CA2337072A1 - Improved process for the preparation of salts and esters of clavulanic acid - Google Patents
Improved process for the preparation of salts and esters of clavulanic acid Download PDFInfo
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Abstract
A process for the production of an amine salt of clavulanic acid and the conversion thereof into a pharmaceutically acceptable salt or ester thereof has been provided. During the crystallisation phase of the amine salt of clavulanic acid either a clavulanic acid containing solution, optionally with a cosolvent, is added to the amine or both reactants are added together to a cristallisation vessel. Also the application of a temperature profile (decreasing in time), profile of speed of addition (increasing in time) and a profile of the ratio amine/clavulanic acid (increasing in time) for this cristallisation process has been provided for.
Description
IMPROVED PROCESS FOR THE PREPARATION OF SALTS AND ESTERS
s OF CLAVULANIC ACID
The present invention relates to a process for the preparation of an amine salt of clavulanic acid and to the conversion thereof into ~o pharmaceutically acceptable alkali metal salts and esters of clavulanic acid, especially potassium clavulanate.
Clavulanic acid and its alkali metal salts and esters are ~3-lactamase inhibitors, able to enhance the effectiveness of penicillins and cephalosporins.
~ s Usually, clavulanic acid is prepared by the fermentation of a microorganism which produces clavulanic acid as for instance Stre tp omyces 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 1508977.
2o Techniques described to remove the biomass are filtration of the broth using e.g. rolling sieves (EP 0 387 178), rotary drum filtration or membrane filtration (EP 0 748 387), optionally after the addition of flocculants or a water miscible solvent. Centrifugation may also be used to separate the biomass. After filtration, purification may be applied e.g.
2s by adsorption and the filtrate may be concentrated by reverse osmosis or evaporation, after which at low pH extraction into an organic solvent occurs using e.g. an extraction column or centrifugal extractors. Also whole broth extraction can be applied (WO 98/21212). Then, usually an amine crystallisation is performed, optionally after a purification step.
ao Subsequently, a recrystallisation might be performed and finally a crystallisation to prepare a pharmaceutically acceptable salt of clavulanic acid, such as potassium clavulanate. Also, processes in which back extraction is applied are described (WO 96/222961.
European patent application EP-A-26044 discloses the use of the tertiary butyl amine salt of clavulanic acid as an useful intermediate in the s preparation of clavulanic acid. Other amine salts of clavulanic acid are disclosed in the patent documents EP-A-387178, EP-A-562583, WO
93/25557, WO 94/22873, WO 96/20199 and WO 96/26944.
Most procedures to recover clavulanic acid suffer of bad crystallisation behaviour when an amine is contacted with clavulanic acid ~o to form an amine clavulanate. Usually, material sticks to the walls in the normally applied solvent solution, resulting in a yield loss. Therefore a water miscible organic solvent (i.e. cosolvent) like a ketone or an alcohol is often added before or during the crystallisation which prevents the tendency of the amine crystals to stick to the walls. This is described for is example in the international patent applications WO 93/25557, WO
96/20199, WO 96/26944, WO 96/33197 and WO 98/21212.
However, 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 zo 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 zs using a minimal amount of solvents. Surprisingly 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 ciavulanic acid solution to the amine solution instead of the usual addition of the amine ao 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 s process as the use of a cosolvent has been minimized or even avoided completely.
Summary of the invention ~o 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. According to another embodiment, also a process containing i s 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). According to another aspect of the invention the 2o 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.
2s Descrir~tion of the invention The essence of the crystallisation process according to the present invention comprises of placing a solution of amine in a solvent, optionally so 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. By applying this method the use of a cosolvent has been minimized. This results in a more economical attractive process as the volume of solvents decreases significantly. Also, if no cosolvent is used at all, recycling of the mother liquid is possible and/or facilitated because no additional process is needed to separate a mixture of solvents. The s invention decreases also pollution effects, as currently mixtures of solvents might be disposed off. Also in case a cosolvent is needed, normally 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~thanoI~VeLhyl acetate is less than 0.15, preferably less than 0.10.
~s A further embodiment of the invention is the simultaneous and separate addition of a solution of clavuianic acid in a solvent and an amine optionally dissolved in a solvent, preferably the same solvent, optionally containing a small amount of cosolvent. Optionally, before starting the addition, a small quantity of either the solvent, the cosolvent, the zo clavuianic acid solution in the solvent, the amine or a combination of the solutions can be placed in the crystallisation vessel. Also, 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 is the crystal quality.
Both in case of the addition of a solution of clavulanic acid to the amine and in case of the simultaneous addition of both reactants to a crystallisation vessel, optionally a cosolvent may be added to one or both of the reactant solutions. It is of course in both cases also within the so scope of the invention that 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.
Crystallisation occurs upon stirring and controlling the temperature between - 50 and + 50 °C, and more specifically between 0 and 40 °C.
s It is also possible to create a temperature profile, i.e. for instance a higher temperature (T = 20-40 °C) during the addition of clavulanic acid or during the simultaneous addition of clavulanic acid and amine solution followed by cooling down directly after the first crystal formation or during the ageing of the crystals (T=0-10 °C). In this way, the aualitv of the ~o crystals can be improved. The period of addition may vary between 2 and 120 minutes, preferably between 30 and 60 minutes.
