CN110759931A

CN110759931A - Preparation method of cefazolin sodium impurity K

Info

Publication number: CN110759931A
Application number: CN201911050273.6A
Authority: CN
Inventors: 袁晓; 林顺权
Original assignee: Pi & Pi Technology Inc
Current assignee: Pi & Pi Technology Inc
Priority date: 2019-10-30
Filing date: 2019-10-30
Publication date: 2020-02-07

Abstract

The invention discloses a preparation method of cefazolin sodium impurity K. The invention obtains the cefazolin sodium impurity K by reacting cefazolin sodium with ammonium carbonate, crystallizing, pulping, filtering and drying. The preparation method disclosed by the invention is mild in reaction conditions, simple in steps, free of ultralow temperature reaction and suitable for pilot scale of laboratories. The cefazolin sodium impurity K 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.

Description

Preparation method of cefazolin sodium impurity K

Technical Field

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

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 provides the preparation method of the cefazolin sodium impurity K, which has mild reaction conditions and simple process steps, does not involve ultralow temperature reaction, and is suitable for pilot scale of laboratories.

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

the chemical structure of the cefazolin sodium impurity K in the invention is shown as the formula (I):

a preparation method of cefazolin sodium impurity K comprises the steps of taking cefazolin sodium as a raw material, reacting with ammonium carbonate, crystallizing, pulping, filtering and drying to obtain cefazolin sodium impurity K, wherein the specific route is as follows:

preferably, dissolving cefazolin sodium in DMF at room temperature, adding ammonium carbonate, heating in an oil bath for reaction, adding water after the reaction to separate out crystals, filtering, adding water for pulping, filtering, and drying to obtain cefazolin sodium impurity K.

Preferably, the addition ratio of the cefazolin sodium to DMF is 1g:1-5 mL.

Preferably, the mass ratio of the cefazolin sodium to the ammonium carbonate is 1: 1-1.5.

Preferably, the temperature of the oil bath heating reaction is 40-50 ℃, and the time of the oil bath heating reaction is 5-10 h.

Preferably, water is added to precipitate crystals after the reaction is finished, and the adding ratio of the cefazolin sodium to the water is 1g:5-15 mL.

Preferably, in the process of pulping by adding water, the adding ratio of the cefazolin sodium to the water is 1g:5-10mL, and the pulping time is 2-3 h.

By optimizing the reaction conditions, the yield of the prepared cefazolin sodium impurity K is 39.8-45.3%, and the purity is 95%.

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

the invention obtains the cefazolin sodium impurity K by reacting cefazolin sodium with ammonium carbonate, crystallizing, pulping, filtering and drying. The preparation method disclosed by the invention is mild in reaction conditions, simple in steps, free of ultralow temperature reaction and suitable for pilot scale of laboratories. The cefazolin sodium impurity K prepared by the method has high yield and high purity, can meet the requirement of the quality research of cefazolin sodium, and provides a technical basis for the improvement of the national quality standard of cefazolin sodium.

Drawings

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

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

FIG. 3 is an NMR spectrum of cefazolin sodium impurity K.

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

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

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.

In the following examples, the cefazolin sodium raw material drug is cefazolin sodium with the purity of 99.9%;

DMF: dimethylformamide (DMF).

Example 1

The preparation method of cefazolin sodium impurity K in the embodiment comprises the following steps: weighing 10g of cefazolin sodium bulk drug at room temperature, dissolving in 20mL of DMF, adding 10g of ammonium carbonate, heating in an oil bath at 50 ℃ for 5 hours to obtain reaction liquid, adding 100mL of water, precipitating crystals, filtering, adding 50mL of water, pulping for 3 hours, filtering and drying to obtain cefazolin sodium impurity K with the purity of 95%, wherein the yield is 40.1%.

