Method for synthesizing ethyl 4-bromo-5-chloro-2-ethyoxyl benzoate
By using 2-fluoro-4-bromobenzonitrile as a raw material, first esterifying and then chlorinating to produce ethyl 4-bromo-5-chloro-2-ethoxybenzoate, the problems of poor selectivity and expensive raw materials in the existing technology are solved, and a high-purity and high-yield synthesis is achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- DALIAN DOUBLE BORON PHARM CHEM CO LTD
- Filing Date
- 2025-12-31
- Publication Date
- 2026-04-21
AI Technical Summary
The existing methods for synthesizing ethyl 4-bromo-5-chloro-2-ethoxybenzoate suffer from poor selectivity, expensive raw materials, and difficult purification, especially the low conversion rate of the N-chlorosuccinimide reaction and the generation of a large number of ortho-isomers.
Using 2-fluoro-4-bromobenzonitrile as a raw material, ethyl 4-bromo-2-ethoxybenzoate is generated through esterification and etherification reactions, followed by chlorination to generate ethyl 4-bromo-5-chloro-2-ethoxybenzoate. Ammonium acetate is used as a catalyst to improve the reaction rate and selectivity.
It improves the selectivity and conversion rate of the reaction, reduces the content of ortho-isomers to below 0.2%, achieves a yield of 90%-95%, and produces a product purity of GC≥99%. The raw materials are inexpensive and readily available.
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Figure CN121895155A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to a method for synthesizing ethyl 4-bromo-5-chloro-2-ethoxybenzoate, belonging to the field of pharmaceutical intermediate synthesis. Background Technology
[0002] Ethyl 4-bromo-5-chloro-2-ethoxybenzoate is a halogenated aromatic compound that can form various C-C and C-B single bonds through the Suzuki reaction, Grignard reaction, and other methods.
[0003] In recent years, the synthesis of halogenated aromatic compounds has received increasing attention. However, there is currently no documented method for the synthesis of ethyl 4-bromo-5-chloro-2-ethoxybenzoate. Typically, this type of compound is synthesized by first preparing ethyl 4-bromo-2-ethoxybenzoate, followed by a chlorination reaction. However, the chlorination reaction of ethyl 4-bromo-2-ethoxybenzoate using N-chlorosuccinimide exhibits poor selectivity, incomplete reaction of the starting material, and a tendency to form ortho-isomers, resulting in a conversion rate of only 40-60%. The formation of isomers also makes product purification difficult. Furthermore, regarding the synthesis of ethyl 4-bromo-2-ethoxybenzoate, two methods have been reported in the literature: Method 1: Typically, 2-hydroxy-4-bromobenzoic acid is used as a starting material in the reaction with iodoethane or bromoethane. Method 2: ethyl 2-fluoro-4-bromobenzoate is prepared by reacting it with ethanol. First, the raw materials for both methods are relatively expensive: 2-hydroxy-4-bromobenzoic acid costs 3335 yuan / 500g, and ethyl 2-fluoro-4-bromobenzoate costs 692 yuan / 100g. Second, the yield of method two is low, only 77%.
[0004] Therefore, it is urgent to find a novel method for synthesizing ethyl 4-bromo-5-chloro-2-ethoxybenzoate. Summary of the Invention
[0005] To overcome the aforementioned technical deficiencies, this invention uses 2-fluoro-4-bromobenzonitrile as a raw material, first undergoing esterification and etherification reactions to generate ethyl 4-bromo-2-ethoxybenzoate, and then proceeding with chlorination to generate ethyl 4-bromo-5-chloro-2-ethoxybenzoate. This method has the advantages of originality, good reaction selectivity, high product purity, and high yield.
