DE2506330A1 - PROCESS FOR MANUFACTURING ENOL DERIVATIVES - Google Patents

Description

Process for the preparation of enol derivatives

The present invention is a Process for the preparation of enol derivatives, in particular 7ß-amino-3-cephem-3-ol-4-carboxylic acid compounds of formula

(IA),

where Rf is hydrogen or an amino protecting group R ^ poses, and r? for hydrogen or an acyl group Ac

away

or R, and R, together represent a divalent amino protective group, R _{2 represents hydroxy or a radical R 2 which forms} a protected carboxyl group together with the carbony group -C (= 0) -, and R 2

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for hydrogen, lower alkyl, or for a hydroxy protecting group and 1-oxides of 3-cephem compounds of the formula IA, and the corresponding 2-cephem compounds of the formula *

(IB)

where R-, R ,, R "and R ~ have the meanings given above, or salts of such compounds with salt-forming groups. '

The enol derivatives of the present invention are ethers of 3-cephem-3-ol or 2-cephem-3-ol compounds.

In 2-cephem compounds of the formula IB with the double bond in the 2,3-position, the optionally split carboxyl group of the formula -C (= O) -R ₂ preferably has the α configuration.

An amino protecting group, R, is one through hydrogen replaceable group, primarily an acyl group Ac, also a triarylmethyl, especially the trityl group, as well as an organic Siiyl-, or an organic

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Stannyl group. A group Ac, which also represents a remainder of R .. can stand, primarily represents the acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, in particular the acyl radical of an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid (incl. Formic acid), as well as the acyl radical of a carbonic acid half derivative.

a b One formed by the radicals R- and R- together

The divalent amino protective group is in particular the divalent acyl radical of an organic dicarboxylic acid, preferably with up to 18 carbon atoms, primarily the diacyl radical of an aliphatic or aromatic dicarboxylic acid, and also the acyl radical of an α preferably substituted in the α position, e.g. containing an aromatic or heterocyclic radical -Aminoacetic acid, in which the amino group is connected to the nitrogen atom via a, preferably substituted, for example two lower alkyl, such as methyl group-containing methylene radical. The radicals R ₁ and R ₁ together can also represent an organic, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic ylidene radical, preferably with up to 18 carbon atoms.

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A split carboxyl group of the formula

-C (= O) -R «is primarily an esterified carboxyl group, but can also have a usually mixed anhydride group or represent an optionally substituted carbamoyl or hydrazinocarbonyl group.

The group R ₂ can therefore be a hydroxyl group etherified by an organic radical, in which the organic radical preferably contains up to 18 carbon atoms, which together with the -C (= 0) group forms 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, as well as heterocyclic or heterocyclic-aliphatic radicals.

The group R "can also represent an organic silyloxy radical, as well as a hydroxyl group etherified by an organometallic radical, such as a corresponding organic Stannyloxy group, especially one through 1 to 3, if appropriate substituted hydrocarbon radicals, preferably with up to 18 carbon atoms, such as aliphatic hydrocarbon radicals, and optionally represented by halogen, such as chlorine-substituted silyloxy or stannyloxy groups.

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A radical R "which forms a primarily mixed anhydride group with a —C (= 0) group is, for example Halogen, such as chlorine or an acyloxy radical, in which acyl is the corresponding radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic carboxylic acid "or a carbonic acid half-derivative, like a carbonic acid half-ester.

One with a -C (= 0) grouping is a carbamoyl group The radical R 1 which forms is an optionally substituted amino group in which substituents are optionally substituted monovalent or divalent hydrocarbon radicals, preferably with 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 optionally functionally modified, in particular free hydroxy, and also etherified or esterified hydroxy, wherein the etherifying or esterifying For example, radicals have the meanings given above and preferably contain up to 18 carbon atoms, as well as

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Acyl residues, primarily of organic carboxylic acids and carbonic acid half-derivatives, preferably with up to 18 Carbon atoms.

In a substituted hydrazinocarbonyl group of

Formula -C ( ⁵ O) -IL, one or both nitrogen atoms can be substituted, the substituents primarily being optionally substituted monovalent or divalent 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, also 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 carbonic acid half-derivatives, preferably with up to 18 carbon atoms, are eligible.

A lower alkyl group R ~ has up to 7, preferably up to 4 carbon atoms and is especially methyl.

A hydroxy protecting group R- is for example an easily cleavable 2-oxa or 2-thia-aliphatic or cycloaliphatic hydrocarbon radical, an easily cleavable one substituted silyl or stannyl group, or one as well Easily cleavable, optionally substituted a-phenyl-lower alkyl such as optionally substituted benzyl or diphenylmethyl group.

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The in the preceding and following toigencreTiTö'ES'cnrexbung The general terms used have the following meanings, for example:

An aliphatic radical, including the aliphatic radical of a corresponding organic carboxylic acid, as well as a corresponding ylidene radical is an optionally substituted monovalent or divalent aliphatic hydrocarbon radical, in particular lower alkyl, as well as lower alkenyl or lower alkynyl, furthermore lower alkylidene, e.g. up to 7, preferably can contain up to 4 carbon atoms. Such radicals can optionally be replaced by functional groups, e.g. by free, etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylene teakiioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylthio or optionally substituted Phenylthio, phenyl-lower alkylthio, heterocyclylthio or heterocyclyl-lower alkylthio, optionally substituted Lower alkoxycarbonyloxy or lower alkanoyloxy, or halogen, also optionally substituted by oxo, nitro Amino, e.g. lower alkylamino, di-lower alkylamino, lower alkylenamino, oxane-lower alkylenamino or aza-lower alkylenamino, and acylamino, such as lower alkanoylamino, lower alkoxy-carbonylamino, halo-lower alkoxycarbonylamino,

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optionally substituted phanyl-lower alkoxycarbonylamino, optionally substituted carbamoylamino, ureidocarbonylamino or guanidinocarbonylamino, also optionally in Salt, such as alkali metal salt form present sulfoamino, azido, Acyl, such as lower alkanoyl or benzoyl, optionally functionally modified carboxyl, such as present in salt form Carboxyl, esterified carboxyl, such as lower alkoxycarbonyl, optionally substituted carbamoyl, such as N-lower alkyl or Ν, Ν-di-lower alkylcarbamoyl, also optionally substituted Ureidocarbonyl or guanidinocarbonyl, or cyano, 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 example optionally substituted lower alkyl, phenyl or phenyl lower alkyl, where O-unsubstituted or O-monosubstituted phosphono also in salt and alkali metal salt form may be present, mono-, di- or polysubstituted.

A divalent aliphatic radical, including the corresponding radical of a divalent aliphatic carboxylic acid is, for example, lower alkylene or lower alkenylene, which is optionally e.g. as an aliphatic radical indicated above, mono-, di- or polysubstituted and / or by heteroatoms, such as Oxygen, nitrogen or sulfur can be interrupted.

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

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An aromatic radical, including the aromatic radical of a corresponding carboxylic acid, is an optional one substituted aromatic hydrocarbon radical, e.g., a mono-, bi- or polycyclic aromatic hydrocarbon rest, especially phenyl, as well as biphenylyl or naphthyl, if necessary, e.g. like the above-mentioned aliphatic and cycloaliphatic hydrocarbon radicals, mono-, di- or polysubstituted.

A divalent aromatic radical, e.g., an aromatic carboxylic acid, is primarily 1,2-arylene, in particular 1,2-phenylene, optionally such as those mentioned above aliphatic and cycloaliphatic hydrocarbon radicals, mono-, di- or polysubstituted.

An araliphatic radical, including the araliphatic radical in a corresponding carboxylic acid, also includes araliphatic ylidene radical is, for example, an optionally substituted araliphatic hydrocarbon radical such as a optionally substituted, e.g. up to three, optionally substituted mono-, bi- or polycyclic, aromatic Aliphatic hydrocarbon radical containing hydrocarbon radicals and is primarily phenyl-lower alkyl or phenyl-lower alkenyl, as well as phenyl-lower alkynyl, furthermore phenyl lower alkylidene, such radicals containing e.g. 1-3 phenyl groups and optionally, e.g. such as

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- li -

Above aliphatic and cycloaliphatic radicals, im aromatic and / or aliphatic part mono-, di- or polysubstituted could be.

Heterocyclic groups, including those in heterocyclic-aliphatic radicals, including heterocyclic groups or heterocyclic-aliphatic groups in corresponding carboxylic acids are, in particular, monocyclic ones, as well bi- or polycyclic aza, thia, oxa, thiaza, thiadiaza, oxaza, diaza, triaza or tetrazacyclic radicals aromatic character, also corresponding partially or fully saturated heterocyclic radicals of this type, such Residues, for example such as the cycloaliphatic radicals mentioned above, may optionally be mono-, di- or polysubstituted. The aliphatic part in heterocyclic-aliphatic radicals has, for example, that for the corresponding cycloaliphatic-aliphatic or araliphatic radicals given meaning.

The acyl radical of a carbonic acid half derivative is preferably the acyl radical of a corresponding half ester, wherein the organic residue of the ester group is an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical or a heterocyclic-aliphatic radical, in the first place

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Line the acyl radical of an optionally substituted lower alkyl half-ester of carbonic acid, e.g. in the α- or ß-position, and a lower alkenyl, cycloalkyl, phenyl or phenyl lower alkyl half ester which is optionally substituted in the organic radical of carbonic acid. Acyl residues of a carbonic acid half ester are also corresponding residues of lower alkyl half esters carbonic acid, in which the lower alkyl part is a heterocyclic group, e.g. one of the above heterocyclic groups of aromatic character, where both the lower alkyl radical, as well as the heterocyclic Group can optionally be substituted. The acyl radical of a carbonic acid half derivative can optionally also be one N-substituted carbamoyl group such as an optionally halogenated N-lower alkylcarbamoyl group. An etherified hydroxy group is primarily optionally substituted lower alkoxy in which substituents primarily free or functionally modified, such as etherified or esterified hydroxyl groups, in particular lower alkoxy or halogen, furthermore lower alkenyloxy, cycloalkyloxy or optionally substituted phenyloxy, and also heterocyclyloxy or heterocyclyl-lower alkoxy, in particular also optionally substituted phenyl-lower alkoxy.

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An optionally substituted aromatic group is, for example, amino, lower alkylamino, di-lower alkylamino, lower alkylenamino, Oxaniederalkylenamino, Thianiederalkylenamino, Azaniederalkylenamino, Hydroxyamino, Niederalkoxyamino, Lower alkanoyloxyamino, lower alkoxycarbonylamino or lower alkanoylamino.

An optionally substituted hydrazino group is, for example, hydrazino, 2-lower alkylhydrazino, 2,2-di-lower alkylhydrazino, 2-lower alkoxycarbonylhydrazino or 2-lower alkanoyl hydrazino.

Lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl or tert-butyl, as well as n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl, while lower alkenyl e.g. vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl, lower alkynyl e.g. propargyl or 2-butynyl, and lower alkylidene, e.g., isopropylidene or isobutylidene.

Lower alkylene is, for example, 1,2-ethylene, 1,2- or 1,3-propylene, 1,4-butylene, 1,5-pentylene or 1,6-hexylene, while lower alkenylene, e.g. 1,2-ethenylene or 2-buten-1,4-ylene is. Lower alkylene interrupted by heteroatoms is, for example, oxane-lower alkylene, such as 3-oxa-l, 5-pentylene, thian-lower alkylene, such as 3-thia-1,5-pentylene, or aza-lower alkylene, such as 3-lower-alkyl-3-aza-1,5-pentylene, e.g. 3-methyl-3-aza-1,5-pentylene.

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Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, as well as adamantyl, cycloalkenyl e.g. cyclopropenyl, 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 3-cycloheptenyl or 1,4-cyclohexadienyl, and cycloalkylidene, for example cyclopentylidene or cyclohexylidene. Cycloalkyl-lower alkyl or -lower alkenyl is, for example cyclopropyl, cyclopentyl, cyclohexyl or Cycloheptylraethyl, -1,1-'or -1,2-ethyl, -1,1-, -1,2- or -1, 3-propyl , vinyl or allyl, while cycloalkenyl lower alkyl or lower alkenyl, for example 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl or 1-, 2- or 3-cycloheptenylmethyl, -1,1- or -1,2-ethyl, -1,1-, -1,2- or -1,3-propyl, vinyl or allyl. Cycloalkyl-lower alkylidene is, for example, 3-Cyclohexenylöiethylen.

Napthyl is 1- or 2-naphthyl while biphenylyl e.g. represents 4-biphenylyl.

Is phenyl-lower alkyl or phenyl-lower alkenyl e.g. benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, Diphenylmethyl, trityl, styryl or cinnamyl, Naphthyl-lower alkyl e.g. 1- or 2-naphthylmethyl, and Phenyl lower alkylidene e.g. benzylidene.

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Heterocyclic radicals are primarily optionally substituted aromatic heterocyclic radicals Character, e.g. corresponding monocyclic, monoaza-, monothia- or monooxacyclic radicals, such as pyrryl, e.g. 2-pyrryl or 3-pyrryl, pyridyl, e.g. 2-, 3- or 4-pyridyl, furthermore Pyridinium, thienyl, e.g. 2- or 3-thienyl, or furyl, e.g. 2-furyl, bicyclic monoaza, monooxa, or monothiacyclic Radicals such as indolyl, e.g. 2- or 3-indolyl, quinolinyl, e.g. 2- or 4-quinolinyl, isoquinolinyl, e.g. 1-isoquinolinyl, Benzofuranyl, e.g., 2- or 3-benzofuranyl, or benzothienyl, e.g., 2- or 3-benzothienyl, monocyclic diaza, triaza, tetraza, oxaza, thiaza or thiadiazacyclic radicals, such as imidazolyl, e.g. 2-imidazolyl, pyrimidinyl, e.g. 2- or 4-pyrimidinyl, triazolyl, e.g. 1,2,4-triazol-3-yl, Tetrazolyl, e.g. 1- or 5-tetrazolyl, oxazolyl, e.g. 2-oxazolyl, isoxazolyl, e.g. 3- or 4-isoxazolyl, Thiazolyl, e.g. 2-thiazolyl, isothiazolyl, e.g. 3- or 4-isothiazolyl or 1,2,4- or 1,3,4-thiadiazolyl, e.g. l, 2,4-thiadiazol-3-yl or l, 3,4-thiadiazol-2-yl, or bicyclic diaza, oxaza- or thiazacyclic radicals, such as benzimidazolyl, e.g. 2-benzimidazolyl, benzoxazolyl, e.g., 2-benzoxazolyl, or benzthiazolyl, e.g., 2-benzthiazolyl. Corresponding partially or completely saturated residues

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are, for example, tetrahydrothienyl, such as 2-tetrahydrothienyl, tetrahydrofuryl, such as 2-tetrahydrofuryl, or piperidyl, e.g. 2- or 4-piperidyl. Heterocyclic-aliphatic radicals are heterocyclic Groups, especially those mentioned above, containing lower alkyl or lower alkenyl. The above-mentioned heterocyclyl residues can, for example, by optionally substituted aliphatic or aromatic hydrocarbon radicals, in particular Lower alkyl, such as methyl, or optionally phenyl substituted, e.g., by halogen, such as chlorine, e.g., phenyl or 4-chlorophenyl, or, e.g. like the aliphatic hydrocarbon radicals, be substituted by functional groups.

Lower alkoxy is e.g. methoxy, ethoxy, n-propyloxy, Isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy or tert-pentyloxy. These groups can be substituted, e.g. as in halo-lower alkoxy, especially 2-halo-lower alkoxy, e.g. 2,2,2-trichloro-, 2-chloro, 2-bromo- or 2-iodoethoxy. Lower alkenyloxy is e.g. vinyloxy or allyloxy, lower alkylenedioxy e.g. methylenedioxy, ethylenedioxy or isopropylidenedioxy, Cycloalkoxy, e.g. cyclopentyloxy, cyclohexyloxy or adamantyloxy, Phenyl-lower alkoxy, e.g. benzyloxy, 1- or 2-phenylethoxy, diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, or heterocyclyloxy or heterocyclyl-lower alkoxy, e.g.

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Pyridyl lower alkoxy, such as 2-pyridyl methoxy, furyl lower alkoxy, such as furfuryloxy, or thienyl-lower alkoxy, such as 2-thenyloxy.

Lower alkylthio is e.g. methylthio, ethylthio or n-butylthio, lower alkenylthio e.g. allylthio, and phenyl lower alkylthio e.g. benzylthio, while heterocyclyl · ^

residues or heterocyclylaliphatic residues etherified. mercapto groups in particular pyridylthio, e.g. 4-pyridylthio, imidazolylthio, Thiazolylthio, e.g., 2-thiazolylthio, 1,2,4- or 1,3,4-thiadiazolylthio, e.g. 1,2,4-thiadiazol-3-ylthio or 1,3,4-thiadiazol-2-ylthio, or tetrazolylthio, e.g., 1-methyl-5-tetrazolylthio are.

Esterified hydroxyl groups are primarily halogen, e.g. fluorine, chlorine, bromine or iodine, as well as lower alkoxycarbonyloxy, e.g. methoxycarbonyloxy, ethoxycarbonyloxy or tert-butyloxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy, e.g. 2,2,2-trichloroethoxycarbonyloxy, 2-bromoethoxycarbonyloxy or 2-iodethoxycarbonyloxy, or arylcarbonylmethoxycarbonyloxy, e.g., phenacyloxycarbonyloxy.

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

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N-lower alkyl or Ν, Ν-di-lower alkyl carbamoyl is, for example, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl or Ν, Ν-diethylcarbamoyl, while N-lower alkylsulfamoyl e.g. N-methylsulfamoyl or N, N-dimethylsulfamoyl represents.

A carboxyl present in alkali metal salt form or sulfo is, for example, one in the sodium or potassium salt form Carboxyl or sulfo.

Lower alkylamino or di-lower alkylamino is e.g. Methylamino, ethylamino, dimethylamino or diethylamino, lower alkylenamino e.g. pyrrolidino or piperidino, oxane lower alkylenamino e.g., morpholino, thian-lower alkylenamino, e.g., thiomorpholines, and aza-lower alkylenamino, e.g., piperazino or 4-methylpiperazino. Acylamino in particular stands for Carbamoylamino, lower alkylcarbamoylamino, such as methylcarbamoylamino, Ureidocarbonylamino, guanidinocarbonylamino, lower alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or tert-butyloxycarbonylamino, halo-lower alkoxycarbonylamino, like 2,2,2-Trichloräthoxycarbonylamino, Phenyl-lower alkoxycarbonylamino, such as 4-methoxybenzyloxycarbonylamino, Lower alkanoylamino, such as acetylamino or propionylamino, also for phthalimido, or optionally sulfoamino present in salt, such as alkali metal, e.g. sodium, or ammonium salt form.

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Lower alkanoyl is, for example, formyl, acetyl, propionyl or pivaloyl.

O-lower alkyl-phosphono is, for example, O-methyl- or O-ethyl-phosphono, 0,0'-di-lower alkyl-phosphono, e.g. 0,0-dimethyl-phosphono or 0,0'-diethyl-phosphono, O-phenyl-lower alkyl-phosphono, e.g. O-benzyl-phosphono, and O- ^{lower alkyl-O 1} -phenyl-lower alkyl-phosphono, for example O-benzyl-0 ¹ -methy1-phosphono.

Mederalkenyloxycarbonyl is e.g. vinyloxycarbonyl, while cycloalkoxycarbonyl and phenyl-lower alkoxycarbonyl, e.g. adamantyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, Diphenylmethoxycarbonyl or α-4-biphenyl-amethyl-ethoxycarbonyl represents. Lower alkoxycarbonyl, in which lower alkyl is e.g. contains monothiacyclic group is e.g. furyl-lower alkoxycarbonyl, such as furfuryloxycarbonyl, or thienyl-lower alkoxycarbonyl, such as 2-thenyloxycarbonyl.

Is 2-lower alkyl and 2,2-di-lower alkyl hydrazino e.g., 2-methylhydrazino or 2,2-dimethylhydrazino, 2-lower alkoxycarbonylhydrazino e.g. 2-methoxycarbonylhydrazino, 2-ethoxycarbonylhydrazino or 2-tert.-butyloxycarbonylhydrazino, and lower alkanoyl hydrazino, e.g., 2-acetyl hydrazino.

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An acyl group Ac stands in particular for one in a naturally occurring or in a bio, semi- or totally synthetically producible, preferably pharmacologically active N-acyl derivative of a 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem-4-carboxylic acid compound containing acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, or an easily cleavable acyl radical, in particular a carbonic acid half-derivative.

One in a pharmacologically active N-acyl derivative of an δ-amino-penam-S-carboxylic acid or 7-amino-3-cephem-4-carboxylic acid compound The acyl radical Ac contained is primarily a group of the formula

R ¹¹

^R 0

(C) _n C (A)

where η is 0 and R is hydrogen or optionally one substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted one heterocyclic radical, preferably of aromatic character, a functionally modified, e.g. esterified or

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denotes etherified hydroxyl or mercapto or an optionally substituted amino group, or in which η denotes 1, R is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic Radical in which the heterocyclic radical is preferably aromatic and / or quaternary Has 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 represents substituted amino group or an azido group, and each of the radicals R and R is hydrogen, or where η is 1, R is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residue or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical preferably aromatic character

-J *

R has an optionally functionally modified, e.g. esterified or etherified hydroxyl 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 one Is phosphono group, or an azido group, and R is hydrogen, or where η is 1, any of R and R radicals are a functionally modified, preferably etherified or esterified hydroxyl group or an optionally is a functionally modified carboxyl group, and R is hydrogen, or in which η is 1, R hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

means aromatic or araliphatic hydrocarbon radical and R and R together are optionally substituted by a double bond with the carbon atom linked aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical, or in which η is 1 and R is a optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic aliphatic A radical in which heterocyclic radicals preferably have an aromatic character, R an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and R is hydrogen or optionally one substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical mean.

In the above-mentioned acyl groups of the formula A, for example, η stands for O and R stands for hydrogen or an optionally preferably in the 1-position by possibly protected Amino, acylamino, in which acyl primarily represents the acyl radical of a carbonic acid half-ester, such as a lower alkoxycarbonyl, 2-halo-lower alkoxycarbonyl or phenyl-lower

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alkoxycarbonyl radical, or one, optionally in salt, e.g. sulfoamino group present in alkali metal salt form, substituted Cycloalkyl group with 5-7 ring carbon atoms, one optionally, preferably by hydroxy, lower alkoxy, e.g. methoxy, acyloxy, in which acyl primarily represents the acyl radical of a carbonic acid half-ester, such as a lower alkoxycarbonyl, 2-halo-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl radical and / or halogen, e.g. chlorine, substituted phenyl, naphthyl or tetrahydronaphthyl group, an optionally, e.g. by lower alkyl, e.g. methyl, and / or phenyl, which in turn has substituents such as halogen, e.g. chlorine, substituted heterocyclic group such as a 4-isoxazolyl group, or a preferably, e.g. by an optionally substituted, such as halogen, e.g. chlorine, containing lower alkyl radical N-substituted amino group, or η for 1, R for an optionally, preferably by halogen, such as chlorine, by optionally substituted, such as hydroxy, acyloxy, in which acyl has the meaning given above, and / or containing halogen, e.g. chlorine Phenyloxy, or by optionally protected amino and / or carboxy substituted lower alkyl group, e.g. for a 3-Amino-3-carboxy-propyl radical with optionally protected Amino and / or carboxy group, e.g. silylated, such as tri-lower alkylsilylated, e.g. trimethylsilylated, amino or

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Acylamino, such as lower alkanoylamino, halo-lower alkanoylamino or phthaloylamino group, and / or silylated, such as tri-lower alkylsilylated, e.g., trimethylsilylated, or esterified, such as by lower alkyl, 2-halo-lower alkyl or phenyl lower alkyl, e.g., diphenylmethyl, esterified Carboxy group, for a lower alkenyl group, for an optionally substituted one, such as optionally, e.g. as above indicated, acylated hydroxy and / or halogen, e.g. chlorine, also optionally protected, e.g. as indicated above, acylated amino lower alkyl, such as aminomethyl, or optionally, e.g., as indicated above, phenyloxy containing acylated hydroxy and / or halogen, e.g., chlorine Phenyl group, optionally protected, e.g. by lower alkyl such as methyl, or optionally protected, e.g. as above stated acylated, amino or aminomethyl, substituted pyridyl, e.g. 4-pyridyl, pyridinium, e.g. 4-pyridinium, Thienyl, e.g. 2-thienyl, furyl, e.g. 2-furyl, imidazolyl, e.g. 1-imidazolyl, or tetrazolyl, e.g. 1-tetrazolyl group, an optionally substituted lower alkoxy, e.g. methoxy group, an optionally substituted one such as optionally protected, e.g. acylated as indicated above. Hydroxy and / or halogen, such as chlorine, containing phenyloxy group, a lower alkylthio, e.g. n-BuCylthio, or lower alkenylthio, e.g. allylthio group, one optionally, e.g.

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-Vb-

Nxederalkyl, such as methyl, substituted phenylthio, pyridylthio, e.g. 4-pyridylthio-, 2-imidazolylthio-, 1,2,4-triazol-3-ylthio-, 1,3,4-triazol-2-ylthio-, l ^^ - Thiadiazol-S-ylthio-, like S-methyl-l ^^ - thidiazol-S-ylthio-, l, 3,4-thiadiazol-2-ylthio-, such as methyl-l, 3,4-thiadiazol-2-ylthio, or 5-tetrazolylthio, such as l-methyl-5-tetrazolylthio, a halogen, in particular chlorine or bromine atom, one optionally functional modified carboxyl group, such as lower alkoxycarbonyl, e.g. methoxycarbonyl or ethoxycarbonyl, cyano or optionally, e.g. by lower alkyl, such as methyl, or phenyl, N-substituted carbamoyl, an optionally substituted one Lower alkanoyl, e.g. acetyl or propionyl, or benzoyl group. or an azido group, and R and R for hydrogen, or η for 1, R for lower alkyl or an optionally, as substituted by optionally acylated hydroxy and / or halogen, e.g., chlorine, e.g. Phenyl, furyl, e.g. 2-furyl, thienyl, e.g. 2- or 3-thienyl or isothiazolyl, e.g. 4-isothiazolyl group, furthermore for a 1,4-cyclohexadienyl group, R for optionally protected or substituted amino, e.g., amino, acylamino such as lower alkoxycarbonylamino, 2-halo-lower alkoxycarbonylamino or optionally substituted, such as lower alkoxy, e.g. methoxy, or nitro-containing phenyl

fä €} P 'S -3 / f) q ^£ v ■■ :;

-JtV

lower alkoxycarbonylamino, e.g. tert-butyloxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, 4-methoxybenzyloxyearbonylamino or DiphenylmethyLoxycarbonylamino, Arylsulfonylamino, e.g. 4-Methylphenylsulfonylami.no, tritylamino, arylthioamino, such as nitrophenylthioamino, e.g. 2-nitrophenylthioamino, or Tritylthioamino or optionally substituted, such as lower alkoxycarbonyl, e.g. ethoxycarbonyl, or lower alkanoyl, e.g. acetyl, containing 2-propylideneamino, such as 1-ethoxycarbonyl-2-propylideneamino, or optionally substituted carbamoylamino, such as guanidinocarbonylamino, or a, optionally in salt, e.g., alkali metal, salt form Sulfoamino group, an azido group, an optionally in salt, e.g. alkali metal salt form or in protected, such as esterified form, e.g. as lower alkoxycarbonyl, e.g. methoxycarbonyl or ethoxycarbonyl, or as phenyloxycarbonyl, e.g., a diphenylmethoxycarbonyl group, a cyano group, a sulfo group, an optional functionally modified hydroxy group, where functionally modified hydroxy in particular acyloxy, such as Formyloxy, as well as lower alkoxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy or optionally substituted, such as lower alkoxy, e.g. methoxy, or nitro-containing phenyl-lower alkoxycarbonyloxy, e.g. tert-butyloxycarbonyloxy, 2,2,2-trichloroethoxycarbonyloxy, 4-methoxybenzyloxycarbonyl-

509836 / 097Q

oxy or diphenylmethoxycarbonyloxy, or optionally substituted lower alkoxy, for example methoxy, or phenyloxy. represents an O- _{lower alkyl or O 5} O ¹ -diniederalkyl-phosphono group, e.g. O-methyl-phosphono or 0,0'-dimethylphosphono, or a halogen atom, e.g. chlorine or bromine, and R for hydrogen, or η for 1, R and R each for halogen, e.g. bromine, or lower alkoxycarbonyl, e.g. methoxycarbonyl, and R for hydrogen, or η for 1, R for an optionally acylated hydroxy and / or halogen, e.g. chlorine, for example by optionally, e.g. as stated above, substituted phenyl, furyl, for example 2-furyl, or thienyl, for example 2- or 3-thienyl, or isothiazolyl, for example 4-isothiazolyl group, also for a 1,4-cyclohexadienyl group, R for optionally, for example as above indicated, slotted aminomethyl, and

III I

R for hydrogen, or η for 1 and each of the group R,

R ¹¹ and R ^{111 represent} lower alkyl, for example methyl.

Such acyl radicals Ac are e.g. formyl, cyclopentylcarbonyl, α-aminocyclopentylcarbonyl or α-amino-eyelohexylcarbonyl (with optionally substituted amino group, e.g. sulfoamino group optionally present in salt form, or one, by one, preferably easily, e.g. when treating with an acidic agent such as trifluoroacetic acid, reductive, e.g. when treating with a chemical reducing agent

509836/0970

-M-

agents, such as zinc in the presence of aqueous acetic acid, or catalytic hydrogen, or hydrolytically cleavable or an acyl radical which can be converted into such, preferably a suitable acyl radical of a carbonic acid half-ester, such as lower alkoxycarbon3> \ L, for example tert. -Butyloxycarbonyl, 2-halo-lower alkylcarbonyl, e.g. 2,2,2-trichloroethyloxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, arylcarbonylmethoxycarbonyl, e.g. phenacyloxycarbonyl, optionally substituted, such as lower alkoxy, e.g. methoxy, or nitro-containing phenyl-lower alkoxycarbonyl, e.g. Methoxybenzyloxycarbonyl or Diphenylmethoxycarbonyl »or a carbonic acid half-amide, such as Garbamoyl or N-substituted, such as N-lower alkyl, eg N-Methylcarbamoy.l, as well as by trityl, also by arylthio» eg 2-nitrophenylthio, ary! Sulfonyl, eg 4-methylphenylsulfonyl or 1-lower alkoxycarbonyl-2-propylidene, 2, B. 1-ethoxycarbonyl-2-propylidene, substituted amino groups 2,6-dimethoxybenzoyl, 5,6,7,8-tetrahydro-naphthoyl, 2-methoxy-1-naphthoyl, 2-ethoxy-l-naphthoyl, benzyloxycarbonyl, hexahydrobenzyloxycarbonyl _s S-methyl- S-phenyi- ^ isoxazolylcarbonyl, 3- (2-chlorophenyl) -5-methyl-4-isoxazolylcarbonyl-, 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarbonyl, 2-chloroethylaminocarbonyl, acetyl, Pr ^ fopionyl, butyryl, pivaloyl, hexanoyl, octanoyl, acrylyl, crotonoyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl,

509836/0970

Butylthioacetyl, allylthioacetyl, methylthioacetyl, chloroacetyl, Bromoacetyl, dibromoacetyl, 3-chloropropionyl, 3-bromopropionyl, Aminoacetyl or 5-amino-5-carboxy-valeryl (with optionally, e.g. as indicated, such as by a monoacyl or diacyl radical, e.g. an optionally halogenated lower alkanoyl radical, such as acetyl or dichloroacetyl, or phthaloyl, substituted amino group and / or optionally functional modified, e.g. in salt, such as sodium salt, or in ester, such as lower alkyl, e.g. methyl or ethyl, or aryl lower alkyl, e.g. Diphenylmethylesterform, present carboxyl group), Asidoacetyl, Carboxyacetyl, Methoxycarbonylacetyl, Aethoxycarbony / acetyl, Bis-methoxy-carbonylacetyi, N-Phenylcarbameylacetyi, Cyanoacetyl, α-cyanopropionyl, 2-cyano-3,3-dimethyl-acrylyl, Phenylacetyl, ot-bromophenylacetyl, a-azidophenylacetyl, 3-chlorophenylacetyl, 2- or 4-aminomethylphenyl-acetyl (with optionally substituted amino group, e.g. as indicated), phenacylcarbonyl, phenyloxyacetyl, 4-trifluoromethylphenyloxyacetyl, benzyloxyacetyl, phenylthioacetyl, Bromophenylthioacetyl, 2-phenyloxypropionyl, a-phenyloxyphenylacetyl, a-methoxyphenylacetyl, a-ethoxyphenylacetyl, α-methoxy-S ^ -dichlorophenylacetyl, α-cyano-phenylacetyl, in particular Phenylglycyl, 4-hydroxyphenylgiycyi, 3-chloro-4-hydroxyphenylglycyl, 3,5-dichloro-4-hydroxyphenylglycyl, a-amino-a- (1,4-cyclohexadienyl) -acetyl, a-amino-α- (1-cyclo-

hexenyl) acetyl, α-amino- - -_

509836/0970

methyl-α-phenylacetyl or a-hydroxyphenylacetyl, where in an amino group present may optionally be substituted for these radicals, for example as indicated above, and / or a Any aliphatic and / or phenolically bound hydroxyl group present, analogous to the amino group, e.g. a suitable acyl radical, in particular by formyl or an acyl radical of a carbonic acid half ester, can be protected), or α-0-methyl-phosphono-phenylacetyl or a-O, O-dimethylphosphono-phenylacetyl, also benzylthioacetyl, benzylthiopropionyl, α-carboxyphenylacetyl (with, if appropriate, e.g. as stated above, a functionally modified carboxy group), 3-phenylpropionyl, 3- (3-cyanophenyl) -propionyl, 4- (3-methoxyphenyl) -butyryl, 2-pyridylacetyl, 4-aminopyridinium acetyl (optionally with, e.g. as stated above, substituted amino group), 2-thienylacetyl, 3-thienylacetyl, 2-tetrahydrothienyl / acetyl, 2-furylacetyl, 1-imidazolylacetyl, 1-tetrazolylacetyl, α-carboxy-2-thienylacetyl or α-carboxy-3-thienylacetyl (optionally with a functionally modified carboxyl group, e.g. as stated above), a-cyano-2-thienylacetyl, α-amino-α- (2-thienyl) -acetyl, α-amino-α- (2-furyl) -acetyl or a-Amino-a- (4-isothiazolyl) -acetyl (optionally with, e.g. as stated above, substituted amino group), a-sulfo-

509836/0970

phenylacetyl (optionally with, 2-B, like the carboxyl group, functionally modified sulfo group), S-methyl-Z-imidazolylthioacetyl, l, 2,4-triazol-3-ylthioacetyl, l, 3,4-triazol-2-ylthioacetyl, 5-methyl-1,2,4-thiadiazol-3-ylthioacetyl, 5-methyl-1,3,4-thiadiazol-2-ylthioacetyl or 1-methyl-5-tetrazolylthioacetyl.

An easily cleavable acyl radical Ac, in particular
of a carbonic acid half-ester, is primarily a through
Reduction, for example when treating with a chemical reducing agent, or by acid treatment, for example with trifluoroacetic acid, cleavable acyl radical of a half ester of carbonic acid, such as one, preferably on the carbon atom in α-position to
Oxy group multiply branched and / or aromatically substituted lower alkoxycarbonyl group or an arylcarbonyl,
in particular methoxycarbonyl group substituted by benzoyl radicals, or lower alkoxycarbonyl radical substituted by halogen atoms in the β-position, for example tert-butyloxycarbonyl, tert-pentyloxycarbonyl, phenacyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or a convertible in the latter
Remainder, such as 2-chloro- or 2-bromoethoxycarbonyl, furthermore, preferably polycyclic, cycloalkoxycarbonyl, for example adamantyloxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, primarily α-phenyl-lower alkoxycarbonyl, in which

5 0 9 8 3 6/0 9 7 0

-Ht-

the α-position is preferably polysubstituted, e.g. diphenylmethoxycarbonyl or α-4-biphenylyl-α-methyl-ethyloxy carbonyl, or furyl-lower alkoxycarbonyl, primarily α-furyl lower alkoxycarbonyl, e.g., furfuryloxycarbonyl.

A b One formed by the two radicals KJ and R ₁

divalent acyl group is e.g. the Δ-cyl radical of a lower alkane or lower alkenedicarboxylic acid, such as succinyl, or one o-arylenedicarboxylic acid, such as phthaloyl.

Away

Another divalent radical formed by the groups R- and R ₁ is, for example, a substituted, e.g. optionally substituted phenyl or thienyl, in particular in the 2-position, and optionally in the 4-position by lower alkyl, such as methyl, mono- or disubstituted l-oxo-3-aza-lj4-butylene radical, for example 4,4-dimethyl-2-phenyl-loxo-3-aza-1,4-butylene.

Together they form an etherified hydroxy group R2 with the carbonyl group a, preferably easily cleavable or easily functionally modified carboxyl group, such as esterified carboxyl group convertible to a carbamoyl or hydrazinocarbonyl group. Such

Group R ₂ is, for example, lower alkoxy, such as methoxy, ethoxy, n-propyloxy or isopropyloxy, which, together with the carbonyl group, forms an esterified carboxyl group which, in particular in 2-cephem compound, easily converts into a free carboxyl group

509836/0970

group or another functionally modified carboxyl group can be transferred.

An etherified hydroxyl group R ", which together with a -C (= 0) grouping forms a particularly easily cleavable esterified carboxyl group, is, for example, 2-halo-lower alkoxy, in which halogen preferably has an atomic weight of more than 19. Such a radical, together with the -C (= 0) group, forms an esterified carboxyl group which can be easily cleaved or which can be split into one when treated with chemical reducing agents under neutral or weakly acidic conditions, for example with zinc in the presence of aqueous acetic acid
easily transferable esterified carboxyl group and is eg
2,2,2-trichloroethoxy or 2-iodoethoxy, also 2-chloroethoxy
or 2-bromoethoxy, which can easily be converted into the latter

leaves.

An etherified hydroxyl group R ", which together with

the -C (= 0) grouping also when treating with chemical reducing agents under neutral or weakly acidic conditions, for example when treating with zinc in the presence of
aqueous acetic acid, further when treating with a suitable nucleophilic reagent, for example sodium thiophenolate, easily
represents cleavable esterified carboxyl group is an arylcarbonylmethoxy group, in which aryl is in particular an optionally substituted phenyl group, and preferably phenacyloxy.

509836/0970

A.
The group R ₉ can also represent an aryl methoxy group

are, in which aryl is in particular a monocyclic, preferably means substituted aromatic hydrocarbon radical. Such a radical forms together with the -C (= 0) group one that can be easily cleaved when irradiated, preferably with ultraviolet light, under neutral or acidic conditions, esterified carboxyl group. An aryl radical in such an arylmethoxy group is in particular lower alkoxyphenyl, e.g. Methoxyphenyl (where methoxy is primarily in the 3-, 4- and / or 5-position), and / or especially nitrophenyl (where Nitro is preferably in the 2-position). Such leftovers are special Lower alkoxy, e.g. methoxy, and / or nitrobenzyloxy, primarily 3- or 4-methoxybenzyloxy, 3,5-dimethoxybenzyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2-nitro-benzyloxy.

A An etherified hydroxy group R ₂ can also be a

Represent radical which together with the -C (= 0) grouping a under acidic conditions, e.g. when treating with trifluoroacetic acid or formic acid, easily cleavable, esterified carboxyl group forms. Such a radical is primarily a methoxy group in which methyl is optionally substituted by Hydrocarbon radicals, especially aliphatic or aromatic hydrocarbon radicals such as lower alkyl, e.g.

