CN109305978A - A kind of new method preparing Clavulanate - Google Patents
A kind of new method preparing Clavulanate Download PDFInfo
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- CN109305978A CN109305978A CN201710615169.1A CN201710615169A CN109305978A CN 109305978 A CN109305978 A CN 109305978A CN 201710615169 A CN201710615169 A CN 201710615169A CN 109305978 A CN109305978 A CN 109305978A
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- Prior art keywords
- clavulanic acid
- clavulanate
- preparation process
- amine salt
- salt
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- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 title claims abstract description 53
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 title claims abstract description 38
- 229940090805 clavulanate Drugs 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title abstract description 9
- 229960003324 clavulanic acid Drugs 0.000 claims abstract description 36
- -1 clavulanic acid amine salt Chemical class 0.000 claims abstract description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 239000011347 resin Substances 0.000 claims abstract description 12
- 229920005989 resin Polymers 0.000 claims abstract description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 9
- 239000007788 liquid Substances 0.000 claims abstract description 9
- 150000001450 anions Chemical class 0.000 claims abstract description 8
- 150000001412 amines Chemical class 0.000 claims abstract description 7
- 238000001179 sorption measurement Methods 0.000 claims abstract description 6
- 229960000935 dehydrated alcohol Drugs 0.000 claims abstract description 4
- 238000005516 engineering process Methods 0.000 claims abstract description 4
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 238000001728 nano-filtration Methods 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 12
- 238000010521 absorption reaction Methods 0.000 claims description 11
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 8
- 238000010828 elution Methods 0.000 claims description 7
- 229960004756 ethanol Drugs 0.000 claims description 7
- 239000012535 impurity Substances 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 239000012530 fluid Substances 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- QIJIUJYANDSEKG-UHFFFAOYSA-N 2,4,4-trimethylpentan-2-amine Chemical compound CC(C)(C)CC(C)(C)N QIJIUJYANDSEKG-UHFFFAOYSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 2
- 239000000284 extract Substances 0.000 claims description 2
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 claims description 2
- 238000011017 operating method Methods 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims 2
- 150000001340 alkali metals Chemical class 0.000 claims 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims 1
- 235000011056 potassium acetate Nutrition 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 238000000855 fermentation Methods 0.000 abstract description 7
- 230000004151 fermentation Effects 0.000 abstract description 7
- 239000002904 solvent Substances 0.000 abstract description 7
- 239000012043 crude product Substances 0.000 abstract description 5
- 239000013078 crystal Substances 0.000 abstract description 4
- 239000003480 eluent Substances 0.000 abstract description 4
- 238000002425 crystallisation Methods 0.000 abstract description 3
- 230000008025 crystallization Effects 0.000 abstract description 3
- 239000000047 product Substances 0.000 abstract description 3
- 150000002148 esters Chemical class 0.000 abstract description 2
- 229960000074 biopharmaceutical Drugs 0.000 abstract 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 238000000605 extraction Methods 0.000 description 5
- ABVRVIZBZKUTMK-JSYANWSFSA-M potassium clavulanate Chemical compound [K+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 ABVRVIZBZKUTMK-JSYANWSFSA-M 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- WOGMLDNCNBLDCA-JSYANWSFSA-M sodium;(2r,3z,5r)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [Na+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 WOGMLDNCNBLDCA-JSYANWSFSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000919 ceramic Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000001223 reverse osmosis Methods 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- SZAZNSHZTGHEOF-UHFFFAOYSA-N ethanol;2-methylpropan-2-amine Chemical compound CCO.CC(C)(C)N SZAZNSHZTGHEOF-UHFFFAOYSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000000837 restrainer Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D503/10—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D503/12—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 unsubstituted in position 6
- C07D503/14—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 unsubstituted in position 6 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, other than a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, attached in position 3
- C07D503/16—Radicals substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical
- C07D503/18—Radicals substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D503/02—Preparation
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention belongs to biopharmaceutical technologies, specifically provide a kind of preparation process of Clavulanate.Firstly, clavulanic acid fermentation liquid adsorbs resin adsorption through alkali anion after rate purifies, clavulanic acid eluent is afforded with NaCL solution；Then it after eluent nanofiltration concentration, is reacted with amine, is freeze-dried to obtain clavulanic acid amine salt crude product with freeze drier；Above-mentioned crude product finally is extracted with dehydrated alcohol, obtains clavulanic acid amine salt sterling through super-critical crystallization.Clavulanic acid amine salt can further react to obtain pharmaceutically acceptable salt or ester.This technique product purity it is high, high-quality.It is not required to solvent crystal, it is environmental-friendly, easy to operate, at low cost.
Description
Technical field
The invention belongs to pharmaceutical manufacturing field, in particular to a kind of method of purification of Clavulanate.
Background technique
The alkali metal salt (such as potassium clavulanate) of clavulanic acid is a kind of mono- lactamase restrainer of β, it and amoxycillin are green
Mycin and the combination of mono- lactam antibiotics of other β can overcome the drug resistance problems got worse, increase substantially phthalein amine in β mono-
The bacteriostatic activity of class antibiotic.
