Title of Invention

A PROCESS FOR THE PREPARATION OF POTASSIUM CLAVULANATE

Abstract

A process for the preparation of potassium clavulanate which comprises the reaction between a salt of clavulanle acid with an organic amine selected from tertiary-butylamine an N,N substituted diamine an N ,N'-monosubstituted symmetric diamines or N,N '-MOnosub8tituted symmetric alkylethylne diamine or tertiary ocylaaine and potassium salt of an organic oarboxylie acid in a liquid medium comprising a liquid fluorinated and/or chlorinated hydrocarbon. The potassium calvulanate formed is separated from the reaction mixture in a known manner.

Full Text

This invention relates to a process for the preparation of salts of clavulanic acid. In particular the invention relates to a process for the preparation of potassium clavulanate from salts of clavulanic acid with organic amines. Clavulanic acid (3-(2-hydroxyethylidene)-7-oxo-4-oxa-l-azabicyclo [3.2.0] heptane-2-carboxylic acid) is a known beta-lactamase inhibitor, i.e. it and its compounds inhibit the beta-lactamase enzymes by means of which bacteria defend themselves against beta-lactam antibiotics such penicillins. Clavulanic acid, particularly in the form of its salts, can therefore be co-administered with such antibiotics, particularly amoxycillin and ticarcillin to overcome beta-lactamase mediated bacterial resistance. Clavulanic acid is normally prepared by the fermentation of a microorganism which produces clavulanic acid, such as microorganisms belonging to various Streptomyces strains such as S. clavuligerus NRRL 3585, S. jumoninensis NRRL 5741, S. katsurahamanus IFO 13716 and Streptomyces sp. P 6621 PERM P2804 e.g. as described in JP Kokai 80-162993. The resulting aqueous brodi 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. Alternatively a "whole broth extraction" process of generally known type may be used to yield a solution of crude clavulanic acid in the organic solvent. To isolate the clavulanic acid from the organic solvent solution one known procedure is to first convert the clavulanic acid into a salt with an organic amine. EP 0026044 discloses the use of the tertiary butylamine ("t-BA") salt of clavulanic acid as a useful intermediate in die isolation of clavulanic acid. This salt may be formed by reaction of the solution of crude clavulanic acid in the organic solvent with tertiary butylamine, resulting in formation of the salt which can be isolated, for example as a crystalline solvate e.g. of acetone. This tertiary butylamine salt of clavulanic acid may be converted to potassium clavulanate by reaction with for example a precursor compound such as potassium 2-ethylhexanoate in a suitable solvent medium such as isopropanol. Numerous other amines may be used in processes for isolation of clavulanic acid. PT.94.908 describes the use of tri-(lower alkyl)amine, e.g. triethylamine, salts and the dtmethylaniline salts of clavulanic acid in a purification process for clavulanic acid in which the triethylamine salt of clavulanic acid is formed and is then converted into a silyl diester of clavulanic acid. EP 0887178A discloses a process for the purification of clavulanic acid in which organic amines may be used to form an intermediate amine salt with clavulanic acid in an impure solution. WO 93/25557 discloses an extensive series of amines which can be used. WO 96/33197, EP 0562583A, WO 94/21647, EP 0594099A, WO 94/22873, WO 95/23870, GB 2298201A and WO 96/20188 all disclose various other amines which can be used in this way. Clavulanic acid and its salts such as potassium clavulanate are unstable, moiture sensitive compounds, and known processes for their preparation all suffer to a greater or lesser extent from problems of degradation resulting from such instability and hydrolysis. It is an object of this invention to provide an improved process which to some extent at least overcomes these problems. According to this invention a process for the preparation of a metal salt of clavulanic acid comprises the reaction between an organic amine salt of clavulanic acid and a metal salt precursor compound, the reaction taking place in a liquid medium which comprises a liquid fluorinated and/or chlorinated hydrocarbon. In a preferred embodiment