NZ204537A - 2,4-substituted azetidin-2-ones - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £04537 Priority Dstfc{s}:. Af.'£77.....

Ccrnplote Spcoification Fi\$d:^?.'t^'£lt Cte; 9°??*??. A.... . .3.P. MAR. 1984 3 plication Date: ; p O. Journal No: l?FM.

IPO 204537 Under the provisions of Regulation 23 (I) the Specification has been ante-datedj to ae-MsL i9 si NEW ZEALAND Divided from No. 19 6902 PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION 3-LACTAM COMPOUNDS, THEIR PREPARATION AND USE X/ We, BEECHAM GROUP p.I.e., a British company, of Beecham House, Great West Road, Brentford, Middlesex, England, hereby declare the invention for which X / we pray that a patent may be granted tojaME/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by la) 20453 7 - la - ^-Lactam Compounds, their Preparation and Use This invention relates to B-lactam compounds and in particular to a class of 2,4-substituted azetidin-2-ones useful as intermediates in the preparation of 6-alkylidene penems; the penems having antibacterial and ^-lactamase inhibitory properties.

Our New Zealand Patent Specification No. 196,902 discloses a class of 6-alkylidene penems of formula (II) R" R C O -S\ / R3 (II) -N— X co2h 2 045 3 7 and pharmaceutical^ acceptable salts and in vivo 1 2 hydrolysable esters thereof, wherein R and R are the same or different and each represents hydrogen, or a hydrocarbon or heterocyclic group optionally substituted 3 with a functional group; and R represents hydrogen or an organic group. 1 2 Suitably R and R are independently hydrogen or a hydrocarbon group, especially alkyl or phenyl. Preferably one of R^" and R^ is hydrogen. 1 2 Preferably one of R and R is methyl, ethyl or phenyl. 3 Suitably R represents hydrogen or an organic group linked through a sulphur or carbon atom. For 3 example R may represent hydrogen or a group of formula 3 ci 3 R or SR where R is an optional substituted 15 hydrocarbon or heterocylic group. Preferably, R"* represents hydrogen, optionally substituted alkyl or optionally substituted C^_alkylthio, wherein the substituent is hydroxy, alkoxy, alkanoyloxy, halogen, mercapto, C-^_g alkylthio, heterocyclicthio, 20 amino, mono- or dialkylamino, alkanoylamino, carboxy, or alkoxycarbonyl.

Pharmaceutically acceptable in vivo hydrolysable esters are those esters which hydrolyse in the human body to produce the parent acid or its salt. Such 25 esters may be identified by administration to a test animal such as a rat or a mouse by intravenous administration and thereafter examining the test animal's body fluids for the presence of the compound of the formula (II) or its salt. / / 2 045 3 7 Suitable ester groups of this type include those of part formulae (a), (b) and (c): A1 - 1 2 C02CH-0.C0.A (a) a4 3 y co2-aj-n^ 5 (b) A ^C02CH2-0A6 (c) wherein A"'" is hydrogen, methyl, or phenyl, A^ is alkyl, C1_6 alkoxy or phenyl; or A1 and A2 together form a 1,2-phenylene group optionally substituted by one or two methoxy groups; A represents alkylene optionally substituted with a methyl or ethyl group- A ^ 6 A and A independently represent ^ alkyl; A represents alkyl. Examples of suitable in vivo hydrolysable ester groups include acetoxymethyl, pivaloyloxymethyl, a-acetoxyethyl, a-acetoxybenzyl, a-pivaloyloxyethyl, ethoxycarbonyloxymethyl, a-ethoxy-carbonyloxyethyl, dimethylaminomethyl, diethylamino-methyl, diethylaminoethyl, phthalidyl and dimethoxy-phthalidyl groups.

Suitable pharmaceutically acceptable salts of the 3-carboxylic acid group of the compound of formula (II) include metal salts, eg aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis-(2- 2045 3 7 _ 4 - hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylamine , N,N—dibenzylethylenediamine, 1-ephenamine, N-ethylpiperidine, N-benzyl-g-phenethyl-amine, dehydroabetiylamine, N,N'-bisdehydroabiety1-ethylenediamine, or bases of the pyridine type such as pyridine, collidine or quinoline, or other amines which have been used to form salts with known penicillins.

In formula (II) , suitable C, c alkyl groups 12. for R and R include methyl, ethyl, n— and iso—propyl, n-, iso, sec- and tert-butyl. 1 ? Preferably one of R and R is hydrogen and the other is methyl Suitable groups for R"^ include hydrogen, or methyl, ethyl, propyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, hydroxymethyl, methoxymethyl, ethoxymethyl, acetoxymethyl, 1-, or 2-acetoxyethyl, aminomethyl, 2-aminoethyl, acetamidomethyl, 2-acetamidoethyl, carboxy-methyl, hydroxymethylthio, 2-hydroxyethylthio, methoxy-methylthio, 2-methoxyethylthio, acetoxymethylthio, aminomethylthio, 2-aminoethylthio, acetamidomethylthio, 2-acetamidoethylthio, carboxymethylthio, or pyridylthio. 3 Particular groups for R are hydrogen, ammo-methyl, aminoethyl, methylthio, ethylthio, 2-aminoethylthio, 2-hydroxyethylthio, methyl, ethyl, acetamidoethyl and pyridylthio.

Specific compounds of formula II include the following: 204537 6-(Z)-ethylidene-2-ethylthiopenem-3-carboxylic acid; 6-(E)-ethylidene-2-ethylthiopenem-3-carboxylic acid; 6-(Z)-ethylidenepenem-3-carboxylic acid; 6-(Z)-ethylidene-2-n-propylpenem-3-carboxylic acid; 2-(2-acetamidoethylthio)-6-ethylidenepenem-3-carboxylic acid; 6-(Z)-ethylidene-2-inethylpenem-3-carboxylic acid; 6-ethylidene-2-(2-pyridylthio)penem-3-carboxylic acid; 2-(2-aminoethylthio)-6-ethylidenepenem-3-carboxylic acid 6-(Z)-benzylidene-2-ethylthiopenem-3-carboxylic acid; 2-ethylthio-6-isopropylidenepenem-3-carboxylic acid.

The compounds of formula (II) may exist in two optically active forms. It is believed that the more active form is that of structure (Ila): The present invention provides a compound of formula (I): R 1 (Ila) X / NH (I) 0 - 6 204537, wherein R1 represents hydrogen, or a hydrocarbon or heterocyclic group optionally substituted with a 1 0 functional group; X is a leaving group and R represents methyl or benzyl.

Suitably R"'" is hydrogen or a hydrocarbon group, especially alkyl or phenyl. Preferably R"*" is methyl, ethyl or phenyl.

Suitable groups for the leaving group X include halogen; a group of formula -0-S09~(0) -R^ 9 9 or -O-CO- (O) -R wherein n is zero or 1 and R is aryl n or C, alkyl optionally substituted with aryl; and . 10 a group of formula -OPO(OR )^ wherein R is alkyl or aryl. 9 Preferred groups of formula -0C0(0)nR are those wherein n is zero and R^ is C. , alkyl, in particular acetoxy. i.

In particular a compound of formula (I) is selected from: (3RS, 4RS)-3[1-(SR)-t^butyldiphenylsilyloxyethyl]-4-methy1sulphonylazetidin-2-one; (3RS, 4SR)-3 11-(RS)-t-butyldiphenylsilyloxyethy1J 4-methylsulphonylazetidin-2-one; (3RS, 4RS)-3-[1-(SR)-acetoxyethy1]-4-methy1sulphonyl-azetidin-2-one; (3RS, 4RS) and (3RS, 4SR)-3-t-Butyldiphenylsilyloxy-methy1-4-methylsulphonylazetidin-2-one; 204537. (3RS, 4SR)—3—11—(RS)-acetoxyethy1]-4-methylsulphony1-azetidin-2-one; (3RS , 4RS) -3- [ 1- (RS) -acetoxy-l-phenylrnethy 1 ] -4-methylsulphonylazetidine-2-one.

The compounds of formula (I) are useful as intermediates in the preparation of the compounds of formula (II).

The compounds of formula (II) may be prepared by dehydration of a compound of formula (III): R x /0h r2/CV- (III) 0 -N C02K x 12 3 wherein R , R and R are as defined with respect to formula (II) above and Rx represents hydrogen, or a carboxyl-blocking group, and thereafter if necessary carrying out one or more of the following steps: i) removal of any carboxyl blocking group R ; ii) converting the product to a pharmaceutically acceptable salt or in vivo hydrolysable ester group. 204537 Suitable carboxyl-blocking derivatives for the group -C02RX in formula (III) include salts, ester, and anhydride derivatives of the carboxylic acid. The derivative is one which may readily be cleaved at a 5 later stage of the reaction. The salts need not be pharmaceutically acceptable. Suitable salts include inorganic salts, for example metal salts such as silver or mercuric salt, or alkali metal salts such as the lithium or sodium salt, tertiary amine salts, 10 such as those with tri-lower-alkylamines, N-ethyl- piperidine, dimethylpiperazine. A preferred salt is with triethylamine.

Suitable ester-forming carboxyl-blocking groups are those which may be removed under conventional con-15 ditions. Such groups for R include benzyl, p-methoxy- benzyl, 2,4,6-trimethylbenzyl, 3,5-di-t-butyl-4-hydroxybenzyl, benzoylmethyl, p-nitrobenzyl, 4-pyridyl-methyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, t-butyl, t-amyl, diphenylmethyl, triphenylmethyl, adamantyl , 2-benzyloxypheny1, 4-methylthiopheny1, tetra- hydrofur-2-yl, tetrahydropyran-2-y1, pentachloropheny1, p-toluenesulphonylethy1, methoxymethy1, a silyl, stannyl or phosphorus-containing group, an oxime radical of formula -N=CHR° where R° is aryl or hetero-25 cyclic, or an in vivo hydrolysable ester radical such as defined above.

The carboxyl group may be regenerated from any of the above esters by usual methods appropriate to y the particular R group, for example, acid - and base - 204537 catalysed hydrolysis, or by enzymically - catalysed hydrolysis, or by hydrogenation. The hydrolysis must of course be carried out under conditions to which the groups on the rest of the molecule are stable.

When it is desired to produce a compound of formula (II) in the form of a free acid or salt by the process of this invention, a compound of formula (III) is generally employed wherein Rx is a carboxyl-blocking group. For the preparation of a compound of formula (II) in the form of a pharmaceutically acceptable ester, it is convenient to employ a compound of formula (III) wherein Rx represents the desired ester group.

The dehydration of the compounds of formula (III) may be effected with a compound of formula (IV): alkyl optionally substituted with aryl; and a compound of formula (V): r4c>2c-n=n-co2r5 (iv) wherein R4 and R5 are independently aryl, or c1_g P (0)aR6 (0)bR7 (0)CR8 (V) wherein a, b and c are independently O or 1, and R , R^ and R® are independently aryl or C^_g alkyl optionally substituted with aryl. 204537 In the compounds of the formula (IV) R^ and R are preferably selected from methyl, ethyl, propyl, butyl, phenyl and benzyl, the ethyl and t-butyl groups being preferred. Thus a preferred compound of formula (IV) is diethyl azodicarboxylate. 4 5 It is often convenient that R and R represent the same group.

Preferred compounds of the formula (V) include triarylphosphines and trialkylphosphites. Preferred fi 7 8 groups R , R and R include methyl, ethyl, n-propyl, n-butyl, benzyl, phenyl and methoxyphenyl. Conveniently, 6 7 R R , R and R represent the same group. A particularly preferred compound of the formula (V) is triphenyl-phosphine.

Generally, approximately two equivalents of the compounds of the formulae (IV) and (V) are used per mole of compound (III).

The elimination reaction is generally carried out at a non-extreme temperature, such as -20 to +100°C. We have found it .convenient to begin the reaction at a depressed temperature, such as 0°C, and then to allow the temperature to rise to about room temperature.

The reaction is performed in an inert aprotic organic solvent. Suitable solvents include tetra-hydrofuran, dioxane, ethyl acetate, benzene and the like.

Alternatively, the dehydration process may be carried out by converting compound (III) into a compound of formula (VI): 20453 - li - x RV I 3 •c /s\ (vi) R"' 3-' v o ^ N Nco2rx and eliminating the elements of a compound of formula 12 3 x H-X therefrom, wherein R , R , R and R are as defined with respect to formula (III) above, and X is as defined in relation to formula (I).

The compounds of formula (VI) may be prepared from the compounds of formula (III) by replacing the hydroxy group by a group X. Alternatively the group X can be introduced into the molecule at an earlier stage in the synthesis of the penem nucleus. In particular 9 9 the groups -OSO„(O) R and -OCO(O) R can be introduced 2 n n at the beginning of, or at any stage during, the synthesis of the penem. In each case, the group X is introduced by replacing a hydroxy1 group. One particular novel intermediate useful for this purpose 15 is a compound of formula (I).

The elimination of the elements of a compound of the formula H-X is most conveniently brought about by treatment of a compound of the formula (VI) with a base in an aprotic medium. The base employed will be 20 a base of low nucleophilicity so that in general primary and secondary amines will not be suitable. Suitable bases include powdered inorganic bases such as alkali metal carbonates, bicarbonates or hydroxides, for example powdered potassium carbonate, or hydrides or 25 1,8-diazabicyclo [5.4.O]undec-7-ene. Suitable solvents for use in this reaction include dimethylformamide, 20453 hexamethylphosphoramide, dichloromethane, tetrahydrofuran and the like.

The elimination may be effected at a non-extreme temperature such as -20 to +70°C, for example +10 to +25°C. The reaction may be conveniently effected at ambient temperature.

The compounds of formula (II) may also be prepared by a process which comprises reacting a sulphoxide of formula (VIII): .1 R - (VIII) wherein R 2 x 13 R and R are as defined above and R represents an organic radical different to the group 3 R ; with a thiol of formula (IX) or a reactive derivative thereof: R - SH (IX) and thereafter if necessary carrying out one or more of the following steps: ,x i) removal of any carboxyl blocking group R ii) converting the product to a pharmaceutically acceptable salt or in vivo hydrolysable ester group. 16 V 6- 2> The process may be carried out in any inert solvent such as N,N-dimethylformamide (DMF), tetra-hydrofuran (THF), dioxane, hexamethylphosphoramide (HMPA) or glyme.' The solvent DMF is preferred. A loyr temperature is preferred, suitably below 0°C, preferably below -20°C especially from about -30°C to about -70°C.

When the thiol compound of formula (IX) itself is employed, the reaction is generally carried out in the presence of a base, although this is not essential. Examples of suitable bases include sodium hydride, potassium hydride, sodium amide, potassium amide, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide, potassium butoxide, triethylamine, and tripropylamine. Advantageously, the base is used in an amount of at least 0.9 equivalent, preferably 1.0 to 1.2 equivalents, per mole of the thiol compound.

Instead of using the base in the reaction, a reactive derivative of the thiol compound of formula (IX) may be used. Preferably the reactive derivative is a salt of the thiol (IX), in particular a salt with an alkali metal, preferably sodium or potassium.

The amount of the thiol compound of formula (IX) or its reactive derivative is not critical. Generally, however, it is used in an amount of at least 1.0 mole, preferably 1.1 to 1.5 moles, per mole of the compound of formula (VIII).

Jyuu i 16 JUiS 1983 RECEIVED^ 2 045 3 Compounds of formula (VIII) may be prepared by S-oxidation of a compound of formula (X) : R S-R 13 (X) wherein R 2 13 x R , R and R are as defined with respect to formula (VIII) above; with a mild oxidisincr agent.

Suitable mild oxidising agents include perbenzoic acid, hydrogen peroxide, selenium dioxide or sodium metaperiodate. Substituted perbenzoic acids such as m-chloroperbenzoic acid are most preferred.

The compounds of formula (II) also provide a pharmaceutical composition as disclosed in our New Zealand Patent Specification No. 196,902 .

The following Preparations and Examples illustrate this invention.

/ Preparation 1(a) (4R5)-3r 5-Pi"bromo-1 (l-metho:xycarbonyl-2-roethyIprop-1-enyl)-4--meth.ylthioazetid±n-2-one Br H (1) COgMe Br SMe Br- f 0 (2) COgMa A mirtnre of methyl 6^ 6-dibromopenicillana.te (JJP. Clayto^ J. Chem. Soc.. (c), 1969, 2123) (42.0 S)3 methyl iodide (42 ml) and finely powdered sodium hydroxide (5-4 g) in dry tetrahydrofuran (400 ml) was stirred at room temperature for 2.5 hours. The mixture was filtered and the filtrate concentrated. The resulting solution was diluted with ethyl acetate (1 litre) and washed with "brine (3 x 100 ml). The dried (MgSO^) organic layer was evaporated and the residue chromatographed on silica gel eluting with ethyl acetate/petroleum ether mixtures to give the secopenicillanate (2) (25.8 g) as 311 oil» Vmax. (CHC15) 1785, 1725; 6 ppm (CDCl^) 2.00 (3H, s), 2.23 .(3H,. s) 2.32 (3H, s), 3.82 (JH, s), 5.52 (1H, s). n-. o n ■ •r: ~ 7 £ U ^ - J - 16 .Preparation 1(b) 4RS)-5—Bromo-^ri —( % )-hydxo:>:yethyl1-l (l-metho>ycarbonyl-2 -me thylprop-1 • erry!Q-4-roethyl1jiioa£etidin-2-orte ■ - Br Br- • SMe Me OH Br'Vy CO^ CO^Me (2) (3) a) Using methyl magnesium "bromide A solution of methyl magnesium bromide (2M in diethyl etherj 14.2 ml) was added^ dropwise over five minutesa to a stirred solution of the dibromosecopenicillanate (2) (10.0 g) in dry te trahydrof uran (200 ml) at -jS°C.

After stirring- at -rj6°C for a further twenty minutes a solution of acetaldehyde (3 ml) in dry te trahydrof uran (10 ml) was added dropwise over five minutes, The mixture was stirred at -76°C for a further ten. minutes treated with a saturated solution of ammonium chloride (10 ml)^ and allowed to attain room temperature. The mixture was diluted with ethyl acetate and the organic phase separated. The organic layer was washed with brinet dried (MgS0^)> and evaporated to give a crude gum. Chromatography of the crude product on silica gel eluting with ethyl acetate/petroleum ether mixtures gave the bromohydrin (3) (7-28 g) .a 9 : .1 mixture of -isomers < as a viscous oila v (CHC1_) ^ * • • -.j , ' max • y 36OO - 3100, 1765, 1725 cm ; 6 (CDCl^) 1.43 (3H, d, J 6%Sz)t 2.04 (3H, s), 2.13 (3H, s), 2.28 (3H, s), 2.53 br (1H, d, J approx. 4Hz, exch. I^O), 3.78 (3H, s)^ 4.05 - 4.40 (1H, collapsing to 4.21# qt J 6-gHz on exch. ^O)^ 5-25 (0.9H/s), 5.32 (0.1H, s).

