A green process for synthesis of 3,5-dichloro-4-methoxybenzoic acid

Abstract

The present application relates to a kind of green, efficient synthesis of gout medicine multi-tinore key intermediate-3, 5-dichloro-4-methoxybenzoic acid New process.The method is with p-hydroxybenzoic acid as starting material, first by dimethyl sulfate etherification obtains p-methoxybenzoic acid;Then, in organic solvent, with specific chloro reagent and catalyst, it is chlorinated, and the target product is obtained by recrystallization.The process is mild and safe, the byproduct is environmentally friendly and easy to handle, and the key reagent can be recycled, thereby effectively improving the reaction selectivity and atomic economy, and building a green and cost-effective path for industrial production.

Description

Technical Field

[0001] This invention pertains to the synthesis of pharmaceutical intermediates, specifically involving a green process for synthesizing 3,5-dichloro-4-methoxybenzoic acid. Background Technology

[0002] Dotinurad is a third-generation, highly selective uric acid inhibitor developed by Fuji Pharmaceuticals in Japan. It was approved for marketing in Japan on January 23, 2020, and received approval from the China National Medical Products Administration on January 22, 2024. As a novel uricosuric drug, dotinurad is characterized by high selectivity and high efficacy, effectively reducing uric acid levels in the blood with minimal impact on liver and kidney function, giving it a significant competitive advantage. ‌ .

[0003] As a key intermediate in dotenorazole, 3,5-dichloro-4-methoxybenzoic acid has limited synthetic methods, and its preparation is not covered in the original research routes. Traditional processes directly use hazardous chlorine gas, posing safety and environmental bottlenecks. Among the improved routes, the method using N-chlorosuccinimide (NCS) as the chlorine source is uneconomical due to expensive reagents and large quantities required. The route utilizing concentrated hydrochloric acid and hydrogen peroxide to generate active chlorine species (such as Cl2 and HClO) in situ faces significant safety risks and scale-up challenges due to the violent exothermic reaction and the potential release of toxic gases. All the existing routes have limitations to varying degrees, failing to achieve an effective balance between high yield, high selectivity, operational safety, and production cost. Summary of the Invention

[0004] The purpose of this invention is to provide a green process for synthesizing 3,5-dichloro-4-methoxybenzoic acid that is mild, produces environmentally friendly byproducts, and allows for the recycling of reagents.

[0005] The present invention adopts the following technical solution: A green process for synthesizing 3,5-dichloro-4-methoxybenzoic acid involves firstly, using p-hydroxybenzoic acid as a raw material, etherifying it with dimethyl sulfate to obtain p-methoxybenzoic acid; then, using p-methoxybenzoic acid as a raw material, chlorinating it with 1,3-dichloro-5,5-dimethylhydantoin as a chlorinating agent under the catalysis of p-toluenesulfonic acid monohydrate to obtain the target product 3,5-dichloro-4-methoxybenzoic acid.

[0006] The specific process route is as follows: .

[0007] Furthermore, the specific steps include the following: (1) p-hydroxybenzoic acid is dissolved in water and cooled to 0°C. Sodium hydroxide is added under stirring and reacted. Dimethyl sulfate is added dropwise at room temperature and stirred. Then the mixture is heated to 70~90°C and reacted for 5~6 h. Sodium hydroxide solid is added and the reaction mixture is stirred at 70~90°C for 4~5 h to hydrolyze the generated methyl p-methoxybenzoate to p-methoxybenzoic acid. After cooling to room temperature, hydrochloric acid is added dropwise under stirring to adjust the pH of the reaction system to 2. A large amount of white solid is produced. The mixture is filtered and the filter cake is dried at 50°C for 5 h to obtain p-methoxybenzoic acid. (2) p-Methoxybenzoic acid was dissolved in an organic solvent at room temperature, and then p-toluenesulfonic acid monohydrate and 1,3-dichloro-5,5-dimethylhydantoin were added in sequence. The reaction system was heated to 110°C and refluxed for 26 hours. The reaction solution was cooled to room temperature, water was added to crystallize, the mixture was filtered, and the filter cake was dried at 50°C for 5 hours to obtain 3,5-dichloro-4-methoxybenzoic acid.

[0008] Furthermore, in step (1), the molar ratio of hydroxybenzoic acid to dimethyl sulfate is 1:4.20~5.24.

