EP0000636A1 - Composés dérivés pénème, procédés pour leur préparation, leur utilisation dans les compositions pharmaceutiques et les azétidinones utilisées dans leur préparation - Google Patents

Composés dérivés pénème, procédés pour leur préparation, leur utilisation dans les compositions pharmaceutiques et les azétidinones utilisées dans leur préparation Download PDF

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EP0000636A1
EP0000636A1 EP78300148A EP78300148A EP0000636A1 EP 0000636 A1 EP0000636 A1 EP 0000636A1 EP 78300148 A EP78300148 A EP 78300148A EP 78300148 A EP78300148 A EP 78300148A EP 0000636 A1 EP0000636 A1 EP 0000636A1
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Prior art keywords
group
formula
solution
minutes
ether
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German (de)
English (en)
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Christopher Michael Donald Beels
John Derek Cocker
Michael Vincent John Ramsay
Nigel Stephen Watson
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Glaxo Group Ltd
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Glaxo Group Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/88—Compounds with a double bond between positions 2 and 3 and 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
    • 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
    • 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
    • C07D205/09—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 with a sulfur atom directly attached in position 4
    • 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

  • This invention relates to novel penems having antibiotic activity, to processes for their preparation, to pharmaceutical compositions containing them and to intermediates of use in the preparation of antibiotics.
  • R 1 represents a C 1-8 alkyl group optionally substituted by a hydroxy, etherified hydroxy or acylated hydroxy group
  • R 2a represents a carboxyl esterifying group or a hydrogen atom
  • B represents a group >S or S ⁇ O
  • Compounds according to the invention may be of use as antibiotics as detailed below or may be useful as intermediates in the preparation of further active compounds or in the purification of active compounds.
  • the compounds according to the invention may exist as individual 5-position isomers or as mixtures thereof. Furthermore, other chiral centres may exist in the molecule and the invention extends to all isomers of the compounds individually or in admixture.
  • B preferably represents the group>S.
  • R may, for example, be a methyl, ethyl, n-propyl, isopropylor butyl group; such groups may optionally be substituted as set out in more detail below.
  • Etherified hydroxyl substituents which may be present in R1 include, for example,groups -OR 3 where R 3 is an unsubstituted or substituted hydrocarbyl group, e.g. an aliphatic, araliphatic or aromatic group or a C-attached heterocyclic group, or a silyl group.
  • R" may be an unsubstituted alkyl, alkenyl or alkynyl group which may contain 1-6 carbon atoms, or such an alkyl group carrying a substituted hydroxy group; a hydroxyalkyl group having 2-6 carbon atoms; an aralkyl group which may have 1-6 carbon atoms in the alkyl portion or an aryl group, such aryl and aralkyl groups preferably being monocyclic; a cycloalkyl group, which may have 3-7 carbon atoms; a carbon-attached saturated or unsaturated 5-7 membered heterocyclic ring containing for example, an oxygen atom; or a silyl group having up to 24 carbon atoms which may carry three groups which may be the same or different selected from alkyl, alkenyl, cycloalkyl, aralkyl and aryl groups.
  • substituents will preferably be C 1-4 alkyl groups e.g. methyl
  • Substituted hydroxy groups as referred to above include acylated and etherified hydroxy groups.
  • acylated hydroxy groups may have the formula R a CO 2 where R a is a hydrocarbyl group as defined for R 3 , relatively simple R a groups such as C 1-4 alkyl, e.g. methyl,being preferred, while etherified hydroxy groups may have the formula R b O, where R b has one of the meanings given for R a , simple groups.such as C 1-4 alkyl, e.g. ethyl, being preferred.
  • R 3 include methyl, ethyl, propyl, isopropyl, butyl, allyl, propargyl, hydroxyethyl, ethoxyethyl, phenyl, benzyl, phenethyl, cyclohexyl, tetrahydropyranyl and t-butyldimethylsilyl.
  • Suitable acylated hydroxyl substituents include, for example, groups -OR4 wherein R 4 preferably represents an acyl group (wherein Y is oxygen or sulphur;and R c is a hydrogen atom, an aliphatic, araliphatic or aromatic group or a C-attached heterocyclic group, for example C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, C 4-15 aryl-C 1-6 alkyl or C 4-15 aryl group, which may be substituted; or an amino or mono- or di-substituted amino group).
  • Suitable substituents on the group R c include, for example, halogen, e.g. fluorine, chlorine or bromine; hydroxy; etherified hydroxy; acyloxy; cyano; nitro; azide; carboxyl or esterified carboxyl; or amino or substituted amino.
  • R 1 carries a carbamoyloxy group as the acylated hydroxy substituent this may, for example,be represented as , where Y is oxygen or sulphur and R d and R e , which may be the same or different, are hydrogen; C 1-5 alkyl; aralkyl e.g. benzyl; aryl e.g. phenyl; or a C-attached heterocyclic group e.g. tetrahydropyranyl, or R d and R e may together with the nitrogen atom to which they are attached form a heterocyclic ring preferably having 5-7 ring members, which may optionally contain another heteroatom, e.g.
  • acylated hydroxy substituent -OR 4 may, for example, be represented as where Y is oxygen or sulphur and R f represents a protecting group, for example an acetyl, trichloroacetyl, chlorosulphonyl or trimethylsilyl group.
  • R c CO- Preferred groups of the formula R c CO-are those wherein R c represents a hydrogen atom; a substituted or unsubstituted lower alkyl group, e.g. C 1-4 , for example methyl, chloromethyl or ethyl groups; a substituted or unsubstituted aralkyl group e.g. benzyl; an aryl group e.g. phenyl; or an amino, methylamino or anilino group. Suitable substituents are defined above.
  • Such groups R 3 and R 4 may serve as protecting groups for the hydroxyl group during the intermediate stages of the synthesis of the compounds of formula (I).
  • the protecting group may if desired, be removed, for example by solvolysis, e.g. by mild acid or base hydrolysis, to yield the compounds of formula (I) in which R 1 carries a free hydroxyl group.
  • Examples of such protecting groups include those in which R 3 is a tetrahydropyranyl, 1-ethoxyethyl or silyl group or R 4 is a formyl or dichloroacetyl group.
  • R 2a represents a carboxyl esterifying group
  • it may for example be an organic group derived from an alcohol (aliphatic or araliphatic), a phenol, a silanol or a stannanol.
  • an alcohol, phenol, silanol or stannanol used to esterify the carboxyl group preferably contains not more than 24 carbon atoms.
  • Salts of compounds of formula (I) include, for example, salts of acidic compounds of the invention formed with inorganic and organic bases. Such salts include alkali metal salts, e.g. sodium, potassium and lithium salts, alkaline earth metal salts, e.g. calcium and magnesium salts, ammonium salts, and substituted ammonium salts. Salts of compounds of formula (I) also include acid addition salts of compounds of formula (I) in which the R 1 group contains a basic nitrogen atom. Compounds of formula (I) in which R 2a is hydrogen and R 1 carries a basic nitrogen atom may exist in zwitterionic forms and such zwitterionic forms are included within the present invention.
  • alkali metal salts e.g. sodium, potassium and lithium salts
  • alkaline earth metal salts e.g. calcium and magnesium salts
  • ammonium salts e.g. calcium and magnesium salts
  • salts of compounds of formula (I) also include acid addition salts of compounds of formula (
  • esters of compounds of formula I in which B is sulphur, and salts of such compounds are the preferred forms for use in medicine.
  • other compounds of the invention are also useful, particularly for the preparation and purification of the preferred compounds just referred to and other compounds.
  • the esters are especially useful as carboxyl-protectedderivatives of the parent compounds.
  • esters which are readily cleaved and are primarily of use in this connection include arylmethyl esters, especially the benzyl, p-nitrobenzyl, benzhydryl and trityl esters as well as the stannyl, e.g. tri-n-butylstannyl, and silyl esters.
  • the ester grouping may be metabolically labile, i.e. it may be converted into the carboxylic acid during general metabolic processes,e.g. in the blood or liver.
  • Metabolically labile esters include for example acyloxymethyl, e.g. acetoxymethyl and pivaloyloxymethyl, esters and phthalidyl esters.
  • the compounds are stable to the action of ⁇ -lactamases produced by pathogenic gram-positive organisms for example those produced by Staphylococcus aureus, and to 3-lactamases produced by gram-negative organisms such as Entarobacter cloacae.
  • the compounds have the ability to inhibit ⁇ -lactamase enzymes; these include enzymes produced by gram-negative organisms, for example, those produced by strains of Enterobacter cloacae.
  • Compounds of formula (I) wherein B is 5 and R 2a represe a hydrogen atom or a metabolically labile ester grouping and physiologically acceptable salts of such compounds may thus be formulated as pharmaceutical (including veterinary) compositions which may if desired contain further ⁇ -lactam antibiotics. Such compositions will normally also contain carriers and/or excipients and may, for example, be in a form adapted for oral or parenteral administration.
  • compositions may thus, for example, take the form of powders, tablets, capsules, lozenges, solutions and syrups suitable for oral administration, and may include, for example, starch, lactose, talc, magnesium stearate, gelatin, distilled water and suspending, dispersing, emulsifying, flavouring or colouring agents.
  • Active compounds of formula (I) may further be formulated in rectal compositions such as suppositories or retention enemas.
  • the compounds may be formulated in ampoules for reconstitution before use.
  • the active compounds of formula (I) will generally be administered to humans at a total daily dosage level of 50 mg to 20 g, preferably from 100 mg to 10 g, which may be in divided doses given 1-4 times per day. Dosage units will in general contain 12.5 mg to 5 g, preferably 50 mg to 1 g of active compound according to the invention.
