Field of the invention The present invention relates to a new process for the preparation of cephalosponns, in particular 3 ^-n orcephalospoπns, such as Cefaclor, Ceftibuten and Ceftizoxime, 3~ ^a lkenylcephalosporιns (Cefixime, Cefprozil), 3-πιercaptomethyl cephalosponns (Ceftπaxone) and 3" methoxymethyl cephalosponns (Cefpodoxime) , in particular comprising reductive dicarbonyl cyclization induced by trialkyl phosphite of {3R,4R) -3-acylamιno-4-thιo-azetιdιnone derivatives obtained from penicillins. State of the art Cephalosponns are usually prepared from 7~ACA. In the case of 3" norcephalospoπns, the intermediates thereof, 3 ^_ hydroxy-3-cephemt. [R.R. Chauvette, P. Penmngton, J. Am. Chem. Soc, 96, 4 86, 1974; R- Scartazzim, H. Bichel, Helv. Chim. Acta, 57. 1919. 1974] are prepared on a commercial scale not only from 7-ACA but also by ozomzation of thiazolme azetidmone (1) to give enol (2) (M. Foglio, G. Franceschi, P. Masi, A. Suarato, GB 1,482,493) followed by cyclization of enol (2) to 3-OH-3-cephem (3) (USP 4,l6θ,Oδ5) (Scheme 1).

Scheme 1

thio-azetidinone derivatives obtained by cleavage of the nucleus of 6- APA derivatives, or of thiazolme azetidinones derived from penicillins. (3R.4R)-3 ^_ acylamιno-4-thιo azetidinones can be prepared by treatment with α-haloesters of thiazolme azetidinones in the presence of urea (GB 1,368,234, Glaxo Labs. Ltd.), or of a 6-APA derivative with the ammo group at C-6 protected as a trityl derivative (E.G. Brain e t a l . , "Syntheses involving 1,2-

Secopenicillms" , in Recent Advances in the Chemistry of β-Lactam Antibiotics, Cambridge, England, 28-30 June, 1976, J. Elks ed., pp. 204-213- Summary Now the Applicant has found a new process for the preparation of intermediates useful for obtaining cephalosponns, in particular 3" norcephalospoπns, such as 3~H-, 3~C1- and ^,-OCh- - cephalosponns; 3 ^_ alkenyl-, 3 ^-m ethylth o- and 3 ^-me thoxymethyl-cephalospor ns , from penicillins or penicillin derivatives, v i a reductive C=0/C=0 or C=0/C=S cyclization induced by a trialkyl phosphite of dicarbonyl compounds of formula (II) described hereinafter.

In particular, the present process comprises the preparation of 3~ cephem derivatives of formula (I)

where A is a protective group of the ammo function selected from the group consisting of R _? , where R is PhoC-, and acyl F C0-, where Ro is H, or a residue Rn of the 6-acylamιno chain present n natural or semisynthetic penicillins;

R is H, a cation (alkali metal or ammonium group or quaternary ammonium group) or a protecting group of the carboxy function;

- X-^ has one of the meanings defined below

a) halogen ; b ) H ; c) -OH, -ORj _j , -0-C0R ₄ , -0S0 ₂ R ₄ , -SH, -SR^ , -S-COR^ , where R^ stands for hydrocarbon residues containing from 1 to 18 carbon atoms, either unsubstituted or substituted with one or more groups containing heteroatoms (halogens, nitro groups); d) -NR[-Rg, where Rr- and R^, together with heteroatom N linked thereto, form an aromatic or non-aromatic heterocyclic residue, either monocyclic or bicyclic, having from 3 to 7 atoms in each cycle, optionally containing, in addition to said heteroatom N, one or more heteroatoms selected from the group consisting of N, 0 and S, said heterocyclic residue being either unsubstituted or substituted with at least a group selected from the group consisting of -OH, =0 and a C^-Cg alkyl; e) -CH ₂ Q, where Q s H or -ORy, where Ry is a C^C alkyl; f) -Ct^-S-Het^ , where Het-^ is an aromatic or non-aromatic heterocyclic residue, either monocyclic or bicyclic, having from 3 to 7 atoms in each cycle, containing one or more heteroatoms selected from the group consisting of N, 0 and S, said heterocyclic residue being either unsubstituted or substituted w th one or more groups selected among

-OH, =0 and a C-J Q alkyl and being linked to atom S through a carbon atom of the cycle; g) an alkenyl group -CH=CHG, where G is selected from the group consisting of H, a straight or branched C-,-C? alkyl, and Het , where Het is an aromatic or non-aromatic heterocyclic residue, either monocyclic or bicyclic, having from 3 to 7 atoms in each cycle, containing one or more heteroatoms selected from the group consisting

of N, 0 and S, said heterocyclic residue being either unsubstituted or substituted with at least one group selected from the group consisting of -OH, =0, and a Cft-Co alkyl, and being linked to the alkenyl group through one of the carbon atoms of a cycle or through one of the heteroatoms of a cycle, by treatment with a trialkyl phosphite of an azetidine oxalimido derivative of formula (II)

where A and R,, have the above meanings, Y is =0 or =S, and X-^g has one of the meanings defined above for _j _A' Provided that X-^g is different from H and from a halogen. The derivatives of formula (I), where X _1A is H, are prepared b treating with a reducing agent the compounds of formula (I) , where X-^ is a), c) or d), which on their turn are prepared from the corresponding compounds of formula (II), where X^g is c) or d) . In particular, the compounds of formula (I) , where X-^^ is a halogen, are prepared by treating with a halogenating agent the compounds of formula (I), where Xi. is c) or d) , which on their turn are prepared from the corresponding compounds of formula (II), where X^ is c) or d). The compounds of formula (I), where X _1A is c), d) , e) , f) or g) are prepared from the corresponding compounds of formula (II) , where Xig is c), d) , e) , f) or g) , respectively.

According to a particular embodiment of the present invention, the preparation of the compound of formula (II), where X _lβ is c) or d), as defined above, comprises the following steps: A.l) treatment of a penicillin of formula (III)

where A is Ph C-, R-^g has one of the meanings above reported for R . for compounds of formula (I) , and is preferably a protective group of the carboxyl function, equal to or different from R^ _A . with a compound of formula (A)

Y

II Z ₁ -CH ₂ -C-X _1B (A) where Xig is c) or d) , Y has the above meaning, and Z^ is a group selected from the group consisting of a halogen or an aliphatic or aromatic sulphonyloxy group, in the presence of a strong base, to give the azetid one derivative of formula (IV)

where A is Ph^C- , and R^g . _j _ and Y have the above meanings ; A . 2 ) t reatment of the compound o f formula ( IV ) ob tained in the preceding step with alkali or alkaline-earth metal permanganate , to

g ve the azetidmone derivative of formula (V)A

where A is PhoC-, and ^g. X^g and Y have the above meanings, and R _j ^

A.3) treatment of the azetidmone derivative of formula (V)A, where A is PhoC-, obtained m the preceding step, with an oxalic acid derivative of formula (B)

where Att-^ is an activating group of the carboxyl function and W is selected from the group consisting of Att and where Att ₂ s an activating group of the carboxyl function, equal to or different from Att- and R-^ has the above meaning, said treatment being followed, when is Att-,, by a treatment with a compound R _1A ~0H, to give the corresponding azetidmone derivative of formula (II), where A is PhoC-, and Rι«, Xig and Y have the above meanings. According to a further embodiment of the present invention, the preparation of the compound of formula (II) , where X _j _g is c) or d) , as. defined above, comprises step A.l) as above defined, followed by: A.4) treatment of the azetidmone of formula (IV), where A is PhoC- obtained from step A.l) with ozone, to give the corresponding oxamide of formula (II), [where A is PhoC-, Y and X are defined as m step A.l), and R,. = Rig of the compound of formula (IV)], available for the final cyclization to the 3-cephem nucleus.

