CA1254891A

CA1254891A - 2-thiacephems

Info

Publication number: CA1254891A
Application number: CA000521772A
Authority: CA
Inventors: Marco Alpegiani; Angelo Bedeschi; Maurizio Foglio; Ettore Perrone; Giovanni Franceschi
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1982-12-08
Filing date: 1986-10-29
Publication date: 1989-05-30

Abstract

Processes for the preparation of a 2-thiacephem derivative of the general formula II:

(see formula I) wherein R1 represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or a cycloalkyl group having 4 to 7 carbon atoms, said alkyl and cyclalkyl groups optionally substituted by hydroxy, protected hydroxy, amino, protected amino, mercapto, protected mercapto, or cyano;
R2 represents a hydrogen atom or a carboxy protecting group and Y represents a hydrogen atom or a halogen atom.
The processes are characterized as commencing with a compound of the general formula IV:

(see formula II) compounds of formula II are useful intermediates in the preparation of (5R) penem compounds useful as pharmaceuticals.

Description

1~54~3~1 This application is a divisional of Canadian Patent Application 442,383 filed December 1, 1983.
DESCRIPTION
The invention relates to a new process for the preparation of (5R) penem compounds, of the. general formula I and their pharmaceutically and/or veterin-arily acceptable salts.
R1 s ~ ~Y
I
N
p OORZ
In the general formula I, Rl represents a hydrogen atom or an organic group; R2 represents a hydrogen atom or a carboxy protecting ~3roup; and Y
represents a hydrogen or halogen atom or an organic group.
Organic groups which R1 may represent include optionally substituted aliphatic or cy~:loaliphatic~
20groups.. The aliphatic groups are preferably alkyl groups having from l to 12 carbon atom. and the op-tional substitue~nts may be one or more hydroxy, amino, cyano and/or mercapto groups. The hydroxx, amino and .mercapto groups may be free or protected. Particularly preferred alkyl groups are methyl and, ethyl, especially the latter, and a preferred sustituent for such.a group is a hydroxy group, ~~,~
o'~o () 1~:~4~3;~1

- 2 -which may be free or protected. the 1-hydroxyethyl group in 6S, BR or 6R, BS configuration is most preferred. The cycloaliphatic groups are preferably monocycloalkyl groups having from 4 to 7 carbon atoms. Cyclopentyl and cyclohexyl groups are especially perferred. Optional substituents are preferably chosen from alkyl groups having 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.
the carboxy protecting group R2 may be any group which, together with the -C00-moiety, forms an esterified carboxy group, Examples of carboxy protecting groups R2 are, in particular, 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 carton atoms, for example 2,2,2-trichloroethyl; alkenyl groups having from 2 to 4 carbon atoms for example allyl;
optionally substituted aryl groups, for example phen~rl and ~-vitro-phenyl; aryl substituted alkyl groups, the alkyl 2p part whereof has from 1 to 6 carbon atoms and the ar:~l part whereof is optionally substituted, for example, benzyl, p.-vitro-benzyl and p-methoxy-benzyl; aryloxy substituted alkyl groups, the alkyl part whereof has from 1 to 6 carbon atoms, for example phenoxy-methyl; or groups such as benzhydryl, o-vitro-benzhydryl, acetonyl, trimethylsilyl, Biphenyl-t-butyl-silyl, and dimethyl-t-butyl-silyl. the definition of R2 as a carboxy protecting 1;~54~~1 .c

- 3 -group also includes any residue, such as acetoxymet.hyl, pivaloyloxymethyl or phthalidyl, leading to an ester group which is known to be hydrolyzed "in vivo" and to have favourably pharmacokinetic properties.
When Y represents a halogen atom, it is preferably a fluorine, chlorine or bromine atom.
When Y represents an organic group, it is preferably a) a free or protected hydroxy,group;
b) a formyloxy group or an acyloxy group having from 2 to 6 carbon atoms, optionally substituted by a halog~:n atom, by an acyl group having from 2 to 6 carbon .atoms, or by an amino, hydroxy or mercapto group, the amino, hydroxy or mercapto group optionally being in a protected form;
~) an unsubstituted or N-alkyl substituted carbamoyloxy group;
d) an alkoxy group having from 1 to 12 carbon atoms or an alkylthio group having from 1 to 12 carbon atoms, either of which is optionally substituted by one or more halogen atoms, formyl groups, acyl groups having from 2 to 6 carbon atoms, and/or amino, hydroxy or merr_apto groups, the amino, hydroxy or mercapto group optionally being in a protected form;
e) a 1-pyridinium group, unsubstituted or substituted in the.meta or para position with the group -CONH2;
f) a heterocyclylthio group -S-Het wherein Het, denoting ~~J4~~~

- 4 -a saturated or unsaturated heterocyclic ring containing at least one oxygen, sulphur and/or nitrogen heteroatom, is preferably:
A) a pentatomic or hexatomic heteromonocyclic ring, containing at least one double bond and at least one oxygen, sulphur and/or nitrogen heteroatom, unsubstituted or substituted by one or more a') alkoxy groups having from 1 to 6 carbon atoms, aliphatic acyl groups having from 2 to 6 carbon atoms, hydroxy groups and/or halogen atoms;
b') alkyl groups having from 1 to 6 carbon atoms, unsubstituted or substitu~_ed by one or more hydroxy groups and/or halogen atoms;
c') alkenyl groups having from 2 to 6 carbon atoms, unsubstituted or substitu~~ed by one or more hydroxy groups and/or halogen atoms;
d') groups of the general formula -S-R3 wherein R3 represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or groups of the general formula -S-CH2-COOR4 ~her~in R4 represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a carboxy-protecting group;
e') groups of the general formula -(CH2)m-COOR4 or -CH=CH-COOR4 or -(CHZ)m-CN or -(CH2)m-CONH2 or -(CH2 m_ -S03H Therein m is zero, 1, 2 or 3 and R4 is as defined above; R

f') groups of the general formula -(CHZ)m-NCR Therein m is es defined above, and each of R5 and R6,5which y C, 1~~~~~~

- 5 -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 R5 and R6 is hydrogen, the other may be also an amino protecting group; or B) a heterobicyclic ring, containing at least two double bonds wherein each of the condensed heteromonocyclic rings, being the same or different, is a pentatomic or hexatomic heteromonocyclic ring containing at least one oxygen, sulphur or nitrogen heteroatom, said heterobicyclic ring being unsubstituted or substituted by one or more substituents selected form a'), b'), c'), e') and f') as defined above.
In the above definitions A) and B) preferred halogens are chlorine, bromine and iodine; preferred alkyl groups are methyl and ethyl; a preferred alkenyl group is allyl; a preferred aliphatic acyl group is acetyl; a carboxy pro'.ecting group may be any of the groups previously indicated for the R2 substituent; and the free sulpho and carboxy groups possibly present~may be salified, e.g. as sod.um or potassium salts. A heteromonocyclic ring of i:he above class A) may be, 1%~~48~1

- 6 -for example, an optionally substituted thiazolyl, triazolyl, thiadiazolyl, tetrazolyl or triazinyl ring. Preferred substituents on such rings are, for example, one or more substitutents chosen from amino, hydroxy, oxo end a Cl-C6-alkyl group preferably methyl or ethyl, urherein the C1-C6-alkyl group may be optionally substituted by a substituent chosen from carboxy, sulpho, cyano, carbamoyl, amino, methylamino or dimethylamino. A heterobicyclic ring of the above class ~) may be for example, a tetrazolopyridazinyl radical optionally substituted by amino or carboxy.
In the above formula I 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 sut~stituted, especially halo-substituted, acyl groups, e.51. acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl, benzoyl or p.-bromophenacyl;
triarylmethyl groups, in particular triphenylmethyl; silyl groups, in particular trimethylsilyl, dimethyl-t-butyl-silyl, Biphenyl-t-butyl silyl- or also groups such as t-butoxycarbonyl, p-nitrobenzyloxycarbonyl, 2,2,2-trichloroethoxyc,arbonyl, benzyl, pyranyl and vitro. When, in particular, the R1 substituent in formula (I) is a hydroxyalkyl group, preferred protecting groups for the hydroxy function are p-vitro-benzyloxycarbonyl; dimethyl-t-butyl-silyl-; Biphenyl-t-butylsilyl; trimethylsilyl;

c ' ~~;ij4~3;~1 2,2,2-trichloroethoxycarbonyl; benzyl; p-bromo-phenacyl;
triphenylmethyl and pyranyl. All the alkyl and alkenyl groups, including the aliphatic hydrocarbon moiety of the alkoxy, alkyl thio and acyloxy groups, may be branched or straight.
The pharmaceutically and/or veterinarily acceptable salts may be both salts with acids, either inorganic acids such as hydrochloric or sulphuric acid, or organic acids such as citric, tartaric, fumaric or methanesulphonic acid, and salts with bases, either inorganic bases such as alkali metal or alkaline-earth metal hydroxides, in particular sodium and potassium hydroxid~:s, or organic bases such as triethylamine, pyridine, b~:nzylarnirre or collidine. Preferred salts are the salts of the compounds of formula I wherein R2 represents a hydrogen atom with one of the bases hereabove specified in particular with sodium hydroxide or potassium hydroxide.
The compounds of the general formula I obtainable by the process of the invention are known compounds, described and claimed in our British Patent Specifications Nos.
2043639A and 8210410. They are potent, broad-spectrum antimicrobial agents, and are therefore useful in the treatment of bacterial infections in warm-blooded animals, especially in humans, by enteral or parenteral administration.

3.~~4~~1 -e-Desulphurative ring contraction of 2-thiacephem of the general formula II
Rl S ~

' 3 N a~ Y
0 ~ II

~uherein Rl, R2 and Y are as above defined is a kno~un rocess for the p preparation of penems, but it suffers from poor or adverse stereoselectivity. Although the carbon atom in position 6 has the R configuration, the desulphurization usually gives (5S)-penems ~uhich are biologically inactive (H.R. Pfaendler et el., J. Am.
Chem. Soc., 101, 1979, 6306) or a mixture of (SS)-ar;d (SR)-penems (A. Henderson et al., J. Chem. Soc. Commun., 1962, 809). We have found and descr~bed-in Tetrahedron Letter's, 24, pag. 3283 (1983) that (5R)-penems can be obtained from such desulphurative ring contractions if the substituE~nts Rl, RZ and Y and the solvent for 2p the process are suitably selected. A more general stereoselective process, operable over the full range of values of the substituents Rl, R2 and Y is, ho~uever, clearly desirable, as it u~ould obviate the losses involved in the formation of the undesired (SS)-isomers and their separation from the desired (5R)-isomers.
The invention provides a process for the preparation of a f;SR) penem having the general formula I as above defined, 1~;;~~~3~~

the process comprising oxidising a 2-thiacephem having the general formula II as above defined and wherein the carbon at position 6 has the R configuration to give a sulphone having the general formula III
,0 R //~1 S.
S

Y Ill wherein Rl, R2 and Y are as above.defined, and ring contracting the sulphone by extrusion of sulphur dioxide;
and, if desired, converting the resultant (5R) penem c~f the general formula I into another compound of the general.
formula I; and/or, if desired, converting the resultant compound of the general formula I into a salt thereof; and/
or, if desired, obtaining a free compound of the general formula I from a salt thereof.
The oxidation may be carried out using oxidizing agents usually used to convert an organic sulphide into the corresponding sulphone. Preferred oxidizing agents are peracids such as m-chloroperbenzoic,acid or peracetic acid. The reaction is generally performed in an inert solvent at a temperature of from 0 to 60°C, preferably from 4 to 30°C.
The ring contraction of the sulphone, urith loss of sulphur dioxide, may be effected simply by heating it in 1~,~~-~~3:~~
- to -an inert organic solvent such as chloroform or benzene.
The ring contraction may, in some cases, even occur spontaneously at room temperature. The.R configuration of the carbon atom in position 6 in the 2-thiacephem II
is retained throughout the process, so that (5R)-penems are obtained exclusively. It is noteworthy that, although loss of sulphur dioxide from thiosulphonates has occasionally been reported. (see, for example, W.L.F.
Armarego and E.E. Turner, ~. Chem. Soc. 1956, 1665;
A. Padwa and R. Gruber, ~. Org. Chem. 35, 1970, 1781), this reaction has hardly any precedent as yields and mildness of operative conditions are concerned and for the first time it has been applied in the synthesis of S-lactam compounds. The present invention also provides routes to obtain the required compounds of formula II
possessing the (5R) configuration.

~2:~4~3;~1 - m -According to the invention, the compounds of the general formula II are prepared by either of the routes shown in the following reaction scheme wherein:
Rl, R2 and Y are as defined above, Z represents i) a group of the formula SRS wherein R~ represents an alkyl group having from 1 to 8 carbon atoms, a phenyl or tolyl group, or, preferably, a hetero-cyclic group, especially a 2-benzothiazolylthio or 1-methyl-tetrazol-5-yl-thio group, i:i) a group of the formula SCORB wherein R8 represents an optionally substituted lower alkyl group, preferably a methyl group, ii:i) a group of the formula -NyOR9' wherein R9 and R10 15 independently represent lower alkyl or aryl groups, or together with the dicarboxyamino gxoup form a heterocvclic zing, preferably a succinimido or phthalimido group, or i~,r) a group of the formula -S~-R~, wherein R~ represents 20 an optionally substituted lower alkyl or aryl group, preferably a methyl, phenyl or p-tolyl group; and L represents a halogen atom, an alkane sulphonyloxy group or an arene sulphonyloxy group, preferably a 25 methanesulphonyloxy group.

1~S48~1 R
SZ

IV
N
~ CH3 .
H ,~ C02R2 Z~SR~
R~ SZ V R VI
yH2 1 ~ SZ
~ OH
!N Y I
O V N
G ~ CH3 . CC~2R2 . .

OH
N ' / Y ~
pi ~ v ~~ / ~ CH3 C02R2 ~ _ C02R2 R1 SZ I, IX ZI tY=H) N ~'' ' O

II

., iWD~~:~1 1 - 13a -In one of its aspects the present invention, provides a process for the preparation of a 2-thiace-phem.derivative of the general formula II:
R1 S\ S .
w N j .Y II~ - .

Z0 wherein Rl represents a~ hydrogen atom,~an alkyl group having 1 to 12 carbon atoms, or a cycloakyl group hav- ' ing 4 to 7 carbon atoms, said alkyl and cycloalky groups woptionally substituted by hydroxy, protected hydroxy, amino, protected amino, mercapto, prcte~cted mercapto or cyano;
R2 represents a hydrogen atom.~or a carboxy protecting group and Y represetns a hydrogen atom, ~a halogen atom, a hydroxy, formyloxy, acetoxy, carbamoy-loxy, N-(tricnloroacetyl) carbamoylozy or l-pyridin.ium 2p group, or a 1-pyridinium group substituted in the mesa . or para posit.ion~with a -CO-NH2 grouF., comprising a process selected from:
(a) a process for the pre~~aration of a . 2-thiacephem derivative of the general , formula II above wherein R1 and R2 are .
v as defined above and Y represents a halogen,atom characterized 'in that a compound of general formula IV:

~'1 C
1~,.)4~;j.~
1 - 13b -SZ

N

.~

wherein R1, R2 are as above defined and Z represents:
(i ) a group of the formula SR.~ wherein R?
represents an alkyl group having from 1 to 8 carbon atoms, a phenyl or tolyl group, or a 2-benzothiazolylthio or 1-methyl-tetrazol-5-yl-thio group, -(ii) a group of the formula SCORB wherein R8 represents a lower alkyl group, ~OR g (iii) a group of the formula -N~ , wherein R9~and R10 independently represE:nt lower alkyl or aryl groups, or together with the dicarboxyamino group form a succinimido or phthalimido group, or ~~
(iv) a group of the formula -S-R~, whe~.vein R~ represents a lower alkyl ar_ aryl group;
is first halogenated to obtain the compound of general formula V:

1 - 13c -V
N .Y

'CO2R2 wherein R1, R2, and Z are as above defined and Y is a halogen atom, and subsequently ozonolyzed to give a compound of general formula VII:

OH
I VII
N Y
~,/

wherein R1, R2, and Z are as defined above and Y is a halogen atom, transforming the hydroxy group into a L group, wherein.L represents a halogen atom, an alkane sulphonyloxy group or an arenesulphonyloxy group, so to obtain a compound of ~leneral formula IX:

L
IX
N Y

2.5 wherein R1, R2, Z and L are as defined above and Y is a halgen atom which is subsequently cyclized to give the desired compound;

l;~;i4~3:~3~
1 - 13d -(b) a process for preparing a 2-thiacephem deriviative of the general formula II above wherein R1 and R2 are as defined above and Y
represents a hydrogen atom charaterized in that a compound of general formula IV:

N IV
'~CH3 H ~C02R2 wherein R1, R2,~:and Z are as defined above is first azonolyzed to give a compound of the general formula VI:

OH
N VI
' ~CH3 wherein R1, R2, and Z are as defined above, converting ';.he hydroxy group into a L group, wherein L is as de-:pined above, to obtain the compound of general formula 'JIII:

L
i N VIII

~.~::~4~~~.
1 - 13e -wherein Rl, R2, Z and L are as defined above, which is subsequently cyclized by treatment with a salt of H2S
with an organic or inorganic base to the desired compound;

(c) a process for the preparation of a 2-thiacephem derivative of general formula II
above wherein R1 and R2 are as defined above and Y is a halogen comprising process (b) above wherein the resultant product of pro-cess (b) is halogenated to give the des:i.red compound;
(d) a process for the preparation of a 2-thiacephem derivative of the general formula 15 II above wherein Rl and R2 are as defined above and Y is a hydroxy group, comprising either process (a) or process (c) above wherein the resultant product therefrom,dis-solved in an acetone-water mixture (2:1 v/v) 20 is reacted for 15 mintues at a temperature of 0°C with a salt of a strong inorganic acid thus obtaining a labile ester of said inor-ganic acid which subsequently hydrolyzes in the same reaction medium to the desired com-25 pound;

1;~;~ ~ x:31 1 - 13f (e) a process for the preparation of a 2--thiacephem derivative of the general formula II above wherein Rl and R2 are as defined above and Y is a formyloxy or acetoxy group, comprising either process (a) or process (c) above wherein the resultant product therefrom, dissolved in dichloromethane is treated. at a i:emperature of 5°C and at daily intervals for. 3 days with a suitable salt of the cor~
re:~ponding carboxylic acid to ..give the de-si;~ed compound ;
(f) a process for the preparation of a 2-thiacephs~n derivative of the general formula II above wherein R1 and R2 are as defined abave and Y is a carbamoyloxy group, compris-ink process (d) above whexei.n the resultant product therefrom, dissol~~ed in dichlorome-thane, is treated, at a temperature of =40'C, with a tr~chloroacetylisocyanate, raising the reaction mixture it, room i:emperature and sub-sequently isolating the desired 2-thiacephem derivative of formula II, wherein R1, R2 are as above defined and Y is a N-trichloroacetyl carbamoyloxy group which, if desired, is sub-mitted to the deprotection of the trichlora-acetyl moiety of the first formed urethane t 1~5~~;31 1 - 13g -adduct by stirring for 20 hours its methanolic solution with silica gel, so to obtain the 2-thiacephem deriviative of formula II, where-in Rl, R2 axe as above defined and Y is a car-bamoyloxy group; and (g) a process for the preparation of a 2-thiacephem derivative of the general formula II above wherein R1 and R2 are as defined above and Y is a 1-pyridinium or a 1-pyrid-inium group substituted in t:he meta or para position with a .-CO-NH2 group, comprising process (a) or process (c) above wherein the resultant product therefrom, is reacted at room temperature with pyridine, nicotinamide or isonicotinamide to give, respectively, after purification by silica gel chromato-graphy, the desired 2-thiacephem compounds product of forrt~ula II, wherE:in R1, R2 are as above defined and Y is a 1-pyridinium group or a 1-pyridinium group substituted in meta or para position by a -CO-NH2 group.

