WO1996023897A1 - PROCESS FOR THE PREPARATION OF A β-LACTAM ANTIBIOTIC - Google Patents
PROCESS FOR THE PREPARATION OF A β-LACTAM ANTIBIOTIC Download PDFInfo
- Publication number
- WO1996023897A1 WO1996023897A1 PCT/NL1996/000052 NL9600052W WO9623897A1 WO 1996023897 A1 WO1996023897 A1 WO 1996023897A1 NL 9600052 W NL9600052 W NL 9600052W WO 9623897 A1 WO9623897 A1 WO 9623897A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- enzyme
- lactam
- acylation
- process according
- core
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 31
- 239000003782 beta lactam antibiotic agent Substances 0.000 title claims abstract description 18
- 239000002132 β-lactam antibiotic Substances 0.000 title claims abstract description 18
- 229940124586 β-lactam antibiotics Drugs 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 108090000790 Enzymes Proteins 0.000 claims abstract description 66
- 102000004190 Enzymes Human genes 0.000 claims abstract description 66
- 238000005917 acylation reaction Methods 0.000 claims abstract description 35
- 230000010933 acylation Effects 0.000 claims abstract description 26
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 150000003952 β-lactams Chemical group 0.000 claims abstract description 22
- 239000011541 reaction mixture Substances 0.000 claims abstract description 13
- 230000002255 enzymatic effect Effects 0.000 claims abstract description 9
- 150000001450 anions Chemical class 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims description 11
- KIYRSYYOVDHSPG-SSDOTTSWSA-N (2r)-2-amino-2-phenylacetamide Chemical compound NC(=O)[C@H](N)C1=CC=CC=C1 KIYRSYYOVDHSPG-SSDOTTSWSA-N 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 108010093096 Immobilized Enzymes Proteins 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims 2
- -1 amino acid ester Chemical class 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 28
- 238000004448 titration Methods 0.000 description 23
- NVIAYEIXYQCDAN-CLZZGJSISA-N 7beta-aminodeacetoxycephalosporanic acid Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)[C@@H](N)[C@@H]12 NVIAYEIXYQCDAN-CLZZGJSISA-N 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 238000002474 experimental method Methods 0.000 description 17
- 230000007423 decrease Effects 0.000 description 15
- 238000004064 recycling Methods 0.000 description 13
- 230000035484 reaction time Effects 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 108700023418 Amidases Proteins 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- WRUZLCLJULHLEY-UHFFFAOYSA-N N-(p-hydroxyphenyl)glycine Chemical compound OC(=O)CNC1=CC=C(O)C=C1 WRUZLCLJULHLEY-UHFFFAOYSA-N 0.000 description 3
- 108010073038 Penicillin Amidase Proteins 0.000 description 3
- 102000005922 amidase Human genes 0.000 description 3
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 3
- 229940106164 cephalexin Drugs 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- PYHRZPFZZDCOPH-QXGOIDDHSA-N (S)-amphetamine sulfate Chemical compound [H+].[H+].[O-]S([O-])(=O)=O.C[C@H](N)CC1=CC=CC=C1.C[C@H](N)CC1=CC=CC=C1 PYHRZPFZZDCOPH-QXGOIDDHSA-N 0.000 description 2
- GXBRYTMUEZNYJT-UHFFFAOYSA-N 2-anilinoacetamide Chemical compound NC(=O)CNC1=CC=CC=C1 GXBRYTMUEZNYJT-UHFFFAOYSA-N 0.000 description 2
- 241000589220 Acetobacter Species 0.000 description 2
- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 2
- 229910017974 NH40H Inorganic materials 0.000 description 2
- 241000589634 Xanthomonas Species 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- WNPVZANXRCPJPW-UHFFFAOYSA-N 5-[isocyano-(4-methylphenyl)sulfonylmethyl]-1,2,3-trimethoxybenzene Chemical class COC1=C(OC)C(OC)=CC(C([N+]#[C-])S(=O)(=O)C=2C=CC(C)=CC=2)=C1 WNPVZANXRCPJPW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 241000607534 Aeromonas Species 0.000 description 1
- 241000726092 Aphanocladium Species 0.000 description 1
- 241001619326 Cephalosporium Species 0.000 description 1
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 241000589565 Flavobacterium Species 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 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 description 1
