CN103304583B - A kind of method reclaiming clavulanic acid from clavulanic acid amine salt crystalline mother solution - Google Patents
A kind of method reclaiming clavulanic acid from clavulanic acid amine salt crystalline mother solution Download PDFInfo
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- CN103304583B CN103304583B CN201310285064.6A CN201310285064A CN103304583B CN 103304583 B CN103304583 B CN 103304583B CN 201310285064 A CN201310285064 A CN 201310285064A CN 103304583 B CN103304583 B CN 103304583B
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Abstract
The present invention relates to a kind of method reclaiming clavulanic acid from clavulanic acid amine salt crystalline mother solution, the method comprises the steps: first to be removed by the acetone in amine salt crystalline mother solution with underpressure distillation, obtain the aqueous solution of clavulanic acid amine salt, then obtained the intermediate amine salt of clavulanic acid by processes such as extraction, reextraction, crystallizations.The present invention creatively develops the method reclaiming clavulanic acid from clavulanic acid amine salt crystalline mother solution, and the method can improve production yield, reduces wastewater discharge, significantly reduces production cost.
Description
Technical field
The invention belongs to biomedicine field, relate to the method reclaiming clavulanic acid from clavulanic acid amine salt crystalline mother solution.
Background technology
The chemical name of clavulanic acid is (2R, 5R, Z)-3-(2-hydroxy ethylene)-7-oxo-4-oxa--1-azabicyclic [3.2.0] heptane-2-carboxylic acid, structure is as follows:
An alkali metal salt of clavulanic acid is current most widely used beta-lactamase inhibitor; can with the serine proteinase activities site irreversible fixation of β-lactamase; thus the activity of protection β-lactam antibitics, fungistatic effect can be made to increase several times even tens times.Along with the continuous enhancing of bacterial drug resistance clinically, its application is also more and more extensive.
Known alkali metal salt manufacture method is divided into three steps: the first step mycelium, most of protein, other solid particulate in the method removing fermented liquids such as centrifugal, filtration, obtain the aqueous solution of clavulanic acid; Second step primary amine, secondary amine or reactive tertiary amine obtain the intermediate amine salt of clavulanic acid; 3rd step changes required an alkali metal salt into by intermediate amine salt.
Wherein the intermediate amine salt pair end product quality of clavulanic acid has vital impact.Industrial production generally adopts the technique of carrying out the crystallization of clavulanic acid amine salt in acetone, and acetone crystalline mother solution is containing the clavulanic acid of the 0.5mg/mL ~ 1.0mg/mL that has an appointment, and remaining quantity is larger.Clavulanic acid in production in acetone mother liquor is all wasted by adding heat collapse when solvent recuperation, and the degraded product of clavulanic acid enters Sewage treatment systems, too increases the environmental protection pressure of sewage works.At present, the research report about reclaiming clavulanic acid from clavulanic acid amine salt crystalline mother solution is had no.
Summary of the invention
The present inventor, by intensive research, successfully develops the method reclaiming clavulanic acid from clavulanic acid amine salt crystalline mother solution.Basic technical scheme is: utilize solvent boiling point different, with underpressure distillation by the acetone removing in amine salt crystalline mother solution, obtain the aqueous solution of clavulanic acid amine salt, remove after impurity through resin, obtained the intermediate amine salt of clavulanic acid by processes such as extraction, reextraction, crystallizations.
In order to realize object of the present invention, contriver is studied by lot of experiments, finally obtains following technical scheme:
From clavulanic acid amine salt crystalline mother solution, reclaim a method for clavulanic acid, comprise the steps:
(1) clavulanic acid amine salt crystalline mother solution is got, at 10 ~ 40 DEG C of temperature, carry out underpressure distillation concentrate, then with 1 ~ 5BV/h(column volume/hour) flow velocity remove impurity by the resin column that ion exchange resin is housed, distill the acetone that obtains through processed, can be used as recrystallisation solvent.