509836/0970

Methyl and / or phenyl, polysubstituted or by a, Electron-donating, substituent-bearing carbocyclic aryl group or one, oxygen or sulfur as a ring member having heterocyclic group of aromatic character is monosubstituted, or then in a polycycloaliphatic Hydrocarbon radical is a ring member or in an oxä- or thiacycloaliphatic radical that the α-position to Means ring member representing oxygen or sulfur atom. Preferred polysubstituted methoxy groups of these Type are tert-lower alkoxy, e.g. tert-butyloxy or tert-pentyloxy, optionally substituted diphenylmethoxy, e.g., diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, also 2- (4-biphenylyl) -2-propyloxy, while one does the above substituted aryl group or methoxy group containing the heterocyclic group, e.g. a-lower alkoxyphenyl-lower alkoxy, such as 4-methoxybenzyloxy or 3,4-dimethoxybenzyloxy, or furfuryloxy, how 2-furfuryloxy is. A polycycloaliphatic hydrocarbon radical in which methyl is the methoxy group represents a, preferably triple, branched ring member is, for example, adamantyl, such as 1-adamantyl, and an above-mentioned oxa- or thiacycloaliphatic radical in which methyl of the methoxy group is the α-position to the oxygen or sulfur atom A representative ring member means, for example, 2-oxa- or 2-thiane-lower alkylene or -lower alkenylene with 5-7 ring atoms, such as

509836/0970

-U-

2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro-2-pyranyl or corresponding sulfur analogues.

The radical R ^ can also be an etherified hydroxyl group represent, which together with the -C (= 0) -group a hydrolytically, e.g. under weakly basic or acidic conditions, forms cleavable esterified carboxyl group. Such a rest is preferably an etherified hydroxyl group which forms an activated ester group with the -C (= 0) group, such as nitrophenyloxy, e.g. 4-nitrophenyloxy or 2,4-dinitrophenyloxy, nitrophenyl-lower alkoxy, e.g. 4-nitrobenzyloxy, hydroxy-lower alkyl-benzyloxy, e.g., 4-hydroxy-3,5-tert-butyl-benzyloxy, polyhalophenyloxy, e.g., 2,4,6-trichlorophenyloxy or 2,3,4,5,6-pentachlorophenyloxy, also cyanomethoxy, and acylaminomethoxy, e.g. phthaliminomethoxy or succinyliminomethoxy.

The group R ~ can also be one, together with the Carbonyl grouping of the formula -C (= 0) - one of hydrogenolytic Conditions represent cleavable esterified carboxyl group-forming etherified hydroxyl group, and is e.g. α-phenyl-lower alkoxy which is optionally substituted, for example by lower alkoxy or nitro, such as benzyloxy, 4-methoxybenzyloxy or 4-nitrobenzyloxy.

A.
The group R ^ can also be one, together with the

Carbonyl group -C (= 0) - one under physiological conditions cleavable esterified carboxyl group forming

509836/0970

25Π633η

ethereal hydroxyl group, primarily an acyloxymethoxy group, in which acyl means, for example, the residue of an organic carboxylic acid, primarily an optionally substituted lower alkanoic acid, or in which acyloxymethyl forms the residue of a lactone. Hydroxy groups etherified in this way are lower alkanoyloxymethoxy, for example acetyloxymethyloxy or 'pivaloyloxymethoxy, amino -lower alkanoyloxymethoxy, in particular a-amino-lower alkanoyloxymethoxy, for example glycyloxymethoxy, L-vally loxymethoxy, L-leucyloxthaloxy, furthermore phthaloxy.

A contains a silyloxy or stannyloxy group IL

preferred substituents optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as lower alkyl, halogen NIE said alkyl, cycloalkyl, phenyl or Phenylniederalkylgruppen, or optionally modified functional groups, such as etherified hydroxy, such as lower alkoxy or halogen -, e.g. chlorine atoms, and is primarily tri-lower alkylsilyloxy, e.g. trimethylsilyloxy, halo-lower alkoxy-lower alkylsilyl, e.g. chloro-methoxy-methyl-silyl, or tri- lower alkylstannyloxy, e.g. tri-n-butylstannyloxy.

An acyioxy radical R "which, together with a -C (= 0) grouping, forms a, preferably hydrolytically, cleavable mixed anhydride group, contains, for example, the acyl radical of one of the organic carboxylic acids or carbons mentioned above.

509836/0970

acid half-derivatives, and is, for example, optionally, as per Halogen, e.g. fluorine or chlorine, preferably in the α-position, substituted lower alkanoyloxy, e.g. acetyloxy, pivalyloxy or trichloroacetyloxy, or lower alkoxycarbonyloxy, e.g. methoxycarbonyloxy or ethoxycarbonyloxy.

One, together with a -C (= 0) grouping one optionally substituted carbamoyl or hydrazinocarbonyl group The radical R "forming is, for example, amino, lower alkylamino or di-lower alkylamino, such as methylamino, ethylamino, dimethylamino or diethylamino, lower alkylenamino, e.g., pyrrolidino or piperidino, oxane-lower alkylenamino, e.g., morpholines Hydroxyamino, hydrazino, 2-lower alkylhydrazino or 2,2-di-lower alkylhydrazino, e.g., 2-methylhydrazino or 2,2-dimethylhydrazino.

A lower alkyl group R "with up to 7, preferably up to 4 carbon atoms, is preferably methyl, or also ethyl, n-propyl, hexyl or heptyl.

The 2-oxa or 2-thia aliphatic or cycloaliphatic Hydrocarbon radical R ~ is primarily a 1-lower alkoxy-l-lower alkyl or 1-lower alkylthio-l-lower alkyl radical, such as 1-methoxy-1-ethyl, 1-ethoxy-1-ethyl, 1-methylthio-1-ethyl or 1-ethylthio-1-ethyl, or a 2-0xa- 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 analogous sulfur compound.

509836/0970

250633Π

Easily split off silyl or stannyl groups Ro are preferably by optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic Hydrocarbon radicals, such as lower alkyl, halo-lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl groups, or optionally modified functional groups, such as etherified hydroxyl, e.g. lower alkoxy groups, or halogen, e.g. Chlorine atoms, substituted. Representative of such groups are primarily tri-lower alkylsilyl, such as trimethylsilyl, Halo-lower alkoxy-lower alkylsilyl, such as chloromethoxymethylsilyl, or also tri-lower alkylstannyl, such as tri-n-butylstannyl.

Further easily split off hydroxy protective groups R "are, for example, α-phenyl-lower alkyl, such as benzyl and Diphenylmethyl, where substituents on the phenyl nuclei are e.g. esterified or etherified hydroxy, such as halogen, e.g. fluorine, chlorine or bromine, or lower alkoxy, such as methoxy, are possible.

Salts are in particular those of compounds of the formulas IA and IB with an acidic group, such as one Carboxy, sulfo or phosphono group, primarily metal or Ammonium salt, such as alkali metal and alkaline earth metal, e.g. sodium, potassium, magnesium or calcium salts, as well as

509836/0970

Ammonium salts with ammonia or suitable organic amines, whereby primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and araliphatic primary, secondary or tertiary mono-, di- or polyamines, as well as heterocyclic bases are possible for the salt formation, such as lower alkylamines, e.g. triethylamine, Hydroxy-lower alkylamines, e.g. 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine or iris- (2-hydroxyethyl) -amine, basic aliphatic esters of carboxylic acids, e.g. 4-aminobenzoic acid-2-diethylamino-ethyl ester, lower alkyleneamines, e.g. 1 -Aethyl-piperidine, cycloalkylamines, e.g. bicyclohexylamine, or benzylamines, e.g. N, N ¹ -dibenzylethylenediamine, also bases of the pyridine type _s e.g. pyridine, collidine or quinoline, compounds of the formulas IA and IB, which have a basic group, can also be acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example trifluoroacetic acid or form p-toluenesulfonic acid. Compounds of the formulas IA and IB with an acidic and a basic group can also be present in the form of internal salts, ie in zwitterionic form. 1-Oxides of compounds of the formula IA with salt-forming groups can also form salts, as described above.

509836/0970

250633Π

The compounds of the present invention have or can have valuable pharmacological properties be used as intermediates in the manufacture of such. Compounds of formula IA in which, for example, R ^ is a in pharmacologically active N-acyl derivatives of 6ß-amino-penam-3-carboxylic acid or 7ß-amino-3-cephem-4-carboxylic acid compounds acyl radical Ac and R for hydrogen

away

or in which R.sup.4 and R.sup.2 together represent a 1-0xo-3-aza-1 substituted in the 2-position, for example by an aromatic or heterocyclic radical, and in the 4-position preferably, for example by 2-lower alkyl, such as methyl , 4-butylene radical, R ″ denotes hydroxy or an etherified hydroxy group R ″ which is easily cleavable under physiological conditions and forms an esterified carboxyl group which is easily cleavable under physiological conditions, and R ₃ denotes lower alkyl, where in an acyl radical R, any functional groups such as amino , Carboxy, hydroxy and / or sulfo, usually in free form, or salts of such compounds with salt-forming groups, are, in the case of parenteral and / or oral administration, against microorganisms such as gram-positive bacteria, e.g. Staphylococcus aureus , Streptococcus pyogenes and Diplococcus pneumoniae , (e.g. in mice in doses of about O ₁ OOl to about 0.02 g / kg sc or po), and gram-negative

509836/0970

Bacteria, e.g. Escherichia coll, Salmonella typhimurium ,
Shigella feixneri , Klebsiella pneumoniae , Enterobacter cloacae , Proteus vulgaris , Proteus rettgeri and Proteus mirabilis ,
(e.g. in mice at doses of about 0.001 to about 0.15 g / kg
S-.c. or po), especially also against penicillin-resistant bacteria, with low toxicity. These new compounds can therefore be used, for example, in the form of antibiotic preparations for the treatment of corresponding infections.

Compounds of the formula IB or 1-oxides of compounds

away

fertilize the formula IA, where R, R-,, R _? and R "have the meanings given in connection with the formula IA, or compounds of the formula IA in which R" has the meaning given above, the radicals R ₁ and R _{1 are} hydrogen, or R is one of a pharmacologically active N Acyl derivatives of
6ß- Amino-penam-3-carboxylic acid- or 7ß-Amino-3-cephem-4-carboxylic acid compounds occurring acyl radical and R, denote hydrogen, or R, and R, together one, of one in the 2-position preferably, for example represented by an aromatic or heterocyclic radical, and preferably in the 4-position, for example by 2 lower alkyl, such as methyl, substituted l-oxo-3-aza-1,4-butylene radical, different divalent amino protective groups, and R _{9 represents} hydroxy,

away
or R ₁ and R, have the meanings given above. R ₂ for

509836/0970

one, together with the -C (= 0) group one, preferably easily cleavable, slotted carboxyl group-forming radical R represents, wherein a carboxyl group protected in this way is different from a physiologically cleavable carboxyl group, and R "has the meanings given above are valuable intermediates, which is simply converted into the above-mentioned pharmacologically active compounds, for example as described below can be transferred.

The invention relates in particular to the production of 3-cephem compounds of the formula IA, in which R ^ is hydrogen or preferably one which can be produced in a fermentatively (ie naturally occurring) or bio-, semi- or totally synthetically, especially pharmacologically active, such as highly active N- Acyl derivative of an acyl radical containing 6β-amino-penam-3-carboxylic acid or 7β-amino-3-cephem-4-carboxylic acid compound, such as one of the abovementioned acyl radicals of the formula A, in which R, R, R and η are primarily _{have the preferred meanings, R 1} is hydrogen, or in which R 1 and R 1 together preferably have one in the 2-position, for example by an aromatic or heterocyclic radical, such as phenyl, and preferably in the 4-position, for example by two lower alkyl, such as Represent methyl, substituted l-0xo-3-aza-1,4-butylene radical, R £ for hydroxy, for optionally, preferably in

509836/0970

α-position, for example by optionally substituted aryloxy, such as lower alkoxyphenyloxy, for example 4-methoxyphenyloxy, lower alkanoyloxy, for example acetyloxy or pivaloyloxy, a-amino-lower alkanoyloxy, for example glycyloxy, L-valyloxy or L-leucyloxy, arylcarbonyl, for example benzoyl, or optionally substituted aryl Phenyl, lower alkoxyphenyl, for example 4-methoxyphenyl, nitrophenyl, for example 4-nitrophenyl, or biphenylyl, for example 4-biphenylyl, or in the β-position by halogen, for example chlorine, bromine or iodine, mono- or polysubstituted lower alkoxy, such as lower alkoxy, for example methoxy , Ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy or tert-pentyloxy, bis-phenyloxy-methoxy optionally substituted by lower alkoxy, for example bis-4-methoxyphenyloxy-methoxy, lower alkanoyloxy-methoxy, for example acetyloxymethoxy or pentyloxy , α-amino-lower alkanoyloxy-methoxy, for example glycyloxymethoxy, phenacyloxy, optionally substituted phenyl-lower alkoxy, in particular 1-phenyl-lower alkoxy, such as phenylmethoxy, such radicals 1-3 may contain phenyl radicals which are optionally substituted, for example by lower alkoxy, such as methoxy, nitro or phenyl, for example benzyloxy, 4-methoxy-benzyloxy, 2-biphenylyl-2-propyloxy, 4-nitro-benzyloxy, diphenylmethoxy, 4,4 ¹ -Dimethoxy-diphenylmethoxy or trityloxy, or 2-halo-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy, also for 2-phthalidyloxy, and for acyloxy, such as

5098 ^ 6/0970

Lower alkoxycarbonyloxy, e.g. methoxycarbonyloxy or aethoxycarbonyloxy, or lower alkanoyloxy, e.g. acetyloxy or pivaloyloxy, for tri-lower alkylsilyloxy, e.g. trimethylsilyloxy, or for amino or hydrazino, for example amino, which is optionally substituted, for example by lower alkyl, such as methyl, or hydroxy, Lower alkyl or di-lower alkylamino, such as methylamino or dimethylamine, Hydrazino, 2-lower alkyl- or 2,2-di-lower alkylhydrazino, e.g. 2-methylhydrazino or 2,2-dimethylhydrazino, or hydroxyamino, and R is hydrogen, lower alkyl, especially methyl, or a hydroxy protecting group, such as tri-lower alkylsilyl, e.g. trimethylsilyl, or optionally, e.g. substituted by halogen or lower alkoxy, benzyl or diphenyl-

darsttlft,
methyl, ^ and the 1-oxides thereof, also the corresponding 2-cephem compounds of the formula IB, or salts of such compounds with salt-forming groups.

Primarily in a 3-cephem compound of the formula IA, and in a corresponding 2-cephem compound of the formula IB, furthermore in a 1-oxide a 3-cephem compound of the formula IA, or in a salt of such a compound salt-forming groups R ₁ for hydrogen or an acyl radical contained in fermentative (ie naturally occurring) or biosynthetically producible N-acyl derivatives of 6ß-amino-penam-3-carboxylic acid or yß-amino-S-cephem-i ^ -carboxylic acid compounds, especially of the formula A, wherein

509836/0970

R, R, R and η are primarily the preferred meanings have, such as a phenylacetyl or phenyloxyacetyl radical which is optionally substituted, for example by hydroxy, furthermore a optionally, for example by lower alkylthio, or lower alkenylthio, and optionally substituted, such as acylated Amino and / or functionally modified, such as esterified carboxyl, substituted lower alkanoyl or lower alkenoyl radical, e.g. 4-hydroxyphenylacetyl, hexanoyl, octanoyl or n-butylthioacetyl, and especially 5-amino-5-carboxy-valeryl, wherein the amino and / or the carboxyl groups are optionally protected and exist, for example, as acylamino or esterified carboxyl, Phenylacetyl or phenyloxyacetyl, or one of the most potent ones N-acyl derivatives of δjS-amino-penam-S-carboxylic acid or 7β-amino-3-cephem-4-carboxylic acid compounds occurring acyl radical, in particular of the formula A, wherein R, R, R and η in the first place Line have the preferred meanings, such as formyl, 2-haloethylcarbamoyl, e.g. 2-chloroethylcarbamoyl, cyanoacetyl; Phenylacetyl, Thienylacetyl, e.g. 2-thienylacetyl, or tetrazolylacetyl, e.g. 1-tetrazolylacetyl, but especially in the α-position by a cyclic, such as a cycloaliphatic, aromatic or heterocyclic, primarily monocyclic Radical and substituted by a functional group, primarily amino, carboxy, sulfo or hydroxyl groups Acetyl, in particular phenylglycyl, in which phenyl optionally,

509836/0970

for example by optionally slotted hydroxy, such as acyloxy, for example optionally halogen-substituted lower alkoxycarbonyloxy or lower alkanoyloxy, and / or by halogen, for example chlorine, substituted phenyl, for example phenyl, or 3- or 4-hydroxy-, β-chloro ^ -hydroxy- or 3,5-dichloro-4-hydroxyphenyl (optionally also with a split, such as acylated hydroxyl group) represents, and in which the amino group can optionally also be substituted and, for example, represents a sulfoamino group which may be present in salt form or an amino group with a hydrolytic substituent cleavable trityl group or primarily an acyl group, such as an optionally substituted carbamoyl, such as an optionally substituted ureidocarbonyl group, for example ureidocarbonyl or N ¹ -trichloromethylureidocarbonyl, or an optionally substituted guanidinocarbonyl group, for example. Guanidinocarbonyl, or one, preferably light, for example when treating with an acidic agent such as trifluoroacetic acid, further reductive, such as when treating with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, or with catalytic hydrogen, or hydrolytically cleavable or one in one such convertible acyl radical, preferably a suitable acyl radical of a carbonic acid half-ester, such as one of the above-mentioned, e.g. optionally halogen or benzoyl-substituted lower alkyloxycarbonyl radicals, e.g. tert-butyloxycarbonyl, 2,2,2-trichloroethyloxy

509836/0970

carbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, or Phenacy |! loxycarbonyl, optionally lower alkoxy- or nitro-substituted phenyl-lower alkoxycarbonyl, e.g. 4-methoxybenzyloxycarbonyl or diphenylmethoxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-methylcarbamoyl, also one with a nucleophilic reagent, such as hydrocyanic acid, sulphurous acid or thioacetic acid amide, removable arylthio or aryl-lower alkylthio radical, e.g. 2-nitrophenylthio or tritylthio, a means arylsulfonyl radical which can be split off by electrolytic reduction, e.g. 4-methylphenylsulfonyl, or one, with an acidic agent, such as formic acid or aqueous mineral acid, e.g. hydrochloric or phosphoric acid, cleavable 1-lower alkoxycarbonyl or l-lower alkanoyl-2-propylidene radical, e.g. 1-ethoxycarbonyl-2-propylidene, also contains α- (l, 4-cyclohexadienyl) -glycyl, α- (l-cyclohexenyl) -glycyl, a-thienylglycyl, such as a-2- or a-3-thienylglycyl, a-furylglycyl, such as a-2-furylglycyl, a-isothiazolylglycyl, such as a-4-isothiazolyl-glycyl, whereby in such The amino group, for example as indicated for a phenylglycyl radical, can be substituted or protected, furthermore α-carboxy-phenylacetyl or α-carboxy-thienylacetyl, e.g., α-carboxy-2-thienylacetyl (if necessary with functionally modified, e.g. in salt, such as sodium salt form, or in ester, such as lower alkyl, e.g. methyl or ethyl, or phenyl lower alkyl, e.g., diphenylmethyl

5098 ^ 6/0970

ester form, present carboxyl group), a-sulfophenylaeetyl (optionally also with, for example, like the carboxyl group, functionally modified sulfo group), a-phosphono, aO-methylphosphono or a-0,0 ¹ -dimethylphosphono-phenylacetyl, or a-hydroxy -phenylacetyl (optionally with a functionally modified hydroxyl group, in particular with an acyloxy group, in which acyl is a, preferably easily, e.g. when treating with an acidic agent such as trifluoroacetic acid, or with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, cleavable or an in such a convertible acyl radical, preferably a suitable acyl radical of a carbonic acid half-ester, such as one of the above-mentioned lower alkoxycarbonyl radicals optionally substituted by halogen or benzoyl, for example 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert. -Butyloxycarbonyl or phenacyloxycarbonyl, also means formyl), and 1-amino-cycloh exylcarbonyl, aminomethylphenylacetyl, such as 2- or 4-aminomethylphenylacetyl, or aminopyridiniumacetyl, for example 4-aminopyridiniumacetyl (optionally also with, for example, as stated above, substituted amino group), or pyridylthioacetyl, for example 4-pyridylthioacetyl, and R, for hydrogen, or R ^ and R. together for one, preferably in the 2-position, optionally by protected hydroxy, such as acyloxy, e.g.

509836/0970

optionally halogen-substituted lower alkoxy-carbonyloxy or lower alkanoyloxy, and / or phenyl substituted by halogen, e.g. chlorine, e.g. phenyl, or 3- or 4-hydroxy-, 3-chloro-4-hydroxy- or 3,5-dich3.or-4-hydroxyphenyl (if necessary also with slotted, e.g. as stated above, acylated hydroxy group) substituted l-oxo-3-aza-1,4-butylene radical stand, which in the 4-position optionally has two lower alkyl, contains such as methyl, and R "represents hydroxy, lower alkoxy, in particular a-polybranched lower alkoxy, e.g. tert-butyloxy, also methoxy or ethoxy, 2-halo-lower alkoxy, e.g. 2,2,2-trichloroethoxy, 2-yo-ethoxy or the easily convertible 2-chloroethoxy or 2-bromoethoxy, Phenacyloxy, 1-phenyl-lower alkoxy with 1-3, optionally through Lower alkoxy or nitro substituted phenyl radicals, e.g. 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy, 4,4'-dimethoxydiphenylmethoxy or trityloxy, lower alkanoyloxymethoxy, e.g. acetyloxymethoxy or pivaloyloxymethoxy, α-amino lower alkanoyloxymethoxy, e.g. oxymethoxy, 2-phthalidyloxymethoxy, lower alkoxycarbonyloxy, e.g. ethoxycarbonyloxy, or lower alkanoyloxy, e.g. acetyloxy, also tri-lower alkylsilyloxy, e.g. trimethylsilyloxy, and R represents hydrogen, lower alkyl, especially methyl, or a hydroxy protecting group, such as tri-lower alkylsilyl, e.g. tri-

509836/0970

methylsilyl, or optionally, for example, by halogen such as chlorine or bromine, or lower alkoxy, such as methoxy, substituted Benzyl or diphenylmethyl.

The invention relates primarily to the preparation of 3-cephem compounds of the formula IA in which R _{1 is} hydrogen or an acyl group of the formula

Ii

R ₃ - (X) _1n -CH-C- (B),

where R is phenyl or hydroxyphenyl, e.g. 3- or 4-hydroxy-

el

phenyl, also hydroxy-chlorophenyl, e.g. 3-chloro-4-hydroxyphenyl- or 3,5-dichloro-4-hydroxyphenyl, in which Radicals hydroxy substituents through acyl radicals, such as optionally halogenated lower alkoxycarbonyl radicals, e.g. tert-butyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl, can be protected, as well as thienyl, e.g. 2- or 3-thienyl, furthermore pyridyl, e.g. 4-pyridyl, aminopyridinium, e.g. 4-aminopyridinium, furyl, e.g. 2-furyl, isothiazolyl, e.g. 4-isothiazolyl, or tetrazolyl, e.g. 1-tetrazolyl, or also 1,4-cyclohexadienyl or 1-cyclohexenyl means X represents oxygen or sulfur, m represents O or 1, and R represents hydrogen or, when m represents O, for amino, as well as protected amino, such as acylamino, e.g. a-poly-

509836/0970

• 5V

branched lower alkoxycarbonylamino, such as tert-butyloxycarbonylamino, or 2-halo-lower alkoxycarbonylamino, e.g. 2,2,2-trichloroethoxycarbonylamino, 2-iodoethoxycarbonylamino or 2-bromoethoxycarbonylamino, or optionally lower alkoxy or nitro-substituted phenyl-lower alkoxycarbonylamino, e.g. 4-methoxybenzyloxycarbonylamino or diphenylmethoxycarbonylamino, or 3-guanylureido, also sulfoamino or tritylamino, as well as arylthioamino, e.g. 2-nitrophenylthioamino, Arylsulfonylamino, e.g. 4-methylphenylsulfonylamino, or l-lower alkoxycarbonyl-2-propylideneamino, e.g. 1-ethoxycarbonyl-2-propylideneamino, Carboxy or in salt, e.g., alkali metal, such as sodium salt form, as well as protected carboxy, e.g. esterified carboxy, such as phenyl-lower alkoxycarbonyl, e.g. Diphenylmethoxycarbonyl, SuIfο or SuIfo present in salt, e.g. alkali metal, such as sodium salt form, as well as protected suIfο, hydroxy, and protected Hydroxy, such as acyloxy, e.g. a-polybranched lower alkoxycarbonyloxy, such as tert-butyloxycarbonyloxy, or 2-halo-lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-Jodäthoxycarbonyloxy or 2-Bromäthoxycarbonyloxy, also formyloxy, or O-lower alkylphosphono or Ο, Ο'-di-lower alkylphosphono, e.g. O-methylphosphono or Ο, Ο'-dimethylphosphono, or an S-amino-S-carboxyvaleryl radical means in which the amino and / or carboxy group

50983-6 / 0970

pen can also be slotted and, for example, as acylamino, for example _{lower alkanoylamino, such as acetylamino, j} halo-lower alkanoylamino, such as dichloroacetylamino, benzoylamino or phthaloylamino, or as an esterified carboxy, such as phenyl-lower alkoxycarbonyl, for example diphenylmethoxycarbonyl, when R is preferably 1 for phenylmethoxycarbonyl , Hydroxyphenyl,

Hydroxychlorphenyl or pyridyl, and m is O and R, is different from hydrogen, if R is phenyl, hydroxyphenyl, hydroxy-chlorophenyl, thienyl, furyl, isothiazolyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, R, is hydrogen, R primarily for hydroxy, also for lower alkoxy, especially a-polybranched lower alkoxy, for example tert-butyloxy, 2-halo-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally, for example by Lower alkoxy, e.g. methoxy, substituted diphenylmethoxy, ^{e.g. diphenylmethoxy or 4,4 1} -dimethoxydiphenylmethoxy, also tri-lower alkylsilyloxy, e.g. trimethylsilyloxy, and R is hydrogen, lower alkyl, e.g. methyl, ethyl or η-butyl, and tri-lower alkylsilyl, e.g. trimethyl silyl, also optionally, for example by halogen, such as chlorine or bromine, or lower alkoxy, such as methoxy, substituted benzyl or diphenylmethyl, and the 1-oxides of such 3-cephem compounds of the formula IA, also the ent -

§09836 / 0970

Speaking 2-cephem compounds of the formula IB, or salts, in particular pharmaceutically usable, non-toxic salts of such compounds with salt-forming groups, such as alkali ■ metal, eg sodium, or alkaline earth metal, eg calcium salts, or ammonium salts, incl. those with amines, of compounds in which R _{2 is} hydroxy, and which contain a free amino group in the acyl radical of the formula B.

Primarily in 3-cephem compounds of the formula IA, furthermore in corresponding 2-cephem compounds the Formula IB, as well as in salts, especially in pharmaceutically acceptable, non-toxic salts of such compounds with salt-forming groups, as in the salts R mentioned in the preceding section, for hydrogen, for the acyl radical of the formula

B, in which R is phenyl and hydroxyphenyl, e.g. 4-hydroxyphenyl, a

Thienyl, e.g., 2- or 3-thienyl, 4-isothiazolyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, X oxygen, m O or 1, and

R, hydrogen or, if m is O, amino, and also protected . - -

tes amino, such as acylamino, e.g. a-polybranched lower alkoxycarbonylamino, such as tert-butyloxycarbonylamino, or 2-halo-lower alkoxycarbonylamino, e.g. 2,2,2-trichloroethoxycarbonylamino, 2-Jodäthoxycarbonylamino or 2-Bromäthoxycarbonylamino, or optionally lower alkoxy- or nitro-substituted phenyl-lower alkoxycarbonylamino, e.g. 4-methoxybenzyloxy-

509836/0970

carbonylamino, or hydroxy, as well as protected hydroxy, such as Acyloxy, e.g. α-polybranched lower alkoxycarbonyloxy, such as tert-butyloxycarbonyloxy, or 2-halo-lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, furthermore formyloxy, or for an S-amino-S-carboxy-valeryl radical, in which the amino and carboxy groups can also be protected and e.g. as acylamino, e.g. lower alkanoylamino, such as acetylamino, halo-lower alkanoylamino, such as dichloroacetylamino, benzoylamino, or phthaloylamino, or as an esterified carboxy, such as phenyl-lower alkoxycarbonyl, e.g. diphenylmethoxycarbonyl, where preferably m is 1 when R is phenyl or hydroxy

el

is phenyl, R ₁ is hydrogen, R ₂ is primarily hydroxy, furthermore, if appropriate, lower alkoxy substituted in the 2-position by halogen, e.g. chlorine, bromine or iodine, in particular α-polybranched lower alkoxy, e.g. tert-butyloxy, or 2-halo-lower alkoxy, for example 2,2,2-trichloroethoxy, such as methoxy-substituted diphenylmethyloxy, for example diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, or p-nitrobenzyloxy, also tri-lower alkylsilyloxy, for example trimethylsilyloxy, and R "denotes Hydrogen, lower alkyl, in particular methyl, tri-lower alkylsilyl, e.g. trimethylsilyl, or a benzyl or diphenyl substituted optionally by halogen, e.g. chlorine or bromine, or lower alkoxy, e.g. methoxy

509836/0970

methyIg rupp e.

The invention relates primarily to manufacture of 7ß- (D-a-Amino-a-R -acetylamino) -3-lower alkoxy-3-

cephem-4-carboxylic acids, in which R is phenyl, 4-hydroxyphenyl,

CL

Is 2-thienyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, and Lower alkoxy contains up to 4 carbon atoms and e.g. ethoxy or n-butyloxy, but primarily methoxy, and the internal salts thereof, and especially the 3-methoxy-7 / 3- (D-aphenyl-glycylamino) -3-cephem-4-carboxylic acid and the inner salt of it; in the above-mentioned concentrations, especially when administered orally, these compounds are excellent antibiotic properties, both against gram-positive and especially against gram-negative bacteria with low toxicity.

According to the inventive method, compounds of the formula IA, üeren 1-oxides, compounds of the formula IB and salts of such compounds with salt-forming groups prepared by adding a compound of the formula

η Η

O:

CH.

N C, wOR,

O = C-R ^

509836/0970

-5 *

from A
wherein R ^ »R- ^ and R ^ have the meanings given under formula IA

have, R "stands for lower alkyl or a hydroxy protecting group, and Y represents a leaving group, treated with a base, and, if desired, in a compound of formula IA or IB obtained, the protected carboxyl group of formula -CC = O) -R. ^ in converts the free or another protected carboxyl group, and / or, if desired, converts the protected hydroxyl group -OR "into a free hydroxyl group and / or the resulting free hydroxyl group or the protected hydroxyl group - ° ~ & 3 into a lower alkoxy group - OR "converts, and / or, if desired, within the definition of the end substances, converts a compound obtained into another compound, and / or, if desired, a compound obtained with a salt-forming group into a salt or a salt obtained into the free compound or converted into another salt, and / or, if desired, separating a mixture of isomeric compounds obtained into the individual isomers.

In a compound of formula II the group -OR 'can stand to the carboxyl group in trans- (Crotonsäurekonfiguration) or in cis-STEL lung (Isocrotonsäurekonfiguration).

In a starting compound of the formula II, a leaving group Y is, for example, a group -SR ,, a group -SO-R bonded to the thio group -S- with the sulfur atom or a group -S-SO-R ₅ .

509836/0970

250633Q

In the group ~ S-R /, R 1 is an optionally substituted one aromatic heterocyclic radical with up to 15, preferably up to 9 carbon atoms, and at least one Ring nitrogen atom and optionally a further ring heteroatom, like oxygen or sulfur, which radical with one of its ring carbon atoms, that with a ring nitrogen atom is linked by a double bond, is bonded to the thio group -S-. Such radicals are monocyclic or bicyclic and can, for example, by lower alkyl, such as methyl or ethyl, lower alkoxy, such as methoxy or ethoxy, halogen, such as Fluorine or chlorine, or aryl, such as phenyl, may be substituted.

Such radicals R are, for example, monocyclic five-membered thiadiazacyclic, thiatriazacyclic, oxadiazacyclic or oxatriazacyclic radicals of aromatic character, but especially monocyclic five-membered diazacyclic, oxazacyclic and thiazacyclic radicals of aromatic character, and or primarily the corresponding benzdiazacyclic, benzoxazacyclic or benzthiazacyclic radicals, in which the heterocyclic part is five-membered and has aromatic character, where R * in radicals substitutable ring nitrogen atom, e.g. by lower alkyl can be substituted. Representative of such groups R are 1-methyl-imidazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, l, 3,4,5-thiatriazol-2-yl, 1,3-oxazol-2-yl, l, 3,4-oxadiazol-2-yl, l, 3,4,5-0xatriazol-2-yl, 2-quinolyl,

509836 / 097Q

l-methyl-benziraidazol-2-yl, benzoxazol-2-yl and in particular Benzthiazol-2-yl. Further groups R, are acyl radicals organic Carboxylic or thiocarboxylic acids, such as optionally substituted, aliphatic ^, cycloaliphatic, araliphatic ^ or aromatic, acyl or thioacyl groups with up to 18, preferably up to 10, carbon atoms, such as lower alkanoyl, e.g. acetyl or propionyl, lower thioalkanoyl, e.g. thioacetyl or thiopropionyl, cycloalkanecarbonyl, e.g. cyclohexanecarbonyl, Cycloalkanethiocarbonyl, e.g., cyclohexanethiocarbonyl, benzoyl, thiobenzoyl, napthylcarbonyl, napthylthiocarbonyl, heterocyclic Carbonyl or thiocarbonyl, such as 2-, 3- or 4-pyridylcarbonyl, 2- or 3-thenoyl, 2- or 3-furoyl, 2-, 3- or 4-pyridyl thiocarbonyl, 2- or 3-thiothenoyl, 2- or 3-thiofuroyl, or corresponding substituted, for example, by lower alkyl, such as methyl, halogen, such as fluorine or chlorine, lower alkoxy, such as Methoxy, aryl such as phenyl, aryloxy such as phenyloxy, mono- or poly-substituted acyl or thioacyl groups.

In the groups -SO ₂ -R and -S-SO ₂ -R ₅ , R _{5 is} an optionally substituted, in particular aliphatic, cycloaliphatic ^ araliphatic or aromatic, hydrocarbon radical with up to 18, preferably up to 10, carbon atoms. Suitable groups R are, for example, optionally substituted, such as by lower alkoxy, such as methoxy, halogen, such as fluorine, chlorine or bromine, aryl, such as phenyl, aryloxy, such as phenyloxy, mono- or polysubstituted alkyl, especially lower alkyl, such as methyl, ethyl or butyl groups,

509836/0970

Alkenyl, such as allyl or butenyl groups, cycloalkyl, such as Cyclopentyl or cyclohexyl groups, or optionally by lower alkyl, such as methyl, lower alkoxy, such as methoxy, halogen, such as fluorine, chlorine or bromine, aryl such as phenyl, aryloxy such as phenyloxy, or nitro, mono- or poly-substituted Naphthyl or, in particular, phenyl groups, for example phenyl /, o-, m- or preferably p-tolyl, o-, m- or preferably p-methoxyphenyl, o-, m- or p-chlorophenyl, p-biphenylyl, p-phenoxyphenyl, p-nitrophenyl or 1- or 2-naphthyl.

In a starting material of the formula II, R " preferably for one with the -C (= 0) grouping, in particular under mild conditions, cleavable, esterified carboxyl group-forming, etherified hydroxyl group, where appropriate existing functional groups in a car

A.
Boxyl protective group R "in a manner known per se, for example such as

J ^ indicated above, may be protected. A group R_ is, for example, in particular an optionally halogen-substituted lower alkoxy group, such as methoxy, α-polybranched lower alkoxy, e.g. tert-butyloxy, or 2-halo-lower alkoxy, in which halogen is, for example, chlorine, bromine or iodine, primarily 2.2 , 2-trichloroethoxy, 2-bromoethoxy, or 2-iodoethoxy, or an optionally substituted, such as lower alkoxy, for example methoxy, or nitro containing 1-phenyl-lower alkoxy

5098'36 / 097O

- 6t -

group, as optionally, e.g. as indicated, substituted benzyloxy or diphenylmethoxy, e.g. benzyloxy, 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, furthermore an organic silyloxy or stannyloxy group, such as tri-lower alkylsilyloxy, e.g. trimethylsilyloxy or halogen, e.g. chlorine. In a starting material of the formula II, the radical R? an amino protective group R_, such as an Aeylgruppe Ac, in which optionally free functional groups present, e.g. amino, hydroxyl, carboxyl or phosphono groups, per se known manner, amino groups e.g. by the above acyl, trityl, silyl or stannyl, as well as substituted Thio or sulfonyl radicals, and hydroxyl, carboxy or phosphono groups e.g. be protected by the above-mentioned ether or ester groups, including silyl or stannyl groups can, and R, hydrogen.

In a starting material of the formula II, Ro is preferably lower alkyl, in particular methyl, or as Hydroxyl protective group, preferably a substituted silyl group, in particular the trimethylsilyl group, as well as an α-phenyl-lower alkyl group, such as the benzyl or the diphenylmethyl group.

509 8 3 6/0970

250633Q

-ft ·.

Bases suitable for the ring closure reaction are, in particular, strong organic or inorganic bases. To be highlighted are in particular bicyclic amidines, such as diazabicycloalkenes, e.g. l, 5-diazabicyclo [4.3.0] non-5-ene or 1,5-Diazabicyclo [5.4.0] undec-5-ene, substituted guanidines, e.g. polysubstituted by lower alkyl, such as tetramethylguanidine, also metal bases, such as hydrides, amides or alcoholates of alkali metals, in particular of lithium, sodium or Potassium, for example sodium hydride, lithium di-lower alkylamides such as lithium diisopropylamide, potassium lower alkanolates such as Potassium tert-butoxide. Compounds of formula II in which R ~ halogen, e.g. chlorine, can also be combined with a tertiary organic nitrogen base, e.g. a tri-lower alkylamine, such as triethylamine, are cyclized, wherein in the presence of an alcohol such as a lower alkanol, e.g. tert-butanol, the corresponding esters of the formula IA and / or. IB can be obtained.

The reaction according to the invention is carried out in a suitable inert solvent, for example in an aliphatic, cycloaliphatic or aromatic Hydrocarbons such as hexane »cyclohexane, benzene or toluene, a halogenated hydrocarbon such as methylene chloride, an ether, such as a di-lower alkyl ether, e.g. diethyl ether,

509836/0970

250633Q

- 6Λ -

a Diniederalkoxyniederalkane, such as dimethyloxyethane, a cyclic ethers, such as dioxane or tetrahydrofuran or a lower alkanol, e.g. methanol, ethanol or tert-butanol, or in a mixture thereof, at room temperature or with gentle heating to 40 to 50 °, if desired in an inert gas such as nitrogen atmosphere.

When treating a compound of the formula II in which Y is a group —SRa>, for example the 2-benzothiazolylthio radical, with one of the bases mentioned, for example with 1,5-diazabicyclo [5.4.0] undec-5-ene, by addition a sulfinic acid of the formula H-SO ₂ -R ₅ , for example p-toluenesulfinic acid, the yield of compounds of the formula IA and IB can be increased.

In the ring closure reaction according to the invention can depending on the starting material and reaction conditions, uniform compounds of the formula IA or IB or mixtures of Compounds of formula IA and IB obtained. Mixtures obtained can in a manner known per se, e.g. with the help of suitable separation methods, e.g. by adsorption and fractional elution, including chromatography (column, paper or Plate chromatography) using suitable adsorbents such as silica gel or aluminum oxide, and Eluents, also by fractional crystallization, Solvent distribution, etc. are separated.

509836/0970

250633Q

Obtained compounds of the formulas Ia and IB, the suitable intermediates for pharmacological preparation are more active end products can be converted into such active end products by various additional measures known per se will.

