Method for synthesizing celecoxib by one-pot aqueous phase method

Abstract

The invention provides a method for synthesizing celecoxib by a one-pot aqueous phase method. The preparation method comprises the following steps: firstly, directly reacting p-methylacetophenone and ethyl trifluoroacetate in one pot under the action of N, N-dimethyl butylamine to obtain a beta-diketone intermediate; in the other pot, p-chlorobenzenesulfonamide and hydrazine hydrate are used as raw materials, a p-hydrazinobenzenesulfonamide solution is generated under the action of N, N-dimethyl butylamine, and the operation is carried out in the two pots at the same time; and finally, adding the p-hydrazinobenzenesulfonamide solution into the beta-diketone intermediate material liquid, combining in two pots, adjusting the acid, heating for reaction, and cooling for crystallization to obtain celecoxib. According to the method disclosed by the invention, the p-hydrazinobenzenesulfonamide aqueous solution is creatively used for participating in the synthesis reaction of the celecoxib, and solid p-hydrazinobenzenesulfonamide hydrochloride does not need to be independently used for participating in the reaction, so that the use of a large amount of acid and the generation of high-temperature acid waste liquid during the production of the p-hydrazinobenzenesulfonamide hydrochloride are avoided. The method does not need any post-treatment operation and high-temperature salt forming link, and is more suitable for industrial production.

Description

Technical Field

[0001] This invention relates to a method for preparing celecoxib, belonging to the field of pharmaceutical chemical synthesis technology. Background Technology

[0002] Celecoxib, chemically known as 4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide, is a novel nonsteroidal anti-inflammatory drug (NSAID). It inhibits the production of prostaglandin E2 by specifically inhibiting cyclooxygenase-2 (COX-2), thus exhibiting anti-inflammatory and analgesic effects. Therefore, celecoxib can be used to treat diseases such as arthritis and rheumatoid arthritis. Due to its good therapeutic effect and lack of serious gastrointestinal side effects, celecoxib is widely used clinically.

[0003] After years of research, several synthetic methods for celecoxib have been developed. CN 108558759 B, CN102746231 A, CN 102863386 B, CN 103570622 B, and CN 103724268 B mention the Claisen condensation of p-methylacetophenone and ethyl trifluoroacetate under the action of a base to obtain a β-diketone intermediate, which is then condensed and cyclized with p-hydrazinobenzenesulfonamide hydrochloride to obtain celecoxib.

[0004]

[0005] CN 109232422 B mentions that p-hydrazinobenzenesulfonamide hydrochloride first reacts with trifluoroacetaldehyde, then 1-(1-bromovinyl)-4-toluene is added and reacted with a base to obtain celecoxib. Regardless of the reaction method used in the above patents, a key material is used: p-hydrazinobenzenesulfonamide hydrochloride. This substance is not only a key intermediate for celecoxib but is also widely used in dyes and agricultural products. CN 114195714 A mentions using trifluoroacetoacetate and toluene as starting materials to circumvent the use of p-hydrazinobenzenesulfonamide hydrochloride. First, under aluminum trichloride catalysis, trifluoroacetoacetate is synthesized into compound I via a Friedel-Crafts reaction. Compound I reacts with p-halobenzenesulfonamide in the presence of hydrazine hydrate under alkaline conditions to obtain celecoxib. However, trifluoroacetoacetate is expensive, which is not conducive to industrial production. Furthermore, the reaction requires a large amount of anhydrous aluminum trichloride, and an anhydrous environment must be maintained during production; otherwise, the process risks increase. Therefore, this method is also not conducive to industrial production. The structural formula of compound I is shown below.

