A preparation method of 2-amino-4-bromo-5-chlorobenzoic acid

Abstract

The present invention belongs to the technical field of compound preparation, and particularly relates to a preparation method of 2-amino-4-bromo-5-chlorobenzoic acid, which includes S1, nitrating p-toluidine in a sulfuric acid system to generate a nitrating solution; S2, synthesizing 2-nitro-4-bromotoluene; S3, synthesizing 2-amino-4-bromotoluene; S4, synthesizing 2-acetamido-4-bromotoluene; S5, synthesizing 2-acetamido-4-bromobenzoic acid; S6, synthesizing 2-amino-4-bromobenzoic acid; S7, synthesizing 2-acetamido-4-bromo-5-chlorobenzoic acid; S8, synthesizing 2-amino-4-bromo-5-chlorobenzoic acid. The beneficial effects of the present invention are that the cost is controllable, and the key intermediates can all be sold as products; almost no laborious purification is required for each step; no solvent is used throughout the process, and the generated wastewater, except for the diazotization wastewater, has extremely high biodegradability, which is very beneficial to the biochemical treatment in the sewage treatment station.

Description

Technical Field

[0001] The present invention relates to the technical field of compound preparation, and specifically to a preparation method of 2-amino-4-bromo-5-chlorobenzoic acid. Background Art

[0002] Halogen-containing aminobenzoic acid compounds have a wide range of biological activities and are an important class of intermediates in new drug research and development. For example, 2-amino-4-bromobenzoic acid, 2-amino-4-fluorobenzoic acid, 3-nitro-4-fluorobenzoic acid, etc. The research on the synthesis methods and active molecules of such compounds has always been very active; and it has always been a very important part of the new drug industrial system. It is very important in the research of materials and new drugs and has broad prospects in the pharmaceutical, pesticide, and chemical industries.

[0003] Through our research and development process, we designed the following route:

[0004]

[0005] The raw materials of this route are extremely cheap, and there is sufficient market demand for almost every intermediate step, such as 2-amino-4-bromotoluene, 2-acetamido-4-bromobenzoic acid, and 2-amino-4-bromobenzoic acid, etc.; through this route, a sufficient industrial chain has been formed. Summary of the Invention

[0006] To solve the problems raised in the above background art, the present invention provides a preparation method of 2-amino-4-bromo-5-chlorobenzoic acid.

[0007] To achieve the above object, the present invention provides the following technical solution: A preparation method of 2-amino-4-bromo-5-chlorobenzoic acid, the production method comprising the following steps:

[0008] S1. In a sulfuric acid system, p-toluidine is nitrated to generate a nitration solution;

[0009] S2. Synthesis of 2-nitro-4-bromotoluene: After the nitration solution is directly hydrolyzed with ice, it is diazotized with sodium nitrite to prepare a diazonium solution. The diazonium solution is pyrolyzed with cuprous bromide as a catalyst and hydrobromic acid as the bottom acid, and the layers are separated to obtain the crude product of 2-nitro-4-bromotoluene;

[0010] S3. Synthesis of 2-amino-4-bromotoluene: The crude product of 2-nitro-4-bromotoluene is subjected to a reduction treatment;

[0011] S4. Synthesis of 2-acetamido-4-bromotoluene: 2-amino-4-bromotoluene is subjected to a solvent-free method with acetic anhydride as a protecting agent. After the reaction is completed, it is directly hydrolyzed with ice to obtain 2-acetamido-4-bromotoluene;

[0012] S5. Synthesis of 2-Acetamido-4-bromobenzoic Acid: 2-Acetamido-4-bromotoluene is oxidized using potassium permanganate with water as the solvent and tert-butanol as the co-solvent. After centrifugation, an aqueous solution of potassium 2-acetamido-4-bromobenzoate is obtained. The pH is adjusted to 1-2 with hydrochloric acid to obtain 2-acetamido-4-bromobenzoic acid.

[0013] S6. Synthesis of 2-Amino-4-bromobenzoic Acid: 2-Acetamido-4-bromobenzoic acid is hydrolyzed with sodium hydroxide, decolorized with activated carbon, and then acidified to obtain 2-amino-4-bromobenzoic acid.

[0014] S7. Synthesis of 2-Acetamido-4-bromo-5-chlorobenzoic Acid: 2-Acetamido-4-bromobenzoic acid is used as the solvent with DMF, and dichlorohydantoin is used as the chlorinating agent to obtain 2-acetamido-4-bromo-5-chlorobenzoic acid.

[0015] S8. Synthesis of 2-Amino-4-bromo-5-chlorobenzoic Acid: 2-Acetamido-4-bromo-5-chlorobenzoic acid is hydrolyzed with sodium hydroxide, decolorized with activated carbon, and then acidified to obtain 2-amino-4-bromo-5-chlorobenzoic acid.