In a compound of the formula IA or IB obtained according to the invention, a hydroxyl protective group R can easily be split off and replaced by hydrogen. A 2-oxa- or 2-thia-aliphatic or cycloaliphatic hydrocarbon radical can, 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 be split off with an acid, _W ; j_ _e acetic acid. An optionally substituted a-phenyl-lower alkyl, e.g. benzyl or diphenylmethyl group is split off, for example, by acidolysis, e.g. 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 3-hydroxy compounds formed are mainly in the 3-cephem form. A hydroxy protective group can optionally be split off selectively, ie

50 9'8 36/0970

without a carboxyl protective group R ^ being split off at the same time will.

Enol ethers, i.e. compounds of the formula IA and / or IB in which R ^ is lower alkyl, are obtained from compounds of the formulas IA or IB, in which R ~ is a protective hydroxyl group The remainder is, by replacing this remainder with hydrogen and subsequent etherification of the free hydroxyl group according to any, processes suitable for the etherification of enol groups. The etherifying reagent used is preferably one the optionally substituted hydrocarbon radical R ~ corresponding diazo compound of the formula Ro- ^ »in the first place Line an optionally substituted diazo lower alkane, e.g. diazomethane, diazoethane or diazo-n-butane, or an optionally substituted a-phenyl-diazo-lower alkane, e.g. phenyl- or Diphenyl-diazomethane. These reagents are used in the presence of a suitable inert solvent, such as an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic Hydrocarbon, e.g. methylene chloride, a lower alkanol, e.g. methanol, ethanol or tert-butanol, or an ether, such as a di-lower alkyl ether, e.g. diethyl ether, or a cyclic ether, e.g. tetrahydrofuran or dioxane, or a solvent mixture, and depending on the diazo reagent with cooling, at room temperature or with gentle heating,

509836/0970

also, if necessary, in a closed vessel and / or under an inert gas, e.g. nitrogen, atmosphere brought.

You can also use enol ethers of the formula IA. and / or IB ' by treatment with a reactive ester of one, the lower alkyl radical or the optionally substituted ot-phenyl-lower alkyl, e.g. benzyl or diphenylmethyl radical R "form the corresponding alcohol of the formula R" -OH. Suitable esters are primarily those with strong inorganic or organic acids, such as mineral acids, e.g. hydrohalic acids, such as hydrochloric, hydrobromic or hydroiodic acid, also sulfuric acid or halosulfuric acids, e.g. fluorosulfuric acid, or strong organic sulfonic acids, as optionally substituted, e.g., by halogen such as fluorine Lower alkanesulphonic acids, or aromatic sulphonic acids, such as, for example, optionally, e.g. by lower alkyl, such as Methyl, halogen, such as bromine, and / or nitro-substituted benzenesulfonic acids, e.g. methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonic acid. These reagents, especially di-lower alkyl sulfates, such as dimethyl sulfate, also lower alkyl fluorosulfates, e.g. methyl fluorosulphate, or optionally halogen-substituted methanesulphonic acid lower alkyl ester, e.g., methyl trifluoromethanesulfonate, are commonly used in the presence of a solvent, such as one, if appropriate

509836/0970

halogenated, such as chlorinated aliphatic, cycloaliphatic or aromatic hydrocarbons, e.g. methylene chloride, an ether such as dioxane or tetrahydrofuran, or a lower alkanol such as methanol, or a mixture is used. It is preferable to use suitable condensing agents, such as alkali metal carbonates or bicarbonates, e.g. sodium or Potassium carbonate or hydrogen carbonate (usually together with a sulfate), or organic bases, as usually sterically hindered, tri-lower alkylamines, e.g. N, N-diisopropyl-N-ethyl-amine (preferably together with lower alkyl halogen sulfates or optionally halogen-substituted ones Methanesulfonic acid lower alkyl esters), with cooling, at room temperature or with heating, e.g. at temperatures from about -20 ° C to about 50 ° C and, if necessary, in a closed vessel and / or in an inert gas, e.g. nitrogen atmosphere is being worked on.

Enol ethers can also be prepared by treatment with a compound containing two or three etherified hydroxyl groups of the formula Ro-O- on the same carbon atom of aliphatic character, ie with a corresponding acetal or orthoester, in the presence of an acidic agent. For example, gem- lower alkoxy-lower alkanes, such as 2,2-dimethoxy-propane, in the presence of a strong organic

509836/0970

250633Q

Sulphonic acid, such as p-toluenesulphonic acid, and a suitable solvent, such as a lower alkanol, e.g. methanol, or a di-lower alkyl or lower alkylene sulfoxide, e.g. dimethyl sulf oxy d, or tri-lower alkyl orthoformate, e.g. triethyl orthoformate, in the presence of a strong mineral acid, e.g. sulfuric acid , or a strong organic sulfonic acid, such as p-toluenesulfonic acid, and a suitable solvent, such as a lower alkanol, e.g. ethanol, or an ether, e.g. dioxane, as an etherifying agent and thus obtain compounds of the formula IA and / or IB, in which R ₃ represents lower alkyl, for example methyl or ethyl.

The enol ethers of the formula IA and / or IB can also be obtained if starting materials of the formula II are mixed with tri-Ro-oxonium salts of the formula (R ₃ KO ^ A ⁰ (so-called sea wine salts), as well as di-RoO-carbenium salts of the formula (R ₃ O) ₂ CH © A® or Di ~ R ₃ -halonium salts of the formula (R ₃ ) _ Hal®A®, where A® is the anion of an acid and Hai® is a halonium, in particular bromonium ion primarily to tri-lower alkyloxpnium salts, as well as di-lower alkoxycarbenium or di-lower alkylhalonium salts, in particular the corresponding salts with complex, fluorine-containing acids, such as the corresponding tetrafluoroborates,

500836/09 70

Hexafluorophosphates, hexafluoroantimonates or hexachlorantimonates. Such reagents are e.g. trimethyloxonium or triethyloxonium hexafluoroantimonate, hexachlorantimonate, hexafluorophosphate, or tetrafluoroborate, dimethoxycarbenium hexafluorophosphate or dimethyl bromonium hexafluoroantimonate. These etherifying agents are preferably used in one inert solvents such as an ether or a halogenated hydrocarbon, e.g. diethyl ether, tetrahydrofuran or methylene chloride, or in a mixture thereof, if necessary, in the presence of a base, such as an organic base, e.g. a preferably sterically hindered, tri-lower alkylamine, e.g. N, N-diisopropyl-N-ethyl-amine, and with cooling, at room temperature or with slight warming, e.g. at about -20 ° C to about 50 ° C, if necessary, in a closed Vessel and / or in an inert gas, e.g. nitrogen

The enol ethers of the formulas IA and / or IB can also be prepared by treating starting materials of the formula II with a 3-substituted lR ^ -triazene compound (ie a compound of the formula Subst.-N = N-NH-R ₃ ), where the substituent of the 3-nitrogen atom is an organic radical bonded via a carbon atom, preferably a carbocyclic aryl radical, such as an optionally sub-

509836/0970

substituted phenyl radical, for example lower alkyl phenyl, such as 4-methylphenyl. Such triazene compounds are 3-aryl-l-lower alkyl-triazenes, e.g. 3- (4-methylphenyl) -l-methyl-triazene, 3- (4-methylphenyl) -1-ethyl-triazene, 3- (4-methylphenyl) - 1-n-propyl-triazene or 3- (4-methylphenyl) -1-isopropyl-triazene, also 3-aryl-1- (α-phenyl-lower alkyl) -triazenes, e.g. 1-benzyl - 3- (4-methyl-phenyl) -triazene. These reagents are usually in the presence of inert solvents, such as optionally halogenated hydrocarbons or ethers, e.g. benzene, or solvent mixtures, and with cooling, at room temperature and preferably at elevated temperature, e.g. at about 20 ° C to about 100 ° C, if necessary, used in a closed vessel and / or in an inert gas, e.g. nitrogen atmosphere.

In the process according to the invention, as well as in optionally Additional measures to be carried out can, if necessary, include free functional parts that do not participate in the reaction Groups in the starting materials or in the compounds obtainable according to the process, e.g. free amino groups e.g. Acylating, tritylating or silylating, free hydroxyl or mercapto groups, e.g. by etherification or esterification, and free Carboxyl groups, e.g. by esterification, including silylation, are temporarily protected in a manner known per se and in each case

509836/0970

- ΤΛ. -

after the reaction has taken place, in a manner known per se, if desired, individually or together, are released. So can one preferably e.g. amino, hydroxy, carboxyl or phosphorus

A b phono groups in an acyl residue R, or R-, e.g. in the form of Acylamino, such as those mentioned above, e.g. 2,2,2-Trichloräthoxycarbonylamino-, 2-bromoethoxycarbonylamino, 4-methoxybenzyloxycarbonylamino, Diphenylmethoxycarbonylamino or tert-butyloxycarbonylamino, of aryl or aryl lower alkylthioamino, e.g. 2-nitrophenylthioamino, or arylsulfonylamino, e.g. 4-methylphenylsulfonylamino, or of 1-lower alkoxycarbonyl-2-propylideneamino groups, or of acyloxy, such as those mentioned above, e.g. tert-butyloxycarbonyloxy, 2,2,2-trichloroethoxycarbonyl

htw. oxy or 2-Bromäthoxycarbonyloxygruppen, dB i te of esterified carboxy, such as the above-mentioned, for example Diphenylmethoxycarbonylgruppen _s or 0, O ¹ disubstituted phosphono, such as the above-mentioned, for example, 0,0'-Diniederalkylphosphono-, eg 0 , 0'-dimethylphosphono groups, slit and subsequently, if necessary after conversion of the protective group, for example a 2-bromoä'thoxycarbonylin, a 2-iodo-methoxycarbonyl group, in a manner known per se and depending on the type of protective group, for example a 2.2 , 2-Trichloräthoxycarbonylamino- or 2-Jodäthoxycarbonylaminogruppe by treatment with suitable reducing agents, such as zinc in the presence of aqueous acetic acid, a

Diphenylmethoxycarbony / amino or tert-butyloxycarbonylamino group by treatment with formic or trifluoroacetic acid, an aryl or aryl-lower alkylthioainino group by treatment with a nucleophilic reagent, such as sulphurous acid, an arylsulphonylamino group by means of electrolytic reduction with propylicarbonyl-2-lower alkoxy aqueous mineral acid or its tert-butyloxycarbonyloxy group by treatment with formic or trifluoroacetic acid, or a 2,2,2-trichloroethycarbonyloxy group by treatment with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid, or a diphenylmethoxycarbonyl group by treatment with ameise - or trifluoroacetic acid or by hydrogenolysis, or a 0,0'-disubstituted phosphono group by treatment with an alkali metal halide, if desired, partially cleave _3%. In a compound obtainable according to the invention

of the formula IA or IB with a protected, especially

A esterified carboxyl group of the formal -C (-O) -R ^ can be converted into the free carboxyl group in a manner known per se, for example depending on the type of group R * 2 », an esterified one, for example by a lower alkyl radical _; , in particular methyl or ethyl, or esterified by a bensyl radical® carboxyl group, in particular in a 2-Gephsravfcr b in & sng der Fo ^ rröl IB * can by ri / drolysis in weak hf. * \ - xnmt tt®ai? &. h ^ ₅ E, ^ -. ^ H ^ a-

S 4J

4Y

act with an aqueous solution of an alkali metal or alkaline earth metal hydroxide or carbonate: s, for example sodium or potassium hydroxide, preferably at a pH of about 9 to 10, and optionally in the presence of a lower alkanol, converted into a free carboxyl group. A carboxyl group esterified by a suitable 2-halo-lower alkyl or aryl carbonyl methyl group can, for example, by treatment with a chemical reducing agent such as a metal, 2.B. Zinc, or a reducing metal salt, would leave a chromium-II-salt, e.g. Together with the metal, it is able to generate nascent vassar, such as an acid, primarily acetic and formic acid, or an alcohol, preferably with water, a carboxyl group esterified by its aryiearbDnylraethyl group, likewise by treatment with a nucleophilic, or optionally salt-forming P.eagans, such as sodium thiophenolate or sodium iodide., eic / 3 carboxyl group esterified by 3.1ne suitable arylaetr.yl grouping, for example by irradiation, preferably with ultraviolet light, for example, below 290 mp ₅ when the arylmethyl group z _s B * a gcgebs.ienfails ix \ 3-, 4 ° and / or 5-position, 2.3. By ITieäamlkoiiy «and / or nitro groups

Bensyireet represents, ocitu "sit i £ ^ e? Wavy Γ lint ;, sB about 290 ΐψ when the. Arylaethvl-

S 01 ^? i 3 e / ^; ί 8? 0

ι & υ ο J ό υ

group means, for example, a benzyl radical substituted in the 2-position by a nitro group, a carboxyl group esterified by a suitably substituted methyl group, such as tert-butyl or diphenylmethyl, for example by treatment with a suitable acidic agent such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole, an activated esterified carboxyl group, and also a present in anhydride form carboxyl group by hydrolysis, ζ.Β "τ acid by treatment with an acidic or weakly basic aqueous agent, such as Sa" ¹ or aqueous sodium bicarbonate or an aqueous potassium phosphate buffer from pH about 7 to about 9, and a hydrogenolytically cleavable esterified carboxyl group can be cleaved by hydrogenolysis, for example by treatment with hydrogen in the presence of a noble metal, for example palladium catalyst.

A protected e.g. by silylation or stannylation Carboxyl group can be added in the usual way, s.B. by Treat with water or an alcohol.

Compounds of the formula IA or IB obtained can be converted into other compounds of the formula in a manner known per se IA or IB are transferred.

In a compound obtained, for example, an amino

Away
protecting group R ₁ or R ,, in particular an easily cleavable acyl group, in a manner known per se, for example an a-pclyver-

503838/0970

250633G

- 38 -

branched lower alkoxycarbonyl group, such as tert-butyloxycarbonyl, by treating with trifluoroacetic acid and a 2-halo-lower alkoxycarbonyl group, such as 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, or a phenacyloxycarbonyl group by treatment with a suitable reducing metal or corresponding metal compound, e.g. zinc, or a chromium-II compound, such as chloride or acetate, advantageously in the presence of a hydrogen nasalizing together with the metal or the metal compound generating agent, preferably in the presence of hydrous acetic acid, are split off.

Furthermore, in a compound of the formula IA or IB obtained, in which a carboxyl group of the formula -CC = O) -IL preferably one, e.g., by esterification, including by silylation, e.g., by reaction with a suitable organic Halosilicon or halotin IV compound, such as Trimethylchlorosilane or tri-n-butyltin chloride, protected

a b represents a carboxyl group, an acyl group R ^ or IL, in which any free functional groups that may be present are protected by treating with an imide halide-forming agent, reacting the resulting imide halide with an alcohol and cleavage of the imino ether formed, be split off, with a protected, e.g. a

: '■% "' S - ■ '' O f S ** · ft tf

250633Q

Protected by an organic silyl radical, carboxyl group can be released during the course of the reaction.

Imide halide forming agents in which I-Ialogens is bound to an electrophilic central atom, are mainly acid halides, such as acid bromides and especially acid chlorides, These are primarily acid halides of

ft. j

inorganic acid, especially phosphoric acids, such as phosphorus oxy-, phosphorus tri- and especially phosphorus pentahalides, e.g. phosphorus oxychloride, phosphorus trichloride, and primarily phosphorus pentachloride, also pyrocatechyl phosphorus trichloride, as well as acid halides, especially chlorides, of sulfur-containing acids or of carboxylic acids, such as thionyl chloride, phosgene or oxalyl chloride.

The reaction with one of the imide halide-forming agents mentioned is usually in the presence of a suitable, in particular organic base, primarily a tertiary amine, for example a tertiary aliphatic mono- or diamine, such as a tri-lower alkyl amine, for example trimethyl, triethyl or Ν, Ν-diisopropyl-N-ethyl-amine, also an N, N, N ¹ , N ¹ -tetra-lower alkyl-lower alkylenediamine, for example Ν, Ν, Ν ', N'-tetramethyl-l ^ -pentylenediamine or Ν, Ν, Ν ', Ν'-tetramethyl-l, 6-hexylenediamine, of a mono or bicyclic mono- or diamine, such as an N-substituted, e.g. N-lower alkylated, alkylene, azaalkylene or ouaalkylene amine,

25C633Q

e.g. N-mefchylpiperidine or N-methylmorpholine, furthermore 2,3,4,6,7,8-hexahydro-pyrrolo [1,2-a] pyrimidine (diazabicyclonic ions; DBN), or a tertiary aromatic amine such as a di-lower alkyl aniline, e.g. Ν, Ν-dimethylaniline, or primarily a tertiary heterocyclic, mono- or bicyclic base, such as quinoline or isoquinoline, in particular Pyridine, preferably in the presence of a solvent such as an optionally halogenated, e.g. chlorinated, aliphatic or aromatic hydrocarbon, e.g. Methylene chloride. You can use approximately equimolar amounts of the imide halide-forming agent and the base use; the latter k & iin but also in excess or shortfall, ζ.B, in about 0.2 to about 1 times the amount or then in about to 10 times, in particular about 3 to 5 times the excess.

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

The imide balogenide product, which is usually processed further without isolation, is made according to the process With an alcohol, preferably in the presence of one of the

$ 03338/0970

250633Q

- 28 -

above-mentioned bases, converted to the iminoether. Suitable alcohols are, for example, aliphatic and araliphatic alcohols, in primarily optionally substituted, such as halogenated, e.g. chlorinated, or additional hydroxyl groups, Lower alkanols, e.g. ethanol, propanol or butanol, in particular Methanol, furthermore 2-halo-lower alkanols, e.g. 2,2,2-trichloroethanol or 2-bromoethanol ·, and optionally substituted phenyl-lower alkanols, such as benzyl alcohol. Usually one uses an excess, e.g. up to about 100 times of the alcohol and preferably operates under cooling, e.g. at temperatures from about -50 ° C to about 10 ° C.

The imino ether product can advantageously --Line Isolation to be subjected to cleavage. The cleavage of the imino ether can be achieved by treatment with a suitable hydroxy compound, preferably by means of hydrolysis, furthermore by alcoholysis, the latter when using an excess of the alcohol can take place directly after the imino ether formation can be achieved. One preferably uses Water or an alcohol, especially a lower alkanol such as methanol, or an aqueous mixture of an organic Solvent · s, such as an alcohol. You usually work in an acidic medium, e.g. at a pH of around 1 to about 5, which can be added, if necessary, by adding a

009836/0870

250633Q

such as hydrochloric acid, sulfuric acid, can adjust basic Mittal, such as an aqueous alkali metal hydroxide, eg sodium or potassium hydroxide, or an acid, eg a mineral acid or organic acid, _s phosphoric acid, fluoboric acid, trifluoroacetic acid or p-toluene-sulfonic acid.

The three-step process for cleavage described above an acyl group is advantageously used 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. Methylene chloride, and / or in an inert gas atmosphere such as a nitrogen atmosphere.

If the intermediate imide halide obtained by the above process is substituted with an alcohol with a salt, such as an alkali metal salt of a carbon, in particular a sterically hindered carboxylic acid, a compound of the formula IA or IB is obtained, in which both R and R. represent acyl groups.

In a compound of the formula IA or IB, in which both

away
de radicals R .. and R .. represent acyl groups, one of these groups, preferably the less sterically hindered one, for example by hydrolysis or aminolysis, can be removed selectively.

6 C j * s ■■ ;. / 0 9? 0

In a compound of the formulas IA or IB, in which R- and R- together with the nitrogen atom form a phthalimido group represent, this can e.g. by hydrazinolysis, i.e. when treating such a compound with hydrazine, into the free amino group are converted.

Certain acyl radicals R-, an acylamino group in compounds obtainable according to the invention, such as the 5-amino-5-carboxy-valeryl radical, in which carboxyl, for example by esterification, in particular by diphenylethyl, and / or the amino group, for example by acylation, in particular by an acyl radical an organic carboxylic acid, such as halogeniaderalkanoyl, such as dichloroacetyl, or phthaloyl, are optionally protected, can also be obtained by treating with a nitrosating agent such as nitrosyl chloride, with a carbocyclic arene diazonium salt such as benzene diazonium chloride ₅ or with a positive halogen donating agent such as an N- Halogen amide or imide, e.g. N-bromosuccinimide, preferably in a suitable solvent or solvent mixture, such as formic acid, together with a nitro or cyano-lower alkane and adding a hydroxyl-containing agent, such as water or a lower alkanol, e.g. methanol, to the reaction product or, if in the 5-amino-5-carboxy-valeryl radical R. the Ami substituted and the carboxy group · protected for example by esterification »; is, and R, preferably represents an acyl radical, but also

ί0982a /. ' ? 3

-M-

May mean hydrogen by standing in an inert solvent such as dioxane or a halogenated aliphatic Hydrocarbon, e.g. Methylene chloride, and if necessary. Working up the free or monoacylated amino compound be split off according to methods known per se.

A formyl IL may also by treatment with an acidic agent, zBpToluolsulfon- or hydrochloric acid, a weakly basic agent such, for example dilute ammonia, or a Decarbcnylierungsmittel, eg tris (triphenylphosphine) -rhodiura: hlorid be cleaved.

A tri ~ .rir.liuatliyl-, such as the trityl group R, can for example, by treatment with an acidic agent such as a mineral acid, e.g., hydrochloric acid.

In a compound of the formula IA or IB, in which R ^ and R, represent hydrogen, one can use the free amino group substitute according to methods known per se, in the first place Line by treating with acids, such as carboxylic acid, or reactive ones Acylate 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, one usually uses suitable condensing agents « such as carbodiimides, for example N, N'-di-

5098 3 8/0970

- ML -

ethyl-,. Ν, Ν'-dipropyl, N ₅ N ¹ -diisopropyl, Ν, Ν'-dicyclohexyl or N-ethyl-N ¹ -B-dimethylaminopropyl-carbodiimides suitable Garbony! Compounds, for example carbonyldiimidazole, or isoxazolinium salts, for example N- Ethyl-5-phenylisoxazolinium-3'-sulfonate and N-tert.-butyl-S-methyl-isqazolinium perchlorate, or a suitable acylamine compound, ζ.B. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-quinoline.

The Kondensa c · ic:;.. Is reactive preferably in one of the below mentioned further, anhydrous reaction media, for example in methylene chloride, dimethylformamide or acetonitrile performed.

An amide-forming, functional derivative of a Acid, preferably with protected optional groups, such as an optional amino group primarily an anhydride of such an acid, including, and preferably, a mixed anhydride. Mixed anhydrides are, for example, those with inorganic acids, in particular with hydrohalic acids, i.e. the corresponding acid halides, e.g. chlorides or bromides, also with hydrazoic acid, i.e. the corresponding acid azides, with a phosphoric acid, e.g. phosphoric acid or phosphorous acid, with a sulphurous acid, 2uB. Sulfuric acid, or with hydrocyanic acid. More mixed Anhydrides are e.g. those with organic acids

ren, such as organic carboxylic acids, as with optionally, e.g. by halogen, such as fluorine or chlorine, substituted lower alkanecarboxylic acids, e.g. pivalic acid or trichloroacetic acid, or with half-esters, especially lower alkyl half-esters, the Carbonic acid ^ such as the ethyl or isobutyl half ester of carbonic acid, or with organic, especially aliphatic or aromatic, sulfonic acids, 2.B. p-toluenesulfonic acid.

Internal anhydrides such as ketenes, e.g. 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-carboxy anhydride or the like Use anhydride of 1-N-carboxyamino-cyclohexanecarboxylic acid.

Further acid derivatives suitable for reaction with the free amino group are activated esters, usually with protected functional groups which may be present, such as esters with vinylogous alcohols (ie enols), such as vinylogous lower alkanols, or aryl esters, such as, for example, by nitro or halogen, such as Chlorine, substituted phenyl esters, for example pentachlorophenyl, 4-nitrophenyl or 2,4-dinitrophenyl esters, heteroaromatic esters, such as benzotriazol esters, or diacyfflimino esters, such as succinylimino or phthalylimino esters.

n) r-: 3 3 / o 3 7

Further acylation derivatives are, for example, substituted formimino derivatives, such as substituted Ν, Ν-dimethylchloroformimino derivatives of acids, or N-substituted N, N-diacylaraines, such as a Ν, Ν-diacy ^ lated aniline.

The acylation with an acid derivative, such as an anhydride and in particular 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. a tertiary amine, such as tri-lower alkylamine, e.g. triethylamine, Ν, Ν-di-lower alkyl aniline, for example, Ν, Ν-dimethylaniline, or a base of the pyridine type, for example pyridine ₅ of an inorganic base, for example an alkali metal or Erdalkalimetallhydrcxic carbonate, or bicarbonate, for example sodium, potassium or Caleium 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 be made, for example in a carboxamide, such as Ν, Ν-di-lower alkylamide, e.g. dimethylformamide, a halogenated hydrocarbon, e.g. methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, e.g. Acetone, an ester, e.g. ethyl acetate, or a

w 9 8 3 8/0 ^{δ tf ύ}

Nitrii, ζ.Β «acetonitrile, or mixtures thereof, and, if necessary at lower or higher temperatures and / or in an inert gas, e.g. nitrogen atmosphere.

In the above N-acylation reactions can be assumed of compounds of formulas IA or IB in which R ~ is lower alkyl or an optionally substituted a-Phenylniederalkyl- _$ example benzyl or diphenylmethyl, and R 'has the above meaning, with compounds having free carboxyl groups of the Formula -C (-O) -R _? , where R _{n is} hydroxy, also in the form of salts, for example ammonium salts, such as with triethylamine, or in the form of a compound rd. phosphorus dihalide, such as methylphosphorus chloride, aechylphosphorodibromide or methoxyphosphorus dichloride with a slotted carboxyl group, can be used; The protected carboxyl group in the obtained a-sylation product can be released in a manner known per se, for example as described above, including * by hydrolysis or alcoholysis.

An acyl group can also be added by

a b one is a compound of the formula IA or IB, in which R- and R, together for a ylid residue (which can also be added later, e.g. by treating a compound wherein R? and R ^ hydrogen represents, nit. an aldehyde, such as an aliphatic, aromatic

509836/0970

- Ms -

4 V

table or araliphatic aldehyde) stands, for example acylated by the methods given above, and the acylation product, preferably in a neutral or weakly acidic medium, hydro ': yüier'c,

An acyl group can also be introduced in stages will. For example, in a compound of the formula IA or IB with a free amino group, a halogen-lower alkanoyl, e.g. Broir.ace "~.:,. .uppe, or e.g. by treating with a carbonic acid dihalide, such as phosgene, a halogenocarbonyl, e.g. chlorocarbonyl group, and an N- (halo-lower alkanoyl) or N- (halo-carbonyl) -amino compound which can be obtained in this way with suitable exchange reagents, such as basic compounds, e.g. tetrazole thio compounds', e.g. 2-mercapto-1-methyl-imidazole, or partial metal salts, e.g. Sodium azide or alcohols such as lower alkanals, e.g. tert-butanol, convert and so to substituted N-lower alkanoyl or N-hydroxycarbony! amino compounds arrive.

Free functional parts can be used in both Groups during the acylation reaction temporarily be protected in a manner known per se and after the acylation by means of methods known per se, eg. as above described, are released.

509336/0873

The acylation can also be carried out by replacing an existing acyl group with another, preferably sterically hindered acyl group, for example by the method described above, by adding the imide halide compound produces, treats this with a salt of an acid and one of the acyl groups present in the product available, usually the less sterically hindered acyl group, cleaved off hydrolytically.

Furthermore, one can, for example, a compound of the formula IA or IB, in which R, a glycyl group, preferably substituted in the α-position, such as phenylglj ^ cyl, and R _{1 is} hydrogen, with an aldehyde, such as formaldehyde, or a ketone, such as lower alkanone, for example acetone, and thus obtain compounds of the formula IA or IB in which R ₁ and R ₁ together with the nitrogen atom are a 5-oxo-1,3-diaza, preferably substituted in the 4-position and optionally substituted in the 2-position represent cyclopentyl radical.

In a compound of formula IA or IB, wherein

away
Ri and R ₁ stand for hydrogen, the free amino group can also be protected by introducing a triarylmethyl group, for example by treatment with a reactive ester of a triarylmethanol such as trityl chloride, preferably in the presence of a basic agent such as pyridine.

§03833 / 03 ^ 0

An amino group can also be protected by introducing a silyl and stannyl group. Such groups are introduced in a manner known per se, for example by treatment with a suitable silylating agent, such as with a dihalo-di-lower alkyl-silane, lower-alkoxy-lower-alkyl-dihalosilane or tri-lower alkyl-silyl halide, e.g. dichloro-dimethylsilane, methoxy-methyl-dichloro silane, or dimethyl-tert-Triniethylsilylehlorid bufcyl-silyl chloride to give such silyl halide compounds preferably in the presence of a base, zBPyridin used mononiederalkylierten N-with an optionally, N, N-di-lower alkylated or _N-s N-triniederalkylsilylierten lower alkyl-N-tri-lower alkylsilylated N- (tri-lower alkylsilyl) amine (see, for example, British Patent No. 1.073.530), or with a silylated carboxylic acid amide, such as a bis-tri-lower alkylsilyl-acetamide, for example bis-tri-ethylsilyl-acetamide, or trifluorosilylacetamide , also with a suitable stannylating agent, such as a bis (tri-lower alkyltin) oxide, for example bis (tri-n-butyltin) oxide, a tri-lower alkyltin hydroxide yd, for example triethyl tin hydroxide, a tri-lower alkyl-lower alkoxy tin, tetra-lower alkoxy tin or tetra-lower alkyl tin compound, as well as a tri-lower alkyl tin halide, sB tri-n-butyl cyan chloride (see e.g. Dutch Auslegeschrift 67/11107).

S ί i? tt i f> / Ö Γ: ν ■> *

In a process according to the process obtainable compound of formula IA or IB, which is a free. Contains carboxyl group of the formula -CC = O) -R ^, such can be converted into a protected carboxyl group in a manner known per se. Ester z “B” is obtained by treating with a suitable diazo compound, such as a diazo lower alkane, eg diazomethane or diazobutane, or a phenyl diazo lower alkane _} eg diphenyldiazomethane, if necessary} in the presence of a Lewis acid, such as boron trifluoride, or reacting with one for esterification suitable alcohol in the presence of an esterifying agent "" such as a carbodiimide sB dicyclohexylcarbodiimide, and carbonyldiimMszol, furthermore with an N, N'-disubstituted or S-substituted isourea or isothiourea, in which an O- and S-3-substitute: i : »Ent, for example, lower alkyl, in particular tert-butyl, phenyl alkyl or cycloalkyl, iind N or N ¹ substituents, for example lower alkyl, in particular isopropyl, cycloalkyl or phenyl, or by any other known and suitable esterification process, such as reaction of a salt of Acid entered a reactive esteras alcohol and a strong inorganic acid, as well as a strong organic one Sulfonic acid. Furthermore, acid halides, such as chlorides (produced sB by treatment with oxalyl chloride), activated esters (formed s, B. With N-hydroxy nitrogen compound, such as N-hydroxysuccinimide) or

S09S36 / 0970

250633U

mixed anhydrides (obtained e.g. with haloformic acid lower alkyl esters, such as ethyl chloroformate or isobutyl chloroformate, or with haloacetic acid halides * such as trichloroacetic acid chloride) by reacting with alcohols, optionally in the presence of a base such as pyridine, into a esterified carboxyl group are converted.

In a compound obtained with an esterified grouping of the formula -CC = O) -IU, this can be converted into another esterified carboxy group of this formula, e.g. 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl by treating with an iodized salt such as sodium iodide in the presence of a suitable solvent such as acetone in 2-iodoethoxycarbonyl.

Mixed anhydrides can be prepared by adding a compound of the formula IA or IB with a free carboxyl group of the formula -C ( ⁵⁵ O) -R ^ *, preferably a salt, in particular an alkali metal ", eg sodium or ammonium, eg triethylammonium salt thereof, with a reactive derivative such as a halide, for example the chloride, an acid, for example a lower alkyl haloformate or a lower alkanecarboxylic acid chloride.

In a compound obtainable according to the process and having a free carboxyl group of the formula -C (-O) -Ro can one such in an optionally substituted car-

509836/0970

bamoyl or hydrazir-.ocarbcnylgruppe be converted, with one preferably reactive, functionally modified ones Derivatives, such as the above-mentioned acid halides, generally esters, as well as the above-mentioned activated esters, or mixed Reacts 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, for example by adding compounds of the formulas IA or IB, in which R "is hydroxy, or salts such as alkali metal salts, for example sodium salts thereof, treated with a suitable silylating or stannylating agent such as one of the aforementioned silylating or stannylating agents; see e.g. British patent no. 1,073,530 or Dutch patent application no. 61/11101.

You can also use modified functional substitutes

Away

Tuenten in groups R- ,, R, and / or R2> such as substituted amino groups, acylated hydroxyl groups, esterified carboxy groups or 0, O ¹ -disubstituted phosphono groups, according to methods known per se, for example those described above,

A b or free functional substituents in groups R, R and / or R, y, such as free amino, hydroxy, carboxy or phosphono groups, according to methods known per se, for example acylation or

b 3 \) ; 0 h * ii

Esterification or substitution, functional modification. For example, an amino group can be treated with sulfur trioxide, preferably in the form of a complex with an organic base such as a tri-lower alkylamine, e.g., triethylamine, into a Convert sulfoamino group. Furthermore, the reaction mixture obtained by reacting an acid addition salt can be 4-guanyl semicarbazide with sodium nitrite, with a compound of formula IA or IB, in which, for example, the amino protecting group R represents an optionally substituted glycyl group,

"at

convert and so convert the amino into a 3 ~ Ou $ ^ yl ~ ureido group. Compounds with aliphatically bonded halogen, for example with an optionally substituted halogen, can also be used a-bromoacety! grouping, with esters of phosphorous acid, such as Tri-lower alkyl phosphite compounds, convert and so to the corresponding Phosphono compounds succeeded ?.

Obtained cephem compounds of the formula IA and IB can by oxidation with suitable oxidizing agents, such as those described below, in 1-oxides of the corresponding 3-cephem compounds of the formula IA are converted. Received Leave 1-oxides of 3-cephem compounds of the formula IA by reduction with suitable reducing agents, such as those described below, to the corresponding 3-cephem compounds the formula IA reduce these

Responses must be ensured * that, if necessary, free f factional groups are protected and, if desired, subsequently released again.

Obtained cephem compounds can be isomerized. Thus, obtained 2-gephem compounds of the formula IB, or obtained mixtures of 2- and 3-cephem compounds, can be converted into the corresponding 3-cephem compounds of the formula IA by converting a 2-cephem compound of the formula IB, or a mixture consisting of a 2- and 3-Ceph9m compound, in which free functional groups, if necessary, s _c B. as indicated, temporarily protected; can be isomerized. It can, for example, to "2-cephem d * r formula IB using"-sorii> the group of the formula -G (= O) "He, a free or protected carboxyl group _r, where a protected carboxyl group each formed during the reaction can be.

A 2-ceph3m compound of the formula IB can thus be ismerisisrun. by ns & ri treated with a basic agent and of an optionally preserved equilibrium mixture of 2- and 3-cephem compounds of the corresponding 3-cephem compound of the formula IA is isolated.

Suitable isomerizing agents are, for example, organic nitrogenous bases, such as tertiary heterocyclic bases of aromatic character, and primarily tertiary ones

509836/0970

aliphatic, azacycloaliphatic or araliphatic bases; such as N, NjN-tri-lower alkylamines _s 2.B. N _S N, N-trimethylamine ₉ Ν, Ν-dimethyl-N-ethylamine, Ν, Ν, Ν-triethylamine or N ₃ N-diisopropyl-N-ethylamine-.n, N-lower alkyl-s.sacyeloalka & e, ζ. Β. N-methyl-piperidine, or -phenyl-lower alkyl-N-di-lower alkylamines _s N N-?, For example N-benzyl-N, N-dimethyl amine, and mixtures thereof _s as the mixture of a base of the pyridine type, for example _pyridine? and one N _s N, N-Tri.nlsderal ^ / Iaailns, e.g. pyridine and triethylamine. In addition, inorganic or organic salts of bases, in particular of moderately strong to strong bases with weak acids, such as alkali metal or ammonium salts, can be added before lower alkanecarboxylic acids, e.g. sodium acetate, triethylamracinine acetate or N-methyl piperidine acetate, as well as other analogous bases or mixtures of these basic agents can be used.

The above isomerization with basic agents can, for example, in the presence of a derivative of a carboxylic acid which is suitable for forming a mixed anhydride, such as its carboxylic acid anhydride or halides, e.g., with pyridine in the presence of acetic anhydride. It works one preferably in an anhydrous medium, in the presence or absence a solvent such as an optionally halogenated one, e.g., chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, or a mixture of solvents, where as the center of the reaction ?. used, under

509836/0870

the reaction conditions ar * liquid bases at the same time as Solvents can serve, 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. nitrogen atmosphere, and / or in a closed vessel.

The thus obtainable 3-cephem compounds of the formula IA can be removed in a manner known per se, e.g. by adsorption and / or crystallization, from any Separate 2-cephem compounds of the formula IB.

The isomerization of 2-cephem compounds of the formula IB can also be carried out by this if desired, an obtainable mixture of isomers is oxidized in the 1-position the 1-oxides of 3-cephem compounds of the formula IA separates, and the 1-oxides of the corresponding 3-cephem compounds of the formula IA obtainable in this way are reduced.

Inorganic ones are suitable oxidizing agents for the 1-position oxidation of 2-cephem compounds Peracids that have a reduction potential of at least +1.5 volts and consist of non-metallic elements, organic peracids or mixtures of hydrogen peroxide and acids, in particular organic carboxylic acids, with a dissociation constant of at least 10 are possible. Suitable inorganic peracids are periodic and persulfuric acid. Organic peracids are corresponding percarbon and per

^; ; ■: η: 2 6 /: 3 ν ....

sulfonic acids, which can be formed in situ by using at least one equivalent of hydrogen peroxide and one carboxylic acid when applied as such. It is advisable to use a large excess of the carboxylic acid if, for example, acetic acid is used as the solvent. Suitable peracids are, for example, performic acid, peracetic acid, pertrifluoroacetic acid, permaleic acid, perbenzoic acid, monoperphthalic acid or p-toluene persulfonic acid,

The oxidation can also be carried out using hydrogen peroxide with catalytic amounts of an acid with a dissociation constant of at least 10 ", whereby low concentrations, for example 1-2% and less, but also larger amounts of the acid can be used. The effectiveness depends on this of the mixture are primarily by the strength of the acid from. Suitable mixtures z _o as those of hydrogen peroxide with acetic acid, or trifluoroacetic acid Perchloräsure.

The above oxidation can be carried out in the presence of suitable catalysts. For example, the oxidation with percarboxylic acids can be catalyzed by the presence of an acid with a dissociation coefficient of at least 10, the effectiveness of which depends on its strength.

Acids suitable as catalysts are, for example, acetic acid and perchloric acid and trifluoroacetic acid. Usually used at least equimolar amounts of the oxidizing agent, preferably a small excess of about 10% to about 20%: The oxidation is preferred under mild conditions, e.g. at temperatures from about -50 ° C to about + 100 ° C from about -10 ° C to about + 40 ° C.

The oxidation of 2-cephem compounds to the 1-oxides of the corresponding 3-cephera compounds can also be carried out by treatment with: ozone, solvents with organic kypchalogenite compounds, such as lower alkyl hypochlorites, e.g. tert-butyl hypochlorite, the presence of inert solvents such as optionally halogenating hydrocarbons, such as methylene chloride, and used at temperatures from about -10 ° C to about + 30 ° C, with peroxide compounds,? ie alkali metal periodates, e.g. potassium period-si ", the itane preferably in an aqueous Medium at a pH of about 6 and at temperatures of about -10 ° C to about + 30 ° C, with iodobenzene dichloride, which is in an aqueous medium, preferably in the presence of an organic base, see e.g. pyridine, and with cooling, for example at temperatures of about -20 ° C to about 0 °, or carried out with any other oxidizing agent which is suitable for converting a thio group into a sulfoxide group.

