CN101696211B - High-purity sulbactam sodium compound - Google Patents
High-purity sulbactam sodium compound Download PDFInfo
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- CN101696211B CN101696211B CN2009101696457A CN200910169645A CN101696211B CN 101696211 B CN101696211 B CN 101696211B CN 2009101696457 A CN2009101696457 A CN 2009101696457A CN 200910169645 A CN200910169645 A CN 200910169645A CN 101696211 B CN101696211 B CN 101696211B
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Abstract
The invention relates to a high-purity sulbactam sodium compound, and particularly provides a method for refining the sulbactam sodium compound. The method comprises the following steps: a, dissolving a sulbactam sodium coarse product into water, regulating the pH value of aqueous solution to less than 7 and collecting solid precipitated from the solution; b, dissolving the solid obtained in the step a into organic solvent to obtain solution to be refined; c, putting the solution to be refined into macroporous absorption resin, performing elution and purification by using eluting agent, and collecting eluent; and d, regulating the pH value of the eluent obtained in the step c to 7 and collecting the precipitated solid to obtain refined sulbactam sodium. The refined sulbactam sodium compound prepared by the method has the purity of over 99.8 percent and the yield of over 90 percent.
Description
Invention field
The present invention relates to a kind of process for purification of highly purified sulbactam sodium compound, belong to medical technical field.
Background technology
Sulbactam (Sulbactam Sodium), chemical name is: (2S, 5R)-3,3-dimethyl--7 oxos-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid sodium-4,4 dioxide, molecular formula: C
8H
10NNaO
5S, molecular weight: 255.23, structural formula is:
Be a kind of white or off-white color crystalline powder; Little have the spy smelly, mildly bitter flavor; In water, be prone to dissolve, slightly soluble in methyl alcohol, almost insoluble in ethanol, acetone or ETHYLE ACETATE.
Sulbactam is semi-synthetic beta lactamase restrainer; NEISSERIA GONORRHOEAE, Neisseria meningitidis and acinetobacter calcoaceticus there is strong anti-microbial activity; Effect to other bacteriums is all very poor, but the lactamase that streptococcus aureus and most Gram-negative bacteria are produced is had very strong irreversible competitive inhibition.When share, the minimum inhibitory concentrations (the English MIC of abbreviation) of the streptococcus aureus of preceding two types of antibiotics resistances, hemophilus influenzae, escherichia coli, bacteroide fragilis etc. is dropped within the sensitive range because of producing enzyme with PCs and cephalosporins.Sulbactam has stronger avidity to the PBP1 of bacterium mirabilis and the PBP2 of acinetobacter calcoaceticus.The associating of sulbactam and PCs or cephalosporins is used to treat urinary tract infections, pulmonary infection, bronchial infection, Otorhinolaryngologic Department infection, abdominal cavity and pelvic infection due to the sensitive organism, biliary tract infection, septicemia, skin soft-tissue infection etc.
It is raw material that the compound method of sulbactam mostly adopts 6-amino-penicillanic acid, through diazotization, bromination, oxidation, reduction, salify, is prepared into sulbactam.Synthetic route is:
This method has realized industrialized production; But in actual mechanical process; Exist that oxidation is incomplete, the difficult control of process; Yield is low, and problem such as finished product purity is not high, so the purity problem of sulbactam bulk drug is one of outstanding problem that influences this drug safety and clinical application in the prior art.
Summary of the invention
The process for purification that the purpose of this invention is to provide a kind of sulbactam sodium compound can significantly improve the purity of sulbactam through this method, has improved the quality of sulbactam product formulation.And the yield of the high purity sulbactam that obtains is high.
One aspect of the present invention provides a kind of process for purification of sulbactam sodium compound, and this method may further comprise the steps:
A. at first that the sulbactam bullion is water-soluble, its pH value of aqueous solution is adjusted to acidity, collect the solid of separating out in the solution;
B. after the solid that step a is obtained is used the organic solvent dissolution that mixes with it, make and treat refined soln;
C. will treat that refined soln places in the macroporous adsorbent resin, eluent wash-out purifying is collected elutriant;
D. the elutriant pH value that obtains of regulating step c is collected the solid of separating out for neutral, obtains the sulbactam highly finished product.
Preferably; In described step a; Employing is selected from hydrochloric acid, sulfuric acid, nitric acid, Citric Acid, acetic acid, boric acid and the phosphoric acid one or several sulbactam pH value of aqueous solution is adjusted to 1.0-4.0, stirs, and filters; Collect the solid of separating out in this solution, and wash the solid of separating out with pure water.
More preferably, the sulbactam pH value of aqueous solution is adjusted to 2.0-3.0.
