CN110759874A - Preparation method of cefdinir impurity A - Google Patents
Preparation method of cefdinir impurity A Download PDFInfo
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- CN110759874A CN110759874A CN201911046751.6A CN201911046751A CN110759874A CN 110759874 A CN110759874 A CN 110759874A CN 201911046751 A CN201911046751 A CN 201911046751A CN 110759874 A CN110759874 A CN 110759874A
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- cefdinir
- impurity
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- cefdinir impurity
- ammonia water
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
- C07D277/593—Z being doubly bound oxygen or doubly bound nitrogen, which nitrogen is part of a possibly substituted oximino radical
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- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a preparation method of cefdinir impurity A, belonging to the field of pharmaceutical chemistry, which comprises the following steps: the cefdinir active new ester reacts with ammonia water, and then cefdinir impurity A is obtained through separation and purification. The preparation method of cefdinir impurity A has mild reaction conditions, does not relate to ultralow temperature reaction, reduces process steps, and is suitable for pilot scale of laboratories; the purity of the prepared cefdinir impurity A 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.
Description
Technical Field
The invention belongs to medicinal chemistry, and particularly relates to a preparation method of cefdinir impurity A.
Background
Cefdinir (Cefdinir) belongs to the third generation of cephalosporins, is a cephalosporin antibiotic developed by Japan Tanzea pharmaceutical industry Co., Ltd, is first marketed in Japan in 10 months in 1991, has a trade name of Cefzon, is marketed in the United states in 1997 12 months, is marketed in Korea in 1999, is approved in China in 2001 to be marketed in China, and is approved in 4 months in 2009 by Haian department of biomedical technology Limited to import raw material drugs, so that the Cefdinir is approved for β -lactamase, stable in antibacterial spectrum, strong in antibacterial action, high in clinical efficacy, low in toxicity, less in allergic reactions, convenient to use, compared with cefixime, cefuroxime, cefaclor, cefprozil and the like, Cefdinir has the strongest antibacterial activity against staphylococcus, and shows good antibacterial ability against gram-positive bacteria such as staphylococcus aureus, streptococcus, pneumococcus and the like.
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 cefdinir impurity A, 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 A comprises the following steps: reacting the cefdinir active new ester with ammonia water, and then separating and purifying to obtain cefdinir impurity A, wherein the chemical structural formula of the cefdinir impurity A is as follows:
the molecular formula of cefdinir impurity A is C5H6N4O2S, the molecular weight is 186, and the specific preparation process of the cefdinir impurity A is as follows:
preferably, the preparation method of cefdinir impurity a comprises the following steps:
weighing cefdinir active new ester, dissolving in tetrahydrofuran, cooling to 0-10 ℃, slowly dropwise adding ammonia water, controlling the temperature to 50-60 ℃ after the reaction is finished, carrying out decompression rotary evaporation to remove the solvent, adding pure water for ultrasonic dissolution, filtering, adjusting the pH value to weak acidity, and finally carrying out separation, elution and fractional freeze drying to obtain cefdinir impurity A with the purity of more than 95%.
Preferably, the amount of tetrahydrofuran used is 2-10mL per gram of cefdinir active neo-ester. By selecting the method, the yield of the cefdinir impurity A can be further improved.
Preferably, the amount of ammonia water is 0.2-0.4mL per gram of cefdinir active new ester, and the mass fraction of the ammonia water is 20% -25%. By selecting the method, the yield of the cefdinir impurity A can be further improved.
Preferably, 0.1 to 0.2mol/L hydrochloric acid is added to adjust the pH to 2 to 5. By selecting the method, the cefdinir impurity A can be prevented from being degraded.
Preferably, the solvent is removed by rotary evaporation under reduced pressure at the temperature of 50-60 ℃ after the reaction is carried out for 2-3 h. By such selection, the temperature can be better controlled to prevent the yield of cefdinir impurity A from decreasing.
Preferably, 10-30mL of pure water is added for ultrasonic dissolution relative to each gram of cefdinir active new ester.
