A process for the preparation of mesalazine

Abstract

The application belongs to the technical field of medicine synthesis and specifically relates to a preparation method of mesalamine. In the application, ethylene glycol is used to replace water as a reaction solvent in a substitution reaction, the reaction temperature can be increased to 130-140 DEG C, the reaction time is shortened to 3-4 hours, after the substitution reaction is completed, direct cooling and crystallization are carried out, 5-nitrosalicylate is separated, and the mother liquor can be directly used for the next batch of substitution reaction after adding alkali, so that the ethylene glycol and excess alkali can be reused, no waste water and waste liquid are generated, the production cycle is short, the process is simple, the operation is simple, the "three wastes" are less, and the application is green and environmentally friendly.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing mesalazine. Background Technology

[0002] Mesalazine, chemically named 5-aminosalicylic acid (5-ASA), has the following structural formula: Developed by a Swiss company, it was first launched in the UK in June 1985 for the treatment of mild to moderate ulcerative colitis and maintenance therapy for ulcerative colitis, showing a significant inhibitory effect on intestinal wall inflammation. Mesalazine can inhibit the synthesis of prostaglandins that cause inflammation and the formation of inflammatory mediators such as leukotrienes, thereby significantly inhibiting inflammation of the intestinal mucosa, with even better effects on the connective tissue of inflamed intestinal walls.

[0003] Numerous methods for synthesizing mesalazine have been reported both domestically and internationally, including the salicylic acid nitration-reduction method, the phenylazosalicylic acid reduction method, and the halogenated aromatic hydrocarbon hydrolysis-reduction method. The halogenated aromatic hydrocarbon hydrolysis-reduction method uses o-chlorobenzoic acid as the starting material, which undergoes nitration to produce 5-nitro-o-chlorobenzoic acid. Alternatively, 5-nitro-o-chlorobenzoic acid can be used directly as the starting material, and based on the hydrolysis principle of halogenated hydrocarbons, it is hydrolyzed under alkaline conditions to obtain 5-nitrosalicylic acid, which is then reduced by zinc powder / hydrochloric acid to obtain the final product. The presence of electron-withdrawing groups on the benzene ring, especially the para-nitro group, makes the hydrolysis reaction of 5-nitro-o-chlorobenzoic acid relatively easy and has good selectivity. However, the substitution reaction is time-consuming and requires a large amount of alkali. Post-treatment requires a large amount of inorganic acid for neutralization and crystallization, resulting in repeated acid-base neutralization, wasting a large amount of material and generating large amounts of high-salt wastewater, causing serious pollution.

[0004] Therefore, developing a simple, environmentally friendly, and industrially viable method for preparing mesalazine is of great significance. Summary of the Invention

[0005] This invention overcomes the shortcomings of existing technologies, such as high production costs, high solvent recovery pressure, and cumbersome operation, and provides a simpler, more efficient, economical, practical, green and environmentally friendly method for preparing mesalazine with a short production cycle, significant cost advantages, and suitability for industrial production.

[0006] To achieve the above objectives, the present invention provides the following technical solution: A method for preparing mesalazine, characterized by comprising the following steps: (1) Substitution reaction: 2-chloro-5-nitrobenzoic acid is added to ethylene glycol solvent and base, stirred and heated, and reacted for 3-4 hours. After the reaction is completed, the temperature is lowered to 10-15℃ to crystallize. 5-nitro-salicylate is obtained by filtration. The mother liquor is reserved for the next batch of substitution reaction. (2) Hydrogenation reaction: Add appropriate amount of palladium on carbon and water to the 5-nitro-salicylate obtained in step (1), replace with nitrogen, introduce hydrogen, heat to 80-90℃, control the pressure to 1-2 MPa, react for about 6 hours, filter, cool the filtrate to room temperature, add hydrochloric acid, adjust the pH to 1-2, cool to 10±5℃ for 2 hours to crystallize, filter, dry the filter cake to obtain mesalazine.

[0007] Furthermore, the alkali in step (1) is any one of potassium hydroxide, sodium hydroxide, or lithium hydroxide.

[0008] Furthermore, in step (1), the weight ratio of ethylene glycol to 2-chloro-5-nitrobenzoic acid is 2 to 20:1.