Preferably, in described step b, the organic solvent that the solid that obtains with step a mixes is selected from one or more in methylene dichloride, ethanol, methyl alcohol, trichloromethane, ETHYLE ACETATE, acetone, the sherwood oil.
More preferably, the organic solvent that the solid that obtains with step a mixes is the mixture of ETHYLE ACETATE and sherwood oil, and the two volume ratio is 3: 2.
Preferably, in described step c, described macroporous adsorbent resin is a styrene tyle macroporous adsorption resin, preferred D101 type macroporous adsorbent resin or AB-8 type macroporous adsorbent resin.
Preferably, in described step c, described eluent is selected from one or more in trichloromethane, methylene dichloride, ethanol, Virahol, the trimethyl carbinol, ETHYLE ACETATE, acetone and the sherwood oil.
Preferably, in described step c, described eluent is the mixture of ethanol and ETHYLE ACETATE, and the volume ratio of the two is 1: 5.
Preferably, in described steps d, the pH value of the elutriant that one or more regulating steps c in employing sodium hydroxide, sodium hydrogencarbonate, yellow soda ash, sodium-acetate, Sodium isooctanoate, Sodium phosphate, dibasic and the Sodium Citrate obtains is 5.0-8.0, is preferably 5.5-6.5.
Preferably, wherein in described steps d: with the solid of separating out, whizzer is centrifugal, collect the solid after centrifugal and use washed with isopropyl alcohol, 50-60 ℃ vacuum-drying 4-6 hour, obtain the sulbactam highly finished product.
Beneficial effect of the present invention is: the sulbactam sodium compound highly finished product that the invention described above method obtains, purity reaches more than 99.0%, particularly can reach more than 99.8%.Compare with existing sulbactam sodium compound preparation method, the inventive method can make highly purified highly finished product, and purity reaches more than 99.8%, and yield surpasses 90%.The inventive method can also obtain a kind of highly purified sulbactam, thereby can improve its stability of corresponding preparations and clinical application effect.The inventive method is simple, easy handling, is suitable for large-scale industrial production.
The detection method of the purity of sulbactam sodium compound of the present invention is:
Chromatographic condition: use octadecylsilane chemically bonded silica to be weighting agent; (get 40% tetrabutylammonium solution 6.6ml with 0.005mol/L tetrabutylammonium solution; Thin up is to 1800ml; Regulate pH value to 5.0 ± 0.1 with the 1mol/L phosphoric acid solution, thin up shakes up to 2000ml again)-acetonitrile (75: 25) is a moving phase; Flow velocity is PM 1ml, and the detection wavelength is 230nm.
These article of getting are an amount of, with the moving phase dissolving and process the solution that contains 5mg among every 1ml approximately, as need testing solution; Precision is measured 1ml, puts in the 100ml measuring bottle, is diluted to scale with moving phase, shakes up, as contrast solution.Get contrast solution 10 μ l; Inject liquid chromatograph, regulate detection sensitivity, the peak height that makes the principal constituent chromatographic peak is the 20%-25% of full range; Precision is measured need testing solution and each 10 μ l of contrast solution; Inject liquid chromatograph respectively, 3 times of record color atlas to principal constituent peak RT, in the need testing solution color atlas if any impurity peaks; Peak area (correction factor 0.3) after the sulbactam Trolovol is proofreaied and correct must not be greater than contrast solution main peak area (1.0%), other each impurity peak area with must not be greater than contrast solution main peak area (1.0%) (in the need testing solution can ignore in any peak less than 0.05 times of contrast solution main peak area).
Embodiment
Below further explain or explanation content of the present invention, but embodiment should not be understood that the restriction to protection domain of the present invention through embodiment.
Used D101 macroporous resin of following examples and AB-8 macroporous resin are available from Liaoyuan, Bengbu novel material ltd.The purity that HPLC detects the sulbactam bullion is 96.1%.
Embodiment 1
Making with extra care of sulbactam
(1) 100g sulbactam bullion is dissolved in 2000ml water, the hydrochloric acid soln adjusting pH value that adds 0.1mol/L is 2.0, stirs and separates out insolubles, filters, and obtains solid after the purified water washing;
(2) with of the mixture 2000ml dissolving of step (1) gained solid with ETHYLE ACETATE and sherwood oil (volume ratio 3: 2); Adding the pillar that is filled with the D101 macroporous resin passes through; Use ethanol and ETHYLE ACETATE (volume ratio 1: 5) mixture 800ml as eluent wash-out purifying again, collect elutriant;
(3) using 5% sodium acetate soln to regulate the pH value step (2) gained elutriant is 5.5, separates out solid, the centrifugal 10min of whizzer; Use the 500ml washed with isopropyl alcohol, 50 ℃ of vacuum-drying 6 hours, highly finished product 91.4g; Yield 91.4%, it is 99.91% that HPLC detects purity.
