Preparation method of salazosulfapyridine

Abstract

The invention relates to the technical field of sulfasalazine, in particular to a synthesis process of salazosulfapyridine. Nitroso compound and ammonia are condensed to obtain salazosulfapyridine; byadopting the technical scheme provided by the invention, the reaction temperature does not need to be strictly controlled, and unstable diazonium salt can be avoided, so that the generation of by-products is avoided, and by utilizing the technical scheme provided by the invention, the product salazosulfapyridine can be directly separated out through simple treatment, and the reaction yield is high.

Description

technical field [0001] The invention relates to the technical field of sulfasalazine, in particular to a synthesis method of sulfasalazine. Background technique [0002] Sulfasalazine (SASP), also known as 5-[p-(2-pyridinesulfamoyl)benzene]azosalicylic acid. Molecular formula is C18H14N4O5S, molecular weight: 398.39. Its molecular structure is as follows: [0003] [0004] SASP is mainly used for the treatment of non-specific ulcerative colitis. This product has a special affinity for connective tissue and plays a therapeutic role by releasing sulfapyridine and 5-aminosalicylic acid in the intestinal wall. It is also used clinically for the treatment of rheumatic joints inflammation. Although this product is an old product, the market demand is still very large, especially its quality requirements are getting higher and higher. [0005] In the prior art, there are few disclosures on its preparation method. British Patent GB 11296655 discloses a synthetic method of su...

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Problems solved by technology

[0006] The starting material 4-(4-acetoxy group-3-carbonylmethoxyphenyl azo)-benzenesulfonyl chloride of this method is not commercially available at present and the comparatively difficult method of synthesis, and source is less; In addition, this method is owing to existence Hydrolysis reaction, its yield and product purity are not ideal

[0007] At present, the synthesis of sulfasalazine mainly uses sulfapyridine as a raw material, sodium nitrite as a diazotization reagent, and is obtained by coupling with salicylic acid after a diazotization reaction in an aqueous phase. For example, refer to the preparation provided in WO2002018330 method; also have isoamyl nitrite as the diazotization reagent, and the reaction is carried out in an organic solvent, for example, can refer to the method provided in Apoptosis2005,10(3), 481-491, but the present synthetic method all has a long reaction time , the local reaction is overheated, the reaction temperature needs to be strictly controlled, the diazonium salt is prone to hydrolysis and other problems, and by-products are produced, resulting in a low yield of sulfasalazine

[0008] Synthetic Chemistry 20(4), 524-526, 2012 has made improvements on the basis of these documents, so that the reaction yield has been improved, but the method it provides needs to be carried out in a tubular reactor, which is difficult for large-scale industrial production There are many limitations, and it can be seen from the published comparative experiments that the temperature will have an impact on the reaction yield. It is also mentioned that the temperature is high, and the diazonium salt is prone to hydrolysis, and the reaction with sodium nitrite is Exothermic, so it is necessary to strictly control the temperature of the reaction solution during the reaction to ensure that the temperature is not too high, so the temperature requirements are higher

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