Synthesis method of 2, 4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene

Abstract

The invention discloses a synthesis method of 2, 4-difluoronitrobenzene and 2-fluorine-5-chloronitrobenzene, and belongs to the technical field of organic chemical industry, 2, 5-dichloronitrobenzene is used as a raw material to generate 2, 4-difluoronitrobenzene and 2-fluorine-5-chloronitrobenzene, 2-fluorine-4-chloronitrobenzene and potassium fluoride are subjected to a reaction in the presence of a phase transfer catalyst and 2-fluorine-5-chloronitrobenzene as a solvent, and 2, 4-difluoronitrobenzene and 2-fluorine-5-chloronitrobenzene are subjected to post-treatment to obtain 2, 4-difluoronitrobenzene and 2-fluorine-5-chloronitrobenzene. The 2, 4-difluoronitrobenzene and the 2-fluorine-5-chloronitrobenzene are reacted to obtain 2, 4-difluoronitrobenzene According to the method, 2, 5-dichloronitrobenzene is obtained through nitration of cheap p-dichlorobenzene, and a route capable of synthesizing 2, 4-difluoronitrobenzene with a high additional value at low cost and a synthesis route capable of improving the fluoridation selectivity of 2, 5-dichloronitrobenzene are found; according to the method, the selectivity of the fluoridation reaction of the 2, 5-dichloronitrobenzene is improved, and the production cost of the 2, 4-difluoronitrobenzene is reduced.

Description

Technical Field

[0001] This application belongs to the technical field of organic chemical industry, and particularly relates to a synthesis method of 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene. Background Technique

[0002] 2,4-Difluoronitrobenzene is an important intermediate in organic synthesis and pharmaceutical chemistry, and is mostly used in the synthesis of drug molecules and bioactive molecules. For example, 2,4-difluoronitrobenzene is a key synthetic intermediate of the antibacterial agent 4-thiazolidinone derivatives. In addition, 2,4-difluoronitrobenzene also has a relatively wide application in the field of materials science. A series of polymer materials with excellent electrical conductivity and thermal conductivity can be synthesized through a specific synthetic route. At the same time, it can also be used as an intermediate for synthesizing dyes, providing important raw materials for industries such as textile and printing.

[0003] 2-Fluoro-5-chloronitrobenzene is mainly used in the laboratory research and development process and the chemical production process, and is an important organic synthesis and pharmaceutical intermediate.

[0004] The domestic synthetic route of 2,4-difluoronitrobenzene is relatively single. It mainly starts from m-dichlorobenzene, undergoes nitration reaction with mixed acid to generate 2,4-dichloronitrobenzene, and then is fluorinated with potassium fluoride under a phase transfer catalyst to obtain 2,4-difluoronitrobenzene.

[0005]

[0006] Patent CN115959995B reported an industrial synthesis method of 2,4-difluoronitrobenzene. Using m-dichlorobenzene as the raw material, it is nitrated with mixed acid in the tank area, the pH value is adjusted during post-treatment, the feeding valve of the fluorination kettle is opened, 2,4-dichloronitrobenzene is pumped in, vacuum dehydration is carried out, organic solvent is pumped in, and then potassium fluoride is added. After secondary vacuum dehydration, polyethylene glycol or 1-ethyl-3-methylimidazolium tetrafluoroborate is added. After high-temperature reflux for a certain time, it is rectified and purified to obtain 2,4-difluoronitrobenzene.

[0007] Patent CN119330833A reported a method starting from 2,4-dichloronitrobenzene, adding a mixed catalyst of phase transfer catalysts tetrabutylammonium bromide, tetrabutylammonium chloride and crown ether, and using potassium fluoride as the fluorination reagent to fluorinate to obtain 2,4-difluoronitrobenzene.

[0008] The above process is mainly limited to the preparation of starting material m-dichlorobenzene. Currently, there are mainly three routes for industrial production of m-dichlorobenzene: one is using nitrobenzene as the raw material and performing stepwise chlorination to obtain m-dichlorobenzene; the other is preparing it by one-step chlorination of m-dinitrobenzene. A large amount of organic wastewater containing nitrobenzene sulfonate will be generated during the production process of the above two nitrobenzene chlorination routes. It has extremely poor biodegradability and seriously pollutes the environment. At the same time, chlorination and nitration will generate isomeric by-products, which are difficult to separate. Since mainly p- and o-dichlorobenzene are obtained in the process of preparing dichlorobenzene from benzene or chlorobenzene, there is currently also a method in the laboratory to produce m-dichlorobenzene by isomerization of p- and o-dichlorobenzene. However, the Lewis acid catalyst that needs to be added in the reaction is difficult to recycle, is prone to water absorption and deactivation, and corrodes equipment, resulting in increased costs and an unclear industrial application prospect. For the above reasons, the price of m-dichlorobenzene remains high, and 2,4-difluoronitrobenzene synthesized with high-price m-dichlorobenzene as the raw material is also expensive.

