NO792265L - AMINOTIASOLFORBINDELSER. - Google Patents

Description

Aminothiazole compounds

The invention relates to new 7P-aminothiazolyl-acetamido-3-cephem-4-carboxylic acid compounds which are unsubstituted in the 2- and 3-position in the -cef.em ring, process for their preparation, pharmaceutical preparations containing such compounds and their use as antibiotics .

The invention relates in particular to 7P-amino-thiazolyl-acetamido-3-cephem-4-carboxylic acid compounds of formula

in which R-^ denotes hydrogen, lower alkyl or an amino protecting group, A denotes methylene or optionally protected amino, hydroxy or sulpho, by oxo, optionally protected or carbamoylated hydroxyimino or methoxyimino-substituted methylene, R~ denotes hydrogen, methoxy or a methoxy replaceable group and Rg denotes hydrogen or a residue with an esterified carboxy group, and salts of such compounds with salt-forming groups.

In the present description of the invention, the term "lower" in groups such as lower alkyl, lower alkylene, lower alkoxy, lower alkanoyl and the like means that corresponding groups contain, if not otherwise expressly defined, up to 7> preferably up to 4 C atoms.

A lower alkyl group R 1 is especially C 1 -C 4 lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl or tert-butyl.

The functional groups in connection with formula I present, especially carboxyl and amino, hydroxy, hydroxyimino and sulfo groups, are optionally protected with protective groups, which are used in penicillin, cephalosporin and peptide chemistry.

Such protective groups an easily cleavable,

i.e. without unwanted side reactions taking place, for example solvolytic, reductive, photolytic or also in the case of psychological conditions.

The protective group of this kind, as well as their cleavage, is described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973>

further in "The Peptides", Volume I, Schroder and Lubke, Academic Press, London, New York, 1965.

An amino protecting group R is preferably an acyl group Ac, a mono-, di- or triarylmethyl group or a silyl or stannyl group.

In an acyl group Ac, the acyl residue is an organic carboxylic acid with up to l8 C atoms, especially a

e.g. with halogen or aryl, substituted aliphatic carboxylic acid or optionally, e.g. with halogen, lower alkoxy or nitro, substituted aromatic carboxylic acid, or a carboxylic acid half-ester. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl. propionyl, halogen-lower alkanoyl, such as 2-haloacetyl, especially 2-chloro-,'2-bromo-, 2-iodo, 2,2-dichloro- or

■2,2,2-trichloroacetyl-, phenylacetyl, f enoxyacetyl, thienylacetyl, benzoyl, 4-chloro-, 4-methoxy- or. 4-nitrobenzoyl, lower alkoxycarbonyl, especially tert.-lower oxycarbonyl, e.g. tert-butyloxycarbonyl, polycycloalkoxycarbonyl, e.g. adamantyloxycarbonyl, arylmethoxycarbonyl, wherein aryl preferably denotes one or two, optionally, e.g. with lower alkyl, especially tert.-lower alkyl, e.g. tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, e.g. chlorine, and/or nitro-,

mono- or polysubstituted phenyl residues, such as optionally substituted benzyloxycarbonyl, e.g. 4-nitro-benzyloxycarbonyl, or substituted diphenylmethoxycarbonyl, e.g. benzhydryloxycarbonyl or di-(4-methoxyphenyl)methoxycarbonyl,

or 2-halo-lower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or acylmethoxycarbonyl,

especially aroylmethoxycarbonyl, in which the aroyl group preferably denotes optionally, e.g. with halogen, such as bromine, substituted ■•*■ benzoyl, e.g. phenacyloxycarbonyl.

In a.mono-, di- or triarylmethyl group R^

are the aryl residues in particular optionally substituted phenyl residues. Such groups are, for example, benzyl, diphenylmethyl or trityl.

A silyl or stannyl group R is preferably an organic silyl or stannyl group, in which silicon or the tin atom preferably contains as a substituent lower alkyl, especially methyl, further lower alkoxy, e.g. methoxy, and/or halogen, e.g. chlorine. Corresponding silyl or stannyl groups are preferably trilower alkylsilyl, especially trimethylsilyl,

further dimethyl-tert-butyl-silyl, lower alkyl-lower alkyl-halo-silyl, e.g. methoxy-methyl-chloro-silyl, or dilave alkyl-halo-silyl, e.g. dimethyl-chloro-silyl, or similarly substituted stannyl, e.g. tri-n-butylstannyl.

Preferred amino protecting groups R-^ are the acyl residues of the 2-halidedioxygen, especially 2-chloroacetyl, as well as of carboxylic acid half-esters, especially tert-lower oxycarbonyl, e.g. tert.-butoxycarbonyl, optionally, e.g. as before

indicated substituted benzyloxycarbonyl or diphenylmethoxycarbonyl, or 2-halo-lower oxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, as well as the trityl group.

The same amino protecting groups can be present

in a protected amino group present in residue A..

An amino group can also be protected in proton form; as anions preferably those of strong inorganic acids, such as halogen hydrogen acids, e.g.

the chlorine or bromine anion,. or of sulfonic acids, such as p-toluenesulfonic acid.

The hydroxy protecting groups present in protected hydroxy or hydroxyimino groups in residue A are e.g. acyl residues, such as 2-haloacetyl, e.g. 2-chloro-

or 2,2-dichloroacetyl or in particular an acyl residue of a carboxylic acid half-ester specified in connection with a protected amino group, in particular 2,2,2,-trichloroethoxycarbonyl, or organic silyl or stannyl residues, further easily cleavable 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon residues, preferably 1-lower oxy-lower alkyl or 1-lower alkylthio-lower alkyl, e.g. 1-methoxy-ethyl, 1-ethoxy-ethyl, 1-methylthio-ethyl or 1-ethyl-thio-ethyl, or 2-oxa- or 2-thiacyclolower alkyl with 5-7 ring atoms, e.g. 2-tetrahydrofuryl or 2-tetrahydropyranyl or corresponding thia analogues, as well as easily cleavable, optionally substituted α-phenyl lower alkyl residues,

as optionally substituted benzyl, diphenylmethyl or trityl, whereby as substituents in the phenyl residues can be used e.g. halogen, such as chlorine, lower alkoxy, such as methoxy and/or nitro.

A carbamoylated hydroxyimino group in the residue A is a group with partial formula =N-0-C(=0)-NHR^ in which R- means lower alkyl, cycloalkyl, aryl lower alkyl or aryl.

A lower alkyl group R 1 is especially C 1 -C 8 lower alkyl, such as methyl, ethyl, propyl, butyl, pentyl or hexyl, which groups may be straight or branched. Branched lower alkyl groups are, for example, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl or neopentyl.

A cycloalkyl group R^ is C^-C^-cycloalkyl,

such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

An aryl lower alkyl group R 1 has 7-10 C atoms

and is, for example, benzyl, phenylethyl, phenylpropyl or pentylbutyl.

An aryl group R has 6-10 C atoms and is, for example, pentyl or naphthyl.

Preferred are R 1 -ethyl, n-propyl, isopropyl, butyl, isobutyl, cyclohexyl and especially methyl.

A protected sulfo group is preferably that with an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic alcohol, such as a lower alkanol, or with a silyl or stannyl residue, such as trilower alkylsilyl, esterified sulfo group. In a sulfo group, the hydroxy group can, for example, be etherified like the hydroxy group in an esterified carboxy group.

A methoxy replaceable group R 1 is, for example, an etherified mercapto group, such as lower alkylthio, e.g. ethyl, propyl, butyl or especially methylthio, or also arylthio, e.g. phenyl- or p-toluylthio.

in the carboxyl group's esterified residue Rg is preferably easily cleavable under gentle conditions, including under physiological conditions. Such residues Rg are. for example lower alkyl, e.g. tert-lower alkyl, e.g. tert.-rbutyl, polycycloalkyl, e.g. adamantyl, arylmethyl, wherein aryl preferably denotes one or two, optionally, e.g. with lower alkyl, especially tert.-lower alkyl, e.g. tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, e.g. chlorine, and/or nitro, mono- or polysubstituted phenyl residues, which optionally, e.g. above indicated substituted benzyl, e.g. 4-nitro-benzyl, or 4-methoxybenzyl, or e.g. as above indicated substituted diphenylmethyl, e.g. benzhydryl or di-(4-methoxyphenyl)-phenyl, or 2-halo-lower alkyl, e.g. with halogen, such as bromine, substituted benzoyl, e.g. phenacyl, or polyhaloaryl, such as pentachlorophenyl. R is further a silyl, especially an organic silyl group or a corresponding stannyl group. These contain silicon or the tin atom is preferably lower alkyl, especially methyl, further lower alkoxy, e.g. methoxy, and/or halogen, e.g. chlorine, as substituents. Suitable silyl resp. stannyl protecting groups are primarily tri-lower alkylsilyl, especially trimethylsilyl, further dimethyl-tert-butyl-silyl, lower-alkyl-lower-alkyl-halo-silyl, e.g. methoxy-methyl-chloro-silyl, or dilave alkyl-halo-silyl, e.g. dimethyl-chloro-silyl, or similarly substituted stannyl compounds, e.g. tri-n-butyl-stannyl.

Preferred protective residues Rg are especially tert-butyl, optionally, e.g. as above substituted benzyl, e.g. 4-nitrobenzyl and diphenylmethyl.

A residue Rg that can be split off under physiological conditions gives the actual active carbonic acid an improved absorption upon oral application and/or an extended duration of action. Numerous such ester groups are known in the field of the penicillins and cephalosporins. For example, -C^CO-O-Rg groups must be stated, in which Rg denotes a methyl group substituted with acyl, acyloxy, acylthio, acylamino, or etherified hydroxy and possibly a further organic residue, whereby the methyl group can be connected to the ^carbonyl group in the acyl group also over a carbon atom containing a bridge, or a 2-aminoaliphatyl group..

In such groups, acyl represents the residue of an organic carboxylic acid with approximately up to 18 C atoms and is, for example, optionally substituted alkanoyl, cycloalkanoyl, aroyl, heterocyclylcarbonyl, e.g. also the heterocyclylcarbonyl residue of a carboxylic acid of formula I, or a biologically active penam-3- or cephem-4-carboxylic acid, or the acyl residue of a carboxylic acid half-ester. Etherated hydroxy in the methyl group is with a hydrocarbon residue, especially with lower alkyl etherified. The organic residue which can be further substituted in the methyl group has up to 7-C atoms and is particularly lower alkyl, such as methyl, or aryl, such as phenyl. The aforementioned carbon bridge contains a to three, especially 2 C atoms, so that there is a lactone, especially a β-lactone. The aliphatyl group in the aforementioned 2-aminoaliphatyl group can be aliphatic or cycloaliphatic in nature and is saturated or unsaturated. The 2-amino group is preferably substituted with two lower alkyl groups or optionally an alkylene containing an oxa group. In such physiologically cleavable ester groups -C(=O)-O-R2, R2 is, for example, lower alkanoyloxymethyl, e.g. acetyloxymethyl or pivaloyloxymethyl, aminolower alkanoyloxymethyl, especially oc-aminoloweralkanoyloxymethyl, e.g. glycyloxymethyl, L-valyloxymethyl, -L-leucyloxymethyl, lower alkoxycarbonyloxymethyl or 1-lower alkoxycarbonyloxyethyl, e.g. 1-ethyloxycarbonyloxyethyl, lower alkanoylthiomethyl, e.g. acetylthiomethyl or pivaloylthiomethyl, lower alkanoylaminomethyl, in which lower alkanoyl may optionally be substituted with halogen, such as chlorine,

e.g. acetylaminomethyl or 2,2-dichloroacetylaminomethyl, aroylaminomethyl, e.g. benzoylaminomethyl, or, as an example of a lactone containing R 1 , phthalidyl. The etherified hydroxymethyl group Rg is, for example, lower alkoxymethyl, especially methoxymethyl. A 2-aminoaliphatyl group R^ is, for example, 2-aminolower alkyl, such as a 2-aminoethyl group,

in which amino is substituted with 2 lower alkyl or optionally an oxa group containing the alkylene, e.g. 2-dimethylaminoethyl, 2-diethylaminoethyl or 2-(1-morpholino)-ethyl, or 2-aminocycloalkyl, e.g. 2-Dimethylaminocyclohexyl. Particularly preferred are acetyloxymethyl, pivaloyloxymethyl, 1-ethyloxy-. carbonylethyl, -and phthalidyl. Salts are particularly such of compounds of formula I with a free carboxyl group, preferably.metal-

or ammonium salts, such as alkali metal and alkaline earth metal, e.g. sodium, potassium, magnesium or calcium salts,

as well as ammonium salts with ammonia or suitable organic amines, preferably aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines, as well as heterocyclic bases for salt formation, such as lower alkylamines, e.g. triethylamine, hydroxyl lower alkylamine, e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine, basic aliphatic esters of carboxylic acids, e.g. 4-&minobenzoic acid-2-diethylaminoethyl ester, lower alkylamines, e.g. 1-ethyl-piperidine, cycloalkylamines, e.g. dicyclohexylamine, or benzylamines, e.g. N,N<f->dibenzyl-ethylenediamine, further bases of the pyridine type, e.g. pyridine, collidine or quinoline. Compounds of formula I with a basic group can form acid addition salts, e.g. with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carbonic or sulphonic acids, e.g. trifluoroacetic acid, as well as with amino acids, such as arginine and lysine. Compounds of formula I with a free carboxyl group and free amino groups can also exist in the form of internal salts, e.g. in zwitterionic form.

The center of asymmetry present in the residue A, namely when A means hydroxymethylene, aminomethylene or sulfomethylene, exists in the R,S- or preferably in the R-configuration. The optionally carbamoylated hydroxyimino and methoxyiminomethylene group A is preferably in the syn form (Z form).

The compounds of formula I, in which the carboxyl group is possibly esterified in physiologically cleavable form and where the functional groups in residue A are in unprotected form, and their pharmaceutically usable, non-toxic salts are valuable, antibiotic active substances, which can especially be used as antibacterial antibiotics . For example, they are effective in vitro against gram-positive and gram-negative cocci, such as Staphylococcus aureus, Streptococcus pyogenes,. Streptococcus faecalis,, Streptococcus pneumoniae, Neisseria gonorrhoeae and Neisseria meningitidis in concentrations of approx. 0.005 to 1 mcg/ml. and against gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Enterobacter sp., Pr oteus sp. indole+ and indole-, Pseudomonas aeruginosa and Haemophilus influenzae, included

against β-lactamase producing strains, in minimum concentrations of <0.01 to 8 mcg/ml. In vivo, when subcutaneously applied to mice, they are, for example, effective against enterobacteria,

as well as against other gram-negative and gram-positive pathogens in minimal doses of ED^q <0.1 mg to 100 mg/kg..

