CA1197841A - 7-oxo-4-thia-1-aza[3,2,0]heptane and 7-oxo-4-thia- 1-aza[3,2,0]-hept-2-ene derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
7-Oxo-4-thia-1-aza[3,2,0]heptane and 7-ozo-4-thia-1-aza-[3,2,0]hept-2-ene derivatives The invention relates to compounds of the formula in which R is an esterifying group R1 is lower alkyl or phenyl, and R2 is hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxy-alkyl, lower acyloxyalkyl or tri-lower alkylsilyloxyalkyl, and a process for their manufacture.
Compounds of the general formula referred to above are useful in the synthesis of substituted penems, and useful as .beta. - lactomase inhibitors and antibacterial compounds.

Description

~ 7Z3~

- 2 - HOE 80/S 019 This invention relates to substituted 7-oxo-4-thia-1-azabicyclo~3,2,07heptane and 7-oxo-4-thia-1-azabicyclo ~3,2,07hept-2-ene derivatives.
7-oxo-4-thia-1-azabicyclo~3,2,07heptane has the following structure.

S ~
> .3 0~ 1 ~

The present invention provides a compound of the general formula Ia and its tautomer Ib N~ ~ P~?--S 2 1 ~ S~l o OOR ~
COCR
Ia Ib in which formulae R represents a carboxyl esterifying group, and R2 represents hydrogen or an aliphatic group. More preferably R2 represents hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxy-methyl, lower acyloxyalkyl or tri-lower alkylsiloxyalkyl, and salts thereof.
The terms "a compound of the general formula I" and "a compound of formula I" are both used hereinafter to denote a compound of the general formula Ia, a compound of the general formula Ib, or any mixture thereof.
R2 may be cis or trans to the carbon-sulfuric mdety at position 5. The stereochemistry at position 5 can be R or S i.e. a compound of formula I may be 5R, 6R, ~, ~:~g~7~

- 3 - HOE 80/S 019 5R, 6S; 5S, R6 or 5S, 6S. It is preferably, however, to have th~ 5R s~ereochemistry, ~as defined by the Cahn-Ingold-Prelog system of nomenclature). A chiral carbon atom is also present at position 2 in formula Ia, giving further R and S isomers.
The present invention also provides a process for the production of a compound of the general formula I, which comprises treating a compound of the general formula II

H~ ~ S

~00~

in which R and R2 are as defined above, and R1 represents a lower alkyl group or a phenyl group and represents especially a methyl group, with a nucleo-philic compound and, if desired, carrying out any one or more of the following steps in any d~sired order:
a~ converting a freee acid of formula I into an ester thereof, b) transesterifying a compound of formula I, c) converting a free acid or an ester of formula I
into a salt, or a salt into the free acid, an ester, or another salt, d) removing any protective groups present other than an esterifying group R.
3 The treatment of the compound of formula II with a nucleophilic compound is generally carried out in a sol-vent, and in some cases the solvent itself may also funct-ion as the nucleophilic compound.
There can be used either an organic nucleophilic com-pound or an inorganic nucleophilic compound. Examples of inorganic nucleophilic compounds are water, alkali metal and alkaline earth metal hydroxides, carbonates and bicar-bonates, for example, sodium hydroxide, sodium carbonate, ~Lg7~41

- 4 - ~OE 80/S 019 sodium bicarbonate, potassium carbonate, potassium bi-carbonate, and magnesium carbonate; borates and phos-phates.
Organic nucleophilic compounds are, fo~ example, amines, for example, primary and secondary aliphatic amines, for example, ethylamine, methylamine, diethyl-amine, and dimethylamine; cycloaliphatic amines, for example, cyclohexylamine; non-aromatic heterocyclic amines, for example, morpholine, piperidine and piper-azine; aromatic heterocyclic amines, for example, pyridineand substituted pyridines, for example, 4-N,N-dimethyl-aminopyridine, imidazole and substituted, especially lower alkyl substituted, imidazoles, for example, methyl-imidazole; aromatic amines, for example, aniline and substituted anilines, for example, methyl-substituted anilines, for example, toluidine; and hydrazlne and hydroxylamine. Preferred are heterocyclic nitxogen bases having a pK between 5 and 9, particularly aromatic nitrogen bases. Most preferred is imidazole.
As mentioned above, the treatment of a compound of formula II with a nucleophilic compound is generally carried out in a solvent. In some cases the solvent itself may function also as the nucleophilic compound, as is the case with water.
The solvent is, for example, a water~miscible ether, for example dioxan or tetrahydrofuran; an alcohol, or example, having up to 4 carbon atoms, for example, methanol, ethanol or propanol; water; an amide for ex-ample dimethylformamide, dimethylacetamide, or hexamethyl-phosphoramide; or dimethylsulphoxide, acetonitrile or sulpholane.
A mixture of any two or more solvents may be used, for example, a mixture of water and another solvent, for example, an amide, an alcohol, or an ether When the nucleophilic compound is, for example, an alkali metal borate or phosphate salt, this is preferably used in the form of a solution thereof in water or in a mixture of water and another solvent~ the solution having (

- 5 - HOE 80/S 019 a pH within the range of from 8 to 11. If the nucleophilic compound is an amine having a pK greater than 7, it is preferable to buffer the reaction mixture so the p~ is within the range of from 6 to 8, fox example, using S~renson's phosphate buffer or Clark and Lubs's borate buffer.
Preferred nucleophilic compounds are alkali metal hydroxides, carbonates and bicarbonates, especially sodium carbonate, and aromatic heterocyclic amines, especially imida~ole. A preferred solvent is a water/dioxan mixture, preferably comprising from 1 to 50 % by volume of water in dioxan, especially from S to 25 % water in dioxan.
The reaction is generally carried out at a tempe-rature within the range of from the freezing point of ~5 the solvent or solvent mixture or -10C (whichever is the higher), to 50C, preferably from 0 to 25C.
'The reaction mixture comprising the resulting com-pound of formula I is preferably diluted with water or an aqueous acid for example, aqueous citric acid, so the resulting mixture has a pH of from 1 to 4, and extracted into an organic solvent, for example, an ester, for example, ethyl acetate or a halogenated hydrocarbon, for example, chloroform. The resulting compound of formula I
is then generally pure enough for furhter use, but if desired, it may be purified further, for example by crystallisation or chromatography.
In the compounds of formulae I and II, R preferably represents a hydrogen atom, or an unsubstituted or sub-stitut~d, straight or branched chain aliphatic group.
An aliphatic group may be a straight or branched chain lower alkyl, alkenyl or alkynyl group, for example, a methyl, ethyl or vinyl group.
The term "lower" as used herein in all instances denotes a molecule, group or radical having up to 8 carbon atoms, and especially up to 4 carbon atoms.
Unless stated otherwise, halogen atoms are fluorine, chlorine, bromine and iodine atoms.
A heterocyclic group preferably has up to 4 hetero-r J
~978~1

- 6 - HOE 80/S 019 atoms, which may be the same ox different, selected from nitrogen, oxygen and sulphur atoms, and up to 14 atoms in total.
The term "known" means in actual use in the art or described in the literature of the art.
An aliphatic group R2 may be substituted, if desired, by one or more substituents, which may be the same or different. Examples of substituents are halogen atoms;
hydroxyl groups; alkoxy and alkylthio groups; alkyl carbonyl groups; carboxy, alkoxycarbonyl and alkylthio-carbonyl groups; alkanoyloxy and alkanoylthio groups;
nitro, cyano and azido groups; amido and imido groups;
amidino and guanidino groups; imino ! amino, mono- and di-alkylamino, mono- and diary~ no groups, and N,N-alkyl-arylamino groups; acylamino groups; carbamoyl and carba-moyloxy groups, and carbamoyl and carbamoyloxy groups substituted on the nitrogen atom by one or two groups selected from alkyl and aryl groups, and the corresponding unsubstituted and substituted groups in which the oxygen atom or each or either oxygen atom is replaced by a sulphur atom.
Any substituent of R2 that is itself capable of substitution may be substituted, for example, by any one or more of the substituents described above.
Preferred substituents for an aliphatic group R2 are hydroxyl groups, which may themselves be substituted for example, by one of the following groups: -R , --Co-NR3R4, -Co-R3, -Co-oR3 " -Co-oR3, -So2-R3, -SO~NH2, and -S03H, SiR3R~R5, in which groups R , R and R , which may be the same or different, if more than one are present, each represents an alkyl group, especially a lower al~yl group, an aryl group or an aralkvl group 7 especially an aryl-lower alkyl group. Furt~ermore, the nitrogen atom present in the group -Co-NR3R4 may be part of an aromatic or non-aromatic heterocyclic ring.
R2 especially represents a hydrogen atom, a lo~er alkyl group, or a hydroxyl-lower alkyl group, for example, a methyl, ethyl, hydroxymethyl, 1-hydroxyethyl (R or S) or 2-hydroxyprop-2-yl group, or a vinyl group.

~ . -

7~

An esterified carboxyl group -COOR is, for example, an ester formed with an unsubstituted or sub stituted ali-phatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heterocyclic or heterocyclic-aliphatic al-cohol having up to 20 carbon atoms, or is, for example,a silyl or stannyl ester. R may represent, for example a straight or branched chain substituted or unsubstituted alkyl, alkenyl or alkynyl group having up to 18 carbon atoms, preferably up to 8 carbon atoms, and especially up to 4 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 group, may be substituted by a cycloalkyl, aryl or heterocyclic group, or R may itself represent a cycloalkyl, aryl or hetero-cyclic group.
A cycloaliphatic group R may have up to 18 carbon atoms and is, for example, a cyclopentyl, cyclohexyl or adamantyl group. An aryl group may have up to 12 carbon atoms and may have two or more fused rings. An aryl group R is, for example, an unsubstituted or substituted phenyl group, and an unsubstituted or substituted aralkyl group is, for example, a benzyl, ~-nitrobenzyl or benzhydryl group.
A heterocyclic group may have one or more hetero-atoms, selected from oxygen, nitrogen and sulphur, and up to 14 atoms in total. A heterocyclic grouP is, for example, an oxygen-containing heterocyclic group, for example, a tetrahydropyranyl or phthalidyl group.
A stannyl group R may have up to 24 carbon atoms, for example, R may represent a stannyl group having three substitutents, which may be the same or different, select-ed from alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy and aralkoxy groups, for example, alkyl groups having up to 4 carbon atoms, for example, n-butyl groups, phenyl and benzyl groups, especially three n-butyl aroups.
A silyl group R may also have up to 24 car~on atoms J
~78~1

- 8 - HOE 80/S 019 and three substituents, which may be the same or different, selected from alkyl, alkenyl, cycloalkyl, aryl and aralkyl groups, for example, alkyl groups having up to 4 carbon atoms, for example, methyl and t-butyl groups.
S Any group R that is capable of substit~ion may be substituted. Examples of substituents are given above in relation to R . Substituents for phenyl groups are, for example, as described above in relation to R2.
The group R may be removable by hydrolysis, by photo-lysis, by reduction or by enzyme action to give the free acid, or two or more methods may be used, for example, reduction followed by hydrolysis. A group ~ that may be removed readily without substantial degrad~on of the rest of the molecule is particularly useful as a carboxyl protecting group. Examples of esters that are readily ~plit by reduction are arylmethyl esters, for example, benzyl, ~-nitrobenzyl, benzhydryl and trityl esters. Re-duction of an ester, for example, an arylmethyl ester, may be carried out using hydrogen and a metal catalyst, for example, a noble metal, for example, platinum, palladium or rhodium, which catalyst may be supported, for example, on charcoal or kieselguhr.
Alternatively, a ~-nitrobenzyl ester may be converted to the free acid, by a two-step method, with an initial reduction of the nitro group, followed by hydrolysis. The nitro group may be reduced by chemical or catalytic reduc-t~on, for example, using a metal reducing agent, for ex-ample, zinc in acetic acid, aqueous tetrahydrofuran or acetone. The pH should be maintained within the range of from 3 to 6, preferably from 4 to 5.5, preferably by the use of aqueous hydrochloric acid. Other reducina agents are, for example, aluminium amalgam in a moist ether, for example, tetrahydrofuran, and iron and ammonium chloride in an aqueous ether, for example, aqueous tetrahydrofuran.
Reduction of the nitro group is followed hy hydrolysis which may occur in situ during reduction of the nitro group or which may be carried out subsequently by treat-ment with an acid or a base. An o-nitrobenzyl ester may ~9~