[0009] Furthermore, in step (2), the organic solvent is acetic acid, ethanol, 1,4-dioxane or trifluoroacetic acid.

[0010] Furthermore, in step (2), the molar ratio of methoxybenzoic acid and 1,3-dichloro-5,5-dimethylhydantoin is 1:1.6~2; the molar ratio of methoxybenzoic acid and p-toluenesulfonic acid monohydrate is 1:0.05~0.3.

[0011] Furthermore, step (2) also includes using the recovered 5,5-dimethylhydantoin as a raw material, reacting it with chlorine to generate 1,3-dichloro-5,5-dimethylhydantoin.

[0012] Furthermore, it also includes step (3): adding sodium hydroxide aqueous solution to the filtrate obtained after crystallization, adjusting the pH of the reaction solution to 11, continuously introducing chlorine gas into the reaction system at 0°C, reacting for 3 hours, stopping the reaction when the pH of the system drops to 7, filtering the mixture, and drying the resulting filter cake at 40°C for 5 hours to obtain 1,3-dichloro-5,5-dimethylhydantoin.

[0013] The beneficial effects of this invention are as follows: This invention uses 1,3-dichloro-5,5-dimethylhydantoin as the chlorination reagent. The reaction conditions are mild, requiring no strong acids or bases, and it does not produce corrosive gases, ensuring safe operation. Its key byproduct, 5,5-dimethylhydantoin, is highly water-soluble, non-toxic, and easily removed by washing with water, simplifying the post-processing. Furthermore, 5,5-dimethylhydantoin can be reconstituted into 1,3-dichloro-5,5-dimethylhydantoin through chlorination, achieving reagent recycling and quantitative consumption of chlorine. This not only improves reaction selectivity but also constructs a low-cost, environmentally friendly material recycling system, possessing significant potential for industrial application. Attached Figure Description

[0014] Figure 1 It is the product p-methoxybenzoic acid from Example 1. 1 H NMR spectrum.

[0015] Figure 2 It is the product 3,5-dichloro-4-methoxybenzoic acid from Example 1. 1 H NMR spectrum.

[0016] Figure 3 It is the product 1,3-dichloro-5,5-dimethylhydantoin from Example 1. 1 H NMR spectrum. Detailed Implementation

[0017] The following embodiments are exemplary descriptions of implementations of the present invention and are not intended to limit its scope. The specific methods described represent some feasible implementations, but the present invention can also be implemented by any other possible processes, methods, or techniques. Example 1

[0018] (1) Preparation of p-methoxybenzoic acid 82.8 g (0.6 mol) of p-hydroxybenzoic acid was added to a 1 L reaction flask and dissolved in 282 mL of water. The mixture was cooled to 0 °C, and 48 g (1.2 mol) of sodium hydroxide was added with stirring. The reaction proceeded for 30 min. Then, 240 mL (2.52 mol) of dimethyl sulfate was added dropwise at room temperature, and the mixture was stirred for 30 min. The mixture was then heated to 90 °C and reacted for 5 h. The pH of the system was monitored using pH paper to ensure the reaction proceeded at a suitable rate. Simultaneously, the conversion of the reactants was tracked using TLC (developing solvent: DCM:MeOH = 10:1) to determine the reaction endpoint. After the p-hydroxybenzoic acid was completely converted, 57.6 g (1.44 mol) of solid sodium hydroxide was added to initiate the hydrolysis of the ester. The reaction mixture was stirred at 90℃ for 4 h to hydrolyze the generated methyl p-methoxybenzoate to sodium p-methoxybenzoate. After cooling to room temperature, 31.9% hydrochloric acid was added dropwise with stirring to adjust the pH of the reaction system to 2, producing a large amount of white solid. This solid was filtered, and the filter cake was dried at 50℃ for 5 h to obtain 84.5 g of the target product, p-methoxybenzoic acid (e.g., ...). Figure 1 (As shown), yield: 92.6%, purity: 99.7%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.62 (br, 1H), 7.89 (d, J =8.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 3.82 (s, 3H).

