EP0000828B1 - Synthetic beta-lactam compounds, a process for their preparation and compositions containing them - Google Patents

Synthetic beta-lactam compounds, a process for their preparation and compositions containing them Download PDF

Info

Publication number
EP0000828B1
EP0000828B1 EP78300231A EP78300231A EP0000828B1 EP 0000828 B1 EP0000828 B1 EP 0000828B1 EP 78300231 A EP78300231 A EP 78300231A EP 78300231 A EP78300231 A EP 78300231A EP 0000828 B1 EP0000828 B1 EP 0000828B1
Authority
EP
European Patent Office
Prior art keywords
hept
ene
oxo
azabicyclo
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP78300231A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP0000828A1 (en
Inventor
Roger John Ponsford
Robert Southgate
Patricia Margaret Roberts
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beecham Group PLC
Original Assignee
Beecham Group PLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0000828A1 publication Critical patent/EP0000828A1/en
Application granted granted Critical
Publication of EP0000828B1 publication Critical patent/EP0000828B1/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/568—Four-membered rings

Definitions

  • the present invention relates to ⁇ -lactam antibacterials, to a process for their preparation and to compositions containing them.
  • French Patent Application 2371449 discloses a wide range of carbapenems obtained by synthesis, which have a carbon-bonded substituent at the C-3 position.
  • British Patent No. 1483142 and J. Chem. Soc., Chem. Comm., 1977, 523 disclose that the compound of the formula (I). and its salts may be obtained by fermentation of strains of Streptomyces olivaceus.
  • a distinct class of synthetic antibacterial agents which contain a ⁇ -lactam ring fused to a pyrroline ring may be prepared.
  • An apt group of compounds within formula (II) includes those wherein:
  • a further apt group of compounds within formula (II) includes those wherein:
  • Suitable esterifying groups R 1 include alkyl groups of up to 12 carbon atoms, alkenyl groups of up to 12 carbon atoms, alkynyl groups of up to 12 carbon atoms, phenyl or benzyl groups or any of the aforesaid inertly substituted by lower alkoxyl, lower acyloxyl, halogen, or nitro group. Used herein 'inertly substituted' means that the resulting group is stable and will not undergo rapid decomposition.
  • Particularly suitable esterifying groups R 1 include lower alkyl groups optionally substituted by lower alkoxyl, the benzyl group optionally substituted by lower alkoxyl, nitro, or chloro and those groups which are known to give rise to rapid in-vivo hydrolysis in penicillin esters.
  • Certain preferred esterifying groups R 1 inciude methyl, ethyl, methoxymethyl, 2-methoxyethyl, benzyl, methoxybenzyl and nitrobenzyl.
  • esterifying groups R 1 include those which give rise to in-vivo hydrolysable esters such as acetoxymethyl, pivaloyloxymethyl, a-ethoxycarbonyloxyethyl and phthalidyl.
  • a preferred group R 1 of those giving rise to in-vivo hydrolysable esters is the phthalidyl group.
  • Preferred groups R 1 are those such that CO 2 R 1 is a carboxylic acid salt.
  • the group CO 2 R 10 may also be a carboxylic acid salt.
  • CO 2 R 1 is a carboxylic acid salt in compounds of the formula (II) also containing the group CO 2 R 10
  • CO 2 R 10 is usually also a carboxylic acid salt, and normally R 1 and R 10 are like cations.
  • salts of compounds of formula (II) are conventional pharmaceutically acceptable salts such as the alkali metal and alkaline earth metal salts, in particular the sodium, potassium, calcium and magnesium salts; ammonium and substituted ammonium salts, for example the t-butylamine salt.
  • Particularly suitable salts are the potassium and sodium salts, especially the sodium salts.
  • R 2 is a phenyl group, optionally mono-substituted.
  • Suitable groups R 2 include the phenyl, p-chlorophenyl, m-chlorophenyl, p-nitrophenyl, m-nitrophenyl, p-ethoxycarbonylphenyl, p-fluorophenyl, p-methylphenyl, p-aminophenyl, p-acetamidophenyl, p-(4'-nitrobenzyloxycarbonylamino)phenyl and p-methoxyphenyl.
  • a preferred sub-group of compounds within formula (II) is of formula (IV): wherein:
  • R 1 1 include acetoxymethyl, pivaloyioxymethyl, a-ethoxycarbonyloxyethyl anc phthalidyl.
  • R 1 1 is preferably phthalidyl.
