NO750625L - - Google Patents

Description

Process for the preparation of enol-

derivatives.

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

a A where R-, denotes hydrogen or an amino-protecting group R, , and R^ b denotes hydrogen or an acyl group Ac, or R^ a and R-^3 together form a divalent amino-protecting group, Rg denotes hydroxy or a residue Rg^ which together with the carbonyl group -Ct^O)- constitutes a protected carboxyl group, and R^ denotes hydrogen, lower alkyl or a hydroxy protecting group, as well as 1-oxides of 3~cephem compounds of formula IA and the corresponding 2-cephem compounds of formula

where R^ a , R^ b, Rg and R^ have the aforementioned meanings, as well as salts of

such compounds with salt-forming groups.

The enol derivatives according to the invention are ethers of 3-cephem-3-ol and 2-cephem-3-ol compounds, respectively.

In 2-cephem compounds with compounds of formula IB which contain the double bond in the 2,3-position, the optionally protected carboxyl group of formula -C^OJ-Rg preferably has the α-configuration.

An amino-protecting group R^ is a group that can be replaced by hydrogen, primarily an acyl group Ac, further a triarylmethyl group, especially a trityl group, as well as an organic silyl group or an organic stannyl group. A group Ac which can also denote the radical R^r is formed primarily by the acyl residue of an organic carboxylic acid with preferably up to 18 C atoms, the acyl residue of a substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic- aliphatic carbonic acid (incl. formic acid), as well as the acyl residue of a carbonic acid half-derivative.

A divalent amino protecting group formed by the residues R^<a>and R^ together is constituted in particular by the divalent acyl residue of an organic dicarboxylic acid, preferably with up to 18 C atoms, primarily the diacyl residue of an aliphatic or aromatic dicarboxylic acid, further the acyl residue of an a -aminoacetic acid which is preferably substituted in the ct position and e.g. contains an aromatic or heterocyclic residue, where the amino group is connected to the nitrogen atom via a preferably substituted methylene residue, e.g. containing two lower alkyl groups such as methyl groups. The residues R-^ a and R^ b can together also form an organic, e.g. an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic ylidene residue, preferably with up to 18-C atoms.

A protected carboxyl group of the formula -C(=O)-Rg^ consists primarily of an esterified carboxyl group, but can also be designated a usually mixed anhydride group or an optionally substituted carbamoyl or hydrazinocarbonyl group.

The group Rg can thus be a hydroxyl group which

is substituted with an organic residue, which preferably contains up to 18 C atoms and which together with the -C(=0) group forms an esterified carboxyl group. Such organic residues are e.g. aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or

araliphatic residues, especially optionally substituted hydrocarbon residues of this type, as well as heterocyclic or heterocyclic-* aliphatic residues.

The group Rg can also denote an organic silyloxy acid residue, as well as a hydroxyl group which is etherified with an organometallic residue, e.g. a corresponding organic stannyloxy group, especially silyloxy group which is substituted with 1 to 3> optionally substituted hydrocarbon residues. preferably containing up to 18 C atoms, for example aliphatic hydrocarbon residues, and optionally substituted with halogen, such as chlorine.

A residue Rg^ which together with the -C^Q) group forms a

primarily mixed anhydride group is e.g. halogen, such as chlorine or an acyloxy acid residue, where acyl denotes the corresponding residue of an organic carboxylic acid, preferably with up to 18 C atoms,

like for example. an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic carboxylic acid or a carbonic acid half-derivative such as a carbonic half-ester.

A residue Rg A which together with one -C(=0) group forms a carbamoyl group is an optionally substituted amino group, where the substituents constitute optionally substituted, monovalent or divalent hydrocarbon residues, preferably with up to 18 C atoms,

like for example. optionally substituted, monovalent or divalent, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residues with up to 18 C atoms, further corresponding heterocyclic or heterocyclic-aliphatic residues with up to 18 C atoms and/or functional groups which are optionally functionally converted, especially free hydroxyl groups, further etherified or esterified hydroxyl groups, where the etherifying or esterifying residues e.g. has previously mentioned meanings and preferably contains up to 18 C atoms, as well as acyl residues, particularly of organic carboxylic acids and of carbonic acid semi-derivatives, preferably with up to 18 C atoms.

In a substituted hydrazinocarbonyl group of formula

-C(=0)-Rg<*>one or both nitrogen atoms may be substituted,

where the substituents primarily denote optionally substituted, monovalent or divalent hydrocarbon residues, preferably with up to 18 C atoms, such as optionally substituted, monovalent or divalent, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

aromatic or araliphatic hydrocarbon residues with up to 18 C atoms, further corresponding heterocyclic or heterocyclic-aliphatic residues with up to 18 C atoms and/or functional groups such as acyl residues, especially of organic carboxylic acids or of carbonic acid semi-derivatives and preferably with up to 18 C atoms.

A lower alkyl group fU has up to 7 and preferably up to 4 carbon atoms and constitutes especially methyl.

A hydroxy protecting group R^ is formed, e.g. of an easily cleavable 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon residue, an easily cleavable substituted silyl or stannyl group, or an easily cleavable, optionally substituted α-phenyl lower alkyl-, e.g. optionally substituted benzyl or diphenylmethyl group.

The general terms that have been used previously and therefore have the following particular meanings: An aliphatic residue, including an aliphatic residue of a corresponding organic carboxylic acid, as well as a corresponding ylidene residue, is an optionally substituted, monovalent or divalent aliphatic hydrocarbon residue, especially lower alkyl or lower alkenyl or lower alkynyl, further the lower alkylidene, containing up to 7" and preferably up to 4 C atoms. Such residues may optionally be substituted with functional groups, such as e.g. free or etherified or esterified hydroxy or mercaptic groups such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkyloxy, lower alkylthio or optionally substituted phenylthio, phenyllower alkylthio, heterocyclylthio or heterocyclylloweralkylthio, eveneutl substituted lower alkyloxycarbonyloxy or lower alkanoyloxy or with halogen and further with oxo, nitro , optionally substituted amino, e.g. lower alkylamino, lower alkylamino, lower alkyleneamino, - oxaloalkyleneamino or azaloweralkylenamino, and acylamino such as lower alkanoylamino, lower alkoxycarbonylamino, halolower alkyloxycarbonylamino, optionally substituted phenyllya alkoxycarbonylamino, optionally substituted carbamoylamino, ureidocarbonylamino or guanidinocarbonylamino, further with eveneutlt salt formed, e.g. alkali metal salt-formed sulfamino, azido, acyl, such as lower alkanoyl or benzoyl, optionally functionally converted carboxyl, for example carboxyl in salt form, esterified carboxyl, such as lower carboxycarbonyl, optionally substituted carbamoyl, such as N-lower alkyl or N,N-dilower alkylcarbamoyl, further optionally substituted ureido -carbonyl or guanidinocarbonyl or cyan, even functionally converted silpho, such as sulphamoyl or sulpho in salt form, or with optionally O-mono- or 0,0-disubstituted phosphono, where the substituents e.g. can denote an even substituted lower alkyl, phenyl or phenyl lower alkyl, and where O-unsubstituted or O-monosubstituted phosphono can also be present in salt form, such as e.g. in alkali metal salt form, and where said aliphatic residues can be mono-, di- or poly-substituted with one or more of the above substituents.

A divalent aliphatic residue, including the corresponding residue of a divalent aliphatic carboxylic acid is e.g. the lower alkylene or the lower alkenylene, which may be mono- or di- or polysubstituted, e.g. as mentioned in the paragraph above in connection with aliphatic residues, or may be interrupted by heteroatoms, such as oxygen, nitrogen or sulphur.

A cycloaliphatic or cycloaliphatic-aliphatic residue, including a cycloaliphatic or cycloaliphatic-aliphatic residue in a corresponding organic carboxylic acid or a corresponding cycloaliphatic or cycloaliphatic-aliphatic ylidene residue is an optionally substituted, mono- or divalent cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon residue, such as . mono-bi- or polycyclic cycloalkyl or cycloalkenyl, further cycloalkylidene, respectively cycloalkyl- or cycloalkenyl-lower alkyl or -lower alkenyl, further cycloalkyl-lower alkylidene or cycloalkenyl-lower alkylidene, where cycloalkyl or cycloalkylidene e.g. have up to 12, for example 3*8 and especially preferably 3-6 ring C atoms, while the cycloalkenyl groups have up to 12, for example 3-8°S especially 5-8 and preferably 5 or 6 ring C atoms, as well as 1 to 2 double bonds and the aliphatic part of a cycloaliphatic-aliphatic residue, e.g. has up to 7, preferably up to 4 C atoms. The above cycloaliphatic or cycloaliphatic-aliphatic residues can optionally be mono-, di- or polysubstituted with functional groups, e.g. with optionally substituted aliphatic hydrocarbon residues of the type previously mentioned, e.g. with optionally substituted lower alkyl groups or as for the aforementioned aliphatic hydrocarbon residues.

An aromatic residue, including aromatic residues of corresponding carboxylic acids, is formed from optionally substituted aromatic hydrocarbon residues such as e.g. a mono-, bi- or polycyclic aromatic hydrocaftone residue, especially phenyl, further biphenylyl or naphthyl, which may optionally be mono-, di- or polysubstituted for the aforementioned aliphatic and cycloaliphatic carbon residues.

A divalent aromatic rst, e.g. an aromatic carboxylic acid is primarily a 1,2-arylene, especially 1,2-phenylene residue, which may be mono-, di- or polysubstituted, e.g. such as the above-mentioned aliphatic and cycloaliphatic hydrocarbon residues.

Araliphatic residues, including araliphatic residues of corresponding carboxylic acids, further araliphatic ylidene residues, are e.g. optionally substituted araliphatic hydrocarbon residues such as e.g. an optionally substituted aliphatic hydrocarbon residue which in turn can be substituted with up to three, optionally substituted mono-, bi- or polycyclic, aromatic hydrocarbon residues, and forms primarily phenyl-lower alkyl or phenyl-lower alkylenyl, as well as phenyl-lower alkylenyl, further the phenyl lower alkylidene, where such residues e.g. contains 1-3 phenyl groups and possibly mono-di- or poly-substituted, e.g. such as the previously mentioned aliphatic or cycloaliphatic residues, in the aromatic and/or aliphatic part.

Heterocyclic groups, including such groups in heterocyclic-aliphatic residues and including heterocyclic or heterocyclic-aliphatic groups in corresponding carboxylic acids, are particularly monocyclic as well as bicyclic or polycyclic aza-, thia-, oxa-, thiaza-, thiadiaza-, oxaza-, diaza-, triaza- or tetraza-cyclic residues of an aromatic character, further corresponding fully or partially saturated heterocyclic residues of this type, where such residues may optionally be mono-, di- or polysubstituted, e.g. such as the aforementioned cycloaliphatic residues. The aliphatic part in heterocyclic-aliphatic residues has e.g. meaning as in the corresponding cycloaliphatic-aliphatic or araliphatic residues.

The acyl residue of a carbonic acid half-derivative is preferably the acyl residue of a corresponding half-ester, where the organic residue in the ester group forms an optionally substituted, aliphatic, cycloaliphatic, aromatic or araliphatic hydrocafcon residue or a heterocyclic-aliphatic residue, primarily an acyl residue of a

lower alkyl half-esters of carbonic acid which may be substituted, e.g.

in the a- or p-position, as well as a lower alkenyl, cycloalkyl, phenyl or phenyl lower alkyl half-ester of carbonic acid, optionally substituted in the organic residue. Acyl residues of carbonic acid half-esters are further corresponding residues of lower alkyl half-esters of carbonic acid, where the lower alkyl part contains a heterocyclic group, such as e.g. one of the above-mentioned heterocyclic groups of an aromatic character, where both the lower alkyl residue and the heterocyclic group may optionally be substituted. The carbonic acid half-derivative's acyl residue can also be an optionally N-substituted carbamoyl group such as, for example an optionally N-halogenated K-lower alkylcarbamoyl group.

Etherated hydroxyl groups are primarily optionally etherified lower alkyloxy, where the substituents in particular denote free or functionally converted, for example etherified or esterified hydroxyl groups, especially lower alkyloxy or halogen, further lower alkenyloxy, cycloalkyloxy or optionally substituted phenyloxy, as well as heterocyclyloxy or heterocyclylHavalkoxy, especially optionally substituted phenylialkoxy.

An optionally substituted amino group is e.g. amino, lower alkylamino, ail-lower alkylamino, lower alkyleneamino, oxalo-lower alkylene-amino, thia-lower alkyleneamino, aza-lower alkyleneamino, hydroxyamino, lower-alkylamino, lower-alkanoyloxyamino, lower-alkylcarbonylamino or lower-alkanoylamino.

