CN101724678A - Method for preparing 3-deacetyl-7-aminocephalosporanic acid - Google Patents
Method for preparing 3-deacetyl-7-aminocephalosporanic acid Download PDFInfo
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- CN101724678A CN101724678A CN200910227960A CN200910227960A CN101724678A CN 101724678 A CN101724678 A CN 101724678A CN 200910227960 A CN200910227960 A CN 200910227960A CN 200910227960 A CN200910227960 A CN 200910227960A CN 101724678 A CN101724678 A CN 101724678A
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- deacetylate
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- 238000000034 method Methods 0.000 title claims abstract description 21
- 229930186147 Cephalosporin Natural products 0.000 claims abstract description 62
- 229940124587 cephalosporin Drugs 0.000 claims abstract description 62
- 150000001780 cephalosporins Chemical class 0.000 claims abstract description 58
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 102000004674 D-amino-acid oxidase Human genes 0.000 claims abstract description 20
- 108010003989 D-amino-acid oxidase Proteins 0.000 claims abstract description 20
- 108090000371 Esterases Proteins 0.000 claims abstract description 19
- 108010034416 glutarylamidocephalosporanic acid acylase Proteins 0.000 claims abstract description 19
- IXUSDMGLUJZNFO-BXUZGUMPSA-N (7R)-7-(4-carboxybutanamido)cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CCCC(O)=O)[C@@H]12 IXUSDMGLUJZNFO-BXUZGUMPSA-N 0.000 claims abstract description 18
- 238000005406 washing Methods 0.000 claims abstract description 15
- 239000007787 solid Substances 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 102000004190 Enzymes Human genes 0.000 claims description 37
- 108090000790 Enzymes Proteins 0.000 claims description 37
- 238000002360 preparation method Methods 0.000 claims description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 10
- -1 cephalosporin ester Chemical class 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 6
- 238000001728 nano-filtration Methods 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 4
- 239000005695 Ammonium acetate Substances 0.000 claims description 4
- 229940043376 ammonium acetate Drugs 0.000 claims description 4
- 235000019257 ammonium acetate Nutrition 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 229960004249 sodium acetate Drugs 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 abstract description 8
- 230000008025 crystallization Effects 0.000 abstract description 5
- 238000005265 energy consumption Methods 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 2
- HOKIDJSKDBPKTQ-GLXFQSAKSA-N cephalosporin C Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(O)=O)[C@@H]12 HOKIDJSKDBPKTQ-GLXFQSAKSA-N 0.000 abstract 4
- 230000020477 pH reduction Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000005303 weighing Methods 0.000 description 10
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 9
- 239000004744 fabric Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000002255 enzymatic effect Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012266 salt solution Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 238000011095 buffer preparation Methods 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000005046 Chlorosilane Substances 0.000 description 1
- 206010009866 Cold sweat Diseases 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 238000004458 analytical method Methods 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
- 239000000872 buffer Substances 0.000 description 1
- 229960003719 cefdinir Drugs 0.000 description 1
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 description 1
- 229960002129 cefixime Drugs 0.000 description 1
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 1
- DKOQGJHPHLTOJR-WHRDSVKCSA-N cefpirome Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 DKOQGJHPHLTOJR-WHRDSVKCSA-N 0.000 description 1
- 229960000466 cefpirome Drugs 0.000 description 1
- 229960000484 ceftazidime Drugs 0.000 description 1
- NMVPEQXCMGEDNH-TZVUEUGBSA-N ceftazidime pentahydrate Chemical compound O.O.O.O.O.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 NMVPEQXCMGEDNH-TZVUEUGBSA-N 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical class Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000019628 coolness Nutrition 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a method for preparing 3-deacetyl-7-aminocephalosporanic acid, which comprises the following steps: catalyzing extract of cephalosporin C serving as a raw material by D-amino-acid oxidase to prepare solution of glutaryl-7-ACA; catalyzing the solution of glutaryl-7-ACA by glutaryl-7-ACA acylase and cephalosporin esterase to prepare solution of 3- deacetyl-7-aminocephalosporanic acid; and performing acidification crystallization, washing and drying to obtain solid 3-deacetyl-7-aminocephalosporanic acid. The method for preparing the3-deacetyl-7-aminocephalosporanic acid only needs two steps of normal temperature reaction and one-time crystallization process and has short process route; solvents are not used basically; the molar yield from the extract of the cephalosporin C to the 3-deacetyl-7-aminocephalosporanic acid can reach 71.5 percent; and the yield of the product is high. In addition, compared with the prior art, the method has much lower energy consumption, power cost, labor cost and environmental cost.
