CN114835584A - Method for post-treatment of esterification reaction of 3-methyl-4-nitrobenzoic acid and alcohol - Google Patents
Method for post-treatment of esterification reaction of 3-methyl-4-nitrobenzoic acid and alcohol Download PDFInfo
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Abstract
The application relates to a method for post-treatment of esterification reaction of 3-methyl-4-nitrobenzoic acid and alcohol, which relates to the field of fine chemical engineering and organic chemical synthesis and comprises the following steps: s1, mixing 3-methyl-4-nitrobenzoic acid with a solvent, and carrying out a heating esterification reaction with alkyl alcohol under the action of an acid catalyst to generate 3-methyl-4-nitrobenzoate; s2, cooling, crystallizing, filtering, separating and drying the reaction liquid to obtain a purified esterification product; s3, concentrating the mother liquor filtered and separated in the step S2 to recover the solvent, and after concentrating and dewatering, recycling the acidic mother liquor to the next batch; s4, the solvent recovered in the step S3 is dehydrated and recycled for the next batch. According to the method, acid catalysts such as sulfuric acid and the like and an esterification reaction solvent are recycled, the cost of waste acid water treatment is greatly reduced, raw materials which do not react completely are recycled to the next batch of production, the yield of products is increased, and the production cost is greatly reduced.
Description
Technical Field
The application relates to the field of fine chemical engineering and organic chemical synthesis, in particular to a method for post-treatment of esterification reaction of 3-methyl-4-nitrobenzoic acid and alcohol.
Background
3-Methyl-4-nitrobenzoic acid, 3-Methyl-4-nitrobenzoic acid in British name, light yellow to yellow crystal powder, and the chemical structural formula is as follows:
the 3-methyl-4-nitrobenzoic acid is mainly used for telmisartan raw materials or organic synthesis after carboxyl esterification protection. The current synthetic route of telmisartan is mainly as follows: the preparation method comprises the following steps of taking 3-methyl-4-nitrobenzoic acid as a main raw material, heating the main raw material and alcohol under the catalysis of sulfuric acid and other acids to perform esterification reaction, performing palladium-carbon catalytic reduction, sequentially reacting with n-butyryl chloride, nitrifying with mixed acid, performing palladium-carbon catalytic secondary reduction, performing cyclization and deesterification, performing dehydration condensation with methyl o-phenylenediamine, performing alkylation reaction with 4-bromomethyl biphenyl-2-methyl formate, and hydrolyzing to obtain telmisartan.
In the synthesis process of telmisartan, the process of generating an esterified substance by the esterification reaction of 3-methyl-4-nitrobenzoate has important significance, and on one hand, the stability and lipid solubility of the structure can be improved through the protection of carboxyl, so that the subsequent series of reaction processes can be effectively carried out; on the other hand, organic by-product impurities brought by the 3-methyl-4-nitrobenzoic acid raw material and poison residues which poison the palladium catalyst can be more effectively removed through the crystallization and purification of the acidic organic solvent phase. Most of the conventional methods in the step use a large amount of sulfuric acid for catalysis, a large amount of water is added for dilution after the reaction is finished to crystallize the product, or the esterification reaction liquid is poured into a large amount of water to crystallize the product and filter the product to obtain the esterification product, and the filtered mother liquor containing a large amount of waste acid, solvent and organic impurities enters a wastewater treatment system. Thus, on the one hand, the quality and the yield of the esterification reaction product are reduced, and organic byproducts and residual heavy metals brought by raw materials are not removed; on the other hand, the difficulty of treating wastewater containing sulfur and the like is greatly increased, and the environment is threatened greatly.
Disclosure of Invention
In order to solve the technical problems, the application provides a post-treatment method for esterification reaction of 3-methyl-4-nitrobenzoic acid and alcohol, which can effectively improve the yield of products, reduce the production cost and reduce the environmental pollution.
The application provides a method for post-treatment of esterification reaction of 3-methyl-4-nitrobenzoic acid and alcohol, which adopts the following technical scheme:
a method for post-treatment of esterification reaction of 3-methyl-4-nitrobenzoic acid and alcohol comprises the following steps:
s1, mixing 3-methyl-4-nitrobenzoic acid with a solvent, and carrying out a heating esterification reaction with alkyl alcohol under the action of an acid catalyst to generate 3-methyl-4-nitrobenzoate;
s2, cooling, crystallizing, filtering, separating and drying the reaction liquid to obtain a purified esterification product;
s3, concentrating the mother liquor filtered and separated in the step S2 to recover the solvent, and after concentrating and dewatering, recycling the acidic mother liquor to the next batch;
and S4, dehydrating the solvent recovered in the step S3, and recycling the solvent for the next batch.