An optionally substituted hydrazino group is e.g. hydrazino-, 2-lower alkylhydrazino, 2,2-dilower alkylhydrazino, 2-lower alkoxycarbonylhydrazino or 2-lower alkanoylhydrazino.

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

The lower alkylene is e.g. 1,2-ethylene, 1,2- or 1,3-propylene, 1,4-butylene, 1,5-pentylene or 1,6-hexylene, while the lower alkenylene group e.g. is 1,2-ethenylene or 2-buten-1,4-ylene. The lower alkyl interrupted by heteroatoms is e.g. the oxaloalkylene such as 3-pxa-1,5-pentylene, the thialower alkylene such as 3-thia-1,5-pentylene or the azalower alkylene, such as 3-lower alkyl«3-aza-1,5-pentylene, for example 3-methyl-3~az® -1,5-pentylene.

Cycloalkyl groups are formed, e.g. of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and of adamantyl, cycloalkenyl e.g. cyclopropenyl, 1-, 2- or 3" cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 3-cycloheptenyl or 1,4-cyclohexadienyl, and the cycloalkylidene is, for example, cyclopentylidene or cyclohexylidene. Cycloalkyl-lower alkyl or -lower alkenyl is eg cyclopropyl-, cyclopentyl-, cyclohexyl- or cycloheptyl-methyl, -1,1- or -1,2-ethyl, -1,1-, -1,2- or -1,3~Propyl»- vinyl or -allyl, and cycloalkenylloweralkyl or -loweralkenyl is, 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 The cycloalkyl-lower alkylidene is, for example, 3-cyclohexenylmethylene.

Waftyl et e.g. 1- or 2-naphthyl, and biphenylyl are e.g. 4-biphenylyl.

Phenyl-lower alkyl or phenyl-lower alkenyl are e.g. benzyl, 1- or 2-phenylethyl, 1-, 2- or 3~phenylpropyl»diphenylmethyl, trityl, styryl or cinnamyl, naphthyl-lower alkyl is e.g. 1- or 2-naphthylmethyl and phenylavalkylidene are e.g. the benzylidene.

Heterocyclic residues are primarily substituted heterocyclic residues of an aromatic character, e.g. corresponding monocyclic, monoaza-, monothia- or monooxacyclic residues, such as pyrryl, e.g. 2-pyrryl or 3-pyrryl»pyridyl as 2-, 3-or 4-pyridyl, further pyridinium, thienyl, as 2- or 3"-thienyl or furyl, as 2-furyl, bicyclic monoaza-, monooxa- or monothiacyclic radicals , such as indolyl, for example 2- or 3~indolyl, quinolinyl, such as 2- or 4-equinolinyl, isoquinolinyl such as 1-isoquinolinyl, benzofuranyl such as 2- or 3"D®nzofuranyi, or benzothienyl, such as 2- or 3-beazothienyl, monocyclic diaza-*triaza-, tetraza-, oxaza-, thiaza- or thiadiazacyclic residues such as imidazolyl, of the type 2-imidaolyl, pyrimidinyl such as 2-or 4-pyrimidinyl, triazolyl such as 1,2,4-triazol-3-yl, tetrazolyl as 1- or 5-tetrazolyl, oxazolyl as 2-oxazolyl, isoxazolyl as 3- or 4-isoxazolyl, thiazolyl as 2-thiazolyl, isothiazolyl, as 3- or 4-isothiazolyl or 1,2,4- or 1,3 ,4-thiadiazolyl, e.g. 1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl, or bicyclic diaza-, oxaza- or thiazacyclic residues such as benzimidazolyl of the type 2-benzimidazolyl, benzoxazolyl, such as 2-benz- oxazolyl or benzthiazolyl such as 2-benzthiazolyl. Corresponding fully or partially melted residues are e.g. tetrahydrothienyl, such as 2-tetrahydrothienyl, tetrahydrofuryl such as 2-tetrahydrofuryl or piperidyl such as 2- or 4-piperidyl, Heterocyclic-aliphatic residues are lower alkyl or lower alkenyl containing heterocyclic groups and especially those mentioned. Said heterocyclyl residues can e.g. be substituted with functional groups such as e.g. optionally substituted aliphatic or aromatic hydrocarbon residues and especially lower alkyl such as methyl or with halogen such as chlorine, substituted phenyl, such as phenyl itself or 4-chlorophenyl, or with aliphatic hydrocarbon residues.

Lower carboxy groups are used e.g. of methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy or tert-£entyloxy. These groups can be substituted e.g. as in halo-lavalkoxy, especially 2-halo-lavalkoxy such as 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 are cf. e.g. cyclo-pentyloxy, cyclohexyloxy or adamentyloxy, phenyl-lavalkoxy such as benzyloxy, 1- or 2-phenylethoxy, diphenylmethoxy or 4,4<*->dimethoxy-diphenylmethoxy, or heterocyclyloxy or hetero-ecyllavalkoxy such as pyridyllavalkoxy such as 2-pyridylmethoxy, furyl-lavalkoxy such as furfuryloxy or thienyl-lavalkoxy such as 2-tenyloxy.

Lower alkylthio constitutes e.g. of methylthio, ethylthio or n-butylthio, lower alkenylthio is e.g. allylthio and phenyllower alkylthio are e.g. benzylthio, while mercapto groups etherified with heterocyclyl residues or heterocyclylaliphatic residues can in particular be pyridylthio such as 4-pyridylthio, imidazolylthio, thiazolylthio such as 2-thiazolylthio, 1,2,4- or 1,3,4-thiadiazolylthio such as 1,2,4-thia- dlazol-3-ylthio or 1,3,4-thiadiazol-2-ylthio or tetrazolylthio such as 1-methyl-5-tetrazolylthio.

Esterified hydroxyl groups are primarily halogen such as fluorine, chlorine, bromine or iodine, as well as lower alkoxycarbonyloxy such as methoxycarbonyloxy, ethoxycarbonyloxy or tert-butyloxycarbonyloxy, 2-halolower alkyloxycarbonyloxy such as 2,2,2-trichloro-

ethoxycarbonyloxy, 2-bromomethoxycarbonyloxy or 2-iodoethoxycarbonyloxy or arylcarbonylmethoxycarbonyloxy, such as phenacyloxycarbonyloxy.

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

W-lower alkyl or N,N-dilower alkylcarbamoyl is e.g.

H-methylcarbamoyl, H-ethylcarbamoyl, N,N-dimethylcarbamoyl or N,N-diethylcarbamoyl, while N-lower alkylsulfamoyl e.g. is H-methyl-sulfamoyl or N,N-dimethylsulfamoyl.

Carboxyl or sulfo in alkali metal salt form is

e.g. carboxyl or sulfo in sodium or potassium salt form.

Lower alkylamlino- or diloweralkylamino are e.g. methylamino, ethylaraino, dimethylamino or diethylamino, lower alkyleneamino is e.g. pyrrolidino or piperidino, oxaloalkyleneamino is e.g. morphollno, thialowalkyleneamino such as thiomorpholino and azalowalkylenamino such as piperazino or 4"-methylpiperazino. Acylamino in particular stands for carbamylamino, lower alkylcarbamoylamino, such as methylcarbamoylamino, ureidocarbonylamino, guanidinocarbonylamino, lower alkoxycarbonylamino such as methoxycarbonylamino} ethoxycarbonylamino or tert-butyloxycarbonylamino, halogenolower carboxycarbonylamino such as 2,2, 2-trichloroethoxycarbonylamino, phenylalkanoylamino such as 4-methoxybenzyloxycarbonylamino, alkanoylamino such as acetylamino or propionylamino, further phthalimido or sulfamino which is in salt form, for example as sodium or ammonium salt.

Lowerealkanoyl can e.g. be formyl, acetyl, orpionyl or pivaloyl.

O-lower alkylphosphono is e.g. O-methyl- or O-ethyl-phosphono, 0,0T<->dilavalkyl-phosphono such as 0,0-dimethyl-phosphono or 0,0'-diethylphosphono, 0-phenyliavalkyl-phosphono, such as 0-benzyl-phosphono and O -laalkyl-O'-phenyl-laalkyl-phosphono as O-benzyl-O'-methyl-phosphono.

Lower alkenyloxycarbonyl is e.g. vinyloxycarbonyl, while cycloalkyloxycarbonyl and phenylaloxycarbonyl, e.g. can be adamantyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or α-4-biphenyl-α-methylethoxycarbonyl. Lower carboxycarbonyl where the lower alkyl group e.g. contains a monocyclic, monoaza-, monooxa- or monothia-cyclic group is e.g. furyylalkyloxycarbonyl as furfuryloxycarbonyl or thienylalkyloxycarbonyl as 2-thenyloxycarbonyl.

2-lower alkyl and 2,2-dilower alkylhydrazino are e.g. 2-methylhydrazino or 2,2-dimethylhydrazino, 2-lower carboxycarbonylhydrazino such as 2-methoxycarbonylhydrazino, 2-ethoxycarbonylhydrazino or 2-tert-butyloxycarbonylhydrazino and loweralkanoylhydrazino such as 2-afacetylhydrazino.

An acyl group Ac denotes in particular an acyl residue in an organic carboxylic acid occurring in natural or biosynthetic, semi-synthetic, or fully synthetic, preferably pharmacologically active N-acyl derivatives of a 6-amino-penam-4-carboxylic acid or 7-amino-3-cephem -4-carbonic acid compound, preferably containing up to 18 C atoms, or an easily cleavable acyl residue, especially a carbonic acid half-derivative.

An acyl residue Ac occurring in pharmacologically active N-acyl derivatives of 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem-4-carboxylic acid compounds forms above all a group with the formula

where n is equal to 0 and R T denotes hydrogen or an optionally substituted cycloaliphatic or aromatic hydrocarbon residue or an optionally substituted heterocyclic residue, preferably of an aromatic character, a functionally converted such as e.g. esterified or etherified hydroxy or mercaptic group, or an optionally substituted amino group, or where n is equal to 1, R* denotes hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residue, or an optionally substituted heterocyclic or heterocyclic-aliphatic residue, where the heterocyclic residue preferably has

aromatic character and/or contains a quaternary nitrogen atom, an optionally functionally converted and preferably etherified or esterified hydroxy or mercapto group, an optionally functionally converted carboxyl group, an acyl group, an optionally substituted amino group or an azido group, and each of the residues R<**> and R*** denotes hydrogen or where n is equal to 1, R<*> denotes a optionally

denotes a substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residue or an optionally substituted heterocyclic or heterocyclic-aliphatic residue, where the heterocyclic residue preferably has an aromatic character, R II denotes an optionally functionally converted and especially esterified or etherified hydroxyl or mercapto group, for example a halogen atom, an optionally substituted amino group, an optionally functionally converted carboxyl or sulfo group, an optionally O-mono- or 0,0'-disubstituted phosphono group or an azido group, and R<*>^<*> denotes hydrogen or where n equals 1,

each of the groups R I and R II denotes a functionally converted and preferably etherified or esterified hydroxy group or an optionally functionally converted carboxyl group, and R III denotes hydrogen, or where n is equal to 1, R denotes hydrogen or an optionally substituted aliphatic, cycloaliphatic , cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residue and R<1*>and R^* together form an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon residue which is connected to the carbon atom through a double bond, or where n is equal to 1, and denotes an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residue or an optionally substituted heterocyclic or heterocyclic-aliphatic residue, where the heterocyclic residues preferably have an aromatic character, R** denotes an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic- cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residue and R*** denotes hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residue.