Using n-butyl lithium The above experiment was repeated using n-butyl lithium (one equivalent) in place of methyl magnesium bromide to give ^ after chromatography# the bxomo-hydrin (3) in 36% yield.

N.Z. PATENT OFF ICE AUG 1983 -- r\:rp Preparation l(c) fgBS. 4RS) and (3RS, 4SR)-3fl-C 5 )-Hydro3qyethyl*]-1 (l-metho:)orcarbonyl-2-n*3 thylprop-1—enyl )-4—me thylthioaze tidin— 2—one " Ma OH oH : (3) (4) The bromohydrin (3) (7 -04- g) was stirred with zinc-silver couple (prepared from 2-60 g zinc dust according to the method of R.D. Clark and C.H. Heathcock, J. Org. Chem.^ 1973, 3^59) in methanol (100 ml) containing glacial acetic acid (0.57 Eil) at room temperature for ten minutes (the mixture was initially cooled with an ice-water "bath in order to moderate a slightly exothermic reaction).

Thiq mixture was filtered through Kieselguhr the residue "being washed with a little methanol. The combined filtrates were evaporated to low volume and diluted with ethyl acetate. The solution was washed successively with H". hydrochloric acid, brine dilute sodium bicarbonate solution, and brine. The dried (MgSO^) organic layer was evaporated &nd' the residual gum, chromatographed on silica gel eluting with ethyl acetate/petroleum ether mixtures •tcv give a 3 • 1 mixture of the cis- and trans-hydrosyethylazetidinones (4) (4.64 as a gum, v (CHCl^) 3^00 — 3200, "1750, 1720 cm ^; 6 ppm (CDCl^) 1.32 and 1.42 (3H# each d, J 6Hz), 1.98 and 2.00 (JH, each s), 2.10, 2.17 and 2.24 (6H, each s) , 2.35 - 2.90 (1H, broad signal, exch. DgO), 3-14 (£H, dd, J 2 and 5Hz), 3.41 (&, dd, J 5 9Hz), 7-75 (3H, s), 4.00 - 4.40 (1H, in, simplifies on exch. D20), 4.90 (£h, d, J 2Hz), 5-04 (f H, d, J 5Hz).

Preparation 1(d) 3 (1—"fa-Butyl diph enyl s ilyl oxye thyl )-1 (1 -me thoxycarb onyl-2-ine thylprop-1-enyl )-4—ae thyl thl oaaeti din-2-one OH H Stfe C02«e (4) \ J 0 P I .SMe He Bu Ph^SiO OSiPhuBu TT * •- (6) + Bu^BigSiO. (7) C02Me to 00 02 in The mixture of cis and trans_-hydro3yethylazetidliiones(4) (2.00 g) was dissolved in dry dimethylformamide (20 ml) and treated with imidazole (1 .10 g) and t—butyldiphenylsilyl chloride (2.21 g) . The mixture was kept at room temperature for eighteen hours, diluted with ethyl acetate, and washed successively with IT. hydrochloric acid, brine, saturated sodium bicarbonate solution, and brine. The dried (MgSO^) organic layer was evaporated and the residue chromatographed on silica gel eluting with ethyl acetate/petroleum ether mixtures to give two fractions. The less polar fraction, the (jRS 4SR)-3 [l-(RS)-t—butyldiphenylsilyloxyethyl]azetidinone (5), contaminated with approxi- I mately 15% of the (3ES, 4SR)-3[l-(SR)-t-butyldiphenylsilyloxyethyl]azetidinone — 1 (6) was obtained as a gum (1 .15 g), v (^HCl^) 1750. 17^5 cm ; 6 ppm * ZQ2-UC • $ * , (CDC15) 1.0 - 1.5 (12H, m), 1.94 (3H, s), 2.05 and 2.08 (3H, each s), 2.19 (3H, s), 3.10 (dd, J 3 and 6Hz) and 3.25 (dd, J 3 and 5Hz) together 1H, 3.63 | :('0.15H, s), 3.69 (0.85H, s), 4.15 - 4.50 (1H, m), 5-11 (1H, d, J 3Hz), 7.2 - 7.8 (10H, m) . The more polar fraction, the (3RS, 4RS)-3[l-(SR)-t-butyldiphenyl- - 19 _ BilyloD:yethyl]az.etidnone (7) (2.20 g), was obtained as a gum v (CBC1..) * * max, j 1750, 1720 cm" ; 6 ppm (CDCl^) 1 .05 (9H, s), 1.24 (3H, d, J 6 Hz), 2.00 (6H, s), 2^20 (5H, b), 3-58 (1H, dd, J 6 and 6Hz), 3.73 (3H, b), 4.36 (1H, dq., J 6 and 6Hz), 4.98 (1H, ■ d, J 6Hz), 7.2 - 7.9 (10H, m). (Found, M+ - Bu* 454.1479. ^24^28^4^^ ;re^ui:res 454.1508).

V-" c_ U T - Preparation 1(e) ( 3BS r 4RS)-3F 1 —(SR)-t-Butylai phenyl silylo^xyethyl 1—4—methyl sulphonylazeti din-2—one Me H H ButPh2SiO Me H H H \ ' « SO^ Bu Pfc^SiO i i (7) o C02Me (8) _HS A solution of m-chloroperbenzoic acid (1.60 g) in ethyl acetate (10 ml) • vas added cLropwise over ten roinutes to a stirred, ice-hath cooled, solution of the (3BS, 4RS) azetidinone (?); (2.16 g) in ethyl acetate (50 ml). The mixture kept at room temperature for two and a half hours and washed with saturated sodium "bicarbonate solution (2 1 15 ml) and brine (3 x 15 ml). The dried (MgSO^) organic layer was diluted to 100 ml with ethyl acetate, cooled to -20°C and ozonised oxygen passed for thirty minutes. The excess ozone was removed by passage of argon and the mixture treated with methanol (50 ml). The mixture was kept at room temperature for forty hours and evaporated to give a crude gum which was chromatographed on silica gel eluting with ethyl acetate/petroleum ether mixtures to give the sulphone (8) (1.57 g) as" a waxy solid, v (CHC1 ) 3400, 1790 cm 1; 6 ppm (CDC1 ) 1.01 (9H, s), max. 1.23 (3H, a, J 6Hz), 2.91 (3H, s), 3-77 (1H, dd, J 5 and 8Hz), 4.67 (1H, d, J 5Hz), 4.87 (1H dq, J 6 and 8Hz), 6.88 br (1H, s), 7.3 -7-8 (10H, m). (Found: M+ - Bu 374.0897- G18H20N°4SSi re^tlires 374.0882). ✓•s O \ • / u 0 ^ ^ - 2 1 - Preparation l(f) j^RS. 4SR)-3ri-(SR)-t-ButyldlphenyIsilyIoxyethYl1-4-ethvlthlothiocar-bonv]thio-azetidin-2-one — r 0 .

A mixture of the sulphone (8) (1 .49 g) in methylene chloride (25 ml) and potassium ethyl" trithiocarhonate (670 mg) in water (5 ml) was stirred vigorously at room temperature. After four hours the organic phase was separated and the aqueous layer extracted with methylene chloride (5 ml). The combined organic layers were washed with "brine (3 1 5 ml), dried (MgSO^) and evaporated. Chromatography of the residue on silica gel eluting with ethyl acetate/petroleum ether mixtures gave the trithiocarhonate (9) (1-29 g) as a yellow solid, m.p. 110 - 111 °C (needles ex ethyl acetate/petroleum ether) X max. (Et0H) 301 mn- (em14'80°); v max. 3410,' 1770 cm"1; 6 ppm (CDClj) 1.02 - 1.12 (12H, s + partially obscured d), 1 .38 (3H, t, J 7Hz), 3.19 (1H, dd, J 2 and 4£Hs), 3-35 (2H, q, J 7Hz), 4.1 - 4.5 (1H, m), 5.63 (1H, d, J 2Hz), 6.59 hr (1H, s), 7-3 - 7-8 (10H, m). (Pound: C, 59-3; H, 6.5; K^2.9; S, 19-4. C24H31N02S5Si requires C, 58.9; H, 6.3; N, 2.9; S, 19.6%) Bu Ph^SiO ne.

H I E B ;n-jJ [W Me r r ■ MH Bu^Ei^SiO H H 0^ _NH (8) (9) N.Z. PATENT OFFICE AUG 1983 1 1 I r\ ^ f ^ 1 "7 ^ u "v Preparation 1(g) j[5RS. 4SR)-5ri-(SR)-t-Butyldiphen.yl3ilvloxvgth.yll-4—eth.ylthiothiocar'faon.ylthio-.1 (1-hydroxy-1-p-nitrobenz.-y-loxycarbon,y3Jiethyl)azeti(iin-2-one Mfi H. | H H Bu 'Ft^SiO ■V" I UH S SEt (9) Bu Ri^SiO The trithiocarhonate . (9) (1.25 g) and jD-nitrobenzyl glyoaylate monohycLrate (1 .16 g) were refluxed in benzene (50 ml) under argon for thirty hours vith provision for removal of -water. The mixture was evaporated' and the residual gum chromatographed on silica gel eluting vith ethyl acetate/ petroleum- ether to give the hydroxy—ester (10<) (1 .51 g), a mixture of stereoisomers . max.

(CHC1 ) 3500 br, 3400 br, 1775, 1750 (slight . as a gum, shoulder) cm 1; 6 ppm (CDCl^) 1.02 (9H, s), 1.35 (3^, t, J 7Hz), 3-24 - 3-49 (3H, m), 3.6 - 3.9 br (1H, m, exch. DgO), 4.2 - 4.5 (1H, m), 5.15 - 5-46 (2 2/3 H, m), 5.5 — 5.7 br (l/3 H, m, collapses to 5-58, s, on exch. B20), 6.3O and 6.35 (1H, each d, J 2jHz), 7.2-7.8 (12H, m), 8.18 and 8.21 (2H, each d, J 8Hz) .

I \J n J - ' - 2 3 - Preparation 1(h) (3RSf 4SB)-3T 1-(SR)-t-Butyldiphenylsilyloxye thyll—1 -(1 -chloro—1 -p-nitrobenzyl-oryc arb onyima thyl) - 4—e thy! thi o thi ooarb onyl thi oaz e t i din- 2-one A solution of thiouyl chloride (384 mg) in dry te trahydrof uran (5 ml) was added dropwise over five minutes to a stirred mixture of the hydroxy-ester (10) (1-50 g) and 2,6-ludidicie (345 nig) in. dry te trahydrof uran (30 ml) at -10°G. The mixture was stirred at -10°C for ten minutes, filtered, and evaporated. The residual gum was re-evaporated from dry toluene (2x5 ml) "to give the chloro-ester @1 ) (1 .55 g) as a gum, v mT (CHCl^) 1785 cm-1 . - 2 4 - Preparation l(i) (5RS. 4SR)-5f 1-(SR)-t-ButyIdi-phen,yIsiIyloyyeth.yll-4—ethylthiothiocar'bonylthio-"1 (1-j^nitroheirzyloxycaxhon.yl—1 —triphenylphosphoranylidenemethyl )azetidin-2-one A mixture containing the chloro-ester (11)(1.55 S), triphenylphosphine ("1 -"13 g), a*1*! 2,6-lutidine (278 mg) in dry dioxan (30 ml) was stirred at 60°C under dry argon for seventy-two hours. The mixture was cooled^ filtered^ and ^ the filtrate concentrated. The mixture was diluted with ethyl acetate (50 ml) and washed with N. hydrochloric acid# brinea saturated sodium "bicarbonate solution^ and "brine. The dried (MgSO^) organic layer was evaporated and the residue chromatographed on silica gel eluting with ethyl acetate/petroleum ether mixtures to give the phosphorane( 12 ) (1.17 g) as an amorphous Bolid^ y (CHCl^) 1745a 1610 cm"1. .

N.2. PaYLZ:.' C 15AUGKS3 F T/:: Preparation l(,j) (5RS- 6SR 8RS) and (^RSf 6R5. 8SR)-p-l<[itrobenzyI 6 (1-t- Butyldiphenylsilyl-oxyeihyl )-2—ethyl thi openein-3-carboxylate H Bu Me .tHa2SiO~'^v P ? r (12) S SEt T ^Pih5 C°2 CH^—(/ y—N0? • SEt o„cH0-f y^o2 (13) A solution of the phosphorane (12) (1.03 g) in xylene (1000 xnl) was refluxed under argon for seven hours. The mixture was evaporated and the residue chromatographed on silica gel eluting with ethyl acetate/petroleum ether mixtures to give the penem ester (13) (440 mg)} a 4 : 1 mixture of (5BS, 631, SHS) and (5RS, 6RS, 6SR) isomerst as an amorphous solid, v .(CHCl^) 1790 and I69O cm 1; 6 ppm (CDCl^) 0.99 and 1.01 (9H, each s), 1.13 (d, J 6Hz), 1.30 (t, J 7Hz) and 1 .35 (t, J 7Hz) together 6h, 2.65 ~ 3-15 (2H, m), 3-55 - 3.95 (1H, m), 3.95 - 4.50 (1H, m), 5-15 and 5.43 (2H, ABq, J 14Hz), 5-4-9 (0.8H, d, J 1^Hz), 5.65 (0.2H, d, J 4Hz), 7.2 - 7.8 (12I; m), 8.14 and 8.16 (2H, each 4 J 9Hz), Unchanged phosphorane (12) (161 mg) was also isolated in this experiment.

N.Z. PATENT OFFICE AUG 1983 _ 26 0 ,-v r,7 2 0 - - ' ^Preparation JIM (5RS, 6SRf 8RS) and (5RSr 6RSf 8SR)-p-Nitrobenz.yl 2-Ethylthio-6(l-hytLroxyethyl)-penem-3—carboxylate (13) (14) + (15) Tetra—n-butyl anmonium fluoride (2.44 ml of a solution containing 0.5 mMole n—Bu^NF. JH^O/ml te trahydrof uran, dried over Holeculax Sieves Type 4A for twenty-four hours) was added over five minutes to an ice-bath cooled solution of the. penem silyl ethers (13) (595 nig) in dry tetrahydrofuxan (20 ml). The mixture was kept at ice-bath temperature for thirty minutes and then allowed to attain room temperature during a further thirty minutes. The mixture was diluted with ethyl acetate (50 ml) and washed with 5% citxic acid (5 ml) and brine (3 x 10 ml). The dried (MgSO^) organic layer was evaporated and the residue chromatographed on silica gel eluting with ethyl acetate/petroleum ether mixtures to give the hydroxyethyl penem (105 mg), a mixture of cis and trans-isomerB, as a solid. Crystallisation of the mixture from ethyl acetate/petroleum ether gave the pure (5&S, 6SR, 8RS) penem (14) (68 mg) as fine needles, m.p. 131 - 134°C, X maz.

(EtOH) 262 (em 15,100) and 339 n.m. (9,800); v ^ (CHCl^) 36OO - 3200, 1790, 1730 and 1690 cm 6 ppm (CDCl^) 1.35 (d, J 6Hz) and 1.36 (t, J 7Hz) together 6H, 2.0 appro*. (1H, brs), 2.80 - 3.15 (2H, m), 3.71 (1H, dd, J 1.6 and 6.6Hz), 4.0 - 4.4 (1H, m), 5.18 and 5.46 (2H, ABq, J 14Hz), 5.64 (1H, d, J 1.6Hz), 7.6O (2H, d, J 8Hz), 8.19 (2H, d, J 8Hz), signals at 1.24 (t, J 7Hz), 2.01 (s), and 4.09 (q, J 7Hz) indicated the presence of approximately 0.5 mole of ethyl acetate of crystallisation; (Found; M+, 410.0593- ^17^-18^2^6^2 requires M, 410.0606). Evaporation of the mother liquors gave the (5RS,6RS,8SR)penem (15) (35 nig) contaminated with approximately 20% of the trans-isomer (14) as an amorphous solidj 6 ppm (CDCl^) (inter alia) 3-84 (0.8H, dd, J 3-9 an<i 10,1Hz), 5-73 (0.8H, d, I J 3.9Hz). n.z.patc:-;ror-:-:cE i S M!SV>& . jf . n * o (■ ,1 R ■- 7 C. U 'I' w w- / Example l(a) ('5BS)-,p-;tIitro'be:nzyl(Z)-6-Ethylidene-2—ethyl thi operiero-3-carboxylate SEt SEt co2CH^- ff NO, (14) (26) The trans-penem ester (14) (82 mg) was dissolved in dry methylene chloride (5 ml), cooled in an ice-bath, and treated with triphentylphosphine (52 mg) and diethyl azodicarboxylate (35 mg) . The mixture was allowed to attain room temperature during fifteen minutes. The mixture was re-cooled in an ice-hath and treated with triphenylphosphine (52 mg) and diethyl azidocarbosylate (35 mg) • The mixture was again allowed to attain room temperature during fifteen minutes and evaporated. The crude product was chromatographed on silica gel eluting with chloroform to give the (Z)-ethylidenepenem ester (26) (44 mg) as a solid, m.p.'l69 - 171°G (fine yellow needles ex ethyl acetate/petrol) X (EtOH) 260 (em 14,520) and 322 n.m. (7,980); (CHCl^) 1785, 1700, br. cm" ; 6 ppm (CDCl^) 1.36 (3H, t, J 7Hz), 1.82 (3H, d, J 7Hz), 2.75 - 3-15 (2H, m), 5.19 and 5.49 (2H, AHq, J 14Hz), 6.16 (1H, s), 6.44 (1H, q, J 7Hz, showing further fine coupling J <1Hz), 7.63 (2H, d, J 8Hz) 8.19 (2H, d, J 8Hz). (Pound: 39i.0503. C17H16N205S2 requires M, 392.0500). 7 PATENT OFFICE 1 J O ^ r ■■ 7 Example 1(b) (5RS)-SocLL'um(z)-6-E fchylidene-2-ethylthiopenem-3-carboxylate The (z)—ethylidenepenem ester (26) (33 mg) was dissolved in. a mixture of dioxan (8 ml) and water (2 ml) and hydrogenated over 5% palladium/charcoal catalyst (48 mg) at S.T.P. for one hour. Further catalyst (33 ms) waa added and ihe hydrogenation continued for a further one and a half hours. A 1% sodium hydrogencarbonate solution (0.71 nil) was added and the mixture filtered through Kieselguhr^ the residual catalyst being washed with a little 50% aqueous dioxan. The combined filtrates were evaporated and the residue chromatographed on Biogel P2 eluting with water. The appropriate fractions were evaporated and the residue re—evaporated from ethanol £ml) and dry toluene (2x2 ml) to give^ after trituration with dry ether, the Z-ethylidenepenem sodium salt (27) (10 mg) as an amorphous solid, X (^2®) ^05 n.m. ( 3280); 6 ppm (i^O) 1.19 (jH^ J 7 Hz), 1.71 (3Ha d, J 7 Hz), 2.4 - 3-1 (2H, m), 6.19 (1H, s), 6.44 (1H, q, J 7 Hz).

