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WO1998056945A1 - PROCEDE DE PREPARATION D'UNE β-LACTAMINE PAR ACTION ENZYMATIQUE ET ANTIBIOTIQUE AINSI PRODUIT - Google Patents

PROCEDE DE PREPARATION D'UNE β-LACTAMINE PAR ACTION ENZYMATIQUE ET ANTIBIOTIQUE AINSI PRODUIT Download PDF

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Publication number
WO1998056945A1
WO1998056945A1 PCT/EP1998/003629 EP9803629W WO9856945A1 WO 1998056945 A1 WO1998056945 A1 WO 1998056945A1 EP 9803629 W EP9803629 W EP 9803629W WO 9856945 A1 WO9856945 A1 WO 9856945A1
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WIPO (PCT)
Prior art keywords
acid
enzyme
lactam
amount
process according
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PCT/EP1998/003629
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English (en)
Inventor
Thomas Van Der Does
Riesk Hendrik Kuipers
Adrianus Franciscus Michael Slobbe
Harold Monro Moody
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Dsm N.V.
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Priority to AU87994/98A priority Critical patent/AU8799498A/en
Publication of WO1998056945A1 publication Critical patent/WO1998056945A1/fr

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    • 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
    • C12P35/04—Preparation of compounds having a 5-thia-1-azabicyclo [4.2.0] octane ring system, e.g. cephalosporin by acylation of the substituent in the 7 position
    • 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
    • C12P37/04—Preparation of compounds having a 4-thia-1-azabicyclo [3.2.0] heptane ring system, e.g. penicillin by acylation of the substituent in the 6 position