The group Y in the compounds of the.general formulae V, III, IX and II may, if it represents a halogen atom, be optionally transformed into any of the other groups which Y may represent except a hydrogen atom. According to a preferred feature of the invention, this transformation is preferably carried out on the compounds of the general formula zI.
The transformation into a group L of the hydroxy group in the enol 'VI or VITI, which may be in equilibrium with the corresponding keto-tautomer, is preferably a mesylation. We have surprisingly found that, when this reaction is carried out in tetrahydrofuran instead of the ubiquitously used halogenated hydrocarbons, mesylates IX or 'VTII having Z alkene geometry, which are the most suitable ones for the subsequent cyclization, are almost exclusively obtained (similar transformation perfoxned in dichloromethane usually affords a 1:1 mixture of E, Z isomers: see T.W. Doyle, et al. 'Can. J. Chem. 1977, 55, 2873; N:.J. Pearson, J. Chem. Soc., Chem. Comm. 1981, 9~7% P-C. Cherry et al. J. Chem. Soc., Chem. Comm. 1979 663). Cyclisation of VIII or ZX may be carried out in a single step, by reaction with a sulphide or hydro-sulphide, such as Na2S, NaHS, Bu9NHS, or with H2S in the presence of a base such as triethylamine or pyridine.
The cyclisation of IX or VIII wherein Z represents a group other than SR7 offers the clear advantage of releasing ~~.~4~~~
_ 15 _ easily separable, usually water soluble by-products 2H
(e.g. phenylsulphinic acid, succinimide), instead of by products R3SH (e. g. mercaptobenzthiazole) which usually require chromatographic separation or precipitation as heavy metal salts (Age, Pb2~).
Against any reasonable expectation, which would rule out the possibility of ha.logenating the 3-methyl group of the compounds Ii (Y=H) owing to the presence of. the disulphide moiety, we have found a method to effect:
such transformation in high yield. We can thus obi:ain the compounds II (Y=halogen), which are invaluable intermediates for the synthesis of highly active pc~nem antibiotics i. A preferred halogenating reagent f~~r such transformation is h-bromosuccinimide, which i;a best used in the presence of a radical initiator, such 'as azobisisobutyronitrile or benzoyl peroxide in the presence of acid scavengers, such as epoxides(e.g.
propylene oxide), alkaline-earth oxides,(e.g. calcium oxide), or molecular sieves, in solvents such as benzene or carbon tetrachloride, ethyl formate at xemperature ranging from 20°C to 130°C.
The compounds II (Y=halogen)can be converted into compounds IT (Y= an organic group) by reactions known e~ r-se; e.g.
1) a compound II (Y=Br or C1)can be converted into a compound II (Y=free or protected OH) by mild ~~548~1 alkaline hydrolysis, or by reaction with .cupxous oxide/dimethylsulphoxide/water or by xeaction 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 estex may be hydrolyzed, subsequently or in the .same reaction medium, to the desired parent alcohoJ_. Preferred salts of this type are AgN03, A.gC109, NaNO3;
2) a compound IT (Y=Br or C1)can be converted into a compound II (.Y= an unsubstituted or N-alkyl substii:uted carbamoyloxy group) by conversion into a compound of II CY=OH) as described abpve followed by reaction with a suitable isocyanate;
for ex~unple, tr3chloroacetyl isocyanate is a preferred reagent for obtaining compounds II
CY=OCO1JH2) , following deprotection ~of the trichloroacetyl moiety on the first foamed urethane adduct;
3) a compound II (Y=Br or C1)can be converted into a compound II (,Y= acyloxy) by reaction with a suitable salt of the corresponding carboxylic acid in a suitable solvent ox under phase-transfer catalysis; or by conversion into a compound IZ (Y=OH) followed by conventional acylation;
9) a compound II (Y= Br or C1) can be converted 1~54~~1 _ 17 _ into a compound II ~Y-S-Het) by reaction with the corresponding HS-Het in the presence of a base, or with a preformed salt of HS-Het with a base, in a suitable solvent, such as tetrahydro-furan, acetone, acetonitxile or dimethylformamide.
suitable base is txiethylamine; a suitable preforrned salt is a sodium salt, e.g. sodium 1-methyl-1,2,3,4-tetrazol-5-yl-mercaptide.
Owing to the pronounced propensity of 3-hydroxvmethyl-2--~iacephem-4-~~axboxylates to lactonize, it is preferable that in the process 1) described above R2 represents a somewhat bulky group, forming with the linked carboxy moiety an ester possessing a relative inextness to«ards nucleophilic ~ittack by the neighbouring hydroxy group, e.g. a tert-bui:yl ester. Alternatively, it may be convenient to deprotect the hydroxy group from a protected form thereof after the ring-contraction step to the corresponding penem I, since 2-hydroxymethylpenem-carboxylates do not lactonize easily. For ex~snple, a 2p compound II (Y=-Bx) may be converted into a compound II
(Y=ON02), which may eas.~ly be isolated, purified if necessary, desulphurized to the corresponding penem I
whose reductive hydrolysis (e. g. Zn/CH3COOH) affords without problems the free hydroxy derivative.
Owing to the different stability of the penem and 2-1~,5~~3;~1 - 1a -thiacephem nucleus towards the conditions required for -COOR2 ester hydrolysis, a distinct advantage of the invention is that ester hydrolyses not compatible with a penem can be performed on the 2-thiacephem precursor, and the ring contraction may be performed on the free acid, or on a salt with an organic or inorganic base, or on a different labile ester, which can be prepared in situ, if desired; e.g. a trimethylsilyl, t-butyldimethylsilyl, or t-butyldiphenylsilyl ester.
The following Examples illustrate the invention. The abbreviations Me, But, Ph, Ms, pNB, THF, EtOAc, DMSO, MeCN, stand respectively far methyl, t-butyl, phenyl, methansulphonyl, 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 90 MHz; separation of inner lines of AB quartets are referred to spectra taken on the latter.

r 1~;~~~891 1 Example 1 Diphenylmethyl ~6,6-dibromopenicillanate , - ti 6r . --~ 6r~ .
~~(.oZH '~ N ~ ~?~H~Z
6,6-Dibromopenici7.lanic acid (90 g) in acetonitrile (450 ml) was treated with ~~ solution of diphenyldiazomethane (49 g) in the same solvent (150 ml). After 1 hour at 20°C the formed solid was collected by filtration and washed with small portions of col~
ethyl ether, thus obtaining 116 g of title product. A second crop (9 g) was obtained by evaporation of the mother liquors and trituration with ethyl ether; yield 95%.
An analytical sample was obtained by crystallization from chloro-form; mp 15?-158a ~ (CHCl film) 1800, 1750 cm 1;
max 3 _ ~ (CDC13) 1.24 and 1.58 (eac:h 3H, s, CMe2), 4.61 (1H, s, N.CH.CO), 5.80 (1H, S, N.CH.S), Ei.91 (1H, s, OCH), and ?.30 ppm (1,OH, s, Ar).
'Found: C, 47.80; H, 3.63; N, 2.64; S, 5.95; Br, 30.49°x.
C21H19Br2N035 requires C, 48.02; H, 3.64; N, 2.67; S, 6.10;
Br, 30.43ro.

1~:i4~3~1 1 Example 2 Tert-butyl 6,6-dibromopenicillanate ~r Br Br "'~ , ~ 8r S '..
o t ~' X02 f~! ° N '' ~Bu Method A) 6,6-Dibromopenici~llanic acid (100 g) in ethyl ether (1 1) at 0°C was sequentially treated with triethylamine (3? ml) and PC15 (56 g). After~l hour stirring, the reaction mixture was evaporated un3er vacuum (dry benzene added and removed) and the crude acyl chloride dissolved in dichloromethane - 10 (200 ml) and stirred for 24 hours with tert-butanol (500 ml) in the presence of CaC03 ( 50 g ) . -rne suspemucu ~n~ .-~ ...-~ .-then filtered off and the solution was washed with aqueous NaHC03 (some unreacted-starting material could be recovered by back-extracticn of the acidified aqueous washings), decolori-15 zed with charcoal and evaporated to afford the title product, which was then crystallized from diisopropyl ether, 69 g (60%);
mp 120-121°C, ~/ (CHC13 film) 1800 and 1140 cm 1; C~ (CDC13) m ax 1.98 (15H, s, But and CH3), 2.05 (3H, s, CH3), 4.38 (1H, s, N.CH.CO), and 5.70 (1H, s, N.CH.S) ppm.

. 1;~;~4~~1 Method B) 6,6-Dibromopenicillanic acid (15 g) in dichloromethane (300 ml) was stirred overnight with 0-tert-butyl-N,N-diisopropyl-isourea (25 g). The reaction mixture was filtered and the solution washed with aqueous NaHC03.
Crystallization of the product from diisopropyl ether gave the title compound, 8 g (47p).

v 12;i4~;~1 1 Example 3 Diphenylmethyl 6d-bromo-6(~-~1(R)-hydroxyethyl,~-penicillanate Oy ~r B~ ~ ~ : S
N
coZCNp~z o'-N -.c~a~cHP~~
Diphenylmethyl 6,6-dibromopenicillanate (120 g) in dry distilled THF (900 ml) under nitrogen at -75°C was treated with a solut-ion of ethylmagnesium bromide in ethyl ether (1 molar equivalent After 20 min at -75°C, acetaldehyde (25.. ml) was added and the mixture further stirred for 20 min at -?5°C. After quenching with saturated aqueous NH4C1 (1E00 ml), partition between water and ethyl ether, followed by removal of the solvent, left the crude product which wa;~ fractionated by silica gel chromatography (benzene-gthyl acetate) to afford the'title compound, 67 g (60~), as a foan, crystallizable(diiso-propyl ether) to a solid, mp 65-70~ ~ m~~ (film) 3450, 1?85 and 1740 cm 1; ~ (CDC13) 1.22 and 1.60 (each 3H, s, CMe2), 1.29 (3H, d, J= 6Hz, CH3.CH), 2.90 (1H, d, OH), 4.17 (1H, m, CH3.CH.OH), 4.58 (1H, s, N.CH.CO), 5.49 ~;lti, s, N.CH.S), 6.90 (1H, s, OCHPh2), and 7.3 (lOH, s, Ar) ppm.
By using a similar procedure, and starting from tert-butyl 6,6-dibromopenicillanate, there was obtained tert-butyl 6at-bromo-6(~-~1(R)-hydroxyethylJ-penicillanate in 65b yield after 1~5~~~1 crystallization from diisopropylether/hexane; mp 93-95°C (dec);
(CDC13) 1.28 (3H, d, J= 6Hz, CH3.CH), 1.54 (12H, s, But and CH3), 1.65 (3H, s, CH3), 2.65 (1H, s, CH.OH), 4.25 (1H, m, CH3.CH(OH).CH), 4.40 (1H, s, N=CH.CO), and 5.51 ppm (1H, s, N.CH.Sj.

1~:~4~~1 1 Example 4 Diphenylmethyl 6c~-~1(R)-hydroxyethylJ-eenicillanate-1-oxide off O
S
. ' ,'G~CHP~'Z ~~N ~~~2~~~2 Diphenylmethyl 6a(-bromo-6~-(1(R)-hydroxyethyl"/-penicillanate (52 g) in 95°~ ethanol (400 ml) was hydrogenated at 30 Psi in the presence of 10°~ Pd/CaC03 (25 g) and CaC03 (11 g). The reaction mixture was filtered and evaporated to afford a residue which was partitioned between brine and dichloro-methane. Removal of~the solvent left crude diphenylmethyl 6d li(R)-hydroxyethyl~-penicillanate, which was oxidize d with 85°~ MCPBA (17 g) in 500 ml of chloroform at O-5°C for 1 hour. The filtered solution was then washed with aqueous NaHC03 and the solvent removed to leave the crude title product as a foam, 40 g (88~), which can be used as such or purified . by silica gel chromatography; ~m~ (CHC13 film) 1790 and 1?50 cm 1; ~ (CDC13) 0.94 and 1.67 (each 3H, s, CMe2), 1.3?
(3H, d, J= 6Hz), 3.55 (iH, dd, J= 2 and 6.5Hz, CH. CH.CH), 4.25 (1H, m, CH3.CH(OH).CH), 4.64 (1H, s, N.CH.CO), 4.98 (iH, d, J= 2Hz, C~1.CH.S), 6.98 (1H, s, OCHPh2), and 7.30 (lOH, s, Ar) ppm.
By using a similar procedure, and starting from tert-butyl 6o~-bromo-6~-~(R)-hydroxyethy ~-penicillanate, there was obtained (75~) tert-butyl 6 -~1(R)-hydroxyethyl,~-penicilla-pate-1-oxide; (film) 3440, 1?85 and 1?40 cm 1.
Ymax ' 1~:i4~~1 1 Example 5 Diphenylmethyl 6d- -~(R)-tent-butyldimethylsilyloxyethyl~-penicillanate-1-oxide ' OH ~ O.~l'~28~
r~ H S ~~~ .S
,_, ~
o N '~ CO~CNP~2 Crude diphenylmethyl 6d-~(R)-hydroxyethylJ-penicillanate -1-oxide, as obtained in Example 4 (40 g), was dissolved in DMF (350 ml) and stirred for 3 hours a.t 50-55°C in the presence of imidazole (18.5 g) and tert-butyldimethylsilyl-chloride (27 g). The reaction mixture was. partitioned between ethyl ether and brine and the organic layer washed several timeswith water. Evaporation of the solvent and silica gel chromatography afforded the title product:, 22. g; ~ m~ (CHC13 film) 1790 and 1755 cm 1; ~ (CDC13) 0.06 .(6H, s, SiMe2), 0.88 (13H, s, But and CH3), 1.3 (3H, d, ;I= 6Hz, CH3.CH), 1.7 (3H, s, CH3), 3.4- (1H, dd, J= 2 and ~~..SHz., CH. CH.CH), 4.40 (1H, m, CH3._CH.CH), 4.55 (1H, s, N.(:H.CO), 4.88 (1H, d, J= 2, CH. CH. S), -6.9 (1H, s, OCHPh2), and 7.25 ppm (lOH,.s, Ar).
By using a similar procedure and starting from tert-butyl 6o(-I1(R)-hydroxyethy ~-penicillanate-1-oxide, there was obtained 1~;~4~~1 ' - 26 -1 tert-butyl 6 -~1(R)-tert-butyldimethylsilyloxyethyl"~-penicilla nate-1-oxide in overall 55~ from the E~-bromo precursor;
_ m ax (CHC13 film) 1785 and 1750 cm l; ~,,~ (CDC13) 0.06 (6H, s, SiMe2), t 0.88 (9H, s, SiBu ), 1.25 and 1.66 (each 3H, s, CMe2), 1.28 t (3H, d, J= 6Hz, CH3.CH), 1.45 (9H, s, OBu ), 3.5 (1H, dd, J= 2 and SHz, CH.CH.CH), 4.4 (iH, s, N.CH.CO), 4.5 1H, m, CH3.CH.CH), and 4.9 ppm (1H, d, J= 2Hz, CH. CH. S) ~;~~4~3~1 _ 27 _ 1 Example 6 Diphen~lmethyl 6o~-~R ) -p-n i t rob enzyl oxycarbonyl oxyethyl~-penicillanate-1-oxide OH o ~COt pNB o S ~,' H T
H .-= '~'~ 5 .
, ~.
o~" -wCOZCNP~z o ''~~NP~Z
Diphenylmethyl 6d-~(R)-hydroxyethy~ penicillanate-1-oxide was acylated with p-nitrobenzylchlorocart>onate by using N,N-dimethylaminopyridine as a base and ethanol-free dichloro-methane as solvent, according to a general method, thus .
obtaining the title product as a foam; ~ (CDC13) 0.96 and 1.70 (each 3H, s, CMe2), 1..52 (3H, d, J= 6Hz, CH3.CH), 3_83 (1H,'dd, J= 2 and 6Hz, CH. CH.CH), 4.66 (:LH, s, N.CH.CO), 4.99 (1H, d, J= 2Hz, CH. CH. S), 5.28 (2H, s, OCH2Fh), 5.35 (1H, m, CH3.CH.CH), 7.01 (1H, s, OCHPh2)t 7.40 (lOH, m, Ar),

7.55 and 8.26 ppm (each 2H, d, J= BHz, A.r).
By following the same experimental procedure, there was obtained tent-butyl 6o~-~(R)-p-nitrobenzyloxycarbonyloxy-ethyl~-penicillanate-1-oxide 1~:i4~;~~

