A method for synthesizing 2-Cl-3-nitrobenzoic acid by nitric acid oxidation

Abstract

This invention discloses a method for synthesizing 2-Cl-3-nitrobenzoic acid by nitric acid oxidation, belonging to the field of chemical synthesis technology. 2-Cl-3-nitrotoluene, an oxidant, and a catalyst are added to a pressure-resistant reaction flask and reacted at 120–140°C to obtain a 2-Cl-3-nitrobenzoic acid solution. Water and ethyl acetate are added to the obtained 2-Cl-3-nitrobenzoic acid mixed solution for extraction and separation, separating the organic phase. An alkaline solution is added to the organic phase to convert 2-Cl-3-nitrobenzoic acid to sodium 2-Cl-3-nitrobenzoate, separating the aqueous phase. An acidic solution is added to the aqueous phase to convert sodium 2-Cl-3-nitrobenzoate to 2-Cl-3-nitrobenzoic acid, followed by extraction and separation with ethyl acetate to separate the organic phase. The organic phase is concentrated under reduced pressure to obtain solid 2-Cl-3-nitrobenzoic acid. This invention uses inexpensive and readily available raw materials, the reaction process is easy to control, the product has high purity and yield, generates little wastewater, and is easy to treat, thus possessing high economic and environmental benefits.

Description

Technical Field

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

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

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

[0004] ①CN101497612A uses 2-chloro-3-nitrotoluene as a raw material. The target product, 2-chloro-3-nitrobenzoic acid, is obtained by oxidation with potassium permanganate or chromium trioxide. 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] ②CN102329237A reports a method for obtaining 15% 2-chloro-3-nitrobenzoic acid and 85% 2-chloro-5-nitrobenzoic acid by nitration in the presence of a mixture of sulfuric acid and nitric acid, using o-chlorobenzoic acid as a raw material. This method is mostly used for the preparation of 2-chloro-5-nitrobenzoic acid, but the yield of 2-chloro-3-nitrobenzoic acid is only 15%, making it unsuitable for industrial production of 2-chloro-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-Cl-3-nitrobenzoic acid from 2-Cl-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-Cl-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-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene, which is carried out according to the following steps:

[0010] (1) 2-Cl-3-nitrotoluene, oxidant and catalyst are added to a pressure-resistant reactor and reacted at 120-140℃. After a period of time, a 2-Cl-3-nitrobenzoic acid solution is obtained.

[0011] (2) The 2-Cl-3-nitrobenzoic acid solution obtained above was transferred to a separatory funnel, and water and ethyl acetate were added for extraction and separation to obtain 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, a slightly excess alkaline solution and an appropriate amount of aqueous solution were added, and the mixture was 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, and the mixture was stirred for 0.5 h. The pH of the solution was adjusted to 5-7, and then ethyl acetate was added to extract the aqueous phase. The organic phase was separated, and the organic phase was concentrated under reduced pressure to obtain solid 2-Cl-3-nitrobenzoic acid. Then, the product 2-Cl-3-nitrobenzoic acid 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. After cooling, solid insoluble matter is precipitated. Water is added and ethyl acetate is used for extraction and separation to obtain an ethyl acetate solution of 2-Cl-3-nitrobenzoic acid. The aqueous phase is removed and recycled. The organic layer is concentrated under reduced pressure to obtain solid 2-3-nitrobenzoic acid.

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

[0015] Specifically, the main catalyst mentioned in step (1) is Cu. 2+ The compound has an auxiliary catalyst that 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 (8-12):1, and the molar ratio of 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 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 3:1.

[0017] Specifically, in step (3), after adding an alkaline solution to the ethyl acetate solution, 2-Cl-3-nitrobenzoic acid is converted into sodium 2-Cl-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-Cl-3-nitrobenzoic acid to sodium bicarbonate is 1:(1~1.1). The pH of the solution is adjusted to 7~9.

[0018] Specifically, the acidic solution mentioned in step (3) is an aqueous solution of hydrochloric acid (10-38%). After its addition, sodium 2-Cl-3-nitrobenzoate is converted into 2-Cl-3-nitrobenzoic acid and its solubility changes, causing it to precipitate 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 nitric acid concentration 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 a 48% aqueous solution of hydrogen bromide, and the molar ratio of 2-Cl-3-nitrotoluene to auxiliary catalyst is 13 / 1. The reaction temperature is 130℃, and the reaction time is 10h.

