PROCESS FOR THE PREPARATION OF PENAM AND PENEM DERIVATIVES

Abstract: The invention provides a process for the preparation of compounds of formula (I) wherein R<1>, R<2>, R<3>, R<4> and R<5> are as defined in the specification; and wherein any functional groups are optionally protected; and salts thereof; which process includes the step of reacting the intermediate formed by heating a compound of formula (II), in an inert solvent, with a compound of the formula S=C(R<3>)R<4> wherein R<1>, R<2>, R<3>, R<4> and R<5> are as defined in the specification and functional groups are optionally protected; and thereinafter, if necessary, removing any protecting groups. The compounds of the formula (I) are useful as intermediates in the preparation of penems and may possess antibacterial properties and/or inhibit beta -lactamase in their own right.

Description: PROCESS FOR THE PREPARAΗON OF PENAM AND PENEM DERIVATIVES The invention relates to a process for the manufacture of penem and penam derivatives which are intermediates for antibiotic compounds, some of which are β-lactamase inhibitors, and some of which are antibiotics in their own right. The invention provides a process for the preparation of compounds of the formula (I): (I) wherein R 1 is hydrogen or optionally substituted: Cι- 6 alkyl, Cι- 6 alkylthio or Ci-ealkoxy; R is hydrogen, halogen or optionally substituted: Cι-6alkyl, C .6alkenyl, arylCι_ alkyl, aryl, heteroaryl C h alky I, heteroaryl, heterocyclyl, heterocyclylCι- 3 alkyl, C 3 . 7 cycloalkyl, C 3 - 7 cycloalkylCι- 3 alkyl, C 5 - 7 cycloalkyenyl, C 5 - 7 cycloalkenylC]. 3 alkyl, C|. 6 alkoxy, C|- 6 alkylthio, arylthio, aryloxy, heteroaryloxy, heteroarylthio, C|- alkoxycarbonylamino, aryloxycarbonylamino, arylCι- 3 alkoxycarbonylamino, heteroaryloxycarbonylamino, heteroarylC ι - 3 alkoxycarbonylamino, C ι -όalkanesulphonylamino , arylsulphonylamino, arylC|- 3 alkylsulphonylamino, heteroarylC ι- 3 alkylsulphonylamino or heteroarylsulphonylamino or R is of the formula R CONH- wherein R is an organic group; or R 1 and R 2 together form an optionally substituted C 3 . 6 alkylene chain wherein one methylene group is optionally replaced by -N(R n )-, -O- or -S-, (C 3 -$alkylene chains wherein one methylene group is optionally replaced by -N(R n )-, -O- or -S- are hereafter referred to as C . 6 heteroalkylene), wherein R n is hydrogen, Cι- 6 alkanoyl, phenylCι. 3 alkyl or Cι- 6 alkyl; or R 1 and R 2 together form a group of the formula: R a >- wherein R a and R b are independently hydrogen or optionally substituted C, ^alkyl, aryl or heteroaryl; or R a and R b , together with the carbon atom to which they are attached, form an optionally substituted C 4 . 7 cycloalkyl, C 4 _ 7 cycloalkenyl or heterocyclyl ring, each optionally fused to a benzene or heteroaryl ring; R 3 and R" are independently: hydrogen, halo, cyano or optionally substituted: C^alkyl, C 3 . 6 alkenyl, arylC,. 3 alkyl, heteroarylC,. 3 alkyl, prop-2-enyl, heteroarylprop-2-enyl, aryl, heteroaryl, C j ^cycloalkenyl, C 5 . 7 cycloalkenylC,. 3 alkyl, heterocyclyl, heterocyclylC,. 3 alkyl, C 3 . 7 cycloalkyl, C 3 . 7 cycloalkylC,. 3 alkyl or of the formula R 7 or R 7 C,. 3 alkyl wherein R 7 is a tricyclic ring system, or of the formula -CO 2 R 8 wherein R 8 is hydrogen or optionally substituted: C,. 6 alkyl, C 3 . 6 alkenyl, C 5 . 7 cycloalkenyl, heterocyclyl, heterocyclylC,. 3 alkyl, C 3 . 7 cycloalkyl, C 3 . 7 cycloalkylC,. 3 alkyl, arylC,. 3 alkyl, heteroarylC ,, 3 alkyl, arylprop-2-enyl, heteroarylprop-2-enyl, heteroaryl or aryl, or of the formula -CONR 9 R 10 wherein R 9 or R 10 are independently hydrogen or optionally substituted: arylC,. 3 alkyl, C,. 6 alkyl, C 3 . 6 alkenyl, heteroarylC,. 3 alkyl, heteroarylprop-2-enyl, arylprop-2-enyl, aryl or heteroaryl or R 9 and R 10 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring, or -SR" wherein R" is optionally substituted: C,. 6 alkyl, arylC,. 3 alkyl, C 3.6 alkenyl, heteroarylC ,. 3 alkyl, arylprop-2-enyl, C 5 . 7 cycloalkenyl, C 5 - 7 cycloalkenylC,. 3 alkyl, heteroarylprop-2-enyl, aryl, heteroaryl, C 2 ^alkynyl, C 3 . 7 cycloalkyl, C 3 . 7 cycloalkylC,.,alkyl, heterocyclyl, heterocyclylC, .3 alkyl, heterocyclylium or heteroarylium, or of the formula -OR" wherein R" is as hereinabove defined, or of the formula -COR 8 wherein R 8 is as hereinabove defined, or of the formula -SeR wherein R 14 is C,. 6 alkyl, arylC 3 alkyl, aryl, C 3 . 6 alkenyl, arylprop-2-enyl, heteroarylC ,. 3 alkyl, heteroaryl or heteroarylprop-2-enyl, or R 3 and R\ together with the carbon atom to which they are attached, form an optionally substituted C 4.7 cycloalkyl, C 4 _ 7 cycloalkenyl or heterocyclyl ring, wherein one methylene group is optionally replaced by -N(R )-, -O- or -S-, (wherein R" is as hereinabove defined) and the chain formed by R 3 and R 4 optionally contains one double bond and is optionally fused to an aryl or heteroaryl ring; R 5 is cyano or of the formula -CO 2 R 19 wherein R 19 is hydrogen or optionally substituted: C^alkyl, arylC,. 3 alkyl, heteroaryl, heteroarylC,. 3 alkyl, C^alkenyl, arylprop-2-enyl or heteroarylprop-2enyl or R 5 is of the formula -COR 20 wherein R 20 is hydrogen or optionally substituted C^alkyl, arylC,. 3 alkyl, heteroarylC,. 3 alkyl, aryl or heteroaryl; and wherein any functional groups are optionally protected; and salts thereof; which process includes the step of reacting the intermediate formed by heating a compound of the formula (II): OO in an inert solvent, with a compound of the formula S=C(R 3 )R 4 wherein R 3 and R 4 are as hereinabove defined and functional groups are optionally protected; and thereinafter, if necessary, removing any protecting groups. The compounds of the formula (I) are useful as intermediates in the preparation of penems and may possess antibacterial properties and/or inhibit β-lactamase in their own right. When compounds of the formula (II) are heated in an inert solvent, an intermediate is formed. This intermediate reacts with thiocarbonyl compounds to give products of formula (I). It is believed, but we do not wish to be bound by theory, that one type of intermediate formed in this reaction by heating the compound of formula (II) in an inert solvent is the stabilised ylide of formula (IVa). In this case the carbon dioxide that is lost in the reaction is lost in a step subsequent to the ring forming step. IVa IVb Other unrelated stabilised 1,3-dipolar species are known to arise by ring openning reactions of Δ -oxazolidines (E. Vedejs and J.W.Grissom, J. Amer. Chem. Soc, 1986. 108, 6433). It is further believed that another type of intermediate formed in this reaction by heating the compound of formula (II) in an inert solvent is the unstabilised ylide of formula (IVb). In this case the carbon dioxide that is lost in the reaction is lost in a step prior to the ring forming step. Other unrelated unstabilised 1,3-dipolar species are known to arise from decarboxylation reactions of iminium salts derived from primary and secondary α-amino acids (see E. Vedejs and F.G. West, Chem. Rev., 1986, 86, 941 ; E. Vedejs, Adv. Cycloaddition, 1988, 1, 33). The relative importance of these two types of intermediate will depend upon the conditions of the reaction, such as temperature and solvent, and on the relative abilities of the co-reagent olefins and acetylenes to react with the different intermediates. For instance, milder reaction conditions and reactive co-reagents will favour the importance of the stabilised intermediate (IVa) whereas higher reaction temperatures and less reactive co-reagent will favour the importance of the unstabilised intermediate (IVb). The normal outcome of the reaction does not depend upon the stage at which the decarboxylation occurs since the same bicyclic ring system arises regardless of the order of the decarboxylation-cycloaddition steps. Under the preferred reaction conditions the stabilised 1,3-dipole (IVa) is believed to be the important reaction intermediate. Preferably the intermediate is formed by reacting the compound of the formula (II) in an inert solvent in a temperature range of 50°C to 180°C. More preferably the intermediate is formed by reacting the compound of the formula (II) in an inert solvent in a temperature range of 80°C to 110°C. Preferably the inert solvent is acetonitrile, propionitrile, toluene, chloroform or o-dichlorobenzene. Most preferably the inert solvent is acetonitrile. In another aspect the intermediate may be formed in the compound of the formula S=C(R 3 )R . This could take the form of a 'melt' depending upon the nature of the reagents. It is envisaged that there will be other ways of preparing the intermediate. In a further embodiment of the invention, compounds of formula (I) can be converted into penem compounds of the formula (III): (III) and salts thereof; wherein R', R 2 and R 5 are as hereinabove defined and R 15 is a substituent R 3 or R 4 , by methods known in the art. In circumstances where R 3 or R 4 is an eliminatable group, a compound of the formula (III) may be prepared from a compound of the formula (I) in situ. Suitable eliminatable groups include methylthio. In circumstances where R 3 or R" may be converted into an eliminatable group, a compound of the formula (HI) may be prepared from a compound of the formula (I) in a separate synthetic step. Suitable eliminatable groups include methylsulfinyl. The compounds of the formula (III) are useful as intermediates in the preparation of other penems and may be of value in the treatement of bacterial infections and/or inhibit β-lactamase. Penem compounds of the formula (III) can be converted into penem compounds of the formula (V): (V) and pharmaceutically-acceptable salts and in vivo hydrolysable esters thereof; wherein R 21 , R 22 , and R 23 are substituents known in the penem art. In particular, the process of the present invention may be used to prepare penem compounds of the formula (V) wherein: R 21 hydrogen and R 22 is 1-hydroxyethyl, hydroxymethyl, l-hydroxy-l-(3-methylisoxazol-5- yl)methyl, 2-(l-methyltriazol-4-yl)ethen-l-yl or thien-2-ylmethylcarbonylamino; or R 21 and R 22 together form ethylene or 2-(fur-2-yl)ethylene; and R 23 is hydrogen, pyrrol-2-ylmethyl, 1-methylpyrroliomethyl, l-oxotetrahydrothien-3-yl, 4- (hydroxymethyl)imidazol-l-yl, 1 -methylimidazol-2-ylmethylthio, 4-carbamoylphenoxy, tetrahydrofuran-2-yl, aminomethyl, imidazol-1-yl, 2-(carbamoyloxy)eth-l-ylthio, 2-fluoroeth- 1-ylthio, 2-aminoprop-l-yl, ethylthio, 4-(pyridiniomethyl)phenyl, 3-carboxyphenyl, N- (carbamoylmethyl)-N-methylaminomethyl, 4-(4-(2-aminopyrid- 1 -ylmethyl)phenyl)phenyl, tetrahydrofuran-2-yl, 6,8-difluoro- 1 -(2-fluoroeth- 1 -yl)-7-(4-methylpiperazin- 1 -yl)-4-oxo- 1 ,4- dihydroquinolin-3-ylcarbonyloxomethy 1, 4-(3-carboxy- 1 -cyclopropyl-6-fluoro-4-oxo- 1 ,4- dihydroquinolin-7-yl)piperazin-4-ylcarbonyloxymethyl or 1 -(3-carboxy-l -cyclopropyl-6,8- difluoro-4-oxo-l,4-dihydroquinolin-7-yl)pyrrol-3-ylcarbonyloxomethyl; and pharmaceutically-acceptable salts and in vivo hydrolysable esters thereof; Most particularly, the process of the present invention may be used to prepare a penem compound of the formula (V) wherein: R 21 hydrogen, R 22 is 1-hydroxyethyl and R 23 is tetrahydrofuran-2-yl; and pharmaceutically-acceptable salts and in vivo hydrolysable esters thereof; The compounds of the formula (V) are of value in the treatement of bacterial infections, and may inhibit β-lactamase. Suitable pharmaceutically-acceptable salts include acid addition salts such as hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulphuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N- ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine. There may be one or more cations or anions depending on the number of charged functions and the valency of the cations or anions. Preferred pharmaceutically-acceptable salts are sodium and potassium salts. However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not. In vivo hydrolysable esters are those pharmaceutically-acceptable esters that hydrolyse in the human body to produce the parent compound. Such esters can be identified by administering, e.g. intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in vivo hydrolysable esters for carboxy include C^alkoxymethyl esters for example methoxymethyl, C,. 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 . 8 cycloalkoxycarbonyloxy C,. 6 alkyl esters for example 1-cyclohexyloxycarbonyloxyethyl; 1 ,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and C,. 6 alkoxycarbonyloxyethyl esters for example 1- methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention. Suitable in vivo hydrolysable esters forming groups for hydroxy include acetyl, propionyl, pivaloyl, C M alkoxycarbonyl for example ethoxycarbonyl and phenylacetyl. The process of the invention may also be used in the preparation of chemical compound libraries. It may be used to provide a common synthetic step at any convenient stage of library synthesis, such as at the penultimate or last stage. The libraries so prepared may comprise any convenient number of individual, and diverse, chemical compounds, such as from tens to hundreds, hundreds to thousands, thousands to tens of thousands, tens of thousands to hundreds of thousands, hundreds of thousands to a million or more individual compounds. Suitable and preferred chemical moieties for inclusion in the library will be apparent to the chemist of ordinary skill. Particular optional substituents for alkyl, alkenyl and aryl groups and ring carbon atoms in heteroaryl groups in R 1 and R 2 include halo, trifluoromethyl, nitro, hydroxy, amino, C alkylamino, diC alkylamino, cyano, C,. 6 alkoxy, carboxy, C, .6 alkylS(O) p ( p is 0, 1 or 2), C,. 6 alkyl (optionally substituted by hydroxy, amino, halo, nitro, cyano, hydroxyimino or C M alkoxyimino), carbamoyl, C M alkylcarbamoyl, di(C alkyl)carbamoyl, C^alkenyl, C^alkynyl, C M alkoxycarbonylamino, C^alkanoylamino, C alkanoyl(N-C i _ 4 alkyl)amino, C alkanesulphonamido, benzenesulphonamido, aminosulphonyl, C alkylaminosulphonyl, di(C alkyl)aminosulphonyl, C alkoxycarbonyl, C alkanoyloxy, C^alkanoyl, formylC M alkyl, trifluoroC,. 3 alkylsulphonyl, hydroxyiminoC,_ 6 alkyl, C M alkoxyiminoC,. 6 alkyl, C,. 6 alkylcarbamoylamino, triazolyl, tetrazolyl and an additional optional substituent on saturated carbon atoms is oxo. Particular optional substituents for alkyl, alkenyl and aryl groups and ring carbon atoms in heteroaryl groups in R 3 and R 4 include halo, trifluoromethyl, nitro, hydroxy, amino, C M alkylamino, diC M alkylamino, cyano, C,. 6 alkoxy, carboxy, C,. 6 aIkylS(O) p (p is 0, 1 or 2), C^alkyl (optionally substituted by hydroxy, amino, halo, nitro, cyano, oxo (=O), hydroxyimino C M alkoxyimino), carbamoyl, C alkylcarbamoyl, di(C,_ 4 alkyl)carbamoyl, carbamoyloxy, C alkylcarbamoyloxy, di(C alkyl)carbamoyloxy, C 3 . 6 alkenyl, C 3 . 6 alkynyl, C alkoxycarbonylamino, C alkanoylamino, C M alkanoyl(N-C M alkyl)amino, C,. 4 alkanesulphonamido, benzenesulphonamido, aminosulphonyl, C M alkylaminosulphonyl, di(C M alkyl)aminosulphonyl, C M alkoxycarbonyl, C M alkanoyloxy, aroyloxy, heterocyclylcarbonyloxy, heteroaroyloxy, C alkanoyloxy arylC , ^alkanoyloxy , heterocyclylC , ^alkanoyloxy , heteroarylC , . 4 alkanoyloxy , arylC,. 3 alkanoyl, C,. 6 alkanoyl, formylC alkyl, aryl, heteroaryl, arylC,. 3 alkyl, heteroarylC,. 3 alkyl, arylprop-2-enyl, heteroarylprop-2-enyl, trifluoroC,. 3 alkylsulphonyl. hydroxyiminoC^alkyl, C alkoxyiminoC,. 6 alkyl, C,. 6 alkylcarbamoylamino, aryloxyalkanoyl, a group of the formula -N=C(R c )R d , -N(R e )C(R f )=NR B , -C(N(R h )R')=NR j or -CON(R )R wherein R e is hydrogen, C M alkyl, amino, C alkylamino or di(C alkyl)amino; R d -R k are independently hydrogen or C alkyl; R p is hydrogen, C alkyl, aryl, heteroaryl, heterocyclyl, heterocyclylene, heterocyclyleneC,. 3 alkyl, cycloalkyl or cycloalkylC,. 