By adopting the technical scheme, the process takes 3-methyl-4-nitrobenzoic acid as a raw material, and the 3-methyl-4-nitrobenzoic acid and alkyl alcohol are subjected to esterification reaction under the heating condition under the catalysis of acid such as sulfuric acid and the like, and then the esterification reaction product is obtained through direct cooling crystallization, filtration separation and drying; concentrating the filtered mother liquor at normal pressure to recover alcohol, and then distilling and concentrating under reduced pressure to recycle the acidic mother liquor with higher boiling point for the next time; the recovered solvent is distilled and dehydrated and then recycled to the next batch. The synthesis method recycles acid catalysts such as sulfuric acid and the like and esterification reaction solvents, and greatly reduces the cost of waste acid water treatment. Meanwhile, as the raw material benzoic acid which is not completely reacted is recycled to the next batch of production along with the acidic mother liquor, the yield of the product is increased, and the production cost is greatly reduced. And as for the crystallization mode of the esterification product, the organic solvent phase is combined with a larger amount of water for crystallization, so that the purity and quality stability of the product are improved, and the quality guarantee is provided for the subsequent procedures. The process has the advantages of mild reaction conditions, less environmental pollution, simple operation and great economic and social values.
Optionally, in step S1, the acid catalyst is any one of concentrated sulfuric acid, dilute sulfuric acid, phosphoric acid, sulfurous acid, and benzenesulfonic acid.
Optionally, the molar ratio of the acid catalyst to the 3-methyl-4-nitrobenzoic acid is (0.1-3.0): 1.
By adopting the technical scheme, the acid catalyst is strong acid with boiling point higher than that of the solvent, such as concentrated sulfuric acid, dilute sulfuric acid, phosphoric acid, sulfurous acid, benzenesulfonic acid and the like. During the esterification reaction of 3-methyl-4-nitrobenzoate, methanol is used as a nucleophile to carry out nucleophilic attack on the carbonyl group of benzoic acid. In particular, in the presence of a protic acid such as concentrated sulfuric acid, the carbonyl group is made more electron deficient and the alkyl alcohol is attracted to undergo a nucleophilic addition reaction with it to form an ester. Under the catalysis of protonic acid such as sulfuric acid, the reaction is difficult to carry out or extremely slow, the esterification reaction is a reversible reaction, and concentrated sulfuric acid breaks the balance of the reaction through dehydration and catalytic action, so that the reaction balance is moved to the direction of ester, the reaction is accelerated, and the carboxylic ester is generated. Tests show that the molar ratio of the addition amount of the acid catalyst to the use amount of the 3-methyl-4-nitrobenzoic acid is (0.1-3.0): 1, so that a better catalysis effect can be achieved, and a better reaction progress promoting effect can be achieved.
Optionally, the solvent is methanol, ethanol, propanol, isopropanol, butanol, toluene or xylene.
By adopting the technical scheme, the solvent in the technical scheme of the application is selected from organic solvents such as methanol, ethanol, propanol, isopropanol, butanol, toluene or xylene, and in the subsequent cooling crystallization process, the organic solvent phase crystallization is compared with the large-scale water crystallization, so that the purity and the quality stability of the product can be effectively improved, and the quality guarantee is provided for the subsequent process.
Optionally, the alkyl alcohol is methanol, ethanol, propanol, isopropanol or butanol.
Optionally, in step S1, the heating temperature of the esterification reaction is 40 to 150 ℃.
By adopting the technical scheme, the alkyl alcohol with a lower boiling point is adopted, the esterification reaction is promoted to rapidly occur by heating, the temperature of the esterification reaction is controlled to be adaptive to the boiling point of the corresponding alkyl alcohol, and the influence on the reaction process and the product yield due to the fact that the alkyl alcohol is heated and evaporated due to overhigh reaction temperature is avoided.
Optionally, the temperature for cooling and crystallizing in the step S2 is-10 to 50 ℃.
