CN101974018A - Sulbenicillin sodium compound and novel method thereof - Google Patents
Sulbenicillin sodium compound and novel method thereof Download PDFInfo
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- CN101974018A CN101974018A CN 201010274845 CN201010274845A CN101974018A CN 101974018 A CN101974018 A CN 101974018A CN 201010274845 CN201010274845 CN 201010274845 CN 201010274845 A CN201010274845 A CN 201010274845A CN 101974018 A CN101974018 A CN 101974018A
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- acid
- sulbenicillin
- sulfocillin
- mixed solvent
- isopropyl ether
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Abstract
The invention provides a sulbenicillin sodium compound and a novel method thereof. The method comprises the following steps of: performing acid-alkali reaction; adding activated carbon into a mixed solvent of dichloromethane/isopropyl ether to adsorb; and separating and purifying by using a chromatographic column to adsorb. The method has the advantages of greatly improving the purity and content of sulbenicillin sodium, optimizing the product quality of preparations, guaranteeing the safety of clinical medicament application, along with simple process, low cost and high yield and purity, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of sulbenicillin sodium compound and novel method thereof, belong to medical technical field.
Background technology
Sulfocillin, and its chemical being called (2S, 5R, 6R)-3,3-dimethyl-6-(2-phenyl-2-sulfo group kharophen)-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid disodium salt, molecular formula C
16H
16N
2Na
2O
7S
2, molecular weight 458.42, structural formula is:
Sulfocillin belongs to wide spectrum semi-synthetic penicillins microbiotic, to enterobacteriaceae lactobacteriaceaes such as escherichia coli, proteus, enterobacter, citric acid bacterium genus, Salmonella and Shigellas, and other gram-negative bacteria such as Pseudomonas aeruginosa, hemophilus influenzae, neisseria has anti-microbial effect; Hemolytic streptococcus, streptococcus pneumoniae and the staphylococcus that do not produce penicillinase are also had an anti-microbial activity; To peptostreptococcus, clostridium interior anerobe also to certain effect is arranged.The mechanism of action of Sulfocillin is for synthesizing the performance germicidal action by suppressing bacteria cell wall.Mainly be applicable to pneumonia due to Pseudomonas aeruginosa to this product sensitivity, some distortion stalk Pseudomonas and other the responsive Gram-negative bacterias, urinary tract infections, complicacy skin soft-tissue infection and septicemia etc.
Sulfocillin is that Japanese military field drug company research and development a kind of has optically active wide spectrum semisynthetic penicillin, in listing in 1973, nineteen ninety the income Chinese Pharmacopoeia, the activity of its levo form be dextrorotatory form 4-8 doubly.Bibliographical information Sulfocillin synthetic mainly be with the toluylic acid be raw material through sulfonation, split obtain D (-)-sulphur toluylic acid after, directly or after the chloride make with the 6-APA condensation.Synthetic route is:
The sulfonation reaction of toluylic acid is comparatively complicated in this method, and the cost height directly uses hydrogen chloride gas corrodibility bigger, split to adopt L (+)-easy racemization of lysine hydrochloric acid product salt, and complicated operation, weak effect, the product purity that obtains is lower.
Summary of the invention
There is the low defective of product purity in the above-mentioned prior art for preparing Sulfocillin in order to overcome, we are by a large amount of tests, acid-base reaction is passed through in discovery, in mixed organic solvents, dissolve then, through charcoal absorption, then use chromatographic column absorption to carry out separation and purification, just can obtain the higher Sulfocillin of purity, especially when mixed solvent is methylene dichloride/isopropyl ether, its separating effect is especially obvious, well beyond the use common organic solvents, and Sulfocillin yield and purity also all are greatly improved.
Therefore, the process for purification of sulbenicillin provided by the invention sodium compound by acid-base reaction, adds charcoal absorption then in the mixed solvent of methylene dichloride/isopropyl ether, then use chromatographic column absorption to carry out separation and purification, improve the purity and the content of Sulfocillin greatly, optimized the quality product of preparation, ensured safety of clinical administration, present method technology is simple, cost is low, and yield, purity height are suitable for suitability for industrialized production.