Embodiment 2
Making with extra care of sulbactam
(1) 100g sulbactam bullion is dissolved in 2000ml water, the phosphoric acid solution adjusting pH value that adds 0.5mol/L is 3.0, stirs and separates out insolubles, filters, and obtains solid after the purified water washing;
(2) with of the mixture 1800ml dissolving of step (1) gained solid with ETHYLE ACETATE and sherwood oil (volume ratio 3: 2); Adding the pillar that is filled with the AB-8 macroporous adsorbent resin passes through; Use ethanol and ETHYLE ACETATE (volume ratio 1: 5) mixture 500ml as eluent wash-out purifying again, collect elutriant;
(3) using 10% Sodium isooctanoate solution to regulate the pH value step (2) gained elutriant is 6.5, separates out solid, the centrifugal 20min of whizzer; Use the 500ml washed with isopropyl alcohol, 60 ℃ of vacuum-drying 4 hours, highly finished product 93.5g; Yield 93.5%, it is 99.88% that HPLC detects purity.
Making with extra care of embodiment 3 sulbactams
(1) 100g sulbactam bullion is dissolved in 2000ml water, the citric acid soln adjusting pH value that adds 1mol/L is 4.0, stirs and separates out insolubles, filters, and obtains solid after the purified water washing;
(2) with of the mixture 2000ml dissolving of step (1) gained solid with ETHYLE ACETATE and sherwood oil (volume ratio 3: 2); Adding the pillar that is filled with the AB-8 macroporous adsorbent resin passes through; Use ethanol and ETHYLE ACETATE (1: 5) mixture 600ml as eluent wash-out purifying again, collect elutriant;
(3) using the 0.1mol/L sodium hydroxide solution to regulate the pH value step (2) gained elutriant is 8.0, separates out solid, the centrifugal 10min of whizzer; Use the 500ml washed with isopropyl alcohol, 55 ℃ of vacuum-drying 5 hours, highly finished product 94.0g; Yield 94.0%, it is 99.93% that HPLC detects purity.
Making with extra care of embodiment 4 sulbactams
(1) 100g sulbactam bullion is dissolved in 2000ml water, the salpeter solution adjusting pH value that adds 0.05mol/L is 1.0, stirs and separates out insolubles, filters, and obtains solid after the purified water washing;
(2) with of the mixture 2000ml dissolving of step (1) gained solid with ETHYLE ACETATE and sherwood oil (volume ratio 3: 2); Adding the pillar that is filled with the D101 macroporous adsorbent resin passes through; Use ethanol and ETHYLE ACETATE (volume ratio 1: 5) mixture 700ml as eluent wash-out purifying again, collect elutriant;
(3) using the 0.1mol/L liquor sodii citratis to regulate the pH value step (2) gained elutriant is 5.0, separates out solid, the centrifugal 20min of whizzer; Use the 500ml washed with isopropyl alcohol, 60 ℃ of vacuum-drying 5 hours, highly finished product 93.8g; Yield 93.8%, it is 99.96% that HPLC detects purity.
Making with extra care of embodiment 5 sulbactams
(1) 100g sulbactam bullion is dissolved in 2000ml water, it is 2.5 that the acetum of adding 1% is regulated the pH value, stirs and separates out insolubles, filters, and obtains solid after the purified water washing;
(2) with of the mixture 1600ml dissolving of step (1) gained solid with ETHYLE ACETATE and sherwood oil (volume ratio 3: 2); Adding the pillar that is filled with the D101 macroporous adsorbent resin passes through; Use ethanol and ETHYLE ACETATE (volume ratio 1: 5) mixture 500ml as eluent wash-out purifying again, collect elutriant;
(3) using 2% sodium hydrogen carbonate solution to regulate the pH value step (2) gained elutriant is 6.0, separates out solid, the centrifugal 10min of whizzer; Use the 500ml washed with isopropyl alcohol, 60 ℃ of vacuum-drying 4 hours, highly finished product 92.2g; Yield 92.2%, it is 99.94% that HPLC detects purity.
Should be appreciated that these embodiment only are the explanations to preferred version of the present invention, and also limit protection scope of the present invention never in any form.Those skilled in the art under the prerequisite that does not deviate from the present invention's spirit and purport, can carry out suitable modification and improvement to the present invention under the instruction of the disclosed content of the present invention, these all will fall within the scope of the present invention.