Optionally, in step S2, the filtering and separating method is filter pressing after centrifugal separation.
By adopting the technical scheme, the reaction solution is cooled at a lower temperature, the esterified substance generated by the reaction in the reaction solution is cooled and crystallized at a low temperature, other raw materials in the reaction solution are kept in a liquid state, and the esterified substance is separated from other components in the reaction solution by filtering, so that the content of impurities in the esterified substance is reduced.
Optionally, in step S3, the acidic mother liquor is recycled for not less than 5 times in a batch.
Through adopting above-mentioned technical scheme, acid mother liquor recycles after the distillation concentration, can save the cost on the one hand, and on the other hand can greatly reduce the cost of spent acid water treatment, and the raw materials that will not have the complete reaction simultaneously along with acid mother liquor retrieval and utilization to next batch's production together can reduce the loss of material and product, and the receipts of the product of increase reduce whole production process's cost by a wide margin.
Optionally, the solvent dehydration method in step S4 is supergravity bed distillation dehydration, rectifying tower distillation dehydration, membrane dehydration, azeotropic distillation dehydration or desiccant drying dehydration.
In summary, the present application includes at least one of the following beneficial technical effects:
1. in the technical scheme, 3-methyl-4-nitrobenzoic acid is used as a raw material, and is heated with alkyl alcohol under the catalysis of acid such as sulfuric acid and the like to perform esterification reaction, and then the esterification reaction product is obtained through direct cooling crystallization, filtration separation and drying; and (3) concentrating the filtered mother liquor at normal pressure to recover alcohol, concentrating by reduced pressure distillation, recycling the acidic mother liquor with a higher boiling point to the next batch, and distilling and dehydrating the recovered solvent to recycle the solvent to the next batch. The synthesis method recycles acid catalysts such as sulfuric acid and the like and esterification reaction solvents, greatly reduces the cost of waste acid water treatment, and simultaneously increases the yield of products and greatly reduces the production cost because the unreacted raw material benzoic acid is recycled to the next batch of production along with the acid mother liquor.
2. According to the technical scheme, the solvent is methanol, ethanol, propanol, isopropanol, butanol, toluene or xylene and other organic solvents, and in the subsequent cooling crystallization process, the organic solvent phase crystallization can effectively improve the purity and quality stability of the product compared with the large-volume water crystallization, so that quality guarantee is provided for the subsequent process.
3. In the technical scheme, the acid mother liquor is recycled for at least 5 times in a whole batch, so that on one hand, the cost can be saved, on the other hand, the cost of waste acid water treatment can be greatly reduced, and meanwhile, the raw materials with completely reacted o-m are recycled to the production of the next batch along with the acid mother liquor, so that the loss of the materials and the products can be reduced, the added products are received, and the cost of the whole production process is greatly reduced.
Detailed Description
The present application will be described in further detail with reference to specific examples. It should be noted that, in the following examples, those not specifically mentioned are performed according to conventional conditions or conditions recommended by the manufacturer; the starting materials used in the following examples are all those conventionally commercially available except where specifically noted.
Examples
Example 1
The first preparation of 3-methyl-4-nitrobenzoic acid methyl ester comprises the following preparation processes:
80.0g (0.442mol) of 3-methyl-4-nitrobenzoic acid and 600mL of methanol are added into a 1000mL four-neck flask, the stirring is started, a condenser is started, 86.5g (0.884mol) of concentrated sulfuric acid is slowly dropped at room temperature, and the temperature of the reaction solution is gradually increased along with the addition of the concentrated sulfuric acid. After the dropwise addition of the concentrated sulfuric acid is finished, the concentrated sulfuric acid is continuously heated to 50 ℃ and is subjected to heat preservation and reflux reaction for 8 hours. And stopping the heating reaction after the content of the 3-methyl-4-nitrobenzoic acid as the raw material is determined to be lower than 5.0 percent through detection.
Directly cooling the reaction solution to below 10 ℃, stirring for 30 minutes, separating out a large amount of solid, filtering, leaching the filter cake with 50ml of methanol once, and leaching with an aqueous solution of sodium bicarbonate to be neutral. The filtered solid was collected and dried to give methyl 3-methyl-4-nitrobenzoate.
