehydration cyclization to obtain the target product caronic anhydride. The method has an original synthesis path, and three wastes generated in the preparation process are harmless nitrogen and a small amount of neutral salt, so that the harm to the environment is obviously reduced. The new process has the characteristics of smooth process, mild reaction condition, easy industrialization, high product purity and the like.
Furthermore, the key intermediate III is hydrolyzed in an acid hydrolysis mode in the preparation method of the caronic anhydride, so that the method is simpler and more convenient than the common post-treatment flow of alkaline hydrolysis reaction, and the waste salt amount generated in the neutralization step is effectively reduced.
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, and the like. The first organic solvent may be used in an amount of 4 to 10 times, for example 5 times, 6 times, 7 times, 8 times, 9 times, the mass of the methyl 2-carbonyl-3-isopropylidene-1, 4-succinate; preferably 6 to 7 times, thereby facilitating the smooth and complete progress of the dehydration condensation reaction.
In some embodiments, in step S1, the molar amount of hydrazine hydrate may be 1.1 to 2.2 times, for example 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 the molar amount of methyl 2-carbonyl-3-isopropylidene-1, 4-succinate; preferably, the reaction is 1.3 to 1.5 times, thereby being more beneficial to the complete reaction of the 2-carbonyl-3-isopropylidene-1, 4-methyl succinate and improving the conversion rate of the 2-carbonyl-3-isopropylidene-1, 4-methyl succinate.
In some further embodiments, a reaction auxiliary agent for enhancing the electropositivity of the carbonyl carbon is further added to the reaction system of step S1. The reaction auxiliary reagent can obviously promote the dehydration condensation reaction of the 2-carbonyl-3-isopropylidene-1, 4-methyl succinate and hydrazine, and has a certain pushing effect on the subsequent intramolecular addition cyclization reaction, thereby further improving the conversion rate of the 2-carbonyl-3-isopropylidene-1, 4-methyl succinate.
Alternatively, the reaction auxiliary reagent may be one or more of acetic acid, propionic acid, benzoic acid, aluminum chloride, zinc chloride, and the like. The molar amount of the reaction auxiliary agent may be 1.3 to 2.0 times, for example 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, the molar amount of hydrazine hydrate.
In some embodiments, step S1 may specifically include:
adding raw materials of 2-carbonyl-3-isopropylidene-1, 4-methyl succinate, hydrazine hydrate, a first organic solvent and a reaction auxiliary reagent into a reaction vessel to form a reaction system, uniformly stirring, heating to a first reaction temperature of 80-120 ℃ for reaction for 3-7 hours, so that the 2-carbonyl-3-isopropylidene-1, 4-methyl succinate and the hydrazine hydrate undergo a dehydration condensation reaction to generate 2-hydrazono-3-isopropylidene-1, 4-methyl succinate, and the 2-hydrazono-3-isopropylidene-1, 4-methyl succinate continuously undergoes intramolecular addition cyclization to generate 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole; and cooling the reaction system to room temperature, adding water into the reaction system, stirring, and then carrying out phase separation to obtain a first organic phase containing the generated 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole.
In practice, methyl 2-carbonyl-3-isopropylidene-1, 4-succinate, hydrazine hydrate, a first organic solvent and a reaction auxiliary reagent may be sequentially added to a reaction vessel (e.g., 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 being dried.
The first reaction temperature may be, for example, about 85 ℃, 90 ℃, 95 ℃, 100 ℃, 105 ℃, 110 ℃, or 115 ℃. In a preferred embodiment, the first reaction temperature may be controlled at 90 to 100℃to further enhance the precise control of the dehydration condensation reaction and the subsequent intramolecular addition cyclization reaction.
As described previously, the 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole obtained in step S1 is contained in the first organic phase. Accordingly, in some embodiments of the present invention, step S2 may specifically include:
adding alkali into a first organic phase containing 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole, heating to a second reaction temperature of 80-120 ℃ under stirring, preserving heat for elimination reaction for 2-5 hours, cooling to room temperature, adding water into a reaction system, stirring, separating phases, drying the obtained organic phase, and desolventizing to obtain a crude product of 3, 3-dimethylcyclopropane-1, 2-methyl diformate.
In some embodiments, the base may be one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium methoxide, sodium ethoxide, and the like. Preferably, the base may be potassium hydroxide and/or sodium methoxide.
The molar amount of the base may be 0.2 to 0.6 times, for example, 0.3 times, 0.4 times, 0.5 times, preferably 0.3 to 0.4 times, the molar amount of 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole, thereby promoting smooth and complete progress of the elimination reaction.
