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Synthesis method of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate

A technology of hydroxyphenyl and methylthiazole, which is applied in the field of drug synthesis, can solve problems such as unfavorable industrial production, inconvenient production operation, and personnel allergies, and achieve the effects of simple production methods, improved work efficiency, and reduced allergenic factors

Active Publication Date: 2017-03-22
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In the above-mentioned synthetic route, urotropine has high allergenicity, if a little mishandling in the production process, it may cause personnel allergy, which brings inconvenience to the production operation, and a large amount of toxic And irritating phosphoric acid, which is easy to cause pollution to the production environment, has brought huge pressure to environmental protection, and is not conducive to industrial production

Method used

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  • Synthesis method of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate
  • Synthesis method of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate
  • Synthesis method of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate

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Effect test

Embodiment 1

[0021] (1) Add 600ml of tetrahydrofuran and 70g of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate into a 2000ml reaction flask, then pass through nitrogen protection, and when the temperature drops to -10°C, slowly drop Add 536ml of 1mol / L n-butyllithium n-hexane solution, after the dropwise addition is complete, stir at -10°C for 15 minutes, then add 22.3g of N,N-dimethylformamide, and stir for 30 minutes;

[0022] (2) Add 48g of glacial acetic acid under temperature control below 10°C, stir for 10 minutes, control the temperature of the water bath at 40°C to concentrate the reaction solution under reduced pressure to dryness, then add 1000ml of purified water to it, add 90g of sodium bicarbonate, stir for 30 minutes, and add to the reaction solution Add 1200ml of ethyl acetate to the solution and extract twice, combine the organic layers, control the temperature of the water bath at 50°C and concentrate the organic solvent under reduced pressure until no fraction fl...

Embodiment 2

[0024] (1) Add 600ml of tetrahydrofuran and 70g of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate into a 2000ml reaction flask, then pass through nitrogen protection, and when the temperature drops to -10°C, slowly drop Add 530ml of n-butyllithium n-hexane solution of 1mol / L, after the dropwise addition is complete, stir at -10°C for 20 minutes, then add 22.0g of N,N-dimethylformamide, and stir for 35 minutes;

[0025] (2) Add 45g of glacial acetic acid at 0-10°C of temperature control, stir for 15 minutes, control the water bath temperature at 40°C to concentrate the reaction solution under reduced pressure to dryness, then add 1000ml of purified water thereto, add 85g of sodium bicarbonate, stir for 30 minutes, and Add 1200ml of ethyl acetate to the reaction solution and extract twice, combine the organic layers, control the temperature of the water bath at 50°C to concentrate the organic solvent under reduced pressure until no fraction flows out, add 210ml of isopr...

Embodiment 3

[0027] (1) Add 600ml of tetrahydrofuran and 70g of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate into a 2000ml reaction flask, then pass through nitrogen protection, and when the temperature drops to -10°C, slowly drop Add 550ml of n-butyllithium n-hexane solution of 1mol / L, after the dropwise addition is complete, stir at -10°C for 12 minutes, then add 23.0g of N,N-dimethylformamide, and stir for 30 minutes;

[0028] (2) Add 50 g of glacial acetic acid under temperature control below 10°C, stir for 10 minutes, control the water bath temperature at 40°C to concentrate the reaction solution under reduced pressure to dryness, then add 1000ml of purified water to it, add 95g of sodium bicarbonate, stir for 30 minutes, and add to the reaction solution Add 1200ml of ethyl acetate to the solution and extract twice, combine the organic layers, control the temperature of the water bath at 50°C and concentrate the organic solvent under reduced pressure until no fraction flows...

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Abstract

The invention discloses a synthesis method of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate. The synthesis method comprises the steps that ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate and N,N-dimethylformamide generate a reaction by taking n-butyllithium as a catalyst and then react with glacial acetic acid to generate ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate. Due to the fact that urotropin is not adopted in the synthesis reaction process, allergenic factors possibly brought in the production process are reduced; meanwhile, the production method is simple and environmentally friendly, the product is high in purity and yield, the cost is reduced, the working efficiency is improved, and the synthesis method is suitable for industrialized production.

Description

technical field [0001] The invention relates to a synthesis method of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate, which belongs to the technical field of medicine synthesis. Background technique [0002] Febuxostat, also known as febuxostat, chemically named 2-[(3-cyano-4-isobutoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid, suitable for gout symptoms Long-term treatment of hyperuricemia. Febuxostat is a new type of non-syringoid xanthin oxidase (XO) inhibitor, which can treat gout patients who are allergic to siasinol. Febuxostat is highly selective to XO, and has significant inhibitory effect on both oxidized and reduced XO. At concentrations up to 100 μM, febuxostat had no effect on the activities of the following enzymes involved in the metabolism of guanine and vijay in vivo: guanine deaminase, hypoxanthine-guanine phosphoribosyltransferase, guanine nuclear Phosphorylase, aromatic phosphoribosyltransferase, and orotate nucleotide desshuttlease,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 赵孝杰夏彩霞张敏
Owner SHANDONG BOYUAN PHARM CO LTD
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