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New preparation method of Cefdinir

A technology of cefdinir and solvent, which is applied to the preparation of cefdinir and the preparation field of cefdinir, and can solve the problems of reduced purity, difficult storage, reduced content and the like

Active Publication Date: 2010-08-11
ZHEJIANG YONGNING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] Example 2: U.S. Patent US 2004 / 0242557 A1 describes: using acetylated aminothiaxamic acid as the starting material, first reacting with benzothiazole disulfide (DM) to generate an intermediate active ester: 2-acetoxyimino-2 -(2-amino-4-thiazolyl)-(z)-benzothiazolyl thioacetate (abbreviated as AT-AE), then condensed with 7-AVCA, and finally hydrolyzed to generate cefdinir, with a yield of 75-80% , but the intermediate active ester AE has poor stability, and the content decreases by 5.2% after six months of storage, and the content drops from 97.4% to 92.2%
The purity is reduced by 2.5%, and it is not easy to store

Method used

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  • New preparation method of Cefdinir
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  • New preparation method of Cefdinir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Add 20g (87.3mmol) (Z)-2-(2-aminothiazol-4-yl)-2-acetoxyiminoacetic acid to a 500ml three-necked sesame cake equipped with mechanical stirring, a constant pressure dropping funnel, and a thermometer (ATAA), 13g (96.0mmol) anhydrous 1-hydroxybenzotriazole (HOBT), 100ml dimethylformamide (DMF), stir at 15--20°C to make it completely dissolved, add dropwise 23.4g (113.5 mmol) dicyclohexylcarbodiimide (DCC), after adding, stir and react at 15--20°C for 30min, filter out the by-product N,N'-dicyclohexylurea, wash with 20ml DMF, add 180ml water to the filtrate, and precipitate A large number of light yellow solids were filtered, and the filter cake was washed with 20ml of DMF solution (volume ratio DMF: water = 1:2), and dried under vacuum at room temperature to obtain 27.8g of 1-[(Z)-2-(2-amino-4-thiazolyl )-2-(acetoxyimino)acetoxy]benzotriazole (AB-AE), yield 92%, purity 98.5%.

[0050] AB-AE 1 HNMR (DMSO-d6):

[0051] &=2.088ppm (s, 3H, COCH3), &=7.431ppm (s, 2H, NH2), ...

Embodiment 2-4

[0054] Embodiment 2-4 is by embodiment 1 method, and the molar ratio of raw and auxiliary materials is also with embodiment 1:

[0055] Example

Embodiment 5

[0057] In the 500ml three-necked sesame cake equipped with mechanical stirring and thermometer, add 16g (70.7mmol) 7-amino-3-vinyl-3-cephalosporin-4-carboxylic acid (7-AVCA), 240ml acetone, 24ml water, Add 9.3g (91.9mmol) triethylamine at 5--10°C to dissolve it completely, then add 28.2g (81.3mmol) AB-AE, react at room temperature until clarification takes about 60min, add 240ml into a 1000ml separating funnel Water, 160ml of dichloromethane to separate layers, transfer the water phase to a 500ml three-necked flask, add saturated sodium carbonate solution dropwise at 5--10°C, control the pH to 8.0-8.5, complete hydrolysis in 45min, and use 5mol / L The sulfuric acid solution was slowly adjusted to pH=3.0. Filter and wash twice with 20ml of water respectively. Dry under vacuum at room temperature. Obtained 25.2 g of light yellow cefdinir, compared with the standard substance, the result was consistent, it was cefdinir, the yield was 90.1%, the purity measured by HPLC: 99.4%, th...

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Abstract

The invention provides a new preparation method of Cefdinir, in particular to a method for preparing Cefdinir from an intermediate of a new active ester. The preparation method comprises the following steps: using (Z)-2-(2-aminothiazole-4-yl)-2-acetoxyiminoacetic acid (ATAA) and 1-hydroxybenzotrizole (HOBT) to be subject to dehydrolysis condensation to generate a new active ester, i.e. 1-[(Z)-2-(2-amino-4-thiazyl)-2-(acetoxyimino) acetoxy] benzotrizole (AB-AE), then using the AB-AE and 7-amino-vinyl-3-cephalosporin-4-carboxylic acid (7-AVCA) as raw materials to be subject to the condensation reaction, and then hydrolyzing to prepare the Cefdinir. The invention has the advantages that the AB-AE has good stability and is convenient to store, the yield of the synthesized Cefdinir is more than 90%, and the process is more applicable to the industrial production.

Description

technical field [0001] The invention provides a new method for preparing cefdinir, in particular, relates to a new method for preparing cefdinir through a novel active ester intermediate. It belongs to the field of medicinal chemistry. Background technique [0002] Cefdinir: (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. The structural formula is as follows: [0003] [0004] It is a third-generation oral cephalosporin developed on the basis of cefixime. Its chemical structure is characterized by the introduction of aminothiazolyl and hydroxylimino groups on the 7-position side chain of the 7-aminocephalosporanic acid skeleton, and the 3-position side chain Introduce vinyl on top. Substituting the hydroxymethoxyimino group on the 7-position side chain of cefixime with a hydroxyimino group not only maintains the antibacterial effect of cefixime on G-bacteria, but also enhances the ef...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/22C07D501/04C07D417/12
Inventor 方善综汤有坚徐辉葛学苏
Owner ZHEJIANG YONGNING PHARMA
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