CN106086151A - 6 aminopenicillanic acids and preparation method thereof - Google Patents
6 aminopenicillanic acids and preparation method thereof Download PDFInfo
- Publication number
- CN106086151A CN106086151A CN201610425622.8A CN201610425622A CN106086151A CN 106086151 A CN106086151 A CN 106086151A CN 201610425622 A CN201610425622 A CN 201610425622A CN 106086151 A CN106086151 A CN 106086151A
- Authority
- CN
- China
- Prior art keywords
- apa
- potassium
- preparation
- stripping agent
- potassium carbonate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000002253 acid Substances 0.000 title abstract description 6
- 150000007513 acids Chemical class 0.000 title abstract 2
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 claims abstract description 69
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims abstract description 60
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 60
- 229940056360 penicillin g Drugs 0.000 claims abstract description 34
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 31
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 30
- 238000000605 extraction Methods 0.000 claims abstract description 14
- YVWSZKXPYSXLLJ-UHFFFAOYSA-N 2-(1,1-dioxothiolan-3-yl)-5-methyl-1h-pyrazol-3-one Chemical compound N1C(C)=CC(=O)N1C1CS(=O)(=O)CC1 YVWSZKXPYSXLLJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000005406 washing Methods 0.000 claims abstract description 8
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 claims description 65
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 238000005336 cracking Methods 0.000 claims description 10
- 108010093096 Immobilized Enzymes Proteins 0.000 claims description 9
- 230000009089 cytolysis Effects 0.000 claims description 9
- 230000002255 enzymatic effect Effects 0.000 claims description 9
- 208000035126 Facies Diseases 0.000 claims description 8
- 238000007233 catalytic pyrolysis Methods 0.000 claims description 7
- 108010087702 Penicillinase Proteins 0.000 claims description 6
- 229950009506 penicillinase Drugs 0.000 claims description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 5
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000012487 rinsing solution Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 28
- 229930182555 Penicillin Natural products 0.000 abstract description 26
- 229940049954 penicillin Drugs 0.000 abstract description 24
- 238000005516 engineering process Methods 0.000 abstract description 18
- 238000002425 crystallisation Methods 0.000 abstract description 11
- 230000008569 process Effects 0.000 abstract description 11
- 230000008025 crystallization Effects 0.000 abstract description 6
- 235000011181 potassium carbonates Nutrition 0.000 description 24
- 239000007788 liquid Substances 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 239000013078 crystal Substances 0.000 description 6
- 239000013067 intermediate product Substances 0.000 description 6
- 238000006555 catalytic reaction Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 4
- 230000000857 drug effect Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 229960003022 amoxicillin Drugs 0.000 description 3
- -1 carbonium ion Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 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 3
- 150000002960 penicillins Chemical class 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000000638 solvent extraction Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- JXYKOZKEXNCSSR-UHFFFAOYSA-N C(C1=CC=CC=C1)[Na].N Chemical compound C(C1=CC=CC=C1)[Na].N JXYKOZKEXNCSSR-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000228143 Penicillium Species 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000009965 odorless effect Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 235000019371 penicillin G benzathine Nutrition 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 229940024554 amdinocillin Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- BWWVAEOLVKTZFQ-ISVUSNJMSA-N chembl530 Chemical compound N(/[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)=C\N1CCCCCC1 BWWVAEOLVKTZFQ-ISVUSNJMSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012531 culture fluid Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940124585 oral penicillin Drugs 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000011218 seed culture Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P37/00—Preparation of compounds having a 4-thia-1-azabicyclo [3.2.0] heptane ring system, e.g. penicillin
- C12P37/06—Preparation of compounds having a 4-thia-1-azabicyclo [3.2.0] heptane ring system, e.g. penicillin by desacylation of the substituent in the 6 position
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and 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
- C07D499/42—Compounds with a free primary amino radical attached in position 6
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The preparation method of a kind of 6 aminopenicillanic acids (6 APA), directly uses the potassium carbonate anti-stripping agent of benzylpenicillin potassium to produce.The molecular formula of described 6 APA is C8H12N2O3S, and molecular weight is 216.26.Use this kind of technique can save crystallisation step, it is to avoid crystallization yield loses.In the technical process of the present invention, penicillin menstruum extraction, washing process are optimized.Present invention employs advanced preparation technology, have higher yields and lower cost.