Description
Technical field
The present invention relates to a kind of preparation method of pharmaceutical raw material, specifically a kind of preparation method of 3-deacetylate-7-amino-cephalosporanic acid.
Background technology
3-deacetylate-7-amino-cephalosporanic acid is called for short D-7-ACA; because 7 bit aminos and 3 hydroxyls of D-7-ACA are more active; thereby can introduce the synthetic a series of cephalosporin analog antibiotics of different side chains as required, as cephalofruxin, cefpirome, S-1108, Cefixime Micronized, Cefdinir, ceftazidime etc.Cephalosporin analog antibiotic has broad spectrum antibacterial, characteristics such as toxic side effect is little are present clinical application microbiotic kinds the most widely, and consumption is very big, and along with the increase of cephalosporin analog antibiotic consumption with to the exploitation of novel cephalosporin analog antibiotic, to the demand of D-7-ACA also in continuous increase.
The method for preparing at present D-7-ACA mainly contains two kinds: a. cephalosporin sodium salt (or zinc salt) obtains 7-ACA (7-amino-cephalosporanic acid) solution by esterification, chlorination, etherificate and hydrolysis four-step reaction, the ammonification water crystallization, and then, obtain D-7-ACA with sodium hydroxide or cephalosporin ester enzymatic lysis with the 7-ACA dissolving.B. the cephalosporin sodium salt obtains 7-ACA solution with D-amino-acid oxidase and glutaryl-7-ACA acylated enzyme catalysis, with the salt acid crystal, and then with the 7-ACA dissolving, obtains D-7-ACA with sodium hydroxide or cephalosporin ester enzymatic lysis.Above-mentioned existing D-7-ACA preparation method: cephalosporin sodium salt (or zinc salt) is grown and all will be experienced to operational path, 7-ACA, three crystallisation processs of D-7-ACA, because the crystallisation process yield losses is many, cause yield low, measuring method a and the b molar yield from the cephalosporin extracting solution to D-7-ACA is respectively 65.2% and 67.8%, in addition, method a adopts chemical cracking, its process consumes a large amount of deep coolings and solvent, and the methylene dichloride that uses in the reaction mass, aniline, chlorosilanes etc. also are poisonous and hazardous strong pollutent, make the production of D-7-ACA will bear heavier energy consumption cost and pollution treatment cost; Method b adopts enzyme process to prepare 7-ACA, and then obtain D-7-ACA with chemical method or enzymatic cleavage, because facing crystalline product during enzymatic cleavage 7-ACA crystallization is clamminess, is difficult to centrifugal and the exsiccant problem, need to add the solvent assisting crystallisation, and use a large amount of separating devices, cause energy consumption and cost of labor to increase.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned the deficiencies in the prior art, and provide that a kind of operational path is short, product yield is high, low cost of manufacture and be applicable to the preparation method of the 3-deacetylate-7-amino-cephalosporanic acid of scale operation.
The present invention solves the technical scheme that its technical problem takes: this operational path is short, product yield is high, low cost of manufacture and be applicable to the preparation method of the 3-deacetylate-7-amino-cephalosporanic acid of scale operation, and it is:
A. be that the cephalosporin extracting solution of 30～50g/L is a raw material with concentration, with D-amino-acid oxidase catalytic preparation glutaryl-7-ACA solution, wherein drop into the charging capacity input 2.5～6.0KU D-amino-acid oxidase of the amount of D-amino-acid oxidase in 1L cephalosporin extracting solution;
B. glutaryl-7-ACA acylase and cephalosporin esterase are mixed in the glutaryl-7-ACA solution of back adding preparation by a certain percentage, catalysis glutaryl-7-ACA makes 3-deacetylate-7-amino-cephalosporanic acid solution, wherein drop into the charging capacity input 3.0～7.0KU glutaryl-7-ACA acylase of the amount of glutaryl-7-ACA acylase, drop into the charging capacity input 1.0～3.5KU cephalosporin esterase of the amount of cephalosporin esterase in 1L cephalosporin extracting solution in 1L cephalosporin extracting solution;
