CN108191667B - Preparation method of 2-nitro-4-trifluoromethyl methyl benzoate - Google Patents
Preparation method of 2-nitro-4-trifluoromethyl methyl benzoate Download PDFInfo
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Abstract
The invention discloses a preparation method of 2-nitro-4-trifluoromethyl methyl benzoate, belonging to the technical field of organic synthesis. The invention aims to solve the technical problem of providing a novel method for preparing 2-nitro-4-trifluoromethyl methyl benzoate. The method comprises the following steps: hydrolyzing 2-nitro-4-trifluoromethyl benzonitrile under base catalysis or acid catalysis to prepare 2-nitro-4-trifluoromethyl benzamide; mixing the 2-nitro-4-trifluoromethyl benzamide with a sulfuric acid-methanol solution for alcoholysis reaction to obtain 2-nitro-4-trifluoromethyl methyl benzoate. The method has mild reaction conditions and simple post-treatment, can obtain high-purity 2-nitro-4-trifluoromethyl methyl benzoate with high yield, and is favorable for realizing industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and relates to a preparation method of 2-nitro-4-trifluoromethyl methyl benzoate.
Background
Methyl 2-nitro-4-trifluoromethylbenzoate is an important pharmaceutical and agrochemical intermediate, such as nitisinone, isoxaflutole, TRPV1 receptor antagonist (CN101228131A), CRF receptor antagonist (CN101166729A), Raf kinase inhibitor (CN1283180A) and the like.
In the literature, the following routes are mainly used for preparing methyl 2-nitro-4-trifluoromethylbenzoate:
a, 2-nitro-4-trifluoromethylbenzoic acid route:
the route prepares an intermediate 2-nitro-4-trifluoromethylbenzoic acid, and the intermediate is directly esterified or is firstly subjected to acyl chlorination and then esterified to obtain the 2-nitro-4-trifluoromethylbenzoic acid methyl ester. This route has the following drawbacks: (1) when 4-trifluoromethyl benzoic acid is used as a raw material to prepare 2-nitro-4-trifluoromethyl benzoic acid, the reaction yield is only 48 percent (CN 1886374A); (2) when 4-trifluoromethyl benzonitrile is used as a raw material to prepare 2-nitro-4-trifluoromethylbenzoic acid, acid catalysis or base catalysis can be adopted. However, when nitrile compounds are hydrolyzed under acidic or basic conditions, there is a problem of reaction selectivity, that is, a mixture of amide and carboxylic acid is generally obtained, and if it is desired to increase the selectivity of carboxylic acid formation, higher hydrolysis conditions, such as high concentration of strong base, strong acid or high temperature, are required, increasing the production cost; and, base catalysis (such as NaOH) is adopted, the reaction is usually carried out in aqueous solution, the obtained product is 2-nitro-4-trifluoromethyl benzyl metal salt, the metal salt is dissolved in water, and the 2-nitro-4-trifluoromethyl benzoic acid can be generated after acidification, so that the 2-nitro-4-trifluoromethyl benzoic acid is separated out from the water. The alkali cannot be recycled, and additional acid is needed, so that the environmental protection pressure is increased, and the production cost is increased.
Bis, 4-trifluoromethylbenzoic acid methyl ester route:
the method comprises the steps of firstly preparing an intermediate 4-trifluoromethyl methyl benzoate, and then nitrifying the intermediate to obtain the 2-nitro-4-trifluoromethyl methyl benzoate. However, the yield is only 69% at the maximum even after optimization of a plurality of parameters due to strong competition of nitration sites (synthetic research of methyl 2-nitro-4-trifluoromethylbenzoate, Shandong chemical engineering, 2015, 44 (19): 18-19).
And thirdly, a carbonylation route:
in the method, 2-nitro-4-trifluoromethyl halogenated benzene is used as a raw material and reacts with methanol and carbon monoxide under the action of a palladium catalyst to prepare the 2-nitro-4-trifluoromethyl methyl benzoate (US 6337418). However, palladium catalysts are expensive and require high pressures to achieve high yields, which is a high process threshold.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel method for preparing 2-nitro-4-trifluoromethyl methyl benzoate, which has the advantages of low cost, mild condition, simple operation and high yield.