1 By following similar experimental procedures, and using trichloroethylchlorocarbonate instead of p-nitrobenzylchloro-carbonate, these were also obtained:
tert-butyl 6~(-/1(R)-p-nitrobenzyloxycarbonyloxyethylT-penicillanate-1-oxide diphenylmethyl 60(-/1(R)-p-nitrobenzyloxycarbonyloxyethyl/-penicillanate-1-oxide 1;~54~~1 1 Example ?
3(S)-~(R)-h~drox~ethylJ-4(R)-benzthiazolyldithio-1-(1-methoxycarbonyl-2-methyl-1-prop-2-eriyl)-azetidin-2-one ON o S_SJS~ C.~
I s .., -.t . I
N o ~-a D '' ~,oz G~3 H 'coz c.~t3 A mixture of methyl 60(-~1(R)-hydroxyethyl7-penicillanate -1-oxide (5 g) and 2-mercaptobenzthiazole (3.04 g) was refluxed for 2 h in dry toluene. The solvent was removed in vacuo and the crude product used as such for the next step.
By using a similar procedure, there were obtained:
3(S)- 1(R)-tent-butyldimethylsilyloxyethyl>-4(R)-benz-thiazolyl-1-(1-methoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin-2-one, starting from methyl 60(-~1(R)-tert-butyl-dimethylsilyloxyethyl,~-penicillanate-1-oxide, and prolong-ing the reaction time up to 6 h; y m~ (CHC13 film) 1?70 and 1?44 cm 1; ~ (CDC13) 0.02 and 0.04 (each 3H, s, SiMe2) 0.84 (9H, s, SiBut), 1.23 (3H, d, J= 6Hz, CH3.CH), 1.91 (3H, s, =C.CH3), 3.38 (1H, dd, J= 2 and 3.5Hz, CH. CH.CH), 3.69 (3H, s, OCH3), 4.23 (1H, m, CH3.CH.CH), 4.82 (1H, s, N.CH.CO), 5.0? (2H, m, CH2=C), 5.42 (1H, d, J= 2Hz, CH. CH. S), and ?.2-7.9 ppm (4H, m, Ar);

1;~54~~1 1 3(S)-~l(R)-hydroxyethyl/-4(R)-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin -2-one, starting from diphenylmethyl 6~-L1(R)-hydroxy-ethyl/-penicillanate-1-oxide; ym~ (CHC13 film) 3400, 1?65 and 1740 cm 1; ~ (CDC13) 1.22 (3H, d, J= 6Hz, CH3.CH), 1.60 (3H, s, =C.CH3), 2.78 (iH, br s, OH), 3.42 (1H, dd, J= 2 and 6Hz, CH. CH.CH), 4.18 (1H, m, CH3.CHOH.CH), 4.93 (1H, s, N.CH.CO), 4.90-5.10 (2H, m, CH2=C), 5.38 (1H, d, J= 2Hz, CH.CH.S), 6.89 (1H, s, OCHPh2), and 7.15-7.90 ppm (14H, m, Ar);
3(S)-/1(R)-tert-butyldimethylsilyloxyethvl%-4(R~-benz-t_hiazolyldithio-1-(1-tert-butoxycarbonyl--2-methyl-1-prop-2-enyl)-azetidin-2-one, starting from test-butyl 6u(-/1(R)-tert-butyldimethylsilyloxyethyl/-penicillanate-1-oxide;
reaction time 6 h; ~ (CDC13) 0.06 (6H, s, SiMe2), 0.9 (9H, s, SiBut), 1.26 (3H, d, J= 6Hz, CH3.CH), 1.48 (9H, .
s, OBut), 1.95 (3H, s, =C.CH3), 3.40 (1H, dd, J= 2 and 4Hz,.CH.CH.CH), 4.20 (1H, m, CH3.CH.CH), 4.?1.(1H, s, N.CH.CO), 5.1 (2H, br s, CH2=C), 5.42 (1H, d, J= 2Hz, CH. CH. S), and ?.2-?.9 ppm (4H, m, Ar);
3(S)-/1(R)-tent-butyldimethylsilyloxyeth;,rl/-4(R?-benzthia-zolycldithio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin-2-one, y m~ (film) 1??2 and 1743 cm ;
t (CDC13) 0.05 (6H, s, SiMe2), 0.80 (9H, s, SiBu ), 1.29 (3H, d, J= 6Hz, CH3.CH), 1.95 (3H, s, =C.CH3), 3.45 (1H, dd, J= 2 and 4Hz, CH. CH.CH), 4.26 (1H, m, CH3.CH.CH), 4.95 (1H, s, N.CH.CO), 5.08 (2H, ABq, separation of inner lines 5Hz, CH2=C), 5.55 (1H, d, J= 2Hz, CH.CH.S), 6.93 (iH, s, OCHPh2), and 7.1-8.0 ppm (14H, m, Ar);

1254~~1 1 3(S)-~1(R)-trichloroethoxycarbonyloxyethyl/-4(R)-benzthiazolyl-dithio-1-(1-methoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin -2- -one, starting from methyl 6~-/1(R)-trichloroethoxycarbonyl-oxyethyl/-penicillanate-1-oxide; ym~ (CHC13) 1775 and 1745 cm 1; ~ (CDC13) 1.48 (3H, d, J= 6Hz, CH3.CH), 1.91 (3H; s, =C.CH3), 3.69 (3H, s, OCH3), 3.70 (1H, dd, CH. CH. CH) 4.68 (s, 2H, OCH2), 4.?6 (1H, s, N.CH.CO), 5.03-5.30 (2H, m, CH2=C), 5.23 (1H, m, CH3.CH.CH), 5.32 (1H, d, J= 2Hz, CH. CH. S), and ?.10-?.96 ppm (4H, m, Ar);
and, in a likenise>. fashion, starting from the corresponding tert-butyl and diphenylmethyl penicillanates, 3(S)-~(R)-trichloroethoxycarbonyloxyethyl/-4(R)-benzthiazolyl-dithio-1-(1-tent-butoxycarbonyl-2-methyl-1-prop-2-enyl)-aze-t; ri; n-7-cane 3(S)-L1(R)-trichlo roethoxycarbonyloxyethyl%-4(R)-benzthiazolyl-dithio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin-2-one;
and, starting from methyl 6~-/1(R)-tert-butyldimethylsilyloxy-ethyl/-penicillan.ate-1-oxide, 3(R)-~1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-benzthiazolyl-~tithio-1-(1-metho:Kycarbonyl-2-methyl-1-prop-2-enyl)-azetidin -2-one.

1;54891 1 Example 8 3(S)-L1(R)-hydroxyethylJ-4(R)-benzthiazolyldithio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one OH ~ DI-I
o ~~ s_s --~~~ ~
s ~~
~s --.
O~-r~ N (z GH
~°1~~3 coZcH3 The crude 3(S)-~1(R)-hydroxyethyl~-4(R)-benzthiazolyl-dithio-1-~1-methoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin -2-one as obtained in Example 6 was diss~~lved in dry dichloro-methane (300 ml) and treated with a stre.3m of ozone at -70°C
until TLC showed that all the starting material had reacted.
The solution was purged with nitrogen an~j then sodium meta-bisulphite (10 ~) was added at -30°C. Th°_ mixture was let rise to room temperature under vigorous stirring, then filtered. The solution was washed with a~3ueous 4°~ NaHC03, dried over Na2S04 and evaporated. The re~~idue was taken up in ethyl ether, the undissolved matter filtered off and the solution was evaporated to give the crud= title product.
An aliquot was purified by flash chrornat~~graphy over silica gel (ethyl acetate-cyclohexane mixture a~~ eluants);
c5 (CDC13) 1.35 (3H, d, J=~7Hz, CH3.CH), 2.11 (3H, s, CH3), 2.75 (1H, br s, OH), 3.44 (1H, dd, J= 2.0 and S.OHz, CH. CH.CH), 3.79 (3H, s, OCH3), 4.26 (1H, m, CH3.CH.CH), 5.29 (1H, d, J= 2.OHz, CH. CH. S), and 7.25-?.95 ppm (4H, m, Ar).

12~~~91 1 By using a similar procedure, there was obtained:
3(S)-~l(R)-tert-butyldimethylsilyloxyethyl7-4(R)-benzthiazolyl-dithio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin -2-one, starting from crude 3(S)-~1(R)-tert-butyldimethyl-silyloxyethyl7-4(R)-benzthiazolyldithio-1-(1-methoxycarbonyl -2-methyl-1-prop-2-enyl)-azetidin-2-one; ,~ (film) 3350, _ max 1770 and 1660 cm 1; ~ (CDC13) 0.05 and 0.07 (6H, each s, SiMe2), 0.87 (9H, s, S:But), 1.27 (3H, d, J= 6.5Hz, CH3.CH), 2.0? (3H, s, =C.CH3). 3.33 (1H, dd, J= 2.2 and 4.2Hz, CH. CH.CH), 3.74 (3H, s, OCH3), 4.26 (1H, m, CH3.CH.CH), 5.36 (1H, d, J= 2.2Hz, CH. CH. S), 7.2-?.9 (4H, m, Ar), and 12.37 ppm (1H, br s, OH);
3(R)-,(1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-benzthia-zolyl~3ithio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azeti3in-2-one, starting from 3(R)-11(R)-tert-butyldimethyl-silyloxyethyl7-4(R)-benzthiazolyldithio-1-(1-methoxycarbonyl -2-methyl-1-prop-2-enyl)=azetidin-2-one; J (film) 3200, _ max 1773, 1710, 1665 and 1620 cm 1; C5(CDC13) 0.20 (6H, s,.SiMe2), 0.94 (9H, s, SiBut), 1.52 (3H, d, J= 6Hz,-CH3.CH), 2.17 (3H, 'Sr s, =C.CH3), 3.6-3.7 (4H, s+dd, OCH3 and CH. CH.CH), 4.4 (1H, m, CH3.CH.CH), 5.25 (1H, d, CH.CH.S), and 7.3-7.9 ppm (4H; m, Ar);
3(S)-/1(R)-hydroxyethyl/-4(R)-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin -2-one, starting from crude 3(S)-L1(R)-hydroxyethyl/-4(R)-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-methyl -1-prop-2-enyl)-azetidin-2-one; ~max (CHC13 film) 3400, 1770, 1730 and,1650 cm ;

~.;~.',;a~~~1 1 3(S)-/1(R)-tent-butyldimethylsilyloxyethyl/-4(R)-benz-thiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one, starting from crude 3(S)-/1(R) tent-butyldimethylsilyloxyethyl/-4(R)-benzthiazolyldithio -1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin-2-one; ym~ (CHC13 film) 3400, 1775, 1735, 1700 sh, 1655, and 1610 cm 1; ~ (CDC13) 0.06 (6H, s, SiMe2), 0.82 (9H, s, But), 1.26 (3H, d, J= 6Hz, CH3.CH), 2.08 (3H, s, =C.CH3), 3.33 (1H, dd, J= 2 and 5.5Hz, CH. CH.CH), 4.18 (1H, rn, CH3.CH.CH), 5.22 (1H, d, J= 2Hz, CH. CH. S), 6.86 (1H, s~, OCHPh2), and 7.2-7.9 ppm (14H, m, Ar);
3(S)-~'1(R)-trichloroethoxycarbonyloxyethyl%-4(R)-benz-thiazolyldithio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-~azetidin-2-one; (f (CDC13) 1.50 (3H, d, J= 6Hz, CH3.CN), 2.14 (3H, s, =C.CH3), 3.67 (1H, dd, J= 2.2 and 5.5Hz, CH.CH.CH), 3.82 (3H,.s, OCH3), 4.62 (2H, ABq, J= 12 Hz, separ~.tion of inner lines 2Hz, OCH2), 5.10-5.40 (2H, m, CH3.Cr:.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 tert-butyl and diphenylmethylester, 3(S)-~1(R)-trichloroethoxycarbonyloxyethyl/-4(R)-benzthiazolyl-dithio-1-(1-tert-butoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one;
3(S)-/1(R)-trichloroethoxycarbonyloxyethyl/-4(R)-benzthiazolyl-dithio-1-(1-diphenylmethoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one;

~':~ ~ ~;~ 1 1 3(S)-~1(R)-tert-butyldimethylsilyloxyethyl%-4(R)-benzthiazolyl-dithio-1-(1-tent-butoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one.

12;~4~i:~1 1 Example 9 3(S)-/1(R)-hydroxyethyl/-4(R)-benzthiazolyldithio 1 (1 methoxycarbonyl-2-methylsulphonyloxy 1 prop 1 enyl) azetidin-2-one ON
CH
H
~ --~~N ~'~OH D ~ OMs cO2 CH3 A solution of 3(S)-~(R)-hydroxyethy~-4(R)-benzthiazolyl-dithi-o-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azeti-din-2-one (130 mg, 0.3 mmol) in anhydrous dichloromethane (8 ml) was sequentially tre.3ted at -40°C with triethylamine (0.043 ml, 0.3 mmol) and me-~hanesulphonyl chloride {0.024 ml, 0.31 mmol). The reaction wa~~ quenched after 5 minutes with cold aqueous 2% NaHC03. Removal of the solvent from the organic layer gave the crudE~ title product (quantitative yield), which was used as such for the next step.
By following the same experimental procedure, there was obtained:
3(S)-'1(R)-tert-butyldimethylsilyloxyethy~-4(R)-benzthiazolil-dithio-1-(1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1-enyl)-azetidin-2-one, starting from 3(S) ~(R)-tert-butyl-dimethylsilyloxyethy~-4(R)-benzthiazolyldithio-1-(1-methoxy-carbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one; an. aliquot of this product was purified by flash chromatography (silica gel; ethyl acetate-cyclohexane mixtures as eluant) to afford ~. ~c:,~ ~~ ~~ 1 1 the pure title compound as a 1:1 mixture of E and _Z isomers;
j~ m~ (film) 1885, 1730, 1363, and 1165 cm 1; ~ (CDC13) 0.05 and 0.10 (each 3H, s, SiMe2), 0.88 (9H, s, SiBut), 1.29 (3H, d, J= 6.5 Hz, CH3.CH), 2.20 and 2.53 (3H, each s, =C.CH3), 3.18 and 3.29 (3H, each s, S02CH3), 3.42 (1H, m, CH.CH.CH), 3.71 and 3.?8 (3H, each s, OCH3), 4.30 (1H, m, CH3.CH.CH), 5.59 and 5.64 (1H, each d, J= 2Hz, CH._CH.S), and ?.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 suppressied,and the pure _Z isomer thus collected;
(CDC13) 0.05 (6H, s, SiMe2), 0.88 (9H, s, SiBut), 1.29 (3H, d, J= 6.5Hz, CH3.OH), 2.53 (3H, s, =C.CH3), 3.29 (3H, s, S02CH3), 3.42 (1H, dd, J= 2 and 5Hz, CH. CH.CH), 3.71 (3H, s, OCH3), 4.30 (1H, m, CH3.CH.Ct1), 5.59 (iH, d, J= 2Hz, CH. CH. S), and 7.12-7.95 ppm ;4H, m, Ar).
By following this last procedure (tetrahydrofuran as a solvent in the mesylation step), there were obtained:
3(R)-/1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-benzthiazolyl-dithio-1-/1-methoxycarbonyl-c-methylsulphonyloxy-1-prop-1-(Z)-enyl%-azetidin-2-one, starting from 3(R)-/1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-benzthiazolyldithio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one;
y m~ (CHC13 film) 1?75, 1735, 1365 and 1165 cm 1; Cj (CDC1 0.18 (6H, s, SiMe2), 0.88 (.9H, s, SiBut), 1.42 (3H, d, J= 6.5Hz, CH3.CH), 2.33 (3H, s, =C.CH3), 3.05 (3H, s, S02CH3), 3.45 (3H, s, OCH3), 3.62 (1H, dd, CH.CH.CH), 4.3 (iH, m, CH3.CH.CH), 5.40 (1H, d, J= 5Hz, CH.CH.S), and 7.15-7.85 ppm (4H, m, Ar);

125 3~1 1 3(S)-(1(R)-hydroxyethyl/-4(R)-benzthiazolyldithio-1-L1-diphenylmethoxycarbonyl-2-methylsulphonyloxy-I-prop-1-(Z)-enyl/-azetidin-2-one, starting from 3(S)-/1(R)-hydroxyethyl/
-4(R)-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one; y (film) 3400, max 1?75, 1730, 1365 and 1170 cm 1; ~ (CDC13) 1.22 (3H, d, J= 6.5Hz, CH3.CH), 2.43 (3H, s, =C.CH3), 3.13 (3H, s, S02CH3), 3.35 (1H, dd, J= 2.5 and 4Hz, CH. CH.CH), 4.1 (1H, m, CH3.CH.CH), 5.40 (1H, d, J= 2.5Hz, CH.CH.S), 6.85 (1H, s, OCHPh2) and 7.1-7.9 ppm (14H, m, Ar);
3(S)-~1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-benzthiazolyl-dithio-1-(1-diphenylmethoxycar:~onyl-2-(Z)-methylsulphonyloxy -1-prop-1-enyl)-azetidin-2-one, starting from 3(S)-/1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-hydr~xy-1-prop-1-enyl)-azetidin-2-one; ~~ (CHC13 film) 177, 1725, 1370, and 1175 cm ;
(CDC13) 0.1 (6H, s, SiMe2), 0.9 (SH, s, SiBut), 1.28 (3H, d, J= 6Hz, CH3.CH), 2.5 (3H, s, =C.CH3), 3.25 (3H, s, S02CH3), 3.35 (1H, dd, J= 2.5 and SHz, CH. CH.CH), 4.20 (1H, m, CH3.CH.CH), 5.50 (1H, d, J= 2.5Hz, CH.CH.S), 6.9 (1H, s, OCHPh2), and ?.1-7.9 ppm (14H, m, Ar);
3(S)-/1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-benzthiazolyl-dithio-1-(1-tert-butoxycarbonyl-2-(Z)-methylsulphonyloxy-1~-prop-1-enyl)-azetidin-2-one, starting from 3(S)-L1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-benzthiazolyldithio-1-(1-tert-butoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one;

1254~3;~1 1 i~m~ (film) 17?3, 1710, 1370 and 1165 cm 1; ~ (CDC13) 0.06 (6H, s, SiMe2), 0.87 (9H, s, SiBut),~1.25 (3H, d, t J= 6Hz, CH3.CH), 1.49 (9H, si, OBu ), 2.45 (3H, s, =C.CH3), 3.25 (3H, s, S02CH3), 3.35 (1H, dd, J= 2.5 and SHz), 4.3 (1H, m, CH3.CH.CH), 5.60 (1H, d, J= 2.5Hz, CH.CH.S), and 7.1-?.9 ppm (4H, m, Ar);
3(S)-/1(R)-trichloroethoxycarbonyloxyethyl/-4(R)-benzthiazolyl-dithio-1-/1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1(Z)-enyl/-azetidin-2-one, starting from 3(S)-(1(R)-trichloro-1() ethoxycarbonyloxyethyl/-4(R)-benzthiazolyldithio-1-(1-methoxy-carbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one; Y
max -1 (CHC13 film) 1780, 1755 sh, 1730, 1380, 1250 and 1167 cm ;
(CDC13) 1.48 (3H, d, J= 6Hz, CH3.CH), 2.52 (3H, s, =C.CH3), 3.25 (3H, s, S02CH3), 3.72 (4H, s+dd, OCH3 and CH. CH.CH), 1-''~ 4.68 (2H, s, OCH2), 5.2 (1H, m, CH3.CH.CH), 5.47 (1H, d, J= 2.5Hz, CH. CH. S), and 7.1-7.9 ppm (4H, m, Ar);
and likewise, starting from the corresponding tert-butyl and diphenylmethyl esters, there was obtained:
3(S)-ll(R)-trichloroethoxy.carbonyloxyethylT-4(R)-benzthiazolyl-2C dithio-1-~1-tert-butoxycarbonyl-2-methylsulphonyloxy-1-prop-1(Z)~
enyl7 azetidin-2-one;
3(S)-~1(R)-trichloroethoxycarbonyloxyethyl%-4(R)-benzthiazolyl-dithio-1-L1-diphenylmethoxycarbonyl-2-methylsulphonyloxy-1-prop-1(Z)-enyl/-azetidin-2-one.