In the above-mentioned acyl groups of formula A, n can be 0

and R<*>form hydrogen or a cycloalkyl group with 5-7 ring C atoms which is optionally substituted in the 1-position with optionally protected amino, acylamino, where acyl primarily stands for the acyl residue of a carbonic acid half-ester such as a lower alkoxycarbonyl-, 2-halogeno-alkoxycarbonyl or phenyl-alkoxycarbonyl residue or gets an optionally salted sulphoamino group, e.g. in alkali metal salt form, a phenyl, naphthyl or tetrahydronaphthyl group which is optionally substituted with preferably hydroxy, lower alkoxy

such as methoxy, acyloxy, where acyl primarily stands for the acyl residue of a carbonic acid half-ester such as a lower alkoxycarbonyl, 2-halolower alkoxycarbonyl or phenyllower alkoxycarbonyl residue, and/or halogen as chlorine, a heterocyclic group such as e.g. a 4-isoxazolyl group, optionally substituted with lower alkyl as

ethyl and/or phenyl, which in turn can be substituents such as halogen, of the chlorine type, or an N-substituted amino group which is preferably substituted with a lower alkyl residue containing a halogen group such as chlorine or n is equal to 1, denotes a lower alkyl group which

is optionally substituted with halogen as chlorine or with phenyloxy which in turn may be substituted with hydroxyl, acyloxy, where acyl has the above meanings, and/or halogen as chlorine, or where the lower alkyl group is protected with amino and/or substituted with carboxyl, e.g. . a 3-amino-3-carboxypropyl residue with an optionally protected amino and/or carboxyl group, e.g. silylated, (lower alkylsilylated, for example trimethylsilylated) amino or acylamino, for example lower alkanoylamino, haloalkanoylamino or phthaloylamino groups and/or silylated (trilower alkylsilylated such as trimethylsilylated) or esterified carboxyl groups, e.g. esterified with lower alkyl such as 2-halo lower alkyl or phenyl lower alkyl such as diphenylmethyl, further a lower alkenyl group, a phenyl group optionally substituted as above with acylated hyroxyl and/or halogen, such as chlorine, further with possibly protected (acylated as above) amino lower alkyl such as aminomethyl or phenyloxy which contains any acylated hydroxyl and/or halogen such as chlorine, further a substituted pyridyl-, e.g. 4-pyridyl-, pyridinium-, e.g. 4-pyridinium, thienyl as 2-thienyl-, furyl as 2-furyl-, imidazolyl as 1-imidazolyl- or tetrazolyl as 1-tetrazolyl group, e.g. substituted with lower alkyl such as methyl or optionally protected as indicated above with acylated amino or aminomethyl, an optionally substituted lower alkoxy group such as e.g. methoxy, an optionally substituted phenyloxy group containing optionally protected (for example acylated as above) hydroxy and/or halogen such as chlorine, a lower alkylthio- such as n-butylthio- or lower alkenylthio- such as allylthio group, a phenylthio-, pyridylthio- such as 4-pyridylthio- , 2-imidazolylthio-, 1,2,4-triazol-3-ylthio-, 1,3,4-triazol-2-ylthio-, 1,2,4-thiadiazol-3-ylthio-, as

5-methyl-1,2,4-thiadiazol-3-ylthio-, 1,3,4-thiadiazol-2-ylthio- as methyl-1,3,4-thiadiazol-2-ylthio or 5-tetrazolylthio, as 1 -methyl-5-tetrazolylthio group which is optionally substituted with lower alkyl such as methyl, a halogen atom such as chlorine or bromine, an optionally functionally converted carboxyl group such as lower alkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl, cyan or N-substituted carbamoyl substituted with e.g. lower alkyl as

methyl or phenyl, an optionally substituted lower alkanoyl such as acetyl or propionyl or benzoyl or an azido group,

and R<**><p>g R**'1* denotes hydrogen, if n is equal to 1, R* denotes lower alkyl or a phenyl-, furyl- or 2-furyl-, thienyl- or 2- or 3' thienyl- or isothiazolyl such as e.g. 4-isothiazolyl group, or substituted with hydroxyl which is optionally acylated as indicated above or substituted with halogen such as chlorine, further

II

denotes a 1,4-cyclohexadienyl group, R denotes optionally protected or substituted amino, such as e.g. amio, acylamino of the type lower alkoxycarbonylamino, 2-halolower alkyloxycarbonylamino or optionally substituted phenyl lower alkyloxycarbonylamino, optionally containing lower alkoxy such as methoxy or nitro, for example tert-butyloxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, 4-methoxybenzyloxycarbonylamino or diphenyl-1-methyloxycarbonylamino, arylsulfonylamino such as 4-methylphenyl- sulfonylamino, tritylamino, arylthioamino such as nitrophenylthioamino of the type 2-nitrophenylthioamino or tritylthioamino or optionally substituted 2-propylideneamino optionally containing lower alkoxycarbonyl such as ethoxycarbonyl or lower alkanoyl such as acetyl, for example l-ethoxycarbonyl-2-propylideneamino, or optionally substituted carbamoylamino, such as guanidinocarbonylamino or a sulfoamino group such as optionally present in salt form as an alkali metal salt, an azido group, a carboxyl group which is optionally salted and e.g. available in alkali metal salt form or in protected form such as e.g. esterified form such as lower alkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl or also phenyloxycarbonyl, for example diphenylmethoxycarbonyl, a cyano group, a sulfo group, an optionally functionally converted hydroxyl group, where functionally converted hydroxyl can in particular be acyloxy such as formyloxy or lower methoxycarbonyloxy, 2-halogenoalkoxycarbonyloxy or possibly phenyl-low-

lower alkoxycarbonyloxy which is optionally substituted with e.g. lower alkyloxy such as methoxy or with nitro, for example tert-butyloxycarbonyloxy, 2,2,2-trichloroethoxycarbonyloxy, 4~methoxybenzyloxycarbonyloxy or diphenylmethoxycarbonyloxy or which constitute optionally substituted lower alkyloxy, such as methoxy or phenyloxy, further an 0-lower alkyl- or O,0' -dilavalkyip-phosphono group such as O-methyl-phosphono or 0,0<1->dimethylphosphono, or a halogen-

III

atom such as chlorine or bromine, and R denotes hydrogen, or n is

equal to 1, R I and R II both denote halogen such as bromine or lower alkoxycarbonyl such as methoxycarbonyl and R<**>'<*>" denotes hydrogen, or n

is equal to 1, R<*> denotes a phenyl-, furyl-, e.g. 2-furyl- or thienyl-such as 2- or 3~thienyl- or isothiazolyl- such as e.g. 4-isothiazolyl group which is optionally substituted with optionally acylated hydroxy, e.g. acylated as described above and/or halogen such as chlorine,

or a 1,4-cyclohexaaienyl group, R II denotes optionally protected aminomethyl and R<***> denotes hydrogen or n is equal to 1 and each of the groups R<1>, R** and R**1 denotes lower alkyl such as methyl.

Such acyl residues Ac are e.g. formyl, cyclopentylcarbonyl, α-aminocyclopentylcarbonyl or α-aminocyclohexylcarbonyl (with optionally substituted amino group, e.g. salt-formed sulfoaraino, or with an amino group which is substituted with a preferably easily cleavable acyl residue, e.g. which can be cleaved

by treatment with an acidic reagent such as trifluoroacetic acid or cleave reductively by treatment with a chemical reducing agent such as zinc in the presence of aqueous acetic acid or with catalytic hydrogen or also hydrolytics, or a residue that can be transferred to such an acyl residue, preferably to a suitable acyl residue of a carbonic acid half-esters such as tert-butyloxycarbonyl, 2-halogenated lower alkylcarbonyl such as 2,2,2-trichloroethyloxycarbonyl, 2-bromomethoxycarbonyl or 2-iodoethoxycarbonyl, arylcarbonylmethoxycarbonyl such as phenacyloxycarbonyl, optionally substituted phenyllower carboxycarbonyl, (containing e.g. lower alkyloxy such as methoxy or nitro ), for example 4-n-ethoxybenzyloxycarbonyl or diphenylmethoxycarbonyl or a carbonic acid amide such as carbamoyl or N-substituted, for example N-lower alkyl-substituted carbamoyl such as N-methylcarbamoyl, or substituted with trityl or with arylthio such as 2-nitrophenylthio, arylsulfonyl such as 4-methylphenylsulfonyl or 1-Lower Alkoxycarbonyl-2-Propylide n as 1-ethoxy-

carbonyl-2-propylidene), 2,6-dimethoxybenzoyl, 5>6»7»8-tetrahydronaphthoyl, 2-methoxy-1-naphthoyl, 2-ethoxy-1-naphthoyl, benzyloxycarbonyl, hexahydrobenzyloxycarbonyl, 5-methyl-3-phenyl -4-isoxazolylcarbonyl, 3-(2-chlorophenyl)-5-methyl-3-phenyl-4-isoxazolylcarbonyl, 3-(2-chlorophenyl)-5-methyl-4-isoxazolylcarbonyl, 3~ 12,6-dichlorophenyl )-5-methyl-4-isoxazolylcarbonyl, 2-chloroethylaminocarbonyl, acetyl, propionyl, butyryl, pivaloyl, hexanoyl, octanoyl, acrylyl, crotonoyl, 3-°utenoyl, 2-pentenoyl, methoxyacetyl, butylthioacetyl, allylthioacetyi, methylthioacetyl, chloroacetyl, bromoacetyl , dibromoacetyl, 3-chloropropionyl, 3-bromopropionyl, aminoethyl or 5-amino-5-carboxyvaleryl (with an amino group optionally substituted as indicated above, e.g. with a monoacyl or diacyl residue, e.g. .with an optionally halogenated lower alkanoyl residue such as acetyl or dichloroacetyl or

phthaloyl, and/or optionally functionally converted carboxyl group, e.g. in salt form such as sodium salt or in ester form such as lower alkyl, for example methyl or ethyl or aryl lower alkyl ester, for example diphenyl methyl ester form), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bis-methoxycarbonylacetyl, K-phenylcarbamoylacetyl, cyanoacetyl, a- cyanpropionyl, 2-cyano-3,3-dimethyl-acrylyl, phenylacetyl, a-bromophenylacetyl, a-azidophenylacetyl, 3-chlorophenylacetyl, 2- or 4-aminomethylphenylacetyl (with amino group optionally substituted as indicated above), phenacylcarbonyl, phenyloxyacetyl, 4-trifluoromethylphenyloxyacetyl, benzyloxyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxy-propionyl, a-phenyloxyphenylacetyl, a-methoxyphenylacetyl, a-ethoxy-phenylacetyl, a-methoxy-3»4-dichlorophenylacetyl, a-cyano-phenylacetyl, especially phenylglycyl , 4-kyd>oxyphenylglycyl, 3-chloro-4-hydroxy-phenylglycyl, 3,5-diyloro-4-hydroxyphenylglycyl, α-amino-α-(1-4-cyclohexadienyl)acetyl, α-amino-α-(1 -cyclohexenyl)acetyl, α-aminomethyl-α-phenylacetyl or α-hydroxyf enylacetyl, where an amino group found in these residues can optionally be substituted as previously indicated and/or an aliphatic and/or phenolically bound hydroxyl group optionally in analogy with the amino group, e.g. may be protected with a suitable acyl residue, in particular with formyl or an acyl residue of a carbonic acid half-ester), or α-0-methylphosphono-phenylacetyl or O-0-0-dimethylphosphono-phenylacetyl, further benzylthioacetyl, benzylthiopropionyl, α-carboxyphenylacetyl

(with carboxyl group which is optionally functionally converted as stated above), 3-phenylpropionyl, 3-(3-cyanophenyl)-propionyl, 4-(3-methoxyphenyl)-butyryl, 2-pyridylacetyl, 4-araino-pyridiniumacetyl (optionally with amino group substituted as described above), 2-thienylacetyl, 3~thienylacetyl»2-tetrahydrothienylacetyl, 2-furylacetyl, 1-imidazolylacetyl, 1-tetrazolylacetyl, aficarboxy*2-tlenylacetyl or α-carboxy-3-thienylacetyl (optionally with carboxyl group converted as described above), α-cyano-2-thienylacetyl, α-amino-α-(2-thienyl)-acetyl, α-amino-α-(2-furyl)-acetyl or α-amino-α-(4- isothiazolyl)-acetyl (optionally with amino group substituted as previously indicated), α-sulfophenylacetyl (optionally with sulfo group if formed functionally in the same way as described for the carboxyl group), 3~met;y1"'2-imidazolylthioacetyl, 1,2,4- triazol-3-ylthioacetyl, 1,3,4-triazol-2-yl-thioacetyl, 5-methyl-1,2,4-thiadiazol-2-ylthioacetyl, 5-methyl-1,3»4-thiadiazol-2- ylthioacetyl or 1-methyl-5-tetrazolylthioacetyl.

An easily cleavable acyl residue Ac, especially the acyl residue

to a carbonic acid half-ester, is constituted in particular by the acyl residue of a carbonic acid half-ester which can be split off by reduction, e.g. by treatment with a chemical reducing agent or by acid treatment with e.g. trifluoroacetic acid, such as a lower alkoxycarbonyl group which is preferably multi-branched on the carbon atom in the a-position to the oxy group and/or is aromatically substituted, or a methoxycarbonyl group which is substituted with arylcarbonyl or especially benzoyl or a lower alkoxycarbonyl residue which is substituted in the p-position with halogen atoms, e.g. tert-butyloxycarbonyl, tert-pentyloxycarbonyl, phenacyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or a residue transferable to the latter such as e.g. 2-Chloro- or 2-bromomethoxycarbonyl, further preferably polycyclic cycloalkoxycarbonyl such as adamantyloxycarbonyl, optionally substituted phenylalkalkoxycarbonyl, primarily a-phenylalkalkoxycarbonyl, where the a-position is preferably more substituted, for example diphenyIme oxycarbonyl or a-4-biphenylyl-a -methyl-ethyloxycarbonyl or furyl-alkoxycarbonyl, especially α-furyl-alkoxycarbonyl such as furfuryl-oxycarbonyl.