Currently, preparing the conventional method of Clavulanate are as follows: first by filtering fermentation liquor, be concentrated to get clavulanic acid water
Solution；Then clavulanic acid is extracted from clavulanic acid aqueous solution, reacts to form stable clavulanic acid amine salt with organic amine；Most
Clavulanic acid amine salt is changed into required alkali metal salt afterwards.There are many patent documents to propose the preparation of Clavulanate
Other schemes.For example, the patent of Patent No. 93103713.1 proposes first with weak base or strong base anion resins absorption gram
Clavulanic acid fermentation liquid, LiCL elution, reverse osmosis unit concentration, dry clavulanic acid lithium salts；Then clavulanic acid lithium salts mistake
732(K+) resin carries out ion exchange into potassium clavulanate saline solution；It is dense through decolorization and impurity removal by active carbon, reverse osmosis unit again
Contracting；Freeze-drying or with solvent crystal, obtains finished product.It for example proposes to be not required in the patent of Patent No. 200810016416.7 again
Clavulanic acid intermediate is formed, and directly prepares potassium clavulanate or pharmaceutically acceptable with alkali carbonate and bicarbonate
Other salt.
But all schemes require to crystallize Clavulanate using a large amount of solvents, such as acetone or isopropanol.This is just
So that preparation process exists, product purity is low, of poor quality, high production cost, complex process, production process are difficult to control, solvent recycling
Difficult, the disadvantages of environmental pollution is serious.
Summary of the invention
A kind of in order to compensate for the shortcomings of the prior art, the present invention provides steps simple, easily operated Clavulanate
Preparation process.
The present invention is achieved through the following technical solutions:
A kind of Clavulanate preparation process includes following operating procedure:
(1) ceramic film process is carried out to clavulanic acid fermentation liquid first, removes mycelium and macromolecular substances, molecule interception
For 50,000 dalton；In turn with organic film process, solid matter and partial pigment in fermentation liquid are removed, molecule interception is 1
Ten thousand dalton；
(2) elution is afforded with weak base or the above-mentioned concentrate of strong alkalinity anion absorption resin adsorption and then with NaCl solution
Liquid；
(3) active carbon decoloring is added in above-mentioned eluent, is centrifuged active carbon or small molecular weight impurity removing or is filtered, finally received
Filter is concentrated to get clavulanic acid sodium salt solution；
(4) organic amine (such as n-butylamine, tert-butylamine, n-octyl amine, t-octanylamine) reaction is added into clavulanic acid sodium salt solution to generate
Stable clavulanic acid intermediate amine salt；It is freeze-dried to obtain clavulanic acid amine salt crude product；
(5) a certain amount of ethyl alcohol is added and extracts clavulanic acid amine salt, be filtered to remove NaCL solid and ethyl alcohol insoluble impurities；
(6) crystallize clavulanic acid amine salt using supercritical technology；
(7) clavulanic acid amine salt is reacted with alkali metal salt (such as sylvite) and generates pharmaceutically acceptable Clavulanate.
Preferably, alkalescent yin absorption resin is used in step (2).
Preferably, the organic amine in step (4) is t-octanylamine.
Preferably, ethyl alcohol used is dehydrated alcohol in step (5).
Preferably, the supercritical fluid that step (6) supercritical technology is selected is CO2。
The beneficial effects of the present invention are: substantially increasing the purity of clavulanic acid amine salt using this programme, further increase
Pharmaceutically receptible metal clavulanate salt or the quality of ester.Compared with traditional method using solvent crystal, cost
It is greatly reduced, it is environmental-friendly, and solve the problems, such as that solvent recycling is difficult, it operates more convenient.
Specific embodiment
Embodiment 1:
Fermentation liquor pretreatment
The water that the clavulanic acid fermentation liquid of 200L is added 5 times is diluted, and PH to 4.8 ~ 5.5 is adjusted, in 4~10 DEG C of item of temperature
First it is the ceramic membrane filter of 50,000 dalton with molecule interception under part, removes mycelium and macromolecular substances；Then molecule retains
Amount is the organic membrane filter of 10,000 dalton, removes some solid suspensions and partial pigment, and flow is 10 ~ 30L/ (m2H),
Obtain filtered solution 950L.
Embodiment 2:
The separation of clavulanic acid sodium
It ferments and filters obtained in weakly-basic anion absorption resin (ratio of height to diameter 6:1, amount of filler 50L) absorption embodiment 1
Cross liquid, adsorption flow rate 150L/h.Resin is cleaned with deionized water, then the NaCL solution for being 4 ~ 6% with concentration elutes, elution stream
Speed is 25 ~ 50L/h.It is slowly added into active carbon in eluent, 0.5h is stirred at 5 DEG C, plate-frame filtering adjusts PH to 6.0 ~ 6.5,
Pressure is 15 ~ 25KPa, and temperature carries out nanofiltration under the conditions of being 0 ~ 5 DEG C and is concentrated into the 1/20 of original volume.(above-mentioned adsorption flow rate VAbsorption、
Elution flow rate VElutionWith the relationship of weakly-basic anion absorption resin extender amount V are as follows: VAbsorption=3V/h；VElution=0.5~1V/h.)
