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Method for preparation of EHATA

The technology of ethyl norfoxamate and ethyl chloroacetoacetate is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of high cost of raw materials, many reaction steps, many three wastes, etc., and achieves simplified operation, shortened reaction period, and reduced three wastes. The effect of pollution

Inactive Publication Date: 2007-08-01
SHANDONG HUIHAI PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing production process has disadvantages such as many reaction steps, long cycle, many wastes, high cost of raw materials and low yield.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0013] Add 300L carbon tetrachloride into the reaction kettle, then turn on the agitator, cool to -30°C, then add 8.4kg of diketene, open the chlorine valve, and start slowly, and keep the chlorine flow rate not greater than 2000g after equilibrium / h, the preferred reaction temperature is not higher than -20°C, stop feeding (i.e. chlorination process) after feeding 7.15kg of chlorine gas. Slowly add 4.6kg of absolute ethanol dropwise to the reactor, and slowly increase the reaction temperature until reflux occurs, and the reaction (ie, the esterification process) can be terminated after about 4 hours of reflux. Then vacuum distillation is carried out, and the product 4-chloroacetoacetate ethyl is distilled out. Transfer ethyl 4-chloroacetoacetate into the reaction kettle, add 30L of mixed solvent of ethanol and tetrahydrofuran (volume ratio = 4:1), cool to 0°C, start stirring, and then slowly pass ethyl nitrite gas (gas To pass into below the liquid level), start stirring, a...

example 2

[0015] Add 300 L of carbon tetrachloride into the reaction kettle, then turn on the agitator, cool to -30°C, add 8.4kg of diketene, open the chlorine valve, and start slowly, and keep the speed of chlorine after the balance. More than 500g / h, and keep the reaction temperature not higher than -20°C, stop feeding after feeding 7.15kg of chlorine gas. Then slowly add 4.6kg of absolute ethanol dropwise to the reactor, while adding the absolute ethanol dropwise, feed nitrogen into the reactor, then slowly increase the reaction temperature until reflux occurs, and the reaction can be terminated after about 4 hours of reflux . Except that an appropriate amount of phase-transfer catalyst benzyltrimethylammonium chloride is used in the cyclization stage, other operating links are the same as Example 1. 17.2 kg of ethyl demethylaminothiaxate was obtained, melting point: 185-188° C., yield 80.1% (calculated as diketene), and content 98.7%.

example 3

[0017] Add 300L of dichloromethane into the reaction kettle, then turn on the agitator, cool to -30°C, then add 8.4kg of diketene, open the chlorine valve, and must slowly feed in at the beginning, and keep the speed of chlorine feeding after equilibrium, not more than 2000g / h, and keep the reaction temperature not higher than -20°C, stop feeding after feeding 7.15kg of chlorine gas. Then slowly add 4.6kg of absolute ethanol dropwise to the reactor, while adding the absolute ethanol dropwise, feed nitrogen into the reactor, then slowly increase the reaction temperature until reflux occurs, and the reaction can be terminated after about 4 hours of reflux . Except using an appropriate amount of phase transfer catalyst tetramethylammonium acetate in the cyclization stage, other operating links are the same as example 1. 14.6 kg of ethyl demethylaminothiaxate was obtained, melting point: 185-187°C, yield 67.9% (calculated as diketene), and content 98.6%.

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Abstract

The invention discloses a new method for preparing ethyl 2-(2-aminothiazole-4-yl)-2-hydroxyimino acetate. The method for preparing ethyl 2-(2-aminothiazole-4-yl)-2-hydroxyimino acetate comprises following steps: taking diketene as raw material and producing intermediate product 4-chloracetyl acetidin through chlorination and esterification, and preparing final product through nitrosation and cyclization reaction. The invention is characterized in that it employs cheaper raw material and phase transition catalysis technology, which simplifies operation process, reduces reaction phase transition, decreases production cost and three- waste pollution, and its industry application value is great.

Description

(1) Technical field [0001] The present invention relates to a preparation method of a pharmaceutical intermediate, a new method for preparing ethyl demethylaminothiaxate, i.e. ethyl (Z)-2-(2-amino-4-thiazole)-2-hydroxyiminoacetate method of preparation. (2) Background technology [0002] (Z)-2-(2-Amino-4-thiazole)-2-Hydroxyiminoacetic acid ethyl ester (referred to as demethylaminothiaxamic acid ethyl ester) is a synthesis of β-lactam antibiotics cefixime, cefotaxime, cephalosporin The important side chain intermediates of trixone, ceftazidime, cefpirome, etc. are one of the high value-added pharmaceutical intermediates with great development prospects. Pneumonia and other serious infections have significant curative effect, basically non-toxic to the kidneys, and are important antibiotics used in the clinical treatment of infectious diseases. China's 2010 medical science and technology development plan clearly stated that it is necessary to selectively develop third-genera...

Claims

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Application Information

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IPC IPC(8): C07D277/593
Inventor 郑庚修李贺赵叶青
Owner SHANDONG HUIHAI PHARMA & CHEM
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