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

Abstract

The invention discloses a method for synthesizing 2-Cl-3-nitrobenzoic acid through nitric acid oxidation, and relates to the technical field of chemical synthesis. The method comprises the following steps: adding 2-Cl-3-nitrotoluene, an oxidant and a catalyst into a pressure-resistant reaction bottle, and reacting at 120-140 DEG C to obtain a 2-Cl-3-nitrobenzoic acid solution; adding water and ethyl acetate into the obtained 2-Cl-3-nitrobenzoic acid mixed solution for extraction and separation, separating out an organic phase, adding an alkaline solution into the organic phase, converting 2-Cl-3-nitrobenzoic acid into 2-Cl-3-sodium nitrobenzoate, and separating out a water phase, adding an acidic solution into the water phase to convert the 2-Cl-3-nitrobenzoic acid into 2-Cl-3-nitrobenzoic acid, adding ethyl acetate to extract and separate out an organic phase, and concentrating the organic phase under reduced pressure to obtain a 2-Cl-3-nitrobenzoic acid solid. The raw materials are cheap and easy to obtain, the reaction process is easy to control, the product purity and yield are high, the amount of generated waste water is small, the waste water is easy to treat, and high economic and environment-friendly benefits are achieved.

Description

Technical Field

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

[0002] 2-Chloro-3-nitrobenzoic acid is a white to pale yellow solid that is slightly soluble in water and soluble in ethyl acetate. It is commonly used in the synthesis of various drugs and pharmaceutical products, including but not limited to the preparation of certain antibacterial and anticancer drugs.

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

[0004] ① CN101497612A uses 2-chloro-3-nitrotoluene as raw material. It is oxidized with potassium permanganate or chromium trioxide to obtain the target product 2-chloro-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] ②CN102329237A reports a method of using o-chlorobenzoic acid as a raw material, and carrying out a nitration reaction in the presence of a mixed acid of sulfuric acid and nitric acid to obtain 15% 2-chloro-3-nitrobenzoic acid and 85% 2-chloro-5-nitrobenzoic acid. This method is mostly used for the preparation of 2-chloro-5-nitrobenzoic acid, and the yield of 2-chloro-3-nitrobenzoic acid is only 15%, which is not suitable for the industrial production of 2-chloro-3-nitrobenzoic acid.

[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-Cl-3-nitrobenzoic acid from 2-Cl-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 existing 2-Cl-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-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene, which is carried out according to the following steps:

[0010] (1) adding 2-Cl-3-nitrotoluene, an oxidant and a catalyst into a pressure-resistant reactor, reacting at 120 to 140° C., and obtaining a 2-Cl-3-nitrobenzoic acid solution after a period of reaction;

[0011] (2) transferring the 2-Cl-3-nitrobenzoic acid solution obtained above into a separatory funnel, adding water and ethyl acetate for extraction and separation, and obtaining an ethyl acetate solution of 2-Cl-3-nitrobenzoic acid;

[0012] (3) The ethyl acetate solution of 2-Cl-3-nitrobenzoic acid obtained above was transferred to a reaction flask, and a slightly excess of alkaline solution and an appropriate amount of aqueous solution were added, stirred for 0.5 h, and 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, and the pH of the solution was adjusted to 5-7, and then ethyl acetate was added to extract the aqueous phase, and the organic phase was separated and concentrated under reduced pressure to obtain 2-Cl-3-nitrobenzoic acid solid. Then, the 2-Cl-3-nitrobenzoic acid product was obtained by cooling, crystallization, filtration, recrystallization, and drying.

[0013] Specifically, in step (1), the reaction is carried out at 120-140° C. for 8-12 hours, and solid insoluble matter is precipitated after cooling. Water is added and extracted and separated using ethyl acetate to obtain an ethyl acetate solution of 2-Cl-3-nitrobenzoic acid. The aqueous phase is removed, the aqueous phase is recycled, and the organic layer is concentrated under reduced pressure to obtain 2--3-nitrobenzoic acid solid.

[0014] Specifically, the oxide in step (1) is nitric acid with a concentration of 40-60%, and the molar ratio of the 2-Cl-3-nitrotoluene to the oxide is 1:(8-12).

[0015] Specifically, the main catalyst in step (1) is Cu 2+ The auxiliary catalyst is a hydrogen bromide aqueous solution with a concentration of 40-70%, the molar ratio of the 2-chloro-3-nitrotoluene to the main catalyst is (8-12):1, and the molar ratio of the 2-chloro-3-nitrotoluene to the auxiliary catalyst is (10-40):1.

[0016] Specifically, in step (2), after the 2-Cl-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 3:1.

[0017] Specifically, after the ethyl acetate solution in step (3) is added with an alkaline solution, 2-Cl-3-nitrobenzoic acid is converted into sodium 2-Cl-3-nitrobenzoate, and its solubility changes, and the 2-Cl-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-Cl-3-nitrobenzoic acid to sodium bicarbonate is 1:(1-1.1), and the pH of the solution is adjusted to 7-9.