The invention provides the process for purification of a kind of sulbenicillin sodium compound, concrete technical scheme is as follows: the process for purification of the sulbenicillin sodium compound of structure shown in a kind of formula (I),
Comprise the steps:
(1) the Sulfocillin crude product is soluble in water, slowly add acid then, stirring reaction is 2-3 to the pH of solution, generation sulbenicillin Acid precipitation filters and obtains sulbenicillin acid solid;
(2) the sulbenicillin acid that step (1) is obtained is dissolved in the mixed solvent of methylene dichloride/isopropyl ether, adds the gac of overall solution volume 0.1-0.5 (g/ml), and 50-60 ℃ is stirred 20-30min, filters decarburization, collects filtrate;
(3) filtrate that step (2) is obtained utilizes the chromatographic column separation and purification to obtain the highly finished product of Sulfocillin, wherein the moving phase used of chromatographic column is the mixing solutions of the alkaline solution of 2: 1 hexanaphthene and pH value 9-11 as volume ratio, fixed phase stuffing is selected from silica gel or aluminum oxide, flow velocity 3.3-4.2ml/min, column temperature 25-30 ℃, collect filtrate, drying under reduced pressure obtains the purified Sulfocillin.
Preferably, above-mentioned described method, wherein the acid described in the step (1) is selected from a kind of in hydrochloric acid, acetate, Citric Acid, sulfuric acid, the phosphoric acid, preferred acetate.
Preferably, above-mentioned described method, wherein the mixed solvent methylene dichloride/isopropyl ether volume ratio described in the step (2) is 1: 1-1: 3, it is preferred that methylene dichloride/the isopropyl ether volume ratio is 1: 2.
Preferably, above-mentioned described method, wherein the alkali described in the step (3) is selected from a kind of in sodium hydroxide, sodium bicarbonate, the yellow soda ash, preferred sodium hydroxide.
The process for purification of sulbenicillin provided by the invention sodium compound, by acid-base reaction, charcoal absorption and chromatographic column absorption and purification, the purity and the content of Sulfocillin have been improved greatly, optimized the quality product of preparation, ensured safety of clinical administration, and present method technology is simple, cost is low, the yield height is suitable for suitability for industrialized production.
Embodiment
Below further explain and describe content of the present invention by embodiment, but embodiment is not to be construed as limiting the scope of the invention.
Purity testing is undertaken by high performance liquid chromatography with reference to Chinese Pharmacopoeia version in 2010.The filling of the preparative chromatography post that uses in the treating process is undertaken by ordinary method.Determine that by nucleus magnetic resonance and infrared spectra the resulting product in refining back is a Sulfocillin.
Embodiment 1The preparation of Sulfocillin
(1) 100g Sulfocillin crude product is dissolved in the 1000ml purified water, slowly adds 20% acetic acid solution then, stirring reaction is 3 to the pH of solution, and generation sulbenicillin Acid precipitation filters and obtains sulbenicillin acid solid 84.6g, yield 93.6%;
(2) the sulbenicillin acid that step (1) is obtained is dissolved in 800ml mixed solvent methylene dichloride/isopropyl ether (volume ratio is 1: 3), adds the gac of overall solution volume 0.8g, and 60 ℃ are stirred 20min, filter decarburization, collect filtrate;
(3) filtrate that step (2) is obtained utilizes the chromatographic column separation and purification to obtain the highly finished product of Sulfocillin, wherein the moving phase used of chromatographic column is that 2: 1 hexanaphthene and pH value are the mixing solutions of 9 sodium hydrogen carbonate solution as volume ratio, fixed phase stuffing is selected from silica gel or aluminum oxide, flow velocity 3.3ml/min, 30 ℃ of column temperatures are collected filtrate, drying under reduced pressure, obtain purified Sulfocillin 93.4g, yield 93.4%, purity is 99.3%.