[0006] A process for synthesizing ethyl 4-bromo-5-chloro-2-ethoxybenzoate, characterized by comprising the following steps:
[0007]
[0008] Step A: Mix 4-bromo-2-fluorobenzonitrile and ethanol, control the temperature at -5 to -5℃, add acyl chloride and keep the reaction at the temperature; after the reaction is complete, add alkali to the reaction solution and heat the reaction; add water to precipitate solid, filter, mix the filter cake with dilute sulfuric acid, filter and dry to obtain ethyl 4-bromo-2-ethoxybenzoate;
[0009] Step B: Mix ethyl 4-bromo-2-ethoxybenzoate, ammonium acetate and organic solvent, and add N-chlorosuccinimide in batches at a controlled temperature of -5 to -5℃ to maintain the reaction. After the reaction is complete, add water, precipitate the solid, filter and dry to obtain ethyl 4-bromo-5-chloro-2-ethoxybenzoate.
[0010] Furthermore, in step A, the acyl chloride is selected from acetyl chloride and propionyl chloride.
[0011] Furthermore, in step A, the alkali is selected from anhydrous potassium carbonate and anhydrous sodium carbonate.
[0012] Furthermore, in step A, the concentration of dilute sulfuric acid is selected from 3% to 20%.
[0013] Further, in step A, the molar ratio of ethyl 4-bromo-5-chloro-2-ethoxybenzoate, acyl chloride, base, and dilute sulfuric acid is 1:1-1.5:2-3:2-6.
[0014] Further, in step A, the mass ratio of ethyl 4-bromo-5-chloro-2-ethoxybenzoate to ethanol is 1:3-15.
[0015] Further, in step B, the organic solvent is selected from acetonitrile, ethyl acetate, isopropyl acetate, dichloromethane, and N,N-dimethylformamide.
[0016] Further, in step B, the molar ratio of ethyl 4-bromo-2-ethoxybenzoate, ammonium acetate, and N-chlorosuccinimide is 1:0.05-0.2:1-1.1.
[0017] Further, in step B, the mass ratio of ethyl 4-bromo-2-ethoxybenzoate to the organic solvent is 1:4-20.
[0018] Beneficial effects of the invention
[0019] 1. This invention uses 2-fluoro-4-bromobenzonitrile as a raw material, first performing esterification and substitution bifunctionalization reactions in a one-pot process to prepare ethyl 4-bromo-2-ethoxybenzoate, and then subjecting it to chlorination to generate ethyl 4-bromo-5-chloro-2-ethoxybenzoate. This method is original and has not been reported in the literature.
[0020] 2. The first step reaction raw material, 2-fluoro-4-bromobenzonitrile, is a pesticide intermediate. It is inexpensive, with a price of less than 1,000 yuan per kilogram. It is readily available in the market and has a large supply, laying the foundation for the commercial production of ethyl 4-bromo-5-chloro-2-ethoxybenzoate.
[0021] 3. The second step involves a chlorination reaction using ethyl 4-bromo-2-ethoxybenzoate as the starting material. The reaction with N-chlorosuccinimide is slow; even after reflux with acetonitrile for 24 hours, 45% of the starting material remains, and the reaction selectivity is poor. Even at room temperature, more than 2% of the ortho-isomer is produced. The ortho-isomer and the product elute in the gas phase within less than 0.5 minutes, and their polarities are extremely similar, making them difficult to purify. This invention introduces ammonium acetate as a catalyst, significantly improving the reaction rate and lowering the reaction temperature. Due to the lower reaction temperature, the reaction selectivity is correspondingly improved, reducing the ortho-isomer content to below 0.2%. This method improves the selectivity and conversion rate, achieving a yield of 90%-95% and a GC purity ≥ 99%.
