CN102911186A - Ceftizoxime sodium preparation and refining method - Google Patents
Ceftizoxime sodium preparation and refining method Download PDFInfo
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- CN102911186A CN102911186A CN2012104528737A CN201210452873A CN102911186A CN 102911186 A CN102911186 A CN 102911186A CN 2012104528737 A CN2012104528737 A CN 2012104528737A CN 201210452873 A CN201210452873 A CN 201210452873A CN 102911186 A CN102911186 A CN 102911186A
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Abstract
The invention relates to a ceftizoxime sodium preparation and refining method through utilizing ceftizoxime acid. The method comprises the following steps: producing product-ceftizoxime sodium through utilizing the ceftizoxime acid by the action of a salt forming agent; achieving the purposes of refining and purifying through recrystallization; and finally obtaining high purityceftizoxime sodium. According to the invention, the product quality of API is improved, the toxic side effect is reduced, and safety is ensured during preparation of anti-bacterial medicines. Compared with the prior art, the method has the advantages of high product purity, simplicity and convenience in operation, low cost, high yield, reduced toxic side effect, and suitability for industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate to a kind of preparation method of Cephalosporins, relate in particular a kind of preparation method of ceftizoxime sodium.
Background technology
Ceftizoxime sodium, English by name: Ceftizoxime Sodium, 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, molecular formula: C13H12N5NaO5S2, molecular weight: 405.38, structural formula is:
Ceftizoxime sodium is by the Third generation Cephalosporins microbiotic of Japanese Fujisawa Pharmaceutical Co., Ltd exploitation, at first goes on the market in Japan in nineteen eighty-two, and commodity are called Ceftizox.This product is as the third generation cephalosporin microbiotic, and its mechanism of action is for the biosynthesizing by the anti-bacteria cell wall mucopeptide reaches germicidal action, has wide spectrum, efficient, anti-enzyme, low toxicity and can be by the characteristics of hemato encephalic barrier.Wide spectrum β-lactamase (comprising penicillinase and cephalosporinase) to multiple gram positive organism and gram-negative bacteria generation is stable.The enterobacteriaceae lactobacteriaceaes such as escherichia coli, Klebsiella Pneumoniae, Proteus mirabilis are had powerful anti-microbial effect, and the Rhodopseudomonas such as Pseudomonas aeruginosa and acinetobacter are poor to this product susceptibility.Ceftizoxime has good anti-microbial effect to hemophilus influenzae and neisseria gonorrhoeae.To the effect of streptococcus aureus and staphylococcus epidermidis than first, second in generation cynnematin for poor, methicillin-resistant staphylococcus aureus and enterococcus spp are to this product resistance, various suis are all extremely sensitive to this product.The anerobes such as dyspepsiacoccus, peptostreptococcus and part Bacteroides are responsive to this product more, and clostridium difficile is to this product resistance.Be used for the treatment of clinically 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 the sensitive organism.
The synthetic method of relevant ceftizoxime sodium, meticulous having delivered with the specialty chemicals magazine is entitled as " study on the synthesis of ceftizoxime sodium " literary composition, and the document is reported take sodium bicarbonate as salt forming agent.But the consumption of anhydrous sodium carbonate had a significant impact reaction times and quality product, the anhydrous sodium carbonate consumption increases, and the reaction times obviously shortens, but the Determination of Content of Ceftizoxime Sodium in the product obviously descends, and the corresponding increase of foreign matter content, product colour be obvious variation also; And easily comprise undissolved sodium bicarbonate in the products obtained therefrom, affect quality product.Mountain Western Medicine S University's journal has been delivered the article that is entitled as " ceftizoxime sodium synthesising process research ", mention ceftizoxime acid soluble in water in the literary composition, drip the triethylamine stirring and dissolving, behind the activated carbon decolorizing, drip the ethanolic soln of Sodium isooctanoate, after regulating pH, drip ethanol, crystallization obtains ceftizoxime acid, there is ethanol in products obtained therefrom, is not easy drying.Chinese patent CN101348492 discloses the method for preparing high-purity ceftizoxime sodium, wants ceftizoxime sodium is converted into ceftizoxime acid in water, obtains the ceftizoxime acid crude with the organic reagent extraction, peroxidation aluminium chromatography column, remove the solvent in the gained moving phase, add the lower alcohol dissolving, add alkali and propose product, the method is used alumina chromatographic column, also will use a large amount of eluents, cost is high, contaminate environment, complicated operation is not suitable for suitability for industrialized production.
Summary of the invention
The shortcoming that the object of the invention is to overcome aforesaid method provides a kind of preparation method of highly purified ceftizoxime sodium newly with not enough, reaches simple to operate, and yield is higher, the purpose that product purity is high.
