IE790852L - Cephalosporin derivatives. - Google Patents

Description

•.

Vw "O-SUBSTITUTED OXIME DERIVATIVES OF 7~CC2-(2-AMINO--THIAZOL-4-YL) -2-HYDROXYIMINO-ACETYL] -AMINO] -CEPH--3-EM-4-CARBOXYLIC ACID".

This invention relates to new O-substituted oxime derivatives of ?-(amino-thiazolyl)-acetamido-ceph-3-em-a--carboxylic acid, processes for preparing them, and the pharmaceutical compositions containing them.

In one aspect the invention provides the new syn isomer 7-(amino-thiazolyl)-acetamido-ceph-5-em-4--carboxylic acid derivatives of the general formula: co^A (wherein: a) B represents a radical R which is:-i) a radical -C-R' in which X represents a sulphur or II x oxygen atom and R' represents: an alkyl or alkoxy radical having from 1 to 4 carbon atoms, or a phenyl radical ^ / 2 or a radical B.

R3 represents 0 or an integer from 1 to a and R2 and R^, which nay be the same or different, each represents a 5 hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or R£ and R^ together with the intervening nitrogen atom form a piperidino, morpholino or phthalimido group; ii) a radical -^K-COgA' in wnich A' represents a hydrogen atom, an alkali metal a^om, an equivalent of an alkaline-earth metal atom or of a magnesium atom, an amnonium group, a; substituted ammonium group derived from an organic amino base or an easily-cleavable ester group, R(i represents a phenyl, IS hydroxyethyl or nitrile radical; iii) the Y-lactone of the formula -A V ; or iv) a radical *-n whi°h 2.' represents an integer of from 1 to 4 and R^ represents: an alkoxy radical containing from 1 to iv carbon 20 atoms or a radical Alk - ^C0)ns- in which Alk represents an alk radical containing from 1 to b. carbon atoms and ns represents 0, 1 or 2, ^-R6 or a radical N in which Rg and Rr;, which V may be the same or different, each represent a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or Rg and Rr, together with the intervening nitrogen atom form a phthalimido or 1-pyridinio group, 5 or, when n' is an integer other than 1, a cyano radical, or a radical - C - NH~ in wnich X' represents ~~ II 2 X' a sulphur atom or, when n' is an integer other than 1, an oxygen atom, or a 'j.-nethyl- or /i-amino-1,3-thiazol-2-yl radical, or a l,2,3,^-tetrazol-5-yl radical, or an azido radical, or an ac,yl radical having from 2 to 4 carbon atoms; b) B represents a radical R„ which is a radical a in wnich R^g represents a halogen atom, or a radical in wnich Rar represents a phenyl radical or a 5- or 6-membered aromatic heterocyclic radical containing from 1 to a heteroatoms selected from sulphur, nitrogen and oxygen, the phenyl and heterocyclic radicals being optionally substituted by one or more radicals selected from amino, nitro and .and cyano radicals' alkyl radicals having from 1 to 4 25 carbon atoms; or c) B represents a radical which is a radical 49867 - it - -(cH2)n,-RSb in wnich represents an imidazolyl, morpholinyl or N-alkyl piperazinyl radical, the N-alkyl radical containing from 1 to 4 carbon atoms; represents a chloro or methoxy radical; or an alkyl, cycloalkyl or alkylthio radical having in each case from 1 to 5 carbon atoms; or a radical -CHg-S-Rj^ in wnich R^ represents an optionally-substituted heterocyclic radical containing nitrogen, an acyl radical having from 2 to a carbon atoms, th° 2-oxo-C3Hj-thiazo]in-4-yl-carbonyl radical or the 3-methyl-l,2-oxazol-S-yl-carbonyl radical; or the acetoxymethyl or carbamoyloxymethyl radical; q U or a radical -ITH-C-Alk; and A represents a hydrogeu atom, or an alkali netal atom, an equivalent of an alkaline-enrth metal atom or of a magnesium atom, an ammonium group, a substituted ammonium group derived from an organic amino base or an easily-cleavable ester group) and acid addition salts of the derivatives of general formula I' formed with the mineral or organic acids.

The compounds of the invention are syn isomers by virtue of the position of the nitrogeu-oxygen bond in tne oxime group relative to the adjacent carbon-nitrogen double bond. All compounds having a similar oxime group which are depicted herein by formulae in wnich the nitrogen-oxygen bond is shown in the same relative: position are also syn isomers.

In the following description and claims all references to general formulae by number are references to those formulae as first defined herein, and all <r substituents and symbols are as first defined herein, unless otherwise stated.

The invention therefore, extends to derivatives of the general formula: o y -~f \t. the derivatives of the general formula: A ^ 0 C0,fl and the derivatives of general formula: CI) 49867 % 0Ka* ± 0RW I . <v cx>%r It is to be understood that the derivatives of general formula I' can exist either in the form indicated by the said fornulal* or in the form depicted in the general formula: S >W hi 06 r COib and all references to compounds of the invention are to be construed accordingly.

When B represents the radical R this may be inter alia an acyl group containing from 1 to 5 carbon atoms such as an acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl or tert-valeryl group, as well as a corresponding sulphur derivative such as the thio-acetyl group. Radical R may also be a methoxycarbonyl, V I ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butoxycarbonyl, isobutyloxycarbonyl or tert-butoxy-carbonyl group, or a corresponding sulphur derivative such as the methoxythiocarbonyl group.

Other possibilities for radical R include the carbamoyl, N-methyl-carbamoyl, N,N-dioethyl-carbamoyl, acinoacetyl, dimethylaminoacetyl, methylaminopropionyl, diiaethylaminopropionyl, aminovaleryl, dimethylanino-vileryl, N-piperidinocarbonyl, N-piperidino-acetyl, 10 N-piperidino-propionyl, N-pnthalinido-carbonyl, N- -phthalinido-acetyl, N-phthalimido-propionyl and benzoyl groups, and the acetylmethyl, acetylethyl, propionyl-methyl, propionylethyl, methoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, methylthiomethyl, methylthio 15 ethyl, ethylthiomethyl and ethylthioethyl groups and oxidised forms of the sulphur-containing radicals such as the methylsulphinylmethyl and methylsulphonylmethyl groups.

Radical R may also represent the aminomethyl, 2C methylaminomethyl, dimet'-ylaminomethyl, dimethylamino-ethyl, dimethylaminopropyl, phthalimidomethyl, phthalinidoethyl, phthalimidopropyl, N-pyridinylmethyl, N-pyridinylethyl, N-pyridinylpropyl, thiocarbamoylmethyl carbamoylethyl, carbamoylpropyl, thiocarbamoylethyl, 25 4-aniino-thiazol-2-yl-methyl, 4-methyl-thiazol-2-yl--methyl, 1,2,3,4-tetrazol-5-yl-methyl and 1,2,3,4--tetrazol-5-yl-ethyl groups.

« O O V I When B represents the radical "(C^^n1 ~^5a' t^ie substituent R^fl may be a halo group such as fluoro, chloro, bromo or iodo; a phenyl group; a 1,2,3-, 1,2,5-, 1,2,4- or 1,3,a-thiadiazolyl group; a 1H-5 -tetrazolyl group; a 1,3-thiazolyl group; a 1,2,3-, 1.2.4- or 1,3,4-triazolyl group; a 1,2,3-, 1,2,4-, 1.2.5- or 1,3,4-oxadiazolyl group; a 2-, 3~ or a--pvridinyl group; a 2- or 3-furyl group; a 2- or 3--thienyl group; or a 2- or 3-pyrolyl group. The phenyl and heterocyclic radicals may be unsubstituted or substituted by one or more radicals selected from the amino, nitro, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and nitrile radicals.

When 3 represents the radical ~(<^2^n,-R5b' 15 substituent R^ may be, for example, a N-alkyl-piperazin -1-vl radical, and especially the a-r.ethyl-, 4-ethyl-, a-propyl-, 4-isopropyl-, a-butyl-, a-sec-butyl- and a-tert-butyl-piperazin-l-yl radicals.

R^ may be inter alia an alkyl group such as a 20 methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, sec-pentyl or tert-pentyl group or a cycloalkyl group such as a cyclopropyl, cyclobutyl or cyclopentyl radical. R^ may also be a methylthio, ethylthio, propylthio, isopropylthio, butylthio, iso-25 butylthio or tert-butylthio group or an acetamido, propionylamido, butyrylamido, isobutyrylamido or valerylamido group.

When R^ represents the radical -CHg-S-R^i ®j_2 nay be, for example a 1,2,3", 1,2,5-, 1,2,4- or 1,3,4--thiadiazolyl radical; a lH-tetrazolyl radical; a 1,3-thiazolyl radical; a 1,2,3~, 1,2,4- or 1,3,4— 5 -triazolyl radical; or a 1,2,3~, 1,2,a-, 1,2,5- or 1,3,a-oxadiazolyl radical, aud each of these heterocyclic radicals nay be unsubstituted or substituted by one or more radicals selected fron alkyl groups such as the methyl, ethyl, propyl and isopropyl groups, 10 alkoxv groups such as the nethoxy, ethoxy, propyloxy and isopropyloxy groups, amino, hydroxycarbonylraethyl, dimethylaminoethyl and diethylaminoethyl radicals. Examples of substituted heterocyclic radicals include the 3-nethyl-, 3-ethyl- and 3-propyl-l,2,4-thiadiazol-15 -5-yl radicals, as well as the 3-methoxy-, 3-ethoxy-and 3-propoxy-l,2,a-thiadiazol-5-yl radicals.

R-^2 may also represent an acyl group such as the acetyl, propionyl and butyryl groups.

A preferred category of derivatives of general 20 formula I' are those in which R^g is acetyl, 1-methyl-tetrazolyl, 2-methyl-l,3,4-thiadiazolyl; 3-methyl-l,2,a-thiadiazol-5-yl; 3-methoxy-l,2,4-thia-diazolyl; 1,3,4-thiadiazol-5~yl; 2-amino-l,3,^-thia-diazol-5-yl; 3-hydroxycarbonylnethyl-l,2,4-thiadiazol-25 -5-yl; 5-methoxy-l,2,4-thiadiazol-3-yl; 4-methyl-5- -hydroxycarbonylmethyl-l,3-thiazol-2-yl or 1-dimethyl-aminoethyl-1,2,3,4-tetrazol-5-yl radical. 4 90U I A may represent a hydrogen atom, in which case the compound of formula I' is an acid, it may represent a metal atom (or equivalent thereof) or a substituted or unsubstituted arjnonium group, in wnich case the 5 compound is a salt, or it may represent an ester group when the compound is obviously an ester. When A represents an equivalent of an alkaline-earth metal atom or of a magnesium atom it represents that proportion of the multivalent atom that corresponds to a 10 single valence.

A may be, for example a sodium, potassium or lithium atom, an equivalent of calcium or magnesium , or an ammonium group. Examples of substituted ammonium groups include those derived from trimethylamine, 15 diethylamine, triethylamine, methylamine, propylamine, N,K-dimethylethanolnmine, tris(hydroxymethyl)- aroino-methane, ethanolamine, pyridine, picoline, dicyclo-hexylamine, N,N'-dibenzylethylenediamine, morpholine, benzyl3mine, procaine, lysine, arginine, histidine and 20 N-methylglucamine.

By the term "easily-cleavable ester group" is meant an ester-forming group that may be removed to form the corresponding acid without modifying the remainder of the molecule other than by removing other 25 similar removable groups. Examples of such groups include methoxymethyl, ethoxymethyl, isopropoxymethyl, a-methoxyethyl, a-ethoxyethyl, methylthiomethyl, ethyl-thiomethyl, isopropylthiomethyl., pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, isobutyryloxymethyl, isovalerlyloxymethyl, propionyloxyethyl, isovaleryloxy-ethyl, 1-acetoxyethyl, 1-acetoxypropyl, 1-acetoxybutyl, 1-acetoxyhexyl and 1-acetoxyheptyl radicals.

The derivatives of general formula I' may also be in the form of salts of organic or mineral acids since they contain at least one salifiable amino radical. Acids with which it is possible to salify the amino group(s) of the derivatives of general formula I' are, inter alia, acetic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, p-toluene -sulphonic, hydrochloric, hydrobromic, hydroiodic, sulphuric and phosphoric acid.

These products of general formula I' in wnich B represents a radical R^, in other words the compounds of formula 1^, can also be in the form of internal salts, and the invention extends to such internal salts Preferred compounds of the invention are the compounds of general formula I wherein: i) R is the radical -CO-R' and R' represents an alkyl radical having from 1 to 4 carbon atoms, a phenyl radical or a radical -(CH2)n-NR2Rj in which n is 0 or 1; ft ii) R is the radical -CH-COOH and R^ represents a phenyl radical or a hydroxyethyl radical, or iii) R is theY-lactone of formula O iv) R is the radical ' *"s ^ or 2 and R^ represents either a radical -NR^R^, a radical -C-NH2, a l,2,3,4-tetrazol-5-yl radical or an acetyl S radical; and R^ represents an alkyl radical having from 1 to 5 carbon atoms, an acetoxymethyl radical or a radical -C^-S-R^ in wnich R^ represents a 2-methyl--1,3,4-thiadiazolyl radical or a 1-methyl-tetrazolyl radical; and A represents a hydrogen atom, an alkali metal atom, an equivalent of an alkaline-earth metal atom or of a magnesium atom, ammonium or a substituted ammonium group.

Among these preferred compounds, a particularly preferred class of compounds are those wherein R represents an acetyl, benzoyl, phthalimidoacetyl, N,N-dinethylcarbamoyl, a-carboxyphenylmethyl, 2-oxo 3-tetrahydropyranyl, 1,&-dihydroxy-l-oxo-2-butyl, phthalimidomethyl, aminoethyl, tetrazol-5-yl-methyl. 2-air.ino-2-thioxoethyl or 2-oxopropyl radical; R-^ represents a methyl, acetoxymethyl, 2-methyl-l,3»4-~ -thiadiazol-5-yl-thiomethyl or 1-methyl-tetrazolyl--thiomethyl radical; and A represents a hydrogen or sodium atom.

Especially preferred compounds of general formula I are those wherein R represents an acetyl, benzoyl, phthalimidoacetyl, tetrazolyl-5-yl-methyl, aminoethyl or a-carboxy-phenylmethyl radical; represents an acetoxymethyl, 2-methyl-l,3,4-thiadiazol-5-yl-thiomethyl or l-methyl-tetrazol-5-yl-thiomethyl radical.

A preferred group of compounds of general formula I are those wherein R_ represents a bromine or iodine atom or a phenylthio, 2-pyridinylthio, 2-amino-l,3»4--thiadiazol-5-ylthio, 1-methyl-lH-tetrazol-5-ylthio, 2-amino-phenylthio, 5-nitro-2-pyridinylthio or 3-cyano--6-methyl-2-pyridinylthio group.

Specific preferred compounds are those described hereinafter in the Examples, and more especially: 3-ac et oxy me thyl-7- C C 2-( 2-amino-thiazol-4-yl) -2-( 2-amino--ethoxyimino-acetyl ] -amino] -ceph-3-em-a-carboxylic acid syn isomer, its salts with alkali metals, alkaline-earth metals, magnesium, ammonium and organic amino bases, aud its esters formed with easily-cleavable ester groups; 3-acetoxymethyl-7-C C2-(2-bromoethoxyimino) -2-(2-amino-thiazol-4-yl) -acetyl ] -amino]-ceph-3-em-4-carboxyl ic acid syn isomer, its salts with alkali metals, alkaline-earth metals, magnesium, ammonium and organic amino bases and its esters formed with easily-cleavable ester groups; 3-acetoxymethyl-7-CC2-(2-iodoethoxyimino)-2-(2-amino-t hia zo 1 -4-yl) -ac etyl ] -amino ] -c eph-3-em-4-carboxyl ic acid syn isomer, its salts with alkali metals, alkaline-earth metals, magnesium, ammonium and organic amino bases and its esters formed with easily-cleavable ester - l/l - groups; 3-acetoxymethyl-7-[ C2-(2-amino-thiazol-/i-yl)-2-(carba-moy loxy imino ) -ac etyl}- amino 3 -ceph-3-em-4--carboxylic acid syn isomer, its salts with alkali metals, alkaline-earth metals, magnesium, ammonium and organic amino bases and its esters formed with easily-cleavable ester groups.

This invention also provides a process for preparing the derivatives of general formula I' wherein A represents a hydrogen atom, in wnich process a compound of the general formula: (wherein represents a protecting group for the amino radical, and B1 is the group B defined hereinbefore with the provisos that when B represents -CHR^CC^A', A' represents an easily-cleavable ester group when R^ represents a phenyl or cyano radical and A' represents an alkali metal atom when R^ represents a hydroxyethyl radical and when B represents -(CI^^-NHg the amino radical carries a protecting group and A"^ represents an easily-cleavable ester group or a hydrogen atom the latter being replaced by an alkali metal atom when A' represents an alkali metal atom) is reacted with one or more of a hydrolysis agent, a h.ydrogenolysis agent and thiourea so as to remove the protecting group(s) and/or salifying group(s) and/or ester group(s) and form an acid of the general formula: (who'-ein B" is the group B defined hereinbefore with the proviso that when B represents -CHR^CC^A'j A' represents a hydrogen atom) which is optionally thereafter esterified and/or salified to form a compound of general formula I' wnerein A, and where appropriate A', is other than hydrogen or an acid addition salt of general formula I'.

Thus, the invention provides processes in which compounds of the general formulae: NH R Coz* 16 1 (iiia) \/ (wherein A" represents an easily-cleavable ester group or a hydrogen atom, and R'^ represents an alkyl radical having from 1 to a carbon atoms, an alkoxy radical having from 1 to i carbon atoms, a phenyl radical or a radical -(CH2)n-NR"2R"5 in which R"2 and R"which may be the same or different, each represent a hydrogen atom or an alkyl radical with the proviso that both R"2 and R"j do not both represent hydropen when n is zero, or R"2 and R"^ together with the intervening nitrogen atom represent a phthalimido, piperidino or morpholino group), WH Rifa S (III'A) (IIIB) (wherein R'/t represents a phenyl or a cyano radical and A"' represents an easily-cleavable ester group) (IIIC) Nri X1 C— OC4. A XX (iii'c) I ■*-"1 J c-o,rt *•"1 (wherein A*^ represents an easily-cleavable ester group or an alkali metal atom and A1 represents an alkali metal atom), (IIID) (wherein R'^ represents an alkoxy radical having from 1 to 4 carbon atoms, a radical Alk-S(0)ng-, or an acyl radical having from 2 to a carbon atoms), H U H H \ \ xQ '•a.'* a -CN I 1 A«» co~A (wherein n2 represents the integer 2,3 or a), (IIIE) MM ft \ °' —c-NH_ X' C^A" (IIIp) k|hR/6 N \ Ws (III'H) o J ^ CMxl.'HrJL «v«" (wherein Hal represents a halogen atom) 40867 NHfc CcHaV N3 °V*" lb CCH,V w *,/'<» °°xA (IIIj) (IIIK) (IH'ir) (iiil) (wherein R^g represents a group removable by acid hydrolysis or by hydrogenolysis or an alkyl radical h-iving from 1 to a carbon atoms and R^q represents a hydrocren atom or an alkyl radical having from 1 to il carbon atoms, or R^g and R^g together with the intervening nitrogen atom form a phthalimido group) \ 0 (m Ki N> \ T 1 ■ _ «• Rb Co^ft' A N J—N \ 1 (HIK \ Co-A" \cH^n-S-Rar wherein R,„ is as defined above, ar are treated with one or more of hydrolysis agents, hydrogenolysis agent3 and thiourea to obtain respectively: the products of the general formula: MM, " 22 - A, x=/ PCX, H X if Xe', ca>n the products of the general formula: A, s F o 1 u o s 1.. <^aw the products of the general formula: Wrt^ A-. ,coNH^ / S" s '*» the products of the general formula: the products of the general formula: Vh-c^H <^h ( I . . y. . I /OLI the products of the general formula: the products of the general formula: ■* o O O Y - 2* - CO^H (Ig) the products of the general formula: MHX "C<:<V -;-^H X' (Ip) the products of the general formula: NH?. s : n the products of the general formula: (Ir.) NHX N \ 1 -7 o» O 1 (ih' \, „ /N< «•«.« '(o^k'-C I N A the products of formula I'jj ' "XX \ n (!•„) CO^H these being compounds of general formula Ig in which A. represents a hydrogen atom and Ra represents -(CH2)niRc;a» R5a rePreservtinB a halogen atom, the products of the general formula: MH- AC s. s ^ N=C|f/C^>"M "--T ( S r4 \ \ ®/=\"wh Vv-vJ <v the products of the general formula: v-o./; °°-h the products of the general formula: the products of the general formula: wherein substituents may be the same or different, the products of the general formula X1 ^; NH_ A conh N \ 0 R \ Rb co2h these being compounds of general formula 1^ wherein A represents a hydrogen atom, and the products of the general formula: these being compounds of the general formula Ia wherein R^a represarts -S-R and A represents a hydrogen atom. sr As will be clear to those skilled in the art, in the general formulae IIIj and Ij given above and in general formula VIj given below, the positive charge on the nitrogen atom may be satisfied either by an external anion which is the residue of a mineral or organic acid, or internally.

The formed compounds of general formulae Ift, IIg, Ic, I'^, S N R 1 jy IE. V IG» V i'h' iJ- i'k- I'b ^ rM my thereafter be salifiec and/or esterified, if desired, using known techniques.

The protecting group may be, for example, an alkyl radical having from 1 to 6 carbon atoms, and preferably is a tert-5 butyl or tert-amyl radical. R^ may also represent an aliphatic acyl group, an aromatic or heterocyclic acyl group or a carbamoyl group. Examples of such acyl groups include alkanoyl groups such as the formyl, acetyl, propionyl, butynyl, isobutynyl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl radicals; alkoxycarbonyl, 10 or cycloalkoxycarbonyl groups such as methoxycarbonyl, ethoxy- carbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxy-carbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, tert-pentoxycarbonyl and hexyloxycarbonyl radicals; the benzoyl, toluoyl, naphthoyl, phthaloyl, mesyl, phenylacetyl and phenyl-15 propicnyl radicals; and arylalkoxycarbonyl groups such as the benzyloxycarbonyl radical.

These acyl groups may be substituted - for example, by a chlorine, bromine, iodine or fluorine atom - and examples of substituted acyl groups are the chloroacetyl, 20 dichloroacetyl, trichloroacetyl, trifluoroacetyl and bromoacetyl radicals.

The substituent R^g may also represent a lower aralkyl group such as the benzyl, 1-methoxy-benzyl, phenylethyl, trityl, 3,4-dimethoxy-benzyl and benzhydryl 25 radicals, a haloalkyl group such as the trichloroethyl radical, a chlorobenzoyl, para-nitrobenzoyl, para-tert-butyl-benzoyl, phenoxyacetyl, caprylyl, n-decanoyl or acryloyl radical, or a methyl- 4 90 V I carbamoyl, phenylcarbamoyl or nnphthylcarbamoyl group or n corresponding thiocarbamoyl group.

The possibilities for substituent listed above do not constitute an exhaustive list, and it will 5 be clear to those skilled in the art that other protecting groups, particularly those known from peptide chemistry, can also be used.

When the substituent A" represents an easily-cleavable ester group this may be one of the groups 10 identified as such hereinbefore or any other "ester group formed with an easlly-renovable radical. Preferred ester groups include alkyl radicals such as the butyl, isobutyl, tert-butyl, pentyl and hexyl radicals, acvloxy radicals such as the acetoxymethyl, propionyl-15 oxymethyl, butyrylo^cymethyl, valeryloxymethyl, pivaloyl-oxyrcethyl, 2-acetoxyethyl, 2-propionyloxyethyl and 2-butyrvlox7/ethyl radicals, or a 2-mesylethyl, 2-iodo-ethyl, G,H,3-trichloroethyl, vinyl, allyl, ethynyl, propynyl, benzyl, /i-methoxybenzyl, a-nitrobenzyl, 20 phenylethyl, trityl, diphenylmethyl, 5 ,/L-dimethoxy- -henzyl, phenyl, '<•-chlorophenyl, tolyl or tert-butyl-phenyl radical.

Among the preferred protecting groups are the fonnyl, acetyl, ethoxycarbonyl, mesyl, trifluoroacetyl, 25 chloroacetyl and trityl radicals.

The aim of the conversion of the compounds of formulae III^ to HIpj into corresponding products of formulae IA to 1^ is to remove the protecting groups in each case, as well as A" when this is other than hydrogen and where appropriate radicals A'" (Illg), AL (III'C) and R18 (IIIL).

The removal of the protecting group R^g is conveniently carried out by hydrolysis, and this may be effected under acidic or basic conditions or by using hydrazine.

Acid hydrolysis is preferably used to remove optionally-substituted alkoxycarbonyl and cycloalkoxycarbonyl groups such as the t^-pentoxycarbonyl or t^-butoxycr^rbonyl radicals, optionally-substituted aralkoxycnrbonyl groups such as the benzyloxycarbonyl radical, or a trityl, tert-butyl or a-aethoxy-benzyl group. In acid hydrolysis the acid is preferably hydrochloric, benzenesulphonic, para-toluenesulphonic, formic or trifluoroacetic acid, although a variety of other mineral or organic acids nay be used. Formic and trifluoroacetic acid are preferred.

Basic hydrolysis is preferably used to remove acyl groups such as the trifluoroacetyl radical. The base which is used is preferably a mineral base such as an alkali metal hydroxide, and especially sodiun hydroxide or potassium hydroxide. It is, however, possible to use magnesium or barium hydroxide or an alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate. A variety of other bases may be used, including sodium or potassium acetate.

The hydrolysis using hydrazine is preferably used to remove groups such as the phthaloyl radical.

The group R^g can also be removed using the zinc/ acetic acid system, particularly where the trichloro-ethyl radical is the protecting group. 3enzhydryl and benzyloxycarbonyl groups are preferably removed by hydrogenolysis using hydrogen in the presence of a catalyst.

A chloroacetyl protecting group may be removed by the action of thiourea in a neutral or acidic medium, such -is by the process described by KASAKI in JA.CS, 90. A5C8, 1968.

As the man skilled in the art will appreciate it is possible to use various other means known in the literature to deprotect the amino radical.

Obviously the choice of protecting group R^g is effected by the nature of the substituent present on the oxyinino radical - substituent 3 and certain protecting groups should not be used with certain oxyimino substituents. Thus, wneu 3 represents an acetyl or other acyl radical, R^g ought not itself to represent an acyl radical since otherwise the removal of R^g would risk causing removal of B which clearly is not « O U | wanted. However, it is within the competence of one skilled in the art to select an appropriate protecting group that will be readily removable without causing unwanted cleavage of the molecule.

The removal of the radical A" when this is other than hydrogen atom, as well as the removal of the radicals A'", and R^g is effected under similar conditions to those described above for the removal of R^g It is possible to use, inter alia, acid or 10 basic hydrolysis.

Acid hydrolysis is preferably used to remove radicals such as substituted or unsubstituted alkyl or aralkyl radicals. Preferred acids include hydrochloric, formic, trif luoroacetic md j>-toluenesulphonic acid, n Other radicals as substituents A", A"', A.^ and R^g may be removed using reagents and techniques well knowu to the skilled man.

Of course it is possible, particularly when R^g and one or taore of the other groups to be removed are 20 of different types, that the compounds III must be reacted with two or more of the specified agents to form the desired compound of general formula I'.

The conversion of compounds of general formula III to compounds of general formula I' is preferably carried 25 out under moderate conditions, - that is to say, at ambient temperature or with gentle heating.

The compounds of general formula I'q may also be prepared by a process in which a compound of general formula Iq is reacted first with a base and then with an acid to yield the corresponding compound I'q. The conditions under which this conversion is carried out 5 are standard for the ring-opening of a a-lactone. The base, for example, may be dilute sodium or potassium hydroxide, sodium carbonate or calcium carbonate.

In the preparations described herein, it is possible that a fraction of the products obtained will 10 be in the form of a ceph-2-em (a2) side-product rather than the desired ceph-3-ea ( Aj) product. In this case the^2 products may be converted into products, and conversions of this type are knowii in the literature for products having a cephen nucleus. Briefly the IS conversion involves, the following steps: The product containing ^ compound is oxidised so ,is to obtain the corresponding sulphoxide, preferably using a peracid such as metachloroperbenzoic acid. The &2 sulphoxide is converted to the sulphoxide in the 20 presence of a hydroxyla'ted solvent or water. Finally, the Aj sulphoxide is reduced in the presence of an acid halide or phosphorus trichloride.

This type of conversion of the ^ products to products has been described for example by KAISER 25 and Colleagues in J.Org. 25., 2&30 (1970), by SPRY and Colleagues in J.Org.aO, 2411 (1975), in American Patent 3,70S,897 and in German Patent 1,937.016. - 5a - An example of such a conversion is set out hereinafter in the Examples.

Where it is desired to salify the products of general formulae 1^ - 1^ this can be carried out using 5 conventional salification techniques.

The salification can, for example, be effected by reacting the acid of formula IA - 1^ or a solvate thereof(for example the ethanolic solvate) or a hydrate thereof with a mineral base such as sodium or potassium 10 hydroxide, sodium or potassium bicarbonate, or sodium or potassium carbonate. It is also possible to use the salts of mineral acids such as trisodium phosphate.

This results in the formation of the corresponding metal salt. It is also possible to employ metal salts of 15 organic acids, and in particular the sodium salts of saturated or unsaturated, straight or branched chain aliphatic carboxylic acids having from 1 to 18, and preferably from 2 to 10, carbon atoms. The aliphatic radicals of these acids can be interrupted by one or 20 more heteroatoms sucn as oxygen or sulphur, or be substituted by aryl radicals such as the phenyl, thienyl or furyl radical, by one or more hydroxy radicals, by one or more halogen atoms such as fluorine, chlorine or bromine (preferably chlorine), by one or more carboxylic 25 or alkoxycarbonyl radicals, (preferably the methoxy- carbonyl, ethoxycarbonyl or propyloxycarbonyl radical) or by one or more aryloxy radicals such as the phenoxy 4»BbV radical. Aromatic acids may also be employed provided they are sufficiently-soluble - for example, benzoic acid, preferably substituted by alkyl radicals, may be used.

Examples of such organic acids are: formic, acetic, acrylic, butyric, adipic, isobutyric, n-caproic, isocaproic, chloropropionic, crotonic, phenylacetic, 2-thienylacetic, 3-thienylacetic, 4-ethyl- phenylacetic and glutaric acid, the monoethyl ester of adipic acid, hexanoic, heptanoic, decanoic, oleic, stearic, palmitic, 3-hydroxy-propionic, 3-methoxypropionic 3-nethylthiobutyric, a-chlorobutyric, 4-phenyl-butyric» 3-phenoxy-butyric, a-ethyl-benzoic and p-iso-propylbenzoic acid.

Preferably, however, sodium acetate, sodium 2-ethylhexanoate or sodium diethylacetate Is used where it is desired to form a sodium salt.

Salification can also be effected by the action of an organic amino base such as triethylamine, 20 diethylanine, trirnethylamine, propylamine, N,N-dimethyl--ethanolanine, tris(hydroxy methyl)-aminomethane, arginine, lysine, methylamine, ethanolamine, pyridine, picoline, dicyclohexylamine, procaine, histidine, N-aethyl-glucamine, morpholine or benzylamine. 25 Obviously, this results in the formation of the corresponding substituted ammonium salt.

This salification is preferably carried out in one or more solvents such as water, diethyl ether, methanol, ethanol or acetone.

The salts may be obtained in amorphous or crystalline form according to the reaction conditions employed. Crystalline salts are preferably prepared by reacting the free acid with one of the aliphatic carboxylic acid salts mentioned above, and preferably with sodium acetate.

Esterification of the products of formulae 1^ - 1^ may also be carried out under standard conditions. In general work is carried out by reacting the acid with a derivative of formula: z - r20 in which Z represents a hydroxy radical or a halofren atom such a fluorin'e, chlorine, bromine or iodine and R20 denotes the ester group to be introduced.

Various of the compounds of general formula III (and thus the compounds of general formulae III^ - IIIjj) may be prepared by reacting a compound of the general formula: ^ib 7 o ■--v- fW N (ii) x CO, A with a compound capable of introducing the desired substituent B1 on the oxime group.

The compounds of general formula IIIA may be prepared by a process in wnich a compound of general S formula II is treated with a functional derivative of the ncid IIO-CX-R'^.

The functional derivative of the acid HO-CX-R*^ may be, for example, an acid halide such as the chloride or the bromide, a symmetric or mixed anhydride, a ketene 10 or an acyl azide. The acylation may be carried out using a haloformate in the case where represents an alkoxy radical; for example a chloroformate may be used. An isocyanate nay be used when R'^ represents a group -KH'^R"^ in which one of R"2 or R"j represents 15 a hydrogen atom.

The acylation of the hydroxy function of the compound II is preferably carried out in an organic solvent and this may be a halogenated hydrocarbon such as methylene chloride, a cyclic ether such as dioxan 20 or tetrahydrofuran, a nitrile such as acetonitrile, a nitro-substituted hydrocarbon such as nitromethane or an ester such as ethyl acetate. Vihen an acyl halide is used, the reaction is preferably carried out in the presence of a base such as triethylamine, pyridine, 25 propylene oxide, magnesium oxide, sodium carbonate or calcium carbonate.

The compounds of general formula III'A may be 49867 prepared by a process in which a compound of general formula II is reacted with a compound of general formula X=C=NH.

This reaction is preferably carried out under similar conditions to those described hereinbefore in relation to the preparation of the compounds III^.

The compounds of general formula Illg may be prepared by a process in which a compound of general formula II is reacted with a radical Y - CHR'^-COg A"', in which Y represents a halogen atom, or a sulphate (i.e.SC^H) cr sulphurate (i.e. crgsnic =»il[trnylcoy) grajp.

The substituent Y may represent, for example, a chlorine, bromine or iodine atom or a sulphate (i.e. SO^H) or sulphonate (i.e. organic sulphonyloxy) group such as the mesylate (methane-sulphonyloxy) or tosylate (p-toluenesulphonyloxy) radical.

The reaction may be carried out in the presence of a base which may be, for example, potassium tert-butylate or sodium hydride. It is also possible to operate in the presence of tertiary amines such as triethylamine or pyridine.

The reaction is preferably carried out in a solvent and preferred solvents include halogenated hydrocarbons such as methylene chloride, cyclic ethers such as tetrahydrofuran or dioxan, N,N-disubstituted amides such as dimethylformamide, or dimethyl sulphoxide.

Separation of the optical isomers created by the asymmetric carbon atom may be carried out, if desired, either before or after the etherification reaction.

The compounds of general formula IIIc may be prepared by a process in which a compound of general formula II is reacted with a compound of the general The preferred groups Y are as defined hereinbefore in relation to the preparation of compounds Illg, and the reaction is desirably carried out under the preferred reaction conditions for that preparation set out above.

The compounds of general formula IIIq may be treated with a base to convert them into compounds of the general formula iii'q. The base is preferably an alkali-metal base sucn as sodium or potassium hydroxide (preferably as a dilute aqueous solution), sodium carbonate or sodium bicarbonate.

The compounds of general formula iiiq may be prepared by a process in which a compound of general formula II is reacted with a compound of the general formula Y -R'a1"* when R'^ represents an alkylthio radical the product nay thereafter be oxidised to the corresponding sulphoxide or sulphone. Again Y is preferably one of the preferred groups defined in relation to the preparation of compounds IHg and IIIq, and desirably the reaction is carried out under the preferred conditions described above in relation to those preparations. formula Y 0 - no- - The compounds of general formula IHg nay be prepared by a process in whicn a compound of general formula II is treated with a compound of the general formula Y ~(®2^n2 ~ a6ain ^he preferred groups Y and the preferred reaction conditions are as set out hereinbefore in relation to the preparation of compounds Illg.