  • Suitable groups R 2 are as so described under formula (II).
  • a second preferred sub-group of compounds within formula (II) is of formula (V): wherein:
  • Particularly suitable salts are the potassium and sodium salts, especially the sodium salts.
  • Suitable groups R 2 are as so described under formula (II).
  • a sub-group of compounds within formula (ll) of interest is of formula (Vl): wherein:
  • a suitable group R 3 is tert-butyl.
  • Another suitable group R 3 1 is methyl.
  • An additional suitable group R 3 1 is benzyl.
  • a suitable group R 3 1 is p-nitrobenzyl.
  • One more suitable group R 3 1 is phthalidyl.
  • a further suitable group R 3 1 is pivaloyloxymethyl.
  • R 3 1 is sodium.
  • p-Nitrobenzyl is a preferred group R 3 1 .
  • Phthalidyl is also a preferred group R 3 1 .
  • Sodium is another preferred group R 3 1 .
  • a suitable group R 1 2 is p-acetamidophenyl.
  • R 1 2 is phenyl
  • a suitable group R 1 2 is p-nitrophenyl.
  • One more suitable group R 1 2 is p-aminophenyl.
  • a further suitable group R 1 2 is p-(4'-nitrobenzyloxycarbonylamino)phenyl.
  • a reaction sequence leading to the compounds of this invention is as follows:
  • R 4 , R 5 and R 6 are each phenyl groups.
  • the ring closure is normally brought about by heating the compound of the formula (VII) in an inert solvent; for example temperatures of 90-120°C and more suitably 100-110°C may be employed in a solvent such as toluene or the like.
  • the reaction is best carried out under dry conditions under an inert gas.
  • the ester of the compound (11) produced may be isolated by any standard method such as fractional crystallisation or chromatography. We have found that is is most convenient to separate the desired product by column chromatography.
  • the ester employed is preferably one which is readily converted to the parent acid or its salt by mild methods of hydrogenolysis.
  • the invention includes a process for preparing a salt or free acid of a compound (II) which process comprises de-esterifying an ester of a compound of formula (11).
  • Particularly suitable esters for use in this process include benzyl esters, optionally substituted in the para position by a lower alkoxy, or nitro group or a halogen atom.
  • a preferred ester for use in this process is the p-nitrobenzyl ester.
  • Esters of compounds (II) may be de-esterified by conventional methods of hydrogenolysis.
  • Suitable methods include hydrogenation in the presence of a transition metal catalyst.
  • the pressure of hydrogen used in the reaction may be low, medium or high but in general an approximately atmospheric or slightly superatmospheric pressure of hydrogen is preferred.
  • the transition metal catalyst employed is preferably palladium on charcoal or on calcium carbonate.
  • the hydrogenation may be effected in a suitable solvent in which the ester is soluble such as aqueous dioxan. If this hydrogenation is carried out in the presence of a base then a salt of compounds (II) is produced.
  • Suitable bases for inclusion include NaHCO 3 , KHCO 3 , Na 2 CO 3 , K 2 CO 3 , CaC0 3 , MgC0 3 , LiHCO 3 , NH 4 0COCH 3 and the like.
  • Suitable bases which may be used to neutralise acids within formula (II) include LiOH, NaOH, NaHCO 3 , KOH, Ca(OH) 2 and Ba(OH) 2 .
  • the salts of acids (II) may be converted to esters in conventional manner, for example by reaction with a reactive halide such as bromophthalide in .soiution in dimethylformamide.
  • a reactive halide such as bromophthalide in .soiution in dimethylformamide.
  • the substituent group or groups within the group R 2 in the compounds of formula (II) may be varied by conventional reactions.
  • a substituent when a substituent is a nitro group it may be reduced in a conventional manner to an amino group, for example by catalysed hydrogenation.
  • an amino group may be acylated to give a substituted amido group, for example by treatment with an acyl halide in the presence of an organic base.
  • Substituents NHCO 2 R 3 where R 3 is a benzyl group substituted as hereinbefore described may be converted to amino groups, for example by hydrogenolysis.
