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WO1994021647A1 - Sel de diclavulanate avec une diamine et son procede de preparation - Google Patents

Sel de diclavulanate avec une diamine et son procede de preparation Download PDF

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Publication number
WO1994021647A1
WO1994021647A1 PCT/GB1994/000482 GB9400482W WO9421647A1 WO 1994021647 A1 WO1994021647 A1 WO 1994021647A1 GB 9400482 W GB9400482 W GB 9400482W WO 9421647 A1 WO9421647 A1 WO 9421647A1
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solvate
salt
clavulanic acid
process according
organic solvent
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PCT/GB1994/000482
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English (en)
Inventor
Michael Allen Cook
Julian Stanley Harber
Victor Witold Jacewicz
Neal Ward
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Smithkline Beecham Plc
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Priority to AU62121/94A priority Critical patent/AU6212194A/en
Publication of WO1994021647A1 publication Critical patent/WO1994021647A1/fr

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    • 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

  • DI.CU VULANATE SALT WITH A DIAMINE AND PROCESS OF PREPARATION
  • the present invention relates to novel alkylenediammonium diclavulanate derivatives, to processes for their preparation and to their use as intermediate compounds for the preparation of clavulanic acid and of pharmaceutically acceptable alkali salts thereof, such as potassium clavulanate.
  • Clavulanic acid is a known compound of the following structure:
  • clavulanic acid and its salts are used in pharmaceutical preparations in order to inhibit the inactivation of b-lactam antibiotics.
  • Commercial preparations contain a stable potassium salt of clavulanic acid (clavulanic acid itself being rather unstable) in combination with amoxycillin trihydrate.
  • Clavulanic acid and its salts were first disclosed in GB 1,508,977.
  • the processes described therein for the preparation of clavulanic acid described therein are time-consuming and is based on exacting purifications by means of various chromatographic methods.
  • the salts of clavulanic acid are obtained by binding the clavulanic anion present in the filtrate of the fermentation broth on an anionic exchange resin, subsequent elution of the clavulanate anion therefrom by means of an electrolyte, desalting the obtained eluate, passing the latter through another anionic exchange resin and a subsequent chromatographic elution therefrom by means of an electrolyte, repeatedly desalting the obtained eluate and removing the solvent.
  • the process describe therein is based on the preparation of the t-butylamine salt of clavulanic acid which is prepared by treating the extract, preferably the ethyl acetate extract, containing crude clavulanic acid, which was prepared according to the process as described in GB 1,508,977, with t- butylamine in an organic solvent such as a ketone, followed by the conversion of the isolated t-butylamine salt of clavulanic acid to clavulanic acid or a pharmaceutically acceptable salt thereof.
  • Clavulanic acid is normally prepared by the fermentation of a microorganism which produces clavulanic acid, such as various microorganisms belonging to various Streptomyces strains such as S. clavuligerus NRRL 3585, S. jumoninensis NRRL 5741, S. katsurahaman s IFO 13716 and Streptomyces sp. P 6621 FERM P2804 e.g. as described in JP Kokai 80-162993.
  • the resulting aqueous broth may be subjected to conventional purification and concentration processes, for example involving filtration and chromatographic purification, such as disclosed in GB 1508977 and JP Kokai 80-62993, before extraction of the aqueous solution with an organic solvent to yield a solution of crude clavulanic acid in the organic solvent.
  • Solvents suitable for the extraction are organic alkyl alkanoyl esters such as ethyl acetate, ketones such as methyl isobutyl ketone or acetone, aliphatic alcohols such as butanol, or mixtures thereof, a preferred solvent being ethyl acetate.
  • the obtained extract in the organic solvent, such as the ethyl acetate extract may also be further subjected to purification such as de-watering and/or a treatment with activated charcoal to eliminate a further quantity of impurities.
  • Novel compounds of clavulanic acid have been discovered which are useful as intermediates in processes for purification of the above-described clavulanic acid extracts. Also improved processes for isolating clavulanic acid from such extracts have been discovered.