Description
Technical field
The present invention relates to a kind of penicillin, a kind of 6-amino-penicillanic acid using advanced technologies and preparation side thereof
Method and purposes.
Background technology
Amoxicillin is a kind of the most frequently used penicillins wide spectrum beta-lactam antibiotic, for a kind of white powder, and half
The phase of declining is about 61.3 minutes.Tool bacteriolysis, cures mainly the bacterial infection caused by susceptible microorganisms.The most steady
Fixed, gastrointestinal absorption rate reaches 90.Amoxicillin bactericidal action is strong, and the ability of penetration cell wall is the strongest.It is that application is the widest at present
One of general oral penicillin, its preparation has capsule, tablet, granule, dispersible tablet etc..
6-amino-penicillanic acid (6-APA) is the important intermediate producing amoxicillin.6-amino-penicillanic acid (6-APA)
Also referred to as unprotected side chain penicillin, its molecular formula is C8H12N2O3S, and molecular weight is 216.26.6-APA not only can be used to produce Ah
Amdinocillin, it is possible to produce the multiple antibiotic ammonia benzyl sodium such as resistance to penicillin class antibiotic, such as ammonia benzyl sodium that narrow.Resist in penicillins
Important role in the raw element manufacturing.
Produce the enzyme catalysis cracking process of 6-APA commonly used solid potassium salt of penicillin, this method technical maturity the most in the world
But yield is relatively low, high expensive, organic solvent usage amount is relatively big simultaneously, and environmental protection aspect puts into more.
Summary of the invention
A kind of 6-amino-penicillanic acid of offer is provided, have employed advanced preparation technology, have higher
Yield and lower cost.
Further object is that the preparation technology that a kind of 6-amino-penicillanic acid is provided, it is possible to increase yield,
Reduce cost.Further object is that the 6-amino-penicillanic acid that a kind of above-mentioned employing advanced person preparation technology is provided
Purposes, it is possible to increase yield, reduces cost.
According to one embodiment of present invention, a kind of 6-amino-penicillanic acid (6-APA), directly use the carbon of benzylpenicillin potassium
Acid potassium anti-stripping agent is produced.
The molecular formula of described 6-APA is C8H12N2O3S, and molecular weight is 216.26.
The potassium carbonate anti-stripping agent of described benzylpenicillin potassium carries out enzymatic lysis reaction.
Described benzylpenicillin potassium is soluble in water, normal saline, glucose solution.Described benzylpenicillin potassium molecular formula is
C16H17KN2O4S, molecular weight is 372.49, and molecular structure is
Described penicillinase cracking reaction can carry out catalytic pyrolysis with immobilized enzyme.
Described potassium carbonate anti-stripping agent makes to be extracted component and generates compound soluble in water.
Described potassium carbonate anti-stripping agent makes to be extracted component and generates the most water insoluble precipitation being also insoluble in organic facies.
The molecular structure of described 6-APA is
The molecular structure of described 6-APA is
According to one embodiment of present invention, the preparation method of a kind of 6-amino-penicillanic acid (6-APA), its feature exists
In, comprise the following steps:
(1) benzylpenicillin potassium is immersed potassium carbonate anti-stripping agent；
(2) directly using the potassium carbonate anti-stripping agent of benzylpenicillin potassium to produce and obtain 6-APA, the molecular formula of described 6-APA is
C8H12N2O3S, molecular weight is 216.26.
Described benzylpenicillin potassium is soluble in water, normal saline, glucose solution.Described benzylpenicillin potassium molecular formula is
C16H17KN2O4S, molecular weight is 372.49, and molecular structure is
The potassium carbonate anti-stripping agent of described benzylpenicillin potassium carries out enzymatic lysis reaction.
Described penicillinase cracking reaction can carry out catalytic pyrolysis with immobilized enzyme.
Described potassium carbonate anti-stripping agent makes to be extracted component and generates compound soluble in water, or described potassium carbonate anti-stripping agent
Make to be extracted component and generate the most water insoluble precipitation being also insoluble in organic facies.
According to one embodiment of present invention, the 6-amino-penicillanic acid (6-of a kind of above-mentioned employing advanced person preparation technology
APA) multiple Penicillin antibiotics can be produced.