(2) with 25% sulfuric acid adjustment concentrated solution pH to 1.5 ~ 3.0, add alkyl acetates or ketones solvent, extraction clavulanic acid is in solvent phase, and the temperature of extraction is 0 ~ 10 DEG C.
(3) organic amine of the solvent phase after extraction regulates pH to 6.0 ~ 7.5, and stratification collects aqueous phase.
(4) acetone adding 20 ~ 50 times in aqueous phase carries out stirred crystallization, and temperature controls 0 ~ 10 DEG C, growing the grain 2 hours.With filtration devices, filtrate is acetone crystalline mother solution; Crystal washing with acetone, vacuum-drying obtains the dry product of clavulanic acid amine salt for 2 hours.
Resin in step (1) is selected from following one: storng-acid cation exchange resin, weakly acidic cation-exchange resin.
Solvent in step (2) is selected from following one: methyl acetate, ethyl acetate, propyl acetate, butylacetate, methyl ethyl ketone, methyl iso-butyl ketone (MIBK); In these solvents, ethyl acetate and methyl iso-butyl ketone (MIBK) are preferred solvent.
Organic amine in step (3) is selected from following one: n-Butyl Amine 99, TERTIARY BUTYL AMINE, n-octyl amine, tert-Octylamine; In these organic amines, TERTIARY BUTYL AMINE and tert-Octylamine are most preferably.
The described method reclaiming clavulanic acid from clavulanic acid amine salt crystalline mother solution, wherein step (1) concentrating under reduced pressure temperature is 10 ~ 40 DEG C, preferably 20 ~ 30 DEG C; In concentrating under reduced pressure rear solution, the concentration of clavulanic acid is preferably 10 ~ 30mg/mL, further preferred 15 ~ 25mg/mL.
The described method reclaiming clavulanic acid from clavulanic acid amine salt crystalline mother solution, wherein step (1) concentrated after the aqueous solution by the flow velocity preferably 1 ~ 2BV/h of resin column.
The described method reclaiming clavulanic acid from clavulanic acid amine salt crystalline mother solution, wherein step (2) 25% sulfuric acid adjustment concentrated solution pH to 1.5 ~ 3.0, preferably 2.0 ~ 2.5; The temperature of extraction controls at 0 ~ 10 DEG C, preferably 0 ~ 5 DEG C.
The described method reclaiming clavulanic acid from clavulanic acid amine salt crystalline mother solution, wherein step (3) solvent phase pH regulator to 6.0 ~ 7.5, preferably 6.5 ~ 7.0.
The described method reclaiming clavulanic acid from clavulanic acid amine salt crystalline mother solution, the acetone wherein adding 20 ~ 50 times in step (4) aqueous phase carries out stirred crystallization, preferably 30 ~ 45 times; Temperature controls 0 ~ 10 DEG C, preferably 0 ~ 5 DEG C.
Compared with prior art, tool of the present invention has the following advantages:
(1) method reclaiming clavulanic acid from clavulanic acid amine salt crystalline mother solution is creatively developed.At present, there is the problems such as fermentation titer is relatively low, downstream purification route is long, production cost is high in clavulanic acid industrial production, the present invention can reclaim clavulanic acid from clavulanic acid amine salt crystalline mother solution, improves and produces yield, decrease wastewater discharge simultaneously, significantly reduce production cost.
(2) the clavulanic acid amine salt of gained and common process is reclaimed (as shown in Fig. 1 left-half, fermented liquid obtains receiving dope through filtering, concentrating, again through extraction, strip, crystallization obtains clavulanic acid amine salt) amine salt produced quite, can be used for the preparation of downstream alkali metal salt in the mass parameters such as content, impurity, transmittance as intermediate.