  • Active compounds of formula (I) may be of use in treating a variety of diseases, in humans and animals, caused by pathogenic bacteria, such as respiratory tract or urinary tract infections.
  • a compound of formula (I) in which B represents a sulphur atom obtained by the above reaction may subsequently be oxidised, as discussed in more detail hereinafter, to yield a compound of formula (I) in which B represents a group>S ⁇ O
  • Other optional subsequent reaction steps include deesterifying a compound of formula (I) in which R 2a is a carboxyl esterifying group whereby a compound of formula (I) in which R 2a represents a hydrogen atom is obtained; reaction of a free acid of formula (I) with 2 base or reaction of a compound of formula (I) wherein the R group contains a basic nitrogen atom with an acid to yield a salt; and/or modification of the R 1 group: all of which optional steps are discussed in more detail hereinafter.
  • Suitable hydrosulphide and sulphide salts iclud. for example, alkali metal, e.g. sodium, potassium and lithium salts; alkaline earth metal, e.g. calcium, salts; and onium salts, for example quaternary ammonium salts wherein the quaternary ammonium ion has the formula where R, R', R" and R"' which may be the sane or different each represents an alkyl or aralkyl group.
  • Examples of such salts include the benzyltrimethyl- amnonium and tetra-n-butylammonium salts.
  • a base either organic or inorganic
  • a base may be desirable to accelerate the reaction, to optimise yields and to curtail excessive acidity. It is in general preferred to use as weak a base as possible which is effective in the reaction.
  • Suitable bases for use in the reaction include amine bases, for example, tertiary amine bases, e.g.trialkylamines, preferably those wherein the alkyl groups have from 1 to 4 carbon atoms such as triethylamine, hindered bases such as 3-azabicyclo- [3,2,2]-nonane or aromatic bases such as pyridine.
  • reaction vill in general be effected at a temperature of from -150°C 0 +50°C, reaction temperatures of from -50°C to +10°C, articularly -15°C to +10°C, being preferred.
  • the reaction is desirably effected in the presence of an inert solvent, stable to the reaction conditions employed.
  • suitable solvents include, for example, cyclic ethers e.g. tetrahydrofuran and dioxan, halogenated hydrocarbons, e.g. methylene chloride, esters, e.g. ethyl acetate and amide solvents, e.g. dimethylformamide.
  • an excess of base may serve as solvent.
  • R 5 represents a group of formula -N R x R y R z
  • the reaction with hydrogen sulphide or a hydrosulphide or sulphide salt is preferably carried out at temperatures of from -30° to +30°C.
  • the reaction is completed by cyclisation to form a penem of formula (I)by heating.
  • He cyclisation reaction is preferably effected above +40°C, e.g. at +50° to +100°C.
  • Cyclisation may if desired be carried out in in-presence of an acid scavenging agent, e.g. an incoluble inorganic base such as solid, anhydrous sodium, potassium or calcium carbonate.
  • an acid scavenging agent e.g. an incoluble inorganic base such as solid, anhydrous sodium, potassium or calcium carbonate.
  • R 5 represents a halogen atom it is preferably a chlorine or bromine atom.
  • R 5 represents a group of formula -N R x R y R z there will be an anion A ⁇ associated with the compound of formula (II).
  • anion A ⁇ will be derived from the reagent used for the introduction of the group R 6 e.g. a halide ion such as a chloride ion, as described hereinafter.
  • R 5 represents a group of formula -N
  • R x R y R z , R x , R y and R z may, for example each represent an alkyl group having up to 8 carbon atoms, e.g. a C 1-6 alkyl group preferably a C 1-4 group, an aralkyl group having up to 6 carbon atoms in the alkyl portion or an aryl group, such aryl and aralkyl groups desirably being monocyclic, e.g. renzyl and phenyl, and such alkyl groups including also cycloaliphatic e.g.
  • R x , R y and R z may together with the nitrogen atom to which they are attached represent a five-, six- or seven-membered heterocyclic ring optionally containing a further oxygen or sulphuratom e.g. a N-alkyl-piperidinium or N-alkyl-morpholinium group; or R x , R y and R z may, together with the nitrogen atom to which they are attached, represent a bicylic, non-aromatic heterocyclic ring system e.g. a quinuclidinium group, or an aromatic ring e.g. pyridinium.
  • a triethylammonium group is particularly preferred.
  • R 6 is preferably the residue of an acid R 6 H having a pK a (in water at 25°C) of 3.5 or less.
  • R 6 represents an acylated or etherified hydroxy group this may, for example, be an aliphatic, cycloaliphatic, aromatic or araliphatic carbonyloxy, sulphcnyloxy or phosphinyloxy group containing 1 to 20 carbon atcms or an aliphatic ether group containing 1 to 6 carbon atoms, e.g. methoxy.
  • Suitable sulphonyloxy groups include, for example, those wherein the aliphatic or aromatic grouping is an alkyl (e.g. C 1-8 ) group, which may be substituted by a halogen atom e.g. fluorine or chlorine, or an aryl (e.g.
  • Suitable phosphinyloxy groups include, for example, groups of formula where R 7 and R 8 , which may be the same or different, may each represent an alkyl, aryl or aralkyl group or may together with the phosphorus atom form a 5- or 6-membered ring.
  • R 7 and/or R 8 may represent groups OR g and OR respectively where R g and R h are as defined for R 7 and R 8 or may together form a divalent 5- or 6-membered ring.
  • R 7 and/or R 8 may represent groups OR g and OR respectively where R g and R h are as defined for R 7 and R 8 or may together form a divalent 5- or 6-membered ring.
  • An example of the latter type of phosphinyloxy group is the group
  • Suitable carbonyloxy groups include, for example, those wherein the aliphatic or aromatic grouping is an- alkyl (e.g. C 1-8 ) group optionally substituted by one or more halogen atoms or an aryl (e.g. C 6-15 ) group optionally substituted by, for example, one or more halogen atoms or nitro groups.
  • R 6 represents a.halogen atom, this is preferably a chlorine or bromine atom.
  • R 6 Preferred meanings for R 6 include methanesulphonyloxy, trifluoromethanesulphonyloxy, p-toluene- sulphonyloxy, benzenesulphonyloxy, dimethoxyphosphinyloxy and chlorine.
  • the initial product of the reaction between the compound of formula (II) and hydrogen sulphide or a hydrosulphide or sulphide salt is an ester of formula (I) wherein B represents a group>S.
  • B represents a group>S.
  • the ester should subsequently be cleaved.
  • an ester of a compound of formula (I) is required different from that originally produced, this may be obtained by deesterification followed by reesterification as described hereinbelow.
  • a silyl or stannyl ester may be cleaved by mild solvolysis e.g. by reaction with water, alcohols, phenols or carboxylic acids e.g. acetic acid.
  • esters which are readily subject to reduction for example arylmethyl esters such as benzyl, benzhydryl, trityl or more preferably, p-nitrobenzyl esters can be cleaved by reduction e.g. by hydrogenolysis, for example using a metal catalyst, e.g. a noble metal such as platinum, palladium or rhodium.
  • the catalyst may be supported e.g. on charcoal or kieselguhr.
  • cleavage may also be effected by reduction of the nitro group (e.g. using a dissolving metal reducing agent such as zinc in acetic acid or zinc in aqueous tetrahydrofuran or acetone controlled in the pH range 3-6, preferably 4-5.5 by the addition of aqueous HC1; aluminium amalgam in a moist ether, e.g. tetrahydrofuran; or iron and ammonium chloride in an aqueous ether such as aqueous tetrahydrofuran) followed by hydrolysis either under the reduction conditions or by subsequent treatment with acid.
  • a dissolving metal reducing agent such as zinc in acetic acid or zinc in aqueous tetrahydrofuran or acetone controlled in the pH range 3-6, preferably 4-5.5 by the addition of aqueous HC1; aluminium amalgam in a moist ether, e.g. tetrahydrofuran; or iron and ammonium chloride in an a
  • a p-nitrobenzyl ester may be cleaved by alkaline hydrolysis using, for example, sodium sulphide in a solvent such as aqueous tetrahydrofuran, dimethylformamide or acetone.
  • an acid may be reacted, e.g. in an appropriate organic solvent with an appropriate base, preferably in equimolar quantities and preferably under conditions favouring precipitation of the salt.
  • an appropriate base e.g. sodium or potassium salts
  • an alkanoate is a preferred base e.g. a 2-ethyl hexanoate.
  • the compound of formula (I) obtained is a compound in which the R group contains a basic nitrogen atom, it may, if desired, subsequently be converted into an acid addition salt by reaction with an appropriate acid.
  • acid addition salts are those formed with hydrochloric, hydrobromic, sulphuric, phosphoric, lactic, citric, fumaric and maleic acids.
  • Sulphoxides of formula (I) according to the invention may be prepared from the corresponding sulphides of formula (I) by, for example, oxidation with peracids such as peracetic, monoperphthalic, m-chloroper. benzoic or metaperiodic acid. Oxidation is preferably effected at a temperature not greater than 10°C and avoiding excess oxidising agent.
  • Esters of the acid of formula (I) may, for example, be prepared by reaction with an alcohol, phenol, silanol or stannanol or a reactive derivative thereof to form the desired ester. Reaction will desirably be effected under mild conditions in order to prevent rupture of the bicyclic nucleus. The use of neutral or mild acidic or basic conditions therefore, at temperatures between -70 0 and +35°C is preferred.