Accordmg to a still further embodiment of the present invention, the preparation of the compound of formula (II), where X-^g is a group linked to the 3 ^_ cephem nucleus through a heteroatom selected between c) and d) , or a group linked to the 3~cephem nucleus through a carbon atom selected between CH ₂ Q, where Q is H, and g) , comprises the following steps: B 1) treatment of thiazolme azetidmone of formula (VI)

where Ro has the above meaning and R _N is H or -C(C00R^ _A )=C(CHo ) ₂ , where Ri. is as above defined for compounds of formula (I) , and is preferably a protective group of carboxyl function, with a compound of formula (A)

Y

I Z ₁ -CH ₂ -C-X _1B (A) where Zγ and Y have the above meanings, X-^ is c) , d) , CH ₂ Q, where Q is H, or g) as defined above, and Z is a group selected from the group consisting of a halogen or an aliphatic or aromatic sulphonyloxy group, m the presence of thallium tnacylate or of a compound having a pK of less than 10 (in water at 25°C) and of a hydroxylated compound, to give the corresponding azetidmone of formula (V)A

AN

where A is RoCO- as defined above, X-^ and Y have the above meanings, and is H or -C(COOR _A )=C(CHo) ₂ , where R has one of the meanings above defined for formula (I), and is preferably a protective group of carboxyl function, B.2) treatment of azetidmone of formula (V)A obtained from B.l), where A is RoCO- and Ro, Y and X _lβ are as defined above in B.l): 1) when R», is H, with an oxalic acid derivative of formula (B)

CO-At^ (B)

CO- where A t-^ is an activating group of the carboxyl function and is selected among Att ₂ and "0R^ _A , where Att ₂ is an activating group of the carboxyl function, equal to or different from Atti, and R _A has the above meaning, said treatment being followed, when W is Att ₂ , by a treatment with a compound Rι ~0H; or alternatively, ii) when R^ is -C(COOR-, ) =C(CHo ) , as above defined, with ozone, to give the corresponding azetidmone derivative of formula (II) where A is RoCO-, . - and X-^g and R _1A are as defined above in B.l).

Accordmg to a still further embodiment of the present process, the preparation of the compounds of formula (II), where Xig is -CHoS-Heti , as defined under f) , or a -CH ₂ 0Ry group, as defined under e) , comprises the following steps:

Cl) treatment of thiazolme azetidmone of formula (VI)

where Ro has the above meaning, and R^ is H or -C(C00R _1A ) =C(CHo )- _> , as above defined, with a compound of formula (C)

where Y has the above meaning , Z-, and Z , identical or different each from another , are selected from the group consisting of a halogen and an aliphatic or aromatic sulphonyloxy group , in the presence o f thallium tnacylate or of a compound having a pK _a of less than 10 ( in water at 25 ° C ) and of a hydroxyl ated compound , to give the corresponding azetidmone of formula ( V)B

where A is RoCO- as defined above, Z ₂ and Y have the above meanings and R _N is H or -C(C0OR _1A )=C(CHo ) ₂ , as above defined;

C.2) treatment of azetidmone of formula (V)B, obtained n the preceding steps, with a thiol derivative Het^-S M , where He ^ has the above meaning and is an alkali or alkalme-earth metal cation, or with an alkox de RyO~M ⁺ , where Ry has the above meaning and M ⁺ is an

alkaline or alkalme-earth metal cation, to give the corresponding azetidmone derivatives of formula (V)C

where A is RoCO- as defined above, X ₂ s S-Het^ or ORy , and R^ is H or -C(C00R _1A )=C(CH ₃ ) ₂ , as above defined; C.3) treatment of azetidmone of formula (V)C obtained m the preceding step and having R^=H with an oxalic acid derivative of formula B)

where Att is an activating group of the carboxyl function and W is selected between Att ₂ and -ORI Λ, where Att is an activating group of the carboxyl function, equal to or different from Att- and R^ _A has the above meaning, said treatment being followed, when W is Att ₂ , by a treatment with a compound R Λ-OH; or alternatively, treatment of azetidinones (V)B of (V)C wherein R _N is - C(C00R _1A )=C(CHo ) ₂ obtained from the preceding steps, with ozone, further followed m the case of azetidmone (V)B bj- treatment according to step C.2), to give the corresponding azetidmone derivative of formula (II), where X^g is - CH ₂ -SHet ₁ or -CH ₂ 0Ry, and A, Y, R _1A , He^ and Ry are as defined above accordmg to Cl) to Cft) ■ According to a particular embodiment of the present invention, the

preparation of the compound of formula (II) as above reported where X-^ is an alkenyl group -CH=CHG, as above defined under g) , comprises the following steps:

D.l) treatment of thiazolme azetidmone of formula (VI), to give azetidmone of formula (V)B, as per step Cl previously reported; D.2) treatment of azetidmone of formula (V)B, obtained from the preceding step, with a triphenylphosphine (e.g. 0°C-4θ°C) , followed by treatment of the corresponding phosphomum salt with a base, and then with an aldehyde (e.g. 20°C-80°C)

H-CO-G where G has the above meaning, to give the corresponding azetidmone of formula ( V) D :

where A, Y, and R^ are defined accordmg to the preceding step and G has the above meaning;

D.3) treatment of azetidmone of formula (V)D obtained in the preceding step: I) where R _j is H, with an oxalic acid derivative of formula B)

CO-Att-, (B)

I

CO- where Atti is an activating group of the carboxyl function and W is

selected between Att and ~0R^ , where Att ₂ is an activating group of the carboxyl function, equal to or different from Atti, and i. has the above meaning, said treatment being followed, when W is Att _p , by treatment with a compound R-^-OH, to give the corresponding azetidmone derivative of formula (II), where X g is an alkenyl group -CH=CHG, as above defined under g) , and the other substituents are as above defined in step D.l) to D.3). Detailed description of the invention When the compound of formula (II) is prepared starting from thiazolme azetidmone of formula (III), group A is preferably the residue RoCO- present in penicillin G or penicillin V, where R is PhCH _p - or PhOCH ₂ -, respectively.

Ro may have other meanings: for example, it may stand for a straight or branched Cι_ alkyl group, optionally substituted with one or more free or protected amino groups and/or free or protected carboxyl groups (for example, Ro may be the D-4-ammo-4-carboxy-butyl group present in penicillin N, with optionally protected ammo and carboxyl groups); Ro may also stand for a Ph—CH(NHP)- group, where P is a protective group of the amino function, such as the formyl group -C0H, the carbobenzoxy group PhCHpO-CO- or the group carbo-2, 2,2- tπchloroethoxy CCloCH ₂ 0-C0-. RoCO- may be either as such, or in protected form.

