CN110759932A - Preparation method of cefazolin sodium impurity C - Google Patents
Preparation method of cefazolin sodium impurity C Download PDFInfo
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- CN110759932A CN110759932A CN201911050271.7A CN201911050271A CN110759932A CN 110759932 A CN110759932 A CN 110759932A CN 201911050271 A CN201911050271 A CN 201911050271A CN 110759932 A CN110759932 A CN 110759932A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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Abstract
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.
Description
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.
Example 1
The preparation method of cefazolin sodium impurity C described in this embodiment includes the following steps:
(1) weighing 2g of tetrazoleacetic acid, adding 10mL of dichloromethane, cooling to-20 ℃, dropwise adding 2.1mL of triethylamine solvent, dropwise adding 4 drops of pyridine for catalysis, slowly dropwise adding 2mL of pivaloyl chloride, and stirring at-20 ℃ for reaction for 2 hours to obtain an intermediate A for later use;
(2) weighing 3.5g of 7-ADCA, adding 17.5mL of dichloromethane, cooling to-20 ℃, adding 2mL of tetramethylguanidine for dissolving and cleaning to obtain a reaction solution;
(3) dropwise adding the reaction liquid into the reaction liquid intermediate A at the speed of 3 drops per second, and reacting for 2 hours at the temperature of minus 20 ℃; separating and purifying the reaction solution by a 70mLC18 column, eluting by 300mL of 0.05% formic acid water, 1% acetonitrile acid water and 3% acetonitrile acid water respectively, diluting the pure fraction by 2 times, loading the diluted pure fraction to a 70mL PIPI-02 column, eluting by 80% acetonitrile, and freeze-drying to obtain cefazolin sodium impurity C with the purity of 95%, wherein the yield is 52.4%.
Example 2
The preparation method of cefazolin sodium impurity C described in this embodiment includes the following steps:
(1) weighing 2g of tetrazoleacetic acid, adding 20mL of dichloromethane, cooling to-20 ℃, dropwise adding 1.7mL of triethylamine solvent, dropwise adding 2 drops of pyridine for catalysis, slowly dropwise adding 1.87mL of pivaloyl chloride, and stirring at-20 ℃ for reaction for 2 hours to obtain an intermediate A for later use;
(2) weighing 3.5g of 7-ADCA, adding 35mL of dichloromethane, cooling to-20 ℃, adding 2mL of tetramethylguanidine for dissolving and cleaning to obtain a reaction solution;
(3) the reaction solution was added dropwise to the reaction solution intermediate A at 3 drops per second, and reacted at-20 ℃. Separating and purifying the reaction solution by a 70mLC18 column, eluting by 300mL of 0.05% formic acid water, 1% acetonitrile acid water and 3% acetonitrile acid water respectively, diluting the pure fraction by 2 times, loading the diluted pure fraction to a 70mLPIPI-02 column, eluting by 80% acetonitrile, and freeze-drying to obtain cefazolin sodium impurity C with the purity of 95%, wherein the yield is 48.9%.
Example 3
The preparation method of cefazolin sodium impurity C described in this embodiment includes the following steps:
(1) weighing 2g of tetrazoleacetic acid, adding 30mL of dichloromethane, cooling to-20 ℃, dropwise adding 2.1mL of triethylamine solvent, dropwise adding 10 drops of pyridine for catalysis, slowly dropwise adding 2mL of pivaloyl chloride, and stirring at-20 ℃ for reaction for 2 hours to obtain an intermediate A for later use;
(2) weighing 3.5g of 7-ADCA, adding 30mL of dichloromethane, cooling to-20 ℃, adding 2mL of tetramethylguanidine for dissolving and cleaning to obtain a reaction solution;
(3) the reaction solution was added dropwise to the reaction solution intermediate A at 3 drops per second and reacted at-20 ℃ for 2.5 hours. Separating and purifying the reaction solution by a 70mLC18 column, eluting by 300mL of 0.05% formic acid water, 1% acetonitrile acid water and 3% acetonitrile acid water respectively, diluting the pure fraction by 2 times, loading the diluted pure fraction to a 70mLPIPI-02 column, eluting by 80% acetonitrile, and freeze-drying to obtain cefazolin sodium impurity C with the purity of 95%, wherein the yield is 48.6%.
Example 4
The preparation method of cefazolin sodium impurity C described in this embodiment includes the following steps:
(1) weighing 2g of tetrazoleacetic acid, adding 30mL of dichloromethane, cooling to-20 ℃, dropwise adding 2.5mL of triethylamine solvent, dropwise adding 4 drops of pyridine for catalysis, slowly dropwise adding 2.43mL of pivaloyl chloride, and stirring at-20 ℃ for reaction for 2 hours to obtain an intermediate A for later use;
(2) meanwhile, 3.5g of 7-ADCA is additionally weighed, 30mL of dichloromethane is added, the temperature is reduced to-20 ℃, and 2.5mL of tetramethylguanidine is added for dissolving and cleaning to obtain reaction liquid;
(3) the reaction solution was added dropwise to the reaction solution intermediate A at 3 drops per second and reacted at-20 ℃ for 3 hours. Separating and purifying the reaction solution by a 70mLC18 column, eluting by 300mL of 0.05% formic acid water, 1% acetonitrile acid water and 3% acetonitrile acid water respectively, diluting the pure fraction by 2 times, loading the diluted pure fraction to a 70mL PIPI-02 column, eluting by 80% acetonitrile, and freeze-drying to obtain cefazolin sodium impurity C with the purity of 95%, wherein the yield is 58.4%.
The HPLC detection spectrum of the cefazolin sodium impurity C prepared in the examples 1-4 is shown in figure 1, and the blank control HPLC detection spectrum is shown in figure 2. The cefazolin sodium impurity C prepared in the embodiments 1-4 is identified through MS/NMR structure, and the structure of the cefazolin sodium impurity C is determined to be as shown in the figure 3, the figure 4 and the figure 5:
the preparation method disclosed by the invention is mild in reaction conditions, does not involve ultralow temperature reaction, reduces process steps, is suitable for laboratory pilot scale, is high in yield of the prepared cefazolin sodium impurity C, reaches the purity of 95%, can be used as a reference substance of impurities in cefazolin sodium raw materials or preparation detection, improves the accurate positioning and qualitative performance of the cefazolin sodium impurity C in production quality control of cefazolin sodium, is beneficial to enhancing the control of the impurities, and improves the quality of a cefazolin sodium preparation, so that the safety and effectiveness of 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 (9)
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.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102219795A (en) * | 2011-07-28 | 2011-10-19 | 哈药集团制药总厂 | Method for preparing ceftezole sodium |
| CN109369682A (en) * | 2018-12-12 | 2019-02-22 | 河北合佳医药科技集团股份有限公司 | A kind of preparation method of Cefazolin -3- methyl analogue |
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- 2019-10-30 CN CN201911050271.7A patent/CN110759932A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102219795A (en) * | 2011-07-28 | 2011-10-19 | 哈药集团制药总厂 | Method for preparing ceftezole sodium |
| CN109369682A (en) * | 2018-12-12 | 2019-02-22 | 河北合佳医药科技集团股份有限公司 | A kind of preparation method of Cefazolin -3- methyl analogue |
Non-Patent Citations (1)
| Title |
|---|
| ALBERTOPALOMO-COLL，等: "Efficient procedure for c "- 3 substitution and c - 7 n-acylation of 7-aminocepha-losporanic acid (7-aca): Synthesis of cefazolin antibiotic and related compounds", 《TETRAHEDRON》 * |
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