Preparation method of 3,4-substitituted thiobenzamide and application of 3,4-substitituted thiobenzamide in febuxostat synthesis

Abstract

The invention relates to a preparation method of 3,4-substituted thiobenzamide. The 3,4-substituted thiobenzamide prepared by the method can be used to synthesis of febuxostat, a novel drug for treating gout.

Description

technical field [0001] The invention discloses a method for preparing 3,4-substituted thiobenzamide, and the product of the method can be used in the synthesis of new anti-gout drug Febuxostat. Background technique [0002] Febuxostat was first approved by the European Medicines Agency (EMA) in April 2008 for the treatment of hyperuricemia and related diseases caused by it, such as gout. The chemical name of febuxostat is: 2-(3-cyano-4-isobutoxy)phenyl-4-methyl-5-thiazolecarboxylic acid, and its chemical structure is as follows. [0003] [0004] The core part of the molecular structure of febuxostat is a 2-substituted phenylthiazole derivative, and its synthesis is mainly based on 3,4-substituted thiobenzamide (2) and 2-halogenated ethyl acetoacetate The ester (3) is formed by cyclization, and the reaction formula is as follows. [0005] [0006] According to the description of the patent EP0513379 / 1992, compound 2 and 2-halogenated ethyl acetoacetate (3) are synthe...

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Problems solved by technology

[0013] The operation steps of the method are to place 4-hydroxybenzonitrile, hydrogen sulfide gas and solvent water in a closed high-pressure device, and heat to 70° C. for an addition reaction to obtain 4-hydroxythiobenzamide. Although the method is short in steps, However, high pressure resistance and airtightness are required for the reactor, and the discharge of three wastes is very polluting, and the operation is cumbersome.

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