The new compounds can therefore also, e.g. in the form of antibiotic active preparations, find application for the treatment of infections caused by gram-positive or especially gram-negative pathogens, especially by enterobacteria such as Escherichia coli, Klebsiella and Proteus (indole + indole-).

Compounds of formula (i), wherein they . functional groups are protected, are used as starting materials for the production of antibiotic active compounds of formula I.

The present invention preferably relates to such compounds of formula I, in which R-^ means hydrogen, lower alkyl, lower alkanoyl or 2-halo-lower alkanoyl,

A denotes methylene, aminomethylene, hydroxymethylene, sulfomethylene, hydroxyiminomethylene, carbamoylated hydroxyiminomethylene,

or methoxyiminomethylene, R^means hydrogen or methoxy and.Rg means hydrogen or, under physiological conditions, a cleavable residue, and their pharmaceutically acceptable salts,

as well as corresponding compounds with protected functional groups.

Particularly preferred are compounds of formula (I), in which R-^ means in particular hydrogen, as well as 2-halolower alkanoyl, such as 2-chlorolower alkanoyl, A denotes hydroxyiminomethylene, N-methylcarbamoyloxyiminomethylene or methoxyiminomethylene,

R^means hydrogen or methoxy and Rg means hydrogen or, under physiological conditions, cleavable acetyloxymethyl, pivaloyloxymethyl, 1-ethyloxycarbonyloxyethyl or phthalidyl, and their pharmaceutical tolerable salts, as well as corresponding compounds with protected functional groups.

The invention relates in particular to the compounds of formula I described in the examples, where their pharmaceutical tolerable salts, as well as the starting materials and intermediates described therein.

The compounds according to the present invention can be prepared according to methods known per se.

Compounds of formula I are thus prepared, as

a) acylates the 7(3-amino group in a compound of formula

in which the amino group is optionally substituted with a group that allows acylation and in which R2 and R^ have the meanings given in formula I, by treatment with one of the acyl residues in a carboxylic acid of formula introducing acylating agent, in which R-^ and A have the meanings given in formula I meanings and in which any existing functional groups exist in protected form, or. b) condenses a compound of formula in which X means halogen, R^, R^ and A have the meanings given in formula I and whose functional groups are optionally protected, or a salt thereof, with a thiourea of formula P^-NH-CS -NHg or a salt thereof, or c) cleaves by ring closure a compound of formula in which Ra, R, and Rcer optionally substituted hydrocarbon residues and R-p Rg, R^ and A have the meanings given in formula I, and in which functional groups are optionally protected , the phosphine oxide (R)(Rfe) (R )P=0, or d) treats with a decarbonylating agent a compound of formula in which R-p Rg, R^ and A have the meanings given in formula I, in which the double bonds are located in 2,3 - or 3>4-position and in which functional groups are optionally protected, or e) cleaves a group H-R^ from a compound of formula

in which R-p Rg, R^ and A have the meanings given in formula I and RQs are hydroxy, esterified hydroxy or optionally substituted amino, or

f) isomers of a compound of formula

in which R-p Rg, R^ and A have the meanings given in formula I, or g) reductively removes the group R^ and replaces with hydrogen in a compound of formula

in which R^ is esterified hydroxy or optionally substituted amino, and in which R-^, A, R^ and R^ have the meanings given in formula I, or

h) for the preparation of a compound of formula I, in which R^ is methoxy, replace R^ in the 7-position with methoxy

in a connection with formula

in which R^ means hydrogen or a group replaceable by methoxy, R-p Rg and A have the meanings given in formula I and in which all functional groups are present in protected form,

or

i) for the preparation of a compound of formula I, wherein A is carbamoylated hydroxyiminomethylene. or methoxyiminomethylene, and in which R-^, Rg and R^ have the meanings given in formula I, carbamoyl or methylate the hydroxyimino group in a compound of formula

wherein Rp Rg and R^ have the meanings given in formula I, or

•j) for the preparation of a compound of formula I, in which R-^ is hydrogen and in which A, Rg and R^ have the meanings given in formula I, the amino protecting group R^ cleaves

and replaces with hydrogen in a compound of formula I,

in which R-^ means an amino-protecting group, and A, RgQg R^ have the meanings given in formula I, or

k) for the preparation of a compound of formula .1, in which Rg denotes an esterifiable residue to the carboxyl group,

and Rp A and R have the meanings given in formula I, transfers the free carboxyl group in the 4-position of the cephem ring, or a reactive derivative thereof, by treatment with an esterification agent in an esterified carboxyl group, or 1) for the preparation of a compound with formula I, in which Rg is hydrogen, and Rp A and R^ have the meanings given in formula I, in a compound of formula I', in which Rg denotes an esterifiable residue to the carboxyl group, and Rp A and R^

have the meanings given in formula I, cleaves off the residue Rg and replaces this with hydrogen or a cation, and if desired, in a compound obtained transfers a residue Rp, Rg or A into another residue Rp Rg or A, and/or, when desired, transfer an obtained compound into a salt or an obtained salt into a free compound or into another salt.

Procedure- a): Any residues present that can

substituting amino groups or which allow acylation in a starting material with formula II are, for example, organic silyl or stannyl groups, also ylidene groups,

which together with the amino group forms a Schiff base.

The specified organic silyl or stannyl groups are, for example,

the same ones that are also able to form with the 4-carboxyl group in the cephem ring a protected carboxyl group. When silencing or stannylating a carboxyl group in a starting material of formula II, the amino group can also be silylated or stannylated, by using an excess silylating or stannylating agent.

The specified ylidene groups are here preferably arylmethylene groups, in which aryl in particular stands for a carbocyclic, primarily monocyclic aryl residue, e.g. for optionally, as in nitro or hydroxy, substituted phenyl; such arylmethyl groups are e.g. benzylidene, 2-hydroxybenzylidene or 4-nitrobenzylidene, further optionally, e.g. with carboxy substituted oxacycloalkylidene, e.g. 3-carboxy-2-oxacyclohexylidene.

Useful acylating agent for the acyl residue i

a carboxylic acid with formula (III) is, for example, the carboxylic acid itself or functional derivatives thereof.

If a free acid of formula III, in which all functional groups apart from the exchangeable carboxyl group are protected, is used as acylating agent, suitable condensing agents such as carbodiimides are usually used, for example N,N<T->diethyl-, N,N'-dipropyl-, N,N<T->diisopropyl, N,N<*->dicyclohexyl- or N-ethyl-N'-3-dimethylaminopropylcarbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or isoxazolinium salts, for example N-ethyl-5-phenyl- isoxazolinium 3'-sulfonate and N-tert-butyl-5-methyl-isoxazolinium perchlorate, or an acylamino compound, e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-quinoline.

The condensation reaction is preferably carried out

in an anhydrous reaction medium, preferably in the presence of a solvent or diluent, e.g. methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran, if desired or necessary, during cooling or heating, and/or

■in an inert gas atmosphere.

A reactive, i.e. amide-forming, respectively ester-forming, functional derivative of an acid with formula III, in which all functional groups apart from the acid group to be reacted are protected or can be protected,

is primarily an anhydride of such an acid, including and preferably a mixed anhydride, but can also be an internal anhydride, i.e. a corresponding ketene. Mixed anhydrides are e.g. those with inorganic acids, such as halohydrogen acids, i.e. corresponding acid halides, e.g. -chlorides or -bromides, further with nitrogen hydrogen acids, e.g. corresponding acid azides, with a phosphorous acid, e.g. phosphoric acid or phosphoric acid, or with a sulphurous acid, e.g. sulfuric acid', or with hydrocyanic acid. Further mixed anhydrides are e.g. those with organic carboxylic acids, as with possibly, e.g.

with halogen, such as fluorine or chlorine, substituted lower alkane carboxylic acids, e.g. pivalic acid or trichloroacetic acid, or with half-esters, especially lower alkyl half-esters of the carboxylic acid,

as ethyl or isobutyl half-esters of the carboxylic acid, or with organic, especially aliphatic or aromatic sulphonic acids, e.g. p-toluenesulfonic acid. From the acid III, when A is hydroxymethylene, a mixed internal anhydride with carboxylic acid esters of the oc-hydroxy group can also be used.

Additional reactive acid derivatives of

an acid of formula III, are activated esters, such as esters with vinylogenic alcohols (ie enols), such as vinylogenic lower alkenols, or aryl esters, such as 4-nitrophenyl or 2,4-dinitrophenyl ester, heteroaromatic esters, such as benz- triazole-, e.g. 1-benztriazole esters, or diacylimino esters, such as succinyl imino or phthalyl imino esters.

The acylation with an acid derivative such as an anhydride, especially with an acid halide, is preferably carried out in the presence of an acid binding agent, preferably an organic base, such as an organic amine, e.g. a tertiary amine, such as trilower alkylamine, e.g. trimethylamine, triethylamine or ethyl-diisopropylamine, or N,N-dilaverealkyl-aniline, e.g. N,N-dimethylaniline, or a cyclic tertiary amine, such as an N-lower alkylated morpholine, such as N-methylmorpholine, or a

base of the pyridine type, e.g. pyridine, an inorganic base,

for example an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate, e.g. sodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate, or an oxirane, for example a lower 1,2-alkylene oxide,

such as ethylene oxide or propylene oxide.

t The above-mentioned acylations are preferably carried out in an inert environment. preferably anhydrous solvent or solvent mixture, for example in a carbonic acid amide, such as a formamide, e.g. dimethylformamide, a halogenated hydrocarbon, e.g. methylene chloride, tetracarbon or chlorobenzene, a ketene, e.g. acetone, an ester, e.g. acetic acid ethyl ester, or a nitrile, e.g. acetonitrile, or mixtures thereof, at room temperature, if necessary, at a reduced or increased temperature, at approx. -40°C to approx. 100°C, preferably at -10°C to + /\. 0°C, and/or in an inert gas, e.g. nitrogen atmosphere.

In an acylating acid of formula III or i

an acid derivative thereof, a protected amino group can also be present in ionic form, i.e. the starting material with formula III,

can be used in the form of an acid addition salt, preferably with a strong inorganic acid, such as a hydrohalic acid, e.g. hydrochloric acid, or sulfuric acid.

Furthermore, an acid derivative, when desired, can be formed in situ. Thus, one obtains e.g. a mixed anhydride by treatment with an acid of formula III with correspondingly protected functional groups, or a suitable salt thereof such as an ammonium salt, e.g. with an organic amine, such as 4-rcethylcrorfoline, or a metal, e.g. alkali metal salt, with a suitable acid derivative, such as a corresponding acid halide or optionally substituted lower alkanecarboxylic acid, e.g. trichloroacetyl chloride, or with a half-ester of - a carbonic acid half-halide, e.g. chloroformic acid ethyl ester or isobutyl ester, and uses the thus obtained mixed anhydride without isolation.

Method b): In a starting compound of formula IV, X is halogen, especially chlorine, but also bromine, iodine or fluorine. Thiourea is used in free form or as a salt, especially as a thiolate of an alkali metal, such as lithium, sodium or potassium, or also as a thiolate of an ammonium compound, in an equivalent amount or up to a 6-fold excess. A compound of formula IV, which contains acidic groups, e.g. when Rg is hydrogen or when. A is sulfomethylene, can optionally be used as a salt, e.g. as an alkali metal or as an ammonium salt, e.g. lithium, sodium, potassium, trilower alkyl such as trimethyl or triethylammonium salt.

The reaction is generally carried out in a solvent such as water or in an organic, non-reactive solvent or in mixtures thereof. Suitable organic solvents are alcohols, such as methanol, ethanol, isoprdpanol, ketones, such as acetone, ethers, such as dioxane or tetrahydrofuran, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride, chloroform or tetracarbon, esters, such as ethyl acetate, or amides, such as dimethylformamide or dimethylacetamide, and similar compounds. The reaction can, if the free compounds are used, be carried out in the presence of a base. Suitable bases are alkali metal hydroxide, such as sodium or potassium hydroxide, alkali metal carbonate, such as sodium or

potassium carbonate, or organic tertiary nitrogen bases, such as tri-lower alkylamines, e.g. trimethylamine, triethylamine,

ethyl-diisopropylamine, pyridine and similar compounds. The reaction temperature is at room temperature, or also lower or higher, preferably between -10 to + 100°C, especially between 0 to 4-0°C.

The reaction can also be carried out in stages, first forming a ring-opened intermediate with the partial formula R1-NH-C(=NH)-S-CH2-C0-A-, which can be dehydrated in a second step. Method c): In the starting material with formula V, each of the groups R 3. , R, D and R C independently of each other primarily means one possibly with functional groups, e.g. with optionally etherified or esterified hydroxy groups, such as lower alkoxy groups and/or halogen atoms or with phenyl, substituted lower alkyl residue or an optionally,.e.g. with aliphatic hydrocarbon residues such as lower alkyl groups, and/

or with functional groups, such as optionally etherified or esterified hydroxy groups, such as lower alkoxy groups or halogen atoms, or nitro groups, substituted phenyl residue. Such residues are in particular methyl, ethyl, propyl, butyl, benzyl or phenyl, which may optionally be substituted: as indicated above. Preference is given to all three residues R&, R^ and Rcphenyl residues.

The cleavage of the phosphine oxide by ring closure occurs spontaneously at room temperature or with

slightly reduced or increased temperature, e.g. at temperatures of approx. -20°C to approx. 100°C, and in a dissolution

or diluent, e.g. by an optionally halogenated hydrocarbon, preferably aliphatic or aromatic in nature, such as benzene or mixtures of such bp solvents, usually already in the preparation of the formyl compound of formula (V).

The formyl compound with formula (V) can be prepared in situ, for example by oxidizing a corresponding carbinol compound (Va) with the partial formula

-S-CH 2 CH 2 OH.

The oxidation of a carbinol compound of formula (Va) is carried out by treatment with an oxidizing organic sulphoxide compound in the presence of agents with water-binding or water-absorbing properties. As oxidizing sulfoxy compounds, aliphatic sulfoxide compounds such as lower alkyl sulfoxides, primarily dimethyl sulfoxide, or lower alkylene sulfoxides, e.g. tetramethylene sulfoxide. Acid anhydrides, especially anhydrides of organic, such as aliphatic or aromatic carboxylic acids, should be mentioned as agents with water-binding or -absorbing properties, e.g. anhydrides of lower alkane carboxylic acids, especially acetic anhydride, further propionic anhydride, or benzene anhydride, as well as anhydrides of inorganic acids, especially of phosphoric acids, such as phosphorus pentoxide. The above-mentioned anhydrides, primarily of organic . carboxylic acids, e.g. acetic anhydride, is preferably used in a 1:1 mixture with sulfoxide oxidizing agent. Further water-binding or -absorbing agents are carbodiimides, primarily dicyclohexylcarbodiimide, further diisopropylcarbodiimide, or ketenimines, e.g. diphenyl-N-p-tolylketenimine; these reagents are preferably used

in the presence of acid catalysts, such as phosphoric acid or pyridine-ium trifluoroacetate or phosphate. Sulfur trioxide can also be used as a water-binding or -absorbing agent, whereby it is preferably used, in the form of a complex, e.g. with pyridine.

