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Method for preparing 2-(3-cyano-4-isobutyl methoxyphenyl)-4-methylthiazol-5-ethyl formate

A technology of isobutyloxyphenyl and methylthiazole, which is applied in the field of chemical drug preparation, can solve the problems of restricting industrialization, and achieve the effect of low production cost and mild reaction conditions

Inactive Publication Date: 2011-05-25
JIANGSU TOHOPE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The reaction of aldehyde group into cyano group, both Japanese patents JP1994329647 and JP11060552 have reported the method of one-step synthesis with formic acid, sodium formate, and hydroxylamine hydrochloride, but considering the odor and corrosiveness of formic acid, it also greatly limits industrialization

Method used

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  • Method for preparing 2-(3-cyano-4-isobutyl methoxyphenyl)-4-methylthiazol-5-ethyl formate
  • Method for preparing 2-(3-cyano-4-isobutyl methoxyphenyl)-4-methylthiazol-5-ethyl formate
  • Method for preparing 2-(3-cyano-4-isobutyl methoxyphenyl)-4-methylthiazol-5-ethyl formate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Reaction steps (1), (2), (4) are the same as above, and reaction steps (3), (5) are:

[0031] (3) Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (compound IV)

[0032] In a 1000mL three-neck flask, add 90g of compound III and 420mL of methyl tetrahydrofuran, after stirring, add 39g of anhydrous magnesium chloride, add 20.5g of paraformaldehyde in batches, add dropwise 41.5g of triethylamine, and react at 60°C for 12 hours , TLC showed that the reaction was almost complete, concentrated most of the solvent, added dilute hydrochloric acid to adjust the pH to weak acidity, poured into a large amount of water, precipitated solid, filtered and dried to obtain 86g of yellow solid, yield 86.4%.

[0033] (5) 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-ethyl formate, the preparation of (compound I)

[0034] In a 500mL three-neck flask, add 70g of compound V and 180mL of DMF, stir, add 16.8g of hydroxylamine hydrochloride, and react a...

Embodiment 2

[0036] Reaction steps (1), (2), (4) are the same as above, and reaction steps (3), (5) are:

[0037] (3) Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (compound IV)

[0038] In a 1000mL three-neck flask, add 90g of compound III and 420mL of methyl tetrahydrofuran, after stirring, add 39g of anhydrous magnesium chloride, add 20.5g of paraformaldehyde in batches, add dropwise 41.5g of triethylamine, and react at 60°C for 12 hours , TLC showed that the reaction was almost complete, concentrated most of the solvent, added dilute hydrochloric acid to adjust the pH to weak acidity, poured into a large amount of water, precipitated solid, filtered and dried to obtain 86g of yellow solid, yield 86.4%.

[0039] (5) 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-ethyl formate, the preparation of (compound I)

[0040]In a 500mL three-neck flask, add 70g of compound V and 180mL of DMF, stir, add 28g of hydroxylamine hydrochloride, and react at 1...

Embodiment 3

[0042] Reaction steps (1), (2), (4) are the same as above, and reaction steps (3), (5) are:

[0043] (3) Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (compound IV)

[0044] In a 1000mL three-neck flask, add 90g of compound III and 420mL of methyl tetrahydrofuran, after stirring, add 39g of anhydrous magnesium chloride, add 20.5g of paraformaldehyde in batches, add dropwise 41.5g of triethylamine, and react at 60°C for 12 hours , TLC showed that the reaction was almost complete, concentrated most of the solvent, added dilute hydrochloric acid to adjust the pH to weak acidity, poured into a large amount of water, precipitated solid, filtered and dried to obtain 86g of yellow solid, yield 86.4%.

[0045] (5) 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-ethyl formate, the preparation of (compound I)

[0046] In a 500mL three-neck flask, add 70g of compound V and 180mL of DMF, stir, add 22.4g of hydroxylamine hydrochloride, and react a...

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Abstract

The invention discloses a method for preparing a midbody of medicine febuxostat of 2-(3-cyano-4-isobutyl methoxyphenyl)-4-methylthiazol-5-ethyl formate, which comprises the following steps: using cyano phenol as raw materials, taking reaction to obtain 4-hydroxide thiobenzamide, carrying out cyclization to obtain 2-(4-hydroxy phenyl)-4-methylthiazol-5-ethyl formate, carrying out formylation to obtain 2-(3-carboxaldehyde-4-hydroxy phenyl)-4-methylthiazol-5-ethyl formate, carrying out isobutyl reaction to obtain 2-(3-carboxaldehyde-4-isobutyl phenyl ether)-4-methylthiazol-5-ethyl formate, and carrying out cyanation to obtain the 2-(3-cyano-4-isobutyl methoxyphenyl)-4-methylthiazol-5-ethyl formate. The raw materials used by the method disclosed by the invention can be easily obtained, the reaction conditions are mild, the cost is lower, and the method is applicable to industrialized production.

Description

technical field [0001] The present invention relates to the preparation method of the intermediate 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-formic acid ethyl ester of busostat, which belongs to the technical field of chemical medicine preparation . Background technique [0002] Febuxostat (Structure VI) is a new type of non-purine selective xanthine oxidase inhibitor developed by Teijin Corporation of Japan. It was registered in the European Union for the first time in 2008 and listed in the United States for the first time in March 2009. It is clinically used to treat hyperuricemia. 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-ethyl carboxylate is an important intermediate in the synthesis of febuxostat, and its structure (I) is as follows Show: [0003] [0004] In the febuxostat structure, there are generally two ways to introduce the 3-position cyano group on the benzene ring. The first is to use the direct substitution reaction of cyanide (repres...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56
Inventor 邹振荣
Owner JIANGSU TOHOPE PHARMA
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