3 alkyl; and on saturated carbon atoms additional optional substituents are oxo, imino and C alkylimino. Optional substituents for ring nitrogen atoms in heteroaryl groups include C alkyl and C M alkanoyl. Any aryl and heteroaryl groups in the optional substituents for R 1 , R 2 , R 3 and R 4 may be optionally substituted by halo, C M alkyl, trifluoromethyl, nitro, hydroxy, amino, C alkylamino, di-(C alkyl)amino, cyano, C alkoxy, carboxy, C M alkanoyl or carbamoyl. A heteroaryl ring system is a monocyclic aryl ring system having 5 or 6 ring atoms wherein 1 , 2 or 3 ring atoms are selected from nitrogen, oxygen and sulphur or a bicyclic aryl ring system having 8 to 10 ring atoms wherein 1 , 2, 3 or 4 ring atoms are selected from nitrogen, oxygen and sulphur. Particular heteroaryl rings include pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, 1,2,4-, 1,2,5- and 1,3,4-thiadiazolyl, thienyl, furyl and oxazolyl and 1,2,3- and 1,2,4-triazolyl. An aryl ring system is phenyl, naphthyl or a tricyclic aryl ring system. Preferably an aryl ring system is phenyl. A heterocyclylium ring is a positively charged saturated or partially saturated monocyclic ring system, having 5 or 6 ring atoms, or a positively charged bicyclic ring system, having 8 to 10 ring atoms, containing one ring nitrogen atom and 0-2 further hetero ring atoms selected from nitrogen, oxygen and sulphur. A heteroarylium ring is a positively charged monocyclic aryl ring system, having 5 or 6 ring atoms, or a positively charged bicyclic aryl ring system, having 8 to 10 ring atoms, containing one ring nitrogen atom and 0 - 2 further hetero ring atoms selected from nitrogen, oxygen and sulphur. A heterocyclyl ring system is a saturated or partially saturated monocyclic ring system having 5 or 6 ring atoms or a saturated or partially saturated bicyclic ring system having 8 to 10 ring atoms, each containing 1 - 3 hetero ring atoms selected from nitrogen, oxygen and sulphur and wherein any ring sulphur and nitrogen atoms are optionally oxidized. For example, piperidyl, pyrrolidinyl, piperazinyl, tetrahydrofuryl, tetrahydrothienyl, morpholinyl, pyrazolinyl, pyrrolinyl and imidazolinyl. Particular examples of tricyclic ring systems include optionally substituted bicyclic heteroaryl ring systems to which is fused a benzene ring. Specific examples of tricyclic rings include, dibenzofuran and dibenzothiophene. A C 3 . 7 cycloalkyl group is a saturated monocyclic ring system having from 3 to 7 ring atoms. A C 5 . 7 cycloalkenyl group is a monocyclic ring system having from 5 to 7 ring atoms and containing one double bond. The term alkyl when used herein includes straight chain and branched chain substituents for example C M alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl. An organic group includes, for example, a group of the formula -C(=R )R r wherein R r is an optionally substituted heteroaryl group and R q is an oxyimino group. The oxyimino group may be, for example, of the formula =NOR 8 wherein R 8 is as hereinabove defined. An organic group also includes C,. 6 alkyl, phenyl, heteroaryl, arylC,. 3 alkyl and heteroarylC,. 3 alkyl. Optional substituents for carbon atoms in C 3 . 6 and C 3 . 7 alkylene and heteroalkylene chains include halo, trifluoromethyl, nitro, oxo, hydroxy, amino, C alkylamino, di(C alkyl)amino, cyano, C^alkoxy, C M alkyl-S(O) p -(p is 0, 1 or 2), C alkanoyl and C alkyl optionally substituted by hydroxy, halo, nitro, cyano or amino; Examples of C^alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl and t-butoxycarbonyl; examples of carboxy C,. 3 alkyl are carboxymethyl, 2-carboxyethyl, 1-carboxyethyl and 3-carboxypropyl; examples of C,. 6 alkoxycarbonylC,. 3 alkyl are methoxycarbonylmethyl, ethoxycarbonylmethyl and methoxycarbonylethyl; examples of tetrazolyC,. 3 alkyl are tetrazolylmethyl and 2-tetrazolylethyl; examples of C M alkoxy are methoxy, ethoxy, propoxy and isopropoxy; an example of C 3 . 6 alkenyl is allyl; an example of C 2 . 6 alkynyl is propynyl; examples of C M alkanoyl are formyl, acetyl, propionyl and butyroyl; examples of halo are fluoro, chloro, bromo and iodo; examples of C alkylamino are methylamino, ethylamino, propylamino and isopropylamino; examples of di(C alkyl)amino are dimethylamino, diethylamino and ethylmethylamino; examples of C alkylS(O) p - are methylthio, methanesulphinyl and methanesulphonyl; examples of C M alkylcarbamoyl are methylcarbamoyl and ethylcarbamoyl; examples of di(C alkyl)carbamoyl are dimethylcarbamoyl, diethylcarbamoyl and ethylmethylcarbamoyl; examples of C,. 6 alkyl are methyl, ethyl, propyl and isopropyl; examples of C,. 4 alkoxycarbonylamino are methoxycarbonylamino and ethoxycarbonylamino; examples of C,. 4 alkanoylamino are acetamido and propionamido; examples of C alkanoyl(N-C M alkyl)amino are N-methylacetamido and N-methylpropionamido; examples of C alkanesulphonamido are methanesulphonamido ?nd ethanesulphonamido; examples of C,. 4 alkylaminosulphonyl are methylaminosulphonyl and ethylaminosulphonyl; examples of di(C alkyl)aminosulphonyl are dimethylaminosulphonyl, diethylaminosulphonyl and ethylmethylaminosulphonyl; examples of C M alkanoyloxy are acetoxy and propionyloxy; examples of formylC M alkyl are formylmethyl and 2-formylethyl; and examples of C M alkoxyimino are methoxy imino and ethoxyimino. Examples of alkylene chains include trimethylene, but-l,4-diyl, pent-l,5-diyl and hex-l,6-diyl. Examples of C^heteroalkylene chains include -CH 2 NHCH 2 -, -CH 2 OCH 2 -, -CH 2 SCH 2 -, -CH 2 CH 2 NHCH 2 - and -O-CH 2 CH 2 CH 2 -, Examples of C 3 . 7 alkylene and heteroalkylene chains optionally containing a double bond and optionally fused to a benzene or heteroaryl ring include: (wherein X and Y are independently NH, oxygen, sulphur, methylene, -CO- or -CH(R m )- wherein R m is hydrogen, halo, nitro, amino, hydroxy, cyano or C alkyl), -CH 2 CH 2 CH=CH-, -CH 2 CH=CHCH 2 CH 2 -, -CH 2 NHCH 2 CH 2 -, -OCH 2 CH=CHCH 2 - and -SCH 2 CH 2 CH 2 -. The present invention relates to all tautomeric forms of the compounds disclosed. Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced by conventional methods. For example see 'Protective Groups in Organic Synthesis', by T.W. Greene et. al., second edition 1991. The skilled chemist will appreciate that it is sometimes necessary to protect certain functional groups in certain reactions. For example, when the functional group is sensitive to the reaction conditions or would cause side-reactions. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule. Specific examples of protecting groups are given below for the sake of convenience, in which "lower" signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below, these are similarly not exhaustive. For example, it will be appreciated that polymer-supported protecting groups are included such as those employed in solid phase synthesis (see Polymer-supported Reactions in Organic Synthesis by P. Hodge and D.C. Sherrington, 1980). The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention. A carboxyl protecting group may be the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (eg. isopropyl, t-butyl); lower alkoxy lower alkyl groups (eg methoxymethyl, ethoxymethyl, isobutoxymethyl); lower aliphatic acyloxy lower alkyl groups, (eg. acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloxyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (eg 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (eg p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (eg trimethylsilyl and t-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (eg trimethylsilylethyl); and (2-6C)alkenyl groups (eg allyl and vinylethyl). Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, base-, metal- or enzymically-catalysed hydrolysis or hydrogenation. Examples of hydroxyl protecting groups include lower alkenyl groups (eg allyl); lower alkanoyl groups (eg acetyl); lower alkoxy carbonyl groups (eg t-butoxycarbonyl); lower alkenyloxycarbonyl groups (eg allyloxycarbonyl); aryl lower alkoxy carbonyl groups (eg benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, β-nitrobenzyloxycarbonyl); tri lower alkylsilyl (eg trimethylsilyl, t-butyldimethylsilyl) and aryl lower alkyl (eg benzyl) groups. Examples of amino protecting groups include formyl, aralkyl groups (eg benzyl and substituted benzyl, eg g-methoxybenzyl. nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (eg t-butoxy carbonyl); lower alkenyloxycarbonyl (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzyloxycarbonyl, β-methoxybenzyloxy carbonyl, o-nitrobenzyloxycarbonyl, g-nitrobenzyloxycarbonyl; trialkylsilyl (eg trimethylsilyl and t-butyldimethylsilyl); alkylidene (eg methylidene); benzylidene and substituted benzylidene groups. Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis, for groups such as p-nitrobenzyloxycarbonyl, hydrogenation and for groups such as o-nitrobenzyloxycarbonyl, photolytically. The invention relates to all enantiomeric and diasteromeric forms unless explicitly indicated otherwise. When R 2 is significantly larger than R 1 , the diastereomer with the 5-position stereochemistry as depicted in formulae (I) and (III) is obtained in significantly larger quantities relative to the other diastereomer. The relative orientation of the substituents in the product is determined by the stereochemistry of the reaction. The indicated hydrogen (the ring junction C5) will be preferably cis to the sterically larger of the substituents R 1 and R 2 . The substituent R 5 will be preferably cis to the indicated hydrogen at C5. When R 1 and R 2 are different and enantiomerically enriched lactone (II) is used, the products of the reaction are similarly enantiomerically enriched and when enantiomerically pure lactone (II) is used, the products of the reaction are similarly enantiomerically pure. When R 1 and R 2 are the same or when racemic lactone (II) is used, the products are also racemic. A particular enantiomer may be isolated from a mixture of the enantiomers by resolution. For example, by reaction with an optically active form of a suitable organic base, for example, N,N,N-trimethyl(l-phenylethyl)ammonium hydroxide, followed by conventional separation of the diastereoisomeric mixture of salts thus obtained, for example by fractional crystal lisaton from a suitable solvent, for example a (l-4C)alkanol, whereafter the optically active form of said compound of formula (I), (III), (V) or (VI) may be liberated by treatment with acid using a conventional procedure. Preferably R 1 is no bigger than R 2 More preferably R 2 is bigger than R 1 . Most preferably R 1 is hydrogen. Preferably R 2 is hydrogen, halo or optionally substituted: C M alkyl, aryl, heteroaryl, arylC,. 3 alkyl, heteroarylC,. 3 alkyl, C,. 6 alkoxy, C^alkylthio or of the formula R 6 CONH-. More preferably R 2 is hydrogen or optionally substituted: C^alkyl, phenylC,. 3 alkyl or phenyl, wherein the optional substituents are selected from hydroxy, halo, nitro, amino, C alkoxy or C M alkylthio and the hydroxy and amino groups are optionally protected. Most preferably R 2 is hydrogen or C^alkyl optionally substituted by hydroxy, protected hydroxy or fluoro. Preferably R 3 and R 4 are groups such that S=C(R 3 )R 4 exists predominantly as the thiocarbonyl tautomer rather than the thioenol tautomer. Preferably R 3 and R 4 are independently hydrogen, optionally substituted: C,. 6 alkyl, arylC,. 3 alkyl, heteroaryl C,. 3 alkyl, aryl, heteroaryl, C 5 . 7 cycloalkenylC,. 3 alkyl, heterocyclyl, heterocycly!C,. 3 alkyl, C 3 . 7 cycloalkyl, C 3 . 7 cycloalkylC,. 3 alkyl, or of the formula R 7 or R 7 C,. 3 alkyl wherein R 7 is a tricyclic ring system, or of the formula -SR n wherein R" is optionally substituted: C,. 6 alkyl, ary!C,_ 3 aIkyl, C 3 . 6 alkenyl, heteroarylC,. 3 alkyl, arylprop-2-enyl, C 5.7 cycloalkenyl, C 5 . 7 cycloalkenylC,. 3 alkyl, heteroarylprop-2-enyl, aryl, heteroaryl, C^alkynyl, C 3 . 7 cycloalkyl, C 3 . 7 cycloalkylC|. 3 alkyl, heterocyclyl, heterocyclylC,. 3 alkyl, heterocyclylium or heteroarylium, or of the formula -SeR 14 wherein R 14 is as hereinabove defined. More preferably R 3 and R 4 are independently hydrogen, optionally substituted: C^alkyl, aryl, heteroaryl, or a tricyclic ring system, or of the formula -SR" wherein R" is optionally substituted: C, .6 alkyl, arylC,_ 3 alkyl, C 3 . 6 alkenyl, heteroarylC, .3 alkyl, arylprop-2-enyl, C 5.7 cycloalkenyl, C 5 _ 7 cycloalkenylC,. 3 alkyl, heteroarylprop-2-enyl, aryl, heteroaryl, C 2.6 alkynyl, C 3.7 cycloaIkyl, C 3 . 7 cycloalkylC alkyl, heterocyclyl, heterocyclylC,. 3 alkyl, heterocyclylium or heteroarylium. Yet more preferably R 3 and R 4 are independently optionally substituted: C h alky 1, aryl, heteroaryl, or a tricyclic ring system, or of the formula -SR" wherein R" is optionally substituted: C^alkyl, arylC,-. 3 alkyl, heteroarylC,. 3 alkyl, aryl, heteroaryl, C 3 . 7 cycloalkyl, C 3 . 7 cycloalkylC,. 3 alkyl, heterocyclyl, heterocyclylC,. 3 alkyl. Most preferably at least one of R 3 and R 4 is of the formula -SR". Preferably R 5 is cyano or of the formula -CO 2 R 17 wherein R π is hydrogen or optionally substituted: Cj. 6 alkyl, C^alkenyl, aryIC,. 3 alkyl, arylprop-2-enyl or aryl, or R 5 is of the formula -COR 18 wherein R ,8 is hydrogen or optionally substituted: C,. 6 alkyl, arylC,. 3 alkyl or aryl. More preferably R 5 is of the formula -CO 2 R 17 wherein R' 7 is as hereinabove defined. Preferred optional substituents for alkyl, alkenyl and aryl groups and ring carbon atoms in heteroaryl groups in R 1 and R 2 include halo, trifluoromethyl, nitro, hydroxy, amino, cyano, C,. 6 alkoxy, carboxy, C w alkylS(O) p ( p is 0, 1 or 2), C,. 6 alkyl, carbamoyl, C alkylcarbamoyl, di(C M alkyl)carbamoyl, C M alkanoylamino, C M alkoxy carbonyl, C alkanoyloxy, C^alkanoyland oxo. Preferred optional substituents for alkyl, alkenyl and aryl groups and ring carbon atoms in heteroaryl groups in R 3 and R 4 include halo, trifluoromethyl, nitro, hydroxy, amino, C alkylamino, diC M alkylamino, cyano, C,. 6 alkoxy, carboxy, C, .6 alkylS(O) p -(p is 0, 1 or 2), C^alkyl (optionally substituted by hydroxy, amino, halo, nitro, cyano, oxo (=O), hydroxyimino C alkoxyimino), carbamoyl, C M alkylcarbamoyl, di(C,. 4 alkyl)carbamoyl, C M alkoxycarbonylamino, C alkanoylamino, aminosulphonyl, C M alkoxycarbonyl, C alkanoyloxy, C^alkanoyl, formylC alkyl, hydroxy iminoC,. 6 alkyl, C alkoxyiminoC M alkyl, C,. 6 alkylcarbamoylamino, a group of the formula -N=C(R c )R d , -N(R e )C(R f )=NR g , -C(N(R h )R j )=NR j or -CON(R k )R' wherein R c is hydrogen or C M alkyl; and R d -R p are as hereinabovedefined; and on saturated carbon atoms additional optional substituents are oxo, imino and C alkylimino. A compound of the formula (II) can be prepared by methods known in the art. For example by the general methods of Scheme 1. A compound of the formula (XI) may be reacted to form a compound of the formula (II) by the methods disclosed in Heterocycies Vol. 16, No. 9, 1981 and European patent application EP 078026 or methods analagous thereto. A compoimd of the formula (XI) may be prepared by reacting a compound of the formula (X) in a diazo exchange reaction with, for example, N-ethyl 2-azidobenzthiazolium fluoroborate using the method disclosed in Heterocycles Vol. 16, No. 9, 1981 or methods analogous thereto. Alternatively, a compound of the formula (XI) may be prepared by reacting a compoimd of the formula (IX), wherein L is acetoxy or preferably chloro, with compounds of the formula R 5 -C(=N 2 )-CO 2 H, wherein R 5 is as hereinabove defined, using the method described in EP 078026. A compound of the formula (IX) wherein L is chloro may be prepared from a compound of the formula (IX) wherein L is acetoxy, by methods known in the art. A compound of the formula R 5 -C(=N 2 )-CO 2 H may be prepared by the method disclosed in EP 078026 or by methods analogous thereto or by the method described in J. Chem. Research (S) 1993, 18-19 or by methods analogous thereto. A compound of the formula (X) may be prepared from a compound of the formula (IX) by reacting the latter compound with a compound of the formula R 5 -CH 2 CO 2 H using the method described in Heterocycles Vol. 16, No. 9, 1981 or methods analogous thereto. Alternatively a compound of the formula (II) may be prepared by ozonolysis of a compound of the formula (XVI) (A.G. Brown, D. F. Corbett, J. Goodacre, J. B. Harbridge, T.T. Howarth, R.J. Ponsford, I. Stirling and T. J. King. J. Chem. Soc, Perkin Trans. I, 1984, 635). A compound of the formula (XVI) may be prepared from a compound of the formula (XV), which in turn may be prepared from a compound of the formula (XIV), using methods described in (E. Hunt, GB Patent No 15299.3) or by methods analogous thereto. A compound of the formula (XIV) may be prepared from a compound of the formula (XIII), which in turn may be prepared from a compound of the formula (XII), by methods described in German patent application DE 4,142,423 or by methods analogous thereto. A compound of the formula (XII) may be prepared from a compound of the formula (IX). A compound of the formula (II), wherein R 1 and R 2 are hydrogen, may be prepared by ozonolysis of a compound of the formula (VI): (VI) wherein R 5 is as hereinabove defined and any functional groups are optionally protected using the method described in GB Patent No 1,509,400, or methods analogous thereto. A compound of the formula (I) may be prepared by reacting the intermediate, formed from a compound of the formula (II), with a compound of the formula S=C(R 3 )R 4 in situ. A compound of the formula (II) may be converted to the intermediate, believed to be of formula (IVa) or (IVb) , by heating it in acetonitrile or in another inert solvent such as other lower alkylnitriles, for example propionitrile, an aromatic hydrocarbon, for example toluene, an ether for example di-isopropyl ether, a halogenated solvent, for example 1,1 ,2-trichloroethane or an aliphatic hydrocarbon such as decalin, in a temperature range of 70-160°C, until the lactone is converted, which is usually between 30 minutes and 24 hours, most usually between 1 and 6 hours. A