Method for synthesizing 2-f-3-nitrobenzoic acid by nitric acid oxidation

Abstract

The application discloses a method for synthesizing 2-F-3-nitrobenzoic acid by nitric acid oxidation, and relates to the technical field of chemical synthesis. First, a catalyst is prepared by dissolving ammonium molybdate and adding iron nitrate, the pH is adjusted to be acidic, and after reaction for 3 hours, a purified solid catalyst is obtained. Then, 2-F-3-nitrotoluene, an oxidizing agent and the catalyst are reacted at 130-150 DEG C to generate a 2-F-3-nitrobenzoic acid solution. Finally, high-purity 2-F-3-nitrobenzoic acid solid is obtained through ethyl acetate extraction, acid-base conversion, extraction and reduced-pressure concentration. The method has the advantages of easy acquisition of raw materials, easy control of reaction, high purity and yield of products, less generation of waste water, simple treatment, and economic and environmental protection benefits.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and in particular to a method for synthesizing 2-F-3-nitrobenzoic acid from 2-F-3-nitrobenzenetoluene. Background Technology

[0002] 2-Fluoro-3-nitrobenzoic acid, a pale yellow solid, is slightly soluble in water and is an important organic synthesis intermediate widely used in the synthesis of pharmaceuticals, active biological enzymes, and other drugs.

[0003] Current reports on the synthesis process of 2-fluoro-3-nitrobenzoic acid mainly include:

[0004] ①CN101497612A uses 2-chloro-3-nitrobenzoic acid as a raw material. It oxidizes the product, 2-fluoro-3-nitrobenzoic acid, with potassium permanganate or chromium trioxide. However, this route uses potassium permanganate or chromium trioxide, and after the reaction, the product mixes with the reduction product of the oxidant, making separation difficult.

[0005] ②CN113024384A uses o-methylphenol as a raw material. o-methylphenol is nitrated with nitrate / p-toluenesulfonic acid to prepare 2-methyl-nitrophenol, then chlorinated to convert the hydroxyl group to a chlorine atom, and then the chlorine atom is converted to a fluorine atom under the action of cesium fluoride. Finally, it is oxidized to obtain the target product 2-fluoro-3-nitrobenzoic acid.

[0006] Both of these synthetic routes are relatively long, have low overall yields, involve many production steps and generate a lot of waste, and make product separation difficult. Summary of the Invention

[0007] The purpose of this invention is to address the shortcomings of existing technologies by providing a synthetic method for producing 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene. This method solves the problems of excessive and difficult-to-treat organic wastewater generated by the oxidation reaction in the existing production process of 2-F-3-nitrobenzoic acid, as well as the low product yield. The chemical reaction equation is as follows:

[0008]

[0009] The technical solution adopted by this invention to solve its technical problem is: a method for synthesizing 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene, which is carried out according to the following steps:

[0010] (1) Dissolve ammonium molybdate in water, stir the solution continuously and keep it heated at 100°C, then weigh ferric nitrate (ferric nitrate can also be replaced by copper sulfate) and slowly add it to the ammonium molybdate solution. Detect and adjust the pH of the mixed solution to be acidic. Under this condition, continue stirring the reaction for 3 to 4 hours and then stop the reaction. Let the solution stand for 30 minutes and then vacuum filter to obtain a solid precipitate. Crystallize and purify the solid to obtain the polyoxometalate main catalyst.

[0011] (2) Add 2-F-3-nitrotoluene, oxidant and catalyst to a pressure-resistant reaction flask and react at 120-160℃. After reacting for a period of time, a 2-F-3-nitrobenzoic acid solution is obtained.

[0012] (3) Transfer the 2-F-3-nitrobenzoic acid solution obtained above to a separatory funnel, add water and ethyl acetate for extraction and separation, and obtain an ethyl acetate solution of 2-F-3-nitrobenzoic acid;

[0013] (4) Transfer the ethyl acetate solution of 2-F-3-nitrobenzoic acid obtained above to a reaction flask, add a slight excess of alkaline solution and an appropriate amount of aqueous solution, stir for 0.5 h, adjust the pH of the solution to 7-9, separate the aqueous phase, add an appropriate amount of acidic solution to the reaction flask, stir for 0.5 h, adjust the pH of the solution to 5-7, add ethyl acetate for extraction and separation, separate the organic phase, concentrate the organic phase under reduced pressure to obtain solid 2-F-3-nitrobenzoic acid. Then, cool and crystallize, filter, recrystallize, and dry to obtain the 2-F-3-nitrobenzoic acid product.

[0014] Specifically, in step (1), ammonium molybdate tetrahydrate is dissolved in water at 90-110°C. Then, ferric nitrate nonahydrate (ferric nitrate can also be replaced with copper sulfate) is weighed and slowly added to the ammonium molybdate solution. The pH of the mixed solution is detected and adjusted to be acidic. After reacting for 3-4 hours, solid insoluble matter is precipitated after cooling. The insoluble matter is obtained by filtration, the solution is removed, and the solution is recycled to obtain a polyoxometalate solid catalyst.

[0015] Specifically, in step (1), the molar ratio of ammonium molybdate tetrahydrate to ferric nitrate nonahydrate is 1:(1-2), and the pH value is maintained at around 2.5-3.5.

[0016] Specifically, in step (2), the reaction is carried out at 130-150°C for 12-16 hours. After cooling, solid insoluble matter is precipitated. The insoluble matter is obtained by filtration, the solution is removed, and the solution is recycled to obtain solid 2-F-3-nitrobenzoic acid.

[0017] Specifically, the oxide in step (2) is nitric acid with a concentration of 40-60%, and the molar ratio of 2-F-3-nitrotoluene to the oxide is 1:(8-12).

[0018] Specifically, the main catalyst in step (3) is the polyoxometalate obtained in step (1), the auxiliary catalyst is an aqueous solution of hydrogen bromide with a concentration of 40-70%, the molar ratio of 2-chloro-3-nitrotoluene to the main catalyst is (16-24):1, and the molar ratio of 2-chloro-3-nitrotoluene to the auxiliary catalyst is (10-40):1.

[0019] Specifically, in step (3), after the 2-F-3-nitrobenzoic acid mixture is added to the extraction separation vessel, water is added to dilute the residual reaction liquid in the mixture. Ethyl acetate is selected as the extractant, and the volume ratio of the aqueous solution to ethyl acetate is approximately 4:1.

[0020] Specifically, in step (4), after adding an alkaline solution to the ethyl acetate solution, 2-F-3-nitrobenzoic acid is converted into sodium 2-F-3-nitrobenzoate, and its solubility changes, causing it to precipitate from the ethyl acetate. After filtration, water is added to dissolve it. The alkaline solution is an aqueous solution of sodium bicarbonate, and the molar ratio of 2-F-3-nitrobenzoic acid to sodium bicarbonate is 1:(1~1.1). The pH of the solution is adjusted to 7~9.

[0021] Specifically, the acidic solution mentioned in step (4) is an aqueous solution of hydrochloric acid (10-38%). After its addition, sodium 2-F-3-nitrobenzoate is converted into 2-F-3-nitrobenzoic acid and its solubility changes, causing it to precipitate from the aqueous solution. The molar ratio of sodium 2-F-3-nitrobenzoate to hydrogen chloride is (1-1.1), and the pH of the solution is adjusted to 5-7.

[0022] Preferably, in step (1), ammonium molybdate tetrahydrate is dissolved in water at 100°C, and the metal salt ferric nitrate nonahydrate is slowly added to the ammonium molybdate solution. The molar ratio of the ammonium molybdate tetrahydrate to the ferric nitrate nonahydrate is 2:3, and the pH value is 3.