According to another aspect of the invention, 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. For ~s instance, 1-10% 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. Furthermore, seeding material may be added to the vessel before addition of the clavufanic acid solution. The concentration of clavulanic acid in the solvent may vary zo between 10 and 100 g/I, preferably between 15 and 50 g/I. The overall molar excess of amine related to clavulanic acid should be between 1.2 and 2.4.
Preferably, the organic solvent comprises an aliphatic carboxylic ester or a substantially water-immiscible aliphatic ketone, such as an Zs 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.
ao 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.
Optionally, a purification step can be applied before or after the amine crystallisation, such as an adsorption.
s 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. Optionally, the liquid is purified before reintroduction, e.g. by adsorption or evaporation. In case a small ~o cosolvent volume is used, which formes an azeotrope with the solvent, 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. Preferably, the amine and clavulanic acid present in the solvent are recovered prior to recycling the solvent. This can be done for ~ s example by extraction with water at low or high pH, by ion exchange or by crystallisation. Thus, according to the present invention, a possible process far 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) zo 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 2s after acidification.
After the extraction, the solution can be purified e.g, by adsorption and coal treatment. Optionally, the extract can be concentrated before or after purification, e.g. by evaporation. Then the amine crystallisation can take place as mentioned above, followed by conversion into purified ao clavulanic acid by acidifying or into a pharmaceutically acceptable salt or ester clavulanate by adding a source of the corresponding salt or ester.
_7_ Optionally, before this final crystallisation, a recrystallisation of the amine clavulanate can be performed. Finally, purified clavulanic acid or the pharmaceutically acceptable ester or salt clavulanate is separated from the solution.
The following examples will illustrate the invention further.
Crystallisation of bis(2-(dimethylamino)ethyl)ether clavulanate from a ~o ciavulanic acid solution in ethyl acetate and conversion thereof into potassium clavulanate The following experiment was carried out in nitrogen atmosphere.
A volume of 1000 ml ethyl acetate containing clavulanic acid, was mixed ~5 during 2 hours with 155 gram Norit SX ultra at T = 0-2 °C. Then the solution was filtrated and washed with 400 ml of ethyl acetate. The wash solution was added to the filtrate, leading to a clavulanic acid concentration of 40 g/I.
500 ml of the carbon treated solution was added to 350 ml of ethyl zo acetate which contained 11.2 gram of 2-(dimethylamino)ethyl)ether. The solution was stirred during 1 hour at T - 0 ° C. The crystals were separated by filtration and washed with 400 ml of ethyl acetate. After drying the wet cake volume in nitrogen atmosphere at room temperature, 32.2 grams of product was obtained, with a purity of 90.5 %.
Purification of bis(2-(dimeth~rlamino)eth~rl)ethPr clavulanate by recrystallisation 20 Grams of these crystals were dissolved in 140 ml of a mixture of ethanol (87%) and water (13%). 2 Grams of Norit SX Ultra were added ao at T - 0-2 °C and the solution was stirred during 15 minutes. After filtration, the cake was washed twice with 50 ml of the ethanol-water mixture. Then during 30 minutes the filtrate was added to 1500 ml of _g_ acetone and the solution was stirred during 1 hour at 10 ° C. The crystals were separated using filtration and the cake was washed twice with 50 ml of acetone. After drying the crystals in nitrogen atmosphere at room temperature, 15.73 g of product was obtained, with a purity of 96.3%.
Crars~allisation of potassium clavulanate using recrystallised bis(2-(dimethylaminolethail)ether clavulanate Grams of these crystals were suspended in 375 ml of acetone and 3.75 ml of water, at a temperature of 10 °C. Then, during circa 25 ~o minutes 220 ml of a 0.34 M potassium 2-ethyl hexanoate solution in acetone was added. The suspension was stirred for an hour at 10 °C
after which the crystals were separated by filtration. The cake was washed using 3 cake volumes of acetone. Then the crystals were dried in nitrogen atmosphere at room temperature. In this way, 12.32 g of ~5 potassium clavulanate was produced, with a purity of 96.4 %.
Crystallisation of bis(2-Idimethylamino)ethyl)ether clavulanate from a zo clavutanic acid solution in ethyl acetate at different temperatures The following experiment was carried out under nitrogen atmosphere. A volume of 700 ml of ethyl acetate containing circa 60 g/I
of clavulanic acid, was mixed during 2 hours with 106 g Norit SX ultra at z5 a temperature of 0-2 °C. Then the solution was filtrated and washed with 265 ml of ethyl acetate. The wash solution was added to the filtrate, leading to a clavulanic acid concentration of 40 g/I. This solution was divided into 5 portions of 100 ml each. Each portion was added in circa minutes to 70 ml of ethyl acetate containing 2.25 g 2-so (dimethylamino)ethyl)ether. The solutions were stirred during 1 hour at a _9_ temperature of -40 ° C, -20 ° C, 0 ° C, 20 ° C and 40 ° C, respectively.
The crystals were separated by filtration and washed with circa 100 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.
