A method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene

Abstract

The present application discloses a method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene, which 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-fluoro-5-chloronitrobenzene. 2-Fluoro-4-chloronitrobenzene and potassium fluoride are reacted with a phase transfer catalyst and 2-fluoro-5-chloronitrobenzene as a solvent to obtain 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene. Starting from 2,5-dichloronitrobenzene obtained by nitrating inexpensive p-dichlorobenzene, a synthetic route is found that can synthesize high-value-added 2,4-difluoronitrobenzene at low cost and can also improve the selectivity of fluorination of 2,5-dichloronitrobenzene. The method improves the selectivity of the fluorination reaction of 2,5-dichloronitrobenzene and reduces the production cost of 2,4-difluoronitrobenzene.

Description

Technical Field

[0001] The present application belongs to the field of organic chemical technology, and in particular relates to a method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene. Background Art

[0002] 2,4-Difluoronitrobenzene is an important organic synthesis and pharmaceutical chemistry intermediate, widely used in the synthesis of drug molecules and bioactive molecules. For example, 2,4-difluoronitrobenzene is a key synthetic intermediate for the antibacterial agent 4-thiazolidinone derivatives. In addition, 2,4-difluoronitrobenzene is also widely used in the field of materials science. Through specific synthetic routes, it can be used to synthesize a series of polymer materials with excellent electrical and thermal conductivity. It can also be used as an intermediate for the synthesis of dyes, providing important raw materials for the textile, printing and other industries.

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

[0004] The domestic synthesis route for 2,4-difluoronitrobenzene is relatively simple, mainly starting from m-dichlorobenzene, which undergoes nitration reaction with mixed acid to produce 2,4-dichloronitrobenzene, and then fluorinated with potassium fluoride under a phase transfer catalyst to obtain 2,4-difluoronitrobenzene.

[0005]

[0006] Patent CN115959995B reports an industrial synthesis method for 2,4-difluoronitrobenzene. The method uses m-dichlorobenzene as the raw material, undergoes mixed acid nitration in a tank area, and undergoes post-treatment to adjust the pH value. The feed valve of the fluorination reactor is opened, 2,4-dichloronitrobenzene is pumped in, vacuum dehydration is performed, an organic solvent is pumped in, and potassium fluoride is added. A second vacuum dehydration step is performed, and polyethylene glycol or 1-ethyl-3-methylimidazolium tetrafluoroborate is added. After high-temperature reflux for a certain period of time, 2,4-difluoronitrobenzene is purified by distillation.

[0007] Patent CN119330833A reports a process for fluorinating 2,4-dichloronitrobenzene by adding a phase transfer catalyst comprising tetrabutylammonium bromide, tetrabutylammonium chloride, and a crown ether catalyst, and using potassium fluoride as a fluorination agent to obtain 2,4-difluoronitrobenzene.

[0008] The above process is primarily limited to the preparation of the starting material, meta-dichlorobenzene. Currently, there are three main routes for the industrial production of meta-dichlorobenzene: one is to use nitrobenzene as the raw material and obtain meta-dichlorobenzene through step-by-step chlorination; the other is to produce it through a single-step chlorination of meta-dinitrobenzene. Both of these nitrobenzene chlorination routes generate large amounts of organic wastewater containing nitrobenzene sulfonate, which is poorly biodegradable and seriously pollutes the environment. Furthermore, chlorination and nitration produce isomeric byproducts that are difficult to separate. Since para- and o-dichlorobenzene are primarily produced in the process of preparing dichlorobenzene from benzene or chlorobenzene, there are currently laboratory methods for producing meta-dichlorobenzene through the isomerization of para- and o-dichlorobenzene. However, the Lewis acid catalyst required for the reaction is difficult to recycle and easily deactivates due to water absorption, corroding equipment, increasing costs and making the prospects for industrial application uncertain. These factors contribute to the high price of meta-dichlorobenzene, and the high price of 2,4-difluoronitrobenzene synthesized from expensive meta-dichlorobenzene is also high.

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

[0010] The book "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 preferentially undergo fluorination over halogen substituents. An example is the fluorinated denitrification of 2,3,5,6-tetrachloronitrobenzene.

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

[0012] The purpose of the present application is to provide a method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene, thereby improving the selectivity of the fluorination reaction of 2,5-dichloronitrobenzene and preparing the widely used 2,4-difluoronitrobenzene from cheap and readily available 2,5-dichloronitrobenzene, thereby greatly reducing the production cost of 2,4-difluoronitrobenzene.