The technical scheme adopted by the invention for solving the technical problems is to provide a preparation method of 2-nitro-4-trifluoromethyl methyl benzoate, which comprises the following steps:
a. hydrolyzing 2-nitro-4-trifluoromethyl benzonitrile by alkali catalysis or acid catalysis to prepare 2-nitro-4-trifluoromethyl benzamide;
b. and c, mixing the 2-nitro-4-trifluoromethyl benzamide obtained in the step a with a sulfuric acid-methanol solution for alcoholysis reaction to obtain the 2-nitro-4-trifluoromethyl methyl benzoate.
In the above preparation method of methyl 2-nitro-4-trifluoromethylbenzoate, in step a, when base catalysis is adopted, the base catalyzed by the base is selected from inorganic bases.
Further, in the above preparation method of methyl 2-nitro-4-trifluoromethylbenzoate, in step a, when base catalysis is adopted, the molar ratio of the inorganic base to 2-nitro-4-trifluoromethylbenzonitrile is 0.1 to 4: 1.
preferably, in the above preparation method of methyl 2-nitro-4-trifluoromethylbenzoate, in step a, when base catalysis is adopted, the molar ratio of the inorganic base to 2-nitro-4-trifluoromethylbenzonitrile is 1 to 4: 1.
further, in the above preparation method of methyl 2-nitro-4-trifluoromethylbenzoate, in step a, when base catalysis is adopted, inorganic base, 2-nitro-4-trifluoromethylbenzonitrile and water are mixed for hydrolysis reaction; the amount of the water is 5-50L/kg 2-nitro-4-trifluoromethyl benzonitrile.
Further, in the above preparation method of methyl 2-nitro-4-trifluoromethylbenzoate, in step a, when base catalysis is adopted, the inorganic base is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
Further, in the above preparation method of methyl 2-nitro-4-trifluoromethylbenzoate, in step a, when base catalysis is adopted, the temperature of the hydrolysis reaction is 0 ℃ to 65 ℃.
Preferably, in the above preparation method of methyl 2-nitro-4-trifluoromethylbenzoate, in step a, when the inorganic base is less basic than potassium hydroxide in the presence of base catalysis, the temperature of the hydrolysis reaction is 15 to 60 ℃.
More preferably, in the above method for preparing methyl 2-nitro-4-trifluoromethylbenzoate, in step a, when the inorganic base is less basic than potassium hydroxide under the catalysis of base, the temperature of the hydrolysis reaction is 45-55 ℃.
Further, in the above preparation method of methyl 2-nitro-4-trifluoromethylbenzoate, in step a, when base catalysis is adopted, and when the inorganic base is potassium hydroxide, the temperature of the hydrolysis reaction is 55 ℃ to 65 ℃.
More specifically, in the above preparation method of methyl 2-nitro-4-trifluoromethylbenzoate, in step a, the base-catalyzed hydrolysis of 2-nitro-4-trifluoromethylbenzonitrile is performed by: mixing 2-nitro-4-trifluoromethyl benzonitrile, inorganic base and water for hydrolysis reaction, and filtering after complete reaction.
In the above preparation method of methyl 2-nitro-4-trifluoromethylbenzoate, in step a, when acid catalysis is adopted, the acid catalyzed by the acid is sulfuric acid.
Further, in the preparation method of methyl 2-nitro-4-trifluoromethylbenzoate, in the step a, when acid catalysis is adopted, the concentration of the sulfuric acid is 80-98%.
Further, in the above preparation method of methyl 2-nitro-4-trifluoromethylbenzoate, in step a, when acid catalysis is adopted, the molar ratio of the sulfuric acid to the 2-nitro-4-trifluoromethylbenzonitrile is 10 to 30: 1.
further, in the above preparation method of methyl 2-nitro-4-trifluoromethylbenzoate, in step a, when acid catalysis is adopted, the temperature of the hydrolysis reaction is 90 ℃ to 100 ℃.