of this invention the metal salt of clavulanic acid prepared by this process is potassium clavulanate. The amine salt may be any amine salt which may be used in a process of the above-described type where clavulanic acid is first isolated as a salt of the amine which is then converted into a metal salt such as potassium clavulanate. In a preferred embodiment the organic amine salt of clavulanic acid is the t-BA salt of clavulanic acid. Other suitable amine salts include the following. (When alky l groups or substituted alkyl groups are referred to herein unless otherwise defined herem they may suitably contain 1 to 6 carbon atoms in the alkyl system.) Those disclosed in WO 93/25557, i.e an amine of formula (I): (I) as an intermediate in a process for the preparation of clavulanic acid or pharmaceutically acceptable salts and esters thereof, wherein R1, R2 and R3 are selected according to the following options: (1) R1 being an optionally substimted cyclic group of general formula: where m is zero or an integer 1 to 5, R is an optionally substituted aliphatic hydrocarbon ring system containing from 3 to 8 ring carbon atoms, R4 is hydrogen or alkyl, amino- or hydroxy- substituted alkyl or substituted amino- substimted alkyl, or a group of the same general formula or R1 above:, R2and R3 may be selected from the same groups from which R1 is selected, or from hydrogen, alkyl, alkenyl, amino- or hydroxy-substituted alkyl or alkenyl, or substimted amino-substituted alkyl or alkenyl: or (2) each of R1 , R2 and R3 are the same or different and are independently selected from hydrogen, alkyl, alkenyl, amino - or hydroxy- or alkoxy- substituted alkyl or alkenyl, or substituted amino- substimted alkyl or alkenyl, but with the exception of t-butylamine, s-butylamine, N,N-dimethylethylamine, 1,2- dimethylpropylamine, neopentylamine and 2-amino-3,3-dimethylbutane: or (3) R1 beine an ootionallv substimted aryl group of general formula: where R4is hydrogen or one or more substiments, and m is zero or an integer 1 to 5, and R2 and R3 are independently selected from hydrogen, alkyl, amino- or hydroxy- substimted alkyl or substimted - amino- substimted alkyl or groups of the same general formula as R1: or (4) R1 and R2, and optionally R3together with the nitrogen atom shown being the residue of an optionally substimted heterocyclic ring system including the nitrogen atom as a ring member, and optionally including one or more additional ring hetero atoms, and if R3 is not part of the ring system it is independently selected from hydrogen, alkyl, amino- or hydroxy- substimted alkyl or substimted amino- substimted alkyl: or (5) R1 being a group of general formula: where R4 and R5 are independently hydrogen, alkyl, amino- substimted alkyl or substimted amino- substimted alkyl, and R2 and R3 are independently selected from hydrogen, alkyl, amino- or hydroxy- substimted alkyl or substimted amino-substimted alkyl, and m is zero or an integer 1 to 5: or (6) One or both of R1 and R2are hydrogen and R3 represents the residue of an amino acid in which the carboxylate group of the amino acid may be esterified or in the form of an amide. Examples of such amines include cyclopentylamine, cyclohexylamine, cycloheptylamine, NN-dimethylcyclohexylamine, dicyclohexylamine, adamantylamine, NN-diethylcyclohexylamine, N-isopropylcyclohexylamine, N-methylcyclohexylamine, cyclopropylamine, cyclobutylamine, norbornylamine, dehydroabietylamine, t-octylamine, (ie 2-amino-2,4,4-trimethylpentane), t-amylamine, l-hydroxy-2-methyl-2-propylamine, tri-n-propylamine, tri-n- octylamine, tri-n-butylamine, dimethylamine, i-propylamine, di-n-hexylamine, di-n-butylamine, diethylamine, 2-aminoethanoI, NN-diethylethanolamine, NN-dimethylethanolamine, ethanolamine, n-butylamine, n-hexylamine, n-octadecylamine, N-ethylethanolamine, 1-hydroxyethylamine, diethanolamine, NN-dimethylethanolamine, N-ethyl diethanolamine, 1, 6-diamino hexane, triethanolamine, diisobutylamine, diisopropylamine, 