[0013] To achieve the above objectives, the technical solution adopted in this application is to provide a method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene, which specifically comprises the following steps:

[0014] (1) Add 2,5-dichloronitrobenzene, tetramethylammonium chloride, potassium nitrite and potassium fluoride to a reaction vessel and heat the reaction; after the reaction is completed, wash with water, collect the organic phase and conduct distillation to obtain a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene;

[0015] (2) Adding the mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene, potassium fluoride and tetramethylammonium chloride into a reaction vessel, and heating the reaction; after the reaction is completed, washing with water is performed, and the organic phase is collected and distilled to obtain 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene.

[0016] In one embodiment,

[0017] In step (1), based on 2,5-dichloronitrobenzene, the chemical equivalent of potassium nitrite added is 0.5-1.0, and the chemical equivalent of potassium fluoride added 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.

[0018] In one embodiment,

[0019] 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 %.

[0020] In one embodiment,

[0021] The temperature of the temperature-raising reaction in step (1) is 120-160°C for 4 hours, preferably, the temperature is 150°C.

[0022] In one embodiment,

[0023] In step (ii), the chemical equivalent of potassium fluoride added is 0.8-1.5 based on the 2-fluoro-4-chloronitrobenzene in the mixture. Preferably, the chemical equivalent of potassium fluoride is 1.2.

[0024] In one embodiment,

[0025] In step (2), the mass equivalent of tetramethylammonium chloride is 0.5-2.0 wt %, preferably, the mass equivalent of tetramethylammonium chloride is 1.5 wt %.

[0026] In one embodiment,

[0027] The temperature of the temperature-raising reaction in step (ii) is 170-200°C for 5 hours, preferably 180°C.

[0028] In one embodiment,

[0029] In step (1), the organic phase is collected and distilled to separate the unreacted 2,5-dichloronitrobenzene for recycling.

[0030] The process route is as follows:

[0031]

[0032] The formation pathway of 2-fluoro-4-chloronitrobenzene is as follows: potassium nitrite and the nitrite ion removed from the fluoronitro group attack the chlorine atom at the ortho-nitro position of 2,5-dichloronitrobenzene and the fluorine atom at the ortho-nitro position 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.

[0033]

[0034] The present application provides a method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene. Compared with the traditional process that starts with 2,4-dichloronitrobenzene produced by nitration of expensive m-dichlorobenzene, the new process starts with 2,5-dichloronitrobenzene produced by nitration of inexpensive p-dichlorobenzene to synthesize 2,4-difluoronitrobenzene, greatly reducing the process cost. At the same time, the limitation point in the industrial fluorination reaction of 2,5-dichloronitrobenzene that originally needed to be suppressed - the nitro group removed from the fluoronitro group attacks the benzene ring, resulting in reduced selectivity - was cleverly utilized by the method. By artificially adding potassium nitrite to provide a nitro source, the by-product is converted into high-value-added 2,4-difluoronitrobenzene, which significantly improves the selectivity of the fluorination of 2,5-dichloronitrobenzene in disguise, providing a new idea for "turning waste into treasure" of fluorination by-products in industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the following briefly introduces the drawings required for use in the embodiments or descriptions of the prior art. 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 any creative work.

[0036] Figure 1 This is the liquid chromatogram of Example 1;

[0037] Figure 2 This is the liquid chromatogram of Example 2;

[0038] Figure 3 This is the liquid chromatogram of Example 3;

[0039] Figure 4 This is the liquid chromatogram of Example 4;

[0040] Figure 5 This is the liquid chromatogram of Example 5;

[0041] Figure 6 This is the liquid chromatogram of Example 6;

[0042] Figure 7 This is the liquid chromatogram of Example 7. DETAILED DESCRIPTION

[0043] In order 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.

[0044] Example 1

[0045] 96.11 g of 2,5-dichloronitrobenzene was placed in a four-necked flask equipped with a thermometer and a mechanical stirring device. After the temperature was raised until the material melted, 1.45 g of tetramethylammonium chloride, 14.65 g of potassium fluoride and 21.33 g of potassium nitrite were added and the temperature was raised to 120 °C. The temperature was slowly raised, and the reaction temperature was controlled at 150 °C for 4 h. After the reaction was completed, the material was slightly cooled and washed with water with 200 wt% of the mass of the feed liquid. The salt and tetramethylammonium chloride in the system were separated and the organic phase was collected. The unreacted 2,5-dichloronitrobenzene (64.39 g) was separated by rectification to obtain 33.01% conversion of 2,5-dichloronitrobenzene and 28.73 g of a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene. According to the liquid chromatography standard curve, 17.14 g of 2-fluoro-4-chloronitrobenzene was obtained with a selectivity of 59.12%; 11.53 g of 2-fluoro-5-chloronitrobenzene was obtained. g, selectivity 39.77%.