[0006]

[0007] p-Aminosulfonylphenylhydrazine hydrochloride is generally purchased as a raw material, which inevitably leads to high production costs for celecoxib. Therefore, the synthesis of p-aminosulfonylphenylhydrazine hydrochloride is being extended. Both CN 117105825 A and CN107573266 A mention using p-aminobenzenesulfonamide as a raw material. First, it reacts with sodium nitrite under acidic conditions to generate a diazonium salt. Then, after reduction, acidification, and crystallization, p-hydrazinebenzenesulfonamide hydrochloride is obtained. Because the diazonium solution is unstable and easily decomposes, the next reaction needs to be carried out rapidly to avoid the decomposition of the diazonium salt. Therefore, the above patents all use microchannel reactors to achieve this function. This method is difficult to operate, requires complex equipment, and places high demands on personnel and workshop conditions. Furthermore, the final salt formation requires high temperatures, generating a large amount of hydrochloric acid gas that severely corrodes equipment and pipelines, and the resulting acidic wastewater is difficult to treat. CN110256304 B mentions the reaction of p-chlorobenzenesulfonamide with hydrazine hydrate at 125°C and 0.8-1.2 MPa to prepare p-hydrazinobenzenesulfonamide, followed by acidification to form a salt for the final product. While this method avoids diazotization, the high temperature and pressure undoubtedly increase production risks, and the poor water solubility of p-chlorobenzenesulfonamide inhibits the reaction. Therefore, the above methods are highly unfavorable for industrial production. There is an urgent need to find a suitable method that can synthesize p-hydrazinobenzenesulfonamide hydrochloride while avoiding the use of excess acid, and can also efficiently and safely synthesize celecoxib. Summary of the Invention

[0008] To address the aforementioned problems, this invention provides a one-pot aqueous phase method for synthesizing celecoxib. First, in one pot, p-methylacetophenone and ethyl trifluoroacetate are reacted directly in the presence of N,N-dimethylbutylamine to obtain a β-diketone intermediate; the feed solution requires no further treatment and can proceed directly to the next reaction. In another pot, p-chlorobenzenesulfonamide and hydrazine hydrate are reacted in the presence of N,N-dimethylbutylamine to generate a p-hydrazinobenzenesulfonamide solution; both pots react simultaneously. Finally, the p-hydrazinobenzenesulfonamide solution is added to the β-diketone intermediate feed solution, and the two pots are combined. After acidification, the temperature is raised, and the reaction is followed by cooling and crystallization to obtain celecoxib. This method eliminates the need for any post-treatment operations and high-temperature salt formation, making it more suitable for industrial production.

[0009] The technical solution of this invention is: a method for synthesizing celecoxib using a one-pot aqueous phase method, characterized by comprising the following steps (see...). Figure 1 ): 1) Synthesis of p-hydrazinobenzenesulfonamide: Using p-chlorobenzenesulfonamide as the starting material, add hydrazine hydrate aqueous solution and N,N-dimethylbutylamine, heat to 50~70℃ and react for 3~5h to obtain p-hydrazinobenzenesulfonamide aqueous solution, keep warm for later use; 2) Preparation of intermediate 4,4,4-trifluoro-1-(4-methylphenyl)-1,3-butanedione: Take ethyl trifluoroacetate and N,N-dimethylbutanediamine methanol solution and stir for 5-10 min, then add p-methylacetophenone, heat to 50-70℃ and react for 2-4 h, and keep warm for later use after the reaction is completed; 3) Preparation of celecoxib: Add the solution from step 1) to the solution from step 2), stir and mix evenly, add hydrochloric acid to adjust the pH of the system to 2~4, heat to 60~70℃ and react for 4~6h; after the reaction is complete, cool down to crystallize, filter, and obtain celecoxib.

[0010] Preferably, the concentration of the hydrazine hydrate aqueous solution in step 1) is 75-85%.

[0011] Preferably, the hydrochloric acid in step 3) is concentrated hydrochloric acid or 10% hydrochloric acid, with 10% hydrochloric acid being preferred.

[0012] Preferably, the crystallization temperature in step 3) is 0~10℃.

[0013] Preferably, in step 1), the molar ratio of p-chlorobenzenesulfonamide and N,N-dimethylbutylamine is 10:0.8~1.2.

[0014] Preferably, in step 2), N,N-dimethylbutylamine participates in the reaction as a base, and the molar ratio of p-methylacetophenone to N,N-dimethylbutylamine and ethyl trifluoroacetate is 3:3.8~4.2:3.8~4.2.

