CN113150010A - 7-aminocephalosporanic acid purification process - Google Patents
7-aminocephalosporanic acid purification process Download PDFInfo
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- CN113150010A CN113150010A CN202110418809.6A CN202110418809A CN113150010A CN 113150010 A CN113150010 A CN 113150010A CN 202110418809 A CN202110418809 A CN 202110418809A CN 113150010 A CN113150010 A CN 113150010A
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- aminocephalosporanic acid
- acid
- aminocephalosporanic
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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
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention belongs to the field of chemistry, and particularly relates to a 7-aminocephalosporanic acid purification process, which comprises the following steps: adding a solvent and 7-aminocephalosporanic acid into a reaction tank, and fully stirring; adding hydrochloric acid into the reaction tank, and fully stirring to obtain a crystallization liquid; carrying out throw filtration on the crystallization liquid by adopting a flat plate type centrifuge to obtain a wet product; and (3) drying the wet product in vacuum to obtain the purified product of 7-aminocephalosporanic acid. The method has the characteristics of simple and convenient process operation and high product yield, the relevant substances of the purified 7-aminocephalosporanic acid are obviously reduced, and the application of the method in the synthesis of cefotaxime sodium can control the relevant substances at a lower level.
Description
Technical Field
The invention belongs to the field of chemistry, and particularly relates to a 7-aminocephalosporanic acid purification process.
Background
Cefotaxime sodium as the third-generation cephalosporin antibiotics has the characteristics of wide antibacterial spectrum and strong antibacterial action. Has high antibacterial activity and strong bactericidal action on gram-negative bacilli and small toxic and side effects. The product can be injected or orally administered; can be used for both human and veterinary use. The dosage of animals is very large, so that the product is not in demand in the market at present, and the dosage of the product is on the rise in recent years.
Cefotaxime sodium can permeate blood brain barrier, has small toxic and side effect, and is the first-line antibiotic medicine. The product is a cephalosporin for the third generation injection, is suitable for pneumonia and other respiratory tract infections, urinary tract infections, meningitis, septicemia, abdominal cavity infections, pelvic cavity infections, skin and soft tissue infections, genital tract infections, bone and joint infections and the like caused by sensitive bacteria, and cefotaxime can be used as a medicine for infant meningitis.
The 7-aminocephalosporanic acid is a starting material for producing cefotaxime sodium, and the production process comprises the steps of preparing cephalothin C through biological fermentation and chemical refining, and then chemically cracking or carrying out enzymolysis on the cephalothin C to obtain the 7-aminocephalosporanic acid. The cephalosporin antibiotics have the functions of inhibiting the synthesis of cell walls, and human cells have no cell walls, so the cephalosporin antibiotics have excellent selectivity, high safety and strong bactericidal power and are the best clinical antibiotics. With the development of cephalosporin series products and the appearance of new generation of cephalosporins, the dosage of 7-aminocephalosporanic acid, a raw material intermediate, is increasing day by day, and the market prospect is good.
Disclosure of Invention
The invention aims to provide a 7-aminocephalosporanic acid purification process, which has the characteristics of simple and convenient process operation and high product yield, the content of relevant substances of the purified 7-aminocephalosporanic acid is remarkably reduced, and the relevant substances can be controlled at a lower level when the 7-aminocephalosporanic acid purification process is applied to the synthesis of cefotaxime sodium.
The invention relates to a 7-aminocephalosporanic acid purification process, which comprises the following steps:
1) adding a solvent and 7-aminocephalosporanic acid into a reaction tank, and fully stirring;
2) adding hydrochloric acid into a hydrochloric acid metering tank;
3) adding hydrochloric acid into the reaction tank, and fully stirring to obtain a crystallization liquid;
4) carrying out throw filtration on the crystallization liquid by adopting a flat plate type centrifuge to obtain a wet product;
5) and (3) drying the wet product in vacuum to obtain the purified product of 7-aminocephalosporanic acid.
Furthermore, in the step 1), the solvent is dichloromethane, acetone or ethanol, and the 7-aminocephalosporanic acid is fully and uniformly dispersed in the solvent. The mass ratio of the solvent to the 7-aminocephalosporanic acid is 5-9: 1, more preferably 7: 1. the temperature range during stirring is 20-25 ℃. The stirring temperature is not suitable to be too high, and the 7-aminocephalosporanic acid related substances are influenced by the too high temperature.
