GB2122186A - Oxapenem derivatives - Google Patents

Abstract

The present invention provides a compound of the general formula II <IMAGE> in which R represents a free or esterified carboxyl group, R<1> represents a hydrogen atom or an unsubstituted or substituted straight or branched chain aliphatic group, and R<2> and R<3>, which may be the same or different, each represents a hydrogen or halogen atom, an amine or substituted amine group, or an unsubstituted or substituted straight or branched chain aliphatic group, and Z represents an unsubstituted or substituted aromatic heterocyclic radical with up to 15, preferably up to 9, carbon atoms and at least one ring nitrogen atom and optionally a further ring heteroatom, which radical is bonded to the dithio group by one of its ring carbon atoms, which is bonded to a ring nitrogen atom by a double bond, or Z represents an acyl radical derived from an organic carboxylic or thiocarboxylic acid, and the corresponding monosulphide of formula IIa <IMAGE> A compound of formula II or IIa may be used in the production of a compound of the general formula I <IMAGE> in which R, R<1>, R<2> and R<3> are as defined above, which has antibacterial properties and is a ???-lactamase inhibitor.

Description

SPECIFICATION Oxapenem derivatives This invention relates to a process for producing oxapenem derivatives, to certain oxapenem derivatives, and to pharmaceutical preparations comprising oxapenem derivatives.

Processes are known for the production of 1-oxapenems. One process uses, as a starting material, clavulanic acid and is described in Belgian Patent Specification No. 858 515. Another process is described by, for example, P. H. Bentley, G. Brooks, M. L. Gilpin, and E. Hunt, J. Chem. Soc. Chem.

Commun., (1977) 905. This procedure does not use a natural product as a starting material and involves a multistep procedure.

We have now found that certain 1 -oxapenem derivatives can be readily prepared from 6-aminopenicillanic acid, a relatively inexpensive and readily available starting material. This process has the additional advantage that it allows the control of the stereo chemistry at positions 5 and 6 of the 1oxapenem structure.

The term "oxapenem" is used herein to denote the structure

When the 6-position is substituted by 1 or more carbon atoms, the following numbering system is used herein

The numbering of the various positions is in accordance with that used in the chemistry of penicillins.

The present invention provides a compound of the general formula ii

in which R represents a free or esterified carboxyl group, R' represents a hydrogen atom or an unsubstituted or substituted straight or branched chain aliphatic group, and R2 and R3, which may be the same or different, each represents a hydrogen or halogen atom, an amine or substituted amine group, or an unsubstituted or substituted straight or branched chain aliphatic group, and Z represents an unsubstituted or substituted aromatic heterocyclic radical with up to 15, preferably up to 9, carbon atoms and at least one ring nitrogen atom and optionally a further ring heteroatom, which radical is bonded to the dithio group by one of its ring carbon atoms, which is bonded to a ring nitrogen atom by a double bond, or Z represents an acyl radical derived from an organic carboxylic or thiocarboxylic acid, and the corresponding monosulphide of formula lia

The present invention also provides a process for the production of a compound of the general formula Il or lla which comprises (a) converting a compound of formula Ill

in which R, R1, R2, R3 and Z are as defined above into the corresponding enol of formula 11, or (b) converting a compound of formula Illa

in which R, R1, R2, R3 and Z are as defined above, into the corresponding enol of formula Ila, or (c) treating a compound of formula Il with a tervalent organophosphorus compound to give the corresponding compound of formula lla.

An aliphatic group R' is, for example, an alkyl, alkenyl or alkynyl group having up to 8 carbon atoms, and especially up to 4-carbon atoms, that is to say, a lower group.

A group R' may be substituted by one or more substituents, as appropriate. Examples of substituents are halogen atoms; oxo groups; hydroxyl and mercapto groups, alkoxy and alkylthio groups; alkylcarbonyl groups, carboxy, alkoxycarbonyl and alkylthiocarbonyl groups; alkanoyloxy and alkanoylthio groups; carbamoyl and carbamoyloxy groups and carbamoyl and carbamoyloxy groups substituted by one or two groups selected from alkyl and aryl group and the corresponding unsubstituted and substituted groups in which the, each or either oxygen atom is replaced by a sulphur atom nitro, cyano and azido groups; amido and imido groups; imino, amino, mono- and di- alkylamino, mono- and di-arylamino groups, and N,N-alkylarylamino groups; acylamino groups; sulphinyl, sulphonyl and sulphonamido groups; cycloalkyl groups; aryl, aryloxy, arylthio, aryloxycarbonyl, arylthiocarbonyl, arylcarbonyloxyl, arylcarbonylthio, aralkoxycarbonyl, aralkylthiocarbonyl, aralkylcarbonyloxy, aralkylcarbonylthio, aralkoxy, and aralkylthio groups; aromatic and non-aromatic heterocyclic groups, aromatic and non-aromatic heterocyclicoxy groups and aromatic and nonaromatic heterocyclicthio groups.

Examples of aromatic heterocyclic groups are 1 -methylimidazol-2-yl, 1 ,3-thiazol-2-yl, 1,3,4thiadiazol-2-yl, 1 ,3,4,5-thiatriazol-2-yl, 1,3-oxazol-2-yl, 1 ,3,4,5-oxatriazol-2-yl, 1 ,3,4,5-tetrazol-2-yl, 2-quinolyl, 1-methyl-benzimidazol-2-yl, benzoxazol-2-yl and benthiazol-2-yl groups, and the corresponding 2-yl-oxy and 2-yl-thio groups.

Any substituent of R that is itself capable of substitution may be substituted, for example, by any one or more of the substituents described above. Alkyl groups are preferably alkyl groups having up to 8 and especially up to 4 carbon atoms.

R' preferably represents a methyl group or a substituted methyl group, preferably~substitutedby one of the groups described above, for example, a methyl group having one or more substituents, for example, bromomethyl, a methoxy methyl group; an etherified or esterified methyl group, for example, a lower alkoxymethylene group, for example, a methoxymethylene group, or a lower alkanoyloxymethylene group, for example, a methylcarbonyloxymethylene group; a methyl group substituted by an azide nitrile or thiocyanate group; a methyl group substituted by a -SHet group in which Het represents an aromatic or non-aromatic heterocyclic group especially an aromatic heterocyclic group as mentioned above; or a methyl group substituted by an amino group or by a mono- or di-lower alkylamino, mono-or di-arylamino or lower alkyl-arylamino group; or a methyl group substituted by an acylamino group.

Preferably one of the radicals R2 and R3 represents a hydrogen or halogen atom with the other representing an unsubstituted or substituted, straight or branched chain aliphatic group. An aliphatic group may be a straight or branched chain lower alkyl, alkenyl or alkynyl group, for example, a methyl, ethyl or vinyl group. An aliphatic group R2 or R3 may be substituted as described above for R'.Preferred substituents for an aliphatic group R2 or R3 are amino, mercapto and hydroxyl groups, which may themselves be substituted, for example, by one of the following groups: --R'O, --COO-NR'OR1', -CO-R10, -CO-OR10, SO2R10, -SQ-OR10 SO3e and, in the case of an amino group, -R10R11, in which groups R10 and R, which may be the same or different, if appropriate, each represents an alkyl group, especially a lower alkyl group, an aryl group or an aralkyl group, especially an aryl-lower alkyl group. Furthermore, a nitrogen atom present as a direct substituent of R2 or R3 or present in the group -CO-NR10R11 may be part of an aromatic or nonaromatic heterocyclic ring.

R2 or R3 preferably represents a hydrogen atom and the other represents a lower alkyl group or a 1-hydroxyl-lower alkyl group. Especially preferred are those compounds in which R2 or R3 represents a hydrogen atom and the other represents a methyl, ethyl, hydroxymethyl or 1-hydroxyethyl group, a chlorine, bromine or iodine atom, or an ethylidene or vinyl group.

A substituted amino group at position 6 may be a mono- or di-alkyl amino group, especially a mono- or di-lower alkylamino group, an acylamino group, or a nitrogen-containing heterocyclic group.

An esterified carboxyl group R is, for example, an ester formed with an unsubstituted or substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic aryl or araliphatic alcohol having up to 1 8 carbon atoms or R may represent a silyl or stannyl ester. The ester moiety may be removable under acidic, neutral or basic conditions to give the free acid.In some cases it may be preferable if R represents an ester group that is removable under physiological conditions, that is to say, the ester group is split off in vivo to give the free acid, for example, an acyloxymethoxy ester, e.g. pivaloyloxymethoxy ester, an aminoalkaneyloxy methoxy ester, for example, an L-glycycloxymethoxy, Lvalyloxymethoxy or L-leucyloxy methoxy ester, or a phthalidyloxy ester, or an optionally substituted 2aminoethoxy ester, for example, a 2-diethylamino-ethoxy or 2-(1 -morpholino)-ethoxy ester. Preferred esters are benzyl, p- and o- nitrobenzyl ester, and o- nitrobenzylhydryl esters.

An aromatic heterocyclic radical Z may be monocyclic or bicyclic and may be substituted, for example, by a lower alkyl group, for example, a methyl or ethyl group, a lower alkoxy group, for example, a methoxy or ethoxy group, a halogen atom, for example, fluorine or chlorine atom or an aryl group, for example, a phenyl group.

A heterocyclic radical Z is, for example, a monocyclic five-membered thiadiazacyclic, thiatriazacyclic, oxadiazacyclic or oxatriazacyclic radical of aromatic character, especially a monocyclic five-membered diazacyclic, oxacyclic or thiazacyclic radical of aromatic character, and above all, the corresponding benzdiazacyclic, benzoxazacyclic or benzthiazacyclic radicals, wherein the heterocyciic part is five-membered and is of aromatic character.

In radicals Z a substitutable ring nitrogen atom can be substituted, for example, by a lower alkyl group. Examples of such groups Z are 1-methyl-imidazol-2-yl, 1 ,3-thiazol-2-yl, 1 ,3,4-thiadiazol-2-yl, 1 ,3,4,5-thiatriazol-2-yl, 1,3-oxazol-2-yl, 1 ,3,4-oxadiazol-2-yl, 1 ,3,4,5-oxatriazol-2-yl, 2-quinolyl, 1 methyl-benzim idazol-2yl, benzoxazol-2-yl and especially benzthioazol-2-yl groups.Z may also represent an acyl radical or organic carboxylic or thiocarboxylic acid, for example, an unsubstituted or substituted aliphatic, cycloaliphatic, araliphatic or aromatic acyl or thioacyl group having up to 18, preferably up to 10, carbon atoms, for example, lower alkanoyl groups, for example acetyl and propionyl groups, lower thioalkanoyl groups, for example thioacetyl and thiopropionyl groups, cycloalkanecarbonyl groups, for example a cyclohexanecarbonyl group, cycloalkanethiocarbonyl group, for example, a cyclohexanethiocarbonyl group, benzoyl, thiobenzoyl, naphthylcarbonyl, and naphthylthiocarbonyl groups, heterocyclic carbonyl and thiocarbonyl groups, for example, 2-, 3- or 4pyridylcarbonyl, 2- or 3-thenoyl, 2- or 3-furoyl, 2-, 3-, or 4-pyridylthiocarbonyl, 2- or 3-thiothenoyl, and 2- or 3-thiofuroyl groups, and corresponding substituted acyl and thioacyl groups, for example acyl and thioacyl groups monosubstituted or polysubstituted by lower alkyl groups, for example, methyl groups, halogen atoms for example, fluorine and chlorine atoms, lower alkoxy groups, for example, methoxy groups, aryl groups for example phenyl groups, and aryloxy groups, for example phenyloxy groups.

Z preferably represents a

group.

The tervalent organophosphorus compound used to desulphurise a compound of formula II or Ill is especially one of the general formula PR4RsR6 wherein R4, R5 or R6, which may be the same or different, each represents an unsubstituted or substituted hydrocarbon group, for example, a straight or branched chain aliphatic group, an unsubstituted or substituted cycloaliphatic group, or an unsubstituted or substituted aryl group or an unsubstituted or substituted hydrocarbon group in which one or more carbon atoms are replaced by hetero atoms, especially nitrogen, oxygen and sulphur atoms, for example, alkyl and alkoxy groups, amine groups, aromatic hydrocarbon groups, aromatic and non-aromatic heterocyclic groups. Preferred tervalent organophosphorus compounds are triphenylphosphine, tributylphosphine, trimethylphosphite and triethylphosphite.

A further preferred group of tervalent organophosphorus compounds are those in which, in PR4R5R6 one or more of the groups R4, R5 and R6 comprises an insoiuble polymer, which aids removal after the reaction. Generally one polymeric substituent is adequate.

Another preferred group of tervalent organophosphorus compounds are those in which, in PR4RsR6 one or more of the groups R4, R5 and R6 comprise a cationic or anionic centre, for example, a quaternary ammonium group or a carboxylate or sulphate group. The presence of a charged group assists removal of the resulting organophosphorus sulphide, for example, by partition or by absorption on an insoluble ion exchange resin or by extraction into an aqueous solution at an appropriate pH, when the sulphide is water soluble.

A compound of formula ll or lla may be used in the production of a compound of the general formula I

in which R, R1, R2 and R3 are as defined above, for example, by treating a compound of formula II with a tervalent organophosphorus compound and, preferably, simultaneously or subsequently with a thiophilic agent as hereinafter defined, and, if desired, carrying out any one or more of the following steps in any appropriate order: (i) converting an ester into another ester or the free acid, (ii) converting a free acid into an ester or a salt, (iii) converting a salt into the free acid or another salt.

The tervalent organs phosphorus compound is preferably as described above, and the thiophilic agent is especially a thiophilic metal salt, for example, a salt of an element of Group Ib, llb or VIII of the Periodic Table of the Elements (cf. Advanced Inorganic Chemistry, F. A. Colter and G. Wilkinson, Interscience), for example, a silver, copper, zinc, nickel, iron, cadmium, mercury or cobalt thiophilic salt, silver and copper salts being preferred.Examples of preferred thiophilic salts are (i) AgNO3, AgOSO2CF3, AgOSO2M3, AgBF4,AgPF6e, CuCI, CuBr, CuCl2,CuBr2, CuOSO2Me, CuOSO2CF3, CuSO4, Cu(NO3)2, and the corresponding nickel, zinc, iron and cobalt salts having the anions given above for Ag2+ and Cu2+, and for Cu+, as appropriate, as counterions; and (ii) Ag2CO3, AgO, Cu(acac)2, Cu(CO3)2, Cu2CO3, CuOR7 in which R7 represents an alkyl group or cycloalkyl group for example, comprising up to 8 carbon atoms, preferably CH3, C2H5, t-butyl.

If the metal salt is itself sufficiently basic, for example, the salts of group (ii) above, it is not necessary to incorporate a base in the reaction mixture. If, however, the metal salt is only weakly basic, for example, the salts of group (i) above, then it is necessary to use a base. The term "thiophilic agent" is used herein to mean a thiophilic metal salt alone, or a thiophilic metal salt plus base, as appropriate.

The base may be inorganic or organic, and preferred organic bases are pyridine, lower alkyl substituted pyridines, alkylamine substituted pyridines, piperidine and lower alkyl substituted piperidine e.g. 2,2,6,6-tetramethylpiperidine, and trisubstituted amines, for example, trialkylamines, for example triethylamine and ethyldi-iso-propyl-amine, and N-alkyl-arylamines, for example, 1 ,8-bis (dimethylamino) naphthalene, or N,N-dimethylphenylamine. Examples of preferred inorganic bases are metal hydrides, e.g. sodium hydride, and metal carbonates, for example, sodium carbonate.

According to the preferred method of carrying out the process, the starting material is reacted with the tervalent organophosphorus compound and simultaneously, a thiophilic agent, especially a metal salt, and where appropriate, a base.

This process of the invention is preferably carried out in the presence of an appropriate, inert, anhydrous solvent or diluent. Any solvent or diluent can be used which is inert to the sulphide, the tervalent phosphorus compound and the final product. Examples of solvents and diluents are benzene, toluene, acetonitrile, ethylacetate, dichloromethane, chloroform, and dioxane. Mixtures of two or more solvents and diluents may also be employed. The process may be carried out at a temperature of from 400 to +800, preferably from 0 to +200.

It is preferable to use 1 equivalent of the tervalent organophosphorus compound, and to incorporate this compound and the thiophilic agent in the reaction mixture.

The treatment of the disulphide of formula II with an organophosphorus compound and, simultaneously or subsequently, a thiophilic agent, gives the corresponding compound of formula I as the major reaction product. Treatment with an organophosphorus compound alone, however, generally gives a mixture of the corresponding compound of formula I and the monosulphide corresponding to formula II i.e. a compound of the general formula Ia

in which R, R', R2, R3 and Z are as defined above. This mixture may be treated with a thiophilic agent, or the compound of formula i and the monosulphide of formula Ila may be separated and the latter treated with a thiophilic agent to produce a compound of formula I.

A compound of the general formula I as defined above or a salt thereof may be produced by a process which comprises treating a compound of the general formula Ila

in which R, R', R2, R3 and Z are defined as above, with a thiophilic agent, as hereinbefore defined and, if desired, carrying out any one or more of the further steps (i) to (iii). The various radicals R to R3 and Z preferably have the preferred meanings given above, and the preferred thiophilic agents and reaction conditions are as indicated above.

A compound of formula II may be produced by converting a compound of formula Ill

in which R, R1, R2, R3 and Z are as defined above, into the corresponding enol.

This is preferably carried out by ozonolysis, generally via an intermediate ozonide of the general formula

Ozone is usually employed in the presence of a solvent, for example, an alcohol, for example a lower alkanol, for example methanol or ethanol, a ketone, for example a lower alkanone, for example acetone, an optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, for example a halogeno-lower alkane, for example methylene chloride or carbon tetrachloride, an ester, for example methyl acetate or ethyl acetate, or a mixture of two or more solvents, including an aqueous mixture, and with cooling or slight warming, for example at temperatures of from -900C to +400C, preferably from -600C to +00.

An ozonide intermediate llb can be split by reduction to give a compound of the formula Ill for which it is possible to use catalytically activated hydrogen, for example hydrogen in the presence of a heavy metal hydrogenation catalyst, for example a nickel catalyst, or a palladium catalyst, preferably on a suitable carrier, for example, calcium carbonate or charcoal, or a chemical reducing agent, for example, a reducing heavy metal, including a heavy metal alloy or amalgam, for example zinc, in the presence of a hydrogen donor, for example, an acid, for example acetic acid, or an alcohol, for example a lower alkanol, a reducing inorganic salt, for example an alkali metal iodide, for example sodium iodide, in the presence of a hydrogen donor, for example, an acid, for example acetic acid, a reducing sulphide compound for example, sulphur di-oxide or a di-lower alkyl sulphide, for example dimethyl sulphide, a reducing organic phosphorus compound, for example a phosphine, which can optionally contain substituted aliphatic or aromatic hydrocarbon radicals as substituents, for example tri-lower alkylphosphines, for example tri-n-butylphosphine, or triarylphosphines, for example triphenylphosphine, also phosphites which contain optionally substituted aliphatic hydrocarbon radicals as substituents, for example tri-lower alkyl phosphites, usually in the form of the corresponding alcohol adduct compounds, for example trimethyl phosphite, or phosphorus acid triamides which contain optionally substituted aliphatic hydrocarbon radicals as substituents, for example hexa-lower alkyl phosphorus acid triamides, for example hexamethyl-phosphorus acid triamide, the latter preferably in the form of a methanol adduct, or tetracyanoethylene. The splitting of the ozonide, which is usually not isolated, is normally carried out under the conditions which are employed for its manufacture, that is to say in the presence of a suitable solvent or solvent mixture, and with cooling or slight warming.

The ozonolysis is preferably carried out in ethyl acetate or dichloromethane which comprises from 0 to 50% by volume of methanol. A mixture of 75% dichloromethane and 25% methanol is particularly preferred. The preferred reducing agents are dimethyl sulphide and sulphur dioxide.

The ozonolysis may result, inter alia, in a mixture of isomers Ic and lid about the double bond i.e.

These isomers are readily interconvertible, and compounds of the formulae llc and lid can also exist in the tautomeric keto form.

It is usual for the subsequent reaction(s) to be carried out on the mixture of isomers, and keto tautomer if present. The presence of the keto tautomer does not adversely affect subsequent reactions.

A compound of formula Ila may be produced, as indicated above, by desulphurizing a compound of formula II using a tervalent organophosphorus compound, or it may be produced by converting a compound of formula Illa.

in which R, R', R2, R3 and Z are as defined above, into the corresponding enol, preferably by ozonolysis as described above. The compound of formula Illa may be produced by desulphurizing the corresponding compound of formula Ill using a tervalent organophosphorus compound as previously described. The reaction is generally conducted in the presence of an inert solvent or diluent, for example, a saturated hydrocarbon, e.g. pentane or hexane; a saturated cyciohydrocarbon, e.g.

cyclohexane; an aromatic hydrocarbon, e.g. benzene, or toluene; acetonitrile or ethylacetate; a chlorinated hydrocarbon, e.g. dichloromethane, or chloroform; or an oxygenated hydrocarbon, e.g.

ethylacetate, acetone, ethanol, tetrahydrofuran or dioxane. Mixtures of two or more solvents may be employed. Preferred solvents are methylene chloride and chloroform, and the preferred temperature is from -40 to +8O0C, especially from -20 to +200C.

Various possible routes for producing a compound of formula I are illustrated by way of example in the following reaction scheme.

A compound of formula III in which R1 represents a methyl group is preferably produced by reacting a compound of formula IVa

in which R, R2 and R3 are as defined above with a compound of formula V H-S-Z (V) in which Z is as defined above.

This reaction may be carried out by merely heating the compound of formula IVa with a compound of formula V, preferably in a nitrogen or argon atmosphere, in an inert solvent or diluent at a temperature from 50 to 1 500, especially from 80 to 1200. Suitable solvents are those which possess a sufficiently elevated boiling point to achieve the necessary reaction temperature and in which the starting materials and product are stable at the temperature of the reaction. Examples of solvent are benzene, toluene, ethyl acetate, acetonitrile, dioxane, N,N-dimethyl formamide and N,Ndimethylacetamide.

When a compound of formula Ill where R is other than a methyl group is required this is preferably produced by reacting a compound of the formula IVb

in which R, R', R2 and R3 are as defined above and R' preferably represents a substituted methyl group.

A substituted methyl group is, for example, a -CH2OH group, a -CH2SR12 group in which R12 represents an aromatic or non-aromatic heterocyclic group, especially one of those mentioned above as a substituent for R', a -CH2 alkyl or -CH2 aryl group, a -CG2Hal group in which Hal represents a halogen atom, a -CH2NHCOR13 group in which R13 represents a lower alkyl group which may be substituted as defined above for R1, a -CH2N3, -CH2SCN or -CH2CN group, or a -CH2OCOR13 group in which R13 is as defined above, with a compound of formula V, preferably under the conditions described above.

Some examples of analogues of compounds possessing the above substituted penam ring system as described in U.S. patents nos. 4081 443 and 4056 521 and may be produced as described therein.

The compound of formula IVa is preferably produced from a compound of formula VI

in which R, R2 and R3 are defined as above, by means of oxidation.

The oxidation may be carried out by any method suitable for oxidising sulphides to the corresponding sulphoxides. Oxidising agents are, for example, hydrogen peroxide, periodates e.g.

sodium periodate, ozone, peracids e.g. peracetic acid, perbenzoic acid, substituted perbenzoic acids, and permanganate salts e.g. potassium permanganate. A preferred oxidising agent is metachloroperbenzoic acid.

The oxidation is preferably conducted in an inert solvent at a preferred temperature of from -20? to +300. Preferred solvents are ethylacetate, methylene chloride, chloroform, acetonitrile, and lower alcohols, for example methanol and ethanol.

A compound of formula VI may be prepared in several ways, for example, a compound in which R2 and R3 both represent hydrogen atoms may be prepared by catalytically hydrogenating a compound of the general formula VII

in which X and Y are the same and each represents a halogen atom, or X represents a hydrogen atom and Y represents a halogen atom, and R is as defined above.

An example of such a process in which R represents a free carboxyl group is given in J. Chem.

Soc. 2623 (1969).

A compound of formula VI in which R2 or R3 represents a hydrogen atom and the other represents an organic substituent as defined above, or both R2 and R3 represent organic substituents, may be prepared by introducing the appropriate group(s) into a compound of formula VII. An example of such process is given in J. Org. Chem. 42, 2960 (1977) where a hydroxyethyl group is introduced into a compound of the formula VII wherein X and Y each represents a bromine atom or X represents a hydrogen atom and Y an iodine atom by the use of an organometallic reagent, for example, nbutyllithium or methylmagnesium bromide in, for example, tetrahydrofuran or diethyl ether, to prepare a metalated compound of formula VIII, where X represents a hydrogen or bromine atom and the metal is Li+, MgBr+.

Subsequent treatment of the metalated compound of formula VIII with acetaldehyde gives a compound of formula VI where R is as defined above, R2 represents an 1-hydroxyethyl group and Rs represents a bromine or hydrogen atom. This reaction may be carried out analogously using other aldehydes.

A compound of formula VI where R2 represents an 1-hydroxyethyl group and R3 a hydrogen atom can be further transformed, according to a procedure described in J. Amer. Chem. Soc. 3251, 100, (1978), to a compound of formula VI where R2 represents an ethyl group and R3 represents a hydrogen atom i.e. the hydroxyl group of the hydroxyethyl group has been replaced by hydrogen.

Other methods of introducing, into a -lactam, alkyl groups, aralkyl groups and 1-hydroxyalkyl groups have been described in the chemical literature, for example Can. J. Chem. 3196, 50 (1972), Can. J. Chem. 3206 52 (1974) and Synthesis 746 (1978).

A compound of formula VI in which R2 represents an unsubstituted or substituted alkyl or aralkyl group and R3 represents a hydrogen atom or vice versa may generally be prepared as follows: A compound of formula VII in which R preferably represents an esterified carboxyl group is treated with an organo-metallic reagent of the formula M&commat;Ras in which Ra(3 represents a lower alkyl or aryl anion, for example, a phenyl anion and Mo represents metal cation e.g. a lithium cation, a cuprous cation, a magnesium bromide, chloride or iodide cation, a zinc bromide, chloride or iodide cation, or a ZnR'4 cation, where R14 represents a lower alkyl group, especially a methyl or ethyl group.Examples of such organometallic reagents are methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, methylmagnesium bromide, tert-butylmagnesium bromide, isopropylmagnesium bromide, and diethyl zinc.

It is preferable that this treatment is conducted in a suitable, inert solvent or diluent, for example, a saturated hydrocarbon ether, for example, diethylether, or 1 ,2-dimethoxyethane; a saturated cyclic ether, for example tetrahydrofuran or 1,4-dioxane; or an aromatic hydrocarbon e.g. toluene.The reaction may be conducted at temperatures from --1200 to 00, but the preferred temperature is from -800 to --600. The resulting metalated compound of formula VIII where Metal has one of the meanings given above for Me, R is as previously defined and X represents a hydrogen or bromine atom is not usually isolated but is preferably treated in situ with a compound of the formula Ra2R3aC=O, in which R2a and Ra have the meanings given for R2 and R3 and may additionally represent aryl. A metalated compound of formula VIII wherein Metal is as defined above for Me obtained with the use of any other suitable organometallic reagent may also be treated with a ketone Ra2R3aC=O.

The resulting compound of formula IXa

wherein R8 has one of the meanings given above for Mo may be treated, for example in situ, with an acid, for example acetic acid to give the corresponding compound of formula IXa where R8 represents a hydrogen atom.

A compound of formula IXa wherein X and R8 each represents a hydrogen atom can be further transformed into a compound of formula IXb where the hydroxyl group has been replaced by a hydrogen atom.

This process may be effected by treatment of a compound of general formula IXa wherein R8 represents a hydrogen atom with a compound which will activate the hydroxyl group. A preferred method is to prepare an alkyl sulphonyl derivative IXa wherein R8 represents SOR2R9, and R9 represents an aromatic hydrocarbon radical, e.g. a phenyl, or 4-methylphenyl radical or a lower alkyl group e.g. a methyl group, for example from a compound IXa wherein R8 represents a hydrogen atom by treatment with an activated sulphonyl derivative R9SO2X represents a halogen atom or-OSO2R9, i.e. a sulphonyl anhydride, in the presence of a base.An organic or inorganic base may be used, preferred organic bases being pyridine, alkylsubstituted pyridines, e.g. 2,6-dimethylpyridine, alkylamino pyridine e.g. 4- N,N-dimethylaminopyridine, trisubstituted amines, e.g. triethylamine, ethyldi-iso-propylamine, and alkyl, aryl amines, e.g. N,N-dimethylaniline. Preferred inorganic bases are metal hydrides, e.g. sodium hydride, and metal carbonates, e.g. sodium carbonate.

The reaction is optimally performed in a suitable inert solvent or diluent at temperatures from 40 to +400C, preferably at temperatures of from -100 to + 1 00C. Examples of solvents and diluents are ethylacetate, benzene, toluene, acetonitrile, chloroform, and methylene chloride, dioxan and tetrahydrofurane.

A compound of formula IXa wherein R8 represents SO2R9, R9 being as defined above, may be further treated with an organic base, e.g. triethylamine,1,4-diazobicyclo[2,2,2]octane, to produce the enelactams of formula IXc

which may have the E- or Z-configuration or position 6.

The process may be conducted in an inert solvent or 20 diluent, for example, benzene, toluene, ethylacetate, or acetonitrile, and at a temperature of from 200 to 1 200C, preferably at a temperature of about 800C.

A compound of formula IXb may be prepared from a compound of formula IXc by means of reduction. The preferred method of reduction is by catalytically activated hydrogen for example with Pd/C, Pd/Ca CO3, or PtO2 in the presence of an inert solvent or diluent, for example, ethylacetate at temperatures of from 0 to 400C and at a pressure of hydrogen of from 1 to 4 atmospheres. A Parr hydrogentor is preferably used for this reduction.

Compounds resulting from the above preferred procedures i.e. compounds of formula IXa and IXb exist as 6R and 6S isomers, and compounds IXa and IXb also exist as R and S isomers at the starred carbon atom, where R28 and R3a are not the same.

The halogen atom present in the compounds IXa and IXd may be removed by reduction, for example, hydrogen in the presence of a noble metal catalyst, for example Pd/C, Pd/CaCO3, Pt; a heavy metal alloy or amalgam for example, Zn/Ag; an organo-stannyl hydride, e.g. tri-n-butyl stannyl hydride.

The reduction may be carried out under the conditions normally employed for the use of these reducing agents. The resulting compounds fall within the general formula VI.

Some compounds of formula VII are known and can be prepared according to known procedures.

One such procedure which is described in J. Chem. Sec., 2623 (1969), involves the treatment of 6amino penicillanic acid simultaneously with nitrous acid and a halogenating agent. The use of sodium bromide as the halogenating agent results in a compound of formula VII in which X represents a hydrogen atom, Y represents a bromine atom and R represents a free carboxyl group, with sodium iodide giving the corresponding compound in which Y represents an iodine atom, and bromine giving the dibromo analogue.

A compound of formula VII in which R represents-CO2CH2Ph, X represents a hydrogen atom and Y represents an iodine atom, and the dibromo analogue thereof, may both be prepared by the process described in J. Org. Chem. 43, 2960 (1977).

Other compounds of formula VII may be prepared analogously.

6-Aminopenicillanic is an advantageous starting material as it is readily available and relatively inexpensive.

The analogues of the various intermediates of formulae VI to IX in which R1 represents other than a methyl group may be prepared analogously to the above described intermediates, for example, starting from the appropriate analogue of 6-aminopenicillanic acid, or compound IVb may be produced as described in the above mentioned U.S. patents.

If a compound of formula II or Ila is to be converted into a compound of formula I, it is advisable to esterify a free carboxyl group in a compound of formula II or Ila prior to cyclisation as a free carboxyl group is nucleophilic and it is undesirable to have this nucleophilic group present in addition to the hydroxyl group. Although an ester group may be introduced immediately prior to cyclisation, it is preferable to esterify the carboxyl group at an earlier stage in the preferred reaction sequence, for example, to esterify a free carboxyl group in a compound of formula VI or VII, to ensure that the carboxyl group does not take part in any of the subsequent reactions.

At each stage of the preferred reaction sequence, the desired compound may be isolated from the reaction mixture and, if desired, purified by appropriate techniques, for example, chromatography.

As indicated above, various intermediates may be produced in the form of mixtures of isomers of various kinds. Such a mixture may be resolved at any stage, or the isomeric mixture may be used per se for subsequent reactions. The isomers of formulae II and Ila that appear to cyclise to give a compound of formula I are

When R2 ahd R3 are other than hydrogen atoms, either may be cis or trans to the -SZ or -S-S-Z group, as mentioned below for formula I.

A compound of formula I may have, independently, the R or S configuration at position65 and 6, i.e. a compound may be 5R, 6R; 5R, 6S; 5S, 6R; or 5S, 6S. Moreover, R2 may be trans to the 1 -oxa group with R3 cis to the 1-oxa group, or vice versa.

An aliphatic group may be joined to the 6-position of the oxapenem by a double bond in either the E or the Z configuration, for example, R2 or R3 may represent an E- or Z-alkylidene or alkenylidene group, for example, an E- or Z-ethylidine group.

The present invention accordingly includes the production of any of the various possible isomers of the compound of formula I, in pure form or in admixture with any one or more other isomer(s). A resulting mixture of isomers may be resolved in the normal manner, if desired.

A compound of formula il or Ila may be used to produce, for example, the following compounds: (i) a compound of the general formula X

in which R, R1, R2, and R3 are as defined for the general formula I, with the exception of those compounds in which R2 or R3 represents an amine or substituted amino group, directly bonded to the ring carbon atom and those in which R2 and R3 both represent hydrogen atoms.Particularly preferred are those compounds in which R1 represents a methyl group; (ii) a compound of the general formula Xl

in which Rb and Rb3 each represents a hydrogen atom, R is as defined for formula I and Ra has the same meaning as R1 in formula I, with the exception of vinyl groups, unsubstituted alkyl groups having up to 3 carbon atoms, methyl groups having one or two phenyl substituents, and ethyl groups substituted by a hydroxy, ether, or acyl group, or an S-containing nucleophilic group; (iii) a compound of the general formula XII

in which Rb represents an unsubstituted or substituted alkyl group having 3 or more carbon atoms, or a substituted methyl or substituted ethyl group; ; (iv) a compound of the general formula XIII

(v) a compound of the general formula XIV

in which R2c has the R or S configuration and represents a methyl, ethyl, hydroxymethyl or 1hydroxyethyl group or a halogen atom, a hydroxymethyl or 1-hydroxyethyl group or a halogen atom preferably being trans to the 1 -oxa group, and Rc1 represents a methyl or substituted methyl group.

A substituted methyl group Rb or Rc is especially a -CH2N3 or -CH2SCN group, a -CH2NHCOR14 or -CH2OCOR14 group wherein R14 represents a lower alkyl group which may be substituted as defined above for Rt, a -CH2Hal or -CH2SHet group wherein Hal represents a halogen atom and Het represents an aromatic or non-aromatic heterocyclic group which may be substituted, especially one of those described above as substituents for Rt.

The following are examples of compounds that may be prepared from a compound of the present invention: TABLE I

In the above compounds R represents a free or esterified carboxyl group especially a free carboxyl group or a p-nitrobenzyloxycarbonyl group and R1 represents-CH3,-CH2N3,-CH2SCN, -CH2NHCOR15 wherein R15 represents a lower alkyl group, -CH2OCOR15, -CH2B and H2SHet wherein Het represents an aromatic or non-aromatic heterocyclic group, which is especially as described above.

A process for the production of compounds of the general formula I is described and claimed in our co-pending application No. 79.10487.

All of the compounds that are described herein may exist in any appropriate isomeric form, as discussed above, either as a pure isomer or as a mixture of any two or more isomers.

The present invention also provides the salts of those compounds of the invention that have saltforming groups, especially the salts of free acids of formulae II and Ila and the acid addition salts of appropriate compounds of formulae II and Ia. The salts are especially physiologically tolerable salts, for example, alkali metal and alkaline earth metal salts, ammonium salts and salts with an appropriate organic amine; also physiologically tolerable acid addition salts with suitable inorganic and organic acids, for example, hydrochloric acid, sulphuric acid, carboxylic and organic sulphonic acids, for example, trifluoroacetic acid and p-toluene-sulphonic acid.

The compounds of formula I and p-lactamase inhibitors, and also possess antibacterial properties themselves.

The following Examples 5 to 8 illustrate the invention. In them, temperatures are expressed in degrees Ceisius and ratios of solvents for chromatography are by volume. Examples 1 to 4 and 7 illustrate the preparation of starting materials and intermediates, and Examples 9 to 18 illustrate the production of compounds of formula I.

Example 1: 4-Nitrobenzylpenicillanate (Vl)

(a) Penicillanic acid (VI) 1 6.7 g of 6,6-dibromopenicillanic acid (VII) were taken up in a solution of 3.9 g of sodium bicarbonate in 250 ml of water and the solution was filtered. 8.5 g of 5% Pd/CaCO3 were added, and the mixture was then hydrogenated at atmospheric pressure with vigorous shaking for 3 hours. TLC analysis (silica gel, chloroform-ether-formic acid 7:2:1) showed the absence of starting material.

The catalyst was removed by filtration through Hyflo Supercel, and the filter bed was washed well with sodium bicarbonate solution (4x50 ml). The combined filtrates were acidified to pH 2, and extracted with ether (6x 100 ml). The combined ether extracts were washed with brine (2x200 ml), dried (MgSO4), and evaporated to leave a pale yellow oil (6.9 g, 74%). This material was unstable and was converted to the ester as soon as possible.

#(CDCl3) 1.57 (3H, s, CH3), 1.70 (3H, s, CH3) 3.05 (1H, dd, J5,6ss2Hz, 6ss-H), 3.62 (1H, dd, J,BAHz, J1 6Hz, (6a-H) 4.47 (1 H, s, 3-H), 5.27 (1 H, dd, 5-H), 9.95 (1 H, s, -COOH).

(b) 4-Nitrobenzylpenicillanic acid (VI) To 6.9 g of penicillanic acid (VI) in 70 ml dimethylacetamide at 0 was added 3.1 g of diisopropylamine. 6.5 g of 4-nitrobenzyl bromide in 20 ml dimethylacetamide was added over 5 minutes and the reaction mixture was stored at 0 for 18 hours.

The white crystalline precipitate was filtered off and the filtrate poured into water (200 ml) whereupon the mixture was adjusted to pH 2 by addition of hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 100 ml) and the extracts washed with dilute hydrochloric acid (pH 2, 2x 100 ml), water (4x 100 ml), sodium bicarbonate (2x50 ml), water (2x50 ml), and brine (2x50 ml).

The organic solution was dried over magnesium sulphate and the solvent evaporated to leave a yellow solid. The solid was triturated with ethyl acetate-ether and dried to leave a white solid (6.2 g). A second crop of crystals yielded further product (0.3 g).

Total yield 6.5 g; 41% on 6,6-dibromopenillianic acid, m.p. 134C (from diethyl ether) y max (CCl4) 1793, 1760 cm-1 3 (CDC13) 1.43 (3H, s, CH3), 1.67 (3H, s,CH3), 3.05 (1 H, dd, J5,6ss2Hz, 6P-H), 3.62 (1 H, J5,6&alpha;4Hz, sQ 16Hz, 6Hz, 6&alpha;-H), 4.53 (1 H, s, 3-H), 5.27 (3H, m, -CH2, 5-H), 7.4-8.4 (4H, m, C6H4).

m/e 336 (M+), 114 (base peak) Example 2: 4-Nitrobenzylpenicillanate 1-oxide

To 6.1 g of 4-nitrobenzylpenicillanate (Vla) in 100 ml ethyl acetate at 0 was added 3.51 g of 3 chloroperbenzoic acid (85% pure solid) in 35 ml ethyl acetate dropwise over 20 min keeping the temperature < 50. The reaction was checked for completion by TLC (silica gel, chloroform-ether-formic acid 7:2:1), then the white precipitate was filtered off and washed with ethyl acetate and ether. Yield 2.62 g.

The filtrate was washed with sodium bicarbonate and brine, dried (MgSO4) and the solvent evaporated. Trituration with ether gave 2.94 g of a white solid, shown to be a mixture of a(R) and p(S) sulphoxides, with the p-sulphoxide predominating.

Total yield 5.65 g, 87%, m.p. 1470 (from ethyl acetate) #max (CHCl3) 1793, 1757 cm-1 # (CDCl3)ss-sulphoxide 1.15 (3H, s, &alpha;-CH3), 1.67 (3H, s, ss-CH3, 3.33 (2H, d, J5,6 3Hz, (6&alpha;, 6ss-H), 4.45 (1 H, s, 3-H), 4.9 (1 H, t, 5-H), 5.25 (2H, s, -CH2-), 7.3-8.2 (4H m, C6H4) a-sulphoxide 1.33 (s, &alpha;-CH3), 1.55 (s, ss-CH3), 3.55 (m, 6&alpha;, 6ss-H), 4.75 (m, 5-H) m/e (352 (M+), 336 (M-O), 136 (base peak, -CH2PhNO2).

Example 3: 4-Nitrobenzyl-2-[4R-(2-benzthiazolyl-dithio)-2-oXo-1 -azetidinyl]-2-(1 -propen-2-yl)-acetate

14.1 g of 4-nitrobenzylpenicillanate 1-oxide (IV) and 6.84 g of 2-mercaptobenzothiazole (V) (98% pure) were heated for about 6 hours in refluxing toluene (250 ml) under nitrogen until TLC analysis (ethyl acetate-cyclohexane 1:2) showed reaction was complete.

The cold reaction mixture was washed with saturated sodium carbonate (1 x40 ml), water (5x50 ml) and brine (2x50 ml), dried (MgSO4) and the solvent evaporated. The product was triturated with ethyl acetate-ether to give a pale yellow solid which was filtered off and dried in vacuo.

Yield 13.7 g (68%).

m.p. 121 (from ethyl acetate).

#max (CH2Cl2) 1778, 1748 cm-1 # (CDCl3) 1.94 (3H, S, CHa), 3.4 (2H, m, 3-H), 4.88, 5.02 (2H, 2s, =CH2), 5.2 (4H, m, -CH2-, 2'- H, 4'-H), 7.2-8.4 (8H, m, C6H4) m/e 334 (M-1 67), 303 (M-167-S), 166 (base peak) Found: C 52.5%; H 3.8%; N 8.5% Calculated: C 52.7%; H 3.8%; N 8.4%.

Example 4: 4-Nitrobenzyl-2-[4S-(2-benzthiazolyl-thio)-2-oxo-1 -azetidinyl]-2-(1 -propen-2-yl)-acetate (I lla)

To 1.0 g of 4-nitrobenzyl-2-[4R-(2-benzthiazolyldithio)-2-oxo-1-azetidinyl]-2-(1-propen-2-yl)- acetate (III) in 3 ml dichloromethane at room temperature was added, with stirring, 0.55 g of triphenylphosphine. The mixture was stirred for 30 minutes then diluted with an equal volume of hexane. The total solution was chromatographed on silica gel, using a dichloromethane-hexane mixture as eluent. Excess triphenylphosphine and triphenylphosphine sulphide eluted first. The eluent was then changed to dichloromethane and compound Illa (4 parts) and its N-bonded isomer (compound IX) (1 part) eluted as a mixture.Fractions containing compounds Illa and IX were combined and solvent evaporated to give a foam (0.675 mg), which was recrystallized from ethyl acetate-cyclohexane (1:1 v/v) to give a white solid (0.38 g, 41%) m.p. 1 10 . By NMR analysis the solid was shown to be the pure compound Illa. The stereo-chemistry at C a was established by further experiments.

More extensive chromatography of the mixture of compounds Illa and IX gave pure compound IX as an oil.

4-Nitrobenzyl-2-[4S-(2-benzthiazolyl-thio)-2-oxo-1-azetidinyl]-2-(1-propen-2-yl) acetate (lila) 8(CDCI3) 1.92(3H,S,CH3),3.18(1H,dd,J3&alpha;,42.5Hz,3&alpha;-H) 3.69 (1H, dd, J3ss,45Hz, J3&alpha;,3ss15Hz, 3ss- H), 5.0 (3H, m, =CH2, 2-H), 5.28 (2H, s, -CH2-), 5.78 (1 H, dd, 4ss-H), 7.2-8.4 (4H, m, C6H4).

#max(CCl4) 1784, 1755 cm-1 m/e 469 (M+),

136 (base peak)

Found: C56.1; H4.0; N9.1%; m/e469.0741 Calculated: C 56.3; H 4.1; N9.0%; m/e 469.0767 Example 5: 4-Nitrobenzyl-2-[4S-(2-benzthiazolyl-thio)-2-oxo-1-azetidinyl]-3-hydroxycrotonate (lla)

1.28 g of 4-Nitrobenzyl-2-[4S-(2-benzthiazolylthio)-2-oxo- 1 -azetidinyl]-2-(1 -propen-2-yl)acetate (Illa) in 30 ml dry dichloromethane at-10 was treated with an air-ozone mixture until TLC analysis (silica gel, ethyl acetate-cyclohexane 1 :1), showed the absence of starting material. The solution was then flushed with air followed by the addition of 1.68 g of dimethyl sulphide, and the mixture stirred for 1 hour.The solvent was then evaporated off and the oily residue was chromatographed on silica gel using dichloromethane-ethyl acetate (9:1) as eluent. Fractions containing the enol were combined and evaporated to give the product as a white foam.

8(CDCla) 2.17 (3H, s,--CH3), 3.17 (H, dd, Jtrans 3Hz 3a-H) 3.69 (1 H, dd, Jcis. 6Hz, Jgem 15 Hz, 3ss-H),5.33 (2H, s, -CH2-), 6.05 (1 H, dd, 4-H), 7.3-8.4 (8H, m, C6H4).

m/e 471 (M+), 277, 262, 167 (base peak).

Found: m/e 471.0499 C21H17N3O6S2 requires m/e 471.0559 Example 6: 4-Nitrobenzyl-2-[4R(2-benzthiazolyl-dithio)-2-oxa-1 -azetidinyl]-3-hydroxy-crotonate (ll)

2.0 g of 4-nitrobenzyl-2-[4R-(2-benzthiazolyldithio)-2-oxo-1-azetidinyl]-2-(1-propen-2-yl)- acetate (III), in a mixture of 45 ml dry dichloromethane and 15 ml dry methanol were cooled to a temperature of from-50 to-78 in a dry ice-acetone bath. An air-ozone mixture was passed through the solution until the analysis (silica gel, ethyl acetate-hexane 1:1) indicated the absence of starting material. 2.0 g of dimethyl sulphide were added at -78 and the solution allowed to warm to room temperature. The solvent was evaporated in vacuo and the residue chromatographed over silica gel using ethylacetate-hexane mixtures as eluent to give pure enol 1.72 g 86% as a colourless foam.

Ymax 1780 cm-1 d(CDCI3) 2.15 (3H, s, CH3),3.1 (1H, dd, J3ss,42Hz, 3ss-H), 3.5 (1 H, dd, J3a,44Hz, J3&alpha;,3ss16Hz,3&alpha;-H), 5.0-5.35 (3H, m, -CH2, 4-H), 7.08-8.4 (8H, m, C6H4), 12.8(1H,s,-OH) m/e 265, 200, 167 (base peak,

167 (-CH2C6H4NO2) Found: C 50.0; H 3.6; N 8.2 Calculated: C50.1; H3.40; N8.3. Example 7: 4-Nitrobenzyl-2-[4R-(2-pyridyl-dithio)-2-oxo-1-azetidinyl]-2-(1-propen-2-yl)-acetate (III)

To a solution of 2 g of 4-nitrobenzylpenicillanate 1-oxide (IV) in 40 ml dry toluene was added 0.63 g 2-mercaptopyridine. The mixture was refluxed under nitrogen for 1.5 hours.The solvent was then evaporated off in vacuo, and the residue was chromatographed on silica gel, eluting with ethyl acetate-hexane to yield pure disulphide 1.932 g (76%) as a colourless syrup.

#max (CHCl3) 1770, 1750 cm-1 #(CDCl3) 1.95 (3H, bs, CH3),3.11(1H, dd J3ss,3&alpha;16Hz, J3ss,43Hz,3-H) 3.44 (1 H, dd,J3&alpha;,3ss16Hz, J3a,44Hz, 3-H) 4.87 (1 H, s,2'-H),5.02-5.29 (3H, m, 4-H, =CH2) 5.35 (2H, s, -CH2-) 7.06-8.70 (8H, m, aromatics).

Example 8: 4-Nitrobenzyl-2-[4R-(2-pyridyl-dithio)-2-oxo-1-azetidinyl]-3-hydroxy-crotonate (II)

0.65 g of 4-nitrobenzyl-2-[4R-(2-pyridyldithio)-2-oxo-2-azetidinyl]-2-(1-propen-2-yl)-acetate in 10 ml dry dichloromethane at -78 were treated with an air-ozone mixture until TLC indicated complete loss of starting material (silica gel, ethyl acetate-hexane). 0.25 ml methyl sulphide were added at 780 and the solution was allowed to warm to room temperature. The solution was evaporated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetatehexane to give the pure crotonate 11 (0.356 9,54.8%) as a colourless oil.

Ymax 1770, 1665 cm-1 b(CDCI3) 2.16 (3H, s, CHa) 3.03 (1H, dd J3&alpha;,3ss15HZ,J3ss,43Hz, 3-H), 3.43 (1H, dd J3&alpha;,3ss15Hz, J3&alpha;,45Hz, 3-H), 5.14(1H, dd J3Hz, 5 Hz, 4-H), 5.15 (1H, d,J 13 Hz,-CH2-), 5.43 (1H, d J 13 Hz, -CH2-) 7.00-8.63 (8H, m, aromatics). 12.22 (1 H, s,-OH).

Example 9: 2-Methyl-3-(4-nitrobenzyloxycarbonyl)-oxapenem (I)

To 35 m g of 4-nitrobenzyl-2-[4S-benzthiazolylthio-2-oxo-1-azetidinyl]-3-hydroxycrotonate (ill) in 0.7 ml CDCla was added 6.4 yI pyridine followed by 25 mg of silver methylsulphonate and the mixture was stirred for 20 minutes at room temperature, then the reaction mixture was centrifuged and the supernatant was examined by NMR spectroscopy and TLC. Both analyses clearly indicated the presence of the oxapenem I, by comparison with a known sample.

Example 10: 2-Methyl-3-(4-nitrobenzyloxycarbonyl )-oxapenem (I) The procedure of Example 9 was carried out except that 6.5 yl of pyridine were used, and 38.1 mg of silver trifluoromethylsulphonate was used instead of the silver methylsulphonate. Both NMR and TLC analyses indicated the presence of the desired oxapenem.

Example 11: 2-Methyl-3-(4-nitrobenzyloxy'carbonyl)-oxapenem To a stirred solution of 0.338 g of silver carbonate and 0.428 g of triphenylphosphine in 4 ml dry chloroform was added dropwise a solution of 0.80 g of 4-nitrobenzyl-2-[4R-benzthiazolyldithio-2-oxo- 1-azetidinyl]-3-hydroxy-crotonate in dry chloroform. The resulting mixture was stirred at room temperature for half an hour and then chromatographed directly (short path rapid chromatography, silica gel H, methylene chloride/hexane) to give 0.195 g (41% of the theoretical yield) of 2-methyl-3 (4-nitrobenzyloxycarbonyl)-oxapenem as a colourless, crystalline solid.

#(CDCl3)2.32(3H,s,CH3)3.42(1H,ddJgem 17Hz Jtrans 1 6-H) 3.86 (1 H, dud gem 17HZJcis 2.5 Hz, 6-H) 5.22 (1H,ABdJ 14Hz,-CH2-) 5.50(1H,ABDJ 14Hz,-CH2-) 5.93 (1H, dd Jtrans 1HzJ 2.5Hz, 5H),ymax=1810, 1710,164Ocm1,mp 128.5129 C.

Example 12: 2-Methyl-3-(4-nitrobenzyloxycarbonyl)-oxapenem To a suspension of 0.024 g of silver oxide and 0.028 g of triphenylphosphine in 0.2 ml deuterochloroform was added dropwise a solution of 0.050 g of 4-nitrobenzyl-2-[4R benzthiazolyldithio-2-oxo-1 -azetidinyl]-3-hydroxy-crotonate in 0.4 ml deuterchloroform. After 10 minutes the reaction mixture was centrifuged, and NMR spectroscopic examination of the supernatant confirmed the presence of 2-methyl-3-(4-nitrobenzyloxycarbonyl)-oxapenem as the main product.

Example 13: 2-Methyl-3-(4-nitrobenzyloxycarbonyl)-oxapenem To a stirred solution of 0.05 g of 4-nitrobenzyl-2-[4R-benzthiazolyldithio-2-oxo-1 -azetidinyl]-3- hydroxy-crotonate and 0.0134 g of copper acetylacetonate in 0.4 ml deuterochloroform was added 0.0267 g of triphenylphosphine in 0.1 ml deuterbchloroform. After 5 minutes the solution was centrifuged. NMR spectroscopy of the solution showed 2-methyl-3-(4-nitrobenzyloxycarbonyl)- oxapenem as the major product. TLC analysis confirmed this result.

Example 14: 2-Methyl-3-(4-nitrobenzyloxycarbonyl)-oxapenem A solution of 0.05 g of 5-nitrobenzyl-2-[4R-benzthiazolyldithio-2-oxo-1-azetidinyl]-3-hydroxy- crotonate and 10 ,ul deuteropyridine in 0.5 ml deuterochloroform was added to a stirred solution of 0.028 g of triphenylphosphine and 0.0201 g of silver methane-sulphonate in 0.3 ml deuterochloroform. After 5 minutes the reaction mixture was centrifuged to remove the precipitated solid, and NMR spectroscopy of the supernatant showed that 2-methyl-3-(4-nitrobenzyloxycarbonyl)oxapenem was the major product. TLC analysis confirmed this result.

Example 15: 2-Methyl-3-(4-nitrobenzyloxycarbonyl)-oxapenem To a solution of 0.05 g of 4-nitrobenzyl-2-[4R-benzthiazolyldithio-2-oxo-1-azetidinyl]-3-hydroxy- crotonate in 0.5 ml deuterochloroform was added 0.028 g of triphenylphosphine in 0.1 ml deuterochloroform. The solution was shaken at room temperature. NMR indicated the formation of 2methyl-3-(4-nitrobenzyloxycarbonyl)-oxapenem and 4-nitrobenzyl-2-[4S-benzthiazolylthio-2-oxo- 1 azetidinyl]-3-hydroxy-crotonate in the ratio 1:4.

Example 16: 2-Methyl-3-(4-nitrobenzyloxycarbonyl)-oxapenem To a solution of 0.075 g of 4-nitrobenzyl-2-[4-pyridinedithio-2-oxo-1-azetidinyl]-3-hydroxy- crotonate in 4 ml dry methylene chloride was added 0.045 g of triphenylphosphine in 1 ml dry methylene chloride. The solution was stirred for 1.5 hour, evaporated in vacuo, and NMR analysis of the residue showed the formation of 2-methyl-3-(4-nitrobenzylcarbonyl)-oxapenem and 4-nitrobenzyl2-[4-pyridinethio-2-oxo-1-azetidinyl]-3-hydroxy-crotonate in the ratio 1:1. The residue was then chromatographed on silica gel (2 g) eluting with ethyl acetate-hexane mixtures to afford triphenyl phosphine sulphide then 10 mg of 2-methyl-3-(4-nitrobenzyloxy)-carbonyl-oxapenem as a colourless oil which crystallised on standing.

3'max 1810 cm-l mp 128.5-1290C.

Example 17: 2-Methyl-3-(4nitrnbenzyloxycarbonyl)-oxapenem To 33 mg of 4-nitrobenzyl-2-[4S-benzth iazolylthio-2-oxo- 1 -azetidinyl]-3-hydroxycrotonate in 0.5 ml of chloroform was added, at room temperature, excess sodium hydride, followed by 25 mg of silver trifluoromethylsulphate, and the mixture was stirred for 6 1/2 hours. The solid by-products were filtered off and the solvent was evaporated to give a crystalline solid, shown by TLC and NMR analysis to be 2-methyl-3-(4-nitrobenzyloxycarbonyl)-oxapenem.

Example 18: 2-Methyl-3-(4nitrobenzyloxycarbonyl)-oxapenem To 200 mg of 4-nitrobenzyl-2-[4S-benzthiazolylthio-2-oxo- 1 -azetidinyl]-3-hydroxy-crotonate in 5 ml of dry chloroform was added, with stirring, 47 mg of triethylamine. After 1 minute, 220 mg of freshly ground silver trifluoromethylsulphonate was added at room temperature, and the mixture was stirred for 1 5 minutes. The precipitate was removed by centrifugation and the solution applied to a short-path silica-gel column. Rapid elution with dichloromethane-hexane gave fractions containing 2methyl-3-(4-nitrobenzyloxycarbonyl)-oxapenem. These fractions were combined and evaporated under reduced pressure to give 27 mg of the product as a white solid.

Example 19: Sodium salt of 2-methyloxapenem To a solution of 0.10 g of 2-methyl-3-(4-nitrobenzyloxycarbonyl)-oxapenem in 7 ml ethyl acetate was added 0.10 9 of palladium on charcoal (10% by weight) and a solution of 0.027 g of sodium bicarbonate in 7 ml of water. The reaction mixture was hydrogenated until the reaction was judged complete (TLC), then the aqueous solution washed with ethyl acetate then lyophilized to afford the sodium salt of 2-methyloxapenem.

Claims (27)

Claims

1. A compound of the general formula II and/or a compound of the general formula Ila

in which R represents a free or esterified carboxyl group, R1 represents a hydrogen atom or a straight or branched chain, unsubstituted or substituted aliphatic group, R2 and R3 which may be the same or different, each represents a hydrogen or halogen atom, an amine or substituted amine group, or an unsubstituted or substituted straight or branched chain aliphatic group, and Z represents an acyl radical derived from an organic carboxylic or thio-carboxylic acid.

2. A compound as claimed in claim 1, wherein Z represents a monocyclic five membered thiadiazacyclic, thiatriazacyclic, oxadiazacyclic, oxatriazacyclic, diazacyclic, oxazacyclic or thiazacyclic radical of aromatic character, or a benzdiazacyclic, benzoxacyclic or benzthiazacyclic radical, wherein the heterocyclic moiety is five membered and of aromatic character, a substitutable ring nitrogen atom being optionally substituted.

3. A compound as claimed in claim 1, wherein Z represents 1 -methyl-imidazol-2-yl, 1 ,3-thiazol- 2-yl, 1 ,3,4-thiadiazol-2-yl, 1 ,3,4,5-thiatriazol-2-yl, 1 ,3-oxazol-2-yl, 1 ,3,4-oxadiazol-2-yl, 1,3,4,5- oxatriazol-2-yl, 2-quinolyl, 1 -methyl-benzimidazol-2-yl, benzoxazol-2-yl or benzthiazol-2-yl group.

4. A compound as claimed in claim 1, wherein Z represents an acyl radical derived from an unsubstituted or substituted aliphatic, cycloaliphatic, araliphatic or aromatic acyl or thioacyl group having up to 18 carbon atoms.

5. A compound as claimed in claim 1, wherein Z represents the group

6. A compound as claimed in any one of claims 1 to 5, wherein R' represents an unsubstituted or substituted alkyl, alkenyl, or alkynyl group having up to 8 carbon atoms.

7. A compound as claimed in claim 6, wherein R' represents an unsubstituted or substituted alkyl, alkenyl, or alkynyl group having up to 4 carbon atoms.

8. A compound as claimed in claim 7, wherein R' represents an unsubstituted or substituted methyl group.

9. A compound as claimed in any one of claims 1 to 8, wherein an aliphatic group R' is substituted by one or more substituents selected from halogen atoms; oxo groups; hydroxyl and mercapto groups, alkoxy and alkylthio groups; alkanoylthio groups; carbamoyl and carbamoyloxy groups alkylthiocarbonyl groups; alkanoyloxy and alkanoythio groups; carbamoyl and carbomoyloxy groups and carbamoyl and carbamoyloxy groups substituted by one or two groups selected from alkyl and aryl groups and the corresponding unsubstituted and substituted groups in which the, each or either oxygen atom is replaced by a sulphur atom; nitro, cyano and azido groups; amido and imido groups; imino, amino, mono- and di- alkylamino, mono- and di-arylamino groups, and N,N-alkylarylamino groups; acylamino groups; suiphinyl, sulphonyl and sulphonamido groups; cycloalkyl groups; aryl, aryloxy, arylthio, aryloxycarbonyl, arylthioacarbonyi, arylcarbonyloxyl, arylcarbonylthio, aralkoxycarbonyi, araikylthiocarbonyl, aralkylcarbonyloxy, aralkylcarbonylthio, aralkoxy, and aral kylthio groups; aromatic and non-aromatic heterocyclic groups, aromatic and non-aromatic heterocyclicoxy groups and aromatic and non-aromatic heterocyclicthio groups.

1 0. A compound as claimed in claim 9, wherein R' represents a methyl group substituted by one or more halogen atoms, an esterified or etherified methyl group, a methyl group substituted by a -SHet group in which Het represents an aromatic or non-aromatic heterocyclic group, a methyl group substituted by an amino, mono- or di-lower alkylamino group, mono- or di-arylamino group or lower alkylarylamino group, or a methyl group substituted by an acylamino group.

11. A compound as claimed in any one of claims 1 to 10, wherein one of the radicals R2 and R3 represents a hydrogen or halogen atom and the other represents an unsubstituted or substituted straight or branched chain aliphatic group.

12. A compound as claimed in claim 11, wherein an aliphatic group is a lower aliphatic group.

13. A compound as claimed in claim 11 or claim 12, wherein an aliphatic group R2 or R3 is substituted by an amino, mercapto, or hydroxyi group, which may itself be substituted.

14. A compound as claimed in claim 13, wherein an amino, mercapto or hydroxyl group is substituted by one of the following groups: -R10, -CO-NR10R, -C0-R10, -CO-OR10, -SO2-R10, -SO2-OR10, SOae, and in the case of an amino group

in which groups R'O and R11, which may be the same or different, if appropriate, each represents an alkyl, aryl or aralkyl group, or a nitrogen atom present as a substituent of R2 or R3 or in the group -CO-NR10R11 may be present as part of an aromatic or non-aromatic heterocyclic ring.

1 5. A compound as claimed in any one of claims 1 to 14, wherein R represents a carboxylic acid esterified with an aliphatic, cycloaliphatic, cycloaliphaticaliphatic, aryl or araliphatic alcohol having up to 18 carbon atoms.

1 6. A process for the production of a compound of the general formula II or Ila as claimed in claim 1, which comprises (a) converting a compound of formula III

in which R, Ri, R2, R3 and Z are as defined in claim 1, into the corresponding enol of formula II, or (b) converting a compound of formula Illa

in which R, R', R2, R3 and Z are as defined in claim 1, into the corresponding enol of formula Ila, or (c) treating a compound of formula II with a tervalent organophosphorus compound to give the corresponding compound of formula Ila.

17. A process as claimed in claim 16, wherein the compound of formula Illa is produced by desulphurizing the corresponding compound of formula Ill as defined in claim 16 by treatment with a tervalent organophosphorus compound.

18. A process as claimed in claim 16 or claim 17, wherein a compound of formula lil is produced by reacting a compound of formula IVc

in which R, R2 and R3 are as defined in claim 1, with a compound of formula V H-S-Z (V) in which Z is as defined in claim 1.

19. A process as claimed in claim 18, wherein a compound of formula IVc in which R' represents a methyl group is produced by oxidising a compound of formula VI

in which R, R2 and R3 are as defined in claim 1.

20. A process as claimed in claim 19, wherein the compound of formula VI is prepared from a compound of the general formula VIII

in which X and Y are the same and each represents a halogen atom, or X represents a hydrogen atom and Y represents a halogen atom, and R is as defined in claim 1, by catalytic hydrogenation to give a compound of formula VII in which R2 and R3 both represent hydrogen atoms, or by introducing one or two radicals R2 and R3.

21. A process as claimed in claim 20, wherein the compound of formula VII is produced from 6amino-penicillanic acid by treatment with nitrous acid and a halogenating agent.

22. A process as claimed in claim 1 6 or claim 17, wherein the tervalent organophosphorus compound has the general formula PR4R5R6 wherein R4, R5 or R6, which may be the same or different, each represents a straight or branched chain unsubstituted or substituted hydrocarbon group, or a straight or branched chain unsubstituted or substituted hydrocarbon group which one or more carbon atoms are replaced by hetero atoms.

23. A process as claimed in claim 22, wherein the tervalent organophosphorus compound is triphenylphosphine, tributylphosphine, trimethylphosphite or triethylphosphite.

24. A process as claimed in claim 22, wherein in PR4R5R6 one or more of the groups R4, R5 and R6 comprises an insoluble polymer.

25. A process as claimed in claim 22, wherein in PR4R5R6 one or more of the groups R4, R5 and R6 comprises a cationic or anionic centre.

26. A process as claimed in claim 16, carried out substantially as described in any one of Examples 5 to 8 herein.

27. A compound of formula II or Ila as claimed in claim 1, whenever produced by a process as claimed in any of claims 1 6 to 26.