CN101941983B - Preparation method of high-purity cefoxitin sodium - Google Patents
Preparation method of high-purity cefoxitin sodium Download PDFInfo
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- CN101941983B CN101941983B CN2010102978311A CN201010297831A CN101941983B CN 101941983 B CN101941983 B CN 101941983B CN 2010102978311 A CN2010102978311 A CN 2010102978311A CN 201010297831 A CN201010297831 A CN 201010297831A CN 101941983 B CN101941983 B CN 101941983B
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- Prior art keywords
- cefoxitin
- sodium
- purity
- preparation
- acid
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- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 title claims abstract description 29
- 229960003016 cefoxitin sodium Drugs 0.000 title abstract description 6
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 239000011347 resin Substances 0.000 claims abstract description 13
- 229920005989 resin Polymers 0.000 claims abstract description 13
- 229960002682 cefoxitin Drugs 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 12
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 claims description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000001179 sorption measurement Methods 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000011146 sterile filtration Methods 0.000 description 6
- 229930186147 Cephalosporin Natural products 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 229940124587 cephalosporin Drugs 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 0 *C1([C@@]2(CNC(Cc3ccc[s]3)=O)I*)SCC(COC(N)=O)=C(*)N1C2=O Chemical compound *C1([C@@]2(CNC(Cc3ccc[s]3)=O)I*)SCC(COC(N)=O)=C(*)N1C2=O 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- WZOZEZRFJCJXNZ-UHFFFAOYSA-N COC(C1SCC(COC(N)=O)=C(C(O)=O)N11)(C1=O)NC(Cc1ccc[s]1)=O Chemical compound COC(C1SCC(COC(N)=O)=C(C(O)=O)N11)(C1=O)NC(Cc1ccc[s]1)=O WZOZEZRFJCJXNZ-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- -1 cephalosporin compound Chemical class 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The invention provides a preparation method of high-purity cefoxitin sodium (I), belonging to the field of chemical pharmaceutical technology. The method comprises the following steps: taking cefoxitin acid as a raw material, adsorbing and purifying the cefoxitin acid with a resin column, and allowing the purified cefoxitin acid to react with sodium salt at the temperature of -20-20 DEG C to obtain the high-purity cefoxitin sodium.
Description
Technical field
The present invention relates to a kind of preparation method of high-purity compound, especially a kind of cephalosporin compound preparing cefoxitin sodium.Belong to technical field of pharmaceutical chemistry.
Background technology
MK-306 (Cefoxitin sodium), chemistry is by name: (6R, 7S)-3-carboxamide oxygen methyl-7-methoxyl group-8-oxo-7-[2-(2-thiazolyl) acetamido]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium salt.Its chemical structural formula is following:
Be the s-generation cephalosporin analog antibiotic of U.S. Merck company development, its antimicrobial spectrum is balanced, and stable to β-Nei Xiananmei.At present because the bacterial drug resistance of cynnematin constantly rises, thereby the cefoxitin that is different from the first-generation and third generation cephalosporin has caused people's attention once more.
Summary of the invention
The present invention adopts new production technique, is raw material with the cefoxitin acid, through the resin column adsorption and purification, reacts down in-20 ℃～20 ℃ with sodium salt, forms highly purified MK-306.
Concrete technical scheme and reaction scheme are following:
The first step: resin absorption purifying
Cefoxitin acid (II) is dissolved in ETHYLE ACETATE (or methyl alcohol) solution, stirred under the room temperature 30 minutes, make it dissolving, add activated carbon decolorizing 30min, filter, filtrating gets into resin column, control flow velocity and pressure, collected post after solution in reaction kettle.
Second step: the preparation of MK-306 (I)
In above-mentioned solution, add ETHYLE ACETATE (or methyl alcohol) solution of sodium salt, stirred 2 hours under the room temperature, suction filtration, drying under reduced pressure obtains MK-306 (C
16H
16N
3NaO
7S
2).
