The synthetic method of febuxostat

Abstract

The invention provides a method for synthesizing febuxostat. The method comprises the following steps of: (a) performing aromatic ring substitution reaction on a compound of a formula I to obtain a compound of a formula II; (b) performing halogen-metal exchange reaction on the compound of the formula II to obtain a compound of a formula III; (c) performing coupling reaction on the compound of the formula III and the compound of a formula VI under the action of a metal catalyst to obtain a compound of a formula IV; and (d) performing hydrolysis reaction on the compound of the formula IV to obtain the compound of a formula V, namely febuxostat, wherein X is I or Br; M is selected from boric acid ester or SnBu3; and R is H or an alkyl group. In the method, a convergent synthesis strategy is adopted, and a carbon-carbon bond is formed by applying metal catalyzed aromatic ring coupling reaction in a key step, so that a system in which a benzene ring is coupled with a thiazole ring is established. The method has the advantages of simple and short steps, high yield and low environmental pollution and can be suitable for industrial production.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, more particularly to an anti-gout drug febuxostat-2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5thiazole Synthesis of formic acid. Background technique [0002] Gout, also known as hyperuricemia, is a disease caused by purine metabolism disorders. With the improvement of people's living standards, its incidence rate is increasing. It is listed by the United Nations as one of the twenty chronic diseases in the 21st century. Febuxostat is a new and highly effective selective xanthine oxidase / xanthine dehydrogenase inhibitor, which can effectively reduce the level of uric acid in gout patients and significantly improve the symptoms of gout patients. At present, most of the reported synthetic methods of febuxostat adopt the traditional method of constructing and synthesizing thiazole, usually the synthetic route is relatively long (generally more than six steps), and the conversion of...

AI Technical Summary

Problems solved by technology

At present, most of the reported synthetic methods of febuxostat adopt the traditional method of constructing and synthesizing thiazole, usually the synthetic route is relatively long (generally more than six steps), and the conversion of functional groups in the molecules involved is very cumbersome; secondly, The starting materials of various synthetic routes are expensive, and even in some steps, highly toxic, corrosive and polluting chemical reagents such as sodium cyanide, trifluoroacetic acid, urotropine, hydrogen sulfide, and phosphorus pentasulfide are required , has a greater adverse effect on the operator and the environment

In addition, some reactions require the use of diazotization reactions, which are not suitable for control in the operation of large-scale reactions, which makes industrial production more difficult

Moreover, the total yield of the synthetic method reported in the existing literature is low, generally lower than 30%, which also makes it unsuitable for industrial production

[0003]In the traditional synthetic method, when constructing and introducing cyano group in the molecule: JP06345724, EP0513379A1, WO9209279, CN101386604 disclose in the raw material through existing on the benzene ring Two substituents, the cyano group positions it; JP10139770 discloses a substitution reaction through the existing leaving group on the benzene ring in the intermediate; WO9209279 in the raw material or intermediate Amino groups undergo diazotization reaction; these methods must use highly toxic potassium cyanide, sodium cyanide and other cyanides, the safety of the process is very low, and the environment is very destructive

[0004] When constructing a ring-closing reaction to generate a thiazole ring, the cyano group in the raw material or intermediate is converted into a thioamide using a thio reagent: US20050075503 and US2005027128 disclose the use of Passing hydrogen sulfide gas into the solution to prepare under pressure, the reaction is very dangerous, highly corrosive, and environmentally destructive, which is not conducive to large-scale production; CN101391988 discloses a one-pot method for the synthesis of thiazole rings, avoiding the use of hydrogen sulfide, but the cost of raw materials is relatively high High; CN101412699 discloses the use of HCl / DMF system to synthesize thiazole ring, avoiding the use of gas operation, and the yield is high, but the reaction cycle is very long and the post-treatment is cumbersome

When converting the amide on the raw material or intermediate benzene ring into thioamide, JP06293746 discloses the use of highly toxic phosphorus pentasulfide, which is not conducive to large-scale production

[0005] When introducing an aldehyde group on the benzene ring of the intermediate after constructing the thiazole ring: JP11060552 and JP1045733 disclose the use of polyphosphoric acid as a solvent, and polymerization occurs during the reaction. Viscous, unfavorable for stirring and low yield, more impurities, unfavorable for production; CN101412699 discloses the use of trifluoroacetic acid as a solvent, and the yield is greatly improved, but the price and cost of trifluoroacetic acid are high, difficult to recycle and highly corrosive , low safety; CN102002017 discloses the use of mixed acids as solvents, but the acid pollution is still not improved

[0006]In the traditional method of constructing thiazole ring, functional group transformation needs to be carried out many times, the transformation is cumbersome, and the reaction steps are increased. Generally, more than six steps are required. For example, China Medical Journal In [2009,40(1):1-5], the final compound was synthesized after nine steps of reaction

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