CN1033164C - Method for purification of 7-amino-cephalosporanic acid - Google Patents
Method for purification of 7-amino-cephalosporanic acid Download PDFInfo
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- CN1033164C CN1033164C CN 93115726 CN93115726A CN1033164C CN 1033164 C CN1033164 C CN 1033164C CN 93115726 CN93115726 CN 93115726 CN 93115726 A CN93115726 A CN 93115726A CN 1033164 C CN1033164 C CN 1033164C
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- cephalosporanic acid
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Abstract
The present invention provides a method for purifying 7-amino-cephalosporanic acid used as an intermediate body of cephalosporin drugs. The method comprises the steps that 7-amino-cephalosporanic acid with excessive high polymer content is dissolved into dilute hydrochloric acid and is absorbed by absorbent; then, the pH value is regulated to 3.3 to 3.5 by aqueous ammonia; finally, the collected products are choice products of the 7-amino-cephalosporanic acid. With the method, the purification rate of the 7-amino-cephalosporanic acid is enhanced by more than 10%, the content descent rate of the high molecular polymer is enhanced by more than 70%, and the method has the advantage of easy operation and is suitable for industrial production.
Description
The invention provides a kind of pharmaceutical intermediate---the process for purification of 7-amino-cephalosporanic acid.
7-amino-cephalosporanic acid (being called for short 7-ACA)
Its chemical structural formula is:
It is the important intermediate of a series of cephalosporinses such as preparation cephazolin sodium, cefotaxime sodium, ceftazidime, rocephin.Because its intramolecularly contains very active beta-lactam nucleus and free primary amino, so less stable.When under long period transportation or room temperature condition, placing overlong time, can part decompose, form high molecular polymer.The too much existence of high molecular polymer among the 7-ACA, can cause with it is the generation of high molecular polymer in the synthetic above-mentioned cephalosporins medicine finished product of intermediate, this impurity easily causes medication patient anaphylaxis, even causing its finished product, defective because of superpolymer transfinites (analysis and research of polymer supersensitivity impurity---are selected from cefotaxime " HR-756 " sodium process trial data compilation---and P130-134) therefore will limit the content of high molecular polymer among the 7-ACA in " HR-756 ", should be below 1500mv/g.
For avoiding in the cephalosporins finished product high molecular polymer problem that transfinites, certainly will to make with extra care the 7-ACA that high molecular polymer content transfinites.
The process for purification of Japan's special permission communique (clear 49-9475) report is, the 7-ACA crude product is directly made double salt with hydrocarbyl sulfonic in organic solvent, or basic salt and the hydrocarbyl sulfonic of 7-ACA made double salt, after removing impurity, double salt is dissociated is the 7-ACA elaboration again, and its quality is fine, but refining rate only 57%, and consume a large amount of organic solvents and auxiliary material, very uneconomical, and complex operation.
It is a kind of with aqueous sodium hydroxide solution dissolving 7-ACA crude product that day disclosure special permission (50-151894) is also reported, and uses in the hydrochloric acid then and the method for crystallization.Domestic also have a similar process for purification, the 7-ACA crude product is dissolved in 7%NaHCO that is:
3In the aqueous solution, control pH7.3-7.4 adds carbon decoloring, transfers pH to 3.5 with acetic acid, collects 7-ACA elaboration (cefotaxime " HR-756 " sodium process trial research data compilation 1985.3) then
More than two kinds of process for purification, refining rate low (73.26%), high molecular polymer rate of descent low (only 10-20%) can not be guaranteed the refining quality of 7-ACA, and this method 7-ACA crystallization is finely powdered, is difficult to filter and dry, is awkward.
The object of the present invention is to provide a kind of improved 7-ACA process for purification.This method, 7-ACA makes with extra care rate height (more than 85%), and superpolymer rate of descent height (more than 90%) is easy and simple to handle.
The object of the present invention is achieved like this: the 7-ACA crude product that high molecular polymer is transfinited is in 0～15 ℃ of dilute hydrochloric acid that is dissolved in 1-10%, add sorbent material and stir after-filtration, filtrate is that the ammoniacal liquor of 10-20% is neutralized to pH3.3-3.5 with concentration, collects product, in dry 7-ACA elaboration.
Dilute hydrochloric acid consumption among the present invention is so that 7-ACA crude product complete molten exceeding.Dilute hydrochloric acid consumption of the present invention is advisable with 3-5 times of volume of 7-ACA crude product charging capacity.Its dilute hydrochloric acid concentration is preferably selected 3-6% for use.