A divalent acyl group which is formed by both groups R^ Å and R^ B together is e.g. an acyl residue of a lower alkane or lower alkenedicarboxylic acid such as succinyl or an o-arylenedicarboxylic acid such as phthaloyl.

Oh B

Another divalent residue formed by the groups Å and B is e.g. a 1-oxo-3-aza-1,4-butylene residue which is mono- or bi-substituted in particular in the 2-position, optionally with substituted phenyl or thienyl, and in the 4-position optionally substituted with lower alkyl such as methyl, for example 4»4 -dimethyl-2-phenyl-1-oxo-3-aza-1,4-butylene.

An etherified hydroxy group Rg adds together with the carbonyl group a preferably easily cleavable esterified carboxyl group or one that can be converted into another functionally converted carboxyl group such as a carbamoyl or hydrazinocarbonyl group. Such a group Rg^ is e.g. lower alkyloxy, such as methoxy, ethoxy, n-propyloxy or isopropyloxy which, together with the carbonyl group, forms an esterified carboxyl group, which, particularly in 2-cephem compounds, can easily be transferred to a free carboxyl group or another functionally converted carboxyl group.

An etherified hydroxy group r/ which together with a -C(=€ ) group forms a particularly easily cleavable esterified carboxyl group is constituted, e.g. of 2-halogeno-alkoxy, where the halogen preferably has an atomic weight of over 19» Such a residue together with the -C(=0 )-group forms an esterified carboxyl group which can be easily split by treatment with chemical reducing agents in a neutral or weakly acidic environment, e.g. e.g. with zinc in the presence of aqueous acetic acid, or a group which can easily be converted into such an esterified carboxyl group, e.g. 2,2,2-trichloroethoxy or 2-iodoethoxy, further 2-chloroethoxy or 2-bromoethoxy, which can easily be transferred to such a group.

An etherified hydroxyl group Rg which, together with the -Cl^O) group forms an esterified carboxyl group which can be easily split by treatment with chemical reducing agents in a neutral or weakly acidic environment, e.g. with zinc in the presence of aqueous acetic acid or by treatment with a suitable nucleophilic reagent such as sodium thiophenolate, is an arylcarbonylmethoxy group, where aryl particularly stands for an optionally substituted phenyl group and preferably phenacyloxy.

The group Rg can also denote an arylmethoxy group where aryl in particular forms a monocyclic and preferably substituted aromatic hydrocarbon residue. A pointed residue together with the -0=0 group forms an esterified carboxyl group which can be easily split by irradiation, preferably by ultraviolet light in a neutral or weakly acidic environment. An aryl residue in such an arylmethoxy group is particularly lower methoxyphenyl, such as methoxyphenyl where the methoxy group is primarily in the 3-, 4- and/or 5-position, and/or preferably nitrophenyl (where the nitro group is preferably in the 2-position). Such residues are particularly low-alkoxy, e.g. methoxy- and/or nitro-benzyloxy, primarily 3* or 4-methoxybenzyloxy, 3,5-dimethoxybenzyloxy, 2-nitroBenzyloxy or 4,5-dimethoxy-2-nitro-benzyloxy.

An etherified hydroxyl group Rg^ can also form a residue which together with the -C(=Q) group constitutes an esterified carboxyl group which can be easily split in an acidic environment, e.g. by treatment with trifluoroacetic acid or formic acid. Such a residue is in particular a methoxy group where the methyl group is polysubstituted with an optionally substituted hydrocarbon residue, in particular aliphatic or aromatic hydrocarbon residues such as lower alkyl, for example methyl and/or phenyl, or monosubstituted with an electron-donating substituted carbocyclic aryl group and a heterocyclic group of an aromatic character containing oxygen or sulfur as a ring member, or denotes, in a polycycloaliphatic hydrocarbon residue, a ring member or constitutes a ring member in an oxa- or thiacycloaliphatic residue which is in the a-position to the oxygen atom or the sulfur atom.

Preferred polysubstituted methoxy groups of this type are tert-laalkyloxy such as tert-butyloxy or tert-pentyloxy, optionally substituted diphenylmethoxy such as phenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, further 2-(4-biphenylyl)-2-propyloxy, where a methoxy group contains such a substituted aryl group or a heterocyclic group, e.g. can be α-lavalkoxyphenyl-lavalkoxy, such as 4-netoxybenzyloxy or 3,4-dimethoxybenzyloxy, respectively furfuryloxy such as 2-furfuryloxy. A polycycloaliphatic hydrocarbon residue where the methyl group in the methoxy acid residue forms a preferably triple branched ring member is e.g. adamantyl such as 1-adamantyl, and one of the aforementioned oxa- or thiacycloaliphatic residues where methyl in the methoxy group occupies the a-position of the oxygen or sulfur atom, are e.g. 2-oxa- or 2-thialaalkylene-

or -lavalkenylene with 5*7 ring atoms, such as 2-tetrahydrofuryl,

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

The residue Rg may also denote an etherified hydroxy group which, together with the -C(=0) group, forms an esterified carboxyl group which can easily be cleaved hydrolytically, e.g. in a weakly basic or acidic environment. Such a residue is preferably an etherified hydroxyl group which together with the -G(aO) group forms an activated ester group, such as nitrophenyloxy of the type 4-nitrophenyloxy or 2,4-dinitrophenyloxy, nitrophenyHavaloxy such as 4-nitrobenzyloxy, hydroxy-lower alkyl benzyloxy such as 4-hydroxy<y->3t5~'tert-butyl-benzyloxy»polybalogen-phenyloxy as 2,4»6-trichlorophenyloxy or 2,3»4»5>6-pentachlorophenyl-oxy, further cyanomethoxy, as acylaminomethoxy, as phthalimino -methoxy or succinyliminomethoxy.

The group Rg* can also form an etherified hydroxy group which together with the carbonyl groups of the formula -C^O)- forms an esterified carboxyl group that can be split under hydrogenolytic conditions' and is e.g. α-Phenyllaalkyloxy, such as Benzyloxy, 4-phenylethoxy-benzyloxy or 4-nitrobenzyloxy, optionally substituted with loweralkyloxy or nitro.

The group Rg* can also form an etherified hydroxy group which together with the carbonyl group -C(**0)- forms an esterified carboxyl group that can be split under physiological conditions, primarily an acyloxymethoxy group, where acyl forms a residue of an organic carboxylic acid, particularly one of the said substituted lower alkane carboxylic acids, or where the acyloxymethyl group forms the remainder of a lactone. Thus, preferred hydroxyl groups are lower alkanoyloxy-methoxy,

such as acetyloxymethyloxy or pivaloyloxymethoxy, amino-lavalkanoyloxymethoxy, especially α-amlno-lavalkanoyloxymethoxy, such as jglycyloxymethoxy, L-valyloxymethoxy, L-leucyloxymethoxy and phthalidyloxy.

A silyloxy or stannyloxy group Rg contains substituents preferably optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon residues such as lower alkyl, halogen-lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl groups, or optionally converted functional groups such as etherified hydroxyl, for example lower alkoxy groups, or halogen atoms such as chlorine, and is formed primarily from tri-lower alkylsilyloxy such as trimethylsilyloxy, halo-lower alkyloxy-lower alkylsilyl such as chloro-methoxy-methyl-silyl or tri-lower alkylstannyloxy such as tri-n-butylstannyloxy.

An acyloxy acid residue Rg A which together with the -C^O) group forms a preferably hydrolytically cleavable mixed anhydride group is constituted, e.g. of the acyl residue of one of the mentioned organic carboxylic acids or carbonic acid half-derivatives and is e.g. lower alkanoyloxy which may be substituted preferably in the a-position with halogen such as fluorine or chlorine, examples are acetyloxy, pivalyloxy or trichloroacetyloxy, or lower alkyloxycarbonyloxy such as methoxycarbonyloxy or ethoxycarbonyloxy.

A residue Rg A which together with the -C(, aa0)» group forms an optionally substituted carbamoyl or hydrazinocarbonyl group is e.g. amino, lower alkylamino or dilower alkylamino such as methylamino, ethylamino, .iimethylamino or diethylamino, lower alkyleneamino such as pyrrolydino or piperidino, oxaloalkyleneamino such as morpholino, hyroxyamino, hy.razino, 2-lower alkylhydrazino or 2,2- iloweralkylhydrazino such as 2-methylhydrazino or 2,2-aimethyl -hydrazino.

A lower alkyl group R with up to 7 and preferably up to 4 C atoms is preferably methyl, or ethyl, h-propyl, hexyl or heptyl.

Deh2-oxa- or 2-thia-aliphatic or - cycloaliphatic hydrocarbon residue R^ is primarily a 1-lower alkoxy-1-lower alkyl or 1-lower alkylthio-1-lower alkyl residue such as 1-methoxy-1-ethyl, 1-ethoxy -1-ethyl, 1-methylthio-1-ethyl or 1-ethylthio-1-ethyl, or a 2-oxa- or 2-thia-lower alkylene or -lower Ikenylene radical with 5~7 ring atoms such as 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-viihydro-2-pyranol or a corresponding analogous sulfur compound.

Easily cleavable silyl or stannyl groups R^ are preferably substituted with optionally substituted, aliphatic, cycloaliphatic, aromatic or araliphatic hyarocarbon residues, such as lower alkyl, halogen-lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl groups, or optionally converted functional groups such as etherified hydroxy -, as lower alkoxy groups or with halogen atoms such as chlorine. Representatives of such groups are primarily tri-lower alkylsilyl such as trimethylsilyl, halo-lower carboxy-lower alkylsilyl such as chloromethoxymethylsilyl or tri-lower alkylstannyl such as tri-n-butylstannyl.

Other easily removable hydroxy protecting groups

Calmness is e.g. α-phenyl-lower alkyl such as benzyl and diphenylmethyl, where the substituents on the phenyl ring e.g. can be esterified or etherified hydroxy such as halogen, of the fluorine, chlorine or bromine type, or lower hydroxy such as methoxy.

Salts are particularly salts of compounds with the formula

M and IB which contain an acidic group such as e.g. a carboxy, sulfo or phosphono group, primarily metal or ammonium salts such as alkali metal and alkaline earth metal salts, such as sodium, potassium, magnesium or calcium salts and ammonium salts with ammonia or suitable organic amines and among these in particular aliphatic, cycloaliphatic, cycloaliphatic - aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines as well as heterocyclic bases that form salts,

such as lower alkylamines of the triethylamine type, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine, basic aliphatic esters of carboxylic acids such as 4-aminobenzoic acid-2-diethylaminoethyl ester, lower alkylene amines such as 1-ethylpiperidine, cycloalkylamines such as bicyclohexylamine, or benzylamines such as N.BT-dibenzylethylamine, further pyriaine-type bases such as pyridine, collidine or quinoline. Compounds of formula IA and IB containing a basic group can also

form acid addition salts e.g. with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid or with suitable organic carbonic or sulphonic acids such as trifluoroacetic acid or p-toluenesulphonic acid. Compounds of formula IA and IB with an acidic and a basic group

can also exist as an inire salt, i.e. as a zwitterion. 1-Oxyers of compounds of formula IA with salt-forming groups can also form salts as described above.

Compounds according to the present invention exhibit valuable pharmacological properties or can be used as intermediates for the production of such substances. Compounds meci formula IA, where e.g. R-j<3>denotes an acyl residue Ac occurring in pharmacologically active N-acyl derivatives of 6^-amino-penam-3-carboxylic acid or 7p-amino-3-cephem-4-carboxylic acid derivatives, and R^<k>denotes hydrogen, or where R^ and b together form a 1-oxo3-aza-1,4-butylene residue which is preferably substituted in the 2-position with e.g. an aromatic or heterocyclic residue, and in the 4-position with e.g. 2-lower alkyl groups such as methyl, Rg denotes hydroxyl or an etherified hydroxy group Rg<*> which, together with the carbonyl group, forms an esterified carboxyl group that is easily cleavable under physiological conditions, and R^ denotes lower alkyl, where any functional groups in the acyl residue %a » as amino, carboxy, hydroxy and/or sulfo, usually present in free form, or salts of these compounds with salt-forming groups, are effective by parenteral and/or oral administration against micro-organisms such as gram-positive bacteria of the type Staphylococcus aureus, Streptococcus pyogenes and Diplococcus pneumøoniae, (e.g. in mice at doses of about 0.001 to about 0.02 g/kg s.c. or p.o.) and gram-negative bacteria such as Escherichia coli, Salmonella typhimurium, Shigella flexneri, Klebsiella pneumoniae, Enterobacter cloacae , Proteus vulgaris, Proteus rettgeri and Proteus mirabilis (e.g. in mice in doses of approx. 0.001 to approx. 0.15 g/kg s.c. or p.o.) and especially against penicillin-resistant bacteria, under at the same time low toxicity. These new compounds can therefore be used as antibiotic pre- . preparations for the treatment of similar infections.

