IE56677B1 - Preparation of 2-thiacephems - Google Patents

Description

DESCRIPTION: The invention relates to processes for the preparation of 2-thiacephems of the general formula II J— M« o & 1 n COORj IS wherein R* represents a hydrogen atom or an organic group* R^ represents a hydrogen atom or a carboxy protecting group and Y represents a hydrogen pr halogen atom or an organic group- These 2-thiacephems are useful as starting materials for the preparation of penems of the general formula I 3$ wherein R*. and Y are as above defined- The conversion of the 2-thiacephems II to the penems I is described and claimed in our Irish Patent Application No. 2877/83, from which this Application is divided.

Organic groups which Rx may represent include optionally substituted aliphatic or cycloaliphatic groups- The aliphatic groups are preferably alkyl groups having from l 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 alkyl groups are methyl and ethyl* especially the latter* and a preferred substituent for such a group is a hydroxy group* - 2 which eaey bs free pr protected® Ihe 1-hydroxyethyl group in 65, 88 or 68, BS configuration is most preferred. ihe cycloaliphatic groups are preferably monocycloalkyl groups having from to 7 carbon atoms. Cyclopentyl and cyclohexyl groups are especially perferred. Optional substituents are preferably chosen from alkyl groups heving from 1 to 6 carbon atoms, for example methyl or ethyl groups, hydroxy, amino and mercapto groups, the hydroxy, amino and mercapto groups being free or protected, ID the carboxy protecting group R^ n,a>' be any group which, together with the -CDO-moiety, forms en esterified carboxy group, Examples of carboxy protecting groups R? are alkyl groups having from 1 to 6 carbon atoms, for instance methyl, ethyl or t~butyl; halo-substituted alkyl groups having from 1 to 6 carbon atoms, for example 2,2«2-trichloroethyl; alkenyl groups having from 2 to carbon atoms^for example allyl; optionally substituted aryl groups® for example phenyl and £-nitro-phenyl; aryl substituted alkyl groups, the alkyl part whereof has from 1 to 6 carbon atoms and the aryl pBrt whereof is optionally substituted, for example bensyl, i^-nitro-bengyl and £-methoxy-benzyl; aryloxy substituted alkyl groups, the alkyl pert whereof has from 1 to 6 carbon atoms, for example phenoxy-methyl; or groups such as benzhydryl, o-nitro-benzhydryl9 acetonyl, trimethylsilyl p diphenyl-t-butyl-eilyl , and dimethyl-ΐ~ hutyl-silyl* Tib© definition of ,3S ® carboxy protecting group also includes any residue, such as acetoxymethyly pivoloyloxymethyl or phthalidyl, leading io an ester group which is known to he hydrolyzed in vivo11 and to have favourably pharmacokinetic properties.

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

* When Y represents en organic group, it is preferably a) a free or protected hydroxy. group; b) s formyloxy group or an acyloxy group having from 2 to 6 carbon atoms, optionally substituted by s halogen stem, by sn acyl group having from 2 to 6 carbon atoms, or by en amino, hydroxy or mercapto group, the Bmino, hydroxy or mercepto group optionally being in b protected form; c) sn unsubstituted or K-slkyl or N-acyl substituted carbamoyloxy group; d) en alkoxy group having from 1 to 12 carbon atoms or an alkylthio group having from 1 to 12 cerbon atoms, either of which is optionally substituted by one or more halogen etoms, formyl groups, acyl groups having from 1 to 6 carbon stoma, and/or smino., hydroxy or mercapto groups, the amino, hydroxy or mercepto group optionally being in a protected form; e) a 1-pyridinium group, unsubstituted or substituted in 25 the meta or para position with the group -CONH^; a f) a heterocyclylthio group -5-Het therein Het, denoting Ss <=» A a setureted or unsetureted heterocyclic ring containing ot least one oxygen, sulphur and/or nitrogen heteroatom, is preferably: A) e pentetomic or hexetomic heteromonocyclic ring, containing et least one double bond end et least one oxygen, sulphur and/or nitrogen heteroatom, unsubstituted or substituted by one or more a1) elkoxy groups having from 1 to 6 carbon etoms, 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; c1) alkenyl groups having from 2 to 6 carbon etoms, unsubstituted or substituted by one or more hydroxy groups end/or halogen atoms; d’) groups of the general formula -S-R^ therein R^ represents a hydrogen atom or en alkyl group having from 1 to 6 cerbon etoms, or groups of the general formula -S-CH^-COOR^ wherein represents e hydrogen etom, en elkyl group having from 1 to 6 carbon atoms or a cerboxy~protecting group; ε’) groups of the general formulae-(CH,)m-C00R^ or -CH=CH-CODR. or -(CH,) -CW or -(CH,) -CONH, or -(CH,) .

A 2m i m 2 2m -SD-H wherein m is sero, ), 2 or ) and R. is as *4 defined above; f·) groups of the general formula ~(CH,) -N wherein * B> m is ss defined above, and each of R^ and R^e which / 6 may be the same or different, represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or an aliphatic acyl group or when one of and R& is hydrogen, the other may be also an amino protecting , group; or ** B) a heterobicyclic ring, containing at le&st two double bonds wherein each of the condensed heteromonocyclic 4 rings, being the same or different, is a pentetomic or hexetomic heteromonocyclic ring containing at least one oxygen, sulphur or nitrogen heteroetom, said heterobicyclic ring being unsubstituted ox substituted by one or more substituents selected form a'), b*), c'), e*) end f’) as defined aboveIn the above definitions A) end B) preferred halogen atcms are lb chlorine, bromine end iodine; preferred alkyl groups ere methyl and ethyl; a preferred alkenyl group is Bllyl; a preferred aliphatic acyl group is acetyl; a carboxy protecting group may be any of the groups previously indicated for the Rg substituent; and the free sulpho end carboxy groups possibly present may be salified, e.g. as sodium or potassium salts. A heteromonocyclic ring « 6 for example, an optionally substituted thlazolyl, triazolyl, thiediazolyl, tetrazolyl or triazinyl ring. Preferred substituents on such rings are, for example, one or more substitutents chosen from amino, hydroxy, oxo and a C^-C^$ alkyl group,preferably methyl or ethyl, wherein the C^-C^elUyl group may be optionally substituted by a substituent chosen from carboxy, sulpho, cyano, carbamoyl, Bmino, methylamino or dimethylamino. A heterobicyclic ring of the above class &) may be for exemple, a ID tetrazolopyridaziny1 radical optionally substituted by amino or carboxy.

In the above 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 may be, for instance optionally substituted, especially halo-substituted, acyl groups, e.g. acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl, benzoyl or o-bromophenecyl; triarylmelhyl groups, in pBTticular triphenylmethyl; silyl 20 groups, in particular trimethylsilyl, dimethyl-t-butylsilyl, diphenyl-t~buty1 silyl; or also groups such as t—butoxycarbonylf o^nitrobenzyloxycarbonyl, 2,2,2trichloroethoxycarbony1, benzyl, pyranyl and nitro. When, in particular, the substituent in formula (1) is a hydroxyalkyl group, preferred protecting groups for the hydroxy function are o-nitro-benzyloxycarbonyl; dimethylt-butyl-si lyl? diphenyl-jt-butyl si lyl; trimethyl si lylj σ' - 7 2.2,2-trichloroethoxycarbonyl; benzyl; joybromo-phenacyl; triphenylmethyl and pyranyl. All the alkyl and alkenyl groups, including the aliphatic hydrocarbon moiety of the alkoxy, alkylthio and acyloxy groups, may be branched or straight.

According to the invention, the 2-thiacephems II in which Y represents a hydrogen atom, i.e- those of the general formula Ila Ila wherein R* and are as above defined, are prepared from an azetidinone derivative of the general formula IV R IV wherein R* and R. are as above defined and Z represents & & (i) a group of the formula sr7 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 SCORg wherein Rg represents an optionally substituted alkyl group having from 1 to 4 carbon atoms (iii) a group of the formula COR, COR wherein and R10 independently represent alkyl groups having from l to 4 carbon atoms or aryl groups, or together with the dicarboxyamino group form a heterocyclic ring, or (iv) a group of - 8 the formula wherein I» represents an optionally substituted alkyl group having from 1 to 4 carbon atoms or an optionally substituted aryl group, by a 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.

Also according to the invention, the 2-thiacephems II in 15 which Y represents a halogen atom, i.e. those of the general formula lib pi wherein R& and R2 are as above defined and Hal represents a halogen atom, are prepared by the aforesaid process according to the invention and the further step of halogenating the methyl group either of the azetidinone IV prior to the steps of the aforesaid process or of the 2-thiacephem after the steps of the aforesaid process. The halogenation of the 2-thlacephero is effected by reaction with a halogenating agent in an inert organic solvent af a temperature of from 20°C fo I3O°C in the presence of a radical initiator and an acid scavenger.

This halogenation of the 3-methyl group of the 2-thiacephems lla is most unexpected. Reasonable - 9 expectation would rule out the possibility of halogenating the 3-methyl group of the 2-thiacephems IIa owing to the presence of the disulphide moiety. Nevertheless, the halogention as described proceeds with high yields· Suitable halogenating agents are N-bromosuccinimide and N-chlorosuccinimide· The radical initiator may be azobisisobutyronitrile 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 io 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 by methods known per se (allyl, ene-type, or electrochemical halogenation, see Tetrahedron Letters, 1980, 71 and 331; 1981. 3193; 1985, 2187).

These processes are illustrated by the following reaction scheme wherein Rj, Rg, 2 and Bal are as above defined and L represents a halogen atom· an alkane sulphonyloxy group or an arene sulphonyloxy group* preferably a methanesulphonyloxy group.

CH C02K2 ν· Z ! coor, Ils (II:X°H) XXb (XX>2«Bal) Compounds of the general formula IV, which are 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 the Examples.

Following the right hand side of the reaction scheme- the compound of the general formula IV is first ozonolysed fo give a compound of the general formula VI. The hydroxy io group is then converted info a group L and the resultant compound of the general formula Vui is cyclised fo 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 formula Hb.

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 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 mesylationWe have surprisingly found that, when this reaction is 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 dlchloromethane usually affords a 1:1 mixture of Ε, Z_ isomers: see T.W. - 12 Doyle et al.. Can. J. Chem. * 1977. 33, 2873s M.J.

Pearson. J. Chem. Soc., Chem. Comm. 1981, 947s P.C. Cherry et al., J. Chem. Soc.. Chem. Comm. 1979, 663).

Cyclisation of VIII or IK may be carried out in a single step, by reaction with a sulphide or hydrosulphide* such as Na^S* NaBS* Bu^NHS, or with H?S in the presence of a base such as triethylamine or pyridine. The cyclisation of IK or VIII wherein Z represents a group other than SR? offers the clear advantage of releasing easily separable* usually wafer 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*).

Finally according fo the invention* the 2-fhiacephems II in which Y represents an organic group may be prepared by the further step of converting the halomethyl group introduced hy the halogenation info a methyl group substituted by the desired organic group. This conversion may be effected af any point after the introduction of the halomethyl group* that is on any of the compounds V, VII* IK and lib. If is, however, preferably carried out on the compound lib. The conversion may be carried out by reactions known per se. por example, l) a compound lib can be converted into a compound II (Y-free or protected OH) by mild alkaline hydrolysis* or by reaction with cuprous oxide/dimefhylsulphoxide/wafer or by reaction with a salt of a strong inorganic acid. e.g. a nitrate or a perchlorate* thus obtaining a labile ester with the said inorganic acid* which ester may be hydrolyzed* subsequently or in the same reaction medium* fo the desired parent alcohol* Preferred salts of this type are AgKOg, AgClo^ and 2) a compound lib can be converted info a compound II (Y=an unsubstituted or N-alkyl substituted carbamoyloxy group) by conversion into a compound 11 (Y«OH) as described above followed by reaction with a suitable isocyanate; for example* trichloroacetyl isocyanate is a preferred reagent for obtaining compounds II (Y-OCONHp, 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 4 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 Owing to the pronounced propensity of 3-hydroxymethyl-2-thiacephem-4-carboxylates to lactonize, it is preferable that ln the process 1) described above Rg represents a 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 t __ abbreviations Me, Bu , Ph, Ms, pHB, THF, EtOAc, DMSO, MeCN, stand respectively for methyl, t-butyl» phenyl# methanesulphonyl, p-nitrobenzyl. tetrahydrofuran. ethyl acetate, dimethylsulphoxide and acetonitrile. NMR spectra were taken either on a Hitachi-Perkin Elmer 60 MHz apparatus, or on a Brucker 90HHz; separation of inner lines of AB quartets are referred to spectra taken on the latter. 'Hitachi* is a Trade Mark.