More specifically, in the above preparation method of methyl 2-nitro-4-trifluoromethylbenzoate, in step a, the operation of acid-catalyzed hydrolysis of 2-nitro-4-trifluoromethylbenzonitrile is as follows: mixing 2-nitro-4-trifluoromethyl benzonitrile and sulfuric acid for hydrolysis reaction, and after the reaction is finished, extracting, washing and concentrating.
In the preparation method of methyl 2-nitro-4-trifluoromethylbenzoate, in the step b, the molar ratio of sulfuric acid in the sulfuric acid-methanol solution to 2-nitro-4-trifluoromethylbenzamide is 3-9: 1.
in the preparation method of methyl 2-nitro-4-trifluoromethylbenzoate, in the step b, the mass concentration of sulfuric acid in the sulfuric acid-methanol solution is 15-40%.
Wherein, in the preparation method of the methyl 2-nitro-4-trifluoromethylbenzoate, in the step b, the temperature of the alcoholysis reaction is 60-80 ℃.
In the preparation method of methyl 2-nitro-4-trifluoromethylbenzoate, in the step b, the alcoholysis reaction time is 13-24 hours.
The invention has the beneficial effects that:
the method of the invention controls the conditions of base catalysis or acid catalysis to hydrolyze the 2-nitro-4-trifluoromethyl benzonitrile at a proper temperature with high selectivity to generate the 2-nitro-4-trifluoromethyl benzamide, and almost no impurities are generated, so that the high-purity 2-nitro-4-trifluoromethyl benzamide can be obtained with high yield; then adding a sulfuric acid-methanol solution, adjusting reaction conditions, improving the conversion rate of the 2-nitro-4-trifluoromethyl benzamide, and reducing side reactions to the greatest extent, so that the 2-nitro-4-trifluoromethyl benzamide can generate the 2-nitro-4-trifluoromethyl methyl benzoate at a proper temperature in a high selectivity manner; the method has mild reaction conditions and simple post-treatment, and is beneficial to realizing industrial production.
Detailed Description
Specifically, the preparation method of the 2-nitro-4-trifluoromethyl benzoic acid methyl ester comprises the following steps:
a. hydrolyzing 2-nitro-4-trifluoromethyl benzonitrile by alkali catalysis or acid catalysis to prepare 2-nitro-4-trifluoromethyl benzamide;
b. and c, mixing the 2-nitro-4-trifluoromethyl benzamide obtained in the step a with a sulfuric acid-methanol solution for alcoholysis reaction to obtain the 2-nitro-4-trifluoromethyl methyl benzoate.
In the step a of the method, the 2-nitro-4-trifluoromethyl benzonitrile can be hydrolyzed by adopting base catalysis or acid catalysis, and the inventor solves the problem of reaction selectivity in the hydrolysis in the step a by screening a large number of reaction conditions, almost no impurity is generated, and thus the high-purity 2-nitro-4-trifluoromethyl benzamide can be obtained with high yield.
In the step a, when base catalysis is adopted, mixing 2-nitro-4-trifluoromethyl benzonitrile, inorganic base and water for hydrolysis reaction, and filtering after complete reaction to obtain the 2-nitro-4-trifluoromethyl benzamide. The inventor conducts a large amount of screening on the conditions of base catalysis, and when the equivalent of the inorganic base is 0.1-4 eq, the hydrolysis reaction effect is good.
In addition, the inventor experimentally found that: in the step a, the temperature of alkali catalysis is a main influence factor; at 0-65 ℃, the inorganic base can be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and other inorganic bases, and the hydrolysis reaction can be carried out as long as the alkaline environment is maintained; the test finds that: when the alkalinity of the inorganic base is weaker than that of potassium hydroxide (for example, the inorganic base is sodium hydroxide, sodium carbonate, potassium carbonate and the like), if the temperature is increased to be more than 60 ℃, although the 2-nitro-4-trifluoromethylbenzonitrile can completely react, the yield of the 2-nitro-4-trifluoromethylbenzamide is low, the number of byproducts is large, and in order to accelerate the hydrolysis reaction efficiency and avoid the increase of the byproducts caused by long-time reaction, the hydrolysis reaction temperature is preferably 15-65 ℃ when the alkalinity of the inorganic base used for base catalysis is weaker than that of the potassium hydroxide, and more preferably, the hydrolysis reaction temperature is 45-55 ℃; the inventor also found that: when the inorganic base is potassium hydroxide, the temperature is controlled to be 55-65 ℃, so that the nitro-4-trifluoromethyl benzonitrile as the raw material can completely react, and the 2-nitro-4-trifluoromethyl benzamide product with high yield is obtained.
