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WO1999031109A1 - COMPLEXES D'ANTIBIOTIQUES AU β-LACTAME ET DE 1-NAPHTHOL - Google Patents

COMPLEXES D'ANTIBIOTIQUES AU β-LACTAME ET DE 1-NAPHTHOL Download PDF

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Publication number
WO1999031109A1
WO1999031109A1 PCT/NL1998/000714 NL9800714W WO9931109A1 WO 1999031109 A1 WO1999031109 A1 WO 1999031109A1 NL 9800714 W NL9800714 W NL 9800714W WO 9931109 A1 WO9931109 A1 WO 9931109A1
Authority
WO
WIPO (PCT)
Prior art keywords
naphthol
lactam
lactam antibiotic
reaction
acylation
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.)
Ceased
Application number
PCT/NL1998/000714
Other languages
English (en)
Dutch (nl)
Inventor
Gerjan Kemperman
René DE GELDER
Petronella Catharina Raemakers-Franken
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Koninklijke DSM NV
Original Assignee
DSM NV
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by DSM NV filed Critical DSM NV
Priority to AU17862/99A priority Critical patent/AU1786299A/en
Publication of WO1999031109A1 publication Critical patent/WO1999031109A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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

Definitions

  • the invention relates to complexes of ⁇ - lactam antibiotics chosen from the group comprising cephradine and cefaclor, and 1-naphthol.
  • ⁇ - lactam antibiotics chosen from the group comprising cephradine and cefaclor, and 1-naphthol.
  • 1-naphthol 1-naphthol.
  • Complexes of ⁇ -lactam antibiotics and hydroxynaphthalenes are known in general terms from O- A-93/12250, which explicitly describes the complexes of cephalexine and cephadroxyl, and 2-naphthol.
  • the complexes according to the invention are in particular useful intermediates, for example in the enzymatic preparation of cephradine and cefaclor, in the recovery of the ⁇ -lactam antibiotics from
  • Cephradine is a ⁇ -lactam antibiotic that can be obtained through acylation of 7- aminodesacetoxycephalosporanic acid (7-ADCA) with D-
  • dihydrophenylglycme or a derivative thereof for " ' ⁇ ” example an amide or an alkyl ester, preferably a lower (1-4 C) alkyl ester; cefaclor is a ⁇ -lactam antibiotic that can be obtained through acylation of 7-amino-3- chloro-ceph-3-em-4-carboxylic acid with D-phenylglycine or a derivative thereof, preferably a lower (1-4 C) alkyl ester, or an amide.
  • the complexes according to the invention can be prepared in a simple manner by bringing the ⁇ - lactam antibiotic into contact with 1-naphthol.
  • the molar ratio of the 1-naphthol and the ⁇ -lactam antibiotic is preferably greater than 0.5 and is in particular between 0.5 and 2.
  • the concentration of the ⁇ -lactam antibiotic is preferably chosen to be as high as possible, preferably greater than 0.01 wt . % ⁇ -lactam antibiotic in the reaction mixture.
  • the temperature applied is not particularly critical and is for example between -10 and 100°C, preferably between -5 and 50°C.
  • the pH at which the complexes are formed is not particularly critical either; the residual concentration of the ⁇ -lactam antibiotic in solution to be obtained after complexing with 1-naphthol proves to be virtually independent of the mixture's pH in a wide range of pH values, for example between 1 and 10, in particular 2 and 9, more in particular 3 and 8. That complex formation can consequently be incorporated in a simple manner at various points in a process for the preparation of ⁇ -lactam antibiotics, for example during an enzymatic acylation reaction, in the hydrolysis of protected ⁇ -lactam antibiotics after a chemical acylation reaction in which use is made of protecting groups, in the purification of antibiotics or in the
  • ⁇ -lactam antibiotics > isolation of ⁇ -lactam antibiotics from a reaction mixture obtained after the acylation reaction or from the mother liquor.
  • a pH value of between 2 and 9, in particular between 4 and 7, is chosen.
  • the ⁇ - lactam antibiotic can be recovered from the complex in a manner that is generally known to those skilled in the art .
  • a particularly suitable application of the complexes according to the invention is in the enzymatic acylation of a ⁇ -lactam nucleus with an acylating agent, 1-naphthol being present in the reaction mixture during at least part of the acylation reaction.
  • acylating agent 1-naphthol being present in the reaction mixture during at least part of the acylation reaction.
  • hydrolysis of the acylating agent and the ⁇ -lactam antibiotic usually occurs during an enzymatic acylation reaction.
  • the concentration at which the enzymatic acylation reaction is carried out is not particularly critical.
  • the concentration of the ⁇ -lactam nucleus and of the acylating agent at the beginning of the acylation reaction is for example between 100 and 2,000 mM, preferably between 400 and 1,000 mM.
  • the ⁇ -lactam nucleus and/or the acylating agent are during at least part of the acylation reaction present in the reaction mixture in a supersaturated form. This can for example be realised by subjecting a mixture in which the ⁇ -lactam nucleus and/or the acylating agent are present in a concentrated form to an increase or reduction in pH or to a reduction in temperature.