The present invention is sorbent used to be gac, or atlapulgite, or SiO 2 powder, or its combination.Its consumption is generally conventional amount used, but for obtaining better adsorption effect, the present invention has increased the consumption of sorbent material, in 7-ACA crude product amount, activated carbon dosage can be 10-20%, and the atlapulgite consumption can be 15-50%, and silicon-dioxide powder consumption can be 10-30%; When it share, according to actual needs, its consumption can correspondingly reduce.
The present invention is owing to taked such scheme, the 7-ACA crude product refining rate that superpolymer content is transfinited improves more than 10%, superpolymer content rate of descent improves more than 70%, with its synthetic cefotaxime sodium high molecular polymer content＜250ppm, ceftazidime high molecular polymer content＜0.4%.Be particulate state with the inventive method gained 7-ACA elaboration in addition, easily filtration, drying have shortened the operating time.
The invention will be further described below by embodiment and comparative example.
Embodiment 1:
With 3.5 gram content is 39%, superpolymer content is that the 7-ACA of 2550mv/g is dissolved in 8% dilute hydrochloric acid of 12ml precooling, interior temperature control is at 10-12 ℃, add gac 0.7 gram after molten entirely, after the insulated and stirred 30 minutes, filter, filtrate is that 15% ammoniacal liquor transfers pH3.3-3.5 to leave standstill 30 minutes after-filtration with concentration, filter cake usefulness 10ml frozen water washed twice, use the drip washing of 5ml refrigerative anhydrous methanol again, drain, get 1.22 gram 7-ACA elaboration after the drying, refining rate is 89.37%, content is 96.6%, superpolymer content is 110mv/g, and superpolymer content rate of descent is 95.68%, filters, counted time of drying 1 hour.
Embodiment 2:
With 4 gram content is 53%, superpolymer content is that the 7-ACA crude product of 2400mv/g is dissolved in 5% dilute hydrochloric acid of 12ml precooling, interior temperature control is at 8-122, moltenly entirely, add a little 5% hydrochloric acid, wait complete molten after, add atlapulgite 2.0 grams, insulated and stirred 30 minutes is filtered, filtrate with concentration be in 10% the ammoniacal liquor with pH to 3.3-3.5, leave standstill filtration in 1 hour, filter crystallization elder generation cold water washing, use cold anhydrous methanol drip washing again, after the drying 7-ACA elaboration 1.85 gram content be 96.8%, refining rate is 87.3%, superpolymer content is 189.3mv/g, and superpolymer content rate of descent is 92.1%, filters, counted time of drying 1 hour.
Embodiment 3:
With 3.5 gram content is 39%, superpolymer content is that the 7-ACA of 2550mv/g is dissolved in 10% dilute hydrochloric acid of 10.5ml precooling, interior temperature control is at 0-5 ℃, add gac 0.35 gram after molten entirely, atlapulgite 0.55 gram, insulated and stirred 20 minutes is filtered, and filter cake transfers pH to 3.3-3.5 to leave standstill filtration in 30 minutes with the ammoniacal liquor of 15% concentration, filter cake is after washing, methanol wash, drying gets 7-ACA elaboration 1.2 grams, and content is 97.2%, refining rate is 87.9%, superpolymer content is 71mv/g, and superpolymer content rate of descent is 97.2, filter, dry, the operating time is the same.
Embodiment 4:
3.5 grams and the crude product 7-ACA of last routine equal in quality are dissolved in the dilute hydrochloric acid that 15ml is chilled to 10-15 ℃ of 1% concentration in advance, after stirring is molten entirely, add gac 0.4 gram, SiO 2 powder 1.0 grams, insulated and stirred was filtered in 15 minutes, filtrate is transferred pH to 3.3-3.5 with the ammoniacal liquor of 20% concentration, left standstill 45 minutes, filter, filter cake after washing, methanol wash, drying, get 7-ACA elaboration 1.17 grams, content is 97.3%, and refining rate is 85.7%, and superpolymer content is 130mv/g, superpolymer content rate of descent is 94.9%, and the operating time is the same.
Embodiment 5:
With 5 gram content is 53%, superpolymer content is that the 7-ACA of 2400mv/g is dissolved in 3% dilute hydrochloric acid of 20ml precooling, interior temperature control is at 5-10 ℃, after treating that 7-ACA is molten entirely, add atlapulgite 1.0 grams, SiO 2 powder 0.5 gram, 40 minutes after-filtration of insulated and stirred, filtrate transfers pH to 3.3-3.5 to leave standstill filtration in 30 minutes with the ammoniacal liquor of 10% concentration, and filter cake is through washing, after the methanol wash, drying, get 7-ACA elaboration 2.25 grams, content is 97.4%, and refining rate is 84.6%, and superpolymer content is 105mv/g, superpolymer content rate of descent is 95.6%, filters, dry, operating time is the same.
