A process for the preparation of 2-fluoro-3-nitrobenzoic acid

Abstract

The application discloses a preparation method of 2-fluoro-3-nitrobenzoic acid and belongs to the technical field of organic synthesis. The preparation method of the 2-fluoro-3-nitrobenzoic acid comprises the following steps: mixing acetic acid and 2-fluoro-3-nitrotoluene, then adding a polyacid catalyst, heating to 120-150 DEG C, and performing an oxidation reaction by introducing pure oxygen to obtain the 2-fluoro-3-nitrobenzoic acid. The preparation method has high reaction selectivity and small environmental pollution.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for preparing 2-fluoro-3-nitrobenzoic acid. Background Technology

[0002] 2-Fluoro-3-nitrotoluene is an important organic synthesis intermediate, widely used in the synthesis of pharmaceuticals, pesticides, and fine chemicals. Traditional oxidation methods for toluene compounds mainly include: Chemical oxidation method: This method uses strong oxidants such as potassium permanganate and chromic acid, but it has problems such as high pollution, poor selectivity, and high cost.

[0003] Air oxidation method: uses air as the oxygen source, but the reaction efficiency is low, there are many by-products, and the reaction time is long.

[0004] Peroxide oxidation method: This method uses peroxides such as hydrogen peroxide, which is costly and poses safety hazards.

[0005] Traditional methods generally suffer from problems such as large amounts of oxidant used, serious environmental pollution, poor reaction selectivity, easy generation of over-oxidation products, difficulty in solvent recovery, high production costs, and difficulty in reusing catalysts, which further increase production costs. Summary of the Invention

[0006] The purpose of this invention is to overcome the above-mentioned technical deficiencies and provide a method for preparing 2-fluoro-3-nitrobenzoic acid, thereby solving the technical problems of poor reaction selectivity and serious environmental pollution in the prior art.

[0007] To achieve the above-mentioned technical objectives, the present invention provides a method for preparing 2-fluoro-3-nitrobenzoic acid, comprising the following steps: mixing acetic acid and 2-fluoro-3-nitrotoluene, then adding a polyacid catalyst, heating to 120-150°C, and introducing pure oxygen to carry out an oxidation reaction to obtain 2-fluoro-3-nitrobenzoic acid.

[0008] In any embodiment, the oxidation reaction takes 8-12 hours.

[0009] In any embodiment, the pressure of the oxidation reaction is 0.2-0.7 MPa.

[0010] In any embodiment, the polyacid catalyst is one or more of phosphotungstic acid, phosphomolybdic acid, and silicotungstic acid.

[0011] In any embodiment, the polyacid catalyst is phosphotungstic acid and phosphomolybdic acid; or, the polyacid catalyst is phosphotungstic acid and silicotungstic acid.

[0012] In any embodiment, the mass ratio of phosphotungstic acid to phosphomolybdic acid is 2-2.5:1; or, the mass ratio of phosphotungstic acid to silicotungstic acid is 2-2.5:1. In any embodiment, the amount of the polyacid catalyst added is 3%-10% of the mass of the 2-fluoro-3-nitrotoluene.

[0013] In any embodiment, the mass ratio of the 2-fluoro-3-nitrotoluene to the acetic acid is 1:3-6.

[0014] In any embodiment, the purity of the pure oxygen is ≥99.5%.

[0015] Compared with the prior art, the beneficial effects of the present invention include: the preparation method of 2-fluoro-3-nitrobenzoic acid proposed in the present invention includes the following steps: mixing acetic acid and 2-fluoro-3-nitrotoluene, then adding a polyacid catalyst, heating to 120-150℃, and introducing pure oxygen to carry out an oxidation reaction to obtain 2-fluoro-3-nitrobenzoic acid. Pure oxygen is used as the oxidant, and the reaction produces water, with no harmful oxidant residue, which conforms to the concept of green chemistry. The polyacid catalyst can effectively control the oxidation depth and improve the selectivity of the target product. Therefore, the preparation method proposed in the present invention has high reaction selectivity and low environmental pollution. Attached Figure Description

[0016] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of 2-fluoro-3-nitrobenzoic acid prepared in Example 1 of this invention.

[0017] Figure 2 This is the carbon nuclear magnetic resonance spectrum of 2-fluoro-3-nitrobenzoic acid prepared in Example 1 of this invention.

[0018] Figure 3 This is a high-performance liquid chromatogram of 2-fluoro-3-nitrobenzoic acid prepared in Example 1 of this invention.