Preferably, the step of separating is: the product after sonication, filtration and pH adjustment 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 A has mild reaction conditions, does not relate to ultralow temperature reaction, reduces process steps, and is suitable for pilot scale of laboratories; the purity of the prepared cefdinir impurity A 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.
Drawings
FIG. 1 is an HPLC detection spectrum of cefdinir impurity A (under the chromatographic conditions of content determination in Chinese pharmacopoeia 2015 edition);
FIG. 2 is a blank control HPLC detection spectrum (chromatographic conditions: under the content determination term of Chinese pharmacopoeia 2015 edition);
FIG. 3 is an NMR detected hydrogen spectrum of cefdinir impurity A;
fig. 4 is a NMR detected carbon spectrum of cefdinir impurity a;
fig. 5 is an HRMS detection mass spectrum of cefdinir impurity a.
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.
Example 1
In an embodiment of the preparation method of cefdinir impurity a of the present invention, the preparation method of the embodiment includes the following steps:
weighing 5g of cefdinir active new ester at room temperature, dissolving in 50mL of tetrahydrofuran, slowly dripping 2mL of 25% ammonia water after cooling to 0-10 ℃, controlling the temperature to 50 ℃ after 2h of reaction, carrying out reduced pressure rotary evaporation to remove the organic solvent, filtering, adjusting the pH value to 2-5 with 0.1mol/L hydrochloric acid, adding 50mL of pure water for ultrasonic dissolution, separating by using a 400mL C18 column, eluting with 1% of acetonitrile water, and freeze-drying fractions to obtain cefdinir impurity A with the purity of 95%, wherein the yield is 35.6%.
Example 2
In an embodiment of the preparation method of cefdinir impurity a of the present invention, the preparation method of the embodiment includes the following steps:
weighing 5g of cefdinir active new ester at room temperature, dissolving in 10mL of tetrahydrofuran, slowly dripping 1mL of 20% ammonia water after cooling to 0-10 ℃, controlling the temperature to 60 ℃ after 2h of reaction, carrying out reduced pressure rotary evaporation to remove the organic solvent, filtering, adjusting the pH value to 2-5 with 0.2mol/L hydrochloric acid, adding 150mL of pure water for ultrasonic dissolution, separating by using a 400mL C18 column, eluting with 1% acetonitrile water, and freeze-drying fractions to obtain cefdinir impurity A with the purity of 95%, wherein the yield is 35.3%.
Example 3
In an embodiment of the preparation method of cefdinir impurity a of the present invention, the preparation method of the embodiment includes the following steps:
weighing 5g of cefdinir active new ester at room temperature, dissolving in 50mL of tetrahydrofuran, slowly dripping 2mL of 25% ammonia water after cooling to 0-10 ℃, controlling the temperature to 50 ℃ after 2h of reaction, carrying out reduced pressure rotary evaporation to remove the organic solvent, filtering, adjusting the pH value to 2-5 with 0.1mol/L hydrochloric acid, adding 50mL of pure water for ultrasonic dissolution, separating by using a 400mL C18 column, eluting with 2% acetonitrile water, and freeze-drying fractions to obtain cefdinir impurity A with the purity of 95%, wherein the yield is 41.2%.
Example 4
In an embodiment of the preparation method of cefdinir impurity a of the present invention, the preparation method of the embodiment includes the following steps:
weighing 5g of cefdinir active new ester at room temperature, dissolving in 50mL of tetrahydrofuran, slowly dripping 2mL of 25% ammonia water after cooling to 0-10 ℃, controlling the temperature to 50 ℃ after 2h of reaction, carrying out reduced pressure rotary evaporation to remove the organic solvent, filtering, adjusting the pH value to 2-5 with 0.1mol/L hydrochloric acid, adding 50mL of pure water for ultrasonic dissolution, separating by using a 400mL C18 column, eluting with 3% acetonitrile water, and freeze-drying fractions to obtain cefdinir impurity A with the purity of 95%, wherein the yield is 39.3%.