Mixing methanol for washing and reaction mother liquor, transferring into a concentration flask, stirring and heating, starting low-temperature circulating cooling liquid, and concentrating under reduced pressure to collect methanol; heating and concentrating continuously until the temperature in the concentration flask reaches 120 ℃, the vacuum degree reaches more than-0.09 MPa, stopping heating and concentrating, recovering methanol, adding a molecular sieve, drying and dehydrating overnight, and directly using for the next batch. The residual acidic mother liquor is directly used for the esterification reaction of the next batch after being concentrated and dewatered.
73.3g of methyl 3-methyl-4-nitrobenzoate is obtained, the yield is 85.3 percent, and the content of related substances is detected to be 99.8 percent; the methanol was recovered in an amount of 610 ml.
Example 2
The preparation of methyl 3-methyl-4-nitrobenzoate was carried out using the methanol and the acidic mother liquor recovered in example 1, the specific procedure being as follows:
a1000 mL four-necked flask was charged with the entire batch of the acidic mother liquor recovered in example 1, 590mL of the methanol recovered in example 1, and 80.0g (0.442mol) of 3-methyl-4-nitrobenzoic acid 8, supplemented with 3.0g of concentrated sulfuric acid and 10mL of methanol, stirred with stirring, and heated to 80 ℃ with reflux by heating with a condenser for 8 hours. And stopping the heating reaction after the content of the 3-methyl-4-nitrobenzoic acid as the raw material is determined to be lower than 5.0 percent through detection.
Directly cooling the reaction solution to below 10 ℃, stirring for 30 minutes, separating out solids, filtering, leaching the filter cake with 50ml of methanol once, and leaching with an aqueous solution of sodium bicarbonate to neutrality. The solid after filtration was collected and dried to obtain methyl 3-methyl-4-nitrobenzoate.
Combining the leached methanol and the reaction mother liquor, transferring the mixture into a concentration flask, stirring and heating the mixture, starting low-temperature circulating cooling liquid, and decompressing and concentrating the mixture to recover the methanol; continuously heating and concentrating until the temperature in the concentration flask reaches 120 ℃, and the vacuum degree reaches more than-0.09 MPa, and stopping concentrating. Recovering methanol, adding the methanol into a molecular sieve, drying and dehydrating overnight, and directly using the methanol in the next batch; the residual acidic mother liquor is directly used for the methyl esterification reaction of the next batch after being concentrated and dewatered.
81.9g of methyl 3-methyl-4-nitrobenzoate is obtained, the yield is 95.0 percent, and related substances are detected to be 99.7 percent; 625ml of methanol is obtained after recovery.
Example 3
The methanol and the acidic mother liquor recovered in example 2 were used to prepare methyl 3-methyl-4-nitrobenzoate, and the specific process was as follows:
a1000 mL four-necked flask was charged with the entire batch of the acidic mother liquor recovered in example 2, 600mL of methanol recovered in example 2, and 80.0g (0.442mol) of 3-methyl-4-nitrobenzoic acid), supplemented with 3.0g of concentrated sulfuric acid, stirred on, the condenser was turned on, and heated to 80 ℃ for reflux reaction for 8 h. And stopping the heating reaction after the content of the 3-methyl-4-nitrobenzoic acid as the raw material is determined to be lower than 5.0 percent through detection.
Directly cooling the reaction solution to below 10 ℃, stirring for 30 minutes, separating out solids, filtering, leaching the filter cake with 50ml of methanol once, and leaching with an aqueous solution of sodium bicarbonate to neutrality. The solid after filtration was collected and dried to obtain methyl 3-methyl-4-nitrobenzoate.
Mixing methanol for leaching and reaction mother liquor, transferring into a concentration flask, stirring and heating, starting low-temperature circulating cooling liquid, and performing reduced pressure concentration to recover methanol; heating for concentration until the temperature in the concentration flask reaches 120 ℃, and stopping concentration when the vacuum degree reaches more than-0.09 MPa. Recovering methanol, adding the methanol into a molecular sieve, drying and dehydrating overnight, and directly using the methanol in the next batch; the residual acidic mother liquor is directly used for the methyl esterification reaction of the next batch after being concentrated and dewatered.
84.0g of methyl 3-methyl-4-nitrobenzoate, 97.5% of esterified product yield and 99.7% of related substances detected; the methanol was recovered and 636ml was obtained.