50S836 / 0970

2 ^ 06330

In the 1-oxides of 3-Gephemverfoindungen of the formula IA obtainable in this way, in particular in those compounds in which R ₁ , R 1 and R "have the preferred conditions given above

J- JL ^

away

have meanings, the groups R ₁ , R- and / or R "can be converted into one another, split off or introduced within the defined framework. A mixture of isomers α- and β-1-oxides can be separated, for example by chromatography.

The production of 1-oxides from 3-G ep hem compounds of the formula IA can be prepared in a manner known per se by treating with a reducing agent, if necessary, in the presence an activating medium. Possible reducing agents are: catalytically activated hydrogen, where noble metal catalysts are used which contain palladium, platinum or rhodium »and the nan used together with a suitable carrier material, such as carbon or barium sulfate; reducing tin, iron, Copper or manganese cations, which are in the form of corresponding Compounds or complexes of an inorganic or organic nature, e.g. as tin (II) chloride, fluoride, acetate or formate, Iron (II) chloride, sulphate, oxalate or succinate, copper (I) chloride, benzoate or oxide, or manganese II chloride, sulfate, acetate or oxide, or as complexes, e.g. with ethylenediamine-

c Π ο. ■: ■ : ί υ / i "} Q 7 ft

tetraacetic acid or nitrate acid can be used; reducing dithionite, iodine or iron (II) cyanide anions, which are in the form of corresponding inorganic or organic Salts, such as alkali metal, e.g. sodium or potassium radithionite, Sodium or potassium iodide or iron (II) cyanide, or in the form of the corresponding acids, such as hydriodic acid, be used; reducing trivalent inorganic or organic phosphorus compounds, such as phosphines, also Esters, amides and halides of phosphinous, phosphonous or phosphorous acid, as well as these phosphorus-oxygen compounds corresponding phosphorus-sulfur compounds, in which organic radicals primarily aliphatic, aromatic or araliphatic radicals »2, B. optionally substituted Represent lower alkyl, phenyl or phenyl lower alkyl groups, such as Tri-phenylphosphine, tri-n-butylphosphine, DiphenylphosphinigsMureiiiethylester, Diphenylcblorphosphine * Phenyldicfalorphosphiri, Benzolphosphonigsäuredimethylester, Butanphosphonigsäuremethylester, Phosphorous acid triphenyl ester, Phosphorous acid trimethyl ester, phosphorus trichloride, phosphorus tribromide » Etc.; reducing halogen compounds, the at least one hydrogen atom bonded to the silicon atom and which also contain halogen, such as chlorine, bromine or iodine, also organic radicals, such as aliphatic or aromatic groups

3>: -S / Q978

pen, for example optionally substituted alkyl or phenyl groups, such as chlorosilane, bromosilane, di- or trichlorosilane, di- or tribromosilane, diphenylchlorosilane, dimethylchlorosilane, etc .; reducing quaternary chloromethyleneiminium salts, in particular chlorides or bromides> in which the irinium group is substituted by one divalent or two monovalent organic radicals, such as optionally substituted lower alkylene or lower alkyl groups, such as N-chloro-methylene-N, N-diethyliminium chloride or Ll-chloro-pyrrolidinium chloride; and complex ie ^ ellh / dtlci-. -fiL ^. Katriuxnborhydrid, in the presence of suitable activating agents such as cobalt-II-chloride, as well as Borandichlcrid «

As activating agents, which are used together with those of the above-mentioned reducing agents ₅ which themselves do not have Lewis acid properties a-jfvjeisan, ie, which are primarily used together with the dithionite-j. Iodine or iron (II) cyanide and the non-logical trivalent phosphorus reducing agents or which are used for catalytic reduction are in particular organic. Carbonic and sulfonic acid halides, also sulfur, phosphorus or silicon halides with the same or greater second order hydrolysis constant than benzoyl chloride, e.g. phosgene, oxalyl chloride, acetic acid chloride or bromide »chloroacetic acid chloride,

. Ü ei * i ά ο / l i, -

i «he -

J ^ ivalinsäurecblorict, 4-Methoxybenzoesäureehlai; id, 4-CyanbenzoesMurechlorid, p-ToluoIsulfonsäurechlorid, Methanesulfonsäurechlorid, Thionylchlorid, Phosphoroxychlorid, phosphorus tribromid, Phenyldichlorphosphine, further suitable as Trylosileanhydan, also Aethansultone, 1,3-propanesultone, 1 * 4-butanesultone or l _s 3 ~ kei; an3ulton, to be mentioned.

The reduction is orsugsweiee ^ in the presence of solvents or mixtures made thereof, the selection primarily by difv solubility of the starting materials '-ad the choice of the Rsditkticr-smittels is determined, for example Niederalkancarbop.sänran or ester as' / on, as Acetic acid and ethyl acetate _{5 are} more catalytic for eggs! Reduction, and, for example, optionally substituted « _; wia felogsniarte or nitrated aliphatic, cycloalivhi? .tisci; aroimtisciifc or araliphatic raw water _{; resources;} For example benzene, methyl, chloride, chloroform or mifcromethane »suitable acid derivatives, such as lower alkanoic acid esters or nitriles, z.3. Ethyl acetate or aeetonis?: !! » or amides of inorganic or organic acids, for example dimethylformamide, dimethylacetamide or hexaa ^ ühyiphospiioramidj ethers, ζ, Β. Diethyl ether * tetrahydrofuran or dioxane, retone _f e.g. acetone _f or sulfones, especially

509836/0970

250633Ü

special aliphatic sulfones, for example diethyl sulfone or tetramethylene sulfone _; etc., together with the chemical reducing agents, these solvents preferably not containing water. Oian usually works at temperatures from about -20 ° C to about 100 ° C _3, whereby the reaction can be carried out at lower temperatures when using very reactive activating agents.

In the so obtained, 3-cephem compounds borrowed from the

Formula IA can m R ?, R., and / or P. « ^w ^ ^e described above, in

away
other groups R ,, R, or R ^ are converted.

Salts of compounds of the formulas IA and IB can be prepared in a manner known per se. Thus, mzn salts of such compounds with acidic groups can be formed, for example, by treatment with metal compounds, such as alkali metal salts of suitable carboxylic acids, for example the sodium salt of ethylcaproic acid, or with ammonia or a suitable organic amine, preferably stoichiometric amounts or only a small Excess of the salt-forming agent used. Acid addition salts of compounds of the formulas IA and IB with basic groups are obtained in the customary manner, for example by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of the formulas IA and IB which contain a salt-forming amino group and a free carboxyl group can

S09836 / 0970

e.g. by neutralizing salts such as acid addition salts, to the isoelectric point, e.g. 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 added to the free compounds in the usual way be converted, metal and ammonium salts, e.g. by treatment with suitable acids, and acid addition salts e.g. by treating with a suitable basic agent.

Mixtures of isomers obtained can be separated into the individual isomers by methods known per se, mixtures of diastereomeric isomers, for example by fractional crystallization, adsorption chromatography (column or thin-layer chromatography) or other suitable separation processes. Racemates obtained can in the usual manner, optionally NACB introduction of suitable salt-forming groupings _t sB by forming a mixture of diastereo ^ e ^ mers salts with optically active salt-forming agents * separating the mixture into the diastereofc & Qmeren Salze.in the free compounds, or by fractional crystallization from optically active solvents into which antipodes are separated.

The method also includes those embodiments according to which compounds obtained as intermediates are used as starting materials and the remaining process

§098-36 / 0970

steps are carried out with these, or the process is terminated at any stage; Furthermore, starting materials used in the form of derivatives or formed during the reaction.

Such starting materials are preferably used and the reaction conditions are chosen such that one leads to the Compounds listed at the beginning as particularly preferred arrives.

In the starting compounds of the formula II, the leaving group Y is preferably a group —SO ₂ —R ₅ , in which R _{5 has} the meaning given, but in particular the preferred meaning given.

The method according to the invention is distinguished from previously known methods in that it protects their reactive groups in any known way from cheap, easily accessible starting materials, such as in particular the 1-oxides of penicillins G or V, which can be produced by fermentation, and 6-amino-penicillanic acid and can easily be released again after the reaction, goes out, and the intermediate products required according to the invention are prepared in high yields.

The starting materials used according to the invention Formula II can be prepared, for example, according to the following reaction scheme »

§09836 / 0 * 76

R ¹

K
N

H f> S

a
1\

HH

O-

(III)

Ii

/ ^CH 3

CH, N HH level 1 b '\ | i / ¹

O = CR ^ O = J

Stage 2a

1\

N H H

-CH ,,

-OH

(VI) - O = C-R '

Via: Y * -SR _{/ 4} VIb : Y = -SO ,, -

VIc : Y

-S-SO ₂ -R ₅

Level 4

1\

N H H

-N

O = J

(II)

Ha: γ = -s-R,

CH, level 3

or:

i Y - -SO ₂ -R Hc: γ * -S-SOg IVa: Y IVb: Y IVc: Y =

-SO ₂ -R ₅

Level 2

1\

N H H o ^.

^CH 2

(V)

Va: Y "

Vb: Y =

Vc : Y =

V> υ C-CH ₃ A

-SO ₂ -R ₅

n ~ Rr

S0S836 / 0970

- 1Θ6 -

Starting compounds of the formula III are known or can be prepared by known processes.

Compounds of the formula IVa are also known or can be prepared according to the Dutch patent 72.08671 can be manufactured. .

The new compounds of the formulas IVb, IVc, Va, Vb, Vc, Via, VIb, VIc, Ha, Hb and Hc, in which R ^, R ^, R ^ and Y have the meaning given under formula II, and processes for their preparation are also the subject matter of the present invention Invention.

Compounds of the formula IVb can be obtained from compounds of the formula III by reaction with a sulfinic acid of the formula HS (^ - R ₅ or a sulfonyl cyanide of the formula N = G-SO ₂ -R _1. Compounds of the formula IVc can be obtained from compounds of the formula III can be obtained by reaction with a thiosulfonic acid of the formula HS-S02 "Rc. The reaction takes place in an inert solvent or solvent mixture, for example an optionally halogenated, such as chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, such as pentane, hexane, cyclohexane, benzene, Toluene, methylene chloride, chloroform or chlorobenzene, an aliphatic, cycloaliphatic or aromatic alcohol, such as lower alkanol, e.g. methanol, ethanol, cyclohexanol or phenol, a polyhydroxy compound, e.g. a polyhydroxyalkane, such as dihydroxy lower alkane, e.g. ethylene or propylene glycol,

509836/0970

a lower ketone such as acetone or methyl ethyl ketone, a ethereal solvents such as diethyl ether, dioxane or tetrahydrofuran, a lower carboxamide such as dimethylform- or dimethylacetamide, a lower dialkyl sulfoxide such as dimethyl sulf oxide and the like or mixtures thereof.

The reaction takes place at room temperature or preferably at an elevated temperature, e.g. at the boiling point of the solvent used, if desired in one Inert gas such as nitrogen atmosphere.

The reaction with the sulfonyl cyanide of the formula NsC-SO ₂ -R ₅ is accelerated by adding compounds which produce halogen anions. Suitable compounds which provide halogen anions are, for example, quaternary ammonium halides, in particular chlorides and bromides, such as those optionally substituted on the lower alkyl groups, for example by aryl, such as phenyl, mono- or polysubstituted tetra-lower alkylammonium halides, such as tetraethyl or benzyl-triethylammonium chloride or bromide Compounds are added in amounts from about 1 to about 50 mole percent, preferably from about 2 to about 5 mole percent.

Compounds of the formula IVb and IVc can also be obtained by adding a compound of the formula IVa to a heavy metal ^{sulfine compound of the formula M 11} " ¹ " (SO ₂ -R ₅ ) ^; or * with .BUMBM Schwe.TTsastiilliihi.osiilfoinsä 'd-sr Fcsss!

250633Q

M ⁿ (S-SO ₂ -R ₅ ) converts, in which M represents a heavy metal cation and η means the valency of this cation. Suitable heavy metal sulfinates or thiosulfonates are in particular those which have a greater solubility product in the reaction medium used than the heavy metal ^{compounds of the formula M n +} (-SR.) Formed during the reaction. Suitable heavy metal cations J ^ ¹⁺ are in particular those which form particularly sparingly soluble sulfides. These include, for example, the monovalent or divalent cations of copper, mercury, silver and tin, with copper and silver cations being preferred.

The heavy metal sulfinate or thiosulfonate can either be used as such or formed in situ during the reaction, for example from a sulfinic acid of the formula HSO ₂ -R ₁ . or a thiosulfonic acid of the formula HS-SO ₂ -R ₁ . or a soluble salt thereof, for example an alkali metal salt, such as sodium, and a heavy metal salt, the solubility product of which is greater than that of the heavy metal sulfinate or thiosulfonate formed, for example a heavy metal nitrate, acetate or sulfate, for example silver nitrate, mercury (II) diacetate or copper (II) sulfate or a soluble chloride, such as tin (II) chloride dihydrate.

§09333 / 0976

250633Q

The implementation of a compound of formula IVa with

the heavy metal sulphate of the formula M ("SO ₀ -R.) or -thio-

2 ya

Sulphonate of the formula M ⁿ ("S-SO ₂ -R ₅ ) can be carried out in an inert organic solvent, in water or in a solvent mixture consisting of water and a water-miscible solvent. Suitable inert organic solvents are, for example, aliphatic, cycloaliphatic or aromatic Hydrocarbons, such as pentane, hexane, cyclohexane, benzene, toluene, xylene, or aliphatic, cycloaliphatic or aromatic alcohols, such as lower alkanols, for example methanol, ethanol, cyclohexanol or phenol, polyhydroxy compounds, such as polyhydroxyalkanes, for example dihydroxy lower alkanes, such as ethylene or propylene glycols , for example lower carboxylic acid lower alkyl esters such as ethyl acetate, lower ketones such as acetone or methyl ethyl ketone * ethereal solvents such as dioxane, tetrahydrofuran or polyethers such as dimethoxyethane, lower carboxamides such as dimethylformamide, lower alkyl nitriles such as acetonitrile or lower sulfoxides such as dimethyl sulfoxide Especially in mixtures of water and one of the solvents mentioned, including emulsions, the reaction usually proceeds much faster than in the organic solvents alone «

509836/0970

-41V

The reaction temperature is usually at room temperature, but may for slowing the reaction decreases or acceleration, up to about the boiling point of the solvent used, _s be increased whereby one can operate at normal or elevated pressure.

In a compound of the formula IV obtained, a group R 1, R. or R ~ can be converted into another group R, R. or R ₉ , it being possible to use reactions analogous to those used for the conversion of these groups in the case of compounds of the formula IA or IB is specified.

In stage 2 and 3 or 2a a connection of the Formula IV can be converted into a compound of the formula VI by oxidative degradation of the methylene group to an oxo group,

The oxidative splitting off of the methylene group in compounds of the formula IV with the formation of an oxo group can to form an ozonide compound of the formula V by treatment with ozone. Ozone is used for this usually in the presence of a solvent «like one Alcohol, e.g. a lower alkanol such as methanol or ethanol, a ketone, e.g. a lower alkanone such as acetone, an optional halogenated aliphatic, cycloaliphatic or aromatic hydrocarbons, e.g. a halo-lower alkane, like methylene chloride or carbon tetrachloride ,, or a solution emitter, incl.

mix, as well as with cooling or slight warming, e.g. with Temperatures from about -90 ° C to about + 40 ° C.

An ozonide of the formula Va obtained as an intermediate can, if appropriate without isolation by conversion with

Jl + -

a heavy metal sulf inate of the formula ET (SO-R _n .) or a thiosulf onate of the formula M ¹¹ ("S-SO ₉ -Rc-), analogous to the

£ * J ii

Conversion of compounds of the formula IVa to compounds of the Formula IVb or IVc, can be converted into a compound of the formula Vb or Vc.

An ozonide of the formula V can be split reductively in step 3 to give a compound of the formula VI, whereby one catalytically activated hydrogen, e.g. hydrogen in the presence of a heavy metal hydrogenation catalyst, such as nickel, also palladium catalyst, preferably on a suitable carrier material such as calcium carbonate or carbon or chemical Reducing agents such as reducing heavy metals including heavy metal alloys or amalgams, e.g. zinc, in the presence a hydrogen donor, such as an acid, e.g. acetic acid, or an alcohol, e.g. lower alkanol, reducing inorganic salts such as alkali metal iodides, e.g. sodium iodide, in the presence of a hydrogen donor, such as an acid, e.g. acetic acid, or reducing sulfide compound, such as a di-lower alkyl sulfide, e.g. dimethyl sulfide, a reducing organic phosphorus compound, like a phosphine »

509836/0970

which may contain optionally substituted aliphatic or aromatic hydrocarbon radicals as substituents, such as Tri-lower alkyl-phosphines, e.g. tri-n-butyl-phosphine, or triarylphosphines, e.g. triphenylphosphine, also phosphnites, which contain optionally substituted aliphatic hydrocarbon radicals as substituents, such as tri-lower alkyl phosphites, usually in the form of corresponding alcohol adduct compounds, such as trimethyl phosphite, or phosphorous acid triamide, which contain optionally substituted aliphatic hydrocarbon radicals as substituents, such as Hexaniederalkylphosphorigsäuretriamide, e.g. Hexamethylphosphorigsäuretriamid, the latter can preferably be used in the form of a methanol adduct, or tetracycline ethylene. The cleavage of the normal catfish not isolated ozonide takes place normally under the conditions that are used for its production applies, i.e. in the presence of a suitable solvent or solvent mixture, as well as with cooling or Just warm up.

Enol compounds of Fcrraal VI can also be used in the tautonate keto form,

An end compound of the formula VIa can be obtained by reacting with a heavy metal sulf inai: the formula M ¹¹ * ("Si ^ -K., -), or thiosulfonate of the formula M ⁿ (" S-SO ₂ -SO, analogously to the

5Q983S / 0970

250633Q

Conversion of compounds of the formula IVa to compounds of the formula IVb or IVc, into a compound of the formula VIb or VIc.

In a compound of the formula VI obtained, a group R-, R, otl ^ r R _{2 can be converted} into another group R? ", R or Rj, it being possible to use reactions analogous to those used for the conversion of these groups in compounds of Formula IA or IB is started.

In the 4th stage, an enol compound obtained is obtained of the formula VI converted into a compound of the formula II by etherification.

Used for the preparation of lower alkyl and optionally substituted a-phenyl-lower alkylenol ethers of the formula II for example, a corresponding diazo compound, e.g. a diazo lower alkane, such as Diazomethane, diazoethane, diazo-n-butane or an optionally substituted a-phenyldlazo-lower alkane, e.g. phenyl- or Diphenyldiazomethane. These reagents are in the presence of a suitable inert solvent, such as an aliphatic, cycloaliphatic or aromatic hydrocarbon, such as hexane, cyclohexane, benzene or toluene, a halogenated one aliphatic hydrocarbon, ζ.B * methylene chloride, one Lower alkanol, e.g. methanol, ethanol or tert.-butanol,

509836 / 0S70

- 3 * 4 -

or an ether, such as a di-lower alkyl ether, e.g. diethyl ether, or a cyclic ether, e.g. tetrahydrofuran or dioxane, or a solvent mixture, and depending on the diazo reagent with cooling, at room temperature or below gentle heating, and if necessary in a closed vessel and / or under an inert gas, e.g. nitrogen atmosphere applied.

Furthermore, lower alkyl and optionally substituted a-phenyl lower alkylenol ethers of the formula II by treating an enol compound of formula VI with a reactive ester of a corresponding alcohol of the Formula R - form OH. Suitable esters are primarily those with strong inorganic or organic acids, such as mineral acids, e.g. hydrohalic acids, such as hydrochloric, Hydrobromic or hydroiodic acid, furthermore Sulfuric acid or halosulfuric acid, e.g. fluorosulfuric acid, or strong organic sulfonic acids, such as optionally substituted lower alkanesulfonic acids, e.g. by halogen, such as fluorine, or aromatic sulfonic acids, such as, for example, optionally, e.g. by lower alkyl, such as methyl, halogen, such as bromine and / or nitro-substituted benzenesulfonic acids, e.g. methanesulphonic, trifluoromethanesulphonic or p-toluenesulphonic acid. These reagents, especially di-lower alkyl sulfates,

509836/0970

- 1 * 5 -

such as dimethyl sulfate, also lower alkyl fluorosulfates, e.g. methyl fluorosulfate, or optionally halogen-substituted ones Methanesulfonic acid lower alkyl ester, e.g. trifluoromethanesulfonic acid methyl ester, or corresponding a-phenyl lower alkyl, e.g. benzyl and diphenylmethyl esters, such as benzyl or diphenylmethyl halides, such as chlorides or bromides, are usually in the presence of a solvent such as a optionally halogenated, such as chlorinated aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. Methylene chloride, an ether such as dioxane or tetrahydrofuran, or a lower alkanol such as methanol, or a solvent mixed used. It is preferable to use suitable condensing agents, such as alkali metal carbonates or bicarbonates, e.g. sodium or potassium carbonate or hydrogen carbonate (usually together with a sulfate), or organic Bases, such as, usually sterically hindered, tri-lower alkylamines, e.g. Ν, Ν-diisopropyl-N-ethylamine (preferably together with lower alkyl halogen sulfates or optionally Halogen-substituted methanesulfonic acid lower alkyl esters), with cooling, at room temperature or with heating, e.g. at temperatures from about -20 ° C to about 50 ° C and, if necessary, in a closed vessel and / or in an inert gas, e.g. nitrogen atmosphere is used.

509836/0970

Through phase transfer catalysis (see E.V. Dehmlow, Angewandte Chemie 5/1974, p. 187) the etherification reaction can be accelerated significantly. As phase transfer catalysts, quaternary phosphonium salts and in particular quaternary ammonium salts, such as optionally substituted tetraalkylammonium halides, e.g. tetrabutylammonium chloride, bromide or iodide, or benzyl triethylammonium chloride can be used in catalytic or up to equimolar amounts. Any of those with water cannot be used as an organic phase Miscible solvents are used, for example one of the optionally halogenated, such as chlorinated aliphatic, cycloaliphatic or aromatic hydrocarbons, such as Tri- or tetrachlorethylene, di-, tri- or tetrachloroethane, chlorobenzene, in particular carbon tetrachloride, or else Toluene or xylene. The alkali metal carbonates or hydrogen carbonates suitable as condensing agents, e.g. potassium or Sodium carbonate or hydrogen carbonate, alkali metal phosphates e.g. Sodium hydroxide, for base-sensitive compounds, can be titrated to the reaction mixture so that the pH value remains between about 7 and 8.5 during the etherification.

Lower alkylenol ethers of Formula II can also be prepared by treating an enol compound of Formula VI with: on the same carbon atom of aliphatic character two or

509836/0 9 70

250633Ü

- 1 * 7 -

three lower alkyl etherified hydroxy groups of the formula

ο
R., - 0-containing compound, ie with a corresponding acetal or orthoester, in the presence of an acidic agent. For example, gem- lower alkoxy lower alkanes, such as 2,2-dimethoxy-propane, in the presence of a strong organic sulfonic acid, such as p-toluenesulfonic acid, and a suitable solvent, such as a lower alkanol, e.g. methanol, or a di-lower alkyl or lower alkylene sulfoxide, e.g. dimethyl sulfoxide , or tri-lower alkyl orthoformate, e.g. triethyl orthoformate, in the presence of a strong mineral acid, e.g. sulfuric acid, or a strong organic sulfonic acid, such as p-toluenesulfonic acid, and a suitable solvent, such as a lower alkanol, e.g. ethanol, or an ether, e.g. dioxane, use as an etherifying agent and thus obtain compounds of formula II,

ο
where R- is lower alkyl, for example methyl or ethyl.

The lower alkylenol ethers of the formula II can also be obtained by using eno! Compounds of the formula VI with tri-lower alkyloxonium salts of the formula (Ry ^ 0®Α ^θ (so-called sea wine salts), and di-RoO-carbenium salts of the formula (R ^ O) "CH® A®, or Di-R “-halonium salts of the formula (R °) ₉ Hal% ^Ö where Α ^{θ is} the anion of an acid and Hai® is a halonium, especially bromonium ion and R ° lower alkyl ·

509836/0970

- us -

mean treated. It is primarily about tri-lower alkyloxonium salts, as well as di-lower alkoxycarbenium or di-lower alkylhalonium salts, especially the corresponding ones Salts with complex, fluorine-containing acids, such as the corresponding tetrafluoroborates, hexafluorophosphates, hexafluoroantimonates or hexachloroantimonates. Such reagents are e.g. Trimethyloxonium or triethyloxonium hexafluoroantimonate, -hexachlorantimonate, -hexafluorophosphate, or -tetrafluoroborate, Dimethoxycarbenium hexafluorophosphate or dimethylbromonium hexafluoroantimonate. These etherifying agents are preferably used in an inert solvent such as an ether or a halogenated hydrocarbon, e.g. diethyl ether, tetrahydrofuran or methylene chloride, or a mixture thereof, if necessary, in the presence of a base, such as an organic base, e.g. one, preferably sterically hindered, Tri-lower alkylamine, e.g. Ν, Ν-diisopropyl-N-ethyl-amine, and with cooling, at room temperature or with slight heating, e.g. at about -20 ° C to about 50 ° C, if necessary, all in one closed vessel and / or in an inert gas, e.g. nitrogen gas atmosphere.

Compounds of the formula II in which the hydroxyl protective group R "is a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic Is a hydrocarbon residue, are acid-catalyzed, for example by a strong mineral acid,

509836/0970

such as sulfuric acid or hydrochloric acid catalyzed addition of α, β-unsaturated aliphatic or cycloaliphatic Ethers or thioethers, such as 1-lower alkoxy-lower alkenes, e.g. 1-methoxyethene or 1-methoxypropene, 1-lower alkylthio-lower alkenes, like 1-methylthio-ethene or 1-methylthio-propene, Oxa- or thia-cycloniederalk-2-enes or -2,4-serve with 5-7 Ring atoms, e.g., 2,3-dihydrofuran, 2H-pyran, 3,4-dihydro-2H-pyran or corresponding analogous sulfur compounds, to the 3-hydroxy group of a compound of the formula VI. The addition can be in an excess of the unsaturated ether or thioether and optionally in an inert one organic solvent, for example an aliphatic, cycloaliphatic or aromatic hydrocarbon, such as Pentane, hexane, cyclohexane, benzene, toluene and the like, can be carried out with the exclusion of water.

The formula II includes silyl or stannyl ethers, i.e. compounds of Formula II wherein R «is substituted Means silyl or stannyl group, become according to any suitable for the silylation or stannylation of enol groups Process obtained, for example, by treatment with a suitable silylating agent, such as with a dihalodin lower alkyl silane, Lower alkoxy-lower alkyl-dihalosilane or Xrin-lower alkyl-silyl-halide, e.g. dichloro-dimethylsilane,

509836/0970

Methoxy-methyl-dichloro-sllane, tri-ethylsilyl chloride or dimethyl-tert.-butyl-silyl chloride, such silyl halide compounds are preferably used in the presence of a base, e.g. Pyridine, used, with an optionally N-mono-lower alkylated, Ν, Ν-di-lower alkylated, N-tri-lower alkylsilylated or N-lower alkyl-N-tri-lower alkylsilylated N- (tri-lower alkylsilyl) amine (see e.g. British patent No. 1.073.530), e.g. with a hexane-lower alkyl disilazane, such as Hexamethyldisilazane, or with a silylated carboxamide, such as a bis-tri-lower alkylsilyl-acetamide, e.g. bis-trimethylsilyl-acetamide, or trifluorosilylacetamide, furthermore with a suitable stannylating agent, such as a bis (tri-lower alkyl-tin) oxide, e.g. bis (tri-n-butyl-tin) oxide, a tri-lower alkyl tin hydroxide, e.g. triethylsinn hydroxide, a tri-lower alkyl-lower alkoxy tin, tetra-lower alkoxy ? inn- or tetra-lower alkyl tin compound, as well as a tri-lower alkyl tin halide, e.g. * tri-n-butyl tin chloride. (see e.g. Dutch export trade ^ i / ft 67/11107).

A compound of the formula Ha, wherein R ° is lower alkyl or a hydroxy group protective radical can be obtained by reacting with a heavy metal sulfinate of the formula

M ^{n +} ("S0 -R) or thiosulfonate of the formula M ^{n +} (~ S-SO -R,), ZDn 2 5 η

analogously to the conversion of compounds of the formula IVa to IVb or IVc, converted into a compound of the formula Hb or Hc will.

509836/0970

- vzt -

In a compound of formula II obtained, a group R ^, R ^, R ^ or R _{3 can be converted} into another group R ^a , R ^,

"Or R _{3 are} converted, it being possible to use reactions analogous to those indicated for the conversion of these groups in the case of compounds of the formula IA or IV.

The pharmacologically acceptable compounds of The present invention can be used, for example, for the production of pharmaceutical preparations which have an effective Amount of active substance together or in a mixture with inorganic or organic, solid or liquid, pharmaceutical contain usable carriers which are suitable for enteral or, preferably, parenteral administration. So used tablets or gelatine capsules, which contain the active ingredient together with diluents, e.g. lactose, dextrose, Sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants such as silica, talc, stearic acid or salts of which, such as magnesium or calcium stearate, and / or polyethylene glycol, exhibit; Tablets also contain binding agents, e.g. magnesium aluminum silicate, starches such as corn, wheat, Rice or arrowroot starch, gelatine, tragacanth, methyl cellulose, Sodium carboxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. starches, agar, Alginic acid or a salt thereof, such as sodium alginate, and / or

509836/0970

Effervescent mixtures, or adsorbents, colorants, flavorings and sweeteners, the new pharmacologically active compounds can also be used in the form of injectable, for example intravenously administrable preparations or of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, it being possible for them to be prepared, for example, from lyophilized preparations which contain the active substance alone or together with a carrier material, for example mannitol, before use. The pharmaceutical preparations can be sterilized and / or contain auxiliary substances, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, can contain further pharmacologically valuable substances, are produced in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes, and contain about 0.3. % to 100%, in particular from about 1% to about 50 ₁ %, lyophilisates up to 100% of the active substance.

In connection with the present description, contain organic radicals designated by "lower", if not expressly defined, up to 7, preferably up to 4 carbon atoms; Acyl radicals contain up to 20, preferably up to 12 and primarily up to 7 carbon atoms.

509836/0970

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

509836/0970

- 5 * 4 -

example 1

-AIS '

For the solution of 133 mg (0.2 mrM) of an isomer mixture consisting of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido ~ 2-oxoazetidin-1-yl] -3-methoxycrotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester in the
Ratio of approximately 4: 1 in 4 ml of dry tetrahydrofuran is a solution of 60 µl within 5 minutes
(2 equivalents) 1,5-diazabicyclo [5.4.0] and cc-5-ene in 1 ml
Tetrahydrofuran was added dropwise. After standing at room temperature for 40 minutes, it is diluted with 20 ml of benzene, im
Cooled ice bath and 10 minutes with 10 ml of a 10%
Citric acid solution stirred. The organic layer is separated, one after the other with saturated saline solution,
Washed 10% sodium bicarbonate solution and brine. The solution, dried over magnesium sulfate, is reduced in vacuo
concentrated and the yellow oil obtained by chromatography filtration on 4 g of acid-washed silica gel (2 kg of silica gel three times with 2 liters of concentrated hydrochloric acid, stir for 10 minutes, decant, wash neutral with distilled water, with
Wash methanol and activate 60 hours at 120 °) with benzene / ethyl acetate 5: 1 as the eluent. The the
Fractions containing a mixture of isomers are combined and

509836/0970

- 1 * 5 -

concentrated in vacuo. A semi-solid isomer mixture is obtained consisting of the 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid-p-nitrobenzyl ester and the 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid-p -nitrobenzyl ester in a ratio of about 1: 3, which can be separated into the two isomers on Woelm silica gel (activity III) with benzene / ethyl acetate 5: 1. The faster running 7ß-phenoxyacetamido-3-methoxy-ceph-Z-em-A-carboxylic acid-p-nitrobenzyl ester x ^ ird from methylene chloride / ether and has the melting point 129-131.5 ° C. The slower running 7ß-phenoxyacetamido-S Methoxy-ceph-S-em-A-carboxylic acid p-nitrobenzyl ester has a melting point of 140.5-142 ° C. (from methylene chloride / ether).

The products can be further processed as follows:

A prepared at 0 ⁰ C solution of 555 mg (1.11 mmol) of a crude mixture consisting of the 7.beta.-phenoxyacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid p-nitrobenzyl ester and the 7.beta.-Phenoxyacetamide-3 Methoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in a ratio of about 3: 1 in 33 ml of tetrahydrofuran is mixed with 16 ml of a 0.1 N potassium hydroxide solution pre-cooled to ^{0 ° C. with stirring.} The mixture is further stirred for 5 minutes at 0 ⁰ C, then treated with 100 ml of ice water and 100 ml vorgekUhltem methylene chloride and stirred briefly.

509836/0970

- 1 * ^ 506330

Addition of 1 ml of saturated aqueous sodium chloride solution causes the two phases to separate. The organic phase is separated off, the aqueous phase is washed again with 20 ml of methylene chloride, then covered with a layer of 50 ml of methylene chloride and acidified with 20 ml of 2N hydrochloric acid. After shaking, the organic phase is separated off and the hydrochloric acid solution is extracted twice with 10 ml of methylene chloride each time. The combined methylene chloride extracts are dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from methylene chloride / diethyl ether / pentane and recrystallized yields the 7.beta.-phenoxyacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid of melting point 142-145 ⁰ C. The starting materials can be obtained as follows:

a) A solution of 36.6 g (0.1 M) 6-phenoxyacetaaiidopenicillanic acid-lß-oxide, 11.1 ml (0.11 M) triethylamine and 23.8 g (0.11 M) p-nitrobenzyl bromide in 200 ml dimethylformamide is stirred for 4 hours at room temperature under nitrogen. The reaction solution is then poured into 1.5 l of ice water entered, the precipitate filtered off., dried and recrystallized twice from ethyl acetate-methylene chloride. The colorless, crystalline 6-Phenoxyacetamidopenicillans acid-pnitrobenzylester-Lß-oxide melts at 179-180 ° C.

509836/0970

- lft? -

b) A solution of 5.01 g (10 mm) 6-phenoxyacetamido ~ penicillanic acid p-nitrobenzyl ester-lß-oxide and 1,674 (10 irM) 2-mercaptobenzothiazole in 110 ml of dry toluene is during Boiled under reflux in nitrogen atmosphere for 4 hours. The solution is concentrated to approx. 25 ml by distillation and diluted with approx. 100 ml of ether. The excreted Product is recrystallized from methylene chloride ether and the 2- [4- (benzthiazol-2-yldithio) -3-phenoxy · - acetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid pnitrobenzyl ester with a melting point of 138-141 ° C.

c) To a solution of 3.25 g (5.0 mM) 2- [4- (Benzthia ^ oi 2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester in 200 ral acetone / water 9: 1 (/ v) 1.06 g of finely powdered silver nitrate is added. Immediately afterwards, the solution of 890 mg (5 mM) Sodium p-toluenesulfinate in 100 ml of the same solvent mixture entered (within ten minutes). A light yellow precipitate forms immediately. After one hour Stirring at room temperature is done with the addition of Celite filtered. The filtrate is diluted with water and extracted twice with ether. The combined ether extracts are

S09836 / 0970

the dried over sodium sulfate and after concentration yield the pale yellow solid 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester. Thin-layer chromatogram on silica gel (toluene / ethyl acetate 2: 1): Rf value = 0.24; IR spectrum (in CH ₂ Cl ₂ ): characteristic bands at 3.90, 5.56, .5.70, 5.87, 6.23, 6.53, 6.66, 7.40, 7.50, 8.10, 8.72, 9.25, 10.95'μ. The product can be used in the subsequent reaction without further purification.

The same connection can also be obtained by the following methods:

ei) To a solution of 3.25 g (5.0 mM) 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester in 200 ml Acetone / water 9: 1 ( ^v / v), 1.58 g (1.2 equivalents) of silver p-toluenesulfinate are added in portions over a period of 10 minutes. The suspension is stirred for one hour at room temperature, filtered and processed further as described in Example Ic). The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylen-butyric acid-p-nitrobenzyl ester] is obtained in quantitative yield.

5098 3'6 / 0970

Silver p-toluenesulfinate is made by combining aqueous solutions of equimolar amounts of silver nitrate and sodium p-toluenesulfinate were obtained as a colorless precipitate. The product is dried in vacuo for 24 hours.

cii) The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester can also analogously to Example lci) from 3.25 g of 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidinl-yl] -3-methylenebutyric acid p-nitrobenzyl ester and 1.87 g (2 equivalents) of copper II-di ~ p-toluenesulfinate in quantitative Yield can be obtained.

The copper-II-di-p-toluene sulfinate is made by reacting of copper sulfate and sodium p-toluenesulfinate (2 eq.) preserved in water. After filtering off, the salt is dried in vacuo at 60 ° C for 12 hours.

ciii) The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester can also analogously to example lci) from 130 mg of 2-14- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester and 85 mg (2 equivalents)

509836/0970

4M

Tin-II-di-p-toluenesulfinate can be obtained.

The tin (II) di-p-toluenesulfinate is obtained by reacting tin (II) chloride (2H ₂ O) and sodium p-toluenesulfinate in water. After filtering off and washing with water, the salt is dried in vacuo at 50-60 ° C. for about 12 hours.

civ) The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetami-

do-2-oxoazetidin-1-yl] -3-tetethylene butyric acid p-nitrobenzyl ester can also analogously to example lci) from 130 mg of 2-14- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-l-ylj-3-methylenebutyric acid p-nitrobenzyl ester and 102 mg (2 equivalents) of mercury-II-di-p-toluenesulfinate are obtained. The mercury-II-di-p-toluenesulfinate is made by reacting mercury-II-di-acetate and sodium-p-toluenesulf inate obtained in water. After filtering off and washing with water, the salt is in vacuo for about 12 hours 50-60 ° C dried.

cv) A solution of 517 mg (1.02 iriM) 6-phenoxyacetamido-

penicillanic acid p-nitrobenzyl ester l / 3-oxide and 187 mg (1.2 mM) ρ-toluenesulfinic acid in 10 ml 1,2-dimethoxyethane (or dioxane) is refluxed for 4.5 hours in the presence of 3.5 g of a molecular sieve 3A and in a nitrogen atmosphere, whereupon another 308 mg (1.98 mM) ρ-toluenesulfine-

509836/0970

- le & b -

acid dissolved in 2 ml of 1,2-dimethoxyethane in five portions at 45 minute intervals. After 4-5 hours, the reaction mixture is poured into 100 ml of 5% strength aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are washed with water and saturated, aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel thick-layer plates with toluene / ethyl acetate 2: 1 and gives the 2- [4- (p-toluenesulfonylthio) -S-phenoxyacetamido ^ -oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester.

cvi) A mixture of 250 mg (0.5 mM) 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester-lβ-oxide, 110 mg (0.61 mM) p-toluenesulphonyl cyanide and 5 mg (0.022 mM) benzyl-triethylammonium chloride in 2 ml dry, peroxide-free Dioxane is stirred at 110 ° C. for 4.5 hours under argon. The solvent is evaporated off in vacuo and the yellow oil that remains is chromatographed on silica gel washed with sMure. Elution with 30% ethyl acetate in toluene gives the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester.