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

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

[0022] Compared with existing synthesis processes, the advantages of this invention are:

[0023] (1) The oxidant used in the process of this invention is 50% nitric acid, which is diluted with only a small amount of water during the treatment process. After the reaction is completed, the product is extracted and separated, and both the catalyst and the auxiliary catalyst remain in the mother liquor. The concentration of nitric acid can be increased by adding 98% nitric acid as needed, and it can be recycled, 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.

[0024] (2) Compared with existing technologies such as o-methylphenol as raw material, the present invention uses 2-Cl-3-nitrotoluene as raw material and obtains 2-Cl-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.

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

[0026] 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%. Detailed Implementation

[0027] 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.

[0028] Example 1

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

[0030] (2) Transfer the 2-chloro-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.

[0031] (3) The ethyl acetate solution of 2-chloro-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 solid 2-chloro-3-nitrobenzoic acid was cooled and crystallized, filtered, recrystallized, and dried to obtain the 2-Cl-3-nitrobenzoic acid product. Finally, 1.121g 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 in Example 1, except that:

[0034] The reaction temperature was controlled at 120℃.

[0035] 40% nitric acid (9.1g, 58mmol) was used as the oxidizing agent;

[0036] Under these conditions, 1.034 g of 2-chloro-3-nitrobenzoic acid was obtained with a chromatographic purity of 96.3% and an overall yield of 85.2%.

[0037] Example 3

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

[0039] The reaction temperature was controlled at 120℃.

[0040] 60% nitric acid (6.1g, 58mmol) was used as the oxidizing agent;

[0041] Under these conditions, 1.048 g of 2-chloro-3-nitrobenzoic acid was obtained with a chromatographic purity of 97.8% and an overall yield of 87.7%.

[0042] Example 4

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

[0044] The reaction was controlled at 140℃.

[0045] 40% nitric acid (9.1g, 58mmol) was used as the oxidizing agent;

[0046] Under these conditions, 1.103 g of 2-chloro-3-nitrobenzoic acid was obtained with a chromatographic purity of 95.1% and an overall yield of 89.7%.

[0047] Example 5

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

[0049] The reaction was controlled at 140℃.

[0050] 60% nitric acid (6.1g, 58mmol) was used as the oxidizing agent;

[0051] Under these conditions, 1.094 g of 2-chloro-3-nitrobenzoic acid was obtained with a chromatographic purity of 94.6% and an overall yield of 88.5%.

[0052] Comparative Example 1

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

[0054] The reaction temperature was controlled at 100℃.

[0055] 60% nitric acid (6.1g, 58mmol) was used as the oxidizing agent;

[0056] Operating under these conditions, the conversion rate of 2-chloro-3-nitrotoluene is too low, with a raw material residue of approximately 95%, indicating an excessively low conversion rate.

[0057] Comparative Example 2

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

[0059] The reaction is controlled at a temperature between 100°C;

[0060] 80% nitric acid (4.6g, 58mmol) was used as the oxidizing agent;

[0061] Operating under these conditions yielded 2-chloro-3-nitrobenzoic acid, but the residual amount of the raw material was greater than 92%, resulting in an excessively low conversion rate.

[0062] Comparative Example 3

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

[0064] The reaction temperature was controlled at 160℃.

[0065] 40% nitric acid (9.1g, 58mmol) was used as the oxidizing agent;

[0066] Under these conditions, 1.041 g of 2-chloro-3-nitrobenzoic acid was obtained with a chromatographic purity of 74.6% and an overall yield of 66.4%.

[0067] Comparative Example 4

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

[0069] The reaction temperature is controlled to be between 160℃;

[0070] 20% nitric acid (18.3g, 58mmol) was used as the oxidizing agent;

[0071] Under these conditions, 1.081 g of 2-chloro-3-nitrobenzoic acid was obtained with a chromatographic purity of 61.1% and an overall yield of 56.5%.

[0072] 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.

