CN101696210B - High-purity antibiotic medicinal compound - Google Patents
High-purity antibiotic medicinal compound Download PDFInfo
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- CN101696210B CN101696210B CN2009101696480A CN200910169648A CN101696210B CN 101696210 B CN101696210 B CN 101696210B CN 2009101696480 A CN2009101696480 A CN 2009101696480A CN 200910169648 A CN200910169648 A CN 200910169648A CN 101696210 B CN101696210 B CN 101696210B
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Abstract
The invention provides a high-purity antibiotic medicinal compound, and in particular relates to a method for refining beta-lactam penicillin antibiotic medicinal compounds. In the method, an acid-base pH method and a macroporous absorption resin method are effectively combined; and beta-lactam penicillin antibiotic medicinal compounds are refined and purified under specific process parameters to prepare over 99.9 percent high-purity beta-lactam penicillin antibiotic medicinal compounds with yield over 90 percent, so that unexpected purification effect is achieved. The high-purity beta-lactam penicillin antibiotic medicinal compounds are prepared by the method, so that the stability of corresponding preparations thereof and clinical application effect can be improved. The method is simple, has low cost, is easily for operation, and is applicable to large-scale industrial production.
Description
Technical field
The present invention relates to a kind of process for purification of highly purified antibiotic medicinal compound, specifically, relate to a kind of process for purification of beta-lactam PCs medical compounds.Belong to medical technical field.
Background technology
Microbiotic is meta-bolites or the synthetic analogue of mikrobe, can suppress microbial growth and survival external, and can not produce serious toxic side effect to the host.In clinical application, most microbiotic are to suppress growth of pathogenic bacteria, are used to treat most of bacterial infection diseases.
Antibiotic of a great variety, the structure more complicated, wherein the beta-lactam PCs is the antibiotic medicinal compound of more common, widely used one type of microbiotic, especially formula (I) structure,
Be a kind of beta-lactam PCs, the beta-lactam nucleus that contains four atoms compositions in the molecule is as the bioactive essential group of performance, and with bacteriological action the time, acylation takes place for beta-lactam nucleus open loop and bacterium, suppresses the growth of bacterium.
Antibiotic medicinal compound suc as formula (I) structure comprises azlocillin sodium, Sodium mezlocillin, T-1220, Amoxicillin Sodium, ampicillin, Staphcillin V, Sodium flucloxacillin, cloxacillin sodium, Stampen etc., is just being represented different compounds respectively by the difference of radicals R.
Antibiotics suc as formula (I) structure is the semi-synthetic penicillins compound; Utilize Penicillin G to be raw material, under the meta-alkalescence condition, carry out enzymolysis through Semacylase; Generate 6-amino-penicillanic acid (6-APA); Carry out condensation with corresponding side-chain acid again, get final product various semisynthetic penicillins, then through generating various salt with basic soln reaction.Its method of condensing has three kinds usually: 1. chloride method: be method commonly used, side-chain acid is processed acyl chlorides, at low temperature, carry out under neutral or near neutral (pH6.5-7.0) condition; 2. acid anhydrides method: side-chain acid is processed acid anhydrides or mixed acid anhydride reacts; 3. DCC method: side-chain acid and 6-APA are carried out condensation in organic solvent, with N, N '-two hexamethylene carbon imines (DCC) is as condensing agent.
At present, suc as formula the PCs compound of (I) structure, it mostly makes through above-mentioned compound method, and the low shortcoming of compound ubiquity purity that makes has caused preparation stability to decline to a great extent, and has influenced its clinical application.
Summary of the invention
The process for purification that the purpose of this invention is to provide a kind of antibiotic medicinal compound has improved its purity, has improved the product formulation quality.
In order to realize the foregoing invention purpose, technical scheme of the present invention is following:
The invention provides a kind of process for purification of beta-lactam PCs medical compounds, it is characterized in that comprising the steps:
(1) bullion of beta-lactam PCs medical compounds is water-soluble, it is acid regulating pH value of aqueous solution, collects the solid of being separated out;
(2) with the resulting solid of step (1) with organic solvent dissolution after, last macroporous adsorptive resins carries out wash-out with eluent, collects the elutriant contain beta-lactam PCs medical compounds;
(3) the pH value of regulating step (2) gained elutriant is collected the solid of being separated out to alkalescence or neutral, the beta-lactam PCs medical compounds after promptly obtaining making with extra care.