Definitions

  • the invention relates to a process for enzymatically preparing a ⁇ -lactam antibiotic and to a ⁇ -lactam antibiotic obtainable thereby.
  • ⁇ -lactam antibiotics such as penicillin and cephalosporin antibiotics
  • This class of antibiotics comprises a great variety of compounds, all having their own activity profile.
  • ⁇ -lactam antibiotics consist of a nucleus, the so-called ⁇ -lactam nucleus, which is linked through its primary amino group to the so-called side chain via a linear amide bond.
  • ⁇ -lactam antibiotics as used herein includes fermentation products, such as penicillin G, penicillin V, cephalosporin C, isopenicillin N, intermediate products such as adipyl-6-aminopenicillanic acid (adipyl-6-APA), adipyl-7-aminodesacetoxycephalosporanic acid (adipyl-7-ADCA), adipyl-7-aminocephalosporanic acid (adipyl-7-ACA), adipyl-7-aminodesacetylcephalosporanic acid (adipyl-7-ADAC),
  • fermentation products such as penicillin G, penicillin V, cephalosporin C, isopenicillin N
  • intermediate products such as adipyl-6-aminopenicillanic acid (adipyl-6-APA), adipyl-7-aminodesacetoxycephalosporanic acid (adipyl-7-ADCA), adipyl-7-aminocephalospora
  • 3-carboxyethylthiopropionyl-7-aminodesacetoxycephalosporanic acid and semi-synthetic products such as Ampicillin, Amoxycillin, Cephalexin, Cephacior and Cephadroxyl.
  • ⁇ -lactam antibiotics have been prepared in chemical procedures.
  • chemical methods have a number of grave disadvantages. They comprise many complex reactions, in which by-products which give rise to effluent and purification problems are formed. Also, because many steps have to be performed in order to obtain the final antibiotic product, the overall yield is quite low.
  • the semi-synthetic routes mostly start from fermentation products such as isopenicillin N, penicillin G, penicillin V and cephalosporin C, which are enzymatically converted to a ⁇ -lactam nucleus, for instance in a manner as has been disclosed in K. Matsumoto, Bioprocess. Technol., J_6, ( 1 993), 67-88, J.G. Shewale & H. Sivaraman, Process Biochemistry, August 1 989, 1 46-1 54, T.A. Savidge, Biotechnology of Industrial Antibiotics (Ed. E.J. Vandamme) Marcel Dekker, New York, 1 984, or J.G. Shewale et al., Process Biochemistry International, June 1 990, 97-103.
  • the obtained ⁇ -lactam nucleus is subsequently converted to the desired antibiotic by coupling to a suitable side chain, as has been described in inter alia EP-A-0 339 751 , JP-A-53 005 1 85 and CH-A-640 240.
  • a suitable side chain as has been described in inter alia EP-A-0 339 751 , JP-A-53 005 1 85 and CH-A-640 240.
  • a D-(-)-phenylglycine side chain may be attached to a 6-aminopenicillanic acid (6-APA) nucleus, in a reaction with a suitable derivative of said D-(-)-phenylglycine acid, to yield Ampicillin, or to a 7-aminodesacetoxycephalosporanic acid (7-ADCA) nucleus to yield Cephalexin.
  • 6-APA 6-aminopenicillanic acid
  • 7-ADCA 7-aminodesacetoxycephalosporanic acid
  • the known enzymatic methods for preparing ⁇ -lactam antibiotics all involve the preparation of a ⁇ -lactam intermediate and the subsequent coupling thereof to a suitable side chain, e.g. in a reaction with a suitable precursor for the desired side chain.
  • References for enzymatic synthesis are: T.A. Savidge, Biotechnology of Industrial Antiobiotics (Ed. E.J. Vandamme) Marcel Dekker, New York 1 984, J.G. Shewale et al., Process Biochemistry International, June 1 990 97-1 03, E.J. Vandamme, Advances in Applied Microbiology, 2J_, (1 977), 89-1 23 and E.J. Vandamme, Enzyme Microb.
  • a problem that is often encountered in the enzymatic conversion of ⁇ -lactam nuclei to ⁇ -lactam antibiotics is the degradation of one or more of the used reactants.
  • the ⁇ -lactam nucleus starting material often decomposes under the reaction conditions usually applied for the conversion reaction.
  • up to 1 0% of the ⁇ -lactam antibiotic production may be lost.
  • the efficiency and economic feasibility of the enzymatic preparation of ⁇ -lactam antibiotics is adversely affected by the degradation reactions.
  • the invention provides a process for enzymatically preparing a ⁇ -lactam antibiotic from a ⁇ -lactam nucleus or a salt thereof and a precursor for a side chain, wherein a large amount of enzyme is used, which amount is at least twice the amount that is normally used.
  • an amount is intended which significantly exceeds the amounts which are generally applied for enzymatic conversions. More in detail, by a large amount of enzyme, an amount is intended which amount is at least twice the amount that is normally used. Due to the high activity and specificity of enzymes on the one hand and the cost of enzymes on the other hand, it is common practice to normally use enzymes in very small amounts. These amounts are often referred to as "catalytic amounts” and lie in the range of 0.1 to 5 mol%, based on one of the reactants in question. In accordance with the invention, it has been found that by using an amount of enzyme which significantly exceeds these usual catalytic amounts, viz.