Described 6-APA has certain bacteriostasis, can introduce different side chains, and obtain the penicillin of various different drug effect.
The present invention directly uses the potassium carbonate anti-stripping agent of benzylpenicillin potassium to carry out enzymatic lysis reaction and produces 6-APA.Use this
Plant technique and can save crystallisation step, avoid crystallization yield to lose.
Lacking crystal refining technique and be likely to result in the reduction of 6-APA productivity and Quality Down, in RB liquid, butyl acetate is residual simultaneously
Allowance is relatively big, may affect the activity of immobilized enzyme.In the technical process of the present invention, to penicillin menstruum extraction, washing process
It is optimized.
Accompanying drawing explanation
Fig. 1 is the preparation technology schematic flow sheet according to one embodiment of the invention.
Fig. 2 is the preparation technology flow process schematic arrangement according to one embodiment of the invention.
Fig. 3 is the preparation technology flow chart according to one embodiment of the invention.
Detailed description of the invention
6-amino-penicillanic acid (6-APA) is also referred to as unprotected side chain penicillin, and its molecular formula is C8H12N2O3S, and molecular weight is
216.26。
According to one embodiment of present invention, the structural formula of a kind of 6-amino-penicillanic acid (6-APA) is as shown below:
Produce at present the enzyme catalysis cracking process of 6-APA commonly used solid potassium salt of penicillin, this method technical maturity but yield
Relatively low, high expensive.
Fig. 3 is the preparation technology flow chart according to one embodiment of the invention.Seeing Fig. 3, the present invention directly uses penicillium sp
The potassium carbonate anti-stripping agent of element potassium carries out enzymatic lysis and reacts the technique producing 6-APA.Catalytic pyrolysis is carbonium ion reaction mechanism
Result coefficient with radical reaction mechanism.Employing enzyme catalysis cracks, and enzyme can accelerate or slow down the effect of chemical reaction.This
Invention facilitates catalytic pyrolysis by enzyme, makes the carbonium ion of infiltration benzylpenicillin potassium in potassium carbonate anti-stripping agent participate in anti-
Should, response speed can be accelerated to a certain extent.
Benzylpenicillin potassium has another name called Kaifeng penicillin, and its this product is white crystal powder, odorless or micro-have specificity smelly, has moisture absorption
Property.Benzylpenicillin potassium is soluble in water, normal saline, glucose solution.Aqueous solution is placed in room temperature and was easily lost efficacy, and meets acid, alkali, oxidant
Deng inefficacy rapidly.Molecular formula is C16H17KN2O4S, and molecular weight is 372.49.
When using solid potassium salt of penicillin to produce 6-APA, solid potassium salt of penicillin first dissolves in a liquid, needs crystallization
Just can complete to generate.
And the present invention is compared with current technology, the potassium carbonate anti-stripping agent of benzylpenicillin potassium is directly used to carry out enzymatic lysis reaction
Produce 6-APA.Using this kind of technique can save crystallisation step, after crystallization is the saturated solution cooling of heat, solute is with crystal
Form separates out.Use this technique of the present invention, this process of crystallisation step can be saved, it is to avoid the crystallization yield of about 10%
Loss.
The present invention uses the potassium carbonate anti-stripping agent of benzylpenicillin potassium.
So-called extraction utilize exactly material in two kinds of immiscible solvents distribution ratio difference to reach separating and extracting
Liquid.Utilize solute difference of dissolubility in immiscible solvent, with a kind of solvent, solute is formed from another solvent
The operational approach extracted in solution.Contrary with extraction process, extract returns the process of aqueous phase from organic facies.Back extraction
Process is an important step in solvent extraction and separation technology flow process.Back extraction can be by organic facies, each is extracted component one by one
Back extraction, to aqueous phase, makes to be separated by separation component；Also once organic facies can will be extracted component back extraction to aqueous phase.
According to one embodiment of present invention, using the potassium carbonate anti-stripping agent of benzylpenicillin potassium, benzylpenicillin potassium is through potassium carbonate
Anti-stripping agent solvent extraction and separation, by extraction component back extraction to aqueous phase from organic facies.