The comparative example 1
Get the raw material identical with embodiment 1 3.5 grams, normal temperature is dissolved in the NaHCO of 5% concentration
3, in the aqueous solution, control pH7.3-7.4, add gac 0.7 gram, stir 30 minutes after-filtration, filtrate with in 5% hydrochloric acid with pH to 3.3-3.5, left standstill 30 minutes, and filtered, filter cake is after water, methanol wash, drying gets finely powdered 7-ACA elaboration 1 gram, and content is 96.05%, refining rate is 73.26%, superpolymer content is 2249mv/g, and superpolymer content rate of descent is 11.8%, and drying and filtration time amount to 4 hours.
The comparative example 2
Get the raw material identical 4 grams, be dissolved in the NaHCO of 7% concentration with embodiment 2, in, pH is controlled at 7.3-7.4, adds gac 0.4 gram, 30 minutes after-filtration of stirring at room, filtrate was left standstill 40 minutes with in 5% hydrochloric acid and pH to 3.3-3.5, filtered, filter cake is after water, methanol wash, and drying gets 7-ACA elaboration 1.57 grams, refining rate is 74%, content is 96.3%, and superpolymer content is 1970mv/g, and rate is 17.9% under the superpolymer content.In the operating process, dry and filtration time is 4 hours.
Show that from embodiment and comparative example's result the inventive method truly has refining rate height, superpolymer content rate of descent height, advantages such as operational cycle weak point.
Among the present invention among the 7-ACA high molecular polymer content assaying method as follows:
Select gel chromatographic columns for use, with the dextran G-10 that handles well, with the buffered soln of the pH7.0 dress post that is mixed, the adjustable column bed volume is 50ml, accurately takes by weighing 7-ACA10mg and is dissolved in 0.5m15%NaHCO
3In the solution, add to the gel top in the post then carefully, treat that solution all oozes to gel, the flow velocity wash-out that divides with 0.3ml/ with the damping fluid of pH7.0, measure with the uv detector, collect the effusive 18ml of beginning left and right sides elutriant, high molecular polymer promptly is contained in this part, measure the absorption peak height of high molecular polymer, calculate its content.
High molecular polymer rate of descent among the present invention=
Claims (4)
1, a kind of process for purification of cephalosporins medicine intermediate 7-amino-cephalosporanic acid, it is characterized in that: the 7-amino-cephalosporanic acid that high molecular polymer content is transfinited is dissolved in the 1-10% dilute hydrochloric acid entirely in 0-15 ℃, add sorbent material whip attachment after-filtration, filtrate is neutralized to pH3.3-3.5 with the ammoniacal liquor of 10-20%, and collecting product is the elaboration of 7-amino-cephalosporanic acid.
2, method according to claim 1 is characterized in that: used dilute hydrochloric acid concentration is preferentially selected 3-6% for use.
3, method according to claim 1 and 2 is characterized in that: sorbent used is gac or atlapulgite or SiO 2 powder or its combination.
4, method according to claim 1 is characterized in that: used dilute hydrochloric acid consumption is advisable with 3-5 times of volume of 7-ACA crude product charging capacity.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 93115726 CN1033164C (en) | 1993-08-11 | 1993-08-11 | Method for purification of 7-amino-cephalosporanic acid |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 93115726 CN1033164C (en) | 1993-08-11 | 1993-08-11 | Method for purification of 7-amino-cephalosporanic acid |
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| CN1085904A CN1085904A (en) | 1994-04-27 |
| CN1033164C true CN1033164C (en) | 1996-10-30 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 93115726 Expired - Fee Related CN1033164C (en) | 1993-08-11 | 1993-08-11 | Method for purification of 7-amino-cephalosporanic acid |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1912130B (en) * | 2005-08-08 | 2011-06-15 | 百瑞全球有限公司 | Two-step enzyme method for preparing 7-aminocephalosporanic acid |
| CN101735247B (en) * | 2008-11-07 | 2011-08-10 | 焦作健康元生物制品有限公司 | Process for drying 7-aminocephalosporanic acid |
| CN101768169B (en) * | 2008-12-30 | 2011-09-21 | 焦作健康元生物制品有限公司 | Mother liquid recovery process for 7-aminocephalosporanic acid production |
| CN103030651B (en) * | 2012-12-25 | 2014-03-12 | 深圳华润九新药业有限公司 | Method for preparing ceftazidime hydrochloride |
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1993
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| CN1085904A (en) | 1994-04-27 |
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