[0018] Specifically, the acidic solution in step (3) is an aqueous solution of hydrochloric acid (10-38%). After addition, sodium 2-Cl-3-nitrobenzoate is converted into 2-Cl-3-nitrobenzoic acid and its solubility changes, and it precipitates from the aqueous solution. The molar ratio of sodium 2-Cl-3-nitrobenzoate to hydrogen chloride is (1-1.1), and the pH of the solution is adjusted to 5-7.

[0019] Preferably, in step (1), the concentration of nitric acid is 50%, and the molar ratio of 2-Cl-3-nitrotoluene to nitric acid is 1:10. The main catalyst is copper sulfate pentahydrate, and the molar ratio of 2-Cl-3-nitrotoluene to copper sulfate pentahydrate is 10:1. The auxiliary catalyst is 48% aqueous hydrogen bromide solution, and the molar ratio of 2-Cl-3-nitrotoluene to auxiliary catalyst is 13 / 1. The reaction temperature is 130°C, and the reaction time is 10 hours.

[0020] Preferably, in step (2), the volume ratio of 2-Cl-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.

[0021] Preferably, the alkaline solution in step (3) is a 30% sodium hydroxide aqueous solution, and the concentration of the hydrochloric acid aqueous solution is 19%.

[0022] Compared with the existing synthesis process, the beneficial effects of the present invention are:

[0023] (1) The oxidant used in the process of the present invention is 50% nitric acid, and 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, and 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; and 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;

[0024] (2) Compared with the prior art using o-methylphenol as raw material, the present invention uses 2-Cl-3-nitrotoluene as raw material and obtains 2-Cl-3-nitrobenzoic acid by reacting with an oxide in one step. The process flow is shorter, the product yield is high, the amount of process wastewater generated is small, and it is easy to treat, which is more economical and environmentally friendly.

[0025] (3) Adding an excess of sodium hydroxide solution to an ethyl acetate solution of 2-Cl-3-nitrobenzoic acid converts 2-Cl-3-nitrobenzoic acid into sodium 2-Cl-3-nitrobenzoate, which is precipitated from ethyl acetate and then added to dilute hydrochloric acid to convert it into 2-Cl-3-nitrobenzoic acid, which can greatly improve the purity and yield of the product.

[0026] 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%. DETAILED DESCRIPTION

[0027] 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.

[0028] Example 1

[0029] To a 25 mL pressure tube, 2-chloro-3-nitrotoluene (1 g, 5.8 mmol), copper sulfate pentahydrate (0.146 g, 0.58 mmol), 48% hydrobromic acid (0.072 g, 0.43 mmol) were added in sequence, and 50% nitric acid (7.3 g, 58 mmol) was added as an oxidant. The temperature was controlled at 130 °C for reaction. After 10 h of reaction, heating was stopped, and solid was precipitated after cooling.

[0030] (2) The 2-chloro-3-nitrobenzoic acid mixed solution 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;

[0031] (3) The ethyl acetate solution of 2-chloro-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 and crystallized, filtered, recrystallized, and dried to obtain the 2-Cl-3-nitrobenzoic acid product. Finally, 1.121 g of 2-chloro-3-nitrobenzoic acid was obtained, with a chromatographic purity of 99.7% and a total yield of 95.6%.

[0032] Example 2

[0033] The method is the same as that of Example 1, except that:

[0034] Control the reaction temperature at 120°C;

[0035] 40% nitric acid (9.1 g, 58 mmol) as oxidant;

[0036] According to the above conditions, 1.034 g of 2-chloro-3-nitrobenzoic acid was obtained with a chromatographic purity of 96.3% and a total yield of 85.2%.

[0037] Example 3

[0038] The method is the same as that of Example 1, except that:

[0039] Control the reaction temperature at 120°C;

[0040] 60% nitric acid (6.1 g, 58 mmol) as oxidant;

[0041] According to the above conditions, 1.048 g of 2-chloro-3-nitrobenzoic acid was obtained with a chromatographic purity of 97.8% and a total yield of 87.7%.

[0042] Example 4

[0043] The method is the same as that of Example 1, except that:

[0044] Control the reaction temperature at 140℃.

[0045] 40% nitric acid (9.1 g, 58 mmol) as oxidant;

[0046] According to the above conditions, 1.103 g of 2-chloro-3-nitrobenzoic acid was obtained with a chromatographic purity of 95.1% and a total yield of 89.7%.

[0047] Example 5

[0048] The method is the same as that of Example 1, except that:

[0049] Control the reaction temperature at 140℃.

[0050] 60% nitric acid (6.1 g, 58 mmol) as oxidant;

[0051] According to the above conditions, 1.094 g of 2-chloro-3-nitrobenzoic acid was obtained with a chromatographic purity of 94.6% and a total yield of 88.5%.

[0052] Comparative Example 1

[0053] The method is the same as that of Example 1, except that:

[0054] Control the reaction temperature at 100°C;

[0055] 60% nitric acid (6.1 g, 58 mmol) as oxidant;

[0056] According to the operation conditions, the conversion rate of 2-chloro-3-nitrotoluene is too low, the residual amount of raw materials is about 95%, and the conversion rate is too low.

