IE871080L - Preparing 2-thiacephems - Google Patents

Description

58677 - I - TITLE: Preparation of 2-Thiacephems DESCRIPTION: The invention relates to processes for the preparation of 2-thiacephems of the general formula II II COOR, wherein group* represents represents protecting group and Y a hydrogen a hydrogen represents acom or an organic atom or a carboxy a hydrogen or halogen atom or an organic group- These 2-thiacephems are useful as starting materials for the preparation of penems of the general formula I wherein Rj, Rj and Y are as above defined- The conversion of the 2-thiacephems II to the penems I is described and claimed in our Xrish patent Application No. 2877/83, from which this Application is divided.

Organic groups which Rj may represent include optionally substituted aliphatic or cycloaliphatic groups. The aliphatic groups are preferably alicyl groups having from l 30 to 12 carbon atoms and the optional substituents may be one or more hydroxy' amino* cyano and/or mercapto groups- The hydroxy, amino and mercapto groups may be free or protected- Particularly preferred alfcyl groups are methyl and ethyl> especially the latter* and a preferred 3 5 substituent for such a group is a hydroxy group* whiefi BiBy l>e free or protected,, Ifie S-hydrouyetfryl group in 65, 8R or 6R, 3S configuration is most preferred. The cycloeliphatic groups a?a preferably monocycloalScyl groups heving from 4 to 7 carbon atoms. Cyclopentyl and cyclohewyl groups are especially perferred. Options! substiiuents are preferably chosen from aliiyl groups heving from 1 to £ carbon atoms, for example methyl or ethyl groups, hydroxy, amino end mercepto groups, the hydroxy, amino and mercapto groups being free or protected.

Ihr csrboxy protecting group Rj may be eny group which, together with the -CDO-moiety, forms en esterified cerboxy group, Examples of cerboxy protecting groups R^ are alkyl groups having from 1 to £ carbon atoms,, for instance methyl, ethyl or t»butyl; halo-substituted alkyl groups having from 1 to 6 carbon atoms, for example 2„2B2-t?ichloroethyl; slicenyl groups heving from 2 to & carbon atoms,for example allyl; optionally substituted sryl groups, for example phenyl end £-nitro-phenyl; aryl substituted alkyl groups, the alkyl pert thereof has from 1 to £ carbon atoms end the aryl pert thereof is optionally substituted, for example bensyl, £~nitro-t>ensyl and g-inethomy-benzyl; aryloxy substituted alf-iyl groups, the alkyl part thereof hes from 1 to 6 carbon atomss for example phenoxy-methyl; or groups such as tiengliydryj, o-nitro-benshydryj 8 oeeionyJP triwethylsilyl, diphanyJ~t-butyl-silyJ, and tfimttiyl-t-t>utyI~silyJ • definition of as a eorbosty ^rot®c®ing group also includes any residue, such as ac<2toiiymethyl, pi we) oy lottymeihyl or phthalidyl, leading sio an aster group tahich is known to be hydrolyzed "in vivo" and to have favourably pharmacokinetic properties.

When V represents a halogen atom, it is preferably a fluorine, chlorine or bromine atom.

When Y represents an organic group, it is preferably e) a free or protected hydroxy.group; b) a formyloxy group or an acyloxy group having from 2 to 6 carbon atoms, optionally substituted by a halogen atom, by an acyl group having from 2 to 6 carbon atoms, or by en amino, hydroxy or mercapto group, the amino, hydroxy or mercBpto group optionally being in b protected form; c) an unsubstituted or K-alkyl or N-acyl substituted caxbarooyloxy group; d) en alkoxy group hBving from 1 to 12 carbon atoms or en albylthio group having from 1 to 12 carbon atoms, either of Nihich is optionally substituted by one or more halogen atoms, formyl groups, acyl groups having from 2 to £ carbon atoms, and/or amino., hydroxy or mercapto groups, the amino, hydroxy or mercapto group optionally being in a protected tform; e) a 1-pyrldinium group, unsubstituted or substituted in the aieta or para position with the group -CONH^; f) a heterocyclylthio group -S-Het therein Het, denoting „ & 9 saturated or unsaturated heterocyclic ring containing at least one oxygen, eulphur and/or nitrogen heteroatom. is preferably: A) a pentatomic or heKBtomic heteromonocyclic ring, containing et least one double bond Bnd Bt least one oxygen, eulphur and/or nitrogen heteroatom, unsubstituted or substituted by one or more a') Blkoxy groups having from 1 to 6 carbon atoms, aliphatic acyl groups heving from 2 to 6 carbon atoms, hydroxy groups and/or halogen atoms; b') alityj groups having from 1 to 6 carbon atoms, unsubstituted or substituted by one or more hydroxy groups and/or halogen atoms; c') alhenyl groups having from 2 to 6 carbon atoms, unsubstituted or substituted by one or more hydroxy groups end/or halogen atoms; d') groups of the general formula -£>-Rg therein R^ represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or groups of the general formula -S-CH^-COOR^ therein R^ represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a carboxy«protecting group; e') groups of the general formulae-(CH,) -C00R. or -CH= CH-C00R. or -(CH,) -CN or -(CH_) -C0NH, or -(CH_) . 4 2 d tn 2 2 tti -SO^H wherein n is 2croe 1, 2 or 3 and R, is as J — defined above; R / 6 f) groups of the general formula -(CH,) -N therein t m tn is as defined above, end each of and R^„ which may be the same or different, represents a hydrogen atom, en alkyl group heving from J to 6 carbon atoms or an aliphatic acyl group or when one of end R& is hydrogen, the other may be also en amino protecting group; or B) a heterobicyclic ring, containing at leBst two double bonds wherein each of the condensed heteromonocyclic rings, being the same or different, is e pentatomic or heKBtomic heteromonocyclic ring containing bI leBst one oxygen, eulphur or nitrogen heteroatom, said heterobicyclic ring being unsubstituted 01 substituted by one or more 6ubstituents selected forrr, a'), b'), c'), e') end f) as defined above-In the ebove definitions A) end B) preferred halogen atcns are chlorine, bromine end iodine; preferred alkyl groups ere methyl and ethyl; a preferred elkenyl group is Bllyl; a preferred aliphatic acyl group is acetyl; a carboxy protecting group may be any of the groups previously indicated for the Rj 6ubstituent; and the free suipho and carboxy groups possibly present may be salified, e.g. as sodium or potessium sells. A heteromonocyclic ?ing of the above cIbss A) may be, for example,; an optionally substituted thiazolyl, iriBzolylg ihiadiazolyl, tsisraxolyl or triazinyl ring. Preferred substituents on such rings are, for example, one or more subsiituienis chosen from amino, hydroxy, oxo and a C^-C^-alkyl group,preferably methyl or ethyl, wherein the C^-C^-elUyl group ffiBy be optionally substituted by a substituent chosen from carboxy, suipho, cyano, carbamoyl, eit.ino, methylemino or dimethylemino. A heterobicyclic ring of the above class may be for example, a tetrazolopyridazinyl radical optionally substituted by srr.inD or carboxy.

In the ebove formula 1 the amino, hydroxy or mercapto protecting groups possibly present may be those usually employed in the chemistry of penicillins and cephalosporins for these functions. They fnBy be, for instance optionally substituted, especially halo-substituted, acyl groups, e.g. acetyl, monochloroacetyl , dichloroacety 1 , trifluoroacetyl, benzoyl or D-bromophenBcyl; trjarylmethyl groups, in particular tnphenylmethy 1; silyl groups, in particular trimethylsilyl, dimethyl-t^butyl-isilyl, diphenyl-t~butyl silyl. or also groups such as t,-butoxycarbonyl, e>~niirobenzyloxycarbony 1, 2,2,2-trichloroethoxycarbony1, benzyl, pyranyl and nitro. When, in particular, the Rj substituent in formula (1) is a hydrottyalkyl group„ preferred protecting groups for the hydrouy function are s-nits'o-benayloxycarbonyl; dimethyl-jt=butyl»silyl; riiphenyl-jt-buiylsilyl; trimethylsilyl; 2.2.2-trichloroethoxycarbonyl; benzyl: jo^bromo-phenacyl: triphenylmethyl and pyranyl. All the alEtyl and alkany1 groups, including the aliphatic hydrocarbon moiety o£ the alkoity. alfcylthio and acyloity groups, may be branched or straight.

According to the invention, the ?.-thiacephems II in which Y represents a hydrogen atom. i.e. those of the general formula Ila _ R1 Ila coorj IS wherein Rj and Rg are as above defined, are prepared from an azetidinone derivative of the general formula IV R, IV coor-, wherein R, and R2 are as above defined and Z represents (i) a group o£ the formula SR? wherein R? 25 represents an Elkyl group having from 1 to 8 carbon atoms, a phenyl or tolyl group, or a heterocyclic group. (ii) a group of the formula SCORg wherein Rg represents an optionally substituted alkyl group having from l to 4 carbon atoms /or5 (iii) a group of the formula wherein Rg COR10 and RJ0 independently represent alkyl groups having from 1 to 4 carbon atoms or aryl groups, or together with the dicarboxyamino group form a heterocyclic ring, or 8 (iv) a group of the formula _SJ_R1X wherein i) represents an optionally substituted alkyl group 3 having from 1 to 4 carbon atoms or an optionally substituted aryl group. by a process comprising ozonolys&ng the carbon-carbon double bond, converting the hydroxy group in the resultant azetidinone to a halogen atom or an elKane sulphonyloxy 10 group or an arene sulphonyloxy group and cyclising the resultant azetidinone by reaction with a sulphide or hydrosulphide in the presence of a base.

Also according to the invention, the 2-thiacephems II in is which Y represents a halogen atom. i.e. those of the general formula lib Vf J ui S ^ s -Hal I coor2 wherein R^ and R2 are as above defined and Hal represents a halogen atom, are prepared by the aforesaid zs process according to the invention and the further step of halogenating the methyl group either of the asetidinone IV prior to the steps of the aforesaid process or of the 3-thiacephem after the steps of the aforesaid process. The halogenation of the 2-thiacephem is effected by reaction 30 with a halogenating agent in an inert organic solvent at a temperature of from 20°C to 130°C in the presence of a radical initiator and an acid scavenger. 33 This halogenation of the 3-methyl group of the 2-thiacephems 12a is most unexpected. Reasonable expectation would rule out the possibility of halogenating the 3-methyl group of the 2-thiacephems Ila owing to the presence of the disulphide moiety. Nevertheless, the halogention as described proceeds with high yields. S Suitable halogenating agents are H-bromosuccinimide and N-chlorosuccinimide. The radical Initiator may be azobisisobutyronitscile or benzoyl peroxide and the acid scavenger may be an epoxide (e.g. propylene oxide), an alkaline earth oxide (e.g. calcium oxide) or a molecular 10 sieve. Suitable solvents are benzene, carbon tetrachloride and ethyl formate.

As stated, the halogenation may alternatively be effected on the azetidinone IV. This halogenation may be effected is by methods known per se (allyl, ene-type. or electrochemical halogenation, see Tetrahedron Letters, 1980. 71 and 331s 1981. 3153; 1983. 2187).

These processes are illustrated by the following reaction 20 scheme wherein Rj. Rj, Z and Hal are as above defined and L represents a halogen atom, an alkane sulphonyloxy group or an arene sulphonyloxy group, preferably a methanesulphonyloxy group* ! ■" cty2 \ \ > S2 CH, Hal C02R2 S2 OK P /~»v\ VJ CH- C05*2 s S2 via OH 1 3al C02K2 RK S2 , 3J£ *K's-^S^' Hal V .82. V133 Yr § CH, C02^ a, Vf8 "s - N COOR- Ila (XXsX-H) •* T-f*KB I 1 J I X? al CO0R2 ISb |XSsl'«»3aI) - II - Compounds of the general formula IV. which ace used as starting materials, are known compounds or can be obtained from known compounds by per se known procedures; the preparation of some representative entities is described in 5 the Examples.

Following the right hand side of the reaction scheme, the compound of the general formula IV is first ozonolysed to give a compound of the general formula VI. The hydroxy 10 group is then converted into a group L and the resultant compound of the general formula Viii is cyclised to give a compound of the general formula Ila. If desired, the methyl group may then be halogenated by the particular method above described to give a compound of the general 13 formula lib. following the left hand side of the reaction scheme, the compound of the general formula IV may first be halogenated by one of the known methods above described. The resultant ■ 20 compound of the general formula V is then ozonolysed; the hydroxy group of the resultant compound of the general formula VII is then transformed into a group L and the resultant compound of the general formula IX is cyclised to give a compound of the general formula lib.

The transformation into a group L of the hydroxy group in the enol VI or VII. which may be in equilibrium with the corresponding keto-tautomer. is preferably a mesylation. We have surprisingly found that, when this reaction is 30 carried out in tetrahydrofuran instead of the ubiquitously used halogenated hydrocarbons, mesylates IX or VIII having Z alkene geometry, which are the most suitable ones for the subsequent cyclization. are almost exclusively obtained (similar transformation performed in dichloromethane 33 usually affords a 1:1 mixture of E_. Z_ isomers: see T.W.

Doyle st al.. Can. J. Chem.. 1977, S3. 2873; £S.J. Pearson. J. Chem. Soc.. Chem. Comm. 1581, 947; P.C. Cherry et al.. J. Chem. Soc.. Chem. Comm. 1579. 653). Cyclisation of VIII or IS may be carried out in a single 5 step, by reaction t-Jith a sulphide or hydrosulphide. such as ^a^S. HaBS. Bu^ftHS, or with H?S in the presence of a base such as triethylamine or pyridine. The cyclisation of IX or VIII wherein Z represents a group other than SR? offers the clear advantage o£ releasing easily separable. 10 usually water soluble by-products ZH (e.g. phenylsulphinic acid, succinimide). instead of by products RgSH (e.g. mercaptobenzthiazole) which usually require chromatographic separation or precipitation as heavy metal salts (Ag . Pb2*>.

