CN1111537C - The preparation method of highly pure crystalline form of cefuroxime axetil - Google Patents
The preparation method of highly pure crystalline form of cefuroxime axetil Download PDFInfo
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- CN1111537C CN1111537C CN97113148A CN97113148A CN1111537C CN 1111537 C CN1111537 C CN 1111537C CN 97113148 A CN97113148 A CN 97113148A CN 97113148 A CN97113148 A CN 97113148A CN 1111537 C CN1111537 C CN 1111537C
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- cefuroxime axetil
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- crystalline form
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- cephalofruxin
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Abstract
The present invention discloses improving one's methods of a kind of production high purity crystalline form cefuroxime axetil (cephalofruxin 1-acetyl 2-ethoxyethyl acetate), it is characterized in that the esterification of carrying out the cephalofruxin inorganic salt under the relative neutral condition of any alkali, and Virahol and normal hexane are carried out the crystallization of cefuroxime axetil as recrystallisation solvent not adding.
Description
The present invention relates to produce improving one's methods of highly pure crystalline form of cefuroxime axetil (cefuroxime axetil).
Compound (6R, 7R)-3-carboxamide oxygen methyl-7-[(Z)-2-(furans-2-yl)-2-methoxy imido kharophen] ceph-3-em-4-carboxylic acid (cephalofruxin) is a kind of microbiotic that Gram-positive and Gram-negative microorganism are had high broad spectrum of activity.Because this compound has very high stability to the β-lactamase (lactamase) of many Gram-positives and Gram-negative microorganisms, therefore strengthened this character.Yet cephalofruxin and salt thereof are difficult to absorb from gi tract, and the content in therefore oral back serum and the urine is very low.
Now known many cephalofruxins that can absorb from gi tract after oral have been arranged.British patent specification 1,571,683 have disclosed many cefuroxime axetil classes with tangible oral antibiotic latent effectiveness.Described cefuroxime axetil is also included within british patent specification 1,571, in the 683 ester classes that disclose.
British patent specification 1,571,683 have disclosed a kind of method of producing cefuroxime axetil.This method comprises usefulness (RS)-1-acetyl oxygen monobromoethane esterification cephalofruxin.Yet, need add alkali when the shortcoming of this method is the esterification cephalofruxin, and comprise step with the dry cefuroxime axetil that generates of anhydrous mineral compound.In addition, british patent specification 1,571,683 described crystallization method can not be used for industrial-scale production effectively, make that the productive rate of crystalline cephem furan monooctyl ester is very low.
British patent specification 2,145,409 have disclosed a kind of preparation method of cefuroxime axetil.The cefuroxime axetil that this method comprises usefulness (RS)-1-acetyl oxygen monobromoethane esterification Cefuroxime sodium and crystallization goes out to generate from the solution of the organic solvent of cefuroxime axetil or water-containing solvent or its mixture.The productive rate of making required cefuroxime axetil with this method is higher.Yet, need add alkali when the shortcoming of this method is esterification, and the crystalline cephem furan monooctyl ester of gained contains the Δ of the 0.05-0.7% cefuroxime axetil of having an appointment
2-isomer and E-isomer impurities.
Therefore, the object of the present invention is to provide improving one's methods of a kind of high productivity production high purity crystalline form cefuroxime axetil, this method has overcome above-mentioned defective of the prior art.
Unexpected is that our high productivity has made high purity crystalline form cefuroxime axetil, and this cefuroxime axetil contains and contains the cefuroxime axetil Δ below 0.05%
2The impurity of-isomer and E-isomer.
Foreign matter content in the crystalline form cefuroxime axetil that makes with the inventive method is starkly lower than with british patent specification 2,145, the foreign matter content in the corresponding crystalline form cefuroxime axetil that method makes described in 409.