In the step a of the method, when base catalysis is adopted, the end point of the hydrolysis reaction can be monitored by methods such as HPLC (high performance liquid chromatography), TLC (thin layer chromatography) and the like, and the reaction can be completed within 3-10 h usually.
In the step a, when base catalysis is adopted, the amount of water is 5-50L/kg 2-nitro-4-trifluoromethyl benzonitrile, so that the pH of a reaction system is controlled within a proper range, and the hydrolysis reaction is facilitated.
In the step a, when acid catalysis is adopted, 2-nitro-4-trifluoromethyl benzonitrile and sulfuric acid are mixed for hydrolysis reaction, and after the reaction is finished, extraction, washing and concentration are carried out. The inventors have conducted extensive screening of acid-catalyzed conditions and found in experiments that: the concentrated hydrochloric acid hardly undergoes hydrolysis reaction; the low-concentration sulfuric acid has poor reaction effect; when the concentration of sulfuric acid is 80-98%, controlling the molar ratio of sulfuric acid to 2-nitro-4-trifluoromethylbenzonitrile to be 10-30: 1, the reaction effect is better.
In order to accelerate the acid-catalyzed hydrolysis reaction, the temperature of the acid-catalyzed hydrolysis is 90-100 ℃; the end point of the reaction can be monitored by methods such as HPLC, TLC and the like, and the reaction is usually complete within 3-10 h.
In step a of the process of the invention, base catalysis is compared with acid catalysis: the reaction condition of the base catalysis is mild, the energy consumption is low, the base catalyzed by the base can be recycled (amide is separated out, the filtered liquid phase is an alkali solution with a certain concentration and can be continuously used for the base catalysis), and the method is more environment-friendly compared with acid catalysis; the HPLC purity of the 2-nitro-4-trifluoromethyl benzamide can reach 99% by acid catalysis, the raw material reaction is more complete, and almost no by-product is generated, so that the two have advantages and disadvantages, and the method can be flexibly selected according to actual production conditions.
In step b of the method of the present invention, through the screening of the sulfuric acid-methanol solution by the inventors, the following results are found in experiments: adopting a sulfuric acid-methanol solution with the mass concentration of sulfuric acid being 15-40%, and controlling the molar ratio of sulfuric acid in the sulfuric acid-methanol solution to 2-nitro-4-trifluoromethyl benzamide to be 3-9: 1, the raw material 2-nitro-4-trifluoromethyl benzamide can react as much as possible to obtain the 2-nitro-4-trifluoromethyl benzoic acid methyl ester with high yield and high purity.
In order to accelerate the alcoholysis reaction and reduce the generation of byproducts, so that a product can be obtained through simple post-treatment, wherein the temperature of the alcoholysis reaction is 60-80 ℃ in the step b; the end point of the reaction can be monitored by methods such as HPLC, TLC and the like, and the reaction is usually complete within 13-24 h.
In the step b of the method, after the alcoholysis reaction is completed, extraction, washing and concentration are required, the extraction is generally carried out for not less than 3 times by adopting organic solvents such as dichloromethane, trichloromethane, ethyl acetate and the like, after organic phases are combined, the organic phase is washed for not less than 3 times by using saturated sodium bicarbonate, then the organic phase is concentrated, and the organic solvent is removed, so that the 2-nitro-4-trifluoromethyl methyl benzoate is obtained.
In the method, the reaction end point of the alkali catalysis hydrolysis and the acid catalysis hydrolysis in the step a or the end point of the alcoholysis reaction in the step b can be detected by HPLC (liquid phase 254nm without special indication), and the reaction is stopped when the reaction of the raw materials is complete.
The present invention is further illustrated by the following test examples and examples, but the scope of the present invention is not limited thereto.
The HPLC purity of the 2-nitro-4-trifluoromethyl benzamide is obtained by measuring through an area normalization method.
Test example 1: conditional screening of base catalyzed hydrolysis of 2-nitro-4-trifluoromethylbenzonitrile
1. Screening of base species
1g of 2-nitro-4-trifluoromethylbenzonitrile (0.0046mol, 1eq), 0.74g of NaOH (0.0184mol, 4eq) and 25mL of water are added into a reaction flask, and the reaction is carried out at 60 ℃ until the raw material 2-nitro-4-trifluoromethylbenzonitrile in the reaction solution is completely reacted through HPLC detection, wherein the HPLC purity of the 2-nitro-4-trifluoromethylbenzamide in the reaction solution is 39%.
1g of 2-nitro-4-trifluoromethylbenzonitrile (0.0046mol, 1eq), 1.03g of KOH (0.0184mol, 4eq) and 25mL of water are added into a reaction flask, and the reaction is carried out at 60 ℃ until the raw material 2-nitro-4-trifluoromethylbenzonitrile in the reaction solution is completely reacted through HPLC detection, wherein the HPLC purity of the 2-nitro-4-trifluoromethylbenzamide in the reaction solution is 91%.
2. Screening of reaction temperature and alkali dosage
1g of 2-nitro-4-trifluoromethylbenzonitrile (0.0046mol, 1eq), 0.55g of NaOH (0.0138mol, 3eq) and 25mL of water are added into a reaction flask, and the reaction is carried out at 80 ℃ until the raw material 2-nitro-4-trifluoromethylbenzonitrile in the reaction solution is completely reacted through HPLC detection, and the HPLC purity of the 2-nitro-4-trifluoromethylbenzamide in the reaction solution is 2%.
1g of 2-nitro-4-trifluoromethylbenzonitrile (0.0046mol, 1eq), 0.28g of NaOH (0.0069mol, 1.5eq) and 25mL of water are added into a reaction flask, and the mixture reacts at 80 ℃ until the raw material 2-nitro-4-trifluoromethylbenzonitrile in the reaction solution is completely reacted through HPLC detection, and the HPLC purity of the 2-nitro-4-trifluoromethylbenzamide in the reaction solution is 9 percent.
1g of 2-nitro-4-trifluoromethylbenzonitrile (0.0046mol, 1eq), 0.18g of NaOH (0.0046mol, 1eq) and 25mL of water are added into a reaction flask, and the reaction is carried out at 45 ℃ until the raw material 2-nitro-4-trifluoromethylbenzonitrile in the reaction solution is completely reacted through HPLC detection, and the HPLC purity of the 2-nitro-4-trifluoromethylbenzamide in the reaction solution is 97%.
1g of 2-nitro-4-trifluoromethylbenzonitrile (0.0046mol, 1eq), 0.37g of NaOH (0.0092mol, 2eq) and 25mL of water are added into a reaction flask, and the reaction is carried out at 45 ℃ until the raw material 2-nitro-4-trifluoromethylbenzonitrile in the reaction solution is completely reacted by HPLC detection, at which time the HPLC purity of the 2-nitro-4-trifluoromethylbenzamide in the reaction solution is 98%.
1g of 2-nitro-4-trifluoromethylbenzonitrile (0.0046mol, 1eq), 0.18g of NaOH (0.0046mol, 1eq) and 25mL of water are added into a reaction flask, and the reaction is carried out at 55 ℃ until the raw material 2-nitro-4-trifluoromethylbenzonitrile in the reaction solution is completely reacted through HPLC detection, and the HPLC purity of the 2-nitro-4-trifluoromethylbenzamide in the reaction solution is 96%.
The above screening tests are combined to find that: when the alkali catalysis temperature is 45-60 ℃, and the equivalent of alkali is more than 1eq, the hydrolysis reaction effect is better; when NaOH is used as a catalyst, the reaction effect is better at 45-55 ℃, and the effect is obviously deteriorated at 60-80 ℃; at 60 ℃, the KOH effect is significantly better than NaOH.