Wherein, above-mentioned described process for purification, wherein said beta-lactam PCs medical compounds preferably has the antibiotic medicinal compound as shown in the formula structure shown in (I):
Wherein, R is other groups that antibiotic medicinal compound contained.
Further; The above-mentioned described process for purification of the present invention, wherein said beta-lactam PCs medical compounds is selected from azlocillin sodium, Sodium mezlocillin, T-1220, Amoxicillin Sodium, ampicillin, Staphcillin V, Sodium flucloxacillin, cloxacillin sodium or Stampen.
Preferably; Above-mentioned described process for purification, in the wherein said step (1), using the pH value of acid-conditioning solution is 2.0～4.5; Be preferably 3.0～4.0, described acid can be selected from a kind of or two or more in hydrochloric acid, sulfuric acid, nitric acid, Citric Acid, acetic acid, boric acid, the phosphoric acid.
Preferably, above-mentioned described process for purification, in the wherein said step (2), described macroporous adsorbent resin is a styrene tyle macroporous adsorption resin; Preferred said macroporous adsorbent resin is D101 type macroporous adsorbent resin or AB-8 type macroporous adsorbent resin.
Preferably, above-mentioned described process for purification, in the wherein said step (2), described eluent is selected from one or more in trichloromethane, methylene dichloride, ethanol, Virahol, the trimethyl carbinol, ETHYLE ACETATE, acetone, the sherwood oil; Preferred described eluent is the mixture of trichloromethane and Virahol, and the volume ratio of the two is 3: 1.
Preferably, above-mentioned described process for purification, in the wherein said step (2), described organic solvent is selected from one or more in methylene dichloride, ethanol, methyl alcohol, trichloromethane, ETHYLE ACETATE, acetone, the sherwood oil; Preferred described organic solvent is the mixture of ethanol and acetone, and the two volume ratio is 5: 1.
Preferably; Above-mentioned described process for purification; In the wherein said step (3); The pH value that adopts alkali to regulate the gained elutriant is 5.0～9.0, is preferably 5.5～7.0, and described alkali is selected from one or more in sodium hydroxide, sodium hydrogencarbonate, yellow soda ash, sodium-acetate, Sodium phosphate, dibasic, the Sodium Citrate.
As one of most preferred embodiment of the present invention, the above-mentioned described process for purification of the present invention is characterized in that comprising the steps:
(1) will treat that purified beta-lactam PCs medical compounds bullion is water-soluble, the pH value that adds acid-conditioning solution is 3.0～4.0, stirs and separates out insolubles, filters, and after the pure water washing, obtains solid;
(2) with step (1) gained solid with organic solvent dissolution after, last D101 macroporous adsorbent resin or AB-8 macroporous adsorbent resin carry out wash-out with eluent; Collect the elutriant of drug compound; Wherein, described organic solvent is the mixture of ethanol and acetone, and the two volume ratio is 5: 1; Described eluent is the mixture of trichloromethane and Virahol, and the two volume ratio is 3: 1;
(3) the pH value with the collected elutriant of alkali regulating step (2) is 5.5～7.0, collects the solid of being separated out, and uses washed with isopropyl alcohol, 50～60 ℃ of vacuum-drying 3～5 hours, highly finished product.
Wherein, Described beta-lactam PCs medical compounds, preferably azlocillin sodium, Sodium mezlocillin, T-1220, Amoxicillin Sodium, ampicillin, Staphcillin V, Sodium flucloxacillin, cloxacillin sodium or Stampen.Through the refining described beta-lactam PCs medical compounds of aforesaid method.The purity of gained highly finished product is not less than 99.9%.