- 9 - HOE 80/S 019 be converted to the free acid by photolysis.
A stannyl ester, for example, a tri-n-butyl stannyl ester, may be split readily by hydrolysis, for example, by solvolysis, for example, using water, an alcohol, a phenol or a carboxylic acid, for example, acetic acid.
Certain ester groups may be split off by base hydrolysis, for examp1e~ acetylmethyl and acetoxymethyl ester groups.
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 the carboxylate, for example, an acyloxy-methyl ester, e.g. an acetoxymethyl or pivaloyloxymethyl ester, an aminoalkanyloxymethyl ester, for example, an L-glycyloxymethyl, L-valyloxymethyl or L-leucyloxymethyl ester, or a phthalidyl ester, or an optionally substituted 2-aminoethyl ester, for example, a 2-diethylamino-ethyl or 2-(1-morpholino)-ethyl ester.
Preferred esters are the ~-nitrobenzyl, phthalidyl, pivaloyloxymethyl, acetylmethyl and acetoxy-methyl esters.
An ester of formula ~, or of any other free acid described herein, may be prepared by reaction with an alco-hol, phenol or st~nn~nol or a reactive derivative thereof.
The reaction is preferably carried out under mild condi-tions in order to prevent rupture of the ring or ringsystem, for example, under neutral or mild acidic or basic conditions, and at temperatures within the range of from -70 to +3SC.
An alkyl, alkoxyalkyl or aralkyl ester may be pre-pared by reaction of an acid of formula I or any otherfree acid with the appropriate diazoalkane or diazoar-alkane for example, diazomethane or di~henyldiazomethane.
The reaction is preferably carried out in an ether, ester or halogenohydrocarbon as solvent, for example, in di-ethyl ether, ethyl acetate or dichloromethane. In general,temperatures below room temperature are preferred, for example, from -15 to +15C.
An ester derived from an alcohol may also be pro-duced by reaction of a reactive derivative of the alcohol, 7~

- 10 - HOE 80/S 019 for example, a halide, for example a chloride, bromide or iodide, or a hydrocarbonsulphonyl derivative, for example, a mesyl or tosyl ester, with a salt of an acid of formula I or another free acid described herein for example, an alkali or alkaline earth metal salt, for example, a lithium, sodium, potassium, calcium or barium salt or an amine salt, for example, a triethylammonium salt. This reaction is preferably carried out in a sub-stituted sulphoxide or amide sol~ent for example, in dimethylsulphoxide, dimethylformamide or hex~methylphos-phoramide or, alternatively, an ester may be prepared by reaction of the acid with the alcohol in the presence of a condensing agent, for example, dicyclohexylcarbodiimide.
A stannyl ester may be formed by reaction of a carboxylic acid of formula I or another free acid des-cribed herein, or a salt thereof with a reactive tetra-valent tin compound, especially a trialkyl tin oxide.
The present invention also provides the salts of those compounds of formula I that have salt-forming groups, especially the salts of free acids of formula I and the acid addition salts of compounds of formula I having a basic group. The salts are especially physiologically tolerable salts, for example, alkali metal and alkaline earth metal salts, for example, sodium potassium, lithium, calcium and magnesium salts, ammonium salts and salts with an appropriate organic amine; also physiologically tolerable acid addition salts. These may be formed, with suitable inorganic and organic acids, for example, hydro-chloric acid, sulphuric acid, carboxylic and organic sulphonic acids, for example, trifluoroacetic acid and ~-toluene-sulphonic acid. Some compounds of ~ormula I
which contain a basic centre may exist as Zwitterions;
such salts are also part of this invention.
A salt of a free acid of formula I may ~e produced by reacting the free acid with the appropriate base in a solvent, preferably under conditions under which the salt precipitates. In the case of an alkali metal salt, for example, a sodium or potassium salt, the preferred base ~g78~1 is an alkoxide.
A salt may be produced directly from an ester by splitting off the ester group under suitable reaction conditions, for example, catalytic reduction of an ester, for example, a ~-nitrobenzyl ester, in an aqueous/organic solvent, for example, comprising water and ethyl acetate, dioxane, or tetrahydrofuran, in the presence of a metal ~alt, especially a bicarbonate, for example, in an equi-valent amount or in a slight excess, yields a salt direct-ly.
A compound of formula II may be prepared by a pro-ce~s which comprises (i) allowing a compound of the general formula III
O Rc I f~e S _ ~C=C
C ~ '--Rd ~a ~b III
~7------N .

~ ~SCOR-.
C02R SCORl in which R and R2 are as defined above, the two radicals R1, which may be the same or different, are each as defined above for R1, and in which Ra, Rb, Rc, Rd and Re, which may be the same or different, each represents a hydrogen atom, an alkyl or alkenyl group having up to 8 and preferably up to 4.carbon atoms r a cycloalkyl or cycloalkenyl gro~p, a free or esterified carboxyl group, a halogen atom or a cyano group, and wherein any two of ~a to Re may form, together with the carbon atom or atoms to and through which they are attached, a cycloaliphatic ring containing from 3 to 10 carbon atoms, there being present zero, one or two of such rings, and wherein Rc is cis or trans to Rd and the group 7~
- 12 ~ HOE 80/S 019 o Rc ~ Re --S--C--C--C
~ ~ Rd Ra ~

is cis or trans to R2 . = =, to react with a trivalent organophosphorus compound to give a compound of formula II, or (ii) reacting a compound of the general formula IV

R2 ' ~;~ ' IV
0 ~ ~ SCOR
~02R

in which R, R1 and R2 are as defined above, with a tri-valent organophosphorus compound.
A compound of formula IV i5 preferably produced by effecting ring closure in a compound of formula III as de-fined above.
:Any of the interconversions a) to d~ described above : in relation to the compound of formula I may be carried out on a compound of formula II.
In the compound of formula III, the group -- C -- C --Ra r~ Rd is preferably one of the following:

-. . ~: . . - . . ;. .

. .

~ 13 - HOE 80/S 019 CH3 ~ ~ /
C~ ~ C ~-CH
2 ~ 2 ~2 . C~3 C'~'C~ ~ C~ ~ C~ ~ < 3 ~3 CH3 S C~ ~ ~ C f ~ CH2 - C~ = CH~
C~3 ~

and especially the group -CH2-CH-CH2.
Ring closure of the compound of formula III occurs spontaneous~y at room temperature, but the reaction is g~nerally carried out at a temperature within the range of fEom 20 to 150C, preferably from 60 to 120C, and generally under an inert gas atmosphere, for example, under an atmosphere of nitrogen or argon. The cyclisation 25 may be carried out in a solvent, which should be capable ~f achieving the desired temperature, for example, benzene toluene or dioxan.
The cyclisation is preferably carried out in the pre-sence of an acid, which reduces significantly the reac-3 tion time. The acid may be a protic inorganic acid aprotic organic acid, or a Lewis acid. Examples of protic inorganic acids are sulphuric acid and phosphoric acid.
A protic organic acid may be a carboxylic acid, for example, formic acid or acetic acid, or a deri~ative 35 thereof, for example, chloroacetic acid, dichloroacetic acid or, especially, trifluoroacetic acid. Su:Lphonic acids are further example of organic acids which may be ~g78~
- 14 - ~OE 80/S 019 present during the cyclisation of the compound of formula III. A sulphonic acid may be an alkyl sulphonic acid, for example, methanesulfphonic acid or d- or l-camphor-10-sulphonic acid; or an aryl sulphonic acid, for example, benzenesulfphonic acid, toluenesulphonic acid, benzene-disulphonic acid or a derivative thereof, for example, a chlorinated sulphonic acid.
A Lewis acid is, for example, boron trifluoride, boron trichloride, aluminium trichloride, titanium tetra-chloride, tin tetrachloride, tin dichloride, zinc chlorideand zinc bromide.
Preferred acids are boron trifluoride, in the form of an etherate eOg. boron krifluoride diethyl therate, and ~luenesulphonic acid. A preferred solvent is dioxan.
It is also preferably to carry out the cyclisation in the presence of water, a lower alkanol, or a mixture of any two or more selected from water and lower alkanols.
The water, lower alkanol, or mixture thereof is preferably used in an amount of from 1 to 20 equivalents, calculated on the compound of formula III. A lower alkanol is prefer-ably methanol, ethanol or a propanol.
The water, lower alkanol or mixture thereof may be used either alone or in addition to the use of an acid.
It is thought that prior to cyclisation, the compound of formula III re-arranges to the compound of formula IIIa Rd ~e ~2 , S O~fC`c Crr~ Ra R~ IIIa 0~ ' ` 1 \ ~SCOR

~0 The compound of formula III may ~e cyclised to give compound IV, which is then treated with a trivalent organo-phosphorus compound, or the compound of formula III may be '7~

convexted into the corresponding compound of formula II in one step. In the former case, the ~ntermediate of formula IV may be isolated, or the treatment with the phosphine compound may be carried out ln situ on the reaction mix-S ture resulting from the cyclisation step.
The trivalent organophosphorus compound is especiallyone of the general formula wherein R6, R7 or R8, which may be the same or different, each represents an unsubstituted or substituted hydro-carbon group, for example, a straight or branched chain aliphatic for example, alkyl group, an unsubstituted or substituted cycloaliphatic for example cyclopentyl or cyclohexyl group, an unsubstituted or substituted aryl for example, phenyl group; or an unsubstituted or sub~
stituted hydrocarbon group in which one or more carbon atoms are replaced by hetexo atoms, especially nitrogen, oxygen and sulphux atoms, or example, alkoxy groups, amine groups, and aromatic and non-aromatic heterocyclic groups. Preferred tervalent organophosphorus compounds are triphenylphosphine, tributylphosphine, trimethyl-phosphite and triethylphosphite.
A further preferred group o~ tervalent organophos-phorus compounds are those in which, in PR6R7R8 one or more of the ~roups R6, R7 and R8 comprises an insoluble polymer, which aids removal after the reaction. Generally one polymeric substituent is adequa~e. (See, for example, H.M. Relles, and R.W. Schluenz, J. Amer. Chem. Soc~ 96 6469, (1974) and S.L. Regen and D.P. Lee, J. Org. Chem.
40, (11), 1669, 11975).
Another preferred group of trivalent organophospho-rus compounds are those in which, in PRZR7R8, one or more of the groups R6, R7 and R8 comprise a cationic or anionic centre, ror example, a quaternar~ ammonium group or a carboxylate or sulphate group. The presence of a charged group assists re~oval of the resulting organophosphorus '7~

sulphide, or example, by partition or by absorption on an insoluble ion exchange resin or by extraction into an aqueous solution at an appropriate pH, when the organo-phosphorus sulphide is water soluble.
The reaction of the compound of formula IV with the trivalent organophosphorus compound is preferably carried out in a dry, inert, aprotic organic solvent or diluent, for example, an ether or an ester, for example, diethylether, tetrahydrofuran or ethyl acetate; an aro-matic hydrocarbon for example, benzene or toluene; a halogenated hydrocarbon, for example, methylene chloride or chloroform; or another organic solvent, for ex~mple, dimethylformamide or acetonitrile. Preferred solvents are methylene chloride and ethyl acetate. A mixture of two or more solvents or diluents may be used. The reac-tion may be carried out at a temperature of rom 0 ~o 80C, preferably from 0 to 20C, and it is preferable to use at least 1 equivalent of the phosphorus compound per equivalent of the compound of formula IV.
The resulting compound of formula II may be isolated from the reaction mixture, f~r example, by chromatography or crystallisation~ The compound of formula II may be obtained as a mixture of the 5R- and 5S-isomers These isomers can be separated by known methods, if desired, or the compound of formula II can be used in the form of an isomeric mixture. The preferred stereochemistry ln com-pound II is generally that of natural penicillins and cephalosporins i.e. 5R.
If R in formula II represents an esterifying group, this may be removed in the usual manner, dependiny on the nature of the ester group, for example, by hydrolysis, xeduction, or enzymatically, to yield the free acid. A
free acid or an ester may be converted into a salt, especially a physiologically tolera~e salt, or a salt may be converted into another salt or the free acid or an ester. An ester may be transesterified, or a free acid converted into an ester, for example, to give an ester capable of removal under physiological conditions. Ex-~ ~ ~'7~

amples of such procedures are g~ven above.
A compound of the general formula II may be pro-duced in various ways, for example, as shown in the reac-tion scheme below, in which S ~ denc~es the group~S~C~ C C
,,~ ~ d o ~a Rb in which Ra to Re are as defined above.

