CH624683A5 - Process for the preparation of 7beta-amino-3-cephem-3-ol-4-carboxylic acid compounds - Google Patents

Abstract

7 beta -Amino-3-cephem-3-ol-4-carboxylic acid compounds of the formula I <IMAGE> in which R@ is hydrogen or an amino protective group R@, R@ is hydrogen or an acyl group Ac, or R@ and R@ together are a divalent amino protective group, and -C(=O)-R@ is a protected carboxyl group, the corresponding isomeric 3-oxo-cepham compounds in which the double bond is in the exo position, and the corresponding isomeric 2-cephem compounds in which the double bond is in the 2,3 position, the mixtures of isomers thereof, and the 1-oxides of 3-cephem compounds of the formula I, and salts of such compounds with salt-forming groups, are prepared by elimination of the hydroxyl protective group which is present as ether group from corresponding compounds in which the 3-hydroxy group is in protected form. The compounds can be used as intermediates for the preparation of compounds with pharmacological properties.

Description

The present invention relates to a process for the preparation of 7β-amino-3-cephem-3-ol-4-carboxylic acid compounds of the formula foO

(I),

0 = C-R |

where Ria represents hydrogen or an amino protecting group RiA, Rib represents hydrogen or an acyl group Ac, or Ria and Rib together represent a bivalent amino protecting group and -C (= 0) -R2A means a protected carboxyl group, the corresponding isomeric 3-oxocepham compounds, wherein the double bond is in the exo position, and the corresponding isomeric 2-cephem compounds, in which the double bond is in 2,3-position, the isomer mixtures thereof, and the 1-oxides of 3-cephem compounds of the formula I, and salts of such compounds with salt-forming groups.

The compounds that can be produced according to the invention are the subject of Swiss Patent No. 590873.

In the compounds which can be prepared according to the invention, the equilibrium lies mainly on the side of the 3-cephem compounds of the formula I, where the double bond is in the 3,4-position. Because of the double bond isomerism, the compounds can also occur in the isomeric 3-oxocepham form or in the 2-cephem form or as mixtures of these isomeric forms. The 1-oxides are usually in the 3-cephem form.

In the 3-oxocepham and 2-cephem compounds, the optionally protected carboxyl group of the formula -C (= 0) -R2a preferably has the a configuration.

An amino protective group RiA is a group which can be replaced by hydrogen, primarily an acyl group Ac, furthermore a triarylmethyl group, in particular the trityl group, and an organic silyl or an organic stannyl group. A group Ac, which can also represent a radical Rib, primarily represents the acyl radical of an organic carboxylic acid, preferably having up to 18 carbon atoms, in particular the acyl radical of an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, aliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid (including formic acid) and the acyl residue of a carbonic acid derivative.

A bivalent amino protecting group formed together by the residues Ria and Rib is in particular the divalent acyl residue of an organic dicarboxylic acid, preferably having up to 18 carbon atoms, primarily the diacyl residue of an aliphatic or aromatic dicarboxylic acid, furthermore the acyl residue of a, preferably substituted in the a-position, e.g. B. containing an aromatic or heterocyclic radical, a-amino-acetic acid, wherein the amino group via a, preferably substituted, for. B. two lower alkyl, such as methyl groups containing methylene radical is connected to the nitrogen atom. The Ria and Rib radicals together can also be an organic, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic ylidene radical, preferably having up to 18 carbon atoms.

A protected carboxyl group of the formula -C (= 0) -R2A is primarily an esterified carboxyl group, but can also represent an optionally substituted carbamoyl or hydrazino carbonyl group.

The group R2A can therefore be a hydroxy group etherified by an organic radical, in which the organic radical preferably contains up to 18 carbon atoms, which together with the -C (= 0> grouping form an esterified carboxyl group. Such organic radicals are, for example aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals, in particular optionally substituted hydrocarbon radicals of this type, and also heterocyclic or heterocyclic-aliphatic radicals.

The group R2A can also be an organic silyloxy radical and a hydroxyl group etherified by an organometallic radical, such as a corresponding organic stannyloxy group, in particular a hydrocarbon radical optionally substituted by 1 to 3, preferably with bis

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to 18 carbon atoms, such as aliphatic hydrocarbon radicals, and optionally by halogen, such as chlorine-substituted silyloxy or stannyloxy group.

A radical Rîa forming a carbamoyl group with a -C (= 0) grouping is an optionally substituted amino group, in which substituents are optionally substituted monovalent or bivalent hydrocarbon radicals, preferably having up to 18 carbon atoms, such as optionally substituted monovalent or bivalent aliphatic, cycloaliphatic, table, cycloaliphatic-aliphatic, aromatic or aliphatic hydrocarbon radicals with up to 18 carbon atoms, furthermore corresponding heterocyclic or heterocyclic-aliphatic radicals with up to 18 carbon atoms and / or functional groups, such as optionally functionally modified, in particular free hydroxy, further etherified or esterified hydroxy, wherein the etherifying or esterifying radicals z. B. have the meanings given above and preferably contain up to 18 carbon atoms, and acyl radicals, primarily of organic carboxylic acids and carbonic acid derivatives, preferably having up to 18 carbon atoms.

One or both nitrogen atoms can be substituted in a substituted hydrazinocarbonyl group of the formula -C (= 0) -R2a, the substituents primarily being optionally substituted monovalent or bivalent hydrocarbon radicals, preferably having up to 18 carbon atoms, such as optionally substituted, monovalent or bivalent aliphatic , cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals with up to 18 carbon atoms, furthermore corresponding heterocyclic or heterocyclic-aliphatic radicals with up to 18 carbon atoms, and / or functional groups, such as acyl radicals, primarily of organic carboxylic acids or of carbon acid half-derivatives, preferably with up to 18 carbon atoms.

The general terms used in the above and following description have z. B. the following meanings:

An aliphatic radical, including the aliphatic radical of a corresponding organic carboxylic acid, and a corresponding ylidene radical, is an optionally substituted monovalent or divalent aliphatic hydrocarbon radical, in particular lower alkyl, and also lower alkenyl or lower alkynyl, furthermore lower alkylidene which, for. B. may contain up to 7, preferably up to 4 carbon atoms. Such residues can optionally by functional groups, for. B. by free, etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylene-dioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylthio or optionally substituted phenylthio, phenyl-lower alkylthio, heterocyclylthio or heterocyclyl-loweroxyalkoxyalkoxyalkoxyoxyoxyalkoxyalkoxyalkoxyoxyoxyalkoxyalkoxyoxyoxyoxy or halogen, furthermore by oxo, nitro, optionally substituted amino, e.g. B. Niederalkylamino, Diniederalkylamino, Niederal-kylenamino, Oxaniederalkylenamino or Azaniederalkylen-amino, as well as Acylamino, such as Niederalkanoylamino, Niederal-koxy-carbonylamino, Halogiederiederalkoxycarbonylamino, optionally substituted Phenylniederalkoxcycarbonyl-amino, optionally substituted Carbamoyanocaminoamino, furthermore in oramino-carbonylamino, uinoaminoaminoaminoamino, uinoamido carbonino, furthermore in oramino-carbonylamino, uinoamino carbonino, also U. - As alkali metal salt form present sulfo-amino, azido, acyl, such as lower alkanoyl or benzoyl, optionally functionally modified carboxyl, such as carboxyl present in salt form, esterified carboxyl, such as lower alkoxycarbonyl, optionally substituted carbamoyl, such as N-lower alkyl or N, N -Di-lower alkylcarbamoyl, furthermore optionally substituted ureidocarbonyl or guanidinocar-

bonyl, or cyan, optionally functionally modified sulfo, such as sulfamoyl or sulfo present in salt form, or optionally O-mono- or 0.0-disubstituted phosphono, in which substituents, for. B. represent optionally substituted lower alkyl, phenyl or phenyl-lower alkyl, where O-unsubstituted or O-monosubstituted phosphono can also be present in salt-like alkali metal salt form, mono-, di- or poly-substituted.

A bivalent aliphatic residue, including the corresponding residue of a bivalent aliphatic carboxylic acid is e.g. B. lower alkylene or lower alkenylene, which, if necessary, for. B. as an above-mentioned aliphatic radical, mono-, di- or poly-substituted and / or interrupted by heteroatoms such as oxygen, nitrogen or sulfur.

A cycloaliphatic or cycloaliphatic-aliphatic radical, including the cycloaliphatic or cycloaliphatic-aliphatic radical in a corresponding organic carboxylic acid, or a corresponding cycloaliphatic or cycloaliphatic-aliphatic ylidene radical is an optionally substituted, mono- or bivalent cycloaliphatic hydrocarbyl or cycloaliphatic, aliphatic, cycloaliphatic, cycloaliphatic, aliphatic, cycloaliphatic, aliphatic, cycloaliphatic, aliphatic, cycloaliphatic, aliphatic, cycloaliphatic, aliphatic, cycloaliphatic, aliphatic, cycloaliphatic, aliphatic, cycloaliphatic, aliphatic, cycloaliphatic, aliphatic, cycloaliphatic, aliphatic, cycloaliphatic, or mono-, bi- or polycyclic cycloalkyl or cycloalkenyl, further cycloalkylidene, or cycloalkyl or cycloalkenyl lower alkyl or lower alkenyl, further cycloalkyl lower alkylidene or cycloalkenyl lower alkylidene, in which cycloalkyl and cycloalkylidene z. B. contains up to 12, such as 3-8, preferably 3-6 ring carbon atoms, while cycloalkenyl z. B. up to 12, such as 3-8, e.g. B. 5-8, preferably 5 or 6 ring carbon atoms, and 1 to 2 double bonds and the aliphatic part of a cycloaliphatic-aliphatic radical z. B. may contain up to 7, preferably up to 4 carbon atoms. The above cycloaliphatic or cycloaliphatic-aliphatic radicals can, if desired, e.g. B. by optionally substituted aliphatic hydrocarbon radicals, such as by the above-mentioned, optionally substituted lower alkyl groups, or then, for. B. like the above-mentioned aliphatic hydrocarbon radicals, mono-, di- or poly-substituted by functional groups.

An aromatic radical, including the aromatic radical of a corresponding carboxylic acid, is an optionally substituted aromatic hydrocarbon radical, e.g. B. a mono-, bi- or polycyclic aromatic hydrocarbon radical, especially phenyl, and biphenylyl or naphthyl, which, if necessary, for. B. how the above-mentioned aliphatic and cycloaliphatic hydrocarbon radicals can be mono-, di- or poly-substituted.

A bivalent aromatic residue, e.g. B. an aromatic carboxylic acid is primarily 1,2-arylene, especially 1,2-phenylene, which, if necessary, for. B. how the above-mentioned aliphatic and cycloaliphatic hydrocarbon radicals, mono-, di- or polysubstituted.

An araliphatic radical, including the araliphatic radical in a corresponding carboxylic acid, furthermore an araliphatic ylidene radical, is e.g. B. an optionally substituted araliphatic hydrocarbon radical, such as an optionally substituted, e.g. B. up to three, optionally substituted mono-, bi- or polycyclic, aromatic hydrocarbon radicals containing aliphatic hydrocarbon radical and primarily phenyl-lower alkyl or phenyl-lower alkenyl,

and phenyl-lower alkynyl, furthermore phenyl-lower alkylidene, such residues being e.g. B. 1-3 phenyl groups and optionally, e.g. B. how the above-mentioned aliphatic and cycloaliphatic radicals, in the aromatic and / or aliphatic part may be mono-, di- or poly-substituted.

Heterocyclic groups, including those in heterocyclic-aliphatic radicals, including heterocyclic or heterocyclic-aliphatic groups in corresponding carboxylic acids, are in particular monocyclic, as well as bi- or

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polycyclic aza-, thia-, oxa-, thiaza-, thiadiaza-, oxaza-, diaza- or -1,2-ethyl, -1,1 -, -1,2- or -1,3-propyl, - vinyl or allyl,

triaza or tetrazacyclic radicals of an aroamtic character, rend cycloalkenyl-lower alkyl or lower alkenyl z. B. 1 -, 2-

furthermore corresponding partially or completely saturated heterocycli- or 3-cyclopentenyl-, 1-, 2- or 3-cyclohexenyl- or 1-, 2-

cal residues of this type, such residues optionally, e.g. B. or 3-cycloheptenylmethyl, -1,1- or -1,2-ethyl, -1,1-, -1,2- or like the above-mentioned cycloaliphatic radicals, mono-, di- or 5 -1,3- propyl, vinyl or allyl. Cycloalkyl-lower alkyl

can be polysubstituted. The aliphatic part in heterocytes is e.g. B. 3-Cyclohexenylmethylene.

clisch-aliphatic residues z. B. for the corresponding naphthyl is 1- or 2-naphthyl, while biphenylyl z. B.

represents cycloaliphatic-aliphatic or araliphatic radicals 4-biphenylyl.

given meaning. Phenyl-lower alkyl or phenyl-lower alkenyl is e.g. B. Ben-

The acyl radical of a carbonic acid derivative is preferably 10-cyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, diphenyl-

as the acyl radical of a corresponding half ester, wherein the methyl, trityl, styryl or cinnamyl, naphthyl-lower alkyl z. B.

organic radical of the ester group an optionally substituted 1- or 2-naphthylmethyl, and phenyl-lower alkylidene z. B. Ben-

acted aliphatic, cycloaliphatic, aromatic or cylidene.

araliphatic hydrocarbon radical or a heterocyclic heterocyclic radicals are primarily optionally a clic-aliphatic radical, primarily the acyl radical 15 substituted heterocyclic radicals of aromatic character,

one if necessary, e.g. B. in a- or ß-position, substituted z. B. corresponding monocyclic, monoaza, monothia or

Lower alkyl half-ester of carbonic acid, and a given monooxacyclic radicals, such as pyrryl, z. B. 2-pyrryl or 3-pyr-

in the organic radical substituted lower alkenyl, ryl, pyridyl, e.g. B. 2-, 3- or 4-pyridyl, further pyridinium, thienyl,

Cycloalkyl, phenyl or phenyl-lower alkyl half ester of the z. B. 2- or 3-thienyl, or furyl, e.g. B. 2-furyl, bicyclic

Carbonic acid. Acyl residues of a carbonic acid semi-ester are further monoaza, monooxa or monothiacyclic residues, such as indo-

corresponding residues of lower alkyl half-esters of carbonyl, e.g. B. 2- or 3-indolyl, quinolinyl, e.g. B. 2- or 4-quinolinyl,

lens acid in which the lower alkyl part is a heterocyclic isoquinolinyl, e.g. B. 1-isoquinolinyl, benzofuranyl, e.g. B. 2- or

Group, e.g. one of the above-mentioned heterocyclic groups 3-benzofuranyl, or benzothienyl, e.g. B. 2- or 3-benzofuranyl,

aromatic character, contains, both the Niederal- or Benzothienyl, z. B. 2- or 3-benzothienyl, monocyclic kylrest, and the heterocyclic group may optionally be substituted 25 diaza, triaza, tetraza, oxaza, thiaza or thiadiazacyclische. The acyl residue of a carbonic acid half residue, such as imidazolyl, e.g. B. 2-imidazolyl, pyrimidinyl, e.g. B. 2-

Derivatives can also be an optionally N-substituted carba- or 4-pyrimidinyl, triazolyl, e.g. B. l, 2,4-triazol-3-yI, tetrazolyl,

moyl group, such as an optionally halogenated N-Niederal-. B. 1- or 5-tetrazolyl, oxazolyl, e.g. B. 2-oxazolyl, isoxazolyl,

be kylcarbamoyl group. e.g. B. 3- or 4-isoxazolyl, thiazolyl, e.g. B. 2-thiazolyl, isothiazo

An etherified hydroxy group is primarily 30 lyl, z. B. 3- or 4-isothiazolyl or 1,2,4- or 1,3,4-thiadiazolyl,

optionally substituted lower alkoxy, wherein substituents in z. B. l, 2,4-thiadiazol-3-yl or l, 3,4-thiadiazol-2-yl, or bicycli primarily free or functionally modified, such as etherified see diaza, oxaza- or thiazacyclic radicals, such as benzimida -

or esterified hydroxy groups, especially lower alkoxy zolyl, e.g. B. 2-benzimidazolyl, benzoxazolyl, e.g. B. 2-benzoxazolyl,

represent or halogen, further lower alkenyloxy, cycloalkyl or benzothiazolyl, e.g. B. 2-Benzthiazolyl. Corresponding par

oxy or optionally substituted phenyloxy, as well as hetero or fully saturated radicals are, for. B. tetrahydrothienyl, such as rocyclyloxy or heterocyclyl-lower alkoxy, in particular also 2-tetrahydrothienyl, tetrahydrofuryl, such as 2-tetrahydrofuryl,

optionally substituted phenyl-lower alkoxy. or piperidyl, e.g. B. 2- or 4-piperidyl. Heterocyclic aliphatic

An optionally substituted amino group is e.g. B. see residues are heterocyclic groups, especially the

Amino, Niederalkylamino, Diniederalkylamino, Niederalkylen- the above-mentioned containing lower alkyl or Niederalkenyl.

amino, Oxaniederalkylenamino, Thianiederalkylenamino, Aza- 40 The above-mentioned heterocyclyl radicals can, for. B. by given

lower alkylenamino, hydroxyamino, lower alkoxyamino, optionally substituted aliphatic or aromatic carbons

Niederalkanoyloxyamino, Niederalkoxycarbonylamino or hydrogen residues, especially Niederalkyl, such as methyl, or

Niederalkanoylamino. if necessary, e.g. B. substituted by halogen such as chlorine

An optionally substituted hydrazino group is e.g. B. phenyl, e.g. B. phenyl or 4-chlorophenyl, or, e.g. B. like the ali-

Hydrazino, 2-Niederalkylhydrazino, 2,2-Diniederalkylhydra- 45 phatic hydrocarbon residues, by functional Grup-zino, 2-Niederalkoxycarbonylhydrazino or 2-Niederalkanoylpen be substituted.

hydrazino. Lower alkoxy is e.g. B. methoxy, ethoxy, n-propyloxy, iso-

Lower alkyl is e.g. B. methyl, ethyl, n-propyl, isopropyl, propyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyl

n-butyl, isobutyl, sec-butyl or tert-butyl, and also n-pentyl, iso-oxy, n-pentyloxy or tert-pentyloxy. These groups can be pentyl, n-hexyl, isohexyl or n-heptyl, while Niederalke- 50 may be substituted, e.g. B. as in halogen-lower alkoxy, in particular

nyl z. B. vinyl, allyl, isopropenyl, 2- or 3-methallyl or their 2-halogeno-lower alkoxy, e.g. B. 2,2,2-trichloro, 2-chloro,

3-butenyl, lower alkynyl e.g. B. propargyl or 2-butynyl, and 2-bromo or 2-iodoethoxy. Lower alkenyloxy is e.g. B. vinyloxy

Lower alkylidene e.g. B. isopropylidene or isobutylidene or allyloxy, lower alkylenedioxy z. B. methylenedioxy, ethyl

can. lendioxy or isopropylidendioxy, cycloalkoxy, e.g. B. Cyclopen-

Lower alkylene is e.g. B. 1,2-ethylene, 1,2- or 1,3-propylene, 55 tyloxy, cyclohexyloxy or adamantyloxy, phenyl-niederal-

1,4-butylene, 1,5-pentylene or 1,6-hexylene, while lower alkoxy, e.g. B. benzyloxy, 1- or 2-phenylethoxy, diphenylme-kenylene z. B. 1,2-ethylene or 2-butene-1,4-ylene. Lower alkylene interrupted by thoxy or 4,4'-dimethoxy-diphenylmethoxy, or heterocyte heteroatoms is e.g. B. oxane lower clyloxy or heterocyclyl lower alkoxy, e.g. B. pyridyl-lower alkoxy, alkylene, such as 3-oxa-l, 5-pentylene, thi-lower alkylene, such as 3-thia-like 2-pyridylmethoxy, furyl-lower alkoxy, such as furfuryloxy,

1,5-pentylene, or azane-lower alkylene, such as 3-lower alkyl-3-aza-eu or thienyl-lower alkoxy, such as 2-thenyloxy.