Claims (12)
1. the process for purification of a sulbactam sodium compound, this method may further comprise the steps:
A. the sulbactam bullion is water-soluble, its pH value of aqueous solution is adjusted to 1.0-4.0, collect the solid of separating out in the solution;
B. after the solid that step a is obtained is used the organic solvent dissolution that mixes with it, make and treat purified solution;
C. will treat that purified solution places in D101 type macroporous adsorbent resin or the AB-8 type macroporous adsorbent resin, eluent wash-out purifying is collected elutriant;
D. the elutriant pH value that obtains of regulating step c is 5.0-8.0, collects the solid of separating out, and obtains the sulbactam after refining.
2. method according to claim 1; Wherein in described step a; Employing is selected from hydrochloric acid, sulfuric acid, nitric acid, Citric Acid, acetic acid, boric acid and the phosphoric acid one or several sulbactam pH value of aqueous solution is adjusted to 1.0-4.0, stirs, and filters; Collect the solid of separating out in this solution, and wash the solid of separating out with pure water.
3. method according to claim 2 wherein in described step a, is adjusted to 2.0-3.0 with the sulbactam pH value of aqueous solution.
4. according to each described method among the claim 1-3, wherein in described step b, described organic solvent is selected from one or more in methylene dichloride, ethanol, methyl alcohol, trichloromethane, ETHYLE ACETATE, acetone, the sherwood oil.
5. method according to claim 4, wherein in described step b, described organic solvent is the mixture of ETHYLE ACETATE and sherwood oil, the two volume ratio is 3: 2.
6. according to each described method among the claim 1-3, wherein in described step c, described eluent is selected from one or more in trichloromethane, methylene dichloride, ethanol, Virahol, the trimethyl carbinol, ETHYLE ACETATE, acetone and the sherwood oil.
7. method according to claim 6, wherein in described step c, described eluent is the mixture of ethanol and ETHYLE ACETATE, and the volume ratio of the two is 1: 5.
8. according to each described method among the claim 1-3, wherein in described steps d, the pH value of the elutriant that regulating step c obtains is 5.5-6.5.
9. according to each described method among the claim 1-3, wherein in described steps d, one or more in employing sodium hydroxide, sodium hydrogencarbonate, yellow soda ash, sodium-acetate, Sodium isooctanoate, Sodium phosphate, dibasic and the Sodium Citrate are as the pH regulator agent.
10. according to each described method among the claim 1-3, wherein in described steps d, collect the solid of separating out, use washed with isopropyl alcohol, 50-60 ℃ vacuum-drying 4-6 hour, the sulbactam after obtaining making with extra care.
11. method according to claim 1 is characterized in that:
A. the sulbactam bullion is water-soluble, its pH value of aqueous solution is adjusted to 1.0-4.0, stir, filter, after the pure water washing, obtain solid;
B. the solid that step a is obtained use volume ratio be 3: 2 the mixture of ETHYLE ACETATE and sherwood oil as dissolution with solvents after, make and treat purified solution;
C. will treat that purified solution is added on the pillar of the macroporous adsorbent resin that is filled with D101 type or AB-8 type, using volume ratio is that 1: 5 the ethanol and the mixture of ETHYLE ACETATE carry out the wash-out purifying as eluent, collects elutriant;
D. the elutriant pH value that obtains of regulating step c is 5.0-8.0, separates out solid, and solid is collected in spinning, after washed with isopropyl alcohol, 50-60 ℃ vacuum-drying 4-6 hour, promptly obtain the sulbactam after refining.
12. method according to claim 11, wherein, the purity of the sulbactam after refining that obtains is not less than 99.8%.
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| CN102993064A (en) * | 2012-12-17 | 2013-03-27 | 江西富祥药业股份有限公司 | Preparation and crystallization method of (2S)-2-animo-3-methyl-3-sulfinobutanoic acid |
| CN103193795B (en) * | 2013-04-03 | 2013-12-11 | 四川省惠达药业有限公司 | Pharmaceutical composition of amoxicillin sodium and sulbactam sodium |
| CN104876946A (en) * | 2015-04-30 | 2015-09-02 | 王雪雁 | Sulbactam compound for treating infectious diseases, and preparation method therefor |
| CN109160919A (en) * | 2017-07-28 | 2019-01-08 | 海南美兰史克制药有限公司 | 1/10 water sulbactam sodium compound of one kind and its drug combination preparation |
| CN108997376B (en) * | 2018-08-01 | 2020-04-07 | 华北制药河北华民药业有限责任公司 | Preparation method of sulbactam acid |
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| CN101322702A (en) * | 2008-08-01 | 2008-12-17 | 海南百那医药发展有限公司 | Piperacillin sodium and sulbactam sodium for injection and preparation of freeze-dried injection thereof |
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| CN101322702A (en) * | 2008-08-01 | 2008-12-17 | 海南百那医药发展有限公司 | Piperacillin sodium and sulbactam sodium for injection and preparation of freeze-dried injection thereof |
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