Example 4
The methanol and the acidic mother liquor recovered in example 3 were used to prepare methyl 3-methyl-4-nitrobenzoate, and the specific process was as follows:
a1000 mL four-necked flask was charged with the entire batch of the acidic mother liquor recovered in example 3, 600mL of the methanol recovered in example 3, and 80.0g (0.442mol) of 3-methyl-4-nitrobenzoic acid), supplemented with 3.0g of concentrated sulfuric acid, stirred on, the condenser was turned on, and heated to 80 ℃ for reflux reaction for 8 h. And stopping the heating reaction after the content of the 3-methyl-4-nitrobenzoic acid as the raw material is determined to be lower than 5.0 percent through detection.
Directly cooling the reaction solution to below 10 ℃, stirring for 30 minutes, separating out solids, filtering, leaching the filter cake with 50ml of methanol once, and leaching with an aqueous solution of sodium bicarbonate to neutrality. The solid after filtration was collected and dried to obtain methyl 3-methyl-4-nitrobenzoate.
Mixing methanol for leaching and reaction mother liquor, transferring into a concentration flask, stirring and heating, starting low-temperature circulating cooling liquid, and performing reduced pressure concentration to recover methanol; heating and concentrating until the temperature in the concentrating flask reaches 120 ℃, and the vacuum degree reaches more than-0.09 MPa, and stopping concentrating. Recovering methanol, adding the methanol into a molecular sieve, drying and dehydrating overnight, and directly using the methanol in the next batch; the residual acidic mother liquor is directly used for the methyl esterification reaction of the next batch after being concentrated and dewatered.
84.5g of 3-methyl-4-nitrobenzoic acid methyl ester, 98 percent of esterified product yield and 99.7 percent of related substances detected; 628ml of methanol is obtained after recovery.
Example 5
The methanol and the acidic mother liquor recovered in example 4 were used to prepare methyl 3-methyl-4-nitrobenzoate, and the specific process was as follows:
a1000 mL four-necked flask was charged with the entire batch of the acidic mother liquor recovered in example 4, 600mL of methanol recovered in example 4, and 80.0g (0.442mol) of 3-methyl-4-nitrobenzoic acid), supplemented with 3.0g of concentrated sulfuric acid, stirred on, the condenser was turned on, and heated to 80 ℃ for reflux reaction for 8 h. And stopping the heating reaction after the content of the 3-methyl-4-nitrobenzoic acid as the raw material is determined to be lower than 5.0 percent through detection.
Directly cooling the reaction solution to below 10 ℃, stirring for 30 minutes, separating out solids, filtering, leaching the filter cake with 50ml of methanol once, and leaching with an aqueous solution of sodium bicarbonate to neutrality. The solid after filtration was collected and dried to obtain methyl 3-methyl-4-nitrobenzoate.
Mixing methanol for leaching and reaction mother liquor, transferring into a concentration flask, stirring and heating, starting low-temperature circulating cooling liquid, and performing reduced pressure concentration to recover methanol; heating and concentrating until the temperature in the concentrating flask reaches 120 ℃, and the vacuum degree reaches more than-0.09 MPa, and stopping concentrating. Recovering methanol, adding the methanol into a molecular sieve, drying and dehydrating overnight, and directly using the methanol in the next batch; the residual acidic mother liquor is directly used for the methyl esterification reaction of the next batch after being concentrated and dewatered.
83.6g of 3-methyl-4-nitrobenzoic acid methyl ester, the yield of the esterified substance is 97.0 percent, and 99.6 percent of related substances are detected; 616ml of methanol is obtained after recovery.
Example 6
The methanol and the acidic mother liquor recovered in example 5 were used to prepare methyl 3-methyl-4-nitrobenzoate, and the specific process was as follows:
a1000 mL four-necked flask was charged with the entire batch of acidic mother liquor recovered by concentration in example 5, 580mL of methanol recovered in example 5, and 80.0g (0.442mol) of 3-methyl-4-nitrobenzoic acid, supplemented with 3.0g of concentrated sulfuric acid and 20mL of methanol, stirred with stirring, cooled with a condenser, and heated to 80 ℃ for reflux reaction for 8 hours. And stopping the heating reaction after the content of the 3-methyl-4-nitrobenzoic acid as the raw material is determined to be lower than 5.0 percent through detection.