compound of the formula (I), wherein at least one of R 3 and R 4 is an eliminatable group, may be converted into a compound of the formula (III) by base-catalysed or thermal elimination. An eliminatable group is a group which can be eliminated together with the hydrogen in >CHR 5 in the penam ring. Examples of base-catalysed eliminatable groups include arylthio and chloro. Examples of thermally eliminatable groups include arylsulphinyl. A compound of the formula (I), wherein neither R 3 nor R 4 is an eliminatable group, may be converted into a compound of the formula (VII): (VII) wherein L is an eliminatable group by standard methods known in the art. A compound of the formula (VII) may then be converted to a compound of the formula (III) by acid-catalysed or base-catalysed or thermal elimination. When R V4 contains a -CH(R)- group (R can be anything as appropriate) via which it is linked to the penam ring, thermal elimination may give a compound of the formula (VIII): (VIII) wherein =C(R)R' is the group R 3/4 in which -CH(R)- has been converted to =C(R)-. A compound of formula (VIII) may be isomerised to a compound of the formula (III) by based-catalysed isomerisation (J.L. Douglas, A.Martel, G. Caron, M. Menard, L. Silveira, and J. Clardy, Canadian Journal of Chemistry, 1984, 62, 2282). Scheme 1 The antibacterial properties of the penems prepared using the process of the present invention may be demonstrated in vivo in conventional tests. The invention will now be illustrated by the following examples: Examnle 1. (±) p-NitrobenzvI (IS.5RV3.3-bis(methylthio)-7-oxo-4-thia-l- azabicvclo [3.2.01 heptane-2-carboxylate. A solution of .-nitrobenzyl (25, 5Λ)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2- carboxylate (0.47 g, 1.53 mmol) and dimethyl trithiocarbonate (0.23 g, 1.68 mmol) in acetonitrile (15 mL) was stirred at 80°C for 3 days then evaporated under reduced pressure. Purification of the residue by flash chromatography (petroleum ether/ethyl acetate 8:2) afforded crude product as a pale yellow solid that was recrystallised from ethyl acetate/petroleum ether to give (±)/?-nitrobenzyl (2S, 5/?)-3,3-bis(methylthio)-7-oxo-4-thia-l- azabicyclo[3.2.0]heptane-2-carboxylate, white crystals (0.37g, 60%), m.p 143-145°C (ethyl acetate/petroleum ether); (Found: C, 44.89; H, 4.30; N, 6.46; C, 5 H l6 O 5 N 2 S 3 requires C, 44.99; H, 4.03; N, 6.99); v max (CH 2 C1 2 ) / cm "1 : 3056, 1787, 1752, 1609, 1526, 1349, 1286, and 1172; δ H : 2.19 (6H, s), 3.35 (1H, dd, J2.2, 16.1), 3.62 (1H, dd, J4.2, 16.1), 4.99 (1H, s), 5.26 (1H, d, J 13.2), 5.36 (1H, d, J 13.2), 5.49 ( 1H, dd, J2.2, 4.2), 7.59 (2H. part of AA'BB', J 8.8), and 8.25 (2H, part of AA'BB', J 8.8); δ c : 15.9, 16.6, 49.7, 62.7, 66.1, 70.3, 84.1, 123.9, 128.9, 141.8, 148.2, 165.6, and 171.2; m/z (C.I): 401 ([M+H] + , 8), 353 (100), 311 (30), 263 (72), 262 (88), 245 (83), 219 (48), 137 (71), 136 (95), and 1 10 (90). -Nitrobenzyl (25, 5R)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2-carboxyIate was prepared by the following method: p-Nitrobenzyl ( )-(2R, 5R)-3(β-hydroxyethyIidene)-7-oxo-4-oxa-l-azabicyclo[3.2.0]- heptane-2-carboxylate ( -nitrobenzyl clavulanate). O i CO 2 PNB To a stirred suspension of lithium clavulanate (1.59 g, 7.76 mmol) in dimethyl formamide (15 mL) under an atmosphere of nitrogen was added -nitrobenzyl bromide (1.85 g, 8.56 mmol). After 72 h the reaction mixture was partitioned between diethyl ether (100 mL) and water (50 mL). The aqueous solution was further extracted with diethyl ether (3 x 50 mL) and the ethereal solutions were combined, washed with brine and dried (Na 2 SO 4 ). The solvent was removed under reduced pressure and the residual oil purified by flash chromatography on Merck 60 (Art. 9385) silica-gel (30 - 75% ethyl acetate : petroleum ether) to give /vnitrobenzyl clavulanate [Reference: A. G. Brown, D. F. Corbett, J. Goodacre, J. B. Harbridge, T. T. Howarth, R. J. Ponsford, I. Stirling and T. J. King, J. Chem. Soc, Perkin Trans. 1. 1984, 635] as a pale yellow oil, which crystallised on standing (1.22 g, 47%); δ H 1.64 (1 H, br s), 3.1 1 (1 H, d, J 16.5), 3.52 (1 H, dd, J 16.5, 2.7), 4.25 (2 H, d, J7.0), 4.92 (1 H, td, J7.0, 1.2), 5.13 (1 H, d, J 1.2), 5.30 (2 H, s), 5.71 (1 H, d, J2.7), 7.52 (2 H, part of AA'BB 1 , J 8.7) and 8.25 (2 H, part of AA'BB', J 8.7). /7-Nitrobenzyl (25, 5/f)-3,7-dioxo-4-oxa-l-azabicycIo[3.2.0]-heptane-2-carboxyIate. H o i C0 2 PNB A stream of ozone was gently passed through a solution of -nitrobenzyl clavulanate (1.00 g, 2.99 mmol) in ethyl acetate (100 mL) at -78 °C for 45 min, after which time the reaction was complete by tic analysis and a colourless precipitate had formed. The reaction mixture was allowed to warm to room temperature while it was flushed with a stream of nitrogen. The reaction mixture was washed successively with water (50 mL) and brine, dried (Na 2 SO 4 ) and the solvent was removed under reduced pressure to give /?-nitrobenzyl (2S. 5/?)-3,7-dioxo-4- oxa-l-azabicyclo[3.2.0]-heptane-2-carboxylate as a colourless solid (0.91 g, 99%). m.p. 131 - 133 °C (dec.) (ethyl acetate / petroleum ether); (Found: C, 51.4; H, 3.3; N, 9.1. C 13 H, 0 N 2 O 7 requires C, 51.0; H, 3.3; N, 9.15%); [α£ + 173.6 (c 1.05, CH 2 C1 2 ); v max / cm-' 1808 (br), 1761, 1609, 1527, and 1350; δ H 3.36 (1 H, dd, J 17.5, 1.0), 3.73 (1 H, dd, J 17.5, 3.0), 5.00 (1 H, s), 5.32 (1 H, part ofAB, J 13.2), 5.40 (1 H, part of AB, J 13.2), 5.83 (1 H, dd, J3.0, 1.0), 7.56 (2 H, part of AA'BB', J 9.0), and 8.27 (2 H, part of AA'BB', J 9.0); δ c (CD 3 CN) 48.3, 60.2, 67.4, 86.0, 124.5, 129.4, 143.4, 148.8, 164.5, 169.3, and 174.1 ; m/z (C , NH 3 ) 324 ([M + NH 4 ] 18%), 280 ([M + NH 4 - CO 2 ] + , 14) and 263 ([M + H - C0 2 ] + , 100). Example 2. (±) p-Nitrobenzyl 5/?-3-methylthio-7-oxo-4-thia-l-azabicyclo[3.2.0jhept-2- ene-2-carboxylate. To a solution of (±) p-nitrobenzyl (2-S, 5Λ)-3,3-bis(methylthio)-7-oxo-4-thia-l- azabicyclo[3.2.0]heptane-2-carboxylate (0.040 g, 0.1 mmol) in dichloromethane (2 mL) at 0°C was slowly added a solution of /w-chloroperbenzoic acid (0.025 g, 0.1 mmol) in 10 dichloromethane (2 mL) then the solution was slowly warmed at room temperature and stirred for 6 hours. The solution was then quenched with saturated aqueous sodium bicarbonate solution and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried (Na 2 SO 4 ) and evaporated under reduced pressure to give a yellow solid that was recrystallised from ethyl acetate/petroleum ether to give (±) p- 15. nitrobenzyl 5 ?-3-methylthio-7-oxo-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate, pale yellow crystals (0.026 g, 74%), m.p 163-165°C (ethyl acetate/petroleum ether); v ma - (CH 2 C1 2 ) / cm 1 : 3066, 1795, 1691, 1604, 1525, 1504, 1328, 1 194, and 1113; δ H : 2.54 (3H, s), 3.53 (1H, dd, J 1.6, 16.4), 3.83 (1H, dd, J3.8, 16.4). 5.25 (1H, d, J 13.7), 5.45 (1H, d, J 13.7), 5.73 ( 1H, dd, J 1.6, 3.8), 7.62 (2H, part of AA'BB', J 8.8), and 8.22 (2H, part of AA'BB', J 8.8); δ c : 20 19.1, 50.2, 62.3, 65.6, 116.7, 124.3, 128.6, 143.7, 160.1, and 172.5. Example 3. (±) p-NitrobenzylJ2S, 3SR. 5R)-3-methyl-3-methylthio-7-oxo-4-thia-l- azabicyclo[3.2.01heptane-2-carboxylate. 25 -,, A solution of/7-nitrobenzyl (25, 5-Λ)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2- carboxylate (0.094 g, 0.3 mmol) and methyl dithioacetate (0.036 g, 0.33 mmol) in acetonitrile (2 mL) was stirred at 80°C for 3 days then evaporated under reduced pressure to give an approximately 80:20 mixture of cycloadduct isomers ('H-nmr analysis). Purification of the residue by flash chromatography (petroleum ether/ethyl acetate 8:2) afforded (±)/?-nitrobenzyl (25, 3SR, 5i?)-3-methyl-3-methylthio-7-oxo-4-thia-l- azabicyclo[3.2.0Jheptane-2-carboxylate, a pale yellow oil (0.040 g, 36%), v max (CH 2 Cl 2 ) / cm " ': 3051, 1782, 1754, 1609, 1526, 1349, 1286, and 1 182; δ H : 1.97 (3H, s), 2.23 (3H, s), 3.1 1 (IH, dd, J 1.8, 15.9), 3.58 (IH, dd, J4.2, 15.9), 4.74 (IH, s), 5.31-5.33 (3H, m), 7.58 (2H, part of AA'BB', J 8.8), and 8.25 (2H, part of AA'BB', J 8.8); δ c : 15.0, 29.4, 44.8, 61.5, 66.1, 72.0, 75.7, 123.8, 128.9, 142.0, 149.6, 166.6, and 172.2; m/z (C.I): 369 ([M+H]\ 8), 368 (M + , 5), 327 (57), 321 ([M-SMef, 49), 280 (40), 279 (100), 136 (60), and 106 (55). Example 4. (±) p-Nitrobenzyl (25. 3SR. 5R)-3-methyl-3-methylsulfinyl-7-oxo-4-thia-l- azabicyclof3.2.01heptane-2-carboxylate. A solution of w-chloroperbenzoic acid (0.167 g, 0.68 mmol) in dichloromethane (15 mL) was added slowly to a stirred solution of a mixture of the diastereomers (+)/?