  • the alkyl, alkoxyalkyl and aralkyl esters may be prepared by reaction of the acid of formula (I) with the appropriate diazoalkane or diazoaralkane e.g. diazomethane or diphenyldiazomethane.
  • the reaction will generally be effected in an ether, ester or a halohydrocarbon solvent, e.g. diethyl ether, ethyl acetate or dichloromethane.
  • reduced temperatures are preferred, for example, -15° to +15°C.
  • esters derived from alcohols may also be produced by reaction of a reactive derivative of the alcohol, for example, a halide such as the chloride, bromide or iodide or a hydrocarbonsulphonyl derivative such as methanesulphonyl or p-toluenesulphonyl ester, with a salt of the acid of formula (I) e.g. an alkali or alkaline earth metal salt such as a lithium, sodium, potassium, calcium or barium salt or an amine salt, such as a triethylammonium salt.
  • a salt of the acid of formula (I) e.g. an alkali or alkaline earth metal salt such as a lithium, sodium, potassium, calcium or barium salt or an amine salt, such as a triethylammonium salt.
  • This reaction is preferably carried out in a substituted sulphoxide or amide solvent e.g.
  • esters may be prepared by reaction of the acid with the alcohol in the presence of a condensing agent such as dicyclohexylca bodi- imide.
  • Stannyl esters may conveniently be formed by reac- tion of the carboxylic acid of formula (I) or a salt thereof with reactive tetravalent tin moieties.
  • Trialkl tin oxides are preferred for the synthesis of tin compoinds in view of their availability and low toxicity.
  • Silyl esters of the acid of formula (I) may be formed by reaction with a reactive tetravalent silicon moiety.
  • Tri- alkylsilyl halides and mono- or bis-silylated acetamides are preferred as silylating agents.
  • Proton acceptors e.g. weak bases such as pyridine may often be used with advantage when hydrogen halides are formed during such esterification.
  • R 1 carries an etherified hydroxy roup may be prepared by etherification of a compound of formula (I) in which R 1 carries a for hydroxy group.
  • Etnerification may be effected, for example, by react on of the appropriate hydroxy ester- with an alcohol r phenol R 3 OH (in which R 3 is a hydrocarbyl or a C- attached heterocyclic group as defined above) or an appropriate reactive derivative thereof.
  • the reaction i desirably effected under mild condit ons in order to p event rupture of the bicyclic nucleus.
  • the reaction temperature is preferably in the range -70 to +70°C
  • the hydroxy ester may be reacted with a diazoalkane or diazoaralkane.
  • This reaction will be preferably effected in the presence of a Lewis acid such as boron trifluoride.
  • the reaction may be effected in a solvent such as an ether e.g. diethyldicher, dioxan or tetrahydrofuran, a hydrocarbon e.g, a light petroleum fraction, or a halogenated hydrocarbon e.g, dichloromethane or chloroform.
  • the reaction temperature is oreferably low e.g. -15°C to +15°C.
  • This method is capable of yielding ethers in which R 3 is an alkyl, alkoxyalkyl or aralkyl group.
  • the ester starting materisl may if desired be formed from the corresponding free acid by reaction with a diazoalkare or diazoaralkane reagent and allowed to react in situ with further reagent together with a Lewis acid e.g. BF 3 to effec the desired etherification.
  • Etherifiction may also be carried out by reaction of the hydroxyester with a vinyl ether.
  • This method is especially useful or production of tetrahydropyranyl ethers, using dihycopyran as reagent, or 1-alkoxyalkyl ethers such as a 1-thoxyalkyl ether, using an alkyl vinyl ether as reager,
  • the reaction is desirably carried out in the presence o strong acid catalyst, for example a mineral acid such as sulphuric acid, or an organic sulphonic acid such as P-toluene sulphonic acid, in a non-hydroxylic, subtantially water-free solvent.
  • suitable sol includes an ether e.g.
  • reaction temperature is preferably in the range -15°C to +35°C.
  • Silyl ethers may be prepared using the appropriate silyl halide e.g. trimethyl silyl chloride or t-butyldimethylsilyl chloride.
  • an ester of formula (I) in which R 1 carries a hydroxy group, or a corresponding free acid may be reacted with a reactive derivative of a carboxylic acid e.g. a halide or anhydride, for example, an acid chloride.
  • reaction may be effected using either the free antibiotic carboxylic acid or, more preferably, an ester thereof, desirably under mild basic conditions e.g. in the presence of a pyridine base in a solvent such as an ether,e.g. tetrahydrofuran or dioxan, or ester, e.g. ethyl acetate,
  • acylating agent e.g. methylene chloride
  • substituted amide e.g. dimethylacetamide
  • the reaction is preferably carried out in the presence of a coupling agent such as dicylohexylcarbodiimide.
  • a mono-N-substituted carbamate may be prepared using an isocyanate or isothiocyanate of formula R e NCY, in which R e and Y are as defined above.
  • the reaction will preferably be carried out by allowing an ester of formula (I) in which R carries a hydroxy group to react with an isocyanate or isothiocyanate, optionally in the presence of a mild organic base e.g. pyridine, to yield the acylated derivative of the compound of formula (I).
  • R d and R e are both hydrogen atoms
  • these may be prepared from mono-N-carbamates (prepared as described above) in which R f is a group which can be readily replaced by a hydrogen atom as defined above.
  • R f may be replaced by hydrogen by mild acid or base hydrolysis using, for example, aqueous sodium bicarbonate or dilute aqueous hydrochloric acid.
  • the carbamates may also be prepared by reaction of an ester of formula (I) in which R 1 carries a hydroxy group with a carbamoyl halide of the formula R d R e NCYX (where Y is as defined above, R d and R e are as defined above other than hydrogen and X is a halogen atom e.g. a chlorine atom) preferably in the presence of a weak base as hydrogen halide acceptor.
  • R 1 carries a hydroxy group
  • the carbamoyl halide may be prepared by reaction of a carbonyl dihalide such as phosgene with a primary or secondary amine.
  • a carbonyl dihalide such as phosgene
  • an ester of formula (I) in which R 1 carries a hydroxy group may be reacted with a carbonyl dihalide followed by reaction with a primary or secondary amine.
  • the compounds of general formula (II) may be prepared by a variety of methods. Thus they may, for example, be prepared by reaction sequences involving clavulanic acid and its derivatives or penicillins as starting materials or they may be prepared by total synthesis.
  • the halogenating agent may, for example, be molecular halogen or an N-halo amide or imide.
  • the N-halo amide or N-halo imide may include a cyclic system, the amide or imide linkage forming part of the cyclic system; examples of such N-halo amides include N-bromo- caprolactam and examples of such N-halo imides include the 1,3-dibromo-5,5-di-(lower alkyl) hydantoins (e.g. 1,3 ⁇ dibromo-5,5-dimethyl-hydantoin); N-bromosuccinimide; N-chlorosuccinimide; N-bromophthalimide etc.
  • Other useful N-halo amides include N-halo loweralkanoamides e.g. N-bromoacetamide.
  • reaction will preferably be carried out in an inert solvent, e.g. a halogenated hydrocarbon, for example methylene chloride.
  • an inert solvent e.g. a halogenated hydrocarbon, for example methylene chloride.
  • Molecular halogen e.g. chlorine or bromine
  • a halogenated hydrocarbon such as carbon tetrachloride
  • Suitable reaction temperatures are from -150°C to 25°C.
  • the use of low temperature e.g. below about 0°C, has been found advantageous in assisting the control of the reaction.
  • Suitable acid binding agents include amides e.g. carboxylic acid amides such as acetamide, metal carbonates e,g. calcium carbonate, oxiranes e.g. propylene oxide, or molecular sieves.
  • the acid binding agent when used, will desirably be present in a quantity which ensures as rapid removal of hydrogen halide as possible.
  • R 10 may be saturated or unsaturated and thus may, for example, be an alkyl or alkenyl group which may contain 1-6 carbon atoms e.g. C 1-4 alkyl such as methyl or butyl, or a cycloalkyl group, which may have 3-7, preferably 5 or 6 carbon atoms.
  • alkyl groups may, optionally, carry one or more etherified hydroxy groups.
  • R 10 is an araliphatic or aromatic group, it will desirably be an aralkyl group which may have 1-6 carbon atoms in the alkyl portion, or an aryl group, the rings in such aryl and aralkyl groups, preferably being monocyclic, e.g. phenyl; and optionally carrying substituents such as C 1-4 alkyl groups e.g. methyl groups.
  • R 10 When R 10 is a heterocyclic group, it will desirably contain a carbon-attached 5-7 membered heterocyclic ring containing one or more heteroatoms such as nitrogen, sulphur or oxygen, which may be aromatic e.g. pyridyl and/or carry one or more alkyl groups, for example containing 1-6 carbon atoms e.g. a methyl group or may have a bicyclic structure, an example of such a group being a benzothiazol-2-yl group.
  • heteroatoms such as nitrogen, sulphur or oxygen
  • R 10 When R 10 is a heterocyclic group, it will desirably contain a carbon-attached 5-7 membered heterocyclic ring containing one or more heteroatoms such as nitrogen, sulphur or oxygen, which may be aromatic e.g. pyridyl and/or carry one or more alkyl groups, for example containing 1-6 carbon atoms e.g. a methyl group
  • R 9 is an acyl group
  • this may, for example, be an alkanoyl or aralkanoyl group containing from 1 to 20, preferably from 1 to 7,carbon atoms.
  • Especially preferred is an acetyl group.