[0015] The beneficial effects of this invention are: 1. Avoid high-temperature salt formation to ensure green and safe production. This invention creatively uses an aqueous solution of p-hydrazinebenzenesulfonamide in the synthesis reaction of celecoxib, eliminating the need for separate solid p-hydrazinebenzenesulfonamide hydrochloride as a feedstock. This greatly avoids the use of large amounts of acid and the generation of high-temperature acidic waste liquid during the production of p-hydrazinebenzenesulfonamide hydrochloride, while also avoiding the harm to personnel and equipment caused by acid gas generated during high-temperature salt formation.

[0016] 2. Replaces hazardous processes, simplifying and streamlining production. p-Hydrazinesulfonamide was prepared from p-chlorobenzenesulfonamide and hydrazine hydrate under normal pressure and low temperature, effectively avoiding high temperature and high pressure conditions. The reaction can proceed smoothly under normal pressure, greatly reducing the requirements for production equipment and production safety risks. At the same time, this method avoids the formation of diazonium salts, reducing the process risks caused by the explosiveness of diazonium liquid and the process instability caused by the easy decomposition of diazonium liquid, greatly reducing the process production risks and difficulties.

[0017] 3. Simplify process operations and improve production efficiency. The β-diketone intermediate and the p-hydrazinobenzenesulfonamide intermediate undergo simultaneous reactions under almost identical conditions, allowing for direct mixing of the reactants and subsequent reactions after the first reaction. Furthermore, the system incorporates the required ratio of good solvent (methanol) and poor solvent (water) for celecoxib crystallization during the initial feed, enabling direct cooling and crystallization after the reaction without the need for additional reagents or opening the container. This significantly simplifies the process, improves production efficiency, and enhances production safety and convenience.

[0018] 4. Each material is specialized and versatile, ensuring safe and accurate material preparation. This invention creatively proposes a concept involving the participation of materials in a multi-step reaction, introducing N,N-dimethylbutylamine to simultaneously participate in a two-pot reaction. Firstly, it acts as a base in the synthesis of the β-diketone intermediate; secondly, it acts as an auxiliary agent in the synthesis of p-hydrazinobenzenesulfonamide. The protonation ability of the nitrogen atom is utilized as an acid-binding agent to promote the formation of p-hydrazinobenzenesulfonamide. Furthermore, the protonated N,N-dimethylbutylamine acts as a cationic surfactant to enhance the solubility of p-chlorobenzenesulfonamide in water, further promoting the reaction. This method significantly improves the utilization rate of materials, increases production efficiency, and reduces preparation pressure and risk, making it highly beneficial for industrial production.

[0019] In summary, the method described in this invention is simple, safe, produces no overly acidic hazardous waste, is environmentally friendly, and has low production costs. Therefore, the method of this invention is very suitable for large-scale industrial production. Attached Figure Description

[0020] Figure 1 This is a schematic diagram of the process flow of the present invention; Figure 2 This is an HPLC chromatogram of celecoxib prepared in Example 1. Detailed Implementation

[0021] The technical solution of the present invention will be further described below with reference to the embodiments, but the scope of protection of the present invention is not limited thereto.

[0022] Example 1 1) Preparation of intermediate 4,4,4-trifluoro-1-(4-methylphenyl)-1,3-butanedione Add 56.83 g (0.4 mol) of ethyl trifluoroacetate and 98 ml (0.4 mol) of N,N-dimethylbutylamine in methanol to a 500 ml three-necked flask. Start stirring at room temperature and stir for 20 min. Then add 40.25 g (0.3 mol) of p-methylacetophenone dropwise to the system. After the addition is complete, heat to 60-70 °C and react for 3 h to obtain the product solution.

[0023] 2) Preparation of p-hydrazinobenzenesulfonamide Add 57.49 g (0.3 mol) of p-chlorobenzenesulfonamide to a 250 ml three-necked flask, start stirring, add 187.5 g (3 mol) of 80% hydrazine hydrate aqueous solution, add 3.1 g (0.03 mol) of N,N-dimethylbutylamine, and after the addition is complete, heat the system to 60 °C and maintain the temperature for 3 h. After the reaction is complete, p-hydrazinebenzenesulfonamide solution is obtained.