Example 1 Diphenylmethyl 6,6-dibromopenicillanate g of 6,6-Dibromopenicillanic acid in 450 ml of acetonitrile was treated with a solution of 49 g of ? diphenyldiazomethane in 150 ml of acetonitrile. After hour at 20°C the formed solid was collected by . filtration and washed with small portions of cold diethyl ether, thus obtaining 116 g of the title product. A second crop (9 g) was obtained by evaporation of the mother liquors and trituration with diethyl ether.

The overall yield was 95%.

Analytical sample was obtained by crystallization from Chloroform; mp 157-158°Ci·»· (CHC1, film) 1800, 1750 cm*1? & (CDCl^) 1*24 and 1.58 (each 3H, s, CI^) r 4.61 (IH, S, N.CH.CO), 5.80 (1H, s, N.CH.S), 6.91 (lH, S. OCH), and 7.30 ppm (10H, s. Ar).

Found: C, 47.80; H, 3,63; N, 2.64; S, 5.95; Br, 30.49%.

C21H19Br2NO3S requires C, 48.02; H, 3.64; N, 2.67; S, 6.10; Bx, 30.43%.

Example 2 t-Butyl6,e-dlbromopenicillanate Method A 100 g of 6,6-dibromopenicillanic acid in 1 litre of diethyl ether at 0°C was sequentially treated with 37 rol of triethylamine and 56 g of phosphorus pentachloride. After hour stirring, the reaction mixture was evaporated under vacuum (dry benzene added and removed). The crude acyl chloride was dissolved in 200 ml of di chloromethane and stirred for 24 hours with 500 ml of t-butanol in 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 unreacted starting material could be recovered by back-extraction of the acidified aqueous washings), decoloured with charcoal and evaporated to afford the title product, which was then crystallized from diisopropyl ether. Yield 69 g (60%); mp 12O-121°C, rjnax (CHClj film) 1800 and 1740 cnf1,· € (CDC13) 1.98 (15H, s, Bufc and CH3), 2.05 (3H, s, CH3), 4.38 (1H,S, N.CH.CO) and 5.70 ppm (1H, s, N.CH.S).

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

Example 3 Diphenylmethyl βΧ-bromo- 68-Q.R-hydroxyethy D-peni cl 1 lanate 120 g of Diphenylmethyl 6,6-dibromopenicillanate, prepared as described in Example 1, in 900 ml of dry distilled THF under nitrogen at -75°C was treated with 1 molar equivalent of a solution of ethy Imagneslum 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 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 chroraatograhy (benzene:ethyl acetate) to afford the title compound, 67 g (60%), as a foam, crystallizable (diisopropyl ether) to a solid, mp 65-7O°C; ^max 3450, 1785 and 1740 cm'1; S (CDC13) 1.22 and 1.60 (each 3H, s, CMe2), 1.29 (3H, d, 3=6Hz, CH-j.CH) , 2.90 (IH, d, OH), 4.17 (IH, m, CHj.CH.OH), 4.58 <1H, s, N.CH.CO), 5.49 (IH, s, N-CH.S), 6.90 (IH, s, OCHPh^) and 7.3 ppm (10H, s. Ar).

Using t-buty1-6,6-dibroroopenicillanate, prepared as described in Example 2, and proceeding similarly, there were obtained t-butyl 6^-bromo-6^- (lR-hydroxyethyl)-penicillanate in 65% yield after crystallization from dllsopropyl ether: hexane; m.p. 93-95°C with decomposition; S (CDC13) 1.26 (3H, d, J=6Hz, CH3-CH), 1.54 <12H, s, Bu4 - 18 and CH3), 1.65 (3H, s, C«3), 2.65 <1H, s, CH.OH), 4.25 11H, M, CH3„CH(OH).CH), 4.40 (IH, s, H-CH.CO) ana 5.51 ppm (1H, 5, N.CH.S).

Example 4 Diphenylmethyl 6X- (lR-hydroxyethyll-penicillanate-l-cotide g of Diphenylmethyl 6fX-brarao-6§- (lR-hydraxyethyl) -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-on10 "calcium carbonate and 11 g of calcium carbonate. The reaction mixture was filtered and evaporated to afford a residue which was partitioned between brine and dichloromethane. Removal of the solvent left crude diphenylmethyl 6K-(IR-hydroxyethyl)-penicilIanate, which was oxidized with 17 g of 85% HCPBA in 500 ml of chloroform at O-5°C for 1 hour. The filtered solution was then washed with aqueous sodium bicarbonate solution and the solvent remoyed to leave 40 g (88%) of the crude title product as a foam, which can be used as such or purified by silica gel chromatography?Traax (CHCl^ 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 (IH, dd, J"2 and 6.5Hz, CH.CH.CH) , 4.25 (IH, jn, CH-j.CH(OH) .CH, , 4.64 (IH, S, N.CH.CO), 4.98 (IH, d, J=2H3, CH.CH.S), 6.98 (IH, s, OCHPhp) and 7.30 ppm (10H, s, Ar). - 19 Using a similar procedure, but starting from t-butyl 6U-bromo-6^- (IR-hydroxyethyl)-penicillanate, prepared as described in Example 3, there was obtained t-butvl 6&- (lR-hydroxyethyl) -penlcillanate-1-oxide: y ie Id 75 %: Y„„ (film) 3440, 1785 and 1740 an"1, max A Example 5 Diphenylmethyl 6’ - (lR-t-buty ldimethy lsilyloxyethy)-penicillanate-l-axide g of crude diphenylmethyl 6^-(IR-hydroxyethyl)-penicillanate-1-oxide, prepared as described in Example 4, was dissolved in 350 ml of DMF and stirred for 3 hours af 5O-55°C in the presence of 18.5 g of imidazole and 27 g of t-butyldimethylsilyl chloride. The reaction mixture was partitioned between diethyl ether and brine and the organic layer washed several times with wafer.

Evaporation of the solvent and silica gel chromatography afforded the title product; yield 22 9;Vmax (CHCl^ film) 1790 and 1755 an"1; S(CDC13) 0.06 (6H, s, SiMej), 0.88 (13H, s, Bu^ and CH3), 1.3 (3H, d, J=6Hz, CH3-CH), 1.7 (3H, s, CH3), 3.4 (IH, dd, 0=2 and 4.5Hz, CH.CH.CH), 4.40 (IH, jo, CH3-CH.CH) 4.55 (IH, s, N.CH.CO), 4.88 (IH, ά, 0=2, CH.CH.S), 6.9 (lH,SOCHPh2), and 7.25 ppm (10H, s. Ar).

By using a similar procedure, but starting from t-butyl 6^-(IR-hydraxyethyl)-penicillanate-1-oxide, prepared as 20described ia Example 4, there was obtained t-butyl £ (lR-t-butyld3msthyisilyloxyethyT) ^benicillanate-i-o^ide in overall yield 55% from the Sifc-braaoprecursar; (CHC13 film) 1705 and 1750 cm*'1; 6 (CDC13) 0.06 (SH, s, Sim,), ΟοΘΘ (.9H, s, SiBu), 1.25 and 1.66 (each 3H, «*» ε, CMe2)f lo28 <3H,d, J=6Hs,' CH .CH), 1.« (9H, s, OBu*), 3.5 Uh, dd, J=2 and 5Ha, CH.CH.CH), 4.4 (IH, s, N.CH .CO), 4.5 (IH, m, CHjoCH^CH) and 4.9 ppm (IH, d, J=2Hs, CM.CHoS).

