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The synthetic method of 2‑(3‑formyl‑4‑isobutoxyphenyl)‑4‑methylthiazole‑5‑ethyl carboxylate

A technology of isobutoxyphenyl and ethyl thiazole formate is applied in the field of synthesis of high-purity ethyl 2--4-methylthiazole-5-carboxylate, and can solve the problems of various types of solvents, long reaction time and environmental pollution Large and other problems, to achieve the effect of short synthesis process and simple synthesis method

Active Publication Date: 2017-04-12
ZHEJIANG HUAYI PHARMA CO LTD OF HANGZHOU HUADONG PHARMA GRP +1
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  • Summary
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Problems solved by technology

[0008] 1. The above-mentioned process uses six-step reactions to obtain the final product. The steps are lengthy, and each step must be separated, resulting in heavy pollution, high energy consumption, low yield, and high cost pressure
[0009] 2. A large amount of chemical raw materials are used in the reaction process, but the conversion rate is low, and it is easy to produce a large amount of waste residue; there are many types and large quantities of solvents, which are not easy to recycle; and a large amount of waste water is generated, causing great pollution
[0010] 3. The product quality often can only reach a purity of more than 90%, which is difficult to meet the needs of high-end customers
(3) The isobutylation reaction is not included in the patent method, but from the perspective of the patent itself, it is also necessary to separate 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid Ethyl ester can be further used in the synthesis of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate, which produces a large amount of waste water and waste gas and increases energy consumption , easy to cause environmental pollution
The preparation method of this patent: (1) sulfurylation reaction needs 48 hours, formylation reaction time needs 24 hours, the reaction time is very long, and the efficiency is low
(2) Use a two-step method to obtain ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, each step of reaction needs to be separated and purified to obtain the product, and the product separated in the first step also needs to be dried , produce a large amount of waste water and waste gas, increase energy consumption, and easily cause environmental pollution
(3) The yield of the first step of sulfonylation reaction is about 87.6%, the yield of the second step of cyclization reaction is about 80.6%, and the yield of the two steps is about 67%, which is low.
(4) The sulfonylation reaction uses high-boiling DMF as a solvent, reclaiming a large amount of solvent, high energy consumption, and large environmental pollution
(5) The patent method does not include the isobutylation reaction, but from the perspective of the patent itself, it is also necessary to separate 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl Esters can be further used in the synthesis of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate. This process produces a large amount of waste water and waste gas, which increases energy consumption. easy to cause environmental pollution

Method used

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  • The synthetic method of 2‑(3‑formyl‑4‑isobutoxyphenyl)‑4‑methylthiazole‑5‑ethyl carboxylate
  • The synthetic method of 2‑(3‑formyl‑4‑isobutoxyphenyl)‑4‑methylthiazole‑5‑ethyl carboxylate
  • The synthetic method of 2‑(3‑formyl‑4‑isobutoxyphenyl)‑4‑methylthiazole‑5‑ethyl carboxylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Using p-cyanophenol and thioacetamide as starting materials, undergo sulfonylation reaction, continue thiazole reaction without separation, and then separate to obtain 2-(4-hydroxyphenyl)-4-methylthiazole-5 - ethyl carboxylate (formula III):

[0053] (1) Sulfurylation reaction: take p-cyanophenol and thioacetamide as starting raw materials, carry out sulphonylation reaction first, in a clean reaction bottle, drop into 70g polyphosphoric acid, 1.5g water, be mixed with Aqueous phosphoric acid system, add 12.7g thioacetamide and 20g p-cyanophenol into the system, stir and heat up to 40-80°C, and the reaction time is 2-8 hours; use HPLC to check whether the reaction is complete, and get 4-hydroxythiobenzene Formamide (formula II);

[0054] (2) Thiazolization reaction: After the sulfurylation reaction is complete, no separation is required, and the next step of thiazolization reaction is continued. 60 g of organic solvent ethanol is added to the reaction system to obtain a...

Embodiment 2

[0059] According to the various steps of Example 1, the thiazole reaction uses anhydrous phosphoric acid and methanol as the reaction solvent, and the rest of the process is the same as in Example 1 to obtain a white solid 2-(3-formyl-4-isobutoxyphenyl)-4 -Methylthiazole-5-ethyl carboxylate (formula I) 30.1 g, HPLC content 99.2%, yield 51.6%.

Embodiment 3

[0061] According to the various steps of Example 1, the formylation reaction uses polyphosphoric acid and phosphoric acid as the reaction solvent, the extraction solvent is ethyl acetate, and the rest of the process is the same as in Example 1 to obtain a white solid 2-(3-formyl-4-iso Butoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (Formula I) 28.9g, HPLC content 99.12%, yield 49.6%.

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Abstract

The invention provides a method for synthesizing high-purity ethyl 2-(3-aldehyde-4-isobutyloxyphenyl)-4-methylthiazole-5-formate. The method comprises the following steps of carrying out thioacylation reaction on p-cyanophenol and thioacetamide as starting materials to obtain 4-hydroxythiobenzamide (II), directly carrying out thiazole reaction on the reaction product which is not separated and separating to obtain ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazole formate (III); carrying out formylation reaction on the compound as shown in the formula (III) to obtain ethyl 2-(3-carbaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazole formate (IV), directly carrying out isobutylation reaction on the reaction product which is not separated to obtain ethyl 2-(3-aldehyde-4-isobutyloxyphenyl)-4-methylthiazole-5-formate (I) of which the purity is equal to or greater than 99% and the content is equal to or greater than 99%. The production process is optimized and thus the quality of the product is greatly improved and the high yield is achieved.

Description

[0001] (1) Technical field [0002] The invention relates to the synthesis of febuxostat intermediates, in particular to a synthesis method of high-purity ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate. [0003] (2) Background technology [0004] Ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate is a key intermediate for the production of the drug febuxostat, and its structural formula is: [0005] [0006] The patent CN103880775A (201210563201.3) literature has reported that p-cyanophenol can be used as a starting material and prepared through isobutylation, chloromethylation, hydrolysis, oxidation, sulfonylation, and cyclization, but the steps are tedious. And step-by-step processing, raw material consumption increases, resulting in greater pollution, and the final product content and yield are low, and its synthetic route is as follows: [0007] [0008] 1. The above-mentioned process uses six steps of reaction to obtain the fina...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 楼航斌王坚强陈婷婷饶新堂
Owner ZHEJIANG HUAYI PHARMA CO LTD OF HANGZHOU HUADONG PHARMA GRP
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