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Preparation method of cefdinir

The technology of cefdinir and organic solvent is applied in the field of synthesis of cephalosporins, and can solve the problems of dark color of cefdinir product, not using low temperature conditions, affecting reaction efficiency, etc., so as to improve solvent recovery rate, reduce reaction impurities, Reduce the effect of hydrolysis side reactions

Active Publication Date: 2014-07-02
ZHEJIANG APELOA TOSPO PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The advantage of this process is that the dinisyl active ester used is easy to buy from the market. The disadvantage is that a strong base is used in the process of hydrolyzing O-acetyl cefdinir, and the resulting cefdinir product has dark color, many impurities, and the yield is not high. (Formula V)
[0014] Chinese patent CN102153566 also adopts the synthetic route of formula V, but does not use low temperature conditions in the condensation reaction
The disadvantage of using immobilized carboxylate hydrolase is that the O-acetyl cefdinirate must be fully diluted so that the immobilized carboxylate hydrolase can perform normal hydrolysis function, thus affecting the reaction efficiency

Method used

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  • Preparation method of cefdinir
  • Preparation method of cefdinir
  • Preparation method of cefdinir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] 10kg of tetrahydrofuran and 6kg of purified water were added to the 50L reactor. The temperature was adjusted to 15±2°C, and 7-AVCA (1.0kg, 4.42mol) and T15-AE active ester (2.1kg, 5.55mol) were put into the reactor. A mixture of triethylamine (0.45kg, 4.46mol) and 2L of tetrahydrofuran was added dropwise. During the dropping process, the dropping speed is controlled so that the reaction temperature T=10±2°C and the pH value is maintained between 8.0 and 8.5. The dropwise addition is completed within 3~4h, and the temperature is kept at 10~20°C for 4~5h. After the reaction solution was dissolved, samples were taken in the control panel to detect the residue of 7-AVCA. When the residual 7-AVCA was less than 1.0%, the reaction was stopped.

[0047] 5 kg of tert-butyl acetate and 4 kg of purified water were added to the system. Leave to layer (the upper layer is lighter than the lower layer). Add 4kg tert-butyl acetate to the obtained aqueous phase, leave to stand and...

Embodiment 2

[0054] Add 10kg of acetone and 5kg of purified water into the 50L reactor. The temperature was adjusted to 20±2°C, and 7-AVCA (1.0kg, 4.42mol) and T15-AE active ester (2.0kg, 5.28mol) were put into the reactor. A mixture of tri-n-butylamine (0.9kg, 4.86mol) and 2L of acetone was added dropwise. During the dropping process, the dropping rate was controlled so that the reaction temperature was 20±2°C and the pH value was maintained between 8.0 and 8.5. The dropwise addition is completed within 3~4h. After the dropwise addition, keep warm at 20±2°C for 4~5h. After the reaction solution was dissolved, samples were taken in the control panel to detect the residue of 7-AVCA. When the residual 7-AVCA is less than 1.0%, stop the reaction.

[0055] 5 kg of propyl acetate and 4 kg of purified water were added to the system. Let stand to layer. Separate the layers, separate the water phase, add 4kg propyl acetate, and stir. Stand to separate layers, combine two propyl acetate phas...

Embodiment 3

[0059] Add 8kg dioxane and 4Kg purified water in the 50L reactor. The temperature was adjusted to 10±2°C, and 7-AVCA (1.0kg, 4.42mol) and T15-AE active ester (1.8kg, 4.86mol) were put into the reactor. A mixture of dicyclohexylamine (0.90kg, 4.98mol) and 2L of dioxane was added dropwise. During the dropping process, the dropping rate is controlled so that the reaction temperature is 10±2° C. and the pH value is maintained between 8.0-8.5. The dropwise addition is completed within 3-4h. After the dropwise addition, keep warm at 10-20°C for 4-5 hours. After the reaction solution is dissolved, take a sample and control it to detect the residue of 7-AVCA. When the residue of 7-AVCA is less than 1.0%, stop the reaction.

[0060] 5 kg of tert-butyl acetate and 4 kg of purified water were added to the system. Stand to separate layers, separate the water phase, add 4kg tert-butyl acetate to the water phase, and stir. Static layering, the tert-butyl acetate phase obtained and the ...

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Abstract

The invention relates to a preparation method of cefdinir, which comprises the following steps: dissolving T15-AE active ester and 7-AVCA in a water system containing water-soluble organic solvent, carrying out condensation reaction at normal temperature under the action of organic alkali, and directly extracting without regulating the pH value to obtain a cefdinir intermediate; under the combined actions of mixed alkalis, efficiently removing an ester group protective agent from the cefdinir intermediate, and precipitating cefdinir compound salts; and dissolving the obtained cefdinir compound salts in water for decolorization, adding the water-soluble organic solvent, and acidifying to crystallize, thereby obtaining the cefdinir product. The invention is simple to operate, has the advantages of high product purity, low production cost and low environmental pollution, and is suitable for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of chemical medicine synthesis, and in particular relates to a synthesis method of cephalosporins. Background technique [0002] Cefdinir (cefdinir), the chemical name is (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-8-oxo -3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, molecular formula C 14 h 13 N 5 o 5 S 2 , the structure is shown in formula (I). [0003] [0004] As a third-generation cephalosporin, cefdinir has broad-spectrum antibacterial activity against G+ and G- bacteria, and can inhibit 90-100% of clinical isolates, such as methicillin-sensitive Staphylococcus aureus (MSSA), grapevine epidermidis Cocci (MSSE), Streptococcus (including Streptococcus pneumoniae), Haemophilus influenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Escherichia coli, even positive for Neisseria gonorrhoeae, Branham catarrhalis, indole Proteus also has a good curative effect,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/22C07D501/04C07D501/12
Inventor 厉昆李兰杰陈亮李啸风付凌燕金龙
Owner ZHEJIANG APELOA TOSPO PHARMA
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