-nitrobenzyl (25, 3SR, 5-/?)-3-methyl-3-methylthio-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylate [obtained by the method of Example 3, (0.250 g, 0.68 mmol)] in dichloromethane (15 mL) at 0°C. The stirred mixture was allowed to warm to room temperature, maintained at room temperature for 3.5 h and then quenched with saturated aqueous sodium bicarbonate solution. The phases were separated, the aqueous phase was extracted with dichloromethane and the organic phases were combined. The combined organic phases were washed with brine, dried (Na 2 SO,,), and evaporated under reduced pressure to leave a mixture of the crude diastereomers of (+)/ nitrobenzyl (25, 3SR, 5Λ)-3-methyl-3-methylsulfinyl-7-oxo-4-thia-l- azabicyclo[3.2.0]heptane-2-carboxylate as a yellow oil that was sufficiently pure for further - 24 - — use. A sample of the oil was purified by flash chromatography (petroleum ether/ethyl acetate 4:6) to give a single diastereomer as a yellow oil, (Found: [M+H] + , 385.0523; C 15 H )7 N 2 O 6 S 2 requires M, 385.0528); v miX (CH 2 C1 2 ) / cm 1 : 3056, 2984, 1792, 1758, 1608, 1526, 1424, 1349, 1269, 1248, and 1050; δ H :1.92 (3H, s), 2.15 (3H, s), 3.24 (IH, dd, J, 2.4, 15.9), 3.32 (IH, dd, J4.2, 15.9), 4.77 (IH, s), 5.22 (IH, d, J 13), 5.29 (IH, d, J 13), 5.32 (IH, dd, J2.4, 4.2), 7.50 (2H, part of AA'BB', J 8.8), and 8.19 (2H, part of AA'BB', J 8.8); δ c : 13.6, 17.6, 36.3, 66.4, 66.7, 72.3, 80.9, 123.9, 129.0, 141.8, 166.5, and 170.5; m/z (C.I): 385 ([M+H] + , 18), 367 ([M-OH] + , 46), 325 (100), 214 (47), 186 (53), 154 (36), 138 (47), and 136 (48). Example 5. (±) p-Nitrobenzyl (25. 5R)-3-methylene-7-oxo-4-thia-l- azabicyclof3.2.0)heptane-2-carboxylate. H O C0 2 PNB A solution of a mixture of the crude diastereomers of (±) 7-nitrobenzyl (25, 3SR, 5R)-3- methyl-3-methylsulfinyl-7-oxo-4-thia-l -azabicyclo[3.2.0]heptane-2-carboxylate [prepared as described in Example 4] in acetonitrile (25 mL) was heated at 80°C for 24 h. The mixture was evaporated under reduced pressure and the residue was purified by flash chromatography (petroleum ether/ethyl acetate 1 :1) to give (±) j-nitrobenzyl (25, 5Λ)-3-methylene-7-oxo-4- thia-1 -azabicyclo[3.2.0]heptane-2-carboxylate, a pale yellow oil, ( 0.152 g, 70%), (Found: M + , 320.0466; C, 4 H 12 N 2 O5S requires M, 320.0469); v max (CH 2 C1 2 ) / cm ': 3061, 2990, 1789, 1753, 1609, 1526, 1422, 1349, 1249, and 1167; δ H : 3.20 (IH, dd, J 1.6, 16.0), 3.69 (IH, dd, J 4.0, 16.0), 5.28-5.30 (IH, m), 5.29 (2H, s), 5.34-5.37 (2H, m), 5.40 (IH, dd, J 1.6, 4.0), 7.51 (2H, part of AA'BB', J8.8), and 8.25 (2H, part of AA'BB', J 8.8); δ c : 48.7, 63.0, 65.1, 66.6, 107.2, 124.5, 129.0, 142.5, 148.3, 167.8, and 171.4; m/z (C.I): 320 (M + , 2). 307 (2), 279 ([M+H-ketene] + , 100), 138 (32), and 126 (20). Example 6. f±) p-Nitrobenzyl 5R-3-methyl-7-oxo-4-thia-l-azabicvclo[3.2.01hept-2-ene-2- carboxylate. A stirred solution of (±) ^-nitrobenzyl (25, 5i?)-3-methylene-7-oxo-4-thia-l- 5 azabicyclo[3.2.0]heptane-2-carboxylate [prepared as described in Example 5 (0.004 g, 0.012 mmol)] in dichloromethane (2 mL) was treated at 0°C with triethylamine (0.002 mL, 0.014 mmol). The mixture was stirred at 0°C for 1.5 h. and then evaporated under reduced pressure to give (±) -nitrobenzyl 5i?-3-methyl-7-oxo-4-thia- 1 -azabicydo[3.2.0]hept-2-ene-2- carboxylate in essentially pure form, (0.004 g, 95%), v„„ (CH 2 C1 2 ) / cm "1 : 3048, 2990. 1791 , 10 1712, 1587, 1525, 1349, and 1316; δ H : 2.39 (3H, s), 3.50 (IH, dd, J 1.7, 16.4), 3.80 (IH, dd, J 3.8, 16.4), 5.24 (IH, d, J 13.7), 5.43 (IH, d, J 13.7), 5.65 (IH, dd, J 1.7, 3.8), 7.62 (2H. part of AA'BB' , J 8.8), and 8.23 (2H, part of AA'BB' , J8.8); δ c : 14.9, 49.5, 60.6, 65.1, 123.8, 128.1, 143.5, and 160.0. 15 (±) p-Nitrobenzyl 5R-3-methyl-7-oxo-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate may also be prepared directly from (±) -nitrobenzyl (25, 3SR, 5/?)-3-methyl-3- methylsulfinyl-7-oxo-4-thia-l -azabicyclo[3.2.0]heptane-2-carboxylate as follows: A stirred solution of (±) -nitrobenzyl (25, 3SR, 5Λ)-3-methyl-3-methylsulfinyl-7-oxo-4-thia- l-azabicyclo[3.2.0]heptane-2-carboxyIate [prepared as described in Example 4 (0.016 g, 0.04 20 mmol)] in dichloromethane (2 mL) was treated at room temperature with triethylamine (0.007 mL, 0.048 mmol). The mixture was heated under reflux for 12 h. and then quenched with saturated aqueous sodium bicarbonate solution. The phases were separated, the aqueous phase was extracted with dichloromethane and the organic phases were combined. The combined organic phases were washed with brine, dried (Na 2 SO 4 ), and evaporated under 25 reduced pressure to leave a yellow oil. The residual yellow oil was purified by flash chromatography (petroleum ether/ethyl acetate 9: 1) to give (±) /?-nitrobenzyl 5Λ-3-methyl-7- oxo-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.008 g, 60%). Example 7. (±) p-Nitrobenzyl (25.35R.5R)-3-methylthio-3-phenyl-7-oxo-4-thia-l- azabicyclo[3.2.01heptane-2-carboxylate. A solution of /.-nitrobenzyl (25, 5Λ)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2- carboxylate (0.40 g, 1.3 mmol) and methyl dithiobenzoate (0.242 g, 1.43 mmol) in acetonitrile (15 mL) was stirred at 80°C for 2 days then evaporated under reduced pressure. 'H-nmr analysis of the crude reaction mixture revealed an 78:22 mixture of cycloadduct isomers. Purification of the residue by flash chromatography (petroleum ether/ethyl acetate 9:1) afforded the mixed diastereomers (±) / nitrobenzyl (25, 3SR, 5Λ)-3-methylthio-3-phenyl-7- oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylate, a pale yellow foam, ( 0.40 g, 71%), (Found: [M+H] + , 431.0731; C2oH 19 N 2 O5S 2 requires M, 431.0735); v max (CH 2 C1 2 ) / cm 1 : 3059, 1785, 1752, 1686, 1609, 1526, 1493, 1445, 1349, and 1290; δ H (2 diastereomers): 1.98 (3H, s), 2.03 (3H, s), 3.14 (2H, dd, J 1.8, 16.0), 3.57 (IH, dd, J4.2, 16.0), 3.64 (IH, dd, J4.2, 16.0), 4.60 (IH, d, J 13.0), 4.88 (IH, d, J 13.0), 5.22 (IH, d, J 13.5), 5.32 (IH, d, J 13.5), 5.45 (IH, dd, J 1.8, 4.2), 5.60 (IH, dd, J 1.8, 4.2), 7.21-7.78 (14H, m), 8.1 1 (2H, part of AA'BB', J 8.8), and 8.21 (2H, part ofAA'BB', J 8.8); m/z (C.I): 431 ([M+H] \ 6), 430 (M\ 3), 429 ([M-H]\ 13), 383 ([M- SMe] \ 100), 341 (25), and 136 (20). Example 8. (±) p-Nitrobenzyl 5 ?-3-phenyl-7-oxo-4-thia-l-azabicvcIo[3.2.0|hept-2-ene-2- carboxylate. A solution of w-chloroperbenzoic acid (0.155 g, 0.63 mmol) in dichloromethane (10 mL) was added slowly to a stirred solution of a mixture of the diastereomers (±) /. -nitrobenzyl (25, 3SR, 5/?)-3-methylthio-3-phenyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylate [obtained by the method of Example 7, (0.270 g, 0.63 mmol)] in dichloromethane at 0°C. The stirred mixture was allowed to warm to room temperature, maintained at room temperature for 4 h and then quenched with saturated aqueous sodium bicarbonate solution. The phases were separated, the aqueous phase was extracted with dichloromethane and the organic phases were combined. The combined organic phases were washed with brine, dried (Na 2 SO 4 ), and 5 evaporated under reduced pressure to leave a yellow oil that was used without further purification. A solution of the yellow oil in dichloromethane (15 mL) was treated dropwise at room temperature with triethylamine (0.17 mL, 1.26 mL). The mixture was heated under reflux for 12 hours and then quenched with saturated aqueous sodium bicarbonate solution. The phases were separated, the aqueous phase was extracted with dichloromethane and the 10 organic phases were combined. The combined organic phases were washed with brine, dried (Na 2 SO 4 ), and evaporated under reduced pressure to leave a yellow oil that was purified by flash chromatography (petroleum ether/EtOAc 9:1) to give (±) ?-nitrobenzyl 5i?-3-phenyl-7- oxo-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate, (0.048 g, 20%), v mιx (CH 2 C1 2 ) / cm " ': 3061, 2986, 1794, 1715, 1607, 1574, 1444, 1424, 1348, and 1315; δ H : 3.63 (IH, dd, J 1.8, 15 16.4), 3.88 (IH, dd, J3.8, 16.4), 5.14 (IH, d, J 13.9), 5.29 (IH, d, J 13.9), 5.79 (IH, dd, J 1.8, 3.8), 7.26-7.58 (7H, m), and 8.13 (2H, part of AA'BB', J, 8.8); δ c : 50.1, 60.4, 65.2, 123.6, 128.2, 128.6, 129.2, 130.4, 142.3, 158.8, and 172.9. Example 9. Benzyl (25. SR. 65) 6-H(R)-/grt-butyldimethylsilyloxyethyIl-3.3- 20 Z>fs(methylthio)-7-oxo-4-thia-l-azabicvclof3.2.01heptane-2-carboxylate and benzyl (5R. 65) 6-ll(R er/-butyldimethylsiIyloxyethyll-3-methylthio-7-oxo-4-thia-l- azabicyclo [3.2.0] hept-2-ene-2-carboxylate. 