- Evidence that the Immediate Biosynthetic Precursor of Clavulanic Acid is its N-aldehyde Analogue
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(3R,5R) Clavulanate-9-aldehyde 1 has been detected in Streptomyces clavuligerus and an NADPH dependent dehydrogenase capable of reducing 1 to clavulanic acid 2 has been isolated from this organism.
- Nicholson, Neville H.,Baggaley, Keith H.,Cassels, Robert,Davison, Mark,Elson, Stephen W.,et al.
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- The Stereochemical Fate of (2RS,5R)- and (2RS,5S)-Ornithine in Clavulanic Acid Biosynthesis
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The 5-pro(R) hydrogen of ornithine is retained in the biosynthesis of clavulanic acid where it assumes the 9-pro(S) position with overall inversion of configuration.
- Townsend, Craig A.,Ho, Meng-fei,,Mao, Shi-shan
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- Process for the isolation of a pharmaceutically acceptable alkali metal salt of clavulanic acid
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The invention relates to the process for the isolation of a pharmaceutically acceptable alkali metal salt of clavulanic acid from a fermentation broth containing impure clavulanic acid comprising the steps of filtration of the fermented broth, extraction of the clavulanic acid to a water immiscible or partly water immiscible solvent at pH from 1.2-2, precipitation of an alkali metal salt A of clavulanic acid by addition of a solution of an alkali metal alkylalkanoate, characterized by the following steps: before the filtration the fermented broth containing clavulanic acid is diluted with water, a flocculating agent is added and the pH is adjusted to 3-5 for further purification the alkali metal salt A of clavulanic acid is converted to clavulanic acid by addition of an inorganic acid and is extracted into a water immiscible or partly water immiscible solvent a solution of a different alkali metal B alkyl alkanoate is added and the alkali metal salt B of clavulanic acid is precipitated.
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- Clavulanic acid aldehyde, beta-lactamase inhibitor
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A compound of formula (I): wherein R = H or Na, or a salt thereof and an enzyme, obtainable from Streptomyces species, having clavulanic acid dehydrogenase activity which is capable of converting (I) into clavulanic acid .
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- Process for the preparation of potassium clavulanate
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A process for preparation of potassium clavulanate by the direct precipitation of clavulanic acid as the potassium salt by providing a solution of clavulanic acid in an organic solvent and mixing a potassium salt with this solution, with between 0.1 % v:v and 7.5 % v:v of water present in the region where the clavulanic acid and potassium salt contact, then isolating the so-formed potassium clavulanate.
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- Process for the isolation of a pharmaceutically acceptable alkali metal salt of clavulanic acid
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The invention relates to the process for the isolation of a pharmaceutically acceptable alkali metal salt of clavulanic acid from a fermentation broth containing impure clavulanic acid comprising the steps of filtration of the fermented broth, extraction of the clavulanic acid to a water immiscible or partly water immiscible solvent at pH from 1.2 - 2, precipitation of an alkali metal salt A of clavulanic acid by addition of a solution of an alkali metal alkylalkanoate, characterized by the following steps: before the filtration the fermented broth containing clavulanic acid is diluted with water, a flocculating agent is added and the pH is adjusted to 3 - 5 for further purification the alkali metal salt A of clavulanic acid is converted to clavulanic acid by addition of an inorganic acid and is extracted into a water immiscible or partly water immiscible solvent a solution of a different alkali metal B alkyl alkanoate is added and the alkali metal salt B of clavulanic acid is precipitated.
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- Process for the preparation of clavulanic acid
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A process for the preparation and/or purification of clavulanic acid or a pharmaceutically acceptable salt or ester thereof comprises i) contacting impure clavulanic acid or an alkali metal salt thereof in an organic solvent, with an amine of formula (II) where R1 is a group of general formula where R4 and R5 are independently hydrogen, alkyl, amino-substituted alkyl or substituted amino-substituted alkyl, and R2 and R3 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; ii) isolating the amine salt of clavulanic acid formed; iii) converting the thus formed salt into clavulanic acid or a pharmaceutically acceptable salt or ester thereof.
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- Process for the preparation of clavulanic acid
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A process for the preparation and/or purification of clavulanic acid or a pharmaceutically acceptable salt thereof comprises i) contacting impure clavulanic acid or an alkali metal salt thereof in an organic solvent, with tertiary octylamine; ii) isolating the tertiary-octylamine salt of clavulanic acid formed; iii) converting the thus formed salt into clavulanic acid or a pharmaceutically acceptable salt or ester thereof.