Sulphoxide oxidizing agent is usually used in excess. Under reaction conditions, liquid sulfoxide compounds, especially dimethyl sulfoxide, e.g. at the same time serve as a solvent; further inert diluents can be used as a solvent, such as possibly halogenated hydrocarbons, preferably of an aliphatic or aromatic character, e.g. benzene, or mixtures of solvents.

The oxidation reaction is, if desired, carried out by cooling, but most often at room temperature or a slightly elevated temperature, e.g. at temperatures of approx.

-20°C to approx. 100°C.

Process d): Carbon monoxide-absorbing heavy metal complexes serve primarily as decarbonylation agents for the decarbonylation of compounds of formula VI. Such heavy metal complexes are in particular platinum metal complexes, whereby one knows a platinum metal. besides plat.in understands e.g. iridium or rhodium, also palladium and osmium.

A carbon monoxide-absorbing platinum metal complex preferably contains organic ligands, whereby these can be connected not only to a carbon atom but also to a heteroatom, especially a phosphorus atom, via side valences (which form non-covalent compounds) with the platinum metal atom. In addition to these organic ligands, the complex can also further contain above the main valences (i.e. covalently) bound. substituents, which

the heteroatom, especially the halogen atom., e.g. chlorine atoms,

or carbonyl groups. Carbon monoxide-absorbing platinum metal complexes of this kind have the property of being able to absorb carbon monoxide via the main valence, i.e. in covalent bonding.

As platinum metal complexes, e.g. phosphorus-containing platinum metal complexes, primarily phosphine-platinum metal complexes, which contain one, two or more phosphines. These phosphines preferably contain optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon residues as substituents, primarily lower alkyl, e.g. n-butyl, or especially optionally substituted phenyl, such as phenyl. Besides phosphorus-containing parts, e.g. the phosphines, the platinum metal complexes can replace further organic ligands, especially such as one, two or more phosphorus-containing ligands, such as phosphines, in an existing phosphorus-containing platinum metal complex, e.g. suitable nitriles, such as acetonitrile,

in non-covalent bonding with metal atoms, and/or the halogen atom, e.g. chlorine, or carbonyl groups in covalent bond with the metal atom.

Preferably one uses bis-trisubstituted phosphine platinum halides, bis-trisubstituted phosphine carbonyliridium halides or tris-substituted phosphine-iridium halides, preferably in tris-substituted phosphine-rhodium halides, in which the substituents in phosphine are preferably lower alkyl, e.g. n-butyl, and preferably phenyl, and the halides are preferably chlorides. •' Such phosphine-platinum metal complexes, which are able to take up carbon monoxide in a covalent bond, are e.g. bis-triphenylphosphine-platinum-II-chloride £~( CgH^ )^P72PtCl2 or bis-tri-phenyl-phosphine-carbonyliridium-II-chloride /~(CgH^)3P72Tr(C0)Cl, as well as tris- triphenylphosphine-iridium-I-chloride /(CgH^)^E7jIrCl, but preferably tris-triphenyl-phosphine-rhodium-I-chloride /CgH^P^RhCl. If desired or necessary, the decarbonylation can be carried out with the above specified heavy metal complexes in the presence of suitable catalysts or activators, e.g. Lewis acid, such as boron trifluoride (which can be used, for example, together with bis-triphenylphosphine-platinum chloride), further a perchlorate, such as alkali metal perchlorate, e.g. e.g. sodium perchlorate (which, for example, can be used the same with bis-triphenyl-phosphine-carbonyliridium chloride).

Preferably you work in the presence of

inert solvents, especially in the presence of hydrocarbons, such as aliphatic or cycloaliphatic, especially aromatic hydrocarbons, e.g. benzene, toluene or xylol, halogenated hydrocarbons, such as corresponding aliphatic or aromatic chlorohydrocarbons, e.g. methylene chloride or chlorobenzene,

ethers, such as aliphatic, cycloaliphatic or aromatic,

further mixed ethers, e.g. di-n-butyl ether, dioxane, diphenyl ether or anisole, nitriles, such as aliphatic or aromatic nitriles, e.g. acetonitrile or benzotriitrile,

or ketones, especially aliphatic ketones, such as lower alkanones, e.g. acetone, ethyl methyl ketone or isobutyl methyl ketone, or mixtures of such solvents. Thereby, the turnover is carried out by cooling, at room temperature or by heating, e.g. at approx. 10°C to approx. 150°C. as at approx.

40°C to approx. 120°C, further if necessary, in a closed vessel and/or in an inert gas atmosphere, e.g. under nitrogen or argon.

In the decarbonylation reaction can be used

a 3-formyl-3-cephem or a 3-formyl-2-cephem compound of formula VI. If a 3-formyl-2-cephem compound is used, an isomerization of the double bond must take place at the same time as the desformylation or in connection with it, which is achieved at an elevated temperature, somewhat above 100°C, and/or in the presence of a base.

Method e): The group Rq in a starting material of formula (VII) can be a free hydroxy, but preferably stands for esterified hydroxy or optionally substituted amino.

An esterified hydroxy group RQ can be esterified with an inorganic or organic acid, such as a strong mineral acid,

e.g. a hydrohalic acid, such as hydrochloric, hydrobromic or hydroiodic acid, or an organic carbonic or sulphonic acid, including formic acid, as a corresponding aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic acids, and may further

be esterified with a carboxylic acid half-derivative. Thus R denoted e.g. halogen, such as chlorine, bromine or iodine, lower alkylsulfonyloxy, e.g. methanesulfonyloxy or ethanesulfonyloxy, arylsulfonyloxy, e.g. benzenesulfonyloxy, or p-toluenesulfonyloxy, lower alkanoyloxy, e.g. acetyloxy or propionyloxy, arylcarbonyloxy, e.g. benzoyloxy, or lower alkoxycarbonyloxy, e.g. methoxycarbonyloxy or ethoxycarbonyloxy. An optionally substituted amino group

R is a primary, secondary or tertiary amino group.

12 12 -N(RQ) (R0), in which RQ and RQ independently of each other mean hydrogen or an optionally substituted aliphatic, cycloaliphatic -aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic residue, or together mean an optionally substituted, optionally with heteroatoms such as oxygen, sulfur or nitrogen, underused polymethylene group. Such amino groups RQ are, for example, amino, mono- or dilavealkylamino, such as methyl-, ethyl-propyl-, dimethyl-, diethyl-, dipropyl-, methyl-ethyl-, or methyl-propyl-amino, mono- or dicyclohexylamino, diphenylamino, benzyl- , dibenzyl- or phenylethyl- or diphenylethylamino,

aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino or 4-lower alkyl pipe.razino.

The cleavage of a compound of formula RQ-H, i.e. from water, an acid or an amine, is preferably carried out by treatment with suitable water, acid or amine cleavage agents. Water and amines are preferably split off in the presence of an acidic water or amine scavenger,

e.g. an acid, preferably a strong organic carboxylic or sulphonic acid, such as a halogen-lower alkane carboxylic acid, e.g. trifluoroacetic acid, or an arylsulfonic acid,

e.g. p-toluenesulfonic acid, a suitable acid derivative, as an anhydride or especially a halide, as a chloride, preferably an inorganic one, e.g. phosphorus- or sulphur-containing, acid, e.g. phosphorus oxychloride or thionyl chloride, whereby such a derivative is used, when water is to be split off, usually in the presence of a base, such as a tertiary organic base, e.g. pyridine, or a suitable acidic ion exchanger, such as a sulfonic acid-based ion exchanger, e.g. a sulfonated polystyrene yield. For off-

splitting of water, you can also use dehydrating carbodiimide compounds, e.g. dicyclohexylcarbodiimide, or dehydrating carbonyl compounds disubstituted on nitrogen atoms, e.g. carbodiimidazole. Thereby, these agents are usually used in the presence of a solvent, such as an optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g., benzene or toluene, or a mixture of solvents, whereby suitable acidic agents, such as trifluoroacetic acid, can be used at the same time

also as a solvent. If necessary, a further water-adsorbing agent or a water separator is used and the work is done under cooling or heating and/or in an inert gas, e.g. nitrogen atmosphere.

Preferably RQ means in a starting material

with formula VII an esterified hydroxy group and according to the invention an acid of formula H-R ■ is split off. Generally, for this purpose, basic acid-splitting and/or neutralizing agents are used, such as e.g. inorganic bases, such as dilute alkali metal hydroxide, e.g. sodium or potassium hydroxide, whereby in addition to water, organic solvents such as suitable ketones, e.g. acetone, or ethers, e.g. dioxane, or aqueous mixtures thereof and works at a pH value of at most approx. 9>if necessary, one works by dressing or warming up and/or

in an inert gas, e.g. nitrogen atmosphere. Preferably. tert-amines are used as acid-releasing agents,

particularly good proton acceptors which do not attack the lactam ring, preferably tert.-aliphatic or tert.-cycloaliphatic mono- and diamines, such as trilower alkylamine, e.g. trimethylamine, triethylamine or ethyl-diisopropylamine, or bicyclic diaza compounds with an amidine-like arrangement of the ring nitrogen atom, e.g. 1,5-dazabicyclo/4,3,0_7non-5-ene or 1,5-diazabicyclo/5)4)P_7undec-5-ene. Furthermore, mari can use basic ion exchangers, e.g. on an ammonium hydroxide basis,

possibly as an acid-releasing agent. Certain esterified hydroxy groups R , especially sulfonyloxy, e.g. methyl-sulfonyloxy groups can be in the form of an acid with the formula RQ-H also by adsorption, e.g. on silica gel, aluminum oxide, etc, and elution (chromatography), cleave from compound with

formula VII.

The above-described acid cleavages are carried out in the absence, but usually in the presence, of a solvent, such as an optionally halogenated hydrocarbon of aliphatic, cycloaliphatic or aromatic character, such as methylene chloride,

a lower alkaryon, e.g. acetone, or ethers, e.g., tetrahydrofuran or dioxane, or in the presence of a mixture of solvents, including an aqueous mixture, if necessary under cooling or heating and/or in an inert gas, e.g. nitrogen atmosphere.

Method f): In a 2-cephem starting material of formula (VIII), the optionally protected carboxyl group in the 4-position preferably has the oc configuration. The 2-cephem compound of formula (VIII) is isomerized by treating these with a weak basic agent and isolating the corresponding 3-cephem compounds.

Suitable isomerizing agents are e.g. organic nitrogen-containing bases, especially tertiary heterocyclic bases of an aromatic character, preferably bases of the pyridine type,

as pyridine itself, as well as collidine or lutidines,

further quinoline, tertiary aromatic bases, e.g. those of the aniline type, such as N,N-dilaverealkylaniline, e.g. N,N-dimethylaniline or N,N-diethylaniline, or tertiary aliphatic, azacycloaliphatic or araaliphatic bases, such as e.g. N,N,N-trilower alkylamines, e.g. N,N,N-trimethylamine, N,N-dimethyl-N-ethylamine, N,N,N-triethylamine or N,N,N-diisopropyl-N-ethylamine, N-lower alkyl-azacycloalkanes,

e.g. N-methyl-piperidine, or N-phenyl-lower alkyl-N,N-dilower alkyl-amine, e.g. N-benzyl-N,N-dimethylamine > as well as mixtures thereof, such as the mixture of a base of the pyridine type and an N,N,N-tri-lower alkylamine, e.g. pyridine and triethylamine. Furthermore, inorganic or organic salts of bases, especially those of medium to strong bases with weak acids, such as alkali metal or ammonium salts of layeralkanecarbon acids, e.g. sodium acetate, triethylammonium acetate or N-methyl-piperidine acetate, as well as other analogous bases or mixtures of such basic agents are used.

By isomerization with basic agents

preferably work in an anhydrous medium, in the presence of

or the absence of a solvent, such as an optionally halogenated one. e.g. chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, or a mixture of solvents, whereby used, under reaction conditions, liquid bases can serve as a reaction agent, at the same time also as a solvent, whereby one works when cooling, at room temperature or during heating, preferably in a temperature range of approx. . -30°C to approx. +100°C, in an inert gas, e.g. nitrogen atmosphere and/or in a closed vessel.

The 3-cephem compounds thus obtainable can be prepared in a manner known per se, e.g. by sdsorption and/or crystallization, separate from possibly still present 2-cephem compounds.

The isomerization of the 2-cephem compound with formula (VIII) can optionally be carried out when one oxidizes these in the 1-position, if desired, separates an obtainable isomeric mixture of 1-oxides and reduces the thus obtainable 1-oxides of the corresponding 3- cef em-f or compounds.

Suitable oxidizing agents for the oxidation of 2-cephem compounds to the i.1 position are inorganic peracids, which have a reduction potential of at least +1.5 volts and which consist of non-metallic elements, organic peracids or mixtures of hydrogen peroxide and acids , special .'. organic carboxylic acids with a dissociation constant of at least 10 ^. Suitable inorganic peracids are periodic and persulphuric acid. Organic peracids are corresponding percarboxylic and persulfonic acids, which can be added as such or by using at least one equivalent of hydrogen peroxide and a carboxylic acid can be formed in situ. Thereby, it is appropriate to use a large excess of the carbonic acid, when e.g. acetic acid is used as a solvent. Suitable peracids are e.g. permauric acid, peracetic acid, trifluoroperacetic acid, permaleic acid, perbenzoic acid, 3-chloro-perbenzoic acid, monoperphthalic acid or p-toluene persulfonic acid.

Oxidation can optionally be carried out by using hydrogen peroxide with catalytic amounts of an acid with a dissociation constant of at least 1<0>"^, whereby low concentrations can be used, e.g. 1-2% or less,

but also larger amounts of acid can be used. Thereby, the activity of the mixture depends preferably on the strength of the acid. Suitable mixtures are e.g. such as hydrogen peroxide with acetic acid, perchloric acid or trifluoroacetic acid.

The above-mentioned oxidation can be carried out in the presence of suitable catalysts. Thus, e.g. oxidation with percarboxylic acid is catalysed in the presence of an acid with a dissociation constant of at least 10"^, whereby the activity depends on its strength. Acids suitable as catalysts are, for example, acetic acid, perchloric acid and trifluoroacetic acid. Usually at least equimolar amounts of the oxidizing agent are used, preferably a smaller excess of about 10% to about 20%, whereby one can also use a larger excess, e.g. up to 10 times the amount of the oxidizing agent or more. The oxidation is carried out under mild conditions, e.g. at temperatures of about -50°C to about +100°C, preferably at about -10°C to about +40°C.