509836/0970

-230-6330

cvii) A mixture of 110 mg (0.61 mM) p-toluenesulphonyl cyanide and 4.5 mg (0.021 mM) tetraethylammonium bromide in 1 ml of pure dioxane is at 110 ° C under argon for 30 Minutes stirred. A suspension of 250 mg (0.5 mM) of o-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester β-oxide is then added in 1 ml of dioxane was added and the resulting solution was stirred for 4 hours at 110 ° C. under argon. The solvent is removed in vacuo, the crude product is dissolved in ethyl acetate and washed with water and saturated aqueous sodium chloride solution washed. The organic phase is dried with magnesium sulfate and freed from the solvent in vacuo and yields crude p-nitrobenzyl 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-ylj-3-methylenebutyric acid.

d) In a solution of 1.92 g (3.0 mM) 2-i4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester in 30 ml dry methyl acetate Introduced 1.1 equivalents of ozone at -78 ° C within 33 minutes. Immediately thereafter, excess ozone is removed by means of a stream of nitrogen (15 min. At -78 ° C.). 2.2 ml of dimethyl sulfide (10 equivalents) are added and the solution is warmed to room temperature. After standing for 5 hours, the solvent is distilled off in vacuo and the remaining colored

S09836 / 0970

loose oil taken up in 100 ml of benzene. The benzene solution is washed with three times 50 ml portions of saturated sodium chloride solution, dried over magnesium sulfate and im Concentrated in vacuo to dryness. After the residue has been recrystallized from toluene, the 2- [4- (p-toluenesulfonylthio) - ^ - pfaenoxyacetamideG-Z-oxoazetidin-1-yl] -S-hydroxycrQtOiisäure-p-nitrQbenzylester obtained from melting point 159-160 ° C.

di) The crude 2-f4- (p- * Toiuolsulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-lyl] -3-methylenebutyric acid-p-nitrobenzyl ester obtained according to Example 1.cvii) is dissolved in 20 ml of methyl acetate and at -70 ^e C ozonated until, according to the eye chromatogram, there is no longer any starting material available. A stream of nitrogen is then passed through the solution and the solution is heated to 0-5 ° C. A solution of 300 mg of sodium bisulfite in 5 ml of water is added and the mixture is stirred for about 5 minutes until no more ozonide can be detected with potassium iodide starch paper. The mixture is diluted with ethyl acetate, the aqueous phase is separated, and the organic phase is washed with water, dried over magnesium sulfate and freed from the solvent in vacuo. The crude product is dissolved in 3 ml of methylene chloride and 15 ml of toluene are added. The precipitate is filtered off and the filtrate is

§09836 / 0970

250 & 38Θ

steamed. The residue is recrystallized from methanol and gives the 2- [4- (p-toluenesulfonylthio) -3-phenoxyaeetamido-Z-oxoazetidin-l-yll-S-hydroxycrotonic acid-p-nitrobenzyl- esters with a melting point of 159-160 ° .C.

e) A solution of 1.93 g of 2- [4- (p-toluenesulfonylthio) -3 ~ phenoxyacetamido-2-oxoazetidin-l-yl] -3-oxobutyric acid-p- nitrobenzyl ester (3.0 mM) in 15 ml dry chloroform. is cooled to 0 ° C and over the course of 10 minutes with 6 ml of an essential diazomethane solution (0.75 molar, corresponding to 1.5 equivalents). The mixture becomes two Hours at 0 °. stirred, excess diazomethane removed with a stream of nitrogen and the solvent in Vacuum removed. The crude product is filtered through Woelm silica gel (activity III, 40-fold amount) with Benzene / ethyl acetate 5: 1 purified. The colorless oil obtained after distilling off the solvent crystallizes in the Stand. After recrystallization from methylene chloride ether, an isomer mixture consisting of 2- [4- (p-toluene sulf

509836/0970

fonylthio) -3-phenoxyacetamido.-2-oxoazetidin-1-yl] -3-methoxycrotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester in a ratio of about 4: 1. Melting point of the mixture 155-156.5 ° C.

Example 2

A solution of 279 mg of 2- [4- (p-toluenesulfonylthio) -

3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester (0.428 mmol) in 4 ml of chloroform and 1 ml of hexamethyldisilazane is refluxed for one hour heated, evaporated in vacuo and the oily residue dried in a high vacuum for one hour. The silylated The crude product consists of the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-trimethylsilyloxycrotonic acid diphenylmethyl ester and the corresponding isoerotonic acid diphenylmethyl ester.

The crude product obtained is taken up in 3 ml of dry chloroform, cooled to 0 ° C. and under nitrogen and with stirring with 0.069 ml (0.47 mmol) 1,5-diazabicyclo

509836/0970

[5 Λ. Ojundec-5-en offset. After a reaction time of 1 hour, 0.3 ml of acetic acid is added to the solution and it is diluted with chloroform. The chloroform solution is washed with dilute malic 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 7/5 phenoxy acetamido-3-hydroxy-ceph-3-etn-4-carboxylic acid dip / methyl methyl ester is obtained. Rf value: 0.13 (silica gel; toluene / ethyl acetate 3: 1).

The crude product obtained is taken up in methanol and treated at 0 ° C. with an excess of ethereal diazomethane solution offset. After a reaction time of 5 minutes, the solution is completely concentrated and. the oily residue on silica gel -Thick layer plates chromated (tolu oil methyl acetate 3: 1). The silica gel of the zone at Rf = 0.19 is extracted with ethyl acetate and gives 7ß-Phenoxyaeetaniido-3-methoxy ceph-S-em-A-carbonic acid diphenylmethyl ester; Melting point

120 ° C (from ether) IR-Spelctrura (in CH ^ Cl ₃ ); 3310, 1775, 1700, 1690, 1600 cm " ¹ .

The starting material is prepared as follows.

S09836 / 0970

a) From 100 g (27.3 mM) 6-phenoxyacetainido-penicillanic acid-lß-oxide, 500 ml of dioxane and 58.4 g (30 mM) of diphenylmethyldiazomethane After about 2 hours, the 6-phenoxyacetamidopenicillanic acid diphenylmethyl ester lp-oxide obtain; Melting point 144-146 ° C (ethyl acetate / petroleum ether).

b) Analogously to Example Ib) is obtained from 292 g (55 inM) 6-phenoxy acetamido-penicillanic acid-diphenylmethylester-lß-oxide and 99 g (59.5 mM) 2-mercaptobenzothiazole of diphenylniethyl 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid obtain; Melting point 140-141 ° C (from toluene / ether).

c) Analogously to Example Ic), from 10 g (14.7 mM) 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid diphenylmethyl ester in 50 ml of ethyl acetate, 4.92 g (24.98 mM) of finely powdered silver p-toluenesulfinate and stirring for 7 hours at room temperature of the diphenylmethyl 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxo-azetidin-1-yl] -3-methylenebutyric acid obtain.

Rf value = 0.28 (silica gel, toluene / ethyl acetate 3: 1); IR spectrum (CHCl ^): 1782, 1740, 1695, 1340, 1150 cm " ¹ .

509836/0970

2L5 £ to 13 O

Diphenylmethyl 2- [4- (p-toluenesulfonylthio) -3-phenoxyaeetamido-2-oxo-azetidin-1-yl] -3-methylenebutyric acid can also be made as follows;

ei) A suspension of 106.5 g of 6-phenoxyacetamido-penicil lanic acid-diphenylmethyiester-lß-oxide and 33.8 g of 2-mercaptobenζ-thiazole in 900 ml of toluene and 9 ml of glacial acetic acid is boiled under nitrogen for 2 hours on a water separator, with about 4.5 ml Water to be separated. The solution is cooled to room temperature, within 1 hour in portions with a total of 85.5 g of silver p-toluenesulfinate are added and then 2 Stirred for hours at 22 °. The mixture is made by Hyflo filtered and the filtrate washed twice with saturated aqueous sodium chloride solution. The organic phase is over Magnesium sulfate dried, concentrated in vacuo to about 1 liter, decolorized with 30 g of Norit and evaporated. The received yellow foam is crystallized from methylene chloride / diethyl ether. Melting point 79-82 ° C. Rf value «0.55 (silica gel; Toluene / ethyl acetate 3: 1). Further amounts can be obtained from the mother liquors by crystallization from methylene chloride / diethyl ether the substance can be obtained.

509836/0970

25 ^ 6330

d) Analogously to example ld), from 10.8 g (16.2 mM) 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidinl_yl] _3_ _iri ethylenebui; tertiary acid diphenylniethyl ester in 1 1 methylene chloride and 1.1 equivalents ozone of the 2 - [4- (p-Toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester obtained; Melting point 142-143 ° C (from ether / pentane).

The ozonization can also be carried out ^{at O 0 C:}

In a solution of 9.23 g (13.8 mmol) 2- [4- (p-toluene-

sulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid, diphenylmethyl ester in 960 ml of methylene chloride is 15.2 at 0 ° C within 19 minutes mmol of ozone introduced. 10 ml of dimethyl sulfide are added to the clear reaction solution and the mixture is kept at 5 ° C. for 20 minutes touched. After concentration in a water jet vacuum and drying of the residue in a high vacuum, a light yellow foam results, which crystallizes from methylene chloride / hexane: melting point of the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxy-crotonic acid diphenylmethyl ester obtained

is 134-138 ° C. Thin-layer chromatogram: Rf value- ^ 0.46 (Silica gel; toluene / ethyl acetate 3: 1).

509836/0970

250 ^ 30

The same connection can also be obtained according to the following methods:

cli) A solution of 684 mg (1 ιτΜ) 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester in 2.0 ml of acetone / water 9: 1 (v /) is added with 341 mg (1.3 mM) of silver p-toluenesulfinate for 60 minutes stirred at room temperature. The yellow reaction mixture is mixed with 50 ml of acetone and filtered. The filtrate is in Evaporated in vacuo and the residue chromatographed on 30 g of acid-washed silica gel with toluene / ethyl acetate 4: 1. The obtained 2-14 »(p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid-diphsnylmethylester is crystallized from ether / pentane and melts at 142-143 ° C.

dii) A solution of 72.9 mg (0.1 nM) of the crude gzonide, obtained by OzDnisisrimg of 68.1 mg (0.1 mM) 2- [4- (Banzthiazol-2-ylthic:} -3-phenoxyac ££ amiäc- "2 -oxoazetidin-1-yI] 2 "Pifcthylenbutter3äuri-aiphanylnat: i \ 7ia £ tar in acetic acid and solvent, in 2 sil Acston / water 9: 1 ( ¹

50S836 / 0970

is with 35 mg (1.3 equivalents) of silver p-toluenesulfinate a Stirred for one hour at room temperature. The reaction mixture is diluted with 3 ml of acetone and filtered. The FiItrat is mixed with 0.2 ml of dimethyl sulfide and two hours at Room temperature (until negative iodine-strong reaction) stirred. The removal of the solvent in vacuo becomes the Residue on 3 g acid-washed silica gel with toluene / Ethyl acetate 4: 1 chromatographed. The obtained 2- [4- (p-toluenesulf onylthio) -3-phenoxyacetainido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester is recrystallized from ether / pentane and melts at 142-143 ° C. After again Umkristsliisiersn from methylene chloride / diethyl ether is a

20th

Melting point of 144-145 ° C (corrected) obtained; [α] «-68 ° + 1 ° (c - 1; chloroform)! Thin-layer chromatogram: Rf value = 0.81 (Silicageli methylene chloride / Aetfaylacstat 8: 2); UV spectrum (Asihylalköhci): ^,. * 261 nm (E = 14 400) % IR spectrum (Nujol): characteristic bands bsi 3.00 = 5e56 | 5.93; 5.98; 6.06; 6.19; 6.25; 6.54; 6.70; 6.82; 7.02; 7.47; 8.03; 8.76; 9.53; 10.23; 10.60; 12.3Oj 13.26; 14.30 p.

509836/0970

Example 3

A solution of 301 mg (0.462 mmol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin- ⁱ l-yl] -3-hydroxycrotonic acid diphenylmethyl ester in 3 ml of 1,2-dimethoxyethane is under 0.12 ml of bis-trimethylsilyl-acetamide (0.508 mmol) were added in a nitrogen atmosphere and the mixture was stirred at room temperature for one hour. The solution is completely concentrated and the oily residue is dried in a high vacuum for one hour. The silylated crude product is taken up in 3 ml of dried 1,2-dimethoxyethane and, after cooling to 0 ° C., 0.075 ml (0.508 mmol) of 1,5-diazabicyclo [5.4.0] undec-5-ene are added. After a reaction time of 6 hours at 0 ° C. under a nitrogen atmosphere, 0.3 ml of acetic acid is added and the mixture is diluted with methylene chloride. The methylene chloride solution is washed successively with dilute sulfuric acid, water and dilute bicarbonate solution. The aqueous phases are extracted with methylene chloride, the combined organic phases are dried with sodium sulfate, concentrated in vacuo and dried in a high vacuum. The crude γβ-phenoxyacetamido-S-hydroxy-ceph-S-em ^ -carboxylic acid diphenylmethyl ester is obtained. The solution of the crude product in

509836/0970

An excess of an ethereal diazomethane solution is added to chloroform at 0.degree. C. and the mixture is left to stand at 0.degree. C. for 5 minutes. It is then completely concentrated and the residue is chromatographed on silica gel as in Example 2. The 7β-phenoxyacetamido-3-ihethoxyceph ~ 3-em-4-carboxylic acid diphenylmethyl ester is obtained; Rf value = 0.19 (silica gel; toluene / ethyl acetate 3: 1); Melting point 120 ° C (from ether) IR spectrum (in CHCl ₃ ): 3310, 1775, 1710, 1690, 1600 cm " ¹ .

Example 4

A solution of 100 mg (0.15 mmol) of a mixture of isomers consisting of the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazeti (fin-l-yl3-3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester in 4 ml of dry 1,2-dimethoxyethane is stirred with stirring in a nitrogen atmosphere with 0.045 ml (0.3 mmol) 1,5-diazabicyclo [5.4.0] undec-5-en offset. The solution is stirred under nitrogen at room temperature for 40 minutes, then cooled with ice and mixed with 0.1 ml of acetic acid. The diluted with methylene chloride solution is successively with dilute sulfuric acid, water and dilute bicarbonate solution

509836/0970

sung washed. The aqueous phases are washed with methylene chloride extracted. The combined organic phases are dried with sodium sulfate and concentrated and completely freed from the solvent in a high vacuum. The oily residue is deposited on a silica gel thick layer plate chromatographed (eluent toluene / ethyl acetate 3: 1, developed once). The two zones at Rf = 0.19 resp. 0.4 will be extracted together with ethyl acetate and the resulting solution was completely concentrated. An oily product is obtained, which consists of "/ ß-Phenoxyacetamido-S-methoxy-ceph-B-em-4-carboxylic acid diphenylmethyl ester and the isomer 7,6-phenoxyacetamido-S-methoxy-ceph ^ -em-A-carboxylic acid diphenylmethyl ester in a ratio of 1: 4. Rf value = 0.14 or 0.32 (Silica gel, toluene / ethyl acetate 3: 1); ± R spectrum (in CHCl,):

3400, 33LO, 1785, 1 // 0, 175G, 1710, 1Ö90, 163O ₅ 1600 cm " ¹ ..

i) The ratio of received Cfeph-2-anisii Ceph-3-em-derivaC depends among other things on the sum of the ring closure silted up Solvent, from the concentration of the starting material and the 1,5-diazäbicyc: lo [5.4.0jundec-5-ene lind also the response time. The following table lists some reactions that are analogous to the previous example each with 100 mg of an isomer mixture consisting of approx 95% 2-14- (p-roluene sulfonylthio) -3-phenoxyacetamido-2 '> o2; o-

■; i "MM 3 6 / ö 9 7 0

azetidin-1-yl] -3-iriethoxy-isocrotonic acid-d.iphenyln: eLhylesL: er and about 5% of the corresponding crotonic acid derivative were carried out. The reaction time was a uniform 20 minutes ten and the work-up was carried out analogously to the previous example.

solvent concentration
at output
material
Weight / volume Ί
ta Equivalents
1,5-diazabicyclo
[5.4.0] undec-5-
en Ratio ei
hold up cep!
2-eivi: Ceph-3-
em-derivai; 1_ acetone 10 Ί 1.5 ~ - 3: toluene 10 ° /
IC 1.5 3 Ethyl acetate 10 la 1.5 10 Ethyl acetate 20th O/
la 1.3 7th Isobutylmethyl
ketone 20th % 1.3 "^ 9: tr Methyl chloride "
shape 20th Ί
la 1.3 ^ 9: "/
1,2-dimthoxy
ethane 20th • 1.3 4 ·
Λ. ' G-;

509836 / 09-70

- 446 -

a) The isomer mixture used as starting material can analogously to Example Ie) from 4g (6.14 iriM) 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxo-azetidin'-l * -yl] -3-hydroxycrotonic acid- diphenyl methyl ester and an excess of ethereal diazoraethane solution. The received Isomer mixture consisting of the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2'-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic murediphenylmethyl ester (about 3: 1) crystallizes from ethyl acetate / pentane and has a melting point of 150-152 ° C.

The isomer mixture used as the starting material, or the crotonic acid derivative and the isoerotonic acid derivative, can be used can also be obtained as follows:

ai) A solution of 698 mg (1 iriM) of an isomer mixture consisting of 2- [4- (benzthiazol-2-ylthio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester in 20 ml acetone / water 9: 1 ( ^V / v) is stirred with 341 mg (1.3 mM) silver p-toluenesulfinate for 1 hour at room temperature. The yellow reaction mixture is mixed with 50 ml of acetone

509836/0970

diluted and filtered. The filtrate is evaporated in vacuo and the residue is chromatographed on 30 g of acid-washed silica gel with toluene / ethyl acetate 2: 1. One receives a Isomer mixture consisting of the 2- [4- (p-Tdluolsulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-rcethoxycrotonic acid diphenylmethyl ester and the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid diphenymethyl ester.

aii) The reaction described under ai) can also be carried out in tetrahydrofuran instead of in acetone / water, with must be stirred for about 24 hours at room temperature.

aiii) A solution of 336 mg (0.5 mM) 2- [4- (p-toluenesulfonylthio) -S-phenoxyacetamido ^ -oxo-azetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester in 4 ml of ethylene chloride is at 0 ° C with 0.21 ml (1.2 mM) of ethyl diisopropylamine and 0.12 ml (1.5 mM) methyl fluorosulfonate are added and Stirred for 30 minutes at 0 ° C. and for a further 30 minutes at room temperature. The reaction mixture is diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution and dilute aqueous sodium bicarbonate solution and washed over sodium sulfate dried. The residual after evaporation

509836/0970

stand is chromatographed on silica gel. Toluene / ethyl acetate 4: 1 initially elutes some starting material. With ToIuöl / ethyl acetate 1: 1 is then an isomer mixture, consisting of the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido ~ 2-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding diphenylmethyl isocrotonate, isolated.

aiv) A solution of 300 mg (0.447 mM) 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3- hydroxycrotonic acid diphenylmethyl ester in 4 ml acetone is mixed with 76 mg (0.55 mM) potassium carbonate and 0.088 ml (0.92 mM) Dimethyl sulfate is added and the mixture is stirred at room temperature for 5 hours. The solution is diluted with ethyl acetate, with water washed and dried over sodium sulfate. After removal of the solvent, the residue is recrystallized from ethyl acetate / pentane and gives a mixture of isomers from 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl ] -3-methoxy-crotonic acid-diphenylinethyl * ester and the corresponding isocrotonic acid diphenylmethyl ester.

50983JB / 0970

av) A solution of 6.73 g of 2- [4- (p-toluenesulfonylthio) -

3-phenoxyacetamido - 2-oxoazetidin-l-yl] -3-hydroxycrotonic acid diphenylmethyl ester (crystalline) in 67 ml of absolute tetrahydrofuran is oil -2O ° C with 1.57 g Ν, Ν'-dinitroso-NjN'-dimethyloxamide and then A solution of 0.57 ml (0.51 g) of ethylenediamine in 5 ml of tetrahydrofuran was added within 15 minutes. After addition the mixture is stirred 1 hour at 0 ⁰ C, 0.53 ml (11 mmol) of glacial acetic acid and 6.7 g of Celite to and filtered off. The residue is washed 5 times with 20 ml of tetrahydrofuran each time. The filtrate and washings are combined, concentrated to approx. 20 g and mixed with 20 ml of hexane. The crystals are filtered off, washed with tetrahydrofuran / hexane 1: 2 and dried in a high vacuum.

The crystals consist mainly of the 2-f4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2 * oxoazetidin-1-yl] -3-methoxy-isocrotonic acid-diphenylmethyiester. A sample is recrystallized from ethyl acetate / dietary ether and gives the following

20 low analytical data: melting point 167-169 ° C; [a] _D = -30 ° + l ° (c ^s l; methylene chloride); Thin-layer chromatogram: Rf value = -0.57 (silica gel; methylene chloride / ethyl acetate / glacial acetic acid 60: 40: 1);

509836/0970

UV spectrum (ethyl alcohol) : X _mav = 260 mu (£ = 16,600);

IH et X

IR spectrum (Nujol): characteristic bands at 2.97; 5.62; 5.90; 6.27; 6.61; 6.66; 7.17; 7.53; 7.70; 7.96; 8.02; 8.20; 8.80; 9.20; 10.26; 12.24; 13.30ji. Nuclear Magnetic Resonance Spectrum (100 megahertz / in CDCl ₃ ): £ 2.32 (s / CH ₃ >; 2.34 (s / CH ₃ ); 3.73 ("s / OCH ₃ ); 4.30 / 4 , 44 (AB; J = 5 / azetidine-4-CH-) _i 6.8-7.5 (m / 19 aromatic Η, ΝΗ) ppm.

In addition to a small amount of IsocrötonsMure derivative, the mother liquor mainly contains 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester; which, after chromatographic purification on silica gel, has a melting point of 146-148 ° (corr., from ethyl acetate / hexane); NMR spectrum (100 megahertz / in CDCl ₃ ): £ 2.08 (s / vinyl-CH ₃ ); 2.26 (s / aromat.-CH _3); 3.70 (s / -OCH ₃ ) j 4.47 -); 4.94 (dd / J - 5 and 8 / azetidine-3-CH-); 5.83 (d / J =

5 / azetidine-4-CH-), 6.8-7.5 (m / 19 aromatic H, -NH-) ppm;

on
[α] ρ - + 21 ° + 1 °; (c = Ij methylene chloride).

avi) A suspension of 6> 72 g (10 mmol) 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -S-hydroxycrotonic acid diphenylmethyl ester (crystalline) and 0.36g (ImMoI) tetra-n-butylammonium iodide in 100 ml Toluene with 3.78 g (30 mmol) of dimethyl sulfate and 30 ml

509836/0970

20 percent aqueous potassium bicarbonate solution added, and 4 Cooked vigorously for hours at room temperature. The solid substance dissolves within the first 15 minutes.

The mixture is diluted with toluene and washed with saturated aqueous Washed sodium chloride solution. After the organic phase has been dried with sodium sulfate and concentrated, it is obtained by crystallization from ethyl acetate / diethyl ether 2- [4- (p-Toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine * - l-yl] -3-methoxy-isocrotonic acid diphenylinethyl ester.

avii) A suspension of 3.36 g (5 mmol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester (crystalline) in 15 ml of carbon tetrachloride and 10 ml of water is added with 1.08 g (3 mmol) Tetrabutylammonium iodide and 1.9 ml (2.52 g, 20 mmol) dimethyl sulfate offset. For the mixture, which is vigorously stirred at room temperature, an automatic titrator adds so much in each case 1 N sodium hydroxide solution is added so that the pH remains constant at 7.0. 1.5-2 equivalents of sodium hydroxide solution are consumed in the course of 4-5 hours. The mixture is diluted with ethyl acetate and water and mixed with a little table salt. The organic phase is dried over sodium sulfate and evaporated. The residue is crystallized from a little ethyl acetate / hexane 1: 1 and gives the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-ylJ-3-methoxy-isocrotonic acid diphenylmethyl ester.

509838 / 0S7C

250633Q
- v & r-

The isomer mixture used as starting material can also be obtained via the corresponding 2-benzoxazole derivatives can be obtained as follows:

aviii) A solution of 10 g of 6-phenoxyacetamido-penicil-Iansäure-diphenylmethylester-lj8-oxide and 3 g of 2-mercaptobenzoxazole in 25 ml of dry tetrahydrofuran is im Vacuum completely evaporated. The remaining foam is heated to 120 ° C (oil bath temperature) in a water jet vacuum for 70 minutes. heated. The melt residue becomes after cooling Chromatographed on 500 g of acid-washed silica gel with toluene / ethyl acetate 6: 1 and then 3: 1. You get the 2- [4- (benzoxazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid diphenylmethyl ester in the form of a white foam; IR spectrum (methylene chloride): characteristic bands at 5.6, 5.75, 5.90, 6.7 and

aix) In a solution, cooled to -70 ° C., of 3.35 g of diphenylmethyl 2- [4- (benzoxazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidln-1-ylJ-3-methylene-butyric acid about one equivalent of ozone (in the form of a 0 ° / 0 ° mixture) is introduced into 125 ml of ethyl acetate, up to thin-layer chromatography (Silica gel; toluene / ethyl acetate 3: 1) no more starting material can be detected. The solution is in Vacuum evaporated to about 50 ml, ———— ——

509836/0970

250633Q
- ι «-

mixed with 5 ml of dimethyl sulfide and stirred until the potassium iodide starch test no more reaction is obtained. The mixture is evaporated in vacuo, the residue in 150 ml Dissolved benzene and washed with water. The organic phase is dried over sodium sulfate and evaporated. Of the The residue is chromatographed on 150 g of acid-washed silica gel with toluene / ethyl acetate 4: 1. You get the Diphenylmethyl 2- [4- (benzoxazol-2-yldithio) -S-phenoxyacetamido-1-oxoazetidin-1-yl] -3-hydroxy-crotonic acid in the form of a white foam; IR spectrum (methylene chloride): characteristic bands at 5.60, 5.90, 6.0 and

ax) To a solution of 1.7 g of 2- [4- (benzoxazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-l-ylj-3-hydroxycrotonic acid-diphenylmethylestar in 12.5 ml of methylene chloride is an ethereal diazomethane solution at 0 ° C with stirring added dropwise until thin-layer chromatography (silica gel; Toluene / ethyl acetate 3: 1) no more starting material can be detected. The mixture is evaporated in vacuo and the residue is chromatographed on 80 g of acid-washed silica gel with toluene / ethyl acetate 2: 1. One receives a Isomer mixture consisting of the 2- {4- (benzoxazol-2-yldithio) - ^ - phenoxyacetamido - ^ - oxoazetidin-l-yl j -3-rnethoxy-

509836/0970

250633Q

crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester in a ratio of about 5: 1; IR spectrum (methylene chloride): characteristic bands at 5.60, 5.85 sh, 5.90, 6.40, 6.65 p.

axi) A solution of 682 mg (1 mM) of an isomer mixture consisting of 2- [4- (benzoxazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-methoxycrotonic acid diphenylmethyl ester and the corresponding Isocrotonsäqre-diphenylmethylester in 20 ml of acetone / water 9: 1 ( ^V / v) is stirred with 350 mg (1.3 mM) of silver p-toluenesulfinate for 90 minutes at room temperature. The mixture is filtered through Celite ^, the filtrate is concentrated in vacuo to 5 ml and extracted with 30 ml of methylene chloride. The methylene chloride phase is dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on 30 g of acid-washed silica gel with toluene-ethyl acetate 1: 1 and gives an isomer mixture consisting of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2 -oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester.

509836/0970

250633Q

Example 5

A solution of 300 mg (0.45 mmol) of the crystallized isomer mixture obtainable according to Example 4a) consisting of the 2- [4- (p-toluenesulfonylthio-3-phenoxacetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester in 4 ml of dry 1,2-dimethoxyethane is stirred with 0.134 ml (0.9 mmol) of 1,5-diazabicyclo [5.4.0] undec-5-ene at room temperature under nitrogen 0 ° C and cooled with 0.4 ml of acetic acid and then with

180 mg (1.36 mmol) of m-chloroperbenzoic acid (85%) are added. The solution is stirred for 10 minutes at 0 ° C under nitrogen, diluted with chloroform and treated with dilute sulfuric acid / Sodium thiosulfate, water and dilute sodium bicarbonate solution washed. The aqueous phases are extracted with chloroform, the combined organic phases over

Dried sodium sulfate, concentrated in vacuo and freed from solvent in a high vacuum. The crude product obtained is separated on silica gel thick-layer plates (mobile phase ethyl acetate, developed once). The silica gel of the zone at Rf * 0.51 is extracted with ethyl acetate, the resulting

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The solution was concentrated and the residue was dried in a high vacuum. The oily residue obtained is the 7/3 phenoxyacetamido-S-methoxy-ceph-S-em-A-carboxylic acid diphenylmethyl ester 1/3 oxide, which crystallizes from methylene chloride / pentane, melting point 115-120 ° C.

By extracting the silica gel of the zone at Rf = 0.22 with ethyl acetate, concentrating the solution on a rotary evaporator and drying the oily residue, the 7β-phenoxyacetamide-3-methoxy-ceph-B-em-A-carboxylic acid diphenylmethyl ester-la-oxide can be obtained, melting point 175-180 ° (from chloroform).

The same compounds can also be used according to example i) or ii) produced:

i) A solution of 24.7 mg (36 mmol) of the crystallized isomer mixture obtainable according to Example 4a) consisting of the 2- [4- (p-Toluolsulfonylthio) -3-phenoxyacetami · do-2-oxoazetidin-1-yl] -S-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester in 247 ml dry 1,2-dimethoxyethane is taken at room temperature Nitrogen with 8.22 ml (54 mmol) 1,5-diazabicyclo [5.4.0] undec-5-ene stirred. After a reaction time of 40 minutes, the

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The solution was cooled to 0 ° C. and 3.73 ml of formic acid and then 37.3 ml (108 mmol) of performic acid (made from 33 ml of perhydrol (30%) and 100 ml of formic acid) were added. The solution is stirred for 10 minutes at 0 ° G under nitrogen, diluted with chloroform and washed with dilute sulfuric acid / sodium thiosulfate, water and dilute sodium bicarbonate solution. The aqueous phases are extracted with chloroform, the combined organic phases are dried over sodium sulfate, concentrated in vacuo and freed from the solvent in a high vacuum. The crude product obtained is crystallized from methylene chloride / pentane to yield the 7.beta.-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl-l / 5-oxide mp. 115-12O ⁰ C.

ü) A solution of 1.5 g (2.19 mmol) of the crystallized isomer mixture obtainable according to Example 4a) consisting of the 2- [4- (p-Toluolsilfonylthio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-methoxy-crotonsMure diphenylmethyl ester and the corresponding isocrotonic acid ester in 7.5 ml of dry 1,2-dimethoxyethane is at room temperature under nitrogen with 0.43 ml (2.84 mmol) 1,5-diazabicyclo [5.4.0] undec-5-en touched. After a reaction time of 40 minutes, the solution is cooled to 0 ° C. and 0.375 ml (6.55 mmol) of acetic acid and other

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finally 0.667 ml (4.8 mmol) of 7.2 N peracetic acid were added. The solution is stirred for 20 minutes at 0 ° C under nitrogen, then with 0.24 ml of sodium bisulfite solution (20%) offset. 22.5 ml of water are added to the reaction mixture with vigorous stirring. The mixture crystallizes of 7ß-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester-1/3 and -la-oxide. The precipitate is filtered off, washed with water and in a high vacuum dried.

iii). To a suspension of 98.8 g (144 mmol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-methoxy-isocrotonic acid-diphenylmethyl ester in 988 ml of 1,2-dimethoxyethane is added 32.9 ml (216 mmol) of 1,5-diazibicyclo [5.4.0] undec-5-ene were added at room temperature under a nitrogen atmosphere within 2 minutes with stirring. The now clear solution is stirred for 25 minutes at room temperature, then cooled to 0 ⁰ C, simultaneously with 14.9 ml (395 mmol) was added formic acid and added dropwise after cooling to -20 ⁰ C and 149 ml of a mixture of 66 ml of perhydrol (v / 30%) and 134 ml of formic acid (432 mmol H _? 0 ~) were added. The reaction solution is then ^{stirred at 0} ° C. for 15 minutes

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and then 37g sodium thiosulphate yellow in 500 ml water. About ml of water are added at 5 ° C. over the course of one hour. After stirring for a further 2 to 3 hours at 5 ° C., the crystalline precipitate, consisting mainly of the 7β-phenoxyacetamido-3-methoxy ~ ceph-3-em-4-carboxylic acid, diphenylmethyl ester-lβ-oxide, is filtered off with cold Washed water (3 ^° C.) and diethyl ether and dried over calcium chloride in a high vacuum.

7 liters of water are added to the filtrate at 5 ° C. with vigorous stirring. The initially oily one Standing overnight, consisting of solidifying precipitates mainly from the 7ß-phenoxyacetamide-3-methoxy-ceph-3-em-4-carboxylic acid-diphenylmethylester-la-oxide, is filtered off, washed with ice-cold water and in a high vacuum over calcium chloride dried.

iv) 34.35 g (50 mmol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid diphenyltethyl ester are added to 340 ml at 20 ° under a nitrogen atmosphere Tetrahydrofuran suspended (most of it will be solved). After the rapid addition of 11.4 ml (75 mmol) of 1,5-diazabicyclo [5.4.0] undec-5-ene, the solution is at Stirred at 20 ° C., then treated with 1.9 ml (30.2 mmol) of glacial acetic acid and concentrated to dryness in vacuo at 30 ° C. Of the

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- L6Q- -

brown, foamed residue is dissolved in 130 ml of methylene chloride dissolved and washed successively with 60 ml of water, 30 ml of 0.5N hydrochloric acid, 30 ml of water, 30 ml of 1M NaHCOo solution and 30 ml of water. The aqueous phases are extracted twice with 10 ml of methylene chloride.

The combined, undried methylene chloride phases are cooled to -10 ° and slowly with 7.0 ml of peracetic acid / acetic acid (containing 50 mmol peracetic acid) added (temperature rise to ~ + 10 °). After stirring for 15 minutes at 0 ° -5 °, the excess peracid with aqueous sodium thiosulfate destroyed. The aqueous phase is separated off and washed with a little methylene chloride. After the solution has dried Ererytion is carried out in vacuo over magnesium sulfate. The light yellow one Residue consisting of a mixture of 7/3 phenoxyacetamido-S-methoxy-ceph-S-em-A-carboxylic acid-diphenylmethyl ester-1-oxide and yβ-phenoxyacetamido-S-methoxy-ceph - ^ - em-A-carboxylic acid-diphenylmethyl ester-1-oxide in a ratio of about 2: 1, is dissolved in 120 ml of monoglyme at room temperature, with 30 ml of water added, whereby first the yjS-phenylacetamido-S-methoxy-ceph-3-em-4-carboxylic acid-diphenylmethyl ester-1ß-oxide crystallized, the thick crystal slurry is first stirred for half an hour, 150 ml of water are then added within about 5 hours at room temperature and with stirring, the corresponding Ια-oxide also crystallized out. After a total of 17 hours

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- v & r-

while stirring, the mixture is cooled in an ice bath for 1 hour, filtered and the residue is washed with a little chilled monoglyme / water 1: 1.5. _{The crystals are dried over P 9} O ₁ - in a high vacuum for 16 hours. The yβ-phenoxyacetamido-S-methoxyeeph-3-em-4-carboxylic acid diphenylmethyl ester-lβ-oxide, which is still affected by the corresponding α-oxide.

The 1-oxides obtained can be further processed as follows will:

a) a solution of 150 mg (0.275 mmol) of 7β-phenoxyacetamido ^ -methoxy-ceph-S-em-4-carboxylic acid-diphenylmethy1-ester-lβ-oxide in 3 ml of methylene chloride and 0.1 ml of dimethylformamide is added after cooling to 0 ° C 188 mg (1.37 mmol) of phosphorus trichloride were added. The solution is stirred at 0 ° C. for 30 minutes, diluted with methylene chloride and washed with aqueous sodium bicarbonate solution. The aqueous phase is extracted with methylene chloride, the combined organic phases are dried over sodium sulfate and concentrated in vacuo. The resulting crude 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is recrystallized from ether, melting point 120.degree .

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ai). A suspension of 5.0 g #. (9.16 mmol) 7/3-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid-diphenylmet; hylester-la-oxide in 25 ml of methylene chloride and 1.25 ml of dimethylacetamide after cooling to 0 ° C., 1.69 ml (19.3 mmol) of phosphorus dichloride are added. The solution is at 0 ° C during Stirred for 30 minutes, diluted with ethyl acetate and washed with aqueous sodium carbonate solution. The aqueous phase is extracted with ethyl acetate, the combined organic phases are dried over sodium sulfate and concentrated in vacuo. The obtained crude 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is recrystallized from ether; Melting point 120 ° C.

b) A solution of 2.0 g (3.78 mmol) of 7/3-phenoxyacetamido-S-methoxy-ceph-S-em-A-carboxylic acid e-diphenylmethyl ester in 5 ml of methylene chloride is mixed with 0.87 ml of anisole, cooled to 0 ° C. and, after adding 1.2 ml of trifluoroacetic acid, left to stand for 1 hour. The reaction mixture is concentrated in vacuo and the residue .from acetone / Aether crystallizes. The 7β-phenoxyacetamido-3-methoxy-ceph-S-em-A-carboxylic acid is obtained with a melting point of 170 ° C (decomp.).

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The same compound can also be obtained without isolating the ester mentioned under a):

bi) A suspension of 3.0 g (5.5 mmol) of a mixture of 7ß-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid-diphenylmethylester-lß- and -la-oxide in 15 ml of methylene chloride and 0.75 ml of dimethylacetamide is after cooling to 0 ° C with 0.966 ml (1.11 mmol) of phosphorus trichloride offset. The solution is stirred at 0 ° C for 40 minutes, then with 4.65 ml (61 mmol ·) of trifluoroacetic acid added and stirred at 0 ° C for a further 30 minutes. The reaction solution is saturated with sodium bicarbonate solution made neutral and the organic phase washed with dilute bicarbonate solution. The combined watery Phases are washed twice with ethyl acetate and brought to pH 2.6 with phosphoric acid. The failing one 7 £ -Phenoxyacetamido ~ 3-methoxy-ceph-3-em-4-carboxylic acid is filtered off »washed with water and dried in a high vacuum, Melting point 170 ° C (decomp.).

bii) A suspension of 53.4 g (97.7 mmol) of 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester-1β-oxide [from Example .5iii] in 320 ml of methylene chloride and 16 ml of dimethylacetamide is cooled to 0 ° and slowly 17.3 ml (19.8 mmol) of phosphorus trichloride were added.

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After 20 minutes of stirring at 0 ° - 5 ° C, 80 ml (1.05 mol) Trifluoroacetic acid added dropwise, t

The clear solution is stirred for a further 20 minutes at 0 ° -5 ° C., then diluted with 1300 ml of ethyl acetate and washed successively with 240 ml of 2 M dipotassium phosphate solution, 100 ml of water and 250 ml of semi-saturated aqueous sodium chloride solution. The 7ß-phenoxyacetamido-3-nr: ethoxyceph "3-em-4-carboxylic acid is extracted from the organic phase with 700 ml of saturated aqueous sodium bicarbonate solution and the aqueous part is washed twice with 400 ml of ethyl acetate. The organic phases are washed twice with a total of 250 ml of a solution of 50 ml of saturated aqueous Natriuirfoicarbonatlb'sung, 100 ml of water and 100 ml saturated aqueous sodium chloride solution was extracted. the combined Bicarbonatausztige be overcoated with 1500 ml of ethyl acetate and the pH of the solution with vigorous stirring with 207 _o phosphoric acid on - * -> 2.5. The aqueous phase is extracted twice with 500 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated in vacuo. The crystallizing residue is dissolved in 130 ml of ethyl acetate

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and incubated overnight at -10 ⁰ C allowed to stand. The pale yellow crystals of the 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid obtained are filtered off, washed with chilled ethyl acetate and dried to constant weight in a high vacuum.

biii) A solution of 23.9 g of 7ß-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid-diphenylmethyl ester-la-oxide [from Example 5iii)] in 140 ml of methylene chloride and 7.2 ml of dimethylacetamide is on cooled to 0 ⁰ C, and slow addition of 7.8 ml of phosphorus trichloride for 20 minutes at 0 ° - 5 ° C stirring continued. The reaction solution is added dropwise 36 ml trifluoroacetic acid, then at 0 ° - 5 further stirred ⁰ C for 20 minutes and then worked up as described under Baispiel 5 bii). The 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid is obtained in the form of pale yellow crystals.

