Industrialized preparation method of mesalazine

Abstract

The invention discloses an industrialized preparation method of mesalazine. The preparation method is characterized by comprising the following steps: 1) taking 2-chlorine-5-nitrobenzoic acid (I) as astarting raw material, adding alkali, and performing substitution reaction at certain temperature to generate 2-hydroxy-5-nitrobenzoic acid (intermediate II); and 2) reducing nitryl by using raney nickel under certain pressure, at certain temperature and under the catalyst and alkaline conditions to prepare the finished product mesalazine. The process synthesis cost is low, the reaction conditionis mild, the whole process takes water as a solvent, a poisonous reagent is not used, the catalyst is recycled, and the whole process adopts green production; and the product prepared by the processhas high yield and high purity.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to an industrial preparation method of mesalazine. Background technique [0002] Mesalazine (Mesalazine), the chemical name is 5-aminosalicylic acid (5-ASA), also known as mesalazine, it is used to treat mild and moderate ulcerative colitis and maintenance therapy of ulcerative colitis. Inflammation of the wall was significantly suppressed. Mesalamine can inhibit the synthesis of prostaglandins that can cause inflammation and the formation of inflammatory mediator leukotrienes, thereby significantly inhibiting the inflammation of the intestinal mucosa, and has a better effect on the connective tissue of the inflamed intestinal wall. At present, 5-ASA is widely used clinically and has become the drug of choice for the treatment of inflammatory bowel disease (IBD). In foreign countries, the research on 5-ASA finished medicine started early, and it was used by the United ...

AI Technical Summary

Problems solved by technology

However, my country's research started late, the quality of research is low, there are few manufacturers, and the production technology is also far behind the level of foreign countries.

[0003] Aniline synthesis method: use aniline as raw material to generate diazonium chloride (2) through diazotization reaction, and then undergo diazo coupling reaction with salicylic acid to obtain methylation to obtain 2-hydroxy-5-phenylazobenzoic acid sodium ((3), then use sodium thiosulfate to remove the azo group to obtain the intermediate (4), and finally use hydrochloric acid to acidify the intermediate (4) to obtain the product: mesalamine (1), as shown in the following process route, the The main deficiency in the process route is: the process route is longer and loaded down with trivial details, and the aniline used in the reaction is more toxic, and the environmental pollution is bigger

[0005] Nitro reduction method: This method uses salicylic acid as a raw material, and uses a mixed acid of concentrated nitric acid and sulfuric acid to nitrate the para-position of the hydroxyl group, thereby obtaining 5-nitrosalicylic acid (5), and then using a metal reducing agent in the presence of hydrochloric acid Under the conditions, the nitro group is reduced to an amino group, thereby obtaining 5-aminosalicylic acid (1). This also results in a low product yield, and at the same time the nitro compounds produced in the intermediate process are brought into the final product, making it difficult for the content of nitro compounds in the 5-ASA product to meet the requirements of pharmaceutical applications

[0007] Kolbe synthetic method: this route takes p-aminophenol as starting raw material, under certain pressure and temperature, and under catalyst, alkaline condition, carry out carboxylation reaction with carbon dioxide and make 5-aminosalicylic acid (1), As shown in the following process route, the main disadvantages of this process route are: the raw material aminophenol is poisonous, the separation and purification requirements are strict, and the reaction conditions require high pressure, high equipment requirements, and the catalyst used affects the environment

[0009] Existing synthetic route has following shortcoming: (1) take salicylic acid as raw material, there will be many isomers to produce when carrying out nitration reaction, cause product yield like this low, simultaneously the nitration produced in intermediate process The content of nitro compounds in 5-ASA products is difficult to meet the requirements of pharmaceutical applications; (2) The overall route is too long and cumbersome, which reduces the total yield of the product and increases the synthesis cost; (3) ) uses dangerous and highly toxic reagents, which requires high equipment and is not conducive to large-scale production

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