- 241000586779 Protaminobacter Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001370 alpha-amino acid derivatives Chemical class 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
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin 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=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- IYNDLOXRXUOGIU-LQDWTQKMSA-M benzylpenicillin potassium Chemical compound [K+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 IYNDLOXRXUOGIU-LQDWTQKMSA-M 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 1
- 229960005361 cefaclor Drugs 0.000 description 1
- 229960002588 cefradine Drugs 0.000 description 1
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical class S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 description 1
- RDLPVSKMFDYCOR-UEKVPHQBSA-N cephradine Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CCC=CC1 RDLPVSKMFDYCOR-UEKVPHQBSA-N 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- SZJUWKPNWWCOPG-UHFFFAOYSA-N methyl 2-anilinoacetate Chemical compound COC(=O)CNC1=CC=CC=C1 SZJUWKPNWWCOPG-UHFFFAOYSA-N 0.000 description 1
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 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
- 150000005331 phenylglycines Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- 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
- C12P35/00—Preparation of compounds having a 5-thia-1-azabicyclo [4.2.0] octane ring system, e.g. cephalosporin
Definitions
- the invention relates to a process for the preparation of a ⁇ -lactam antibiotic by enzymatic acylation of a ⁇ -lactam core by means of an acylation agent.
- the enzyme to be applied should be suitable to be re-used many times (for instance more than 50 times, in particular more than 100 times) without much loss of activity.
- the object of the invention is to obtain a process for the enzymatic acylation of a ⁇ -lactam core whereby said drawback is eliminated.
- the enzyme activity in successive cycles depends on the concentration of the inorganic salts in the reaction mixture during the enzymatic acylation reaction, as well as on the sum of the concentrations of the ⁇ -lactam antibiotic and the ⁇ -lactam core.
- ⁇ -lactam cores that can be used in the process according to the invention are penicillic acid derivatives, for instance 6- aminopenicillic acid (6-APA), and cephalosporanic acid derivatives, for instance 7-aminocephalosporanic acid (7- ACA), 7-aminodesacetoxy-cephalosporanic acid (7-ADCA) and 7-amino-3-chlorocephalosporanic (7-ACCA) .
- penicillic acid derivatives for instance 6- aminopenicillic acid (6-APA)
- cephalosporanic acid derivatives for instance 7-aminocephalosporanic acid (7- ACA), 7-aminodesacetoxy-cephalosporanic acid (7-ADCA) and 7-amino-3-chlorocephalosporanic (7-ACCA) .
- Suitable acylation agents that can be used in the process according to the invention are for instance ⁇ - amino acid derivatives, in particular amides and esters of phenyl glycine, p-hydroxyphenyl glycine and dihydrophenyl glycine.
- any enzyme can be used that is suitable as catalyst in the coupling reaction.
- Such enzymes are for instance the enzymes that are known under the general designations 'penicillin amidase' and 'penicillin acylase'.
- suitable enzymes are enzymes derived from Acetobacter, Aeromonas, Alcali ⁇ enes, Aphanocladium, Bacillus SD. , Cephalosporium. Escherichia. Flavobacterium, Kluvvera, Mvcoplana, Protaminobacter, Pseudomonas and Xanthomonas, in particular Acetobacter pasteurianum, Alcali ⁇ enes faecalis, Bacillus me ⁇ aterium.
- Escherichia coli and Xanthomonas citrii Preferably an immobilized enzyme is used, since the enzyme can be easily re-used then. Immobilized enzymes are known as such and are commercially available. Highly suitable enzymes have appeared to be the Escherichia coli enzyme from Boehringer Mannheim GmbH, which is commercially available under the name 'Enzygel*', the immobilized Penicillin-G acylase from Recordati, the immobilized Penicilline-G acylase from Pharma Biotechnology Hannover, and an Escheria coli penicilline acylase isolated as described in WO-A-92/12782 and immobilised as described in EP-A-222462.