Compounds of formula IB and 1-oxides of compounds of formula IA where R^<a>, R^, Rg and R^ have the meaning indicated in connection with formula IA, or compounds of formula IA, where RQ has the previously indicated meaning, the residues R-,a and

b <.3a

R^ stands for hydrogen or R-^ denotes an amino-protecting group which is different from an acyl residue occurring in pharmacologically active K-acyl derivatives of 6f3-amino-penam-3-carboxylic acid- or 7P-amino-3-cef em-4 -carboxylic acid compounds and R^ denotes halogen, or Ri<a>and R^ together form a divalent amino protecting group which is different from a 1-oxo-3-aza-1,4-butylene residue which is substituted e.g. by an aromatic or heterocyclic residue in the 2-position and in the 4-position, preferably substituted by e.g. two lower alkyl groups such as methyl, and where Rg stands for hydroxy, or R^a and R-j^ have the meanings given above, Rg denotes a residue Rg* which together with the -C^O) group forms a preferably easily cleavable protected carboxyl group, where a such a protected carboxyl group is different from a physiologically cleavable carboxyl group, and R^ has the above meaning, are valuable intermediates which in a simple way, as it e.g. to be described later, can be converted into the relevant, pharmacologically active compounds.

The invention relates in particular to the production of v J-cephem compounds of formula IA, where R-^s denotes hydrogen and I is preferably an acyl residue occurring in a fermentatively producible (i.e. natural) or biosynthetically, semi-synthetically or fully synthetically producible and particularly pharmacologically active, in particular highly active N-acyl derivative of a 6(3-amino-penam-3-carboxylic acid or 70-afflino-3-cefera-4-carboxylic acid compound, such as one of

In II

the above-mentioned acyl residues of formula A, where the groups R , R and R III as well as n in these residues primarily have the aforementioned preferred

B ab meaning, R^ stands for hydrogen, or where R-^ and R1 together represent a 1-oxo-3-aza-1,4-butylene residue which is substituted in the 2-position, preferably mea e.g. an aromatic or heterocyclic residue such as phenyl and preferably in the 4-position with e.g. two lower alkyl groups such as methyl, Rg denotes hydroxy and lower alkoxy which are optionally mono- or poly-substituted, preferably in the a-position, with e.g. optionally substituted aryloxy, such as low alkyloxyphenyloxy of the 4-methoxyphenyloxy type, low alkanoyloxy such as acetyloxy or pivaloyloxy, α-aminolowalkanoyloxy such as glycyloxy, L-valyloxy or L-leucyloxy, arylcarbonyl such as benzoyl or optionally substituted aryl such as phenyl, low alkyloxy phenyl such as 4-nietoxyphenyl, nitrophenyl as 4-nitrophenyl jsller biphenylyl1 as 4-biphenylyl or in the f3 position with halogen such as chlorine, bromine or iodine, examples are lower alkyloxy such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy or tert-pentyloxy, optionally lower alkyloxy-substituted bis-phenyloxy-methoxy, such as bis-4-methoxyphenyloxy-methoxy, lower alkanoyloxy-methoxy such as acetyloxymethoxy or pivaloyloxymethoxy, α-amlinolalkanoyloxy-methoxy such as glycyloxymethoxy, phenacyloxy, optionally substituted phenyllower alkyloxy, in particular 1-phenylaalkyloxy, such as phenylmethoxy , where such residues may contain 1-3 phenyl residues which are optionally substituted with e.g. lower alkoxy, such as methoxy, nitro or phenyl, examples are benzyloxy, 4-roethoxy-benzyloxy»2-biphenylyl-2-propyloxy, 4-nitro-benzyloxy, diphenylmethoxy, 4»4'-dimethoxy-diphenylmethoxy or trityloxy, or 2-halogeno-lower oxy such as 2,2,2-trichloroethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy, further 2-phthalidyloxy or acyloxy, such as lower alkoxycarbonyloxy of the type methoxycarbonyloxy or ethoxycarbonyloxy, or also lower alkanoyloxy such as acetyloxy or pivaloyloxy, further for trilower alkylsilyloxy, such as trimethylsilyloxy , or amino or hydrazino which is optionally substituted with lower alkyl such as methyl, or hydroxy, examples are amino, lower alkyl or dilower alkylamino, such as methylamino or dimethylamino, hydrazino, 2-lower alkyl or 2,2-dilower alkylhydrazino, such as 2-methylhydrazino or 2, 2-dimethylhydrazino or hydroxyamino, and R^ denotes hydrogen, lower alkyl, especially methyl, or a hydroxy-protecting group such as trilower alkylsilyl of the trimethylsilyl type, or benzyl or diphen ylmethyl, which is optionally substituted with e.g. halogen or lower alkoxy as well as the 1-oxides of these compounds, as well as the corresponding 2-cephem compounds of formula IB or salts thereof with salt-forming groups.

In a 3-cephem compound of formula IA and in a corresponding 2-cephem compound of formula IB, further in a 1-oxyct of a 3-cephem compound of formula IA, or in a salt of such a compound with salt-forming groups, Rl denotes hydrogen or an acyl residue found in a fermentatively producible (ie naturally) or biosynthetically producible N-acyl derivative of 6B-amino-penam-3-carboxylic acid or 7B-amino-3-cephem-Æ-carboxylic acid -

I II III

compounds, especially with formula A, where R , R , R and n in particular have the previously mentioned preferred meanings, or for an optionally substituted, e.g. hydroxy substituted phenylacetyl or phenyloxyacetyl residue, further a lower alkanoyl or lower alkenoyl residue which is optionally substituted with e.g. lower alkylthio or lower alkenylthio, or with esterified carboxyl substituted with e.g. acylated amino and/or functionally converted esterified carboxyl, examples are 4-hydroxy-phenylacetyl, hexanoyl, octanoyl or n-butyl-thioacetyl, and especially 5-amino-5-carboxy-valeryl, where the amino and/or carboxyl groups are possibly protected and e.g. exists as acylamino or esterified carboxyl, phenylacetyl or phenyloxyacetyl, or an acyl residue occurring in highly active N-acyl derivatives of 66-amino-penam-3-carboxylic acid or 7B-amino-3-cephem-4-carboxylic acid compounds, especially with formula A, where R I , R II , R III and n primarily have the previously indicated preferred meanings such as formyl, 2-haloethylcarbamoyl of the 2-chloroethylcarbamoyl type, cyanoacetyl, phenylacetyl, thienylacetyl as

2-thienylacetyl or tetrazolylacetyl as 1-tetrazolylacetyl,

but in particular acetyl which is substituted in the a-position with a cyclic and especially monocyclic residue" or a cycloaliphatic, aromatic or heterocyclic residue and with a functional group, primarily amino, carboxy, sulfo or hydroxy, among these especially phenylglycyl, where the phenyl group can optionally be substituted with e.g. optionally protected hydroxyl, such as acyloxy, for example optionally halogen-substituted lower alkoxycarbonyloxy or lower alkanoyloxy and/or with halogen as chlorine, for example phenyl, 3~ or 4-hydroxy-, 3~^Gr"4-nyhydroxy- or 3»5~dichloro- 4-hydroxy-phenyl (optionally also with a protected, e.g. acylated hydroxy group), and where the amino group can optionally also be substituted and, for example, form a salt-formed sulfoamino group or an amino group which, as substituents, has a hydrolytically cleavable trityl group or in first row an acyl group, for example an optionally substituted carbamoyl group such as an optionally substituted ureidocarbonyl group of the type ureidocarbonyl or N<*->trichloromethylureidocarbonyl, or an optionally substituted guanidinocarbonyl group such as guanidinocarbonyl or a preferably easily cleavable acyl residue, such as .can be cleaved by treatment with an acidic reagent such as trifluoroacetic acid or

reductively by treatment with a chemical reducing agent such as zinc in the presence of aqueous acetic acid or with catalytic hydrogen, or can be cleaved off hydrolytically, or a residue which can be transferred to such an acyl residue, preferably a suitable acyl residue of a carbonic acid half-ester such as e.g. one of the previously mentioned, for example optionally halogen- or benzoyl-substituted lower alkyloxycarbonyl residues such as tert-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl or phenacyloxycarbonyl, optionally lower alkyloxy- or nitro-ssubstituted phenylalkalkoxycarbonyl such as 4-methoxybenzyloxycarbonyl or diphenylmethoxycarbonyl, or a carbonic acid amide such as carbamoyl or K-methylcarbamoyl, further an arylthio or aryl alaalkylthio residue which can be cleaved off with a nichleophilic reagent of the hyurogenianic acid, sulfuric acid or thioacetic acid type, examples are 2-nitrophenylthio or tritylthio, an arylsulfonyl residue which can be cleaved off by means of electrolytic reduction, e.g. 4-niethylphenylsulfonyl or a 1-lower carboxycarbonyl or

1- lower alkanoyl-2-propylidene residue which can be cleaved off with an acidic reagent such as formic acid or aqueous mineral acid such as hydrochloric or phosphoric acid, e.g. 1-ethoxycarbonyl-2-propylidene, further a-(1,4-cyclohexadienyD-glycyl, a- (1-cyclohexenyl)-glycyl, α-thienyl-glycyl as α-2- or α-3-thienylglycyl, α-furylglycyl as α-2-furylglycyl, α-isothiazolylglycyl as α-4-fcsotiazolylglycyl,

where the amino group in these residues may be substituted or protected, e.g. as indicated for the phenylglycyl residue, further α-carboxy-phenylacetyl or α-carboxy-thienylacetyl, such as α-carboxy-2-thienylacetyl (possibly with a functionally converted, e.g. salt-ionized carboxyl group, for example in sodium salt form, or in ester-, as lower alkyl form, for example methyl, or ethyl or phenyl lower alkyl as diphenylmethyl ester form), a-sulfo-phenylacetyl (possibly also with a sulfo group converted e.g. as the carboxyl group), a-phosphono, a-O-methylphosphono- or a-0 ,0'-dimethyl-phosphono-phenylacetyl, or α-hydroxyphenylacetyl (possibly with a functionally converted hydroxyl group, in particular with an acyloxy group where the ayl group denotes an acyl residue which can preferably be easily cleaved by treatment with an acidic reagent such as trifluoroacetic acid or with a chemical reducing agent such as zinc and aqueous acetic acid or can be transferred to such an acyl residue, preferably a suitable acyl residue of a carbonic acid half-ester, for example one of the above, e.g. a lower alkoxycarbonyl residue which is optionally sub substituted with halogen or benzoyl, for example 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert-butyloxycarbonyl or phenacyloxycarbonyl, or formyl), as well as 1-amlno-cyclohexylcarbonyl, amino-raethylphenylacetyl as 2- or 4-arainomethylphenylacetyl, or amino-pyridinium acetyl such as 4-aminopyridinium acetyl (optionally also with amino group substituted as above), or pyridylthioacetyl, such as 4-pyridylthioacetyl, and R-,<*5>denotes hydrogen, or

ab'

R^ and R^ together form a 1-oxo-3-aza-butylene residue which

is substituted preferably in the 2-position with optionally protected hydroxyl such as acyloxy, e.g. optionally halogen-substituted lower alkoxycarbonyloxy or lower alkanoyloxy, and/or with

phenyl substituted with halogen such as e.g. chlorine, examples are phenyl or 3- or 4-hydroxy-, 3-chloro-4-hydroxy- or 3,5-dichloro-4-hydroxy-phenyl (possibly also with protected hydroxyl group, e.g. acylated hydroxy group as described above ),

which 1-oxo-3-aza-1,4-butylene residue is optionally also substituted in the 4-position with 2-lower alkyl groups such as methyl, and Rg denotes hydroxyl, lower alkyloxy, especially α-polybranched lower alkyloxy such as tert-butyloxy, further methoxy or ethoxy . is substituted with lower methoxy or nitro, for example 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy, lower alkanoyloxy methoxy such as acetyloxymethoxy or pivaloyloxy methoxy, α-aminolower alkanoyloxy methoxy as glycyloxy methoxy, 2-phthalidyloxy methoxy, lower alkyloxycarbonyloxy as ethoxycarbonyloxy or lower alkanoyloxy such as acetyloxy, further tri-lower alkylsilyloxy, such as trimethylsilyloxy, and R^ denotes hydrogen, lower alkyl, especially methyl or a hydroxy protecting group such as tri-lower alkylsilyl such as trimethylsil yl, or benzyl or diphenyl-methyl which is optionally substituted with halogen such as chlorine or bromine, or with lower alkoxy such as methoxy.