As used herein, the expression "protective group of the carboxyl function" means a (chemically labile) protective group, which is usual in the chemistry of penicillins and cephalosponns.

The protective groups of the carboxyl function R _1A and Rι _β may be equal or different each from another and are preferably: straight or

branched C-^-Cg alkyl groups, either saturated or containing from 1 to 3 unsaturations, for example double bonds, or from 1 to 3 substituents such as halogens and Ri bemg for instance tert-butyl, 2.2 , 2- trichloroethyl or allyl groups); or Cy-C ₂ g arylalkyl groups, optionally substituted on the aryl portion with from 1 to 3 groups selected from the group consisting of C-^-Cg alkoxy groups, halogens and nitro groups ^{OΓ R} 1B being for instance benzyl, 4'- methoxybenzyl, 4'-nitrobenzyl , benzhydryl, trityl); or tπalkylsilyl groups, where each alkyl group is an alkyl containing from 1 to 4 carbon atoms ( IΔ ^OΓ ^lB bein ^ ^or instance trimethylsilyl).

Substituents c) and d) , depending on the meaning of groups R _/ , , Rr- and R contained therein, may be those present m therapeutically active 3-norcephalospoπns, or groups suitable for a subsequent conversion into other therapeutically useful groups, such as H or halogen. Preferably, in the present process, A is PhoC- or RoCO, where Ro is PhCH - or PhOCH-,-; R^ _A and R^ are selected from the group consisting of benzyl. 4' -methoxybenzyl , ' -nitrobenzyl, benzhydryl, trityl, tert- butyl, 2 ,2,2-trichloroethyl , methyl and allyl. Furthermore, Y is preferably =0, both in the compound of formula (I) and in the compound of formula (II) .

The organic radicals R_ _| present in groups -ORj _j , -0-C0-R^ , -0S0 ₂ -R^ , SR or -S-CORj _j may be optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic (heterocyclic or carbocyclic) and araliphatic C^-C^g groups. When λ-, _A and X^g are as defined under c), ^ may particular be a Ci-C alkyl group (methyl, terbutyl) , optionally substituted with from 1 to 3 halogen groups (e.g -CFo); a carbocyclic, mono- or

bicyclic-, aromatic group havmg from 5 to 12 atoms m the cyclic portion (ring), and being optionally substituted with from 1 to 3 1 groups containing 1 to 6 carbon atoms (e.g. p-methyIphenyl) ; an aromatic heterocyclic group having 5 ° ^r 6 atoms in the ring, containing from 1 to 4 heteroatoms selected from the group consisting of N, 0 and S (such as 1, 3 ^_ πιιdazol-l-yl) , optionally fused with a benzene ring or with another heterocyclic aromatic group as defined above (to give for instance 4,5~benzo-l , 3-thιazol-2-yl or 1,3~ ιmιdazol-2-yl) . In particular, when ^ _A or X^g is -0R^ or -SR^, R^ is preferably -CHo, ethyl, tert-butyl, 4,5~benzo-l,3~thιazol-2-yl, ,5~benzo-l,3-ιmιdazol- 2-yl or phenyl. According to a typical embodiment of the present invention, X-^ _A = X-^g = -SR _/ ι. When X _1A or X _lβ is -0-COR^ or -S-COR^, R^ is preferably CHo or CFo. When X _lβ is -0-S0 ₂ R^, R^ is preferably CHo, CFo or p-methylphenyl.

When X _1A or X-^g is as defined under d) , -NR,-Rg may in particular be in particular a heterocyclic aromatic group havmg ° ^r atoms the cycle and containing 1 to 4 heterocycies selected from the group consisting of N, 0 and S, such as 1,3 ^_ ιmιdazol-l-yl, optionally fused with a benzene ring, such as ,5-benzo-l , 3 ^_ ιmιdazol-l-yl ; or a heterocyclic non-aromatic group having 5 or 6 atoms in the cycle and containing from 1 to 2 heteroatoms selected from the group consisting of K, 0 and S, such as 4-morpholyl or 1-pyrrolιdyl. When X _1A or X _lβ has the meaning defined under e) (-CH ₂ -0Ry) , they are in particular -CH ₂ 0CHo (as in Cefpodoxime) .

Groups Heti and Het present in substituents f) and g) are each in particular an aromatic or non-aromatic heterocyclic group having or

6 atoms in the cycle, containing 1 to 4 heteroatoms selected from the group consisting of N, 0 and S, optionally substituted as mentioned above with 1 to 3 groups selected among =0, -OH and Ci-C- alkyl When the heterocyclic group is aromatic, it may be further iused with a benzene ring or with another aromatic heterocyclic group as defined above.

Examples of said heterocyclic groups are triazoljl, tetrazolyl, thiadiazolyl, benzoxazolvl, benzothiazolyl When X _1A or λ _lβ has the meaning defined under f) (-CH ₂ ~S-Hetι ) , Heti is preferably 1,2,5.6-tetrahydro-2-methyl-5,6-dιoxo-l,2,4-tπazm-3-yl (as in Ceftπaxone) or 1-methyl-lH-tetrazol-yl-5-yl (as in Cefamandole)

When Xi » or X^ has the meaning defined m f) (-CH=CHG), G is preferably H (as in Cefixime) or CHo as in Cefprozil, or Het-, = 4- methvl-1 ,3-thιazol-5-yl•

The meanings indicated as being preferred for substituents Y, X-, _A and Xig of the compounds of formula (I) and formula (II) are obviously also valid for the various intermediates of the present process and for reagents (A), (B), (C), and (D) used for their preparation. In some cases, substituents R , Ro, R^ . R^g. and R _/ ι may vary during the reaction or their work out and may be either restored or converted to other substituents depending on the requirements

Groups Zγ and Z ₂ are typically a halogen, such as Cl or Br, or sulphonylox -0S0 R _/ , where R^ is typically CHo, CFo or p—methylphenyl

Cyclization of the compound of formula (II) with trialkyl phosphite As used herein, the term "dicarbonyl cyclization" means either a

C=0/C=0 or a C=0/C=S condensation.

The trialkyl phosphite used for said dicarbonyl cyclization typically contains C^-C^ alkyl groups and is preferably trimethyl-, tπethyl- or tπ sopropyl-phosphite. The reaction is preferably accomplished in an anhydrous aprotic organic solvent, typically selected among an aromatic solvent, such as toluene and xylene; a halogenated hydrocarbon solvent, such as chloroform, provided that it is substantially free from hydroxylated stabilizers, such as ethanol; and acyclic or cyclic ether, such as ethyl ether, tetrahydrofuran, dioxane.

The reaction is effected by heating at temperatures generally in the range of from about +6θ°C to about +120°C, but temperatures other than those indicated may be adopted. Substrates of formula II which are subjected to cyclization according to the present invention are for instance those mentioned in the Examples hereinafter reported.

According to a typical embodiment of the present process, at least 2 moles of trialkyl phosphite per mole of substrate of formula (II) are used, said trialkyl phosphite being added to the substrate of formula (II) at a slow rate.