Sodium salt described in the above-mentioned preparation method is meant Sodium isooctanoate, yellow soda ash or sodium hydrogencarbonate.Used resin is the gama-alumina resin.
Present method is simple to operate, and after resin absorption, the impurity in the solution is adsorbed, and has removed a large amount of organic impuritys and the macromolecule impurity that can introduce in the product, has improved quality product greatly, for clinical drug safety provides guarantee.
Embodiment
Embodiment 1
The first step: get 2.00 kilograms of cefoxitin acids, ETHYLE ACETATE 20L drops in the reaction kettle, stirs under the room temperature and makes dissolving, adds activated carbon decolorizing 30min, filters, and filtrating gets into resin column, control flow velocity and pressure, collected post after solution in reaction kettle.Solution gets in the sterilisable chamber after Sterile Filtration.
Second step: with Sodium isooctanoate 780 grams, after the ETHYLE ACETATE 6.5L stirring and dissolving, sterile filtration is pressed into sterilisable chamber, places the high-order groove that drips.The Sodium isooctanoate bacteria-free filtrate is slowly dropped in the cefoxitin acid bacteria-free filtrate, and agitation and dropping is about 1.5 hours under the room temperature.Dropwise slow stirring 2 hours.Filter, filter cake washs with ETHYLE ACETATE, drains, and vacuum-drying gets 1.88 kilograms of white crystalline powders (being MK-306), yield: 94.0%, and chromatographic purity 99.60%.
Embodiment 2
The first step: get 2.00 kilograms of cefoxitin acids, ETHYLE ACETATE 20L drops in the reaction kettle, stirs under the room temperature and makes dissolving, adds activated carbon decolorizing 30min, filters, and filtrating gets into resin column, control flow velocity and pressure, collected post after solution in reaction kettle.Solution gets in the sterilisable chamber after Sterile Filtration.
Second step: with Sodium isooctanoate 780 grams, after the ETHYLE ACETATE 6.5L stirring and dissolving, sterile filtration is pressed into sterilisable chamber, places the high-order groove that drips.The Sodium isooctanoate bacteria-free filtrate is slowly dropped in the cefoxitin acid bacteria-free filtrate, and agitation and dropping is about 1.5 hours under the room temperature.Dropwise slow stirring 2 hours.Filter, filter cake washs with ETHYLE ACETATE, drains, and vacuum-drying gets 1.89 kilograms of white crystalline powders (being MK-306), yield: 94.5%, and chromatographic purity 99.58%.
Embodiment 3
The first step: get 2.00 kilograms of cefoxitin acids, ETHYLE ACETATE 20L drops in the reaction kettle, stirs under the room temperature and makes dissolving, adds activated carbon decolorizing 30min, filters, and filtrating gets into resin column, and control flow velocity and pressure were collected behind the post in the solution and reaction kettle.Solution gets in the sterilisable chamber after Sterile Filtration.
Second step: with Sodium isooctanoate 780 grams, after the ETHYLE ACETATE 6.5L stirring and dissolving, sterile filtration is pressed into sterilisable chamber, places the high-order groove that drips.The Sodium isooctanoate bacteria-free filtrate is slowly dropped in the cefoxitin acid bacteria-free filtrate, and agitation and dropping is about 1.5 hours under the room temperature.Dropwise slow stirring 2 hours.Filter, filter cake washs with ETHYLE ACETATE, drains, and vacuum-drying gets 1.90 kilograms of white crystalline powders (being MK-306), yield: 95.0%, and chromatographic purity 99.56%.
