阅读说明：本技术 一种头孢唑林钠杂质c的制备方法 (Preparation method of cefazolin sodium impurity C ) 是由 袁晓 林顺权 于 2019-10-30 设计创作，主要内容包括：本发明公开了一种头孢唑林钠杂质C的制备方法。本发明采用四氮唑乙酸与特戊酰氯生成中间体A,中间体A再与母核7-ADCA反应,通过分离纯化得到头孢唑林钠杂质C,该制备方法中反应条件温和,不涉及超低温反应,减少了工艺步骤,适用于实验室中试放大。本发明制备得到的头孢唑林钠杂质C收率高,纯度达到95％,能满足头孢唑林钠质量研究需要,为头孢唑林钠国家质量标准提升提供了技术基础。(The invention discloses a preparation method of cefazolin sodium impurity C. According to the preparation method, the intermediate A is generated by adopting the tetrazoleacetic acid and the pivaloyl chloride, the intermediate A is then reacted with the mother nucleus 7-ADCA, and the cefazolin sodium impurity C is obtained through separation and purification. The cefazolin sodium impurity C prepared by the method has high yield, the purity reaches 95 percent, the requirement of the quality research of the cefazolin sodium can be met, and the technical basis is provided for the improvement of the national quality standard of the cefazolin sodium.)

1. A preparation method of cefazolin sodium impurity C is characterized in that an intermediate A is generated by tetrazoleacetic acid and pivaloyl chloride, the intermediate A reacts with 7-ADCA, and the cefazolin sodium impurity C is obtained through separation and purification, and the specific route is as follows:

2. the method for preparing cefazolin sodium impurity C according to claim 1, which comprises the following steps:

(1) weighing tetrazoleacetic acid, adding dichloromethane, cooling, dropwise adding triethylamine solvent, dropwise adding pyridine for catalysis, dropwise adding pivaloyl chloride, and stirring for reaction to obtain an intermediate A for later use;

(2) weighing 1.0-1.2 molar equivalent of 7-ADCA, adding dichloromethane, cooling, adding tetramethylguanidine for dissolving to obtain reaction liquid;

(3) and dropwise adding the reaction solution into the intermediate A, and after the reaction is finished, separating, purifying, freezing and drying the final reaction solution to obtain the cefazolin sodium impurity C.

3. The method for preparing cefazolin sodium impurity C according to claim 2, wherein in step (1), the ratio of tetrazoleacetic acid to dichloromethane is 1g: 5-15 mL.

4. The method for preparing cefazolin sodium impurity C according to claim 2, wherein in step (1), the amount of triethylamine reagent added is 0.8-1.2 molar equivalents of tetrazoleacetic acid.

5. The method for preparing cefazolin sodium impurity C according to claim 2, wherein in step (1), the amount of pivaloyl chloride added is 1.0-1.3 molar equivalents of tetrazoleacetic acid.

6. The method for preparing cefazolin sodium impurity C according to claim 2, wherein in step (2), the ratio of 7-ADCA to dichloromethane is 1g:5-10mL.

7. The method for preparing cefazolin sodium impurity C according to claim 2, wherein in step (2), the tetramethylguanidine solvate is added in an amount of 1.0 to 1.2 molar equivalents of 7-ADCA.

8. The process for preparing cefazolin sodium impurity C according to claim 2, wherein in step (3), the reaction is carried out at-20 ℃ for 2-3 h.

9. The method for preparing cefazolin sodium impurity C according to claim 2, wherein in step (3), the final reaction solution is separated and purified by a C18 column, then eluted with aqueous formic acid, aqueous acetonitrile acid and aqueous acetonitrile acid, the pure fractions are diluted and then applied to a PIPI-02 column, and after elution with acetonitrile, the fractions are freeze-dried.

Technical Field

The invention relates to the field of pharmaceutical impurities, and in particular relates to a preparation method of cefazolin sodium impurity C.

Background

Cefazolin sodium (Cefazolin sodium), also known as pioneer V, is the strongest cephalosporin of the first generation, has the advantages of strong bactericidal power, broad-spectrum antibacterial property, relative enzyme resistance, high efficiency, low toxicity, ideal pharmacokinetics and the like, has good antibacterial activity to other gram-positive cocci, and is the semi-synthetic cephalosporin commonly used in clinic at present. Due to the production process and structural characteristics of antibiotics, research on related substances (impurities) is a key and difficult point in the quality control of medicines. Due to different processes, related substances of cephalosporin drugs have different sources, side reactions are introduced in the synthesis process, and starting materials and intermediates, degradation and the like are introduced, so that the quality of the drugs is reduced, and meanwhile, the impurities can cause reactions such as antibiotic allergy and the like, and even endanger life in severe cases. Therefore, the research on the cefazolin sodium impurities is particularly important, the synthesis and separation of the impurity monomers are essential to the research on the structure, toxicity and quality control of the cefazolin sodium impurities, the contrast is provided for the research on the quality of the medicine impurities, the safety limit of the impurities is controlled, and the medicine quality and the medication safety are improved.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide the preparation method of the cefazolin sodium impurity C, the reaction condition in the preparation method is mild, the ultralow temperature reaction is not involved, the process steps are few, and the preparation method is suitable for pilot scale laboratory.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