  • an “amount” of enzyme as used herein may be expressed in terms of mass or volume enzyme in relation to the amount of reaction mixture, or in terms of enzyme activity.
  • the enzyme is present in an amount of at least about 60 ASU per litre reaction mixture.
  • the unit ASU, or Amoxicillin Synthesis Unit is defined herein as the activity required for formation of 1 g amoxicillin trihydrate per hour at 20 ° C and a pH of approximately 6.3, from 6-APA and D-4-hydroxyphenylgiycine methyl ester.
  • the amount of enzyme to be used is defined in terms of activity.
  • the enzyme is present in an amount of at least about 60 ASU, preferably at least about 1 00 ASU, more preferably at least about 1 20 ASU, per litre reaction mixture.
  • the enzyme is present in an amount of at least about 200 grams wet nett weight of enzyme per litre reaction mixture, preferably about 250 grams wet nett weight of enzyme per litre reaction mixture, which usually corresponds to about 20 vol.%, more preferably about 25 vol.%, based on the reaction volume.
  • the upper limit of the amount of enzyme to be used is determined by the amount which can physically be introduced in a reaction vessel wherein the process is to be performed and at which amount of enzyme there remains sufficient space for the other reactants present in a process according to the invention. In practice, this amount will be between about 330 and about 500 grams wet nett weight of enzyme per litre reaction mixture.
  • an enzyme which has an activity of at least about 300, preferably more than about 400 ASU per kilogram nett wet weight. It was found that an enzyme having the above specified activity is particularly suitable for suppressing the degradation of any reactants in the preparation of a ⁇ -lactam antibiotic, when used in a large amount.
  • a ⁇ -lactam antibiotic is prepared starting from a ⁇ -lactam nucleus or a salt thereof.
  • Ro is hydrogen or C 1 .3 alkoxy
  • Y is CH 2 , oxygen, sulphur, or an oxidized form of sulphur
  • Ri is hydrogen, hydroxy, halogen, d- 3 alkoxy, optionally substituted, optionally containing one or more heteroatoms, saturated or unsaturated, branched or straight C1.5 alkyl, optionally substituted, optionally containing one or more heteroatoms, C 5 . 8 cycloalkyi, optionally substituted aryl or heteroaryl, or optionally substituted benzyl, is preferably used as starting material.
  • an oxidized form of sulphur is meant to include groups such as sulfoxide and sulphone.
  • groups such as sulfoxide and sulphone.
  • alkyl, cycloalkyi, aryl, heteroaryl and benzyl, groups are intended, which have substituents such as alkyl groups of from 1 to 3 carbon atoms, halogen or hydroxy.
  • Formula ( I ) is intended to encompass all ⁇ -lactam nuclei as disclosed in "Cephalosporins and Penicillins, Chemistry and Biology", Ed. E.H. Flynn, Academic Press, 1 972, pages 1 51 -1 66, and "The Organic Chemistry of ⁇ -Lactams", Ed. G.I. Georg, VCH, 1 992, pages 89-96, which are incorporated herein by reference.
  • a suitable salt of a ⁇ -lactam nucleus to be converted in accordance with the invention is any non-toxic salt, such as an alkali metal salt (e.g. lithium, potassium, sodium), an alkali earth metal salt (e.g. calcium, magnesium), an ammonium salt, or an organic base salt (e.g. trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, ⁇ , ⁇ '-dibenzyl diethyiene diamine).
  • an alkali metal salt e.g. lithium, potassium, sodium
  • an alkali earth metal salt e.g. calcium, magnesium
  • an ammonium salt e.g. trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, ⁇ , ⁇ '-dibenzyl diethyiene diamine.
  • the ⁇ -lactam nucleus is a cephalosporanic acid, a penicillanic acid, or a salt thereof.
  • Most preferred ⁇ -lactam nuclei are 6-aminopenicillanic acid (6-APA), 7-aminocephalosporanic acid (7-ACA), 3-chloro-7-aminodesacetoxydesmethylcephalosporanic acid (7-ACCA), 7-aminodesacetylcephalosporanic acid (7-ADAC), 7-aminodesacetoxycephalo- sporanic acid (7-ADCA), or
  • the ⁇ -lactam nucleus that is used to prepare a ⁇ -lactam antibiotic in a method according to the invention may be obtained by enzymatic hydrolysis of a fermentation product, such as penicillin V, penicillin G, isopenicillin N or cephalosporin C, or a ring enlarged analogue thereof, such as V-DCA or G-DCA, or a derivative thereof, as for instance has been described in EP-A-0 532 341 .
  • a fermentation product such as penicillin V, penicillin G, isopenicillin N or cephalosporin C
  • a ring enlarged analogue thereof such as V-DCA or G-DCA, or a derivative thereof, as for instance has been described in EP-A-0 532 341 .
  • any by-products resulting therefrom such as phenylacetic acid or phenoxyacetic acid, are removed to an extent, which is sufficient for the efficiency of the enzymatic preparation of a ⁇ -lactam antibiotic to be not unacceptably adversely affected by the presence of said by-products.
  • the person skilled in the art will be able to determine to what extent said by-products need to be removed in order to obtain the most economically feasible process.