The invention primarily relates to the preparation of 3-cef em-f compounds of formula IA, where R-^a denotes hydrogen or an acyl group of formula

where RGa t denotes phenyl or hydroxygenyl, such as e.g. 3- or 4-hydroxyphenyl, further hydroxy-chlorophenyl such as 3-chloro-4-hydroxyphenyl or 3,5-dichloro-4-hydroxy-phenyl, where in such residues the hydroxy substituents can be protected with acyl residues, for example optionally halogenated lower alkoxycarbonyl esters such as tert -butyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl, further thienyl, as 2- or J-thienyl, as well as pyridyl, as 4-pyridyl, aminopyridinium as 4-aminopyridinium, furyl as 2-furyl, isothiazolyl as 4-isothiazolyl or tetrazolyl as 1-tetrazolyl or also 1,4-cyclohexaaienyl or 1-cyclohexenyl, X denotes oxygen or sulphur, m is equal to 0 or 1, and R^ denotes hydrogen, or when m is equal to 0, amino and protected amino such as acylamino,

for example α-polybranched lower alkoxycarbonylamino such as tert-butyloxycarbonylamino or 2-halolower alkoxycarbonylamino,

of the type 2,2,2-trichloro et oxycarbonylamino, 2-iodoethoxycarbonylamino or 2-bromomethoxycarbonylamino, or optionally lower alkoxy- or nitro-substituted phenylalkoxycarbonylamino such as 4-methoxybenzyloxycarbonylamino or diphenylmethoxycarbonyl-amine or 3-guaylureido»further sulfoamino or tritylamino as well as arylthioamino, which 2-nitrophenylthioamino, arylsulfonylamino such as 4-niethylsulfonylamino, or 1-laalkylcarbonyl-2-propylideneamino such as 1-ethoxycarbonyl-2-propylideneamino, carboxy or carboxy present in salt form e.g. as an alkali metal salt of the sodium salt type, as well as protected carboxy, for example esterified carboxy, such as phenyl alkoxycarbonyl of the diphenylmethoxycarbonyl type, sulfo or sulfo in salt form, for example alkalimet a Unsalt or sodium salt, as well as protected sulfo, hydoxy, as well as protected hydroxy, such as acyloxy, e.g. α-Polybranched lower alkyloxycarbonyloxy, such as tert-butyloxycarbonyloxy or 2-halolower alkyloxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromomethoxycarbonyloxy, 2-iodoethoxycarbonyloxy, further formyloxy or O-lower alkylphosphono or 0,0'-diloweralkylphosphono such as O -methylphosphono or 0,CP<->dimethylphosphono, or denotes a 5-amino-5-carboxy-valeryl residue, where the amino or carboxy group may be protected and e.g. denotes acylamino, for example lower alkanoylamino as acetylamino, haloalkanoylamino as dichloroacetylamino, benzoylamino or fbaloylamino, or may exist as esterified carboxy as phenyllower carboxycarbonyl of the diphenylmethoxycarbonyl type, where n is preferably equal to 1, when R_ denotes phenyl, hydroxyphenyl, hydroxychlorophenyl or pyridyl and m is equal to 0 and Rb different from hydrogen when RQ is equal to phenyl, hydroxyphenyl, hydroxychlorophenyl, thienyl, furyl, isothiazolyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, R^<b>denotes hydrogen, Rg primarily denotes hydroxy, further lower alkoxy, in particular α-polybranched lower alkyloxy, such as tert-butyloxy, 2-halo-lower alkyloxy such as 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromomethoxy, or diphenylmethoxy which is optionally substituted with e.g. lower alkoxy such as methoxy, for example diphenylmethoxy or 4,4J-dimethoxy-

diphenylmethoxy, further tri-lower alkylsilyloxy, such as trimethylsilyloxy, and R^ denotes hydrogen, lower alkyl such as methyl, ethyl or n-butyl, as well as tri-lower alkylsilyl such as trimethylsilyl, further benzyl or diphenylmethyl which is optionally substituted with halogen such as chlorine or bromine or lower alkyloxy, such as methoxy, and 1-oxides of such 3-cephem compounds of formula IA, further the corresponding 2-cephem compounds of formula IB or their salts* especially pharmaceutically usable non-toxic salts of such compounds containing salt-forming groups such as alkali metal salts, for example sodium or alkaline earth lime take 11-, e.g. calcium salts or ammonium salts, including salts with amines of compounds where Rg stands for hydroxyl and which in the acyl residue included in formula B contains a free amino group.

In 3-cephem compounds of formula IA and further in the corresponding 2-cephem compounds of formula IB as well as in salts, especially in pharmaceutical non-toxic salts of such compounds with a salt-forming group, including the above-mentioned salts, R^<a>mainly stands for hydrogen, for acyl residue of formula B, where

Rfl_ denotes phenyl or hydroxyphenyl such as 4-hydroxyphenyl,

thienyl such as 2- or 3-thienyl, 4-isothiazolyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, X denotes oxygen, m is equal to 0 or 1, and Rk denotes hydrogen or when m is equal to 0, denotes bamino as well as protected amino as acylamino, for example α-multi-branched lower alkoxycarbonylamino such as tert-butyloxycarbonylamino or 2-halolower alkoxycarbonylamino, such as 2,2,2-trichloroethoxycarbonylamino, 2-iodoethoxycarbonylamino or 2-bromomethoxycarbonylamino, or optionally lower alkoxy- or nitro-substituted phenylalkoxycarbonylamino such as 4-methoxybenzyloxycarbonylamino or hydroxy, which protected hydroxy , for example acyloxy such as <x-multi-branched lower alkyloxycarbonyloxy of the type tert-butyloxycarbonyloxy or 2-halolower alkyloxycarbonyloxy such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromomethoxycarbonyloxy, further formyloxy or stands for 5-amino-5-carboxy-valeryl residue, where the amino and carboxy group can also be protected and e.g. exist as acylamino of the type lower-alkykanoylamino such as acetylamino, haloalkanoylamino such as dichloroacetylamino, benzoylamino or phthaloylamino, respectively

as esterified carboxy as phenyl lower carboxycarbonyl of the diphenyl methoxy carbonyl type, where preferably m is equal to 1, when Ra is equal to phenyl or hyaroxyphenyl, R^ denotes hydrogen, Rg denotes primarily hydroxy, further lower alkoxy which is optionally substituted in the 2-position with halogen, chlorine -, bromo- or iodo, especially α-multi-branched lower alkyloxy such as tert-butyloxy or 2-halolower alkyloxy such as 2,2,2-trichloroethoxy, for example methoxy-substituted diphenylmethyloxy such as diphenylmethoxy or 4j4'-dimethoxy-diphenylmethoxy or p-nitrobenzyloxy, further trilower alkylsilyloxy such as trimethylsilyloxy, and R^ denotes hydrogen, lower alkyl especially methyl trilower alkylsilyl such as trimethylsilyl or a benzyl or diphenylmethyl group which is optionally substituted with halogen, chlorine or bromine, or with lower alkoxy such as methoxy.

Even more particularly, the invention relates in particular to the production of 78-(D-B-amino-α-R-acylamino)-3-laalkyloxy-3-cephem-4-carboxylic acids where RG_1 denotes phenyl, 4-bydroxyphenyl, 2-thienyl, 1'4-cyclohexadienyl or 1-cyclohexenyl, and the lower alkoxy group contains up to 4 C atoms and e.g. is ethoxy or n-butyloxy, but above all methoxy, and the internal salts of these compounds, and in particular 3-methoxy-73-(D-a-phenyl-glycylamino)-3-cephem-4-carboxylic acids and its internal salt, In said concentrations, especially when administered orally, these compounds have outstanding ahtiB-biotic properties both against gram-positive and especially against gram-negative bacteria while simultaneously having a low degree of toxicity.

According to the method of the invention, compounds of formula IA, their 1-oxides, compounds of formula IB and salts thereof with salt-forming groups are prepared by a compound of formula

where R-^ a , R^ b and Rg A have the meanings given to formula IA,

R^° denotes lower alkyl or a hydroxy protecting group, and T denotes a leaving group, treated with a base and, if desired, 1 a prepared compound of formula IA or IB transfers the protected carboxyl group of formula -C(=0)-Rg<*> to a free or another protected carboxyl group and/or if desired, transfers a protected hydroxyl group -0-R^° to a free hydroxyl group and/or transfers the second free hydroxyl group or the protected hydroxyl group -0-R^° to a lower alkoxy group - O-R^, and/or if desired converts a manufactured compound into another compound within the definition of the end product, and/or if desired transfers a manufactured compound with a salt-forming group into a salt, or a manufactured salt into a free compound or another salt, and/or if desired separates a prepared mixture of isomeric compounds into the individual isomers.

In a compound of formula II, the group -O-R^°

stand in the trans configuration (crotonic acid configuration) or in the cis position (isocrotonic acid configuration) to the carboxyl group.

In a starting compound of formula II, the leaving group Y is e.g. a group -S-R^, a group -SOg-R^ which is bonded with the sulfur atom to the thio group -S- or a group -S-SOg-R^.

In the group -S-R^, R^ denotes an optionally substituted aromatic, heterocyclic residue with up to 15 and preferably up to 9 C atoms and at least one ring nitrogen atom, and optionally a further ring heteroatom such as oxygen or sulphur, which residue is bound to the thio group -S - with one of the ring C atoms connected to a ring nitrogen atom by a double bond. Such residues are monocyclic or bicyclic and can e.g. be substituted with 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.

Such residues R^ are e.g. monocyclic five-membered, thiadiazacyclic, thiatriazacyclic, oxadiazacyclic or oxa-triazacyclic residues of an aromatic character, but especially monocyclic, five-membered diazacyclic, oxazacyclic and thiazacyclic residues of an aromatic character, and primarily the corresponding benzdiazacyclic, benzoxazacyclic or benzthiazacyclic residues, where the heterocyclic part is five-membered and has an aromatic character, and where one substitutable ring nitrogen atom in the residues R^, e.g. may be substituted with lower alkyl. Examples of such groups R^ are a methyl-imidazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,3,4,5-thiatriazol-2- yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,3,4»5-oxatriazol-2-yl, 2-quinolyl, 1-methyl-benzimidazol-2- yl, benzoxazol-2-yl and especially benzthiazol-2-yl. Other groups R^ are acyl residues of organic carbonic or thiocarbonic acids, such as e.g. optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic acyl or thioacyl groups with up to 18 and preferably up to 10 C atoms, such as lower alkanoyl of the acetyl or propionyl type, lower thioalkanoyl such as thioacetyl or thiopropionyl, cycloalkanecarbonyl such as cyclohexanecarbonyl, cycloalkanethiocarbonyl such as cyclohexanethiocarbonyl, benzoyl, thiobenzoyl , naphthylcarbonyl, naphthylthiocarbonyl, heterocyclic carbonyl or thiocarbonyl such as 2-, 3- or 4-pyridylcarbonyl, 2- or 3-thenoyl, 2- or ^- furyoyl, 2-, 3" or 4-pyridylthiocarbonyl, 2- or 3-thenoyl .

In the groups -SOg-R^ and -S-SOg-R^, R denotes an optionally substituted, especially aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbon residue with up to 18 and preferably up to 10 C atoms. Suitable groups R^ are e.g. mono- or polysubstituted alkyl groups, especially lower alkyl, such as methyl, ethyl or butyl groups where the substitution groups e.g. is lower alkoxy such as methoxy, halogen such as fluorine, chlorine or bromine, aryl such as phenyl, aryloxy such as phenyloxy, alkenyl groups such as allyl or butenyl groups, cycloalkyl groups such as cyclopentyl or cyclohexyl groups, or mono or polysubstituted naphthyl or especially phenyl groups which are again optionally substituted with 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, especially phenyl, o-, m- or preferably p-tolyl, o-, m- or preferably p-methoxyphenyl , o-, m- or preferably p-chlorophenyl, p-biphenylyl, p-phenoxyphenyl, p-nitrophenyl or 1- or 2-naphthyl.