IS Finally according to the invention, the 2-thiacephems II in which Y represents an organic group may be prepared by the further step of converting the halomethyl group introduced by the halogenation into a methyl group substituted by the 20 desired organic group. This conversion may be effected at any point after the introduction of the halomethyl group, that is on any of the confounds V, VII, IX and lib. It is, however, preferably carried out on the compound lib. The conversion may be carried out by reactions known per se. 23 For example. 1) a compound lib can be converted into a compound II (Y=free or protected OB) by mild alkaline hydrolysis, or by reaction with cuprous ohide/dimethylsulphoxide/water or by reaction with a salt of a strong inorganic acid. e.g. a 30 nitrate or a perchlorate, thus obtaining a labile ester vith the said inorganic acid, which ester may be hydrolyzed. subsequently or in the same reaction medium, to the desired parent alcohol- Preferred salts of this type are AgN03. AgClO^ and EaEOj. 3 3 2) a compound lib can be converted into a compound II (Y=an unsubstituted or H-alkyl substituted carbamoyloxy group) by conversion into a compound II (Y=OH) as described above followed by reaction with a suitable isocyanate; for example> trichloroacetyl isocyanate is a preferred S reagent for obtaining compounds II (Y-OCONHj), following deprotection of the trichloroacetyl moiety on the first ® formed urethane adduct; 3) a compound lib can be converted into a compound II (Y-acyloxy) by reaction with a suitable salt of the i corresponding carboxylic acid in a suitable solvent or under phase-transfer catalysis; or by conversion into a compound II (Y=OH) followed by a conventional acylation; 4) a compound lib can be converted into a compound II (Y-S-Het) by reaction with the corresponding HS-Het in the 13 presence of a base, or with a preformed salt of HS-Het with a base, in a suitable solvent, such as tetrahydrofuran. acetone, acetonitrile or dimethylformamide. A suitable base is triethylamine: a suitable preformed salt is a sodium salt. e.g. sodium i-methyl-i.2.3.4-tetrasole-S-yl-30 -mercaptide.

Owing to the pronounced propensity of 3-hydroxymethyl-2--thiacephem-4-carboxylates to lactonize, it is preferable that in the process 1) described above R2 represents a 23 somewhat bulky group, forming with the linked carboxy moiety an ester possessing a relative inertness towards nucleophilic attack by the neighbouring hydroxy group, e.g. a tert-butyl ester.

The following Example illustrate the invention* The abbreviations £Se, Bu^, Ph. Ms. pHB, THF, EtOAc. DMSO.

MeCN, stand respectively for methyl, t^butyl. phenyl, methanesulphonyl. g^nitrobenzyl. tetrahydrofuran. ethyl acetate, dimethylsulphoxide and acetonitrile. ®3R spectra 3 5 were taken either on a Bitachi-Perkin Elmer 60 MHz apparatus, or on a Brucksr SOEiHz; separation of inner lines of ftB quartets are referred to spectra taken on the latter. 'Hitachi' is a Trade Mark.

Example 1 Djphenvlmethyl 6,6-dihromopenicillanate 90 g of 6,6-Dibromopenicillanic acid in 450 ml of acetonitrile was treated with a solution of 49 g of 5 diphenyldiazomethane in 150 Jul of acetonitrile. After 1 hour at 20°C the formed solid was collected by filtration and washed with sir.all portions of cold diethyl ether, thus obtaining 116 g of the title product. A second crop (9 g) was obtained by evaporation of the 10 mother liquors and trituration with diethyl ether. The overall yield was 95%.

Analytical sample was obtained by crystallization from chloroform; mp 157-158°C;-r (CHC1, film) 1800, 1750 * JDldX cm"1; o (CDCl-j) 1.24 and 1.58 (each 3H, s, CMe2) • 4.61 15 (1H, s, N.CH.CO), 5.80 (1H, s, N.CH.S), 6.91 (1H, S. OCH) , and 7.30 ppn (10H, s. Ar).

Found: C, 47.80; H, 3,63; N, 2.64; S, 5.95; Br, 30.49%. C21H19Br2N03S requires C, 48.02; H, 3.64; N, 2.67; S, 6.10; Br, 30.43%.

Example 2 t-Butyl 6,6-dlbromopenicillanate Method A lOO g of 6,6-dihromopenicillanic acid in 1 litre of diethyl ether at 0°C was sequentially treated with 37 ml of 25 triethylamine and 56 g of phosphorus pentachloride. After 1 hour stirring, the reaction .mixture was evaporated under •vacuum (dry benzene added and removed). The crude acyl chloride was dissolved in 200 ml of dichloromethane and stirred for 24 hours with 5OO ml of t-butanol in 5 the presence of 50 g of calcium carbonate. The suspended salts were then filtered off, and the solution was washed with aqueous sodium bicarbonate solution (some linreacted starting material could be recovered by back--extraction of the acidified aqueous washings), lO decoloured with charcoal and evaporated to afford the title product, which was then crystallized from diisopropyl ether. Yield 69 g (60%); mp 120-121°C, Vmay (CHC13 film) 1800 and 1740 era-1; € (CDCI3) 1.98 (15H, s, Bufc and CH3), 2.05 (3H, s, CH3), 4.38 (1H,S, 15 N.CH.CO) and 5.70 pptn (1H, s, N.CH.S).

Method B g of 6,6-dihromopenicillanic acid in 300 jnl of dichloromethane was stirred overnight with 25 g of 0-t--butyl-N,N-diisopropyl-isourea. The reaction .mixture 20 was filtered and the solution washed with aqueous sodium bicarbonate solution. Crystallization of the product from diisopropyl ether gave the title compound, 8 g (47%).

Example 3 Diphenylmethyl fe4-bramo- (3-Q-R-hydraxyethyD-peni ci 1 lanate 120 g of Dipheny lmethyl 6,6-dibroraopenicillanate, prepared as described in Example 1, in 900 ml of dry 5 distilled THF -under nitrogen at -75°C was treated with 1 molar equivalent of a solution of ethyl-magnesium bromide in diethyl ether. After 20 min at -75°C, 25.7 ml of acetaldehyde was added and the mixture was further stirred for 20 min at -75°C. After quenching with 400 10 ml of saturated aqueous ammonium chloride, partition between water and diethyl ether followed by removal of the solvent left the crude product. This was fractionated by silica gel chroinatograhy (benzene:ethyl acetate) to afford the title compound, 67 g (60%), as a foam, crystallizable 15 (diisopropyl ether) to a solid, mp 65-70°C; 3450, 1785 and 1740 cm"1; S (CDC13) 1.22 and 1.60 (each 3H, s, CMe2), 1.29 (3H, d, J=6Hz, CH-j.CH) , 2.90 (1H. d, OH), 4.17 (1H, m, CHj.CH.OH), 4.58 (1H, s, N.CH.CO), 5.49 (1H, s, N.CH.S), 6.90 (1H, s, 0CHPh2) and 7.3 ppm (lOH, 20 s. Ar).

Using t-buty1-6,6-dibromopenicillanate, prepared as described in Example 2, and proceeding similarly, there were obtained t-butyl 6r<-broidq-6p- (lR-hydroxyethyl)--peniclllanate in 65% yield after crystallization from 25 diisopropyl edisr: hexane; m.p. 93-95°C with decomposition; S (CDC13) 1.28 (3H, d, J=6Hz, CH3-CH), 1-54 (12H, s, But and CH3), 1.65 (3H, s, CHj), 2.65 <1H, s, CH.OH), 4.25 (1H, W, CH3.CH(OT).CH), 4.

Example 4 Dipheny lmethyl 6K- (lR-hydroxyethyl)-penicillanate-l-Qxide 52 g of Dipheny lmethyl 6s£-brorao-<®- (lR-hydroxyethyl) --penicillanate, prepared as described in Example 3, in 400 ml of 95% ethanol was hydrogenated at 20700 pascals in the presence of 25 g of 10% by weight palladium-on-10 -calcium carbonate and 11 g of calcium carbonate. The reaction jointure was filtered and evaporated to afford a residue which was partitioned between brine and dichloro-jtie thane. Removal of the solvent left crude diphenyl-methyl 6H-(lR-hydroxyethyl)-penicillanate, which was 15 oxidized with 17 g of 85% MCPEA in 500 ml of chloroform at 0-5°C for 1 hour. The filtered solution was then washed with aqueous sodium bicarbonate solution and the solvent removed to leave 40 g (88%) of the crude title product as a foam, which can be used as such or purified 20 by silica gel chromatography;Ynax (CHC13 film) 1790 and 1750 cm-1; S (CDC13) 0.94 and 1.67 (each 3H, s. CMe2), 1.37 (3H, d, J=6Hs), 3.55 (1H, dd, J=2 and 6.5Ha, CH_CH.CH), 4.25 (1H, jn, CH3.CH(0H).CH), 4.64 (1H, S, N.CH.CO), 4.98 (1H, d, J=2H3, CH.CH.S), 6.98 (1H, s, 25 OCHPhj) and 7.30 ppm (10H, s, Ar).

Using a similar procedure, but starting from t-butyl 6^-broroo-6p-(lR-hydroxyethyl)-penicillanate, prepared as described in Example 3, there was obtained t-butvl 6sj-(lR-hydroxvethyl)-penlclllanate-l-oxide: yield 75%: (film) 3440, 1785 and 1740 cm"1. lucLX J.

Example 5 Diphenylmethyl 6' -(lR-t-butyldimethylsllyloxyethy)--penlcillanate-1-oxlde 40 g of crude diphenylmethyl 6*1-(lR-hydroxyethyl)-10 -penicillanate-l-oxide, prepared as described in Example 4, was dissolved in 350 ml of DMF and stirred for 3 hours at 50-55°C in the presence of 18.5 g of imidazole and 27 g of t-butyldlmethylsilyl chloride. The reaction mixture was partitioned between diethyl ether and brine 15 and the organic layer washed several times with water.

Evaporation of the solvent and silica gel chromatography afforded the title product; yield 22 9',Vmax (CHClj film) 1790 and 1755 cm"1) S(CDC13) 0.06 (6H, s, Sifitej), 0.88 (13H, s, Bu* and CH3), 1.3 (3H, d, J=6Hz, CH3-CH), 1.7 (3H, s, CH3), 3.4 (1H, dd, J=2 and 4.5Hz, CH.CH.CH), 4.40 (1H, jo, ch3-CH.CH) 4.55 (1H, s, N.CH.CO) , 4.88 (1H, a, 0=2, CH.CH.S), 6.9 UH,S0CHPh2) , and 7.25 ppm (10H, s. Ar).

By using a similar procedure, but starting from t-butyl 25 6*1-(lR-hydroxyethyl)-penicillanate-l-oxide, prepared as descjribed Am Bjsemple 4, there was obtained t-butyl 5-~ (lR"t»4wtyld jMsthylsilvlcKysthy'l-) "^niCillanate-l-oMide in overall yield 55% from the SK-bsraxoopireciirso*; (CHC13 film) 1385 and 1750 cm"1,- 6 (CDCI3) 0.06 (SH, s, 5 SiH©,), OoOO C9H, s, SiBu"), 1.35 and 1.36 (each 3H, s, CMe2), 1.28 (3H, d, J=6Hs, CH^CH), l.«5 (9H, s, OBue), 3.5 C1H, dd, J=2 4sad 5Hs, CH.CH.CH), 4.4 (1H, s, H.CH.CO), 4.5 (lH, a>, CHj.Ca.CH) and 4.9 ppm (IB, d, J=2Hs, CM.CH.S).

Example 6 D1 phenyl iae thy 1 6c; - (IR-p-nltrobenzy loxycarboriy loityethy 1) --oenicillate-l-airide Dipheny lmethyl 6K- (m-hydroHyethyl)"penicIllanate-l-astide„ prepared as described in Example 4, was acylated with jj--nitsobenssylchlorocarbonata by using EJ jM-diniethyleiaino-15 '-pyridine as a bass and athanol-xree dichloromethane as solirent, according to a general method, thus obtaining the title product as a Joisnt; € (CDClj) 0.S6 and 1.70 (each 3H, 3, CHe3), 1.52 (3H, d, J=6Hs, Cg3.CH), 3.83 C1H, dd, J=2 and 6Hz, CH.CH.CH), -3.56 (1H, s, N.CH.CO), 20 4.99 U.H, A, J=2Bse CH.CB.S), 5.28 (2H, s, OCH^Ph), 5.35 (1H, m, CH3.CH.CH)D 7.01 (19, 3, OCHPh,), 7.40 (10H, a, Ar), 7.55 and 8.26 ppm (sach 2B, A, J=8JHz, Ar). ■following the seme Using similar procedures, there were obtained: 3S- (lR-t-butyldimethylsilyloxyethyl) -4R-benzthlazolyl-dlthio-1-(l-methoxycarbonyl-2-methyl-l-prop-2-enyl)--azetidin-2-one, starting from methyl 6K- (lR-t-butyl-2Q dimethylsilylaxyethyl)-penicillanate-l-oxide, and prolonging the reaction time up to 6 hours ;*"y (CHC1, itlOA W film) 1770 and 1744 cm"1, h (CDC 1-j) 0.02 and 0,04 (each 3H, s, SiMegJj, 0.84 (9H, s, SiBu1) , 1.23 (3H, d, J=6Hz, CHj.CH), 1.91 (3H, s, =C.CH3), 3.38 (1H, dd, J=2 and 3.5Hs, CH.CH.CH), 3.69 (3H, s, OCH3), 4.23 (1H, m, CH3.CH.CH), 4.82 (1H, s, H.CH.CO), 5.07 (2H, m. CH2=C), 5.42 (1H, d, J=2Hs, CH.CH.S) and 7.2-7.9 ppm (4H, m, Ar); 3S-(lR-hydroxyethyl)-4R-benzthlazolvldithlo-l-(1--diphenylmethoxvcarbonyl~2-methyl-l-prop-2-envl)-azetldin--3-one. starting from diphenylraethyl 6s%-(lR-hydro»y-ethyl)-penicillanate-l-oxide; (CHCI3 film) 3400, 1765 and 1740 cm-1; % (CDC 13) 1.22 (3H, d, J=6Hz, CH3.CH), 1.60 (3H, s, =C.CH3), 2.78 (1H, Br s, OH), 3.42 (1H, dd, J=2 and 6Hz, CH.CH.CH), 4.18 (1H, m, CH3.CHOH.CH), 4.93 (1H, s, N.CH.CO), 4.90-5.10 (2H, m, CH2=C), 5.38 (1H, d, J<=2Hz, CH.CH.S), 6.89 (1H, s, 0CHPh=) and 7.15-7.90 ppm (14H, m. Ar); 3S-(IR-t-butyldimethyIsllyloxyethyl)-4R-ben20thlaz0lyl~ dithio-1-(l-t-butoxvcarbonyl-2-methyl-l-prop-2-enyl)--azetidin-2-one. starting from t-butyl 6Kr(lR-t-butyl-dimethylsilyloxyethyl) -penicillanate-l-oxide; reaction time 6 hours; (cdci3) 0.06 (6H, s, SiMe^), 0.9 (9H, s, SiBut), 1.26 (3H, d, J=6Ha, CH^CH) , 1.48 (9H, S, OBu^, 1.95 (3H, s, =C„CH3), 3.40 (1H, dd, J<=2 and 4Hz, CH.CH.CH), 4.20 (1H, m, CH3.CH.CH), 4.71 (1H, s, N.CH.CO), 5.1 2H, br s, CH2=C), 5.42 (1H, d, J=2Hz, CH.CH.S) and 7.2-7.9 ppm (4H, m, Ar); 3S-(IR-t-butyldimethyIsllyloxyethyl)-4R-benzthlazolyl- dithio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2- -enyl)-azetidin-2-one,V (film) 1722 and 1743 cm 1; a .. - i max S(CDC13) 0.05 (6H, s,SiMe2), 0.80 (9H, s, SiBut), 1.29 (3H, d, J=6Hz, CH3.CH), 1.95 (3H, s, =C.CH3), 3.45 (1H, S dd. J=2 and 4Hz, CH.CH.CH), 4.26 <1H, m, CH3.CH.CH), 4.95 (1H, s, N.CH.CO), 5.08 (2H, ABq, separation of inner lines 5Hz, CH2=C), 5.55 (1H, d, J*=2Hz, CH.CH.S), 6.93 (1H, s, OCHPhj) and 7.1-8.0 ppm (14H, m, Ar); 3S-(lR-trichloroethoxycarbonyloxyethyl)-4R-ben2thiazolyl-10 dithio-1-(1-methoxycarbonyl-2-methyl-1-prop-2-enyl)- -azetidin-2-one, starting from methyl 664-(lR-trichloro ethoxycarbonyloxyethyl)-penici1lanate-1-oxide: °^max (CHC13) 1775 and 1745 cm-1; 6(CDC13) 1.48 (3H, d, J=6Hz, CHj.CH), 1.91 (3H, s, =C.CH3), 3.69 (3H, s, OCH3) , 3.70 15 (1H, dd, CH„CH.CH), 4.68 (s, 2H. OCHj), 4.76 (1H, s, N.CH.CO), 5.03-5.30 (2H, m, CH2=C), 5.23 (1H, m, CH-j.CH.CH), 5.32 (1H, d, J=2Hz, CH.CH.S) and 7.10-7.96 ppm (4H, m, Ar); and, in a likewise fashion, starting from the corresponding 20 t-butyl and diphenylmethyl penicillanates, 3S-(lR-trichloroethoxvcarbonyloxyethy1)-4R-benzfchiazolyl-dithio-1-(l-t-butoxycarbonyl-2-methyl-l-prop-2-enyl)--azetidin-2-one; 3S-(lR-trichloroethoxycarbonyloxyethyl )-4R-benzthiazolyl-25 dithio-1-(1-dipheny lmethoxycarbonyl-2-methyl-l-prop-2--enyl)-azetidin-2-one; and starting from methyl 6|l-(lR-t-butyldimethylsilyloxy-ethyl)-penici11anate-1-oxide, 3R-(lR-t-butvldimethy1si1vloxyethvl)-4R-benzthiazolvl--dithio-l-(l-methoxycarbonvl-2-methvl-l-prop-2-envl)-5 -azetidin-2-one.