- the enzymatic acylation reaction is mostly carried out at a temperature between -5 and 35°C, in particular between 5 and 35°C preferably between 0 and 28°C, most preferably between 15 and 28°C.
- the pH at which the acylation reaction is carried out is mostly between 6 and 8.5.
- the optimum pH depends on, among other things, the antibiotic, since the stability and the solubility of the ⁇ -lactam antibiotic as well as the ⁇ -lactam core depend on the pH.
- the pH is preferably between 6.2 and 8.5, most preferably between 7 and 8; if a p-hydroxyphenyl glycine derivative is used as acylation agent the pH is preferably between 6 and 7.5, most preferably between 6 and 7.
- the enzyme activity is also pH-related.
- the acylation reaction is mostly carried out in water.
- the reaction mixture may also contain an organic solvent or a mixture of organic solvents, preferably less than 30 vol.%.
- organic solvents that can be used are alcohols with 1-7 carbon atoms, for instance a monoalcohol, in particular methanol or ethanol; a diol, in particular ethylene glycol or a triol, in particular glycerol.
- concentration of the ⁇ -lactam antibiotic and the concentration of the ⁇ -lactam core are chosen such that the sum of the two concentrations is between 200 and 800 mM.
- concentrations are chosen such that the sum of the two concentrations is between 300 and 700, most preferably between 300 and 600 mM.
- the molar ratio between the acylating agent and the ⁇ -lactam core is between 0.5:1 and 2:1, preferably between 0.7:1 and 1.3:1, most preferably between 0.8:1 and 1.2:1.
- the molar ratio between the acylating agent and the ⁇ -lactam core is preferably chosen such that the pH of the reaction mixture throughout the process does not exceed the above-mentioned limits, without titration with acid.
- inorganic salts will accumulate in the reaction mixture in the presence of anions, for instance Cl", S0 4 2 ", P0 4 3 ", N0 3 ". It has been found that if the concentration of inorganic salts becomes too high, for instance higher than 1000:n mM, where n is the valency of the anion, the enzyme activity declines strongly after several cycles.
- concentration of inorganic salts in the process according to the invention is therefore kept below 1000:n mM, preferably below 700:n mM, with n as defined above, which implies that for chlorides and nitrates n is 1 and for sulphates it is 2. In order to keep the concentration of inorganic salts low, it is preferred to ensure that the amount of inorganic salts formed during the enzymatic acylation reaction is restricted to a minimum.
- acylation agents are phenyl glycine and p-hydroxyphenyl glycine derivatives, for instance their amides or esters.
- these are often used in the form of the salt of a strong acid, for instance phenyl glycine amide.HC1, phenyl glycine amide.*$H 2 S0 4 , phenyl glycine methyl ester.HC1 or dihydrophenyl glycine methyl ester.HC1.
- the free amide or the free ester is preferably used in order to prevent the formation of additional inorganic salts as a result of neutralization of the salts of the acylation agents.
- Free amides in solid form are particularly suitable for this purpose.
- D-PGA D-phenyl glycine
- Enzyme recycling experiment with 600 mM of D-PGA and 400 mM of 7-ADCA, pH 7.5 - ⁇ 7.8, and titration with 12N H 2 S0 4 .
- Carried out analogously to example I with 20 g of wet enzyme and a feed consisting of 45.0 g of free D- PGA, 43.7 g of 7-ADCA, 1.8 g of D-PG, 413 ml of water and 5 ml of 25 mass% aqueous NH 4 0H.
- Initial pH - 7.6, final pH 7.8, kept constant by means of titration with 12N H 2 S0 4 . Reaction time: 2 hours.
- Enzyme recycling experiment with 600 mM of D-PGA.> $ H 2 S0 4 and 400 mM of 7-ADCA, pH 7.2 - ⁇ 7.5, in the presence of 100 mM of (NH 4 ) 2 S0 4 .
- Enzyme recycling experiment with 500 mM of D-PGA and 500 mM of 7-ADCA, pH 7.3 ⁇ 7.4, in the presence of 1000 mM of NH 4 C1.