Furthermore, in the step 2), the mass ratio of the hydrochloric acid to the 7-aminocephalosporanic acid is 1.8-2: 1, more preferably 1.85: 1. the dosage of the hydrochloric acid is not suitable to be too high, and the yield of the 7-aminocephalosporanic acid is influenced by the too high dosage of the hydrochloric acid.
Furthermore, in the step 3), hydrochloric acid is added to control the temperature in the reaction tank to be 20-25 ℃, and the stirring time is 1-2 hours. The temperature range is not suitable to be too high, and the 7-aminocephalosporanic acid related substances are influenced by the too high temperature.
Furthermore, in step 4), the filter throwing rotation speed is 1100-.
Furthermore, in the step 5), the vacuum degree of vacuum drying is 0.085-0.098 MPa, the drying temperature range is 40-50 ℃, and the drying time is 8-10 hours. The drying temperature is not suitable to be too high, and the 7-aminocephalosporanic acid related substances are influenced by the too high temperature.
By utilizing the technical means, the yield range of the purified product of the 7-aminocephalosporanic acid is controlled to be 70.00-85.00%.
The invention has the advantages that: the method has the advantages of simple and convenient process operation and high product yield, and the related substances of the 7-aminocephalosporanic acid are obviously reduced, so that the related substances of the cefotaxime obtained by synthesis are controlled at a lower level.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1:
a7-aminocephalosporanic acid purification process comprises the following steps:
1900kg of dichloromethane and 275kg of 7-aminocephalosporanic acid are added into a reaction tank, and the temperature is controlled at 20 ℃ to ensure that the materials are fully stirred. Then, 510kg of hydrochloric acid was metered into the reaction tank, and the mixture was sufficiently stirred at 20 ℃ for 1.5 hours to obtain a crystallization liquid. And carrying out spin filtration on the crystallization liquid by adopting a flat plate type centrifuge under the conditions that the spin filtration rotating speed is 1100-1400r/min to obtain a wet product. And finally, performing vacuum drying on the wet product, controlling the vacuum degree to be 0.085-0.098 MPa, controlling the drying temperature to be 40 ℃, and drying for 8-10 hours to obtain 235kg of 7-aminocephalosporanic acid purified product, wherein the yield is 85%. The specific quality index is shown in Table 1.
Example 2:
a7-aminocephalosporanic acid purification process comprises the following steps:
1900kg of acetone and 275g of 7-aminocephalosporanic acid are added into a reaction tank, and the temperature is controlled at 25 ℃ to ensure that the mixture is fully stirred. Then, 510kg of hydrochloric acid was metered into the reaction tank, and the mixture was sufficiently stirred at 25 ℃ for 1.5 hours to obtain a crystallization liquid. And carrying out spin filtration on the crystallization liquid by adopting a flat plate type centrifuge under the conditions that the spin filtration rotating speed is 1100-1400r/min to obtain a wet product. And finally, performing vacuum drying on the wet product, controlling the vacuum degree to be 0.085-0.098 MPa, controlling the drying temperature to be 45 ℃, and drying for 8-10 hours to obtain 226kg of 7-aminocephalosporanic acid purified product, wherein the yield is 82%. The specific quality index is shown in Table 1.
Example 3:
a7-aminocephalosporanic acid purification process comprises the following steps:
1900kg of ethanol and 275g of 7-aminocephalosporanic acid are added into a reaction tank, and the temperature is controlled at 20 ℃ to ensure that the materials are fully stirred. Then, 510kg of hydrochloric acid was metered into the reaction tank, and the mixture was sufficiently stirred at 20 ℃ for 1.5 hours to obtain a crystallization liquid. And carrying out spin filtration on the crystallization liquid by adopting a flat plate type centrifuge under the conditions that the spin filtration rotating speed is 1100-1400r/min to obtain a wet product. And finally, performing vacuum drying on the wet product, controlling the vacuum degree to be 0.085-0.098 MPa, controlling the drying temperature to be 50 ℃, and drying for 8-10 hours to obtain 220kg of 7-aminocephalosporanic acid purified product, wherein the yield is 80%. The specific quality index is shown in Table 1.