C. obtain solid 3-deacetylate-7-amino-cephalosporanic acid by adding acid crystal, washing, drying.
Concrete preparation process can be:
1. the cephalosporin extracting solution (the cephalosporin concentrated solution that the cephalosporin nanofiltration concentrated solution that sodium bicarbonate is resolved, the cephalosporin nanofiltration concentrated solution that sodium-acetate is resolved or ammonium acetate are resolved) of getting concentration and be 60～100g/L is mixed with the solution of 30～50g/L with no salt solution, puts among the enzyme reactor I;
2. in charging capacity input 2.5～6.0KU D-amino-acid oxidase of 1L cephalosporin extracting solution, taking by weighing the D-amino-acid oxidase puts among the enzyme reactor I, dripping concentration is the ammoniacal liquor of 3mol/L, the pH of reaction control is 7.1～7.6, temperature is 20～28 ℃, oxygen-supply quantity is 0.1～0.3vvm, and tank pressure is 1.0～2.0bar, reaction times 60～120min.After reaction finishes,, the glutaryl-7-ACA solution that generates is transferred among the enzyme reactor II by enzyme reactor bottom screen cloth entrapped enzyme;
3. in charging capacity input 3.0～7.0KU glutaryl-7-ACA acylase, 1.0～3.5KU cephalosporin esterase of 1L cephalosporin extracting solution; take by weighing and put among the enzyme reactor II after glutaryl-7-ACA acylase and cephalosporin esterase mix; dripping concentration is the ammoniacal liquor of 3mol/L; the pH of reaction control is 8.0～8.5; temperature is 20～28 ℃, reaction times 80～110min.After reaction finishes,, the D-7-ACA solution that generates is transferred in the beaker by enzyme reactor bottom screen cloth entrapped enzyme;
4. D-7-ACA solution is cooled to 0～10 ℃; drip 10% hydrochloric acid and regulate pH to 5.0～5.8 to the solution muddiness; growing the grain 30min; continue dripping hydrochloric acid then to pH3.8～4.2; growing the grain 4h; suction filtration, with acetone water mixed liquid washing in 1: 1,40～50 ℃ of drying 2～4h obtained solid 3-deacetylate-7-amino-cephalosporanic acid again.
The preparation method of this 3-deacetylate-7-amino-cephalosporanic acid provided by the present invention; preparation 3-deacetylate-7-amino-cephalosporanic acid only needs two step normal-temperature reaction and one time of crystallization; operational path is short; and do not use solvent substantially; molar yield from the cephalosporin extracting solution to 3-deacetylate-7-amino-cephalosporanic acid can reach 71.5%; the product yield height; in addition; compared with prior art; no matter be energy consumption; or power cost; cost of labor; the environmental protection cost is all much lower than the method a and the b of prior art, uses present method production cost can reduce about 40% than the method a of prior art, can reduce about 30% than the method b of prior art.
Embodiment
Analytical procedure among the embodiment:
1.D-the enzyme activity determination of amino-acid oxidase (DAAO):
Cephalosporin (CPC) solution of preparation 5% (with the phosphoric acid buffer preparation of 100mmol/L pH8.0), get 50ml preparation liquid and place the 100ml beaker, 25 ℃ of controlled temperature, aerating oxygen (flow 40L/h), stir and timing 5min, sampling detects with HPLC, writes down initial cephalosporin peak area.Get 2g D-amino-acid oxidase and pour in the above-mentioned reaction solution, 25 ℃ of controlled temperature, aerating oxygen (flow 40L/h) stirs, timing 10min, sampling detects with HPLC, record cephalosporin peak area.D-amino-acid oxidase enzyme is lived and is defined as: when 1 D-amino-acid oxidase enzyme unit alive (U) was meant 25 ℃, under test condition, per minute transformed the amount of the required enzyme of cephalosporin of 1 μ mol.
2. the enzyme activity determination of glutaryl-7-ACA acylase (GAC):
Glutaryl-7-ACA (GL-7-ACA) solution of preparation 2% (with the phosphoric acid buffer preparation of 50mmol/L pH8.0); get 50ml preparation liquid and place the 100ml beaker; 25 ℃ of controlled temperature; sodium hydroxide control pH8.0 with 0.1mol/L; taking by weighing 0.5g glutaryl-7-ACA acylase pours in the above-mentioned reaction solution; timing 10min, the sodium hydroxide consumption of record 2min, 10min.Glutaryl-7-ACA acidated enzyme is lived and is defined as: 1 glutaryl-7-ACA acidated enzyme unit (U) that lives is meant in the time of 25 ℃, and PH8.0 in 1 minute changes into 1 μ mol glutaryl-7-ACA the amount of the required enzyme of 7-ACA.