The compounds of general formula Hip may be prepared by a process in which a compound of the general 10 formula: (IV) a. is treated either with hydrogen sulphide or, when n' is an integer other than 1, by hydrolysis in the presence of a base to obtain the corresponding product of general formula Hip.

The conversion of the compounds of general formula IV into products IIIp in wnich X' represents a sulphur atom aud n" is an integer from 1 to 4 is carried out by the action of hydrogen sulphide, and this reaction is preferably carried out in the presence 20 of a base, and most preferably a tertiary amine such as triethylamine. The reaction is also preferably carried - Hi - out in dioethylformamide as solvent.

The conversion of the compounds of general formula IV into products IIIp in which X' represents an oxygen atom and n' is an integer from 2 to 4, is carried out by careful hydrolysis in a basic medium. Preferably dilute sodium hydroxide is used to effect this hydrolysis.

The compounds of general formula IIIq may be prepared by a process in which a compound of general formula Illp wherein X is a sulphur atom (which is preferably prepared as described hereinbefore) is treated with a compound of the general formula R'^-CO-CHj-IIal.

The substituent Hal preferably represents a chlorine or a bromine atom. The reaction of the compound Illp with the compound R -CO-CH^-Hal may be carried out with or without catalysis. When no catalyst is employed the initial product is a thiazole halohydrate, which is converted into the free base by work-up using a base, and preferably an alkali-netal base, such as sodium bicarbonate.

The reaction can alternatively be catalysed with a base nnd preferably with an alkali metal bass such as sodium bicarbonate.

The compounds of general formula IIIjj may be prepared by a process in which a compound of the general formula IV is treated with an azide. Preferably the azide employed is an alkali metal azide such as sodium or potassium azide. Sodium azide is particularly pre- * O O D ( - /i.2 - ferred. It is also possible to employ an azide of an organic amine such as tetramethyl guanidine azide or triethylanine azide. Ammonium azide prepared in situ by the action of ammonium chloride on sodium azide may 5 also be used.

The reaction is preferably carried out in dimethyl-formanide, but an alcohol such as ethanol can also be used.

The compounds of general formula III *H may be 10 prepared by a process in wnich a compound of general formula II is treated with a compound of the general formula Hal-CCi^)^ -Hal wherein the two Hal substituents may be the same or different. The Hal substituent in the product of general formula ih'jj is preferably a bromine 15 or iodine atom, but 'it may also be a chlorine atom.

The compounds of general formula HIj may be prepared by a process in which a compound of general formula III'jj (preferably prepared as described hereinbefore) is treated with pyridine. This reaction is 20 preferably carried out in a solvent such as dimethyl-formamide.

The compounds of general formula III^ may be prepared by a process in which a compound of general formula IH'jj is treated with an azide. 25 The treatment with an azide is preferably carried out using the preferred reagents and conditions described hereinbefore in relation to the preparation of compounds - /i 3 - IIIH« The products of general formula IHg nay be treated with a reducing ageut to convert them into the corresponding products of general formula Ill'g.

The reducing agent wnich is used to convert the products IHjf into the products IH'g is preferably hydrogen sulphide used in the presence of triethylamine, which is tantamount to using triethylammonium hydro-sulphide formed in situ. This reaction is preferably 10 carried out in a solvent such as dimethylformamide.

It is also possible to employ otner methods of gentle, specific reduction such as those wnich use alkaline hydroiiulphides (and particularly sodium, potassium or ammonium hydrosulphide) or stannous IS chloride.

The compounds of general formula III^ may be prepared by a process in which a compound of general formula IH'g is treated with an amine of the general formula NHR^gR^g.

When R^g is a removable group this is preferably a trityl radical, although it may be any of the protecting groups mentioned hereinbefore, subject of course to the consideration that the group must be removable without causing undesirable cleavage of the 25 molecule.

The reaction with the amine NHR^gR^g is preferably carried in a solvent such as dimethylformamide. 4 98 67 - h/i - The compounds of general formula IIImay be prepared by a process in which a compound of geueral formula IH'jj is reacted with imidazole, morpholine or an N-alkyl piperazine.

The reaction with imidazole, morpholine or an N-alkyl piperazine is preferably carried out in the presence of an uptake agent which will neutralize and thus effectively remove formed hydrohalic acid. It is possible, for example, to use an organic base such as triethylamine. It is also possible to use a mineral base such as an alkali metal carbonate or bicarbonate, and the sodium salts are preferred.

It is also possible to employ the compound III'tj in the form of a salt ahd preferably as an amine salt such as the diethylamine salt.

Tho reaction can also be carried out in the presence of a quaternary ammonium salt such as methyl tricaprylammonium chloride.

The compounds of general formula III^ may be prepared by a process in which a compound of general formula IH'jj is reacted with a compound of the general formula R -3H. This reaction is preferably carried out ar in the presence of an uptake assent for formed hydrohalic acid, and preferred agents are as mentioned above.

Again the compound of general formula III'jj may be in the form of a salt such as the diethylamine salt.

The reaction can also be carried out in the - a <5 - presence of a quaternary ammonium salt such as methyl tricaprylammonium chloride.

It is also possible to use an alkali metal derivative of the compound of general formula Rar~s_H such as the lithium derivative and to carry out the reaction in the presence of a catalyst such as an alkali metal halide, for example lithium iodide.

The compounds of general formula IV used as starting materials in some of the preparations described hereinbefore are, when n'is 2,3 or 4, compounds of general formula Illg, and they may of course be prepared from compounds of general formula II by a process as described hereinbefore for the preparation of compounds III-,. The compounds of general formula IV where n' is SZj 1 may be prepared from compounds of general formula II by an analogous process employing a compound of the general formula and preferably chloroaceto- nitrile.

The starting materials of general formula II which n-e employed in several of the preparations described hereinbefore may themselves be prepared by a process in which a compound of the general formula: V9SOY - II6 - A. /6 N/ \ _ CH-» \ I C—OCR I e<n. i .ii co^A (D) is treated with an aqueous mineral acid, and preferably with dilute hydrochloric acid.

The compounds of general formula D may in turn be prepared by a process in which a compound of the general formula: tfHR, Nf-ll\,L. .x: N co-. H C-H- c OCHi I CV*-, (c) or a functional derivative thereof, such as the symmetric anhydride, is reacted with a product of the general formula: (IX) CO,A' to obtain the corresponding compound D. - tl? ~ The starting materials of general formula G may be prepared by a process in which a compound of the general formula: H (V) ^OM is treated with ?-methoxypropene. The compounds of peneral formula V are known, being described, for example, in Belgian Patent No. 850,662.

This invention also provides, in another aspect, alternative processes for the preparation of the various compounds of general formula III, in which a compound of the general formula; .A •/M N <VI> (wherein B" is the group B defined hereinbefore with the provisos that when B represents -CHR^CK^A', represents a phenyl or cyano radical and A' represents an easily-cleavable ester group and when B represents the amino radical carries a protecting group), or a functional derivative thereof, is reacted with a compound of general formula IX to obtain the corresponding compound of general formula III.

Thus, the invention provides processes in which compounds of the general formulae: C0%H rl N -C -fc' « * x uhp.lb H NQ-C-NH, II x (via) C0-H tJ (viB) cOa.H H ^O-CtHCO^A'" I - *l9 - k)HP>H, CO M \ KlHR/fc S ^ coah \o-CcH,V * a'« (VI,) (VID) A:.

N C<?9.H \ ^.C-M (VIE) A Si COjri M ->c-NlHa (VIp) (ria) r^y<- HvoO "V Wy HM (h,ia) T°H M HlCoO 9/ Vs VHN (hia) f M /-t., ^HO?"Ox N 9/ I. c V VHN (°ia) 1(St o")-< - Oi - '"tjHN fJHft tb tJ co-.h N N0-CCH,\,-N3 (vik) WHR /(, co,.h M (viL) vl v*^/b .A-h Cx?%M Rb Cvi"L) nhr ^ /b CCXH '0£«O. -5-A ,or Cvi„) or their functional derivatives are reacted with a compound of general formula IX, to obtain, respectively, the compounds of general formulae IIIA, III'A1 Hlg. iiic, iiid, iiie, iiip, iiig, iiih, lil'H» IIIj, IHK) IIIL, HI'L and IHpi* In a preferred method of carrying out this process the compound of general formula ix is treated with a functional derivative of one of the products of formulae VIA to VIj.j, set out above, and preferred functional 10 derivatives include the halide, symmetric or mixed anhydride, ?.mide and activated ester.

By way of example, the mixed anhydride may be that formed with isobutyl chloroformate. An example of an activated ester is the ester formed with 2,4-15 -dinitrophenol or 1-hydroxy-benzo-l-triazole. Preferred halides are the chloride and the bromide.

It is also possible to employ the acid azide or acid amide.

The anhydride can be formed in situ by the action 20 of iyj1 -disubstituted-carbodiimides such as N,H-dicyclo-hexylcarbodiimide.

The acylation reaction is preferably carried out in an organic solvent such as methylene chloride. It is, however, possible to use other solvents such as 25 tetrahydrofuran, chloroform or dimethylformamide.

When the compound of general formula VIA - VI^ is in the form of an acid halide or a mixed anhydride - S3 - formed with isobutyl chloroformate, the reaction is preferably carried out in the presence of a base, and this may be an inorganic base such as sodium or potassium hydroxide, sodium or potassium carbonate or sodium or potassium bicarbonate, or an organic base such as sodium acetate, triethylamine, pyridine, rr.orpholine or K-methyl-morpholine.

The reaction temperature is conveniently maintained at or below ambient temperature.

The invention is especially concerned -with a process as described above in which substituent R^g in the compound of general formula VIA - VI^ is a trityl, chloroacetyl, tert-pentoxycarbonyl, tert-butoxy-carbonyl or benzyloxycarbonyl radical.

The products of general formula IIIq may of course be converted into compounds of general formula III'q by treatment with a base, as described above.

The various starting materials of general formula VI may be prepared directly or indirectly from compounds of general f ormula V.

The compounds of general formula VI ^ may be prepared by a process in which a compound of general formula V is treated with a functional derivatives of the acid HO-CX-R'^, and this reaction is preferably carried out under the preferred conditions described above for the analogous reaction to prepare compounds IIIA.

The compounds of geueral formula VI' ^ may be prepared by a process in which a compound of general formula V is reacted with a compound of formula X=C=NH.

The compounds of general formula VIg may be prepared by a process in wnich a compound of general formula V is reacted with a compound of the general formula Y-CHR^-COgA"' .

The compounds VI^ may be prepared by reacting a compound of general formula V with a compound of the general formula The compounds VID may be prepared by reacting a compound of the general formula V with a compound of the general formula. Y-CCHg^n'"®'5* The compounds VI^, may be prepared by reacting a compound of general formula V with a compound of the general formula Y-(CHp)np-CN.

The compounds VIp may be prepared by a process in wnich a compound of the general formula: C (VII) \0 is treated either with hydrogen sulphide or, wnen n' - <55 - is an integer other than 1, by hydrolysis in the presence of a base, to obtain the corresponding product of formula VTp.

The compounds of general formula VIp wherein X1 5 represents a sulphur atom may be treated possibly with a compound of the general formula R'^-CO-CI^-Hal to obtain a compound of general formula VIq.

The compounds of geueral formula VII may also be trented with an azide to obtain the corresponding 10 compound of general formula VIjj.

As in the preparation of the compounds of general formula VIA, the preferred conditions for the preparation of compounds VIA, , VIg, VI^, VIq, VI^., VIp, VIq and VI-, are as described above in relation to the analogous n compounds of general formulae III'^, IHg, IIIq. IIIj. IIIE, IIIp, IIIG and IIIj.

The starting materials of general formula VII wherein n1 is 2, 3 or n. are compounds of general formula VIv and may be prepared by the process described 20 hereinbefore. The compounds VII wherein n* is 1 may be prepared by an analogous process in which a compound of general formula V is reacted with a compound of the general formula Y-CHg-CN, and preferably chloroaceto-nitrile.

The compounds of general formula VI*^ may be prepared as follows: a product of the general formula: 56 - MHR/6 (V) (wherein Rg represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms) - which are compound V and their alkyl esters - is treated with a compound of the general formula Hal^Cr^n' "Hal 5 (wherein the substituents Hal nay be the same or different) to obtain a product of the general formula: which product of formula VI"H when R0 represents a hydrogen atom is a compound VT'jj, and when Rg represents an alkyl radical having from 1 to 4 carbon 10 atoms, is treated first with a base and then with an acid to jield a compound VI' y.

The compound of general formula: Hal^CHg)^-Hal, in wnich Hal preferably represents a bromine or iodine atom, is preferably reacted with the compound V' in 15 the presence of a base to neutralize the hydrohalic acid formed. Suitable bases include mineral bases such as sodium or potassium carbonate or bicarbonate, «HR«, - r>7 - and organic amine bases such as are known to the skilled man.

The saponification of the esters of general-formula VIwherein Rg represents an alkyl radical having from 1 to 4 carbon atoms is carried out under typical known conditions for such reactions. It is possible, for example, firstly to react the ester with a base such as sodium hydroxide, potassium hydroxide or barium hydroxide, and then with an acid such as dilute hyrochloric acid, acetic acid or formic acid.

The compounds of general formula VI j may be prepared by a process in wnich a compound of general formula VI'jj is reacted with pyridine.

The compounds of general formula VI^ may be prepared by a process in wnich a compound of general * i formula VI'^ is reacted with an azide.

The compounds of general formula VI^ may be prepared by a process in wnich a compound of general formula VI'^ is reacted with an amine of general formula NHR^gR^g.

The compounds of geueral formula VI'^ may be prepared by a process in which a compound VI'^ is reacted with imidazole, morpholine or an N-alkyl piperazine.

The compounds of general formula VI^ may be prepared by a process in wnich a compound VI H is reacted with a compound of general formula Rar~^H« 49867 The preparation of the compounds of general formulae vij. VI£» VIL' VI'l VIM are Preferatly carried out under the preferred conditions described hereinbefore in relation to the preparation of the 5 compounds HIj, III^, m'j, The derivatives of general formula I' and their salts have snovm very good antibiotic activity against Gram positive bacteria such as staphylococci and streptococci, and especially against the penicillin-10 resistant staphylococci. In addition, their efficacy against the Grnm negative bacteria, especially against the coliform bacteria, Klebsiella, Salmonella and Proteus, is particularly remarkable.

These antibiotic properties make the compounds 15 of the invention suitable for use as medicaments in the treatment of diseases caused by sensitive microorganisms and especially in the treatment of staphylococcal infections such as staphylococcal septicaemia, malignant facial or skin staphylococcal infections, 20 pyodermatitis, septic or suppurating sores, anthrax, phlegmons, erysipelas, acute primary or post-influenza staphylococcal infections, bronchopneumonia and pulmonary suppurations.

These products can also be used as medicaments 25 in the treatment of colon bacillus infections and associated infections, in infections caused by Froteus, Klebsiella and Salmonella and in otner diseases caused by Gram negative bacteria. 4 s# a o ( The invention therefore also extends to the ijeriva-tives of general formula I', as well as their addition salt-i with the pharmaceutically-acceptable mineral or organic acids, for use as antibiotics in a method of 5 treatment of the human or animal body by therapy.

Before using them in medicine however, it is preferred to form the compounds of the invention into pharmaceutical compositions, by association with pharmaceutically-acceptable vehicles. 10 Accordingly, in a further aspect, this invention provides pharmaceutical compositions containing as active ingredient one or more derivatives of general formula I' and/or one or more addition salts thereof formed with pharmaceutically-acceptable mineral or organic acids, in association with a pharmaceutically-acceptable vehicle.

The compositions of the invention preferably contain those compounds mentioned hereinbefore as being preferred.

The description "pharmaceutically-acceptable" is used herein to exclude any possibility that the vehicle or the acid, considered of course in relation to the <* a a o f route by wnich the composition is to be administered, could be harmful to the patient to be treated. The choice of suitable vehicles or acids is believed to be within the competence of those accustomed to the 5 preparation of pharmaceutical formulations.

The compositions of the invention may conveniently be administered by a buccal, rectal, parenteral or intramuscular route, or locally by topical application to the skin or mucous membranes. In respect of these 10 routes the pharmaceutical vehicle is preferably: a) the ingeatible excipient of a tablet or pill, such as a sugar-coated compressed tablet; the ingestible container of a capsule, and particularly a gelatin capsule; the ingestible pulverulent solid carrier of a IS powder or granules;'or the ingestible liquid medium of a syrup, solution or suspension; b) the solid or liquid medium of a paste, cream, ointment or gel, or the liquified propellent gas of an aerosol; , c) a sterile injectable liquid solution or suspension medium; or d) a base material of a suppository.

Whilst the pharmaceutical vehicles just listed represent those most likely to be employed, they do 25 not necessarily exhaust the possibilities and other pharmaceutical forms may dictate the use of different vehicles.

By way ol* illustration it is pointed out that the vehicles employed will generally be composed of those excipients commonly employed in the formulation of pharmaceutical compositions. Such excipients may be 5 solid or liquid as appropriate to the pharmaceutical form chosen, and may include a wide range of organic and inorganic solids, and aqueous and non-aqueous liquids; examples include talc, gun arabic, starch, lactose, magnesium stearate or fatty substances of 10 animal or vegetable origin such as cocoa butter, paraffin derivatives or glycols. These excipients may be compounded with one or more wetting, dispersing or emulsifying aprents and/or one or more preservatives.

These compositions of the invention may also be IS presented in the form of a powder intended for extemporaneous formulation into a solution by dissolution in in appropriate vehicle such as apyrogenetic sterile water.

The dose of the active ingredient to be adminis-20 tered may be varied according to the disease treated, the person concerned, the route of administration and the product under consideration. By way of illustration, a desirable dose in man is from 0.250 g to 4 g per day, for the compounds described in Examples 15, 25 38 and 43 administered orally, or from 0.500 g to 1 g when administered three times daily by intramuscular route. <*aou i 62 The derivatives of general formula I1 and their acid addition salts may also be used as disinfectants, especially for use on surgical instruments. Accordingly this invention also provides a method of disinfecting a locus, in which there is applied 5 to the locus an effective disinfecting amount of a derivative of general formula I' or an acid addition salt thereof.

Certain of the intermediates described hereinbefore are themselves both new and part of this invention. Accordingly, this invention extends to these useful intermediates per se and in one 10 such aspect this invention provides the compounds of the general formula: nh (a) \ \ r r i c02a" wherein R^ represents: a radical -cx-r; a radical —CX—NH^; a radical -CHR'^-CC^A"'; a radical a radial -(CH^ (-R'^; a radical -(CHgJ^CN; a radical -(Q^^.CX'-NR,; a radical - 63 N-N a radical -(CH_) \ | N-N l H a radical -(CH2^n' a radical (CH.,)nI-Nj; or a radical (CH2)n,-NR1gR.)g, with the proviso that Rl6 cannot represent a chloroacetyl radical when R.^ rejnsserits -CX-CRj and R1 represents an acetoxymethyl radical.

In another such aspect the invention further provides the compounds of the general formula: \ I R! (CH2)n1~Ra C02A" (xii) and particularly the compounds of the formula: h2-r- (xii1) wherein R'-jg represents a trityl or chloroacetyl radical, n'. represents 1 or 2; Hal' represents a bromine or iodine atom and R11 represents a hydrogen atom, an acetoxy or carbamoyloxy radical 49867 or a 1-methyl-tetrazol-5-yl or 2-methyl-1.S.^-thiadiazol-S-yl radical.

Flirthermore, certain other intermediates described hereinbefore are the subject of our co-pending Application No. 243/85 5 divided from the present Application, which describes and claims compounds of the general formula: 2 to 1 carbon atoms, an alkoxy group having from 1 to 4 carbon 10 atoms, a phenyl radical or a radical -(Q^^-NR'^R"^; a radical -CHR'-CC^A"'; (B) N ns^or"1 wherein R"^ represents: a radical -CX-R'^ in which R'^ represents an alkyl having from a radical 0 a radical a radical -(CH^^-CN; a radical -(CH^.-CX'-NH^ a radical a radical (CH_) . K „ d n n—N I H © a radical (G^jji-N a radical -(CH2^n,-R5a in which R5a 13 a halo8en atom> or a radical -S-R _ in which R _ represents a phenyl ar ar radical or a 5- or 6-membered aromatic heterocyclic radical containing from 1 to 4 heteroatoms selected from sulphur, nitrogen and oxygen, the phenyl and heterocyclic radicals being optionally substituted by one or more radicals selected from amino, nitro and cyano radicals and alkyl radicals having from 1 to 4 carbon atoms; a radical RK which is a radical -(CH_) ,-RKK in which b 2 n1 bb R^b represents an imidazolyl, morpholinyl or N-alkyl piperazinyl radical, the N-alkyl radical containing from 1 to 4 carbon atoms; a radical -(CH0) ,-N0: or d n i a radical -(CH2 )n ,-NR^gR.^. «7 O U # The following Examples and Formulations are given only by way of illustration, to show certain preferred aspects of the invention.

Example 1; The syn isomer of 3-acetoxymethyl-7~C2-(2-5 -a7iinothiazol-,t-yl)-2-acetoxyimino-acetylamino3ceph-3--em-'i-carboxylic acid.

At ambient temperature, a solution of 0.756 g of the syn isomer of diethyl ammonium 3-acetoxymethyl-7-2--[2-tritylamino-thiazol-a-yl]-2-hydroxyimino-acetylamino)-10 -ceph-3-em-/i.-carboxylate, as prepared below in 1 ml of pyridine and 0.5 ml of acetic anhydride was asritated for 30 minutes. 3 ml of water were added, followed by 2N hydrochloric acid until the pH of the whole was 1. The whole was then vacuum-filtered, and the solid thus 15 obtained was washed with water and dried to give 0.75 g of crude acylated product. In a water bath, at &5°C, a suspension of 0.520 g of the crude product thus obtained in 1 ml of aqueous formic acid 2:1) was agitated for five minutes, after which 0.5 ml of 20 water were added and the agitation in the water bath continued for 10 minutes at ii5°C. After the subsequent addition of 5 ml of ethanol, the whole was concentrated under reduced pressure, and the concentrate taken up with diethyl ether. After evaporating to dryness under 25 reduced pressure, washing and drying, 0.30/a. g of impure product (containing some deacylated derivative) were obtained. The impure product was dissolved in 1 ml of acetic anhydride and 2 drops of pyridine, from which the purified expected product (0.30 g) was precipitated with 10 ml of diethyl ether and then recovered.

Hicroanalysis: ci7Iii708Nsi32 : ^25.0 5 Calculated: C?.' 44.80 H& 3.75 H# 14.70 S?S 12.26 Pound : 44.6 3.8 14.5 11.7 N.II.R. Spectrum 2.05 p.p.m. : OAc 6.75 p.p.m. : H,. of the thiazol.

Preparation of the syn isomer of diethyl ammonium 3-acetoxyr-ethyl-7-C?-( 2-tritylnroinothiazol-a-yI )-2- -hydroxyimino-acetylaminol-ceph-3-em-^-carboxylate. 3ta_ge_ A: The syn isomer of 2-(2-tritylaminothiazol-'^-yl)- -2^( 1-methyl-l-methoxy-ethoxyimino)acetic acid.

IS At ambient temperature, 12.9 g of the syn isomer of 2-hydroxyimino 2-(2-tritylaminothiazol-4-yl)acetic x 3 acid in 120 cnr of methylene chloride and 12 cm of 2-methoxy propene were agitated for 20 minutes. The whole was concentrated to dryness and after the 3 3 addition of 50 cm of methylene chloride and 12 cm of methoxy propene, agitation was continued for 30 minutes.

The whole was then concentrated to dryness under reduced pressure to obtain the expected product, wnich was used in the following stage without further purification. ota/e The syn isomer of diethyl ammonium 3_3cetoxymethyl- -7-C2-(2-tritylaminothiazol-/'-yl)-2-( 1-methyl-l-aiethoxy- ^etn£X2iHino)_ iic£tvlanino]^ceph-j$-em_^4-£arbox2la_te.

V w u V I - GQ - One dissolves the amount of syn isomer of 2-( 2- trityl aminothiazol -4-yl)-2-( 1-methyl-l-methoxy--ethoxyimino)acetic acid obtained by following the procedure described in Stage A after starting with 5 '17.25 g of 2-h;/droxyimino-2-(2-tritylaminothiazol-4-yl)- T. -acetic acid, in 230 cm of methylene chloride. 12.5 g of dicyclohexyl carbodiimide were added, and the whole was agitated for an hour at ambient temperature. The dicyclohexylurea thus formed was separated by vacuum- filtration md rinsed with a little methylene chloride (9.82 g of dicyclohexylurea were formed). To the filtrate (and rinsings) were added a solution of 13.6 g of 7-aroino-cephalosporanic acid in 70 cm^ of methylene chloride and l/i cm of triethylamine, and the whole was aritated for two hours at ambient temperature. After x wishing in ampoule form with 350 cnr of N hydrochloric acid, decanting, washing with water, drying and concentrating to dryness, a residue was obtained, wnich was dissolved in 100 cm^ of ethyl acetate. Crystallisation 20 was then initiated, and after 30 minutes 5.5 g of starting product were recovered by vacuum-filtration. The filtrate remaining was concentrated to dryness, and the formed residue agitated for 30 minutes with 200 cm^ of isopropyl ether. After vacuum-filtration and drying 25 37-35 g of crude product was obtained, wnicn was purified as follows.

The product was dissolved in 148 cnr of ethyl 4»BO Y - 69 " acetate, and 5.5 cm' of diethylamine were added. The product was then precipitated under intense agitation by adding 650 cm' of diethyl ether, aud after vacuum-filtration, washing with diethyl ether and drying 5 26.35 g of the expected purified product were obtained. To obtain a second yield of product, the filtrate from the vacuum-filtrntion wan concentrated to dryness and the residue formed takeu up with 50 cm' of ether. After drying 2.8 g of product identical to that of the first 10 yield in T.L.C. were obtained. The combined products were used without any further treatment in the following stage.

N.K.R. Soectrum (CDC1,) 60 MHz 2 CH,(a) (a)=1.5/j. d.d.ui.

\ I IS 0 j—CH^(a) (b) = 3.27 p.o.m. 0CH,(b) 3 proton of the thiazol ring: 6.73 p.p.m.

Stage £: The s.yn isomer of diethyl ammonium 3-acetoxy-• methyl-7-C2-( 2-t_ri_t^l aminot hia_zol^'x^y l) ^_2^hjdrp jcy i.min£-20 -a c_e t^'_ln m i no ]_-£B£h^3^.e m-^_-c_a rb^jr^l a t e_. 7.6 g of the syn isomer of diethyl ammonium 3-acetoxy--aethyl-7-(2-C2-tritylininothiazol-a-ylj-2-[l-methyl-l--methoxy-ethoxyininoJ-acetylamino)-ceph-3-em-a-cirboxyl- ate, prepared in Stage B above, were dissolved in 30 3 ~*i cm of acetone aud 10 cm of 2N hydrochloric acid.

The whole was agitated for a0 minutes at ambient temperature, nfter which 20 cm' of water were added and the acetone was driven off at 30°C under reduced pressure. 25 cm' of ethyl acetate were added, and after decanting, re-extracting, washing with water, drying aad vacuum-* filtering, 1 cnr of diethylamine was added to the 5 filtrate. After crushing and freezing the product formed was separated by vacuum-filtration and washed with ether to Rive 6 g of pure product.

Analysis: u 38^/10^7^ 6"*2 Calculated :C?: 60.50 Hf 5.53 Kf 11.10 iif." 8.47 10 Found : 60.5 5.7 10.9 8.2 ".H.R. Spectrum (CDCl^) 60 MHz 6.65 p.p.r;. : thiazol proton 7.35 p.p-m. : trityl proton llxamnle 2: The syn isomer of 5-acetoxymethyl-7-C2-(2-15 -arrinothiazol-zi -yl)-2-(phth3linidoacetoxyimino) acetyl-amino 3-ceph-5-em-4-carboxylic acid.

In ti ml of methylene chloride were put into suspension under agitation 0.756 g of diethylaminium 5-acetoxyuiethyl-7-C2-(2-tritylamino-thiazol-/i-yl)-2-20 -hydroxyimino-acetylaminoJ-ceph-5-em-/J--carboxylate, syn isomer prepared in Example 1. 0.555 g of phthalimido acetyl chloride were added, and after 5 minutes at ambient temperature the product was precipitated by the introduction of 10 ml of isopropyl ether, and then 25 recovered by vacuum-filtration, pasting with water and drying. The crude product obtained was agitated for 20 minutes at 55-40°C in 2 ml of aqueous formic acid - ?1 (formic acid: water 2:1), and the product recovered again by adding 10 ml of water, vacuum-filtering, taking up with ether, vacuum-filtering again and theu drying. The product thus recovered was further 5 purified by dissolving it in & ml of acetone, vacuum-filtering away the insoluble matter and then precipitating with 10 ml of ether. In this way 0.280 g of purified product were obtained.

Analysis : Oj^H^O^QNgOg : 628.16 10 Calculated 13.77 3T' 10.20 Pound 12.5 .4 U.V. Spectrum (ethanol) Max. 217 - 218 nm Ej = 782 Inf. 300 nm HC1 N/10 (ethanol) Max. 217-^18 nm Inf. 260 nm Inf. 231 nm 4 - 773 E* = H29 Max. 239 nm Inf. 280 nm N.M.R. Spectrum DKJO 25 7-18 p.o.m. : thiazol Max. 258 nm E^ = 286 E\ * 230 49867 Example 3: The rsvn isomer of 3-acetoxymethyl-?-C2-(2--■•minothinKoi-'i-.yl )-2-N .N-( dimethyl -carbamoyloxy-iniino)"ic.et;.vl.,imino]-ceph-3-em-4-carboxylic acid In ti ml of methylene chloride were put into 5 suspension under agitation 0.756 g of diethyl ammonium 3-acetoxymethyl-7-C2-(2-tritylamino-thiazol-<i-yl)2--hydroxyimino-acetylaminoJ-ceph-3~em-4-carboxylate, syn isomer, prepared in Example 1. 0.2 nil of pyridine and 0.2 ml of dimethylcarbamoyl 10 chloride were added, and after dissolving, the wnole was washed with water and then with water acidified to pH 2.

The organic phase was dried, concentrated to dryness and crushed with ether, after which 0.6 g of 15 crude product was recovered by vacuum filtration. This was agitated for 15 minutes at aO°C with 2 ml of aqueous formic acid (formic acidiwater 2:1), then 5 ml of ethauol were added and the wnole was concentrated to dryness to give a residue which was taken up with 20 ethyl acetate. 0.384 g of crude product were recovered and then purified by dissolving in an acetone methanol mixture (1:1), adding ether until light floculation occurs, vacuum-filtering away the insoluble matter and precipitating the product from the filtrate with ether. 25 In this way 0.^13 g of purified product were obtained. Analysis : C^gH-jQOgNg^ : 511.52 98t»7 Calculated: N/-> 16.4 Pound : 15.2 I.R. Spectrum Nujol (Trade Mark) 3 lactam 1770 cm ^ C=0 1724 cm"^ _i 1 Amide 1667 cm Amide II 1532 cm ^ U.V. Spectrum EtOH Max. 230 nm E* = 3^7 e 18 300 Inf. 251 nm E^ = 261 Max. 300 nm E^ = 87 EtOH HC1 N/10 Max. 256 nm E^ = 270 e 13 800 Inf. 280 nm E* = 218.

N.M.R. Spectrum DMSO 10.3 p.p.ns. = thiazol.

Examcle ><-•. The syn isomer of 3-acetoxymethyl-7-C2-(2--;v?inothinzol-'i-yl)-2-( Phthalimido-aethyloxyiTnino) ncecvlamino]-cenh-^-eTTt-'i-carboxylic acid triflnoro-20 acetnte.

Stage _A: Di£he,nxlmeth2.1_3^,ac.et.oxyraeth2.1^7i:^~X2-trityl,-_ ^mTjiothir^rTl z!lzyl) £h^hj^l j^mi^do-niethy_loxyiriino ) acetyl - aminoJ ^c ejhem-/t^c^rb_02cy l.a£.ei At ambient temperature a mixture containing 0.085 g 25 of diphenylmethyl 3-acetoxymethyl-7-C2-(2-tritylnmino-thiazol-"-yl)-2-hydroxyimino-acetylamino]-ceph-3-em-4--carboxylate as prepared below, 0.12 g of bromoethyl phthalimide, 0.069 g of potassium carbonate and 0.4 ml 4 9867 of dimethylsulphoxide, was agitated briskly for 15 minutes. 10 ml of 0.1N hydrochloric acid were added to form a precipitate, wnich was vacuum-filtered, washed with water and dried to obtain 0.121 g of crude product. 5 This was dissolved in 1 ml of ethyl acetate and treated with active charcoal, and after eliminating the solvent the residue was crumbled with ether and vacuum-filtered to obtain 0.075 g of purified product.

I.R. Spectrum CHCl^ NH 3"-08 cm"1 3 lactam ) ) 1782 cm phthalimide I ) -1 phthalimide II ) ) 1730 cm ester ) amide 1655 cm 1 C=C, C=N ) 161a cm-1 aromatic ) 1599 cm 1 > -1 amide II ) 1511 cm ) NH ) 1493 cm C-N-OR 1033 cm"1 N.N.R. Spectrum CDC1 3 7.03 p.p.m. aromatics(trityl- and diphenylmethyl) 7.8 p.p.m.:phthalimide 6.9 p.p.m. : COp CH "^d> 3./i p.p.m. : Ci^S Stage Bi The syn isomer of 3-acetoxymnthyl-7_J[2K^-ciraino-thiazol-ft-yl )-2-(jph_thalimido-rneth:yloxyimino) acetyl aaino3_2 m—L—c—r—°^yii— £cid_t£i_fluoro£C£tal.£.

To 0.32 g of the product obtained in Stage A were 5 added 3 ml of trifluoroacetic acid, ;nd the whole was agitated briskly for 10 minutes at nmbient temperature, and then concentrated at 30°C under reduced pressure. The residue was crumbled in 30 ml of isopropyl ether, vacuum-filtered and rinsed with isopropyl ether to 10 obtain 0.21 g of the expected product.

Preparation: The syn isomer of diphenylmethyl 3-acetox,y-methyl-7-C2-(2-tritylaminothiazolwi -yl)-2-hydroxyimino--acetylamino]-ceph-3-em-a-carboxylate.

A) The syn isomer of diphenylmethyl 3-acetoxymethyl-7^ 15 - [j2-£2^t rity l/Jmino£hiajsol_-^-vl^-£-£jL^met hyl.-l.-ine thox^- -eth£xvimino_}_a_ce_tyl_amino2-c_e_nhj;3^en-/L-c^^i2b£x^l_ate_. a.IS g of the product obtained in Stage B of the 3 preparation of Example 1 were introduced into &0 cm 3 of methylene chloride and SS cm of 0.1N hyrochloric acid. The whole was agitated for 10 minutes at ambient temperature, and after decanting the organic phar.e was 7, twice washed with 25 cm of water, then dried, vacuum-filtered and rinsed with methylene chloride. Over ten minutes and under agitation, IS cm' of SS'- diazodiphenyl 25 methane in benzene were added; the whole was agitated for 15 minutes at ambient temperature after which the solvents were evaporated under reduced pressure at 30° to give a residue which was taken up and crumbled in • isopropyl ether. After a^ain evaporating the solvent under reduced pressure and taking up with isopropyl ether, the solid was vacuum-filtered, rinsed and dried to obtain a.al g of expected product. 5 K.K.R. Spectrum (CDCl^) 60 MHz a = 1.53 p.p.m. b= 2.01 p.p.m. c = 3-26 p.p.m. d = 6.78 p.p.m. e = 7-33 p.p.m.

B) The syn is£mer_o_f diphenylmethyl 3-«cetoxymethyl-"^-Ci-LS-t-i^l^ininothiazoi-a-^l^-^-hydroxvimino-15 ~!tvl amino ]_-c_e£h^3^em-/i-c arb^x^latei. 2.775 z of the product obtained above were placed z 3 in la cnr of acetone and u.5 cm of N hyrochloric acid.

