WO1997020848A1 - Process for the preparation of cephalosporins via reductive dicarbonyl cyclization induced by trialkyl phosphite of 4-thioazetidinone derivatives obtained from penicillins - Google Patents

Abstract

The following description sets forth a reductive cyclization induced by a trialkyl phosphite of a derivative of formula (II) to give a cephalosporin of formula (I), where A is a protective group of the amino function, R1A is H, a cation or a protecting group of the carboxyl function, X1A is: a) a halogen; b) H; c) -OH, -OR4, -O-COR4, -OSO2R4, -SH, -SR4, -S-COR4, where R4 is a hydrocarbon residue containing 1 to 18 carbon atoms; d) -NR5R6, where R5 and R6, together with N, form a heterocycle; e) -CH2-OR7, where R7 is a C1-C8 alkyl; f) -CH2-S-Het1, where Het1 is a heterocycle; g) -CH=CHG, where G is H; a C1-C3 alkyl or a heterocycle Het2O; Y is =O or =S, and X1B is defined as X1A, provided that it is different from H and from a halogen.

Description

PROCESS FOR THE PREPARATION OF CEPHALOSPORINS VIA REDUCTIVE DICARBONYL CYCLIZATION INDUCED BY TRIALKYL PHOSPHITE OF 4-THIOAZETIDINONE DERIVATIVES OBTAINED FROM PENICILLINS

Field of the invention

The present invention relates to a new process for the preparation of cephalosporins, in particular 3-norcephalosporins, such as Cefaclor, Ceftibuten and Ceftizoxime, 3-alkenylcephalosporins (Cefixime, Cefprozil), 3-mercaptomethyl cephalosporins (Ceftriaxone) and 3" methoxymethyl cephalosporins (Cefpodoxime), in particular comprising reductive dicarbonyl cyclization induced by trialkyl phosphite of (3R,4R)-3-acylamino-4-thio-azetidinone derivatives obtained from penicillins.

State of the art

Cephalosporins are usually prepared from 7-ACA. In the case of 3" norcephalosporins, the intermediates thereof, 3-hydroxy-3-cephems

[R.R. Chauvette, P. Pennington, J. Am. Chem. Soc, 96, 4986, 1974; R.

Scartazzini, H. Bichel, Helv. Chim. Acta, 57. 1919. 1974] are prepared on a commercial scale not only from 7-ACA but also by ozoinzation of thiazoline azetidinone (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 4,160,085) (Scheme 1).

thio-azetidinone derivatives obtained by cleavage of the nucleus of 6- APA derivatives, or of thiazoline azetidinones derived from penicillins. (3R,4R)-3-acylamino-4-thio azetidinones can be prepared by treatment with α-haloesters of thiazoline azetidinones in the presence of urea (GB 1,368,234, Glaxo Labs. Ltd.), or of a 6-APA derivative with the amino group at C-6 protected as a trityl derivative (E.G. Brain e t a l . , "Syntheses involving 1,2- Secopenicillins", 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 cephalosporins, in particular 3" norcephalosporins, such as 3-H-, 3-Cl- and 3-OCH₃- cephalosporins; 3-alkenyl-, 3-methylthio- and 3-methoxymethyl-cephalosporins, from penicillins or penicillin derivatives, v i a reductive C=O/C=O or C=O/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 amino function selected from the group consisting of R₂, where R₂ is Ph₃C-, and acyl R₃CO- , where R₃ is H, or a residue R₃ of the 6-acylamino chain present in natural or semisynthetic penicillins;

R_1A is H, a cation (alkali metal or ammonium group or quaternary ammonium group) or a protecting group of the carboxy function;

- X_1A has one of the meanings defined below: a) halogen;

b) H;

c) -OH, -OR₄, -O-COR₄, -OSO₂R₄, -SH, -SR₄, -S-COR₄, where R₄ 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) -NR₅R₆, where R₅ and R₆, 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, O and S, said heterocyclic residue being either unsubstituted or substituted with at least a group selected from the group consisting of -OH, =O and a C₁-C₈ alkyl;

e) -CH₂Q, where Q is H or -OR₇, where R₇ is a C₁-C₈ alkyl;

f) -CH₂-S-Het₁, where Het₁ 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, O and S, said heterocyclic residue being either unsubstituted or substituted with one or more groups selected among

-OH, =O and a C_1-8 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 C₁-C₃ alkyl, and Het₂, where Hetp 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, O and S, said heterocyclic residue being either unsubstituted or substituted with at least one group selected from the group consisting of -OH, =O, and a C₁-C₈ 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_1A have the above meanings, Y is =O or =S, and X_1B has one of the meanings defined above for X_1A, Provided that X_1B is different from H and from a halogen.

The derivatives of formula (I), where X_1A is H, are prepared bv treating with a reducing agent the compounds of formula (I), where X_1A is a), c) or d), which on their turn are prepared from the corresponding compounds of formula (II), where X_1B is c) or d).

In particular, the compounds of formula (I), where X_1A is a halogen, are prepared by treating with a halogenating agent the compounds of formula (I), where X_1A is c) or d), which on their turn are prepared from the corresponding compounds of formula (II), where X_1B 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 X_1B 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_1B is c) or d), as defined above, comprises the following steps:

A.l) treatment of a penicillin of formula (III)

where A is Ph₃C-, R_1B has one of the meanings above reported for R_1A for compounds of formula (I), and is preferably a protective group of the carboxyl function, equal to or different from R_1A, with a compound of formula (A)

where X_1B is c) or d), Y has the above meaning, and Z₁ 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 azetidinone derivative of formula (IV)

where A is Ph₃C-, and R_1B, X_1B and Y have the above meanings;

A.2) treatment of the compound of formula (IV) obtained in the preceding step with alkali or alkaline-earth metal permanganate, to give the azetidinone derivative of formula (V)A

where A is Ph₃C-, and R_1B, X_1B and Y have the above meanings, and R_N is H;

A.3) treatment of the azetidinone derivative of formula (V)A, where A is Ph₃C-, obtained in the preceding step, with an oxalic acid derivative of formula (B)

where Att₁ is an activating group of the carboxyl function and W is selected from the group consisting of Att₂ and -OR_1A, where Att₂ is an activating group of the carboxyl function, equal to or different from Att-p and R_1A has the above meaning, said treatment being followed, when W is Att₂, by a treatment with a compound R_1A-OH, to give the corresponding azetidinone derivative of formula (II), where A is Ph₃C-, and R_1A, X_1B 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_1B is c) or d), as. defined above, comprises step A.l) as above defined, followed by:

A.4) treatment of the azetidinone of formula (IV), where A is Ph₃C-obtained from step A.l) with ozone, to give the corresponding oxamide of formula (II), [where A is Ph₃C-, Y and X_1B are defined as in step A.l), and R_1A = R_1B of the compound of formula (IV)], available for the final cyclization to the 3-cephem nucleus. According to a still further embodiment of the present invention, the preparation of the compound of formula (II), where X_1B 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 CH₂Q, where Q is H, and g), comprises the following steps:

B 1) treatment of thiazoline azetidinone of formula (VI)

where R₃ has the above meaning and R_N is H or -C(COOR_1A)=C(CH₃)₂, where R_1A is as above defined for compounds of formula (I), and is preferably a protective group of carboxyl function, with a compound of formula (A)

where Z₁ and Y have the above meanings, X_1B is c), d), CH₂Q, where Q is H, or g) as defined above, and Z₁ is a group selected from the group consisting of a halogen or an aliphatic or aromatic sulphonyloxy group, in the presence of thallium triacylate 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 azetidinone of formula (V)A

where A is R₃CO- as defined above, X_1B and Y have the above meanings, and R_N is H or -C (COOR_1A) =C (CH₃)₂ , where R_1A has one of the meanings above defined for formula (I), and is preferably a protective group of carboxyl function,

B.2) treatment of azetidinone of formula (V)A obtained from B.1), where A is R₃CO- and R₃, Y and X_1B are as defined above in B.1): i) when R_N is H, with an oxalic acid derivative of formula (B)

where Att₁ is an activating group of the carboxyl function and W is selected among Att₂ and "OR_1A, where Att₂ is an activating group of the carboxyl function, equal to or different from Att₁, and R_1A has the above meaning, said treatment being followed, when W is Att₂, by a treatment with a compound R_1A-OH; or alternatively, ii) when R_N is -C(COOR_1A)=C(CH₃)₂, as above defined, with ozone, to give the corresponding azetidinone derivative of formula (II) where A is R₃CO-, R₃, Y and X_1B and R_1A are as defined above in B.1).

