Preparation method of intermediates of Febuxostat

Abstract

The invention relates to a preparation method of important intermediates, such as 2-(3-formaldehyde radical-4-hydroxyl phenyl)-4-methyl-5-thiazole ethyl formate, of Febuxostat. The method is as follows: reacting thioacetamide and 4-cyanol phenol which are used as raw materials in concentrated hydrochloric acid solution to obtain 4-hydroxythiobenzamide; reacting 4-hydroxythiobenzamide with 2-chloracetyl ethyl acetate to prepare 2-(4-hydroxyl phenyl)-4-methyl-5-thiazole ethyl formate; and reacting 2-(4-hydroxyl phenyl)-4-methyl-5-thiazole ethyl formate with hexamethylenetetramine in the presence of polyphosphoric acid and methanesulfonic acid to obtain 2-(3-formaldehyde radical-4-hydroxyl phenyl)-4-methyl-5-thiazole ethyl formate. In the invention, the operation is simple and convenient, the yield is high, the preparation process is stable, and the production cost is low, thus the preparation method is suitable for industrial production and application.

Description

Technical field: [0001] The invention relates to the field of medicinal chemistry, in particular to 4-hydroxythiobenzamide (III), 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester (II), 2-(3 - a preparation method of ethyl formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (I), which are all important intermediates for preparing the anti-hyperuricemia drug febuxostat. technical background: [0002] 4-Hydroxythiobenzamide (III), ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (II), 2-(3-formyl-4-hydroxyphenyl )-4-methyl-5-thiazole ethyl carboxylate (I) is an important intermediate in the process of synthesizing the anti-hyperuricemia drug febuxostat. [0003] [0004] There are many literatures and patents on the preparation methods of the compounds of formula (I), formula (II) and formula (III). [0005] Japanese Patent JP11060552 reported that compound (III) was prepared by reacting p-cyanophenol and thioacetamide in polyphosphoric a...

AI Technical Summary

Problems solved by technology

[0008] In the technology of above-mentioned preparation formula (I), formula (II), formula (III) compound, following shortcoming is arranged: (1) take polyphosphoric acid as solvent, it can produce polymerization and become viscous in reaction process, does not It is beneficial to stirring, and the yield is low, which is not conducive to industrial production; (2) by hydrogen sulfide as a raw material pressurized preparation process, because hydrogen sulfide high-pressure reaction is very dangerous, it is not conducive to industrial production; (3) using phoxim and p-cyanophenol Reaction and thioacetamide and p-cyanophenol react in HCl / DMF, and the reaction time is long, and aftertreatment is loaded down with trivial details, and yield is not high, and production cost is higher; (4) in the technique for preparing compound (I), with multiple Polyphosphoric acid is a solvent, which becomes viscous as the reaction proceeds at high temperature, which is unfavorable for stirring, and the yield is low, which is unfavorable for industrial production; (5) the yield of each compound is all low

This method uses HCl / DMF as the reaction solvent system, avoids the use of hydrogen sulfide, and the yield is greatly improved, but the reaction cycle is long, the post-treatment is cumbersome, and the recovery and treatment cost is high

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