N.2. PATENT C-'" <a pf"r" 'ir"" \ .Preparation 2(a) 4SR.)-5f""l-(RS)-t—Butyldiphenylsilyloxyethyl"l-4—methyl sulpbonylazetidin-2-one Bu ■S SiO CO^ Bu fh^SiO Me i -— H H SO^ 0^ (18) jm A solution of m-chloroperben2oic acid (930 nig) i31 ethyl acetate (5 ml) was added dropwise over five minutes to a stirred, ice—hath cooled, solution of the impure azetidinone (5) (1 .25 g) in ethyl acetate (25 ml). The mixture was kept at room temperature for one hour and washed with saturated sodium hydrogencarbonate solution (2x5 ml) brine (3. x 5 ml)» dried (MgSO^) organic layer was treated with ozonised oxygen and methanol as in Preparation 1(e) to give, after chromatography the sulphone (l8)$94- mg) contaminated vith 15% of the (3RS, 4SR ) -3 [ 1 - ( SR) -t-butyldiphenylsilyloxyethyl] isomer as a gum, v maJC (CHC1 ) 3420, 3270 br, 1790 cm"1; 6 ppm (CDGl^) 1.01 and 1.05 (9H, each s), 1.27 (3H, d, J 6.1Hz), 2.70 (0.85H, s), 2.91 (0.15H, s), 3.5O - 3.65 (1H m), 4.15 - 4.50 (m) and 4.43 (d, J 2.0Hz), together 1 .85H, 4.82 (0.15H, d, J 2Hz) 6.92 (1H, broad s), 7.3-7.8 (10H, m).

L u - Preparation 2(b) (5B5. ' 4SR)-5l~ 1-(RS)-t-Butyldiphenylsilyloxyethyl'|-4—ethyl thiothiocarbonylthio-azetidin-2—one Me iJP ? Me SiO' SO^ H. I H ■fc Bu Ph2SiO^^ -NH SEt (18) 6^ (19) A mixture of the impure sulphone (18) (890 mg) in methylene chloride (15 ml) and potassium ethyl trithiocarhonate. (400 mg) in water (3 ml) was Btirred vigorously at room temperature. After eighteen hours the mixture was worked up as in Preparation 1 (f) to give the trithiocarhonate. (19)0*50 mg) as a yell gum, X (EtOH) 303 n.m. (^ 13,700); v (CHCl^) 3420, 1775 cm-1; ' 6 ppm (CDClj) 1.05 (9H, s), 1 .23 (d, J 6Hz) and 1.34 (t, J 7h2) together 6H, 3-15 - 3-45 (3H, m), 4.22 (1H, dq, J 3 and 6Hz>, 5.62 (1H, d, J 2Hz), 6.59 (1H, brs), 7.3 - 7.8 (10H, m). (pound: M+ - Bu"^ 432.0580. C^^^O^^Si requires 432.0579). ®ie starting sulphone (18) (252 mg) was also isolated in this experiment.

Treatment of the recovered sulphone (18) vith fresh potassium ethyl trithiocarhonate gave the trithiocarhonate (19) (126 mg).

Preparation 2(c) (4SR)-3f 1-(RS)-t-Butyldiphenylsilyloxyethy I"] -4—ethy 1 thi o thi o caxb ony Ith£o-1 (1 -liydrozy-1 -p-ni t r o"b enzyloxyc axb onyl tm e thy 1) az e t i din-2 - one H Bu H^SiO Me.

H . S i/ L J (19) Me H'J B^R^iO-"^ H H (20) i/ IT SEt 0 co^^o The trithiocarhonate (19) (570 mg) was treated with jwiitrobenzyl glyoxylate monohydxate (530 mg) as in Example 7 to give the hydroxy-ester (20) (676 mg), a mix-tore of stereoisomers, as an amorphous solid, v max (CHCl^) 3520 br, 1780, I76O slight shoulder cm 1; 6 ppm (CDCl^) 1.0 -1.5 (15H, m), 3-2 - 3-5 (3H, m), 3-75 (2/3H, d, J 9Hz), 3-91 0/5H, d, J 9Hz), 4.1 - 4.5 (1H, m), 5.18 - 5.50 (2 2/3H, m), 5-56 (1/5H, d, J 9Hz),. 6.15 - 6.25 (1H, m), 7.2-7.8 (12H, in), 8.21 (2H, d, J 8Hz). 2045:7 - 3 2- Preparation 2(d) (5RS r A SR'Mf 1 ■- (R5)-t-Butyldiphenylsilyloxyethyll-1 -(1 -chloro-l-p-nitrohenzyl-oxycarhonyT mg th.yl)-4—ethyl thi. o thi ocarh onyl thl oazetidin-2-one Me Bu JfruSiO "9- i c\^ - ? ? « S / SEt 1/ -h (20) Y n^-oh .

CQgCHf-C3-^°2 Bu Ri^SiO (21) CO2ch2-^^HIO2 Ji A solution of thionyl chloride (169 mg) in dry te trahydrof uran (2 ml) was added^ dropwise over three minutes^ to a stirred mixture of the hydroxy— ester (20) (660 mg) and 2j 6-lutidine (1J?2 ng) in dry te trahydrof uran (10 ml) at -10°C. The mixture was stirred at -10°C for ten minutes^ filtered^ and evaporated. The residual gum was re-evaporated from diy toluene (2x2 ml) to give the chloro-ester (21) (679 mg) as a gum^ * max. (CHC13> 1"° cn' -1 n.2:pmenic o n Au- 7 c. <-> ' ^ ~ 1 Preparation 2(e) (5R5f 4SR)-3r 1-(RS)-t--Butyldiphenylsilylo:>:yethyl~]--4—ethyl thiothiocarbonylthio-1-( 1-p-nltroben2yloxycarhonyl-1-triphenylpho9phoraii.ylidenemethyl)azetid±n-2-one Me H H ButPh2Si(r'* * cT (21) /S SEt Y CI co2CK^/\ Me t ■>.

Bu R^SiO^ H H j ^ j / SEt 0^ 0, (22) ^PHl3 C02CH2—NO.

A mixrfcure containing the chloro-ester (21) (&79 , tripheuylphosphine (1.02 g)^ and. 2j6-lutidine (125 mg) in dry dioxan (15 ml) was stirred at 60°C under dry argon for forty-eight hours. The mixture was worked up as in Preparation 1 (i) to give the phosphorane (22) (640 mg) as an amorphous solid^ v (CHCl^) 1750, 1620-cm"1. max.

Preparation 2(f) (5RSj 6SRf 8SR)-p-Hitro"ben2yl 6(1 -t-Bubyldiphenyls il yloxyethyl)-2-e thylthio-penem-3-caj"boxyIate A solution of the phosphorane (22) (640 mg) in xylene (640 ml) was re fluxed, under argon for nine hours. The mixture was evaporated and the residue j chromatographed on silica gel eluting with ethyl acetate/petroleum ether mixtures to give the penem ester (23) (229 mg) as a gum X (EtOH) 261 ' TTlciX • ^ (em 13,800) and 339 n.m. (9, 600); v (CHCl^ 1790, 1690 cm ; 6 ppm (CDCl^) 1.00 (9H, s), 1.24 (3H, d, J 6Hz), 1.34 (3H, t, J 7Hz), 2.80 - 3.15 (2H, m), 3.71 (1H, dd, J 3.3 and 1.5Hz), 4.00 - 4.40 (1H, m), 5-19 and 5.42 (2H, ABq, J 13Hz), 5-53 (1H, d, J 1 .5Hz), 7.1 - 7.8 (12H, m), 8.14 (2H, d, J 8Hz) (Pound: M+, 648.1776. C H^^O^Si requires 648.1781).

Preparation 2(k) (5RS. 6SRr 8SR)-p-Uitrobe:nzyl 2-Ethylthio—6 (-1 —hydroxysthyl)penem~3~car"boxylate (23) (24) Tetra-n-hutylaiomonium fluoride (1.39 ml of a solution containing 0.5 mMole n-Bu^WIF.JH^O/ml te trahydrof uran, dried over Molecular Sieves Type 4A for twenty-four hours) was added over five minutes to an ice-hath cooled solution of the penem silyl ether (23'),. (225 in dry te trahydrof uran (10 ml). The mixture was kept at ice-hath temperature for thirty minutes and then allowed to attain room temperature during a further thirty minutes. Vork-up of the mixture as in Preparation l(k) gave the trans-penem ester (24) (52 mg) as a solid, m.p. 170 - 1 °C (yellow needles ex ethyl acetate/petroleum ether), X (EtOH) _ 261 (em 15,700) and 340 nm (10,000); v (CHCl^) 1790, 1690 cm~1; 6 ppm (CDCl^) 1 .28 - 1.46 (6H, m), approx. 1.6 (1H, hroad signal), 2.84 - 3.14 (2H, m), 3.85 (1H, dd, J 1.5 and 4-5Hz) 3.95 - 4.45 (1H, m), 5.19 and 5-50 (2H, ABq., J 14Hz), 5.63 (1H, d, J 1.5Hz), 7.62 (2H, d, J 8.8Hz), 8.21 (2H, d, J 8.8Hz). (Pound: M+, 410.0615. C^^^g^OgSg re1'ui:res 410.0606).

M.Z. PAT - v*' o' AUGW^ ... w i - 36 ■- Example 2(a) (5RS)-p-ITitrobenzyl (E)-6-Ethylidene-2—ethyl thiopenero-3-carboxylate H ^ H H ' xi \ ii (24) .SEt Wr<> N0„ H Me' L// ^2^2 HO, (28) The trans-penem ester (100 mg) was dissolved in dry methylene chloride (10 ml), cooled in an ice-bath, and treated with triphenylphosphine (2 x 64 mg) and diethyl azodicarboxylate (2 x 42 mg) as in Example 1 (a). The mixture was evaporated and chromatographed on silica gel eluting with ethyl acetate/ petroleum ether mixtures to give the (E)-ethylidenePenem ester (28) (48 mg) as a solid, X max (EtOH) 260 (e m 14,050) and 322 (7,640); (CHCl^) 1780, 1690 cm"1; 6 ppm (CDCl^) 1 .35 (3H, t, J 7Hz), 2.10 (3H, d, J 7Hz), 2.8-3 (2H, m), 5.20 and 3.50 (2H, ABq, J 14Hz), 5.98 (1H, q, J 7Hz), 6.12 (1H, s), 7.64 (2H, d, J 8Hz), 8.21 (2H, d, J 8Hz). (Found: M+, 392.0463. requires M, 392.0500) .

Example 2 JM (5RS)-Sodium (E)-6-Ethylidene-2-ethylthiopenem-3-carboxylate SEt co2CH^ -NO, (28) (29) se*fc C02ONa© The (E)-ethylidenepenem ester (28) (45 ing) was dissolved in. a mixture of dioxan (8 ml) and water (2 ml) and hydrogenated over 5% palladium/charcoal catalyst (68 mg)at S.T.P. for one hour. Further catalyst (45 mg) was added and the hydrogenation continued for a further two and a half hours. A 1% sodium hydrogencarbonate solution (0.96 ml) was added and the mixture worked up as in Example 1 (b)to give the (E)-ethylidenepenem sodium salt (29) (14 mg) as an amorphous solid, X O^O) 212 (e^ 8,410) and 306 n.m. (5, 180). 38 Preparation 3(a) (Z)-2-Carboethoxyvinylisothiuronium Chloride S HC1 HN A + ^-C02Et *> 1V-\=/^Et NH 2 (31) A solution containing ethyl propiolate (9.8 g) in methanol (20 ml) was added to a solution of thiourea (7.6 g) in 2N hydrochloric acid at a rate which allowed the temperature of the exothermic reaction to be maintained at approximately 50°C. After the addition was complete the mixture was stirred for 2 hours and evaporated. The residue was re-evaporated from dry toluene (3 x 20 ml) and crystallised from propan-2-ol to give the isothiuronium chloride (31) (14.2 g), mp 134 - 136°C (rods); '/max (Nujol) 3600 - 2500, 1700, 1675, 1660 cm-1; 6 ppm [(CD^SO] 1.28 (3H, t, 3 7Hz), 3.69 br (1H, s, exch. D20), 4.26 (2H, q, 3 7Hz), 6.40 (1H, d, 3 10 Hz), 7.96 (1H, d, 3 10 Hz), 10.02 br (3H, s, exch. D20). (Found: C, 34.1; H, 5.2; N, 13.3; S, 15.2. C6H11N2C102S recluires C> 34*2; H> 5.2; N, 13.3; S, 15.2%). - 39 Preparation 3(b) (3R5>^SR)-3[l-(SR)-t-Butyldiphenylsilyloxyethyl] -4-[2-(Z)-ethoxycarbonylvinylthio]azetidin-2-one Bu Ph2SiO H S02Me He "J H Bu Ph^SiO 0' ' .S CO^Et \=/ 2 -NH (8) (32) A IN solution of sodium hydroxide (8-64 ml) was added, dropwise over 2 minutes, to a stirred solution of the isothiuronium chloride (31) (910 mg) in ethanol (20 ml) at -10°C. The resulting mixture was treated, in 2 minutes, with a pre-cooled (-10°C) solution of the sulphone (8) (1.86 g) in ethanol (40 ml). After stirring at -10°C for 30 minutes the mixture was allowed to attain room temperature (30 minutes), diluted with ethyl acetate (400 ml) and washed with brine (3 x 50 ml). The aqueous washings were back-extracted with ethyl acetate (50 ml). The dried (MgSO^), combined, organic layers were evaporated and the residue chromatographed to give the azetidinone (32) (1.68 g) as an amorphous solid, max (CHCl^) 3410, 1775, 1695 cm <5 ppm (CDCl^) 1.00 - 1.20 (m) and 1.28 (t, 3 7Hz) together 15H, 3.15 - 3.28 (1H, m, sharpens * to 3.22, dd, 3 2.2 and 4.4 Hz on irradiation of the signal at 6.45 ppm), 4.1 - 4.4 (m) and 4.19 (q, 3 7Hz) together 3H, 4.92 (1H, d, 3 2.2 Hz), 5.94 (1H, d, 3 10 Hz), 6.45 (1H, s), 7.14 (1H, d, 3 10 Hz), 7.3 - 7.8 (10H, m). (Found: [M-But] + , 426.1201. C^H^NO^SSi requires 426.1195).

Preparation3 (c) (3RS,ttSR)-3[l-(SR)-t-Butyldiphenylsilyloxyethyl] -^-[2-(Z)~ ethoxycarbony1vinylthio]-1(1-hydroxy-1-p-nitrobenzyloxycarbonylmethyl) 1 azetidin-2-one (32) (33) The azetidinone (32) (1.74 g) and p-nitrobenzyl glyoxylate monohydrate (1.63 g) were heated in refluxing benzene (40 ml) under argon for 7 hours with provision for removal of water. The mixture was evaporated and chromatographed to give the hydroxyester (33) (2.25 g), a mixture of stereoisomers, as an amorphous solid, max (CHCl^) 3520, 1775, 1760 sh, 1695 cm 6 ppm (CDCl^) 1.0 - 1.4 (15H, m), 3.15 - 3.30 (1H, m), 3.6 - 3.9 (1H, broad signal, exch. D20), 4.0 - 4.4 (3H, m), 5.0 - 5.7 (4H, m, simplifies on exch. D^O), 5.82 and 5.87 (1H, each d, 3 10 Hz), 7.02 and 7.11 (1H, each d, D 10 Hz), 7.3 - 7.8 (12H, m), 8^21 (2H, d, 3 8.5 Hz).

Preparation 3(d) (3RS ,4SR)-3[l-(SR)-t-[3utyldi phonyIsilyloxyethy1] - I- (3-chJoro-l-p-nitrobenz.yloxycarbonylmethyl)-4-[2-(Z)-ethoxycarbonylvinylthio] azetidin-2-one \J 1 V_/' / Bul'Ph2SiO C0_,Et Bu Pl^SiO N^,C1 Wo NO (33) (34) A solution of thionyl chloride (573 mg) in dry tetrahydrofuran (10 ml) was added, dropwise over 10 minutes, to a stirred mixture of the hydroxyester (33) (2.22 g) and 2,6-lutidine (515 mg) in dry tetrahydrofuran (40 ml) at -10°C. After stirring at -10°C for a further 10 minutes the mixture was filtered and evaporated. The residue was re-evaporated from dry toluene to give the chloro-ester (34) (2.32 g) as a gumj'xTmax (CHCl^) 1785 br, 1695 cm""''.

Preparation3 (e) (3RS,4SR)-3-[l-(SR)-t-Butyldiphenylsilyloxyethyl] -4-[2-(Z)-ethoxycarbonylvinylthio]-l-(l-p-nitrobenzyloxycarbonyl-l-triphenylphosphoranylidenemethyl)azetidin-2-one I A Bu Ph^SiO .S C0_Et ^ W 2 Nx. .CI co2ch2- / w no. f i^H Bu Ph^SiO ' .5 CO-Et X^/ 2 -N PPh.

T CO^CH^y VNO (34) (35) A mixture of the chloroester (34) (2.32 g), triphenylphosphine (3.42 g) and 2,6-lutidine (420 mg) in dry dioxan (40 ml) was heated at 60°C under dry argon for 16 hours. The mixture was worked up as for preparation l(i) to give the phosphorane (35) (2.82 g) as an amorphous solid, -o' max (CHCl^) 1750, 1695, 1625 cm-^.

N.Z- r •r"15' isf? I ■") r\ ' r • w Preparation 3(f) (3RS,4SR)-4-[2-(Z)-Ethoxycarbonylvinylthio]-3-[l-(SR)-hydroxyethyl] ■ l-(1-p-nitrobenzyloxycarbonyl-l-triphenylphosphoranylidenemethyl) .. azetidin-2-one Bul'Ph2SiO C02CH2A V-NO.