According to the present invention, under the condition that does not add any alkali, will mix with the inorganic salt (Cefuroxime sodium or cephalofruxin potassium) of cephalofruxin with (RS)-1-acetyl oxygen monobromoethane that acetyl bromide and acetaldehyde reaction make, for crystallization from solution goes out cefuroxime axetil, Virahol and normal hexane are used as recrystallisation solvent then.
The invention provides the improving one's methods of high purity crystalline form cefuroxime axetil that a kind of production has following structure (I):
This method comprises that usefulness (RS)-1-acetyl oxygen monobromoethane esterification has the cephalofruxin of structure (II), the cefuroxime axetil that crystallization goes out to form from organic solvent solution, drying and separated product then, it is characterized in that the esterification of carrying out the cephalofruxin inorganic salt under the relative neutral condition of any alkali not adding, and Virahol and normal hexane carried out the crystallization of cefuroxime axetil as recrystallisation solvent
M is Na or K in the formula.
Recrystallisation solvent Virahol that the present invention is used and normal hexane both can use its mixture also can use separately, promptly added Virahol earlier, added normal hexane then.
A preferred aspect of the present invention is that crystallization was carried out 1-4 hour under 10-45 ℃ temperature.
In the inventive method of producing crystalline cephem furan monooctyl ester, for the esterification of compound (RS)-1-acetyl oxygen monobromoethane and cephalofruxin inorganic salt, need not any alkali.Therefore, this step that shows the inventive method is than british patent specification 1,571, and 683 and 2,145, the correlation method described in 409 is easier.
In addition, though the crystalline cephem furan monooctyl ester that makes with the inventive method contain and be lower than 0.05% and contain the cefuroxime axetil Δ
2The impurity of-isomer and E-isomer, but the stoichiometric ratio of R isomer and S isomer approached 1: 1 in the product.Therefore, the purity of the crystalline cephem furan monooctyl ester that makes with the inventive method is than with british patent specification 1,571,683 and 2,145, and the corresponding cefuroxime axetil that method makes described in 409 is high 10 times or higher.So clearly the inventive method has produced more commercial benefits than existing method.
Embodiment
The invention will be further described with following embodiment now, but the present invention never is confined to these embodiment.
Embodiment 1
10 gram Cefuroxime sodiums and 50 milliliters of N,N-DIMETHYLACETAMIDEs are mixed, stir the mixture, and make it be cooled to 3 ℃.In the mixture that is stirring, add 5.63 gram acetate (1-bromine second) esters.With this mixture restir 3 hours, reaction mixture is added in the mixture of 150 milliliters of ethyl acetate and 100 milliliters of sodium bicarbonate aqueous solutions, continue to stir 1 hour.Separate organic phase, wash with 50 milliliters of 1N aqueous hydrochloric acids and 50 milliliter of 20% sodium chloride aqueous solution successively.Separate organic phase, wash with 15 milliliter of 2% sodium bicarbonate aqueous solution and 50 milliliter of 20% sodium chloride aqueous solution successively.Organic phase is filtered with 1.0 gram activated carbon decolorizings, with 20 milliliters of ethyl acetate washings.Filtrate underpressure distillation in the time of 40 ℃ restrains in vacuum-evaporation to 30 then.In the enriched material that forms, add 33 milliliters of Virahols.Mixture was stirred 1 hour, till the well-crystallized carries out.Add 66 ml n-hexanes, continue to stir 1 hour, crystallization is carried out fully.Filter the crystal that forms,,, obtain 9.56 gram crystalline cephem furan monooctyl esters 35 ℃ of dryings with the mixture washing of Virahol and normal hexane.[α]
D1% solution in the (diox) :+38NMR (δ, CDCl
3+ DMSO-d): 1.53 (d, 3H), 2.07 (s, 3H), 3.57 (br.S, 2H), 3.97 (s, 3H), 4.83 (br.S, 2H), 5.85 (ABq, 1H), 6.20 (br.S, 2H), 6.47～6.8 (m, 2H), 6.90～7.20 (q, 1H), 7.60 (br.S, 1H), 9.63 (d, 1H) impurity that record of 1: 1.06 usefulness HPLC of ratios of the isomers (HPLC): Δ
2Isomer is 0.02%, and the E-isomer is 0.03%.