[0019] (2) Preparation of 3,5-dichloro-4-methoxybenzoic acid In a 500 mL three-necked flask, 40 g (262.90 mmol) of p-methoxybenzoic acid was added and dissolved in 200 mL of acetic acid at room temperature. Then, 5 g (26.29 mmol) of p-toluenesulfonic acid monohydrate and 82.87 g (420.64 mmol) of 1,3-dichloro-5,5-dimethylhydantoin were added sequentially. The reaction system was heated to 110 °C and refluxed for 1 hour. The starting material, p-methoxybenzoic acid, rapidly converted to the intermediate monochloro derivative. After continuing reflux for another 25 hours, the intermediate monochloro derivative gradually and completely converted to the target product, the dichloro derivative (the reaction process was monitored by TLC). n The reaction mixture was cooled to room temperature, and water (1200 mL) was added to induce crystallization. The mixture was filtered, and the filter cake was dried at 50 °C for 5 h to obtain 44.63 g of 3,5-dichloro-4-methoxybenzoic acid, with a yield of 76.8% and a purity of 98.8%. 1H NMR (400 MHz, DMSO- d 6 ) δ 13.53 (br, 1H), 7.93 (s, 2H), 3.89 (s, 3H). (e.g.) Figure 2 As shown.

[0020] (3) Preparation of 1,3-dichloro-5,5-dimethylhydantoin Add a 10% sodium hydroxide aqueous solution (sodium hydroxide, 96.56 g, 2.41 mol) to the filtrate obtained after crystallization to adjust the pH of the reaction solution to 12. Then, continuously purge chlorine gas into the reaction system at 0°C for 4 hours. Monitor the reaction progress by pH, and stop the reaction when the pH drops to 7. Post-process the mixture, filter, and dry the resulting filter cake at 40°C for 5 hours to obtain 69.28 g of white powder solid, which is 1,3-dichloro-5,5-dimethylhydantoin (e.g., ...). Figure 3 As shown in the figure, the yield was 83.6% and the purity was 94.3%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 1.24 (s, 6H). Example 2

[0021] The preparation of 3,5-dichloro-4-methoxybenzoic acid is as follows: (1) Preparation of p-methoxybenzoic acid 41.4 g (0.3 mol) of p-hydroxybenzoic acid was added to a 500 mL reaction flask and dissolved in 141 mL of water. The mixture was cooled to 0 °C, and 24 g (0.6 mol) of sodium hydroxide solid was added with stirring. The reaction proceeded for 30 min. Then, 120 mL (1.26 mol) of dimethyl sulfate was added dropwise at room temperature, and the mixture was stirred for 30 min. The mixture was then heated to 70 °C and reacted for 6 h. The pH of the system was monitored using pH paper during the reaction to ensure that the reaction proceeded at a suitable rate. Simultaneously, the conversion of the reactants was tracked using TLC (developing solvent: DCM:MeOH = 10:1) to determine the reaction endpoint. After the p-hydroxybenzoic acid in the system was completely converted, 28.8 g (0.72 mol) of sodium hydroxide solid was added to initiate the hydrolysis of the ester. The reaction mixture was stirred at 70°C for 5 h to hydrolyze the generated methyl p-methoxybenzoate to sodium p-methoxybenzoate. After cooling to room temperature, 31.9% hydrochloric acid was added dropwise with stirring to adjust the pH of the reaction system to 2, producing a large amount of white solid. The solid was filtered and the filter cake was dried at 50°C for 5 h to obtain 39.4 g of the target product, with a yield of 86.4% and a purity of 98.9%.

[0022] (2) Preparation of 3,5-dichloro-4-methoxybenzoic acid In a 250 mL three-necked flask, 10 g (65.73 mmol) of p-methoxybenzoic acid was added and dissolved in 50 mL of acetic acid at room temperature. Then, 2.50 g (13.15 mmol) of p-toluenesulfonic acid monohydrate and 20.72 g (105.16 mmol) of 1,3-dichloro-5,5-dimethylhydantoin were added sequentially. The reaction system was heated to 110 °C and refluxed for 1 hour. The starting material, p-methoxybenzoic acid, rapidly converted to the intermediate monochloro derivative. After continuing reflux for another 25 hours, the intermediate monochloro derivative gradually and completely converted to the target product, the dichloro derivative (the reaction process was monitored by TLC). n -Heptane∶EtOAc = 3∶1). The reaction solution was cooled to room temperature, and water (300 mL) was added to induce crystallization. The mixture was filtered, and the filter cake was dried at 50 °C for 5 h to obtain 10.58 g, with a yield of 72.8% and a purity of 98.4%.