2-methoxyethylamine, hydroxylamine, ammonia, methylamine, ethylamine, n-propylamine, n-butylamine, n-pentylamine, n-hexylamine, n-heptylamine, n-octylamine, n-nonylamine, n-decylamine, n-undecylamine, n-dodecylamine, n-prop-2-ylamine, n-but-2-yIamine, n-pent-2-ylamine, n-hex-2-yl-amine, n-hept-2-ylamine, n-oct-2-ylamine, n-non-2-ylamine, n-dec-2-ylamine, n-undec-2-ylamine, n-dodec-2-ylamine, n-hex-3-ylamine, n-hept-3-ylamine, n-oct-3-ylamine, n-non-3-ylamine, n-dec-3-yl-amine, n-undec-3-ylamine, n-dodec-3-ylamine, n-oct-4-ylamine, n-non-4-ylamine, n-dec-4-ylamine, n-undec-4-ylamine, n-dodec-4-ylamine, n-non-5-ylamine, n-undec-5-ylamine, n-dodec-5-ylamine, and n-octadecylamine, 1-phenylethylamine, p-toluidine, p-aminobenzoic acid, p-bromoaniline, ethyl-4-aminobenzoate (ie benzocaine), benzylamine, diphenylamine, p-methylaminobenzene sulphonamide, m-nitroaniline, N,N'-dibenzylethylenediamine (ie benzathine), diphenylmethylamine, 4-methylbenzylamine, 4-phenylbutylamine, piperidines and optionally substituted piperidines, for example where the substituents are selected from alkyl, hydroxy alky 1, halogen, amino, substituted amino and amino-substimted alkyl, e.g N-ethyl piperidine, 2, 6-dimethyl piperidine, 2-methyl-N-hydroxypropyl piperidine (ie cyclo- methycane), 4-methyl piperazine, l-methyl-4-phenyl piperazine, N-ethyl morpholamine, hexamethylenimine, pyridine, 2-propylpyridine, 3-chloro-2-aminopyridine, morpholamine, 1, 5-diazabicyclo [4, 3, 0] non-5-ene, 1, 4-diazabicyclo [2, 2, 2] octane, pyrrolidone, quinuclidine, xanthinol, NN-diethylethylene diamine, NN'-diisopropylethylenediamine and triethylene tetramine, naturally occurring amino acids, such as arginine, ornithine, histidine, lysine, benzylglycine, 3-amino-3-methylbutanoic acid, L-ethyl lysinate, L-methyl histidinate, methyl N-carbobenzyloxy-L-lysinate, methyl L-phenylalanate, ethyl glycyl glycinate, ethyl p-hydroxy phenyl glycinate, ethyl p-hydroxy phenyl glycinate, ethyl glycinate, ethyl L-tyrosinate, p-methoxybenzyl a-aminophenylacetate, n-butyl a-aminophenylacetate, methyl arginate, benzylglycine, benzyl phenylglycine, 1-nitrobenzyl phenyl glycine, n-butyl phenylglycine, p-methoxybenzyl phenylglycine, ethyl phenyl glycine, p-nitrobenzyl p-hydroxyphenyl-glycine, p-nitrobenzylserine, n-butyl serine, methyl arginine, dimethyl glutamate, p-nitrobenzyl tyrosinate, p-nitrobenzyl glycinate, benzylglycinate, p-nitrobenzyl a-amino-p-hydroxy-phenyl acetate, p-nitrobenzyl a-aminophenylacetate, ethyl a-amino-p-hydroxy phenyl acetate, ethyl L-tyrosinate. When the amine (I) contains more than one nitrogen aton the clavulanic acid may form a salt with one or more of the nitrogen atoms, for example as in NN'-diisopropylethylenediamine diclavulanate. Of the amines last mentioned above, preferred amines are: phenylethylamine, t-amylamine, t-octylamine, l-hydroxy-2-methyl-2-propyIamine, cyclopentylamine, cycloheptylamine, 1-adamantanamine, N-ethylpiperidine, N'N'-diisopropylethylenediamine and N N-dimethylcyclohexylamine. Those disclosed in WO 96/33197, i.e having the general formula (II): where the substiments R1, R2 , R3and R4are independently hydrogen, C(.g) straight or branched alkyl, C(24) hydroxyalkyl or wherein the groups NR1R2 and NR3R4 jointly denote a heterocyclic group having 3 to 6 methylene groups optionally substituted with oxygen, sulphur or an imino group; and wherein R5 denotes hydrogen or methyl, and n is an integer from 1 to 3. Examples of such last mentioned amines include symmetrical N,N'-alkylethylene diamines, such as N,N'-diisopropylethylenediamine, N,N'-diethylenediamine, N.N'-dibenzylethylene-diamine, N, N, N', N' -tetramethylethylenediamine. Those disclosed in EP 0562583 and WO 94/21647, i.e. of formula (II) with the additional possibilities that R1, R2 R3 and R4may independently be an arylalkyl group, for example with the alkyl moiety being methyl or ethyl, and the aryl group, for example phenyl, which may be substituted, particularly in its para- position, with an alkyl e.g methyl, alkoxy e.g methoxy, nitro or halogen; a C2-4hydroxyalkyl group, a C2 aminoalkyl group, for example substimted by a 1 to 4 carbon atom containing N-alkyl or N,N-dialkyl group; or R1, R2, R3and R4may together form an alkylene ring system with 3 to 6 methylene groups, in which one of these groups may be substituted or replaced by an oxygen or sulphur atom or an imino group. Those disclosed in WO 94/22873, i.e of formula (III): R1` .R2N-(CH2)„ - CHX -(CH2)m-NR3R4 (HI) wherein R1' and R2 are each C1-8 alkyl, C3.