Example 6 Diphenylmethyl 6c- (IR-p-nitrobenzyloxycarbonyloxyethyl) -penicillate-1-oxide Dipheny Imethyl (IR-hydraxyethyl^penicillanate-l-oxidej, prepared as described in Example 4, was acylated with o-nitrobenzylchlorocarbonate by using N?H-dimethylamino15 «-pyridine ss a base and ethanol-free dlchloromethane as solvent, according to a general method, thus obtaining the title product as a foam; S (CDCl^) 0.9S and 1.70 (each 3H, 3, CMe^), 1.52 (3H, d, 3«=6Hs, CH^.CH), 3.83 (IH, dd, J«3 and SHz, CH.CH.CH), 4.56 (IH, s, H.CH.CO), 4.99 UH, ά, J=2HSP CH.CH.S), 5.26 (2H, s, OCH^Ph), 5.35 (IH, m, CHj.CH.CH)» 7.01 (13, 3, GCHPh,), 7.40 (10H, m, Ar), 7.55 and 8.26 ppea (each 2H, 4, J^SHz, Ar). following the same experimental procedure, there was obtained t-butyl 6K- (IR-p-nitrobehzy loxycarbony Icutye thy l) -penicillanate-l^oxlde Following similar experimental procedures, but using trichloroethylchlorocarbonate instead of g-nitrobenzylchlorocarbonate, there were also obtained: t-butyl-(lR-trichloroethyloxycarbonyloxyethyl) 5 -penicillanate-1-oxide diphenylmethyl 6l&- (lR-trichloroethyloxycarbony loxyethyl) -penicillanate-1-oxide Example 7 3S- (lR-hydroxyethyl) - 4R-ben2 thiazoly ldi thio-1- (l-methoxvlo cartoonY3-'2_ Using similar procedures, there were obtained: 3S- (IR-t-butyldimethylsilyloxyethyl) -4R-benzthiazolyldithio-1- (i-methoxycarbonyl-2-methyl-l-prop-2-enyl) -azetidin-2-one, starting from methyl 6K-(lR-t-butyl20 dimethylsily loxyethyl) -penicillanate-l-oxide, and prolonging the reaction time up to 6 hours;ηζ(CHCl, max o film) 1770 and 1744 can-1, b (CDClj) 0.02 and 0.04 (each 3H, s, SiMe2)f0.84 (9H, s, SiBu1), 1.23 (3H, d, J=6Hz, CHj.CH), 1.91 (3H, s, =C.CH3)„ 3.38 (IH, dd, J=2 and 3.5Hs, - 22 CH.CH.CH), 3,69 (3H, s, CCHg), 4.23 (IH, m, CH3°CHOCH), 4.82 (IH, s, N.CH.CO), 5.07 (2H, m. CH2=C), 5.42 (IH, d, J»2Hz, CH.CH.S) and 7.2-7.9 ppm (4H, m, Ar); 3S- (lR-hydroxyethyl)-4R-benzthiazolyldi thio-1- (1° -dipheny lme thoxycar bony l*2-methyl-l-prop-2-enyl)-azetldin-2-one, starting from diphenylmethyl 6st- (lR-hydroxyethyl)-penicillanate-1-oxide; (CHci^ film) 3400, 1765 and 1740 can-1; S (CDC13) 1.22 (3H, d, J=6Hz, CH3„CH), 1.60 (3H, S, =C.CH3), 2.78 (IH, Br S, OH), 3.42 (IH, dd, J=2 and 6Hz, CH.CH.CH) , 4.18 (IH, m, CH^CHOH.CH) , 4.93 (IH, s, N.CH.CO), 4.90-5.10 (2H, m, CH2=C), 5.38 (IH, d, J=2Hs, CH.CH.S), 6.89 (IH, s, OCH Ph.,) and 7.15-7.90 ppm (14H, m. Ar); 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-benzothlazoly115 dithio-1-(l-t-butoxycarbonyl-2-methyl-l-prop-2-enyl)-azetidin-2-one, starting from t-butyl 6H.-(IR-t-butyldimethylsilyloxyethyl)-penicillanate-1-oxide; reaction time 6 hours; *(CDCI3) 0.06 (6H, S, SiMe2) , 0.9 (9H, s, SiBut), 1.26 (3H, d, J=6H3, CH^CH) , 1.48 (9H, S, OBuS , 1.95 (3H, s, =C„CH3), 3.40 (IH, dd, J=2 and 4Hs, CH.CH.CH), 4.20 (IH, m, CH3.CH.CH), 4.71 (IH, S, N.CH.CO), 5.1 2H, br S, CH2=C), 5.42 (IH, d, J»2Hz, CH.CH.S) and 7.2" 7.9 pgno (4H, m, Ar); 3S-(IR-t-butyldimethylsilyloxyethyl) -4R-benzthiezolyl23 dithio-1-(l-diphenylmethoxycarbonyl-2-methyl-l-prop-2-enyl )-azetidin-2-one, V_____ (film) 1722 and 1743 cm 1; S(CDC13) 0.05 (6H, s,SiMe2), 0.80 (9H, s, SiBut), 1.29 <3H, d, J=6Hz, CH-j.CH), 1.95 (3H, s, =C.CH3), 3.45 (IH, dd, J=2 and 4Hz, CH.CH.CH), 4.26 (IH, m, CHj.CH.CH), 4.95 (IH, s, N.CH-CO), 5.08 (2H, ABq, separation of inner lines 5Hz, 01^=0), 5.55 (1H, d, J=2Hz, CH.CH.S), 6.93 (IH, St 0CHPh2) and 7.1-8.0 ppm (14H, m, Ar); 3S-(lR-trichloroethoxycarbonyloxyethyl )-4R-benzthiazolyldithio-1- (1-methoxycarbonyl -2-methyl -1-prop-2-eny1) -azetidin-2-one, starting from methyl 6&C-(lR-trichloro ethoxycarbonyloxyethyl)-penici1lanate-1-oxide: ^max (CHC13) 1775 and 1745 cm1; £(CDC13) 1.48 <3H, d, J=6Hz, CH3.CH), 1.91 (3H, S, ~C.CH3), 3.69 <3H, s, OCH.*), 3.70 (lH, dd, CHeCR.CH), 4.68 (s, 2H, OCH2), 4.76 (1H, s, N.CH.CO), 5.03-5.30 (2H, m, CH^C), 5.23 (IH, m, CH3.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 t-butyl and diphenylmethyl penicillanates, 3S-(lR-trichloroethoxycarbonyloxyethyl)-4R-benzthiazolyldithio-1- (l-t-butoxycarbonyl-2-methy 1-1-prop-2-enyl )-azetidin-2-one; 3S-(lR-trichloroethoxycarbonyloxyethyl )-4R-benzthiazoiyldithio-1-(1-diphenylmethoxycarbonyl-2-methyl-l-prop-2-enyl)-azetidin-2-one; - 24 and starting from methyl 6j§-(lR-t-butyldimethylsilyloxyethyl)-penicillanate-1-oxide, 3R-(lR-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyl-dithio-l-(l-methoxycarbonyl-2-methyl-l-prop-2-enyl)5 -azetidin-2-one, Example 8 3S-(lR-hydroxyethyl )-4R-benzthiazolyldithio-l-(l-methoxycarbonyl-2-hydroxy-l-prop-1-enyl)-azetidin-2-one The crude 3S-(lR-hydroxyethyl)-4R-benzthiazolyldithio10 -1-(1-methoxycarbonyl-2-methyl-1-prop-2-eny1)-azetidin-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 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 2Q evaporated. The residue was taken up in diethyl ether, the undissolved matter was filtered off and the solution I was evaporated to give the crude title product. An aliquot was purified by flash chromatography over silica gel (ethyl acetate:cyclohexane as eluant); S (CDCip 1.35 (3H, d, J=7Hz, CH^CH), 2.11 (3H, s, CH3), 2.75 (1HP Br s, OH), 3.44 (lH, dd, 3=2.0 and 5.0Hz, CH.CHoCH), 3.79 <3H, s, OCH3), 4.26 (1H, m, CH3.CH.CH), 5.29 (IH, 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-butyldimethylsilyloxyethyl)-4R-ben2thiazolyldithio-l-( 1-methoxycarbonyl-2-hydroxy-l-prop-1-enyl )-azetidin-2-one, starting from crude 3S-(lR-t-butyldimethyl -silyloxyethyl)-4R-benzthiazolyldithio-1-(1-methoxycarbony1-2-methyl- l-prop-2-enyl)-azetidin-2-one; V (film) 3350, 1770 and 1660 cm-1; C(CDC1,) 0.05 and 0.07 (6H, each s, SiMe2), 0.87 (9H, s, SiBu1), 1.27 (3H, d, J=6.5Hz, CHj.CH), 2.07 (3H, s, =C.CH3), 3.33 (lH, dd, J=2.2 and 4.2Hz, CH-CH.CH), 3.74 (3H, s, OCH3>, 4.26 (IH, m, CH3.CH.CH), 5.36 (IH, d, J=2.2Hz, CH.CH.S), 7.2-7.9 (4H, m, Ar) and 12.37 ppm (IH, br s, OH); 3R-( IR-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyldi thio-1-(l-methoxycarbonyl-2-hydroxy-l-prop-l-enyl)-a2etidin-2-one, starting form 3R-(lR-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyldithio-l-(1-methoxycarbonyl-2-methyl-l-prop-2-enyl)-azetidin-2-one; Yn,=„ (film) 3200, 1773, 1710, 1665 and 1620 cm'1; max £(CDClj) 0.20 (SH, s, SiMej), 0.94 (9H, s, SiBufc), l. 52 (3H, d, J=6Hz, CHj.CH), 2.17 (3H, br s, =C.CH3>, 3.6-3.7 (4H, s*dd, OCH3 and CH.CH.CH), 4.4 (IH, m, CHj.CH.CH), 5.25 (IH, d, CH.CH.S) and 7.3-7.9 ppm (4H, m, Ar); 3S-(lR-hydroxyethyl >-4R-benzthiazolyldithio-l-(1-diphenylmethoaycarbonyl-2-hydroxy-l-prop-l-eny1) -azetidin-2-one, starting from crude 3S-(lR-hydroxyethyl)r -4R-benzthiazolyldithio*l- (l-diphenylmethoxycarbonyl-25 -methyl-l-prop"2-enyl>-2-azetidin‘-2"one;(CHC1, film) max a 3400, 1770, 1730 and 1650 cm-1; 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-benzthiazolvldithio-l-( l-diphenylmethoxycarbonyl-2-hydroxy-l-prop-l-enyl)-azetidin-2-one, starting from crude 3s|( IR-t-butylI —* dimethylsilyloxyethyl)-4R-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-methyl-l-prop-2-enyl)-azetidin-2-one;*>’ „ (CHC1, film) 3400, 1775, 1735, 1700 Sh, 1655 and 1610 cm1; S(CDC13) 0.06 (6H, s, SiMe2), 0.82 (9H, s, Bu1), 1.26 (3H, d, J=6Hz, CH-j.CH), 2.08 <3H, s, =C.CH3), 3.33 (IH, dd, J=3 and 5.5Hz, CH.CH.CH), 4.18 (IH, m, CHj.CH.CH), 5.22 (IH, d, J=2Hz, CH.CH.S), 6.86 (IH, s, OCHPhp and 7.2-7.9 ppm (14H, m, Ar); and 3SX lR-trichloroethoxycarbonyloxyethyl )-4R-benzthiazolyl20 dithio-l-(l-methoxycarbonyl-2-hydroxy-l-prop-l-enyl )-azetidin-2-one; U(CDCl^) 1.50 (3H, d, J=6Hz, CH^.CH), 2.14 (3H, s, =C.CH3), 3.67 (lH, dd, J=2.2 and 5.5Hz, CH.CH.CH), 3.62 (3H, s, OCH^, 4.62 (2H, ABq, J=12Hz, separation of inner lines 2Hz, OCH^), 5.10-5.40 (2H, m, 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-trichloroethoxycarbonyloxyethy1)-4R-benzthiazolyldi thio-1-(1-t-butoxycarbony1-2-hydroxy-1-prop-1-eny1)-azetidin-2-one; 3S-(lR-trichloroethoxycarbonyloxyethyl)-4R-benzthiazolyldithio-1-(l-diphenylmethoxycarbonyl-2-hydroxy-l-prop-l-enyl)-azetidin-2-one; and 3S-(lR-t-butyldimethy1silyloxyethyl)-4R-benzthiazolyldithio-l-(l-t-butoxycarbonyl-2-hydroxy-l-prop-l-enyl)-azetidin-2-one.

Example 9 3S-(lR-hydroxyethyl)-4R-benzthiazolyldithio-l-(1-methoxycarbonyl-2-methylsulphonyloxy-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 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 methanesulphonyl chloride. The reaction was quenched after 5 minutes with cold 2% aqueous sodium bicarbonate solution. Removal of the solvent from the organic layer gave the crude title product (quantitative yield), which - 28 was used as such for the next step.

By following the same experimental procedure, there was obtained: -(lR-t-butyldimethylsilyloxyethyl)-4R-ben2thiazolyl5 dithio-1- (l-methoxycarbonyl-2-methylsulphonyloxy-l-prop-1-enyl)-azetidin-2-one, starting from 3S-(IR-t-buty1dimethylsilyloxyethy1)*4R-benzthia2olyldithio-l-(l-methoxycarbonyl-2-hydroxy-l-prop-l-enyl)-azetidin-2-one; an aliquot of this product was purified by flash chromatography (silica gel; ethyl acetate-cyclohexane as eluant) to afford the pure title compound as a 1:1 mixture of E and Z isomers;v v (film) 1885, 1730, — — max -1 Γ 1363 and 1165 cm 1; © (CDC1.,) 0.05 and 0.10 (each 3H, s, SiMe2), 0.88 (9H, s, SiBut), 1.29 (3H, d, J=6.5Hz.

CH^.CH), 2.20 and 2.53 (3H, each s, =C.CH3), 3.18 and 3.29 (3H, each s, SOjCHg), 3.42 (IH, m, CH.CHCH), 3.71 and 3.78 (3H, each s, OCHj), 4.30 (IH, m, CHj.CH.CH), 5.59 and 5.64 (IH, each d, J~2Hz, 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;€(CDClj) 0.05 (6H, s, SiMe2), 0.88 (9H, s, SiBu1), 1.29 (3H, d, J=6.5Hz, CHjOH), 2.53 (3H, s, =C.CH3>, 3.29 (3H, s, SO2CH3), 3.42 (IH, dd, J=2 and 5Hz, CH.CH.CH), 3.71 (3H, s, OCH}), 4.30 <1H, m, CH3.CH.CH), 5.59 (IH, d, J=2Hz, CH.CH.S) and 7.12-7.95 ppm (4H, m.

Ar).

By following this last procedure (tetrahydroduran as a 5 solvent in the mesylation step), there were obtained: 3R-(lR-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyldithio-1-tl-methoxycarbonyl-2-methy1sulphony1oxy-1-prop-l-(Z)-enyl ]-azetidin-2-one, starting from 3R-(1R-1-butyldimethylsilyloxyethyl)-4R-benzthiazolyldithio-110 -(1-methoxycarbonyl-2-hydroxy-l-prop-1-enyl)-azetidin-2-one;V (CHC1-. film) 1775, 1735, 1365 and 1165 cm S (CDCl-j) 0.18 (6H, s, SiMe2», 0.88 (9H, s, SiBu1), 1.42 (3H, d, J=6.5Hz, CH3.CH), 2.33 (3H. S, =C.CH3), 3.05 (3H, s, SO2CH3), 3.45 (3H, s,0CH3>, 3.62 (IH, dd, CH.CH.CH), 4.3 (lH, m, CH^CH.CH), 5.40 (IH, d, J=5Hz, CH.CH.S) and 7.15-7.85 ppm (4H, m, Ar); 3S-(lR-hydroxyethyl)-4R-benzthiazolyldithio-l-U-diphenylmethoxv carbonyl-2-methylsulphony 1oxy-1-prop-1(Z)-enyl]-a2etidin-2-one, starting from 3S-(lR-hydroxy20 ethyl)-4R-benzthiazolyldithio-l-(l-diphenylmethoxycarbonyl-2-hydroxy-l-prop-l-enyl )-azetidin-2-one; Vnax 3400, 1775* 1730' 1365 and 1170 «n'b S (CDClj) 1.22 (3H, d, J=6.5Hz, CHj.CH), 2.43 (3H, s, =C.CH3), 3.13 (3H, s, SO2CH3), 3.35 (IH, dd, J=2.5 and 4Hz, CH.CH.CH), 4.1 (IH, m, CHj.CH.CH), 5.40 (IH, d, J=2.5Hz, CH.CH.S), 6.85 (1H, s, OCHPhp and 7.1-7.9 ppm (14H, m, Ar); 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyl* dithio-1- ll-diphenylmethoxycarbonyl-2-(Z)-methylsulphonyl5 oxy-1-prop-1-enyl ]-azetidin-2-one, starting from 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyldithio-l-(l-diphenylmethoxycarbonyl -2-hydroxy-l-prop-l-enyl)-azetidin-2-one;(CHCl^ film) 1775, 1725, 1370 and 1175 cm1; S(CDCl3) 0.1 (6H, s, SiMe2), 0.9 (9H, s, SiBu*), 1.28 (3H, d, J-6HZ, CH3.CH), 2.5 (3H, s, C-CH^), 3.25 (3H, s, SO2CH3), 3.35 (IH, dd, 3=2.5 and 5Hz, CH.CH.CH), 4.20 (IH, m, CH3.CH.CH), 5.50 (IH, d, J=2.5Hz, CH.CH.S), 6.9 (IH, s, 0CHPh2) and 7.1-7.9 ppm (14H, m, Ar) ; 3S-(1R-t-butyldimethylsilyloxyethyl )-4R-benzthiazolyldithio-l-I1-t-butoxycarbony1-2-(Z)-methylsulphonyloxy-1-prop-l-enyll-azetidin-2-one, starting from 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyldithio-l-(1-t-butoxycarbony1-2-hydroxy-1-prop-1-eny1)-azetidin20 -2-one; Tmax 1773, 1710, I370 and 1165 cm'1; S3) 0.06 (6H, s, SiMe2), 0.87 (9H, s, SiBut), 1.25 (3H, d, J=6Hz, CHj.CH), 1.49 (9H, si, OBu1), 2.45 (3H, s, =C.CH3>, 3.25 (3H, s, SOjCHj), 3.35 (IH, dd, J=2.5 and 5H2), 4.3 (IH, m, CH.CH.CH), 5.60 (IH, d, J=2.5Hz, CH.CH.S) and 7.1-7.9 ppm (4H, m, Ar); and 3S-(lR-trichloroethoxycarbonyloxvethyD-lR-benzthiazolyldithio-l- Il-mechoxycarbonyl-2-methylsulphonyloxy-l~prop-1(Z)-enyl]-azetidin-2-one, starting from 3S-(1R-trichloroethoxycarbonyloxyethyl)-4R-benzthiazolyldithio-1-(l-methoxycarbonyl-2-hydroxy-l-prop-1-enyl)-azetidin-2-one;Vmav (CHCK film) 1780, 1755 sh, 1730, 1380, max 3 1250 and 1167 cm ; <&(CDC13) 1.48 (3H, d, J=6Hz, CH-j.CH), 2.52 (3H, S, -C.CH3), 3.25 <3H, s, SO2CH3), 3.72 <4H, s+dd, OCH3 and CH.CH.CH), 4.68, (2H, s, OCHj), 5.2 (IH, m. Ch^CH.CH), 5.47 (IH, 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-trichloroethoxycarbonyloxyethyl)-4R-benzthia2oIyΙό ithio-1- [1-t-butoxycarbonyl-2-methylsulphonyloxy-l-prop-1(Z)-enyl]-azetidin-2-one; and 3S-(lR-trichloroethoxycarbonyloxyethyl)-4R-benzthiazolyldithio-1- [1-diphenylmethoxycarbony1-2-methylsulphonyloxy-1-prop-1 (Z)-enyl]-azetidin-2-one.

