One-pot ceftazidime side-chain acid ethyl ester synthesis method

A side-chain acid ethyl ester and ceftazidime technology, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of difficult wastewater treatment, large water consumption per ton, and high environmental protection pressure, so as to achieve stable production process, reduce environmental pollution, and reduce wastewater volume effect

Active Publication Date: 2016-05-18
SHANDONG JINCHENG PHARMACCUTICAL CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route uses DMF as a solvent, the solvent has a high boiling point, the wastewater treatment is difficult, the water consumption per ton is large, and the environmental protection pressure is high

Method used

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  • One-pot ceftazidime side-chain acid ethyl ester synthesis method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] (1) Add 209g of ethyl 4-bromoacetoacetate and 300g of water into the reaction flask, stir and dissolve, and at -5°C, start to drop an aqueous solution of sodium nitrite (equivalent to 138g of sodium nitrite) and a mass fraction of 15% Sulfuric acid, to ensure that the pH of the solution is 1, the dripping is completed in 1 hour, heat is released during the dropping process, the temperature rises to 5°C, and the reaction is continued for 3.5 hours. After the reaction was completed, dichloromethane was added for extraction, the extract was washed with saturated potassium carbonate aqueous solution, and the organic layer was distilled under reduced pressure to obtain an oximation solution.

[0035] (2) 76g of thiourea is added to the mixed solution of 600g of water and methanol, and the oximation solution prepared in step (1) is added dropwise at 20° C., and after 3.5 hours of dripping, a solution of ethyl demethylthiaxamate is obtained; The specific gravity of the mixed l...

Embodiment 2

[0038] (1) Add 209g of ethyl 4-bromoacetoacetate and 300g of water into the reaction flask, after stirring and dissolving, at 0°C, start to dropwise add sodium nitrite (equivalent to 172g of sodium nitrite) aqueous solution and sulfuric acid with a mass fraction of 20% , to ensure that the pH of the solution is 2.5, and the dripping is completed in 1.5 hours. Heat is released during the dropping process, and the temperature rises to 10° C., and the reaction is continued for 4 hours. After the reaction was completed, dichloromethane was added for extraction, the extract was washed with saturated potassium carbonate aqueous solution, and the organic layer was distilled under reduced pressure to obtain an oximation solution.

[0039] (2) 133g of thiourea is added to the mixed solution of 1000g of water and methanol, and the oximation solution prepared in step (1) is added dropwise at 28° C., and after 4 hours, the oximation solution is obtained to obtain the ethyl desmethionine so...

Embodiment 3

[0042] (1) Add 209g of ethyl 4-bromoacetoacetate and 300g of water into the reaction flask, after stirring and dissolving, at 5°C, start to dropwise add sodium nitrite (equivalent to 207g of sodium nitrite) aqueous solution and sulfuric acid with a mass fraction of 25% , to ensure that the pH of the solution is 3.5, after 2 hours of dripping, heat is released during the dropping process, the temperature rises to 20 ° C, and the reaction is continued for 4.5 hours. After the reaction was completed, dichloromethane was added for extraction, the extract was washed with saturated potassium carbonate aqueous solution, and the organic layer was distilled under reduced pressure to obtain an oximation solution.

[0043] (2) 190g of thiourea is added to the mixed solution of 1500g of water and methanol, and the oximation solution prepared in step (1) is added dropwise at 35° C., and after 4.5 hours, the oximation solution is obtained to obtain the ethyl desmethionine solution; The spec...

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Abstract

The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a one-pot ceftazidime side-chain acid ethyl ester synthesis method. The method comprises the following steps that 1, ethyl 4-bromoacetoacetate is dissolved in water, a sodium nitrite water solution and 15%-25% of sulfuric acid are added dropwise, heat preservation reaction is performed after adding is completed dropwise, extraction is performed after the reaction is completed, the extracting solution is washed with a saturated potassium or sodium carbonate solution, and distillation is performed to obtain an oximation solution; 2, thiourea is added into a water and methanol mixed solution, and then the oximation solution is added dropwise to obtain an ethyl 2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate solution; 3, the pH of the ethyl 2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate solution is regulated, then tert-butyl alpha-bromoisobutyrate and a phase transfer catalyst are added for heat preservation reaction, and after the reaction is completed, cooling and suction filter are performed to obtain the ceftazidime side-chain acid ethyl ester. The simple processing of the product is simple, the purity and the yield are high, and the yield is up to 96.5% or above.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a method for synthesizing ethyl ceftazidime side chain acid in one pot. Background technique [0002] Ceftazidime is one of the very important third-generation semi-synthetic cephalosporin antibiotics. Its upstream products-ceftazime side-chain acid ethyl ester, ceftazime side-chain acid and its active ester are not only important intermediates for the production of ceftazidime drugs, but also the production of the first The intermediate of the fourth-generation cephalosporin antibiotics has broad application prospects. [0003] The quality and yield of ceftazidime side chain acid ethyl ester directly affect the quality and cost of the synthesized ceftazime. At present, the synthesis of ceftazidime side chain acid ethyl ester mainly contains the following three routes: [0004] Route 1: Under alkaline conditions (with anhydrous potassium carbonate as the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/593
CPCC07D277/593
Inventor 房正薇赵奇付宝友张林
Owner SHANDONG JINCHENG PHARMACCUTICAL CHEM CO LTD
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