-8 cycloalkyl or C3-8cycloalkyl Cl-8 alkyl group, optionally having one or more inert substiments or being interlinked to form a ring of 4-7 ring atoms; R3and R'4 are each C8alkyl, C3-8 cycloalkyl or C-8 cycloalkyl C1-8 alkyl group, optionally having one or more inert substiments or being interlinked to form a ring of 4-7 ring atoms; X is hydrogen or a hydrogen bridge forming group; and m and n are each independently 0-5. Preferred moieties for such substiments are as disclosed in WO 94/22873, and examples of such « amines include N,N,N',N'-tetramethyl-l,2-diaminoethane, l,3-bis(dimethylamino)-2-propanol, N,N,N',N'-tetramethyl-l,4-diaminobutane, N,N,N',N'-tetramethyl-1,6-diaminohexane, 1,2-dipiperidinoethane and dipiperidinomethane. Those disclosed in GB2298201A, i.e of formula (IV): (IV) wherein each of R1and R2independently denote hydrogen or a pharmaceutically acceptable substituent, for example lower alkyl, haloalkyl, alkoxyl or acyloxy. An example of such an amine is benzhydrylamine. Those disclosed in WO 96/20199, i.e of formula (V): (V) wherein Rl is an alylene group (the term alkylene encompassing cycloalkylene and alkyl substituted cycloalkylene), optionally having one or more inert substiments; and each of R2 and R3 is a hydrogen atom or an alkyl group (which may be cycloalkyl), optionally having one or more inert substiments. An example of such an amine is bis-(2-dimethylaminoethyleether). The contents of these forementioned patent publications are included herein in their entirety by way of reference. Where the amine base contains two or more basic nitrogen atoms, one, or more than one up to all of these basic nitrogen atoms may be combined in the amine salt with a respective clavulanate ion. The metal salt precursor compound may be a salt or salt-like compound, or a basic compound, of a metal cation with a suitable counter anion. The metal is suitably a pharmaceutically acceptable alkali metal such as sodium or particularly potassium, or an alkaline earth metal. The metal salt precursor compound may be a salt of the metal with an organic carboxylic acid, for example a salt of an alkanoic acid of formula (I): a) wherein R10 is an alkyl group, containing for example from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms. Examples of suitable salts include acetate, propionate or ethylhexanoate salts, potassium 2-ethylhexanoate and sodium 2- ethylhexanoate being preferred. Alternatively the metal salt precursor compound may be a basic compound, for example a carbonate, bicarbonate or hydroxide of the metal. It is preferred that a stoichiometric excess of the metal salt precursor compound over the organic amine salt of clavulanic acid is used to ensure complete reaction of the organic amine salt of clavulanic acid. For example around a 1.3 : 1 ratio of metal salt precursor compound : organic amine salt of clavulanic acid may be used. The liquid medium is preferably a gas at ambient temperature but which can be liquefied at ambient temperamre by pressure. Suitably the fluorinated and/or chlorinated hydrocarbon is a compound of formula CnHmXpYr where X is fluorine, Y is chlorine n and m are whole numbers, p and r are zero or whole numbers provided both p and r are not zero and (m + p + r) equals 2n + 2. The liquid medium is preferably a fluorinated non-chlorinated hydrocarbon. Preferably the medium is a fluorinated non-chlorinated compound of formula CnHMFp where n, m and p are whole numbers and (m + p) equals 2n + 2. The lower and upper limits of n are determined more by the practical considerations of achieving a boiling point which is low enough to allow easy evaporation but not so low that high pressures are needed for liquefaction. For example a suitable boiling point for the liquid non-chlorinated fluorinated hydrocarbon is -10 to -SO'C at ambient atmospheric pressure, and typically n is between 1 and 10. Preferably in such a compound n is 2 or 3, preferably 2 so that the compound is an ethane, preferably p is 3, 4 or 5, especially 4 so that the compound is a tetrafluoroethane. A preferred fluorinated hydrocarbon is 1,1,1,2 -tetrafluoroethane. Other suitable fluorinated/chlorinated hydrocarbons include fluoroform, methyl