1,5-pentylene, e.g. B. 3-methyl-3-aza-1,5-pentylene. Lower alkylthio is e.g. B. methylthio, ethylthio or n-butyl

Cycloalkyl is e.g. B. cyclopropyl, cyclobutyl, cyclopentyl, thio, lower alkenylthio z. B. allylthio, and phenyl-lower alkyl

Cyclohexyl or cycloheptyl, as well as adamantyl, cycloalkenyl thio z. B. Benzylthio, while by heterocyclyl or z. B. cyclopropenyl, 1-, 2- or 3-cyclopentyl, 1-, 2- or heterocyclylaliphatic radicals etherified mercapto groups 3-cyclohexenyl, 3-cycloheptenyl or 1,4-cyclohexadienyl, and e: in particular pyridylthio, e.g. B. 4-pyridylthio, imidazolylthio,

Cycloalkylidene e.g. B. cyclopentylidene or cyclohexylidene. Thiazolylthio, e.g. B. 2-thiazolylthio, 1,2,4- or 1,3,4-thiadiazolyl

Cycloalkyl-lower alkyl or lower alkenyl is e.g. B. cycloprotio, e.g. B. 1,2,4-thiadiazol-3-ylthio or 1,3,4-thiadiazol-2-ylthio,

pyl-, cyclopentyl-, cyclohexyl- or cycloheptylmethyl, -1,1- or tetrazolylthio, e.g. B. are l-methyl-5-tetrazolylthio.

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Esterified hydroxy groups are primarily halogen, e.g. B. fluorine, chlorine, bromine or iodine, and lower alkoxycarbonyl-oxy, z. B. methoxcycarbonyloxy, ethoxycarbonyloxy or tert-butyloxycarbonyloxy, 2-halo lower alkoxycarbonyloxy, e.g. B. 2,2,2-trichloroethoxycarbonyloxy, 2-bromoethoxycarbonyloxy or 2-iodoethoxycarbonyloxy, or arylcarbonylmethoxoxycarbonyloxy, e.g. B. Phenacyloxycarbonyloxy.

Lower alkoxycarbonyl is e.g. B. methoxycarbonyl, ethoxy-carbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl or tert-pentyloxycarbonyl.

N-lower alkyl or N, N-di-lower alkyl carbamoyl is e.g. B. N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl or N, N-diethylcarbamoyl, while N-lower alkylsul-famoyl z. B. N-methylsulfamoyl or N, N-dimethylsulfamoyl

A carboxyl or sulfo present in alkali metal salt form is e.g. B. a present in sodium or potassium salt form carboxyl or sulfo.

Niederalkylamino- or Diniederalkylamino is e.g. B. methyl-amino, ethylamino, dimethylamino or diethylamino, Niederalkylenamino z. As pyrrolidino or piperidino, oxa-lower alkylene amino z. B. Morpholino.Thianiederalkylenamino z. B. Thiomorpholino, and Azaniederalkylenamino z. B. Piperazino or 4-methylpiperazino. Acylamino stands in particular for carbamoylamino, lower alkylcarbamoylamino, such as methylcarbamoylamino, ureidocarbonylamino, guanidinocarbonylamino, lower alkoxycarbonylamino, e.g. Example, methoxycarbonyl-amino, ethoxycarbonylamino or tert-butyloxycarbonylamino, halogen-lower alkoxycarbonylamino, such as 2,2,2-trichloro-ethoxycarbonylamino, phenyl-lower alkoxycarbonylamino, such as 4-methoxybenzyloxycarbonylamino, lower alkanoylamino, such as acetylamino, or optionally for phthalylamino, or optionally for phthalylamino or propionylamino, or for phionylamino -, such as alkali metal, e.g. B. sodium or ammonium salt form, present sulfoamino.

Niederalkanoyl is e.g. B. formyl, acetyl, propionyl or pivaloyl.

O-lower alkyl phosphono is e.g. B. O-methyl or O-ethyl-phosphono, O.O'-di-lower alkyl-phosphono, e.g. B. 0.0-dimethyl-phosphono or 0.0'-diethylphosphono, O-phenyl-lower alkyl-phosphono, e.g. B. O-benzyl-phosphono, and O-lower alkyl-O'-phenyl-lower alkyl-phosphono, e.g. B. O-Benzyl-O'-methyl-phos-phono.

Lower alkenyloxycarbonyl is e.g. Vinyloxycarbonyl, while cycloalkoxycarbonyl and phenyl-lower alkoxycarbonyl, e.g. B. adamantyloxycarbonyl, benzyloxycarbonyl, 4-methoxy-benzyloxycarbonyl, diphenylmethoxycarbonyl or a-4-biphenyl-a-methyl-ethoxycarbonyl. Niederalkoxycarbonyl, wherein Niederalkyl z. B. contains a monocyclic, monoaza, monooxa or monothiacyclic group, z. B. furyl-lower alkoxycarbonyl, such as furfuryloxycarbonyl, or thienyl-lower alkoxycarbonyl, such as 2-thenyloxycarbonyl.

2-Lower alkyl and 2,2-di-lower alkylhydrazino is e.g. B. 2-methylhydrazino or 2,2-dimethylhydrazino, 2-lower alkoxyoxycarbonylhydrazino z. B. 2-methoxycarbonylhydrazino, 2-ethoxycarbonylhydrazino or 2-tert-butyloxycarbonylhydrazino, and lower alkanoylhydrazino z. B. 2-Acetylhydrazino.

An acyl group Ac stands in particular for a N-acyl derivative of a 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem-4 which is preferably naturally pharmacologically active and which can be prepared in a naturally occurring or in a bio-, semi-synthetic or totally synthetic way carboxylic acid-containing acyl radical of an organic carboxylic acid, preferably having up to 18 carbon atoms, or an easily removable acyl radical, in particular a carbonic acid derivative.

An acyl radical Ac contained in a pharmacologically active N-acyl derivative of a 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem-4-carboxylic acid compound is primarily a group of the formula

R * (C) n C (A),

R111

wherein n is 0 and R1 is hydrogen or an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably aromatic in character, a functionally modified, e.g. B. esterified or etherified hydroxy or mercapto or an optionally substituted amino group, or wherein n is 1, R1 is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocy- cisch-aliphatic radical, in which the heterocyclic radical preferably has an aromatic character and / or a quaternary nitrogen atom, an optionally functionally modified, preferably etherified or esterified hydroxy or mercapto group, an optionally functionally modified carboxyl group, an acyl group, an optionally substituted amino group or an azido group represents, and each of the radicals R11 and R111 is hydrogen, or wherein n is 1, R1 is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aroma table or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical preferably has an aromatic character, R "is an optionally functionally modified, for. B. esterified or etherified hydroxy or mercapto group, such as a halogen atom, an optionally substituted amino group, an optionally functionally modified carboxyl or sulfo group, an optionally 0-mono- or 0.0'-disubstituted phosphono group, or an azido group, and Rm represents hydrogen, or in which n represents 1, each of the radicals R1 and Rn represents a functionally modified, preferably etherified or esterified, hydroxyl group or an optionally functionally modified carboxyl group, and Rm represents hydrogen, or in which n represents 1, R1 is hydrogen or a optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and Rn and Rm together represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic ko bonded to the carbon atom by a double bond represent hydrogen radical, or in which n is 1, and R1 is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which heterocyclic radicals preferably have an aromatic character, RI! an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and Rm is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical.

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In the abovementioned acyl groups of the formula A are, for. B. halogen, e.g. B. chlorine, substituted phenyl, furyl, e.g. B. 2-furyl, n for 0 and R1 for hydrogen or an optionally, pre-thienyl, e.g. B. 2- or 3-thienyl, or isothiazolyl, e.g. B. 4-Isothia-preferably in the 1-position by optionally protected zolyl group, further for a 1,4-cyclohexadienyl group, R11 for

Amino, acylamino, wherein acyl is primarily protected or substituted amino, e.g. B. a carbonic acid semi-ester, such as a lower alkoxycarbonyl, 5 amino, acylamino, such as lower alkoxycarbonylamino, 2-halo-2-halo-lower alkoxycarbonyl- or phenyl-lower alkoxycar- genenniederalkoxycarbonylamino or optionally substituted-bonylrest, or one, optionally in salt, z. B. alkali, such as lower alkoxy, for. B. methoxy, or nitro-containing metal salt form present sulfoamino group, substituted phenyl lower alkoxycarbonylamino, e.g. B. tert-butyloxycar-cycloalkyl group with 5-7 ring carbon atoms, a counter-bonylamino, 2,2,2-trichloroethoxycarbonylamino, 4-methoxy optionally, preferably by hydroxy, lower alkoxy, for. B. io benzyloxycarbonylamino or diphenylmethyloxycarbonyl-methoxy, acyloxy, wherein acyl is primarily for the acyl radical amino, arylsulfonylamino, e.g. B. 4-methylphenylsulfonylamino, a carbonic acid semi-ester such as a lower alkoxycarbonyl, tritylamino, arylthioamino such as nitrophenylthioamino, e.g. B. 2-halo-lower alkoxycarbonyl or phenyl-lower alkoxycar- 2-nitrophenylthioamino, or tritylthioamino or gegebe-bonylrest, and / or halogen, for. B. chlorine, substituted or unsubstituted, such as lower alkoxycarbonyl, z. B. ethoxy

Phenyl, naphthyl or tetrahydronaphthyl group, a counter carbonyl, or lower alkanoyl, e.g. B. acetyl containing 2-Proenbenfalls, z. B. by lower alkyl, e.g. As methyl, and / or Phe- pylidenamino, such as l-Äthoxycarbonyl-2-propylidenamino, or nyl, which in turn substituents, such as halogen, for. B. chlorine, optionally substituted carbamoylamino, such as guanidino gene, substituted heterocyclic group, such as a 4-isocarbonylamino, or one, optionally in salt, for. B. alkali xazolyl group, or a preferably, for. B. by a metal salt form present sulfoamino group, an azido-likewise substituted, such as halogen, z. B. chlorine containing 20, optionally in salt, z. B. alkali metal salt form lower alkyl radical N-substituted amino group, or n for 1, R1 or in protected, such as esterified form, for. B. as a lower alkoxy for an optionally, preferably by halogen, such as xycarbonyl, z. B. methoxycarbonyl or ethoxycarbonyl,

Chlorine, optionally substituted, such as hydroxy, acyl or as phenyloxycarbonyl, e.g. B. Diphenylmethoxycarbonyl-oxy, wherein acyl has the meaning given above, and / or group present carboxyl group, a cyano group, a halogen, for. B. chlorine, containing phenyloxy, or by against sulfo group, an optionally functionally modified optionally protected amino and / or carboxy substituted hydroxy group, with functionally modified hydroxy ins-lower alkyl group, e.g. B. for a 3-amino-3-carboxy-propyl- special acyloxy, such as formyloxy, and lower alkoxycarbo radical with optionally protected amino and / or carboxy-nyloxy, 2-halogeno lower alkoxycarbonyloxy or given group, for. b. silylated, such as tri-lower alkylsilylated, e.g. B. tri- if substituted, such as lower alkoxy, z. B. methoxy, or nitro silylated, amino or acylamino, such as Niederalkanoyl- 30 containing phenyl-lower alkoxycarbonyloxy, e.g. B. tert-butylamino, Halo'genniederalkanoylamino- or Phthaloylamino- oxycarbonyloxy, 2,2,2-Trichloräthoxycarbonyloxy, 4-methoxy group, and / or silylated, such as triiederalkylsilylierter, z. B. benzyloxycarbonyloxy or diphenylmethoxycarbonyloxy, trimethylsilylated, or esterified, such as by lower alkyl, or optionally substituted lower alkoxy, e.g. B. methoxy, 2-halo-lower alkyl or phenyl-lower alkyl, e.g. B. represents diphenyl or phenyloxy, an O-lower alkyl or 0.0 '-dinieder-methyl, esterified carboxy group, for a lower alkenyl 35-alkyl-phosphono group, e.g. B. O-methyl-phosphono or 0.0'-group, for an optionally substituted, such as given- dimethylphosphono, or a halogen atom, e.g. B. chlorine or if, e.g. B. as indicated above, acylated hydroxy and / or bromine, and Rm for hydrogen, or n for 1, R1 and R11 each for halogen, for. B. chlorine, further optionally protected, z. B. halogen, e.g. B. bromine, or lower alkoxycarbonyl, e.g. B. metho-as indicated above, acylated amino-lower alkyl, such as amino-xycarbonyl, and R "1 for hydrogen, or n for 1, R1 for a methyl, or optionally, for example as indicated above, acylated- 40 optionally, for example a phenyl group which optionally contains, for example, phenylene group containing, for example, hydroxy and / or halogen, for example chlorine, acylated hydroxy and / or halogen, for example chlorine, substi-nyloxy , e.g. tuned phenyl, furyl, e.g. 2-furyl, or thienyl, e.g. 2- or by lower alkyl, such as methyl, or optionally protected 3-thienyl, or isothiazolyl, e.g. 4-isothiazolyl group, further tes, for example acylated, amino or amino for a 1,4-cyclohexadienyl group, Rn for optionally, e.g. methyl, substituted pyridyl, e.g. 4-pyridyl -, pyridinium, e.g. 45 as stated above, protected aminomethyl, and RIn for 4-pyridinium, thienyl, e.g. 2-thienyl, furyl, e.g. 2-furyl, imida hydrogen, or n for 1 and each of R1, R "and R111 for zolyl, e.g. B. 1-imidazolyl, or tetrazolyl, e.g. B. 1-tetrazolyl lower alkyl, e.g. B. are methyl.

group, an optionally substituted lower alkoxy, e.g. B. Such acyl radicals Ac are e.g. B. formyl, cyclopentylcarbo-

Methoxy group, an optionally substituted such as gegebe- nyl, a-aminocyclopentylcarbonyl or a-amino-cyclohexylcar-if protected, z. B. as stated above, acylated, 5c bonyl (with optionally substituted amino group, for example hydroxyl and / or halogen, such as chlorine, containing phenyloxy, optionally in salt form sulfoamino group, a lower alkylthio, for example n-butylthio , or Niederal or one, by one, preferably slightly, e.g. in the case of the Behan-kenylthio, e.g. Allylthio group, one optionally, e.g. by your with an acidic agent such as trifluoroacetic acid, reductive, lower alkyl, such as methyl, substituted phenylthio-, pyridylthio-, e.g. when treated with a chemical reducing agent, e.g. 4-0pyridylthio-, 2-imidazolylthio-, l, 2,4-triazol-3-ylthio-, 55 as Zinc in the presence of aqueous acetic acid, or catalyti-l, 3,4-triazol-2-ylthio-, l, 2,4-thiadiazol-3-ylthio-, such as 5-methyl-hydrogen, or hydrolytically removable or one, 1,2,4-thidiazol-3-ylthio-, 1,3,4-thiadiazol-2-ylthio-, such as methyl, can be converted into such an acyl radical, preferably a 1,3,4-thiad iazol-2-ylthio, or 5-tetrazolylthio, such as l-methyl-5 suitable acyl radical of a carbonic acid half-ester, such as Niederal-tetrazolylthio group, a halogen, in particular chloro or koxycarbonyl, for. B. tert-butyloxycarbonyl, 2-halogen-Niederal bromine, an optionally functionally modified Car 60 kylcarbonyl, z. B. 2,2,2-trichloroethyloxycarbonyl, 2-bromoetho-boxyl group, such as lower alkoxycarbonyl, e.g. B. methoxycarbo- xycarbonyl or 2-iodoethoxycarbonyl, arylcarbonylmethoxy-nyl- or ethoxycarbonyl, cyano or optionally, for. B. carbonyl, e.g. B. phenacyloxycarbonyl, optionally substituted

by lower alkyl, such as methyl, or phenyl, N-substituted ated, such as lower alkoxy, e.g. B. methoxy, or nitro-contain carbamoyl, an optionally substituted lower alkanoyl, the phenyl lower alkoxycarbonyl, e.g. B. 4-methoxybenzyloxycar-z. B. acetyl or propionyl, or benzoyl group, or a 65 bonyl or diphenylmethoxycarbonyl, or a carbonic acid azido group, and R! I and Rm for hydrogen, or n for 1, R1 rehalbamids, such as carbamoyl or N-substituted, such as for Lower alkyl or an optionally as given by N-lower alkyl, e.g. B. N-methylcarbamoyl, and by trityl, if necessary, for. B. as indicated above, acylated hydroxy and / or further by arylthio, e.g. B. 2-nitrophenylthio, arylsulfonyl, e.g. B.

624 683 8

4-methylphenylsulfonyl or l-lower alkoxycarbonyl-2-propy-lower alkoxycarbonyl group or one through arylcarbonyl,

liden, e.g. B. 1-ethoxycarbonyl-2-propylidene, substituted ami- especially benzoyl radicals substituted methoxycarbonyl-

nogruppe), 2,6-dimethoxybenzoyl, 5,6,7,8-tetrahydro-naph- group, or thoyl, 2-methoxy-l-naphthoyl, 2-athoxy-l-naphthoyI, benzylo substituted in the β-position by halogen atoms - Lower alkoxycarbonyl radical, e.g. B. tert-butyloxycarbonyl, tert.-

xycarbonyl, hexahydrobenzyloxycarbonyl, 5-methyl-3-phenyl- 5 pentyloxycarbonyl, phenacyloxycarbonyl, 2,2,2-trichloroetho-

4-isoxazolyIcarbonyI, 3- (2-chlorophenyl> 5-methyl-4-isoxazolyl-xycarbonyl or 2-iodoethoxycarbonyl or a carbonyl-, 3- (2,6-dichlorophenyl> 5-methyl-4-isoxazolylcarbonyl-, convertible in the latter Radical, such as 2-chloro or 2-bromoethoxycarbonyl,

2-chloroethylaminocarbonyl, acetyl, propionyl, butyryl, piva- further, preferably polycyclic, cycloalkoxycarbonyl, e.g. B. loyl, hexanoyl, octanoyl, acrylyl, crotonoyl, 3-butenoyl, 2-pen adamantyloxycarbonyl, optionally substituted phenyl-tenoyl, methoxyacetyl, butylthioacetyl, allylthioacetyl, Met-> o lower alkoxycarbonyl, primarily a-phenylhylthacetacyl, , Bromoacetyl, dibromoacetyl, 3-chloro-bonyl, wherein the a-position is preferably multiply substituted propionyl, 3-bromopropionyl, aminoacetyl or 5-amino-5-car-, e.g. B. diphenylmethoxycarbonyl or <x-4-biphenylyl-a-me-boxy-valeryl (with optionally, for example as indicated, such as thyl-ethoxycarbonyl, or furyl-lower alkoxycarbonyl, first of all by a monoacyl or diacyl radical, for example a given line a-furyl-lower alkoxycarbonyl, for example furfuryloxycarbonyl, if halogenated lower alkanoyl radical, such as acetyl or diehlo-15. the acyl radical of a lower alkane or optionally functionally modified, for example in hydrochloric acid, such as lower alkenedicarboxylic acid, such as succinyl, or an o-arylene sodium salt acid, or in ester, such as lower alkyl, for example methyl or dicarboxylic acid like phthaloyl.

Ethyl, or aryl-lower alkyl, e.g. B. Diphenylmethylterform, Another, formed by the groups RiA and Rib present carboxyl group), azidoacetyl, carboxyacetyl, 20 bivalent radical z. B. a, especially in the 2-position,

Methoxycarbonylacetyl, Äthoxycarbonylacetyl, bis-methoxy- ierter, z. B. optionally substituted phenyl or thienyl carbonylacetyl, N-phenylcarbamoylacetyl, cyanoacetyl, a-cyano-containing, and in the 4-position optionally by Niederal-

propionyl, 2-cyano-3,3-dimethyl-acrylyl, phenylacetyl, a-bromo-alkyl, such as methyl, mono- or disubstituted l-oxo-3-aza-l, 4-

phenylacetyl, a-azidophenylacetyl, 3-chlorophenylacetyl, 2-butylene radical, e.g. B. 4,4-Dimethyl-2-phenyl-l-oxo-3-aza-l, 4-butylene.

or 4-aminomethylphenyl acetyl (with optionally, for example as 25 An etherified hydroxyl group Rîa forms together with the specified substituted amino group), phenacylcarbonyl, the carbonyl grouping a, preferably easily cleavable

Phenyloxyacetyl, 4-trifluoromethylphenyloxyacetyl, benzylo- or slightly different carboxyl-

xyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenylo group, such as in a carbamoyl or hydrazinocarbonyl

xypropionyl, a-phenyloxyphenylacetyl, a-methoxyphenylace group convertible, esterified carboxyl group. Such a tyl, a-ethoxy-phenylacetyl, a-methoxy-3,4-dichlorophenylacetyl, 30 group Rîa is e.g. B. lower alkoxy, such as methoxy, ethoxy, n-pro

a-cyanophenylacetyl, especially phenylglycyl, 4-hydroxypyloxy or isopropyloxy, which together with the carbonyl

phenylglycyl, 3-chloro-4-hydroxy-phenylglycyl, 3,5-dichloro-4 grouping an esterified carboxyl group, which in particular

hydroxy-phenylglycyl, a-amino-a- (1,4-cyclohexadienyl) -acetyl, especially in 2-cephem compound, easily into a free carboxyl

a-amino-a- (1 -cyclohexenyl) -acetyl, a-amino-methyl-a-phenyla- group or in another functionally modified carboxyl-

cetyl or a-hydroxyphenylacetyl, in which a group can be converted into these residues.

amino group present, if necessary, for. An etherified hydroxyl group RzA, which can be substituted together with give and / or an existing, aliphatic or a -C (= 0) grouping a particularly easily cleavable

forms table and / or phenolically bound hydroxy group esterified carboxyl group, z. B. for 2-halogen low

likewise, analogously to the amino group, e.g. B. by a suitable alkoxy, in which halogen preferably has an atomic weight of ten acyl radical, in particular by formyl or an acyl radical 40 through 19. Such a radical forms together with the -C (= 0) -

a carbonic acid semi-ester), or grouping one, when treated with chemical reducing agents

a-O-methyl-phosphono-phenylacetyl or a-0,0-dimethylphosphating agents under neutral or weakly acidic conditions,

sphono-phenylacetyl, also benzylthioacetyl, benzylthiopro-. B. with zinc in the presence of aqueous acetic acid, slightly pionyl, a-carboxyphenylacetyl (with optionally, for example, such as cleavable esterified carboxyl group or a functionally modified carbocy group given in such above), 45 easily convertible esterified carboxyl group and is z . B.

3-phenylpropionyl, 3- (3-cyanophenyl) propionyl, 4- (3-methoxy-2,2,2-trichloroethoxy or 2-iodoethoxy, furthermore 2-chloroethoxy phenyl> butyryl, 2-pyridylacetyl, 4-aminopyridiniumacetyl or 2-bromoethoxy, which can easily be converted into the latter (optionally substituted with, for example, as indicated above, an etherified hydroxy group R2A, which together with the amino group), 2-thienylacetyl, 3-thienylacetyl, 2-tetrahydro- -C (= 0> grouping see also reducing agents under treatment with chemi-thienylacetyl, 2-furylacetyl, 1-imidazolylacetyl, 1-tetrazolyla- 50 neutral or weakly acidic cetyl, a-carboxy-2-thienylacetyl or a-carboxy -3-thienylacetyl conditions, e.g. when treating with zinc in the presence of (optionally with functional, e.g. as stated above, aqueous acetic acid, furthermore when treating with a suitably converted carboxyl group), a-cyano- 2-thienylacetyl, a-amino neten nucleophilic reagent, eg sodium thiophenolate, slightly a- (2-thienyl) -ac ethyl, a-amino- <x- (2-furyl) acetyl or cleavable esterified carboxyl group is an arylcar-a-amino-a- (4-isothiazolyl) acetyl (optionally with, e.g. B. 55 bonylmethoxy group, in which aryl is in particular for an opposite, substituted amino group), a-sulfophenyla- also substituted phenyl group, and preferably cetyl (optionally with, for example, like the carboxyl group, functional phenacyloxy.

nell modified sulfo group), 3-methyl-2-imidazolylthioa- The Rîa group can also be an arylmethoxy group cetyl, 1,2,4-triazol-3-ylthioacetyl, 1,3,4-triazol-2-yl-thioacetyl , where aryl is in particular a monocyclic, pre-

5-methyl-l, 2,4-thiadiazol-3-ylthioacetyI, 5-methyl-l, 3,4-thiadia- t.o optionally substituted aromatic hydrocarbon radical zol-2-ylthioacetyl or l-methyl-5-tetrazolylthioacetyl. means. Such a residue together with the -C (= 0) -

An easily removable acyl residue Ac, in particular a grouping one when irradiated, preferably with ultraviolet

Carbonic acid semi-ester, is primarily a by reduction, latent light, under neutral or acidic conditions easily z. B. when treated with a chemical reducing agent, cleavable, esterified carboxyl group. An aryl residue in such a

or by acid treatment, e.g. B. with trifluoroacetic acid, m chen arylmethoxy group is in particular Niederalkoxyphe-

cleavable acyl radical of a half ester of carbonic acid, such as nyl, e.g. B. Methoxyphenyl (where methoxy is primarily in 3-, 4-

one, preferably on the carbon atom in the a-position to the oxy- and / or 5-position), and / or especially the nitrophenyl group which is multiply branched and / or aromatically substituted (nitro preferably being in the 2-position). Such leftovers

9 624683

are particularly lower alkoxy, e.g. B. methoxy, and / or nitro-a-amino-lower alkanoyloxymethoxy, e.g. B. Glycyloxymet

berzyloxy, primarily 3- or 4-methoxybenzoyloxy, hoxy, L-valyloxymethoxy L-leucyloxymethoxy, furthermore phthalic

3,5-dimethoxybenzyloxy, 2-nitrobenzyloxy or 4,5-dimethyloxy.

hoxy-2-nitro-benzyloxy. A silyloxy or stannyloxy group Rîa contains

An etherified hydroxyl group RzA can also be a residue, preferably optionally substituted aliphatic

represent, together with the -C (= 0) grouping a see, cycloaliphatic, aromatic or araliphatic carbon

under acidic conditions, e.g. B. when treating with trifluorosulfide residues, such as lower alkyl, halogen-lower alkyl,

acetic acid or formic acid, easily cleavable, esterified carbocycloalkyl, phenyl or phenyl-lower alkyl groups, or against xyl group. Such a residue is first and foremost a modified functional group, such as etherified xy group, in which methyl is substituted by optionally substituted'-hydroxy, e.g. B. lower alkyloxy groups, or halogen, z. B.

ated hydrocarbon radicals, in particular aliphatic or chlorine atoms, and primarily tri-lower alkylsilyloxy,

aromatic hydrocarbon radicals, such as lower alkyl, e.g. B. for example trimethylsilyloxy, halogen-lower alkoxy-lower alkylsilyl, methyl and / or phenyl, polysubstituted or by one, for example chloro-methoxy-methyl-silyl, or tri-lower alkylstannyloxy,

Tron-donating, substituent-containing carbocyclic, for example tri-n-butylstannyloxy.

Aryl group or one, oxygen or sulfur as ring member 15 A, together with a —C (= 0) grouping a heterocyclic group of aromatic character which may have a substituted carbamoyl or hydrazinocabonyl

is monosubstituted, or then in a polycycloaliphatic group-forming radical R2A z. B. amino, lower alkylamino see hydrocarbon residue a ring member or in an oxa- or di-lower alkylamino, such as methylamino, ethylamino,

or thiacycloaliphatic radical which has the a position to the acid dimethylamino or diethylamino, lower alkylene amino, e.g. B.

Ring member representing material or sulfur atom. 20 pyrrolidino or piperidino, oxane lower alkylene amino, e.g. Mor-

Preferred polysubstituted methoxy groups of this type pholino, hydroxyamino, hydrazino, 2-lower alkylhydrazino are tert-lower alkoxy, e.g. B. tert-butyloxy or tert-pentyl or 2,2-di-lower alkylhydrazino, e.g. B. 2-methylhydrazino or loxy, optionally substituted diphenylmethoxy, e.g. 2,2-dimethylhydrazino.

Diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, fer salts are especially those of compounds of the ner 2- (4-biphenyl) -2-propyloxy, while one of the above-mentioned formula I or their isomers or 1-oxides, with a acid substituted aryl group or the heterocyclic group de-grouping, such as a carboxy, sulfo or phosphono

holding methoxy group z. B. a-Niederalkoxy-phenylniederal- group, primarily metal or ammonium salt, such as alkali

koxy, such as 4-methoxybenzyloxy or 3,4-dimethoxybenzyloxy, metal and alkaline earth metal, e.g. B. sodium, potassium, magnesium

or furfuryloxy, such as 2-furfuryloxy. A polycycloaliphatic or calcium salts, as well as ammonium salts with ammonium

shear hydrocarbon radical in which methyl methoxy-30 niac or suitable organic amines, in the first group a, preferably triple, branched ring member, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic

is z. B. adamantyl, such as 1-adamantyl, and an obgenann- see and araliphatic primary, secondary or tertiary ter oxa- or thiacycloaliphatic radical, wherein methyl of the mono-, di- or polyamines, and heterocyclic bases for

Methoxy group that may be in the a-position for oxygen or salt formation, such as lower alkylamines, e.g.

Ring member representing sulfur atom means e.g. 2-oxa-35 triethylamine, hydroxy-lower alkylamines, e.g. 2-hydroxyethyl

or 2-thiane lower alkylene or lower alkenylene with 5-7 ring amine, bis (2-hydroxyethyl) amine or tris- (2-hydroxyethyl) -

atoms such as 2-tetrahydrofuryl, 2-tetrahydropyranyl or amine, basic aliphatic esters of carboxylic acids, e.g.

2,3-dihydro-2-pyranyl or corresponding sulfur analogs. 4-aminobenzoic acid-2-diethylamino-ethyl ester, lower alkylene-The rest of R2A can also contain an etherified hydroxy group amines, e.g. B. 1-ethyl piperidine, cycloalkylamines, e.g. B. Bicyclohe-

represent, together with the -C (= 0> grouping a 40 xylamine, or benzylamines, e.g. N, N'-dibenzylethylenediamine,

hydrolytic, e.g. B. under weakly basic or acidic conditions, also bases of the pyridine type, e.g. Pyridine, collidine or chino

formable, cleavable esterified carboxyl group. A sol line, compounds of formulas 1 and 2-cephem compounds,

rather the rest is preferably one with the -C (= 0) grouping which have a basic group, can also acid ad-

etherified hydroxy-addition salts forming an activated ester group, e.g. B. with inorganic acids, such as hydrochloric acid,

group such as nitrophenyloxy, e.g. B. 4-nitrophenyloxy or 45 sulfuric acid or phosphoric acid, or with suitable organic

2,4-dinitrophenyloxy, nitrophenyl-lower alkoxy, e.g. B. 4-nitronic carbonic or sulfonic acids, for. B. trifluoroacetic acid benzyloxy, hydroxy-lower alkyl-benzyloxy, e.g. B. form 4-hydroxy or p-toluenesulfonic acid. Compounds of the formulas 1

3,5-tert-butyl-benzyloxy, polyhalophenyloxy, e.g. B. 2,4,6- with an acidic and a basic group can also in trichlorophenyloxy or 2,3,4,5,6-pentachlorophenyloxy, further form of internal salts, i.e. H. in zwitterionic form, vorlie-cyanomethoxy, and acylaminomethoxy, z. B. Phthaliminomet- so gen. 1-Oxides of compounds of formula 1 with salt-forming hoxy or succinyliminomethoxy. Groups can also form salts as described above.

The group R2A can also have one, together with the carbo-. The compounds of the present invention can be used as nyl grouping of the formula -C (= 0) - an esterified carboxyl group which is cleavable under hydrogenolytic intermediates for the preparation of compounds with excellent conditions becoming etherified hydroxy group, and is z. B. against.

if necessary, e.g. substituted by lower alkoxy or nitro The invention particularly relates to the preparation of a-phenyl-lower alkoxy, such as benzyloxy, 4-methoxybenzyloxy 3-cephem compounds of the formula I, in which RiA is hydrogen or 4-nitrobenzyloxy. or preferably one in a fermentative (i.e. natural

The group R2A can also produce one which occurs together with the carbo-) or is bio-, semi-synthetic or totally synthetic.

nyl grouping -C (= 0) - an etherified N-acyl derivative of a 6β-amino-penam-3-carboxylic acid or which forms under physiological conditions, in particular pharmacologically active, such as highly active gene-cleavable esterified carboxyl group

Hydroxy group, primarily an acyloxymethoxy-7ß-amino-3-cephem-4-carboxylic acid compound group, wherein acyl z. B. the rest of an organic carbon acyl radical, such as one of the abovementioned acyl radicals of the formula A.

acid, primarily an optionally substituted one, in which R1, R11, R111 and n are primarily the

Lower alkane carboxylic acid, or in which acyloxymethyl have 65 preferred meanings, Rib represents hydrogen,

forms the rest of a lactone. Hydroxy groups etherified in this way or in which Ria and Rib together have a preferred 2-position

are lower alkanoyloxymethoxy, e.g. B. acetyloxymethyloxy, e.g. B. by an aromatic or heterocyclic or pivaloxymethoxy, amino-lower alkanoyloxymethoxy, the rest, such as phenyl, and in the 4-position preferably, for. B. by special two lower alkyl, such as methyl, substituted l-oxo-3-aza-l, 4-

624683 10

represent butylene radical, and Rîa for optionally, preferentially ocjer hydroxy groups substituted acetyl, in particular Phe-

wise in a position z. B. by optionally substituted nylglycyl, wherein phenyl optionally, e.g. B. by given

Aryloxy, such as lower alkoxyphenyloxy, e.g. B. 4-methoxypheny- if protected hydroxy, such as acyloxy, e.g. B. if necessary

Ioxy, lower alkanoyloxy, e.g. B. acetyloxy or pivaloyloxy, halogen-substituted lower alkoxycarbonyloxy or lower

a-amino lower alkanoyloxy, e.g. B. glycyloxy, L-valyloxy or 5 alkanoyloxy, and / or by halogen, e.g. B. chlorine, substituted

L-leucyloxy, arylcarbonyl, e.g. B. benzoyl, or optionally phenyl, e.g. B. phenyl, or 3- or 4-hydroxy, 3-chloro-4-hydroxy

substituted aryl such as phenyl, lower alkoxyphenyl, e.g. B. 4-Me or 3,5-dichloro-4-hydroxy-phenyl (optionally also with thoxyphenyl, nitrophenyl, e.g. 4-nitrophenyl, or biphenylyl, protected, such as acylated hydroxy group), and z. B. 4-biphenylyl, or in the β position by halogen, for. B. chlorine, in which the amino group may also be substituted

Bromine or iodine, mono- or polysubstituted lower alkoxy,) 0 can and z. B. an optionally present in salt form

such as lower alkoxy, e.g. B. methoxy, ethoxy, n-propyloxy, isoprofoamino group or an amino group, which as a substi-

pyloxy, n-butyloxy, tert-butyloxy or tert-pentyloxy, where appropriate, a hydrolytically removable trityl group or, if necessary, bisphenyloxy-me, which is substituted by lower alkoxy, primarily an acyl group, such as an optionally substituted

thoxy, e.g. B. bis-4-methoxyphenyloxy-methoxy, lower alkanoyl ated carbamoyl, such as an optionally substituted ureido

oxy-methoxy, e.g. B. acetyloxymethoxy or pivaloyloxyme- l5 carbonyl group, e.g. B. ureidocarbonyl or N'-trichloromethyl

thoxy, a-amino lower alkanoyloxy methoxy, e.g. B. Glycyloxyme- lureidocarbonyl, or an optionally substituted guani-

thoxy, phenacyloxy, optionally substituted phenyl lower dinocarbonyl group, e.g. B. guanidinocarbonyl, or one,

alkoxy, especially 1-phenyl-lower alkoxy, such as phenyl, preferably slightly z. B. when treated with an acidic agent,

thoxy, such residues 1 -3 optionally, e.g. B. by like trifluoroacetic acid, further reductive, as in the treatment with

Lower alkoxy such as methoxy, nitro or phenyl substituted 2o a chemical reducing agent such as zinc in the presence

May contain phenyl radicals, e.g. B. benzyloxy, 4-methoxy-ben- of aqueous acetic acid, or with catalytic hydrogen,

zyloxy, 2-biphenylyl-2-propyloxy, 4-nitro-benzyloxy, diphenyl- or hydrolytically removable or an acyl radical which can be converted into such a methoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy, preferably a suitable acyl radical

or 2-halogeno lower alkoxy, e.g. B. 2,2,2-trichloroethoxy, 2-chloro residue of a carbonic acid semi-ester, such as one of the above,

räthoxy, 2-bromoethoxy or 2-iodoethoxy, further for 2-phthali- 25 z. B. optionally halogen or benzoyl substituted dyloxy, for tri-lower alkylsilyloxy, e.g. B. trimethylsilyloxy, or lower alkyloxycarbonyl, e.g. B. tert-butyloxycarbonyl, 2,2,2-

for if necessary, e.g. B. by lower alkyl, such as methyl, or trichloroethyloxycarbonyl, 2-chloroethoxycarbonyl, 2-bromo

Hydroxy substituted amino or hydrazino, e.g. B. amino, ethoxycarbonyl, 2-iodoethoxycarbonyl, or phenacyloxycarbo-

Lower alkyl- or di-lower alkylamino, such as methylamino or nyl, optionally lower alkoxy- or nitro-substituted Phe-

Dimethylamino, hydrazino, 2-lower alkyl or 2,2-diniederal 30 nylniederalkoxycarbonyl, e.g. B. 4-methoxybenzyloxycarbonyl kylhydrazino, e.g. B. 2-methylhydrazino or 2,2-dimethylhydra or diphenylmethoxycarbonyl, or a carbonic acid

zino, or hydroxyamino, and the 1-oxides thereof, feramides, such as carbamoyl or N-methylcarbamoyl, furthermore the corresponding 3-oxocepham and 2-cephem compound with a nucleophilic reagent, such as hydrocyanic acid,

fertilize or salts of such compounds with salt-forming sulphurous acid or thioacetic acid amide, cleavable aryl

the groups. 35 thio or aryl-lower alkylthio, e.g. B. 2-nitrophenylthio or

First and foremost, a 3-cephem compound is the For-Tritylthio, a

mel I, as well as in a corresponding 2-oxocepham-connecting arylsulfonyl radical, e.g. B. 4-methylphenylsulfonyl, or one,

dung, further in a 1-oxide of a 3-cephem compound with an acidic agent such as formic acid or aqueous

Formula I, or in a salt of such a compound with salt-mineral acid, e.g. B. hydrochloric or phosphoric acid,

forming groups Ria for hydrogen or a 1-lower alkoxycarbonyl or 1-lower alkanoyl

tiv (i.e. naturally occurring) or biosynthetically prepared 2-propylidene residue, e.g. B. l-ethoxycarbonyl-2-propylidene,

N-acyl derivatives of 6ß-amino-penam-3-carboxylic acid- also a- (1,4-cyclohexadienyl) -glycyl, a- (l-cyclohexenyl) -gly-

or 7β-amino-3-cephem-4-carboxylic acid compounds containing cyl, a-thienylglycyl, such as a-2- or a-3-thienylglycyl, a-furylgly-

tenacyl radical, in particular of the formula A, in which R>, R ", R>" cyl, such as a-2-furylglycyl, a-isothiazolylglycyl, such as a-4-isothiazo-

and n primarily have the preferred meanings, such as 45 lylglycyl, in which radicals the amino group, e.g. B. as an optionally, for. B. by hydroxy, substituted Phe- for a phenylglycyl radical, substituted or nylacetyl or phenyloxyacetyl radical, furthermore a given - may be protected, further a-carboxy-phenylacetyl or a-car-

if, e.g. B. by Niederalkylthio, or Niederalkenylthio, and boxy-thienylacetyl, z. B. a-Carbonxy-2-thienylacetyl (given

optionally substituted, such as acylated amino and / or optionally with functionally modified, for. B. in salt such as sodium

functionally modified, such as esterified carboxyl, substituted salt form, or in ester, such as lower alkyl, z. B. methyl or lower alkanoyl or lower alkenoyl, z. B. ethyl, or phenyl-lower alkyl, e.g. B. diphenylmethyl ester form,

4-hydroxy-phenylacetyl, hexanoyl, octanoyl or n-butyl- present carboxyl group), a-sulfo-phenylacetyl (given

thioacetyl, and in particular 5-amino-5-carboxy-valeryl, in which case also with, for. B. as the carboxyl group, functionally the amino and / or the carboxyl groups, optionally modified sulfo group), a-phosphono, a-O-methylphos

are protected and z. B. present as acylamino or esterified carbo- i3 phono- or a-0,0'-dimethylphosphono-phenylacetyI, or xyl, phenylacetyl or phenyloxyacetyl, or one in a-hydroxy-phenylacetyl (optionally with functionally

highly effective N-acyl derivatives of 6ß-amino-penam-3-car-converted hydroxy group, especially with an acyloxy

bonic acid or 7β-amino-3-cephem-4-carboxylic acid compound group, in which acyl is a, preferably slightly z. B. the gene occurring acyl radical, in particular of formula A, treatment with an acidic agent such as trifluoroacetic acid,

wherein R1, R ', R "1 and n primarily have the preferred meaning or can be split off with a chemical reducing agent, such as zinc, such as formyl, 2-haloethylcarbamoyl, for example the presence of aqueous acetic acid, or one

2-Chloräthylcarbamoyl, Cyanacetyl, Phenylacetyl, Thienylace- such a convertible acyl radical, preferably a tyl, z. B. 2-thienylacetyl, or tetrazolylacetyl, e.g. B. 1-tetrazo-suitable acyl radical of a carbonic acid half-ester, such as a lylacetyl, but especially in the a-position by a cyclic, the above, z. B. optionally by halogen or Ben-

such as a cycloaliphatic, aromatic or heterocycli- M zoyl substituted lower alkoxycarbonyl radical, e.g. B. 2,2,2-tri-

, primarily monocyclic radical and by a radio chloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxy

tional group, primarily monocyclic radical and by carbonyl, 2-iodoethoxycarbonyl, tert-butyloxycarbonyl or a functional group, primarily amino, carboxy, sulfo phenacyloxycarbonyl, furthermore means formyl), and 1-amino-

11

624683

cyclohexylcarbonyl, aminomethylphenylacetyl, such as 2- or 4-aminomethylphenyIacetyl, or aminopyridiniumacetyl, e.g. B. 4-aminopyridiniumacetyI (optionally also with, for example as indicated above, substituted amino group), or pyridylthioacetyl, e.g. B. 4-pyridylthioacetyl, and rib for hydrogen, or Ria and rib together for one, preferably in the 2-position, optionally by protected hydroxy, such as acyloxy, e.g. B. optionally halogen-substituted lower alkoxycarbonyloxy or lower alkanoyloxy, and / or by halogen, e.g. B. chlorine, substituted phenyl, e.g. B. phenyl, or 3- or 4-hydroxy, 3-chloro-4-hydroxy or 3,5-dichloro-4-hydroxy-phenyl (optionally also with a protected, for example as indicated above, acyliçrter Hydroxy group) substituted l-oxo-3-aza-1,4-butylene radical, which in the 4-position optionally contains two lower alkyl, such as methyl, and Rîa represents lower alkoxy, in particular a-polybranched lower alkoxy, e.g. B. tert-butyloxy, also methoxy or ethoxy, 2-halogeno-lower alkoxy, e.g. B. 2,2,2-trichloroethoxy, 2-iodoethoxy or easily convertible into this 2-chloroethoxy or 2-bromoethoxy, phenacyloxy,

1-phenyl-lower alkoxy with 1-3, optionally substituted by lower alkoxy or nitro phenyl radicals, e.g. B. 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy, lower alkanoyloxy-methoxy, e.g. B. acetyloxymethoxy or pivaloyloxymethoxy, a-amino lower alkanoyloxymethoxy, e.g. B. glycyloxymethoxy,

2-phthalidyloxymethoxy, further tri-lower alkylsilyloxy, e.g. B. tri-methylsilyloxy.

The invention relates primarily to the production of

3-cephem compounds of the formula I, wherein Ria is hydrogen or an acyl group of the formula

R

(X)

m

GH

0

II

c

(B),

* b wherein Ra is phenyl or hydroxyphenyl, e.g. B. 3- or 4-hydroxy-phenyl, further hydroxy-chlorophenyl, z. B. 3-chloro-4-hydroxy-phenyl- or 3,5-dichloro-4-hydroxy-phenyl, wherein in such radicals hydroxy substituents by acyl radicals, such as optionally halogenated lower alkoxycarbonyl radicals, for. B. tert-butyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl, can be protected, and thienyl, z. B. 2- or 3-thienyl, further pyridyl, z. B. 4-pyridyl, aminopyridinium, e.g. B. 4-aminopyridinium,

Furyl, e.g. B. 2-furyl, isothiazolyl, e.g. B. 4-isothiazolyl, or tetra-zolyl, e.g. B. 1-tetrazolyl, or also 1,4-cyclohexadienyl or 1-cyclohexenyl, X represents oxygen or sulfur, m represents 0 or 1, and Rb represents hydrogen or, if m represents 0, amino, and also protected amino, such as acylamino, e.g. B. a-polybranched lower alkoxycarbonylamino, such as tert-butyl-oxycarbonylamino, or 2-halo-lower alkoxycarbonylamino, e.g. B. 2,2,2-trichloroethoxycarbonylamino, 2-iodoethoxycarbonylamino or 2-bromoethoxycarbonylamino, or optionally lower alkoxy- or nitro-substituted phenyl-lower-ralkoxycarbonylamino, e.g. B. 4-methoxybenzyloxycarbonyla-mino or diphenylmethoxycarbonylamino, or 3-guanylu-reido, also sulfoamino or tritylamino, and arylthioa-mino, e.g. B. 2-nitrophenylthioamino, arylsulfonylamino, e.g. B. 4-methylphenylsulfonylamino, or l-lower alkoxycarbonyl-2-propylidenamino, e.g. B. 1-Äthoxycar-bonyl-2-propylidenamino, carboxy or in salt, e.g. B. alkali metal, such as sodium salt form present carboxy, and protected carboxy, z. B. esterified carboxy, such as phenyl-lower alkoxycarbonyl, e.g. B. diphenylmethoxycarbonyl, sulfo or in salt, e.g. B. alkali metal, such as sodium salt form present sulfo, and protected sulfo, hydroxy, and protected hydroxy, such as acyloxy, e.g. B. a-polybranched lower alkoxycarbonyloxy, such as tert-butyloxycarbonyloxy, or 2-halogeno lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxy-5 carbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, furthermore formyloxy, or O-lower alkylphosphono or 0, 0'-di-lower alkylphosphono, e.g. B. O-methylphosphono or 0.0'-dimethylphosphono, or means a 5-amino-5-car-boxyvalerylrest, in which the amino and / or carboxy-lo groups can also be protected and z. B. as acylamino, e.g. B. Niederalkanoylamino, such as acetylamino, Halogenniederal-kanoylamino, such as dichloroacetylamino, benzoylamino or phthaloylamino, or as esterified carboxy, such as phenylniederalkoxycarbonyl, e.g. B. Diphenylmethoxycarbonyl, vorlie-i5 gene, where preferably m is 1 if Ra is phenyl, hydroxyphenyl, hydroxychlorophenyl or pyridyl, and m is 0 and Rb is different from hydrogen if Ra is phenyl, hydroxyphenyl, hydroxychlorophenyl, thienyl, Represents furyl, isothiazolyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, 20 means rib hydrogen, and Rîa primarily for lower alkoxy, especially a-polybranched lower alkoxy, e.g. B. tert-butyloxy, 2-halogeno-lower alkoxy, e.g. B. 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally, e.g. B. by lower alkoxy, e.g. B. methoxy, substituted diphenylme-25 thoxy, e.g. B. diphenylmethoxy or 4,4'-dimethoxydiphenylme-thoxy, further tri-lower alkylsilyloxy, e.g. B. trimethylsilyloxy, means, and the 1-oxides of such 3-cephem compounds of the formula I, and also the corresponding 3-oxoce-pham and 2-cephem compounds or salts, in particular 30 pharmaceutically usable, not -toxic salts of such compounds with salt-forming groups.

Primarily in 3-cephem compounds of the formula I, furthermore in corresponding 3-oxocepham and 2-cephem compounds, 1-oxides, and in salts, in particular in pharmaceutically usable, non-toxic salts of such compounds with salt-forming groups, such as in the salts Ria for hydrogen mentioned in the preceding section, for the acyl radical of the formula B, in which Ra is phenyl, and also hydroxyphenyl, e.g. B. 4-hydroxy-phenyl, thienyl, e.g. B. 2- or 3-thienyl, 40 4-isothiazolyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, X oxygen, m 0 or 1, and Rb is hydrogen or, if m represents 0, amino, and also protected amino, such as acylamino , e.g. B. a-polybranched lower alkoxycarbonylamino, such as tert-butyl-oxycarbonylamino, or 2-halo-lower alkoxycarbonyl-45 amino, e.g. B. 2,2,2-trichloroethoxycarbonylamino, 2-iodoethoxycarbonylamino or 2-bromoethoxycarbonylamino, or optionally lower alkoxy- or nitro-substituted phenyl-lower-ralkoxycarbonylamino, e.g. B. 4-methoxybenzyloxycarbonyla-mino, or hydroxy, and protected hydroxy, such as acyloxy, 5o z. B. a-polybranched lower alkoxycarbonyloxy, such as tert-butyloxycarbonyloxy, or 2-halogeno-lower alkoxycarbo-nyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, furthermore formyloxy, or for a 5-amino- 5-carboxy-valeryl radical, where 55 the amino and carboxy group can also be protected and z. B. as acylamino, e.g. B. Niederalkanoylamino, such as acetylamino, halogen-lower alkanoylamino, such as dichloroacetylamino, benzoylamino, or phthaloylamino, or as esterified carboxy, such as phenyl-lower alkoxycarbonyl, e.g. B. diphenylmethoxy-60 carbonyl, are present, preferably m being 1 when Ra is phenyl or hydroxyphenyl, rib is hydrogen, and R2a is primarily optionally in the 2-position halogen, e.g. B. chlorine, bromine or iodine-substituted lower alkoxy, especially a-polybranched lower alkoxy, e.g. B. tert-buty-65 loxy, or 2-halogeno-lower alkoxy, e.g. B. 2,2,2-trichloroethoxy, such as methoxy-substituted diphenylmethyloxy, e.g. B. diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, or p-nitrobenzyloxy, further tri-lower alkylsilyloxy, e.g. B. Trimethylsilyloxy.

624683

12

According to the inventive method compounds of formula I, the corresponding isomeric 3-oxoce-pham and 2-cephem compounds, or isomer mixtures thereof, and 1-oxides of compounds of formula I, and salts of such compounds with salt-forming groups are prepared by: from a compound of formula II

Ef-N H H

u / ys \

* 1 o-i k J — 0-r3 <"> '

0 = C- * 2

wherein Ria, Rib and R2A have the meanings given above and R3 denotes a hydroxyl protective group present as an ether group, from a 1-oxide thereof, from a corresponding isomeric 2-cephem compound, or from an isomer mixture of the 3- and 2-cephem compounds or from a salt such a compound with salt-forming groups, which splits off the hydroxyl protective group R3 by solvolysis or hydro-genolysis and replaces it with hydrogen.

In a starting material of the formula II, a 1-oxide, one of the isomers mentioned or a salt thereof, Rîa preferably represents an etherified group with which the -C (= 0> grouping forms an esterified carboxyl group which can be split, in particular under mild conditions Hydroxy group, it being possible for functional groups present in a car-boxyl protective group R2A to be protected in a manner known per se, for example as indicated above, for example A group R2A is in particular an optionally halogen-substituted lower alkoxy group such as methoxy, a-polybranched lower alkoxy, e.g. tert-butyloxy, or 2-halogeno-lower alkoxy, where halogen represents e.g. chlorine, bromine or iodine, primarily 2,2,2-trichloroethoxy, 2-bromoethoxy, or 2 Iodoethoxy, or an optionally substituted 1-phenyl-lower alkoxy group, such as lower alkoxy, for example methoxy, or nitro, such as optionally substituted, for example as indicated, benzyloxy or diphenylmethoxy, for example benzyloxy, 4-Me thoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, also an organic silyloxy or stannyloxy group, such as tri-lower alkylsilyloxy, e.g. B.Trimethylsi-lyloxy or halogen, z. B. chlorine. Preferably in a starting material the radical Ria is an amino protecting group RiA, such as an acyl group Ac, in which any free functional groups present, e.g. B. amino, hydroxy, carboxyl or phosphono groups, in a conventional manner, amino groups such. B. by the abovementioned acyl, tri-tyl, stilyl or stannyl, and substituted thio or sulfonyl radicals, and hydroxyl, carboxy or phosphono groups, for. B. can be protected by the above-mentioned ether or ester groups, including silyl or stannyl groups, and rib hydrogen.