^c ) To a suspension of 2.55 g (7 mmol) of 7ß-phenoxyacetamido-3-methoxy-ceph-3-era ~ 4-earbonsStire and 2.9 ml (22.4 mmol) of Ν, Ν-bimethylaniline in 11 ml of absolute methylene chloride 0.7 ml (5.7 mmol) of dimethyl-dichloro-silane are added under nitrogen at 20 ° C. and blended for 30 minutes

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stirred at the same temperature. The resulting clear solution is cooled to -20 ° C., 1.6 g (7.7 mmol) of solid phosphorus pentachloride are added and the mixture is stirred for 30 minutes. At the same temperature, a precooled (-20 ° C) mixture of 0.9 ml (7 mmol) of N, N-dimethyl aniline and 0.9 ml of n-butanol is added within 2 to 3 minutes, followed quickly by 10 ml of precooled (- 20 ° G) n-butanol was added and then stirred for 20 minutes at -20 ° C and 10 minutes without cooling. 0.4 ml of water is added at about -10 ° C., the mixture is stirred in an ice bath (0 ° C.) for about 10 minutes, then 11 ml of dioxane is added and, after stirring for a further 10 minutes at 0 ° C., about 4.5 ml of Tri-n -butylamine is added in portions until the samples diluted with water have a constant pH value of 3.5. After stirring for 1 hour at 0 ° C., the precipitate is filtered off, washed with dioxane and recrystallized from water / dioxane. The 7β-amino-3-methoxy-ceph-3-em 4-carboxylic acid hydrochloride dioxanate obtained has a melting point of over 300 ° C. Thin-layer chromatogram: Rf value 0.17 (silica gel; system n-butanol / carbon tetrachloride / methanol / Formic acid / water 30: 40: 20: 5: 5).

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ei) A suspension of 11.75 g of 93 percent: iger (corresponding to 10.93 g of 100%) 7β-phenoxyacetaniido-3-methoxyceph-3-em-4-carboxylic acid and 13.4 ml (12 ,, N-47 Diniethylanilin in abs 73 g) 1 \ ml. methylene chloride (over _P? 0 ^ is) added distilled at + 20 ⁰ C under nitrogen with 3.6 ml (3.87 g) of dimethyldichlorosilane, and subsequently 30 minutes at The now clear solution is cooled to -18 ° / -19 ° and treated with 7.8 g of solid phosphorus pentachloride, the internal temperature rising to -10 °. After 30 minutes of stirring in the -20 ° bath, the clear solution within about 7 minutes, added dropwise to a mixture, cooled to -20 °, of 47 ml of n-butanol (anhydrous, dried over Sikkan) and 4.4 ml (4.18 g) of dimethylaniline The mixture is stirred for 30 minutes - initially in a -20 ° bath, later in an ice bath (0 °), so that a final internal temperature of -10 ° is reached. At this temperature, a mixture of 47 ml of dioxane and 1, 6 ml of water added dropwise (duration about 5 minutes). The product slowly crystallizes out. After stirring for a further 10 minutes, the mixture is stirred in an ice bath by adding about 9.5 ml of tri-n-butylamine in portions within about 1 hour (first 5 \ νλ%

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06330

added in the first 5 minutes) brought to a pH between 2.2 and 2.4 and maintained. It is then filtered off, washed in portions with approx. 30 ml of dioxane, then approx. 3.5 ml of methylene chloride, and the crystalline 7β-amino-3-methoxy-ceph-3-em-4-carboxylic acid hydrochloride-dioxanate is obtained ; Melting point above 300 ⁰ C; UV spectrum (in 0.1 N sodium bicarbonate): } \ = 270 rough (£ = 7600); IR spectrum (Nu j oil):

Max /

characteristic bands at 5.62; 5.80; 5.88; 6.26; 6.55; 7.03; 7.45; 7.72; 7.96; 8.14; 8.26; 8.45; 8.64; 8.97, 9.29, 10.40; 11.47 mu; [cc] ^ ⁰ »+ 134 ° ± 1φ \ α - 1; 0.5 N sodium bicarbonate solution).

The hydrochloride dioxanate obtained can be converted into

put a 20% aqueous solution thereof with 2N sodium hydroxide solution to a pH of 4.1 (isoelectric point) the zwitterion of 7β-amino-3-methoxy-ceph-3-em-4-carboxylic acid can be obtained filtered off and dried, has a melting point of over 300 ° C. UV spectrum (in 0.1 N sodium bicarbonate solution) = 270 nm (E = 7600). Thin-layer chromatography: Rf value identical to that of the hydrochloride (silica gel, same system); [α) ί = + 232 ° ± V (c ~ 1; 0.5 N sodium bicarbonate solution).

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d) A suspension of 1 g (2.82 mmol) of 7β-amino-3-methoxyceph-S-em-A-carboxylic acid hydrochloride-dioxanate in 20 ml of dry methylene chloride is mixed with 1.65 ml of bis- (trimethylsilyl) acetamide added. After 40 minutes, the clear solution is cooled to 0 ° C. and 900 mg (4.37 mmol) of solid D-oc-phenylglycylic acid chloride hydrochloride are added. Five minutes later, 0.7 ml (10 mmol) of propylene oxide are added. The suspension is then stirred for 1 hour at 0 ° C. under a nitrogen atmosphere, then 0.5 ml of methanol is added, the 7β- (Da-phenylglycylamino) -3-methoxy-ceph-3-em-4-carboxylic acid hydrochloride in precipitates in crystalline form. The hydrochloride is filtered off, turns yellow in 9 ml of water and the solution is adjusted to pH 4.6 with 1N sodium hydroxide solution. The precipitating dihydrate of the inner salt of 7ß- (Da-Fhenylglycylamino) -3-methoxy-ceph-3-eiP "4-carboxylic acid is filtered off, washed with acetone and diethyl ether and dried, melting point 174-176 ° (decomposition); Μ _Ό ° = + 132 ° (c = 0.714; in 0.1 N hydrochloric acid); thin-layer chromatogram (silica gel): Rf value ^ 0.18 (system: n-butanol / acetic acid / water 67:10:23). UV spectrum (in 0, 1 N aqueous sodium bicarbonate solution) ^ _nv = 269 u (E = 7000); IR spectrum (in

IIlclX

Mineral oil): characteristic bands at 5.72, 5.94, 6.23 and 6.60 u.

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di) A suspension of 993 mg (4.32 mmol) of 7β-amino-3-methoxy-ceph-3-em-4-carboxylic acid (inner salt) in 10 ml of methylene chloride is mixed with 1.37 ml (5.6 mmol) of .N, N-bis (trimethylsilyl) acetamide added and stirred for 45 minutes at room temperature under a nitrogen atmosphere. The clear one The solution is cooled to 0 ° C. and 1.11 g (5.4 mmol) of D-α-phenylglycylic acid chloride hydrochloride are added. To 0.4 ml (5.6 mmol) of propylene oxide is added for 5 minutes. The suspension is then 1 hour at 0 ° C under a Stirred in a nitrogen atmosphere and then with 0.6 ml Methanol added. The 7β- (D-α-Pheriylglycylamido) -3-methoxy-ceph-3-eai-4-carboxylic acid hydrochloride which crystallizes out is filtered off, dissolved in 15 ml of water at 0 ° C and

the solution is adjusted to about pH 4 with 5 ml of IN sodium hydroxide solution. The solution, warmed to room temperature, is brought to about pH 4.8 with triethylamine, whereupon the 7β- (D-a-phenylglycylamido) -3-methoxy-ceph-3-em-4-carboxylic acid crystallized out in the form of the dihydrate.

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Example 6

To a solution of 0.697 g (1.0 roM) of an isomer mixture consisting of 2- [4- (benzthiazol-2-yldithio) ~ 3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester the solution of 0.228 g (1.5 mM) 1,5-diazabicyclo [5.4.0] undec-5-ene is dissolved in 4 ml of dry tetrahydrofuran given in 10 ml of tetrahydrofuran. The mixture is stirred for 40 minutes at room temperature, with Diluted 200 ml of benzene and washed successively with dilute hydrochloric acid, sodium bicarbonate solution and water. The organic Phase is dried over sodium sulfate and the solvent is removed in vacuo. The crude product obtained is chromatographed on 30 g of hydrochloric acid-washed silica gel. Toluene / ethyl acetate 7: 1 elutes initially 2-mercaptobenzothiazole and then the 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester. IR spectrum (in CH ^ Cl *): 5.60, 5.74, 5.90, 8.28 and

The ester obtained can be converted into the free acid as follows:

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i) A mixture of 53 mg (0.1 mmol) of 7/3-phenoxyacetamido-S-methoxy-ceph-Z-em-Aa-carboxylic acid diphenylmethyl ester, 0.07 ml of trifluorosetic acid, 0.06 ml of anisole and 0.5 ml of methylene chloride is stirred at 0 ° C. for 15 hours. The mixture is diluted 3: 1 with 5 ml of pentane / diethyl ether and shaken vigorously. The white, amorphous 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid which precipitates is filtered off and washed with pentane / diethyl ether 3: 1. IR spectrum (CH ₂ Cl ₂ ): 5.60, 5.90, 8.27, and the like.

The starting material can be obtained as follows:

^a ) In the cooled to -70 ° C solution of 681 mg (1.0 mM) 2- [4- (Benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxo-azetidin-l-yl] -3-methylene Diphenylmethyl butyric acid in 30 ml of ethyl acetate is passed in 1 equivalent of ozone (diluted with oxygen). The reaction solution is allowed to warm up, it is concentrated in vacuo to 10 ml, 1.0 ml of dimethyl sulfide is added and it is stirred for 15 hours at room temperature.

Solvent ^ and excess reagent are removed in vacuo removed and the residue chromatographed on 30 g of acid-washed silica gel with toluene / ethyl acetate 4: 1 (fractions a ml). The 2- [4- (benzthiazol-2-yldithio) -3-phenoxy

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acetamidO "2-oxo-azetJ.din-l-yl] -3-hydroxycrotonic acid diphenylmethyl ester as a solid amorphous substance. j [al = 130 ° -1 ° (CIICl.,; c = 0.8) IR spectrum (CH ₂ Cl ₂ ): 2.95, 5.60, 5.92, April 6, 8, 10 ji.

b) A solution of crude 2- [4- (benzthiazol-2-yl-dithio) -

S-phenoxyacetainido - ^ - oxo-azetidin-l-yl) -3-hydroxycroton - acid diphenylmethyl ester, obtained by ozonation of 681 mg (1.0 km) 2-14- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxo-azetidin-1-yl] -3-methylenebutyric acid dipheiiylmethyl ester, in 5 ml of methylene chloride is added to an ethereal, distilled diazomethane solution (containing 1.3

niM diazomethane) added. The mixture is stirred for one hour at 0 ° C., washed with water and the organic layer is dried over sodium sulfate. The solvents are removed in vacuo and the residue is chromatographed on 35 g of acid-washed silica gel with toluene / ethyl acetate 2: 1. An isomer mixture is obtained consisting of the 2- [4- (benzthiazoi-2-yldithio) -3-phenoxyacetamido-2-oxoa: i; etidin-l ~ yl] -3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester. IR spectrum (in 5.60, 5.88, 6.67, 9.15, 9.92 μ.

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Example 7

Analogously to Example 4, 200 ^ S (0.307 mM) becomes one Isomer mixture consisting of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid-2,2,2-trichloroethyl ester and the corresponding isocrotonic acid 2,2,2-trichloroethyl ester and 0.09 ml (0.6 iM) 1,5-diazabicyclo [5.4.0] undec-5-en the isomer mixture by stirring for 30 minutes at room temperature in 3 ml of 1,2-dimethoxyethane consisting of the 7/3 phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid 2,2,2-trichloroethyl ester and the 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid 2,2,2-trichloroethyl ester (in a ratio of about 1: 1). Rf values *. 0.36 or 0.18 (silica gel; toluene / ethyl acetate 3: 1)

The finishing material can be obtained as follows:

a) Analogously to Example Ib), 498 mg (1 nM) 6-phenoxy-

acetamido-penicillanic acid-2,2,2-trichloroethyl ester and 200.7 mg (1.2 mM) 2-mercaptobenzothiazole der 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-. butyric acid 2,2,2-trichloroethyl ester obtained; Melting point 144-149 ° C (from methylene chloride / pentane), Rf value = 0.5 (silica gel; Ether).

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b) Analogously to Example 6a), from 647 nig (1 rriM) 2-14- (benzthiazol-2-yldithio) -3-phcnoxyacetar.iido ~ 2-oxo-afi; etidin-1-yl ] -3-methylenebutyric acid-2, 2, 2 - trichloroethyl ester and 1.2 equivalents of ozone and subsequent cleavage of the Ozonide with dimethyl sulfide of 2- [4- (benzthiazol-2 ~ yldithio) -S-phenoxyacetamido ^ -oxoazetidin-1-yl] -3-hydroxycrotonic acid 2,2,2-trichloroethyl ester manufactured; Melting point 129-130 ° C (ether / petroleum ether).

c) Analogously to Example 6b), from 5 g (7.71 mM) 2- [4- (Benzthiazol-2-yldithio) -3-phenoxyacetand.do-2-oxoazet; idinl-yl] H? ^ ^t i ^ -3- 2,2,2-trichloroethyl hydroxycrotonate and an excess of diazomethane, the isomer mixture consisting of 2- [4 ~ (benzthiazol-2-yldithio) -3-ρhenoxyacetamido-2 · - oxoazetidin-1-yl] -3-methoxycrotonic acid -2 ₎ 2,2-trichloroethyl ester and the corresponding isocrotonic acid 2,2,2-trichloro-ethyl ester obtained melting point 170-174 ° C (from methylene chloride / ether).

d) Analogously to Example Ic), 1.9 g (2.87 mM) are converted into one Isomer mixture consisting of 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid 2,2,2-trichloroethyl ester and the corresponding

509836/0970

Isocrotonic acid 2,2,2-trichloroethyl ester by five hours Stir at room temperature with 0.8 g (4.05 mM) silver p-fcoluenesulfinate in 35 ml of acetonitrile / ethyl acetate 3: 4, an isomer mixture consisting of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid-2,2,2- trichloroethyl ester and the corresponding isocrotonic acid 2,2,2-trichloroethyl ester; Melting point 155-158 ° C (from ethyl acetate / ether).

Example 8

A solution of 100 mg (0.146 mmol) of 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] ~ 3-hydroxycrotonic acid diphenylmethyl ester in 2 ml of dry methylene chloride at 0 ° C. with 0.02 ml (0.16 mmol) of trimethylchlorosilane offset. 0.0477 ml (0.32 mmol) of 1,5-diazabicyclo [5.4.0] undec-5-ene were added to this solution under nitrogen and with stirring and stirring at 0 ° C for a further 1 hour. After adding 0.2 ml of acetic acid, methylene chloride is used diluted. The organic phase is successively mixed with dilute sulfuric acid, water and aqueous sodium bicarbonate * solution washed, dried over sodium sulfate and concentrated to dryness in vacuo.

5098 ^ 6/0970

The obtained crude YSS-phenoxyacetamido-S-hydroxyceph-3-em-4-carboxylic acid diphenylmethyl ester is dissolved in methanol and diazomethane solution was added at O ^Q C with an ethereal. After 10 minutes, the solution is carefully concentrated and the residue is dried in a high vacuum. The residue is purified by thick layer chromatography (toluene / ethyl acetate 3: 1, silica gel). After eluting the silica gel of the zone at Rf = 0.17 with ethyl acetate and concentrating the solution on a rotary evaporator, diphenylmethyl 7β-phenoxyacetamido-3-methoxy-ceph-3-em-A-carboxylate is obtained; Melting point 120 ° C (from ether).

Example 9

A solution of 266 mg (0.5 mM) of a crude mixture consisting of 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid chloride and 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid chloride in 5 ml of dry methylene chloride is stirred at 0 ° C within 15 minutes to a solution of 0.10 ml of triethylamine in

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0.5 ml of dry tert-butanol and 3 ml of methylene chloride dripped. After stirring for a further 15 minutes, the reaction mixture is diluted with methylene chloride and diluted with water Hydrochloric acid and again water, washed, dried over sodium sulfate and evaporated in vacuo. The residue will Chromatographed on 10 g of acid-washed silica gel with toluene / ethyl acetate (4: 1) as the mobile phase. You get the 7ß-Phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid-tert. butyl ester. IR spectrum (in CILCI «): characteristic bands at 5.60, 5.77, 5.90, 8.29 and

The starting material can be obtained as follows:

a) To a solution of 698 mg (1 mM) of a mixture consisting of the 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -S-methoxycrotonic acid diphenylmethyl ester and the 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid diphenylmethyl ester in 1.5 ml of methylene chloride, a mixture of 0.7 ml of trifluoroacetic acid is slowly added at 0 ° C. with stirring, 0.6 ml of anisole and 2.5 ml of methylene chloride are added. The reaction mixture is stirred for 3 hours at 0 ° C, with 100 ml of ether / pentane 1: 3 shaken and the precipitate

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filtered off. The precipitate consists of a mixture the 2- [4- (Benzthiazol-2-yldithio) -S-phenoxyacetamido - ^ - oxoazetidin-1-yl] -S-methoxy-crotonic acid and 2- [4- (benzthiazol-2-yldithio) -S-phenoxyacetamido ^ -oxoazetidin-1-yl] -3-methoxy-isocrotonic acid is washed with 25 ml of ether / pentane 1: 3 and dried in vacuo. IR spectrum (in CH ^ Cl): characteristic bands at 5.60, 5.80, 5.94, 8.55, 9.95 and

b) A solution of 532 mg (1.0 mM) of a mixture "consisting of 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-methoxycrotonic acid and the 2-14- (Benzthiazol-2-yldithio) -S-phenoxyacetamido ^ -oxoazetidin-1-yl] -3-methoxy-isocrotonic acid in 5 ml of dry dioxane containing 10% oxalyl chloride is stirred for 15 hours at room temperature and then evaporated in vacuo. The solid, non-crystalline residue consisting of a mixture of 2- [4- (benzthiazol-2-yldithio) -S-phenoxyacetamido ^ -oxoazetidin-1-ylJ-S-methoxycrotonic acid chloride and 2- [4- (benzthiazole -2-yldithio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid chloride can be processed further without further purification. IR spectrum (in CHUCl _? ): Characteristic bands at 5.58, 5.90, 9.95 ji

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- in -

Example 10

A solution of 367 mg (0.5 mM) of a mixture consisting of the 2- [4- (p-nitrobenzenesulfonylthio) -3-phenoxy · acetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid diphenyl · methyl ester and the corresponding diphenylmethyl isocrotonate, and 152 mg (1.0 mM) 1 »5-diazabicyclo [5.4.0] un ~ dec-5-ene in 10 ml of dry tetrahydrofuran is stirred for 40 minutes at room temperature. The reaction mixture is diluted with benzene, washed successively with dilute hydrochloric acid, water and dilute aqueous sodium bicarbonate solution, dried over sodium sulfate and freed from the solvent in vacuo. The residue is chromatographed on acid-washed silica gel with toluene / ethyl acetate 7: 1 as the eluent, pure 7β-phenoxyacetamido-3-niethoxyceph-2-em-4-carboxylic acid diphenylmethyl ester being obtained. Elution with toluene / ethyl acetate 2: 1 mixture is subsequently isolated, in addition to the 7.beta.-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester and the 7 β -Phenoxyacetamido-3-methoxy-ceph Contains diphenylmethyl 3-em-4-carboxylate.

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The starting materials can be prepared as follows will:

a) As in Example 4ai), 348.5 becomes rag (0.5 ruM) of an isorcera mixture consisting of the 2- [4- (benzthiazol-2-ylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylir.ethyl ester and the corresponding isocrotonic acid diphenyl methyl ester, and 200 mg (0.68 mM) silver p-nitrobeazole sulfate by stirring for one hour at 60 ° C in 10 nil acetone / water 9: 1 a mixture consisting of the 2- [4- (p-Nitrobenzenesulfonylthio) -3-phenoxyacetamido ~ 2-oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester.

Silver p-nitrobenzenesulfinate becomes more aqueous by combining Solutions of equimolar amounts of silver nitrate and sodium p-nitrobenzenesulfinate obtain. The precipitate is filtered off and dried in vacuo at 50-60 ° C. for 24 hours.

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Example 11

Analogously to Example 10, 351.5 mg (0.5 mM) are converted into one Isomer mixture consisting of the 2- [4- (p-methoxybenzenesulfonylthio) -S-phenoxyacetamido - ^ - oxoazetidin-l-yll ^ -methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester, and 152 mg (1 mM) 1,5-diazabicyclo [5.4.0] undec-5-ene a mixture consisting of the 7ß-phenoxyacetamido ^ -methoxy-ceph ^ -em ^ -carboxylic acid diphenylmethyl ester and the 7ß-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester, obtained, which can be separated into the two isomers by chromatography.

The starting materials can be obtained as follows will:

a) Analogously to Example 4ai) is one from 697 mg (1 mM)

Isomer mixture consisting of 2- [4- (benzthiazol-2-yl ~ thio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -S-methoxy-cro ^ tonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester, and 361 mg (1.3 niM) silver pmethoxybenzenesulfinate by stirring for one hour at room temperature in 20 ml of acetone / water 9: 1 a mixture consisting from 2- [4- (p-Methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylniethyl ester

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and the corresponding isocrotonic acid diphenylmethyl ester. IR spectrum (in CHpCl ₂ ): characteristic bands at 5.60, 5.88, 6.18, 8.76 u.

Silver p-methoxybenzenesulfinate is made by combining obtained aqueous solutions of equimolar amounts of silver nitrate and sodium p-methoxybenzenesulfinate. The precipitation is filtered off and dried in vacuo at 50-60 ° C. for 24 hours.

Example 12

Analogously to Example 10, 336.3 mg (0.5 iriM) becomes one Isomer mixture "consisting of 2- (4-benzenesulfonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxycrotonic acid diphenylmethyl ester and the corresponding Isocrotonsiiurediphenylmethylester, and 152 mg (1 mM) 1,5-diazabicyclo [5.4.0] undec-5-ene, a mixture consisting of the 7β-phenoxy-acetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester and the 7j3-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester, obtained, which can be separated into the two isomers by chromatography.

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- te * -

The starting materials can be obtained as follows:

a) Analogously to Example 4ai), 697 mg (1 πιΜ7 of an isomer mixture consisting of 2- [4- (benzthiazol-2-ylthio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-methoxy-crotonic acid -diphenylmethylester and the corresponding isocrotonic acid-diphenylmethylester, and 324 mg (1.3 mM) Silberbenzenesulfinat by stirring for 90 minutes at room temperature in 20 ml of acetone / water 9: 1 a mixture consisting of the
2 ~ (4-Benzolsulfonylthio-3-phenoxyacetamido-2-oxoazetidin-1yl) -3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester.
IR spectrum (in CH2Cl2): characteristic bands at 5.60, 5.88, 8.74 and

Silver benzene sulfinate becomes more aqueous by combining Solutions of equimolar amounts of silver nitrate and sodium benzene sulf inat received. The precipitate is filtered off and im Vacuum dried for 24 hours at 50-60 ° C.

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Example 13

Analogously to Example 1, from the isomer mixture consisting of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester by stirring for 12 to 14 hours at room temperature with tetramethylguanidine in tetrahydrofuran an isomer mixture consisting of the 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester and the 7β-phenoxyacetamido-3-methoxy · ceph-2-em-4-carboxylic acid p-nitrobenzyl ester.

Example 14

A mixture of 104.5 mg (0.15 mM) of an isomer mixture consisting of 2- [4- (benzthiazol-2-ylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid * diphenylmethyl ester, 35 mg (0.225 mM) p-toluenesulfinic acid and 80 mg (0.525 mM) 1,5-diazabicyclo [5.4.0] undec-5 ~ ene in 3 ml of dry tetrahydrofuran is stirred for 40 minutes at room temperature. The mixture is diluted with benzene and

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successively with dilute hydrochloric acid, dilute sodium chloride solution, 0.5 N sodium hydroxide solution and again washed dilute aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and freed from solvent in vacuo. Chromatography of the residue on 3.5 g of acid-washed silica gel with toluene / ethyl acetate 7: 1 initially gives the pure 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid diphenylmethyl ester. Toluene / ethyl acetate 2: 1 then elutes the 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester.

Example 15

A mixture of 141 mg (0.2 mM) 2- [4- (o-methoxybenzenesulfonylthio) -S-phenoxyacetamido - ^ - oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester and 61 mg (0.4 mM) 1,4-diazabicyclo [5.4.0] undec-5-ene in 4 ml dry tetrahydrofuran is stirred for 70 minutes at room temperature. Working up as in Example 10 gives a crude mixture from the 7β-phenoxyacetamido-3-methoxy-ceph-2-emr4acarboxylic acid diphenylmethyl ester and the 7β-phenoxyacetamide-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester in a ratio of about 4.4: 1 that indicated by chromatography Silica gel can be separated into the two isomers analogously to Example 10.

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The two compounds are formed in approximately the same ratio if 141 g (0.2 mM) 2- [4- (o-Methoxybenzenesulf onylthio) -3-phenoxyacetamide-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid diphenylmethyl ester treated analogously.

The two isomeric starting materials can be obtained as follows:

a) 3.49 g (5 mM) of an isomer mixture consisting of the 2- [4- (benzthiazol-2-ylthio) ^ - phenoxyacetamido - ^ - oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester and the corresponding Diphenylmethyl isocrotonate in a ratio of about 4: 1 is stirred with 1.82 g (6.5 mM) of silver o-methoxybenzenesulfinate in 100 ml of acetone / water 9: 1 for 130 minutes at room temperature. The mixture is filtered and the filtrate is evaporated in vacuo. The residue is chromatographed on 140 g of acid-washed silica gel with toluene / ethyl acetate 1: 1. 50 ml fractions are collected, of which fractions 7 to 13 contain pure 2- [4- (o-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid diphenylmethyl ester, IR spectrum (CH ₉ Cl ₇ ): 5.60, 5.90, 8.72, 915 u, and fraction 25 and the following fractions of pure 2- [4- (o-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine-1 -yl] -3-methoxy-crotonic acid diphenylmethyl ester, IR spectrum (CH "C1 _? ): 5.60,

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- ω * -

5.90, 8.20, 8.30, 8.72, 9.80 p. Fractions 14 to 24 contain mixtures of the two isomers.

Example 16

A mixture of 57 mg (0.1 mM) crude 2- [4- (o-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidinl-yl] -3-methoxy-isocrotonic acid chloride and 43 mg (0.3 mM) 1,5-diazabicyclo [5.4.0] -undec-5-ene in 2 ml dry methylene chloride is stirred for 80 minutes at room temperature. the The mixture is diluted with methylene chloride, washed with dilute hydrochloric acid and water, and dried over sodium sulfate and freed from the solvent in vacuo. The residue turns yellow in 0.5 ml of methylene chloride with 5 ml of pentane / diethyl ether 3: 1 offset and shaken. The precipitate is filtered off and washed with pentane / diethyl ether 3: 1. It consists of the fairly pure 7ß-phenoxyacetamido-3-methoxy-ceph-2-em-4x-carboxylic acid.

The starting material can be obtained as follows:

a) A mixture of 703 mg (1 mM) of pure 2- [4- (o-Methoxybenzenesulfonylthio) -S-phenoxyacetamido ^ -oxoazetidine-

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Diphenylmethyl l-yll-S-methoxy-isocrotonic acid, 0.7 ml of trifluoroacetic acid and 0.66 ml of anisole in 4 ml of methylene chloride is stirred at 0 ° C. for 3 hours. The mixture is then mixed with 50 ml of pentane / diethyl ether 3: 1 and shaken vigorously. The white precipitate of pure 2- [4- (o-methoxybenzenesulfonylthio) -S-phenoxyacetamido ^ - oxoazetidin-1-yl] -3-methoxy-isocrotonic acid is filtered off and washed with pentane / diethyl ether 3: 1. IR spectrum (CH ₂ Cl ₂ ): 5.60, 5.93, 6.25, 8.72 and the like.

b) To a solution of 54 mg (0.1 mM) 2- [4- (o-Methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetiain-l-yl] -3-methoxy-isocrotonic acid in 0.5 ml of a 10 % strength oxalyl chloride solution in dioxane is added to a drop of dimethylformamide in dioxane, whereupon gas is immediately evolved. The mixture is stirred for 2 hours at room temperature and the solvent and excess oxalyl chloride are evaporated off in vacuo. The residue is dried in a high vacuum and gives the 2- [4- (o-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid chloride in the form of a slightly orange-colored foam, IR spectrum (CH ₂ Cl ₂ ): 5.60, 5.90, 8.70 ρ.

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Example 17

A solution of 200 mg (0.254 mM) 2- [4- (p-toluenesulfonylthio) -3- (D-a-tert-butyloxycarbonylamino-a-phenylacetylamino) -2-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester in 2 ml of dimethylformamide, 57 μl (0.38 mM) of 1,5-diazabicyclo [5.4.0] undec-5-ene are added for 30 minutes stirred at room temperature, then treated with ethyl acetate and with water and 2N hydrochloric acid until acidic and washed with saturated aqueous sodium chloride solution until neutral. The organic Phase is dried over sodium sulfate and evaporated in vacuo. The residue is attached to silica gel thick-film plates chromatographed with toluene / ethyl acetate 1: 1 as the mobile phase. The 7β- (D-a-tert-butylcarbonylamino-a-phenylacetylamino) -3-methoxy-ceph-2-em-4α-carboxylic acid diphenylmethyl ester is obtained melting point 166-168 ° C (methylene chloride / pentane); Thin-layer chromatogram (silica gel; diethyl ether):

Rf value λ, 0.51; UV spectrum (in ethanol):> = 257 mu

Max *

(E = 3500); IR spectrum (in methylene chloride): characteristic Bands at 2.96, 5.63, 5.74, 5.85 (shoulder), 5.92, 6.16, 6.64 and 6.72 u; and the 7ß- (D-a-tert-buty! carbonyl-

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-Wi-

amino-a-phenyl-acetylamino) -3-ynethoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester of melting point 162-163 ° C (diethyl ether); Thin-layer chromatogram: Rf value: α. 0.33 (silica gel; diethyl ether); UV spectrum (in ethanol) λ _max = 265 mu (£ = 6600); 280 mp (shoulder) (£ = 6200); IR spectrum (in methylene chloride): 2.92, 5.58, 5.64 (shoulder), 5.82, 6.22 and 6.67 ρ.

The compounds obtained can be further processed as follows:

a) A mixture of 8.8 g of 7ß- (Da-tert.Butyloxycarbonylamino-a-phenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, 8.6 ml of anisole and 145 ml of trifluoroacetic acid is during Stirred for 15 minutes at 0 ° C, then treated with 400 ml of pre-cooled toluene and evaporated under reduced pressure. The residue is dried under high vacuum, digested with diethyl ether and filtered off. The trifluoroacetate of 7β- (Da-phenyl-glycylamino) -S-methoxy-S-cephem ^ -carboxylic acid, which is dissolved in 20 ml of water, is obtained in powder form . It is washed twice with 25 ml of ethyl acetate each time and the pH is adjusted to about 5 with a 20% strength triethylamine solution in methanol, a colorless precipitate being formed. The mixture is stirred for one hour in an ice bath, then 20 ml of acetone are added and the mixture is left to stand at about 4 ° C. for 16 hours. Of the

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colorless precipitate is filtered off, washed with acetone and diethyl ether and dried under reduced pressure. This gives the 7ß- (Da-phenyl-glycylamino) -S- in the form of a microcrystalline powder

organic acid as the inner salt, which is also present in the form of a hydrate, mp 174-176 ° C (with decomposition); Mt = + 149 ° (c = 1.03 in 0.1N hydrochloric acid); Thin-layer chromatogram (silica gel; developing with iodine): Rf ^ 0.36 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6; 30); Ultraviolet absorption spectrum (in 0.1 n .. aqueous sodium hydrogen carbonate solution): λ = 267u (& = 6200); Infrared absorption spectrum (in mineral oil): characteristic bands at 5.72 u, 5.94 p, 6.23 μ and 6.60 μ, among others.

t 1

b) A mixture of 0.063 g of 7/3 (D-a-tert-butyloxycarbonylamino-a-phenylacetylamino) -3-methoxy-2-cephem-4-acarboxylic acid diphenylmethyl ester, 0.1 ml of anisole and 1.5 ml of trifluoroacetic acid are left to stand at 0 ° C. for 15 minutes and then evaporated under reduced pressure. The residue is digested with diethyl ether, filtered off and dried. The colorless and powdery trifluoroacetate of 7β- (D-a-phenyl-glycylamino) -3-methoxy-2-cephem-4a-carboxylic acid which can be obtained in this way is dissolved in 0.5 ml of water and the pH of the solution by adding dropwise a

50983-6 / 0970

10% solution of triethylamine in methanol adjusted to about 5. The mixture is stirred for one hour in an ice bath, the colorless precipitate is filtered off and dried in a high vacuum. The 7β- (Da-phenyl-glycylaniino) -3-methoxy-2-cephem-4a-carboxylic acid is thus obtained as an inner salt, thin-layer chromatogram (silica gel; development with iodine): Rf 'V 0.44 (system: n-butanol / Pyridine / acetic acid / water 40:24: 6:30); Ultraviolet absorption spectrum (in 0.1 n. Aqueous sodium hydrogen carbonate solution):} shoulder ^{= 26} ° ^μ *

c) A solution of 0.63 g of 7j3- (D-atert. -Butyloxycarbonylamino-a-phenyl-acetylamino) -3-methoxy-2-cephem-4a-carboxylic acid diphenylmethyl ester in 25 ml of methylene chloride is mixed with a solution of 0.20 g of 3-chloro-perbenzoic acid added in 5 ml of methylene chloride. The mixture is stirred for 30 minutes at 0 ° C. with 50 ml of methylene chloride added and successively with 25 ml each of a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The residue is crystallized from a mixture of methylene chloride and diethyl ether; this gives the 7β- (D-a-tert-butyloxycarbonylamino-aphenyl-acetyl-amino) -3-methoxy-3-cephem-4-carboxylic acid-di-

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phenylmethylester-l-oxide in the form of colorless needles, 172-175 ° C; Thin-layer chromatogram (silica gel): Rf α / 0.44 (system: ethyl acetate; development with iodine vapor); Ultraviolet absorption spectrum (in ethanol):

277 mu (% = 7200); Infrared absorption spectrum (in

Methylene chloride); characteristic bands at 2.96 μ, 5.56 μ, 5.71 µ, 5.83 µ, 5.90 µ, 6.27 µ and 6.67 µ.

d) A solution, cooled to -10 ° C, of 1.30 g of 7β- (Da-tert-butyloxycarbonylamino-a-phenyl-acetyl-amino) -3-methoxy-3-cephem-4-carboxylic acid diphenyl methyl ester 1-oxide in 30 ml of dimethylformamide is mixed with 2.80 g of phosphorus trichloride with the exclusion of air. After standing for 15 minutes, the reaction mixture is poured onto a mixture of ice and an aqueous dipotassium hydrogen phosphate solution; the aqueous mixture is extracted twice with 100 ml of ethyl acetate each time. The organic extract is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel; the amorphous 7β- (D-ot-tert-butyloxycarbonylamino-a-phenyl-acetyl-amino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is eluted with diethyl ether as a substance pure by thin layer chromatography, Rf 1.0, 39 (system: dietary ethyl ether; development with iodine vapor); [a) _O = 1 ° + 1 ° (c = 0.981 in chloro-

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- 3-95 -

shape); Ultraviolet absorption spectrum (in ethanol): ^

Max

= 264 ρ (£. = 6300; infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 ρ, 5.62 ρ, 5.84 μ, 5.88 ρ, 6.25 μ and 6.70 ρ.

The starting material can be obtained as follows:

e) To a cooled to -15 ⁰ C solution of 31.2 g (0.12 mmol) DN-t-butyloxycarbonyl-phenylglycine and 16.7 ml (0.12 mmol) of triethylamine in 300 ml of tetrahydrofuran is treated with 16.5 ml (0.12 mmol) isobutyl chloroformate and the mixture is stirred at -10 ° C. for 30 minutes. A solution of 21.6 g (0.10 mmol) 6-amino-penicillansMure and 15.4 ml (0.11 mmol) triethylamine in 300 ml tetrahydrofuran / water 2: 1 is then added. The reaction mixture is stirred at 0 ° C. for 1 hour and at room temperature for 2 hours, the pH being kept constant at about 6.9 by adding triethylamine. The reaction mixture is adjusted to pH 2.0 at 5 ° C. with phosphoric acid, saturated with sodium chloride and extracted three times with 500 ml of ethyl acetate each time, the organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The received in the form of a light yellow foam

509836/0970

ne crude N-tert .Butyloxycarbonyl-airipicillin has in the thin-layer chromatogram the Rf value ^ 0.65> (Silica gel; ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6: 1.0.

f) A solution of 57.22 g of crude N-tert-butyloxyearbonyl-ampicillin in 100 ml of glacial acetic acid is mixed with 21.6 ml of 30% hydrogen peroxide (0.25 M) within 10 minutes added and stirred for 2.5 hours at room temperature. Dcκ The reaction mixture is then poured onto 2 l of ice water, which is in the form of a voluminous precipitate ^ N-tert-butyloxycarbonyl-ampicillin-1-oxide filtered off, washed well with water and dried in vacuo. Extraction of the filtrate with ethyl acetate allows further Obtained quantities of crude N-tert-butylcarbonyl-ampicillin-1-oxide will. Thin-layer chromatogram (silica gel / ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10) Rf value ^ 0.30.

g) A mixture of 67.7 g of crude N-tert.Butyloxycarbonyl-ampicillin-1-oxide in 380 ml of dioxane is mixed with a solution of 42 g (0.23 M) of diphenyldiazomethane in 130 ml of dioxane and for 2.5 hours Room temperature stirred. After adding 5 ml of glacial acetic acid, it is evaporated in vacuo. Of the

509836 / Ό970

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The residue is digested with petroleum ether, the petroleum ether extract discarded and the residue crystallized from methylene chloride / ether / hexane. The N-tert-butoxy-carbonyl-ampicillin-1-oxide-diphenylmethyl ester is obtained from the

On

Melting point 164-166 ° C; [α] ΖΤ = + 117 ° + 1 ° (c = 1, CHCl.,); IR spectrum (methylene chloride): characteristic bands at 2.91, 2.94, 5.54, 5.69, 5.82 (shoulder), 5.88, 6.60, 6.68 ji; Thin-layer chromatogram: Rf value λ, 0.23 / (silica gel; toluene / ethyl acetate 3: 1).

h) A mixture of 11.2 g (17.7 mmol) of N-tert-butyloxycarbonyl-ampicillin-1-oxide-diphenymethyl ester and 3.26 | (19.5 mmol) mercaptobenzothiazole in 170 ml of toluene is for 3 hours in a reflux apparatus with a water separator cooked and then evaporated. The residue is on silica gel with toluene / ethyl acetate 3: 1 as Eluent is chromatographed and gives the amorphous 2- [4- (Benzthiazol-2-yldithio) -3- (a-tert-butyloxycarbonylamino-a-phenylacetylamino) -2-oxoazetidin-1-yl] -3-methylenebutyric acid diphenylmethyl ester, Thin-layer chromatogram: Rf-WerfuO, 37 (silica gel; toluene / ethyl acetate 3: 1); IR spectrum (Methylene chloride): characteristic bands at 2.94, 5.64, 5.76, 5.86 (shoulder), 5.91 and 6.71 and the like.