1;~~48;~1 _~,o-1 Example 10 3(S)-L1(R)-methylsulphonyloxyethyl,J-4(R)-benzthiazolyl dithio-1-(1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1-enyl)-azetidin-2-one OH N OSo2~
H
S_S'.1C ~~ H S_5~. ~l S ~ 5 i ~.~, ~~ ~/ o- " A~ Ut i~oN ~ 3 Co2GH3 CotcH3 When in the reaction described in Example 8 the starting materia~ywas exposed to an excess (2 molar equivalents) of methanesulphonylchloride / triethylamine, the title product was obtained as a foam in quantitative yield as a mixture of 1« E (20°x) 2.nd _Z (80i ) isomers;- ~m~ (film) 1780, 1733, 1360 and '1170 cm 1; ~ (CDC13) 1.58 (3H, d, J= 6Hz, CH3.CH), 2.22 and 2.56 (3H, each s, =C.CH3 of E and Z isomers), 3.00 (3H, s, CH3S02 on the hydroxyethyl chain), 3.20 (1H, dd, J= 2.2 and 4.5Hz, CH. CH.CH), 3.28 (3H, s, CH3S02 on 'the crotonic appendage), 3.76 (3H, s, OCH3), 5.11 (1H, m, CH3.CH.CH), 5.52 (1H, d, J=~ 2.2Hz, CH.CH.S), and 7.3~~-7.95 ppm (4H, m, Ar).
By following the same procedure, but using THF as a solvent, 3(S)-L1(R)-methylsulphonyloxyethy~.%-4(R)-benzthiazolyldithio--1-~l-diphenylmethoxycarbonyl-2-methylsulphonyloxy-1-prop-1-(Z) enyl7-azetidin-2-one was prepared and displayed the following 1~s4~~i 1 spectral data: ~~ ~ (film) 1777, 1728, 1360 and 1170 cm ;
(CDC13) 1.50 (3H, d, J= 6Hz, CH3.CH), 2.52 (3H, s, =C.CH3), 2.9 (3H, s, CH3S02 on the hydroxyethyl chain), 3.23 (3H, s, CH3S02 on the crotonic appendage), 3.62 (1H, dd, J= 2.5 and 5.5Hz, CH.CH.CH), 5.05 (1H, m, CH3.CH.CH), 5.45 (1H, d, J= 2.5Hz, CH.CH.S), 6.95 (1H, s, OCHPh2), and 7.10-7.95 ppm (14H, m, Ar).

1 Example il 3(S)-/1(R)-tent-butyldimethylsilyloxyethylJ-4(R)-benzthiazolyl-dithio-1-(1-methoxycarbonyl-2-trifluoromethylsulphonyloxy-1-Erop-1-enyl)-azetidin-2-one OS;HejBut OS~Me2~u~
$-S- ~S ~ H $ S-~~~I
~ ~N~/~c~H O~Y/~ZOSpZCF3 ~'.oZMe.
Crude 3(S)-/1(R)-t.ert-butyldimethylsilyloxyethyl7-4(R)-benz-thiazolyldithio-1-~(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one (3U0 mg) in THF (5 ml) at -40°C was sequentially treated with triei.hylamine (170 ul) and trifluoromethansulphonic anhydride (180 ul). Work-up and chromatography gave the two separate geometrical isomers of the title product, as foams:
. -1 E isomer: ym~ (C:HC13) 1778, 1730, 1420, 1215, and 1135 cm ;
t (CDC13) 0.08 (f~H, s, SiMe2), 0.86 (9H,.s, SiBu ), 1.26 (3H, d, J= 6Hz, Ctl3.CH), 2.05 (3H, s, =C.CH3), 3.46 (1H, dd, 2.2 and 4Hz, CH.CtI.CH), 3.81 (3H, s, OCH3), 4.28 (1H, m, CH3.CH.CH), 5.?6 I1H, d, J= 2.2Hz, CH. CH. S), and 7.25-7.90 (4H, m, Ar); Z isomer (inter alia) ~ (CDC13) 2.45 (3H, s, =C.CH3), 3.40 (1H, dd, J= 2 and 4Hz, CH.CH.CH), 3.64 (3H, s, OCH3), 4.30 (1H, m, CH3.CH.CH), and 5.65 ppm (1H, d, J= 2Hz, CH. CH. S).

- 43 - Z~J~~:~1.
1 Example 12 Methyl (?S,6R)-?-~1(R)-tent-butyldimethylsilyloxyethyl/-3-methyl-2-thiacephem-4-carboxylate ~S~ Het dug ~ Si HetBu s_5 ;/ 101 ~ s.s s~
~-N ~ S w./

~ ~~3 CoZ cH3 A solution of triethylamine (0.5 ml) in dichloromethane (10 ml) was saturated at -50°C with hydrogen sulphide.
After purging with nitrogen, 0.34 cc. of this solution was added to a cold (-50°C) solution of 3(S)-/1(R)-tert-butyl-dimethylsilyloxyethyl/-4(R)-benzthiazolyldithio-1-(1-methoxy-carbonyl-2-methylsulphonyloxy-1-prop-1-enyl)-azetidin-2-one (?5 mg, 0.121 mmol). , The mixture was allowed to warm up to room temperature and then washed with water, dried (Na2S04) and evaporated.
Separation of the new compound from the formed 2-mercapto-. benzthiazole and minor impurities was achieved by silica gel chromatography (ethyl acetate-cyclohexane as eluants), thus obtaining the title compound 2.s white crystals (19 mg, 200), mp 85-87°C, ~ m~ (EtOH') 223 (~ = 4,773), 2?7 (6,335), and 326 (2,922) nm, ~m~ (CHC13 film) 1?85 and 1730 cm 1;
t C~ (CDC13) 0.08 (6H, s, SiMe2), 0.88 (9H, s, SiBu ), 1.25 (3H, d, J= 6H2, CH3.CH), 2.22 (3H, s, CH3), 3.07 (1H, dd, J= 2.2 and 3.5 Hz, CH. CH.CH), 3.8 (3H, s, OMe), 4.36 (iH, m, CH3.CH.CH), and 4.62 ppm (1H, d, J= 2.2Hz, CH. CH. S).

1 Found: C, 49.08; H, 6.96; N, 3.52; S, 15.16. C16H27N04SiS2 requires C, 49.32; H, 6.99; N, 3.60; S, 16.46.
When, instead of H2S/NEt3, a solution of NaSH (0.9 mol equiv.) in DMF was used, and quenching (partition between H20 and EtOAc) followed within 1 minute at O°C, the isolated yield of the pure title product raised to 40-45°x.
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.
By following the same experimental procedure, methyl (7R,6R)-7-~1(R)-tent-butyldimethylsilyloxyethyl>-3-methyl-2-thiacephem-~1-carboxylate was obtained starting from 3(R)-/1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-benz-thiazolyldithio-1-(1-methoxycarbonyl-2-methylsulphonyloxy--1-prop-1-enyl)-azetidin-2-one; (film) 1785 and 1725 cm 1;
max ~~(CD3COCD3) 0.03 and 0.05 (each 3H, s, SiMe2), 0.84 (9H, s, SiBu.), 1.19 (3H, d, 6.5Hz, CH3.C1-i), 2.08 (3H, s, CH3), 3.72 (3H, s, OCH3), 4.11 (1H, dd, J= 5.5 and B.OHz, CH. CH.CH), 4.20 (1H, m, CH3.C'~I.CH), and 5.01 ppm (1H, d, J= 5.5Hz, CH. CH. S).

1~~4~391 1 Example 13 Methyl (7S,6R)-7-L1(R)-hydroxyethy~-3-methyl-2-thiacephem -4-carboxylate OH off N S_5~~~ ~~~ S~S
N
o'-~ ~OSUZUt3 O
CDICH~
(92c.u3 The crude 3(S)-/1(R)-hydroxyethyl%-4(R)-benzthiazolyldithio--1-(1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1-enyl)-azetidin-2-one (145 mg, 0.287 mmol), as obtained in Example 9, was dissolved in anhydrous dimethylformamide (2 mi) and treated at +20°C with a freshly prepared solution of NaHS
(16 mg, 0.28? mmol) in the same solvent(1.6 ml). The mixture was stirred for 2 minutes and then partitioned between ethyl acetate and water.
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 eluants) to give the pure title product in 45°~ yield as a white powder;

ym~ (nujol) 3400, 1170 and 1720 cm ; ~ (CDC13) 1.37 (3H, d, J= 7Hz, CH3.CH), 2.22 (3H, s, CH3), 2.40 (1H, br s, OH), 3.12 (1H, dd, J= 2.0 and 4.5Hz, CH. CH.CH), 3.86 (3H, s, OCH3), 4.35 (1H, m, CH3.CH.CH), and 4.65 ppm (1H, d, J= 2.OHz, CH. CH. S).
~t grade mufk 1~~4~91 1 By following a similar experimental procedure, there were obtained:
Diphenylmethyl (7S,6R)-?-/1(R)-hydroxyethyl/-3-methyl-2-thiacephem-4-carboxylate, starting from 3(S)-~(R)-hydroxy-ethyl/-4(R)-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl -2-methylsulphonyloxy-1-prop-1-enyl)-azetidin-2-one;
max (EtOH) 281 ( ~ = 5,900) and 326 (3,670) nm; y m~ (KBr) 3550-3250, 3080, 3060, 3020, 2960, 2920, 2840, 1775, 1720, 1660 and 1490 cm 1; ~ (CDC13) 1.36 (3H, d, J= 6.5Hz, CH3.CH), 2.17 (3H, s, CH3), 3.12 (1H, dd, J= 2.0 and SHz, CH. CH.CH), 4.36 !1H, m, CH3.CH.CH), 4.76 (1H, d, J= 2.OHz, CH. CH. S), 6.97 ;1H, s, OCH2Ph), and 7.30 (lOH, m, Ar);
Diphenylmethyl (7.S,6S)-7-~(R)-tert-butyldimethylsilyloxy-ethyl7-3-methyl-2-thiacephem-4-carboxylate, starting from 3(S)-~'1(R)-tert-butyldimethylsilyloxyethyl7-4(R)-benzthiazolyl-dithic>-1-(1-diphenylmethoxycarbonyl-2-methylsulphonyloxy-1-prop-:.-enyl)-azetidin-2-one; ~ (CDC13) 0.06 (6H, s, SiMe2), 0.83.i;9H, s, SiBut), 1.27 (3H, d, J= 6.5Hz, CH3.CH), 2.05 (3H, ~~, CH3), 3.08 (1H, dd, J= 3.O and 5.OHz, CH.C-H.CH), 4.32 I1H, m, CH3.CH.CH), 4.60 (1H, d, J= 3.OHz, CH. CH. S), 7.02 L1H, s, OCHPh2), and 7.30 ppm (lOH, s, Ar);
Tert-t~utyl (7S,6R)-7-~1(R)-tert-butyldimethylsilyloxyethyl/--3-mei:hyl-2-thiacephem-4-carboxylate, starting from 3(S)-/1(R)-tert-butyldimethylsilyloxyethyl7-4(R)-benzthiazolyldithio-1-(1-tert-butoxycarbonyl-2-methylsulphonyloxy-1-prop-1-enyl)-azetidin-2-one; ~m~ (CHC13) 278 ( F= 6,300) and 327 nm 2, 560); ~m~ (CHC13 film) 1780 and 1720 cm 1; ~ (CDC13) - 47 - ~~J'~~:~~
t 1 0.12 (6H, s, SiMe2), 0.88 (9t3, s, SiBu ), 1.25 (3H, d, J= 6Hz, CH3.CH), 1.52 (9H, s, OBut), 2.10 (3H, s, CH3), 3.02 (1H, dd, J= 2.5 and SHz, CH.CH.CH), 4.28 (1H, m, CH3.CH.CH), and 4.53 ppm (1H, d, J= 2.5Hz, CH. CH. S);
Methyl (7S,6R)-7-/1(R)-methylsulphonyloxyethyl%-3-methyl -2-thiacephem-4-carboxylate, starting from 3(S)-/1(R)-methylsulphonyloxyethyl/-4(R)-benzthiazolyldithio-1-(1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1-enyl)-azetidin-2-one; ym~ 1?80, 1725, 1360 and 1175 cm 1; ~ (CDC13) 1.60 (3H, d, J= 6.5Hz, CH3.CH), 2.25 (3H, s, CH3), 3.0?
(3H, s, CH3S02), 3.27 (1H, dd, J= 2.2 and,5Hz, CH. CH.CH), 3.83 (3H, s, OCH3), 4.70 (1H, d, J= 2.2H, CH.CH.S) and 5.24 ;ppm (1H, m, CH3.CH.CH). ..
Diphenylmethyl (7S,6R)-7-/1(R)-methylsulphonyloxyethyl%-3-me, thyl-2-thiacephem-4-carboxylate, starting from 3(S)-/1(R)-methylsulphonyloxyethyl/-4(R)-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-methylsulphonyloxy-1-prop-1-enyl)-aze-tidin-2-one ~m~(CHC13) 282 ( ~= 7,080) and 330 (3,96b) nm;
(CDC1 ) ymax (CHC13 film) 1778, 1720, 1255 and 1170 cm 1; 3 1.53 (3H, d, J= 6Hz, CH3.CH), 2.10 (3H, s, CH3), 2.71 (3H, s, CH3S02), 3.22 (1H, dd, J= 2.5 and 5.5Hz, CH. CH.CH), 4.67 (1H, . d, J= 2.5Hz, CH. CH. S), 5.05 (1H, m, CH3.CH.CH); 6.90 (1H, s, OCNPh2), and 7.25 (lOH, s, Ar);
Methyl (7~,6R)-7-/1(R)-trichloroethoxycarbonyloxyethyl/-3-methyl-2-thiaceph-em-4-carboxylate, starting from 3(S)-/1(R)-trichloroethoxycarbonyloxyethyl/-4(R)-benzthiazolyldithio-1-' 1,54891 1 (1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1-enyl)-azetidin-2-one; Amax (f.ilm) 1787, 1760 sh, 1725 and 1250 cm 1;
d(CDC13) 1.54 (3H, d, J= 5.5Hz, CH3.CH), 2.23 (3H, s, CH3) 3.30 (1H, dd, J= 2 and 7.5Hz, CH. CH.CH), 3.84 (3H, s, OCH3), 4,68 (1H, d, J-_ 2Hz, CH.CH.S), 4,78 (2H, s, OCH2), and 5,37 ppm (1H, m, CH3.CH.CH);
Diphenylmeth 1 (7S,6R)-7-[1(R)-p_nitrobenzyloxycarbonyloxyethyl]--3-methyl-2-thiacephem 4 carboxylate, starting from (3S)-[1(R)-p-nitrobenzyloxycarbonyloxyethyl].(4R)-benzthiazolylditio--1-(1-diphenylmethoxycarbonyl-2-methylsulphonyloxy-1-prop-1--enyl)-azetidin-2-one; vmax 1787, 1745, 1720 sh cm 1; d(CLC13) 1.53 (3H, d, CH3-CH), 2.17 (3H, s, CH3), 3.28 (1H, dd, J= 2 and 6.5 Hz, CH-CH-CH), 4.65 (1H, d, J= 2Hz, CH. CH.S),,5.15 (2H, ;~, OCH2), 5.28 (1H, m, CH2.CH.CH), 6.97 (1H, s, O_CHPh2), 7.2-7,5 (12H, m, Ar) and 8.17 ppm (2H d J-_ 9Hz, Ar);
> >
and, __ikewise, there were obtained:
tert-butyl (7S,6R)-7 -[1(R)-trichloroethox carbon lox ethil]--3-met-hyl-2-thiacephem-4-carboxylate;
diphen~rlmethyl (7S,6R)-7-[1(R)-trichloroethoxycarbonyloxvethv7l -3-metal-2-thiacephem-4-carbox late;
trichloroeth 1 (7S 6R)-7-[1(R)-trichloroethox carbon lox eth 1]--3-methyl-2-thiacephem-4-carboxylate;
trichloroethyl (7S,6R)-7-[1(R)-tert-butyldimethylsilvloxvet_h_v1_~--3-methyl-2 -thiace~hem-4-carboxylate;
acetoxymethvl (7S 6R)-7-[1(R)-trichloroethox carbon lox eth 1]-1;~~4~3~1 _ 49 --3-methyl-2-thiacephem-4-carboxylate;
acetoxymeth yl (7S,6R)-7-[1(R)-tert-butyldimethylsilyloxyethylJ--3-methyl-2-thiacephem-4-carboxylate;
acetoxymethyl (7S,6R)-7-(1(R)-trimethylsilyloxyethyl]-3-methyl--2-thiacephem-carboxylate.

1;~~~~:31 1 Example 14 3(S)-~(R)-tent-butyldimethylsilyloxyeth~7.7-4(R)-succinimido-thio-1-(1-methoxycarbonyl-2-methyl-1-prop-2-envl)-azetidin-2-one OS;Yfe~ Bu o OS;MezB~~ o J N ~ _--~ ~ o o' .~ZCH3 0 ~°t«3 Methyl 6~(-/1(R)-tert-butyldimethylsilyloxyethyl%-penicillanate -1-oxide (2.32 g) dissolved in dimethylacetamide (35 ml) was treated with acetic acid (0.15 ml), purged with nitro;~en, and heated for 3 1/2 hours at 105°C in the presence of N-trimethyl-5ilylsuccinimide (5 g). After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and cold water. Fractionation of the material.obtaine3 from the organic layer (silica gel chromatography, ethyl acetate-cyclohexane) afforded the title product as a white foam, 1.2 g (430); Lm~ (CHC13 film) 1770, 1735, 1710 sh, and t 1680 cm 1; ~ (CDC13) 0.08 (6H, s, SiMe2), 0.87 (9H, s, SiHu ), 1.32 (3H, d, J= 6.5Hz, CH3.CH), 1.84 (3H, s, =C.CH3); 2.85 (4H, s, CO.CH2.CH2.C0), 3.29 (1H, dd, J= 3 and 4.5Hz, CH. CH.CH), 3.73 (3H, s, Ohle), 4.24 (iH, m, CH3.CH.CH), 4.66 (1H, s, N.CH.CO), 4.85 (1H, d, J= 2.5Hz, CH.CH.S), and 5.00 ppm (2H, br s, CH2=C).