In a starting material of the formula II, a hydroxyl protective group R3 is, for example, an easily removable 2-oxa or 2-thiaaliphatic or -cycloaliphatic hydrocarbon radical, an easily removable substituted silyl or stannyl group, or an easily removable optionally substituted a-phenyl-lower alkyl such as optionally substituted benzyl or diphenylmethyl group.

The 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical R3 is primarily a 1-lower alkoxy-1-lower alkyl or 1-lower alkylthio-1-lower alkyl radical, such as 1-methoxy-1-ethyl, 1-ethoxy l-ethyl, 1-methylthio-l-ethyl or 1-ethylthio-l-ethyl, or a 2-oxa or 2-thia-lower alkylene or lower alkenyl radical, with 5-7 ring atoms, such as 2-tetrahydrofuran, 2-tetrahydropyranyl or 2,3-dihydro-2-pyranyl or a corresponding analog sulfur compound.

Easily removable silyl or stannyl groups R3 are preferably substituted by optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as lower alkyl, halogeno-lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl groups, or, if appropriate, modified functional groups, such as etherified hydroxy , e.g. B. lower alkoxy groups, or halogen, z. B. chlorine atoms, representative of such groups are primarily tri-lower alkylsilyl, such as trimethylsilyl, halo-gen-lower alkoxy-lower alkylsilyl, such as chloromethoxymethylsi-io lyl, or tri-lower alkylstannyl, such as tri-n-butylstannyl.

Other easily removable hydroxyl protective groups R3 are, for example, optionally substituted a-phenyl-lower alkyl, such as benzyl or diphenylmethyl, z. B. esterified or etherified hydroxy, 15 such as halogen, z. B. fluorine, chlorine or bromine, or lower alkoxy, such as methoxy, come into question.

In a starting material of the formula II, a 1-oxide, one of the isomers mentioned or a salt thereof, R3 as the hydroxyl protective group preferably denotes a substituted-20 ized silyl group, in particular the trimethylsilyl group, and an α-phenyl-lower alkyl group, such as the benzyl or the diphenylmethyl group.

From a compound of formula II, a 1-oxide, one of the isomers mentioned or a salt thereof, a 25 hydroxyl protective group R3 is easily split off and replaced by hydrogen. A 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical is, for example, by acid hydrolysis, a silyl or stannyl group by hydrolysis, alcoholysis or acidolysis, for example by treatment with water or with an alcohol, such as methanol or ethanol, or else with an acid, such as acetic acid. The cleavage of an optionally substituted a-phenyl-lower alkyl, e.g. B. benzyl or diphenyl methyl group takes place, for example, by acidolysis, for. B. by treatment with a suitable inorganic or organic acid, such as hydrochloric acid, sulfuric acid, formic acid or in particular trifluoroacetic acid, or by hydrogenolysis, for example by treatment with hydrogen in the presence of a catalyst such as palladium. The resulting 3-hydroxyver-4o bonds are mainly in the 3-cephem form. A hydroxy protective group R3 is split off selectively, i.e. i.e. without a carboxyl protecting group Rîa being split off simultaneously.

In the process according to the invention, as well as in 45 additional measures to be carried out, if necessary, free functional groups not participating in the reaction can be present in the starting materials or in the compounds obtainable according to the process, e.g. B. free amino groups such. B. by acylation, tritylation or silylation, free hydroxy-50 or mercapto groups z. B. by etherification or esterification, and free carboxyl groups such. B. by esterification, including Silylie-tion, temporarily protected in a conventional manner and released after the reaction, in a conventional manner, if desired, individually or together. 55 So you can preferably z. B. amino, hydroxyl, carboxyl or phosphono groups in an acyl radical RiA or Rib z. B. in the form of acylamino, such as those mentioned above, for. B. 2,2,2-trichloroethoxycarbonylamino, 2-bromoethoxycarbonylamino, 4-methoxybenzyloxycarbonylamino, diphenylmethoxycarbonyl-bo amino or tert-butyloxycarbonylamino, of aryl or aryl-lower alkylthioamino, e.g. B. 2-nitrophenylthiamino, or aryl sulfonylamino, e.g. B. 4-methylphenylsulfonylamino, or of l-lower alkoxycarbonyl-2-propylidene amino groups, or of acyloxy, such as those mentioned above, e.g. B. tert-butyloxycarbonyl-65 oxy-, 2,2,2-trichloroethoxycarbonyloxy or 2-bromoethoxycar bonyloxy groups, or of esterified carboxy, such as those mentioned above, e.g. B. diphenylmethoxycarbonyl groups, or 0.0'-disubstituted phosphono, such as those mentioned above, for. B. 0.0'-di-lower alkylphosphono, e.g. B. 0,0'-dimethyl-phosphono-

13 624683

group, protect and subsequently, if necessary with an acidic or weakly basic aqueous agent,

Conversion of the protecting group, e.g. B. a 2-bromoethoxycar- such as hydrochloric acid or aqueous sodium bicarbonate or bonyl- in a 2-iodoethoxycarbonyl group, in a known manner- an aqueous potassium phosphate buffer of pH about 7 to ter manner and depending on the type of protective group, for. B. a 2,2,2- about 9, and a hydrogenolytically cleavable esterified carbo-

Trichloräthoxycarbonylamino- or 2-Jodäthoxycarbonylami- 5 xylgruppe by hydrogenolysis, for. B. by treatment with nogruppe by treatment with suitable reducing agents, hydrogen in the presence of a noble metal, for. B. Palladium Ka-

how to split zinc in the presence of aqueous acetic acid, a dipetalizer.

nylmethoxycarbonylamino- or tert-butyloxycarbonylamino- A z. B. protected by silylation or stannylation group by treatment with formic or trifluoroacetic acid, carboxyl group in the usual manner, for. B. by treating an aryl or aryl-lower alkylthioamino group by treating with water or an alcohol.

your compounds of the formula I obtained according to the invention with a nucleophilic reagent, such as sulphurous acid,

an arylsulfonylamino group using electrolytic reduc-1-oxides, isomers or salts thereof, can be known per se

tion, an 1-lower alkoxycarbonyl-2-propylidene amino group in other compounds of the formula 1,1 -oxides, iso-

by treatment with aqueous mineral acid, or a tert-mer or salts thereof.

Butyloxycarbonyloxy group by treating with ants i s in a compound obtained can e.g. B. an amino or trifluoroacetic acid, or a 2,2,2-trichloroethoxycarbonyl protective group RiA or Rib, in particular an easily cleaved

oxy group by treatment with a chemical reducible acyl group, in a manner known per se, e.g. B. an a-poly

tion agents, such as zinc in the presence of aqueous acetic acid, branched lower alkoxycarbonyl group, such as tert-butyloxy

or a diphenylmethoxycarbonyl group by treating carbonyl, by treating with trifluoroacetic acid and one with formic or trifluoroacetic acid or by hydrogeno-20 2-halogeno-lower alkoxycarbonyl group, such as 2,2,2-trichloroate

lysis, or a 0,0'-disubstituted phosphono group by hoxycarbonyl or 2-iodoethoxycarbonyl, or a phenacylo-

Treating with an alkali metal halide, if desired, xycarbonyl group by treating with a suitable e.g. B. partially split. reducing metal or corresponding metal compound,

In the reaction according to the invention, care must be taken, for. As zinc, or a chromium-II compound, such as chloride, or that the protected carboxyl group —C (= 0) —R2A, if possible, 25 acetate, advantageously in the presence of one, is retained together with. the water or nascent metal in a compound of the substance-generating agent obtainable according to the invention, preferably in the presence of formula I, a 1-oxide, one of the isomers mentioned or water-containing acetic acid.

a salt thereof, with a protected, in particular protected, furthermore. In a compound obtained in which an esterified carboxyl group of the formula -C (= 0) -R2A, this carboxyl group of the formula -C (= 0) -R2A can preferably be a

namely depending on the type of group R2A, also in the free Carz. B. by esterification, including by silylation, e.g. B. be transferred by boxyl group. An esterified, e.g. B. by reacting with a suitable organic halogen silicon

a lower alkyl radical, in particular methyl or ethyl, or or halogen-tin-IV compound, such as trimethylchlorosilane, carboxyl group esterified by a benzyl radical, can be carboxyl group protected by or tri-n-butyl-tin chloride.

Hydrolysis in weakly basic medium, e.g. B. by Behan- 35 stentj ejne acyl group Ria or Rib, in which optionally

deln with an aqueous solution of an alkali metal or Erdal- handene free functional groups optionally protected kalimetallhydroxyds or carbonate, z. B. are sodium or potassium, by treatment with an imide halide-forming agent

umhydroxyd, preferably at a pH of about 9 to tel, reacting the resulting imide halide with a

10, and optionally in the presence of a lower alkanol, split off in alcohol and columns of the imino ether formed, a free carboxyl group can be converted, one by "o, a protected one, for example one by an organic

a suitable 2-halogeno lower alkyl or an arylcarbonyl see silyl radical, carboxyl group already esterified in the course of a methyl group carboxyl group can e.g. B. can be released by the reaction.

Treat with a chemical reducing agent, such as an imide halide forming agent, in which halogen on

Metal, e.g. B. zinc, or a reducing metal salt, such as electrophilic central atom, are mainly acid

a chromium II salt, e.g. B. chromium (II) chloride, usually in 45 halides, such as acid bromides and in particular acid chlorides.

Presence of a hydrogen-donating agent that comes together. These are primarily acid halides of inorganic

To generate hydrogen nascent with the metal see acids, especially of phosphoric acids, like.

like an acid, primarily vinegar, and ants, phosphoroxy, phosphorus tri and especially phosphorus penta-

acid, or an alcohol, preferably water halides, e.g. B. phosphorus oxychloride, phosphorus trichloride, and admits, an esterified by an arylcarbonylmethyl group so j primarily phosphorus pentachloride, also pyrocatechyl

Carboxyl group, likewise by treatment with a nucleophosphorus trichloride, and also acid halides, in particular philic, preferably salt-forming reagents, such as sodium thio-chlorides, of sulfur-containing acids or of carboxylic acids,

phenolate or sodium iodide, one by a suitable aryl such as thionyl chloride, phosgene or oxalyl chloride.

methyl grouping esterified carboxyl group z. B. by reaction with one of the imide halide mentioned

Irradiate, preferably with ultraviolet light, e.g. B. among 55 forming agents is usually in the presence of a suitable

290 mn when the arylmethyl group e.g. B. an optionally neten, especially organic base, primarily a ter-

in 3-, 4- and / or 5-position, e.g. B. by lower alkoxy and / or tertiary amine, for. B. a tertiary aliphatic mono- or

Nitro groups substituted benzyl, oer with län-diamine, such as a tri-lower alkyl amine, for. B. trimethyl, tri

wavy ultraviolet light, e.g. B. over 290 m ^ i if the ethyl or N, N-diisopropyl-N-ethyl-amine, further one

Arylmethyl group e.g. B. in the 2-position by a nitro-eo N, N, N ', N'-tetraniederalkyl-lower alkylenediamine, e.g. B.

group-substituted benzyl radical means one substituted by a gene N, N, N ', N'-tetramethyl-1,5-pentylene-diamine or N, N, N', N'-

is suitable substituted methyl group, such as tert-butyl or diphe-tetramethyl-l, 6-hexylenediamine, a mono or bicyclic nylmethyl, esterified carboxyl group z. B. by treating mono- or diamine, such as an N-substituted, e.g. B. N-low

with a suitable acidic agent such as formic acid or alkylated, alkylene, azaalkylene or oxaalkylene amines, e.g. B.

Trifluoroacetic acid, optionally with the addition of a nucleic N-methylpiperidine or N-methylmorpholine, further 2,3,4,6,7,8-

phile compound such as phenol or anisole, an activated verhexahydro-pyrrolo [1,2-a] pyrimidine (diazabicyclonones;

esterified carboxyl group, also one in anhydride form (DBN), or a tertiary aromatic amine such as a carboxyl group by hydrolysis, e.g. B. by treating diniederalkyl aniline, e.g. B. N, N-dimethylaniline, or in the first

624683

14

Line of a tertiary heterocyclic, mono- or bicyclic base, such as quinoline or isoquinoline, especially pyridine, preferably in the presence of a solvent, such as an optionally halogenated, e.g. B. chlorinated, aliphatic or aromatic hydrocarbon, e.g. B. methylene chloride. Approximately equimolar amounts of the imide halide forming agent and the base can be used; the latter can also in the oversupply, eg. B. in about 0.2 to about 1-fold amount or then in an approximately to 10-fold, in particular an approximately 3 to 5-fold excess.

The reaction with the imide halide forming agent is preferably carried out under cooling, e.g. B. at temperatures from about -50 ° C to about +10 ° C, but also at higher temperatures, d. H. e.g. B. up to about 75 ° C, can work if the stability of the starting materials and products allow an elevated temperature.

The imide halide product, which is usually processed further without isolation, is reacted according to the process with an alcohol, preferably in the presence of one of the bases mentioned, to give the imino ether. Suitable alcohols are, for example. aliphatic and araliphatic alcohols, primarily optionally substituted, such as halogenated, for. B. chlorinated, or having additional hydroxyl groups, lower alkanols, for. As ethanol, propanol or butanol, especially methanol, furthermore 2-halogeno-lower alkanols, e.g. B. 2,2,2-trichloroethanol or 2-bromoethanol, and optionally substituted phenyl-lower alkanols, such as benzyl alcohol. Usually one uses, e.g. B. up to about 100 times, excess of the alcohol and preferably works under cooling, e.g. B. at temperatures from about -50 ° C to about 10 ° C.

The imino ether product can advantageously be subjected to cleavage without isolation. The imino ether can be cleaved by treatment with a suitable hydroxy compound, preferably by hydrolysis, furthermore by alcoholysis, the latter being able to take place directly after the formation of the imino ether if an excess of the alcohol is used. It is preferably water or an alcohol, especially a lower alkanol, e.g. As methanol, or an aqueous mixture of an organic solvent, such as an alcohol. One usually works in an acidic medium, e.g. B. at a pH of about 1 to about 5, which, if necessary, by adding a basic agent such as an aqueous alkali metal hydroxide, e.g. B. sodium or potassium hydroxide, or an acid, e.g. B. a mineral acid, or organic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, borofluoric acid, trifluoroacetic acid or p-toluenesulfonic acid.

The three-step process described above for cleaving an acyl group is advantageously carried out without isolating the imide halide and imino ether intermediates, usually in the presence of an organic solvent which is inert to the reactants, such as an optionally halogenated hydrocarbon, e.g. B. methylene chloride, and / or in an inert gas atmosphere, such as a nitrogen atmosphere.

If the imide-halide intermediate product obtainable by the above process is reacted with a salt, such as an alkali metal salt of a carboxylic acid, in particular a sterically hindered carboxylic acid, instead of with an alcohol, a compound of the formula I is obtained in which both Ria and Rib radicals Represent acyl groups.

In a compound of formula I, a 1-oxide, an isomer or a salt thereof, in which both radicals Ria and Rib represent acyl groups, one of these groups, preferably the less sterically hindered, e.g. B. selectively removed by hydrolysis or aminolysis.

In a compound of formula I a 1-oxide, an isomer or a salt thereof, in which RiA and Rib together with the nitrogen atom represent a phthalimido group, this can e.g. B. by hydrazinolysis, d. H. when treating such a compound with hydrazine, be converted into the free amino group.

Certain acyl residues RiA an acylamino grouping in compounds obtainable according to the invention, such as. B. the 5-amino-5-carboxy-valeryl radical, wherein carboxyl, z. B. by esterification, in particular by diphenylmethyl, and / or the amino group, for. B. by acylation, in particular by an acyl radical of an organic carboxylic acid, such as Halogenniederal-kanoyl, such as dichloroacetyl, or phthaloyl, optionally protected, can also by treatment with a nitrosating agent, such as nitrosyl chloride, with a carbocyclic arene diazonium salt, such as Benzene diazonium chloride, or with a positive halogen donor, such as an N-halo-amide or imide, e.g. B. N-bromosuccinimide, preferably in a suitable solvent or solvent mixture, such as formic acid, together with a nitro or cyano-lower alkane and adding the reaction product with a hydroxyl-containing agent, such as water or a lower alkanol, e.g. B. methanol, or, if in the 5-amino-5-carboxy-vale-rylrest RiA the amino group is substituted and the carboxy group z. B. is protected by esterification, and Rib preferably represents an acyl radical, but may also be hydrogen, by standing in an inert solvent such as dioxane or a halogenated aliphatic hydrocarbon, e.g. As methylene chloride, and, if necessary, working up the free or monoacylated amino compound by methods known per se, be split off.

A formyl group RiA can also be treated with an acidic agent, e.g. B. p.Toluenesulfonic or hydrochloric acid, a weakly basic agent, e.g. B. dilute ammonia, or a decarbonylating agent, e.g. B. tris (tri-phenylphosphine> rhodium chloride) are split off.

A triarylmethyl, such as the trityl group RiA z. B. by treatment with an acidic agent such as a mineral acid, e.g. As hydrochloric acid, are split off.

In a compound of formula I, a 1-oxide, an isomer or a salt thereof, in which Ria and Rib represent hydrogen, the free amino group can be substituted by methods known per se, primarily by treatment with acids, such as carboxylic acid, or acylate reactive derivatives thereof.

If a free acid, preferably with protected, optionally present functional groups, such as an optionally present amino group, is used for the acylation, suitable condensing agents, such as carbodiimides, for example N, N'-di-ethyl, N, N'- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexyl or N-ethyl-N'-3-dimethylaminopropyl-carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or isoxazolinium salts, for example N-ethyI-5- phenyl-isoxazolinium-3'-sulfonate and N-tert-butyl-5-methyl-isoxazolium-nium perchlorate, or a suitable acylamino compound, e.g. B. 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline.

The condensation reaction is preferably carried out in one of the anhydrous reaction media mentioned below, for example in methylene chloride, dimethylformamide or acetonitrile

An amide-forming, functional derivative of an acid, preferably with protected optionally present groups, such as an optionally present amino group, is primarily an anhydride of such an acid, including, and preferably, a mixed anhydride. Mixed anhydrides are e.g. B. those with inorganic acids, especially with hydrohalic acids, d. H. the corresponding acid 5

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halides, e.g. B. chlorides or bromides, further with hydrochloric acid, d. H. the corresponding acid azides, with a phosphoric acid, e.g. As phosphoric acid or phosphorous acid, with a sulfuric acid, e.g. As sulfuric acid, or with hydrocyanic acid. Other mixed anhydrides are e.g. B. those with organic acids, such as organic carboxylic acids, such as with, if necessary, for. B. by halogen, such as fluorine or chlorine, substituted lower alkane carboxylic acids, for. B. pivalic acid or trichloroacetic acid, or with half-esters, especially lower alkyl half-esters of carbonic acid, such as the ethyl or isobutyl half-ester of carbonic acid, or with organic, especially aliphatic or aromatic, sulfonic acids, for. B. p-toluenesulfonic acid.

Furthermore, internal anhydrides such as ketenes, e.g. B. diketene, isocyanates (i.e. internal anhydrides of carbamic acid compounds) or internal anhydrides of carboxylic acid compounds with carboxy-substituted hydroxy or amino groups, such as mandelic acid-O-carboxane hydride or the anhydride of 1-N-carboxyamino-cyclohexane-carboxylic acid.

Other acid derivatives suitable for reaction with the free amino group are activated esters, usually with protected, optionally present functional groups, such as esters with vinylogenic alcohols (i.e. enols), such as vinyl-lower alkanols, or aryl esters, such as preferably, e.g. B. by nitro or halogen, such as chlorine, substituted phenyl esters, for. B. pentachlorophenyl, 4-nitrophenyl or 2,4-dinitrophenyl ester, heteroaromatic esters such as benzotriazole esters, or dia-cylimino esters such as succinylimino or phthalylimino esters.

Other acylation derivatives are e.g. B. substituted formi-amino derivatives, such as substituted N, N-dimethylchlorformimi-noderivate of acids, or N-substituted N, N-diacylamines, such as an N, N-diacylated aniline.

Acylation with an acid derivative, such as an anhydride and especially with an acid halide, can be carried out in the presence of an acid-binding agent, for example an organic base, such as an organic amine, e.g. B.

a tertiary amine such as tri-lower alkylamine, e.g. B. triethylamine, N, N-di-lower alkyl-aniline, e.g. B. N, N-dimethylaniline, or a base of the pyridine type, e.g. B. pyridine, an inorganic base, for example an alkali metal or alkaline earth metal hydroxide, carbonate, or bicarbonate, e.g. As 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 acylation can be carried out in an aqueous or preferably non-aqueous solvent or solvent mixture, for example in a carboxylic acid amide such as N, N-di-lower alkyl amide, e.g. B. Dimethylforma-mid, a halogenated hydrocarbon, e.g. B. methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, e.g. B. acetone, an ester, e.g. B. ethyl acetate, or a Nitrii, z. B. acetonitrile, or mixtures thereof, and, if necessary, at reduced or elevated temperature and / or in an inert gas, for. B. nitrogen atmosphere.

An acyl group can also be introduced by using a compound of the formula I, a 1-oxide, an isomer or a salt thereof, in which Ria and Rib together represent a ylidene residue (which can also be added subsequently, e.g. by treating a compound, wherein Ria and Rib represents hydrogen, with an aldehyde, such as an aliphatic, aromatic or araliphatic aldehyde can introduce), for. B. acylated by the methods given above, and the acylation product, preferably in neutral or weakly acidic medium, hydrolyzed.

An acyl group can also be introduced in stages. So you can z. B. in a compound of formula I, a 1-oxide, an isomer or a salt thereof, with a free amino group a halogen-lower alkanoyl, z. B. bromoacetyl group, or z. B. by treatment with a carbonic acid di-halide, such as phosgene, a halocarbonyl, e.g. B. chlorocarbyl group, introduce and so obtainable N- (halogen-5-lower alkanoyl) - or N- (halocarbonyl) amino compound with suitable exchange reagents, such as basic compounds, eg. B. tetrazole, thio compounds, e.g. B. 2-mercapto-l-methyl-imidazole, or metal salts, e.g. B. sodium azide, or alcohols, such as lower alkanols, for. B. tert-butanol, implement and so io come to substituted N-lower alkanoyl or N-hydroxycarbonyl amino compounds.

In both reactants, free functional groups can be temporarily protected in a manner known per se during the acylation reaction and after acylation using methods known per se, e.g. B. released as described above.

The acylation can also be done by replacing an existing acyl group with another, preferably sterically hindered acyl group, e.g. B. by the above-described process, take place by preparing the imide halide compound, treating it with a salt of an acid and hydrolytically cleaving off one of the acyl groups present in the product thus obtainable, usually the less sterically hindered acyl group.

25 You can also z. B. a compound of formula I, a 1-oxide, an isomer or a salt thereof, wherein Ria represent a, preferably in the a-position substituted glycyl group, such as phenylglycyl, and Rib hydrogen, with an aldehyde, e.g. B. formaldehyde, or a ketone, such as lower alkanone, e.g. B. Ace-30 ton, and thus to give compounds of the formula 1,1-oxides, isomers or salts thereof, in which RiA and Rib together with the nitrogen atom a, preferably substituted in the 4-position, optionally substituted in the 2-position 5-Oxo-l, 3-diaza-cyclopentyl radical.

35 In a compound of formula I, a 1-oxide, an isomer or a salt thereof, wherein Ria and Rib are hydrogen, the free amino group can also by introducing a triarylmethyl group, e.g. B. by treatment with a reactive ester of a triaryl methanol, such as Tritylchlö-40 rid, preferably in the presence of a basic agent such as pyridine.

An amino group can also be protected by introducing a silyl and stannyl group. Such groups are introduced in a manner known per se, e.g. B. by treating 45 with a suitable silylating agent, such as with a dihalo gene-di-lower alkyl-silane, lower alkoxy-lower alkyl-dihalogenyl or tri-lower alkyl-silyl halide, e.g. B. dichloro-dimethylsi-lan, methoxy-methyl-dichloro-silane, trimethylsilyl chloride or dimethyl-tert-butyl-silyl chloride, such silyl halo-5o nid compounds preferably in the presence of a base, e.g. B. pyridine, used with an optionally N-mono-lower alkyl, N, N-di-lower alkylated, N-tri-lower alkyl silylated or N-lower alkyl-N-tri-lower alkyl silylated N- (tri-lower alkyl-silyl) amine (see e.g. British Patent No. 1,073,530), or 55 with a silylated carboxamide, such as a bis-tri-lower alkylsilyl acetamide, e.g. B. bis-trimethylsilyl-acetamide, or trifluorosilylacetamide, further with a suitable stannylating agent, such as a bis- (tri-lower alkyl tin) oxide, e.g. B. bis (tri-n-butyltin) oxide, a tri-lower alkyltin hydroxide, e.g. B. <= '- triethyl tin hydroxide, a tri-lower alkyl-lower alkoxytin, tetra-lower alkoxytin or tetraniederalkyl-tin compound, and a tri-lower alkyltin halide, e.g. B. tri-n-butyltin chloride (see e.g. Dutch specification 67/11107).

In a compound obtainable according to the process which contains a free carboxyl group in the groups RiA and Rib, such a compound can be converted into a protected carboxyl group in a manner known per se. So you get esters z. B. by treating with a suitable manner in a protected

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Carboxyl group are transferred. So you get esters z. B. by treatment with a suitable diazo compound, such as a diazo lower alkane, e.g. As diazornethan or diazobutane, or a phenyldiazoniederalkan, e.g. B. Diphenyldiazome-than, if necessary, in the presence of a Lewis acid, such as. B. boron trifluoride, or also reacting with an alcohol suitable for esterification in the presence of an esterifying agent such as a carbodiimide, e.g. B. dicyclohexylcarbodiimide, and carbonyldiimidazole, further with an N, N'-disubstituted O or. S-substituted isourea or isothiourea, wherein an O and S substituent is e.g. B. lower alkyl, especially tert-butyl, phenyl-lower alkyl or cycloalkyl, and N or N'-substituents such. B. lower alkyl, especially isopropyl, cycloalkyl or phenyl, or by any other known and suitable esterification process, such as reaction of a salt of the acid with a reactive ester of an alcohol and a strong inorganic acid, and a strong organic sulfonic acid. In addition, acid halides such as chlorides (prepared e.g. by treatment with oxalyl chloride), activated esters (formed e.g. with N-hydroxy nitrogen compound such as N-hydroxysuccinimide) or mixed anhydrides (obtained e.g. with haloformates of lower alkyl esters, such as ethyl chloroformate or isobutyl chloroformate, or with haloacetic acid halides, such as trichloroacetic acid chloride) by reaction with alcohols, optionally in the presence of a base such as pyridine, into an esterified carboxyl group.

In a compound obtained with an esterified carboxyl group, e.g. B. the formula -C (= 0) -R2A, this can be converted into another esterified carboxy group, for. B. 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.

In a compound with a free carboxyl group obtainable according to the process, such a compound can also be converted into an optionally substituted carbamoyl or hydrazinocarbonyl group, preferably using reactive, functionally modified derivatives, such as the abovementioned acid halides, generally esters, and also the abovementioned activated esters, or mixed anhydrides of the corresponding acid with ammonia or amines, including hydroxylamine, or hydrazines.

A carboxyl group protected by an organic silyl or stannyl group can be formed in a manner known per se, e.g. B. by appropriate compounds of formula I, or salts such as alkali metal, for. B. sodium salts thereof, treated with a suitable silylating or stannylating agent, such as one of the abovementioned silylating or stannizing agents; see e.g. B. British Patent No. 1 073 530 and Dutch Patent No. 67/17107.

Furthermore, modified functional substituents in groups RiA, Rib and / or Rîa, such as substituted amino groups, acylated hydroxyl groups, esterified carboxy groups or 0.0'-disubstituted phosphono groups, by methods known per se, e.g. B. the above described, release, or free functional substituents in groups RiA, Rib and / or Rîa, such as free amino, hydroxyl, carboxy or phosphono groups, according to known methods, eg. B. acylating or esterifying or substituting functionally. For example, B. an amino group by treatment with sulfur trioxide, preferably in the form of a complex with an organic base, such as a tri-lower alkylamine, e.g. B. triethylamine, convert into a sulfoamino group. Furthermore, the reaction mixture can be obtained by reacting an acid addition salt of a 4-guanylsemicarbazide with sodium nitrite, with a compound of formula I, a 1-oxide, an isomer or salt thereof, in which e.g. B. the amino protecting group RiA represents an optionally substituted glycyl group, implement and thus convert the amino into a 3-guanylu-reido group. Furthermore, compounds with aliphatic halogen, e.g. B. with an optionally substituted a-bromoacetyl grouping, with esters of phosphorous acid, such as tri-lower alkyl phosphite compounds, and so arrive at corresponding phosphono compounds.

Cephem compounds of the formula I obtained, isomers or salts thereof, can be converted into 1-oxides of the corresponding 3-cephem compounds of the formula I by oxidation with suitable oxidizing agents, such as those described below. Obtained 1-oxides of 3-cephem compounds of the formula I can be reduced by suitable reducing agents, such as. B. reduce the described below to the corresponding 3-cephem compounds of formula I. In these reactions, care must be taken to ensure that, if necessary, free functional groups are protected and, if desired, subsequently released again.

Cephem compounds obtained can be isomerized. Thus, 2-cephem compounds obtained, or mixtures of 2- and 3-cephem compounds obtained, can be converted into the corresponding 3-cephem compounds of the formula I by using a 2-cephem compound or a mixture consisting of a 2- and 3-cephem compound in which free functional groups if necessary, e.g. B. may be temporarily protected as indicated, isomerized.

For example, a 2-cephem compound can be isomerized by treating it with a basic agent and isolating the corresponding 3-cephem compound of the formula I from an equilibrium mixture of the 2- and 3-cephem compounds which may be obtained.

Suitable isomerizing agents are e.g. B. organic nitrogen-containing bases, such as tertiary heterocyclic bases of aromatic character, and primarily tertiary aliphatic, aza-cycloaliphatic or araliphatic bases, such as N, N, N-triniederalkylamines, e.g. B. N, N, N-trimethylamine, N, N-dimethyl-N-ethylamine, N, N, N-triethylamine or N, N-diisopropyl-N-ethylamine, N-lower alkyl azacycloalkanes, e.g. B. N-methyl-piperidine, or N-phenyl-lower alkyl-N, N-diniederal-kylamine, e.g. B. N-benzyl-N, N-dimethylamine, and mixtures thereof, such as the mixture of a base of the pyridine type, for. B. pyridine, and an N, N, N-tri-lower alkylamine, e.g. B. 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, for. B. natriu-acetate, triethylammonium acetate or N-methyl-piperidine acetate, as well as other analog bases or mixtures of such basic agents can be used.

It is preferably carried out in an anhydrous medium, in the presence or absence of a solvent, such as an optionally halogenated, for. B. chlorinated, aliphatic, cycloaliphatic or aroamtic hydrocarbon, or a solvent mixture, wherein used as a reagent, liquid bases under the reaction conditions can also serve as a solvent, if necessary, with cooling, or heating, preferably in a temperature range of about -30 ° C to about +100 ° C, in an inert gas, e.g. B. nitrogen atmosphere, and / or in a closed vessel.

The 3-cephem compounds of the formula I thus obtainable can be prepared in a manner known per se, e.g. B. by adsorption and / or crystallization, from any 2-cephem compounds still present.

The isomerization of 2-cephem compounds can also be carried out by placing them in the 1-position

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If desired, an available mixture of isomers can oxidize ren a- and ß-l-oxides, e.g. B. chromatographically, the 1-oxides separated from 3-cephem compounds of the formula I are separated.

and the 1-oxides of the corresponding 3-cephem compounds obtainable in this way. The reduction of the 1-oxides of 3-cephem compounds reduces compounds of the formula I. of the formula I can be carried out in a manner known per se. As suitable oxidizing agents for the oxidation in 1 position with a reducing agent, if necessary, in the presence of 2-cephem compounds, inorganic agents of an activating agent are used. Possible reduc acids which have a reduction potential of at least +1.5 volt are: catalytically activated products and which consist of non-metallic elements, hydrogen, using noble metal catalysts, organic peracids or mixtures of hydrogen peroxide, which are palladium and platinum or rhodium, and which one and acids, especially organic carboxylic acids, with an io, if appropriate, together with a suitable carrier mate dissociation constant of at least 10 ~ 5 in question. Appropriate, such as coal or barium sulfate; reducing tin, nete inorganic peracids are periodic and persulphuric iron, copper or manganese cations, which in the form of diacid. Organic peracids are corresponding percarbonate-speaking compounds or complexes of inorganic and persulfonic acids, which are added as such or by organic or organic type, for. B. as tin-II-chloride, fluoride, acetate use of at least one equivalent of hydrogen pero- or 15-formate, iron-II-chloride, sulfate, oxalate or succinate, xyd and a carboxylic acid can be formed in situ . Copper I chloride, benzoate or oxide, or manganese II chloride, it is expedient to use a large excess of the car sulfate, acetate or oxide, or as complexes, for. B. to use with ethylene acid when z. For example, acetic acid is used as a solvent with diamine tetraacetic acid or nitrilotriacetic acid. Suitable peracids are e.g. B. perform ants; reducing dithionite, iodic or iron-II-cyanide-anioic acid, peracetic acid, pertrifluoroacetic acid, permaleic acid, 20 nen, which in the form of corresponding inorganic or perbenzoic acid, monoperphthalic acid or p-toluenesulfonic organic salts, such as alkali metal, z. B. sodium or potassium acid. umdithionite, sodium or potassium iodide or iron-II-cyanide, the oxidation can also be used using water or in the form of the corresponding acids, such as hydrogen iodide peroxide with catalytic amounts of an acid with an acid; reducing trivalent inorganic dissociation constant of at least 10 ~ 5 or organic phosphorus compounds, such as phosphines, can be carried out using low concentrations, e.g. B. 1 -2% and less esters, amides and halides of phosphinous, phos-ger, but also larger amounts of the acid can be used. Phonophonic or phosphorous acid, as well as this phosphorus acid. The effectiveness of the mixture depends primarily on phosphorus-sulfur compounds corresponding to the material compounds - on the strength of the acid. Suitable mixtures are e.g. B. bonds in which organic radicals are primarily aliphatic, those of hydrogen peroxide with acetic acid, perchloric acid 30 aromatic or araliphatic radicals, for. B. optionally or trifluoroacetic acid. substituted lower alkyl, phenyl or phenyl lower alkyl group

The above oxidation can be in the presence of suitable pens such as e.g. B. tri-phenylphosphine, tri-n-butylphos-

Katralysators are carried out. So z. B. the oxidophine, diphenylphosphinous acid methyl ester, diphenylchloropho-

tion with percarboxylic acids through the presence of an acid sphin, phenyldichlorophosphine, benzene phosphonic acid dimethyl

with a dissociation constant of at least 10 ~ 5 cataly- 35 methyl ester, butanephosphonous acid methyl ester, phosphorous acid

be based, their effectiveness of their starch triphenyl ester, trimethyl phosphate, phosphorus

depends. Acids suitable as catalysts are e.g. B. acetic acid, phosphorus tribromide, etc .; reducing halosilane

acid, perchloric acid and trifluoroacetic acid. Usually, bonds which have at least one bonded to the silicon atom have at least equimolar amounts of the oxide hydrogen atom and which, in addition to halogen, such as chlorine,

tion agent, preferably a small excess of 40 bromine or iodine, also organic residues, such as aliphatic or about 10% to about 20%: The oxidation is carried out under mild conditions aromatic groups, for. B. optionally substituted compounds, e.g. B. at temperatures from about -50 ° C to about lower alkyl or phenyl groups, such as chlorine

+100 ° C, preferably from about -10 ° C to about +40 ° C silane, bromosilane, di- or trichlorosilane, di- or tribromosilane,

carried out. Diphenylchlorosilane, dimethylchlorosilane, etc .; reducing

The oxidation of 2-cephem compounds to the 1-oxi-45 quaternary chloromethyleneiminium salts, in particular -chlo-

that of the corresponding 3-cephem compounds can also be ride or bromides, in which the iminium group is replaced by a biva-

by treatment with ozone, further with organic hypohalents or two monovalent organic residues, as given

genite compounds such as lower alkyl hypochlorites, e.g. B. ternally substituted lower alkylene or lower alkyl groups

Butyl hypochlorite, which is substituted in the presence of inert solution such as N-chloromethylene-N, N-diethyliminium chloro

agents such as optionally halogenated hydrocarbon or N-chloromethylene-pyrrolidinium chloride; and complex fen, e.g. B. methylene chloride, and at temperatures of about metal hydrides, such as sodium borohydride, in the presence of suitable

-10 ° C to about +30 ° C used with periodate-linked activating agents, such as cobalt-II chloride, and borane

conditions such as alkali metal periods, e.g. B. potassium periodate, which is dichloride.

preferably in an aqueous medium at pH. As activating agents used together with those of about 6 and at temperatures from about -10 ° C to about 55 above-mentioned reducing agents which sel- + 30 ° C uses, with iodobenzene dichloride which one does not have Lewis acid properties, d. H. which in aqueous medium, preferably in the presence of an organic first line together with the dithionite, iodine or iron-II base, for. B. pyridine, and with cooling, e.g. B. with temperatu-eyanide and the non-halogen-containing trivalent phosphorus from about -20 ° C to about 0 °, used, or with any reducing agents or in the catalytic reduction some other oxidizing agent which is <. 0 are used, in particular organic carbon and sulphide to convert a thio group into a sulfoxide group, and also sulfur, phosphorus or silicon net. halides with the same or greater hydrolysis constant

In the 1-oxides of 3-cephem compounds of second order available as benzoyl chloride, e.g. B. phosgene, oxalyl chloride

gene of the formula I, in particular in those compounds, in rid, acetic acid chloride or bromide, chloroacetic acid chloride,

which Ria, Rib and R2A the preferred 65 pivalic acid chloride, 4-methoxybenzoic acid chloride, 4-cyano-

Meanings, the groups Ria, Rib and / or RzA benzoic acid chloride, p-toluenesulfonic acid chloride, methanesulfonyl

converted into one another within the defined framework, fonic acid chloride, thionyl chloride, phosphorus oxychloride, phosphorus

split off or be introduced. A mixture of isomorphorichloride, phosphorus tribromide, phenyldichlorophosphine,

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Benzene phosphonous dichloride, dimethylchlorosilane or trichlorosilane, furthermore suitable acid anhydrides, such as trifluoroacetic anhydride, or cyclic sultones, such as ethane sultone, 13-propane sultone, l, 4-butane sultone or 1,3-hexane sultone, to mention.