Embodiment 3:
The preparation of carat dimension amine salt
The H of 2mol/L is added in concentrate2SO4Solution adjusts PH to 1.5 ~ 2.0, and tert-butylamine solution, 0 ~ 5 DEG C of progress is then added
Reaction, is freeze-dried to obtain clavulanic acid tert-butylamine crude product 4Kg after fully reacting.
48L dehydrated alcohol is added into above-mentioned crude product, dissolution is sufficiently stirred, is filtered to remove insoluble impurities, obtains 49.4Kg's
Clavulanic acid tert-butylamine ethanol solution.
Super-critical crystallization
By extraction feed (i.e. the mixed solution of clavulanic acid tert-butylamine and ethyl alcohol), prior charging feedstock basket is simultaneously put into extraction kettle
In, CO2Fluid is through CO2Pump enters extraction kettle, and alcohol component is by CO2Fluid extraction is taken away, by filter, heat exchanger, decompression
Enter separating still afterwards, is extracted ingredient clavulanic acid tert-butylamine crystal and stays in extraction kettle, the CO of circulation2Fluid is through low pressure mistake
Filter, cooler and condenser are condensed into the CO of liquid2, and enter solvent tank, so as to recycled.
Embodiment 4:
The preparation of potassium clavulanate
(1) isooctyl acid potassium-aqueous isopropanol configuration
Isopropanol is mixed with isooctyl acid potassium, revolving speed 35Hz is controlled, 30min is sufficiently stirred.
(2) dissolution of clavulanic acid tert-butylamine
The isopropanol of 2.5CKg and the purified water of 0.6CKg are added into container, opens stirring, controls stirring rate 35Hz, it will be warm
Degree control adds preprepared clavulanic acid tert-butylamine at 30 ~ 35 DEG C, stirs 30min.
(3) reactive crystallization
Under the conditions of controlling 20 ~ 25 DEG C of temperature, speed of agitator 35z, into clavulanic acid tert-butylamine solution, a dropping step (1) is matched
Isooctyl acid potassium-aqueous isopropanol, time for adding 30min.0 ~ 5 DEG C, 4 ~ 6h of insulated and stirred is cooled to after being added dropwise, revolving speed is
35Hz。
Last centrifugal filtration, vacuum drying obtain potassium clavulanate 1.22Kg.
Claims (6)
1. a kind of preparation process of Clavulanate, it is characterised in that: including following operating procedure:
(1) alkali anion absorption resin adsorption clavulanic acid filtered solution, the elution of NaCL solution；
(2) active carbon decoloring is added, is centrifuged active carbon or small molecular weight impurity removing or is filtered；
(3) amine aqueous solution is added, reaction generates stable clavulanic acid intermediate amine salt；
(4) nanofiltration concentration, be freeze-dried clavulanic acid amine salt, NaCL and impurity hybrid solid and use acetone washing；
(5) a certain amount of ethanol solution is added and extracts clavulanic acid amine, be filtered to remove NaCL and ethyl alcohol insoluble impurities；
(6) crystallize clavulanic acid amine salt using supercritical technology；
(7) clavulanic acid amine salt is reacted with alkali metal salt and generates pharmaceutically acceptable Clavulanate.
2. a kind of preparation process of Clavulanate according to claim 1, it is characterised in that the alkalinity yin in step (1)
Nonionic adsorption resin can be strong alkalinity anion absorption resin and be also possible to weakly-basic anion absorption resin.
3. a kind of preparation process of Clavulanate according to claim 1, it is characterised in that the amine aqueous solution in step (3)
Including n-butylamine, tert-butylamine, n-octyl amine, t-octanylamine.
4. a kind of preparation process of Clavulanate according to claim 1, it is characterised in that the ethyl alcohol in step (5) is molten
Liquid can be the ethanol water that dehydrated alcohol is also possible to arbitrary proportion.
5. a kind of preparation process of Clavulanate according to claim 1, it is characterised in that overcritical skill in step (6)
The supercritical fluid that art selects is supercritical fluid CO 2.
6. a kind of preparation process of Clavulanate according to claim 1, it is characterised in that the alkali metal in step (7)
Salt includes isooctyl acid potassium, potassium acetate.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113979872A (en) * | 2021-11-09 | 2022-01-28 | 国药集团威奇达药业有限公司 | Comprehensive recovery method of effective components in potassium clavulanate kettle residual liquid |
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| 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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| CN105384758A (en) * | 2015-12-01 | 2016-03-09 | 国药集团威奇达药业有限公司 | Preparation method of clavulanic acid amine salt |
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2017
- 2017-07-26 CN CN201710615169.1A patent/CN109305978A/en active Pending
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| CN113979872A (en) * | 2021-11-09 | 2022-01-28 | 国药集团威奇达药业有限公司 | Comprehensive recovery method of effective components in potassium clavulanate kettle residual liquid |
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