[0022] 4. The method of the present invention has potential technical advantages, good reaction selectivity, high product purity, and cheap and readily available raw materials, providing a good method for the synthesis of ethyl 4-bromo-5-chloro-2-ethoxybenzoate. Attached Figure Description
[0023] Figure 1 The image shows the 1H NMR spectrum of ethyl 4-bromo-5-chloro-2-ethoxybenzoate from Example 1. Specific Implementation
[0024] Example 1
[0025] Step A: Add 20.0g of ethyl 4-bromo-5-chloro-2-ethoxybenzoate and 100g of ethanol to a glass bottle. While stirring, maintain the temperature at -5 to -5℃ and add 11.3g of acetyl chloride dropwise. After the addition is complete, maintain the temperature and allow the reaction to proceed. Once the reaction is complete, add 34.6g of anhydrous potassium carbonate in portions to the reaction solution. React at 40℃ for 10 hours. Once the reaction is complete, add 300g of water to the reaction flask, causing a solid to precipitate. Stir at 10-15℃ for 0.5 hours, filter, and add the filter cake in portions to 260g of 10% dilute sulfuric acid. Stir at room temperature for 2 hours, filter, and wash the filter cake with 100g of water. Dry the filter cake to obtain 26.8g of white solid product ethyl 4-bromo-2-ethoxybenzoate, GC≥99.8%, yield 98%.
[0026] Step B: Add 26.8g of ethyl 4-bromo-2-ethoxybenzoate, 0.8g of ammonium acetate, and 160g of acetonitrile to a glass bottle. While stirring, control the temperature at -5 to -5℃, and add 14.4g of N-chlorosuccinimide in batches. Maintain the temperature at -5 to -5℃ for 1 hour. Control the temperature until the reaction is complete, with the ortho-isomer content at 0.1%. Add 320g of water to the reaction solution, and a solid precipitates. Stir at 10 to -15℃ for 0.5 hours, filter, wash the filter cake with water, and dry the filter cake to obtain 28.6g of white solid product ethyl 4-bromo-5-chloro-2-ethoxybenzoate, GC≥99.4%, yield 95%.
[0027] Example 2
[0028] Step A: Add 30.0g of ethyl 4-bromo-5-chloro-2-ethoxybenzoate and 300g of ethanol to a glass bottle. While stirring, control the temperature at -5 to -5℃ and add 21.3g of acetyl chloride dropwise. After the addition is complete, maintain the temperature and control the reaction until it is complete. Add 62.2g of anhydrous potassium carbonate in portions to the reaction solution and react at 50℃ for 5 hours. Control the reaction until it is complete. Add 900g of water to the reaction bottle, and a solid precipitates. Stir at 10-15℃ for 0.5 hours, filter, and add the filter cake in portions to 1060g of 5% dilute sulfuric acid. Stir at room temperature for 2 hours, filter, wash the filter cake with 150g of water, and dry the filter cake to obtain 38.5g of white solid product ethyl 4-bromo-2-ethoxybenzoate, GC≥99.2%, yield 94%.
[0029] Step B: Add 38.5g of ethyl 4-bromo-2-ethoxybenzoate, 0.5g of ammonium acetate, and 380g of ethyl acetate to a glass bottle. While stirring, control the temperature at -5 to -5℃, and add 19.8g of N-chlorosuccinimide in batches. Maintain the temperature at -5 to -5℃ for 1 hour. The reaction is controlled at the center until complete, with an ortho-isomer content of 0.17%. Add 380g of water to the reaction solution, allowing the layers to separate. Concentrate the organic layer and cool to 5 to -10℃. The solid precipitates. Stir for 0.5 hours, filter, and dry the filter cake to obtain 39g of white solid product ethyl 4-bromo-5-chloro-2-ethoxybenzoate, with GC ≥ 99.5% and a yield of 90%.
[0030] Example 3
[0031] Step A: Add 30.0g of ethyl 4-bromo-5-chloro-2-ethoxybenzoate and 200g of ethanol to a glass bottle. While stirring, maintain the temperature at -5 to -5℃ and add 21.3g of acetyl chloride dropwise. After the addition is complete, maintain the temperature and allow the reaction to proceed. Once the reaction is complete, add 62.2g of anhydrous potassium carbonate in portions to the reaction solution and react at 50℃ for 5 hours. Once the reaction is complete, add 400g of water to the reaction flask, causing a solid to precipitate. Stir at 10-15℃ for 0.5 hours, filter, and add the filter cake in portions to 700g of 7.5% dilute sulfuric acid. Stir at room temperature for 2 hours, filter, and wash the filter cake with 100g of water. Dry the filter cake to obtain 39.3g of white solid product ethyl 4-bromo-2-ethoxybenzoate, GC≥99.1%, yield 96%.