25 To a solution of benzyl (25, 5R, 6R) 6-[l(Λ)-tert-butyldimethylsilyloxyethyl]-3,7-dioxo-4- oxa-l-azabicyclo[3.2.0]heptane-2-carboxylate [prepared from azetidinyl benzyl diazomalonate (447 mg, 1.0 mmol), see below] in acetonitrile (4.0 mL) was added dimethyl trithiocarbonate (147 mg, 1.07 mmol) and the solution heated in a sealed tube at 1 10 °C for 24 h. The solvent was removed under reduced pressure and the residue was purifued by flash chromatography (5 - 10% ethyl acetate : petroleum ether) afforded benzyl (25, 5R, 65) 6- [1 (Λ)-tert-butyldimethylsilyloxyethyl]-3,3-ό -y(methylthio)-7-oxo-4-thia- 1 - azabicyclo[3.2.0]heptane-2-carboxylate, a colourless oil (77.3 mg, 15%) (Found: C, 54.01; H, 5 7.10; N, 2.46; C 2 3H35NO 4 S 3 Si requires C, 53.77; H, 6.87; N, 2.73%); [α] + 60.8 (c 0.88, CH 2 C1 2 ); v max (CH 2 C1 2 ) / cm" 1 2306, 1781, and 1750; δ H 0.03 (3 H, s), 0.05 (3 H, s), 0.84 (9 H, s), 1.22 (3 H, d, J6.2), 2.16 (3 H, s), 2.16 (3 H, s), 3.48 (1 H, dd, J5.1 , 2.2), 4.20 (1 H, qd, J6.2, 5.1), 4.92 (1 H, s), 5.17 (1 H, part of AB, J 12.3), 5.24 (1 H, part of AB, J 12.3), 5.46 (1 H, d, J2.2), and 7.34 - 7.40 (5 H, m); δ c -5.1, -4.3, 15.7, 16.6, 17.9, 22.3, 25.5, 64.8, 65.1, 10 67.5, 69.9, 71.3, 84.2, 128.6, 134.8, 165.7, and 171.9; m/z (E.I.) 498 (M-Me] + , 1%), 466 ([M- <Bu] + , 83), 159 (69) and 91 (100) and benzyl {SR, 65) 6-[l(Λ)-tert- butyldimethylsilyloxyethyl]-3-methylthio-7-oxo-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate, a colourless oil (25 mg, 5%) (Found: M + , 465.1464; C 22 H 3 ] NO 4 S Si requires , 465.1464); v max (CH 2 C1 2 ) / cm" 1 1789 and 1685; δ H 0.03 (3 H, s), 0.05 (3 H, s), 0.87 (9 15 H, s), 1.24 (3 H, d, J6.2), 2.50 (3 H, s), 3.67 (1 H, dd, J4.8, 1.5), 4.23 (1 H, qd, J6.2, 4.8), 5.24 (2 H, s), 5.61 (1 H, d, J 1.5), and 7.28 - 7.44 (5 H, m); m/z (E.I.) 465 (M + , 4%), 450 ([M- Me] \ 1), 408 ([M-*Bu] + , 22), 159 (55), and 91 (100). The benzyl (25, 5R, 6R)-6-[l(R)-ter/-butyIdimethylsilyloxyethyI]-3,7-dioxo-4-oxa-l- 20 azabicyclo[3.2.0]heptane-2-carboxylate may be prepared in the following way: (35, 4R)-3-[l(R)-ter/-butyldimethylsilyloxyethyI]-4-chloro-2-azetidinone. 25 A gentle stream of chlorine was passed into a solution of (35, 4R)-3-[)(R)-tert- butyldimethylsilyloxyethyl]-4-methylthio-2-azetidinone [Reference M. Murakami, T. Aoki, M. Matsuura and W. Nagata, J. Antibiot., 1990, 43, 1441] (1.32 g, 4.80 mmol) in dichloromethane (10 mL) at -20 °C (bath temp.) until consumption of the starting material was 30 complete (as judged by tic analysis) and a yellow coloured solution just persisted. Solvents were removed under reduced pressure to give a colourless solid residue which was slurried in cold n-hexane. Filtration yielded (35, 4Λ)-3-[l(/?)-tert-butyldimethylsilyloxyethyl]-4-chloro- 2-azetidinone as a colourless solid (1.05 g, 83%), m.p. 75-77°C (dec.) (lit. 84-85 °C) [Reference M. Endo, Can. J. Chem., 1987, 65, 2140]; δ H 0.06 (3 H, s), 0.08 (3 H, s), 0.86 (9 H, s), 1.28 (3 H, d, J6.4), 3.44 (1 H, m), 4.24 (1 H, qd, J6.4, 3.1), 5.69 (1 H, d, J 1.3) and 6.32 (1 H, br s). Potassium benzyl diazomalonate. 10 CO 2 K N 2=< CO 2 Bn To a stirred pale yellow solution of dibenzyl diazomalonate (29.6 g, 95.5 mmol) in benzyl alcohol (100 mL) at room temperature was added a solution of potassium hydroxide (5.35 g, 15 95.5 mmol) in benzyl alcohol (80 mL). A deep yellow viscous solution resulted immediately followed by dense precipitation within 5 min. After stirring for a further 30 min the mixture was diluted with diethyl ether (200 mL) and filtered. The residue was washed well with diethyl ether to give the mono potassium salt as a pale yellow solid (17.3 g, 70%), decomposes at 170 °C without melting (Found: C, 46.10; H, 2.60; N, 10.66. C 10 H 7 N 2 O 4 K 20 requires C, 46.50; H, 2.73; N, 10.85%); v max (mull) / cm- 1 21 15, 1706, 1603, 1455, 1386, 1283 and 1096; δ H (D 2 O) 5.24 (2 H, s) and 7.35 - 7.45 (5 H, m). Benzyl (3R, 4R)-3-[l(R)-ter/-butyldimethyIsiIyloxyethyI]-2-azetidinone-4-yl diazomalonate. 25 To a solution of (35, 4i?)-3-[l( ?)-tert-butyldimethylsilyloxyethyl]-4-chloro-2-azetidinone (5.27 g, 20 mmol) in tetrahydrofuran (40 mL) at room temperature under nitrogen was added 30 potassium benzyl diazomalonate (5.16 g, 20 mmol). The mixture was stirred for 4 h and then partitioned between EtOAc (150 mL) and water (50 mL). The organic solution was washed with brine, dried (Na 2 SO 4 ) and concentrated under reduced pressure to a viscous yellow oil. Crystallisation from petroleum ether afforded benzyl (3R, 4R)-3-[\(R)-terl- butyldimethylsilyloxyethyl]-2-azetidinone-4-yl diazomalonate as a colourless solid (5.37 g, 60%), m.p. 96 - 97.5 °C (diethyl ether/ petroleum ether); (Found: C, 56.38; H, 6.85; N, 9.37. C 21 H 2 9N 3 O 6 Si requires C, 56.35; H, 6.54; N, 9.39%); [αf D 3 +43.7 (c 2.00, CHC1 3 ); v max (CH 2 C1 2 ) / cm" 1 3407, 2146, 1791, 1758, 1732 and 1694; δ H 0.06 (3 H, s), 0.07 (3 H, s), 0.86 (9 H, s), 1.24 (3 H, d, J6.4), 3.21 (1 H, dd, J3.3, 1.2), 4.22 (1 H, qd, J6.4, 3.3), 5.28 (2 H, s), 6.00 (1 H, d, J 1.2), 6.69 (1 H, br s) and 7.37 (5 H, s); m/z (E.I.) 390 ([M - f Bu] + , 1%) and 91 (100). Benzyl (25, SR, 6R)-6-[l R)-ter/-butyldimethylsilyloxyethyl]-3,7-dioxo-4-oxa-l- azabicyclo[3.2.0]heptane-2-carboxylate. To a solution of benzyl (3R, 4Λ)-3-[l(Λ)-tert-butyIdimethylsilyloxyethyl]-2-azetidinone-4-yl diazomalonate (250 mg, 0.56 mmol) in dichloromethane (2.0 mL) was added Rh 2 (OAc) 4 (5 mol%) and the reaction mixture heated at reflux for 3 h. Removal of solvent under reduced pressure gave benzyl (25, 5R, 6i?)-6-[l(Λ)- rt-butyldimethylsilyloxyethyl]-3,7-dioxo-4-oxa- l-azabicyclo[3.2.0]heptane-2-carboxylate; v max (CH 2 C1 2 ) / cm" 1 1801 (br) and 1756; δ H 0.05 (3 H. s), 0.07 (3 H, s), 0.86 (9 H, s), 1.30 (3 H, d, J6.2), 3.42 (1 H, dd, J3.7, 0.7), 4.29 (1 H, qd, J 6.2, 3.7), 4.92 (1 H, s), 5.24 (2 H, s), 5.78 (1 H, d, J0.7) and 7.37 (5 H, s), which was used (above) without further purification. Example 10. (±) p-Nitrobenzyl (25, 5_ff)-3,3-pentamethylene-7-oxo-4-thia-l- azabicyclo|3.2.0] heptane-2-carboxylate. H A solution of p-nitrobenzyl (2S, 5R)-3,7-dioxo-4-oxa-l -azabicyclo[3.2.0]heptane-2- carboxylate (0.317 g, 1.03 mmol) and thiocyclohexanone (0.13 g, 1.13 mmol) in acetonitrile (8 ml) was stirred at 80 °C for 80 hours then evaporated under reduced pressure. Purification _ 3J _ _ of the residue by flash chromatography (petroleum ether/ethyl acetate 9:1) afforded (±) p- nitrobenzyl (2S, 5R)-3,3-pentamethylene-7-oxo-4-thia-l-azabicyclo[3.2.0] heptane-2- carboxylate, a colourless solid, (0.187 g, 48%), m.p 132-134°C (dichloromethane/petroleum ether); (Found: C, 57.64; H, 5.51 ; N, 7.18. C 18 H2oN 2 O 5 S requires C, 57.43; H, 5.36; N, 5 7.44%); υ max (CH 2 C1 2 ) / cm "1 3052, 2940, 2860, 1766; δ H 1.11-1.89 (10H, m), 3.09 (IH, dd, J 1.8, 15.9), 3.56 (IH, dd, J4.0, 15.9), 4.60 (IH, s), 5.23 (IH, dd, J 1.8, 4.0), 5.24 (IH, d, J 13.1), 5.31 (IH, d, J 13.1), 7.56 (2H, part of AA'BB', J 8.8), 8.26 (2H, part of AA'BB', J 8.8); δ c : 24.2, 24.9, 25.3, 35.1, 41.5, 48.0, 60.1, 65.6, 69.9, 72.9, 123.9, 128.8, 142.0, 148.2, 167.6, 172.1 ; m/z (C.I): 377 ([M+H] + , 1), 376 (M\ 1), 335 ([M-ketene+H] + , 100), 200 (60), 10 154 (8), 138 (26), 122 (12), 106 (16). Example 11. (±) p-Nitrobenzyl (25, 5R)-3.3-diphenyl-7-oxo-4-thia-l-azabicvclo13.2.01 heptane-2-carboxylate. 15 A solution of p-nitrobenzyl (2S, 5R)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2- carboxylate (0.172 g, 0.56 mmol) and thiobenzophenone (0.123 g, 0.62 mmol) in acetonitrile (5 ml) was stirred at 80 °C for 80 hours then evaporated under reduced pressure. Purification of the residue by flash chromatography (petroleum ether/ethyl acetate 9: 1) afforded (±)p- nitrobenzyl (25, 5Λ)-3,3-diphenyl-7-oxo-4-thia-l-azabicyclo[3.2.0] heptane-2-carboxylate, a 20 colourless solid, (0.132 g, 51 %), m.p 168-170 °C (dichloromethane/petroleum ether); (Found: M + , 460.1092. C 25 H 20 N 2 O 5 S requires M, 460.1092); υ max (CH 2 C1 2 ) / cm "1 1782, 1751 ; δ H 2.99 (IH, dd, J2.0, 15.9), 3.50 (IH, dd, J4.0, 15.9), 4.52 (IH, d, J 13.0), 4.86 (IH, d, J 13.0), 5.55 (IH, dd, J2.0, 4.0), 5.82 (IH, s), 7.15-7.39 (10H, m), 7.53 (2H, part of AA'BB', J 8.8), 8.13 (2H, part of AA'BB', J 8.8); δ c : 48.2, 61.6, 65.7, 67.7, 80.5, 123.7, 25 127.8, 127.9, 128.0, 128.5, 128.7, 128.9, 140.4, 141.5, 144.5, 147.7, 167.3, 170.5; m/z (C.I): 461 ([M+H] + , 5), 460 (M\ 1), 419 ([M-ketene+H]\ 100), 308 (12), 284 (22), 240 (36), 222 (32), 199 (33), 138 (60), 122 (22), 106 (30), 61 (43).