[0016] Preferably, the reduction treatment in S3 is that the crude product of 2-nitro-4-bromotoluene is treated with steam to remove the contained tar, and then pd / C hydrogenation reduction is carried out.

[0017] Preferably, the reduction treatment in S3 is to carry out iron powder reduction. After reduction, 2-amino-4-bromotoluene is directly obtained by steam.

[0018] Preferably, the pyrolysis temperature in S2 is 60°C.

[0019] The beneficial effects of the present invention are as follows:

[0020] 1) Starting from the most initial raw materials, the cost is controllable. Although there are many steps, the key intermediates can all be sold as products. Especially for 2-amino-4-bromobenzoic acid, the market demand is strong, and our company has already carried out pilot production at the tonnage level.

[0021] 2) Although there are many steps in this route, almost no laborious purification is required for each step to obtain 2-amino-4-bromobenzoic acid and 2-amino-4-bromo-5-chlorobenzoic acid with a pure white color, excellent properties, a content of more than 99.5%, and a single impurity less than 0.2, meeting the use standards of pharmaceutical intermediates.

[0022] 3) The present invention completely avoids the use of a large amount of solvents in the literature, does not use solvents throughout the process, and the generated wastewater, except for diazotization wastewater, has extremely high biodegradability, which is very beneficial to the biochemical treatment of the sewage treatment station. Brief Description of the Drawings

[0023] Figure 1 Shows the HPLC chromatogram of 2-nitro-4-bromotoluene.

[0024] Figure 2 Shows the HPLC chromatogram of 2-amino-4-bromotoluene.

[0025] Figure 3 Shows the HPLC chromatogram of 2-acetamido-4-bromotoluene.

[0026] Figure 4 Shows the HPLC chromatogram of 2-acetamido-4-bromobenzoic acid.

[0027] Figure 5 Shows the HNMR spectrum of 2-acetamido-4-bromobenzoic acid.

[0028] Figure 6 Shows the HPLC chromatogram of 2-amino-4-bromobenzoic acid.

[0029] Figure 7 Shows the HNMR spectrum of 2-amino-4-bromobenzoic acid.

[0030] Figure 8 Shows the HPLC chromatogram of 2-acetamido-4-bromo-5-chlorobenzoic acid.

[0031] Figure 9 Shows the HNMR spectrum of 2-acetamido-4-bromo-5-chlorobenzoic acid.

[0032] Figure 10 Shows the HPLC chromatogram of 2-amino-4-bromo-5-chlorobenzoic acid.

[0033] Figure 11 Shows the HNMR spectrum of 2-amino-4-bromo-5-chlorobenzoic acid. Detailed implementation manners

[0034] The preferred implementation manners of the present invention will be described below with reference to the accompanying drawings. Those skilled in the art should understand that these implementation manners are only used to explain the technical principle of the present invention and are not intended to limit the protection scope of the present invention.

[0035] Example 1:

[0036] 1) Synthesis of 2-nitro-4-bromotoluene: Add 1 kg of sulfuric acid to a 1 L flask. Gradually add 200 g of p-toluidine that has been pre-crushed in batches, controlling the temperature not to exceed 60 °C. After adding, stir at 50 - 60 °C for 1 h to ensure that all p-toluidine forms a salt. After the materials are completely dissolved, cool down to 0 - 5 °C (the system will be very thick). Weigh 136 g of sulfuric acid and add 136 g of fuming nitric acid to prepare a mixed acid. Dropwise add the mixed acid. During the dropping process, heat is released violently, control the temperature not to exceed 5 °C. After dropping, stir for 1 hour. Take a sample (add the sample to a small beaker, add water and stir, adjust the pH to 8 - 9 with liquid alkali, filter by suction to obtain the solid) to measure the liquid phase. The raw materials have reacted. Quench the above reaction solution into 2 L of water, controlling the temperature not to exceed 80 °C. After quenching, stir at 80 - 85 °C to dissolve all the materials. After dissolution, slowly cool down. After the materials precipitate, the cooling rate can be accelerated. When the temperature is 0 - 5 °C, start to dropwise add 50% aqueous sodium nitrite solution, controlling the temperature at 0 - 5 °C. During the dropping process, the materials will slowly dissolve. After dropping, stir at 0 - 5 °C for 1 hour to prepare the diazonium solution for standby. In another flask, add 630 g of hydrobromic acid and 20 g of cuprous bromide, heat up to 65 °C, and dropwise add the above diazonium solution into it, controlling the temperature at 60 - 65 °C. After dropping, heat up to 70 - 75 °C and keep warm for 1 hour, then let it stand for 1 hour to separate layers. Obtain about 377 g of 2-nitro-4-bromotoluene. The representative spectrum of 2-nitro-4-bromotoluene is as shown in Figure 1 shown.