Preparation of the compounds of formula (I) wherein Xι _A is H Accordmg to a preferred embodiment of the present process, the product of formula (I) is the one with X-_ = H. Said product is prepared from the corresponding derivative of formula (I), where X _j _ _A is a), c) or d) as mentioned above, by treatment with a reducing agent, such as Zn in an acidic medium, e.g. in the presence of acetic acid or formic acid, or H ₂ in the presence of a catalyst,

such as Ni-Raney, e.g. in an alcoholic solvent.

Preferably, the reduction is effected on the derivatives of formula (I), where X _1A is -SR _/j . where R^ is -CHo, tert-butyl, 4,5-benzo-l,3- thιazol-2-yl or ,5-benzo-l,3 ^_ ιmιdazol-2-yl ; -SCOR^ , where R is CH _o or CF^, or -NR-^Rg, where R^Rg is 1,3-ιm dazol-l-yl, 4,5-benzo-l ,3- ιmιdazol-1-yl, 4-morpholyl and 1-pyrrolιdyl , by treatment with H-,, in the presence of Ni-Raney.

Preparation of the compounds of formula (I) where Xig is a halogen Accordmg to a further particular embodiment of the present process, the product of formula (I) is the one with X^ _A = a halogen, preferably Cl or Br, prepared by treating with a halogenating agent a compound of formula (I) where Xι _A has the meaning defined under c) or d) . The halogenating agent is typically a phosphorus tn-halide or penta- halide (PC1 ₃ , PC1 _5> PBr ₃ « PBrj) (USP 4,281,117). phosgene, tnphosgene, or a tnaryl phosphite.Hal complex, where Hal is in particular Cl or Br, such as (PPhoO).Cl ₂ (Eli Lilly, USP 4,226,986), in an organic solvent inert to halogenating agents, e.g. m a halogenated hydrocarbon solvent (methylene chloride, dichloroethane), or in an aromatic solvent, e.g. nitrobenzene, at temperatures generally lower than 30°C

According to a particular embodiment of the present process, the derivatives of formula (I) where X^ _A is a halogen, are the ones with Xι = Cl or Br, prepared from the corresponding compounds of formula (I) where X _1A is -SRj _j , where R^ is -CHo, tert-butyl, 4,5-benzo-l,3- thιazol-2-yl or 4,5-benzo-l, 3-ιmιdazol-2-yl; -SCOR _/j , where R^ is CHo or CFo, or -NR^, where NRr-Rg is 1,3-ιmιdazol-l-yl, ,5-benzo-l ,3- ιmιdazol-1-yl , 4-morpholyl and 1-pyrrolιdyl , by treatment with a

halogenating agent such as phosphorus tn- or penta-halide, or complex (PPh ₃ 0).Cl ₂ .

Preparation of the compounds of formula (II)

According to the present process, 3~cephem derivatives are in any case prepared starting from penicillins or penicillm-derived raw materials- for example, the derivatives of formula (II) are prepared either from penicillins of formula (III) via steps A.l)-A.3) and A.l)-A.4) of the present process, or from thiazolme azetidinones of formula (VI), v i a steps B.l)-B.2) , C.l)-C,3) or D.l)-D.3) of the present process.

In fact, the compounds of formula (VI) are on their turn prepared from penicillin of formula (III), where A is RoCO- as defined above (and in particular A is the acyl of penicillin G or V) and R^g is H or a protective group of the carboxyl function, by oxidation to sulphoxide (typically by treatment, e.g. with a peracid, an inorganic peroxide, or NalO , in the range of from +20°C to +25°C) , followed by reductive rearrangement by treatment with a trialkyl phosphite (e.g. trimethyl- or triethyl phosphite, typically in an organic solvent, such as toluene, in the range of from 6θ°C to 110°C) , to give a thiazolme azetidmone with a pentenoic "appendage" (chain) linked to β-lactam nitrogen [R.D.G. Cooper, F.L. Jose, J.Am.Che .Soc. , 92, 2 75 (1970]. Said derivative or the isomer thereof obtained by treatment with bases such as pyridine or triethylamine (typically in the range of from 0°C to +30°C) was treated with an oxydant such as potassium permanganate (topically in an organic solvent, such as pyridine, or in water- alcohols mixtures at about 0°C to +30°C), to give the compound of formula (VI) [L. Ghosez et a l . , Tetrahedron, 39, 15. 2493-2 03, 1 83] .

Preparation of 4-thioazetidinone of formula (IV) from penicillin of formula (III) via step A.l)

Penicillins of formula (III) are well known compounds or, in anj case, can be prepared from 6-ammo penicillanic acid (6-APA) by conventional methods.

Step A.l) is preferably effected by reacting a penicillin of formula (III), where A is PhoC- and R-^ is selected from the group consisting of benzyl, '-methoxybenzyl, 4' -nitrobenzyl, benzhydryl, trityl, tert- butyl, 2,2,2-trιchloroethyl , methyl and allyl with a compound of formula (A), where Zγ is a halogen, typically Cl or Br, Y is =0, and Xig, depending on the compound of formula (I) to be prepared, has one of the meanings indicated above as being preferred or particular for X,, or Xig. Examples of penicillin of formula (III) and of compounds of formula (A) are those mentioned in the Examples hereinafter reported.

Step A.l) is carried out, e.g., in the presence of bases such as alkali and alkalme-earth metal alkoxides, such as potassium or sodium tert-butylate, methylate or ethylate, alkaline metal hydrides (NaH) , in an organic solvent, such as a C^-C^ alcohol (e.g. methanol), ethyl ether, tetrahydrofuran.

For instance, THF: t-BuOH mixtures can be used. Reaction temperatures are for instance comprised between 0°C to +50°C, and typically room temperature can be used (e.g. about +20°C/+30°C) . Oxidation of the pentenoic chain linked to the β-lactam nitrogen of the compound of formula (IV)

Said oxidation can take place by total demolition as per step A.2) or b^ partial demolition as per step A.4) above reported.

Step A.2) is typicalft, accomplished by treatment with potassium permanganate in an organic solvent, e.g. pyridine, or in an aqueous medium, e.g. water/alcohols mixtures, such as ethanol, methanol; the temperature of step A.2 may range, e.g. from about 0°C to +30°C, preferably in the range of from +15°C to +20°C. An example of substrate subjected to said oxidation is that formula (IV) hereinafter mentioned in Example 1.

Accordmg to a preferred embodiment of the present invention, the alkali or alkalme-earth metal permanganate is used in combination with a periodic acid or a salt thereof (sodium penodate or another alkali or alkalme-earth metal penodate).

Typically, potassium permanganate is used, in combination with catalytic amounts of sodium penodate, in pyridine. When, in the compound of formula (IV), R-^g is H, permanganate in an alkaline aqueous medium is preferably used.

To the Applicant's knowledge, the aforementioned oxidation of the compound of formula (IV), where R-^g is H, is unknown to the prior art. Ozonization steps Oxamide derivatives of formula II can be direcetly obtained through ozonization at low temperature of the corresponding derivatives of formula (IV), as well as of those of formula (V)A, V(B) , V(C) or (V)D, wherein R _N is the "C-appendage" -C (C00R _1A ) =C (CH, ) ₂ , typically accomplished under the conditions hereinafter reported for step A.4). Step A. ) above is preferably carried out in an organic solvent, e.g. in a halogenated hydrocarbon solvent, such as methylene chloride or chloroform, typically in the substantial absence of hydroxylated compounds, at temperatures generally ranging from about -8θ°C to about

-20°C, typically at about -70°C

Ozone is typically in stoichiometric excess with respect to the substrate to be reacted, the reaction mixture being preferably saturated with with it. Examples of substrates of formula (IV) or (V)A-D which can be typically subjected to ozonization are those mentioned the Examples hereinafter reported.