chloride, difluorodichloromethane, monofluoromethane, difluoromethane, trifluoromethane, pentafluoroethane, 1,1,1-trifluoroethane, 1,1-difluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,2,2,3,3-heptafluoropropane, 1,1,1,3,3,3-hexafluoropropane, 1,1,1,2,2-pentafluoropropane, 1,1,1,2,2,3-hexafluoropropane, 1,1,2,2,3,3-hexafluoropropane, and 1,1,1,2,3,3-hexafluoropropane. Such fluorinated/chlorinated hydrocarbons, particularly fluorinated non-chlorinated hydrocarbons have the advantages as media for the process of the invention that they are odourless and colourless gases at ambient temperature, liquefy at around 5 bar at ambient temperamre, are chemically inert, are non¬flammable, are non-toxic, are non-corrosive, have a neutral pH, are non-ozone depleting and are approved for use in food processing by the EEC. The liquid medium may comprise a mixture of such fluorinated and/or chlorinated hydrocarbons, e.g a mixture of fluorinated non-chlorinated hydrocarbons, for example to achieve a convenient boiling point. The liquid medium may also include other organic solvents, for example to modify the polarity of the medium, and suitable such organic solvents include alcohols and ethers, for example C1 - C5 aliphatic alcohols and ethers. Such organic solvents may be solvents for the metal salt precursor compound. When the metal salt precursor compound is a salt of the metal with an organic carboxylic acid, for example a salt of an alkanoic acid of formula (I) as mentioned above, such as potassium 2- ethyl hexanoate, suitable solvents include C1 - C5 aliphatic alcohols such as isopropanol. Typically when a solvent for the metal salt precursor compound is present in the medium this may be present in a volume:volume ratio non-chlorinated fluorinated hydrocarbon : solvent for the metal salt precursor compound of 1 : 0-0.5, for example around 1 : 0.1-0.35. It is preferred that the liquid medium also includes water as the presence of water appears to be desirable to achieve a crystalline product. Preferably water is present in the liquid medium in the range 0.1 -3.0 % v.v, but excessive amounts of water in the medium should be avoided to minimise aqueous degradation of the clavulanate salt product. Suitably ca. 0.5 - 2.5 % v:v water may be present. The reaction may be carried out over a broad concentration range of the organic amine salt of clavulanic acid, and the consequent concentration of the metal salt precursor compound as mentioned above. For example the concentration of the amine salt in the medium may lie in the range 0.05-5M. In one form of the process of the invention the amine salt of clavulanic acid may be dissolved or suspended in an organic solvent, which may be a solvent for the metal salt precursor compound, in a suitable reactor vessel. The reactor vessel may then be charged with the fluorinated hydrocarbon solvent and pressurised to a pressure at which the fluorinated hydrocarbon solvent is a liquid, e.g. typically ca 4-6 bar. With the resulting solution or suspension of the amine salt may then be mixed a solution or suspension of the metal salt precursor compound, for example in a solvent as described above. As explained above the reaction medium should contain a trace of water, and this may be included in the solution or suspension of the amine salt, or in the solution or suspension of the metal salt precursor compound added thereto, or water may be added to the reaction mixture. Metal salts of clavulanic acid are generally insoluble in the type of liquid medium resulting from this form of the process and the product metal salt of clavulanic acid will normally precipitate out from the reaction medium, so that it can easily be isolated by filtration. In the case of potassium clavulanate such a precipitate may comprise the known needle or rosette crystal forms. The filtered product may then be washed, for example with the fluorinated hydrocarbon. When the fluoripated hydrocarbon is a gas at room temperature excess fluorinated hydrocarbon may then conveniently be removed by reduction of the pressure in the reactor or filter. In the above-described form of the process, if the metal salt precursor compound is a salt of an alkanoic acid of an acid of formula (I), for example potassium 2-ethylhexanoate, then the solution