  • a diclavulanate salt with a diamine, of formula (I) is provided:
  • R ⁇ , R2, R3 and R4 denote; a hydrogen atom, a straight chain or a branched chain Cj.g alkyl group, an arylalkyl group wherein the alkyl group is a methyl or ethyl group and the aryl group is a phenyl group, which is optionally substituted by an N-alkyl or N,N-dialkyl group wherein the alkyl groups are Cj .4 alkyl, or; R , R2, R3 and R4 jointly independently denote a cyclic alkylene ring having 3 to 6 methylene groups, one of these groups being optionally substituted by an oxygen or a sulphur atom or by an amino group and R5 denotes a hydrogen atom, or a methyl group; and n denotes an integer from 1 to 3; in the form of solvate of the salt with an organic solvent or with water.
  • the solvates of the salts (I) may be solvates in which the solvating solvent is an organic solvent such as an organic alkyl alkanoate ester such as ethyl acetate, ketones such as acetone etc, or hydrates in which the solvating solvent is water.
  • the solvating solvent is an organic solvent such as an organic alkyl alkanoate ester such as ethyl acetate, ketones such as acetone etc, or hydrates in which the solvating solvent is water.
  • Such solvates are found to be stable forms of the salts (I), that in these salts may. be readily isolated as these solvates and kept for a convenient time, or handled, without excessive decomposition of the salt molecule itself or loss of solvating solvent.
  • the solvates may be of various stoichiometries of clavulanic acid : solvent, but ce ⁇ ain solvates have a ratio clavulanic acid : solvent of >1 : 1, for example approximately 2 : 1.
  • the overall stoichiometry of such solvates is consequently clavulanic acid : diamine : solvent 2 : 1 : ca. 1.
  • Preferred solvates of which the stability can be demonstrated by inter alia easy formation, are solvates with organic alkyl esters such as ethyl acetate, ketones such as acetone, and hydrates. Examples of such solvates include those formed between up to one molecule of ethyl acetate or acetone, and one molecule of the salt
  • Suitable salts are those in which the diamine is an N,N'-disubstituted symmetric ethylenediamine having an alkyl chain of medium length, e.g. Cj.g, for example, wherein R] and R3 denote an ethyl or an isopropyl group, R2 and R4 denote a hydrogen atom and n denotes 1.
  • a preferred diamine is N,N'- diisopropylethylenediamine.
  • Suitable solvates of salts (I) are:
  • the clavulanic acid is used in the form of the free acid, but suitable labile derivatives include silyl esters.
  • the organic solvent in which the reaction takes place may suitably be a solvent used to extract clavulanic acid from the aqueous solution obtained from the fermentation process as described above.
  • a preferred solvent is ethyl acetate.
  • the initial source of the clavulanic acid is a broth resulting from • fermentation of a clavulanic acid-producing microorganism, such as those mentioned above, then to obtain a solvent extract of a suitable concentration of clavulanic acid for use in this process it may be desirable not to extract the broth itself, but to at least remove some of the suspended solids in the broth, e.g by filtration prior to extraction. It is also desirable to pre-concentrate the aqueous solution of clavulanic acid obtained in fermentation, so that for example the aqueous solution of clavulanic acid is several times more concentrated in clavulanic acid than the starting broth, for example pre- concentrated to a concentration of ca. 10 - 25 g/L clavulanic acid.
  • Suitable pre-concentration processes include absorption of the clavulanic acid onto an anion exchange resin, followed by elution of the clavulanic acid therefrom with an aqueous solution of an electrolyte such as sodium chloride, and optionally de ⁇ salting. It is also preferred to acidify the aqueous solution, e.g the broth or the pre- concentrated aqueous solution prior to solvent extraction, e.g to pH 1 to 3, e.g around pH 1.5 to 2.5. It is also preferred to dry or de-water the organic solvent extract prior to formation of the salt (I), e.g to less than 6g/L of water, although as discussed below, the presence of small quantities of water in the solvent may be advantageous in achieving crystallisation of the solvate.
  • an electrolyte such as sodium chloride
  • a suitable concentration for the clavulanic acid or its labile derivative in the organic solvent is at least 1.0 g/L, for example in the range 1.0 to 4.0 g/L of clavulanic acid. It may be advantageous to further concentrate the solvent extract, for example by evaporation, to a concentration of clavulanic acid in excess of this, e.g greater than 10 g/L, e.g. greater than 20 g/L.
