Process for the preparation of o-bromoanisole

Abstract

The application discloses a preparation method of o-bromoanisole. The o-bromoanisole is synthesized through three steps, anisole is used as raw material, p-sulfonic anisole is first synthesized, 2-bromo-4-sulfonic anisole is synthesized on the basis, and finally, the sulfonic group is removed to obtain o-bromoanisole. Since anisole is used as raw material, the problems of multiple by-products, low yield and low purity existing in the synthesis path of phenol are avoided. Meanwhile, all the raw materials of the application have low cost, the process steps are simple, and etherification is not needed. Meanwhile, since anisole is used as raw material, hydrobromic acid and hydrogen peroxide can be used in the intermediate step, the hydrobromic acid is oxidized to generate bromine, the reaction rate can be controlled, the reaction efficiency is improved, the waste of bromine is reduced, the purity of the prepared product can reach 99.4%, the yield reaches 96.26%, and the product can be applied on a large scale in industry.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and specifically to a method for preparing o-bromoanisole. Background Technology

[0002] o-Bromoanisole is an intermediate material in the field of synthesis, playing an important role in the fragrance and pharmaceutical industries. Currently, there are many synthetic processes for its preparation. The synthesis of o-Bromoanisole mainly consists of two steps: the synthesis of o-bromophenol and the etherification of o-bromophenol.

[0003] The main methods for synthesizing o-bromophenols include direct bromination of phenol, diazotization of o-aminophenol, and sulfonation bromination. Direct bromination of phenol involves directly substituting phenol with bromine to produce o-bromophenol, p-bromophenol, and dibromophenol. These products are then separated. However, after bromination, not only o-bromophenol is generated, but also byproducts such as p-bromophenol and dibromophenol, which have similar properties and are difficult to separate. Diazotization of o-aminophenol to synthesize o-bromoanisole involves first synthesizing o-aminophenol and then diazotizing it to obtain o-bromophenol. However, this method is complex, has a low yield (less than 30%), and is costly. Sulfonation bromination is the most commonly used industrial method. It involves introducing a sulfonic acid group at the para-position of phenol, allowing bromine substitution to occur only at the ortho-position. This method is low-cost and produces less pollution, but the yield of o-bromophenol is only about 40%. In the existing technology, Li Yingchun synthesized o-bromoanisole using phenol, bromine, and dimethyl sulfate as raw materials (Li Yingchun, Teng Junjiang. Synthesis of o-bromoanisole [J]. Applied Chemical Industry, 2004, (04)). Although he obtained a high yield by adjusting the ratio and reaction conditions, on the one hand, he also synthesized o-bromobenzene first and then obtained o-bromoanisole through etherification. On the other hand, the yield limitation of the multi-step reaction prevented the yield of o-bromoanisole from being maximized.

[0004] In summary, current techniques for synthesizing o-bromoanisole exhibit varying degrees of complexity. Some processes offer high yields but come at high costs, while others are simpler but yields are low, resulting in significant raw material waste. Furthermore, the etherification process, involving dimethyl sulfate, requires large quantities of strong inorganic bases and generates substantial amounts of inorganic salts, complicating reaction separation. To address these issues, this application proposes an improved synthetic approach, synthesizing o-bromoanisole from other raw material anisole. This method avoids byproducts, thereby achieving high purity and high yield of o-bromoanisole.

[0005] Technical content

[0006] This application provides a method for preparing o-bromoanisole, the technical solution of which is as follows.

[0007] Methods for preparing o-bromoanisole, including

[0008] Step 1: Synthesis of p-sulfonanisole

[0009] p-Sulfoanilide is synthesized by reacting anisole with chlorosulfonic acid as a raw material.

[0010] Step 2: Synthesis of 2-bromo-4-sulfonyl anisole

[0011] After the reaction in step 1 is completed, hydrobromic acid and hydrogen peroxide are added to the solution after the reaction is completed. After the addition is completed, the reaction is kept at a constant temperature to obtain 2-bromo-4-sulfonyl anisole.

[0012] Step 3: Synthesis of o-bromoanisole

[0013] In the reaction solution of step 2, concentrated sulfuric acid was added, the mixture was heated to reflux, allowed to stand and separated, and the oil phase was distilled to obtain high-purity o-bromoanisole.

[0014] In step 1, the molar ratio of anisole to chlorosulfonic acid is 1:1 to 1.3.

[0015] In step 2, the molar ratio of hydrobromic acid to hydrogen peroxide is 1:1 to 1.2.

