Classifications

• • 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
  • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
  • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
  • C12P17/188—Heterocyclic compound containing in the condensed system at least one hetero ring having nitrogen atoms and oxygen atoms as the only ring heteroatoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

• the present invention relates to a process for the preparation of an amine salt of clavulanic acid and to the conversion thereof into pharmaceutically acceptable alkali metal salts and esters of clavulanic acid, especially potassium clavulanate.
• Clavulanic acid and its alkali metal salts and esters are ⁇ - lactamase inhibitors, able to enhance the effectiveness of penicillins and cephalosporins.
• clavulanic acid is prepared by the fermentation of a microorganism which produces clavulanic acid as for instance Streptomvces strains such as Streptomyces clavuligerus.
• the resulting aqueous broth is normally subjected to conventional purification and concentration processes, such as disclosed in British patent GB 1 508977. Techniques described to remove the biomass are filtration of the broth using e.g.
• European patent application EP-A-26044 discloses the use of the tertiary butyl amine salt of clavulanic acid as an useful intermediate in the preparation of clavulanic acid.
• Other amine salts of clavulanic acid are disclosed in the patent documents EP-A-3871 78, EP-A-562583, WO 93/25557, WO 94/22873, WO 96/201 99 and WO 96/26944.
• a disadvantage of using a cosolvent is the fact that the resulting mother liquid consists of a mixture of solvents. Therefore, an additional separation step is needed in order to recycle the solvents. In case of azeotrope formation, separation will be very difficult. Also, raw material costs increase due to the use of a cosolvent.
• the aim of the present invention is to prepare clavulanic acid and its pharmaceutically acceptable salts, such as potassium clavulanate with the desired substance obtained in a high yield and of high purity, while using a minimal amount of solvents.
• the volume of cosolvent to be added to ensure proper crystallisation can be significantly reduced or avoided completely, if the order of addition of the clavulanic acid solution and the amine is reversed, i.e. upon addition of the clavulanic acid solution to the amine solution instead of the usual addition of the amine solution to the clavulanic acid solution or in case the clavulanic acid solution and the amine solution are added simultaneously to the crystallisation vessel.
• the crystallisation can further be improved by applying a temperature profile, a variable speed of addition of reactants and/or a variable ratio of reactants during addition. This method, which has not been described earlier, results in a more economical attractive process as the use of a cosolvent has been minimized or even avoided completely.
• the present invention provides a process for the crystallisation of an amine salt of clavulanic acid involving the addition of clavulanic acid in an organic solvent to a solution of amine preferably in the same organic solvent.
• a process containing simultaneous addition of a solution containing clavulanic acid and a solution of the amine is provided. Both processes optionally include the application of a temperature profile (decreasing in time), profile of speed of addition (increasing in time) and/or profile of ratio amine/clavulanic acid (increasing in time).
• the advantageous conversion of the amine clavulanate formed according to anyone of these processes into pure clavulanic acid or a pharmaceutically acceptable salt or ester thereof has been provided.
• the essence of the crystallisation process according to the present invention comprises of placing a solution of amine in a solvent, optionally containing a small volume of cosolvent in a crystallisation vessel. Subsequently, a solution of clavulanic acid in a solvent, preferably the same solvent, optionally containing a small volume of cosolvent is added to the vessel.
• a solution of clavulanic acid in a solvent preferably the same solvent, optionally containing a small volume of cosolvent is added to the vessel.
• the volume thereof can be reduced significantly compared to the process in which the amine solution is added to the extract containing clavulanic acid instead of the other way around. Recycling of the mother ⁇ o liquid wil be economically attractive, even in case of azeotropic mixtures.
• the volumes used depend on the solvent and cosolvent applied. For instance, in case ethylacetate is used as solvent, it is preferred to use ethanol in such a volume that V ethanol /V ethyl acetate is less than 0. 1 5, preferably less than 0.1 0.
• a further embodiment of the invention is the simultaneous and separate addition of a solution of clavulanic acid in a solvent and an amine optionally dissolved in a solvent, preferably the same solvent, optionally containing a small amount of cosolvent.
• the amine or a combination of the solutions can be placed in the crystallisation vessel.
• the ratio of the amount of clavulanic acid added to the amount of amine added can be varied in time. For example, the concentration of amine relative to that of clavulanic acid can be increased in time in this way, which might improve
• a cosolvent may be added to one or both of the reactant solutions. It is of course in both cases also within the
• this cosolvent is added as a third stream, besides the reactants, optionally also in case cosolvent has been added to one or both of the reactants.
• the period of addition may vary between 2 and 1 20 minutes, preferably between 30 and 60 minutes.
• a profile of addition velocity may advantageously be applied, i.e. slowly until the first crystals are formed after which the addition velocity may be increased.
• 1 -1 0% of the volume may be added in about 50% of the addition time, while the rest of the volume may be added during the later 50%. In this way, formation of lumps is prevented.
• seeding material may be added to the vessel before addition of the clavulanic acid solution.
• the concentration of clavulanic acid in the solvent may vary between 1 0 and 1 00 g/l, preferably between 1 5 and 50 g/l.
• the overall molar excess of amine related to clavulanic acid should be between 1 .2 and 2.4.
• the organic solvent comprises an aliphatic carboxylic ester or a substantially water-immiscible aliphatic ketone, such as an acetate as ethyl acetate, methyl acetate, propyl acetate, or butyl acetate, or a methyl ethyl ketone, methyl isobutyl ketone or an n-butyl alcohol.
• Suitable co-solvents are alcohols such as methanol, ethanol, propanol, isopropanol, butanol and isobutanol and ketones such as acetone, propanone, etc.
• Suitable amines are for instance N,N,N,N- tetramethylethylenediamine, 1 ,3-bis(di-methylamino)-2-propanol, N,N'- diisopropylethylenediamine, t-butylamine, t-octylamine, benzhydrylamine and bis (2-(dimethyl-amino)ethyl)ether.
• a purification step can be applied before or after the amine crystallisation, such as an adsorption.
• Another advantage of the process of the invention which contributes to an increased economically process involves the recovery of the mother liquid, which can be reintroduced in the process, e.g. during the extraction phase.
• the liquid is purified before reintroduction, e.g. by adsorption or evaporation.
• the azeotropic mixture can either be discharged, after which the solvent is reused, or the azeotropic mixture is reused as such in the subsequent crystallisation.
• the amine and clavulanic acid present in the solvent are recovered prior to recycling the solvent.
• This can be done for example by extraction with water at low or high pH, by ion exchange or by crystallisation.
• a possible process for the preparation of a pharmaceutically acceptable salt or ester of clavulanic acid can be fermentation of a clavulanic acid producing micro-organism followed by separation of the biomass by (membrane) filtration, optionally after addition of a water miscible solvent or a flocculant. Then, optionally the filtrate can be concentrated, e.g. by reverse osmosis or evaporation. Subsequently, the clavulanic acid is extracted to an organic solvent at low pH. Another possibility of simultaneous biomass removal and extraction is whole broth extraction after acidification.
• the solution can be purified e.g. by adsorption and coal treatment.
• the extract can be concentrated before or after purification, e.g. by evaporation.
• the amine crystallisation can take place as mentioned above, followed by conversion into purified clavulanic acid by acidifying or into a pharmaceutically acceptable salt or ester clavulanate by adding a source of the corresponding salt or ester.
• a recrystallisation of the amine clavulanate can be performed before this final crystallisation.
• purified clavulanic acid or the pharmaceutically acceptable ester or salt clavulanate is separated from the solution.
• the solutions were stirred during 1 hour at a temperature of -40 °C, -20 °C, 0 ° C, 20 ° C and 40 ° C, respectively.
• the crystals were separated by filtration and washed with circa 1 00 ml of ethyl acetate. After drying the wet cake in nitrogen atmosphere at room temperature, the mass of the product was 7.83, 7.97, 7.79, 7.64 and 7.44 g, respectively.
• the purities were 86.7, 86.3, 87.7, 87.7 and 89.6%, respectively.
• the crystals were washed with ethyl acetate.
• the crystals were dried under a vacuum atmosphere at room temperature to yield 53.59 , 53.96 and 54.87 grams, respectively.
• the purities of the crystals were 91 .7%,
• the crystal suspensions were cooled to 1 0°C and immediately after reaching this temperature the crystals were collected by filtration. The crystals were washed with ethyl acetate. The crystals were dried under a vacuum atmosphere at room temperature to yield 47.1 7 , 47.94 , 48.37, 48.99 and 49.73 grams, respectively. The purities of the crystals were 90.0%, 89.9%, 89.7%, 88.3% and 87.0%, respectively.