~o Crystallisation of bis(2-(dimethylamino)ethyf)ether clavulanate from a clavulanic acid solution by simultaneous addition of clavulanic acid and amine The following experiment was carried out under nitrogen ~s atmosphere. A volume of 100 ml of ethyl acetate was added to an empty crystallisation vessel at a temperature of 10 ° C. Then in circa 20 minutes simultaneously a solution of 11.2 g of 2-(dimethylamino)ethyl)ether in 350 ml of ethyl acetate and a 500 ml solution of ethyl acetate containing clavufanic acid fca 40 g/I) were added to the crystallisation vessel. The 2o temperature was decreased to 5 °C and the solution was stirred during 1.5 hours. The crystals were separated by filtration and washed with circa 500 ml of ethyl acetate. After drying the wet cake in nitrogen atmosphere at room temperature, the mass of the product was 28.04 g.
2s Examl I~ a 4 Crystallisation of bis(2-(dimethylamino)ethyl)ether clavulanate from a clavulanic acid solution by simultaneous addition of clavufanic acid and amine using a profile for both speed of addition and temperature.
The following experiment was carried out under nitrogen atmosphere. A
volume of 250 ml of dry ethyl acetate was added to an empty vessel.
s OF CLAVULANIC ACID
The present invention relates to a process for the preparation of an amine salt of clavulanic acid and to the conversion thereof into ~o pharmaceutically acceptable alkali metal salts and esters of clavulanic acid, especially potassium clavulanate.
Clavulanic acid and its alkali metal salts and esters are ~3-lactamase inhibitors, able to enhance the effectiveness of penicillins and cephalosporins.
~ s Usually, clavulanic acid is prepared by the fermentation of a microorganism which produces clavulanic acid as for instance Stre tp omyces 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 1508977.
2o Techniques described to remove the biomass are filtration of the broth using e.g. rolling sieves (EP 0 387 178), rotary drum filtration or membrane filtration (EP 0 748 387), optionally after the addition of flocculants or a water miscible solvent. Centrifugation may also be used to separate the biomass. After filtration, purification may be applied e.g.
2s by adsorption and the filtrate may be concentrated by reverse osmosis or evaporation, after which at low pH extraction into an organic solvent occurs using e.g. an extraction column or centrifugal extractors. Also whole broth extraction can be applied (WO 98/21212). Then, usually an amine crystallisation is performed, optionally after a purification step.
ao Subsequently, a recrystallisation might be performed and finally a crystallisation to prepare a pharmaceutically acceptable salt of clavulanic acid, such as potassium clavulanate. Also, processes in which back extraction is applied are described (WO 96/222961.
European patent application EP-A-26044 discloses the use of the tertiary butyl amine salt of clavulanic acid as an useful intermediate in the s preparation of clavulanic acid. Other amine salts of clavulanic acid are disclosed in the patent documents EP-A-387178, EP-A-562583, WO
93/25557, WO 94/22873, WO 96/20199 and WO 96/26944.
Most procedures to recover clavulanic acid suffer of bad crystallisation behaviour when an amine is contacted with clavulanic acid ~o to form an amine clavulanate. Usually, material sticks to the walls in the normally applied solvent solution, resulting in a yield loss. Therefore a water miscible organic solvent (i.e. cosolvent) like a ketone or an alcohol is often added before or during the crystallisation which prevents the tendency of the amine crystals to stick to the walls. This is described for is example in the international patent applications WO 93/25557, WO
96/20199, WO 96/26944, WO 96/33197 and WO 98/21212.
However, 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 zo 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 zs using a minimal amount of solvents. Surprisingly 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 ciavulanic acid solution to the amine solution instead of the usual addition of the amine ao 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 s process as the use of a cosolvent has been minimized or even avoided completely.
Summary of the invention ~o 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. According to another embodiment, also a process containing i s 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). According to another aspect of the invention the 2o 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.
2s Descrir~tion of the invention The essence of the crystallisation process according to the present invention comprises of placing a solution of amine in a solvent, optionally so 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. By applying this method the use of a cosolvent has been minimized. This results in a more economical attractive process as the volume of solvents decreases significantly. Also, if no cosolvent is used at all, recycling of the mother liquid is possible and/or facilitated because no additional process is needed to separate a mixture of solvents. The s invention decreases also pollution effects, as currently mixtures of solvents might be disposed off. Also in case a cosolvent is needed, normally 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~thanoI~VeLhyl acetate is less than 0.15, preferably less than 0.10.
~s A further embodiment of the invention is the simultaneous and separate addition of a solution of clavuianic acid in a solvent and an amine optionally dissolved in a solvent, preferably the same solvent, optionally containing a small amount of cosolvent. Optionally, before starting the addition, a small quantity of either the solvent, the cosolvent, the zo clavuianic acid solution in the solvent, the amine or a combination of the solutions can be placed in the crystallisation vessel. Also, 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 is the crystal quality.
Both in case of the addition of a solution of clavulanic acid to the amine and in case of the simultaneous addition of both reactants to a crystallisation vessel, optionally a cosolvent may be added to one or both of the reactant solutions. It is of course in both cases also within the so scope of the invention that 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.