Test example 2: conditional screening for acid catalyzed hydrolysis of 2-nitro-4-trifluoromethylbenzonitrile
1g of 2-nitro-4-trifluoromethyl benzonitrile and 5mL of 36-38% concentrated hydrochloric acid are added into a reaction bottle, reflux reaction is carried out for 3h, HPLC detection shows that the HPLC content of the 2-nitro-4-trifluoromethyl benzamide in the reaction solution is 0%, and the raw materials are almost not reacted.
1g of 2-nitro-4-trifluoromethylbenzonitrile (0.0046mol, 1eq) and 5mL of 98% (9.2g, 0.092mol, 20eq) concentrated sulfuric acid are added into a reaction bottle to react for 3h at 100 ℃, and HPLC detects that the raw material 2-nitro-4-trifluoromethylbenzonitrile in the reaction solution completely reacts, at which time the HPLC purity of the 2-nitro-4-trifluoromethylbenzamide in the reaction solution is 99%.
Adding 1g of 2-nitro-4-trifluoromethyl benzonitrile and 5mL of 80% (16eq) concentrated sulfuric acid into a reaction bottle, carrying out reflux reaction for 3h, and detecting by HPLC that the raw material 2-nitro-4-trifluoromethyl benzonitrile in the reaction liquid is completely reacted, wherein the HPLC purity of the 2-nitro-4-trifluoromethyl benzamide in the reaction liquid is 99%.
The above screening tests are combined to find that: acid catalysis, wherein concentrated hydrochloric acid hardly reacts, preferably sulfuric acid, and more preferably sulfuric acid with the mass concentration of 80-98%; the advantages of the base catalysis and the acid catalysis are respectively: the acid catalysis can ensure that the HPLC content of the 2-nitro-4-trifluoromethyl benzamide in the reaction liquid reaches 99 percent, and the reaction is more complete; the reaction condition of the base catalysis is mild, the energy consumption is low, the base catalyzed by the base can be recycled, and the method is more environment-friendly compared with acid catalysis.
Test example 3: screening of the methanol sulfate solution
1. Without preparing a solution of sulfuric acid in methanol
Adding 10mL of methanol into a reaction bottle, cooling in an ice bath, slowly dropwise adding 0.75g of 98% concentrated sulfuric acid (9eq), stirring for 5 minutes after dropwise adding, then adding 0.2g of 2-nitro-4-trifluoromethylbenzamide (1eq), and heating to reflux for 24 hours to generate 94% of methyl 2-nitro-4-trifluoromethylbenzoate and 6% of 2-nitro-4-trifluoromethylbenzoic acid.
Adding 8mL of methanol into a reaction bottle, cooling in ice bath, slowly adding 0.25g of 98% concentrated sulfuric acid (3eq) dropwise, stirring for 5 minutes after the dropwise addition is finished, adding 0.2g of 2-nitro-4-trifluoromethylbenzamide (1eq), heating to reflux and reacting for 24 hours to generate 27% of 2-nitro-4-trifluoromethylbenzoic acid methyl ester, and the balance of 2-nitro-4-trifluoromethylbenzamide and 2-nitro-4-trifluoromethylbenzoic acid.
2. Prefabricated methanol sulfate solution
Preparing a methanol solution of sulfuric acid with the mass fraction of 15 percent: adding 85g of methanol solution into a 500mL single-neck bottle, cooling in ice bath, stirring, and slowly dropwise adding 15g of concentrated sulfuric acid (98%); 2g (3.6eq) of a 15% methanol sulfate solution and 0.2g of 2-nitro-4-trifluoromethylbenzamide were added to the reaction flask, and the mixture was refluxed for 13 hours to produce 75% methyl 2-nitro-4-trifluoromethylbenzoate by HPLC detection and the remaining 23% methyl 2-nitro-4-trifluoromethylbenzamide.
Preparing a methanol solution of sulfuric acid with the mass fraction of 30 percent: adding 70g of methanol solution into a 500mL single-neck bottle, cooling in ice bath, stirring, and slowly dropwise adding 30g of concentrated sulfuric acid (98%); 1g (3.6eq) of a 30% methanol sulfate solution and 0.2g of 2-nitro-4-trifluoromethylbenzamide were added to the reaction flask, and the mixture was refluxed for 13 hours to produce 87% methyl 2-nitro-4-trifluoromethylbenzoate by HPLC detection, and the remaining 10% methyl 2-nitro-4-trifluoromethylbenzamide was added.
