CN102617604A - Method utilizing coupling reaction crystallization to prepare cefuroxime sodium - Google Patents
Method utilizing coupling reaction crystallization to prepare cefuroxime sodium Download PDFInfo
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- CN102617604A CN102617604A CN201210043997XA CN201210043997A CN102617604A CN 102617604 A CN102617604 A CN 102617604A CN 201210043997X A CN201210043997X A CN 201210043997XA CN 201210043997 A CN201210043997 A CN 201210043997A CN 102617604 A CN102617604 A CN 102617604A
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Abstract
The invention relates to a method utilizing coupling reaction crystallization to prepare cefuroxime sodium, which comprises dissolving cefuroxime acid in a mixed solvent at 20-30 DEG C to prepare a solution with the concentration to be 0.025g/ML-0.1g/Ml; adding an alkaline sodium salt water solution into the solution; mixing for 10-20min at constant temperature to enable a reaction to be complete, and adding cefuroxime sodium seed crystal; adding an elution agent after 10-20min; cooling the temperature of the solution to 0-5 DEG C, and keeping at the constant temperature for 0.5-2h; filtering, washing and drying the obtained suspension, and obtaining a cefuroxime sodium product. The method reduces the adsorption filtration process of activated carbon and avoids loss of yield. The method achieves coupling of reactions and crystallization, and the methods of elution crystallization and cooling crystallization are combined with each other in the crystallization process, the crystallization process is controlled easily, the particle size of the product is uniform, the liquidity is greatly improved, the purity is higher than 99.5%, and the yield is over 92%.
Description
Technical field
The invention belongs to the crystallization technique field, particularly a kind of coupling reaction crystallization of antibiotics prepares the method for Cefuroxime sodium.
Background technology
Cefuroxime sodium belongs to β-Nei Xiananleikangshengsu; Be possess the first-generation and third generation cephalosporin advantage classic two generation cynnematin; Not only gram-positive cocci there is stronger anti-microbial activity; And also have excellent antibiotic active to some gram negative bacterium, and especially in the treatment of Gram-positive and gram negative bacterium polyinfection, the medicine of preferentially selecting for use especially.Cefuroxime sodium is not in vivo by liver metabolism, so to the liver nontoxicity; From urine, drain through kidney with original shape, so,, the newborn infant is had good pharmacokinetics and security so its medication is as safe as a house to the almost non-toxic spinoff of kidney.
The Cefuroxime sodium molecular structural formula is following:
Cephalofruxin is succeeded in developing by Ge Lansu company, and patent protection in 1996 expired in U.S.'s listing in 1988.This medicine has promptly become world's situation of selling well medicine since listing.1993, cephalofruxin got into preceding 10 of world's drug market antibiotic product sales volume.At present, cephalofruxin still keeps good sales momentum.
Itself there is the shortcoming of poor heat stability in the Cefuroxime sodium product, and normal temperature stores down and is prone to take place degraded and causes the look level to raise, 2000 editions " Chinese pharmacopoeia requires it to preserve at shady and cool dry place, and 2005 editions " Chinese pharmacopoeia requires it to preserve at cold place.Even preserve at cold place, the Cefuroxime sodium product ubiquity look level of producing both at home and abroad at present is high, is prone to the problem of degraded.And the product granularity that obtains in the production process is little, and filtration time is very long, and is difficult dry, causes the production cycle of product long, and production cost is high, directly affects the economic benefit of enterprises and the market competitiveness.
In Chinese patent 200910118718 and the Chinese patent 200910203695 with cefuroxime acid with an amount of acetone and water dissolution, after weak lyes reactions such as charcoal absorption decolouring back and Sodium.alpha.-hydroxypropionate, the crystallization of dropping acetone.The product that this method obtains is clamminess, the solid-liquid separation difficulty, and the product washing is long time of drying.Chinese patent 200910162867 directly dissolves cefuroxime acid with sodium hydrogencarbonate alkali lye, through the charcoal absorption decolouring, adopts absolute ethyl alcohol and acetone mixed solvent dilution crystallization to obtain Cefuroxime sodium then again.This method is not controlled reaction process, and introduces two dissolved agent at crystallisation process, has increased difficult solvent recovery.And all need in operating process, may introduce insoluble particle in the existing Cefuroxime sodium preparation process, and cause yield to descend complicated operation through the charcoal absorption decolouring.
Summary of the invention
To the deficiency of above preparation Cefuroxime sodium method, the present invention is a raw material with the cefuroxime acid, has proposed the method that the coupling of a kind of new reaction and crystallisation process prepares Cefuroxime sodium.Its advantage is that operating process reduces, and product look level is low, and operational condition is easy to control, and " product of Chinese pharmacopoeia standard has favorable industrial application prospect directly to obtain meeting 2005 editions.
Be used to realize that the technological method of above-mentioned purpose of the present invention is following:
Under 20～30 ℃, cefuroxime acid is dissolved in the mixed solvent, be mixed with the solution that concentration is 0.025g/mL～0.1g/mL; To wherein adding the alkaline sodium salt aqueous solution, constant temperature stirring 10～20min makes and reacts completely then; Add the Cefuroxime sodium crystal seed; Add the dissolved agent behind the 10-20min; Then solution temperature is reduced to 0～5 ℃, constant temperature 0.5～2h; With the suspension filtered that obtains, washing, drying, obtain the Cefuroxime sodium product.