- Example IX Enzyme recycling experiment with 400 mM of D-PGA and 400 mM Of 7-ADCA, pH 7.3 ⁇ * 7.8.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Wood Science & Technology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (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)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU48462/96A AU4846296A (en) | 1995-02-02 | 1996-02-01 | Process for the preparation of a beta -lactam antibiotic |
| EP96904337A EP0815256A1 (en) | 1995-02-02 | 1996-02-01 | Process for the preparation of a beta-lactam antibiotic |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BE9500081A BE1009071A3 (nl) | 1995-02-02 | 1995-02-02 | Werkwijze voor de bereiding van een beta-lactam antibioticum. |
| BE9500081 | 1995-02-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996023897A1 true WO1996023897A1 (en) | 1996-08-08 |
Family
ID=3888755
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/NL1996/000052 WO1996023897A1 (en) | 1995-02-02 | 1996-02-01 | PROCESS FOR THE PREPARATION OF A β-LACTAM ANTIBIOTIC |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0815256A1 (enrdf_load_stackoverflow) |
| AU (1) | AU4846296A (enrdf_load_stackoverflow) |
| BE (1) | BE1009071A3 (enrdf_load_stackoverflow) |
| IN (2) | IN181940B (enrdf_load_stackoverflow) |
| WO (1) | WO1996023897A1 (enrdf_load_stackoverflow) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999020786A1 (en) * | 1997-10-17 | 1999-04-29 | Dsm N.V. | PROCESS FOR THE PREPARATION OF A β-LACTAM ANTIBIOTIC |
| US6218138B1 (en) * | 1998-05-26 | 2001-04-17 | Unifar Kimya Sanayi Ve Ticaret A.S. | Synthesis of beta-lactam antibiotics with immobilized penicillin amidase |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991009136A1 (es) * | 1989-12-12 | 1991-06-27 | Consejo Superior Investigaciones Cientificas | Procedimiento de sintesis de antibioticos semisinteticos en sistemas termodinamicamente controlados agua-cosolventes organicos miscibles apolares con el empleo de penicilina g acilasa |
| WO1992001061A1 (en) * | 1990-07-04 | 1992-01-23 | Novo Nordisk A/S | PROCESS FOR PREPARATION OF β-LACTAMS |
-
1995
- 1995-02-02 BE BE9500081A patent/BE1009071A3/nl not_active IP Right Cessation
-
1996
- 1996-02-01 EP EP96904337A patent/EP0815256A1/en not_active Ceased
- 1996-02-01 WO PCT/NL1996/000052 patent/WO1996023897A1/en not_active Application Discontinuation
- 1996-02-01 IN IN162MA1996 patent/IN181940B/en unknown
- 1996-02-01 AU AU48462/96A patent/AU4846296A/en not_active Abandoned
- 1996-02-01 IN IN161MA1996 patent/IN182469B/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991009136A1 (es) * | 1989-12-12 | 1991-06-27 | Consejo Superior Investigaciones Cientificas | Procedimiento de sintesis de antibioticos semisinteticos en sistemas termodinamicamente controlados agua-cosolventes organicos miscibles apolares con el empleo de penicilina g acilasa |
| WO1992001061A1 (en) * | 1990-07-04 | 1992-01-23 | Novo Nordisk A/S | PROCESS FOR PREPARATION OF β-LACTAMS |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999020786A1 (en) * | 1997-10-17 | 1999-04-29 | Dsm N.V. | PROCESS FOR THE PREPARATION OF A β-LACTAM ANTIBIOTIC |
| US6287799B1 (en) | 1997-10-17 | 2001-09-11 | Dsm N.V. | Process for the preparation of aβ-lactam antibiotic |
| US6218138B1 (en) * | 1998-05-26 | 2001-04-17 | Unifar Kimya Sanayi Ve Ticaret A.S. | Synthesis of beta-lactam antibiotics with immobilized penicillin amidase |
Also Published As
| Publication number | Publication date |
|---|---|
| IN181940B (enrdf_load_stackoverflow) | 1998-11-14 |
| AU4846296A (en) | 1996-08-21 |
| BE1009071A3 (nl) | 1996-11-05 |
| IN182469B (enrdf_load_stackoverflow) | 1999-04-17 |
| EP0815256A1 (en) | 1998-01-07 |
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