Examp1e 10 3S-(lR-methylsulphony!oxyethyl)-4R-benzthia2olyldithio-1-(l-methoxycarbonyl-2-methylsulphonyloxy-l-prop-l-enyl )-azetidin-2-one.

When in the reaction described in Example 9 the starting material was exposed to an excess (2 molar equivalents) of methanesulphonylchloride and triethylamine, the title product was obtained as a foam in quantitative yield as a mixture of E (20%) and Z (80%) isomers; (film) 1780, 1730, 1360 and 1170 cm1,- StCDClj) 1.58 (3H, d, J=6Hz, CH-j.CH), 2.22 and 2.56 (3H, each s, =C.CH3 of E and Z isomers), 3.00 (3H, s, CH^SOg on the hydroxyethyl chain), 3.20 (IH, dd, J-2.2 and 4.5Hz, CH.CH.CH), 3.28 <3H, s, CH^SOg on the crotonic appendage), 3.76 (3H, s, OCH^), .11 (IH, m, CH3-CH.CH), 5.52 (IH, d, J=2.2Hz, CH.CH.S) and 7.30-7.95 ppm (4H, m, Ar).

By following the same procedure, but using THF as a solvent, 3S-(lR-methylsulphonyloxyethyl)-4R-benzthia2ojyldithio-1- Π dipheny lmethoxycarbonyl-2-methyl sulphonyloxy-1-prop-1-(2)-enyl)-azetidin-2-one was prepared and displayed the following spectral data:*v (film) 1777, max 1728, 1360 and 1170 cm1; SlCDClj) 1.50 (3H, d, J=6Hz, CH3-CH), 2.52 (3H, s, "C.CHj), 2.9 (3H, s, CH3SO2 on the hydroxyethyl chain), 3.23 (3H, s, CH^SOg on the crotonic appendage ), 3.62 (IH, dd, J=2.5 and 5.5Hz, CH.CH.CH), .05 (IH, m, CH.CH.CH), 5.45 (IH, d, J«2.5Hz, CH.CH.S), 6.95 (IH, s, OCHPhg) and 7.10-7*95 ppm (14H, m, Ar).

Example 11 -(lR-t-butyldimethvlsilyloxyethyl )-4R-benzthiazolyldithio-l-(l-methoxycarbonyl-2-trif luorome thyl sulphonyloxy25 -1 -prop-1 -enyl j_-azetid_in-2-one 300 mg of crude 3S~ (lR-t-butyldimethylsilyloxyethyl) -henzthiazolyldithio-l- (l-methoxycarbonyl-2-hyaraxy-l~pr©p*l"enyl)-azetidin-2~one in 5 ml of THF at -40°C was sequentially treated with 0.170 ml of triethylamine and 0.160 ml of trif luorome thane sulphonic anhydride.

Work-up and chromatography gave the two separate geometrical isomers of the title product, as foams: E isomer: (CHClJ 1778, 1730, 1420, 1215 and 1135 — max j cm-1} S(CDCl3)0.O8 (6H, 8, SiMe2), 0.86 (9H, s, SiBu1), 1.26 (3H, d, 3=6Hz, CH3.CH), 2.05 (3H, s, =C.CH3), 3.46 (IH, dd, 2.2 and 4Hz, CH.CH.CH), 3.81 (3H, s, OCHj), 4.28 (lH, jn, CH3.CH.CH), 5.76 (IH, d, J=2.2Hz, CH.CH.S) and 7.25-7-90 (4H, b, Ar); Z isomer (inter alia) (CDClj) 2.45 (3H, s, =C.CH3>, 3.40 (IH, dd, J=2 and 4Hz, CH.CH.CH), 3.64 (3H, S, OCH3), 4.30 (lH, m, CHj.CH.CH) and 5.65 ppm (lH, d, J-2Hz, CH.CH.S).

Example 12 Methyl (7S, 6R) -7- (iR-t-butyldimethy Isilyloxyethyl) -3-methy 1-2 - thiacephem- 4 -carboxy late A solution of 0o5 ml of triethylamine in 10 ml of dichlorornethane was saturated at ~50°C with hydrogen sulphide. After purging with nitrogen, 0.34 ml of this solution was added to a cold (-50°C) solution of 75 mg (0.121 mmol) of 3S- (IR-t-butyldimethylsilyloxyethyl) "4R-bensthiazolyldi thio-1- (l-methoxycarbonyl-2-methyl34 sulphonylOKy-l-prop-l-enyD-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 formed 2*mexcaptobenzthiazole and minor impurities was achieved by silica gel chromatography (ethyl acetates cyclohexane as eluant), thus obtaining the title compound as white crystals (19 mg» 20S), mp 85-87°C, (EtOH) 223 (£= 4,77$, 277 (6,335), and 326 (2,922) nm, Vmax (CHC13 film) 1785 and 1730 cm"1; S’ (CDClj) 0.08 (6H, s, SiMe^), 0.88 (9H, s, SiBu1) » 1-^25 (3H, d, J=6Hz, CH^CH) , 2.22(3H, s, CH3), 3.07 (IH, dd, J»2.3 and 3.5Hz, CH.CH.CH), 3.8 (3H, s, OMe), 4.36 (IH, m. CH3*£HoCH) and 4„62 ppm (IH, d, J-2.2HZ, CH.CH.S).

Found: C, 49.08; H, 6.96; N, 3.52; S, 15.16. C16H27NO4SiS2 requires C, 49,32; H, 6.99; N, 3.60; S, 16.46/. · When, instead of hydrogen sulphide and triethylamine, a solution of NaHS (0.9 mol equiv) in DMF was used, and quenching (partition between wafer and ethyl acetate) followed within 1 minute af 0°C, the isolated yield of the pure title product was raised fo 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 afforded only a very low amount of the title product. - 35 By following the same experimental procedure, methyl (7R,6R)-7-(IR-t-butyldbnethylsilyloxyethyl)-3-methyi-2-thiacephem-4-carboxylate was obtained starting from 3R- (lR-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyldi thio-1-(1-me thoxy carbony 1-2-me thylsu|phonyloxy-l-prop-l-enyl)-azetidin-2-one? >’ a„ (film) 1785 and 1725 cm \ £ 3C0CD3) 0,03 and 0.05 (each 3H, s, SiMe2), 0.84 (9H, e, SiBuS, 1.19 (3H, d, 6.5Hz, CHj.CH), 2.08 (3H, B, CH3), 3.72 (3H, s, OCH3), 4.11 (IH, dd, J=5.5 and 8.0Hz, CH.CH.CH), 4.20 (IH, m, CH3.CH.CH) and 5.01 ppm (IH, d, J-5.5HZ, CH.CH.S).

Example 13 Methyl (7S,6R)-7-(lR-hydrQxyethyl)^3-methyl-2-thiacephem-4 -carboxylate 145 mg (0.287 mmol) of crude 35- After repeated washings with water, the solvent was removed leaving a residue which was purified by pressure chromatography on silica gel (ethyl acetate:cyclohexane as eluant) to give the pure title product in 45¾ yield as a white powder; (nujol) 3400, 1770 and 1720 oa ; >QSU* S(CDC13) 1.37 (3H, d, J«7Hz, CH3.CH,; 2.22 (3H, s, CH-j), 2.40 (IH, br s, OH), 3.12 (IH, dd, J=2.0 and 4.5Hz, CH.CH.CH), 3.86 (3H, 6, OCH3), 4.35 (IH, m, CH3.CH.CH, and 4.65 ppm (IH, d, J=2.0Hz, CH.CH.S).