  • the ⁇ -lactam nucleus starting material is in accordance with the invention reacted with a precursor for a side chain.
  • This precursor for a side chain is chosen such that, starting from a certain ⁇ -lactam nucleus starting material, a ⁇ -lactam antibiotic having a desired activity profile is obtained.
  • Preferred precursors for a side chain in accordance with the invention are D-(-)-phenylglycine, D-(-)-4-hydroxyphenylglycine,
  • the precursor for a side chain is preferably an activated form, such as an ester or amide, of the side chain.
  • Suitable esters in this respect are for instance lower alkyl esters, such as methyl, ethyl, n-propyl or isopropyl esters.
  • Suitable amides are in this respect for instance amides which are unsubstituted or substituted at the -CONH 2 group.
  • the precursor for a side chain may also be a salt, e.g. an HCI or an H 2 S0 4 salt, of the side chain, or of an ester or amide thereof. It is possible to use the precursor in an activated form, but it is also possible that an activated form is formed in situ.
  • the enzyme which is used for enzymatically preparing a ⁇ -lactam antibiotic in accordance with the invention may be any enzyme catalyzing the reaction in question. Suitable enzymes are for instance those that have been referred to as penicillin amidase or penicillin acylase in the literature, and those that have been classified as E.C. 3.5.1 .1 1 .
  • the enzyme may also be a so-called ampicillin hydrolase, acylase or amidase.
  • Organisms that have been found to produce penicillin acylase are, for example, Acetobacter, Aeromonas, Alcaligenes, Aphanocladium, Bacillus sp., Cephalosporium, Escherichia, Flavobacterium, Kluyvera, Mycoplana, Protaminobacter, Pseudomonas or Xanthomonas species.
  • Enzymes derived from Acetobacter pasteurianum, Alcaligenes faecalis, Bacillus megaterium, Escherichia coli, Kluyvera citrophila and Xanthomonas citrii have particularly proven to be successful in a method according to the invention.
  • the enzyme may be used as free enzyme, but it is preferred to use it in a suitable reusable form, such as an entrapped or immobilized form, for instance as has been described in WO-A-97/04086.
  • a suitable reusable form such as an entrapped or immobilized form
  • functional equivalents of the enzyme wherein for instance properties of the enzyme, such as pH dependence, thermostability or specific activity is affected by chemical modification or cross-linking, without significant consequences for the activity, in kind, not in amount, of the enzymes in a method according to the invention.
  • functional equivalents such as mutants or other derivatives, obtained by classic means or via recombinant DNA methodology, biologically active parts or hybrids of the enzymes may be used.
  • modification, chemical or otherwise may be beneficial in a method according to the invention, as is part of the standard knowledge of the person skilled in the art.
  • reaction conditions applied in a method according to the invention depend on various parameters, in particular the type of reagents, the concentration of reagents, reaction time, titrant, temperature, pH, enzyme concentration, and enzyme morphology. Given a specific ⁇ -lactam nucleus that is to be reacted with a given precursor for a side chain, using a given enzyme, to a given ⁇ -lactam antibiotic, the person skilled in the art will be able to suitably choose the optimum reaction conditions.
  • the optimum reaction temperature in a method according to the invention lies between about -1 0 and about 50 ° C, preferably between about -5 and about 40 ° C. It is to be noted, that the higher the temperature chosen for the enzymatic preparation of a ⁇ -lactam antibiotic according to the invention, the higher the productivity of said process. However, it has been found that at lower temperatures, the degradation of any reactants is more efficiently suppressed. The skilled person will be able to choose the optimum temperature for a process in accordance with the invention, taking into account the effect on the productivity of the conversion reaction on the one hand, and the extent wherein any reactants are degraded on the other hand.
  • the optimum pH in the preparation of a ⁇ -lactam antibiotic according to the invention lies between about 4.5 and about 9.0, preferably between about 5.5 and about 8.5.
  • the enzyme has proven to catalyze the conversion reaction most efficiently in an aqueous environment. If desired, however, it is also possible to add an organic cosolvent to the reaction system.
  • the reagents will be present in amounts ranging between 0.01 , preferably 0.5, and 3 mol per kilogram reaction mixture, preferably 2 mol per kilogram reaction mixture.
  • Suitable titrants are inorganic acids and bases, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, ammonium hydroxide, and so forth, or organic acids, such as formic acid, acetic acid, succinic acid, adipic acid, glutaric acid and so forth.