According to a still further embodiment of the present process, the preparation of the compounds of formula (II), where X_1B is -CH₂S-Het₁, as defined under f), or a -CH₂OR₇ group, as defined under e), comprises the following steps: C.1) treatment of thiazoline azetidinone of formula (VI)

where R₃ has the above meaning, and R_N is H or -C(COOR_1A)=C(CH₃)₂, as above defined, with a compound of formula (C)

where Y has the above meaning, Z₁, and Z₂, 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 of thallium triacylate or of a compound having a pK_a of less than 10 (in water at 25°C) and of a hydroxylated compound, to give the corresponding azetidinone of formula (V)B

where A is R₃CO- as defined above, Z₂ and Y have the above meanings and R_N is H or -C(COOR_1A) =C(CH₃)₂, as above defined;

C.2) treatment of azetidinone of formula (V)B, obtained in the preceding steps, with a thiol derivative Het₁-S-M⁺, where Het₁ has the above meaning and M⁺ is an alkali or alkaline-earth metal cation, or with an alkoxide R₇O-M⁺ , where R₇ has the above meaning and M⁺ is an alkaline or alkaline-earth metal cation, to give the corresponding azetidinone derivatives of formula (V)C

where A is R₃CO- as defined above , X₂ is S-Het₁ or OR₇ , and R_N is H or -C ( COOR_1A) =C ( CH₃ ) ₂ , as above defined ;

C . 3 ) treatmen t of azetidinone o f formul a ( V ) C ob t ained in the preceding step and having R_N=H with an oxalic acid derivative of formula B )

where Att₁ is an activating group of the carboxyl function and W is selected between Att₂ and -OR_1A, where Att₂ is an activating group of the carboxyl function, equal to or different from Att_1, and R_1A has the above meaning, said treatment being followed, when W is Att₂, by a treatment with a compound R_1A-OH; or alternatively, treatment of azetidinones (V)B of (V)C wherein R_N is - C(COOR_1A)=C(CH₃)₂ obtained from the preceding steps, with ozone, further followed in the case of azetidinone (V)B by treatment according to step C.2), to give the corresponding azetidinone derivative of formula (II), where X_1B is -CH₂-SHet₁ or -CH₂OR₇ , and A, Y, R_1A, Het₁ and R₇ are as defined above according to C.1) to C.3).

According to a particular embodiment of the present invention, the preparation of the compound of formula (II) as above reported where X_1B is an alkenyl group -CH=CHG, as above defined under g), comprises the following steps:

D.1) treatment of thiazoline azetidinone of formula (VI), to give azetidinone of formula (V)B, as per step 0.1 previously reported;

D.2) treatment of azetidinone of formula (V)B, obtained from the preceding step, with a triphenylphosphine (e.g. 0°C-40°C), followed by treatment of the corresponding phosphoinum 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 azetidinone of formula ( V) D :

where A, Y, and R_N are defined according to the preceding step and G has the above meaning;

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

where Att₁ is an activating group of the carboxyl function and W is selected between Att₂ and -OR_1A, where Att₂ is an activating group of the carboxyl function, equal to or different from Att₁, and R_1A has the above meaning, said treatment being followed, when W is Att₂, by treatment with a compound R_1A-OH, to give the corresponding azetidinone derivative of formula (II), where X_1B is an alkenyl group -CH=CHG, as above defined under g), and the other substituents are as above defined in step D.1) to D.3).

Detailed description of the invention

When the compound of formula (II) is prepared starting from thiazoline azetidinone of formula (III), group A is preferably the residue R₃CO- present in penicillin G or penicillin V, where R₃ is PhCH₂- or PhOCH₂-, respectively.

Ro may have other meanings: for example, it may stand for a straight or branched C_1-6 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-amino-4-carboxy-butyl group present in penicillin N, with optionally protected amino and carboxyl groups); R₃ may also stand for a Ph-CH(NHP)- group, where P is a protective group of the amino function, such as the formyl group -COH, the carbobenzoxy group PhCH₂O-CO- or the group carbo-2,2,2-trichloroethoxy CCl₃CH₂O-CO-, R₃CO- 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 cephalosporins.

The protective groups of the carboxyl function R_1A and R_1B may be equal or different each from another and are preferably: straight or branched C₁-C₈ alkyl groups, either saturated or containing from 1 to 3 unsaturations, for example double bonds, or from 1 to 3 substituents such as halogens (R_1A and R_1B being for instance tert-butyl, 2 , 2 , 2-trichloroethyl or allyl groups); or C₇-C₂₀ arylalkyl groups, optionally substituted on the aryl portion with from 1 to 3 groups selected from the group consisting of C₁-C₈ alkoxy groups, halogens and nitro groups (R_1A or R_1B being for instance benzyl, 4'-methoxybenzyl, 4'-nitrobenzyl, benzhydryl, trityl); or trialkylsilyl groups, where each alkyl group is an alkyl containing from 1 to 4 carbon atoms (R_1A or R_1B being for instance trimethylsilyl).

Substituents c) and d), depending on the meaning of groups R₄, R₅ and RA contained therein, may be those present in therapeutically active 3-norcephalosporins, or groups suitable for a subsequent conversion into other therapeutically useful groups, such as H or halogen.

Preferably, in the present process, A is Ph₃C- or R₃CO, where R₃ is PhCH₂- or PhOCH₂-; R_1A and R_1B are selected from the group consisting of benzyl, 4'-methoxybenzyl, 4'-nitrobenzyl, benzhydryl, trityl, tert-butyl, 2,2,2-trichloroethyl, methyl and allyl. Furthermore, Y is preferably =O, both in the compound of formula (I) and in the compound of formula (II).

The organic radicals R₄ present in groups -OR₄, -O-CO-R₄, -OSO₂-R₄, SR₄ or -S-COR₄ may be optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic (heterocyclic or carbocyclic) and araliphatic C₁-C₁₈ groups.

When X_1A and X_1B are as defined under c), R₄ may in particular be a C₁-C₆ alkyl group (methyl, terbutyl), optionally substituted with from 1 to 3 halogen groups (e.g -CF₃); a carbocyclic, mono- or bicyclic-, aromatic group having from 5 to 12 atoms in the cyclic portion (ring), and being optionally substituted with from 1 to 3 alk\ 1 groups containing 1 to 6 carbon atoms (e.g. p-methyIphenyl); an aromatic heterocyclic group having 5 or 6 atoms in the ring, containing from 1 to 4 heteroatoms selected from the group consisting of N, O and S (such as 1,3-imidazol-1-yl), optionally fused with a benzene ring or with another heterocyclic aromatic group as defined above (to give for instance 4,5-benzo-1,3-thiazol-2-yl or 1,3-imidazol-2-yl).