[0016] The molar ratio of anisole to hydrobromic acid is 1:1 to 1.2;

[0017] In step 3, the mass ratio of anisole to concentrated sulfuric acid is 1:0.4 to 0.6;

[0018] In step 1, the reaction temperature is 10-20 ℃; the chlorosulfonic acid is added dropwise; the dropwise addition time is 3-5 h; and the temperature is maintained for 3-6 h after the dropwise addition is completed.

[0019] In step 2, the reaction temperature is -5 to 5°C, the hydrogen peroxide is added at a slightly faster rate than hydrobromic acid, and the dropping time is 3-4 hours; after the dropping is completed, the temperature is maintained for 3-5 hours.

[0020] In step 3, the concentrated sulfuric acid is added over a period of 1 to 3 hours; the addition method is dropwise; the stirring and heating range is 190-200℃; and the reflux time is 6 to 9 hours.

[0021] Technical Principles

[0022] The o-bromoanisole of this application is synthesized through three steps. Using anisole as a raw material, p-sulfonanisole is first synthesized, followed by 2-bromo-4-sulfonanisole, and finally, the sulfonic acid group is removed to obtain o-bromoanisole. In the second step, during the reaction with hydrobromic acid and hydrogen peroxide, hydrogen peroxide oxidizes the hydrobromic acid to bromine, which then reacts with p-sulfonanisole to generate 2-bromo-4-sulfonanisole. The advantage is that the presence of hydrogen peroxide allows the slow-reacting hydrobromic acid to be oxidized to elemental bromine, which is more reactive, allowing p-sulfonanisole to react more fully to generate 2-bromo-4-sulfonanisole. This improves the efficiency of bromine utilization and avoids the waste of resources caused by incomplete reaction when using bromine directly.

[0023]

[0024] Technical effect

[0025] The method for preparing o-bromoanisole in this application avoids the problems of numerous byproducts, low yield, and low purity associated with the phenol synthesis route by using anisole as the raw material. Furthermore, all the reactants used in this application are low-cost, and the process steps are simple. Unlike conventional sulfonation processes using phenol as a raw material, this application uses anisole, which is low-cost and eliminates the need for etherification. The reaction raw material is hydrobromic acid, which is oxidized to bromine using hydrogen peroxide. This method controls the reaction rate, improves reaction efficiency, reduces bromine waste, and avoids the need for bromine storage and transportation. Using anisole as a raw material also avoids other byproducts, thus significantly improving the purity and yield of o-bromoanisole. The o-bromoanisole product prepared in this application achieves a purity of 99.4% and a yield of 96.26%. Moreover, the synthesis process is simple, eliminating the need for multiple reaction stages. All reactions can be carried out in the same reaction vessel, reducing multi-step synthesis and lowering production costs, making it suitable for large-scale industrial application. Detailed Implementation

[0026] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments. The technical solutions in the embodiments of the present invention will be clearly and completely described. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0027] Example 1

[0028] 108g of anisole was added to the reactor and stirred. The temperature was maintained at 20°C. 140g of chlorosulfonic acid was then added dropwise over 4 hours, controlling the temperature. After the addition, the reaction was maintained at 20°C for another 4 hours until the reaction was complete. The reactor temperature was then lowered to 0°C, and hydrobromic acid and hydrogen peroxide were added dropwise simultaneously. The hydrobromic acid was 212.6g of a 40% (w / w) hydrobromic acid solution, and the hydrogen peroxide was 27.5% (w / w) hydrogen peroxide. The feed amount was 13g / w. 0.3g of hydrogen peroxide was added, with the dropping rate controlled slightly faster than that of hydrobromic acid. The material was added dropwise over 3 hours, and then kept at 0 degrees Celsius for 5 hours. Then, concentrated sulfuric acid with a mass fraction of 98% was added dropwise to the reaction solution over 3 hours. After the addition was complete, the mixture was stirred and heated to 190 degrees Celsius and refluxed for 7-8 hours. The mixture was then allowed to stand and separated. The lower layer was a pale yellow oily liquid. The oil phase was separated and distilled to obtain 180g of o-bromoanisole with a purity of 99.4% and a yield of 96.26%.

