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WO1999031109A1 - COMPLEXES OF ss-LACTAM ANTIBIOTICS AND 1-NAPHTHOL - Google Patents

COMPLEXES OF ss-LACTAM ANTIBIOTICS AND 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
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Prior art keywords
naphthol
lactam
lactam antibiotic
reaction
acylation
Prior art date
Application number
PCT/NL1998/000714
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French (fr)
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/en

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    • 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)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Genetics & Genomics (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

The invention relates to complexes of cephradine and cefaclor and 1-naphthol. It has been found that 1-naphthol shows better complexing behaviour then for example 2-naphthol. The invention also relates to a process for the preparation of such complexes, the corresponding ß-lactam antibiotic being prepared through acylation of the corresponding ß-lactam nucleus with a suitable acylating agent and 1-naphthol being present in the reaction mixture during at least part of the acylation reaction. The acylation is preferably carried out in the presence of an enzyme. The ß-lactam antibiotic can subsequently be released from the complex in a known manner.

Description

COMPLEXES OF β-LACTAM ANTIBIOTICS AND 1-NAPHTHOL
The invention relates to complexes of β- lactam antibiotics chosen from the group comprising cephradine and cefaclor, and 1-naphthol. 0 Complexes of β-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 applicant has now found that the
15 formation of a complex of cephradine and cefaclor, which β-lactam antibiotics proved to show comparable complexing behaviour, proceeds faster and more completely with 1-naphthol than with 2-naphthol, whereas the opposite holds for other β-lactam
20 antibiotics.
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 β-lactam antibiotics from
25 reaction mixtures obtained after a chemical or enzymatic acylation reaction and the purification of β- lactam antibiotics. Cephradine is a β-lactam antibiotic that can be obtained through acylation of 7- aminodesacetoxycephalosporanic acid (7-ADCA) with D-
30 dihydrophenylglycme or a derivative thereof, for " '■" example an amide or an alkyl ester, preferably a lower (1-4 C) alkyl ester; cefaclor is a β-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 β- lactam antibiotic into contact with 1-naphthol. The molar ratio of the 1-naphthol and the β-lactam antibiotic is preferably greater than 0.5 and is in particular between 0.5 and 2. The concentration of the β-lactam antibiotic is preferably chosen to be as high as possible, preferably greater than 0.01 wt . % β-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 β-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 β-lactam antibiotics, for example during an enzymatic acylation reaction, in the hydrolysis of protected β-lactam antibiotics after a chemical acylation reaction in which use is made of protecting groups, in the purification of antibiotics or in the
> isolation of β-lactam antibiotics from a reaction mixture obtained after the acylation reaction or from the mother liquor. Preferably a pH value of between 2 and 9, in particular between 4 and 7, is chosen. The β- 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 β-lactam nucleus with an acylating agent, 1-naphthol being present in the reaction mixture during at least part of the acylation reaction. With a kinetically controlled coupling, hydrolysis of the acylating agent and the β-lactam antibiotic usually occurs during an enzymatic acylation reaction. Owing to the presence of 1-naphthol in the reaction mixture, and consequently the formation of the complexes according to the invention, a higher synthesis/hydrolysis ratio (S/H) , the molar ratio of the synthesis product (β-lactam antibiotic) and the hydrolysis product, is obtained and less decomposition of the β-lactam antibiotic occurs as a result of the complexing. In addition, a higher reaction rate was realised, as a result of which the decomposition of the β-lactam antibiotic and the β-lactam nucleus is restricted.
The concentration at which the enzymatic acylation reaction is carried out is not particularly critical. The concentration of the β-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. Preferably the β-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 β-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.
As the enzyme in the acylation reaction any enzyme can in principle be used that is suitable for use as a catalyst in the coupling reaction. Such enzymes are 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
Biochemistry International, June 1990, pp. 97-103. Examples of suitable enzymes are enzymes derived from Acetobacter, in particular Acetobacter pasteurianum. Aeromonas , Alcaligenes, in particular Alcaligenes faecalis, Aphanocladium. Bacillus sp.. in particular Bacillus meσaterium. 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.
Preferably use is made of an immobilised enzyme, because the enzyme can then be separated and reused in a simple manner. Of the commercially available 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 (CLECs™) . 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.
Preferably 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.
After the reaction has been virtually stopped when the maximum degree of conversion has been reached, 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, for example the preparation of the supersaturated mixtures, 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 . % . Examples of 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 β-lactam nucleus, i.e. the total amount of acylating agent supplied divided by the total amount of β-lactam nucleus supplied expressed in moles, is smaller than 2.5. Preferably 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.
Examples
7 -ACCA : 7-amino-3-chloro-ceph-3-em-4-carboxylic acid
7 -ADCA : 7-aminodesacetoxycephalosporanic acid
6 -APA : 6-aminopenicillanic acid
CC1 : cefaclor
CEX : cephalexine
PG : D-phenylglycine
PGA : D-phenylglycine amide
HPG : D-p-hydroxyphenylglycine
HPGM : D-p-hydroxyphenylglycine methyl ester
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.3H20 per hour from 6-APA and HPGM (at 20°C) ; 6.5% 6-APA and 6.5% HPGM) . Example I
Complexing of cephradine using 1-naphthol or 2-naphthol
(comparative experiment) as the complexing agent.
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. Next, an equimolar amount of 1-naphthol or 2- naphthol was added at room temperature .
Samples were taken at different moments during a stirring incubation. After these samples had been filtered through a 0.45 μ filter, the concentration of the cephalosporine in question present in the filtrate was determined with the aid of HPLC. The results are presented in Table 1.1.
Table 1.1
Complexing of cephradine using 1-naphthol or 2-naphthol as the complexing agent .
Figure imgf000010_0001
* comparative experiment Example II
Example I was repeated for cefaclor instead of cephradine; now at a pH of 7.0.
The results are presented in Table 1.2.
Tible 1,2
Complexing of cefaclor using 1-naphthol or 2-naphthol as a complexing agent (pH 7.0, room temperature).
Figure imgf000011_0001
* comparative experiment
Comparative Experiment A Example I was repeated for cefadroxil instead of cephradine. The results are presented in Table 1.3.
Table 1 . 3
Complexing of cefadroxyl using 1-naphthol or 2-naphthol as the complexing agent .
Figure imgf000012_0001
Example III
Complexing of cephradine using 1-naphthol as the complexing agent at various pH values . A(n aqueous) cephradine solution having a(n initial) concentration of 1.8 percent by mass was divided between 3 reaction vessels. With the aid of a diluted sulphuric acid solution the cephradine solution in one of the reaction vessels was brought to a pH of 4.5. The pH values of the cephradine solutions in the other reaction vessels were brought to 6.3 and 7.0 respectively, with a diluted ammonia solution. Next, an equimolar amount of 1-naphthol was added at room temperature. Samples were taken at various moments during a stirring incubation.
The concentrations of cephradine present in filtrate samples are indicated in Table 2.1.
Figure imgf000013_0001
Table 2.1
Complexing of cephradine using 1-naphthol as a complexing agent at various pH values
Figure imgf000013_0002
Example IV
To an aqueous solution (temperature 10°C) containing 10 g of PGA (454 mM) and 11.3 g of 7-ACCA (328 mM) was added 3.4 g of 1- or 2-naphthol (160 mM) at T = 10°C.
Before Assemblase™ (24 g) was added, the pH was brought to 7.0 with the aid of 2N H2S04. Samples were taken at various moments and analysed with the aid of HPLC. The degree of conversion (the number of moles of cefaclor formed relative to the number of moles of 7-ACCA with which the reaction began) is shown in Table 3.1.
Table 3.1
Enzymatic synthesis of cefaclor in the presence of 1- naphthol or 2-naphthol (10°C)
Figure imgf000014_0001