The mixed solvent of described dissolving cefuroxime acid is selected from any two kinds mixture of acetone, ethanol, Virahol or water.
Described alkaline sodium salt is selected from yellow soda ash, Sodium isooctanoate or its mixture, and the mol ratio of alkaline sodium salt and cefuroxime acid is 1-1.05: 1, and the alkaline sodium salt concentration of aqueous solution is 0.2g/mL～0.4g/mL.
Described dissolved agent is selected from acetone, ethanol or Virahol, with the dissolving cefuroxime acid identical organic solvent is arranged, and the consumption of dissolved agent is 2～6 times of cefuroxime acid liquor capacity.
Described Cefuroxime sodium crystal seed quality is 4%～8% of a cefuroxime acid quality.
Described drying conditions is: 20～30 ℃ of temperature, vacuum tightness 0.08～0.1MPa.
Among the above-mentioned preparation method, add after the crystal seed, add the dissolved agent and carry out dilution crystallization, control secondary nucleation process, further control crystal nucleation and growth in the crystallisation by cooling process again.
The preparation method of Cefuroxime sodium of the present invention has the following advantages: this method has reduced the charcoal absorption filtration procedure, has avoided the loss of yield.This method has realized reaction and crystalline coupling, and in crystallisation process, dilution crystallization combines with the crystallisation by cooling mode, makes crystallisation process be easy to control, has improved the process yield; Shorten product and be in the time under the high temperature, reduced its degraded at high temperature.Product granularity is more even, and flowability is improved greatly, is easy to washing, filters and drying.The look level of product is lower than standard color solution Y2 or YG2 (Chinese Pharmacopoeia version in 2005), and purity is higher than 99.5%, and yield is more than 92%.
Embodiment
Embodiment 1:
In mold, add acetone 70ml, pure water 10ml, drop into cefuroxime acid 7g, temperature control is stirred to complete dissolving for 20 ℃.With concentration is the aqueous sodium carbonate 4.4ml of 0.2g/ml, is added drop-wise in the cephalofruxin acid solution, and constant temperature stirring 10min makes and reacts completely.Add Cefuroxime sodium crystal seed 0.28g, constant temperature 10min drips acetone 480ml.Be cooled to 5 ℃ then, constant temperature 0.5h.Suction filtration, washing with acetone, dry 3 hours of 20 ℃, vacuum tightness 0.08MPa obtain the Cefuroxime sodium product.The look level of product is lower than Y1 or YG1, purity 99.6%, yield 95.3%.
Embodiment 2:
In mold, add acetone 145ml, alcohol 95 ml, drop into cefuroxime acid 10g, temperature control is stirred to complete dissolving for 25 ℃.With concentration is aqueous sodium carbonate 2.2ml and the Sodium isooctanoate aqueous solution 6.7ml mixed solution of 0.3g/ml, is added drop-wise in the cephalofruxin acid solution, and constant temperature stirring 15min makes and reacts completely.Add Cefuroxime sodium crystal seed 0.5g, drip alcohol 95 0ml behind the constant temperature 20min.Then and be cooled to 0 ℃, constant temperature 1h.Suction filtration, washing with alcohol, 20 ℃, dry 2 hours of vacuum tightness 0.1MPa obtains the Cefuroxime sodium product.The look level of product is lower than Y1 or YG1, purity 99.5%, yield 93.7%.
Embodiment 3:
In mold, add acetone 70ml, pure water 20ml, drop into cefuroxime acid 9g, temperature control is stirred to complete dissolving for 30 ℃.With concentration is the Sodium isooctanoate aqueous solution 8.9ml of 0.4g/ml, is added drop-wise in the cephalofruxin acid solution, and constant temperature stirring 20min makes and reacts completely.Add Cefuroxime sodium crystal seed 0.54g, constant temperature 15min, the back drips acetone 450ml.Be cooled to 2 ℃ then, constant temperature 1.5h.Suction filtration, washing with acetone, dry 1.8 hours of 30 ℃, vacuum tightness 0.09MPa obtain the Cefuroxime sodium product.The look level of product is lower than Y2 or YG2, purity 99.5%, yield 92.1%.
Embodiment 4:
In mold, add acetone 320ml, Virahol 80ml, drop into cefuroxime acid 10g, temperature control is stirred to complete dissolving for 24 ℃.With concentration is the aqueous sodium carbonate 4.4ml of 0.3g/ml, is added drop-wise in the cephalofruxin acid solution, and constant temperature stirring 15min makes and reacts completely.Add Cefuroxime sodium crystal seed 0.8g, constant temperature 15min drips Virahol 800ml.Be cooled to 2 ℃ then, constant temperature 2h.Suction filtration, washed with isopropyl alcohol, dry 1.8 hours of 25 ℃, vacuum tightness 0.1MPa obtain the Cefuroxime sodium product.The look level of product is lower than Y2 or YG2, purity 99.6%, yield 96.4%.