  • Specific groups -(S) n R 9 which may be mentioned include, for example, pyrid-2-yldithio; C 1-5 alkanoylthio e.g. acetylthio; methylsulphinyl; P-tolylthio: benzo- thiazol-2-yldithio; C 1-4 alkylthio e.g. n-butylthio, methylthio and ethylthio; benzylthio; and C 2-5 alk-1-enylthio groups.
  • Compounds of formula (III) may, for example, be prepared from compounds of formula (IV), (wherein R 1 , R 2 , R 9 and n are as hereinbefore defined) by reaction with one or more reagents serving to replace the enolic hydroxy group by, or convert the enolic hydroxyl group into, a leaving group e.g. a halogen atom or an acyloxy or ether group.
  • a leaving group e.g. a halogen atom or an acyloxy or ether group.
  • Compounds of formula (III) in which R 6 represents a halogen atom may, for example, be prepared by treating a compound of formula (IV) with dimethylformamide and phosphorus trichloride at a temperature of from -20° to +40°C,
  • Compounds of formula (III) in which R 6 is an acyloxy group may be prepared by reacting a compound of formula so (IV) with an appropriate acylating agent, e.g. an acyl halide or anhydride.
  • an acylating agent e.g. an acyl halide or anhydride.
  • Such an acyl halide will desirably to be a phosphinyl or sulphonyl halide, the phosphinyl and sulphonyl portions being as defined above.
  • the compound of formula (IV) may be reacted with an alkane sulphonyl halide or aryl sulphonyl halide for example methanesulphonyl halide, p-toluene sulphonyl halide or a dialkoxyphosphinyl chloride e.g. dimethoxy- phosphinyl chloride.
  • Reaction is normally carried out in a solvent, e.g. an ether such as diethyl ether or tetrahydrofuran or a halogenated hydrocarbon such as methylene chloride.
  • Reaction temperatures are generally from -30 to +30°C, preferably from -15 to +20°C.
  • the reaction will normally be effected in the presence of an acid binding agent, e.g. a tertiary amine such as triethylamine, pyridine or collidine or an oxirane such as propylene oxide.
  • an acid binding agent e.g. a tertiary amine such as triethylamine, pyridine or collidine or an oxirane such as propylene oxide.
  • Compounds of formula (III) in which R 6 is an ether group may, for example, be prepared from compounds of formula (IV) by reaction with a diazoalkane, e.g. diazomethane, optionally in the presence of a Lewis acid catalyst such as boron trifluoride etherate.
  • the reaction may be effected in a solvent such as an ether e.g. diethylether, dioxan or tetrahydrofuran, a hydrocarbon e.g. light petroleum fraction. or a halogenated hydrocarbon e.g. dichloromethane or chloroform.
  • the reaction temperature is preferably low, e.g. -15° to +15°C,
  • a compound of formula (II) where R 6 is as defined above and R 5 represents a halogen atom may be prepared from a compound corresponding to formula (II) but where R 6 is hydroxyl, by reaction with one or more reagents serving to replace the hydroxyl group by or convert it into a leaving group, e.g. a halogen atom or an acyloxy or ether group.
  • reagents may be of the type previously described in relation to compounds of formula (IV).
  • an acid binding agent will normally be present, e.g. an oxirane such as propyleno. oxide or a base; where a base is used, this is preferably a weak base such as pyridine.
  • the compounds corresponding to formula (II) in which R 5 is halogen but in which R 6 is hydroxyl may be prepared from compounds of formula (IV) by reaction with an electrophilic halogenating agent e.g. of the type described above in relation to the compounds of formula (III).
  • R 9 represents a group of formula -SR 10 as defined above and R represents an ethyl group optionally substituted in the ⁇ -position by a hydroxyl, etherified hydroxyl or acylated hydroxyl group
  • R 2 is as defined above and R 1a represents an ethyl group optionally substituted in the ⁇ -rosition by a hydroxyl, etherified hydroxyl or acylated hydroxyl group
  • R 10 is as defined above.
  • the thiol R 10 SH will preferably be present in excess as compared with the starting material of formula (V).
  • the reaction will desirably be carried out in an aprotic organic solvent, e.g. an ether solvent such as tetrahydrofuran although the thiol may itself serve as the medium for the reaction.
  • the reaction will desirably be carried out at or above ambient temperature, e.g. at from + 20° to +80°C.
  • the compounds of formula (V) may be prepared from compounds of formula (VI) (wherein R 1b is an ethylidene group optionally substituted in the ⁇ -position by a hydroxyl, etherified hydroxyl or acylated hydroxylgroup and R 2 has the above meanings) as described in Belgian Patent No. 858515.
  • Compounds of formula (II) wherein R 5 represents a group of formula -NR x R y R z may be prepared by reaction of compounds of formula (VII) (where R 1 , R 2 , R X , R y and R z have the above meanings) by reaction with an appropriate reagent serving to introduce the group R 6 .
  • the introduction of the group R may be effected by the procedures described above for the formation of compounds of formula (III).
  • the compound of formula (VII) may be reacted with a sulphonylatiig agent e.g. a methanesulphonylating agent such as metha l esulphonyl chloride.
  • a product of formula (II) in which R 6 is methanesulphonyloxy in which R 6 is methanesulphonyloxy.
  • an anion A ⁇ derived from the reagent used for introuction of the group R 6 , e.g. a halide ion such as a chloride ion will be associated with the compound of formula (II) thus formed.
  • the reaction may be effected in the presence of a base for example a tertiary base such as pyridine.
  • the latter may serve as solvent or a further solvent may be present, e.g. a halogenated hydrocarbon such a methylene chloride or 1,2-dichloroethane.
  • a compound of formula (VII) may be used in the presence of pyridine to prepare a compound of formula (II) in situ which compound may then be directly cyclised to a compound of formula (I) by addition of triethylamine and passing in hydrogen sulphide. Heating, e.g. to about 70°C completes the reaction.
  • a compound of formula (IIa) is prepared from a compound of formula (VII) Without isolation of the compound of formula (II), the compound of formula (IIa) may be partly in the form of an acid addition salt with an acid HA (where A is as defined above) such as HCl.
  • Compounds of formula (VII) may, for example, be prepared by reaction of a compound corresponding to formula (II)(in which R 5 is halogen but in which R 6 is a hydroxyl group)with a tertiary base NR x R Y R 2 in the presence of a solvent such as ethyl acetate at temperatures of from 0 to 30°C, preferably at ambient temperature.
  • a solvent such as ethyl acetate
  • Clavulanic acid i.e. the compound of formula (VI) wherein R 1b is 2-hydroxyethylidene and R 2 is hydrogen
  • the esters thereof are described in, for example, German OLS 2657081 and Sout African Patent Specification No. 76/1953.
  • Compounds of general formula (VI) wherein R 1b represents an ethylidene group are described in Belgian Patent Specification N. 849,474.
  • Compounds of general formula (VI) wherein R 10 represents an etherified 2-hydroxyethylidene group are described in German OLS 26570L8 and South African Patent Specification No. 76/5560.
  • the group R may be modified between the various reaction stages set out, although remaining within the stated definition.
  • R may be necessary to protect this group during certain stages of the reaction sequence .
  • a clavulanic acid ester of formula (VI) in which R 1b carries a hydroxyl group and either at that stage or at a later stage, etherify or acylate the hydroxyl group in order to produce eventually a compound of formula (I) in which R 1 carries an etherified or acylated hydroxyl group.
  • R1 carries a hydroxyl group
  • the R 1 group may be modified between the various reaction stages by methods analogous to those described above for the modification of R 1 in the compounds of formula (I)..
  • the compounds of formula (IV) wherein R 1 represents a methyl group may be obtained from compounds of formula (VIII), (wherein n, R 2 and R 9 are as defined above) by means od ozomolysis followed by treatment with a mild reducing agent.
  • Ozonolysis is preferably effected with ozone in the presence of an organic solvent such as for example dichloromethane and/or methanol and at low temperatures e.g about -78°C.
  • the mild reducing agent may, for example, comprise aqueous sodium metabisulphite or dimethylsulphide.
  • the desulphurising agent may, for example, be a trivalent phosphorus compound of formula P R 11 R 12 R 13 where R 11 and R12 are hydrocarbyl, hydrocarbyloxy or hydrocarbylamino groups or R 11 and R 12 may together with the phosphorus atom to which they are attached form a ring and R 13 is as defined for R 11 and R 12 or re p re - sents a hydroxyl group.
  • Particular reagents which may be used include di- and tri- alkyl phosphites, preferably the latter e.g. trimethyl phosphite, and tri-substituted phosphines. Reduction of a disulphide to a monosulphide may thus be carried out either before or after the conversion of the compound of formula (VIII) into the compound of formula (IV).
  • Compounds of formula (VIII) wherein n is 1 and R 9 represents an acyl group may be obtained from a compound or formula (IX) as defined above by treatment with a trivalent phosphorus compound in the presence of an appropriate acylating agent such as, for example, an anhydride or mixed anhydride.
  • the triva ont phosphorus compound may, for example, be a tri-lower lkyl phosphite e.g. trimethyl phosphite.
  • the reaction is preferably effected in an inert soivant e.g. a hydrocarbon such as benzene or toluene, an ester such as ethyl acetate or an excess of the acylating agent, where liquid.
  • oxidation to form the sulphoxide or sulphone may be effected at a later stage in the reaction sequence.