Potassium carbonate is white crystalline powder.Density 2.428g/cm3, fusing point 891 DEG C, decomposes during boiling point, relative molecular weight
138.21.Potassium carbonate is dissolved in water, and aqueous solution is alkalescence, insoluble in ethanol, acetone and ether.Hygroscopicity is strong, exposes in atmosphere
Energy absorbing carbon dioxide and moisture, be changed into potassium bicarbonate, should pack.Hydrate has a water thing, two water things, three water things.
Wet chemical is alkalescence.
Through back extraction and gained strip liquor after processing further, just obtain the finished product of separated object.Stripped
Journey has simple, convenient to operate and that the cycle is short feature.Potassium carbonate anti-stripping agent makes to be extracted component and generates chemical combination soluble in water
Thing, or generate the most water insoluble precipitation being also insoluble in organic facies.
The present invention directly uses the potassium carbonate anti-stripping agent of benzylpenicillin potassium to carry out enzymatic lysis reaction and produces 6-APA.Use this
Plant technique and can save crystallisation step, avoid crystallization yield to lose.
But, lack crystal refining technique and be likely to result in the reduction of 6-APA productivity and Quality Down, acetic acid fourth in RB liquid simultaneously
Ester (BA) residual quantity is relatively big, may affect the activity of immobilized enzyme.
The problem being likely to result in the aspects such as the reduction of 6-APA productivity and Quality Down owing to lacking crystal refining technique, this
Bright extractive technique is carried out comprehensive optimization.According to one embodiment of present invention, in technical process, to penicillin menstruum
Extraction, washing process are optimized, and filter out the pH value control point 5-7 that extraction process is optimal, and reasonably filtrate and vinegar
The ratio of acid butyl ester, the butyl acetate extract (first BA) of water-washing process benzylpenicillin and the ratio of water are 2:1.
Fig. 1 is the preparation technology schematic flow sheet of the embodiment of the present invention.See Fig. 1, the preparation technology flow process of the present invention with
Benzylpenicillin potassium is raw material, by the salt that dissociates, is layered, becomes, be dried etc. a series of operation prepare respectively.Then by them according to one
Fixed ratio quantitatively mixes to prepare.In preparation technology of the present invention, benzylpenicillin potassium is at potassium carbonate anti-stripping agent, by washing, shape
Become stock solution, form 6-APA through penicillinase cracking.According to one embodiment of present invention, wherein, penicillinase cracking is permissible
Catalytic pyrolysis is carried out with immobilized enzyme.The many poly chains of enzyme catalysis are from internal or end cracking.After refined, directly prepare 6-
APA。
According to one embodiment of present invention, according to the preparation technology of Fig. 1, sand spore makes single bacterium colony, then makes tiltedly
Face spore, Semen setariae spore, obtain seed culture fluid, then make fermentation liquid, be made into penicillin filtrate, obtain solvent extraction liquid BA,
Make washing BA again, be made into RB stock solution, add penicillin immobilized enzyme, crack through penicillin immobilized enzyme, finally obtain 6-
APA。
Use freezing and activated carbon decolorizing technique to control to wash BA color level, reduce organic heteroacid and macromolecule egg in BA liquid
White content, to ensure the quality of final products, adjusts the concentration in K2_CO_3 anti-stripping agent, increases decompression co-boiling distiling unit
To reduce the butyl acetate content in RB liquid.
6-amino-penicillanic acid (6-APA) is also referred to as unprotected side chain penicillin, and its molecular formula is C8H12N2O3S, and molecular weight is
216.26。
According to one embodiment of present invention, the structural formula of a kind of 6-amino-penicillanic acid (6-APA) is as follows:
Such as methyl CH3 in 6-APA molecular structural formula is side chain.6-APA has certain bacteriostasis, can introduce difference
Side chain, and obtain the penicillin of various different drug effect.
According to one embodiment of present invention, see Fig. 2, benzylpenicillin potassium is immersed in potassium carbonate anti-stripping agent, its point by figure
Minor is
Adding PCl3 wherein, form intermediate product 1, its molecular formula is
Obtained intermediate product 1 adds PCl5, forms intermediate product 2, and its molecular formula is
Obtained intermediate product 2 adds n-C4H9OH, forms intermediate product 3, and its molecular formula is
Obtained intermediate product 3, through hydrolysis, can obtain
I.e. 6-APA.
6-APA fusing point is 208～209 DEG C, and character is white crystal.6-APA is slightly soluble in water, insoluble in general organic molten
Agent.Alkaline solution can be dissolved in.