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- The Incorporation of DL- Ornithine into Clavulanic Acid and N0Acetylglycylclavaminic Acid
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Both the carbon and deuterium label of DL- ornithine were incorporated into the novel β-lactam metabolite N-acetylglycylclavaminic acid, whereas only the carbon label was incorporated into clavulanic acid.
- Bycroft, Barrie W.,Penrose, Audrey,Gillett, Janet,Elson, Stephen W.
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p. 980 - 981
(2007/10/02)
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- Amine salts of clavulanic acid as antibacterial agents
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The present invention provides the salts of the formula (II): STR1 wherein R1 is a hydrogen atom or a lower alkyl, aralkyl, phenyl or inertly substituted lower alkyl, aralkyl or phenyl group; R2 is a hydrogen atom or a lower alkyl, aralkyl, phenyl or inertly substituted lower alkyl, aralkyl or phenyl group; and R3 is lower alkyl, aralkyl, phenyl or inertly substituted lower alkyl, aralkyl or phenyl group; any of said groups R1, R2 and R3 being optionally interlinked to form a ring of 5-7 ring atoms. The compounds are antibacterials.
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- Clavulanic Acid and its Derivatives. Structure Elucidation of Clavulanic Acid and the Preparation of Dihydroclavulanic Acid, Isoclavulanic acid, Esters and Related Oxidation Products
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Clavulanic acid, a novel β-lactamase inhibitor from Streptomyces clavuligerus, has been shown to be Z-(2R,5R)-3-(β-hydroxyethylidene)-7-oxo-4-oxa-1-azabicycloheptane-2-carboxylic acid (1).The structure and absolute stereochemistry was confirmed by X-ray analysis of the p-nitrobenzyl and p-bromobenzyl esters, (14) and (15).The conversion of clavulanic acid into a variety of esters and acyl derivatives is described.An account of its isomerisation to the E isomer (30) and the formation of an oxetane (45) as a by-product of the photolysis of the phenacyl ester (18) is given.The reduction and oxidation of acid (1) under a variety of conditions has also been examined in detail.
- Brown, Allan G.,Corbett, David F.,Goodacre, Jennifer,Harbridge, John B.,Howarth, T. Trefor,et al.
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p. 635 - 650
(2007/10/02)
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- Esters of clavulanic acid
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A new antibacterially active agent has been isolated from Streptomyces clavuligerus. This new compound which is designated clavulanic acid has the formula (I): STR1 In addition to being a broad spectrum antibiotic of medium potency, clavulanic acid and its salts and esters have the ability to enhance the effectiveness of β-lactam antibiotics against many β-lactamase producing bacteria.
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- Process for the purification of clavulanic acid
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The invention provides the compound (2R,5R,Z)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo-[3,2,0]-heptane-2-carboxylic acid and its salts in purified form and pharmaceutical compositions containing them and a process for the purification of such compounds by conversion in aqueous media to the lithium salt of the above acid and precipitation thereof.
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- ≈-lactam containing compounds
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Compounds of the formula (II) STR1 wherein R1 is CH3, CH2 OH, CHO or CH2 OCOR4 wherein R4 is a hydrocarbon of 1-7 carbon atoms and R2 is a group of the formula R3 or COR3 wherein R3 is a hydrocarbon of 1-7 carbon atoms optionally inertly substituted by halogen are useful as antibacterial agents and β-lactamase inhibitory agents.
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- Isoclavulanic acid as an antibacterial and a β-lactamase inhibitor
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β-Lactamase inhibitory and antibacterial compounds of the formula: STR1 wherein R is a hydrogen atom or an acyl group and salts and esters thereof, procedure for their preparation and pharmaceutical compositions containing the same.
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- Clavulanic acid amides
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Amides of the compound of the formula STR1 are useful for their β-lactamase inhibitory activity.
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- Clavulanic acid sulphates
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Clavulanic acid sulphates of the formula STR1 wherein M1 is trimethylamine, dimethylalanine, pyridine, N-methylpyridine or N-methylmorpholino, are useful for their antibacterial activity and are also useful as intermediates for the production of antibacterially active compounds.
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