Method for synthesizing 2-F-3-nitrobenzoic acid through nitric acid oxidation

Abstract

The invention discloses a method for synthesizing 2-F-3-nitrobenzoic acid through nitric acid oxidation, and relates to the technical field of chemical synthesis. The method comprises the following steps: dissolving ammonium molybdate, adding ferric nitrate to prepare a catalyst, adjusting the pH to be acidic, and reacting for 3 hours to obtain a purified solid catalyst; then, the 2-F-3-nitrotoluene, an oxidizing agent and a catalyst are subjected to a reaction at the temperature of 130-150 DEG C, and a 2-F-3-nitrobenzoic acid solution is generated. And carrying out ethyl acetate extraction, acid-base conversion, extraction and vacuum concentration to finally obtain a high-purity 2-F-3-nitrobenzoic acid solid. According to the method, raw materials are easy to obtain, reaction is easy to control, product purity and yield are high, less wastewater is generated, treatment is simple, and economic and environment-friendly benefits are achieved.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a synthesis method for producing 2-F-3-nitrobenzoic acid from 2-F-3-nitrobenzene toluene. Background Art

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

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

[0004] ① CN101497612A uses 2-chloro-3-nitrobenzoic acid as raw material. It is oxidized with potassium permanganate or chromium trioxide to obtain the target product 2-fluoro-3-nitrobenzoic acid. This route uses potassium permanganate or chromium trioxide. After the reaction is completed, the product is mixed with the reduction product of the oxidant, which is difficult to separate.

[0005] ②CN113024384A uses o-methylphenol as raw material. o-methylphenol is nitrated with nitrate / p-toluenesulfonic acid to prepare 2-methyl-nitrophenol, and then the hydroxyl group is converted into chlorine atoms by chlorination, and then the chlorine atoms are converted into fluorine atoms under the action of cesium fluoride, and finally the target product 2-fluoro-3-nitrobenzoic acid is obtained by oxidation.

[0006] These two synthetic process routes are relatively long, the overall yield is not high, the production process generates a lot of three wastes, and the product separation is difficult. Summary of the invention

[0007] The purpose of the present invention is to provide a method for synthesizing 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene in order to overcome the shortcomings of the prior art, which solves the problems of large amounts of organic wastewater generated by oxidation reaction in the production process of the prior art 2-F-3-nitrobenzoic acid, the difficulty in treating the wastewater, and the low product yield. The chemical reaction equation is as follows:

[0008]

[0009] The technical solution adopted by the present invention to solve the technical problem is: a synthetic method for producing 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 maintain heating at 100° C., then weigh ferric nitrate (ferric nitrate may also be replaced by copper sulfate) and slowly add it to the ammonium molybdate solution, detect and adjust the pH value of the mixed solution to be acidic, continue stirring the reaction in this state for 3 to 4 hours, then stop the reaction, let the solution stand for 30 minutes and then perform vacuum filtration to obtain a solid precipitate, purify the solid crystals, and thus obtain a polyoxometalate main catalyst.

[0011] (2) adding 2-F-3-nitrotoluene, an oxidant and a catalyst into a pressure-resistant reaction bottle, reacting at 120 to 160° C., and obtaining a 2-F-3-nitrobenzoic acid solution after a period of reaction;

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

[0013] (4) The ethyl acetate solution of 2-F-3-nitrobenzoic acid obtained above was transferred to a reaction flask, a slightly excessive amount of alkaline solution and an appropriate amount of aqueous solution were added, stirred for 0.5 h, the pH of the solution was adjusted to 7-9, and the aqueous phase was separated. An appropriate amount of acidic solution was added to the reaction flask, stirred for 0.5 h, the pH of the solution was adjusted to 5-7, ethyl acetate was added for extraction and separation, the organic phase was separated, and the organic phase was concentrated under reduced pressure to obtain 2-F-3-nitrobenzoic acid solid. Then, the 2-F-3-nitrobenzoic acid product was obtained by cooling, crystallization, filtration, recrystallization, and drying.

[0014] Specifically, in step (1), ammonium molybdate tetrahydrate is dissolved in water at 90-110° C., then iron nitrate nonahydrate (iron nitrate can also be replaced by copper sulfate) is weighed and slowly added to the ammonium molybdate solution, the pH value of the mixed solution is detected and adjusted to be acidic, and after reacting for 3-4 hours, solid insoluble matter is precipitated after cooling, the insoluble matter is obtained by suction 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 the ammonium molybdate tetrahydrate to the ferric nitrate nonahydrate is 1:(1-2), and the pH value is maintained at about 2.5-3.5.