Directly cooling the reaction solution to below 10 ℃, stirring for 30 minutes, separating out solids, filtering, leaching the filter cake with 50ml of methanol once, and leaching with an aqueous solution of sodium bicarbonate to neutrality. The solid after filtration was collected and dried to obtain methyl 3-methyl-4-nitrobenzoate.
And (3) combining methanol for leaching and reaction mother liquor, transferring the mixture into a concentration flask, stirring and heating, starting low-temperature circulating cooling liquid, concentrating at normal pressure to recover methanol, cooling the concentrated solution to below 15 ℃, performing secondary crystallization to separate out solid, filtering, leaching a filter cake with 15ml of methanol once, leaching with a sodium bicarbonate aqueous solution to be neutral, collecting the filtered solid, and drying to obtain 10.5g of a secondary 3-methyl-4-nitrobenzoate crystal. Heating and concentrating the reaction liquid until the temperature in the concentrating flask reaches 120 ℃, and stopping concentrating when the vacuum degree reaches more than-0.09 MPa to obtain 120ml of secondary recovered methanol. Recovering methanol, adding the methanol into a molecular sieve, drying and dehydrating overnight, and directly using the methanol in the next batch; the residual acidic mother liquor is directly used for the methyl esterification reaction of the next batch after being concentrated and dewatered.
84.9g of methyl 3-methyl-4-nitrobenzoate is obtained by the first crystallization, the yield is 98.5 percent, and related substances are detected to be 99.8 percent; the first recovery yielded 500ml of methanol.
Example 7
The preparation method of the 3-methyl-4-ethyl nitrobenzoate comprises the following specific processes:
80.0g (0.442mol) of 3-methyl-4-nitrobenzoic acid and 600mL of ethanol are added into a 1000mL four-neck flask, the stirring is started, a condenser is started, 86.5g (0.884mol) of concentrated sulfuric acid is slowly added dropwise at room temperature, and the temperature of the reaction solution is gradually increased along with the addition of the concentrated sulfuric acid. After the sulfuric acid is added dropwise, heating to 70 ℃, and carrying out heat preservation and reflux reaction for 5 hours. And stopping the heating reaction after the content of the 3-methyl-4-nitrobenzoic acid as the raw material is determined to be lower than 5.0 percent through detection.
Directly cooling the reaction solution to below 10 ℃, stirring for 30 minutes, separating out solids, filtering, leaching the filter cake with 50ml of ethanol once, and leaching with sodium bicarbonate aqueous solution until the filter cake is neutral. The filtered solid was collected and dried to give ethyl 3-methyl-4-nitrobenzoate.
And mixing the methanol for leaching and the filtered mother liquor, transferring the mixture into a concentration flask, stirring and heating, starting the low-temperature circulating cooling liquid, and performing reduced pressure concentration to recover the ethanol. And stopping concentration until the temperature in the concentration flask reaches 120 ℃ and the vacuum degree reaches more than-0.09 MPa. Recovering ethanol, adding molecular sieve, drying overnight, and directly using in next batch; the residual acidic mother liquor is directly used for the next batch of ethyl esterification reaction after being concentrated and dewatered.
78.0g of ethyl 3-methyl-4-nitrobenzoate is obtained, the yield is 84.5 percent, and related substances are detected to be 99.7 percent; 615ml of ethanol is obtained.
Example 8
The ethanol and the remaining acidic mother liquor recovered in example 7 were used to prepare ethyl 3-methyl-4-nitrobenzoate by the following specific procedure:
a1000 mL four-necked flask was charged with the entire batch of the acidic mother liquor recovered by concentration in example 7, 580mL of the ethanol recovered in example 7, 80.0g (0.442mol) of 3-methyl-4-nitrobenzoic acid, and supplemented with 3.0g of concentrated sulfuric acid and 20mL of ethanol, stirred, cooled by a condenser, and heated to 70 ℃ for reflux reaction for 5 hours. And stopping the heating reaction after the content of the 3-methyl-4-nitrobenzoic acid as the raw material is determined to be lower than 5.0 percent through detection.
Directly cooling the reaction solution to below 10 ℃, stirring for 30 minutes, separating out solids, filtering, leaching the filter cake with 50ml of ethanol once, and leaching with sodium bicarbonate aqueous solution until the filter cake is neutral. The solid after filtration is collected and dried to obtain the ethyl 3-methyl-4-nitrobenzoate 88.7.
