Method for preparing febuxostat intermediate

Abstract

The invention discloses a new method for preparing a febuxostat intermediate 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate (in a formula II). In the method, a compound in a formula III is subjected to three steps of reaction, namely formylation reaction, aldoxime dehydration and mitsunobu etherification in the presence of a catalyst to form the febuxostat intermediate (II). The method avoids introducing high boiling point solvents and toxic catalysts, has the characteristics of simple posttreatment, low cost, low energy consumption, environmental friendliness, no toxicity and high yield, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to the preparation of febuxostat intermediate 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester for the treatment of gout Preparation. Background technique [0002] Febuxostat, whose chemical name is 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid (as shown in formula I), is a new generation of xanthine Oxidase inhibitors, clinically used to treat hyperuricemia (gout). [0003] At present, there are many methods for preparing febuxostat, but there are great differences in the selection of the reaction process, the use of catalysts, the reaction conditions and the control of related substances and there are some limitations, which limit the use of febuxostat in Industrial application. [0004] Formula II compound 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester is an important intermediate for the synthesi...

AI Technical Summary

Problems solved by technology

More importantly, the aldehyde group contained in the etherification substrate is a very active and unstable group. Under the high temperature conditions of etherification, side reactions are prone to occur, resulting in high levels of related substances in the product and increasing the subsequent separation. Difficulty of purification

Not only that, this etherification reaction also uses bromoisobutane, which is highly toxic, as an etherification reagent, and uses more than 5 times the equivalent to promote the complete progress of the reaction. Excess bromoisobutane cannot be recovered, which is harmful to environmental protection. cause great pressure

[0013] (3) Japanese patent JP1998045733 used polyphosphoric acid with high viscosity as solvent and catalyst in the formylation step reaction, the reaction was difficult to stir, and the post-treatment was complicated, thus limiting its application in industrial production

[0014] (4) In the technical solutions disclosed in Chinese patents CN101497589 A and CN 101863854A, highly toxic KCN or NaCN is still used, and the reaction route is long, the total yield is low, and the industrial value is not great

[0015] (5) In the technical scheme disclosed in Chinese patent CN101665471A, Lewis acid SnCl is used 4 As a catalyst for formylation, but due to SnCl 4 It is easy to produce colloidal precipitation, which makes it difficult to separate the product, and the colloidal precipitation is easy to adsorb the product

The problem is that the raw materials used are very strong protic acids, and they also contain water.

One of them is to use methanol as a solvent and react with hydroxylamine hydrochloride to obtain an intermediate. The disadvantage of this method is that the aldehyde group on the substrate is easy to become acetal, and the ester group is prone to transesterification reaction, resulting in methyl ester

Another method mentioned using N,N-dimethylformamide, N-methylpyrrolidone, etc. are all solvents with a very high boiling point. Since there is no participation of an acidic catalyst, a very high reaction temperature is required to complete the reaction. It is easy to stay in the intermediate aldoxime stage, and it is difficult to carry out complete

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