As can be seen from the above screening test, the presence or absence of the preparation of the sulfuric acid-methanol solution has no influence on the reaction, and the key point is that the concentration of sulfuric acid in the sulfuric acid-methanol solution is lower, and the reaction effect is poorer when the concentration of sulfuric acid in the sulfuric acid-methanol solution is lower, so that the concentration of sulfuric acid in the sulfuric acid-methanol solution is preferably not lower than 15%.
Example 1: the method is adopted to prepare the 2-nitro-4-trifluoromethyl benzoic acid methyl ester
Adding 1g of 2-nitro-4-trifluoromethyl benzonitrile (0.023mol, 1eq), 0.09g of NaOH (0.0023mol, 0.1eq) and 30mL of water into a reaction bottle, heating to 50 ℃, reacting until the raw material 2-nitro-4-trifluoromethyl benzonitrile in the reaction solution is completely reacted by HPLC detection, finishing the reaction, and filtering to obtain 4.9g of the target product 2-nitro-4-trifluoromethyl benzamide, wherein the HPLC purity is 99% and the yield is 90%;
preparing a methanol solution of sulfuric acid with the mass fraction of 40 percent: adding 60g of methanol solution into a 500mL single-neck bottle, cooling in ice bath, stirring, and slowly dropwise adding 40g of concentrated sulfuric acid (98%);
adding 12.4g (5.8eq) of 40% sulfuric acid methanol solution and 2g of 2-nitro-4-trifluoromethyl benzamide into a reaction bottle, refluxing for 24h, stopping the reaction when the content of the product is more than 99% by HPLC (high performance liquid chromatography), adding 3 x 5mL of dichloromethane for washing 3 times, combining organic phases, washing the organic phase for 3 times by using saturated sodium bicarbonate, taking the organic phase for rotary evaporation to obtain 1.9g of 2-nitro-4-trifluoromethyl methyl benzoate, wherein the HPLC purity is more than 99%, and the yield is 90%.
Claims (5)
- A preparation method of 1.2-nitro-4-trifluoromethyl benzoic acid methyl ester is characterized in that: the method comprises the following steps:a. mixing inorganic base, 2-nitro-4-trifluoromethyl benzonitrile and water for hydrolysis reaction to prepare 2-nitro-4-trifluoromethyl benzamide;b. mixing the 2-nitro-4-trifluoromethyl benzamide obtained in the step a with a sulfuric acid-methanol solution for alcoholysis reaction to obtain 2-nitro-4-trifluoromethyl methyl benzoate;in the step a, the inorganic alkali is sodium hydroxide or potassium hydroxide;in the step a, when the inorganic base is sodium hydroxide, the temperature of the hydrolysis reaction is 45-55 ℃; when the inorganic base is potassium hydroxide, the temperature of the hydrolysis reaction is 55-65 ℃.
- 2. The process for producing methyl 2-nitro-4-trifluoromethylbenzoate according to claim 1, characterized in that: the molar ratio of the inorganic base to the 2-nitro-4-trifluoromethyl benzonitrile is 0.1-4: 1.
- 3. the process for producing methyl 2-nitro-4-trifluoromethylbenzoate according to claim 2, characterized in that: in the step a, the using amount of the water is 5-50L/kg of 2-nitro-4-trifluoromethyl benzonitrile.
- 4. The process for producing methyl 2-nitro-4-trifluoromethylbenzoate according to claim 1, characterized in that: in the step b, the molar ratio of sulfuric acid in the sulfuric acid-methanol solution to 2-nitro-4-trifluoromethyl benzamide is 3-9: 1; the mass concentration of sulfuric acid in the sulfuric acid-methanol solution is 15-40%.
- 5. The process for producing methyl 2-nitro-4-trifluoromethylbenzoate according to any one of claims 1 to 4, characterized in that: in the step b, the temperature of the alcoholysis reaction is 60-80 ℃.
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