7.;~ 'J'~~3;~1 1 By follovring a similar experimental procedure, there were also obtained:
3-(S)-,~1(R)-tent-butyldimethylsilyloxyethyl/-4(R)-succinimido-thio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin-2-one, and 3-(S)-/1(R)-tent-butyldimetY~ylsilyloxyethyl~-4(R)-phthalimido-thio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-azetic~in-2-one, both isolated as crude materials and used as such in the following steps.

_ 52 _ 1 Example 15 3(S)-L1(R)-tent-butyldimethylsilyloxyethvl>-4(R)-phthalimido-thio-1-~1-methoxycarbonyl-2-methylsulphcnyloxy-1-prop-1-(Z)-enyl%-azetidin-2-one 0 5: MeZBu OS;~ezsu o " 5 SJS ~ N S-NJ D
1~~~
~'N OMS ---r I
o ~ ~ o ~--NW
cni cN3 ~oZ cu3 A solution of 3(S)-/1(R)-tert--butyldimethylsilyloxyethyl/-4(R)-benzothiazolyldithio-1-/1-methoxycarbonyl-2-methylsulphonyloxy--1-prop-1-(2)-enylJ-azetidin-~.'-one (lOC mg) in acetone (9 cc) was treated with AgN03 (34 mg;~, soon followed by an ethanolic slurry of potassium phthalimic~e (30 mg). After 30 min. stirring at room temperature, the prec:~pitate was collected~partitioned between water and EtOAc, and purified by short silica gel chromatography to afford the -:itle product (55°x); ~m~ (film) 1 ~ CDC13) 0.1 (6H, s, SiMe2), 0.89 1?80, 1?45, and 1?25 cm ;
(9H, s, But), 1.4 (3H, d, CH3.CH), 2.2 (3H, s, =C.CH3), 3.05 (3H, s, S02.CH3), 3.4 (iH, m, CH. CH.CH), 3.6 (3H, s, OCH3), 4.2 (1H, m, CH3.CH.CH), 5.45 (1H, d, J= 2Hz, CH.CH.S); and ?.8 ppm (4H, m, Ar).

1~'S4891 1 Example 16 3(S)-~1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-succinimido-thio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin -2-one OS~Mela~ o OS;Ne28u o 5_N H S_nl s _~ .-j. ~ o 0 ~--N ~~ o.- N ~- o N
H
cot f1e cozMe The title product was obtained by ozonolysis of 3(S)-/1(R)-tert-butyldimethylsilyloxyethyl~-4(R)-succinimidothia-1-(1-methoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin-2-one in dichloromethane according to the procedure described in Example 8, and used as such for further reactions. A sample gas characterized as its dimethylketal (MeOH/dry HC11:
1- ~ (CDC13) 0.04 and 0.09 1770, 1730 and 1715 sh cm , m ax (each 3H, s, SiMe2), 0.90 (9H, s, SiBut), 1.31 (3H, ~i, J= 5Hz, :3.CH), 1.49 (3H, s, CH3), 2.84 (4H, s, COCH2.CH2C0), 3.21 and 3.26 (each 3H, s, ketal OCH3), 3.24 (1H, dd, J= 2.5 and 3.73 (3H, s, ester OCH3), 4.20 (1H, m, CH3.CH.CH), 4.43 (1H, s,~I~.CH.CO), and 4.94 ppm (1H, d, J= 2.5Hz).
Likewise, 3(S)-/1(R)-tert-butyldimethvlsilyloxyethyl%-4(R)-hthalimidothio-1-(1-di henylmethyoxycarbonvl-2-hydroxy-1-Prop-1-enyl)-azetidin-2-one, was obtained starting from 3( -S)-/1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-phthalimido-thio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin-2-one.

:~;~ 5 4 ~3;~ 1 1 Example 17 Methyl (7S,6R) 7 L1(R)-tent-butyldimethylsilyloxyeth~l/-3-methyl-2-thiacephem-4-carboxylate t f pS;McIBu o~~ OS;MeIBv '~ S lr~ ~~ ~H S ~ S

OSo2CN3 0 ~t~ Hj A solution of 3(S)-~1(R)-tent-butyldimethylsilyloxyethyl%
-4(R)-phthalimidothio-1-~1-methoxycarbonyl-2-methylsulphonyloxy--1-prop-1-(Z)-enylJ azetidin-2-one (400 mg) in dimethylformamide (4 ml) was treated with finely ground NaSH (50 mg) unc.er vigorous stirring. As soon as the last reagent was dissolved, 1(I the reaction was quenched by partition between ethyl ether and water. Work-up gave the title compound, identical with the sample described in Ex. 12.

_ 55 - Ii~J4 1 Example 18 Methyl (7S,6R)-?-L1(R)-tent-butyldimethylsilyloxyethy~/-3-methyl-2-thiacephem-4-carboxylate OS;MeIg~ o OS~M~18~~
N S_N~~ ~ N 5.5 ~--N 0 I
O
N . Go?C~I3 ~1C N3 3(S)-/1(R)-tent-bttyldimethylsilyloxyethyl%-4(R)-succinimido-thio-1-(1-methoxycarbonyl-1-prop-2-enyl)-azetidin-2-one (0.8 g) in dichloromethane~ was ozonized at -?O°C until tlc showed complete conversion. Excess ozone was purged with-nitrogen and dimethylsulphide (1 ml) was added. After 1 hour at room temperature, any volatile material was removed in vacuo and the residue reacted with equimolecular amounts of triethyl-amine and mesyl chloride (CH2 I2,-20°to O°C) until conversion of the enol into the mesylates was judged complete by tlc.
The mixture was concentracted in vacuo and partitioned between ethyl acetate and gold, aqueous NaHC03. 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 p~ocedure 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.

- 56 - ~IG ~J4~:~~
1 By a similar procedure, Diphenylmethyl (7S,6R)-7-/1(R)-tert-butyldimethylsilyloxy-ethyl/-3-methyl-2-thiacephem-4-carboxylate was obtained, starting from 3(S)-~(R)-tert-butyldimethylsilyloxyethyl/-4(R) -phthalimidothio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin-2-one, and showed the same spectral properties of the material previously described (Example 13).

~~54891 _ 5? _ 1 Exampl a 19 Methyl (7S,6R)-?-C1(R)-tert-butyldimethylsilyloxyethy~/-3-(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl-2-thiacephem-4-carboxvlate OS~~'le2B~ N-N OS;MeZB~
H S_S ~N N -~ ~~N 5~5 N_.N
c', N3 l~!-N ~ S .J) N
D ~~ ~ 5 ~ ~ o ~-rv ~.,/
N
H cOzCH3 GH3 LOZcN~ CH3 3(S)-/1(R)-tent-butyldimethylsilyloxyethy:l/-4(R)-(1-methyl--1,2,3,4-tetrazol-5-yl)-dithio-1-/1-methoaycarbonyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl-~1-prop--2-enyl/-azetidin-2-one (120 mg) in dichloromethan~°_ was subjected to the same reaction sequence reported in Example 17 (ozonolysis, mesylation, reaction with NaHS). The crud~° product was parritior~
between ethyl acetate and aqueous NaHC03, thus removing the liberated mercaptotetrazole; the organic layer was washed several time with water, evaporated and t;~e residue fractionated by silica gel chromatography to afford the title product, i7 mg (17~); ym~ (film) 1787, 1725, 1587, 1360 and 1250 cm ;
t (CDC13) 0.10 (6H, s, SiMe2), 0.89 (9H, s, SiBu ), 1.26 (3H, d, J= 6Hz, CH3-CH), 3.15 (1H, dd, J= 2.2 and 3.5Hz, CH.CH.CH), 3.88 (3H, s, OMe), 3.92 (3H, s, NMe), 4.38 (1N, m, CH3.CH.CH), 4.46 (2H, ABq, J= l4Hz, separation of inner lines 1-1Hz) and 4.68 ppm (1H, d, J= ~2.2Hz, CH. CH. S).

- 5s - 1;~~4L~~~
1 Exampl a 20 3(S)-~1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-phenyl-sulphonVlthio-1 fl-methoxycarbonyl-2-methyl-1-prop-2-enyl~-azetidin-2-one t 05; M~ZB~ ~ oS~ MP~B~ o H . S_S ~S~ H 5_5 _P~
----~ o o' CD C H

3(S)-~1(R)-tert-butyldimethylsilyloxyethyl~-4(R)-benzthiazolyl-dithic-1-(1-methoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin--2-one (2.6 g) in acetone (160 ml) and water (18 ml) was treated under vigorous stirring with silver nitrate (0.98 g), immediately followed by sodium benzenesulphinate (0.79 g) in water (60 mlj. After 1 hour at ropm 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); it (KBr) 3080, 3020, 2960, 2930, 2900, 2860, 170, 1750, 1330 and 1145 cm 1; d (CDC13) 0.05 (6H, s, Si~le~), 0.98 (12H, s+d, SiBut and CH3.CH), 1.84 (3H, s, =C.CH3), 3.22 (1H, dd, J= 2 and 2.5Hz, CH. CH.CH), 3.75 (3H, s, OMe), 4.19 (1H, m, CH3.CH.CH), 4.58 (1H, s, N.CH.CO), 5.00 (2H, m, C=CH2), 5.37 (1H, d, J= 2Hz, CH. CH. S), 7.60 and ?.96 ppm (3 and 2H, each m, Ar).

1~~~~~1 1 Found: C, 53.69; H, 6.99; N, 2.?O; S, 12.42ro. C23H35N06SiS2 requires C, 53.77; H, 6.87; N, 2.?4; S, 12.480.
By following the same procedure, there were also obtained:
3(S)-/1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-phenyl-sulphonylthio-1-(1-tent-butoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin-2-one;
3(S) /1(R) tent-butyldimethylsilyloxyethyl/-4(R)-phenylsulphonyl thio-1-(1-diphenylmethoxycarbonyl-2-methvl-1-prop-2-enyl)-azetidin-2-one;
3(S)-/1(R)-trichloroethoxycarbonyloxyethyl/-4(R)-phenylsulphonyl thio-1-(1-methoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin -2-one;
_3(S)-/1(R)-trichloroethoxycarbonyloxyethyl)-4(R)-phenylsul-Ehonylthio-1-(1-trichloroethoxycarbcnvl-2-methyl-1-prop-2-enyl)-azetidin-2-one.

3~;~~4891 1 Example 21 3(S)-L1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-phenyl-sulphonylthio-1-L1-methoxycarbonyl-2-methylsulphonyloxy--1-~ro~-1(Z)-enyl/-azetidin-2-one OSi Me2gu A~ " S _ sot P~

D ~--N
t C,aZCH3 ~ DSiMetB~
S-502~~
oso2CN3 O~J~'te28u p g N S-S-C ~ O
S ~ (!J2 CNj O~
~pZCN3 Procedure A) The material from Example 20 (1 g) in dry dichloromethane was ozonized at -?O°C. After purging with nitrogen, dimethyl-sulphide (3.5 ml) was added and the mixture stirred f~~r 3 hours zt room temperature. After removal of any volatile material ~n vacuo, the residue was partitioned between ethyl acetate and water. Evaporation of the solvent left the intermediate 3(S)-/1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-phenyl-sulphonylthio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one; ~l 3450, 1?78, 1658 and 1620 cm 1; ~ (CDC13) m a~:
0.08 (6H, s, SiMe2), 0.90 (9H, s, SiBut), 1.13 (3H, d, J= 6Hz, CH3.CH), 1.90 (3H, s, =C.CH3), 3.12 (1H, dd, J= 2.5 - 6' - 1~;~~8~1 1 and 4Hz, CH. CH.CH), 3.73 (3H, s, OMe), 4.2 (1H, m, CH3.CH.CH), 5.52 (1H, d, J= 2.5Hz, CH.CH.S), ?.4-8.0 (5H, m, Ar), and 13 ppm (1H, s, OH).
This material was mesylated with triethylamine (272 ~1) and mesyl chloride (151 ~1) in dry THF (10 ml) according to the general procedure - see Example 10 -thus obtaining the title product as a foam, 550 mg after silica gel chromatography;
(CDC13) it (film) 1780, 1730, 1640, 13?O and 1145 cm 1;
0.05 (6H, s, SiMe2), 0.80 (9H, s, SiBut), 0.97 (3H, d, J= 6Hz, 1() CH3.CH), 2.50 (3H, s, =C.CH3), 3.15 (4H, m, S02CH3 and CH.CH.CH), 3.76 (3H, s, OCH3), 4.13 (1H, m, CH3.CH.CH), 5.7 (1H, d, J= 2.8Hz, CH. CH. S), and ?.6-8.0 ppm (5H, m, Ar).
Procedure B) 3(S) 11(R)-tert-butyldimethylsilyloxyethyl7-4(R)-benzthiazolyl-1!i dithio-1-/1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1(Z)-enyl/-azetidin-2-one (100 mg) in acetone-water 9:1 (10 ml) was sequentially treated under stirring with silver nitrate (34:3 mg) and an aqueous solution of sodium benzenesulphinate (26.6 mg in 4 ml). After 15 min stirring at room temperature 2U the precipitated silver benzthiazolmercaptide was removed by filtration and the solution partitioned between CH2C1~ and water. Removal of the solvent left the title product as a syrup (quantitative yield), sharing the same spectral properties with the sample from procedure A).

~z~~891 1 According to the same methodology, there were obtained:
3(S)-~(R)-tert-butyldimethylsilyloxyethyl/-4(R)-phenyl-sulphonylthio-1-/1-tert-butoxycarbonyl-2-methylsulphonyloxy--1-prop-1(Z)-enyl/-azetidin-2-one;
3(S)-/1(R)-trichloroethoxycarbonyloxyethyl/-4(R)-phenyl-sulphonylthio-1-/1-trichloroethoxycarbonyl-2-methylsulphonyl-oxy-1-prop-1(Z)-enyl/-azetidin-2-one.

:~254~91 1 Example 22 Methyl (?S,6R)-7-~1(R)-tert-butyldimethylsilylox~ethyl/-3-methyl-2-thiacephem-4-carboxylate OS. Met Bu OS;N~ZB~
VN S_SOZ~~ ~ H S~S
OSD LH
0 ~ N s 3 o f-- N
CDZCH3 . ~ICN3 3(S)-/1(R)-tent-butyldimethylsilyloxyethy:_/-4(R)-phenylsulphonyl-thio-1-/1-methoxycarbonyl-2-methylsulphon~rlo~;y-1-prop-1(Z)-enyl%-azetidin-2-one was allowed to react with NaHS in DMF
following the procedure described in Example 13 thereby obtain-ing the title product, identical with the material previously described. This preparation_allows for a ~~impler purification o.f the product, since the by-product, sodium benzenesulphinate, is soluble in water and does not need chromatographic separat-ion or fractional crystallization to be removed (different from, e.g., mercaptobenzthiazole).
According to the same methodologies, there were obtained:
Tert-butyl (?S,6R)-7-%1(R)-tent-butyldimethylsilyloayethyl/--3-methyl-2-thiacephem-4-carbox~~late;
Trichloroethyl (?5,6R)-?-/1(R)-trichloroethoxycarbonvloxy-ethyl/-3-methyl-2-thiacephem-4-carboxylate.

- 64 - ~~~48~1 1 Example 23 3(S)-rl(R)-trichloroethoxycarbonyloxyethylJ-4(R)-acetyldithio-1-L1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1(Z)-envlJ
azetidin-2-one OGOZ(,HZ~CQj ~\tptcH~~c~3 S ~ S-s GoUlg ~ 50 U( --' ~ ~N Z 3 ~ QSO1C.!!3 GO Z c.~3 CD 1 U13 A solution of 3(S)-~1(R)-trichloroethoxycarbonyloxyethyl7-4(R)-benzothiazolyldithio-1-/1-methoxycar~bonyl-2-methyl-sulphonyloxy-1-prop-1(Z)-enyl%azetidin-2-one (340 mg) in THF (5 ml) was treated with thioacetic acid (43 ~1).
Five minutes later the mixture was evaporated and the crude reaction product freed from 2-mercaptobenzothiazole by chroma-tography to obtain the pure title compound as a colourless syrup, 280 mg (96°x); ~m~ (film) 1??5, 1760 sh, 1730 br cm l;
(CDC13) 1.50 (3H, d, CH3.CH), 2.48 (3F1, s, =C.CH3), 2.62 (3H, s, COCH3), 3.29 (3H, s, S02CH3), 3.~r4 (1H, dd, CH. CH.CH), 3.83 (3H, s, OMe), 4.77 (2H, ABq, J= 11.'~Hz, separation of inner lines 2Hz), 5.24 (1H, d, CH. CH. S), 5.25 (1H, m, CH3.CH.CH) ~.ic: 'J~ t~~..~'' ~.
1 Example 24 Methyl (7S,6R)-7-~(R)-trichloroethoxycarbonvloxyethylJ-3-methyl-2-thiacephem-4-carboxylate OLO~~i~CCp~
S
~S
. oSaz UI3 ---a o'-N p i-N w (p2LH3 L,OzC.N3 A solL:.tion of 3(S)-/1(R)-trichloroethoxycarbonyloxyethyl/-4(R)-acetyldithio-1-/1-methoxycarbonyl-2-methylsulphonyloxy--1-prcp-1(Z)-enyl/azetidin-2-one (140 mg) in THF (10 ml) was treated at O°C with a solution of tetrabutylammonium hydrogen sulphide (65 mg) in the same solvent.
Work-up and chromatography afforded the title product: ~1 m ax (EtOH) 280 (~ 4,974) and 327 nm (2,262); Y m~ (film) 1787, 1760 sh, 1725 cm 1; O (CDC13) 1.54 (3H, d, CH3.CH), 2.23 (3H, s, CH3), 3.30 (1H, dd, 2 and 7.5 Hz, CH. CH.CH), 3.84 (3H, s, Ohle), 4.68 (1H, d, CH. CH. S), 4.78 (2H, s, OCH2CC13), and 5.3H ppm (1H, m, CH3.CH.CH), followed by some recovered starting material.