  • the compound of the formula (VII) may be prepared by the reaction of a corresponding compound of the formula (VIII): wherein R 4 , R 5 and R 6 are as defined in relation to formula (VII) with a diloweralkylphosphorochloridate and a triloweralkylamine followed by reaction with a derivative of the formula (IX): where L ⁇ is a sodium or thallium (I) cation or an ammonium ion substituted by-up to three organic groups, and R 2 is as defined in relation to formula (11).
  • L ⁇ is a substituted ammonium ion
  • it is preferably a tertiary ammonium ion, such as the triethylammonium ion. It is conveniently generated in situ by the reaction of a compound of the formula HSR 2 with an amine, preferably a tertiary amine.
  • Favourably L ⁇ is a thallium (I) cation.
  • Favourably L ⁇ is a sodium cation.
  • a particularly suitable diloweralkylphosphorochloridate is diethylphosphorochloridate.
  • a particularly suitable triloweralkylamine is triethylamine.
  • the reaction is generally carried out in an inert organic solvent such as tetrahydrofuran at a non- extreme temperature such as 0 to 40°C, for example 15-25°C.
  • an inert organic solvent such as tetrahydrofuran at a non- extreme temperature such as 0 to 40°C, for example 15-25°C.
  • the compound of the formula (VIII) may be prepared by the reaction of the compound of the formula (X): wherein R 4 1 , R 4 , R 5 and R 6 are as defined in relation to formula (VIII) with ozone in the presence of trifluoroacetic acid followed by m-chloroperbenzoic acid.
  • the ozonolysis is generally performed at a depressed temperature such as -40 to -80°C, for example about -70°C and in solution in an inert solvent such as methylene chloride. Excess ozone is removed by flushing with an inert gas and thereafter a solution of the peracid is added to the reaction mixture.
  • the compound of the formula (X) may be prepared from the corresponding compound of the formula (XI): wherein R 4 1 is as defined in relation to formula (X) with a phosphine of the formula (XIl): where R 4 , R 5 and R 6 are as defined in relation to formula (X).
  • This reaction is normally effected in the presence of at least one equivalent of a base of relatively low nucleophilicity such as 2,6-Iutidine at an ambient temperature in a dry solvent such as dioxan, or tetrahydrofuran.
  • a base of relatively low nucleophilicity such as 2,6-Iutidine
  • the compound of the formula (XI) may be prepared from the corresponding carbinol of the formula (XIII): wherein R 4 1 is as defined in relation to formula (XI) by reaction with thionyl chloride.
  • This reaction is also normally effected in the presence of at least one equivalent of a base of relatively low nucleophilicity in a dry solvent such as dioxan or tetrahydrofuran but in this instance the reaction is performed at a depressed temperature, for example -30 to -10°C.
  • the preceding carbinol may be prepared by the reaction of a compound of the formula (XIV): with a glyoxylic acid ester of the formula (XV): wherein R 4 , is as defined in relation to formula (VII).
  • this reaction is carried out in an inert solvent at an elevated temperature, for example in dry benzene under reflux.
  • the compound of the formula (XIV) may be prepared as described in Description 1 hereinafter.
  • the present invention provides the compounds of the formulae (Vil) and (VIII), as useful intermediates.
  • the process for the preparation of these compounds also forms part of this invention.
  • the present invention also provides a pharmaceutical composition which comprises a compound of the formula (II) as hereinbefore defined and a pharmaceutically acceptable carrier.
  • composition of the invention includes those in a form adapted for oral, topical or parenteral use and may be used for the treatment of bacterial infection in domestic animals or humans.
  • compositions of this invention include. tablets, capsules, creams, syrups, suspensions, solutions, reconstitutable powders and sterile forms suitable for injection or infusion.
  • Such compositions may contain conventional pharmaceutically acceptable materials such as diluents, binders, colours, flavours, preservatives and disintegrants in accordance with conventional pharmaceutical practice in the manner well understood by those skilled in the art of formulating antibacterial agents.
  • the compound of the formula (II) present in such compositions will be in-vivo hydrolysable to the parent acid or its salt.
