Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
  • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
  • C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
  • C07D205/095—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4 and with a nitrogen atom directly attached in position 3
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to a new process for the preparation of cephalosponns, in particular 3 -n orcephalospo ⁇ ns, such as Cefaclor, Ceftibuten and Ceftizoxime, 3 ⁇ a lkenylcephalospor ⁇ ns (Cefixime, Cefprozil), 3- ⁇ ercaptomethyl cephalosponns (Ceft ⁇ axone) and 3" methoxymethyl cephalosponns (Cefpodoxime) , in particular comprising reductive dicarbonyl cyclization induced by trialkyl phosphite of ⁇ 3R,4R) -3-acylam ⁇ no-4-th ⁇ o-azet ⁇ d ⁇ none derivatives obtained from penicillins.
• cephalosponns in particular 3 -n orcephalospo ⁇ ns, such as Cefaclor, Ceftibuten and Ceftizoxime, 3 ⁇ a lkenylcephalo
• Cephalosponns are usually prepared from 7 ⁇ ACA.
• 3" norcephalospo ⁇ ns 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,l6 ⁇ ,O ⁇ 5) (Scheme 1).
• 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 _ acylam ⁇ no-4-th ⁇ o azetidinones can be prepared by treatment with ⁇ -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 .
• the present process comprises the preparation of 3 ⁇ cephem derivatives of formula (I)
• 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-acylam ⁇ no 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 consist
• 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.
• the preparation of the compound of formula (II), where X l ⁇ is c) or d), as defined above comprises the following steps: A.l) treatment of a penicillin of formula (III)
• 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)
• 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
• 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 R ⁇ «, Xig and Y have the above meanings.
• the preparation of the compound of formula (II) where X j _g is c) or d) , as.
• 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)
• 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)
• 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)
• 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
• 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 C ⁇ _ 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- t ⁇ chloroethoxy CCloCH 2 0-C0-. RoCO- may be either as such, or in protected form.
• protecting 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 R ⁇ ⁇ 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 O ⁇ R 1B being for instance benzyl, 4'- methoxybenzyl, 4'-nitrobenzyl , benzhydryl, trityl); or t ⁇ alkylsilyl groups, where each alkyl group is an alkyl containing from 1 to 4 carbon atoms ( I ⁇ O ⁇ ⁇
• Substituents c) and d) may be those present m therapeutically active 3-norcephalospo ⁇ ns, or groups suitable for a subsequent conversion into other therapeutically useful groups, such as H or halogen.
• A is PhoC- or RoCO, where Ro is PhCH - or PhOCH-,-; R ⁇ A and R ⁇ are selected from the group consisting of benzyl.
• 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.
• ⁇ 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.
• R ⁇ is preferably -CHo, ethyl, tert-butyl, 4,5 ⁇ benzo-l,3 ⁇ th ⁇ azol-2-yl, ,5 ⁇ benzo-l,3- ⁇ m ⁇ dazol- 2-yl or phenyl.
• R ⁇ is preferably CHo or CFo.
• X l ⁇ is -0-S0 2 R ⁇
• R ⁇ is preferably CHo, CFo or p-methylphenyl.
• -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 _ ⁇ m ⁇ dazol-l-yl, optionally fused with a benzene ring, such as ,5-benzo-l , 3 _ ⁇ m ⁇ dazol-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-pyrrol ⁇ dyl.
• X 1A or X l ⁇ has the meaning defined under e) (-CH 2 -0Ry) , they are in particular -CH 2 0CHo (as in Cefpodoxime)
• the heterocyclic group is aromatic, it may be further iused with a benzene ring or with another aromatic heterocyclic group as defined above.
• heterocyclic groups are triazoljl, tetrazolyl, thiadiazolyl, benzoxazolvl, benzothiazolyl
• X 1A or ⁇ l ⁇ has the meaning defined under f) (-CH 2 ⁇ S-Het ⁇ )
• Heti is preferably 1,2,5.6-tetrahydro-2-methyl-5,6-d ⁇ oxo-l,2,4-t ⁇ azm-3-yl (as in Ceft ⁇ axone) or 1-methyl-lH-tetrazol-yl-5-yl (as in Cefamandole)
• 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.