The reduction of the 1-oxides of 3-cephem compounds can be carried out in a manner known per se by treatment with a reducing agent, if necessary, in the presence of an activating agent. Examples of reducing agents that come into consideration are: catalytically activated hydrogen, whereby noble metal catalysts are used, which contain palladium, platinum or rhodium, and which are optionally used together with a suitable carrier material, such as carbon or barium sulphate; reducing tin, iron, copper or manganese cations, which are used in the form of corresponding compounds or complexes of an inorganic or organic nature, e.g. such as tin II chloride, fluoride, acetate or formate, iron II chloride, sulphate, oxalate or succinate, copper I chloride, benzoate or oxide, or Manganese II chloride, -sulphate, -acetate or -oxide, or as complexes, e.g. with ethylenediaminetetraacetic acid or nitrilotriacetic acid, reducing dithionite, iodide or iron II ryanide anions,

which are used in the form of corresponding inorganic or organic salts, such as alkali metal, e.g. sodium or potassium dithionite, sodium or potassium iodide or iron II cyanide,

or in the form of corresponding acids, such as hydroiodic acid;

reducing trivalent inorganic or organic phosphorus compounds, such as phosphines, further esters, amides and halides of phosphinic acids, phosphonic acids or phosphoric acid, as well as these phosphorus oxide compounds corresponding to phosphorus-sulfur compounds, in which organic residues indicate preferably aliphatic, aromatic or araliphatic residues, e.g. optionally substituted lower alkyl, phenyl or f phenyl lower alkyl groups, such as e.g. trif enyl phosphine, tri-n-butyl phosphine, diphenyl phosphinic acid methyl ester, diphenyl chloro-•

■phosph in, f phenyldichlorophosph in, benzeneph osf Dnic acid dimethyl ester, butanephosphonic acid methyl ester, phosphoric acid triphenyl ester, phosphoric acid trimethyl ester, phosphoric trichloride, phosphoric tribromide, etc; reducing halosilane compound, which contains at least one hydrogen atom bound to the silicon atom, and which, in addition to halogen, such as chlorine, bromine or iodine, also contains organic residues, such as aliphatic or aromatic groups, e.g. optionally substituted lower alkyl or phenyl groups, such as chlorosilane, bromosilane, di- or tri-chlorosilane, di- or tribromosilane, diphenylchlorosilane, dimethylchlorosilane, etc.; reducing quaternary chloromethylene iminium salts, especially -chlorides or -bromides, wherein

the iminium groups are substituted with a bivalent or di-monovalent organic residue, such as optionally substituted lower alkylene or lower alkyl groups, such as N-chloromethylene-N,N-diethyliminium chloride or N-chloromethylene-pyrrolidinium chloride; and complex metal hydrides, such as sodium borohydride,

in the presence of suitable activating agents, such as cobalt II chloride and borane dichloride.

As activating agents, which together with those

of the above-mentioned reducing agents, which do not themselves have Lewis acid properties, i.e. those which are preferably used together with dithionite, iodide or iron II cyanide and

■non-halogen-containing trivalent phosphorus reducing agents or in the case of catalytic reductions, organic carbon and sulphonic acid halides, further sulphur, phosphorus or silicon halides with an equal or greater hydrolysis constant of the second degree as benzoyl chloride, e.g. phosgene, oxalyl chloride, acetic acid chloride or bromide, .chloroacetic acid chloride; pivalin-

acid chloride, 4-methoxybenzoic acid chloride, 4-cyanobenzoic acid chloride, p-toluenesulfonic acid chloride, methanesulfonic acid chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phenyldichlorophosphine, benzenephosphonic acid dichloride, diethylchlorosilane,

or trichlorosilane, further suitable acid anhydrides, such as trifluoroacetic anhydride, or cyclic sultones, such as ethanesultone, 1,3-propanesultone, 1,4-butanesultone or 1,3-hexanesultone.

The reduction is preferably carried out in person

of the solvent or mixtures thereof, which selection

is preferably determined by the solubility of the starting materials

and choice of reducing agents, then e.g. lower alkanecarboxylic acid or esters thereof, such as acetic acid and acetic acid ethyl ester, by catalytic reduction, and e.g. optionally substituted, such as halogenated or nitrated aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, e.g. benzene, methylene chloride, chloroform or nitromethane,

suitable acid derivatives, such as lower alkane carboxylic acid esters or nitriles, e.g. acetic acid ethyl ester or acetonitrile, or amides of inorganic or organic acids, e.g. dimethylformamide or hexamethylphosphoramide, ether, e.g. diethyl ether, tetrahydrofuran or dioxane, ketones, e.g. acetone,

or sulfones, especially aliphatic sulfones, e.g. dimethyl sulfone or tetramethylene sulfone, etc, together with d.e

the chemical reducing agents, whereby these solvents preferably do not contain water. In this way, you usually work at temperatures of approx. -20°C to approx. 100°C, whereby by using highly reactive activators, the reaction can be carried out at lower temperatures.

Procedure g:) In a starting material with formula

IX, RQ has the same meaning as the esterified hydroxy group or optionally substituted amino group RQ. As an esterified hydroxy group, RcQ l is especially halogen, such as chlorine,

bromine or iodo, or a lower alkylsulfonyloxy or arylsulfonyloxy group, such as methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy or p-toluenesulfonyloxy.

As an optionally substituted amino group, RQ cl is especially amino, mono- or dilower alkylamino, such as methyl-, ethyl-, propyl-, .dimethyl-, diethyl-, dipropyl-, methyl-ethyl-, or methyl-propylamine<p>, mono - or dicyclohexylamino, diphenylamino, benzyl-, dibenzyl- or phenylethyl- or diphenylethylamino, azirdino, pyrrolidino, piperidino, morpholino, thiomorpholino or 4-lower alkylpiperazino.

The reductive elimination of Ro is carried out on

in and of itself - known way, e.g. analogous to the U.S. patent 4*065.6l8, U.S. patent 4.0.81,595 or DT-OS 2.824.OO4, with the help of

a reducing agent, which can replace RQ with a hydrogen;

An esterified hydroxyl group Ra can be replaced by hydrogen by treatment with a reducing metal or amalgam in the presence of a proton-donating solvent. Suitable metals are alkali metals, such as sodium or potassium, alkaline earth metals, such as calcium or magnesium, or also zinc, tin or iron and the like or amalgams thereof. Proton-donating solvents are, for example, water, alcohols, such as lower alkanols, e.g. methanol or ethanol, organic or inorganic acids, such as lower alkane carboxylic acids, e.g. formic or acetic acid, or mineral acids, such as hydrochloric or sulfuric acid, or also alkali hydroxides,

as sodium hydroxide. Preferred reducing agents of this kind are zinc in the presence of acetic acid or formic acid. The reductions are carried out in the indicated proton-donating solvents alone or optionally by adding a neutral organic solvent, such as a halogenated hydrocarbon, such as methylene chloride, an ether, such as tetrahydrofuran, or an amide such as dimethylformamide, and the like, by cooling or heating until the boiling point of the solvent used, preferably at approximately room temperature, i.e. at approx. 15° to 25°C.

An amino group Ra is eliminated and replaced with hydrogen by treatment with diborane in the presence of an inert solvent. Suitable inert solvents are, for example, water-free ether, such as diethyl ether, ethylene glycol dimethyl ether, dioxane or especially tetrahydrofuran. The reaction is carried out by slight cooling or heating, at approx. 5° to 35°> preferably at room temperature.

Procedure h) : In an obtained connection- with

formula I, in which Ro is hydrogen or a group replaceable by methoxy, and all functional groups are present in protected form, the 7a-methoxy group R can be introduced in a manner known per se.

For example, the aforementioned compound, where R₂ means hydrogen, is treated successively with an anion-binding agent, an N-halogenating agent and methanol and in this way methoxy is introduced.

A suitable anion-forming agent is preferably an organometallic base, especially an alkali metal, preferably a lithium organobase. Such compounds are particularly corresponding alcoholates, such as suitable lithium lower alkanolates, preferably lithium methyllate, or corresponding metal hydrocarbon bases, such as lithium lower alkanes and lithium phenyl. Reaction with the anion-forming organometallic base is usually carried out by dressing, e.g. at approx. 0°C to approx. -80°C, in the presence of a suitable solvent or diluent, e.g. an ether, such as tetrahydrofuran, using lithium methylate also in the presence of methanol, and, if desired in a closed vessel and/or in a inert gas, e.g. nitrogen atmosphere.

As an N-halogenating agent, a sterically hindered, organic hypohalogenite, especially -chlorite, is usually used, and in a corresponding aliphatic hypohalogenite, e.g. -chlorite, as a tert-lower alkyl hypohalide, e.g. -chlorite. Tert-butyl hypochlorite is preferably used. which is reacted with the non-isolated product ay - the anionization reaction.

The N-half-generate intermediate is formed

in the presence of an excess of the anion-forming base, especially lithium methylate, under reaction conditions and without being isolated into a 7-acyliminocephem compound, and this is converted into a 7a-me"toxy-cephem compound by the addition of methanol. If necessary, the elements of hydrogen halides, especially hydrochloric acid, must be split off from the N-halogenated intermediate by adding a hydrogen halide-splitting base, such as a suitable alkali metal lower alkanolate, e.g. lithium tert-butylate , whereby this reaction

usually takes place under conditions of anion- and N-halogen compound-forming reaction, whereby one works

in the presence of methanol and instead of the acylimino compound can directly obtain the 7a-methoxy-cephem compound. One usually starts from a compound, with formula I, in which

if hydrogen and functional groups are present in a protected form, these react with an excess of anion-forming agent, e.g. lithium methylate or phenyllithium, in the presence of methanol, then treated with the N-halogenating agent, e.g. tert-butyl hypochlorite, and thus obtains directly the desired compound of formula I, in which R^ is methoxy and functional groups are protected. The methanol can also be added later, whereby the dehydrohalogenation and addition of methanol can be carried out at somewhat higher temperatures than those used in the reactions for the formation of anion and N-halogen compounds, e.g. at approx. 0°C to approx. -20°C, if necessary, in a closed vessel and/or in an inert, e.g. nitrogen atmosphere.

In a further method, in a compound of formula I, in which R 1 is a methoxy replaceable group, this group can be replaced by methoxy.

Then one can replace an etherified mercapto group R^, especially methylthio, in a manner known per se by treatment with methanol in the presence of a mercury solv(II)-,

the thallium (III), bismuth (V) or lead (IV) salt with the methoxy group. Suitable salts are, for example, corresponding acetates, trifluoroacetates, nitrates, fluorides, chlorides or bromides, or also salts derived from organic or inorganic acids. Mercury solv(II) acetate and thallium trinitrate are preferred. The salts are used in equimolar amounts of the starting compound of formula I or in excess, up to approximately twice the equimolar amount.

The reaction takes place in an excess of methanol, thereby improving the solubility as well

can be mixed with other inert solvents, for example tetrahydrofuran, methylene chloride or chloroform. The reaction temperature is usually at room temperature, i.e. at about 15° to 25°, whereby lower or higher temperatures can be used to carry out the reaction more slowly or

faster.

Process i): The carbamoylation or methylation of a hydroxyiminomethylene group A in a compound of formula I is carried out in a manner known per se by treatment with a carbamoylation or methylating agent. In the starting material, in addition to the hydroxyimino group, any present,

functional groups preferably protected.

Suitable carbamoylating agents are, for example. isocyanates of the formula R^-NCO, in which R^ has the above meaning. The carbamoylation is carried out in the presence or absence of an inert solvent and optionally in the presence of a catalyst. Suitable inert solvents are, for example, ketones, such as acetone, diethyl ketone or methyl ethyl ketone, nitriles, such as acetonitrile, ethers such as diethyl ether, dioxane or tetrahydrofuran, amides, such as dimethylformamide, dimethylacetamide, esters, such as ethyl acetate, possibly halogenated hydrocarbons, such as benzene, toluene, chlorobenzene or methylene chloride, and similar inert solvents. Suitable catalysts are tertiary amines, such as trilayer alkylamine, e.g. triethylamine, lower alkyl-lower cycloalkyl- ■ amine, such as N,N-dimethyl-cyclohexylamine, N,N-diethyl-cyclohexyl-amine, N-methyl-dicyclohexylamine, or cyclic amines,

such as N-methylmorpholine, N-ethylmorpholine, N-methylpiperidine or pyridine, or tertiary diamines, such as N,N,N,N<T>,N'-tetramethyl-1,3-propanediamine or N,N,N',N '-tetramethyl-1,4-butanediamine, and the like. The carbamoylation reaction is carried out by cooling or heating at temperatures between approx.

-30°C to approx. 100°C, preferably at approx. 10° to 50°.

Suitable methylating agents are, for example, diazomethane, reactive esters of methanol, such as methyl halides, e.g. methyl iodide, sulfonic acid ester,

e.g. Methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid methyl ester, or sulfuric acid ester, e.g. dimethyl sulfate, dimethyl acetals, e.g. 2,2-dimethoxypropane, orthoester, e.g. orthoformic acid trimethyl ester, trimethyl oxonium salts, e.g. trimethyloxonium fluoroantimonate,

-hexachloroantimonate-hexafluorophosphate or -tetrafluoroborate, dimethoxycarbonium salt, e.g. dimethoxycarbonium-hexa-fluorophosphate, or dimethylhalonium salts, e.g. dime.tyl-

bromonium hexafluoroantimonate, or 3-aryl-1-methyl-triazen compounds, e.g. 3-P-tosyl-1-methyltriazene. The methylation is carried out in a manner known per se, usually in an inert solvent, e.g. an ether, dioxane or tetrahydrofuran, or in an optionally halogenated hydrocarbon, such as benzene, chlorobenzoyl, methylene chloride,

or the like, possibly in the presence of a suitable condensation agent, such as bases or acids, when cooling or heating, e.g. at temperatures between approx. -20°C to

about. 100°C.

