Preparation method of mesalazine intermediate
By using 2-chlorobenzoic acid as the starting material in mesalazine synthesis, nitration reaction and hydrolysis, the purity and impurity control of the mesalazine intermediate 5-nitrosalicylic acid were successfully improved, and the problem of difficult to balance synthesis efficiency, economy and environmental protection in the prior art was solved, and an efficient, economical and environmentally friendly synthesis process was achieved.
Patent Information
- Application Number
- CN202311453090.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-11-03
- Publication Date
- 2025-05-06
AI Technical Summary
The existing mesalazine synthesis methods are difficult to achieve balance in terms of synthesis efficiency, economy, environmental protection and impurity control, poor selectivity of nitration reaction, low product yield, difficulty in separation and purification of intermediates, and problems such as safety risks and high equipment requirements.
2-chlorobenzoic acid is used as the starting material and nitration reaction is carried out under suitable conditions to obtain 2-chloro5-nitrobenzoic acid, and then hydrolyzed in an alkaline aqueous solution to obtain the synthetic intermediate 5-nitrosalicylic acid of mesalazine. By controlling the reaction conditions and process flow, the high purity and low impurity content of the intermediate are ensured.
The high-purity production of mesalazine intermediate 5-nitrosalicylic acid was achieved, with impurity content controlled below 5%, and other impurity content less than 0.5%, with mild process conditions, cheap and easy to obtain using raw materials, and no dangerous and highly toxic reaction conditions were involved.
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Abstract
Description
Technical Field
[0001] The invention relates to the field of drug synthesis, and in particular to a method for preparing a mesalazine intermediate. Background Art
[0002] Mesalazine is a molecule with a salicylic acid derivative structure, and its structure is 5-aminosalicylic acid. It has a significant inhibitory effect on inflammation of the intestinal wall and is currently mainly used to treat ulcerative colitis.
[0003] Many methods for synthesizing mesalazine have been reported in the prior art, but these methods have various shortcomings. A common method is to use salicylic acid as a raw material, synthesize 5-nitrosalicylic acid through a nitration reaction, and then reduce it to obtain 5-aminosalicylic acid. This nitration reaction has poor selectivity, easily generates 3-substituted impurities, has a low product yield, and is difficult to separate and purify the intermediate.
[0004] Another synthetic route uses aniline as the raw material, which is diazotized to form a diazonium salt, which is then coupled with salicylic acid and reduced to obtain mesalazine. Although this route has fewer by-products, the reaction route is longer and requires the use of unstable diazonium compounds, which poses certain safety risks.
[0005] There are also reports on the synthesis of mesalazine using the Kolber-Schmidt reaction. This method uses sodium p-aminophenol as the starting material and reacts with carbon dioxide under high temperature and high pressure to directly produce mesalazine. This method has a short process route, good reaction selectivity, and high total yield, but the reaction conditions are harsh and the production equipment requirements are high.
[0006] In addition to the above-mentioned relatively mature process routes, there are also reports on the use of metal catalysis to synthesize mesalazine, such as a process in which 5-halogenated-2-hydroxybenzoic acid is used as the starting material and copper salt is used as a catalyst to react with ammonia water at a certain temperature to generate mesalazine. However, this type of method will cause the problem of metal residues in the product, which will cause certain difficulties in quality control, and the use of ammonia water in the production process will also increase the cost of wastewater treatment and air pollution. Summary of the invention
[0007] As can be seen from the above, there are still some problems about the mesalazine synthesis method at present, and it is difficult to achieve a good balance in terms of synthesis efficiency, economy, environmental protection and impurity control. Therefore, the present invention proposes a process for the synthesis of mesalazine, using 2-chlorobenzoic acid as a starting material, nitration reaction occurs under suitable conditions, 2-chloro-5-nitrobenzoic acid is obtained with higher selectivity, and then hydrolyzed in an alkaline aqueous solution to obtain the synthetic intermediate 5-nitrosalicylic acid of mesalazine. The content of 3-isomer impurities in the intermediate 5-nitrosalicylic acid product is controlled to be less than 5%, and the total content of other impurities is less than 0.5%. This process condition is mild, and the raw materials used are cheap and easy to obtain, and do not involve dangerous and highly toxic reaction conditions. Specifically include the following process:
[0008] (1) dissolving o-chlorobenzoic acid in concentrated sulfuric acid as a solvent, controlling the temperature at 0-10°C, slowly adding a mixture of concentrated nitric acid and concentrated sulfuric acid, and maintaining the temperature at 0-10°C for reaction; the mass ratio of concentrated nitric acid to concentrated sulfuric acid in the mixture is 1:3; (2) After the reaction is completed, the reaction solution is added dropwise into ice water, naturally returned to room temperature, and filtered to obtain a crude product of 2-chloro-5-nitrobenzoic acid; (3) Dissolve the crude 2-chloro-5-nitrobenzoic acid in 30% sodium hydroxide solution, heat to 80°C for reaction, add hydrochloric acid to adjust the pH to 2 after the reaction is completed, cool naturally to room temperature for crystallization, filter to obtain 5-nitrosalicylic acid, and dry in a vacuum oven.
