Synthetic method of febuxostat

Abstract

The invention discloses a synthetic method of febuxostat. The synthetic method of febuxostat comprises the following steps: (1) preparing 4-hydroxy-1, 3-phthalic aldehyde; (2) preparing 4-hydroxy-1, 3-diphenyl nitrile; (3) preparing 4-isobutoxy-1, 3-diphenyl nitrile; (4) preparing 2-isobutoxy-5-sulfobenzyl acylamino cyanophenyl; (5) preparing 2-(3-cyan-4-isobutyl phenyl ether)-4-methylthiazole-5-ethyl formate; and (6) preparing febuxostat. According to the synthetic method, the low-price salicylaldehyde is adopted as the starting material and is subjected to aldehydizing, alkylating, thioacid amidating, cyclizing, and hydrolyzing so as to obtain the end product; the toxic agents such as sodium cyanide and the highly-corrosive agent like trifluoroacetic acid are not used; the raw materials in use are low in price and easy to obtain; the reaction condition is mild; the operation is simple and convenient; the total recovery is high; the obtained product is easy to purify; and the industrial production is easy to realize.

Description

technical field [0001] The invention relates to a synthesis method of febuxostat, a gout drug, and belongs to the field of medicinal chemistry. Background technique [0002] Febuxostat is a new generation of non-purine selective xanthine oxidase inhibitors developed by Teijin Corporation. It is clinically used to treat chronic hyperuricemia with urate deposition (including gout or gouty disease that has occurred or is present). arthritis). The company filed for listing in Japan in early 2004 and in the United States at the end of 2004. Its partner, Ipsen, was approved by the European Union on May 5, 2008 (trade name: ADENURIC) to be marketed in France. Compared with the original allopurinol, a commonly used drug for the treatment of gout, the therapeutic effect of this drug is more significant. At present, the main related synthetic methods at home and abroad are as follows: [0003] 1. The synthesis process of febuxostat disclosed in U.S. Patent No. 5,614,520 is as follo...

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Problems solved by technology

[0008] This process is an industrial preferred route, and the problem of this process is: the starting material p-hydroxybenzenethiocarboxamide is more expensive and difficult to prepare, and the preparation of 2-(3-formyl-4-hydroxyphenyl)-4-methyl- Ethyl thiazole-5-carboxylate uses trifluoroacetic acid, which is more corrosive to equipment and difficult to industrialize

[0009] 3. The febuxostat synthesis method disclosed in Japanese Patent JPl998045733: polyphosphoric acid is used to prepare 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester Solvent, not suitable for industrialization because polyphosphoric acid is too viscous

[0010] 4. p-Hydroxythiobenzamide is an important intermediate for the preparation of febuxostat. In U.S. Patent US20050027128, p-hydroxybenzonitrile and hydrogen sulfide gas are added to synthesize p-hydroxythiobenzamide. Since hydrogen sulfide has Strong odor and serious environmental pollution, not suitable for industrialization

[0016] In this process, the starting material is three-substituted benzene, and the price itself is relatively expensive; in the process of introducing the second aldehyde group, the amount of brominated reagent NBS has reached more than 50 equivalents, and the use of a large excess of NBS will cause costs. The increase and the corresponding problems of post-treatment, and this step of the reaction also uses the highly toxic solvent carbon tetrachloride, these factors will limit the mass production of the process

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