• substituents R , Ro, R ⁇ . R ⁇ g. and R / ⁇ may vary during the reaction or their work out and may be either restored or converted to other substituents depending on the requirements
• Groups Z ⁇ 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
• the trialkyl phosphite used for said dicarbonyl cyclization typically contains C ⁇ -C ⁇ alkyl groups and is preferably trimethyl-, t ⁇ ethyl- or t ⁇ 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.
• reaction is effected by heating at temperatures generally in the range of from about +6 ⁇ °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.
• 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.
• 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.
• 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.
• the reduction is effected on the derivatives of formula (I), where X 1A is -SR /j .
• R ⁇ is -CHo, tert-butyl, 4,5-benzo-l,3- th ⁇ azol-2-yl or ,5-benzo-l,3 _ ⁇ m ⁇ dazol-2-yl ;
• -SCOR ⁇ where R is CH o or CF ⁇ , or -NR- ⁇ Rg, where R ⁇ Rg is 1,3- ⁇ m dazol-l-yl, 4,5-benzo-l ,3- ⁇ m ⁇ dazol-1-yl, 4-morpholyl and 1-pyrrol ⁇ dyl , by treatment with H-,, in the presence of Ni-Raney.
• 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
• a halogenating agent such as
• 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.
• 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 6 ⁇ °C to 110°C) , to give a thiazolme azetidmone with a pentenoic "appendage" (chain) linked to ⁇ -lactam nitrogen [R.D.G. Cooper, F.L. Jose, J.Am.Che .Soc. , 92, 2 75 (1970].
• 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.
• 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.
• bases such as alkali and alkalme-earth metal alkoxides, such as potassium or sodium tert-butylate, methylate or ethylate, alkaline metal hydrides (NaH)
• an organic solvent such as a C ⁇ -C ⁇ alcohol (e.g. methanol), ethyl ether, tetrahydrofuran.
• THF t-BuOH mixtures
• 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) .
• 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.
• 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).
• potassium permanganate is used, in combination with catalytic amounts of sodium penodate, in pyridine.
• R- ⁇ g is H
• permanganate in an alkaline aqueous medium is preferably used.
• 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 -8 ⁇ °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.
• substrates of formula (IV) or (V)A-D which can be typically subjected to ozonization are those mentioned the Examples hereinafter reported.
• reaction products i.e. the corresponding azetidinones of formula (V)A-D wherein R * , is H
• reaction products i.e. the corresponding azetidinones of formula (V)A-D wherein R * , is H
• R * is H
• 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
• 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.
• Att ⁇ may be: a halogen, preferably Cl or Br; R ⁇ -C0-0- , where R ⁇ is as defined above and is preferably CHo or
• R ⁇ -S0 2 -0- where R ⁇ is as defined above and is preferably CHo
• Att ⁇ may be a group Rg-S-, where Rg is a C ⁇ -C alkyl group, or a heterocyclic aromatic group, such as 1 ,3 ⁇ benzoth ⁇ azol-2- yl, 1,3 _ benzo ⁇ m ⁇ dazol-2-yl or 1 ,3- ⁇ m ⁇ dazol-l-yl.
• Successive treatment with R I ⁇ 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 ⁇ C.
• a base e.g. EtoN, Py
• an inert organic solvent e.g. CH 2 Cl- > , toluene
• 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 -4 ⁇ °C to about +4 ⁇ °C, more preferably from -20°C to +20°C, for instance at about 0°C/ +5°C
• a base is typically an inorganic base, such as CaCOo, or an organic base, such as a tertiary amine (e.g.
• the compound of formula (C) preferably used steps Cl) and D.l) is the one with and Z are both a halogen, e.g.
• 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.
• 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
• 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.
• 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-d ⁇ methylformam ⁇ de or N,N-d ⁇ methyl 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.
• an alcohol e.g. methanol, ethanol
• an ether e.g. ethyl ether or tetrahydrofuran
• acetone water
• 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.
• the derivatives of formula (I) obtained by the present process may be therapeutically active compounds or precursors thereof.
• the compounds of formula (I) are converted to the corresponding therapeutically active cephalosponns by deprotection of the amine function at the 6-pos ⁇ t ⁇ on 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.
• 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.

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