Example 8 3S-(lR-hvdroxvethvl)-4R-benz'chiazolyldithio-1-(1-methoxv-carbonvl-2-hydroxy-l-prop-l-enyl)-azetidin-2-one The crude 3S-(lR-hydroxyethyl)-4R-benzthiazolyldithio-10 -l-(l-methoxycarbonyl-2-methyl-l-prop-2-enyl)-a2etidin--2-one obtained in Example 7 was dissolved in 300 ml of dry dichloromethane and treated with a stream of ozone at-70°C until TLC showed that all the starting material had reacted. The solution was purged with nitrogen and 15 then 10 g of sodium metabisulphite was added at -30"C. The mixture was allowed to rise to room temperature under vigorous stirring, and then filtered. The soltuion was washed with 4 % aqueous sodium bicarbonate solution, dried over anhydrous sodium sulphate and 20 evaporated. The residue was taken up in diethyl ether, the undissolved matter was filtered off and the solution was evaporated to give the crude title product. An aliquot was purified by flash chromatography over silica gel (ethyl acetate:cyclohexane as eluant); S (CDCl^) 25 1.35 (3H, d, J=7Hz, CHj.CH), 2.11 (3H, s, CH3), 2.75 (1H„ Br s, OH), 3.44 (1H, dd, J=2.0 and 5.0Hz, CH.CH.CH), 3.79 (3H, s, OCHj), 4.26 (1H, m, CHj.CH.CH), 5.29 (1H, d, J=2.0Hz, CH.CH.S) and 7.25-7.95 ppm (4H, m. Ar).

By using a similar procedure, there were obtained : 3S< lR-t-butyldimethylsilvloxyethyl)-4R-benzthiazolyl-5 dithio-1- (1 -methoacycarbonvl-2-hydroxy -l-prop-1 -enyl) - -azetidin-2-one. starting from crude 3S-(lR-t-butyldimethyl -silyloxyethyl)-4R-benzthiazolyldithio-l-(l-methoxy-carbonyl-2-methyl- l-prop-2-enyl)-azetidin'-2-one; Tmax (film) 3350, 1770 and 1660 cm"1; C(CDC13) 0.05 10 and 0.07 (6H, each s, SiMe2>, 0.87 (9H, s, SiBu*), 1.27 (3H, d, J=6.5Hz, CHj.CH), 2.07 (3H, s, =C.CH3), 3.33 (1H, dd, J=2.2 and 4.2Hz, CHCH.CH), 3.74 (3H, s, OCH3), 4.26 (1H, m, CH3.CH.CH), 5.36 (1H, d, J=2.2Hz, CH.CH.S), 7.2-7.9 (4H, m, Ar) and 12.37 ppm (1H, br s, OH); 3R-(lR-t-butvldimethylsilyloxyethyl)-4R-benzthiazolyl-dithio-1-(l-methoxycarbonvl-2-hydroxy-l-prop-l-enyl)--azetidin-2-one. starting form 3R-(lR-t-butyldimethyl-silyloxyethyl)-4R-benzthiazolyldithio-l-(1-methoxy-carbonyl-2-methy1-1-prop-2-enyl)-azetidin-2-one; 20 (film) 3200, 1773, 1710, 1665 and 1620 cm"1; s?(CDCip 0.20 (SH, s, SiMe2), 0.94 (9H, s, SiBufc), 1.52 (3H, d, J=6Hz, CH3.CH), 2.17 (3H, br s, =C.CH3>, 3.6-3.7 (4H, s-5-dd, OCH3 and CH.CH.CH), 4.4 (1H, m, CHj.CH.CH), 5.25 (1H, d, CH.Ol.S) and 7.3-7.9 ppm (4H, 25 m, Ar); 3S-(lR-hydroxyethyl)-4R~benzthiazolvldithio-1- (1--diphenvlmethoxycarbonyl-2-hydroxy-l-prop-l-enyl)--azetidin-2-one. starting from crude 3S-(lR-hydroxyethyl)r -4R-benzthiazolyldithio~l-(l-diphenylmethoxycarbonyl-2-5 -methyl-l-prop-2-enyl)-2-azetidin-2-one;V__„ (CHC1, film) IuaX j 3400, 1770, 1730 and 1650 cm-1; 3S-(lR-t-butyldimethylsilvloxvethyl)-4R-benzthiazolvl- dithio-l-(l-diphenylmetho«vcarbonvl-2-hydro3ty-l-prop-l- -envl)-azetidin-2-one, starting from crude 3s/( 1R-t-butyl- dimethylsilyloxyethyl)-4R-benzthiazolyldithio-l-(1- -diphenylmethoitycarbony1-2-methyl-1-prop-2-any1)- -azetidin-2-one (CHC1, film) 3400, 1775, 1735, '• max o 1700 Sh, 1655 and 1610 cm"1; €(CDC13) 0.06 <6H, s, SiMe2), 0.82 (9H, s, But), 1.26 (3H, d, J=6Hz, CH-j.CH), 15 2.08 (3H, s, =C.CH3), 3.33 (1H, dd, J=3 and 5.5Hz, CH.CH.CH), 4.18 (1H, m, CHj.CH.CH), 5.22 <1H, d, J=2Hz, CH.CH.S), 6.86 (1H, s, OCHPhj) and 7.2-7.9 ppm (14H, m, Ar); and 3S4 lR-trichloroethoxycarbonyloxyethyl)-4R-benzthiazolyl-20 dithio-1-(l-methoxycarbonyl-2-hydroxy-l-prop-l-enyl )--azetidin-2-one; C(CDClj) 1.50 (3H, d, J=6Hz, CHj.CH), 2.14 (3H, s, =C.CH3), 3.67 (1H, dd, J-2.2 and 5.5Hz, CH.CH.CH), 3.82 (3H, S, OCHj), 4.62 (2H, ABq, J=12Hz, separation of inner lines 2Hz, OCH^), 5.10-5.40 (2H, m, 25 CHj.CH.CH and CH.CH.S), 7.20-8.00 <4H, m, Ar) and 12.40 ppm (1H, br s, OH); and in a likewise fashion, starting from the corresponding t-butyl and diphenylmethyl ester, 3S-(lR-trichloroethoxycarbonvloxvethyl)-4R-benzthiazolyl-5 dithio-1-(l-t-butoxvcarbonyl-2-hvdroxy-l-prop-l-enyl)--azetidin-2-one; 3S-(lR-trichloroethoxycarbonyloxyethyl)-4R-benzthiazolvl-dithio-1-(l-diphenylmethoxycarbonvl-2-hvdroxy-l-prop-l--enyl)-azetidin-2-one; and 10 3S-(lR-t-butyldimethylsilyloxvethyl)-4R-benzthiazolyl-dithio-1-(1-t-butoxycarbony1-2-hydroxy-1-prop-1-eny1)--azetidin-2-one.

Example 9 3S-(lR-hydroxyethyl)-4R-benzthiazolyldithio-1-(1-15 -methoxvcarbonvl-2-methvlsulphonvloxy-l-prop-l-enyl)--azetidin-2-one A solution of 130 mg (0.03 mmol) of 3S-(lR-hydroxyethyl )--■4R-benzthiazolyldithio-l-(l-methoxycarbonyl-2-hydroxy--1-prop-l-enyl)-azetidin-2-one, prepared as described in 20 Example 8, in 8 ml of anhydrous dichloromethane was sequentially treated at -40°C with 0.043 ml (0.3 mmol) of triethylamine and 0.024 ml (0.31 mmol) of methane-sulphonyl chloride. The reaction was quenched after 5 minutes with cold 2% aqueous sodium bicarbonate 25 solution. Removal of the solvent from the organic layer gave the crude title product (quantitative yield), which was used as such for the next step.

By following the same experimental procedure, there was obtained: 3S-(lR-t-butyldimethylsilvloxvethyl)-4R-benzthiazolvl-5 dithio-1-(1-methoxvcarhonv1-2-methylsulphonvloxv-1-prop--1-envl)-azetidin-2-one. starting from 3£-(1R-t-butyl-dimethylsilyloxyethyl)-4R-benzthia20lyldithi0-l-(1--methoxycarbonyl-2-hydroxy-l-prop-l-enyl)-azetidin-2--one; an aliquot of this product was purified by flash 10 chromatography (silica gel; ethyl acetate-cyclohexane as eluant) to afford the pure title compound as a 1:1 mixture of E and Z isomers;y___ (film) 1885, 1730, ID9X -1 f 1363 and 1165 cm 1; © (CDCl.,) 0.05 and 0.10 (each 3H, s, SiMe2), 0.88 (9H, s, SiBut), 1.29 (3H, d, J=6.5Hz, 15 CHj.CH), 2.20 and 2.53 (3H, each s, =C.CH3), 3.18 and 3.29 (3H, each s, S02CH3>, 3.42 (1H, m, CH.CHCH), 3.71 and 3.78 (3H, each s, OCHj), 4.30 (1H, m, CH3.CH.CH), 5.59 and 5.64 (1H, each d, Js2Hz, CH.CH.S) and 7.12-7.96 ppm (4H, m, Ar).

When tetrahydrofuran was used instead of dichloromethane as a solvent, the formation of the undesired E isomer was almost suppressed, and the pure Z isomer thus collected;^(CDC13) 0.05 (6H, s, SiMe2>, 0.88 (9H, s, SiBu*), 1.29 (3H, d, J=6.5Hz, CH30H), 2.53 (3H, s, =C.CH3>, 25 3.29 (3H, s, S02CH3), 3.42 (1H, dd, J=2 and 5Hz, CH.CH.CH), 3.71 (3H, s, OCHj), 4.30 (1H, m, CH3.CH.CH), 5.59 (1H, d, J=2Hz, CH.CH.S) and 7.12-7.95 ppm (4H, m. Ar).