  • composition of this invention may beneficially also comprise a penicillin or cephalosporin.
  • penicillins for use in these compositions include amoxycillin trihydrate and sodium amoxycillin.
  • the present invention also provides a method of treatment and/or prophylaxis of bacterial infections in human beings or domestic animals, which method comprises the administration to the sufferer of an effective amount of a compound of the formula (II).
  • 1,4 Pentadiene(d1) (30g) and chlorosulphonyl isocyanate (d2) (35.4 ml) were mixed and allowed to stand at room temperature for 3 days, in a pressure bottle.
  • the thick, dark syrup obtained was diluted with methylene chloride (500mi) and added dropwise to a stirred solution of sodium sulphite (66g) in water (240mi).
  • the pH was maintained between 6.5 and 7.5 by the addition of 10% aqueous potassium hydroxide (600ml in total).
  • the lower organic phase was separated and the aqueous phase extracted (x 2) with ethyl acetate.
  • the crude ester (d 13) (4.7 g) was dissolved in dry tetrahydrofuran (80 ml) and stirred at -20° under argon. It was treated with 2,6-lutidine (3.7 ml) followed over a period of 5 minutes by a solution of thionyl chloride (2.3 ml) in tetrahydrofuran (20 ml). The reaction was allowed to warm to ambient temperature over a period of hour and then filtered. The solid was washed with dry toluene and the combined filtrates concentrated under reduced pressure. The vestigial thionyl chloride was removed by two further evaporations from toluene to give the chloride (d14) as a brown oil.
  • the chloride (d 14) was dissolved in dry dioxane (80 ml) and treated with triphenylphosphine (8.2 g) and 2,6-lutidine (3.7 mi). The reaction mixture was stirred overnight and then filtered; the filtrate concentrated and re-dissolved in ethyl acetate (100 mi). This solution was washed free of base with N/10 hydrochloric acid (ca 100 ml) and then washed with brine and dried over sodium sulphate. The solution was concentrated and then chromatographed on silica gel 60 ( ⁇ 230 mesh) 63 ⁇ m eluting with ethyl acetate/60-80° petroleum ether 7:3 to give a foam.
  • the acid (2a) was further characterised by treatment with benzyl bromide and potassium carbonate in dimethylformamide to give the benzyl ester (2b), obtained as white crystals (ex ether) m.p. 176.5-178°C. ⁇ max (CHCl 3 ) 1735, 1640, 1610cm -1 . (Found: C, 72.20; H, 6.59; N, 2.28; C 36 H 38 NO 5 P requires C, 72.83; H, 6.11; N, 2,36%).
  • the acid (2a) (754mg; 1.5 mmol) was dissolved in dry THF (15ml) containing Et 5 N (167mg; 1.6 mmol) and stirred at RT.
  • a solution of diethylphosphorochloridate (272mg; 1.6 mmol) in THF (5ml) was added dropwise to the solution under argon. Stirring was continued for 3h.
  • the solution was filtered, and to the solution was added thallium (1) phenylthiolate (500mg; 1.6 mmol). Stirring was continued overnight.
  • the acid (8a) was characterised by treatment with benzyl bromide and potassium carbonate in dimethylformamide to give the benzyl ester (8b), as white crystals (ex ethyl acetate/petroleum ether), mp 146-8°C, ⁇ max (CHCl 3 ) 1740, 9 620cm -1 (Found: C, 71.71; H, 5.67; N, 2.44. C 33 H 30 NO 5 P requires C, 71.87; H, 5.44; N, 2.54%.
  • the acid (8a) (461 mg; 1 mmol) was dissolved in dry THF containing Et 3 N (110mg; 1.1 mmol) and stirred at RT whilst a solution of diethylphosphorochloridate (152mg; 1.1 mmol) in THF (5mi) was added dropwise at RT under argon. The solution was filtered, and thallium (1) phenylthiolate (345 mg; 1.1 mmol) was added to the filtrate. Stirring was continued overnight, the solution filtered, the solvent evaporated and the residue chromatographed to yield the phosphorane (9) as an oil (400mg).
  • Trituration with ether yielded the phosphorane as a microcrystalline solid mp 172-3°C, ⁇ max 1740, 1700, 1620cm -1 (Found: C, 68.84; H, 5.24; N, 2.33. C 32 H 28 NO 4 SP requires C, 69.43; H, 5.06; N, 2.53%).
  • the phosphorane (13) (150mg) was refluxed in dry toluene (100ml) under argon for nine hours. The solvent was evaporated and the product chromatographed on Merck Kieselgel 60 using ethyl acetate/petrof as eluant to yield the title compound (14) as the major product (25 mg; 30%), ⁇ max (CHCl 3 ) 1790, 1705 cm- 1 .