  • ozonolysis of a compound of formula (VIII) where in n is 0 and R 9 represents a group of formula -SR 10 may lead to the formation of some compound of formula (IV) wherein n is 0 and R 9 represents a group of formula as well as the compound of formula (IV) wherein n is 0 and R 9 represents a group of formula -S-R 10 , particularly if the ozonolysis is carried out over prolonged periods of time.
  • both compounds of formula (IV) may be processed through to the desired compound of formula (I) as described hereinabove.
  • Compounds of formula (IX) may be prepar example, by oxidation of a compound of formula (wherein R 1 and R 2 are as defined above) for example by the peracid oxidation described above. In the present case it is preferred to avoid using excess oxidising agent, to minimise sulphone formation.
  • the compounds of formula (X) may in turn be prepared from penicillanic acid of formula (XI)
  • a carboxyl blocking group R 2 may be effected according to methods known per se e.g. esterification such as described above.
  • An alternative method of obtaining the compounds of formula (IV) wherein n is 0 and R 9 represents a group -SR 10 is from a compound of formula (XII), (wherein R 1 , R 2 and R 10 are as defined above, m is (wherein R 1 , R 2 and are as defined above, m is 0, 1 or 2 and Hal represents a halogen atom e.g. a chlorine cr bromine atom) by reduction with magnesium/iodine or magnesium iodide, preferably in the presence of an anhydrous organic solvant e.g. tetrahydrofuran.
  • a proton source such as, for example, acetic acid is preferably present or added subsequently.
  • a compound of formula (XII) may, if desired be directly converted into a compound of formula (III) wherein R 6 is a phosphinyloxy group by heating with a trivalent phosphorus compound e.g. a trialkyl phosphite, preferably in the presence of an inert solvent such as benzene.
  • Compounds of formula (XII) may themselves be obtained, if desired, by reaction of a compound of formula (XIII) (wherein R , R 2 , R 10 and m are as defined above), with an appropriate halogenating agent, for example, a phosphorus halide, oxalyl chloride or thionyl chloride, preferably in the presence of a base e.g.
  • reaction is preferably effected in the presence of an inert anhydrous organic solvent e.g. dichloromethane.
  • Compounds of formula (XIII) may be prepared, for example, by reaction of a compound of formula (XIV), (wherein R 1 and R 2 are as defined above) or a solvated, e.g. hydrated, form thereof with a compound of formula (XV), (wherein R 10 and m are as defined above), preferably in the presence of an inert solvent such as benzene and preferably at the boiling point of the reaction mixture.
  • an inert solvent such as benzene and preferably at the boiling point of the reaction mixture.
  • the reaction is effected under conditions allowing for azeotropic distillation.
  • Compounds of formula (XV) may be obtained, for example, from a compound of formula (XVI), (wherein Q represents a leaving group preferably an acylated hydroxy group such as exemplified hereinbefore in connection with R 6 ) by reaction with a metal salt of an appropriate compound of formula H S(O) m R 10 .
  • Compounds of formula (XIV) may, for example, be obtained from a compound of formula (XVII), (wherein R 1 and R 2 are as defined above) by treatment with an oxidising agent such as nitrogen dioxide preferably in the presence of an organic solvent such as ether.
  • an oxidising agent such as nitrogen dioxide preferably in the presence of an organic solvent such as ether.
  • Compounds of formula (XVII) may be formed, for example, via the diazonium salt by reaction of a compound of formula (XVIII), (wherein R 1 and R 2 are as defined above) with an aqueous acidic solution of an alkali metal nitrite,e.g. sodium nitrite in the presence of aqueous acetic acid.
  • a compound of formula (XVIII) wherein R 1 and R 2 are as defined above
  • an alkali metal nitrite e.g. sodium nitrite in the presence of aqueous acetic acid.
  • a compound of formula (IV) wherein n is 0 and R 9 represents a group -SR 10 may be obtained by reaction of a compound of formula (XIX), . (wherein R 2 , R 10 and m are as defined above) with a compound of formula (XX), (wherein R 1 is as defined above and Hal" represents a halogen, e.g. chlorine, atom) in the presence of a strong base, e.g. lithium di(trimethylsilyl)amide, preferably : in the presence of a solvent such as tetrahydrofuran.
  • a strong base e.g. lithium di(trimethylsilyl)amide
  • Compounds of formula (XIX) may be formed, for example, from a compound of formula (XV) as hereinbefore defined by reaction with a compound of formula (XXI) (wherein R 2 is as defined above and Hal" is as defined above e.g. a bromine atom) in the presence of a base , e.g. sodium hydride, preferably in the presence of an anhydrous organic solvent such as dimethylformamide.
  • a base e.g. sodium hydride
  • R 1 represents a group -CHR 14 R 15 (wherein R 14 represents a hydrogen atom or an optionally substituted alkyl group and R 15 represents a hydroxymethyl group or a 1-hydroxyethyl group), n is 0 and R 9 represents a methylthio group are described in South African Patent Specification No. 77/0435.
  • DMSO dimethylsulphoxide
  • Dichloromethane, toluene and tetrahydrofuran were dried by passage through basic alumina and stored over molecular sieves (Type 4A).
  • N,N-dimethylformamide was passed through acidic alumina and stored over sieves.
  • Nitrogen dioxide was bubbled into a solution of the product of Preparation 2 (17.05 g, 64 mmole) in ether (450 ml) at 0° for 5 hours. Concentration of the solution in vacuo at ⁇ 20° afforded an oil, which was purified by chromatography (B) (ether:dichloromethane - 0:100 to 50:50). Appropriate fractions were evaporated to give the title compound (9.296 g). A similar sample had ⁇ max (CHCl 3 ) 265 nm ( 383), inflection at 291.5 nm ( 98).
  • Penicillanic acid (58,5g, 0.29 mole) in N,N-dimethylformamide (110ml) was treated with sodium bicarbonate (24.4g,' 0.29 mole) and p-nitrobenzyl bromide (59.7g, 0.28 mole).
  • the mixture was stirred at 25° for 48 hours and then partitioned between ethyl acetate (2 1.) and water (2 1.).
  • the aqueous layer was separated off and further extracted with ethyl acetate (1 1.).
  • the organic layers were washed with water (2 x 1 1.), dried and evaporated.
  • the resulting oil crystallised, and the mixture was diluted with ether and then filtered.
  • the solid was washed with ether and dried to give the title ester (37.5g), m.p. 132°, [ ⁇ ] D +205°(c 1.1 , CHCl 3 ).
  • Triethylamine (10.9 ml, 78.8 mmole) in purified tetrahydrofuran (200 ml) at 5° was stirred under nitrogen and a stream of hydrogen sulphide was passed through for 20 minutes.
  • the product of Example 98 (16.5 g, 39.4 mmole) in purified tetrahydrofuran (100 ml) was added, and the mixture was stirred for 1/4-hour. Excess hydrogen sulphide was removed at reduced pressure; the solution was then diluted with ether (2 1.) and washed with water (4 x500ml), 0.05 N hydrochloric acid (500 ml), and brine (2 xl 1.). It was then dried and evaporated until crystallisation began.
  • Example 5 The product of Example 5 (1.00 g, 3.1 mmole), [a] D -13° (CHCl 3 ) in ethyl acetate (80 ml) with 20% palladium on charcoal (2.0 g) was vigorously shaken under an atmosphere of hydrogen for 3 hours. The catalyst was filtered off and washed with ethyl acetate (2 x 15 ml).. The combined filtrate and washings were treated with sodium 2-ethylhexanoate (2.0 mmole) in ethyl acetate (18ml); the resulting suspension was diluted with ether (150 ml, sodium dried) and then cooled to 5° for 11 ⁇ 2 hours. The product was filtered off, washed with dry ether and dried in vacuo over phosphorus pentoxide to give the title sodium .salt (278 mg), (c 0.87, dimethyl sulphoxide).
  • the resulting suspension was diluted with 1,2-dichloroethane (300 ml) and heated rapidly to reflux temperature for ca. 2 minutes while being purged with a fast stream of nitrogen. The . stream of nitrogen was maintained while the reaction mixture was cooled in ice to room temperature. The mixture was washed successively with 0.5 N hydrochloric acid (2 x 500 ml). The organic solution was dried and concentrated to ca. 600 ml. Chromatographic silica gel (ca. 50 g) was added and the mixture evaporated to give a powder.
  • Acetyl chloride (0.38 ml) was added to a stirred solution of the product of Example 8 (0.934 g) in ethyl acetate (65 ml), maintained at 5°, and containing dry pyridine (1.43 ml). The reaction mixture was allowed to warm to ambient temperature and was stirred for 65 minutes. The resulting mixture was diluted with ethyl acetate and then washed successively with 0.5N aqueous HCl, 0.5N aqueous Na HCO 3 , and saturated brine. The organic phase was dried .and then evaporated to dryness.
  • Phenylacetyl chloride (0.8 ml) was adde to a stirred, ice-cooled solution of the product of Example 8 (1.05 g) in dry THF (21 ml) containing dry pyridine (1.62 ml).
  • Trichloroacetylisocyanate (0.12 ml) was added to a stirred suspension/solution of product of Example 8 (0.35 g) in ethyl acetate (20 ml) at 5°. After 20 minutes the solution was diluted with ethyl acetate and washed with 0.5N aqueous NaHCO 3 , water (x 2), and saturated brine. The dried organic phase was evaporated to low volume, silica gel was added, and the mixture was -;evaporated to dryness. The impregnated silica'gel was placed on top of a dry silica gel column and eluted with ether:petroleum ether (40-60°) (1':1) followed by ether.