[0009] At the same time, in industrial production, there are problems of low conversion rate and low selectivity in the synthesis process of preparing 2-fluoro-5-chloronitrobenzene by fluorination of 2,5-dichloronitrobenzene. The low selectivity is mainly due to the side reaction of fluoride ion substituting the nitro group during the fluorination process. At the same time, the removed nitro group will also continue to attack the benzene ring and occur other side reactions.

[0010] "Fine Chemicals Containing Fluorine, Bromine, and Iodine" edited by Li Heping points out that nitro compounds of aromatic nitro compounds are also unstable. When the nitro group in the molecule is activated by other electron-withdrawing groups, the nitro group will be fluorinated prior to the halogen substituent. For example, the fluorination and denitration of 2,3,5,6-tetrachloronitrobenzene.

[0011] The literature "Synthesis of 3,4-Difluorobenzonitrile by Direct Nitro Fluorination Method [J]. Pesticides, 2009, 48(10): 718-719." reports a method for directly fluorinating the nitro group to prepare 3,4-difluorobenzonitrile using 3-nitro-4-fluorobenzonitrile as the raw material and tetramethylammonium fluoride as the phase transfer catalyst at the optimal reaction temperature of 120 - 140 °C and the optimal solvent dimethyl sulfoxide. The reaction conditions are relatively mild, and the yield is 86.7%. Summary of the Invention

[0012] The purpose of the implementation of this application is to provide a synthesis method for 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene, which can improve the selectivity of the fluorination reaction of 2,5-dichloronitrobenzene. At the same time, it can prepare widely used 2,4-difluoronitrobenzene with cheap and easily available 2,5-dichloronitrobenzene, greatly reducing the production cost of 2,4-difluoronitrobenzene.

[0013] To achieve the above purpose, the technical solution adopted in this application is: to provide a synthesis method for 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene, which specifically includes the following steps: (1) Add 2,5-dichloronitrobenzene, tetramethylammonium chloride, potassium nitrite and potassium fluoride into a reaction vessel, and raise the temperature for reaction; after the reaction is completed, perform water washing, collect the organic phase and carry out rectification to obtain a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene; (2) Add the mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene, potassium fluoride and tetramethylammonium chloride into a reaction vessel, and raise the temperature for reaction; after the reaction is completed, perform water washing, collect the organic phase and carry out rectification to obtain 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene.

[0014] In one embodiment, In step (1), based on 2,5-dichloronitrobenzene, the chemical equivalent of the added potassium nitrite is 0.5 - 1.0, and the chemical equivalent of the added potassium fluoride is 0.5 - 1.0. Preferably, the chemical equivalent of potassium nitrite is 0.8, and the chemical equivalent of potassium fluoride is 0.8.

[0015] In one embodiment, In step (1), the mass equivalent of the tetramethylammonium chloride is 0.5 - 2.0 wt%, preferably, the mass equivalent of the tetramethylammonium chloride is 1.5 wt%.

[0016] In one embodiment, In step (1), the temperature for the temperature-raising reaction is 120 - 160 °C, and the time is 4 h. Preferably, the temperature is 150 °C.

[0017] In one embodiment, In step (2), based on 2-fluoro-4-chloronitrobenzene in the mixture, the chemical equivalent of the added potassium fluoride is 0.8 - 1.5. Preferably, the chemical equivalent of potassium fluoride is 1.2.

[0018] In one embodiment, In step (2), the mass equivalent of the tetramethylammonium chloride is 0.5 - 2.0 wt%, preferably, the mass equivalent of the tetramethylammonium chloride is 1.5 wt%.

[0019] In one embodiment, In step (2), the temperature for the temperature-raising reaction is 170 - 200 °C, and the time is 5 h. Preferably, the temperature is 180 °C.

[0020] In one embodiment, In step (1), after collecting the organic phase and carrying out rectification, the unreacted 2,5-dichloronitrobenzene can be separated and recycled.