Compare with existing antibiotic medicinal compound preparation method; The inventive method, through with acid adjustment alkali pH, macroporous adsorbent resin separation and combination, and under the special process parameter; Can make with extra care and obtain highly purified highly finished product; Purity reaches more than 99.9%, and the yield yield is obtained unexpected purification effect above 90%.The inventive method can also obtain a kind of high purity beta-lactam penicillin medicine compound, thereby can improve its stability of corresponding preparations and clinical application effect.The inventive method is simple, with low cost, easy handling, is suitable for large-scale industrial production.
The detection method of beta-lactam PCs medical compounds purity of the present invention is:
Sample thief is an amount of, and accurate the title decides, and also quantitatively is diluted to the solution that contains 2mg among every 1ml with the mobile phase A dissolving, as need testing solution; It is an amount of that other gets reference substance, accurate claim fixed, with the mobile phase A dissolving and quantitatively dilution process contain 20 μ g among every 1ml solution as contrast solution.Measure according to HPLC (Chinese Pharmacopoeia appendix V D), use octadecylsilane chemically bonded silica to be weighting agent; Mobile phase A is 0.05mol/L phosphate buffered saline buffer (get the 0.05mol/L potassium dihydrogen phosphate, regulate pH value to 5.0 with the 2mol/L sodium hydroxide solution)-acetonitrile (99: 1); Mobile phase B is 0.05mol/L phosphate buffered saline buffer (pH value 5.0)-acetonitrile (80: 20); Flow velocity is PM 1.0ml; The detection wavelength is 254nm.Earlier with mobile phase A-Mobile phase B (92: 8) isocratic elution, treat the main peak wash-out finish after immediately according to the form below carry out linear gradient elution.Theoretical plate number is calculated by main peak and is not less than 2000.Get contrast solution 20 μ l and 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 20 μ l of contrast solution again; Inject liquid chromatograph respectively; The record color atlas; If any impurity peaks, single impurity peak area must not be greater than contrast solution main peak area (1.0%) in the color atlas of need testing solution, each impurity peak area with must not be greater than 3 times (3.0%) of contrast solution main peak area.(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.HPLC detects refining preceding bullion purity and is respectively: azlocillin sodium 96.5%, Sodium mezlocillin 95.8%, T-1220 96.0%, Amoxicillin Sodium 96.3%, Sodium flucloxacillin 95.2%, ampicillin 94.4%.
Making with extra care of embodiment 1 azlocillin sodium
(1) the 100g azlocillin sodium is dissolved in 1000ml water, the hydrochloric acid soln adjusting pH value that adds 1mol/L is 3.0, stirs and separates out insolubles, filters, and obtains solid after the purified water washing;
(2) with of the mixture 1500ml dissolving of step (1) gained solid, add the pillar that is filled with the D101 macroporous resin and pass through, use trichloromethane and Virahol (3: 1) mixture 500ml wash-out purifying again, collect elutriant with ethanol and acetone (5: 1);
(3) using 10% 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 5 hours, highly finished product 94.5g; Yield 94.5%, it is 99.96% that HPLC detects purity.
Making with extra care of embodiment 2 Sodium mezlocillins
(1) the 100g Sodium mezlocillin is dissolved in 1000ml water, the phosphoric acid solution adjusting pH value that adds 5mol/L is 4.0, stirs and separates out insolubles, filters, and obtains solid after the purified water washing;
(2) with of the mixture 1300ml dissolving of step (1) gained solid, add the pillar that is filled with the AB-8 macroporous resin and pass through, use trichloromethane and Virahol (3: 1) mixture 600ml wash-out purifying again, collect elutriant with ethanol and acetone (5: 1);
(3) using 10% liquor sodii citratis to regulate the pH value step (2) gained elutriant is 7.0, separates out solid, the centrifugal 20min of whizzer; Use the 500ml washed with isopropyl alcohol, 60 ℃ of vacuum-drying 3 hours, highly finished product 92.8g; Yield 92.8%, it is 99.94% that HPLC detects purity.