[0032] Step B: 39.3 g of ethyl 4-bromo-2-ethoxybenzoate, 0.6 g of ammonium acetate, and 380 g of dichloromethane were added to a glass bottle. Under stirring, the temperature was controlled at -5 to -5°C. 20.2 g of N-chlorosuccinimide was added in portions, and the reaction was maintained at -5 to -5°C for 5 hours. The reaction was controlled until complete, with an ortho-isomer content of 0.2%. 380 g of water was added to the reaction solution, and the layers separated. The organic layer was concentrated, and the temperature was lowered to 5 to -10°C, causing the solid to precipitate. The mixture was stirred for 0.5 hours, filtered, and the filter cake was dried to obtain 40.3 g of the white solid product, ethyl 4-bromo-5-chloro-2-ethoxybenzoate, with GC ≥ 99.0% and a yield of 91%. Comparison Example 1 (chlorination reaction using acetic acid as a catalyst):
[0033] Step B: Add 26.8g of ethyl 4-bromo-2-ethoxybenzoate, 0.5g of acetic acid, and 380g of acetonitrile to a glass bottle. While stirring, control the temperature at -5 to -5℃, and add 19.8g of N-chlorosuccinimide in batches. Slowly raise the temperature to 25℃ and react for 10 hours. Control the temperature, and the reaction will stop. The remaining raw material is 19%, and the ortho-isomer content is 5%. Add 770g of water to the reaction solution, and a solid precipitates. Stir at 10-15℃ for 0.5 hours, filter, wash with water, and dry the filter cake to obtain 28.2g of white solid product ethyl 4-bromo-5-chloro-2-ethoxybenzoate, GC≥94.5%, yield 65%.
[0034] Compare with Example 2 (chlorination reaction using acetic acid as a catalyst):
[0035] Step B: Add 26.8g of ethyl 4-bromo-2-ethoxybenzoate, 20g of acetic acid, and 380g of acetonitrile to a glass bottle. While stirring, control the temperature at -5 to -5℃, and add 19.8g of N-chlorosuccinimide in batches. Slowly raise the temperature to 25℃ and react for 10 hours. Control the temperature to stop the reaction. The remaining raw material is 3.5%, and the ortho-isomer content is 8%. Add 770g of water to the reaction solution, and a solid precipitates. Stir at 10-15℃ for 0.5 hours, filter, wash with water, and dry the filter cake to obtain 35.6g of white solid product ethyl 4-bromo-5-chloro-2-ethoxybenzoate, GC≥91.5%, yield 82%.
[0036] Compare with Example 3 (chlorination reaction using water as a catalyst):
[0037] Step B: Add 26.8g of ethyl 4-bromo-2-ethoxybenzoate, 19g of water, and 380g of acetonitrile to a glass bottle. While stirring, control the temperature at -5 to -5℃, and add 19.8g of N-chlorosuccinimide in batches. Slowly raise the temperature to 25℃ and react for 10 hours. Control the temperature and stop the reaction. The remaining raw material is 5%, the ortho-isomer content is 3.5%, and the content of 4-bromo-2-ethoxybenzoic acid, a hydrolysis impurity in the raw material, is 5.8%. Add 770g of water to the reaction solution, and a solid precipitates. Stir at 10-15℃ for 0.5 hours, filter, wash with water, and dry the filter cake to obtain 31.7g of white solid product ethyl 4-bromo-5-chloro-2-ethoxybenzoate, GC≥96.8%, yield 73%.