[0057] Comparative Example 2

[0058] The method is the same as that of Example 1, except that:

[0059] Control the temperature to react between 100℃;

[0060] 80% nitric acid (4.6 g, 58 mmol) as oxidant;

[0061] When operated under these conditions, 2-chloro-3-nitrobenzoic acid was obtained, but the residual amount of the raw material was greater than 92%, and the conversion rate was too low.

[0062] Comparative Example 3

[0063] The method is the same as that of Example 1, except that:

[0064] Control the reaction temperature at 160°C;

[0065] 40% nitric acid (9.1 g, 58 mmol) as oxidant;

[0066] According to the above conditions, 1.041 g of 2-chloro-3-nitrobenzoic acid was obtained with a chromatographic purity of 74.6% and a total yield of 66.4%.

[0067] Comparative Example 4

[0068] The method is the same as that of Example 1, except that:

[0069] Control the reaction temperature between 160℃;

[0070] 20% nitric acid (18.3 g, 58 mmol) as oxidant;

[0071] According to the above conditions, 1.081 g of 2-chloro-3-nitrobenzoic acid was obtained with a chromatographic purity of 61.1% and a total yield of 56.5%.

[0072] 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.

[0073] 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-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene, characterized in that Follow these steps: (1) adding 2-Cl-3-nitrotoluene, an oxidant and a catalyst into a pressure-resistant reactor, reacting at 120 to 140° C., and obtaining a 2-Cl-3-nitrobenzoic acid solution after a period of reaction; (2) transferring the 2-Cl-3-nitrobenzoic acid solution obtained above into a separatory funnel, adding water and ethyl acetate for extraction and separation, and obtaining an ethyl acetate solution of 2-Cl-3-nitrobenzoic acid; (3) The ethyl acetate solution of 2-Cl-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, and then ethyl acetate is added to extract the aqueous phase, the organic phase is separated, and the organic phase is concentrated under reduced pressure to obtain 2-Cl-3-nitrobenzoic acid solid; then the 2-Cl-3-nitrobenzoic acid product is obtained by cooling, crystallizing, filtering, recrystallizing, and drying.

2. A method for producing 2-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene according to claim 1, characterized in that In step (1), the reaction is carried out at 120-140° C. for 8-12 hours, and solid insoluble matter is precipitated after cooling. Water is added and extracted and separated using ethyl acetate to obtain an ethyl acetate solution of 2-Cl-3-nitrobenzoic acid. The aqueous phase is removed, the aqueous phase is recycled, and the organic layer is concentrated under reduced pressure to obtain a 2--3-nitrobenzoic acid solid; In step (1), the oxide is nitric acid with a concentration of 40-60%, and the molar ratio of the 2-Cl-3-nitrotoluene to the oxide is 1:(8-12).

3. A method for producing 2-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene according to claim 1, characterized in that The main catalyst in step (1) is Cu 2+ The auxiliary catalyst is a hydrogen bromide aqueous solution with a concentration of 40-70%, the molar ratio of the 2-chloro-3-nitrotoluene to the main catalyst is (8-12):1, and the molar ratio of the 2-chloro-3-nitrotoluene to the auxiliary catalyst is (10-40):

1.

4. A method for producing 2-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene according to claim 1, characterized in that In step (2), after the 2-Cl-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 3:

1.

5. A method for producing 2-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene according to claim 1, characterized in that After the ethyl acetate solution in step (3) is added with an alkaline solution, 2-Cl-3-nitrobenzoic acid is converted into sodium 2-Cl-3-nitrobenzoate, and its solubility changes. The 2-Cl-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-Cl-3-nitrobenzoic acid to sodium bicarbonate is 1:(1-1.1). The pH of the solution is adjusted to 7-9.

6. A method for producing 2-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene according to claim 1, characterized in that The acidic solution in step (3) is an aqueous solution of hydrochloric acid (10-38%). After addition, sodium 2-Cl-3-nitrobenzoate is converted into 2-Cl-3-nitrobenzoic acid and its solubility changes, and it precipitates from the aqueous solution. The molar ratio of sodium 2-Cl-3-nitrobenzoate to hydrogen chloride is (1-1.1), and the pH of the solution is adjusted to 5-7.

7. A method for producing 2-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene according to claim 3, characterized in that In step (1), the concentration of nitric acid is 50%, and the molar ratio of 2-Cl-3-nitrotoluene to nitric acid is 1:

10.

8. A method for producing 2-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene according to claim 4, characterized in that The main catalyst is copper sulfate pentahydrate, and the molar ratio of 2-Cl-3-nitrotoluene / copper sulfate pentahydrate is 10:1; the auxiliary catalyst is 48% hydrogen bromide aqueous solution, and the molar ratio of 2-Cl-3-nitrotoluene / auxiliary catalyst is 13 / 1; the reaction temperature is 130°C, and the reaction time is 10 hours.

9. A method for producing 2-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene according to claim 5, characterized in that In step (2), the volume ratio of 2-Cl-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-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene according to claim 1, characterized in that In step (3), 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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