[0009] Furthermore, the mass ratio of o-chlorobenzoic acid to the solvent concentrated sulfuric acid is 1:6-1:8, and the mass ratio of o-chlorobenzoic acid to the mixed solution of concentrated nitric acid and concentrated sulfuric acid is 1:4.
[0010] Furthermore, the ratio of the mass grams of 2-chloro-5-nitrobenzoic acid to the volume milliliters of the sodium hydroxide solution is 1:3-1:5.
[0011] Beneficial effects: Compared with the prior art, this scheme has the advantages of mild reaction conditions and high product purity. The content of 5-nitrosalicylic acid, the intermediate of mesalazine, reaches more than 95%, the content of 3-isomer impurities is controlled below 5%, and other impurities are all below 0.5%. Implementation Example 1
[0012] Dissolve 10g of o-chlorobenzoic acid in 60g of concentrated sulfuric acid, control the temperature at 10℃, slowly drop a mixture of 10g of concentrated nitric acid and 30g of concentrated sulfuric acid, keep the reaction at 10℃, add the reaction solution dropwise to ice water after the reaction is completed, naturally warm up to room temperature, and filter to obtain 12.2g of crude 2-chloro-5-nitrobenzoic acid. Dissolve the obtained crude 2-chloro-5-nitrobenzoic acid in 40 ml of 30% sodium hydroxide solution, heat to 80℃ and heat to react. After the reaction is completed, return to room temperature, add hydrochloric acid to adjust pH=2, cool to room temperature, crystallize and filter, and dry in a vacuum oven to obtain 8.9g of 5-nitrosalicylic acid, with a yield of 76% and a purity of 95.0%. Example 2
[0013] Dissolve 500 mg of o-chlorobenzoic acid in 4 g of concentrated sulfuric acid, control the temperature at 10 ° C, slowly drop a mixture of 500 mg of concentrated nitric acid and 1.5 g of concentrated sulfuric acid, keep the reaction at 10 ° C, add the reaction solution dropwise to ice water after the reaction is completed, naturally warm up to room temperature, and filter to obtain 602 mg of crude 2-chloro-5-nitrobenzoic acid. The obtained crude 2-chloro-5-nitrobenzoic acid was dissolved in 2 ml of 30% sodium hydroxide solution, heated to 80 ° C and heated for reaction. After the reaction is completed, return to room temperature, add hydrochloric acid to adjust pH = 2, cool to room temperature, crystallize and filter, and dry in a vacuum oven to obtain 415 mg of 5-nitrosalicylic acid, with a yield of 71% and a purity of 96.3%.
Claims
1. A method for preparing 5-nitrosalicylic acid, a mesalazine intermediate, comprising the following steps: (1) dissolving o-chlorobenzoic acid in concentrated sulfuric acid as a solvent, controlling the temperature at 0-10°C, slowly adding a mixture of concentrated nitric acid and concentrated sulfuric acid, and maintaining the temperature at 0-10°C for reaction; the mass ratio of concentrated nitric acid to concentrated sulfuric acid in the mixture of concentrated nitric acid and concentrated sulfuric acid is 1:3; (2) After the reaction is completed, the reaction solution is added dropwise into ice water, naturally returned to room temperature, and filtered to obtain a crude product of 2-chloro-5-nitrobenzoic acid; (3) Dissolve the crude 2-chloro-5-nitrobenzoic acid in 30% sodium hydroxide solution, heat to 80°C for reaction, add hydrochloric acid to adjust the pH to 2 after the reaction, cool naturally to room temperature for crystallization, and filter to obtain 5-nitrosalicylic acid.
2. method as claimed in claim 1, in step 1, the mass ratio of o-chlorobenzoic acid to the solvent concentrated sulfuric acid is 1:6-1:8, and the mass ratio of o-chlorobenzoic acid to the concentrated nitric acid and concentrated sulfuric acid mixed solution is 1:
4.
3. method as claimed in claim 1, in step 3, the mass grams of 2-chloro-5-nitrobenzoic acid and the volume milliliters of sodium hydroxide solution are in a ratio of 1:3-1:5.