The second reaction temperature may be, for example, about 85 ℃, 90 ℃, 95 ℃, 100 ℃, 105 ℃, 110 ℃, or 115 ℃. In a preferred embodiment, the second reaction temperature may be controlled between 95 and 105 ℃, further enhancing the precise control of the abatement reaction.
In some embodiments of the present invention, step S3 may specifically include:
adding the methyl 3, 3-dimethylcyclopropane-1, 2-diformate obtained in the step S2 and water into a reaction vessel, slowly adding an acid solution to a pH value of 1.0-2.5 under stirring, heating to a temperature of 40-70 ℃, preserving heat for acid hydrolysis reaction, cooling to room temperature, and extracting the reaction solution with a second organic solvent to obtain a second organic phase containing the generated 3, 3-dimethylcyclopropane-1, 2-diformate.
Specifically, the extraction process may be performed a plurality of times (e.g., 2 to 3 times), the organic phases obtained from each extraction are combined, the combined organic phases are dried and filtered to obtain a second organic phase containing the produced 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid, which is directly used in the next reaction. The second organic solvent may be selected from organic solvents having a polarity suitable for extracting the product from the reaction liquid, such as one or more of ethyl acetate, methyl acetate, chloroform, 1, 2-dichloroethane, and the like.
The pH of the acidic environment is in the range of 1.0 to 2.5, e.g. 1.2, 1.4, 1.5, 1.7, 1.9, 2.0, 2.2, 2.3, 2.4.
The acid solution may be any suitable strong acid solution such as sulfuric acid solution, hydrochloric acid solution, benzenesulfonic acid solution, p-toluenesulfonic acid solution, and the like.
In a specific embodiment, the acid solution is an aqueous sulfuric acid solution, which can ensure that the required pH value is achieved and reduce the cost of raw materials.
Further, the mass fraction of the aqueous sulfuric acid solution may be 30% to 70%, for example 40%, 50%, 60%; the molar amount of sulfuric acid in the aqueous sulfuric acid solution may be 0.5 to 2 times, for example, 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 the molar amount of methyl 3, 3-dimethylcyclopropane-1, 2-dicarboxylate to ensure the completion of the acid hydrolysis reaction.
More preferably, the mass fraction of the sulfuric acid aqueous solution is 40% -50%, and the molar amount of sulfuric acid in the sulfuric acid aqueous solution is 0.8-1.2 times the molar amount of methyl 3, 3-dimethylcyclopropane-1, 2-dicarboxylate.
In practice, it can be determined whether the acid hydrolysis reaction has been completed by monitoring the conversion of intermediate III (methyl 3, 3-dimethylcyclopropane-1, 2-dicarboxylate).
As previously described, the 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid obtained in step S3 is contained in the second organic phase. Accordingly, in some embodiments of the present invention, step S4 may specifically include:
adding a second organic phase containing 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid and a cyclization dehydrating agent into a reaction container, heating to 75-80 ℃ under stirring to extract a second organic solvent in the second organic phase, continuously heating to 130-140 ℃ for reflux, carrying out intramolecular dehydration cyclization reaction for 3-4 hours under heat preservation, cooling to below 70 ℃, and separating by a filler column to obtain a finished product of the caronic anhydride.
The cyclization dehydrating reagent can be any reagent suitable for promoting a dehydration cyclization reaction. In a specific embodiment, the cyclized dehydrating reagent may be acetic anhydride.
In some further embodiments, the step of separating by a packed column may specifically comprise:
adding the cooled reaction liquid into a filling column, heating and steaming to remove acetic acid and residual acetic anhydride in the reaction liquid under the condition of reduced pressure, and collecting fractions at 70-90 ℃ to obtain a finished product of the caronic anhydride. The pressure reduction condition may be, for example, -0.095 MPa. The packing column can generally adopt glass packing or Dixon stainless steel packing, etc.
The following embodiments of the present invention will be described by way of specific, non-limiting examples, and other advantages and effects of the present invention will be readily apparent to those skilled in the art from the disclosure herein. The invention may be practiced or carried out in other embodiments that depart from the specific details, and the details of the present description may be modified or varied from the spirit and scope of the present invention.
