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

Info

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
Application number
PCT/NL1998/000714
Other languages
English (en)
Dutch (nl)
Inventor
Gerjan Kemperman
René DE GELDER
Petronella Catharina Raemakers-Franken
Original Assignee
Dsm N.V.
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 N.V. filed Critical Dsm N.V.
Priority to AU17862/99A priority Critical patent/AU1786299A/en
Publication of WO1999031109A1 publication Critical patent/WO1999031109A1/fr

Links

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.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • 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 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
NL1007828 1997-12-18
NL1007828A NL1007828C2 (nl) 1997-12-18 1997-12-18 Complexen van beta-lactam antibiotica en 1-naftol.

Publications (1)

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

Family

ID=19766208

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NL1998/000714 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.
WO2005003367A2 (fr) * 2003-07-03 2005-01-13 Dsm Ip Assets B.V. 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 (6)

* 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
WO2005003367A2 (fr) * 2003-07-03 2005-01-13 Dsm Ip Assets B.V. Procédé de préparation de céphradine
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

Similar Documents

Publication Publication Date Title
RU2136759C1 (ru) Способ получения производного бета-лактама
US6048708A (en) Process for preparation of β-lactams at constantly high concentration of reactants
KR100455252B1 (ko) 항생제제조방법
WO1997004086A1 (fr) Penicilline g acylase immobilisee amelioree
EP1023454B1 (fr) Procede de preparation d'un antibiotique de (beta)-lactame
WO1999031109A1 (fr) COMPLEXES D'ANTIBIOTIQUES AU β-LACTAME ET DE 1-NAPHTHOL
US5874571A (en) Process for the recovery of cephalexin
WO1999055710A1 (fr) Procede de cristallisation d'une beta-lactamine
CA2168923C (fr) Methode pour la synthese enzymatique d'antibiotiques de type .beta.-lactames en presence d'inhibiteurs enzymatiques
EP1017698A1 (fr) Methode de recuperation d'un beta-lactamine antibiotique
EP1416054B1 (fr) Procédé enzymatique simple pour préparer du cefazolin
EP0988393B1 (fr) Procede de preparation de l'ampicilline
NL1007827C2 (nl) Complexen van beta-lactam antibiotica.
JP2000512860A (ja) β―ラクタム抗生物質を調製する方法
WO1998056945A1 (fr) PROCEDE DE PREPARATION D'UNE β-LACTAMINE PAR ACTION ENZYMATIQUE ET ANTIBIOTIQUE AINSI PRODUIT
EP0869962A1 (fr) Procede de recuperation d'un beta-lactame antibiotique
MXPA00003769A (en) PROCESS FOR THE PREPARATION OF A&bgr;-LACTAM ANTIBIOTIC
MXPA00010537A (en) A METHOD FOR CRYSTALLIZING A&bgr;-LACTAM ANTIBIOTIC

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AU BA BB BG BR CA CN CU CZ EE GD GE HR HU ID IL IN IS JP KP KR LC LK LR LT LV MG MK MN MX NO NZ PL RO SG SI SK SL TR TT UA US UZ VN YU

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: KR

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA