DD144779A5 - PROCESS FOR THE PREPARATION OF 7 BETA-AMINOTHIAZOLYL-ACETAMIDO-3-CEPHEM-4-CARBONIC ACID COMPOUNDS - Google Patents

Abstract

These compounds have antibiotic activity and can be used to combat infections. According to the invention 7/3 Amirю thiazolyl-acetamido-3 - cephem-4 - carboxylic acid compounds

Description

Application of the invention

The invention relates to a process for the preparation of novel aminothiazole compounds.

The compounds according to the invention are used in the form of pharmaceutical preparations as antibiotics. ^:

Characteristic of the known technical solutions

There is no information on which compounds have been used as antibiotics. There are also no known data on processes for the preparation of aminothiazole compounds. "

The aim of the invention is to provide a simple and economical process for preparing antibiotically active aminothiazole compounds _B

The object of the invention is to find compounds with an antibiotic effect and processes for their preparation.

According to the invention, new 7β-aminothiazolylacetamido-3-cephem-4-carboxylic acid compounds are prepared which are unsubstituted in the 2'-position and 3'-position of the cephem ring.

In particular, 7 /: J ^t -Aminothiazolyl-acetamido ~ 3 * - cephem - ^ - carboxylic acid compounds of the formula

-1 - OWH

COOK

fi, I -β "

manufactured,

wherein R ^ is hydrogen, lower alkyl, or an amino protecting group, A methylene or by optionally protected amino, hydroxy or SuIf ο, by oxo, optionally protected or carbamoylated Hydrozyimino or methoxyimino substituted methylene, E, hydrogen, methoxy

or a methoxy-substitutable group and R 1 represents hydrogen or a radical esterifying the carboxyl group, and salts of such compounds having salt-forming groups.

In the present specification of the invention: the term "lower" in groups such as lower alkyl, lower alkylene, lower alkoxy, lower alkanoyl and the like means that the corresponding groups, unless expressly defined otherwise, contain up to 7, preferably up to 4 C atoms.

A lower alkyl group R 1 is in particular C 1 -C 3 -lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl or tert-butyl.

The functional groups present in compounds of formula I, especially carboxyl and amino, hydroxy, hydroxyimino and sulfo groups, are optionally protected by protecting groups used in penicillin, cephalosporin and peptide chemistry.

Such protective groups are easy, that is, without unwanted side reactions take place, for example, solvolytic, reductive, photolytic or even under physiological conditions, cleavable.

Protecting groups of this type, such as their cleavage, are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, also in "The Peptides", Vol. I, Schröder and LuBke, Academic Press, London, New York, 1965.

An amino-protecting group R is primarily an acyl group Ac, a mono-, di- or triarylmethylg-group or a silyl or stannous group.

An acyl group Ac 'is the acyl radical of an organic carboxylic acid having up to 13 carbon atoms, in particular an optionally, e.g. by halogen or aryl, substituted aliphatic carboxylic acid or given. if, e.g. by halogen, lower alkoxy or nitro, substituted aromatic carboxylic acid, or a carbonyl

s8urehalb.es Cers. Such acylphenylalanine groups are for example lower alkanoyl, such Formy1, acetyl, propionyl, halo-lower alkanoyl, such as 2-haloacetyl, in particular 2 _s-chloro-, 2-Brpm-., 2-iodo, 2,2-dichloro- or 2,2,2 Trichloroacetyl, phenylglycyl, phenoxyacetyl, thienylacetyl, benzoyl, Α-chloro, 4-methoxy or 4-nitrobenzoyl, lower alkoxy ™carbonyl, especially tert.-lower alkoxycarbonyljZ.B. tert.-butyloxycarbonyl, polycycloalkoxycarbonyl, for example adamantyloxycarbonyl, arylmethoxycarbonyl, in which aryl preferably one or two, optionally, for example by lower alkyl, in particular tert-lower alkyl, for example tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, for example chlorine, and or nitro, mono- or polysubstituted phenyl, such as optionally substituted Bensyloxycarbonylj eg 4-nitro-benzyloxycarbonyl, or substituted diphenylmethoxycarbonyl, for example benzhydryloxycarbonyl or di- (4-methoxyphenyl) methoxycarbonyl, or 2-halo-lower alkoxycarbonyl, eg 2,2,2-trichloroethoxycarbonyl, 2-chloro-methoxycarbonyl, 2-bromo-athoxycarbonyl or 2-iodoethoxycarbonyl, or acylmethoxycarbonyl, in particular aroylmethoxycarbonyl ,. wherein the Aroylgrtrppe preferably optionally, for example. by halogen, such as bromine, substituted benzoyl, for example phenacyloxycarbonyl. ·

In a mono-, di- or triarylmethyl group R, the aryl radicals are in particular optionally substituted phenyl radicals. Such groups are, for example, benzyl, diphenylmethyl or trityl.

A silyl or stannyl group R- is primarily an organic silyl or stannyl group, wherein the silicon or tin atom is preferably lower alkyl, in particular methyl, furthermore lower alkoxy, e.g. Methoxy, and / or halogen, for example, chlorine, as a substituent.

Corresponding silyl or stannous groups are primarily tri-lower alkylsilyl, especially trimethylsilyl, furthermore dimethyl-tert-butyl-silyl, lower alkoxy-lower alkyl-halo-silyl, e.g. Methoxy-methyl-chloro-silyl, or di-lower alkyl-halo-silyl, e.g. Dimethylchlorosilyl, or appropriately substituted stannyl, e.g. Tri-n-Butyl. tanny 1.

Preferred amino-protecting groups R 1 are the acyl radicals of 2-haloacetic acid, in particular 2-chloroacetyl, and of carbonic monoesters, in particular tert-lower alkoxycarbonyl, e.g. tert-butoxycarbonyl, optionally, e.g. as indicated, substituted benzyloxycarbonyl or diphenylmethoxycarbonyl, or 2-halo-lower alkoxycarbonyl such as 2,2,2-trichloroethoxycarbonyl, as well as the trityl group.

The same amino-protecting groups may be present in a protected amino group in the A residue.

An amino group can also be protected in protonated form; as anions those coming primarily from strong inorganic acids such as hydrogen halide acids, for example the chlorine or Broinanion, or sulfonic acids such as _p-s in question.

-m- «« & B% fef -5-

The Hydroxysehutζgruppen present in protected hydroxy or hydroxyimino groups in the Rast A are e.g. Acyl radicals, such as 2-haloacetyl, e.g. 2-chloro or 2,2-pichloroacetyl, or in particular one of the mentioned in connection with a protected amino group acyl radicals of carbonic monoesters, in particular 2,2,2-trichloromethoxycarbonyl, or organic silyl or Stam.iylre.ste, further easily cleavable second -oxa or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radicals, primarily 1-lower alkoxy-niederaikyl or 1-lower alkylthio-lower alkyl, for example 1-methoxy-

ethyl, 1-ethoxyethyl, 1-methylthio-ethyl-1 or 1-ethylthio-methyl, or 2-oxo or 2-thiacape-cyanoalkyl of 5-7 ring atoms, e.g. 2-tetrahydro-uryl or 2-tetrahydropyranyl or end-related thia analogues, as well as easily cleavable «optionally substituted a-phenyl lower alkyl radicals, such as unsubstituted or substituted benzyl, diphenylmethyl or trityl, v / obei as substituents of the phenyl radicals, e.g. Halogen, such as chlorine, lower alkoxy, such as methoxy and / or nitro come into question.

A carbamoylated hydroxyimino group in the A group is a group of the partial formula = N ~ O-C (= O) -NHR where R is lower alkyl, cycloalkyl, aryl-lower alkyl or aryl.

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

1 A '\

A cycloalkyl group R is C -C -cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

An aryl-lower alkyl group R has 7-10 C atoms and is, for example, benzyl, phenylethyl, phenylpropyl or phenylbutyl.

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

R is preferably ethyl, n-propyl, isopropyl, butyl, isobutyl, cyclohexyl and in particular methyl.

A protected sulfo group is primarily a sulfo group esterified with an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic alcohol such as a lower alkanol or with a silyl or stannyl radical such as tri-lower alkylsilyl. In a sulfo group, for example, the hydroxy group may be etherified as the hydroxy group in an esterified carboxy group.

For example, a methoxy-substituted group R is 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.

The radical R ^ esterifying the carboxyl group is preferably readily cleavable under mild conditions, including under physiological conditions. Such radicals S are, for example, lower alkyl, in particular tert-lower alkyl, for example tert-butyl, polycycloalkyl, for example adamantyl, arylmethyl, wherein aryl preferably one or two, optionally, for example by Kiederalkyl, .insbesondere tert-lower alkyl, eg tert . ™ butyl, lower alkoxy such as methoxy, hydroxy, halogen, 55 _"Β β chlorine, and / or nitro, mono- or represents phenyl polysubsSituierte, such as optionally, for example, .as above mentioned substituted benzyl, for example 4-nitro-benzyl, or 4-methoxybenzyl, or, for example, substituted diphenylmethyl as mentioned above, for example benzhydryl or di- (4-methoxyphenyl) -methyl, or 2-halo-lower alkyl, for example 2,2,2-trichloro-methyl, in particular methyl! wherein the aroyl group is preferably optionally, 2.B. by halogen, such as bromine, substituted benzoyl, for example phenacyl,. or polyhalo-diaryl, such as pentachloro-phenyl. B ^ is furthermore a silyl, in particular an organic silyl group or a corresponding stannyl group. In these, the silicon or Zinnatoni preferably contains lower alkyl, in particular methyl, further lower alkoxy, eg, keto, and / or halogen, for example chlorine, as substituents. Suitable silyl or stannyl protecting groups are primarily tri-lower alkylsilyl, in particular trimethylsilyl, furthermore dimethyl-tert-butyl-silyl, lower alkoxy-lower alkyl-halo-silyl, for example methoxy-methyl-chloro-silyl, or di-lower alkyl-halogen-silyl, for example Dimethylchlorosilyl, or appropriately substituted stannyl compounds, eg tri-n-butyl-stannyl ..

Preferred protective radicals R ₃ are in particular tert-butyl, optionally, for example, as mentioned, substituted benzyl, for example 4-nitrobenzyl and diphenylmethyl.

A cleavable under physiological conditions residue R "is the actually effective carboxylic acids improved absorption by oral application and / or prolonged activity. Numerous such ester groups are known in the field of penicillins and cephalosporins. Mention may be made of, for example, -C (-O) -O-IL, groups in which R "is a methyl group substituted by acyl, acyloxy, acylthio, acylamino or etherified hydroxy and optionally a further organic radical, the methyl group having the carbonyl of the acyl group may also be linked via a carbon-containing bridge, or represents a 2-aminoaliphatyl group. In such groups, acyl is the residue of an organic carboxylic acid having about up to IS carbon atoms and is, for example, optionally substituted alkanoyl, cycloalkanoyl, aroyl, heterocyclylcarbonyl, e.g.

also the heterocyclylcarbonyl radical of a carboxylic acid of the formula I, or of a biologically active penam-3- or cephem-4-carboxylic acid, or the acyl radical of a monoester of carbonic acid. Etherified hydroxy in the methyl group is etherified by a hydrocarbon radical, in particular by lower alkyl. The organic radical optionally substituted by the methyl group has up to 7 carbon atoms and is in particular lower alkyl, such as methyl, or aryl, such as phenyl. The named carbon bridge contains one to three, in particular 2 C atoms, so that a lactone, in particular a γ-lactone, is present. The aliphatic group in said 2-aminoaliphatyl group may be aliphatic or cycloaliphatic in nature and is saturated or unsaturated. The 2-amino group is preferably by two

«I ¹ W -9- '

Substituted lower alkyl or optionally containing an oxo group alkylene. In such physiologically cleavable ester groups -C (= O) -O-R ₉ , R _{9 is,} for example, lower alkanoyloxy-methyl, for example acetyloxymethyl or pivaloyloxyraethyl, aniinone-lower alkanoyloxymethyl, in particular a-amino-lower alkanoyloxymeth-yl, for example glycyloxymethyl, L-vallyloxymethyl, Leucyloxymetbyl, Niederalkoxyearbonyloxymethyl or 1-Niederalkoxycarb.onyloxyäthyl, for example 1-Äethyloxycarbonyloxyäthyl, Niederalkanoylthiomethyl such Acetylthiornethyl or Fivaioylthiomethyl, Niederalkanoylaminomethyl wherein lower alkanoyl _s may be such as chlorine, optionally substituted by Ha.logen, for example acetyl ™ aminomethyl or 2,2-Dicbloracetylaniinomethyl, Aroylaminomethyl, eg Banzoylaminomethyl, or, as an example of a lactone-containing R ₉ , phthalidyl. The esterified hydroxymethyl group R ₉ is, for example, lower alkoxymethyl, in particular methoxymethyl. A 2-aminoaliphatic group R ₉ is, for example, 2-amino-lower alkyl, such as a 2-aminoethyl group, in which amino is substituted by two lower alkyl or optionally oxo containing alkylene, for example 2-dimethylethylamine, 2-diethylaminoethyl or 2- (2-aminoethyl) i-morpholino) ethyl, or 2-aminocycloalkyl, eg 2-dimethylaminocyclohexyl. Particularly noteworthy are acetyloxymethyl, pivalolyloxymethyl, 1-Aethyloxycarbonyloxyäthyl, and phthalidyl.

Salts are especially those of compounds of formula I having a free carboxyl group, primarily metal or ammonium salts, such as alkali metal and alkaline earth metal ta11-, e.g. Sodium, calcium or magnesium salts, and ammonium salts with ammonia or suitable organic amines, all of which are primarily

"sr via? _1Q_

phatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines, 'as well as heterocyclic bases for salt formation are suitable, such as lower alkylamines, eg triethylamine, Hydroxyniederalky! amine ,. For example, 2-hydroxyethylamine, bis (2-hydroxyäthyi) amine or tris (2-hydroxyä'thyl) amine, basic aliphatic esters of carboxylic acids, eg 4-aminobenzoic acid 2-diethylaminoäthylester, lower alkyleneamines, eg 1-Aethylpiperidin, cycloalkylamines , For example, dicyclohexylamine, or benzylamines, for example N, N- ^1- dibenzyl-ethylenediamine, further bases of the pyridine type, for example pyridine, collidine or quinoline. Compounds of formula I having a basic group can form acid addition salts, for example with inorganic acids such as hydrochloric acid ₃ sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, eg Triflucressigsäure, and with amino acids such as arginine and lysine. Compounds of the formula I having a free carboxyl group and a free amino group may also be present in the form of internal salts, ie in zwitterionic form.

The asymmetric truin optionally present in the radical A, namely when A is hydroxymethylene, aminomethylene or sulfomethylene, is present 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 the formula I in which the carboxyl group is optionally esterified in physiologically cleavable form and the functional groups in the radical A are in unprotected form, and their phanna-. _zeutisch} usable non-toxic salts are valuable antibiotic substances, which can be in particular antibiotic used as an antibacterial. For example, they are iiLJiiSiP. S ^s S ^s granrpositive and Gram-negative cocci, such as ^ ta ^ ^ o £ jiy O_ccu £ ^ _{_aurejLi:} s_, Streptococcus

Streptococcus

giti-.DIS in minimum concentrations of from about 0.005 to 1 mcg / ral and against gram-negative bacteria such as rictila CoJLi _-, Klebsiella pneumoniae, Šejn ^ tia marcescens,

monas ae_ruginosa. and Haemop hiIu s ^ in flu e za e, inclusive against / 5-lactamase-producing strains, in minimum concentrations of ¹ C 0.01 to 8 mcg / τηΐ effective. In vivo, in the case of a subcutaneous mouse application, they are, for example, active against enterobacteria, as well as against other Gram-negative and Gram-positive pathogens in minimal doses of ED "- 0/1 mg to 100 mg / kg v / v. The novel compounds can therefore also be used correspondingly, for example in the form of antibiotically active preparations, for the treatment of infections caused by Gram-positive or, in particular, Gram-negative infective agents, in particular by enterobacteria, such as Eseherichia coli, Klebsiella and Proteus (indole + indole).

Compounds of the formula (I) in which the functional groups are protected. Are used as starting materials for the preparation of "antibiotically active compounds of the formula I.

The present invention relates in the first place to those compounds of the formula I in which R is hydrogen, lower alkyl, lower alkanoyl or 2-halo-lower alkanoyl, A is methylene, aminomethylene, hydroxymethylene, sulfomethylene, hydroxyiminomethylene, carbamoylated hydroxyiminomethylene, or methoxy-ininomethylene, R is hydrogen or methoxy and R represents hydrogen or a radical cleavable under physiological conditions, and their pharmaceutically acceptable salts, as well as the corresponding compounds having protected functional groups.

Particular mention should be made of compounds of the formula (I) in which R _{1 is,} in particular, hydrogen and 2-halo-lower alkanoyl, such as 2-chloro-lower alkanoyl, A is hydroxyiminomethylene, N-methylcarbamoyloxyiminomethylene or methoxyiminomethylene,

R is hydrogen or methoxy and R is hydrogen or physiologically cleavable acetyloxymethyl, pivaloyloxymethyl, 1-Aethyloxycarbonyloxyäthyl or Phthalidyl, and their pharmaceutically acceptable salts, and the corresponding compounds having protected functional groups.

The invention relates to the compounds of formula 1 described in the examples, their pharmaceutically acceptable salts, and the starting materials and intermediates described therein.

The compounds of the present invention are prepared by methods known per se.

Thus, compounds of formula I are prepared by

a) the 7_ß-amino group in a compound of formula

^R 3

H _O N- ² '' (II),

COOR ₂

wherein the amino group is optionally substituted by an acylation-permitting group and wherein R ^ and. R have the meanings given under formula I, by treating with an acyl radical of a carboxylic acid of formula

(III)

A-COOH

introducing acylating agent, wherein R and A have the meanings given under formula I and wherein optionally present furrktionelle groups are in protected form, acylated, or b) a compound of formula

* 3

.X-CH ^ CO-A-CONH

(IV),

COOR ₂

in which X is halogen, R ₀ , R and Ά have the meanings given under formula I and in which functional groups are optionally protected, or a salt thereof, with a thiourea of the formula R-NH-CS-NH or a salt thereof condensed, or c) from a compound of the formula

R ₁ -NH

A-CONH -τ

O = J

S-CH ₂ CH = O

COOR ₂ in which R, R and R optionally substituted carbonyl

el D C

are hydrogen radicals and L, R, R and A have the meanings given under formula I, and in which the groups are optionally protected, with ring closure the phosphine oxide (R) (R,) (R) P = 0, or

el D C

d) a compound of the formula

S-

N_

R.

A-CONH

(VI),

CHO

COOR,

wherein R _1, R "y ^R -3 ^{un <^ A} ^ ^ie given for formula I have, wherein the double bond in 2,3- or 3,4-position is and functional groups are protected if necessary, treated with a Decarbonylierungsmittel , or e) from a compound of the formula

, S-T,

R ₁ -NH

• ^R 3

A-CONH

COOR,

(VII)

wherein R

R and A are those given under formula I.

Have meanings and R is hydroxy, esterified hydroxy or optionally substituted amino, cleaves a group H-R, or f) a compound of the formula

-NH - / j

? 3

A-CONH ·

COOR ₉

(VIII),

wherein R, R ₀ , R and A have the meanings mentioned under formula I, isomerized, or

g) from a compound of the formula

A-CONH

(Ix)

COOR.

v / orin R is esterified hydroxy or optionally substituted amino, and wherein R, A, R ₉ and R are as defined under

Formula I have given meanings, the group R "reductively removed and replaced by hydrogen, or

h) for the preparation of a compound of the formula I in which R is methoxy, in a compound of the formula

- I "1 IUM ', -iq" / Q # μ (\ ;:,?, > ,

R ₁ -HN - <ζ

A - CONH-

0:

(D

 Ν-

COOR ₉

in which R is hydrogen or a methoxy-substituted group, R ₁ , R ^ and A have the meanings given under formula I and in which all functional groups are in protected form, R in the 7-position replaced by methoxy, or

i) for the preparation of a compound of the formula I in which A is carbamoylated hydroxyiminomethylene or methoxyiminomethylene, and in which R-, R "and R have the meanings given for formula I, in a compound of the formula

- HN - <

wherein R, R and R have the meanings given under formula I, the hydroxyimino group carbamoylated or methylated, or

j) for the preparation of a compound of formula I, wherein R ^ is hydrogen, and wherein A, R ₂ and R have the meanings given under formula I, of a compound of formula I, wherein -R represents an amino protecting group, and R is the Formula I given meanings

and A,

have the Ainino Schutzgruppe R split off and replaced by "hydrogen, or

k) for the preparation of a compound of formula I, wherein R is a radical esterifying the carboxyl group, and R, A and R are as defined for formula I, in a compound of formula I, wherein R is hydrogen, and wherein R, A and R have the meanings given under formula I, the free carboxy group in the 4 - position of the cephem ring, or a reactive functional derivative thereof, by treatment with an esterifying agent in an esterified carboxyl group, or

1) for the preparation of a compound of the formula I in which R "is hydrogen and R ₁ , A and R have the meanings given for formula I, in a compound of the formula I in which R 1 represents a radical esterifying the carboxyl group, and R ₁ , Ä and R_ have the meanings mentioned under formula ¹ I, this R radical is split off and replaced by hydrogen or a cation, and if desired in a compound obtained R, R or A in another radical R, R "or A transferred, and / or, if desired, converted a compound obtained in a salt or a salt obtained in a free compound or in another salt.

I 4 1 4 8 -18-

Method a); Optionally present radicals which substitute the amino group and permit their acylation in a starting material of the formula II are, for example, organic silyl or stannyl groups, and also ylidene groups which form a Schiff base together with the amino group. The said organic silyl or stannyl groups are e.g. the same ones that are able to form a protected carboxyl group with the 4-carboxy group on the cephem ring. In the silylation or stannylation of a carboxyl group in a dough material of formula II, when using an excess of the silylating or stannylating agent, the amino group may also be silylated or stannylated.

The said ylidene groups are primarily arylmethylene groups in which aryl is in particular a carbocyclic, primarily monocyclic aryl radical, e.g. optionally substituted as nitro or hydroxy substituted phenyl; such arylmethyl groups are e.g. Benzylidene, 2-hydroxybenzylidene or 4-nitrobenzylidene, further optionally, e.g. carboxy-substituted qxacycloalkylidene, e.g. 3-carboxy-2-Oxacyclohexyliden.

The acylating agent which introduces the acyl radical of a carboxylic acid of the formula (III) are, for example, the carboxylic acid itself or reactive functional derivatives thereof. ,

If a free acid of the formula III in which all functional groups except the reactive carboxyl group are protected is used as the acylating agent, it is customary to use suitable condensing agents.

; ^: 2. t-4 14 B ' -i9-'

sierungsmittel, such as carbodiimides, for example Η, Ν'-diethyl-j NjN'-dipropyl-j N, N'-diisopropyl, N, N ¹ -Bicyclohexylτ

or N-Aethy 1-N ^'1 -S-diraethylaminopropyl-carbodiimide, suitable carbonyl compounds, for example carbonyl "diimidazolj or Isoxazoliniumsalza, for example ^{N-Äethyl-5-phanyl-isoxa2olinium-3!} sulfonate and N-tert-butyl-5-methyl-isoxazolinium perchlorate, or an acylamino compound, eg 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, with cooling or heating and / or in an inert gas atmosphere.

A reactive, i. Amide-forming, or ester-forming, fractional derivative of an acid of formula III wherein all functional groups other than the reacting acid group are protected are primarily an anhydride of such an acid, inclusive and preferably a mixed anhydride , but also an internal anhydride, ie a corresponding ketene. Mixed anhydrides are e.g. those with inorganic acids, such as hydrohalic acids, i. the corresponding acid halides, e.g. chlorides or bromides, further with hydrazoic acid, i. the corresponding acid azides, with a phosphorhaltige.n. Acid, e.g. Phosphoric acid or phosphorous acid, or with a sulfur-containing acid, 2.B. Sulfuric acid, or with hydrogen cyanide. Other mixed anhydrides are e.g. those with organic carboxylic acids, such as with optionally, e.g. haloalkanecarboxylic acids substituted by halogen, such as fluorine or chlorine, e.g. Pivalic acid or

Trichloroacetic acid, or with half-esters, especially lower alkyl halides of carbonic acid, such as the ethyl or isobutyl half-ester of carbonic acid, or with organic, in particular aliphatic or aromatic, sulfonic acids, e.g. p-toluene sulfonic acid. Of the acid III, when A is hydroxymethylene, a mixed internal anhydride can also be used with the carbonic monoester of the α-hydroxy group.

Other reactive acid derivatives of an acid of formula III are activated esters such as esters with vinylogous alcohols (i.e., enols) such as vinylogous loweralkenols, or aryl esters such as 4-nitrophenyl or 2,4-dinitrophenyl esters, heteroaromatic esters such as benztriazole, e.g. 1-benzotriazole esters, or diacylimino esters such as succinylimino or phthalylimino esters.

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, for example an organic base, such as an organic amine, e.g. a tertiary amine such as tri-lower alkylamine, e.g. Trimethylamine, triethylamine or ethyl-diisopropylamine, or Ν, Ν-di-lower alkyl-aniline, e.g. N, N-dimethyl, aniline, or a cyclic tertiary amine, such as an N-lower alkylated morpholine, such as N-methylmorpholine, or a pyridine-type base, e.g. Pyridine, an inorganic base, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. Sodium, potassium or calcium hydroxide, carbonate or bicarbonate, or an oxirane, for example a lower 1,2-alkylene oxide, such as ethylene oxide or propylene oxide.

The above acylations are preferably in an inert, preferably anhydrous solvent

or solvent mixture, for example in a carboxylic acid amides such as a formamide, e.g. Di-ethylformamide, a halogenated hydrocarbon, e.g. Methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, e.g. Acetone, an ester, e.g. Ethyl acetate, or a nitrile, e.g. Acetonitrile, or mixtures thereof, at room temperature, if necessary, at reduced or elevated temperature, such as from -40 to about 100, preferably from -10 to +40, and / or in an inert gas, e.g. Nitrogen atmosphere.

In an acylating acid of formula III or in an acid derivative thereof, a protected amino group may also exist in ionic form, i. the starting material of formula III may be 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 can be used.

Further, an acid derivative may be formed if desired. Thus, for example, a mixed anhydride by treating an acid of formula III with appropriately protected functional groups, or a suitable salt thereof, such as an ammonium salt, e.g. with an organic amine, such as 4-methylmorpholine, or a metal, e.g. Alkali metal salt, with a suitable 'acid derivative, such as a corresponding acid halide of an optionally substituted Niederalkancarbon-'. acid, e.g. Trichloroacetyl chloride, or with a half ester of a carbonyl halide, e.g. Ethyl chloroformate or isobutyl ester, and uses the thus obtained mixed anhydride without isolation.

In a starting compound of the formula IV, X is halogen, in particular ' chlorine , but also bromine, iodine or fluorine. The thiourea is in free form

14 1

or as a salt, especially as a thiolate of an alkali metal; metal, such as lithium, sodium or potassium, or as a thiolate of an ammonium compound, in an equivalent amount or in up to six-fold excess used. A compound of formula IV containing acidic groups, z-.B. when R 1 is hydrogen or when A is sulfomethylene, it may also be used as a salt, e.g. as an alkali metal or as an ammonium salt, e.g. as lithium, sodium, potassium, Triniederalkyl-, such as trimethyl or Triäthylaimnoniumsalz be used.

The reaction is generally carried out in a solvent such as water or an organic non-reactive solvent or a mixture thereof. Suitable organic solvents are alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, ethers such as dioxane or tetrahydrofuran, nitriles such as acetonitrile, halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride, esters such as ethyl acetate, or amides such as Dimethy! Formamide or dimethylacetamide, and the like. The reaction. For example, if the free compounds are used, they can be carried out in the presence of a base. Suitable bases are alkali metal hydroxides, such as sodium or potassium hydroxide, alkali metal carbonates, such as sodium or potassium carbonate, or organic tertiary nitrogen bases, such as tri-lower alkylamines, e.g. Trimethylamine, triethylamine, ethyl-diisopropylamine, pyridine and the like. The reaction temperature is at room temperature, or even lower or higher, preferably between -10 to + 100 C, in particular between 0 to 40 C.

The reaction can also be carried out stepwise, by first forming the ring-open intermediate with the partial formula R ₁ -NH-CC = NH) -S-CH ₂ -CO-A-, which is then dehydrated in the second stage.

Process c) : In the starting material of the formula V, each of the groups R, R and R, independently of one another, is primarily an optionally functional group, for example optionally hydroxylated or esterified hydroxy groups, such as lower alkoxy groups and / or halogen atoms or Phenyl, substituted lower alkyl radical or a given oil, for example by aliphatic hydrocarbon radicals, such as lower alkyl groups, and / or by functional groups, such as etherified or esterified hydroxy groups, such as lower alkoxy groups or Halogenatotna, or nitro groups, substituted phenyl radical. Such radicals are in particular methyl, ethyl, propyl, butyl, benzyl or phenyl, which are optionally substituted as indicated. Preferably, all three E.este R, R, and R are phenyl radicals.

Cleavage of the phosphine oxide with ring closure occurs spontaneously at room temperature or slightly reduced or elevated temperature, e.g. at temperatures from about -20 G to about 100 C, and in a solvent or diluent, e.g. an optionally halogenated hydrocarbon, preferably aliphatic. or of an aromatic character, such as benzene, or mixtures of such solvents, usually already in the preparation of the formyl compound of the formula (V).

The formyl compound of formula (V) can be prepared by, for example, oxidizing a corresponding carbino compound (Va) with the partial formula -S-CH ₂ CH ₂ OH.

The oxidation of a carboline compound of the formula (Va) is carried out by treatment with an oxidizing organic sulfoxide compound in the presence of agents having dehydrating or water-absorbing properties. The oxidizing sulfoxide compounds are primarily aliphatic sulfoxide compounds

mm, - -24-

in question, such as di-lower alkyl sulfoxides, primarily dimethyl sulfoxide, or lower alkylene sulfoxides, for example tetramethylene sulfoxide. As agents with dehydrating or -aufnehmenden properties are primarily to call anhydrides, in particular anhydrides of organic, such as aliphatic or aromatic carboxylic acids, for example anhydrides of lower alkanecarboxylic acids, especially acetic anhydride, propionic anhydride, or benzoic anhydride, and anhydrides of inorganic acids, in particular of phosphoric acids, such as phosphorus pentoxide-The above anhydrides, primarily of organic carboxylic acids, eg acetic anhydride, are preferably used in an approximately 1: 1 mixture with the sulfoxide oxidizing agent. Further dehydrating or absorbing agents are carbodiimides ₃ primarily dicyclohexylcarbodiimide, furthermore diisopropylcarbodiimide, or keteniiaines, eg diphenyl-Np-toiylketenimin; these . Reagents are preferably used in the presence of acidic catalysts such as phosphoric acid or pyridinium trifluoroacetate or phosphate. Sulfur trioxide may also be used as a dehydrating or receiving agent, usually in the form of a complex, for example pyridine.

Usually, the sulfoxide oxidizing agent is used in excess. Under the reaction conditions, liquid sulfoxide compounds, especially the dimethylsulfoxide, may e.g. simultaneously serve as a solvent; In addition, inert diluents, such as optionally halogenated hydrocarbons, preferably of aliphatic or aromatic character, e.g. Benzene, or mixtures of solvents.

The oxidation reaction is, if desired, under cooling, but usually at room temperature or slightly

w -25.-

elevated temperature, e.g. at temperatures of about -2O ° C to about 100 ° C performed.

Process d): The decarbonylating agents used in the decarboxylation of compounds of the formula VI are primarily carbon monoxide-absorbing heavy metal complexes. Such heavy metal complexes are, in particular, platinum metal complexes, whereby, under a platinum metal other than platinum, e.g. Iridium or rhodium, also understood as palladium and osmium. A carbon monoxide-accepting platinum metal complex preferably contains organic ligands, which apart from a carbon atom may also be linked to it by a heteroatom, in particular a phosphorato, via the secondary valences (which form non-covalent bonds) of the platinum metal atom Carbon monoxide-accepting PiatinmeCaI! complexes of this kind are able to take up carbon monoxide via main valencies, ie in covalent bond, via the main valencies (ie covalently bonded) substituents, such as heteroatoms, in particular halogens, such as chlorine atoms or carbonyl groups.

As platinum metal complexes, e.g. phosphorus. Platinum metal complexes, primarily phosphine-platinum metal complexes containing one, two or more phosphines. These phosphines preferably contain as substituents optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, in particular lower alkyl, e.g. η-butyl, or in particular optionally .substituted ..- phenyl, such as phenyl. , In addition to the phosphorus-containing parts, for example the phosphines, the platinum metal complexes may contain further organic ligands, in particular those which contain one, two or more phosphorus-containing ligands, such as phosphines

4 14'Θ -26-

can replace an existing phosphorus-containing platinum metal complex, e.g. suitable nitriles, such as acetonitrile, in non-covalent bond with the metal atom, and / or halogen atoms, e.g., chlorine, or carbonyl groups in covalent bond with the metal atom.

Preferably, bis-trisubstituted phosphine-platinum halides, bis-tri-substituted phosphincarbonyl-iridium halides or tris-substituted phosphine-iridium halides, primarily tris-substituted phosphine-rhodium halides, wherein the substituents of the phosphine are preferably lower alkyl, for example η-butyl, and especially phenyl and the halides are primarily chlorides. Such phosphine-platinum-metal complexes which are capable of covalently binding carbon monoxide are, for example, bis-triphenylphosphine-platinum-II-chloride [(CgH ₅ ) -P] "PtCl" or bis-tri- phenyl-phosphine-carbonyliridium-II-chloride [(CgH,) 3P] η Ir (CO) Cl, and also tris-triphenylphosphine iridium-I-chloride [(Cg) ₃ ] PK IrCl, but primarily tris-triphenyl-phosphine-rhodium-I-chloride [( CgH ₅ )., P] ₃ RhCl.

If desired or necessary, the decarbonylation with the aforementioned heavy metal complexes in the presence of suitable catalysts or activating agents, e.g. Lewis acid such as boron trifluoride (which may be used, for example, together with the bis-triphenylphosphine-platinic chloride), further a perchlorate such as alkali metal perchlorate, e.g. Sodium perchlorate (which may be used, for example, together with bis-triphenyl-phosphine-carbonyl-iridium chloride).

Preference is given to working in the presence of inert solvents, in particular of hydrocarbons, such as aliphatic or cycloaliphatic, in particular aromatic hydrocarbons, e.g. Benzene, toluene or xylene, halogenated. Hydrocarbons, such as

• w ·> * - *? \ s * »_ 27 -

corresponding aliphatic or aromatic chlorinated hydrocarbons, for example methylene chloride or chlorobenzene, ethers, such as aliphatic, cycloaliphatic or aromatic, furthermore mixed ethers, for example di-n-butyl ether. Dioxane ₃ diphenyl ether or anisole, nitriles, such as aliphatic or aromatic nitriles, for example acetonitrile or benzonitrile, or ketones, in particular aliphatic ketones, such as lower alkanones, sB, acetone, ethyl methyl ketone or isobutyl methyl ketone, or mixtures of such solvents. The reaction is carried out under cooling, at room temperature or under heating, for example at about 10 ⁰ G to about 150 ⁰ C, such as at about 40 ° C to about 120 ° C, further, if necessary, in a closed vessel and / or in an inert gas atmosphere, eg with nitrogen or argon.

In the decarbonylation reaction, a 3 - formyl-3 »cepheni- or a 3-formyl-2-cephem compound of the formula VI can be used. If a 3-formyl-2-cephem compound is used, it is necessary to take place simultaneously with the desformylation or subsequently an isomerization of the double bond, which is achieved by elevated temperature, for example above 100 °, and / or the presence of a base.

The group R in a starting material of the formula (VII) may be free hydroxy, but is preferably esterified hydroxy or optionally substituted amino. An esterified hydroxy group R can be an inorganic or organic acid, such as a strong mineral acid, eg a hydrohalic acid, such as hydrochloric, hydrobromic or hydroiodic acid, or an organic carboxylic or succinic acid, including formic acid, such as a corresponding aliphatic, cycloaliphatic, Cycloaliphatic-aliphatic aromatic, araliphatic, heterocyclic

__ mW -28- V ·.

or heterocyclic-aliphatic acid, further esterified by a carbonic acid half-derivative. For example, R represents

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. An optionally substituted amino group R is a primary, secondary or tertiary

° 1 2 1 2

Amino group -N (R) (R) in which R and R independently of one another are hydrogen, or an optionally substituted aliphatic, cycloaliphatic, aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic radical, or together represent an optionally substituted, optionally heteroatom , such as oxygen, sulfur or nitrogen, mean interrupted polymethylene group. Such amino groups R are, for example, amino, mono- or di-lower alkylamino, such as methyl, ethyl, propyl, dimethyl, diethyl, dipropyl, methyl-ethyl or methyl-propylamino, mono- or dicyclohexylamino, diphenylamines, benzyl , Dibenzyl or phenylethyl or diphenylethylamino, aziridino, pyrrolidino, piperidino, morpholine thiomorpholino or 4-lower alkylpiperazino.

The cleavage of a compound of the formula R ₀ -H, ie of water, an acid or an amine, is preferably carried out by treatment with suitable water, acid or amine scavengers. Water and amines are preferably in the presence of an acidic water- or amine-cleaving agent, z.3. an acid, preferably a strong organic carboxylic or sulphonic acid, such as a halo-lower alkanecarboxylic acid, eg trifluoroacetic acid, or an arylsulphonic acid, eg p-toluenesulphonic acid, of a suitable acid derivative,

such as an anhydride or, in particular, a halide such as chloride, primarily an inorganic, e.g., phosphorus or sulfur containing, acid, e.g. Phcsphoroxy "chloride or thionyl chloride, wherein such a derivative 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. split off a sulfonated polystyrene ion exchanger j. For the removal of water, dehydrating carbodiimide compounds, e.g. Dicyclohexylcarbodiimide or dehydrating nitrogen atom disubstituted carbonyl compounds, e.g. Carbodiimidazole, use. 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 solvent mixture, it being possible to use suitable acidic agents such as trifluoroacetic acid simultaneously as a solvent. If necessary, one additionally uses a water-adsorbing agent or a water separator and operates under cooling or heating and / or in an inert gas, e.g. Nitrogen atmosphere,

Preferably, R in an initial material of the formula VII is an esterified hydroxy group and, according to the invention, an acid of the formula H-R is split off. fortunately, for this purpose, basic acid-releasing and / or neutralizing agents are used, such as 2.B. inorganic bases such as dilute alkali metal hydroxides, e.g. Sodium or potassium hydroxide, in addition to. Water also includes organic solvents such as suitable ketones, e.g. Acetone, or ether, e.g. Use dioxane, or aqueous mixtures thereof, and at a ρH value of at most

about 9, if necessary, under cooling or heating and / or in an inert gas, e.g. Nitrogen atmosphere can work. Preferably used as acid eliminating agents are tertiary amines, especially good proton acceptors that do not attack the lactam ring, primarily tertiary aliphatic or tertiary cycloaliphatic mono- and diamines such as tri-lower alkylamines, e.g. Trimethylamine, triethylamine or ethyl-diisopropylamine, or bicyclic diaza compounds having an amidine-type arrangement of the ring nitrogens, e.g. 1,5-diazabicyclo [4,3,0] non-5-ene or 1,5-diazabicyclof5,4, O] undec-5-ene. Furthermore, basic ion exchangers, e.g. based on the ammonium hydroxide, also as acid-splitting agents. Certain esterified hydroxy groups R, especially sulfonyloxy, e.g. Methylsulfonyloxy groups can also be in the form of an acid of the formula R -H

by adsorption, e.g. on silica gel, alumina, etc., and elution (chromatography) from compounds of formula VII.

The acid eliminations described above are 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 alkanone, e.g. Acetone, or ethers, e.g. Tetrahydrofuran or dioxane, or a solvent mixture, including an aqueous mixture, if necessary with cooling or heating and / or in an inert gas, e.g. Nitrogen atmosphere made.

Process f) : In a 2-cephem starting material of formula (VIII), the optionally protected carboxy group in A-pitch preferably has the α-configuration.

2-cephem compounds of formula (VIII)

& -I- * » ^{e 6} ^ w -31-

isomerized by treating it with a weakly basic agent and isolating the corresponding 3-cephem compound. Suitable isomerizing agents are, for example, organic nitrogen-containing bases, in particular tertiary heterocyclic. Aromatic bases, in particular pyridine-type bases, such as pyridine itself, and collidines or lutidines, furthermore quinoline, tertiary aromatic bases, for example those of the aniline type, such as N, N-di-lower alkyl anilines, for example Ν, Ν-dimethylaniline or N, N-diethylaniline, or tertiary aiiphatic, azacycloaliphatic or araliphatic bases, such as Ν, Ν, Ν-tri-lower alkylamines, eg N, N, N-triethylamine, Ν, Ν-dimethyl-N-ethylamine, Ν, Ν, Ν Triethylamine or Ν, Ν, Ν-diisopropyl-N-ethylamine, N-lower-alkyl-azacycloalkanes, eg N-methyl-piperidine, or N-phenyl-lower-alkyl-N, N-lower-alkyl-amines, eg N-benzyl-NjN- dimethylamine, as well as mixtures thereof, such as the mixture of a pyridine-type base and an N, N, N-tri-lower alkylamine, eg, pyridine and triethylamine. Furthermore, inorganic or organic salts of bases, in particular of medium to strong bases with weak acids, such as alkali metal «or ammonium salts of lower alkanecarboxylic acids, eg / - sodium acetate, triethylammonium acetate or N-methyl-piperidinacetat, as well as other analogous bases or mixtures of such basic agents are used.

When isomerization is carried out with basic agents, preferably in anhydrous medium, in the presence or absence of a solvent such as an optionally halogenated one, e.g. chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, or a solvent mixture. whereby bases which are liquid under the reaction conditions and which are used as agents may simultaneously also serve as solvents, with cooling, at room temperature or with heating, preferably

* -32-

in a temperature range of about -30 ⁰ C to about +100 C, in an inert gas, eg nitrogen atmosphere, and / or in a closed vessel.

The 3-cephem compounds thus obtained can be read in a manner known per se, e.g. by adsorption and / or crystallization, of any remaining 2-cephem compounds.

The isomerization of 2-cephem compounds of the formula (VIII) can also be carried out if these are oxidized in the 1-position, if desired separating an available isomeric mixture of the 1-oxides, and the 1-oxides thus obtainable of the corresponding 3 -Cephemverbindimgen reduced.

Suitable oxidizing agents for the oxidation in! -Position of 2-cephem compounds are inorganic peracids having a reduction potential of at least +1.5 volts and consisting of non-metallic elements, organic peracids or mixtures of hydrogen peroxide and acids, in particular organic Carboxylic acids, with a dissociation constant of at least 10 ~ in question. Suitable inorganic peracids are periodic and persulfuric acid. Organic peracids are corresponding percarbon and persulfonic acids, which may be added as such or formed in situ by use of at least one equivalent of hydrogen peroxide and a carboxylic acid. It is expedient to use a large excess of the carboxylic acid, if, for example, acetic acid is used as the solvent. Examples of suitable peracids are performic acid, peracetic acid, trifluoroperacetic acid, permaleic acid, perbenzoic acid, S-chloroperbenzoic acid, monoperphthalic acid or p-toluenesulfonic acid.

The oxidation can also be carried out using hydrogen peroxide with catalytic amounts of

Scture can be carried out with a dissociation constant of at least .10 using low concentrations, e.g. 1-2% and less, but can also use larger amounts of acid. The effectiveness of the mixture depends primarily on the strength of the acid. Suitable mixtures are e.g. those of hydrogen peroxide with acetic acid, perchloric acid or trifluoroacetic acid.

The above oxidation can be in the presence of

suitable catalysts are carried out. For example, the oxidation with percarboxylic acids can be catalyzed by the presence of an acid having a dissociation constant of at least 10, the effectiveness of which depends on its strength. Acids suitable as catalysts are, for example, acetic acid, perchloric acid and trifluoroacetic acid. Usually one uses at least equimolar amounts of the oxidizing agent, preferably a slight excess of about 10% to about 20%, whereby one can also use larger surpluses, ie up to 10 times the amount of the oxidizing agent or above. The oxidation is carried out under mild conditions, for example at temperatures of about -50 C to about 4-100 C, preferably from about -10 ⁰ C to about +40 ⁰ G. ,

The reduction of the 1-oxides of 3-cephene 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. Suitable reducing agents are, for example:

Catalytically activated hydrogen using noble metal catalysts containing palladium, platinum or rhodium which are optionally employed together with a suitable support material such as carbon or barium sulfate: reducing tin, iron, copper or manganese cations, which in the form of

SiUUi '* 137 9 * 8 UB

 »^ -34-

ing compounds or complexes of inorganic or organic nature, for example as stannous chloride, fluoride, acetate or formate, ferrous chloride, sulfate, oxalate or succinate, cuprous chloride, benzoate or -Oxyd, or manganese-IX-chloride, -sulfate, -acetate or -oxyd, or as complexes, eg with ethylenediaminetetraacetic acid or nitrilotriacetic acid; reducing dithionite, iodide or iron (II) cyanide ariones, which are in the form of corresponding inorganic or organic salts, such as alkali metal, eg sodium or potassium dithionite, sodium or potassium iodide or iron II cyanide, or in Form the corresponding acids such as hydriodic acid, reducing trivalent inorganic or organic phosphorus compounds such as phosphines, furthermore esters, amides and halides of phosphinous, phosphonous or phosphorous acid, as well as phosphorus sulfur compounds corresponding to these phosphorus oxygen compounds, wherein organic radicals are primarily aliphatic , aromatic or araliphatic radicals, for example optionally substituted Miederalkyl- * phenyl or Phenylniederalky! groups represent, such as triphenylphosphine, tri-n-butylphosphine, Diphenylphosphinig acid methyl ester, Diphenylchlorphosphin, Phenyldichlorphosphin, Benzolphosphcnigsäuredimethyles cer, Butanphosphonigsauremethyles tsr, Phosphorigsäu recriphenyl ester, trimethyl phosphite, phosphorus trichloride, phosphorus tribromide, etc .; reducing halosilane compounds which have at least one hydrogen atom bonded to the silicon atom and, besides halogen, such as chlorine, bromine or iodine, may also have organic radicals, such as aliphatic or aromatic groups, for example optionally substituted lower alkyl or phenyl groups, such as chlorosilane, Bromsiian, di- or Tr.ichlorsilan, di- or tribromosilane, diphenylchlorosilane, Oi

η.,. O ί ί V '; - /

roethchlorosilane, etc .; reducing tertiary chloromethylene-iminium salts, especially chlorides or bromides, in which the iminium group is substituted by one or two monovalent organic radicals, such as optionally substituted lower alkylene or lower alkyl groups, such as N-chloromethylene-N, N-di-methyliminiine chloride or N -Chlormethylen-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 are used together with those of the abovementioned reducing agents which themselves do not have Lewis acid properties, i. which are used primarily in conjunction with the dithionites, iodide or iron (II) cyanide and the non-halogenous trivalent phosphorus reducing agents or catalytic reduction, are in particular organic carboxylic and sulfonic acid halides, furthermore sulfuric, phosphorus or silicon halides with the same or greater second order hydrolysis constant than benzoyl chloride, eg Phosgene, oxalyl chloride, acetic acid chloride or bromide, chloroacetic acid chloride; Pivaloyl chloride, ^ -methoxybenzoic acid chloride, 4-cyanobenzoic acid chloride, p-toluenesulfonyl chloride, methanesulfonic acid chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phenyldichlorophosphine, benzenecarbonylacetic acid dichloride, dimechylchlorosilane or trichlorosilane, acid anhydrides suitable for such an acid as trifluoroacetic anhydride, or cyclic sultone such as ethanesultone, 1,3- Propanesultone, 1,4-butanesultone or 1,3-hexanesultone.

<α η 7 Q #. K Γ

ί Α ί ΔΆ -36-

The reduction is preferably carried out in the presence of solvents or mixtures thereof, the selection of which is determined primarily by the solubility of the starting materials and the choice of reducing agent, e.g. Lower alkanecarboxylic acids or esters thereof, such as acetic acid and ethyl acetate, in the catalytic reduction and, for example, ' 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 alkanecarboxylic acid esters or nitriles, e.g. Acetic acid ethyl ester or acetonitrile, or amides of inorganic or organic acids, e.g. Dimethylformamide or hexamethylphosphoramide, ethers, e.g. Diethyl ether, tetrahydrofuran or dioxane, ketones, e.g. Acetone, or sulphones, especially aliphatic ^ sulfones, ζ.3. Dimethyl sulfone or tetramethylene sulfone, etc., together with the chemical reducing agents, these solvents preferably containing no water. It usually works at temperatures of about -20 ° C to about 100 ° C, which can be carried out at lower temperatures when using very reactive activating agents, the reaction.

Process g) t in a starting material of the formula IX R ^{a has} the same meaning as the esterified hydroxy group or optionally substituted. Amino group R. As the esterified hydroxy group, R is especially halogen, such as chlorine, bromine or iodine, or a lower alkylsulfonyloxy or arylsulfonyloxy group, such as methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy or p-toluenesulfonyloxy. As an optionally substituted amino group R is in particular amino, mono- or di-lower alkylamino, such as methyl, ethyl, propyl, dimethyl, diethyl, dipropyl, methyl ethyl, or methyl propylainirio, mono- or dicyclohexylamino, diphenylamino, Benzyl, dibenzyl or phenylethyl or diphenylethylamino, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholine or 4-lower alkylpiperazino,

The reductive elimination of R is carried out in a manner known per se, e.g. analogously to U.S.?. 4,065,618, U.S.P. 4,081,595 or DT-OS 2,824,004, with the aid of a reducing agent which can replace R by hydrogen.

An esterified hydroxyl group R is 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 else 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 alkanecarboxylic acids, e.g. Formic acid or acetic acid, or mineral acids such as hydrochloric acid or

* -38-

Sulfuric acid, or alkali metal hydroxides, such as sodium hydroxide. A preferred reducing agent of this type is zinc in the presence of acetic acid or formic acid. The reduction is carried out in said proton donating solvent alone or optionally with the addition of 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 under cooling or heating until Boiling point of the solvent used, preferably at about room temperature, ie at about 15 ° to 25 °.

An amino group R is eliminated by treatment with diborane in the presence of an inert solvent and replaced by hydrogen. Examples of suitable inert solvents are anhydrous ethers, such as diethyl ether, ethylene glycol dimethyl ether, dioxane or, in particular, tetrahydrofuran. The reaction is carried out with gentle cooling or heating, at about 5 ° to 35 °, preferably at room temperature.

Process h): In an obtained compound of the formula I in which R_ is hydrogen or a methoxy-substitutable group and all functional groups are in protected form, the 7cc-methoxy group R can be introduced in a manner known per se.

For example, the said compound wherein R is hydrogen may be sequentially treated with an anion-forming agent, an N-halogenating agent and methanol to introduce methoxy.

A suitable anion-donating agent is primarily an organo-metallic base, especially an alkali metal, primarily a lithium-organic base. Such compounds are, in particular, corresponding alkoxides, such as suitable lithium lower alkanolates, primarily lithium acrylate, or corresponding metal hydrocarbon bases, such as lithium lower alkanes and lithium phenyl. The reaction with the anion-forming metal-organic base is usually under cooling, for _o example, from about 0 ° C to about -80 ° C, and in the presence of a suitable solvent or diluent, for example an ether such as tetrahydrofuran, with the use of Lithiutnraethylat also in the presence of methanol, and, if desired, in a closed vessel and / or in a "inert gas, eg nitrogen atmosphere made.

As the N-halogenating agent, there is usually used a hindered organic hypohalite, especially chlorite, and especially a corresponding aliphatic hypohalite, e.g. -chlorite, such as a tertiary nickel alkyl hypohalite, 2.B. -chlorit.

In the first place, the tert-butyl hypochlorite is used, which is reacted with the uninsulated product of the anionization reaction. ·

The N-halogenated intermediate compound is converted to a 7-acyliminocephem compound in the presence of an excess of the anion-forming base, especially Li thiurame thy la t _s under the reaction conditions and without being isolated, and converted into a 7 ( . X-MeChOXy-CePhGm compound converted, if necessary, must be made of the N-halogenated intermediate the elements of hydrogen halide, especially hydrogen chloride Sure be cleaved;. this

is carried out with the addition of a hydrogen halide off-base tant, such as a suitable alkali metal lower alkanolate, for example lithium tert-butyiat, this reaction usually takes place under the conditions of the anion and N-Ha-1ogenverbindungbildenden reaction, wherein in the presence of methanol, and instead of the acylimino compound can directly obtain the Va-methoxy-cephem compound. It is customary from a compound of formula I, wherein R is hydrogen and functional groups are in protected form, this is reacted with an excess of the anion-forming agent, for example lithium methylate or phenyllithium, in the presence of methanol, then treated with the N Haloierungsaittel, for example tert-butyl hypochlorite, and thus obtains directly the desired compound of formula I, wherein R is methoxy and functional groups are protected. It is also possible to add the methanol subsequently, wherein the dehydrohalogenation and the addition of methanol at slightly higher temperatures than the anion and N-halogen compound forming reactions, 2 .B. at about ⁰ ° C to about -20 ° C, if necessary, in a closed vessel and / or in an inert gas, eg nitrogen atmosphere can perform.

In another compound, in a compound of formula I wherein R is a methoxy-substituted group, one can replace this group with methoxy.

Thus, an etherified mercapto group R, in particular methylthio, can be replaced in a manner known per se by treatment with methanol in the presence of a mercury (II), thallium (III), bismuth (V) or lead (IV) salt through the methoxy group become. Suitable salts are

for example, the corresponding acetates, trifluoroacetates, nitrates, fluorides, chlorides or bromides, or other derived from organic or inorganic acids salts. Preference is given to mercury (II) acetate and thallium trinitrate. The salts are used in an amount which is equimolar to the starting compound of the formula I or else in excess, up to about twice the equimolar amount.

The reaction takes place in an excess of methanol, wherein other inert solvents, for example tetrahydrofuran, methylene chloride or chloroform, can be mixed in to improve the solution. The reaction temperature is generally at room temperature, i. at about 15 to 25 °, which can be cooled or heated to slow down or accelerate the reaction.

Method i); The carbamoylation or methylation of a Hydroxyiminomethylengruppe A in a compound of formula I is carried out in a conventional manner by treatment with a Cärbamoylierungs- or methylating agent. In the starting material, all other optional functional groups are preferably protected in addition to the Hydroxyiminogruppe.

Suitable carbamoylating agents are, for example, isocyanates of the formula R-NCO, in which R. has the abovementioned 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,

Diraethylacetamide, esters, such as ethyl acetate, optionally halogenated hydrocarbons, such as benzene, toluene, chlorobenzene or methylene chloride, and similar inert solvents. Suitable catalysts are tertiary amines, such as, tri-lower alkylamines, eg triethylamine, lower alkyl ^: lower cycloalkylamines, such as Ν, Ν-dimethylcyclohexylamine, NiN-diethylcyclohexylamine, 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.etramethyi-l, 3-propanediamine or N, N, N ^1, N'-tetramethyl-l, 4-butanediamine, and the like. The carbamoylation reaction is carried out under cooling or heating at temperatures between about -30 ° to about + 100 °, preferably at about 10 °.

Suitable methylating agents are, for example, diazomethane, reactive esters of methanol, such as methyl halides, 3-methyl iodide, sulfonic acid esters, e.g. Methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonic acid methyl ester, or sulfuric acid esters ,. e.g. Dimethyl sulfate, dimethyl acetals, e.g. 2,2-dimethoxypropane, orthoester, e.g. Trimethyl orthoformate, trimethyloxonium salts, e.g. Trimethyloxonium fluoroantimonate, hexachloroantimonate, hexafluorophosphate or tetrafluoroborate, dimethoxycarbonium salts, e.g. Dimethoxycarbonium hexafluorophosphate, or dimethylhalonium salts, e.g. Dimethylbromonium hexafluoroantimonate, or 3-aryl-1-methyltriazene compounds, e.g. 3-p-tosyl-l-methyltriazeno. The methylation is carried out in a manner known per se, usually in an inert solvent, such as

Aether, e.g. Dioxane or tetrahydrofuran, or an optionally halogenated hydrocarbon such as benzene, chlorobenzoyl, methylene chloride, or the like, optionally in the presence of suitable condensing agents such as bases or acids, with cooling or heating, e.g. at temperatures between about -20 ° to about 100 °.

Methods j); The cleavage of an amino protecting group R from a compound of the formula I is carried out, if appropriate selectively, in a manner known per se and, depending on the nature of the protective group, in a different manner, for example by solvolysis or reduction. A 2-halo-lower alkoxy. carbonyl group (optionally after conversion of a 2-bromo-lower alkoxycarbonyl group to a 2-iodo-lower alkoxycarbonyl group), an acylmethoxycarbonyl group or a 4-nitrobenzyloxycarbonyl group R may be prepared, for example, by treatment with a suitable chemical reducing agent such as zinc in the presence of aqueous acetic acid Aroylmethoxycarbonylgruppe also by treatment with a nucleophilic, preferably salt-forming reagent such as Natriumthiophenolat, and a 4-nitro - benzyloxycarbonylgruppe also by treatment with an alkali metal, for example, sodium dithionite, a Diphenylmethoxycarbony1, tert-Niederalköxycarbonyl- or Polycycloalkoxycarbonylgruppe by treating eg with " Formic or trifluoroacetic acid, an optionally substituted benzyloxycarbonyl group, for example by means of hydrogenolysis by treatment with hydrogen in the presence of a hydrogenation catalyst, such as a palladium catalyst, a trialkylmethyl group, for example

, r, a P.! ' Αΐ \ / U; ·. K ' i ^] / i', '

til

by treatment with aqueous mineral acid, and an organic silyl or stannyl group R e.g. split off by hydrolysis or alcoholysis and replaced by hydrogen. A 2-haloacetyl such as 2-chloroacetyl group R can be cleaved off by treatment with thiourea in the presence of a base, or with a thiolate salt such as an alkali metal thiolate of the thiourea and subsequent solvolysis such as alcoholysis or hydrolysis of the resulting condensation product.

These solvolysis or reduction reactions are optionally carried out in the presence of a solvent involved in the reaction or else an inert solvent with cooling or heating, e.g. at temperatures from about -20 ° to about 100 °.

Method k); The esterification of a free carboxyl group, or a reactive functional derivative thereof, in the 4-position of the cephem ring in a compound of formula I, optionally under protection of other funtkionulären groups, in a conventional manner.

Thus, esters are obtained, for example, by treating a free carboxyl group -COOR ₉ with a suitable diazo compound, such as a diazonium-lower alkane, eg diazomethane or diazobutane, or a phenyl-diazo-lower alkane, eg diphenyl-diazomethane, if necessary, in the presence of a Lewis acid, such as boron trifluoride, or else reacting with an alcohol R_-OH suitable for the esterification in the presence of an esterifying agent, such as a carbodiimide, eg dicyclohexylcarbodiimide, as well as carbonyldiimidazole, furthermore with an N, N ¹ -disubstituted O- or S-substituted isourea or isothio

urea, wherein an O and S substituent e.g. Lower alkyl, in particular tert-butyl, phenyl-lower alkyl or cycloalkyl, and N- or N'-substituents, e.g. Lower alkyl, especially isopropyl, cycloalkyl or phenyl, or any other known and suitable esterification process, such as reaction of a salt of the acid with a reactive ester of an alcohol of the formula R "-OH and a strong inorganic acid or a strong organic sulfonic acid. Further, acid halides, such as chlorides (prepared, for example, by treatment with oxalyl chloride), activated esters (formed eg with N-hydroxy nitrogen compound, such as N-hydroxysuccinimide) or mixed anhydrides (obtained, for example, with haloformic acid lower alkyl esters, such as chloroformic acid or isobutyl chloroformate, or with Halogenessigsäurehalogeniden, such as trichloroacetic acid chloride) are converted by reaction with alcohols of the formula R-OH, optionally in the presence of a base such as pyridine, in an esterified carboxyl group -COOR.

In an obtained compound having an esterified moiety of the formula -COOR ", it may be converted to another esterified carboxy group of this formula, e.g. 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl 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 by reacting a compound of formula I having a free carboxyl group of the formula -COOR _9, preferably a salt, especially an alkali metal such as sodium _f, or ammonium, for example Triäthylammoniurnsalz thereof, with a reactive derivative such as a halide, eg, the

Chloride, an acid, e.g. a haloformic acid lower alkyl ester or a lower alkanecarboxylic acid chloride.

The physiologically cleavable ester groups -COOR- are preferably formed in one of the aforementioned ways,

A carboxyl group protected by an organic silyl or stannyl group may be formed in per se known manner / e.g. by reacting compounds of the formula I in which R is hydrogen, or salts, such as alkali metal, e.g. Sodium salts thereof, treated with a suitable silylating or stannylating agent; see, e.g. British Patent No. 1,073,530 and Dutch Patent Application No. 67/17107, respectively.

The esterification reaction can be carried out in the presence or absence of an inert solvent, such as an optionally halogenated hydrocarbon, for example methylene chloride, benzene, chlorobenzene, an amide, for example dimethylformamide, a sulfoxide, ζ.B. Dimethyl sulfoxide, a nitrile such as acetonitrile, or the like, or optionally also in an excess of the alcohol R ₂ -OH with cooling or heating, for example, depending on the method between about -50 ° and 100 °, are performed.

Process 1): The conversion of an esterified carboxyl group -COOR, with cleavage of the esterifying radical R, into a free or present in salt carboxyl group, ie wherein R is hydrogen or a cation, in a compound of formula I, is carried out per se known Manner, in particular by solvolysis, such as hydrolysis, alcoholysis or acidolysis, or by reduction, such as hydrogenolysis or chemical reduction.

So you can, for example a tert-Niederalkoxyearbonyl-, Polycycloalkoxycarbonyl- or Diphenylmethoxycarbonylgruppe by treatment with a suitable acidic agent, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol or anisole, in the free carboxyl group. An optionally substituted benzyloxycycloyl group may be e.g. be liberated by hydrogenolysis by treatment with hydrogen in the presence of a hydrogenation catalyst, such as a palladium catalyst. In addition, certain substituted benzyloxycarboxyl groups, such as 4-nitrobenzyloxycarbonyl., Can also be obtained by means of chemical reduction, e.g. by treating with an alkali metal, e.g. Sodium dithionite, or with a reducing metal, e.g. Zinc, or metal salt, such as a Chr οοι «ΊΙ ~ salt, for example ' Chromium-II-chloro id, usually in the presence of a hydrogen donating agent capable of producing nascent hydrogen with the metal, such as an acid, primarily acetic, as well as formic acid, or an alcohol, preferably adding water transfer the free carboxyl group. By treating with a reducing metal or metal salt as described above, one can also use a 2-halo-lower alkoxycarbonyl group (optionally after conversion of a 2-bromo-lower alkoxycarbonyl group

into a 2-iodo-lower alkoxycarbonyl group) or an acylmethoxycarbonyl group into the free carboxyl group, wherein an aroylmethoxycarbonyl group can also be cleaved by treatment with a nucleophilic, preferably, salt-forming reagent such as sodium thiophenolate or sodium iodide. A polyhaloaryicycarbony group, such as the pentachlorophenyloxycarbonyl group, becomes mildly basic, such as in dilute caustic soda or organic bases in the presence

of water, saponified to the free carboxyl group.

A e.g. The carboxyl group protected by silylation or stannylation may be prepared in a conventional manner, e.g. by treatment with water or an alcohol.

In basic hydrolysis or alcoholysis, the salt of the carboxylic acid can be obtained.

The reaction is carried out in the solvolyzing agent alone, if it is a solvent, or optionally in an inert solvent, or in a Geräisch thereof, depending on the method at reduced or elevated temperature, for example between about -50 ° and 100 °.

Reoperations:

A compound of the formula I obtained can be converted into another compound of the formula I, where the radicals R, R or A are converted into other radicals R, R or A within the scope of their meanings. This affects, in the first place, the elimination of protective groups, unless they have already been anticipated by the application of one of the methods i) to 1), e.g. of Schutsgruppen in the rest A, but also the subsequent modification of A.

In the obtained compounds of the formula I in which fractional groups are protected, these, e.g. protected carboxyl, amino, hydroxyl, mercapto and / or sulfo groups, in manner known per se, such as by solvolysis, in particular hydrolysis, Alkohoiyse ode: AcidoIyse, or by reduction, in particular hydrogenolysis or chemical reduction, optionally gradually or simultaneously liberated ,

So you can 2.B. a tert-Niederalkoxycarbonyl-, Polycycloalkoxycarbonyl- or Diphenyimethoxycarbonylgruppe by treatment with a suitable acidic Ren agent, such as formic acid or trifluoroacetic acid, optionally with the addition of a nuelophile, such as phenol or anisole, in the free carboxyl group. An optionally substituted benzyloxycarbonyl group may e.g. be liberated by hydrogenolysis by treatment with hydrogen in the presence of a Kydrierkatalysators, such as a palladium catalyst. Further, bestially substituted benzylaxycarbonyl groups such as 4-nitrobenzyloxycarbonyi can also be obtained 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 salt, such as a chromium-XI salt, e.g. Chromium-II-chloride, usually in the presence of a hydrogen donating agent capable of producing nascent hydrogen with dexs metal, such as an acid, primarily acetic, as well as formic acid, or an alcohol, preferably water transfer the free 'carboxyl group. By treating with a reducing metal of the metal salt as described above, one can also obtain a 2-halo-lower alkoxycarbonyl group (optionally after-conversion, a 2-3-rom lower alkoxycarbonyl group

into a 2-iodo-lower alkoxycarbonyl group) or an acylmethoxycarbonyl group into the free carboxyl group, where an aroylmethoxycarbonyl group can also 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 the free carboxyl group under mild basic conditions, such as dilute sodium hydroxide or organic bases in the presence of water.

A e.g. carboxy! group protected by silylation or stannylation can be prepared in a conventional manner, e.g. by treatment with water or an alcohol, to be set free.

A protected amino group is used in a manner known per se and in various ways, depending on the nature of the protecting group, e.g. by solvolysis or reduction. A 2-halo-lower alkoxycarbonyl-amino group (optionally after conversion of a 2-bromo-lower alkoxycarbonyl group to a 2-iodo-lower alkoxycarbonyl group), an acylmethoxycarbonylamino group or a 4-nitrobenzyloxycarbonylamino group can be e.g. by treating with a suitable chemical reducing agent, such as zinc in the presence of aqueous acetic acid, an aroylmethoxycarbonylamino group also by treatment with a nucleophilic, preferably salt-forming, reagent such as sodium thiophenolate and a 4-nitrobenzyloxycarbonylamino group also by treatment with an alkali metal, e.g. Sodium dithionite, a diphenylmethoxycarbonyl

amino, tert-Niederalkoxycarbonylamino- or Polycycloalkoxycarbonylaraino group by treating e.g. with formic or trifluoroacetic acid, an optionally substituted benzyloxycarbonyl inino group e.g. by means of hydrogenolysis by treatment with hydrogen in the presence of a hydrogenation catalyst, such as a palladium catalyst, a triarylaryl group e.g. by treatment with aqueous mineral acid, and an amino group protected with an organic silyl or stannyl group, e.g. be released by hydrolysis or alcoholysis. An amino group protected by 2-haloacetyl, such as 2-chloroacetyl, may be prepared by treatment with thiourea in the presence of a base, or with a thiolate salt, such as. Alkalimetallthiolat of thiourea s and subsequent solvolysis, such as alcoholysis or hydrolysis, the resulting condensation product liberated ^ become.

A hydroxy group protected by an acyl group, a silyl or stannyl group, or an optionally substituted ex-phenyl-lower alkyl group is liberated as a suitably protected amino group. A hydroxy group protected by a 2-oxa or 2-thia-aliphatic or cycloaliphatic hydrocarbon radical is liberated by acidolysis.

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

14!

The protecting groups can be chosen so that they can all be split off simultaneously, for example acidolytically, as by treatment with trifluoroacetic acid or formic acid, or reductively, as by treatment with zinc and glacial acetic acid, or with hydrogen and a hydrogenation catalyst, such as palladium / carbon. Catalyst.

By choosing suitable reaction conditions, the protective groups can also be cleaved selectively. For example, a diphenylmethoxycarbonyl group may be converted to the free carboxyl group with trifluoroacetic acid at 0 °, while a co-existing tert-butoxycarbonylamino group with the same reagent may be converted only at a higher temperature, e.g. at room temperature, and optionally also longer reaction time can be converted into a free amino group.

Incidentally, the decomposition reactions described are carried out under conditions known per se, if necessary with cooling or heating, in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere.

The conversion of a free carboxyl group in an obtained compound of the formula (I) into an esterified carboxyl group which is cleavable under physiological conditions is carried out by esterification methods known per se, for example by

A compound of the formula (I) in which other functional groups, such as amino, hydroxy or sulfo groups, optionally in protected form, or a functional derivative thereof reactive with respect to the carboxyl group to be esterified, or a salt thereof, with a corresponding alcohol _t or a reactive functional derivative, for example a halide, such as chloride

of it, esterified.

In an obtained compound of the formula (I), a hydroxymethylene group A can be oxidized to an oxomethylene group. The oxidation can be carried out, if appropriate while protecting a free amino and carboxyl group, in a manner known per se, ie, as known for the oxidation of hydroxy groups to oxo groups. be "Suitable oxidizing agents are oxidizing oxides such as those of manganese, chromium, nitrogen or sulfur, such as manganese dioxide, chromium trioxide, for example, Jones reagent, or chromium trioxide in the presence of acetic acid, sulfuric acid or pyridine, dinitrogen tetroxide _s dimethylsulphoxide optionally in the presence of dicyclohexylcarbodiimide or oxygen, and Peroxides such as hydrogen peroxide, oxygenated acids such as permanganic acid, chromic acid or hypochlorous acid or salts thereof, such as potassium permanganate, sodium or potassium dichromate or potassium hypochlorite in question. The hydroxymethylene group can also be converted into the oxomethylene group by the Oppenauer oxidation, ie by treatment with

the salt of a 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 way of converting the hydroxymethylene group into the oxomethyl group is by dehydration, e.g. with Raney nickel

The oxidation is carried out depending on the oxidizing agent in water or an optionally aqueous solvent at temperatures of about 0 ° to about 100 °.

In an obtained compound of the formula (I) in which A is an oxomethylene group, this may, optionally protected by functional groups, by treatment with hydroxylamine, O-protected or O-carbamoylated hydroxylamine or O-methylhydroxylamine in a Hydroxyiminomethylengruppe wherein hydroxy if appropriate in slotted or carbamoylated form, or converted into a methoxyiminomethylene group. ,

The reaction of the oxomethylene group with the hydroxy laminate compound is carried out in a conventional manner, e.g. by mixing the two reactants in a solvent such as water or an organic solvent such as an alcohol, e.g. Methanol, at slightly elevated or reduced temperature, optionally in an inert gas, such as nitrogen atmosphere, react. The hydroxylamine compound can, also in situ,. from one of its 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,

AP O 07 D / 214- 14-8 55 768 18

wLe.Triäthylamin or ethyl-diisopropylamine, or a heterocyclic tertiary base _{ such as pyridine, be set free *

In an obtained compound of formula (I) wherein A is methylene _s , the methylene group z. B ₀ analogous to BB-PS 855 953 »be converted by nitrosation into a Hydroxyiminogruppe, wherein the hydroxy group then, if desired, in a known manner protected, carbamoylated or converted by methylation in a -methoxy group · Furthermore, a methylene group A to a SuIfomethylengruppe be sulfonylated, for example, _c by treating with the complex, eg. B. analogous to DE-CS 2 638 028.

Salts of compounds of the formula (I) can be prepared in a manner known per se. Thus, salts of compounds of the formula I with acidic groups, Z ₀ B »can be obtained by treatment with metal compounds, such as alkali metal salts of suitable carboxylic acids, eg. B _{0 form} the sodium salt of CL-ethylcaproic acid or sodium bicarbonate _s or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of compounds of the formula I are obtained in a customary manner , z, B, by B _e «act with an acid or a suitable AnionenaustaiLschreagens» Inner Salae of compounds of formula (I) which contain a free carboxyl group, Z ₉ B ₀ by neutralizing, salts such as Sväureadditionssalz.en, ee the isoelectric point z »B,

AP C 07 D / 214 55 768 18

with weak bases, or by treatment with liquid ion exchangers.

The processes also include those embodiments in which compounds obtained as intermediates are used as starting materials and the rust-free process steps are carried out with them, or the process is stopped at any stage; furthermore, starting materials in the form of derivatives can be used or formed in situ, optionally under the reaction bonds.

The starting compounds of the formulas II to VIII are known or can be prepared analogously to known processes.

Thus, starting compounds of the formula II, in which IU is V / ererstoff, from DE-OS 2,151,567 known. Starting compounds of formula II wherein R 1 is methoxy or a methoxy-convertible group can be prepared in a manner known per se, for example by introducing etherified mercapto into compounds of formula II wherein R 1 is hydrogen, and replacing etherified mercapto with methoxy ,

Starting compounds of the formula III are known, for example, from BE-PS 852 971, BE-PS 853 5 * 5, DE-OS "2 556 736 and 2 638 028.

Starting compounds of the formula IV can be obtained by acylation of compounds of the formula II with an acid

C 07 D / 214 148 55 763 18

of the formula X-CHo-CO-A-COOH or a reactive functional derivative thereof, for example analogously to process a).

Starting compounds of the formula V or Va can analogously to DiIi-OS 2 151 56? and starting compounds of the formula VI are prepared analogously to ITL-AS 68 15631 or AT-PS 263 768 and 264 537,

Starting compounds of the formula VII in which R is hydroxyl or esterified hydroxy can be prepared analogously to DD-PS 10 6652.

Starting compounds of the formula VII in which R is optionally substituted amino can, analogously to DE-OS 2 60S 192, be treated with amines of corresponding 3-hydrosy-3-cephem compounds or according to DE-OS 2,606,196 ", B * cyclization of the corresponding 2 '- ^{(4-Tosylthio-3>} ~ scylamido-2-oxoa2ietidin "~ l-yl) -3-subst ·. amino-crotonic acid esters are obtained

Starting compounds of the formula VIII can be used in the careful de carbonylation of 3 '~} ^{! 1-} methyl-2-cephem compounds of formula VI are obtained

Starting compounds of the formula IX can be prepared analogously to the process a) by acylation of compounds of the formula II _s in which R _{0 is} a group R _Q ». Further possibilities for the preparation: such compounds subject en From the exchange of a group E ^ 'against another group E, Eg of p-toluenesulfonyloxy to amino (see U.S. Patent No. ^l l · 065 618),

- 58 -

AP O Ο? D / 214 148 55 768 18

14 14

The starting compounds of the formula I ₁ required in process h) in which R 1 is a group which can be replaced by methoxy, in particular an etherified mercapto group such as methylthio, are expediently prepared from corresponding compounds of the formula IV according to process b).

The new starting materials and processes for their preparation are also the subject of the present invention.

Pharmacologically particularly valuable compounds which can be prepared by dom inventive method, are the following:

7ß ~ ^ 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido7-3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

7β - ^ - (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido-1-cephem-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

7.beta. ^t - ^ 5- (2-tert _e butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido7-3 ~ cephem-4-carboxylic acid lester pivaloyloxymeth3 ⁷ ·

7β ~ _< / 2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetamide q7-3-cephem- ^ -carboxylic acid pivaloyloxymethyl ester ·

7ß- ^ J3, L-2-tert-Butoxycarbonylamino-2- (2 ~ amino-4-thiazolyl) acetamido7-3-cephem-4-carboxylic acid diphenylmethyl ester.

AP C Ο? D / 2Ί4 55 768 18

-SS-

7β-iL-2-amino-2- (2-amino-α-thiazolyl) -acetamido-β-cephem-4-carboic acid or a pharmaceutically acceptable SaIa thereof

irineaacetamide q7-7ot-inethoxy-3 ° -cephe] n-4 · carboxylic acid diphenylmethyl ester.

methosy-3-c ^e pb.em-4-carboxylic acid or a pharmaceutically salt thereof anneiimbares "

2-hydroxyiminoacetamido-3-cephem-f-carboxylic acid ediphenyme methyl e st er. "

7β'-2- (2-amino-4-thiazolyl) -2-hydroxy-aminoacetamido-7,3'-cepheni-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

7ß "^ 2- (2-amino-4-thiazolyl) -acetamido7-3 * -cephem-4-carboxylic acid e-diphenyline methyl ester.

acid or a pharmaceutically acceptable salt thereof «

7.beta. · - ^ 5- (2'-amino-Λ-thiazolyl) ~ ^2> -l · I-methylcarbamoyloxyxminoaceta midqj ^ -cepheia.-ii-carboxylic acid diphenylmethylestere

ac8tamido _r 7 ~ 3 ~ cephein »^ - carboxylic acid or a pharmaceutically acceptable salt thereof *

AP σ Ο? D / 214 148 55 768 18

For example, the pharmacologically useful compounds of the present invention can be used to prepare pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with inorganic or organic, solid or liquid pharmaceutically acceptable excipients which are enteral or parenteral administration. For enteral administration tablets or gelatin capsules containing the active ingredient together with diluents "e.g. Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, ζ, Β. Silica, 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, disintegrants, e.g. Starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. Suppositories. are primarily fat emulsions or suspensions.

IP-O 07 D ¹ Z 214 55 768 18

Preferable to use the pharmacologically active compounds of the present invention in the form of injizierbarenj _ζ β Β β intravenously or subcutaneously _r administrable preparations or of infusion solutions · Such solutions are preferably isotonic -wäßrige solutions or suspensions s which z _e B "from lyophilized preparations" which contain the active substance alone or together with a carrier material, ζ _β Β "mannitol", can be prepared before use. The pharmaceutical preparations can be sterilized and / or adjuvants, z 'i B _e Konservier ", stabilizers, wetting agents and / or emulsifiers, solubilisers, salts for regulating the oemotischen pressure and / or buffers · The present pharmaceutical preparations, if desired, may contain other pharmacologically valuable substances are prepared in a conventional manner, for example by means of conventional mixing, solution or Lyophilißierungsverfahren, and contain from about 0.1 % to 100 % _t, in particular from about 1 % about .50. % _t lyophilisates up to 100 % of the active ingredient _e- Je. Depending on the type of infection, the condition of the infected organism is used daily doses of about 0.5 g to about 5 g Se c ", for the treatment of warm-blooded animals weighing about 70 kg»

The following examples serve to illustrate the invention; Temperatures are given in Calsius degrees

Ef data for Düniischichtchromatögraphies DS; On silica gel precast slab SL 254 from Antec, Birsfelden.

2 14

The composition of the eluent is as follows:

52A: n-butanol / glacial acetic acid / water 67:10:23

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

101: n-butanol / pyridine / glacial acetic acid / water 38: 24: 8: 3O

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

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

a) A solution of 1.14 g of 2- (2-chloroacetamido-4-thiazalyl) -2-methQxyiminoessigsä "acid in 15 ml of tetrahydrofuran at -10 ° with 0.85 g of N, N ¹ and 0.56 -Bicyclohexylcarbodiimid g l-Kydroxybenztriazol .. and at about -5 ° to -10 ° under nitrogen for 1 1/2 hours.

; the touched. After addition of a solution of 1.0 g 7ß-: amino-S-cephem - ^ - carboxylic acid diphenylmethyl ester in 15 ml of tetrahydrofuran is first stirred for 1 hour at the same temperature and then for 4 hours at room temperature. The. The reaction mixture is filtered, and the filtrate is evaporated in vacuo. The evaporation residue is taken up in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. This residue is taken up in ethyl acetate and evaporated again after Abfiltra'cion the insoluble material. By chromatography, on silica gel with toluene and increasing proportions of ethyl acetate (up to 30%), the 7ß- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiniinoacetamido] -3-cephem-4-carbonsäure- recovered diphenylmethyl ester.

DS: RfAyO, 57 (ethyl acetate); IR spectrum (GH ₂ Cl ^): absorption bands at 3350.3200, 1782 _s 177Osh, 1724, 1705, 1684, 1540 cm ^-1 .

b) A mixture of 1.25 g of 7ß- [2- (2-chloroacetamido-4-thiazolyl) -, 2 ~ taethoxyiminoacetamido] -3-cephem-4-carboxylic acid dip henylmethylest er, 12 ml of methylene chloride, 0.6S ml Anisole and 3.4 ml of trifluoroacetic acid are stirred for 30 minutes while cooling with ice. After dropwise addition of 100 ml of diethyl ether is stirred for 45 minutes at the same temperature, stirring , the precipitated 7ß- [2- <2-chloroacetamido-4-thiazolyl) -2-methoxyiininoacetamido] -3-cephem-4-carboxylic acid is filtered off, with Diäthyläther.washed and dried.

DS: Rf 0.37 (n-butanol: glacial acetic acid. «Water 67:10:23). c) A solution of 700 mg of 7j3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -S-cephem-A-carboxylic acid in 17 ml of N, N'-dimethylacetamide is mixed with 260 mg of thiourea and Stirred for 19 hours at room temperature. By adding 200 ml of diethyl ether and decanting the solvent. The precipitate obtained is washed with 100 ml of diethyl ether and dissolved in 25 ml of water. The cloudy solution is ice-cooled and adjusted to pH 7 with sodium bicarbonate. The precipitate is filtered off, washed with water and filtrate and washing liquid added to a column of 180 ml Amberlite XÄD-2. The column is washed through with water and then with water: isopropanol 85:15. The fractions containing the 7β- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid, sodium salt are combined and evaporated The sodium salt is triturated with acetone, filtered off and dried : Rf / viO, 19 (n-butanol: glacial acetic acid: water 67:10:23), UV spectrum (ethanol): Λ = 233 rnu "(£ = 15'50O) and 290 mu

ΙΏ3.Χ I ι

sh (£ - 5 ^r 5OO).

; / & 1 M i m W -45-

Example 2 ;

a) To a solution of 3.31 g of 2- (2-tert-thiazoly) -methoxyiminoacetic acid in 35 ml of tetrahydrofuran is added: 1.50 g of 1-hydroxybenzotriazole and 2.27 g of N, N'-dicyclohexylcarbodiimide and kept at 0 for 2 hours The reaction mixture is admixed with a solution of 3.76 g of diphenylmethyl 7β-amino-3-cephem-4-carboxylate in 45 ml of tetrahydrofuran and stirring is continued for 1 hour at 0 ° and 4 hours at room temperature filtered off, the filtrate concentrated in vacuo and the residue worked up with ethyl acetate, citrate buffer, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution drying the organic phase over sodium sulfate, evaporation in vacuo, column chromatography of the resulting crude product on silica gel with toluene / ethyl acetate 4: 1 as Eluticnsmittel and crystallization of the purified product from methylene chloride / diethyl ether gives the 7β- [2- (2-tert-Butoxyca.rbonyla methyl 4-methoximinoacetamide d '] - 3-cephem-4-carboxylic acid diphenyimethyl ester of melting point 154-157 °; DS: Rf * - 0.37 (toluene / ethyl acetate 1: 1); UV spectrum (in ethanol):

λ max = 234 my * (6 = 15 500), 295 πψ, (shoulder); IR spectrum (in CH ₂ Cl ₂ ): absorption bands at 3400; 1792; 1775s; 1728; 1680; 1640; 1545 cm " ^l .

Example 3:

A solution of 840 mg of 2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetic acid in 9 ml of methylene chloride. and 0.26 ml of pyridine is added at -15 ° under nitrogen with 0.5 ml Diäthylphosphorobromidat and stirred for 30 minutes at this temperature. After adding 1.00 g of 7β-aminc-3-cephe23-4-carboxylic acid diphenylmethyiester at -15 °, the reaction solution at room temperature for 2 hours

4 1

stirred, 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 thick-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 7β- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid diphenylmethyl ester in 75 ml of methylene chloride and 75 ml of trifluoroacetic acid is added 1 h at room temperature stirred, treated with cold toluene and evaporated in vacuo. The residue is digested with diethyl ether, filtered off and dried. The resulting pale beige, powdered trifluoroacetate of 7β- [2- (2-amino-4-tlxazolyl) -2-methoxyiminoacetamido] -3-ceph em-4-carboxylic acid is suspended in 90 ml of water. The pH of the suspension becomes set to 7.1 with 2N NaOH. The solution is clear 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 pale yellowish 7β- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid na triumsaIz. IR spectrum (Nu jo 1): Characteristic absorption bands at 330Ob; 1770; 1670 b; 1600; 1532; 1460 cm " ¹ .

A solution of 100 mg of the obtained sodium salt in 5 ml of water is adjusted to pH 3.5 with 0.5N hydrochloric acid. The precipitated 7β- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid is filtered off, washed thoroughly with water and acetone and dried in vacuo.

Example 5:

A solution of 3.3 g of 7β- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-me thoxyiminoacetamido] -3-cephem-4-carboxylic acid ediphenylmethyl ester in 35 ml of methylene chloride is mixed with 15.4 ml of trifluoroacetic acid Stirred for 30 min. At 0 °, treated with cold toluene and evaporated in vacuo. The residue is digested with Diätbylätber, filtered and dried. The resulting yellow powder is dissolved in 10 ml of methanol, treated with a methanolic solution of Natriumäthylhexanoat and, to complete the precipitation, with diethyl ether and stirred for 1.5 hr. With ice cooling. The resulting sodium salt of 7β- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid is filtered off, washed well with diethyl ether and dried. DS: Rf - 0.47 (n-butanol: acetic acid: water-67: 10: 23); UV spectrum (water): X max «233 mpA (£ * 15500), 290 m ^ (shoulder).

For transfer to the free. Acid 1.5 g of the resulting sodium salt are suspended in ethyl acetate and acidified with 2N 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 50% increasing) and finally pure ethyl acetate. The obtained 70- [2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid is recrystallized from methanol / diethyl ether / hexane. Melting point: at 210 ° (decomposition); DS: Rf ₁ . ₉ ^ 0.42; UV spectrum '(ethanol): A max = 260 nm (£, = 1'683O); 232 nm (t- 19900); 224 nru '(' £ - = 20000); IR spectrum (Nujol); Absorption bands at 3270; 3180; 1782; 1713; 1654 cm.

/ · R. p. u: -i D 7 C \ *; -ί ί; i ^v -i ' Ί

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 at room temperature for 3 hours. The mixture is treated with a solution of 2.6 g of 7β- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid sodium salt in 50 ml of dimethylformamide and treated for 1 h. further stirred at room temperature. After concentration 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 vacuo is chromatographed on silica gel. Elution with toluene containing 20-30% of ethyl acetate gives the 7β- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid pivaloyloxymethyl ester. DS: Rf ^ 0.61 (ethyl acetate); UV spectrum (ethanol): Xmax * 234 m ^ (£ - 1600), 293 mp (shoulder); IR spectrum (in CH ₂ Cl ₂ ): absorption bands at 3380; 1789; 1773 sh .; 1725; 1680; 1638; 1545 cm " ¹ V

Example 7:

A solution of 1.7 g of 7β- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] '- 3-cephem-4-carboxylic acid pivaloyloxymethyl ester in 8.7 ml of methylene chloride is treated with 8.7 ml of trifluoroacetic acid staggered and stirred for 1 hour at Radiant temp era door. After addition of cold toluene is evaporated in vacuo. The residue is stirred with diethyl ether hexane 1: 1, filtered off and dried. The resulting 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 off

and dried in a high vacuum. The obtained 7.beta.-f2- (2-Amino-4 th iazoIy1) - 2-me thoxyiminoac e tamido] - 3-c eph-em-4-carboxylic acid decomposes check from about 130 ⁰ C. DS: Rf 0.28 (ethyl acetate ); UV spectrum (ethyl acetate): λ max = 235 m ^ (£ = 16320); 295 m ^ (shoulder); IR spectrum (in ClkC ^): characteristic absorption bands at 3480; 3390; 3330; 1782; 1753; 1680; 1620; 1530 ^cm-l '.

