CN102807573B - Method for preparing ceftizoxime - Google Patents
Method for preparing ceftizoxime Download PDFInfo
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- CN102807573B CN102807573B CN201210299826.3A CN201210299826A CN102807573B CN 102807573 B CN102807573 B CN 102807573B CN 201210299826 A CN201210299826 A CN 201210299826A CN 102807573 B CN102807573 B CN 102807573B
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- ceftizoxime
- sodium
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- ethyl acetate
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- YPWFISCTZQNZAU-UHFFFAOYSA-N C1CCSCC1 Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
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- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a method for preparing ceftizoxime. The method comprises the following steps of: (1) dissolving 2-(2-amino-4-thiazolyl)-2-methoxy-imine acetic acid in an organic solvent, and reacting with N-succinimide under the catalysis of dicyclohexyl carbodiimide/dimethylamino pyridine (DCC/DMAP) to obtain active ester; (2) dissolving the active ester in dichloromethane, and adding 7-amino-3-demethylation-3-cephalosporanic acid (7-ANCA) and alkali for reacting to obtain ceftizoxime acid; and (3) reacting the ceftizoxime acid with a salifying agent to obtain the ceftizoxime, wherein the salifying agent is sodium acetate, sodium ethoxide, sodium 2-ethylhexanoate, sodium isocaproate, sodium bicarbonate or sodium hydroxide.
Description
Technical field
The present invention relates to a kind of preparation method of ceftizoxime sodium, belong to medical technical field.
Background technology
Ceftizoxime sodium is developed by Japanese Fujisawa Pharmaceutical Co., Ltd the earliest, and first in Japan, go on the market in nineteen eighty-two, it is English by name: Ceftizoxime, molecular formula is: C13H13N5O5S2, chemical name is: (6r, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino acetamido] assorted two ring [4.2.0] oct-2-ene-2-carboxylic acid sodium salts of-8-oxo-5-thia-1-ammonia, structural formula is:
Ceftizoxime sodium belongs to third generation cephalosporin, has broad-spectrum antibacterial action, stable to the wide spectrum β-lactamase (comprising penicillinase and cephalosporinase) of multiple gram-positive microorganism and Gram-negative bacteria generation.Ceftizoxime sodium has powerful anti-microbial effect to escherichia coli, Klebsiella Pneumoniae, Proteus mirabilis, and hemophilus influenzae and neisseria gonorrhoeae are had to good anti-microbial effect.Ceftizoxime sodium reaches sterilization functions by the biosynthesizing of anti-bacteria cell wall mucopeptide.At present, ceftizoxime sodium is mainly used in treating the disease such as meningitis and Simple gonorrhea due to lower respiratory infection, urinary tract infections, abdominal cavity infection, pelvic infection, septicemia, skin soft-tissue infection, bone and the infection of joint, streptococcus pneumoniae or the hemophilus influenzae due to sensitive organism clinically, and the diseases such as wound and burn are also had to extraordinary result for the treatment of.
About the synthetic method of ceftizoxime sodium, in U.S. Pat 4427674, two lines are disclosed, article one, be take 7-phenylacetylamino-3-cephalosporin-4-carboxyl acid to methoxybenzyl ester as raw material, at C7 position side chain, introduce the cis-methoxyimino-2-of 2-(2-formamido group) thiazolyl acetic acid, slough afterwards the blocking group that C4 introduces side chain, obtain ceftizoxime sodium; Another is take 7-amino-3-demethyl-3-Cephalosporanic acid (7-ANCA) as raw material and cefotaxime acetic acid direct polycondensation obtains ceftizoxime sodium, and this route side reaction is more, and products therefrom need be through column chromatography purification.
The people such as Zhang Fengxia have carried out improving (referring to " synthesizing of ceftizoxime sodium " to above-mentioned the 2nd article of route, Zhang Fengxia etc., ACAD J GCP, the 23rd the 3rd phase of volume, 2007), take 7-ANCA as raw material, make ceftizoxime acid, then react and obtain ceftizoxime sodium with salt forming agent with 2-(2-amino-4-thiazolyl)-2-methoxy imino acetyl benzothiazole thioesters (2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester) condensation.The method adopts active ester method, and technique is simple, reaction conditions gentleness, and products therefrom impurity is few, and the yield that 7-ANCA and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester condensation make ceftizoxime acid is 90.3%.But easy residual 2-mercaptobenzothiazole (captax) in the method product is harmful.
Summary of the invention
In order to overcome the defect of prior art, the invention provides a kind of preparation method of ceftizoxime sodium.The product yield obtaining according to method of the present invention significantly improves, and residual harmful substance not in product.
For achieving the above object, the invention provides following technical scheme:
The preparation method who the invention provides a kind of ceftizoxime sodium, it comprises the steps:
(1) 2-(2-amino-4-thiazolyl)-2-methoxyimino Acetic Acid is dissolved in organic solvent, under DCC/DMAP catalysis, reacts and obtain active ester with N-succinimide, described organic solvent preferred alcohols kind solvent, preferred alcohol;
(2) active ester is dissolved in methylene dichloride, adds 7-ANCA and alkali reaction to obtain ceftizoxime acid; One in described buck sodium hydroxide, potassium hydroxide, sodium bicarbonate, triethylamine, diethylamine, preferably triethylamine;
(3) ceftizoxime acid is reacted and is obtained ceftizoxime sodium with salt forming agent, and described salt forming agent is sodium acetate, sodium ethylate, Sodium isooctanoate, isocaproic acid sodium, sodium bicarbonate or sodium hydroxide, preferably sodium bicarbonate.