3. the enzyme activity determination of cephalosporin esterase (CE):
Cephalosporin (CPC) solution of preparation 5% (with the phosphoric acid buffer preparation of 20mmol/L pH8.0), get 40ml preparation liquid and place the 100ml beaker, 25 ℃ of controlled temperature, sodium hydroxide control pH8.0 with 0.1mol/L, taking by weighing the 0.3g cephalosporin esterase pours in the above-mentioned reaction solution, timing 5min, the sodium hydroxide consumption of record 2min, 5min.The cephalosporin esterase enzyme is lived and to be defined as: 1 cephalosporin esterase enzyme unit (U) that lives is meant in the time of 25 ℃, and PH8.0 in 1 minute changes into 1 μ mol cephalosporin the amount of the required enzyme of deacetylcephalosporinC (D-CPC).
4.HPLC testing conditions
Chromatographic column: C
185 μ m, 250 * 4.6mm
Moving phase: the ammonium acetate buffer of 20mmol/L pH6.0: acetonitrile=960: 40, flow velocity 1.5ml/min
Detect wavelength: 260nm
Detection method: accurately get the 1ml diluted sample to suitable concentration,, inject 20 μ l solution to HPLC with 0.45 μ m membrane filtration.
Retention time: D-CPC 2.0min, D-7-ACA 2.2min, CPC 5.8min, 7-ACA6.8min, GL-7-ACA 9.0min
Embodiment 1
A kind of operational path is short, product yield is high, low cost of manufacture and be applicable to the preparation method of the 3-deacetylate-7-amino-cephalosporanic acid of scale operation, and concrete preparation process is:
1. getting concentration and be cephalosporin nanofiltration concentrated solution that the sodium bicarbonate of 83.3g/L resolves, to prepare 1L concentration with no salt solution be the cephalosporin solution of 31.5g/L, puts among the 1.5L enzyme reactor I;
2. take by weighing 2.5KU D-amino-acid oxidase, with putting into after the salt-free water washing among the enzyme reactor I, stirring velocity 400rpm, ammoniacal liquor control pH with 3mol/L is 7.1～7.5,20 ℃ of temperature, oxygen-supply quantity 0.1vvm, tank pressure 1.0～1.2bar, behind the reaction 60min, change reaction solution among the enzyme reactor II (the D-amino-acid oxidase is held back by enzyme reactor bottom screen cloth);
3. take by weighing 3.0KU glutaryl-7-ACA acylase and 1.0KU cephalosporin esterase respectively and mix the salt-free water washing in back, put among the enzyme reactor II, stirring velocity 400rpm, ammoniacal liquor control pH with 3mol/L is 8.0,20 ℃ of temperature, behind the reaction 80min, change reaction solution in the 2L beaker (glutaryl-7-ACA acylase and cephalosporin esterase are held back by enzyme reactor bottom screen cloth);
4. reaction solution is cooled to 5 ℃; drip 10% hydrochloric acid and regulate pH to 5.56; leave standstill growing the grain 30min; continue dripping hydrochloric acid then to pH4.01, growing the grain 4h, suction filtration; wash secondary with 100ml; with 1: 1 acetone washing secondary of 100ml, 50 ℃ of dry 3h obtain solid 3-deacetylate-7-amino-cephalosporanic acid, total molar yield 72.5%.
Embodiment 2
A kind of operational path is short, product yield is high, low cost of manufacture and be applicable to the preparation method of the 3-deacetylate-7-amino-cephalosporanic acid of scale operation, and concrete preparation process is:
1. getting concentration and be cephalosporin nanofiltration concentrated solution that the sodium-acetate of 95.1g/L resolves, to prepare 1L concentration with no salt solution be the cephalosporin solution of 33.5g/L, puts among the 1.5L enzyme reactor I;
2. take by weighing 4.0KU D-amino-acid oxidase, with putting into after the salt-free water washing among the enzyme reactor I, stirring velocity 400rpm, ammoniacal liquor control pH with 3mol/L is 7.1～7.6,20 ℃ of temperature, oxygen-supply quantity 0.2vvm, tank pressure 1.4～1.5bar, behind the reaction 60min, change reaction solution among the enzyme reactor II (the D-amino-acid oxidase is held back by enzyme reactor bottom screen cloth);
3. take by weighing 5.0KU glutaryl-7-ACA acylase and 2.0KU cephalosporin esterase respectively and mix the salt-free water washing in back, put among the enzyme reactor II, stirring velocity 400rpm, ammoniacal liquor control pH with 3mol/L is 8.5,22 ℃ of temperature, behind the reaction 80min, change reaction solution in the 2L beaker (glutaryl-7-ACA acylase and cephalosporin esterase are held back by enzyme reactor bottom screen cloth);
4. reaction solution is cooled to 5 ℃; drip 10% hydrochloric acid and regulate pH to 5.51; leave standstill growing the grain 30min; continue dripping hydrochloric acid then to pH 4.12, growing the grain 4h, suction filtration; wash secondary with 100ml; with 1: 1 acetone washing secondary of 100ml, 50 ℃ of dry 3h obtain solid 3-deacetylate-7-amino-cephalosporanic acid, total molar yield 73.1%.