[0029] Example 2

[0030] 108g of anisole was added to the reactor, and the temperature was maintained at 20 degrees Celsius. 120g of chlorosulfonic acid was then added dropwise, with the temperature controlled. The addition was carried out over 4 hours. After the addition, the reactor was kept at 20 degrees Celsius for 3 hours until the reaction was complete. The reactor temperature was then lowered to 0 degrees Celsius, and hydrobromic acid and hydrogen peroxide were added dropwise simultaneously. The hydrobromic acid was 212.6g of a 40% (w / w) hydrobromic acid solution, and the hydrogen peroxide was 27.5% (w / w) hydrogen peroxide. The total feed amount was 130g. Add 3g of hydrogen peroxide at a rate slightly faster than that of hydrobromic acid, and let the mixture drip over 3 hours. After the dripping is complete, keep the mixture at 0 degrees Celsius for 5 hours. Then, add concentrated sulfuric acid (98% by mass) to the reaction solution over 3 hours. After the dripping is complete, stir and heat to 190 degrees Celsius and reflux for 7-8 hours. Let the mixture stand and separate the layers. The lower layer is a pale yellow oily liquid. Separate the oil phase and distill to obtain 175g of o-bromoanisole with a purity of 99.1% and a yield of 93.86%.

[0031] Example 3

[0032] 108g of anisole was added to the reactor, and the temperature was maintained at 20 degrees Celsius. 120g of chlorosulfonic acid was then added dropwise, with the temperature controlled. The addition was carried out over 4 hours. After the addition, the reactor was kept at 20 degrees Celsius for another 4 hours to complete the reaction. The reactor temperature was then lowered to 0 degrees Celsius, and hydrobromic acid and hydrogen peroxide were added dropwise simultaneously. The hydrobromic acid was 177.2g of a 48% (w / w) hydrobromic acid solution, and the hydrogen peroxide was 27.5% (w / w) hydrogen peroxide. The total feed amount was 130g. Add 3g of hydrogen peroxide at a slightly faster rate than hydrobromic acid, and let the mixture drip over 3 hours. After the dripping is complete, keep the mixture at 0 degrees Celsius for 5 hours. Then, add 98% concentrated sulfuric acid to the reaction solution over 3 hours. After the dripping is complete, stir and heat to 190 degrees Celsius and reflux for 7-8 hours. Let the mixture stand and separate the layers. The lower layer is a pale yellow oily liquid. Separate the oil phase and distill to obtain 173g of o-bromoanisole with a purity of 99.5% and a yield of 92.42%.

[0033] Example 4

[0034] 108g of anisole was added to a reaction vessel, and the temperature was maintained at 20°C. 120g of chlorosulfonic acid was then added dropwise over 4 hours, with the temperature controlled. After the addition, the reaction vessel was kept at 20°C for another 4 hours until the reaction was complete. The temperature of the reaction vessel was then lowered to 0°C, and hydrobromic acid (177.2g of a 48% hydrobromic acid solution) was added dropwise over 3 hours. After the addition was complete, the reaction vessel was kept at 0°C for 5 hours. Then, 98% concentrated sulfuric acid was added dropwise to the reaction solution over 3 hours. After the addition was complete, the mixture was stirred and heated to 190°C and refluxed for 7-8 hours. The mixture was then allowed to stand and separate. The lower layer was a pale yellow oily liquid. The oil phase was separated, and distilled to obtain 124g of o-bromoanisole with a purity of 95.1% and a yield of 63.1%.

[0035] Comparative Example

[0036] Prepared according to the synthesis method of Li Yingchun in the background art:

[0037] A mixture of 47 g (0.5 mol) phenol and 175 g (95 mL, 1.75 mol) concentrated sulfuric acid was added to a three-necked flask and heated in a boiling water bath for 3 hours with stirring. The mixture was then cooled to room temperature in an ice-water bath. A solution prepared with 140 g (3.5 mol) NaOH and 350 mL of water was carefully added, turning the mixture dark brown. The mixture was stirred for 2 minutes, and after a white solid formed, stirring continued for 10 minutes until the solution turned dark brown. The alkaline solution was then cooled to room temperature. 80 g (0.5 mol) bromine was added dropwise over 30 minutes with stirring, while maintaining the reaction temperature at 50°C. After the bromine was added, stirring continued for another 30 minutes. The solution remained alkaline and contained a small amount of white suspended matter. Stirring was then stopped, and the mixture was placed in a 150°C oil bath for evaporation until a thick, paste-like gray residue remained. The evaporation time was 40 minutes. The slurry was cooled to room temperature to obtain a yellow solid. 400 mL of concentrated sulfuric acid was added to the solid, which dissolved and turned dark green. The mixture was heated to 200°C in an oil bath and subjected to steam distillation. The distillate was a yellow-green oil. The distillate was extracted with diethyl ether, and after the ether was removed by evaporation, the residue was distilled at atmospheric pressure. The fraction collected at 190–200°C yielded 79.1 g of a light yellow oily liquid, with a yield of 91.52%.