  • Titrant concentration may vary between 0.01 and 8 M, depending on the scale of the reaction and the solubility of the titrant.
  • the invention also encompasses a ⁇ -lactam antibiotic obtainable by a method as disclosed hereinabove.
  • ⁇ -lactam antibiotics wherein the ⁇ -lactam nucleus starting material and the precursor for a side chain are chosen such that the ⁇ -lactam antibiotic is ampicillin, amoxicillin, cefaclor, cephalexin, cephadroxil, cephadrine, epicillin, or cefamandole.
  • AssemblaseTM is an immobilized Escherichia coli penicillin acylase from
  • E. coli ATCC 1 1 105 as described in patent application WO 97/04086, which is incorporated herein by reference. Immobilization was carried out as described in European patent application No. 0 222 462, which is also incorporated herein by reference, using gelatin and chitosan as gelling agents and glutaric dialdehyde as crosslinking agent. Final activity of the Escherichia coli penicillin acylase was determined by the amount of enzyme added to the activated beads.
  • the Amoxicillin Synthesis activity of pen acylases was determined as follows: 6-APA (purified as described in Example 6, 6.48 g, 30 mmoles), D-4-hydroxyphenylglycin methyl ester (6.26 g, 35 mmoles) and phenylacetic acid (0.65 mg) were suspended in water. Total volume was 1 00-x ml, wherein x is the amount of enzyme (in grams) to be tested. The mixture was thermostated to 20 ° C. The incubation was started by addition of x g enzyme. During incubation, samples were taken and the amount of amoxicillin formed was determined by HPLC analysis. Up until about 80 mM, formation of amoxicillin was linear with time.
  • amoxicillin formation rate can be expressed in g amoxicillin trihydrate per hour. Dividing this amoxicillin formation rate by x/1000 gives the specific activity of the enzyme in ASU per kg enzyme (ASU: Amoxicillin Synthesis Unit). 1 ASU is defined as the activity required for formation of 1 g amoxicillin trihydrate per hour under conditions mentioned in this example at a pH of approximately 6.3 without adding any acid or base.
  • EXAMPLE 2 Preparation of ampiciilin A cylindrical vessel (volume 1 .5 I, diameter 1 1 cm) equipped with a sieve bottom with 180 ⁇ m slots, thermometer and pH electrode was charged with AssemblaseTM (300 g nett wet weight, specific activity 400 ASU per kg nett wet weight). A separate vessel was charged with 6-APA ( 1 31 .6 g, 0.600 moles), D-phenylglycineamide (30.2 g, 0.200 moles) and water (400 ml). The temperature of this mixture was adjusted to 1 0 ° C. The mixture was stirred during 1 5 minutes at 1 0 ° C, and subsequently transferred to the vessel with the sieve bottom.
  • AssemblaseTM 300 g nett wet weight, specific activity 400 ASU per kg nett wet weight
  • 6-APA 1 31 .6 g, 0.600 moles
  • D-phenylglycineamide 30.2 g, 0.200 moles
  • water 400 ml
  • Remnants were rinsed to the vessel with the sieve bottom with water ( 100 ml).
  • the contents of the vessel with the sieve bottom were stirred, and during 283 minutes 423.7 g of the solution prepared as described in Example 1 (containing 0.8 mol D-phenylglycineamide. 1 / H 2 SO 4 ) was added at constant rate.
  • the temperature was kept at 10 ° C, the pH was approximately 6.3.
  • a cylindrical vessel (volume 1 .5 I, diameter 1 1 cm) equipped with a sieve bottom with 1 80 ⁇ m slots, thermometer and pH electrode was charged with AssemblaseTM (300 g nett wet weight, specific activity 400 ASU per kg nett wet weight).
  • a cylindrical vessel (volume 1 .5 I, diameter 1 1 cm) equipped with a sieve bottom with 1 80 ⁇ m slots, thermometer and pH electrode was charged with AssemblaseTM (300 g nett wet weight, specific activity 400 ASU per kg nett wet weight).
  • a separate vessel was charged with water (500 ml) and D-phenylglycineamide (143.2 g, 0.950 moles). The mixture was stirred and kept at 1 0 ° C, while 6-APA ( 1 31 .6 g, 0.600 moles) was added in portions in the course of 1 5 minutes.
  • 6-APA may contain phenylacetic acid. Phenylacetic acid retards the enzymatic conversion. Therefore, phenylacetic acid was removed by extraction.
  • EXAMPLE 6 Synthesis of amoxicillin 6-APA (purified as described in example 5, 1 2.97 g, 60.0 mmoles) and D-4-hydroxyphenylglycine methyl ester (14.78 g, 81 .6 mmoles) and enzyme were suspended in water. A solution of phenylacetic acid in water (10 ml of a 0.01 3% by weight solution, 0.01 mmoles phenylacetic acid) was added in order to simulate industrial conditions where 6-APA often contains a certain amount of phenylacetic acid.
  • 6-APA stock By first purifying 6-APA and subsequently adding a known amount of phenylacetic acid, a 6-APA stock is obtained which may be used for experiments of which the results are to be compared, without a possible impact of differences in phenylacetic acid concentrations on those results.
  • CLEC The Cross-Linked Enzyme Crystal from penicillin acylase, obtained from Altus Biologies Inc., Cambridge, USA, Product Number: CEC-1 -G-S. Description ChiroClec-EC, lot nr. EC96-004.