Embodiment 3
A kind of operational path is short, product yield is high, low cost of manufacture and be applicable to the preparation method of the 3-deacetylate-7-amino-cephalosporanic acid of scale operation, and concrete preparation process is:
1. getting concentration and be cephalosporin concentrated solution that the ammonium acetate of 67.3g/L resolves, to prepare 1L concentration with no salt solution be the cephalosporin solution of 40.2g/L, puts among the 1.5L enzyme reactor I;
2. taking by weighing 6.0KU D-amino-acid oxidase puts among the enzyme reactor I after with salt-free water washing, stirring velocity 400rpm, ammoniacal liquor control pH with 3mol/L is 7.1～7.6,20 ℃ of temperature, oxygen-supply quantity 0.3vvm, tank pressure 1.4～1.5bar behind the reaction 70min, changes reaction solution among the enzyme reactor II (the D-amino-acid oxidase is held back by enzyme reactor bottom screen cloth);
3. take by weighing 7.0KU glutaryl-7-ACA acylase and 3.5KU cephalosporin esterase respectively and mix the salt-free water washing in back, put among the enzyme reactor II, stirring velocity 400rpm, ammoniacal liquor control pH with 3mol/L is 8.5,28 ℃ of temperature, behind the reaction 80min, change reaction solution in the 2L beaker (glutaryl-7-ACA acylase and cephalosporin esterase are held back by enzyme reactor bottom screen cloth);
4. reaction solution is cooled to 5 ℃; drip 10% hydrochloric acid and regulate pH to 5.70; leave standstill growing the grain 30min; continue dripping hydrochloric acid then to pH3.91, growing the grain 4h, suction filtration; wash secondary with 100ml; with 1: 1 acetone washing secondary of 100ml, 50 ℃ of dry 3h obtain solid 3-deacetylate-7-amino-cephalosporanic acid, total molar yield 71.5%.
Claims (6)
1. the preparation method of a 3-deacetylate-7-amino-cephalosporanic acid is characterized in that:
A. be that the cephalosporin extracting solution of 30～50g/L is a raw material with concentration, with D-amino-acid oxidase catalytic preparation glutaryl-7-ACA solution, wherein drop into the charging capacity input 2.5～6.0KU D-amino-acid oxidase of the amount of D-amino-acid oxidase in 1L cephalosporin extracting solution;
B. glutaryl-7-ACA acylase and cephalosporin esterase are mixed in the glutaryl-7-ACA solution of back adding preparation by a certain percentage, catalysis glutaryl-7-ACA makes 3-deacetylate-7-amino-cephalosporanic acid solution, wherein drop into the charging capacity input 3.0～7.0KU glutaryl-7-ACA acylase of the amount of glutaryl-7-ACA acylase, drop into the charging capacity input 1.0～3.5KU cephalosporin esterase of the amount of cephalosporin esterase in 1L cephalosporin extracting solution in 1L cephalosporin extracting solution;
C. obtain solid 3-deacetylate-7-amino-cephalosporanic acid by adding acid crystal, washing, drying.
2. the preparation method of 3-deacetylate-7-amino-cephalosporanic acid according to claim 1 is characterized in that: the cephalosporin concentrated solution that cephalosporin nanofiltration concentrated solution that the cephalosporin nanofiltration concentrated solution that the cephalosporin extracting solution that uses is resolved as sodium bicarbonate, sodium-acetate are resolved or ammonium acetate are resolved.
3. the preparation method of 3-deacetylate-7-amino-cephalosporanic acid according to claim 1; it is characterized in that: be raw material with the cephalosporin extracting solution; in the process with D-amino-acid oxidase catalytic preparation glutaryl-7-ACA solution; dripping concentration is the ammoniacal liquor of 3mol/L; the pH of reaction control is 7.1～7.6, and temperature is 20～28 ℃, and oxygen-supply quantity is 0.1～0.3vvm; tank pressure is 1.0～2.0bar, reaction times 60～120min.