[0019] Figure 4 This is a photograph of 2-fluoro-3-nitrobenzoic acid prepared in Example 1 of this invention. Detailed Implementation

[0020] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60~120 and 80~110 are listed for a specific parameter, it is also expected that ranges of 60~110 and 80~120 are also included. Furthermore, if minimum range values ​​of 1 and 2 are listed, and if maximum range values ​​of 3, 4, and 5 are listed, then the following ranges are all expected: 1~3, 1~4, 1~5, 2~3, 2~4, and 2~5. In this application, unless otherwise stated, the numerical range "a~b" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0~5" indicates that all real numbers between "0~5" have been listed in this article; "0~5" is simply a shortened representation of these numerical combinations. Furthermore, when a parameter is stated as an integer ≥2, it is equivalent to disclosing that the parameter is, for example, an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0021] Unless otherwise specified, the terms "comprising" and "including" as used in this application can be open-ended or closed-ended. For example, "comprising" and "including" can mean that other components not listed may also be included, or that only the listed components may be included.

[0022] Unless otherwise specified, the term "or" is inclusive in this application. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, the condition "A or B" is satisfied by any of the following conditions: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist).

[0023] This specific embodiment provides a method for preparing 2-fluoro-3-nitrobenzoic acid, comprising the following steps: mixing acetic acid and 2-fluoro-3-nitrotoluene, then adding a polyacid catalyst, heating to 120-150°C, and introducing pure oxygen for an oxidation reaction for 8-12 hours, wherein the pressure of the oxidation reaction is 0.2-0.7 MPa, to obtain 2-fluoro-3-nitrobenzoic acid; the polyacid catalyst is one or more of phosphotungstic acid, phosphomolybdic acid, and silicotungstic acid; the amount of the polyacid catalyst added is 3%-10% of the mass of the 2-fluoro-3-nitrotoluene; the mass ratio of the 2-fluoro-3-nitrotoluene to the acetic acid is 1:3-6; and the purity of the pure oxygen is ≥99.5%.

[0024] In some embodiments, the polyacid catalyst is phosphotungstic acid and phosphomolybdic acid, wherein the mass ratio of phosphotungstic acid to phosphomolybdic acid is 2-2.5:1.

[0025] In some embodiments, the polyacid catalyst is phosphotungstic acid and silicotungstic acid, wherein the mass ratio of phosphotungstic acid to silicotungstic acid is 2-2.5:1.

[0026] Beneficial effects also include: Polyacid compounds possess unique electronic structures and redox properties, effectively controlling the oxidation depth and reducing over-oxidation. The catalysts exhibit good stability and can be reused multiple times. Using pure oxygen as the oxidant produces no harmful byproducts (water is generated in the reaction) and leaves no harmful oxidant residue, aligning with green chemistry principles. Polyacid catalysts effectively control the oxidation depth, improve the selectivity of target products, are recyclable, reduce production costs, operate under mild conditions, and are easily scaled up industrially. The use of strong oxidants is avoided, improving production safety.

[0027] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0028] In this invention, the terms "some embodiments," "this embodiment," and examples are used to describe a subset of all possible embodiments. However, it is understood that "some embodiments" can be the same subset or different subsets of all possible embodiments and can be combined with each other without conflict.

[0029] If the application documents contain similar descriptions such as "first / second", the following explanation shall be added: In the following description, the terms "first / second / third" are used only to distinguish similar objects and do not represent a specific ordering of objects. It is understood that "first / second / third" may be interchanged in a specific order or sequence where permitted, so that the embodiments described herein can be implemented in an order other than that illustrated or described herein.

[0030] In this embodiment, the term "and / or" is merely a description of the relationship between related objects, indicating that there can be three relationships. For example, object A and / or object B can represent three situations: object A exists alone, object A and object B exist simultaneously, and object B exists alone.

[0031] The following describes embodiments of this application. The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all conventional products that can be obtained commercially.

[0032] Example 1

[0033] This embodiment proposes a method for preparing 2-fluoro-3-nitrobenzoic acid, comprising the following steps: mixing 480g of acetic acid and 120g of 2-fluoro-3-nitrotoluene, then adding 3.6g of phosphotungstic acid, heating to 120℃, and purifying with pure oxygen for an oxidation reaction for 10 hours. The pressure of the oxidation reaction is 0.2-0.7MPa, thereby obtaining 2-fluoro-3-nitrobenzoic acid; the purity of the pure oxygen is ≥99.5%. The obtained 2-fluoro-3-nitrobenzoic acid was further purified by the following steps to obtain purified 2-fluoro-3-nitrobenzoic acid: the product obtained from the reaction was added to a 50% (v / v) methanol aqueous solution to dissolve it, the temperature was raised to 40°C, it was completely dissolved, and the product was cooled and recrystallized to obtain a white crystalline product with a purity of over 99%.