The invention discloses the straight-through technique of complete set, and be applied in industrialized production, make benzylpenicillin potassium carry
Taking total recovery and bring up to 90%, 6-APA productivity and quality are identical with prior synthesizing method, and production cost significantly declines simultaneously,
Obtain considerable economic benefit and significant social benefit.
Meanwhile, the production technology commonly used solid potassium salt of penicillin of existing 6-APA, organic solvent usage amount is relatively big, ring
Guarantor's aspect puts into more.The present invention directly uses the potassium carbonate anti-stripping agent of benzylpenicillin potassium to carry out enzymatic lysis reaction and produces 6-APA
Technique, it is possible to reduce solvent consumption, production cost is greatly reduced.
Embodiment one
Proportioning raw materials:
Using benzylpenicillin potassium, infiltration is in potassium carbonate anti-stripping agent.Benzylpenicillin potassium has another name called Kaifeng penicillin, and its this product is white
Crystallographic powder, odorless or micro-have specificity smelly, there is hygroscopicity.
According to one embodiment of present invention, raw material can use precision to weigh, and " precision weighs " means that weighing weight answers
Accurately to the one thousandth of weighed weight." precision measures " means that the accuracy measuring volume should meet in national standard this
The required precision of volume pipet.
The present invention directly uses the potassium carbonate anti-stripping agent of benzylpenicillin potassium to carry out enzymatic lysis reaction and produces 6-APA.Penicillin
The carbonium ion of potassium participates in reaction, can accelerate response speed to a certain extent.Penicillinase cracking can be with immobilized enzyme
Carry out catalytic pyrolysis.The many poly chains of enzyme catalysis are from internal or end cracking.
The butyl acetate extract (first BA) of water-washing process benzylpenicillin and the ratio of water are 2:1.
Through subtractive process, such as by dissociating, be layered, become salt, a series of operation such as be dried and prepare 6-amino penicillium sp
Alkanoic acid (6-APA).6-amino-penicillanic acid (6-APA) is also referred to as unprotected side chain penicillin, and its molecular formula is C8H12N2O3S, molecule
Amount is 216.26.
According to one embodiment of present invention, the structural formula of a kind of 6-amino-penicillanic acid (6-APA) is as follows:
According to one embodiment of present invention, there is the 6-APA of molecular structure as implied above, different sides can be introduced
Chain, and obtain the penicillin of various different drug effect.
Embodiment two
According to another embodiment of the invention, generation has the 6-APA of molecular structure as follows
6-APA can introduce different side chains, and obtains the penicillin of various different drug effect.
Claims (8)
1. the preparation method of a 6-amino-penicillanic acid (6-APA), it is characterised in that comprise the following steps:
(1) benzylpenicillin potassium is immersed potassium carbonate anti-stripping agent；
(2) directly use the potassium carbonate anti-stripping agent of benzylpenicillin potassium to produce and obtain 6-APA.
2. preparation method as claimed in claim 1, it is characterised in that extraction process pH value controls at 5-7.
3. preparation method as claimed in claim 1, it is characterised in that also include water-washing process, the 6-that will obtain in step (2)
APA washes, in rinsing solution: butyl acetate extract is 2:1 with the ratio of water.
4. preparation method as claimed in claim 1, the molecular formula of described 6-APA is C8H12N2O3S, and molecular weight is 216.26,
Described benzylpenicillin potassium is soluble in water, normal saline, glucose solution, and described benzylpenicillin potassium molecular formula is C16H17KN2O4S, point
Son amount is 372.49, and molecular structure is
5. preparation method as claimed in claim 1, the potassium carbonate anti-stripping agent of described benzylpenicillin potassium carries out enzymatic lysis reaction, institute
Stating penicillinase cracking reaction can be with immobilized enzyme to carry out catalytic pyrolysis.
6. preparation method as claimed in claim 1, described potassium carbonate anti-stripping agent makes to be extracted component and generates change soluble in water
Compound, or described potassium carbonate anti-stripping agent makes to be extracted component and generates the most water insoluble precipitation being also insoluble in organic facies.