Crystallisation occurs upon stirring and controlling the temperature between - 50 and + 50 °C, and more specifically between 0 and 40 °C.
s It is also possible to create a temperature profile, i.e. for instance a higher temperature (T = 20-40 °C) during the addition of clavulanic acid or during the simultaneous addition of clavulanic acid and amine solution followed by cooling down directly after the first crystal formation or during the ageing of the crystals (T=0-10 °C). In this way, the aualitv of the ~o crystals can be improved. The period of addition may vary between 2 and 120 minutes, preferably between 30 and 60 minutes.
According to another aspect of the invention, 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. For ~s instance, 1-10% 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. Furthermore, seeding material may be added to the vessel before addition of the clavufanic acid solution. The concentration of clavulanic acid in the solvent may vary zo between 10 and 100 g/I, preferably between 15 and 50 g/I. The overall molar excess of amine related to clavulanic acid should be between 1.2 and 2.4.
Preferably, the organic solvent comprises an aliphatic carboxylic ester or a substantially water-immiscible aliphatic ketone, such as an Zs 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.
ao 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.
Optionally, a purification step can be applied before or after the amine crystallisation, such as an adsorption.
s 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. Optionally, the liquid is purified before reintroduction, e.g. by adsorption or evaporation. In case a small ~o cosolvent volume is used, which formes an azeotrope with the solvent, 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. Preferably, the amine and clavulanic acid present in the solvent are recovered prior to recycling the solvent. This can be done for ~ s example by extraction with water at low or high pH, by ion exchange or by crystallisation. Thus, according to the present invention, a possible process far 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) zo 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 2s after acidification.
After the extraction, the solution can be purified e.g, by adsorption and coal treatment. Optionally, the extract can be concentrated before or after purification, e.g. by evaporation. Then the amine crystallisation can take place as mentioned above, followed by conversion into purified ao clavulanic acid by acidifying or into a pharmaceutically acceptable salt or ester clavulanate by adding a source of the corresponding salt or ester.
_7_ Optionally, before this final crystallisation, a recrystallisation of the amine clavulanate can be performed. Finally, purified clavulanic acid or the pharmaceutically acceptable ester or salt clavulanate is separated from the solution.
The following examples will illustrate the invention further.
Crystallisation of bis(2-(dimethylamino)ethyl)ether clavulanate from a ~o ciavulanic acid solution in ethyl acetate and conversion thereof into potassium clavulanate The following experiment was carried out in nitrogen atmosphere.
A volume of 1000 ml ethyl acetate containing clavulanic acid, was mixed ~5 during 2 hours with 155 gram Norit SX ultra at T = 0-2 °C. Then the solution was filtrated and washed with 400 ml of ethyl acetate. The wash solution was added to the filtrate, leading to a clavulanic acid concentration of 40 g/I.
500 ml of the carbon treated solution was added to 350 ml of ethyl zo acetate which contained 11.2 gram of 2-(dimethylamino)ethyl)ether. The solution was stirred during 1 hour at T - 0 ° C. The crystals were separated by filtration and washed with 400 ml of ethyl acetate. After drying the wet cake volume in nitrogen atmosphere at room temperature, 32.2 grams of product was obtained, with a purity of 90.5 %.
Purification of bis(2-(dimeth~rlamino)eth~rl)ethPr clavulanate by recrystallisation 20 Grams of these crystals were dissolved in 140 ml of a mixture of ethanol (87%) and water (13%). 2 Grams of Norit SX Ultra were added ao at T - 0-2 °C and the solution was stirred during 15 minutes. After filtration, the cake was washed twice with 50 ml of the ethanol-water mixture. Then during 30 minutes the filtrate was added to 1500 ml of _g_ acetone and the solution was stirred during 1 hour at 10 ° C. The crystals were separated using filtration and the cake was washed twice with 50 ml of acetone. After drying the crystals in nitrogen atmosphere at room temperature, 15.73 g of product was obtained, with a purity of 96.3%.
Crars~allisation of potassium clavulanate using recrystallised bis(2-(dimethylaminolethail)ether clavulanate Grams of these crystals were suspended in 375 ml of acetone and 3.75 ml of water, at a temperature of 10 °C. Then, during circa 25 ~o minutes 220 ml of a 0.34 M potassium 2-ethyl hexanoate solution in acetone was added. The suspension was stirred for an hour at 10 °C
after which the crystals were separated by filtration. The cake was washed using 3 cake volumes of acetone. Then the crystals were dried in nitrogen atmosphere at room temperature. In this way, 12.32 g of ~5 potassium clavulanate was produced, with a purity of 96.4 %.
Crystallisation of bis(2-Idimethylamino)ethyl)ether clavulanate from a zo clavutanic acid solution in ethyl acetate at different temperatures The following experiment was carried out under nitrogen atmosphere. A volume of 700 ml of ethyl acetate containing circa 60 g/I
of clavulanic acid, was mixed during 2 hours with 106 g Norit SX ultra at z5 a temperature of 0-2 °C. Then the solution was filtrated and washed with 265 ml of ethyl acetate. The wash solution was added to the filtrate, leading to a clavulanic acid concentration of 40 g/I. This solution was divided into 5 portions of 100 ml each. Each portion was added in circa minutes to 70 ml of ethyl acetate containing 2.25 g 2-so (dimethylamino)ethyl)ether. The solutions were stirred during 1 hour at a _9_ temperature of -40 ° C, -20 ° C, 0 ° C, 20 ° C and 40 ° C, respectively.