Method j): Cleavage of an amino protecting group R-^ from a compound of formula I is carried out, optionally selectively, in a manner known per se, and depending on the nature of the protecting group, in different ways, e.g. by means of solvolysis or reduction. A 2-halogen-lower oxycarbonyl group (optionally after conversion of a 2-bromo-lower oxycarbonyl group into a 2-iodo-lower oxycarbonyl group), an acylmethoxycarbonyl group or a 4-nitrobenzyloxycarbonyl group R-^can e.g. by treatment with a suitable chemical reducing agent, such as zinc in the presence of aqueous acetic acid, an aroylmethoxycarbonyl group also after treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophen enolate, and a 4-nitro-benzoyloxycarbonyl group. also by treatment with an alkali metal, e.g. sodium dithionite, a diphenylmethoxycarbonyl, tert.-lower-alkoxycarbonyl<1>.- or polycycloalkoxycarbonyl group by treatment, e.g. with formic or trifluoroacetic acid, an optionally substituted benzyloxycarbonyl group, e.g. by of hydrogenolysis by treatment with hydrogen in the presence of a hydrogenation catalyst, such as a palladium catalyst, a trialkylmethyl group e.g. by treatment with aqueous mineral acid, and an organic silyl or stannyl group R-^ e.g. by means of hydrolysis or alcoholysis is cleaved off and replaced by hydrogen. t, as an alkali metal thiolate of thiourea and' subsequent sololysis, such as alcoholysis or hydrolysis split off the formed condensation product.

These solvolysis or reduction reactions are possibly carried out in the presence of a reaction participant or also in an inert solvent by cooling or heating, e.g. at temperatures of approx. -20° to approx. 100°C.

Process k): The esterification of a free carboxyl group or, a reactive functional derivative thereof, in the i- position of the cephem ring in a compound of formula I,

possibly carried out by protection of other functional groups, in a manner known per se.

Thus, esters are obtained, e.g. by. treatment of a free carboxyl group -COORg with a suitable diazo compound, such as a diazolaveralkane, e.g. diazomethane or diazobutane, or a phenyldiazoleveralkane, e.g. diphenyl-diazomethane, if necessary, in the presence of a Lewis acid,

like for example. boron trifluoride, or also by reaction with et

for the esterification suitable alcohol Rg-OH in the presence of an esterifying agent, such as a carbodiimide, e.g. dicyclohexylcarbodiimide, as well as carbonyldiimidazole, further with an N,N'-disubstituted 0-resp. S-substituted isourea or isothio-urea, in which an 0- and S-substituent e.g. lower alkyl, especially tert.-butyl, phenyl lower alkyl or cycloalkyl, and N-resp. N'-substituent e.g. lower alkyl, esp

isopropyl, cycloalkyl or phenyl, or by any other known and suitable method, such as reaction of a salt of an acid with a reactive ester of an alcohol of formula Rg-OH and a strong inorganic acid or a strong organic sulphonic acid. Furthermore, acid halides,

as -chlorides (prepared e.g. by treatment with oxalyl chloride) activated esters (formed e.g. with N-hydroxy-nitrogen compound, such as N-hydroxysuccinimide) or mixed anhydrides (obtained e.g. with haloformic acid lower alkyl esters, such as ethyl chloroformate - or chloroformate isobutyl ester, or with haloacetic acid halides, such as trichloroacetic acid-

chloride) by reaction with alcohols of the formula Rg-OH, optionally in the presence of a base, such as pyridine, is transferred into an esterified carboxyl group -COORg.

In an obtained compound with an esterified grouping with the formula -COORg, these can be transferred into another esterified carboxyl group with this formula, e.g. 2-chloroethoxycarbonyl or 2-bromomethoxycarbonyl by treatment with an iodine salt, such as sodium iodide, in the presence of a suitable solvent, such as acetone', in 2-iodoethoxycarbonyl.

Mixed anhydrides can be prepared in this way

a compound of formula I is reacted with a free carboxyl group of the formula -COORg, preferably a salt, especially an alkali metal-, e.g. sodium-', or ammonium-, e.g. triethylammonium salt thereof, with a reactive derivative,' as a halide, e.g.

the chloride, an acid, e.g. haloformic acid lower alkyl ester or a lower alkane carboxylic acid chloride.

Physiologically cleavable ester groups -COOR^ are preferably formed in one of the ways indicated above.

A carboxyl group protected with an organic silyl or stannyl group can be formed in a manner known per se, e.g. while treating compounds.'

with formula I, in which Rg stands for hydrogen, or salts, such as alkali metal, e.g. sodium salt thereof, with a suitable silylating or stannylating agent; see e.g. British Patent No. 1,073«530 respectively Holland's Explanatory Document No. 67A7IO7.

The esterification reaction can be carried out in the presence or absence of an inert solvent, such as an optionally halogenated hydrocarbon, e.g. methylene chloride, benzene, chlorobenzene, an amide, e.g. dimethylformamide, a sulfoxide, e.g. dimethyl sulfoxide, a nitrile, e.g. acetnitrile,

or the like, or possibly also in an excess of the alcohol R^-OH during cooling or heating, e.g. according to which method is used between approx. -50°C and 100°C.

Method l): Transfer of an esterified carboxyl group -COORg, by cleavage of the esterified residue Rg, in a free or in a carboxyl group present in salt form, i.e. in which R^ is hydrogen or a cation,

in a compound of formula I, carried out in a manner known per se, in particular by solvolysis, such as hydrolysis, alcoholysis

or acidolysis, or, by reduction, as hydrogenolysis

or chemical reduction.

Thus, one can e.g. transfer a tert.—lower alkoxycarbonyl, polycycloalkoxycarbonyl, or diphenylmethoxycarbonyl group by treatment with a suitable

acidic agent, such as formic acid or trifluoroacetic acid,

optionally by adding a nucleophilic compound,

as phenol or anisole in free carboxyl group. An optionally substituted benzyloxycarbonyl group can be released, e.g. by hydrogenolysis by treatment with hydrogen in the presence of a hydrogenation catalyst, such as a palladium catalyst. Furthermore, certain substituted benzoyloxycarbonyl groups, such as 4-nitrobenzyloxycarbonyl, can also be transferred by means of chemical reduction, e.g. by treatment with an alkali metal, e.g. sodium dithionite, or with a reducing metal, e.g. sin, or metal salt, such as a chromium II salt, e.g. chromium II chloride, usually in the presence of et

hydrogen-releasing agent, which together with the metal is able to produce nasalizing hydrogen, as an acid, preferably acetic, as well as formic acid, or an alcohol, whereby water is preferably added, in the free carboxyl group.

By treatment with a reducing metal or metal salt, as described above, one can also convert a 2-halo-lower-alkoxycarbonyl group (possibly after conversion of a 2-bromo-lower-alkoxycarbonyl group into a 2-iodo-lower-alkoxycarbonyl group) or an acylmethoxycarbonyl group

in the free carboxyl group, whereby an aroylmethoxycarbonyl group can optionally be cleaved by treatment with a nucleophile,

preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide. A polyhaloaryloxycarbonyl group, such as a pentachlorophenyloxycarbonyl group, can under mild basic conditions, such as dilute caustic soda or organic bases in the presence of water, be saponified into free carboxyl groups.

An e.g. by silylation or stannylation, the protected carboxyl group can be used in the usual way, e.g. when treated with water or an alcohol, is released.

By the basic hydrolysis or alcoholysis

the salt of the carbonic acid can be formed.

The reactions are carried out in the solvolysing agent alone, if a solvent is involved, or possibly in an inert solvent, or in a mixture thereof, according to which methods are used at a reduced or elevated temperature, for example between approx. -50° and 100°.

A war opera. j ons:

An obtained compound of formula I can be converted into another compound of formula I, whereby the residues R 1 , R 2 or . A within the framework of their meaning can be transferred into other residues R-^, Rg or A. It preferably relates to removal of protective groups provided that these have not already been carried out using one of the methods i) to 1), e.g. by protecting groups in the residue A, but also by subsequent change of A.

In the obtained compounds of formula I, in which functional groups are protected, these become,

e.g. protected carboxyl, amino, hydroxymercapto and/or sulfo groups, in a manner known per se, such as by means of solvolysis, especially hydrolysis, alcoholysis or acidiolysis, or by means of reduction, especially hydrogenolysis or chemical reduction, optionally gradually or simultaneously released.

Thus one can transfer in the free. the carboxyl group e.g. a tert.-lower oxycarbonyl, polycycloalkoxycarbonyl or diphenylmethoxycarbonyl group by treatment with a suitable acid-binding agent, such as formic acid or trifluoroacetic acid, optionally by adding a nucleophilic compound, such as phenol or anisole. An optionally substituted benzyloxycarbonyl group can be released, e.g. by means of hydrogenolysis by treatment with hydrogen in the presence of a hydrogenation catalyst such as a palladium catalyst. Furthermore, certain substituted benzyloxycarbonyl groups, such as 4-nitrobenzyloxycarbonyl, can also be transferred by means of chemical reduction, e.g. by treatment, with an alkali metal, e.g. sodium dithionite, or with a reducing metal, e.g. zinc, or metal salts, such as a chromium II salt, e.g. chromium II chloride, usually in the presence of a hydrogen-releasing agent, which, together with the metal, is capable of producing nascent hydrogen, such as an acid, preferably acetic, as well as formic acid, or an alcohol, whereby water is preferably added, in free carboxyl group. When treated with a reducing metal. or metal salt, as described above, it is also possible to convert a 2-halo-lower alkylcarbonyl group (possibly after conversion of a 2-bromo-lower alkylcarbonyl group into a 2-iodla<y>eryloxycarbonyl group) or an acylmethoxycarbonyl group into a free carboxyl group, whereby,

an aroylmethoxycarbonyl group can optionally be cleaved by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide. A polyhaloaryloxycarbonyl group, such as the pentachlorophenyloxycarbonyl group, is saponified to free carboxyl groups under mild basic conditions, such as with dilute caustic soda or organic bases in the presence of water.

An e.g. by silylation or stannylation, the protected carboxyl group can be used in the usual way, e.g. when treated with water or an alcohol, is released.

A protected amino group is formed in a manner known per se and according to the nature of the protecting group in different ways, e.g. by means of solvolysis or reduction, released. A 2-halo-lower oxycarbonylamino group (optionally after conversion of a 2-bromo-lower oxycarbonyl group into a 2-iodo-lower oxycarbonyl group),

an acylmethoxycarbonylamino group or a 4-nitro-benzyloxy-carboxylamino group can e.g. by treatment with suitable chemical reducing agents, such as zinc in the presence of aqueous . acetic acid, an aroylmethoxycarbonylamino group also by treatment with a nucleophilic, preferably salt-forming reagent, sodium thiophenolate, and a 4-nitro-benzyloxycarbonylamino group also by treatment with an alkali metal-,.

e.g. sodium dithionite, a diphenylmethoxycarbonylamino, tert.-lower oxycarbonylamino or polycycloalkoxycarbonylamino group by treatment, e.g. with formic or trifluoroacetic acid, an optionally substituted benzyloxy-. carbonylamino group e.g. by means of hydrogenolysis by treatment with hydrogen in the presence of a hydrogenation catalyst, such as a palladium catalyst, a triarylmethyl group e.g. by treatment with aqueous mineral acid, and one with an organic one

silyl or stannyl group protected, amino group e.g.

by means of hydrolysis or alcoholysis, is released. An amino group protected by 2-haloacetyl, such as 2-chloroacetyl, can be freed from condensation products formed by treatment with thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate of thiourea and subsequent solvolysis, such as alcoholysis or hydrolysis.

A hydroxy group protected with an acyl group, a silyl or stannyl group or with an optionally substituted α-phenyl lower alkyl residue is released as a corresponding protected amino group. A hydroxy group protected by a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon residue is released by acidolysis.

A protected sulfo group is released analogously to a protected carboxyl group'.

The protecting groups can be selected so that they can all be cleaved at the same time, for example acidolytically, as in treatment with trifluoroacetic acid or formic acid, or reductively, as in treatment with zinc and glacial acetic acid, or with hydrogen and a hydration catalyst, such as a palladium/carbon catalyst.

By choosing suitable reaction conditions, the protecting group can also be selectively removed. For example, a diphenylmethoxycarbonyl group can be transferred with trifluoroacetic acid at 0° in a free carboxyl group, while a simultaneously present tert-butoxycarbonylamino group with the same reagent only at a higher temperature, e.g. at room temperature, and possibly a longer reaction time can be transferred into a free amino group.

The cleavage reactions described are carried out according to known conditions, if necessary by cooling or heating, in a closed vessel and/or in an inert gas, e.g. nitrogen atmosphere.

The transfer of a free carboxyl group in an obtained compound of formula (I) into an esterified carboxyl group, which is cleavable under physiological conditions, is carried out according to esterification methods known per se, for example by esterifying a compound of formula (I), in which other functional groups, such as amino, hydroxy or sulfo groups, optionally present in protected form, or a reactive functional derivative thereof, or a salt thereof, belonging to the carboxyl group to be esterified, with a corresponding alcohol or a functional derivative, for example a halide , as chloride.

In an obtained compound of formula (I),

a hydroxymethylene group A can be oxidized to an oxomethylene group. The oxidation can be carried out, optionally by protection of a free amino and carboxyl group, 'on. known in and of itself, i.e. for oxidation of the hydroxy to oxo group in a known manner. As an oxidizing agent, oxides, such as those of manganese, chromium, nitrogen or sulphur, come into consideration.

such as manganese dioxide, chromium trioxide, e.g. Jones Reagent,

or chromium trioxide in the presence of acetic acid, sulfuric acid or pyridine, dinitrogen tetraoxide, dimethylsulfoxide optionally in the presence of dicyclohexylcarbodiimide or oxygen, and peroxides, such as hydrogen peroxide, oxygen-containing acids,

such as permanganic acid, chromic acid or hypochlorous acid or salts thereof, such as potassium permanganate, sodium or potassium dichromate or potassium hypochlorite. The hydroxyl methyl group can also be transferred to the oxomethylene group by Oppenauer oxidation,

ie by treatment with the salt of a sterically hindered alcohol, such as aluminum or potassium tert-butoxide, -isopropoxide or -phenoxide in the presence of a ketone, such as acetone, cyclohexanone or fluorenone. Another possibility for transferring the hydroxymethylene group into the oxomethylene group consists in dehydration, e.g. with Raney nickel.

The oxidation is carried out according to the nature of the oxidizing agent in water or in a possibly aqueous solvent at temperatures of approx. 0° to approx. 100°.

In an obtained compound of formula (I),

in which A means an oxomethylene group, this can optionally be transferred by protection of functional groups, by treatment with hydroxy amine, 0-protected or 0-carbamoylated hydroxylamine or O-methylhydroxylamine in a hydroxyiminomethylene group, in which hydroxy is optionally present in protected or carbamoylated form, respectively in a methoxyimino-methylene group.

The reaction of the oxomethylene group with the hydroxylamine compound is carried out in the usual way, e.g. allowing both reaction partners to react in a solvent such as water or an organic solvent such as an alcohol, e.g. methanol, at a slightly elevated or reduced temperature, possibly in an inert gas atmosphere, such as nitrogen. The hydroxylamine compound can, also in situ, be set free from one of their salts, for example a hydrohalide, such as hydrochloride, by treatment with an inorganic base, such as an alkali metal hydroxide, e.g. sodium hydroxide, or an organic base, such as a tertiary amine, e.g. a tri-lower alkylamine, such as triethylamine or ethyl diisopropylamine, or a heterocyclic tertiary base, such as pyridine.