[0046] Example 2

[0047] This embodiment differs from embodiment 1 in that the mass of potassium fluoride is 23.25 g, and the other operations are the same, to obtain 52.14 g of unreacted 2,5-dichloronitrobenzene with a conversion rate of 45.75%, and 39.34 g of a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene. Calculated by a liquid chromatography standard curve, 22.73 g of 2-fluoro-4-chloronitrobenzene with a selectivity of 56.55% and 16.56 g of 2-fluoro-5-chloronitrobenzene with a selectivity of 41.21% were obtained.

[0048] Example 3

[0049] This embodiment differs from embodiment 1 in that the mass of potassium fluoride is 34.05 g, and the other operations are the same, to obtain 52.52 g of unreacted 2,5-dichloronitrobenzene with a conversion rate of 45.35%, and 37.93 g of a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene. Calculated by a liquid chromatography standard curve, 26.89 g of 2-fluoro-4-chloronitrobenzene with a selectivity of 67.50% and 10.96 g of 2-fluoro-5-chloronitrobenzene with a selectivity of 27.51% were obtained.

[0050] Example 4

[0051] This example differs from Example 3 in that the reaction temperature is controlled at 120° C., and the other operations are the same, yielding 81.57 g of unreacted 2,5-dichloronitrobenzene with a conversion rate of 15.13% and 12.81 g of a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene. Calculation based on a liquid chromatography standard curve yields 8.89 g of 2-fluoro-4-chloronitrobenzene with a selectivity of 66.88% and 3.86 g of 2-fluoro-5-chloronitrobenzene with a selectivity of 29.02%.

[0052] Example 5

[0053] This example differs from Example 3 in that the reaction temperature is controlled at 160° C., and the other operations are the same, yielding 49.03 g of unreacted 2,5-dichloronitrobenzene with a conversion rate of 48.99% and 41.40 g of a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene. Calculation by liquid chromatography standard curve yields 24.52 g of 2-fluoro-4-chloronitrobenzene with a selectivity of 56.98% and 16.84 g of 2-fluoro-5-chloronitrobenzene with a selectivity of 39.12%.

[0054] Example 6

[0055] This embodiment differs from embodiment 3 in that the equivalent of tetramethylammonium chloride is 0.5 wt% (0.48 g), and the remaining operations are the same, yielding 68.39 g of unreacted 2,5-dichloronitrobenzene with a conversion rate of 28.84% and 24.21 g of a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene. Calculation by liquid chromatography standard curve yields 17.00 g of 2-fluoro-4-chloronitrobenzene with a selectivity of 67.11%; and 7.18 g of 2-fluoro-5-chloronitrobenzene with a selectivity of 28.32%.

[0056] Example 7

[0057] This embodiment differs from Example 1 in that the mass of potassium fluoride is 23.24 g, the mass of potassium nitrite is 34.14 g, and the other operations are the same, to obtain 49.09 g of unreacted 2,5-dichloronitrobenzene with a conversion rate of 48.92%, and 41.52 g of a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene. Calculated by a liquid chromatography standard curve, 29.62 g of 2-fluoro-4-chloronitrobenzene is obtained with a selectivity of 68.93%; and 11.85 g of 2-fluoro-5-chloronitrobenzene is obtained with a selectivity of 27.58%.

[0058] Example 8

[0059] The operation method of Example 7 was repeated multiple times to accumulate and mix the materials to obtain a mixture of 70.10% of 2-fluoro-4-chloronitrobenzene and 29.85% of 2-fluoro-5-chloronitrobenzene. 87.82 g of the mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene was added to a four-necked flask equipped with a thermometer and a mechanical stirring device, followed by the addition of 0.93 g of tetramethylammonium chloride and 20.38 g of potassium fluoride. After stirring evenly, the temperature was raised to 180° C. The reaction temperature was controlled at 180° C. and the reaction was continued for 5 h. After the reaction was completed, the material was slightly cooled and washed with water having a mass of 200 wt% of the feed liquid. The salt and tetramethylammonium chloride in the system were separated, and the organic phase was collected and separated by rectification to obtain 50.29 g of 2,4-difluoronitrobenzene with a yield of 90.12%. 25.95 g of 2-fluoro-5-chloronitrobenzene was recovered with a recovery rate of 99.01%.

[0060] Example 9

[0061] The difference between this embodiment and embodiment 8 is that the mass of potassium fluoride is 24.46 g. The other operations are the same. 53.27 g of 2,4-difluoronitrobenzene is separated by distillation, with a yield of 95.46%; 25.72 g of 2-fluoro-5-chloronitrobenzene is recovered, with a recovery rate of 98.12%.