[0037] 2) Synthesis of 2-amino-4-bromotoluene: Add 2000 g of water, 380 g of iron powder, and 38 g of hydrochloric acid to a 3 L flask. Heat up to 90 °C and start to add 377 g of 2-nitro-4-bromotoluene in batches, controlling the temperature not to exceed 100 °C. After adding, stir at 100 °C (with slight reflux) for 1 hour. Take a sample for monitoring. After the raw materials have reacted, directly obtain 267 g by steam distillation. The representative spectrum of 2-amino-4-bromotoluene is as shown in Figure 2 shown.

[0038] 3) Synthesis of 2-acetamido-4-bromotoluene: Add 1000 g of 2-amino-4-bromotoluene to a 3 L flask. Dropwise add 603 g of acetic anhydride under stirring, controlling the temperature not to exceed 80 °C. During the dropping process, a large amount of solid precipitates. After heating up to 80 °C, the system becomes clear. After dropping, stir for 1 h, pour it into 1000 g of water, filter by suction, and dry to obtain 1090 g of 2-acetamido-4-bromotoluene. The representative spectrum of 2-acetamido-4-bromotoluene is as shown in Figure 3 shown.

[0039] 4) Synthesis of 2-Acetamido-4-bromobenzoic Acid: Add 3500 g of water, 500 g of tert-butanol, and 400 g of 2-acetamido-4-bromotoluene into a 5 L flask and heat up. When the temperature reaches 85 °C, add 1104 g of potassium permanganate in batches. Start with a smaller amount at first as there will be gas bubbles generated and a relatively large reflux. After the bubbles disappear, continue to add. Divide it into 20 equal portions and add one portion every half hour. It takes about 10 hours to add them all. Control the temperature between 80 - 85 °C throughout the process. After adding, check the filter paper every hour. When the color fades, take a sample for testing. After the raw materials have reacted completely, cool down to 30 °C, centrifuge, and wash with an appropriate amount of water. Adjust the pH to 1 - 2 with hydrochloric acid, centrifuge, and wash with an appropriate amount of water. The obtained product is dried to obtain 340 - 360 g. The representative spectrum of 2-acetamido-4-bromobenzoic acid is as shown in Figure 4 as shown, and the HNMR is as shown in Figure 5 as shown.

[0040] 5) Synthesis of 2-Amino-4-bromobenzoic Acid: Add 472 g of liquid alkali, 1500 g of water, and 340 g of 2-acetamido-4-bromobenzoic acid into a 3 L flask, heat up to 95 - 100 °C, and keep it at this temperature for three hours. Then start sampling for testing. After the raw materials have reacted completely, cool down to 80 °C, add 5% activated carbon based on the amount of raw materials, stir at 80 °C for 1 hour, and then filter by suction. After suction filtration, add 1500 ml of water again. First, adjust the pH to about 9 with hydrochloric acid and stir for 30 minutes to ensure that the solids inside can dissolve. Then adjust the pH to about 6 with acetic acid. At this time, a large amount of solids will precipitate. Cool down to 20 °C and centrifuge, wash with an appropriate amount of water, and dry to obtain about 260 - 280 g of 2-amino-4-bromobenzoic acid. The representative spectrum of 2-amino-4-bromobenzoic acid is as shown in Figure 6 as shown, and the HNMR is as shown in Figure 7 as shown.

[0041] 6) Synthesis of 2-Acetamido-4-bromo-5-chlorobenzoic Acid: Add 600 g of DMF and 200 g of 2-acetamido-4-bromobenzoic acid into a 2 L flask and stir to dissolve. Heat up to 35 °C to obtain a 2-acetamido-4-bromobenzoic acid solution. In another flask, add 200 g of DMF and 100 g of dichlorohydantoin and stir to dissolve to obtain a dichlorohydantoin solution. Drop the dichlorohydantoin solution into the 2-acetamido-4-bromobenzoic acid solution, control the temperature at 35 - 40 °C. After dropping, react at 40 °C for 3 h, then heat up to 80 °C and react for 3 h. Take a sample to measure the liquid phase. When the raw materials are ≤ 0.5%, the reaction ends. Without cooling, drop the reaction solution into 2400 g of water, cool down to below 20 °C, filter by suction, wash with an appropriate amount of water, and the purity is about 94%. Add an equal amount of methanol to the crude product and reflux and slurry for 1 h. Cool down to below 10 °C, filter by suction, and obtain a refined product with a purity of over 99%. Air-dry to obtain about 200 g of 2-acetamido-4-bromo-5-chlorobenzoic acid. The representative spectrum of 2-acetamido-4-bromo-5-chlorobenzoic acid is as shown in Figure 8 as shown, and the HNMR is as shown in Figure 9 as shown.