In one obtained compound of formula (I), in which A means methylene, the methylene group can e.g. analogous to BE-PS 855-953" is transferred into a hydroxyimino group, by nitrosation, in which the hydroxy group can then, if desired, in a manner known per se protected, carbamoylated or by methylation be transferred into a methoxy group. Furthermore, a methylene group A can be sulfonylated to a sulfomethylene group,

e.g. by treatment with the SO^/dioxane complex, e.g. analogous to DT-OS 2.638.028.

Salts of compounds of formula (i) can be prepared in a manner known per se. Thus, one can form salts of compounds of formula I with acidic groups, e.g. by treatment with metal compounds, such as alkali metal salts of suitable carboxylic acids, e.g. the sodium salt of α-ethylcaproic acid or sodium bicarbonate, or with ammonia or a suitable organic amine, whereby stobiometric amounts or only a small excess of salt-forming agents are preferably used. Acid addition salts of compounds of formula I are obtained in the usual way, e.g. by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of formula (i), which contain free carboxyl groups, can be formed, e.g. by neutralization of salts, such as acid addition salts, at the isoelectric point, e.g. with weak bases, or wood

treatment with liquid ion exchangers.

The method also includes such embodiments, after which compounds formed as intermediates are used as starting materials and remaining method steps are carried out with these, or the method is interrupted at any step; furthermore, starting substances can be used in the form of derivatives or formed in situ, possibly under reaction conditions.

The starting compounds of formulas II to VIII

are known or can be prepared analogously to known methods.

Thus, starting compounds of formula II, in which hydrogen is, are known from DT-OS 2151,567. Starting compounds of formula II, in which R^ is methoxy or a group transferable to methoxy, can be prepared in a manner known per se, for example by introducing etherified mercapto into compounds of formula II, in which R^ is hydrogen, and yielding etherified mercapto against methoxy.

Starting compounds of formula III are known, e.g. from BE-PS 852,971, BE-PS 853,545, DT-OS 2,556,736 and DT-OS 2,638,028.

Starting compounds of formula IV can be prepared by acylation of compounds of formula II with an acid of formula X-CHg-CO-A-COOH or a reactive functional derivative thereof, e.g. analogous procedure a).

Starting compounds with formula V or -Va respectively can be prepared analogously to DT-OS 2151.567 and starting compounds with formula VI analogously to the Dutch interpretation script. 68.I563I or Austrian Patent Nos. 263,768 and 264,537.

Starting compounds of formula VII,

in which R^ is hydroxy or esterified hydroxy, can be prepared analogously to DDR patent 10.6652.

Starting compounds of formula VII,

in which RQ is optionally substituted amino, can be obtained analogously to DT-OS 2.606.192 by treatment with amines of corresponding 3-hydroxy-3-cephem compounds or according to DT-OS 2.606.196 e.g. by ring closure of corresponding 2-(4 -tosylthio-3-acylamido-2-oxoazetidin-1-yl)-

3-subst. amino-crotonic acid esters.

Starting compounds of formula VIII can be obtained by gentle decarbonylation of 3-formyl-2-cephem compounds of formula VI.

Starting compounds of formula IX can be prepared analogously to method a) by acylation of compounds of formula II, in which RQ is a group Raq. Further possibilities for the production of such compounds

relates to the substitution of a group R cl for another group ■e

RQ, e.g. of p-toluenesulfonyloxy to amino (see US Pat

No. 4.O65.618).

Those required by procedure h).

.starting compound of formula I, in which R-^ is a med

methoxy replaceable group, especially an etherified mercapto group, such as methylthio, is conveniently prepared from corresponding compounds of formula IV by the method

b).

The new starting materials and the procedure for

production of these is likewise an object of the present invention.

The. pharmacologically useful compounds

according to the present invention can be used, for example, for the production of pharmaceutical preparations, which contain an effective amount of the active substance together ■ or in a mixture with inorganic or organic, solid or

liquid, pharmaceutically acceptable carriers, suitable for enteral or parenteral administration. For

enteral administration uses tablets or gelatin capsules, which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and thickeners, e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene

glycol; tablets also contain binders, e.g. magnesium aluminum silicate, starches, such as corn, wheat,

rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone,

and if desired, explosives, e.g. starches, agar, aligic acid or a salt thereof, such as sodium alginate, and/or

soft drink mixtures, or adsorbents, colourings, flavorings and sweeteners. Suppositories are preferably fat emulsions or suspensions.

Preferably, the pharmacologically active compounds according to the present invention are used in the form of injectables, e.g. intravenously or subcutaneously, administrable preparations or in the form of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, whereby these can be prepared for use, e.g. from lyophilized preparations,

.which contain the active substance alone or together with

a carrier material, e.g. mannite. The pharmaceutical preparations may be sterilized and/or contain excipients. e.g. preserving, stabilizing, wetting and/or emulsifying agents, solubility mediators, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations, which, if desired, can contain additional pharmacologically valuable substances, prepared in a manner known per se, e.g. using conventional mixing, dissolving or lyophilization methods and contains from approx. 0.1% to approx. 100%, especially from approx. 1% to approx. 50%, lyophilisates up to 100% of the active substance.

Depending on the type of infection, condition of the infected organism, daily doses from approx. 0.5 to approx. 5 g s.c.

for the treatment of warm-blooded creatures weighing approximately 70 kg.

The following examples serve to illustrate the invention; temperatures are given in degrees Celsius.

Rf indication for thin layer chromatography:

DS: On silica gel finished plates SL 254 from

company Antec, Birsfelden.

The composition of the lip balm is as follows: 52 A : n-butanol Acetic acid/water 67:1023

67 n-butanol/ethanol/water 40:10:50 (upper phase)

101 : n-butanol/pyridine/glacial acetic acid/water 38:24:8:30

101A : n-butanol/pyridine/glacial vinegar/water 42:24:4:30

In the aminothiazole-2-methoxyiminoacetic acid compounds, the 2-methoxyimino group has the syn configuration.

Example 1

a) A solution of 1.14 g of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetic acid in 15 ml of tetrahydrofuran

is added at -10° CO, 85 g of N,N'-dicyclohexylcarbodiimide and 0.56 g of 1-hydroxybenztriazole and stirred at approx.~5° to

-10° 1 l/2 hours under nitrogen. After adding a solution of 1.0 g of 7P-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in 15 ml of tetrahydrofuran, the mixture is first stirred for 1 hour at the same temperature and then for 4 hours at room temperature. The reaction mixture is filtered and the filtrate evaporated in

vacuum. The evaporation residue is taken up in ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated in vacuo. This residue is taken up in ethyl acetate and, after filtration from undissolved material, evaporated again. By chromatography on silica gel with toluene with increasing proportions of ethyl acetate (up to 30%), 7(3-(2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido7-3-cephem-4-carboxylic acid diphenyl methyl ester) is recovered from it.

DS: RfrvO,57 ( ethyl acetate),v IR spectrum (CH2C12): Absorption bands at 335O, 3200, I782, 1770sh, 1724, 1705, I684, 1540 cm"<1.>b) A mixture of 1.25 g 7 (3-(2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido7-3-ref e'm-4-carboxylic acid diphenyl methyl ester, 12 ml of methylene chloride, 0.68 ml of anisole and 3.4 ml of trifluoroacetic acid are stirred 30 minutes under ice-cooling After the dropwise addition of 100 ml of diethyl ether, the mixture is stirred for a further 45* minutes at the same temperature.

The precipitated 7(3-(2-(2-chloroacetamido-4-thiazolyl)-2-methoxy-iminoacetamido7-3-cephem-4-carboxylic acid) is filtered off, washed with diethyl ether and dried.

DS: Rf 0.37 (n-butanol:glacial acetic acid:water 67:10:23).

c) A solution of 700 mg of 7P-(2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido7-3-cephem-4-carboxylic acid

260 mg of thiourea are added to 17 ml of N,N'-dimethylacetamide and stirred for 19 hours at room temperature. That by adding 200 ml of diethyl ether and decanting the solvent

precipitates obtained are washed with 100 ml of diethyl ether and dissolved in 25 ml. water. The cloudy solution is cooled and adjusted to pH 7 with sodium bicarbonate. The precipitate is filtered off, washed with water and the filtrate and washing liquid is filled onto a column with 180 ml "Amberlite XAD-2". The column is first washed through with water and then with water:isopropanol 85:15' The obtained fractions containing 7P_Z~2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido_7-3-cef em-4-carbonic acid sodium salt are combined and evaporated.

The sodium salt is added to acetone, filtered off and dried.

DS: RfX/0.19 (n-butanol:glacial acetic acid:water 67:10:23);

UV spectrum (ethano<l>)<:>X max=233 rryu (£=15<T>500) and 290rryu sh (£ = 5'500).

Example 2

a) A solution of 3>31 g of 2-(2-tert..butoxycarbonylamino-4-thiazolyl)-2-methoxyiminoacetic acid in 35 ml of tetrahydrofuran is added 1.50 g of 1-hydroxybenztriazole and 2.27 g of N ,N'-dicyclohexylcarbodiimide and stirred for 2 hours at 0°. A solution of 3>66 g of 7P-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 45 ml of tetrahydrofuran is added to the reaction mixture and is further stirred for 1 hour at 0°C and 4 hours at room temperature. The precipitated urea is filtered off, the filtrate evaporated in vacuo and the residue worked up with acetic acid ethyl ester, citrate buffer, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. Treatment of the organic phase over sodium sulfate, evaporation in vacuo, flash chromatography of the crude product obtained on silica gel with toluene/ethyl acetate 4:1 as eluent and crystallization of the purified product from methylene chloride/diethyl ether gives 7P~Z2-(2-tert.butoxyca' carbonylamino-4-thiazolyl)-2-methoxyiminoacetamido7-3-cephem-4-carboxylic acid diphenyl methyl ester with melting point 154-157°C; DS: RfN/"0.37

(toluene-ethyl acetate 1:1); UV spectrum (in ethanol) : X may. s 234 m/u [ i = 15,500), 295 n<y>u (shoulder); IR spectrum (in C<H>2C12): absorption band at 34OO; 1792; 1775 sh; 1728;

I68O; 1640; 1545 cm"<1.>

Example 3:

A solution of 840 mg of 2-(2-tert.butoxy-carbonylamino-4-thiazolyl)-2-methoxyiminoacetic acid in 9 ml of methylene chloride and 0.26 ml of pyridine is added at -15°C under nitrogen to 0.5 ml of diethyl phosphorous bromide and stirred 30 minutes at this temperature. After adding 1.00 g of 7(3-amino-3-cephem-4-carboxylic acid diphenyl methyl ester at -15°C,

the reaction solution was stirred at room temperature for 2 hours, then diluted with chloroform, washed successively with dilute sulfuric acid, water, aqueous sodium bicarbonate solution and aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue is purified by preparative thin-layer chromatography on silica gel with toluene/ethyl acetate 1:1. The compound described in example 2 is obtained.

Example 4:

A solution of 15.0 g of 7(3-/~2-(2-tert. butoxycarbonylamino-4-thiazolyl)-2-methoxyiminoacetamido7-3-cephem-4-carboxylic acid diphenyl methyl ester in 75 ml methylene chloride and 75 ml trifluoroacetic acid. is stirred for 1 hour at room temperature, cold toluene is added and evaporated in vacuo. The residue is digested with diethyl ether, filtered off and dried. The obtained light beige, powdery trifluoroacetate of 7P-Z~2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido7-3-cephem-4-carboxylic acid is suspended in 90 ml of water. The pH value of the suspension is adjusted with 2N NaOH to 7.1. The solution is clearly filtered and chromatographed on 1200 ml "Amberlite XAD-2". Elution with water/15% isopropanol and lyophilization of the combined fractions containing the desired product gives the slightly yellowish 7(3-(2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido7-3-cef) -4- carboxylic acid sodium salt. IR spectrum (Nujol): characteristic absorption bands at 3300 b; 1770; 1670 b; 1600; 1532; 460 cm"<1>.

A solution of 100 mg of the sodium salt obtained in 5 ml of water is adjusted to pH 3>5 with 0.5 N hydrochloric acid. The precipitated 7(3-(2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido7-3-cephem-4-carboxylic acid) is filtered off, washed briefly with water and acetone and dried in vacuo.

Example ^ :

A solution of 3>3g 7 (~>-Z2-(2-tert. butoxy-carbonylamino-4-thiazolyl)-2-methoxyiminoacetamido7-3-cephem-4-carboxylic acid diphenyl methyl ester in 35 ml methylene chloride- is stirred with 15, 4 ml of trifluoroacetic acid for 30 minutes at 0°C, cold toluene added and evaporated in vacuo. The residue is digested with diethyl ether, filtered off and dried. The yellow powder obtained is dissolved in 10 ml of methanol, a methanolic solution of sodium ethyl hexanoate is added and, for complete dissolution of the precipitate, added diethyl ether and stirred for 1.5 hours under ice-cooling. filtered off, washed well with diethyl ether and dried. DS: Rf rJ 0.47 (n-butanol: acetic acid: water 67.: 10:23); UV spectrum (water) : Xmax= 233 m/u (£■= 15500 ), 290 rryu (shoulder).