[0062] Example 10

[0063] The difference between this embodiment and embodiment 8 is that the mass of potassium fluoride is 16.31 g. The other operations are the same. 40.92 g of 2,4-difluoronitrobenzene is separated by distillation, with a yield of 73.32%; 25.72 g of 2-fluoro-5-chloronitrobenzene is recovered, with a recovery rate of 98.12%.

[0064] Example 11

[0065] This embodiment differs from embodiment 9 in that the mass of tetramethylammonium chloride is 0.31 g. The remaining operations are the same. 45.02 g of 2,4-difluoronitrobenzene is separated by distillation, with a yield of 80.67%; 25.87 g of 2-fluoro-5-chloronitrobenzene is recovered, with a recovery rate of 98.67%.

[0066] Example 12

[0067] This embodiment differs from embodiment 9 in that the mass of tetramethylammonium chloride is 1.23 g. The remaining operations are the same. 53.14 g of 2,4-difluoronitrobenzene is separated by distillation, with a yield of 95.23%; 25.63 g of 2-fluoro-5-chloronitrobenzene is recovered, with a recovery rate of 97.77%.

[0068] Example 13

[0069] This embodiment differs from embodiment 9 in that the reaction temperature is controlled at 170° C. The other operations are the same. 49.05 g of 2,4-difluoronitrobenzene is separated by distillation, with a yield of 87.90%; 25.68 g of 2-fluoro-5-chloronitrobenzene is recovered, with a recovery rate of 97.98%.

[0070] Example 14

[0071] This embodiment differs from embodiment 9 in that the reaction temperature is controlled at 200° C. The other operations are the same. 50.97 g of 2,4-difluoronitrobenzene is separated by distillation, with a yield of 91.33%; 25.24 g of 2-fluoro-5-chloronitrobenzene is recovered, with a recovery rate of 96.30%.

[0072] The present application provides a method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene, which comprises the following steps: using 2,5-dichloronitrobenzene as a raw material, adding potassium nitrite and potassium fluoride in the presence of a phase transfer catalyst (tetramethylammonium chloride), generating a certain ratio of 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene in one pot, rectifying the mixture, recovering the unreacted 2,5-dichloronitrobenzene, and further deep fluorinating 2-fluoro-4-chloronitrobenzene with potassium fluoride in the presence of a phase transfer catalyst and 2-fluoro-5-chloronitrobenzene as a solvent to obtain 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene; and The process improvement has created a new synthetic route for 2,4-dichloronitrobenzene. Starting from 2,5-dichloronitrobenzene obtained by nitration of inexpensive p-dichlorobenzene, this method cleverly utilizes the phenomenon that in the traditional fluorination of chloronitrobenzene, "the nitro group removed in the fluorination reaction will continue to attack the benzene ring to form a by-product." This has led to a synthetic route that can synthesize high-value-added 2,4-difluoronitrobenzene at low cost while also improving 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.

[0073] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of the technical features being referred to. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of the features. Throughout the description of this application, "plurality" means two or more, unless otherwise specifically defined.

[0074] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent replacements and improvements made within the spirit and principles of the present application should be included in the scope of protection of the present application.

Claims

1. A method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene, characterized in that: The specific steps include: (1) Add 2,5-dichloronitrobenzene, tetramethylammonium chloride, potassium nitrite and potassium fluoride to a reaction vessel and heat the reaction; after the reaction is completed, wash with water, collect the organic phase and conduct distillation to obtain a mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene; (2) adding the mixture of 2-fluoro-4-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene, potassium fluoride and tetramethylammonium chloride into a reaction vessel and heating the reaction vessel; washing with water after the reaction is completed, collecting the organic phase and performing distillation to obtain 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene; In step (1), based on 2,5-dichloronitrobenzene, the chemical equivalent of potassium nitrite added is 0.5-1.0, the chemical equivalent of potassium fluoride added is 0.5-1.0; the mass equivalent of tetramethylammonium chloride is 0.5-2.0 wt%; In step (2), based on the 2-fluoro-4-chloronitrobenzene in the mixture, the chemical equivalent of potassium fluoride added is 0.8-1.5, and the mass equivalent of tetramethylammonium chloride is 0.5-2.0 wt%.

2. The method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene according to claim 1, wherein: The temperature of the temperature-raising reaction in step (1) is 120-160°C and the time is 4 hours.

3. The method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene according to claim 1, wherein: The temperature of the temperature-raising reaction in step (2) is 170-200°C and the time is 5 hours.

4. The method for synthesizing 2,4-difluoronitrobenzene and 2-fluoro-5-chloronitrobenzene according to claim 1, wherein: In step (1), the organic phase is collected and distilled to separate the unreacted 2,5-dichloronitrobenzene for recycling.

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