  • Trichloroacetyl isocyanate (1.79 ml) was added to a stirred solution/suspension of product of Example 8 (4.20g) in dry ethyl acetate (240 ml) maintained at 0°. After 30 minutes the mixture was diluted with ethyl acetate and washed successively with 0.5N aqueous NaHCO 3 , water, and saturated brine, and the organic phase was then dried. Evaporation gave an oil which was dissolved in methanol (180 ml) and treated with saturated aqueous NaHC0 3 (21 ml).
  • Methanesulphonyl chloride (4.77 ml) was added to a stirred, ice-cooled solution of 1-methoxycarbonyl-l-(2-oxo-4-triethylammonioazetidin-l-yl)but-l-en-2-olate (6.13 g) in dry 1,2-dichloroethane (112 ml) containing dry pyridine (8.31 ml). After 20 minutes hydrogen sulphide was passed through the stirred solution under nitrogen, and an excess of triethylamine was added in. portions over 10 minutes. The resulting mixture was diluted with dry 1,2-dichloroethane (100 ml) and heated to boiling for 5 minutes.
  • N hydrochloric acid 80 ml was added and stirring was continued for a further 5 minutes.
  • Example 25 The product of Example 25 (0.205 g) was dissolved in ethyl acetate (20 ml) and 20% Pd-C (0.41 g) was added. The stirred suspension was treated with hydrogen (2 atmospheres pressure) at 23° for 2 3 /4 hours.
  • Triethylamine (0.087 ml, 0.62 mmole) in dry N,N-dimethylformamide (3 ml) was added, under nitrogen,to a solution of hydrogen sulphide (0.465 mmole) in N,N- dimethylformamide (0.26 ml) and the mixture was cooled to -42°.
  • Example 4 The product of Example 4 (0.500 g, 1.435 mmole) was dissolved in ethyl acetate (45 ml) and 20% Pd-C (I g) was added. The suspension was stirred at ca 25 0 and hydrogen was passed for 3 hours. The suspension was filtered and the filtrate poured into a stirred solution of sodium bicarbonate (0.24 g, 2.87 mmole) in water (50 ml). After 2 to 3 minutes the organic phase was separated and extracted with sodium bicarbonate (0.12 g, 1.435 mmole) in water (25 ml). The combined aqueous extracts were covered with ethyl acetate (50 ml) and acidified to ca pH 2.5 with phosphoric acid.
  • Potassium periodate (0.690 g) was added to a stirred solution of the product of Example 32 (0.475 g) in water (10 ml) at ambient temperature. After 31 ⁇ 2 hours the mixture was freeze dried and the residue was chromatographed on an XAD-2 resin column eluting with water. Appropriate fractions were combined and freeze-dried to afford the title salt (0.171 g), ⁇ max (Nujol) 1780 ( ⁇ -lactam), 1618 cm -1 (CO 2 - ).
  • Methanesulphonyl chloride (0.058 g) was added to a stirred solution of 1-(p-nitrobenzyloxycarbonyl)-1-(2-6xo-4-triethylammonioazetidin-l-yl)-4-(tetrahydropyran-2-yloxy)but-l-en-2-olate (0.105 g) in dry pyridine (1 ml). After 2 hours triethylamine (0.050 g) was added to the reaction mixture through which was passed a steady stream of hydrogen sulphide. The solution was diluted with ethyl acetate (20 ml) and then heated gently to 65 for 15 minutes.
  • Example 123 A suspension of the product of Example 123 (0.108 g) in ethyl acetate (30 ml) was heated gently to reflux for 5 minutes. The resulting solution was evaporated to afford the title ester (0.087 g), whose. spectroscopic properties resembled those as described in Example 38.
  • Methanesulphonyl chloride (0.126 g) was added to a stirred solution of 1-(p-nitrobenzyloxycarbonyl)-1-(2-oxo-4-triethylammonioazetidin-1-yl)but-1-en-2-olate (0.419 g) in dry pyridine (1.5 ml). After 4 hours triethylamine (0.202 g) was added to the reaction mixture through which was passed a steady stream of hydrogen sulphide. After 15 minutes the solution was diluted with ethyl acetate (50 ml) and heated gently to 70° for 10 minutes. The organic solution was washed with 0.1 N aqueous HC1 followed by saturated brine, and then dried. Evaporation-afforded the title ester (0.050 g) whose spectroscopic properties resembled those as described in Example 30.
  • Example 121 A suspension of the product of Example 121 (0.127 g) in ethyl acetate (30 ml) was heated gently to reflux for 5 minutes. The organic solution was evaporated to afford the title ester (0.02 g) whose spectroscopic properties resembled those as described in Example 30.
  • Zinc powder (26.0 g) was added in portions to a stirred solution of the product of Example 38 (2.17g) in 25% aqueous THF (100 ml) at 0° and maintained at pH 4.3 by the addition of 1 N aqueous HC1. After 4.25 hours the mixture was filtered through kieselguhr. The filtrate was saturated with NaCl, covered with ethyl acetate (1.1L) and, with stirring, acidified with 2N aqueous HC1.
  • the organic phase was concentrated to ca 400 ml and then extracted with pH 7 aqueous buffer (2 x 700 ml), The combined aqueous extracts, saturated with NaCl, were covered with ethyl acetate (1L) and, with stirring, were acidified with 2 N aqueous HC1.
  • the aqueous phase was re-extracted with ethyl acetate (800 ml) and the combined organic solutions were dried, then concentrated to 116 ml, and treated with a solution of potassium 2-ethyl- hexanoate (0.416 g) in ethyl acetate (15 ml)
  • the resulting suspension was concentrated to ca. 30 ml and was then diluted with ether.
  • the precipitated solid was collected and dried in vacuo to afford the title salt (0.56 g), m.p. 122-126°, ⁇ max 300 nm ( ⁇ 3, 500).
  • This foam was purified by column chromatography (C) (10 g) using 1% ether in dichloromethane as eluant. Collection of the appropriate fractions and evaporation to dryness gave the title compound (45 mg) as a gum, ⁇ max (CHBr 3 ) 1790 ( ⁇ -lactam), 1712 (CO 2 R) and 1522 and 1346 cm -1 (NO 2 ).
  • reaction mixture was filtered through kieselguhr and the filtrate was treated with a solution of potassium ethyl hexanoate in ethyl acetate (0.69 M, 2.4 ml).
  • the mixture was reduced to ca. 20 ml and ether was added dropwise to assist precipitation.
  • Benzoyl chloride (1.16 ml) was added to a stirred solution/suspension of the product of Example 8 (1.75 g) in ethyl acetate (100 ml) maintained at 5° and containing dry pyridine (2.7 ml). The reaction mixture was allowed to warm to room temperature and after 22 hours was diluted with ethyl acetate and washed successively with 0.5-N aqueous HCl, water, and saturated brine and then dried. Silica gel (10 g) was added to the filtered organic solution and the mixture was evaporated to dryness.
  • Example 68 The product of Example 68 (2.01g, 4.0 mmole) in dichloromethane.(20ml) at -15° was stirred and treated with trimethyl phosphite (0.48ml, 4.0 mmole) added dropwise over 5 minutes. After 15 minutes the solution was evaporated and the residue was chromatographed (B) (0 to 12% ethyl acetate in toluene). Evaporation of fractions containing the main product gave the title ester (1,16g), +7° (c 0,97, CHC13).
  • n-Butyl lithium in hexane (1.3 molar solution, 3.5 ml, 4.55 mmole) was added dropwise under nitrogen to a cooled (-70°) solution of hexamethyldisilazane (0.97 ml, 4.55 mmole) in dry tetrahydrofuran (15 ml).
  • Example 68 The product of Example 68 (2.01 g, 4.0 mmole) in dichloromethane (20 ml) at -15° was stirred and treated with methanesulphonyl chloride (0.46 ml, 6.0 mmole) and triethylamine (0.46 ml, 3.3 mmole). The solution was stirred at -15° for 20 minutes, warmed to 25° over 40 minutes, then cooled to -15° and treated with more triethylamine (0.23 ml, 1.65 mmole) and methanesulphonyl chloride (0.23 ml, 3.0 mmole).
  • Example 79 The product of Example 79 (0.58 g, 1.0 mmole), in dichloromethane (20 ml) at -15° was stirred and treated with trimethyl phosphite (0.13 ml, 1.1 mmole). The solution was allowed to warm to 25° over 1 hour and was then evaporated to an oil. This was chromatographed (B) (0 to 30% ethyl acetate in toluene) and evaporation of appropriate fractions gave the title ester (0.085 g), +13° (c 1.03, CHCl 3 ).
  • Example 69 The product of Example 69 (1.15 g, 2.3 mmole) in dichloromethane (20 ml) at -15 0 was stirred and treated with triethylamine (0.30 ml, 2.2 mmole) and then with methanesulphonyl chloride (0.30 ml, 4.0 mmole). The solution was allowed to warm to 25° over 3/4 hour; it was then cooled to-15° and more triethylamine (0.30ml) and methanesulphonyl chloride (0.30 ml) were added. After 10 minutes at -15° the solution was washed with2N sulphuric acid, then dried and evaporated to an oil.
  • Trifluoromethanesulphonic anhydride (0.355 ml) was added dropwise to a stirred solution of the product of Example 73 (0.817 g) in dry dichloromethane (18 ml) containing triethylamine (0.345 ml) at 0°. After 5 minutes the solution was diluted with dichloromethane (30 ml) and washed with 0.5N aqueous HCl followed by water, then dried, and evaporated to afford the title ester (0.98 g), ⁇ max (CHBr 3 ) 1772 ( ⁇ -lactam), 1728 (CO 2 R), 1520 and 1345 cm -1 (NO 2 ).