[0024] 3) Preparation of crude celecoxib Add the solution obtained in step 2) to the solution obtained in step 1), and add 10% hydrochloric acid to adjust the pH of the solution to 3-4. Heat the solution to 70-80℃ and maintain the temperature for 3.5 hours. After the reaction is complete, cool to 5℃ and maintain the temperature for crystallization for 2.5 hours. Filter to obtain 106.63 g of crude celecoxib with a purity of 99.65% (see [link to product description]). Figure 2 ).

[0025] Comparative Example 1: 1) Preparation of intermediate 4,4,4-trifluoro-1-(4-methylphenyl)-1,3-butanedione Add 56.83 g (0.4 mol) of ethyl trifluoroacetate and 98 ml (0.4 mol) of N,N-dimethylbutylamine in methanol to a 500 ml three-necked flask. Start stirring at room temperature and stir for 20 min. Then add 40.25 g (0.3 mol) of p-methylacetophenone dropwise to the system. After the addition is complete, heat to 60-70 °C and react for 3 h to obtain the product solution.

[0026] 2) Preparation of crude celecoxib 67.11 g (0.3 mol) of p-hydrazinobenzenesulfonamide hydrochloride was added to the reaction solution in step 1), and 10% hydrochloric acid was added to adjust the pH of the solution to 3-4. The solution was heated to 70-80℃ and kept at this temperature for 3.5 h. After the reaction was completed, the temperature was lowered to 5℃ and kept at this temperature for 2.5 h to allow crystallization. The product was then filtered to obtain 42.44 g of crude celecoxib with a purity of 87.31%.

[0027] Comparative Example 1 used p-hydrazinobenzenesulfonamide hydrochloride as raw material, without adding water before crystallization, resulting in low yield and purity.

[0028] Comparative Example 2 1) Preparation of intermediate 4,4,4-trifluoro-1-(4-methylphenyl)-1,3-butanedione Add 56.83 g (0.4 mol) of ethyl trifluoroacetate and 98 ml (0.4 mol) of N,N-dimethylbutylamine in methanol to a 500 ml three-necked flask. Start stirring at room temperature and stir for 20 min. Then add 40.25 g (0.3 mol) of p-methylacetophenone dropwise to the system. After the addition is complete, heat to 60-70 °C and react for 3 h to obtain the product solution.

[0029] 2) Preparation of crude celecoxib 67.11 g (0.3 mol) of p-hydrazinobenzenesulfonamide hydrochloride was added to the reaction solution in step 1), and 10% hydrochloric acid was added to adjust the pH of the solution to 3-4. The solution was heated to 70-80℃ and reacted for 3.5 h. After the reaction was completed, 50 ml of water was added, the temperature was lowered to 5℃, and crystallization was carried out for 2.5 h. The product was filtered to obtain 103.99 g of crude celecoxib with a purity of 99.37%.

[0030] Comparative Example 2 used p-hydrazinebenzenesulfonamide hydrochloride as raw material. Water was added before crystallization, resulting in high yield and purity, but a large amount of high-temperature acidic aqueous solution was generated.

[0031] Comparative Example 3 1) Preparation of intermediate 4,4,4-trifluoro-1-(4-methylphenyl)-1,3-butanedione Add 56.83 g (0.4 mol) of ethyl trifluoroacetate and 98 ml (0.4 mol) of N,N-dimethylbutylamine in methanol to a 500 ml three-necked flask. Start stirring at room temperature and stir for 20 min. Then add 40.25 g (0.3 mol) of p-methylacetophenone dropwise to the system. After the addition is complete, heat to 60-70 °C and react for 3 h to obtain the product solution.

[0032] 2) Preparation of p-hydrazinobenzenesulfonamide Add 57.49 g (0.3 mol) of p-chlorobenzenesulfonamide to a 250 ml three-necked flask, start stirring, and add 187.5 g (3 mol) of 80% hydrazine hydrate aqueous solution. After the addition is complete, heat the system to 60 °C and maintain this temperature for 3 h. After the reaction is complete, a p-hydrazinebenzenesulfonamide solution is obtained.