Example 1
Step 1: preparation of 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole
Sequentially adding methyl 2-carbonyl-3-isopropylidene-1, 4-succinate (40.0 g/0.20 mol), hydrazine hydrate (20.8 g/0.26 mol) with the mass fraction of 40% in a 500ml single-port bottle, uniformly stirring and mixing the mixture, 1, 2-dichloroethane 280ml and glacial acetic acid (21.8 g/0.36 mol), heating the mixture to reflux for 4 hours, sampling and monitoring the content of the raw material methyl 2-carbonyl-3-isopropylidene-1, 4-succinate to be less than 1.0% (HPLC-Area%), stopping heating, cooling the reaction solution to room temperature, adding 80ml of water into the reaction bottle, standing and phase-separating after stirring for 10min, drying the organic phase by anhydrous sodium sulfate, and filtering the organic phase for the next reaction.
Step 2: preparation of methyl 3, 3-dimethylcyclopropane-1, 2-dicarboxylate
Sequentially adding the organic phase obtained in the step 1 and potassium hydroxide (3.4 g/0.06 mol) into a 500ml single-port bottle, heating while stirring to reflux for 3h, sampling and monitoring until the content of an intermediate II (3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole) is less than 1.0 percent (HPLC-Area percent), stopping heating, cooling the reaction liquid to room temperature, adding 100ml of water into the reaction bottle, stirring for 10min, standing for phase separation, drying the organic phase by anhydrous sodium sulfate, filtering, and desolventizing to obtain 29.6g of a solid crude product of an intermediate III (3, 3-dimethylcyclopropane-1, 2-dimethyl formate) with the content of 95.35 percent.
The two-step yields of steps 1 and 2 were 75.9%.
Step 3: preparation of 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid
A250 ml single-port bottle is sequentially filled with crude product of intermediate III (29.6 g/0.15 mol) and 30g of water, sulfuric acid aqueous solution (weight percentage: 40%) (29.4 g/0.12 mol) is slowly added while stirring, after the addition is finished, the temperature is raised to 50-55 ℃, the reaction is kept for 2 hours, sampling is carried out until the content of intermediate III (3, 3-dimethylcyclopropane-1, 2-methyl diformate) is monitored to be less than 2.0% (HPLC-Area%), heating is stopped, the reaction solution is cooled to room temperature, 50ml of ethyl acetate is used for extraction for 3 times, the organic phases are combined, the mixture is dried by anhydrous sodium sulfate and filtered, and the filtrate is directly used for the next reaction.
Step 4: preparation of Carlong anhydride
Sequentially adding the organic phase obtained in the step 3 and acetic anhydride (61.2 g/0.60 mol) into a 250ml single-port bottle, heating to 75-80 ℃ while stirring, extracting solvent ethyl acetate, continuously heating to 130-140 ℃ for reflux, carrying out heat preservation reaction for 3h, stopping heating and cooling to below 70 ℃, adding a 10cm filling column, vacuumizing by an oil pump (-0.095 Mpa), heating and steaming to remove acetic acid and residual acetic anhydride in a reaction system, collecting fractions with the top temperature of 70-90 ℃, and cooling to obtain 9.7g of a product of the caronic anhydride with the content of 99.01%.
The two-step yields of steps 3 and 4 were 45.8%.
The total yield of the four-step reaction was 34.4%.
Example two
Step 1: preparation of 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole
Sequentially adding 2-carbonyl-3-isopropylidene-1, 4-methyl succinate (40.0 g/0.20 mol), hydrazine hydrate (24.0 g/0.30 mol) with the mass fraction of 40% by weight, 1, 2-dichloroethane 240ml and glacial acetic acid (28.8 g/0.48 mol) into a 500ml single-port bottle, stirring and mixing uniformly, heating to reflux reaction for 5h, sampling and monitoring until the content of the raw material 2-carbonyl-3-isopropylidene-1, 4-methyl succinate is less than 0.7% (HPLC-Area%), stopping heating, cooling the reaction solution to room temperature, adding 80ml of water into the reaction bottle, standing and phase-separating after stirring for 10min, drying an organic phase by anhydrous sodium sulfate, and filtering for the next reaction.
Step 2: preparation of methyl 3, 3-dimethylcyclopropane-1, 2-dicarboxylate
Sequentially adding the organic phase obtained in the step 1 and sodium methoxide (4.4 g/0.08 mol) into a 500ml single-port bottle, heating and raising the temperature to reflux for 3h while stirring, sampling and monitoring the mixture until the content of an intermediate II (3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole) is less than 1.0 percent (HPLC-Area percent), stopping heating, cooling the reaction liquid to room temperature, adding 90ml of water into the reaction bottle, stirring for 10min, standing and splitting phases, drying the organic phase by anhydrous sodium sulfate, filtering and desolventizing to obtain 28.0g of a solid crude product of an intermediate III (3, 3-dimethylcyclopropane-1, 2-dimethyl formate) and 96.13 percent.
