A kind of preparation method of lodoxamide tromethamine intermediate

Abstract

The invention belongs to the technical field of medicine chemical engineering, and particularly discloses a preparation method of a lodoxamide tromethamine intermediate of lodoxamide. The method comprises the following steps of (1) dissolving 3,5-diamino-4-chlorobenzonitrile into an organic solvent to form a solution A; (2) dissolving oxalyl chloride into the organic solvent to form a solution B;(3) slowly dripping the solution A into the solution B; in the dripping process, controlling the temperature of the reaction liquid at -20 to 0 DEG C; after the reaction is completed, slowly drippinga certain amount of ice water into the reaction liquid; after the dripping is completed, continuously performing stirring for 0.5 to 1h; then, performing suction filtering; drying obtained filter caketo obtain lodoxamide. The reaction steps of the method are few; the operation is facilitated; the yield is greatly improved and can reach 90 percent or higher; meanwhile, the related impurities of the product lodoxamide are few; the product purity is high; the HPLC purity can reach 99.5 percent or higher; great significance is realized on the synthesis of the lodoxamide tromethamine medicine.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a preparation method of lodoxamide tromethamine intermediate. Background technique [0002] Lodoxamide tromethamine is a new generation of anti-allergy drugs. It can prevent the chemotaxis of eosinophils while stabilizing mast cell membranes, so it has double anti-allergic effects. Its stabilizing effect on mast cell membranes is 2500 times that of cromolyn sodium, so it is effective for spring catarrhal conjunctivitis, seasonal Conjunctivitis, atopic conjunctivitis, and other ocular allergies (such as allergic reactions to chemicals, dust, and contact lenses) have a fairly good effect. A large number of clinical studies at home and abroad have shown that the curative effect of lodoxamide tromethamine on allergic conjunctivitis is better than 20% cromolyn sodium eye drops, and it has good safety and generally has no adverse reactions. Lodoxamid...

AI Technical Summary

Problems solved by technology

[0011] The second step in the above process needs to be hydrolyzed in an alkaline environment, resulting in a chemical change of the substituent -CN, resulting in a substituent of -CONH 2 and -COOH impurities, low product purity

In addition, the product hydrolyzed in an alkaline environment is the sodium salt form of lodoxamide. During the subsequent acidification process, part of the sodium salt will be wrapped and cannot be removed, resulting in incomplete acidification, and eventually the final product lodoxamide will remain amines, thereby also affecting the residue on ignition of the API lodoxamide tromethamine

The process is complicated to operate and has high requirements on the process. The prepared lodoxamide has low purity and large residue on ignition, which is difficult to meet the production requirements of lodoxamide tromethamine raw material

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