[0033] 3) Preparation of crude celecoxib Add the solution obtained in step 2) to the solution obtained in step 1), and adjust the pH of the solution to 3-4 with 10% hydrochloric acid. Heat the solution to 70-80℃ and maintain the temperature for 3.5 hours. After the reaction is complete, cool the solution to 5℃ and maintain the temperature for 2.5 hours to allow crystallization. Filter the solution to obtain 37.98g of crude celecoxib with a purity of 93.21%. In step 2) of Comparative Example 3, N,N-dimethylbutylamine was not used, resulting in lower yield and purity.

[0034] Comparative Example 4 1) Preparation of intermediate 4,4,4-trifluoro-1-(4-methylphenyl)-1,3-butanedione Add 56.83 g (0.4 mol) of ethyl trifluoroacetate and 98 ml (0.4 mol) of N,N-dimethylbutylamine in methanol to a 500 ml three-necked flask. Start stirring at room temperature and stir for 20 min. Then add 40.25 g (0.3 mol) of p-methylacetophenone dropwise to the system. After the addition is complete, heat to 60-70 °C and react for 3 h to obtain the product solution.

[0035] 2) Preparation of p-hydrazinobenzenesulfonamide Add 57.49 g (0.3 mol) of p-chlorobenzenesulfonamide to a 250 ml three-necked flask, start stirring, add 187.5 g (3 mol) of 80% hydrazine hydrate aqueous solution, and add 3.03 g (0.03 mol) of triethylamine. After the addition is complete, heat the system to 60 °C and maintain this temperature for 3 h. After the reaction is complete, a p-hydrazinebenzenesulfonamide solution is obtained.

[0036] 3) Preparation of crude celecoxib Add the solution obtained in step 2) to the solution obtained in step 1), and adjust the pH of the solution to 3-4 with 10% hydrochloric acid. Heat the solution to 70-80℃ and maintain the temperature for 3.5 hours. After the reaction is complete, cool the solution to 5℃ and maintain the temperature for 2.5 hours to allow crystallization. Filter the solution to obtain 66.12 g of crude celecoxib with a purity of 94.42%. In step 2) of Comparative Example 4, N,N-dimethylbutylamine was not used; instead, triethylamine was used. The yield and purity were still relatively low, but slightly higher than those of Comparative Example 4.

[0037] Comparative Example 5 1) Preparation of intermediate 4,4,4-trifluoro-1-(4-methylphenyl)-1,3-butanedione Add 56.83 g (0.4 mol) of ethyl trifluoroacetate and 98 ml (0.4 mol) of N,N-dimethylbutylamine in methanol to a 500 ml three-necked flask. Start stirring at room temperature and stir for 20 min. Then add 40.25 g (0.3 mol) of p-methylacetophenone dropwise to the system. After the addition is complete, heat to 60-70 °C and react for 3 h to obtain the product solution.

[0038] 2) Preparation of p-hydrazinobenzenesulfonamide Add 57.49 g (0.3 mol) of p-chlorobenzenesulfonamide to a 250 ml three-necked flask, start stirring, add 187.5 g (3 mol) of 80% hydrazine hydrate aqueous solution, then add 3.03 g (0.03 mol) of triethylamine and 2.14 g (0.005 mol) of TWEEN-80. After the addition is complete, heat the system to 60 °C and maintain this temperature for 3 h. After the reaction is complete, a p-hydrazinebenzenesulfonamide solution is obtained.

[0039] 3) Preparation of crude celecoxib Add the solution obtained in step 2) to the solution obtained in step 1), and add 10% hydrochloric acid to adjust the pH of the solution to 3-4. Heat the solution to 70-80℃ and maintain the temperature for 3.5 hours. After the reaction is complete, cool to 5℃ and maintain the temperature for 2.5 hours to allow crystals to precipitate. Filter to obtain 96.21 g of crude celecoxib with a purity of 98.76%. In step 2) of Comparative Example 5, N,N-dimethylbutylamine was not used; instead, triethylamine and TWEEN-80 were used, resulting in higher yields and purity, but still lower than in Example 1.

