阅读说明：本技术 一种头孢地尼杂质b的制备方法 (Preparation method of cefdinir impurity B ) 是由 袁晓 林顺权 于 2019-10-30 设计创作，主要内容包括：本发明涉及一种头孢地尼杂质B的制备方法,属于药物化学领域,所述制备方法为：将头孢地尼与双氧水反应,然后通过分离纯化得到头孢地尼杂质B。本发明头孢地尼杂质B的制备方法,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；制备得到的头孢地尼杂质B纯度达到95％以上,能满足质量研究需要,同时为头孢地尼国家质量标准提升提供了技术基础。(The invention relates to a preparation method of cefdinir impurity B, belonging to the field of pharmaceutical chemistry, and the preparation method comprises the following steps: reacting cefdinir with hydrogen peroxide, and then separating and purifying to obtain cefdinir impurity B. The preparation method of cefdinir impurity B has mild reaction conditions, does not involve ultralow temperature reaction, reduces process steps, and is suitable for pilot scale of laboratories; the purity of the prepared cefdinir impurity B reaches more than 95 percent, the quality research requirement can be met, and meanwhile, a technical basis is provided for the national quality standard improvement of cefdinir.)

1. A preparation method of cefdinir impurity B is characterized by comprising the following steps: reacting cefdinir with hydrogen peroxide, and then separating and purifying to obtain cefdinir impurity B, wherein the chemical structural formula of the cefdinir impurity B is as follows:

2. a process for the preparation of cefdinir impurity B as claimed in claim 1, comprising the steps of:

weighing cefdinir, adding pure water, starting stirring, gradually dripping ammonia water until the ammonia water is just dissolved, adding hydrogen peroxide, starting temperature control reaction, adjusting the pH value to 4-6 after the reaction is finished, separating, eluting, and freeze-drying fractions to obtain cefdinir impurity B with the purity of more than 90%.

3. A process for the preparation of cefdinir impurity B as claimed in claim 2, wherein the amount of purified water used is 2-60mL per gram of cefdinir.

4. The process for preparing cefdinir impurity B as claimed in claim 2, wherein ammonia water with a mass fraction of 1-10% is gradually dropped until just dissolving.

5. The method for preparing cefdinir impurity B as claimed in claim 2, wherein the amount of hydrogen peroxide added is 1-4mL per gram of cefdinir, and the mass fraction of hydrogen peroxide is 10-30%.

6. The process for preparing cefdinir impurity B according to claim 2, wherein the temperature control reaction is carried out at 0-30 ℃ for 2-4 h.

7. A process for the preparation of cefdinir impurity B as claimed in claim 2, wherein the separation step is: the reacted product was separated on a 400ml C18 column.

8. A process for the preparation of cefdinir impurity B as claimed in claim 2, wherein the elution step is: the elution is carried out with acetonitrile water in a volume fraction of 1-3%.

Technical Field

The invention belongs to medicinal chemistry, and particularly relates to a preparation method of cefdinir impurity B.

Background

Cefdinir (Cefdinir) belongs to the third generation of cephalosporins, is a cephalosporin antibiotic developed by Japan Tengze pharmaceutical industry Co., Ltd, is firstly listed in Japan in 10 months in 1991 with the trade name of Cefzon, is listed in the United states in 1997 12 months, is listed in Korea in 1999, is approved to be listed in China in 2001, and applies for import of raw material medicines by Haian special biological medicine technology Limited company in 4 months in 2009 to obtain SFDA approval. Cefdinir is stable to beta-lactamase, has wide antibacterial spectrum, strong antibacterial effect, high clinical curative effect, low toxicity, less anaphylactic reaction and convenient use. Compared with the drugs such as cefixime, cefuroxime, cefaclor, cefprozil and the like, cefdinir has the strongest antibacterial activity on staphylococcus, and has good antibacterial ability on gram-positive bacteria such as staphylococcus aureus, streptococcus, pneumococcus and the like. The chemical structure of the compound is characterized in that aminothiazolyl and hydroxyimino are introduced to the side chain at the 7-position of a 7-aminocephalosporanic acid skeleton, and vinyl is introduced to the side chain at the 3-position. Cefdinir can be used for treating acute bronchitis, otitis media, pharyngolaryngitis, pneumonia, gonococcal urethritis, mastitis, postoperative wound secondary infection, lymphangitis, skin and soft tissue infection, etc. clinically.