Accordmg to an alternative pathway, oxamides of formula (II) can be obtained by total demolition of the "C-appendage" -C(C0ORι _A )=C(CH _o ) ₂ of compounds of formula (IV), or (V)A-D under the conditions of step

A.2), then subjecting the reaction products thus obtained (i.e. the corresponding azetidinones of formula (V)A-D wherein R _* , is H) , to oxalylation, under the conditions of steps A.3). B.2), C.3) or D.3).

Typically, the crude reaction mixtures coming from oxalylation steps or from ozonization steps, are directly subjected to phosphite induced cyclization, without separating the intermediate oxamides of formula

(II) therein contained.

Oxalylation steps A.3), B.2), C.3) and D.3)

The compounds of formula (B) used in steps A.2), B.3), C.3). and D.3) are generally known, or are prepared by conventional techniques.

In the compound of formula (B) , Att^ may be: a halogen, preferably Cl or Br; R^-C0-0- , where R^ is as defined above and is preferably CHo or

CFo; or R^-S0 ₂ -0-, where R^ is as defined above and is preferably CHo,

CFo or p-methylphenyl. Furthermore, Att^ may be a group Rg-S-, where Rg is a C^-C alkyl group, or a heterocyclic aromatic group, such as 1 ,3~benzothιazol-2- yl, 1,3 ^_ benzoιmιdazol-2-yl or 1 ,3-ιmιdazol-l-yl.

According to a typical embodiment of the present invention, the compound of formula (B) used is the one with Att^ = a halogen, preferably Cl or Br, and W = -0R _1A , where R _1A is selected from the group consisting of benzyl, ' -methoxybenzyl , 4 ' -nitrobenzyl , benzhydryl, trityl, tert-butyl, 2, 2, 2-trιchloroethyl , methyl and allyl.

According to a further embodiment of the present invention, the compound of formula (B) used is the one with W = Attp, where

preferably chlorine. Successive treatment with R _{I Λ} OH IS typically effected the presence of a base (e.g. EtoN, Py), in an inert organic solvent (e.g. CH ₂ Cl- _> , toluene), generally at -20°C/+20 ^β C.

Step A.3). as well as steps B.2), C.3) and D.3) are preferably effected in the presence of a base, m an aprotic organic solvent, at temperatures generally ranging from about -4θ°C to about +4θ°C, more preferably from -20°C to +20°C, for instance at about 0°C/ +5°C Compounds of formula (B) and substrates of formula (V)A to (V)D which can be subjected to oxalylation according to the present invention are for instance those mentioned in the Examples hereinafter reported. The base is typically an inorganic base, such as CaCOo, or an organic base, such as a tertiary amine (e.g. triethylamine, ethyldiisopropylamme) , or mixtures thereof, and the aprotic organic solvent is typically a halogenated hydrocarbon solvent, such as methylene chloride or chloroform. Preparation of 4-thioazetidinones from thiazoline azetidinones of formula (VI) as per steps B.l), Cl) and D.l) Several thiazolin azetidinones of formula (VI) are known, havmg been

disclosed, e.g., by R.D.C Cooper, F.L. Jose, J.Am.Chem.Soc. , 94, 1021 (1972) and L. Ghosez et a l . , Tetrahedron, 39, 15, 24 3-2503, I983. Thiazol azetidinones of formula (VI) wherein R _N is -C(COOR^g)=C(CHo) ₂ , are known compounds and can be prepared according to known procedures.

The thiazoline azetidmone of formula (VI), where Ro is PhCH _p - or PhOCH- _> , is preferably used.

The compound of formula (A) used in step B.l) is typically the one with γ - a halogen, typically Cl or Br, Y is =0, and i , depending on the compound of formula (I) to be prepared, has one of the meanings indicated above as being preferred or particular for X or Xig. The compound of formula (C) preferably used steps Cl) and D.l) is the one with and Z are both a halogen, e.g. Cl or Br, preferably Steps B.l), Cl) and D.l) are carried out in the presence of a thallium tnacylate typically derived from carboxylic acids of the aliphatic, aromatic or araliphatic series, typically from alky] - carboxylic acids containing a straight or branched saturated alkyl containing 1 to 6 carbon atoms, such as thallium triacetate, or of a compound having a pK of less than 10, such as urea or acids, such as acetic acid or p-toluensulphonic acid, in the presence of a hydroxylated compound such as water, or a C-Cg alcohol (e.g. methanol or ethanol) at temperatures ranging from about +10°C to about +8θ°C, for instance from about +20°C to about +6θ°C The compound with a pK _fl lower than 10 is typically used m at least stoichiometric amount with respect to compound (VI). The reaction as per steps B.l), Cl) and D.l) may be carried out in

the presence of an organic solvent, e.g. a halogenated hydrocarbon solvent (methylene chloride, chloroform, CCl _/j ), a sulphoxide (e.g. dimethylsulphoxide) , a ketone (e.g. acetone or methyl ethyl ketone), an amide (e.g. N,N-dιmethylformamιde or N,N-dιmethyl acetamide), an alcohol (e.g. methanol, ethanol), an ether (e.g. ethyl ether or tetrahydrofuran), e.g. in acetone: water or DMF: water mixtures with a water content of about 1%-5% by volume.

The reaction is preferably carried out with urea m water or in dimethylformamide containing small amounts of water, or acetic ac d in water (in particular as in steps Cl) and D.l) effected with the compound of formula (C) , where Zi and Z- _> are both a halogen. Compounds of formula (VI) and of formula (A) are for instance those mentioned in the Examples hereinafter reported. The reaction is preferably conducted in the presence of an antioxidant, e.g. phenol.

Step C.2) s preferably carried out in the presence of preformed Heti- S ^~ M ⁺ or RyO ^~ M ⁺ , obtained from the corresponding thiols or alcohols by treatment with appropriate bases, for example an alkali or alkalme- earth metal hydroxide (e.g. NaOH) in the case of thiols, or NaH m the case of alcohols. Step C.2) is typically carried out in an alcoholic solvent (e.g methanol, ethanol) or in an ether solvent (tetrahydrofuran, ethyl ether), for instance at -20°C/+20°C. Step D.2) is carried out under operating conditions (e.g. temperature) analogous to those of the ittig reactions, using as a base, e.g. butvllithium, sodium amide, an alkali metal hydride (NaH) or an alkaline or alkalme-earth metal alkoxide, in an organic solvent, such as ethyl ether or tetrahydrofuran.