RQ
~llII s RC
2 ~ 1 Ra_CI ~--C"~,Rd R2 ~ S~
~NH O~

YCH~ COOR
Y ~ Yl R ~S ~ CS2~ b~se~ R~ ~S

o~ N~SCOR~ nCy~ n9 ugent .~
~ C~2 COOR SCDR1 l oxidise CnOR
~ t o R2~,S~ III
~SCOR1 nd triY~lent org~nophosphorus compound ~ \

~S~S triyQlent S IISCOR1 D~` ~SC~R~ or~nopho~us ~N 5 compound D
CO~R CD

7~

ln which R, R~ and R2 are as defined above, ~ denotes that a reaction requires uptake of heat from an external source, Y represents a group that is capable of being re-placed by a nucleophilic group and is, for example, a halogen atom, for example, a chlorine, bromine or iodine atom, or a substituted, activated hydroxy group, for example, a sulphonyloxy group, for example, a radical of the formula in which R9 represents an aliphatic, cycloaliphatic, aryl or araliphatic group having up to 18 carbon atoms, which may be substituted or unsubstituted, fox example, as described above for R2. ~n aliphatic group R9 is, for example, an alkyl group having up to 8 car~on atoms which may be substituted by one or more halogen atoms, for ex-ample, chlorine and bromine atoms. An aryl group R9 has,for example, up to ~5 carbon atoms, and may be substi-tuted by one or more substituents, which may be the same or different, selected from alkyl and alkoxy ~roups, for example, methyl and methoxy groups, nltro groups, and halogen atoms, especially bromine atoms, R9 preferably represents an unsubstituked or substituted aryl group having up to 18 carbon atoms, for example/ a phenyl, p-tolyl, ~-bromophenyl or ._-nitrophenyl group, or an un-substituted or substituted alkyl group, especially with 1 to 4 carbon atoms, and preferably a methyl or tri-fluoromethyl group~
Y preferably represents a bromine or iodine atom or a methylsulphonate, trifluoromethylsulphonate, tolylsulpho-nate or benzenesulphonate group.
y1 represents a group that is capable of being re-placed by a nucleophilic group and is, for example, es-pecially an activated hydroxy group, more especially, an acyloxy group, for example, an acetoxy group, or a sul-'7~

phonyl group, for example, of the formula -So2Ra9 in which Ra represents an alkyl group having from 1 to 4 carbon atoms, an aryl group, for example, a phenyl group, or y1 represents a halogen atom, for example, a chlorine or bromine atom.
A compound of formula VIII may be prepared as des-cribed in, for example, Liebigs Annalen Chemie 1974, pp.
539-560, Claus, Grimm and Prossel; DT-OS 1 906 401; UK
Specification ~o. 2 013 674; Japanese Published Appli-cation JA 80641; or H.R. Pfaendler, J. Gosteli and R.B.Woodward, J.A.C.S. 102:6 (1980), 2039-2043; Belgian Patent Specification No. 882.764. A compound of formula VIII may be converted into a compound of formula VII by reaction with a compound of formula Rc ~'1 S C - C~
~ ~ ~ ~ Rd VII

~a Rb in which R10 represents a hydrogen atom or an alkali metal atom especially a sodium or potass.ium atom, and Ra to Re are as defined above.
The reaction is generally carried out in a solvent, preexably a protic solvent, for example, water or an alcohol, or a non-protic, water-miscible solvent which is preferably polar, for example, dimethyl formamide, di~
methyl sulphoxide, tetrahydrofuran or dioxane. The reac-tion temperature is, for example, from -20 to +100C, preferably from -10 to +20C.
A compound of formula VII may be reacted with a _ompound of formula IX

in which Y and R are as defined above in the presence of a base, to give a compound of formula ~I.

1:~$7~
- 21 - HOE 80/$ 019 The base mav be inorganic, organic or organometallic, for examp]e, an alkali metal or alkaline earth metal hydxoxide, oxide~ carbonate, bicarbonate or hydride, for example, sodium hydroxide, magnesium oxide, potassium carbonate, potassium bicarbonate or sodium hydride; an amine, for example, a dialkylamine or trialkylamine, for example, triethylamine, dabco (diazabicyclo(2,2,2)octane), - pyridine, or an alkyl-substituted or amino-substituted or dialkylamino-substituted pyridine for example, N,N-di-methylaminopyridine, or collidine; a guanidine, for ex-ample, tetramethylguanidine; DBN (diazabicyclononene) or DBU ~diazabicycloundecene), a polymeric base i.e. a base attached to an inert polymeric support e.g. Hunig's base (diisopropylethylamine attached to e.g. polystyrene); a metallated amine, or example, a metallated alkyl or arylamine, for example, lithium diisopropylamide (LDA), lithium hexamethyldisilazide, lithium piperidide, lithium 2,2,6,6-tetramethylpiperidide~ or a Grignard reagent.
Preferred bases are, for example, potassium carbonate, sodium hydride, lithium diisopropylamide and triethyl-amine.
The reaction is generally carried out in a solvent or diluent that is inert under the reaction conditions, for example, an amide, for example, dimethylformamide, dimethylacetamide or hexamethylphosphoramide; a hydro~
carbon, for example, benzene or toluene; an inert, aprotic solvent or diluent, for example, an ester, for example, ethyl acetate, or an ether, for example, diethylether, tetrahydrofuran or dioxane; a chlorinated hydrocarbon, for ~xample, methylene chloride or chloroform; or aceto-nitrile, nitromethane, dimethyl-sulphoxide, or sulpholane.
~imethylformamide and dimethylacetamide are preferred. A
mixture o t~o or more solvents and/or diluents may be used.
The reaction may be carried out at a temperature within the ranae of from -80C to the reflux point of the reaction mixture, preferably from -40 to +50CI and especially from - 0 to +30C.

3'7l~
- 22 - HOE 80/S 0l9 From 1 to 1.~ moles of compound IX are preferably used per mole of compound VII, especially from 1 to 1.1 mole of IX per mole of VII. The base is used in an amount for example, from 1 to 4 moles of base per mole of com-pound VII.
The reaction is preferabyl carried out by dissolv-ing compound VII in a solvent, advantageously in dimethyl-formamide with stirring, adding the base, addina the compound of formula IX and reacting at the desired tempe-rature~ The resulting compound of formula VI may be workedup and isolated in the usual manner~ for example, using chromatographic and/or cr~stallisation technigues, or the subsequent reaction may be carried out directly on the resulting reaction mixture after removal of any solvent that is not compatible with the su~sequent reaction.
I R in formula VI represents a carboxyl esterify-ing group, this group may be converted into another esterifying g.roup R, for example, to introduce a group R
that is more easily removable under desired cond~ions.
This transesterification is generally carried out as follows: the ester of formula VI is hydrolysed in known manner using, for example, acid or alkaline hydrolysis, preferably an alkali metal hydroxide, especially sodium or potassium hydroxide. The ester of formula VI for example, a methyl ester, is preferably hydrolysed using an al.~ali metal hydroxide especially one mole thereof per mole oE the ester of formula VI in a solvent, for example ethanol, methanol or water, or an aqueous-organic solvent, for example, tetrahydrofuran/water, ethanol/
water, or acetonitrile/water.
The reaction mixture is then generally acidified, and the free acid is preferably isolated and, if desired, the free acid is then esterified wit~ an esterifying agent capable of introducing a different esterifying 3~ group R, for example with an alcoho1 ROH in the presence of an acid or another activating agent, for example, dicyclohexylcarbodiimide, or with an alkylating agent RY in which Y is as defined above. ~sterirication methods - 23 - HOE 80tS 019 are described above in xelation to the compound of formula I.
Transesterification may be carried out on compound VI as described abo~e, or on any other intermediate or on the final product of formula I.
As indicated in the reaction scheme above, com-pound VI may be converted to compound III by the addition of the group SCOR
=C
\
SCO~<
to the side chain attached to the nitrogen atom, followed by oxidation of the sulphur atom attached to position 3 of the azetidinone ring.
A compound of formula VI may be converted into a compound of formula V by trea~ment with a base in the pre-sence of carbon disulphide followed by reaction with an acylating agent, or by treatment with a base, then with carbon disulphide, and finally reaction with an acylating agent. An acylating agent is generally an activated carboxylic acid.
The activated carboxylic acid may be any activated acid derivative comprising the group R1. Such derivatives are well known in the art, and include acid chlorides, acid anhydrides, and activated esters.
An anhydride may be symmetrical or asymmetrical.
An activated acid may comprise an unsubstituted or sub-stituted carbonic, sulphonic or phosphoric ester group.
The acylating agent may have the general formula X

in which Z represents a halogen atom, especially achlorine atom, -OCOR~1 in which R11 is as defined for R1 and may be the same as R1 or different, -02COR12 or -OSO~R1~, in which R12 is as defined above for R9, ~7~

--O--P
,_R1 , i~ ~hich l14 R13 and R14, which may be the same or different, each represents an unsubstituted or substituted alkyl, aryl or aralkyl group, or R13 and R14 togetherwith the phosphorus atom may form a 5- or 6-membered ring, or either or both of R13 and R14 may represent a group ~QRa3 or -OR14 respectively, in which Ra3 and Ra4 are as defined above for R and ~ respectively and, in the case when R13 represents -CR13 and R1 represents ~ORa ~ Ra3 and R14 may together represent a 5- or 6 membered ring.
The compound of formula VI is preferably reacted first with a base, then with carbon disulphide, and then finally with the acylating agent.
The base preferably has a pK ~20, and is preferably a metallated amine. Examples of preferred bases are l~hium diisopropylamide, lithium 2,2,6,6-tetramethyl~
piperidide, lithium cyclohexyl isopropylam~de, lithium hexamethyl disilazide, and sodamide.
The reaction is generally carried out in an inert solvent, for example, an oxygenat~d hydrocarbon, preferab-ly an ether, for èxample, diethyl ether, tetrahydrofuran,dioxane, glyme or diglyme- The reaction temp~rature is, for examp]e, from -120 to +30C, preferably rom -100 to The amount of base used is for example, from 1 to 4 moles, calculated per mole of compound VI, preferably from 2.0 to 3.0 moles of base. Carbon disulphide is preferably used in an amount of from 1 to 5 moles, espe-cially from 2 to 3 moles, per mole of compound VI.
The reaction is preferably carried out as follows:
to a stirred solution of compound VI under an inert atmosphere is added the base then a solution of carbon disulphide in the same or a different solvent and finally the acylating agent to complete the reaction.

1:~$'~
~ 25 - HOE 80/S 019 There may then be admixed a protic source havit~g a pX less than 10, and especially from 5 to 2, for ex-ample, acetic,citric, oxalic or formic acid.
Oxidation of the resulting compound V may be car-ried out by any method capable of converting a sulphideinto a sulphoxide, for example, there may be us~d an oxidising agent, for example, hydrogen peroxide, a periodate e.g. sodium periodate, ozone, a peracid e.g.
peracetic acid or perben~oic acid, a substituted perbenzoic acid e.g. m-chloroperbenzoic acid, or a permanganate salt, e.g. potassium permanganate. Preferred oxidising agents are hydrogen peroxide and m-chloroperbenzoic acid. Over oxidation should be avoided, for example, by using only one equivalent of a peracid.
The oxidation is preferably conducted in an inert solvent at a preferred temperature o from -40 to ~30C.
Preferred solvents are ethyl acetate, methylene chloride, chloroform, acetonitrile, and lower alcohols, for example methanol and ethanol.
The resulting compound of formula III may be iso-lated and worked up using known methods.
It is advisable to esterify a free carboxyl group in a compound of formula III prior to cryclisation.
Although an ester group may be introduced immediately prior to cyclisation, it is preferable to esterify the carboxyl group at an earl~r stage in the preferred reaction sequence, for example, to esterify a free carboxyl group in a compound o formula V or ~I to ensure that the carboxyl group does not take part in any of the subsequent reactions. An esterifying group may be transesterified to another ester group having more des-irable properties for a particular stage of the reaction sequence.
Furthermore, it is advisable to protect any reactive moiety present in any of R, R1 and R2 so that such a moiety does not take part in anv subsequent reaction. Examples of such moieties are hvdroxy, carboxy and amine m~eties.
Groups suitable for proiecting such reactive moie~ies are '7~

well known, as are methods for their removal. tcf Protective Groups in Organic Chemistry, editor J.F.W.
McOmi e, Plenum Press, 1973).
Examples of groups suitable for protecting hydroxyl moieties are tetrahydropyranyl groups, methoxyethoxymethyl groups, acyl groups, for example, acetyl, chloroacetyl and formyl groups, and silyl groups, for example, as described above for R, for example, trimethyl silyl and t-butyl-trimethylsilyl groups. Carboxy protecting groups are, for example, as described above for R. Amino protecting - groups are, for example, t-butyloxycarbonyl, benzyloxy-carbonyl, ~nitrobenzyloxycarbonyl, ~-nitrobenzenesul-phenyl and trityl groups.
Reactive mo~ties may be pro~ected at any appropriate point in the react~on sequence, and the protective groups are preferably removed during or after the formation of the compound of formul~ I.
In a compound of formula II any one or more of the above steps a), to d) may be carried out, if appropriate, before conversion to a compound of formula I.
At each stage of the preferred reaciion sequence, the desired compound may be isolated from the reaction mixtuxe and, if desire, purified by appropriate techniques ~enerally used for the purification of organic compounds, for example, chromatography or crystallisation.
As indlcated abo~Je, various intexmediates may be produced in the form of mixtures of isomers of various kinds. Such a mixture may be separated or resolved at any stage, ox the isoermic mixture may be used per se for subsequent reactions.
All of the compounds that are provided by the in-vention may exist in anv appropriate isomeric orm, as discussed above, either as a pure isomer or as a mixture OL any two or more isomers.
A compound of the general formula I may exist in the tautomeric forms of formulae Ia and Ib, and each of these forms may have the R or S stereochemistry inde-pentently at positions 5 and 6 and also, in formula Ia, at position 2. Further isomeric forms will occur when any - 27 - HOE 80~S 019 substituent contains a chiral atom. Any mixture of any two or more isomeric `forms may be resolved, if desired, and/or an isomeric mixture may be prepared.
The compounds of the general formula I are parti-cularly useful in the synthesis of substituted penems.For this purpose the compound of formula I are reacted ~ an excess of in an inert solvent in the presence of'a base, preferably 1 to 2 e~uivalente and an excess of an alkylating agent, preferably 1 to 3 equivalents.
Preferred bases sre organic bases such as secondary or tetiary alkylamines, e.g. triethylamine, diisopropylamine, methyl-diisopropylamine or inorganic bases such as Na2CO3, K2CO3, NaHC03. Preferreci alkylating agents are alXyl halides preferably brominated or iodinated lower alkyls.
The reaction is carried out ln an appropriate sol-vent such as tetrahydorfuran, dioxane, ethylacetate, methylene chloride, chloroform, dimethylformamide.
The preferred reaction temperature is 0 to 40C.
The compounds of formula I ànd salts thereof are B-lactamase inhibitors, and the compounds are generally stable to the action of B-lactamases produced by gram posîtive organisms, for example~ by Staphylococcus aureus and gram negative organisms, for example, Entero-bactercloacae. They also possess antibacterial properties themselves and may be used in humans and other animals, for example, to treat bacterial infections caused by gram positive and gram negative bacteria, for example, Staphylococcus aureus~ Streptomyces pyogenes~ Bacillus subtilis, E. coli, Pseudomonas aeruginosa, and Proteus inorganii, some strains of which are pencillin-resistant.
The invention accordingly provides a pharmaceutical preparation which comprises a compound of formula I
or a physiologically tolerable salt of a compound of formula I or a 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 o.her pharmaceutically ~ ~'7~

active substances, for examp1e, another antibacterial substance, especially one which has a B-lactam ring. The preparation may be in a form suitable for enteral or parenteral administration, for example, for oral, intra-venous, or intramuscular administration, for example, as tablets, capsules, syrups, or sterile injectable or infusible solu~ions. The preparat~ons are advantageously in unit dosage form and preferably comprise from 10 to 2000 mg of the active insredient. The daily dosage of the active substance is generally from 20 to 8000 mg, in divided doses, generally up to 4 doses.
The invention also provides the use of an active compound as defined above as a B-lactamase inhibitor and/or as an antibacterial agent.
The invention further provides a pharmaceutical preparation which comprises an active compound as defined above, or a physiologically tolerable salt thereof, or a mixture of two or more such substances, in unit dosage form.
The invention also provides a pharmaceutical pre-paration which comprises an active compound as defined above, or a physiologica-ly tolerable salt thereof or a mixture of two or more such substances, and one or more further pharmaceutically active substances, for example, as described above and, for example, in unit dosage form.
Vnit dosages are preferably as described above.
The followin~ Examples illustrate the invention.
In them, temperatures are expressed in degrees Celsius.
E X A M P L E
3O4-~llylthioazetidin-2-one.