4. according to the preparation method of claim 1 or 3 described 3-deacetylate-7-amino-cephalosporanic acids; it is characterized in that: making in the process of 3-deacetylate-7-amino-cephalosporanic acid solution with glutaryl-7-ACA acylase and cephalosporin ester enzyme catalysis glutaryl-7-ACA; dripping concentration is the ammoniacal liquor of 3mol/L; the pH of reaction control is 8.0～8.5; temperature is 20～28 ℃, reaction times 80～110min.
5. according to the preparation method of claim 1 or 3 described 3-deacetylate-7-amino-cephalosporanic acids; it is characterized in that: it is to regulate pH to 5.0～5.8 by drip 10% hydrochloric acid in the 3-deacetylate-7-amino-cephalosporanic acid solution that makes; growing the grain 30min; continue dripping hydrochloric acid then to pH 3.8～4.2; growing the grain 4h; suction filtration, with the washing of 1: 1 acetone water mixed liquid, 40～50 ℃ of drying 2～4h obtain solid 3-deacetylate-7-amino-cephalosporanic acid again.
6. the preparation method of 3-deacetylate-7-amino-cephalosporanic acid according to claim 4; it is characterized in that: it is to regulate pH to 5.0～5.8 by drip 10% hydrochloric acid in the 3-deacetylate-7-amino-cephalosporanic acid solution that makes; growing the grain 30min; continue dripping hydrochloric acid then to pH 3.8～4.2; growing the grain 4h; suction filtration, with the washing of 1: 1 acetone water mixed liquid, 40～50 ℃ of drying 2～4h obtain solid 3-deacetylate-7-amino-cephalosporanic acid again.
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| CN102321721A (en) * | 2011-10-25 | 2012-01-18 | 石药集团河北中润制药有限公司 | Process for preparing 3-deacetylate-7-aminocephalosporanic acid |
| CN102505035A (en) * | 2011-10-25 | 2012-06-20 | 石药集团河北中润制药有限公司 | Preparation process of 3-deacetylated-7-amino-cephalosporanic acid |
| CN102827912A (en) * | 2012-08-31 | 2012-12-19 | 山东鲁抗立科药业有限公司 | Technology for preparing medicine intermediate D-7-ACA by two enzyme carriers one-step method |
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| CN110964770A (en) * | 2018-09-29 | 2020-04-07 | 北京科技大学 | Method for continuously preparing 3-deacetyl-7-aminocephalosporanic acid |
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| CN102505035A (en) * | 2011-10-25 | 2012-06-20 | 石药集团河北中润制药有限公司 | Preparation process of 3-deacetylated-7-amino-cephalosporanic acid |
| CN102321721B (en) * | 2011-10-25 | 2013-09-11 | 石药集团中诺药业（石家庄）有限公司 | Process for preparing 3-deacetylate-7-aminocephalosporanic acid |
| CN102505035B (en) * | 2011-10-25 | 2014-07-09 | 石药集团中诺药业（石家庄）有限公司 | Preparation process of 3-deacetylated-7-amino-cephalosporanic acid |
| CN102827912A (en) * | 2012-08-31 | 2012-12-19 | 山东鲁抗立科药业有限公司 | Technology for preparing medicine intermediate D-7-ACA by two enzyme carriers one-step method |
| CN102827912B (en) * | 2012-08-31 | 2014-06-25 | 山东鲁抗立科药业有限公司 | Technology for preparing medicine intermediate D-7-ACA by two enzyme carriers one-step method |
| CN110214188A (en) * | 2016-08-26 | 2019-09-06 | 艾美科健株式会社 | The high concentration production of 7-amino-cephalosporanic acid recombinates the manufacturing method of cephalosporium acremonium bacterial strain and utilizes bacterial strain manufactured by its method |
| CN110214188B (en) * | 2016-08-26 | 2023-06-06 | 艾美科健株式会社 | Method for producing recombinant Cephalosporium acremonium strain with high concentration of 7-aminocephalosporanic acid and strain produced by using method |
| CN110964770A (en) * | 2018-09-29 | 2020-04-07 | 北京科技大学 | Method for continuously preparing 3-deacetyl-7-aminocephalosporanic acid |
| CN110317215A (en) * | 2019-07-26 | 2019-10-11 | 伊犁川宁生物技术有限公司 | A method of reducing DO-7-ACA impurity content in D-7-ACA |
| CN111875621A (en) * | 2020-08-26 | 2020-11-03 | 山东鲁抗医药股份有限公司 | Preparation method of cephalosporin salt for injection |
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