The two-step yields of steps 1 and 2 were 72.4%.
Step 3: preparation of 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid
A250 ml single-port bottle is sequentially filled with crude product of intermediate III (28.0 g/0.14 mol) and 30g of water, sulfuric acid aqueous solution (weight percent: 50%) (27.4 g/0.14 mol) is slowly added while stirring, after the addition is finished, the temperature is raised to 65-70 ℃, the reaction is kept for 1.5 hours, sampling is carried out until the content of intermediate III (3, 3-dimethylcyclopropane-1, 2-methyl diformate) is monitored to be less than 2.0% (HPLC-Area%), heating is stopped, the reaction solution is cooled to room temperature, 50ml of ethyl acetate is used for extraction for 3 times, the organic phases are combined, the mixture is dried by anhydrous sodium sulfate and filtered, and the filtrate is directly used for the next reaction.
Step 4: preparation of Carlong anhydride
Sequentially adding the organic phase obtained in the step 3 and acetic anhydride (61.2 g/0.60 mol) into a 250ml single-port bottle, heating to 75-80 ℃ while stirring, extracting solvent ethyl acetate, continuously heating to 130-140 ℃ for reflux, carrying out heat preservation reaction for 3h, stopping heating and cooling to below 70 ℃, adding a 10cm filling column, vacuumizing by an oil pump (-0.095 Mpa), heating and steaming to remove acetic acid and residual acetic anhydride in a reaction system, collecting fractions with the top temperature of 70-90 ℃, and cooling to obtain 8.8g of a product of the caronic anhydride with the content of 99.18%.
The two-step yields of steps 3 and 4 were 44.7%.
The total yield of the four-step reaction was 31.3%.
According to the preparation method of the caronic anhydride, a brand new synthetic route is adopted, 2-carbonyl-3-isopropylidene-1, 4-methyl succinate and hydrazine hydrate are used as basic raw materials, key intermediate dimethyl caronate is obtained through the steps of dehydration condensation, intramolecular addition cyclization, elimination and the like, and a target product is obtained through the steps of ester hydrolysis and intramolecular dehydration cyclization. The synthetic route has the characteristics of innovative significance, relatively mild reaction conditions of each step, simple and smooth post-treatment, less three wastes, easy industrialization and the like, and has quite practical potential.
In the description provided herein, numerous specific details are set forth. However, it is understood that embodiments of the invention may be practiced without these specific details. In some instances, well-known methods, structures and techniques have not been shown in detail in order not to obscure an understanding of this description.
By now it should be appreciated by those skilled in the art that while a number of exemplary embodiments of the invention have been shown and described herein in detail, many other variations or modifications of the invention consistent with the principles of the invention may be directly ascertained or inferred from the present disclosure without departing from the spirit and scope of the invention. Accordingly, the scope of the present invention should be understood and deemed to cover all such other variations or modifications.
Claims (10)
1. A method for preparing caronic anhydride, comprising the following steps:
step S1: the method comprises the steps of carrying out dehydration condensation reaction on raw material 2-carbonyl-3-isopropylidene-1, 4-methyl succinate and hydrazine hydrate in a first organic solvent to generate 2-hydrazono-3-isopropylidene-1, 4-methyl succinate, and continuously carrying out intramolecular addition cyclization on the 2-hydrazono-3-isopropylidene-1, 4-methyl succinate to generate 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole;
step S2: in the presence of alkali, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole is subjected to elimination reaction to generate 3, 3-dimethylcyclopropane-1, 2-dimethyl formate;
step S3: acid hydrolyzing methyl 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid in an acidic environment to generate 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid; and
step S4: in the presence of a cyclization dehydrating agent, carrying out intramolecular dehydration cyclization on 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid to generate the caronic anhydride.
2. The method for preparing the caronic anhydride according to claim 1, wherein in the step S1, the first organic solvent is one or more of dichloroethane, dichloropropane, toluene, sulfolane and diethylene glycol monomethyl ether, and the volume amount of the first organic solvent is 4-10 times the mass of the methyl 2-carbonyl-3-isopropylidene-1, 4-succinate;
the molar quantity of the hydrazine hydrate is 1.1 to 2.2 times of that of the methyl 2-carbonyl-3-isopropylidene-1, 4-succinate;
preferably, the volume dosage of the first organic solvent is 6-7 times of the mass of the methyl 2-carbonyl-3-isopropylidene-1, 4-succinate, and the molar quantity of the hydrazine hydrate is 1.3-1.5 times of the molar quantity of the methyl 2-carbonyl-3-isopropylidene-1, 4-succinate.