The whole was agitated for two hours at ambient temperature, after which the acetone was driven off under (c) 5 3 c -N" C0oCI!0„ - (e) 49867 reduced pressure. 20 cm of ethyl acetate were added, and after agitating and decanting, the organic phase was washed four times with 10 cm' of slightly salted A water. The wash waters were extracted witn 5 cm of 5 ethyl acetate, and the organic fractions were combined and dried, vacuum-filtered, rinsed with ethyl acetate and thon evaporated under reduced pressure to drive off the solvent. The residue formed was taken up with ether and crystallised, and the drystals were crumbled, 10 vacuum-filtered and rinsed with ether, to obtain, after drying, 1.88 g of desired product.

Rf = 0.5 (eluant = ether with 20% acetone). N.M.R. Spectrum (CDCl^) 60 KHz 6.88 p.p.m. : proton of the thiazol cycle 15 7.33 p.p.a. : proton of the phenyl nuclei.

Example 5: The svn isomer of sodium [Vacetoxyniethyl-7-2-(2--aminothi.-izol-* -yl)-?-( nhthaiinido-nethyloxyasino) acetyl&minol -cePh-?-em-/i-carboxyl ate. 0.21 g of the product obtained in Example 4 was 20 dissolved in O./i ml of methanol, and with agitation, 0.6 ml of a molar solution of sodium acetate in methanol were slowly added to the solution. 2 ml of ethanol were then slowly added, and the resultant precipitate was vacuum-filtered and rinsed with ethanol 25 then ether to give 0.127 g of the desired product. II.V. Spectrum HC1 N/^q (ethanol) Max. 217 nm e &6,500 Inf. 237 nm e 20,000 Max. 252 nm e 16,300 Inf. 301 nm e 7,^-OC Inf. 320 nm e 5,850.

^ N.M.R. Spectrum DMSO 8.05 p.p.m. aromatic 2 p.p.m. 0A.c I.R. Spectrum in nujol C=0 1776 - 176a - 172a cm"1 10 Amide 1639 cm 1 C=C, C=N ) 1659 cm"1 Aromatic ) 1611 cm Anide II ) 1545 cm CO* ) 1525 cm"1 1511 cm"1 Example 6: The syn isomer of 3~^cetoxymethyl-7~C2-(2---iminothi^ zol-'i-yl) -2-(u-carboxybenzyloxy-imino) acetyl -amino]ceph-3-em-a-carboxylic acid trifluoroncetafce.

Stage _A: The syn isomer of diethyl ammonium J-acetoxymethyl-•:-0 -7^T2-{_2-tritvl3ginothiazol-4-yl)-2-(a-t-b;»to:cy~ £nr^b£n^lbenz;£l£X^imino^a£e^v]ji^i J2o2c£Ph-^-j}m^;lp^i^bp_x7^_ At ambient temperature, a mixture of 1.37 g of 3-acetoxynethyl-7-[2-(2-trityl''.minothiazol-'L-yl)-2-25 -hydroxyinino-acetylamino]-ceph-5-,5m-"..-carboxylic acid, obtained in the course of Star;® C of the previous preparation of Example 1, and 20 ml of methylene chloride was agitated. 20 ml of water were added, and 2.8 ml of triethylamine slowly added. A solution of ".8 g of t-butyl u-bromophenylacetate in S ml of methylene chloride was introduced to the emulsion 5 obtained, and the whole was agitated for 23 hours at ambient temperature before acidifying to oH 1 by the addition of 10 nl of 2N hydrochloric acid. After extracting with chloroform, washing the extracts with water, drying and distilling to dryness under reduced 10 pressure at a maximum temperature of 3C°C, 6.1 g of browr. oil were obtained. This was dissolved in S ml of ethyl acetate, and C.2S ml of diethylamine followed by ml of isopropyl ether were added to the solution. The solid "btained was separated by vacuum-filtration to is give 1.11 g of impure product and the mother liquors gave a second portion of 0.1 g of product identical to the first. The two portions of impure product were purified by dissolving in 5 ml of ethyl acetate, filtering the solution and evaporating the solvent to 2C dryness to ,-ive a residue which was taken up with ether. recovered again by vacuum-filtration, rinsed with ether and dried at ambient temperature under reduced pressure. 0.96 g of the desired product were obtained, which were used in the following stage without further treatment. 2S I.R. Spectr\jm CHCl^ NH + associate : 3372 cm 1 3 lactam : 1781 cm 1 C II 0 AcO ester 1738 shoulder : 1729 cm -1 amide COS : 1681 cm \ 1602 cm 1526 cm amide II / 1493 cnr C=N=GR 1063 cm" U.V. opectrum EtOH E£ = 304 Inf. 230 nm Inf. 260 nm E^ = 189 Inf. 303 nm E1 = 60 e 9,700 Max. 4/4-7 nm 3^ = 8 Inf. 515 nm E1 = 3 EtOH HC1 N/1q Max. 267 nm 2^ = 160 e 15,000 ii.M.R. Spectrum 6.8 p.p.m. thiazol.

Stage B: The irm i_somer__o£ 3~ac£t£xymethyl-7-C2-(2-^amin0^hiia^0i-4-^l^_-2-^(X^carb£X2be^nzyl-02cyimin£)acet2l^ c_ej2h^3^.em-^_-c_arb_ox^li_c_ac_id £r^f^uoroacetate^ At ambient temperature 0.882 g of the product of Stage A above and 8.9 ml of trifluoroacetic acid were agitated together for 10 minutes. After dissolution the solution was concentrated under reduced pressure at a maximum temperature of 30°C to a volume of about 3 ml, which volume, after cooling, was taken up with 30 ml of isopropyl ether and agitated therein at ambient temperature fore 10 minutes. After vacuum-filtrntion, rinsing with isopropyl ether and drying under reduced pressure at 20-25°, 0.512 g of impure product were 5 obtained. This was taken up with 2 ml of acetone containing V/- water and agitated therein for 5 minutes at ambient temperature, before slowly diluting under agitation with 20 ml of diethyl ether. After 10 minutes the product was separated by vacuum-filtration, 10 rinsed with diethyl ether and dried at ambient temperature under reduced pressure to give 0.'i43 g of purified product.

Example 7: The syn isomer of sodium 3-acetoxymethyl~7-C2-(2-aininothiazol-4-yl)-2-(a-carbox.ybenzyloxyimino) IS acetylamino3ceph-3-em-4-carboxylate.

At ambient temperature, 0.421 g of the product of Example 5 were dissolved in 2.1 ml of a 1M methanolic sodium acetate solution and 2.1 ml of methanol. The formed solution was treated with 40 mg of active 20 charcoal and vacuum-filtered on silica, and the filtrate was concentrated under reduced pressure at a maximum temperature of 30°C to a volume of 1 ml. To this was added 10 ml of 100% ethanol, and the resultant precipitate was separated by vacuum-filtration, rinsed 25 with ethanol then ether and dried under reduced pressure at ambient temperature to give 0.275 g of the desired product.

Analysis Calculated Pound '23H19°9^5S2^a2 * 619•5 T/o 44.59 H% 3.09 11.3 S% 10.35 44.8 3.5 11.3 10.2.

U.V. Spectrum EtOH/HCl N/^q 5 Max. 260 nm E^ = 266 e 16,500 Inf. 276 nm eJ « 222 e 13,700 Inf. 395 nm E1 = 8 I.R. Spectrum Nujol P lactam 1761 cm-1 Amide II 1532 cm"1 C=N-0R 1027 cm"1 Example 8; The syn isomer of 3-acetoxymethyl-7-[2--(2-aminothiazol-4-yl)-2-(2-oxotetrahydrofuran-3-yloxy-imino)acetylamino3ceph-3~em-4-carboxylic acid.

Stage A: Mixture of. the A £_and isomers of the syn isomer_o£ di£henj[lmeth2l_3^a£etoxymeth^l^7^[2-(2-trityl-^.minat hi^,z o^ wt^yjJ ^2zS. 2.-^^t^trahy4r2.furan^3^1pxyz. im^n£)^ce^tylamino_3ce£h23-em-4-carboxylat£.

At ambient temperature, 1.7 g of diphenylmethyl 20 3-acetoxymethyl-7-C2-(2-tritylaminothiazol-4-yl)-2--hydroxyimino-acetylamino3ceph-3-em-4-carboxylate, obtained in the preparation of Example 4, was dissolved in 8.5 ml of dimethylformamide. Under agitation, 0.69 g of anhydrous potassium carbonate then 3.2 ml a-bromo- -25 -butyrolactone were added, and the resultant suspension was agitated for 45 minutes at ambient temperature and under an inert atmosphere, after which 20 ml of water, 12 ml of N hydrochloric acid and 30 ml of ethyl acetate were added. The organic phase was separated by decanting and washed with water containing sodium chloride until a neutral pH was achieved. After drying and evaporating the solvent to dryness under reduced pressure at a temperature lower than 35°, 6.6 g of a clear brown oil were obtained, which was taken up with 20 ml of isopropyl ether and agitated therein for minutes at 40°C. The isopropyl ether phase was separated by decanting, and the operation described above was repeated to obtain a dry extract of about 2.5 g, which was treated in the same way with diethyl ether.

The residue was taken up with 20 ml of diethyl ether and agitated therein at ambient temperature for 15 IS minutes. The insoluble matter was then separated by vacuum-filtration, rinsed with diethyl ether and dried under reduced pressure to prive 1.513 g of an amorphous yellow product, which was used in the following stage without further treatment.

I.R. Spectrum NH 3395 cm"1 3 lactam ) _-i ) 1785 cm 1 lactone ) OAc + ester 17^/i cm-1 Amide 1691 cm 1 1381)7 - 84. - C=C C=N ) 1655 cm-1 Amide II ) 1599 cm 1 ) , Aromatic ) 1588 cm ) -I ) 1515 cm A ) _1 ) 1495 cm N.M.R. Spectrum CDC1^ 6.80 p.p.m. thiazol Stage B: The syn isomer of diphenylmethyl 1-oxo-3-^ace£0xyme£h£l^7;i£^-L2:Lt£it^liai]un0jthia£0jL-&-2l^--2_-£2^ -oxotetrahydrofuran-5-yloxy-imino)acetylamino3ceph-5~ ^em-a-c_q r;b_o x^l_a t e_.

Under an inert atmosphere and under agitation, 1 .525 g of a mixture of the^ and isomers obtained in the previous stage were dissolved in 8 ml of methylene 15 chloride. The solution was cooled to 0° - +5°C with a bath of iced water, and at that temperature and over a period of 20 minutes 0.420 g of metachloroperbenzoic acid in 8 ml of methylene chloride were added. The whole was agitated for one hour at the same temperature 20 and concentrated under reduced pressure without heating to give a residue, which was taken up with 20 ml of ethyl acetate and washed therein with a solution of sodium bicarbonate and then with a solution of sodium chloride until neutrality was reached. The organic 25 phase was then dried and distilled to dryness under reduced pressure at a temperature lower than 30°C to obtain a second residue, which was taken up with 10 ml of diethyl ether. The insoluble matter was separated by vacuum-filtration at ambient temperature and rinsed with diethyl ether to give 1.590 g of yellow product. I.R. Spectrum (CHCl^) lactone + 0 lactam 1737 cm 1691 cm 1797 cm -1 -1 1044 - 1035 - 1025 cm NH 3386 cm C=0 OAc conjugated ester amide 10 C=C C=N aromatic Amide II S=0 possible + oxime ether 15 U.V. Spectrum (EtOH) Inf. 257 nm Inf. 305 nm (EtOH Max. 265 nm 20 Inf. 300 nm K.M.R. Spectrum (CDCl^) 2 p.p.m. : OAc 6.73 and 6.77 p.p.m. : thiazol ■4> 6.7 p.p.m. : -COO CH 25 7-3 p.p.m. aromatics. -1 -1 1634 - 1599 - 1587 - 1523 - 1595 cm" -1 4 = 196 A = - ~ 53 e^5,000 HC1 N/1Q) E1 = —200 E^ = — 85 e —19,000 e ^ 8,100 St ape The syn isomer of diphenylmethyl 3-acetoxymethyl- ^7^[2-J^2^triiyJLaminothia^ol.-4-2lJ--2-£2^oxpt,etirah2^£o^: £uj;a nimin£) jjc^t^l anuno ] c_e2.h^3 - em-4-^art^x^l a_t_e. 1.328 g of the product obtained in the preceding stage were dissolved in 6.6 ml of dimethyl formamide. The solution was cooled to -20°C, and under an inert atmosphere 0.6 ml of phosphorus trichloride were added over 30 seconds. The whole was agitated for 5 minutes at -20°C, and then 30 ml of ethyl acetate, 30 ml of a saturated solution of sodium bicarbonate and 15 g of ice were introduced. After extracting and decanting, the product was re-extracted with 20 ml of ethyl acetate and washed therein with a solution of sodium chloride until neutrality was reached. After drying and distilling to dryness under reduced pressure and at a temperature lower than &0°C, a residue was obtained which was taken up with 10 ml of diethyl ether, recovered by vacuum-filtration, rinsed and then dried under reduced pressure and at ambient temperature to obtain 1.039 g of product, which was purified on silica by eluting with methylene chloride containing 10% ether. After distilling to dryness and taking up with ether, vacuum-filtering at ambient temperature and drying, 0.751 g of product were obtained.

N.M.R. Spectrum CDCl^ 2 p.p.m. : OAc 6.8 p.p.m. : thiazol 4 a a t» 7 - 8? - 4> 7.3 p.p.m. : aromatics.

Stage D: ?-acetoxymethyl-7-C2-(2-aminothiazol-4-yl)-^2-( 2-oxo. ^.et.rah2droXuran-j5-£l oxj^-imino )ace tj 1 amino 3-5 ^ceph-^-£mwi^c£rbp2S7l.i£ acid At 20°-25°C and for 10 minutes, 7.2 ml of trifluoroacetic acid and 0.720 g of diphenylmethyl 3-acetoxyinethyl-7-C2-(2-tritylaminothiazol-4-yl)-2--(2-oxot et rahydro furan-3-y1oxy-imino)ac ety1amino 3 c eph-10 -3-em-4-carboxylate, 3yn isomer, obtained in the previous st.ige, were agitated together. The whole was concentrated under reduced pressure at a temperature lower than 30°C to a volume of about 2 ml, which was taken up, while cooling with a water and ice bath, with 15 30 ml of isooropyl ether. After agitating for 10 minutes at ambient temperature and then vacuum-filtering, 0./I.83 g of product were obtained. 0.a80 g of the product were taken up with 0.5 ml of anisole and 4.8 ml of trifluoroacetic acid, and the whole was agitated 20 for 5 minutes at ambient temperature and then concentrated to a volume of about 1 ml, which was taken up with 20 ml of isopropyl ether. After vacuum-filtering 0.472 g of product were obtained, and to 0.458 g of this were added 1.8 ml of formic acid containing 50% 25 water. The whole was heated to 50°C for 10 minutes in an inert atmosphere, and whilst still hot was filtered to separate a light insoluble matter. The filtrate was then placed in a water bath not exceeding 30°C and after cooling was concentrated to dryness under reduced pressure to r;ive a residue which was taken up with 3 ml of water. After vacuum-filtering, rinsing with a very little water and then with ether, 0.283 g of product were obtained and used without further treatment in the following example.

Example 9: The syn isomer of sodium 3~acetoxymethyl--7-C2-( 2-aminothiazol-/i-yl)-2-(2-oxotetrahydrofuran-5--yloxy-inino)acetylaniino jceph-3-em-a.-carboxylate. 0.283 g of 3_acetoxymethyl-7-C2-(2-aminothiazol-4--yl)-2-(2-oxotetrahydrofuran-3-yloxy-imino)acetylaminoJ ceph-3-em-a-carboxylic acid obtained in Example 8 were dissolved in 1 ml of 1 M methanolic sodium acetate solution and 1 ml of methanol. The solution was treated with 30 g of active charcoal, filtered on silica and rinsed 3 times with methanol, and the filtrate obtained was concentrated under reduced pressure to a volume of 1 ml at a temperature not exceeding 30°G. The 1 ml volume was diluted with 10 ml of ethanol at 100°, and after vacuum-filtering, rinsing with ethanol at 100° and then with ether, 0.16S g of product were obtained.

Analysis : C^gH^gOgN^S^a : 547-5 Calculated: C% /1I.68 li% 3.31 12.79 S% 11.72 Na% 4.1 Found : C?i 'i3.8 H% 3.5 N% 11.8 S% 10.7 Na% 4.2 U.V. Spectrum EtOH/HCl N/10 Inf. 220 nm E1 = 255 Max. 260 nm = 302 e 16,500 I.R. Spectrum Nujol 3 lactam ) , ) 1765 cm \ lactone ) Amide 1673 cm-1 C=C C=N ) . ) 1611 cm"1 10 COO" ) Amide II 1535 cm"1 N.K.K. Spectrum DMS0 1.98 p.p.m. : OAc 6.78 p.p.m. : thiazol 15 4.33 p.p.m. : COOCH^ Example 10: The syn isomer of the disodfum salt of 3-acetox.ymethyl-7-C2-( 2-aminothiazol-4-yl)-2-(l-carboxy--3-hydroxypropoxy-imino)acet.ylaaino3ceph-3-em-4-carboxylic acid. 0.257 g of sodium salt obtained in Example 9 were agitated with 2.7 ml of a 0.0865 M aqueous solution of sodium carbonate for 4 hours at ambient temperature. After leaving for a further 12 hours, the whole was distilled to dryness under reduced pressure at a 25 maximum temperature of 30°C to give a residue which was taken up with 2 ml of methanol. The resulting solution was filterod to eliminate the brown insoluble matter and distilled to dryness to give a second residue, which was taken up with 2.S ml of ethanol. After recovering the insoluble matter by filtration and rinsing with ethanol then ether, 0.226 g of the desired product 5 were obtained.

Analysis : C^gH^gO^QNagSgN,. : 587.5 Calculated: C% 38.84 H% 3.26 Wo 11.92 S% 10.91 Na% 7.82 Found: C* 39.8 3.7 NfS 10.7 S% 10.1 Na% 7.6 10 U.V. Spectrum EtOH/HCl N/^q Inf. 224 nm E^ = 198 Max. 262 nm E1 = 225 el5,000 Il.M.R. Spectrum D2O 7.03 p.p.m. thiazol.

I.R. Spectrum P lactam 1763 cm-1 amide 1667 cm""1 COO" 1575 cm""1 Example 11: The syn isomer of 3-acetoxymethyl-7~£2-(2-20 -acinothiazol-a-yl)-2-( 2-oxotetrahydrofuran-3-yloxy--imino)acetylamino3ceph-5-em-4-carboxylie acid.

Stage A: _ Dieth^latpnQnfyn) 5-acetoxymethyl-7-C2-(2-trityl-amin£thi^z£lwi^yl.)2-^.22pxot.et.rahxdrofuran-^-x'!.oxi-_ _^iaino^_ac_etvl_a^ino_].ceph-_^-em_^'i^iC£rbo2cyl.at_ei Under agitation and under an inert atmosphere, 1-367 g of 3-acetoxymethyl-7~C2-(2-tritylaminothiazol--4-yl)-2-hydroxyimino-ac etylamino 3 c eph-3-em-4-carboxy1ic acid, obtained as an intermediate in Stage C of the preparation of Example 1, were dissolved in 20 ml of methylene chloride. 20 ml of water, 2.8 ml of triethylamine and then 1 ml of a-bromo -butyrolactone 5 were added, and the whole was agitated for 17 hours at ambient temperature before adding another 1 ml of a-bromo -butyrolactone followed three hours later by 1.4 ml of triethylamine and, after a further 5 hours' agitation, by yet another 1.5 ml of a-bromo -butyrol-10 actone and 1.4 ml of triethylamine. The agitation was then continued for 16 hours, after which 20 ml of 2N hydrochloric acid were added for acidification. The organic phase was decanted, washed with water until neutral, dried and distilled to dryness under reduced IS pressure to give a residue which was taken up with 10 ml of ethyl acetnte. The insoluble matter was separated by vacuum-filtration and rinsed, after which the filtrate (and rinsings) was dried and distilled to dryness. The resultant residue was taken up in 10 ml 20 of ethyl acetate, to which was slowly added 0.2 ml of diethylamine, and the diethylamine salt of the starting product was separated by vacuum-filtration at ambient temperature and rinsed with ethyl acetate then diethyl ether. The filtrate and rinsings were 25 distilled to dryness and the formed residue was taken up with 2 ml of ethyl acetate, to which was then added 20 ml of isopropyl ether. Finally, the precipitate obtained was recovered by vncuum-filtration to Rive 0.500 g of the desired product.

U.V. Spectrum EtOH - HC1 N/1Q Max. 265 nm E^ = 179 e 15,000 N.M.R. Spectrum (CDCl^) 6.76 p.p.m. thiazol Stage B: The_ syn _isorner_o£ j^-<ic£t£X£m ethj ^aminothia^oll-a-^1^^2-^2^oxot-et-r^h^drofuran-5.-ilox^-_ 3jnino>)acetj^l^mi^n£]^e£h^5^em-j4;-carbox2lic_acid trifluoro-10 ac_etate. 0.5 g of diethylamine salt obtained in Stage A were introduced into 5 cm of trifluoroacetic acid, and the whole was agitated for 15 minutes at ambient temperature before distilling under reduced pressure to a volume of 15 about 2 cm . 20 cm, of isopropyl ether were then added in one portion, and after agitating for 15 minutes at ambient temperature, separating the product by vacuum-filtration, rinsing 5 times witu 2 cm of isopropyl ether and then drying under reduced pressure, 20 the desired product was obtained.

Stage C: The sjyn isomer_o£ ^-ac£tox^methy]^-7-_^2-^( 2-_ ^arcino£hiazol.-/L-2l_}_--2-£2^oxot_etrahidro^uran-2.-xlox2r-imi_n£)ac£t£laninoJce£h^-em-4-carba>c2.1ic_acid.

The trifluoroacetate obtained above was placed in 25 a mixture consisting of 2 cm of a 1:1 methylene 2 chloride/methanol solution and 0.5 cnr of a 1M ethanolic solution of pyridine, and pasted therein for 15 minutes 98 6 7 at ambient temperature. Over a period of two minutes, z the whole was diluted with 8 cm of sulphuric ether containing 2% ethanol, and then agitated. The desired product was recovered by vacuum-filtering, ringsing 5 with diethyl ether and drying under reduced pressure.

Example 12: The syn isomer of sodium 3-acetoxymethyl-7-[j-(2--aminothi a zol -yl) -2-t etrazol-5-yl -methoxyimino) ac ety 1 -amino3ceph-3-em-a-carboxylate.

Stage A: ThjJ syn isomer_o£ 2^-£2j-t_ri_tyl_amir^o_thi^a£ol_-^L-10 t_et_ra_zo_1^5^yl.-me_th2X2.imin.o_}_a^e_tic. .acid^ 2./t3 g of 2-(2-tritylaminothiazol-a-yl)-2-cyano-methaxyimino-acetic acid, the preparation of which is described below, were agitated in 12 ml of dimethylformamide. 1.5 g of sodium azide and 1.5 g of 15 ammonium chloride were added and the whole was heated for 5 hours at 75°C and then left to cool at ambient temperature before adding 120 ml of distilled water, 40 ml of ethyl acetate and 30 ml of formic acid. The precipitate thu3 formed was separated by vacuum-filtra-20 tion, rinsed with water, ethyl acetate then diethyl ether and dried to give 1.275 g of the desired product. 0.127 g of product were recovered from the filtrate. Analysis : C2gHp^0^N^S = 511.55 Calculated: C% 61.0 H% a.1 19.2 S% 6.3 25 Found : 61.1 4.6 17.8 5.8. U.V. Spectrum (EtOH) (+ DM30) Inf. 259 nm -9 ft - Inf. 265 nm e 11,000 Inf. 271 nm Inf. 294 nm e 6,600 EtOH / HC1 N/1C> Inf. 270 nm Max. 275 nm e 13,700 N.M.R. Spectrum DMSO 7.28 p.p.m. : trityl 6.88 p.p.m. : thiazol. 10 I.R. Spectrum -1 Aromatic 1608 cm NH 1624 cm" C=N N=N 1580 cm" C0o- ( 1557 cm" 2 ( ( 1^-91 cm r Stn^re B: Th£ syn isomer_o£ ^-buty^ ^acetoxymethyl^-?-^C2-^_2^t£ityl_aminot,hiiazpli-4-xl^.~2-l.t£tra^oJ_-5.-xl^i -m^t hoxyimin£)^c^t2.1^mi no ] £e£h^3-em-4-£a rb^x^ljl te.

To 1.024 g of 2-(2-tritylaminothiazol-4-yl)-2-20 -(tetrazol-5-yl-methoxyimino)acetic acid prepared in the previous stage were added 0.656 mg of .t-butyl 7-amino--3-acetoxymethyl-ceph-3-em-4-carboxylate and 2 ml of pyridine. After the addition of 0.5 g of dicyclohexyl-carbodiimide in 5 ml of methylene chloride, the whole 25 was agitated for an hour at ambient temperature, and then the dicyclohexylurea precipitate thus formed was eliminated by vacuum-filtration. 25 ml of N hydrochloric acid were added to the filtrate, and after agitating for 5 minutes, the organic phase was separated by decanting, washed with 25 ml of water and dried. The organic solvent was then distilled away under reduced 5 pressure to give a residue, which was taken up with isopropyl ether and crumbled therein. The solid matter was recovered by vacuum-filtration and rinsed with isopropyl ether, and after drying 1.778 g of crude product were obtained. This was dissolved in 4 ml 10 of ethyl acetate, treated with active charcoal and filtered on silica. Then, over 5 minutes and under agitation, 20 ml of isopropyl ether were added to the filtrate, and the whole agitated for a further 5 minutes. Finally, the solid was separated by vacuum-filtration, 15 rinsed with isopropyl ether and dried to give 1.412 g of a white product. M.p. = 158°C.

Analysis : G^oH39°7N9S2 Calculated: C% 58.5 H% 4.8 15.3 3% 7«8 Found : 58.5 5.0 14.7 7*6 20 U.V. Spectrum (EtOH - HC1 N/^q) Max. 267-268 nm e = 19,4-00 Inf. 290 nm I.R. Spectrum (CHCl^) 3 lactam 1787 cm 1 25 Esters 1738 cm 1 Amide ( 1686 cm 1 £ 1673 cm-1 N.M.R. Spectrum (CDGl^) 7.2 p.p.m. : trityl 6.75 p.p.m.: thiazol 1.5 p.p.m. : t-butyl 5 2.05 p.p.m.: acyl Stage, C: The syn isomer of 3-acetoxymethyl-7-C2-(2-amim>-thiazpl^-il^-^-^tjjtrazol^-^l^m^thoxyimin^acet^ljiminoJ c_e£h^3^em-/i_-c_arb£x^_li_c_ac_id ;t r if luoro a ce ta te_j_ At ambient temperature, 1.226 g of t^-butyl 3~ 10 -acetoxymethyl-7-C2-(2-tritylaminothiazol-a-yl)-2--(tetrazol-5-yl-methoxyimino)acetylamino3ceph-3-em--/i-carboxylate and 12 ml of trifluoroacetic acid were agitated together for 30 minutes, after which the acid was partially evaporated under reduced pressure and a 15 precipitate thrown down by the addition of 120 ml of isopropyl ether. The precipitate was separated by vacuum-filtration, rinsed with isopropyl ether and dried to give 1.061 g of a product containing some starting material, which had only partially reacted, 20 as an impurity. However by repeating the whole operation twice, starting with trifluoroacetic acid, 0.879 g of 1he desired product were obtained.

Stage D: The syn isomer_o£ sodium 3~acetoxymethyl-7~ - [2~^2^aminoth i a z o 1-/f-y 1) -2-(tetrazol-5-yl-methoxyimino_) 2 5 acet^lamino] £e_£h-3^em-a-carbo_x2.1atji.

The trifluoroacetate obtained in the previous ■x stage was dissolved in 1.8 cm of methanol, and under 4 9 8 6 7 agitation and at ambient temperature, 2.8 cm' of a molar solution of methanolic sodium acetate were x slowly added, followed over 5 minutes by 18 cnr of ethanol. The agitation was continued for 15 minutes 5 whilst cooling in a bath of iced water, and the solid formed was separated by vacuum-filtration, rinsed with ethanol then diethyl ether and dried to give 0.aja_7 g of the desired sodium salt in the form of crystals. Analysis : C^r7II^,-?0^NgS2 MW = 523.5 Calculated: C% 37.a 3-0 N% 23.1 S# 11.8 Found : 37.8 3-2 21.1 11.1 N.M.R. Spectrum (deuterochloroform) 6.73 p.p.m. : thiazol 7.25 p.p.m. : trityl 15 The preparation of the syn isomer of 2-(2-tritylamino-thiazol-<i.-yl)-2-cynnomethoxyimino-acetic acid used as starting material in Stage A. 1) The syn _isomer o£ £yanomethyl 2-( 2-1rity£amino Ilthiiizol^'L^O^^cianomel^hxlax^imino^acetate^ Under an inert atmosphere, 12.9 g of 2-(2-trityl- aminothiazol-'i.-yl)-2-hydroxyimino-acetic acid, syn 3 isomer, 9-12 g of neutral potassium carbonate, 60 ci x of dry dinet.iyl formamide and 7-6 cnr of chloroaceto-nitrile were mixed together, and agitated. The mixture 25 then congealed, after which it was left for 6S hours in an enclosed atmosphere before being poured into a 3 3 mixture of 750 cm of water, 130 cm of normal hydro- x choric acid and 150 cnr of ethyl acetate. After agita tion, the insoluble matter was separated by vacuum-filtration and rinsed with ethyl acetate and then with water. The phases of the filtrate were separated T, by decanting, and after washing with 100 cm of water 5 and re-extracting with 3 x 100 cm' of ethyl acetate, the organic phase was dried. Insoluble matter was removed by vacuum-filtration, and after rinsing, the filtrate was concentrated to dryness to give a residue, which was chromatographed on a column of silica, eluting 10 with ether. The ether was then driven off, and 8.69 g of the desired product were obtained in the form of oil. N.N.R. Spectrum : CDCl^ 60 MHz Thiazol proton : 6.8 p.p.m.

Trityl proton : 7-37 p.p.m. 2) The syn £s£d£r_2-( 2-trityl amino thiazol^^.Ti.^Z'^L ^c2.anomet^h£X2_imino-ac_etic acid^ 8.69 g of the product obtained in l) were placed in 52 cm' of dioxan, and the whole was cooled in an ice * bath. Over twenty minutes, 17«1 cm of a normal 20 solution of sodium hydroxide were added dropwise, after which the whole was left to reheat spontaneously. 10.5 cm' of 2N hydrochloric acid were then added, and the dioxan and almost all the water were driven off ■5 3 before adding 20 cm of water and 30 cm of diethyl ether and agitating for 15 minutes. The crystals formed were separated by vacuum-filtration, rinsed with water then diethyl ether and dried to give a.32 g of the 4 a B b 7 desired produce, melting at about 1S0°C with d ec omposi t i on.

N.M.R. Spectrum : CDC1, 60 MHz 5 4.7 p.p.m. : OCH2CN 5 6.7 p.p.m. : thiazol proton 7.3'j. p.p.m.: trityl proton.

Example 13: The syn isomer of 3~acetoxymethyl-7~£2--(2-aninothiazol-4--yl)-2-benzoyloxyimino-acetylajnino3 ceph-5-en-a-carboxylic acid.

Stage A: The ayn isomer of dietjiyainium_3-acetoxy^ me thil^7z^ 2-(_2^t i^i tyl,amino thia zo 1^-a-xl lr^.~^.eH.z2Jl.0^yz. ^mj^n^-ac^t^lamino,] c_e£h^3^_era-4.-c_arbox2.1a^tei.

To a solution of 0.683 6 of the syn isomer of 3-acetoxymethyl-7-[2-(2-tritylaminothiazol-/J--yl)-2- -hydroxyimino-acetylaminoJceph-3-em-4-carboxylic acid -1 3 in 10 cm of methylene chloride, were added 0.2 cm of pyridine and 0.2 cm' of benzoyl chloride. The whole was agitated for 10 minutes at ambient temperature and then washed in a separating funnel with water acidified to pH 1, and after drying, vacuum-filtering and concentrating to dryness 0.737 g of a crude product were obtained.

This was dissolved in 5 cm' of ethyl acetate, and 0.1 cm' of diethylamine were added to the solution. After minutes the whole was vacuum-filtered to obtain 0.27 g of the desired diethylamine salt.

Stage B: JThe _syn J.somer_ of ^-acetoxymethyl-7-C2-(^2- -aainothiazol-/t.-yl)-2-benzoyloxyimino-ac etylaminoIceph- laaoy -:5-^em-a-£arbox2.1ic_a£id.

The 0.27 g of diethylamine salt were agitated for 10 minutes at 4-5°C with 2 cm' of 50% aqueous formic acid, after which the whole was distilled to dryness 5 and the residue obtained ground with diethyl ether. 0.155 g of crude product were separated and dissolved in 0.5 cm' of methanol, from which a solid was I precipitated by introducing 5 cm of diethyl ether. The solid was separated to give 0.1a g of desired 10 product.

Analysis : ^22^19^6^5^2 ^ = 513.5 Calculated: N% 13.4 Found : 13.4 Example la: The syn isomer of 3-acetoxymethyl-7~C2-(2-15 -aminothiazol-A-yl)-2-(2-aminoethoxyimino)ac etylamino] ceph-3-em-a-carboxylic acid bis trifluoroacetate.

Stage A: The s;yn £somer_o.f ethy£ 2-(2-tritylamino-thi_aj5ol.-^-£l2~2,"JL2;^trit-ylamino£thoxyimino)^a£et.ate.s_ Under an inert atmosphere 12.2 g of the syn isomer 20 of ethyl 2-(2-tritylaminothiazol-a-yl)-2-(2-iodoethoxy-imino) acetate were introduced into 80 cm' of anhydrous dimethyl formamide and 12.A g of triethylamine. The whole was heated to 100°C for 5 hours after which 6.2 g of tritylamine were added. The temperature was 25 maintained for a further 7 hours at 100°C, before beine; allowed to return to ambient temperature, at which stage 1600 cm' of distilled water were introduced. 43867 3 The product was extracted with 6 x 250 cm of benzene and after washing with water then with a saturated solution of sodium bicarbonate then with a saturatpd solution of sodium chloride and drying, 23.5 g of a resin were obtained. This was chromatographed on silica, eluting with a benzene ether (95:5) mixture, and the principal was again chromatographed over silica, this time eluting with pure methylene chloride. 3.6 g of pure product were obtained.

N.M.R. Spectrum (CDCl^) Thiazol proton = 6.4.6 p.p.m.

CHg-NH triplet centred on 2.4-5 p.p.m. ( J = 5 Hz) Stage The gyn isomer__o£ 2-£2^trity£aminoth£azol-4-yl)-2-(2-trityIaminoethoxYimino) £cetic_acid.

Whilst under nitrogen, 2 g ofthe ethyl ester 3 prepared in Stage A were introduced into 10 cm of 3 3 dioxan and 66 cm of absolute ethanol, and 3 cm of normal sodium hydroxide solution were added to the formed mixture. After leaving for 65 hours, the precipitate formed was separated by vacuum-filtration 3 and washed three times with 3.5 cm of dioxan ethanol (1:6.6) mixture. A first yield of 1.44-5 g of sodium salt was obtained. The above process, which is one of sapoiification, was repented under identical conditions 25 in respect of the mother liquors remaining, which gave a second yield of 0.4A0 g of sodium salt.