For conversion into free acids, 1.5 g of the sodium salt obtained is suspended in ethyl acetate and acidified with 2 N hydrochloric acid. The organic phase is washed with water and aqueous sodium chloride solution, dried and evaporated in vacuo. The residue is chromatographed on silica gel (deactivated with 5% water) with methylene chloride, methylene chloride/ethyl acetate (from 10 to ^ 0% increasing)

and finally with pure ethyl acetate. It obtained ^^-/ Z- tert. butoxycarbonylamino-4-thiazolyl)-2-methoxyiminoacetamido7-3-cephem-4-carboxylic acid is recrystallized from methanol/diethyl ether/hexane. Melting point: approx. 210° (cleavage);

DS: Rf^2A^' 0.42; UV spectrum (ethanol): X max = 260 nm

(£ = I688O); 232 nm (6= 19900); 224 nm (£ = 20000); IR spectrum (Nujol); absorption band at 327O; 3l80; 1782; 1718; 1654 cm"<1.>

Example 6:

A mixture of 2.25 ml of chloromethyl pivalate and

9.0 g of sodium iodide in 30 ml of acetone is stirred for 3 hours at room temperature. A solution of 2j5 g of 7P-Z~2-(2-tert.butoxycarbonylamino-4-thiazolyl)-2-methoxyiminoacetamido7~3-cephem-4-carboxylic acid sodium salt is added to the mixture.

in 50 ml of dimethylformamide and further stirred for 1 hour at

room temperature. After evaporation in vacuo, the residue is dissolved in ethyl acetate and the solution is washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The crude product obtained after evaporation in vacuum is chromatographed on silicon dioxide gel. Elution with toluene containing 20 - 30% ethyl acetate gives 7(3-(2-(2-tert.butoxycarbonylamino-4-thiazolyl)-2-methoxy-iminoacetamido7-3-cephem-4-carboxylic acid pivaloyloxymethyl ester. DS: Rf', -0.61 (ethyl acetate); UV spectrum (ethanol): "Xmax = 234 n<y>u (£ = 1600), 293 rryu (shoulder); IR spectrum (in CH2C<1>2): absorption band at 338O; 1789; 1773 sh; 1725;

1680; I638; 1545 cm"<1.>

Example 7:

A solution of 1.7 g of 7-(3-/2-(2-tert-butoxy-carbonylamino-4-thiazolyl)-2-methoxyiminoacetamido7-3-cephem-4-carboxylic acid pivaloyloxymethyl ester in 8.7 ml of methylene chloride is added 8.7 ml of trifluoroacetic acid and stirred for 1 hour at room temperature. After addition of cold toluene, it is evaporated in vacuo. The residue is stirred with diethyl ether-hexane .1:1, filtered off and dried. The obtained brown powder is taken up in ethyl acetate, washed with cold saturated sodium bicarbonate and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue is digested with diethyl ether, filtered and dried in high vacuum. It obtained 7|3-,/<_>2-(2-amino-4 -thiazolyl)-2-methoxyiminoacetamido/-3-cephem-4-carboxylic acid pivaloyloxymethyl ester decomposes at about 130°C.

DS: Rf = 0.28 (ethyl acetate); UV spectrum (ethyl acetate):

"Xmax = 235 nyu ( £. = 16320); 295 nyu- (shoulder); IR spectrum (in CH2C12): characteristic absorption bands at 3480; 3390; 3330; 1782;<1>753; 1680; 1620; 1530 cm" <1>.

Example 8

A mixture of 0.11 ml of chloromethyl pivalate and 0.45 g of sodium iodide in 1.5 ml of acetone is stirred for 3 hours at room temperature. The suspension is then added to 0.202 g of 7P-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido7-3-c'ephem-4-carboxylic acid sodium salt in 3 ml of dimethylformamide and further stirred for 3 hours at room temperature.

The reaction mixture is diluted with ethyl acetate,

equipped with saturated anhydrous sodium chloride solution,

dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate 1:1 and ethyl acetate to give 7(3-(2-(2-amino-4-thiazolyl)-.2-methoxyiminoacetamido_7-3-cef em-4-carboxylic acid pivaloyloxymethyl ester .

Example 9-'a) A solution of 2.0 g (3.2 m mol) 7(3-/0, L-2-tert. butoxycarbonylamino-2-(2-amino-4-thiazolyl-acetamido)-3 -cephem-4-carboxylic acid diphenyl methyl ester and 2 ml of anisole in 10 ml of methylene chloride are added to 10 ml of trifluoroacetic acid and stirred for 1 hour at 20-25° C. in the absence of moisture in a nitrogen atmosphere. After addition of 200 ml of diethyl ether to it at 0 °C cooled solution, the trifluoroacetate of 7(3-β, L-2-amino-2-(2-amino-4-thiazolyl)-acetamido)-3-cephem-4-carboxylic acid formed in crystalline form is filtered off, washed with diethyl ether and dried.

The aqueous solution (25 ml) of the crude trifluoroacetate is extracted (3*15 m) with ethyl acetate, adjusted at 0° with 2N sodium hydroxide solution at pH = 5>55 concentrated to approx. 10 ml and added dropwise isopropanol (40 ml).

The precipitate formed is filtered off, further re-ground

from water-acetone 1:4 and finally dissolved twice in a little ■ water, to remove organic solvents and evaporated in a rotary evaporator, after which after

in high vacuum, 7(3-/P> L-2-amino-2-(2-amino-4-thiazolyl)-

acetamido7-3-cef em-4-carbonic acid dihydrate in the form avo et amorphous

.powder. DS: RH = 0.12 (n-butanol: glacial acetic acid: water 67:10: 23); £~ 27n°=<+>76 i1° (0.1N HCl:0.33%); UV spectrum (in 6.IN HCl): Imax.<=>250 nm ( 12400);

The starting material can be obtained as follows: b) A cooled solution of 2.24 g (5 m MOL) D,L-2-tert.butoxycarbonylamino-2-(2-trichloroethoxycarbonyl-amino-4-thiazolyl)-acetic acid at -20° and 0.56 ml of N-methylmorpholine in 50 ml of absolute methylene chloride is added with stirring and in the absence of moisture to 0.65 ml of chloroformate isobutyl ester and is allowed to react for 1 hour. To the thus obtained mixed anhydride is added at -15°C 1.83 g (5 m mol) 7P-amino-3-cephem-4-carboxylic acid dimethyl ester in one portion. After a reaction time of 30 minutes at -15°C and 2 l/2 hours at room temperature, the reaction mixture is diluted with ethyl acetate (200 ml), washed twice with ice water and saturated aqueous sodium chloride solution, dried over sodium sulfate and freed from solvent in a rotary evaporator, from which 7P~ZP>L-2-tert.butoxycarbonylamino-2-(2-trichloroethoxycarbonyl-amino-4-thiazolyl)-acet-amido7~3-cephem-4- carboxylic acid diphenyl methyl ester as amorphous yellow powder. DS: Rf = 0.59 (silica gel; emollient: ethyl acetate). c) To a 0°C cooled solution of 3>0 g (3.76 m Mol) 7(3-/D,L-2-tert.-butoxycarbonylamino^-^-trichloroethoxy-carbonylamino^-thiazolyl)-acetamido7 -3- cef em-4-carboxylic acid diphenyl methyl ester in 30 ml acetonitrile-acetic acid 1:1 is added by approx. 10 minutes under strong stirring with added portion ice 3 g of zinc stbv. After one hour, the reaction mixture is diluted with acetic acid ethyl ester (200 ml), separated from zinc dust by filtration, washed twice with ice water and saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and freed from solvent in a rotary evaporator, from which 7P-/D)L-2 is obtained -tert.butoxycarbonylamino-2-(2-amino-4-thiazolyl)-acetamido7-3-cephem-4-carboxylic acid diphenyl methyl ester with sufficient purity for the next synthesis step. DS: Rf = 0.47 (silicon dioxide gel; emollient: ethyl acetate).

Example 10:

A solution of 2.40 g of 7(3-/~2-(2-tert. butoxycarbonylamino-4-thiazolyl)-2-methoxy-yiminacetamido7-7a-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester in 10 ml of methylene chloride is added to 15 ml of trifluoroacetic acid and stirred for 1 hour at room temperature in the absence of moisture. Then

reaction mixture is poured. none on an ice-cold mixture of petroleum ether

(400 ml) and diethyl ether (200 ml), the trifluoroacetate formed is filtered off, washed with petroleum ether and dried in

vacuum at room temperature. The crude 7P-Z~2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido7-7a-methoxy-3-cephem-4-carboxylic acid trifluoroacetate is slurried in 20 ml of water, by adding

of 1N sodium bicarbonate solution adjusted to a pH value of 6.5, the suspension is stirred for 15 minutes at room temperature, then undissolved product (little)

by treatment with activated carbon and filtration through "Celite" separated. A lot of ethanol is added to the clear filtrate, the pH value is corrected to 6.0 and the solution is evaporated in a rotary evaporator (high vacuum) at 45°C«

The aqueous solution is evaporated several times with ethanol, finally 7P-Z~~2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido7-7a-methoxy-3-cephem-4-carboxylic acid- the sodium salt precipitated by addition of ethanol, separated and washed with ethanol, ethanol-diethyl ether (1:1) and diethyl ether. The product can be further purified by dissolving in water and evaporation or precipitation with ethanol. Melting point from 199°C (decomposition). DS: Rf = 0.33; Rf 67 ~ °>20> Rfi01= °>^ >

<Rf>101A<=0>'45.

The starting material can be prepared as follows: The following reactions are carried out in a nitrogen atmosphere. A solution of 4>90 g of 7P-/~2-(2-tert.butoxy-carbonylamino-4-thiazolyl)-2-methoxyiminoacetamido/-3-cephem-4-carboxylic acid diphenyl methyl ester in ^00 ml of absolute tetrahydrofuran is cooled to -75°G (ice-acetone bath) and a prefused solution of lithium methoxide in methanol (210 mg of lithium dissolved in 20 ml of methanol) is added dropwise over 2 minutes, whereby the temperature rises to

-70°C and an orange-coloured solution occurs. The reaction mixture is stirred for a further 2 minutes at -75°C, then 0.10 ml of tert-butyl hypochlorite is added and further stirred at -75°C. After 8 minutes, a further 0.60 ml of tert-butyl hypochlorite is added to the solution. After 30 minutes, 10 ml of glacial acetic acid and a solution of 400 g of sodium thiosulphate in 5 ml of water are successively added dropwise to the reaction mixture. The Kjblebath is removed and the solution is warmed to room temperature. The mixture is diluted with ethyl acetate, the tetrahydrofuran is evaporated in the rotary evaporator at 45°C, the ethyl acetate solution is washed successively with water, 1N sodium bicarbonate and water, dried over sodium sulfate and evaporated. the solvent is evaporated. The crude product is chromatographed

on the 20-fold amount of silica gel. The fraction with methylene chloride and 1% methyl acetate as eluent is combined. The product is dissolved in a little ethyl acetate, precipitated with a mixture of petroleum ether (500 ml) and diethyl ether (200 ml), filtered off and washed with petroleum ether.

7P-(2-tert.butoxycarbonylamino-4-thiazolyl)-2-methoxyiminoacetamido7-7a-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained. DS (propellant: toluene-ethyl acetate (3:2)): Rf = 0.40.

Example 11:

a) A solution of 1.60 g of 7P-/2-(2-amino-4-thia-.zolyl)-2-hydroxyiminoacetamido7~3-cephem-4-carboxylic acid diphenyl methyl ester in 15 ml of methylene chloride is stirred with 0.50 ml of anisole and 2.35 ml of trifluoroacetic acid for 30 minutes in an ice bath, added 100 ml of cold toluene and evaporated in vacuo. The residue is digested with diethyl ether, filtered off and

dried. The obtained trifluoroacetate of 7P-Z~2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido7-3-ref em-4-carboxylic acid is suspended in 10 ml of water/methanol 1:2 and the pH of the suspension is adjusted to 4.1- with 10% methanolic triethylamine solution. After stirring for 30 minutes at 0°, the precipitated 7(3-/~2-(2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido7-3-cephem-4-carboxylic acid) is filtered off, washed with acetone and diethyl ether and dried Melting point about 170°C (dec) DS : Rf^2A~'0.03.

The starting material is obtained as follows:

b) A solution of 3)25 ml ('v 42.5 m. mol) diketene in 15 ml methylene chloride is added at -25°C a

solution of 2.20 ml 42.5 m mol) bromine in 15 ml methylene chloride and stirred for 30 minutes at -25° • The reaction mixture is added dropwise over the course of 20 minutes to a cooled solution of 13.0 g (^, 35.5m mol) 7(3-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 3>45 ml pyridine and 90 ml methylene chloride and further stirred for 30 minutes at -25°C. After addition of ethyl acetate, the organic phase is successively washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo.

The residue is chromatographed on /\. 00 g silica gel.

With toluene/ethyl acetate 9:1, 7P-(4-bromoaceto-acetamido)-3-cephem-4-carboxylic acid diphenyl methyl ester is obtained as a yellowish foam. DS: Rf 20.53 (toluene/ethyl acetate 1:1); IR spectrum (in CH2C12): absorption bands at 3400, 3320, 1790, 1728,

1686, 1621, 1520 cm"1.

c) A solution of 2.65 g (5 m mol) 7P-(4-brc-rri-aceto-acetamido)-3-cephem-4-carboxylic acid diphenyl methyl ester in 27 ml of glacial acetic acid is added at 15°C dropwise with a dissolving 380 mg (5.5 m mol) of sodium nitrite in 4 ml of water and stirring for 1 hour at room temperature. The reaction mixture is poured into 100 ml of ice-cold, saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue is digested with diethyl ether/hexane 2:1, filtered off and dried. 7P-(4-Drom-2-hydroxyiminoacetoacetamido)-3-cephem-4-carboxylic acid diphenyl methyl ester is obtained with Rf = 0.50 (toluene/ethyl acetate (1:3)); IR spectrum (in CHgClg): absorption bands at 3250 b, 1795, 1724 sh, 1712, I64O, 1540 cm"<1.>

d) A solution of 2.45 g (4.38 m mol) 7p<->

(4-bromo-2-hydroxyimino-acetoacetamido)-3-cephem-4-carboxylic acid diphenylmethyl ester in 25 ml of dioxane is added to a solution of 0.37 g (4>5m mol) of thiourea in 4 ml of water and stirred for 30 minutes at room temperature. The reaction mixture becomes

added ethyl acetate, washed alternately with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate - and evaporated in vacuo. The residue is digested with diethyl ether, filtered off and dried. 7P-Z2"-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamide p_7-3-cef em-4-carboxylic acid diphenyl methyl ester is obtained as light beige powder with R^gA^'(-*.54" Decomposition temperature approx. 150°; UV spectrum (ethanol) :X= 251 nm = 12900); IR spectrum (CH 2 Cl 2 ); absorption bands at 3450, 3360, 3190 sh-, 1792, 1728,.I68O, I64O, I607, 1540, 1512 cm "1.