By following this last procedure (tetrahydroduran as a solvent in the mesylation step), there were obtained: 3R-(lR-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyl- dithio-1-[l-methoxycarbony1-2-methylsulphonyloxy-1-prop- -l-(Z)-enyl ]-azetidin-2-one. starting from 3R-(lR-t- -butyldimethylsilyloxyethyl)-4R-benzthiazolyldithio-1- -(l-methoxycarbonyl-2-hydroxy-l-prop-l-enyl)-azetidin- -2-one;V (CHC1, film) 1775, 1735, 1365 and 1165 cm 1 max 3 (CDClj) 0.18 (6H, s, SiMe2), 0.88 (9H, s, SiBu*), 1.42 (3H, d, J=6.5Hz, CH3.CH), 2.33 (3H. S, =C.CH3), 3.05 (3H, s, S02CH3), 3.45 (3H, s,0CH3), 3.62 (1H, dd, 15 CH.CH.CH), 4.3 (1H, m, CH3.CH.CH), 5.40 (1H, d, J=5Hz, CH.CH.S) and 7.15-7.85 ppm (4H, m, Ar); 3S-(lR-hvdroxvethyl)-4R-benzthiazolvldithio-l-Il--diphenylmethoxvcarbonyl-2-methylsulphonvloxy-l-prop-l-(Z)-enyl]-azetidin-2-one, starting from 3S-(lR-hydroxy-20 ethyl )-4R-benzthiazolyldithio-l-(l-diphenylmethoxy-carbony1-2-hydroxy-1-prop-1-eny1)-azetidin-2-one; 1rmax (filn,) 3400' 1775' 1730' 1365 and 1170 S (CDClj) 1.22 (3H, d, J=6.5Hz, CHj.CH), 2.43 (3H, s, =C.CH3), 3.13 (3H, s, S02CH3), 3.35 (1H, dd, J=2.5 and 25 4Hz, CH.CH.CH), 4.1 (1H, m, CH3.CH.CH), 5.40 (1H, d, J=2.5Hz, CH.CH.S), 6.85 (1H, s, OCHPh..) and 7.1-7.9 ppm (14H, m, Ar); 3S-(lR-t-butvldimethvlsilyloxyethyl)-4R-benzthiazolyl- dithio-1- U-diphenvlmethoxvcarbonyl-2-(Z)-methylsulphonyl- oxy-1-prop-1-eny1 ]-azetid in-2-one. starting from 3S-(1R- -t-butyldimethylsilyloxyethyl)-4R-benzthiazolyldithio- -1-(1-diphenylmethoxycarbonyl -2-hydroxy-l-prop-l-enyl)- -azetidin-2-one;V__„ (CHC1, film) 1775, 1725, 1370 and max 3 1175 cm"1; S{CDC13) 0.1 (6H, s, SiMe2), 0.9 (9H, s, 10 SiBu*), 1.28 (3H, d, J=6Hz, CHj.CH), 2.5 (3H, s, =C.CH3>, 3.25 (3H, s, S02CH3), 3.35 (1H, dd, J=2.5 and 5Hz, CH.CH.CH), 4.20 (1H, m, CH3-CH.CH), 5.50 (1H, d, J=2.5Hz, CH.CH.S), 6.9 (1H, s, OCHPhj) and 7.1-7.9 ppm (14H, m, Ar); 3S-(1R-t-butvldimethylsilyloxyethyl)-4R-benzthiazolyl- dithio-1-11-t-butoxvcarbonvl-2-(Z)-methylsulphonyloxy-1--prop-l-enyl]-azetidin-2-one, starting from 3S-(lR-t--butyldimethylsilyloxyethyl)-4R-benzthiazolyldithio-l--(1-t-butoxycarbonyl-2-hydroxy-l-prop-l-enyl)-azetidin-20 -2-one; (film) 1773, 1710, 1370 and 1165 cm"1; S(CDC13) 0.06 (6H, s, SiMe2), 0.87 (9H, s, SiBut), 1.25 (3H, d, J=6Hz, CHj.CH), 1.49 (9H, si, OBut), 2.45 (3H, s, =C.CH3), 3.25 (3H, s, S02CH3), 3.35 (1H, dd, J=2.5 and 5Hz), 4.3 (1H, m, CHj.CH.CH), 5.60 (1H, d, J-2.5HZ, 25 CH.CH.S) and 7.1-7.9 ppm (4H, m, Ar); and 3S-(lR-trichloroethoxvcarbonvloxvethvl)-4R-benzthiazolvl- dithio-1- II-methoxvcarbony1-2-methylsulphonvloxv-1 -prop- -1(Z)-envll-azetidin-2-one. starting from 3S-(1R- -trichloroethoxycarbonyloxyethyl)-4R-benzthiazolyldithio- -1-(l-methoxycarbonyl-2-hydroxy-l-prop-l-enyl)-azetidin- -2-one; "V*(CHC1, film) 1780, 1755 sh, 1730, 1380, max 1 1250 and 1167 cm-1; fiMCDClj) 1.48 (3H, d, J=6Hz, O^.CH), 2.52 (3H, s, »C.CH3), 3.25 (3H, s, sojchj), 3.72 <4H, s+dd, OCH3 and CH.CH.CH), 4.68, (2H, s, OCHj), 5.2 (1H, 10 m. Chj.CH.CH), 5.47 (1H, d, J=2.5Hz, CH.CH.S) and 7.1-7.9 ppm (4H, m, Ar); and likewise, starting from the corresponding t-butyl and diphenylmethyl esters, there was obtained: 3S-(lR-trichloroethoxvcarbonyloxvethyl)-4R-benzthiazolyl-15 dithio-1- [l-t-butoxvcarbonvl-2-methvlsulphonyloxy-l-prop--1(Z)-envl1-azetidin-2-one: and 3S-(lR-trichloroethoxvcarbonvloxyethyl)-4R-benzthiazolyl-dithio-1- [1-diphenvlmethoxycarbony1-2-methylsulphonvloxv--1-prop-l (Z) -enyl 1 -azeti.din-2-one.

Example 10 3S-(lR-methylsulphonylo«yethvl)-4R-benzthia2olyldithio--1-(l-methoxycarbonyl-2-methvlsulphonvloxy-l-prop-l-envl)--azetidin-2-one.

When in the reaction described in Example 9 the starting 25 material was exposed to an excess (2 molar equivalents) ~ 33 •* of methanesulphonylchloride and triethylamine, -the title product was obtained as a foam in quantitative yield as a mixture of E (20S) and Z (60S) isomers(film) 1780, ■" ~ UlaX 1730, 1360 ana 1170 cm"1; StCDClj) 1.58 (3H, d, J=6Hz, 5 CHj.CH), 2.22 and 2.56 (3H, each s, =C.CH3 of E and Z isomers), 3.00 (3H, s, CH^SC^ on the hydroxyethyl chain), 3.20 (1H, dd, J=2.2 and 4.5Hz, CH.CH.CH), 3.28 (3H, s, CH3SC>2 on the crotonic appendage), 3.76 (3H, s, OCH3), 5.11 (1H, m, CH.j-CH.CH), 5.52 (1H, d, J=2.2Hz, CH.CH.S) 10 and 7.30-7.95 ppm (4H, m, Ar).

By following the same procedure, but using THF as a solvent, 3S-(lR-methylsulphonyloxvethyl)-4R-benzthiazolyl- aithio-1- (1-aiphenylmethoxycarbony1-2-methvlsulphonylosty- -1-prop-1-(2)-enyl1-azetidin-2-one was prepared and displayed the following spectral data:!? (film) 1777, max 1728, 1360 and 1170 cm-1; % ( CDC13) 1.50 (3H, d, J=6Hz, CH3-CH), 2.52 (3H, s, =C.CH3), 2.9 (3H. s, CHjSOj on the hydroxyethyl chain), 3.23 (3H, s, CHjSC^ on the crotonic appendage ), 3.62 (1H, dd, J=2.5 and 5.5Hz, CH.CH.CH), 20 5.05 (1H, m, CHj.CH.CH), 5.45 (1H, d, J=2.5Hz, CH.CH.S), 6.95 (1H, s, 0CHPh2) ana 7.10-7.95 ppm <1«H, m, Ar).

Example 11 3S- (lR-t-butvldimethylsilvloxvethyl)-4R-benzthiazolvl-dithio-1-(l-niethoKVCairbonvl-2-tirif luoromethvlsulphonyloxv- -1-prop-1-enyl)-azetidin-2-one 300 mg o£ crude 3S-(lR-t-butyldimethylsilylo»yethyl)"4R--henzthiazolyldithio-l- (l-methoicycarbonyl-2-hydrajty-l--prop~l-enyl)-azetidin-2*-one in 5 ml of THF at -40°C was sequentially treated with 0.170 ml of triethylamine 5 and 0.160 ml of trifluoramethanesulphonic anhydride.

Work-up and chromatography gave the two separate geometrical isomers of the title product, as foams: E isomer:Y,™. (CHCl,) 1778, 1730, 1420, 1215 and 1135 — IQCUi J cm"1; S" (CDC13)0.08 <6H, s, sihe2) , 0.86 (9H, s, SiBufc), 10 1.26 (3H, d, 0=6Hz, ch3.CH), 2.05 (3H, s, =C.ch3>, 3.46 (1H, dd, 2.2 and «Hz, CH.CH.CH), 3.81 (3H, s, OCH3), A.28 (1H, m, ch3.CH.CH), 5.76 (1H, d, J=2.2Hz, CH.CH.S) and 7.25-7.90 (4H, m. As:); Z isomer (inter alia) «§>{CDC13) 2.A5 (3H, s, =C.CH3), 3.40 (1H, dd, J=2 and 4Hz, 15 CH.CH.CH), 3.64 (3H, s, och3) , 4.30 (1H, m, CH.CH.CH) ana 5.65 ppm (1H, d, J-2Hz, CH.CH.S).

Example 12 Methyl (7S,6R)-7-(IR-t-butyldimethylsilyloxyethyl)-3--methyl-2-thiacephem-4-carboaylate 20 A solution of 0.5 ml of triethylamine in 10 ml of dichloromethane was saturated at -S0°C with hydrogen sulphide. After purging with nitrogen, 0.3<3 ml of this solution was added to a cold (~50°C) solution of 75 jng (0.121 mmol) of 3S*-(IR-t-butyldimethyIsilyloayethyl)-25 -4R-bensthiazolyldithio-l-(l-methoxycarbonyl-2-methyl- sulphonylooiy-l-prop-l-enyl)-asetidin-2-one. The mixture was allowed to warm up to room temperature and then washed with water, dried on anhydrous sodium sulphate and evaporated. Separation of the new compound from the 5 formed 2~mercaptobenzthiasole and minor impurities was achieved by silica gel chromatography (ethyl acetate: cyclohexane as eluant), thus obtaining the title compound as white crystals (19 ®g, 206) , mp 85-87°C, (EtOH) 223 (£= 4,77$, 277 (6,335), and 326 (2,922) nm, y 10 (CHC13 film) 1785 and 1730 cm"1; S° (cdci3) 0.08 (6H, s, SiMe2), 0.88 (9H, s, SiBu*), 1.2b (3H, d, J=6Hs, CHj.CH), 2.22(3H, s, CH3), 3.07 (1H, dd, J=2.2 and 3.5Hz, CH.CH.CH), 3.8 (3H, s, OMe), 4.36 (1H, m. CH3-CH.CH) and 4.62 ppm (1H, d, J-2.2HZ, CH.CH.S).

Found: C, 49.08; H, 6.96; N, 3.52; S, 15.16. C16H27H04SiS2 requires C, 49,32; H, 6.99; N, 3.60; S, 16.46/. • When, instead of hydrogen sulphide and triethylamine, a solution of ftaHS (0.9 mol equiv) in DMF was used, and quenching (partition between water and ethyl acetate) 20 followed within 1 minute at 0°C, the isolated yield of the pure title product was raised to 40-45%.

When the above process was performed on the geometrical Z isomer of the starting material, the yield was further enhanced (up to 60-65%). On the contrary, the E isomer 25 afforded only a wry low amount of the title product.

By following the same experimental procedure, methyl (7R,6B)-7-(IR-t-feutyldiiaefchvlsilvloxyethyl)-3- -methyl-2-thiacephem-4-carboxylate was obtained starting from 3R-(lR-t-buayldimethylsilyloxyethyl)-4R-benzthiazolyl- dithio-1-(l-jnethoxycarbonyl-2-methylsu^phonyloxy-l-prop- -l-enyl)-azetidin-2-one; V__„ (film) 1785 and 1725 cm max £ (CD3CCCD3) 0.03 and 0.05 (each 3H, s, SiMe2), 0.84 (9H, s, SiBu*), 1.19 (3H, d, 6.5Hz, CHj.CH), 2.08 (3H, s, CH3), 3.72 (3H, s, 0CH3), 4.11 (1H, dd, J=5.5 and 8.0Hz, 10 CH.CH.CH), 4.20 (1H, m, ch3.CH.CH) and 5.01 ppm (1H, d, J-5.5HZ, CH.CH.S).

Example 13 Methyl (7S,6R)-7-(lR-hydroxyethyl)-3-methyl-2-thiacephem--4-carboitylate 145 mg (0.287 mmol) of exude 3S-(lR-hydroxyethyl)-4R--benzothiazolyldithio-l-(l-jnethoxycarbonyl-2-methyl-sulphonyloxy-1-prop'-1-enyl)-azetidin-2-one, prepared as described in Example 9, was dissolved in 2 ml of anhydrous dimethylformamide and treated at +20°C with 20 a freshly prepared solution of 16 mg (0.287 mmol) of NaHS in 1.6 ml of the same solvent. The mixture was stirred for 2 minutes and then partitioned between ethyl acetate and water.

After repeated washings with water, the solvent was 25 removed leaving a residue which was purified by pressure chromatography on silica gel (ethyl acetate:cyclohexaae as eluant) to give the pure title product in yield -1 as a white powder; *y ^ (nujol) 3400, 1770 and 1720 cai ; S(CDC13) 1.37 (3H, d, J=7Hz, CH3.CH); 2.22 (3H, s, CH3), 5 2.40 (1H, br s, OH), 3.12 (1H, dd, J=2„0 and 4.5Hz, CH.CH.CH), 3.86 (3H, 6, OCH3), 4.35 (1H, m, CH3.CH.CH) and 4.65 ppm (1H, d, J=2.0Hz, CH.CH.S).