[0009] Furthermore, in step (1), the molar ratio of 2-chloro-5-nitrobenzoic acid to the base is 1:3 to 15.

[0010] Furthermore, in step (1), the reaction temperature is 130–140°C.

[0011] The substitution reaction of this invention uses ethylene glycol instead of water as the reaction solvent, which can raise the reaction temperature to 130-140°C and shorten the reaction time to 3-4 hours, greatly improving production efficiency and making it suitable for industrial production. The mother liquor after the substitution reaction can be reused for the next batch of substitution reaction, realizing the reuse of ethylene glycol and alkali, reducing the amount of alkali used, and saving production costs.

[0012] After the substitution reaction is complete, the solution is directly cooled to crystallize without complex post-processing, yielding 5-nitrosalicylate. The mother liquor can be reused for the next batch of substitution reactions after adding alkali, achieving the reuse of ethylene glycol and excess alkali. No wastewater or waste liquid is generated. The substitution reaction process flow chart shows that the obtained sodium 2-hydroxy-5-nitrobenzoate can be directly fed into the hydrogenation reaction without the need to add sodium carbonate to adjust the pH, reducing material consumption, shortening the production cycle, increasing capacity, simplifying the process, making operation convenient, reducing "three wastes" (waste gas, wastewater, and solid waste), and making solvent recovery easier, making it green and environmentally friendly.

[0013] Comparison of the raw material and auxiliary material usage of the process of this invention with that of a certain company

[0014] As can be seen from the table above, the amount of raw materials such as hydrochloric acid and water used in the preparation of mesalazine using this process is reduced, sodium carbonate is not required to adjust the pH, the waste liquid generated by the substitution reaction and hydrogenation reaction is reduced by about 4 times, and the production time is shortened by about 3 times. Attached Figure Description

[0015] Figure 1 The liquid chromatogram of salazine from Example 1 is shown below. Figure 2The liquid chromatogram of salazine from Example 4 is shown below. Figure 3 It is a substitution reaction using a flowchart. Detailed Implementation

[0016] The present invention is further illustrated by the following examples, but these are not intended to limit the invention. Example 1

[0017] 1. Substitution reaction Add 300g of 2-chloro-5-nitrobenzoic acid, 750g of ethylene glycol, and 298g of sodium hydroxide to a three-necked flask. After the addition is complete, stir and heat to 130-140℃ and react for 3-4 hours. Take a sample for testing. After the reaction is complete, cool to 10-15℃ to precipitate crystals. Filter to obtain sodium 5-nitro-salicylate. The mother liquor can be reused for the next batch of substitution reaction.

[0018] 2. Hydrogenation reaction The total amount of the above-mentioned sodium 5-nitro-salicylate was added to a 2L hydrogenation reactor, along with 1g of palladium on carbon and 1500g of water. The reactor was purged with nitrogen three times, and hydrogen was introduced. The temperature was raised to 80-90℃, and the pressure was controlled at 1-2 MPa. The reaction was carried out for about 6 hours. Samples were taken for testing. After the reaction was completed, the reactor was filtered, cooled to room temperature, and hydrochloric acid was added to adjust the pH to 1-2. The reactor was then cooled to 10±5℃ to crystallize for 2 hours, filtered, and dried. 210g of mesalazine was obtained, with a yield of 92% and a purity of 99.98%.

[0019] Synthesis route: Example 2

[0020] 1. Substitution reaction Add 300g of 2-chloro-5-nitrobenzoic acid, 900g of ethylene glycol, and 416.7g of potassium hydroxide to a three-necked flask. After the addition is complete, stir and heat to 130-140℃ and react for 3-4 hours. Take a sample for testing. After the reaction is complete, cool to 10-15℃ to precipitate crystals. Filter to obtain potassium 5-nitro-salicylate. The mother liquor can be reused for the next batch of substitution reaction.