And mixing the ethanol for leaching and the filtered mother liquor, transferring the mixed solution into a concentration flask, stirring and heating, starting low-temperature circulating cooling liquid, performing reduced pressure concentration to recover ethanol, continuously heating and concentrating until the temperature in the concentration flask reaches 120 ℃ and the vacuum degree reaches more than-0.09 MPa, and stopping concentration. Recovering ethanol, adding into molecular sieve, drying, dehydrating overnight, and directly using in next batch; the residual acidic mother liquor is directly used for the next batch of ethyl esterification reaction after being concentrated and dewatered.
88.7g of ethyl 3-methyl-4-nitrobenzoate is obtained, the yield is 96.0 percent, and related substances are detected to be 99.8 percent; 635ml of ethanol is obtained.
Example 9
The ethanol and the remaining acidic mother liquor recovered in example 8 were used to prepare ethyl 3-methyl-4-nitrobenzoate by the following specific procedure: a1000 mL four-necked flask was charged with the acidic mother liquor recovered by concentration in example 8, 600mL of ethanol recovered in example 8, and 80.0g (0.442mol) of 3-methyl-4-nitrobenzoic acid, supplemented with 2.0g of concentrated sulfuric acid, stirred, cooled in a condenser, and heated to 70 ℃ for reflux reaction for 5 hours. And stopping the heating reaction after the content of the 3-methyl-4-nitrobenzoic acid in the raw material is determined to be lower than 5.0 percent through detection.
Directly cooling the reaction solution to below 10 ℃, stirring for 30 minutes, separating out solids, filtering, leaching the filter cake with 50ml of ethanol once, and leaching with sodium bicarbonate aqueous solution to be neutral. The solid after filtration is collected and dried to obtain the 3-methyl-4-nitrobenzoic acid ethyl ester. And mixing the leached ethanol and the filtered mother liquor, transferring into a concentration flask, stirring and heating, starting low-temperature circulating cooling liquid, performing reduced pressure concentration to recover 620ml of ethanol, continuing heating and concentrating until the temperature in the flask reaches 120 ℃ and the vacuum degree reaches more than-0.09 MPa, and stopping concentration. And recovering ethanol, adding the ethanol into a molecular sieve, drying and dehydrating overnight, and directly using the ethanol in the next batch, and concentrating and dehydrating the residual acidic mother liquor to be directly used for the ethyl esterification reaction of the next batch.
89.6g of ethyl 3-methyl-4-nitrobenzoate is obtained, the yield is 97.0 percent, and related substances are detected to be 99.7 percent; 620ml of ethanol is obtained.
Example 10
The ethanol and the remaining acidic mother liquor recovered in example 9 were used to prepare ethyl 3-methyl-4-nitrobenzoate by the following specific procedure:
a1000 mL four-necked flask was charged with the entire batch of the acidic mother liquor recovered in example 9, 600mL of the ethanol recovered in example 9, and 80.0g (0.442mol) of 3-methyl-4-nitrobenzoic acid, supplemented with 2.0g of concentrated sulfuric acid, stirred, cooled by a condenser, and heated to 70 ℃ for reflux reaction for 5 h. And stopping the heating reaction after the content of the 3-methyl-4-nitrobenzoic acid as the raw material is determined to be lower than 5.0 percent through detection.
Directly cooling the reaction solution to below 10 ℃, stirring for 30 minutes, separating out solids, filtering, leaching the filter cake with 50ml of ethanol once, and leaching with sodium bicarbonate aqueous solution until the filter cake is neutral. The solid after filtration is collected and dried to obtain the 3-methyl-4-nitrobenzoic acid ethyl ester. And (3) combining the leached ethanol and the filtered acidic mother liquor, transferring the mixed solution into a concentration flask, stirring and heating, starting low-temperature circulating cooling liquid, carrying out reduced pressure concentration to recover ethanol, continuing heating and concentrating until the temperature in the concentration flask reaches 120 ℃ and the vacuum degree reaches more than-0.09 MPa, and stopping concentration. The recovered ethanol is added into a molecular sieve for drying and dehydration overnight and then can be directly used for the next batch of reaction, and the residual acidic mother liquor is concentrated for dehydration and then is directly used for the next batch of ethyl esterification reaction.