By following a similar experimental procedure, there were obtained: Dipheny lmethyl (7S,6R)-7-(lR-hydroxyethyl)-3-methy1-2--thiacephem-4-carboxylate. starting from 3S-(lR-hydrojiy-ethyl)-4R-benzthiazolyldithio-l-(1-dipheny lmethQKycarbony1--2-methylsulphonyloxy-l-prop-1-enyl)-azetidin-2-one; (EtOH) 281 (€= 5,900) and 326 (3,670) nm; f- „ (KBr) waX iUGJi 3550-3250, 3080, 3060, 3020, 2960, 2920, 2840, 1775, 1720, 1660 and 1490 cm"1;$(CDCI3) 1.36 (3H, d, J=6.5Ha, CH3„CH), 2.17 (3H, s, CH3), 3.12 (1H, dd, J=2„0 and 5Hs, CH.CH.CH), 4.36 (1H, m. ch3.CH.CH), 4.76 (1H, d, J=2.0Hz, CH.CH.S), 6.97 (1H, s, OCHjPh) and 7.30 (10H, m, Ar); Diphenvlmethyl (7S.6R)-7-(1R—t-butyldimethvlsilylc«yethyl)--3-methyl-2-thiacephem-4-carboatylate, starting from 3S-(1R--t-butyldimethylsilyloxyethyl)-4R-benzthiazolyldithio-l--(1-diphenylmethoxycarbony1-2-met.hylsulphonyloxy-1-prop-- 1-enyl)-azetidin-2-one; S(CDC13) 0.06 (SH, s, SiMe2) ? 25 0.83 (9H, s, SiBufc); 1.27 (3H, 6. J=6.5Hs, CH3.CH), 2.05 (3H, s, CH3), 3.06 (1H, dd, J=3„0 and 5.0Hz, CH.CH.CH), 4.32 (1H, CH3..CH.CH), 4.60 (1H, d, J=3.0Hz, CH.CH.S), 7.02 (1H, s, OCHPh2) and 7.30 ppm (lOH, s. Ar); t-Butyl (7S,6R)-7-(1R-t-butyId JunethyIsilyloxyethy1)-3--niethyl-2~thiacephezn-4-carboxy late. starting from 3S~(IR-t-butyldimethy Isllyloxyethyl)-4R-ben2thiazolyldithio-l--(l-t-butaxycarbonyl-2-methylsulphonylojcy-l-prop-l- enyl)-azetidin-2-one; Jj „=„ (CHC1-.) 278 (£= 6,300 ) and 327 nm JDaX J (£= 2,56°)m9x (CHC13 film) 1780 and 1720 cm-1; S(CDCI3) 0.12 (6H, s, SiMe2), 0.88 (9H, s, SiBufc), 1.25 (3H, d, 0=6h2, ch3.CH), 1.52 (9H, s, 0B«0, 2.10 <3H, s, CH3), 3.02 (1H, dd, J=2.5 and 5Hz, CH.CH.CH), 4.28 (1H, m, CH3.OJ.CH) and 4.53 ppm (1H, d, J=2.5Hz, CH.CH.S); Methyl (7S,6R)-7-(lR-roethylsulphonyloayethy1)-3-methy1--2-thiacephem-4-carboxylate, starting from 3S-(lR-methyl-sulphonylosyethyl)-4R-benzthiazolyldithio-l-(1-methoxy-carbonyl-2-methylsulphonyloxy-l-prop-1-enyl)-azetidin-2--one;>. „ 1780/ 1725, 1360 and 1175 cm'*1; i'(CDCl,) luoX ' V 1.60 (3H, d, J»6.5HZ, CH3.CH) «, 2.25 (3H, s, CH3) , 3.07 (3H, s, CH3S02), 3.27 (1H, dd, J=2.2 and 5Hz, CH.CH.CH), 3.83 (3H, s, OCH3), 4.70 (1H, d, J=2.2Hz, CH.CH.S) and 5.24 ppm (1H, m, CH.jCH.CH) Dipheny lmethyl (7S,6R)-7-(lR-methylsulphonyloxyethyl)-3--inethvl"2"thi.acapheai-4"cagbQKvlate, starting from 3S-(1R--methylsulphonyloxyethy1)-£R-benzt.hiazolyldithio-1-{1- - ♦ -dipheny lmethcotycarbonyl-2-methy lsulphony losty-l-prop-1- -enyl)-azetidin-2-one; «^ (CHCI3) 282 (£= 7,080) and 330 (3,966) ran; (CHCI3 film) 1778, 1720, 1255 and 1170 cm-1; S (CDCI3) 1.53 (3H, d, J=6Hz, CH-j.CH), 2.10 (3H, s, CH3), 2.71 (3H, s, CH3S02), 3.22 (1H, dd, J=2.5 and 5.5 Ha, ch.ch.ch), 4.67 (1H, d, J=2.5Hz, ch.CH.S), 5.05 10 (1H, m, ch3.CH.CH); 6.90 (1H, s, OCHPhj) and 7.25 (IOH, s, Ar); Methyl (7S,6R)-7-(lR-trichloroethcfltycarbonvloxvethyl)-3--•me thy l-2-thiacephem-4-car bcety late, starting from 3S-(1R--trichloroethaxycarbonyloxyethyl)-4R-benzthiazolyldithio-15 -1-(l-methaxycarboRyI-2»methylsulphonyloxy-l-prop-l-enyl)--azetidin-2-one;v (film) 1787, 1760 sh, 1725 and JDcuC 1250 cm"1; S (CDCI3) 1.54 (3H, d, J=5.5Hz, CH3.CH), 2.23 (3H, s, CH3), 3.30 (1H, dd, J=2 and 7.5Hz, CH.CH.CH), 3.84 (3H, s, OCH3), 4.68 (1H, d, J=2Hz, CH.CH.S), 4.78 20 (2h, s, CCH2) and 5.37 ppm (1H, m, CH3.CH.CH); and Piphenvlroethvl (7S.6R)-7-(lR-p-nltrobenzyloxycarbonyloxyethyl) -3-methy1-2-thiacephem-4-carbQHylate, starting from (3S) - (IR-p-niti-oben^yloxy carbony loxyethyl) -4R -benz-thiazoly ldichio--1- (1-dipheny laetboxy carbony 1-2 -methy 1-25 sulphonylasy-l-prop-1-enyl) -asetidi.n-2-one; f 1787, lUQA 1745, 1720 sh can-1; £" (CDC13) 1.53 (3H, d, CH3CH), 2.17 (3H, s, CH3), 3.28 (1H, dd, and 6.5Ha, CH-CH-CH), 4.65 (1H, d, J=2Hz, CH.CH.S), 5.15 (2H, s, OCHa), 5.28 (1H, m, CHj.CH.CH), 6.97 (1H, S, 0CHPh2), 7.2-7.5 (12H, 5 m, Ar) and 8.17 ppm (2H, d, J=9Hz, Ar); and, likewise, there were obtained: t-butyl (7S,6R)-7-(1R-trichloroethoxycarbonvloxyethyl)--3-methyl-2-thiacephem-4-carboxylate; diphenylmethyl (7S,6R)-7-(lR-trichloroethoxvcarbonyloxy-10 ethyl)-3-methy1-2-thlacephem-4-carboxylate; trichloroethy1 (7S,6R)-7-(1R-trichloroethoaycarbonyloxyethyl) -3-methy1-2-thiacephem-4-caxbOxylate; trIchloroethy1 (7S,6R)-7-(IR-t-butyldimethyIsllyloxyethyl)--3-methyl-2-thiacephem-4-carboxylate; acetaxymethyl (7S,6R)-7-(lR-trichloroethoxycarbonyloxyethyl) -3-methyl-2-thlacephem-4-carboxylate; acetoxymethyl (7S.6R)-7-(IR-t-butvldimethylsilyloxyethyl)--3-roethy1-2-thiacephem-4-carboxylate; and acetoxvmethv1 (7S.6R)-7-(IR-tr Imethylsilvloacvethy1)-3-20 -roethvl-2-thiacephem-carboxylate.

Example 14 3S-(IR-t-butyldimethylsilyloxvethyl)-4R-succinlmidothio--1-(l-methoxycarbonyl-2-methyl-l-prop-2-enyl)-azetldin--2-one A solution of 2.32 g of methyl (IR-t-butyldimethy1-silyloxyethyl)-penicillanate-l-oxide in 35 ml of dimethylacetamide was treated with 0.15 ml of acetic acid, purged with nitrogen, and heated for 3$ hours at 105"C in the presence of 5 g of SJ-trimethylsilyl-succinimide. After cooling to room temperature, the 5 reaction mixture was partitioned between ethyl acetate and cold water. Fractionation of the material obtained from the organic layer (silica gel chromatography, ethyl acetatezcyclohexane) afforded the title product as a white foam, 1.2 g 1434);^^ (CHClj film) 1770, 1735, 10 1710 sh and 1680 cm-1; ^(CDClj) 0.08 (6H, s, SiMe2>, 0.87 (9H, s, SiBut), 1.32 (3H, d, J=6.5Hz, CHj.CH), 1.84 (3H, s, =C.CH3), 2.85 (4H, s, CO.CH2.CH2.CO), 3.29 (1H, dd, J=3 and 4.5Hz, CH.CH.CH), 3.73 (3H, s, OMe), 4.24 (1H, m, CH3-CH.CH), 4.66 (1H, s, N.CH.CO), 4.85 (1H, d, 15 J=2.5Hz, CH.CH.S) and 5.00 ppm (2H, br s, CH2=C).

By following a similar experimental procedure, there were also obtained: 3S-(lR-t-butvldimethvlsilvloxvethvl)-4R-succinimidothio--1-(l-diphenvlmethoxvcarbonvl-2-methvl-l-prop-2-envl)-20 -azetidin-2-one. and 3S-(lR-t-butvldimethylsilyloxyethyl)-4R-phthalimidothio--1-(l-diphenylmethoxycarbonyl-2-methvl-l-prop-2-envl)--azetidin-2-one. both isolated as crude materials and used as such in the following steps.

Example 15 3S-(lR-t-butyldimethylsilvloxyethyl)-4R-phthalimidothio--1-[1-methoxycarbony1-2-methylsulphony1oxy-1-prop-1—(2 ) — -enyl1-azetidin-2-one 5 A solution of 100 mg of 3S-(lR-t-butyldimethylsilyloxy-ethyl)-4R-benzothiazolyldithio-1-[1-methoxycarbony1-2--methylsulphonyloxy-l-prop-1-(Z)-enyl]-azetidin-2-one in 9 ml of acetone was treated with 34 mg of silver nitrate, soon followed by an ethanolic slurry of 30 mg 10 of potassium phthalimide. After 30 minutes stirring at room temperature, the precipitate was cx>llected partitioned beti«een water and ethyl acetate, and purified by short silica gel chromatography to afford the title product <55§);,ymax (film) 1780, 1745 and 1725 15 cm"1; C(CDC13) 0.1 (6H, s, SiM©2), 0.89 (9H. s, Bu*), 1.4 (3H, d, CH3.CH), 2.2 (3H, s, -C.CHj), 3.05 (3H, s, S02.CH3), 3.4 (1H, m, CH.CH.CH), 3.6 (3H, s, OCH3), 4.2 (1H, m. CH3.CH.CH), 5.45 (1H, d, J-2Hz, CH.CH.S) and 7.8 ppm (4H, m, Ar).

BxampJe 16 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-succinimidothio--1-(l-methoxycarbonyl-2-hydroxy-l-prop-l-enyl)-azetidin--2-one The title product was obtained by ozonolysis of 3S-(lR-t-25 -butyldimethylsilyloxyethyl)-4R-succinimidothio-l-(l- -methoxycarbonyl-2-methyl-l-prop-2-enyl)-azetidin-2-one in dichloromethane according to the procedure described in Example 8, and used as such for further reactions. A sample was characterized as its dimethylketal (MeOH/dry HC1): ymax 1770» 1730 and 1715 sh S (CDClj) 0.04 and 0.09 (each 3H, s, SiMe2), 0.90 (9H, s, SiBu^), 1.31 (3H, d, J=5Hz, CH3.CH), 1.49 (3H, s, CHj), 2.84 (4H, s, COCH2.CH2CO), 3.21 and 3.26 (each 3H, s, ketal OCH3>, 3.24 (1H, dd, J=2.5 and 5Hz)r3.73 (3H, s, ester OCHj), 4.20 (1H, m, CH3.CH.CH), 4.43 (1H, s, N.CH.CO) and 4.94 ppm 10 (1H, d, J=2.5Hz).

Likewise, 3S-(lR-t-butyldimethylsilyloxyethyl)-4R--phthalimidothio-1-(l-diphenylmethoxycarbonyl-2-hydroxy--1-prop-1-enyl)-azetidin-2-one was obtained starting from 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-phthalimido-15 thio-1-(l-diphenylmethoxycarbonyl-2-methyl-l-prop-2-enyl )--azetidin-2-one.

Example 17 Methyl (7S,6R)-7-(lR-t-butyldimethylsilvloxyethvl)-3--methyl-2-thiacephem-4-carboxylate 20 A solution of 400 mg of 3S-(lR-t-butyldimethylsilyloxy-ethyl)-4R-phthalimidothio-1-[l-methoxycarbonyl-2-methyl-sulphonyloxy-l-prop-1-(Z)-enyl]-azetidin-2-one in 4 ml of dimethylformamide was treated with 50 g of finely ground NaHS under vigorous stirring. As soon as the 25 last reagent was dissolved, the reaction was quenched by partition between diethyl ether and water. Work-up gave the title compound, identical with the sample described in Example 12.

Example 18 Methyl (7S,6R)-7-(lB-t-butvldimethylsilyloxyethyl)-3- -methyl-2-thiacephem-4-carboxylate > 0.8 g of 3S-(lR-t-butyldimethylsilyloxyethyl)-4R--succinimidothio-1-(l-methoxycarbonyl-l-prop-2-enyl)--azetidin-2-one in dichloromethane was ozonized at -70°C 10 until tic showed complete conversion. Excess ozone was purged with nitrogen and 1 ml of dimethylsulphide was added. After 1 hour at room temperature, any volatile material was removed in vacuo and the residue reacted in dichloromethane at -20°C to 0°C with equimolar amounts 15 of triethylamine and mesyl chloride until conversion of the enol into the mesylates was judged complete by tic.

The mixture was concentrated in vacuo and partitioned between ethyl acetate and a cold, aqueous solution of sodium bicarbonate. The organic layer was evaporated 20 to afford the crude mixture of E,Z mesylates which without purification was treated with NaHS in DMF according to the prcoedure described in Example 13.

Purification of the resulting product by silica gel chromatography afforded the title compound, identical 25 with the material obtained according to Example 12. t By a similar procedure, Diphenylmethvl (7S.SR)-7-(lR-t-butvldimethvlsilvloxy-ethvl) -3-methy1-2-thiacephem-4-carboxylate was obtained, starting from 3S-(lR-t-butyldimethylsilyloxy-5 ethyl)-4R-phthalimidothio-1-(l-diphenylmethoxycarbonyl-2--methyl-l-prop-2-enyl)-azetidin-2-one, and showed the same spectral properties as the material previously described (Example 13).

Example 19 Methyl (7S,6R)-7-(lR-t-butyldimethylsilyloxvethyl) — 3 —[(1--methyl-5-tetrazolylthio)-methyl]-2-thiacephem-4--carboxylate 120 mg of 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-(1--methyl-5-tetrazolyldithio)-l-fl-methoxycarbonyl-2-[(1-15 -methyl-5-tetrazolylthio)-methyl]-l-prop-2-enyl|-azetidin--2-one in dichloromethane was subjscted to the reaction sequence reported in Examples 8, 9 and 17 (ozonolysis, mesylation, reaction with NaHS). The crude product was partitioned between ethyl acetate and aqueous sodium 20 bicarbonate solution, thus removing the liberated mercaptotetrazole; the organic layer was washed several times with water, evaporated and the residue fractionated by silica gel chromatography to afford the title product, 17 mg (film) 1787, 1725, 1587, 1360 and 1250 cm-1; £(CDClj) 0.10 (6H, s, SiMe2>, 0.89 (9H. s, SiBut), 1.26 (3H, d, J=6Hz, CHj-CH), 3.15 (1H, dd, J=2.2 and 3.5Hz CH.CH.CH), 3.88 (3H, s, OMe), 3.92 (3H, s, NMe), 4.38 (1H, m, CH^.CH.CH), 4.46 (2H, ABq, J=14Hz, separation of inner lines 14Hz) and 4.68 ppm (1H, d, J=2.2Hz, CH.CH.S).