[0034] Combination Figure 1 , Figure 2 and Figure 3 It can be seen that this invention successfully prepared 2-fluoro-3-nitrobenzoic acid. Combined with... Figure 4 It can be seen that the 2-fluoro-3-nitrobenzoic acid obtained by this invention is a white crystalline solid.

[0035] Example 2

[0036] This embodiment proposes a method for preparing 2-fluoro-3-nitrobenzoic acid. The difference from Example 1 is that an equal amount of phosphomolybdic acid is used instead of phosphotungstic acid, while the other reaction conditions are the same as in Example 1.

[0037] Example 3

[0038] This embodiment proposes a method for preparing 2-fluoro-3-nitrobenzoic acid. The difference from Example 1 is that an equal amount of silicotungstic acid is used instead of phosphotungstic acid, while the other reaction conditions are the same as in Example 1.

[0039] Example 4

[0040] This embodiment proposes a method for preparing 2-fluoro-3-nitrobenzoic acid, comprising the following steps: mixing 360g of acetic acid and 120g of 2-fluoro-3-nitrotoluene, then adding 6g of phosphotungstic acid, heating to 150℃, and purifying with pure oxygen for an oxidation reaction for 8 hours. The pressure of the oxidation reaction is 0.2-0.7MPa, thereby obtaining 2-fluoro-3-nitrobenzoic acid; the purity of the pure oxygen is ≥99.5%. The obtained 2-fluoro-3-nitrobenzoic acid was further purified by the following steps to obtain purified 2-fluoro-3-nitrobenzoic acid: the product obtained from the reaction was added to a 50% (v / v) methanol aqueous solution to dissolve it, the temperature was raised to 40°C, it was completely dissolved, and the product was cooled and recrystallized to obtain a white crystalline product with a purity of over 99%.

[0041] Example 5

[0042] This embodiment proposes a method for preparing 2-fluoro-3-nitrobenzoic acid, comprising the following steps: mixing 720g of acetic acid and 120g of 2-fluoro-3-nitrotoluene, then adding 12g of phosphotungstic acid, heating to 130℃, and introducing pure oxygen for an oxidation reaction for 12 hours. The pressure of the oxidation reaction is 0.2-0.7MPa, thereby obtaining 2-fluoro-3-nitrobenzoic acid; the purity of the pure oxygen is ≥99.5%. The obtained 2-fluoro-3-nitrobenzoic acid was further purified by the following steps to obtain purified 2-fluoro-3-nitrobenzoic acid: the product obtained from the reaction was added to a 50% (v / v) methanol aqueous solution to dissolve it, the temperature was raised to 40°C, it was completely dissolved, and the product was cooled and recrystallized to obtain a white crystalline product with a purity of over 99%.

[0043] Example 6

[0044] This embodiment proposes a method for preparing 2-fluoro-3-nitrobenzoic acid, comprising the following steps: mixing 480g of acetic acid and 120g of 2-fluoro-3-nitrotoluene, then adding 2.4g of phosphotungstic acid and 1.2g of phosphomolybdic acid, heating to 120°C, and purifying with pure oxygen for an oxidation reaction of 10 hours. The pressure of the oxidation reaction is 0.2-0.7MPa, thereby obtaining 2-fluoro-3-nitrobenzoic acid; the purity of the pure oxygen is ≥99.5%. The obtained 2-fluoro-3-nitrobenzoic acid was further purified by the following steps to obtain purified 2-fluoro-3-nitrobenzoic acid: the product obtained from the reaction was added to a 50% (v / v) methanol aqueous solution to dissolve it, the temperature was raised to 40°C, it was completely dissolved, and the product was cooled and recrystallized to obtain a white crystalline product with a purity of over 99%.

[0045] Example 7

[0046] This embodiment proposes a method for preparing 2-fluoro-3-nitrobenzoic acid, comprising the following steps: mixing 480g of acetic acid and 120g of 2-fluoro-3-nitrotoluene, then adding 2.4g of phosphotungstic acid and 1.2g of silicotungstic acid, heating to 120°C, and purifying with pure oxygen for an oxidation reaction of 10 hours. The pressure of the oxidation reaction is 0.2-0.7MPa, thereby obtaining 2-fluoro-3-nitrobenzoic acid; the purity of the pure oxygen is ≥99.5%. The obtained 2-fluoro-3-nitrobenzoic acid was further purified by the following steps to obtain purified 2-fluoro-3-nitrobenzoic acid: the product obtained from the reaction was added to a 50% (v / v) methanol aqueous solution to dissolve it, the temperature was raised to 40°C, it was completely dissolved, and the product was cooled and recrystallized to obtain a white crystalline product with a purity of over 99%.