Embodiment 2
Except adding the mixed solvent of 70 milliliters of Virahols and normal hexane together, rather than add 33 milliliters of Virahols and 66 ml n-hexanes respectively by embodiment 1 and carry out carrying out basis by embodiment 1 identical method beyond the crystallization
Embodiment.The impurity that 1: 1.06 usefulness HPLC of ratios of the isomers (HPLC) records: Δ
2Isomer is 0.03%, and the E-isomer is 0.03%.
Claims (2)
1. a production has the method for the high purity crystalline form cefuroxime axetil of following structure (I):
This method comprises i) do not adding the cephalofruxin inorganic salt that have structure (II) with the esterification of (RS)-1-acetyl oxygen monobromoethane under the relative neutral condition of any alkali,
M is Na or K in the formula;
Ii) crystallization goes out the cefuroxime axetil of formation from organic solvent solution;
Iii) drying and separated product make to contain and contain the cefuroxime axetil Δ below 0.05%
2The pure crystalline form cefuroxime axetil of the impurity of-isomer and E-isomer;
It is characterized in that, add Virahol earlier and make the cefuroxime axetil crystallization that add normal hexane then and make crystallization complete, the additional proportion of Virahol and normal hexane is 1: 2.
2. the method for claim 1 is characterized in that crystallization was carried out 1 to 4 hour under 10-45 ℃ of temperature.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97113148A CN1111537C (en) | 1997-05-15 | 1997-05-15 | The preparation method of highly pure crystalline form of cefuroxime axetil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97113148A CN1111537C (en) | 1997-05-15 | 1997-05-15 | The preparation method of highly pure crystalline form of cefuroxime axetil |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1199735A CN1199735A (en) | 1998-11-25 |
| CN1111537C true CN1111537C (en) | 2003-06-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97113148A Expired - Fee Related CN1111537C (en) | 1997-05-15 | 1997-05-15 | The preparation method of highly pure crystalline form of cefuroxime axetil |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IN190849B (en) * | 2000-07-17 | 2003-08-23 | Ranbaxy Lab Ltd | |
| CN100448879C (en) * | 2004-07-22 | 2009-01-07 | 北京化工大学 | Method for preparing unformed cefuroxime axetil |
| CN102633817A (en) * | 2012-03-30 | 2012-08-15 | 李莎 | Cefoxitin esterified prodrug compound and oral preparations |
| CN109705144A (en) * | 2019-03-05 | 2019-05-03 | 安徽丰原利康制药有限公司 | A kind of production method of CEFUROXIME AXETIL high yield pulp1 |
| CN109705143A (en) * | 2019-03-05 | 2019-05-03 | 安徽丰原利康制药有限公司 | A kind of method of CEFUROXIME AXETIL purification |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4267320A (en) * | 1976-02-16 | 1981-05-12 | Glaxo Laboratories Limited | Cephalosporin antibiotics |
| GB2145409A (en) * | 1983-07-29 | 1985-03-27 | Glaxo Group Ltd | Crystalline cefuroxime axetil |
| DE3914658A1 (en) * | 1988-05-03 | 1989-11-16 | Glaxo Group Ltd | CHEMICAL PROCESS |
-
1997
- 1997-05-15 CN CN97113148A patent/CN1111537C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4267320A (en) * | 1976-02-16 | 1981-05-12 | Glaxo Laboratories Limited | Cephalosporin antibiotics |
| GB2145409A (en) * | 1983-07-29 | 1985-03-27 | Glaxo Group Ltd | Crystalline cefuroxime axetil |
| DE3914658A1 (en) * | 1988-05-03 | 1989-11-16 | Glaxo Group Ltd | CHEMICAL PROCESS |
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| Publication number | Publication date |
|---|---|
| CN1199735A (en) | 1998-11-25 |
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