The reduction is preferably carried out in the presence of solvents or mixtures thereof, the selection of which is primarily determined by the solubility of the starting materials and the choice of the reducing agent, e.g. B. lower alkane carboxylic acids or esters thereof, such as acetic acid and ethyl acetate, in the catalytic reduction, and z. B. optionally substituted, such as halogenated or nitrated aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, e.g. B. benzene, methylene chloride, chloroform or nitromethane, suitable acid derivatives, such as lower alkane carboxylic acid esters or nitriles, e.g. B. ethyl acetate or acetonitrile, or amides of inorganic or organic acids, for. B. dimethylformamide, dimethylacetamide or hexamethylphosphoramide, ether, z. B. diethyl ether, tetrahydrofuran or dioxane, ketones, e.g. As acetone, or sulfones, especially aliphatic sulfones, e.g. As dimethyl sulfone or tetramethylene sulfone, etc. together with the chemical reducing agents, these solvents preferably containing no water. It is usually carried out at temperatures from about -20 ° C. to about 100 ° C., and the reaction can be carried out at lower temperatures if very reactive activating agents are used.

In the 3-cephem compounds of the formula I obtainable in this way, Ria, Rib and / or R2A can be converted into other groups Ria, R: b or Rîa as described above.

Salts of compounds of the formula I of 1-oxides or isomers thereof can be prepared in a manner known per se. So you can salts of such compounds with acidic groups such. B. by treatment with metal compounds such as alkali metal salts of suitable carboxylic acids, e.g. B. the sodium salt of a-ethyl caproic acid, 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 formula I with basic groups are obtained in a conventional manner, e.g. B. by treatment with an acid or a suitable anion exchange reagent.

Internal salts of compounds containing a salt-forming amino group and a free carboxyl group can e.g. B. by neutralizing salts, such as acid addition salts, to the isoelectric point, e.g. B. with weak bases, or by treatment with liquid ion exchangers. Salts of 1-oxides of compounds of the formula IA with salt-forming groups can be prepared in an analogous manner.

Salts can be converted into the free compounds in a conventional manner, metal and ammonium salts e.g. B. by treatment with suitable acids, and acid addition salts z. B. by treatment with a suitable basic agent.

Obtained mixtures of isomers can be separated into the individual isomers by methods known per se, mixtures of diastereomeric isomers z. B. by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation process. Racemates obtained can in the usual manner, optionally after the introduction of suitable salt-forming groups, for. B. by forming a mixture of diastereomeric salts with optically active salt-forming agents, separating the mixture into the diastereomeric salts and converting the salts into the free compounds or by fractional crystallization from optically active

Solvents into which antipodes are separated.

Such starting materials are preferably used and the reaction conditions are selected so that the compounds 5 mentioned at the beginning as particularly preferred are obtained

The method according to the invention is distinguished from previously known methods in that it starts from cheap, easily accessible starting materials.

The starting materials used according to the invention can be produced, for example, according to Swiss Patent No. 601310.

In connection with the present description, organic radicals labeled “lower” contain, unless expressly defined, up to 7, preferably up to 4 carbon-15 atoms; Acyl residues contain up to 20, preferably up to 12 and primarily up to 7 carbon atoms.

The following examples serve to illustrate the invention; Temperatures are given in degrees Celsius. The cephem compounds mentioned in the examples have the R configuration in the 20 6- and 7-position and the azetidinone compounds mentioned in the 3- and 4-position.

example 1

A solution of 279 mg of 2- [4- <p-toluenesulfonylthio> 3-phe-25 noxyacetamido-2-oxoazetidin-l-yl] -3-hydroxycrotonic acid diphenylmethyl ester (0.428 mmol) in 4 ml of chloroform and 1 ml of hexamethyldisilazane is added heated under reflux for one hour, evaporated in vacuo and the oily residue was dried under high vacuum for one hour. -3-trimethylsilyloxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester.

The crude product obtained is taken up in 3 ml of dry chloro-35 form, cooled to 0 ° C. and mixed with 0.069 ml (0.47 mmol) of 1,5-diazabicyclo [5.4.0] undec-5-ene under nitrogen and with stirring After a reaction time of 1 hour, the solution is mixed with 0.3 ml of acetic acid and diluted with chloroform. The chloroform solution is washed with dilute 40 sulfuric acid, water and dilute sodium bicarbonate solution. The aqueous phases are extracted with chloroform, the combined organic phases are dried over sodium sulfate and concentrated in vacuo. The crude 7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-45 carboxylic acid diphenylmethyl ester is obtained. Rf value: 0.13 (silica gel; toluene / ethyl acetate 3: 1).

The crude product obtained is taken up in methanol and an excess of ethereal diazomethane solution is added at 0 ° C. After a reaction time of 5 minutes, the solution is concentrated completely and the oily residue is chromatographed on thick silica gel plates (toluene / ethyl acetate 3: 1). The silica gel of the zone at Rf = 0.19 is extracted with ethyl acetate and gives 7-phenoxyacetamido-3-methoxyceph-3-em-4-carboxylic acid diphenylmethyl ester; Melting point 120 ° C 55 (from ether) IR spectrum (in CHCh); 3310, 1775, 17090, 1690, 1600 mc "1.

The starting material is prepared as follows: a) From 100 g (27.3 mM) 6-phenoxyacetamido-penicillanic acid-L-oxide, 500 ml dioxane and 58.4 g (30 mM) diphenylme-

60 thyldiazomethane, the 6-phenoxyacet-amidopenicillanoic acid diphenylmethyl ester lß-oxide is obtained after about 2 hours; Melting point 144-146 ° C (ethyl acetate / petroleum ether).

b) Analogous to example lb) of CH patent 601310, 6-phenoxyacetamido-penicillanic acid-diphenylmethyl- from 292 g (55 mM)

65 ester-1 ß-oxide and 99 g (59.5 mM) 2-mercaptobenzothiazole of 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazeti-din-l-yl] -3-methylenebuttenic acid- obtained diphenylmethyl ester; Melting point 140-141 ° C (from toluene / ether).

19 624683

c) Analogous to example le) of CH patent 601310, from 10 g evaporation of the solvent, in 2 ml acetone / water 9: 1 (v / v) (14.7 mM) 2- [4- (benzthiazol-2-yldithio) - 3-phenoxyacetamido-2 is stirred with 35 mg (1.3 equivalents) of silver p-toluenesulfinate and an oxoazetidin-l-yl] -3-methylene butyric acid diphenyl methyl ester for hour at room temperature. The reaction mixture in 50 ml of ethyl acetate, 4.92 g (24.98 mM) of finely powdered silver is diluted with 3 ml of acetone and filtered. The filtrate is mixed with p-toluenesulfinate and constant stirring at room temperature 5 0.2 ml of dimethyl sulfide and two hours at room temperature 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxo-aze- perature (until the negative iodine starch reaction) stirred. Obtained after diphenylmethyl ester of tidin-l-yl] -3-methylenebutyrate. Removal of the solvent in vacuo, the residue Rf value = 0.28 (silica gel, toluene / ethyl acetate 3: 1); IR spectrum on 3 g of acid-washed silica gel with toluene / ethyl acetate 4: 1 (CHCh): 1782.1740.1695, 1340, 1150 cm-1. chromatographed. The 2- [4- (p-toluenesulfonylthio) -3-

The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxo-io phenoxyacetamido-2-oxoazetidin-l-yl] -3-hydroxycrotonic acid-azetidin-l-yl] -3-methylenebutyric acid diphenylmethyl ester can become diphenylmethyl ester recrystallized from ether / pentane can also be produced as follows: and melts at 142-143 ° C. After recrystallization

ci) A suspension of 106.5 g of 6-phenoxyacetamido-penisize from methylene chloride / diethyl ether becomes a molten cillanic acid e-diphenylmethyl ester Lß-oxide and 33.8 g of 2-mercapto point of 144-145 ° C ( corrected) received; [a] g ° = -68 ° ± 1 ° (c benzthiazole in 900 ml of toluene and 9 ml of glacial acetic acid is made with Sticks = 1; chloroform); Thin layer chromatogram: Rf value = substance boiled for 2 hours on a water separator, 0.81 (silica gel; methylene chloride / ethyl acetate 8: 2); UV spec- about 4.5 ml of water can be separated. The solution is cooled to volume (ethyl alcohol): A ™ ax = 261 nm (e = 14 400): IR spectrum room temperature, portions within 1 hour (Nujol): characteristic bands at 3.00; 5.56; 5.93; 5.98; 6.06; as a total of 85.5 g of silver p-toluenesulfinate and 6.19; 6.25; 6.54; 6.70; 6.82; 7.02; 7.47; 8.03; 8.76; 9.53; 10.23; 10.60; then stirred further at 22 ° for 2 hours. The mixture 20 12.30; 13.26; 14.30 ji.

is filtered through Hyflo and the filtrate is washed twice with saturated aqueous sodium chloride solution. The organic example 2

see phase is dried over magnesium sulfate, in vacuo a solution of 301 mg (0.462 mmol) of 2- [4- (p-toluenesulfon) is concentrated to about 1 liter, decolorized with 30 g of Norit and nylthio) -3-phenoxyacetamido-2 -oxoazetidin-l-yl} -3-hydroxycro-vapors The yellow foam obtained is crystallized from methylene chloride 25-diphenyl methyl ester in 3 ml of 1,2-dimethoxyethane / diethyl ether. Melting point 79-82 ° C. Rf value under nitrogen atmosphere with 0.12 ml bis-trimethylsilyl-aceta- = 0.55 (silica gel; toluene / ethyl acetate 3: 1). From the mother liquor (0.508 mmol) and stirred for one hour at room gene by crystallization from methylene chloride / diethyl temperature. The solution is completely evaporated down and more quantities of the substance are obtained. the oily residue for one hour under high vacuum d) analogous to example ld) of CH patent 601310 is dried from 10.8 30. The silylated crude product is taken up in 3 ml of dried g (16.2 mM) 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-tem 1,2-dimethoxyethane and after cooling to oxoacetid''-1-yl] -3-methylenebutyric acid diphenylmethyl ester 0 ° C with 0.075 ml (0.508 mmol) 1,5-diazabicyclo [5,4,0] undec-

in 11 methylene chloride and 1.1 equivalents of ozone of 2- [4- (p- 5-ene. After a reaction time of 6 hours at 0 ° C. under toluenesulfonylthio> 3-phenoxyacetamido-2-oxoazetidin-l-yl] -3- a nitrogen atmosphere Diphenylmethyl ester of hydroxycrotonic acid mixed with 0.3 ml of acetic acid is obtained, diluted in 35 and diluted with methylene chloride, the methylene chloride solution at 142-143 ° C. (from ether / pentane) is successively diluted with sulfuric acid, water and

Ozonation can also be carried out at 0 ° C: washed dilute bicarbonate solution. The aqueous Pha-In a solution of 9.23 g (13.8 mmol) of 2- [4- (p-toluenesulfosene are extracted with methylene chloride, the combined nylthio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] - 3-methylene organic phases dried with sodium sulfate, concentrated in a vacuum butyric acid diphenylmethyl ester in 960 ml methylene chloride 40 and dried in a high vacuum. 15.2 mmol of ozone, crude 7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carbon-is conduced within 19 minutes at 0 ° C. The clear reaction solution is diphenylmethyl ester with 10 ml of dimethyl sulfide. The solution of the crude product is added and the mixture is stirred at 5 ° C. for 20 minutes. After one-chloroform, an excess of an ethereal diazomethane solution is seen at 0 ° C. in a water-jet vacuum and drying of the residue, and 5 minutes at 0 ° C. steam high vacuum results in a light yellow foam which has been left in solution. The mixture is then concentrated completely and the ethylene chloride / hexane crystallizes: Melting point of the residue obtained is chromatographed on silica gel as in Example 2. nen 2 {4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoaceti-7ß-phenoxyacetamido-3-methoxy-ceph-3-em-4-din-1-yl] -3-hydroxy-crotonic acid is obtained -diphenylmethyl ester is diphenylmethyl carboxylate; Rf value = 0.19 (silica gel; 134-138 ° C. Thin layer chromatogram: Rf value ~ 0.46 (silicon toluene / ethyl acetate 3: 1); melting point 120 ° C (from ether) IR-cagel; toluene / Ethyl acetate 3: 1). 50 spectrum (in CHCh): 3310.1775.1710.1690.1600 cm-1.

The same compound can also be obtained according to the following methods: Example 3

di) A solution of 684 mg (1 mM) 2- [4- (benzthiazol-2-yldi) A solution of 100 mg (0.146 mmol) 2- [4- (benzthiazol-2-thio) -3-phenoxyacetamido-2 -oxoazetidin-l-yl] -3-hydroxycroton-yIdithio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-hydroxy acid diphenylmethyl ester in 20 ml acetone / water 9: 1 (v / v) 55 Diphenylmethyl crotonic acid in 2 ml of dry methyl is stirred with 341 mg (1.3 mM) of silver p-toluenesulfinate for 60 minutes with lenchloride at 0 ° C. with 0.02 ml (0.16 mmol) of trimethyl room temperature. The yellow reaction mixture is mixed with chlorosilane. To this solution was added 50 ml of acetone under nitrogen and filtered. The filtrate is mixed with and while stirring 0.0477 ml (0.32 mmol) of 1,5-diazabicy-

Evaporated in vacuo and the residue in 30 g of acid-washed clo [5,4,0] undec-5-ene and stirring continued at 0 ° C for 1 hour. After silica gel with toluene / ethyl acetate 4: 1 chromatographic addition of 0.2 ml of acetic acid, the mixture is evaporated with methylene chloride. The obtained 2- [4- (p-toluenesulfonylthio) -3-phenoxyacet- thins. The organic phase is successively diluted with amido-2-oxoazetidin-l-yl] -3-hydroxycrotonic acid-diphenylme- sulfuric acid, amasser and aqueous sodium bicarbonate solution, is recrystallized from ether / pentane and melts, washed, dried over sodium sulfate and at 142-143 ° C. Vacuum concentrated to dryness.

dii) A solution of 72.9 mg (0.1 mM) of crude ozonide, 6 pounds. The crude 7β-phenoxyacetamido-3-hydroxy-ceph obtained is obtained by ozonization of 68.1 mg (0.1 mM) of 2- [4- (benz-3-em-4-carboxylic acid) diphenylmethyl ester in methanol, thiazole-2 -ylthio) -3-phenoxyacetamido-2-oxoazetidin-l-yl> 3-met- dissolved and at 0 ° C with an ethereal solution of diazomethane, diphenylmethyl methylene butyrate in ethyl acetate and added. After 10 minutes, the solution is carefully soaked up

624 683 20

concentrated and the residue dried under high vacuum. The 1-yl] -3-benzyloxy-crotonic acid p-nitrobenzyl ester and the 2- [4-

The residue is purified by thick layer chromatography (p-To! UoIsulfonyIthio) -3-phenoxyacetamido-2-oxoazetidin-l-yI] -

(Toluene / ethyl acetate 3: 1, silica gel). After eluting the silica gel 3-benzyloxy-isocrotonic acid p-nitrobenzyl ester in the ratio of the zone at Rf = 0.17 with ethyl acetate and concentrating the solution of about 1: 1, the 7ß-phenoxyacet-5 is obtained by repeated chromatography as on a rotary evaporator can be separated into the individual isomers. IR

amido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl spectrum of the faster-running crotonic acid derivative (meth-

received; Melting point 120 ° C (from ether). ethylene chloride): characteristic bands at 5,6,5,80,5,90,8,75

p .; NMR spectrum (deuterochloroform): characteristic

Example 4 bands at 2.2 (s), 5.05 (dd), 5.93 (d) ppm; Thin layer chrome

A solution of 731 mg (1 mmol) of a 1: 1 mixture io togramm: Rf value ~ 0.3 (silica gel; toluene / ethyl acetate 2: 1): IR

consisting of the 2 {4- (p-toluenesulfonylthio) -3-phenoxyacet spectrum of the slower-running isocrotonic acid derivative amido-2-oxoazetidin-l-yl] -3-benzyloxy-croton- and the ent- (methylene chloride): characteristic bands in 5,6,5,85 sh,

speaking -isocrotonic acid-p-nitrobenzyl ester is characterized in a 5,90,8,75 p .: NMR spectrum (Deuterochloroform): characteristic