the chemical structure of the cefazolin sodium impurity C is shown as the formula (I):

a preparation method of cefazolin sodium impurity C comprises the steps of generating an intermediate A by using tetrazoleacetic acid and pivaloyl chloride, reacting the intermediate A with 7-ADCA, and separating and purifying to obtain the cefazolin sodium impurity C, wherein the specific route is as follows:

preferably, the preparation method of cefazolin sodium impurity C specifically comprises the following steps: (1) weighing tetrazoleacetic acid, adding dichloromethane, cooling, dropwise adding triethylamine solvent, dropwise adding pyridine for catalysis, dropwise adding pivaloyl chloride, and stirring for reaction to obtain an intermediate A for later use;

(2) weighing 1.0-1.2 molar equivalent of 7-ADCA, adding dichloromethane, cooling, adding tetramethylguanidine for dissolving to obtain reaction liquid;

(3) and dropwise adding the reaction solution into the intermediate A, and after the reaction is finished, separating, purifying, freezing and drying the final reaction solution to obtain the cefazolin sodium impurity C.

Preferably, the preparation method of cefazolin sodium impurity C specifically comprises the following steps:

(1) weighing tetrazoleacetic acid, adding dichloromethane, cooling to-20 ℃, dropwise adding triethylamine solvent, dropwise adding pyridine for catalysis, dropwise adding pivaloyl chloride, and stirring at-20 ℃ for reaction for 2 hours to obtain an intermediate A for later use;

(2) weighing 1.0-1.2 molar equivalent of 7-ADCA, adding dichloromethane, cooling to-20 ℃, adding tetramethylguanidine for dissolving to obtain a reaction solution;

(3) and dropwise adding the reaction solution into the intermediate A, reacting at-20 ℃, and finally separating, purifying, freezing and drying the reaction solution to obtain the cefazolin sodium impurity C. By optimizing the reaction temperature and the reaction time, the yield of the cefazolin sodium impurity C is improved.

Preferably, in the step (1), the ratio of the tetrazoleacetic acid to the dichloromethane is 1g: 5-15 mL.

Preferably, in the step (1), the addition amount of the triethylamine solvent is 0.8-1.2 molar equivalents of the tetrazoleacetic acid.

Preferably, in the step (1), the addition amount of pivaloyl chloride is 1.0-1.3 molar equivalents of tetrazoleacetic acid.

Preferably, in the step (2), the ratio of 7-ADCA to dichloromethane is 1g:5-10mL.

Preferably, in the step (2), the tetramethylguanidine solvate is added in an amount of 1.0 to 1.2 molar equivalents based on 7-ADCA.

Preferably, in the step (3), the reaction is carried out at-20 ℃ for 2-3 h.

Preferably, in the step (3), the final reaction solution is separated and purified by a C18 column, and then eluted with aqueous formic acid, aqueous acetonitrile acid, and aqueous acetonitrile acid, respectively, and the pure fractions are diluted and then applied to a PIPI-02 column, eluted with acetonitrile, and then freeze-dried.

According to the invention, by optimizing the reaction conditions such as the raw material dosage, the reaction temperature, the reaction time and the like, the yield of the prepared cefazolin sodium impurity C is high, and the purity reaches 95%.

Compared with the prior art, the invention has the beneficial effects that:

according to the preparation method, the intermediate A is generated by adopting the tetrazoleacetic acid and the pivaloyl chloride, the intermediate A is then reacted with the mother nucleus 7-ADCA, and the cefazolin sodium impurity C is obtained through separation and purification. The cefazolin sodium impurity C prepared by the method has high yield, the purity reaches 95 percent, the requirement of the quality research of the cefazolin sodium can be met, and the technical basis is provided for the improvement of the national quality standard of the cefazolin sodium.

Drawings

FIG. 1 is an HPLC detection spectrum (chromatographic conditions: European pharmacopoeia 9.0) of cefazolin sodium impurity C.

FIG. 2 is an HPLC detection spectrum of a blank control (chromatographic conditions: European pharmacopoeia 9.0 edition).

FIG. 3 is an NMR detected hydrogen spectrum of cefazolin sodium impurity C.

FIG. 4 is a carbon spectrum of the NMR detection of cefazolin sodium impurity C.

FIG. 5 is the HRMS detection mass spectrum of cefazolin sodium impurity C.

Detailed Description

To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples. It will be understood by those skilled in the art that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.