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Technical method for reducing ceftazidime impurity H

A technology for ceftazidime tert-butyl ester and pyridine active ester is applied in the field of preparation of antibacterial drug ceftazidime, can solve the problems of unstable acid chloride preparation, high cost, difficult industrialization control and the like, achieves good color grade, mild and easy-to-control reaction conditions, The effect of improving product market competitiveness

Active Publication Date: 2019-06-21
辽宁美亚制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

That is, hedidine side chain acid and DFCCS synthesize acid chloride preparation, and then synthesize hedidine tert-butyl ester with 7-APCA under low temperature conditions. The whole process requires ultra-low temperature reaction, industrial control is difficult and costly, and the acid chloride preparation is unstable

Method used

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  • Technical method for reducing ceftazidime impurity H
  • Technical method for reducing ceftazidime impurity H
  • Technical method for reducing ceftazidime impurity H

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0042] Add 520ml of chloroform and 30ml of tert-butanol into a clean and dry four-necked reaction flask, and cool down to 0-5°C. Add 70g of 7-APCA and 105g of histidine active ester, and add triethylamine dropwise under temperature control to adjust the pH to 7.0-9.0. Control the temperature at 0-10°C and react for 20-24 hours. After the reaction is complete, add 150ml of pure water, stir for 1-2 hours, and separate the chloroform. Dropping isopropanol into the liquid medicine to precipitate ceftazidime tert-butyl ester, stirring and growing crystals at 0-10°C for 2 hours. Filter with suction, wash with isopropanol, and dry to obtain the dry product of ceftazidime tert-butyl ester.

[0043] Weight yield: 145%, purity 98.9%,

Embodiment 1-2

[0045] Add 54ml of formic acid and 36ml of concentrated hydrochloric acid into a clean and dry four-necked reaction flask, and stir to mix. Add 60 g of ceftazidime tert-butyl ester, react at 15-20° C. for 3 hours, and add acetone dropwise at room temperature until ceftazidime hydrochloride is completely precipitated. 0-10°C crystal growth for 2 hours. Suction filtration, washing with acetone, and drying to obtain dry product of ceftazidime hydrochloride.

[0046] Weight yield: 88%, purity 99.3%, H: 0.07%.

Embodiment 1-3

[0048]Add 20ml of water for injection and 30ml of acetone into a clean and dry four-necked reaction bottle, and stir to mix. Add 50 g of ceftazidime hydrochloride, add dropwise 4N NaOH, and adjust the pH to 6.0-6.5 to dissolve it. After dissolving, add 1 g of activated carbon and decolorize for 10 minutes. Filtration, the filtrate was added dropwise with 4M H 3 PO 4 , until the crystals were completely precipitated. 0-10 ℃ stirring crystal growth for 1 hour. Filter with suction, wash with acetone, and dry to obtain the dry product of ceftazidime pentahydrate.

[0049] Weight yield: 80%, purity 99.6%, H: 0.06%.

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Abstract

The invention provides a technical method for reducing a ceftazidime impurity H. The technical method is characterized in that one or more of dichloromethane, trichloromethane, carbon tetrachloride, tetrahydrofuran, acetonitrile and 2-methyltetrahydrofuran as a main solvent, tert-butyl alcohol or a mixed solvent of tert butyl alcohol and methyl alcohol is taken as a cosolvent, 7-APCA and BPTA aresubjected to a condensation reaction under the alkaline condition, ceftazidime tert-butyl ester is generated and subjected to water treatment, solvent crystallization is performed, and ceftazidime isobtained. Content of the impurity ceftazidime methyl ester (H) obtained with method in the product is smaller than 0.1%, and unknown impurities can be controlled to be 0.05% or smaller.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of an antibacterial drug ceftazidime. Background technique [0002] The chemical name of ceftazidime is (6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(1-hydroxy-2-methyl-1- Oxopropan-2-yl)oxyiminoacetyl]amino]-8-oxo-3-(pyridin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2. 0] Oct-2-ene-2-carboxylic acid. It is the third-generation cephalosporin antibiotic product for injection. [0003] According to the analysis of the structural formula of ceftazime methyl ester (H) included in the EP Pharmacopoeia, the impurity most likely to be produced in the preparation process of ceftazime is due to the trace amount of the impurity in the synthesis process of ceftazime tert-butyl ester or in the raw material of ceftazime active ester. It has been confirmed by relevant research literature that the use of solvent methanol should be controlled in both the synthesis of his...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/06C07D501/04C07D501/46
Inventor 于永宏王凤一侯微
Owner 辽宁美亚制药有限公司
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