By following a similar experimental procedure, there were obtained: Diphenylmethyl (7S,6R)-7- (lR-hydroxyethyl)-3-aaethy 1-2-thiacephem-4-carboxy late, starting from 3S- (lR-hydroxy™ ethyl)-4R-benzthiazoly ldi thio-1-(1-diphenylmethoxycarbonyl -2-methylsulphonylQxy-l-prop-l-enyl)-azetidin-2-one? Ϊ „„ (EtOH) 281 (g= 5,900) and 326 (3,670) nm:y (KBr) max jugji 3550-3250, 3080, 3060, 3020, 2960, 2920, 2840, 1775, 1720, 1660 and 1490 cm1;S(CDC13, 1.36 (3H, d, J=6.5Ha, CH3°CH), 2.17 (3H, s, CH3,, 3.12 (IH, dd, J=2.0 and 5Hs, CH.CH.CH), 4.36 (IH, jn. CH3.CH.CH), 4.76 (IH, d, J=2.0Hz, CH.CH.S), 6.97 (IH, s, OCHjPh) and 7.30 (10H, n, Ar,; Diphenylmethyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl) -3-methy l-2-thiacephem-4-carbOixy_late, starting from 3S**(1R - t-butyldime thy lsilyloxyethyl)-4R-benzthiazoly ldi thio-1- (1-dipheny lmethoxy carbony 1-2-methy lsulphonyloxy-1-prop-l-enyl,-azetidin-2~one; S(CDCl3) 0*06 (6H, s, SWe^) ? 0.83 (9H, s, SIBu*,; 1.27 (3H, d. J=6.5Hs, CH3„CH), 2.05 (3H, s, CH3) , 3.08 (IH, dd, J«=3„0 and 5.0Hz, CHoCH.CH) , 4.32 (IH, B, CH3.CH.CH), 4.60 (1H, d, J=3.0Hz, CH.CH.S), 7.02 (IH, 5, 0CHPh2) and 7.30 ppm (10H, s, Ar)? t-Butyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3-methy3.-2-thiacephem-4-carboxylate, starting from 3S-(1Rt-butyldimethylsilyloxyethyl)-4R-ben2thiazolyldithio-l- (l-t-butoxycarbonyl-^-methylsulphonyloxy-l-prop-l- enyl) azetidin-2-one; (CHC13) 278 (E- 6,300 ) and 327 nm (S= 2,560) (CHC1, fihn) 1780 and 1720 cm-1; &(CDC13) 0.12 (6H, G, SiMe2), 0.88 (9H, S, SiBufc), 1.25 (3H, d, 3=6H2, CH3.CH), 1.52 (9H, s, OBu), 2.10 <3H, s, CH3), 3.02 (IH, dd, 3=2.5 and 5Hz, CH.CH.CH), 4.28 (1H, m, CH3.CH-CH) and 4.53 ppm (IH, d, 3=2.5Hz, CH.CH.S); Methyl (7S, 6R)-7- (lR-roethylsulphonyloxyethyl) -3-methy 1-2-thiacephem-4-carboxylate, starting from 3S-(lR-methy1sulphonyloxyethyl) -4R-benzthia20lyldithio-l-(l-methoxycarbonyl-2-methylsulphonyloxy-l-prop-l-enyl)-azetidin-2-one,->· „ 1780/ 1725, 1360 and 1175 cm1; S (CDCl,) max * j 1.60 (3H, d, J*6o5Hz, CH3.CH)2.25 (3H, s, CH3), 3.07 (3H, s, CH3SO2), 3.27 (lH, dd, J«2,2 and 5Hz, CH.CH.CH), 3.83 (3H, s, OCH3), 4.70 (IH, d, 3=2.2Hs, CH.CH.S) and 5.24 ppm (IH, m, CH3CH .CH) - 38 Diphenylmethyl (7S , 6R)-7-(IR-methy lsulphonyloxyethy!)-3-methyl^2~thiacfephem-4-cagbQxylate, starting from 3S-(1R-methylsulphony loxyethy IJ ™4R-benzthia2OlyldithiO"l" (1~ ' ♦ -dipheny lmethoxycarbonyl-2-methy lsulphony loxy-l-prop-15 -enyl)-azetidin-2-one; X (CHCX^) 282 (£" 7,080) and 330 (3,966) ran; V wax (CHC13 film) 1778, 1720, 1255 and 1170 cm1; S (CDC13) 1.53 (3H, d, J=6Hz, CH3.CH), 2.10 (3H, s, CH3), 2.71 (3H, s, CH3SO2), 3.22 (IH, dd, 3=2.5 and 5.5 Hz, CH.CH.CH), 4.67 (IH, d, J=2.5Hz, CH.CH.S), 5.05 (IH, m, CH3.CH.CH); 6.90 (IH, 5, OCHPh2) and 7.25 (10H, s, Ar); Methyl (7S,6R)-7-(lR-trichloroethoxycarbonvloxyethyl)-3-me thyl-2 -1 hiacephem-4 - carboxy late, starting from 3S-(1R-trichloroethoxycarbonyloxyethyl)"4R-benzthiazolyldithio15 -1- (l-methoxycarbonyi-2-methy lsulphony loxy-l-prop-l-enyl) -azetidin-2-one; V (film) 1787, 1760 sh, 1725 and max 1250 cm-1; 5 3) 1.54 (3H, d, J=5.5Hz, CH3.CH), 2.23 (3H, s, CH3), 3.30 (IH, dd, J=2 and 7.5Hz, CH.CH.CH), 3.84 (3H, s, OCH3), 4.68 (IH, d, J=2Hz, CH.CH.S), 4.78 (2h, s, CCH2) and 5.37 ppm (IH, m, CH.CH.CH); and Piphenv Imethy l'(75,6R) -7-(lR-p-nitrobenzyloxycarbonyloxyethvl)-3-me thy l-2-thiacephem-4-car boxy late, starting from (3S) - (IR-p-nitrobenzyloxycarbonyloxyethyl) -4R -benze thiazoly ldi thio- 1θ (1-dipheny lmethoxy carbony 1- 2 thy 125 sulphonyloxy-l-prop-l-enyl) -asetidin-2-one ? y 1787, max 1745, 1720 sh cm1; C (CDC13) 1.53 (3H, d, CH3CH), 2.17 (3H, s, CH3), 3.28 (1H, dd, J*=2 and 6-5Hz, CH-CH-CH), 4.65 (IH, d, J=2Hz, CH.CH.S), 5.15 (2H, s, OCH2), 5.28 (1H, m, CHj.CH.CH), 6.97 (IH, S, OCHPh^, 7.2-7.5 (12H, m, Ar) and 8.17 ppm (2H, d, J=9Hz, Ar); and, likewise, there were obtained: t-butyl (7S,6R)-7-(lR-trichloroethoxycarbonyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate; diphenylmethyl (7S,6R)-7-(lR-trichloroethoxycarbonyloxyethyl)-3-methy1-2-thiacephem-4-carboxylate; trichloroethyl (7S,6R)-7-(lR-trichloroethoxycarbonyloxyethyl) -3-methy l-2-thiacephem-4-carboxy late; trichloroethyl (7S,6R)-7-(lR-t-butyldimethylsilylcoEyethyl) - 3-methy1-2 - thiacephem- 4 - carboxy la te ? acetoxymethyl (7S,6R)-7-(lR-trichloroethoxycarbonyloxyethyl) -3-methyl-2-_thiacephem-4-carbQxy late; acetoxymethyl (7S,6R)-7-(IR-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate; and acetoxymethyl (7S_,_6R)-7- (lR-trimethylsily loxyethyl) -3-methyl-2-thiacephem-carbaxylate.

Example 14 -(lR-t-butyldimethylsilyloxyethyl)-4R-succinimidothip-1-(l-methoxycarbonyl-2-methyl-l-prop-2-enyl)-azetidin-2-one A solution of 2o32 g of methyl 6λ- (lR-t-butyldimethylsilyloxyethyl)-penicillanate-1-oxide in 35 ml of - 40 dimethylacetamide was treated with 0.15 ml of acetic acid, purged with nitrogen, and heated for 3j hours at 105°C in the presence of 5 g of N-trimethylsilylsuccinimide. After cooling fo room temperature, the reaction mixture was partitioned between ethyl acetate and cold water. Fractionation of the material obtained from the organic layer (silica gel chromatography, ethyl acetate:cyclohexane) afforded the title product as a white foam, 1.2 g (43%)jv., , (CHCl- film) 1770, 1735, max λ 1710 sh and 1680 cm-1; ί (CDClj) 0.08 (6H, s, SiMep, 0.87 (9H, s, SiBu1), 1.32 (3H, d, J=6.5Hz, CHj.CH), 1.84 (3H, s, =C.CH3>, 2.85 (4H, s, CO.CH2.CHj.CO), 3.29 (IH, dd, J=3 and 4.5Hz, CH.CH.CH), 3.73 (3H, S, OMe), 4.24 (IH, m, CH3.CH.CH), 4.66 (IH, s, N.CH.CO), 4.85 (IH, d, 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-butyldimethylsilyloxyethyl)-4R-succinimidothio-I-(l-diphenylmethoxycarbonyl-2-methyl-l-prop-2-enyl)20 -azetidin-2-one, and 3S-(lR-t-butvldimethylsilyloxyethyl)-4R-phthalimidothio-l-(l-diphenylmethoxycarbonyl-2-inethyl-l-prop-2-enyl)-azetidin-2-one, both isolated as crude materials and used as such in the following steps.

Example 15 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-phthalimidothio-I-(l-methoxycarbonyl-2-methylsulphonyloxy-l-prop-l-(Z)-enyl]-azetidin-2-one A solution of 100 mg of 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-benzothiazolyldithio-1-[1-methoxycarbonyl-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 of potassium phthalimide. After 30 minutes stirring at room temperature, the precipitate was collected partitioned between water and ethyl acetate, and purified by short silica gel chromatography to afford the title product (55%) (film) 1780, 1745 and 1725 cm1; C(CDC13) 0.1 (6H, s, SiMe2), 0.89 (9H, s, Bu1), 1.4 (3H, d, CH3.CH), 2.2 (3H, s, «C.CH3), 3.05 <3H, s, SO2.CH3), 3.4 (IH, m, CH.CH.CH), 3.6 <3H, s, OCH3), 4.2 (IH, m. CH3.CH.CH), 5.45 (IH, d, J=2Hz, CH.CH.S) and 7.8 ppm (4H, m, Ar).

Bxamplg 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-butyldimethylsilyloxyethyl)-4R-succinimidothio-l-(l-methoxycarbonyl-2-methyl-l"prop-2-enyl)-azetidin-2-one in dichlorornethane according fo the procedure described in Example 8, and used as such for further reactions. A sample was characterized as its dimethylkefal (MeOH/dry HC1): 1770, 1730 and 1715 Sh CbT1 ; S (CDC1,) 0.04 max j and 0.09 (each 3H, ε, SiMe2), 0.90 (9H, s, SiBu^), 1.31 (3H, d, J=5Hz, CH3.CH), 1.49 (3H, s, CH3), 2.84 (4H, S, COCH2.CH2CO), 3.21 and 3.26 (each 3H, s, ketal OCH3), 3.24 (IH, dd, J=2.5 and 5Hzb 3.73 (3H, s, ester OCH3), 4.20 (lH, m, CH^CH.CH), 4.43 (IH, s, N.CH.CO) and 4.94 ppm (IH, 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-phthalimido15 thio-1-(l-diphenylmethoxycarbonyl-2-methyl-l-prop-2-enyl)-azetidin-2-one.

Example 17 Methyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate A solution of 400 mg of 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-phthalimidothio-l-[l-methoxycarbonyl-2-methylsulphonyloxy-l-prop-1-(2)-enylJ-azetidin-2-one in 4 ml of dimethylformamide was treated with 50 g of finely ground NaHS under vigorous stirring. As soon as the 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 <75,6R)-7-(lR-t-butyldiroethylsilyloxyethyl)-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 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 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 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 with the material obtained according to Example 12. * By a similar procedure, Diphenylmethyl (7S,SR )-7-(lR-t-butyldimethylsilyloxyethvl)-3-methyl-2-thiacephem-4-carboxylate was obtained, starting from 3S-(lR-t-butyldimethylsilyloxy5 ethyl)-4R-phthalimidothio-l-(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-butyldimethylsilyloxyethyl)-3-((1-methyl-5-tetrazolylthio)-methyl]-2-thiacephem-4-carboxylate 120 mg of 3S-n]l-methoxycarbonyl-2-[ (115 -methyl-5-tetrazolylthio)-methylJ-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 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 (17%)?ym (film) 1787, 1725, 1587, 1360 and 1250 cm-1; $ (CDCip 0.10 (6H, s, SiMep, 0.09 <9H, s, SiBuS, 1.26 (3H, d, J=6Hz, CHj-CH), 3.15 (IH, dd, J=2.2 and 3.5Hz CH.CH.CH), 3.8B (3H, S, OMe), 3.92 (3H, s, NMe), 4.38 - 45 (IH, m, CH^.CH.CH), 4.46 (2H, ABq, J=14Hz, separation of inner lines 14Hz) and 4.68 ρρπι (IH, d, J=2.2Hz, CH.CH.S).

Example 20 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-phenylsulphonylthio-1-(l-methoxycarbonyl-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 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, 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) (3H, s, =C.CH3), 3.22 (IH 3080, 3020, 2960, 2930, 2900, 2860, 1770, 1750, 1330 and 1145 cm'1; C (CDC13) 0.05 (6H, s, SiMe2), 0.98 (12H, s+d, SiBi!* and cHj.CH), 1.84 (3H, s, =C.CH3>, 3.22 (IH, dd, J=2 and 2.5Hz, CH.CH.CH), 3.75 (3H, s, OMe), 4.19 (IH, m, CHj.CH.CH), 4.58 (IH, C=CH2), 5.37 (IH, d, J=2Hz, C ri - 46 (3 and 2H, each m, Ar).

Founds C, 53.69; H, 6.99; N, 2.70; S, 12.42%, c23H35NO6SiS2 requires C, 53.77, H, 6.87; N, 2.74; 5, 12.48%.

By following the same procedure, there were also obtained: 3S-(lR-t-butyldimethylsi.lyloxyethyl l-^R-phenylsuIphonylthio-l- (l-t-butoxycarbonyl-2-ntethyl-l-prop-2-enyl )-azetidin-2-one; 3S-(IR-t-butyldimethylsilyloxyethyl)-4R-phenylsulphonylthio-1-(l-diphenYlmetho«ycarbonyl-2-methyl-l-prop-2-enyl)10 -azetidin-2-one; 3S-(lR-trichloroethoxycarbonyloxyethyl)-4R-phenylsulphonylthio-1-(1-methoxycarbonyl-2-methyl-l-prop-2-enyl)-azetidin-2-one; 3S-(lR-trichloroethoxycarbonyloxyethyl)-4R-phenylsulphony115 thi_o-l-(I-trichloroethoxycarbonyl-2-methyl-l-prop-2-enyl)-azetidin-2-one.

Example 21 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-phenylsulphonylt hio-1 - [ 1 -methoxycarbonyl -2-methy1sulphony 1 oxy-1 -prop-1 20 (2)-enyl]-a2etidin-2-one Procedure A g of 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-phenylsulphonyl thio-1-(l-methoxycarbonyl-2-roethyl-l-prop-2-enyl)-azetidin-2-one, prepared as described in Example , in dry dichlorornethane was ozonized at -70°C. After - 47 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 acetate and water. Evaporation of the solvent left the intermediate 3S-(lR-t-butyldimethylsilyloxyethyl )-4R-phenylsulphonylthio-1-(l-methoxycarbonyl-2-hydroxy-l-prop-l-enyl)-azetidin-2-one;fV max 3450, 1778, 1658 and 1620 cm1; S (CDC13) 0.08 (6H, s, SiMe2), 0.90 (9H, s, SiBut), 1.13 (3H, d, J=6Hz, CH^CH), 1.90 (3H, s, =C.CH3), 3.12 (IH, dd, J=2.5 and 4Hz, CH.CH.CH), 3.72 (3H, s, OMe), 4.2 (IH, m, CH3.CH.CH), 5.52 (IH, d, J=2.5Hz, CH.CH.S), 7.4-8.0 (5H, m, Ar) and 13 ppm (IH, s, OH).