The 1.44.5 g of the first yield was poured into 30 cm' of water and 30 cm' of chloroform and, under •* a o o t vigorous agitation, normal hydrochloric acid was added until pH 2 was obtained (about 1.9 cm'). The organic phase was decanted and washed until neutral with 4 x 10 cm' of water, each fraction of washing 3 S water being subsequently re-extracted with 3 cm of chloroform. The total chloroformic phase was then dried and evaporated to dryness to give a white powder, 3 which was pasted twice with 2 cm of dichloroethane 3 and then twice with 2 cm of isopropyl ether. After 10 drying under reduced pressure vmtil a constant weight, 1.202 g of product were obtained. H.p = 176°C with decomposition.

The second yield of O./i/iO g of sodium salt was treated in the same way to give 0.325 g of desired 15 product. M.p. = 176°C with decomposition.

Thus 1.527 g of product were obtained in total. N.M.R. Spectrum (CDCl^) 6.65 p.p.m. : proton in 5 of the thiazol 2.95 p.p.n. : C^-N 20 Sta;T;e C,: The syn isomer diphenylmethyl 3-acetoxymethyl--7-C2-C 2-tritvlarninothiazol-'i-yl)-2-( 2-tritylamino-£thpxyiain£)_ac_etyl_amino2cj^h-j5-£m^v-carboxyl_a_te_;_i Under nitrogen, 0.286 g of the acid prepared in Stage B were introduced into 2 cm' of methylene chloride. 25 The suspension thus formed was agitated and to it were 3 added dropwise 0.4 cm of a solution prepared extempor- 3 aneously by mixing 1.4 cnr of triethylamine and a 4 9 O w • X quantity of methyl chloride sufficient to obtain 10 cnr of solution. The whole was cooled in a bath of acetone and dry ice to -20°C and left for 5 minutes to balance the formed solution, after which whilst 3 under agitation O./i cnr of a solution prepared extemporaneously by mixing 1.25 cnr of pivaloyl chloride with a sufficient quantity of methylene chloride to obtain 10 cm' of solution, were added dropwise. The bath was subsequently allowed to warm to -10°C, and was 10 left at this temperature for 30 minutes before being allowed to warm further to 10°C in 10 minutes. 0.176 g of diphenylmethyl 7-amino-cephalosporanate were then immediately alcohol, and the whole was allowed to return to ambient temperature. After leaving for an hour and 15 20 minutes, a further 17.6 mg of the diphenylmethyl ester were added, and the whole was then agitated for 30 minutes at ambient temperature, placed for 15 hours in a refrigerator, allowed to return to ambient temperature and subsequently evaporated to dryness under 20 reduced pressure. Finally, the residue was filtered on silica, eluting with a benzene ethyl acetate (8:2) mixture, to give 0.208 g of the desired product. N.H.R. Spectrum (CDClj) 1.99 p.p.m. = 0-C-CH, II * 0 4.38 p.p.m. = N-O-CH2 «90 V f 6.71 p.p.m. = proton in 5 of thiazol 6.88 p.p.m. = C02CH <j> 2 Stage D: The syn isomer of 3-acetoxymethyl-7-[2-(2-amino-thiazol,-i-ilJ.-2_-l2_3aminoethoxyimino)_acet;£ljimin£]c_e£h-. 5 _-3j-em-£i_-£arbox^l_ic_aciid bis_ trifluor£ac_etate_;. 186 mg of diphenylmethyl 3-acetoxymethyl-7-C2-(2--tritylaminothiazol-4-yl)-2-(2-tritylaminoethoxyimino) acetylamino3ceph-3-em-4-carboxylate prepared in Stage C was introduced into 1.8 cm' of pure trifluoroacetic 10 acid. The yellow solution thus obtained was agitated for 3 minutes at ambient temperature and then, in an 3 inert atmosphere and in an iced water bath, 18 cm of isopropyl ether were rapidly added. The whole was agitated for 10 minutes, after which the solid formed was separated by vacuum-filtration, rinsed with isopropyl ether then diethyl ether and dried to give 100 mg of a white powder. M.P. = about 210°C (decomposition), N.M.R. Spectrum DMSO 2.03 p.p.m. = 0-C-CH, II ' 0 3.17 p.p.m. = =N-0-CH2 6.85 p.p.m. = proton in 5 of thiazol.

The preparation of the syn isomer of ethyl 2-(2-trityl-aminothiazol-a-yl)-2-(2-iodoethoxyimino) acetate used as starting material in Stage A. a) _The syn isomer of jethyl J2^2j-tjri^^amijiothiazol-4- i 2-bromoetho^iminp2 acetic_acid.

In an inert atmosphere, a mixture of 4.9& g of ethyl 2-(2-tritylaminothiazol-4-yl)-2-hydroxyimino acetate hydrochloride syn isomer, was introduced 3 into 10 cm of dimethyl formamide, and at ambient temperature and over 3 minutes, 4.14 g of potassium carbonate were added. The whole was agitated for 20 o ^ minutes at 20 C after which 8.6S cnr of 1,2-dibromo- ethane were added. After agitation for a further 30 hours the whole was poured into a medium containing 3 3 100 en of distilled water and 20 cm of methylene chloride. The aqueous and organic phases were then separated by decanting, and after re-extracting with methylene chloride, washing with distilled water and 15 re-extracting again, the combined organic phases were vacuum-filtered, with rinsing, and distilled to dryness. The crude product obtained was chomatographed on silica eluting with benzene containing 5% diethyl ether; and a first fraction was collected which was 20 recrystallised in methanol after dissolution at 50-60°C and vacuum-filtering at 0° - +5°C 1.15 g of cream white product were obtained. M.p. = 117°C.

A homogenous fraction of 1.258 g was subsequently obtained.

N.M.R. Spectrum » p.p.m. (CDClj.) triplet = 3.55 triplet = 4.51 J = 7 Hz CH2 Br J = 6 Hz N-O-CH^ «oo f single 6.55, thiazol proton cycle. b) The syn isomer of ethyl 2-(2-tritylaminothiazol-4- ^^)^2^(2-iodo.ethoxyimino)_ac_etateJL 6 g of ethyl 2-(2-tritylaminothiazol-4-yl)-2-5 -(2-bronoethoxyimino) acetate syn isomer prepared in a) were introduced into 60 cm' of methylethylketone and 2.I'll g of sodium iodide. The whole was taken to reflux for one hour and 10 minutes and then evaporated under reduced pressure to give a residue, which was taken up with 120 cm' of methylene chloride. After ■3 washing five times with 40 cm of water, each washing 3 being re-extracted with 2 cm of methylene chloride, the combined organic phases were dried and evaporated to dryness to give a resin, which was mixed with 15 diethyl ether. After drying under reduced pressure, 6.22 g of product were obtained. M.p. = 110°C.

II.K.R. Spectrum = (CDCl^) C&2 1 = triplet centred at 3.31 p.p.m. (J - 7 Hz) Proton at 5 of thiazol : 6.53 p.p.m.

Example 15: The syn isomer of 3-acetoxymethyl-7~C2--(2-aminothiazol-4-yl)-2-(2-aminoethoxyimino) acetyl-amino ] ceph-3-em-4-carboxylic ac id. 220 mg of the bis trifluoroacetate prepared in 3 Example 14 were introduced into a tube and 1.6 cnr of 25 a molar solution of sodium acetate in methanol were added. The whole was agitated until complete dissolution was obtained, and then the sides of the tube were rinsed with 0.66 cm' of methanol before the addition 3 of 18.6 cm of absolute ethanol. Precipitation then occurred and at that time an equivalent mixture obtained in the same way but starting with 100 mg of 5 bis trifluroacetate was added. After 1 hour 50 minutes, the combined mixtures were vacuum-filtered to separate the insoluble matter, which was washed with ethanol then with diethyl ether and dried until constant weight under reduced pressure to give 181 mg of a 10 white powder melting at 270°C with decomposition. Rf = 0.12 (ethyl acetate ethanol water - 60:25:15) The white powder was purified as follows: 120 mg of the powder were introduced into 1 cm' of distilled water. After agitating for 5 minutes, 15 pyridine was slowly added until a pH of 7.0 to 7-2 was obtained. After a further 15 minutes of agitation, the whole was vacuum-filtered, rinsed with 0.5 cm5 of water and nO cm' of acetone were added to the filtrate, which was then agitated for 5 minutes, left to rest for 20 20 minutes and vacuum-filtered to recover the product. After washing three times with acetone and drying, 99.5 mg of a purified white powder were obtained. U.V. Spectrum Max. 261 nm = $n8 Example 16: The syn isomer of 3-acetoxymethyl-7-C2-(2--aminothiazol-4-yl)-2-(2-amino-2-thioxo-ethoxyimino) acetylamino]ceph-3-em-a-carboxylie acid. «9BDt 0.502 g of sodium 3-acetoxymethyl-7-C2-(2-amino- thiazol-'«--yl)-2-cyanomethoxyimino-acetyl3ceph-3-em- -4-carboxylate, syn isomer, were placed in 2 cm' of dimethylformamide and 0.14 cm' of triethylamine. After total dissolution, some gaseous hydrogen sulphide was slowly introduced (bubble by bubble) over 15 minutes, and then the whole was left under „gitation at ambient temperature for 30 minutes. 20 cm' of isopropyl ether were subsequently added and after agitation the isopropyl ether phase was separated, leaving an oil remaining at x the bottom of the container. 7 cnr of ethanol were added to that oil, and after agitation an insoluble substance was formed, which was separated by vacuum- filtration, rinsed with ethanol and dried to isolate 0.388 g of crude product. This was purified by dissolving (0.309 g in 1.5 cm' of water, adding 30 mg of charcoal, agitating and removing the charcoal by vacuum-filtration whilst rinsing with water. 5 drops of pure formic acid were added to the filtrate, and the precipitated product was rinsed with water and dried to obtain 0.195 g of p-. rified product.

N.M.R. Spectrum; (CHj^O NH2 (e) j 2 [ -A. ; n 0 II / \ /V (f) s J1 (b) YV>" so H2°S"CH3 (a) —C C°ZH ° NH 2 (a) single 2.02 p.p.m. (d) single 6.83 p.p.m. (b) " 3.55 p.p.m. (e) " 7.25 p.p.m. (c) " a.75 p.p.m. (f) double centred on 9.73 p.p.m. (J=8Hz) 5 U.V. Spectrum (in ethanol, N/^q hydrochloric acid) max. 265 nm E^ = 468 e = 2'<-,100 The preparation of the syn isomer of sodium 3-acetoxy-methyl~7~ C2-(2-aminothiazol-a-yl)-2-cyanomethoxyimino--acetylamino3ceph-3rem-4-carboxylate used in Example 10 16 as starting material; A) The syn £somer of t^-butyl^ 3-ac£toxymethyl-7-C2-(2-_ ^tri^jiamino-thiaz^°l_-4-ilJ.-^-£ya_n£niethyl_02£ylmin£-£c-etJ2l_^ £min£3£ej>h^-em-4-£arb£Xilate.

In an inert atmosphere 1.875 S of the syn isomer 15 of 2-(2-tritylaminothiazol-4-yl)-2-cyanomethyloxyimino--acetic acid obtained as in the preparation of Example 12 were mixed with 1.312 g of t^-butyl 7-aminocephlo-sporanate in 12 cm' of dry methylene chloride. The whole was agitated, and a solution of 960 mg of 20 dicyclohexyl carbodiimide in 12 cm' of dry methylene chloride added. After agitating and leaving at ambient temperature for one hour 45 minutes, 457 mg of formed dicyclohexylurea were separated by vacuum-filtration. The filtrate was then concentrated to dryness to give a residue, which was chromatorgraphed on silica while eluting with methylene chloride then diethyl ether. The resulting rich fractions were collected, and the diethyl ether therein was driven off, the residue being taken up with ether. Crystallisation was subsequently initiated, and the whole was left in the refrigerator whilst the product slowly crystallised. The crystals were separated by vacuum-filtration, rinsed with diethyl ether at 0°C by pasting and then dried to isolate 776 mg of desired product. M.F. = 180°C with decomposition.

N.M.R. Spectrum : 60 MHz CDCl^ 4.9 p.p.m. : O-CHg- CN 6.8 p.p.m. : proton of the thiazol cycle 7.31 p.p.m. : proton of trityl.

B) The s^yn i_somer_o£ 3^acetoxymethy£-7-_C_2^( 2-amino-thi_azol_-a-£l_}_-2-£yanomethylpxyim^n£-jicj3tjEljamino_]cej>h2 Jl3;iem-ji-carbox2lic_acid trifluoroac_et_atei 779 mg of the product obtained in A) were * introduced into U- cm of trifluoroacetic acid, and agitated until dissolution. 17 minutes after the x introduction the solution was poured into 40 cm of isopropyl ether, and after agitation the insoluble - Ill - matter was separated by vacuum-filtration and dried to isolate 523 mg of the desired product. c) The sgi is£mer_o£ sodium 3;ace^o xyme£hy l^^C 2-(2^ ^aminottviazol-a-yl) -2-cyanomethyloxyimino-acetylamino ] 5 ceph-3-em-a-carboxylate.

The 523 mg of trifluoroacetate obtained in B) 3 were dissolved in 2 cm of a normal methanlic solution of sodium acetate, and the formed solution 3 was diluted with 6.6 cnr of ethanol and agitated for 10 10 minutes. The insoluble matter was separated by vacuum-filtration, rinsed with ethanol and dried to give 226 mg of the desired sodium salt. M.p. = about 200°C with decomposition.

JN.M.R. Spectrum : CDClj,60 MHZ 15 /i.98 p.p.m. : 0-CH2" CN 6.86 p.p.m. : proton of the thiazol cycle.

Analysis : ,_0r7NgS2Na Calculated: C?& 4-0.64. E% 3-01 Na% 4.57 Pound : 40.2 3.3 4.5 Example 17: The syn isomer of 3~acetoxymethyl-7-[2-(2--aminothiazol-a-yl)-2-( 2-amino-2-thioxoethoxyimino) acetylamino3ceph-3-em-/i-carboxylic acid.

Stage A,: 2^-^2^tritjliami£o_thi_a_zol.-a-^l_}_-2-{_2_2Hjriiao_22-_2thi_oxo_-_eth°2tyimin£)_a£e_tic_ acidi 25 2.81a g of 2-(2-tritylaminothiazol-a-yl)-2-(cyano- methoxyimino)acetic acid obtained in the preparation of 3 Example 12 were introduced into 12 cnr of a solution 3 containing 1.6 cm of triethylamine diluted with 20 cm' of dimethylformamide. At ambient temperature, gaseous hydrogen sulphide was introduced for 3° minutes, after which the mixture was corked and left 3 for 2 hours 10 minutes under agitation. 100 cm of 3 water followed by 14..4 cnr of normal hydrochloric acid were then added, and the whole was agitated vigorously before removing the insoluble matter formed by vacuum-filtration and rinsing with water. 10 Methylene chloride was added to the filtrate, and the crystals formed were separated by vacuum-filtration, rinsed and dried to isolate 2.i>7 g of the desired acid. M.P. = 180°C.

N.M.R. Spectrum - (CHj^SO 15 6.96 p.p.m. : trityl, 7.33 p.p.m. proton in 5 of thiazol.

Stage B: The syn isomer of 3-acetoxymethyl-7-C2-(2-^t£i^laminpthi.a£Ol,-a-xl}.-£_£2-amino^2^thioxo-ethoxy-^ mino)acetylaaino]ceph-3-em-4-carboxylic acid^ 20 1.01 g of the acid obtained in Stage A and 0.656 mg of 7-aminocephalosporanic acid were introduced into 2 cm' of pyridine. After dissolution, 0.5 g 3 of dicyclohexyl carbodiimide in 5 cm of methylene chloride were added, and the whole was agitated for 25 one hour at ambient temperature. The formed precipitate was then removed by vacuum-filtration, rinsing with methylene chloride, and dried to isolate about 0.5 g of dicyclohexylurea. The filtrate was poured into 25 cm' of normal hydrochloric acid. After agitating for 5 minutes, the organic phase was separated by decanting, washed with 25 cnr of water, dried and vacuum-filtered and the solvent was driven off from the filtrate to leave a residue, which was taken up and crumbled in isopropyl ether. The insoluble matter was then separated by vacuum-filtration and rinsed to obtain the desired product in impure form. This was dissolved in ft cm' of ethyl acetate, and 0.18 g of active charcoal were added, which were subsequently removed by vacuum-filtration, rinsing with ethyl acetate. The x filtrate was agitated, and over 5 minutes 20 cnr of isopropyl ether were introduced before continuing the agitation for a further 5 minutes. The insoluble matter t was recovered by vacuum-filtration, rinsing with isopropyl ether, to obtain after drying the desired purified product.

Stage C: The £yn isomer of _3-a_cetoxymethyl-7~[2-(2- ^aminothi_az_ol_-a-jl_)_-2i-^_2j2amino^2^thi£X£-£thoxy^mi_n£) acet£laminoJce]3h;^-em-a-carb£X2lic_acid.

The product obtained in Stage B was introduced into 12 cm' of trifluoroacetic acid, and the whole was agitated for 30 minutes at ambient temperature. The acid wa3 partially evaporated under reduced pressure x and precipitation was initiated with 120 cnr of isopropyl ether. The precipitate was crumbled and then 4 8 8 6 7 recovered by vacuum-filtration, rinsing with isopropyl ether, to obtain after drying, a product identical to that of Example 16.

Example 18; The syn isomer of 3-acetoxymethyl-7-C2-(2- aninothia zol -4-y 1) -2-( 2-oxo-propoxyinino ) ac etyl amino ] ceph-5-em-4-carboxylic acid trifluoroacetate.

Stage A: The gyn is£mer_of ^-£C£t£xym£thy£-£-[2^(2-_ ^t_rityl_aminot_hi_az^ol_-a-xlJ.-^-i.2^oxo^proEp327_iEiin£)ac_et^l^ amin£]cie£h^3^em-a-c>arb£^5rli>c__ac.id. 7.6 g of diethyl ammonium 3-acetoxymethyl-7-C2-(2- -tritylaninothiazol-a-yl)-2-hydroxyimino-acetylamino] ceph-3-em-a-carboxylic acid, syn isomer, prepared in z Example 1, was introduced into 114 cnr of methylene chloride and 11a cm' of distilled water. Then at 20°C 15 and under agitation, la cm' of triethylamine were added. The whole was agitated for 5 minutes, after which 8.45 cm' of bromoacetone were added at 20°-25°C. After agitation at 25°C for 5 hours, the whole was acidified . to pH 1-2 at 15°G with 6 cm' of hydrochloric acid. The 20 organic phase was separated by decanting, and product was extracted from the aqueous phase with 250 cnr methylene chloride. The organic phases were combined and washed with water, and after re-extracting the product from the washing waters, the total orgaic phase 25 was dried and distilled to dryness to obtain 8.48 g of a resin. This was dissolved in 8.5 cm of methylene chloride, and precipitation therefrom was then induced by the addition of 85 cm' of diethyl ether. After agitation for 2 hours at ambient temperature, the precipitate was separated by vacuum-filtration, rinsed three times with 10 cm' of ether and dried to obtain 6.27 g of the desired product.

Purification by converting to the diethyl ammonium salt: The product obtained above was taken up in 62 cm'* of ethyl acetate, and pasted thereon at ambient temperature for 5 minutes. Insoluble matter was removed by vacuum-filtration, rinsing with ethyl acetate, and the filtrate was concentrated to 50 cnr before the T. introduction in one portion of 0.6 cnr of diethylamine. After agitation, the gram formed was rinsed three times with 5 cm' of ethyl acetate. The filtrate was diluted with 130 cm' of isopropyl ether, and the precipitate thus formed was agitated in the mother liquor for 15 minutes before being separated by vacuum-filtration, rinsing with isopropyl ether. After drying, 3-27 g of the desired salt were obtained. 3 3.25 g of this salt were dissolved in 25 cnr cf ■z 3 distilled water and 98 cnr of ethyl acetate, and 50 cnr of a saturated aqueous solution of sodium chloride were added. One gum was decanted, it being recovered with the aqueous phase. After acidification to pH 1-2 with 2.r5 cm' of concentrated hydrochloric acid, in the presence of 50 cm' methylene chloride, product was extracted from the aqueous phase with methylene chloride 4 9 8 8? (50 cm' twice). The organic phase was then washed with water, dried, vacuum-filtered with rinsing and distilled to obtain 1.79 g of a resinous product. This was dissolved in 4 cm' of methylene chloride, and after j dilution with 40 cnr of diethyl ether, the insoluble matter was recovered by vacuum-filtration, rinsed with diethyl ether and dried to obtain 1.22 g of the desired product.

N.M.R. Spectrum - CDCl^ 2.03 p.p.m. 0-C-CHj 0 2.13 p.p.m. Oi0-C-CH, 2 li 2 0 6.8 p.p.m. proton in 5 of thiazol.

Stage_ B: The syn isomer_o£ ^-ac£toxym£thy£-7-£2_2(J!-_ ^amino£hia£0^-a-£l^-2-£2-oxoj;^ro£oxyimino)acet£lamino] c_e]3h:J5zem-4-carbox2lic_aci(l trifluoroace.tate^ 1.22 g of the product obtained in Stage A were introduced into 12 cm' of trifluoroacetic acid and agitated therein for 15 minutes at 20-22°C. The whole x was reduced in vacuo to 6 cm and then diluted with 20 60 cm' of isopropyl ether, and the precipitate thus formed was agitated at ambient temperature for 15 minutes before being separated by vacuum-filtration, * rinsing five times with 5 cnr of isopropyl ether, to obtain, after drying under reduced pressure, 0.97 g of 25 crude product.

This was purified by dissolving in 4 cm' of acetone containing 1% water and then adding 0.2 g of active charcoal, which, after agitating for 5 minutes at 20-22°C, was separated by filtration and rinsing 3 ' five times with 1 cm of acetone containing 1% water.

At 20°-22°C, 90 cm' of diethyl ether were added to the filtrate, and after agitation at 20-22°C for one hour the insoluble matter was separated by vacuum- filtration, rinsing with diethyl ether and dried to obtain 0.57 g of the desired product.

Example 19; The syn isomer of sodium 5-acetoxymethyl-7~ -[2-(2-aminothiazol-4-yl)-2-(2-oxo-propoxyimino)acetyl- amino]ceph-3-em-4-carboxylate. 0.57 g of the trifluoroacetate obtained in Example X 18 was dissolved in a mixture of 0.25 cm of distilled water, 2.3 cnr of methanol and 2.3 cnr of a normal methanlic solution of sodium acetate. The light insoluble matter obtained was removed by vacuum-filtration rinsing with 2.3 cm' of methanol, and the filtrate was x concentrated to about 3 cnr to obtain a coloured solution, which was diluted with 20 cm of ethanol.

After agitating at 20-22°C for 10 minutes, the insoluble matter was separated by vacuum-filtration, rinsing three times with 3 cm' of ethanol, and dried to obtain 0.38 g of the desired sodium salt.

By concentrating the mother liquors it was possible to obtain by vacuum-filtration a second portion 49BOI " 118 - of 0.12 g of sodium salt, which was pasted at 20°C for 7. minutes in 0.6 cnr of methanol. After dilution with 6 cm' of ethanol and subsequently rinsing, 0.07 g of sodium salt were obtained.

The sodium salt thus obtained (0.&5 g) was purified by dissolving at ambient temperature in 2 cm' of distilled water, and slowly and under agitation at o 5 C adding 12 cm of acetone. The precipitated gums were removed by vacuum-filtration, and the filtrate was brought to dryness to obtain a residue. The residue was treated as just-described, starting with 7. 7. 1.5 cm of distilled water and 10 cm of acetone, and 7. the resulting residue was taken up with 5 cnr of pure ethanol. The insoluble matter was then vacuum-filtered o ^ at 20 C, rinsing three times with 1 cm of ethanol, and dried under reduced pressure to obtain 0.26 g of the desired product.

H.M.R. Spectrum (CH^^SO 2 p.p.m. : O-j^-CH^ 0 ~ 2.13 p.p.m. : CH0-C-CH, 0 2 o 6.78 p.p.m. : proton at 5 position of thiazol.

Example 20: The syn isomer of 5~methyl-7-C2-(2-amino-thiazol-a.-yl)-2-(2-amino-ethoxyimino)acetylamino]ceph- -3-em-a-carboxylic acid bis trifluoroacetate.

Stage JV: The syn isomer of diphenylmethyl 3-methyl-7- tjlamir^thiazol_2U_^yJ.)_;2_^(2-_trit2lamino-_etho_2cyj; _imino)acet7 lami n.o ]_c e_phj; 3j; em - c arbo 33 l_a te. 0.923 g of the syn isomer of 2-(2-tritylamino-thiazol-4-yl)-2-(2-tritylamino-ethoxyimino)acetic acid, prepared according to the method described in Stage B of Example 14, were introduced into and then dissolved 3 in 6.5 cm of methylene chloride and 1.3 cnr of a solution of triethylamine, the triethylamine solution being prepared by mixing 1.4 cnr of triethylamine and a sufficient quantity of methylene chloride to obtain cm' of solution. After dissolution, the whole was cooled to -20°G, and 1.3 cm' of a solution of pivaloyl chloride (prepared by mixing 1.25 cm' of pivaloyl and a quantity of methylene chloride sufficient to obtain cm' of solution) were added. The temperature was then allowed to rise to -10°C and maintained there fore minutes, before being allowed to rise further to +10°C, at which point O./1.94 g of benzhydryl 7-amino- -desacetoxy-cephalosporanic acid were added. The whole was left to attain ambient temperature and was agitated for 1 hour 20 minutes, after which a further 77 mg of benzhydryl 7-amino-desacetoxy-cephalosporanic acid were added. After agitating for one hour and evaporating to dryness under reduced pressure, the residue was chromatographed on silica, eluting with a benzene ethyl acetate mixture (8:2), to obtain O.5O4 g of the desired 49867 product.

N.M.R. Spectrum (CDC1,) ' j 2.1 p.p.m. : methyl at 3 position 6.93 p.p.m.: proton of diphenylmethyl CH(f>2 5 Stage B: Th£ ^yn isomer__o£ ^-met_h^l^T^Gf (2-amino- thi a z,o 1.-4-^1 X-2.-L2^aminp3_ethox2_imino^-a.c_etvlaminoIceph--em-a-cartwx^lic_ac,id bis^ toifiuoroacetate^ 357 mg of the product obtained in Stage A were introduced into 3 cnr of trifluoroacetic acid, and 10 the solution formed was agitated for 2 hours 30 minutes and then placed in a bath of iced water before quickly adding under agitation a.0 cm' of a mixture (50:50) of isopropyl ether and petroleum ether (fraction 64-75°C). The whole was agitated for 10 minutes and the insoluble 15 matter was then vacuum-filtered, rinsed with isopropyl ether then diethyl ether and dried until constant weight to obtain 200 mg of white powder. M.p. * about 250°C with decomposition.

N.K.R. Spectrum (CH^gSO 20 2.03 p.p.m. : methyl at 3 position 6.88 p.p.m. : proton at 5 position of thiazol.

Example 21; The syn isomer of 3-acetoxymethyl-7~C2-(2--nmi nothiazol-a.-yl)-2-(2-bromoethoxyimino)acetvlamino] ceph-3-em-a-carboxylic acid trifluoroacetate.

St ape A: The syn isomer of t^-butyl 3-acetoxymethyl-7-C2-^( 2 - tr it^l a nd n ot h ia z ol ^a^y 1_) - 2^.( 2-bromo- et ho xy im in£ ) _ acet^l amino] ^ejJhj^^em-a-^arb oxalate.. 1.185 g of the syn isomer of 2-(2-tritylamino-thiazol-4-yl)-2-(2-bromo-ethoxyimino)acetic acid and 0.725 g of t^-butyl 7-amino-cephalosporanate were introduced into 20 cm' of methylene chloride. The whole was 3 cooled, and then under an inert atmosphere, 4.75 cnr of 0.5M dicyclohexylcarbodiimide solution in methylene chloride were slowly introduced. After agitating at 0° - +5°C for one hour 30 minutes dicyclohexylurea crystallises out, which after agitating for a further one hour at 20-25°G was separated by vacuum-filtration at 20°C, rinsing with methylene chloride. 0.293 g of dicyclohexylurea were obtained. The filtrate was brought to dryness under reduced pressure to obtain 2.09 g of impure product, which was purified by chromatography on silica, eluting with a mixture of benzene and sulphuric acid (1:1) to obtain 1.129 g of the desired product.

Stage B: The_jyra_isomer of 3~acetoxymethyl~7~C2-(2-jam in ot hi z£l ) z^-Z ( £-bromo_-et h ojcy imino ) ac et^l^ amino.]cefihj23-em-4-c_arbo_x2.li.c_ac.id. trifluoroacetate^ 1.301 g of product obtained from Stage A were introduced into 13 cm' of trifluoroacetic acid, and the whole was agitated at ambient temperature for 10 minutes, with total dissolution occurring after one minute of agitation in an inert atmosphere. The formed solution was distilled under reduced pressure to drive off trifluoroacetic acid whilst in a water «»867 bath at a temperature lower than 35°C, the distillation 3 being continued until a residual volume of about 5 cm was obtained. Whilst cooling further with an ice bath and whilst under agitation, U.2 cm' of isopropyl ether 5 were added, and a yellow precipitate was obtained, which after agitation at ambient temperature for a further 30 minutes was separated by vacuum-filtration, rinsed three times with 2.6 cm' of isopropyl ether and dried under reduced pressure at ambient temperature to 10 obtain 0.893 g of the desired product.

The preparation of the syn isomer of 2-(2-tritylamino-thiazol-ii.-yl)-2-(2-bromo-ethoxyimino) acetic acid used a3starting material in Stage A. a) Th£ 3jyn isomerjo£ ethyl _2-(2-trit^laminothiazol-15 _zaz7i)z2^(2-br£m£-ethoxyimi.no.)_a.cet.ate_I_ Under argon, a mixture of 4.94 g of ethyl 2-(2-tritylamino-<i-thiazolyl)-2-hydroxyimino-acetate hydrochloride, syn isomer, were introduced into 10 cm' of dimethyl formamide, and at ambient temperature 20 and over 3 minutes, 4.14 g of potassium carbonate were added. The whole was agitated for 20 minutes at 20°C before the addition of 8.65 cm' of 1,2-dibromoethane, and after agitation for a further 30 hours, the whole X was poured into a medium containing 100 cur of distilled 25 water and 20 cm' of methylene chloride. The organic aqueous phases were separated by decanting before extracting product from the aqeuous phase with methylene chloride, washing the combined organic phases with distilled water and re-extracting product from the washings. The entire organic phase was then dried, vacuum-filtered and distilled to dryness to give a 5 crude product, which was chromatographed on silica, eluting with benzene containing 5% diethyl ether.

A first fraction was collected, which was recrystallised from methanol after dissolving at 50-60°C and vacuum-filtering at 0° - +5°C. 1.16 g of cream white product 10 were obtained, m.p. = 11?°C, and subsequently a homogenous fraction of 1.258 g was obtained. b) The syn isomer of 2-(2-tritylaminothiazol-4-yl)-2-zJi 2 -bromo - et]i o xj imin^ ) a c et ic _a ci d.

Under argon, 2.88 g of ethyl 2-(2-tritylamino-15 thiazol-'!-yl)-2-(2-bromo-ethoxyimino) acetate, syn isomer, obtained from a), were introduced into 4.3 cm' of dioxan. The whole was agitated at ambient temperature in an inert atmosphere until dissolution after which over 3 minutes and at 20-25°C were added 30.6 20 cm' of 0.5M ethanolic solution of potassium in ethanol. After agitating at ambient temperature in an inert atmosphere for 24 hours, the potassium salt, which had crystallised out after 2 to 3 hours of reaction, was separated by vacuum-filtration at ambient temperature, 25 rinsing with 1 cm' of diethyl ether then three times with 2 cm' of methylene chloride, to obtain 1.6g of the desired salt. This was taken up with a mixture of cm' of distilled water, 10 cm' of methylene chloride and 1 cm' of 2N hydrochloric acid, which was then agitated in an ampoule for several minutes before the z x addition of 10 cnr of distilled water, 10 cm of 5 methylene chloride and 1 cm' of 2N hydrochloric acid. The methylene chloride phase was washed to neutrality with three times 20 cm' of distilled water, and the product was re-extracted from the washing waters with 10 cm' of methylene chloride. The methylene chloride 10 phases were then combined, dried, vacuum-filtered with rinsing and distilled to dryness to obtain 1.465 g of 3 resin. This was purified by taking up with 15 cnr of 1,2-dichloroethane and dissolving therein whilst heating to about 40°C. The temperature was then brought down to 20°G, when crystallisation started and the whole was agitated for 3 hours at 20°C. After vacuum- filtration, rinsing with 0.5 cm' of 1,2-dichloroethane and drying 1.185 g of a white product were obtained.

PI.p. = 150°C. Rf. = 0.65 (acetone containing 5% water).

Analysis : Calculated: 0% 58.21 H?4 4.13 W* 7-82 S% 5.98 Br% 14.89 Pound : C#58.0 E% 4.2 N% 7.8 S% 5.9 Br# 15.2 N.M.R. Spectrum CDCl^ p.p.m. 3,/i4 : (triplet) -CHg-Br J = 7.5 Hz 25 4.3 : (triplet) -N-O-CHg- J = 7 Hz 6.55 single : proton in 5-position of the thiazole.

Example 22: Sodium salt of 3-acetoxymethyl-7-C2-(2--aminothiazol-4-yl)-2-(2-bromoethoxyimino)-acetyl--amino]-ceph-3-em-a-carboxylic acid, syn isomer. 0.893 g of the trifluoroacetate obtained in x Example 21 and 3.5 cm of a molar methanolic solution of sodium acetate were mixed and agitated at ambient temperature under an inert atmosphere until dissolved, X then filtered and rinsed first with 1 cm , then twice 3 with 0.5 cm , of pure anhydrous methanol. 40 cur of absolute ethanol were added. Some cloudiness was observed and then the sodium salt precipitated. After agitation for 2 hours at ambient temperature, the salt formed was vacuum-filtered and rinsed three times with x x 1 cnr of absolute ethanol then three times with 3 cnr of diethyl ether. The salt was dried at ambient temperature under reduced pressure to obtain 0.545 g of product. Rf. =0.6 acetone containing 10% water Ca]2^ = +'.5° - 1.5° (c = 1% in H20) . Analysis : Calculated: C% 35.80 E% 3.00 N% 12.28 S% 11.2a Br% la.01 Found : C% 36.0 H% 3-1 11.9 S% 11.2 Br# 13.7 N.M.R. Spectrum (CDj)2S0. (p.p.m.) 2.0 : -0-g-CH^ 0 ~ 3.62 (triplet): -CH2~Br J = 6Hz a.33 (triplet): =N-0-CH2- J = 6Hz 48867 6.75 : proton in 5-position of the thiazole.

Example 23 •' The syn isomer of 3-acetoxymethyl-7~(2-(2--am-i nothiazol-a-yl )-C2-( 2-[2-aminophenvlthio3 -ethoxy---imi nr>')-acetylamino]-ceph-3-em-a.-carboxvlic acid.

Stage A: The s^yn ^S£mer_o_f ^-acjjtoxymethyl^- ;M2-(2-jtrityl-- a minojth^a^o-^1^.-2-^_2 - [ 2_ aminophenyithio]-_-eth£xx-i.iiii.n£)^:a£etyl.amino_]_-c_e£h^3^em-^_-£arbo_x^li^c_ac_id.

Successively 790 mg of 3-acetoxymethyl-7-C2-(2-trityalminothiazol-/:-yl)-2-(2-bromoethoxy-imino)-acetyl-10 amino]-ceph-3-em-a-carboxylic acid, 8 ml of benzene and 0.28 ml of pure triethylamine were introduced into the reaction vessel. After total dissolution, 0.14 ml of 2-ainino-thiophenol, 5 ml of distilled water and several mg of methyltricaprylammonium chloride were added. The 1^ mixture was agitated briskly for one right, then 2 ml of 1M hydrochloric acid were added and the mixture was extracted with ethyl acetate, washed with water, dried and concentrated to dryness. The residue was taken up with diethyl ether, and vacuum-filtered to obtain 690 20 mg of 3-acetoxymethyl-7_C2-(2-tritylaminothiazol-a-yl)--2-(2-C2-aminophenyl-thio3-ethoxy-imino)-acetylamino]--ceph-3-em-^-carboxylie acid.