The invention discloses for achieving the above object following technology contents:
A kind of preparation method of ceftizoxime sodium is characterized in that the method may further comprise the steps:
(1) at a certain temperature, ceftizoxime acid (II) is soluble in water, under stirring, adds salt forming agent in batches, after stirring reaction is complete, activated carbon decolorizing, gained filtrate is regulated about pH value to 7 with glacial acetic acid, stirs lower, slowly drip acetone, then stir 1h, filter, obtain ceftizoxime sodium (I);
(2) at room temperature, with water dissolution ceftizoxime sodium (I), behind the activated carbon decolorizing, in filtrate, slowly drip acetone, then stir 1-2h, filter, after the drying, obtain more highly purified ceftizoxime sodium (I).
Each step reaction formula is as follows:
In step (2), at room temperature, with water dissolution ceftizoxime sodium (I), behind the activated carbon decolorizing, in filtrate, slowly drip acetone, then stir 1-2h, filter, after the drying, obtain more highly purified ceftizoxime sodium (I), water: the volume ratio of acetone is 4-20.
The positively effect that the ceftizoxime sodium of the present invention's preparation compared with prior art has is: preparation ceftizoxime sodium of the present invention is simple to operate, cost is low, and the yield height can reach 88.3%, further behind the refining purifying, improve quality product, guaranteed patient's drug safety.
Embodiment
Below will be described in detail the preferred embodiments of the present invention; Should be appreciated that preferred embodiment only for the present invention is described, rather than in order to limit protection scope of the present invention.
Embodiment 1
Synthesizing of ceftizoxime sodium (I)
In the 100ml reaction flask, add the 25ml deionized water, be cooled to 5-10 ℃, add ceftizoxime acid 12.6g(0.03mol), under stirring, add Sodium isooctanoate 6.0g(0.036ml in batches), stir 1.5h and react completely, add the 0.2g activated carbon decolorizing, suction filtration, a small amount of water washing is poured filtrate in the 250ml reaction flask into, regulating pH is 7, in 20-25 ℃, in filtrate, slowly drip acetone 150ml, stirring and crystallizing, suction filtration, filter cake after the drying, obtains ceftizoxime sodium 10.7g with washing with acetone, yield is 88.3%, HPLC normalization method purity 99.3%.
Embodiment 2
Making with extra care of ceftizoxime sodium (I)
Under the room temperature, in the 100ml reaction flask, add pure water 20ml, add ceftizoxime sodium 10g, after the stirring and dissolving, add the 0.2g gac, behind the stirring 30min, suction filtration, a small amount of water washing is poured filtrate into the 250ml reaction flask, stir down, slowly drip acetone 120ml, stir 1-2h after, filter, with washing with acetone, obtain more highly purified ceftizoxime sodium 9.5g after the drying, yield 95%.Product purity 〉=99.5%(HPLC).
Ultimate analysis:
Theoretical value: C:38.52% H:2.98% N:17.27% O:19.73% S:15.81%
Measured value: C:38.48% H:2.97% N:17.25% O:19.75% S:15.86%
1H-NMR(DMSO-d6?)?δ:?3.?35?(?2H,?m)?,?3.?47?(3H,?s)?,?4.?95(1H,?d,?J?=?3.?9?Hz)?,?5.?62?(?1H,?dd,?J?=?3.?8?Hz,?6.?6Hz)?,?5.?96?(1H,?m),?6.?71?(1H,?s),?7.?23?(2H,?s),?9.51(1H,?d,?J?=?6.?6?Hz)。Theoretical value: C:38.52% H:2.98% N:17.27% O:19.73% S:15.81%
Measured value: C:38.49% H:2.97% N:17.25% O:19.74% S:15.85%
1H-NMR(DMSO-d6?)?δ:?3.?35?(?2H,?m)?,?3.?47?(3H,?s)?,?4.?95(1H,?d,?J?=?3.?9?Hz)?,?5.?62?(?1H,?dd,?J?=?3.?8?Hz,?6.?6Hz)?,?5.?96?(1H,?m),?6.?71?(1H,?s),?7.?23?(2H,?s),?9.51(1H,?d,?J?=?6.?6?Hz)。
Claims (4)
1. the preparation method of a ceftizoxime sodium is characterized in that the method may further comprise the steps:
(1) under-10～30 ℃ of conditions, ceftizoxime acid is dissolved in the deionized water, under whipped state, drips organic salt forming agent Sodium isooctanoate under 5-10 ℃ in batches, after stirring reaction is complete, activated carbon decolorizing, suction filtration, deionized water wash, gained filtrate is regulated about pH value to 7, under whipped state with glacial acetic acid, slowly drip acetone, after stirring 1 ~ 2h, stirring and crystallizing, suction filtration, filter cake obtains ceftizoxime sodium with washing with acetone;
(2) at room temperature, the ceftizoxime sodium that step (1) obtains with deionized water dissolving after, add gac and stir 30min ~ 1h, suction filtration, deionized water wash, filtrate is poured into reaction flask, in filtrate, slowly drip acetone under 5-10 ℃, then stir 1-2h, filter, after the vacuum-drying, obtain more highly purified ceftizoxime sodium.