Landscapes

• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Life Sciences & Earth Sciences (AREA)
• Zoology (AREA)
• Wood Science & Technology (AREA)
• Health & Medical Sciences (AREA)
• General Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Biotechnology (AREA)
• Biochemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Microbiology (AREA)
• General Health & Medical Sciences (AREA)
• Genetics & Genomics (AREA)
• Preparation Of Compounds By Using Micro-Organisms (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Cephalosporin Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (3)

Applications Claiming Priority (2)

Publications (1)

Family

ID=8233939

Family Applications (1)

Country Status (6)

Cited By (3)

Families Citing this family (3)

Citations (11)

• 1999
  • 1999-07-13 WO PCT/EP1999/005026 patent/WO2000004028A1/en not_active Application Discontinuation
  • 1999-07-13 TR TR2001/00082T patent/TR200100082T2/xx unknown
  • 1999-07-13 CA CA002337072A patent/CA2337072A1/en not_active Abandoned
  • 1999-07-13 CN CN 99809491 patent/CN1312814A/zh active Pending
  • 1999-07-13 AU AU54110/99A patent/AU5411099A/en not_active Abandoned
  • 1999-07-13 EP EP99940010A patent/EP1095046A1/de not_active Withdrawn

Patent Citations (11)

Also Published As

Similar Documents

Legal Events