OAc - S ~===
~ r 35 O,~ ~ NH

A solution of 42.9 g of sodium hydroxide in 500 ml of water was made up ~nder nitrogen and cooled to room ~'7l3'~

temperature, 108 ml of allyl mercaptan was added and the mixture stirred under nitrogen for 30 minutes. 138.7 g of 4-acetoxyazetidin-2-one was added to the mixture over 10 minutes under nitrogen and the reaction mixture was stirred overnight in an air atmosphere. The reaction was checked for completion by T.L.C. (hexane-ethyl acetate) and extracted into dichloromethane (6 x 250 ml). The organic layer was washed with water ( 2 x 250 ml), dried over magnesium sulphate and evaporated in vacuo to dry-ness. Purification, over silica gel and elution withhexane-ethyl acetate afforded the above product as a yellow oil. (112.1 g, 73 ~ of the theoretical yield).
~max = 1769, 1778 (sh) cm 1.
~(CDCl3) 2.86 (1H~ ddd~ JNH~3B1 4~3 J3~ ,3B15 Hz, 3B-H) 3.28 ~2H, d, J 7 EIz, S-C~I2), 3.37 (lH, ddd, JNH 3~ 1-5 Hzr J~3~ 6 ~Z~ J3B~3~
6~ -H), 4.71 (lH, dd, J3~ 4 3 Hz~ J3~ 4 6 Hz~ 4-H~ ~ 4.93 ~ 5.38 (2H~ m, = CH2), 5.49 - 6.24 ~1H, m, CH=), 7.43 (1H, bs, N~).
m/e 143.0405 (M~).

4l-Nitrobenzyl 2-(4-allylthioazetidin-2-on-l yl)acetate ~ . N0~ . . .
~ 1`

0 ~ ~ 0 ~ D ~ .
3 ` ~ Q ` ~

~H20CCH2Br ~ ~ 0~
2--~0~ ~;

~5

11~5 g of 4-nitrobenzylbromoacetate in 30 ml of di-methylformamide was added to 5.0 g of 4-allylthioazetidin-2-one dissolved in 70 ml of dimethylformamide with stirr-~g'7~
- 30 - ~OE 80/S 019 ing under argon at room temperature. After 5 mins, 10.61 g of potassium carbonate was added to the solution. During the follo~ing 20 mins there was a colour change in the mixture from yellow to dark brown. ~tirring was continued for a further 3 hrs 40 mins when TLC analysis indicated completion of reaction. The mixture was poured into water (300 ml), extracted into ethyl acetate ( 4 x 100 ml) and ~he combined organic extracts washed with water ~3x200 ml).
The organic layer was dried with MgSO4 and evaporated to leave a yellow oil.
The crude product was chromatographed on silica gel using ethyl acetate/hexane mixtures as eluent. 5.89 g of product was obtained (50 % of the theoretical yield)~
S (CDC13) 3.05 (1H,2d,J trans 3Hz,3-H), 3.17 t1H,S,S~
~5 CH2-).
3.30 (1H,S, S-CH21, 3.53 (1H,2d,J cls SHz,J
gem 15Hz, 3-H), 3.84 and 4.38 (2H,ABq,J18Hz,-N-CH2-), 4.95 llH,2d,4-H), 5.00-5,34 ~2H,m, =CH2), 5.34 (2H,S,-O-CH2), 5.54-6.40 (1H,rn, =CH), 7.53-8.38 l4H~m,-C6H~) o~ max (CDCl3) 1769,1758 cm m/e 336.0525 (M ), 295.0391 (M-CH2CHCH2), 136.0385 (base peak) Methyl 2-(4-allylthioazetidin-2-on-1-yl)acetate t BXCH2C02CH3 r --0~ ' ~ 2C~3 21.8 ml of methyl bromoacetate in 220 ml of dimethyl-formamide was added to 31.1 g o 4-allylthioazetidin-2-one dissolved in 420 ml of dimethylformamide, with stirr-ing~ under argon, at room temperature. After 5 mins, 66.0 g of anhydrous potassium carbonate was added to the solution. The suspension was then stirred for a further 3'7~

18 hours. I
The mixture was poured into water (2.5 l), extracted into ethyl acetate (3x1200 ml) and washed with water ~3x2 l). The organic layer was dried with MgSO~ and 5 evaporated to leave a yellow oil.
The crude product was chromatographed on silica gel using ethyl acetate/hexane mixtures as eluent, 22.0 g of the above product was obtained. (47 % o~ the theoretical yield) ~ ~CDCl3) 2.97 (1H,2d,J trans 3Hz,3-H), 3.16 (lH,S, ~-CH2-), 3.26 (1H,S, S-CH2-), 3.45 ~1~,2~,J cis 5Hz,J gem 15Hz, 3-H), 3.66 and 4.23 (2H,ABq,J 17Hz,-N-CH2-), 3.72 3H,S,CH3), 4.86 (1H,2d,4-H), 4.95-5.27 (~H,m, -CH2~, 5.50-6.15 (1H,m, =CH) max (CHCl3) 1766, 1749 cm 1 m/e 215,0539 ~M ), 142.0456 (base peak) Methyl 2-~4-allylthioazetidin-2-on-l-yl)acetate . S~ ' ' ~ ~ ~ ~

0~ ' ~B,CrI~C02CH3 0~
C2~I~3 , 0.070 ml of methylbromoacetate in 1 ml of dimethyl-formamide was added to 0.100 g of 4-allylthioazetidin-2-one dissolvea in 2 ml of dimethylformamide with stirring under argon at 0~. ~fter 5 mins, 0.040 g of hexane washed sodium hydride, was added to the solution. The cooling bath was removed and stirring continued for a further ~5 mins, when TLC analysis indicated completion of reac-tion.
The mixture was poured into water (15 ml~, extracted into ethyl acetate (2x12 ml) and washed with water (3x15 ml)~ The organic layer was dried with MqSO~ and evaporated ~78'~

to leave a yellow oil.
Yield: 0.089 g, (59 ~ of the theoretical yield)~
(For spectral data see Example 3) 2-(4~Allylthioazetidin-2-on-1-yl)acetic acid ' S ~, _ S ,~

C2~H3 2 2.34 g of potassium ~ydroxide dissolved in a mixture of 285 ml of ethanol and 15 ml of water was added to 6.0 g S of methyl 2-(4-allylthioazetidin-2-on-1-yl) acetate with stirring at room temperature. The solution was poured into 720 ml 1M hydrochloric acid, extracted into dichloro-methane (2.650 ml), the organic layer extracted with saturated sodium bicarbonate solution and the agueous 2~ phase acidi~ied to pHl with SM hydrochloric acid. This solution was extracted into dichloromethane t5x650 ml), dried with MgSO4 and evaporated to leave a colourless oil.
Yield: 5.37 g t96 ~) S (CDC13) 3.06 (1H,2d,J trans 3Hz,3-H), 3.19 ~1H,S, S-CH2- ), 3.30 (1H,S,S-CH2), 3.53 (1H,2d,J cis 5Hz,J
gem 16 Hz,3-H), 3.75 and ~.36 (2H,ABg,J18Hz,N-CH~-~, 4.96 3G (1H,2d,4-H), 5.03-5.34 (2H,m, =CH2), 5.58-626 t1H~m~H~c=) ~ max (CDCl3) 1765, 1730 cm 1 m/e 201.0500 (M ), 86.0239 tbase peak).

Pivaloyloxymethyl 2-(4-allylthioazetidin-2-on-1-yl~-2-acetate S ,c~. S ~;, ' . E~ l O _____3 ~ ~ ~ ~Z5~~~ ~ O CH CO C(CH_~
.~00~ 2 2 To a solution o~ 14 mls of diisopropylamine and 20.4 g of 2-(4-allylthioazetidin-2-on-l-yl) acid in 450 ml of dlmethylformamide, at 0C, was added dropwise 14 ml of chloromethylpivalate. The solution was wanmed to room temperature and stirred for 5 days until TLC analysis (silica gel: hexane-ethyl acetate) showed absence of starting material. The reaction mix~ure was poured into water (500 ml), and extracted into ethyl acetate (3x500 ml); the organic layer was washed with hydrochloric acid (pH 2.0, 400 ml), then water ~2xSOO ml), dried over magnesium sulphate and evaporated to dryness.
The crude product was purified over silica gel eluting ~ith hexaneethyl acetate to give the above product as a pale yellow oil (20.1 g, 63 ~).
max = 1760, 1768, 1776 cm 1 tCDC13) 1.20 (9~, s. C(CH3)3, 2.99 (lH, dd, J4 3B 3Hz J3~ 3B 16Hz, 3B-H), 3.27 (2H, d, J 7 Hz, S-CHz), ~5 3.53 (lH, dd, J4,3~ 5Hz~ J3g~3~
4.G8 (2H, q, J 18Hz, N-CH2), 4.93 (1H, dd, 3~ ,4 ' 3B,4 3Hz, 4-H~, 5.03-5 5G (2H
m, =C~2), 5.57-6.23 (1H, m, CH=), 6~80 ~2H, 3'C02CH2) Methyl 3,3-di(acetylthio)-~-(4-allylthioazetidin-2-on-1-yl) propenoate S ~ . . ' S
'3~ SCC~C~
1 ~ ~ 3 C2CH3 ~--SCO_~
' ' -C02CI~3 '7~
- 34 - ~0~ 80/S 01 E X A ~I P L E 7a A solution of lithium hexamethyldisilazide was pre-pared by the addition of 5.12 ml of a 1.6M solution of n-butyllithium in hexan to 1.75 ml of hexamethyldisilazane in 25 ml of dry THF at -1Q with stirring, under argon.
The solution was cooled to -78 and added to 1.0 g of methyl 2-(4-allylthioa~etidin-2-on-l-yl)acetate in 12 ml of dry tetrahydrofuran at -78, with stirring, under argon. After 5 min, 0.846 ml of carbon disulphide was 1Q added by syringe. 1.77 ml of acetic anhydride was then ~dded, followed by 1.07 ml of glacial acetic acid. The solution was allowed to warm to room tPmperature and evaporated to leave a yellow oil.
The crude product was chromatographed on silica gel using ethyl acetate/hexane mixtures as eluent. 1.14 g (66 ~) of the above product was obtained~
o (CDC13) 2.38 (6H,S,-C-CH3), 3.17 (lH, 2d, J trans 3Hz, 3-H), 3.35 (lH,S,S-CH2-), 3.45 t1H,S, S-CH2-), 3.43-3.78 11~,2d,J gem 15Hz, 3-H), 3.86 ~3H,S, -O~CH3), 5.06-5.45 (3H,m,=CH2,4-H), 5.63-638 (1H,m,=CH) ~ maX1786, 1740, 1715 cm 1 S~C~I2 m/c 157( ~C-N ~ C - S ), 127( ~ ~, 73(S-~C~)J

.~0 ~3(COCH3) (base peak) E X A M P L E 7b A solution of lithium hexamethyldisilazide was prepared by the addition of 32.9 ml of a 1.6M solution of n-butyllithium in hexane to 11.25 ml of hexamethyl-disilazane in 125 ml of dry THF at -10 with stirring, under argon. The solution was cooled to -78 and ~dded to 5.0 g of methyl 2-(4-allylthioazetidin-2-on-l-yl) acetate in 60 ml of dry tetrahydrofuran at -78, with stirring, under argon. A ter 5 min, 4.23 ml of carbon li 7 ~
~ 35 - HOE 80/S 019 disulphide was ad~ed by syrlnge. 885 ml of acetic an~
hydride was then added. The solution was allowed to warm to room temperature and evaporated to leave a yellow oil.
The crude product was purified by extraction using chloroform and water, and the resulting organic phase was evaporated to give a yellow oil, having the characteristics given in Example 7a.

