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Method for preparing 2-(4-hydroxyl phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester by one pot method

A technology of hydroxyphenyl and ethyl carboxylate, which is applied in the field of preparation of thiazole derivative pharmaceutical intermediates, can solve the problems of difficult operation control, high equipment requirements, complicated purification, etc., and achieve simple operation, high yield and purity, The effect of simple reaction conditions

Inactive Publication Date: 2009-03-25
NANJING UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above several methods mainly have the following disadvantages: 1. Hydrogen sulfide or hydrogen chloride gas needs to be prepared and reacted under a certain pressure, which requires high equipment and is difficult to control in operation.
2. Use of carcinogenic or highly toxic substances: thioacetamide, pyridine, phoxim, etc.
3. Low yield or complicated purification
There are also reports in the literature that the one-pot method is used to combine the above two steps to simplify the operation (US20050075503), but in this method, hydrogen sulfide gas pressurization reaction is still required, and there is still great inconvenience

Method used

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  • Method for preparing 2-(4-hydroxyl phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester by one pot method

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Experimental program
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Effect test

Embodiment 1

[0014] Put p-hydroxybenzonitrile (12g, 100mmol), sodium sulfide (7.8g, 100mmol), ferric chloride hexahydrate (13.5g, 50mmol) N, N-dimethylformamide (100mL) on a thermometer, Condensate and reflux and stir in the reactor of the stirring device, stir to dissolve the solid, and stir and react at 25°C for 2 hours. Measure ethyl acetate (150 mL) and ethyl 2-chloroacetoacetate (16.4 g, 100 mmol) into the reaction solution, raise the temperature to 82° C., and react under reflux for 3 hours. After the reaction, 1mol / L hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 6, filtered to remove the precipitate, the filtrate was poured into 5 times the volume of the reaction solution under stirring, a large amount of white floccules precipitated, filtered to obtain a solid before use After washing with a large amount of water twice, after drying, 19.7 g of the target product 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-ethyl acetate with higher purity can be obtai...

Embodiment 2

[0017] Place p-hydroxybenzonitrile (12g, 100mmol), sodium hydrosulfide (5.6g, 100mmol), ferric chloride hexahydrate (13.5g, 50mmol) pyridine (100mL) in a reaction with a thermometer, reflux and stirring device In the kettle, stir to dissolve the solids, and stir and react at 30°C for 4 hours. Measure chloroform (150 mL) and ethyl 2-chloroacetoacetate (16.4 g, 100 mmol) into the reaction solution, raise the temperature to 65° C., and react under reflux for 5 hours. After the reaction, 3mol / L nitric acid was added dropwise to adjust the pH of the reaction solution to 6.5, and the precipitate was removed by filtration. The filtrate was poured into 5 times the volume of the reaction solution under stirring. A large amount of white flocs precipitated out. The solid was filtered and then used in a large amount. After washing 3 times with water, after drying, 21.0 g of 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-ethyl acetate, the target product with higher purity, can be obtained, and t...

Embodiment 3

[0020] Put p-hydroxybenzonitrile (12g, 100mmol), sodium sulfide (7.8g, 100mmol), copper chloride dihydrate (12.7g, 75mmol) toluene (100mL) in a reactor equipped with a thermometer, reflux and stirring device , Stir to dissolve the solid, stir and react at 35°C for 2 hours. Measure ethanol (200 mL) and ethyl 2-chloroacetoacetate (16.4 g, 100 mmol) into the reaction solution, raise the temperature to 80° C., and react under reflux for 6 hours. After the reaction, 2mol / L hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 7, and the precipitate was removed by filtration. The filtrate was poured into 5 times the volume of the reaction solution under stirring. A large amount of white floccules precipitated out. The solid was filtered and used again. After washing with a large amount of water for 3 times, after drying, 22.2 g of 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-ethyl acetate, a target product with higher purity, can be obtained, with a yield of 8...

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Abstract

The invention relates to a method for preparing 2-(4-hydroxyphenyl)-4-methyl-1, 3-thiazole-5-carboxylic acid ethyl ester by using a one-pot method, which comprises the steps: p-hydroxybenzonitrile, sulphid or sulfohydrate and water-soluble metal chloride are dissolved in an organic solvent, the temperature is controlled, p-hydroxyl-thiobenzamide is generated by reaction; a refluxing solvent is added into a p-hydroxyl-thiobenzamide reaction system generated by the reaction, and 2-halogenated acetoacetate ethyl ester is dropped into the system, the temperature is raised and the reflux reaction is carried out, the reaction liquid is acidulated after the reaction is finished, then the target product, 2-(4-hydroxyphenyl)-4-methyl-1, 3-thiazole-5-carboxylic acid ethyl ester, is obtained by post treatment. The invention has the advantages of low-cost and easily-obtained raw materials, simple reaction conditions, simple and convenient operation, small toxicity and pollution, simple post treatment, high yield and purity and being suitable for industrial production.

Description

Technical field: [0001] The invention relates to a preparation method of thiazole derivative pharmaceutical intermediates, more specifically, a one-pot method for preparing 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid The ethyl ester method. Background technique: [0002] 2-(4-Hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester is an important intermediate for the treatment of gout and hyperuricemia drug TEI-6720. The existing synthesis method is mainly divided into two steps, the first step is the preparation of p-hydroxythiobenzamide, and the second step is the formation of the thiazole ring. In the two-step reaction, the reaction method of the second step is relatively uniform, and the yield is stable. It is generally used to form 2-(4-hydroxyphenyl)-4-methyl with ethyl 2-chloroacetoacetate and p-hydroxythiobenzamide. Ethyl-1,3-thiazole-5-carboxylate. The synthesis methods of the first step product are diverse, and current research mainly focuses ...

Claims

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Application Information

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IPC IPC(8): C07D277/56
Inventor 王德才唐春雷米珊李新华刘华权欧阳平凯
Owner NANJING UNIV OF TECH
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