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 hrs. At room temperature. The suspension is subsequently admixed with 0.202 g of 7β- [2- (2-amino-4-thiazolyl) -2-metboxyiminoacetamido] -3-cephem-4-carboxylic acid sodium salt in 3 ml of dimethylformamide and stirring is continued for 3 hours at room temperature. The reaction mixture is diluted with ethyl acetate, with

shaken out saturated aqueous 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 the 7β ~ [2- (2-amino-4-thiazolyl) -2-metboxyiminoacetamido] -3-cephem-4-carboxylic acid pivaloyloxymethyl ester.

Example 9:

a) A solution of 2.0 g (3.2 _m mol) of 70- [D, L-2-tert. Butoxycarbonylamino-2- (2-amino-4-thiazolylacetamido) -3-cephem-4-carboxylic acid diphenylmethyl ester and 2 ml of anisole in 10 ml of methylene chloride is treated with 10 ml of trifluoroacetic acid and for 1 hour at 20-25 ° 'exclusion of moisture in a Nitrogen atmosphere stirred. After addition of 200 ml of diethyl ether to the solution cooled to 0 °, the trifluoroacetate obtained in crystalline form of the 73- [D, L-2-amino-2- (2-amino)

4-thiazolyl) acetamido] -3-cephem-4-carboxylic acid filtered off, washed with diethyl ether and dried. The aqueous solution (25 ml) of the crude trifluoroacetate is extracted with ethyl acetate (3x15 ml), adjusted to pH = 5.5 at 0 ° with 2N sodium hydroxide solution, concentrated to ca. 10 ml and treated dropwise with isopropanol (40 ml). The formed precipitate is filtered off,

reprecipitated from water-acetone 1: 4 and finally dissolved twice in a little water to remove organic solvents and concentrated on a rotary evaporator, from which after drying under high vacuum, 7β- [D, L-2-amino-2- (2-amiho-4- thiazolyl) acetamido] -3-cephem-4-carboxylic acid dihydrate in the form of an amorphous powder. DS: Rf = 0.12 (n-butanol: glacial acetic acid: water 67:10:23); Ia] Jj ⁰ = + 76 + _ 1 ° (O, 1N HCl: 0.33%);

UV spectrum (in O, 1N HCl): K = 250 nm ( ί 12400);

Max

The starting material can be obtained as follows:

b) A solution of 2.24 g (5 mmol) of D, L-2-tert-butoxycarbonylamino-2- (2-trichloroethoxycarbonylamino-4-thiazolyl) acetic acid cooled to -20 ° and 0.56 ml of N-methylmorpholine in 50 ml of absolute methylene chloride is added with stirring and exclusion of moisture with 0.65 ml of isobutyl chloroformate and allowed to react for one hour. To the thus obtained mixed anhydride are added at -15 ° 1.83 g (5m mol) of 7ß-amino-3-cephem-4-carboxylic acid diphenylmethylester in one portion. After a reaction time of 30 minutes at -15 ° and 2 1/2 hours at room temperature, the reaction mixture is diluted with ethyl acetate (200 ml), washed twice each with ice-water and saturated aqueous sodium chloride solution, dried over sodium sulfate and dried on a rotary evaporator.

Evaporator freed of solvent, from which 73- [D, L-2-tert.-Butoxycarbonylamino-2- (2-trichloroethoxycarbonylamino-4-thiazolyl) acetamido] -S-cephem - ^ - carboxylic acid diphenylmethylester as amdrhpes yellow powder. DS: Rf = 0.59 (silica gel, eluant: ethyl acetate).

c) To a cooled solution of 3.0 g (3.76m mol) of 7 / 3- [D, L-2-tert-butoxycarbonylamino-2- (2-trichloroethoxycarbonylamino-4-thiazolyl) -acetamido] - 3-cephem-4-carboxylic acid diphenylmethyl ester in 30 ml of acetonitrile-acetic acid 1: 1 are added in portions over 3 minutes with vigorous stirring 3 g of zinc dust.After one hour, the reaction mixture is diluted with ethyl acetate (200 ml), zinc dust separated by filtration, washed twice each with ice water and saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and freed on a rotary evaporator from the solvent, from which 7ß - ^, L ^ tert.Butoxycarbonylamino ^ - ^ - amino - ^ - thiazolyl) acetamido] -S -cephem ^ -carboxylic acid diphenylmethyl ester of sufficient purity for the next step in the synthesis is obtained DS: Rf = 0.47 (silica gel, eluant: ethyl acetate).

Example 10: A solution of 2.40 g of diphenylmethyl 70- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminacetamido] -7a-methoxy-3-cephem-4-carboxylate in 10 ml of methylene chloride mixed with 15 ml of trifluoroacetic acid and stirred under exclusion of atmospheric humidity for 1 hour at room temperature. Then the reaction mixture is poured onto an ice-cold mixture of petroleum ether (400 ml) and diethyl ether (200 ml), the resulting

on aMf-. -KIT ti * ft n &

Drained with trifluoroacetate, washed with petroleum ether and dried under high vacuum at room temperature. The crude 73- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] 7a-methoxy-3-cephem-4-carboxylic acid trifluoroacetate is slurried in 20 ml of water by adding 1N sodium bicarbonate solution to a pH from 6.5, the suspension stirred for 15 min. At room temperature, then the undissolved product (little) separated by treatment with activated charcoal and filtering through Celite. The clear filtrate is mixed with a lot of ethanol, the pH is corrected to 6.0 and the solution is concentrated on a rotary evaporator (high vacuum) at 45 °. The aqueous solution is evaporated several times with ethanol, finally lent lent the 73- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido1-7 a-methoxy-3-cephem-4-carboxylic acid sodium salt by adding Precipitated ethanol and washed successively with ethanol, ethanol-diethyl ether (1: 1) and diethyl ether. The product can be further purified by dissolving in water and evaporating or precipitating with ethanol. F. from 199 ° (decomposition). DS: Rf = 0.33; Rf ₆₇ = 0.20, Kf ₁₀₁ = 0.46; Rf _101A = 0.45.

The starting material can be prepared as follows:

The following reaction is carried out in a nitrogen atmosphere. A solution of 4.90 g of methyl [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate. in 500 ml of absolute tetrahydrofuran is cooled to -75 ° (dry ice-acetone bath) and a precooled solution of lithium methoxide in methanol (210 mg of lithium dissolved in 20 ml of methanol) within 2 minutes is added dropwise, the temperature rises to -70 °

and an orange-colored solution is formed. The reaction mixture is stirred for a further 2 minutes at -75 °, then added 0.10 ml of tert-butyl hypochlorite and stirred at -75 °. After 8 minutes, the solution is treated with another 0.60 ml of tert-butyl hypochlorite. After 30 minutes, 10 ml of glacial acetic acid and a solution of 4.00 g of sodium thiosulfate in 5 ml of water are successively added dropwise to the reaction mixture. The cooling bath is removed and the solution warmed to room temperature. The mixture is diluted with ethyl acetate, the tetrahydrofuran is evaporated on a rotary evaporator at 45 °, the ethyl acetate solution successively washed with water, IN sodium bicarbonate and water, dried over sodium sulfate and the solvent evaporated. The crude product is chromatographed on 20 times the amount of silica gel. The fractions with methylene chloride and 1% methyl acetate as the eluent are 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 with suction and washed with petroleum ether.

This gives the 70- [2- (2-tert.-Butoxycarbonylamino-4-thiazolyl) -2-methoxyiminacetarcido] -7a-methoxy-3-cephem ~ 4-carboxylic acid diphenylmethyl ester, DS (solvent: toluene-ethyl acetate (3: 2 )): Rf = 0.40.

QfS Λ siK In 7 ^c ] * Ki) 8 7 Zi

1 4 ί

Example 11: ·

a) A solution of 1.60 g of 7β- [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -S-cephem- ^ -carboxylic acid diphenylmethyl ester in 15 ml of methylene chloride is mixed with O, 50 ml of anisole and 2, Stirred 35 ml of trifluoroacetic acid for 30 minutes in an ice bath, treated with 100 ml of cold toluene and evaporated in vacuo. The residue is digested with diethyl ether, filtered off and dried. The obtained trifluoroacetate of 7/3 [2- (2-amino-4-thiazolyl) 2-hydroxyiminoacetamido] -3-cephem-4-carboxylic acid is suspended in 10 ml of water / methanol 1: 2 and the pH of the suspension adjusted to 4.1 with 10% methanolic triethylamine solution. After stirring for 30 minutes at 0 °, the precipitated 7β- [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3-cephem-4-carboxylic acid is filtered off, washed with acetone and diethyl ether and dried. Melting point around 170 ° (decomposition); DS: Rf _52A ^ 0.03.

The starting material is obtained as follows:

b) A solution of 3.25 ml (/ -v- 42.5 m mol / j ods in

15 ml of methylene chloride are added at -25 ° with a solution of 2.20 ml (, -. 42.5 m mol) of bromine in 15 ml of methylene chloride and stirred for 30 minutes at -2 5 °. The reaction mixture is within 20 minutes to a cooled to the same temperature solution of 13.0 g (^, 35.5 mol) of 7ß-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 3.45 ml of pyridine and 90 ml Methylene chloride was added dropwise and stirred at -25 ° for 30 minutes. After addition of ethyl acetate, the organic phase is washed successively with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, over sodium sulfate.

dried sulfate and evaporated in vacuo. The residue is chromatographed on 400 g of silica gel. With toluene / ethyl acetate 9: 1 gives the 73- (4-Bromacetoacetamido) ^ - cephem ^ -carboxylic diphenylmethyl ester as a yellowish foam. DS: Rf / **. 0/53 (toluene / ethyl acetate 1: 1); IR spectrum (in CH Cl): absorption bands at 3400, 3320, 1790, 1728, 1686, 1621, 1520 cm ^-1 .

c) A solution of 2.65 g (5m mol) of 70- (4-bromoacetoacetamido) -3-cephem-4-carboxylic acid diphenylmethy] ester in 27 ml of glacial acetic acid is added dropwise at 15 ° with a solution of 380 mg (5.5 m mol) sodium nitrite in 4 ml of water and stirred for 1 hour at room temperature. The reaction mixture is poured onto 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. This gives the 70- (4-bromo-2-hydroxyiminoacetoacetamido) -S-cephem ^ -carbonsäurediphenylmethylester of Rf = 0.50 (toluene / ethyl acetate

(1: 3)); IR spectrum (in CH Cl): absorption bands at 3250 b, 1795, 1724 sh, 1712, 1640, 1540 cm ^-1 .

d) A solution of 2.45 g (4.38 m mol) of 73- (4-bromo-2-hydroxyimino-acetoacetamido) -S-cephem ^ -carboxylic acid diphenylmethyl ester in 25 ml of dioxane is treated with a solution of 0.37 g ( 4.5m mol) thiourea in 4 ml of water and stirred for 30 minutes at room temperature.

The reaction mixture is treated with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried on sodium sulfate and in vacuo

- _., · .. ι r-. ι η. _:, C) ί ι ν * / ')

evaporated. The residue is digested with Diäthylather, filtered off and dried. The 7 (3- [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3-cephem-4-carboxylic acid diphenylmethyl ester is obtained as a pale beige powder of R.sub.f - 0.54 decomposition point by 150.degree UV spectrum (ethanol): Λ = 251 nm (i = 12900);

IQ 3.X

IR spectrum (CH "C1); Absorption bands at 3450, 3360, 3190 sh, 1792, 1728, 1680, 1640, 1607, 1540, 1512 cm ^-1 .

Example 12;

a) A solution of 1.2 g of 70- [2- (2-amino-4-thiazolyl) -acetamido] -S-cephem ^ -carboxylic acid diphenylmethyl ester in 12 ml of methylene chloride is mixed with 0.39 ml of anisole and 1.83 ml of trifluoroacetic acid for 30 minutes in an ice bath, treated with 100 ml of cold toluene and evaporated in vacuo. The residue is digested with diethyl ether and filtered off. The obtained trifluoroacetate of 7/3 [2- (2-amino-4-thiazolyl) acetamido-3-cephem-4-carboxylic acid is suspended in 10 ml of water / methanol 1: 1 and the pH of the suspension with 10% methanolic Träthylaminlösunq adjusted to about 4. After one hour of stirring under ice cooling, the precipitate is filtered off, washed with acetone and diethyl ether and dried qetrocknet. This gives the 70- [2- (2-amino-4-thiazolyl) -acetamido] -3-cephem-4-carboxylic acid of melting point by 210 ° (decomposition). DS: Rf ₁ -, - ~ 0, .05; IR spectrum (Nujol): absorbance bands at 3480 b, 3280, 1745 sh, 172O, 1670, 1545 cm ^-1 .