Stage B: The syn isomer_o£ 3-ac^t^xymethyl-^-C2_-(2-_ zaminothiazoi-^-£l2-2-£_2-[2-aminophenyl-thiol-ethoxy- ^imino j-ac etyl amino>1 -ceph-3~em-&-carboxyl ic acid^ To the product obtained in Stage A 5.3 ml of 66°A aqueous formic acid were added, and the mixture was 4 9 O V I heated to 55°C for 15 minutes, cooled, and vacuum-filtered. The solvents were driven off from the filtrate by distillation under reduced pressure, and the residue was taken up with ethanol then distilled 5 to dryness under reduced pressure. The desired product was obtained and used without further purification in the following example.

The starting material for Stage A of this Example was prepared as follows. 26.85 g of the syn isomer of 2-(2-tritylanino-thiazol-4-yl)-2-(2-bromoethoxy-imino)-acetic acid prepared in Example 1, 7.25 g of 1-hydroxy 1 H-benzo-15 -triazol, 12 g of dicycloexylcarbodiimide and 350 ml of anhydrous methylene chloride were mixed and agitated for 23 hours at ambient temperature. The dicyclohexylurea thus formed was removed by vacuum-filtration, and the filtrate was washed with water, with a 1M aqueous 20 solution of sodium bicarbonate, then with water. The filtrate was dried, then concentrated to dryness under reduced pressure. The residue was taken up with 150 ml of ether and 25.4 g of crystals were obtained which were dissolved in 235 ml of anhydrous methylene chloride. 25 To the solution were added 10.56 g of 7~amino-cephalo-sporanic acid, 200 ml of anhydrous methylene chloride and 10.9 ml of triethylamine, and the mixture was agitated for 65 hours. 350 ml of water and 45 ml of 490U I 2N hydrochloric acid were then added and the formed mixture was agitated to effect extraction. The organic phase was washed then dried and concentrated to dryness under reduced pressure. The residue was taken up with 5 75 ml of ethyl acetate and diluted with 520 ml of diethyl ether, then vacuum-filtered to obtain 2a.75 g of the desired product.

Example 24: Sodium salt of 3-acetoxymethyl-7-C2-(2--arainothia2ol-4-yl)-2-(2-[2-aminophen,yl-thio3-ethoxy-10 -imino)-acetylamino3-ceph-3-em-carboxylic acid, syn isomer.

To the product obtained in Example 23 there were added 1.5 ml of a molar methanolic solution of sodium acetate and 1 ml of methanol. This was mixed, then 15 diluted with 6 ml of ethanol. The precipitated product was vacuum-filtered off, washed with ethyl alcohol, then made into a paste with ether to yield 235 mg of the desired product.

Analysis : Cg^^^^^^Na pM 614.65 20 Calculated: C% 44.94 H% 3.77 13.67 S% 15.65 Found : 4a.8 3.7 13.3 14.8 N.M.R. Spectrum (CD^gSO (p.p.m.) 1.99 . 4.08 : =N-0-CH2-25 6.73 : proton in 5-position of thiazole. 4 » » OY Example 25: The syn isomer of 3-aeetoxymethyl-7-C2-(2--aminothiazol-/i-yl)-2-([2-amino-l.3.4-thiadiazol-5-yl3--thio-ethoxy-imino)-acetylamino]-ceph-3-eI2-a-ca^boxylic acid.

Stage A: ^-£C£t£^nethyl>-2,-i2^>(2-trit2laminothia^25£l^4^ ^7l_)^2^(X.2^amino^lj3aa.-thiadi.az^ol_-^-jil^thio_]^e_th£XX-_ ^imino_}_-^ce^tilamiin.o>]^ceph-^-em-4^c-arbo2cyl.ic> .acidj. a) 1.9 g of 2-amino-5-mercapto-l ,3,4-thiadiazole were mixed with 15 ml of a molar solution of lithium methylate 10 in methanol. After total dissolution, the solution was concentrated to.dryness under reduced pressure to obtain the lithium derivative of 2-amino-5-thiol-l,3»i'—thia-diazole in the form of a resin which was used in that form. b) 7.91 g of the syn isomer of 3-acetoxymethyl-7-C2--(2-tritylaminothiazol-4-yl)-2-(2-bromoethoxy-imino)--acetylamino]-ceph-3-em-4-carboxylic acid prepared in Example 3 were introduced into 30 ml of anhydrous dimethylformamide and 670 mg of lithium iodide. After 20 dissolution the lithium derivative obtained above was added with 15 ml of dimethylformamide. The mixture was agitated for 5 and a half hours at ambient temperature, then 450 ml of water and 1 ml of formic acid were added. Then the mixture was extracted with ethyl 25 acetate, dried and concentrated to dryness under reduced pressure. The residue was chromatographed on silica eluting with a 70-20-10-1 ethyl acetate-methanol-water- » » O O 7 triethylamine mixture, to obtain 2.36 g of the desired product.

Stage B: j5-acetox;^j;tt^-2-J|2^( 2-jimJjiothiazo 1^4^.1 X.2^am i n °_^1_1.3j.4j^t h i £id ia^oj. -^-jl^t h io ]^e_tho_X2_-i.mi.n^-_ ^a£etjlamino]_-c_eEh^^em-4-c_arbox£lic_acid. 8&3 mg of the tritylated product of Stage A were agitated for 15 minutes at 55°C with 6.4 ml of 66% aqueous formic acid. The mixture was concentrated to dryness under reduced pressure and the residue was taken 10 up with 5 ml of ethanol and 50 ml of diethyl ether, then vacuum-filtered to obtain 606 mg of desired crude product.

Example 26; Sodium salt of 3-acetoxymethyl-7-C2-(2--aminothiazol-a-yl)-2-([2-amino-l.3.4-thiadiazol-5-yl-15 -thio ] -ethoxy-imino) -ac etyl amino ] -ceph-3-em-4-carboxyti.c acid, syn isomer.

The product obtained in Example 25 was mixed with 1.5 ml of molar sodium acetate in methanol and 0.5 ml of dimethylformamide. 5 ml of ethanol were added and the 20 precipitate thus formed was vacuum-filtered off, taken up with 7 ml methanol and refluxed, then cooled and vacuum-filtered to remove impurities. The filtrate was concentrated to dryness under reduced pressure, and the residue was broken up in ethanol, vacuum-filtered 25 and dried to obtain 146 mg of the desired product. Analysis : C^gH^gO^NgS^Na HI : 622.66 Calculated: C% 36.65 H% 3.08 N% 17.99 S% 20.60 Found : 37.0 3.7 17-5 19.8 ... 498 67 I J, N.M.R. Spectrum (CD^^SO p.p.m. 1.99 : -0-C-CHj 0 a. 25 : =N-0-CH~, 6.76 : proton in 5-position of thiazole.

Example 27: 3-acetoxymethyl-7-C2-(2-aminothiazol-4-yl)--2-(2-C 5-nitro-2-pyrid inyl-thio 3-ethoxy-imino)-ac ety1-amino]-ceph-3-em-a.-carboxylic acid, syn isomer.

Stage A: a^cet^xjmethjj^-T.-XS-(2_~trit£lamin£thiazo 1_24-Zjl) n2 - ( 2-_[_5-ni_t£0^2^pxr i_d irvjlut bio.] ^e£h£xj-imi. n o ) ^ 10 .^acetylami no]_-c_e_oh^3^em-a-c_arb£x^li.c_ac_i^.

Into a reaction vessel, 396 mg of 3-acetoxymethyl--7-[2-(2-tritylaminothiazol-4-yl)-2-(2-bromoethoxy-imino)--acetylamino]-ceph-3-em-4-carboxylic acid prepared in Example 3» a ml of benzene and 0.14 ml of trietfcyalmine 15 were successively introduced.

After dissolution 92 mg of 2-mercapto-5-nitro--pyridine, 5 ml of distilled water and several mg of ■ methyltricaprylammonium chloride were added, and the mixture was agitated for 72 hours at ambient temperature. 20 Then 1 ml of N hydrochloric acid was added and the whole extracted with ethyl acetate. The organic phase was dried then concentrated to dryness under reduced pressure. The residue was taken up with diethyl ether, and vacuum-filtered to obtain 416 mg of the tritylated product. 25 Stage B: ac et ox^met hy 1_-2~_C2_-( 2-amin ot hi a L? ~_ ^[^-nitro_-2-Eyridinyl_-thio_]_-ethoxy-imino^-jic£t2lamino]^ ^ceph-j5-£m-4-carboxyl^ic_ jicid^ 49867 To the product obtained there were added 3*2 ml of 66% aqueous formic acid and the mixture was heated to 55°C for 15 minutes. The triphenylcarbinol thus formed was removed by vacuum-filtration, and the 5 filtrate was concentrated to dryness under reduced pressure. The residue was taken up with ethanol and concentrated to dryness again to obtain the desired product.

Example 28; Sodium salt of 3-acetoxymethyl-7-C2-(2-10 -aminothiazol-4-yl)-2-(2-[5-nitro-2-pyridinyl-thio]--ethoxy-imino)-acetylamino]-ceph-3-em-a-carboxylic acid, syn isomer.

A little methanol was added to the product obtained in Example 27, followed by 2ml of a molar methanolic 15 solution of sodium acetate. The traces of insoluble matter were removed by vacuum-filtration, and the filtrate was concentrated to dryness under reduced pressure. The residue was taken up with ethanol, and vacuum-filtered to obtain 153 mg of the desired sodium 20 salt.

Analysis : ^2^20® PM = 645-63 Calculated: C% 40.93 3.12 N% 15.19 S% 14.90 Found : 39.0 3.3 13.2 12.9 N.M.R. Spectrum p.p.m. 2.0 : -0-fjl-CHj 0 0*3.86 - 4.3 - 4.4 : =N-0-CH2- 6.76 : proton in 5-position of thiazole. 49867 ( Evample 2Q; The syn isomer of 5-acetoxymethyl-7-C2-(2--aainothiazol-a-yl)-2-(-C 3-cvano-6-methyl-2-pyridinyl--thio3-etyoxy-imino)-acetylamino3-ceph-3-em-a-carboxylic acid.

Stage A: i-^c^t2xjTiiethyl.-2-I.2^.(2-tritila^minothiaz£l^--y]J ^2^(, £-X.3z.ciano_6^me>t hy I72,-jjyri diny1 -1 h io3_- ethoxy-imi,no)-ac>etyl^aminoj_-c.e£h^3-em-a-c>arboiX2li,c_ac.id. 791 mg of 3-acetoxymethyl-7-C2-(2-tritylamino-thiazol-a-yl)-2-(2-bromoethoxy-imino)-acetylamino3-ceph-10 3-em-a-carboxylic acid prepared in Example 23 were mixed with 326 mg of 2-mercapto-3-cyano-6-methyl-pyridine, 10 ml of benzene, 0.'i2 ml of triethylamine, 10 ml of water and several milligrams of methyltricaprylaomonium chloride. The mixture was agitated for aa hours at ambient 15 temperature, then acidified with 3 ml of N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and concentrated to dryness under reduced pressure. The residue was taken up with diethyl . ether, and vacuum-filtered to obtain 877 mg of a crude 20 product.

Stage B: The syn isomer of 3-acetoxymethyl-7-£2-(2-^ j2aninot_hiazol-Ai.-^l^-2^2^[^-cyano--6-methxl-22PZT,idin2.1.z ^t hi o_3 ^ej; h ox^-mino ) -acetyl amino -c e ph- 3 -em-a-c arboxylie acid_.

To the product obtained in Stage A there was added 7 ml of 66% aqueous formic acid and the mixture was heated to 55°C for 15 minutes with agitation, then * a a or cooled and vacuum-filtered. The solvents were driven off from the filtrate by distillation under reduced pressure, and the residue was taken up with ethanol and concentrated to dryness to obtain a crude product which was purified by forming the sodium salt and treating this with formic acid.

Analysis : 02^2^0^^^ FM * 617.69 Calculated Found C% 46.67 H% 3.75 N% 15.87 S06 15.57 46.2 3.8 15.2 la.5 N.M.R. Spectrum (DMSO) p.p.m. 2.0 : 0-C-CH, « l 0 ^&.2 - 4.3 - 4.a : =N-0-CH2 6.8 : proton in 5-position of thiazole.

Example 30: Sodium salt of 3-acetoxymethyl-7-C2-(2-15 -aninothiazol-»-yl)-2-(2-C3-cyano-6-methyl-2-pyridinyl--thio3-ethoxy-imino)-acetylamino]-ceph-3-em-*i-carboxylic acid, syn isomer.

To the product obtained in Example 29 there were added 5 ml of methanol then 4 ml of a methanolic 20 solution of sodium acetate. The mixture was concentrated to dryness under reduced pressure, then the residue was broken up in ethanol and vacuum-filtered to obtain 505 mg of the desired sodium salt.

Example 31: The syn isomer of 5-acetoxymethyl-7-C2-(2-25 -aminothi a zol -4--y 1) -2-C 2- [ 1 -methyl -t etrazol -5-y 1 -thio ] --ethoxy-imino)-acetylamino]-ceph-3-em-a.-carboxylic acid. 49867 Stage A: Thje syn is£nier_o_C 3-acetoxymethyl-7-C2-(2- zt r_ityia mi no_thi_az_o 1^-/1^-^1 1,-m e th^l etra_zo_l-5,-^1^ amino ^th>io_]^eth£Xj-imin£)-a£e_ty^^ce£h-3^em-^-c_arb£X2.1ic_ acid. 432 mg of the diethylamine salt of 3-acetoxymethyl- -7-C 2-(2-tritylaminothiazol-a-y1)-2-(2-bromo ethoxy--imino)-acetylamino]-ceph-3-em-4-carboxylic acid, syn isomer were mixed with 6a mg of l-methyl-5-mercapto-l, 2,3,4-tetrazole and 2.2 ml of anhydrous dimethyl-10 formamide. The mixture was heated for 1 hour 50 minutes in a water bath at 50°C with agitation, then maintained for 1 hour 30 minutes at ambient temperature, and finally for 1 hour 10 minutes at 55°C. The mixture was cooled, diluted with 20 ml of water, agitated and 15 the formed precipitate was vacuum-filtered to obtain a06 mg of a crude product.

Stage B: The ssyn isomer o£ 3- acet£xymethy2 ^aminothj1az:ol.-a-xli-£-i^-I.lz.ni£thyl-tetraz^lj;5^yl.-thio2.-j^etho_x;£-imino) -acetylamino-ceph-3-em-a-carboxylic a.c_id^_ 20 /^06 mg of the product obtained in Stage A were dissolved in 3.2 ml of 66% aqueous formic acid, and the solution was heated in a water bath at 55°C for 15 minutes. The triphenylcarbinol formed was removed by vacuum-filtration and the aqueous formic acid was 25 driven off by distillation under reduced pressure. The residue was taken up with ethanol and again concentrated to dryness. 3 ml of methanol were added to dissolve the residue and the solution was diluted with 50 ml of diethyl ether, and the precipitate formed was vacuum-filtered to obtain 201 mg of a crude produce which was dissolved in 1 ml of hot methanol and reprecipitated 5 by adding 5 ml of ether. Vacuum-filtration yielded 171 mg of the desired product.

Analysis : <^19^21^7N9®3 Calculated: C% 39.10 H% 5.63 N?S 21.6 S% 16.a8 Pound : 39.6 3.7 20.9 16 N.M.R. Spectrum (CD^^O p.p.m. ,o3 , -o-ri а.33 (triplet): sN-O-CHg (J • 6 Hz) б.76 : proton at 5-position of thiazole 3.91 (single) : =N-CH5 The diethylamine salt of 3-acetoxymethyl-7-C2-(2- -tritylaminothiazol-a-yl)-2-(2-bromoethoxy-imino)-acetyl-aminoJ-ceph-3-em-'i-carboxylic acid, syn isomer, was prepared as-follows: 0.79 of 3-acetoxymethyl-7-C2-(2-tritylamino-20 -thiazol-4.-yl)-2-(2-bromoethoxy-imino)-acetylaninoJ- -ceph-5~em-4.-carboxylic acid was added to 5 cm of ethyl acetate. On total dissolution, 0.12 cm' of diethylamine were added, and the mixture was agitated, vacuum-filtered and rinsed with ethyl acetate to obtain the desired salt 25 after drying.

Example 52; The syn isomer of 5-acetoxymethyl-7-E2-(2--aininothiazol-a-yl)-2-(2-azido-ethoxy-imino)-acetylamino3- -ceph-5-em-a-carboxylic acid.

Stage A; Thje syn isomer_of 2-(2-1ri£yl^amino_thi^az^o 1^-a _=yl^)-2^(£-_azid£-e>tho2cy_^imino^_-ace_ti_c_ac.id.

For one hour in a water bath at 50 °C, 2a.8 g of sodium 2-(2-tritylamino-thiazol-4--yl)-2-(2-bromoethoxy--imino)-acetate were agitated with 125 ml of dimethylformamide and 7.5 g of tetramethylguanidine azidide.

After agitation for a further 45 minutes a clear brown solution was obtained, and this was cooled to ambient temperature. 500 ml of water and 50 ml of 2N hydro chloric acid were added, and the mixture was vacuum-filtered, made into a paste three times with water, then ground up in methylene chloride. The filtrate was decanted, washed with water then dried. After concentration to 50 ml under reduced pressure 250 ml of diethyl ether were gently added, and the mixture was vacuum-filtered to obtain 15.58 g of the acid.

The sodium salt of 2-(2-bromoethoxy-imino)-2--(2-tritylaminothiazol-4-yl)-acetic acid, syn isomer, was prepared as follows: 6 g of sodium carbonate pellets were added to 280 cm' of absolute ethanol. 28.2 g of ethyl 2-(2--bromo-ethoxy-imino)-2-(2-tritylamino-thiazol-4-yl)--acetate, syn isomer (described in Example 21) were added, and the mixture was agitated for 65 hours at ambient temperature. The sodium salt separated, and this was vacuum-filtered, washed with ethanol and dried in vacuo to obtain 29.82 g of the desired product as a 12% solvate.

Stage B: Th£ syn isomer_of 5 -acetoxyme t h y 1_~7 ^tritylaminothiazpi-a-^l^-^-^^a^ida^ethax^imino)^ ^ac_etyl_aminoJ_-c.e£h^i5^em-a-c_arbo-3(2;li_c_ac_id in_the__fjorm £f_i£s_die;th£lainine salt^ 2.54 g of 7-amino-cephalosporanic acid, 25 ml of 10 anhydrous methylene chloride and 2.6 ml of triethylamine were agitated for 15 minutes at ambient temperature. 6.02 g of the 2-(2-tritylamino-thiazol-4-yl)-2--(2-azido-ethoxy-imino)-acetate of 1-hydroxy-lH-benzo-triazole were added and the mixture was agitated for 45 15 hours at ambient temperature. 25 ml of water and 5 ml of N hydrochloric acid were added. The mixture was separated by decantation, and the organic phase was washed with water, dried and concentrated to dryness under reduced pressure. The residue was taken up with 20 30 ml of ethyl acetate, and after dissolution, 2.4 ml of diethylamine were added. The mixture was cooled to 0°C and vacuum-filtered to jaeld 5.9 g of the diethylamine salt.

The 2-(2-tritylamino-thiazol-4-yl)-2-(2-azido-25 -ethoxy-imino)-acetate of 1-hydroxy-lH-benzotriazole used in Stage B was prepared in the following way: 9.84 g of 2-(2-tritylamino-thiazol-4-yl)-2-(2- -azido-ethoxy-imino)-acetic acid was mixed with 2.95 g of 1-hydroxy-lH-benzotriazole, a.86 g of dicyclohexyl-carbodiimide and 130 ml of anhydrous methylene chloride, and the mixture was agitated for 20 hours at ambient temperature. The dicyclohexylurea formed was removed by vacuum-filtration, and the filtrate was washed with water to which had been added sodium bicarbonate, then with water alone. The washed filtrate was dried and concentrated to dryness under reduced pressure. The residue was taken up with ethyl acetate, cooled for half an hour at 0°C and suction-dried to obtain 7.31 g of the desired product. A further 1.5 g of product was recovered from the mother liquors.

Stape C: The syn isomer_o_f 3-£C£toxym£thyl-7~£2^(£-_ ^aminotMazpl.-/t-;£l^T2-_(_2-a^i4o-ethj>X£-imino)^acet,yl-amino]eph-c^rboxyl_ic_ acidj.

For 15 minutes at 50°G 1.238 g of the product obtained in Stage B were agitated with 6 ml of 70% formic acid. The triphenylcarbinol formed was removed by vacuum-filtration and the filtrate was concentrated to dryness under reduced pressure. The residue was taken up with water, broken up, vacuum-filtered and dried to obtain 0.358 g of the acid.

Example 35: Sodium salt of 5-acetoxymethyl-7-C2-(2--amino-thiazol-4--yl)-2-(2-azido-ethoxy-imino)-acetyl-amino]-ceph-5-em-a-carboxylic acid, syn isomer. 0.585 g of the acid obtained in Example 32 was - laO - mixed with 1 ml of a methanolic molar solution of sodium acetate. To the clear solution thus obtained were slowly added 5 ml of ethanol. The mixture wgs vacuum-filtered and rinsed with ethanol, then with diethyl ether to obtain 0.215 g of the sodium salt.

Analysis : = 532. 49 Calculated: C% 38.4 H% 3.2 N% 21.0 S% 12.0 Found : 38.3 3.2 20.4 12.1 N.M.R. Spectrum /(CD^^SO p.p.m. 1.98 = -0-C-CH3 0 4.18 (triplet) : =N-0-CH2- J=5 Hz 6.76 : proton at 5 of thiazole.

Example 34: The syn isomer of 3~acetoxymethyl-7-C2-(2--ainino-thiazol-a-yl)-2-(2-anino-ethoxy-imino)-acetyl-15 amino]-ceph-3-em-a-carboxylic acid.

Stagjs A: The syn isom£r_of 2"£C£t£X^£thyl-7-£2_2( 2-_ ^trityl_aininotihi>az^c)jL-4-2,l^_-2-^2^amino^thoxy^iminp2-a^ce^t2.1^ a.nuno]?irb oxy li £ acid^ 0.752 g of 3-acetoxymethyl-7-C2-(2-tritylamino-20 -thiazol-4-yl)-2-(2-azido-ethoxy-imino)-acetylamino3- -ceph-5~em-4-carboxylic acid prepared in Example 32 were mixed with 4 ml of dimethylformamide and 0.7 ml of anhydrous triethylamine. Hydrogen sulphide was bubbled into the mixture £or 15 minutes, and 40 ml 25 of water then 0.7 ml of acetic acid were added. After vacuum-filtration 0.70? g of a crude product were obtained. «09 V | Stage B: Th£ syn i^som£r_o£ .3~iLc£t £X^£t hy 1-72^(2- ^aminoihiaiolrii-2lX~2-£22amino^ethoxj-imino_)^ac.etyl>-amino]-cephem^^c^rboxyiic, jicicL. 1.054 g of the product obtained in Stage A were heated for 15 minutes at 50°C in 5 ml of 70% formic acid. The triphenyl carbinol formed was removed by vacuum-filtration and the filtrate was concentrated under reduced pressure. The dry residue was taken up with water and the insoluble matter eliminated. The filtrate was concentrated to dryness and taken up with ethanol, broken up and vacuum-filtered to obtain 0.125 g of the acid.

Example 35? Sodium salt of 3-acetoxymethyl-7~C2-(2--aminothiazol-&-yl)-2-(2-amino-ethoxy-imino)-acetyl-amino3-ceph-3-em-4-parboxylic acid, syn isomer.

The product obtained in Example 34 was dissolved in 0.2 ml of a molar solution of sodium bicarbonate. 0.4 ml of ethanol were carefully added, and the insoluble matter was removed by vacuum-filtration. The filtrate was concentrated to dryness under reduced pressure, and the residue was taken up with ethanol, crumbled and vacuum-filtered to obtain O.O/1.7 8 the desired salt.

Example 36: The syn isomer of 3~C(l-methyl-lH--t etrazol-5-yl)-thiomethyl3-7-[2-C 2-aminothiazol-a--yl)-2-(2-azido-ethoxy-imino)-acetylamino3-ceph-3-em--a-carboxylic acid.

Stage A: The syn isomer_o£ ^^Lz2.1^— ^]J^thiom£tl^l.3^7z^-£2^t^i^]^aminothiazpl.-^L-;£l2~2-_ ^(2-^zid£^ethoxy2imino2_acetj£la^mino3-ceph-2-jein-''i^ ^carbosgylic acid.

For 15 minutes at ambient temperature 0.652 g of 7-amino-3-C(l-methyl^etrazol^-yO-thio-methyl]--ceph-3-em-/i-carboxlic acid were agitated with 6.5 ml of methylene chloride and 0.56 ml of triethylamine. 1.29 g of the a-(2-azido-ethoxy-imino)-2-(2-tritylamino-10 -thiazol-4-yl)-acetate of 1-hydroxy-lH-benzotriazole prepared as described in Example 32, Stage B, were added, and the mixture was agitated for 20 hours at ambient temperature. 10 ml of water and 3 ml of 2N hydrochloric acid were added. The mixture was separated 15 by decanting and the organic phase was washed with t water, dried and concnetrated to dryness under reduced pressure. The residue was taken up with 5 ml of ethyl acetate and 10 ml of diethyl ether were added. The mixture was agitated for half an hour at ambient 20 temperature, and vacuum-filtered to obtain 1.416 g of a crude product.

Stage B: Th£ syn isomer of J-^C^-methyl-lH-^e^r^zol^^yl)^ -thiomet hy 1] z.7— ^ ii-iL2^amino thi_a zo l^-^-^l^-^-^^a^i do_2 -et hoxy-imino ) -ac etyl amino ] -ceph-^-jsm^a-c arbojgrjjlf: acid^ 25 For 15 minutes at 50°C 1.336 g of the product obtained in Stage A were agitated in 7 ml of formic acid. Tne triphenylcarbinol formed was removed by vacuum-filtration and the filtrate was concentrated to dryness under reduced pressure. The residue was taken up with water, broken up and vacuum-filtered to obtain 0.77 g of a crude product which was dissolved in a 5 minimum amount of a 10% sodium bicarbonate solution. 0.07 6 of active charcoal were added, and the mixture was vacuum-filtered. To the filtrate formic acid was added to give a pH of 2. The purified acid was vacuum-filtered to obtain 0.171 g of the desired product. 10 Example 37; Sodium salt of 3-C(l-methyl-lH-tetrazol-5-yl)--thiomethyl]-7-C2-( 2-aminothiazol-'!-yl)-2-( 2-azido--ethoxy-imino)-acetylamiho]-ceph-3~em-a-carboxylic acid, syn isomer. 0.162 g of the purified acid obtained in Example 15 36 were dissolved in 0.3 ml of a molar solution of sodium bicarbonate. 1 ml of ethanol was added and the insoluble matter was vacuum-filtered off. The filtrate was concentrated to dryness under reduced pressure, and the residue was taken up with ethanol, broken up Tnd 20 vacuum-filtered to obtain 0.09 g of the sodium salt. Analysis : C^yH^Oj-N^S^Na ; = 588.58a Calculated: C% 34.7 H% 2.9 N% 28.5 S% 16.3 Pound : 34.5 3-2 25.3 15.3 N.M.R. Spectrum (CDj)2S0 p.p.m. 3.9 : N-C£j 6.76 : proton in 5-position of thiazole, 9.35-9-^8 : -CONH- - 1/lii - Example 58: The syn isomer of 3-£(l~methyl-lH-tetrazol--5-yl)-thiomethyl]-7-C 2-(2-aminothiazol-ft--yl)-2-(2--amino-ethoxy-imino)-aeetylamino]-ceph-3-em-4--cstrboxylic acid.

Stage A: l_-meth^l-lH-t>e_traz£l-5^yl.)^thiomethyJL]-7-^[2-i.2-tritjl>amino-thi^zol^4iyl.)^2;C^-amino.-etho2y-j^imino.}_-jice tjr 1 amino];ic eph-_2-em-a-carboxyl_ic_ .acid^ .91 g of sodium 3-C(l-methyl-lH-tetrazol-zi-yl)--thiomethylJ-?-2-(2-tritylamino-thiazol-a-yl)-2-(2-10 -azido-ethoxy-imino)-acetylamino]-ceph-5-em-a.-carboxylate were dissolved in 39 ml of dimethylformamide. 20 ml of water were slowly added, followed by 9.75 ml of triethylamine. Hydrogen sulphide was bubbled into the mixture. After 4.5 minutes, 3-9 ml of triethylamine were added and 15 the bubbling in of hydrogen sulphide continued for a further 15 minutes. The mixture was poured into a solution of dilute hydrochloric acid at 10°C, and the whole was heated for 15 minutes at 30°C under agitation, . then cooled, and vacuum-filtered. The precipitate was 20 washed until neutral and rinsed with diethyl ether to obtain 2 g of the desired product.

The sodium 5-C(l-methyl lH-tetrazol-5-yl)-thio-methyl]-7-C2-(2-tritylamino-thiazol-'i.-yl)-2-(2-azido-ethoxy-imino)-acetylamino]-ceph-5-em-/i-carboxylate used 25 at the beginning of the Example wa3 prepared as follows: For one hour at ambient temperature 8.47 g of the syn isomer of 2-(2-tritylaminothiazol-ii-yl)-2-(2-azido--ethoxy-imino)-acetic acid obtained in Example 32 were *«BO( - 145 " agitated with 50 ml of methylene chloride and 1.93 6 of dicyclohexylcarbodiimide. The dicyclohexylurea was removed by vacuum-filtration. The filtrate was added, over 20 minutes, to a mixture consisting of 3.07 g of 5 3-C(l-methyl-lH-tetrazol-5-yl)-thiomethyl]-7_amino-ceph--3-em-4--carboxylic acid, /i-O ml of anhydrous methylene chloride and 3-9 ml of triethylamine. After agitation for a further hour the mixture was concentrated to dryness under reduced pressure. The residue was taken 10 up with 50 ml of ethyl acetate at 20°C, acidified with 0.2 ml of acetic acid and vacuum-filtered. The filtrate was washed with N hydrochloric acid, then with water until neutral. The organic phase was dried *nd made up to a volume of 50 ml, then 1.7 ml of diethylamine were added. The salt of the starting acid crystallised, and » was removed by vacuum-filtration. The filtrate was precipitated with 115 nil of isopropyl ether. The precipitate was vacuum-filtered to obtain 7.62 g of the diethylamine salt. 5.9 E of this salt was taken up 20 and dissolved under agitation in a mixture of 60 ml of water, 60 ml of methlene chloride and 3.5 ml of 2N hydrochloric acid. The mixture was separated by decanting and the organic phase was washed with water, dried and concentrated to dryness under reduced pressure. 25 The residue was taken up with 20 ml of isopropyl ether and vacuum-filtered to obtain 5.6 g of the free acid.

This latter was dissolved in a mixture of 9.5 ml of 49867 methanol and 6.7 ml of a 1M methanol solution of sodium acetate. The sodium salt was precipitated with 27 ml of isopropanol containing 25% ethanol, then diluted with 270 ml of isopropanol to obtain 4.21 g of 5 the desired product.

Stage B: The syn isomer of 3CQ.-methyl-lH-tetrazol-5-yl)-ctbiom® t hy_l ] j^7 ~ £ 2-£_2 - a mi n oM; h ia z ol .^2 - ( 2-ja mino- eth o xy^im i n o X-^c^t;£l ami no ] -c eph-c ji rb oxyl ic_ jicid^ 2g of the product obtained in Stage A were heated 10 to /iO-&5°C under agitation with 5 ml of formic acid. ml of water were added and the temperature maintained for 15 minutes. The mixture was then cooled and the triphenylcarbinol formed was vacuum-filtered off. The filtrate was concentrated to dryness under reduced 15 pressure. The residue was taken up with 10 ml of ethanol, broken up, vacuum-filtered and rinsed with ethanol then with diethyl ether to obtain 1.36 g of a crude product which was taken up with 15 ml of 2N hydrochloric acid. The insoluble matter was vacuum-20 filtered off and the filtrate was then brought to pH 4 by the addition of 3 ml of an aqueous 1M solution of lithium acetate, then an aqueous solution of lithium hydroxide. The mixture was vacuum-filtered and the filtrate was concentrated to dryness under reduced 25 pressure. The residue was taken up with 30 ml of ethanol, broken up and vacuum-filtered to obtain 515 mg. of the desired product. 133 mg of the product were 49867 / recovered from the mother liquors. The two products were treated again in the same way as the crude product and /j-30 mg of a white product were isolated. N.M.R. Spectrum (CD^gSO p.p.m. 6.86 : proton at 5-position of thiazole Example 39; Trifluoroacetate of 5-acetoxymethyl-7-C2--(2-aminothiazol-a.-yl)-2-(2-iodoethoxy-imino)-acetyl-amino] -ceph-3-em-ft-carboxylic acid, syn isomer.

Stage A; Benzhydr2£l_3^a£etp2grmeth;£l-7-[2-i.2~tri_tyl__ aminot hiazol -4-;j^-2-£2^i<3doe thoxjr-imino.) ^_a£etyl_amino_]_--ceph-3-em-a-carboxylate, syn isomer.

Under an inert atmosphere 1.28 g of the syn isomer of 2-(2-iodo-ethoxyimino)2-(2-tritylamino-thiazol--a-yl)-acetic acid solvated with 1,2-dichloroethane (being 15 in fact 1.09 g of pure product) were mixed with 1.&5 g of the benzh.ydryl ester of 7-amino-cephalosporanic acid in 22 cm' of anhydrous methylene chloride. The mixture was cooled in an ice bath and, drop by drop, . 5 cm' of a 0.5M solution (being 103 g/litre) of 20 dicyclohexylcarbodiimide in methylene chloride were introduced. After agitation at 0° to *5°C for one hour thirty minutes, then for one hour at 25°C, the precipitated dicyclohexylurea was vacuum-filtered off, rinsing with methylene chloride. The filtrate and the 25 washing waters were evaporated to dryness at a temperature lower than /iO°C under reduced pressure to obtain 2.98 g of a product which was chromatographed on silica eluting with a 92-8 methylene chloride-ethyl taoo i acetate mixture. 1.12 g of white product were obtained. U.V. Spectrum (Ethanol/N hydrochloric acid) T no max. = 269 nm = 209 I.R. Spectrum (chloroform) = p-lactam : 1791 cm 5 G=N-0R: 1042 cm"1; C=C: 1638 cm"1 N.M.R. Spectrum (CDCl^) proton at 5-position of thiazole: 6.75 p.p.m.

Stajre B: Trifluoroacetate_of c j? t oxjm et hyl-_2-£2 - ( ^ami ri o_t hd^a^.0 l_-ii-2.1^_-£-X.2j;i£d o.e tho,X2-i.mlno )j; a^ejt y lam i no_]_-10 -c e nh - 5 - e m-4-carb£xylic_acidsjnis ome r. 960 mg of the product obtained in Stage A were Z introduced into 10 cnr of pure trifluoroacetic acid.

The mixture was agitated for 3 minutes at ambient temperature, cooled for one minute in an ice bath and x then precipitated by the addition of 100 cnr of iced isopropyl ether. After agitation for 10 minutes at ambient temperature, the precipitate was vacuum-filtered rinsing it with isopropyl ether then with diethyl ether, and dried under reduced pressure to obtain 460 mg of 20 the desired product, m.p.^ 2l4°C.

Analysis : C^^H^gN(-0r7SI, CFjCO^ Calculated: N% 9-87 S% 9.0a Found : 9.7 9.2 U.V. Spectrum (Ethanol; N hydrochloric acid) , to max. 262 nm EJ = 290 N.M.R. Spectrum /(CDg)^^/ proton at 5-position of thiazole : 6.83 p.p.m.