[0042] 7) Synthesis of 2-amino-4-bromo-5-chlorobenzoic acid: Add 1000 g of water, 275 g of liquid alkali, and 200 g of 2-acetamido-4-bromo-5-chlorobenzoic acid into a 2 L reaction flask. Stir and heat up. At first, it may be difficult to stir, but it will gradually dissolve clearly as the temperature rises. Heat up to 95 - 100 °C and keep warm for 2 h. Take a sample and spot plate to check if the raw materials have reacted completely, then cool down. When the temperature reaches 50 °C, start to adjust the pH to 5 - 6 with acetic acid, control the temperature between 50 - 60 °C. After adjustment, stir naturally for 1 h, then cool down to below 20 °C, filter by suction, wash with an appropriate amount of water and dry to obtain 120 - 130 g of 2-amino-4-bromo-5-chlorobenzoic acid. The representative spectrum of 2-amino-4-bromo-5-chlorobenzoic acid is as shown in Figure 10 shown, and the HNMR is as shown in Figure 11 shown.

[0043] Example 2

[0044] The difference between Example 2 and Example 1 lies in the different reduction methods in Step 5:

[0045] 5) Take 377 g of the crude product of 2-nitro-4-bromotoluene, add 2000 g of water, and obtain 320 g of the crude product by water vapor. Add 320 g of 2-nitro-4-bromotoluene, 640 g of methanol, and 3.2 g of 5% palladium-carbon. Replace with nitrogen 3 times, then fill with hydrogen, with a pressure of 2 atm. The temperature rises, and the maximum reaches 75 °C. When the hydrogen absorption stops, monitor that the reaction is complete, filter by suction to remove the palladium-carbon, and concentrate and dry to obtain 240 g of the product.

[0046] The above-described embodiments only represent several implementation manners of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the patent of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the appended claims.

Claims

1. A preparation method of 2-amino-4-bromo-5-chlorobenzoic acid, characterized in that: It includes the following steps: S1. Nitrate p-toluidine in a sulfuric acid system to generate a nitrating solution; S2. Synthesis of 2-nitro-4-bromotoluene: After directly ice-hydrolyzing the nitrating solution, diazotize it with sodium nitrite to prepare a diazonium solution. Use cuprous bromide as a catalyst and hydrobromic acid as the bottom acid for pyrolysis, and layer to obtain the crude product of 2-nitro-4-bromotoluene; S3. Synthesis of 2-amino-4-bromotoluene: Carry out reduction treatment on the crude product of 2-nitro-4-bromotoluene; S4. Synthesis of 2-acetamido-4-bromotoluene: For 2-amino-4-bromotoluene, adopt the solvent-free method, use acetic anhydride as a protecting agent, and directly ice-hydrolyze after the reaction to obtain 2-acetamido-4-bromotoluene; S5. Synthesis of 2-acetamido-4-bromobenzoic acid: Oxidize 2-acetamido-4-bromotoluene with potassium permanganate, use water as a solvent and tert-butanol as a co-solvent, centrifuge to obtain an aqueous solution of potassium 2-acetamido-4-bromobenzoate, and adjust the pH to 1-2 with hydrochloric acid to obtain 2-acetamido-4-bromobenzoic acid; S6. Synthesis of 2-amino-4-bromobenzoic acid: Hydrolyze 2-acetamido-4-bromobenzoic acid with sodium hydroxide, decolorize with activated carbon, and adjust the acidity to obtain 2-amino-4-bromobenzoic acid; S7. Synthesis of 2-acetamido-4-bromo-5-chlorobenzoic acid: Use DMF as a solvent and dichlorohydantoin as a chlorinating agent for 2-acetamido-4-bromobenzoic acid to obtain 2-acetamido-4-bromo-5-chlorobenzoic acid; S8. Synthesis of 2-amino-4-bromo-5-chlorobenzoic acid: Hydrolyze 2-acetamido-4-bromo-5-chlorobenzoic acid with sodium hydroxide, decolorize with activated carbon, and adjust the acidity to obtain 2-amino-4-bromo-5-chlorobenzoic acid.

2. The preparation method of 2-amino-4-bromo-5-chlorobenzoic acid according to claim 1, characterized in that: The reduction treatment in S3 is that for the crude product of 2-nitro-4-bromotoluene, after removing the contained tar with water vapor, carry out hydrogenation reduction with Pd / C.

3. The preparation method of 2-amino-4-bromo-5-chlorobenzoic acid according to claim 1, wherein: The reduction treatment in S3 is to carry out reduction with iron powder, and directly obtain 2-amino-4-bromotoluene with water vapor after reduction.

4. The preparation method of 2-amino-4-bromo-5-chlorobenzoic acid according to claim 1, characterized in that: The pyrolysis temperature in S2 is 60 °C.

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