[0021] The process route is as follows:

[0022] The formation pathway of 2-fluoro-4-chloronitrobenzene is as follows: potassium nitrite and the nitrite ions removed from the fluorinated nitrobenzene attack the chlorine atom at the ortho position of the nitrate of 2,5-dichloronitrobenzene and the fluorine atom at the ortho position of the nitrate of 2-fluoro-5-chloronitrobenzene to generate 3,4-dinitrochlorobenzene intermediate. The intermediate is unstable and is quickly attacked by the fluoride ions in the system to generate 2-fluoro-4-chloronitrobenzene.

[0023] The present application provides a method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene. Compared with the traditional process of starting from 2,4-dichloronitrobenzene generated by nitration of expensive m-dichlorobenzene, the new process starts from 2,5-dichloronitrobenzene generated by nitration of inexpensive p-dichlorobenzene to synthesize 2,4-difluoronitrobenzene, which greatly reduces the process cost; at the same time, the limitation point in the industrial fluorination reaction of 2,5-dichloronitrobenzene that originally needs to be suppressed - the nitrate group removed from the fluorinated nitro group attacks the benzene ring, which leads to reduced selectivity, is cleverly utilized by us, and the by-product is converted into high-value-added 2,4-difluoronitrobenzene by artificially adding potassium nitrite to provide a nitro source, which greatly improves the selectivity of fluorination of 2,5-dichloronitrobenzene in disguise, and provides a new idea for "turning waste into treasure" of fluorination by-products in industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative labor.

[0025] Figure 1 It is the liquid chromatogram of Example 1; Figure 2 It is the liquid chromatogram of Example 2; Figure 3 It is the liquid chromatogram of Example 3; Figure 4 It is the liquid chromatogram of Example 4; Figure 5 It is the liquid chromatogram of Example 5; Figure 6 It is the liquid chromatogram of Example 6; Figure 7 This is the liquid chromatogram of Example 7. DETAILED DESCRIPTION

[0026] To make the technical problems, technical solutions, and beneficial effects to be solved by this application more clear and understandable, this application is further described in detail. It should be understood that the specific embodiments described herein are only used to explain this application and are not used to limit this application.

[0027] Example 1 Put 96.11 g of 2,5-dichloronitrobenzene into a four-necked flask equipped with a thermometer and a mechanical stirring device. After heating up and melting the materials, add 1.45 g of tetramethylammonium chloride, 14.65 g of potassium fluoride, and 21.33 g of potassium nitrite, and heat up to 120 °C. Then slowly heat up, and control the reaction temperature at 150 °C for 4 h during the process. After the reaction is completed, wait for the materials to cool slightly, and then wash with water with a mass of 200wt% of the material liquid. Separate the liquid to remove the salts and tetramethylammonium chloride in the system, collect the organic phase, and rectify and separate 64.39 g of unreacted 2,5-dichloronitrobenzene, with a conversion rate of 33.01%, a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene of 28.73 g. By calculating through the liquid chromatography standard curve, 17.14 g of 2-fluoro-4-chloronitrobenzene is obtained, with a selectivity of 59.12%; 11.53 g of 2-fluoro-5-chloronitrobenzene is obtained, with a selectivity of 39.77%.

[0028] Example 2 The difference between this example and Example 1 is that the mass of potassium fluoride is 23.25 g, and the rest of the operations are the same. 52.14 g of unreacted 2,5-dichloronitrobenzene is obtained, with a conversion rate of 45.75%, a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene of 39.34 g. By calculating through the liquid chromatography standard curve, 22.73 g of 2-fluoro-4-chloronitrobenzene is obtained, with a selectivity of 56.55%; 16.56 g of 2-fluoro-5-chloronitrobenzene is obtained, with a selectivity of 41.21%.

[0029] Example 3 The difference between this example and Example 1 is that the mass of potassium fluoride is 34.05 g, and the rest of the operations are the same. 52.52 g of unreacted 2,5-dichloronitrobenzene is obtained, with a conversion rate of 45.35%, a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene of 37.93 g. By calculating through the liquid chromatography standard curve, 26.89 g of 2-fluoro-4-chloronitrobenzene is obtained, with a selectivity of 67.50%; 10.96 g of 2-fluoro-5-chloronitrobenzene is obtained, with a selectivity of 27.51%.