1;~,;:i ~ ~:~ 1 1 Example 25 MethVl (?5,6R)-7-L1(R)-tent-butyldimethylsilyloxyethyl_/-3-bromometh yl-2-thiacephem-4-carboxylate OS:Mei6~~ OS~HetCiu N
--~. --~ S ~5 J
p'!N ~ o ~ ~ Br UJ2CH3 (,p2CH~
Methyl (7S,6R)-7-/1(R)-tert-butyldimethylsilyloxyethyl/-3-methyl-2-thiacephem-4-carbo:Kylate (0.52 g)~propylene oxide (0.95 ml) and N-bromosuccinimide (0.52 g) and azobis-isobutyronitrile (0.05 g) in ~~arbon tetrachloride (40 ml) 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 -exane mixtures, thus obtaining the title product as a yellowish oil (80ro); ~ m~ (CHC13) 282 and 336 nm; Y m~ (CHC13 film) 1785, 1730 cm-1; ~ (CDC13) 0.10 (6H, s, SiMe2), 0.89 (9H, s, SiBut), 1.28 (3H, d, CH3.CH.OSi), 3.23 (1H, dd, J= 2.0 and 3.5Hz, CH. CH.CH), 3.87 (3H, s, OCH3), 4.65 (2N, center ABq, s.i.l. 4Hz, J= 11.5Hz, CH2Br), 4.30 (1H, m, CH3.CH.CH), 4.76 (1H, d, J= 2.OHz, CH.CH.s) ppm Found: C, 41.1; H, 5.64; N, 3.01; S, 13.55; Br, 17.20;
C16H26BrN704Si52 requires C, 41.02; H, 5.59; N, 2.99; 5, 13.69;
Br, 1.06.

_ 67 _ 1;~548~1 1 By following a similar procedure, there were obtained:
tert-butyl (7S,6R)-7-[1(R)-tert-butyldimethylsilyloxyethil]--3-bromomethyl-2-thiacephem-4-carboxylate;
Amax (CHC13) 283 and 332 nm; vmax (film) 1787 and 1720 cm 1;

8 (CDC13) 0.9 (6H, s, SiMe2), 0.9 (9H, s, SiBut), 1.28 (3H, d, CH3.CH), 1.55 (9H, s, OBut), 3.18 (1H, dd, J= 2.5 and 4.5Hz, CH.CH.CH), 4,35 (3H, m, CH2Br and CH3.CH.CH), and 4,71 ppm (1H, d, J= 2.5Hz, CH. CH. S);
p-nitrobenzyl (7S,6R)-7-(1(R)-p-nitrobenzyloxycarbonyloxyethyl]--3-bromomethyl-2-thiacephem-4-carboxylate; d(CDC13) 1.45 (3H, d, CH3.CH), 3.43 (1H, dd, J= 2.5 and 6 Hz, CH. CH.CH), 4.45 (2H, ABq, J= l2Hz, CH2Br), 4.80 (1H, d, J= 2.5 EIz, CH. CH. S), 5.2, 5.5 (5H, m, two OCI-I2Ar and C~3.CH.CH); 7.47 and 7.60 (each 2H, d, J= 8.5Hz, Ar), and 8.20 ppm (4H, d, J= 8.5Hz, Ar);
1~ diphenylmethyl (7S,6R)-7-(1(R)-p-nitrobenzyloxycarbonylox~ethyl~ --3-bromomethyl-2-thiacephem-4-carboxylate; d(CDC13) 1.45 (3H, d, Cf~3.CH), 3.32 (1H, dd, J= 3 and 6Hz, CH. CH.CH), 4.18 (2H, ABq, J-_ ll.Hz, CIi2Br), 4.70 (1H, d, J= 3Hz, CH. CH. S), 5.20 (2H, s, OCH2Ar), 5.30 (1H, m, CH3.CH.CH), 6.97 (1H, 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-C1(R)-tert-butyldimethylsilyloxyethyl)--3-bromomethyl-2-thiacephem-4-carboxylate; vmax(film) 1790 and 1730 cm-1; d(CDC13) 0.05 (6H, s, SiMe2), 0.8 (9H, s, SiBut), 1.22 (3H, d, J= 6.5 Hz, CH3.CH), 3.10 (1H, dd, J= 2.7 and 4.5 Hz, ~1;~~4891 1 CH. CH.CH), 4.05 (2H, s, CH2Br), 4.2 (1H, m, CH3.CH.CH), 4.63 (1H, d, J= 2.7 Hz, CH.CH.S), 6.92 (1H, s, OCHPh2), and 7.05-7.40 ppm (10H, m, Ar); amax (CHC13) 283 (e= 7.867) and 336 nm (e - 3.533); and, likewise:
trichloroethyl (7S,6R)-7-[1(R)-tert-butyldimethylsilyloxy-ethyl)-3-bromomethyl-2-thiacephem-4-carboxylate;
trichloroethyl (7S,6R)-7-(1(R)-trichloroethox~carbonyloxy~
ethyl)-3-bromomethyl-2-thiacephem-4-carboxylate.

lzs4~~~
_ 69 _ 1 Example 26 MethrLl (?S,6R)-7-~1(R)-tent-butyldimethylsilyloxyethylJ--3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-2-thiacephem--4-carboxylate a S; ale t t~~' GS;~1z28~' H
S ,,5 ~~ H 5 .S N~N
S
N ~ B r U ~'-i~ .~/~ N
Uf ~~ Me. CGZfnz A THF solution of crude methyl (7S,6R)-?-/1(R)-tert-butyl-dimethylsilyloxyetryl%-3-bromomethyl-2-thiacephem-4-carboxy-late was kept overnight in the presence of sodium 1-methyl-1,2,3,4-tetrazol-5-thiolate bihydrate (3 mol equiv.).
Work-up and chromatography afforded the title product as an oil in 85p yield; ~ (EtOH) 281 and 333 nm; y m~ (film) _ max 1 ~ (CDC13) 0.10 (6H, s, Sihle2), 0.89 (9H, 1790~and 1725 cm ;
s, But), 1.26 (3H, d, CH3.CH), 3.15 (1H, dd, J= 2.2 and 3.5Hz, CH. CH.CH), a.88 (3H, s, OMe), 3.92 (3H, s, N.CH3), 4.38 (1H, m, CH3.Cri.CH), 4.46 (2H, ABq, sep. of inner lines l4Hz, J= l4Hz), 4.t>8 (1H, d, CH.CH.S, J= 2.2Hz) 1~5489~1 1 By following a similar procedure, there was obtained:
tent-butyl (?S,6R)-?-~1(R)-tert-butyldimethylsilyloxyethyl/--3-(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl-2-thiacephem -4-carboxylate, starting from tert-butyl (7S,6R)-?-/1(R)-tent-butyldimethylsilyloxyethyl/-3-bromomethyl-2-thiacephem -4-carboxylate;
diphenylmethyl (?5,6R)-?-~(R)-tert-butyldimethylsilyloxyethylJ--3-(8-aminotetrazolo~l,5-b~pyridazin-6-yl)thiomethyl-2-thiace-phem-4-carboxylate szs4~~1 1 Example 27 (5aR,6S)-6-L1(R)-tert-butyldimethylsilyloxyethyl~-5a,6-dihydro-3H,7H-azetoL2,1-cJ furoj~3,4-e_~-1,2,4-dithiazine-1,7-dione Osvl''h' j Bud O~il~eZ$vt H S.5 H S~S
o ~-N ~~ 8 z o J r~ ~~
WZ~H3 Procedure A): A solution of methyl (?S,6R)-?-/1(R)-tert-butyld:imethylsilyloxyethyl/-3-bromomethyl-2-thiacephem-4-carbox:~late (15 mg) in DMSO (2 ml) and water (1.5 ml) was stirred with Cu20 (50 mg) at 50°C for 2.5 hours.
The re;3ction mixture was partitioned between water and ethyl acetate. Evaporation and chromatography of the organic extracts afforded the title product as a white powder; Y (CHC1 max 3 film) 1800-1760 br cm 1; ~(CDC13) 0.06 (3H, s, SiCH3), 0.11 ~.3H, s, SiCH3), 0.90 (9H, s, But),'1.33 (3H, d, CH3.CH), 3.33 '1H, dpi, J= 2.5 and 4.5Hz, CH. CH.CH), 4.44 (1H, m, CH3.CH.CH), 4.62 (LH, d, J= 2.5Hz, CH. CH. S), and 4.98 (2H, s, CH20) Procedure B): The 2-bromomethyl precursor (250 mg) in 2:1 acetone-water (35 ml) was stirred for 15 min at O°C with AgC104 (753 mg). The reaction mixture was partitioned between H20/EtOAc and the organic layer evaporated to leave a residue.
Silica gel chromatography afforded the title product, identical with the sample~described above under A).

1 Example 28 tert-Butyl (75,6R)-?-/1(R)-tent-butyldimethylsilyloxyethyl/-3-hydroxymethyl-2-thiacephem-4-carboxylate OS~M~ zg~t OS; M~ZBut ,5 ~ ~ S.s o w ~~ B Z o ~.o ~ ut c Z
5 tert-Butyl (?5,6R)-7-/1(R)-tent-butyldimethylsilyloxyethyl/-3-bromomethyl-2-thiacephem-4-carboxylate (300 mg) in 2:1 acetone-water (10 ml) was stirred for' 15 min at O°C with AgC104 (150 mg) Removal of the solvent, followed by H20/EtOAc partition and work-up of the organic layer, gave 250 mg (96~) of the title product; 1 m~ (CHC13) 281 ar~d .335 nm; y (film) 3450, m ax 1?85 and 112 cm 1; ~ (CDC13) O.1 (6H, s, SiMe2), 0.86 (9H, s, SiBut), 1.25 (3H, d, CH3CH), 1.50 (9H, s, OBtit), 3.13 (1H, dd, J= 2.5 and 4.5Hz, CH. CH.CH), 4.25 (centre of ABq, J= l3Hz, CH20H), 4.3? (1H, m, CH3.CH.C:H), and 4.60 ppm (1H, d, J= 2.5Hz, CH. CH. S).

- 73 - ~2548~~.
1 Example 29 tert-Butyl (7S,6R)-7-~1-(R)-tert-butyldimethylsilyloxyethyl/--3-(N-trichloroacetyl)carbamoyloxymethyl-2-thiacephem-4-carbo-xylate OS.He2~~
OStH eZ~a H H
'S'S S~S
OOH -' o ~ ~ OCONN COtCt3 COz B,~ (,oz Bsi tert-Butyl (7S,6R)-7-~1(R)-teat-butyldimethylsilyloxyethyl/-3-hydroxymethyl-2-thiacephem-4-c;3rboxylate (250 mg) in ethanol-free dichloromethane (2.5 ml) was treated at -40°C with trichloro-acetylisocyanate(80 ~1). The mixture was let rise to room temperature and then sequentially washed with aqueous 2~ NaHC03 and brine. Evaporation of the solvent from the organic layer gave'the title product in quantitative yield;' 1 (EtOH) m ax max ~ ( CD3CN ), O . 1 275 and 329 nm; iJ 1795 and 1725 br cm-1;
(6H, s, SiMe2), 0.9 (9H, s, SiBut), 1.3 (3H, d, CH3.CH) 1.5 (9H, s, OBut), 3.40 (1N, dd, J= 3 and 4Hz, CH. CH.CH), 4.35 (1H, m, CH3.CH.CH), 4.80 (1H, d, J= 3Hz, CH.CH.S), and 5.0 ppm (centre of ABq, CH20C0).

- 1;54891 1 Example 30 tent-Butyl (7S,6R)-7-/1(R)-tert-butYldimethylsilyloxyethyl/--3-carbamoyloxvmethyl-2-thiacephem-4-carboxylate OSs M~2Bv OSJ'1eZ 6v S,S ~ S.S
' , ocor~H co cc~~ o ~ ~ ocoiuHy o'~"
C028ut ~28~
5- A methanolic solution of tert-butyl (?S,6R)-7-~1(R)-tert-butyldimethylsily'__oxyethyl/-3-(N-trichloroacetyl)carbamoyloxy-methyl-2-thiacephc:m-4-carboxylate 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; ~ (CDC13) O.1 (6H, s, SiMe2l, 0.9 (9H, s, SiBut), 1.35 (3H, d, CH3.CH), 1.60 (9H, s, OButl, 3.1 (1H, dd, CH. CH.CH), 4.3 (1H, m, CH3.C~.C'.
4.75 (1H, d, J= 31~z, CH. CH. S), and 5.0 ppm (centre of ABq, OCH2C0).

125481.
_ 75 _ 1 Example 31 Methyl (7S,6R)-7-L1(R)-tent-butyldimethylsilyloxyethylJ-3-nitrooxymethyl-2-thiacephem-4-carboxylate ~si/''~et gu H S'S N S
'S
-- ,I BZ ~ oHaz o N ~ o A solution of methyl (7S,6R)-?-/1(R)-tert-butyldimeth_ylsilyl-oxyethyl/-3-bromonethyl-2-thiacephem-4-carboxylate (200 mg) in acetone (20 ml) was stirred for 20 min in the presence of AgN03 (100 mg). The filtered reaction mixture was fractionated by silica gel chromatography to obtain the title product, 120 mg; ~lm~ (CHC13) 280 and 337 nm; ~ (film) 1790, 1730, m ax 1640 and 1280 cm 1; C~(CDC13) 0.08 (6H, s, SiMe2), 0.87 (9H, s, SiBut), 1.38 (3H, d, CH3.CH), 3.18 (1H, dd, J= 2.5 and S.SHz, CH._CH.CH), 3.85 (3H, s, OMe), 4.38 (1H, m, CH3.CH.CH), 4.73 (1H, d, J= 2.SHz, CH. CH. S), and 5.36 ppm (2H, ABq, J= 13.5Hz, , s.i.l. 29.5Hz, CH20N02); further elution then afforded some of the lactone described in Example 27.

1 Example 32 Methyl (7S,6R)-7-L1(R)-tert-butyldimethylsilyloxyethylJ-3-formyloxymeth~l-2-thiacephem-4-carboxylate Os~l' 2 ~ a OSi M~~ ~ a S~S oG~to Bz I
O
COZCN3 Coz~H3 Methyl (7S,6R)-7-~1(R)-tent-butyldimethylsilyloxyethyl/-3-bromomethyl-2-thiacephem-4-carboxylate (200 mg) in CH2C12 was treated at daily intervals with tetrabutylammonium formiate (3 x 600 mg). After 3 days at 5°C tlc showed 80°k conversion in the product (ethyl acetate/light petroleum 1:2).
Elution through a short silica gel column gave the title t material; ~ (CDC13) O.1 (6H, s, SiMe2), 0.9 (9H, s, SiBu ), 1.35 (3H, d, CH3.CH), 3.20 (1H, dd, 2.5 and 7Hz, CH. CH.CH), 3.9 (3H, s, OMe), 4.5 (1H, m, CH3.CH.CH), 4.74 (1H, d, 2.5Hz, CH. CH. S), 5.13 (center of ABq, CH20).
In a similar way, starting from the corresponding tert-butyl and diphenylmethyl esters, there were obtained:
tert-butyl (7S,6R)-?-rl(Rl-tert-butyldimethylsilyloxyethy~/-3-formyloxymethyl-2-thiacephem-4-carboxylate;

- ~,~548~1 1 diphenylmethyl (7S,6R)-?-/1(R)-tert-butyldimethylsilyloxy-ethyl_/-3-formyloxymethyl-2-thiacephem-4-carboxylate and, in a likewise fashion, the corresponding acetates were obtained:
methyl (7S,6R)-7-ll(R)-tert-butyldimethylsilyloxyethyl./-3-acetoxymethyl-2-thiacephem-4-carboxylate;
tert-outyl (7S,6R)-7-/1(R)-tent-but~ldimethylsilvloxyethyl_%--3-acetoxymethyl-2-thiacephem-4-carboxylate;
d_iphenylmethvl (7S,6R)-7-~1(R)-tent-butyldimethylsilyloxyethvl/-ZO -3-acetox5~methyl-2-thiacephem-4-carboxylate;
trichloroethvl (7S,6R)-7-ll(R)-trichloroethoxycarbonyloxyethylJ--3-acetoxymethyl-2-thiacephem-4-carboxylate ~.254~~~
1 Example 33 Methyl (?S,6R)-?-L1(R)-hydroxyethy~/-3-methyl-2-thiacephem--4-carboxylate OS;Melgu CN
H SOS H S .S
--:
O ,,.-N ~ O
GOZC H3 _ Zt~3 Methyl (?S,6R)-?-/1(R)-tert-butyldimethylsilyloxyethy~.%-3-methyl-2-thiacephem-4-carboxylate (0.75 g) was added i:o a solution of tetrabutylammonium fluoride trihydrate (2.03 g) in acetic acid (1.23 ml) and THF (10 ml).
Work-up after 20 hours gave the tile compound (virtua:lly quantitative yield), showing the spectral properties described for the sample obtained in'Example 13.
By following a similar experimental procedure, there ,Here obtained:
Methyl (7S,6R)-7-/1(R)-hydroxyethyl~-3-bromomethyl-2-thiacepherri -4-carboxylate, starting from methyl (?S,6R)-?-/1(R)-tert-butyldimethylsilyloxyethyl/-3-bromomethyl-2-thiacephe;n-4-carboxylate; y (film) 1??5, 1?30 cm 1; ~ (CDC13) 1.35 m ax (3H, d, CH3.CH'), 3.38 (1H, dd, CH. CH.CH), 3.60 (1H, br s, OH), 3.9? (3H, s, OMe), 4.33 (1H, m, CH3.CH.CH), 4.46 (2H, centre of ABq, J= llHz, sep. of inner lines 4Hz, CH2Br), and 4.88 ppm (1H, d, J= 2.2Hz, CH. CH. S);

- ~9 - lzs~S91 1 Methyl (7S,6R)-7-/1(R)-hydroxyethyl/-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-2-thiacephem-4-carboxylate, starting from methyl (7S,6R)-7-L1(R)-tent-butyldimethylsilyloxyethyl/--3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-2-thiacephem-4-5' carboxylate; (KBr) 1765 and 1707 cm 1; ~ (CD3COCD3) 1.30 Ymax (3H, d, CH3.CH), 3.39 (1H, dd, CH. CH.CH), 3.79 (3H, s, NCH3), 3.97 (3H, s, OCH3), 4.0 (1H, m, CH3.CH.CH), 4.38 (2H, centre of ABq, J= l6Hz, separation of inner lines l3Hz, CH2.S), 4.77 (1H, d, J= 2.2Hz, CH. CH. S) and 5.0 ppm (1H, br s, OH);
and, analogously, the corresponding tert-butyl, diphenylmethyl and trichloroethyl esters were also prepared.