In a starting substance of formula II, Rg<*>preferably stands for an etherified hydroxyl group which together with the -Cl^O) group forms an esterified carboxyl group, which can be cleaved particularly under mild conditions, where any functional groups in a carboxyl protecting group R« * may be protected in an otherwise known manner, e.g. as previously stated. A group Rg Pl is e.g. in particular an optionally halogen-substituted lower alkoxy group such as methoxy, cc-multi-branched lower alkoxy such as tert-butyloxy or 2-halo-lower alkoxy, where halogen e.g. chlorine, bromine or iodine, primarily 2,2,2-trichloroethoxy, 2-bromomethoxy or 2-iodoethoxy, or an optionally substituted, e.g. lower alkoxy, for example methoxy- or nitro-substituted 1-phenyl lower alkoxy group such as e.g. benzyloxy, or diphenylmethoxy, substituted as previously stated, examples are benzyloxy, 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy or 4,4,-dimethoxy-diphenylmethoxy, via an organic silyloxy or stannyloxy group such as tri-lower alkylsilyloxy, for example trimethylsilyloxy or halogen such as chlorine. Preferably, the residue R,<a>in a starting substance of formula II denotes an amino protecting group R^, for example an acyl group Ac, where any free functional groups such as amino, hydroxy, carboxyl or phosphono groups can be protected in an otherwise known manner, the amino group f .ex. by the above-mentioned acyl, trityl, silyl or stannyl groups, as well as with substituted thio or sulfonyl residues, and hydroxy, carboxy or phosphono groups can be protected, e.g. with the above-mentioned ether or ester groups, including silyl or stannyl groups, and R^ denotes hydrogen.

In a starting material with formula II, R 10 preferably denotes lower alkyl, especially methyl, or as a hydroxy protecting group preferably a substituted silyl group, especially the trimethylsilyl group, as well as an a-phenyl lower alkyl group such as benzyl or the diphenylmethyl group.

B Bases suitable for the ring closure reaction are particularly strong organic or inorganic bases. Among these, bicyclic amidines such as diazabicycloalkenes of the type 1,5-diazabicyclo/~4.3.07non-5-ene or 1,5-diazacyclo/~5.4.07undec-5-ene, substituted guanidines, e.g. polysubstituted with lower alkyl, for example tetramethylguanidine, further metal bases such as hydrides, amides or alcoholates of alkali metals, especially of lithium, sodium or potassium, e.g. sodium hydride, lithium dilave alkyl amides such as lithium diisopropylamide, potassium lava Icanolates such as potassium tert-butylate. Compounds with formula II where Rg denotes halogen as chlorine can also be ring-closed with a tertiary organic nitrogen base such as a tri-lower alkylamine, of the triethylamine type, whereby the corresponding ester with formula IA and/or IB can be obtained in the presence of an alcohol such as e.g. a lower alkanol of the t-butanol type.

The reaction according to the invention is carried out in a suitable inert solvent such as e.g. an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated hydrocarbon such as methylene chloride, an ether such as e.g. a di-lower alkyl ether of the diethyl ether type, a di-lower alkyl alkane such as dimethyloxyethane, a cyclic ether such as dioxane or tetrahydrofuran or also a lower alkanol such as methanol, ethanol or tert-butanol or a mixture thereof, at room temperature or under gentle heating at 40 to 50° C, if desired under an inert gas atmosphere such as nitrogen.

When treating a compound of formula II, wherein

Y denotes a group -S-R^, e.g. The 2-benzthiazolylthiorestene, with

one of the aforementioned bases, e.g. with 1,5-diazabic<y>klo/~5.4.07undec-5-ene, the yield of compounds of formula IA and IB can be increased by adding a sulfinic acid of formula H-SOg-R^, e.g. p-toluenesulfinic acid.

According to the ring closure reaction according to the invention, depending on the starting material and reaction conditions, uniform compounds of formula IA or IB or mixtures of compounds of formula IA and IB can be obtained. Prepared mixtures can be separated in an otherwise known manner, e.g. by suitable separation methods such as adsorption and fractional elution, including chromatography (column, paper or plate chromatography), by means of suitable adsorbents such as silica gel or aluminum oxide and elution agents, further by fractional crystallization, solvent distribution, etc.

Prepared compounds of formula IA and IB which are suitable intermediates for the preparation of pharmacologically active end products can be transferred to such active end products in various known ways.

In a prepared compound of formula lay or IB

a hydroxy protecting group R^ can easily be cleaved off and replaced by hydrogen. A 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon residue can e.g. decomposed 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 with an acid such as acetic acid. The removal of optionally substituted α-phenyl lower alkyl, such as benzyl or diphenylmethyl groups, e.g. by acidolysis, for example by treatment with a suitable inorganic or organic acid,

as hydrochloric acid, as sulfuric acid, formic acid or especially trifluredacetic acid, or by hydrogenolysis as e.g. 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. The removal of a hydroxy protecting group can optionally be carried out - selectively, i.e. without the carboxyl protecting group Rg<*> being removed at the same time.

Enoleters, i.e. compounds of formula IA and/or

IB where R^ stands for lower alkyl, is obtained from compounds of formula

IA or IB, where R^ is a hydroxy-protecting residue, by replacing this residue with hydrogen followed by addition of the free hydroxy group according to a suitable method for etherification of enol groups. Preferably, a diazo compound of the formula R^-Wg is used as the etherification reagent, which corresponds to the optionally substituted hydrocarbon residue R^> primarily an optionally substituted diazolalkane such as diazomethane, diazoethane or diazo-n-butane, or an optionally substituted a-phenyl-diazolalkane , such as phenyl- or diphenyl-diazomethane. These reagents are used in the presence of a suitable inert solvent such as e.g. an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon such as methylene chloride,

a lower alkanol such as methanol, ethanol or tert-butanol or an ether such as a di-lower alkyl ether of the diethyl ether type, or a cyclic ether such as tetrahydrofuran or dioxane, or a solvent mixture, and depending on the diazo reagent, under cooling,

at room temperature or under gentle heating, further if necessary in a closed container and/or under an inert gas atmosphere such as nitrogen.

Enol ethers of formula IA can also be prepared

and IB by treatment with a reactive ester of an alcohol of formula R^-OH corresponding to the lower alkyl residue or the optionally substituted α-phenyl lower alkyl residue such as benzyl or diphenylmethyl residue R^. Suitable esters are particularly those with strong inorganic or organic acids such as mineral acids of the hydrohalide acid type, for example hydrochloric acid, hydrobromic acid or hydroiodic acid, further sulfuric acid or halosulphuric acid such as fluorosulphuric acid or strong organic sulphonic acids such as e.g. halogen

as fluorine-substituted lower alkanesulphonic acids or aromatic sulphonic acids such as e.g. lower alkyl, for example methyl, halogen, such as bromo- and/or nitro-substituted benzenesulfonic acids, examples are methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonic acid.

These reagents, in particular the di-lower alkyl sulfates such as dimethyl sulfate, further lower alkyl fluorosulfates such as methyl fluorosulfate or optionally halogen-substituted methanesulfonic acid lower alkyl esters, such as trifluoromethanesulfonic acid methyl ester, are usually used in the presence of a solvent such as e.g. an optionally halogenated, for example chlorinated aliphatic, cycloaliphatic or aromatic hydrocarbon of the methylene chloride type, an ether, such as dioxane or tetrahydrofuran or a lower alkanol such as methanol, or a mixture of these. One preferably uses suitable condensation agents such as alkali metal carbonates or hydrogen carbonates of the sodium type

or potassium carbonate or hydrogencarbonate (usually together with a sulfate), or organic bases which are usually sterically hindered tri-lower alkylamines such as ft,N-diisopropyl-N-ethylamine (preferably together with lower alkyl halogen sulfates or optionally halogen-substituted methanesulfonic acids-lower alkyl esters), and uses cooling, room temperature or heating, i.e. works at temperatures from approx. -20 to approx. 50°C and if necessary in a closed container and/or under an inert gas atmosphere such as nitrogen.

Enol ethers can optionally be produced by treatment

with a compound which on the same carbon atom of an aliphatic character has two or three etherified hydroxyl groups of the formula R^-0-,

i.e. by treatment with a corresponding acetal or ortho-ester,

in the presence of an acidic reagent. Thus one can use gem-lower methoxy-lower alkanes such as 2,2-aimethoxy-propane in the presence of a strong organic sulphonic acid such as p-toluenesulphonic acid and a suitable solvent such as a lower alkanol of the methanol type or a di-lower alkyl or

a di-lower alkyl or lower alkylene sulfoxide such as amethyl sulfoxide, or orthoformic tri-lower alkyl ester such as orthoformic triethyl ester in the presence of a strong mineral acid such as 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 such as dloxane, as an etherifying agent and thus arrive at compounds of formula IA and/or IB, where R^ denotes lower alkyl such as methyl or ethyl.

Enolets of formula IA and/or IB can likewise be prepared by treating starting materials of formula II with tri-Rq-oxonium salts of formula (Ro)oO A (so-called Meerwein salts), or di-RQ0-carbenium salts of formula (Ro0)9CH A or di-R^-halonium salts with the formula (R^JgHal A where A denotes an acid ion and Hal^ denotes a halogen ion, especially a bromonium ion. These are primarily tri-lower alkyl oxonium salts and di-lower alkyl oxycarbenium or di-lower alkyl haonium salts, especially the corresponding salts with complex fluorine-containing acids, such as corresponding tetrafluoroborates, hexafluorophosphates, hexafluoroantimonates or hexachloroantimonates. Such reagents are, for example, trimethyloxonium or triethylosonium hexafluoroantimonate, -hexachloroantimonate, -hexafluorophosphate or -tetrafluoroborate, dimethoxycarbenium hexafluorophosphate or dimethylbromonium hexafluoroantimonate These etherification agents are preferably used in an inert solvent such as an ether or a halogenated hydrocarbon, for example a diethyl ether, tetrahydrofuran or methylene chloride or mixtures thereof, if necessary in the presence of a base such as an organic base, e.g. a preferably sterically hindered, tri-lower alkylamine, such as N,K-diisopropyl-N-ethylamine and, if necessary, using cooling, room temperature or gentle heating, e.g. between approx. -20 to 50°C and possibly closed enclosures under inert gas such as nitrogen.

Enol ethers of formula IA and/or IB can also be prepared by treating starting materials of formula II with a 3-substituted 1-R^-triazaene compound (i.e. a compound of formula subst-M=K-NH-R^), where the substituent is 3 -the nitrogen atom of an organic residue which is bound via a carbon atom, preferably a carbocyclic residue, such as e.g. an optionally substituted phenyl residue, for example lower alkylphenyl such as 4-methylphenyl. Such triazene compounds are 3-aryl-l-lower alkyl triazene such as 3-(4-methylphenyl)-l-methyl-triazene, 3-H-methylphenyl)-l-ethyl-triazene, 3-,(4-1&ethylphenyl)-l-n -propyl-triazene or 3-(4-methylphenyl)-1-methyl-triazene, further 3-aryl-1-(a-phenyllower alkyl)-triazene, such as 1-benzyl-3-(4-methyl-phenyl)-triazene . These reagents are usually used in the presence of inert solvents such as optionally hydrogenated hydrocarbons or ethers, for example benzene, or solvent mixtures and under cooling, room temperature or preferably at an elevated temperature, such as e.g. between approx. 20 and 100°C, and if necessary in a closed container and/or under inert gas such as nitrogen.

In the method according to the invention and in case of any additional reactions, if necessary, free functional groups in the starting materials or in the products, and which do not participate in the reaction, e.g. free amino groups, are temporarily protected e.g. by acylation, tritylation or silylation, free hydroxy or mercapt© groups e.g. by etherification or etherification and free carboxyl groups are protected by e.g. esterification, including silylation, in a generally known manner, and can be released individually or collectively after completion of the reaction in a generally known manner, when this is desired. Thus, one can e.g. and preferably protect e.g. amino, hydroxy, carboxyl or phosphono groups in an acyl residue R-^* respectively R-j^ in the form of acylamino groups,

e.g. the previously mentioned 2,2,2-trichloroethoxycarbonylamino-, 2-bromomethoxycarbonylamino-, 4-methoxybenzyloxycarbonylamino-, diphenylmethoxycarbonylamino- or tert-butyloxycarbonylamino-, or in the form of aryl- or arylloweralkylthioamino-, such as 2-nitrophenylthioamino- or arylsulfonylamino-, for example, 4-methyl-phenylsulfonylamino or 1-la carboxycarbonyl-2-propylideneamino groups, or protect them in the form of acyloxy groups such as e.g. ie the above-mentioned tert-butyloxycarbonyloxy-, 2,2,2-trichloroethoxycarbonyloxy- or 2-bromomethoxycarbonyloxy groups respectively in the form of esterified carboxy groups such as the above-mentioned diphenyl-methoxycarbonyl groups respectively 0,0'-disubstituted phosphono groups such as the above-mentioned 0,0'-dilavalkylphosphono groups as 0,0'-dimethyl-phosphono groups, and then, optionally after conversion of a protecting group such as e.g. a 2-bromomethoxycarbonyl to a 2-joi-ethoxycarbonyl group, cleaved in an otherwise known manner,

possibly partially cleaved" depending on the nature of the protecting group, e.g. cleave a 2,2,2-trichloroethoxycarbonylamino or 2-iodoethoxycarbonylamino group by treatment with a suitable reducing agent such as zinc in the presence of aqueous acetic acid, a diphenylmethoxycarbonylamino or tert-butyloxycarbonylamino group is cleaved by treatment with formic acid or trifluoroacetic acid, an aryl or arylalkylthioamino group by treatment with a nucleophilic reagent such as sulfuric acid, an arylsulfonylamino group is cleaved by means of electrolytic reduction, a 1-lavalkoxycarbonyl2-propylideneamino group by treatment with aqueous mineral acid such as e.g. a tert-butyloxycarbonyloxy group by treatment with formic acid or trifluoroacetic acid or a 2,2,2-trichloroethoxycarbonyloxy group can be cleaved by treatment with a chemical reducing agent such as zinc with aqueous acetic acid, respectively a diphenyl-1-methoxycarbonyl group by treatment with formic acid or trifluoroacetic acid or by hydrogenolysis is cleaved , e.g. an 0,0'-disubstituted phosphono group by treatment with an alkali metal halide.