Claims (1)
1. one kind prepares high purity MK-306 (I); That is: (6R; 7S)-method of 3-carboxamide oxygen methyl-7-methoxyl group-8-oxo-7-[2-(2-thiazolyl) acetamido]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium salt (I); It is characterized by: (II) is raw material with cefoxitin acid, and cefoxitin acid is at ETHYLE ACETATE
After the middle dissolving,, react down in-20 ℃～20 ℃, form highly purified MK-306 (I) with Sodium isooctanoate, yellow soda ash or sodium hydrogencarbonate through the resin column adsorption and purification;
Wherein used resin is the gama-alumina resin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102978311A CN101941983B (en) | 2010-09-25 | 2010-09-25 | Preparation method of high-purity cefoxitin sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102978311A CN101941983B (en) | 2010-09-25 | 2010-09-25 | Preparation method of high-purity cefoxitin sodium |
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| Publication Number | Publication Date |
|---|---|
| CN101941983A CN101941983A (en) | 2011-01-12 |
| CN101941983B true CN101941983B (en) | 2012-07-25 |
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| CN2010102978311A Active CN101941983B (en) | 2010-09-25 | 2010-09-25 | Preparation method of high-purity cefoxitin sodium |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102358744B (en) * | 2011-09-02 | 2013-11-06 | 山东罗欣药业股份有限公司 | Cefoxitin sodium crystal compound and cefoxitin sodium composition powder injection |
| CN102399234A (en) * | 2011-12-06 | 2012-04-04 | 苏州中联化学制药有限公司 | Preparation method for Cefoxintin sodium |
| CN103304582B (en) * | 2013-06-28 | 2015-02-11 | 四川省惠达药业有限公司 | Cefoxitin sodium compound, preparation method and pharmaceutical composition thereof |
| CN103432137B (en) * | 2013-08-28 | 2015-01-28 | 芦红代 | Medicinal composition of cefoxitin |
| CN104926836A (en) * | 2015-05-28 | 2015-09-23 | 浙江长典医药有限公司 | Cefoxitin sodium compound entity for children and preparation of cefoxitin sodium compound entity for children |
| CN112851693B (en) * | 2021-01-22 | 2022-08-16 | 华北制药河北华民药业有限责任公司 | Preparation method of cefoxitin acid |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004083217A1 (en) * | 2003-03-20 | 2004-09-30 | Orchid Chemicals & Pharmaceuticals Ltd | An improved process for the preparation of cefoxitin |
| CN101007812A (en) * | 2007-01-26 | 2007-08-01 | 深圳信立泰药业有限公司 | Antibacterial drugs cefoxitin preparation process |
| CN101235045A (en) * | 2008-02-26 | 2008-08-06 | 芦红代 | Method for preparing cefoxitin sodium |
-
2010
- 2010-09-25 CN CN2010102978311A patent/CN101941983B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004083217A1 (en) * | 2003-03-20 | 2004-09-30 | Orchid Chemicals & Pharmaceuticals Ltd | An improved process for the preparation of cefoxitin |
| CN101007812A (en) * | 2007-01-26 | 2007-08-01 | 深圳信立泰药业有限公司 | Antibacterial drugs cefoxitin preparation process |
| CN101235045A (en) * | 2008-02-26 | 2008-08-06 | 芦红代 | Method for preparing cefoxitin sodium |
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|---|---|
| CN101941983A (en) | 2011-01-12 |
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Denomination of invention: Preparation method of high-purity cefoxitin sodium Effective date of registration: 20180428 Granted publication date: 20120725 Pledgee: China Everbright Bank Co.,Ltd. Haikou Branch Pledgor: Hainan Tianhuang Pharmaceutical Co.,Ltd. Registration number: 2018460000002 |
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Date of cancellation: 20220222 Granted publication date: 20120725 Pledgee: China Everbright Bank Co.,Ltd. Haikou Branch Pledgor: Hainan Tianhuang Pharmaceutical Co.,Ltd. Registration number: 2018460000002 |
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Effective date of registration: 20221028 Address after: 311400 1278 Gongwang street, Fuchun street, Fuyang District, Hangzhou City, Zhejiang Province Patentee after: ZHEJIANG WHITESON PHARMA Co.,Ltd. Address before: 570203 No. 6 Airport North Road, Meilan District, Hainan, Haikou Patentee before: Hainan Tianhuang Pharmaceutical Co.,Ltd. |
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Addressee: Patents of Hainan Tianhuang Pharmaceutical Co.,Ltd. The person in charge Document name: Notice of Conformity |
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