Example 2

The preparation method of cefazolin sodium impurity K in the embodiment comprises the following steps: weighing 10g of cefazolin sodium bulk drug at room temperature, dissolving in 20mL of DMF, adding 15g of ammonium carbonate, heating in an oil bath at 40 ℃ for 6 hours to obtain reaction liquid, adding 150mL of water, precipitating crystals, filtering, adding 100mL of water, pulping for 2 hours, filtering and drying to obtain cefazolin sodium impurity K with the purity of 95%, wherein the yield is 45.3%.

Example 3

The preparation method of cefazolin sodium impurity K in the embodiment comprises the following steps: weighing 10g of cefazolin sodium bulk drug at room temperature, dissolving in 50mL of DMF, adding 12g of ammonium carbonate, heating in an oil bath at 45 ℃ for reaction for 10h to obtain reaction liquid, adding 50mL of water, precipitating crystals, filtering, adding 90mL of water, pulping for 2.5h, filtering and drying to obtain cefazolin sodium impurity K with the purity of 95%, wherein the yield is 42.2%.

Example 4

The preparation method of cefazolin sodium impurity K in the embodiment comprises the following steps: weighing 10g of cefazolin sodium bulk drug at room temperature, dissolving in 10mL of DMF, adding 15g of ammonium carbonate, heating in an oil bath at 40 ℃ for reaction for 10h to obtain reaction liquid, adding 150mL of water, precipitating crystals, filtering, adding 80mL of water, pulping for 2h, filtering and drying to obtain cefazolin sodium impurity K with the purity of 95%, wherein the yield is 39.8%.

The HPLC detection spectrum of the cefazolin sodium impurity K prepared in the examples 1-4 is shown in figure 1, and the HPLC detection spectrum of the blank control is shown in figure 2. The cefazolin sodium impurity K prepared in the examples 1-4 is identified by MS/NMR structure, and the structure of the cefazolin sodium impurity K is determined to be as shown in the formula (I):

the preparation method disclosed by the invention is mild in reaction conditions, simple in preparation process, free from ultralow temperature reaction and suitable for pilot scale of a laboratory. According to the invention, by optimizing reaction conditions, the yield of the prepared cefazolin sodium impurity K is 39.8-45.3%, the purity is 95%, the cefazolin sodium impurity K can be used as a reference substance of impurities in cefazolin sodium raw material or preparation detection, the accurate positioning and qualitative determination of the cefazolin sodium impurity K in the production quality control of cefazolin sodium are improved, the control of the impurities is favorably strengthened, the quality of the cefazolin sodium preparation is improved, and the safety and effectiveness of the clinical use of the cefazolin sodium preparation are ensured.

Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. A preparation method of cefazolin sodium impurity K is characterized in that cefazolin sodium is used as a raw material and reacts with ammonium carbonate, and after crystallization and pulping, filtration and drying are carried out to obtain cefazolin sodium impurity K, wherein the specific route is as follows:

2. the method for preparing cefazolin sodium impurity K according to claim 1, wherein cefazolin sodium is dissolved in DMF at room temperature, ammonium carbonate is added, the reaction is carried out by heating in an oil bath, water is added after the reaction to separate out crystals, the crystals are filtered, water is added for pulping, and the cefazolin sodium impurity K is obtained after filtering and drying.

3. The method for preparing cefazolin sodium impurity K according to claim 2, wherein the ratio of cefazolin sodium to DMF is 1g:1-5 mL.

4. The method for preparing cefazolin sodium impurity K according to claim 2, wherein the mass ratio of cefazolin sodium to ammonium carbonate is 1: 1-1.5.

5. The process for preparing cefazolin sodium impurity K according to claim 2, wherein the reaction temperature in the oil bath is 40-50 ℃ and the reaction time in the oil bath is 5-10 h.

6. The method for preparing cefazolin sodium impurity K according to claim 2, wherein water is added after the reaction to precipitate crystals, and the addition ratio of cefazolin sodium to water is 1g:5-15 mL.

7. The method for preparing cefazolin sodium impurity K according to any one of claims 2-6, wherein the ratio of cefazolin sodium to water is 1g:5-10mL, and the pulping time is 2-3 h.