Making with extra care of embodiment 3 T-1220s
(1) the 100g T-1220 is dissolved in 800ml water, the salpeter solution adjusting pH value that adds 2mol/L is 3.5, stirs and separates out insolubles, filters, and obtains solid after the purified water washing;
(2) with of the mixture 1200ml dissolving of step (1) gained solid, add the pillar that is filled with the AB-8 macroporous resin and pass through, use trichloromethane and Virahol (3: 1) mixture 500ml wash-out purifying again, collect elutriant with ethanol and acetone (5: 1);
(3) using the 0.1mol/L sodium hydroxide 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, 55 ℃ of vacuum-drying 4 hours, highly finished product 93.7g; Yield 93.7%, it is 99.93% that HPLC detects purity.
Making with extra care of embodiment 4 Amoxicillin Sodiums
(1) the 100g Amoxicillin Sodium is dissolved in 1000ml water, adding 2% citric acid soln adjusting pH value is 2.5, 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, add the pillar that is filled with the D101 macroporous resin and pass through, use trichloromethane and Virahol (3: 1) mixture 800ml wash-out purifying again, collect elutriant with ethanol and acetone (5: 1);
(3) using 5% sodium hydrogen carbonate solution 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, 50 ℃ of vacuum-drying 4 hours, highly finished product 95.2g; Yield 95.2%, it is 99.97% that HPLC detects purity.
Making with extra care of embodiment 5 Sodium flucloxacillins
(1) the 100g Sodium flucloxacillin is dissolved in 1200ml water, the acetum adjusting pH value that adds 1mol/L is 2.0, stirs and separates out insolubles, filters, and obtains solid after the purified water washing;
(2) with of the mixture 800ml dissolving of step (1) gained solid, add the pillar that is filled with the AB-8 macroporous resin and pass through, use trichloromethane and Virahol (3: 1) mixture 400ml wash-out purifying again, collect elutriant with ethanol and acetone (5: 1);
(3) using the 0.2mol/L disodium phosphate soln to regulate the pH value step (2) gained elutriant is 7.5, separates out solid, the centrifugal 10min of whizzer; Use the 500ml washed with isopropyl alcohol, 60 ℃ of vacuum-drying 4 hours, highly finished product 91.8g; Yield 91.8%, it is 99.95% that HPLC detects purity.
Making with extra care of embodiment 6 ampicillins
(1) the 100g ampicillin is dissolved in 1000ml water, the hydrochloric acid soln adjusting pH value that adds 0.1mol/L is 4.5, stirs and separates out insolubles, filters, and obtains solid after the purified water washing;
(2) with of the mixture 1000ml dissolving of step (1) gained solid, add the pillar that is filled with the D101 macroporous resin and pass through, use trichloromethane and Virahol (3: 1) mixture 600ml wash-out purifying again, collect elutriant with ethanol and acetone (5: 1);
(3) using 5% sodium carbonate 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, 50 ℃ of vacuum-drying 3 hours, highly finished product 92.2g; Yield 92.2%, it is 99.92% 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 (8)
1. the process for purification of a beta-lactam PCs medical compounds; Wherein said beta-lactam PCs medical compounds is azlocillin sodium, Sodium mezlocillin, T-1220, Amoxicillin Sodium, ampicillin or Sodium flucloxacillin, it is characterized in that comprising the steps:
(1) bullion of beta-lactam PCs medical compounds is water-soluble, it is acid regulating pH value of aqueous solution, collects the solid of being separated out;
(2) with the resulting solid of step (1) with organic solvent dissolution after, last macroporous adsorptive resins carries out wash-out with eluent, collects the elutriant contain beta-lactam PCs medical compounds; Wherein said organic solvent is the mixture of ethanol and acetone, and the two volume ratio is 5: 1; Described eluent is the mixture of trichloromethane and Virahol, and the volume ratio of the two is 3: 1; Described macroporous adsorbent resin is a styrene tyle macroporous adsorption resin;
(3) the pH value of regulating step (2) gained elutriant is collected the solid of being separated out to alkalescence or neutral, the beta-lactam PCs medical compounds after promptly obtaining making with extra care.