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

[0017] Specifically, the oxide in step (2) is nitric acid with a concentration of 40-60%, and the molar ratio of the 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 to 70%, the molar ratio of the 2-chloro-3-nitrotoluene to the main catalyst is (16 to 24):1, and the molar ratio of the 2-chloro-3-nitrotoluene to the auxiliary catalyst is (10 to 40):1.

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

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

[0021] Specifically, the acidic solution in step (4) is an aqueous solution of hydrochloric acid (10-38%). After addition, sodium 2-F-3-nitrobenzoate is converted into 2-F-3-nitrobenzoic acid and its solubility changes, and it precipitates 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 slowly added to the ammonium molybdate solution is ferric nitrate nonahydrate. The molar ratio of the ammonium molybdate tetrahydrate to the ferric nitrate nonahydrate is 2:3, and the pH value is 3.

[0023] Preferably, in step (2), the reaction temperature is 140° C. and the reaction time is 14 h. 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 co-catalyst is a 48% aqueous solution of hydrogen bromide, and the molar ratio of 2-F-3-nitrotoluene to the co-catalyst 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, the alkaline solution in step (4) is a 30% sodium hydroxide aqueous solution, and the concentration of the hydrochloric acid aqueous solution is 19%.

[0026] Compared with the existing synthesis process, the beneficial effects of the present invention are:

[0027] (1) The oxidant used in the process of the present invention is 60% nitric acid. Only a small amount of water is added during the treatment process for dilution. After the reaction is completed, the product is extracted and separated. The catalyst and the auxiliary catalyst are left in the mother liquor. 98% nitric acid can be appropriately added to increase the nitric acid concentration and recycled, which reduces the difficulty of wastewater treatment. No additional solvent is required 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 the prior art using o-methylphenol as raw material, the present invention uses 2-F-3-nitrotoluene as raw material and obtains 2-F-3-nitrobenzoic acid by reacting with an oxide in one step. The process flow is shorter, the product yield is higher, the amount of process wastewater generated is less, and it is easier to handle, which is more economical and environmentally friendly.

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

[0030] The raw materials of the invention are cheap and easily available, the reaction process is easy to control, the product purity can reach more than 99%, and the product yield can reach more than 95%. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0032] Figure 2 (NH4)3[FeMo6O 18 (OH)6] XRD spectrum. DETAILED DESCRIPTION

[0033] The present invention will be further described in detail below in conjunction with specific embodiments, but the implementation scope of the present invention is not limited thereto.

[0034] Example 1

[0035] (1) First, prepare and synthesize Fe-Anderson type heteropoly acid catalyst: The first step is to prepare solution 1, weigh 15.92g of ammonium molybdate tetrahydrate and dissolve it in 100ml of deionized water, heat and stir to 100℃, at this time, solution 1 is a colorless transparent clear liquid. The second step is to prepare solution 2, dissolve 4.85g of ferric nitrate nonahydrate in 50ml of deionized water, stir and dissolve to obtain solution 2. The third step is to slowly add solution 2 to solution 1, and detect and adjust the pH value of the mixed solution to keep its pH value at about 3.0. After the mixed solution is stirred 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 the precipitate is dried and added to deionized water for dissolution and filtration, light yellow crystals are cultured and collected by liquid phase diffusion single crystal culture technology. The crystal is the Anderson type heteropoly acid (NH4)3[FeMo6O 18 The relevant characterization data are shown in the attached figure, and after comparison with the standard spectrum, it is confirmed that the compound is a Fe-Anderson type heteropoly acid.

[0036] (2) 2-Fluoro-3-nitrotoluene (0.9 g, 5.8 mmol), (NH4)3[FeMo6O 18 (OH)6] (0.320 g, 0.29 mmol), 48% hydrobromic acid (0.072 g, 0.43 mmol), add 60% nitric acid (6.09 g, 58 mmol) as an oxidant, control the temperature at 140 ° C, stop heating after 14 hours of reaction, and solid precipitates after cooling;