The present invention's a kind of coupling reaction crystallization open and that propose prepares the method for Cefuroxime sodium, and those skilled in the art can be through using for reference this paper content, and links such as appropriate change raw material, processing parameter realize.Method of the present invention and product are described through preferred embodiment; Person skilled obviously can be in not breaking away from content of the present invention, spirit and scope to method as herein described with product is changed or suitably change and combination, realize the present invention's technology.Special needs to be pointed out is, the replacement that all are similar and change apparent to those skilled in the artly, they are regarded as and are included in spirit of the present invention, scope and the content.
Claims (6)
1. a coupling reaction crystallization prepares the method for Cefuroxime sodium, it is characterized in that under 20～30 ℃, cefuroxime acid being dissolved in the mixed solvent, is mixed with the solution that concentration is 0.025g/mL～0.1g/mL; To wherein adding the alkaline sodium salt aqueous solution, constant temperature stirring 10～20min makes and reacts completely then; Add the Cefuroxime sodium crystal seed; Add the dissolved agent behind the 10-20min; Then solution temperature is reduced to 0～5 ℃, constant temperature 0.5～2h; With the suspension filtered that obtains, washing, drying, obtain the Cefuroxime sodium product.
2. the method for claim 1 is characterized in that the mixed solvent of described dissolving cefuroxime acid is selected from any two kinds mixture of acetone, ethanol, Virahol or water.
3. the method for claim 1 is characterized in that described alkaline sodium salt is selected from yellow soda ash, Sodium isooctanoate or its mixture, and the mol ratio of alkaline sodium salt and cefuroxime acid is 1-1.05: 1, and the alkaline sodium salt concentration of aqueous solution is 0.2g/mL～0.4g/mL.
4. the method for claim 1 is characterized in that described dissolved agent is selected from acetone, ethanol or Virahol, with the dissolving cefuroxime acid identical organic solvent is arranged, and the consumption of dissolved agent is 2～6 times of cefuroxime acid liquor capacity.
5. the method for claim 1 is characterized in that described Cefuroxime sodium crystal seed quality is 4%～8% of a cefuroxime acid quality.
6. the method for claim 1 is characterized in that described drying conditions is: 20～30 ℃ of temperature, vacuum tightness 0.08～0.1MPa.
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| CN201210043997XA CN102617604A (en) | 2012-02-24 | 2012-02-24 | Method utilizing coupling reaction crystallization to prepare cefuroxime sodium |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110950892A (en) * | 2019-12-16 | 2020-04-03 | 山东金城柯瑞化学有限公司 | Method for optimizing and removing impurities from cefuroxime intermediate (3-decarbamoyl-cefuroxime acid) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4277601A (en) * | 1979-02-15 | 1981-07-07 | Glaxo Group Limited | Preparation of sodium cefuroxime |
| US4298732A (en) * | 1978-01-17 | 1981-11-03 | Glaxo Group Limited | Crystallization process |
| KR20020030563A (en) * | 2000-10-19 | 2002-04-25 | 손 경 식 | Process for preparing sodium cefuroxime |
| CN101812076A (en) * | 2009-02-24 | 2010-08-25 | 丽珠医药集团股份有限公司 | Cefuroxime sodium and preparation method thereof |
| CN101955492A (en) * | 2009-07-15 | 2011-01-26 | 上海新先锋药业有限公司 | Preparation method of cefuroxime sodium |
-
2012
- 2012-02-24 CN CN201210043997XA patent/CN102617604A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4298732A (en) * | 1978-01-17 | 1981-11-03 | Glaxo Group Limited | Crystallization process |
| US4277601A (en) * | 1979-02-15 | 1981-07-07 | Glaxo Group Limited | Preparation of sodium cefuroxime |
| KR20020030563A (en) * | 2000-10-19 | 2002-04-25 | 손 경 식 | Process for preparing sodium cefuroxime |
| CN101812076A (en) * | 2009-02-24 | 2010-08-25 | 丽珠医药集团股份有限公司 | Cefuroxime sodium and preparation method thereof |
| CN101955492A (en) * | 2009-07-15 | 2011-01-26 | 上海新先锋药业有限公司 | Preparation method of cefuroxime sodium |
Non-Patent Citations (1)
| Title |
|---|
| 李爱军等: "头孢呋辛钠合成工艺优化", 《天津大学学报》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110950892A (en) * | 2019-12-16 | 2020-04-03 | 山东金城柯瑞化学有限公司 | Method for optimizing and removing impurities from cefuroxime intermediate (3-decarbamoyl-cefuroxime acid) |
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Address after: 300072 Tianjin City, Nankai District Wei Jin Road No. 92, Tianjin University Applicant after: Tianjin University Applicant after: SHENZHEN CHINA RESOURCES GOSUN PHARMACEUTICAL CO., LTD. Address before: 300072 Tianjin City, Nankai District Wei Jin Road No. 92, Tianjin University Applicant before: Tianjin University Applicant before: SHENZHEN CHINA RESOURCES GOSUN PHARMACEUTICAL Co., Ltd |
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Application publication date: 20120801 |