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The synthetic method of ceftazidime side chain acid ethyl ester

A side-chain acid ethyl ester and ceftazidime technology, which is applied in the field of medicine, can solve the problems of large water consumption per ton and long reaction cycle, and achieve high reaction efficiency, facilitate recycling, and increase production capacity.

Active Publication Date: 2021-10-22
SHANDONG JINCHENG PHARMACCUTICAL CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction cycle of this route is too long, and the heat preservation reaction alone takes 24 hours, and the water consumption per ton is relatively large, causing environmental protection pressure

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] (1) Add 43g of sodium nitrite, 270g of water, and 77g of ethyl acetoacetate into the reaction flask, start to add 43g of acetic acid dropwise at an internal temperature of 18°C, finish adding dropwise in 3.5h, keep warm for 1h, then separate the liquid, and extract with 180g of ethyl acetate , Combine the organic phases to obtain 300 g of the organic phase, the trans oximide is 0.8%, and the purity is 99.2%.

[0049] (2) Distill the organic phase under normal and reduced pressure to 85°C, after distilling off the solvent, add 30g of ethanol for dehydration, 0.6% of water, add 20g of methanol, 0.4g of concentrated sulfuric acid for chlorination, and control the temperature at 15-20°C Chlorine was passed through for 5 hours, and the residual oximate was 3.4%, and 148 g of chloride was obtained.

[0050] (3) 43g of thiourea, 280g of methanol, and 0.8g of catalyst tetrabutylammonium bromide were added to the reaction flask, and 230g of potassium carbonate buffered saline so...

Embodiment 2

[0053] (1) Add 45g of sodium nitrite, 280g of water, and 77g of ethyl acetoacetate into the reaction flask, start to add 44.6g of acetic acid dropwise at an internal temperature of 20°C, finish the dropwise addition in 4 hours, separate the liquid after keeping it warm for 1 hour, and extract with 190g of ethyl acetate , Combine the organic phases to obtain 295 g of organic phases, oximide trans 0.3%, purity 99.7%.

[0054] (2) Distill the organic phase under normal and reduced pressure to 83°C. After distilling off the solvent, add 30g of ethanol for dehydration, 0.6% of water, add 20g of methanol and 0.5g of concentrated sulfuric acid for chlorination, and control the temperature at 18-20°C Chlorine was passed for 5 hours, and the residual oximate was 4.0%, and 152 g of chloride was obtained.

[0055] (3) 43g of thiourea, 260g of methanol, and 1.1g of catalyst tetrabutylammonium bromide were added to the reaction flask, and 232g of potassium carbonate buffered saline solutio...

Embodiment 3

[0058] (1) Add 44g of sodium nitrite, 290g of water, and 77g of ethyl acetoacetate into the reaction bottle, start to add 44g of acetic acid dropwise at an internal temperature of 20°C, finish adding dropwise in 3.7h, separate the liquid after keeping it warm for 1h, and extract with 155g of ethyl acetate , the organic phase was combined to obtain 310 g of the organic phase, the trans oximide was 0.20%, and the purity was 99.8%.

[0059] (2) Distill the organic phase under normal and reduced pressure to 85°C, after distilling off the solvent, add 30g of ethanol for dehydration, 0.6% of water, add 20g of methanol, 0.4g of concentrated sulfuric acid for chlorination, and control the temperature at 15-20°C Chlorine was passed through for 4.5 hours, and the oximate residue was 3.5%, and 154 g of chloride was obtained.

[0060] (3) Add 44g of thiourea, 290g of methanol, and 1.0g of catalyst tetrabutylammonium bromide into the reaction flask, configure 235g of potassium carbonate bu...

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Abstract

The invention belongs to the technical field of medicine, in particular to a method for synthesizing ceftazidime side chain acid ethyl ester. Add sodium nitrite and ethyl acetoacetate to water, add acetic acid to react, extract, and collect the organic phase; carry out atmospheric and vacuum distillation on the collected organic phase to obtain the oximide, and add alcohol, catalyst and chlorine after the dehydration treatment of the oximide. Chlorination reaction, obtains chloride; Methanol, thiourea, phase-transfer catalyst, buffered saline solution and chloride reaction, obtain demethylaminothiaxamate ethyl ester solution; Demethylaminothiaxamate ethyl ester solution obtains demethylaminothiaxate ethyl ester and buffer salt, add α-bromoisobutyrate tert-butyl ester, condensation catalyst and solvent to react, and prepare ceftazidime side chain acid ethyl ester. Compared with the previous process, the present invention is more efficient, simple, environment-friendly and has high quality yield, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a method for synthesizing ceftazidime side chain acid ethyl ester. 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, ceftazidime side chain acid and its active ester are not only important intermediates for the production of ceftazime drugs, but also important for the production of The intermediate of the fourth-generation cephalosporin antibiotics has broad application prospects. [0003] The quality and yield of ethyl ceftazidime side chain acid directly affect the quality and cost of the synthesized drug ceftazidime. The synthesis of ceftazidime side chain acid ethyl ester mainly contains following two routes: [0004] Route 1: The product can be obtained by reacting ethyl demethylaminothiaxate and tert-butyl α-bromoisobutyrate under a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/593
CPCC07D277/593
Inventor 侯乐伟王瑞阴华栋孙兴董玉龙周文峰
Owner SHANDONG JINCHENG PHARMACCUTICAL CHEM CO LTD
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