Claims: Claims 1. A process for preparing a compound of the formula (I): (D wherein R 1 is hydrogen or optionally substituted: Cι- 6 alkyl, Cι- 6 alkylthio or Ci-βalkoxy; R 2 is hydrogen, halogen or optionally substituted: Cι- 6 alkyl, C 3 . 6 alkenyl, arylC]. 3 alkyl, aryl, heteroarylC |. 3 alkyl, heteroaryl, heterocyclyl, heterocycIylC]- 3 alkyl, C 3 . 7 cycloalkyl, C 3 - 7 cycloalkylCι- 3 aIkyl, C 5 . cycloalkyenyl, C 5 . cycloalkenylCι- 3 alkyl, Cι. 6 alkoxy, Cι- 6 alkylthio, arylthio, aryloxy, heteroaryloxy, heteroarylthio, C i - 6 alkoxycarbonylam.no, aryloxycarbonylamino, arylC i . 3 alkoxycarbonylamino, heteroaryloxycarbonylamino, heteroarylCι. 3 alkoxycarbonylamino, Cι- 6 alkanesulphonylamino, arylsulphonylamino, arylCι. 3 alkylsulphonylamino, heteroarylC ι- 3 alkylsulphonylamino or • y f f \ heteroarylsulphonylamino or R is of the formula R CONH- wherein R is an organic group; or 1 * ) R and R together form an optionally substituted C 3 - 6 alkylene chain wherein one methylene group is optionally replaced by -N(R n )-, -O- or -S-, (C . 6 alkylene chains wherein one methylene group is optionally replaced by -N(R n )-, -O- or -S- are hereafter referred to as C 3 - 6 heteroalkylene), wherein R n is hydrogen, Ci-βalkanoyl, phenylCι. 3 alkyl or Ci-βalkyl; or R 1 and R 2 together form a group of the formula: wherein R a and R b are independently hydrogen or optionally substituted C^alkyl, aryl or heteroaryl; or R a and R b , together with the carbon atom to which they are attached, form an optionally substituted C 4 . 7 cycloalkyl, C 4 . 7 cycloalkenyl or heterocyclyl ring, each optionally fused to a benzene or heteroaryl ring; R 3 and R 4 are independently: hydrogen, halo, cyano or optionally substituted: C^alkyl, C^alkenyl, arylC,_ 3 alkyl, heteroarylC,. 3 alkyl, prop-2-enyl, heteroarylprop-2-enyl, aryl, heteroaryl, C 5 . 7 cycloalkenyl, C 5 . 7 cycloalkenylC,. 3 alkyl, heterocyclyl, heterocyclylC,. 3 alkyl, C 3 . 7 cycloalkyl, C 3 . 7 cycloalkylC, .3 alkyl or of the formula R 7 or R 7 C,. 3 aIkyl wherein R 7 is a tricyclic ring system, or of the formula -CO 2 R 8 wherein R 8 is hydrogen or optionally substituted: C,. 6 alkyl, C 3 . 6 alkenyl. C 5 . 7 cycloalkenyl, C 5.7 cycloalkenylC,. 3 alkyl, heterocyclyl, heterocyclylC,. 3 alkyl, C 3 . 7 cycloalkyl, C 3 . 7 cycloalkylC, .3 alkyl, arylC^alkyl, heteroarylC,., alkyl, arylprop-2-enyl, heteroarylρrop-2-enyl, heteroaryl or aryl, or of the formula -CONR'R 10 wherein R 9 or R 10 are independently hydrogen or optionally substituted: arylC,. 3 alkyl, C,. 6 alkyl, C^alkenyl, heteroarylC alkyl, heteroarylprop-2-enyl, arylprop-2-enyl, aryl or heteroaryl or R 9 and R 10 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring. or -SR" wherein R' 1 is optionally substituted: C,. 6 alkyl, arylC,.,alkyl, C 3 . 6 alkenyl, heteroarylC ! . 3 alkyl, arylprop-2-enyl, C 5 . 7 cycloalkenyl, C 5 . 7 cycloalkenylC,. 3 alkyl, heteroarylprop-2-enyl, aryl, heteroaryl, C 2 . 6 alkynyl, C 3 . 7 cycloalkyl, C 3 . 7 cycloalkylC, .3 alkyl, heterocyclyl, heterocyclylC,. 3 alkyl, heterocyclylium or heteroarylium, or of the formula -OR" wherein R" is as hereinabove defined, or of the formula -COR 8 wherein R 8 is as hereinabove defined, or of the formula -SeR 14 wherein R' 4 is C,. 6 alkyl, arylC,. 3 alkyl, aryl, C 3 . 6 alkenyl, arylprop-2-enyl, heteroarylC ,. 3 alkyl, heteroaryl or heteroarylprop-2-enyl, or R 3 and R 4 , together with the carbon atom to which they are attached, form an optionally substituted C 4 . 7 cycloalkyl, C 4.7 cycloalkenyl or heterocyclyl ring, wherein one methylene group is optionally replaced by -N(R n )-, -O- or -S-, (wherein R n is as hereinabove defined) and the chain formed by R 3 and R 4 optionally contains one double bond and is optionally fused to an aryl or heteroaryl ring; R 5 is cyano or of the formula -CO 2 R 19 wherein R' 9 is hydrogen or optionally substituted: C,. 6 alkyl, arylC,. 3 alkyi, heteroaryl, heteroarylC,. 3 alkyl, C^alkenyl, arylprop-2-enyl or heteroarylprop-2enyl or R 5 is of the formula -COR 20 wherein R 20 is hydrogen or optionally substituted C,. 6 alkyl, arylC,. 3 alkyl, heteroarylC, . 3 alkyl, aryl or heteroaryl; and wherein any functional groups are optionally protected; and salts thereof; which process includes the step of reacting the intermediate formed by heating a compound of the formula (II): (II) in an inert solvent, with a compound of the formula S=C(R 3 )R 4 wherein R 3 and R 4 are as hereinabove defined and functional groups are optionally protected; and thereinafter, if necessary, removing any protecting groups. 2. A process according to claim 1 which comprises the step of heating a compound of the formula (II) as defined in claim 1 in an inert solvent. 3. A process for preparing a compound of the formula (III): (III) and salts thereof; wherein R 1 , R 2 and R 5 are as defined in claim 1 and R 15 is either R 3 or R as defined in claim 1 and functional groups are optionally protected; which process includes the steps of : a) preparing a compound of the formula (I) according to claim 1 ; and b) converting the resulting compound of the formula (I) into a compound of the formula (III); and thereinafter if necessary removing any protecting groups. 4. A process for preparing a compound of the formula (V): (V) and pharmaceutically-acceptable salts and in vivo hydrolysable esters thereof; wherein R 21 , R 22 , and R 23 are substituents known in the penem art; which process includes the steps of a) preparing a compound of the formula (III) accoring to claim 3; and b) converting the resulting compound of the formula (III) into a compound of the formula (V); and thereinafter if necessary: i) removing any protecting groups; ii) forming a pharmaceutically-acceptable salt; iii) esterifying to form an in vivo hydrolysable ester. 5. A process according to claim 4 wherein: R 21 hydrogen and R 22 is 1-hydroxyethyl, hydroxymethyl, 1 -hydroxy- l-(3-methylisoxazol-5- yl)methyl, 2-(l-methyltriazol-4-yl)ethen-l-yl or thien-2-ylmethylcarbonylamino; or R 2! and R 22 together form ethylene or 2-(fur-2-yl)ethylene; and R 23 is hydrogen, pyrrol-2-ylmethyl, 1-methylpyrroliomethyl, l-oxotetrahydrothien-3-yl, 4- (hydroxymethyl)imidazol- 1 -yl, 1 -methylimidazol-2-ylmethylthio, 4-carbamoylphenoxy, tetrahydrofuran-2-yl, aminomethyl, imidazol-1-yl, 2-(carbamoyloxy)eth-l-ylthio, 2-fluoroeth- 1-ylthio, 2-aminoprop-l-yl, ethylthio, 4-(pyridiniomethyl)phenyl, 3 -carboxy phenyl. N- (carbamoylmethyl)-N-methylaminomethyl, 4-(4-(2-aminopyrid- 1 -ylmethyl)phenyl)phenyl, tetrahydrofuran-2-yl, 6,8-difluoro- 1 -(2-fluoroeth- 1 -yl)-7-(4-methylpiperazin- 1 -yl)-4-oxo- 1 ,4- dihydroquinolin-3-ylcarbonyloxomethyl, 4-(3-carboxy-l-cyclopropyl-6-fluoro-4-oxo-l,4- dihydroquinolin-7-yl)piperazin-4-ylcarbonyloxymethyl or l-(3-carboxy-l-cyclopropyl-6.8- difluoro-4-oxo-l,4-dihydroquinolin-7-yl)pyrrol-3-ylcarbonyloxomethyl. 6. A process according to claim 4 wherein: R 21 hydrogen, R 22 is 1 -hydroxyethyl and R 23 is tetrahydrofuran-2-yl. 7. A process according to claim 4 wherein the compound of the formula (V) forms part of a chemical compound library. RMT/PHM70192

Inventors: GALLAGHER TIMOTHY CHARLES, HALES NEIL JAMES, PLANCHENAULT DENIS, WISEDALE RICHARD, GALLAGHER, TIMOTHY, CHARLES, HALES, NEIL, JAMES, PLANCHENAULT, DENIS, WISEDALE, RICHARD
Applicants: GALLAGHER TIMOTHY CHARLES, HALES NEIL JAMES, PLANCHENAULT DENIS, WISEDALE RICHARD, ZENECA LTD, GALLAGHER, TIMOTHY, CHARLES, HALES, NEIL, JAMES, PLANCHENAULT, DENIS, WISEDALE, RICHARD, ZENECA LIMITED
Application year: 1997
Main classification: C07D499
IPC codes: A61K31, C07D263, C07D499