[0038] 52g of o-bromophenol was mixed with 40g of 10% dilute sodium hydroxide solution and stirred. The mixture was then cooled to below 5°C in an ice-water bath. 42g of dimethyl sulfate was then slowly added while stirring. The mixture turned into a milky white paste. After the addition was complete, cooling was stopped, and the mixture was heated to 45°C. The mixture turned into a yellow oily liquid. After stirring and maintaining the temperature for 2 hours, the mixture was discharged and poured into a separatory funnel. After standing for 4 hours, the layers separated. The upper layer was a colorless liquid, and the lower layer was a pale yellow oily liquid. The oil layer was separated, and the upper layer was extracted with diethyl ether. The extract was evaporated to remove the diethyl ether and combined with the oil layer. The mixture was washed with water until neutral and dried with anhydrous calcium chloride to obtain 47.8g of pale yellow transparent oily liquid o-bromoanisole, with a yield of 85.1%.

[0039] As can be seen from the examples, when the reactant is hydrobromic acid, although it can undergo bromination, its reaction efficiency is low, with a significant amount of bromine remaining unreacted. The yield of o-bromoanisole is around 60%. If the industrial phenol bromination method is used to synthesize o-bromophenol from phenol, the yield of o-bromophenol is below 50%, much lower than the yield using anisole as a raw material. Even when using the comparative synthesis method, although the yield of o-bromophenol can reach over 90%, the yield of o-bromophenol etherification can also reach over 80%, but the overall yield is below 80%, lower than the over 90% yield of this application. Furthermore, its complex process... This results in high production costs. Furthermore, in the preparation of o-bromophenol from phenol, bromine must be used instead of hydrobromic acid and hydrogen peroxide. This is mainly because hydrobromic acid has low reaction efficiency. Once an oxidant is added, the phenol will be oxidized, preventing the formation of o-bromophenol. It is precisely because anisole is a more stable raw material that hydrobromic acid and hydrogen peroxide can be used. This way, only hydrobromic acid will be oxidized, and the ether will not be oxidized to form 2-bromo-4-sulfonyl anisole. Experiments show that by controlling the addition of hydrogen peroxide to generate bromine during the reaction, the amount of hydrobromic acid used in this application is reduced compared to directly using bromine as a raw material, and the efficiency of bromine utilization is significantly improved.

[0040] Therefore, it is evident that the yield of anisole as a raw material in this application is significantly higher than that of phenol. Furthermore, the production of o-bromoanisole does not require multiple separations; the reaction can be completed in a single reactor, simplifying the process. This process effectively reduces byproducts, offering advantages such as lower pollution and cost, as well as higher yield and purity—advantages unmatched by using phenol as a raw material for o-bromoanisole production.

Claims

1. A method for preparing o-bromoanisole, characterized in that, The preparation method consists of the following steps: Step 1: Synthesizing p-sulfonanisole, using anisole as a raw material, adding chlorosulfonic acid to react with anisole to synthesize p-sulfonanisole; Step 2: Synthesize 2-bromo-4-sulfonylanisole. After the reaction in Step 1 is completed, hydrobromic acid and hydrogen peroxide are added to the solution after the reaction is completed. After the addition is completed, the reaction is kept at a constant temperature to obtain 2-bromo-4-sulfonylanisole. Step 3: Synthesize o-bromoanisole. Add concentrated sulfuric acid to the reaction solution in step 2, heat to reflux, allow to stand and separate the liquids, and distill the oil phase to obtain high-purity o-bromoanisole. In step 1, the molar ratio of anisole to chlorosulfonic acid is 1:1 to 1.3, and the reaction temperature is 10 to 20°C; in step 2, the molar ratio of hydrobromic acid to hydrogen peroxide is 1:1 to 1.2; the molar ratio of anisole to hydrobromic acid is 1:1 to 1.2; the reaction temperature in step 2 is -5 to 5°C; in step 3, the mass ratio of anisole to concentrated sulfuric acid is 1:0.4 to 0.

6.

2. The method for preparing o-bromoanisole according to claim 1, characterized in that, In step 1, the chlorosulfonic acid is added by dripping; the dripping time is 3-5 hours; and the temperature is maintained for 3-6 hours after the dripping is completed.

3. The method for preparing o-bromoanisole as described in claim 1, characterized in that, In step 2, the hydrogen peroxide is added at a slightly faster rate than hydrobromic acid, and the addition time is 3-4 hours; after the addition is completed, the mixture is kept warm for 3-5 hours.

4. The method for preparing o-bromoanisole as described in claim 1, characterized in that, In step 3, the concentrated sulfuric acid is added over a period of 1-3 hours; the addition method is dropwise; the stirring and heating range is 190-200℃; and the reflux time is 6-9 hours.

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