C0-,Et N^RPh3 c°2ch2-/ ^ (35) (36) Hydrogen chloride was passed into an ice-bath cooled solution of the phosphorane (35) (1.32 g) in methanol (25 ml) until the concentration was approximately 15% w/v. The mixture was kept at room temperature for 3 hours, diluted with ethyl acetate (150 ml) and neutralised with saturated sodium bicarbonate solution. The organic layer was separated and washed with brine (3 x 25 ml). The dried (MgSO^) organic layer was evaporated and the residue chromatographed to give the phosphorane (36) (745 mg) as an amorphous solid, max (CHC13) 3700 - 3100, 1750, 1695, 1620 cm"1. ' v, C, ' 7 c U ' v - - ' Prcparation3 (g) (5R5,6SR,8RS)-p-Nitrobenzy1 6-(1-Hydroxyethyl)penem-3-carboxylate /W^Et PPh. co£ch2 no2 co2ch2 (36) (37) The phosphorane (36) (745 mg) was dissolved in ethyl acetate (15 ml) and treated with trifluoroacetic acid (3.27 ml) at room temperature. After 10 minutes the mixture was cooled to -76°C and ozonised oxygen passed till a pale blue colour persisted. Excess ozonised oxygen was removed by passage of argon and the mixture was treated with a solution of triphenylphosphine (280 mg) in ethyl acetate (3 ml). The mixture was allowed to reach 0°C and was neutralised with saturated sodium bicarbonate solution. The organic tayer was separated and washed with brine (3 x 5 ml), dried (MgSO^)-and heated at 50°C under argon for 45 minutes. The mixture was evaporated and the residue chromatographed to give the penem ester (37) (293 mg) as a solid, m.p. 119 - , 120°C (needles ex ethyl acetate/petroleum ether); ^ max (EtOH) 262 (e^, 12730) and 317 nm (8490)max (CHC13) 3600 - 3100, 1790, 1720 cm-1; 6 ppm (CDC13) 1.38 (3H, d, 3 6.3 Hz), 2.10 (1H, d, 3 4.7 Hz), 3.85 (1H, ddd, 3 6.3, 1.5 and 1.0 Hz), 4.29 (1H, ddq, 3 6.3, 6.3 and 4.7 Hz), 5.26 and 5.43 (2H, ABq, 3 14 Hz), 5.79 (1H, d, 3 1.5 Hz), 7.34 (1H, d, 3 1.0 Hz), 7.59 (2H, d, 3 8 Hz), 8.24 (2H, d, 3 8 Hz). (Found: C, 51.1; H, 4.0; N, 7.8; S, 8.9; M+, 350.0557. Ci5HiifN2°65 recluires C) 51.4; H, 4.0j^N, 8.0; S, 9.0% M, 350.0573).

Example 3(a) (5RS,6SR,8RS)-p-Nitrobenzyl 6-(1-methylsulphonyloxyethyl)- penem-3-carboxylate (37) (38) A solution of the penem ester (37) (145 mg) in methylene chloride (5 ml), was cooled to -10°C and treated with triethylamine (84 mg) and methane-sulphonyl chloride (95 mg). After stirring at -10°C for 15 minutes the mixture was diluted with ethyl acetate (25 ml) and washed with brine (3 x 5 ml). The dried (MgSO^) organic layer was evaporated to give the crude mesylate (38) (191 mg) as a gum,max (CHCl^) 1795, 1720 cm 6 ppm (CDCl^) 1.61 (3H, d, 3 7 Hz), 3.28 (3H, s), 4.12 (1H, dd, 3 2 and 7 Hz)., 5.20 (dq, 3 7 and 7 Hz) plus 5.28 and 5.52 (ABq, 3 14 Hz) together 3Hy 5.94 (1H, d, 3 2 Hz), 7.46 (1H, s), 7.66 (2H, d, 3 8 Hz), 8.29 (2H, d, 3 8 Hz).

Example 3 (b) (5RS)-p-Nitrobenzyl (Z)-6-Ethylidenepenem-3-carboxyjate Me02S0 MeCH co2CH2 (38) (39) The crude mesylate (38) (191 mg) was dissolved in dry methylene chloride (5 ml), cooled to -10°C and treated with a solution of 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) (63 mg) in dry methylene chloride (1 ml) dropwise over 1 minute. After stirring at -10°C for 10 minutes the mixture was treated with DBU (25 mg). After stirring for a further 10 minutes at -10°C the mixture was diluted with ethyl acetate (30 ml) and washed with 5% citric acid solution (3 ml), brine (2 x 3 ml), saturated sodium bicarbonate solution (3 ml), and brine (3x3 ml). The dried (MgSO^) organic layer was evaporated and the residue chromatographed to give the 6-ethylidenepenem ester (39) (113 mg), a 5 : 2 mixture of (Z) and (E)-isomers as determined by nmr. Fractional crystallisation of the mixture from ethyl acetate/petroleum ether afforded the pure (Z)-isomer, m.p. 164 - 166°C (rods); X max (EtOH) 265 (£ , 12010) and 296 nm (inflection)max (CHCl^) 1790 and 1720 cm-1; 6 ppm (CDCl^) 1.86 (3H, d, 3 7.1 Hz with further fine coupling), 5.28 and 5.45 (2H, ABq, 3 13 Hz), 6.32 (1H, d, 3 1.1 Hz with further fine coupling), 6.53 (1H, dq, 3 7.1 and 1.1 Hz), 7.37 (1H, s), 7.61 (2H, d, 3 9 Hz), 8.24 (2H, d, 3 9 Hz). (Found: C, 54.2; H, 3.4; N, 8.3; S, 9.5; M+, 332.0474. C15H12N2°5S requires C, 54.2; H, 3.6; N, 8.4; S, 9.656; M, 332.0464). c ■ lL U '-t - Example 3(c) (5RS)-Sodium(Z)-6-Ethylidenepenem-3-carboxylate (39) (40) The (Z)-ethylidenepenem ester (39) (56 mg) was dissolved in a mixture of dioxan (8 ml) and water (2 ml) and hydrogenated over 5% palladium/charcoal catalyst (84 mg) at S.T.P. for 45 minutes. Further catalyst (56 mg) was added and the hydrogenation continued for 30 minutes. A 1% sodium bicarbonate solution (1.42 ml) was added and the mixture worked up as in example (lb) to give the sodium salt (40) (20 mg) as a buff-coloured amorphous solid, X max (H-,0) 288 nm (£ 3590);-^ max (KBr) 3700 - 2300, 1765, 1700, 1600, 1560 sh.cnf1 c rn 6 ppm (D20) 1.64 (3H, d, 3 7 Hz), 6.20 (1H, s), 6.34 (1H, q, 3 7 Hz), 6.90 (1H, s).

Preparation 4 (a) o r • £ U ' : ■- (3RS,frSR)-3[l-(5R)-t-Butyldiphenylsilyloxycthyl3 -4-n-butyryIthioazetldin-2-one H",,J ^ - SO?Me Bu Ph^SiO ^ : " / 0^ Bu Ph^SiO H-XH H MH <7 / Y 0 (ch2)2ch3 NH (8) (41) The sulphone (8) (2.00 g) was dissolved in dioxan (40 ml), cooled in an. ice-bath, and treated with a solution of thiolbutyric acid (965 mg) in IN sodium hydroxide (9.28 ml). The mixture was stirred at ice-bath temperature for 40 minutes, diluted with ethyl acetate and washed with brine. The dried (MgSO^) organic layer was evaporated and chromatographed to give the thiol-ester (41) (1.73 g) as a solid, m.p. 82 - 83°C (rods ex petroleum ether); max (CHC13) 3420, 1770, and 1690 cm-1; 6 ppm (CDClj) 0.95 - 1.15 (15H, m), 1.70 (2H, dq, 3 7 and 7 Hz), 2.58 (2H, t, 3 7 Hz), 3.14 (1H, dd, 3 2.3 and 4.8 Hz), 4.25 (1H, dq, 3 4.8 and 6 Hz), 5.30 (1H, d, 3 2.3 Hz), 6.30 br (1H, s, exch. D20), 7.3 - 7,8. (10H, m). (Found: C, 66.3; H, 7.3; N, 3.0; S, 6.7; C25H33N03SSi requires C, 65.9; H, 7.3; N, 3.1; S, 7.0%). 1 •-) r ~7 (L \j "i —' I - 49 ~ Preparation 4(b) (3RS,4SR)-3[l-(SR)-t-Butyldiphenylsilyloxyethyl]-4-n-butyrylthlo-l-(l-hydroxy-l-p-nitrobenzyloxycarbonylmethyl) azetidin-2-one ^ H H Bu tPh2SiO (41) o,s^(CH2)2CH3 0 > NH He H '/J H H Bu Ph2SiO (42) /SY^CH2^2CH3 0 ^ ^OH C02CH J VNQ, The thiolester (41) (1.80 g) and p-nitrobenzylglyoxylate monohydrate (1-80 g) were heated in refluxing benzene (40 ml) under argon for 7 hours with provision for removal of water. The mixture was evaporated and chromatographed to give a partial separation of the stereisomers of the hydroxyester (42). The less polar isomer was obtained as a gum (420 mg^-i/max (CHCl^) 3600 -3100, 1780, 1760, 1690 cm-1; 6 ppm (CDC13) 0.85 - 1.10 (15H, m), 1.40 - 1.85 (2H, m), 2.48 (2H, t, 3 7 Hz), 3.20 (1H, dd, 3 2.8 and 4.9 Hz), 4.24 (1H, dq, 3 4.9 and 6 Hz), 4.41 (1H, d, 3 11 Hz, exch. D20), 5.23 (2H, s), 5.53 (1H, d, 3 11 Hz collapses to s on exch. D20), 5.58 (1H, d, 3 2.8 Hz), 7.3 - 7.8 (12H,m), 8.20 (2H, d, 3 9 Hz). The more polar isomer was also obtained as a gum (691 mg), Vmax (CHC13) 3600 - 3100, 1775, 1760 sh., 1700 cm -1 6 ppm (CDC13) 0.85 - 1.10 (15H, m), 1.50 - 1.85 (2H, m), 2.58 (2H, t, 3 7 Hz), 3.25 (1H, dd, 3 2.7 and 4.9 Hz), 3.55 - 3.80 (1H, br signal, exch. D20), 4.25 (1H, dq, 3 4.9 and 6 Hz), 5.15 - 5.50 (3H, m, collapses to 5.23, s, plus 5.22 and 5.41, ABq, 3 13 Hz on exch. D20), 5.62 (1H, d, 3 2.7 Hz), 7.3 - 7.8 (12H, m), 8.19 (2H, d, 3 9 Hz). Also obtained was a mixture of the two stereoisomers as a qum (884 mg). J w.z. PATENT C^FSOS AUG 1933 Preparation 4 (c) (3RS,4SR)-3-[l-(SR)-t-Butyldiphenylsilyloxyethyl] -*f-n-butyrylthio-1-(1-chloro-l-p-nitrobenzyloxycarbonylmethyl) azetidin-2-one Bu Ph2SiO /-(ch2)2CH3 Me I- -I Bu Ph2SiO 0 .^SY(CH2)2CH3 0 CI C02CH2 \ / N0; (42) (43) A solution of thionyl chloride (535 mg) in dry tetrahydrofuran (10 ml) was added, dropwise over 10 minutes, to a stirred mixture of the hydroxyester (42) (1.99 g) and 2,6-lutidine (482 mg) in dry tetrahydrofuran (40 ml) at -10°C. After stirring at -10°C for a further 15 minutes, the mixture was filtered and the filtrate evaporated. The residue was re-evaporated from dry toluene (2x5 ml) to give the chloroester (43) (2.08 g) as a gum, XT' max (CHCl-j) 1785 br, 1700 cm"1.

Preparation 4(d) (3RS,^SR) -3-[l-(5R)-t-Butyldiphenylsilyloxyethyl] -4-n-butyrylthio-l-(1-p-nitrobenzyloxycarbony1-1-triphenylphosphoranylidene- methyl)azetidin-2-one h Me A H Bu Ph2SiO (f K Me 0 CI Bu Ph2SiO H H co2ch2- // w 4^s\1|^(ch2)2ch3 ; r1 ^ PPh- NO. co2ch2- // W ■NO (43) (44) A mixture of the chloroester (43) (2.08 g), triphenylphosphine (3.14 g) and 2,6-lutidine (384 mg) in dry dioxan (40 ml) was heated at 60°C under dry argon for 22 hours. The mixture was worked up as for preparation l(i) to give the phosphorane (44) (1.46 g) as an amorphous solid, ■i/' max (CHC1,) 1750, 1695, 1620 and 1610 sh. cm . The chloroester (43) (587 mg) which was recovered from this experiment was retreated with triphenylphosphine (900 mg) and 2,6-lutidine (111 mg) in dioxan (10 ml) at 60°C for 30 hours to give, after work-up, the phosphorane (44) (490 mg). ^ "" 7 L. V Preparation 4 (e) (5RS, 6SR, 8R5)-p-Nitr obenzy 1 6- (1-t-Butyldiphenylsilyloxyethyl )r-2-n- The phosphorane (44) (1.75 g) was heated in refluxing toluene (400 mg) under dry argon for 12 hours. The mixture was evaporated and chromatographed to give the penem ester (45) (960 mg) as a solid, m.p. 121 - 123°C (rods ex ethyl acetate/petroleum ether); X max (EtOH) 264 (£m> 12,285) and 316 run (8435); 1/ max (CHClj) 1785, 1710 cm"1; 6 ppm (CDC13) 0.85 - 1.35 (m) plus 1.01 (s) and 1.16 (d, 3 6 Hi) together 15H, 1.40 - 1.80 (2H, m), 2.50 - 3.08 (2H, m), 3.72 (1H, dd, 3 5.5 and 2 Hz), 4.23 (1H, dq, 3 5.5 and 6 Hz), 5.15 and 5.43 (2H, ABq, 3 14 Hz), 5.46 (1H, d, 3 2 Hz), 7.3 - 7.8 (12H, m), 8.16 (1H, d, 3 8.5 Hz). (Found: C, 64.7; H, 6.2; N, 4.4; S, 5.0. c34H38N2°6ssi rec?uires c> H> 6-°; N> kA'> s> 5.1%). propylpenem-3-carboxylate Me Me (44) (45) orv/r. ' 7 / \j ~ ' - 53 - •£" Prcparation 4(f) (5RS, 6SR, 8RS)-p-Nitrobenzyl 6- (1-HydroxyethyI )-2-n-propylpenem-3-carboxylate (45) (46) Tetra-n-butylammonium fluoride (6.04 ml of a solution containing 0.5 m.Mole n-Su^NF.BH^O/ml in tetrahydrofuran, dried over molecular sieves Type 4A for 24 hours) was added over five minutes to a stirred, ice-bath cooled, solution of the penem ester (45) (950 mg) in dry tetrahydrofuran (20 ml). The mixture was kept at ice-bath temperature for 30 minutes and then allowed to attain room temperature during a further 30 minutes. The mixture was worked up as for Example l(k) to give the hydroxyethylpenem ester (46) (190 mg) as a solid, m.p. 118 - 119°C (needles ex ethyl acetate/petroleum ether); \ max (EtOH] 263 (£m 12,720) and 316 nm (9,380); V max (CHClj) 3630 - 3150, 1785, 1710 cm"3 fi'ppm (CDC13) 0.96 (3H, t, 3 7 Hz), 1.37 (d, 3 6 Hz) overlaying 1.3 - 1.8 (m) together 5H, 2.03 (1H, broad signal), 2.69 and 2.93 (2H, each dt, 3 14 and 7 Hz), 3.71 (1H, dd, 3 1.6 and 6.4 Hz), 4.0 - 4.5 (1H, m, simplifies on irradiation of signal at 2.03 ppm), 5.19 and 5.47 (2H, ABq, 3 14 Hz), 5.59 (1H, d, 3 1.6 Hz), 7.62 (2H, d, 3 8 Hz), 8.22 (2H, d, 3 8 Hz). (Found: C, 55.1; H, 5.3; N, 7.2. C^H^N^S requires C, 55.1; H, 5.1; N, 7.1%). '■> rv A r '7 \j ^ _• W I Examplc4 (a) (5RS,6SR, 8RS)-p-Mitrobenzy 1 6-(141 ethylsulphonyloxycthy1)2-n- propylpenem-3-carboxylate (ch2)2ch3 C02CH2 / ^ Me0250 NO. ^~<CH2>2CH3 C02CH2 (46) (47) A solution of methanesulphonyl chloride (88 mg) in dry methylene chloride (1 ml) was added dropwise over 1 minute to a stirred mixture of the hydroxyethylpenem ester (46) (150 mg) and triethylamine (77 mg) in dry methylene chloride (5 ml) with cooling at -10°C. After 20 minutes at -10°C the mixture was diluted with ethyl acetate (20 ml) and washed with brine (3x2 ml).

The dried (MgSO. ) organic layer was evaporated to give the crude mesylate -1 (47) (181 mg) as a gum, -i/ max (CHCl^) 1785, 1715 cm N.Z. PATENT OFT.'OE AUG 1983 Example 4 (b) (5RS)-p-Nitrobenzy1 (Z)-6-Ethylidene-2-n-propylpenem-3-carboxylate Me02S0 il>^CH3 H S MeCH t^/(CH2>ZCH3 h S cr / NO 2 NO 2 (47) (48) The crude mesylate (47) (181 mg) was dissolved in dry methylene chloride (5 ml), cooled to -10°C, and treated with a solution of 1,8-diazobicyclo-[5,4.0]undec-7-ene (58 mg) in dry methylene chloride (1 ml) dropwise over 1 minute/ After stirring at -10°C for 10 minutes the mixture was treated with DBU (23 mg). The mixture was stirred at -10°C for a further 10 minutes, diluted with ethyl acetate (20 ml) and washed with 5% citric acid (2 ml), brine (2 ml), saturated sodium bicarbonate solution (2 ml) and brine (3x2 ml) The dried (MgSO^) organic layer was evaporated and chromatographed to give the 6-ethylidenepenem ester (48) (116 mg), a mixture of (Z) and (E)-isomers, as a gummy solid. Fractional crystallisation of the mixture from ethyl acetate/ petroleum ether gave pure (Z)-isomer (42 mg), m.p. 101 - 102°C (rods), X max (EtOH) 267 (£m 12,190) and approximately 296 nm (10,500); <f max (CHCl^) 1775 and 1710 cm"1; 6 ppm (CDC13) 0.92 (3H, t, 3 7 Hz), 1.35 - 1.70 (2H, m), 1.79 (3H, d, 3 7 Hz), 2.50 - 3.00 (2H, m), 5.16 and 5.44 (2H, ABq, 3 14 Hz), 6.06 (1H, slightly broadened s), 6.41 (1H, dq, 3 7 and approximately 1 Hz), 7.60 (2H, d, 3 8 Hz), 8.19 (2H, d, 3 8 Hz). (Found: M"\ 374.0900. ^"18^18^2^5^ recluires M,' 374.0936).

Example 4(c) (5RS)-Sodium(Z)-6-Eihylidene-2-n-propylpenem-3-carboxylate H H MeCR Me 0 NO 2 4 (48) (49) The (Z)-ethylidenepenem ester (48) (40 mg) was dissolved in a mixture of dioxan (8 ml) and water (2 ml) and was hydrogenated over 5% palladium/ charcoal catalyst (60 mg) at S.T.P. for 30 minutes. Further catalyst (40 mg) was added and the hydrogenation continued for 30 minutes. A 1% sodium bicarbonate solution (0.90 ml) was added and the mixture worked up as for Example 1(b) to give the sodium salt (49) (4.4 mg) as an amorphous solid, "X. max (1^0) approximately 270 (£ m 5610) and 288 nm (5940).