of the precursor compound may be made by dissolving the compound in a suitable solvent, or alternatively the precursor compound may be prepared in situ by reaction between a suitable metal-containing base such as potassium hydroxide and the parent acid, such as 2-ethyl hexanoic acid in the solvent. Suitable apparams for performing the process of the invention will be apparent to those skilled in the art. One suitable apparams comprises a reaction vessel in which the reaction can take place, which can be charged with the fluorinated hydrocarbon and with the reagents and any other solvents, water etc. from appropriate sources, and which can be pressurised to a pressure at which the fluorinated hydrocarbon is a liquid, a receiver in fluid communication with the reaction vessel and into which liquid medium from the reaction vessel may be transferred after the reaction has taken place, with a filter between and in fluid communication with the reaction vessel and receiver, and which can retain particles of the product metal salt of clavulanic acid. Preferably the reaction vessel and receiver are also capable of evacuation so that the fluorinated hydrocarbon can be easily evaporated off, and the apparatus also preferably includes a compressor to remm the fluorinated hydrocarbon to the source or to the reactor. Within such a general description various constructions of apparatus will be apparent to those skilled in the art. Accordingly the present invention provides a process for the preparation of potassium clavulanate comprising reacting an organic amine salt of clavulanic acid, said organic amine being selected from tertiary butyl amine, an N,N'-substituted diamine, an N, N'-monosubstituted symmetric diamine or N,N'-monosubstituted symmetric alkylethylene diamine or tertiary octylamine with a metal salt precursor such as a potassium salt of an organic carboxylic acid of formula I (I) wherein R10 is an alkyl group containing 1 to 20 carbon atoms, potassium carbonate, bicarbonate or hydroxide in a liquid reaction medium of a liquid fluorinated and/or chlorinated hydrocarbon of the formula CnHmXpYr wherein X is fluorine, Y is chlorine, n and m are whole numbers, p and r are zero or whole numbers, provided both p and r are not zero and (m + p + r) equals 2n +2, and thereafter isolating potassium clavulanate from the reaction medium in a known manner. The method of the invention has the advantages that the reaction is simple and rapid, can achieve yield improvements, and reduction in solvent usage. The invention will now be described by way of example with reference to Figure 1 in the accompanying drawing which schematically shows a reaction assembly. Example 1. Equipment The equipment used for this work consisted of a 5 L reaction/ extraction vessel (1) and a 5 L receiver/ evaporation vessel (2), both vessels being jacketed, a 1,1,1,2-tetrafluoroethane gas cylinder (3) and compressor (4). The whole was connected together with a system of pipes, pressure gauges (5), thermometers (6), valves (7), condenser (8), etc. to allow a multi task function. The reactor was equipped with a stirrer (9), a pH port (10) and a burette (11) designed to introduce reagents whilst the system was pressurised. After materials were charged into the reaction/ extraction vessel, the whole system could be evacuated then 1,1,1,2-tetrafluoroethane gas charged into the reaction/extraction (1) to a pressure of 5 bar. Reagents could then be introduced via the burette (11). When the reaction or extraction was complete, the mixture could be discharged to the evaporator (2) via a transfer line (12) and an inline filter (13). The 1,1,1,2-tetrafluoroethane gas could be evaporated using the compressor (4) and condensed into liquid form in condenser (8), and could be either charged back into the cylinder (3) or recycled through the reactor/ extractor (1). Experimental Data Method: Expts. 1-3 t-BA clavulanate was charged to the reactor followed by isopropanol and water. The vessel was sealed and evacuated then 1,1,1,2-tetrafluoroethane was charged until system pressure equilibrated at 5 bar. Potassium ethyl hexanoate ("KEH") / isopropanol ("IPA") was charged to the burette then added to the reactor whilst stirring over 30 minutes. At the end of a further 20 minute stirring, the contents of the reactor where transferred to die receiver via the in-line filter. 