- so - 12~48~1 1 Example 34 (?S,6R)-7-L1(R)-methylsulphonyloxyethyl/-3-methyl-2-thia-~hem-4-carboxylic acid 0 S~Z~H3 0 S~ZCH3 SOS N S.S
D ~-N ~ O i-_ N ~L.
~oZC H P~ ~ CazH
5~ Diphenylmethyl (7S,6R)-7-/1(R)-methylsulphonyloxyethyl/-3-methyl-2-thiacephem-4-carboxylate was dissolved in cold trifluoroacetic acid (0°C, neat). After 15' stirring at the same temperature, carbon tetrachloride was added and the solution thoroughly evaporated under vacuum without external heating. The residue was triturated in CC14 and collected, thus obtaining the title product; ~1 (CHC1 ) 281 and 326 nm;
max 3 ~ (CHC13) 3000-.2300, 2970, 2930, 2850, I775, 1710, 1530 and 1170 cm 1; ~ (CD3COCD3) 1.58 (3H, d, CH3.CH), 2.23 (3H, s, Me), 3.16 (3H, s, S02Me), 3.66 (1H, dd, J= 2 and 6Hz, CH. CH.CH), 4.85 (1H, d, J= 2Hz, CH. CH. S), and 5.30 ppm (1H, m, CH3.CH.CH).
The same material was obtained by TFA-hydrolysis of the corresponding t-butyl ester, but prolonging the reaction time to about 1 hour.
Similarly hydrolysis of the t-butyl or diphenylmethyl precursors gave the following products:

i~548~1 ' , - 81 -1 (?S,6R)-7-L1(R)-tert-butyldimethylsilyloxyethyl/-3-methyl -2-thiacephem-4-carboxylic acid;
(?S,6R)-?-L1(R)-hydroxyethyl/-3-methyl-2-thiacephem-4-carboxylic acid;
(?S,6R)-?-l1(R)-hydroxyethylJ-3-acetoxymethyl-2-thiacephem--4-carboxylic acid;
(7S,6R)-?-!1(R)-hydroxyethyl%-3-carbamoyloxymethyl-2-thia-cephem-4-carboxylic acid;
(?S,6R)-?-~1(R)-hydroxyeth~l~-3-(1-methyl-1,2,3,4-tetrazol--5-_~thiomethyl-2-thiacephem-4-carboxylic acid 1 Example 35 (7S,6R)-7-(1(R)-tort-butyldimethylsilyloxyethul)-3-methyl-4-methoxycarbonyl-2-thiacephem-1,1-dioxide ~5~ /PLC Z sut ~5;~ Z gut H ~ ,o S
--N --~ ~ .S

caZCH3 Precedure a) A solution of 117 mg of (7S, 6R)-7-/I(R)-t-butyldimethylsilY
loxyethyl;-3-methyl-4-met.,hoxycarbonyl-2-thiacephem in 5 ml of chloroform was treated with. 220 mg of m-chloroperbenzoic acid at 0oC under stirring. After 3D
minutes the reaction mixture was partitioned between dichloromethane and a 2o by weight aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulphate and the solvent was evaporated off. The residue was purified by ~.hort-path chromatography to afford the title product {89 mg) as a syrup; Y max (CH2C12 film) 1800, 1735 cm l;
d(CDC13) 0.10 (6H,s, Me2Si), 0.90 (9H,s, ButSi), 1.27 (3H,d, CH3-CH), 2.18 (3H,s,CH3), 3.81-3.83 (lH,dd,+3H,s, CH-CH-CH and OCH3), 4.35 (lH,m, CH3-CH-CH),5.05 (lH,d, J=2.0 Hz, CH-CH-S) ppm; Amax (hexane) 276 (E=5.084) and 297 (sh, E=3.745) nm.

~zs~s~s 1 Procedure b) 'A solution of 500 mg of (7S,6R)-7-/1(R)-t-butyldimethy--lsilyloxyethyi; -3-methyl-4-methoxycarbonyl-2-thiacephem in 25 ml of chloroform was treated with 276 mg of 80°o m-chloroperbenzoic acid at 20°C. The temperature was allowed to rise to + 20°C within 30 minutes and then, 4o by weight aqueous sodium bicarbonate solution was added.
The organic layer was dried over anhydrous sodium sulphate, and the solvent was evaporated off. The residue was separated by silica gel chromatography to afford in the following order:
the 1,1 - dioxide, syrupy 35 mg; NMR and IR date as above;
- the 2-oxide, syrup, 60 mg; v max (CH2C12 film) 1795, 1740 5 cm 1; d (CDC13) 0.10 (6H,s, Me2Si); 0.90 (9H,s, 8utSi), 1:24 (3H,d, CH3-CH), 2.35 (3H,S,CH3); 2.85-3.90 (lH,dd, + 3H, s, CH-CH-CH and OCH3), 4.35 (1H, m, CH3-CH-CH), 5.27 (1H, d, J=2.5 Hz, CH-CH-S) ppm; Amax (hexane) 276 (E =5.092)nm;
10 - the 1-oxide, white powder, m.p. 90-93°C, 330mg; Ymax (CH2C12 film) 1790, 1730 cm l; 40.10 (6H,s, Me2Si), 0.90 (9H,S,ButSi) 1.28 (3H,d,CH3-CH), 2.24 (3H,s, CH3), 3.60 (lH,dd, J=2.0 and 4.OHz, CH-CH-CH), 3.87 (3H,s, OCH3), 4.35 (lH,m, CH3-CH-CH), 4.67 (lH,d, J=2.OHz CH-CH-S) ppm;
15 Amax (hexane) 273 (e=4.862), 309 (sh,e=2,721) nm.
The solution of 300 mg of the 1-oxide in 30 ml of chloroform was stirred for 1 hour at room temperature in the presence of 160 mg of m-chloroperbenzoic acid.
The reaction mixture was washed with aqueous sodium 20 bicarbonate solution concentrated and purified by flash-chromatography (silica gel, cyclohexane:ethyl acetate as eluent) thus obtaining a further 280 mc~ of the title product.

1z~4~~1 _ g5 _ 1 Example 36 Hethyl (6S,SR)-6-~1(R)-tert-butyldimethylsilyloxyethyl/-?-methylpenem-3-carboxylate OSiMe2w OS~Me~Bu H o,S~v H S
w a tolcH3 ~°z~ ~3 A solution of 300 mg of (7S,6R)-7-~'1(R)-t-butyldimethylsi lyloxyethyl~-3-methyl-4-methoxycarbonyl-2-thiacephem-l,l-.dioxide in chloroform Was heated at 50oC for 5 hours.
Removal of the solvent afforded the title compound, free of stereoisomers, in nearly quantitative yield (250 mg);
Amax (CHC13) 1795, 1715 cm l; d(CDC13) 0.08 (6H,s, Me2Si), 0.89 (9H,s, ButSi), 1.23 (3H,d,CH3-CH; 2.33 (3H,s, CH3), 3.61 (lH,dd, J=1.B and 5.0 Hz, CH-EH-CH), 3.75 (3,s, OCH3), 4.21 (lH,m, CH3-CI-i-CH), 5.50 (lH,d, J=1.SHZ, CH-CH-S);
Amax (EtOH) 257, 314 nm.
The above reaction occurred even at room temperature; e.g.
after 16 hours standing in chloroform NMR analysis revealed a mixture 1:2 of the title product and the starting material.

- 1;54891 1 EXAMPLE 3~
(7S,6R)-7-/~I(R)-hydroxyethyl~~ 3-methyl-4-methoxycarbonyl-2-thiacephem-1,1-dioxide ~H off os~o 'I
o N
U~tCN3 c~cN3 A solution of 40 mg of (7S,6R)-7-/ 1(R)-hydroxyethyl/-3-methyl-4-methoxycarbonyl-2-ghiacephem in 1 ml of chloroform was stirred at 0°C for 15 minutes in the presence of 60 mg of m-chloroperbenzoic acid.
Partition between ethyl acetate and an acqueous solution of sodium bicarbonate and removal of the solvent left the title compount~, which vas further purified by silica gel chromatography; d (CDC13) 1.36 (3H,d, 0=6.4Hz, G H-CH3-CH), 2.21 (3H,s., CH3), 3.80-3.88 (4H,m;CH-CH and OCH3), 4.40 (lH,m,CH3-CH-CH), 5.08 (lH,d, ~=l.6Hz, CH-CH-S).

~iG~~~~~~

Methyl (6S,5R)-6-/I(R)-hydroxyethyl ~ 2 methvlnP.,Pm 3 carboxylate OH
S,~
~S
a J N' Cozctt3 ~~~3 When a solution of the compound prepared in Example 3~-in an inert solvent (e. g. chloroform or benzene) eras alloured to stand for a fear days, or briefly heated at 50-80°C, the title compound uras formed, free of diastereomers, in virtually quantitative yield.
b(CDC13) 1.34 (3H,d, J=6.4Hz, CH3-CH) 2.35 (3H,s, CH3), 3.68 (lH,dd, J=6.6 and l.SHz, CH-CH-CH), 3.80 (3H,s, OCH3), 4.40 (lH,m, CH3-CH-Cli), 5.56 (lH,d, J=l.SHz, CH-CN-S).

~.~?548~~.
_88_ 1 Example 39 hiethyl (6S, 5R)-6-1 1(R)-tert-butyldimethylsilyloxyethyl/-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethylpenem-3-carboxylate OS I'~et Gut OS i Me Z But N _ S 'S S -11 iv '-----~. ~ S S _ N-N

o,-N ~ v. ..~" I
CoiCH3 3 ~z~H3 A solution of methyl (7S, 6R)-7-/1(R)-tert-butyldimethylsilyloxy-etht~l%-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-2-thiacephem--4-carboxylate in chloroform was stirred at 0°C with m-cloroperbenzoic acid (2.5 molar equivalent) for 30 minutes, and then washed with aqueous PJaHC03. The dried organic layer was refluxed for a few hours (t.l.c. monitoring).
Evaporation of the sol~~ent and silica gel chromatography afforded the title product; d(CI)C13) 0.07 (6H,s, SiMe2), 0.82 (9H, s, Sit3ut), 1.20 (3H,d, CH3-CH), 3.68 (1H, dd, 1.8 and 4Hz, CH. CH.CH), 3.80 (3H, s, PJ-Me), 3.81 (3li, s, OMe), 4.22 (1H, m, CH3-CH-CH), 4.69 (2H, centre of AE3q, ~= 14 Hz, separation of inner lines 11.5 Hz, CH2S), and 5.54 ppm (iii, d, ~= 1.8 Hz, CH-CH-S).

1 Example 40 p-Nitrobenzyl (7S,6R)-7-/1(R)-p-nitrobenzyloxycarbonyloxyethyl/--3-methyl-2-thiacephem-4-carboxylate ou~2 pHB OroZ~Ke H
S~5 O ~--N J G~ -~ o ~ ~ut3 ~z ~pNB
GOZ GH f'j, 2 A solution of diphenylmethyl (7S,6R)-7-/1(R)-p-nitrobenzyloxy-carbonyloxyethyl/-3-methyl-2-thiacephem-4-carboxylate (200 mg) in dichloromethane (25 ml) was treated for 30 min at 0°C with trifluoroacetic acid (0.4 ml). Evaporation under vacuum in the cold left the crude 2-thiacephem-4-carboxylic acid, which was dissolved in acetonitrile-dimethylformamide (2:1, 10 ml) and treated with triethylamine (0.050 ml) and p-nitrobenzylbromide (100 mg). After 1 hour at 25°C, the mixture was partitioned between ethyl acetate and aq. NaHC03.
The dried (MgS04) organic layer was concentrated and the residue passed through a short colum of Si02 (ethyl acetate - light petrol as eluants) to afford the pure title product, 150 mg (79~); d (CDC13) 1.45 (3H, d, CH,3.CH), 3.43 (1H, dd, ~= 2.5 and 6 Hz, CH-CH-CH), 4.45 (2H, ABq, ~= 12 Hz, CH2Br), 4.80 (1H, d, ~= 2.5 Hz, CH-CH-S), 5.2 - 5.5 (5H, m), 7.47 and 7.60 (each 2H, d, Ar), and 8.20 ppm (4H, d, Ar).

1~.'~9~8~1.

' 1 Example 41 (7S,6R)-7-/1(R)-tert-butyldimethylsilyloxyethyl/-4-diphenyl-methoxycarbonyl-2-thiacephem-3-(~yridinium)methyl bromide ~S~ M.e? Su* OS i 4l2 ~ ~3u~
N H
s~.s J
'-co~c~ P~, Z CyctdP~~
A solution of diphenylmethyl (7S, 6R)-7-/ 1(R)-tert-butyldimethylsilyloxyethyl/-3-bromomethyl-2-thiacephem-4--carboxilate (310 mg) in dry acetone (15m1) was treated with pyridine (0.4 m1). 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 CH2C12-HOAc-MeOH 70:15:15) were collected and freed from the solvents to leave the title compound as a syrup; v max (CHC13 film) 1790, 1715 cm 1; d(CDC13~ (inter alia) 1.32 (3H, d, ~= 6.5 Hz), 3.33 (1H, dd), 4.45 (1H, m), 5.0 (1H, d, 0 < 2Hz), 7.11 (1H, s); Amax (CHC13) 283 and 337 nm (e = 4.060).
In a likewise manner, and starting from p-nitrobenzyl (7S,6R)--7-/1(R)-p-nitrobenzyloxycarbonyloxyethyl/-3-bromomethyl-2--thiacephem-4-carboxylate, there was obtained:
(75,6 ~)-7-/ 1(R)-p-nitrobenzyloxycarbonyloxyethyl/-4-p--nitrobenzyloxycarbonyl-2-thiacephem-3-(pyridinium) methyl bromide.

12548~~.

1 Example 42 (7S,6R)-7-/ 1(R)-tert-butyldimethylsilyloxyethyl/-4-carboxy--2-thiacephem-3-(pyridinium) methyl trifluoroacetate s~
O5~ Hez p5;
H
S.s ~,r-N r~ N
~Z(NPI~Z $ ~ Coz~l cF3coZo A solution of the d.iphenylmethyl ester (obtained in Example 41) in dichlorometh,ine (10 ml) was treated with trifluoroacetic acid (2 ml) at 0°C vor 15 min.
After evaporation in vacuo, the residue was taken up in a small amount of chloroform. Ethyl ether was added under stirring and then d~:canted off, to leave the crude title product; vmax (CHC1:; film) 3420, 1785, 1715 and 1635 br cm 1 ;
d(CDC13) (inter alia) 1.30 (3H,d, ~= 6.5 Hz), 3.23 (1H, dd), 4.38 (1H, m), 4.76 ~;1H, d) ppm; Amax (CHC13) 262 and 334 nm.

i;~~4~9~1 1 Example 43 (7S,6R)-7-/1(R)-p-nitrobenzyloxycarbonyloxyethyl/-4-p-vitro benz~loxycarbonyl-2-thiacephem-3- (3-carbamoylpyridinium) methil bromide ocoZ fnlB ocoiP~B
H
s s j ~ \~ ~ o A ~-'N ~ ~ r o. ~--nr ~~~ N~ ~r colPNg ~ . ~~ corvNZ
2~
A solution of p-nitrobenzyl (7S,6R)-7-/ 1(R)-p-nitrobenzyloxy-carbonyloxyethyl/-3-bromomethyl-2-thiacephem-4-carboxylate (460 mg) in DMF (5 ml) was stirred overnight in the dark in the presence of nicotinamide (200 mg). Most of the solvent was distilled off z.nd the residue taken up in tetrahydrofuran (150 ml). This solution was repeatedly washed with a solution of NaCl in 0.1 N HC'1 (2x50 ml), with brine (2x50 ml)dried (Na2S04) and evaporated. The residue was charged on the top a column packed with silanised silica gel (Merck, Art. 7719).
Excess nicotinamide: and impurities were eluted with EtOAc, then the product w<<s collected by eluting with EtOAc-HOAc (9:1). Evaporation in vacuo left the title product; v max (CHC13) 1800, 1725, 1695 cm l; d (deuteroacetone; 200 MHz) 1.67 (3H,d,~= 6.4 Hz, CH3-CH), 4.14 (1H, dd, ~= 2.5 and 4.7 Hz, CH-CH-CH), 5.30 (1H, d, ~= 2.5 Hz, CH-CH-S), 5.4-5.7 (7H,m, 2xCH20Ar, CH2N+, and CH3-CH,-CH), 7.7-8.4 (BH,m, Ar), and 8.0, 8.7, 9.5 and 9.7 ppm (each 1H, br s, pyridinium).

12~4~~

Analogously, by using isonicotinamide instead of nicotinamide, there was obtained (7S,6R)-7-/1(R)-p-nitrobenzyloxycarbonyloxyethyl/-4-p-nitrobenzyloxycarbonyl-2-thioacephem-3-(4-carbamoylpyridi-nium)methyl bromide.