N.Z. PATENT OFFICE ,1-1 r: ~ u KJ -. ~ / Preparation 5(a) Potassium 2-Acetamidoethyltrithiocarbonate S S0 K® Y s (50) ' (51) 2-Acetamidoethanethiol (50) (3.57 g) was added to a solution of potassium hydroxide (1.62 g) in ethanol (25 ml) at room temperature. After 15 minutes the stirred mixture was cooled in an ice-bath and treated with carbon disulphide (3.6 ml). After 15 minutes at ice-bath temperature the stirred mixture was allowed to attain room temperature during 30 minutes. The yellow solid which had crystallised was filtered, washed with dry ether, and dried under vacuum to give the trithiocarhonate (51) (4.79 g),<^ max (Nujol) 3390, and 1640 cm-1; 5 ppm [(COj^SO] 1.82 (3H, s), 3.0 - 3.4 (4H, m), 8.1 (1H, broad signal, exch. D2O). (Found: C, 25.6; H, 3.4; N, 5.8; S, 41.0. C^HgNOS^K requires C, 25.8; H, 3.4; N, 6.0; S, 41.2%).

.SH h3cochn• h3cochn- n.2. pa7i~ T? f 1 t" L. U ^ ~ Preparatlon5 (b) (3RS>4SR)-4(2-Acetaroidoethylthiothiocarbonylthio)-3-[l-(SR)-t-butyldiphenylsilyloxyethyl]azetidin-2-one He Me H, BuVh^iO-^V = = S02Me +- H H Bu Ph^SiO y \ " 0= HH s NH (8) (52) The sulphone (8) (2.05 g) was dissolved In methylene chloride (20 ml) and was treated with a solution of potassium 2-acetamidoethyltrithiocarbonate (51) (2.22 g) in water (4 ml). The mixture was stirred at room temperature for 4 hours, diluted with methylene chloride (20 ml) and washed with brine (10 ml). The dried (MgSO^ organic layer was evaporated and the residue chromatographed to give the trithiocarhonate (52) (1.20 g) as an amorphous solid, X max (CH^CN) 302 nra ( £ 12,880); -t/ max (CHCl^ 3440, 3400, 1775, 1670 cm-1; 6 ppm (CDC13) 1.05 - 1.15 (12H, m), 1.98 (3H, s), 3.21 (1H, dd, 3 2.5 and 4.5 Hz), 3.5 - 3.6 (4H, m), 4.1 - 4.4.(1H, m), 5.67 (1H, d, 3 2.5 Hz), 5.75 - 6.0 (1H, broad signal, exch. D2O), 6.70 br (1H, s, exch. D2O), 7.3 - 7.8 (10H, m).

M.2.PA a v 1 ■ o : r ■ • L. \J . .... w "7 / Preparation 5(c) (3R5,45R)-4-(2-AcetafT)idoethylthiothiocarbonylthio)-3-[1-(SR)-t-butyldiphenylsilyloxyethyl]-l-(l-hydroxy-l-p-nitro-benzyloxycarbonylmethyl)azetidin-2-one BuTh^iO NHAc Bu Ph^SiO (52) (53) The trithiocarhonate (52) (1.26 g) and p-nitrobenzyl glyoxylate mono-hydrate (1.05 g) were heated in refluxing benzene (25 ml) under argon for 24 hours with provision for removal of water. The mixture was evaporated and chromatographed to give the hydroxyester (53) (1.04 g), a mixture of stereoisomers, as an amorphous solid, max (CHC1-.) 3600 - 3000, 1775, 1755 slight -1 shoulder, 1670 cm 204b37 Preparation 5(d) (3RS>4SR)-4-(2-Acetamidoethylthiothiocarbonylthio)-3-[1-(SR)-t-butyldiphenylsilyloxyethyl]-l-(l-chloro-I-p-nitro-benzyloxycarbonylmethyl)azetidin-2-one H ButPh2SiO Me "J H 0 s N JO H NHAc Bu"Ph2SI0^ co2ch2- / w •NO. (53) (54) A solution of thionyl chloride (246 mg) in dry tetrahydrofuran (5 ml) was added, dropwise in 5 minutes, to a stirred mixture of the hydroxyester (53) (1.04 g) and 2,6-lutidine (221 mg) in dry tetrahydrofuran (20 ml) at -10°C. After stirring at -10°C for 15 minutes the mixture was filtered and the filtrate evaporated. The residue was re-evaporated from dry toluene (2 x 5 ml) to give the chloroester (54) (1.04 g) as an amorphous solid,a/ max (CHCl^) 3430, 1785, 1760 slight shoulder, 1670 cm"1.

'N p ■*. 1 v / Preparation 5(e) (3RS >4SR)-4-(2-Acetamidoethylthiothiocarbonylthio)-3-[l-(SR)-t-butyldiphenylsilyloxyethyll-l-(l-p-nitrobenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidin-2-one Me H. LI LI /, | n rl ~ Bu Ph^SiO CI NHAc Mp %] g Bu^Ph^SiO C02CH2-(f yN02 NHAc N PPh "Y°3 C02CH2-r' V NO, (5*0 (55) A mixture of the chloroester (54-) (1.05 g), triphenylphosphine (1.44 g) and 2,6-lutidine (177 mg) was heated in dry dioxan (20 ml) at 60°C under dry argon for 32 hours. The mixture was worked up as for preparation l(i) to give the phosphorane (55) (662 mg) as an amorphous solid, AT" max (CHC1.,) 3430, -1 1755, 1670, 1620, 1605 shoulder cm . Also obtained was recovered chloroester (54) (245 mg) which was recycled to give the phosphorane (55) (195 mg). t^AUG f9$3 204SJ/ Preparation 5(f) (3RS>ASR)-4-(2-Acetamidoethylthiothiocarbonylthio)-3-[I-(SR)-hydroxyethyl]-l-(1-p-nitrobenzyloxycarbonyl-l-triphenyl-phosphoranylidenemethyl)azetidin-2-one Bu Ph2SiO NHAc (55) (56) The phosphorane (55) (800 mg) was dissolved in methanolic hydrogen chloride (15% w/v HC1, 20 ml) and the mixture kept at room temperature for 7 hours. The mixture was diluted with ethyl acetate and neutralised with saturated sodium bicarbonate solution. The organic layer was separated and washed with brine. The dried (MgSO^) organic layer was evaporated and chromatographed to give the phosphorane (56) (397 mg) as an amorphous solid, AT' max (CHC13) 3600 - 3100, 1755, 1670, 1625, 1610 shoulder cm"1.

Preparations (q) (5RS,6SR,8RS) and (5RS,6R5T8SR)-p-Nitrobenzyl 2-(2-Acetamidoethylthi'o)-6- (1 -hydr oxye thy 1 )penem-3-car boxy late H He J H HO O* II NHAc S r PPh- C02CH2-\ VN02 NHAc C02CH2 \ / N°2 (56) (57) The phosphorane (56) (375 mg) was heated in refluxing xylene (375 ml) under dry argon for 5 hours. The mixture was evaporated and the residue chromatographed to give a mixture of the cis and trans isomers of the hydroxy-ethylpenem (57) (150 mg). Fractional crystallisation of the mixture from methanol gave the pure (5RS,6SR,8RS) isomer of the penem ester (57) (50 mg) as neefdles, m.p. 199 - 202°C; X max (EtOH) 261 (£ 12,360) and 338 nm (7,760); ■if max (Nujol) 3520, 3290, 1800, 1670 and 1635 cm"1; 6 ppm [(CD^SO] 1.17 (3H, d, 3 6 Hz), 1.80 (3H, s), 2.95 - 3.17 (2H, m), 3.26 - 3.36 (2H, m), 3.86 (1H, dd, 3 1.5 and 5.5 Hz), 3.92 - 4.06 (1H, m, collapsing to dq, 3 5.5 and 6 Hz on exch. D20), 5.2 - 5.5 (3H, m, 1H exch. D^O leaving 5.28 and 5.33, 2H, ABq, 3 14 Hz), 5.74 (1H, d, 3 1.5 Hz), 7.68 (2H, d, 3 8 Hz), 8.15 (1H, t, 3 5 Hz, exch. D20), 8.23 (2H, d, 3 8 Hz). (Found: C, 48.6; H, 4.4 ; N, 8.7. ^19^21^3^7^2 reclu:'-res 48.8; H, 4.5; N, 9.0%). Evaporation and re-chromatography of the mother liquors gave the impure (5RS,6RS,8SR) isomer (57) (53 mg), 5 ppm [(CD^CO] (inter alia) 1.51 (3H, d, 3 6 Hz), 2.01 (3H, s), 4.12 (1H, dd, 3 4.0 and 10.5 Hz), 4.28 - 4.45 (1H, m), 4.54 (1H, d, 3 5.5 Hz), 5.98 (1H, d, 3 4.0 Hz).

Ai.Z. PATENT OFFICE IS AUG 1983 Example 5(a) (5RS)-p-Nitrobenzyl 2-(2-Acetamidoethylthio)-6-ethylidenepenem-3-carboxylate ) H H''-J H H Me V MeCH (57) (58) The (5RS,6SR,8RS) isomer of the penem ester (57) (40 mg) was suspended in dry dioxan (10 ml), cooled in an ice-water bath,and treated with triethyl-amine (17 mg) and methanesulphonyl chloride (20 mg). After stirring at room temperature for 30 minutes the mixture was treated with a further 1 equivalent of each reagent. The mixture was stirred for a further 30 minutes, cooled in an ice-water bath and treated with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (39 mg). The mixture was allowed to' attain room temperature, stirred for 10 minutes, and treated with further DBU (26 mg). After stirring at room temperature for 20 minutes the mixture was evaporated to low volume, diluted with ethyl acetate (20 ml) and washed successively with 5% citric acid (4 ml), brine (4 ml), saturated NaHCO^ solution (4 ml) and brine (3x4 ml). The dried (MgSO^) organic layer was evaporated and chromatographed to give the ethylidenepenem ester (58) -(26 mg), a 2 : 1 mixture of (E) and (Z) isomers, as an amorphous solid, X max (EtOH) 265 and 318 nm; max (CHCl^) 3440, 1780 and 1675 cm"1; 6 ppm (CDC13) 1.84 and 2.10 (3H, each d, 3 7 Hz), 1.94 (3H, s), 2.95 - 3.65 (4H, m), 5.19 and 5.49 (2H, ABq, 3 13 Hz), 6.02 (2/3H, q, 3 7 Hz), 6j.l3 and 6.17 (1H, each s), 6.46 (1/3H, q, 3 7 Hz), 7.4 - 7.8 (3H, broad signal plus d, 3 9 Hz), 8.21 (2H, d, 3 9 Hz).

Similar treatment of the impure (5RS,6RS,8SR) isomer of the penem ester (57) (40 mg) gave a 4 : 1 mixture of the (E) and (Z) isomers of the ethylidenepenem ester (58) (18 mg).

Example 5(b) (5RS)-Sodium 2-(2-Acetamidoethylthio)-6-ethylidenepenem-3-carboxylate MeCH H MeCH NHAc ^n© .. © CO,, Na (58) (59) The ethylidenepenem ester (58) (40 mg) was dissolved in a mixture of dioxan (8 ml) and water (2 ml) and hydrogenated over 5% palladium/charcoal catalyst (60 mg) at S.T.P. for 40 minutes. Further catalyst (40 mg) was added and the hydrogenation continued for 30 minutes. A 1% sodium bicarbonate solution (0.75 ml) was added and the mixture worked up as for Elxample 1(b) to give the sodium salt (59) (9.9 mg), a 2 : 1 mixture of (E) and (Z) isomers, as-an amorphous solid, A max (H20)302 nm; 6 ppm (D^O) 1.83 (1/3 CH^, d, 3 7 Hz), 1.98 (3H, s), 2.04 (2/3 CH3> d, 3 7 Hz), 2.87 - 3.20 (2H, m), 3.35 -3.55 (2H, m), 6.18 (2/3H, s), 6.20 (2/3H q, 3 7 Hz), 6.27 (1/3H, s), 6.54 (1/3H, q, 3 7 Hz)..

Preparation 6 (a) _ 66 _ •-> ,'v r ' 7 -t J u I 3-(l-Acetoxycthyl)-l-(l-mcthoxycarbonyl-2-mcthylprop-l-enyl)■ 4-methylthioazetidin-2-one Me H 0: SMe H,J AcO N-v^" 0- CO^Me H H SMe y~.

CO^Me Me OAc H H SMe Y C02Me (5) (60) (61) AcO 15AU3B33 L1 (63) CO£Me A solution of acetic anhydride (292 mg) in dry methylene chloride (2 ml) was added dropwise over 3 minutes to a stirred, ice-bath cooled, mixture of the hydroxyethylazetidinones (4) (650 mg), triethylamine (288 mg) and 4-dimethyl-aminopyridine (26 mg) in dry methylene chloride (10 ml). After 45 minutes at ice-bath temperature the mixture was evaporated to low volume, diluted with ethyl acetate, and washed with dilute hydrochloric acid, brine, sodium bicarbonate solution, and brine. The dried (MgSO^) organic layer was evaporated and chromatographed to give two fractions. The less polar fraction, the (3RS,4SR)-3-[l-(RS)-acetoxyethyl]azetidinone (60), contaminated with approximately 25% of the (3RS,4SR)-3-[l-(SR)-acetoxyethyl]azetidinone (61), was obtained as a gum (204 mg), max (CHCl^) 1760, 1730 sh. cm 6 ppm (CDCl^) 1.41 and 1.43 (3H, each d, 3 7 Hz), 1.98 - 2.23 (12H, m), 3.18 - 3.37 (1H, m), 3.76 (3H, s), 4.91 (0.75 H, d, 3 2 Hz), 4.99 (0.25 H, d, 3 2 Hz), 5.15 - 5.50 (1H, m).

O -"vK 1 ~ 67 ~ The more polar fraction, the (3RS,4RS)-3-[l-(SR)-acetoxyethyl]azetidinone (63) (502 mg) was obtained as a waxy solid, m.p. 73 - 5°C (cubes ex ethyl - -acetate/petroleum ether), -c/ max (CHCl^) 1760, 1750 sh, 1730 sh. cm-1; 6 ppm (CDC13) 1.47 (3H, d, 3 6.5 Hz), 1.99, 2.03 and 2.24 (12H, each s), 3.63 (1H, dd, 3 5 and 9 Hz), 3.76 (3H, s), 5.07 (1H, d, 3 5 Hz), 5.29 (1H, dq, 3 6.5 and 9 Hz). (Found: C, 53.5; H 6.7; N, 4.4; S, 10.5; M+, 315.1149. C1ZfH21N05S requires C, 53.3; H, 6.7; N, 4.4; S, 10.2%; M, 315.1137).

Preparation 6(b) (?R5j4R5)-3-f1-(SR)-Acetoxyethyll-4 -methylsulphonylazetidin-2-one AcO v AcO H H . S02Mq — NH cr (64) A solution of m-chloroperbenzoic acid (J>0^ mg) in. ethyl acetate (5 nil) was added dropviae over 3 minutes to a stirred^ ice-hath cooled^ solution of the (3BSj4RS) azetidinone (63) (255 ^s) in. ethyl acetate. (10 ml); The mixture vas allowed to attain room temperature during 45 minutes and was washed with saturated sodium "bicarbonate solution (2x5 ml) a*1"! "brine (315 Etl) • dried (MgSO^) organic layer was diluted with ethyl acetate (25 ml), cooled to -20and ozonised oxygen passed until the starting material had been consumed (t.l.c.). The excess ozone was removed by passage of argon and the mixture was treated with methanol (20 ml). After stirring at room temperature for 20 hours the mixture was evaporated and the residue triturated with ether to give the sulphone (64) (137 ™g) as a solidj m.p. 139 - 141 °C (plates ex —1 chloroform/ether); v (CHC1^) 34-00^ 3340^ 1790, 1735, cm S 6 PPm [CDC13 + (CD )2C0] 1.44 (3H, d, J 6 Hz), 2.01 (3H, s), 2.97 (3H, a), 3.86 (1H, dd, J 5 and 10 Hz with further slight coupling to the NH proton as revealed by a decoupling experiment)j 4.83 (1H, ^ J 5 Hz), 5-65 (1H, dq,- J.6;and 10 Hz), 7.99 (1H, hroad signal). (Found: C, 41.2; H, 5-6; 3^.5-9* S, 13.7- CqH^^ITO-S requires C 40.9; H 5-5; H 6.0; S, 13.6%). o lp y * J * 3 "7 ,, -v .i rr 2 0 4 J -> t Preparation 6(c) (^R5J 4SR)-3-n-(SR)-Acetoxyethyl"l-4—ethylthiothiocarbonylthioazetidin-2-one H Me AcO' H H : S02lfe I AcO 0^ (64) NH SEt (65) Potassium ethyltrithiocaxbonate (82 mg) was added to a stirred, ice-bath cooled, mixture of the sulphone (64) (100 mg), methylene chloride (8 ml) and water (2 ml). After 10 mirrutes the stirred mixture was allowed to attain room temperature during $0 minutes. The mixture was worked up as for preparation 1(f) to give, after chromatography, the trithiocarhonate (65) (100 mg) as a as a yellow solid m.p. 101 — 5°C (ethyl acetate/petroleum ether); \ * IB3JC + (EtOH) 300 (effl 13,700) and 236 nm (3,700); (CHCl^) 3420, I78O, 1740 cm 6 ppm 1.36 (t, J 7 Hz) and 1.37 (d, J 6 Hz) together 6H, 2.03 (3H, s), 3-35 (q, J 7 Sa) superimposed on m, together 3H-, 5-30 (1H, dq_, J 6 and 6Hz), 5-58 ("IS, d, J 2.5 Hz), 6.80 (1H, broad signal). (Found: C, 41.3; H, 5-2; N, 4.7; S, 33.2. requires C, 41.0; H, 5.1; N, 4.8; S, 32.8%). -1 2o:3:7 Preparation 6(d) (3RSj 4SR)-3~r 1-(SR)-Acetoxyethyl1-4— ethylthiothiocarboiyylthio-1-( 1-hydroxy-1-p-nitroben2yloxycarbon,ylmethyl)azetidin-2-one Me Hv , H H xlv l n. n 1 «H (65) . r -> The trithiocarhonate (65) (100 mg) and ]>-nitro"benzyl glyoxylate monohydrate (116 mg) were heated in refluxing "benzene (5 ml) "under argon for 26 hours with provision for removal of water. The mixture was evaporated and chromatographed to give the hydroxyester (66) (112 mg), a 1 : 1 mixture of stereoisomers, as a gnrn, (CHClj) 3600 - 3000, 1780, 1750 cm-1; 6 ppm (CDCl^) .1.25 - 1.45 (63, m), 2.*00 (3H, s), 3.22- - 3.60 (3H, m, plus q, 7 Hz), 3-90 (2H, d, J 8 Hz, exch. D20), 4.04 (4h, d, J 9 Ha, exch. BgO), 5-25 - 5-45 (3iS, m), 5-56 (|H, d, J 9 Hz, collapses to s on exch. 6.08 (-|H, d, J 2-g- Hz), 6.11 (-§H, d, J 2£ Hz), 7.54 and 7.56 (2H, each d, J 8 Hz), 8.24 (2H, d, J 8 Hz).