Example 20 3S-(lR-t-butyldimethylsilyloxvethyl)-4R-phenylsulphonyl-5 thio-1-(l-methoxvcarbonyl-2-methyl-l-prop-2-enyl)--azetidin-2-one 2.6 g of 3S-(lR-t-butyldimethylsilyloxyethyl)-4R--benzthiazolyldithio-1-(l-methoxycarbonyl-2-methyl-l--prop-2-enyl)-azetidin-2-one, prepared as described 10 in Example 7, in 160 ml of acetone and 18 ml of water was treated under vigorous stirring with 0.98 g of silver nitrate, immediately followed by 0.79 g of sodium benzenesulphinate in 60 ml of water. After 1 hour at room temperature the white precipitate was filtered off, 15 and the filtrate concentrated in vacuo and then partitioned between water and ethyl acetate. Removal of the solvent from the organic layer left the title product as a yellowish powder (2.43 g, 98%), recrystallizable from cyclohexane (white leaflets, mp 105-106°C); ir (KBr) 20 3080, 3020, 2960, 2930, 2900, 2860, 1770, 1750, 1330 and 1145 cm"1; 6 (CDClj) 0.05 (6H, s, SiMe2), 0.98 (12H, s+d, SiBu* and CHj.CH), 1.84 (3H, s, =C.CH3>, 3.22 (1H, dd, J=2 and 2.5Hz, CH.CH.CH), 3.75 (3H, s, OMe), 4.19 (1H, m, CH3.CH.CH), 4.58 (1H, s, N.CH.CO), 5.00 (2H, m, 25 C=CH2), 5.37 (1H, d, J=2Hz, CH.CH.S), 7.60 and 7.96 ppm (3 and 2H, each m, Ar).

Found: C, 53.69; H, 6.99; N, 2.70; S, 12.42%, C23H35N06SiS2 requires C, 53.77, H, 6.87; N, 2.74; S, 12.488.

By following the same procedure, there were also obtained: 5 3S-(lR-t-butyldimethylsilvloxyethyl)-4R-phenvlsulphonvl-thio-1-(l-t-butoxvcarbonvl-2-methyl-l-prop-2-envl)--azetidin-2-one; 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-phenvlsulphonyl-thio-1-(l-diphenylmethoxycarbonvl-2-methyl-l-prop-2-enyl)-10 -azetidin-2-one: 3S-(lR-trichloroethoxvcarbonvloxyethyl)-4R-phenyl-sulphonylthio-1-(l-methoxvcarbonyl-2-methyl-l-prop-2--enyl)-azetidin-2-one; 3S-(lR-trichloroethoxycarbonyloxvethyl)-4R-phenylsulphony1-15 thio-1-(l-trichloroethoxvcarbonyl-2-methvl-l-prop-2-enyl)--azetidin-2-one.

Example 21 3S-(lR-t-butvldimethvlsilvlo«vethyl)-4R-phenylsulphonyl-thio-l-[1-methoxycarbonvl-2-methylsulphonyloxy-1-prop-1-20 (2)-enyl]-azetidin-2-one Procedure A 1 g of 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-phenyl-sulphonylthio-1-(1-methosycarbonyl-2-methyl-1-prop-2--enyl)-azetidin-2-one, prepared as described in Example 25 20, in dry dichloromethane was ozonized at -70°C. After purging with nitrogen, 3.5 ml of dimethylsulphide was added and the mixture was stirred for 3 hours at room tmeperature. After removal of any volatile material in vacuo, the residue was partitioned between ethyl 5 acetate and water. Evaporation of the solvent left the intermediate 3S-(IR-t-butyldimethylsilyloxyethyl)-4R--phenylsulphonylthio-1-(l-methoxycarbonyl-2-hydroxy-l--prop-l-enyl)-azetidin-2-one;,w'max 3450, 1778, 1658 and 1620 cm-1; S (CDC13) 0.08 (6H, s, SiMe2>, 0.90 (9H, s, 10 SiBu1), 1.13 (3H, d, J=6Hz, CH3,CH), 1.90 (3H, s, =C.CH3), 3.12 (1H, dd, 3=2.5 and 4Hz, CH.CH.CH), 3.72 (3H, s, OMe), 4.2 (1H, m, CHj.CH.CH), 5.52 (1H, d, J=2.5Hz, CH.Ol.S), 7.4-8.0 (5H, m, Ar) and 13 ppm (1H, s, OH).

This material was mesylated with 0.272 ml of triethylamine 15 and 0.151 ml of mesyl chloride in 10 ml of dry THF according to the procedure of Example 10, thus obtaining the title product as a foam, 550 mg after silica gel chromatography; ir (film) 1780, 1730, 1640, 1370 and 1145 cm"1; % (CDClj) 0.05 (6H, s, SiMe2), 0.80 (9H, s, 20 SiBu*"), 0.97 (3H, d, J=6Hz, CHj.CH), 2.50 (3H, s, =C.CH3), 3.15 (4H, m, S02CH3 and CH.CH.CH), 3.76 (3H, s, OCHj), 4.13 (1H, m, CH3.CH.CH), 5.7 (1H, d, J=2.8Hz, CH.CH.S) and 7.6-8.0 ppm (5H, m, Ar).

Procedure B 100 mg of 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-benz- thiazolyldithio-l-ll-methoxycarbonyl-2-methylsulphonyloxy--1-prop-l(2)-enyll-azetidin-2-one in 9 ml of acetone and 1 ml of water was sequentially treated under stirring with 34.3 mg of silver nitrate and 26.6 mg of sodium benzene-5 sulphinate in 4 ml of water. After 15 minutes at room temperature the precipitated silver benzthiazole-mercaptide was removed by filtration and the solution partitioned between dichloromethane and water. Removal of the solvent left the uitle product as a syrup 10 (quantitive yield), having the same spectral properties as the sample from procedure A.

According to the same methodology, there were obtained: 3S-(lR-t-butvldimethylsilyloxyethyl)-IR-phenylsulphonyl-thio-1-[l-t-butoxvcarbonyl-2-roethylsulphonvloxv-l-prop-15 -1(Z)-enyl )-azetidin-2-one; and 3S-(lR-trichloroethoxycarbonyloxyethyl)-4R-phenyl-sulphonylthio-1-H-trichlorðoKycarbonyl-2-methyl-sulphonyloxy-l-prop-l(Z)-enyl1-azetidin-2-one.

Example 22 Methyl (7S.6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3--methvl-2-thiacephem-4-carboxylate 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-phenylsulphonyl-thio-1-(l-methoxycarbonyl-2-methylsulphonyloxy-l-prop--12-enyl)-azetidin-2-one was allowed to react with WaHS 25 in DMF following the procedure described in Example 13 thereby obtaining the title product, identical with the material previously described. This preparation allows for a simpler purification of the product, since the by-product, sodium benzenesulphinate, is soluble in water 5 and does not need chromatographic separation or fractional crystallization to be removed (unlike, e.g. mercapto-benzthiazole).

According to the same methodologies, there were obtained: t-Butyl (7S,6R)-7-(1R-t-butyldimethylsi 1yloxyethyl)-3-10 -methyl-2-thiacephem-4-carboxylate; and Trichloroethyl (7S,6R)-7-(lR-trichloroethoxycarbonyloxy-ethyl)-3-methyl-2-thiacephem-4-carboxy late.

Example 23 3S-(lR-trichloroethoxycarbonyloxyethyl)-4R-acetyldithio-15 -1-(1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1Z-enyl)--azetidin-2-one A solution of 340 mg of 3S-(lR-trichloroethoxycarbonyloxy-ethyl)-4R- benzthiazolyldithio-1-(1-methoxycarbony1-2--methy lsulphony loxy-1-prop-1 Z-enyl)-azetidin-2-one in 5 ml 20 of THF was treated with 0.043 ml of thioacetic acid.

Five minutes later the mixture was evaporated and the crude reaction product freed from 2-mercaptobenzthiazole by chromatography to obtain the pure title compound as a colourless syrup, 280 mg(96§);ymax (film) 1775, 1760 25 sh, 1730 br cm-1; £ (CDC13> 1.50 (3H, d, CHj.CH), 2.48 „ 50 - (3H, s, =C.CH3), 2.62 (3H, s, COCH-j), 3.29 (3H, s, S02CH3), 3.44 (1H, dd, CH.CH.CH), 3.83 (3H, s, OMe), 4.77 (2H, ABg, J=11.5Hz, separation of inner lines 2Hz), 5.24 (1H, d, CH.CH.S) and 5.25 (1H, m, CH^CH.CH).

Example 24 Methyl (7S,6R)-7-(lR-trichloroethoxycarbonyloxyethyl)-3--methyl-2-thiacephem-4-carboxylate A solution of 140 mg of 3S-(lR-trichloroethoxycarbonyloxy-ethyl)-4R-acetyldithio-l-(l-methoxycarbonyl-2-methyl-10 sulphonyloxy-1-prop-1Z-enyl)-azetidin-2-one, prepared as described in Example 23, in 10 ml of THF was treated at 0°C with a solution of 65 mg of tetrabutylammonium hydrogen sulphide in the same solvent.

Work-up and chromatography afforded the title product: * (EtOH) 280 (€4„974) and 327 nm (2,262);V (film) max * max 1787, 1769 sh, 1725 cm"1; % (CDCl-j) 1.54 (3H, d, CH-j.CH), 2.23 (3H, s, CH3), 3.30 (1H, dd, 2 and 7.5Hz, CH.CH.CH), 3.84 (3H, s, OMe), 4.68 (1H, d, CH.CH.S), 4.78 (2H, s, OCHjCCl3) and 5.37 ppm (1H, m, CHj.CH.CH), followed by 20 some recovered starting material.

Example 25 Methyl (7S,6R) -7-(lR-t-butyldimethylsilyloxyethyl)-3- -bromomethyl-2-thiacephem-4-carboxylate 0.52 g of methyl (7S.6R)-7-(lR-t-butyldimethylsilyloxy- ethyl)-3-methyl-2-thiacephem-4-carboxylate, 0.95 ml of propylene oxide, 0.52 g of N-bromosuccinimide and 0.05 g of azobisisobutyronitrile in 40 ml of carbon tetrachloride were refluxed for six hours. The reaction 5 mixture was cooled to room temperature and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column eluting with ethyl acetate: hexane mixtures, thus obtaining the title product as a yellowish oil (80%); Amax (CHClj) 282 and. 336 nm; 'f (CHC1, film) 1785 ,1730 cm-1; S (CDC1,) max 3 * 3 0.10 <6H, s, SiMe2), 0.89 (9H, s, SiBu1), 1.28 (3H, d, CHj.CH.OSi), 3.23 (1H, dd, J=2.0 and 3.5Hz, CH.CH.CH), 3.87 (3H, s, 0CH3), 4.65 (2H, center ABq, s.i.l. 4Hz, J=11.5Hz, CHjBr), 4.30 (1H, m, CH3-CH.CH) and 4.76 ppm 15 (1H, d, 3-2.0Hz, CH.CH.S).

Found C, 41.1; H, 5.64; N, 3.01; S, 13.55; Br, 17.20; Cj^HjgBrTO^SiSj requires C, 41.02; H, 5.59; N, 2.99; S, 13.69; Br, 17.06.

By following a similar procedure, there were obtained: t-butyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethvl)-3- bromomethyl-2-thiacephem-4-carboxylate; (CDC1,) 283 and 332 nm; V „ (film) 1787 and 1720 max 3 max cm"1; S (CDC13) 0.9 (6H, s, SiMe2), 0.9 (9H, SiBu1), 1.2B (3H, d, CH3.CH), 1.55 (9H, s, OBut), 3.18 (1H, dd, 25 J=2.5 and 4.5Hz, CH.CH.CH), 4.35 (3H, m, CHjBr and CH3-CH.CH) and 4.71 ppm (1H, d, J=2.5Hz, CH.CH.S); ■■■ 52 - p-nitrobenzyl (7S.6R)-7-(lR-p-nitrobenzyloxycarbonyloxy-ethyl)-3-bromomethy1-2-thiacephem-4-carboKylate; S (CDCl^) 1.45 (3H, d, CHj.CH), 3.43 (1H, dd, J=2.5 and 6Hz, CH.CH.CH), 4.45 (2H, ABq, J=12Hz, CHjBr), 4.80 (1H, d, 5 J-2.5Hz, CH.CH.S), 5.2, 5.5 (5H, m, two OCHjAr and CH3.CH.CH); 7.47 and 7.60 (each 2H, d, J=8.5Hz, Ar), and 8.20 ppm (4H, d, J=8.5Hz, Ar); diphenylmethyl (7S,6R)-7-(lR-p-nitrobenzyloxycarbonyloxy-ethyl)-3-bromomethyl-2-thiacephem-4-carboxylate; 10 £ 0.05 (6H, s, SiMej), 0.8 (9H, s, SiBu*), 1.22 (3H, d, J=6.5Hz, CHj.CH), 3.10 (1H, dd, J=2.7 and 4.5Hz, CH.CH.CH), 4.05 (2H, s, CH2Br), 4.2 (1H, m, CH-j.CH.CH), 4.63 (1H, d, J=2.7Hz, CH.CH.S), 6.92 (1H, s, OCHPh,), and 7.05-7.40 ppm (10H, m, Ar):l (CHC1,) — £. max j 283 (£= 7,867) and 336 nm (£ =3,533); trichloroethyl (7S,6R)-7-(lR-t-butyldimethylsilyloxy-ethyl)-3-bromoniethvl-2-thiacephem-4-carboxylate; and trichloroethyl (7S.6R)-7-(lR-trichloroethoxycarbonyloxy-ethyl)-3-bromomethvl-2-thiacephem-4-carboxvlate.

Example 26 Methyl (7S,6R)-7-(lR-t-butvldimethvlsilyloxvethyl)—3—I(1-5 -methyl-5-tetrazolylthio)-methyll-2-thiacephem-4--carboxylate A THF solution of crude methyl (7S,6R)-7-(lR-t-butyl- d imethy1silyloxyethy1)-3-bromomethy1-2-thiacephem-4- -carboxylate was kept overnight in the presence of sodium l-methyl-tetrazole-5-mercaptide bihydrate (3 mol equiv). Work-up and chromatography afforded the title product as an oil in 85% yield; X max (EtOH) 281 and 333 nm;V „„ (film) 1790 and 1725 cm 1; b (CDC1,) 0.10 (6H, s, max j SiMe2), 0.89 (9H, s, But), 1.26 (3H, d, CH.J.CH), 3.15 15 (1H, dd, J=2.2 and 3.5Hz, CH.CH.CH), 3.88 (3H, s, OMe), 3.92 (3H, s, N.CH3), 4.38 (1H, m, CH-j.CH.CH), 4.46 (2H, ABq, sep. of inner lines 14Hz, J=14Hz) and 4.68 ppm (1H, d, CH.CH.S, J=2.2Hz).