3. The method for preparing the carbanionic anhydride according to claim 1 or 2, wherein a reaction auxiliary agent for enhancing the electropositivity of carbonyl carbon is further added into the reaction system of the step S1, and the step S1 specifically comprises:
adding raw materials of 2-carbonyl-3-isopropylidene-1, 4-methyl succinate, hydrazine hydrate, the first organic solvent and the reaction auxiliary reagent into a reaction vessel to form a reaction system, uniformly stirring, heating to a first reaction temperature of 80-120 ℃ and reacting for 3-7 hours to enable the 2-carbonyl-3-isopropylidene-1, 4-methyl succinate and the hydrazine hydrate to carry out dehydration condensation reaction to generate 2-hydrazono-3-isopropylidene-1, 4-methyl succinate, and enabling the 2-hydrazono-3-isopropylidene-1, 4-methyl succinate to continuously carry out intramolecular addition cyclization to generate 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole;
and cooling the reaction system to room temperature, adding water into the reaction system, stirring, and then carrying out phase separation to obtain a first organic phase containing the generated 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole.
4. The method for preparing the caronic anhydride according to claim 3, wherein 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 1.3-2.0 times of that of hydrazine hydrate;
preferably, the molar quantity of the reaction auxiliary reagent is 1.4-1.7 times of that of hydrazine hydrate, and the first reaction temperature is 90-100 ℃.
5. The method for preparing caronic anhydride according to claim 1, wherein the 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole obtained in step S1 is contained in a first organic phase, and step S2 specifically comprises:
adding the alkali into the first organic phase containing 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole, heating to a second reaction temperature of 80-120 ℃ under stirring, preserving heat for elimination reaction for 2-5 hours, cooling to room temperature, adding water into a reaction system, stirring, separating phases, drying the obtained organic phase, and desolventizing to obtain the 3, 3-dimethylcyclopropane-1, 2-methyl diformate.
6. The process for producing a carbaryl anhydride according to claim 5, 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 to 0.6 times the molar amount of 3, 3-dimethyl-4, 5-dimethoxycarbonyl-2, 4-dihydropyrazole;
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;
the second reaction temperature is 95-105 ℃.
7. The method for preparing the caronic anhydride according to claim 1, wherein the step S3 specifically comprises:
and (2) adding the 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid methyl ester obtained in the step (S2) and water into a reaction vessel, slowly adding an acid solution to a pH value of 1.0-2.5 under stirring, heating to a temperature of 40-70 ℃, carrying out acid hydrolysis reaction at a temperature of 40-70 ℃, cooling to room temperature, and extracting the reaction solution with a second organic solvent to obtain a second organic phase containing the generated 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid.
8. The method for producing a carbaryl anhydride according to claim 7, wherein the acid solution is an aqueous sulfuric acid solution having a mass fraction of 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;
the second organic solvent is one or more of ethyl acetate, methyl acetate, chloroform and 1, 2-dichloroethane;
preferably, the mass fraction of the sulfuric acid aqueous solution is 40% -50%, and the molar amount of sulfuric acid in the sulfuric acid aqueous solution is 0.8-1.2 times of the molar amount of 3, 3-dimethylcyclopropane-1, 2-dimethyl formate.
9. The method for preparing caronic anhydride according to claim 1, wherein the 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid obtained in step S3 is contained in a second organic phase, and step S4 specifically comprises:
adding the second organic phase containing 3, 3-dimethylcyclopropane-1, 2-dicarboxylic acid and the cyclization dehydrating agent into a reaction container, heating to 75-80 ℃ under stirring, extracting a second organic solvent in the second organic phase, continuously heating to 130-140 ℃ for reflux, carrying out intramolecular dehydration cyclization reaction for 3-4 hours under heat preservation, cooling to below 70 ℃, and separating by a packing column to obtain a finished product of the caronic anhydride.
10. The process for preparing a caronic anhydride according to claim 9, wherein the cyclized dehydrating agent is acetic anhydride;
the step of separating by a packed column comprises:
adding the cooled reaction liquid into the filling column, heating and steaming to remove acetic acid and residual acetic anhydride in the reaction liquid under the condition of reduced pressure, and collecting fractions at 70-90 ℃ to obtain a finished product of the caronic anhydride.
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