[0047] Example 8

[0048] This embodiment proposes a method for preparing 2-fluoro-3-nitrobenzoic acid, comprising the following steps: mixing 480g of acetic acid and 120g of 2-fluoro-3-nitrotoluene, then adding 2.4g of phosphomolybdic acid and 1.2g of silicotungstic acid, heating to 120°C, and introducing pure oxygen for an oxidation reaction for 10 hours. The pressure of the oxidation reaction is 0.2-0.7MPa, thereby obtaining 2-fluoro-3-nitrobenzoic acid; the purity of the pure oxygen is ≥99.5%. The obtained 2-fluoro-3-nitrobenzoic acid was further purified by the following steps to obtain purified 2-fluoro-3-nitrobenzoic acid: the product obtained from the reaction was added to a 50% (v / v) methanol aqueous solution to dissolve it, the temperature was raised to 40°C, it was completely dissolved, and the product was cooled and recrystallized to obtain a white crystalline product with a purity of over 99%.

[0049] Comparative Example 1 The difference between this comparative example and Example 1 is that no polyacid catalyst was added, while the other steps and reaction conditions were the same as in Example 1.

[0050] Table 1

[0051] As can be seen from Table 1, the phosphotungstic acid catalytic effect of Example 1 is better than that of Examples 2 and 3, and the conversion rate and selectivity are higher than those of Examples 2 and 3. The catalytic effect, conversion rate and selectivity of Examples 6 and 7 are even better.

[0052] Repeated trials The catalyst from Example 1 was reused five times, and the yields of 2-fluoro-3-nitrobenzoic acid are shown in Table 2. It should be noted that the catalyst is soluble in acetic acid, while 2-fluoro-3-nitrobenzoic acid has low solubility in acetic acid at room temperature. Therefore, only solid-liquid separation (i.e., filtration) is required, and the catalyst can be added appropriately when the mother liquor is recycled for further testing.

[0053] Table 2

[0054] As can be seen from Table 2, the yield of the catalyst remained at around 90% after 5 cycles, indicating that the catalyst can be reused multiple times, thus reducing production costs.

[0055] The specific embodiments of the present invention described above do not constitute a limitation on the scope of protection of the present invention. Any other corresponding changes and modifications made in accordance with the technical concept of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing 2-fluoro-3-nitrobenzoic acid, characterized in that, Includes the following steps: Acetic acid and 2-fluoro-3-nitrotoluene are mixed, then a polyacid catalyst is added, the temperature is raised to 120-150℃, and pure oxygen is introduced to carry out an oxidation reaction to obtain 2-fluoro-3-nitrobenzoic acid.

2. The method for preparing 2-fluoro-3-nitrobenzoic acid according to claim 1, characterized in that, The oxidation reaction takes 8-12 hours.

3. The method for preparing 2-fluoro-3-nitrobenzoic acid according to claim 1, characterized in that, The oxidation reaction is carried out at a pressure of 0.2-0.7 MPa.

4. The method for preparing 2-fluoro-3-nitrobenzoic acid according to claim 1, characterized in that, The polyacid catalyst is one or more of phosphotungstic acid, phosphomolybdic acid, and silicotungstic acid.

5. The method for preparing 2-fluoro-3-nitrobenzoic acid according to claim 4, characterized in that, The polyacid catalyst is phosphotungstic acid and phosphomolybdic acid; or, the polyacid catalyst is phosphotungstic acid and silicotungstic acid.

6. The method for preparing 2-fluoro-3-nitrobenzoic acid according to claim 5, characterized in that, The mass ratio of phosphotungstic acid to phosphomolybdic acid is 2-2.5:1; or, the mass ratio of phosphotungstic acid to silicotungstic acid is 2-2.5:

1.

7. The method for preparing 2-fluoro-3-nitrobenzoic acid according to claim 1, characterized in that, The amount of the polyacid catalyst added is 3%-10% of the mass of the 2-fluoro-3-nitrotoluene.

8. The method for preparing 2-fluoro-3-nitrobenzoic acid according to claim 1, characterized in that, The mass ratio of the 2-fluoro-3-nitrotoluene to the acetic acid is 1:3-6.

9. The method for preparing 2-fluoro-3-nitrobenzoic acid according to claim 1, characterized in that, The purity of the oxygen is ≥99.5%.

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