  • any enzyme in principle be used that is suitable for use as a catalyst in the coupling reaction is for example the enzymes known under the general name of penicillin amidase or penicillin acylase.
  • Such enzymes are for example described in J.G. Shewale et al . , Process Biochemistry, August 1989, pp. 146-154, and in J.G. Shewale et al., Process
  • suitable enzymes are enzymes derived from Acetobacter, in particular Acetobacter pasteurianum. Aeromonas , Alcaligenes, in particular Alcaligenes faecalis, Aphanocladium. Bacillus sp.. in particular Bacillus me ⁇ aterium. Cephalosporium. Escherichia. in particular Escherichia coli. Flavobacterium. Fusarium. in particular Fusarium oxysporum and Fusarium solani. Kluyvera, Mycoplana. Protaminobacter , Proteus, in particular Proteus rettgeri. Pseudomonas and Xanthomonas . in particular Xanthomonas citrii.
  • an immobilised enzyme Preferably use is made of an immobilised enzyme, because the enzyme can then be separated and reused in a simple manner.
  • immobilised enzymes the Escherichia coli enzyme of Boehringer Mannheim GmbH that is commercially available under the name of Enzygel ® , the immobilised Penicillin-G acylase of Recordati and the immobilised Penicillin-G acylase of Pharma Biotechnology Hannover for example have proved to be very suitable.
  • Enzymes can also be used as a crystalline substance (CLECsTM) .
  • the temperature at which the enzymatic acylation reaction is carried out is not particularly critical and is, on account of the enzyme's stability, usually lower than 40°C, preferably between -5 and 35°C.
  • the pH at which the enzymatic acylation reaction is carried out is usually between 5.5 and 9.5, preferably between 6.0 and 9.0.
  • the reaction is almost completely stopped as soon as almost the maximum degree of conversion has been reached.
  • a suitable mode of stopping the reaction is lowering the pH, preferably to a value of between 4.0 and 6.3, in particular between 4.5 and 5.7.
  • Another suitable mode is lowering the temperature of the reaction mixture as soon as the maximum degree of conversion has been reached.
  • a combination of the two modes is also possible.
  • the reaction mixture is usually present in the form of a suspension containing several solid substances, for example the antibiotic and D-phenylglycine, while immobilised enzyme may also be present .
  • the immobilised enzyme is preferably recovered, in view of process economics. This can for example be carried out in a suitable manner by filtering the reaction mixture through a sieve, with stirring, the stirrer's direction of rotation preferably being chosen so that the suspension is pumped upwards at the centre of the stirrer.
  • Valuable b components for example the antibiotic and PG, can subsequently be recovered, for example with the aid of a change in pH.
  • a reduction in pH can in the context of the invention for example be effected by adding an acid.
  • Suitable acids are for example mineral acids, in particular sulphuric acid, hydrochloric acid or nitric acid, and carboxylic acids, for example acetic acid, oxalic acid or citric acid.
  • An increase in pH can for example be effected by adding a base.
  • Suitable bases are for example inorganic bases, in particular ammonia, potassium hydroxide or sodium hydroxide, and organic bases, for example triethylamine and D-phenylglycine amide. Preferably ammonia is used.
  • the enzymatic acylation reaction and the indicated measures can be carried out in water.
  • the reaction mixture may optionally also contain an organic solvent or a mixture of organic solvents, preferably less than 30 vol . % .
  • organic solvents that can be u ed are alcohols with 1-7 C atoms, for example a onoalcohol, in particular methanol or ethanol; a diol, in particular ethylene glycol, or a triol, in particular glycerol .
  • the molar ratio of the acylating agent and the ⁇ -lactam nucleus i.e. the total amount of acylating agent supplied divided by the total amount of ⁇ -lactam nucleus supplied expressed in moles, is smaller than 2.5.
  • the molar ratio is between 0.5 and 2.0, in particular between 0.7 and 1.8.
  • the enzymatic apylation reaction is preferably carried out as a batch process. It is optionally also possible to carry out the reaction continuously.
  • the invention will be further elucidated with reference to the examples without however being limited thereby.
  • Assemblase is an immobilised Escherichia coli penicillin acylase from E. coli ATCC 11105, as described in WO-A-97/04086.
  • the immobilisation was carried out as described in EP-A-222462, using gelatine and chitosan as the gelling agents and glutaraldehyde as a crosslinker.
  • the ultimate activity of the Escherichia coli penicillin acylase is determined by the amount of enzyme added to the activated spheres and was 3 ASU/g of dry weight, 1 ASU (Amoxicillin Synthesis Unit) being defined as the amount of enzyme that generates 1 g of Amoxicillin.3H 2 0 per hour from 6-APA and HPGM (at 20°C) ; 6.5% 6-APA and 6.5% HPGM) .
  • 1 ASU Amoxicillin Synthesis Unit
  • a basic solution was added, drop by drop, to a(n aqueous) solution of cephradine having a concentration of 1.0 m.% until a pH of 6.3 was obtained.
  • an equimolar amount of 1-naphthol or 2- naphthol was added at room temperature .
  • Example I was repeated for cefaclor instead of cephradine; now at a pH of 7.0.