1,1,1,2-tetrafluoroethane gas was compressed back into the reservoir cylinder. The filtered product in the reactor was slurried twice in 1,1,1,2-tetrafluoroethane to remove isopropanol residues and associated impurities. This had the effect of producing dry product with very little solvent and water contamination. Method: Expts. 4 and 5 2-ethyl hexanoic acid (lOlg) was charged into a beaker containing isopropanol (300ml). The solution was chilled to 10°C and potassium hydroxide (40.8g) was added whilst stirring vigorously. When all the potassium hydroxide was dissolved, isopropanol was added to make up a total volume of 420ml. This solution was transferred to the burette vessel of the 1,1,1,2-tetrafluoroethane rig. t-BA clavulanate (154g) and isopropanol (500ml) were charged to the reaction vessel and continued as above. Results All products passed on appearance, water content and purity. Stability studies using DVS showed poor results for Expt. 2 suggesting that water presence during the reaction is essential to crystal formation. The stability of the product from Expt. 4 was very good and Expt.5 produced products of exceptional stability. The following table shows data obtained from reactions using 2.5L 1,1,1,2-tetrafluoroethane and standard potassium ethyl hexanoate/ isopropanol solution (concentration = 2N and water content = 2%) •ity pfa ■8 A .8 •ity pfa .3 .6 WE CLAIM: 1. A process for the preparation of potassium clavulanate comprising reacting an organic amine salt of clavulanic acid, said organic amine being selected from tertiary butyl amine, an N,N'-substituted diamine, an N, N'- monosubstituted symmetric diamine or N,N'-monosubstituted symmetric alkylethylene diamine or tertiary octylamine with a metal salt precursor such as a potassium salt of an organic carboxylic acid of formula I R10COOH (I) wherein R10 is an alkyl group containing 1 to 20 carbon atoms, potassium carbonate, bicarbonate or hydroxide in a liquid reaction medium of a liquid fluorinated and/or chlorinated hydrocarbon of the formula CnHmXpYr wherein X is fluorine, Y is chlorine, n and m are whole numbers, p and r are zero or whole numbers, provided both p and r are not zero and (m + p + r) equals 2n +2, and thereafter isolating potassium clavulanate from the reaction medium in a known manner. 2. The process as claimed in claim 1, wherein the liquid medium comprises a mixture of the liquid fluorinated and/or chlorinated hydrocarbon and optionally containing a C1-5 organic aliphatic alcohol or ether. 3. The process as claimed in claim 1 or 2, wherein the salt of potassium with the said organic carboxylic acid of formula (I) is the salt of potassium 2-ethylhexanoate. 4. The process as claimed in any one of claims 1 to 3, wherein the liquid medium is a gas at ambient temperature which can be liquefied at ambient temperature by pressure. 5. The process as claimed in claim 4, wherein the boiling point for the liquid fluorinated and/or chlorinated hydrocarbon is -10 to 50°C at ambient atmospheric pressure. 6. The process as claimed in any one of claims 1 to 5, wherein the liquid medium is a fluorinated non-chlorinated hydrocarbon. 7. The process as claimed in claim 1, wherein n is 2 or 3. 8. The process as claimed in claim 1, wherein the fluorinated and/or chlorinated hydrocarbon is selected from 1,1,1,2 - tetrafluoroethane, fluoroform, methyl chloride, difluorodichloromethane, monofluoromethane, difluoromethane, trifluoromethane, pentafluoroethane, 1,1,1 -trifluoroethane, 1,1 -difluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,2,2,3,3-heptafluoropropane, 1,1,1,3,3,3-hexafluoropropane, 1,1,1,2,2-pentafluoropropane, 1,1,1,2,2,3- hexafluoropropane, 1,1,2,2,3,3-hexafluoropropane and 1,1,1,2,3,3- hexafluoropropane. 9. A process for the preparation of potassium clavulanate substantially as herein described and exemplified.

Documents:

724-mas-1998 abstract.pdf

724-mas-1998 claims.pdf

724-mas-1998 correspondence others.pdf

724-mas-1998 description (complete).pdf

724-mas-1998 drawing.pdf

724-mas-1998 form-2.pdf

724-mas-1998 form-26.pdf

724-mas-1998 form-4.pdf

724-mas-1998 form-6.pdf