Cefdinir impurity is a kind of component without any drug effect in the medicine, and part of impurities have carcinogenicity and teratogenicity, and the impurities have adverse reaction, thus seriously affecting the medication safety and bringing immeasurable risk to the user.

The cephalosporium imitation drugs in China have various preparation processes, so that the produced impurities are different, and different from the original drug research process, the impurity content and the type of the cephalosporium imitation drugs also have different contents, but the domestic research on the generation mechanism, the synthesis preparation, the separation and purification and the pharmacology of the impurities cannot be systematically and comprehensively carried out, and the separation and purification technology is limited by a plurality of tautomers of some impurities, so that monomer impurities are difficult to obtain, the systematic research cannot be carried out, and the quality of the imitation drugs is obviously inferior to that of the original drug research. Therefore, the method is particularly important for the research of impurities, and the synthesis and separation of the impurity monomer are essential for the research of structure, toxicity and quality control of the impurity monomer, and have important significance for the improvement of the quality of domestic medicines.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides the preparation method of the cefdinir impurity B, which has mild reaction conditions, does not relate to ultralow temperature reaction, has few process steps and is suitable for pilot scale of laboratories.

In order to achieve the purpose, the invention adopts the technical scheme that:

a preparation method of cefdinir impurity B comprises the following steps: reacting cefdinir with hydrogen peroxide, and then separating and purifying to obtain cefdinir impurity B, wherein the chemical structural formula of the cefdinir impurity B is as follows:

the molecular formula of cefdinir impurity B is C₁₄H₁₃N₅O₆S₂And the molecular weight is 411, the specific preparation process of cefdinir impurity B provided by the invention is as follows:

preferably, the preparation method of cefdinir impurity B comprises the following steps:

weighing cefdinir, adding pure water, starting stirring, gradually dripping ammonia water until the ammonia water is just dissolved, adding hydrogen peroxide, starting temperature control reaction, adjusting the pH value to 4-6 after the reaction is finished, separating, eluting, and freeze-drying fractions to obtain cefdinir impurity B with the purity of more than 90%.

Preferably, the amount of pure water is 2-60mL per gram of cefdinir.

Preferably, ammonia water with the mass fraction of 1-10% is gradually dropped until just dissolving.

Preferably, the adding amount of the hydrogen peroxide is 1-4mL and the mass fraction of the hydrogen peroxide is 10-30% relative to each gram of cefdinir. The selection is favorable for the full reaction of the raw materials to generate cefdinir impurity B.

Preferably, the temperature of the temperature control reaction is 0-30 ℃, and the reaction time is 2-4 h. The selection is favorable for the full reaction of the raw materials to generate cefdinir impurity B.

Preferably, the step of separating is: the reacted product was separated on a 400ml C18 column.

Preferably, the step of eluting is: the elution is carried out with acetonitrile water in a volume fraction of 1-3%.

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

the preparation method of cefdinir impurity B has mild reaction conditions, does not involve ultralow temperature reaction, reduces process steps, and is suitable for pilot scale of laboratories; the purity of the prepared cefdinir impurity B reaches over 90 percent, the quality research requirement can be met, and meanwhile, a technical basis is provided for the national quality standard improvement of cefdinir.

Drawings

FIG. 1 is an HPLC detection spectrum of cefdinir impurity B (under the chromatographic conditions of the related substances in Chinese pharmacopoeia 2015 edition);

FIG. 2 is a blank control HPLC detection spectrum (chromatographic conditions: under the measurement items of related substances in Chinese pharmacopoeia 2015 edition);

FIG. 3 is an NMR detected hydrogen spectrum of cefdinir impurity B;

fig. 4 is a NMR detected carbon spectrum of cefdinir impurity B;

fig. 5 is an HRMS detection mass spectrum of cefdinir impurity B.

Detailed Description

To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to the accompanying drawings and specific embodiments.