Comparative example 1:
a7-aminocephalosporanic acid purification process comprises the following steps:
1900kg of ethanol and 275g of 7-aminocephalosporanic acid are added into a reaction tank, and the temperature is controlled at 20 ℃ to ensure that the materials are fully stirred. Then, 650kg of hydrochloric acid was measured and added to the reaction tank, and the mixture was sufficiently stirred at 25 ℃ for 1.5 hours to obtain a crystallization liquid. And carrying out spin filtration on the crystallization liquid by adopting a flat plate type centrifuge under the conditions that the spin filtration rotating speed is 1100-1400r/min to obtain a wet product. And finally, performing vacuum drying on the wet product, controlling the vacuum degree to be 0.085-0.098 MPa, controlling the drying temperature to be 50 ℃, and drying for 8-10 hours to obtain 133kg of 7-aminocephalosporanic acid purified product, wherein the yield is 48%. The specific quality index is shown in Table 2.
Comparative example 2:
a7-aminocephalosporanic acid purification process comprises the following steps:
1900kg of dichloromethane and 275kg of 7-aminocephalosporanic acid are added into a reaction tank, and the temperature is controlled at 30 ℃ to ensure that the materials are fully stirred. Then, 510kg of hydrochloric acid was metered into the reaction tank, and the mixture was sufficiently stirred at 20 ℃ for 1.5 hours to obtain a crystallization liquid. And carrying out spin filtration on the crystallization liquid by adopting a flat plate type centrifuge under the conditions that the spin filtration rotating speed is 1100-1400r/min to obtain a wet product. And finally, performing vacuum drying on the wet product, controlling the vacuum degree to be 0.085-0.098 MPa, controlling the drying temperature to be 40 ℃, and drying for 8-10 hours to obtain 231kg of 7-aminocephalosporanic acid purified product, wherein the yield is 84%. The specific quality index is shown in Table 2.
Comparative example 3:
a7-aminocephalosporanic acid purification process comprises the following steps:
1900kg of acetone and 275g of 7-aminocephalosporanic acid are added into a reaction tank, and the temperature is controlled at 25 ℃ to ensure that the mixture is fully stirred. Then, 510kg of hydrochloric acid was metered into the reaction tank, and the mixture was sufficiently stirred at 25 ℃ for 1.5 hours to obtain a crystallization liquid. And carrying out spin filtration on the crystallization liquid by adopting a flat plate type centrifuge under the conditions that the spin filtration rotating speed is 1100-1400r/min to obtain a wet product. And finally, performing vacuum drying on the wet product, controlling the vacuum degree to be 0.085-0.098 MPa, controlling the drying temperature to be 60 ℃, and drying for 8-10 hours to obtain 227kg of 7-aminocephalosporanic acid purified product, wherein the yield is 83%. The specific quality index is shown in Table 2.
Table 1 quality results:
table 2 quality results:
Claims (8)
1. a7-aminocephalosporanic acid purification process is characterized by comprising the following steps:
1) adding a solvent and 7-aminocephalosporanic acid into a reaction tank, and fully stirring;
2) adding hydrochloric acid into a hydrochloric acid metering tank;
3) adding hydrochloric acid into the reaction tank, and fully stirring to obtain a crystallization liquid;
4) carrying out throw filtration on the crystallization liquid by adopting a flat plate type centrifuge to obtain a wet product;
5) and (3) drying the wet product in vacuum to obtain the purified product of 7-aminocephalosporanic acid.
2. The process for purifying 7-aminocephalosporanic acid as claimed in claim 1, wherein: in the step 1), the solvent is dichloromethane, acetone or ethanol.
3. The process for purifying 7-aminocephalosporanic acid as claimed in claim 1, wherein: in the step 1), the mass ratio of the solvent to the 7-aminocephalosporanic acid is 5-9: 1.
4. the process for purifying 7-aminocephalosporanic acid as claimed in claim 1, wherein: in the step 1), the temperature range during stirring is 20-25 ℃.
5. The process for purifying 7-aminocephalosporanic acid as claimed in claim 1, wherein: in the step 2), the mass ratio of the hydrochloric acid to the 7-aminocephalosporanic acid is 1.8-2: 1.
6. the process for purifying 7-aminocephalosporanic acid as claimed in claim 1, wherein: and 3), adding hydrochloric acid to control the temperature in the reaction tank to be 20-25 ℃, and stirring for 1-2 hours.
7. The process for purifying 7-aminocephalosporanic acid as claimed in claim 1, wherein: in the step 4), the filter throwing rotation speed is 1100-1400 r/min.