Methyl 3,3-di(acetylthio)2-(4-allylsulphinylazetidin-2-on-l-yl)propenoate O
5. ' ~S
~ ~ .
SCO~3 ~ 3 SCOC~3 S N ~ N ~
O~r~~~ ~ SCOCH3 O~ ~ ~ SCOCH3 C2C~3 C2 H3 E X ~ M P L E 8a 0.549 g of 3-chloroperbenzoic acid (81 ~ pure) in 7 ml of ethyl acetate (7 ml) was added dropwise over 20 mins to a stirred solution of 0.939 g of methyl 3,3-di (acetylthio-2-(4-allylthioazetidin-2-on-l-yl) propenoate in 18 ml of ethyl acetate at about -3SC. The solution was evaporated to dryness, slurried with dichloromethane and chromato~raphed on silica gel using ethyl acetate/
hexane mixtures as eluent. 0.659 g ~67 ~) of the above product was obtained.
3(CDCl3) 2.33 (3H,S-C-CH3), 2.42 (3H,S-C-CH3~
3~ 3.06-3.70 (4H,m,3-H,S-CH2-), 3.87 ~3H~S,-O-CH3), 5.24-6.55 (4H,m,HC=CH2, 4-H).
(CDCl3) 1796, 1730 cm 1 S--O
35 m~e l9l (H:~=C _ '~OC.H3 ), 175( ~ ), 43(CCCH3) co2c,~3 -~CH-C~-S (base peak) E X A M P L E ~b 5.50 g of 3-chloroperbenzoic acid in 30 ml of ethyl acetate was added dropwise over 30 mins to a stirred solution of the methyl 3,3-ditacetylthio-2-~4-allylthio-azetidin-2-on-1-yl) propenoate obtained in Example 7b, in 50 ml of ethyl acetate at about -35C. The solution was evaporated to dryness, slurried with dichloromethane and chromatographed on silica gel using ethyl acetate/hexane mixtures as eluent. 6.26 g of the title product was ob-tained. (69 ~ of the theoretical yield, calculated onthe starting material of Example 7b. Anal~tical data as in Example 8a).

Methyl 3~acetylthio-8-oxo-4,5-dithia-1-azabicyclo S /4,2,070ct-2-ene-2-carboxylate C~
-S~ , ~ S ~

3 . O ~ ~ ~ SCOCX3 C2C~3 C2 3 2S E X A M P L E 9a 0.050 g of methyl 3,3-di(acetylthio)~2-l4-allyl~
sulphinylazetidin-2-on-1-yl) propenoate was refluxed ln 5 ml of dioxan until TLC analysis indicated complete consumption o~ starting material (3 hrs). The crude pro~
duct was chromatographed on silica gel ~sing ethyl acetate/hexane mixtures as eluent. 0.009 g (24 %) of the above product was obtained.

~ (CDC13) 2.44 13H,S,-C-CH3), 3.15 l1H,2d,J tra~s 3Hz, 7-H), ~
3.88 ~1H,2d,J cis 5~z,J gem 17Hz,7-H~, 3.90(3H, S,-0 CH3), 4.89 (1H,2d,6-H) - 37 - ~IOE 80/S 019 ~ max (CDCl3) 17~4, 1939 cm m/e 2~0.9743 (M ), 43.0211 (base peak).
E X A M P L E 9b 0.250 g of methyl 3,3-di(acetylthio)-2-14-allylsul-phinylazetidin-2-on-l-yl) propenoate and 80.2 ~l of boron trifluoride diethyl etherate were refluxed in 12 ml of dioxan for 40 minutes, when TLC analysis indicated complete consumption of starting ma~erial. The crude product was evaporated to dryness and chromatographed on silica gel using ethyl acetate/hexane mixtures as eluent. 0.090 g ~4~ %) of the title product was obtained.
E X A M P L E 9c 0.500 g of methyl 3,3-di(acetylthio)-2-(4-allyl sulphinylazetidin-2-on-l-yl) propenoate and 0.242 g of 4-toluenesulphonic acid hydrate were heated under reflux in 25 ml of dioxan for 40 minutes, when TLC analysls indicated complete consumption of the starting material.
Purification of the crude product was carried out as described in Example 9b. 0.120 g (32 %), of the purified product was obtained.
E X A M P L E 9d The procedure described in Example 9c was carried out, substituting 0.30 ml of trifluoroacetic acid for the 0~242 g of 4-toluenesulphonic acid hydrate, and re-2~ fluxing for 2 hours. 0.064 g of purified product wasobtained (17 ~ of the theoretical yield).

Methyl 3-acetylthio-7-oxo-4-thia-l-azabic~clo ~3,2,07hept-2-ene-2-carboxylate 3o S~

~ N ~ SCOCH3 o C2CH3 . CO~CH~

~'7~
~ 38 - HOE 80~S 019 0.064 g of methyl 3-acetylthio~8-oxo-4,5-dithia-l-azabicyclo~4,2,0/oct-2-ene-2-carboxylate was dissolvea in 1 ml of deuterochloroform and 0.063 g of triphenylphos-phine added. TLC and NMR analysis indicated complete conversion of starting material to product. The crude product was chromatographed on silica gel using ethyl acetate/hexane as eluant to give 0.035 g (61 %) of puri-fied product.
o )I
(CDCl3) 2.47 (3H,S,-C-CH3), 3.15-4 r 05 ¦5H,m,J trans 2Hz, Jcis 4Hz, jgem 17 Hz, -O-CH3, 6-H), 3.85 (3H,S,-O-CH3), 5.73 (1H,2d,5-H) ~ max (CDC13) 1798, 1710 CM-l m/e 258.9970 (M ), 174.9745 ~base peak) Pivaloyloxymethyl 3,3 di(acetylthio)-2-t4-allylthlo-azetldln-2-on-l-yl) propenoate S ~ ', ~S ~
I j ¦ ~ t SCOCH3 CO C~2CO C(C~3)3 / ~SCOCH
2 2 C~2cH~co2c(cH3~3 A solution of lithium hexamethyldi~ilazide was pre-pared by the addition of 3.53 ml of a 1~6 M solution of n-butyllithium in hexane to 1.19 ml of hexamethyldi-silazane in 25 ml of dry tetrahydrofuran at -10 with stirring under argon. The solution was cooled to -7~ and added by cannula to 1.02 g of pivaloyloxymethyl 2-(4-allylthioazetidin-2-on-l-yl) acetate in 10 ml of dry tetrahydrofuran at -78 with stirring under argon.
After 5 minutes 582 ~1 of carbon disulphide was added by syringe. After 15 minutes, 1.?~ ml of aeetic anhydride was added followed by 0.74 ml of glacial acetic acid. The solution was allowed to warm to room tempe-rature and the tetrahydrofuran solvent was removed by ~'7~
39 ~ HOE 80/S 019 evaporation to leave an oily residue.
The crude product was chromatographed on silica gel using ethyl acetate/hexane mixtures as eluent. 0.755 g (49 ~) o purified product was obtained. o ~ (CDC13) 1.25 (9H,S, C(CH3)3), 2.28 (6H,S,CH3C-), 3.0-3.7 (4H,m,3-H and S-CH2-), 5.0-6.1 (6H,m,4-H and -CH=CH2 and o-CH~-) r max (C~Cl3) 1784, 1753, 1746(sh), 1720(sh) cm Pivaloyloxymethyl 3,3-di~acetylthio)-2-(4-allyl-sulphinyla2etin-2-on-l-yl) propenoate O

5 ~ S
15 1 >

~ N sC~CH3 0~ ~ S~OC~3 / SCOCH3 / ~ SCt )CH3 Co2c~co~c(c~3)3 C02CH2C02c(c~3)3 363 mg of 3-chloroperbenzoic acid in 3 ml of ethyl acetate was added portionswise to a stirred solution of 673 mg of pivaloyloxymethyl 3,3-di(acetylthlo)-2-(4-allylthioazetidin-2-on-l-yl) propenoate in lO ml of ethyl acetate. The solution was then allowed to warm to room temperature, evaporated to dryness and chromato-graphed on silica gel using ethyl acetate/hexane mixtures as eluent. The product was obtained as a mixture of R
and S sulphoxides which were partially separated during the chromatography. Total yield of product, a yellow oil, was 0.502 g ~72 ~). O
(CDCl3) 1.24 (9H,S,CMe3), 2.42 (6H,S,CH3C-), 3.0-4.0 (4H,m,3-H and S-CH2-), 5.2-61. (6H,m, 4-H and -CH=CH2 and 0-CH2-) ~ max ~CDCl3) 1791, 1750 cm 1 7~
~ 40 - HOE 80/S 019 Pivaloyloxymethyl 3-acetyl~hio~8-oxo-4,5-dithia-l-azabi-cyclo~4,2,070ct-2 ene-2-carboxylate ~S ~ _~S~ .

10N ~ SCOCH3 ~ ~ ~ SCOC~3 ~ SCOCH3 CO C~ CO CtC~H ) CO C~2co2c ( Cti 3)3 2 2 2 3 3 A solution of 82 mg of pivaloyloxymethyl 3,3-di(acet-ylthio)-2~(4-allylsulphinylazetidin-2-on~l-yl) propenoate and 32 mg of 4-toluenesulphonic acid hydrate in 10 ml of dioxan was heated rapidly to reflux and maintained under re1ux for 1 hour. The solvent was removed by evaporation and the residue chromatographed on silica gel using ethyl acetate~hexane mixtures as eluent. The product (35 mg, 54 ~ was obtained as a yellow oil.

~(CDCl3) 1.25 (9H,S,C(CH3)3), 1.61 (3H,S,-CCH3), ~ trans 3Hz, 7-H), 3.88 (lH,2d, J~is5Hz' Jgem 16Hz, 7-H), 5.87 (2H,S,-OCH2-), 4~83 (lH,2d,6-H).
~ (CDC13~ 1796, 1757 cm Pivaloyloxymethyl 3-acetylthio-7-oxo-4-thia-l-azàbicyclo-/3,~,07hept-2-ene-2-carboxylate ~S ' ~ S
> I ~S~OC~
35 o ~ SCocII3 ,~,___ N ~ 3 ~02cH2c~2ctcH3~3 C~2CH2co2c(cH3~3 - 41 - HO~ 80~S 019 To a solution of 22 mg o~ pivaloyloxymethyl 3-acet-ylthio-8-oxo-4,5-dithia-l-azabicyclo/4,2,070ct-2-ene-2-carboxylate in deuterochloroform was added 14.7 mg of triphenylphosphine.TLC analysis indicated complete conversion of the starting material and the product was shown by IR and NMR analysis to be the title com~ound.
This product was isolated by chromatography on silica gel using ethyl ace~ate/hexane mixtures as solvent. The y~eld of product was 13 mg (65 %) o S(CDC13) 1.22 (9H S -C(CH3)3) 2 47 (3H,S, CH3C-), 3.5 (1H,2d,J~ranS 2Hz, 6-H), 3.9 ~1H,2d, cis gem 17HZ~ 5.7 (1H,2d,5-H) 5.9 (2~1 S
-CH20-).
~ (CHCl3) 1801, 1750, 1719 cm 1 4-Nitrobenzyl 3, 3-di(acetylthio)-2-~4-allylthio-azetidin-2-on-l-yl)propenoate -S ~ S~
¦ ~ ¦ SCOCH3 ~ o~ ~ ~ / SCOC~13 c02C~I~ ~ No2 CC2CH2 ~ N02 X A M P L E 15a A solution of lithium hexamethyldisilazide was pre-pared by the ~ddition of 5.12 ml of a 1.6 M solution of n-butyllithium in he~ane to 1.75 ml of hexamethyldisil-azane in 25 ml of dry THF at -10 with stirring, under argon. The solution was cooled to -78 and added by cannula to 1.57 g of 4-nitrobenzyl 2-(4-allylthioazeti-din-2-on-l-yl) acetate in 12 ml of dry THF at -78, with stirring under argon. After 5 minutes 0.846 ml o carbon-disulphide was added by syringe. 1.77 ml of acetic an-hydride was then added, followed by 1.07 ml of glacial acetic acid. The solution was allowed to warm to room ~ 42 - HOE 80/S 019 temperatur and evaporated to leave an orange oil.
The crude product was chromatographed on silica gel using dichloromethane/hexane mixtures as eluent. 0.541 g (23 %) o~ pure product was obtained.
O
(CDCl3) 2.26 ~3H,S, -C-CH3), 2.38 ~3H,S, -C-CH3) 3. 00-3.72 (4H,m,3-H, S-CH2-~
5~01-6.44 ~6H ,m, HC=CH2, -O-CH2, 4-H) 7.33~8~34 (4H,m, C5H4) ~max (CDCl3) 1,85, 1742, 1716 cm ~ SCOCH3 m/e 354 (O=C-N-C ~ SH
~ COOCH2C6H4N02), 73 (S~J~
43(COCH3) (base peak) E X A M P L E 15b A solution of lithium hexamethyldisilazide was pre-pared by the addition of 8.66 ml of a 1.6 ~5 solution of n-butyllithium in hexane to 2.96 ml of hexamethyldisilazane -in 30 ml oE dry THF at -10 with stirring under argon.
The solution was cooled to -78 and added by cannula to 2.07 g of 4-nitrobenzyl 2-(4-allylthioazetidin-2-on-l-yl) acetate in 15 ml of dry THF at -78, with stirring, under argon. After S minutes 1~11 ml of carbon disulphide was added by syringe. 2.33 ml of acetic anhydxide was then added. The solution was allowed to warm to room tempera-ture and evaporated to gi~e an o~ange oil. The oil was mlxed with watex (40 ml) and chloroform ~40 ml), the organic layer separated and the aqueous layer extracted with additional chloroform (2x40 ml). The combined organic phase was dried (MgSO4) and evaporated to give an orange oil, which was used without further purification as the - starting material for Example 16b.