  • the phosphorane (2.82g) in dry methylene chloride (125ml) was treated with trifluoroacetic acid (4ml) at 0°. The solution was cooled to -70° and treated with ozone until blue. Argon was passed through to remove excess ozone, and m-chloroperbenzoic acid (0.9g) in methylene chloride (20ml) was added, and the mixture was stirred at RT overnight. The solvent was evaporated, and the resulting white solid was dissolved in ethyl acetate and chromatographed on silica gel. Elution with 10% ethanol/ethyl acetate gave the product as the trifluoroacetic acid salt.
  • the phosphorane (17) (550mg) was refluxed in dry toluene (500ml) for 24 hours with removal of water (Dean-Stark) under argon. The solvent was evaporated and the product chromatographed on florisil (200-300 U.S. mesh) using ethyl acetate/petrol (60-80°) as eluant to yield the title compound (52mg; 18%) as a crystalline solid from benzene/petrol (60-80°C) mp 112-4°C. v max (CHC1 3 ) 1790, 1705 cm -1 .
  • This thioester (19) was also prepared substituting the sodium thiolate mixture by solid thallium (I)p-acetamidophenylthiolate. A comparable yield was obtained.
  • the phosphorane (19) (136mg) was suspended in dry toluene (10ml) and the mixture was evaporated to dryness. The residue was suspended in dry toluene (60ml), and the mixture was degassed and heated, under argon, under reflux with a Dean-Stark head. After 5 hours the pale yellow solution was cooled to room temperature, and the solvent was evaporated. The residue was taken up in ethyl acetate (12ml), and left overnight at 5°, when buff coloured crystals were obtained. These were collected (97.5mg) and shown by thin layer chromatography to be recovered starting material.
  • the phosphorane (21) (0.461g) was taken up in dry toluene, and the mixture was evaporated to dryness.
  • the residue was suspended in dry toluene (250ml), and the mixture was degassed and heated to reflux. A pale yellow solution was obtained. After refluxing for 6.5 hours the solution was left in the refrigerator overnight.
  • the toluene solution was decanted from some gummy material and evaporated to dryness. Trituration of the residue with dry diethyl ether gave recovered (21) as a solid (414mg).
  • the phosphorane (23) (850mg) was suspended in dry toluene (500mi) and heated under an atmosphere of argon under reflux using a Dean-Stark apparatus to remove water. A clear, pale yellow solution was obtained. After refluxing for 6.5 hours the slightly darker solution was cooled and reduced by evaporation to about 150ml. On storing overnight at 5°, recovered starting material (551 mg) was precipitated. The solution was evaporated, and the residue was chromatographed on florisil (200-300 U.S. mesh).
  • the p-nitrobenzyl ester (18) (70mg) was dissolved in 30% aqueous dioxan containing 5% Pd/C (90mg) [prehydrogenated for twenty minutes].
  • the solution was hydrogenated at ambient temperature and pressure for one hour. Examination of the solution by u.v. showed a shift of chromophoric absorption of 316 nm and 266 nm for the p-nitrobenzyl ester to 314 nm and 251 nm respectively for the product.
  • the solution was treated with one equivalent of NaHCO 3 (14.7mg) in water (2ml) and filtered through keiselguhr.
  • the phosphorane (d15, prepared as in Description 5) (258mg) was dissolved in dry methylene chloride (15ml) containing trifluoroacetic acid (0.8ml) and stirred at RT. for ten minutes. The solution was cooled to -70° and ozonised for 15 minutes until a blue colour persisted. Argon was passed through the solution to remove excess ozone and m-chloroperbenzoic acid (90mg) in methylene chloride (5ml) was added. The mixture was allowed to warm up to RT. and stirred overnight.
  • the phosphorane (30) (218mg) was refluxed in dry toluene (250ml) under argon for 18 hours.
  • the solvent was evaporated and the residue chromatographed on florisil (200-300 U.S. mesh) using slight pressure and ethyl acetate/petrol (60-80) as eluant.
  • the title compound (31 ) was collected as a colourless oil (6mg; 5%) v max (CHCl 3 ) 1780, 1750, 1725cm -1 .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP78300231A 1977-08-06 1978-08-02 Synthetic beta-lactam compounds, a process for their preparation and compositions containing them Expired EP0000828B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB3303777 1977-08-06
GB3303777 1977-08-06