By following a similar procedure, there were obtained: 20 t-butyl (7S,6R)-7-(lR-t-butyldimethylsilyloxvethvl)-3--[(1-methyl-5-tetrazolylthio)-methyl]-2-thiacephem-4--carboxylate, starting from t-butyl (7S,6R)-7-(lR-t-butyldimethy1silyloxyethyl-3-bromomethy1-2-thiacephem-4-carboxylate; and diphenylmethyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)--3- /(8-aminotetrazolof1,5-b]pyridazin-6-ylthio)-methyl\-2--thi acephen-4-carboxy1ate Example 27 (5aR.6S)-6-(1R—t-butyldimethylsilvloxyethyl)-5a,6-dihydro--3H.7H-azeto[2.1-c]furo[3,4-e] 1,2, 4-dithiazine-l,7-dione Procedure A): A solution of 15 mg of methyl (7S.6RJ-7-5 (lR-t-butyldimethylsilyloxyethyl)-3-bromomethyl-2- -thiacephem-4-carboxylate in 2 ml of DMSO and 1.5 ml of water was stirred with 50 mg of cuprous oxide at 50°C for 2^ hours. The reaction mixture was partitioned between water and ethyl acetate. Evaporation and 10 chromatography of the organic extracts afforded the title product as a white powder;°¥,max (CHC13 film) 1800- 1760 br cm"1; 6 (CDC13> 0.06 (3H, s, SiCH3), 0.11 (3H, s, SiCHj), 0.90 (9H, 5, Bu*), 1.33 (3H, d, CHj.CH), 3.33 1H. dd, J=2.5 and 4.5Hz, CH.CH.CH), 4.44 (lH, m, 15 CH-j.CH.CH), 4.62 (1H, d, J=2.5Hz, CH.CH.S) and 4.98 ppm (2H, s, CHjO).

Procedure B); 250 mg of the 2-bromomethyl precursor in 35 ml of acetone:water (2:1 by volume) was stirred for 15 minutes at 0°C with 153 mg of silver perchlorate. 20 The reaction mixture was partitioned between water and ethyl acetate and the organic layer was evaporated off to leave a residue. Silica gel chromatography afforded the title product, identical with the sample described above under A).

Example 2S t-3utyl (7S,5R)-7-(lR-t-butyltiimethylsilyloxyethyl)-3- -hydroxymethyl-2-thiacephem-4-carboxylate 300 mg of t-Butyl (7S,6R)-7-(lR-t-butyldimethylsilyloxy- ethyl)-3-bromomethyl-2-thiacephem-4-carboxylate in 10 ml of a 2:1 by volume acetone:water mixture was stirred for minutes at 0°C with 150 mg of silver perchlorate.

Removal of the solvent, followed by water:ethyl partition and work-up of the organic layer, gave 250 mg (96%) of the title product; max (CFClj)281 nnd 335 nm; T (film) 3450, 1785 and 1712 cm-1; 5 (Cnrj„) 0.1 (6H, max i s, SiMe2), 0.86 (9H, s, SiBu1), 1.25 (3H, d, t^CH), 1.50 (9H, s, OBut), 3.13 (1H, dd, J=2.5 and 4.5Hz, CH.CH.CH), 4.25 (centre of ABq, J=13Hz, CHjOH), 4.37 (1H, m, CH-j.CH.CH) and 4.60 ppm (1H, d, J=2.5Hz, CH.CH.S).

Example 29 t-Butyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3--(N-trichloroacetylcarbamoyloxymethyl)-2-thiacephem-4--carboxvlate 250 mg of t-Butyl (7S,fK!-7-(lR-t-butyldimethylsilyloxy-ethyl)-3-hydroxymethyl-2 Liiiacephem-4-carboxylate in 2.5 ml of ethanol-free dichloromethane was treated at -40°C with 0.080 ml of trichloroacetyl-isocyanate. The mixture was allowed to rise to room temperature and then sequentially washed with 2% aqueous sodium bicarbonate solution and brine. Evaporation of the solvent from the organic layer gave the title product in quantitative yield; kmax (EtOH) 275 and 329 nm; y 1795 and 1725 br cm 1; CtCD^CN), 0.1 (6H, s, 5 SiMe2), 0.9 (9H, s, SiBu1), 1.3 (3H, d, CH3-CH)#1.5 (9H, s, OBu1), 3.40 (1H, dd, J=3 and 4Hz, CH.CH.CH), 4.35 (1H, m, CHj.CH.CH), 4.80 (1H, d, J=3Hz, CH.OJ.S) and 5.0 ppm (centre of ABq, CH^OCO).

Example 30 t-Butyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3--carbamoyloxymethyl-2-thiacephem-4-carboxylate A methanolic solution of t-butyl (7S,6R)-7-(lR-t-butyl-dimethylsilyloxyethyl)-3-(N-trichloroacetylcarbamoyloxy-mcthyl)-2-thiacephein-4-carboxylate, prepared as 15 described in Example 29, was stirred with silica gel for 20 hours. The slurry was then charged onto a silica gel column and the product eluted with ethyl acetate; SjCDCl^) 0.1 (6H, s, SiMe2), 0.9 (9H, s, SiBu1") 1.35 (3H, d , CH3.CH), 1.60 (9H, s, OBu*), 3.1 (1H, dd, 20 CH.CH.CH), 4.3 (1H, m, CH.CH.CH) 4.75 (1H, d, J=3Hz, CH.CH.S) and 5.0 ppm (centre of ABq, OCH^CO).

Example 31 Methyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3--nitrooxvmethyl-2-thiacephem-4-carboxylate 25 A solution of 200 mg of methyl (7S,6R)-7-(lR-t-butyl- dimethylsilyloxyethyl)-3-bromomethy1-2-thiacephem-4- -carboxylate in 20 ml of acetone was stirred for 20 minutes in the presence of 100 mg of silver nitrate.

The filtered reaction mixture was fractionated by silica gel chromatography to obtain the title product, 120 mg; „ (CHC1,) 280 and 337 nm;vm=„ (film) 1790, luax j max 1730, 1640 and 1280 cm-1; ff(CDCl3) 0.08 (6H, s, SiMe2) , 0.87 (9H, s, SiBu1), 1.38 (3H, d, CH3-CH), 3.18 (1H, dd, J=2.5 and 5.5Hz, CH.CH.CH), 3.85 (3H, s, OMe), 4.38 (1H, 10 m, CH3.CH.CH), 4.73 (1H, d, J=2.5Hz, CH.CH.S) and 5.36 ppm (2H, ABq, J=13.5Hz, s.i.l. 29.5Hz, CHjONOj); further elution then afforded some of the lactone described in Example 27.

Example 32 Methyl (7S,6R )-7-(lR-t-butyldimethylsilyloxyethyl)-3--formyloxymethyl-2-thiacephem-4-carboxylate 200 mg of methyl (7S,6R)-7-(lR-t-butyldimethylsilyloxy-ethyl)-3-bromomethyl-2-thiacephem-4-carboxylate in dichloromethane was treated at daily intervals with 20 tetrabutylammonium formate (3 x 600 mg). After 3 days at 5DC, tic showed 80% conversion in the product (ethyl acetate:light petroleum 1:2 by volume). Elution through a short silica gel column gave the title material; S(CDCl3) 0.1 (6H, s, SiMe2), 0.9 (9H, s, SiBu1), 1.35 25 (3H, d, CH3.CH), 3.20 (1H, dd, 2.5 and 7Hz, CH.CH.CH), 3.9 (3H, s, OMe), 4.5 (1H, m, CHj.CH.CH), 4.74 (1H, d, 2.5Hz, CH.CH.S) and 5.13 ppm (centre of ABq, CH^O).

In a similar way, starting from the corresponding t-butyl and diphenylmethyl esters, there were obtained: t-butyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3-5 -formyloxvmethyl-2-thiacephem-4-carboxylate; and diphenylmethyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)--3-formyloxymethyl-2-thiacephem-4-carboxylate and, in a likewise fashion, the corresponding acetates were obtained: methyl (7S.6R)-7-(lR-t-butvldimethvlsilyloxyethyl)-3--acetoxvmethvl-2-thiacephem-4-carboxylate; t-butyl (7S.6R)-7-(lR-t-butvldimethyl silyloxyethyl)-3--acetoxvmethvl-2-thiacephem-4-carboxvlate; diphenylmethyl (7S.6R)-7-(lR-t-butyldimethylsi 1vloxy-15 ethyl)-3-acetoxymethyl-2-thiacephem-4-carboxylate; and tri chloroethyl (7S.6R)-7-(IR-trichloroethoxycarbonvloxyethyl )-3-acetoxymethvl-2-thiacephem-4-carboxvlate.

Example 33 Methyl (7S,6R)-7-(lR-hydroxyethyl)-3-methyl-2-thiacephem-20 -4-carboxylate 0.75 g of methyl (7S,6R)-7-(lR-t-butyldimethylsilyloxy-ethyl)-3-methyl-2-thiacephem-4-carboxylate was added to a solution of 2.03 g of tetrabutylammonium fluoride trihydrate in 1.23 ml of acetic acid and 10 ml of THF. 25 Work-up after 20 hours gave the title compound (virtually quantitative yield), showing the spectral properties described for the sample obtained in Example 13.

By similar experimental procedures, there were obtained Methyl <7S.6R)-7-(lR-hydroxyethyl)-3-bromomethyl-2- -thiacephem-4-carboxylate, starting from methyl (7S.6R) -7-(lR-t-butyldimethylsilyloxyethyl)-3-bromomethy1-2- thiacephem-4-carboxylate;v__„ (film) 1775, 1730 cm-1; ■ max S (CDC13) 1.35 (3H, d, CH-j.CH), 3.38 (1H, dd, CH.CH.CH) 3.60 (1H, br s, OH), 3.97 (3H, s, OMe), 4.33 (1H, m, CH^.CH.CH), 4.46 (2H, centre of ABq, J=llHz, sep. of inner lines 4Hz, CH^Br)) and 4.88 ppm (1H, d, J=2.2Hz, CH.CH.S); Methyl (7S,6R)-7-(lR-hydroxyethyl)-3-[(l-methyl-5--tetrazolylthio)-methyl]-2-thiacephem-4-carboxylate, starting from methyl (7S,6R)-7-(lR-t-butyldimethyl-silyloxyethyl)—3—[(l-methyl-5-tetrazolylthio)-methylJ-2 -thiacephem-4-carboxylate;^flnaj{ (KBr) 1765 and 1707 cm S(CD3COCD3), 1.30 (3H, d, CH3.CH), 3.39 (1H, dd, CH.CH.CH), 3.79 (3H, s, NCH3), 3.97 (3H, s, 0CH3), 4.0 (1H, m, CHj.CH.CH), 4.38 (2H, centre of ABq, J=16Hz separation of inner lines 13Hz, CH^.S), 4.77 (1H, d, J=2.2Hz, CH.CH.S) and 5.0 ppm (1H, br s, OH); and, analogously, the corresponding t-butyl, diphenylmethyl and trichloroethyl esters were also prepared.

Example 34 (7S.6R)-7-(lR-methvlsulphonyloxyethyl)-3-methyl-2--thiacephem-4-carboxylic acid Diphenylmethyl (7S, 6P,)-7- (lR-nsthylsulphonyloxyethyl)-3-methy 1 - -2-thiacephem-4-carboxylate was dissolved in cold trifluoroacetic acid (0°C , neat). After 15 minutes stirring at the same temperature, carbon tetrachloride was added and the solution thoroughly evaporated under vacuum without external heating. The residue was triturated in carbon tetrachloride and collected, thus obtaining the title product; (CHClj) 281 and 326 nm; V (CHC10 3000-2300, 2970, 2930, 2850, 1775, 1710, max j 1530 and 1170 cm-1; S (CD3COCD3> 1.58 (3H, d, Ctj^.CH), 2.23 (3H, s, Me), 3.16 (3H, s, SC>2Me), 3„66 (1H, dd, 15 J=2 and 6Hz, CH.CH.CH), 4.85 (1H, d, J=2Hz, CH.CH.S) and 5.30 ppm (1H, m, CH3.CH.CH).

The same material was obtained by trifluoroacetic acid hydrolysis of the corresponding t-butyl ester, but prolonging the reaction time to about 1 hour.

Similarly hydrolyses of the t-butyl or diphenylmethyl precursors gave the following products: (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3-methvl--2-thiacephem- 4- carboxvlic acid; (7S,6R)-7-(lR-hydroxyethyl)-3-methyl-2-thiacephem-4-25 -carboxvlic acid; - SI - (7S.6R)-7-(lR-hvdro«vethvl)-3-acetQKvmethyl-2-thiacepheiB--•l-carbOKvlic acid; (7S.6R)-7-(IR-hvdrogyethvl)-3-carbamovloxvmethvl-2--thiacephem-4-carbQHVlic acids and 3 (7S.6R)-7-(lR-hydroxyethyl)-3-[(l-methvl-3-tetragolvlthio)--methvll-2-thiacephem-4-cagbo«ylic acid• Example 3 3 p-Nltrobenzvl (7S.gR)-7-(iR-p-nitrobenzyloxycarbonvlo«y-10 ethyl) -3-methyl-2-thiacephem- was concentrated and the residue passed through a short silica column (ethyl acetate: light petrol as eluants) to afford the pure title 23 product. ISO mg (79%)-. 6 (CDClg) 1.43 (3H. d. CHj.CH) 3.43 (1H. dd. J=2.S and 6Hz, CH-CH-CH). 4.4S (2H. ABq. J=12 Hz. CHjBr) . 4.80 (1H, d. J*2.S Har, CH-CH-S) . 5.2-3.3 (3H. m). 7.47 and 7.SO (each 2H, d. Ar) and 8.20 ppm HH, d. Ar).