4-Nitrobenzyl 3,3-di(acetylthio)~2-(4-allylsulphinyl-azetidin-2-on-l-yl) propenoate 7~

- S :~ S ~
¦ SCOCH3 ~ ¦ SC~CH3 So~ ~ SCOCH3 ~ N ~ ~SCOCH3 C02CH2 ~ N02 C02CH2 ~ N2 tO E X A M P L E 16a 0.241 g of 3-chloroperbenzoic acid (81 % pure) in 5 ml of ethyl acetate was added dropwise over 20 minutes to a stirred solution of 0.S34 g of 4-nitrobenzyl 3,3-ditacetylthio-2-(4-allylthioazetidin~2-on-l-yl) propenoate in 10 ml of ethyl acetate at about -35. When rrLc analysis ~5 indicated almost complete converslon o the starting material to product, the solution was evaporated to dry-ness, slurried with dichloromethane and chromatographed on silica gel using ethyl acetate/hexane mixtures as eluent. 0.310 g (56 ~) of purified product was obtained.
~0 3 (CDC13) 2.26 (3H,S, -C-CH3), 2.42 (3~,S, -C-CH3), 3.07-3.97 t4H,m,3-H, S-CH2), 5.23-6.39 (6H,m, HC=CH2, -O-C~12-, 4-H), 5.38 (2E~,S, -O-CH2-), Z5 7.57-8.37 t4H,m, -C6H~) ~max (CDCl3) 1795, 1732 cm 1 E X A M P L E 16b 3.13 g of 3-chloroperbenzoic acid in 20 ml of ethyl acetate were added dropwise over 20 minutes to a stirred solution in 10 ml of ethyl acetate of the 4-nitrobenzyl 3,3-di(acetylthio)-2~(4-allylthioazetidin-2-on-l-yl) propenoate obtained in Example 1Sb at about -35. TLC
analysis indicated almost complete conversion o~ the starting material to product. The solution was then evaporated to dryness, slurried with dichloromethane and chromatographed on silica gel using ethyl acetate/

~'7~
- 44 - HOE 80/5 0l9 hexane mixtures as eluent 1.09 g of pure product was ob-tained. 135 % of the theoretical yield, calculated on the starting material of Example 15b.) For analytical data see Example 16a.

4-N1trobenzyl 3-acetylthio-B-oxo-4,5-dithio-1-azabicyclo /4,2,07Oct-2-ene~2-carboxylate 1. S
S~ ~ ~ S
SCOC~3 ~
N 4 SCOCH3 ~?--- N ~ CCOC~3 C 2 2 ~ No2 C2CH2 ~ ~ No2 E X A M P L E 17a 0.500 g of 4-nitrobenzyl 3,3-di(acetylthio)-2-(4-allylsulphinyl-azetidin-2-on-l-yl) propenoate and 0.192 g of toluenesulphonic acid hydrate were heated under reflux in 25 ml of dioxan with stirring, under argon for 50 minutes, when TLC analysis indicated completion of reac-tion. The crude product was evaporated to dryness and chromatographed on silica gel using ethyl acetate/hexane mixtures as eluent. 0.192 g ~46 %) of pure product was obtained.

(CDCl3) 2.37 (3H,S, -C-CH3), 3.17 (1H,2d,JtranS 3Hz, - 7-H~, 3.88 (1H,2d~JCis 5Hz~ Jgem 4.88 (1H,2d, 6-H), S.38 (2H,S, -O-CH2-) - 7.50-8.28 (4H,m, -C6H4) max (CDCl3~ 1793, 1739 cm m/e 4.119933 (M ), 43.0209 (COCH3) (base peak) E X A M P L E 17b The procedure described in Example 17a was carried out, refluxing Q.300 g of the propenoate and 75.9 ~1 of boron trifluoride diethyl etherate for 45 minutes. 0.102 g 7~
- 45 ~ HOE BO/S 019 (41 ~) of purified product was obtained.
E X A M P L E 17c The procedure described in Example 17a was carried out, using 0.200 g of the propenoate and 98 ~l of boron S trifluoride diethyl ~therate and 50 ml of water in 5 ml of dioxan, and xefluxing ~or 30 minutes. 0.087 g (54 %) of purified product was obtained.
E X A M P L E 17d The procedure described in Example 17a was carried out, refluxing 0.200 g of the propenoate, 45 ~l of stannic chloride, 50 ~l of water and 5 ml of dioxan for 60 minutes. 0.052 g (32 %) of purified product was ob-tained.

S 4-Nitrobenzyl 3-acetylthio-7-oxo-4-thia-1-aza~icyclo ~3,2,07hept-2-ene-2-carboxylate ~ 5 ~ S
~ ~ SCOC~3 0 9 ___ ~ SCOCH3 O ~~~~ ~
~ 2 ~ No2 C2 ~ ~ 2 0.186 g of 4-nitrobenzyl 3-acetylthio-8-oxo-4,5-dithia-1-azabicyclo~4,2,070ct-2-ene-carboxylate was dissolved in 1~S ml o deuterochlorofoxm and 0.118 g of triphenylphosphine was added. TLC and NMR analysis 3 indicated completion of the reaction. The crude product was chromatographed on silica gel and eluted with ethyl acetate/hexane mixtures. 0.106 g ~62 %) of pure product was obtained.
m.p. 145 (from ethyl acetate/hexane) o (CDCl3) 2.45 (3H,S, -C-CH3), 3.55 (1H,2d,JtranS 2Hz, 6-H), 3.93 (1H,2d,J i 4Hz, Jgem 17Hz, 6-H) '7~ ~

5.20 and 5.48 (2H, ABq, J 14Hz, -O-CH~-) 5.73 (1H, 2d, 5-H), 7.55-8.32 (4H,m, -C6H4) ~ max (CDCl3) 1800, 1714 cm m~e 380.0196 (M ), 43.0210 (COCH3) ~base peak) 4-Nitrobenzyl 7-oxo-3-thio-4-thia-1-azabicycl~/3,2 ,o7 heptane-2-carboxylate I ~ SCOCH3 > . ¦ ~ S
~zs~ N ~

COOCH2 ~ NO COOC~ ~ N2 1 ,~
To a stirred solution of 100 mg of 4-nitrobenzyl 3-acetylthlo-7-oxo-4-thia-1-azabicyclo~,2,O7hept-2-ene-2-carboxylate in a mixture of 2 ml of dioxan and 0~2 ml of water was added 19.6 mg of imidazole. A~ter 10 minutes the reaction mixture was diluted with 5 ml of lM a~ueous acid solutlon and extracted with dichloromethane (2x5 ml).
The organic extracts were combined and backwashed with water (2x5 ml), then brine (5 ml), and finally dried and evaporated. The residue was chromatographed on silica gel, with elution by means of ethyl acetate/hexane mixtures.
Fractions containillg th~ purified product were combined and evaporated to leave an orange oil (43 mg, 48 %).

~ (CDC13) 3.5 (1H~2d~Jtrans 2Hz~ Jgem 4.1~ (1H,2d,JCis 4Hz, 6-H), 5.4 (2H,S, -CH2-), 5.5 (lH,S, ~CH)~ 5.98 (lH,2d, 5-H), 7.5-8.5 (4H,m, -C6H4);
(CDC13) 1800, 1754 cm m/e 338.0003 (M ~, 262~M-CS2), 234(M-CS2-CO), 136(C!~2~ ~ ~12)' 1~6 (1l ~ 7~ 2)~ 54(~"-''' n~

7~

47 - HOE, 80/S 019 Methyl 7-oxo-3-thio-4-thia-1-azabicyclo/3,2,07heptane~
2-carboxylate 0~ ~
C2 3 CO~CH3 ~) To a stirred solution of 120 mg of methyl 3-acetyl-thio-7-oxo-4-thia-1-azabicy~o~3,2,07hept-2 ene-2-carboxy-late in a mixture of 2 ml o dioxan and 0~2 ml of water was added 32 mg of imidazole. After 15 minutes the reaction mixture was diluted with 5 ml of a 1 M aqueous citxic acid solutio~ and extracted with ethyl acetate (2x5ml). The ethyl acetate extracts were evaporated to dryness, the residue slurried with chloroform and washed with water (2x5 ml). The chloroform layers were dried and evaporated to leave a yellow oil (83 mg, 83 %).

J (CDC13) 3-4 (1H'2d'Jtrans 2Hz~ Jg~m 3 8 ~3H S, -CH3), 3.9 (1H,2d,JCis 5.3 (1H,S, 2-H), 5.84 (1H,2d, 5-H).
~ (CDCl3) 1798, 1750 cm m/e 216.987S (M ), 141 ( n o~ CHCOOCH3 3o H
~S
116(~ ~ S)., 113 ~CH2CHNC~COOCH3~, 76 (CS2~, 54 ~k~se pe~X).

7~

_ ~B - HOE 80/S 019 ` EXAMPLE 21 4-Allylthio-3-ethylazetidinone To a solution of 1.06 g of sodium hydroxide in 14 ml of water was added 2.82 ml of allylthiol. The solution ~as stirred under an argon atmosphere for 10 minutes.
To this solution was added, over a period of 1 minute, a solution of 3.79 g of ethyl acetoxyazetidinone in 6 ml of water. After about 15 minutes, when the starting material had been consumed, the solution was extracted three times with dichloromethane. The combined organic extracts were back-extracted with water, then dried over magnesium culphate, evaporated in vacuo, and chromato-graphed over silica gel, eluting with ethy~ acetate/
hexane mixtures. The main product ~2.84 g) was trans 4-allylthio-3-ethylazetidinone, wh~ch contained a trace amount of the cis lsomer.
(Yield 2.84 g) maX (CDCl3) 1766 cm ~ (CDC13) 1.04 (3H, t, J7Hz) 1.75 (2H, q, J7Hz) 2.96 - 3.18 (1H, m, 3-H) 3.31 (2H, d, J7Hz) 4 ( ' ' Jtrans 5.04 - 6.46 (3~, m) 6.81 ~1H, s) ~XAMPLE 22 Methyl (~-allylthio-3-ethylazetidin-2-on-1-~l)acetate To a solution of 2.34 g of 4-allylthio-3-ethylaze-tidinone in 20 ml of redistilled dimethylformamide was added 1.37 ml of methy1 bromoacetate ~nd 4.16 g of ground potassium carbonate. The solution was stirred overnight then filtered through a pad of Hyflo, (Hyflo being a Trade Mark), poured into 75 ml of water, and extracted five times with ethyl acetate. The combined organic extracts were washed with water, dried over magnesium sulphate, and evaporated in vacuo to give the title ~ 9 - HOE 80/S 019 compound. ~Yield 3 g) ~max(CDC13) 1763, 1748 cm 1 (CDC13) 1.07 (3H, t, J7Hz) 1.77 (2H, q, 7Hz) 3.04 - 3. 36 (3H, m, 3-H~
3.24 (2H, d, J6Hz) 3.67 and 4.31 (2H, ABq, J18Hz) 4-64 (lH~ d~ Jtrans 2H~, 4-H) 4.94 - 5.40 (2H, m) 5.55 - 6.30 (lH, m) (4-Allylthio-3-ethylazetidin-2-on-l-yl)acetic acld To a solution of 3 g o Methyl-(4-allylthio-3-ethylazetldin-2-on-l-yl)acetate in 10 ml of absolute ethanol was added, at room temperature and dropwise over 5 minutes, a solution o~ 0.90 g of potassium hydroxide in a mixture of 12 ml of ethanol and 1 ml of water.
The resulting solution was then poured into 10 ml of dichloromethane~ 13 ml of 2M hydrochloric acid and ~0 ml of water were added, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane, and then the combined dichlormethane extracts were re-extracted with aqueous sodium bicarbo nate ~2.7 mol equivalents in 27 ml) and then disc`arded.
The aqueous bicarbonate layer was then layered with dichloromethane and acidi~ied to pH 1.5 with hydro-chloric acid. The aqueous ]ayer was then further extrac ted with dichloromethane. The combined organic layer was dried over magnesium sulphate and evaporated in vacuo to give the title compound as a co]ourless cry-stalline solid. (Yield 2.56 g) '7~
- S - EIO~ 80/S 019 r d (CDCl3) 1.05 (3~, t, J7Hz) 1.75 12H, q, 7Hz) 2~95 - 3.33 (3H, m, 3 - H) 3. 19 (2H, dr J6Hz) 3.65 and 4.29 (2H, ABq, Jl8Hz) 4.56 11H, d, ;r2HZ~ 4-H) 4, 90 - 5 . 33 (2H, m) S.45 - 6.19 ~2H, m) 10. 41 ~1H, s) .
1~

4-Nitroben~yl-(4-allylthio-3-ethylazetidin-2-on-1-yl) acetate To a solution of 2.5 g of (4-allylthio-3-ethylaze-tidin-2-on-l-yl)acetic acid in 8 ml of dimethylacetamide was added 0.636 g of freshly ground sodium carbonate.
After stirring for 20 minutes, 2.591 g of 4-nitrobenzyl bromide were added in one batch. After about 45 minutes, whe~ the starting material h~d been consumed, the solution was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, water and saturated brine, and then dried over magnesium sulphate, evaporated in vacuo and chromatographed on silica gel~ eluting with 2S ethyl acetate/hexane mixtures to give the title compound as a pale yellow oil. ~Yield 3.08 g) ~ maX (CDcl3) 1750 cm 1 S (CDCl3~ 1.05 (3H, t, J7Hz) 1.78 (2~1, q, J7Hz) 3.06 - 3.44 (3H, m, 3 H) 3.22 (2Hr d, J7Hz) 3.77 and 4.38 (2H, ABq, J19Hz) 4.63 (1H, d, J2Hz, 4-Y) 4~93 - 6.30 (5H,m) 5~20 (?H, s) 7.41 - 8.50 (4H, m).