The crystals were separated by filtration and washed with circa 100 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.
~o Crystallisation of bis(2-(dimethylamino)ethyf)ether clavulanate from a clavulanic acid solution by simultaneous addition of clavulanic acid and amine The following experiment was carried out under nitrogen ~s atmosphere. A volume of 100 ml of ethyl acetate was added to an empty crystallisation vessel at a temperature of 10 ° C. Then in circa 20 minutes simultaneously a solution of 11.2 g of 2-(dimethylamino)ethyl)ether in 350 ml of ethyl acetate and a 500 ml solution of ethyl acetate containing clavufanic acid fca 40 g/I) were added to the crystallisation vessel. The 2o temperature was decreased to 5 °C and the solution was stirred during 1.5 hours. The crystals were separated by filtration and washed with circa 500 ml of ethyl acetate. After drying the wet cake in nitrogen atmosphere at room temperature, the mass of the product was 28.04 g.
2s Examl I~ a 4 Crystallisation of bis(2-(dimethylamino)ethyl)ether clavulanate from a clavulanic acid solution by simultaneous addition of clavufanic acid and amine using a profile for both speed of addition and temperature.
The following experiment was carried out under nitrogen atmosphere. A
volume of 250 ml of dry ethyl acetate was added to an empty vessel.
Then, in approximately 5 minutes under vigorous stirring simultaneously 2 vol-% of 1000 ml of a solution of clavulanic acid in ethyl acetate, with a concentration of ca 40 g/I of clavulanic acid, and 2 vol-% of a solution of 22.9 grams of amine in 250 ml of ethyl acetate are added. The temperature during addition was 37°C. After crystallisation the remaining 98 vol-% of both clavulanic acid solution and amine solution were added in ratio in approximately 5 minutes. In the meantime, cooling was started to reach 18°C at the time the addition of the solutions was finished.
Cooling was proceeded until 0 - 5°C and the crystal slurry was stirred at 1o this temperature for one hour. The crystals were separated by filtration and washed twice with 100 ml of ethyl acetate. The crystals were dried under vacuum atmosphere at room temperature to yield 64.32 grams.The purity of the crystals was 87.9% and the yield was 99.5%.
Crystallisation of bis(2-(dimethylamino)ethylether clavulanate from a clavulanic acid solution by simultaneous addition of clavulanic acid and a zo solution of amine using 8% ethanol as a co-solvent and conversion thereof into potassium clavulanate.
The following experiment was carried out under Nitrogen atmosphere. A volume of 150 ml of dry ethyl acetate was added to an z5 empty vessel. 0.6 grams of bis(2-(dimethylamino)ethylether were added as seeding crystals. Then, in approximately 60 minutes 1200 ml of a solution of clavulanic acid in ethyl acetate (ca 40 g/I), and a solution of 29.4 g of amine in 150 ml of ethanol (99.5%) and 300 mf of ethyl acetate were added to the stirred vessel. The temperature during the so addition was 20 ° C. The crystal slurry was cooled to 10 ° 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 76.32 grams. The purity of the crystals was 95.7 % and and the yield was 100%.
s Purification of bisf2-(dimethylaminolethy .thPr ~yulanate by recr~,stalfisation 65 Grams of these crystals were dissolved in 433 ml of a mixture of ethanol (87%) and water (13%). The solution was filtrated through an active carbon containing filter plate followed by a 0.45 p,m filter. During ~ o filtration the temperature was kept a 0 - 5 ° C. The filters were rinsed with 81 ml of the ethanol/water mixture. The filtrates were collected in an empty vessel. Then, during one hour, 3088 ml of acetone was added while the temperature was kept at 10°C. After addition the temperature was decreased to 5°C and the crystal suspension was stirred during one i s hour at this temperature. The crystals were collected by filtration, the crystals were washed with acetone.
Crystallisation of potassium clavulanate using recrystal~ bis(2-(dimethylamino)ethyl)ether clavulanate 2o The wet recrystallised bis(2-(dimethylamino)ethylether clavuianate crystals were suspended in 1437 ml of acetone and 14.4 grams of water.
Then, during one hour, 847 ml of 0.34M potassium 2-ethyl hexanoate in acetone was added. The temperature during the addition was 10°C. The suspension was stirred for one hour at 10°C after which the crystals is were collected by filtration. The crystals were washed with acetone. The crystals were dried under a vacuum atmosphere to yield 47.29 grams of potassium clavulanate with a purity of 96.0%.
Crystallisation of bis(2-(dimethylamino)ethylether clavulanate from a s clavulanic acid solution by simultaneous addition of clavulanic acid and a solution of amine at different temperatures using 8% ethanol as a co-solvent.
The following experiments were carried out under Nitrogen ~o atmosphere. A volume of 100 ml of dry ethyl acetate was added to an empty vessel and 0.4 grams of bis(2-(dimethylamino)ethylether were added as seeding crystals. Then, in approximately 60 minutes 800 mf of a solution of clavulanic acid in ethyl acetate, containing ca 40 g/I, and a solution of 19.8 g of amine dissolved in 100 ml of ethanol (99.5%) ~s together with 200 ml of ethyl acetate were added to the stirred vessel.
The temperatures during the addition were, respectively 40, 30 and 20°C. The crystal suspensions were cooled to 10°C and immediately after reaching this temperature the crystals were collected by filtration.
The crystals were washed with ethyl acetate. The crystals were dried zo 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%, 90.5% and 90.6%, respectively.
zs Exam Il~ a 7 Crystallisation of bis(2-(dimethylamino)ethylether clavulanate from a clavulanic acid solution by simultaneous addition of clavulanic acid and a solution of amine using different amounts of ethanol as co-solvent.
The following experiments were carried out under Nitrogen atmosphere. A volume of 100 ml of dry ethyl acetate was added to an empty vessel and 0.4 grams of bis(2-(dimethylamino)ethylether were added as seeding crystals. Then, in approximately 60 minutes 800 ml of a solution of clavulanic acid in ethyl acetate, containing ca 40 g/I, and a solution of 17.5 g amine dissolved in, respectively 100, 75, 50, 25 and 0 ml ethanol (99.5%) together with, respectively 200, 225, 250, 275 and 300 ml of ethyl acetate were added to the stirred vessel. The temperature during the addition was 20°C. The crystal suspensions were cooled to 10°C and immediately after reaching this temperature the crystals were collected by filtration. The crystals were washed with ethyl acetate. The ~o crystals were dried under a vacuum atmosphere at room temperature to yield 47.17 , 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.
Cooling was proceeded until 0 - 5°C and the crystal slurry was stirred at 1o this temperature for one hour. The crystals were separated by filtration and washed twice with 100 ml of ethyl acetate. The crystals were dried under vacuum atmosphere at room temperature to yield 64.32 grams.The purity of the crystals was 87.9% and the yield was 99.5%.
Crystallisation of bis(2-(dimethylamino)ethylether clavulanate from a clavulanic acid solution by simultaneous addition of clavulanic acid and a zo solution of amine using 8% ethanol as a co-solvent and conversion thereof into potassium clavulanate.
The following experiment was carried out under Nitrogen atmosphere. A volume of 150 ml of dry ethyl acetate was added to an z5 empty vessel. 0.6 grams of bis(2-(dimethylamino)ethylether were added as seeding crystals. Then, in approximately 60 minutes 1200 ml of a solution of clavulanic acid in ethyl acetate (ca 40 g/I), and a solution of 29.4 g of amine in 150 ml of ethanol (99.5%) and 300 mf of ethyl acetate were added to the stirred vessel. The temperature during the so addition was 20 ° C. The crystal slurry was cooled to 10 ° 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 76.32 grams. The purity of the crystals was 95.7 % and and the yield was 100%.
s Purification of bisf2-(dimethylaminolethy .thPr ~yulanate by recr~,stalfisation 65 Grams of these crystals were dissolved in 433 ml of a mixture of ethanol (87%) and water (13%). The solution was filtrated through an active carbon containing filter plate followed by a 0.45 p,m filter. During ~ o filtration the temperature was kept a 0 - 5 ° C. The filters were rinsed with 81 ml of the ethanol/water mixture. The filtrates were collected in an empty vessel. Then, during one hour, 3088 ml of acetone was added while the temperature was kept at 10°C. After addition the temperature was decreased to 5°C and the crystal suspension was stirred during one i s hour at this temperature. The crystals were collected by filtration, the crystals were washed with acetone.
Crystallisation of potassium clavulanate using recrystal~ bis(2-(dimethylamino)ethyl)ether clavulanate 2o The wet recrystallised bis(2-(dimethylamino)ethylether clavuianate crystals were suspended in 1437 ml of acetone and 14.4 grams of water.
Then, during one hour, 847 ml of 0.34M potassium 2-ethyl hexanoate in acetone was added. The temperature during the addition was 10°C. The suspension was stirred for one hour at 10°C after which the crystals is were collected by filtration. The crystals were washed with acetone. The crystals were dried under a vacuum atmosphere to yield 47.29 grams of potassium clavulanate with a purity of 96.0%.
Crystallisation of bis(2-(dimethylamino)ethylether clavulanate from a s clavulanic acid solution by simultaneous addition of clavulanic acid and a solution of amine at different temperatures using 8% ethanol as a co-solvent.
The following experiments were carried out under Nitrogen ~o atmosphere. A volume of 100 ml of dry ethyl acetate was added to an empty vessel and 0.4 grams of bis(2-(dimethylamino)ethylether were added as seeding crystals. Then, in approximately 60 minutes 800 mf of a solution of clavulanic acid in ethyl acetate, containing ca 40 g/I, and a solution of 19.8 g of amine dissolved in 100 ml of ethanol (99.5%) ~s together with 200 ml of ethyl acetate were added to the stirred vessel.
The temperatures during the addition were, respectively 40, 30 and 20°C. The crystal suspensions were cooled to 10°C and immediately after reaching this temperature the crystals were collected by filtration.
The crystals were washed with ethyl acetate. The crystals were dried zo 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%, 90.5% and 90.6%, respectively.
zs Exam Il~ a 7 Crystallisation of bis(2-(dimethylamino)ethylether clavulanate from a clavulanic acid solution by simultaneous addition of clavulanic acid and a solution of amine using different amounts of ethanol as co-solvent.
The following experiments were carried out under Nitrogen atmosphere. A volume of 100 ml of dry ethyl acetate was added to an empty vessel and 0.4 grams of bis(2-(dimethylamino)ethylether were added as seeding crystals. Then, in approximately 60 minutes 800 ml of a solution of clavulanic acid in ethyl acetate, containing ca 40 g/I, and a solution of 17.5 g amine dissolved in, respectively 100, 75, 50, 25 and 0 ml ethanol (99.5%) together with, respectively 200, 225, 250, 275 and 300 ml of ethyl acetate were added to the stirred vessel. The temperature during the addition was 20°C. The crystal suspensions were cooled to 10°C and immediately after reaching this temperature the crystals were collected by filtration. The crystals were washed with ethyl acetate. The ~o crystals were dried under a vacuum atmosphere at room temperature to yield 47.17 , 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.
Claims (13)
1, A process for the preparation of an amine sail of clavulanic acid comprising:
(a) producing clavulanic acid by fermentation of a clavulanic acid-producing microorganism in a fermentation broth;
(b) extracting the clavulanic acid from the fermentation broth with a water immiscible organic solvent to form an organic extract containing clavulanic acid;
(c) optionally, purifying by adsorption the organic extract containing clavulanic acid;
(d) converting the clavulanic acid into an amine salt thereof by adding the organic extract containing clavulanic acid to a crystallization vessel containing an amine solution comprising an organic solvent that may be the same as the water immiscible solvent used to extract clavulanic acid from the fermentation broth; and (e) separating the amine salt of clavulanic acid from solution;
whereby, optionally, each of the extracted organic solution containing clavulanic acid and the amine dissolved in the water immiscible solvent may comprise a cosolvent that is miscible with the solvent.
(a) producing clavulanic acid by fermentation of a clavulanic acid-producing microorganism in a fermentation broth;
(b) extracting the clavulanic acid from the fermentation broth with a water immiscible organic solvent to form an organic extract containing clavulanic acid;
(c) optionally, purifying by adsorption the organic extract containing clavulanic acid;
(d) converting the clavulanic acid into an amine salt thereof by adding the organic extract containing clavulanic acid to a crystallization vessel containing an amine solution comprising an organic solvent that may be the same as the water immiscible solvent used to extract clavulanic acid from the fermentation broth; and (e) separating the amine salt of clavulanic acid from solution;
whereby, optionally, each of the extracted organic solution containing clavulanic acid and the amine dissolved in the water immiscible solvent may comprise a cosolvent that is miscible with the solvent.
2. A process according to claim 1, characterized by varying the temperature from 20-4C°C during the addition of the organic extract containing clavulanic acid to the amine solution in the crystallization vessel to form crystals and lowering the temperature to 0-10°C upon aging of the crystals.
3. A process according to claim 1 or 2, characterized by starting with a slow addition of the organic extract containing clavulanic acid to the amine solution until the first crystals ace formed and thereafter increasing the velocity of the addition.
4. A process according to any one of claims 1-4, characterized in that the amine is a member selected from the group consisting of N,N,N',N'-tetramethytethylenediamine, 1,3-bis (dimethylamino)-2-propanol, N,N'-diisopropylehtyienediamine, t-butylamine, t-octylamine, benzhydryloamine and bis (2-(dimethylamino)ethyl) ether.
5. A process according to any one of claims 1-5, characterized in that solids are removed from the clavulanic acid containing fermentation broth before extraction, preferably by filtration or centrifugation, optionally upon adding a flocculation agent to the fermentation broth,
6. A process according to any one of claims 1-6, characterized in that an alcohol or a ketone acts as a cosolvent.
7. A process according to claim 6, characterized in that the alcohol is a member selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol; acetone and propanone.
8. A process according to any one of claims 1-7, characterized in that the clavulanic acid is extracted with an acetate.
9. A process according to claim 8, characterized in that the amine is dissolved in the same type of acetate used to extract the clavulanic acid.
10. A process according to claim 8 or claim 8, characterized in that the acetate is ethyl acetate.
11. A process for the preparation of isolated clavulanic acid or a pharmaceutically acceptable salt or ester of clavulanic acid by conversion of an amine clavulanate solution formed according to the process of any one of claims 1-10, optionally after recrystallisation, into purified clavulanic acid by acidifying or by conversion into a pharmaceutically acceptable salt or ester clavulanate by adding a source of the corresponding salt or ester, followed by separation of the calvulanic acid or pharmaceutically acceptable salt or ester clavulanate formed.
12. A process for the preparation of potassium clavulanate according to claim characterized in that an extracted solution of clavulanic acid comprising ethyl acetate is added to a recrystallisation vessel containing an amine solution comprising ethyl acetate to form a clavulanate amine salt, the amine solution optionally containing alcohol in such a volume that V ethanol/V ethyl acetate is less than 0.15%, whereby the process may optionally comprise the steps of recrystallisation and conversion of the clavulanate amine salt into postassium clavulanate using potassium ethylhexanoate.
