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Febuxostat intermediate synthetic method

A technology of febuxostat and synthetic method, which is applied in the field of synthesis of febuxostat intermediates, can solve the problems of complex reaction conditions of methionine, difficulty in realizing industrial production, difficult industrial production, etc., and achieve increased yield and purity , Easy to operate, controllable, and easy to operate

Active Publication Date: 2019-04-05
ANHUI QINGYUN PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Although this route is comparatively novel in the design of route, this route is longer, and overall yield is low, and the introduction of chloromethyl and hydrolysis two-step reaction are more complicated, and in addition, it is comparatively complicated to introduce methionamide reaction condition to make This route is difficult to achieve industrial production
[0015] Through the above review, it can be seen that the current synthetic route about the febuxostat intermediate 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-ethyl carboxylate may be due to the use of a relatively Expensive reagent raw materials, or because of the use of highly toxic reagents, or because of the long route and low yield, it is difficult to achieve industrial production, so the development of green, environmentally friendly, and highly operable synthetic febuxostat intermediates The route has great prospects

Method used

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Embodiment 1

[0059] A synthetic method of febuxostat intermediate, comprising the steps of: 3-methyl-4-hydroxybenzonitrile and isobutyl bromide are reacted in aqueous sodium hydroxide solution to obtain 3-methyl-4-isobutoxy Base benzonitrile; then react with hydrogen peroxide, hydrogen bromide, tetramethylpiperidine nitrogen oxide to obtain substance A; then react with sodium hydrosulfide and sodium hydroxide to obtain substance B; then react with 2-chloroacetoacetic acid The ethyl ester is reacted to obtain the febuxostat intermediate.

Embodiment 2

[0061] A kind of synthetic method of febuxostat intermediate, comprises the steps:

[0062] Mix sodium hydroxide aqueous solution and 3-methyl-4-hydroxybenzonitrile, add tetrabutylammonium chloride, add isobutyl bromide dropwise, heat up to 30°C, keep warm for 12 hours, adjust the pH to neutral, The organic phase was extracted with ethyl acetate, dried, and concentrated to obtain 3-methyl-4-isobutoxybenzonitrile, wherein the molar ratio of 3-methyl-4-hydroxybenzonitrile to sodium hydroxide was 1 : The molar ratio of 2,3-methyl-4-hydroxybenzonitrile to isobutyl bromide is 1:1.05;

[0063] Mix 3-methyl-4-isobutoxybenzonitrile and acetonitrile evenly, add hydrogen bromide and tetramethylpiperidine nitrogen oxide, then add hydrogen peroxide dropwise, react at room temperature for 12 hours, adjust the pH to neutral, add Sodium bisulfite destroys the oxidizing property, just keep the starch potassium iodide test paper from turning blue, extract the organic phase with ethyl acetate,...

Embodiment 3

[0067] A kind of synthetic method of febuxostat intermediate, comprises the steps:

[0068] Mix sodium hydroxide aqueous solution and 3-methyl-4-hydroxybenzonitrile, add tetramethylammonium chloride, drop isobutyl bromide, heat up to 60°C, keep warm for 18 hours, adjust the pH to neutral, The organic phase was extracted with ethyl acetate, dried, and concentrated to obtain 3-methyl-4-isobutoxybenzonitrile, wherein the molar ratio of 3-methyl-4-hydroxybenzonitrile to sodium hydroxide was 1 : 1.2, The molar ratio of 3-methyl-4-hydroxybenzonitrile to isobutyl bromide is 1:1.5;

[0069] Mix 3-methyl-4-isobutoxybenzonitrile and acetonitrile, add hydrogen bromide, tetramethylpiperidine nitrogen oxide, then drop hydrogen peroxide, react at room temperature for 4 hours, adjust the pH to neutral, add Sodium bisulfite destroys the oxidizing property, just keep the starch potassium iodide test paper from turning blue, extract the organic phase with ethyl acetate, dry, and concentrate to...

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Abstract

The invention discloses a Febuxostat intermediate synthetic method, including the steps of subjecting 3-methyl-4-hydroxybenzonitrile and isobutyl bromide to reaction in sodium hydroxide solution to obtain 3-methyl-4-isobutoxybenzonitrile; subjecting 3-methyl-4-isobutoxybenzonitrile, hydrogen peroxide, hydrogen bromide and 2,2,6,6-tetramethylpiperidinooxy to reaction to obtain a substance A; subjecting the substance A, sodium bisulfide and sodium hydroxide to reaction to obtain a substance B; subjecting the substance B and ethyl 2-chloroacetoacetate to reaction to obtain the Febuxostat intermediate. The synthetic route has good selectivity and is green and environmental friendly, raw materials for preparing the intermediate are cheap and easy to obtain, the method is convenient to operate and easy to control and low in cost, is adaptable to industrial production and has high yield; the Febuxostat intermediate prepared by the method has high purity.

Description

technical field [0001] The invention relates to the technical field of preparation of chemical substances, in particular to a method for synthesizing a febuxostat intermediate. Background technique [0002] Febuxostat (English name: febuxostat, trade name: Adenuric, also known as: TEI26720; TMX267) is a new type of non-purine XO inhibitor, which is clinically used for the prevention and treatment of hyperuricemia and the gout caused by it. Studies have shown that febuxostat has good efficacy and safety in the treatment of hyperuricemia and gout caused by it. Japan's Teijin Corporation applied for listing in Japan in early 2004, and in the United States at the end of the same year. The European Union approved its listing in May 2008, and the FDA approved it for listing in February 2009. [0003] Febuxostat is a new non-purine highly efficient selective xanthine oxidase inhibitor, an effective substitute for allopurinol allergic or intolerant gout patients, especially for gou...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 黄欢黄庆云李凯张宏远
Owner ANHUI QINGYUN PHARMA & CHEM