Preparation method of cefdinir

A technology for cefdinir and cephalosporin, which is applied in the field of preparation of cefdinir, can solve the problems of affecting the purity of the final compound, difficult to realize large-scale production, complicated operation steps and the like, and achieves the effects of high recovery, low pollution and simple operation process

Inactive Publication Date: 2013-09-25
CHENGDU BRILLIANT PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

For example, in the patent No. WO9724358, the solvents used are N,N-dimethylacetamide (DMAC), p-toluenesulfonic acid (p-tsoH) and ether (Diethylether), which must be used when using toluenesulfonic acid A large amount of anti-solvent diethyl ether, and when removing the trityl protecting group, high-boiling point acid needs to be distilled under reduced pressure, the operation steps are cumbersome, and it is difficult to achieve large-scale production
The anti-solvent ether has a low flash point, and the risk factor in the production process is large, and the p-toluenesulfonic acid treatment process will also cause a large impact on the environment
In addition, a common disadvantage of the anti-solvent method is that due to concentration supersaturation, impurities are precipitated out together with the product. In prior art anti-solvent crystallization, the formation of agglomerates or the occurrence of morphological instability is often observed, affecting the Purity of final compound prepared

Method used

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  • Preparation method of cefdinir
  • Preparation method of cefdinir

Examples

Experimental program
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Effect test

Embodiment 1

[0027]A preparation method of cefdinir, comprising the following steps: (1) 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene -2-carboxylic acid (7-AVCA) in dichloromethane system, in the presence of tri-n-butylamine, with (Z)-2-(2-aminothiazol-4-yl)-2-trityloxyimino Thioacetic acid (S-2-benzothiazole) ester reacts to obtain cefdinirate liquid, dichloromethane is evaporated to obtain tan viscous cefdinirate solid; (2) cefdinirate obtained in (1) The ester solid was purified to obtain cefdinir. The specific operation is to add 7-AVCA, (Z)-2-(2-aminothiazol-4-yl)-2-trityloxyiminothioacetic acid (S-2-benzothiazole) into the reaction flask Esters, dichloromethane and tri-n-butylamine, start stirring reaction. In the preparation method of this cefdinir, the mol ratio of tri-n-butylamine and 7-AVCA is in the range of 2:1~3:1; the volume ratio range of dichloromethane and 7-AVCA is in the range of 15:1~20:1 In (1), the range of the reaction temperature in (1) is 20-30°C as...

Embodiment 2

[0029] As a further optimization, on the basis of Example 1, in this example, the purification in (2) is specifically divided into two steps: (21) Use the cefdiniroid solid prepared in (1) to Dissolve the acetonitrile, add phosphoric acid, after the solid is precipitated, filter and vacuum dry to obtain cefdinir phosphate; (22) dissolve the cefdinir phosphate obtained in (21) in a weak base, add activated carbon for decolorization and filtration, Cefdinir was obtained by acid gradient crystallization. The volume ratio of acetonitrile in (21) to 7-AVCA in (1) described in this implementation is 13:1~18:1; the molar ratio of phosphoric acid to 7-AVCA in (1) is 8:1~ 12:1, (21) The temperature of the vacuum oven in (21) is 20-40°C and the pressure is below -0.08Mpa to carry out the purification process. The selectivity of the purification process is strong, various impurities can be removed more effectively, and the molar yield of the synthetic compound of cefdinir is guaranteed ...

Embodiment 3

[0031] On the basis of Example 2, the reaction parameters were further optimized. In this example, 8.5g 7-AVCA, 22.92g (Z)-2-(2-aminothiazol-4-yl)- 2-trityloxyiminothioacetic acid (S-2-benzothiazole) ester, this ester is referred to as active ester, 183g methylene chloride, 18.16g tri-n-butylamine, start stirring. The temperature was 26°C, the temperature was kept and stirred for 5 hours, and the sample was taken to detect that 7-AVCA was less than 1%, and the reaction was stopped. At a pressure of -0.085Mp and a temperature of 24°C, dichloromethane was distilled off to obtain a tan viscous cefdiniroid solid.

[0032] Dissolve the cefdiniril solid with 127.8ml of acetonitrile, add 39.2g of phosphoric acid, stir until a large amount of light yellow solid precipitates, filter with suction, rinse the filter cake twice with a small amount of acetonitrile, the filter cake is at a pressure of -0.08Mpa and a temperature of 28°C After drying, 23g of yellow-white solid was obtained, a...

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Abstract

The invention discloses a preparation method of cefdinir, which comprises following steps: (1) letting 7-amino-3-vinyl-8-oxo-5-sulfur heterocyclic-1-aza-bicycle [4.2.0] symplectic-2-alkene-2-carboxylic acid (7-AVCA) react with (Benzothiazol-2-yl)-(Z)-2-trityloxyimino-2-(2-aminothiazole-4-yl)-thioacetate with the existence of Tributylamine in a dichloromethane system to obtain a cefdinir ester solution, then conducting steaming to remove the dichloromethane in order to obtain a sepia and thick cefdinir ester solid; (2) purifying the cefdinir ester solid obtained in (1) to obtain the cefdinir. In the invention, a cefdinir synthetic product with high recovery rate and high purity can be produced in the method without the application of a counter solvent. The preparation process of the product has the advantages that reaction conditions are gentle, operation processes are simple and pollutions are fewer etc. Therefore, the method is applicable in industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of cefdinir. Background technique [0002] Cefdinir, English name Cefdinir, chemical name is (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-8-oxo Substituent-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 , molecular weight 395.42, structural formula: [0003] [0004] Cefdinir is the third-generation broad-spectrum oral cephalosporin, which has the characteristics of broad antibacterial spectrum, strong antibacterial effect, high clinical efficacy, low toxicity, less allergic reactions, and convenient use. Compared with drugs such as cefixime, cefpodoxime, cefuroxime, cefaclor and cefprozil, it has the strongest antibacterial activity against staphylococci and is stable against β-lactamase. Widely used for cefdinir-sensitive Staphylococcus, Streptococcus, Pneumoc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/22C07D501/04C07D501/12
Inventor 苏忠海郭永军兰阳山
Owner CHENGDU BRILLIANT PHARMA CO LTD
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