Claims

L A M S
1. Complex of a β-lactam antibiotic chosen from the group comprising cephradine and cefaclor and 1-
5 naphthol .
2. Process for the preparation of a complex according to Claim 1, in which the corresponding β-lactam antibiotic is brought into contact with l- naphthol . 0 3. Process for the preparation of a complex according to Claim 1, in which the corresponding β-lactam antibiotic is prepared through acylation of the corresponding β-lactam nucleus with a suitable acylating agent and in which 1-naphthol is present
15 in the reaction mixture during at least part of the acylation reaction. 4. Process according to Claim 3, in which the acylation is carried out in the presence of an enzyme . 0 5. Process according to Claim 3 or Claim 4, in which the complex is isolated and the β-lactam antibiotic is released from the complex.
6. Process for the recovery of a β-lactam antibiotic chosen from the group comprising cephradine and
25 cefaclor, a mixture containing the β-lactam antibiotic being brought into contact with 1- naphthol and the complex formed being recovered.
7. Process according to Claim 6, the β-lactam antibiotic subsequently being released from the
W complex.
PCT/NL1998/000714 1997-12-18 1998-12-14 COMPLEXES OF ss-LACTAM ANTIBIOTICS AND 1-NAPHTHOL WO1999031109A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL1013402C2 (en) * 1999-10-27 2001-05-01 Dsm Nv Method for the preparation of a beta-lactam antibiotic.
WO2005003367A3 (en) * 2003-07-03 2005-05-26 Dsm Ip Assets Bv Process for the preparation of cephradine
CN103757085A (en) * 2013-11-28 2014-04-30 湖南福来格生物技术有限公司 Cefaclor and synthetic method thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110408670A (en) * 2019-08-19 2019-11-05 苏州盛达药业有限公司 A kind of method of Enzyme catalyzed synthesis Cefaclor

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS50130778A (en) * 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 (en) * 1991-12-19 1993-06-24 Novo Nordisk A/S AN IMPROVED METHOD FOR THE PREPARATION OF CERTAIN β-LACTAM ANTIBIOTICS

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS50130778A (en) * 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 (en) * 1991-12-19 1993-06-24 Novo Nordisk A/S AN IMPROVED METHOD FOR THE PREPARATION OF CERTAIN β-LACTAM ANTIBIOTICS

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 (en) * 1999-10-27 2001-05-01 Dsm Nv Method for the preparation of a beta-lactam antibiotic.
WO2001030783A1 (en) * 1999-10-27 2001-05-03 Dsm N.V. PROCESS FOR THE PREPARATION OF A β-LACTAM ANTIBIOTIC
WO2005003367A3 (en) * 2003-07-03 2005-05-26 Dsm Ip Assets Bv Process for the preparation of cephradine
US7588913B2 (en) 2003-07-03 2009-09-15 Dsm Ip Assets B.V. Process for the preparation of cephradine
CN103757085A (en) * 2013-11-28 2014-04-30 湖南福来格生物技术有限公司 Cefaclor and synthetic method thereof

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