Accompanying drawing explanation
Fig. 1, process flow sheet
Embodiment
Embodiment 1
Get the clavulanic acid amine salt crystalline mother solution 5.0 liters (mother liquor contains 0.51mg/mL clavulanic acid) in industrial production, 10 DEG C of underpressure distillation are to 226mL, and detecting it containing clavulanic acid is 10.7mg/mL.Concentrated solution removes impurity with the flow velocity of 2BV/h by the resin column of the AmberliteFPC22H storng-acid cation exchange resin that the production of 0.2L ROHM AND HAAS is housed, pH to 3.0 is regulated afterwards with the sulphuric acid soln of 25%, add isopyknic methyl acetate control temperature 0 DEG C extraction three times, combining extraction liquid.Under rapid mixing conditions, regulate extraction liquid pH to 6.0 with n-Butyl Amine 99, leave standstill 10 minutes, separate aqueous phase.Under low rate mixing condition, slowly add 20 times of acetone and carry out crystallization, temperature controls at 0 DEG C, low rate mixing growing the grain 2 hours.Crystal solution is filtered, and with washing with acetone crystal three times, 30 DEG C of vacuum-drying 2 hours, obtains 2.86g clavulanic acid n-Butyl Amine 99 salt, yield 75.29%.
Embodiment 2
Get the clavulanic acid amine salt crystalline mother solution 5.0 liters (mother liquor contains 0.51mg/mL clavulanic acid) in industrial production, 40 DEG C of underpressure distillation are to 160mL, and detecting it containing clavulanic acid is 15.2mg/mL.Concentrated solution removes impurity with the flow velocity of 1BV/h by the resin column of 732 storng-acid cation exchange resins that the Samsung production of 0.2L Anhui is housed, pH to 2.5 is regulated afterwards with the sulphuric acid soln of 25%, add isopyknic ethyl acetate control temperature 2 DEG C extraction three times, combining extraction liquid.Under rapid mixing conditions, regulate extraction liquid pH to 6.5 by TERTIARY BUTYL AMINE, leave standstill 10 minutes, separate aqueous phase.Under low rate mixing condition, slowly add 30 times of acetone and carry out crystallization, temperature controls at 2 DEG C, low rate mixing growing the grain 2 hours.Crystal solution is filtered, and with washing with acetone crystal three times, 30 DEG C of vacuum-drying 2 hours, obtains 3.10g clavulanic acid tert-butylamine salt, yield 81.18%.
Embodiment 3
Get the clavulanic acid amine salt crystalline mother solution 4.0 liters (mother liquor contains 0.64mg/mL clavulanic acid) in industrial production, 35 DEG C of underpressure distillation are to 120mL, and detecting it containing clavulanic acid is 20.1mg/mL.Concentrated solution removes impurity with the flow velocity of 1BV/h by the resin column of 724 weakly acidic cation-exchange resins that the Samsung production of 0.2L Anhui is housed, pH to 2.0 is regulated afterwards with the sulphuric acid soln of 25%, add isopyknic propyl acetate control temperature 5 DEG C extraction three times, combining extraction liquid.Under rapid mixing conditions, regulate extraction liquid pH to 7.0 by n-octyl amine, leave standstill 10 minutes, separate aqueous phase.Under low rate mixing condition, slowly add 40 times of acetone and carry out crystallization, temperature controls at 10 DEG C, low rate mixing growing the grain 2 hours.Crystal solution is filtered, and with washing with acetone crystal three times, 30 DEG C of vacuum-drying 2 hours, obtains 3.58g clavulanic acid n-octyl amine salt, yield 78.13%.
Embodiment 4
Get the clavulanic acid amine salt crystalline mother solution 3.0 liters (mother liquor contains 0.82mg/mL clavulanic acid) in industrial production, 30 DEG C of underpressure distillation are to 71mL, and detecting it containing clavulanic acid is 34.0mg/mL.Concentrated solution removes impurity with the flow velocity of 2BV/h by the resin column of the AmberliteFPC3500 weakly acidic cation-exchange resin that the production of 0.2L ROHM AND HAAS is housed, pH to 1.5 is regulated afterwards with the sulphuric acid soln of 25%, add isopyknic butylacetate control temperature 10 DEG C extraction three times, combining extraction liquid.Under rapid mixing conditions, regulate extraction liquid pH to 7.5 with tert-Octylamine, leave standstill 10 minutes, separate aqueous phase.Under low rate mixing condition, slowly add 35 times of acetone and carry out crystallization, temperature controls at 6 DEG C, low rate mixing growing the grain 2 hours.Crystal solution is filtered, and with washing with acetone crystal three times, 30 DEG C of vacuum-drying 2 hours, obtains 3.85g clavulanic acid tert-Octylamine salt, yield 86.18%.