Depending on the meanings of substituents A, Rι , Xi _A and Y, the derivatives of formula (I) obtained by the present process may be therapeutically active compounds or precursors thereof. In particular, the compounds of formula (I) are converted to the corresponding therapeutically active cephalosponns by deprotection of the amine function at the 6-posιtιon of the penicillanic nucleus, followed by reacylation to introduce with the appropriate chain in C- 6, if substituent A does not correspond to that of the therapeutically active cephalosporin, or, if substituent A corresponds to that of the therapeutically active cephalosporin in the protected form, by removal of the protective groups, if any, present in group A. Furthermore, when R _1A is different from H, the protective group R^ _A of the carboxyl function is removed, using the most adequate conventional techniques according to the nature of said protective group. For example, the compound of formula (I), where A is PhoC- and Ri. is p-mtrobenzyl, is converted to the compound of formula (I), where A is H and R- _j . is H, by simultaneous deprotection of the amine function and of the carboxyl function, by treatment with CFoCOOH, an organic solvent, typically an aromatic solvent, such as anisole. The following examples are reported for illustrative, but not limitative purposes. EXAMPLE 1

Preparation of 4-(ethoxycarbonylmethylthio)- -(triphenylmethylammo)- azetιdm-2-one [{V)A: A=Ph ₃ C; = 0 ; X _lβ = OEt; R _N =H] A stirred solution of methyl-6β-(tπphenylammo)penιcιllanate [(III): A= PhoC; R _lβ = Me) (28g) and ethyl bromoacetate [(A): Z- _L =Br; Y=0; X _1B = OEt] (9.4g) in 200 ml of tetrahydrofuran and 200 ml of t-

buthylalcohol was treated, under nitrogen and dropwise over 5h at room temperature, with a solution of potassium t-butoxide (6.3g) dissolved in tetrahydrofuran (30 ml) and t-buthanol (30 ml). After stirring at room temperature for an additional hour, the solution was concentrated to small volume, diluted with ethylacetate and washed with water. The organic phase was dried (MgSO^) and evaporated to a residual gum. The solid was separated by chromatography (silica gel Merck for column chromatography; elution: exane- ethylacetate by step gradient) nto unchanged starting penicillanate (7-8 g) and amorphous 1- (l-methyloxycarbonyl-2-methylprop-l-enyl)-4-(ethoxycarbonyl- methylthιo)-3-(trιphenylmethylamιno)-azetιdm-2-one [(IV) : R _1B = Me; Y=0; X _lβ = -OEt] (14.8 g) .

The obtained azetιdm-2-one (14.4 g) was dissolved m pyridine (180 ml) and water (13 ml). To the solution cooled at 0-2°C in an ice-bath, powdered potassium permanganate (6g) was added in portions over 30 min. under vigorous stirring and the mixture, cont ously stirred, left in the cold overnight. After dilution with ethylacetate and brine, sodium hydrogen sulphite was added and then the layers were separated. The organic phase was washed successively with aqueous sodium hydrogen carbonate, water, diluted hydrochloric acid and water again, then dried (MgS0[) and evaporated under vacuum.

The residual oil was separated by chromatography on silica gel (exane-ethylacetate, gradient elution) to give (4- (ethoxycarbonylmethylthio)-3-(tnphenylmethylammo)-azetιdιn -2-one

[(V)A: A=Ph ₃ C Y=0; X _1B =0Et; R _N =H] (5g; 43/.) . H-NMR(CDC1 ₃ , cf [ppm]) : 1.26 (t, J _V1C = 6.8 HZ: -CH ₂ -CH^); 2.93 and 3-H (2d. J _gem = 16.0 Hz:

S-CH ₂ C0); 2.99 (s. broad, exchangeable with D ₂ 0: NH); 4.11 (q. J _V1C =6.8 Hz: CH ₂ -CH ₃ ); 4.52 (s. broad:H-3 and H-4); 6.24 (s. broad, exchangeable with D Q: NH) ; 7-0-7-6 (m.: 3 phenyl groups). EXAMPLE 2 4- (carboxymethylthio)-3 ^~ (triphenylmethylammo)-azetιdm-2-one [<V)A: A=Ph ₃ C; Y=0; X _lβ = OH; R _N =H]

The 4-(ethoxycarbonylmethylthιo)-3 ^_ (triphenylmethylammo)-azetιdm-2- one [(V)A: A=Ph ₃ C; Y=0; X _lβ = OEt; R _N =H] (4.75 g= 10.6 mml ) was dissolved in acetone (100 ml) and the solution ice-cooled. Under stirring a solution of NaOH 2.5 N ( 8.60 ml) in acetone (4θ ml) was dropwise added in 20 mm. After 0-5 h the mixture diluted with water and extracted with ethylacetate. The aqueous phase was then acidified to pH 3 with HCI and immediately reextracted with ethyl acetate. The organic phase was dried (MgSO _/j ) and evaporated to give on oil from which the acid 4-(carboxymethylthio)-3~(triphenylmethylammo) azetιdιn-2-one [(V)A: A=Ph ₃ C0; Y=0; X _lβ = OH; R _N =H] was obtained as amorphous product (1.8 g; 4l_) by chromatography on silica gel (hexane: ethyacetate; stepwise gradient elution). H-NMR (DMSO-dg, cf [ppm]): 2.85 (s. broad: s-CH ₂ -C0) ; .18 (d. after D ₂ 0 exchange, J _V1C = 4.5 Hz: H-4); 4.37 (d. J _V1C = 4.5 Hz: H-3) ; 7-0-7.6 (m. : 2 NH and 3 phenyl groups); 8.4 (s. broad, exchangeable with D ₂ 0: COOH). EXAMPLE 3

1- (l-methoxycarbonyl-2-methylprop-l-enyl)-4-(phenylthiocarbony l- methylthio)~3~(triphenylmethylammo)azetιdιn-2-one [(IV): Me; Y=0; X _lβ = SPh]

To a stirred solution of the methylester of 6β-(triphenylmethylammo) penicillme [ (III) :A=PhoC; R- _L g=Me] (10 g) and thiophenylbromoacetate

[(A): Z ₁ =Br; Y=0; X _lβ = -SPh] (5-38 g) in tetrahydrofuran (75 ml) and t-buthyl alcohol (75 ml) was added dropwise in 5 h, at room temperature and under nitrogen, a solution of potassium t-butoxide (2.24 g) in tetrahydrofuran (80 ml) and t- buthyl alcohol (26 ml). After additional stirring at room temperature for 1 h more, the solution was concentrated to small volume, diluted with ethylacetate (150 ml) and washed with water The organic phase was dried (MgSO ) and evaporated. The residual gum was separated by chromatography on silica gel (hexane: ethylacetate; stepwise gradient elution) into unchanged starting methylpenicillanate (2.8 g) and amorphous 1-(1- methoxycarbonyl-2-methylprop-l-enyl)-4-(phenylthiocarbonylme thylthio)- 3- ( triphenylmethylammo) azetιdιn-2-one (2.15 g) . ¹ H-NMR (CDClo ; ^[ppm]); 2.0 and 2.2 (2s.: = C(CH ₃ ) ₂ ); 2.80 and 3-16 (2d., J _gem = 16.5 Hz. -S-CH ₂ -C0) ; 2. -3.2 (m. exchangeable with D ₂ 0: NH) ; 3.68 (s.: 0CH ₃ ); 4.67 (d. after D ₂ 0 exchange, J _vχc = 5-5 Hz: H-3); 4-99 (d. J _vιr = 5-5 Hz: H-4); 7-0-7-6 (m. : 4 phenyl groups). EXAMPLE 4