Embodiment 2The preparation of Sulfocillin
(1) 100g Sulfocillin crude product is dissolved in the 1000ml purified water, slowly adds 10% hydrochloric acid soln then, stirring reaction is 2 to the pH of solution, and generation sulbenicillin Acid precipitation filters and obtains sulbenicillin acid solid 83.9g, yield 92.8%;
(2) the sulbenicillin acid that step (1) is obtained is dissolved in 1000ml mixed solvent methylene dichloride/isopropyl ether (volume ratio is 1: 1), adds the gac of overall solution volume 5g, and 50 ℃ are stirred 30min, filter decarburization, collect filtrate;
(3) filtrate that step (2) is obtained utilizes the chromatographic column separation and purification to obtain the highly finished product of Sulfocillin, wherein the moving phase used of chromatographic column is that 2: 1 hexanaphthene and pH value are the mixing solutions of 11 sodium hydroxide solution as volume ratio, fixed phase stuffing is selected from silica gel or aluminum oxide, flow velocity 4.2ml/min, 25 ℃ of column temperatures are collected filtrate, drying under reduced pressure, obtain purified Sulfocillin 92.6g, yield 92.6%, purity is 99.2%.
Embodiment 3The preparation of Sulfocillin
(1) 100g Sulfocillin crude product is dissolved in the 1000ml purified water, slowly adds 15% phosphoric acid solution then, stirring reaction is 2.5 to the pH of solution, and generation sulbenicillin Acid precipitation filters and obtains sulbenicillin acid solid 85.3g, yield 94.4%;
(2) the sulbenicillin acid that step (1) is obtained is dissolved in 800ml mixed solvent methylene dichloride/isopropyl ether (volume ratio is 1: 2), adds the gac of overall solution volume 2.4g, and 55 ℃ are stirred 25min, filter decarburization, collect filtrate;
(3) filtrate that step (2) is obtained utilizes the chromatographic column separation and purification to obtain the highly finished product of Sulfocillin, wherein the moving phase used of chromatographic column is that 2: 1 hexanaphthene and pH value are the mixing solutions of 10 sodium hydroxide solution as volume ratio, fixed phase stuffing is selected from silica gel or aluminum oxide, flow velocity 3.8ml/min, 30 ℃ of column temperatures are collected filtrate, drying under reduced pressure, obtain purified Sulfocillin 94.5g, yield 94.5%, purity is 99.6%.
Embodiment 4The preparation of Sulfocillin
(1) 100g Sulfocillin crude product is dissolved in the 1000ml purified water, slowly adds 5% citric acid soln then, stirring reaction is 3 to the pH of solution, and generation sulbenicillin Acid precipitation filters and obtains sulbenicillin acid solid 82.8g, yield 91.5%;
(2) the sulbenicillin acid that step (1) is obtained is dissolved in 1000ml mixed solvent methylene dichloride/isopropyl ether (volume ratio is 1: 2), adds the gac of overall solution volume 3g, and 60 ℃ are stirred 30min, filter decarburization, collect filtrate;
(3) filtrate that step (2) is obtained utilizes the chromatographic column separation and purification to obtain the highly finished product of Sulfocillin, wherein the moving phase used of chromatographic column is that 2: 1 hexanaphthene and pH value are the mixing solutions of 10.5 sodium hydroxide solution as volume ratio, fixed phase stuffing is selected from silica gel or aluminum oxide, flow velocity 4.0ml/min, 25 ℃ of column temperatures are collected filtrate, drying under reduced pressure, obtain purified Sulfocillin 94.3g, yield 94.3%, purity is 99.6%.
Embodiment 5Embodiment 1-4 is made product determine that by nucleus magnetic resonance and infrared spectra the resulting product in refining back is a Sulfocillin.