The starting material is prepared as follows:

b) A solution of 2.65 g of 7/3 (4-bromoacetoacetamido) 3-cepheni-4-carboxylic acid diphenylinethyi ester in 30 ml of dioxane is treated with a solution of 0.42 g of thiourea in 5 ml of water, and 30 Stirred for 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 of the 7ß- [2- (2-amino-4-thiazolyl) acetamido] -3-cephem-4-carboxylic acid ~ diphenylmethylester eluted. The crude product is digested with diethyl ether. DS: Rf - 0.29 (ethyl acetate); Melting point 105-115 °

(Decomposition); UV spectrum (ethanol): A = 256 nm

Max

max = 11100); IR spectrum (CH Cl): absorption bands at

" ¹

3496; 3396; 1791; 1728, 1685, 1640, 1603, 1515 cm

Example 13:

a) A solution of 760 mg of 70- [2- (2-amino-4-thiazolyl) -2-N-methylcarbamoyloxyiminoacetamido] -S-cephem ^ -carboxylic acid diphenylmethyl ester in 7 ml of methylene chloride is mixed with 0.21 ml of anisole and 1 ml of trifluoroacetic acid stirred for 30 minutes in an ice bath, treated with 50 ml of cold toluene and evaporated in vacuo. The residue is digested with diethyl ether, ice-cooled, filtered off and dried. The resulting trifluoroacetate of 70- [2- (2-amino-4-thiazo-IyI) -2-N-methylcarbamoyloxyiminoacetamido] -3-cephem-4-carboxylic acid is suspended in about 6 ml of water / methanol 1: 4 and the pH of the suspension is adjusted to about 4 with 10% methanolic triethylamine solution. After stirring for 30 minutes at 0 °, the precipitated 70- [2- {2-arainc-4-thiazolyl) -2-N-methylcarbamoyloxyiminoacetamido] -3-cephem-4-carboxylic acid is filtered off, with water

2'1-4 14

and diethyl ether and dried over phosphorus pentoxide. Decomposition point around. 215 °; DS: Rf, " _Ä 0.24; IR spectrum (Nujol); Absorption bands at

1775s; 1757; 1664; 1625 cm- ' ¹ ,

The starting material is obtained as follows:

b) A solution of 4.3 g of 7ß- (4-bromo-2-hydroxyiminoacetoacetamido) -3-cephem-4-carboxylic acid diphenylmethyl ester in 19 ml of acetonitrile is added under ice cooling with 7.7 ml of methyl isocyanate and 15 minutes under ice cooling and Stirred for 30 minutes at room temperature. The reaction mixture is diluted with ethyl acetate and concentrated 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 resulting 7) 3- (4-bromo-2-N-methylcarbamoyloxyiminoacetoacetamido) -3-cephem-4-carboxylic acid diphenylmethyl ester is digested with diethyl ether, filtered off and dried. Melting point 112-117 °; DS: Rf ^ 0.3 (toluene / ethyl acetate 1: 1); IR spectrum absorption bands at 3400; 1788; 1727; 1698; 1640; 1520 cm.

c) A solution of 1.2 g of 7β- (4-bromo-2-N-methylcarbamoyloxy-imino-acetoacetamido) -3-cephem-4-carboxylic acid diphenylmethyl ester in 12 ml of dioxane is treated with a solution of 163 g of thiourea in 2 ml of water and stirred at room temperature for 60 minutes. The reaction mixture is mixed with ethyl acetate, successively

 -73-

washed 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 40 g of silica gel with ethyl acetate and ethyl acetate containing 10% acetone. This gives the 7 / 3- [2- (2-amino-4-thiazolyl) -2-N-methylcarbamoyloxyiminoacetamido] -3-cephem-4-carboxylic acid diphenylmethyl ester in the form of brownish crystals of melting point ^ - 150 ° (decomposition). DS: Rf 0.45 (chloroform / methanol 8: 2); IR spectrum (CH-Cl-): absorption bands at 3360; 1782b; 1731; 1684; 1620; 1528 cm " ¹ .

Example 14 :

Capsules containing 0.250 g of 7β- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-A-carboxylic acid sodium salt are prepared as follows:

Composition, (100,000 capsules):

ηρ. [2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetamidol-S-cepheni-A-carboxylic acid _9ς , _ηηπ sodium _salt ¹ _~ ^uuu ^

Wheat starch " ² ' ^{500 g}

'_ · I'ooo g

magnesium stearate

The 7β- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -S-cephem-A-carboxylic acid sodium salt, the wheat starch and the magnesium stearate are well mixed together and filled into capsule no.

Ut

-w-

Example 15;

Capsules containing 0.5 g of 7β- [2- (2-amino-A-thiazolyl) -2-methoxyiminoacetamido] -O-cephem-A-carboxylic acid sodium salt are prepared as follows:

Composition (for 2000 capsules):

7β- [2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetamido] -β-cephem-A-carboxylic acid sodium salt 1000'00 g

Polyvinylpyrrolidone, .15 * 00 g

Cornstarch 115 * 00 g

Magnesium stearate 20 * 00 g

The 7β-ί2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -S-cephem-A-carboxylic acid sodium salt is moistened with 300 ml of a solution of the polyvinylpyrrolidone in 95% ethanol, the mixture is driven through Sieve with 3 mm mesh size and dried the granules under reduced pressure at 40-50 °. Sieve through a sieve of 0.8 mm mesh size, add the corn starch and the magnesium stearate, mix and fill the mixture in capsules (size 0). ·

Example 16:

Dry ampoules or vials containing 0.5 g of 7β- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid, sodium salt are prepared as follows:

Composition (for 1 ampoule or vial)

7β-1 2- (2-Amino-4-chiazolyl) -2-methoxyiminoacetamido] -S-cephem-1-carboxylic acid sodium salt 0.5 g

Mannitol 0.05 g

A sterile aqueous solution of the 7β- [2- (2-amino-A-thiazol-yl) -2-methoxyiminoacetamido] -S-cephem-A-carboxylic acid, sodium salt and mannitol is added under aseptic conditions in 5 ml. Vials or 5 ml. Vials closed and tested.

Example 17; ,

Dry ampoules or vials containing 0.25 g of 7β- [2- (2-amino-O-4-thiazolyl) -2-methoxyiminoacetamido] -S-cephem-A-carboxylic acid sodium salt are prepared as follows:

Zusjtm nensetzung (for 1 ampoule or vial)

7.beta. ~ [2- (2-amino-4-thiazolyl) -2-methoxy-

iminoacetamido] -o-cephern-A-carboxylic acid

sodium salt 0.25g

Mannitol 0.05 g

A sterile aqueous solution of the 7β- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid, sodium salt and mannitol is added under aseptic conditions in 5 ml. Or 5 ml Vials closed and tested.

Claims (2)

invention claim 1, "Process for the preparation of 7ß" -Aminothiazolylacetamido-B-cephem - ^ - carboxylic acid compounds of the formula -A - CONH- (D, COOR, wherein R ^ is hydrogen, Mederalkyl or an amino, A is methylene or substituted by optionally protected amino, hydroxy or SuIfο, by oxo, optionally protected or carbamoylated hydroxyimino methylene, R ^ is hydrogen, M _e thoxy or a replaceable by methoxy group uni Rp is hydrogen or a group esterifying the carboxyl group, and salts of such compounds having salt-forming groups, characterized in that a) the 7β-amino group in a compound of the formula H ₂ H ^R 3 (II) COOR IP C 07 D / 214 148 55 768 18 wherein the amino group is optionally substituted by an acylating group and wherein E ₂ and IU are as defined for formula I by treating with an acyl radical of a carboxylic acid of the formula (III) A-COOH introducing acylating agent, in which E. and A have the meanings given under formula I and in which optionally present functional group are present in protected form, acylated, or b) a compound of the formula X-CH ₂ CO-A-COlTE COOE, (IV), wherein X is halogen, B ₂ , E ^ and A have the meanings mentioned under formula I and in which functional groups are optionally protected, or a salt thereof, with a thiourea of the formula R ^ or a salt thereof, or c) a compound of the formula AP O 07 D / 214 55 768 18 CONH S-CH ₂ CH = O COOE, wherein R, R ^ and R are optionally substituted hydrocarbon radicals and R., R ₂ , R ^ and A have the meanings given under formula I, and in which functional groups are optionally protected, with ring closure the phosphine oxide (R _o ) (R,) (R ^) P = O splits off, or d) a compound of the formula -A-CONH CHO COOR, wherein R ^ ₁ R and A is the one given under formula I. ^ ₁ Rp, R Have meanings in which the double bond is in the 2 * 3 or 3,4 position and functional groups are optionally protected, treated with a decarbonylating agent, or e) from a compound of the formula AP C 07 D / 214 148 55 768 18 - ff- N- • A-COM (VII) COOR, »Ro and A given under Fonael I. where R ₁ « Have meanings and R is hydroxy, esterified or optionally substituted amino, cleaves off a group HR ₀ , or f) a compound of the formula -A-COHH (YIII), COOR ₂ wherein R ₁ , R ₂ , R and A have the meanings mentioned under formula I, isomerizes, or ' g) from a compound of the formula A COKH R ' (XO, COOR ₂ esterified hydroxy or optionally sub- AP C 07 D / 214 55 768 18 is substituted amino, and wherein R ^ ₁ , A, R ₀ and R ₀ XC. J) have given meanings under formula I, the group R ^ reductively removed and replaced by hydrogen, or h) for the preparation of a compound of the formula I in which Eo is methoxy, in a compound of the formula - in the J ' X -A - CONS COOR, where R ~ is hydrogen or one substituted by methoxy Rp and A under formula group means R 1,
I have given meanings and in which all functional groups are in protected form, replacing Ro in the 7-position by methoxy, or i) for the preparation of a compound of the formula I in which A is carbamoylated hydroxyiminomethylene or methoxyiminomethylene, and in which R ₁ , R ₂ and R ₄ have the meanings given for formula I, in a compound of the formula O - CONH It N OH (D, COOR, •wherein and P- the meaning given under formula I AP C Q7 D / 214 148 55 768 18 have the hydroxyimino group carbamoylated or methylated, or j) for the preparation of a compound of the formula I in which R _{7 is} hydrogen and in which A, H ₂ and Rv are as defined for formula I, from a compound of the formula I in which R 1 is an amino-protecting group, and A, R ₂ and R ^ have the meanings given under formula I have split off the amino protecting group R and replaced by hydrogen, or k) for the preparation of a compound of formula I, wherein R _{0 is} a radical esterifying the carboxyl group _s and R,., A and R- have the meanings given under the formula I, in a compound of formula I, wherein R _{2 is} hydrogen and wherein R,., A and R- have the meanings given for formula I, the free carboxy group in the 4-position of the cephem ring, or a reactive functional derivative thereof, overfilled by treatment with an esterifying agent in an esterified carboxyl group, or 1) to prepare a compound of formula I wherein R ₂ is hydrogen, R ^ ,, and A and R have the meanings given under formula I, in a compound of formula I wherein R _{t 2,} the carboxyl group is an esterifying radical, and R ^, A and R ^ have the meanings given under formula I, these R ₂ split off and replaced by hydrogen or an Eatbn, and if desired, in an obtained compound a radical R ^, R _p or A in one AP C 07 D / 214 148 55 768 18 other radical 3L *, R ₂ or A, and / or, if desired, converting a compound obtained into a salt or a salt obtained into a free compound or into another salt. 2. The method of item 1, characterized in that one of a corresponding starting material, starting a compound of formula (I) wherein R ^, is hydrogen, lower alkyl, Fiederalkanoyl or 2- HaIogenniederalkanoyl, A is _methylene,: aminomethylene, hydroxymethylene, Sulfomethylen, Hydroxyninomethylene, carbamoylated hydroxyiminomethylene, or methoxyiminomethylene, R 1 represents hydrogen or methoxy, and R g represents hydrogen or a radical cleavable under physiological conditions, or produces a pharmaceutically acceptable salt thereof. ♦ Method according to item 1, characterized in that, starting from a corresponding starting material, a compound of the formula (I) in which R 1 represents hydrogen or 2-halo-lower alkanoyl, A represents hydroxyiminomethylene, N-methylcarbamoyloxyiminomethylene or methoxyiminomethylene, R 0 is hydrogen or Methoxy, and Ro represents hydrogen or acetyloxymethyl, pivaloyloxymethyl, -I-ethyloxycarbonyloxyethyl or phthalidyl cleavable under physiological conditions, or a pharmaceutically; acceptable salt thereof · 4, Method according to Pankt 1, characterized in that AP C 07 D / 214-55 768 18 starting from a starting material of this type, preparing the 7β- / 5- (2-amino-4-thiazolyl) -2-methoxy, ureoacetamido, J ^ 3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof 5 "method according to item 1, characterized in that starting from a corresponding starting material, the 7ß ~ ^ 5" (2-chloroacetamido-4-thia2iolyl) -2-methoxyiminoacetamidoj '- cephem- ^ l-carboxylic acid or a pharmaceutically acceptable salt of which manufactures 6 * Process according to item 1 _1, characterized in that starting from a corresponding starting material (fen 7ß ~ ^ - (2-tert, Butoxycarbonylamino-4-thiazolyl) -2 "methoxy iminoacetamido / ^ -cephem - ^ - prepared carboxylic acid pivaloyloxymethylester · Process according to item 1, characterized in that - starting from an appropriate starting material, the 7β-> 2 "- (2-amino-4-thiazolyl) -2-methosyimino- ester produces · 8 * Method according to item 1 _9, characterized in that starting from a corresponding starting material, starting from the '7ß- ^ Ss £ -2-tert-Butoxycarbonylamino-2 ~ (2-amino-^-thiazolyl) acetamido / "3-cephem-4 -carboxylic acid diphenylmethyl ester produces * 9 »Method according to item 1 ( _t) characterized in that, starting from a corresponding starting material,» AP C 07 D / 214 768 18 which produces the 7β-E, L-2-amino-2α (2-amino-4-thiazolyl) acetamide q7-3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof. 10 »method according to item 1, characterized in that starting from a corresponding starting material, the 7ß ^ 5- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminacetamido / -7 & -methoxy-3-cephem ~ -carboxylic acid diphenylmethyl ester, Process according to item 1, characterized in that, starting from an appropriate starting material, the 7β- (2-amino-4-thiazolyl) -2-methoxyiminoacetamide q7-7 oo -methoxy-3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof. 12e method according to item 1, characterized in that one prepares starting from a corresponding starting material, the 7ß - ^ - (2 ~ amino-4-thiazolyl) -2-hydroxyiminoacetamido7-3-cephem-4- ~ carboxylic acid diphenylmethylester. 13 «method according to item 1, characterized in that starting from a corresponding starting material, the 7ß- _< / 5- (2-amino- ⁱ } -thiazolyl) -2-hydroxyiminoacetamidQ7-3-cephem-4-carboxylic acid or a pharmaceutically acceptable Salt made from it » Process according to item 1, characterized in that one starts from a corresponding starting material AP C 07 D / 214 55 768 18 preparing the 7β-2- (2-amino-4-thiazolyl) -acetamide q7-3 · cephem-4-carboxylic acid diphenylmethyl ester The process according to item 1, characterized in that starting from a starting material of its own, the 7β * - ^ 2 - (2-amino-4-thia2-yl) '- acetamido7 "3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof is prepared therefrom , Process according to item 1, characterized in that starting from an appropriate starting material, the 7β- [5 (2-amino-4-thi5i2iolyl)] - 2-N-methylcarbarfloyloxyiminoacetamido7 "3- ^TO- cephem-" 4-carboxylic acid diphenylmethyl ester is prepared. 17 Method according to item 1, characterized in that starting from a corresponding starting material, the 7β- (2-amino-4-thiazolyl) -2'-H-methyicarbamoylo2-yl-2-ylacetamido-7-oocarbonate · - acid Odei ¹ a pharmaceutically acceptable salt thereof produces © 18, method according to one of the items 1 -5t 9 »11» 13 * oder.17 * gekennze ichnet thereby »that a 4-öarbonsäiirverbindung obtained in the corresponding Natriurasalz transferred ·.