In particular, when X_1A or X_1B is -OR₄ or -SR₄, R₄ is preferably -CH₃, ethyl, tert-butyl, 4,5-benzo-1,3-thiazol-2-yl, 4,5-benzo-1,3-imidazol-2-yl or phenyl. According to a typical embodiment of the present invention, X_1A = X_1B = -SR₄.

When X_1A or X_1B is -O-COR₄ or -S-COR₄, R₄ is preferably CH₃ or CF₃. When X_1B is -O-SO₂R₄, R₄ is preferably CH₃, CF₃ or p-methylphenyl.

When X_1A or X_1B is as defined under d), -NR₅Rg ₆ay in particular be in particular a heterocyclic aromatic group having 5 or 6 atoms in the cycle and containing 1 to 4 heterocycies selected from the group consisting of N, O and S, such as 1,3-imidazol-1-yl, optionally fused with a benzene ring, such as 4,5-benzo-1,3-imidazol-1-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 N, O and S, such as 4-morpholyl or 1-pyrrolidyl.

When X_1A or X_1B has the meaning defined under e) (-CH₂-OR₇), they are in particular -CH₂OCH₃ (as in Cefpodoxime).

Groups Het₁ and Het₂ present in substituents f) and g) are each in particular an aromatic or non-aromatic heterocyclic group having 5 or 6 atoms in the cycle, containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, optionally substituted as mentioned above with 1 to 3 groups selected among =O, -OH and C₁-C₆ alkyl When the heterocyclic group is aromatic, it may be further fused with a benzene ring or with another aromatic heterocyclic group as defined above.

Examples of said heterocyclic groups are triazoljl, tetrazolyl, thiadiazolyl, benzoxazolyl, benzothiazolyl

When X_1A or X_1B has the meaning defined under f) (-CH₂-S-Het₁), Het₁ is preferably 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-yl (as in Ceftriaxone) or 1-methyl-1H-tetrazol-yl-5-yl (as in Cefamandole)

When X_1A or X_1B has the meaning defined in f) (-CH=CHG), G is preferably H (as in Cefixime) or CH₃ as in Cefprozil, or Het₂ = 4-methyl-1,3-thiazol-5-yl.

The meanings indicated as being preferred for substituents Y, X_1A and X_1B 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 R₂, R₃, R_1A, R_1B, and R₄ may vary during the reaction or their work out and may be either restored or converted to other substituents depending on the requirements.

Groups Z₁ and Z₂ are typically a halogen, such as Cl or Br, or sulphonyloxy -OSO₂R₄, where R₄ is typically CH₃, CF₃ or p-methylphenyl.

Cyclization of the compound of formula (II) with trialkyl phosphite As used herein, the term "dicarbonyl cyclization" means either a C=O/C=O or a C=O/C=S condensation.

The trialkyl phosphite used for said dicarbonyl cyclization typically contains C₁-C₄ alkyl groups and is preferably trimethyl-, triethyl- or triisopropyl-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 +60°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 X_1A is H

According to a preferred embodiment of the present process, the product of formula (I) is the one with X_1A = H.

Said product is prepared from the corresponding derivative of formula (I), where X_1A 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 H₂ 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 -SR₄, where R₄ is -CH₃, tert-butyl, 4,5-benzo-1,3-thiazol-2-yl or 4,5-benzo-1,3-imidazol-2-yl; -SCOR₄, where R₄ is CH₃ or CF₃, or -NR₅R₆, where NR₅R₆ is 1,3-imidazol-1-yl, 4,5-benzo-1,3-imidazol-1-yl, 4-morpholyl and 1-pyrrolidyl, by treatment with H₂, in the presence of Ni-Raney.

Preparation of the compounds of formula (I) where X_1B is a halogen According to a further particular embodiment of the present process, the product of formula (I) is the one with X_1A = a halogen, preferably Cl or Br, prepared by treating with a halogenating agent a compound of formula (I) where X_1A has the meaning defined under c) or d).

The halogenating agent is typically a phosphorus tri-halide or pentahalide (PCl₃, PCl₅, PBr₃, PBr₅) (USP 4,281,117). phosgene, triphosgene, or a triaryl phosphite.Hal₂ complex, where Hal is in particular Cl or Br, such as (PPh₃O).Cl₂ (Eli Lilly, USP 4,226,986), in an organic solvent inert to halogenating agents, e.g. in 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_1A is a halogen, are the ones with X_1A = Cl or Br, prepared from the corresponding compounds of formula (I) where X_1A is -SR₄, where R₄ is -CH₃, tert-butyl, 4,5-benzo-1,3-thiazol-2-yl or 4,5-benzo-1,3-imidazol-2-yl; -SCOR₄, where R₄ is CH₃ or CF₃, or -NR₅R₆, where NR₅R₆ is 1,3-imidazol-1-yl, 4,5-benzo-1,3-imidazol-1-yl, 4-morpholyl and 1-pyrrolidyl, by treatment with a halogenating agent such as phosphorus tri- or penta-halide, or complex (PPh₃O).Cl₂.

Preparation of the compounds of formula (II)

According to the present process, 3-cephem derivatives are in any case prepared starting from penicillins or penicillin-derived raw materials: for example, the derivatives of formula (II) are prepared either from penicillins of formula (III) via steps A.1)-A.3) and A.1)-A.4) of the present process, or from thiazoline azetidinones of formula (VI), v i a steps B.1)-B.2), C.1)-C.3) or D.1)-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 R₃CO- as defined above (and in particular A is the acyl of penicillin G or V) and R_1B 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 NalO₄, 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 60°C to 110°C), to give a thiazoline azetidinone with a pentenoic "appendage" (chain) linked to β-lactam nitrogen [R.D.G. Cooper, F.L. Jose, J. Am.Chem.Soc., 92, 2575 (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, 2493-2503, 1983]. Preparation of 4-thioazetidinone of formula (IV) from penicillin of formula (III) via step A.1)

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

Step A.1) is preferably effected by reacting a penicillin of formula (III), where A is Ph₃C- and R_1B is selected from the group consisting of benzyl, 4'-methoxybenzyl, 4'-nitrobenzyl, benzhydryl, trityl, tert- butyl, 2,2,2-trichloroethyl, methyl and allyl with a compound of formula (A), where Z₁ is a halogen, typically Cl or Br, Y is =O, and X_1B, depending on the compound of formula (I) to be prepared, has one of the meanings indicated above as being preferred or particular for X_1A, or X_1B. Examples of penicillin of formula (III) and of compounds of formula (A) are those mentioned in the Examples hereinafter reported.

Step A.1) is carried out, e.g., in the presence of bases such as alkali and alkaline-earth metal alkoxides, such as potassium or sodium tert-butylate, methylate or ethylate, alkaline metal hydrides (NaH), in an organic solvent, such as a C₁-C₄ 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 by 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.

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

Typically, potassium permanganate is used, in combination with catalytic amounts of sodium periodate, in pyridine.

When, in the compound of formula (IV), R_1B 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_1B 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(COOR_1A)=C(CH₃)₂, typically accomplished under the conditions hereinafter reported for step A.4). Step A.4) 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 -80°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 in the Examples hereinafter reported.