The syn isomer of 2-(2-iodoethoxyimino)-2-(2--tritylaminothiazol-4-yl)-acetic acid used at the beginning of Example 39 was prepared as follows: a) Ethyl 2-J[_2j;i£doe^hox2iminoJ_-2-X.2_2tr^ijtylaminoj; thia zo 1 -Ji -yl) -ac^t ate ,_sjn_isomer. 6 g of Ethyl 2-(2-bromoethoxyimino)-2-(2-trityl-aninothiazol-4-yl)-acetate, syn isomer (prepared as in Example l) were introduced into 60 cm' of of methyl-ethylketone and 2.141 g of sodium iodide. The mixture was refluxed for an hour and 10 minutes, and then was evaporated under reduced pressure. The residue was taken up with 120 cm' of methylene chloride and washed five times in 40 cm of water. Each washing was re-extracted with 2 cm' of methylene chloride and the organic phase was dried and evaporated to dryness. The resin obtained was added to diethyl ether, and dried under reduced pressure to obtain 6.22 g of product. M.p. = 110°C. b) Thji syn isomer of 2-(2-iodoethoxyimino)-2-(2-^tritjlaminojthi.azpl_-_^-;£l_)_-.acetic_acid.

Under an inert atmosphere 6.7 6 ethyl ester prepared in Stage a) were introduced into 5.5 cm of dioxan and 44 cm' of absolute ethanol. Drop by drop 5.5 cm' of a 2N solution of sodium carbonate were added then 7 cm' of absolute ethanol were added, and the mixture was agitated for one night at ambient temperature. The sodium salt thus formed was vacuum-filtered rinsing twice with 3 cm' of a 4-1 ethanol-dioxan 49867 solution and then formed into a paste with diethyl ether. The product obtained was treated in a separating funnel with 100 cm' of water and 100 cm' of chloroform. The pH was adjusted to 2 with normal hydrochloric acid.

The organic phase was decanted, washed with a saturated solution of sodium chloride, dried and evaporated under reduced pressure. The resin thus obtained was dissolved at 40°C in 35 cm' of dichloroethane. Crystallisation was initiated, and the solution was left at ambient 10 temperature for 72 hours. The formed precipitate was vacuum-filtered, rinsed and dried.to obtain 5,a g of a white product solvated with dichloroethane (being 4.61 g of pure product) m.p. = 161°C.

Analysis 15 Calculated Found G26H22°3N3SI = 583-'s N% 6.16 S% 4.70 .9 4.8 U.V. Spectrum (Ethanol. N hydrochloric acid) i To 278 nm = 235 N.M.R. Spectrum (CDCl^) proton at 5-position of thiazole : 6.58 p.p.m.

Example a.0; N-C2-( 2-C ( 2-carboxy-3-methyl-8-oxo-5-thia- -l-azabicyclo[4.2.03oct-2-en-7-yl)-amincil-l-[2-amino- thiazol-4-yl]-2-oxo-ethyl)-iminoxy-ethyl3-pyridinium iodide trifluoroacetate double salt, syn isomer.

Stage A: Benzhydr^l_3jimethyl.-2-X.2^(£-t_ri.t^laimi_n£thi^Z£lj: z4l^i);;2^(2-bromoeth£x;£-imin£)^acetylamino]_-cenhz.3z.eJIi- -'i-carboxylate, syn isomer. 49867 - 1S1 - Under an inert atmosphere 536 mg of the syn isomer of 2-(2-bromoethoxyimino)-2-(2-tritylaminothiazol--a-yl)-acetic acid were introduced into 380 mg of the beniiydryl ester of 7~amino-3-desacetoxycephalosporanic x acid and 6 cm of anhydrous methylene chloride. The mixture was cooled in an ice bath and after 5 minutes 230 mg of dicyclohexylcarbodiimide were added and rinsed * with 2 cnr of methylene chloride. The mixture was kept for two hours at 0° to +5°C, then for one hour at 10 ambient temperature, and vacuum-filtered washing the insoluble matter three times with methylene chloride (and collecting 111 mg of product). The filtrate was brought to dryness and 1.02 g of resin were isolated. Thi3 product was purified by fixing it on 100 g of 15 silica and eluting with a 17~3 benzene-ethyl acetate mixture. 5a.8 mg of resin were obtained. Rf = 0.27-0.28 with preceding eluant.

N.M.R. Spectrum proton at 5-position of thiazole: 6.75 p.p.m.

-CI^-Br - triplet centred on 3.58 p.p.m. J « 7 Hz.

Stage B: N-_[_2^(2-_[_(2-di£hen<2.1methj^l£arbqnylox^-2-metJi)yTj8^ ^°xo^5^thi a-^-az abi c£c lo_T4JL2Ap2pat^2^en-2-Z.li.-ami n£] ^1^ [2-trity1aminothiazol-4-yl]-2-oxo-ethyl)-iminooxy-ethyl]- ^pyrj^dinium iodide^ j3yn £soraer.

Under an inert atmosphere 500 mg of the product obtained in Stage A were introduced into 115 mg of x pyridine iodhydrate in 5 cnr of pyridine. The mixture 49867 was heated at 50°C for 15 hours then evaporated under reduced pressure at a temperature lower than 40°C. The residue was taken up with methanol and evaporated four times in succession to drive off residual pyridine, 5 then dried under reduced pressure to obtain 620 mg of a crude product. This crude product was purified by chromatography on silica, eluting with a 85-15 chloroform-methanol mixture, to obtain 348 mg of a purer product in the form of resin.

N.M.R. Spectrum (CD^gSO proton at 5-position of thiazole : 6.81 p.p.m.

Stage C: N-_C2^(2-_[_(£-£arb£X^-^.-ne_th^l^8-0X0^52.thia-l^-_ -azabicyclo[4.2.0]oct-2-en-7-yl)-amino]-1-C 2-amino-thia^°i-a-jl2-2-£xo-£thyl)^iminqox2]eithyil]^P2ridiruum 15 £odide_trifluoroac£t?at£_doubl£ salt^ jyn isomer^ 300 mg of the product obtained in Stage B were added to 3 cnr of pure trifluoroacetic acid. The solution was agitated for 3 minutes at ambient temperature and cooled for 20 seconds in an ice bath. A 2 precipitate was formed by adding 40 cnr of an iced 1-1 mixture of isopropyl ether and petroleum spirit B (boiling fcoint between 65 and 75°C). The precipitate was vacuum-filtered, rinsed with isopropyl ether, then with diethyl ether and dried to obtain 152 mg of a 25 powder, m.p. 222°C.

Rf = 0.05 (acetic acid-ethyl acetate-water 70-35-10) U.V. Spectrum (Ethanol; N hydrochloric acid) 49867 max. = 260 nm E^ = 355 I.R. Spectrum p-lactam 1768 cm 1 0=N-0R 1038 cm-1 N.M.R. Spectrum /(CDj^SO/ proton at 5-position of thiazole = 6.76 p.p.m.

Example /tl; Trifluoroacetate of 3-acetoxymethyl-7-C2--( 2-aminothiazol-a-yi)-2-(2-diinethyIaminoethoxy-imino)--acetylamino]-ceph-3-em-a-carboxylic acid, syn isomer. 10 Stage _A: ^driodic. _of_2^(£-d_imet_h^l_ami_n£etho.x^imino_}_-2^- ^-Jfcr^tylam^nothiazol^-yO^acetij: gTg. is£.m£r^_ 3 At ambient temperature 120 cnr of a 9:1 mixture of chloroform and dimethylamine and 10 mg of the syn isomer of 2-(2-iodoethoxyimino)-2-(2-tritylaminothiazol-15 -4-yl)-acetic acid Were agitated for about 3 hours. The mixture was evaporated to dryness without the temperature exceeding /tO°C and the residue was taken up with 100 cm' of isopropyl ether, ground, agitated for minutes at ambient temperature, vacuum-filtered and 3 rinsed. The residue was taken up with 50 cm of acetone, refluxed for 5 minutes then vacuum-filtered at ambient temperature, dried and the solvents removed by evaporation under reduced pressure. 9-33 g of product were obtained which were taken up with 46 cm' of water, agitated, then vacuum-filtered 3 and rinsed. The residue was taken up with 80 cm of acetone, agitated, vacuum-filtered and dried under 4»Ut>7 reduced pressure to give the desired product. M.p. = 208-210°C (decomposition).

N.M.R. Spectrum (D2O + C^D,-N) : p.p.m.

Triplet centred on 4.55 (J = 5 Hz) : "N-O-CHg single at 6.98 : proton at 5-position of thiazole single at 7.33 : -C(Ph)j U.V. Spectrum (Ethanol, N hydrochloric acid) 1 10 infl. 270 nm Ej = 271 max. 275 nm = 280 e = 14,000 infl. 284 nm E1 = 260 Stage B: Benzhyd^r,2rl_3j:ac.etoxymet^h2l^7z.t£~L2z.',Ji1::2^minJ2~ ihia^ol.-4-il^^2-X.2j2dimethyl.aminoe.thoxy-imino2-a.c£t2.1-anin£] —eph-^-£m^4^c jirboxy^ate^ syn isomer. 1 g of the acid prepared in Stage A was dissolved ■z z in a mixture of 15 cnr of chloroform and 1.5 cnr of methanol and 30'i mg of triethylamine hydrochloride were added. The mixture was heated for 5 minutes at 60°C then evaporated to dryness. The residue was taken up in 15 cm' of- chloroform, and brought to 0° to +5°C by 3 means of an ice bath. Drop by drop, 2 cnr of a solution of pivaloyl chloride (prepared by making 1.25 g of pivaloyl chloride up to 10 cm' with chloroform) were added. The mixture was left to return to ambient temperature.

At the end of two hours, 1.1 g of benzhydryl 7- -amino-cephalosporanate were added.

At the end of one hour thirty minutes the mixture 1SOOY was evaporated to dryness and chromatographed on silica eluting with chloroform containing 5% methanol, to obtain 430 mg of the desired product.

Stage C: Trifluoroaceta_te_o_f acji tjDX£m£t hy 2-_ amino,thia.zol^4^yi)^2^.C 2-dime^h£ljamino_ethoxi-imino)^ -acetylamino]-ceph-3-em-4-carboxylic_acid,_s^n isomer.

A mixture of 100 mg of the product obtained in Stage B in 1 cm' of trifluoroacetic acid was agitated for 3 minutes at ambient temperature. A precipitate 10 was formed by adding ether, which was taken up with 0.2 cm' of methanol. Again a precipitate was formed with 2 cm' of ether. This was formed into a paste with chloroform then vacuum-filtered and rinsed with chloroform, then with ether, to obtain 40 mg of the 15 desired product. M.p. = 230°C.

N.M.R. Spectrum (CD^jSO (p.p.m.) single at 6.8 : proton at 5-position of thiazole U.V. Spectrum Ethanol max. 23a nm E1 = 305 e = 15,600 20 infl. 254 nm E^ = 247 e = 12,650 infl. 296 nm E^ = 103 e = 5,300 Ethanol; N hydrochloric acid i 10 max. 260 nm E^ = 279 e = 1^,300 infl. 276 nm E^ = 2/t3.

Example 42: Trifluoroacetate of 5-acetoxymethyl-7~ -C2-(2-a;ninothiazol-a-yl)-2-(2-pyridylethoxy-imino)--acetylamino3-ceph-3-em-4-carboxylic acid, syn isomer (in the form of internal pyridinium salt).

Stage A: S.vn isomer of 2-(2-tritylamino-thiazol-/i-yl)---2^( ^?-j2yridyl_-ethoxy^imino_^-a^,£ti_c_a£id t_he^ _form_ of_internal. £yridinium_saljt)i g of the syn isomer of 2-(2-iodo-ethoxy-imino)-5 2-(2-tritylaminothiazol-4-yl)-acetic acid solvated with dichloroethane,(corresponding to 4.27 6 pure compound and obtained as described in Example 39) were heated to 60°C for 24 hours in 30 cm' of pyridine then left for 56 hours at ambient temperature. The precipitate thus 10 formed was vacuum-filtered, rinsed with pyridine then with ether and dried to obtain 1.66 g of product, m.p. = 250°C (decomposition).

K.M.R. Spectrum (CDjCOCDj, D£0 = 1-1) 6.8 p.p.m. : H,. of thiazole 15 7.5 to 8 p.p.m. : pyridyl proton 4.58 to 5.08 p.p.m. : = N-O-CH^-CH^ U.V. Spectrum (EtOH-HCl N/10) Max. 260 nm E^ = 32& I.R. Spectrum (nujol) Stage B: Benzhydrjl_3za£ejfc 03grme£h£l^7j^ C j?-£2-t ri;t yJL-_ amin£thiazolj^^l_)^2^(2-£yridyl.ethox2imino2-acetvl^ 25 amino ] -ceph-3-em-4-carboxylate_iod£d£, _3gn_isomer. 540 mg of the product obtained in Stage A were agitated for 20 minutes at ambient temperature with C02 ^ C = C 1639 cm"1 1583 cm 1 1523 cm"1 C = N 49867 210 mg of pyridine hydriodide, 4.20 mg of dicyclohexylcarbodiimide, 350 mg of benzhydryl 7-aniino-3-acetoxy- 3 methyl-ceph-3-em-a-carboxylate and 5 cm of anhydrous dimethylformamide. The dicyclohexylurea precipitate 5 formed is vacuum-filtered and rinsed with dimethylformamide, and the filtrate was poured into 60 cm' of diethyl ether, where it formed a gum. The whole was agitated for 5 minutes at ambient temperature, decanted and the supernatent liquid was removed. The gum was 10 taken up and ground in 60 cm' of diethyl ether. The precipitate formed was vacuum-filtered to obtain 754 mg of a crude product. This was purified by agitation for 3 minutes with 1.6 g of magnesium silicate in 7.5 cnr of dichloroethane. The insoluble matter was vacuum-15 filtered off and washed with 0.5 cm' of 1,2-dichloroethane, then the filtrate was evaporated to dryness to obtain 368 mg of the desired product.

Stage £: Triflu£ro_ac_e_ta_te_o_f i-iiCjit£X2methyl_-2_l2^(^-_ _2aminoth_ia^o]i-Il-ilJ.-2.-i.2^p2ri.dileitho2cy^.imin.oJ[_-ac£tvl-_ amino]-ceph-3-em-a-carboxylic_ a_c£d^ syn isomer.

The 368 mg of product obtained in Stage B were 3 agitated for 3 minutes at ambient temperature in 3 cm of pure trifluoroacetic acid. The insoluble matter was rapidly vacuum-filtered off. A precipitate was formed 25 in the filtrate by adding 40 cm' of diethyl ether and agitating for 5 minutes. The precipitate was vacuum-filtered and rinsed with diethyl ether to form 49867 3 a hygroscopic product which was taken up with 0.35 cnr 3 of methanol and precipitated with 4 cnr of diethyl ether. The reformed precipitate was vacuum-filtered and rinsed with diethyl ether to obtain 1'lO mg of the desired 5 product. M.p. » 205°C (decomposition).

N.M.R. Spectrum (DMSO) 2.06 p.p.m. : OAc 6.86 p.p.m. : H,. thiazole 8.9-9.1 p.p.m. : ^ and Hg ) 8.55 to 8.78 p.p.m. : j O N 8.03 to 8.26 p.p.m. : H^ and H,- ) U.V. Spectrum (EtOH, HC1 N/10) Max. 260 nm 318 I.R. Spectrum (nu.iol) 3 lactam : 1777 cm"1 OAc : 17&0 cm 1 I CM o o : 1633 cm"1 C=N0-R : 1037 cm"1 Example a.3: Trifluoroacetate of 3-acetoxymethyl-7-C2-(2- -3minothiazol-/i--yl) -2-( 2-imidazol-l-yl-ethoxy-imino) --acetylaminol-ceph-3-em-a-carboxylic acid, syn isomer. Stage A: The syn jLS£mer_of 2-£2-tri£y_laminoth£a_zo]1-4-yl2--2j^(2-imidazol-l-yl-ethoxy-imino)-acetic acid £_in the forin_of i.nt_ernal_imidaz^ol_ium_salt_). 3 g of the syn isomer of 2-(2-tritylaminothiazol- -'x-yl)-2-(2-iodoethoxyimino)-acetic acid, solvated with 1,2-dichloroethane (corresponding to 2.56 g pure compound) 4986? were agitated for 3 hours at ambient temperature with A.2 g ofimidazole and 10 cm' of dimethylacetamide. A further 10 cm' of dimethylacetamide were added and the agitation continued for 40 hours at ambient temperature.

The mixture was poured into 200 cm' of isopropyl ether, agitated for 30 minutes, left to separate and then the supernatent liquid was removed. The gum thus obtained was taken up by grinding in 200 cm' of isopropyl ether, and again in 300 cm' of diethyl ether, then agitated 10 for 30 minutes, vacuum-filtered, rinsed with diethyl ether, taken up with 30 cm' of acetone, agitated for one hour, vacuum-filtered, rinsed with acetone then with diethyl ether and dried to obtain 1.2 g of the desired product. M.p. = 280°C (decomposition). 15 N.M.R. Spectrum (DMSO) •"•35 p.p.m. N-O-CH2-CH2 — 6.8 p.p.m. H,. of thiazole N — 7.82 p.p.m.

// N U.V. Spectrum (EtOH, HC1 N/10) 20 Max. 277 nm E* = 259 I.R. Spectrum (nujol) CO2 ~ 1614 cm 1 aromatic 1^92 cm 1 heterocyclel527 cm 1 «»8b7 Stage B: Benzhyd-r^l_5^a£et_02cyme_th^l_^7r^£~£j^t ri ty l.-i_ ?min£thiazol^/i^l.)^2-(2-imidazol^l^l.-£thoxy-iminoj-- -a£etyl.amin.o]_-c.e£h^5^em-4-£arboxj_la^te,. 780 mg of the product obtained in State A were 5 agitated vigorously in a bath of iced water with 315 mg of pyridine hydriodide, 630 mg of dicyclohexylcarbodiimide, 600 mg of benzhydryl 7-amino-3-acetoxymethyl-ceph--3-em-/!-carboxylate and 6 cm' of anhydrous dimethylformamide- Dicyclohexylurea precipitated. The mixture 10 was taken to ambient temperature and the agitation was continued for 20 minutes. The insoluble matter was removed by vacuum-filtration and rinsed with dimethyl- z formamide. The filtrate was treated with 120 cnr of diethyl ether to form a precipitate, then agitated for 15 20 minutes and left to separate. The supernatent liquid was removed and the gum obtained was taken up and triturated in 100 cm' of diethyl ether. This mixture was agitated for 10 minutes at ambient temperature, ■teacuum-filtered, rinsed with diethyl ether and dried to 20 obtain 1.3 g of a product which was chromatographed on silica, eluting with a 8-1-0.5 mixture of ethyl acetate-ethanol-water to obtain 332 mg of the desired product.

H.M.R. Spectrum (CDClj) 2 p.p.m. : OAc 6.75 p.p.m. : Hj- syn thiazole I.R. Spectrum (CHCl^) (3 lactam : 1788 cm 1 ester and OAc: 1759 cm 1 o o v ' - 161 -heterocycles : 1525 cm 1 Stage G: Tr^fluor£a£etate_o_f ^-£C£t_oxim_ethyl_-2-X2^.(2-_ -aminol^hiazpl^-4-jl2-2-X2;:imida^ol.-l_-2l^eth£3C2-i;mi,n£)^ acetylamino]_-ce_ph- 3_-em^J.-^ca_rboxylic ac£d_j_ syn £somer. 5 230 mg of the product obtained in Stage B were agitated for 3 minutes at ambient temperature with 2 cm' of pure trifluoroacetic acid. The formed solution was poured into a 1-1 mixture of isopropyl ether-diethyl ether and agitated for 20 minutes at ambient temperature. 10 The formed precipitate was rinsed with diethyl ether, 7. then taken up in 0.4 cnr of methanol and again precipitated with 4 cm' of diethyl ether, agitated for 10 minutes at ambient temperature, vacuum-filtered, rinsed with diethyl ether and dried to obtain 140 mg of the 15 desired product. M.p. « 205°C (decomposition). N.M.R. Spectrum (DMSO) 2.03 p.p.m. : OAC 6.8 p.p.m. : H,- syn thiazole 7.66 and 7-71 p.p.m. : and ) imidazole 8.95 p.p.m. : Hg U.V. Spectrum (EtOH, NCI N/10) Max. 260 nm E1 = 271.

Example 44: Trifluoroacetate of 3-acetoxymethyl-7-E2-(2--aminothiazol-4-yl)-2-(ethoxycarbonyloxy-imino)-acetyl-25 amino!-ceph-3-em-4-carboxylic acid, syn isomer.

Stage A: Di£thyl_amine_salt_ of_3^a£etoxymeth£l-7-C 2 --1rit^laminothia zo1-4-y 1)-2-(ethoxycarbonyloxy-imino)--ac e t vl amino ] -c eph-3-em-4-c arboxylic _a ci d. jn^i so m e r.

Under agitation and in an inert atmosphere 1.67 g of the syn isomer of 3-acetoxymethyl-7-f2-(2-trityl- aminothiazol-4-yl)-2-hydroxyimino-acetylamino]-ceph-3- 3 -em-4-carboxylie acid were dissolved in 25 cm of 5 methylene chloride and 0.37 cm' of pyridine. The solution was cooled in an ice bath, and then over five 3 minutes 2-7 cnr of a molar solution of ethyl chloro-formate in methylene chloride were added. After 10 minutes and still at 0° to +5°C, 20 cm' of water and 3 2.7 cnr of N hydrochloric acid were added. This mixture was agitated, then separated. The organic phase was washed with water until neutral and then dried. The solvent was distilled off under reduced pressure and the residue was taken up with 10 cm' of 3 IS ethyl acetate, then 0.23 cm of diethylamine were added. The diethylamine salt was precipitated by adding 10 cm' of isopropyl ether. The salt was vacuum-filtered and rinsed with a 1-1 mixture of isopropyl ether-ethyl acetate, then with isopropyl ether, to obtain 1.50 g 20 of a product which was dissolved in 5 cm' of methylene chloride and 10 cm' of ethyl acetate. The solution was concentrated under reduced pressure to obtain a final 3 3 volume of about 6 cnr and then diluted with 5 cnr of isopropyl ether, vacuum-filtered and rinsed as 25 previously to obtain 1.4-7 g of the desired product. N.M.R. Spectrum (CDClj) 2.03 p.p.m. : OAc . 49867 ( 6.95 p.p.m. : H,. of thiazole 7.66 p.p.m. : trityl 4.13 - 4.25 - 4.36 - 4.48 p.p.m. : CH^ of CC^Et I.R. Spectrum (CHCl^) 0 lactam 1781 cm 1 OAc 17&0 cm-1 amide 1694 cm 1 C02~ 1634 cm"1 otage B: Tri.f lu£r£ac_et,at_e_o_f ^-^c£t£X2mj5thyl~Z~L^z(R~ ^arni no_t hi. a z,o_l-a-j^l 2.-£-^.ethox2c_arb ony loxy nimino^- ac et^lj; amino] -c er h- 3-em^a--cjirboxy 1 ic_ac id, _s^n_i s^omer. 1.43 g of the product obtained in Stage A were agitated for 20 minutes at ambient temperature with x x .7 cnr of trifluoroacetic acid. 57 cnr of isopropyl ether were rapidly added and the mixture was agitated for a further 15 minutes, then vacuum-filtered and rinsed with isopropyl ether to obtain 1.04 g of a crude x product which was dissolved m 4 cm of acetone con-. taining 1% water. To the solution was added 12 cm' 20 of diethyl ether to precipitate 0.69 g of the desired product. A further 0.11 g of identical product were recovered from the mother liquors.

Example 45: Sodium salt of 3-acetoxymethyl-7~C2-(2--aEinothiazol-,t-yl)-2-(ethoxycarbonyloxy-imino)^ 25 -acetylaninoj-ceph-3-em-a-carboxylic acid, syn isomer. 0.8 g of the product obtained in Example 4/i were dissolved in n cm' of a 1M nethnnolic solution of sodium acetate and 2 cm' of methanol. The solution was treated •» o a o t ■Z with active charcoal and diluted with 20 cm of anhydrous ethanol then concentrated to a final volume of 10 cm' by distilling under reduced pressure at 30°C maximum. The precipitate obtained was vacuum-filtered, 5 rinsed with ethanol and then with ether to obtain /1.20 mg of product. 580 mg of product prepared in this way were taken up with 5.8 cnr of methanol and while agitating 1.2 cnr of ethanol were slowly added. The precipitate was vacuum-filtered off and the filtrate was diluted with 10 cm' of ethanol then concentrated by distilling under reduced pressure at 30°C maximum to a final volume of 5 cm'. This was vacuum-filtered and rinsed with ether to obtain 'i60 mg of product which was treated again in the same manner to obtain >i20 mg of the desired product.

N.M.R. Spectrum (DMSO) 1.13 - 1-25 - 1-36 p.p.m. ) ) C02Et n.03- 4.16 - 4.28 - ti.4 p.p.m. ) 1.98 p.p.m. : OAc 7.03 p.p.m. : of thiazole U.V. Spectrum (EtOH/HCl N/10) Max. 259 nm E^ = 324 e 17.3I30 Infl. 278 nm E^ = 252 25 I.R. Spectrum (nujol) P lactam : 1763 cm 1 OAc : 1726 cm 1 COg : 1609 cm 1 C=N-0 : 1038 cm"1 ^ O U | Example 4.6: 3-acetoxyiuethvl-7-C2-( 2-aminothiazol-a.--vl)-2-(2-:norpholino-ethoxy-imino)-acetylamino3-ceph--3-em-4-carboxylic acid, syn isoner in the form of internal salt.

Stage a: £-£2^tritylaminothiazpl_-a-£l^-£-£2^m£r3>holino-ethoxy-imino)-acetic acid, syn isomer in_the_form of i_nt_e rna l_s £l_t. 2 g of the syn isomer of 2-(2-tritylaminothiazol--4--yl)-2-(2-iodoethoxy-imino)-acetic acid solvated with 10 1,2-dichloroethane (corresponding to 1.71 g of pure compound) were dissolved in 7 cm' of morpholine. The solution was agitated for one hour at ambient temperature then concentrated in a current of nitrogen, and taken up with 30 cm' of ethyl acetate, agitated for twenty 15 minutes at ambient temperature and vacuum-filtered, rinsing with ethyl acetate. The product was agitated 3 for fifteen minutes in 15 cnr of 1,3-dimethoxypropane then vacuum-filtered and rinsed with the same solvent. The 3 product was then taken up with 15 cnr of ether, 20 agitated for 15 minutes, vacuum-filtered and rinsed with diethyl ether to obtain 2.3 g of product, m.p. = 180°C (decomposition), which was used for the following stage in that form. 100 mg of the product was purified by recrystal-25 lisation from 0.5 cm' of ethanol to obtain 46 mg of recrystallised product, m.p. : 182-184°C (decomposition). N.M.R. Spectrum (CDCl^) 7.33 p.p.m. : trityl 6.75 p.p.m. : H,. syn thiazole U.V. Spectrum (EtOH, HC1 N/10) Max. 276 nm E^ = 172 5 I.R. Spectrum (GHClj) COg" and aromatics 1606 - 1529 and 1495 cm ^;-NH 3399 cm 1 Stage B: Benzhydr^lj. ^-acetox^pethy_1 2~i2-(2-1rit^l^ ^inothi£Z£l^i-yl^)j22^(^-morphol^ino^eth£X2,-i;min£]j; -ac etylamino 3 -c£ph-^-£m-4-c axboxy la£e_hydr iod id£, _sjn_ 10 isomer^ lg of the product obtained in Stage A, 0.38 g of pyridine hydriodide, 0.63 g of dicyclohexylcarbodiimide and 0.60 g of benzhydryl 3-acetoxymethyl-7-amino- 3 -ceph-3-em-4-carboxylate were dissolved in 5 cnr of 15 anhydrous dimethylfprmamide. The solution was agitated for 30 minutes at ambient temperature. The dicyclohexylurea thus formed was removed by vacuum-filtration; 100 cm' of diethyl ether were added to the filtrate, and the mixture was agitated for ten minutes, vacuum-20 filtered, rinsed with diethyl ether and chromatographed on silica eluting with a 7-1 ethyl acetate-ethanol mixture to obtain 0.524 g of product. M.p. : 167°C (decomposition).

N.M.R. Spectrum (CDClj) 2.03 p.p.m. : OAc 3.72 p.p.m. : CHgO 6.75 p.p.m. : H,. syn thiazole «90U I U.V. Spectrum (EtOH, HC1 N/10) Max. 268 nm E1 = 165 e=15,900 I.R. Spectrum (CHCl^) 3 lactam 1791 cm 1 ester and OAc 1740 cm 1 amide 1678 cm 1 Stage C.: ^-jic£to^m£thyl^2-JL2_2(2-ami.n£thijiz£l_2't\^yl.).I.2.l - ( 2-morpholinoethoxy-imino)-acetylainino ] j;ceph-^-em^4j; -carboxylic acid_j_ syn. isomer^ in the_form £f_internal 10 Haiti. 0.42 g of the product obtained in Stace B were agitated for two minutes at ambient temperature with 3 cm' of trifluoroacetic acid. The insoluble matter was vacuum-filtered off and rinsed with trifluoroacetic 7. acid. The filtrate,was collected in 30 cnr of diethyl ether and agitated for 15 minutes at ambient temperature.

The precipitate formed was vacuum-filtered, rinsed with x ether and dissolved in 0.5 cnr of methanol. Then it 7. was again precipitated with 5 cm of diethyl ether. 20 After agitation for 5 minutes, the precipitate is vacuum-filtered off to obtain 208 mg of product, m.p. = 212-2l4°C (decomposition), which was salified in various ways, and in particular by trifluoroacetic acid.

N.M.R. Spectrum (DMSO) 2.05 p.p.m. : OAc 3.17 to 4.66 p.p.m. : C^-N and CHgO 6.85 p.p.m. : H,- syn thiazole 498 U.V. Spectrum (EtOH, HC1 N/10) Max. 260 nm E^ = 253 I.R. Spectrum (CHClj) 3 lactam 1797 cm 1 CO2- 1634 cm"1 amide 1667 cm 1 Example a.7: 3-acetoxymethyl-7-C2-( 2-arainothiazol-a-y 1) --2-(2-[4-me thy1-pipera zin-1-yl3-ethoxy-imino)-ac ety 1 -amino3-CBph-3-em-4-carboxylic acid, syn isomer, in the form of internal salt (trifluoroacetate) Stage A; 2~X.2^.tritjl.amin0t^hi-aZi0l_-a-^lj_-£-^_2^C^_-meth2.1_^ -piperazin-l-yl 3-ethoxy-imino)-acetic acidj_ in_the__ form_of int_erna.1 _s al t_. x 2.22 g of N-methyl-piperazine in 15 cnr of dioxan and 3.325 g of the syn isomer of 2-(2-tritylaminothiazol- 1 -4-yl)-2-(2-iodoethoxy-imiuo3-acetic acid solvated with dichloroethane, (corresponding to 2.84 g pure compound and prepared as in Example 39) were agitated vigorously for 16 hours at ambient temperature. The N-methyl piperazine Hydriodide thus formed was vacuum-filtered off and the filtrate was concentrated under reduced 3 3 pressure to a volume of about 5 cm, then 200 cnr of isopropyl ether were added and the mixture was agitated for 30 minutes. The mixture was vacuum-filtered and the product was taken up with 10 cnr of dimethoxypropane, agitated for thirty minutes, vacuum-filtered, taken up with 24 cm' of water, agitated for ten minutes, then again vacuum-filtered. The insoluble matter was 49867 agitated for two hours in 100 cm' of 1-1 isopropyl ether-diethyl ether mixture, then vacuum-filtered off and recrystallised from ethanol at 100° to obtain 1.4-7 g of product. M.p. : 220°C (decomposition).

N.M.R. Spectrum (CDClj) 2.52 p.p.m. : -NCH^ 3.0 p.p.m. : CHpN 6.7 p.p.m. : H,- of thiazole U.V. Spectrum (EtOH/HCl N/10) Max. 277 nm ^ - 257 e 1ft,300 I.R. Spectrum (nujol) C02~ 1602 cm"1 heterocycle 1529 cm 1 absence of CO^ Stage B: Benzhyd.r2,l_3^a£etoxynethjrl^7z£2-.£.22trityJ.-simin£thijiz£l^&^]i)^2^(^-£&^m£t^i-j>i£era2;in-<l-£l]_-^ethox2.-_tmino)^acetyl/amin£]j2ceph-^-emj^&^cjirbo2cy.lat_ej_ syn isomer. 560 mg of product obtained in Stage A was heated 20 to 60°C for ten minutes with 140 mg of triethylamine hydrochloride in 5 cm' of chloroform and 5 cm' of methanol. The solvents were evaporated off under reduced pressure, and the residue was taken up with 20 cm' of methylene chloride then cooled to -20°C. Over ~3 ten minutes 1 cm of a 12.5% solution of pivaloyl chloride in methylene dichloride was added and the whole agitated for an hour at ambient temperature. The o oy - 1?0 - solution was cooled to -10°C and, in one go, 350 mg of benzhydryl 7-amino-3-acetoxymethyl-ceph-3-em-4-carboxylate were added. The mixture was agitated for three hours, then concentrated to dryness under reduced 5 pressure at a maximum of 30°C. The residue was taken up with 50 cm' of an 8-2 benzene-ethyl acetate mixture, and the insoluble matter was eliminated. The solution was evaporated to dryness under reduced pressure, and the residue taken up with 25 cm' of 1,2-dichloroethane. 1.5 g 10 of activated magnesium silicate were added and the mixture was agitated for 30 minutes, then vacuum-filtered and • rinsed with 1,2-dichloroethane. The filtrate was evaporated under reduced pressure at 30°C maximum to obtain 870 mg of white resin.

N.M.R. Spectrum (CDCl^) 2.02 - 2.03 p.p.m. : OAc 6.87 p.p.m. : Hg of thiazole 2.45 p.p.m. : N-CH3 U.V. Spectrum (EtOH, HC1 N/10) Max. 267-268 tim : 14,700.

Stage C: 2-acetox^ethyl-2-[2-(2-aminothiazol;4;yl)-2-£ 2-C4-methyl;pipe razin^1-ylJ^ethoxy-imino)-ac etylamino.]-ceph-3-em-4-carboxylic acid, syn isomer, in the form of internal_salt ^trifluoroacetate) 524 mg of the product obtained in Stage B were dissolved in 3 cm' of pure trifluoroacetic acid and the solution agitated for one minute at ambient temperature. 9867 A precipitate was formed by adding 30 cm' of isopropyl ether and the whole was agitated for a further 5 minutes, then vacuum-filtered to obtain 320 mg of a hygroscopic product. This was dissolved in 1 cm' of methanol and x caused to precipitate by adding 10 cm of diethyl ether. The mixture was agitated for 5 minutes, vacuum-filtered, rinsed with diethyl ether, made into a paste with chloroform then with ether to yield 220 mg of a salified product (trifluoroacetate) M.p. = 245°C.

N.M.R. Spectrum (DMSO) 2.03 p.p.m. : OAc 2.75 to 3-67 p.p.m. : CH^ 6.78 p.p.m. : H,- of thiazole U.V. Spectrum (EtOH, HC1 N/10) Max. 262 nm : 14,200 I.R. Spectrum (nu.iol) (3 lactam 1773 cm 1 OAc 1726 cm 1 C02O 1627 cm"1 C = NO- 1035 cm"1 Example 48; Bis trifluoroacetate salt of 3-acetoxymethyl--7-[2-(2-aminothiazol-4-yl)-2-(2-aminoethoxr-imino-acetyl-- amino ]-ceph-3-em-4-carboxylic acid, syn isomer Stage A: 2-£2-1rity1aminoethoxyimino) -2- (2-tritylamino-25 thiazol-4-yl)-acetic acid, syn isomer A mixture of 75 g of tritylamine, 50 g of ethyl t » O O 7 and 100 cm' of dimethyl sulphoxide was placed under argon, and the suspension was agitated for 82 hours at 60°C.