') \) Zl l ' / C. \j i v-> _• / Preparation 6(e) (5BSj 4SR)-3-f 1-(SR)-Acetoxyethyl1-1-(l-chloro—1-p-mtrobenzyloxyoarboiyyligothyl)-4—eth.vlthlothiocajbonylthloazetidin-2-one S Ne H H Ao/S Q i ;'Y xp^0; CO^CKg- SEt NO, (66) AcO ,S .SEt ' Y -N 'Y^C1 C02CH—(f y— NO„ (67) A solution Df thionyl chloride (39 ng) in dry tetrahydrofuran (0.5 ml) was added dropwise to a stirred mixture of the hydroxyester (66) (110 mg) and 2,6-lutidine (35 ^g) in. dry tetrahydrofuran (5 nil) at -10°G. The mixture was stirred at -10°C for 10 minutes, filtered, and evaporated. The residue was re—evaporated from dry toluene (2x3 nil) "to give the chloroester (67) (114 mg) as a gum, v (CHCi) 1790, 1745 cm" max. 3 ' -1 rv ' c; "* 7 U 4 ^ ^ / - 72 " Preparation 6(f) (3BS| 4SB)-3~r 1-(SR)-Acetoxyethyl"]-4—ethyl thiothiocarbonylthio-l-fl-p-nitrobeznyl-03Cycarbonyl-1-triphenylphosphoranylide:nemethyl)az,etidin-2-one Me ° y S Vp H H AcO^^ (T .SEt ' Y- ' Hv AcO' r 1'itt CI COgCE^ (67) ■HO, COgCHg- / ^ (68) A mixture containing the chloroester (67) (114 mg), tripheiiylphoaphinje (115 nig) and 2,6-lutid ine (28 mg) in dry dioxan (5 ml) was stirred at 60°C under dry argon for 26 hours. The mixture was worked up for preparation l(i) to give, after chromatography, the phosphorane (68) (77 ™g) as 311 amorphous solid, v max (CHCl^) I76O, 1620, 1605 shoulder cm \ Preparation 6 (ft) ■(*)RS 6SR8RS) and (5RSj 6RSj8SR)-p-NitrobenzyI-6-(l-Aceto:>ryeth.yl)-2-ethylthio-•peneo-3-carbo:xylate AcO' Me SEt Ac H H <r -N- co2ch2 (68) (69) + (70) A solution of the phosphorane (68) (1 .0 g) in ixylene (1000 ml) vas refluxed under argon for 10 hours. The mixture was evaporated and chromatographed to give two products. The less polar product, the (5RS,6RS,8SR) penem ester (69) (120 mg) was obtained as a solid, m.p. 131 - 133°C (needles ex ethylacetate/ petroleum ether), X (EtOH) 260 (16,200) and 334 n.m. (11,000); v TO1f (CHClj) 1795, 1730 and 1695 cm-1; 6 ppm (CDGl^) 1.37 (3H, t, J 7-7 Hz) 1.54 (3H, d, J 6.3 Hz), 2.04 (3H, s), 2.76 - 3.26 (2H, m), 4.00 (1H, dd, J 4.0 and 9.9 Hz), 5-18 a~nd 5.48 (ABq, J 14 Hz) overlaying a m, together 3s, 5-73 (1H, J 4.0 Hz), 7.6O (2H, d, J 8 Hz), 8.21 (2H, d, J 8 Hz). (Found: c, 50.5; H, 4.2; n, 6.1; S, 13.8; M+, 452.0729. c-j^q^o s2 requires c, 50.5; H, 4.4; IT, 6.2; S, 14.2%; M, 452.0712). The more polar product, the (5RS,6SR,8RS) penem ester (70) (221 mg), was obtained as a solid, m.p. 131 - 132°C (needles ex ethyl acetate/petroleum ether), x (EtOH) 261 (e 16,500) and 339 n.m. (11,000); v (CHCl^ 1795, 1740, and 1695 cm-1; 6 ppm (CDClj) i.29 - 1 .46 (6h, m), 2.05 (3h, s), 2.70 - 3.16 (2h, m), 3.84 (1h, dd, j 1.6 and 7.7 Hz), 5.21 and 5.47 (ABq, j 14 Hz) overlaying a m, together 3h, 5-62 (1h, d, j 1.6 Hz), 7.62 (2H, d, j 8 Hz) ^ 8.21 (2h, d, j 8 Hz). (Found: c, 50.4; H, 4.2; N, 6.1; S, 13-9; M+, 452.0707. C^H^I^O,^ requires C, 50-5; H, 4.4; H, 6.2; S, 14.2%; M, 452.0712).

C. U ' t J J l rumple 6 (5R3)-p-Nitrobenzyl 6-Bth,ylidene-2-ethylthiopenem-5-carboxyIate tt OAc ? v-VSEt 0^ set 1.

COgCH^ (26) / NOr -NO, 2 Me SEt (26) In ice-bath cooled solution of the penem ester (70) (45 mg) in <icy methylene chloride (1 ml) was treated with 1,8-diazabicyclo[5-4.0]undec-7-ene (UBU) (0.1 ml of a solution containing 166 mg UBU/ml methylene chloride). After stirring at ice-bath temperature for 15 minutes the mixture was diluted with ethyl acetate (10 ml) and washed with 5% citric acid (2 ml), brine (2 ml), saturated sodium bicarbonate solution (2 ml) and brine (3x2 ml) . The dried (MgSO^) organic layer was evaporated and the residue chromatographed on silica gel eluting with methylene chloride to give the E-ethylidenepenem ester (28) (7 mg) and the Z-ethylidenepenem ester (26) (14 mg) . o p /i 7 Preparation 7(a) (3 £, 4R5)-5-Bromo-3-hydroy/roeth,yl-1-(l-mgthox?/isar"bon.Yl-2-niethylprop-1-eriyl)-4-rDe-bhylthioazetidin-2-one Br H0CH2 Br- SMe <r r " J~0- SMa COJfe CO_Tfe (2) (77) A solution of methyl magnesium "bromide (2M in diethyl ether, 0.7 ml) "was added dropwise to a stirred solution of the dibromosecopenicillanate (2) (0 -5 s) in dry tetrahydrofuran ("10 ml) at ~rj6°C. After stirring at -"J6°0 for 10 minutes a stream of argon was passed, first over dry paraformaldehyde (0.5 g) heated at 150°C and then over the surface of the vigorously stirred reaction mixture. [During a 10 minutes reaction time approximately 0.2 g of formaldehyde was generated]. The argon/formaldehyde stream was then interrupted, stirring was maintained for 5 minutes, then a saturated aqueous solution of ammonium chloride ,(1 ml) was added and the stirred mixture was allowed to reach room temperature. The mixture was then diluted with ethyl acetate, washed with water and brine, dried (MgSO^) and evaporated to give a crude gum. Chromatography of the crude product on silica gel eluting with ethyl acetate/petroleum ether mixtures gave the bromohydrin (77) (0.23 g, 53%) n.3 a clear gum, v (CHCl^) 3570, 3350 (b), 17&5, 1720, 1625 (w) cm ^ . 6 (CDCl^) 2.03 (3H, s), 2.14 (3H, s), 2.26 (3H, s) 2.86 (1H, t, J 7 Hz exch. I^O) 3.78 (s) 4.1 (m, collapses to ABq, centres 3-92 and 4.17, J 12 Hz with D^O) two signals together 4H, 5-39 (1H, s)» <•> *, n. C U '"f - 7 76 - Preparation 7(b) (3R5 4RS) and (3KSj4SR)-3-Hydroxyraethyl-1-(l--ii!ethoxycarbonyl--2--methyl"Prop-1--eny I) -4—me thy 1th ioaae t idin- 2- one HOCH.

Br- SMe y-: C02Me (77) HOCH SMe G02Mb (78) The bromohydrin (77) (100 mg) in tetrahydrofuran (1 ml) cooled in ice/salt mixture was stirred with zinc dust (200 mg) and H/l aqueous ammonium acetate solution (0. 2 ml). After 10 minutes in the cold and 10 minutes at room temperature the reaction mixture was filtered, diluted with ethyl acetate and washed with N/10 aqueous hydrochloric acid then brine. The solution was dried (MgSO^) and evaporated to an oil. Chromatography on silica gel eluting with ethyl acetate/petroleum ether mixture gave an 85 : 15 mixture of the cis and trans-hydroxymsthylazetidinone s (78) (54 nig, 70%) (CHC13) 3450 (b), 1760, 1725, 1630 cm-1. 6 (CDC13) 2.0 (3H, s) 2114 (3H, sj 2.24 (3H, s) 2.4 - 2.8 (1H, m, exch. D20) 3.2 - 3.7 (1H, m), 3-75 (3H, s), 3.9 - 4.1 (2H, m), 5-03 (d, J 3 Hz) 5-10 (d, J 5 Hz) together 1H.

Preparation 7(c) 3-t-Butyldiphenylsilyloxyroethyl-1-(l-methoxycart>o:nyl-2-met}tvlprop-1-enyl-4— roethylthioazetidinone HOCH^- SMe Bu EhgSiOCH^ SMe 0^ i COgMe ccyfe (78) (79) The mixture of cis and trans^hydroxymethylazetidinones (78) (O.65O g) in. dry dime thyl f onnami de (20 ml) was treated with t-butyldiphenylsilyl chloride (1.25 g) and imidazole (0.34 g) at room temperature for 2-Sr hours. Most of the solvent was evaporated off in vacuo and the residue was partitioned between ethyl acetate and water. The solvent layer was then separated, dried (MgSO^) and evaporated. The residue was chromatographed on silca gel eluting with ethylacetate/petroleum ether mixtures. First to "be eluted was the fraction containing the trans isomer (240 mg), then a mixed cis/trans fraction (45 mg) and finally the cis isomer (825 mg). The less polar fraction, the (3RS,4SR)-3-t-butyldiphenylsilyloxymethylazetidin-2-one was obtained as a gum v (CHC1-.) . * ULcLX • j 1755, 1725, 1630 cm"1. 6 (CDCl^) 1.12 (9H, s) 2.05 (3H, s) 2.15 (3H, s), 2.30 (3H, s) 3.2 - 3-55 (1H, m) 3-77 (3H, s) 4.08 (2H, b.d., J 4 Hz) 5.25 (1H, d, J 3 Hz) 7.35 - 8.0 (10H, m). The more polar fraction, the (3RS,4RS)-3—t-*butyl-diphenylsilyloxymethylazetidin-2-one was obtained as a gum, \> (CHCl^) 1755, 1725, 1630 cm"1; 6 (CDCl^) 1.10 (9H, s) 2.08 (3H, s) 2.17 (?H, s) 2.28 (3H, s) 3.79 (3H, s) 4.0 - 4.45 (3H, m) 5 .23 (1H, d, J 6 Hz) 7.2 - 8.1 (10H, m).' 204537 _ 7b - Preparation 7(d) f5BS 4RS) and (3HSj 4SR)~3-t-ButyIdi"phenylsilyIo3cyiaethyl-4—methylsulphoiiyl- azetidin-2-one BuEh2SiOCH2_ SMe COgMe 3u R^SiOCH^. >02Me 0 (80) A solution of m-chloroperbenzoic acid (0.85 g) in ethyl acetate (10 ml) was added dropwise over ten minutes to a stirred, ice-cooled solution of the azetidinone (79) (cis/trans mixture) in ethyl acetate (JO ml). After 10 minutes the temperature was raised to room temperature for half an hour.

The reaction mixture was washed with saturated aqueous sodium "bicarbonate, water and "brine. The dried (MgSO^) organic layer was evaporated. The white amorphous residue was redissolved in methylene dichloride, cooled to -20°C, and ozonized oxygen was passed for 45 minutes. Methanol (50 ml) and 2,6-lutidine (10 drops) were then added and the mixture was kept at room temperature for 1 hour -then evaporated to give a gum. This was redissolved in ethyl acetate, washed with 5% aqueous citric acid, then brine, dried (MgSO^) and evaporated.

The residual gum was chromatographed on silica gel eluting with ethyl acetate/ petroleum ether mixtures to give the sulphone (80) as a gummy mixture of — 1 cis/trans isomers (500 id^)j v m3JC (CHCl^) 3400j 1790^ 1320^ 1150 cm 6 (CDCl^) 1.1 (9H, s) 3.1 (3H, s) 3.65 - 4.65 (m, C^OSi, C-3-H and C-4-H trans) 4.78 (d, J 4 Hz, C-4—H cis) together 4H, 7-2 - 7-9. (11H, one H exch. I>20) . 204537 Preparation7 (e) (3RS^SR)-3-(t-ButyldiphcnylBilyIoyynieth,yl)-4-ethylthj.othioc.nrborwlthio-a2etidin-2-one t„ „ t, ->t. U.UU1, . 2 2V .' 2* Bu Pt^SiOCH SOJfe 311 SCSJBt 1' —> ■m NH cT (80) (81) A mixture of the sulphone (80) (cis/trana mixture^ 1.8 g) in methylene chloride (50 ml) and potassium ethyl trithiocarhonate '(*l -52 g) in water (50 ml) was stirred vigorously at room temperature. After 6 hours the solvent layer was separated^ washed with water^ dried (MgSO^) and evaporated. The residue was a yellow crystalline mass which was washed with a little toluene/ petroleum ether mixture (1 .22 g) . Recrystallisation from ethyl acetate/ petroleum ether gave the pure trans azetidinone (81) as yellow needles^ m.p. 142° v (CHC1 ) 3420^ 1780 cm-1 6 (CDC1 ) 1 .06 (9H s) 1.38 (JH t ^ IELSJt • ^ ^ ^ ^ ^ J 8 Hz) 3-40 (q^ J 8 Hz) overlaying (m)^ together 3H, 3-95 - 4.15 (2H^ m), 5.76 (1H^ d, J 2 Hz) 6.78 (lHa h.s.) 7.25 - 7.9 (10H, m). (Pound: C, 57-8; 6.0; 2.9; S> 20.3. CgjHg^MOgS^Si requires 58.1; H^ 6.1; N^ 3-0; Sj 20.2%).

N.2. PATENT OFFiCE ^ f * AUG I983 1 fx ■ CV "i- *. n. u 1 - 80 Preparation 7 (f) (BS^ 4SR)-3-t-But,yldiphenylsilylo>^rmethyl-4-ethylthiothiocarbon.'ylthio-1-(l-h,'ydxoxy-1-i p-m.trobenzyloxycar'bonyiEethyl )azetid±n-2-o:ne Bu R^SiOC^ SCSJEt 2 Bu 'Ph2SiOCH2 ^SCS^Et or □L ' ' ■» (81) tjh^OH io2CE^==\^2 (82) The trithiocarhonate (81) (3*10 mg) and j^-nitrohenzyl glyoxylate monohydrate (300 mg) were refluxed in benzene (20 ml) under argon for 24 hours with provision for removal of water. The mixture was evaporated and the residual gum chromatographed on silica gel eluting with ethyl acetate/petroleum ether mixtures to give the hydroxy-ester (82) as a' mixture of diastereoisomers (420 mg)j a yellow amorphous solid. v max (OHCl^) 3500^ 1780^ 1760 cm T.06 (9H; s) 1.45 (3H, tj J 8 Hz) 3.40 (q^ J 8 Hz) 3.52 (b.d. J 2 Hz) together 3H, 4.1 (2H, b.s.) 4.34 and 4.4 (1H; 2 dj J 8 Hz^ exch. 3>20) 5.35 (s) 5.47 and 5.73 (2 dj J 8 Hz) together 3H, 6.3 and 6.44 (1H, 2 dj J 2 Hz) 7.3 - 8 .5 (14H, m). -1 6 (CDCl^) o c. a r* 0 4 b 7 Preparation 7 (g) (3BS 4SR)-3-t~Butyldiphenyl3ilyloxyTOethyl-4—ethylthiothiocarbonylthio-1-(l-P-nitrobenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)a2etidin--2-one Bu Ph2SiOC V: T J3CS0Et " <L (82) OH. C02CH2-/^y N02 Bu Jh^SiOCH, 2\ pCS2Et CHClC0„CHr-(\ cT 2 ^ (83) -K0r Bu Ph.SiOCH 2 2> SCS0Et c. i jt PPh.. (84) C02CH2"\\ -NO, The hydroxy-ester (82) (4-20 mg) in tetrahydrofuran (20 ml) at -20°C vas treated with 2^6-lutidine (99 mg) and thionyl chloride (0.07 ml) and allowed to reach room temperature over 0.5 hours. The solution was then filtered and evaporated under high vacuum to give the crude chloro-ester (83). This was redissolved in dioxan (20 ml) then 2^6-lutidine (29 mg) and triphenylphosphine (320 mg) were added. The stirred mixture was kept at 60 °C under argon for 7 days and was then evaporated to dryness in vacuo. The residue was dissolved in ethyl acetate and washed successively with 1% aqueous citric acid solutio^ sodium bicarbonate solution and brine. The dried (MgSO^) organic layer was evaporated the residue chromatographed on silica gel eluting with ethyl acetate/petroleum ether mixtures to give the phosphorane (84) as an amorphous yellow solid (370 nig) v (CHCl^) 1750, 1615 1605 cm"1.