  • Methanesulphonyl chloride (0.03 ml) was added dropwise to a stirred solution of the product of Example 71 (0.122 g) in dry dichloromethane (5 ml) containing triethylamine (0.051 g) at 0°. After 20 minutes the reaction mixture was diluted with dichloromethane and washed with 0.5 N aqueous HCl followed by saturated brine. The organic phase was dried and then evaporated to an oil which was chromatographed on silica gel plates eluting with ether. The major band was isolated and stirred with ethyl acetate for 10 min. The mixture was filtered and the filtrate evaporated to afford the title ester (0.08 g) ⁇ max 264.5 nm ( ⁇ 15,600), ⁇ max (CHBr 3 ) 1766cm -1 ( ⁇ -lactam).
  • Methanesulphonyl chloride (0.47 ml) was added dropwise to a stirred solution of the product of Example 72 (1.90 g) in dichloromethane (30 ml) containing triethylamine (0.758 g) at 0°. After 30 mins the reaction mixture was diluted with dichloromethane (200 ml) and washed with 0.5 N aqueous HCl followed by saturated. brine. The organic phase was dried and then evaporated to an oil which was chromatographed on a column of silica gel eluting with ether-petroleum ether (40 - 60°) (2:1).
  • Methanesulphonyl chloride (4.30 ml) was added dropwise to a stirred solution of the product of Example 73 (20.42 g) in dichloromethane (150 ml) containing triethylamine (10.45 ml) at 0°. After 40 min. the reaction mixture was diluted with dichloromethane (200 ml) and washed with 0.5 N aqueous HCl (300 ml) followed by water (3 x 200 ml). The organic phase was dried and evaporated to an oil (23.36 g). A portion of- the crude product (0.48 g) was chromatographed on silica gel plates eluting with ether-petroleum ether (40-60°).. (2:1).
  • Methanesulphonyl chloride (0.51 ml) was added dropwise to a stirred solution of the product of Example 7 4 (.3.05 g) in dry dichloromethane (20 ml) containing triethylamine (1.25 ml), at 0°. After 30 minutes the reaction mixture was diluted with dichloromethane and washed with 0.1N aqueous HC1 followed by saturated brine and then dried. Evaporation gave the title ester (3.52 g) v (CHBr3) 1766 ( ⁇ -lactam), 1728 (CO 2 R), 1522 and 1348 cm -1 (NO 2 ).
  • Methanesulphonyl chloride (0.19 ml) was added to a stirred solution of the product of Example 75 (0.99 g) in dry dichloromethane (12 ml)containing triethylamine (0.41 ml) at 0°. After 35 minutes the mixture was allowed to warm to room temperature and stirred for a further 60 minutes. The resulting mixture was diluted with dichloromethane and washed successively with 0.5 N aqueous HC1, water, and brine, then dried and evaporated to an oil which was chromatographed on a dry silica gel column eluting with ether. Appropriate fractions were combined and evaporated to give the title ester (0.472 g), ⁇ max (EtOH) 265 nm ( ⁇ 16600), ⁇ max (CHBr 3 ) 1765 cm -1 ( ⁇ -lactam).
  • Example 79 The product of Example 79 (8.25 g, 14.2 mmole) in dichloromethane (50 ml) at -15° was stirred and treated with a solution of chlorine in carbon tetrachloride (0.8M, 10 ml, 8 mmole chlorine) added dropwise. More chlorine solution (10 ml each time) was added after 1 ⁇ 2-hour and 1 hour. After 1 hour the suspension was filtered. The filtrate was evaporated to an oil which was chromatographed (B) (0 to 15% ethyl acetate in toluene). Appropriate fractions were combined and evaporated to small volume.
  • B chromatographed
  • Example 80 The product of Example 80 (0.92 g, 1.67 mmole) in dichloromethane (20 ml) at -15° was stirred and treated with a solution of chiorine in carbon tetrachloride (1.7 ml, 1.1M, ca. 1.8 mmole chlorine). After 1 hour at -15°'more chlorine solution (1.7 ml) was added and the solution was allowed to warm to 25° over 1 ⁇ 2-hour. It was then evaporated to a slurry and ethyl acetate (20 ml) was added. The suspension was stirred until the solid was.uniform and then filtered. The filtrate was concentrated to give a second crop of solid which was also filtered off.
  • a solution of chiorine in carbon tetrachloride 1.7 ml, 1.1M, ca. 1.8 mmole chlorine
  • Methanesulphonyl chloride (0.15 ml) was added to a stirred solution of 4-(1-ethoxyethoxy)-1-(p-nitrobenzyloxycarbonyl)-1-(2-oxo-4-triethylammonioazetidin-1-yl)but-1-en-2-olate (0.495 g) in dry dichloromethane (9 ml) at 0°. After 15 minutes the reaction mixture was allowed to warm to ambient temperature, stirred for a further 45 minutes, and then added, with stirring, to ether (200 ml).
  • p-Toluenesulphonyl chloride (0.223 g) was added to a stirred solution of 4-(1-ethoxyethoxy)-1-(p-nitrobenzyloxycarbonyl)-1-(2-oxo-4-triethylammonioazetidin-1-yl)but-1-en-2-olate (0.495 g) in dichloromethane (9 ml) containing pyridine ( 1 drop) at 0°. After 20 minutes the solution was allowed to warm to room temperature, stirred for a further 45 minutes and then added, with stirring, to ether (200 ml). The supernatant was decanted from the resulting precipitate and the latter was then agitated with more ether (50 ml).
  • the product was dissolved in dichloromethane and the solution was washed with aqueous sodium metabisulphite solution and brine. The washings were repeated and the organic solution was dried (sodium sulphate) and evaporated to dryness to give the crude product (0.627 g).
  • the product was purified by chromatography (B) (deactivated with 5% water) (dichloromethane: ethyl acetate 20:1). Appropriate fractions were collected and evaporated to dryness.
  • N-Chlorosuccinimide (0.04 g) was added in portions to a stirred solution of the product of Example 72 (0.06 g) in dry dichloromethane (8ml)at room temperature. After 4 hours the mixture was filtered. The filtrate was diluted with dichloromethane (50 ml) then washed with water (15 ml) followed by saturated brine (15 ml) and dried over magnesium sulphate. Evaporation afforded the title ester (0,05 g) whose spectral properties resembled those as described in Example 115.
  • Methanesulphonyl chloride (1.28 ml) was added dropwise to a stirred solution of 4-(tert-butyldimethylsilyl- oxy)-1-(p-nitrobenzyloxycarbonyl)-1-(2-oxo-4-triethylamm- onioazetidin-1-yl)but-1-en-2-olate(3,02 g) in dry dichloromethane (20 ml) containing dry pyridine (3.8 ml) and maintained at 5°. After 10 minutes the solution was allowed to warm to room temperature and stirred for 5 hours. The solution was. cooled to 5° and hydrogen sulphide was passed through the reaction mixture under nitrogen.
  • Methanesulphonyl chloride (0.2 ml) was added to a stirred solution of 1-(p-nitrobenzyloxycarbonyl)-1-(2-oxo-4-triethylammonioazetidin-l-yl)but-l-en-2-olate (0.42 g) in dry dichloromethane (2 ml) containing dry pyridine (0.4 ml) at 5°.
  • Methanesulphonyl chloride (2.35 ml) was added in portions to a stirred solution of 1-(p-nitrobenzyloxycarbonyl)-1-(2-oxo-4-triethylammonioazetidin-1-yl)-4-(tetrahydropyran-2-yloxy)but-l-en-2-olate (5.2 g) in dry dichloromethane (30 ml) containing pyridine (4.0 ml) at 0°. The reaction mixture was allowed to warm to room temperature and after 3 hours hydrogen sulphide was passed through the stirred solution at 0°. The reaction mixture was allowed to warm to ambient temperature and after 30 minutes was filtered.
  • Methanesulphonyl chloride (0.70 ml) was added dropwise to a stirred solution of 1-(p-nitrobenzyloxycarbonyl)-1-(2-oxo-4-triethylammonioazetidin-1-yl)but-1-en-2-olate(1.257g) in dry dichloromethane(10ml) containing pyridine (1.21 ml) at 0°.
  • the reaction mixture was allowed to warm to room temperature and after 2.5 hours hydrogen sulphide was passed through the stirred solution at 0°.
  • the reaction mixture was allowed to warm to ambient temperature and hydrogen sulphide was passed through the mixture for a further 10 minutes.
  • Methanesulphonyl chloride (6.72 ml) was added dropwise to a stirred solution of 4-methoxy-1-(p-nitrobenzyloxycarbonyl)-1-(2-oxo-4-triethylammonioazetidin-1-yl)but-1-en-2-olate (13.0g) in dry dichloromethane (73ml) containing pyridine (11.7ml)at 0°. After 10 minutes the reaction mixture was allowed to warm to room temperature and after a further 3 hours hydrogen sulphide was passed through the stirred solution at 0°. After 20 minutes the reaction mixture was allowed to warm to ambient temperature and hydrogen sulphide was passed for a further 30 minutes.
  • Methanesulphonyl chloride (3.83 ml) was added to a stirred solution of 4-(1-ethoxyethoxy)-1-(p-nitrobenzyloxycarbonyl)-1-(2-oxo-4-triethylammonioazetidin-1-yl)but-1-en-2-olate (8.38 g) in dry dichloromethane (110 ml) containing dry pyridine (6.65 ml) at 5°. After 5 minutes the solution was allowed to warm to room temperature and after a further 18 hours hydrogen sulphide was passed through the stirred solution at 0° under nitrogen. After 5 minutes the reaction mixture was allowed to warm to ambient temperature and hydrogen sulphide was passed for a further 15 minutes..
  • a plasticizer and suitable colour may be included in the film coating solution.
  • the tablet cores may be film coated as described in Example A.
  • sterile potassium (5RS)-2-(2-carbamoyloxyethyl)-pen-2-em-3-carboxylate aseptically into glass vials under a blanket of sterile nitrogen such that each vial contains an amount equivalent to 500 mg of the antibiotic free acid.
  • 5RS sterile potassium-2-(2-carbamoyloxyethyl)-pen-2-em-3-carboxylate
  • each vial contains an amount equivalent to 500 mg of the antibiotic free acid.
  • Empicol LZ is sodium lauryl sulphate available from Marchon Ltd.; Explotab is sodium.starch glycolate available from Greeff Fine Chemicals Ltd., Croydon, Surrey, England; Avicel PH 101 is microcrystalline cellulose available from FMC Corporation, U.S.A.; Emcompress is dicalcium phosphate dihydrate NF; and Ae rosil 200 is finely divided silicon dioxide.
  • Example 36 and 43 when administered intraperitoneally to mice gave LD 50 values of greater than 500 mg/kg.

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EP78300148A 1977-07-13 1978-07-12 Composés dérivés pénème, procédés pour leur préparation, leur utilisation dans les compositions pharmaceutiques et les azétidinones utilisées dans leur préparation Withdrawn EP0000636A1 (fr)

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2393805A1 (fr) * 1977-06-07 1979-01-05 Pfizer 1-oxyde de l'acide penicillanique et de ses esters utiles comme intermediaires chimiques
FR2405950A1 (fr) * 1977-05-09 1979-05-11 Ciba Geigy Ag Nouveaux 1 oxydes de l'acide penicillanique utiles dans la synthese de medicaments
EP0002210A1 (fr) * 1977-11-17 1979-06-13 Merck & Co. Inc. Acides pen-2-em-3-carboxyliques substitués en position 6- et 2- ou en position 6,6- et 2-; leurs procédés de préparation et compositions pharmaceutiques les contenant
EP0003892A1 (fr) * 1978-02-16 1979-09-05 Glaxo Group Limited Composés bêta-lactames, procédés pour leur préparation, compositions pharmaceutiques les contenant et les intermédiaires pour leur préparation
EP0010358A1 (fr) * 1978-09-20 1980-04-30 Glaxo Group Limited Composés de bêta-lactame, procédés pour leur préparation, compositions les contenant, intermédiaires utilisables dans leur préparation et méthodes pour leur production
DE2950898A1 (de) * 1978-12-18 1980-07-03 Bristol Myers Co Neue penemverbindungen, verfahren zu deren herstellung und arzneimittel
EP0013067A1 (fr) * 1978-12-22 1980-07-09 Beecham Group Plc Agents antibactériens à cycle bêta-lactame bicyclique, leur utilisation dans des compositions pharmaceutiques, procédés pour leur préparation et intermédiaires à utiliser dans de tels procédés
DE3006273A1 (de) * 1979-02-24 1980-09-04 Erba Farmitalia Verbindungen mit beta - lactamgeruest, verfahren zu deren herstellung und diese enthaltende pharmazeutische zubereitungen
FR2449092A1 (fr) * 1978-11-24 1980-09-12 Erba Farmitalia Derives de 7-oxo-4-thia-1-aza-bicyclo-(3,2,0)-heptane, procede pour les preparer et leur application comme medicaments
FR2453162A1 (fr) * 1979-04-06 1980-10-31 Erba Farmitalia Procede pour la preparation de derives de 4-acetoxy-azetidine-2-one par condensation avec un b-thiocetoester et composes obtenus
EP0076621A2 (fr) * 1981-10-01 1983-04-13 Ajinomoto Co., Inc. Dérivés d'azétidinone
US4595539A (en) * 1983-06-10 1986-06-17 Pfizer Inc. Preparation of penem derivatives and azetidinone intermediates
US4725678A (en) * 1983-06-10 1988-02-16 Pfizer Inc. Azetidinone intermediates for the preparation of penem derivatives
EP0297042A1 (fr) * 1987-06-23 1988-12-28 Ciba-Geigy Ag Dérivés de pénème substitués
EP3763922A1 (fr) 2019-07-09 2021-01-13 3M Innovative Properties Company Mat de montage à utiliser dans des dispositifs antipollution

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101061764B1 (ko) * 2008-02-29 2011-09-05 (주)에스에이치제약 신경보호효과를 가지는 피루베이트 유도체, 이의 제조방법 및 이를 포함하는 약제학적 조성물

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1368074A (en) * 1971-02-04 1974-09-25 Beecham Group Ltd Substituted beta-lactams and their preparation
DE2655298A1 (de) * 1975-12-08 1977-06-23 Ciba Geigy Ag Bicyclische ungesaettigte thia-azaverbindungen
DE2740527A1 (de) * 1976-09-09 1978-03-16 Glaxo Lab Ltd Clavulansaeureabkoemmlinge und deren herstellung

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1368074A (en) * 1971-02-04 1974-09-25 Beecham Group Ltd Substituted beta-lactams and their preparation
DE2655298A1 (de) * 1975-12-08 1977-06-23 Ciba Geigy Ag Bicyclische ungesaettigte thia-azaverbindungen
DE2740527A1 (de) * 1976-09-09 1978-03-16 Glaxo Lab Ltd Clavulansaeureabkoemmlinge und deren herstellung

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2405950A1 (fr) * 1977-05-09 1979-05-11 Ciba Geigy Ag Nouveaux 1 oxydes de l'acide penicillanique utiles dans la synthese de medicaments
FR2393805A1 (fr) * 1977-06-07 1979-01-05 Pfizer 1-oxyde de l'acide penicillanique et de ses esters utiles comme intermediaires chimiques
EP0002210A1 (fr) * 1977-11-17 1979-06-13 Merck & Co. Inc. Acides pen-2-em-3-carboxyliques substitués en position 6- et 2- ou en position 6,6- et 2-; leurs procédés de préparation et compositions pharmaceutiques les contenant
EP0003892A1 (fr) * 1978-02-16 1979-09-05 Glaxo Group Limited Composés bêta-lactames, procédés pour leur préparation, compositions pharmaceutiques les contenant et les intermédiaires pour leur préparation
EP0010358A1 (fr) * 1978-09-20 1980-04-30 Glaxo Group Limited Composés de bêta-lactame, procédés pour leur préparation, compositions les contenant, intermédiaires utilisables dans leur préparation et méthodes pour leur production
FR2449092A1 (fr) * 1978-11-24 1980-09-12 Erba Farmitalia Derives de 7-oxo-4-thia-1-aza-bicyclo-(3,2,0)-heptane, procede pour les preparer et leur application comme medicaments
FR2476089A1 (fr) * 1978-12-18 1981-08-21 Bristol Myers Co Nouveaux derives substitues de 7-oxo-4-thia-1-azabicyclo(3.2.0) hept-2-ene, procede et composes intermediaires pour leur production, composition pharmaceutique les contenant et leur application a la lutte contre des infections bacteriennes
DE2950913A1 (de) * 1978-12-18 1980-07-31 Bristol Myers Co Neue substituierte penemverbindungen, verfahren zu deren herstellung und arzneimittel
DE2950898A1 (de) * 1978-12-18 1980-07-03 Bristol Myers Co Neue penemverbindungen, verfahren zu deren herstellung und arzneimittel
EP0013067A1 (fr) * 1978-12-22 1980-07-09 Beecham Group Plc Agents antibactériens à cycle bêta-lactame bicyclique, leur utilisation dans des compositions pharmaceutiques, procédés pour leur préparation et intermédiaires à utiliser dans de tels procédés
DE3006273A1 (de) * 1979-02-24 1980-09-04 Erba Farmitalia Verbindungen mit beta - lactamgeruest, verfahren zu deren herstellung und diese enthaltende pharmazeutische zubereitungen
FR2449690A1 (fr) * 1979-02-24 1980-09-19 Erba Farmitalia Composes derives d'acides 2-penem-3-carboxyliques, procede pour les preparer et leur usage comme medicaments
FR2453162A1 (fr) * 1979-04-06 1980-10-31 Erba Farmitalia Procede pour la preparation de derives de 4-acetoxy-azetidine-2-one par condensation avec un b-thiocetoester et composes obtenus
EP0076621A2 (fr) * 1981-10-01 1983-04-13 Ajinomoto Co., Inc. Dérivés d'azétidinone
EP0076621A3 (en) * 1981-10-01 1984-03-28 Ajinomoto Co., Inc. Azetidinone derivatives
US4595539A (en) * 1983-06-10 1986-06-17 Pfizer Inc. Preparation of penem derivatives and azetidinone intermediates
US4725678A (en) * 1983-06-10 1988-02-16 Pfizer Inc. Azetidinone intermediates for the preparation of penem derivatives
EP0297042A1 (fr) * 1987-06-23 1988-12-28 Ciba-Geigy Ag Dérivés de pénème substitués
EP3763922A1 (fr) 2019-07-09 2021-01-13 3M Innovative Properties Company Mat de montage à utiliser dans des dispositifs antipollution

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AU3796278A (en) 1980-01-17
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IT1156863B (it) 1987-02-04

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