[0037] (3) The 2-fluoro-3-nitrobenzoic acid mixture obtained above was transferred to a separatory funnel, and 25 ml of water and 30 ml of ethyl acetate were added for extraction and separation to 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, 6 g of saturated sodium bicarbonate aqueous solution and 30 g of water were added, the pH of the solution was adjusted to 7-9, the aqueous phase was separated, 0.629 g of hydrochloric acid was added thereto, the pH of the solution was adjusted to 7-9, the precipitated 2-chloro-3-nitrobenzoic acid solid was cooled for crystallization, filtered, recrystallized, and dried to obtain the 2-fluoro-3-nitrobenzoic acid product. Finally, 1.042 g 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 that of Example 1, except that:

[0041] Control the reaction temperature at 150°C;

[0042] 50% nitric acid (7.3 g, 58 mmol) as oxidant;

[0043] According to the above conditions, 0.981 g of 2-fluoro-3-nitrobenzoic acid was obtained with a chromatographic purity of 97.1% and a total yield of 88.7%.

[0044] Example 3

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

[0046] Control the reaction temperature at 130℃.

[0047] 70% nitric acid (5.22 g, 58 mmol) as oxidant;

[0048] According to the above conditions, 0.993 g of 2-fluoro-3-nitrobenzoic acid was obtained with a chromatographic purity of 96.4% and a total yield of 89.2%.

[0049] Example 4

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

[0051] Control the reaction temperature at 150°C;

[0052] 50% nitric acid (7.3 g, 58 mmol) as oxidant;

[0053] According to the above conditions, 1.000 g of 2-fluoro-3-nitrobenzoic acid was obtained with a chromatographic purity of 97.9% and a total yield of 91.2%.

[0054] Example 5

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

[0056] Control the reaction temperature at 130℃.

[0057] 70% nitric acid (5.22 g, 58 mmol) as oxidant;

[0058] According to the above conditions, 1.012 g of 2-fluoro-3-nitrobenzoic acid was obtained with a chromatographic purity of 94.5% and a total yield of 89.1%.

[0059] Example 6

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

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

[0062] According to the above conditions, 0.982 g of 2-fluoro-3-nitrobenzoic acid was obtained with a chromatographic purity of 95.4% and a total yield of 87.3%.

[0063] Comparative Example 1

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

[0065] Control the reaction temperature at 110°C;

[0066] 70% nitric acid (5.2 g, 58 mmol) as oxidant;

[0067] According to the operation conditions, the conversion rate of 2-fluoro-3-nitrotoluene is too low, the residual amount of raw materials is about 96%, and the conversion rate is too low.

[0068] Comparative Example 2

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

[0070] Control the temperature to react between 110℃;

[0071] 90% nitric acid (4.1 g, 58 mmol) as oxidant;

[0072] According to the operation conditions, the conversion rate of 2-fluoro-3-nitrotoluene is too low, the residual amount of raw materials is about 94%, and the conversion rate is too low.

[0073] Comparative Example 3

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

[0075] Control the reaction temperature between 170℃;

[0076] 50% nitric acid (7.3 g, 58 mmol) as oxidant;

[0077] According to the above conditions, 0.961 g of 2-fluoro-3-nitrobenzoic acid was obtained with a chromatographic purity of 75.2% and a total yield of 67.3%.

[0078] Comparative Example 4

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

[0080] Control the reaction temperature at 170°C;

[0081] 30% nitric acid (12.1 g, 58 mmol) as oxidant;

[0082] According to the above conditions, 1.021 g of 2-fluoro-3-nitrobenzoic acid was obtained with a chromatographic purity of 67.4% and a total yield of 64.1%.

[0083] Compared with the prior art, the raw materials of the present invention are cheap and easy to obtain, the reaction process is easy to control, the product purity can reach more than 99%, and the product yield can reach more than 95%; the oxidant used in the present invention is dilute nitric acid, which is cheaper than traditional oxidants such as potassium permanganate and chromium trioxide, and no metal inorganic salts are produced, which is easy to handle. The reaction is more controllable to avoid the generation of organic wastewater, reduce the difficulty of wastewater treatment, and the product obtained by the reaction is easy to separate.

[0084] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. A method for synthesizing 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene, characterized in that Follow the steps below: (1) dissolving ammonium molybdate in water, stirring the solution continuously and maintaining the solution at 100° C., then weighing ferric nitrate (ferric nitrate may also be replaced by copper sulfate) and slowly adding it to the ammonium molybdate solution, detecting and adjusting the pH value of the mixed solution to be acidic, and in this state, continuing to stir the reaction for 3 to 4 hours before stopping the reaction, leaving the solution to stand for 30 minutes and then vacuum filtering to obtain a solid precipitate, and purifying the solid crystals to obtain a polyoxometalate main catalyst; (2) adding 2-F-3-nitrotoluene, an oxidant and a catalyst into a pressure-resistant reaction bottle, reacting at 120 to 160° C., and obtaining a 2-F-3-nitrobenzoic acid solution after a period of reaction; (3) transferring the 2-F-3-nitrobenzoic acid solution obtained above to a separatory funnel, adding water and ethyl acetate for extraction and separation to obtain an ethyl acetate solution of 2-F-3-nitrobenzoic acid; (4) The ethyl acetate solution of 2-F-3-nitrobenzoic acid obtained above is transferred to a reaction flask, a slightly excess of alkaline solution and an appropriate amount of aqueous solution are added, stirred for 0.5 h, the pH of the solution is adjusted to 7-9, and the aqueous phase is separated. An appropriate amount of acidic solution is added to the reaction flask, stirred for 0.5 h, the pH of the solution is adjusted to 5-7, ethyl acetate is added for extraction and separation, the organic phase is separated, and the organic phase is concentrated under reduced pressure to obtain a 2-F-3-nitrobenzoic acid solid; then, the 2-F-3-nitrobenzoic acid product is obtained by cooling, crystallizing, filtering, recrystallizing, and drying.

2. The method for producing 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene according to claim 1, characterized in that In step (1), ammonium molybdate tetrahydrate is dissolved in water at 90-110° C., then iron nitrate nonahydrate (iron nitrate may also be replaced by copper sulfate) is weighed and slowly added to the ammonium molybdate solution, the pH value of the mixed solution is detected and adjusted to be acidic, and the reaction is continued for 3-4 hours. After cooling, solid insoluble matter is precipitated, the insoluble matter is obtained by suction filtration, the solution is removed, and the solution is recycled to obtain a polyoxometalate solid catalyst; In step (1), the molar ratio of the ammonium molybdate tetrahydrate to the ferric nitrate nonahydrate is 1:(1-2), and the pH value is maintained at about 2.5-3.

5.

3. The method for producing 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene according to claim 1, characterized in that In step (2), the reaction is carried out at 130-150° C. for 12-16 hours, and solid insoluble matter is precipitated after cooling. The insoluble matter is obtained by suction filtration, and the solution is removed and recycled to obtain 2-F-3-nitrobenzoic acid solid; In step (2), the oxide is nitric acid with a concentration of 40-60%, and the molar ratio of the 2-F-3-nitrotoluene to the oxide is 1:(8-12).

4. The method for producing 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene according to claim 1, characterized in that In step (3), the main catalyst is the polyoxometalate obtained in step (1), the auxiliary catalyst is an aqueous solution of hydrogen bromide, the concentration of which is 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), after the 2-F-3-nitrobenzoic acid mixture is added to the extraction separation kettle, water is added to dilute the residual reaction liquid in the mixture, and ethyl acetate is selected as the extractant, and the volume ratio of the aqueous solution to ethyl acetate is about 4:

1.

5. The method for producing 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene according to claim 1, characterized in that After the ethyl acetate solution in step (4) is added with an alkaline solution, 2-F-3-nitrobenzoic acid is converted into sodium 2-F-3-nitrobenzoate, and its solubility changes. The 2-F-3-nitrobenzoic acid is precipitated from ethyl acetate, filtered, and dissolved in water. The alkaline solution is an aqueous sodium bicarbonate solution, 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.

6. The method for producing 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene according to claim 1, characterized in that The acidic solution in step (4) is an aqueous solution of hydrochloric acid (10-38%). After addition, sodium 2-F-3-nitrobenzoate is converted into 2-F-3-nitrobenzoic acid and its solubility changes, and it precipitates 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.

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

8. The method for producing 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene according to claim 3, characterized in that In step (2), the reaction temperature is 140° C. and the reaction time is 14 h; 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 an Fe-Anderson type heteropolyacid catalyst and the molar ratio of 2-F-3-nitrotoluene to the main catalyst is 20:1; the co-catalyst is a 48% aqueous hydrogen bromide solution and the molar ratio of 2-F-3-nitrotoluene to the co-catalyst is 13 / 1.

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

1.

10. The method for producing 2-F-3-nitrobenzoic acid from 2-F-3-nitrotoluene according to claim 1, characterized in that In step (4), the alkaline solution is a 30% sodium hydroxide aqueous solution, and the concentration of the hydrochloric acid aqueous solution is 19%.

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