Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• the present invention relates to a process for the preparation of certain ethers of clavulanic acid.
• Ethers of clavulanic acid are disclosed in Belgian Patent No: 847045. It has been found that ethyl and propyl ethers of clavulanic acid and derivatives thereof can conveniently be prepared via the vinyl and propenyl ethers of clavulanic acid.
• the reduction reaction is effected by hydrogenation in the presence of a catalyst such as a transition metal catalyst, such as platinum oxide, palladium or the like.
• a catalyst such as a transition metal catalyst, such as platinum oxide, palladium or the like.
• An approximately atmospheric pressure of hydrogen is generally most convenient for laboratory use, but sub-atmospheric pressures may also be employed, so long as extreme conditions are avoided.
• a compound of the formula (I) per se or a salt thereof may be obtained by de-esterifying a suitable ester of the compound, for example, by the hydrolysis of a methoxymethyl or like ester or by the hydrogenolysis of a benzyl, p-methoxybenzyl or like ester optionally in the presence of a base, for example, as described in Belgian Patent No: 847045.
• the hydrogenation of the vinyl or propenyl group and hydrogenolysis of the ester may occur at the same time, by selecting a suitable catalyst and solvent, for example, by using a tetrahydrofuran - containing solvent system and by using a palladium or mixed platinum oxide/palladium catalyst.
• esters of the compounds of the formula (II) included those wherein the esterifying moiety is a group A or CHA 2 A 3 wherein A is an alkyl group of 1-8 carbon atoms optionally substituted by halogen or by a group of the formula OA 4 , OCOA 4 , SA 4 , S0 2 A 4 wherein A4 is a hydrocarbon group of up to 6 carbon atoms;
• a 2 is a hydrogen atom, an alkyl group of up to 4 carbon atoms or a phenyl group optionally substituted by halogen or by a group A 5 or OA S where A 5 is an alkyl group of up to 6 carbon atoms; and
• A3 is a phenyl group optionally substituted by halogen or nitro or by a group A 6 or OA 6 where A 6 is an alkyl group.
• the ester of the compound of the formula (II) is such that the corresponding ester of the compound of the formula (I) is a readily hydrolysable or hydrogenolysable ester.
• Suitable esters of this type include the methoxymethyl, ethoxymethyl, benzyl, methoxybenzyl, nitrobenzyl and the like esters.
• a particularly preferred ester of the compounds of the formula (II) is the p-nitrobenzyl ester.
• Suitable salts of the compounds of the formula (II) include alkali metal, alkaline earth metal and ammonium and substituted ammonium salts.
• the salt is a pharmaceutically acceptable salt.
• the compounds of formula (II) possess useful ⁇ -lactamase inhibitory properties which allow them to be utilised in antibacterial compositions.
• compositions may be utilised as described in the aforementioned patent specification and may advantageously contain a penicillin or cephalosporin.
• the preparation of the compounds of the formula (II) and salts and esters thereof comprise the reaction of an ester of clavulanic acid with a compound of the formula (III) or (IV): wherein R 3 is an alkyl group of up to 6 carbon atoms, in the presence of mercuric ions as catalyst, and thereafter, if desired, de-esterifying the resulting ester of the compound of the formula (II).
• R 3 in formulae (III) and (IV) is an ethyl group.
• the catalyst is mercuric acetate or mercuric trifluoroacetate.
• reaction may take place in an inert organic solvent, or if a large excess of the compound of the formula (III) or (IV) is used, this may act as solvent.
• the reaction may be effected at a non-extreme temperature such as about -10 to 60°C, for example from about 0 to 30°C. Low temperatures in this range are preferred when using a compound of the formula (IV).
• Compounds of the formula (II) and salts thereof may be formed by cleavage of the corresponding p-nitrobenzyl ester. This cleavage may be effected using a reducing agent which reduces the nitro group to an amino group, for example, as described in Dutch Patent Application No: 7702027.
• a suitable reducing agent is iron powder/ammonium chloride solution.
• N.m.r.: 8 (CDCI 3 ) 3.00 (1 H, d, J 17Hz), 3.43 (1 H, dd, J 3Hz and 17Hz), 3.95 (1 H, dd, J 7Hz and 3Hz), 4.13 (1 H, dd, J 3 and 14Hz), 4.26 (2H, d, J 7Hz), 4.81 (1 H, broad t, J 7Hz), 5.05 (1 H, s), 5.13 (2H, s), 5.64 (1 H, d, J 3Hz), 6.33 (1 H, dd, J 14 and 7Hz), 7.27 (5H, s)
• p-Nitrobenzyl 9-0-vinyl-clavulanate (190 mg) was dissolved in tetrahydrofuran (6 ml) and to the resulting stirred solution 1M ammonium chloride solution (6 ml) and iron powder (0.8 g) were added. The mixture was stirred for 20 minutes and then more iron powder (0.8 g) and 1M ammonium chloride solution (0.5 ml) were added. The mixture was stirred for a further 15 minutes and was then diluted with ethyl acetate (100 mi). The resulting mixture was stirred rapidly while hydrogen sulphide was bubbled through it for 5 minutes. The mixture was filtered and the solid was washed well with water.
• the aqueous layer of the filtrate was saturated with sodium chloride and the mixture was filtered again.
• the filtrate was treated with 1N HCI (3 ml), was shaken, and the layers were separated.
• the organic layer was dried (sodium sulphate) and filtered.
• the resulting solution was extracted with 1/15 M phosphate buffer (pH 7; 3 x 30 ml).
• the combined extracts were overlayed with ethyl acetate (50 mi) and were treated with 1N HNI (5 ml).
• the mixture was shaken and the layers were separated.
• the organic layer was dried (magnesium sulphate) and the solvent was evaporated under reduced pressure.
• the resulting residue was immediately dissolved in tetrahydrofuran (5 ml).
• MIC minimum inhibitory concentrations

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Communicable Diseases (AREA)
• Pharmacology & Pharmacy (AREA)
• Oncology (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Cephalosporin Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

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• 1978
  • 1978-07-10 EP EP78300135A patent/EP0000804B1/en not_active Expired
  • 1978-07-10 DE DE7878300135T patent/DE2862385D1/de not_active Expired
  • 1978-07-27 CA CA308,302A patent/CA1107739A/en not_active Expired
  • 1978-08-01 JP JP9501178A patent/JPS5427595A/ja active Pending
  • 1978-08-02 IT IT50575/78A patent/IT1106618B/it active
  • 1978-08-03 ES ES472335A patent/ES472335A1/es not_active Expired

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