Cefdinir impurity A prepared in examples 1-4 is identified by MS/NMR structure, and the spectra are shown in figure 3, figure 4 and figure 5. The structure of the prepared cefdinir impurity A is as shown in formula (1):
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 cefdinir impurity A is characterized by comprising the following steps: reacting the cefdinir active new ester with ammonia water, and then separating and purifying to obtain cefdinir impurity A, wherein the chemical structural formula of the cefdinir impurity A is as follows:
2. a process for the preparation of cefdinir impurity a as claimed in claim 1, comprising the steps of:
weighing cefdinir active new ester, dissolving in tetrahydrofuran, cooling to 0-10 ℃, slowly dropwise adding ammonia water, controlling the temperature to 50-60 ℃ after the reaction is finished, carrying out decompression rotary evaporation to remove the solvent, adding pure water for ultrasonic dissolution, filtering, adjusting the pH value to weak acidity, and finally carrying out separation, elution and fractional freeze drying to obtain cefdinir impurity A with the purity of more than 95%.
3. The process for preparing cefdinir impurity a according to claim 2, wherein the amount of tetrahydrofuran used is 2-10mL per gram of cefdinir active neo-ester.
4. The method for preparing cefdinir impurity A according to claim 2, wherein the amount of ammonia water is 0.2-0.4mL per gram of cefdinir active new ester, and the mass fraction of the ammonia water is 20% -25%.
5. The process for preparing cefdinir impurity A according to claim 2, wherein 0.1-0.2mol/L hydrochloric acid is added to adjust the pH to 2-5.
6. The process for preparing cefdinir impurity A as claimed in claim 2, wherein the solvent is removed by rotary evaporation under reduced pressure at 50-60 ℃ after reaction for 2-3 h.
7. The process for preparing cefdinir impurity A according to claim 2, wherein 10-30mL of pure water is added per gram of cefdinir active novel ester for ultrasonic dissolution.
8. A process for the preparation of cefdinir impurity a as claimed in claim 2, wherein the separation step is: the product after sonication, filtration and pH adjustment was separated on a 400ml C18 column.
9. A process for the preparation of cefdinir impurity a 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%.
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| CN201911046751.6A CN110759874A (en) | 2019-10-30 | 2019-10-30 | Preparation method of cefdinir impurity A |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101565427A (en) * | 2009-06-11 | 2009-10-28 | 浙江昂利康制药有限公司 | Preparation method of cefdinir |
| CN102516261A (en) * | 2011-12-20 | 2012-06-27 | 浙江国邦药业有限公司 | Preparation method of cefdinir |
| CN105130925A (en) * | 2015-07-28 | 2015-12-09 | 天津医药集团津康制药有限公司 | Preparation method of 2-(Z)-(2-aminothiazol-4-yl)-2-acetoxyiminoacetic acid-2-benzothiazolthioester |
| CN106967090A (en) * | 2017-04-19 | 2017-07-21 | 广州牌牌生物科技有限公司 | A kind of Cefdinir impurity M preparation method |
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2019
- 2019-10-30 CN CN201911046751.6A patent/CN110759874A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101565427A (en) * | 2009-06-11 | 2009-10-28 | 浙江昂利康制药有限公司 | Preparation method of cefdinir |
| CN102516261A (en) * | 2011-12-20 | 2012-06-27 | 浙江国邦药业有限公司 | Preparation method of cefdinir |
| CN105130925A (en) * | 2015-07-28 | 2015-12-09 | 天津医药集团津康制药有限公司 | Preparation method of 2-(Z)-(2-aminothiazol-4-yl)-2-acetoxyiminoacetic acid-2-benzothiazolthioester |
| CN106967090A (en) * | 2017-04-19 | 2017-07-21 | 广州牌牌生物科技有限公司 | A kind of Cefdinir impurity M preparation method |
Non-Patent Citations (1)
| Title |
|---|
| 国家药典委员会: "《中华人民共和国药典2015年版 二部》", 30 June 2015, 北京：中国医药科技出版社 * |
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