  • the solvates of salts (I) may be formed in the process of the invention by solvation of the salts of formula (I), formed by reaction between clavulanic acid or the labile derivative thereof and the diamine (II), with the organic solvent in which the reaction is carried out, or as a hydrate with water present as an impurity in this solvent.
  • the process may be carried out in a non-solvating solvent, which is admixed with a solvating solvent.
  • Suitable and preferred diamines (II) are those described above, especially N,N'-diisopropylethylenediamine.
  • the diamine (II) can be used either as such or in the form of a solution in an organic solvent, such as the above-described extraction solvents, for example acetone or ethyl acetate.
  • an organic solvent such as the above-described extraction solvents, for example acetone or ethyl acetate.
  • the salt (I) of the clavulanic acid preferably at least one equivalent of the selected diamine (II) per mole of clavulanic acid should be used.
  • the solvates of the salt (I) are generally insoluble in organic solvents, and if they are formed by a reaction which takes place in an organic solvent they generally precipitate out.
  • the solvent may suitably contain around 0.25-0.6 g/L of water as it is believed that such a quantity of water may assist in crystallisation.
  • the solvate of the salt (I) is to be isolated in a solid form it may suitably be filtered off, and is preferably then washed with an organic solvent, which may be the same organic solvent that the reaction to prepare salt (I) is carried out in, for example ethyl acetate.
  • the solvate may be washed with a different solvent to that in which the salt is prepared, for example acetone in the case of an ethyl acetate solvate, although this may lead to formation of a solvate of the solvent used for washing.
  • the solvent-wet solvate may then be dried, e,g in vacuo or may be further used wet.
  • the solid solvate as filtered off may be redissolved in a solvent, such as water, or an alcohol such as methanol, or a water: acetone mixture, and then reprecipitated by admixing the solution with an organic solvent, for example acetone (thereby increasing the proportion of acetone if the solvate has been redissolved in water : acetone) or an alkyl alkanoate ester such as ethyl acetate. It is preferred to redissolve the solvate in the minimum of solvent and then admix the solution with an excess of the organic solvent. The reprecipitated solvate may then be collected, e.g. by filtration and optionally washed and dried as above.
  • a solvent such as water, or an alcohol such as methanol, or a water: acetone mixture
  • an organic solvent for example acetone (thereby increasing the proportion of acetone if the solvate has been redissolved in water : acetone) or an alkyl alkanoate este
  • the reaction between the clavulanic acid or its labile derivative and the diamine (II) may be carried out at around ambient temperature, e.g. ca. 20°C, but preferably the reaction is carried out at a temperature lower than ambient, e.g.-15 to +15°C, e.g 0 to 15°C, e.g. 0 to 10°C suitably 0 to 5°C.
  • the use of such lower temperatures may advantageously result in a higher yield of the solvate.
  • the use of temperatures lower than ambient appears to be of advantage generally in improving yield in processes in which salts (I) are prepared, whether these salts are obtained in a solvated or non-solvated form.
  • an improved process for the preparation of a salt of formula (I) as defined above in a non-solvated form in which a solution of clavulanic acid or a labile derivative thereof in an organic solvent, such as the solvent extract obtained in the above-described manner, is reacted with a substituted diamine of formula (II) as defined above to yield a substituted diammonium diclavulanate salt of general formula (I) as defined above, wherein the reaction is carried out at a temperature lower than ambient.
  • this last-described process is carried out at a temperature of 0 to 15° C, e.g. 0 to 10°C, e.g. 0 to 5°C.
  • the solvated salts of formula (I) may be used as intermediates in the preparation of substantially pure clavulanic acid or pharmaceutically acceptable salts of clavulanic acid, because these solvates can be obtained in a substantially pure form, from which impurities in the clavulanic acid solution, e.g. in the above- mentioned extracts, have been substantially removed.