[0021] 2. Hydrogenation reaction The above-mentioned potassium 5-nitro-salicylate was added to a 2L hydrogenation reactor, along with 1g palladium on carbon and 1500g water. The reactor was purged with nitrogen three times, and hydrogen was introduced. The temperature was raised to 80-90℃, and the pressure was controlled at 1-2 MPa. The reaction was carried out for about 6 hours. Samples were taken for testing. After the reaction was completed, the reactor was filtered, cooled to room temperature, and hydrochloric acid was added to adjust the pH to 1-2. The reactor was then cooled to 10±5℃ to crystallize for 2 hours. After filtration and drying, 206g of mesalazine was obtained, with a yield of 90% and a purity of 99.91%. Example 3

[0022] 1. Substitution reaction Add 300g of 2-chloro-5-nitrobenzoic acid, 1500g of ethylene glycol, and 240g of sodium hydroxide to a three-necked flask. After the addition is complete, stir and heat to 130-140℃ and react for 3-4 hours. Take a sample for testing. After the reaction is complete, cool to 10-15℃ to precipitate crystals. Filter to obtain sodium 5-nitro-salicylate. The mother liquor can be reused for the next batch of substitution reaction.

[0023] 2. Hydrogenation reaction The total amount of the above-mentioned sodium 5-nitro-salicylate was added to a 2L hydrogenation reactor, along with 1g of palladium on carbon and 1500g of water. The reactor was purged with nitrogen three times, and hydrogen was introduced. The temperature was raised to 80-90℃, and the pressure was controlled at 1-2 MPa. The reaction was carried out for about 6 hours. Samples were taken for testing. After the reaction was completed, the reactor was filtered, cooled to room temperature, and hydrochloric acid was added to adjust the pH to 1-2. The reactor was then cooled to 10±5℃ to crystallize for 2 hours, filtered, and dried. 204g of metharazin was obtained, with a yield of 89% and a purity of 99.90%. Example 4

[0024] 1. Substitution reaction Take the mother liquor obtained from the substitution reaction in Example 1, add 179g of sodium hydroxide and 300g of 2-chloro-5-nitrobenzoic acid, stir and heat to 130-140°C, react for 3-4 hours, take a sample for testing, after the reaction is complete, cool to 10-15°C to precipitate crystals, filter to obtain sodium 5-nitro-salicylate, and use the mother liquor for the next batch of substitution reaction.

[0025] 2. Hydrogenation reaction The total amount of the above-mentioned sodium 5-nitro-salicylate was added to a 2L hydrogenation reactor, along with 1g of palladium on carbon and 1500g of water. The reactor was purged with nitrogen three times, and hydrogen was introduced. The temperature was raised to 80-90℃, and the pressure was controlled at 1-2 MPa. The reaction was carried out for about 6 hours. Samples were taken for testing. After the reaction was completed, the reactor was filtered, cooled to room temperature, and hydrochloric acid was added to adjust the pH to 1-2. The reactor was then cooled to 10±5℃ to crystallize for 2 hours, filtered, and dried. 207.5g of demesalazine was obtained, with a yield of 91% and a purity of 99.98%.

[0026] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing mesalazine, characterized in that... Includes the following steps: (1) Substitution reaction: 2-chloro-5-nitrobenzoic acid is added to ethylene glycol solvent and base, stirred and heated, and reacted for 3-4 hours. After the reaction is completed, the temperature is lowered to 10-15℃ to crystallize. 5-nitro-salicylate is obtained by filtration. The mother liquor is reserved for the next batch of substitution reaction. (2) Hydrogenation reaction: Add appropriate amount of palladium on carbon and water to the 5-nitro-salicylate obtained in step (1), replace with nitrogen, introduce hydrogen, heat to 80-90℃, control the pressure to 1-2 MPa, react for 5-7 hours, filter, cool the filtrate to room temperature, add hydrochloric acid, adjust the pH to 1-2, cool to 10±5℃ for 1-3 hours to crystallize, filter, dry the filter cake to obtain mesalazine.

2. The method according to claim 1, characterized in that, The alkali used in step (1) is any one of potassium hydroxide, sodium hydroxide, or lithium hydroxide.

3. The method according to claim 2, characterized in that, In step (1), the weight ratio of ethylene glycol to 2-chloro-5-nitrobenzoic acid is 2 to 20:

1.

4. The method according to claim 3, characterized in that, In step (1), the molar ratio of 2-chloro-5-nitrobenzoic acid to the base is 1:3 to 15.

5. The method according to claim 4, characterized in that, In step (1), the reaction temperature is 130-140℃.

Images