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  • 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)
  • Cephalosporin Compounds (AREA)

Abstract

Cette invention se rapporte à des complexes de céphradine et de céphaclor et de 1-naphtol. On a découvert que le 1-naphtol possède un meilleur comportement complexant que le 2-naphtol, par exemple. Cette invention se rapporte également à un procédé de préparation de ces complexes, à l'antibiotique au β-lactame correspondant, préparé par acylation du noyau de β-lactame correspondant avec un agent d'acylation approprié et le 1-naphtol étant présent dans le mélange de réaction pendant au moins une partie de la réaction d'acylation. L'acylation est de préférence effectuée en présence d'une enzyme. L'antibiotique au β-lactame peut être ensuite libéré du complexe d'une façon connue.
PCT/NL1998/000714 1997-12-18 1998-12-14 COMPLEXES D'ANTIBIOTIQUES AU β-LACTAME ET DE 1-NAPHTHOL Ceased WO1999031109A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU17862/99A AU1786299A (en) 1997-12-18 1998-12-14 Complexes of beta-lactam antibiotics and 1-naphthol

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NL1007828A NL1007828C2 (nl) 1997-12-18 1997-12-18 Complexen van beta-lactam antibiotica en 1-naftol.
NL1007828 1997-12-18

Publications (1)

Publication Number Publication Date
WO1999031109A1 true WO1999031109A1 (fr) 1999-06-24

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NL1998/000714 Ceased WO1999031109A1 (fr) 1997-12-18 1998-12-14 COMPLEXES D'ANTIBIOTIQUES AU β-LACTAME ET DE 1-NAPHTHOL

Country Status (3)

Country Link
AU (1) AU1786299A (fr)
NL (1) NL1007828C2 (fr)
WO (1) WO1999031109A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL1013402C2 (nl) * 1999-10-27 2001-05-01 Dsm Nv Werkwijze voor de bereiding van een beta-lactam antibioticum.
WO2005003367A3 (fr) * 2003-07-03 2005-05-26 Dsm Ip Assets Bv Procédé de préparation de céphradine
CN103757085A (zh) * 2013-11-28 2014-04-30 湖南福来格生物技术有限公司 头孢克洛及其合成方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110408670A (zh) * 2019-08-19 2019-11-05 苏州盛达药业有限公司 一种酶催化合成头孢克洛的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS50130778A (fr) * 1974-04-02 1975-10-16
US4003896A (en) * 1974-12-17 1977-01-18 Novo Industri A/S Method of preparing a sparingly soluble complex of cephalexin
WO1993012250A1 (fr) * 1991-12-19 1993-06-24 Novo Nordisk A/S PROCEDE AMELIORE POUR LA PREPARATION DE CERTAINES β-LACTAMINES

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS50130778A (fr) * 1974-04-02 1975-10-16
US4003896A (en) * 1974-12-17 1977-01-18 Novo Industri A/S Method of preparing a sparingly soluble complex of cephalexin
WO1993012250A1 (fr) * 1991-12-19 1993-06-24 Novo Nordisk A/S PROCEDE AMELIORE POUR LA PREPARATION DE CERTAINES β-LACTAMINES

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 84, no. 21, 24 May 1976, Columbus, Ohio, US; abstract no. 150644, KODAMA T. ET AL.: "Purification of cephalosporins" XP002059554 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL1013402C2 (nl) * 1999-10-27 2001-05-01 Dsm Nv Werkwijze voor de bereiding van een beta-lactam antibioticum.
WO2001030783A1 (fr) * 1999-10-27 2001-05-03 Dsm N.V. ELABORATION D'UNE β-LACTAMINE
WO2005003367A3 (fr) * 2003-07-03 2005-05-26 Dsm Ip Assets Bv Procédé de préparation de céphradine
US7588913B2 (en) 2003-07-03 2009-09-15 Dsm Ip Assets B.V. Process for the preparation of cephradine
CN103757085A (zh) * 2013-11-28 2014-04-30 湖南福来格生物技术有限公司 头孢克洛及其合成方法

Also Published As

Publication number Publication date
NL1007828C2 (nl) 1999-06-21
AU1786299A (en) 1999-07-05

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