Publications (2)

Publication Number Publication Date
EP0000828A1 EP0000828A1 (en) 1979-02-21
EP0000828B1 true EP0000828B1 (en) 1983-03-09

Family

ID=10347670

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78300231A Expired EP0000828B1 (en) 1977-08-06 1978-08-02 Synthetic beta-lactam compounds, a process for their preparation and compositions containing them

Country Status (3)

Country Link
EP (1) EP0000828B1 (ja)
JP (1) JPS5448786A (ja)
DE (1) DE2862198D1 (ja)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2652606A1 (de) * 1976-11-19 1978-05-24 Bayer Ag Isothiazolanthronfarbstoffe
AU531084B2 (en) * 1977-10-19 1983-08-11 Merck & Co., Inc. Azetidine derivatives
US4446146A (en) * 1978-07-26 1984-05-01 Beecham Group Limited β-Lactam containing compounds, their preparation and use
IE52147B1 (en) * 1980-03-27 1987-07-08 Merck & Co Inc 4-(3-carboxy-2-oxopropyl)-azetidin-2-ones and process for their preparation
JPS56142260A (en) * 1980-04-09 1981-11-06 Toyama Chem Co Ltd 2-azetidinone and its preparation
JPS56145271A (en) * 1980-04-11 1981-11-11 Dai Ichi Seiyaku Co Ltd 2-azetidinone derivative
JPS57103057A (en) * 1980-12-19 1982-06-26 Meito Sangyo Kk Automatic measuring method for hdl-cholesterol and its precipitant
US4992542A (en) * 1984-01-24 1991-02-12 Merck & Co., Inc. 2-substituted-6-carbadethiapen-2-em-3-carboxylic acids
GB9103034D0 (en) * 1991-02-13 1991-03-27 Fujisawa Pharmaceutical Co Processes for preparing carbapenem derivatives
US5541317A (en) * 1991-05-31 1996-07-30 Sankyo Company, Limited Azetidinone compounds useful in the preparation of carbapenem antibiotics and process for preparing carbapenem and penem compounds
FI104822B (fi) * 1992-09-09 2000-04-14 Sankyo Co Menetelmä karbapeneemi- ja peneemiyhdisteiden valmistamiseksi