13. A process according to any one of claims 1-5 or 8-13, comprising recycling a mother liquor formed from the solvents used in preparing the amine salt of clavulanic acid.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP98202390.5 | 1998-07-16 | ||
| EP98202390 | 1998-07-16 | ||
| PCT/EP1999/005026 WO2000004028A1 (en) | 1998-07-16 | 1999-07-13 | Improved process for the preparation of salts and esters of clavulanic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2337072A1 true CA2337072A1 (en) | 2000-01-27 |
Family
ID=8233939
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002337072A Abandoned CA2337072A1 (en) | 1998-07-16 | 1999-07-13 | Improved process for the preparation of salts and esters of clavulanic acid |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1095046A1 (en) |
| CN (1) | CN1312814A (en) |
| AU (1) | AU5411099A (en) |
| CA (1) | CA2337072A1 (en) |
| TR (1) | TR200100082T2 (en) |
| WO (1) | WO2000004028A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2408853C (en) * | 2000-05-13 | 2012-01-10 | Smithkline Beecham P.L.C. | Process |
| WO2008065160A1 (en) * | 2006-12-01 | 2008-06-05 | Dsm Ip Assets B.V. | Process for the production of clavulanic acid |
| CN103304583B (en) * | 2013-07-09 | 2016-01-20 | 山东新时代药业有限公司 | A kind of method reclaiming clavulanic acid from clavulanic acid amine salt crystalline mother solution |
| CN104450813B (en) * | 2014-11-22 | 2017-04-12 | 太原理工大学 | Synthesis method for benzhydrylamine |
| CN109305978A (en) * | 2017-07-26 | 2019-02-05 | 山东睿鹰先锋制药有限公司 | A kind of new method preparing Clavulanate |
| CN109535184B (en) * | 2017-09-21 | 2020-11-20 | 联邦制药(内蒙古)有限公司 | Method for preparing potassium clavulanate from clavulanic acid tert-octylamine |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1578739A (en) * | 1976-07-23 | 1980-11-05 | Beecham Group Ltd | Amine salts of clavulanic acid methods for their preparation and compositions containing them |
| ES2010143A6 (en) * | 1989-03-01 | 1989-10-16 | Pharma Mar S A Pharmar | A new process for obtainment of Z(2R,5R)-3-(2-hydroxyethyliden)-7-oxo-4-oxa-1-azabicyclo(3,2,0)-heptane-2-carboxylic acid and pharmaceutically acceptable salts and esters thereof, from fermentation broths of Streptomyces sp. |
| AT400033B (en) * | 1992-03-10 | 1995-09-25 | Biochemie Gmbh | NEW METHOD FOR ISOLATING AND PURIFYING CLAVULANIC ACID AND FOR PRODUCING PHARMACOLOGICALLY COMPATIBLE SALTS THEREOF |
| AT399155B (en) * | 1992-03-26 | 1995-03-27 | Lek Tovarna Farmacevtskih | NEW ALKYLENE DIAMMONIUM DICLAVULANATE DERIVATIVES, METHOD FOR THE PRODUCTION AND USE THEREOF |
| SI9300296B (en) * | 1992-06-11 | 1998-06-30 | Smithkline Beecham P.L.C. | Process and intermediates for the preparation of clavulanic acid |
| KR100200239B1 (en) * | 1992-10-21 | 1999-06-15 | 김충환 | Process for preparing salts of clavulanic acid |
| GB9305565D0 (en) * | 1993-03-18 | 1993-05-05 | Smithkline Beecham Plc | Novel compounds and processes |
| US5741903A (en) * | 1993-03-26 | 1998-04-21 | Gist-Brocades N.V. | Diamine salts for purification of clavulanic acid |
| CZ284855B6 (en) * | 1993-03-26 | 1999-03-17 | Dsm N.V. | Salts of clavulanic acid with diamines, process of their preparation, and antibacterial pharmaceutical compositions based thereon |
| WO1998021212A1 (en) * | 1996-11-11 | 1998-05-22 | Gist-Brocades B.V. | Process for the preparation of salts and esters of clavulanic acid |
| WO1999024441A1 (en) * | 1997-11-10 | 1999-05-20 | Dsm N.V. | Crystallization of beta-lactam compounds |
-
1999
- 1999-07-13 CA CA002337072A patent/CA2337072A1/en not_active Abandoned
- 1999-07-13 TR TR2001/00082T patent/TR200100082T2/en unknown
- 1999-07-13 AU AU54110/99A patent/AU5411099A/en not_active Abandoned
- 1999-07-13 WO PCT/EP1999/005026 patent/WO2000004028A1/en not_active Application Discontinuation
- 1999-07-13 EP EP99940010A patent/EP1095046A1/en not_active Withdrawn
- 1999-07-13 CN CN 99809491 patent/CN1312814A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP1095046A1 (en) | 2001-05-02 |
| TR200100082T2 (en) | 2001-06-21 |
| CN1312814A (en) | 2001-09-12 |
| AU5411099A (en) | 2000-02-07 |
| WO2000004028A1 (en) | 2000-01-27 |
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