509836/0970

i) A solution of 2.34 g (3.0 mmol) 2- [4- (Benzthiazol-2-yldithio) -3 - (α-tert -butyloxycarbonylamino-aphehyl-acetylamino) -2-oxoazetidin-1-yl] -3-methylene-butyric acid diphenylmethyl ester in 30 ml of acetone / water 9: 1, 0.868 g (3.46 mmol) of silver toluenesulfinate are added at 0 ° C and stirred in an ice bath for 1 hour. The precipitate which has separated out is filtered off. The filtrate is in toluene and taken up with saturated aqueous sodium chloride solution shaken out. The organic phase is dried over sodium sulfate and, after evaporation, gives the amorphous 2- [4- (p-toluenesulfonylthio) r3- (α-tert.butyloxycarbonylamino-a-phenylacetylamino) -2-oxoazetidin-l-yl] -3-methylene-butyric acid, diphenylmethyl ester, Thin-layer chromatogram: Rf value λ. 0.33 (silica gel; toluene / ethyl acetate

1 1

3: 1); IR spectrum (methylene chloride): characteristic bands at 2.93, 5.57, 5.70, 5.82, 6.21, 6.65 p.

j) In a solution of 2.30 g cooled to -70 ° C

(3.0 mmol) 2- [4- (p-toluenesulfonylthio) -3- (α-tert.butyloxycarbonylamino-ot-phenylacetylamino) -2-oxoazetidin-1-yl] 3-methylene-butyric acid diphenylmethyl ester in 230 ml of methylene chloride is an ozone / oxygen stream for 7 minutes (0.5 mmol ozone per minute) initiated. After adding 1 ml of dimethyl sulfide, the solution is 1 hour without

509836/0970

Z50633Q

Cooling continued, then evaporated in vacuo. Of the The residue is recrystallized from methylene chloride / ether / hexane and gives the 2- [4- (p-toluenesulfonylthio) -3- (atert.butyloxycarbonylamino-a-phenyl-acetylamino) -2-oxoazetidin-1-ylj-S-hydroxycrotonic acid diphenylmethyl ester from melting point 182-184 ° C; UV spectrum (ethanol): ^

XCici X.

= 259 mu (£ = 13400); IR spectrum (methylene chloride): characteristic Bands at 2.92, 5.59, 5.83, 5.92, 6.03 (shoulder), 6.18, 6.68 u; Thin-layer chromatogram: Rf-WertvO.55 (Silica gel; toluene / ethyl acetate 1: 1) ..

k) A solution of 0.54 g (0.7 mmol) 2- [4- (p-toluenesulfonylthio) -3- (a-tert.butyloxycarbonylamino-a-phenylacetylamino) -2-oxo-azetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester in 20 ml of methylene chloride / methanol 1: 1 is at 0 ° C with an excess of an ethereal Diazomethanlb'sung stirred for 15 minutes and then evaporated in vacuo. Preparative layer chromatography of the residue on silica gel with toluene / ethyl acetate 1: 1 as eluent and elution of the zone visible in UV light yields the 2- [4- (p-toluenesulfonylthio) -3- (atert.butyloxycarbonylamino-a-phenyl-acetylamino) -2-oxoazetidin-1-yl] - 3-methoxy-crotonsMure diphenylmethyl ester, the

509836/0970

recrystallized from methylene chloride / diethyl ether / hexane will. Melting point 204-206 ° C; UV spectrum (ethanol):

> = 259 lop (E = 16,000); IR spectrum (Nujol): charakmax *

teristic bands at 2.93, 5.58, 5.80, 5.84, 5.93, 6.24, 6.57 u; Thin-layer chromatograms: Rf value τ, 0.33 (silica gel; Toluene / ethyl acetate 1: 1).

Example 18

A mixture of 670 mg (1 mmol) 2-14- (p-toluene

sulfonylthio) -3-phenylacetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester, 6.7 ml 1,2-dimethoxyethane and 0.22 ml 1,5-diazabicyclo [5.4.0] undec-5-ene Stirred for 25 minutes at room temperature under a nitrogen atmosphere. The reaction mixture is diluted with toluene and washed successively with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. After preparative thick layer chromatography on silica gel with toluene / ethyl acetate 1: 1, the residue gives the 7β- phenylacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid ~ diphenyl-

509836/0970

methyl ester with a melting point of 166-169 ° C (from methylene chloride / hexane), UV spectrum (ethanol) :) = 258 mu (t> «4500),

Max

IR spectrum (methylene chloride): characteristic bands at 2.93, 5.62, 5.73, 5.93, 6.66 p, Rf value τ / 0.54 (silica gel; system toluene / ethyl acetate 1: 1) and the amorphous 7ß-phenylacetamido-S-methoxy-ceph-S-em-A-carboxylic acid-diphenylmethyl-

ester, UV spectrum (ethanol):) * = 258-mu (£ - = 6350),

Tiicix

264 mp (Z = 6350), 282 ΐπμ (^ = 5600) (shoulder), IR spectrum (methylene chloride): characteristic bands at 2.94, 5.63, 5.83, 5.94, 6.26 ,. 6.66 μ, Rf-value-w 0.37 (silica gel; system

Toluene / ethyl acetate 1: 1), in a ratio of 8: 1.

Further processing can be carried out as follows will:

The 7β-phenylacetamido-3-methpxy-ceph-2-em-4a-carboxylic acid diphenylmethyl ester can analogously to Example 17c) into the 7β-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester-1-oxide with a melting point of 152-155 ° (from acetone / diethyl ether), Rf value 0.31 (silica gel; system:

Ethyl acetate), UV spectrum (in 95% ethanol) Λ . =

Max

288 mjj (X - 3610) and shoulder at *) = 247 mu; IR spectrum (methylene chloride): characteristic bands at 2.94, 5.59, 5.81, 5.95, 6.22 and 6.61 u, are transferred.

509836/0970

'A.OV

A purer product, consisting mainly of the

7p -Phcnylacetaitiido-S-methoxy-ceph- 3- em-4-carboxylic acid-diphe-Dyliiic-thylciKLor-1ß-oxide exists can be obtained as follows:

A solution of 6.7 g (10 inMol) 2- [4- (p-toluenesulfonylth: Lo) -3-phenylacetamidc -P.-oxoazetidin-1-yl] -3-methoxy-isocrotonsiuire-diphenylmethyl-ster in 67 ml abs. Tetrahydrofuran is gerlihrt with 2.28 ml (15 mmol) of?, S-Diazabicyclop ^ jO] undec-5-ene for 15 minutes at 20 ⁰ C., mixed and evaporated with 0.7 ml of glacial acetic acid followed by in vacuo. The oily, dark residue is dissolved in 30 ml of methylene chloride and extracted successively with 15 ml of water, .0 ml of 0.5 N hydrochloric acid, 10 ml of saturated aqueous sodium carbonate solution and 10 ml of water. Äsen the aqueous Pt are reextracted with 10 ml of methylene chloride, the organic extracts combined and strength at 0 ⁰ C with 2.24 ml of 40% peracetic acid gerlihrt 15 minutes in the ice bath. The reaction mixture is then mixed with a solution of 1.50 g (6 mmol) of sodium thiosulfate pentahydrate in 20 ml of water, stirred for 10 minutes and the aqueous phase is separated off. The organic phase is washed with 10 ml of water, dried over sodium sulfate and evaporated in vacuo. Crystallization of the solid residue from methylene chloride / petroleum ether gives this

509836/0970

7β-phenylacetamido-3-methoxy ~ ceph-3-a-4-carboxylic acid diphenylmethyl ester-lβ-oxide of melting point 175-176 ° C; Thin-layer chromatogram (silica gel): Rf value - ^ 0.1 (toluene / ethyl acetate 1: 1) _> UV spectrum (ethanol): ^ \ = 279 mu (i = 7300); IR spectrum (methylene chloride): characteristic bands at 2.94; 5.56; 5.78; 5.91; 6.20; 6.67u.

From the 1-oxides, analogously to Example 17e) the 7β-phenylacetamido-3-methoxy-ceph-3-ei] i-carboxylic acid diphenylmethyl ester get v / earth.

The crude 7β-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid can be obtained from the latter by saponification analogously to Example 17a), which can be obtained by chromatography on silica gel (containing 5% water) with methylene chloride containing 30-50% Acetone and subsequent lyophilization from dioxane can be purified, UV spectrum (in 95% ethanol ·):) = 265 mp (£ = 5800); IR spectrum (methylene chloride): characteristic bands at 3.03, 5.60, 5.74, 5.92, 6.24 and 6.67 and the like.

The starting material and intermediates can be made as follows:

a) A mixture of 37.24 g (0.1 mol) of penicillin G potassium salt in 90 ml of water, 7.3 ml of acetone and 150 ml of chloroform is added to 19.4 ml of 40-40 minutes while stirring at 0 ° C. percent peracetic acid added. After another 15 minutes, por-

509836/0970

- 2-Θ4 -

In portions, 28 g (0.15 mol) of benzophenone hydrazone, then 6.3 ml of 1 percent aqueous potassium iodide solution and then a mixture of 32.5 ml of 10 percent sulfuric acid and 28 ml of 40 percent peracetic acid were added dropwise over a period of 1.5 hours. After the addition is complete, the mixture is stirred for 30 minutes at 0 ° C., warmed to 15 ° and diluted with 400 ml of chloroform. The aqueous phase is separated off and the organic phase is washed successively with 300 ml of 5 percent aqueous sodium bisulfite solution, 300 ml of saturated aqueous sodium bicarbonate solution and 300 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The evaporation residue is recrystallized from ethyl acetate / petroleum ether and gives diphenylmethyl ester-lβ-oxide, o-phenylacetamidopenicillanic acid, melting point 139 ° C .; Thin-layer chromatogram (silica gel): Rf value χ 0.4.0 (system toluene / ethyl acetate 1: 1), IR spectrum (methylene chloride): characteristic bands at 2.94, 5.56, 5.70, 5.92 and 6.57; x.

b) A mixture of 5.165 g (10 mmol) of 6-phenylacetamidopenicillanic acid diphenylmethyl ester-lβ-oxide in 50 ml of toluene and 0.5 ml of glacial acetic acid, 1.83 g (11 mmol) of 2-mercaptobenzothiazole are added and 2 hours in one with one

C Π OQ Off? / fi P 7 0

Boiled reflux apparatus provided with a water separator. On cooling, the 2- [4- (benzthiazol-2-yldithio) -3-phenylacctamido-2-oxoazetidin-1-yl] -3-methylcn-butyric acid diphenylmethyl ester spontaneously crystallizes out. After recrystallizing once from methylene chloride / diethyl ether, crystals with a melting point of 134-136 ° C are obtained; Thin-layer chromatogram (silica gel): Rf value-vO.52 (system toluene / ethyl acetate 1: 1), UV spectrum (ethanol): ^ = 269 mu ( t = 12700); IR spectrum (methylene chloride): characteristic bands at 2.90, 5.60, 5.72, 5.92 and 6.61p.

c) The product obtained under b) needs further processing not to be isolated. After cooling, the reaction mixture can be diluted directly with 30 ml of toluene, add 3.95 g (15 mmol) of silver p-toluene sulphate and stir for 2 hours at room temperature. The fancy, yellow one The precipitate is filtered off through Hyflo and washed with toluene rewashed. The filtrate is extracted by shaking with saturated aqueous sodium chloride solution and dried over sodium sulfate and evaporated in vacuo. The evaporation residue is taken up in toluene and petroleum ether is added. The precipitate is filtered off and from ethyl acetate /

509836/097 0

■ Ä0V

Recrystallized Petroläfher. The obtained 2- [4- (p-toluenesulfonylthio) -3-phenylacetamido-2-oxqazetidin-1-yl] -3-methylenebutyric acid-diphenylmethyl ester has a melting point of 75 ° C; Thin-layer chromatography (silica gel): Rf value Λ »0.47 (toluene / ethyl acetate system 1: 1), UV spectrum

(Ethanol):, Λ = ²⁵⁹ mu (£ = 4300); IR spectrum (Methymax *

lene chloride): characteristic bands at 2.92, 5.62, 5.74, 5.94 and 6,

d) A solution of 655 mg (1 κΜ) 2- [4 ~ (p-toluenesulfonylthio) -3-phenylacetamido-2-oxoazetidin-l-yl] -3-methylene-butyric acid diphenylmethyl ester in 65% methylene chloride is at -65 ° C treated with an ozone / oxygen mixture until it turns a light blue. After adding 0.5 ml of dimethyl sulfide, the mixture is allowed to warm to room temperature and evaporated in vacuo. The crude 2- [4- (p-toluenesulfonylthio) -3-phenylacetamido-2-oxoazetidin-1-yl] -3-hydroxy-crotonic acid diphenylmethyl ester, Rf-V7ert % 0.46 (silica gel; system toluene / ethyl acetate 1 : 1), IR spectrum (methylene chloride): characteristic bands at 2.95, 5.60, 5.98, 6.18, 6.61 ρ, can be processed further without further purification.

509836/0970

e) The crude product obtained under d) is in 20 ml Dissolved methanol and at 0 ° C with ethereal diazomethane solution up to a permanent yellow color. After evaporation of the solvent in vacuo, the residue becomes purified by preparative thick layer chromatography on silica gel with toluene / ethyl acetate 1: 1 as the mobile phase. Man receives the 2- [4- (p-toluenesulfonylthio) -3-phenylacetarnido-2-oxoazetidin-l-yl] -3-methoxycrotonic acid diphenymethyl ester, Pvf value λ, 0.2 (silica gel; system toluene / ethyl acetate 1: 1), IR spectrum (methylene chloride): characteristic bands at 2.94, 5.61, 5.96, 6.24, 6.62 μ, in addition to a little 2- [4- (p-Toluenesulfonylthio) ~ 3-phenylacetamido-2-oxoazetidinl-yl] -3-methoxy-isocrotonic acid diphenylmethyl ester.

Example 1.9

To a solution of 6.06 g (10 mmol) of a 3 ^ mixture of the isomeric 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-l - yl] -3-methoxy-croton- and isocrotonic acid benzyl ester and 2.33 g (15 mmol) of p ~ toluenesulfinic acid in 200 ml of absolute tetrahydrofuran are added at room temperature with stirring for 5 _s, 20 ml (35 mol) of 1 ^ 5-diaza bicyclof5.4.0] undec-5-ene . The mixture is stirred for 40 minutes at room temperature, with 500 ml of methyl

5098.36 / 0970

250633Q

Lene chloride added and successively with 200 ml of 0.5 N Hydrochloric acid, 200 ml water, 200 ml 0.5 N sodium bicarbonate and washed 200 ml of water. The methylene chloride phase is dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on 200 g of acid-washed silica gel toluene / ethyl acetate 3: 1, with addition from diethyl ether to the fractions of the 7ß ~ phenoxyacetamido-3-methoxy-ceph-2-em-4a- carboxylic acid benzyl ester with a melting point of 148-151 ° C is obtained. IR spectrum (methylene chloride)

20 characteristic bands at 5 _} 6O, 5.75, 5.90, S, 25u; [α] = + 284 ° + 1 ° (c = 1; chloroform).

Toluene / ethyl acetate 2: 1 elutes the 7β-phenoxyacetamido-3-methoxyceph-3-em-4-carboxylic acid benzyl ester, which can also be precipitated with diethyl ether from melting point 89-91 ° C; IR spectrum (methylene chloride): characteristic bands at 5.60, 5.85, 5.90; [a] ^ = + 47 ° + 1 ° (c = 1; chloroform).

The ratio of the Ceph-2-em to the Ceph-3-em compound is about 3: 1.

The connections can be further processed as follows:

509836/0 9 70

A solution prepared at O ⁰ C of 454 mg (1 mmol) of an approx. 3: 1 mixture of ß-phenoxyacetamido-S-methoxy-ceph- · 2-em-4oc-carboxylic acid benzyl ester and 7ß-phenoxyacetamido-3- methoxy-ceph-3-em-4-carboxylic acid benzyl ester in 30 ml of tetrahydrofuran is admixed with 15 ml of precooled 0.1 N potassium hydroxide solution while stirring. The mixture is ^{stirred for a further 5 minutes at 0} ° C., then 100 ml of ice water and 100 ml of pre-cooled methylene chloride are added and the mixture is stirred vigorously. Addition of a little saturated aqueous sodium chloride solution causes a separation into two phases. The methylene chloride phase is separated off and the aqueous phase is washed with a further 30 ml of methylene chloride. The aqueous phase is covered with a layer of 50 ml of methyl chloride, 10 ml of 2N hydrochloric acid are added and the mixture is shaken. After the organic phase has been separated off, it is extracted twice more with 30 ml of methylene chloride each time. The combined methylene chloride extracts are dried over sodium sulfate and evaporated in vacuo. The white foam obtained crystallizes on addition of chloroform and diethyl ether and gives 7β-phenoxyacetamido-3-methoxyceph-2-em-4oc-carboxylic acid with a melting point of 142 ° C. (decomposition). IR spectrum (KBr): characteristic bands at 5.65 , 5.75, 5.95 / !.

509836/0970

The starting material can be produced as follows:

a) 20 ml (14.6 g, 0.145 mol) of triethylamine and 17 ml (24th , 5 g, 0.143 mol) of benzyl bromide was added. The mixture is stirred at room temperature for 20 hours, then poured onto ice water. The precipitate is filtered off with suction, washed with about 1000 ml of water, dried in vacuo at 40 ° for 2 days, then taken up in 200 ml of methylene chloride and dried again with sodium sulfate. The white foam remaining after evaporation of the solvent in vacuo is dissolved in 150 ml of ethyl acetate and left to stand first at room temperature, then at -20 °, whereupon pure 6-phenoxyacetaniido-penicillanic acid benzyl ester-lß-oxide crystallizes. Melting point 139-140 ⁰ C; IR spectrum (methylene chloride); characteristic bands at 5.55, 5.75, 5.9Ou; [a] fr = + 174 ° + 1 ° (c = 1, chloroform).

The mother liquor can be chromatographed on 250 g of acid-washed silica gel with toluene-ethyl acetate (1: 1) additional amounts of the crystalline benzyl ester isoxide can be obtained.

509 8.3 6/0970

• Au-

b) 4.56 g (10 mmol) of 6-phenoxyacetainido-penicillanic acid benzyl ester-1β-oxide and 1.84 g (11 mmol) of 2-mercaptobenzothiazole are refluxed (bath temperature 135 °) in 100 ml of toluene for 5 hours. The mixture is left to stand the 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid benzyl ester crystallized out. The crystals are filtered off with suction, washed with 50 ml of toluene and dried in a high vacuum. By chromatography the mother liquor to 70 g of acid-washed silica. gel with toluene-ethyl acetate (3: 1) can be further amounts of the crystalline product can be obtained. Melting point of the pure product 150-153 ° C; IR spectrum (methylene chloride):

20th

characteristic bands at 5.6Oj 5.75, 5.9O _- U; f ⁰ ^ ™ ⁼ -112 ° + 1 ° (c = 1; chloroform).

c) By a solution of 6.06 g (10 mmoles) of 2- [4- (benzthiazol-2-yldithio) -3-phenoxy-acetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid benzyl ester in 300 ml of methylene chloride is passed as long as an oxygen / ozone mixture at -20 ⁰ C, is completely ozonized until the starting material '(control by thin-layer chromatography, silica gel, toluene / Aethylncetat 1: 1). 50 ml of 10% aqueous sodium bisulfite solution are then added to the mixture and the mixture is stirred (5 minutes) until no more ozonide is used with potassium iodide starch

509836/0970

is demonstrable. 300 ml of water are added to the mixture and the product is distributed between the two phases formed. The organic phase is dried over sodium sulfate and freed from the solvent. The residue is dissolved in 100 ml of ether-pentane (1: 1) triturated at 0 ⁰ C, followed by the 2- [4-feenzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxy benzyl crotonic acid crystallized out, melting point 58-62 ° C; IR spectrum (methylepchloride): charac-

20 teristic bands at 5.60, 5.90, 6.00u; [α] = -92 ° + 1 ° (c = 1, chloroforai).

d) 6.08 g (O.OlMol) 2- [4- (Benzthiazol-2-yldithio) -3-phenoxyacetamido-2- Qxoazetidin-1-yl] -3-hydroxy-crotonic acid benzyl ester and 3.50 g (0.013 mol) of silver p-toluenesulfinate stirred in 200 ml of acetone-water (9: 1) for 60 minutes at room temperature. The yellow precipitate formed is filtered off over cellite, the residue washed with acetone and the filtrate is concentrated in vacuo to a volume of about 20 ml. The product is then partitioned between methylene chloride and dilute aqueous sodium sulfate solution. the

509836/0970

organic phase is dried over sodium sulfate and the solvent is evaporated off in vacuo. The residue is taken up in 70 ml of ethyl acetate, if necessary with warming, filtered from something insoluble and evaporated again. 2- [4- (p-Toluolsulfonylthio) -3-phenoxyacetamido-2-oxoazetidin ~ ~ l-yl] -3-hydroxy-crotonsä * acid benzyl ester crystallized by adding 100 ml of ether-pentane at 0 ⁰ C from the melting point 151 -152 ° C; IR spectrum (methylene chloride): characteristic

on bands at 5.60, 5.90, 6.00, 8.75u; [a] * - -16 ° + 1 ° (c = 1; chloroform).

e) To a solution of 5.97 g (0.01 mol) of pure 2- [4- (p-toluenesulfonylthio) -S-phenoxyacetamido - ^ - oxazetidinl-yl] -3-hydroxycrotonic acid benzyl ester in 50 ml of methylene chloride * chloride is added dropwise with stirring, ⁰ C solution of diazomethane in an ethereal O is fully methylated until the starting material (control: thin layer chromatography on silica gel, toluene / ethyl acetate 1: 1). Excess diazomethane is neutralized with a few drops of glacial acetic acid (avoid excess glacial acetic acid), whereupon the mixture is evaporated in vacuo. The yellowish, foam-like back *

509 8.3 6/0970

stand is brought to crystallization from diethyl ether / pentane (1: 1) and a mixture of isomers is obtained consisting of the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoa2etidin-1-yl] -3-methoxycrotonic acid benzyl ester and the 2- [4- (p-toluene sulfonyl thio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid benzyl ester in a ratio of about 3: 1.

The two isomers can be separated by repeated chromatography on silica gel with toluene / ethyl acetate 1: 1 will. The obtained 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-methoxy-crotonic acid-

2Ω

benzyl ester has a melting point of 166-168 ° C; W ^ = -36 ° + 1 ° (c = 1; chloroform); IR spectrum (methylene chloride): characteristic bands at 5.60, 5.80, 5.90, 8.72 μ; NMR spectrum (chloroform): characteristic bands at 2.12 (s); 5.00 (dd); 5.90 (d) ppm; Thin-layer chromatogram: Rf value λ.0.10 (silica gel; toluene / ethyl acetate 1: 1). The obtained 2- [4- (p-Töluenesulfonylthio) -S-phenoxyacetamido ^ -oxoazetidin-1-yl] -3-methoxy-isocrotonic acid benzyl ester has the melting point 59-63 ° C;

[aJ _D = -1 ° + 1 ° (c = 1; chloroform); IR spectrum (methylene chloride): characteristic bands at 5.60, 5.87 sh. 5.90, 8.72 p; Nuclear Magnetic Resonance Spectrum (chloroform): characteristic bands at 2.32 (s), 5.45 (d, d), 5.72 (d) ppm; Thin-layer chromatogram: Rf value λ, 0.13 (silica gel; toluene / ethyl acetate 1: 1).

509836/0970

- 045 -

Example 20

A solution of 534 rag (1 mmol) of a mixture consisting of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamiäo-2-oxoazetidin-1-yl) -3-methoxy-isocrotonic acid methyl ester and methyl 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxycrotonate in a ratio of about 4: 1 in 20 ml of tetrahydrofuran is added, while stirring, with 302 mg (2 mmol) of 1,5-diazabicyclo [5.4.0] undec-5-ene added and stirred for 40 minutes. The mixture is diluted with 70 ml of methylene chloride and successively with diluted Hydrochloric acid, water, dilute aqueous sodium bicarbonate solution and again water. The organic phase will

dried over sodium sulfate and evaporated in vacuo. The residue is poured onto 15g of acid-washed silica gel Toluene / ethyl acetate 2: 1 and then 1: 1 chromatographed, initially the pure 7ß-phenoxyacetamido-3-methoxyceph-2-em-4a-carboxylic acid methyl ester, IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.70, 5.90, 8.25p, and then the pure 7ß-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid methyl ester, IR spectrum (in methylene chloride): characteristic bands at 5.60,

509836/0970

5.85, 5.90, 7, iqu, in the form of colorless foams, are eluted.

The compounds obtained can be further processed as follows:

To a solution, cooled in an ice bath, of 382 mg of 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4ocTcarboxylic acid methyl ester 15 ml of cooled 0.1 N aqueous potassium hydroxide solution are added in 30 ml of tetrahydrofuran with stirring. After 5 minutes, 100 ml of water and 70 ml of methylene chloride are added and the mixture is made aqueous by adding 10 ml of 1N Acidified hydrochloric acid. The methylene chloride phase is separated off and the aqueous phase is extracted with 30 ml of methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. The residue will brought to crystallization from chloroform / diethyl ether and gives the 7ß-phenoxyacetamido-3-methoxy-ceph-2-em-4occarboxylic acid with a melting point of 142 ° (decomposition).

The same compound with a melting point of 142 ° (decomposition) is obtained when the methyl 7ß-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylate, as described above, is saponified with 0.1 N potassium hydroxide solution.

The starting materials can be made as follows:

509 8'36 / 0970

- aw -

a) A solution of 19.25 g (50 mmol) of 6-phenoxyacetamido-penicillanic acid methyl ester-lß-oxide and 9.4 g (55 mmol) of 2-mercaptobenzothiazole in 500 ml of dry toluene is refluxed for 8 hours and then im Reduced vacuum. The residue is dissolved with warming (-v- 80 °) in 400 ml of ethyl acetate, treated with 0.2 g of activated charcoal and suction filtered through an electrically heated glass frit. On cooling, the 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butter'-methyl ester with a melting point of 132 "^ 134 ° C separates Further quantities of this compound can be obtained from the mother liquors (melting point 135 ° -v 137 ° C.).

b) Through a solution of 20.6 g (40 mmol) of 2- [4- (benzothiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidinl-yl] -3-methylene-butyric acid methylester in 400 ml of acetone at -20 ⁰ C, an ozone / oxygen mixture is passed until dUnnschichtchromatogr aphis ch (silica gel, toluene / Aethylace ¹ tat 1: 1) no more starting material is detectable "The mixture is then mixed with 40 ml dimethyl sulfide, and

509836/0970

Stirred for 3 days at room temperature until no more ozone can be detected with potassium iodide starch. The mixture is concentrated in vacuo and the liquid residue is poured onto 400 ml of ice water. The precipitate is filtered off, washed with 200 ml of ice water, brought to crystallization under reduced pressure and dried at 0 ⁰ C from diethyl ether / pentane. The obtained 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] ^ - hydroxycrotonic acid-mathyl-

ester has a melting point of 127-130 ° C; IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.90, 6.00, 8.10 yes. By chromatography of the mother liquors Further amounts of the product can be obtained on silica gel with toluene / ethyl acetate 3: 1.

c) To a solution of 4.85 g (0.01 mol) of methyl 2- {4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidinl-ylJ-S-hydroxycrotonate in 50 ml of methylene chloride is added so much ethereal diazomethane solution at 0 ° C. with stirring given until after 15 minutes of stirring by thin layer chromatography (silica gel, toluene / ethyl acetate 1: 1) no more starting material can be detected.

509836/0970

Excess diazomethane is used with the minimal amount Acetic acid neutralized and the mixture evaporated in vacuo. The residue consists of a mixture of 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidinl-ylj-S-methoxy-isocrotonic acid methyl ester and methyl 2- [4- (benzthiazol-2-yldithio-3-phenoxyacetamide-2-oxoazetidin-1-yl] -β-methoxycrotonate in a ratio of about 4: 1. IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.85, 5.90, 9.05, 10.0 Ou.

d) A mixture of 5.03 g (0.01 mol) of a mixture consisting of 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetami do-2-oxoazetidin-1-yl] -S-methoxy methyl isocrotonate and the corresponding methyl crotonate in a ratio of about 4: 1, 3.50 g (0.013 mol) of silver p-toluenesulfinate and 200 ml of acetone / water 9: 1 is stirred for 40 minutes at room temperature and then through cellite filtered. The filter residue is washed with acetone and the combined filtrates are concentrated in vacuo to a volume of about 20 ml. After adding 100 ml of methylene chloride and 100 ml of dilute aqueous sodium sulfate solution, the mixture is shaken, the aqueous phase is separated off and the methylene chloride phase

509836/0 97 0

250633Q

dried over sodium sulfate and evaporated in vacuo. The residue is triturated for Reinigtang at 0 ⁰ C with diethyl ether / pentane and filtered. A mixture of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamide-2-oxoazetidinl-yl) -3-methoxy-isocrotonic acid methyl ester and 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetarine is obtained. rido-2-oxoazetidin-1-ylJ-3-methoxy-crotonic acid methyl ester in a ratio of about 4: 1 in the form of a white powder. IR spectrum (in methylene chloride) characteristic bands at 5.60, 5.85, 5.90, 8.75 p.

Example 21

A solution of 731 mg (1 mmol) of a 1: 1 mixture consisting of the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-benzyloxy-croton- and the corresponding -isocrotonic acid-p-nitrobenzyl ester is in a mixture of 0.185 ml (1.2 mmol) of 1,5-diazabicyclo [5.4.0] undec-5-ene in 20 ml of dry tetrahydrofuran for exactly 35 minutes stirred at room temperature. The mixture is mixed with 50 ml of methylene chloride and successively with dilute hydrochloric acid, Water and dilute aqueous sodium bicarbonate solution washed. The organic phase is dried over sodium sulfate and evaporated in vacuo. The residue is on

5098 3'6 / 0970

250633Q

- 32 * -

25 mg of acid-washed silica gel is chromatographed with toluene / ethyl acetate (3: 1). A mixture is obtained consisting of the ceph-2-em and ceph-3-em connection in proportion of about 3: 1, which can be separated into the pure isomers by repeated chromatography, whereby the yβ-Phenoxyacetamido-S-benzyloxy-ceph - ^ - em-Aa-carboxylic acid pnitrobenzyl ester melting point 160 ° -162 ° C. (diethyl ether / pentane) # IR spectrum (methylene chloride): characteristic bands at 5.6, 5.7, 5.9, 7.4 p, and the 7β-phenoxyacetamido-3-benzyloxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in the form of a colorless foam, IR spectrum (methylene chloride): characteristic bands at 5.6, 5.8 sh, 5.9, 7.9, 8.4 u, are obtained.

The isomer mixture obtained can be further processed as follows:

The isomer mixture obtained consists of the 7β-phenoxyacetamido-3-benzyloxy-ceph-2-em-4a-carboxylic acid pnitrobenzyl ester and the 7β-phenoxyacetamido-3-benzyloxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in a ratio of about 3: 1 is dissolved in 8 ml of trifluoroacetic acid and during Stirred for 90 minutes at room temperature. The reaction mixture is evaporated in vacuo and residues of trifluoroacetic acid expelled several times with toluene. The residue is poured onto 20 g of acid-washed silica gel with toluene / ethyl acetate (3: 1)

509836/0970

-UV

chromatographed, the Zβ-Phenoxyacetaiiiido-S-hydroxyceph-3-em-4-carboxylic acid p-nitrobenzyl ester is obtained in the form of a colorless foam. IR spectrum (methylene chloride): characteristic bands at 2.95, 3.3, 5.6, 5.75 sh, 5.9, 5.95 sh, 6.55, 7.45, 8.15, 8.3 p; NMR spectrum (deuterochloroform): characteristic bands at 3.4 (2h, AB q, J = 17 Hz), 4.57 (2H, s), 5.06 (IH, d, J = 5 Hz), 5.35 (2H, ABq, J = 14 Hz), 5.7 (IH, dd, J = 5, 10 Hz), 6.8-8.4 (1OH, c), 11.4 (IH, br.s.) ppm.

The starting material can be produced as follows:

To a solution of 1,282 g (2 mmol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid p-nitrobenzyl ester 30 ml of an "in situ" solution of 1.2 g (approx 10 mmol) phenyldiazomethane in ether (from N-benzyl-N-nitrotoluenesulfonamide prepared) added at room temperature. The mixture is for 6 hours at 45 ° C bath temperature on Boiled under reflux, diluted with 100 ml of methylene chloride and then washed with 100 ml of water. The organic phase is over Sodium sulfate dried, evaporated in vacuo and in high vacuum • dried. The yellow oil obtained is poured onto 100 g of acid-washed silica gel with toluene / ethyl acetate 3: 1 and

509836/0970

Chromatographed 2: 1 as eluent. A mixture of isomers is obtained consisting of the 2- {4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-ylj-3-benzyloxy-crotonic acid p-nitrobenzyl ester and the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-benzyloxy-isocrotonic acid p-nitrobenzyl ester in a ratio of about 1: 1, obtained by repeated chromatography can be separated into the individual isomers as before. IR spectrum of the faster running crotonic acid derivative (Methylene chloride): characteristic bands at 5.6, 5.80, 5.90, 8.75 μ; NMR spectrum (deuterochloroform): characteristic Bands at 2.2 (s), 5.05 (dd), 5.93 (d) ppm; Thin-layer chromatogram: Rf value λ. 0.3 (silica gel; toluene / ethyl acetate 2: 1); IR spectrum of the slower running isocrotonic acid derivative (methylene chloride): characteristic bands at 5.6, 5.85 sh, 5.90, 8.75 µ; NMR spectrum (deuterochloroform): characteristic bands at 2.5 (s), 5.41 (dd), 5.77 (d) ppm; Thin-layer chromatogram: Rf-value-v, 0.25 (silica gel; toluene / Ethyl acetate 2: 1).

509836 / 097G

Example 22

405 mg (0.5 mmol) of an isomer mixture consisting of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido 2-oxoazetidin-l-yl] -3-diphenylmethoxy-crotonic acid p-nitrobenzyl ester and the corresponding isomeric isocrotonic acid ester in 8 ml of dry tetrahydrofuran, the 0.9 ml (0.6 mmol) of 1,5-diazabicyclo [5.4.0] undec-l-en contains and stirs for exactly 45 minutes at room temperature. The yellow reaction mixture will diluted with 25 ml of methylene chloride and washed with 0.5 N hydrochloric acid, water and dilute, aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulfate and evaporated.

An isomer mixture is obtained consisting of the 7 / J-phenoxyacetamido ^ -diphenylmethoxy-ceph ^ -6111-4Ot-Ca ^ OnSaUrB-p-nitrobenzyl ester and the 7/3-phenoxyacetamido-3-diphenylmethoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester, IR spectrum (methylene chloride): characteristic bands at 5.60, 5.70, 5.90, 6.55, 7.40 µ.

The obtained isomer mixture of the two compounds can be further processed as follows:

A solution of 340 mg of the isomer mixture obtained consisting of the 70-phenoxyacetamido-3-diphenylmethoxyceph-2-em-4a-carboxylic acid p-nitrobenzyl ester and the 7ß-phenoxy

5098 ^ 6/0970

acetamido-S-diphenylmethoxy-ceph-S-em ^ -carboxylic acid p-nitrobenzyl ester in a mixture of 0.5 ml of trifluoroacetic acid and 9.5 ml of methylene chloride for 40 minutes at room temperature touched. The mixture is evaporated in vacuo, toluene is added to the residue and the mixture is evaporated again. The residue obtained (still contains trifluoroacetic acid) is poured onto 15 g of acid-washed silica gel with toluene / ethyl acetate (3: 1) chromatographed, the 7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester receives} IR spectrum (methylene chloride): characteristic bands at 2.95, 3.3, 5.6, 5.75 sh, 5.9, 5.95 sh, 6.55, 7.45, 8.15, 8.3 u; NMR spectrum (deuterochloroform): characteristic bands at 3.4 (2H, AB q, l = 17 Hz), 4.57 (2H, s), 5.06 (IH, d, 3 - 5 Hz), 5.35 (2H, AB q,} - 14 Hz), 5.7 (IH, dd,} - 5, 10 Hz), 6.8-8.4 (10 H, c), 11.4 (IH, br. S.), Ppm.

The starting material can be obtained as follows:

To a solution of 641 mg (1 mmol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid p-nitrobenzyl ester a solution of 350 mg (1.75 mmol) of diphenyldiazomethane is obtained in 0.5 ml of distilled dioxane added to 0.3 ml of dioxane and the reaction mixture was heated to 50 ° C. for 36 hours without stirring. The mixture is in Evaporated in vacuo, the remaining dioxane with toluene through

509836/0970

driven off again evaporation and the residue to 20 g acid-washed silica gel with toluene / ethyl acetate (7: 1) and (3: 1) chromatographed.

An isomer mixture consisting of the 2- [4- (p-toluenesulfonylthio) ^ - phenoxyacetamido - ^ - oxoazetidin-1-ylJ-S-diphenylmethoxycrotonic acid p-nitrobenzyl ester is obtained and the 2- [4- (p-toluenesulfonylthio) -S-phenoxyacetamido ^ -oxoazetidin-l-yl] -3-diphenylmethoxy-isocrotonic acid p-nitrobenzyl ester, IR spectrum (methylene chloride): characteristic bands at 5.6, 5.85 sh, 5.9, 6.25, 6.55, 7.43, 8.75 μ.

Example 23

A solution of 933 mg (1.5 mmol) of a mixture of isomers consisting of the 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-benzyloxy-crotonic acid methyl ester and the corresponding methyl isocrotonate in a ratio of about 1: 1 and 350 mg (2.25 mmol) of p-toluenesulf in acid in 30 ml of dry tetrahydrofuran is mixed with 800 mg (5.25 mmol) of 1,5-diazabicyclo [5.4.0] undec-5-ene and exactly Stirred for 40 minutes at room temperature. The reaction mixture is diluted with 100 ml of benzene and diluted with aqueous hydrochloric acid, water, dilute aqueous sodium hydroxide solution

B09836 / 0970

and washed again with water. The benzene phase is over Dried sodium sulfate and evaporated in vacuo. By chromatography with toluene / ethyl acetate (5: 1) on silica gel an isomer mixture is obtained consisting of the 7β-phenoxyacetamido-S-benzyloxy-ceph-S-em-A-carboxylic acid methyl ester and the 7ß-phenoxyacetamido ~ 3-benzyloxy-ceph-2-em-4-carboxylic acid methyl ester: IR spectrum (methylene chloride): characteristic bands at 5.60, 5.72, 5.85 sh, 5.90 ρ.

The starting material can be produced as follows:

A solution of 483 mg (1 mmol) of 2- [4-benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-hydroxycrotonic acid methyl ester in 1.5 ml of methylene chloride / diethyl ether is mixed with 960 mg ( about 8 mmol) of freshly distilled phenyldiazomethane are added and the mixture is stirred at 0 ° C. for 20 hours. The reaction mixture is diluted with methylene chloride and washed with water. The organic phase is dried over sodium sulfate, evaporated in vacuo and dried in a high vacuum. The residue is chromatographed on 10 g of acid-washed silica gel with toluene / ethyl acetate (2: 1) and gives an isomer mixture consisting of 2- [4- (benzthiazol · 2-yldithio) -S-phenoxyacetamido ^ -oxoazetidin-1-yl ] -3-benzyloxy-crotonic acid methyl ester and the corresponding isocroton

509836/0970

250633Q

acid methyl ester in a ratio of about 1: 1; IR spectrum (Methylene chloride): characteristic bands at 5.6, 5.85 sh, 5.9, 9.9 ji. -.