[0038] Compare with Example 4 (chlorination reaction using water as a catalyst):
[0039] Step B: Add 26.8g of ethyl 4-bromo-2-ethoxybenzoate, 5g of water, and 380g of acetonitrile to a glass bottle. While stirring, control the temperature at -5 to -5℃, and add 19.8g of N-chlorosuccinimide in batches. Slowly raise the temperature to 25℃ and react for 10 hours. At the intermediate temperature, the reaction stops. The remaining raw material is 9%, the ortho-isomer content is 4.5%, and the hydrolysis impurity of 4-bromo-2-ethoxybenzoic acid is 1.8%. Add 770g of water to the reaction solution, and a solid precipitates. Stir at 10-15℃ for 0.5 hours, filter, wash with water, and dry the filter cake to obtain 29.5g of white solid product ethyl 4-bromo-5-chloro-2-ethoxybenzoate, GC≥95.3%, yield 68%.
[0040] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the claimed invention.
Claims
1. A process for synthesizing ethyl 4-bromo-5-chloro-2-ethoxybenzoate, characterized in that, Includes the following steps: Step A: Mix 4-bromo-2-fluorobenzonitrile and ethanol, control the temperature at -5 to -5℃, add acyl chloride and keep the reaction at the temperature; after the reaction is complete, add alkali to the reaction solution and heat the reaction; add water to precipitate solid, filter, mix the filter cake with dilute sulfuric acid, filter and dry to obtain ethyl 4-bromo-2-ethoxybenzoate; Step B: Mix ethyl 4-bromo-2-ethoxybenzoate, ammonium acetate and organic solvent, and add N-chlorosuccinimide in batches at a controlled temperature of -5 to -5℃ to maintain the reaction. After the reaction is complete, add water, precipitate the solid, filter and dry to obtain ethyl 4-bromo-5-chloro-2-ethoxybenzoate.
2. The method for synthesizing ethyl 4-bromo-5-chloro-2-ethoxybenzoate according to claim 1, characterized in that: In step A, the acyl chloride is selected from acetyl chloride or propionyl chloride.
3. The method for synthesizing ethyl 4-bromo-5-chloro-2-ethoxybenzoate according to claim 1, characterized in that: In step A, the alkali is selected from anhydrous potassium carbonate or anhydrous sodium carbonate.
4. The method for synthesizing ethyl 4-bromo-5-chloro-2-ethoxybenzoate according to claim 1, characterized in that: In step A, the concentration of dilute sulfuric acid is selected from 3-20%.
5. The method for synthesizing ethyl 4-bromo-5-chloro-2-ethoxybenzoate according to claim 1, characterized in that: In step A, the molar ratio of ethyl 4-bromo-5-chloro-2-ethoxybenzoate, acyl chloride, base, and dilute sulfuric acid is 1:1-1.5:2-3:2-6.
6. The method for synthesizing ethyl 4-bromo-5-chloro-2-ethoxybenzoate according to claim 1, characterized in that: In step A, the mass ratio of ethyl 4-bromo-5-chloro-2-ethoxybenzoate to ethanol is 1:3-15.
7. The method for synthesizing ethyl 4-bromo-5-chloro-2-ethoxybenzoate according to claim 1, characterized in that: In step B, the organic solvent is selected from acetonitrile, ethyl acetate, isopropyl acetate, dichloromethane, or N,N-dimethylformamide.
8. The method for synthesizing ethyl 4-bromo-5-chloro-2-ethoxybenzoate according to claim 1, characterized in that: In step B, the molar ratio of ethyl 4-bromo-2-ethoxybenzoate, ammonium acetate and N-chlorosuccinimide is 1:0.05-0.2:1-1.
1.
9. The method for synthesizing ethyl 4-bromo-5-chloro-2-ethoxybenzoate according to claim 1, characterized in that: In step B, the mass ratio of ethyl 4-bromo-2-ethoxybenzoate to the organic solvent is 1:4-20.