Embodiment 5
Get the clavulanic acid amine salt crystalline mother solution 3.0 liters (mother liquor contains 0.90mg/mL clavulanic acid) in industrial production, 25 DEG C of underpressure distillation are to 83mL, and detecting it containing clavulanic acid is 29.8mg/mL.Concentrated solution removes impurity with the flow velocity of 1BV/h by the resin column of the AmberliteIRC50 weakly acidic cation-exchange resin that the production of 0.2L ROHM AND HAAS is housed, pH to 1.8 is regulated afterwards with the sulphuric acid soln of 25%, add isopyknic methyl ethyl ketone control temperature 8 DEG C extraction three times, combining extraction liquid.Under rapid mixing conditions, regulate extraction liquid pH to 6.2 with n-Butyl Amine 99, leave standstill 10 minutes, separate aqueous phase.Under low rate mixing condition, slowly add 25 times of acetone and carry out crystallization, temperature controls at 8 DEG C, low rate mixing growing the grain 2 hours.Crystal solution is filtered, and with washing with acetone crystal three times, 30 DEG C of vacuum-drying 2 hours, obtains 3.32g clavulanic acid n-Butyl Amine 99 salt, yield 82.22%.
Embodiment 6
Get the clavulanic acid amine salt crystalline mother solution 2.5 liters (mother liquor contains 0.99mg/mL clavulanic acid) in industrial production, 20 DEG C of underpressure distillation are to 96mL, and detecting it containing clavulanic acid is 25.0mg/mL.Concentrated solution removes impurity with the flow velocity of 1BV/h by the resin column of the AmberliteFPC23H storng-acid cation exchange resin that the production of 0.2L ROHM AND HAAS is housed, pH to 2.2 is regulated afterwards with the sulphuric acid soln of 25%, add isopyknic methyl iso-butyl ketone (MIBK) control temperature 5 DEG C extraction three times, combining extraction liquid.Under rapid mixing conditions, regulate extraction liquid pH to 7.0 by TERTIARY BUTYL AMINE, leave standstill 10 minutes, separate aqueous phase.Under low rate mixing condition, slowly add 45 times of acetone and carry out crystallization, temperature controls at 5 DEG C, low rate mixing growing the grain 2 hours.Crystal solution is filtered, and with washing with acetone crystal three times, 30 DEG C of vacuum-drying 2 hours, obtains 3.38g clavulanic acid tert-butylamine salt, yield 91.13%.
Because to it amendment carried out or optimization on basis of the present invention, can accomplish for those skilled in the art, so the amendment carried out without departing from theon the basis of the spirit of the present invention or optimization, all belong to protection scope of the present invention.
Checking example
In the mass parameters such as content, transmittance, impurity quite, design parameter is as follows for the amine salt that the clavulanic acid amine salt of the inventive method recovery gained and common process are produced:
From table, the clavulanic acid n-Butyl Amine 99 salt that the content of clavulanic acid n-Butyl Amine 99 salt that the inventive method reclaims and transmittance and common process are produced is very nearly the same, while both impurity (always mixing) content be all less than 0.05%, foreign matter content is all very low, and quality is fine.The amine salt that other several amine salt of clavulanic acid that the inventive method reclaims also are produced with common process quite, can be used for the preparation of downstream alkali metal salt in the mass parameters such as content, transmittance, impurity as intermediate.