'7l~

4-Nitrobenzyl-2-(4-allylthio-3-ethylazetidin-2-on-l-yl)-3,3-bis(acetylthio)propenoate To a well stirred solution of 12 g of 4-nitrobenzyl (4-allylthio-3-ethylazetidin-2-on-l-yl)acetate in 75 ml of dry tetrahydrofuran, which was cooled to -78C and held under an argon atmosphere, was added a solution of performed lithium hexamethyldisilazane (prepared by adding 45.6 ml of butyllithium to a solution of 15.6 ml of hexamethyl-disilazane in 75 ml of tetrahydxofuran cooled to -~0C ~nd then cooled to -78C). Af~er stixring for 10 minutes, 3.96 ml of carbon disulphide were added in one batch, and stirring was continued for a uxther 5 minutes. 12~8 ml of acetic anhydride were then added, and the solution was allowed to warm to room temperature.
The solution was then extracted using ethyl acetate and water. The aqueous phase was extracted again with ethyl acetate. The com~ined organic extracts were evaporated in vacuo and chromatographed ove~ silica gel, eluting with ethyl acetatethexane mixtures to give the title compound as a yellow oil. (Yield 12.19 g) (CDCl3) 1.06 (3H, t, J8Hz) 1.75 (2H, q, J8Hz) 2.28 (3H`, s) 2.39 (3H, s) 3.12 - 3.r)4 (3~l m) 3.~5 (2H, d, J7~z, 3-H) 5.06 (1H, d, Jtxans 3Hz, 4-H) 6.09 - 6.35 (5H, m) 5.41 (2H, s) 7.54 - 8.45 ~4H, m~.

4-Nitrobenzyl-2-(~-allylsulphinyl-3-ethylazetidin-2-on 1-yl)-3,3-bis(acetylthio) propenoate To a solution, cooled to -45C, of 0.94 g of 4-nitro-benzyl ~-(4-allylthio-3-ethylazetidin-2-on-l-yl)-3,3-bis-(acetylthio)propenoate in 10 ml of ethyl acetate was '7~ ~
~ 52 _ HOE 80/S 019 added portionwise a solution of 0.386 g of m-chloroper-benzoic acid in 10 ml of ethyl acetate. When the reaction was complete, the solution was diluted with ethyl ace-tate, and then washed with potassium metabisulphite, with saturated sodium bicarbonate, with water, and inally with saturated brine. The resultinq solution was dried over magnesium sulphate and evaporated in vacuo to give the title compound. (Yield 0.96 g).

~ (CDCl3) 0.84 - 1.30 t3H, m) 2.25 (3H, s) 2.39 (3~, s) 3.23 - 3.70 (3H, m) 3.24 - 3.71 (2H, m) 3.47 (2H, d, J6Hz) 4-97 (1H~ d~ Jtrans 3~Z~ 4 H) 5.15 - 6.21 ~SH, m) 5.35 (2H, s) 7.39 - 8.40 (4H, m) 4-Nitrobenzyl 7-ethyl-8-oxo-3-acetylthio-4,5-dithia-l-azabicyclo~4,207Oct-2-ene-2-carboxylate To a solution of 0.96 g of 4-nitrobenzyl 2-(4-ailyl-sulphinyl-3-ethyla~etidin-2-on-l-yl)-3,3-bis~acetyl-thio)-propenoate in 25 ml of dioxan was added 0.52 ml of ethanol and 0.44 ml of boron trifluoride diethyl-stherate.
The solution, which was held under a positive pressure of argon, was placed in a~ oil bath preheated to 130C, and allowed to reflux. When the sulphoxide had been consumed, the solution was cooled quckly, and was then diluted with ethyl acetate, washed with water and then with saturated brine, and was then dried, and evapora-ted in vacuo to yield the iitle compound in crude form as an orange-yellow gum. (Yield 0.90 g).

(CDCl3) 0O86 - 1.34 13H, m) 1.75 - 2.22 12H, m) _ 53 ~ HOE 80/S 019 2.36 (3H, s) 3~13 - 3.76 (1H, m. 7-H) (1 ~ d~ Jtrans z, 6 H) 5.40 (2H, s) 7.49 - 8.44 (4~, m) 4-Nitrobenzyl 6-ethy}-7-oxo-3-acetylthio-4-thia-1-aza-bicyclo/3,2,07hept-2-ene-2-carboxvlate To a solution of 0.90 g of 4-nitrobenzyl 7-ethyl-8-oxo-3-acetylthio-4~5-dithia-l-azabicyclo/4~2~o/oct-2-ene 2-carboxylate in 2 ml of dichloromethane was added, in one batch, a solution of 0.59 g o~ triphenylphosphine in 3 ml of dichloromethane. After 10 minutes, the reac tion mixture was chromatographed directly on silica gel, eluting with ethyl acetate/hexane mixtures, to give the title compound as a yellow crystalline solid.(Yield 0.2S g) 3 ~C~C13) 1.02 (3H, t, J7Hzj 1.~3 (2H, q, J7Hz) 2~40 (3H, s) 3.45 - 4.14 ~1H, mt 6-H) 5.07 and 5.39 (2H, ~Bq, J14~z) 5.65 (1H, d, Jcis 4Hz~ 5-H~
7.27 - 8.16 (4H, m).

4-Nitrobenzyl 6~ethyl-7-oxo-3-thioxo-4~thia-1-azabicyclo-/3,2,07heptane 2-carboxylate To a stirred solution of 0.25 g of 4~nitrobenzyl 6-ethyl-7-oxo-3-acetylthio-4-thia-l-a2abicyclo/3,2,07hept-2-ene 2-carboxylate in 4 ml of dioxan and 0~5 ml of water was added, in one batch, 0.046 g of imidazole. A~ter 10 minutes, the solution was diluted with 10 ml of 1M citric acid and extracted twice with dichloromethane. The com-bined organic extracts were washed with water, dried over magnesium sulphate, and evaporated in vacuo to give the title compound in a quantitative yield.

~37~
~ 54 ~ HOE 80/S 019 S (CDC13) 1.04 (3H, t, J7Hz) 1.81 (2H, q, J7Hz) 3.53-4.08 t1H, m, 6-H) 5.22-5.39 (3H, m, 2-H) 5.28 (2H, s) ( ' ' cis 7.35-8.33 (4H, m~.

41R)-Allylthio-3(S)-/1(R)-~ dimethyl- ~2-methylprop-2-yl}-sil~loxy¦ ethyl7azetidin-2-one To a stirred solution of 1.14 ml o~ allyl mercaptan and 0.4 g o sodium hydroxide in 25 ml of watex under an argon atmosphere was added a solution of 2.87 g of 4-acetoxy-3(S)-/1(R)- ¦dimethyl- ~2-methylprop-2-yl~
silyloxy3 ethyl/azetidin-2-one in 10 ml o methanol.
Atex 30 minutes, the mixture was partltioned between dichloromethane and wate~. The separated organic layer - was washed with water, was dried over magnesium sulphate~
e~aporated to dryness, and then chromatographed on 5llica gel. Elution with ethyl acetate/hexane mixtures afforded 1.8 g of the title compound as white crystals.

~max) 3 3420, 1767 cm 1 ~ (CDC13) 0.05 (6EI, s) 0.88 (9H, s) 1.20 ~3H, d, J6Hz) 2.9 - 3.2 (3H, m) 3.9 - 4.3 (lH, m, H-1') 4.84 (1H, d J3 4 2Hz, H-4) 4.~5 - 6.3 (3H, m) 7.28 (1H, broad s) EXAMPLE 31 a Methyl 2-(4-lR)-allylthio-3(S)-/1(R)-~ dimethyl- ~ 2~
methylprop-2-yl~ silyloxy~ ethyl7azetidin-2-on-1-yl~
aoetate To a stirred solution of 1~76 g of 4(R~-allylthio-3(S)-/1(R)- ~dimethyl-¦2-methylprop-2-yl}silyloxy~ethyl7 ~ ~ ~'7~
- Ss ; HOE 80/S 019 azetidin-2-one in 60 ml of dry dimethylformamid~ was added 3.52 g of finely ground potassium carbonate and o.6 ml of methyl bromoacetate. After 18 hours, the mixture was filtered and then partitioned between ethyl acetate and water. The separated organic layer was washed with water and dried over magnesium sulphate.
Evaporation in vacuo afforded a crude product which was chromatographed on silica gel. Elution with ethyl acetate/hexane mixtures afforded 1. 56 g of the title compound as a pale yellow oil.

CDCl3 1753, 1768 cm (CDCl3) 0.06 (6H, s~
0.86 (9~, s) 1.23 (3H, d J6.5Hz) 3.2 (3H, m) 3.70 ~3H, s) 3-6 - 4.3 13H, m) 4.87 (lH, d J 2Hz, H-4) 4.9 - 6.3 (3H, m)-EXAMPLE 31 b Methyl 2-(4(S)-allylthio-31S)-~1(R)-dimethyl~2-methylprop-2-yl 7 silyloxy ethyl/azetidin-2-on-l-yl)acetate This compound was prepared analogously to its 4(R) isomer, as described in Example 31 a, using the corres-ponding 4(S) starting material.
EX~MPLE 32 ~
4-Nitrobenzyl 2-(4(R)-allylthio-3(S)-/1~R)- ~dimethyl-

12-methylprop-2-yl} silyloxy }ethyl7a`zetidin-2-on-l-yl) acetate To a stirred solution of 3.04 g of potassium hydroxide in 80 ml of 95 % ethanol was added a solution of 16 g of methyl 2-(4(R)-allylthio-3(S)-/1(R)-~dimethyl-~2-methyl prop-2-yl~ sil yloxy3 ethyl/azetidin-2-on-l-yl)acetate.
After 10 minutes, the mixture ~-as evaporated to about 1/5 o its original volumei 2 ml of dimethyl acetamide were added, followed by a solution of 9.25 g of 4-nitro-benzyl bromide in 50 ml of dimethylacetamide. After 1 hourJ

_ 56 HOE 80/S 019 the mixture was partitioned between 0.01M HCl and ethyl acetate. The separated organic layers were washed with 0.01M HCl, with water, with cold, saturated sodium bi-carbonate, and with brine, and were then dried and evaporated. The resulting crude product was chromato-graphed over silica gel; elution with ethyl acetate/hexane mixtures afforded 19.5 g of the title compound as an oil.