[0030] Example 4 The difference between this example and Example 3 is that the reaction temperature is controlled at 120 °C, and the rest of the operations are the same. 81.57 g of unreacted 2,5-dichloronitrobenzene is obtained, with a conversion rate of 15.13%, and a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene of 12.81 g. By calculating with the standard curve of liquid chromatography, 8.89 g of 2-fluoro-4-chloronitrobenzene is obtained, with a selectivity of 66.88%; 3.86 g of 2-fluoro-5-chloronitrobenzene is obtained, with a selectivity of 29.02%.

[0031] Example 5 The difference between this example and Example 3 is that the reaction temperature is controlled at 160 °C, and the rest of the operations are the same. 49.03 g of unreacted 2,5-dichloronitrobenzene is obtained, with a conversion rate of 48.99%, and a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene of 41.40 g. By calculating with the standard curve of liquid chromatography, 24.52 g of 2-fluoro-4-chloronitrobenzene is obtained, with a selectivity of 56.98%; 16.84 g of 2-fluoro-5-chloronitrobenzene is obtained, with a selectivity of 39.12%.

[0032] Example 6 The difference between this example and Example 3 is that the equivalent of tetramethylammonium chloride is 0.5 wt% (0.48 g), and the rest of the operations are the same. 68.39 g of unreacted 2,5-dichloronitrobenzene is obtained, with a conversion rate of 28.84%, and a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene of 24.21 g. By calculating with the standard curve of liquid chromatography, 17.00 g of 2-fluoro-4-chloronitrobenzene is obtained, with a selectivity of 67.11%; 7.18 g of 2-fluoro-5-chloronitrobenzene is obtained, with a selectivity of 28.32%.

[0033] Example 7 The difference between this example and Example 1 is that the mass of potassium fluoride is 23.24 g and the mass of potassium nitrite is 34.14 g, and the rest of the operations are the same. 49.09 g of unreacted 2,5-dichloronitrobenzene is obtained, with a conversion rate of 48.92%, and a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene of 41.52 g. By calculating with the standard curve of liquid chromatography, 29.62 g of 2-fluoro-4-chloronitrobenzene is obtained, with a selectivity of 68.93%; 11.85 g of 2-fluoro-5-chloronitrobenzene is obtained, with a selectivity of 27.58%.

[0034] Example 8 By repeatedly implementing the operation method of Example 7, accumulating materials and mixing the materials, a mixture of 2-fluoro-4-chloronitrobenzene with a proportion of 70.10% and 2-fluoro-5-chloronitrobenzene with a proportion of 29.85% was obtained; 87.82 g of the mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene was put into a four-necked flask equipped with a thermometer and a mechanical stirring device. Subsequently, 0.93 g of tetramethylammonium chloride and 20.38 g of potassium fluoride were added. After stirring evenly, the temperature was raised to 180 °C, and the reaction temperature was controlled at 180 °C for 5 h during the process; after the reaction was completed, after the material was slightly cooled, it was washed with water with a mass of 200 wt% of the material liquid, and the salts and tetramethylammonium chloride in the system were removed by liquid separation. The organic phase was collected, and 50.29 g of 2,4-difluoronitrobenzene was separated by rectification, with a yield of 90.12%; 25.95 g of 2-fluoro-5-chloronitrobenzene was recovered, with a recovery rate of 99.01%.

[0035] Example 9 The difference between this example and Example 8 is that the mass of potassium fluoride is 24.46 g, and the rest of the operations are the same. 53.27 g of 2,4-difluoronitrobenzene was separated by rectification, with a yield of 95.46%; 25.72 g of 2-fluoro-5-chloronitrobenzene was recovered, with a recovery rate of 98.12%.

[0036] Example 10 The difference between this example and Example 8 is that the mass of potassium fluoride is 16.31 g, and the rest of the operations are the same. 40.92 g of 2,4-difluoronitrobenzene was separated by rectification, with a yield of 73.32%; 25.72 g of 2-fluoro-5-chloronitrobenzene was recovered, with a recovery rate of 98.12%.

[0037] Example 11 The difference between this example and Example 9 is that the mass of tetramethylammonium chloride is 0.31 g, and the rest of the operations are the same. 45.02 g of 2,4-difluoronitrobenzene was separated by rectification, with a yield of 80.67%; 25.87 g of 2-fluoro-5-chloronitrobenzene was recovered, with a recovery rate of 98.67%.

[0038] Example 12 The difference between this example and Example 9 is that the mass of tetramethylammonium chloride is 1.23 g, and the rest of the operations are the same. 53.14 g of 2,4-difluoronitrobenzene was separated by rectification, with a yield of 95.23%; 25.63 g of 2-fluoro-5-chloronitrobenzene was recovered, with a recovery rate of 97.77%.