  • Such pharmaceutically acceptable salts may be prepared from these solvates of salts (I) or the non-solvated salts (I) by double decomposition.
  • pharmaceutically acceptable salts of clavulanic acid herein is meant salts of clavulanic acid with a pharmaceutically acceptable cation.
  • a pharmaceutically acceptable salt of clavulanic acid is prepared by reacting a solvate of a clavulanic acid salt of formula (I), as defined above, with a salt precursor compound of a pharmaceutically acceptable cation.
  • the precursor compound is a compound of the cation with a counter anion which can exchange with clavulanate anion to form a pharmaceutically acceptable clavulanate salt of the cation.
  • the cation is a metal cation.
  • Suitable metals include alkali metals, particularly potassium so that potassium clavulanate is formed which is preferred for its stability.
  • Suitable counter anions include carbonate, hydrogen carbonate, hydroxide or C ⁇ . ⁇ Q alkanoate, such as butanoates, pentanoates, hexanoates, heptanoates, octanoates, and alkyl-substituted forms of these particularly 2-ethylhexanoate, a preferred salt precursor compound being potassium 2-ethylhexanoate.
  • the counter anion may be present in the form of an anionic resin.
  • the reaction between the solvate of the salt (I) and the salt precursor may be carried out in solution or suspension, for example in an organic solvent or organic solvent: water mixture.
  • the solvate and the precursor may be respectively made up in separate solutions or suspension and mixed.
  • a suitable solvent for the solvate of salt (I), particularly for ethyl acetate solvates, is an isopropanol: water mixture, for example having an isopropanol: water ratio between the inclusive ranges 50:1 and 1:50.
  • the solvent: water mixture may be made up first, and the solvate of salt (I) then dissolved in the mixture.
  • a preferred solvent for the salt precursor is isopropanol.
  • a stoichiometric excess of the salt precursor, e.g. potassium 2-ethylhexanoate, over the salt (I) or solvate is used.
  • the product pharmaceutically acceptable salt of clavulanic acid may then be obtained in the form of crystals separating from the reaction mixture and may be collected by, conventional procedures.
  • the reaction between the solvate and the salt precursor may be carried out ambient temperature, e.g. ca 20°C, but preferably the reaction is carried out at a temperature lower than ambient, e.g. 0 to 15°C, e.g. 0 to 10°C, suitably 0 to 5°C.
  • ambient temperature e.g. ca 20°C
  • the reaction is carried out at a temperature lower than ambient, e.g. 0 to 15°C, e.g. 0 to 10°C, suitably 0 to 5°C.
  • the use of such lower temperatures may advantageously result in a higher yield of the salt product.
  • temperatures lower than ambient appears to be of advantage generally in improving yield in processes in which pharmaceutically acceptable salts of clavulanic acid are prepared by reaction between a salt (I) and a salt precursor, whether the salt (I) is in a solvated or non-solvated form.
  • a pharmaceutically acceptable salt of clavulanic acid is prepared by reacting a clavulanic acid salt of formula (I) as defined above in a non-solvated form, with a salt precursor compound of a pharmaceutically acceptable cation at a temperature below ambient.
  • a suitable temperature is between 0 to 15°C, e.g. 0 to 10°C, e.g. 0 to 5°C.
  • (I) may be isolated in a separate solid form, (I) e.g. by filtration, it is also possible to extract the salt (I) or solvate from the organic solvent in which it is formed, it this solvent is substantially imiscible with water, into a separate aqueous phase of water or a water : organic solvent mixture to form a concentrated aqueous solution of the solvate in the phase.
  • the solvate may then for example be reprecipitated from this concentrated solution analogously as described above by admixing this concentrated solution with a organic solvent such as acetone.
  • Example 1 Solvent Extraction.
  • Rotary vacuum filter filtrate 150L
  • ex-clavulanate production was acidified inline to pH 1.6 with 25% v/v sulphuric acid and continuously extracted into ethyl acetate (160L).
  • a solvent to aqueous feed ratio of approximately 1:1 in conjunction with the lower pH (cf pH 2.0) was employed to maximise the solvent titre.
  • the resulting rich solvent extract was chilled to 3°C and dewatered via a dewatering centrifuge and then dried with magnesium sulphate (200g per 15L rich ethyl acetate).
  • the dried rich ethyl acetate was then passed down a CPG carbon column (5.0L) at a flow rate of 600 ml/min.