~ maX(CDCl3) 1755, 1769 cm ~ (CDCl3) 0.07 and 0.09 (6H, two singlets) 0.88 (9H, s) 1.25 ~3H, d J6Hz) 3.2 (3H, m) 3.7 - 4.5 (3H, m) 4.95 (1H, d J2Hz, H-4) 4.9 - 6.3 tSH, m) 7.5 - 8.35 (4H, m) EXAMPLE 32 b 4-Nitrobenzyl-2-(4(S)-allylthio-3(S)-/1(R)- ~dimethyl-l 2-methylprop-2-yl} silyloxy ~ ethyl7azetidin-2-on-l-yl) acetate This compound was prepared analogously to its 4(R) isomer, as described in Example 32 a, using the corres-ponding 4(S) starting material.
EXAMPLE 33 a 4-Nitro~enzyl 3,3-bis(acetylthio)-2-l4(S)-allylthio-/l(R) dimethyl- { 2-methylprop-2-yl~ silyloxy kthyl7 azetidin-2-on-l-yl) propenoate A solution of lithium hexamethyldisilazide was prepared by the addition of n-butyllithium in hexane (2.79 ml of a 1.6M solution) to 0.982 ml of hexamethyl-disilazane in 8 ml of dry tetrahydrofuran at -10C, ~hile stirring under argon. The solution was cooled to -78C and added by cannula to a solution of 0.98 g of 4-nitroben~yl 2-(4(R)-allylthio-3(S)-~1(R)-~dimethyl-~2-methylprop-2-yl~silyloxy~ethyl7azetidin-2-on-l-yl)aceta-te in 8 ml of dry tetrahydro~uran at 78C, with stirring under argon. After 5 minutes, 0.357 ml of carbon disulphide was ~7~

_ ~7 _ HOE 80/S 019 added by styringe, followed by 0~748 ml of acetic anhy-drids. The mixtures was allowed to warm to room tempera-ture, and 30 ml of dichloromethane was added, followed by 30 ml of water. The o~ganic layer was separated, and the aqueous layer was extracted with further dichloro-methane. The combined organic extracts were washed with 1M HCl, with water, and with a 12 ~ sodium chloride solution, and were then dried over magnesium sulphate and evaporated to give 1.38 g of an orange oil. 1.21 g of this crude product was chromatographed on silica gel using ethyl acetate/hexane mixtures as eluent to give 0.800 g of the title compound in purified form~

~(CDCl3) 0~10 (6H, s) 0.88 ~9H, s) 1.35 (3H, d, J7Hz) 2.24 (3H, s) 2.37 (3H, s) 3.15 - 3.64 (3H, m, 3-H) 3.30 (2H, d, J7Hz~
4.00 - 4.46 (1~, m) 4.91 - 6.21 (6H, m) 5.30 (2H, s) 7.40 - 8.36 (4H, m).
EX~MPLE 33 b 4-Nitroben2yl 3,3-di(acetylthio)-2-((3S, 4R)-4-allyl-thio-~l~R)-~dimethyl-{2-methylprop-2-yl~silyloxy3ethyl7azetidin-2-on-1-yl) propenoate The above compound was prepared analogously to its 4~S) isomer, as described in Example 33 a, using the corresponding 4(R) starting material.

maX(cDcl3) 1778, 1745 cm ~ (C~Cl3) 0.06 (6H, s) 0.85 (9H, s) 1.26 (3H, d, J6Hz) 2.25 (3H, s) 2.35 (3H, s) '7~
~ 58 _ ~OE 80/S 019 3.11 - 3.52 (3H, m, 3-H) 3.35 (2H, d, J6Hz) 4.14 - 4.39 (1H, m) 4.95 - 6.30 (6H, m) 5.35 (2H, s) 5.56 (1H, d, J3Hz, 4-H~
7.44 - 8.38 (4H, m).
EX~MPLE 34 a 4-Nitrobenzyl 3,3-di(acetylthio)-2-((3S,4S)4-allylsul-phinyl-3-/llR)-~dimethyl-l2-methylprop-2-yl~si ethyl7azetidin-2-on-l-yl)propenoate 0~080 g of 3-chloroperbenzoic acid in 2 ml of ethyl acetate was aaded dropwise over 3 minutes ~o a stirred solution of Q.200 g of 4-nitrobenzyl 3,3-di(acetylthio)-2-~3S,4S)4-allylthio-3-/1(R)-Ldim~thyl- ~-methylp.rop-2-yl~silyloxy~ethyl/azetidin-2~on-1-yl propenoate in 3 ml of eth~l acetate at 10 - 35C. The organLc solution was washed wlth a potassium metabisulphite solution (0.5 y in 5 ml), with saturated sodium bicarbonate solu-tion and then with 12 ~ brine. The resulting organicsolution was then dried over magnesium sulphate and evaporated to ~ive a pale yellow foam. 0.2Q5 g of the title compound was obtained.

~CDC13) 0.12 (6H, s) Q.90 (9H, s) l~20 - 1.60 (3H, m) 2.26 (3H, s) 2.40 (3H, s) 3.39 - 4.01 (3H, m, 3-H) 3.57 (2H, d, J6Hz) 4.37 - 4.85 (lH, m) 5.15 and 5019 (1H~ 2d~ J4B,3B6HZ' 5.22 - 6.28 (5~, m) 5.36 (2H, s~
7.45 - 8.4S (4H, m~.

_ 59 _ HOE 30/S 01g EX~MPLE 34 b 4-Nitrobenzyl 3,3-di(acetylthio)-2-((3S,4R)4-allylsul-phinyl-3-/1(R)-Idimethyl-l2-methylprop-2-}silyloxy}ethyl7 azetidin-2-on-1-yl)propenoate The above compound was prepared analogously to its 4~S) isomer, as described in Example 34 a, using the corresponding 4(R) starting material.
EXAMPLE 35 a 4-Nitrobenzyl 6(S), 3-acetylthio-7(S)-/ltR)-hydroxyethyl7-8-oxo-4,5-dithia-1-azabicyclo /4,2,O7Oct-2-en-2-carboxylate To a solution o 0.205 g of 4-nitrobenzyl 3,3-di-(acetylthio~-2-([3S,4S)-4-allylsulphinyl-3-/1(R)-[dimethyl-~ 2-methylprop-2-yl~ silylo~y}ethyl7-2-a2etidin-2-on-1-yl) propenoate in 5 ml of dioxan was added 27 ~1 of water ~ollowed by 61 ~1 of boron trifluoride diethyletherate.
The mixture was then heated rapldly to reflux with s~irring and under an ar~on atmosphere for 40 minutes. 5 ml of water were added to the reaction mixture, which was then extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulphate, eva-porated, and chromatographed on silica gel using ethyl acetate/hexane mixtures as eluant. 0.047 g of the title compound was obtained.

~ max (CD~13) 1783, 1739 cm 1 3 ~CDC13) 1.45 13H, d, J6Hz) 2.23 (IH, s) 2.38 (3H, s) 3.97 (lH, 2d, J6Hz, J10Hz, 7-H) 4.22 - 4.65 ~lH, m) 5.20 - lH, d, 6-H) 5.41 (2H, s) 7.46 - 8.46 (4H, m) EXP~lPLE 35 b 4-Nitrobenzyl 6(R), 3-acetylthio-7(S)- 1~R)-h~ydroxyethyl-6-oxo-4,5-dithia-1-a~abicyclo/4,2,O7Oct-2-en-2-carboxylate This compound was prepared analogously to its 6(S) isomer, as described in Example 35 b, using the corres-~ 60 ~ HOE 80/S 019ponding 4(R) starting material (described in Example 34b).
EXAMPI.E 36 ~
4-Nitrobenzyl 3-acetylthio-6(S)-/1(R)-hydroxy ethyl7-7-oxo-4-thia-l-azabicyclo/3,2,07hept-2-ene-2-carboxylate 0.121 g of 4-nitrobenzyl 6(S), 3-acetylthio-7(S)-(R)-hydroxyethyl7-8-oxo-4,5-dithia-l-azabicycloL4,2,07 oct-2-en-2-carboxylate was dissolved in 3 ml of dentero-chloroform 2nd 0.070 g of triphenylphosphine was added, with stirring at room temperature. After 5 minutes, the crude product was chromatographed on silica gel using dichloromethane/hexane and ethyl acetate/dichloromethane mixtures as eluent. 0.039 g of a mixture of the SR and 5S
isomers of the title compound were obtained.
~(CDCl3) 1.37 and 1.48 (3H, 2d, J7Hz) 2.00 (1H, s) 2.46 (3H, s) 3.52 ~ 4.12 (1H, m, 6-H) 4.12 - 4.57 (lH, m) 5.07 - 5.69 (2H, m) 5.75 and 5.81 (1H, 2d, J5~ 6B 2Hz 5a,6B 5Hz, 5-H) 7.~4 - 8.~6 ~4H, m, -C6H4) EXAMPLE 36 b 4~Nitrobenzyl 3-acetylthio-6(R)-/1(R)-hydroxyethyl7-7-oxo-4-thia-l-azabicyclo/3,2,07hept-2-ene-2-carboxylate This compound was prepared analogously to its 6(S) isomer, as described in Example 36 a using the corresponding 6(R) starting material (described in Example 35 b). A mixture of the 5(R) and 5(S) isomers was obtained.
EXAMPLE 37 a 4-Nitrobenzyl 6(S)-(1(R)-hydroxyethyl)-7-oxo-3-thio-4-thia-l-azabicyclo/3,2,07heptane-2-carboxylic acid To a stirred solution of 0.039 g of 4-nitrobenzyl 3-acetylthio-6(S)-(1(R)-hydroxyethyl)-7-oxo-4-thia-l-azabicyclo/3,2,0/hept-2-en-2-carboxylate in a mixture '7~
- 61 ~ HOE 80/S 019 o~ 1.S ml of dioxan and 0.15 ml of water was added 0.0069 g of imidazole at room temperature. Ater 5 minutes the mixture was diluted with 3 ml of 1~ hydrochloric acid and 5 ml of water, and then extracted into ethyl ace~ate. The combined organic extracts were washed with water ~nd dried over magnesium sulphate. The resulting solution was evaporated to give a mixture of the 5R and SS isomers of the title compound as a foam.

~maX(CDCl3) 1790, 1753 cm 1 (CDC13) 1.10 - 1.61 (3H, m) 2.28 ~1H, s) 3.57 - 4.05 11EI, m, 6-H~
4.14 - 4.52 (IH, m) 1 S~35 (2H, s) 5.41 11H, s, 2-H) 5.89 and 6.06 (1~, 2d~ J5~, J5B 6B4R~, 5-H) 7.35 - 8.40 (4H, m, -C6H~) EXAMPIE 37 b 4~Nitrobenzyl 6(R)-/1(R)-hydroxyethyl/-7-oxo-3-thio-4-thia-l-azabicyclo/3,2,07heptane 2-carboxylic acid This compound was prepared analogous to its 6~S) isomer, as described in Example 37 a, using the corres-ponding 6(R) starting materiai (described in Example36 b). A mixture of the 5(R) and 5(S) isomers was obtained.

4-Nitrobenzyl 6-ethyl-3-ethylthio-7-oxo-4-thia-azabi-cyclo /3,2,07hept-2-ene 2-carboxylate To a solution of 0.5 g of 4-nitrobenzyl 6-ethyl-7-oxo-3-thio-4-thia-l-azabicyclo/3,2,07he~tane 2-carboxy-late in 2 ~l of dioxane was added, in one batch, 0.57 ml of N-ethyldiisopropylamine, then 0.10 ml of bromomethane.
When the reaction was complete, the solution was evapora-ted in vacuo and chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures to give the title product. (Yield 0.300 g) ~'7~

~m X(CDCl3) 1789 cm (CDCl3) 0.85 - 1.49 (6H, m) 1.77 - 2.26 (4H, m) 3.58 - 4.12 (1H, m, 6-H) 5.16 and 5.50 (2H, ABq, J14Hz) 5.41 and 5.77 ~1H~ 2d~ Jtrans2HZ~ Jcis 5Hz, 5-H) 7.41 - 8.31 (4H, m).
EXAMPLE 3g ~-Nitrobenzyl 3-ethylthio-6(S)-/1(R)hydroxyethyl/-7-oxo-4-thia-l-azabicyclo/3,2,07hept-2-en-2-carboxylate To 0.200 ml of diisopropylamine was added to 0.426 g of 4-nitrobenzyl 6(S)- ~ (R)-hydroxyethyl7-7-oxo-3-thio-~-thia-l-azabicyclo/3,2,0/hept~ne-2-carboxylate in ~ry tetrahydrofuran with stirring. 0.2S2 ml of iodo-ethane was then added and stirring was continued for 16 hours at room temperature. The reaction mixture was then evaporated to dryness and chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures, to give the title product as a mixture of SR and 5S isomers.

3 ICDCl3) 1.38 (3H, d J6Hz) 1.39 (3H, t) 2.02 (1H, s) 2.97 (2~, q) 3.64 - 3.81 (1H, m, 6-H) 3.55 ~ 4.52 (1H, m) 5.15 and 5.48 ~2H, ABq) 5.64 (lH, d J1Hz, 5-H) 7.48 - 8.33 (4H, ABq).

4-Nitrobenzyl 3-ethylthio-7-oxo-4-thia-l-azabicyclo-f3,2,07hept-2-ene 2-carboxylate To a solution of 0.5 g of 4-Nitrobenzyl 7-oxo-3-thio-4-thia-l-azabicyclo/3,2,07heptane 2-carboxylic acid in 2 ml of dioxane and 0.25 ml of water was added, in one batch, 0.57 ml of N-ethyldiisopropylamine and then 0.11 ml of bromoethane. When th~ reaction was com-~ 63 ~ HOE 80/S 019 plete the solution was evaporated in v~cuo and chromato- ;
graphed on silica gel, eluting with ethyl acetate/
hexane mixtures, to give 0.19 g of the title compound ~max(CDC13) 1791 cm ~iCDCl3) 1.25 (3H, t, J7Hz) 3-45 ~1H, 2d, Jtrans2~z) 3.86 (lH, 2d, Jcis4Hz, J~em16H2) 4.08 (2H, q, J7Hz) 5.13 and 5.43 (2H, d, J14H2) 5.66 (1H, 2d) 7.37 - 8.22 (4H, m).

Claims (3)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the formula I

I

wherein R is an esterifying group, R1 is lower alkyl or phenyl, and R2 is hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxy-alkyl, lower acyloxyalkyl or tri-lower alkylsilyloxyalkyl, in which a compound of the formula is reacted with a tervalent phosphorous compound of the formula wherein R6, R7 and R8 are phenyl, lower alkyl, lower alkoxy or di-lower alkyl amino each.

2. A process as claimed in claim 1 wherein R6, R7 and R8 are phenyl.

3. A compound of the formula I as defined in claim 1, whenever obtained according to a process as claimed in claim 1 or claim 2 or by an obvious chemical equivalent thereof.