According to an alternative pathway, oxamides of formula (II) can be obtained by total demolition of the "C-appendage" -C(COOR_1A) =C(CH₃)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_N 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), Att₁ may be: a halogen, preferably Cl or Br; R₄-CO-O-, where R₄ is as defined above and is preferably CH₃ or

CF₃; or R₄-SO₂-O-, where R₄ is as defined above and is preferably CH₃,

CF₃ or p-methylphenyl.

Furthermore, Att₁ may be a group R₈-S-, where R₈ is a C₁-C₆ alkyl group, or a heterocyclic aromatic group, such as 1,3-benzothiazol-2-yl, 1,3-benzoimidazol-2-yl or 1,3-imidazol-1-yl. According to a typical embodiment of the present invention, the compound of formula (B) used is the one with Att₁ = a halogen, preferably Cl or Br, and W = -OR_1A, where R_1A is selected from the group consisting of benzyl, 4'-methoxybenzyl, 4'-nitrobenzyl, benzhydryl, trityl, tert-butyl, 2,2,2-trichloroethyl, methyl and allyl.

According to a further embodiment of the present invention, the compound of formula (B) used is the one with W = Att₂, where Att₂=Att₁=halogen, preferably chlorine. Successive treatment with R_1AOH is typically effected in the presence of a base (e.g. EtoN, Py), in an inert organic solvent (e.g. CH₂Cl₂, toluene), generally at -20°C/+20ºC.

Step A.3). as well as steps B.2), C.3) and D.3) are preferably effected in the presence of a base, in an aprotic organic solvent, at temperatures generally ranging from about -4θ°C to about +40°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 CaCO₃, or an organic base, such as a tertiary amine (e.g. triethylamine, ethyldiisopropylamine), 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.1), C.1) and D.1)

Several thiazolin azetidinones of formula (VI) are known, having been disclosed, e.g., by R.D.G. Cooper, F.L. Jose, J .Am.Chem.Soc., 94, 1021 (1972) and L. Ghosez et a l . , Tetrahedron, 39, 15, 2493-2503, 1983. Thiazolin azetidinones of formula (VI) wherein R_N is -C(COOR_1B)=C(CH₃)₂, are known compounds and can be prepared according to known procedures.

The thiazoline azetidinone of formula (VI), where R₃ is PhCH₂- or PhOCH₂, is preferably used.

The compound of formula (A) used in step B.l) is typically the one with Z₁ = a halogen, typically Cl or Br, Y is =O, and X_1B, depending on the compound of formula (I) to be prepared, has one of the meanings indicated above as being preferred or particular for X_1A or X_1B.

The compound of formula (C) preferably used in steps C.l) and D.l) is the one with Z₁ and Z₂ are both a halogen, e.g. Cl or Br, preferably Br, and Y is =O.

Steps B.1), C.1) and D.1) are carried out in the presence of a thallium triacylate typically derived from carboxylic acids of the aliphatic, aromatic or araliphatic series, typically from alkyl-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 C₁-C₆ alcohol (e.g. methanol or ethanol) at temperatures ranging from about +10°C to about +80°C, for instance from about +20°C to about +6θ°C.

The compound with a pK_a lower than 10 is typically used in at least stoichiometric amount with respect to compound (VI).

The reaction as per steps B.1), C.1) and D.1) may be carried out in the presence of an organic solvent, e.g. a halogenated hydrocarbon solvent (methylene chloride, chloroform, CCl₄), a sulphoxide (e.g. dimethylsulphoxide), a ketone (e.g. acetone or methyl ethyl ketone), an amide (e.g. N,N-dimethylformamide or N,N-dimethyl 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 in water or in dimethylformamide containing small amounts of water, or acetic acid in water (in particular as in steps C.1) and D.1) effected with the compound of formula (C), where Z₁ and Z₂ 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) is preferably carried out in the presence of preformed Het₁- S-M⁺ or R₇O-M⁺, obtained from the corresponding thiols or alcohols by treatment with appropriate bases, for example an alkali or alkaline- earth metal hydroxide (e.g. NaOH) in the case of thiols, or NaH in 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 Wittig reactions, using as a base, e.g. butvllithium, sodium amide, an alkali metal hydride (NaH) or an alkaline or alkalnie-earth metal alkoxide, in an organic solvent, such as ethyl ether or tetrahydrofuran. Depending on the meanings of substituents A, R_1A, X_1A 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 cephalosporins by deprotection of the amine function at the 6-position 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_1A 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 Ph₃C- and R_1A is p-nitrobenzyl, is converted to the compound of formula (I), where A is H and R_1A is H, by simultaneous deprotection of the amine function and of the carboxyl function, by treatment with CF₃COOH, in 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)-3-(triphenylmethylamino)azetidin-2-one [{V)A: A=Ph₃C; Y = O ; X_1B= OEt; R_N=H]

A stirred solution of methyl-6β-(triphenylamino)penicillanate [(III): A= PhoC; R_1B = Me) (28g) and ethyl bromoacetate [(A): Z₁=Br; Y=O; 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 (MgSO₄) and evaporated to a residual gum. The solid was separated by chromatography (silica gel Merck for column chromatography; elution: exane- ethylacetate by step gradient) into unchanged starting penicillanate (7.8 g) and amorphous 1-(1-methyloxycarbonyl-2-methylprop-1-enyl)-4-(ethoxycarbonylmethylthio)-3-(triphenylmethylamino)-azetidin-2-one [(IV): A=Ph₃C; R_1B= Me; Y=O; X_1B= -OEt] (14.8 g).

The obtained azetidin-2-one (14.4 g) was dissolved in 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, continously 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 (MgSO₄) and evaporated under vacuum.

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

[(V)A: A=Ph₃C Y=O; X_1B=OEt; R_N=H] (5g; 43%). H-NMR (CDCl₃, δ [ppm]): 1.26 (t, J_vic= 6.8 HZ: -CH₂-CH₃); 2.93 and 3-H (2d. J_gem = 16.0 Hz: S-CH₂CO); 2.99 (s. broad, exchangeable with D₂O: NH); 4.11 (q. J_vic=6.8 Hz: CH₂-CH₃); 4.52 (s. broad:H-3 and H-4); 6.24 (s. broad, exchangeable with D₂₀: NH); 7-0-7-6 (m.: 3 phenyl groups).

EXAMPLE 2

4-(carboxymethylthio)-3-(triphenylmethylamino)-azetidin-2-one

[(V)A: A=Ph₃C; Y=O; X_1B= OH; R_N=H]

The 4-(ethoxycarbonylmethylthio)-3-(triphenylmethylamino)-azetidin-2-one [(V)A: A=Ph₃C; Y=O; X_1B= 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 min. After 0-5 h the mixture diluted with water and extracted with ethylacetate. The aqueous phase was then acidified to pH 3 with HCl and immediately reextracted with ethyl acetate. The organic phase was dried (MgSO₄) and evaporated to give on oil from which the acid 4-(carboxymethylthio)-3-(triphenylmethylamino)azetidin-2-one [(V)A: A=Ph₃CO; Y=O; X_1B= OH; R_N=H] was obtained as amorphous product (1.8 g; 41%) by chromatography on silica gel (hexane: ethyacetate; stepwise gradient elution). ¹H-NMR (DMSO-d₆, δ [ppm]): 2.85 (s. broad: s-CH₂-CO); 4.18 (d. after D₂O exchange, J_vic = 4.5 Hz: H-4); 4.37 (d. J_vic= 4.5 Hz: H-3); 7.0-7.6 (m. : 2 NH and 3 phenyl groups); 8.4 (s. broad, exchangeable with D₂O: COOH).