[0073] 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-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene, characterized in that The following steps are taken: (1) 2-Cl-3-nitrotoluene, oxidant, main catalyst and auxiliary catalyst are added to a pressure-resistant reactor, and the reaction is carried out at 120-140°C for a period of time, after which a 2-Cl-3-nitrobenzoic acid solution is obtained; (2) The 2-Cl-3-nitrobenzoic acid solution obtained above is transferred to a separatory funnel, water and ethyl acetate are added for extraction and separation, and a 2-Cl-3-nitrobenzoic acid ethyl acetate solution is obtained; (3) The 2-Cl-3-nitrobenzoic acid ethyl acetate solution obtained above is transferred to a reaction bottle, a slight excess of a basic solution and an appropriate amount of an aqueous solution are added, stirring is carried out for 0.5 h, the solution pH is adjusted to 7-9, the aqueous phase is separated out, an appropriate amount of an acidic solution is added to the reaction bottle, stirring is carried out for 0.5 h, the solution pH is adjusted to 5-7, then ethyl acetate is added to extract the aqueous phase, the organic phase is separated out, the organic phase is concentrated under reduced pressure, and 2-Cl-3-nitrobenzoic acid solid is obtained; then cooling crystallization, filtration, recrystallization and drying are carried out to obtain 2-Cl-3-nitrobenzoic acid product; The main catalyst in step (1) is Cu 2+ The compound, the auxiliary catalyst is hydrogen bromide aqueous solution, the concentration is 40~70%, the molar ratio of the use amount of 2-Cl-3-nitrotoluene and the main catalyst is (8~12):1, the molar ratio of the use amount of 2-Cl-3-nitrotoluene and the auxiliary catalyst is (10~40):

1.

2. A process for the synthesis of 2-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene as claimed in claim 1, wherein In step (1), the reaction is carried out at 120-140°C for 8-12 h, after cooling, insoluble solids are precipitated, water is added and ethyl acetate is used for extraction and separation, thereby obtaining a 2-Cl-3-nitrobenzoic acid ethyl acetate solution, the aqueous phase is removed, and the aqueous phase is recycled, the organic layer is concentrated under reduced pressure to obtain 2-Cl-3-nitrobenzoic acid solid; In step (1), the oxidant is nitric acid, the concentration is 40-60%, and the molar ratio of 2-Cl-3-nitrotoluene to the oxidant is 1:(8-12).

3. A process for the synthesis of 2-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene as claimed in claim 1, wherein In step (2), after the 2-Cl-3-nitrobenzoic acid mixture is added to the extraction and separation kettle, water is added to dilute the residual reaction solution in the mixture, the extractant is ethyl acetate, and the volume ratio of the aqueous solution to ethyl acetate is 3:

1.

4. A process for the synthesis of 2-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene as claimed in claim 1, wherein In step (3), after the ethyl acetate solution is added to the basic solution, the 2-Cl-3-nitrobenzoic acid is converted into 2-Cl-3-nitrobenzoic acid sodium, the solubility changes, and it is precipitated from ethyl acetate, is filtered, is dissolved in water, the basic solution is a sodium bicarbonate aqueous solution, the molar ratio of 2-Cl-3-nitrobenzoic acid to sodium bicarbonate is 1:(1-1.1), and the solution pH is adjusted to 7-9.

5. A process for the synthesis of 2-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene as claimed in claim 1, wherein In step (3), the acidic solution is a 10-38% mass concentration hydrochloric acid aqueous solution, after being added, the 2-Cl-3-nitrobenzoic acid sodium is converted into 2-Cl-3-nitrobenzoic acid and the solubility changes, it is precipitated from the aqueous solution, the molar ratio of 2-Cl-3-nitrobenzoic acid sodium to hydrogen chloride is 1-1.1, and the solution pH is adjusted to 5-7.

6. A process for the synthesis of 2-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene as claimed in claim 1, wherein The main catalyst is copper sulfate pentahydrate, the molar ratio of 2-Cl-3-nitrotoluene to copper sulfate pentahydrate is 10:1, the auxiliary catalyst is 48% hydrogen bromide aqueous solution, the molar ratio of 2-Cl-3-nitrotoluene to the auxiliary catalyst is 13:1, the reaction temperature is 130°C, and the reaction time is 10 h.

7. The method for synthesizing 2-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene according to claim 2, 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. The method for synthesizing 2-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene according to claim 3, characterized in that... The volume ratio of the 2-Cl-3-nitrobenzoic acid mixture to water in step (2) is 2:

1.

9. The method for synthesizing 2-Cl-3-nitrobenzoic acid from 2-Cl-3-nitrotoluene according to claim 5, characterized in that... The basic solution in step (3) is a 30% sodium hydroxide aqueous solution, and the concentration of the hydrochloric acid aqueous solution is 19%.

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