8. The process for purifying 7-aminocephalosporanic acid as claimed in claim 1, wherein: in the step 5), the vacuum degree of vacuum drying is 0.085-0.098 MPa, the drying temperature range is 40-50 ℃, and the drying time is 8-10 hours.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202110418809.6A CN113150010A (en) | 2021-04-19 | 2021-04-19 | 7-aminocephalosporanic acid purification process |
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| CN202110418809.6A CN113150010A (en) | 2021-04-19 | 2021-04-19 | 7-aminocephalosporanic acid purification process |
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1360770A (en) * | 1963-03-27 | 1964-05-15 | Glaxo Lab Ltd | Process for preparing 7-aminocephalosporanic acid |
| KR20030029500A (en) * | 2001-10-06 | 2003-04-14 | 종근당바이오 주식회사 | Method for crystallization of 7-aminocephalosporanic acid |
| CN102286597A (en) * | 2011-07-12 | 2011-12-21 | 福建省福抗药业股份有限公司 | Method for preparing 7-aminocephalosporanic acid |
| CN103014114A (en) * | 2012-12-27 | 2013-04-03 | 华北制药河北华民药业有限责任公司 | Method for preparing 7-aminocephalosporanic acid via enzymic method |
| CN203095921U (en) * | 2012-12-25 | 2013-07-31 | 厦门市天泉鑫膜科技股份有限公司 | 7-aminocephalosporanic acid decolorization and purification device based on ultra-filtration membrane technology |
| CN104651439A (en) * | 2015-03-23 | 2015-05-27 | 石药集团中诺药业（石家庄）有限公司 | Enzymatic preparation process of 7-aminocephalosporanic acid |
| CN110283869A (en) * | 2019-07-05 | 2019-09-27 | 国药集团威奇达药业有限公司 | The preparation method of 7-amino-cephalosporanic acid |
| CN110423241A (en) * | 2019-07-05 | 2019-11-08 | 国药集团威奇达药业有限公司 | The preparation method of cephalosporin C Sodium and 7-amino-cephalosporanic acid |
| RO133836A2 (en) * | 2018-07-25 | 2020-01-30 | Universitatea Tehnică "Gheorghe Asachi" Din Iaşi | Process for separating 7-aminocephalosporanic acid |
-
2021
- 2021-04-19 CN CN202110418809.6A patent/CN113150010A/en active Pending
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1360770A (en) * | 1963-03-27 | 1964-05-15 | Glaxo Lab Ltd | Process for preparing 7-aminocephalosporanic acid |
| KR20030029500A (en) * | 2001-10-06 | 2003-04-14 | 종근당바이오 주식회사 | Method for crystallization of 7-aminocephalosporanic acid |
| CN102286597A (en) * | 2011-07-12 | 2011-12-21 | 福建省福抗药业股份有限公司 | Method for preparing 7-aminocephalosporanic acid |
| CN203095921U (en) * | 2012-12-25 | 2013-07-31 | 厦门市天泉鑫膜科技股份有限公司 | 7-aminocephalosporanic acid decolorization and purification device based on ultra-filtration membrane technology |
| CN103014114A (en) * | 2012-12-27 | 2013-04-03 | 华北制药河北华民药业有限责任公司 | Method for preparing 7-aminocephalosporanic acid via enzymic method |
| CN104651439A (en) * | 2015-03-23 | 2015-05-27 | 石药集团中诺药业（石家庄）有限公司 | Enzymatic preparation process of 7-aminocephalosporanic acid |
| RO133836A2 (en) * | 2018-07-25 | 2020-01-30 | Universitatea Tehnică "Gheorghe Asachi" Din Iaşi | Process for separating 7-aminocephalosporanic acid |
| CN110283869A (en) * | 2019-07-05 | 2019-09-27 | 国药集团威奇达药业有限公司 | The preparation method of 7-amino-cephalosporanic acid |
| CN110423241A (en) * | 2019-07-05 | 2019-11-08 | 国药集团威奇达药业有限公司 | The preparation method of cephalosporin C Sodium and 7-amino-cephalosporanic acid |
Non-Patent Citations (1)
| Title |
|---|
| 王水 等: "7-氨基头孢烷酸结晶过程聚结现象与晶体表面性质", 天津大学学报, vol. 39, no. 5, pages 585 - 591 * |
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