It was then cooled to ambient temperature and caused to precipitate with 10 volumes of water. The precipitate was vacuum-filtered, washed with water, and then put into 5 solution in one litre of chloroform and washed with water, then with a saturated solution of sodium chloride. The solution was dried and evaporated under reduced pressure at a temperature lower than 40°C. The crude product was taken up with a mixture of 320 cm' of dioxan, 2 litres 10 of absolute ethanol and 200 cm' of 2N sodium carbonate, and agitated for 24 hours at ambient temperature, then evaporated to dryness under reduced pressure at a temperature lower than or equal to 40°C. x This product was pasted 5 times with 60 cnr of a 1-7 15 dioxan-methanol mixture. The product was taken up with a mixture of a litre of chloroform and a litre of water.

Under agitation normal hydrochloric acid was added to adjust the pH to 2. The organic phase was separated, washed with water and then with a saturated solution of 20 sodium chloride, dried and evaporated to dryness under reduced pressure at a temperature lower than HO°C. The product thus obtained was suspended in 300 cm'of 1 #2-dichloro-ethane and heated for 15 minutes at 50°C. Then it was vacuum-filtered after returning to ambient temperature 25 under light vacuum, and rinsed with dichloroethane then with isopropyl ether and finally with diethyl ether.

After being dried to constant weight 40 g of powder were obtained. M.p. - 176°C.

N.M.R. Scectrum (CDCl^) 6.68 p.p.m. : proton at 5 of thiazole 2.95 p.p.m. : CH^-H Stage B: 2-£?~tritylaminoethoxy^imino)-2-^2-tritylaminos thiazol-a-yl)-acetate of hydroxy-benzotriazole, syn isomer_ 6.97 E of the acid obtained in Stage A were mixed with 1.54 E of hydroxy 1-benzotriazole in 35 cm^ of methylene chloride, and agitated in an ice bath. Drop by drop a solution of 2.44 g of dicyclohexylcarbodiimide in 35 cm' of methylene chloride was added. After being left to return to ambient temperature, the mixture was agitated for three hours thirty minutes. The dicyclohexylurea formed was vacuum-filtered off and rinsed with methylene chloride. The filtrate was washed with sodium bicarbonate, then with water, then finally v/ith a saturated solution of sodium chloride, dried and evaporated to drynesn under reduced pressure. The resin thus obtained was taken up with 50 cm' of jLpocropyl ether and agitated vigourously for one hour at ambient temperature. The precipitate thus obtained wac vacuum-filtered, rinsed with isorronyl ether and dried to constant weight to obtain 8.046 g of product. M.p. = 150-152°C (decomposition).

N.M.R. Spectrum (CJCl^) 6.68 p.p.m. : proton at 5 of thiazole 2.36 p.p.m. : -CHp-N Stage C: Diphenylmethyl_3-acetoxymethyl-7-[2-£2;trityl-_ aminoethoxy-imino)-2-(2-tritylamino-thiazol-4-j'l}-acetj,l; amino]-ceph-3-em-4-carboxylate, syn isomer 11.55 S °f the activated ester product prepared in Stage B were mixed with the equivalent of 7*65 g of the diphenylmethyl ester of 7-amino cephalosporanic acid in 75 x cnr of methylene chloride. The mixture was agitated for 18 hours at ambient temperature, evaporated under reduced pressure and chromatographed on silica and under pressure, eluting with an 85-15 benzene-ethyl acetate mixture to obtain 9.1 g of the desired product.

Stage D: Bis trifluoroacetate_salt of_3-acetoxymethyl-7- H [2-^22 aminothiazo l-4-yl2~2-£2-aminoethoxy-imino2-acetyl-amino ]-ceph- 3~em-4-carboxylie acid, syn isomer Diphenylmethyl 3-acetoxymethyl-7-C2-(2-tritylamino- thiazol-4-yl)-2-(2-tritylaminoethoxy-imino)-acetylamino]- ceph-3_em-4-carboxylate prepared in Stage C were introduced x into 1.8 cnr of pure trifluoroacetic acid. The yellow solution thus obtained was agitated for 3 minutes at ambient temperature, then under an inert atmosphere in a x bath of iced water when 18 cnr of isopropyl ether were rapidly added. The mixture was agitated for 10 minutes, vacuum-filtered, rinsed with isopropyl ether then with diethyl ether and dried to obtain 100 mg of a white powder. M.p. a about 210°C (decomposition).

Formulation 1: Injectable Preparation An injectable composition was prepared from the 49867 following: The syn isomer of 3-acetoxymethyl-7-C2--(2-amir.othiazol-4-yl)-2-(2-aminoethoxy-imino)-acetylamino]-ceph-3-eia-4-carboxylic acid 500 mg Aqueous sterile excipient q.s Formulation 2: Injectable Preparation An injectable composition was prepared from the following: The syn isomer of 3-acetoxymethyl-7-C2-10 -(2-aminothiazol-4-yl)-2-acetoxyimino-acetyl- amino J-ceph~3-em-4-carboxylic acid 500 mg Aqueous sterile excipient q.s Formulation ^: Gelatin capsules Gelatin capsules were prepared as follows: The syn isomer of 3-acetoxymethyl-7-£2- -(2-aminothiazol-4-yl)-2-(2-amino ethoxy-imino)--acetylamino]-ceph-3-em-4-carboxylic acid 250 mg Excipient q.s. for a geltain capsule 400 mg Formulation 4: Injectable Preparation An injectable composition was prepared from the following: Sodium salt of 3-acetoxymethyl-7-[2- (2-aminothiazo1-4-yl)-2-(2-bromoethoxy--imino)-acetylamino]-ceph-3-ein-4-carboxylic « a a o y acid, syn isomer Sterile aqueous excipient q.s Formulation 5-' Injectable Preparation An injectable composition was prepared from 5 the following: The syn isomer of 3-[(l-methyl-l,2,3t4-tetrazol-5-yl)-thiomethyl]-7-C2-(2-aminothiazol--4-yl)-2-(2-aminoethoxy-imino)-acetylamino]-ceph--3-em-4-carboxylic acid 500 mg 3 Sterile aqueous excipient q.s 5 cm Formulation 6: Injectable Preparation An injectable composition was prepared from the following: Trifluoroacetate of 3-acetoxymethyl-7-15 -[2-(2-aminothi azo1-4-yl)-2-(2-iodoethoxy-imino)-acetylamino]-ceph-3~e®-4-carboxylic acid, syn isomer 500 mg Sterile aqueous excipient q.s Formulation 7' Gelatin capsules Gelatin capsules were prepared as follows: The syn isomer of 3-C(l-methyl-l,2,3»4-tetrazol-5-yl)-thiomethyl]-7-[2-(2-amino-thiazol-4-yl)-2-(2-aminoethoxy-imino)-acetyl-amino]-ceph-3-eo-4-carboxylic acid 250 mg Excipient q.s. for a gelatin capsule 400 mg 49867 Formulation 8: Injectable Preparation An injectable composition was prepared from the following: The syn isomer of 3-acetoxymethyl-7-5 -[2-(2-aminothiazol-4-yl)-2-(2-imidazol-l-yl-ethoxy-imino)-acetylamino]-ceph-3-em-4-carboxylic acid 500 mg 3 Sterile aqueous excipient q.s 5 cnr Formulation 9t Injectable Preparation 10 An injectable composition was prepared from the following: Sodium salt of 3-acetoxyraethyl-7-C2--(2-aminothiazo1-4-yl)-2-(2-ethoxycarbonyloxy-imino)-acetylamino]-ceph-3-em-4-carboxylic 15 acid, syn isomer 500 mg 3 Sterile aqueous excipient q.s 5 cm Formulation 10: Gelatin capsules Gelatin capsules were prepared as follows: Sodium salt of 3-acetoxymethyl-7-C2-20 -(2-aminothiazol-4-yl)-2-(2-ethoxycarbonyloxy-imino)-acetylamino]-ceph-3-em-4-carboxylic acid, syn isomer 250 mg Excipient q.s. for a gelatin capsule 400 mg 49867 The following Pharmacological Studies and the results obtained thereby are now set out, though only by way of illustration, to show the relative activities of various compounds of the invention in relation to a 5 number of strains of bacteria. An amount of the compound to be tested was introduced into each tube, so that the amount introduced increases from tube to tube in the series. Then each tube was inoculated with a bacterial strain. After twenty-four or forty-eight hours' incuba-10 tion in the oven at 37°C, inhibition of growth was assessed by transillumination, and by observing the inhibition in each tube relative to the amount of compound present the minimum inhibiting concentrations (H.I.C.) was determined for the bacterial strain. The results 15 obtained are set out in the following tables in terms of M.I.C. expressed in mg/cm' for a number of bacterial strains. <* tt a o # PRODUCT OP EXA.MPUJ 2 2 STRAINS M.I.O 24H in ug/nl 48H , , Penicillin-Staphylococcus aureus ATCC 6 538 sensitive 0.5 1 . , • Penicillin-Staphylococcus aureus UC 1 123 resistant 1 1 Staphylococcus aureus exp.?J"54 1-16 1 1 Streptococcus pyogenes A 561 «0.02 40. 02 Streptococcus faccalis 5 432 2 Streptococcus faecalis S9 F 74 >40 0.2 1 Escherichia Co 1 i sensitive toTetrr.cyclinc ATCC 9 ^37 1 1 Escherichia Coli resistant to S'etracycliv.s ATCC 11 303-.- ' 0.2 0 .2 Escherichia Coli TC_-B- 26 6 0.5 0.5 Escherichia Coli resistant to Gentamycin 1 t/> 1 • 1 o 1 1 1 1 0.5 Klebsiella pneumoniae Exp. 52 145 0.2 0.5 Klebsiella pneumoniae 2 536 resist ait to Gen-tarn yc in. 2 2 Proteus rairabilis (ir.dol-) A "235 0.2 1 1 n • o ! 2 Pxovidencia Du 48 ........................

Serratiaresistant to Gentaraycin 2 532 PRODUCT OF EXAMPLE 24 STRAINS M.I.C., 24H in yg/nl 48H Staphylococcus aureus ATCC 6 538 sensitive*1" 1 1 Staphylococcus aureus UC 1 12 8 Pen^ci11"1-* resistant 1 1 Staphvlococcus aureus exD.N" 54 146 1 1 Streptococcus pyogcr.es A 561 ^0. 02 4*0,02 Streptococcus faecalis 5 432 2 Bacillus subtiiis ATCC 6 633 0. 5 0.5 Escherichia Coli sensitive toTntracycline ATCC 9 5 37 " 2 2 Escherichia .Coli resistant to Tetracycline ATCC 11 30 3' 1 1 Escherichia Coli E:-:p. TO^^Bg 2 3 Escherichia Coli resirtant to Gentaniyein Tobramycin R 55 123 D 1 2 1 1 Klebsiella pnnuraoniae 2 5 36 resistant to Gen- Proteus mirabilis (indol-) A 235 1 1 Salmonella typhiraurium 420 2 • 3 Serratia resistant to Gentamycln 2 532 4 0 O w I PRODUCT OF EXAMPLS26 1 ■ 1 STRAINS H.I.C. in ug/ml 24H 48H „ , _ __ Penicillin- Staphylococcus aureus ATCC 6 5 38 sensjtive 2 2 Stapnvlococcus aurcux UC 1 12 8 Penicillin- resistant 2 2 Staphylococcus aureus exp. n°54 146 2 2 Streptococcus pyogenes A 551 *0.02 -$0.02 Streptococcus faecalis 5 4 32 3 >40 Streptococcus faecalis 99 F 74 >40 Dacillus r.ubti.lis ATCC 6 633 1 1 Escherichia Coli sensitive toTetracycline ATCC 9 537 2 2 Escherichia Coli resistant to Tetracycline ATCC 11 303 1 2 Escherichia Coli Exp.TOpgB^ 2 2 Escherichia Coli resistant to Gentamycin 1 2 Klebsiella pneumoniae Exp. 52 145 1 1 Klebsiella pneumoniae 2 5 36 resistant to Gen- Proteus nirabilis (indol-) A 235 0.5 0.5 Salmonella typhiaurium 420 . 2 2 40 40 Ssrratia resistant to Gcntamycin 2 5 32.

PRODUCT OF EXAMPLE 28 STRAINS M.I.C. in. ug/ml 24K 48H . , . Penicillin-Staphylococcus aureus ATCC 6 5 38 sensitive 0.5 1 Staphylococcus aureus L'C 1 128 Penicillin- 1 rasAAiauk [ 1 • . 1 Staphylococcus aureus exp.n°54 146 1 1 Streptococcus pyogenes A 561 <0.02 <0.02 1 2 Escherichia Coli sensitive to Tetracycline ATCC 9 637 3 3 Escherichia Ccli resistant to Tetracycline ATCC 11 303 1 1 Escherichia-Coli Exp. T02gSg 2 2 Escherichia Coli resistant to Gentamycin Tobramycins R 55 12 3 D 2 2 Klebsiella pneumoniae Ex.p. 52 145 1 1 Klebsiella pneumoniae 2 536 resistait to Gentamycin Proteus mirabilis (indol-) A 23S 1 1 Salmonella typhimurium 420 2 2 40 Providencia Du 48 Serratia resistant to Gentamycln • 2 532. 4 99DI PRODUCT OF EXAMPLE 30 • STRAINS ' M.I.C. 24H in ugAU 48H Staphylococcus aureus ATCC 6 5 38 genitive"" 2 2 Staphylococcus aureus UC " 1 128 penicillin-r resistant 2 2 Staphylococcus aureus exp.n°54 146 2 2 Streptococcus pyogenes A 561 in o 0 o 0.05 Bacillus subtilis ATCC 6 633 1 1 Escherichia Coli sensitive to Tetracycline ATCC 9 637 Escherichia Coli resistant to Tetracycline ATCC 11 3 03 2 2 Escherichia Coli Exo. TO_.B 26 6 3 3 Escherichia Coli resistant to Gentamycin Tobramycin P. 55 12 3 D.... 3 3 Klebsiella pneumoniae Exp. 52 145 1 1 Klebsiella pneumoniae 2 536 resistant toGen-tar»yc in....

Proteus nirabilis (indol-) A 235 2 2 Salmonella typhimurium 420 • 3 Providencia DU 48 Serratia resistant to Gentamycin.' 2 532 \ « a a oy PRODUCT OP EXAJMPLE 31 STRAINS H.I.C. 24H in Ug/nvl 48H Staphylococcus aureus ATCC 6 53o Penl"llin-c - sensitive 2 2 Staphylococcus aureus UC 1 128 Penfci11fn- resistant 2 2 •2 2 St.reptococcus pyogenes A S61 .50.02 40.02 StrcsDtococcus faecalis 5 432 3 40 Bacillus subtiiis ATCC 6 633 •2 3 Escherichia Coli sensitive toTeiracycline ATCC •) 637 3 3 Escherichia- Coli resistant to Tetracycline ATCC li 303 3 3 Escherichia Coli Exp. TO^B^ 2 2 Escherichia Coli resistant to Gentamycin 2 2 0.5 0.5 Klebsiella pneumoniae 2 535 resistant to Gen-tainycir. 1 1 Salmonella typhimurium 420 2 2 Providencia Du 4S 'Serratia resistant to Gentanvycinv 2.532 3 ■ \ PRODUCT OP EXAMPLE 33 STRAINS M.I.C. 24H in ug/ml 48H Penicillin- Staphylococcus aureus ATCC 6 538 sensitive 2 2 Staohylococcus aureus UC 1 128 PenicjHin- . ■ J resistant 2 2 Staphylococcus aureus ox?.n° 54 1-56 2 2 Streptococcus pyogenes A 561 0.05 0.05 Str*ptococcus faecalis 5 432 3 40 Bacillus subtiiis ATCC 6 633 ' 2 2 Escherichia Coli sensitive toTetracycline ATCC 9 6 37 1 2 Escherichia Coli resistant to Tetracycline ATCC 11 30 3 0.5 0.5 Escherichia Coli Exp- TOjgB^ 1 1 Escherichia Coli resistant to Gentamycin Tobramycin R 55 123 D '. 1 1 Klebsiella pneumoniae Exp. 52 145 ' 0.1 0.5 1 Klebsiella pneumoniae 2 536 resistant to Gen-tamycin . 2 3 Proteus mirabilis (indol-) A 235....- 0.2 0 .2 Salmonella tvphimuri\jra 420 1 1 Providencia Du'48.........................

Serratia resistant to Gentamycin 2 532 2 3 4986? PRODUC.T OF EXAMPLE 71 STRAINS M.I.C. in vg/ml 24H 48H Staphylococcus aureus ATCC 6 538 1 1 Staohyloccccuc aureus UC 1 12 3 Pe^"11"4 • J resistant 1 1 Staphylococcus aureus exp. n"54 146 1 1 .

Streptococcus pyogenes A 561 l/> O • O 0.05 Bacillus- subtiiis ATCC 6 633 .' 1 2 Escherichia Coli sensitive toTetracyclir.e ATCC 9 637 ' 2 2 Escherichia Coli resistant to Tetracycline ATCC 11 303 0.5 0 .5 Escherichia Coli Exp. T0?gBg 1 1 Escherichia Coli resistant to Gentamycin Tobramycin R 55 123 D 2 2 Klebsiella pneumoniae Exp. 52 145 0,05 • 0 .05 Klebsiella pneumoniae 2 536 resistant to Gentamycin 3 3 Proteus mirabilis (indol-) A 235 0.5 0 .5 Salmonella typhimurium 420 3 3 ' 10 Providencia Du 48 Serratia resistant to Gentamycin. 2 532 2 3 ! t 4 » o o i I " - 187 - i PRODUCT . OF EXAMPLE 38 j • I i • STRAINS M.I.C. 24H in ug/ml 4 8H Penicillin- Staphylococcur. aureus ATCC 6 538sengitive 2 3 . , ,,'r. ,,o Penicillin- '■ , Staphylococcus aureus UC 1 128 ^ 3 Staphylococcus aureus exp. n°54 146 | 3 Streptococcus pyogenes A 561 ><0 .02 ^<0 .02 Strectcc3ccus faecalis 5 432 2 40 Strrjotococcus faccalis 99 F 74 | 40 1 >4 0 Bacillus subtiiis ATCC 6 6 33 .1 2 Escherichia Ccli r-cncitive to Tetracycline ATCC 9 637 0 .5 0. 5 Escherichia .Ccli resistant to Tetracycline ATCC 11 30 3 0. 1 0. 1 Escherichia Coli Exp. T02gBg 0. 2 1 1 tn • o Escherichia Coli resistant to Gentor.iycin Tobramycin R 55 123 D 0. 2 0. 2 Klebsiella pneumoniae Exp. 52 145 o • o 0-05 Klebsiella pneumoniae 2 536 resistant to Gentamycin 2 2 Proteus numbi.lis (indol + ) A 232 1 2 Proteus m-irabilis (indol-) A 235 0. 2 1 0. 2 tn • o Enterobacter cloacae 681 2 3 Providencia Du 4 8...... 2 3 Serratia resistant to Gentamycin. 2 5 32 1 1 49867 PRODUCT OF EXAMPLE 39 STRAINS M.I.C. 2.4 H in wg/ml 48H _ - ^ Penicillin-Staphylococcus aureus ATCC C 5 30sensjtive 1 1 Staphylococcus aureus UC 1 12 8 Penicillln-r resistant 1 2" Staphylococcus aureus oxo.n" 5 4 li6 1 1 Streptococcus pyogenes A 561 /A O » o to 1 1 1 <N 1 O 1 • 1 O 1 V/| Streptococcus faecalis 5 4 32 2 Bacillus subtiiis ATCC 6 633 1 Escherichia Coli sensitive toTetracycline ATCC 9 637 3 Escherichia Coli resistant to Tetracycline ATCC 11 30 3 0.5 0.5 t Escherichia Coli Exp. TC^gBg 2 2 Escherichia Coli resistant to Gentamycin Tobramycin R 55 123 D 2 2 Klebsiella pneumoniae Exp. 52 145 0. 2 0.2 Klebsiella pneumoniae 2 5 36 resistant to Gentamycin Proteus rnirabilis (indol-) A 235 0. 5 0.5 Salmonella typhimurium 420 1 1 Providencia Du 48 i 49867 - 189 -product of example w STRAINS H.I.C. 24H * in ug/ml • 4 8U O.CS 0 .1 Eschsrichia Coli sensitive to Tetracycline ATCC 9 637 2 3 Escherichia Coli resistant to Tetracycline ATCC 11 303 1 1 Escherichia Coli Exp. 2 2 Escherichia Coli resistant to Gentaanyc in Tobramycin R 55 123 D 3 3 Klebsiella pneumoniae Exp. 52 145 • 1 1 Klebsiella pneumoniae 2 536 resistant to Gen- Proteus rnirabilis (indol-) A 235 1 .1 Salmonella typhimurium 420 3 Serratia resistant to Gentamycin 2 532... 4 9 8 6 7 PRODUCT OF EXAMPLE kl STRAINS M.I.C. 24H In ug/nl 48H . , -„ Penicillin-Staphylococcus aureus ATCC 6 5 38sensitive . . 10 Staphylococcus aureus UC 1 12 5 Pe1"-"11"*-1 J resistant Staphylococcus aureus exp. a" 54 i4G Streptococcus pyogenes A 561 0 .02 0.02 Bacillus subtiiis ATCC 6 633 2 2 Escherichia Coli nmsitive toTetracyclir.e ATCC 9 6^7 • 1 1 Escherichia Coli resistant to Tetracycline ATCC 1J 30 3 0 .05 0. 1 Escherichia Coli K:;?. TO^gB^. 0 .5 0 .5 Escherichia Coli resistant to Gentamycin Tobramycin R 55 123 D 0.5 0.5 Klebsiella pneumoniae Exp. 52 145 0 .2 0.2 •Klebsiella pneumoniae 2 5 36 resistant to Gentamycin 2 2 Proteus rnirabilis (indol-) A 235 0.2 0 2 Proteus rnirabilis (indol+) A 2 32 Salmonella typhimurium 420 ........... 0.5 1 • Providencia Du 48 3 3 Secratia RGlstant to. Gentamycin 2 532 1 2 PRODUCT OF EXAMPLE 1 STRAINS M.I.C. in yg/ml • 24H 48H •> Penicillin-Staphylococcus aureus ATCC 6 5 38 ncnsitive 0- 5 1 Penicillin- Staphylococcus aureus UC 1 128 resistant 1 1 Staphylococcus aureus exp.- n°54 146 1 1 Streptococcus pyogenes A 561 0.1 0.1 Streptococcus faecalis 5 4 32 » Streptococcus faecalis 99 F 74 Bacillus subtiiis ATCC 6 633 >. 1 2 Escherichia Coli sensitive toTetracycline ATCC 9 6 37 0. 1 0.1 Escherichia Coli rcni-itnnt to Tetracycline ATCC 11 303 0. 1 0.1 Escherichia Coli Exp. T02gBg 0. 1 o.l Escherichia Coli resistant to Gsntamycin Tobramycin R 55 123 D 0.5 0 .5 Klebsiella, pneumoniae Exp. 52 145 0.05 0 .1 Klebsiella pneumoniae 2 536 resistant to Genta- in • o 2 ProliMi:. m 1 r,il> M 1 n (Iik1'<1-) A 215 0. 1 0 - 1 0.2 0 .2 Enterobacter cloacae 681 *10 • 49867 - 192 - • PRODUCT OF EXAMPLE 2 STRAINS ' . M.I.C. 24H inyg/ml 48H Staphylococcus aureus ATCC 6 538 s'jjgitive11" 0.5 0.5 Staphylococcus aureus UC 1 128 resistant"" 1 1 0.5 1 Streptococcus pyogenes A 561 0.05 0.05 Streptococcus faccalis 5 432 1 1 Escherichia Coli sensitive to Tetracycline ATCC 9 637 0.2 0.2 iEschcrichia Coli resistant to Tetracycline ATCC 11 303 $ 0.1 0 .1 0.05 0 .05 Escherichia Coli resistant to Gtentamycin 0.5 0 .5 Klebsiella pneumoniae Exp. 52 145 0.05 0 .05 Klebsiella pneumoniae 2 536 resistant to Gbn ta- 0.5 0 .5 0. 1 0..1 o.i 0 .2 2 * • 4 tf B o r PRODUCT OF EXAMPLE 3 STRAINS •J 24H n_yg^ml_ 48H Penicillin- Staphylococcus aureus .ATCC 6 5 38 sensitive 1 2 Penicillin- Staphylococcus aureus UC 1*128 regiStant 2 2 Staphylococcus aureus exp. N°5 4 146 2 2 Streptococcus pyogenes A 561 0,2 (N • O Bacillus subtiiis ATCC 6 633 2 3 Escherichia Coli sensitive to Tetracycline ATCC 9 6 37 ()• 5 0.5 Escherichia Coli reaistant to Tetracycline ATCC 11 303 r i CM • o 0.2 Escherichia Coli Exp. TOjgBg 1 H * o 0. 1 Escherichia Coli resistant to Cfentamycin 0. 5 1 0. 1 o • N> Klebsiella pneumoniae 2 536 reeistant to. Genta- 1 l Proteus rnirabilis (indol-) A 235 0. 2 0.2 0.5 0.5 Enterobactor cloacae 681 .. .• 40 3 3 PRODUCT OF EXAhPLE 5 498 STRAINS M.I.C. 24H In. ug/ml 4811 Staphylococcus aureus ATCC 6 538 sensitive*1" 2 3 , , . , _ „ Penlcillin- StaphyJococcus aureus UC 1 128 resistant Staphylococcus aureus exp. N*54 146 2 3 Streptococcus pyogenes A 561 0.5 0.5 Bacillus subtiiis ATCC 6 633 Escherichia Coli sensitive to Tetracycline ATCC 0.5 0. 5 Escherichia Coli resistant to Tetracycline ATCC 11 303 0. 1 0. 1 • 0. 5 0.5 Escherichia Coli resistant to Gantamycin 2 2 1 Klebsiella pneumoniae Exp. 52 145 0.2 0.2 Klebsiella' pneumoniae 2 536 resistant toChntaray- 2 2 0.2 0.2 0.5 1 o t Ul 49867 PRODUCT OF EXAMPLE 7 STRAINS M.I.C. 24H tnUg/ml 4 8H Staphylococcus aureus ATCC 6 538 sensitive"- " 5 Staphylococcus aureus UC I 128 . reaistant"" 0.5 1 Bacillus subtiiis ATCC 6 633 Escherichia Coli sensitive to Tetracycline ATCC 0 637 1 i 1 Escherichia Coli resistant toTetracycline ATCC 11 30 3 0.5 1 1 1 | Escherichia Coli reaistant to Gbntamycin 1 1 I 0.5 i l ! Klebsiella pneumoniae 2 536 resistant to Genta- 2 2 0. 1 0 . 1 1 2 1 1 PRODUCT OF EXAMPLE 9 STRAINS.

M.I.C. in wg/ml 2«H 4 81! Staphylococcus aureus ATCC 6 538 Pcnicillin- r 1 sensitive J . 2 2 ."•taphylococcus aureus UC 1 128 resistant""" 3 3 Staphylococcus aureus exp. N" 54 146 3 3 0. 2 0.2 Bacillus subtiiis ATCC 6 6 33 1 2 Escherichia Coli sensitive to Tetracycline ATCC 9 6 37 0.5 0.5 Escherichia Coli resistant to Tetracycline ATCC 11 30 3 0. 1 0. 1 Escherichia Coli Exp. TOjgB^g 1 I 1 Escherichia Coli resistant to Cfentamycin Tobramycin R 55 123 D 0.5 0.5 Klebsiella pneumoniae Exp. 52 145 0 . 1 0.1 Klebsiella pneumoniae 2 536 resistant to Gfenta- 1 1 Proteus rnirabilis (indol-) A 235 0. 1 0. 1 Proteus vulgaris (indol + ) A 2 32 " 1 1 0.5 1 >40 3 3 3 49867 PRODl£T OF EXAM>LE 10 STRAIKC M.I.C. in" ug/ml 24H Staphylococcus aureus ATCC 6 538 Penic illin-sennitive Staphylococcus aureus UC 1' 12 8 Penic illin-resistar. t Staphylococcus aureus exp. n°54 146 1 Streptococcus pyogenes A 561 Bacillus subtiiis ATCC 6 633 Escherichia Coli sensitive to Tetracycline ATCC 9 637 0.5 Escherichia Coli resistant to Tetracycline ATCC 11 30 3 0.5 0.5 Escherichia Coli Exp. T02gBg Escherichia Coli resistant to Gentamycin Tobramycin P. 55 12 3 D Klebsiella pneumoniae Exp. 52 145 0.5 Klebsiella pneumoniae 2 5 36 resistant to Cfentarn yc in Proteus rnirabilis (indol-) A 235 0 .1 Proteus vulgaris (indol+) A 232 0.2 0.5 Salmonella typhimurium 420 Entcrobacter cloacae 681 2 ' 10 Providencia Du 4 8 Serratia reaistant to Gentamycin 2 532. 490V I PRODIC T OF EXAMPLE i? STRAINS . M. I.e. la yg/ml 24H 48H Penicillin- Staphylococcus aureus ATCC 6 i>38 sensitive Penicillin- Staphylococcus aureus UC 1 128 resistant Staphylococcus aureus exp. n°54 146 Streptococcus pyogenes A 561 0. 1 0.1 .

Streptococcus Caecalis 5 4 32 >40 Bacillus subtiiis ATCC 6 633 Escherichia Coli sens it ivo toTetracycline ATCC 9 637 0.2 0.2 Eschp.richia Coli resistant to Tetracycline ATCC 11 303 0.05 0.05 Escherichia Coli Exp. T02(,Bg 0. 2 0.2 Escherichia Coli resistant to Gbntainycin 0. 5 0.5 Klebsiella pneumoniae Exp. 52 145 0.1 0.1 Klebsiella pneumoniae 2 536 resistant to Genta- 0.2 0. 2 I'roteus rnirabilis (indol-) A 235 ; 0.02 0.02 Proteus vulgaris (indol+) A 232 1 1 0.5 0.5 40 40 - Serratia resistant to Gentamycin 2 532 2 - 4 9 8 6 7 _ 201. — PKODUCT OF EXAM'LE l5 STRAINS M.I.C. in vg/ml 24H 48H Staphylococcus aureus ATCC 6 5 38 Peni<|illii»- Staphylococcus aureus UC 1 128 Penicillin- Ecaisfeivpi Staphylococcus aureus exp. n°54 146 Streptococcus pyogenes A 561 ^ 0.02 4 0.02 Streptococcus faccalis 5.432 >40 Qacillus subtiiis ATCC 6 633 1 2 Escherichir. Coli sensitive to Tetracycline ATCC 9 6 37 0 . 1 0.3 [Escherichia. Coli resistant to Tetracycline jATCC 11 30^ 0,05 0.05 Escherichia Col'i Exp. TO_,Br Jo o 0. 1 0. 1 • Escherichia Coli resistant to Gtentamycin Tobramycin R 55 12 3 D 0. 1 0. 1 Klebsiella pneumoniae Exp. 52 145 0.05 0.05 Klebsiella pneumoniae 2 536 resistant to Gbnta-mycin 0.2 0.2 Proteus rnirabilis (indol-) A 235 0.1 0.2 Proteus vulgaris (indol+) A 232 1 2 0.1 0. 1 2 2 1 1 Serratia resistant toCfentamycin 2 532 0.5 1 49867 PRODUCT OP EXAI-PLE 16 STRAINS M.I.C. ir 24H ug/n>i 48H . , „renicillin-Stophylococcus aureus ATCC 6 538 oensitive 1 1 . Penicillin- Str.phylococcus aureus UC 1 128 resistant 1 2 Staphylococcus aureus exp. n°54 146 2 2 Streptococcus pyogenes A 561 0.05 1 1 o • 1 o KA Streptococcus faecalis 5 432 40 Streptococcus faecalis 99 F 74 > 40 ! Bacillus subtiiis ATCC 6 633 2 1 I 3 Escherichia Coli sensitive to Tetracycline ATCC 9 537 0 5 1 1 Escherichia Coli resistant to Tetracycline ATCC 11 303 0 .05 1 1 1 1 1 o 1 • 1 1 O 1 1 l/l 1 0.5 0.5 : Escherichia Coli resistant toG&ntamycin 0.2 i 0.2 0.2 0.2 Klebsiella pncunicniae 2 536 resistant to Gfenta- 1 1 Proteus rnirabilis (indol-) A 235 0.1 0.1 0.5 0.5 Serratia resistant toCbntamycin 2 532 2 2 49867 - 203 — PRODUCT OF E>CAK>LE t? STRAINS M.I.C. i. 24H n yg/ml 4811 ^enicillin- Staphylococcus aureus ATCC 6 5J8 sensitive . 1 1 Penicillins' taphvlococcus aureus UC 1 128 resistant 2 2 Staphylococcus aureus exp. n°54 1-15 2 2 0. 1 0.1 Streptococcus faccalis 5 4 32 40 ! Uacillus subtiiis ATCC 6 633 3 | I Escherichia Coli sensitive to Tetracycline i/\TCC 9 6 37 0.5 1 1 0.5 'lyncher i.ehia Coli resistant to Tetracycline iATCC 1 1 30 3 *. 0 .05 1 0.05 1 • (Escherichia Coli Exp. T02(-0g 0.2 0.2 : I Escherichia Coli resistant to Gsntamycin 0.5 0.5 : » [Klebsiella pneumoniae Exp. 52 145 1 1 1 1 o 1 • I o 1 \J% • 1 in 1 O 1 • 1 O I 1 1 1 Klebsiella pneumoniae 2 536 resistant toGenta-mycin 0.5 1 1 Proteus mi-rabilis (indol-) A 235 0.1 i 0.1 1 0.1 0 .1 3 Serratia resistant to Gentamycin 2 532 i id-'L/U^ 1 ,\JF bA.ih'll J'U "I 4y«B7 STRAINS Staphylococcus aureus ATCC 6 538 Penicillin-sensitive ••••••••••••••« .M.I.C. in /-c/ml Zk II t 48 II • Staphylococcus aurous UC 1 128 Penic illin-resistant v» •••••••••• Staphylococcus aurous oxp.n® 5^ 1^6 Stroptococcua pyoffanoa A 561..... c°- 02 C°-02! Stroptocoscun 1'c.ocalio 5 *»32' > ho Ducilluf r.uht.ilio ATCC 6 633.

Eaclioricliia Coli sensitive to Totr.icyc 1 ino ATCC 9 637.....

Eschoriclxia Coli resistant to Totracyclino ATCC 11 303••••< 0.2 0.2 Eschorichia Ccli Exp.TC-.-3 ZG"G' 0.2 0.5 Erachoriahia Coli resistant to Gontumycin « Tobramycin U 55 123 D 0.5 0.5 KlobBiolla i*houtnoniao Exp. 52 1-45« Klebsiella pnouaonino 2 536 resistant to Gontaiuycin 1 Protouo rnirabilis (indol—) A 235*• Salnonolla typhimurium 420. 0.5 Entorobaotor cloccao 68t< Providoncia DU kQ, Serratia resistant to Gentamycin 2532 .

STRAINS • M.I.C 24 X 1 • 1 H-1 0 - - 1 Afc/1711 j 48 I! / 1 Staphylococcus aureus ATCC 6 538 2 3 Staphylococcus fturoua UC 1 128 3 3 * Staphylococcus aureus oxn« n°54 146. 2 3 ' 0 .05 1 0.05 ^ 40 \ i 1 2 < ■ Eachoi-ichia Coil sensitive to Totracyclirio ATCC 9 637 1 t 1 < • Escherichia Coli -resistant to Totrc.cycliixo ATCC 11 303•»«»*»•« 0. 05 0.05 : 0. 2 0,2 : \ ► «: Ecofcoriohia Coli resistant -to Gontaniyciu, Tobramycin U 55 123D0 0, O JU 0.2 < 1 Klebsiella prsnumoniao Esp, 52 145 0. 2 0.2 ► ► Uloboiolla pr.ounonlao 2 536 1 1 Proteus rnirabilis (indol-) A 235•• 0. 1 0.1 • 1 • 1 | .