[0023] Preferably, the reaction temperature in step (2) is 140℃, and the reaction time is 14h. The nitric acid concentration is 60%, and the molar ratio of 2-F-3-nitrotoluene to nitric acid is 1:10. The main catalyst is a Fe-Anderson type heteropolyacid catalyst, and the molar ratio of 2-F-3-nitrotoluene to the main catalyst is 20:1. The cocatalyst is a 48% aqueous solution of hydrogen bromide, and the molar ratio of 2-F-3-nitrotoluene to the cocatalyst is 13 / 1.

[0024] Preferably, in step (3), the volume ratio of 2-F-3-nitrobenzoic acid mixture / water is 2:1, the extractant is ethyl acetate, and the volume ratio of aqueous solution / ethyl acetate is 4:1.

[0025] Preferably, in step (4), the alkaline solution is a 30% sodium hydroxide aqueous solution and the hydrochloric acid aqueous solution has a concentration of 19%.

[0026] Compared with existing synthesis processes, the advantages of this invention are:

[0027] (1) The oxidant used in the process route of this invention is 60% nitric acid. Only a small amount of water is added for dilution during the treatment process. After the reaction is completed, the product is extracted and separated. Both the catalyst and the auxiliary catalyst remain in the mother liquor. 98% nitric acid can be added appropriately to increase the nitric acid concentration for recycling, which reduces the difficulty of wastewater treatment. In addition, no additional solvent needs to be added during the reaction process, saving costs. Compared with the manganese dioxide solid precipitate generated after potassium permanganate oxidation, which is difficult to separate and treat, the reaction process is easy to control and treat.

[0028] (2) Compared with existing technologies such as o-methylphenol as raw material, the present invention uses 2-F-3-nitrotoluene as raw material and obtains 2-F-3-nitrobenzoic acid in one step by reacting with oxides. The process flow is shorter, the product yield is higher, the amount of process wastewater generated is less, and it is easier to treat, making it more economical and environmentally friendly.

[0029] (3) Adding excess sodium hydroxide solution to the ethyl acetate solution of 2-F-3-nitrobenzoic acid converts 2-F-3-nitrobenzoic acid into sodium 2-F-3-nitrobenzoate, which is then precipitated from the ethyl acetate. Adding this sodium 2-F-3-nitrobenzoate into dilute hydrochloric acid converts it into 2-F-3-nitrobenzoic acid, which can greatly improve the purity and yield of the product.

[0030] The raw materials used in this invention are inexpensive and readily available, the reaction process is easy to control, the product purity can reach over 99%, and the product yield can reach over 95%. Attached Figure Description

[0031] Figure 1 (NH4)3[FeMo6O 18 Infrared spectrum of [(OH)6];

[0032] Figure 2 (NH4)3[FeMo6O 18 XRD pattern of [(OH)6]. Detailed Implementation

[0033] The present invention will be further described in detail below with reference to specific embodiments, but this is not intended to limit the scope of the invention.

[0034] Example 1

[0035] (1) First, prepare the Fe-Anderson type heteropolyacid catalyst: First, prepare solution 1 by dissolving 15.92g of ammonium molybdate tetrahydrate in 100ml of deionized water and heating and stirring to 100℃. Solution 1 is a colorless and transparent clear liquid. Second, prepare solution 2 by dissolving 4.85g of ferric nitrate nonahydrate in 50ml of deionized water and stirring thoroughly to obtain solution 2. Third, slowly add solution 2 to solution 1 and adjust the pH of the mixed solution to maintain it at around 3.0. Continue stirring the mixed solution at 100℃ for 3 hours. When a large amount of yellow-brown precipitate is produced in the solution, stop the reaction, let the solution stand for 30 minutes, and then vacuum filter to obtain 13.73g of yellow-brown precipitate. After drying the precipitate and dissolving it in deionized water, filter it and then cultivate and collect light yellow crystals using liquid-phase diffusion single crystal culture technology. This crystal is the Anderson type heteropolyacid (NH4)3[FeMo6O3] with iron atoms replacing the central atom. 18 [(OH)6] pure product. Relevant characterization data are shown in the attached figure. After comparison with standard spectra, the compound was confirmed to be a Fe-Anderson type heteropolyacid.