2. the preparation method of a kind of ceftizoxime sodium as claimed in claim 1 is characterized in that: wherein ceftizoxime acid temperature soluble in water is 5-10 ℃ in the step (1).
3. the preparation method of a kind of ceftizoxime sodium as claimed in claim 1 is characterized in that: wherein in the step (1): the mol ratio 1:1-1.5 of ceftizoxime acid and salt forming agent Sodium isooctanoate; Temperature of reaction is-10～30 ℃.
4. the preparation method of a kind of ceftizoxime sodium as claimed in claim 1 is characterized in that: preparation method claimed in claim 1, wherein water in the step (2): the volume ratio of acetone is 4-20.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105037390A (en) * | 2015-05-28 | 2015-11-11 | 浙江长典医药有限公司 | Children ceftizoxime sodium compound entity and preparation thereof |
| CN111777625A (en) * | 2020-06-05 | 2020-10-16 | 华北制药河北华民药业有限责任公司 | Preparation method of ceftizoxime sodium for injection |
| CN112442048A (en) * | 2020-11-10 | 2021-03-05 | 华北制药河北华民药业有限责任公司 | Preparation method of cefpiramide sodium |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0048915A2 (en) * | 1980-09-26 | 1982-04-07 | Fujisawa Pharmaceutical Co., Ltd. | New cephem compounds, processes for preparation thereof and pharmaceutical composition comprising the same |
| CN101606910A (en) * | 2009-07-20 | 2009-12-23 | 山东罗欣药业股份有限公司 | A kind of ceftizoxime sodium medicine injectable powder and preparation method thereof, and synthetic method of bulk drug ceftizoxime sodium |
| CN102219794A (en) * | 2011-08-03 | 2011-10-19 | 天津华药医药有限公司 | Preparation method of ceftizoxime sodium |
| 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 |
| CN102718779A (en) * | 2012-05-25 | 2012-10-10 | 深圳致君制药有限公司 | Ceftizoxime sodium for injection and preparation method thereof as well as synthetic method for ceftizoxime sodium serving as crude drug |
-
2012
- 2012-11-13 CN CN201210452873.7A patent/CN102911186B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0048915A2 (en) * | 1980-09-26 | 1982-04-07 | Fujisawa Pharmaceutical Co., Ltd. | New cephem compounds, processes for preparation thereof and pharmaceutical composition comprising the same |
| CN101606910A (en) * | 2009-07-20 | 2009-12-23 | 山东罗欣药业股份有限公司 | A kind of ceftizoxime sodium medicine injectable powder and preparation method thereof, and synthetic method of bulk drug ceftizoxime sodium |
| CN102219794A (en) * | 2011-08-03 | 2011-10-19 | 天津华药医药有限公司 | Preparation method of ceftizoxime sodium |
| 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 |
| CN102718779A (en) * | 2012-05-25 | 2012-10-10 | 深圳致君制药有限公司 | Ceftizoxime sodium for injection and preparation method thereof as well as synthetic method for ceftizoxime sodium serving as crude drug |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105037390A (en) * | 2015-05-28 | 2015-11-11 | 浙江长典医药有限公司 | Children ceftizoxime sodium compound entity and preparation thereof |
| CN111777625A (en) * | 2020-06-05 | 2020-10-16 | 华北制药河北华民药业有限责任公司 | Preparation method of ceftizoxime sodium for injection |
| CN112442048A (en) * | 2020-11-10 | 2021-03-05 | 华北制药河北华民药业有限责任公司 | Preparation method of cefpiramide sodium |
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Address after: No.16, LingHang Road, Tianjin Binhai New Area pilot free trade zone (Airport Economic Zone), 300450 Patentee after: Qingsong Pharmaceutical Group Co.,Ltd. Address before: 300308 3-618, No.82, West 2nd Road, Airport Economic Zone, Dongli District, Tianjin Patentee before: TIANJIN GREENPINE CHINESE MEDICINE PHARMACEUTICAL Co.,Ltd. |