TO.

Surratia resistant to Gontooycin 2 532 1 - 1 j Pr>ODUCT___OF _KX AMPL.E_ STRAINS Staphylococcus r.urouo ATCC 6 538 Penicillin-sensitiva •••••••*•••••• Staphylococci aureus UC 1 128 Penicillin-resistant Staphylococcus auraus oxp.n°54l46 Stroytococcun pyeconoo A 561.

Sti'optooocous Tuocalia 5 432, Ba.cs.llua subtilin ATCC 6 633 < Eoc:Iioa*a.cliia Col.i sensitive to Tetracyclics ATCC 9 637 LechcrJ.ohia Coli resistant to Totracyellno ATCC 11 303....

, Eochorichia Coli Exp. T0_^B.j, 1 f-O o Eoclioriohia Coli resistant to Gonta— nycin, . Tobraciycia R 55 123 D,.., Klobainlln pnounoaiuo Exp. 52 145.

Klobsioiia pno\i:?i»niao 2 536 resistant-toGontaniycin Proi,ouM liiiira'oiiia (indol—JA -35..

Salmonolla typhircuriura 420, Entorobaotor cloauao 681, Ps*»vi»lonQi t» Thi 4Q, * ao u r M.I.C► in - /-c/wi 24 II « 48 II 0.05 0.5 0.05 0.2 0.2 0.05 0.5 0.05 0.2 0.05 0.05 0.2 0.2 0.05 0.5 0.05 0.2 3 Sorratia resistant to GontcuiTycln 2 532 2 - <l\Jf - PRODUCT OF i^XAiirLr: <»6 1 • STRAINS, ' M.I.C-. in 1 24 11 48 II ^ Staphylococcus aurouo ATCC 6 538 i Penicillin-sensitive* ••••••••••••••• i 5 \ Staphylococcus aurouo UC 1 120 i 5 ! ( StaphyJoooocua aurons oxp.n8 54 146. | » 0.05 0.05 ! t 1 2 | , Escherichia Coli sensitive to Tetra-oyoli.no ATCC 9 637 \ 3 3 i Escherichia Coll resistant to | Totrexcyclino ATCC 1i 303..... : 0.2 0.5 j Eachorichia Coli Exp. TOU^D.- *■ 26 o Escherichia. Coli resistant" toGcnta— ciycin Tobramycin R 55 123 D0,»0.

Klabaio.lla pneumoniae Exp* 52 145«i 0.5 KlobBioJ.ta pnauraonico Z 536 resistant to Gentamycin ••••••< Proteua rnirabilis (indol-) A 235...

Salmonolla typhimuriuni 420, Providonoia Du 40, 40 40 Sorrntia resistantjto Gontamycin 2 532, 49867

Claims (3)

1. CLAIMS 1. The new syn isomer 7-(amino-thiazolyl)-acetamido- ceph-3-em-4-carboxylic acid derivatives of the general formula: U Li (!') Co% A (wherein: 5 a) B represents a radical R which is:- i) a radical in whicl1 x represents a sulphur or X oxygen atom and R* represents: an alkyl or alkoxy radical having from 1 to 4- carbon atoms; 10 or a phenyl radical or a radical in which n E3 represents 0 or an integer from 1 to 4 and Rg and Rj, which may be the same or different, each represents a hydrogen atom or an alkyl radical having from 1 to 4 15 carbon atoms, or and Rj together with the intervening nitrogen atom form a piperidino, morpholino or phthalimido group; 4986? - 209 - ii) a radical -CH-COgA' in which A' represents a hydrogen atom, an alkali metal atom, an equivalent of an alkaline-earth metal atom or of a magnesium atom, an ammonium group, a substituted 5 ammonium group derived from an organic amino base or an easily-cleavable ester group, and R^ represents a phenyl, hydroxyethyl or nitrile radical; iii) the y-lactone of the formula ; or 0 iv) a radical -(CH2)n.-R^ in which n' represents an 10 integer of from 1 to 4 and R^ represents: an alkoxy radical containing from 1 to 4 carbon atoms or a radical Alk - S(0) - in which Alk represents an us alkyl radical contaiiling from 1 to 4 carbon atoms and ns represents 0, 1 or 2, /Re 15 or a radical —N in which Rg and R^, which N may be the same or different, each represent a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or Rg and Ry together with the intervening nitrogen atom form a phthalimido or 1-pyridinio group, 20 or, when n/ is an integer other than 1, a cyano radical, or a radical - C - NH~ in which X' represents — II 2 X' a sulphur atom or, when n' is an integer other than 1, * «7 U W I - 210 - an oxygen atom, or a 4-methyl- or 4-amino-1,3-thiazol-2-yl radical, or a l,2,3»4-tetrazol-5~yl radical, 5 or an azido radical, or an acyl radical having from 2 to 4 carbon atoms; b) B represents a radical R , which is a radical el -(CH2)ni-R^a in which V represents a halogen atom, or 10 a radical -S-Rar in which Rap represents a phenyl radical or a 5" or 6-membered aromatic heterocyclic radical containing from 1 to 4 heteroatoms selected from sulphur, nitrogen and oxygen, the phenyl and heterocyclic radicals being optionally substituted by one or more radicals sel- * 15 ected from amino, nitro and cyano radicals and alkyl radicals having from 1 to 4 carbon atoms; or c) B represents a radical R^ which is a radical -(CHg^i-R^ in which R^ represents an imidazolyl, morpholinyl or N-alkyl piperazinyl radical, the N-alkyl 20 radical containing from 1 to 4 carbon atoms; R^ represents a chloro or methoxy radical; or an alkyl, cycloalkyl or alkylthio radical having in each case from 1 to 5 carbon atoms; or a radical -CHg-S-Rj^ in which Rj^ represents 25 an optionally-substituted heterocyclic radical containing nitrogen, an acyl radical having from 2 to 4 carbon atoms, the 2-oxo-C3H]-thiazolin-4-yl-carbonyl radical or the 3-methyl-l,2-oxazol-5-yl-carbonyl radical; -211 or the acetoxymethyl or carbamoyloxymethyl radical; q 1/ or a radical -NH-C-Alk; and A represents a hydrogen atom, or an alkali metal atom, an equivalent of an alkaline-earth metal atom or of a magnesium atom, an ammonium group, a substituted ammonium group derived from an organic amino base or an easily-cleavable ester group) and acid addition salts of the derivatives of general formula I' formed with mineral or organic acids.
2. 2. Derivatives of the general formula: R, R.j and A are as defined in claim 1. Derivatives of the general formula: 1 wherein (I) 3. 1 Co.^ wherein R , Ri and A are as defined in claim 1.
3. 3 I 49867 - 212 - Derivatives of the general formula: M 1 C02A wherein Rg, R-j and A are as defined in claim 1. 5. A compound as claimed in any of the preceding claims, wherein represents the radical -CHg-S- R12 in which is a 1»2,3~, l,2,5~i 1>2,4- or 1,3,4- -thiadiazolyl radical; a lH-tetrazolyl radical; a 1,3-thiazolyl radical, a 1,2,3- or 1,2,4- -triazolyl radical; or a 1,2,3-, 1*2,4-, 1,2,5- or 1,3,4-oxadiazolyl radical, and each of these heterocyclic radicals being either unsubstituted or substituted by one or more radicals selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyloxy and isopropyloxy, amino, hydroxycarbonylmethyl, dimethylaminoethyl and diethylaminoethyl radicals. 6. A compound as claimed in any of Claims 1 to 4, wherein R^ represents the radical -CHg-S-R^g which R^g is an acetyl, propionyl or butyryl group. 7. A compound as claimed in any of Claims 1 to 4, wherein R^ represents the radical -CHg-S-R^g which R^g is the acetyl, 1-methyl-tetrazolyl, 2-methyl-l,3,4-thia-diazolyl; 3-methyl-l,2,4-thiadiazol-5-yl; 3-methoxy-1,2,4-thiadiazolyl; l,3,4-thiadiazol-5-yl; 2-amino-l,3»4-»-thia-diazol-5-yl; 3-hydroxycarbonylmethy1-1,2,4-thiadiazol-5~ yl; 5-methoxy-l,2,4-thiadiazol-3-yl» 4-methyl-5~hydroxy- - 213 - carbonylmethyl-l,3-thiazol-2-yl or 1-dimethylaminoethyl-l,2,3,4-tetrazol-5-yl radical. 8. A compound as claimed in Claim 2, wherein: i) R is the radical -CO-R' and R' represents an 5 alkyl radical having from 1 to 4 carbon atoms, a phenyl radical or a radical -(CHg^-NRgR^ in which n is 0 or 1; I4 or ii) R is the radical -CH-COOH and R^ represents a phenyl radical or a hydroxyethyl radical, or iii) R is the y lactone of formula » 10 or iv) R is the radical -(CHgJ^-R^, n' is° 1 or 2 and R^ represents either a radical -NRgR^, a radical -C-NHg, a l,2,3,a-tetrazol-S-yl radical or an acetyl S radical; and R-^ represents an alkyl radical having from 1 to 5 carbon atoms, an acetoxymethyl radical or a radical 15 -CHg-S-R^g in which R^g represents a 2-methyl-l,3,4-thia-diazolyl radical or a 1-methyl-tetrazolyl radical; and A represents a hydrogen atom, an alkali metal atom, an equivalent of an alkaline-earth metal atom or of a magnesium atom, ammonium or a substituted ammonium 20 group. 9. A compound as claimed in Claim 8, wherein R represents an acetyl, benzoyl, phthalimidoacetyl, N,N-dimethyl-carbamoyl, a-carboxyphenylmethyl, 2-oxo-3~tetrahydro-pyranyl, l,4-dihydroxy-l-oxo-2-butyl, phthalimidomethyl, 25 aminoethyl, tetrazol-5-yl-methyl, 2-amino-2-thioxoethyl \ 49867 - 214 - or 2-oxopropyl radical; R^ represents a methyl, acetoxymethyl, 2-methyl-l,3,4-thiadiazol-5-yl-thiomethyl or 1-methyl-tetrazolyl-thiomethyl radical; and A represents a hydrogen or sodium atom. 5 10. A compound as claimed in Claim 9, wherein R represents an acetyl, benzoyl, phthalimidoacetyl, tetrazol-5-yl-methyl, aminoethyl or a-carboxy-phenylmethyl radical; R^ represents an acetoxymethyl, 2-methyl-l,3,z^~thiadiazol-5-yl-thiomethyl or l-methyl-tetrazol-5-yl-thiomethyl 10 radical. 11. A compound as claimed in Claim 3i wherein R^0 represents a bromine or iodine atom or a phenylthio, 2-pyridinylthio, 2-amino-l,3,4-thiadiazol-5-ylthio, 1-methyl-lH-tetrazol-5-ylthio, 2-amino-phenylthio, 5-nitro-2- 1 15 pyridinylthio or 3-cyano-6-methyl-2-pyridinylthio group. 12. 3-Acetoxymethyl-7-C[2-(2-amino-thiazol-4-yl)-2-(2-aminoethoxyimino-acetyl]-amino]-ceph-3-em-A^carboxylic acid syn isomer, its salts with alkali metals, alkaline-earth metals, magnesium, ammonium and organic amino bases, 20 and its esters formed with easily-cleavable ester groups. 13. 3-Acetoxymethyl-?-[[2-(2-bromoethoxyimino]-2-(2-amino-thiazol-4-yl)-acetyl]-amino]-ceph-3-em-4-carboxylic acid syn isomer, its salts with alkali metals, alkaline-earth metals, magnesium, ammonium and organic amino 25 bases and its esters formed with easily-cleavable ester groups. 14. 3-Acetoxymethyl-7-C C2-(2-iodoethoxyimino)-2-(2- 4 9 8 6 7 - 215 - amino-thiazol-4-yl)-acetyl3-amino3-ceph-3-em-4-carbox7lic acid syn isomer, its salts with alkali metals, alkaline-earth metals, magnesium, ammonium and organic amino bases and its esters formed with easily-cleavable ester groups. 5 15. 3-Acetoxymethyl-7-[[2-(2-amino-thiazol-4-yl)-2- (carbamoyloxyimino)-acetyl J-amino]^ceph-3-em-4-carboxylic acid syn isomer, its salts with alkali metals, alkaline-earth metals, magnesium, ammonium and organic amino bases and its esters formed with easily-cleavable ester groups. 10 16. A process for preparing the derivatives of general formula I' wherein A represents a hydrogen atom, in which process a compound of one of the general formulae: (wherein R,, represents a protecting group for the amino radical 15 A" represents an easily-cleavable ester group ' or a hydrogen atom, and R'^ represents an alkyl radical having from 1 to 4 carbon atoms, an alkoxy radical having from 1 to 4 carbon atoms, a phenyl radical or a radical -(CHg)n-NR"2®"5 which R"2 and R"^ which may be the same 20 or different, each represent a hydrogen atom or an alkyl radical with the proviso that both R"g not both represent hydrogen when n is zero, or R"2 and together with the intervening nitrogen atom represent a phthalimido, 49867 - 216 - piperidino or oorpholino group) I (III'A) 1 L I „ | (inB) R'4 ' (wherein R\ represents a phenyl or a cyano radical and A''' represents an easily-cleavable ester group) 0 NH <? lb , CBTc) Ctt,*" vc— CH^-CH OH <U3^± (Hie) 49867 - 217 - (wherein A*^ represents an easily-cleavable ester group or an alkali metal atom and A^ represents an alkali metal atom), X. WH H tC CJOo.^ (IIID) (wherein R'^ represents an alkoxy radical having from 1 to 4- carbon atoms, a radical Alk-S(0)_ or an acyl radical ns having from 2 to 4 carbon atoms), A- . tfH \ s _C-M \ CCM.J) a! (wherein n2 represents the integer 2, 3 or 4), /V, ft \ o(cvO„'—c-nh_ X1 Ca^h" (IIIp) o - 218 - N \ '7^, 'W' (iliG) (wherein R'^ represents a methyl or amino radical) mhr(6 M XX. ^HR,t ccH»V\ y A Y H N V XX \ * A " \o4,\. (wherein Hal represents a halogen atom) CIIIH) »irH) 49867 NHfs,, A. - 219 - MH. \ r YHR/6 S N \ ®/==\ co-x.f>1' Uh^\J (Illj) H \ "Xl \ \ 1 CchO^/% <Afl" a; ■ rj r~T \ ° . \ I -1 V V COA" MHR<fa ✓'S 0 o NH \ <"V <ni's) X ' S> (CH,V *'1 C°'- (IIIl.) 498 - 220 - (wherein R^g represents a group removable by acid hydrolysis or by hydrogenolysis or an alkyl radical having from 1 to 4 carbon atoms and R^g represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or R18 and R^^ together with the intervening nitrogen atom form a phthalimido group) (iii'l) an„) is treated with one or more of hydrolysis agents, hydrogenolysis agents and thiourea to obtain respectively: a product of the general formula: 49867 - 221 - a product of the general formula: NHX O NH —r— M J—hi li i II X CQ^H a product of the general formula: NH, 0 \ M I a product of the general formula: NH, V^"~P'ST Xt Co^H (iB) (In) 4»8B7 - 222 - a product of the general formula MH, A, i -s C?WH O-CK-CO^H CH^CH^OH to^H a product of the general formula: (I'r) c?MH XX, a product of the general formula: NH, A, <?UH XX \ " T ^ XcK^-Crt CO^H a product of the general formula: Hr«'NH:< C0«-H x* (ijj) dE) <V 49867 - 223 - product of the general formula: mh, A lOUH ^ ^5^ NaR'7 CC^H product of the general formula: .X dr.) o kfh hf \ XX a product of formula I'H 'oc^v^T} j Rj c?(jh *\ ° OCCU^- Hal c ct^h product of the general formula: "X^, **w-sQ C<VH "h> (!•„) (It) - 22a - product of the general formula: NH, Lh (IK) a product of the general formula: S <?|JH N \ °v I ~ COaH a product of the general formula: (I'K) c?tJH H tCX \ " 1 CO^H wherein substituents R^g may be the same or different, a product of the general formula;. 49867 - 225 - tfH., 'a s .a: N \ coUH (rb) OO^H or a product of the general formula: X S bi COKiH \ CM \ CA^H 4»« b7 17. A process as claimed in Claim 16, in which a formed compound of general formula 1^, is reacted first with a base and then with an acid to yield the corresponding compound 1'^. 18. A process as claimed in Claim 16 or Claim 17, in which the formed 5 acid of general formula IA> I'A, Ig, Ic> l'c, ID> Ilp, Ig, IH> I'H> IK' *'k' XL' *'b or *M *s therea^ter salified and/or esterlfled to form a salt or an ester of general formula I' in which A is as defined in claim 1 except that it does not represent a hydrogen atom. 19. A process as claimed in Claim 18, in which sali-10 fication is carried out in one or more of water, diethyl" ether, methanol, ethanol and acetone. 20. A process as claimed in Claim 18, in which esteri fication is carried out by reacting the acid with a derivative of the general formula: 15 2 ~ K20 in which Z represents a hydroxy radical or a halogen atom and R2Q denotes the ester group to be introduced. 21. A process as claimed in Claim 16, in which the compound of general formula IH^ is prepared by treating 20 a compound of general formula II with a functional derivative of the acid HO-CX-R'^. 22. A process as claimed in Claim 21, in which the functional derivative of the acid HO-CX-R'^ is an acyl halide, a symmetric or mixed anhydride, a ketene or an 25 acyl azide, or a haloformate when R'^ represents an alkoxy radical, or an isocyanate when R'^ represents a group 4 98 67 - 227 - -NR'^R'^ and one of R''^ or R"^ represents a hydrogen atom. 23. A process as claimed in Claim 21 or Claim 22, in which the acylation is carried out in a solvent, the solvent being a halogenated hydrocarbon, a cyclic ether, a 5 nitrile, a nitro-substituted hydrocarbon or an ester. 24. A process as claimed in Claim 22, in which the functional derivative is an acyl halide and the reaction is carried out in the presence of triethylamine, pyridine, propylene oxide, magnesium oxide, sodium carbonate or 10 calcium carbonate. 25. A process as claimed in Claim 16, in which the compound of general formula III'^ is prepared by reacting a compound of general formula II with a compound of general formula X * C « NH. 15 26. A process as claimed in Claim 25, carried out in a solvent as defined in Claim 23. 27. A process as claimed in Claim 16, in which the compound of general formula IHg is prepared by reacting a compound of general formula II with a compound of the 20 general formula Y - CHR'^-COg AA •' in which Y represents a halogen atom, or an SO^H or organic sulphonyloxy group. 28. A process as claimed in Claim 27, in which Y represents a chlorine, bromine or iodine atom or an S04H, methanesulphonyloxy . or p-toluenesulphony1oxy radical. 25 29. A process as claimed in Claim 27 or Claim 28, in which the reaction is carried out in the presence of potassium tert-butoxide, sodium hydride or a tertiary amine. « O O W I - 228 - 30. A process as claimed in any of Claims 27 to 29, in which the reaction is carried out in a solvent, the solvent being a halogenated hydrocarbon, a cyclic ether, an N,N-disubstituted amide or dimethyl sulphoxide. 5 31. A process as claimed in Claim 16 or Claim 17« in which the compound of general formula IIIq is prepared by reacting a compound of general formula II with a compound of the general formula: O 32. A process as claimed in Claim 311 in which Y is as 10 defined in Claim 28. 33. A process as claimed in Claim 31 or Claim 32, which is carried out under the conditions defined in Claim 29 or Claim 30. 34. A process as claimed in any of Claims 31 to 33, in 15 which the formed product of general formula IIIq is treated with a base to form the corresponding compound of general formula III'q. 35- A process as claimed in Claim 16, in which the compound of general formula III^ is prepared by reacting a 20 compound of general formula II with a compound of the general formula Y -(CHg^i-R'y 36. A process as claimed in Claim 35> in which, when R'^ represents an alkylthio radical, the product of general formula IIIq is thereafter oxidised to the corre- 25 sponding sulphoxide or sulphone of general formula III^. 37. A process as claimed in Claim 35 or Claim 36, in -V 4-9 8 6 7 - 229 - which Y is as defined in Claim 28. 38. A process as claimed in any of Claims 35 to 37» in which the reaction is carried out under the conditions defined in Claim 29 or Claim 30« 5 39. A process as claimed in Claim 16, in which the compound of general formula IHg is prepared by treating a compound of general formula II as defined herein with a compound of the general formula Y -(CH?)np - CN. 40. A process as claimed in Claim 39> in which Y is as 10 defined in Claim 28. 41. A process as claimed in Claim 39 or Claim 40, in which the reaction conditions are as defined in Claim 29 or Claim 30. 42. A process as claimed in Claim 16, in which the com-15 pound of general formula IIIp is prepared by treating a compound of the general formula: either with hydrogen sulphide or, when n' is an integer other than 1, by hydrolysis in the presence of a base to obtain the corresponding product of general formula IIIj.. 20 43. A process as claimed in Claim 42, in which the reaction of the compound of general formula IV with hydrogen sulphide is carried out in the presence of a tertiary amine. 4986? - 230 - 44. A process as claimed in Claim 42 or Claim 43, in which the reaction is carried out in dimethylformamide as solvent. 45. A process as claimed in Claim 42, in which the 5 hydrolysis of the compound of general formula IV in which X' represents an oxygen atom and n* is an integer from 2 to 4 is carried out using a dilute sodium hydroxide solution. 46. A process as claimed in Claim 16, in which the compound of general formula IIIq is prepared by reacting a 10 compound of general formula HIj. wherein X is a sulphur atom with a compound of the general formula R'^-CO-CHg-Hal. 47. A process as claimed in Claim 46, in which the compound of general formula IIIj. is prepared by a process as defined in any of Claims 42 to 44. 15 48. A process as claimed in Claim 46 or Claim 47» in which Hal represents a chlorine or a bromine atom. 49. A process as claimed in Claim 16, in which the compound of general formula IHjj is prepared by treating a compound of the general formula TV with an azide. 20 50. A process as claimed in Claim 49 > in which the azide is sodium azide. 51. A process as claimed in Claim 49 or Claim 50» i** which the reaction with the azide is carried out in dimethylformamide. 25 52. A process as claimed in Claim 16, in which the compound of general formula lH'g is prepared by treating a compound of general formula II with a compound of the 49867 - 231 - general formula Hal-CCHg^i-Hal wherein the two Hal substituents may be the same or different. 53. A process as claimed in Claim 52., in which Hal represents a bromine or iodine atom. 5 54. A process as claimed in Claim 16, in which the compound of general formula IHj is prepared by treating a compound of general formula Ill'g with pyridine. 55- A process as claimed in Claim 5^1 in which the reaction is carried out in dimethylformamide as solvent. 10 56. A process as claimed in Claim 16, in which the compound of general formula III^ is prepared by treating a compound of general formula HI'jj with an azide. 57. A process as claimed in Claim 56, in which the azide is sodium azide^ 15 58. A process as claimed in Claim 56 or Claim 57» in which the product of general formula Hlg is reduced to form the corresponding product of general formula Ill'g. 59. A process as claimed in Claim 581 in which the reduction is effected using hydrogen sulphide in the pres- 20 ence of triethylamine. 60. A process as claimed in Claim 591 which is carried out in dimethylformamide. 61. A process as claimed in Claim 16, in which the compound of general formula IHj, is prepared by treating 25 a compound of general formula III'jj with an amine of the general formula NHR^gR^. 62. A process as claimed in Claim 61, in which R18 is - 232 t 49867 a trityl radical. 63. A process as claimed in Claim 61 or Claim 62, in which the reaction with the amine NHR^gR^g is carried in dimethylfo nnamide. 5 64. A process as claimed in Claim 16, in which the compound of general formula HI'jj is prepared by a compound of general formula Hl'g with imidazole, morpholine or an N-alkyl piperazine. 65. A process as claimed in Claim 64, in which the 10 reaction is carried out in the presence of triethylamine, or an alkali metal carbonate or bicarbonate. 66. A process as claimed in Claim 64 or Claim 65» in which the compound Hl'jj is used in the form of a salt. 67. A process as claimed in Claim 66, in which the 15 diethylamine salt of the compound IH'g is used. 68. A process as claimed in Claim 64, in which the reaction is carried out in the presence of a quaternary ammonium salt. 69. A process as claimed in Claim 16, in which the 20 compound of general formula IIIM is prepared by reacting a compound of general formula Ill'jj with a compound of the general formula Rar~SH. 70. A process as claimed in Claim 69, in which the reaction is carried out in the presence of triethylamine, 25 or an alkali metal carbonate or bicarbonate. 71. A process as claimed in Claim 69 or Claim 70, in which the diethylamine salt of the compound of general formula UI'jj is used. 49867 - 233 - 72. A process as claimed in Claim 69, in which the reaction is carried out in the presence of a quaternary ammonium salt. 73. A process as claimed in Claim 69» in which an 5 alkali metal derivative of the compound of general formula K -S-H is used and the reaction is carried out in the ar presence of an alkali metal halide. 74. A process as claimed in any of Claims 54- to 73* in which the compound IH'jj is prepared by a process as 10 defined in Claim 52 or Claim 53. 75» A process as claimed in any of Claims 42 to 45 and 49 to 51i in which the compound of general formula IV wherein n' is 2, 3 or 4 is prepared by a process as defined in any of Claims 39 to 41 for the preparation of compounds 15 IIIE. 76. A process as claimed in any of Claims 42 to 45 and 49 to 51% in which the compound of general formula IV wherein n/ is 1 is prepared by reacting a compound of general formula II with a compound of the general formula 20 Y-CH2-CN. 77. A process as claimed in any of Claims 21 to 41, and 52 and 53i in which the starting material of general formula II is prepared by treating a compound of the general formula: 4U8 67 NW/? S hi lb - 234 - CoWH \ rXX, ^c—ncM I CoxA' CM-, (D) with an aqueous mineral acid. 78. A process as claimed in Claim 77» in which the compound of general formula D is prepared by reacting a compound of the general formula: C*VH S^M Nl CH, (X ( f C— CH, I OCWi (C) 5 or a functional derivative thereof, with a product of the general formula: (IX) 79. A process as claimed in Claim ?8, in which the compound of general formula C is prepared by a process in which a compound of the general formula: 49867 - 235 - X >£*■>* i tJ \oH (V) is treated with 2-mefchoxypropene. 80. A process for the preparation of the compounds of general formula Hlgi IIIqi IIIG, IIIH, IHj, IHK, IHL, III'l or IIIM, in which a compound of one of the general formulae: COj. K nj * (»iA) S 'CQ^H ""V *0— £-NH^ N * MHR(t (VI'A> S^jvJ " R', N '0— CK-CC^A ui (VIB) (*ia) (3ia) cqia) / N H <00' J= N,ar no-zvQ»O)-O, N HzCO N^5 ^'cJHN (°ia) H**0} n N^<5 n,^HN ■9^h JL W-cOy 7=\ - stz - '"-awi 49867 NUfcife " 257 " M CO^H M"°~Cch^vX'7 MR*, s^rt cj02h M //S,~NS NJ — N l H NH£ifc s/Ssl CO^W N> O-CcH^-HaL NH^fc S-^fsJ Co^H <M @> . (vir) (VIH) (VI'„) (VI.) - 238 - N. caj* -o-(c h^/-^ C<\H N (vik) MHR,fe s^^Nl I N Cjd^W (VIT) CO,,H N (vi1L) (V!„) - 239 - or a functional derivative of a compound of one of these general formulae is reacted with a compound of general formula IX, to obtain, respectively, the compounds of general formulae III^, III'A, IHg» *IIq> ***0' IIIF, IIIG, IIIH, III'H, IIIj, IIIK, IIIL, HI'L and IIIM. 81. A process as claimed in Claim 80, in which the functional derivative is an acyl halide, symmetric or mixed anhydride, amide or activated ester. 82. A process as claimed in Claim 80 or Claim 81, in which the reaction is carried out in an organic solvent. 83. A process as claimed in Claim 81, in which, when the compound of general formula IX is reacted with an acyl halide or a mixed anhydride formed with isobutyl chloro-formate, the reaction is carried out in the presence of a base. 84. A process as claimed in Claim 83% in which the base is sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, sodium acetate, triethylaminei pyridine, morpholine or N-methyl-morpholine. 85. A process as claimed in any of Claims 80 to 84, in which substituent is a trityl, chloroacetyl, tert-pentyloxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl radical. 86. A process as claimed in any of Claims 80 to 851 ia which the formed compound of general formula IIIq is treated with a base to form a corresponding compound of general formula III'q. - 2/1.0 - 49867 87. A process as claimed in any of Claims 80 to 85i in which the compound of general formula VIA is prepared by treating a compound of general formula V with a functional derivative of the acid HO-CX-R'^. 5 88. A process as claimed in any of Claims 80 to 85» in which the compound of general formula VI*^ is prepared by reacting a compound of general formula V with a compound of formula X=C=NH. 89. A process as claimed in any of Claims 80 to 85» in 10 which the compound of general formula VIg is prepared by reacting a compound of general formula V with a compound of the general formula Y-CHR'^-COgA'''. 90. A process as claimed in any of Claims 80 to 86, in which the compound VI_ is prepared by reacting a compound v 15 of general formula V with a compound of the general formula 0 91. A process as claimed in any of Claims 80 to 85* in which the compound VID is prepared by reacting a compound of the general formula V with a compound of the general 20 formula Y-CCHg^t-H' y 92. A process as claimed in any of Claims 80 to 85» in which the compound VI^ is prepared by reacting a compound of general formula V with a compound of the general formula Y-(CH2)n2-CM . 25 93. A process as claimed in any of Claims 80 to 85* in which the compound VI^, is prepared by a process in which -O. - 241 - a compound of the general formula: N CVII) is treated either with hydrogen sulphide or, when n1 is an integer other than 1, by hydrolysis in the presence of a base, to obtain the corresponding product of formula VI^. 94. A process as claimed in any of Claims 80 to 85» in which the compound of general formula VI^ is prepared by treating the compound of general formula VIj, wherein x' represents a sulphur atom with a compound of the general formula R'^-CO-CHj-Hal. 95. A process as claimed in any of Claims 80 to 85, in which the compound of general formula VIjj is prepared by treating the compound of general formula VII with an azide. 96. A process as claimed in Claim 95 or Claim 95« in which the compoxmd of general formula VII wherein n' is 2, 3 or 4 is prepared by a process as defined in Claim 92 in relation to compounds VI^.. 97. A process as claimed in Claim 93 or Claim 95» in which the compound VII wherein n* is 1 is prepared by reacting a compound of general formula V with a compound of the general formula Y-CHg-CN. 98. A process as claimed in any of Claims 80 to 85» in which the compound of general formula VI*^ is prepared by - 242 - 49867 reacting a compound of the general formula: W , v ^OH (v'5 (wherein Rg represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms) with a compound of the general formula Hal-(CH2)nt—Hal (wherein the substituents Hal may be the same or different) to obtain a product of the general formula: MHR.y X a. z. ° . „ (vr'n) which product of formula when RQ represents an alkyl radical having from 1 to 4 carbon atoms, is treated first with a base and then with an acid. 20 99. A process as claimed in Claim 98, in which Hal represents a bromine or iodine atom. 100. A process as claimed in Claim 98 or Claim 99» in which the compound of general formula Hal-(CH2)ni-Hal is reacted with the compound V' in the presence of a base to 15 neutralize the hydrohalic acid formed. 101. A process as claimed in any of Claims 98 to 100, in which the ester of general formula VI"g wherein Rg N - 2*. 5 - represents an alkyl radical having from 1 to 4 carbon atoms is reacted firstly with sodium hydroxide, potassium hydroxide or barium hydroxide, and then with dilute hydrochloric acid, acetic acid or formic acid. 102. A process as claimed in any of Claims 80 to 85» in which the compound of general formula VIj is prepared by reacting a compound of general formula VI'jj with pyridine. 103. A process as claimed in any of Claims 80 to 85, in which the compound of general formula VI^ is prepared by reacting a compound of general formula VI'^ with an azide. 104. A process as claimed in any of Claims 80 to 85, in which the compound of general formula VI^ is prepared by reacting a compound of general formula VI'jj with an amine of general formula NHR^gR^. 105. A process as claimed in any of Claims 80 to 85, in which the compound of general formula VI' ^ is prepared by reacting a compound of general formula VI1 jj with imidazole, morpholine or an N-alkyl piperazine. 106. A process as claimed in any of Claims 80 to 85» in which the compound of general formula VI^ is prepared by reacting a compound of general formula VT'g with a compound of general formula Rar-SH. 107. A process as claimed in any of Claims 102 to 106, in which the compound VI* g is prepared by the process defined in any of Claims 98 to 101. 108. A process for the preparation of a derivative of general formula I' or a salt thereof as defined in Claim 1 substantially as described herein with reference to any 49867 - 244 -one of the Examples. 109. A derivative of general formula l'or a salt thereof as defined in Claim 1 whenever prepared by a process as claimed in any of Claims 16 to 79 and 108. 5 1 10. A derivative of general formula I' as-defined in Claim 1 or an addition salt thereof formed with a pharmaceutically-acceptable mineral or organic acid for use in a method of treatment of the human or animal body by antibiotic therapy. 111. A derivative of general formula I' as claimed in any of 10 Claims 2, 3 and 4 or an addition salt thereof formed with a pharmaceutically-acceptable mineral or organic acid for use in a method of treatment of the human or animal body by antibiotic therapy. 112. A compound of general formula I* as defined in any of Claims 5 to 15 for use in a method of treatment of the human or animal 15 body by antibiotic therapy. 113. Pharmaceutical compositions containing as active ingredient one or more derivatives of general formula I' and/or one or more addition salts thereof formed with pharmaceutically-acceptable mineral or organic acids, 20 in association with a pharmaceutically-acceptable vehicle. 114. A composition as claimed in Claim 113, in which the active ingredient is or includes one or more compounds as claimed in any of Claims 2 to 15. 115. A method of disinfecting a locus excluding on human 25 beings, in which there is applied to the locus an effective disinfecting amount of a compound as claimed in Claim 1. 116. The compounds of the general formula: 49867 5 lb - 245 - \ o o* V ■«* tx wherein R^ represents: a radical -CX-R'^; a radical -CX-NI^; a radical -CHR'^-CC^A'''; a radical O v° o a radical -(CHg^i-R* a radical -(CI^^CN; a radical -(CH^.CX'-NH^ a radical -(CH2)ni HX N ^7 tvS—M 10 a radical -(CH^>n, ft ! H (A) a radical *9887 - 246 -a radical (CHgJ^-Nj; a radical (CH2)n,-NR18Rig, with the proviso that R1& cannot represent a chloroacetyl radical when R^ represents -CX-CHj and represents an acetoxymethyl radical. 11?. The compounds of the general formula: NHR A 16 N CONH N \ 0< °-(CH2)n1-Ra ' "l 2 n ~Ra COgA" (XII) 118. The compounds of the general formula: CONH i ^^n' .-Hal' f "vS (XII') co^- CHg-R'j wherein R'16 represents a trityl or chloroacetyl radical, n'^ represents 1 or 2; Hal' represents a bromine or >49 867 - 2*7 - iodine atom and R'^ represents a hydrogen atom, an acetoxy or carbamoyloxy radical or a 1-methyl--tetrazol-5-yl or 2-methyl-l,3,4-thiadiazol-c>-yl radical. 5 119. The compounds of general formula Dated this 8th day of August 1979, TOMKINS &_C0., (signed) 5 Dartmouth Road, DUBLIN 6 Having regard to the provisions of Section 14 of the Patents Act, 1964, attention is directed to claims 15 and 16 of our Patent No. 45015, and to the claims of Patent No. 46674, and Patent No. 45597. I