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1593524A (en) * 1976-11-19 1981-07-15 Merck & Co Inc 1-carba-2-penem-3-carboxylic acids

Also Published As

Publication number Publication date
DE2862198D1 (en) 1983-04-14
JPS5448786A (en) 1979-04-17
EP0000828A1 (en) 1979-02-21

Similar Documents

Publication Publication Date Title
US4282236A (en) β-Lactam antibacterial agents, their use in pharmaceutical compositions, and intermediates
US4223038A (en) Bicyclic β-lactam antibiotics
EP0000828B1 (en) Synthetic beta-lactam compounds, a process for their preparation and compositions containing them
US4446146A (en) β-Lactam containing compounds, their preparation and use
US4153714A (en) 3-Thio-5-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid esters, their production and use
US4210661A (en) Synthetic β-lactam compounds, a process for their preparation and compositions containing them
EP0008514B1 (en) Beta-lactam anti-bacterials, compositions containing them and a process for their preparation
GB2159818A (en) Carbapenem intermediates
EP0008888B1 (en) Beta-lactam antibacterial compounds, their preparation and pharmaceutical compositions containing them
FR2533568A1 (fr) Nouveaux antibiotiques de la classe des carbapenems, et leur application pharmaceutique
EP0034443B1 (en) Beta-lactam antibacterial compounds, their preparation and pharmaceutical compositions containing them
US4258050A (en) Antibacterial agents
EP0003740B1 (en) Beta-lactam antibiotics, a process for their preparation and pharmaceutical compositions containing them
EP0005349A1 (en) Alkylcarbapenems, their preparation, use in pharmaceutical compositions and intermediates
US4263314A (en) β-Lactam antibiotics, a process for their preparation and their use in pharmaceutical compositions
US4255441A (en) β-Lactam antibiotics, a process for their prepaeration and their use in pharmaceutical compositions
EP0033209B1 (en) Beta-lactam containing compounds, their preparation and use
IE55225B1 (en) Carbapenem antibiotics
US4293501A (en) β-Lactam antibiotics, a process for their preparation and their use in pharmaceutical compositions
GB2037277A (en) beta -Lactam antibacterial agents, their use in pharmaceutical compositions, processes for their preparation and intermediates for use in such processes
GB2105329A (en) Penem-3-carboxylic acid derivatives their preparation and their use as antimicrobial agents
JPS6187682A (ja) カルバペネム抗生物質
US4192801A (en) Novel phosphorane intermediates for use in preparing penem antibiotics
CA1117948A (en) Clavulanic acid derivatives
BE899094A (fr) Procede de preparation de derives carbapenem, nouveaux intermediaires de synthese et procede de preparation de ces intermediaires.

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): CH DE FR GB NL

17P Request for examination filed
RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BEECHAM GROUP PLC

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Designated state(s): CH DE FR GB NL

ET Fr: translation filed
REF Corresponds to:

Ref document number: 2862198

Country of ref document: DE

Date of ref document: 19830414

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19830722

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 19830819

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 19830826

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 19830901

Year of fee payment: 6

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Effective date: 19840831

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Effective date: 19850301

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19850430

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19850501

GBPC Gb: european patent ceased through non-payment of renewal fee
REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Effective date: 19881117

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT