GB2179350A

GB2179350A - Penem derivatives

Info

Publication number: GB2179350A
Application number: GB08620063A
Authority: GB
Inventors: Michael David Cooke; Stephen Connolly
Original assignee: Hoechst UK Ltd
Current assignee: Sanofi Aventis UK Holdings Ltd
Priority date: 1985-08-16
Filing date: 1986-08-18
Publication date: 1987-03-04
Also published as: GB8620063D0; GB2179350B

Description

SPECIFICATION 7-Oxo-4-thia-l -azabicyclo[3.2.0]hept-2-ene derivatives This invention relates to 7-oxo-4-thia-1 -azabicyclo-[3,2,0]hept-2-ene derivatives, to a process for their preparation, to pharmaceutical preparations comprising them, and to intermediates for use in the preparation of substances having antibacterial activity and/or p-lactamase inhibitory and/or inactivating activity.

The penicillins as a ciass have in common the p-lactam structure A known semi-systematically as the "penam" nucleus. The introduction of a double bond between carbon atoms 2 and 3 in this structure gives rise to the "penem" nucleus B.

The penem nucleus B is given the systematic name "7-oxo-4-thia-1 -azabicyclo[3,2,0]hept-2-ene", with the numbering as shown in formula C. Aside chain at position 6 is numbered as shown in formula D.

It iswell known that penicillin antibiotics have been used extensivelyfor manyyearsto combat bacterial infections in humans and other animals. The first ofthe penicillin antibiotics to come into general therapeutic use was benzylpenicillin, and this compound still finds widespread use today.

There is, however, a continuing need for new antibiotics, not only to combat bacterial pathogens that do not respond satisfactorily to treatment with conventional penicillins, but also to combat those strains of bacteria which, although once susceptibleto penicillin treatment, are now resistantto such therapy. Accord- ingly, in the search for new types of antibiotics, the discovery of compounds which possess a wide spectrum of activitytogetherwith an ability to combat infections caused by penicillin-resistant organisms is an importantgoal.

Various specifications disclose penem derivatives having a phenyl or substituted phenyl group at the 2- position. EP 000221 0A describes penem derivatives having a wide selection ofsubstitutents at the 2-and 6-positions, as does GB 2042 515A. EP 0 002 210A includes in a Table of compounds those having a 1hydroxyethyl group at position 6 and a phenyl, aminomethylphenyl, aminophenyl ortrifluoromethylphenyl group at position 2.

2 S1SAsimilarly includes in a Table of compounds a 6-hydroxyethyl penem derivative having a phenyl group at position 2, that phenyl group being unsubstituted. EP 0070 204A discloses penems with certain very specific substituted phenyl groups at the 2-position in combination with a hydrogen atom or an optionally protected hydroxyethyl group at position 6. Those Examples that relate to substituted phenyl groups at position 2 do so in combination with a hydrogen atom at position 6.

We have made and tested certain 6-hydroxyethyl-2-substituted phenyl derivatives disciosed generally in the prior art, and we have found that although they have activity in a representative antibacterial screen,there remains a need for compounds having higher activities.

The present invention provides a compound offormula I

in which R represents a hydrogen atom ora carboxylicacid esterifying group R1 represents (i) one ofthefollowing groups

in which Ra and Rb, which may be the same or different, each represents an alkyl group having from 1 to 4 carbon atoms, or (ii) a -CONH(CH2)mQ or - NHCO(CH2)mQ group, in which m represents an integer offrom 1 to 3, and Q represents one of the following groups

in which Rc represents a methyl or ethyl group, or (iii) a -CO2Rd group, in which Rd represents a methyl or ethyl group which is unsubstituted or is substituted by one or more substituents, which may be the same or different, selected from (a) halogen atoms and vinyi groups, (b) phenyl groups which are unsubstituted or are substituted by one or more groups selected from alkoxy groups having from 1 to 4 carbon atoms, nitro groups and halogen atoms, (c) silyl groups SiReRfRg,the groups Re, Rf and Rg being the same or different, each representing a phenyl group oran alkyl group having from 1 to 4 carbon atoms, and (d) groups Qas defined above; or (iv) a -CO2SiReRfRg group, in which Re, Rf and Rg are defined as in (c) above, or (v) a -CO2-phenyl group, in which the phenyl moiety is unsubstituted or substituted as defined in (b) above; R2 represents (i) a hydrogen atom, (ii) a group as defined above for R1 (R1 and R2 being the same or different), or (iii) a chlorine, bromine or iodine atom, an alkyl group having from 1 to 4carbon atoms, an -NH2, -NHRa or -NRaRb group, an -OH or -ORa group, or an -OCOCH3 group, Ra and Rb being defined as above, and R3 represents a hydrogen atom or a hydroxy protecting group; and in which R1 and R2, independently of each other, may be in any position on the phenyl ring; and salts thereof; and isomers thereof.

In a compound offormula I, a protected carboxy group -COOR is preferably esterified carboxy group that can be converted by hydrolysis, by photolysis, by oxidation, by reduction or, especially, by esterase enzyme action, to give the free acid offormula I. Moreover, in a compound offormula I, a hydroxy protecting group R3 is preferably a group that can be converted by hydrolysis, by photolysis, by reduction or, especially, by esterase enzyme action, to give a compound offormula I having a free 8-hydroxy group. Details of such carboxyand hydroxy protecting groups are given below.

Groups that can be removed by esterase action are groups that can be cleaved in vivo. Compounds having such groups are known as "prodrugs". Preferred compounds of formula I are those in which, independently, R represents a hydrogen atom, a physiologically tolerable saltforming group, ora groupthat can be cleaved in vivo to give the free carboxy group or a carboxylate group, and R3 represents a hydrogen atom or a group that can be cleaved in vivo to give the free hydrogen group.

The present invention provides salts of a compound offormula I, especially physiologically tolerable salts thereof. A salt may be formed atthe2-carboxylic acid group or at any acidic or basic centre present. More over, when both an acidic centre and a basic centre are present, a compound offormula I may exist in a zwitterionic form. A carboxylic acid salt of a compound offormula I is preferable to the free acid if solubility is important.

In the definitions of R1 and R2, an alkyl group Ra or Rb is preferably a methyl or ethyl group, especiallya methyl group. The symbol "m" preferably denotes the integer 1 or 2.

Of the groups R1 given above, the following are preferred

Ra, Q and m being as defined above, and especially having the preferred meanings given above. Particularly preferred as R1 are -CO NH2, -CONHCH3, -NHCHO and -NHCOCH3 groups.

Acompound offormula I may exist in various isomericforms, all of which are part ofthe present invention, for example, a substituent R1 may be present at any position on the phenyl ring when R2 represents a hydrogen atom. When R2 represents otherthan a hydrogen atom, R1 and R2 may occupy any two positions on the ring, subject to known constraints regarding, for example, stereochemical considerations. Moreover, some substituents R1 and R2 may themselves exist in various tautomeric and/or geometric isomericforms, for example, an oxime may be in syn orantiform. As mentioned above, all isomers are part of the present invention.

The stereochemistry at positions 5,6 and 8 of a compound of formula I can be R or S, independently (Rand S being as defined by the Cahn-lngold-Prelog system of nomenclature). The preferred stereochemistry at position 5 is R, at position 6 is S, and at position 8 is R. 5R, 6S, 8R-stereochemistry is particularly preferred.

The present invention also provides a process for the production of a compound offormula I, which comprises (A) treating a compound offormula 11

in which R3 is as defined above, R4 represents a carboxy protecting group, R5 represents a group R1 as defined above ora group that can be converted into a group R1, R6 represents a group R2 as defined above or a group that can be converted into a group R2, R7 represents a phenyl group oran alkyl group having from 1 to 4carbon atoms,and R8 represents a bromine or chlorine atom, especiallya chlorine atom,with a base; or (B) effecting cyclisation of a compound of formula III

in which R3, R4, R5 and R6 are defined as above, X represents an oxygen or sulphur atom, and the group P(Z)3 represents a group derived from a trivalent organophosphorus reagent, or (C) treating a compound offormula IVorV

in which X, R3, R4, R5, R6 and R8 are defined as above, with a triva!ent organophosphorus compound and effecting cyclisation, or (D) reacting a compound offormula VI

inwhich R3, R4andthe group P(Z)3 are defined as above,and R19 represents Cu(ll), Pb(ll) or Hg(ll), inwhich case n represents 2, or rips representsAg(l), in which case n represents 1, with a compound offormula VII

in which R11 represents an activating group, for example, an activating ester group or, preferably a halogen atom, and especially a chlorine atom, and X, R5 and R6 are defined as above, and effecting cyclisation, and (E) in an appropriate compound in which R5 and/or R6 represents a group that can be converted into a group R1 and/or R2, respectively, converting such a group or groups Re and/or R6 into such a group or groups R1 and lor R2 and, (F) if desired or required, in an appropriate compound converting a group R1 and/or a group R2 into another group R1 and/or R2, respectively; and (G) if desired or required, carrying out any one or more ofthefollowing steps in any desired order: a) hydrolysing a 2-carboxylic ester group in an appropriate compound to give the corresponding free acid, b) treating an appropriate free acid or a salt thereof with an agent capable of forming a 2-carboxylic acid ester, for example, with an alcohol, a phenol or a reactive derivative thereof, to give a 2-carboxylic acid ester thereof, c) carrying outan acid- or base-catalysed ester interchange on an appropriate 2-carboxylic acid ester to give a different ester ofthat compound, d) treating an appropriate free acid compound with a base to give a salt at the carboxy group at position 2, e) treating an appropriate free acid or 2-carboxylic acid ester having a basic group present with an acid to give an acid addition saltthereof, treating a salt of an appropriate compound with an acid to give a free acid ofthatcompound, g) removing a hydroxyprotecting group from an appropriate compound having a protected8-hydroxy groupto give the corresponding compound having a free8-hydroxygroup, h)treating an appropriate compound having a free hydroxy group at the position with an organic acid derivative to form an ester at the 8-position, and i) treating an appropriate compound to effect a change in the stereochemical configuration.

In formula I, R3 may represent a hydrogen atom or a protecting group. In certain of the processes involved in the production of a compound offormula I, it may be preferable to protect the 5-hydroxy group. Similarly, it may be preferable or essential to protect the 2-carboxy group during the formation of a compound offormula I. Hydroxy and carboxy protecting groups and methods fortheir introduction and removal are known (that is to say, in actual use in the art or described in the literature of the art) see, for example, McOmie, Protecting Groups in Organic Chemistry, Plenum Press, London, 1973 and T.W. Greene, Protective Groups in Organic Synthesis, J. Wiley & ons Inc. 1981. Hydroxy and carboxy protecting groups preferably used in the present invention and methods for their introduction and removal are described in more detail below.

Hydroxy and carboxy protecting groups may be present independently of each other in a compound of formula I orin any intermediate involved in the formation thereof. Moreover, protecting groups may be introduced and removed at any appropriate point in a reaction sequence.

A compound offormula II is treated with a baseto give a compound offormula I or a precursor thereof. The carboxy group in the compound offormula I is protected, but the hydroxy group may be free or protected. The base may be inorganic or organic, for example, ammonia, oran alkali metal, especially a sodium orpotassium, carbonate, bicarbonate, or hydroxide; a primary amine, for example, methylamine, ethylamine, ani line or benzylamine; an alkali metal alkoxide, for example, sodium methoxide; or a heterocyclic base, for example, having a pKa within the range offrom 5 to 9, forexample, imidazole, pyridine or a substituted pyridine, for example, an alkyl-, amino-, monoalkylamino- or dialkylamino-substituted pyridine,forexample, 4-methylpyridine or 4-dimethylaminopyridine. Imidazole is particularly preferred.

The reaction is generally carried out in a solvent or diluent, the choice of which is wide, provided that itis inert under the reaction conditions. Examples of solvents and diluents are oxygenated hydrocarbons, for example, ethers, for example, having up to 4 carbon atoms, for example, diethyl ether, also tetrahydrofu ran and dioxane; ketones, for example, having up to 4 carbon atoms, for example, acetone and methyl ethyl ketone; esters, for example, methyl acetate and ethyl acetate; and amides, for example, dimethylformamide and dimethylacetamide; also chlorinated hydrocarbons, for example, chloroform, methylene chloride and carbon tetrachloride; aromatic hydrocarbons, for example, benzene and toluene; and other solvents for example, acetonitrile and nitromethane.A mixture oftwo or more solvents may be used, and solvents are preferably used in admixture with water; preferably a water-miscible solvent is used in admixture with 5to 20C (v/v) water.

The reaction is generally carried out at a temperature within the range of from 0 to 40 C, preferably from 0 to 20 C.

Acompound offormula la, that is to say, a compound analogous to compound I but having groups RCand R6, may be prepared as shown in the following Reaction Scheme I: REACTION SCHEMEI

in which R3, R4, R5, R6 R7 and R8 are defined as above, R9 represents an alkyl group having from 1 to 8, preferably from 1 to 4 carbon atoms, an alkenyl group having from 2 to 4 carbon atoms, or a phenyl group, and R10 represents a group -SO2-Rh or -CORh in which Rh represents an alkyl group having from 1 to 4 carbon atoms, an optionally substituted phenyl group, or a polyfluoroalkyl group, especially a tri fluoromethyi group.

Some compounds of for mula VIII are known, see for example, GB2 102 798A and Belgian Patent 887,886.

Other compounds of formula VIII may be prepared analogously.

To obtain compound IX, compound VIII is reacted, in the presence of a base, with an activated carboxylic acid derivative of formula VIIa

in which R5, Re and R11 are as defined above.

Many compounds offormula Villa are known, and the others may be prepared by methods analogous to those described for the preparation of the known compounds, see for example, Organic Syntheses, Collective Volume 4, page 715, Wiley, NewYork, 1963, or Collective Volume 2, page 528,1943.

The reaction between compound VIII and compound Vlla is carried out in the presence of a base, preferably having a pKa#20, preferably a metallated amine, and examples of preferred bases are lithium diisopropylamide, lithium hexamethyldisilazide, lithium 2,2,6,6-tetramethylpiperidide, lithium cyclohexyl isopropylamide, and sodamide.

The reaction is generally carried out in an aprotic solvent, for example, an oxygenated hydrocarbon, preferably an ether,forexample, diethyl ether,tetrahydrofuran, dioxane, glyme ordiglyme. The reactiontemperature is, for example, from -120 to +30 C, preferablyfrom -78 to -20 C.

The amount of base used is, for example, from 1 to 3 moles, calculated per mole of compound VII I, preferably from 1 .5to 2.5 moles of base. The compound of formula Villa is preferably used in an amountoffrom 1 to 1.5 moles per mole of compound VIII, preferably from 1 to 1.1 moles of compound Vlla per mole of compound VIII.

The reaction may be carried out as follows: The base may be added to a stirred solution of compounds VIII and Vlla. Alternatively,to a stirred solution of compound VIII under an inert atmosphere is added the base and subsequently a solution of compound Vlla in the same ora different solvent.

Compound IX is generally obtained in the form of a mixture of isomers generally comprising theE, Z and oxo isomers. Such isomers may be separated, but this is not generally necessary. (The terms E and Z are as defined on page 142 of Allingeretal, eta!, "Organic Chemistry" 1971,Worth, New York.) Compound IX is reacted, in the presence of a base, with a compound offormula XII R10 - R11 (all) in which R10 is as defined above, and represents, for example, a methylsulphonyl, phenylsulphonyl orpolyfluoroalkylsulphonyl group, especially a trifluoromethylsulphonyl group, or a trifluoroacetyl group and R represents an activating group as defined above, to produce a compound offormula X.

The base used in the reaction between compounds IX and XII may be organic or inorganic and is, for example, a tertiary amine, for example, a trialkylamine, especiallytriethylamine orethyldiisopropylamine, or a heterocyclic base, for example, pyridine oran alkyl-, dialkyl-, amino, monoalkylamino- ordialkylaminosubstituted pyhridine, for example, 4-dimethylaminopyridine. The reaction is generally carried out in a solvent or diluent, for example, a chlorinated hydrocarbon, for example, dichloromethane, an ether, for example, diethyl ether ortetrahydrofuran, or an ester, for example, ethyl acetate. Thetemperature of the reaction is generally within the range offrom -80to + 200C. Compound X is generally produced in the form of a mixture of isomers generally comprising the E- and Z-isomers.Such isomers may be separated, but this is not generally necessary.

Compound X is converted into compound Xl by reaction with a compound offormula XIII R7COSH (mull) in which R7 is as defined above and preferably represents a methyl or, especially, t-butyl group. Compound XIII is preferably in the form of a reactive derivative thereof, for example, as an alkali metal, alkaline earth metal or organic amine salt. Compound XIII may be converted into salt form in situ.

The reaction between compound X and compound XIII is generally carried out in a polar solvent, for example, acetonitrile, dimethylformamide or dimethyl sulphoxide. The reaction temperature is generally within the range of from 0 to 400C, conveniently room temperature.

The -SCOR10 group in the resulting compound offormula Xl maybe or Z to the -COOR4 group. The isomers may be separated for the subsequent reaction, but this is not generally necessary, and the isomeric mixture is generally used as both isomers give a compound offormula I.

The resulting compound Xl is then halogenated to give a compound of formula II, using an agent capable of splitting a carbon-sulphur bond and of introducing a halogen atom. Such agents are well known in the artand include, for example, molecular chlorine, sulphuryl chloride, t-butyl hypochlorite, cyanogen chloride and molecular bromine.

The reaction is generally carried out at a temperature within the range offrom -60 to +20 C. The reaction is generally carried out in a solvent or diluent that is non-protic, and is inertunder the reaction conditions, forexample, an ether, a hydrocarbon or a halogenated hydrocarbon, for example, dioxane, benzene, chloroform or dichloromethane. A mixture of two or more solvents may be used. Examples of halogenating systems are: chlorine in chloroform, chlorine in benzene and t-butyl hypochlorite in benzene. In the lattertwo cases,the temperature is preferably from 5to 20"C, and normally from 5to 10 C. Generally, 1 to 2 moles ofthe halo genating agent are used per mole of compound Vlla, cf. S. Kukolja, J. Amer.Chem.Soc. (1971), 93, 6267and P.C. Cherry, C.E. Newall and N.S. Watson, J.C.S. Chem.Comm. 1979 p. 663.

The resulting compound offormula II may be converted into a compound of formula las described above.

In the Reaction Scheme I described above, it is preferable that the 8-hydroxy group in compound VIII is protected, to prevent itfrom reacting with the activated acid derivative offormula Vlla. The hydroxy group is also preferably protected during the reaction between compound IX and compound XII. A hydroxy protecting group may be retained in compounds XI and II, but it has been found that if a compound offormula Xl having S-stereochemistry at position 3 and having a protected hydroxy group at position 8 is halogenated, the resulting compound offormula I has the less desirable 5S stereochemistry, and it is then necessary to change the sterochemistry at position 5, for example, by heating under reflux, ifthe 5R stereochemistry iswanted.

Accordingry, it is generally preferableto protectthe 8hydroxy group until compound X has been formed, and to remove the hydroxy protecting group before halogenating compound Xl to give compound II.A hydroxy protecting group may be removed from compound X before it is converted into compound Xl, orit may be removed afterformation of compound Xl.

One type of preferred protected group -OR3 is that from which the protecting group R3 can be removed under acidic conditions. Such protected groups are well known in the art and are, for example, tetrahydropyranyloxy and tetrahydrofuranyloxy groups; acetal and ketal groups, for example, offormula

in which R12 and R13, which may be the same or different, each represents a hydrogen atom or a loweralkyl group, preferably a methyl group, or R'2 and R'3togetherwith the carbon atomsto which they areattached, represent a cycloalkyl ring having from 4to 7 carbon atoms, and R'4 represents a lower alkyl group, preferably a methyl or ethyl group, or R12 and R14, together with the carbon atom and the oxygen atom to which they are attached, respectively, represent a tetrahydropyranyl ring; also silyl ethers, for example, havingthreesubsti- tuents on the silicon atom, and preferably up to 24 carbon atoms in total, the thrne substituents being the same or different, and selected from alkyl, alkenyl and cycloalkyl groups, and phenyl and phenalkyl groups which may be unsubstituted or substituted as defined above, for example, -OSiReRfRg groups, in which Re, Rf and Rg are as defined above, that is to say, they may be the same or different, and each represents an alkyl group having from 1 to 4 carbon atoms ora phenyl group, for example, giving trimethylsilyloxy,triethylsilyloxy, diphenyl-t-butylsilyloxy, dimethyl-t-butylsilyloxy, and methyldiphenylsilyloxy groups.

Preferred hydroxy protecting groups R3 are tetrahydropyranyl, 2-methoxyprop-2-yl, trimethylsilyl and, especially, triethylsilyl and t-butyldimethylsilyl groups.

Such groups may be removed by acid hydrolysis, for example, using 0.1 to 2M, preferably 0.5M hydrochloric acid, for example, using the appropriate amount of 6M HCI in,forexample,tetrahydrofuran, cf. Belgian Patent Specification No. 012; n-Bu4N F in an acidic medium, for example, in acetic acid, of. Belgian Patent Specification No. 882 764; or aqueous hydrogen fluoride, for example, in the presence of acetonitrile, cf. J.

Chem. Soc. Perkin 1, 1981,2055.

Acompound offormula Ia may be produced from a compound offormula Ill, IV, VorVI, as shown in the following Reaction Scheme II: Acompound offormula Ill will cycliseto give a compound offormula I at room temperature if leftfor sufficient time, but generally heat is applied to accelerate the reaction. The cylisation is preferably carried out in a solvent, for example, an ether, for example, diethyl ether, dioxane ortetrahydrofuran, an aromatic hydro carbon, for example, benzene, toluene orxylene, a halogenated hydrocarbon, for example, chloroform or dichloromethane, or dimethylformamide or dimethyl sulphoxide. The temperature used may befrom room temperature to the reflux temperature of the reaction mixture.

A compound of formula III may be produced from a compound of formula IV, V or VI, as shown in Reaction Scheme II, and may be isolated, if desired. Each of compounds IV, V and VI may, however, give a compound of formula la directly, also as shown in Reaction Scheme II. In general, if compound offormula IV, VorVI is reacted at lowertemperatures, a compound offormula III is formed, and may be isolated and then preferably heated as described above to give a compound of formula la. If higher reaction temperatures are used, a compound of formula la isthe reaction product obtained. The latter reaction may proceed via a compound of formula Ill orvia another intermediate. Further details of these procedures are given below.

REACTIONSCHEMEII

In Reaction Scheme II R3, R4, R5, R6, R8, X and Z are defined as above, and L represents a leaving group, that is to say, a group that can be replaced in a nucleophilic displacement reaction, for example, a halogen atom, especially a chlorine atom; an alkylcarbonyloxy group in whcich the alkyl moiety has from 1 to 4 carbon atoms, has a straight or branched chain, and may be substituted by an electron-withdrawing group, for example, a halogen atom, especially a fluorine atom, for example, an acetoxy ortrifluoroacetoxy group; a phenylcarbonyloxy group, for example a benzoyloxy group; a phenylcarbonyloxy group, for example a benzoyloxy group; or an -SO2Rj group in which Rj represents an alkyl group having from 1 to 4 carbon atoms ora phenyl group. L preferably represents an acetoxy group.

Certain compounds offormula XIV are known, for example, when R3 represents a dimethyl-t-butylsilyloxy group (Beigian Patent Specification No.882764), and when R3 represents a p-nitrobenzylcarbonyl group (EPO 002 210A). Other compounds offormula XIV may be prepared analogously.

Acompound offormula XV may be prepared by reacting a compound offormula XIV with a compound of formula XVII

in which X, R5 and R6 are defined asabove,and M represents a hydrogen atom oran alkali metal oralkaline earth metal atom, oran ammonium group that is unsubstituted or substituted by, for example, one to four groups selected from alkyl groups having from 1 to 4 carbon atoms. (When M represents hydrogen the reaction is carried out in the presence of a base, see below).

Compound XVII is generally prepared in situ and is not generally isolated before reaction with compound XIV.

AcompoundXVll may be prepared (i) by reacting a compound offormula VII

in which X, R5, Re and R11 are defined as above, with a compound offormula MSH or M2S, in which M isas defined above, (when M represents hydrogen the reaction is carried out in the presence of a base, for example, pyridine or a tri-alkylamine in which each alkyl moiety has from 1 to 4 carbon atoms); or (ii) by reacting a compound offormula XVIII

in which M1 represents an alkali metal or alkaline earth metal radical,togetherwith a counter-ion, if required in the case where M1 represents a diva lent metal ion, with carbon disuiphide orcarbon oxysulphide, giving a compound offormula XVII in which M represents an alkali metal or alkaline earth metal atom.

In process (ii) above, the compound offormula XVIII is an organo-metallic derivative, for example, a phenyl lithium or phenyl magnesium halide derivative, and may be prepared, for example, by using the corresponding phenyl halide, especially the phenyl bromide or iodide, with the appropriate metal,for example, lithium or magnesium, in an inertsolventordiluent,forexample, an ether,forexample, diethyl ether, oran aromatic hydrocarbon, for example, toluene, or by using a metal-alkyl compound, for example, n-butyllithium ort butyllithium, in an inert solvent, for example, an ether, for example, diethyl ether ortetrahydrofuran.

In each ofthe processes (i) and (ii) above, the reaction is generally carried out in a solvent that is inert under the reaction conditions, for example, in an ether, for example, diethyl ether, dioxane ortetrahydrofuran, an aromatic hydrocarbon, for example, benzene, toluene orxyiene, or a halogenated hydrocarbon, forexample, chloroform, carbon tetrachloride or dichloromethane.

Acompound offormula XV is then acylated using a compound offormulaXIX

in which R4 is as defined above and R15 represents a group that can be displaced by the azetidinone nitrogen in the compound offormula XV to give a compound offormula IV.

Agroup R15 is, for example, a halogen atom, an imidazolidegroup, ora mixed anhydride group,forexample, a group -OCORk or -OC(O)ORk in which Rk represents a straight or branched chain alkyl group having from 1 to 4 carbon atoms. R15 preferably represents a halogen atom, especially a chlorine atom.

The reaction between compound XV and the acylating agent offormula XIX is carried out in the presence of a base, for example, atertiary amine, preferablyatrialkylamine (each alkyl moietyhavingfrom 1 to 4carbon atoms and having a straight or branched chain, the three alkyl moieties being the same or different), and especiallytriethylamine or ethyldiisopropylamine; or pyridine or a substituted pyridine, for example, 4- dimethylaminopyridine. Particularly preferred bases aretriethylamine and ethyldiisopropylamine. A mixture oftwo or more bases may be used, and a base may be polymer-bound.

In addition to an organic base as described above, it is preferable to include an acid binding agent in the reaction mixture. Examples of acid binding agents are alkali metal and alkaline earth metal carbonates and bicarbonates, and organic epoxides, for example, propylene oxide. Calcium carbonate is a commonly-used binding agent.

In general, for each mole of compound XV there is used from 1 to 2 moles of the acylating agent XIX, from 1 to4 moles ofan amine base (ora total offrom 1 to 4 moles of a mixture ofamine bases), and from Oto 10 moles ofthe acid binding agent, if present.

The compound offormula XV and the acylating agent offormula XIX are generally reacted in a solventor diluentthat is inert to the reaction, for example, in a halogenated hydrocarbon, for example, dichloromethane or chloroform, in an oxygenated hydrocarbon, for example, an ether, for example, tetrahydrofuran, dioxane or diethyl ether, or in an aromatic hydrocarbon, for example, benzene ortoluene.The reaction is generally carried out at a temperature within the range of from -20 to +60 C, preferably from 0 to 20"C.

Compound IV, the product ofthe acylation reaction, may be isolated if desired, but is generally reacted withoutfurther purification with a trivalent organophosphorus reagent to give a compound offormula Ill orto give a compound offormula la directly.

Compound IV may alos be obtained by oxidation of a compoundformulaXXVll

in which R3, R4, R5, R6 and X are defined as above.

Asuitable oxidising agent is ozone or a higher oxide of a metal for example, a higher oxide of a metal selected from one of Groups la, Vb, Vlb, Vllb or VIII of the periodic table of the elements (seethe CRC Hand book of Chemistry and Physics, 52nd Ed., CRC Press, Cleveland, 1971 for example, osmium tetroxide, ruthe- nium tetroxide, an alkali metal peroxide, for example, potassium superoxide; a periodate, for example, an alkali metal periodate,for example, sodium periodate; or an alkali metal permanganate, for example, potassium permanganate. A combination of two or more oxidising agents, forexample, selected from those particularly described above, may also be used. The reaction is generally carried out at a temperature within the range offrom -80 to +50 C.An inert solvent or diluent may also be used, for example water; a halogenated hydrocarbon, for example, dichloromethane; or acetonitrile. Particularly preferred conditions are ozone in dichloromethane at a temperature of -80to 0 C, potassium permanganate in water at a temperature within the range 0 to +40 C.

A compound offormula XXVII may be obtained by reacting a compound offormula XXXVIII

in which n, R3, R4and R19 are defined as above, with a compound offormula VII in an inertsolventordiluent, for example an ether, for example diethyl ether, tetrahydrofuran ordioxane; a halogenated hydrocarbon,for example chloroform or dichloromethane; acetonitrile; an ester, for example ethyl acetate; or an aromatic hydrocarbon,forexampletoluene. The reaction is generally carried out at a temperaturewithin the range -80 to + 60"C, prefe ra bly from -40 to 20 C.Optionally a base may also be used: examples aretriethylamine, pyridine, and 4-dimethylaminopyridine.

Some compounds of formula XXVIII are known (M. Alpegiani et al, J. Amer.Chem.Soc., 107,6398(1985)), and others may be prepared analogously.

Examples oftrivalent organophosphorus reagents which may be used to convert compound IVto compound III or compound la are phosphites and phosphoramides, for example, of the following formulae XX and XXI, and phosphines offormula XXII in combination with phosphites offormula XX

in which formulae R16, R17, R18 and R19, which may be the same or different, each represents a straightor branched chain alkyl group having from 1 to 6 carbon atoms or a phenyl group which may be unsubstituted or substituted, for example, by a methyl group, especially a para-methyl group; also cyclictrialkyl phosphites, each alkyl moiety having from 1 to 4 carbon atoms, for example, offormula XXIII

in which each group A denotes an alkylene group having from 1 to 4 carbon atoms; and also catechol phosphites and catechol dimer phosphites,for example, of the following formulae XXIV and XXV, respectively:

in which Ra6and A are defined as above. Atrivalent organophosphorus compound may be bound to an inert polymer.

A preferred trivalent organophosphorus reagent is a phosphite or phosphoramide offormula XX or XXI respectively, or a combination of a phosphine of formula XXII with a phosphite offormula XX. Particularly preferred are the trialkyl phosphites, and especially trimethyl phosphite and triethyl phosphite.

When the organophosphorus reagent used is a phosphite or phosphoramide, generallyfrom 2to 3 moles thereof are used per mole of compound IV. When a phosphine is chosen, from 1 to 3 moles are generally used per mole of compound IV, in combination with a phosphite, generally 1 mole thereof. The phosphite is preferably added slowly to a mixture ofthe phosphine and the compound IV.

As described above, a resulting compound offormula Ill may be isolated and then cyclised to a compound offormula la, or a compound offormula IV may be reacted with the organophosphorus reagent and cyclised in sftuto give a compound Ia. In the latter case, the reaction may proceed via compound Ill or via another intermediate.

The cyclisation reaction is generally carried out in a refluxing solvent. When X in compound IV orcompound Ill represents a sulphur atom, preferred solvents are aromatic hydrocarbons, for example, benzene, toluene and xylene, and halogenated hydrocarbons, forexample, dichloromethane, chloroform and 1,2dichloroethane. When X in compound Ill or IV represents an oxygen atom, preferred solvents are benzene, toluene and xylene.

In a compound of formula III, it can be seen that the group -P(Z)3 is derived from the trivalent organophosphorus reagent or mixture of reagents used, which reagent or mixture of reagents is preferably selected from the reagents offormulae XX to XXVI described above. As mentioned above, the or- ganophosphorus reagent may be polymer-bound, in which case a resulting compound offormula III will also be polymer-bound.

Compound la may be produced from compound Xl by an alternative route via compounds XVI, V, and optionally lil as shown in Reaction Scheme II.

By this route, a compound of formuia XV is reacted with a glyoxylic ester offormula XXVI

in which R4 is as defined above, or with a reactive derivative thereof, for example, a hydrate or hemiacetal,a hemiacetal preferably being formed with an alcohol having from 1 to 4 carbon atoms, for example, ethanol.

When a hydrate of a compound offormula XXVI is used, the water formed during the reaction is preferably removed, for example, azeotropically or by use of a dehydrating agent, for example, a molecularsieve.

The reaction is generally carried out in a solvent or diluentthat is inert under the reaction conditions, for example, an ether, for example, tetrahydrofuran, dioxane or diethyl ether, an aprotic solvent, for example, dimethylacetamide or dimethylformamide, or an aromatic hydrocarbon, for example, benzene ortoluene. A mixture of two or more solvents may be used. The reaction is generally carried out at a temperature within the range of from 0 to 100OC. Preferably from 1 to 2 moles of the glyoxylate derivative are used per mole of compound XXII.

The resulting compound offormula XVI is obtained as a mixture ofthe R- and S-isomers atthe > CH-OH group. These isomers may be separated, if desired, but the R,S-mixture is generally used for the next reaction.

In the next step, the alcohol offormula XVI is converted into a halide offormula V. The halogenation may be carried out in a conventional manner using an appropriate agent, for example, thionyl chloride or bromide, phosphorus oxychloride or oxybromide, or a phosphorus halide, for example, phosphorus pentachloride or pentabromide, or a mixture of two or more thereof.

The reaction is preferably carried out in the presence of a base, for example, a heterocyclic base, forexample, pyridine, 4-dimethylaminomethylpyridine, or lutidine, or a trialkylamine, for example, triethylamine or diisopropylethylamine. The base may be polymer-bound.

The reaction is generally carried out in a solvent, for example, an ether, for example, diethyl ether or dioxane. The reaction temperature is generally within the range of from -40to +40 C, preferably room temperature and, if desired, the reaction may be carried out under an inert atmosphere.

The resulting compound of formula V is obtained as a mixture of the R- and S-isomers at the > CH-CI or > CH-Br group. As in the case of compound XVI, the isomeric mixture may be separated into the individual isomers, butgenerallythe R,S-mixture is used.

Acompound offormula V may be converted into a compound offormula la. This reaction may proceed via a compound offormula Ill or via another intermediate. If desired, a compound offormula V may be phosphorylated to give a compound offormula III, which may then be isolated and cyclised to give a compound of formula la.

Acompound offormula V maybe converted into a compound offormula la orofformula Ill by reaction atan appropriate temperature with a trivalent organophosphorus reagent, for example, a compound offormula XX, XXI, XXII, XXIII, XXIV or XXV as described above. (In the present case, a phosphine offormula XX may be used alone.) The reaction is preferably carried out in the presence of a base, for example, an organic amine, for example, atertlary amine, for example, pyridine or a pyridine derivative, or a trialkylamine, for example, triethylamine ordiisopropylethylamine.The reaction is generally carried out in a solvent that is inert underthe reaction conditions, for example, an aromatic hydrocarbon, for example, benzene ortoluene, or an ether, for example, diethyl ether,tetrahydrofuran ordioxane.

The reaction temperature is generally within the range offrom - 10 to 1 50 C. As mentioned above, the use of lowertemperatures, for example, mom temperature or below, generally enables a compound Ill to be isolated, whereas highertemperatures, for example, above room temperature, generally lead to compound la directly.

A compound offormula la may be produced by a third method, which is also shown in Reaction Scheme II.

This method comprises reacting a heavy metal mercaptide offormula VI

in which =P(Z)3, R3 and R4 are defined as above, and R79 represents Cu(ll), Pb(ll) or Hg(ll) in which case n representsthe integer2, or R19 represents Ag(1), in which case n represents the integer 1, with a compound of formula VII

in which R5, R6, R11 and X are defined as above.

A compound offormula VI inwhich Z represents a phenyl group is described in GB 204251 5A,which also described a processforthe production thereof. Other compounds offormula VI may be produced analogously, using the appropriate trivalent organophosphorus reagent.

CompoundsVI and VII are generally reacted in a solvent, for example, an ether,for example, diethyl ether or dioxane, an aromatic hydrocarbon, for example, benzene, toluene orxylene, an ester, for example, ethyl acetate, a halogenated hydrocarbon, for example, dichloromethane or chloroform, or an aprotic solvent, for example, dimethylformamide or dimethylacetamide. The reaction temperature is generally within the range offrom -40 to lOO'C, preferably from Oto 4O0C.

Compound VI may be converted to compound la either viva compound Ill or via another intermediate, or compound VI may be converted into compound III, which maythen be isolated and converted to compound la. Lowertemperatures,for example,from -40"Cto room temperature, generally enable compound Illto be isolated,whereas higher temperatures, for example, from room temperature to 1 50 C, generally lead to com pound.

In all the various intermediates involved in the production of a compound offormula la by the procedures described in Reaction Scheme II, the 8-hydroxy group and the 2-carboxy group, when present, are preferably protected, with removal of the protecting groups preferably being delayed until after compound la has been formed and, if appropriate, until any conversions of groups R5 and/or R6, and any interconversions of groups R1 and/or R2 have been carried out.

As mentioned above, a final product offormula I may have R- or S-stereochemistry at position 5, 5R- stereochemistry being preferred. The stereochemistry at the 6-position is preferably S.

In process (A),the stereochemistry at position 5in compound I is predominantly inverse two that at position 4 in the precursor azetidinone compound II. In the preceding reaction steps shown in Reaction Scheme I, halogenation of compound Xl when R3 represents a radical otherthan a hydrogen atom gives a compound of formula II with a mainly trans relationship between R8 and and the protected hydroxyethyl group atthe 8-position. The resulting penem compound offormula I then has a predominantly cis relationship between the ring sulphur atom and the protected hydroxyethyl group.Conversely, halogenation of a compound of formula XI in which R3 represents hydrogen generally yields a compound offormula II with R8 mainly cisto the free hydroxyethyl group, the resulting compound of formula I being predominantlytrans.

In processes (B), (C) and (D), the stereochemistry of compound I at position 5 is predominantly determined by the stereochemistry ofthe attachment of the sulphur atom at position 4 ofthe azetidinone ring in the precursor compounds III, IV, V and VI. In these compounds, and in the precursor compounds shown in Reaction Scheme II, this sulphur atom is generally almost always trans to the optionally protected hydroxyethyl group at position 3, implying also a trans relationship at the hydrogen atoms at positions 3 and 4. Thus, in Reaction Scheme II, compound I with 6S-stereochemistry will naturally acquire SR-stereochemistry, with the hydrogen atoms at positions 5 and 6 being trans.

In the formation of a compound offormula I, some degree of thermal equilibration at position 5 does occur, and this effect can be used in the production of compounds having a different relationship between the hydrogen atoms at positions 5 and 6. In particular, the equilibration process is facilitated, for example, by heating,forexample, in a solvent or diluent at atemperature generally within the range offrom 60to 150 C, especially at the reflux temperature ofthe solvent system used.

As mentioned above, R5 and/or Re may represent a groupthatcan be converted into a group R1 and/orR2, respectively. Such a group R5 and/or Re may be converted into the appropriate group R1 and/or R2 in any compound in which it appears, such a conversion being partofthe presentinvention.

Moreover, a group R1 and/or a group R2 may be converted into another group R1 and/or R2. As described above for R5 and R6, such a conversion may be carried out on any ofthe compounds containing such groups, and such a conversion is also part of the present invention.

The possibility of modifying substituents on the phenyl ring is particularly useful for the production of compoundsofformula I having a substituent R1 and/or R2that is potentially unstable in any ofthe reactions involved in the production of compound I, or incompatiblewith anyofthe reagents used. In such a case,a group R5and/or R6, or another group R1 and/or R2, may function as a protected form ofthe desired group, or there may be used a different but stable or compatible group that can be converted into the desired group.

The conversion step is, accordingly, carried out after the reaction or reactions in which the desired substituent is potentially unstable or incompatible.

Although a conversion may be carried out, if appropriate, on a precursor of a compound offormula I, it is generally preferable to retain convertible group(s) until after formation of a compound offormula I orformula la. (As shown above, a compound offormula la is a compound analogous to compound I but having groups R5 and/or R5 that can be converted into groups R1 and/or R2, respectively.) In a compound of formula I or la, a conversion may be carried out before or after the removal of a protecting group from the 8-hydroxy group, and before or after the removal of a 2-carboxy protecting group, having regard to the potential reactivity of a free hydroxy group and of a free carboxy group in the reaction under consideration.

Examples of such conversions (including conversions of radicals forming a part of a larger group) arethe following: (i) -COORd, -COOSiReRfRg or -COO-phenyl to -COOH (ii) -COOH to -CONH2, -CONHRa or -CONH(CH2)mQ (iii) -COOH to -COOR4 or -CO2CH2Q or -CO2CH2CH2Q or -CO2CH(CH3)Q (iv) -COOH to -CORa (v) -NHRm or -NRmRn in which Rm and Rn are protecting groups, to -NH2 (vi) -NH2to

(vii) -CONRaRm, Rm being a protecting group,to -CONHRa (viii) - N3 to - NH2, which is then optionally converted to a group R1 as described in (v) above, (ix) halogen to -CN or -COOH (x) -SRa to -SORa or -SO2Ra (xi) -CN to -CH2NH2, which is then optionally converted to a group as defined in (v) above.

(xii) -SORa to -SO2Ra (xiii) - NO2 to -N H2, which may then converted further as described in (vi) above.

The conversions described above may be used in any appropriate combination, for example, conversion of a halogen atom to a nitrile group which may then be converted into an aminomethyl group, which may be reacted further. In some cases, the group that is converted may not be a group R1 or R5 itself, but may be a moiety forming part of such a group, for example, an -NH2 group may be a group Qas defined above orthe terminal moietyofa group 0.

Many of the methods for carrying out such reactions are knownperse in the art, fdrexample, (i) a carboxy protecting group may be removed by conventional methods, for more details, see below; (ii) a carboxy group may be amidated using an amine and a condensing agent, for example, a carbodiimide, or by reacting an amine with an activated carboxylic acid derivative, for example, an active ester or an an- hydride (symmetrical or asymmetrical), oran acid chloride; (iii) a carboxylic acid group may be esterified using an alcohol and an activated carboxylic acid derivative, for example, an active ester, acid an hydride or acid chloride; (iv) a carboxy group may be converted to a ketone by reaction with an alkyllithium compound, forexample, RaLi;; (v) and (vii) a protected amine group may be deprotected by conventional methods, for example, as descri bed in McOmie,loc. cit. and in Greene1loc. cit.; (vi) substitution ofthe amine group by an acyl group oran alkyl or substituted alkyl group as defined in (vi) may be carried out conventionally, for example, an amino group may be acylated with, for example, an acid chloride oran acid an hydride, for example, acetyl chloride or acetic anhydride, or with the appropriate acid derivative; (viii) an azide group may be converted into an amino group by catalytic reduction;; (ix) a halide, especially an iodide, may be treated with an organometallic compound, for example, an or ganolithium compound, especially t-butyllithium, the resulting complex being treated with cyanogen to give the -CN group; (x) an alkylthio group may be oxidised, preferably with a carboxylic peracid, especiallym-chloroperbensoic acid, to give the corresponding alkylsulphinyl oralkylsulphonyl group; (xi) a cyano group may be converted to an amino group by reduction, for example, using a metal hydride, which amino group is then reacted further as described above (xii) an alkylsulphinyl group may be oxidised to an alkylsulphonyl group as described in (x) above; (xiii) a nitro group may be reduced to an amino group by noble metal catalysed hydrogenation, for ex ample, using platimum or 10% palladium on carbon, c.f. M.Freifelder, Catalytic Hydrogenation in Organic Synthesis, Wiley Interscience, 1978, page 26, and P.N. Rylander, Catalytic Hydrogenation over Platinum Metals, Academic Press, 1967, Chapter 11, and the amino group is then reacted further as described in (vi) above.

In process (A), and in Reaction Scheme I, it is not generally necessary to protect the 8-hydroxy group, and the special considerations regarding protection and deprotection ofthe 8-hydroxy group in the formation of a compound offormula II are discussed above. In processes (B), (C) and (D), and in Reaction Scheme II, however, it is generally preferable to protect the 8-hydroxy group, and to remove the protecting group as one of the lastsleps in theformation of compound 1. Accordingly, in compounds offormulae III, IV, V,VI, XIV, XVand XVI, R3 preferably represents a hydroxy protecting group.

As mentioned above, hydroxy protecting groups and methods for their introduction and removal are well known see, for example, McOmie loc citand Greene loccit.

Particularly useful hydroxy protecting groups R3 and methods for their removal are described in detail above.

In a compound offormula I, the 8-hydroxy group, if esterified, is preferably esterified with a group that can be removed in vivo to give the free hydroxy group, that is to say, an ester group that can be removed under physiological conditions. Examples of suitable esterifying groups are carboxylic acid acyi groups oftheformula R20CO- in which R20 represents a hydrogen atom ora straightorbranched chain alkyl group having from 1 to 6 carbon atoms, especially a methyl, ethyl or t-butyl group, or represents a phenyl group ora phenoxyalkyl group in which the alkyl moiety is straight-chained or branched and has from 1 to 4carbon atoms, and is especially a methylene group.

A non-physiologically removable protecting group R3 is generally removed from a resulting compound of formula I, and may be replaced by a physiologically removable group, if desired. In some cases, a carboxylic acid acyl group R3 mayfulfil a protective role during the synthesis of compound I. Such a dual function protective group may be removed, retained or replaced in formula I, as desired.

An ester group at the 8-position may be the only ester group present, or it may be present in addition to an ester group at the 2-carboxyl group. As mentioned above, a physiologically removable group may be present asa protecting group R3duringtheformation of a compound offormula I, or it may be introduced atthefree 8-hydroxy group of a compound offormula I, after removal of a non-physiologically removable hydroxy protecting group, if present. An esterifying group may be introduced at the 8-hydroxy group by a reaction with an organic acid derivative in known manner. A particularly convenient method is to react a compound of formula I with an activated acid derivative, for example, an acid anhydride in the presence of an organic base, for example, 4-dimethylaminopyridine.

As indicated above, a compound offormula I may be in the form of an ester at the carboxy group at position 2. Such an ester is particularly one that can be converted into the free acid by hydrolysis, photolysis, reduction oxidation or esterase enzyme action. Examples of such esters arethoseformed with unsubstituted orsubstituted aliphatic alcohols or phenols having up to 20 carbon atoms in total.In an esterified carboxygroup -COOR, the group R may be, for example, a straight or branched chain substituted or unsubstituted alkyl, alkenyl or alkyl group having up to 18 carbon atoms, preferably up to 8 carbon atoms, and especially up to 6 carbon atoms, for example, a methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, tert-butyl,n- pentyl, n-hexyl, allyl or vinyl group. An aliphatic group R, especially a methyl or ethyl group, may be substituted, for example, by an acyloxy group (further details of such groups are given below); by an aminoalkanoyloxy group; byan optionally substituted amino group; or, inthe case of a methyl group, by one ormore unsubstituted or substituted phenyl groups. A phenyl group, eitheras a phenol or as a substituent of a methyl group, may be substituted, for example, by one or more substituents, selected from methoxy and nitro groups and halogen atoms. Examples of phenyl substituted-aliphatic groups, are benzyl, nitrobenzyl, meth oxybenzyl, dimethoxybenzyl, benzhydryl and trityl groups.

As indicated above, an ester group is especially one that can be removed by hydrolysis, photolysis, oxidation, reduction or enzyme action, or two or more ofthese methods may be used, for example, reduction followed by hydrolysis. A group R that can be removed readilywithout substantial degradation of the restof the molecule is particularly useful as a carboxy protecting group R4. Examples of esters that are readily split by reduction are trichloroethyl esters, and phenyl substituted-methyl esters, which may be unsubstituted or substituted, for example, benzyl p-nitrobenzyl, benzhydryl and trityl esters.

Reduction of an ester, for example, a phenyl substituted-methyl ester, for example, a p-nitrobenzyl ester, may be carried out using hydrogen and a metal catalyst,for example, a noble metal catalyst, forexample, platinum, palladium or rhodium, which catalyst may be supported,forexample, on charcoal orkieselguhr.

Such reductions may be carried out in the presence of a salt forming agent, for example, sodium or potassium bicarbonate, if it is desired to form directly a salt at the 2-carboxylic acid group offormula I.

Alternatively, a p-nitrobenzyl ester may be converted into the corresponding free acid by a two-step method, with an initial reduction ofthe nitro group followed by hydrolysis. The nitro group may be reduced by noble metal catalysed hydrogenation, for example, using platinum, or palladium on carbon, orbya metal reducing agent, for example, zinc in acetic acid. Other metal reducing agents area, for example, aluminium amalgam, and iron and ammonium chloride, see for example, British Patent Specification No. 1,582,960.

Reduction of the nitro group is followed by hydrolysis which may occur in situ during reduction ofthe nitro group orwhich may be carried out subsequently by treatment with an acid or a base.

An o-nitrobenzyl ester may be converted into the corresponding free acid by photolysis.

Certain ester groups may be split off by base hydrolysis, for example, acetylmethyl, acetoxymethyl and phenoxyethyl esters.

Some ester groups may be cleaved by oxidative hydrolysis, for example, the dimethoxybenzyl group.

Other cleavable esters include, for example, silyl esters, for example, trialkylsilyl and trialkylsilyalkyl esters, in which alkyl moieties have, independently, from 1 to 4carbon atoms, for example, trimethylsilyl and trimethylsilylethyl esters.

In the above process, removal of esterifying groups by oxidative and reductive processes may be achieved electrochemically.

There may be used an esterifying group that is removable under physiological conditions, that is to say, the esterifying group is split off in vivo to give the free acid or a carboxylate, for example, an acyloxymethyl or acyloxyethyl ester having from 2 to 12 carbon atoms in the acyl moiety, for example, an acetoxymethyl, 1' (acetoxy)ethyl or pivaloyloxymethyl ester, a 5-methyl-i ,3-dioxalen-2-on-4-yl-methyl ester, an ami noalkanoyloxymethyl ester having from 2 to 12 carbon atoms in the alkanoyl moiety, for example, a glycyloxymethyl, L-valinyloxymethyl or L-leucyloxymethyl ester, or a phthalidyl ester, or a I' (alkoxycarbonyloxy)ethyl ester, for example, a 1 '-(methoxy-carbonyloxy)ethyl or 1' (ethoxycarbonyloxy)ethyl ester, or an optionally substituted 2-aminoethyl ester, for example, a 2diethylaminoethyl or 2-(1 -morpholino)-ethyl ester.

Preferred esters are the p-nitrobenzyl, phthal idyl, pivaloyloxymethyl, ethoxycarbonyloxymethyl, 5-methyl dioxalen-2-on-4-yi-methyl, acetylmethyl, acet-oxymethyl, 1 '-(acetoxy)ethyl, 1 '(acetyl)ethyl and 1' (ethoxy-carbonyloxy)ethyl esters.

An ester at any position in a compound offormula I orofany otherfree acid described herein, maybe prepared by reaction of the appropriate free acid or activated derivative thereof with an alcohol, a phenol ora reactive derivative thereof. The reaction is preferably carried out under mild conditions in order to prevent rupture of the ring system, for example, under neutral or mild acidic or basic conditions, and attemperatures within the range of from -70 to +35 C.

An ester derived from an alcohol may also be produced by reaction of a reactive derivative ofthe alcohol, for example, a halide, for example, a chloride, bromide or iodide, or hydrocarbonsu Iphonyl derivative, for example, a mesyl ortosyl ester, with a salt of an acid offormula I or of anotherfree acid described herein,for example, an alkali or alkaline earth metal salt, for example, a lithium, sodium, potassium, calcium orbarium salt, or an amine salt, forexample, a triethyiammonium salt.The reaction is preferably carried out in a substituted sulphoxide or amide solvent, for example, in dimethyl sulphoxide, dimethylformamide, or hexamethylphosphoramide or, alternatively, an ester may be prepared by reaction of an alcohol or phenol with the acid, for example, in an activated form, for example, in the presence of a condensing agent, for example, dicyclohexylcarbodiimide.

The present invention also provides salts of those compounds offormula I that have salt-forming groups, especially the salts of a free acid offormula I and acid addition salts of compounds offormula I having a basic group. The salts are especially physiologicallytolerablesalts, for example, alkali metal and alkaline earth metal salts, for example, sodium, potassium, lithium, calcium, and magnesium salts, ammonium salts, and salts with organic amines; also physiologicallytolerable acid addition salts. These may be formed with a suitable inorganic or organic acid, for example, hydrochloric acid, sulphuric acid, or an organic carboxylic or organic sulphonic acid, forexample,p-toluene-sulphonic acid.

A salt of a free acid offormula I may be produced by reacting the free acid with the appropriate base in a solvent, preferably under those conditions under which the salt precipitates. A preferred base is potassium 2-ethylhexanoate.

Asalt may be produced directlyfrom an ester by splitting off the ester group under suitable reaction conditions, for example, catalytic reduction of an ester, for example, ap-nitrobenzyl ester, in an aqueous/ organic solvent, for example, comprising water and ethyl acetate, dioxane ortetrahydrofuran, in the presence of a metal salt, especially a metal bicarbonate,forexample, in an equivalent amount or in a slight excess, yields the salt directly.

When an acidic centre and a basic centre are both present in a compound offormula I, the compound may exist in zwitterionicform.

Protecting groups may be introduced or removed at any appropriate point in the reactions involved in the production ofa compound offormula I.

Atanystage in the production ofa compound offormula I, a compound produced may be isolated from the reaction mixture in which itwas prepared and, if desired, purified by the appropriatetechniques used forthe purification of organic compounds, for example, chromatography and crystallisation.

As indicated above, various intermediates may be produced in the form of mixtures of isomers of various kinds. Such mixtures may be separated or resolved at any stage, or an isomeric mixture may be used perse for subsequent reactions.

Acompound offormula I may have the R or S stereochemistry independently at positions 5,6 and 8. Any mixture of two or more isomeric form may be resolved, if desired, or a compound of formulal can be usedin the form of an isomeric mixture. The preferred stereochemistry at position 5 in compound I is generally R, corresponding to thatin naturally occurring penicillins and cephalosporins, at position 6 is Sand at position 8 is R.

Compounds offormula I possess excellent activity against gram positive bacteria and gram negative bacteria. Moreover,the compounds offormula land salts thereof show activity against these organisms in the presence of ss -lactamase enzymes produced by both gram positive organisms, for example,Staphylococcus aureus and gram negative organisms, for example, Enterobactercloacae, thus indicating resistance to these enzymes.

Compounds offormula I are also inhibitors of -lactamase enzymes.

The compounds offormula land physiologicallytolerable salts thereof may be used in humans and other animals to treat, for example, bacterial infections caused by both gram positive and gram negative bacteria, for example, Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, Bacillus substilis and Proteus morganii, some strains of which are resistantto conventional penicillin therapy.

It has been found that compounds offormula I (and esters thereof at the 2-carboxylic acid group) having an esterified hydroxygroup at the position also have antibacterial and/or -lactamase inhibiting properties, in particular since the tester group can be cleaved in vivo by esterases. In addition, esterification at the 8 hydroxygroup can enhance the degree of absorption on oral administration.

Compounds ofthe present formula I have certain advantages with respectto antimicrobial activity compared with the corresponding unsubstituted phenyl and also the 4-chloro-, 4-fluoro-, 4-methoxy-, 4-methylthioand 3-methylthiophenyl compounds for example, SR,3-(3-aminocarbonylphenyl)-6S- (1 R-hydroxyethyl)-7oxo-4-that-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate and the corresponding (4-aminocarbonylphenyl), (3 formylaminophenyl) and (4-formylaminophenyl) com pou nds have g reater antibacterial activity against a variety of microorganisms, particularly p-lactamase producing organisms than do the above comparision compounds, as shown in the Table below: The antimicrobial activity was determined by measuring the Minimum Inhibitory Concentration (MIC).The MIC ofthe compounds was determined by a standard test, the "agar dilution test" according to Lorian (Antibiotics in Laboratory Medicine, Williams and Wilkins, Baltimore/London 1980) as follows: Atwo-fold decreasing concentration series of each compound was prepared in Petri dishes containing 15 ml of Mueller Hinton agar (Difco). One Petri dish containing onlythe MuellerHinton agarserved as control for bacterial growth.Each Petri dish was inoculated with a multi-point inocuiator (Denley), which transferred 0.61 of a 1:100 diluted 18 hours culture ofthe appropriate test bacterium.After 16to 18 hours of incubation at 370C the Petri dishes were exa m ined fo r g rowth of bacteria. The lowest concentration ofthe compound which causes complete inhibition of growth istaken as the MIC exceptthatthe growth of a single colony ora haze is not taken as evidence of growth.

Table ofan timicrobial activity (mg/I)

In all the compounds in the Table below, R3 is hydrogen, R2 is hydrogen, and the stereochem istry is 5R,6S,8R.

Organism R1 = H 4-F 4-Cl 4-NHCHO 3-CONH2 R= H K K K Na Str.pyogenes77A < 0.05 < 0.05 < 0.05 < 0.013 0.013 Str.pyogenes3O8A < 0.05 < 0.05 < 0.05 < 0.013 0.006 Str.faecium D 1.56 3.13 1.56 0.78 1.56 Staph.aureus SG511 0.1 0.19 0.05 0.05 0.05 Staph.aureus285 0.19 0.19 0.1 0.1 0.1 Staph.aureus503 0.1 0.19 0.1 0.1 0.1 Bac.subt.ATCC6633 0.1 0.1 0.05 0.025 0.05 E.coli 055 0.78 1.56 3.13 0.19 0.1 E.coli DCO 3.12 25 25 0.78 0.39 E.coli DC2 0.39 1.56 0.39 0.19 0.1 E.coliTEM 1.56 6.25 12.5 0.39 0.19 E.coli 1507E 1.56 6.25 12.5 0.39 0.19 E.coli KN 126 3.12 6.25 12.5 0.39 0.1 Kl.aerog. 1082E 0.78 1.56 0.78 0.19 0.1 Kl.aorog.1532E 1.56 12.5 12.5 0.39 0.19 Ent.cloacae P99 12.5 25 50 6.25 1.56 Ent.cloacae 1321E 1.56 3.13 6.25 0.39 0.1 Salm.typh. MZII 0.78 3.13 6.25 0.39 0.19 Organism R1= 4-SCH3 3-SCH3 4-OCH3 3-NHCHO 4-CONH2 R= K K K H H Str.pyogenes77A < 0.05 < 0.05 < 0.05 < 0.025 0.013 Str.pyogenes3O8A < 0.05 < 0.05 < 0.05 < 0.025 0.013 Str.faecium D 3.13 1.56 3.13 1.56 1.56 Staph.aureus SG511 (ND) 0.1 0.1 0.1 0.05 Staph.aureus 285 0.19 0.19 0.19 0.19 0.1 Staph.aureus 503 0.19 0.19 0.19 0.19 0.1 Rac.subt.ATCC6633 0.1 0.05 0.1 0.1 0.05 E.coliO55 6.25 3.13 3.13 0.39 0.19 E.coli DCO 50 12.5 25 1.56 0.78 E.coli DC2 0.78 0.39 0.78 0.39 0.39 E.coliTEM 25 6.25 12.5 0.78 0.39 E-coli 1507E 25 6.25 12.5 0.78 0.39 E.coli KN126 12.5 6.25 12.5 0.39 0.39 Kl.aerog 1082E 0.78 0.39 0.78 0.39 0.39 Kl.aerog 1522E 25 6.25 12.5 0.39 0.39 Ent.cloacaeP99 50 50 100 12.5 6.25 Ent.cloacae 1321E 12.5 6.25 12.5 0.39 0.39 Salm.typh. MZII 12.5 6.25 6.25 0.39 0.39 ND implies not determined The present invention accordingly provides a pharmaceutical preparation which comprises a compound of formula I, or a physiologically tolerable salt thereof, ora mixture of two or more such substances as active ingredient, in admixture or conjunction with a pharmaceutically suitable carrier. The preparation may also comprise one or more other pharmaceutically active substances, for example, another antibacterial substance, especially one having a -lactam ring and most especially a cephalosporin antibiotic. The preparations may be in a form suitable for enteral or parenteral administation, for example, for oral, intravenous orintramuscular administration, for example, as tablets, capsules, syrups, our sterile injectable or infusion solutions.

The preparations are advantageously in unit dosage form and preferably comprise from 10 to 2000 mg ofthe active ingredient per unit dose. The daily dosage of the active ingredient is generally from 20 to 8000 mg, in divided doeses,generally upto 4doses.

The invention also provides the use of a compound of formula I or a physiologically tolerable ester orsalt thereofforthe manufacture of a medicamentforthe treatment of bacterial infections.

The invention further provides a method of treating mammals, especially humans, to combat a bacterial infection, which comprises administering to the mammal a compound offormula I ora physiologicallytoler able ester or saltthereof.

The invention further provides a pharmaceutical preparation which comprises an active ingredient as defined above, in unit dosageform.

The invention also provides a pharmaceutical preparation which comprises an active ingredient as defined above, ora physiologically tolerable salt thereof or a mixture of two or more such substances, and one or morefurther pharmaceutically active substances, in unit dosage form. Unit dosages are preferably as descri- bed above.

Compounds offormula I are also useful in the production of the antibacterially active compounds.

Particularly interesting compounds offormula I are (i) 3-(3-aminocarbonylphenyl)-6-(l -hydroxyethyl)-7-oxo-4-thia-1 -azabicyclo[3.2.0]hept-2-ene 2-carboxyl ic acid; (ii) 3-(4-am inocarbonyl phenyl)-6-(1 -hydroxyethyl )-7-oxo-4-thia-1 -azabicyclo[3.2.0]hept-2-ene 2-carboxylic acid; (iii) 3-(3-formylaminophenyl)-6-(1-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene2-carboxylic acid; (iv) 3-(4-formylaminophenyl)-6-(1 -hydroxyethyl)-7-oxo-4-thia-1 -azabicyclo[3.2.0]hept-2-ene 2 carboxylic acid.

Of thess compounds, the 3-aminocarbonylphenyl compound (i) and the 4-formylaminophenyl compound (iv) are particularly preferred.

In each of compounds (i) to (iv) above,5R,6S,8R-stereochemistry is preferred. The compounds may be in the forum of esters or salts as described above.

The present invention also provides compounds of formulae II, III, IV, V, IX, XXI, XV and XVI.

The following Examples illustrate the invention, but are not limiting.

In the Examples, temperatures are given in degrees Celcius, and ratios of solvents are calculated by volume.

Example 1 4-Nitrobenzyl 3-(4-cyanophenyl)-2-(3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-Rethylthioazetidin-2-on- 1-yl'J-3-hydroxypropenoate A mixture of 4-nitrobenzyl 2-{3S-[1 R-(dimethyl(2-methylprop-2-ylsilyloxy)-ethyl]-4R-ethylthioazetidin-2- on-1-yl}acetate (9.659) and 4-cyanobenzoyl chloride (3.979) in tetrahydrofuran (1 OOml) was cooled to -40" and treated with a solution of lithium hexamethyldisilazide [prepared from n-butyl lithium in tetrahydrofuran (1.6M,28.1 Oml ) and hexamethyldisilazane (1 O.46ml)j. The mixture was stirred for 1 hour then glacial acetic acid (4.80g) was added. Evaporation gave a residue which was partitioned between ethyl acetate and water.

The organic layerwas separated, washed with saturated aqueous sodium bicarbonate and brine and evap- orated. Chromatography of the resulting oil with ethyl acetate-hexane mixtures over silica gel afforded the title compound as a brown gum (10.189) whose 1H n.m.r. spectrum showed itwas a complex mixture of E and Z isomers and the corresponding keto-tautomer.

8 (CDCI3) interalia 3.02 (1 H,m) 4.26(1 H,m), 5.62(1 H,d,J = 1.5Hz).

Example 2 4-Nitrobenyl 3-(4-cyanophenyl)-2-[3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl)-4Rethylthioazetidin-2-on-1-yl)-3-(methylsulphonyloxy)propenoate A solution of 4-nitrobenzyl 3-(4-cyanophenyl)-2-(3S-[1 R-(dimethyl (2-methylprop-2-yl) silyloxy)ethyl]-4Rethylthioazetidin-2-on-1 -yl}3-hydroxypropenoate (4.049) in dichloromethane (1 OOml) was cooled to -60 , treated with triethylamine (1.00g)foilowed by methanesulphonyl chloride (1.13g) and stirred for 1 hour. The solution was washed successively with O.SM aqueous hydrochloric acid, saturated aqueous sodium bi- carbonate and brine, and evaporated.The resulting gum was chromatographed with ethyl acetate-hexane mixtures over silica gel to give the product as a pale yellow foam (2.29g) as a mixture of E and Z isomers.

b(CDCI3) 0.00-0.01 (6H,m); 0.96-1.06 (9H,2xs); 2.16-2.46 (6H,m); 2.50 and 2.77 (2H,2q,J = 8.4Hz); 3.08 (3H,2xs); 3.10 and 3.40 (1 H,2xdd,J= 2.6 and 3.0Hz); 4.26 and 4.43(1 H,m); 5.07 and 5.40 (2H,2xAB,Jgem=1 2.9Hz); 7.23-7.27 (1 H,m); 7.56-8.14 (5H,m); 8.21-8.27 (2H,2xd,J = 8.9Hz).

Example 3 4-Nitrobenzyl 3(4-cyanophenyl)-2-[4R-ethylthio-3S-(1R-hydroxyethyl)azetidin-2-on-1-yl]-3-(methylsulphonyloxy)-propenoate Amixture of 4-nitrobenzyl 2-[3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ehyl]-4R-ethylthioazetidin-2ethylthioazetidin-2-on-1 -yl}-3-(methylsulphonyloxy)-propenoate (4.369) in tetrahydrofuran (60m I) was trea ted with water (2.0ml) and concentrated (35%) hydrochloric acid (1 .949) and stirred at room temperaturefor 22 hours. Thetetrahydrofuran was removed in vacuo and the aqueous residue was neutralised with saturated aqueous sodium bicarbonate.After extraction with ethyl acetate, the organic extract was dried over an- hydrous magnesium sulphate and evaporated, and the residue was chromatographed with ethyl acetatehexane mixtures over silica gel to give the title compound (2.26g) as a mixture of E and Z isomers.

3 (CDCl3) 0.96-1.30 (6H,m); 2.30 and 2.60 (2H,2xm); 2.10 (3H,s); 2.98 and 3.28(1 H,2xdd,J = 2.6 and 4.3 Hz); 4.15 and 4.30 (1 H,2xm); 5.05 and 5.31 (2H,2xAB,J = 13.2Hz); 4.74 and 5.33 (1 H,2xd,J = 2.6Hz); 8.22-8.80 (6H,m); 8.10-8.15 (2H,2xd,J = 8.7Hz).

Example 4 4-Nitrobenzyl 3-(4-cyanophenyl)-3-(2,2-dimethylpropanoylthio)-2-[4R-ethylthio-3S-(1Rhydroxyethyl)azetidin-2-on- 1-ylGpropenoate A stirred solution of 4-n itrobenzyl 3-(4-cyanophenyl)-2-[4R-ethylthio-3S-(l R-hyroxyethyl )azetidin- 2-on-1 yl]-3-(methylsulphonyloxy)propenoate (1.329) in acetonitrile (100ml)was treated with potassium 2,2- (dimethyl)thiopropanoate (0.54g). After 4.5 hours the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulphate and evaporated.The resulting gum was chromatographed with ethyl acetate-hexane mixtures over silica gel to afford the title compound as a yellow gum (0.579) which was a mixture of E and Z isomers.

3 (CDCI3) 1.00-1.40 (15H,m); 2.45 and 2.68 (2H,2xm); 3.15 and 3.37(1 H,2xdd,J=2.9 and 4.3Hz); 4.23 and 4.31 (1 H,2xm); 4.93,5.13 and 5.27,5.44 (2H,2xAB,Jgem = 13.0Hz); 4.43 and 5.45(1 H,2xd,J = 2.7Hz); 7.18-7.30 (1 H,m); 7.40-7.68 (5H,m); 8.10-8.26 (2H,m).

Example 5 4-Nitrobenzyl2-f4S-chloro-3S-( 1R-hydroxyethyl)-azetidin-2-on- 1-y,l-3-(4-cyanophen yI)- 3-(2,2dimethylpropanoylthio)propenoate A solution of 4-nitrobenzyl 3-(4-cyanophenyl )-3-(2,2-di methylpropanoylthio)-2-[4R-ethylthio- 3S-(1 Rhydroxyethyl)azetidin-2-on-1 -yl]propenoate (0.57g) in CDCl3 (1 5ml) was cooled to -60 treated with a solution of chlorine in carbon tetrachloride (30mg/ml, 2.5ml) and stirred for 1 hour. The mixture was evaporated and the resulting gum was chromatographed with ethyl acetate-hexane mixtures over silica gel to afford the title compound as ayellow foam (0.34g) as a mixture of E and Z isomers.

3 (CDCl3) 1.10-1.50 (12H,m); 3.47 and 3.58 (1 H,2xdd,J = 4.0Hz and 9.5Hz); 4.25 and 4.49(1 H,2xm); 5.04 and 5.44 (2H,2xAB,Jgem= 12.7Hz); 5.28 and 6.31(1 H,2xd,J= 4.0Hz); 7.18-7.80 (6H,m); 8.16-8.27 (2H,m).

Example 6 4-Nitrobenzyl 5R,3-(4-cyanophenyl)-6S-(1R-hydroxyphenyl)-7-oxo-4-thia- 1- azabicyclo[3.2. 0] hept-2-enecarboxylate To a solution of 4-nitrobenzyl 2-[4S-chloro-3S-(1 R-hydroxyethyl)azetidin-2-on-1-yl]-3- (4-cyanophenyl)-3 (2,2-dimethylpropanoylthio)propenoate (0.049) in dioxane (5mi) was added a solution of imidazole (7 mg) in water (0.5mi) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was chromatographed directly with ethyl acetate-hexane mixtures over silica gel to afford the title compound as a yellow gum (0.03g).

Vmax(CDCI3) 3400 br, 1790 and 1720cm-1 3 (CDCI3) 1.41 (3H,d,J = 6.3Hz); 3.89(1 H,dd,J= 1.6 and 6.3Hz); 4.32 (1 H,m); 5.12,5.33 (2H,AB,Jgem = 13.6Hz); 5.80(1 H,d,J = 1.6Hz); 7.55,7.66 (4H,AA'BB',J = 8.5Hz); 7.50,8.20 (4H,AA'BB', J = 8.5Hz).

Example 7 Potassium 5R, 3-(4-cyanophen yl)-6S- (iR-h ydroxyeth yl)-7-oxo-4-thia- 1-azabicyclo [3.2. Ojhep t-2-ene-2- carboxylate 4-Nitrobenzyl 5R-3-(4-cyanophenyl )-65-( 1 R-hydroxyethyl )-7-oxo-4-thia-1 -azabicyclo [3.2.0] hept-2-ene-2carboxylate (0.11 g) was dissolved in dioxane (1 OmI) and mixed with a solution of potassium hydrogen carbonate (24mg) in water (10 ml). The mixture was hydrogenated at375kPa (4 atm) over 10% paliadium-oncharcoal (0.11g) for 1 hour then filtered through Hyflo*. The filtrate was freeze-dried. The resldue was dissolved in water, washed with ethyl acetate and freeze-dried to give the title compound as a paleyellow powder (0.08g).

3 (D20) 1.31 (3H,d,J = 6.5Hz); 4.02 (1 H,m); 4.25 (1 H,m); 5.82(1 H,d,J = 1.4Hz); 7.55,7.75 (4H,AA'BB',J= 8.1 Hz).

(*Hyflo is a Trade Mark.) Example 8 4-Nitrobenzyl 3-(3-cyanophenyl)-2-[3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-4Rethylthioazetidin-2-on- 1-yl-3-hydroxypropenoate By a method analogous to that described in Example 1, and using 4-nitrobenzyl 2-{3S-[1 R-(dimethyl(2 methyl-prop-2-yl)silyloxy)ethyl]-4R-ethylthioazetidi n-2-on-1 -yl}acetate (1 4.48g), ),3-cyanobenzoyl chloride (5.969), n-butyl lithium in tetrahydrofuran (1.6M, 42.2ml), hexamethyldisilazane (15.70ml), glacial acetic acid (7.209) and tetrahydrofuran (200ml),the title compound was obtained as a brown foam (1 9.479) whose 1 H n.m.r. spectrum showed it was a complex mixture of E and Z isomers and the corresponding ketotautomer.

#max(CDCl3) 1800, 1750 and 1700 cm-1 3 (CDCI3) interalla 3.04(1 H,m); 4.25(1 H,m); 5.60(1 H,d,J = 5.6Hz).

Example 9 4-Nitrobenzyl 3-(3-cyanophenyl)-2-{3S-[1R-dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-4R-ethylthioazetidin2-on-1-yl}-3-(methylsulphonyloxy)propenoate According to the method of Example 2 and using 4- nitrobenzyl 3-(3-cyanophenyl)-2-(3S-[1 R- (dimethyl-(2 [methylprop-2-yl)silyloxy)ethyl]-4R-ethylthioazetidin-2-on-1-yl}-3-hydroxypropenoate (19.47g), triethylamine (4.85g), methanesuiphonyl chloride (5.50g) and dichloromethane (1 50ml) the title compound was obtained as an orange gum (20.47g) comprising a mixture of E and Z isomers.

#(CDCl3) 0.00-0.10 (6H,m); 0.81-0.91 (9H,2xs); 1.09-1.31 (6H,m); 2.41 and 2.66 (2H,2xq,J = 7.5Hz); 3.06 and 3.08 (3H,2xs); 2.94 and 3.28 (1H,2xdd,J = 2.7 and 4.3Hz); 4.13 and 4.31 (1 H,2xm); 5.08 and 5.41 (2H,2xs); 5.01 and 5.43(1 H,2xd,J = 2.7Hz); 7.24-7.28(1 H,m); 7.43-7.74 (4H,m); 7.94-8.28 (3H,m).

Example 10 4-Nitrobenzyl 3-(3-cyanophenyl)-2-[4R-ethylthio-3S-(1R-hydroxyethyl)azetidin-2-on- 1-yl]-3 (methylsulphonyloxy)-propenoate According to the method of Example 3 and using 4-nitrobenzyl 3-(3-cyanophenyl)-2-{3S-[1 R-(dimethyl(2 methylprop-2-yl)silyloxy)ethyl]-4R-ethylthioazetidin-2-on-1 -yl}-3-(methylsul phonyloxy)propenoate (20.47g), water (18.2ml), concentrated (35%) hydrochloric acid (18.1 5g) and tetrahydrofuran (174ml) the title com pound was obtained as a mixture of E and Z isomers in the form of an orange foam.

3 (CDCI3) 1.03-1.38 (6H,m); 2.40 and 2.70 (2H,2xm); 3.19 (3H,s); 3.07 and 3.33 (2H,2xdd,J = 2.7 and 4.3Hz); 4.24 and 4.38 (2H,2xm); 5.13 and 5.39 (2H,2xs); 4.75 and 5.40(1 H,2xd,J = 2.7Hz); 7.56-8.25 (8H,m).

Example 11 4-Nitrobenzyl 3-(3-cyanophenyl)-3-(2,2-dimethyl-propanoylthio)-2-[4R-ethylthio-3S-(1R-hydroxyethyl)azetidin-2-on- 1-ylGpropenoate According to the method of Example 4 and using 4-nitrobenzyl 3-(3-cyanophenyl)-2-[4R-ethylthio-3S- (1 Rhydroxyethyl)azetidin-2-on-1-yl]-3-(methylsulphonyloxy)-propenoate (5.76g), potassium 2,2 (dimethyl)thiopropanoate (2.34g) and acetonitrile (250ml) the title compound was obtained as an orange gum (2.65g) comprising a mixture of E and Z isomers.

3 (CDCI3) 1.40 (15H,m); 2.50 and 2.75 (2H,2xq,J =7.5Hz); 3.13 and 3.42 (1 H,2xdd, J = 2.7 and 4.3Hz); 4.25and 4.35(1 H,2xm); 5.04,5.16 and 5.27,5.40 (2H,2xAB,Jgem = 13.0Hz); 5.43 and 5.44(1 H,2xd,J = 2.7Hz); 7.26-7.40 (3H,m); 7.45-7.84(3H,m); 8.14-8.20 (2H,2xd, J =8.7Hz).

Example 12 4-Nitrobenzyl 2-[4S-chloro-3S-(1R-hydroxyethyl)-azetidin-2-on-1-yl]3-(3-cyanophenyl)-3-(2,2dimethylpropanoylthio)propenoate According to the method of Example Sand using 4-nitrobenzyl 3-(3-cyanophenyl)-3-(2,2dimethylpropanoylthio)- 2-[4R-ethylth io-3S-(1 R-hydroxyethyl)azetidin-2-on-1 -yl)propenoate (1 .39g), chlorine in carbon tetrachloride (33mg/ml, 5.76ml) and CDCl3 (30ml),thetitle compound was obtained as a yellow gum (0.53g) comprising a mixture of E and Z isomers.

#max (CDCl3) 1780 and 1700 cm-1 # (CDCl3) 1.10-1.50 (12H,m); 3.36 and 3.58 (1H,2xdd,J = 4.3 and 9.3Hz); 4.20 and 4.50(1 H,2xm); 5.07 and 5.37 (2H,2xAB,Jgem = 13.6Hz); 5.42 and 6.32 (1 H, 2xd, J = 4.3Hz); 7.16-7.36 (2H,m); 7.47-7.79 (4H,m); 8.14-8.28 (2H,2xd,J = 8.7Hz).

Example 13 4-Nitrobenzyl 5R,3-(3-cyanophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia- 1-azabicyclo J3. 2. Oihep t-2-ene-2- carboxylate According to the method of Example 6 and using 4-nitrobenzyl 2-[4S-chloro-3S-(1R-hydroxyethyl)azetidin2-on-1-yl]-3-(4-cyanophenyl)-3-(2,2-dimethylpropanoylthio)-propenoate (0.53g), dioxane (10ml), imidazole (95mg) and water (1 ml) the tile compound was obtained as a yellow gum (0.1 6g).

#max(Nujol mull)* 3440,2220,1770, and 1700 cm-1 # (CDCl3) 1.40 (3H,d,J = 6.3Hz) ; 3.90 (1H,dd,J= 1.6 and 6.3Hz); 4.31 (1H,m); 5.13,5.32 (2H,AB,Jgem=13.6Hz); 5.80 (1H,d,J = 1.6Hz); 7.43-7.52 (3H,m); 7.66-7.74 (3H,m); 8.18 (2H,d,J = 8.8Hz).

(* Nujol is a Trade Mark).

Example 14 Potassium 5R,3-(3-cyanophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo [3.2.0]hept-2-ene-2carboxylate According to the method of Example 7 and using 4-nitrobenzyl 5R,3-(3-cyanophenyl)-6S-(1 Rhydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.16g), dioxane (10ml), potassium bicarbonate (35mg) water (10ml) and palladium-on-charcoal (0.16g) the title compound was obtained as a pale yellow powder (0.09g).

3 (D20) 1.27 (3H,d, J = 5.8Hz); 3.97 H,dd,J = 1.4 and 4.2Hz); 4.26(1H,m); 5.76 (1H,d,J = 1.4Hz); 7.43-7.97 (4H,m).

Example 15 4-Meth ylthio-thiobenzoic acid To a stirred solution of 4-methylthiobenzoyl chloride (9.829) in dichloromethane (1 50ml) at 0 was added dropwise pyridine (8.5)ml); then after the mixture had been stirred for a further 10 minutes hydrogen sulphide (excess) was bubbled through. After a further 60 minutes stirring the mixture was extracted with saturated aqueous sodium bicarbonate. The aqueous extract was washed with dichloromethane, then acidified to pH2 with dilute hydrochloric acid, and extracted with ethyl acetate. This organic extract was washed with water, and brine, dried over anhydrous sodium sulphate and evaporated in vacuoto afford the title compound as a yellow solid (5.72g).

3 (CDCl3) 2.53 (3H,s); 5.40 (1H,bs); 7.28,7.83 (4H,AA'BB', J = 8.0Hz).

Example 16 3S-{1R-[Dimethyl-(2-methylprop-2-yl)silyloxy]ethyl}-4R-(4-methylthiobenzoylthio)azetidin-2-one To a stirred solution of 4-methylthio-thiobenzoic acid (5.7g) in 1 OOmI acetone was added 1 M sodium hydroxide until the pH was 8.5 followed by a solution of 4-acetoxy-3R-{1 R-[dimethyl-(2-methylprop-2-yl) silyloxy]ethyl)azetidin-2-one (7.41 g) in acetone (1 00ml). After having been stirred for a further 1 hour, the mixture was partitioned between ethyl acetate and water; the organic phase was washed with water, with saturated aqueous sodium bicarbonate, with water, and with brine, was dried over an hydrous magnesium sulphate, and evaporated in vacuo to afford a yellowish solid (11 g) chromatography over silica gel, and elution with ethyl acetate-hexane mixtures afforded the title compound (9.9g).

max (CDCl3) 1770 cm- 3 (CDCI3) 1.23 (3H,d,J = 6.4Hz); 2.52 (3H,s); 3.27(1 H,dd, J = 2.5 and 3.6Hz); 4.30 (1 H,m); 5.46(1 H,d, J = 2.5Hz); 6.50(1 H,bs); 7.25 (2H,d,J = 8.7Hz); 7.81 (2H,d,J = 8.7Hz).

Example 17 4-Nitrobenzyl{3S-[1R-(dimethyl(2-methylprop-2-yl)-silyloxy)ethyl]-4R-(4-methylthiobenzoylthio)azetidin-2 on-1yl}oxoacetate To a stirred mixture of 3S-{1 R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl}-4R-(4- methylthiobenzoylthio)azetidin-2-one (9.89g), calcium carbonate (10g) and diisopropylethylamine (6.27ml) at 0 was added a solution of 4-nitrobenzyl chlorooxoacetate (6.99g) in dichloromethane (1 50ml). Afterthe mixture had been stirred for a further 30 minutes, it was partitioned between water and dichloromethane; the organic layer was washed successively with dilute hydrochloric acid, with water, and with brine, and was dried over anhydrous sodium sulphate.Evaporation of the solvent afforded the title compound (15.6g) as an orange oil.

3 (CDCI3) 0.09 (6H,s); 0.82 (9H,s); 1.26 (3H,d,J=6.3Hz); 2.53 (3H,s); 3.63(1 H,t, J = 3.0Hz); 4.40(1 H,m); 5.39 (2H,AB, Jgem = 13.0Hz); 6.20(1 H,d,J = 3.0Hz); 7.25 and 7.63 (4H,AA'BB', J = 8.6Hz); 7.56 and 8.21 (4H,AA'BB', J = 8.8Hz).

Example 18 4-Nitrobenzyl 5R,6S,-{1R-[dimethyl(2-methylprop-2-yl)-silyloxy]ethyl}-3-(4-methylthiophenyl)-7-oxo-4-thia 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate A mixture of 4-nitrobenzyl {3S-[1 R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-4R-(4- methylthiobenzoylthio)-azetidinyl-2-on-1 -yl}oxoacetate (1 5.6g), triethyl phosphite (8.23m1) and o -xylene (100ml) were heated under reflux (bath temperature 1300) for 12 hours, and then evaporated in vacuo.Chromatography of the residue over silica gel, and elution with diethyl ether-hexane mixtures afforded the title compound (6.879).

max (CDCI3) 1783cm- 3 (CDCl3)0.06 (3H,s); 0.08 (3H,s); 0.85 (9H,s) 1.27 (3H,d, J = 6.3Hz); 2.48 (3H,s); 3.80 (1H,dd,J = 1.6 and 4.2 Hz); 4.30 (1H,m); 5.21 (2H,AB,Jgem = 13.8Hz); 5.68 (1H,d,J= 1.6Hz); 7.18(2H,d,J= 8.5Hz); 7.41 (4H,m); 8.16 (2H,d,J = 8.8Hz).

Example 19 4Nitrobenzyl 5R,6S-(1R-hydroxyethyl)-3-(4-methylthio-phenyl)-7-oxo-4-thia- 1- azabicyclo[3.2.01hept-2-ene- 2-carboxylate To a stirred solution of4-nitrobenzyl 5R,6S-{1 R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl}- 3-(4 methylthiophenyl )-7-oxo-4-thia-1 -azabicyclo[3.2.0]-hept-2-ene-2-carboxylate (6.879) in dry tetrahydrofu ran (100ml) was added glacial acetic acid (9.37ml) and a 1 M solution oftetra-n-butylammonium fluoride in tetrahydrofuran (35ml).Afterthe mixture had been stirred for 16 hours it was partitioned between ethyl acetate and water; the organic layer was successively washed with saturated aqueous sodium bicarbonate, with water, with brine, was dried over anhydrous magnesium sulphate and evaporated in vacuo.Chromatography ofthe crude residue over silica gel, and elution with ethyl acetate-hexane mixtures afforded the title compound as a yellow solid (3.3g).

3 (CDCl3) 1.19 (3H,d,J = 6.3Hz); 2.38 (3H,s); 3.78(1 H,dd,J =1.5 and 6.3Hz); 4.08(1 H,m); 5.14 (2H,AB,Jgem = 14.0Hz); 5.71 (1H,d,J = 1.5Hz); 7.11,7.31 (4H,AA'BB',J=8.5Hz); 7.39,8.06 (2H,AA'BB',J = 9.0Hz).

Example 20 4-Nitrobenzyl 5R,6S-(1R-hydroxyhethyl)-3-(4-methylsulphinyl-phenyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept2-ene-2-carboxylate To a mixture of 4-nitrobenzyl 5R,6S-(1 R-[hydroxy-ethyl )-3-(4-methylthiophenyl)-7-oxo-4-thia-1 azabicyclo[3.2.0] hept-2-ene-2-carboxylate (306mg), ethyl acetate (1 Oml) and acetone (1 Oml) at was added a solution of 80% 3-chloroperbenzoic acid (154mg) in ethyl acetate (1 OmI). Afterthe mixture had been warmed over two hours to 0 , and this stirred for a further one hour at room temperature, it was partitioned between ethyl acetate and 5% aqueous potassium metabisulphite.The organic layer was washed with saturated aqueous sodium bicarbonate, with water and with brine, and then evaporated to dryness. Chromatography over silica gel, and elution with ethyl acetate-hexane mixtures afforded the title compound (173mg).

max (CDCl3) 1780 cm- 3 (acetone-d6) 1.19 (3H,d,J = 6.3Hz); 2.59 (3H,s); 3.84(1 H,dd,J = 1.5 and 6.1 Hz); 4.09 (1H,m); 5.07,5.22 (2H,AB,Jgem = 13.8Hz); 5.79 (1H,d,J = 1.5Hz); 7.41,8.06(4H,AA'BB', J = 8.4Hz); 7.56(4H,s).

Example 21 Potassium 5R,6S-(1R-hydroxyethyl)-3-(4-methylsulphinyl-phenyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2ene-2-carboxylate The title compound (140mg) was obtained by a procedure analogous to that described in Example 7 and using 4-nitrobenzyl 5R,6S-(1 R-hydroxyethyl )-3-(4-methylsu Iphinyl phenyl )-7-oxo-4-thia-1 -azabicyclo [3.2.0]hept-2-ene-2-carboxylate (170mg), potassium bicarbonate (35.3mg), 10% palladium on charcoal (170mg), dioxane (5ml) and water(5ml).

3 (D20) 1.26 (3H,d,J = 6.3Hz); 2.83 (3H,s); 3.96(1 H,dd,J = 1.5 and 5.8Hz); 4.22(1 H,m); 5.76(1 H,d,J = 1.5Hz); 7.56,7.64 (4H,AA'BB', J = 8.2Hz).

Example 22 4-Nitrobenzyl 5R,6S-(1R-hydroxyethyl)-3-(4-methyl-sulphonylphenyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept 2-ene-2-carboxylate The title compound (148mg) was obtained by a procedure analogous to that described in Example 20 by using 4-nitrobenzyl 5R,6S-(1 R-hydroxyethyl)-3-(4-methyl-thiophenyl)-7-oxo-4-thia-1-azabicyclo[3.2.0] hept 2-ene-2-carboxylate (1.00g), 80 3-chloroperbenzoic acid (1.009), ethyl acetate (35ml) and acetone (15ml).

vmax (CDCl3) 1780cm- 3 (acetone-d6) 1.31 (3H,d, J = 6.3Hz); 3.13 (3H,s); 3.98 (1H,dd,J = 1.6 and 6.0Hz); 4.22 (1 H,m); 5.26 (2H,AB,Jgem = 13.8Hz); 5.94(1 H,d,J = 1.6Hz); 7.52,7.93 (4H,AA'BB', J = 8.4Hz); 7.73,8.18 (4H,AA'BB',J = 8.7Hz).

Example 23 Potassium 5R,6S-(1R-hydroxyethyl)-3-(4-methylsulphonyl-phenyl)-7-oxo-4-thia-1-azabicyclo [3.2.0]hept-2 ene-2-carbaxylate The title compound (91 mg) was obtained by a procedure analogous to that described in Example 7 by using 4-nitrobenzyl 5R,6S-(1 R-hydroxyethyl)-3-(4-methylsulphonylphenyl)-7-oxo-4-thia-1 -azabicyclo[3.2.0]- hept 2-ene-2-carboxylate (148mg), potassium bicarbonate (29.7mg) 10% palladium on charcoal (70mg),water (5ml) and dioxane (5ml).

3 (D20) 1.29 (3H,d,J = 6.3Hz); 3.25 (3H,s); 4.02(1 H,dd,J = 1.5 and 5.9Hz); 4.25(1 H,m); 5.82(1 H,d, J = 1.5Hz); 7.64,7.91 (4H,AA'BB',J = 8.5Hz).

Example 24 4-Cyanothiobenzoic acid Asolution of 4-cyanobenzoyl chloride (1.66g) in dichloromethane (50ml) was treated with pyridine (0.81 ml) and saturated with hydrogen sulphide for 30 minutes. The mixture was flushed with nitrogen then evapora ted and the residue was partitioned between ethyl acetate and 2M aqueous hydrochloric acid. The organic layer was separated and extracted with saturated aqueous sodium bicarbonate. The basic aqueous extract was acidified with 2M aqueous hydrochloric acid and extracted with ethyl acetate. After drying over an hydrous magnesium sulphate the organic extract was evaporated to give 4-cyanothiobenzoic acid as a yellow solid (1 .25g).

vmax(Nujol mull) 2500,2230 and 1700 cm-' 8 (acetone-d6) 7.90,8.20 (4H,AA'BB',J = 8.0Hz) Example 26 4R-r4-Cyanobenzoylthio)-354 1R-(dimethyl(2-methylprop-2-yl)sllyaxyjethyJ}-azetidin-2-ane A solution of 4-cyanothiobenzoic acid (0.349) in acetone (5ml) was treated with 1 M aqueous sodium hydroxide (2.1 ml) and the mixture was added dropwise to a cooled (0") solution of 4R-acetoxy-3R-f1 R-[dimethyl(2- methylprop-2-yl)silyloxy]ethyl}-azetidin-2-one (0.58g)in acetone-water (70.30) (10ml). The mixture was stirred for 45 minutes then partitioned between ethyl acetate and brine. The organic phase was separated, dried overanhydrous magnesium sulphate and evaporated.Chromatography ofthe resulting oil with ethyl acetate-hexane mixture over silica gel afforded the title compound as a colourless oil (0.56g).

8 (CDCl3) 0.07 (6H,s); 0.89 (9H,s); 1.25 (3H,d,J = 6.2Hz); 3.32(1 H,m); 4.32(1 H,m); 5.50(1 H,d,J = 2.3Hz); 6.46 (1 H,bs); 7.80,8.00 (4H,AA'BB',J = 8.5Hz).

Example 26 4-Nitrobenzyl 4R-(4-cyanobenzoylthio)-3S-[1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl}-azetidin-2-on-1yl-oxoacetate A solution of4R-(4-cyanobenzoylthio)-3S-[1 R-dimethyl(2-methylprop-2-yl)silyloxyeth azetidin-2-one (0.769) in dichloromethane (15ml) was cooled (0 ) and stirred. Solid calcium carbonate (0.499) was added followed by diisopropylethylamine (0.51ml). A solution of 4-nitrobenzyl chlorooxoacetate (0.57g) in dichloromethane (6ml) was introduced dropwise and stirring was continued for 30 minutes. The mixture wasfiltered and the filtrate was washed with 0.1 M aqueous hydrochloric acid, dried over anhydrous magnesium sulphate and evaporated to afford the title compound as a yellow foam (1.1 6g).

3 (CDCl3) 0.03 (3H,s); 0.09 (3H,s); 0.87 (9H,s); 1.26 (3H,d,J = 6.4Hz); 3.63(1 H,m); 4.41(1 H,m); 5.43 (2H,s); 6.17(1 H,d,J = 3.5Hz); 7.57,8.04 (4H,AA'BB',J = 8.8Hz); 7.80,8.23 (4H,AA'BB',J = 8.8Hz).

Example 27 4-Nitrobenzyl 5R,3-(4-cyanophenyl)-6S-{1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl}-7-oxo-4-thia-1azabicyclo[3.2.0]hept-2-ene-2-carboxylate A solution of 4-nitrobenzyl 4R-(4-cyanobenzoylthio) 3S-{1 R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl}- azetidin-2-on-1-yl-oxoacetate (1.16g) in xylene (25ml) was warmed to 70 and treated with triethyl phosphite (0.67ml). The mixture was heated to reflux for 1 hour then evaporated and the residue was chromatographed in ether-hexane over silica to afford the product as a yellow oil (0.61 g).

3 (CDCI3) 0.05 (3H,s); 0.09 (3H,s); 0.89 (9H,s); 1.27 (3H,d,J = 6.2Hz); 3.86(1 H,dd,J = 1.6 and 3.8Hz); 4.33 (1H,m); 5.12,5.31 (2H,AB,Jgem = 13.6Hz); 5.79(1H,d,J = 1.6Hz); 7.50,7.66 (4H,AA'BB',J=8.5Hz); 7.56,8.18 (4H,AA'BB',J = 8.5Hz).

Example 28 4-Nitrobenzyl 5R,3-(4-cyanophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2 carboxylate To a stirred solution of 4-nitrobenzyl 5R,3-(4-cyanophenyl )-6Sg1 R-[dimethyl(2-methylprop-2- yl)-silyloxy]- ethyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.29g) in tetrahydrofuran (10ml), cooledto 0% was added glacial acetic acid (0.309). A solution oftetra-n-butylammonium fluoride in tetrahydrofuran (1 M, 1 .47mI) was introduced dropwise and the stirring was continued for 65 hours. Evaporation gave are sidue which was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and brine.The organic extract was dried over anhydrous magnesium sulphate, evaporated and the resulting gum was chromatographed with ethyl acetate-hexane mixtures over silica gel to afford the title compound as a yellow gum (0.11g). This compound had IR and 1H n.m.r. spectra identical to that ofthe compound prepared in Example 6.

Example 29 4-(2,4-Dimethoxybenzloxycarbonyl)thiobenzoic acid Asolution ofterephthaloyl chloride (20.309) in dioxane (250ml) was treated dropwise with a solution of 2,4-dimethoxybenzyl alcohol (20.18g) in dioxane (40ml). Triethylamine (1 6.70ml) was added and the mixture was stirred for 1 hour before being filtered. The filtrate was evaporated and the resulting gum was dissolved in dichloromethane (200ml), treated with pyridine (9.71ml) and saturated with hydrogen sulphide for40 minutes. The mixture was flushed with nitrogen then evaporated and the residue was partitioned between ethyl acetate and 2M aqueous hydrochloric acid. The organic layer was separated and extracted with saturated aqueous sodium bicarbonate.The basic aqueous extract was acidified with 2M aqueous hydrochloric acid and extracted with ethyl acetate. After drying over anhydrous magnesium sulphate the organic extract was evaporated to afford the title compound as a yellow solid (18.009).

max(CDCl2)258O, 1720, and 1700 cm - 3 (CDCl3) 3.85 (6H,s); 5.39 (2H,s); 6,53 (3H,m); 7.40 (1H,d,J=9.0Hz); 8.10 (4H,m).

Example 30 4R-[4-(2,4-Dimethoxybenzyloxycarbonyl)benzoylthio]-3S-{1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl}azetidin-2-one A solution of 4-(2,4-dimethyloxybenzyloxycarbonyl)thiobenzoic acid (16.29) in acetone (1 50ml) was treated with 1 M aqueous sodium hydroxide (62ml) and the mixture was added dropwise to a cooled (0 ) solution of 4R-acetoxy-3R-{1 R-[dimethyl (2-methyl prop-2-yl)silyloxy]ethyl}-azetidin-2-one (11 .5g) in acetone water (70:30) (100ml). The mixturewas stirred for45 minutesthan partitioned between ethyl acetate and brine. The organic phase was separated, dried over anhydrous magnesium sulphate and evaporated. Chromatography of the resulting oil with ethyl acetate-hexane mixtures over silica gel gave the title compound as a colourless foam (17.409).

i'max(CDCl3) 3420, 1775 and 1720 cm-1 3 (CDCl3) 0.07 (6H,s); 0.87 (9H,s); 1.24 (3H,d,J = 6.3Hz); 3.82 (6H,s); 4.30(1 H,m); 5.34 (2H,s); 5.49(1 H,d,J = 2.4Hz); 6.49 (2H,m); 6.61(1 H,bs); 7.32(1 H,d,J = 8.9Hz) 7.93,8.13 (4H,AA'BB',J = 8.5Hz).

Example31 4-Nitrobenzyl 4R-[4-(2,4-dimethyloxybenzyloxycarbonyl)benzoylthio]-3S-{1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl-azetidin-2-on-1yl-oxoacetate To a cooled (0'), stirred solution of4R-[4-(2,4-dimethoxybenzyloxycarbonyl )benzoylthioj-3S-fl R- [dim- ethyl(2-methylprop-2-yl)silyloxy]ethyl}-azetidin-2-one(5.60g) in dichloromethane (50ml) was added calcium carbonate (2.059) followed by diisopropylethyl-amine (2.61 ml). A solution of 4-nitrobenzyl chloro-oxoacetate (2.92g) in dichloromethane (1 OmI) was added dropwise and after 30 minutes the mixture was filtered, washed with 0.1 M aqueous hydrochloric acid, dried over anhyrous magnesium sulphate and evaporated to afford the title compound as a paleyellowfoam (7.679).

5 (CDCl3) 0.01 (3H,s); 0.08 (3H,s); 0.82 (9H,s); 1.27 (3H,d,J = 6.3Hz); 3.64(1 H,dd,J = 2.7 and 3.5Hz); 3.82 (6H,s); 4.39 (1 H,dq,J = 2.7 and 6.3Hz); 5.35 (2H,s); 5.40 (2H,s); 6.18 (1H,d,J = 3.5Hz); 6.49 (2H,m); 7.32(1H,d,J = 8.9Hz); 7.96,8.12 (4H,AA'BB', J = 8.6Hz); 7.57,8.22 (4H,AA'BB',J = 8.7Hz).

Example 32 4-Nitrobenzyl 5R,3-[4-(2,4-dimethyloxybenzyloxycarbonyl)-phenyl]-6S-{ 1R-[dimeth yI(2- methylprop-2yl)silylxoy]-ethyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate A solution of 4-nitrobenzyl 4R-[4-(2,4-dimethyoxybenzyloxyca rbonyl ) benzoylthio]-3S-{1 R-[dimethyl(2 methylprop-2-yl)siiyioxy]ethyl)-azetidi n-2-on-1 -yl-oxoacetate (7.67g) in xylene (100m I) was warmed to 70 and treated with triethyl phosphite (3.43ml). The mixture was heated to reflux for 4 hours then evaporated and the residue was chromatographed with ether-hexane mixtures over silica gel to afford the product as a yellow foam (4.38g).

8 (CDCl3) 0.07 (3H,s); 0.08 (3H,s); 0.85 (9H,s); 1.27 (3H,d,J = 6.2Hz); 3.82 (7H,m); 4.30(1 H,m); 5.09,5.27 (2H,AB, Jgem = 13.6Hz); 5.34 (2H,s); 5.75(1 H,d,J = 1.6Hz); 6.48 (2H,m); 7.32(1 H,d,J=8.4Hz); 7.40,8.03 (4H,AA'BB',J = 8.6Hz); 7.48,8.13 (4H,AA'BB', J = 8.7Hz).

Example 33 4-Nitrobenzyl 5R,3-(4-carboxyphenyl)-6S-{1R-[dimethyl-(2-methylprop-2-yl)silyl]oxy}ethyl)- 7-oxo-4-thia-1 azabicyclo[3.2. O]hepf-2-ene-2-carboxylate A solution of 4-nitrobenzyl 5R,3-[4-(2,4-dimethoxy benzyl oxyca rbonyi)p henyl]-6S-(l R- [dimethyl (2- methylprop-2-yl)silyloxy]ethyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.02g) in dichloromethane (100ml) containing water (1 ml) was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1 .63g). The mixture was stirred at room temperature for 30 hours then evaporated and the residue was chromatographed with ethyl acetate-hexane mixtures over silica gel to afford the title compound as a brown foam (1.lIg).

Vmax(CDCl3) 3660br, 1790, 1720 and 1700 cm- 5 (acetone-d6) 0.07 (3H,s); 0.10 (3H,s); 0.86 (9H,s); 1.29 (3H,d,J = 6.3Hz); 4.04 (1 H,dd,J = 1.6 and 3.5Hz); 4.36 (1 H,dq, J = 3.5 and 6.3Hz); 5.15,5.31 (2H,AB,Jgem = 13.7Hz); 5.91 (1H,d,J=1.6Hz); 7.59,7,98 (4H,AA'BB',J=8.6Hz); 7.52,8.14(4H,AA'BB',J= 8.9Hz).

Example 34 4-Nitrobenzyl 5R,3-(4-aminocarbonylphenyl)-6S-(1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl}-7-oxo-4thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate To a stirred solution of 4-nitrobenzyl 5R,3-(4-carboxyphenyl)-6S-fl R-[dimethyl(2-methylprop-2-yl) silyloxy]ethyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.41) in acetonitrile (10ml) was added a solution of 1 -hydroxybenzotriazole hydrate (HOBT) (0.1 9g) in tetrahydrofuran (2ml) followed by l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.20g). After 20 minutes a solution of ammonia in ethanol (39mg ml-1, 1 ml) was introduced and the mixture was stirred for a further 10 minutes.

Evaporation and chromatography of the resulting residue over silica gel and elution with ethyl acetate hexane mixtures gave the product as a yellow oil (0.25g).

#(CDCl3)0.04(3H,s); 0.07 (3H,s); 0.85 (9H,s); 1.26 (3H,d,J = 6.3Hz); 3.83(1 H,dd,J = 1.6 and 4.0Hz); 4.29(1 H,dq, J = 4.0 and 6.3 Hz); 5.08,5.26 (2H,AB,Jgem = 13.7Hz); 5.75(1 H,d,J = 1.6Hz); 6.32 (2H,bs); 7.49,7.78 (4H,AA'BB',J = 8.3Hz); 7.42,8.13 (4H,AA'BB',J = 8.7Hz).

Example 35 4-Nitrobenzyl 5R,3-(4-aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2ene-2-carboxylate A solution of 4-nitrobenzyl 5R,3-(4-aminocarbonylphenyl)-6S-{1- R-[dimethyl (2-methylprop-2-yl )silyloxy] ethyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.41 g) in tetrahydrofuran (20ml) cooled (0 ) and treated with glacial acetic acid (0.42g) followed by a solution oftetra-n-butylammonium fluoride intera- hydrofuran (1 M,2.1 ml). The mixture was stirred for 45 hours then evaporated and the resulting gum was chromatographed with ethyl acetate over silica gel to afford the title compound as a pale yellow powder (0.139).

vmax (Nujol mull) 3460-3260br, 1775, 1705 and 1650 cm-1 8 (acetone-de) 1.31 (3H,d,J = 6.3Hz); 3.94(1 H,dd,J = 1.6 and 6.2Hz); 4.21 (1 H,m); 5.18,5.31 (2H,AB,Jgem=13.9Hz); 5.89(1 H,d,J = 1.6Hz); 6.73(1 H,bs); 7.54,7.90 (4H,AA'BB',J = 8.4Hz); 7.46,8.14 (4H,AA'BB',J = 8.9Hz).

Example 36 Potassium 5R,3-(4-aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia- 1-azabicycla[3.2. 0]hept-2-ene- 2-carboxylate 4-Nitrobenzyl 5R,3-(4-aminocarbonylphenyl)-6S-(1 R-hydroxyethyl )-7-oxo-4-thia-1 -azabicyclo[3.2.OJ hept2-ene-2-carboxylate (0.1 2g) was dissolved in dioxane (1 OmI), potassium hydrogen carbonate (25mg) was dissolved in water (10ml) and the two solutions were mixed and hydrogenated at375KPa (4atm) over 10% palladium-on-charcoal (0.1 2g) for 1 hour. The mixture was filtered through Hyflo and the filtrate was freezedried.The residue was dissolved in water, washed with ethyl acetate and freeze-dried to give the title compound as a pale yellow powder (0.09g).

8 (D2O) 1.30 (3H,d,J = 6.3Hz); 3.99(1 H,dd,J = 1.1 and 5.9Hz); 4.26(1 H,m); 5.79(1 H,d,J = 1.1Hz); 7.50,7.80 (4H,AA'BB',J = 8.3Hz).

Example 37 4-Nitrobenzyl 5R,3-(4-carboxyphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2carboxylate A solution of 4-nitrobenzyl 5R,3-(4-ca rboxyphenyl)-6S-{1 R-[dimethyl(2-methyl prop-2-yl)si lyloxylethyl}-7- oxo-4-thia-1-azablcyclo[3.2.0]hept-2-ene-2-carboxylate (0.209) in tetrahydrofuran (1 Oml) was cooled (0 ) and treated with glacial acetic acid (0.20g) followed by a solution oftetra-n-butylammonium fluoride in tetra hydrofuran (1 M, 1.02ml). Th e mixture was stirred for 24 hours then evaporated and the residue was part itioned between ethyl acetate and saturated aqueous sodium bicarbonate.The basic aqueous layerwas separated, carefully acidified to pH6 with 2M aqueous hydrochloric acid and extracted with ethyl acetate.

Evaporation ofthe extract afforded the title compound as a brown oil (0.08g).

vmax(Nujol mull) 1770 and 1700cm-1 8 (acetone-d6) 1.31 (3H,d,J = 6.3Hz); 3.95(1H,dd,J = 1.6and6.4Hz);4.21 (1H,m); 5.16,5.30 (2H,AB,Jgem = 13.8Hz); 5.94(1H,d,J = 1.6Hz); 7.55,7.98 (4H,AA'BB',J = 8.4Hz); 7.47,8.13 (4H,AA'BB', J = 8.8Hz).

Example 38 4-Nitrobenzyl 5R,3-(4-aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2 ene-2-carboxylate A solution of 4-n itrobenzyl 5R,3-(4-carboxyphenyl)-6S-(1 R-hydroxyethyl )-7-oxo-4-thia-1 azabicyclo[3.2.0] hept -2-ene-2-carboxylate (0.08g) in acetonitrile (1 Om I ) was stirred and treated with a sol ution of 1 -hydroxybenzotriazole (HOBT) (0.04g) in tetrahydrofuran (2ml) followed by 1 -(3 dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.05g). After 1 hour a solution of ammonia in ethanol (50mgml-1, 0.5ml) was added and stirring was contrinued for a further 10 minutes.The mixture was evaporated and the residue dissolved in dichloromethane, washed with 1 M aqueous citric acid, saturated aqueous sodium bicarbonate and brine. Evaporation of the organic extract afforded the title compound (0.07g) with properties identical to those ofthe compound prepared in Example 35.

Example 39 4-Nitrobenzyl 5R,3-[4-(2,4-dimethyloxybenzyloxycarbonyl)-phenyl]-6S-(1R-hydroxyethenyl)-7-oxo-4-thia-1 azabicyclo-[3.2.0ghept-2-ene-2-carboxylate A solution of4-nitrobenzyl 5R,3-[4-(2,4-dimethoxybenzyloxycarbonyl)phenyl]-6S-{1 R-[dimethyl(2- methyl prop-2-yl)silyloxy]ethyl}-7-oxo-4-thia-1 -azabicyclo[3.2.0] hept-2-ene-2-carboxylate (1 .009) in tetrahydrofu ran (40ml) was cooled (0O) and treated with glacial acetic acid (0.829) followed by a solution oftetra-n butylammonium fluoride in tetrahydrofuran (1 M, 4.1 ml). The mixture was stirred for 24 hours then evaporated and the residue was chromatographed over silica gel and eluted with ethyl acetate-hexane mixturesto give the title compound as a yellow oil (0.279).

8 (CDCl3) 1.38 (3H,d, J = 6.3Hz); 3.82 (6H,s); 3.87(1H,dd,J = 1.6 and 6.3Hz); 4.30(1H,m); 5.08,5.25 (2H,AB,Jgem = 13.6Hz); 5.33 (2H,s); 5.77(1 H,d,J = 1.6Hz); 6.48 (2H,m); 7.31 (3H,m); 7.45,7.99 (4H,AA'BB',J = 8.5Hz); 8.11 (2H,d,J=8.7Hz).

Example 40 4-Nitrobenzyl 5R,3-(4-carboxyphenyl)-6S-(1R-hydroxy-ethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2 carboxylate A solution of 4-nitrobenzyl 5R,3-[4-(2,4-dimethoxybenzyloxycarbonyl)phenyl]-6S-(1 R-hydroxyethyl)-7 oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.279) in dichloromethane (20ml) containing water (1 ml) was stirred and treated with 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone (DDQ) (O.2Og). After 24 hours the mixture was evaporated and the residue partitioned between ethyl acetate and water.The organic layer was separated, dried over anhydrous magnesium sulphate, evaporated and the resulting gum was chromat ographed over silica gel with ethyl acetate-hexane mixtures to afford the title compound (0.139) with prop erties identical to the compound prepared in Example 37.

Example 41 4-Nitrobenzyl 5R,3[4-[N-(cyanomethyl)aminocarbonyl]phenyl}-6S-{ 1R-fdimeth yl(2- meth ylprop-2yl)silyloxy]ethyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate To a stirred solution of 4-nitrobenzyl 5R,3-(4-carboxyphenyl )-6S-f1 R-[dimethyl(2-methyl prop-2yl)silyloxy]ethyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.36g) in acetonitrile (10ml) was added a solution of 1 -hydroxybenzotriazole (HOBT) (0.179) in tetrahydrofuran (2ml)followed by 1 -(3- dimethylamino-propyl)- 3-ethylcarbodiimide hydrochloride (O.18g). After 30 minutes aminoacetonitrile hydrochloride (0.1 7g) was added closely followed bytriethylamine (0.26ml), and stirring was continued fora further 30 minutes. The mixture was evaporated, the residue was dissolved in ethyl acetate and washed with 2M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine, and evaporation ofthe organic phase gave a brown gum which was chromatographed with ethyl acetate-hexane mixtures oversilica gel to afford the product as a yellowfoam (0.249).

vmax(Nujol mull) 3400-3300br, 1790, 1720 and 1665cm-1 #(CDCl3) 0.04 (3H,s,); 0.06(3H,2); 0.84 (9H,s); 1.25 (3H,d,J = 6.3Hz); 3.82(1H,dd,J=1.6 and 3.9Hz); 4.28 (1 H,dq,J = 3.9 and 6.3Hz); 4.35 (2H,d,J 5.9Hz); 5.08,5.26 (2H,AB,J gem 13.6Hz); 5.75(1H,d,J = 1.6Hz);6.67 (1H,bt,J = 5.9Hz); 7.51,7.72 (4H,AA'BB',J = 8.5Hz); 7.43,8.12 (4H,AA'BB',J = 8.7Hz).

Example 42 4-Nitrobenzyl 5R,3-{4-[N-(cyanomethyl)aminocarbonyl-phenyl}-6S-(1R-hydroxyethyl)-7-oxy-4- thia- 1azabicyclo-[3.2.0]hept-2-ene-2-carboxylate To a cooled (0 ) solution of 4-nitrobenzyl 5R,3-{4-[N-{cyanomethyl)aminocarbonyl]phenyl}-6S-{ 1 R [dimethyl(2-methylprop-2-yl )silyloxy]ethyl}J-oxo-44hia-1 -azabicyclo[3.2.0] hept-2-ene-2-carboxylate (0.239) in tetrahydrofuran (50ml) was added glacial acetic acid (0.229) and a solution oftetra-n-butylammonium fluoride in tetrahydrofuran (1 M,1 .1 ml). The mixture was stirred for 40 hours then evaporated and the residue was chromatographed with ethanol-ethyl acetate mixtures over silica gel to afford the title compound as a pale yellow solid (0.10g).

(acetone-d6) 1.31 (3H,d,J = 6.3Hz); 3.95(1H,dd,J = 1.7 and 6.2Hz);4.21 (1H,m); 4.41 (2H,d,J =3.3Hz); 5.17,5.31 (2H,AB,Jgem = 13.8Hz);5.90 (1 H,d,J = 1.7Hz); 7.57,7.68 (4H,AA'BB',J = 8.5Hz);7.49,8.15 (4H,AA'BB',J = 8.8Hz); 8.51 (1 H,bt,J = 3.3Hz).

Example 43 Potassium 5R,3-{4-[N-(cyanomethyl)aminocarbonyl] phenyl}-6S-( 1 R-hydroxyethyl)-7-oxo- 4-thia-1 - azabicyclo[3.2.0]-hept-2-ene-2-carboxylate 4-Nitrobenzyl 5R,3-{4-[N-(cyanomethyl)aminocarbonyl]phenyl-6S-(1 R-hydroxyethyl )-7-oxo-4-thia- 1 azabicyclo-[3.2.0]hept-2-ene-2-carboxylate (0.1 0g) was dissolved in dioxane (10ml), potassium hydrogen car bonate (1 9mg) was dissolved in water(10ml) and the two solutions were mixed and hydrogenated at about 375pKa (4 atmospheres) over 10% palladium-on-charcoal (0.10g) for 1 hour. The mixture was filtered through Hyflo (Trade Mark) and the filtrate was freeze-dried.The residue was dissolved in water, washed with ethyl acetate and freeze-dried to afford the title compound as a pale yellow powder (O.07g).

(D2O) 1.30 (3H,d,J = 6.4Hz); 4.00 (1 H,dd,J 1.4 and 5.9Hz); 4.25 (1 H,m); 4.36 (2H,s); 5.79 (1 H,d,J = 1.4Hz); 7.51 and 7.75 (4H,AA'BB',J = 8.5Hz).

Example 44 4-(Methoxyaminocarbonyl)thiobenzoic acid To a solution ofterephthalyl chloride (7.09) in dichloromethane (250ml) was added a 25% aqueous solution of methoxyamine hydrochloride (15ml) followed by a solution oftriethylamine (12.5ml) in dichloromethane (250ml). Afterthe mixture had been stirred for 1 hour, pyridine (4.2ml) was added, and then gaseous hydrogen sulphide (excess) was bubbled through over 30 minutes. After it had been stirred for a further 30 minutes the mixturewasflushed with nitrogen, and partititoned between ethyl acetate and aqueous citric acid. The organic layer was washed with water and then extracted with saturated aqueous sodium bicarbonate.This aqueous extract was washed with ethyl acetate, and then reacidified to pH2 with 11 M hydrochloric acid. Extraction with ethyl acetate, gave giving an organic extract which was then washed with water and with brine, and evaporated in vacuo, to afford a residue, which was chromatographed over silica gel.

Elution with ethyl acetate-hexane mixtures afforded the title compound (2.0g).

8 (acetone-d6) 3.80 (3H,s); 7.79-8.30 (4H,m).

Example 45 3S-{1R-[Dimethyl(2-methylprop-2-yl)silyloxy]ethyl}-4R-(4-methoxyaminocarbonylbenzoylthio)-azetidin-2one The title compound (1.85g) was prepared by a procedure analogous to that described in Example 16 by using 4-acetoxy-3R-{1 R[-dimethyl[2-methylprop-2-yl)sily[oxy]ethyl}azetidinons (21.99), 4- (methoxyaminocarbonyl)thiobenzoic acid (1.9g), 1M sodium hydroxide (8.7ml) and acetone (10ml).

v max (film) 1758, 1665cm1 8 (CDCl3) 0.10 (6H,s); 0.90 (9H,s); 1.25 (3H,d,J = 6.3Hz); 3.30(1 H,dd,J = 2.4 and 3.7Hz); 3.93 (3H,s); 4.30-4.35(1 H,m); 5.49(1 H,d,J = 2.4Hz); 6.52 (1 H,bs); 7.85,7.98 (4H,AA'BB',J = 8.4Hz); 9.13(1 H,bs).

Example 46 4-Nitrobenzyl{3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-4R-[4-(methoxy-(4-nitrobenzyloxy-carbonyl-carbonyl)-aminocarbonyl)benzoylthio]-azetidin-2-on-1-yl}oxoacetate The title compound (4.1 mmol) was prepared by a procedure analogous to that described in Example 17 by using 3S-{1R-[dimethyl(2-methylprop-2-yl)silyoxy]ethyl}-4R-(4-methoxyaminocarbonylbenzoylthio) azetidin-2-one (1.8g), 4-nitrobenzylch[orooxoacetate (2.5g), calcium carbonate (1.8g), diisopropylethylamine (2.2 ml) and dichloromethane (20ml).

vmax(CDCI3) 1815 cm- #(CECl3) 0.10(6H,s); 0.84 (9H,s); 1.27 (3H,d,J = 6.3Hz); 3.64-3.68 (1H,m); 3.90 (3H,s); 4.40-4.43 (1 H,m); 5.39-5.44(4H,m); 6.19 (1 H,d,J =3.4Hz); 7.55-8.26 (12H,m).

Example 47 4-Nitrobenzyl5R,6S-{1R-[dimethyl(2-prop-2-yl)silyloxy]-ethyl}-3-{4-[methoxy-(4-nitrobenzyloxycarbonylcarbonyl)-aminocarbonyl]phenyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2carboxylate The title compound (1 13mg)was obtained buy a procedure analogous to that described in Example 18 by using 4-nitrobenzyl {3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-4R-[4-(methoxy-(4-nitrobenzyloxycarbonylcarbonyl)-aminocarbonyl)benzoylthtio]-azetidin-2-on-1-yl}-oxoacetate (1.25mmol), triethyl phosphite (4281l1) and xylene (5ml).

Vmax (film) 1775, 1748 and 1725cm-1 8 (CDCI3) 0.07 (6H,s); 0.83 (9H,s); 1.25 (3H,d,J=6.3Hz); 3.80-3.83(1 H,m); 3.89 (3H,s); 4.30-4.38(1 H,m); 5.07,5.20 (2H,AB,J = 13.6Hz); 5.37 (2H,s); 5.75(1 H,d,J = 1.5Hz); 7.39,7.98 (4H,AA'BB',J = 8.6Hz); 7.45,8.09 (4H,AA'BB',J = 8.3Hz); 7.50,8.22 (4H,AA'BB',J = 8.7Hz).

Example 48 4-Nitrobenzyl 5R,6S-(1R-hydroxyethyl)-3-(4-methoxyamino-carbonylphenyl)-7-oxo-4-thia-1-azabicyclo [3.2.01hept-2-ene-2-carboxylate The title compound (250mg) was obtained by a procedure analagoustothat described in Example 19, using 4-nitrobenzyl 5R,6S-{1R-[dimethyl(2-prop-2-yl)silyloxy]ethyl}-3-{4-[methoxy-{4-nitrobenzyloxycarbonyl carbonyl)-aminoca rbonyl] phenyl)-7-oxo-4-thia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxyla (670mg), acetic acid (570 l), 1M tetra-n-butylammonium fluoride in tetrahydrofuran (2.88ml), and tetrahydrofuran (1 OmI).

vmax(film) 1788,1722cm-1 8 (CDCl2) 1.41 (3H,d, J = 6.3Hz); 3.88 (1H,dd,J = 1.6 and 6.4Hz); 3.94 (3H,s); 4.28-4.35(1 H,m); 5.10,5.26 (2H,AB,Jgem = 13.5Hz); 5.79 (1H,d,J=1,6Hz); 7.32,7.98(4H,AA'BB',J=8.5Hz); 7.47,8.13(4H,AA'BB'J=8.7Hz).

Example 49 Potassium 5R,6S-(1R-hydroxyethyl)-3-(4-methoxyaminocarbonylphenyl)-7-oxo-4-thia-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylate The title compound (28mg) was obtained by a procedure analogous to that described in Example 7 by using 4-nitrobenzyl 5R,6S-(1R-hydroxyethyl)-3-(4-methoxyaminocarbonylphenyl)-7-oxo-4-thia-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylate (60mg), 10% palladium-on-charcoal (60mg), potasslum blcarbonate(12mg), dioxane (5ml) and water (5ml).

8 (D2O) 1.29 (3H,d, J = 6.4Hz); 3.90 (3H,s); 4.00(1 H,dd,J = 1.5 and 5.9Hz); 4.21-4.28(1 H,m); 5.79(1 H,d, J = 1.5Hz); 7.49,7.97 (4H,AA'BB', J=8.5Hz).

Example 50 4-(Methylaminocarbonyl)thiobenzoic acid The title compound (3.19) was obtained by a procedure analogous to that described in Example 44 by using terephthaloyl chloride(10.0g), dichloromethane (300ml), methylamine hydrochloride (4.2g), triethylamine (17.4ml), pyridine (7.76ml), and excess hydrogen sulphide.

8 (acetone-d6) 2.90 (3H,s); 7.96,8.10 (4H,AA'BB',J = 8.4Hz).

Example 51 3S-{1R-[Dimethyl(2-methylprop-2-yl)silyloxy]ethyl}-4R-(4-methylaminocarbonylbenzoylthio)-azetidin-2-one The title compound (1 .7g) was obtained by a procedure analogous to that described in Example 16, by using 4-acetoxy-3R-fl R-[dimethyl(2-methylprop-2-yl )-silyloxy]ethyl}-azetidin-2-one (3,0g),4-(methylamio- carbonyl)thiobenzoic acid (3.Og), 1 M sodium hydroxide (15.6ml), and acetone (50ml).

vmax(film) 1765, 1660 cm-1 # (CDCl3)0.08(6H,s); 0.88 (9H,s); 1.23 (3H,d,J = 6.3Hz); 3.03 (3H,d,J = 4.8Hz); 3.28(1 H,dd,J = 2.4Hz and 3.8Hz); 4.28-4.32 (1 H,m); 5.47(1 H,d,J = 2.4Hz); 6.37(1 H,bd,J = 4.8Hz); 6.54(1 H,bs); 7.83,7.94 (4H,AA'BB',J = 8.5Hz).

Example 52 4-Nitrobenzyl{3S-[1R-(dimethyl(2-methylprop-2-yl)-silyloxy)ethyl]-4R-[4-methylaminocarbonyl)-benzoylthio]-azetidin-2-on-1-yl}oxoacetate The title compound (2.5g) was obtained by a procedure analogous to that used in Example 17 by using 4-nitrobenzyl chlorooxoacetate (1.1 7g), 3S-(1 R-fdimethyl-(2-methylprop-2-yI )silyloxy}ethyl})-4R-(4-methyl- aminocarbonylbenzoylthio)-azetidin-2-one (1.79), calcium carbonate (1.7g), diisopropylethylamine (1.05ml), and dichloromethane (15ml).

8 (CDCI3) 0.09 (6H,s); 0.86 (9H,s); 1.27 (3H,d,J= 6.3Hz); 3.04 (3H,d,J = 4.9Hz); 3.63(1 H,dd,J = 3.4 and 2.7Hz); 4.39-4.43 (1 H,m); 5.35,5.43 (2H,AB,Jgem = 13.7Hz); 6.19(1 H,d,J = 3.4Hz); 7.57,7.97 (4H,AA'BB',J = 8.1Hz); 7.86,8.22 (4H,AA'BB',J = 8.7Hz).

Example 53 4-Nitrobenzyl5R,6S-{1R-[dimethyl(2-methylprop-2-yl)-silyloxy]ethyl}-3-(4-methylaminocarbonylphenyl)-7oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate The title compound (0.66g) was obtained by a procedure analogous to that used in Example 18 by using 4-nitrobenzyl{3S-[1R-(dimethyl(2-methylprop-2-yl)-silyloxy)ethyl]-4R-[4-(methylaminocarbonyl)benzoyl thio]-azetidin-2-on-2-yl)oxoacetate (2.5g), triethyl phosphite (1.37ml), hydroquinone (5mg), o-xylene (15ml).

Vmax(film) 1778, 1715cm-1 8 (CDCl3) 0.082 (6H,s); 0.90 (9H,s); 1.22 (3H,d,J = 6.3Hz); 3.01 (3H,d,J = 4.6Hz); 3.83(1H,dd,J = 1.5 and 4.2Hz); 4.12-4.19(1 H,m);5.10,5.27 (2H,AB,J gem = 13.6Hz); 5.76(1 H,d,J = 1.5Hz); 6.15(1 H,bd,J = 4.6Hz); 7.43,7.71 (4H,AA'BB',J=8.4Hz); 7.46,8.14 (4H,AA'BB', J = 8.7Hz).

Example 54 4-Nitrobenzyl 5R,6S-(1R-hydroxyethyl)-3-(4-methylamino-carbonylphenyl)-7-oxo-4-thia-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylate The title compound 175mg) was obtained by a procedure analogous to that used in Example 19 by using 4-nitrobenzyl5R,6S-(1R-[dimethyl(2-methylprop-2-yl)-silyloxy]ethyl}-3-(4-methylaminocarbonylphenyl)-7oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (660mg), glacial acetic acid (660 1), 1 M tetra-nbutylammonium fluoride in tetrahydrofuran (3.3ml), and tetrahydrofuran (5ml).

Vmax (KBr) 1770cm-1 8 (DMSO-d6) 1.17 (3H,d,J = 6.1 Hz); 2.78 (3H,d,J = 4.5Hz); 3.96-4.02 (2H,m); 5.20 (2H,m); 5.82(1 H,d,J = 1.5Hz); 7.32,7.76 (4H,AA'BB',J=7.2Hz); 7.46,8.10 (4H,AA'BB',J = 8.6Hz); 8.49 (1 H,bd,J= 4.0Hz).

Example 55 Potassium 5R,6S-(1R-hydroxyethyl)-3-(4-methylamino-carbonylphenyl)-7-oxo-4-thia-1-azabicyclo[3.2.0] hept-2-ene-2-carbaxylate The title compound (11 7g) was obtained by a procedure analogous to that used in Example 7 by using 4-nitrobenzyl 5R,6S-(1 R-hydroxyethyl)-3-(4-methylamino-carbonylphenyl)-7-oxo-4-thia-1 -azabicyclo[3.2.0] hept-2-ene-2-carboxylate (175mg), 10% palladium on charcoal (175mg), potassium bicarbonate (36.2mg), dioxane (5ml) and water (5ml).

8 (D2O) 1.26 (3H,d, J = 6.4Hz); 2.86 (3H,s); 3.96(1 H,dd, J = 1.3 and 6.0Hz); 4.19-4.26(1H,m); 5.75(1 H,d, J = 1.3Hz); 7.44,7.64 (4H,AA'BB',J = 8.3Hz).

Example 56 4-(Propylaminocarbonyl)-thiobenzoic acid The title compound (3.4g) was obtained by a procedure analogous to that used in Example 44 by using terephthaloylchloride (10.0g), propylamine (4.84ml), triethylamine (10.2ml), pyridine (8.36ml), excess hydrogen sulphide and dichioromethane (300ml).

8 (acetone-d5) 0.93 (3H,t, J = 7.4Hz); 1.60 (2H,m); 3.30-3.40 (2H,m); 7.96-8.13 (4H,m).

Example 57 3S-{1R-[Dimethyl(2-methylprop-2-yl)silyloxy]ethyl}-4R-(4-propylaminocarbonylbenzoylthio)azethdine-2-one The titie compound (250mg) was obtained by a procedure analogous to that used in Example 16 by using 4-(propylaminocarbonyl)-thiobenzoic acid (330mg), 4-acetoxy-3R-{1 R-[dimethyl (2-methylprop-2-yl ) silyloxy]-ethyl}azetidin-2-one (280mg) 1 M sodium hydroxide solution (1.46ml), water (1.5ml), and acetone (7ml).

max (film 1758, 1660 cm-1# (CDCl3) 0.10 (6H,s); 0.90 (9H,s); 0.93 (3H,t, J =7.3Hz); 1.19(3H,d,J J =6.2Hz); 1.43-1.63 (2H,m); 3.23(1 H,dd, J = and 3,8Hz); 3.34(2H,m); 4.23-4.27(1H,m); 5.42 (1H,d,J = 2.4Hz); 6.18(1H,bs); 6.41 (1H,bs); 7.78,7.91 (4H,AA'BB', J = 8.6Hz).

Example 58 4-Nitrobenzyl{3S-[1R-(dimethyl(2-methylprop-2-yl)-silyloxy)ethyl]-4R-[4-(propylaminocarbonyl)benzoylthio)-azetidin-2-on-1-yl}oxoacetate The title compound (361 mg) was obtained bya procedure analogous to that used in Example 17 by using procedure analogous to that used in Example 17 by using 3S-{1 R-[dimethyl-(2-methylprop-2-yl)silyloxy]ethyl}-4R-(4-propylaminocarbonylbenzoylthio)azetidin-2-one (250 mg), 4-nitrobenzyl chlorooxoacetate (162mg), diisopropylethylamine (0.145ml), calclum carbonate (250mg), and dichloromethane (5ml).

a (CDCl2) 0.11 (6H,s); 0.92 (9H,s); 1.01 (3H,t, J = 7.3Hz); 1.27 (3H,d,J = 6.3Hz); 1.53-1.65 (2H,m); 3.46-3.51 (2H,m); 3.66(1H,dd,J = 2.8 and 3.5Hz); 4.32-4.39(1 H,m); 5.43 (2H,s); 6.22(1 H,d, J = 3.5Hz); 7.57-8.30 (8H,m).

Example 59 4-Nitrobenzyl 5R,6S-{1R-[dimethyl(2-methylprop-2-yl)-silyloxy]ethyl}-7-oxo-3-[4-(propylaminocarbonyl) phenyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate The title compound (45mg) was obtained by a procedure analogous to that used in Example 18 by using 4-nitrobenzyl {3S-[1 R-(d imethyl-(2-methyl prop-2-yl)-silyloxy)ethyl]-4R-(4- propylaminoca rbonyl benzoylthio)azetidin-2-on-1-yl}oxoacetate (361mg), triethyl phosphite (0.185ml), and o-xylene (5ml).

Vmax (film) 1789cm-1 8 (CDCl3) 0.90 (6H,s); 0.94 (9H,s); 1.04 (3H,t, J = 7.4Hz); 1.23 (3H,d,J = 6.3Hz); 1.27-1.34(2H,m); 3.44-3.52 (2H,m); 3.89 (1H,dd,J = 1.6 and 4.2Hz); 4.19-4.30(1 H,m); 5.15 and 5.34 (2H,AB,Jgem = 13.6Hz); 5.81(1 H,d, J = 1.6Hz); 6.10(1 H,bs); 7.40,7.80 (4H,AA'BB', J = 9Hz); 7.56,8.22 (4H,AA'BB', J = 8.7Hz).

Example 60 4-Nitrobenzyl 5R,6S-(1R-hydroxyethyl)-7-oxo-3-[4-(propylaminocarbonyl)phenyl]-4-this-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate The title compound (50mg) was obtained by a procedure analogous to that used in Example 19 by using 4-nitriobenzyl 5R,6S-{1R-[dimethyl(2-methylprop-2-yl)-silyloxy]ethyl}-7-oxo-3-[4-(propylaminocarbonyl) phenyl]-4-thia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylate (670mg), glacial acetic acid (0.64ml), tetrahydrofuran (5ml), and 1 M tetra-n-butylammonium fluoride in tetrahydrofuran (3.2ml).

Vmax (CDCl3) 1788, 1728cm-1 a (CDCl3) 0.99 (3H,t, J = 7.4Hz); 1.29 (2H,m); 1.39 (3H,d, J = 6.3Hz); 3.38-3.47 (2H,m); 3.87 (1 H,dd, J = 1.6 and 6.6Hz); 4.2-4.3(1H,m); 5.11,5.30(2H,AB,Jgem = 13.7Hz);5.70 (1H,d,J=1.6Hz); 6.10 (1H,bt); 7.41,7.72 (4H,AA'BB',J = 8.5Hz); 7.50,8.15 (4H,AA'BB',J = 8.9Hz).

Example 61 Potassium 5R,6S-(1R-hydroxyethyl)-7-oxo-3-[4-propyl-aminocarbonyl)phenyl]-4-thia-1azabicycolo[3.2.0]hept-2-ene-2-carboxylate The title compound (30mg) was obtained by a procedure analogous to that used in Example 7 by using 4-nitrobenzyl 5R,6S-(1 R-hydroxyethyl )-7-oxo-3-[4-(propylaminocarbonyl)phenyl]- 44hia-1 -azabicycl [3.2.0]hept-2-ene-2-carboxylate (50mg), 10% palladium on charcoal (50mg), potassium bicarbonate (9.8mg), dioxane (5ml), and water (5ml).

#(D2O)0.91 (3H,t, J = 7.3Hz); 1.28 (3H,d,J = 6.4Hz); 1.50-1.59 (2H,m); 3.27-3.37 (2H,m);3.96(1H,dd,J =1.5 and 5.9Hz); 4.20-4.26 (1 H,m); 5.76 (1 H,d, J = 1.5Hz); 7.46and 7.65 (4H,AA'BB',J = 8.3Hz).

Example 62 4gAcetylamino)-thiobenzoic acid To a sitrred suspension of 4-acetylaminobenzolc acid (10.0g) in dry dichloromethane (50ml) at - 15 was added triethylamine (6ml) followed by ethyl chloroformate (6ml). After 3 hours hydrogen sulphide (excess) was bubbled through; the mixture was warmed to room temperature, treated with 2M hydrochloric acid and filtered. The filtrate was partitioned and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with water, with brine, were dried and were evaporated in vacuo.Chromatography ofthe residue over silica gel and elution with ethyl acetate-hexane mixtures afforded the title compound (2.2g).

6 (acetone-ds) 2.17 (3H,s); 3.42(1H,bs); 7.90,8.01 (4H,AA'BB',J = 8.8Hz).

Example 63 4R-(4-Acetylaminobenzoylthio)-3S-{1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl}-azetidin-2-one The title compound (0.85g) was obtained by a procedure analogous to that used in Example 16 by using 4-(acetylamino)-thiobenzoic acid (2.Og), 4-acetoxy-3R-f1 R-[dimethyl(2-methyl prop-2-yl )silyloxy]ethyl}azetidin-2-one (2.2g) sodium hydroxide (0.44g), water (2ml), dichloromethane (5ml) and tetrahydrofuran (2ml).

Vmax (CDCl3) 1769, 1700 1655 cm-1 #(CDCl3) 0.09 (6H,s); 0.89 (9H,s); 1.24(3H,d,J = 6.3Hz); 2.23(3H,s); 3.28(1H,dd,J = 2.4 and 4.0Hz); 4.24-4.36 (1 H,m); 5.47 (1 H,d,J = 2.4Hz); 6.41(1 H,bs); 7.41(1 H,bs); 7.62,7.88 (4H,AA'BB',J = 8.8Hz).

Example 64 4-Nitrobenzyl{4R-[4-(acetylamino)benzoylthio]-3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl-azetidin2-on-1-yl}oxoacetate The title compound (151 mg) was obtained by a procedure analogous to that used in Example 17 by using 4R-(4-acetylaminobenzoylthio)-3S-(1R-{dimethyl-2.(2-methylprop-2-yl)-silyloxy}ethyl)-azetidin-2-one (100mg),4-nitrobenzyl choro-oxoacetate (69mg), calcium carbonate (100mg), diisopropylethylamine (49 l), and dichloromethane (4ml).

Vmax (CDCl3) 1813,1760 cm-1 #(CDCl3) 0.09 (6H,s); 0.83 (9H,s); 1.26 (3H,d,J = 6.3Hz); 2.22(3H,s); 3.60(1H,dd,J = 3.0 and 3.4Hz); 4.35 (1 H,m); 5.41 (2H,s); 6.15(1 H,d,J = 3.4Hz); 7.4-8.3 (8H,m).

Example 65 4-Nitrobenzyl 5R,3-(4-acetylaminophenyl)-6S-{1R-[dimethyl-(2-methylprop-2-yl)silyloxy)ethyl}-7-oxo-4-thia 1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylate The title compound (430mg) was obtained by a procedure analogous to that used in Example 18 by using 4-nitrobenzyl}4R-[4-(acetylamino)benzoylthio]-3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl- azetidin2-on-1-yl}oxoacetate (1.0g), triethyl phosphite (0.566ml), and o-xylene (8ml).

Vmax(CDCl3) 1785, 1705 cm-1 a (CDCI3) 0.08 (6H,s); 0.85 (9H,s); 1.27 (3H,d, J = 6.3Hz); 2.19 (3H,s); 3.78(1 H,dd,J = 1.6 and 4.2Hz); 4.30 (1 H,m); 5.10,5.30 (2H,AB, Jgem = 13.7Hz); 5.65(1 H,d, J = 1.6Hz); 7.29-8.19 (8H,m).

Example 66 4-Nitrobenzyl5R,3-(4-acetylaminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azablcyclo[3.2.0]hept-2-ene2-carboxylate The titel compound (131mg) was obtained by a procedure analogous to that used in Example 19 by using 4-nitrobenzyl5R,3-(4-acetylaminophenyl)-6S-{1R-[dimethyl-(2-methylprop-2-yl)-silyloxy]ethyl}-7-oxo-4thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylate (430mg), glacial acetic acid (0.534ml), tetrahydrofuran (10ml), and 1 m tetra-n-butylammonium fluoride in tetrahydrofuran (2.7ml).

Vmax (CDCl3) 1786 cm-1 8 (CDCI3) 1.40 (3H,d, J = 6.3Hz); 1.63(1 H,bs); 2.20 (3H,s); 3.60(1 H,dd, J = 1.6 and 6.6Hz); 4.2(1 H,m); 5.10,5.29 (2H,AB,Jgem=1 13.7Hz); 5.70(1 H,d,J 1.6Hz); 7.23-8.16 (8H,m).

Example 67 Potassium 5R,3-(4-acetylaminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2carboxylate The title compound (65mg) was obtained by a procedure analogous to that used in Example 7 by using 4-nitrobenzyl 5R,3-(4-acetylaminophenyl)-6S-(1 R-hyd roxy-ethyl)-7-oxo-4-thia-1 -azabicyclo[3.2.0]hept-2-ene2-carboxylate (123mg), 10% palladium on charcoal (123mg), potassium bicarbonate (33.3mg), dioxane (5ml) and water (5ml).

8 (D2O) 1.34 (3H,d,J) = 6.4Hz); 2.19 (3H,s); 4.00(1 H,dd,J = 1.6 and 6.1 Hz); 4.17-4.28(1 H,m); 5.79(1 H,d,J = 1.6Hz); 7.46 (4H,s).

Example 68 3-(Methylaminocarbonyl)-thiobenzoic acid The title compound (4.59) was obtained by a procedure analogous to that used in Example 44 by using isophthaloyl chloride (10.0g), triethylamine (17.8ml), methylamine hydrochloride (5g), dichloromethane (200ml), pyridine (7.5ml), and hydrogen sulphide (excess).

8 (acetone-d5) 2.91 (3H,d, J = 1.2Hz); 7.5-8.3 (4H,m).

Example 69 3S-{1R-[Dimethyl(2-methylprop-2-yl)silyloxy]ethyl}-4R-[3-(methylaminocarbonyl)benzoylthio]azetidin-2one The title compound (1.0g) was obtained by a procedure analogous to that used in Example 16 by using 4-acetoxy-3R-f1 R-[dimethyl (2-methylprop-2-yl )silyloxy]-ethyl}azetidin-2-one (2.04g) 3 (methylaminocarbonyl)-thiobenzolcacid (4.59), 1 M sodium hydroxide (21 mi), and acetone (50ml).

Vmax(film 1768, 1655 cm-1 8 (CDCl3) 0.10 (6H,s); 0.89 (9H,s); 1.24 (3H,d,J=6.3Hz); 3.03(3H,d,J=4.8Hz); 3.29 (1H,dd,J=2.4 and 3.8Hz); 4.30-4.36(1H,m); 5.49(1H,d,J = 2.4 Hz); 6.96(1H,bs,J = 4.8Hz); 7.14 (1H,bs); 7.53-8.30(4H,m).

Example 70 4-Nitrobenzyl{3S-[1R-(dimethyl(2-methylprop-2-yl)-silyloxy)ethyl]-4R-[3-(methylaminocarbonyl)benzoylthio]-azetidin-2-on-1-yl}oxoacetate The title compound (1.43g)was obtained buy a procedure analogous to that used in Example 17 by using 3S-{1R-[dimethyl-(2-methylprop-2-yl)-silyloxy]ethyl}-4R-(3-methylaminocarbonylbenzoylthio)-azetidin-2 one(l.Og), 4-nitrobenzyl chloro-oxoacetate (720mg), dichloromethane (10ml), calcium carbonate(l.Og), and diisopropylethylamine (0.60ml).

8 (CDCl3) 0.09 (6H,s); 0.83 (9H,s); 1.25 (3H,d, J = 6.3Hz); 3.04 (3H,d, J = 4.9Hz); 3.60-3.66 (1 H,m); 4.30-4.40(1 H,m); 5.38,5.42 (2H,AB, J = 13.0Hz); 6.19 (1 H,d,J=3.4Hz); 7.53-8.26 (8H,m).

Example 71 4-Nitrobenzyl 5R,6S-{1R-[dimethyl(2-methylprop-2-yl)-silyloxy]ethyl}-3-[3-(methylaminocarbonyl)phenyl]7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate The title compound (0.48g) was obtained by a procedure analogous to that used in Example 18 by using 4-nitrobenzyl f3S-[1 R-(dimethyl (2-methylprop-2-yl)-silyloxy)ethyl]-4R-[3-(methylaminoca rbonyl) benzoylthio]-azetidin-2-on-1 -yl}oxoacetate (1.43g), triethyl phosphite (0.78ml), hydroquinone (5mg), and o-xylene (10ml).

Vmax(film) 1779 cm-1 8 (CDCl3) 0.08 (6H,s); 0.86 (9H,s); 1.25 (3H,d,J = = 6.4Hz); 3.01 (3H,d, J = 4.9Hz); 3.81(1 H,dd,J = 1.6 and 4.2Hz); 4.10-4.25(1 H,m); 5.20,5.28 (2H,AB, J = 13.6Hz); 5.74(1 H,d,J = 1.6Hz); 6.11(1 H,bd, J = 4.9Hz); 7.39-8.29 (8Hz,m).

Example 72 4-Nitrobenzyl5R,6S-(1R-hydroxyethyl)-3-[3-(methyl-aminocarbonyl)phenyl]-7-oxo-4-thie-1azabicyclo[3.2.0]-hept-2-ene-2-carboxylate The title compound (160mg) was obtained bya procedure analogous to that used in Example 19 by using 4-nitrobenzyl 5R,6S-{1R-[dimethyl{2-methylprop-2-yl)-siyloxy]ethyl}-3[3-(methylaminocarbonyl)phenyl]-7oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (480mg), glacial acetic acid (0.48ml), tetrahydrofuran (10ml)and 1 M tetra-n-butyalmmonium fluoride in tetrahydrofuran (2.4ml).

Vmax(KBr) 1785cm-1 8 (CDCl3) 1.41 (3H,d, J = 6.3Hz); 1.68(1 H,bs); 3.01 (3H,d, J = 4.9Hz); 3.87(1 H,dd,J = 1.6 and 6.5Hz); 4.28-4.35 (1 H,m); 5.13,5.30 (2H,AB,J = 13.6Hz); 5.77(1 H,d,J = 1.6Hz); 6.08(1 H,bs); 7.37-8.17 (8H,m).

Example 73 Potassium 5R,6S-(1R-hydroxyethyl)-3-[3-(methylamino-carbonyl)phenyl]-7-oxo-4-thia-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylate The title compound (80mg) was obtained by a procedure analogous to that used in Example 7 by using 4-nitrobenzyl 5R,6S,-(1R-hydroxyethyl)-3-[3-methylamino-carbonyll)phenyl]-7-oxo-4-thia-1azabicyclo[3.2.0]hept- 2-ene-2-carboxylate (160mg), 10% palladium on charcoal (1 60mg), potassium bicarbonate (33.1mg), water (5ml) and dioxane (5ml).

#(D2O) 1.30 (3H,d,J = 6.4Hz); 2.89 (3H,s); 3.99(1 H,dd, J = 1.2 and 5.8Hz); 4.21-4.29(1 H,m); 5.78(1 H,d, J = 1.2Hz); 7.44-7.79 (4H,m).

Example 74 4- (Nitra)-thiobenzoic acid The title compound (9.8g) was obtained by a procedure analogous to that used in Example 24 by using 4-nitrobenzoyl chloride (10.09), dichloromethane (200ml), pyridine (8.6ml); and hydrogen sulphite (excess).

#(acetone-d6) 4.30 (1H,bs); 8.30,8.37 (4H,AA'BB',J 9.9Hz).

Example 75 3S-{1R-[Dimethyl(2-methylprop-2-yl)silyloxy]ethyl}-4R-(4-nitrobenzylithio)azetidin-2-one The title compound (2.69) was obtained by a procedure analogous to that used in Example 16 by using 4-acetoxy-3R-f1 R-[dimethyl (2-methyl prop-2-yl)silyloxy]ethyl)azetidin-2-one (2.0g), 4-(nitro)-thiobenzoic acid (1.7g), dichloromethane (50ml), water (50ml), and sodium hydroxide (0.36g).

Vmax(CDCl3) 1775cm-1 8 (CDCl3) 0.10 (6H,s); 0.89 (9H,s); 1.27 (3H,d, J = 6.3Hz); 3.32(1H,dd,J = 2.3 and 3.8Hz); 4.30(1H,m); 5.51 (1 H,d, J = 2.3Hz); 6.50(1 H,bs); 8.07,8.32 (4H,AA'BB', J = 9.0Hz).

Example 76 4-Nitrobenzyl{3S-[1R-(dimethyl(2-methylprop-2-yl)-silyloxy)ethyl]-4R-(4-nitrobenzoylthio)azetidin-2-on-1yl}oxoacetate The title compound (754mg) was obtained by a procedure analogous to that used in Example 17 by using 3S-{1 R-[dimethyl (2-methyl prop-2-yl)silyloxy]ethyl}-4R-(4-nitrobenzoylthio)azetidin-2-one (0.59), calcium carbonate(0.5g), 4-nitrobenzylchlorooxoacetate (0.36g), dichloromethane (10ml) and diisopropylethylamine (0.255ml).

Vmax(film) 1817, 1712cm-1 #(CDCl3) 0.10 (6H,s), 0.84 (9H,s); 1.28 (3H,d, J = 6.3Hz); 3.64(1 H,dd, J = 3.0 and 3.4Hz); 4.38-4.47(1 H,m); 5.41 (2H,s); 6.18(1 H,d,J = 3.4Hz); 7.57,8.22 (4H,AA'BB', J = 8.8Hz); 8.08,8.33 (4H,AA'BB',J = 8.9Hz).

Example 77 4-Nitrobenzyl 5R,6S-{1R-[dimethyl(2-methylprop-2-yl)-silyloxy]ethyl}-3-(r-nitrophenyl)-7-oxo-4-thia-1azabicyclo[3.2,0]hept-2-ene-2-carboxylate The title compound (21 5mg) was obtained by a procedure analogous to that used in Example 18 by using 4-nitrobenzylf3S-[1 R-(dimethyl(2-methylprop-2-yl)silyl-oxy)ethyl]-4R-(4-nitrobenzoylthio)azetidin-2-on-1 - yl}-oxoacetate (754mg), triethyl phosphite (0.418 ml), and o-xylene (5ml).

Vmax(CDCl3) 1778cm-1 8 (CDCI2) 0.09 (6H,s); 0.86 (9H,s); 1.27 (3H,d, J = 6.3Hz); 3.87 (1 H,dd, J = 1.5 and 4.0Hz); 4.29 (1 H,m); 5.12, 5.30 (2H,AB,Jgem = 13.6Hz); 5.81 (1H,d,J = 1.5Hz); 7.51,8.16 (4H,AA'BB',J=8.6Hz); 7.62,8.20(4H,AA'BB',J= 8.8Hz).

Example 78 4-Nitrobenzyl 5R,6S-(1R-hydroxyethyl)-3-(4-nitrophenyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2carboxylate The title compound (106mg) was obtained by a procedure analogous to that used in Example 19 by using 4-nitrobenzyl 5R,6S,-{1R-dimethyl(2-methylprop-2-yl)silyl-oxy]ethyl}-3-(4-nitrophenyl)-7-oxo-4-thia-1 azabicyclo-[3.2.0] hept-2-ene-2-carboxylate (200mg), glacial acetic acid (0.204ml), tetrahydrofuran (5ml), and 1 M tetra-n-butylammonium fluoride in tetrahydrofuran (1.02ml).

Vmax (film) 1790, 1712cm-1 8 (CDC6) 1.41 (3H,d, J = 6.3Hz); 1.61(1 H,bs); 3.91(1 H,dd,J = 1.6,6.4Hz); 4.20-4.39(1 H,m);5.12,5.31 (2H,AB, Jgem = 13.5Hz); 5.82 (1H,d,J = 1.6Hz); 7.47,8.17(4H,AA'BB',J=8.7Hz); 7.58,8.21 (4H,AA'BB',J = 8.9 Hz).

Example 79 Potassium SR,3-(4-aminophenyll-6S-l IR-h ydroxyethyl)-7-oxo-4-thia- 1-azabicyclo[3.2.0]hept-2-ene-2- carboxylate The title compound (44mg) was obtained by a procedure analogous to that used in Example 7 by using 4-nitrobenzyl 5R,6S-(1 R-hydroxyethyl)-3-(4-nitrophenyl )-7-oxo-4-thia-1 -aza bicyclo[3.2.0] hept-2- ene-2carboxylate (100mg), 10% palladium on charcoal (100mg), potassium bicarbonate (21.2mg), water (5ml), and dioxane (5ml).

8 (D2O) 1.33 (3H,d,J = 6.3Hz); 3.93 (1H,dd,J = 1.4 and 5.3Hz); 4.23 (1H,m); 5.70 (1H,d,J = 1.4Hz); 6.80,7.30 (4H,AA'BB',J=8.4Hz).

Example 80 Potassium 5R-3-(4-acetylaminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2carboxylate A solution of 4-nitrobenzyl 5R,3-(4-aminophenyl )-6S-(1 R-hydroxyethyl)-7-oxo-4-th ia-1 -azabicyclo[3.2.0] hept-2-ene-2-carboxylate (33mg) in water (0.5ml) and dioxane (0.5ml) was treated at 0 with acetic anhydride (0.05ml), The mixture was warmed over 30 minutes to room temperature and stirred a further hour. Lyophilisation followed by partition of the solid between ethyl acetate and water, and lyophilisation of the aqueous layer afforded the title compound (29mg) with properties identical to those given in Example 67.

Example 81 2-(Trimethylsllyl)ethyl chlorooxoxacetate To a stirred solution of oxalyl chloride (12.79) in dry diethyl ether (25ml) at 0 C was added dropwise 2 (trimethylsilyl)ethanoi (11 .8g). The mixture was stirred for a further 16 hours, and then distilled to afford the title compound (19.9g) bp8O'/Smm.

8 (CDCI3) 0.83 (9H,s); 1.16 (2H,m); 4.46 (2H,m).

Example 82 2-(Trimethylsilyl)ethyl{3S-1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-4R-(4-nitrobenzoylthio)azetidin2-on- 1-yl'Joxoacetate The title compound (8.0g) was obtained by a procedure analogous to that used in Example 17 by using 4-acetoxy-3S-{1R-[dimethyl(2-methylprop-2-yl)silyloxy]-ethyl}-azetidin-2-one (5.0g), calcium carbonate (5.0g), 2-(trimethylsilyl)ethyl chlorooxoacetate (3.35ml), dichloromethane(l 00ml) and diisopropylethylam- ine (4.2ml).

8 (CDCl3) 0.07 (9H,s); 0.12 (6H,s); 0.88 (9H,s); 1.11 (2H,t,J = 8.4Hz); 1.29 (3H,d,J = 6.3Hz); 3.62(1 H,t,J = 3.3Hz); 4.40 (3H,m); 6.18(1 H,d,J = 3.3Hz); 8.11, 8.34 (4H,AA'BB',J = 8.8Hz).

Example 83 2-(Trimethylsilyl)ethyl 5R,6S-{1R-[dimethyl(2-methyl-prop-2-yl)silyloxy]ethyl}-3-(4-nitropenyl)-7-oxo-4-thia 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate The title compound (2.869) was obtained by a procedure analogous to that used in Example 18 by using 2-(trimethylsilyl )ethyl f3S-[1 R-(dimethyl (2-methylprop-2-yl )silyloxy)ethyl]-4R-(4-nitrobenzylthio)azetidin- 2on-1 -yl}oxoacetate (8.0g), triethyl phosphite (4.2ml), o-xylene (100ml), and hydroquinone (10mg).

Vmax(film) 1796, 1711 cm-1 #(CDCl3) 0.01 (9H,s); 0.11 (3H,s); 0.12 (3H,s); 0.91 (11H,m); 1.28(3H,d,J = 6.3Hz); 3.82(1H,dd,J = 1.6 and 4.6Hz); 4.18 (2H,m); 4.29(1 H,m); 5.76(1 H,d,J = 1.6Hz); 7.64,8.23 (4H,AA'BB',J =8.9Hz).

Example 84 2-(Trimethylsiyl)ethyl 5R,6S-(1R-hydroxyethyl)-3-(4-nitrophenyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2 ene- 2-carbaxylate The title compound (142mg)was obtained buy a procedure analogous to that used in Example 19 by using 2-(trimethylsiyl)ethyl 5R,6S-{1R-[dimethyl(2-methyl-prop-2-yl)silyloxy]ethyl}-3-(4-nitrophenyl)-7-oxo-4 thia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylate (360mg), glacial acetic acid (0.4ml), tetrahydrofuran (1 Oml), and 1 M tetra-n-butylammonium fluoride in tetrahydrofuran (2ml).

Vmax(CDCl3) 1789, 1710cm-1 #(CDCl3) 0.01 (9H,s); 0.92 (2H,m); 1.40 (3H,d,J = 6.3Hz); 3.86 (1H,dd,J = 1.6 and 6.6Hz); 4.20 (2H,m); 4.30 (1 H,m); 5.79(1 H,d,J = 1.6Hz). 7.63,8.24 (4H,AA'BB', J = 8.9Hz).

Example 85 2-(Trimethylsilyl)ethyl 5R,6S-(1R-hydroxyethl)-3-(4-hydroxyaminophenyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate A mixture of 2-(trimethylsilyl)ethyl 5R,6S-(1 R-hydroxyethyl)-3-(4-nitrophenyl)-7-oxo-4-thia-1- azabicyclo[3.2.0] hept-2-ene-2-carboxylate 2.19), 10% palladium on charcoal (2.lg)and dioxane (50ml)was hydrogenolysed at 375 kPa (4 atm) for 2 hours, was filtered through diatomaceous earth and evaporated in vacuo.Chromatography at the residue over silica gel and elution with ethyl acetate-hexane mixtures afforded the title compound (1.5g).

8 (acetone-d6) 0.02 (9H,s); 0.95 (2H,m); 1.31 (3H,d,J = 6.3Hz); 3.76(1 H,dd,J = 1.5 and 7.0Hz); 4.17 (3H,m); 4.42 (1 H,d,J = 4.9Hz); 5.69(1 H,d,J= 1.5Hz) 6.95 and 7.43 (4H,AA'BB',J = 8.6Hz); 7.90 (1H,broad);8.15(1 H, broad).

Example 86 2-(Trimethylsilyl)ethyl 5R,3-(4-aminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]-hept-2ene-2-carboxylate A mixture of 2-(trimethylsilyl)ethyl 5R,6S-(1 R-hydroxyethyl )-3-(4-hydroxyaminophenyl )-7-oxo-4-thia- 1 azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1 .49), platinum dioxide (500mg), and dry ethyl acetate (30ml) was hydrogenolysed at 375 kPa (4 atm) at 20 , and then filtered and evaporated in vacuo.Chromatography ofthe residue oversilica gel and elution with ethyl acetate-hexane mixtures afforded the title compound (1.06g).

vmax(KBr) 1780,1706 cm- 8 (acetone-d6) 0.01 (9H,s); 0.96 (2H,m); 1.29 (3H,d,J = 6.3Hz); 3.70(1 H,dd,J = 1.5 and 7.1Hz); 4.15 (3H,m); 5.20(1 H,broad); 5.60(1 H,d,J = 1.5Hz); 6.63 and 7.33 (4H,AA'BB',J = 8.8Hz).

Example 87 2-(Trimethylsilyl)ethyl 5R,3-(4-formylaminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate To a stirred solution of 2-(trimethylsilyl)ethyl 5R,3-(4-aminophenyl)-6S-(1 R-hydroxyethyl)-7-oxo-4-thia-1- acabicyclo [3.2.0]hept-2-ene-2-carboxylate (200mg) in deuterochloroform (5ml) at 0 was added formic acid (22.3 l), followed by 1 -(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (11 3mg). The mixture was stirred a further 15 minutes, and was then partitioned between water and chloroform.The organic layer was washed with 1 M citric acid, with water, with saturated aqueous sodium bicarbonate, with brine, was dried over anhydrous sodium sulphate and was evaporated in vacuaChrnmatogrnphy of the residue over silica gel and elution with ethyl acetate-hexane mixtures afforded the title compound (162mg).

vmax(Kbr) 1777,1702 and 1623cm-1 8 (DMSO-d6) 0.01 (9H,s); 0.84(2H,m); 1.18 (3H,d,J = 6.3Hz); 3.85(1H,dd,J = 1.5 and 6.3Hz); 4.00(1H,m);4.10 (2H,m); 5.23(1 H,d,J = 4.8Hz); 5.71(1 H,d,J = 1.5Hz); 7.42 and 7.61 (4H,AA'BB',J = 8.5Hz); 8.31(1 H,s); 10.31 (1H, broad).

Example 88 Potassium 5R,3-(4-formylaminophenyl)-6S-(1R-hydroxy-ethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene2-carboxylate To a stirred solution of 2-(trimethylsily)ethyl 5R,3-(4-formylaminophenyl)-6S-(1 R-hydroxyethyl)-7-oxo-4 thia-1 - azabicyclo[3.2.0]hept-2-ene-2-carboxylate (80mg) in tetrahydrofuran (3ml) at 0' was added a solution of a 1 M tetra-n-butylammonium fluoride in tetrahydrofuran (0.1 84ml) which had been dried over4A molec ular sieves. After 16 hours the mixture was treated with an aqueous solution of potassium bicarbonate (18.4mg).The aqueous solution was washed with ethyl acetate, and then lyophilised to afford a crude product (11 Omg). Purification either by chromatography over HP20A resin or by acidification/neutralisation or prepar ative high pressure liquid reverse phase chromatography (C18-silica gel) and elution with water-acetonitrileformic acid mixtures afforded, after lyophiiisation and reneutralisation with potassium bicarbonate the title compound (50mg).

#((D2O) 1.35 (3H,d,J = 6.3Hz); 3.95(1 H,dd, J = 1.5 and 5.5Hz); 4.25 (1 H,m); 5.75(1 H,d,J = 1.5Hz); 7.43 and 7.49 (4H,AA'BB', J = 8.9Hz); 8.25 (1 H, bs).

Example 89 2-(Trimethylsilyl)ethyl 5R,6S-(1R-hydroxyethyl)-3-{4-[(methylamino)carbonylamino]phenyl}-7-oxo-4- thia- 1azabicyclo[3.2.0]hept-2-ene-2-carboxylate A mixture of 2-(trimethylsilyl)ethyl SR,3-(4-aminophenyl)-6S-( 1 R-hydroxyethyl)-7-oxo-4-thia-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (200mg), dry tetrahydrofuran (5ml) and methyl isocyanate (0.3ml)was stirred at room temperature for 16 hours, and then partitioned between ethyl acetate and water. The organic layer was washed with water and with brine, was dried over anhydrous sodium sulphate and evaporated in vacuo.Chromatography ofthe residue over silica gel, and elution with ethyl acetate-hexane mixtures afforded the title compound (86 mg).

Vmax(film) 1785 cm-1 8 (acetone-d6) 0.01 (6H,s); 0.93 (2H,m); 1.29 (3H,d,J = 6.3Hz); 2.73 (3H,d,J = 4.6Hz); 3.77(1 H,dd,J = 1.6 and 6.9Hz); 4.15 (3H,m); 4.37 (1 H,d,J = 5.9Hz); 5.70(1 H,d,J = 1.6Hz); 5.78(1 H, broad); 7.41 and 7.52 (4H,AA'BB',J = 8.8Hz); 8.21(1 H, broad).

Example 90 Potassium 5R,6S-(1R-hydroxyethyl)-3-{4-[(methylamino)-carbonylamino]phenyl}-7-oxo-4-thia-1azabicyclo[3.2.0]-hept-2-ene-2-carboxylate The title compound (55mg) was obtained by a procedure analogous to that used in Example 88, using 2-(trimethylsilyl)ethyl 5R,6S-(1 R-hydroxyethyl @-3-{4-[(methylamino)carbonylamino] phenyl}-7-oxo-4-thia-1 azabicyclo[3.2.0]hept-2-ene-carboxylate (80mg), a dried solution of 1 M tetra-n-butylammonium fluoride in tetrahydrofuran (0.17ml),tetrahydrofuran (5ml) and potassium bicarbonate (17.3mg).

a (D20) 1.3 (3H,d,J=6.3Hz); 2.71 (3H,s); 3.91 (1 H,dd,J=1.5 and 5.8Hz); 4.23(1 H,m); 5.70(1 H,d,J = 1.5Hz); 7.26 and 7.36 (4H,AA'BB',J =8.7Hz).

Example 91 4-Nitrobenzyl 5R,3-(3-carboxyphenyl)-6S-{1R-[dimethyl-(2-methylprop-2-yl)silyloxy}-7-oxo-4-thie-1-aza bicyclo[3.2.0]hept-2-ene-2-carbonate By a procedure analogous to that used in Example 29, but starting from a solution of isophthaloyl chloride (10.159) in dioxane (150ml), a solution 2,4-dimethoxybenzyl alcohol (10.09g) in dioxane (20ml),triethylamine (8.35ml), dichloromethane (100m I), pyridine (4.85ml), and hydrogen sulphide (excess), there was obtained 3-(2,4-dimethoxybenzyloxycarbonyl)thiobenzoic acid (11.69): Vmax2550,1721,1675 and 1615cm-1; #(acetone-d6)3.72(3H,s);3.77; (3H,s); 5.26(2H,s); 6.44 (1H,dd,J=2.4 and 8.3Hz); 6.50 (1H,d,J=2.3Hz); 7.28 (1H,d,J=8.3Hz); 7.60 (lH,m); 8.16 (2H,m); 8.53(1 H,m).

Asolution ofthisthiobenzoicacid (10.9g) in acetone (70ml)wastreated in a procedureanalogoustothat used in Example 30 with 1M-sodium hydroxide (43ml) and a solution of 4-acetoxy-3R-{1R-[dimethyl(2 methyl-prop-2-yl)silyloxy]ethyl}-azetidin-2-one (7.85g) in acetone-water (3:1) (100ml) to afford 4R-[3-r2,4dimethoxybenzoyloxycarbonyl)benzoylthiol-35-{ IR-[dimethyl(2-methyIprop-2- yl)silyloxy]ethyl}azetidin-2-one (7.66g): Vmax (CDCl3) 3418, 1772, 1719cm-1; s (CDC6) 0.07 (6H,s); 0.86 (9H,s); 1.22 (3H,d,J=6.3Hz); 3.27(1 H,dd,J=2.5 and 4Hz); 3.80 (3H,s); 3.81 (3H,s); 4.29 (3H,m); 5.34 (2H,s); 5.46(1 H,d,J=2.5Hz); 6.47 (2H,m); 6.54(1 H,s); 7.30 (1 H,d,J =8.9Hz); 7.51 (1H,t,J=7.8Hz); 8.05(1H,dd,J=1.4 and 7.8Hz); 8.25 (1H,dd,J=1,4 and 7.8Hz); 8.54 (1H,t,J=1.4Hz).

A solution of this azetidinone (2.8g) in dichloromethane (20ml) was treated in a procedure analogous to that used in Example 31 with calcium carbonate (1.25g), diisopropylethylamine (0.979), and a solution of4 nitrobenzyl chlorooxalate (1.46g) in dichloromethane (5ml) to afford as a yellowfoam 4-nitrobenzyl 4R-[3-(2,4-dimethoxybenzyloxycarbonyl)-benzoylthio]-3S-{1R-[dimethyl(2-methylprop-2 yl)siyl-oxy]ethyl}azetidin-2-on-1-yl]oxoacetate (3.8g).

Vmax (film) 1818, 1761 and 1720 cm-1; 8 (CDCl3) 0.01 (3H,s); 0.09 (3H,s); 0.83 (9H,s); 1.26 (3H,d,J=6.3Hz); 3.64 (1 H,t,J=3Hz); 3.82 (3H,s);3.83 (3H,s); 4.40 (1 H,m); 5.36 (2H,s); 5.40 (2H,s); 6.19 (1 H,d,J=3.4Hz); 6.50 (1 H,m); 7.32 (1 H,d,J=8.9Hz); 7.55 (3H,m); 8.09 (1H,d,J=7.9Hz); 8.21 (2H,d,J=8.8Hz); 8.29 (1H,d,J=7.9Hz); 8.57 (1H,dJ=1.7Hz).

A solution of this foam (3.8g) in xylene (100ml) was treated in a procedure analogous to that used in Example 32 with a solution of triethyl phosphite (1 .66g) in xylene (1 0ml) to afford 4-nitrobenzyl 5R,3-[3-(2,4-dimethoxybenzyloxycarbonyl)-phenyl]-6S-{1R-]dimethyl(2-methylprop-2-yl)silyl oxy]ethyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.84g); Vmax(CDCl3) 1790 and 1721 cm-1; 8 (CDCl3) 0.07 (3H,s); 0.08 (3H,s); 0.85 (9H,s); 3.82 (3H,s+m); 4.30(1 H,m); 5.08,5.25 (2H ,AB,J gem=13.7Hz); 5.32 (2H,s); 5.74(1 H,d,J= 1.5Hz); 6.48 (2H,m); 7.31(1 H,d,J =8.9Hz); 7.40 (3H,m); 7.59(1 H,m); 8.08 (4H,m); Asolution of this 4-nitrobenzyl carboxylate (1 .849) in dichloromethane (100ml) was treated in a procedure analogous to that used in Example 33 with water (1 ml) and 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone (DDQ) (1.14g) to afford the title 3-carboxyphenyl compound (0.98g): #(CDCl3) 0.07 (3H,s); 0.09 (3H,s); 0.86 (9H,s); 1.28 and 1.29 (3H,2xd,J=6.3Hz); 3.83 (1H,dd,J=1.6 and 4Hz); 4.31(1 H,m); 5.12,5.28 (2H,AB,Jgem=13.6Hz); 5.77(1 H,d,J=1.5Hz); 7.46 (3H,m); 7.70(1 H,m); 8.15 (4H,m).

Example 92 4-Nitrobenzyl 5R,3-[3-(2,4-dimethoxybenzyloxycarbonyl)-phenyl]-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1 azabicyclo-[3.2. O]hept-2-ene-2-carboxylate The title compound (6.6g) was prepared by a procedure analogous to that used in Example 37 by using 4-nitrobenzyl 5R,3-[3-(2,4-dimethoxybenzyloxycarbonyl)-phenyl]-6S-{1R-[dimethyl(2-methylprop-2-yl) silyloxy]-ethyl}-7-oxo-4-thia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylate (8.0g), glacial acetic acid (6.5g) and a 1 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (32.6ml).

a (CDCl3) 1.31 (3H,d,J=6Hz); 3.75 (6H,s); 3.80 (1H,dd,J=1.2 and 6.5Hz); 4.03(1 H,m); 5.00,5.17 (2H,AB,Jgem=13.6Hz); 5.25 (2H,s); 5.69(1H,d,J=1.2Hz); 6.42 (2H,m); 7.2-7.5 (5H,m); 7.9-8.2 (4H,m).

Example 93 4-Nitrobenzyl 5R,3-(3-carboxyphenyl)-6S-(1R-hydroxy-ethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2 carboxylate The title compound (1.39g) was obtained by a procedure analogous to that used in Example 40 using 4-nitrobenzyl 5R,3-[3-(2,4-dimethoxybenzyloxyca rbony)-phenyl]-6S-(1 R-hydroxyethyl)-7-oxo-4-thia- 1 azabicyclo-[3.2.0]hept-2-ene-2-carboxyla (6.2g), dichloromethane (200ml), water(l0ml) and DDQ (4.549): 8 (acetone-d6) 1.20 (3H,d,J=6.3Hz); 3.84(1 H,dd,J= 1.7 and 6.4Hz); 4.10(1 H,m); 5.06,5.19 (2H,AB,Jgem=13.8Hz); 5.79 (1H,d,J=1.7Hz); 7.35-7.45 (3H,m); 7.61 (1H,dd,J=7.8 and # 1.4Hz); 7.90-8.06 (4H,m).

Example 94 4-Nitrobenzyl SR,S--aminocarbon ylphen yll-6S-( 1R-[dimethyl-(2-methylprop-2-yl)silyl]oxyethyl}- 7-oxo-4- thia-1-acabicyclo[3.2.0]hept-2-ene-2-carboxylate By a procedure analogous to that used in Example 34, but using 4-nitrobenzyl SR,3-(3-carboxyphenyl)-6S- {1R-[dimethyl-(2-methlprop-2-yl)silyloxy]ethyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (786mg), HOBT (365mg), acetonitrile 840ml), tetrahydrofuran (4ml), 1-(3-dimethylaminopropyl)-3 ethylcarboxiimide hydrochloride (389mg) and a solution of ammonia in ethanol (36 g.1 -1, 2ml) the title compound was obtained: 8 (acetone-d6) 0.08 (3H,s); 0.10 (3H,s); 0.93 (9H,s); 1.28 (3H,d,J=6.3z); 4.02(1 H,dd,J=6.3z); 4.02 (1H,dd,J=1.7 and 3.6Hz); 4.35 (1H,dp,J=3.6 and 6.3 Hz); 5.30, 5.15(2H,AB,Jgem=13.9Hz); 5.87 (1H,d,J=1.7Hz); 6.92 (1 H,bs); 7.47 (1 H,t,J =7.8Hz); 7.54,8.13 (4H,AA'BB',JAB=8.6Hz); 7.64 (1 H,dt,J=1 .4 and 7.8Hz); 8.00 (1 H,dt,J=1.4 and 7.8Hz); 8.07 (1 H,t,J = 1.4Hz).

Example 95 4-Nitrobenzyl 5R,3-(3-aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicylo[3.2.0]hept-2ene-2-carboxylate By a process analogous to that used in Example 38, but using 4-nitrobenzyl 4-nitrobenzyl 5R,3-(3carboxyphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (492mg), 1hydroxybenzotriazole (HOBT) (283mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 8301 mg) and a solution of ammonia in ethanol (29.8 g.1-1, 1.78ml), acetonitrile (50ml) and tetrahydrofuran 82ml), the title compound (392mg) was obtained.

#(acetone-d6)) 1.30 (3H,d,J=6.3Hz); 3.93 (1H,dd,J=1.6 and 6.3Hz); 4.18 (1H,m); 5.16,5.29 (2H,AB,Jgem=14.0Hz); 5.88 (1H,d,J=1.6Hz); 6.79(1H,bs); 7.48(3H,m); 7.62(1H,dt,J=1.3Hz); 7.97(1H,dt,J=1.3 and 7.8Hz); 8.03 (1 H,t,J = 1.3Hz); 8.13 (2H,d,J=8.8Hz).

Alternatively, the title compound (31 3mg) was obtained from the corresponding dimethyl-(2-methylprop2-yl)silyloxyethyl compound (744mg) prepared in Example 94 by a procedure analogous to that used in Example 35 by using glacial acetic acid (766mg) and a solution oftetra-n-butylammonium fluoride in tetrahydrofuran (iM,3.84ml).

Example 96 Potassium 5R,3-(3-aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azablcyclo[3.2.0]hept-2-ene2-carboxylate By a procedure analogous to that used in Example 36, and using 4-nitrobenzyl SR,3-(3-aminocarbonyl phenyl)-6S-(1 R-hydroxyethyl)-7-oxo-4-thia-1 -azabicyclo-[3.2.0]hept-2-ene-2-carboxylate (250mg), dioxane (1 ml), potassium bicarbonate (51 mg), water (10ml) and 10% pailadium-on-charcoal (250mg),thetitle compound (125mg) was obtained.

8 (D2O) 1.30 (3H,d,J =6.3Hz); 3.98 H,dd,J= 1.5 and 5.9Hz); 4.25 (1H,m); 5.78 (1H,d,J=1.5Hz); 7.48 (1H,t,J=8.0Hz); 7.60(1 H,dt,J= 1.4 and 7.9Hz); 7.75-7.79 (2H,m).

Example 97 4-Nitrobenzyl 5R,3-(3-aminocarbonylmethylaminocarbonyl-phenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1azabicyclo-[3.2.0]hept-2-ene-2-carboxylate By a process analogous to that used in Example 38, but using 4-nitrobenzyl SR,3-(3-carboxyphenyl)- 6S-(1 R hydroxyethyl)-7-oxo-4-thia-1 -azabicycl [3.2.0]hept-2-ene-2-carboxylate (243mg), HOBT (140mg),1 -(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (148mg), acetonitrile (20ml), tetrahydrofuran (2ml), glycinamide hydrochloride (285mg) and triethylamine (261 mg) the title compound was obtained as a yellow solid (132mg).

8 (acetone-d6) 1.32 (3H,d,J =6.3Hz); 3.96(1 H,dd,J=1 .7 and 6.3Hz); 4.03 (2H,d,J=5.6Hz); 4.22(1 H,m); 4.47 (1H,d,J=4.8Hz); 5.18 and 5.31 (2H,AB,Jgem=13.8Hz); 5.91 (1H,d,J=1.6Hz); 6.44(1H,bs); 7.05 (1H,bs); 7.49 and 8.16 (4H,AA'BB',J=8.8Hz); 7.52 (1H,m); 7.64(1H,dt,J=1.3 and 7.8Hz); 7.97 (1H,dt,J=1.4 and 7.8 Hz); 8.04 (1 H,m).

Example 98 Potassium 5R,3-(3-aminocarbonylmethylaminocarbonyl-phenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1azabicyclo[3.2.0]hept-2-ene-2-carboxylate By a procedure analogous to that used in Example 36, and using 4-nitrobenzyl 5R,3-(3-amino- car bonyl methyl-aminocarbonylphenyl )-6S-( 1 R-hydroxyethyl)-7-oxo-4-thia-l -azabicyclo[3.2.0]hept-2-ene-2- carboxylate (130mg), dioxane (10ml), potassium bicarbonate (24.7mg), water (1 Oml) and 10% palladium-oncharcoal (1 30mg), the title com pou nd (1 02m g) was obtained.

(D2O) 1.30 (3H,d,J=6.4Hz); 4.00 (1H,dd,J=1.4 and 5.9Hz); 4.08(2H,s); 4.24(1H,m); 5.80 (1H.d.J=1.4Hz); 7.48-7.82 (4H,m).

Example 99 5R,3-(3-Cyanomethylaminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-thia-1-azabicyclo[3.2.0]hept-2ene-2-carboxylicacid By a procedure analogous to Example 34, but using (4-nitrobenzyl SR,3-(3-carboxy- phenyl)-6S-{1 R [dimethyl-(2-methyl prop-2-yl)silyloxy]ethyl}-7-oxo-4-thia-1 -azabicyclo [3.2.0]hept-2-ene-2-carboxylate (400mg), HOB1(186mg), acetonitrile(l Oml),tetrahydrofuran (2ml) and l-(3-dimethylaminopropyl)-3- ethylcarboxiimide hydrochloride (198mg), triethylamine (209mg), and aminoacetonitrile hydrochloride (192mg), and aminoacetonitrile hydrochloride (192mg), there was obtained 4-nitrobenzylSR,3-(3- cyanomethylaminocarbonyl-phenyl)-6S-{1R-[dimethyl-(2-methylprop-2-yl)silyloxy]-ethyl}-7-oxo-4-thia-1azabicyclo[3.2.0]hept-2-ene-2-carboxylate (165mg).

(CDCl3) 0.05 (3H,s); 0.08 (3H,s); 0.84 (9H,s); 1.26 (3H,d,J=6Hz); 3.83(1 H,m); 4.27(1 H,m);4.33 (2H,d,J=5.7Hz); 5.08 and 5.25 (2H,AB,Jgem=13.7Hz); 5.75 (1H,d,J=1.5Hz); 7.11 (1H,t,J=5.7Hz); 7.41 and 8.12 (4H,AA'BB',J=8.9Hz); 7.45 (1 H,m); 7.61 (1 H,dt,J =7.9 and 1 .4Hz);7.80 (1H,dt,J=1.4 and 7.9Hz); 7.94 (1 H,t,J = 1.4Hz) This product(159mg) was treated by a process analogous to that used in Example 35 but using glacial acetic acid (187mg) and a solution oftetra-n-butyl-ammonium fluoride in tetrahydrofuran (1 M, 0.93ml) and tetrahydrofuran (5ml)to afford 4-nitrobenzyl 5R,3-(3-cyanomethylaminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1 azabicycla[3.2.O]hept- 2-ene-2-carboxylate as a viscous yellow oil (89mg): (acetone-de) 1.22 (3H,d,J=6.3Hz); 3.86 (1H,dd,H=1.6 and 6.3Hz); (4.13 (1H,m); 4.31 (2H,d,J=5.7Hz); 4.50 (1H,broad); 5.08 and 5.21 (2H ,AB,Jgem = 1 3.8Hz);5.81 (1H,d,J=1.6Hz); 7.39 and8.05 (4H,AA'BB',J=8.5Hz); 7.44 (1 H,m); 7.59 (1 H,dt,J= 1.5 and 7.6Hz); 7.86(1 H,dt,J = 1.5 and 7.6Hz); 7.92 (1 H,t,J = 1.5Hz).

This 4-nitrobenzyl ester (89mg) was treated in a process analogous to that used in Example 36 with water (10ml), dioxane (10ml), potassium bicarbonate (17.5mg) and 10% palladium-on-charcoal (90mg) to afford the corresponding potassium salt (66mg). This crude product was chromatographed overa silylated silica gel, and elution with acetonitrile-water-formic acid mixtures afforded the title carboxylic acid (20mg).

(D2O containing KHCO3) 1.30 (3H,d,J=6.4Hz); 3.99 (1 H.dd,J=1.5 and 4.8Hz); 4.25(1 H,m); 4.36 (2H,s); 5.78 (1H,d,J=1.5Hz); 7.63 (1H,d,J=8Hz); 7.77 (2H,m).

Example 700 Potassium 5R,6S-(1R-hydroxyethyl)-3-[4-(2-hydroxyethyl)-aminocarbonylphenyl]-7-oxo-4-thia-1azabicyclo[3.2.0]-hept-2-ene-2-carboxylate By a procedure analogous to that used in Example 34 and using 4-nitrobenzyl SR,3-(3-carboxyphenyl)-6S- {1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (117mg), acetonitrile(10ml),HOBT(54mg), tetrahydrofuran (2ml) and 1-(3-dimethylaminopropyl)-3-ethylcarboxiimide hydrochloride (58mg) and ethanolamine (13.4mg) there was obtanied as a yellow foam 4-nitrobenzyl 5R,6S-{1R-[dimethyl-(2-methylprop-2-yl)-silyloxy]ethyl}-3-[4-(2-hydroxyethyl)amino-car bonyl-phenyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (94mg).

(CDCl2) 0.06 (3H,s); 0.08 (3H,s); 0.85 (9H,s); 1.27 (3H,d,J=6.3Hz); 3.58 (2H,m); 3.78 (2H,m); 3.84 (1 H,dd,J=1.6 and 4Hz); 4.29 (1H,m); 5.08 and 5.26 (2H,AB,Jgem=13.7Hz); 5.76(1 H,d,J=1.6Hz); 7.06(1 H,broad m); 7.41 (2H,d,J =8.7Hz); 7.46 (2H,d,J=8.4Hz); 7.73 (2H,d,J =8.4Hz); 8.13 (2H,d,J=8.7Hz).

This product (94mg) was treated by a process analogous to that used in Example 35 using glacial acetic acid (9Omg), a solution oftetra-n-butylammonium fluoride intetrahydrofuran (1 M, 0.45 ml) andtetrahydrofuran (lOml)to afford 4nitrobenzyl 6S-(1R-hydroxyethyl)-3-[4-(2-hydroxyethyl)aminocarboxylphenyl]-7-oxo-4-thia- 1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (30mg).

(acetone-d6) 1.31 (3H,d,J=6Hz); 3.53 (2H,m); 3.70 (2H,m); 3.95(1H,dd,J=1.3 and 6.3Hz); 4.22 (1H,m); 5.18 and 5.31 (2H,AB,Jgem=14z); 5.90 (1H,d,J=1.3Hz); 7.46 (2H,d,J=8.7Hz); 7.53 (2H,d,J=8.3Hz); 7.89 (2H,d,J =8.3Hz); 8.15 (2H,d,J = 8.7 Hz) This product (30mg) was treated in a process analogous to that used in Example 36 but using dioxane (5ml), water (5ml). potassium bicarbonate (5.9mg) and 10% palladium-on-charcoaI (30mg) to afford ihe titlepot- assium salt (24mg).

8 (D2O) 1.30 (3H,d,J =6.4Hz); 3.53 (2H,m); 3.76 (2H,m); 3.94'1 H,m); 4.28 (1H,m); 5.81 (1 H,d,J=1 .5Hz); 7.51 and 7.73 (4H,AA'BB',J=8.3Hz).

Example 101 2-(Trimethylsiyl)ethyl 5R,3-(3-aminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2ene-2-carboxylate By a process analogous to that used in Example 24and using 3-nitrobenzoyl chloride (10 g),dichlorom- ethane (200 ml), pyridine (8.7 ml) and hydrogen sulphide (excess) there was obtained 3-(nitro)-thiobenzoic acids a pale yellow solid (9.3 9).

8 (CDCl3) 4.8(1 H,broad); 7.72 (1 H,t,J =8.0Hz); 8.23 (1H,dt,J=1.4 and 7.8Hz); 8.47 (1 H,dt,J=1.2 and 8.2Hz); 8.74 (1H,t,J=1.8Hz).

This 3-(nitro)-thiobenzoic acid (9.3 9) was reacted by a procedure analogous to that used in Example 16 with a mixture of 4-acetoxy-3R-f1 R-[dimethyl(2-methylprop-2-yl)silyloxy)ethyl}-azetidin-2-one (10g), and sodium hydroxide (2.089) in acetone (250ml) and water (52ml) to afford 3S-{1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl}-4R-(3-nitrobenzoylthio)azetidin-2-one(13g) Vmax (film) 1770 cm-1 8 (CDCl3) 0.10 (6H,s); 0.90 (9H,s); 1.26 (3H,d,J=6.3Hz); 3.34 (1H,-t,J-3Hz); 4.33(1 H,m); 5.53 (1H,d,J=2.4Hz); 6.54(1H,s); 7.72(1H,t,J=8Hz); 8.25(1H,ddd,J=1.2 and 8Hz); 8.49 (1H,ddd,J=1,2 and 8Hz); 8.76 (1 H,t,J=2Hz).

Treatmentofthis azetidinone (139) in a procedure analogous to that used in Example 17 by using dichloromethane (300ml), calcium carbonate (139), diisopropylethylamine (11 ml) and 2-(trimethylsilyl)ethyl chlorooxoacetate (8.9ml) afforded 2-(trimethylsilyl)-ethyl{3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)-ethyl]-4R-(3-nitrobenzoylthio) azetidin2-on- 1-yl'-oxoacetate 8 (CDCl3) 0.08 (6H,s); 0.09 (9H,s); 0.91 (11 H,s and m); 1.27 (3H,d,J =6.7Hz); 3.65 (1 H,t,J =3Hz); 4.42 (3H,m); 6.23(1 H,d,J=3Hz); 7.72(1H,t,J=8Hz); 8.28(1H,ddd,J=1,2 and 8Hz); 8.49(1 H,ddd,J=1,2 and 8Hz); 8.80 (1 H,t,J=2Hz).

This oxoacetatewas immediatelytreated in a procedure analogous to that used in Example 18 with triethyl phosphite (10.8ml), hydroquinone (1 Omg) and o-xylene (300ml) to afford 2-(trimethylsilyl)ethyl 5R,6S-{1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl}-3-(3-nitrophenyl)-7-oxo-4-thia 1-azabicycl[3.2.0]hept-2-ene-2-carboxylate (10.5g) Vmax(CDCl3) 1792, 1710, 1535cm-1; 8(CDCl3) 0.01 (9H,s); 0.10(3H,s); 0.12(3H,s); 0.94(11H,s and m); 1.28(3H,dd=6.3Hz); 3.82(1H,dd,J = 1.6 and 4.6Hz); 4.15-4.42 (3H,m); 5.75 (1H,d,J=1.6Hz); 7.57 (1H,t,J=8Hz); 7.80 (1H,dt,J=1 and 8Hz); 8.25 (1H,ddd,J=1,2 and 8Hz); 8.36 (1H,t,J=2Hz).

Treatment ofthis silylated penem (1g) in a procedure analogous to that used in Example 19 with glacial acetic acid (1 ml), tetrahydrofuran (20ml) and a solution oftetra-n-butylammonium fluoride in tetrahydrofuran (1 M, 5.6ml) afforded 2-(trimethylsilyl)-ethyl 5R,6S-(1R-hydroxyethyl)-3-(3-nitrophenyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2ene-2-carboxylate (300mg) Vmax(CDCl3) 1785, 1710, 1532cm-1 #(CDCl3) 0.01 (9H,s); 0.91 (2H,m); 1.39 (3H,d,J =6.3Hz); 3.86(1 H,dd,J = 1.6 and 6.6Hz); 4.1-4.3 (3H,m); 5.78 (1H,d,J=1.6Hz); 7.57 (1 H,t,J=8Hz); 7.79 (1 H,dt,J=1 and 8Hz); 8.26 (1 H,ddd,J=1, 2 and 8Hz); 8.35 (1 H,t,J =2Hz).

A solution of this 3-nitrophenyl-penem-carboxylate (4,5g) in dry ethyl acetate (1 00ml) was hydrogenolysed at 375 kPa (4 atm) at 20 in the presence of platinum dioxide (1.1 g), was filtered and evaporated in vacua.

Chromatography of the residue over silica gel, and elution with ethyl acetate - hexane mixtures afforded the title 3-aminophenyl compound Vmax(CDCl3) 3600(broad,3400(broad), 3178, 1710, 1621cm-1 #(CDCl3) 0.01 (9H,s); 0.93 (2H,m); 1.36 (3H,d,J=6.3Hz); 2.84 (2H,broad); 3.78 (1H,dd,J=1.5 and 6.6Hz);4.1 8 (3H,m); 5.67 (1H,d,J=1.5Hz); 6.70(1 H,dd,J=2.2 and 7.3Hz); 6.77(1 H,m); 6.83(1 H,dd,J=7.7 and 1Hz); 7.14(1H,t,J=7.7Hz).

Example 102 Potassium 5R,3-(3-formylaminophenyl)-6S-(1R-hydroxy-ethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene2-carboxylate Bya procedure analogous to that used in Example 87 and using 2-(trimethylsilyl)ethyl 5R,3-(3aminophenyl)-6S-(1 R-hydroxyethyl )-7-oxo-4-thia-1 -azabicyclo[3.2.0]-hept-2-ene-2-carboxylate (200mg) in dry dichloromethane (5ml), formic acid (0.022ml) and 1-(3-dimethylaminopropyl)- 3-ethylcarboxiimide hydrochloride (113mg) there was obtained 2-(trimethylsilyl)ethyl 5R,3-(3-formyl-aminophenyl)-6S-(1Rhydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (171mg): vmaX (CDCl2) 3500(sh), 3320(broad), 1787, 1695 cm-1; 8(CDCl3) [observed as a mixture of both formamide conformers] (a) 0.01 (6H,s); 0.91 (2H,m); 1.36 (3H,d,J=6.3Hz); 2.73(1 H,broad); 3.80 (2H,m); 4.17 (3H,m); 5.70 (1H,d,J=1.4Hz); 7.1-7.6 (4H,m); 7.81 (1 H,d,J=1 .6Hz); 8.33 (1 H,d,J=1.6Hz); and (b) 0.01 (6H,s); 0.91 (2H,m); 1.37 (3H,d,J =6.3Hz); 2.68 (1 H,broad); 3.80 (2H,m); 4.17(3H,m); 5.72 (1H,d,J=1.4Hz); 7.1-7.6(4H,m); 8.19 (1H,d,J=11.3Hz); 8.67 (1H,d,J=11,3Hz).

A solution of this product (1 68mg) in tetrahydrofuran (5ml) was then treated by a process analogous to that used in Example 88 with a dry solution oftetra-n-butylammonium fluoride in tetrahydrofuran (1 M,0.38ml) and finally with potassium hydrogen carbonate (38.7mg) to afford the crude product (218mg). Purification as in Example 88 then afforded the title compound (37mg).

8 (D2O) 1.31 (3H,d,J=6.5Hz); 3.98(1H,dd,J=1.3 and 5.8Hz); 4.24(1 H,m); 5.77 (1H,d,J=1.3Hz); 7.22-7.27 (2H,m); 7.39(1 H,t,J=7.4Hz); 7.48(1 H,m); 8.24(1 H,s).

Example 103 Potassium 5R,3-(3-acetylaminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2carboxylate A mixture of 2-(trimethylsilyl)ethyl 5R,3-(3-aminophenyl )-6S-( 1 R-hydroxyethyl)-7-oxo-4-thia-1 -azabicyclo [3,2,0]hept-2-ene-2-2-carboxylate (200mg), tetrahydrofuran (3ml), acetic anhydride (0.051 ml) and Nmethylmorphline(0.06ml) was stirred at 20 for 1 hour, was then partitioned between ethyl acetate and water. The organic layerwas washed with water, with 1 M-citric acid, with saturated sodium bicarbonate solution, and dried.Evaporation 2-(trimethylsilyl)ethyl 5R,3-(3-acetylaminophenyl)-6S-(1R-hydroxyethytl)-7- oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (210mg); Vmax(CDCI3) 3350(broad), 1782,1680 cm-1; 8 (CDCl3) 0.01 (9H,s); 0.95 (2H,m); 1.39 (3H,d,J =6.3Hz); 2.18 (3H,s); 3.81(1 H,dd,J = 1.5 and 6.8Hz); 4.1-4.3 (3H,m); 5.70(1 H,d,J =1.5Hz); 7.1-7.7 (5H,m).

This material (1 94mg) was treated in a process analogous to that used in Example 88 with drytetrahydrofuran (5ml), a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1 M,0.433ml) and potassium hydrogen carbonate (43.3mg), to afford crude title compound (260mg). Purification as in Example 88 afforded pure title compound (47mg).

8 (D20) 1.30 (3H,d,J=6.4Hz); 2.14 (3H,s); 3.98 (1 H,dd,J =5.9 and 1.4Hz); 4.25 (1 H,m); 5.77 (1 H,d,J= 1.4Hz); 7.23 (1 H,dt,J=7.2 and 1.4Hz); 8.3-7.5 (3H,m).

Example 104 5R,3-(4-[Cyanoacetamido]phenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2carboxylic acid To a stirred solution of 2-(trimethylsilyl)ethyl 5R,3-(4-aminophenyl)-6S-(1 R-hydroxyethyl)-7-oxo-4-thia- 1 azabicyclo[3.2.0]hept-2-ene-2-carboxyiate (400mg) in tetrahydrofu ran (20ml) was added cyanoacetic acid (126mg) and dicyclohexylcarbodiimide (304mg). After 30 minutes, the mixture was filtered; the filtrate was partitioned between ethyl acetate and water. The organic layer was washed with 1 M-citric acid, with saturated aqueous sodium bicarbonate and brine, was dried and evaporated in vacuo.Chromatography ofthe residue over silica gel and elution with hexane - ethyl acetate mixtures afforded 2-(trimethylsllyl)ethyl 5R,3-(4-[cyanoacetamido]phenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia- 1- azabicyclo[3.2.0]-hept-2-ene-2-carboxylate (177m Vmax(CDCl3) 1788 and 1710 cm-1; 8 (CDCl3) 0.01 (9H,s); 0.98 (2H,m); 1.38 (3H,d,KsJ=6.3Hz); 3.59 (2H,s); 3.80 @1H,dd,J=1.6 and 7.1 Hz); 4.20 (3H,m); 5.68(1 H,d,J=1.6 Hz); 7.53 (4H,m); 8.14(1 H,s).

In a process analogous to that used in Example 88, a solution ofthis ester (177mg) in drytetrahydrofuran (5ml) was treated with a 1 M solution of dry tetrabutylammonlum fluoride (0.374ml), with addition of potassium hydrogen carbonate (37mg) to afford a crude product (145mg) which was purified by reverse-phase HPLCto afford the titleacid (9mg): #(D2O,containing a trace of KHCO3) 1.30 (3H,d,J=6.4Hz); 3.96(1 H,dd,J= 1.4 and 6.0Hz); 4.25(1 H,m); 5.75 (1 H,d,J=1.4Hz); 7.44 (4H,s).

Example 105 5R,6S-(1R-Hydroxyethyl)-3-(4-[methylaminothioformylamino]phenyl)-7-oxo-4-thia-1-azabicylo[3.2.0]hept2-ene-2-carboxylic acid A mixture of 2-(trimethylsily)ethyl 5R,3-(4-aminophenyl)-6S-(1 R-hydroxyethyl )-7-oxo-4-thia-1 - azabicyclo [3.2.01hept-2-ene-2-carboxylate (200mg), tetrahydrofuran (5ml) and methyl isothiocyanate (72mg) was stir red for 16 hours, and was then partitioned between ethyl acetate and water. The organic layer was washed with water, with cold 1 M-hydrochloric acid, with water, with saturated aqueous sodium bicarbonate, with brine and was evaporated in-vacuo.Chromatography ofthe residue over silica gel and elution with ethyl acetate - hexane mixtures afforded 2-(trimethylsily)ethyl 5R,6S-(1R-hydroxyethyl)-3-(4-[methylaminothioformylamino]-phenyl)-7-oxo-4-thia-1aza-bicyclo[3.2.0]hept-2-ene-2-carboxylate (80mg): #max(CDCl3) 3600, 3410 1788, 1708 cm-1; 8(CDCl3) 0.01 (9H,s); 0.99 (2H,m); 1.39 (3H,d,J=6.3Hz); 1.96(1 H,broad); 3.16 (3H,d,J =4.5Hz); 3.81 (1H,dd,J=1.6 and 6.6Hz); 4.23 (3H,m); 5.71 (1H,d,J=1.6Hz); 6.24 (1H,broad); 7.20 and 7.55 (4H,AA'BB',J=8.5Hz); 7.74 (1 H,s).

This ester(200mg) was treated in a process analogous to that used in Example 88 with tetrahydrofuran (10ml) and a solution ofdrytetrabutylammonium fluoride in tetrahydrofuran (1 M, 0.417ml),with addition of potassium bicarbonate (42mg). After ion-exchange and reverse-phase chromatography there was obtained the titleacid(l6mg): 8 (D20, containing KHCO3) 1.29 (3H,d,J=6.4Hz); 2.96 (3H,s); 3.96 (1H,dd,J=1.3 and 5.9Hz); 4.24(1 H,m); 5.75 (1 H,d,J = 1.3Hz); 7.23 and 7.43 (4H,AA'BB',J = 8.6Hz).

Example 106 Potassium 5R,6S-(1R-hydroxyethyl)-3-(3-methylsulphinyl-phenyl)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2 ene-2-carboxylate By procedures analogous to those used in Examples 15,16,17,18 and 19, and starting from 3-(methylthio) benzoic acid there was obtained 4-nitrobenzyl 5R,6S-(1R-hyddrodxyethyl)-3-(3-methylthiophenyl)-7-oxo-4thia- 1-azabicyclo[3.2.0]hept- 2-ene-2-carboxylate as a yellow foam: 8 (CDCl3) 1.40 (3H,d,J=6.4Hz); 2.10(1 H,d,J =4.3Hz); 2.44 (3H,s); 3.86 (1 H,dd,J = 1.5 and 6.4Hz); 4.31 (1 H,m); 5.12 and 5.28 (2H,AB,Jgem=13.8Hz); 5.75(1H,d,J=1.5Hz); 7.17 (1H,m); 7.28 (3H,m); 8.13 (2H,d,J=8.8Hz).

This sulphide (183mg) was treated by a process analogous to that used in Example 20 with 80% 3 chloroperbenzoic acid (92mg) to affo rd afford 4-nitrobenzyl 5R,6S-(1R-hydroxyethyl)-3-(3-methylsulphinylphenyl)- 7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylate (107mg) 8(acetone-d6) 1.33 (3H,d,J6.3Hz); 2.67 (3H,s); 3.98(1H,dd,J=1.7 and 6.2Hz); 4.23(1 H,m); 4.48 (1 H,d,J =4.9Hz); 5.21 and 5.35 (2H,AB,Jgem=14.2Hz); 5.93(1 H,d,J= 1.7Hz); 7.51 and 8.16 (4H,AA'BB',J =8.5Hz); 7.6-7.8 (4H,m).

In a process analogous to that used in Example 7this sulphoxide (107mg) was hydrogenolysed in the presence of 10% palladium-on-charcoal (100mg), potassium hydrogen carbonate, dioxane (6ml) and water (6ml) to afford the title compound (65mg); 8 (D2O) 1.29(3H,d,J=6.5Hz); 2.85 (3H,s); 3.99(1 H,dd,J=1.5 and 6Hz); 4.25(1 H,m); 5.79(1H,d,J = 1.5Hz); 7.58-7.80 (4H,m).

Example 107 Potassium 5R,6S-(1R-hydroxyethyl)-3-(3-methylsulphonylphenyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2ene-2-carboxylate By a procedure analogous to that used in Example 22, and using 4-nitrobenzyl 5R,6S-(1 R-hydroxyethyl)-3- (3-methylsulphinylphenyl)-7-oxo-4-thia-1-azabicyclo-[3.2.0]hept-2-ene-2-carboxylate (414mg), 80% 3chloroperbenzoic acid (165mg) and ethyl acetate (40ml), there was obtained 4-nitrobenzyl 5R,6S-(1R hydroxwethyl)-3-{3-methylsulphonylphenyl)-7-oXo-4-thia- 1-azabicyclo[3.2. 01- hept-2-ene-2-carboxylate (76mg): 8 (acetone-d6) 1.33 ((3H,d,J =6.3Hz); 2.84 (3H,s); 4.00(1 H,dd,J=1.7 and 6.1 Hz); 4.23 (1 H,m); 4.47 (1H,d,J=4.9Hz); 5.20 and 5.35 (2H,AB,Jgem=14Hz); 5.95(1H,d,J=1.7Hz); 7.52 and 8.18 (4H,AA'BB',J=8.9Hz); 7.70(1 H,t,J =7.6Hz); 7.85 (1 H,-d,J =7.4Hz); 8.00 (1 H,dd,J= 1.2 and 7.3Hz); 8.06 (1 H,m).

In a procedure analogous to that used in Example 7, this sulphone (76mg) was hydrogenolysed in the presence of 10% palladium-on-charcoal (75mg), potassium hydrogen carbonate (15.3mg), dioxane (4ml) and water (4ml) to afford the title potassium salt (39mg); 8 (D20) 1.31 (. (3H,d,J=6.4Hz); 3.25 (3H,s); 4.00(1 H,dd,J=1.4and 5.9Hz)4.26 (1 H,m); 5.80(1 H,d,J=1.4Hz); 7.63 (1 H,t,J =7.8Hz); 7.77 (1 H,m); 7.91 (1 H,dm,J#7.8Hz); 7.98 (1 H,t,J~1.6Hz).

Example 108 2-(Trimethylsllyl)ethyl SR, 6S-(1R-acetoxyethyl)-3-(4-formylaminophenyl)-7-oxo-4-thia- 1-aza-bicycloj3.2. 0] hept-2-ene-2-carboxylate A mixture of 2-(trimethylsilyl)ethyl 5R,3-(4-formylamino)phenyl-6S-(1 R-hydroxyethyl )-7-oxo-4-thia-1 - azabicyclo[3.2.0]hept-2-ene-2-carboxylate (500mg), tetrahydrofuran (10ml), 4-dimethylaminopyridine (15mg) and acetic anhydride (1.09ml) was stirred at room temperature for 30 min., and then partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium bicarbonate, with brine, was dried over anhydrous sodium sulphate, and evaporated in vacuo.Chromatography on silica gel and elution with ethyl acetate - hexane mixtures afforded the title compound (211 mg).

8 (CDCl3) 0.00 (9H,s); 0.97 (2H,m); 1.42 (3H,d,J=6.4Hz); 2.08 (3H,s); 3.90 (1 H,dd,J=1.5 and 7.6Hz); 4.20 (2H,m); 5.29(1H,m); 5.64 and 5.62(1H,2d,J=1.5Hz); 7.06 (#0.8H,d,J=8.6Hz); 7.4-7.6(#3.8H,m);7.88 (-0.4H,d,J=11.4Hz); 8.37 (#0.6H,d,J=1.6Hz) and 8.75 (#0.4H,d,J=11.4Hz).

8 (DMSO-d6) 0.00 (9H,s); 0.84 (2H,t,J=7.5Hz); 1.30 (3H,d,J=6.3Hz); 2.03 (3H,s); 4.12 (2H,m); 4.21 (1H,dd,J=1.5 and 5.5Hz); 5.17 (1H,m); 5.78(1H,d,J=1.5Hz); 7.43 and 7.62 (4H,AA'BB',JAB=8.8Hz); 8.31 (#0.8H,d,J=1.5Hz); 8.89(#0.2H,d,J=11.5Hz); 9.36(#0.2H,d,J=11.5Hz) and 10.44 (#0.8H,d,J=1.5Hz).

Example 109 5R,6S-(1R-Acetoxyethyl)-3-(4-formylaminophenyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid The crude product obtained by a procedure analogous to that used in Example 88 but using 2 (trimethylsilyl)-ethyl 5R,6S-( 1 R-acetoxyethyl)-3-(4-formyla minophenyl)-7-oxo-4-thia-1 -azabicyclo[3.2.0] hept-2-ene-2-carboxylate (200 mg), tetrahydrofuran (1 Oml) and a solution of drytetrabutylammonium fluoride in tetrahydrofuran (1M,0.41ml), with addition of potassium bicarbonate (41mg), was purified by ion-exchange and reverse-phase chromatography to afford the pure title compound (49mg): 8 (D2O) 1.41 (3H,d,J=6.3Hz); 2.15 (3H,s); 4.21 (1 H,dd,J=1.5 and 5.5Hz); 5.30 (1 H,m); 5.82 (1 H,d,J=1.5Hz); 7.45 and 7.50 (4H,AA'BB',JAB=8.8Hz); 8.25 (1 H,bs).

Example 110 4-nitrobenzyl 5S,3-(3-aminocarbonylphenyl)-6S-(1R-hydroxyethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2 ene-2-carboxylate A mixture of 4-nitrobenzyl 5R,3-(3-aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabi cyclo-[3.2.0]hept-2-ene-2-carboxylate (120mg) and acetonitrile (7.5ml) was heated in a sealed flask at 85#3 for 20 hours, and was then evaporated in vacuo. Chromatography of the residue afforded some starting trans-penem, and the title compound (20mg): 8 (DMSO-d6) 1.48 (3H,d,J=6.3Hz); 4.02 (1 H,dd,J=3.8 and 5.5Hz); 4.30 (1 H,m); 5.15 and 5.30 (2H,AB,Jgam= =13.8Hz); 5.95 (1 H,d,J =3.8Hz); 7.2-8.1(1 OH,m).

Example 111 Potassium 5S,3-(3-aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene 2-carboxylate By a procedure analogous to that used in Example 36, and using 4-nitrobenzyl 5S,3-(3-amino carbonyl phenyl)-6S-(1 R-hydroxyethyl)-7-oxo-4-th ia-1 -azabicyclo-[3.2.0] hept-2-ene-2-carboxylate (50mg), dioxane (5ml),water(5ml), potassium bicarbonate (1 Omg) and 10% palladium-on-charcoal (50mg),thetitle compound 27mg) was obtained (27mg): 8 (D2O) 1.42 (3H,d,J=6.3Hz); 4.05 (1 H,dd,J =4 and 6 Hz); 4.26 (1 H,m); 5.90 (1 H,d,J =4Hz); 7.4-7.8 (4H,m).

Example 112 4-Nitrobenzyl 5R,3-[3-(allyloxycarbonyl)phenyl]-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept2-ene-2-carboxylate By a procedure analogous to that used in Example 39, but starting from a solution of isophthaloyl chloride (60.9g) in dioxane (400ml), allyl alcohol (20.9g), triethylamine (36.4g), dichloromethane (600ml), pyridine (28.5g) and hydrogen sulphide (excess) there was obtained 3-(alloxycarbonyl)thiobenzoic acid Vmax 2550, 1725 cm-1; 8 (CDCI3) 5.0 (2H,m); 5.5 (3H,broad m); 6.0(1 H,m); 7.5-9.1 (4H,m).

A solution of this thiobenzoic acid (5g) in acetone (35ml) was treated in a procedure analogous to that used in Example 30 with a mixture of 1M-sodium hydroxide solution (22ml) and a solution of 4-acetoxy-3R-{1R [dimethyl(2-methylprop-2-yl)silyloxy]ethyl}-azetidin-2-one(4.3g) in acetone: water (3:1) (50ml) to afford 4R [3-(allyloxycarbonyl]benzoylthio]-3S-{1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl}azetidin-2-one(4.3g): #(CDCl3) 0.00 (6H,s); 0.80 (9H,s); 1.15 (3H,d,J=6.3Hz); 3.22 (1H,dd,J=2.5 and 3.6 Hz); 4.22(1H,m); 4.76 (1H,dd,J=1.1 and 6.8Hz); 5.2-5.4 (2H,m); 5.41 (1H,d,J=2.5Hz); 5.92 (1H,m); 6.64 (1H,s); 7.5-8.6(4H,m).

Asolution of this azetidinone (22.1 g) in dichloromethane (250ml) was treated in a procedure analogous to that used in Example 31 with calcium carbonate (12.3g), and diisopropylethylamine (9.5g) and a solution of 4-nitrobenzyl chlorooxalate (14.4g) in dichloromethane (25ml) to afford as a yellow oil 4-nitrobenzyl{4R,3-[3allyloxycarbonyl)benzoylthio]-3S-{1R-[dimethyl(2-methylprop-2-yl)siyloxy]ethyl}-azetidin-2-on-1 ylJ'oxoacetate #(CDCl3) 0.00 (3H,s); 0.09 (3H,s); 0.83(9H,s); 1.26 (3H,d,J=6.3Hz); 3.65 (1H,#t,J=3.5Hz); 4.41 (1H,m); 4.85 (2H,#d,J=5.8Hz); 5.30-5.45 (4H,m); 6.02(1H,m); 6.20 (1H,d,J=3.5Hz); 7.5-7.6(3H,m); 8.09-8.3(4H,m); 8.60 (1H,t,d= 1.6Hz}.

A solution of this oil in xylene (500ml) was treated in a procedure analogous to that used in Example 32 with a solution of triethyl phosphite (16.3g) in xylene (100ml) to afford 4-nitrobenzyl 5R,3-[3-(allyloxycarbonyl)phenyl]-6S-{1R-[dimethyl(2-methylprop-2-yl)silyloxy]-ethyl}-7-oxy-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2carboxylate (25.3g) 8 (CDCl3) 0.06 (3H,s); 0.08 (3H,s); 0.85 (9H,s); 1.27 (3H,d,J=6.3Hz); 3.83 (1 H,dd,J=1.3 and 3.9Hz); 4.28(1 H,m); 4.81 (2H,d,J=5.5Hz); 5.09(1 H,d,J=13.7Hz); 5.2-5.4 (3H,m); 5.75(1H,d,J=1.3Hz); 6.00(1 H,m).

A solution of this 4-nitrobenzyl carboxylate (34.2g) in tetrahydrofuran (70ml) was treated in a procedure analogous to that used in Example 37 with glacial acetic acid (32.8g) and a 1 M solution oftetra butylammonium fluoride in tetrahydrofuran (163ml)to afford the title hydroxyethyl compound(20.4g): 8 (CDCl3) 1.40 (3H,d,J=6.3Hz); 3.88 H,dd,J=1 .6 and 6.5Hz); 4.31 H,m); 4.80 (2H,m); 5.10 (1H,d,J=13.7Hz); 5.2-5.5 (3H,m); 5.79 (1H,d,J=1.6Hz); 6.00(1 H,m); 7.33 (2H,d,J=8.8Hz); 7.44(1 H,t,J=7.8z); 7.61(1 H,m); 8.05-8.23 (4H,m).

Example 113 4-Nitrobenzyl 5R,6S-(1R-acetoxyethyl)-3-[3-(allyloxycarbonyl)phenyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept 2-ene-2-carboxylate A mixture of 4-nitrobenzyi 5R,3[3-(allyloxycarbonyl)phenyl]-6S-(1 R-hydroxyethyl )-7-oxo-4-thia-1 - azabicyclo [3.2.0]hept-2-ene-2-carboxylate (1.0g) drytetrahydrofuran (15ml), acetic anhydride (1.0g) and 4dimethylaminopyridin (23mg) was stirred under a nitrogen atmosphere for 30 min., and then partitioned between ethyl acetate and water. The organic layer was washed with water, with saturated aqueous sodium bicarbonate solution and was then dried and evaporated in vacua.Chromatography ofthe residue over silica gel and elution with ethyl acetate - hexane mixtures afforded the title compound (0.9g); 8 (CDCl3) 1.45 (3H,d,J=6.3Hz); 2.09 (3H,s); 3.99 (1H,dd,J=1.8 and 5.8Hz); 4.81 (2H,#d,J=5.8Hz)); 5.13 (1 H,d,J = 13.7Hz); 5.2-5.4 (4H,m); 5.73 (1 H,d,J = 1.8Hz); 6.01(1 H,m); 7.35 (2H,d,J=8.7Hz); 7.45 (1 H,#t,J=7.9Hz); 7.62 (1 H,m); 8.07-8.16 (4H,m).

Example 114 4-Nitrobenzyl 5R,6S-(1R-acetoxyethyl)-3-(3-carboxyphenyl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2carboxylate A mixture of 4-nitrobenzyl 5R,6S-(1R-acetoxyethyl)-3-[3-allyloxycarbonyl)phenyl]-7-oxo-4-thia-1-azabicylco [3.2.0]hept-2-ene-2-carboxylate (0.9g), dichloromethane (1 Oml), potassium 2-ethylhexanoate (0.46g), triphenylphosphine (17mg) andtetrakis-(triphenylphosphine)palladiu (38mg)was stirred at room tem- perature for one hour, and the pH was then adjusted to 4.4 by addtion of potassium dihydrogen phosphate solution. The resulting mixture was extracted with ethyl acetate, which was then dried and evaporated in vacuo.Chromatography ofthe residue and elution with hexane - ethyl acetate -formic acid mixtures afforded the title compound: 8 (CDCls) 1.45 (3H,d,J =6.4Hz); 2.09 (3H,s); 3.99 (1 H,dd,J=1.5and 7.5Hz); 5.13 and 5.26 (2H,AB, Jgam= 13.1Hz); 5.31(1H,m); 5.73(1H,d,J=1.5Hz); 7.36 (2H,d,J=8.8Hz); 7.45-7.72 (2H,m); 7.9-8.2 (4H,m).

Example 115 4-Nitrobenzyl 5R,6S-(1R-acetoxyethyl)-3-(3-amino-carbonylphenyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2ene-2-carboxylate To a stirred suspension of 4-nitrobenzyl 5R,6S-(1 R-acetoxyethyl)-3-(3-carboxyphenyl)-7-oxo-thia-1 azabicyclo [3.2.0]hept-2-ene-2-carboxylate (200mg) in dry dichloromethane (10ml) at 0 was added triethylam- ine (0.11 ml) and ethyl chloroformate (47mg), followed after one hour by a solution of ammonia (20mg) in ethanol (1 ml). The mixture was stirred a further hour, and was then evaporated in vacuo. The residuewas chromatographed on silica gel.Elution with ethyl acetate - hexane mixtures afforded the title compound (98mg): 8 (DMSO-d6) 1.42 (3H,d,J=6.3Hz); 2.13 (3H,s); 4.22 (1H,dd,J=1.5 and 6 Hz); 5.15 and 5.30 (2H,AB, Jgem= 13.8Hz); 5.14(1 H,d,J =6Hz); 5.92 (1 H,d,J= 1.5Hz); 6.85(1 H,bs); 7.47-7.8 (4H,m); 7.99(1 H,dt,J= 1 and 8Hz); 8.03 (1 H,t,J=1 Hz); 8.13 (2H,d,J=8.8Hz).

Alternatively, the title compound (83mg) was obtained by a procedure analogous to that used in Example 113 by using 4-nitrobenzyl 5R,3-(3-aminocarbonylphenyl)-6S-(1 R-hydroxyethyl)-7-oxo-4-thia-1 -azabicyclo [3.2.0]hept-2-ene-carboxylate (200mg), dry tetrahydrofuran (3ml), acetic anhydride (0.2ml) and 4- dimethylaminopyridine (1 Omg).

Example 116 Potassium SR,6S-(1R-acetoxyethyl)-3-(3-aminacarbonylphenyl)-7-oxo-44hia- 1-azabicyclo[3.2.01hept-2-ene- 2-carboxylate By a procedure analogous to that used in Example 36, and using 4-nitrobenzyl 5R,6S-(1R-acetoxyethyl)- 3-(3-aminocarbonylphenyl)-7-oxo-4-thia-1 -azabicyclo-[3.2.0]hept-2-ene-2-carboxylate (100mg), dioxane (1 ml), potassium bicarbonate (19mg),w ater (1 ml) and 10% palladium-on-charcoal (100mg), the title compound (57mg) was obtained: 8 (D20) 1.38 (3H,d,J =6.3Hz); 2.13 (3H,s); 4.20 (1 H,dd,J= 1.4 and 5.9Hz); 5.31 (1 H,m); 5.88(1 H,d,J = 1.4Hz); 7.48 (1 H,t,J=SHz); 7.60 (1 H,dt,J = 1.4 and 8Hz); 7.7-7.8 H.(2H,m).

Example 117 2-(Trimethylsilyl)ethyl 2-[3S-[1R-(dimthyl(2-methyl-prop-2-yl)silyloxy)ethyl]-4R-[4-nitrobenzoylthio] azetidin-2-on-1-yl-3,3,3-triethoxy-3-phosphapropenoate To a solution of 2-(trimethylsilyl)ethyl 3S-[1 R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-4R-[4- nitrobenzoylthiojazetidin-2-on-1 -yl]oxoacetate (330mg) in toluene (5m I) at 100 was added dropwise over 30 minutes a solution of triethyl phosphite (0.24ml) in toluene (1 ml). Afterthe mixture had been heated at 100 for a further hour, it was evaporated in vacua to afford a residue which was chromatographed over silica gel.

Elution with hexane-ethyl acetate mixtures afforded the title compound (150mg) as a yellow gum.

v(CDCI3) 1752,1670 and 1620cm-1; 8 (CDCl3) 0.10 (6H,s); 0.84(11 H,m); 1.22 (3H,d, J =6.3Hz); 1.33 (9H,t,J =7Hz); 3.27 (1 H,m); 4.21 (9H,m); 5.81 (1 H,broad); 8.10 and 8.33 (4H,AA'BB',JAB=8.8Hz) Amixture ofthis phosphorane (1 50mg) and o-xylene (3ml)was heated at 140 for one hour, and then evaporated in vacuo. Chromatography ofthe residue over silica gel and elution with hexane - ethyl acetate mixtures afforded 2-(trimethylsily) 5R,6S-{1 R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl}-3-(4-nitrophenyl)- 7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (97mg) with properties identical to those described in Example 83.

Example 118 4-Nitrobenzyl 2-{4R-[3-aminocarbonylbenzoylthio]-3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]azetidin-2-on- 1-yls-3-methylpropenoate.

A solution of silver 3S-{1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl-1-[2-methyl-1-(4 nitrobenzyloxycarbonyl)propenyl]-azetidin-2-one-4R-thiolate (400 mg) in acetonitrile (10 ml) was added dropwise to a stirred solution of isophthaloyl chloride (612 mg) in acetonitrile (29 ml) at 0'. After 30 minutes a solution of ammonia (90 mg) in chloroform (5 ml) was added; the mixture was filtered and the filtrate evap- orated in vacua. Chromatography ofthe residue on silica gel, and elution with hexane - ethyl acetate mixtures afforded the title compound (206 mg).

(CDCl) 0.03 (3H,s); 0.06 (3H,s); 0.82 (9H,s); 1.26 (3H,d,J=6.3Hz); 2.03 (3H,s); 2.21 (3H,s); 3.36 (1H,dd,J=2.6 and 5.6 Hz); 4.25 (1 H,m); 5.34 (2H,s); 5.90 (1 H,d,J =2.6Hz); 6.2 (2H, broad); 7.50-7.61 (3H,m); 8.17-8.36 (5H,m).

Example 119 4-Nitrobenzyl 2-{4R-[3-aminocarbonylbenzoylthio]-3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]azetidin-2-on- 1-yl}oxoacetate A solution of 4-nitrobenzyl 2-{4R-[3-aminocarbonylbenzoylthio]-3S-[1 R-(dimethyl(2-methylprop-2yl)silyloxy)ethyl]-azetidin-2-on-1 -yl}-3-methylpropenoate (182 mg) in dry dichloromethane (30 ml) was trea- ted at-78 with ozone (excess); oxygen was then bubbled through the mixture for 5 minutes, and dimethyl sulphide (excess) was added. The mixture was warmed to room temperature, was evaporated in vacuo. The resulting oil was partitioned between ethyl acetate and water; the organic layer was separated, was washed with water, with brine, was dried and evaporated in vacuo to afford the title compound (140 mg).

8 (CDCl3) 0.03 (3H,s); 0.06 (3H,s); 0.82 (9H,s); 1.27 (3H,d,J =6Hz); 3.64 (1H,#t,J=3Hz); 4.40 (1H,m); 5.36 and 5.43 (2H,AB,J =12.9Hz); 6.20(1 H,d,J =3.5Hz); 6.2 (2H,broad); 7.5-7.7 (3H,m); 8.1-8.4(5H,m).

Example 120 4-Nitrobenzyl 5R,3-(3-aminocarbonylphenyl)-6S-{1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl}-7-oxo-4thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate To a mixture of 4-n itrobenzyl 2-{4R-[3-aminoca @bonylbenzoylthio]-3S-[1 R-(dimethyl (2-methylprop-2-yl)silyloxy)ethyl]-azetidin-2-on-1-yl}oxoacetate (140 mg) in xylene (15 ml) at 130 was added a mixture of triethyl phosphite (0.073 mi) in xylene (5 ml). The mixture was heated a further hour at 130 , and then cooled and evaporated in vacuo. Chromatography ofthe residue on silica gel, and elution with hexaneethyl acetate mixtures afforded the title compond (100 mg) with properties identical to those described in Example 94.

Example 121 1-(Acetoxyethyl) 5R,3-(3-aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0.]hept2-ene-2-carboxylate Under a nitrogen atomosphere a stirred mixture of potassium 5R,3-(3-aminocarbonylphenyl)-6S-(1 Rhydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (100 mg) sodium iodide (80 mg) and dry dimethylformamide (2.5 ml) was treated at room temperature with a solution of 1-chloroethyl acetate (164 mg) in chloroform (0.26 ml). After 18 hours the mixture was partitioned between ethyl acetate and water; the organic layerwas evaporated to dryness and chromatographed on silica gel. Elution with ethyl acetateethanol mixtures afforded the title compound (16 mg) as a yellow gum as a mixture of diastereoisomers.

8(CDCl3) 1.37 (6H, d, J=6.5 Hz); 2.01 (3H,s); 3.82 (1 H, dd,J1.5 and 6.7 Hz); 4.27 (lH, m); 5.73(1 H, d,J=1.5 Hz); 5.95 (lH, broad); 6.57 (lH, broad); 6.79 (1H, m); 7.48 (1H, #t,J=7.8 Hz); 7.60 (lH, m); 7.91 H, m).

Example 122 Acetoxymethyl 5R,3-(3-aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]-hept 2-ene-2-cartoxylate By a procedure analogous to that used in Example 121, but using potassium 5R,3-(3aminocarbonylphenyl)-6S-(1 R-hydroxyethyl )-7-oxo-4-thia-1 -azabicyclo[3.2.0]-hept-2-ene-2-carboxylate (100 mg), sodium iodide (80 mg), dry dimethylformamide (2 ml) and chloromethyl acetate (150 mg), the title compound (25 mg) was obtained as a yellow gum.

8(CD3CN) 1.22 (3H, d, J =6.3Hz); 2.01 (3H, s); 3.85(1H,dd,J=1.5 and 6 Hz); 4.2(1H,m); 5.75(1H, d, J=1.5 Hz); 5.72 and 5.80 (2H, AB, J=6 Hz); 6.0 and 6.9 (2H, broad s); 7.50(1 H, #t,J=8 Hz); 7.60(1 H, m) and 7.92 (lH, m).

Claims

1. A compound offormula I

in which R represents a hydrogen atom or a carboxylic acid esterifying group; R1 represents (i) one of the following groups

in which Ra and Rb, which may be the same or different, each represents an alkyl group having from 1 to4 carbon atoms, or (ii) a -CONH(CH2)mQor - NHCO(CH2)mQ group in which m represents an integer offrom 1 to 3, and Q represents one ofthefollowing groups

in which Re represents a methyl or ethyl group, or (iii) a -CO2Rd group, in which Rd represents a methyl or ethyl group which is unsubstituted or is substitu- ted by one or more substituents, which may be the same or different, selected from (a) halogen atoms and vinyl groups, (b) phenyl groups which are unsubstituted or are substituted by one or more groups selected from alkoxy groups having from 1 to 4 carbon atoms, nitro groups and halogen atoms, (c) silyl groups SiReRfRg, the groups Re, Rf and Rg being the same or different, each representing a phenyl group or an alkyl group having from 1 to 4 carbon atoms, and (d) groups Qas defined above; or (iv) a -CO2SiReRfRg group, in which Re, Rf and Rg are defined as in (c) above, or (v) a -CO2-phenyl group, in which the phenyl moiety is unsubstituted or substituted as defined in (b) above; R2 represents (i) a hydrogen atom, (ii) a group as defined above for R7 (R1 and R2 being the same or different), or (iii) a chlorine, bromine or iodine atom,an alkyl group having from 1 to4carbon atoms, an -NH2, -NHRa or -NRaRb group, an -OH or -ORa group, or an -OCOCH3 group, Ra and Rb being defined as above, and R3 represents a hydrogen atom or a hydroxy protecting group; and in which R1 and R2, independently of each other, may be present at any position on the phenyl ring; and and salts thereof, especially physiologicallytolerable salts; and isomers thereof.

2. Acompound as claimed in claim 1,wherein in a group containing the group Ra or Rb, Ra orRb isa methyl or ethyl group; and in a group containing the sym boi " m", "m " denotes the integer 1 or 2.

3. A compound as claimed in claim 1 ,wherein R1 represents one of the following groups;

wherein Q is as defined in claim 1 and Ra and mare as defined in claim 2.

4. 5R,3-(4-Aminocarbonylphenyl)-6S-(1 R-hydroxyethyl)-7-oxo-4-thia-1 -aza bicyclo[3.2.0] hept-2-ene-2carboxylic acid, or an ester thereof atthe 8- and/or2-position, ora saltthereof.

5. SR,3-(3-Aminocarbonylphenyl)-6S-(1 R-hydroxyethyl)-7-oxo-4-thia-l -azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid, oran esterthereof at the 8-and/or2-position, or a saltthereof.

6. 5R,3-(4-Formylaminophenyl)-6S-(1 R-hydroxyethyl)-7-oxo-4-thia-l -azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid, or an ester thereof at the 8-and/or 2-position, or a saltthereof.

7. 5R,3-(3-Formylaminophenyl )-6S-(l R-hydroxyethyl)-7-oxo-4-thia-l -azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid, or an ester thereof at the 8-and/or 2-position, or a saltthereof.

8. Acompound as claimed in anyone of claims 4to 7, wherein an esterifying group atpostion 8 is a hdryoxy protecting group R3

9. Acompound as claimed in anyone of claims 1 to 4orclaim 8, wherein a hydroxy protecting group R3is a group that can be converted by hydrolysis, by photolysis, by reduction or by esterase enzyme action to give a compound offormula I having a free 8-hydroxy group.

10. A compound as claimed in any one of claims 1 to 4 or claimS, wherein a hydroxy protecting group R3 can be removed under physiological conditions.

11. A compound as claimed in claim 9, wherein a group R3 is a carboxylic acid acyl group oftheformula R20CO- in which R20 represents a hydrogen atom or a straight or branched chain alkyl group having from 1 to 6 carbon atoms, or represents a phenyl group or a phenoxyalkyl group in which the alkyl moiety is straightchained or branched and has from 1 to 4 carbon atoms.

12. A compound as claimed in claim 11,wherein R20 represents a methyl, ethyl ort-butyl group, or a phenoxymethyl group.

13. A compound as claimed in any one of claims 1 to 12 having, at position 2, an esterified carboxy group that can be converted by hydrolysis, by photolysis, by oxidation, by reduction or by esterase enzyme action to give the free acid offormula I.

14. A compound as claimed in any one of claims 1 to 13, wherein an ester at the 2-carboxy group informed with an unsubstituted or substituted aliphatic alcohol or phenol having up to 20 carbon atoms in total.

15. A compound as claimed in claim 13, wherein in an esterified 2-carboxy group -COOR, the group R is a phenyl group or isa methyl or ethyl group optionally substituted by an acyl oracyloxy group; and by an alkoxycarbonyloxy group; by an aminoalkanoyloxy group; by an optionally substituted amino group; or, in the case of a methyl group, by one or more unsubstituted or substituted phenyl groups; and wherein a phenyl group, eitheras R or as a substituent of a methyl group, is optionally substituted by one or moresubstituents selected from methoxy and nitro groups and halogen atoms; or R represents a phenoxyethyl ortrichloroethyl group; or R represents a trialkylsilyl ortrialkylsilylalkyl ester in which alkyl moieties have from 1 to 4carbon atoms; orR represents a phthalidyl group.

16. A compound as claimed in claim 15, wherein R represents a benzyl, nitrobenzyl, methoxybenzyl, dimethoxybenzyl, benzhydrdryl, trityl, trimethylsilyl ortrimethylsilylethyl group.

17. A compound as claimed in claim 15,wherein, R represents an acyloxymethyl oracyloxyethyl group having from 2to 12 carbon atoms in the acyl moiety, an aminoalkanoyloxymethyl group having from 2 to 12 carbon atoms in the alkanoyl moiety, a 1 '-(alkoxycarbonyloxy)-ethyl group, or an optionally substituted 2aminoethyl group.

18. A compound as claimed in claim 17, wherein R represents a glycyloxymethyl, L-valinyloxymethyl or L-leucyloxymethyl group, a 1 '-(methoxycarbontloxy)-ethyl group, or a 2-diethylaminoethyl or 2-(1 morpholino)ethyl group.

19. A compound as claimed in claim 17, wherein R represents a pivaloyloxymethyl, eth oxycarbonyloxymethyl, 5-methyl-dioxalen-2-on-4-yl-methyl, acetyl methyl, acetoxymethyl, '- (acetoxy)ethyl, 1 '-(acetyl)ethyl or 1 '-(ethoxycarbonyloxy)ethyl group.

20. A compound as claimed in any one of claims 1 to 3 or claim 8 wherein, independently of each other, R represents a hydrogen atom or a physiologically tolerable salt-forming group or a group that can be cleaved in vivo to give the free carboxy group ora carboxylate group, and R3 represents a hydrogen atom or a group that can be cleaved in vivo to give the free hydroxy group.

21. Acompound as claimed in anyone of claims 1 to 3 and 9to 20, having, independently or in any combination,5R-stereochemistry,6S-stereochemistry and 8R-stereochemistry.

22. A compound as claimed in any one of claims 1 to 3 and 9 to 20, having 5R,6S,8R stereochemistry.

23. A physiologically tolerable salt of a compound as claimed in anyone of claims 1 to 22 having asaltforming group.

24. A process for the production of a compound offormula I as claimed in claim 1,whichcomprises (A) treating a compound offormula II

in which R3 is as defined in claim 1, R4 represents a carboxy protecting group, R5 represents a group R1 as defined in claim 1 ora group that can be converted into a group R1 R6 represents a group R2 as defined in claim 1 or a group that can be converted into a group R2, R7 represents a phenyl group or an alkyl group having from 1 to 4 carbon atoms, and R8 represents a bromine or chlorine atom,with a base; or (B) effecting cyclisation of a compound offormula Ill

in which R3, R4, R5 and R6 are defined as above, X represents an oxygen our sulphur atom, and the group P(Z)3 represents a group derived from a trivalent organophosphorus reagent, or (C) treating a compound offormula IV orV

in which X, R3, R4, R5, R6 and R8 are defined as above, with a trivalent organophosphorus compound and effecting cyclisation or;; (D) reacting a compound offormula VI

in which R3, R4andthegroup P(Z)3 are defined as above, and R19 represents Cu(ll), Pb(ll) orHg(ll), in which case n represents 2, or R'9 represents Ag(l), in which case n represents 1,with a compound offormula VII

in which R11 represents an activating group, and X, R5 and R6 are defined as above, and effecting cyclisation, and (E) in an appropriate compound in which R and/or R6 represents a group that can be converted into a group R1 and/or R2, respectively, converting such a group or groups R5 and/or R6 into such a group or groups R and/or R2and, (F) if desired or required, in an appropriate compound converting a group R1 and/or a group R2 into another group R1 and/or R2, respectively; and (G) if desired or required, carrying out any one or more ofthefollowing steps in any desired order: a) hydrolyzing a 2-carboxylic ester group in an appropriate compound to give the corresponding free acid, b) treating an appropriate free acid or a saltthereof with an agent capable of forming a 2-carboxylic acid ester thereof, c) carrying outan acid- or base-catalysed ester interchange on an appropriate 2-carboxylic acid ester to give a different ester of that compound, d) treating an appropriate free acid compound with a base to give a salt at the carboxy group at position 2, e) treating an appropriate free acid or 2-carboxylic acid ester having a basic group present with an acid to give an acid addition salt thereof, treating a salt of an appropriate compound with an acid to give a free acid of that compound, g) removing a hydroxy protecting group from an appropriate compound having a protected 8-hydroxy group to give the corresponding compound having a free 8-hydroxy group, h)treating an appropriate compound having a free hydroxy group at the 8-position with an organic acid derivative to form an ester atthe 8-position, and i) treating an appropriate compound to effect a change in the stereochemical configuration.

25. A process as claimed in claim 24(A), wherein the base is ammonia, or an alkali metal carbonate, bicarbonate, or hydroxide; a primary amine; an alkali metal alkoxide; or a heterocyciic base having a pKa within the range offrom 5to 9.

26. A process as claimed in claim 25, wherein the heterocyclic base is imidazole, pyridine ora substituted pyridine.

27. A process as claimed in claim 24(A), claim 25 or claim 26, wherein a compound offormula II is produced by halogenating a compound offormula Xl

in which R3 is as defined in claim 1, R4, R5, R6, and R7 are as defined in claim 24, and R9 represents an alkyl group having from 1 to 8 carbon atoms, an alkenyl group having from 2 to 4 carbon atoms, ora phenyl group, using an agent capable of splitting a carbon-sulphur bond and of introducing a halogen atom.

28. A process as claimed in claim 27, wherein the halogenating agent is molecular chlorine, sulphuryl chloride, t-butyl hypochlorite, cyanogen chloride or molecular bromine.

29. A process as claimed in anyone of claims 24(A) and 25to 28, wherein in compound land in compound Xl, R3 is a hydrogen atom.

30. A process as claimed in any one of claims 27 to 29, wherein a compound offormula XI is produced by reacting a compound of formula X

in which R3 is as defined in claim 1, R4, R5 and R6 are defined as in claim 24, R9 is defined as in claim 27, and R10 represents a group -SO2-Rh or -CORh in which Rh represents an alkyl group having from 1 to 4carbon atoms, an optionally substituted phenyl group, or a polyfluoroalkyl group, with a compound offormula XIII R7COSH (mull) in which R7 is as defined in claim 24.

31. A process as claimed in claim 30, wherein R7 represents a methyl ort-butyl group.

32. A process as claimed in claimed 30 or claim 31, wherein compound XIII is in the form of a reactive derivative thereof.

33. A process as claimed in claim 32, wherein a reactive derivative of compound XIII is an alkali metal, alkaline earth metal or organic amine salt thereof.

34. A process as claimed in any one of claims 30to 33, wherein in compound X, R3 represents a hydroxy protecting group, which protecting group is removed before or aftertheformation of compound Xl.

35. A process as claimed in any one of claims 30 to 34, wherein a compound offormula X is produced by reacting a compound offormula IXoratautomerthereof.

in which R3 is as claimed in claim 1, R4, R5 and R6 defined as in claim 24, and R9 is defined as in claim 27, in the presence of a base with a compound offormula XII R10-R11 (XII) in which R10 is as defined in claim 30, and R11 represents an activating group.

36. A process as claimed in claim 35, wherein R10 represents a methylsulphonyl phenylsulphonyl ortrifluoromethylsulphonyl group, or a trifluoroacetyl group.

37. A process as claimed in claim 35 or claim 36, wherein the base is a tertiary amine or a heterocyclic base.

38. A process as claimed in anyone of claims 35 to 37, wherein a compound offormula IX is produced by reacting a compound offormulaVIII

in which R3 is as defined in claim 1, R4 is defined as in claim 24, and R9 is defined as in claim 27, in the presence of a base with an activated carboxylic acid derivative offormula Vlla

in which R5 and R6 are defined as in claim 24, and R11 is defined as in claim 35.

39. A process as claimed in claim 38, wherein the base has a pKa#20.

40. A process as claimed in claim 36, wherein the base is a metallated amine.

41. Aprocess as claimed in anyone of claims 35 to 40, wherein in compounds VIII, IX andX R3 representsa hydroxy protecting group.

42. A process as claimed in claim 24(B), wherein a compound offormula I is produced by heating a solution of a compound offormula III.

43. A process as claimed in claim 24(C), wherein a compound offormula I is produced by reacting a compound offormula IV orformula Vwith a trivalent organophosphorus reagent at room temperature or above.

44. A process as claimed in claim 43, wherein the reaction is carried out in a solvent or mixture of solvents, and at the reflux temperature of the solvent system used.

45. A process as claimed in claim 43 or claim 44, wherein the organophosphorus reagent comprises one or more reagents selected from phosphites and phosphoramides, phosphines (in the case of compound V), phosphines in combination with phosphites (in the case of compound IV), cyclictrialkyl phosphites, and catechol phosphites and catechol dimer phosphites.

46. A process as claimed in claim 45, wherein the trivalent organophosphorus reagent is selected from phosphites, phosphoramides and phosphines of the following formulae XX, XXI and XXII

in which the formulae Rive, R17, R15, and R19,which may be the same ordifferent, each represents a straightor branched chain alkyl group having from 1 to 6 carbon atoms or a phenyl group which may be unsubstituted; cyclictrialkyl phosphites offormula XXIII

in which each group A denotes an alkylene group having from 1 to 4 carbon atoms; catechol phosphites and catechol dimer phosphites ofthe following formulae XXIV and XXV, respectively:

in which R15 and A are defined as above; the trivalent organophosphorus reagent optionally being bound to an inert polymer.

47. A process as claimed in claim 45 or claim 46, wherein the trivalent organophosphorus reagent is trimethyi phosphiteortriethyl phosphite.

48. A process as claimed in claim 24(B) or claim 42, wherein a compound offormula III is produced by reacting a compound offormula IV orformula Vwith a trivalent organophosphorus reagent.

49. A process as claimed in claim 48, wherein the trivalent organophosphorus reagent is as defined in any one of claims45 to 47.

50. A process as claimed in claim 48 or claim 49, carried out at room temperature or below.

51. Aprocess as claimed in any one of claims 24(C) and 43to 50, wherein a compound offormula IVis produced by reacting a compound offormula XV

in which R3 is defined as in claim 1, and R5, R6 and X are defined as in claim 24, with a compound offormula XIX R400C - COR'5 (XIX) in which R4 is as defined in claim 24, and R15 represents a group that can be displaced by the azetidinone nitrogen in the compound of formula XV to give a compound of formula IV, or by oxidising a compound of formula XXVII

in which R3, R4, R5, R5 and X are as defined in claim 1, by treatment with an oxidising agent.

52. A process as claimed in claim 51,wherein R15 represents a halogen atom, an imidazolidegroup ora mixed anhydride group.

53. A process as claimed in claim 51 or 52, carried out in the presence of a base that is optionally polymerbound.

54. A process as claimed in claim 53, wherein the base is a tertiary amine, pyridine or a substituted pyridine.

55. A process as claimed in any one of claims 51 to 54, carried out in the presence of an acid binding agent.

56. A process as claimed in claim 55,wherein the acid binding agent is an alkali metal oralkalineearth metal carbonate or bicarbonate, or an organic epoxide.

57. A process as claimed in any one of claims 24(C) and 43 to 50, wherein a compound offormula V is produced by halogenating a compound offormula XVI

in which R3 is defined as in claim 1, and R4, R5, R6 and X are defined as in claim 24.

58. A process as claimed in claim 57, wherein the halogenating agent is thionyl chloride or bromide, phosphorus oxychloride or oxybromide, or a phosphorus halide, ora mixture of two or morethereof.

59. A process as claimed in claim 57 or claim 58, carried out in the presence of a base that is optionally polymer-bound.

60. A process as claimed in any one of claims 57to 59, wherein a compound of formula XVI is produced by reacting a compound offormula XV as defined in claimed 51,with a glyoxylicesterofformulaXXVI

in which R4 is as defined in claim 24, or with a reactive derivative thereof.

61. A process as claimed in any one of claims 51 to 60, wherein a compound offormula XV is produced by reacting a compund offormulaXIV

in which R3 is as defined in claim land L represents a leaving group, for example, a halogen atom, an alkylcarbonyloxy group in which the alkyl moiety has from 1 to 4 carbon atoms, has a straight or branched chain, and may be substituted by an electron-withdrawing group, for example, a halogen atom, especially a fluorine atom, a phenylcarbonyloxy group,oran -SO2Rj group in which Rj represents an alkyl group having from 1 to 4 carbon atoms ora phenyl group, and is preferably an acetoxy group, with a compound offormula XVII

in which R5, R6 and X are defined as in claim 24, and M represents a hydrogen atom or an alkali metal or alkaline earth metal atom, or an ammonium group that is unsubstituted or substituted (when M represents hydrogen the reaction is carried out in the presence of a base).

62. A process as claimed in claim 61,wherein a compound offormula XVII is preferably produced (i) by reacting a compound offormula VII

in which X, R5, R6are defined as in claim 14, and R11 is defined as in claim 25, with a compound offormula MSH or M2S, in which M is as defined above, (when M represents hydrogen the reaction is carried out in the presence of a base); or (ii) by reacting a compound of formula XVIII

in which M1 represents an alkali metal or alkali earth metal radical, together with a counter-ion, if required in the case were M1 represents a divalent metal ion, with carbon disulphide or carbon oxysulphide, giving a compound offormula XVII in which M represents an alkali metal or alkaline earth metal atom.

63. A process as claimed in claim 24(D), wherein a compound offormula I is produced by reacting a compound offormula VI with a compound offormula VII at a temperature within the range of from -40to 180"C.

64. A process as claimed in claim 63, wherein the temperature is within the range offrom roomtem peraturetol50"C.

65. Aprocess as claimed in claim 24(B), wherein a compound offormula III is produced by reacting a compound offormula VI as defined in claim 24(D) with a compound offormula VII as defined in claim 24(D).

66. A process as claimed in claim 65, carried out at a temperature within the range of from -40 to room temperature.

67. A process as claimed in any one of claims 24to 66, wherein a protected group -OR3 is a protected groupfrom which the protecting group R3 can be removed under acidic conditions.

68. A process as claimed in claim 67, wherein a protected hydroxy group is a tetrahydropyranyloxy or tetrahydrofuranyloxy group; an acetal or ketal group; or a silyl ether.

69. Aprocess as claimed in claim 68, wherein an acetal or metal group has the formu la

in which R12 and R13, which may be the same or different, each represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, or R12 and R13togetherwith the carbon atoms to which they are attached, represents a cycloalkyl ring having from 4to 7 carbon atoms, and R14 represents an alkyl group having from 1 to 4 carbon atoms, or R12 and R14, together with the carbon atom and the oxygen atom to which they are attached, respectively, represent tetrahydropyranyl ring; and a silyl ether has three substituents on the silicon atom and up to 24 carbon atoms in total, the three substituents being the same or different, and selected from alkyl, alkenyl and cycloalkyl groups, and phenyl and phenalkyl groups which may be unsubstituted or substituted.

70. A process as claimed in claim 69, wherein a protected hydroxy group is an -OSiReRfRg group in which Re, Rf and Rg are as defined in claim 1.

71. A process as claimed in claim 70, wherein a hydroxy protecting group R3 is a tetrahydropyranyl, 2-methoxyprop-2-yl, trimethylsilyl, triethylsilyl or t-butyldimethylsilyl group.

72. A process as claimed in any of claims 24to 71,wherein in a compound offormula I oranyappropriate precursorthereof, any one or more ofthe following conversions are carried out: (a) a group R5to a group R1 orto another group R5, (including conversin of a radical present as partofa group R5); (b) a group R6to a group R2orto anothergroup R6, (including conversion of a radical present as partofa group R6); (c) a group R1 to anothergroup R1, (including conversion of a radical presentas part a group R1); (d) a group R2to a group R2, (including conversion of a radical present as part of a group R2); the conversion being carried out as follows: (i) -COORd, -COOSiReRfRg or -COO-phenyl to -COOH (ii) -COOHto -CONH2, -CONHRa or -CONH (CH2)mQ (iii) -COOH to -COOR4 or -CO2CH2Q or -CO2CH2CH2Q or -CO2CH(CH3)Q iv) -COOHto -CORa (v) -NHRm or -NRmRn in which Rm and Rn are protecting groups, to -NH2 (vi) -NH2 to

(vii) -CONRaRm, Rm being a protecting group, to -CONHRa (viii) -N3 to -NH2, which is then optionally converted to a group R1 as described in (v) above, (ix) halogen to -CN or -COOH (x) -SRa to -SORa or -SO2Ra (xi) -CN to -CH2NH2,which is then optionally converted to a group as defined in (v) above, (xii) -SORa to -SO2Ra (xiii) - NO2 to NH2, which is then optionally converted further as described in (v) above.

73. A process as claimed in claim 24, carried out substantially as described in any one of Examples 6,7,12, 13,18,19,20,2,22,23,27,28,32 to 43,47 to 49,53 to 55,59 to 61,65 to 67,71 to 73,77 to 80,83 to 92,94 to 113, 115to117and120to122herein.

74. Acompound as claimed in claim 1,whenever produced buy a process as claimed in any one of claims 24 to73.

75. Acompound as claimed in claim 1, substantially as described in any one of Examples 6,7,12,13,18, 19,20,2,22,23,27,28,32 to 43,47 to 49,53 to 55, 59to 61,65 to 67,71 to 73,77to80 and 83to 91 herein.

76. A pharmaceutical preparation which comprises a compound offormula I as claimed in any one of claims 1 to 23,75 and 76, ora physiologicallytolerable salt thereof, ora mixture of two or more such sub- stances as active ingredient, in admixture or conjunction with a pharmaceutically suitablecarrier.

77. A pharmaceutical preparation as claimed in claim 76, which also comprises one or more other pharm- aceutically active substances.

78. A pharmaceutical preparation as claimed in claim 77, wherein the other pharmaceutically active sub- stance(s) is or are selected from cephalosporin antibiotics.

79. A pharmaceutical preparation as claimed in any one ofclaims 76to 78, in a form suitable for enteral or parenteral administration.

80. A pharmaceutical preparation as claimed in any one of claims 76to 79, in unit dosage form.

81. Acompound offormula las claimed in any one of claims 1 to 23,74 and 75, ora physiologically tolerable saltthereoffor use in the manufacture of a medicamentforthetreatment of bacterial infections.

82. A method of treating mammals two combat a bacterial infection, which comprises administering to the mammal a compound offormula las claimed in any one of claims 1 to 23,75to 76, or a physiologically tolerable esterorsaltthereof.

83. Acompoundofformula II

in which R3 is as defined in claim 1 and R4, R5, R6, R7 and R8 are as defined in claim 24.

83. A pharmaceutical preparation which comprises an active ingredient as defined in claim 76, in unit dosage form.