EXAMPLE 3

1-(1-methoxycarbonyl-2-methylprop-1-enyl)-4-(phenylthiocarbonylmethylthio)-3-(triphenylmethylamino)azetidin-2-one [(IV): A=PhoC; R_1B= Me; Y=O; X_1B= SPh]

To a stirred solution of the methylester of 6β-(triphenylmethylamino)penicilline [(III):A=Ph₃C; R_1B=Me] (10 g) and thiophenylbromoacetate [(A): Z₁=Br; Y=O; X_1B = -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 (MgSO₄) 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-1-enyl)-4-(phenylthiocarbonylmethylthio)-3-(triphenylmethylamino) azetidin-2-one (2.15 g). ¹H-NMR ( CDCl₃ ; δ[ppm]); 2.0 and 2.2 (2s.: = C(CH₃)₂); 2.80 and 3.16 (2d., J_gem= 16.5 Hz. -S-CH₂-CO); 2.9-3.2 (m. exchangeable with D₂O: NH) ; 3.68 (s.: OCH₃); 4.67 (d. after D₂O exchange, J_vic = 5.5 Hz: H-3); 4-99 (d. J_vic= 5-5 Hz: H-4); 7-0-7-6 (m.: 4 phenyl groups).

EXAMPLE 4

Methyl-7-triphenylmethylamino-3-phenylthio-3-cephem-4-carboxylate

[(I): A=Ph₃C; X_1A=-SPh; R_1A=Me]

A cooled solution (-75°C; Me₂CO+solid CO₂) of 1-(1- methoxycarbonyl-2-methylprop-1-enyl)-4-(phenylthiocarbonylmethylthio)-3-(triphenylmethylamino) azetidin-2-one [(IV): A=PhoC; R_1B= Me; Y=O; X_1B=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 (MgSO₄). After evaporation, toluene (30 ml) was added to the oily residue and the resulting solution [containing the oxalimide derivative (II): A = Ph₃C ; Y=O; X_1B= -SPh; R_1A= CH₃] was treated with triethylphosphite (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.

¹H NMR [CDCl₃;δ [ppm]): 2.98 and 3.05 (two d., J_gem= 17.5 Hz: C(2)H₂); 3.18 (d., J_vic=12.0 Hz, exchangeable with D₂O: NH); 3.68 (s.: OCH₃); 4.42 (d., J_vic= 4.5 Hz: H6); 4.49 (d., after D₂O exchange, J_vic = 4.5 H: H-7; 7.1-7.7 (m: 4 phenyl groups).

EXAMPLE 5

1-(1-p-nitrobenzyloxycarbonyl-2-methylprop-1-enyl)-3-(phenylacetamino)-4-(phenylthiocarbonylmethylthio) azetidin-2 one

[(V)A : A = PhCH₂CO-; Y=O; X_1B= -SPh; R_N=-C(COOR_1A) =C(CH₃)₂; R_1A= _PNO₂C₆H₄CH₂].

To a stirred solution of 6-(1-p-nitrobenzyloxycarbonyl-2-methylprop-1-enyl-3-benzyl-4-thia-2,6-diazabicyclo [3,2,0] hept-2-en-7-one [(VI): R₃= PhCH₂-; R_N=-C(COOR_1A)=C(CH₃)₂; R_1A= p-NO₂C₆H₄CH₂] (6.77 g: 15 mmol) in acetone-water 98:2 (250 ml), bromophenylthioacetate [(A): Z₁= Br; Y=O; X_1B = -SPh] (0.4 g: 45 mmoli) and p-toluensulphonic acid (2.85 g: 15 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 (MgSO₄) 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).

¹H NMR (CDCl₃; δ [ppm]): 2.07 and 2.26 (two s.: = C(CH₃)₂); 3.26 and 3-31 (two d., J_gem 15-5 Hz, s-CH₂-CO); 3-66 (s.: C₆H₅-CH₂-CO); 5.13-5.28 (m: H-4, and COO-CH₂-C₆H₄-pNO₂) ; 5-31 (d. , J=4.5 Hz: H- 3); 6.18 (d., exchangeable with D₂O: NH); 6.95-7.55 (m.: two phenyl groups and two H meta to NO₂ group); 8.10-8.25 (two H ortho to NO₂). EXAMPLE 6

p-Nitrobenzyl-7-phenylacetamino-3-phenylthio-3-cephem-4-carboxylate.

[(I). A=PhCH₂CO; X_1A=-SPh; R_1A= pNO₂C₆H₄-CH₂-]

Ozone was bubbled at -70°C through a solution of 1-(1-p-nitrobenzyloxycarbonyl-2-methylprop-1-enyl)-3-(phenylacetamino)-4-(phenylthiocarbonylmethylthio)-azetidin-2-one [(V)A: A=PhCH₂CO; Y=O; X_1B =-SPh; R_N-C(COOR_1A)=C(CH₃)₂; R_1A=pNO₂C₆H₄-CH₂-] (900 mg) in dry dichlorometane (60 ml), until a violet coloration was obtained (about 30 min.) 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. After water washing the mixture was dried (MgSO₄) and evaporated to an oily residue [containing compound (II): A =PhCH₂-CO- ; Y=O; X_1B=-SPh; R_1A= pNO₂C₆H₄-CH₂] to which toluene (60 ml) and triethylphosphite (0.7 ml) were added.

The solution was heated at 90°C for 70 min. and then washed with water, dried (MgSO₄) 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-nitrobenzyl-7-phenylacetamino-3-phenylthio-3-cephem-4-carboxylate. ¹H-NMR (CDCl₃; δ [ppm]) 3-24 and 3-33 (two d. J_gem = 17.4 Hz: C(2) H₂), 3 b4 (s.: C₆H₅-CH₂-CO); 5.14-5.29 (m.: H-6 and COO-CH₂- C₆H₅-PNO₂); 5.33 (d., J_vic = 4.5 Hz: H-7); 6.20 (d., exchangeable with D₂O: NH); 6.98 - 7-56 (m.: two phenyl groups and two aromatic protons meta to NO₂ group); 8.10-8.25 (two aromatic protons ortho to NO₂ group). EXAMPLE 7

4-(phenylthiocarbonylmethylthio)-3-(phenylacetamino)-azetidin-2-one [(V)A: A=PhCH₂CO; Y=O; X_1B=-SPh; R_N=H]

Urea (2.7 g) and bromophenylthioacetate [(A): Z₁= Br; Y=O; X_1B= -SPh] (1.8 g, 7.8 mmol) were added to a solution of 3-benzyl-4-thia-2,6-diazabicyclo [3.2,0] hept-2-en-7-one [(VI):R₃=Ph-CH₂-; R_N=H] (1.4 g: 6.4 mmol) in 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-(phenylacetamino)azetidin-2-one (1g). [(V)A: A=PhCH₂CO; Y=O; X_1B=SPh; R_N=H].

¹H-NMR [CDCl₃; δ [ppm]): 3.44 (s.= S-CH₂-CO), 3-62 (s.: C₆H₅-CH₂-CO); 5.02 (d., J_vic= 4.5 Hz: H-4); 5.46 (d. after D₂O exchange J_vic: 4.5 Hz: H-3); b.43 (d. broad, exchangeable with D₂O: NH-C(3)]; 6.56 (s. broad, exchangeable with D₂O: β lactam N-H): 7.2 - 7.5 (m.: 2 phenyl groups). EXAMPLE 8

Allyl-7-phenylacetamino-3-phenylthio-3-cephem-4-carboxylate [ ( I ) : A =PhCH₂CO- , X_1A= S-Ph , R_1A=allyl ) . A solution of 4-phenylthiocarbonylmethylthio-3-phenylacetaminoazetidin-2-one [(V)A: A=PhCH₂CO-; Y=O; X_1B=-SPh; R_N=H] (0.184 g) in methylene chloride was treated under nitrogen with allyloxalyl chloride, [(B): Att₁=Cl; W=O-R_1A; R_1A= allyl] (0.288 g, in 3 ml of methylene chloride) in the presence of CaCO₃ (0.2 g) at 0°C.