90.5g of 3-methyl-4-ethyl nitrobenzoate is obtained, the yield is 98.0 percent, and related substances are detected to be 99.7 percent; 630ml of ethanol is obtained.
By combining all the embodiments, the method for post-treatment of esterification reaction of 3-methyl-4-nitrobenzoic acid and alcohol, provided by the technical scheme of the application, can be used for concentrating and recovering the acid catalyst and the organic solvent in the synthetic reaction process for recycling, can greatly reduce the treatment cost of waste acid water, and can fully utilize the raw materials which are not completely reacted in the residual mother liquor in the process of recycling for many times, thereby further increasing the material collection of products and greatly reducing the production cost. And in addition, as for the crystallization mode of the esterification product, the organic solvent phase is combined with a larger amount of water for crystallization, so that the purity and the quality stability of the product are improved, and the quality guarantee is provided for the subsequent procedures. The method has the advantages of mild reaction conditions, less environmental pollution, simple operation, great innovation of post-treatment mode and great economic and social values.
The above embodiments are preferred embodiments of the present application, and the protection scope of the present application is not limited by the above embodiments, so: all equivalent changes made according to the structure, shape and principle of the present application shall be covered by the protection scope of the present application.
Claims (8)
1. The method for post-treatment of esterification reaction of 3-methyl-4-nitrobenzoic acid and alcohol is characterized by comprising the following steps:
s1, mixing 3-methyl-4-nitrobenzoic acid with a solvent, and carrying out a heating esterification reaction with alkyl alcohol under the action of an acid catalyst to generate 3-methyl-4-nitrobenzoate;
s2, cooling, crystallizing, filtering, separating and drying the reaction liquid to obtain a purified esterification product;
s3, concentrating the mother liquor filtered and separated in the step S2 to recover the solvent, and after concentrating and dewatering, recycling the acidic mother liquor to the next batch;
s4, the solvent recovered in the step S3 is dehydrated and recycled for the next batch.
2. The method for post-treatment of esterification reaction of 3-methyl-4-nitrobenzoic acid and alcohol according to claim 1, which is characterized in that: in step S1, the acid catalyst is any one of concentrated sulfuric acid, dilute sulfuric acid, phosphoric acid, sulfurous acid, and benzenesulfonic acid.
3. The method for the post-treatment of the esterification reaction of 3-methyl-4-nitrobenzoic acid and alcohol according to claim 1, wherein: the molar ratio of the acid catalyst to the 3-methyl-4-nitrobenzoic acid is (0.1-3.0): 1.
4. The method for post-treatment of esterification reaction of 3-methyl-4-nitrobenzoic acid and alcohol according to claim 1, which is characterized in that: the solvent is methanol, ethanol, propanol, isopropanol, butanol, toluene or xylene.
5. The method for post-treatment of esterification reaction of 3-methyl-4-nitrobenzoic acid and alcohol according to claim 1, which is characterized in that: the alkyl alcohol is methanol, ethanol, propanol, isopropanol or butanol.
6. The method for post-treatment of esterification reaction of 3-methyl-4-nitrobenzoic acid and alcohol according to claim 1, which is characterized in that: in step S1, the heating temperature of the esterification reaction is 40-150 ℃.
7. The method for post-treatment of esterification reaction of 3-methyl-4-nitrobenzoic acid and alcohol according to claim 1, which is characterized in that: the temperature of the cooling crystallization in the step S2 is-10 to 50 ℃.
8. The method for post-treatment of esterification reaction of 3-methyl-4-nitrobenzoic acid and alcohol according to claim 1, which is characterized in that: the solvent dehydration method in the step S4 is supergravity bed distillation dehydration, rectifying tower distillation dehydration, membrane dehydration, azeotropic distillation dehydration or desiccant drying dehydration.
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| CN1211736A (en) * | 1996-11-14 | 1999-03-24 | 罗姆和哈斯公司 | Use of certain amides as probes for detection of antitubulin activity and resistance monitoring |
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| CN1211736A (en) * | 1996-11-14 | 1999-03-24 | 罗姆和哈斯公司 | Use of certain amides as probes for detection of antitubulin activity and resistance monitoring |
| JPH11228513A (en) * | 1998-02-12 | 1999-08-24 | Sumika Fine Chemicals Co Ltd | 4-acetylamino-3-methylbenzoic acid compound, its production and production of 1h-indazole-5-carboxylic acid using the same |
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