CN1305876C - One-step method for preparing high-purity cefpoxime proxetil - Google Patents
One-step method for preparing high-purity cefpoxime proxetil Download PDFInfo
- Publication number
- CN1305876C CN1305876C CNB2004100156938A CN200410015693A CN1305876C CN 1305876 C CN1305876 C CN 1305876C CN B2004100156938 A CNB2004100156938 A CN B2004100156938A CN 200410015693 A CN200410015693 A CN 200410015693A CN 1305876 C CN1305876 C CN 1305876C
- Authority
- CN
- China
- Prior art keywords
- cefpodoxime
- acid
- potassium
- sodium
- proxetil
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 15
- 229950000033 proxetil Drugs 0.000 title abstract description 4
- LTINZAODLRIQIX-FBXRGJNPSA-N cefpodoxime proxetil Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(=O)OC(C)OC(=O)OC(C)C)C(=O)C(=N/OC)\C1=CSC(N)=N1 LTINZAODLRIQIX-FBXRGJNPSA-N 0.000 claims description 18
- 229960004797 cefpodoxime proxetil Drugs 0.000 claims description 18
- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 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 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 235000011056 potassium acetate Nutrition 0.000 claims description 3
- BWILYWWHXDGKQA-UHFFFAOYSA-M potassium propanoate Chemical compound [K+].CCC([O-])=O BWILYWWHXDGKQA-UHFFFAOYSA-M 0.000 claims description 3
- 239000004331 potassium propionate Substances 0.000 claims description 3
- 235000010332 potassium propionate Nutrition 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 235000015424 sodium Nutrition 0.000 claims description 3
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 claims description 3
- 239000004324 sodium propionate Substances 0.000 claims description 3
- 235000010334 sodium propionate Nutrition 0.000 claims description 3
- 229960003212 sodium propionate Drugs 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- -1 salt sodium acetate Chemical class 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 229960005090 cefpodoxime Drugs 0.000 description 4
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 description 4
- 150000003983 crown ethers Chemical class 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 101000807533 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 26 Proteins 0.000 description 1
- 102100037180 Ubiquitin carboxyl-terminal hydrolase 26 Human genes 0.000 description 1
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229940124588 oral cephalosporin Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The present invention belongs to the technical field of medicine synthesis. The present invention provides a one-step process for preparing high-purity cefpoxime proxetil form cefpoxime acid. The process of the present invention is simple and feasible, and is suitable for large-scale production. The product prepared by the process of the present invention is high in purity, and the content of the side product (cefpoxime proxetil isomer) (delta<2>) is lower than 1 %.
Description
Technical field
The invention belongs to technical field of medicine synthesis.Be specifically related to prepare the method for high purity Cefpodoxime Proxetil with Cefpodoxime acid.
Background technology
Cefpodoxime Proxetil Cefpodoxime proxetil, (R, S)-1-(isopropoxy carbon acyloxy) ethyl-(+)-(6R, 7R)-7-[2-(2-amino-4-thiazolyl)-2-((z)-methoxyimino) kharophen]-3-methoxymethyl-8-oxygen-5-sulphur-1-azabicyclo [4,2, O] oct-2-ene-2-carboxylicesters (I) is antibiotic wide spectrum, high stability to β-Nei Xiananmei, third generation oral cephalosporin medicine.
Document (J.of Antibiotics, Vol 40,370 (1987)) report, by make Cefpodoxime (II) in the presence of strong organic bases such as dicyclohexyl amine with iodine alkyl carbonate prepared in reaction Cefpodoxime Proxetil.The product that this method obtains, its by product is the isomer Δ especially
2Higher relatively, generally more than 3%.
World patent (WO01/34611) discloses the use crown ether and has made catalyzer, prepares Cefpodoxime Proxetil from cefpoxime proxetil.At first, need to use crown ether to prepare Cefpodoxime Proxetil, not only cost is higher, and the toxicity of crown ether is disadvantageous for last directly preparation finished product, simultaneously, if without crown ether, the isomer that forms will reach 6～8% (weight) scope, therefore defectiveness still in preparation.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, a kind of easy method for preparing the high purity Cefpodoxime Proxetil of research and design.
The invention provides the method for preparing the high purity Cefpodoxime Proxetil with Cefpodoxime acid, this method is a raw material with Cefpodoxime (acid) II, with sodium acetate, Sodium Propionate, Sodium isooctanoate, potassium acetate, potassium propionate or isocaprylic acid potassium organic weak base reactant salt after, add iodo-ester III and directly obtain I.
Synthetic route:
R=CH
3, CH
3CH
2Or CH
3(CH
2)
3CH (C
2H
5)
M=Na or K.
The mol ratio of RCOOM used in the present invention and raw material II allows at 1～3 times.Temperature of reaction-5～25 ℃, reasonable temperature range is 0～10 ℃, impurity in products＜4%, yield 70～75%.
The Cefpodoxime Proxetil purity height that makes with the inventive method detects wherein Δ through the HPLC method
2Isomer is less than 1%.If use the separation sensitivity of the HPLC collection of illustrative plates of WO01/34611 patent disclosure, the present invention produces the isomer Δ
2Will be less than 0.5%, total impurities is less than 4%, and American Pharmacopeia USP26 stipulates relative substance＜6%.Illustrate that the product that the inventive method makes is better than USS.