Methy1-7-triphenylmethylammo- -phenylth o-3-cephem-4-carboxylate [(I): A=Ph ₃ C; X _1A =-SPh; R _1A =Me] A cooled solution (-75°C; Me ₂ C0+solιd C0 ₂ ) of 1-(1- methoxycarbonyl-2- methylprop-1-enyl)-4-(phenylthiocarbonylmethylthio)-3-(triph enyl¬ methylammo) azetιdm-2-one [(IV): A=PhoC; R _lβ = Me; Y=0; X _lβ =SPh] (0.5 g) in dry dichloromethane (25 ml) was saturated with ozone until appearance of violet coloration and disappearance of the starting material on T.L.C. Nitrogen was then bubbled to remove the ozone excess and a few drops of diraethylsulphyde were added. The mixture was allowed to reach room temperature, then washed with water and dried

(MgSO/ _j ). After evaporation, toluene (30 ml) was added to the oily residue and the resulting solution [containing the oxalimide derivative (II): A = Ph ₃ C; Y=0; X _lβ = -SPh; R _1A = CH ₃ ] was treated with tnethylphosphite (0.4 ml) and heated at reflux for 2h. After water washing, the mixture was concentrated and the residue purified by silica gel column chromatography eluting with exane-ethylacetate (2:1) to give the title compound as a foam. ^λ H NMR [CDC1 ₃ ;^ [ppm]): 2.98 and 3-05 (two d. , J _gem = 17.5 Hz: C(2)H_ ₂ ); 3.18 (d., J _V1C =12.0 Hz, exchangeable with D ₂ 0: NH) ; 3.68 (s.: OCH ) ; 4.42 (d., J _V1C = 4.5 Hz: H6) ; 4.49 (d., after D ₂ 0 exchange, J _V1C = 4.5 H: H-7; 7-1-7-7 (m: 4 phenyl groups). EXAMPLE 5

1- (l-ρ-nιtrobenzyloxycarbonyl-2-methylρrop-l-enyl)-3-(pheny lacetamino)- 4-(phenylthiocarbonylmethylthio) azetιdιn-2 one [(V)A : A = PhCH ₂ C0-; Y=0; X _lβ = -SPh; R _N =-C(C00R _1A )=C(CH ₃ ) ₂ ; R _1A = _P N0 ₂ C ₆ H ₄ CH ₂ ].

To a stirred solution of 6- (l-p-nιtrobenzyloxycarbonyl-2-methylprop-l- en^l-3-benz;yl-4-thιa-2,6-dιazabιcyclo [3,2,0] hept-2-en-7~one [(VI): R ₃ = PhCH ₂ -; R _N =-C(C00R _1A )=C(CH ₃ ) ₂ ; R _χA = p-NO^H^] (6.77 g: 15 mmol) in acetone-water 98:2 (250 ml), bromophenylthioacetate [(A): Z ₁ = Br; Y=0; X _lβ = -SPh] (0.4 g: 45 mmoli) and p-toluensulphonic acid (2.85 g: mmol) were added under nitrogen. The mixture was left under nitrogen at ro temperature for 24 h. After cooling (0°C) sodium hydrogen carbonate was added, the solution was partially concentrated and diluted with ethyl acetate. After washing with water the organic phase was dried (MgS0j _| ) and evaporated to an oily residue. Chromatographic separation of the obtained product on silica gel

(hexane: ethylacetate 1:1 as eluent) gave, as less polar constituent, the title compound (2g).

¹ H NMR (CDC1 ₃ ; 6 [ppm]): 2.07 and 2.26 (two s. : = C(CHo) ₂ ); 3.26 and 3-31 (two d. , J _gem 15-5 Hz, s-CH ₂ -C0) ; 3-66 (s.: C ₆ H ₅ -CH ₂ - CO); 5.13-5.28 (m: H-4, and COO-CH ₂ -C ₆ H _i| -pN0 ₂ ) ; 5-31 (d. , J=4.5 Hz: H- 3); 6.18 (d., exchangeable with D ₂ 0: NH) ; 6.95~7•55 (m.: two phenyl groups and two H meta to N0 group); 8.10-8.25 (two H ortho to NOp). EXAMPLE 6 p-Nitrobenzyl-7-phenylacetammo-3-phenylthιo- ^~ cephem-4-carboxylate. [(I). A=PhCH ₂ C0; X _1A =-SPh; R _1A = pN0 ₂ C ₆ H _i| -CH ₂ -]

Ozone was bubbled at -70°C through a solution of l-(l-p- nιtrobenzyloxycarbonyl-2-methylprop-l-enyl)-3-(phenylacetam mo)-4- (phenylthιocarbonylmethylthιo)-azetιdm-2-one [(V)A: A=PhCH ₂ C0; Y=0; X _1B =-SPh; R _N -C(C00R _1A )=C(CH ₃ ) ₂ ; R _1A =pN0 ₂ C ₆ H ₄ -CH ₂ -] (900 mg) m dry dichlorometane (60 ml), until a violet coloration was obtained (about 30 mm.) and TLC control indicated almost complete conversion of the starting product. Then nitrogen was bubbled and the solution treated with dimethylsulphide and left to reach room temperature. Af er water washing the mixture was dried (MgSO _j ) and evaporated to an oily residue [containing compound (II):A =PhCH ₂ -C0-; Y=0; X _lβ =-SPh; R _1A = pN0 ₂ CgHi-CH ₂ ] to which toluene (60 ml) and tnethylphosphite (0.7 ml) were added.

Tne solution was heated at 90°C for 70 mm. and then washed with water, dried (MgSO^) and evaporated under vacuum. The residual oil was separated by chromatography on silica gel (light petroleum 6θ-8θ°C: ethyl acetate 1:1 as solvent) to give amorphous p-n trobenzyl-7- phenylacetamino-3-phenylthio-3-cephem-4-carboxylate.

² H-NMR (CDC1 ₃ ; f [ppm]) 3-24 and 3-33 (two d. J _gem -= 17-4 Hz: C(2) H ₂ ), 3 b4 (s.: C ₆ H ₅ -CH ₂ -CO) ; 5-14- - 9 (m. : H-6 and C00-CH ₂ - CgH _c - PN0 ₂ ); 5.33 (d., J _V1C = 4.5 Hz: H-7); 6.20 (d. , exchangeable with D ₂ 0: NH) ; 6.98 - 7-56 (m. : two phenyl groups and two aromatic protons meta to NO group); 8.10-8.25 (two aromatic protons ortho to NOp group). EXAMPLE 7

4-(phenylthiocarbonylmethylthio ⁾ -3-(phenylacetammo)-azetιdm-2-one [(V)A: A=PhCH ₂ C0; Y=0; X _lβ =-SPh; R _N =H] Urea (2.7 g) and bromophenylthioacetate [(A): -SPh] (1.8 g, 7-8 mmol) were added to a solution of 3~benzyl-4-thιa-2,6- diazabicyclo [3.2,0] hept-2-en-7-one [ (VI) :R ₃ =Ph-CH ₂ -; R _N =H] (1.4 g: 6.4 mmol) m a mixture of dimethylformamide (18 ml) and water (1 ml). The solution was stirred for 6h at 6θ°C until conversion to a less polar product was detected by T.L.C. The mixture was then diluted with ethyl acetate and washed with water three times. The organic layer was dried and evaporated to an oily residue which was separated by chromatography on silica gel (methylene chloride: ethylacetate stepwise gradient elution) to give amorphous 4-phenylthiocarbonylmethylthio) -3 ^_ (phenylacetammo) - azetιdm-2-one (lg). [(V)A: A=PhCHp_C0; Y=0; X _1B =SPh; R _N =H].