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

The mixture was stirred for 4θ minutes in 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 CH₂CO-; Y=O; X_1B= -SPh; R_1A=allyl] was treated with P(OEt)₃

(0.256 ml in 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.

¹H-NMR ( CDCl₃,δ ): 3.29 and 3,37 (two d, J_gem= 18 Hz, C(2) H₂);

3.62 (s, C₆H₅CH₂ CO-), 4.8-4.9(d.t., J_vic = 5Hz, Jallylic = 1 Hz, -COOCH₂-), 5.05-5.65 (m. CH₂=, H-6 and H-7). 5.85-6.10 (m. CH=), 6.54

(br. s. exchangeable with D₂O, -CONH-), 7.1-7.6(m, 2 phenyl groups).

EXAMPLE 9

4 -t- buthylthiocarbonylmethylthio-3-phenylacetamino-azetidin-2-one

[ ( V ) A : A = Ph-CH₂CO- , Y = O , 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 ) : R₃ = PhCH₂- ; R_N=H and from

( A ) : Z₂ =Br ; Y=O ; X_1B = -S- tButyl . ¹H-NMR (CDCl₃, δ): 1.47 (s., C-(CH₃)₃), 3-29 (singlet, S-CH₂-CO-), 3-66 (s., C₆H₅-CH₂-CO), 5-06 (d, J_vic=5.0 Hz, H-4), 5.52 (d. after exchange with D₂O, J_vic=5-0 Hz, H-3), 6.67 (broad d. exchangeable with D₂O, CONH, C(3)), 6,73 (broad s. exchangeable with D₂O, β-lactam NH), 7.2-7.4 (m. phenyl group).

EXAMPLE 10

Allyl-7-phenylacetamino-3-t-butylthio-3-cephem-4-carboxylate [(I),A=Ph-CH₂CO-, X_1A=S-t. butyl; R_1A=allyl]

By following the procedure described in Example 8 and starting from 4-t-butylthiocarbonylmethylthio-3-phenylacetamino-azetidin-2-one obtained according to Example 9 [(V): A = PHCH₂CO-; Y=O; X_1B =S- Butyl; R_N= H] (0.25 g) and allvloxalyl chloride [(B): Att₁=Cl; Att₂= -OR_1A; R_1A=allyl] (0.4 g) the title compound was obtained.

2H-NMR (CDCl₃, δ ): 1.47 (s.t.butyl), 3.58 (s. Ph-CH₂CO), 3.61 and 3.69 (two d, J_gem =17Hz, C(2)H₂), 4,6-4 . 8 (m, -COO-CH₂-), 5.03 (d, J_vic= 5.5Hz, H-6), 5.2-5.5 (m, CH₂= and H-7), 5.85-6.10 (m. -CH=), 6.90 (br.s., exchangeable with D₂O, CONH-) 7.2-7.6 (m, phenyl group), EXAMPLE 11

P-Nitrobenzyl-7-phenylacetamino-3^_t-butylthio-3-cephem-4-carboxylate. [(I): A = PhCH₂CO-, X_1A=-S-tButyl, R_1A= p-NO₂-C₆H₄CH₂-) .

By following the procedure described in Example 8, starting from 4-t- butylthiocarbonylmethylthio-3-phenyl acetamino-azetidin-2-one (0.150 g) [(V)A: A= PhCH₂CO-; Y=O X_1B =-StButyl; R_N=H] and p-Nitrobenzyloxalyl chloride [(B): Att₁=Cl; W= -OR_1A, R_1A = pNO₂-C₆H₄CH₂] (0.45g), and directly subjecting to cyclization the reaction mixture containing the oxamide of formula (II) wherein A= Ph₂CH₂CO-; Y=O, X_1B= S-tButyl and R_1A = pNO₂-C₆H₄CH₂, without isolating compound (II), the title compound has obtained.

¹H-NMR(CDCl₃, δ ): 1.44 [s., (CH₃)₃C]; 3.63 and 3.79 (two d, J_gem=17Hz, C(2)H₂); 3.70 (s., C₆H₅CH₂CO); 5.25-5.5 (m,COOCH₂- and H-6); 5.74 (d, after exchange with D₂O, J_vic = 4 Hz, H-7); 6.65-6.80 (broad s, exchangeable with D₂O, N-H); 7.2-7.5 (m., phenyl group); 7.5-7.7 (m, aromatic protons meta to NO₂); 8.15-8.3 (m, aromatic protons ortho to NO₂).

Claims

1. A process for the preparation of a cephalosporin of formula (I), starting from a penicillin or a penicillin derivative, wherein said cephalosporin has the following formula (I):

where

A is a protective group of the amino function selected from the group consisting of R₂, where R₂ is Ph₃C-, and acyl R₃CO-, where R₃ is H or a residue R₃ of the 6-acylamino chain present in natural or semisynthetic penicillins;

R_1A is H, an alkali metal cation, an ammonium group, a quaternary ammonium group or a protective group of the carboxyl function;

X_1A has one of the meanings defined below:

a) halogen;

b) H;

c) -OH, -OR₄, -O-COR₄, -OSO₂R₄, -SH, -SR₄, -S-COR₄, where R₄ stands for C₁-C₁₀ hydrocarbon residues, either unsubstituted or substituted with one or more groups containing heteroatoms;

d) -NR₅R₆, where R₅ and R₆, 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, O and S, said heterocyclic residue being either unsubstituted or substituted with at least a group selected among -OH, =O and a C₁-C₈ alkyl;

e) -CH₂Q, where Q is H or -OR₇, where R₇ is a C₁-C₈ alkyl;

f) -CH₂-S-Het₁, where Het₁ 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, O and S, said heterocyclic residue being either unsubstituted or substituted with one or more groups selected among -OH, =O and a C₁-C₈ alkyl, being linked to atom S through a carbon atom of the cycle;

g) an alkenvl group -CH=CHG, where G is selected from the group consisting of H, a straight or branched C₁-C₃ alkyl, and Het₂, where Het₂ 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, O and S, said heterocyclic residue being either unsubstituted or substituted with at least a group selected among -OH, =O, and a C₁-C₈ alkvl 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 comprising treating with a trialkyl phosphite an azetidine oxalimido derivative of formula (II)

where A and R_1A have the above meanings, Y is =O or =S, and X_1R has one of the meanings defined above for X_1A, provided that X_1R is different from H and from a halogen.

2. A process as claimed in claim 1, wherein the trialkyl phosphite is trimethyl-, triethyl- or triisopropyl- phosphite.

3. A process as claimed in claim 1, carried out in a solvent selected from the group consisting of an aromatic solvent, a halogenated hydrocarbon solvent, and acyclic or cyclic ether.

4. A process as claimed in claim 3, wherein the aromatic solvent is toluene or xylene; the halogenated solvent is chloroform; the ether is ethyl ether, tetrahydrofuran or dioxane.