Embodiment
Embodiment 1
With 20g (0.0468 mole) Cefpodoxime (acid) II, put among the 120ml DMA, stirring and dissolving, add 4.6g sodium acetate and 1g water, stirring at room reaction 30min is cooled to 5 ℃, adds 15g iodo-ester III, at 5～10 ℃ of reaction 1.5h, be poured into 200ml ethyl acetate and 100ml 5%NaHCO
3In the mixed solution, stir, tell organic phase, water 100ml ethyl acetate extraction, merge organic phase, wash secondary with saturated common salt, organic phase adds 10g anhydrous magnesium sulfate and 10g activated carbon decolorizing 30min, filter, be evaporated to 80g, add the 500ml isopropyl ether fast, the high degree of agitation after-filtration, vacuum-drying gets in vain to off-white powder 19g.(yield: 73%)
Embodiment 2
With 20g Cefpodoxime (acid) II, put among the 120ml DMA stirring and dissolving, add 8.5g Sodium isooctanoate stirring at room reaction 30min, be cooled to 5 ℃, add 16g iodo-ester III, at 5～10 ℃ of reaction 1.5h, be poured into 200ml ethyl acetate and 100ml 5%NaHCO
3In the mixed solution, stir, tell organic phase, water 100ml ethyl acetate extraction, merge organic phase, wash secondary with saturated common salt, organic phase adds 10g gac and 10g anhydrous magnesium sulfate decolouring 30min, filter, be evaporated to 80g, add the 500ml isopropyl ether fast, after the high degree of agitation, filter, vacuum-drying gets white to off-white powder 19.5g.(yield: 75%)
Claims (2)
1. method for preparing high purity Cefpodoxime Proxetil I with Cefpodoxime acid II, it is characterized in that this method is is raw material with Cefpodoxime acid II, with sodium acetate, Sodium Propionate, Sodium isooctanoate, potassium acetate, potassium propionate or isocaprylic acid potassium organic weak base reactant salt after, add iodo-ester III and directly obtain I;
Synthetic route:
R=CH
3, CH
3CH
2Or CH
3(CH
2)
3CH (C
2H
5)
M=Na or K.
2. a kind of method for preparing high purity Cefpodoxime Proxetil I with Cefpodoxime acid II according to claim 1 is characterized in that the mol ratio of wherein said organic weak base salt sodium acetate, Sodium Propionate, Sodium isooctanoate, potassium acetate, potassium propionate or isocaprylic acid potassium and Cefpodoxime acid II is 1～3: 1; Temperature of reaction is-5-25 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100156938A CN1305876C (en) | 2004-01-08 | 2004-01-08 | One-step method for preparing high-purity cefpoxime proxetil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100156938A CN1305876C (en) | 2004-01-08 | 2004-01-08 | One-step method for preparing high-purity cefpoxime proxetil |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1640879A CN1640879A (en) | 2005-07-20 |
| CN1305876C true CN1305876C (en) | 2007-03-21 |
Family
ID=34868046
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100156938A Expired - Fee Related CN1305876C (en) | 2004-01-08 | 2004-01-08 | One-step method for preparing high-purity cefpoxime proxetil |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1305876C (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102532165A (en) * | 2010-12-20 | 2012-07-04 | 广州白云山制药股份有限公司广州白云山制药总厂 | Preparation method for cefathiamidine crystals |
| CN103275102B (en) * | 2013-05-28 | 2014-07-09 | 四川省惠达药业有限公司 | Cefpodoxime proxetil compound as well as preparation method and medicinal composition thereof |
| CN106046024B (en) * | 2016-06-30 | 2019-01-15 | 齐鲁动物保健品有限公司 | A kind of preparation method of Cefpodoxime Proxetil |
| CN115093431B (en) * | 2022-06-15 | 2023-09-22 | 艾美科健（中国）生物医药有限公司 | A kind of method for synthesizing cefpodoxime proxetil |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002083634A2 (en) * | 2001-04-17 | 2002-10-24 | Ranbaxy Laboratories Limited | Process for the preparation of cefpodoxime acid |
| CN1387533A (en) * | 1999-11-08 | 2002-12-25 | 韩美药品工业株式会社 | Method for prepairng highly purity cefpodoxime proxetil |
-
2004
- 2004-01-08 CN CNB2004100156938A patent/CN1305876C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1387533A (en) * | 1999-11-08 | 2002-12-25 | 韩美药品工业株式会社 | Method for prepairng highly purity cefpodoxime proxetil |
| WO2002083634A2 (en) * | 2001-04-17 | 2002-10-24 | Ranbaxy Laboratories Limited | Process for the preparation of cefpodoxime acid |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1640879A (en) | 2005-07-20 |
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| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee |
Owner name: SHANGHAI ZHONGXI SUNVE PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: SHANGHAI SUNVE PHARMACEUTICAL CO., LTD. |
|
| CP03 | Change of name, title or address |
Address after: 200331 No. 50, Yongdeng Road, Shanghai, China Patentee after: Shanghai Zhongxi Sunve Pharmaceutical Co., Ltd. Address before: 200331 No. 50, Yongdeng Road, Shanghai, Putuo District Patentee before: Shanghai Sunve Pharmaceutical Co., Ltd. |
|
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070321 Termination date: 20140108 |