^X H-NMR [CDC1 ₃ ; f [ppm]): 3.44 (s.= S-CH ₂ ~C0) , 3-62 (s.: C ₆ H ₅ -CH ₂ -C0) ; 5.02 (d., J _V1C = 4.5 Hz: H-4); 5.46 (d.after D ₂ 0 exchange J _V1C : 4.5 Hz: H-3); b.43 (d. broad, exchangeable with DpO: NH-C(3)]; 6.56 (s. broad, exchangeable with D _? 0: β lactam N-H) : 7-2 - 7-5 ( -: phenyl groups). EXAMPLE 8

Allyl-7-phenylacetammo-3-phenylthιo-3-cephem-4-carboκyl ate [ ( I ) : A = PhCH ₂ C0- , X _1A = S-Ph , R _1A =allyl ) .

A solution of 4-phenylthiocarbonylmethylthio-3-phenylacetamino- azet dm-2-one [(V)A: A=PhCH ₂ C0-; Y=0; X _1B =-SPh; R _N =H] (0.184 g) m methylene chloride was treated under nitrogen with allyloxalyl chloride, [(B): Att ₁ =Cl; W=0-R _1A ; R _1A = allyl] (0.288 g, m 3 ml of methylene chloride) in the presence of CaC0 (0.2 g) at 0°C.

Then a solution of diisopropylethylamine in few milliliters of methylene chloride was added dropwise such that the temperature remained below 4°C

The mixture was stirred for 4θ minutes m an ice bath, toluene (4θ ml) was added and the solution was concentrated to 15 ml and washed with water, the organic phase was dried over MgSO _/ ..

The resulting solution containing the intermediate oxalamide [(II):

A=Ph CHpCO-; Y=0; X _1B = -SPh; R _1A =allyl] was treated with P(0Et)

(0.256 ml m 10 ml of toluene) and heated at 90°C for 90 minutes, then the solution was evaporated to give an oil that was purified on silica gel column (hexane-ethylacetate gradient elution) to give the title compound.

^X H-NMR(CDC1 ₃ , cf ): 3.29 and 3,37 (two d, J _gem = 18 Hz, C(2) H ₂ );

3.62 (s, C ₆ H ₅ CH ₂ C0-), 4.8-4.9(d.t. , J _vic = 5Hz, Jallylic = 1 Hz, -C00CH ₂ -), 5.05-5.65 (m. CH_ ₂ =, H-6 and H-7). 5-85-6.10 (m. CH=) , 6.54

(br. s. exchangeable with D ₂ 0, -C0NH-) , 7-l-7-6(m, 2 phenyl groups).

EXAMPLE 9

4 -t- buthylthιocarbonylmethylthιo-3-phenylacetamιno-azet dm-2-one

[ ( V ) A : A = Ph-CH ₂ C0- , Y = 0 , X _1B = S-t . butyl , R _N =H] By fol lowing the procedure of Example 7 the t i tle compound was obtained (yield 52% ) starting from (VI ) : R ₃ = PhCH ₂ - ; R _N =H and from

( A ) : Z ₂ =Br ; Y=0 ; X _lβ = -S- tButyl .

¹ H-NMR (CDClg, cf ): 1.47 (s., C-(CH ₃ ) ₃ ), 3-29 (singlet, S-CH ₂ -C0-), 3-66 (s., C ₆ H ₅ -CH ₂ -CO), 5-06 (d, J _vlc =5-0 Hz, H- ) , 5-52 (d. after exchange with Dp_0, J _vlc =5-0 Hz, H-3), 6.67 (broad d. exchangeable with D ₂ 0, CONH, C(3)), 6,73 (broad s. exchangeable with D ₂ 0, β-lactam NH) , 7-2-7-4 (m. phenyl group). EXAMPLE 10

Allyl-7-phenylacetammo-3-t-butylthio-3-cephem-4-carboxyla te [ (I) , A=Ph-CH ₂ C0-, X _1A =S-t.butyl; R _1A =allyl] By following the procedure described in Example 8 and starting from 4- t-butylthιocarbonylmethylthιo-3 ^_ phenylacetamιno-azetιdm-2-one obtained according to Example 9 [(V): A = PHCH ₂ C0- ; Y=0; X _χβ =S-

-iutyl; R _N = H] (0.25 g) and all loxalyl chloride [(B): Att ₁ =Cl; Att ₂ = -0R _1A ; R- _j _ =allyl] (0.4 g) the title compound was obtained. ² H-NMR (CDC1 _3? 6 ): 1-47 (s.t.butyl), 3- 8 (s. Ph-CH _? C0) , 3.6l and 3-69 (two d, J _gem =17Hz, C(2)H ₂ ), 4 , 6-4.8 (m, -C00-CH ₂ - ) , 5-03 (d. J _V1C = 5-5Hz, H-6). 5-2-5-5 (m, CH ₂ = and H-7). 5-85-6.10 (m. ^CH=) , 6.90 (br.s., exchangeable with D ₂ 0, CONH-) 7-2-7-6 (m, phenv1 group), EXAMPLE 11 P-Nitrobenzyl-7-phenylacetammo-3 ^_ t-butylthio-3-cephem-4-carboxylate. [(I): A = PhCH ₂ C0-, X _1A =-S-tButyl, R _χA = p-N0 ₂ -C ₆ H^CH ₂ -) .

By following the procedure described in Example 8, starting from 4-t- butylthιocarbonylmethylthιo-3-phenyl acetamιno-azetιdm-2-one (0.150 g) [(V)A: A= PhCH ₂ C0-; Y=0 X _1B =-StButyl; R _N =H] and p- Nitrobenzyloxalyl chloride [(B): Att ₁ =Cl; W= -0R _1A , R _1A = pN0 ₂ - C^H^CH ] (0.45g), and directly subjecting to cyclization the reaction mixture containing the oxamide of formula (II) wherein A= Ph ₂ CH- _> C0-; Y=0, ^ _β = S-tButyl and R _1A = pN0 ₂ -CgH^CH ₂ , without isolating compound

(II), the title compound has obtained.

¹ H-NMR(CDC1 ₃ , cj ) : 1.44 [s. , (CH^C]; 3-63 and 3-79 (two d, J _gem =17Hz, C(2)H ₂ ); 3-70 (s. , C ₆ H ₅ CH ₂ C0) ; 5-25~5-5 (m,C00CH ₂ - and H- 6) ; 5-74 (d, after exchange w th D ₂ 0, J _γιc = 4 Hz, H-7); 6.65-6.80 (broad s, exchangeable with D ₂ 0, N-H) ; 7-2-7-5 (m. , phenyl group); 7.5-7.7 (m, aromatic protons meta to N0 ₂ ) ; 8.I5-8.3 (m, aromatic protons ortho to NOp) .