5. A process as claimed in claim 1, wherein the operating temperature ranges from +60°C to +120°C.

6. A process as claimed in claim 1, wherein 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.

7. A process as claimed in claim 1 wherein X_1A = X_1B = SR₄.

8. A process as claimed in claim 1, wherein A is Ph₃C- or R₃CO, where R₃ is PhCH₂- or PhOCH₂-; R_1A and R_1B are selected from the group consisting of benzyl, 4'-methoxybenzyl, 4'-nitrobenzyl, benzhydryl, trityl, tert-butyl, 2,2,2-trichloroethyl, methyl and allyl; and Y is =O.

9. A process as claimed in claim 1, wherein X_1A and X_1B are as defined under c).

10. A process as claimed in claim 9. wherein X_1A and X_1B are selected from the group consisting of: -OR₄ or -SR₄, where R₄ is -CH₃, ethyl, tert-butyl, 4,5-benzo-1,3-thiazol-2-yl, 4,5-benzo-1,3-imidazol-2-yl or phenyl; -O-COR₄ or -SCOR₄, where R₄ is CH₃ or CF₃; and -OSO₂R₄, where R₄ is CH₃, CF₃ or p-methylphenyl.

11. A process as claimed in claim 1, wherein X_1A and X_1B are -NR₅R₆, as defined under d).

12. A process as claimed in claim 11, wherein -NR₅R₆ is selected from the group consisting of 1,3-imidazol-1-yl, 4,5-benzo-1,3-imidazol-1-yl, 4-morpholyl and 1-pyrrolidyl.

13. A process as claimed in claim 1, wherein X_1A and X_1B are -CH₃OR₇, as defined under e).

14. A process as claimed in claim 13, wherein R₇ is -CH₃.

15. A process as claimed in claim 1, wherein X_1A and X_1B are -CH₂-S- Het₁, as defined under f).

16. A process as claimed in claim 15, wherein Het₁ is 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-yl or 1-methyl-1H-tetrazol-5-yl.

17. A process as claimed in claim 1, wherein X_1A and X_1B are -CH=CHG,s defined under g).

18. A process as claimed in claim 17, wherein G is selected from the group consisting of H, CH₃ and 4-methyl-1,3-thiazol-5-yl.

19. A process as claimed in claim 1, for the preparation of a compound of formula (I), where X_1A is H, further comprising the treatment with a reducing agent of a compound of formula (I), where X_1A is a), c) or d), prepared from the corresponding compound of formula (II), where X_1B is c) or d),

20. A process as claimed in claim 19 wherein the reducing agent is Zn in an acid medium or H₂ in the presence of a catalyst.

21. A process as claimed in claim 1, for the preparation of a derivative of formula (I), where X_1A is a halogen, also comprising a treatment with a halogenating agent of a compound of formula (I), where X_1A is c) or d), prepared from the corresponding compound of formula (II), where X_1B is c) or d).

22. A process as claimed in claim 21 for the preparation of a derivative of formula (I), where X_1A is Cl or Br.

23. A process as claimed in claim 21, wherein the halogenating agent is selected from the group consisting of phosphorus tri- or pentahalide, phosgene, triphosgene, and a triarjl phosphite. Halo complex, where Hal is a halogen, and is used at temperatures lower than 30°C.

24. A process as claimed in claim 1, wherein penicillin is as per formula (III)

where A is Ph₃C-, R_1B has one of the meanings above reported for R_1A and is preferably a protective group of the carboxyl function, equal to or different from R_1A, wherein said penicillin of formula (III) is converted to a compound of formula (II) where X_1B is c) or d), as defined above, via a process comprising the following steps:

A.1) treatment of said penicillin of formula (III) with a compound of formula (A)

where X_1B is c) or d), Y has the above meaning, and Z₁ is a group selected from the group consisting of a halogen and an aliphatic or aromatic sulphonyloxy group, in the presence of a strong base, to give the azetidinone derivative of formula (IV)

where A is Ph₃C- , and R_1B, X_1B and Y have the above meanings;

A.2) treatment of the compound of formula (IV) obtained in the preceding step with alkali or alkaline-earth metal permanganate, to give the azetidinone derivative of formula (V)A

where A is Ph₃C-, and R_1B, X_1B and Y have the above meanings, and R N is H;

A.3) treatment of the azetidinone derivative of formula (V)A, obtained in the preceding step, with an oxalic acid derivative of formula (B)

where Att₁ is an activating group of the carboxyl function and W is selected from the group consisting of Att₂ and -OR_1A, where Att₂ is an activating group of the carboxyl function, equal to or different from Att₁, and R_1A has the above meaning, said treatment being followed, when W is Att₂, by a treatment with a compound R_1A-OH, to give the corresponding azetidinone derivative of formula (II), where A is Ph₃C-, and R_1A, X_1B and Y have the above meanings.

25 A process as claimed in claim 1, wherein penicillin is as per formula (III)

where A is Ph₃C-, R_1B has one of the meanings above reported for R_1A and is preferably a protective group of the carboxvl function, equal to or different from R_1A, wherein said penicillin is converted to the compound of formula (II) where X_1B is c) or d) as defined above, vi a a process comprising the following steps:

A.1) treatment of said penicillin of formula (III) with a compound of formula (A)

where X_1B is c) or d), Y has the above meaning, and Z₁ is a group selected between of a halogen and an aliphatic or aromatic sulphonyloxy group, in the presence of a strong base, to give the azetidinone derivative of formula (IV)

where A is Ph₃C-, and R_1B, X_1B and Y have the above meanings;

A.4) treatment of the azetidinone of formula (IV) where A is Ph₃C- with ozone, to give the corresponding oxamide of formula (II) where A is Ph₃C-.

26. A process as claimed in claim 27, wherein in said penicillin of formula (III) R_1B is selected from the group consisting of benzyl, 4'- methoxybenzyl, 4'-nitrobenzyl, benzhydryl, trityl, tert-butyl, 2 , 2 , 2- trichloroethyl, methyl and allyl, and in the compound of formula (A) Z₁ is Cl or Br, and Y is =O.

27. A process as claimed in claim 24, wherein step A.1) is carried out in the presence of a base selected from the group consisting of alkali or alkaline-earth metal alkoxides and alkali metal hydrides, in an organic solvent.

28. A process as claimed in claim 24, wherein step A.2) is carried out bv treatment with potassium permanganate, in an organic solvent, or in an aqueous medium, at a temperature ranging from 0°C to +30°C.

29. A process as claimed in claim 24, wherein when in the compound of formula (IV) R_1B is H, the permanganate is used in an alkaline aqueous medium.

30. A process as claimed in claim 25 wherein step A.4) is carried out in a halogenated hydrocarbon solvent, in the absence of hydroxylated compounds, at temperatures ranging from -80"C to -20°C.