Preparation 7(h) (5BS 4SR^-3-HydroxymethYl-4-ethylthiothiocar"bonyIthio-1-(l-p-nitro"ben2yloyy-carbonyl )-1-triphenylphosphoranyIidenemethyl )azetidin-2-one ButPh„SiOC SCS_Et / ^ HOCH, 2\ 0^ ■ M . -SCS2Et 'Ph. (85) C02Ca2-C=^'M°2 A solution of the phosphorane (84) (1 .75 S) i*1 15% methanolic hydrogen chloride (30 ml) was kept for 1 hour at room temperature. It was then neutralised with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The solvent layer was dried (MgSO^) and evaporated then the residue was chromatographed on silica gel eluting with ethyl acetate - petroleum ether mixtures. The pure product (85) was isolated as a yellow amorphous solid (1.09 e)a v (chci3) 3400 (b), 1760, 1620, 1610 cm -1 204 _ 83 - .■> 7 ^ / Preparation 7 (i) (6R5 5SR) and (6RS t 4RS)-p-Nitrobenzyl 6-H.Ydroxymethyl-2-eth,Ylthiopenem-3'~ carboxylate HOCHp^ ^SCSgEt HOCH^ » PPh5 °2(S2^ //~m2 (85) A solution of the phosphorane (85) (54-7 ing) was refluxed in xylene (150 n^) under argon for 10 hours. The mixture was evaporated and the residue chromatographed on silica gel eluting with ethyl acetate/petroleum ether mixtures to give the cis and trans penems (86) 260 mg trans/cis 7/3- Careful re—chromatography allowed pure samples of the trans and cis isomers to "be separated. The more polar trans isomer was a cream crystalline solid, Tn.p. 162 - 163° (from ethyl acetate/petroleum ether) X (EtOH) 338 n.m. (e 10,025) 261 (13_,050) v 3600, 3400 (b), 1790, 1695, 1610 cm '. 6 (250 m.c. (CDCl^) 1.35 (3H, t, J 7 Hz) 2.90 - 3-20 (2H, m) 3.94 - 4.10 (3H, m, 4.38 (1H, t, J 5 Hz, exch. I>20) 5.28 and 5.53 (2H, ABq, J 14 Hz) 5.81 (1H, d, J 1.5 Hz) 7.78 (2H, d, J 7 Hz) 8.26 (2H, d, J 7 Hz). (Found: M+, 396.480. ^16^16^2^6^2 re<iui-res 396.0446) . The less polar cis isomer was also a cream solid, m.p. 150 - 155°, v (CHC1 ) 36OO, 3400 (b), 1790 1690 cm-1. 6 (CDCl ) 1.37 (3H, t, J 7 Hz) 3.06 (2H, q, with fine coupling, J 7 Hz) 2.75 (1H, s, exch. D20) [4.03 and 4.05 (2H, q, J 7 and 9 Hz) 4.34 (1H, ddd, J 9, 7, 4 Hz) these signals described with D20 exch.] 5-27 and 5-50 (2H, ABq, J 14 Hz) 5./-90 (1H, d, J 4 Hz) 7.75 (2H, d, J 7 Hz) 8.24 (2H, d, J 7 Hz). (Found: M+, 396.0480, ^16^16^2^6^2 re(3-inres 396.0446).

Example 7 (R5)-T>-Nitro"ben2,yl 6-Methylene-2-ethylthiopenem-3-carboxylate HOCH^ SEt jr-*- C02^3.2~\\ (86) NOc MeO S0CHo 2 -V£_ cr SEt -N- (87) \ao2 CH2 (T ,SEt (88) t:O.

// -NOr The hydroxymethylpenem (86) (102 mg) in methylene chloride (15 ml) at 0°C vas treated with triethylamine (33 ®g) followed by methanesulphonyl chloride (33 n^) • The mixture was then kept at room temperature for 0.5 hours, evaporated to dryness and redissolved in ethyl acetate. The solution was washed with brinej dried (MgSO^) and again evaporated to give the crude methane sulphonate (87). This was dissolved in methylene chloride (10 ml) cooled to 0°C and treated with DBU (43 nig) . The mixture was then kept at room temperature for 0.5 hours. This was then evaporated and chromatographed on silica gel eluting with ethyl acetate/petroleum ether mixtures to give the methylene penem (88) (47 mg) as a yellow crystalline solid, m.p. 146 - 147°C (from ethyl acetate), X . (EtOH) 267 n.m. (e 18,500) 302 njn. (infl.) (11,500) 343 n.m. (infl.) (5,400), 6 (CDCl^) 1.38 (3H, t, J 7 Hz) 2.96 and 2.98 (2H, 2 d, J 7 Hz) 5.20 and 5-48 (2H, ABq, J 14 Hz) 5-48 (1H, dd, J 2.4 and 0.7 Hz) 5.98 (1H, dd, J 2.4 and 1 .3 Hz) 6.19 (1H, dd J 1 .3 and 0.7 Hz) 7.63 and 8.20 (4H, 2 d, J 8 Hz). (Found: M+ 378 .0333 . C^H^MgO^Sg requires M, 378.0342). - 85 _ Preparaticm 8 (a) (3RSj 4SR)-3-T 1-(R5)-Acetoxyethyl~l-4-methylsulpho:ny3-a2etidin-2-one Me AcO 'A H -i COgMe (60) , .SOgMe (89) A solution of m-chlbroperbenzoic acid (241 mg) in ethyl acetate (3 ml) was added dropwise over 2 minutes to a stirred, ice "bath cooled, solution of the impure azetidinone (60) (200 mg) in ethyl acetate (10 ml). The stirred mixture was allowed to attain room temperature during 45 minutes and was washed with saturated sodium bicarbonate solution (2x5 n^-) and. brine (3^5 m^) • The dried (MgSO^) organic layer was diluted with ethyl acetate (15 ml) and treated with ozonised oxygen and methanol as in preparation ~\ (e) to give, after chromatography, the sulphone (89) ("137 mg) contaminated with approximately 25% of the (JRS 4SR)-3-[l~(SR)-acetoxyethyl] isomer as a gum, v (CHCl,.) * * IB3X my v. 3550 br, 3410, 3300 br, 1795^ 1745 cm ; 6 ppm (CDCl^) 1.41 and 1.43 (3H, each d, J 6.5 Hz), 2.03 and 2.08 (3H, each s) 2.95 (3H, s), 3.68 (dd, J 2 and 7 Hz) and 3.79 (dd, J 2 and 5 Hz) together 1H, 4.53 (fH, d, J 2 Hz), 4.73 (^H, d, J 2 Hz) 5.14 - 5.45 (1H, m), 7.05 (1H, br. signal). 204 537 86 ~ Preparation 8(b) (3RS 4SR)-3-f 1-(RS)-Acetoxyethyl1-4-ethylthiothiocarbonylthioazetidin-2-one H Me.

H H AcO • SOgMa KH 0^^ (89) ^ \ ^ SEt AcO (90) A solution of the impure sulpihone (89) (110 mg) .in methylene chloride (5 ml) was cooled in an ice bath and treated vith a solution of potassium ethyl trithiocarhonate (91 mg) in vater (1 ml). After 10 minutes at ice bath temperature the stirred mixture as allowed to attain room .temperature during 30 minutes. The mixture was worked up as for preparation 1(f) to give^ after chromatography, the (3RSj4SR)-3-[l-(RS)-acetoxyethyl]azetidinone (90) (97 mg) containing approximately 20% of the (3RS>4SR)-3-[l-(SR)-acetoxyethyl] isomer as impurity, v (CHCl^) 3^10, 3410, 1780, 1740 cm 1; 6 ppm (CDCl^) 1-35 . (t, J 7 Hz), 1.37 (d, J 6 Hz) and 1.41 (d, J 6.5 Hz) together 6H, 2.03 and 2.07 (JH, each s), 3-2 - 3-5 (3H, m), 5-17 - 5-5 (1H, m), fc.43, 0 .8H, d, J 2 Ha), 5.58 (0.2H, ^ J 2 Hz), 6.5 - 6.8 br (1H). \ 87 - ) \ ' Al u t Preparation 8(c) (5RS 4SR)~3-n-(RS)-Acetoxyethvll p-ni'lro'benzyloxycar'bon.ylmethyl ;az -4— ethylthiothiocaJbonyIthio-1-(l-hydroxy-1-azetidin-2-one H AcO S cT ■NH (90) H AcO' • Me 'M H H „ ! S (r r SEt >H . COgCHg ' (91) NO,.

The impure azetidinone (90) (1 .0 g) and £-nitro"benzyl glyozzylate mono-hydrate (1 .55 g) were heated in refluxing "benzene (40 ml) under argon with I provision for removal of vater for 22 hours. The mixture was evaporated and chromatographed to give the hydroxyester (91) (1-51 g), a mixture of stereoisomers as a gum, (CHCl^) 36OO - 3100, 178O, 1745 cm" _ 88 - 204537 Preparation 8(d) (5RSj 4SR)~5—I" 1-(RS)-Aceto3Cirethyll-1- (l-chIoro-1-p~nitroben^y3 o:xycarbony line thyl )-4—ethylthiothiocarbonylthioazetid±n-2-one SEt C02CS^ y-m2 (91) (92) A solution of thionyl chloride (537 e^) tetrahydrofuran (5 ml) was added dropwise over 10 minutes to a stirred mixture of the hydroxyester (91) (1.51 g) and 2,6-lutid ine (485 Eig) in dry tetrahydrofuran (30 ml) at -10°C. The mixture was stirred at -10°C for 10 mirrutes, filtered and evaporated. The residual gum was re-evaporated from dry toluene (2x5 IQl) to give the chloroester (92) (1 -57 s) as a S™, v 1745 cm"1.

(CHCl..) 1790 and max. v 3 Preparation 8 (e) L.

G-vj j i (3RS 4SR)-3-ri-(RS)-Acetoxyethyl1-4— eth.Ylthiothiocar"bon.yIthio-1-(l-p-nitroben2yloxycarboriyI-1-triphenyIphosphoranylide:nemethyl)azetidin-2-one Me AcO 1 H H - SEt T CI CO, (92) X -NO, Hx Me AcO S SEt Y COgCHg" (93) " \ A mixture containing the chloroester (92) ("1-57 ^), triphenylphosphine ("I -58 g) and 2,6-lutidine (387 mg) in dry dioxan (30 ml) was stirred at 60 °C under dry argon for 24 hours. The mixture was worked up as for preparation l(i) to give the phosphorane (93) (1 -12 g) as an amorphous solid max.

(CHCl^) 1760, 1625 cm -1 n r; • tiu't Preparation 8 (f) (*)RS| 6SRj8SR) and (5RSj6RSj8RS)-p-Nitrobenzyl 6-(l-Acetoxyeth.yl)-2-ethylthiopenem-3—carboxylate -> COgCH^—// \ (93) The phosphorane (93) 0 -04 g) vas heated in refluxing xylene (1000 ml) under dry argon for 10 hours. The mixture vas evaporated and chromatographed to give two products. The less polar product, the (5RS,6SR,8SR) penem ester (94) (262 mg) vas obtained as a solid, m.p. 143 - 144°C (needles ex ethyl acetate/petroleum ether); X (EtOH) 339 (e 9,600) and 261 n.m. (14,400); v (CHC15) 1785, 1740, 1695 cm"1; 6 ppm (CDCl^ 1.37 (3H, t, J 7.4 Hz), 1.44 (3H, d, J 6.4 Hz), 2.09 (3H, s), 2.84 - 3-13 (2H, m), 3.96 (1H, dd, J 1.6 and 4.0 Hz), 5.1 - 5.5 (3H, m), 5.54 (1H, d, J 1.6 Hz), 7.62 (2H, d, J 8.6 Hz), 8.22 (2H, d, J 8.6 Hz). (Found: C, 50.5; H, 4.4; N, 6.2; S, 14.0; M+, 452.0721 . Oj^QNgO S2 requires C, 50.5; H, 4.4; N, 6.2; S, 14.2%; M, 452.0712). The more polar product, the (5RS,6RS,8RS)penem ester (95) (15 i°g) was also obtained as a solid, m.p. 179 - 181 °C (needles ex ethyl:acetate/ petroleum ether); X (EtOH) 33^ ( 10,300) and 261 n.m. (15,500); V ^ (CHCl^) 1795, 1735, 1690 cm"1; 6 ppm (CDOl^) 1.21 - 1.39 (6H, m), 2.09 (3H, s), 2.87 - 3.14 (2H, m), 4.04 (1H, dd, J 4.1 and 7.8 Hz), 5.09 - 5-55 (3H, m), 5-73 (1H, d, J 4.1 Hz), 7.61 (2H, d, J 8.7 Hz), 8.22 (2H, d, J 8.7 Hz). (Found: M+, 452.0692. C^q^O Sg requires 452 .0712).

L. ■ '< ■> < (. ~7 > 0 'H - J / Preparation 8(g) (5RS| 6SRt 8SR)-p-Nitrobenzyl 6-(l-Acetoxyethyl)-2-ethylsulpbinylpenem-3-carboxylate AcO H If :^SEt COgCHg- r % NO, )(94) (96) A solution of m-chloroperbenzoic acid (45 mg) in methylene chloride (1 ml) was added, in one portion, to a vigorously stirred, ice-bath cooled, mixture of the penem ester (94) (90 mg), methylene chloride (5 ml) and saturated sodium bicarbonate solution (5 ml)• The mixture was stirred at ice-hath temperature for 10 minutes and diluted with methylene chloride (10 ml). The organic layer was separated and washed with brine (3x2 ml), dried (MgSO^), evaporated and chromatographed to give the sulphoxide (9&) (53 mg), an approximately 1 : 1 mixture of isomers, as an amorphous solid, (CHCl^) 1805, 1740 and 1710 • cm-1; 6 ppm (CDCl^) 1 .32 - 1 .50 (6H, m), 2.10 (3H, s), 2.9 - 3.3 (2H, m), 4.11 (1H, dd, J 2 and 4 Hz), 5.23 and 5.46 (ABq., J 14 Hz) plus 5.1 - 5.5 (m) together 3H, 5-59 (iH, d, J 2 Hz), 5.7O (£H, d, J 2 Hz), 7.59 and 7.60 (2H, eaoh d, J 8 Hz)^ 8.25 (2H, d, J 8 Hz). ."v .1 r ~7 C u ''4 J J 1 Preparation 8(h) 6SRj 8SR)-p-Nitroben'zyl 6-(l-Acetoxyethyl)-2-(2-pyridylthio)pGnero-3-carboxylate AcO A stirred, ice-bath, cooled, mixture of the penem sulphoxide (96) (50 mg), methylene chloride (5 ml) and vater (2 ml) was treated vith sodium 2-mercapto-pyridine (16 mg) followed by benzyl dime thy 1-n-hexadecylaxnmonium chloride (47 mg) portionwise over 5 minutes. The cooled mixture was stirred for a further minutes, diluted with methylene chloride (10 ml) and washed successively with 5% citric acid (2 ml), brine (2 ml), saturated sodium bicarbonate solution (2 ml) and brine (3x2 ml). The dried (MgSO^) organic layer was evaporated and chromatographed to give the penem ester (97) (22 mg) as a solid, m.p. 140 - 142°C (needles ex ethyl acetate/petroleum ether); X (EtOH) 262 TTW3X« «« (em 17,790) and 339 n.m. (12,090); v (CHCl^ 1790, 1735, 1700 cm"1; 6 ppm (CDClj) 1.43 (3H, d, J 7 Hz), 2.10 (3H, s), 3.96 (1H, dd, J 1.7 and 3.9 Hz), 5.22 - 5.32 (1H, m), 5.30 and 5-50 (2H, ABq, J 14 Hz), 5.44 (1H, d, J 1.7 Hz), 7.25 - 734 (1H, m), 7-54 - 7-74 (4H, m), 8.20 - 8.27 (2H, m),. 8.58 - 8.62 (1H, M0. (Pound: C, 52.8; H, 4.0; N, 8.2; S, 12.5. ^i^O?^ requires C, 52'tf; H, 3 -8; N, 8.4; S, 12.8%).

Example 8 (a) (5RS)-p-Mtrobenzyl 6-Ethylidene-2-(2-pyridylthio)penem-3-carboxylate (97) (98) A solution of the penem ester (97) (55 nig) in dry methylene chloride (2 ml) was cooled to -20^0 and treated with a solution of 1,8 -diazabicyclo— [5.4.0]midec-7-ene (UBU) (20 mg) in dry methylene chloride (1 .2 ml). After stirring a -20°C for 10 minutes the mixture was treated with DBU (5 mg) in dry methylene chloride (0.3 ml). After a further 10 minutes at — 20°C the mixture vas diluted with ethyl acetate (15 ml) and washed with 5% citric acid (2 ml), "brine (2 ml), saturated sodium "bicarbonate solution. (2 ml), and brine (3x2 ml).

The dried (I'lgSO^) organic layer was evaporated and chromatographed to give the 6-ethylidenepenem ester (98) (26 mg), an approximately 2:1 mixture of Z_ and E isomers as a solid X (EtOH) 261 (16 860) and approximately 3 "16 n.m. ^ max • * m (inflection); v (CHOI ) 1780 and 1700 cm ; 6 ppm (CDC1 ) 1 .76 (2/3 CH max• p p p d, J 7 Hz), 2.08 (1/3 CH^, d, J 7 Hz), 5.25 and 5.51 (2H,. ABq, J 14 Hz), 5.95 (q, J 7 Hz) plus 6.03 and 6.08 (each s) together 1 1/3 H, 6.44 (2/3 H, q, J 7 Hz), 7.2 - 7.4 (1H, m), 7.5 - 7-75 (4H, m), 8.21 (2H, d, J 8 Hz), 8.5-8.7 (1H, m). (Pound: M+, 441 .0461. C20H^1T^0^S2 requires 441.0452). - 94 204537 Example 8 (h) (txRS)-Sodium 6-Eth.Ylidenc-2-(2-f.yi,id,ylthio)poncm-5-cnrboxylnte MeCK MeCH H Nlt 0^ O -Wo © C02^Na (98) (99) The 6-ethylidenepenem ester (98) (24 mg) was dissolved in a mixture of dioxan (8 ml) and water (2 ml) and hydrogenated over 5% palladium/charcoal catalyst (36 mg) at S.T.P. for 40 minutes. Farther catalyst (24 mg) was added and the hydrogenation continued for 40 minutes. A 1% sodium "bicarbonate solution (0.46 ml) was added and the mixture was worked up as for Example 1(b) to give the sodium salt (99) (8.2 mg) as a yellow amorphous solid^ X 294 n.m. (6960) .

(H2O) Preparation 9 (a) ci'xj '-s 3 S I (3£,4 RS) -3-Bromo-3~ {1 - ( £ ) -hydroxy- 1 -phony lme thy 1} -1 - (1 -methoxy-carbony1-2-methylprop-1-enyl)-4-methylth ioazet id in-2-one (2) >h0 H Br- le 0 -N clo^Me (104) A solution of methyl magnesium bromide (2M in diethyl ether, 17.1 ml) was added, dropwise over 15 minutes, to a stirred solution of the dibromosecopenicillanate (2) (12.0 g) in dry tetrahydrofuran (120 ml) at -76°C. After stirring at -76°C for a further 20 minutes a solution of redistilled benzaldehyde (3.96 g) in dry tetrahydrofuran (10 ml) was added dropwise over 10 minutes. The mixture was stirred at -76°C for a further 10 minutes, treated with saturated ammonium chloride solution (60 ml) and allowed to attain room temperature. The mixture was diluted with ethyl acetate and the organic layer was separated. After washing with brine the dried (MgSO^) organic layer was evaporated to give, after trituration with ether, the bromohydrin (104) (11.7g) as a solid, m.p. Ill - 112°C (plates ex ethyl acetate/hexane) v (CHC1,) 3600 - 3100, 1765, 1720 cm"1; 6 p.p.m. (CDC1-) 1.85 ITlclX • {3H, s), 2.02 (3H, s), 2.19 (3H, s), 2.88 (1H, d, J 3 Hz), 3.49 (3H, s), 5.18 (1H, s), 5.25 (1H, d, J 3 Hz), 7.2 - 7.7 (5H, m) .

(Found: C, 49.5; H, 4.8; N, 3.6; S, 7.6.

C17H20NBr°4S requires C, 49.3; H, 4.