Mixture of 0.185 ml (1.2 mmol) of 1,5-diazabicyclo [5.4.0] undecstic bands at 2.5 (s), 5.41 (dd), 5.77 (d) ppm; Thin-

5-ene in 20 ml of dry tetrahydrofuran during exactly 35 is layer chromatogram: Rf value -0.25 (silica gel; toluene /

Minutes at room temperature. The mixture becomes ethyl acetate 2: 1).

mixed with 50 ml of methylene chloride and successively with dilute hydrochloric acid, water and dilute aqueous sodium example 5

washed bicarbonate solution. The organic phase is dissolved in 405 mg (0.5 mmol) of an isomer mixture

Dried sodium sulfate and evaporated in vacuo. The 20 consisting of the 2 {4- (p-toluenesulfonylthio) -3-phenoxyaceta-

Residue is made up to 25 mg of silica gel washed with acid mido-2-oxoazetidin-l-yl} -3-diphenylmethoxy-crotonic acid-p-

chromatographed with toluene / ethyl acetate (3: 1). A nitrobenzyl ester and the corresponding isomeric isocroton

Mixture consisting of the ceph-2-em and the ceph-3-em acid ester in 8 ml of dry tetrahydrofuran, the 0.9 ml (0.5

bond in the ratio of about 3: 1, which contains, by repeated mmol) l, 5-diazabicyclo [5,4,0] undec-l-ene and stirs

Chromatography is separated into the pure isomers for 25 minutes, exactly 45 minutes at room temperature. The yellow can, whereby the 7β-phenoxyacetamido-3-benzyloxy-ceph reaction mixture is diluted with 25 ml of methylene chloride

2-em-4a-carboxylic acid p-nitrobenzyl ester of melting point and with 0.5 N hydrochloric acid, water and dilute, aqueous 160 ° -162 ° C (diethyl ether / pentane); IR spectrum (methylene-sodium bicarbonate solution washed. The organic phase chloride): characteristic bands at 5,6,5,7,5,9,7,4 n, and the is dried over sodium sulfate and evaporated. 7ß-Phenoxyacetamido-3-benzyloxy-ceph-3-em-4-carboxylic acid-p- 30 This gives an isomer mixture consisting of the nitrobenzyl ester in the form of a colorless foam, IR-spec-7ß-phenoxyacetamido-3-diphenylmethoxy-ceph-2 -em-4a-car-trum (methylene chloride): characteristic bands in 5,6,6,8 b-p-nitrobenzyl ester and the 7ß-phenoxyacetamido-3-sh, 5,9,7,9,8,4 | i , receives diphenylmethoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester,

The mixture of isomers obtained can be further processed as follows: IR spectrum (methylene chloride): characteristic bands are used: 35 5,60,5,70,5,90,6,55,7,40 jx.

The isomer mixture obtained consisting of the 7β-Phe- The obtained isomer mixture of the two compounds noxyacetamido-3-benzyloxy-ceph-2-em-4a-carboxylic acid-p-nitro- can be processed further as follows:

benzyl ester and the 7ß-phenoxyacetamido-3-benzyloxy-ceph- A solution of 340 mg of the isomer mixture obtained

3-em-4-carboxylic acid p-nitrobenzyl ester in a ratio of approximately 5% consisting of the 7β-phenoxyacetamido-3-diphenylme-3: 1 is dissolved in 8 ml of trifluoroacetic acid and during 90 40 thoxy-ceph-2-em-4a- carboxylic acid p-nitrobenzyl ester and the minutes stirred at room temperature. The reaction mixture 7ß-phenoxyacetamido-3-diphenyImethoxy-ceph-3-em-4-carbon mixture is evaporated in vacuo and residues of trifluoric acid p-nitrobenzyl ester in a mixture of 0.5 ml trifluoroacetic acid several times with toluene expelled. The residue is acetic acid and 9.5 ml of methylene chloride is stirred for 40 minutes on 20 g of acid-washed silica gel with toluene / ethyl acetate at room temperature. The mixture is chromatographed in (3: 1), the 7β-phenoxyacetamido-3-45 vacuum being evaporated the residue is mixed with toluene and the hydroxyceph-3-em-4-carboxylic acid p-nitrobenzyl ester is again evaporated in the form. The residue obtained (which still contains a colorless foam is obtained. IR spectrum (methyltrifluoroacetic acid) is applied to 15 g of acid-washed silica gel lenchloride ): characteristic bands at 2.95.3.3.5.6.5.75, sh, chromatographed with toluene / ethyl acetate (3: 1), giving 5.9.5.95 sh, 6.55.7 , 45,8,15,8,3 p,: NMR spectrum (deuterochloride 7ß-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carbon-roform): characteristic bands at 3.4 (2H, AB q, J = 17 Hz), 50 acid p-nitrobenzyl ester; IR spectrum (methylene chloride-4.57 (2H, s), 5.06 (1H, dj = 5 Hz), 5.35 (2H, AB, q, J = 14 Hz), 5.7 rid): characteristic Bands at 2.95.3.3.5.6.5.75 sh, 5.9.5.95 (1H, dd, J = 5.10 Hz), 6.8-8.4 (10H, c ), 11.4 (1H, br.s.) ppm. sh, 6.55.7.45.8, 15.8.3 | i; NMR spectrum (deuterochloroform):

The starting material can be produced as follows: characteristic bands at 3.4 (2H, AB, q, 3— = 17 Hz), 4.57 (2H,

To a solution of 1.282 g (2 mmol) of 2- [4- (p-toluenesulfos), 5.06 (1H, d, 3- = 5 Hz), 5.35 (2H, AB q, jH = 14 Hz), 5.7 (1H, dd,} =

nylthio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-hydroxycro- 55 5.10 Hz), 6.8-8.4 (10 H, c), 11.4 (1H, br. s .) ppm.

p-nitrobenzyl ester in 4 ml of distilled dioxane. The starting material can be obtained as follows:

30 ml of an «in situ» solution of 1.2 g (about 10 to a solution of 641 mg (1 mmol) of 2- [4- (p-toluenesulfo-

mmol) phenyldiazomethane in ether (from N-benzyl-N-nitrotolunylthio) -3-phenoxyacetamido-2-oxoazetidin-l -yl] -3-hydroxycro-

olsulfonamide produced) added at room temperature. p-nitrobenzyl ester in 0.5 ml of distilled dioxane

The mixture is boiled under reflux for 6 hours at 45 ° C. bath temperature, such as a solution of 350 mg (1.75 mmol) of diphenyldiazomethane, mixed with 100 ml of methylene chloride and 0.3 ml of dioxane, and the reaction mixture for 36

thin and then washed with 100 ml of water. The organic hours are heated to 50 ° C. without stirring. The mixture is dried over sodium sulfate in the see phase, evaporated in vacuo, the remaining dioxane is evaporated with toluene and dried in a high vacuum. The resulting obtained is driven off by evaporation again and the residue on yellow oil is poured onto 100 g of silica gel washed with acid and 20 g of acid-washed silica gel with toluene / ethyl acetate (7: 1).

Toluene / ethyl acetate 3: 1 and 2: 1 as the eluent, chromatographed and (3: 1) chromatographed, giving an isomer mixture consisting of which gives an isomer mixture consisting of 2- £ 4- (p-

2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine-toluenesulfonylthio> 3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-

21st

624683

Diphenylmethoxy-crotonic acid p-nitrobenzyl ester and the 2 {4- (p-toluenesulfonylthio> 3-phenoxcyacetamido-2-oxoazetidin-l-yl] -3-diphenylmethoxy-isocrotonic acid p-nitroenzyl ester, IR spectrum (methylene chloride): characteristic bands at 5.6, 5.85 sh, 5.9.6, 25.6, 55.7, 43.8.75 | i.

Example 6

The following compounds can be prepared analogously from suitable intermediates obtainable according to the invention:

7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester,

7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester,

7β-amino-3-hydroxy-3-cephem-4-carboxylic acid diophenyl methyl ester,

7β- [D-a-tert-butyloxycarbonylamino-a-phenylacetylamino> 3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester,

7ß- (5-benzoylamino-5-diphenylmethoxycarbonyl-valeryl-aminoV3-hydroxy-3-cephem-4-carboxylic acid-diphenylmethyl ester,

7β- [D-a-tert-butyloxycarbonylamino-a- (4-hydroxyphenyl) acetylamino} 3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester,

7ß- [D-a-tert-butyloxycarbonylamino-a- (2-thienyl) acetyl-

amino] -3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester,

7β- [D-a-tert-butyloxycarbonylamino-a- (3-thienyl) acetylamino> 3-hydroxy-3-cephem-4-carboxylic acid-diphenylmethyl-5 ster,

7ß- [D-a-tert-butyloxycarbonylamino-a- (2-furyl> acetyl-amino-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester,

7ß- [D-a-tert-butyloxycarbonylamino-a- (4-isothiazolyl> ace-10 ty! Amino] -3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester,

7β- [D-a-tert-butyloxycarbonylamino-a- (1,4-cyclohexadienyl) -acetylamino] -3-hydroxy-3-cephem-4-carboxylic acid diphenyl methyl ester,

15 7β- (2-thienyl) acetylamino-3-hydroxy-3-cephem-4-carbonic acid diphenylmethyl ester,

7ß <l-tetrazolyl) acetylamino-3-hydroxy-3-cephem-4-carbonic acid diphenylmethyl ester,

7ß- (4-pyridylthio) acetylamino-3-hydroxy-3-cephem-4-car-20 bonic acid diphenylmethyl ester,

7ß- (4-aminopyridinium acetylamino> 3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, and

7ß- [D-a- (2,2,2-trichloroethoxycarbonyloxy) -a-phenylacetylamino] -3-hydroxy-3-cephem-4-carboxylic acid-diphenylmethyl-

25th

ster.

Summary

7ß-Amino-3-cephem-3-ol-4-carboxylic acid compounds of the formula I.

(I),

0 = C-R | -

where Ria represents hydrogen or an amino protecting group RiA, Rib represents hydrogen or an acyl group Ac, or Ria and Rib together represent a bivalent amino protecting group and -C (= 0) -R2a is a protected carboxyl group means the corresponding isomeric 3-oxo cepham compounds in which the double bond is in the exo position, and the corresponding isomeric 2-cephem compounds in which the double bond is in the 2,3-position, the isomer mixtures thereof, and the 1-oxides of 3-cephem compounds in 55

Formula I, and salts of such compounds with salt-forming groups, are prepared by splitting off the hydroxyl protective group present as an ether group from corresponding compounds, in which the 3-hydroxyl group is present in protected form.

The compounds can be used as intermediates for the preparation of compounds with pharmacological properties.

Claims (18)

624683 PATENT CLAIMS 1. Process for the preparation of 7β-amino-3-cephem-3-ol-4-carboxylic acid compounds of the formula -H (I) o = c-r; where Ria represents hydrogen or an amino protecting group RiA, Rib represents hydrogen or an acyl group Ac, or Ri "and Rib together represent a divalent amino protecting group and -C (= 0) -R2a represents a protected carboxyl group, the corresponding isomeric 3-oxocepham compounds and 2-cephem compounds, the isomer mixtures thereof, and the 1-oxides of 3-cephem compounds of the formula I, and salts of such compounds with salt-forming groups, characterized in that a compound of the formula II 20th 25th 30th (II) -0-R, 40 in which Ria, Rib and R2a have the meanings given above and Rj denotes a hydroxyl protective group present as an ether group, from a 1-oxide thereof, from a corresponding isomeric 2-cephem compound, or from a mixture of isomers of 3- and 2- Cephem compounds, or from a salt of such a compound with salt-forming groups, the hydroxyl protective group R3 is split off by solvolysis or hydro-genolysis and replaced by hydrogen. 50 2. The method according to claim 1, characterized in that that one uses starting materials of the formula II, in which Ria represents an amino protecting group RiA which stands for an acyl group Ac, in which free functional groups which may be present can be protected, Rib denotes hydrogen 55, Rîa one esterified with the -C (= 0> grouping) Represents etherified hydroxy group forming carboxyl group, where functional groups present in R, an esterified carboxyl group of the formula -C (= Ó) -R2A c can be protected, and R3 means a hydroxyl protective group present as an ether group. 3. The method according to claim 2, characterized in that Rîa is an optionally substituted 1-phenyl-lower alkoxy, such as benzyloxy, p-nitrobenzyloxy or diphenylmethoxy group, or an optionally halogen-substituted b5 lower alkoxy group, such as methoxy, a-polybranched lower alkoxy, e.g. B. tert-butyloxy, or 2-halogeno-lower alkoxy, such as 2,2,2-trichloroethoxy. 4. The method according to claim 1 or 2, characterized in that R3 is an easily removable 2-oxa- or 2-thia-aliphatic or cycloaliphatic hydrocarbon radical, such as 1-lower alkoxy-1-lower alkyl or 1-lower alkylthio-1-lower al- alkyl radical, such as 1-methoxy-l-ethyl, 1-ethoxy-l-ethyl, 1-methylthio 1-ethyl or 1-ethylthio-l-ethyl, or a 2-oxa- or 2-thia-lower alkylene or lower alkenylene radical, with 5-7 ring atoms, such as 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro- 2-pyranyl or a corresponding analog sulfur compound, or a substituted silyl group, such as tri-lower alkylsilyl, such as trimethylsilyl. 5. The method according to claim 1 or 2, characterized in that R3 a-phenyl-lower alkyl, such as benzyl or diphenyl-methyl, wherein as substituents of the phenyl nuclei, for. B. esterified or etherified hydroxy, such as halogen, z. B. fluorine, chlorine or bromine, or lower alkoxy, such as methoxy, means 6. The method according to claim 5, characterized in that a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical R3 by acid hydrolysis, a silyl or stannyl group R3 by hydrolysis, alcoholysis or acidolysis and by hydrogen replaced. 7. The method according to claim 5, characterized in that an optionally substituted a-phenyl-lower alkyl radical R3 is split off by acidolysis or by hydrogenolysis and replaced by hydrogen. 8. The method according to any one of claims 1-7, characterized in that in an obtained compound in which Ria or Rtb is an acyl group, such an acyl group, for. B. by treatment with an imide halide-forming agent, reacting the resulting imide halide with an alcohol and cleaving the imino ether formed, split off and replaced by hydrogen. 9. The method according to any one of claims 1-8, characterized in that protecting a free amino group in a compound obtained, for. B. acylated. 10. The method according to any one of claims 1-9, characterized in that free functional groups not participating in the reaction are temporarily protected. 11. The method according to any one of claims 1-10, characterized in that a compound of formula I obtained, or a mixture obtained consisting of a compound of formula I, and an isomer thereof, in a 1-oxide of a compound of formula I. converts. 12. The method according to any one of claims 1-11, characterized in that reducing an obtained 1-oxide of a compound of formula I to a compound of formula I. 13. The method according to any one of claims 1-12, characterized in that 3-cephem compounds of the formula I, isomers, 1-oxides thereof or salts of such compounds with salt-forming groups in which Rib is hydrogen, Ria is hydrogen or a Acyl group of the formula 0 II - ÇH - C - ■ (B) Rl in which Ra represents phenyl, hydroxyphenyl, hydroxychlorophenyl, thienyl, pyridyl, aminopyridinium, furyl, isothiazyl, tetrazolyl or 1,4-cyclohexadienyl, in which radicals hydroxy substituents can be protected by acyl radicals, X represents oxygen or sulfur, m represents 0 or 1, and Rb represents hydrogen or, if m denotes 0, optionally 624683 protected amino, carboxy, sulfo or hydroxy, or Is 0-lower alkylphosphono or 0.0'-di-lower alkylphosphono, or denotes a 5-amino-5-carboxyvaleryl radical, wherein the amino and carboxy groups are optionally protected, and R2A have the meanings given in claim 3. 14. The method according to claims 13, characterized in that 3-cephem compounds of the formula I, isomers, 1-Oxides or salts of such compounds with salt-forming groups in which Ria is hydrogen or an acyl-io radical of the formula B in which Ra is phenyl, hydroxyphenyl, e.g. B. 4-hydroxyphenyl, thienyl, e.g. b. 2- or 3-thienyl, 4-isothiazolyl or 1,4-cyclohexadienyl, X is oxygen, m is 0 or 1 and Rb is hydrogen or, if m is 0, amino, protected amino, such as acylamino, e.g. B. a-polybranched 15 lower alkoxycarbonylamino, such as tert-butyloxycarbonylamino, or 2-halogeno-lower alkoxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, 2-iodoethoxycarbonylamino or 2-bromo-ethoxycarbonylamino, or optionally lower alkoxy- or nitro-subsubstituted phenylnino carbonylamino. B. 20 4-methoxy-benzyloxycarbonylamino, or hydroxy, and also protected hydroxy, such as acyloxy, e.g. B. a-polybranched lower alkoxycarbonyloxy, such as tert-butyloxycarbonyloxy, or 2-Halogen-lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycar- 25 bonyloxy, furthermore formyloxy, or for a 5-amino- 5-carboxy-valeryl radical, in which the amino and carboxy group can also be protected and z. B. as acylamino, e.g. B. Niederalkanoylamino, such as acetylamino, Halogenniederal-kanoylamino, such as dichloroacetylamino, benzoylamino, or 30 phthaloylamino, or as esterified carboxy, such as phenyl-lower alkoxycarbonyl, z. B. Diphenylmethoxycarbonyl, are present, preferably m being 1 when Ra is phenyl or hydroxylphenyl, rib is hydrogen, and R2A is optionally in the 2-position halogen, z. B. chlorine, bromo or iodine-sub- 35 substituted lower alkoxy, especially a-polybranched lower alkoxy, e.g. B. tert-butyloxy, or 2-halogeno-lower alkoxy, e.g. B. 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally lower alkoxy, such as methoxy-substituted diphenylmethyloxy, e.g. B. Diphenylmethoxy or 4,4'-Dime- 40 thoxy-diphenylmethoxy, p-nitrobenzyloxy, further Triniederal-kylsilyloxy, z. B. trimethylsilyloxy. 15. The method according to any one of claims 1-14, characterized in that the 7ß-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester is produced. 16. The method according to any one of claims 1-14, characterized in that the 7ß-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester is prepared. 50