This material was mesylated with 0.272 ml of triethylamine 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 cm1; ‘fe (CDC13) 0.05 (6H, s, SiMe2), 0.80 (9H. s, SiBut), 0.97 (3H, d, J=6Hz, CHj.CH), 2.50 (3H, s, «C.CHj), 3.15 (4H, m, SOjCHj and CH.CH.CH), 3.76 (3H, s, OCHj), 4.13 (IH, m, CHj.CH.CH), 5.7 (IH, 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- 48 thiazolyldithio-l-[l-methoxycarbonyl-2-methyl sulphonyloxy-1-prop-l(2)-enyl)-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 benzene5 sulphinate in 4 ml of water. After 15 minutes at room temperature the precipitated silver benzthiazolemercaptide was removed by filtration and the solution partitioned between dichloromethane and water. Removal of the solvent left the title product as a syrup (quantitive yield), having the same spectral properties as the sample from procedure A.

According to the same methodology, there were obtained: 3S-(IB-t-butyldimethylsilyloxyethyl)-4R-phenylsulphonylthio-1-[1-t-butoxycarbonyl-2-methylsulphonyloxy-l-prop15 -1(z)-enyl)-a2etidin-2-one; and 3S-(iB-trichloroethoxycarbonyloxyethYl )-4R-phenylsulphonylthio-1-(1-trichlorpethoxycarbonyl-2-methylsulphonyloxy-1-prop-1 (Z )-enyl ]-a_zetidin-2-one.

Example 22 Methyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethy1)-3-methy1-2-thi acephem-4-carboxylate 3S-(lR-t-butyldimethylsilyloxyethyl)-4R-phenylsulphonylthio-1-(l-methoxycarbonyl-2-methylsulphonyloxy-l-prop-12-enyl)-azetidin-2-one was allowed to react with NaHS 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 and does not need chromatographic separation or fractional crystallization to be removed (unlike, e.g. mercaptobenzthiazole) .

According to the same methodologies, there were obtained: t-Buty] (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate; and Trichloroethyl (7S,6R)-7-(lR-trichloroethoxycarbonyloyyethyl )-3-methyl-2-thiacephem-4-carboxylate.

Example 23 3S-(lR-trichloroethoxycarbonyloxyethyl)-4R-acetyldithio-1-(1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-lZ-enyl)-azetidin-2-one A solution of 340 mg of 3S-(lR-trichloroethoxycarbonyloxyethyl)-4R- benzthia2olyldithio-l-(l-methoxycarbonyl-2-methylsulphonyloxy-l-prop-lZ-enyl )-azetidin-2-one in 5 ml 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%);-1; 6 (CDC13) 1.50 (3H, d, CH^CH), 2.48 (3H, s, *C.CH3), 2.62 <3H, s, C0CH3), 3.29 <3H, s, SO2CH3), 3.44 <1H, dd, CH.CH.CH), 3.83 <3H, s, OMe), 4.77 (2H, ABq, J^ll.SHz, separation of inner lines 2Hz), 5.24 (IH, d, CH.CH.S) and 5.25 (lH, m, CH.CH.CH).

Example 24 Methyl (7S,6R)-7-(IR-trichloroethoxycarbonyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate A solution of 140 mg of 3S-(lR-trichloroethoxycarbonyloxy ethyl)-4R-acetyldithio-1- Work-up and chromatography afforded the title product: λ (EtOH) 280 (®,4„974) and 327 nm (2,262) (film) max * max 1787, 1769 sh, 1725 cm1; $ (CDClj) 1.54 (3H, d, CH-j.CH), 2.23 (3H, s, CH3), 3.30 (IH, dd, 2 and 7.5Hz, CH.CH.CH), 3.84 (3H, s, OMe), 4.68 (IH, d, CH.CH.S), 4.78 (2H, s, OCHjCClj) and 5.37 ppm (IH, m, CHj.CH.CH), followed by some recovered starting material.

Example 25 Methyl (7S,6R) -7-(lR-t-butyldimethylsilyloxyethyl)-3-bromome thy1-2-thi acephem-4-ca rboxy1ate 0.52 g of methyl (7S,6R)-7-(lR-t-butyldimethylsilyloxy51 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 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 (CHCip 282 and. 336 nm;¥ (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 (IH, dd, J=2.0 and 3.5Hz, CH.CH.CH), 3.87 (3H, s, OCH3), 4.65 (2H, center ABq, s.i.l. 4Hz, J=11.5Hz, CH2Br), 4.30 (1H, m, CH3-CH.CH) and 4.76 ppm (IH, d, J=2.0Hz, CH.CH.S).

Found C, 41.1; H, 5.64; N, 3.01; S, 13.55; Br, 17.20; ^1^26^^4^^2 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-butyl dimethyl silyloxyethyl)-3bromomethyl-2-thiacephem-4-carboxylate; (CDC1,) 283 and 332 nm; (film) 1787 and 1720 max 3 max cm'1; S (CDClj) 0.9 (6H, s, SiMe2>, 0.9 (9H, SiBu1), 1.28 (3H, d, CHj.CH), 1.55 (9h, s, OBu1), 3.18 (IH, dd, j=2-5 and 4,5Hz, CH.CH.CH), 4.35 (3H, m, CHjBr and CHj.CH.CH) and 4.71 ppm (IH, d, J=2.5Hz, CH.CH.S); p-nitrobenzyl (7S,6R)-7-(lR-p-nitrobenzyloxycarbonyloxyethyl )-3-bromomethyl-2-thiacephem-4-carboxylate; S> (CDC13) 1.45 (3H, d, CH^.CH), 3,43 (IH, dd, J=2.5 and 6Hz, CH.CH.CH), 4.45 (2H, ABq, J=12Hz, CH2Br), 4.80 (IH, d, J=2.5Hz, CH.CH.S), 5.2, 5.5 (5H, m, two OCH2Ar and CH^.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-nitrobenzyloxycarbonyloxyethyl)-3-bromomethvl-2-thiacephem-4-carboxylate; £ (CDC13) 1.45 (3H, d, CH^CH), 3.32 (lH, dd, J=3 and 6Hz, CH.CH.CH), 4.18 (2H, ABq, J=llHz, CHjBr), 4.70 (IH, d, J=3Hz, CH.CH.S), 5.20 (2H, E, OCHjAr), 5.30 (IH, m, CHj.CH.CH), 6.97 UH, s, OCHPh2), 7.10-7.40 (10H, br s, Ar), 7.45 and 8.15 ppm (each 2H, d, J-9Hz, Ar); diphenylmethyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate;γmax (film) 1790 and 1730 cm-1; lS(CDCl3) 0.05 (6H, s, SiMe2), 0.8 (9H, s, SiBu1), 1.22 (3H, d, J=6.5Hz, CHj.CH), 3.10 (lH, dd, J=2.7 and 4.5Hz, CH.CH.CH), 4.05 (2H, s, CH2Br), 4.2 (lH, m, CH3.CH,CH), 4.63 (lH, d, J=2.7Hz, CH.CH.S), 6.92 (IH, s, OCHPh-), and 7.05-7.40 ppm (10H, m, Ar):l___(CHCl,) 283 (g« 7,867) and 336 nm (g-3,533); trichloroethyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-_3rbromomethyl -2-thiacephem-4-carboxylate; and - 53 trichloroethyl (7S,6R)-7-(iR-trichloroethoxycarbonyloxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate.

Example 26 Methyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3-((1-methyl-S-tetrazoIylthio)-methyl)-2-thiacephem-4-carboxylate A THF solution of crude methyl (7S,6R)-7-(lR-t-butyld imethy1si 1y1oxyethy1)-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; max (EtOH) 281 and 333 nmjv (film) 1790 and 1725 cm 1; S (CDC1-.) 0.10 (6H, s, max j SiMe2), 0.89 (9H, s, But), 1.26 (3H, d, CHj.CH), 3.15 (IH, dd, J=2.2 and 3.5Hz, CH.CH.CH), 3.88 (3H, s, OMe), 3.92 (3H, s, N.CH3), 4.38 (IH, m, CHj.CH.CH), 4.46 (2H, ABq, sep. of inner lines 14Hz, J=l4Hz) and 4.68 ppm (IH, d, CH.CH.S, J=2.2Hz).

By following a similar procedure, there were obtained: t-butyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3-[(1-methyl-5-tetrazolylthio)-methyl]-2-thiacephem-4-carboxylate, starting from t-butyl (7S,6R)-7-(lR-tbutyldimethylsilyloxyethyl-3-bromomethyl-2-thiacephem-4carboxylate; and diphenylmethyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3- /(8-aminotetra_zolo[1,5-b]pyridazin-6-ylthio)-methyl^-2-thiacephem-4-carboxylate Example 27 (5aR,6S)-6-(lR-t-butyldimethylsilyloxyethyl)-5a,6-dihydro-3H,7H-azeto[2 ,1-c]furo[3,4-e)1,2,4-dithiazine-1,7-dione Procedure A): A solution of 15 mg of methyl (7S,6R)-75 (1R-t-butyldimethy1si1yloxyethyl)-3-bromomethy1-2-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 chromatography of the organic extracts afforded the title product as a white powder;vmax (CHC13 film) 18001760 br cm'1; 6 (CDCip 0.06 (3H, s, SiCH3), 0.11 (3H, s, SiCHj), 0.90 (9H, s, ΒιΛ), 1.33 (3H, d, CHj.CH), 3.33 IH, dd, J=2.5 and 4.5Hz, CH.CH.CH), 4.44 (lH, m, CH3.CH.CH), 4.62 (IH, d, J=2.5Hz, CH.CH.S) and 4.98 ppm (2H, s, CH2O).

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.

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 (73,SR )-7-(lR-t-butyldimethylsilyloxyethyl)-3-hydroxymethyl-2-thiacephem-4-carboxylate 300 mg of t-Butyl (7S,6R)-7~(lR-t-butyldimethylsilyloxyethyl)-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; & (CHCl-)281 ·τηά 335 nm; max j r (film) 3450, 1785 and 1712 cm1; S (Cnrj,) 0.1 (6H, max s, SiMe2), 0.86 (9H, s, SiBu1), 1.25 <3H, d, t^CH), 1.50 (9H, s, OBu1), 3.13 (IH, dd, J=2.5 and 4.5Hz, CH.CH.CH), 4.25 (centre of ABq, J=13Hz, CHjOH), 4.37 (IH, m, CHj.CH.CH) and 4.60 ppm (IH, d, J=2.5Hz, CH.CH.S).

Example 29 t-Buty1 (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3-(N-trichloroacetylcarbamoyloxymethyl)-2-thiacephem-4-carboxylate 250 mg of t-Buty1 (7S,fP.'-7-(lR-t-butyldimethylsilyloxyethyl)-3-hydroxymethyl-2 Lhiacephem-4-carboxylate in 2.5 ml of ethanol-free dichloromethane was treated at -40°C with 0.080 ml of trichloroacetylisocyanate. 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; A v (EtOH) 275 and 329 nm; y 1795 and 1725 br cm StCD-CN), 0.1 (6H, s, ΙΠ3Χ 3 SiMe2), 0.9 (9H, s, SiBu1), 1.3 (3H, d, CHj.CHJ^l.5 (9H, s, OBu1), 3.40 (lH, dd, J=3 and 4Hz, CH.CH.CH), 4.35 (IH, m, CHj.CH.CH), 4.80 (IH, d, J=3Hz, CH.CH.S) and 5.0 ppm (centre of ABq, CH2OCO).

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-butyldimethylsilyloxyethyl)-3-(N-trichloroacetylcarbamoyloxymethyl)-2-thiacephem-4-carboxylate, prepared as 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; SiCDCl^) 0.1 (6H, s, SiMe2), 0.9 (9H, s, SiBu1), 1.35 (3H, d , CH^.CH), 1.60 (9H, s, OBu1), 3.1 (IH, dd, CH.CH.CH), 4.3 (IH, m, CH.CH.CH) 4.75 (IH, d, J«3Hz, CH.CH.S) and 5.0 ppm (centre of ABq, OCH2CO).