[0036] (2) Add 0.9 g (5.8 mmol) of 2-fluoro-3-nitrotoluene and (NH4)3[FeMo6O to a 25 mL pressure-resistant tube in sequence. 18 [(OH)6] (0.320 g, 0.29 mmol), 48% hydrobromic acid (0.072 g, 0.43 mmol), and 60% nitric acid (6.09 g, 58 mmol) were added as oxidants. The reaction was controlled at 140 °C. Heating was stopped after 14 h of reaction. After cooling, solid precipitated.

[0037] (3) Transfer the 2-fluoro-3-nitrobenzoic acid mixture obtained above to a separatory funnel, add 25 ml of water and 30 ml of ethyl acetate for extraction and separation, and obtain an ethyl acetate solution of 2-chloro-3-nitrobenzoic acid.

[0038] (4) The ethyl acetate solution of 2-fluoro-3-nitrobenzoic acid obtained above was added to a reaction flask, along with 6g of saturated sodium bicarbonate aqueous solution and 30g of water. The pH of the solution was adjusted to 7-9. The aqueous phase was separated, and 0.629g of hydrochloric acid was added to it. The pH of the solution was adjusted to 7-9. The precipitated 2-chloro-3-nitrobenzoic acid solid was cooled and crystallized, filtered, recrystallized, and dried to obtain the 2-fluoro-3-nitrobenzoic acid product. Finally, 1.042g of 2-fluoro-3-nitrobenzoic acid was obtained, with a chromatographic purity of 99.8% and a total yield of 96.9%.

[0039] Example 2

[0040] The method is the same as in Example 1, except that:

[0041] The reaction temperature was controlled at 150℃.

[0042] 50% nitric acid (7.3g, 58mmol) was used as the oxidizing agent;

[0043] Operating under these conditions, 0.981 g of 2-fluoro-3-nitrobenzoic acid was obtained with a chromatographic purity of 97.1% and an overall yield of 88.7%.

[0044] Example 3

[0045] The method is the same as in Example 1, except that:

[0046] The reaction was controlled at 130℃.

[0047] 70% nitric acid (5.22g, 58mmol) was used as an oxidizing agent;

[0048] Operating under these conditions, 0.993 g of 2-fluoro-3-nitrobenzoic acid was obtained with a chromatographic purity of 96.4% and an overall yield of 89.2%.

[0049] Example 4

[0050] The method is the same as in Example 1, except that:

[0051] The reaction temperature was controlled at 150℃.

[0052] 50% nitric acid (7.3g, 58mmol) was used as the oxidizing agent;

[0053] Under these conditions, 1.000 g of 2-fluoro-3-nitrobenzoic acid was obtained with a chromatographic purity of 97.9% and an overall yield of 91.2%.

[0054] Example 5

[0055] The method is the same as in Example 1, except that:

[0056] The reaction was controlled at 130℃.

[0057] 70% nitric acid (5.22g, 58mmol) was used as an oxidizing agent;

[0058] Under these conditions, 1.012 g of 2-fluoro-3-nitrobenzoic acid was obtained with a chromatographic purity of 94.5% and an overall yield of 89.1%.

[0059] Example 6

[0060] The method is the same as in Example 1, except that:

[0061] (NH4)4[CuMo6O 18 [(OH)6](0.319g, 0.29mmol)

[0062] Operating under these conditions, 0.982 g of 2-fluoro-3-nitrobenzoic acid was obtained with a chromatographic purity of 95.4% and an overall yield of 87.3%.

[0063] Comparative Example 1

[0064] The method is the same as in Example 1, except that:

[0065] The reaction temperature was controlled at 110℃.

[0066] 70% nitric acid (5.2g, 58mmol) was used as an oxidizing agent;

[0067] Operating under these conditions, the conversion rate of 2-fluoro-3-nitrotoluene is too low, with a residual amount of approximately 96% in the raw material, indicating an excessively low conversion rate.