The present invention has changed the lower defect of domestic and international ceftizoxime sodium raw material production moderate purity, the active ester reactive behavior that the present invention adopts is higher, 7-ANCA and active ester condensation make the yield of ceftizoxime acid up to more than 95%, reduce the generation of impurity, especially avoided the easily generation of residual harmful 2-mercaptobenzothiazole (captax) in prior art.
Embodiment
By 2-(2-amino-4-thiazolyl)-2-methoxyimino Acetic Acid (2.01g, 10mmol) be dissolved in 20ml ethanol, add DMAP(1.83g, 15mmol) and DCC(3g, 6.0mmol) after stirring at room half an hour, add N-hydroxy-succinamide (1.2g, 10mmol), after stirring at room half an hour, add after saturated NH4Cl solution stirring, ethyl acetate extraction, separate ethyl acetate layer, organic phase is washed through saturated common salt, anhydrous sodium sulfate drying, steaming desolventizes, column chromatography (ethyl acetate/methanol=10:1) wash-out, obtain active ester 2.8g, yield 94%.
Active ester (2.8g, 9.4mmol) is dissolved in 20ml methylene dichloride, adds 7-ANCA(1.9g, 9.4mmol) and triethylamine 10ml stirring at room reaction after 8 hours, with the hydrochloric acid soln acid adjustment (PH=2.0) of 1mol/l, and react 2h at-5 ℃.Dichloromethane extraction, activated carbon decolorizing, dry rear concentrated ceftizoxime acid 3.5g, the yield 97% of obtaining.MS(m/z):384(M+H)+。
Ceftizoxime acid (3.5g, 9.1mmol) is dissolved in 10ml ethyl acetate, splashes into the ethyl acetate 20ml that is dissolved with 5g sodium bicarbonate, 25 ℃ of stirring and crystallizing, the white crystal 3.6g of 30 ℃ of decompression dryings, it is 99.1%, MS (m/z) that HPLC detects purity: 406 (M+H)+.
According to above-described embodiment, the present invention is described in detail.It should be noted that, above embodiment is only used to illustrate.Do not departing under the prerequisite of the present invention's spirit and essence, those skilled in the art can design multiple alternative of the present invention and improvement project, within it all should be understood to protection scope of the present invention.
Claims (1)
1. a preparation method for ceftizoxime sodium, it comprises the steps:
2.01g 2-(2-amino-4-thiazolyl)-2-methoxyimino Acetic Acid is dissolved in 20ml ethanol, adds 1.83g DMAP and 3g DCC, after stirring at room half an hour, add 1.2g N-hydroxy-succinamide, after stirring at room half an hour, add saturated NH
4after Cl solution stirring, ethyl acetate extraction, separates ethyl acetate layer, and organic phase is washed through saturated common salt, anhydrous sodium sulfate drying, and steaming desolventizes, column chromatography wash-out, eluent is ethyl acetate/methanol=10:1, obtains active ester 2.8g, yield 94%;
Gained 2.8g active ester is dissolved in 20ml methylene dichloride, add 1.9g 7-ANCA and the reaction of 10ml triethylamine stirring at room after 8 hours, with the hydrochloric acid soln acid adjustment of 1mol/l to pH=2.0, and react 2h at-5 ℃, dichloromethane extraction, activated carbon decolorizing, the dry rear concentrated ceftizoxime acid 3.5g that to obtain, yield 97%, MS (m/z): 384 (M+H)
+;
The acid of gained 3.5g ceftizoxime is dissolved in 10ml ethyl acetate, splash into the ethyl acetate 20ml that is dissolved with 5g sodium bicarbonate, 25 ℃ of stirring and crystallizing, 30 ℃ of decompression dryings obtain white crystal ceftizoxime sodium 3.6g, it is 99.1%, MS (m/z) that HPLC detects purity: 406 (M+H)
+.
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| CN102807573B true CN102807573B (en) | 2014-04-16 |
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| CN102977121A (en) * | 2012-12-25 | 2013-03-20 | 菏泽睿智科技开发有限公司 | Synthetic method of ceftizoxime acid |
| CN117105956A (en) * | 2023-08-25 | 2023-11-24 | 海南灵康制药有限公司 | A kind of ceftizoxime sodium crystal compound and its preparation method and application |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102382124A (en) * | 2011-08-31 | 2012-03-21 | 郑州大学 | Ceftizoxime alapivoxil synthesized from cephalosporin drug intermediate and preparation method thereof |
| CN102603771A (en) * | 2012-02-23 | 2012-07-25 | 苏州中联化学制药有限公司 | Preparation method of ceftizoxime sodium |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102382124A (en) * | 2011-08-31 | 2012-03-21 | 郑州大学 | Ceftizoxime alapivoxil synthesized from cephalosporin drug intermediate and preparation method thereof |
| CN102603771A (en) * | 2012-02-23 | 2012-07-25 | 苏州中联化学制药有限公司 | Preparation method of ceftizoxime sodium |
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