31. A process as claimed in claim 1, where said penicillin derivative is thiazoline azetidinone of formula (VI)

where R₃ has the above meaning, and R_N is H or -C(COOR_1A) =C(CH₃)₂, where R_1A is as above defined, and is preferably a protective group of carboxyl function, wherein said thiazoline azetidinone is converted to a compound of formula (II) where X_1B 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 out of - CH₂Q , where Q is H, and g), via a process comprising the following steps:

B.1) treatment of said thiazoline azetidinone of formula (VI) with a compound of formula (A)

where Z₁ and Y have the above meanings, X_1B is c), d), CH₂Q, or g) as defined above, and Z₁ is a group selected between a halogen or an aliphatic or aromatic sulphonyloxy group, in the presence of a thallium triacylate or of a compound having a pK_a of less than 10 (in water at 25°C) and of a hydroxylated compound, to give the corresponding azetidinone of formula (V)A

where A is R₃CO- as defined above, X_1B and Y have the above meanings, and R_N is H or -C(COOR_1A)=C(CH₃)₂, where R_1A is as above defined, and preferably is a protective group of carboxyl function; B.2) treatment of the azetidinone of formula (V)A, where A is R₃CO- as defined above: 1) when R_N is H, with an oxalic acid derivative of formula (B)

where Att₁ is an activating group of the carboxy function and W is selected between Att₂ and -OR_1A, where Att₂ is an activating group of the carboxyl function, equal to or different from Att₁, and R_1A has the above meaning, said treatment being followed, when W is Att₂, by a treatment with a compound R_1A-OH; or, alternatively,

ii) when R_N is -C(COOR_1A)=C(CH₃)₂ with ozone, to give the corresponding azetidinone derivative of formula (II) as defined above.

32. A process as claimed in claim 1, wherein the penicillin derivative is a thiazoline azetidinone of formula VVI)

where R₃ has the above meaning, and R_N is H -C(COOR_1A)=C(CH₃)₂, where R_1A is as above defined and preferably is a protective group of the carboxyl function,

wherein said thiazoline azetidinone of formula (VI) is converted to a compound of formula (II) where Xig is -CH₂S-Het₁ as defined under f), or a group -CH₂OR₇ as defined under e), via a process comprising the following steps:

C.1) treatment of said thiazoline azetidinone of formula (VI) with a compound of formula (C)

where Y has the above meaning, Z₁ and Z₂, equal or different from each other, are selected from the group consisting of a halogen and an aliphatic or aromatic sulphonyloxy group, in the presence of a thallium triacylate or of a compound having a pK_a of less than 10 (in water at 25°C) and of a hydroxylated compound, to give the corresponding azetidinone of formula (V)B

where A is R₃CO- as defined above, Z₂ and Y have the above meanings and R_N is H or -C(COOR_1A) =C(CH₃)₂ as above defined;

C.2) treatment of the azetidinone of formula (V)B, obtained in the preceding step, with a thiol derivative Het₁-S-M⁺, where Het₁ has the above meaning and M is an alkali or alkaline-earth metal cation, or with an alkoxide R₇O-M⁺ , where R₇ has the above meaning and M⁺ is an alkali or alkaline-earth metal cation, to give the corresponding azetidinone derivatives of formula (V)C

where A is R₃CO- as defined above, X₂ is S-Het₁ or OR₇, and R_N is H or -C(COOR_1A)=C(CH₃)₂ as defined above;

C.3) treatment of azetidinone of formula (V)C obtained in the preceding step ii) when R_N is H, with an oxalic acid derivative of formula B)

where Att₁ is an activating group of the carboxyl function and W is selected between Att₂ and -OR_1A, where Att₂ is an activating group of the carboxyl function, equal to or different from Att₁, and R_1A has the above meaning, said treatment being followed, when W is Att₂, by a treatment with a compound R_1A-OH; or, alternatively,

1) treatment with ozone of azetidinones (V)B or (V)C wherein R_N is -C(COOR_1A)=C(CH₃)₂ obtained from the preceding steps, further followed in the case of (V)B by treatment according to step C.2), to give the corresponding azetidinone derivative of formula (II), where X_1B is -CH₂-SHet₁ or -CH₂OR₇, as defined above.

33. A process as claimed in claim 1, wherein the penicillin derivative is a thiazoline azetidinone of formula (VI)

where R₃ has the above meaning, and R_N is H or -C(COOR_1A)=C(CH₃)₂, where R_1A is as above defined and preferably is a protective group of the carboxyl function,

wherein said thiazoline azetidinone is converted to a compound of formula (I) where X_1B is -CH=CHG as defined under g), via a process comprising the following steps:

D.1) treatment of said thiazoline azetidinone of formula (VI) with a compound of formula (C)

where Y has the above meaning, Z₁ is selected from the group consisting of a halogen and an aliphatic or aromatic sulphonyloxy group and Z₂ is a halogen, in the presence of a thallium triacylate or of a compound having a pK of less than 10 (in water at 25°C) and of a hydroxylated compound, to give azetidinone of formula (V)B

where A is R₃CO- as defined above, Y has the above meaning, Z₂ is a halogen and R_N is H or -C(COOR_1A)=C(CH₃)₂;

D.2) treatment of the azetidinone of formula (V)B, obtained in the preceding step, with a triphenylphosphine, followed by a treatment of the corresponding phosphonium salt with a base, and then with an aldehyde

H-CO-G

where G has the above meaning, to give an azetidinone of formula (V)D,

whrein A, Y, R_N and G are as above defined;

D.3) treatment of the azetidinone of formula (V)D obtained in the preceding step: 1) where R_N is H, with an oxalic acid derivative of formula B)

where Att₁ is an activating group of the carboxyl function and W is selected between Att₂ and -OR_1A, where Att₂ is an activating group of the carboxyl function, equal to or different from Att₁, and R_1A has the above meaning, said treatment being followed, when W is Att₂, by a treatment with a compound R_1A-OH, to give the corresponding azetidinone derivative of formula (II), where X_1B is -CH=CHG.

34. A process as claimed in claim 31. wherein in the thiazoline azetidinone of formula (VI) R₃ is PhCH₂- or PhOCH₂, and in the compound of formula (A) Z₁ is Cl or Br, and Y is =O.

35. A process as claimed in claim 32 or 33. wherein in the thiazoline azetidinone of formula (VI) R₃ is PhCH₂- or PhOCH₂, and in the compound of formula (C) Z₁ and Z₂ are a halogen and Y is =O.

36. A process as claimed in claim 35, wherein in compound (C) Z₁ = Z₂ = Br.

37. A process as claimed in claim 31-33, wherein in step B.1), C.1) or D.1, thallium triacylate is thallium triacetate, the compound having a pK_a of less than 10 is urea, acetic acid, or p-toluenesulphonic acid, the hydroxylated compound is water or C₁-C₆ alcohol.

38. A process as claimed in claim 31-33, wherein step B.1), C.1) or D.1) is earried out at temperatures ranging from +10°C to +80ºC.

39. A process as claimed in claim 31-33, wherein step B.1), C.13 or D.1) is carried out with urea in water or in dimethylformamide containing small water, or with acetic acid in water.

40. A process as claimed in claim 24, 31-33, wherein in step A.3), B.2), C.3) or D.3) in the compound of formula (B) Att₁ is Cl or Br, and W is OR_1A, where R_1A is selected from the group consisting of benzyl, 4'-methoxybenzyl, 4'-nitrobenzyl, benzhydryl, trityl, tert-butyl, 2,2,2-trichloroethyl, methyl and allyl.

41. A process as claimed in claim 24, 31-33. wherein in step A.3), B.2), C.3) or D.3) in the compound of formula (B) where Att₁ is Cl, and W is Attp, Att₂ = Att₁ = Cl.

42 A process as claimed in claim 24, 31-33. wherein step A.3), B.2), C.3) or D.3) is carried out in the presence of a base, in an aprotic organic solvent, at a temperature ranging from -40°C to +40ºC.

43. A process as claimed in claim 33. wherein step D.2) is carried out with a base selected from the group consisting of butyllithium, sodium amide, alkaline metal hydride and alkaline metal or alkaline-earth metal alkoxide, in an organic solvent.

44. Azetidine oxalimido derivative of formula II, as defined in claim 1.

45. The azetidine oxalimido derivative according to claim 44, wherein X_1B is -SR₄.