[0068] Comparative Example 2

[0069] The method is the same as in Example 1, except that:

[0070] The reaction temperature is controlled to be between 110℃;

[0071] 90% nitric acid (4.1g, 58mmol) was used as the oxidizing agent;

[0072] Operating under these conditions, the conversion rate of 2-fluoro-3-nitrotoluene is too low, with a residual amount of approximately 94% in the raw material, indicating an excessively low conversion rate.

[0073] Comparative Example 3

[0074] The method is the same as in Example 2, except that:

[0075] The reaction temperature is controlled to be between 170℃;

[0076] 50% nitric acid (7.3g, 58mmol) was used as the oxidizing agent;

[0077] Under these conditions, 0.961 g of 2-fluoro-3-nitrobenzoic acid was obtained with a chromatographic purity of 75.2% and an overall yield of 67.3%.

[0078] Comparative Example 4

[0079] The method is the same as in Example 2, except that:

[0080] The reaction temperature was controlled at 170℃.

[0081] 30% nitric acid (12.1g, 58mmol) was used as the oxidizing agent;

[0082] Under these conditions, 1.021 g of 2-fluoro-3-nitrobenzoic acid was obtained with a chromatographic purity of 67.4% and an overall yield of 64.1%.

[0083] Compared with existing technologies, the raw materials of this invention are inexpensive and readily available, the reaction process is easy to control, the product purity can reach over 99%, and the product yield can reach over 95%. The oxidant used in this invention is dilute nitric acid, which is cheaper than traditional oxidants such as potassium permanganate and chromium trioxide, and does not produce any inorganic metal salts, making it easier to process. The reaction is more controllable, avoiding the generation of organic wastewater, reducing the difficulty of wastewater treatment, and the products obtained from the reaction are easy to separate.

[0084] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A method for the synthesis of 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene, characterized in that The following steps are taken: (1) Dissolve ammonium molybdate in water, continuously stir the solution and maintain heating at 100°C, then weigh iron nitrate (iron nitrate can also be replaced by copper sulfate) and slowly add it into the ammonium molybdate solution, detect and adjust the pH value of the mixed solution to be acidic, continue stirring the reaction for 3-4 hours, then stop the reaction, let the solution stand for 30 minutes, and then perform vacuum filtration to obtain solid precipitate, purify the solid crystal to obtain a polyoxometalate main catalyst; (2) Add 2-F-3-nitrotoluene, an oxidizing agent and a catalyst into a pressure-resistant reaction bottle, and perform reaction at 120-160°C, after a period of time, 2-F-3-nitrobenzoic acid solution is obtained; (3) Transfer the 2-F-3-nitrobenzoic acid solution obtained above into a separatory funnel, add water and ethyl acetate to extract and separate, and obtain 2-F-3-nitrobenzoic acid ethyl acetate solution; (4) Transfer the 2-F-3-nitrobenzoic acid ethyl acetate solution obtained above into a reaction bottle, add a little excess of alkaline solution and an appropriate amount of aqueous solution, stir for 0.5 h, adjust the pH value of the solution to be 7-9, separate the aqueous phase, add an appropriate amount of acidic solution into the reaction bottle, stir for 0.5 h, adjust the pH value of the solution to be 5-7, add ethyl acetate to extract and separate, separate the organic phase, and concentrate the organic phase under reduced pressure to obtain 2-F-3-nitrobenzoic acid solid; then perform cooling crystallization, filtration, recrystallization and drying to obtain 2-F-3-nitrobenzoic acid product.

2. A process for the synthesis of 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene as claimed in claim 1, wherein In step (1), dissolve ammonium molybdate tetrahydrate in water at 90-110°C, then weigh iron nitrate nonahydrate (iron nitrate can also be replaced by copper sulfate) and slowly add it into the ammonium molybdate solution, detect and adjust the pH value of the mixed solution to be acidic, after 3-4 h of reaction, solid insoluble substances are precipitated after cooling, the insoluble substances are obtained by filtration, the solution is removed and recycled, and a polyoxometalate solid catalyst is obtained. In step (1), the molar ratio of the ammonium molybdate tetrahydrate to the iron nitrate nonahydrate is 1:(1-2), and the pH value is kept at about 2.5-3.

