Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
1999-09-30
2001-10-09
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
active
06300495
ABSTRACT:
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-1-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 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. 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 the 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 dimethylaniline 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, moisture 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 alkyl groups or substituted alkyl groups are referred to herein unless otherwise defined herein 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):
as an intermediate in a process for the preparation of clavulanic acid or pharmaceutically acceptable salts and esters thereof, wherein R
1
, R
2
and R
3
are selected according to the following options:
(1) R
1
being an optionally substituted cyclic group of general formula:
R—(CHR
4
)
m
—
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, R
4
is hydrogen or alkyl, amino- or hydroxy-substituted alkyl or substituted amino-substituted alkyl, or a group of the same general formula or R
1
above:, R
2
and R
3
may be selected from the same groups from which R
1
is selected, or from hydrogen, alkyl, alkenyl, amino- or hydroxy-substituted alkyl or alkenyl, or substituted amino-substituted alkyl or alkenyl: or
(2) each of R
1
, R
2
and R
3
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-substituted alkyl or alkenyl, but with the exception of t-butylamine, s-butylamine, N,N-dimethylethylamine, 1,2dimethylpropylamine, neopentylamine and 2-amino-3,3-dimethylbutane: or
(3) R
1
being an optionally substituted aryl group of general formula:
where R
4
is hydrogen or one or more substituents, and m is zero or an integer 1 to 5, and R
2
and R
3
are independently selected from hydrogen, allyl, amino- or hydroxy-substituted alkyl or substituted—amino-substituted alkyl or groups of the same general formula as R
1
: or
(4) R
1
and R
2
, and optionally R
3
, together with the nitrogen atom shown being the residue of an optionally substituted heterocyclic ring system including the nitrogen atom as a ring member, and optionally including one or more additional ring hetero atoms, and if R
3
is not part of the ring system it is independently selected from hydrogen, alkyl, amino- or hydroxy-substituted alkyl or substituted amino-substituted alkyl: or
(5) R
1
being a group of general formula:
where R
4
and R
5
are independently hydrogen, alkyl, amino-substituted alkyl or substituted amino-substituted alkyl, and R
2
and R
3
are independently selected from hydrogen, alkyl, amino- or hydroxy-substituted alkyl or substituted amino-substituted alkyl, and m is zero or an integer 1 to 5: or
(6) One or both of R
1
and R
2
are hydrogen and R
3
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-imethylcyclohexylamine, dicyclohexylamine, adamantylamine, NN-diethylcyclohexylamine, N-isopropylcyclohexylamine, N-methylcyclohexylamine, cyclopropylamine, cyclobutylamine, norbornylamine, dehydroabietylamine, t-octylamine, (ie 2-amino-2,4,4-timethylpentane), t-amylamine, 1-hydroxy-2-methyl-2-propylamine, tri-n-propylamine, tri-n-octylamine, tri-n-butylamine, dimethylamine, i-propylamine, di-n-hexylarnine, di-nbutylamine, diethylamine, 2-aminoethanol, NN-diethylethanolamine, NN-dimethylethanolamine, ethanolamine, n-butylamine, n-hexylamine, noctadecylamine, N-ethylethanolamine, 1-hydroxyethylamine, diethanolamine, NNdimethylethanolamine, 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-heptylam
Cook Michael Allen
Nicola Mazin
Dinner Dara L.
Kinzig Charles M.
McKenzie Thomas C
Shah Mukund J.
SmithKline Beecham p.l.c.
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