Example 24

Analogously to Example 5 d, by converting 1.16 g (3 mmol) according to the invention obtainable 7β-amino-3-methoxyceph-S-em- ^ carboxylic acid hydrochloride-dioxanate with 1.5 ml (6.2 mmol) bis ( trimethylsilyl) acetamide and then a) with 765 mg (3.6 mmol) da-amino- (2-thienyl) -acetic acid chloride hydrochloride the 7ß- [D-oc-amino-ot- (2-thienyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid in the form of the inner salt, mp 140 ° (with decomposition); Thin layer chromatogram (silica gel; identification with iodine): Rf ~ 0.22 (system: n-butanol / acetic acid / water 67:10:23) and Rf ~ 0.53 (system: isopropanol / formic acid / water 77: 4: 19) ; Ultraviolet absorption spectrum:) t _max - 235 mu (£ * = 11400) and / \ _shoulder - 272 mu (£ »6100) in 0.1-n. Hydrochloric acid, and ^ _mav " ² 38 νψ. (B - 11800) and λ _shoulder ^{β 267} W ^" ^{65OO) in} ° » ¹ " ⁿ ' aqueous sodium hydrogen carbonate solution,

509836/0970

b) with 940 mg (4.5 mmol) of D-ct-amino (1,4-cyclob: exadienyl) acetic acid chloride hydrochloride, the 7β- [Da-amino-oc- (1,4-cyclohexadienyl) acetylamino ] -3-methoxy-3-cephem-4-carboxylic acid in the form of the inner salt, mp 170 ° (with decomposition); Thin-layer chromatogram (silica gel; identification with iodine): Rf - «- '0.19 (system: n-butanol / acetic acid / water 67:10:23) and Rf ^ 0.58 (system: isopnopanol / formic acid / water 77: 4 : 19); Ultraviolet absorption spectrum: ^ ■ = 267 my (^ = 6300) in 0.1-n. Hydrochloric acid, and ^ = 268 rough (6 = 6600) in 0.1-n.

aqueous sodium hydrogen carbonate solution _i [a] ^ ° -. + 88 ° + 1 ° (C = 1.06; 0.1 N ^ hydrochloric acid), and

c) with 800 mg (3.6 mmol) of D-α-amino-4-hydroxyphenylacetic acid chloride- ^ hydrochloride, the 7β- [D-α-amino-α- (4-hydroxyphenyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid in the form of the inner salt, F - 243 - 244.5 ° C (from 231 ° start of sintering) (with decomposition); Thin-layer chromatogram (silica gel; identification with iodine): Rf-> • 0.24 (system: n-butanol / acetic acid / water 67:10:23) and Rf "^ 0.57 (system: isopropanol / Formic acid / water 77: 4: 19); Ultraviolet absorption

spectrum: ^ _β - 228 mu (^ = 12000) and 271 mu (£ «» 6900) in max / /

0.1-n. Hydrochloric acid, andA _max * 227 mu (6 = 10500) and /) h _u i _te r ⁼

509836/0970

262 mu (if = 8000) in 0.1-n. aqueous sodium hydrogen carbonate solution, [α] ^ ° - + 165 ° + 1 ° ψ = 1.3; 0.1 N hydrochloric acid).

Example 25

Analogously, can be obtained according to the invention from suitable Intermediate products the following compounds are made:

7ß-Amino-3-methoxy-3-cephem-4-carboxylic acid diphenyl methyl esters or salts thereof,

S-n-Butyloxy-yß-phenylacetylamino-S-cephem-'i-carboxylic acid diphenylmethyl ester, - ·.

3-n-Butyloxy-7ß ~ (D-a-tert.-butyloxycarbonylaminoa-phenyl-acetyl-amino) -3-cephem-4-carboxylic acid-diphenylinethylpster, '

3-n-Buty.loxy-7β- (D-a-phenyl-glycylamirio) -3-cephem-4-carboxylic acid or salts thereof,

3-methoxy-7ß-phenylacetylamino-3-cephem-4-carboxylic acid methyl ester,

3-Aethoxy-7ß- (D-a-tert-butyloxycarbonylamino-aphenyl-acetylamino) -3-CePhCm-A-Ca ^ OnSMUr e-diphenyl methyl ester, -.

509836/0970

- 2-ST -

3-ethoxy-7β- (D-a-phenyl-glycylamino) -3-cephem-4 ~ carboxylic acid or salts thereof,

3-Benzyl oxy-7 / 3- (D-ct-tert-butyloxycarbonylanu.noa-phenyl-acetylamino) -3-cephem-4-carboxylic acid-diphenylmethyl ester,

3-BeIZyIoXy-JjS- (D-a-phenyl-glycylamino) -3-cephem-4-carboxylic acid or salts thereof,

7β- (5-Benzoylamino-5-diphenylmethoxycarbonyl ~ valerylani5.no) -S-methoxy ^ -cephem-A-carboxylic acid diphenylmethyl ester,

7 β- (Da-tert-butyloxycarbonylamino-a-phenylacetyl-amino) -3-methoxy-3-cephem-4-carboxylic acid or salts thereof,

7 / 3- [D-a-tert. -Butyloxycarbonylamino-a- (2-thienyl) acetylarai.no] -3-methoxy ~ 3-cephem-4-carboxylic acid diphenyl methyl ester,

7 / 5- [D-a-tert-butyloxycarbonylamino-a- (1,4-cyclohexadienyl) -acetylamino] -3-raethoxy-3-cepheIn-4-carboxylic acid diphenylmethyl ester,

509836/0970

-ÄS *

7 / 3- [D-α-Amino-α- (ϊ-cyclohexen-1-yl) -acetylamino] 3-raethoxy-3-cephem-4-carboxylic acid or salts thereof,

7ß- [D-a-tert-butyloxycarbonylamino-a- (4-hydroxyphenyl) -acetylaniino] -S-methoxy-S-cephem ^ -carboxylic acid-di- phenyl methyl ester,

7β- [Da-tert-Butyloxyc & rbonylamino-a- (4-isothiazolyl) -acetylamino] -3-met; hoxy-3-ceρhem-4-carboxylic acid diphenylmethyl ester,

7ß ~ (Da-tert-butyloxycarbonylamino-oc-phenyl-

acetylaitiino) -3-methoxycarbonyloxy-3-cephem-4-carboxylic acid dipheny! methyles ter j

as well as the corresponding Ceph-2-em compounds and the isomer mixtures consisting of the Ceph- ⁱ 3-one and the Ceph-2-em compounds, as well as the 1-oxides of the corresponding Ceph-3-em compounds.

Claims (1)

Claims ίί.1 Process for the preparation of 7ß-amino-3-cepheni-3-ol-4-carboxylic acid compounds of the formula O-R. (IA) O = C-R, B. A wherein IL. Represents hydrogen or an amino protecting group R, and L stands for hydrogen or an acyl group Ac away !, or R, and R ^ zusamnien represent a bivalent amino protective group, R2 is hydroxy or ei.nen, together with the carbonyl grouping -C (--- 0) - a protected carboxyl group-forming group is IU, and Pv "is hydrogen , Lower alkyl, or a hydroxy protecting group, and also of 1-oxides of 3-cephem compounds of the formula IA, and the corresponding 2-cephem compounds of the formula 509836/0970 O-R, (IB), OC-K, where R ^, R ^, R ^ and R "have the meanings given above, or salts of such compounds with salt-forming groups, characterized in that a compound of Formula. O: H
J / SY 9 ^{! I} 3 (II) from A
vorin R ₁ , R ₁ and R _{9 have} the meanings given under formula IA, R ^ stands for lower alkyl or a hydroxyl protecting group, and Y represents a leaving group, treated with a base and, if desired, in a compound of formula IA or IB obtained the protected carboxyl group of the formula -C (= 0) -Rp is converted into the free or into another protected carboxyl group, and / or, if desired, the protected hydroxyl group -0-R into a free one 509836/0970 250633Q Hydroxy group is converted and / or the free hydroxy group or the protected hydroxy group -0-R _{3 is converted} into a lower alkoxy group -CR ₀ , 'and / or, if desired, within the definition of the end products, a compound obtained is converted into another compound, and / or, if desired, a compound obtained with a salt-forming group is converted into a salt or a salt obtained is converted into the free compound or into another salt, and / or, if desired, a mixture of isomers obtained separates compounds into the individual isomers. 2, ■ The method according to claim 1, characterized in that starting materials of the formula II are used in which 'a A • K., represents an amino protective group R ₁ , which for a Acyl group Ac, in which any free functional groups that may be present may be protected, B ... hydrogen A.
IL ₁ denotes halogen or an etherified hydroxyl group which forms an esterified carboxyl group with the -C (= 0) group, it being possible for functional groups which may be present in an esterified carboxyl group of the formula -CC = O) -R ^ to be protected , R ^ Hisderalkyl or a hydroxy protecting group, and Y a group -SR ,, a group -SO ₉ -R- bonded to the thio group -S- with the sulfur atom, or a group. .-S-SO ₀ -Rj. means"' . . :. " 509 836/0970 3. The method according to claim 2, characterized in that R _{2 is} an optionally substituted 1-phenyl-lower alkoxy, such as benzyloxy, p-nitrobenzyloxy or diphenylmethoxy group, or an optionally halogen-substituted lower alkoxy group, such as methoxy, a-polybranched lower alkoxy, eg tert. -Butyloxy, or 2-halo-lower alkoxy, such as 2,2,2-trichloroethoxy, or halogen, such as chlorine. 4. The method according to claim λ or 2, characterized in that R ^ is lower alkyl, such as methyl, or a substituted silyl group, such as trimethylsilyl ₅ . 5. The method according to claim 1 or 2, characterized in that Y is a group ~ ^s * " ^r a ^ ^{st) where r} a ^e i- ⁿ g ^e S ^e " optionally substituted aromatic heterocyclic radical with up to 15, preferably up to 9 carbon atoms, and at least one ring nitrogen atom and optionally a further ring heteroatom, such as oxygen or sulfur, which radical is bonded to the thio group -S- with one of its ring carbon atoms, which is connected to a ring nitrogen atom by a double bond. 6. The method according to any one of claims 1, 2 or Jf, characterized in that R, 1-methyl-imidazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,3,4,5-thiatriazol-2-yl, 1,3-0xazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,3,4,5- Oxatriazol-2-yl, 2-quinolyl, 1-Kethyl-beuzimida £ ol-2-yl, Benzoxazol-2-yl and in particular benzthiazol-2-yl denotes. 7. The method according to claim 1 or 2, characterized in that R, an optionally substituted aliphatic, cycloaliphatic, araliphatic or aromatic acyl or thioacyl group with up to 18, preferably up to to 10, carbon atoms such as lower alkanoyl e.g. acetyl or propionyl, lower thioalkanoyl e.g. thioacetyl or Thiopropionyl, cycloalkanecarbonyl, e.g. Cyclohexanecarbonyl, Cycloalkanethiocarbonyl, e.g. cyclo- hexanthiocarbonyl, benzoyl, thiobenzoyl, naphthylcarbonyl, Caphthylthiocarbonyl, heterocyclic carbonyl or thiocarbonyl, such as 2-, 3- or 4-pyridylcarbonyl, 2- or , 3-thenoyl, 2- or 3-furoyl, 2-, -3- or 4-pyridylthiocarbonyl, 2- or 3-thiothenoyl, 2- or 3-thiofuroyl or a corresponding substituted one, for example by lower alkyl, such as methyl, halogen such as fluorine or chlorine, lower alkoxy such as methoxy, aryl such as phenyl, aryloxy such as phenyloxy, mono- or poly-substituted acyl or thioacyl group. 8. The method according to claim 1, 2, 5 or 6, characterized in that R, is benzthiazol-2-yl. 9. The method according to claim 1, 2 ,. 5 or 6, characterized in that R 1 is benzoxazol-2-yl. 10. The method according to claim 1 or 2, characterized in that Y is a group -SO ^ -R, wherein R ₁ - an optionally substituted, aliphatic eycloaliphatic, araliphatic or aromatic hydrocarbon radical with up to 18, preferably up to to 10 carbon atoms. 11. The method according to claim 1. or 2, characterized in that Y is a group ^ S-SO ^ -R ^, wherein R _{5 is} an optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbon radical with up to 18, preferably up to 10 Is carbon atoms. 12. * The method according to any one of claims 1, 2, 10 or 11, characterized in that R _{5 is} an optionally substituted, such as by lower alkoxy, such as methoxy, halogen, such as fluorine, chlorine or bromine, aryl, such as phenyl, aryloxy, such as Phenyloxy, mono- or polysubstituted alkyl, especially lower alkyl, such as methyl, ethyl or butyl, alkenyl, such as allyl or butenyl, cycloalkyl, such as cyclopentyl or cyclohexyl, or optionally by lower alkyl, such as methyl, lower alkoxy, such as Methoxy, halogen, such as fluorine, chlorine or bromine, aryl, such as phenyl, aryloxy, such as phenyloxy, or nitro, mono- or poly-substituted kaphthyl or, in particular, phenyl group, for example 509836/0970 se phenyl, o-, m- or preferably p-tolyl, o-, m- or preferred p-methoxyphenyl, o-, m- or p-chlorophenyl, p-biphenylyl, represents p-phenoxyphenyl, p-nitrophenyl or 1- or 2-naphthyl. 13. The method according to any one of claims 1, 2, 10, 11 or 12, characterized in that Y means a group -SO ₉ -R ₁ -, wherein R ₁ - phenyl, p-tolyl, p-methoxyphenyl or p-nitrophenyl is. . . 14. The method according to any one of claims 1 to 13, characterized in that the base is a bicyclic amidine is used. 15. The method according to any one of claims 1 to 14, characterized in that the base is a diazabicycloalkene, like 1,5-diazabicycloI4.3.0jnon-5-eii or 1,5 ~ diazabicyclo [5.4.03non-5-en is used. 16.. A method according to any one of claims 1 to 13, by DA in that as bases substituted, for example by Kiederalkyl multiply substituted guanidines, such as tetramethylguanidine, or tri-lower alkylamines such as triethylamine are used. 17. The method according to any one of claims 1-16, characterized in that in a compound obtained, the hydroxy protecting group R is split off and replaced by hydrogen . . . 509836/0970 18. The method according to claim 17, characterized in that one has a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic Hydrocarbon residue R ~ by acid hydrolysis, a silyl or stannyl group R by hydrolysis, alcoholysis * or acidolysis. 19. The method according to any one of claims 1-18, characterized characterized in that one obtained a compound wherein R. means hydrogen by etherification into a compound converted, wherein R "means lower alkyl. 20. The method according to any one of claims 1-19, characterized in that a compound obtained in which R ~ means hydrogen by etherification into a compound transferred, where R ~ is methyl. 21. The method according to any one of claims 19 or 20, characterized in that the etherification with a Diazo lower alkane of the formula R ~ -1> L, such as diazomethane, carries out. ' 22. The method according to any one of claims 19 or 20, characterized in that the etherification is carried out by treatment with a reactive ester of a lower alkanol of the formula R ₃ -OH. SO * 830/0970 23. ■ The method according to any one of claims 1-22, characterized characterized in that in a compound obtained, away
wherein R, or R- denotes an acyl group, cleaving a suitable acyl group, for example by treatment with an imide halide-forming agent, reacting the imide halide formed with an alcohol and cleaving the iminoether formed, and replacing it with hydrogen. 24. The method according to any one of claims 1-23, characterized in that one obtained in a compound . free amino group protects, e.g. acylated. 25. The method according to any one of claims 1-24, characterized in that in the inventive method or in any additional measures to be carried out ·. free functional groups not participating in the reaction in the starting materials or in those available in accordance with the process Compounds are temporarily protected and, if desired, released after the reaction has taken place. 26. The method according to any one of claims 1-25, characterized in that a compound obtained is a protected carboxyl group of the formula -CC = O) -R ₂ by alkaline or acidic hydrolysis, alcoholysis, acidolysis, or by treatment with a reducing agent or by 50983S / 0970 Irradiation converted into a free carboxyl group. 27. The method according to any one of claims 1-2 $, characterized in that a compound of the formula IB or a mixture obtained consisting of a compound of the formula IB and a compound of the formula IA is converted into a 1-oxide of a compound of the formula IA converts. 28. The method according to any one of claims 1-27, characterized in that a 1-oxide of a compound is obtained of the formula IA reduced to a compound of the formula IA. 29. The method according to any one of claims 1-28, characterized in that there is obtained as intermediate products Compounds used as starting materials and the remaining process steps carried out with these, or the process breaks off at any stage. 30. The method according to any one of claims 1-29, characterized characterized that one starting materials in the form of derivatives used or formed during the reaction. 31. The method according to any one of claims 1-30, characterized characterized in that 3-cephem compounds of the formula IA according to claim 1 or 1-oxides thereof, furthermore the ent- 509836/0970 Speaking 2-cephem compounds of the formula IB according to claim 1, as well as making salts of such compounds having salt-forming groups, wherein R ₁ is hydrogen or a in a fermentation or bio, semi- or totally synthetically obtainable M-acyl derivative of 6β-amino- acyl radical contained R. "hydroxy, optionally substituted lower alkoxy, acyl oxy, tri-lower alkylsilyloxy ρenam-3-carboxylic acid or 7.beta.-amino-3-C £ PHEM ~ 4-carboxylic acid compound, R is ₁ FLIR hydrogen, or optionally substituted amino, or Is hydrazino, and R1 is hydrogen, lower alkyl, or a hydroxy protecting group. 32. The method according to any one of claims 1-31, characterized in that 3-cephem compounds of the formula IA according to claim 1 or 1-oxides thereof, as well as corresponding · - de 2-cephem compounds of the formula IB according to claim 1, furthermore salts of such compounds with salt-forming • 3 Groups are prepared in which R, is hydrogen, a produced in fermentation TIV or biosynthetically N-acyl derivatives of OSS-amino-penam-S-carboxylic acid or 7.beta.-amino-3-cephem-4-carboxylic acid compounds containing acyl group, or in highly effective N-acyl derivatives of ß-amino-penam-S-carboxylic acid or 7ß-amino-3-cephem-carboxylic acid compounds. 509836/0970 25Ö6330 coming acyl radical, R is hydrogen, R _{9 is} hydroxy, lower alkoxy, 2-rJIalogenniederalkoxy, Phenacyloxy, 1-Phenylniederalkoxy with 1-3 phenyl radicals optionally substituted by lower alkoxy or nitro, Niederalkanoyloxymethoxy, Niederalkoxycarbonyloxy or Niederalkanoyloxy, and R ^ is hydrogen, Lower alkyl, or an Ilydroxyschutzgruppe, or in which R ₂ and R "denotes the above have the same meanings and R, and R, together for one, in the 2-position by optionally substituted phenyl substituted l-oxo-3-aza-l, 4-butylene radical, which is in • 4-digit, possibly contains two Niederalk / igruppen. 33. The method according to any one of claims 1-32, characterized in that 3-cephem compounds of the formula IA according to claim 1 or 1-oxides thereof, as well as corresponding- ■ ' de 2-cephem compounds of the formula IB according to claim 1, furthermore salts of such compounds with salt-forming groups away
pen in which R _{1 and R 1 have} the meanings given in claim 32, R _{2 is} hydroxy, lower alkoxy, 2-halo-lower alkoxy, phenacyloxy, 1-phenyl-lower alkoxy with 1-3 phenyl radicals optionally substituted by lower alkoxy or nitro, lower alkanoyloxymethoxy, α-amino lower alkanoyloxyinethoxy , Lower alkoxycarbonyloxy or lower alkanoyloxy H '■: P ■■ $ * · ν -1 and R is lower alkyl, or a hydroxy protecting group, such as tri-lower alkylsilyl, or in which R _? and R "have the meanings given above, and R ₁ and R together represent a l-0xo-3 ~ aaa-l _s 4-butylene radical which is substituted in the 2-position by optionally substituted phenyl, which in the 4-position optionally has two, Contains kiederslkyl groups. 34. The method according to any one of claims 1-33, characterized in that 3-cephem compounds of the formula IA according to claim 1 or 1-oxides thereof, as well as corresponding 2-cephem compounds of the formula IB according to claim 1, furthermore salts of such compounds with salt-forming groups where R ₁ , R 2 and R have the meanings given in claim 33 , and Rf "is hydrogen or a group of the formula R ¹¹ Ill where η is O and R is hydrogen or an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally sub- , "P--: *« * ** ■ #S f \ / fi O Ϊ5 Λ
i »· ■« · w * * » '- * $ ί U ^p ϊ * β ν - 2 * 6 - -MV " statuted heterocyclic radical, preferably aromatic Character, a functionally modified, e.g. esterified or etherified hydroxyl or mercapto group. or one if applicable substituted amino group, or in which η is 1, R is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted one heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical is preferably aromatic Has character and / or a quaternary nitrogen atom, an optionally functionally modified, preferably etherified or esterified hydroxyl or mercapto group, an optionally functionally modified carboxyl group, represents an acyl group, an optionally substituted araino group or an azido group, and each of the radicals R and R denote hydrogen, or in which η denotes 1, R an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or optionally one substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic The remainder preferably has an aromatic character, 509836/0970 250633Q R a possibly functionally modified, e.g. Hat * zn tit . _t esterified or etherified hydroxy or mercapto groups, an optionally substituted amino group, an optionally functionally modified carboxyl group or sulfo group, an optionally O-mono- or disubstituted phosphono or
group ^ denotes an azido group, and R denotes hydrogen, or in which η denotes 1, each of the radicals R and R denotes a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and R denotes hydrogen, or in which η is 1, R is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and R and R together represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical connected to the carbon atom by a double bond , or where η is 1, and R is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or a 509836/0970 250633Q η r η _ optionally substituted heterocyclic or heterocyclic-aliphatic A radical in which heterocyclic radicals preferably have an aromatic character, R an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic Hydrocarbon radical and R is hydrogen or an optionally substituted aliphatic, cycloaliphatic, mean cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical, or where R "and R" have the meanings given above and _a U »U? /> RJ .Along for one, in the 2-position is optionally substituted phenyl containing l-oxo-3-aza-l, 4-butylene radical are, in the 4-position optionally contains two lower alkyl groups. 35. The method according to any one of claims 1-34, characterized in that 3-cephem or 2-cephem compounds of the formula IA or IB according to claim 1 or salts hersUI / t of such compounds with salt-forming groups ,, in which b a R, denotes hydrogen, R, denotes hydrogen, an acyl group the formula (X) _m -CH-C- (B) - ■ '·, fi · ■■ * *' ■ * e · * t {* · γ ■ - · .- Ö -J i> · ■ J vt U where R is phenyl, hydroxyphenyl, hydroxychlorophenyl, thienyl, pyridyl, aminopyridinium, furyl, isothiazyl, tetrazolyl or 1,4-cyclohexadienyl, with hydroxy substituents in such radicals being protected by acyl radicals, X being oxygen or sulfur, m for 0 or 1 ″, and R 1 is hydrogen or, if in is 0, optionally protected amino, carboxy, sulfo or hydroxy, or O-lower alkylphosphono or O, O ¹ -di-lower alkyl-phosphonc, or a 5-amino-5 -carboxy-valeryl radical in which the amino and carboxy groups are optionally protected} and R 1 and R 1 have the meanings given in claim 33. ■ 36. The method according to any one of claims 1-35, characterized in that 3-cephem compounds of the formula IA • according to claim 1, as well as their 1-oxides, furthermore the corresponding 2-cephem compounds of the formula IB according to claim 1, or salts of such compounds with salt-forming compounds Produces groups in which Pv., Hydrogen, or an acyl radical of formula B in which R is phenyl, hydroxyphenyl, e.g. 4-hydroxyphenyl, thienyl, e.g. 2- or 3-thienyl, Is 4-isothiazolyl or 1,4-cyclohexadienyl, X is oxygen, m is 0 or 1, and R, is hydrogen or, when m is 0, amino, protected amino, such as acylamino, 3 8/0870 -JLS *
e.g. α-polybranched lower alkoxycarbonylainino, such as tert-butyloxycarbonylamino, or 2-halogeno-lower alcohol:;. ycarbonylamino, 2,2,2-trichloroethoxycarbynylamino, 2-iodoethoxycarbonylamino or 2-bromoethoxycarbonylamino, or optionally lower alkoxy-4-methoxycarbonylamino, e.g. benzyloxycarbonylamino, or hydroxy, and protected hydroxy, such as acyloxy, for example α-polybranched lower alkoxycarbonyloxy, such as tert-butyloxycarbonyloxy, or 2-halo-lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, furthermore 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy mean, or for an S-amino-S-carboxy-valeryl- itect / rest ^ in which the amino and carboxy groups are also protected and can be present, for example, as acylamino, for example lower alkanoylamino, such as acetylamino, halo-lower alkanoylamino, such as dichloroacetylamino, benzoylamino, or phthaloylamino, or as esterified carboxy, such as phenyl-lower alkoxycarbonyl, for example diphenylmethoxycarbonyl, where preferably m is 1, when R is phenylmethoxycarbonyl or, if R is hydroxyphenyl ₁ hydrogen a j. represents, R_ hydroxy, optionally halogen in the 2-position, e.g., chlorine, bromine or iodine substituted lower alkoxy, especially α-polybranched lower alkoxy, e.g. tert-butyloxy, or 2-halo-lower alkoxy, e.g. 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or given 509836/0970 otherwise lower alkoxy, viie methoxy-substituted di'phenylmethyloxy, e.g. diphenylmethoxy or 4,4, '- dimethoxy-diphenylmethoxy ", p-nitrobenzyloxy, also tri-lower alkylsilyloxy, e.g. trimethylsiiyloxy, and R ^ is hydrogen,
Is lower alkyl, especially methyl, or tri-lower alkylsilyl. 37. The method according to any one of claims 1-36, characterized in that 7/3 (Da-amino-a-R_-acetylamino) -3-lower alkoxy-3-cephem-4-carboxylic acids, above all R for phenyl ,
4-hydroxyphenyl, 2-thienyl or 1,4-cyclohexadienyl is ₃
and lower alkoxy contains up to 4 carbon atoms and prepares the internal salts thereof. 38. The method according to any one of claims 1-36, characterized in that the 7ß-phenoxyacetarnido-3-methoxyceph-3-em-4-carboxylic acid p-nitrobenzyl ester manufactures. 39. The method according to any one of claims 1-36, characterized in that the 7j3-phenoxyacetamido-3-methoxyceph-2-em-4-carboxylic acid p-nitrobenzyl ester manufactures. 40. The method according to any one of claims 1-36, characterized characterized in that the 7jß-phenoxyacetanido-3-hydroxyceph-3-em-4-carboxylic acid diphenylinethyl ester manufactures. 509836/0970 41. The method according to any one of claims 1-36, characterized in that the 7β-phenoxyacetamido-3-methoxyceph-3-em-4-carboxylic acid diphenylmethyl ester: he manufactures. 42. The method according to any one of claims 1-36, characterized in that the 7β-phenoxyacetamido-3-methoxyceph-2-em-4-carboxylic acid diphenylri _i ethyl ester is prepared. 43. The method according to .einem of claims 1-36, characterized characterized in that the 7ß-phenoxyacetamido-3-methoxyceph-3-em-4-carboxylic acid-diphenylmethyle3-ter-l-oxide manufactures, 44. The method according to any one of claims 1-36, characterized in that the 7ß-phenoxyacetamido-3-methoxyceph-3-em-4-carboxylic acid-2,2,2-tr: u_uloräthylester manufactures. 45. The method according to any one of claims 1-36, characterized in that the 7ß-phenoxyacetamido-3-methoxyceph-2-em-4-carboxylic acid 2,2,2-trichloroethyl ester manufactures. 46. The method according to any one of claims 1-36, characterized characterized in that the 7/3-Phenoxyacetamido-3-Giethoxyceph-2-em-4-carboxylic acid tert-butyl ester manufactures. 47. The method according to any one of claims 1-36, characterized in that characterized in that one has the 3-methoxy-7/3-phenylacetylamino-3-carboxylic acid or making salts thereof. 48. 'The method according to any one of claims 1-37, characterized characterized in that the 3-methoxy-7 / 3- (D-ct-tert.-butyloxy-carbonylamino-σ.-phenylacetyl-amino) Diphenylmethyl -3-cephem-4-carboxylate manufactures. 49. The method according to one of claims 1-37, characterized in that characterized in that the 3-methoxy-7 / 3- (D-ct-phenylglycylamino) -3-cephem-4-carboxylic acid or making salts thereof. 50. The method according to any one of claims 1-37, characterized in that the inner salt of 3-methoxy-7ß- (p-ct-phenylglycyl-amino) -S-cephem-A-carboxylic acid manufactures. 51. The method according to any one of claims 1-37, characterized in that the 3-n-butyloxy-7ß- (D-a-phenylglycylamino) -3-cephem-4-carboxylic acid or making salts thereof. 52. The method according to any one of claims 1-37, characterized in that the 7β-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester or making salts thereof. 5G9836 / Q97Q 53. The method according to any one of claims 1-37, characterized in that the 7β- [Da-amino-a- (2-thienyl) acetylamino] -S-methoxy-S-cephem ^ -carboxylic acid or salts thereof are prepared. 54. The method according to any one of claims 1-37, characterized in that the 7 ß- [Da-amino-a- (4-hydroxyphenjO.) -Acetylamino) -S-methoxy-S-cephem ^ -carboxylic acid or salts thereof manufactures. '■. 55. The method according to any one of claims 1-37 _s, characterized in that 3-ethoxy-7β- (Da-phenyl-glycylamino) -S-cephem-A-carboxylic acid or salts thereof are prepared. 56. The method according to any one of claims 1-37, characterized characterized in that the 3-benzyloxy-7ß- (D-a-phenylglycylamino) -3-cephem-4-carboxylic acid or making salts thereof. 57. The method according to any one of claims 1-37, characterized in that the 7β- [Da-amino-a- (1,4-cyclohexadienyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid or making salts thereof. 509836 / 097Ö 58. The method according to any one of claims 1-37, characterized in that the 7ß-AraIno-3-inethoxy-3-cephem-4-carboxylic acid or making salts thereof. 59. The method according to any one of claims 1-37, characterized in that the 7β- (5-benzoylamino-5-diphenylmethoxycarbonyl-valerylamino) -S-acid diphenylmethyl ester is prepared. 60. The process described in Examples 1- ^ t ₅ for the preparation of the compounds described in claim 1. 61. The method according to any one of claims 1-9 and
14-59, characterized in that a compound of the formula II in which Y is a group -SR, and in which R-, R and R2 have the meanings given under formula IA
and R «represents lower alkyl or a hydroxy protecting group
and R, which has the meanings given in claims 5-9, in the presence of a sulfinic acid of the formula HSCL-R ₁ - with
treated a base. 62. The method according to claim 61, characterized in that R 1 is benzthiazol-2-yl. 509836/0970 63. The method according to any one of claims 61 or 62, characterized in that R ^ phenyl, p-tolyl, ο- or ■ is p-methoxyphenyl or p-nitrophenyl. 64. The method according to any one of claims 61-63, characterized in that a bicyclic amidine is used as the base will. 65. The method according to any one of claims 61-64, characterized in that the base is a diazabicycloalkene, such as 1,5-diazabicyclo [4.3.0] non-5-en or l _s 5-diazabicyclo [5.4.0] non-5 -en is used. 66. The method described in Examples 6, 5i, 5ii, 5ai, 5bi, 5c, 5d and 14 to 18 for the preparation of the compounds described in claim 1, 67. The method according to any one of claims 1-34 and 61-66, characterized in that 3-cephem compounds of the formula IA, in which R 1 is an acyl group of the formula (B) in which R is 1-cyclohexenyl. 68. The method described in Examples 1, 4i, 5iii, 5biii, 5ci, 19 and 20 for the preparation of the im Claim 1 described compounds. ? <> S 8 c- 8/0 S 7 G * 69. The method according to any one of claims 1-16, 21, 23-35, 61, 67 and 68, characterized in that compounds of the formula IA and their 1-oxides, compounds of the formula IB, as well as salts of compounds with salt-forming groups in which R "is an easily split off optionally substituted cc-phenyl-lower alkyl group means. 70. The method according to claim 69, characterized in that R- is an optionally substituted benzyl or Means diphenylmethyl group. · 71. The method described in Examples 5iv, 21, 22 and 23 for the preparation of those described in claim 1 Links. 72. Compounds of Formula I CH ₀ < ^IV > VC-CH, 0-CR ₂ 509638/0970 wherein R,, R, and R2 have the meanings given under formula II and Y is a group of the formula -SO ₉ -Rc or ρ .Ine group of the formula -S-SO ₂ -Rc bonded to the thio group -S-bonded to the sulfur atom - means in which R ₁ . is an optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbon radical with up to 18 carbon atoms. 73. 2- [4- (p-Toluenesulfonylthio) -S-phenoxyacetamido ^ - oxoazetidin ~ l-yl] -3-methylenebutyric acid p-nitrobenzyl ester or the 2- [4- (p-toluenesulfonylthio) -S-phenoxyacetamido ^ - oxoazetidin-1-yl] -3-methylenebutyric acid diphenylinethyl ester, 2- [4- (p-toluenesulfonylthio) -3- (D-a-tert.butyloxycarbonylamino-a-phenylacetamido) -2-oxoazetidin-1-yl] -3-methylenebutyrate-diphenylmethyl ester and 2- [4- (p-toluenesulfonylthio) 3-phenylacetamido-2-oxoazetidin-1-yl] -3-methylenebutyrate re-diphenylmethyl ester according to claim 72. 74. Compounds of Formula In. ή ■ -it N "ο ν NpC-OH a b A vorin R ^, R, R ₂ and Y have the meanings given under formula II. 509836/0970 75. 2- [4- (p-Toluenesulfonylthlo) »i-pharicxyacetaniido-2-oxoazetidin-1-yl3-3-hydroxy-2ro £: or: £ iure-p-nitrobenzyl ester, 2- [4- (p-toluenesulfonylthic ) -3-phenoxyacetamido »2-oxoazetI-din-l-YLJ-3-hydroxycrotonsSure diphenylmethyl ester, 2- [4- (benzothiazol-2-yldithio) -S-phenoxyacatamido - ^ - oxo-azetidin-l-YLJ-S -hydroxycrotonic acid diphenylmethyl ester, 2- [4- (BenzfchIazol-2-yldithic) -3-phenoxyacetamido-2-oxo-azet3-dinl-yl] -3-hydroxycrotonic acid-2,2,2-trichloroethyl ester, 2-ί4- ( p-Toluenesulfonylthio) -3- (Da-tert, butyloxycarbonylamino-a-pheny! acetamido) -2-oxoazetidin-l-yl3-3-hydroxycrotonic acid diphenylniethyl ester, 2- [4- (p-toluenesulfonylthio) -3-phenylacetamido- 2-oxoazetidin-l-yl] -3-hydroxycrotonic acid diphenylraethyl ester, 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetaniido-2-oxoazet j.üin-1-yl j -3-hydroxycrotonic acid-mei: ethyl ester and 2-14- (benzoxazbl-2-yldithio) -3-phenoxyacαtaInido-2-oxoazetidin-1-yl] -S-hydroxycrotonic acid diphenylniethyl ester according to claim 74. 76. Compounds of Formula HH
-. -SY. \ Lf (II) 509836/0970 where Rt, R ₁ and R "have the meaning given under formula IA, R- stands for lower alkyl or a hydroxyl protective group and Y represents a leaving group" 77. 2- [4- (p-Toluenesulfonylthio) -S-phenoxyaeetainido-Z- oxoazetidin-1-yl] -3-trimethylsilyv.oxy-crotonic acid diphenylmethyl ester, 2- [4- (p-toluenesulfonylihio) -3-phenoxyacetamido-2- oxoazetidin-1-yl] r3-trimethylsiiyloxy-isocrotanoic acid diphenylmethyl ester, 2- [4- (p-Toluenesulronylthio) -3-phynoxyacetamJ.do-2-oxoazetidin-1-yl] -3-niethoxy-irotonic acid diphenylmethyl ester, 2- [4- (p-toluenesulfonylthio) -Z -phenoxyacctamido-2 -oxoazetidin-l-yl] -3-mefchoxy-isoerothonic acid diphenylmethy1-ester, 2- {4- (benzthiazol-2-yldithio) »3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy ^ f- erotonic acid diphenylmethyl ester, 2- [4-Ben? .thiazol-2-yldithio) ^ -phenoxyacetamido ^ -oxoazetidin-l-yl] -3-methoxy-isocrotonic acid diphenyliuethyl ester, 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetaalido-2-oxoazetidin-1-yl] -3-methox} '- crotonic acid-2,2,2-tricolorethylester, 2- [4- (benzthiazol-2-yldithio) ^ -phenoxyacetamido ^ -oxoazetidin-1 -yl] -3-methoxy-isocrotonic acid-2,2.2 "trichloroethyl ester, 2- [4- (p-toluenesulfonylthio) ^ -phenoxyacetamido ^ -oxoazetidinl-yl] -3-methoxy-crotonic acid-2,2,2 -trich lorätlTylester, 2- [4- (p-toluenesulfonylthio) -S-phenoxyacetamido ^ -oxoazctidiril-yl] -3-methoxy-isocrotonic acid-2,2,2-trichloroethyl ester, 2-14- (Benzthiazol-2-yldIthio) -S-phenoxyacetamido ^ -oxoazetidin-l-yl] -3-trimethylsilyloxy-crotonic acid diphenylmethyl ester, 2- [4- (benzthiazol-2-yldithio) -S-phenoxyacetamido ^ - oxoazetidin-l-ylj-S-trimethylsilyloxy-isocrotonic acid-diphenylinethyiester, 2- | 4- (BenzthiazoL-2-yIdifchio) -3-phenoxyacetamido-2-oxoazetidine-l "" vI] -3-nietho3-: y-croi: acid chloride, 2- [4- (Benzthiazoi-2-yldithio) -S-phenoxyaeetamido - ^ - oxoazetidin-l ~ yl3-3-methoxy-isocrotonic acid chloride, 2- [4- (p-Kitrobenzenesulfonylthio) -3-phenoxyacetaπ ^ ido » 2-oxoa2etidin-l-ylj 3-methoMy-crotonic acid-diphenylmethylesteri 2- [4- (p-nitrobenzenesulfonylthio) -3-phenoxyacetidin-l-yl] 3-methoxy-isocrotonic acid-diphenylmethylester, 2- [ 4- (p-Methoxybenzenesulfonylthio) -3 »phenoxyacetamido-2-oxoazetidin-1-yl] -3-raethoxy-crotonic acid-diphenylraethyl ester, 2- [4- (p-methoxybenzenesulfonylthio) ^ -phenoxyacetamido ^ -oxoazetidin-1-ylj -3-methoxy-isocrotonic acid-diphenyln: ethyl ester, 2- (4-benzenesulfonylthio-3-phenoxyacetamido ~ 2-oxoazetidine-1 -yl) -3-methoxycrotonic acid diphenylmethyl ester, 2- (4-benzoisulfonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-isocrotonic acid diphenylmethyl ester, 2- [4- (o-methoxybenzenesulfonylthio) - 3-pher.es:-:> Acetamido-2-oxoazetidin-l-yl] -3-methoxy-crotonic acid-diphenylmethyl ester, 2- [4- (o-methoxybenzenesulfonylthio) -3-phenoxyecetamido-2-oxoazetidin-1-ylJ -3-methoxy-isocrot: onic acid diphenylmethyl ester, 2- [4- (o-methoxybenzenesulfonylthio) -3- - wt - phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid, 2- [4- (o-methoxybenzenesulfonylthio) -3-phenoxyacetido-2-oxoazetidin-1-yl3-3-inethoxy-isocrotonic acid: .uchlcrid _} 2 - | 4- (p-Toluenesulfonylthio ^ -iD-a-tert.butyloxycarbonylamino-aphenylacetamido) -3-oxoazetidin-1-yi] -3-methoxy-crotonic acid diphenylmethyl ester, 2- [4- (p-toluenesulfonylthio) - S-phenj / lacetamido ^ -oxoazetidin-l-ylj-S-methoxy-crotonic acid-diphenylmethyl ester, 2- [4- (p-toluenesulfonylthio) -3-phenylacetamido-2-oxoazetidin-l-yl3-3-methoxy- Diphenylnethyl isccrotonic acid, methyl 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetaraido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid, methyl 2- [4- (benzthiazole -2-yldithio) -3-phenoxyacetamido-2-oxoa2: etidin-l-ylJ-S-methoxy-isocrotonic acid methyl ester, 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine-1- yl3-3-methoxy-crotonic acid methyl ester, the 2- [4- (p-toluene sulfonylithio) -3-phenoxyacetainido-2-oxoazetidin-1-yl3-3-methox3'-isocrotonic acid methyl ester, 2- {4 - (Benzox azol-2-yldithio) -3-phenoxyacetarnido-2-oxoazetidin-1-yl 3 -S-methoxy-crotonic acid-diphenylmeth} '! - ester, the 2- [4- (benzoxazol-2-yldithio) -3- phenoxyacetaniido-2-oxoazetidin-l-yl 3-S-methoxy-isocrotonic acid diphenylmethyl ester and the isomer mixtures thereof, consisting of crotonic and the corresponding isocrotonic acid derivatives, according to claim 76. 509836/0 9 70