2. process for purification according to claim 1 is characterized in that in the said step (1), and using the pH value of acid-conditioning solution is 2.0～4.5, and described acid is selected from a kind of or two or more in hydrochloric acid, sulfuric acid, nitric acid, Citric Acid, acetic acid, boric acid, the phosphoric acid.
3. process for purification according to claim 2 is characterized in that in the said step (1), and the pH value of using acid-conditioning solution is for being 3.0～4.0.
4. process for purification according to claim 1 is characterized in that said macroporous adsorbent resin is D101 type macroporous adsorbent resin or AB-8 type macroporous adsorbent resin.
5. according to each described process for purification of claim 1-3; It is characterized in that in the said step (3); The pH value that adopts alkali to regulate the gained elutriant is 5.0～9.0, and described alkali is selected from one or more in sodium hydroxide, sodium hydrogencarbonate, yellow soda ash, sodium-acetate, Sodium phosphate, dibasic, the Sodium Citrate.
6. process for purification according to claim 5 is characterized in that in the said step (3), and the pH value that adopts alkali to regulate the gained elutriant is 5.5～7.0.
7. process for purification according to claim 1 is characterized in that comprising the steps:
(1) will treat that purified beta-lactam PCs medical compounds bullion is water-soluble, the pH value that adds acid-conditioning solution is 3.0～4.0, stirs and separates out insolubles, filters, and after the pure water washing, obtains solid;
(2) with step (1) gained solid with organic solvent dissolution after, last D101 macroporous adsorbent resin or AB-8 macroporous adsorbent resin carry out wash-out with eluent; Collect the elutriant of drug compound; Wherein, described organic solvent is the mixture of ethanol and acetone, and the two volume ratio is 5: 1; Described eluent is the mixture of trichloromethane and Virahol, and the two volume ratio is 3: 1;
(3) the pH value with the collected elutriant of alkali regulating step (2) is 5.5～7.0, collects the solid of being separated out, and uses washed with isopropyl alcohol, 50～60 ℃ of vacuum-drying 3～5 hours, highly finished product.
8. process for purification according to claim 7, wherein the purity of gained highly finished product is not less than 99.9%.
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| CN2009101696480A CN101696210B (en) | 2009-08-28 | 2009-08-28 | High-purity antibiotic medicinal compound |
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| CN2009101696480A CN101696210B (en) | 2009-08-28 | 2009-08-28 | High-purity antibiotic medicinal compound |
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102086196B (en) * | 2011-01-28 | 2012-06-13 | 海南灵康制药有限公司 | Novel method for refining aztreonam |
| CN102285998B (en) * | 2011-06-17 | 2013-12-18 | 桂林理工大学 | Preparation method of amorphous and three polymorphic substances of flucloxacillin sodium |
| CN103288852B (en) * | 2011-06-17 | 2015-05-20 | 桂林理工大学 | Preparation method of flucloxacillin sodium crystal form II |
| CN103059045B (en) * | 2013-01-29 | 2014-08-20 | 黄明芳 | Novel amoxicillin sodium and clavulanate potassium compound and pharmaceutical composition thereof |
| CN103265561B (en) * | 2013-06-09 | 2015-09-09 | 四川省惠达药业有限公司 | Azlocillin sodium compound, its preparation method and pharmaceutical composition thereof |
| CN104910181A (en) * | 2015-05-28 | 2015-09-16 | 浙江长典医药有限公司 | Children azlocillin sodium compound entity and drug preparation thereof |
| CN108084206B (en) * | 2018-02-09 | 2019-04-26 | 国药集团威奇达药业有限公司 | The method of ampicillin is recycled from the mother liquor of enzymatic clarification ampicillin |
| CN109456338A (en) * | 2018-12-18 | 2019-03-12 | 四川仁安药业有限责任公司 | A kind of preparation method of low polymer Cefixime |
| CN110028486B (en) * | 2019-04-28 | 2021-10-29 | 山东睿智医药科技有限公司 | Method for extracting duloxetine intermediate |
| CN110841608A (en) * | 2019-11-28 | 2020-02-28 | 朱润栋 | Preparation method of penicillin fermentation liquor refined adsorbent |
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