  • the carbon treated rich solvent was immediately preconcentrated from 150L to 1 IL on a cyclic evaporator, and yielded a potency of 9.815 ⁇ g/ml.
  • Preconcentrate (5.0L) was further concentrated on a rotary evaporator to give a final concentrate titre of 20,007 ⁇ g/ml.
  • Solvent extract moisture levels (% v/v): post dewatering centrifuge: 2.86 post magnesium sulphate: 2.24 preconcentrate: 0.06
  • Example 3 N,N'-Diisopropylethylenediammonium diclavulanate.
  • N,N'-Diisopropylethylenediamine was added to the extract, maintained at 5°C, with rapid stirring, at the rate of 9.0 ml over ten minutes.
  • the resulting slurry was stirred, at 5°C for a further 30 minutes, then filtered, using standard Whatman filter paper.
  • the wet cake was washed with acetone, in order to remove the mother liquors.
  • the wet cake was redissolved, using 20mls water. Acetone at the rate of 400 mis over 5 minutes was added, and thus the N,N'-diisopropylethylenediammonium diclavulanate was precipitated.
  • the product was filtered off and washed with acetone, then dried under vacuum at 20°C overnight with a nitrogen bleed. The product was obtained as fine needles which were clumped and granular.
  • Example 4 N,N'-Diisopropylethylenediammonium diclavulanate. 1 litre of concentrated clavulanate rich ethyl acetate extract from Example 2, at a titre of 20,000 ⁇ g/ml was adjusted to 6g/L water by addition of de-ionised water. N,N'-Diisopropylethylenediamine (9.0ml) was added over a period of ten minutes, maintaining the temperature at 5°C, while stirring rapidly. The resulting slurry was stirred, at 5°C for a further 30 minutes, then filtered, using standard Whatman filter paper.
  • Example 5 N,N'-Di_sopropylethylenediammonium diclavulanate.
  • Example 6 N,N'-Diisopropyiethylenediam ⁇ _onium diclavulanate conversion to potassium clavulanate.
  • Example 7 N,N'-Diisopropylethylenediammonium Diclavulanate conversion to Potassium Clavulanate 25g of the diamine salt produced in Example 4 was dissolved in 25ml of water and 475ml IPA, with stirring. To this was added 2N potassium 2-ethyl hexanoate, at the rate of 38.0ml over 15 minutes. The slurry was stirred, at 5°C for a further 30 minutes. The product was filtered off and washed with 2 x 20mls IPA then 1 x 50 mis acetone. The wet cake was dried under vacuum overnight with a nitrogen bleed, at 20°C. The product was obtained as large needles.
  • Example 9 N,N'-diisopropylethylene diamine salt of clavulanic acid - ethyl acetate solvate.
  • An ethyl acetate extract of clavulanic acid was obtained as above and dried over magnesium sulphate.
  • a portion of the dried extract (360ml, clavulanic acid content ca. 12,800 ⁇ g/ml) was cooled in an ice bath to 0 to 5°C and treated with a mixture of N,N'-diisopropylethylene diamine (3.6ml) and ethyl acetate (50ml) over ca. 10 minutes with stirring.
  • the mixture was stirred at 0 to 5°C for a further 30 minutes, the needle crystals collected by filtration, washed with ethyl acetate (2 x 50ml) and dried in vacuum. (Yield 7.29g)
  • Example 10 Recrystallisation as the ethyl acetate solvate: i) The ethyl acetate solvate of example 9 (l.Og) was dissolved in methanol (1.0ml) and cooled in ice. The solution was diluted with ethyl acetate (20ml) to give needle crystals. These were collected, washed with ethyl acetate and dried. (Yield 0.9g)
  • Example 11 Preparation of the acetone solvate.
  • Example 12 Conversion of ethyl acetate solvate to potassium clavulanate
  • the ethyl acetate solvate (2.70g) was dissolved in a mixture of IPA (5.0ml) and water (2.15ml) at ca. 5°C.
  • the solution was diluted with IPA (25ml), and treated with an excess of potassium-2-ethyl hexanoate (6.0ml of a 2.16M solution in IPA) with cooling in ice.
  • the mixture was stirred at 0 to 5°C for 30 minutes, the crystalline product collected, washed with IPA (2 x 10ml), then with acetone (20ml) and dried. (Yield 1.50g, 74%).
  • Example 13 Conversion of acetone solvate of N,N'-diisopropyI- ethylenediamine diclavulanate to hydrate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un sel de diclavulanate avec une diamine, selon la formule (I) dans laquelle R1, R2, R3, R4 et R5 sont des substituants et n est un nombre entier de 1 à 3, sous la forme d'un solvate du sel avec un solvant organique ou avec de l'eau. L'invention concerne également un procédé pour l'utilisation de tels sels dans la purification de l'acide clavulanique.
PCT/GB1994/000482 1993-03-18 1994-03-11 Sel de diclavulanate avec une diamine et son procede de preparation WO1994021647A1 (fr)