Example 12:

a) A solution of 1.2 g of 7(3-(2-(2-amino-4-thiazolyl)-acetamido7-3-cephem-4-carboxylic acid diphenylmethyl ester)

in 12 ml of methylene chloride is stirred with 0.39 ml of anisole and 1.83 ml of trifluoroacetic acid for 30 minutes in an ice bath, 100 ml of cold toluene is added and evaporated. in vacuum. The residue is digested with diethyl ether and filtered off. The obtained trifluoroacetate of 7(3-Z2-(2-amino-4-thiazolyl)-acetamido-3-cephem-4-carboxylic acid is suspended in 10 ml of water/methanol 1:1 and the pH value of the suspension is adjusted of about 4-,

with 10% methanolic triethylamine solution. After stirring for one hour with ice, the precipitate is filtered off, washed with acetone and diethyl ether and dried. 7(3-[2-(2-amino-4-thiazolyl)-acetamido7-3-cephem-4-carboxylic acid is obtained

with melting point approx. 210°C (decomposition). DS: Rf^2^/0.05,”

(Nujol): absorption bands at 348O b, 328O, 1745 sh, 1720, 1670, 1545 cm"<1.>

The starting material is produced as follows:

b) A solution of 2.65 g of 7(3-(4-bromoacetoacetamido)-3-cephem-4-carboxylic acid diphenyl methyl ester in 30 ml of dioxane is

added a solution of 0.42 g of thiourea in 5 ml of water and

about 30 minutes at room temperature. The mixture is diluted with ethyl acetate, washed successively with water,

saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium

sulfate and evaporated in vacuo. The residue is chromatographed on 50 g of silica gel. With toluene/ethyl acetate 1:1, 7(3^/2-(2-amino-4-thiazolyl)-acetamido7-3-cef em-4-carboxylic acid diphenyl methyl ester is eluted. The crude product is digested with diethyl ether. DS: Rf 0 .29 (ethyl acetate), mp 105-115°

(fission); UV spectrum (ethanol): "Kmaj<:S = 256 nm

(= 11100); IR spectrum (CHgClg): absorption band at

3496; 3396; 1791 ;17.28, I685, 1640, 1603, 1515 cm"<1.>

Example 13:

a) A solution of 760 mg of 7(3-/2-(2-amino-4-thiazol-yl)-2-N-methylcarbamoyloxyiminoacetamido7-3-cephem-4-carboxylic acid diphenyl methyl ester in 7 ml of methylene chloride is stirred with 0, 21 ml of anisole and 1 ml of trifluoroacetic acid for 30 minutes in an ice bath, added 50 ml of cold toluene and evaporated in vacuo.

The residue is digested with diethyl ether, ice-cooled, filtered off and dried. The obtained trifluoroacetate of 7P-Z~2-(2-amino-4-thiazolyl)-2-N-methylcarbamoyloxyiminoacetamido7-3-cephem-4-carboxylic acid is suspended for approx. 6 ml water/methanol 1:4 and the pH value of the suspension is adjusted to approx. 4 with 10% methanolic triethylamine solution. After-30 minutes

stirring at 0° 0, the precipitated 70-Z~2-(2-amino-4-thiazolyl)-2-N-methylcarbamoyloxyiminoacetamido7-3-cephem-4-carboxylic acid is filtered off, washed with water, diethyl ether and dried over phosphorus pentoxide. Decomposition point about 215°C; DS: Rf^gA0.24; IR spectrum (Nujol); absorption band at 1775 sh;

1757; 1664; 1625 cm<-1.>

The starting material is produced as follows:

b) A solution of 4) 3 g of 70-(4-bromo-2-hydroxyiminoacetoacetamido)^3-cephem-4-carboxylic acid-diphenyl-. methyl ester in 19 ml of acetonitrile under ice-cooling

added 7) 7 ml of methyl isocyanate and stirred for 15 minutes under ice-cooling and 30 minutes at room temperature. The reaction mixture is diluted with ethyl acetate and evaporated in vacuo. The residue is digested with diethyl ether, filtered off, dried and chromatographed on 150 g of silica gel with toluene/ethyl acetate 3:1. The obtained 70-(4-bromo-2-N-methyl-carbamoyloxyiminoacetoacetamido)-3-cephem-4-carboxylic acid diphenyl methyl ester is digested with diethyl ether, filtered off and dried. Melting point 112-117°C; DS: Rf'^0.3 (toluene/

ethyl acetate 1:1); IR spectrum (CHgClg): absorption band

at 3400; 1788; 1727; I698; 1640; 1520 cm"<1.>

c) A solution of 1.2 g of 7P-(4-bromo-2-N-methylcarbamoyloxy-imino-acetoacet.amido)-3-cephem-4-carboxylic acid edi-phenylmethyl ester in 12 ml of dioxane is added to a dissolving 163 g of thiourea in 2 ml of water and stirring for 60 minutes at room temperature. Ethyl acetate is added to the reaction mixture, washed successively with water, saturated aqueous sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with ethyl acetate and 10% acetone containing ethyl acetate. 70-/2-(2-amino-4-thiazolyl)-2-N-methylcarbamoyloximino-acetamido7-3-cephem-4-carboxylic acid diphenyl methyl ester is obtained in the form of brownish crystals with melting point -v-'150°C (decomposition ). DS: Rf 0.45 (chloroform/methanol 8:2); IR spectrum (CH 2 Cl 2 ): absorption band at 3360; I782 b; 1731; I684;

1620; 1528 cm"1.

Example 14:

Capsules, containing 0.250 g of 70-/2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamide_7-3-cef em-4-carboxylic acid- sodium salt is produced as follows: Composition (for 100,000 capsules): 70-/2-(2-amino-4-thiazolyl)-2-methoxy-iminoacetamido7-

The 70-/2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido7-3-cephem-4-carboxylic acid sodium salt, the wheat starch and the magnesium stearate are mixed well together and filled into No. 1 capsules.

Example 15:

Capsules. containing 0.5 g of 70-/2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido7~3-cephem-4-carboxylic acid sodium salt is prepared as follows: Composition (for 2000 capsules): 70-/2-( 2-amino-4-thiazolyl)-2-methoxy-iminoacetamido_7-3-cef em.-4-carboxylic acid-

70-/2-(2-amino-4-thiazolyl)-2-methoxy-iminoacetamido7-3-cephem-4-carboxylic acid sodium salt is moistened with 300 ml of a solution of polyvinylpyrrolidone in 95% ethanol, the mixture is passed through a sieve with a mesh size of 3 mm and dry the granules under reduced pressure at 40-50°C. Sieve through a sieve with a mesh size of 0.8 mm, add the corn starch and magnesium stearate, mix and fill the mixture into capsules (magnification 0).

Example 16

Dry ampoules or Vials, containing 0.5 g

■7(3-/2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido7-3-cephem-4-carboxylic acid sodium salt is prepared as follows:

Composition (for 1 ampoule or vial)

A sterile aqueous solution of 7(3-(2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido/-3-cephem-4-carboxylic acid sodium salt) and mannitol is filled and sampled under aseptic conditions in 5 ml.- ampoules or 5ml vial.

Example 17:

Dry ampoules or vials, containing 0.25 g of 7-(3-/""2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido/-3-cephem-4-carboxylic acid sodium salt were prepared as follows:

Composition (for 1 ampoule or vial)

A sterile aqueous solution of 7(3-/<2->(2-amino-4-thiazolyl)-2-methoxyiminoacetamido7~3-cephem-4-carboxylic acid sodium salt and mannitol is filled under aseptic conditions and sampled in 5 ml. ampoules or 5 nil vials.

Claims (2)

1. Process for the preparation of 7P~ amino-thiazolyl-acetamido-3-cephem-4-carboxylic acid compounds of formula in which R-j _' is hydrogen, lower alkyl or an amino protecting group, A is methylene or optionally protected amino, hydroxy or sulfo,.with oxo, optionally protected or carbamoylated hydroxyimino substituted methylene, R^ is hydrogen, methoxy or a methoxy replaceable group and R2 is hydrogen or a residue for esterification of the carboxyl group, and salts of such compounds with salt-forming groups, characterized by a) acylating the 7P_amino group in a compound with formula in which the amino group is optionally substituted with a group that allows acylation and in which R^ and R^ have that of formula I indicated meaning when treated with one of the acyl residues i a carboxylic acid of formula introducing acylating agent, in which R-^ and A have the meaning given in formula I and in which any functional groups present are in protected form, or b) condenses a compound of formula in which X means halogen, Rg, R^ and A have those in formula In the meanings indicated, and in which functional groups are possibly protected, or a salt thereof, with a thiourea with the formula R^ -NH-CS-NHg or a salt thereof, or c) ' cleaves off a compound by ring closure with formula in which Ra., R^ and Rc are optionally substituted hydrocarbon residues and R^, Rgj R^ and A have the meanings given in formula I,, and in which functional groups are possibly protected, the phosphine oxide (R 3. )(RK0 ) (R C ) P=0, ord) treats with a decarbonylating agent a compound of formula in which R-^ , Rg> R~° g A- have the meanings given in formula I, in which the double bonds are in the 2,3 or 3,4 position and in which functional groups are possibly. protected, or e) cleaves a group H-RQ from a compound of formula . in which R-p Rg', R^ and A have the meaning given in formula I and RQ is hydroxy, esterified hydroxy or optionally substituted amino, orf) i.isomerizes a compound of formula in which R-^ , ^3 °S ^ when the meanings given in formula I, or g) removes the reductive group R^ and replaces with hydrogen, in a compound of formula in which R a is esterified hydroxy or optionally substituted amino, and in which R-^ , A, Rg and R^ have the meanings given in formula I, or h) for the preparation of a compound of formula I, wherein. R^ means methoxy, replacing R^ in the 7-position with G~ methoxy in a compound, of formula 1 wherein R^ means hydrogen or a group replaceable by methoxy, R-p Rg and A have the meanings given in formula I, and in which all functional groups are present in protected form,, or i) for the preparation of a compound of formula. IN in which A is carbamoylated hydroxyiminomethylene or methoxyiminomethylene, and in which R^ , and R^ have those indicated in formula I meanings, carbamoylates or methylates the hydroxyimino group in a compound of formula in which R-p Rg° S ^3 ^ar ^e in formula I given meanings, or j) for the preparation of a compound of formula I, wherein R-j_ is. hydrogen, and in which A, Rg and R^ have the meanings given in formula I, cleaves off the amino protecting group R-^ and replaces with hydrogen in a compound of formula I, in which R-^ means an amino protecting group, and A, Rg and R^ have . the meanings given in formula I, or k) for the preparation of a compound of formula I, in which R2 denotes an esterifiable residue to the carboxyl group, and Rp A and R^ have the meanings given in formula I, transfers the free carboxyl group in the 4-position of the cephem ring, or a reactive derivative thereof , by treatment with an esterification agent in an esterified carboxyl group, or 1) for the preparation of a compound of formula I, in which Rg is hydrogen, and Rp A and R^ have the meanings given in formula I, in a compound of formula I, in which R^ denotes an esterifiable group to the carboxyl group, bg Rp A and R^ have the meanings given in formula I, cleave off the residue R2 and exchange this with hydrogen or a cation, and if requested, in an obtained connection transfers one residue Rp Rg or A in another residue Rp Rg or A, and/or, if desired, transfers a compound obtained in a salt or a salt obtained in a free compound or in another salt. 2. Procedure according to claim 1, characterized in that a compound with is produced from a corresponding starting material formula (I), in which R^ means hydrogen, lower alkyl, lower- alkanoyl or 2-halolower alkanoyl, A means methylene, aminomethylene, hydroxymethylene, sulfomethylene, hydroxy- iminomethylene, carbamoylated hydroxyiminomethylene, or methoxyiminomethylene, R^ means hydrogen or methoxy and Rg is hydrogen or a residue that can be split off under physiological conditions, or a pharmaceutically acceptable salt thereof. ■3' Method according to claim 1, characterized in that a compound of formula (i) is prepared from a corresponding starting material, in which R-^ means hydrogen or 2-halogen-lower alkanoyl, A denotes hydroxyiminomethylene, N-methylcarbamoyloxyiminomethylene or methoxyiminomethylene, R^ means hydrogen or methoxy and R£ means hydrogen or, under physiological conditions, cleavable acetyloxymethyl, pivaloyloxymethyl, 1-ethyloxycarbonyloxyethyl or phthalidyl, or a pharmaceutically acceptable salt thereof. 4« Process according to claim 1, characterized in that one prepares from a corresponding starting material 7(3-/2-(2-arnino-4-thiazolyl)-2-methoxyiminoacetamide£7-3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof. 5. Process according to claim 1, characterized in that 7(3-(2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido7-3-cephem-4-carboxylic acid or a pharmaceutical tolerable) is produced from a corresponding starting material salt thereof. 6. Process according to claim 1, characterized in that 7(3-/2-(2-tert. butoxycarbonylamino-4-thiazolyl)-2-metoxyiminoac et ami dp_7-3-cef em- is prepared from a corresponding starting material 4-carboxylic acid piyaloyloxymethyl ester. 7. Method according to claim 1, characterized in that 7(3-(2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido/-3-cephem-4-carboxylic acid pivaloyloxymethyl ester) is prepared from a corresponding starting material. 8. Method according to claim 1, characterized in that 7P-/P> L-2-tert.butoxycarbonyl-amirio-2-(2-amino-4-thiazolyl)acetamido7-3-cephem- is prepared from a corresponding starting material 4-carbonic acid- diphenyl methyl ester. 9. Procedure according to claim 1, characterized in that 7(3-/ <P>> L-2-amino-2-(2-amino-4-thiazolyl)-acetamido7-3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt is prepared from a corresponding starting material hence. 10. Procedure according to claim 1, characterized by producing 7(3-/ <2-> i 2-tert. butok s <y> carb on <y>l amino- 4-thiazolyl)-2-methoxyiminacetamide £7-7a-methoxy-3-cephem-4-carboxylic acid diphenyl methyl ester. 11. Method according to claim 1, characterized in that from a corresponding starting material, 713^/2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido7-7a-methoxy-3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof. 12th; Procedure according to requirements. 1, characterized in that 7(3-(2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido/-3-cephem-4-carboxylic acid diphenyl methyl ester) is prepared from a corresponding starting material. 13. Procedure according to requirements. 1, characterized in that one from. a corresponding starting material produces 7(3-(2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido-3-cephem-4-carboxylic acid) or a pharmaceutically acceptable salt thereof. 14. Method according to claim 1, characterized in that 7P-/2-(2-amino-4-thiazolyl)-acetamido7-3-cephem-4-carboxylic acid diphenyl methyl ester is prepared from a corresponding starting material. 15. Method according to claim 1, characterized in that 7(3-(2-(2-amino-4-thiazolyl)-acet-amido7-3-cephem-4-carboxylic acid) is produced from a corresponding starting material or a pharmaceutically acceptable salt thereof. 16. Process according to claim 1, characterized in that 7(3-(2-(2-amino-4-thiazolyl)-2-N-methylcarbamoyloxyiminoacetamido7-3-cephem-4-carboxylic acid is prepared from a corresponding starting material) -diphenyl methyl ester. 17. Process according to claim 1, characterized in that from a corresponding starting material, 7(3-(2-(2-amino-4-thiazolyl)-2-N-methylcarbamoyloxyiminoacetamido7-3-cephem-4-carboxylic acid or a pharmaceutical tolerable salt thereof. 18. Method according to claims 1-5 > 9, 11, 13) 15 or 17, characterized in that a 4-carboxylic acid compound obtained is transferred into the corresponding sodium salt.