1;54891 1 Example 44 (6S,5R)-6-/1(R)-hydroxyethyl/-2-(piridinium)methyl penem-3--carboxylate O~sPNB
~H
S~S ~ H S
l"_'N
c~3coz ° ~o ~P
_ A solution of (7S,6R)-7-/1(R)-p-nitrobenzyloxycarbonyloxy-ethyl/-4-p-nitrobenzyloxycarbonyl-3-(pyridinium)methyl-2-thiacephem acetate (prepared from the corresponding bromite by conventional treatment SYl.th silver acetate or an ion-exchange resin) in chloroform was treated with peracetic acid (2 mol. equivalent) at 0°C. Work-up and gentle heating, according to the general procedure described in Examples 37-39, gave (6S,5R)-6-/1(R)-p-nitrobenzyloxy~~arbonyloxyethyl/
-3-p-nitrobenzyloxycarbonyl-2-(pyridinium)methylpenem acetate;
v (KBr) 1795, 1740, 1705 cm l; 8(CDC13 + ~ieuteroacetone) max 1.4 (3H,d, 3= 6.5 Hz, CH3-CH), 4.10 (1H, dd, 3= 1.7 and 8 Hz, CH-CH-CH), 5.20 and 5.31 (each 2H, s, OCH2Ar), 5.2 (lH,m, CH3-CH-CH), 5.77 (1H, d, ~= 1.7 Hz, CH-CH-S), 6.05 (2H, ABq, 3= 15 Hz, CH2N), 7.4-8.3 (11H, m, Ar) and 9.15 ppm (2H, d, ~= 6 Hz, o-Pyr).
This material (300 mg) in tetrahydrofuran-water (1:1, 40 ml) was treated with ammonium chloride (5 g) under stirring to 1;~J~8~1 obtain a clear solution.
After cooling to about 10°C, iron powder (2.5 g) was added under vigorous stirring; the reaction could be monitored by TLC (H20-MeOH-NaCl 9:1:1) by following the development of the product as a faster running spot. After about one hour, celite~(3 g) was added and the whole filtered through a glass septum, washing with demineralised water. Removal of the organic solvent, followed by washing' with ethyl ether, left an aqueous solution of the title product and inorganic salts.
The former was obtained pure after reverse-F~hase chromatography and freeze-drying; d (D20, 200 MHz) 1.27 (3f1, d, g=6.5 Hz, CH3CH), 3.98 (1H, dd, 0=1.4 and 5.8 Hz, CH-(:H-CH), 4.24 (1H, m, CH3-CH-CH), 5.69 (1H, d, 0= 1.4 Hz (:H-CH-S), 5.94 (2H, ABq, 0= 14.9 Hz, CH2N), 8.10 (2H, t, 0=: 6.6Hz, pyridinium m-H), 8.61 (1H, bd, ~= 7.7 Hz, pyridinium p-.H), 8.95 (2H, d, = 6.6 Hz, pyridinium o-H) ppm.
In a likewise manner, starting from the comE~ounds described in Example 43, there was obtained:
(6S,5R)-6-/1(R)-hydroxyethyl/-2-(3-carbamoyl_pyridinium) methylpenem-3-carboxylate;
(6S,5R)-6-/1(R)-hydroxyethyl/-2-(4-carbamoylpyridinium)methyl-penem-3-carboxylate "'(' cad e. '(''n a r k 1~:;i~8~1 1 Example 45 (6S,5R)-6-/1(R)-hydroxyethyl/-2-(1-methyl-1,2,3,4-tetrazol--5-yl) thiomethylpenem-3-carboxylic acid, sodium salt B
N wN
,_ s~s _~ ~' ~:
N S .N,N
N ~'~'13 totPN6 ~3 Co2lJ~
A solution of p-nitrobenzyl (7S,6R)-7-/1(R)-p-nitrobenzyloxy-earbonyloxyethyl/-3-(1-methyl-1,2,3,4-tetrazal-5-yl)thiomethyl--2-thiacephem-4-carboxy,late in chloroform was oxidized with m-chloropebenzoic acid, as described in Example 37, to give the corresponding sulphone. lYithout purification, this material was heated at 60°C in dry distilled tetrahydrofuran under a stream of nitrogen until extrusion of S02 was complete.
Removal of the solvent and silica gel chromatography gave p-nitrobenzyl (6S,5R)-6-/1(R)-p-nitrobenzylorycarbonyloxyethyl/--2-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyJ.penem-3-carboxylate;
d (COC13) 1.48 (3H, d, 3=7 Hz. CE13-CH) 3.84 L1H, dd, 3=2 and 5.5 Hz, CH-CH-CH), 3.96 (3H, s, NCH3), 4.69 (2H, ABq, J=
14 Hz, CH2S), 5.20 (1H, m, CH3-CH-CH), 5.24 (2H, s, OCH2Ar), 5.27 (2H, ABq, 3= 13 Hz, OCH2Ar), 5.61 (1H, d, 3= 2 Hz), 7.51 and 7.82 (each 2H,d,~= BHz, Ar), 8.02 ppm (4H, d, ~= 8 Hz, Ar). Reaction of the above material with Fe/NH4C1, according to the procedure described in Example 44, afforded the title 1;~',i~~391 1 product; d (D20) 1.28 (3H, d, 3=6.5 Hz), 3.87 (1H, dd, ~=1.4 and 6.3 Hz, CH-CH-CH), 4.10 (3H, s, NCH3), 4.19 (1H, m, CH3-CH-CH), 4.40 (2H, ABq, 3= 16 Hz, CH2S), 5.59 ppm (1H, d, 3= 1.4 Hz, CH-CH-S); Amax (H20) 315 nm.

12S4~3~1 1 Example 46 Methyl (6S,SR)-6-/ 1(R)-tert-butyldimethylsilyloxyethyl/--2-nitrooxymethylpenem-3-carboxylate DSi1'~Z gut OSi I~ B
t H
---~S ~ oN r7 2 o''~' ~N ~2 ,...
v co2c~~ ~°x~3 A solui:ion of methyl (7S,6R)-7-/1(R)-tert-butyldimethylsily-loxyethyl/-3-nitrooxymethyl-2-thiacephem-4-carboxylate (prepared as described in Example 31) in chloroform was treated with m-chloroperbenzoic acid (2 molar equiv, 0°C) to give the 1-sulphone. Aqueous hydrogen carbonate was added to extract m-chlorobenzoic acid, and then the dried organic solution was gently refluxed (t.l.c. monitoring), to give a solution of the title penem compound; d(CDC13) (inter alia) 5.64 (1H, d, 3= 2 H~:, CH-CH-S) and 5.65 ppm (2H, ABq, 3= 15 Hz, sep. of inner line 46 Hz, CH20N02); vmax (CHC13) 1790 and 1710 cm 1.
In a likewise manner, starting from trichloroethyl (7S,6R)--7-/1(F;)-trichloroethoxycarbonyloxyethyl/-3-nitrooxymethyl--2-thiacephem-4-carboxylate, there was obtained:
Trichloroethyl (6S,SR)-6-L1(R)-trichloroethoxycarbonyloxyethyl/--2-nitrooxymethylpenem-3-carboxylate 1;~~4~~i 1 Example 47 Plethyl (6S,5R)-6-/1(R)-tert-butyldimethylsilyloxyethyl/-2--hydroxymethylpenem-3-carboxylate OS~Melgu~ ~Sil~(QZ$u H
H
~S oNOt ~ 5 /~ Ol-l p~N
CO1CN3 0 (pl A solution of crude methyl (6S,5R)-6-/1(R)-tert-butyldimethyl-silyloa:yethyl/-2-nitrooxymethylpenem-3-carboxylate (obtained from 4'~ mg of the corresponding 3-bromomethyl-2-thiacephem precur:,or, according to Examples 31 and 46) in dichloromethane (2 ml) was stirred for 5 min at U°C with zinc dust (0.1 g) and acetic acid (0.1 ml). The reaction mixture was filtered and the solution was evaporated to give the crude title product, which was purified by silica gel chromatography (ethyl acetate - light petrol, from 1:4 to 1:1); vmax (CHC13 film) 1785, 1710 cm l; d(CDC13) 0.07 (6H, s, Sitle2), 0.88 t (9H, s, SiBu ), 1.23 (3H, d, CH3-CH), 3.70 (1H, dd, ~= 1.8 and 4.5 Hz, CH-CH-CH), 4.25 (1H, m, CH3-CH-CH), 4.59 (2H, s, CH20H) and 5.57 ppm (1H, d, ~= 1.8 Hz, CH-CH-S).

~254~~1 - ioo -1 By operating in an analogous way on trichloroethyl (6S,5R)--6-/1(R)-trichloroethoxycarbonyloxyethyl/-2-nitrooxymethyl-penem-3-carboxylate, complete deblocking of the protecting groups was achieved, thus obtaining after aq. NaHC03 work up and reverse phase chromatography (water as eluant);
(6S,5R)-6-/1(R)-hydroxyethyl/-2-hydroxymethylpenem-3-carboxylic acid, sodium salt; d(D20) 1.30 (3fa, d, CH3-CH), 3.88 (1H, dd, ~= 1 and 6.3 Hz, CH-CH-CH), 4.~3 (1H, m, CH3-CH-CH), 4.63 (2H, ABq, 3= 14.5 Hz, separation of inner lines 4 Hz, CH20H), and 5.62 ppm (1H, d, ~= lHz, CH-CH-Si; vmax tKBr) 1765 and 1610-1590 cm 1.

~;~~4~~1 1 Example 48 (6S,5R)-6-/1(R)-hydroxyethyl/-2-carbamoyloxyemethylpenem--3-carboxylic acid, sodium salt 0 Go~,C~, C(y OH
~'5 ~ 5 oGoNffZ
~OCpNH2 ° ~ ~ o ~ cozN a (.c~cK2~ce3 ~~h chloroform solution of trichloroethyl (7S,6R)-7-/1(R)-trichl.oroethoxycarbonyloxyethyl/-3-carbamoyloxyethyl-2-thiacE:phem-4-carboxylate was treated with m-chloroperbenzoic acid according to the general procedure of Example 37. After work-up, brief heating of the resulting 1-sulphone in an inert solvent (benzene) gave trichloroethyl (6S,5R)-6-/1(R)--tricliloroethaxycarbonyloxyethyl/-2-carbamoyloxymethylpenem--3-carboxylatc; 8(CDC13) 1.5 (3H,d, CH3-CH),3.94 (1H, dd, J= 2 and 8 Hz, CH-CH-CH), 4.73 and 4.82 (each 2H, s, OCH2CC13), E
E
4.8 (:lH, m, CH3-CH-CH) 5.25 (2H, ABq, J= lOHz, CH20CONH2), 5.62 ;1H, d, J= 2Hz, CH-CH-S).
A THF solution of this material was treated with Zn dust (approx. 6 parts by weight) and 1M aq. NaH2P04 under stirring.
After 3 hours stirring at 25°C, another portion of Zn was added and the mixture kept stirring for 3 hours. Work-up and reverse-phase chromatography afforded the title product;
8 (D20) 1.31 (3H, d, J= 6.5 Hz, CH3-CH), 3.91 (1H, dd,J= 1.5 and 6Hz, CH-CH-CH), 4.25 (1H, m, CH3-CH-CH), 5.19 (2H, ABq, J= 14.5 Hz., CH20C0) and 5.66 ppm (1H, d, J= 1.5 Hz, CH-CH-S).

Claims

The embodiments of an invention in which an exclusive property or privilege is claimed are defined as follows:
1. A process for the preparation of a 2-thiacephem derivative of the general formula II:

wherein R1 represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or a cycloalkyl group having 4 to 7 carbon atoms, said alkyl and cycloalkyl groups optionally substituted by hydroxy, protected hydroxy, amino, protected amino, mercapto, protected mercapto or cyano;
R2 represents a hydrogen atom or a carboxy protecting group and Y represents a hydrogen atom or a halogen atom, comprising a process selected from the group consisting of:
(a) a process for the preparation of a 2-thiacephem derivative of the general formula II above wherein R1 and R2 are as defined above and Y represents a halogen atom characterized in that a compound of general formula IV:

Claim 1 continued....

wherein R1, R2 are as above defined and Z represents:
(i) a group of the formula SR7 wherein R7 represents an alkyl group having from 1 to 8 carbon atoms, a phenyl or tolyl group, or a 2-benzothiazolylthio or 1-methyl-tetrazol-5-yl-thio group, (ii) a group of the formula SCOR8 wherein R8 represents a lower alkyl group, (iii) a group of the formula wherein R9 and R10 independently represent lower alkyl or aryl groups, or together with the dicarboxyamino group form a succinimido or phthalimido group, or (iv) a group of the formula wherein R7 represemts a lower alkyl or aryl group;
is first halogenated to obtain the compound of general formula V:

Claim 1 continued....

wherein R1, R2, and Z are as above defined and Y is a halogen atom, and subsequently ozonolyzed to give a compound of general formula VII:

wherein R1, R2, and Z are as defined above and Y is a halogen atom, transforming the hydroxy group into a L
group, wherein L represents a halogen atom, an alkane sulphonyloxy group or an arenesulphonyloxy group, so to obtain a compound of general formula IX:

wherein R1, R2, Z and L are as defined above and Y is a halogen atom which is subsequently cyclized to give the desired compound of formula II above wherein R1 and R2 are as defined above and Y is a halogen atom, (b) a process for preparing a 2-thiacephem derivative of the general formula II above wherein R1 and R2 are as defined above and Y

Claim 1 continued...

represents a hydroyen atom characterized in that a compound of general formula IV:

wherein R1, R2, and Z are as defined above is first ozonolyzed to give a compound of the general formula VI:

wherein R1, R2, and Z are as defined above, converting the hydroxy group into a L group, wherein L is as defined above, to obtain the compound of general formula VIII:

wherein R1, R2, Z and L are as defined above, which is subsequently cyclized by treatment with a salt of H2S
with an organic or inorganic base to the desired 2-thiacephem of the general formula II wherein R1 and R2 are as defined above and Y represents a hydrogen atom; and

Claim 1 continued....

(c) a process for the preparation of a 2-thiacephem derivative of general formula II
above wherein R1 and R2 are as defined above and Y is a halogen comprising process (b) above wherein the resultant product of process (b) is halogenated to give the desired 2-thiacephem compound of formula II wherein R1 and R2 are as defined above and Y is a halogen atom.
2. Process (a) of Claim 1.
3. Process (b) of Claim 1.
4. Process (c) of Claim 1.
5. The process of Claim 3 or 4 wherein L
represents a methanesulphonyloxy group.
6. The process of claim 4 wherein Y is bromine or chlorine and said resultant product of process (b) is halogenated by being treated at a temperature of 20°
to 130°C, dissolved in an inert organic solvent with N-bromosuccinimide or N-chlorosuccinimide in the presence of azobisisobutyronitrile or benzoyl peroxide and in presence of acid scavengers to give the desired 2-thiacephem compound of formula II wherein R1 and R2 are as above defined and Y is a bromine or chlorine atom.
7. The process of Claim 1 wherein Y represents a flourine, chlorine or bromine atom.
8. A process for the preparation of a 2-thiacephem derivative of the general formula II:

wherein R1 represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or a cycloalkyl group having 4 to 7 carbon atoms, said alkyl and cycloalky groups optionally substituted by hydroxy, protected hydroxy, amino, protected amino, mercapto, protected mercapto or cyano;
R2 represents a hydrogen atom or a carboxy protecting group and Y represents a hydrogen atom, a halogen atom, a hydroxy, formyloxy, acetoxy, carbamoyloxy, N-(trichloroacetyl) carbamoylozy or 1-pyridinium group, or a 1-pyridinium group substituted in the meta or para position with a -CO-NH2 group, comprising a process selected from:
(a) a process for the preparation of a 2-thiacephem derivative of the general formula II above wherein R1 and R2 are as defined above and Y represents a halogen atom characterized in that a compound of general formula IV:

Claim 8 continued.....

wherein R1, R2 are as above defined and Z represents:
(i) a group of the formula SR7 wherein R7 represents an alkyl group having from 1 to 8 carbon atoms, a phenyl or tolyl group, or a 2-benzothiazolylthio or 1-methyl-tetrazol-5-yl-thio group, (ii) a group of the formula SCOR8 wherein R8 represents a lower alkyl group, (iii) a group of the formula wherein R9 and R10 independently represent lower alkyl or aryl groups, or together with the dicarboxyamino group form a succinimido or phthalimido group, or iv) a group of the formula , wherein R7 represents a lower alkyl or aryl group;
is first halogenated to obtain the compound of general formula V:

Claim 8 continued....

wherein R1, R2, and Z are as above defined and Y is a halogen atom, and subsequently ozonolyzed to give a compound of general formula VII:

wherein R1, R2, and Z are as defined above and Y is a halogen atom, transforming the hydroxy group into a L group, wherein L represents a halogen atom, an alkane sulphonyloxy group or an arenesulphonyloxy group, so to obtain a compound of general formula IX:

wherein R1, R2, Z and L are as defined above and Y is a halgen atom which is subsequently cyclized to give the desired compound;

Claim 8 continued....

(b) a process for preparing a 2-thiacephem deriviative of the general formula II above wherein R1 and R2 are as defined above and Y
represents a hydrogen atom charaterized in that a compound of general formula IV:

wherein R1, R2, and Z are as defined above is first ozonolyzed to give a compound of the general formula VI:

wherein R1, R2, and Z are as defined above, converting the hydroxy group into a L group, wherein L is as defined above, to obtain the compound of general formula VIII:

Claim 8 continued....

wherein R1, R2, Z and L are as defined above, which is subsequently cyclized by treatment with a salt of H2S
with an organic or inorganic base to the desired compound;
(c) a process for the preparation of a 2-thiacephem derivative of general formula II
above wherein R1 and R2 are as defined above and Y is a halogen comprising process (b) above wherein the resultant product of process (b) is halogenated to give the desired compound;
(d) a process for the preparation of a 2-thiacephem derivative of the general formula II above wherein R1 and R2 are as defined above and Y is a hydroxy group, comprising either process (a) or process (c) above wherein the resultant product therefrom dissolved in an acetone-water mixture (2:1 v/v) is reacted for 15 minutes at a temperature of 0°C with a salt of a strong inorganic acid thus obtaining a labile ester of said inorganic acid which subsequently hydrolyzes in the same reaction medium to the desired compound;

Claim 8 continued....

(e) a process for the preparation of a 2-thiacephem derivative of the general formula II above wherein R1 and R2 are as defined above and Y is a formyloxy or acetoxy group, comprising either process (a) or process (c) above wherein the resultant product therefrom, dissolved in dichloromethane is treated at a temperature of 5°C and at daily intervals for 3 days with a suitable salt of the corresponding carboxylic acid to give the desired compound;
(f) a process for the preparation of a 2-thiacephem derivative of the general formula II above wherein R1 and R2 are as defined above and Y is a carbamoyloxy group, comprising process (d) above wherein the resultant product therefrom, dissolved in dichloromethane, is treated, at a temperature of -40°C, with a trichloroacetylisocyanate, raising the reaction mixture it room temperature and subsequently isolating the desired 2-thiacephem derivative of formula II, wherein R1, R2 are as above defined and Y is a N-trichloroacetyl carbamoyloxy group which, if desired, is submitted to the deprotection of the trichloroacetyl moiety of the first formed urethane
Claim 8 continued....

adduct by stirring for 20 hours its methanolic solution with silica gel, so to obtain the 2-thiacephem deriviative of formula II, wherein R1, R2 are as above defined and Y is a carbamoyloxy group; and (g) a process for the preparation of a 2-thiacephem derivative of the general formula II above wherein R1 and R2 are as defined above and Y is a 1-pyridinium or a 1-pyridinium group substituted in the meta or para position with a -CO-NH2 group, comprising process (a) or process (c) above wherein the resultant product therefrom, is reacted at room temperature with pyridine, nicotinamide or isonicotinamide to give, respectively, after purification by silica gel chromatography, the desired 2-thiacephem compounds product of formula II, wherein R1, R2 are as above defined and Y is a 1-pyridinium group or a 1-pyridinium group substituted in meta or para position by a -CO-NH2 group.
9. Process (d) of Claim 8.
10. Process (e) of Claim 8.
11. Process (f) of Claim 8.
12. Process (g) of Claim 8.
13. The process of claim 6 wherein said acid scavengers are selected from propylene oxide, alkaline-earth oxides and molecular sieves.