5.

3. A process for the synthesis of 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene as claimed in claim 1, wherein In step (2), perform reaction at 130-150°C for 12-16 h, solid insoluble substances are precipitated after cooling, the insoluble substances are obtained by filtration, the solution is removed and recycled, and 2-F-3-nitrobenzoic acid solid is obtained. In step (2), the oxidizing agent is nitric acid with a concentration of 40-60%, and the molar ratio of the 2-F-3-nitrotoluene to the oxidizing agent is 1:(8-12).

4. The process for the synthesis of 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene as claimed in claim 1, wherein In step (3), the main catalyst is the polyoxometalate obtained in step (1), the auxiliary catalyst is hydrogen bromide aqueous solution with a concentration of 40-70%, the molar ratio of the 2-chloro-3-nitrotoluene to the main catalyst is (16-24):1, and the molar ratio of the 2-chloro-3-nitrotoluene to the auxiliary catalyst is (10-40):

1. In step (3), the 2-F-3-nitrobenzoic acid mixture was added into the extraction separation kettle, and then water was added to dilute the residual reaction solution in the mixture. The extraction agent was ethyl acetate, and the volume ratio of the aqueous solution to ethyl acetate was about 4:

1.

5. The process for the synthesis of 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene as claimed in claim 1, wherein In step (4), after the ethyl acetate solution was added into the alkaline solution, the 2-F-3-nitrobenzoic acid was converted into sodium 2-F-3-nitrobenzoate, and the solubility changed, so that the sodium 2-F-3-nitrobenzoate was precipitated from the ethyl acetate. The sodium 2-F-3-nitrobenzoate was filtered and dissolved in water. The alkaline solution was a sodium bicarbonate aqueous solution, and the molar ratio of 2-F-3-nitrobenzoic acid to sodium bicarbonate was 1:(1-1.1). The pH of the solution was adjusted to 7-9.

6. The process for the synthesis of 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene as claimed in claim 1, wherein In step (4), the acid solution was a hydrochloric acid aqueous solution (10-38%), and after the sodium 2-F-3-nitrobenzoate was added, the sodium 2-F-3-nitrobenzoate was converted into 2-F-3-nitrobenzoic acid and the solubility changed, so that the 2-F-3-nitrobenzoic acid was precipitated from the aqueous solution. The molar ratio of sodium 2-F-3-nitrobenzoate to hydrogen chloride was (1-1.1), and the pH of the solution was adjusted to 5-7.

7. The method for synthesizing 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene according to claim 2, characterized in that... In step (1), the ammonium molybdate tetrahydrate was dissolved in water at 100°C, and the metal salt in the ammonium molybdate solution was iron nitrate nonahydrate. The molar ratio of the ammonium molybdate tetrahydrate to the iron nitrate nonahydrate was 2:3, and the pH value was 3.

8. The method for synthesizing 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene according to claim 3, characterized in that... In step (2), the reaction temperature was 140°C, the reaction time was 14h, the concentration of nitric acid was 60%, the molar ratio of 2-F-3-nitrotoluene to nitric acid was 1:10, the main catalyst was Fe-Anderson type heteropoly acid catalyst, the molar ratio of 2-F-3-nitrotoluene to the main catalyst was 20:1, and the co-catalyst was 48% hydrogen bromide aqueous solution. The molar ratio of 2-F-3-nitrotoluene to the co-catalyst was 13:

1.

9. The method for synthesizing 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene according to claim 4, characterized in that... In step (3), the volume ratio of the 2-F-3-nitrobenzoic acid mixture to water was 2:1, the extraction agent was ethyl acetate, and the volume ratio of the aqueous solution to ethyl acetate was 4:

1.

10. A process for the synthesis of 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene as claimed in claim 1, wherein In step (4), the alkaline solution was a 30% sodium hydroxide aqueous solution, and the concentration of the hydrochloric acid aqueous solution was 19%.

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