N, 3.4; S, 7.7%). 96 - Preparation 9 (b) <1 " 7 (3RS,4 RS)-3-{1-(RS)-Hydroxy-1-phonylmethy1) and (3RS,4SR)-3-{1 -(SR)-Hydroxy-1-phenylmethyl)-1 -(1-methoxycarbony1-2-methylprop-1-enyl)-4-methylthioazetidin-2-ones Ph OH Br- >Me C02Me (104) H ?h H I H HO a SMe y~ CO_Mc (105) H.

HO Ph H H f/S Me Cr CO^Me (106) A stirred, ice-bath cooled, mixture of the bromohydrin (104) (11.7 g) , tetrahydrofuran (120 ml) and aqueous ammonium acetate solution (1M. , 24 ml) was treated with zinc powder (23.4 g) .

After stirring at ice-bath temperature for 30 minutes the mixture was treated with a further portion of zinc powder (2 g) . The mixture was stirred at ice-bath temperature for a further 10 minutes and filtered through Kieselguhr, the residual zinc being washed with a little tetrahydrofuran. . The combined filtrates were evaporated to low volume, diluted with ethyl acetate (300 ml) and washed successively with 1N. hydrochloric acid (20 ml), brine (20 ml), saturated sodium bicarbonate solution (20 ml) and brine (3 x 20 ml) . The dried (MgSO^) organic layer was evaporated and chromatographed to give an approximately 1 : 1 mixture of the (3RS,4RS)-3-{1 -(RS)-hydroxy-1-phenylmethyl} and (3RS , 4SR)-3-{ 1 -(SR)-hydroxy-1-phenylmethyl} azetidinones (105) and (1 06) (8.60 g) , v (CHC1 ) 3600 - 3200, 1760, 1 725 cm"1; max« -j p.p.m. (CDC13) 1.92 (3H, s), 2.01 (3H, s), 2.19 CH3, s), 2.24 (h CH^, s) , 2.5 - 3.3 (1H, broad signal, exch. D20) , 3.49 (%H, dd, J 3 and 6h Hz), 3.68 CH3, s), 3.73 (h CH3, s), 3.91 (h H, dd, J 5 and 7k Hz), 4.82 (h H, d, J 3 Hz), 4.95 - 5.35 {1^ H, m, collapses on exch. D^O to 5.07 (d, J 6h Hz), 5.09 (d, J 5 Hz) and 5.21 (d, J 1\ Hz)j, 7.2 - 7.6 (511, m) . 9 7 Preparation 9(c) (3RS,4RS)-3-{ 1-(RS)-Acetoxy-1-phenylmethyl} and ( 3RS,4SR)~3~{ 1 -(SR) -Acetoxy-1-phenylmethyl}-1 - (1 -methoxycarbonyl-2-methylprop-1-enyl)-4-methylthioazetidin-2-ones Acetic anhydride (3.14 g) was added dropwise over 5 minutes to a stirred, ice-bath-cooled, mixture of the azetidinones (105) and (106) (a 1 : 1 mixture, 8.60 g) , triethylamine (3.11 g) and 4-dimethylaminopyridine (282 mg) in dry methylene chloride (100 ml) The mixture was stirred at room temperature for 1 hour and washed successively with 5% citric acid (30 ml) , brine (30 ml) , saturated: sodium bicarbonate solution (30 ml) and brine (3 x 30 ml). The i dried (MgSO^) organic layer was evaporated and chromatographed j to give two fractions. The less polar product, the (3RS,4SR)-3- j {1 -(SR)-acetoxy-1-phenylmethyl} azetidinone (108) (4.20 g) was obtained as a solid, m.p. 102 - 104°C (cubes ex ethyl acetate/ hexane) ; v (CHCIO 1760 and 1725 cm 6 p.p.m. (CDC1-,)1.89 (3H max • «j ^ i s) 1.99 (3H, s) , 2.11 (3H, s) , 2.19 (3H, s), 3-55 - 3.75 (4H, m) , 4.82 (1H, d, J 2\ Hz), 6.20.(1H, d, J 5 Hz), 7.2 - 7.6 (5H, m) .

(Found: C, 60.6; H, 6.1; N, 3.6; S, 8.3. C^gH23NO^S requires C, 60.5; H, 6.1; N, 3.7; S, 8.5%). The more polar product, the ( 3RS,4RS)-3-{1 -(RS)-acetoxy-1-phenylmethyl} azetidinone (107) (3.64 g) was obtained as a solid, m.p. 96 - 97°C (needles ex ethyl acetate/hexane); v (CHCl^) 1765 and 1725 cm 1; 6 p.p.m. max» o i (CDC13) 1.96 (3H, s), 2.05 and 2.07 (6H, each s), 2.21 (3H, s), j 3.71 (3H, s) , 4.03 (1H, dd, J 5 and 9 Hz), 5.13 (1H, d, J 5 Hz), 6.16 (1H, d, J 9 Hz), 7.2 - 7.6 (5H, m). (Found: C, 60.9; H, 6.1; N, 3.6; S, 8.4. C19H23NC>5S requires C, 60.5; H, 6.1; N, 3.7; S, 8.5%) . (1 05) + (1 06) (107) (108) 98 - o <"• l""" 7 Preparation 9 (d) (3RS,4RS)-3-{1-(RS)-Acetoxy-1-phenylmethyl)-4-methylsulphonyl-azetidin-2-one « Ph | H H "-I 1 ] SMe (107) H.

Ph i y - H AcO JxS02Me (109) The dried (MgSO^) organic A solution of m-chloroperbenzoic acid (3.53 g) in ethyl acetate (20 ml) was added dropwise over 15 minutes to a stirred, ice-bath-cooled, solution of the cis-azetidinone (107) (3.50 g) in ethyl acetate (70 ml). The mixture was stirred at room temperature for 1 hour when a solid precipitated. The mixture was diluted with methylene chloride (100 ml) and the resulting solution was washed with saturated sodium bicarbonte solution (2 x 50 ml) and brine (3 x 50 ml). layer was cooled to -20°C and treated with ozonised oxygen for 1 hour. The excess ozone was removed by passage of argon and the; mixture evaporated. The residue was dissolved in a mixture of methanol (100 ml) and methylene chloride (400 ml) and treated with 2,6-lutidine (40 drops). The mixture was stirred at room temperature for 10 minutes and evaporated to give, after trituration with ether, the sulphone (109) (2.44 g), as a solid, m.p. 178 - 82°C (fine needles ex acetone/ether); v (Nujol) - max« 3370, 1795, 1730 cm ; 5 p.p.m. {(CD^CO} 3.03 (3H, s) , 4.38 (1H, dd, J 5 and 12 Hz with further fine coupling which collapsed on exch. D20), 5.10 (1H, d, J 5 Hz), 6.43 (1H, d, J 12 Hz), 7.2 - 7.5 (5H, m), 8.1 - 8.4 (1H, broad signal, exch. D20).

(Found: C, 52.7; H, 5.1; N, 4.6; S, 10.7. C^H NOgS requires C, 52.5; H, 5.1; N, 4.7; S, 10.8%).

N.Z. PATENT OFFICE AUG 1983 ;:c£iv?.a Preparation 9(e) _ ,— -~7 ^ r\ ^ '■ i L u '-v - (3RS,4SR)-3~{1 -(RS)-Acetoxy-1-phenylmothyl)-4-ethylthiothio-carbonylthioazet idin-2-one U Ph Hn I H H ' I^SO Me 3 AcO o^ NH (109) H^H H AcO cr NH (110) Potassium ethyltrithiocarbonate (1/50 g) was added to 'an ice-bath cooled mixture of the sulphone (109) (2.30 g), methylene chloride (200 ml) and water (40 ml). The mixture was stirred at room temperature for 1% hours and worked up as for preparation 1(f) to give the trithiocarbonate (110) (2.01 g) -1 as a yellow gum, v (CHCl.,) 341 0 , 1 785, 1750 shoulder cm ; max • 6 p.p.m. (CDC13) 1.34 (3H, t, J 7 Hz), 2.10 (3H, s), 3.32 (2H, q, J 7 Hz), 3.66 (1H, dd, J 2 and 5 Hz), 5.65 (1H, d, J 2 Hz), 6.19 (1H, d, J 5 Hz), 6.62 br (1H, s, exch. D20), 7.32 (5H, s).

N.Z. PATENT OFFICE AUG 1983 FIECEiV7:D ■1 .•> r- /, r: / \j Preparation 9(f) (3RS,4 SR)-3-{1-(RS)-Acetoxy-1-phenylmethyl}-4-ethylthiothio-carbonylthio-1 -(1 -p-nitrobenzyloxycarbony1-1-triphenylphosphorany1-idenemethyl)azetidin-2-one AcO (110) TT Ph ^ I H H SEt ,SX SEt f T s X^PPh-. ^ CO^CH^—^ \_NO, 2 2 (113) H Ph Ac H SEt ✓ N^OH ,C02CH2—V v—NO. (111) H ?h V AcO .-'S^SEt -N & Vci t (112) °2CH2-< VN02 A mixture of the trithiocarhonate (110) (2.01 g) and £-nitrobenzyl glyoxylate monohydrate (1.42 g) was heated in refluxing benzene (100 ml) in a Dean and Stark apparatus containing molecular sieves (type 4A). After 1 hour the mixture was cooled and treated with triethylamine (57 mg). The mixture was kept at room temperature for 15 minutes and evaporated to give the crude hydroxyester (111), v (CHCl.,) 3700 - 3100, 1 785, 1755 cm \ rricix • -3 A solution of thionyl chloride (1.01 g) in dry tetrahydrofuran (5 ml) was added, dropwise over 5 minutes, to a stirred solution of the crude hydroxyester (111) and 2,6-lutidine (910 mg) in dry tetrahydrofuran (60 ml) at -10°C. The mixture was stirred at -10°C for 10 minutes, filtered and evaporated. The residue was re-evaporated from dry toluene (2 x 10 ml) to give the crude chloroester (112) as a gum, v (CHCl.,) 1 795, 1 760 cm ^ max • O p K" • 7 /lj 1^- A mixture containing the crudc clilorocst.cr (1 12) , triphenylphosphine (2.97 g) and 2,6-lutidine (727 mg) in dry dioxan (60 ml) was stirred at 60°C under dry argon for 36 hours.

The mixture was worked up as for preparation 1(i) to give, after chromatography, the phosphorane (113) (3.17 g) as an amorphous solid, v a (CHC1-) 1765, 1620, 1610 shoulder cm"1. max • j iSi.Z. PATEMTOFFICE AUG 1983 102 ^ 'i .I '' 7 L. U 'T ^ ~ ' Preparation 9(g) (5RS,6SR,8SR)- and (5RS,6RS,8RS)-p-Nitrohenzyl 6-(1-Acetoxy-1 -phenylmethyl)-2-ethylthiopenem-3-carboxylate H - y AcO , <r .S SEt 1 yph3j io2 CHF\ (113) V ■NO, AcO (114) (115) A solution of the phosphorane (113) (2.97 g) in xylene (1500 ml) was refluxed under argon for 8^ hours. The mixture was evaporated and chromatographed to give two products. The less polar product, the (5RS,6RS,8RS) penem ester (115) (195 mg), was obtained as a pale yellow solid, m.p. 1 76 - 178°C (plates ex ethyl acetate/hexane); X (EtOH) 260 (e 1 5,860) and 335 n.m. (10,650) ; v (CHC13) 1795, 1745, 1690 cm -1 6 p.p.m. (CDC13) max. 1.39 (3H, t, J 7 Hz), 2.06 (3H, s), 2.9 - 3.2 (2H, m), 4.42 (1H, dd, J 4 and 10 Hz), 5.12 and 5.40 (2H, ABq, J 14 Hz), 5.78 (1H, d, J 4 Hz), 6.11 (1H, d, J 10 Hz), 7.38 (5H, s), 7.52 (2H, d, J 9 Hz), 8.14 (2H, d, J 9 Hz). (Found: C, 56.1; H, 4.4; N, 5.4. C24H22N2°7S2 rec3uires C' 56.0; H, 4.3; N, 5.4%). The more polare product, the (5RS,6SR,8SR) penem ester (1 14) (740 mg) , was obtained as pale yellow solid, m.p. 157 - 159°C (plates ex ethyl acetate/hexane; A (EtOH) 261 (c 15,930) and 339 n.m. max. ' " m (9840); v (CHC1-,) 1 795, 1 740, 1 690 cm" 1 ; max. 1.34 (3H, t, J 7 Hz), 2.10 (3H, s), 2.78 - 3.12 (2H, m) , 4.1 8 (1H,! dd, J 1.7 and 6 Hz), 5.19 and 5.42 (2H, ABq, J 14 Hz), 5.64 (1H, d 7.3 3 (5H, s; (Found: C, 56 H , 4.3; N , 5.4 fe-t-r- J 1.7 Hz), 6.18 (1H, d, J 6 Hz) J 9 Hz), 8.19 (2H, d, J 9 Hz). 6 p.p.m. (CDC13) 7.58 (2H, d, C24H22N2°7S2 rec3uires C' 56.0; ;r-3-; 1], 4 -.-4-? N, 5, IM.Z. PAT' AUG 1983 103 .-\ f V. 7 2 U 'H J J i Exampl e 9-1 ( a) (5RS)-p-Nltrobenzyl (Z)-G-Benzylidene-2-ethylthiopenem-3-carboxylate SEt (114) "co2CH2-C VN02 + Ph"^ .N.

SEt Nx^chj^ -NO (116) (117) A solution of 1,8-diazabicyclo{5.4.0}undec-7-ene (44 mg) in dry methylene chloride (1 ml) was added, dropwise over 1 minute, to a stirred solution of the trans-penem ester (114) (100 mg) in dry methylene chloride (4 ml) at -40°C. After stirring at -40°C for 10 minutes the mixture was diluted with methylene chloride (10 ml) and washed with 5%.citric acid (2 ml), brine (2 ml), saturated sodium bicarbonate solution (2 ml) and brine (3x2 ml). The dried (MgSO^) organic layer was evaporated and chromatographed to give two fractions. The less polar product, the (E)-benzyl- idenepenem ester (117) v 12 mg) was obtained as a yellow solid, ' (CHC13) 1770, 1690 cm -1 ;6 p.p.m. (CDC13) 1.37 (3H, t, max.

J 7 Hz) , 2.73 - 3 .25 (2H, m) , 5.23 and 5.51 (2H, ABq, J 14 Hz), 6.29 (1H, s), 6.61 (1H, s), 7.3 - 7.5 (3H, m), 7.67 (2H, d, J 9 Hz) 7.85 - 8.05 (2H, m), 8.23 (2H, d, J 9 Hz). The more polar j product, the (Z)-benzylidenepenem ester (116) (64 mg) v/as obtained as a yellow solid, m.p. 171 hexane);X ' ' max ( inflection) ; 179 C (fine needles ex ethyl acetate/ hexane);X (EtOH) 286 (e 31,450) and approximately 328 n.m. max. m _ ^ (CHC1-.) 1 780, 1 690 cm ; 6 p . p. m. .. (CDC1 _ ) v max, o ,-v (L <J - 104 1.35 (3H, t, J 7 Hz), 2.65 - 3 . 25 (211, m) , 5.22 and-5.49 (211, ABq, J 14 Hz), 6.49 (1H, s), 7.12 (1H, s), 7.2 - 7.5 (5H, m) , 7.65 (2H, d, J 9 Hz), 8.20 (2H, d, J 9 Hz). (Found: M+, 454.0686 . C22H18N2°5S2 rec3uires 454.0654 ).

Example 9(b) 204537 (5RS)-Sodium (Z) -6-Benzy1idene-2-ethy1thiopenem-3-carboxylate Ph H (116) (118) The (Z)-benzylidenepenem ester (116) (50 mg) was dissolved in a mixture of dioxan (8 ml) and water (2 ml) and hydrogenated over 5% palladium/charcoal catalyst at S.T.P. for 40 minutes. Further catalyst (50 mg) was added and the hydrogenation continued for 40 minutes. A 1% sodium bicarbonate solution (0.93 ml) was added and the mixture worked up as for Example 1 (b) to give 4 the sodium salt (118) (12.6 mg) as a yellow-orange amorphous solid, X (H_0) 291 (e 21 ,870) and 380 n.m. (2,140); Sp.p.m. ' max. v 2 m V (D20) 1.27 (3H, t", J 7 Hz), 2.68 - 2.98 (2H, m) , 6.49 (1H, s), 7.10 (1H, s), 7.32 - 7.56 (5H, m). 204537

Claims (6)

1. WHAT WE CLAIM IS:

   A compound of formula (I)

   SO^R12

   (I)

   NH

   wherein. R"*" represents hydrogen, or a hydrocarbon or heterocyclic group optionally substituted with a functional group;

   methyl or benzyl.

   12

   functional group; X is a leaving group and R represents
2. 2 A compound as claimed in claim 1, wherein

   R"*" represents hydrogen or a c^_io hydrocarbon group.
3. 3 A compound as claimed in either claim 1 or claim 2, wherein R^ represents hydrogen, methyl, ethyl or phenyl.
4. 4 A compound as claimed in any of claims 1-3

   wherein X is selected from halogen; a group of formula

   9 9

   -O-SO -(O) -R or -O-CO-(O) -R wherein n is zero or 1 2 n n and R is aryl or Cn , alkyl optionally substituted with

   10 10

   aryl; and a group of formula -OPO(OR )^ wherein R is

   C1_g alkyl or aryl.
5. 5 A compound as claimed in any one of claims 1-4 wherein

   9

   X is a group of formula -O-CO-(O) -R wherein n is zero and

   9 n

   R is C^_6 alkyl.
6. 6 A compound as claimed in claim 5 wherein X is acetoxy. A compound selected from the following^

   rb

   2 c,4

   107

   (3 RS, 4RS)-3[1-(SR)-t-butyldiphenylsilyloxyethy1]-4-methylsulphonylazetidin-2-one*

   (3RS, 4SR)-3[1-(RS)-t-butyldiphenylsilyloxyethyl] -4-methylsulphonylazetidin-2-one;

   (3RS, 4RS)-3-[1-(SR)-acetoxyethy1]-4-methylsulphonyl-azetidin-2-one ,*

   (3RS, 4RS) and (3RS, 4SR)-3-t-£>utyldiphenylsilyloxy-methyl-4-niethylsulphonylazetidin-2-one;

   (3RS, 4SR)-3-[l-(RS)-acetoxyethy1]-4-methylsulphony1-azetidin-2-one* and

   (3RS , 4RS)-3-[1-(RS)-acetoxy-l-phenylmethyl]-4-methylsulphonylazetidine-2-one.

   g A compound as claimed in claim 1, substantially as hereinbefore described with particular reference to Preparations le, 2a, 6b, 7d, 8a and 9d.

   BATED THIS 00.^0AY OF

   A. J. PARK &, SON

   22NQVW83

   HECHSVED