[0040] Comparative Example 6 1) Preparation of intermediate 4,4,4-trifluoro-1-(4-methylphenyl)-1,3-butanedione Add 56.83g (0.4mol) of ethyl trifluoroacetate and 72ml (0.4mol) of sodium methoxide methanol solution to a 500ml three-necked flask. Start stirring at room temperature. After stirring for 20min, add 40.25g (0.3mol) of p-methylacetophenone dropwise to the system. After the addition is complete, raise the temperature to 60-70℃ and react for 3h to obtain the product solution.

[0041] 2) Preparation of p-hydrazinobenzenesulfonamide Add 57.49 g (0.3 mol) of p-chlorobenzenesulfonamide to a 250 ml three-necked flask, start stirring, add 187.5 g (3 mol) of 80% hydrazine hydrate aqueous solution, add 3.1 g (0.03 mol) of N,N-dimethylbutylamine, and after the addition is complete, heat the system to 60 °C and maintain the temperature for 3 h. After the reaction is complete, p-hydrazinebenzenesulfonamide solution is obtained.

[0042] 3) Preparation of crude celecoxib Add the solution obtained in step 2) to the solution obtained in step 1), and add 10% hydrochloric acid to adjust the pH of the solution to 3-4. Heat the solution to 70-80℃ and keep it at that temperature for 3.5 hours. After the reaction is complete, cool it to 5℃ and keep it at that temperature for 2.5 hours to allow crystals to precipitate. Filter the solution to obtain 106.17g of crude celecoxib with a purity of 99.56%.

[0043] In Comparative Example 6, step 1) does not use N,N-dimethylbutylamine but uses sodium methoxide, resulting in higher yield and purity. However, in Example 1 of this invention, both steps use the same alkali, which is more advantageous for actual production.

Claims

1. A method for synthesizing celecoxib using a one-pot aqueous phase process, characterized in that... Includes the following steps: 1) Synthesis of p-hydrazinobenzenesulfonamide: Using p-chlorobenzenesulfonamide as the starting material, add hydrazine hydrate aqueous solution and N,N-dimethylbutylamine, heat to 50~70℃ and react for 3~5h to obtain p-hydrazinobenzenesulfonamide aqueous solution, keep warm for later use; 2) Preparation of intermediate 4,4,4-trifluoro-1-(4-methylphenyl)-1,3-butanedione: Mix ethyl trifluoroacetate and N,N-dimethylbutylamine in methanol, then add p-methylacetophenone, heat to 50~70℃ and react for 2~4 h, and keep warm after the reaction is completed. 3) Preparation of celecoxib: Add the solution from step 1) to the solution from step 2), stir and mix evenly, add hydrochloric acid to adjust the pH of the system to 2~4, heat to 60~70℃ and react for 4~6h; after the reaction is complete, cool down to crystallize, filter, and obtain celecoxib.

2. The method for synthesizing celecoxib using a one-pot aqueous phase method as described in claim 1, characterized in that, The concentration of the hydrazine hydrate aqueous solution in step 1) is 75-85%.

3. The method for synthesizing celecoxib using a one-pot aqueous phase method as described in claim 1, characterized in that, In step 3), the hydrochloric acid is concentrated hydrochloric acid or 10% hydrochloric acid.

4. The method for synthesizing celecoxib using a one-pot aqueous phase method as described in claim 1, characterized in that, The crystallization temperature in step 3) is 0~10℃.

5. The method for synthesizing celecoxib using a one-pot aqueous phase method as described in claim 1, characterized in that, In step 1), the molar ratio of p-chlorobenzenesulfonamide and N,N-dimethylbutylamine is 10:0.8~1.

2.

6. The method for synthesizing celecoxib using a one-pot aqueous phase method as described in any one of claims 1-5, characterized in that, In step 2), N,N-dimethylbutylamine participates in the reaction as a base, and the molar ratio of p-methylacetophenone to N,N-dimethylbutylamine and ethyl trifluoroacetate is 3:3.8~4.2:3.8~4.2.

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