[0023] (3) Preparation of 1,3-dichloro-5,5-dimethylhydantoin A 10% sodium hydroxide aqueous solution (22.4 g, 560 mmol) was added to the filtrate obtained after crystallization to adjust the pH of the reaction solution to 11. Chlorine gas was then continuously bubbled into the reaction system at 0°C for 3 hours. The reaction was monitored by pH, and stopped when the pH dropped to 7. The mixture was post-treated by filtration, and the resulting filter cake was dried at 40°C for 5 hours to obtain 17.65 g of a white powder solid, namely 1,3-dichloro-5,5-dimethylhydantoin, with a yield of 85.2% and a purity of 92.1%.

[0024] The embodiments described above are merely examples to facilitate a thorough understanding of the present invention and are not intended to limit the scope of protection of the present invention. Any equivalent substitutions or modifications made by those skilled in the art based on the principles of the present invention shall fall within the scope of protection of the present invention.

Claims

1. A green process for synthesizing 3,5-dichloro-4-methoxybenzoic acid, characterized in that, First, p-hydroxybenzoic acid was prepared by etherification with dimethyl sulfate. Then, p-methoxybenzoic acid was used as a raw material and chlorinated with 1,3-dichloro-5,5-dimethylhydantoin as a chlorinating agent under the catalysis of p-toluenesulfonic acid monohydrate to obtain the target product 3,5-dichloro-4-methoxybenzoic acid.

2. The green process for synthesizing 3,5-dichloro-4-methoxybenzoic acid according to claim 1, characterized in that, Specifically, it includes the following steps: (1) p-Hydroxybenzoic acid is dissolved in water and cooled to 0°C. Sodium hydroxide is added under stirring and reacted. Dimethyl sulfate is added dropwise at room temperature and stirred. Then the mixture is heated to 70-90°C and reacted for 5-6 hours. Sodium hydroxide solid is added and the reaction mixture is stirred at 70-90°C for 4-5 hours. The mixture is cooled to room temperature and hydrochloric acid is added dropwise under stirring to adjust the pH of the reaction system to 2. A large amount of white solid is produced. The mixture is filtered and the filter cake is dried to obtain p-methoxybenzoic acid. (2) p-Methoxybenzoic acid was dissolved in an organic solvent at room temperature, and then p-toluenesulfonic acid monohydrate and 1,3-dichloro-5,5-dimethylhydantoin were added in sequence. The reaction system was heated to 100~120℃ and refluxed for 24~27 hours. The reaction solution was cooled to room temperature, water was added for crystallization, filtered, and the filter cake was dried to obtain 3,5-dichloro-4-methoxybenzoic acid.

3. The green process for synthesizing 3,5-dichloro-4-methoxybenzoic acid according to claim 2, characterized in that, In step (1), the molar ratio of hydroxybenzoic acid to dimethyl sulfate is 1:4.20~5.

24.

4. The green process for synthesizing 3,5-dichloro-4-methoxybenzoic acid according to claim 3, characterized in that, In step (2), the organic solvent is acetic acid, ethanol, 1,4-dioxane or trifluoroacetic acid.

5. The green process for synthesizing 3,5-dichloro-4-methoxybenzoic acid according to claim 4, characterized in that, In step (2), the molar ratio of methoxybenzoic acid and 1,3-dichloro-5,5-dimethylhydantoin is 1:1.6~2; the molar ratio of methoxybenzoic acid and p-toluenesulfonic acid monohydrate is 1:0.05~0.

3.

6. The green process for synthesizing 3,5-dichloro-4-methoxybenzoic acid according to claim 1, characterized in that, It also includes the process of using recycled 5,5-dimethylhydantoin as a raw material, reacting it with chlorine to generate 1,3-dichloro-5,5-dimethylhydantoin.

7. The green process for synthesizing 3,5-dichloro-4-methoxybenzoic acid according to claim 2, characterized in that, It also includes step (3): adding sodium hydroxide aqueous solution to the filtrate obtained after crystallization, adjusting the pH of the reaction solution to 11, continuously introducing chlorine gas into the reaction system at 0°C, reacting for 3 hours, stopping the reaction when the pH of the system drops to 7, filtering the mixture, and drying the resulting filter cake to obtain 1,3-dichloro-5,5-dimethylhydantoin.

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