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Abstract

L'invention concerne un procédé permettant de préparer une β-lactamine par action enzymatique à partir d'un noyau de β-lactame ou d'un sel de ce noyau, et d'un précurseur d'une chaîne latérale. Selon ce procédé, on utilise une grande quantité d'enzymes, cette quantité étant au moins deux fois supérieure à la quantité normalement utilisée.
PCT/EP1998/003629 1997-06-10 1998-06-10 PROCEDE DE PREPARATION D'UNE β-LACTAMINE PAR ACTION ENZYMATIQUE ET ANTIBIOTIQUE AINSI PRODUIT WO1998056945A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU87994/98A AU8799498A (en) 1997-06-10 1998-06-10 Process for enzymatically preparing a beta-lactam antibiotic and this antibiotic

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP97201689.3 1997-06-10
EP97201689 1997-06-10

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WO1998056945A1 true WO1998056945A1 (fr) 1998-12-17

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002018618A2 (fr) * 2000-08-28 2002-03-07 Dsm N.V. PROCEDE DE PREPARATION D'UN NOYAU DE β-LACTAME ET APPLICATION DE CE DERNIER
JP2002316991A (ja) * 2001-04-18 2002-10-31 Otsuka Chem Co Ltd ペニシリン及びセファロスポリン化合物
CN103193800A (zh) * 2013-04-08 2013-07-10 中国医药集团总公司四川抗菌素工业研究所 一种从头孢克洛酶促反应液中分离纯化各组分的方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0473008A2 (fr) * 1990-08-28 1992-03-04 RECORDATI S.A. CHEMICAL and PHARMACEUTICAL COMPANY Procédé amélioré pour la préparation de pénicillines et céphalosporines
WO1992012782A1 (fr) * 1991-01-25 1992-08-06 Novo Nordisk A/S Procede de separation de deux constituants solides
EP0567323A2 (fr) * 1992-04-24 1993-10-27 Eli Lilly And Company Procédé amélioré pour la préparation de céphalosporines
WO1996002663A1 (fr) * 1994-07-18 1996-02-01 Gist-Brocades B.V. PROCEDE DE PREPARATION DE β-LACTAMINES AU MOYEN DE REACTIFS PRESENTS A UNE CONCENTRATION CONSTAMMENT ELEVEE
EP0730036A1 (fr) * 1995-02-28 1996-09-04 ACS DOBFAR S.p.A. Procédé pour la synthèse enzymatique d'antibiotiques bèta-lactame en présence d'un inhibiteur d'enzyme

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0473008A2 (fr) * 1990-08-28 1992-03-04 RECORDATI S.A. CHEMICAL and PHARMACEUTICAL COMPANY Procédé amélioré pour la préparation de pénicillines et céphalosporines
WO1992012782A1 (fr) * 1991-01-25 1992-08-06 Novo Nordisk A/S Procede de separation de deux constituants solides
EP0567323A2 (fr) * 1992-04-24 1993-10-27 Eli Lilly And Company Procédé amélioré pour la préparation de céphalosporines
WO1996002663A1 (fr) * 1994-07-18 1996-02-01 Gist-Brocades B.V. PROCEDE DE PREPARATION DE β-LACTAMINES AU MOYEN DE REACTIFS PRESENTS A UNE CONCENTRATION CONSTAMMENT ELEVEE
EP0730036A1 (fr) * 1995-02-28 1996-09-04 ACS DOBFAR S.p.A. Procédé pour la synthèse enzymatique d'antibiotiques bèta-lactame en présence d'un inhibiteur d'enzyme

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002018618A2 (fr) * 2000-08-28 2002-03-07 Dsm N.V. PROCEDE DE PREPARATION D'UN NOYAU DE β-LACTAME ET APPLICATION DE CE DERNIER
WO2002018618A3 (fr) * 2000-08-28 2002-05-30 Dsm Nv PROCEDE DE PREPARATION D'UN NOYAU DE β-LACTAME ET APPLICATION DE CE DERNIER
JP2002316991A (ja) * 2001-04-18 2002-10-31 Otsuka Chem Co Ltd ペニシリン及びセファロスポリン化合物
CN103193800A (zh) * 2013-04-08 2013-07-10 中国医药集团总公司四川抗菌素工业研究所 一种从头孢克洛酶促反应液中分离纯化各组分的方法
CN103193800B (zh) * 2013-04-08 2016-03-02 中国医药集团总公司四川抗菌素工业研究所 一种从头孢克洛酶促反应液中分离纯化各组分的方法

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