The structural identification data:
[α]
20：+179°～+181°。
IR(KBr)v：2965(phCH，stretching)，1767(lactamC＝O)，1673(-CONH-)，1608(-COO-)，1527，1404，1316，1214，1047(-SO
3H)，697cm
-1；
1HNMR(D
2O)δ：1.409(6H，t-CH
3×2)，4.130(1H，d，-CH-COONa)，4.983(1H，d，Ar-CH-C＝O)，5.446(2H，m，lactam?C-H)，7.442(5H，m，Ar-H)。
Claims (7)
1. the sulbenicillin sodium compound of structure shown in the formula (I),
Comprise the steps:
(1) the Sulfocillin crude product is soluble in water, slowly add acid then, stirring reaction is 2-3 to the pH of solution, generation sulbenicillin Acid precipitation filters and obtains sulbenicillin acid solid;
(2) the sulbenicillin acid that step (1) is obtained is dissolved in the mixed solvent of methylene dichloride/isopropyl ether, adds the gac of overall solution volume 0.1-0.5 (g/ml) again, and 40-60 ℃ is stirred 20-30min, filters decarburization, collects filtrate;
(3) filtrate that step (2) is obtained is utilized the chromatographic column separation and purification, wherein the moving phase used of chromatographic column is the mixing solutions of the alkaline solution of 2: 1 hexanaphthene and pH value 9-11 as volume ratio, fixed phase stuffing is selected from silica gel or aluminum oxide, flow velocity 3.3-4.2ml/min, column temperature 25-30 ℃, collect filtrate, drying under reduced pressure obtains the purified Sulfocillin.
2. method according to claim 1, wherein the acid described in the step (1) is selected from hydrochloric acid, acetate, Citric Acid, sulfuric acid or phosphoric acid.
3. method according to claim 1, the wherein preferred acetate of the acid described in the step (1).
4. method according to claim 1, wherein the mixed solvent methylene dichloride/isopropyl ether volume ratio described in the step (2) is 1: 1-1: 3.
5. method according to claim 1, wherein the mixed solvent methylene dichloride/isopropyl ether volume ratio described in the step (2) is preferably 1: 2.
6. method according to claim 1, wherein the alkali described in the step (3) is selected from sodium hydroxide, sodium bicarbonate or yellow soda ash.
7. method according to claim 1, the wherein preferred sodium hydroxide of alkali described in the step (3).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2010102748451A CN101974018B (en) | 2010-09-08 | 2010-09-08 | Sulbenicillin sodium compound and novel method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102748451A CN101974018B (en) | 2010-09-08 | 2010-09-08 | Sulbenicillin sodium compound and novel method thereof |
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| Publication Number | Publication Date |
|---|---|
| CN101974018A true CN101974018A (en) | 2011-02-16 |
| CN101974018B CN101974018B (en) | 2012-02-15 |
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|---|---|---|---|
| CN2010102748451A Expired - Fee Related CN101974018B (en) | 2010-09-08 | 2010-09-08 | Sulbenicillin sodium compound and novel method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5084593A (en) * | 1973-11-30 | 1975-07-08 | ||
| JPS5250799A (en) * | 1975-10-21 | 1977-04-23 | Canon Inc | Card processing device |
| JPS55102584A (en) * | 1979-01-30 | 1980-08-05 | Toho Iyaku Kenkyusho:Kk | Preparation of alpha-sulfobenzylpenicilin and its salt |
-
2010
- 2010-09-08 CN CN2010102748451A patent/CN101974018B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5084593A (en) * | 1973-11-30 | 1975-07-08 | ||
| JPS5250799A (en) * | 1975-10-21 | 1977-04-23 | Canon Inc | Card processing device |
| JPS55102584A (en) * | 1979-01-30 | 1980-08-05 | Toho Iyaku Kenkyusho:Kk | Preparation of alpha-sulfobenzylpenicilin and its salt |
Non-Patent Citations (1)
| Title |
|---|
| 《中国药科大学学报》 20071231 向红琳等 磺苄西林钠的合成工艺改进 496-498 1-7 第38卷, 第6期 2 * |
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| CN101974018B (en) | 2012-02-15 |
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