Example 31 Methyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3-nitrooxymethyl-2-thiacephem-4-carboxylate A solution of 200 mg of methyl (7S,6R)-7-(lR-t-butyl- 57 dimethy1silyloxyethy1)-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; 1(CHC1,) 280 and 337 nm(film) 1790, 1730, 1640 and 1280 cm*1; ff(CDC13) 0.08 (6H, s, SiMe2), 0.87 <9H, s, SiBu*), 1.38 (3H, d, CH-j.CH), 3.18 (IH, dd, J-2.5 and 5.5Hz, CH.CH.CH), 3.85 (3H, s, OMe), 4.38 (IH, m, CH^CH.CH), 4.73 (IH, d, J=2.5Hz, CH.CH.S) and 5.36 ppm (2Hj ABq, J=13.5Hz, s.i.l. 29.5Hz, CH2ONO2); 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-butyldimethylsilyloxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate in dichlorornethane was treated at daily intervals with tetrabutylammonium formate (3 x 600 mg). After 3 days at 5°C, tic showed 80% conversion in the product (ethyl acetateslight petroleum 1:2 by volume). Elution through a short silica gel column gave the title material; S(CDC13) 0.1 (6H, s, SiMe2), 0.9 (9H, s, SiBu1), 1.35 (3H, d, CH3.CH), 3.20 (IH, dd, 2.5 and 7Hz, CH.CH.CH), 3.9 (3H, s, OMe), 4.5 (IH, m, CHj.CH.CH), 4.74 (IH, d, - 58 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)-35 -formyloxymethyl-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-butyldimethylsilyloxyethyl)-3-acetoxymethyl-2-thiacephem-4-carboxylate; t-butyl (7S,6R)-7-(IR-t-butyldimethylsilyloxyethyl)-3-acetoxvmethyl-2-thiacephem-4-carboxvlate; diphenylmethyl (7S,6R)-7-(lR-t-buty1dimethylsilyloxy15 ethyl)-3-acctoxymethyl-2-thiacephem-4-carboxylate; and trichloroethyl (7S,6R)-7-(lR-trichloroethoxycarbonyloxyethyl)-3-acetoxymethyl-2-thiacephem-4-carboxylate.

Example 33 Methyl (7S,6R)-7-(lR-hydroxyethyl)-3-methyl-2-thiacephem20 -4-carboxylate 0.75 g of methyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-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.

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-25 -thiacephem-4-carboxy1ate, starting from methyl (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3-bromomethyl-2thiacephem-4-carboxylate;(film) 1775, 1730 cm1; * max S (CDC13) 1.35 (3H, d, CH-j.CH), 3.38 (IH, dd, CH.CH.CH), 3.60 (IH, br s, OH), 3.97 (3H, s, OMe), 4.33 (IH, m, CH^.CH.CH), 4.46 (2H, centre of ABq, J=llHz, sep. of inner lines 4Hz, CH^Br)) and 4.88 ppm (IH, 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-butyldimethylsilyloxyethyl)—3—[(l-methyl-5-tetrazolylthio)-methyl)-2-thiacephem-4-carboxylate;eymax (KBr) 1765 and 1707 cm1; S(CD3COCD3), 1.30 (3H, <3, CHICHI, 3.39 (IH, dd, CH.CH.CH), 3.79 (3H, s, NCH3), 3.97 (3H, s, OCH3), 4.0 (IH, m, CHj.CH.CH), 4.38 (2H, centre of ABq, J=16Hz, separation of inner lines 13Hz, CH^.S), 4.77 (IH, d, J=2.2Hz, CH.CH.S) and 5.0 ppm (IH, br s, OH); and, analogously, the corresponding t-butyl, diphenylmethyl and trichloroethyl esters were also prepared.

Example 34 (7S,6R)-7-(lR-methylsulphonyloxyethy1)-3-methyl-2-thiacephem-4-carboxylic acid Diphenykscthyl (7S,6PJ-7-(lR-nsthylsulphonyloxyethyl )-3-methyl -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; (CHC1,) 281 and 326 max <3 nm; V (CHC133000-2300, 2970, 2930, 2850, 1775, 1710 max j 1530 and 1170 cm'1; S (CD3COCD3) 1.58 (3H, d, CHICHI, 2.23 (3H, s, Me), 3.16 (3H, s, SC^Me), 3.66 (IH, dd, J=2 and 6Hz, CH.CH.CH), 4.85 (IH, d, J=2Hz, CH.CH.S) and 5.30 ppm (IH, m, CHj.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-butyldimethylsilyloxyethy1)-3-methyl-2-thiacephem- 4- carboxylic acid; (7S,6R)-7-(lR-hydroxyethyl)-3-methyl-2-thiacephem-425 -carboxylic acid; (7S.6R)-7-(iR-hydroxvethyl)-3-acetoxymethyl-2-thiacephem-4-carboxylic acid; (7S.6R)-7-(lR-hydroavethyl)-3-carbamoyloxymethyl-2-thiacephem-4-carboxylic acids and (7$,6R)-7-(lR-hydroxyethyl)-3-[(i-methyl-3-tetrazolylthio) -methyl)-2-thiacephem-4-carboxylic acid· Example 33 p-Nitrobenzyl (7S.6R)-7-(iR-p-nitrobenzyloxycarbonyloxy10 ethyl)-3-methyl-2-thiacephem-4-carboxylate A solution of 200 mg of diphenylmethyl (7S,6R)-7-(lR-p-nitrobenzyloxycarbonyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate in 25 ml of dichloromethane was treated for 30 min at 0°C with 0.4 ml of trifluoroacetic acid. is Evaporation under vacuum in the cold left the crude 2-thiacephera-4-carboxylic acid, which was dissolved in 10 ml of acetonitrile:dimethylformamide (2:1 by volume) and treated with 0.050 ml of triethylamine and 100 mg of p-nitrobenzyl bromide· After i hour at 23°C, the mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer, dried over anhydrous magnesium sulphate, was concentrated and the residue passed through a short silica column (ethyl acetate: light petrol as eluants) to afford the pure title product, ISO mg <7»M; 6 (CDClg) 1.45 <3B, d, CBg.CH) 3.43 (IH. dd. Je2.S and 6Hz, CH-CH-CH). 4.43 <2H, ABq. J»12 Hz. CH2Br) . 4.80 (IH. d. J-2.S Hr, CH-CH-S) . 5.2-3.3 (3H. m). 7.47 and 7.60 (each 2H, d, Ar) and 8.20 ppm (4H, d. Ar).

Example 36 (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-4-diphenylmethoxycarbonyl-3-(pyridinium-methyl)-2-thiacephem bromide A solution of 310 mg of diphenylmethyl (7S,6R)-7-(lR-t33 -butyldimethylsilyloxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate in 15 ml of dry acetone was treated with 0.4 ml - sa of pyridine. After 20 hours at room temperature the solvent was distilled off and the residue purified by silica gel chromatography. The product-containing fractions (eluted with dichloromethane:acetic acid: methanol 70:13:13 by volume) were collected and freed from the solvents to leave the title compound as a syrup; „„„ (CHC1, film) 1790. 1713 cm_1i δ (CDC1-) max 3 3 (inter alia) 1.32 (3H, d. J-6.3 Hz). 3.33 (IH. dd), 4.43 (IH. m), 5.0 (IH, d, J 2 Hs) and 7.11 ppm (IH, s); (CHC1«) 283 and 337 nm (s-4,060). In a likewise manner, and starting from p-nitrobenzyl (7S,6R)-7-(iRp-n it robenzyloxycarbonyloxyethyl)-3-bromomethyl-a-thiacephem-4-carboxylate, there was obtained: (7S,SR)-7-(iR-p-nitrobenzyloxycarbonyloxyethyl)-4-p13 -n it robenzyloxvcarbonyl-3-(pyr id in ium-methyl)-2-thiacephem bromide Example 37 (7S,6R)-7-(lR-t-butyldimethylsilyloxyethyl)-4-carboxy-320 -(pyridinium-methyl)-2-thiacephem trifluoroacetate A solution of (7S,SR)-7-(lR-t-butyldimethylsilyloxyethyl>-4-diphenylmethoxycarbonyl-3-(pyr id inium-methyl)-thiacephem bromide* prepared as described in Example 36, in 10 ml of dichloromethane was treated with 2 ml of trifluoroacetic acid at 0°C for is minutes. After evaporation in vacuo, the residue was taken up in a small amount of chloroform· Diethyl ether was added under stirring and then decanted off· to leave the crude title product; (CBClg film) 3420,1785, 1715 and 1635 br cm-1; & (CDCl^) (inter alia) 1.30 (3H. <3, J-S.5 Hz), 3.23 (IH, dd), 4.38 (IH, m) and 4.76 ppm (IH, d); (CHC1*) 262 and 334 nm. max 3 Example 38 (7S,6R)-7-(IR-p-nitrobenzyloxycarbonyloxyethyl)-4-p63 -nitrobenzyloxycarbonyl-3-(3-carbamoylpyridinium-methyl)-2-thiacephem bromide* A solution of 460 mg of o^nitrobenzyl (7S,6R)-7-(lR-g7 -nitrobenzyloxycarbonyloxyethyl>-3-bromomethyl-23 -thiacephem-4-carboxylate in 3 ml of DMF was stirred overnight in the dark in the presence of 200 mg of nicotinamide. Most of the solvent was distilled off and the residue taken up in 130 ml of tetrahydrofuran. This solution was washed with a solution of sodium chloride in 0.1 N hydrochloric acid (2 x 30 ml) and with brine (2 x 30 ml), dried on anhydrous sodium sulphate and evaporated fo dryness. The residue was charged fo the top of a column packed with silanised silica gel (Merck, Art. 7719). Excess nicotinamide and impurities were eluted with ethyl 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; 3> 1800, 1723, 1695 cm"1; 6 (Deuteroacef one; 200 MHz) 1.67 (3H, d, J-6.4 Hz, CH3-CH), 4.14 (IH, dd, J-2.3 and 4.7 Hz, CH-CH-CH) . 3.30 (IH, d, J-2.5 Hz, CH-CH-S) , 3.4-5.7 (7H, m, ZxCH^OAr, CH^M*, and CHj-CH-CH) . 7.7-8.4 (8H, m, Ar), and Q.O, 8.7, 9.5 and 9.7 ppm (each IH, br s, pyridinium). Analogously, by using isonicofinamide instead of nicotinamide, there was obtained: 23 (7S.6R)-7-(lR-p-nitrobenzyloxycarbonyloxyethyl)-4-p-nitroben2yloxycarbonyl"3-(4-carbamoylpyridinium-methyl)-2- thiacephem bromide-

Claims (7)

CLAIMS:

1.· A process for tbe preparation of a 2-thiacephem derivative of tbe general formula Ila Ila wherein represents a hydrogen atom or an organic group 10 and Rg represents a hydrogen atom or a carboxy protecting group from an azetidinone derivative of the general formula IV R, COOR 2 IV wherein R^ and Rg are as defined in this claim and z represents (i) a group of the formula SR ? wherein R ? represents an alkyl group having from i to S carbon atoms, a phenyl ot tolyl group, or a heterocyclic group, (ii) a group of tbe formula SCOR g wherein Rg represents an optionally substituted alkyl group having from 1 to 4 carbon atoms (iii) a group of the formula -] z° s \ OR. wherein R COR and R lo independently represent alkyl groups having from i to 4 carbon atoms or aryl groups, or together with the dicarboxyamino group form a heterocyclic ring, or (J (iv) a group of the formula wherein R al O represents an optionally substituted alkyl group having from i to 4 carbon atoms or an optionally subst ituted ary1 group, the process comprising ozonolysing the carbon-carbon double 5 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. 15 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-butyldimethylsilyloxy20 ethyl)-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1. 5. t^Butyl <7S,6R)-7-(lR-fc-bufcyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate prepared according to 25 claim 1. 6, Trichloroethyl (7S.6R)-7-(iR-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate prepared according to claim X. 7. Acetoxymethyl (7S,6R)-7-(iR-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1. 35 8. (7S.6R)-7-(lR-t-butyldimethylsilyloxyethyl)-3-methyl~2-thiacephem-4-carboxylic acid prepared according - ss to claim x P. Methyl (7S,SR)-7-(lR-hydroxyethyl)-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1» x0. Diphenylmethyl (7S.SR)-7-(1R-hydroxyethy!)-3-methyl2-thiacephem-4-carboxylate prepared according to claim 1. XI. (7S.SR)-7-(lR-hydroxyethyl)-3-methyl-2-thiacephem10 -^-carboxylic acid prepared according to claim X. 12. Methyl <7S,SR)-7-(iR-methyl8ulphonyloxyethyl)-3-methyl-2-thiacephem-4-carbo»ylate prepared according to claim X. 13. Diphenylmethyl (7S.3R)-7- 20 14. (7S,SR)-7-(IR-methylsulphonyloxyethyl)-3-wethyl-2-thiacephem-4-carboxylic acid prepared according to claim X. 15. Methyl (7S,SR)-7-(lR-trichloroethosycarbonyloxy23 ethyl)-3-methyl-2-thiacephew-$-carboxylate prepared according to claim x. is. t-Butyl (7S,SR)-7-(lR-trichloroethoxycarbonyIoxyethyl)-3-methyl-2-thiacephem-a}-carboxylate prepared so according to claim x. 17. Diphenylmethyl (7S.SR)-7-(iR-trichloroethoxycarbonyloxysthyl>-3-methyl-2-thiacepheui-&-carboxylate prepared according to claim 1. - 67 18. Trichloroethyl (7S,6R)-7-(lR-trichloroethoxycarbonyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1.