Claims (7)
1. from clavulanic acid amine salt crystalline mother solution, reclaim a method for clavulanic acid, it is characterized in that, comprise the steps:
(1) get clavulanic acid amine salt crystalline mother solution, carry out underpressure distillation and concentrate at 10 ~ 40 DEG C of temperature, then remove impurity with the flow velocity of 1 ~ 5BV/h by the resin column that ion exchange resin is housed, wherein flow rate BV/h is that column volume is per hour;
(2) with 25% sulfuric acid adjustment concentrated solution pH value to 1.5 ~ 3.0, add alkyl acetates or ketones solvent, extraction clavulanic acid is in solvent phase, and the temperature of extraction is 0 ~ 10 DEG C;
(3) organic amine of the solvent phase after extraction regulates pH to 6.0 ~ 7.5, stratification, and collect aqueous phase, wherein said organic amine is TERTIARY BUTYL AMINE or tert-Octylamine;
(4) acetone adding 30 ~ 45 times in aqueous phase carries out stirred crystallization, and temperature controls 0 ~ 5 DEG C, growing the grain 2 hours; With filtration devices, filtrate is acetone crystalline mother solution; Crystal washing with acetone, vacuum-drying obtains the dry product of clavulanic acid amine salt for 2 hours.
2. from clavulanic acid amine salt crystalline mother solution, reclaim the method for clavulanic acid according to claim 1, it is characterized in that, step (1) underpressure distillation thickening temperature is 20 ~ 30 DEG C.
3. from clavulanic acid amine salt crystalline mother solution, reclaim the method for clavulanic acid according to claim 1, it is characterized in that, the resin in step (1) is selected from following one: storng-acid cation exchange resin, weakly acidic cation-exchange resin; Concentrated solution is 1 ~ 2BV/h by the flow velocity of resin column.
4. from clavulanic acid amine salt crystalline mother solution, reclaim the method for clavulanic acid according to claim 1, it is characterized in that, step (2) adjustment concentrated solution pH value to 2.0 ~ 2.5; The temperature of extraction is 0 ~ 5 DEG C.
5. from clavulanic acid amine salt crystalline mother solution, reclaim the method for clavulanic acid according to claim 1, it is characterized in that, the alkyl acetates in step (2) or ketones solvent are selected from the one in methyl acetate, ethyl acetate, propyl acetate, butylacetate, methyl ethyl ketone and methyl iso-butyl ketone (MIBK).
6. from clavulanic acid amine salt crystalline mother solution, reclaim the method for clavulanic acid according to claim 5, it is characterized in that: the alkyl acetates in step (2) or ketones solvent are ethyl acetate or methyl iso-butyl ketone (MIBK).
7. from clavulanic acid amine salt crystalline mother solution, reclaim the method for clavulanic acid according to claim 1, it is characterized in that, step (3) solvent phase pH regulator to 6.5 ~ 7.0.
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| CN108546269B (en) * | 2018-05-22 | 2019-10-11 | 国药集团威奇达药业有限公司 | The method of clavulanic acid tert-butylamine salt is recycled from crystalline mother solution |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1112928A (en) * | 1992-06-11 | 1995-12-06 | 史密丝克莱恩比彻姆有限公司 | Novel method for preparation and/or purification of clavulanic acid or pharmaceutical salt or ester of same |
| CN1175952A (en) * | 1995-02-25 | 1998-03-11 | 斯勃苛尔脱有限公司 | Clavulanic acid salts and method for preparing same |
| CN1064364C (en) * | 1995-05-16 | 2001-04-11 | 株式会社钟根堂 | Method for mfg. clavulanic acid salt |
| CN1312814A (en) * | 1998-07-16 | 2001-09-12 | Dsm公司 | Improved process for preparing salts and esters of clavulanic acid |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1112928A (en) * | 1992-06-11 | 1995-12-06 | 史密丝克莱恩比彻姆有限公司 | Novel method for preparation and/or purification of clavulanic acid or pharmaceutical salt or ester of same |
| CN1175952A (en) * | 1995-02-25 | 1998-03-11 | 斯勃苛尔脱有限公司 | Clavulanic acid salts and method for preparing same |
| CN1064364C (en) * | 1995-05-16 | 2001-04-11 | 株式会社钟根堂 | Method for mfg. clavulanic acid salt |
| CN1312814A (en) * | 1998-07-16 | 2001-09-12 | Dsm公司 | Improved process for preparing salts and esters of clavulanic acid |
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