7. 6-APA as claimed in claim 1, the molecular structure of described 6-APA is
8. 6-APA as claimed in claim 1, the molecular structure of described 6-APA is
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610425622.8A CN106086151A (en) | 2016-06-14 | 2016-06-14 | 6 aminopenicillanic acids and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610425622.8A CN106086151A (en) | 2016-06-14 | 2016-06-14 | 6 aminopenicillanic acids and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106086151A true CN106086151A (en) | 2016-11-09 |
Family
ID=57236355
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610425622.8A Pending CN106086151A (en) | 2016-06-14 | 2016-06-14 | 6 aminopenicillanic acids and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106086151A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109535179A (en) * | 2017-09-22 | 2019-03-29 | 联邦制药(内蒙古)有限公司 | A kind of improved 6-APA extracting method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101058824A (en) * | 2006-04-21 | 2007-10-24 | 北京化工大学 | Immobilized enzyme biological catalyst, preparation method and application |
| CN102925526A (en) * | 2012-11-23 | 2013-02-13 | 华北制药河北华民药业有限责任公司 | Preparation method for 6-amino penicillanic acid |
-
2016
- 2016-06-14 CN CN201610425622.8A patent/CN106086151A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101058824A (en) * | 2006-04-21 | 2007-10-24 | 北京化工大学 | Immobilized enzyme biological catalyst, preparation method and application |
| CN102925526A (en) * | 2012-11-23 | 2013-02-13 | 华北制药河北华民药业有限责任公司 | Preparation method for 6-amino penicillanic acid |
Non-Patent Citations (1)
| Title |
|---|
| 赵自成: "6-氨基青霉烷酸（6-APA）生产工艺研究", 《中国优秀硕士学位论文全文数据库工程科技I辑》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109535179A (en) * | 2017-09-22 | 2019-03-29 | 联邦制药(内蒙古)有限公司 | A kind of improved 6-APA extracting method |
| CN109535179B (en) * | 2017-09-22 | 2020-05-22 | 联邦制药(内蒙古)有限公司 | Improved 6-APA extraction method |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104004002B (en) | A kind of method directly being prepared 6-amino-penicillanic acid by penicillin fermentation liquid | |
| Haykir et al. | Ionic liquid pretreatment allows utilization of high substrate loadings in enzymatic hydrolysis of biomass to produce ethanol from cotton stalks | |
| JP5794609B2 (en) | Cellulose biomass processing method | |
| CN102659882B (en) | Method for extracting tartaric acid acetylisovaleryl tylosion | |
| CN103709121B (en) | The preparation method of pharmaceutical grade 2-benzothiazolyl mercaptan and derivative DM thereof | |
| CN101928292B (en) | Method for preparing cefuroxime acid | |
| NZ598775A (en) | Substrate-selective co-fermentation process | |
| CN106086151A (en) | 6 aminopenicillanic acids and preparation method thereof | |
| CN104557969A (en) | Production technique of clopidogrel hydrogen sulfate | |
| CN106008554A (en) | Preparation method and product of ceftriaxone sodium sterile powder | |
| CN102286597A (en) | Method for preparing 7-aminocephalosporanic acid | |
| CN106928191A (en) | A kind of preparation technology of Lansoprazole | |
| CN104762338A (en) | Method of producing nicotinamide by catalysis of rhodococcus | |
| CN105039466B (en) | A kind of preparation method of Vidarabine Monophosphate | |
| CN111378704A (en) | Method for producing 4-AA intermediate by ketoreductase | |
| CN117384704A (en) | Whole ganoderma lucidum spore oil and preparation method thereof | |
| CN102603639B (en) | Production method of 4-amino-antipyrine oil | |
| CN104262415B (en) | D arabinose production methods | |
| CN109371095A (en) | A kind of method of enzymatic clarification Amoxicillin | |
| CN104725402B (en) | A kind of method of 6 aminopenicillanic acid continuous crystallization | |
| CN100469750C (en) | Method for extracting calcium gluconate from mother liquor after calcium gluconate crystallization | |
| CN106866441A (en) | A kind of preparation method of high-purity grade of Ferric Sodium Edetate | |
| CN104724891B (en) | A kind of processing method of oxytetracycline crystallization mother liquor waste water | |
| CN105254650A (en) | Synthesis method of antibacterial drug cefoxitin | |
| CN113005168B (en) | Preparation method of 6-aminopenicillanic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20161109 |