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Application Number Priority Date Filing Date Title
AU62121/94A AU6212194A (en) 1993-03-18 1994-03-11 Diclavulanate salt with a diamine and process of preparation

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GB939305565A GB9305565D0 (en) 1993-03-18 1993-03-18 Novel compounds and processes
GB9305565.5 1993-03-18

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WO1994021647A1 true WO1994021647A1 (fr) 1994-09-29

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Cited By (15)

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GB2287026A (en) * 1992-06-11 1995-09-06 Smithkline Beecham Plc Preparation or purification of clavulanic acid or its salts or esters
EP0719778A1 (fr) * 1993-03-26 1996-07-03 Gist-Brocades N.V. Sels de diamine de l'acide clavulanique
WO1996020199A3 (fr) * 1994-12-24 1996-09-12 Spurcourt Ltd Sels de di-clavulanate avec un ether diamino et son procede de preparation
WO1996033197A1 (fr) * 1995-04-20 1996-10-24 Lek Pharmaceutical And Chemical Co. D.D. Preparation de sels clavulanate
GB2282810B (en) * 1992-06-11 1997-02-26 Smithkline Beecham Plc Preparation or purification of clavulanic acid
WO1998021212A1 (fr) * 1996-11-11 1998-05-22 Gist-Brocades B.V. Procede de preparation de sels et d'esters d'acide clavulanique
WO1998023622A1 (fr) * 1996-11-27 1998-06-04 Biochemie Gesellschaft Mbh Purification d'acide clavulanique fermente
JP2839955B2 (ja) 1993-03-26 1998-12-24 ギスト ブロカデス ナムローゼ フェンノートシャップ クラブラン酸のジアミン塩
US5859238A (en) * 1992-03-26 1999-01-12 Lek, Tovarna Farmacevtskih Alkylenediammonium diclavulanate derivatives, a process for the preparation thereof as well as the use thereof
EP0918520A4 (fr) * 1996-06-13 2000-01-12 Smithkline Beecham Corp Processus de preparation d'un clavulanate de potassium
WO2000004028A1 (fr) * 1998-07-16 2000-01-27 Dsm N.V. Procede ameliore de preparation de sels et d'esters d'acide clavulanique
US6207428B1 (en) 1994-03-02 2001-03-27 Lek Pharmaceutical & Chemical Co. D.D. Process for the isolation of clavulanic acid and of pharmaceutically acceptable salts thereof from the fermentation broth of streptomyces sp. P 6621 FERM P 2804
US6300495B1 (en) 1997-04-04 2001-10-09 Smithkline Beecham P.L.C. Process for the preparation of a metal salt of clavulanic acid
WO2008046003A2 (fr) 2006-10-11 2008-04-17 Deciphera Pharmaceuticals, Llc Inhibiteurs de kinase utiles pour le traitement de maladies myéloproliférantes et d'autres maladies proliférantes
US7767823B2 (en) 2000-05-13 2010-08-03 Smithkline Beecham Limited Process for the purification of a salt of clavulanic acid

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AU678752B3 (en) * 1992-06-11 1997-06-05 Smithkline Beecham Plc Process for the preparation of clavulanic acid

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EP0026044A1 (fr) * 1979-08-24 1981-04-01 Beecham Group Plc Sel amine de l'acide clavulanique, sa préparation et son utilisation
EP0387178A1 (fr) * 1989-03-01 1990-09-12 Smithkline Beecham Plc Procédé de préparation de l'acide clavulinique et de ses sels pharmaceutiquement acceptables à partir de bouillons de fermentation de Streptomyces sp.
EP0562583A1 (fr) * 1992-03-26 1993-09-29 LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d. Dérivés d'alkylènediammonium diclavulanates, procédés pour leur préparation et pour leur utilisation

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EP0026044A1 (fr) * 1979-08-24 1981-04-01 Beecham Group Plc Sel amine de l'acide clavulanique, sa préparation et son utilisation
EP0387178A1 (fr) * 1989-03-01 1990-09-12 Smithkline Beecham Plc Procédé de préparation de l'acide clavulinique et de ses sels pharmaceutiquement acceptables à partir de bouillons de fermentation de Streptomyces sp.
EP0562583A1 (fr) * 1992-03-26 1993-09-29 LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d. Dérivés d'alkylènediammonium diclavulanates, procédés pour leur préparation et pour leur utilisation

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5859238A (en) * 1992-03-26 1999-01-12 Lek, Tovarna Farmacevtskih Alkylenediammonium diclavulanate derivatives, a process for the preparation thereof as well as the use thereof
EP0747383A3 (fr) * 1992-06-11 1996-12-18 Smithkline Beecham Plc Sels de polyamine d'acide clavulanique
DE4345311C1 (de) * 1992-06-11 1996-02-01 Smithkline Beecham Plc Verfahren zur Herstellung und/oder Reinigung von Clavulansäure
EP0699682A1 (fr) * 1992-06-11 1996-03-06 Smithkline Beecham P.L.C. Procédé de préparation et/ou purification de l'acide clavulanique
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