3. 19. Acetoxymethyl (7S,6R)-7-(iS-trichloroethoxycarbonyloxyethyl)-3-*methyl-2-thiacephem-4-carboxylate prepared according to claim 1. 20. Acetoxymethyl (7S,6R)-7-(IR-trimethylsilyloxyethyl)10 -3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1. 21. Diphenylmethyl (7S,6R)-7-(iR-p-nitrobenzyloxycarbonyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate prepared is according to claim 1. 22. p-Witrobenzyl (7S,6R)-7-(2R-p-nitrobensyIoxycarbonyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1. 23. A process for the preparation of a 2-thiacephem derivative of the general formula lib wherein R £ and R ? are as defined in claim 1 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 - tfg solvent at a temperature of from 20°c fo 13O°C in the presence of a radical initiator and an acid scavenger· 24. a process according fo claim 23 in which the 5 halogenation of the 2-thiacephem is effected by reaction with N-bromosuccinimide or N-chlorosuccinimide. 25. A process according to claim 23 or claim 24 in which the radical initiator present during the halogenation of 10 the 2-thiacephem is azoblsisobutyronitrile or benzoyl peroxide26. A process according to any of claims 23 fo 23 in which the acid scavenger present during the halogenation of is the 2-thiacephem is an epoxide, an alkaline earth oxide or a molecular sieve27. A process according to any of claims 23 to 26 in which the inert organic solvent in which the halogenation 20 of the 2-thiacephem is effected is benzene· carbon tetrachloride or ethyl formate· 28. Methyl (7S,6R)-7-(lR-t7butyldimethylsilyloxyethyl)-3-bromomefhyl-2-thiacepbem-4-c&rboxyl&fe prepared 25 according fo any of claims 23 to 27. 29. DiphenyImethyl (7S,6R) -7 -(IR-t-butyld imethyls ilyloxyethyl)-3-bromomethyl-2-thiacephera-4-carboxylate prepared according fo any of claims 23 to 27. 30. Trichloroefhyl (7S,6R)-7-(2R-t^bufyldimethylsilyloxyefhyl)-3-bromomethyl-2-thiacephem-4-carboxylafe prepared according fo any of claims 23 to 27. 33 31. t^Butyl (7S.6R)-7-(iR-t^butyldimethylsilyloxyethyl)3 prepared - Ο -3-bromomethyl-2-thiacephem-4-carboxylate according to any of claims 23 to 27. 32. Trichloroethyl (7S,6R)-7-(lR-trichloroethoxycarbonyloxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate prepared according to any of claims 23 to 27. ’ 33. Diphenylmethyl (7S,6R)-7-(lR-pjnitrobenzyloxycarbonyloxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate I prepared according to any of claims 23 fo 27. 34. gfHitrobenzyl (7S,6R)-7-(lR-g7nitrobenzyloxycarbonyloxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate prepared according fo any of claims 23 to 27. 35. Hethyl (7S,6R)-7-(lR~hydroxyethyl)-3-bromoraethyl-2-thiacephem-4-carboxylate prepared according to any of claims 23 fo 27. 3ti. A process for the preparation of a 2-thiacephem derivative of the general formula II wherein Rj and R^ are as defined in claim 1 and Y represents an organic group, the process being according fo any of claims 23 fo 27 and further comprising converting the halomethyl group introduced by the halogenation info a methyl group substituted by the desired organic group· the conversion being effected at any point after the halogenation70 37. A process according to claim 33 in which the conversion is effected on the 3-halomethyl-2-thiacephem derivative· 3 38. Methyl (7S,SR)-7-(iR-t-butyldimethylsilyloxyethyl)-3-nitrooxyraethyl-2-thiacepbera-4-carboxylate prepared according to claim 33 or claim 37, 39. A process according to claim 37 in which ? represents io a hydroxy group and the conversion is effected by reacting the 3-halomethyl-2-thiacaphem 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 39 in which the salt is 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 20 o°c for 15 minutes, and the subsequent hydrolysis is carried out in the same reaction medium. 42. t-Butyl (7S.3R>-7 *(IR-tHoutyldimethylsilyloxyethyl)-3-hydroxymethyl-2-thiacephem-4-carboxylate prepared 23 according to any of claims 39 to 41. 43. A process according to claim 39 in which V represents an unsubstltutsd or N-alkyl or N-acyl substituted carbamoyloxy group and the conversion is carried out 30 according to any of claims 39 to followed by reacting the 3-hydroxymethyl-2-thiacephem derivative with an alkyl isocyanate or an acyl isocyanate and, if desired, deprotecting the carbamoyloxy group. 35 44. A process according to claim 43 in which the reaction - 71 of the 3-hydroxymethyl-2-thiacephem with the isocyanate is carried out in dichloromethane at -40°c. 45. A process according to claim 43 or claim 44 in which 5 the deprotection is carried out by stirring with silica gel in methanol for 20 hours. 46. t-Buty1 (7S,6R)-7--3-(N-trichloroacetylcarbamoyloxymefhyl)-2-thiacephem-410 -carboxylate prepared according to any of claims 43 to 45. 47. t-Butyl <7S.6R)-7- 48. (7S,6R)-7-(lR-hydroxyethyl)-3-carbainoyloxymethyl-2-thiacephem-4-carboxylic acid prepared according to any of claims 43 fo 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-halomefhyl-2-fhiacephem with a carboxylic acid salt, 50. A process according to claim 49 in which the reaction 25 is carried out in dichloromefhane at s°c with addition of the salt portionwise in three days. 51. Methyl (7S,6R)-7-(lR-t-butyldimethylsiloxyethyl>-3-formyloxymethyl-2-thiacephem-4-carboxylate prepared 30 according fo claim 49 or claim 50. 52. t-Buty1 (7S.6R)-7-(lR-t-butyldimethylsiloxyethyl)-3-formyloxymethyl-2-fhiacephem-4-carboxylate prepared according fo claim £9 or claim 50. t 33. Diphenylmethyl (zS.6R)-7-(iR-t7butyldiaethylsiloxy-ethyl)“3-formyloxymetbyl-2-thiacephem-4-carbosylate prepared according fo claim 49 or claim 30. 3 34. Methyl (7S.6R)-7-(iR-f^butyldimethylsiloxyethyl)-3-acetoxymethyl-2-thiacephem-4-carboxylate prepared according fo claim 49 or claim 30. 5 3. tHButyl (7 S.6R)-7-(XR-tfbutyld imethyls iloxyethyl>-3 10 -acefoxymefhyl-2-thiacephem-4-carboxylafe prepared according to claim 49 or claim 30. 66. Diphenylmethyl (7S.6R)-7-(lR-t7butyldimethylsiloxyefhyl)-3-acetoxymethyl*2-thiacephem-4-carboxylate prepared is according fo claim 49 or claim so. 57. Trichloroefhyl (7$,6R)-7-(lR-trichloroethosycarbonyloxyethyl)-3-acetoxyraethyl-2-thiacephem-4-carboxylate prepared according to claim 49 or claim 30. 38. (7S,6R)-7-(iR-hydroxyethyl)-3-acetoxymethyl-2-thiacephera-4-carboxylic acid prepared according fo claim 49 or claim 30. 23 59. A process according fo claim 37 in which ϊ represents a -S-Het group wherein Het denotes a saturated or unsaturated hefrocyclic ring containing at least one oxygen· sulphur and/or nitrogen heteroafom, and is preferably: 30 A) a penfatomic or hexafomic heteromonocyclic ring, containing at least one double bond and at least one oxygen* sulphur and/or nitrogen heteroafom, such as a thiazolyl, triazolyl, thladiazolyl, tetrazolyl, triazinyl group, unsubstituted or 33 substituted by one or more a') alkoxy groups having from l to fi carbon atoms, aliphatic acyl groups having from 2 to 6 carbon atoms, hydroxy groups and/or halogen atoms? b’) alkyl groups having from i to fi carbon atoms, unsubst ituted or substituted by one or more j hydroxy groups and/or halogen atoms? c r ) alkenyl groups having from 2 to 6 carbon atoms unsubst ituted or substituted by one or j more hydroxy groups and/or halogen atoms? d') groups of the general formula -S-Rg wherein Rg represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms? or groups of the general formula -S-CHg-COOR^ wherein R^ 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 -(CHp^-COOR^, or -CH-CH'COOR. or -(CH-) -

4. A m -CN or -(CH.) -CONH- or -(CH-) 2 m a 2 m -SOgH wherein m is zero, l, 2 or 3 and R^ is as defined above? B) f’> groups of the general formula -(CHg)^· wherein m_ is as defined above, and each of Rg and R fi , which may be the same or different, represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or an aliphatic acyl group or when one of Rg and Rg is hydrogen, the other may be also an amino protecting group? and a heterobicyclic ring, containing af least two double bonds wherein each of the condensed heteromonocylcic rings· being the same or t — — is a pentatomic or hexatomic ring containing at least one or nitrogen heteroatom* said ring being unsubstituted or different* hete romonocyc1 ic oxygen* sulphur he t e r ob ic yc 1 ic ίο is substituted by one or more substituents selected from a f ), b'). c’), e*) and P> 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 base or with a preformed sodium salt of the compound HS-Het, 60. A process according to claim 59 in which the organic solvent is tetrohydrofuran. aqetone* acetonitrile or dimethylformamide. 61. A process according to claim 39 or claim 60 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-(lR-V-bufcyldimethylsiloxyethyl)-S-( 6 4. fcjButy1 < 7S,6R)-7-(iR-t^butyld imethyls iloxyethyl)-3-I(i-methyl-3-tetrazolylthio)-methyl)-2-thiacephem-4-carboxylate prepared according to any of claim 59 to 62. 63. D iphenylmethyl (7 S.6R)-7-(iR-t^butyld imethyls iloxyethyl)-3-(( 8-aminotetrazol[i*5-b]pyridazin-6-ylthio)-methyl)-2-thiacephem-4-carboxylate prepared according to any of claim 59 to 62. - 75 66. (7S,6R)-7-(lR-hydroxyethyl)-3-[(i-methyl-5-tetrazolylthio)-methyl]-2-thiacephem-4-carboxylic acid prepared according to any of claim 59 to 62.

5. 67. Methyl (7S,

6. R)-7-(lR-hydroxyethyl)-3-[(l-methyl-5-tetrazolylthio)-methyl]-2-thiacephem-4-carboxylic acid -j prepared according fo any of claim 59 fo 62. 68. A process according fo claim 37 in which Y represents j 10 a 1-pyridinium group, unsubstituted or substituted in the meta or para position with a carbamoyl group· and the conversion is effected by reacting the 3-halomethyl-2-thiacephem derivative with pyridine· nicotinamide or isonicotinamide· 69. (7S,6R)-7--4“ -diphenylmethoxycarbonyl-3-(pyridinium-methyl)-2-thiacephem bromide prepared according fo claim 63. 20 70. (7S.6R)-7-(iR-p-nitrobenzyloxycarbonyloxyefhyl)-4-(p-nitrobenzyloxycarbonyl)-3-(pyridinium-methyl)-2-fhiacephem bromide prepared according fo claim 68. 71. (7S.6R)-7-(iR-p-nitrobenzyloxycarbonyloxyethyl)-425 -(p-n it roben zyloxycarbonyl)-3-(3-carbamoylpyr idin ium-mefhyl)-2-thiacephem bromide prepared according fo claim 68. 72. (7S.6R)-7-(iR-p-nifcrobenzyloxycarbonyloxyethyl)-4 30 -(p-nitrobenzyloxycarbonyl)-3-(4-carbamoylpyridinium-methyl)-2-thiacephem bromide prepared according to claim 68.

7. 3. (7S.6R)-7-(lR-t-butyld imethyls ilyloxyethyl)-435 -carboxy-3-(pyridinium-methyl)-2-thiacephem e trifluoroacetate prepared according to claim 6