Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1998-05-11
2000-10-17
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C07D50308
Patent
active
061334413
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the production of pharmaceutically acceptable salts of clavulanic acid of formula ##STR2## Pharmaceutically acceptable salts of clavulanic acid are known and various production processes, for example via acid thereof into a pharmaceutically acceptable salt of clavulanic acid
Fermentation step a) may be carried out, for example, as generally described e.g. in GB 1508977 and WO 93/25557. A particular fermentation process, is disclosed, e.g. in EP 182 522 by continuously or intermittently feeding a carbon source during fermentation; e.g. in WO 96/18743 by keeping low levels of ammonium and urea; e.g. in EP 349 121; WO 95/03416; CA 2108113; WO 94/18326; WO 94/12654; and WO 96/10084; by production of clavulanic acid from a host transformed with a vector comprising a DNA or a DNA fragment that is encoding at least one enzyme involved in clavulanic acid production. An appropriate micro-organism may be for example a micro-organism of the genus Streptomyces, such as S. clavuligerus, i.e. strain NRRL 3585, or Streptomyces sp. P6621 FERM 2804 (Japanese patent 55,162,993) or other mutants.
Fermentation under appropriate conditions is in more detail known from various publications, e.g. from references cited under step a), the content of which, including prior art citations therein, is incorporated herein by reference.
Isolation step b) may be carried out, for example, by extraction of the acidified fermentation broth with a water-immiscible solvent in which clavulanic acid is soluble, e.g. by direct extraction of the fermentation broth, or after removing at least part of the suspended solids suspended in the fermentation broth. Solids may be removed, for example by flocculation, filtration, e.g. by microfiltration, or by centrifugation. A water-miscible solvent may be added to the fermentation broth in order to improve filterability of the broth prior to solid removal. The aqueous, clavulanic acid containing liquid may be pre-concentrated, conveniently prior to acidification and extraction, to achieve specific concentration ranges, e.g. by anion exchange or osmotic methods. The solution of clavulanic acid in an organic solvent, for example obtainable by extraction, may be e.g. back-extracted into water for further purification. Phase separation of the aqueous and the organic phase may be facilitated, for example by centrifugation methods. The solution of clavulanic acid in an organic solvent may be dried to achieve specific water ranges prior to further processing. Isolation processes using appropriate conditions are in more detail known from various publications, e.g. from EP 387 178; WO 93/25557; WO 95/11295; WO 95/34194: WO 96/28452; WO 96/22296. The content of references cited under step b), including prior art citations therein, is incorporated herein by reference.
Purification step c) may for example be carried out by chromatography or via salt formation, for example via formation of a salt of clavulanic acid that may precipitate, for example crystallise, from the solvent used. Such a salt may be, for example the lithium salt of clavulanic acid, e.g. as described in GB 1543563, or GB 1508977, or an amine salt. Suitable amines which form a salt with clavulanic acid are described in various publications, such as tert.butylamine in EP 26 044; N,N-(di)alkyl-alkylene-diamines, such as diisopropyl-ethylendiamine in EP 562 583; N,N,N',N'-tetramethyl-ethylendiamine in EP 719 778; tert.octylamine for example in GB 2264944; or for example a class of amines in WO 93/25557, wherein are described amines of formula ##STR3## wherein R.sub.1, R.sub.2 and R.sub.3 are selected according to the following options: from 3 to 8 ring carbon atoms substituted amino-substituted alkyl; or a group of the same general formula R.sub.1 above; which R.sub.1 is selected; or from hydrogen; alkyl; alkenyl; amino- or hydroxy-substituted alkyl or alkenyl; or substituted amino-substituted alkyl or alkenyl; independently selected from hydrogen; alkyl; alkenyl; amino- or hydroxy- or alkoxy-substituted alkyl or alkenyl
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Berch Mark L.
Biochemie Gesellschaft m.b.H.
Dohmann George R.
Kalinchak Stephen G.
McNally Lydia T.
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