[0039] Example 13 The difference between this example and Example 9 is that the reaction temperature is controlled at 170 °C, and the rest of the operations are the same. After rectification and separation, 49.05 g of 2,4-difluoronitrobenzene is obtained with a yield of 87.90%; 25.68 g of 2-fluoro-5-chloronitrobenzene is recovered with a recovery rate of 97.98%.

[0040] Example 14 The difference between this example and Example 9 is that the reaction temperature is controlled at 200 °C, and the rest of the operations are the same. After rectification and separation, 50.97 g of 2,4-difluoronitrobenzene is obtained with a yield of 91.33%; 25.24 g of 2-fluoro-5-chloronitrobenzene is recovered with a recovery rate of 96.30%.

[0041] This application provides a synthesis method of 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene. Using 2,5-dichloronitrobenzene as the raw material, under the condition of a phase transfer catalyst (tetramethylammonium chloride), potassium nitrite and potassium fluoride are added to generate a certain proportion of 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene in one pot. After rectification, the unreacted 2,5-dichloronitrobenzene is recovered and reused. 2-Fluoro-4-chloronitrobenzene and potassium fluoride continue to undergo deep fluorination under the conditions of a phase transfer catalyst and using 2-fluoro-5-chloronitrobenzene as the solvent to obtain 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene; through the improvement of the process, a new synthesis route of 2,4-dichloronitrobenzene is created. Starting from 2,5-dichloronitrobenzene obtained by nitrating cheap p-dichlorobenzene, the phenomenon that "the nitro group removed in the fluorination reaction will continue to attack the benzene ring to generate by-products" in the traditional fluorination of chloronitrobenzene is cleverly utilized to find a synthesis route that can not only synthesize high-value-added 2,4-difluoronitrobenzene at low cost but also improve the selectivity of the fluorination of 2,5-dichloronitrobenzene; this method improves the selectivity of the fluorination reaction of 2,5-dichloronitrobenzene and reduces the production cost of 2,4-difluoronitrobenzene.

[0042] In addition, the terms "first" and "second" are only used for descriptive purposes and cannot be construed as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, the features defined with "first" and "second" may explicitly or implicitly include one or more of such features. In the description of this application, "a plurality" means two or more unless otherwise specifically defined.

[0043] The above are only the preferred embodiments of this application and are not intended to limit this application. Any modifications, equivalent replacements, and improvements made within the spirit and principle of this application shall be included within the protection scope of this application.

Claims

1. A method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene, characterized in that, Specifically, it includes the following steps: (1). Add 2,5-dichloronitrobenzene, tetramethylammonium chloride, potassium nitrite and potassium fluoride into a reaction vessel, and raise the temperature for reaction; after the reaction is completed, carry out water washing, collect the organic phase and carry out rectification to obtain a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene; (2). Add the mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene, potassium fluoride and tetramethylammonium chloride into a reaction vessel, and raise the temperature for reaction; after the reaction is completed, carry out water washing, collect the organic phase and carry out rectification to obtain 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene.

2. The synthesis method of 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene according to claim 1, characterized in that, In step (1), based on 2,5-dichloronitrobenzene, the chemical equivalent amount of potassium nitrite added is 0.5 - 1.0, and the chemical equivalent amount of potassium fluoride added is 0.5 - 1.

0.

3. A method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene according to claim 1, characterized in that, In step (1), the mass equivalent of tetramethylammonium chloride is 0.5 - 2.0 wt%.

4. A method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene according to claim 1, characterized in that, In step (1), the temperature of the temperature-raising reaction is 120 - 160 °C, and the time is 4 h.

5. A method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene according to claim 1, characterized in that, In step (2), based on 2-fluoro-4-chloronitrobenzene in the mixture, the chemical equivalent amount of potassium fluoride added is 0.8 - 1.

5.

6. A method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene according to claim 1, characterized in that, In step (2), the mass equivalent of tetramethylammonium chloride is 0.5 - 2.0 wt%.

7. A method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene according to claim 1, characterized in that, In step (2), the temperature of the temperature-raising reaction is 170 - 200 °C, and the time is 5 h.

8. A method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene according to claim 1, characterized in that, In step (1), after collecting the organic phase and carrying out rectification, the unreacted 2,5-dichloronitrobenzene can be separated and recycled.

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