Example 36 (7S.SR)-7-(iR-t-butyldimethvlsilyloxvethyl)-4-diPhenyl-methoxycarbonyl-3-(pyridinium-methyl)-2-thiacephem bromide A solution of 310 mg of diphenylmethyl (7S,6R)-7-(lR-tj 3 3 -butyldimethylsilyloxyethyl)-3-bromomethyl-2-thiacephem-4- -carboxylate in 13 ml of dry acetone was treated with 0.4 ml - - -4-diphenylmethoxycarbonyl-3---2-thiacephem bromide- A solution of 460 mg of ojnitrobenzyl (7S. SR)-7-7 -nitrobenzyloxycarbonyloxyethyl)-3-bromomethyl-2-5 -thiacephem-4-carboxylate in 5 ml of DMF was stirred overnight in the dark in the presence of 200 mg of nicotinamide. Host of the solvent was distilled off and the residue taken up in 150 ml of tetrahydrofuran. This solution was washed with a solution of sodium chloride in 10 0.1 N hydrochloric acid (2 x SO ml) and with brine (2 x 30 ml), dried on anhydrous sodium sulphate and evaporated to dryness. The residue was charged to the top of a column packed with silanised silica gel (Merck, Art. 7719). Excess nicotinamide and impurities were eluted with ethyl IS acetate, and the product was then collected by eluting with ethyl acetate:acetic acid (9:1 by volume). Evaporation in vacuo left the title product; ma# (CHClj) 1800, 17 23. ISPS cm-*; 6 (Deuteroacetone; 200 MHz) 1.61 (3H. d, J=6.4 Hz. CH.-CH) . 4.14 (1H. dd. 0-2.3 and 4.7 —g Hz, CH-CH-CH) , S.30 <1H. d, Hz. CH-CH-S) , 3.4-5-7 (7H, m, 2xCH;OAr. CHjH+. and CHj-CH-CH) . 7.7-8.4 (8H, m. Ar). and 0.0, 8.7, 9.3 and 9.7 ppm (each IB. br s, pyridinium). Analogously, by using isonicotinamide instead of nicotinamide, there was obtained: 25 (7S.SR)-7-(lR-p-nitrobenzvloxvcarbonvloxvethyl)-4-p- -nitrobenzvloxvcarbonvl-3-(4-carbamovlpyridinium-methvl)--2- thiacephem bromide. - 64 —

Claims (9)

1. claims: 1. A process for the preparation of a 2-thiacephem derivative of the general formula Ila • S II a coor2 wherein R1 represents a hydrogen atom or an organic group 10 and R, represents a hydro gen atom or a carboxy protecting group from an azetidinone derivative of the general formula IV r, 13 30 iv coor 2 wherein Rj and Rg are as defined in this claim and Z represents (i) a group o£ the formula SR? wherein R? represents an alkyl group having from 1 to 8 carbon atoms, a phenyl or tolyl group, or a heterocyclic group. (ii) a group of the formula SC0Rg wherein Rg 2 5 represents an optionally substituted alfcyl group having from 1 to 4 carbon atoms /COR, (iii) a group of the formula -19 wherein R? ^"io and R10 independently scepresent alEiyl groups having from i to 4 carbon atoms or aryl groups, or together with the dicarboxyamino group form a heterocyclic ring, or (iv) a group of the formula -k-R^ wherein RX1 30 - 65 - represents an optionally substituted alkyl group having from l to 4 carbon atoms or an optionally substituted aryl group. the process comprising ozonolysing the carbon-carbon double bond, converting the hydroxy group in the resultant azetidinone to a halogen atom or an alkane sulphonyloxy group or an arene sulphonyloxy group and cyclising the resultant azetidinone by reaction with a sulphide or hydrosulphide in the presence of a base.

2. Methyl (7S.6R)-7-(lR-t-butyldimethylsilyloxyethyl)--3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1.

3. Methyl (7R.6R)-7-(iR-t-butyldimethylsilyloxyethyl)--3-methyl-2-thiacephem-4-carboxylate prepared according to claim l.

4. Diphenylmethyl (7S»6R)-7-(iR-t-bufcyldimethylsilyloxy-ethyl)-3-methyl-2-thiacephera-4-carboxylate prepared according to claim 1.

5. tjButyl <7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3--methyl-2-thiacephem-4-carboxylate prepared according to claim 1.

6. Trichloroethyl (7S.6R)-7-(iR-t-butyldimethylsilyloxy-ethyl)-3-methyl-2-thiacephem-4-carboxylate prepared according to claim %.

7. Acetoxymethyl (7S,SR)-7-(iR-t-butyldimethylsilyloxy-ethyl)-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1.

8. (7S.6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3--methyl-2-thiacephem-4-carboxylic acid prepared according to claim i. - s>6 - P. Methyl (™S.3R)-7-(lR-hydrojiyethyl)-3-methyl-2--thiacephem-4-carboi[ylate prepared according to claisi 1. 10. Diphenylmethyl <7S»SR)-7-(aR-hydronyethyl)-3-saathyl-2-thiacephem-4-carboKylate prepared according to claim 11. (7S.6R)-7-(lR-hydrojtyethyl)-3-methyl-2-thiacephem--4-carboxylic acid prepared according to claim *. 12. Methyl <7S,SR)-7-(iR-methylsulphonyloityethyl)-3--methyl-2-thiacephem-'3-carbo»ylate prepared according to claim l. 13. Diphenylmethyl (7S.SR)-T-dR-methylBulphonyloiiy-ethyl)-3-methyl-2-thiacephem-4-casboaylate prepared according to claim 1. 14. (7S,SR)-7-(IR-methylsulphonylouyethyl)-3-methyl-3--thiacephem—«-carboitylic acid prepared according to claim 1. 13. Methyl (7S.6R)-7-(lR-trichloroett»osycarbonyloay-ethyl)-3-aethyl-2-thiacephejo-^-casboaylate prepared according to claim 1. id. t-Butyl (7S.SR)-7-(iR-tEichloroethO}tycarbonylosy-ethyl)-3-methyl-S-thiacephem—s-cerboxylate prepared according to claim l. 17. Diphenylmethyl (7S. SR)-7-( IR-tr ichlosroethojiy-carb0nyl0Kyethyl)-3-methyl-S-thiacsphem-4-earb0sylate prepared according to claim i. - 67 - 18. Trichloroethyl (7S.6R)-7-(aR-trichloroethoxy-carbonyloiiyethyl) -3-methyl-2-thiacephem-<3-carbosyiate prepared according to claim 1. 5.IS. Acetoxymethyl (7S.SR)-7-(lK-trichloroethoxycarbonyl-oxyethyl)-3-inethyl-2-thiecephero-4-carbo:!ylafce prepared according to claim X. 20. Acetoxymethyl (»S,6R)-?-(aR-trimsthylsilylonyetbyl)-10 -3-methyl-2-thiacephem-4-carboxylate prepared according to claim l. 21. Diphenylmethyl (7S,SR)-™-(lR-p-nitroben3ylojtycarbonyl-oxyethyl)-3-methyl-2-thiacephem-<4-carboxylate prepared is according to claim i. 22. p-Hitrobenzyl (7S.6R)-7-(lR-p-nitrobensyloxycarbonyl-oxyethyl)-3-methyl-2-thiacephem—a-carboxylate prepared according to claim 1. 20 23. A process for the preparation of a 2-thiacephem derivative of the general formula lib Rr\. >|S -*s ,s 1 1 J »al nb ^ I coor2 wherein Rj and Rg are as defined in claim 3. and Hal 30 represents a halogen atom, the process being according to claim 1 and further comprising halogenating the methyl group either of the azetidinone IV prior to the steps of claim l or of the 2-thiacephem after the steps of claim 1. the halogenation of the 2-thiacephem being effected by 33 reaction with a halogenating agent in an inert organic - u g - solvent at a temperature of from 20°c to 130°C in the presence of a radical initiator and an acid scavenger. 34. a process according to claim 23 in »hich the S halogenation of the 2-thiacephem is effected by reaction with ft-bromosuccinimide or ft-chlorosuccinimide. 23. h process according to claim 23 or claim 34 in which the radical initiator present during the halogenation of 10 the 2-thiacephem is asobisisobutyronitrile or benzoyl peroxide- 26. A process according to any of claims 23 to 23 in which the acid scavenger present during the halogenation of IS the 2-thiacephem is an eposide< an alkaline earth oxide or a molecular sieve- 27. A process according to any of claims 23 to 3$ in which the inert organic solvent in »hicb the halogenation 30 of the 2-thiacephem is effected is benzene* carbon tetrachloride or ethyl formate- 28. Methyl (7S,oR)-?-(lS-tjbutyldimethyisilyloityethyl)--3-bromomethyl-2-thiacepb@m-4-carboxyl(;te prepared 23 according to any of claims 23 to 27. 2

9. Diphenylmethyl (7 S. 6R) -7 -QR-t-butyldimethylsilyl-oxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate prepared according to any of claims 23 to 27. 30 30. Trichloroethyl <7S,SR)-7-(SR-t^butyldimethylsilyl-oxyethyl)-3-bromomethyl-3-thiacephem-^-carboxylate prepared according to any of claims 23 to 27. 33 31. t-Butyl (VS.SR)-7-(iR-t^batyldimeibyleilyloxysthyl)- _ flp _ -S-bromoniethyl-2-thiacephein—3-carboxylate prepared according to any of claims 23 to 27. 32. Trichloroethyl <7S,6R)-7-(lR-trichloroethoaycarbonyl-3 oxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate prepared according to any of claims 23 to 27. ' 33. Diphenylmethyl (7S,5R)-7-(lR-Ejnitrobenzylo*y- carbonyloxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate * 10 prepared according to any of claims 23 to 27. 34. g^Nitrobenzyl (7S,6R)-7-(lR-gjnitrobenzyloxy-carbonyloxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate prepared according to any of claims 23 to 27. 15 35. Methyl (7S,6R)-7-(lR-hydroxyethyl)-3-bromomethyl--2-thiacephem-4-carboxylate prepared according to any of claims 23 to 27. 20 36. ft process for the preparation of a 2-thiacephem derivative of the general formula II v II COOR 30 wherein R1 and R2 are as defined in claim 1 and Y represents an organic group, the process being according to any of claims 23 to 27 and further comprising converting the halomethyl group introduced by the halogenation into a methyl group substituted by the desired organic group- the 3 5 conversion being effected at any point after the halogenation- I - 70 - Si. h process according to claim 33 in which the conversion is effected on the 3-halomethyl-2-thiacephem derivative- 3 38. Methyl (7S,(5R)-7-(JR-t-butyldimgthylsilylouyethyl)--3-nitrooityraethyl-2-thiacepheia-^-cairboitylete prepared according to claim 36 or claim 37. 39. A process according to claim 37 in which Y represents io a hydroxy group and the conversion is effected by reacting the 3-halomethyl-2-thiacephem derivative with a salt of a strong inorganic acid and hydrolysing the resultant labile ester of the inorganic acid* is 40. A process according to claim 3$ in which the salt i6 silver nitrate, silver perchlorate or sodium nitrate. 41. A process according to claim 39 or claim 40 in which the reaction is carried out in an acetone-.water mixture at ?.o o°c for IS minutes, and the subsequent hydrolysis is carried out in the same reaction medium. 42. t-Butyl (7S.SR)-7-(SR-tjbutyldimethylsilyloxyethyl)--3-hydroxymethyl-a-thiacaphem-^-carboxylate prepared 23 according to any of claims 39 to •ai. 43. h process according to claim 39 in which It represents an unsubstituted or H-alkyl or M-acyl substituted carbaiaoyloxy group and the conversion is carried out 30 according to any of claims 39 to --3-utyldimethylsilyloxyethyl)--3-carbamoyloxymethyl-2-thiacephem-'J-carboxylate prepared according to any of claims 43 to 43. is 4 8. (7S.SR)-7-(lR-hydroxyethyl)-3-carbamoyloxymethyl-2--thiacephem-4-carbosylic acid prepared according to any of claims 43 to 43. 20 49. A process according to claim 37 in which Y represents an acyloxy group and the conversion is effected by reacting the 3-halomethyl-2-thiacepbem with a carboxylie acid salt. SO. A process according to claim 49 in which the reaction 23 is carried out in dichloromethane at 3°C with addition of the salt portionwise in three days. 31. fflethyl (7S,-3-10 -acetoxymethyl-2-thiacephem-4-carboxylate prepared according to claim 4P or claim 30. 3S. Diphenylmethyl (7S.SR)-7-(lR-tjbutyldiinethylsiloxy-ethyl)-3-acetoaymethyl-2-thiacephem-4-carboitylate prepared 15 according to claim 49 or claim 30. 37. Trichloroethyl (7S.SR)-7-(aR-trichloroethosycarbonyl-OKysthyl) -3-acet oxymethyl-2-thiacephem-4-cairboiiylets prepared according to claim 45 or claim 30. 20 38. (7 S. SR) -7 - (iR-hyd roxyethyl)-8-acetoxymethyl-S--thiacephem-4-carboxylic acid prepared according to claim 49 or claim 30. 23 39. A process according to claim SI in »hich Y represents a -S-Het group wherein Het denotes a saturated or unsaturated hetrocyclic ring containing at least one oxygen. sulphur and/or nitrogen heteroatom. and is pre£erably: 30 a) a pentatomic or hexatomic heteromonocyclic ring. containing at least one double bond and at least one oxygen* sulphur and/or nitrogen heteroatom. such as a thiasolyl. triazolyl. thiadiazolyl. tetrazolyl, triazinyl giroup. unsubstituted or 33 substituted by one or more ) a') alkoiry groups having from 1 to S carbon atoms, aliphatic acyl groups having from 2 to 6 carbon atoms, hydroxy groups and/or halogen atoms! b') alkyl groups having from 1 to 6 carbon atoms, unsubstituted or substituted by one or more hydroxy groups and/or halogen atoms! c') alkenyl groups having from 2 to S carbon atoms unsubstituted or substituted by one or more hydroxy groups and/or halogen atoms? d') groups of the general formula -S-R3 wherein R3 represents a hydrogen atom or an alkyl group having from l to 6 carbon atoms! or groups of the general formula -S-CHj-COOR^ wherein R4 represents a hydrogem atom, an alkyl group having from 1 to 6 carbon atoms or a carboxy-protecting group! e') groups of the general formula -(CHjj^-COOR^ or -CH-CH-COOR, or - - is a pentatomic or bejiatoaic heteromonocyclic ring containing at least one oxygen* sulphur or nitrogen heteroatom* said heterobicyclic ring being unsubstituted or 5 substituted by one or more substiiuents selected from a'), b'). c'). e') and £') as defined above, the process conversion being effected by the 3-halomethyl-2-thiacephem derivative in an organic solvent with a compound of the formula HS-Het in the presence of a 10 base or with a preformed sodium salt of the compound HS-Het. 60. A process according to claim 39 in which the organic solvent is tetrohydrofuran* acetone* acetonitrile or is dimethylformamide. 61. A process according to claim 39 or claim SO in which the reaction is carried out overnight at room temperature• 20 62. A process according to any of claims 39 to 61 in which the base is triethylamine. 63. Methyl (7S.6R)-7-(iR-tjbutyldimethylsilOHyethyl)-S--I(l-methyl-3-fcetrasolylthio)-methyll-2-thiacephem-<4- 23 -carbostylate prepared according to any of claim §9 to 62. 64. t-Butyl <7S,6R)-7-(iR-tjbutyldimethylsiloityethyl)-3--I(i-methyl-5-tetrasolylthio)-methyl]-2-thiacephem-4--carbonylate prepared according to any of claim 39 to 62. 30 63. Diphenylmethyl (7S.6R)-7-(iR-tjbutyldimethyl6il0Ky-ethyl)-3-{(3-aminotetrazolU.5-blpyridazin-S-ylthio)--methyl)-2-thiacephem-