In a compound of formula Ia or IB prepared according to the invention, containing a protected, especially esterified carboxyl group of formula -CfOj-Rg<*>, this can be transferred in an otherwise known manner to a simple free carboxyl group, depending on the nature of the group Rg a. An esterified carboxyl group e.g. esterified with a lower alkyl residue, such as methyl or ethyl, or with benzyl, especially in a 2-cephem compound of formula IB, can be converted by hydrolysis in a weak basic medium, e.g. by treatment with an aqueous solution of an alkali metal or alkaline earth metal hydroxy or iso-carbonate, such as sodium* or potassium hydroxide, preferably at a pH value of approx. 9 to 10, and optionally in the presence of a lower alkanol, to a free carboxyl group. A carboxyl group which is esterified with a suitable 2-halo lower alkyl or arylcarbonylmethyl group can be cleaved, e.g. by treatment with a chemical reducing agent such as a metal of the zinc type or with a reducing metal salt such as a chromium II salt, e.g. chromium II chloride, usually in the presence of a hydrogen-releasing reagent, which together with the metal forms nascent hydrogen, e.g. an acid and primarily acetic or formic acid or an alcohol with the addition of water, a carboxyl group esterified with an arylcarbonylmethyl group can be cleaved by treatment with a nucleophilic and preferably salt-forming reagent such as sodium thiophenolate or sodium iodide, a carboxyl group esterified with a suitable arylmethyl group can be cleaved e.g. by irradiation, preferably with ultraviolet light with wavelengths unier 29O n<y>u,

when the arylmethyl group e.g. denotes a benzyl residue substituted in the 3-, 4- and/or 5-position, with e.g. lower carboxy and/or nitro groups, or cleaved with ultraviolet light of longer wavelengths, e.g. over 2$) n<y>u, when the arylmethyl group denotes a benzyl residue such as e.g. is substituted in the 2-position with a nitro group, a carboxyl group which is esterified with a suitable substituted methyl group such as e.g. tert-butyl or diphenylmethyl can be split, e.g. by treatment with a suitable acidic reagent of the type formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole, an activated esterified carboxyl group and furthermore a carboxyl group that exists in anhyoria form can be split by hydrolysis, e.g. with acidic or weakly basic agents such as hydrochloric acid or ordinary sodium bicarbonate or an ordinary potassium phosphate buffer with a pH of approx. 7 to 9, and a hydrogenolytically cleavable esterified carboxyl group can be cleaved by hydrogenolysis by e.g. treatment with hydrogen in the presence of a noble metal that takes light such as e.g. palladium catalyst.

A carboxyl group that is protected by silylation or stannylation can be released in the usual way, e.g. by be-han iling with water or an alcohol.

Prepared compounds of formula IA or IB can

in otherwise known manner is applied to other compounds of formula IA or IB.

In a manufactured connection, e.g. an amino protecting group R-^ A or B, in particular an easily cleavable acyl group is cleaved off in an otherwise known manner, e.g. an α-multi-branched lower alkoxycarbonyl group such as tert-butyloxycarbonyl can be cleaved off by treatment with trifluoroacetic acid and a 2-halo-lower alkoxycarbonyl group such as 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or a phenacyloxycarbonyl group can be cleaved off by treatment with a suitable reducing number or corresponding metal compound such as zinc or a chromium-II compound which

-chloride or -acetate, preferably in the presence of a reagent which

together with the metal or metal compound forms nascent hyarogen.and preferably in the presence of aqueous acetic acid.

In a predominantly oxygen compound of formula IA or IB where a carboxyl group of formula -Cf^OJ-Rg preferably forms a carboxyl group which is protected e.g. by esterification including silylation, e.g. by reaction with a suitable organic halogen-silicon or halogen-tin-IV compound such as trimethylchlorosilane or tri-n-butyltin chloride, an acyl group R^a or R^ can be split off, e.g. by treatment with an imidate halide-like agent, reaction of the imidate halide formed. with an alcohol and cleavage of the imino-ether formed, in which groups any functional groups are protected, whereby a protected carboxyl group, e.g. protected meo. an organic silyl residue, can already be released during the reaction.

Imidhalide-forming reagents where the halogen is bound to an electrophilic central atom are above all acid halides such as acid bromides and especially acid chlorides. These are primarily acid halides of inorganic acids, above all phosphorus-containing acids such as phosphorus oxy-, phosphorus tri- and especially phosphorus pentahalides, for example phosphorus oxychloride, phosphorus trichloride and especially phosphorus pentachloride. further pyrocatechyl phosphorus trichloride and acid halides, especially chlorides of sulphurous acids or of carboxylic acids such as thionyl chloride, phosgene or oxalyl chloride.

Reaction with one of the aforementioned imide halide-forming agents is preferably carried out in the presence of a suitable and particularly organic base, above all a tertiary amine, e.g. a tertiary aliphatic, mono- or diamine such as a tri-lower alkyl amine of the type trimethyl-, triethyl or N,N-diisopropyl-N-ethylamine, further an N,NtH»,N'-tetralower alkyl-lower alkylene diamine such as N,N,N <*>,W'-tetramethyl-1,5-pentylene-iamine or K,N,W',W'-tetramethyl-1,6-hexylenediamine, a mono- or bicyclic lmono- or diamine as a W-substituted, e.g. N-lower alkylene-, azaalkylene- or oxaalkylene amine, e.g. N-methylpiperidine or W-methylmorpholine, further 2,3,4,6,7,8-hexahydro-pyrrolo/~1,2-α7pyrimiline (diazabicyclonones: DBJtf) or a tertiary aromatic amine such as a di-lower alkyl anline of the type W,N-dimethylaniline or primarily a tertiary, heterocyclic, mono- or bicyclic base such as quinoline or isoquinoline, especially pyridine, preferably in the presence of a solvent

like for example. an optionally halogenated, e.g. chlorinated, aliphatic or aromatic hydrocarbon such as methylene chloride. One can thereby use roughly equimolar amounts of imide halide-forming agent and base, but the latter can also be used in excess or deficit, e.g. in an amount of 0.2 to 1 in ratio, or in amounts of up to 10 times and especially in 3 to 5 times excess.

The reaction with imide halide-forming agent is preferably carried out during cooling, e.g. at temperatures between approx. -50 and +10°C, but you can also use higher temperatures of up to e.g. 75°C, if the stability of the starting materials and products allows this.

The imidohalogen product, which is usually processed further without isolation, is reacted according to the method with an alcohol, preferably in the presence of one of the aforementioned bases, forming an iminoether. Suitable alcohols are e.g. aliphatic or araliphatic alcohols, primarily optionally substituted, e.g. halogenated of the type chlorinated lower alkanols or lower alkanols containing additional hydroxy groups, e.g. ethanol, propanol or butanol, especially methanol, further 2-halo-lavalkanols such as 2,2,2-trichloroethanol or 2-bromoethanol, as well as optionally substituted phenyllavalkanols such as benzyl alcohol. Usually an excess of up to approx.* 100 times alcohol is used and preferably cooling down to temperatures between approx. -50 and +10°C.

The iminoether product can advantageously be cleaved without isolation. The cleavage of the imino ether can be done by treatment with a suitable hydroxy compound, preferably by means of hydrolysis, further by alcoholysis, whereby the cleavage can be done by using an excess of alcohol directly after the imino ether formation. Water or an alcohol, in particular a lower alkanol such as ethanol or an aqueous mixture of an organic solvent such as an alcohol, is preferably used here. An acidic medium is usually used>e.g. at a pH value of approx. 1 to 5, which is adjusted if necessary by the addition of a basic reagent of the aqueous alkali metal hydroxy type such as e.g. sodium or potassium hydroxide or with an acid such as a mineral acid or an organic acid, examples are hydrochloric acid, sulfuric acid, phosphoric acid, borofluorohydrogen acid, trifluoroacetic acid or p-toluenesulfonic acid.

The above-described three-step method for cleaving an acyl group is advantageously carried out without isolation of the imide halide and the iminoether intermediates, usually by means of an organic solvent which is inert to the reactants, such as e.g. an optionally halogenated hydrocarbon of the methylene chloride type and/or under an inert gas atmosphere such as nitrogen.

If the imide halide intermediate prepared by the above method is reacted with a salt instead of with an alcohol, e.g. an alkali metal salt of a carboxylic acid and in particular a sterically hindered carboxylic acid, a compound of formula IA or IB is obtained, where

a b

both residues R-^ and R^ constitute acyl groups.

In a compound of formula IA or IB where both residues R^ and R^ denote acyl groups, one of these groups, preferably the sterically least hindered, can be selectively removed, e.g.

«red hydrolysis or aminolysis.

In a compound of formula IA or IB where Rna and R^ together with the nitrogen atom form a phthalimido group, this can be transferred to a free amino group, e.g. by hydra zinoljrs e, dept. by treating this compound with hydrazine.

A

Certain acyl residues R-^ belonging to acylamino groups in compounds produced according to the invention, e.g. The 5-am*n°~5-carboxy-valeryl residue, where the carboxyl group is optionally protected, e.g. by esterification and especially with diphenylmethyl and/or the amino group is protected, e.g. by acylation and in particular with an acyl residue of an organic carboxylic acid such as haloalkanoyl such as dichloroacetyl or phthaloyl, can also be cleaved by treatment with a nitrosating agent such as nitrosyl chloride with a carbocyclic arendiazonium salt such as benzenediazonium chloride or with an agent that emits a positive halogen such as e.g. a W-halo-amide or

-imide such as BJ-bromosuccinimide, preferably in a suitable solvent or solvent mixture such as formic acid, together with a nitro- or cyano-lower alkane by adding to the reaction product a hydroxyl-containing agent such as water or a lower alkanol such as methanol, or, if the amino group in 5" *the amino-5-carboxy-valeryl residue R is substituted and the carboxyl group is e.g. protected by esterification and R-^stands for an acyl residue, or for hydrogen, is cleaved by standing in an inert solvent such as dioxane or a halogenated aliphatic hydrocarbon which methylene chloride, even

usually followed by preparation of the free or monoacylated amino compound according to otherwise known methods.

A formyl group R-j* can also be split off by treatment with an acidic reagent such as p-toluenesulfonic or hydrochloric acid, a weakly basic reagent such as e.g. dilute ammonia or a decarbonylation agent such as tris-(triphenylphosphine)rhodiuric chloride.

A triarylmethyl group such as the trityl group R^* can be split off, e.g. by treatment with an acidic reagent such as a mineral acid of the hydrochloric acid type.

In a compound of formula IA or IB where R-j3 and R^b constitute hydrogen, the free amino group can be substituted in otherwise known ways, primarily by treatment with acids such as carbonic acid, or by reactive amino derivatives can be acylated.

If a free acid, preferably with possibly protected functional groups such as e.g. an amino group is used for the acylation, suitable condensation agents such as carbodiimides are advantageously used, for example W,WT-diethyl-, N,W'-dipropyl-, N,N<T->di-isopropyl-, N,W'-dicyclohexyl- or N-ethyl-Kf'-3-dimethylamino-propyl-carbodiimide, suitable carbonyl compounds such as carbonyldiimidazole or isoxazolinium salts, for example N-ethyl-5-phenyl-isoxazolinium-3<»->sulfonate and N-tert-butyl-5-methyl -isoxazoninium perchlorate or a suitable acylamino compound such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-quinoline.

The condensation reaction is advantageously carried out in a

of the later mentioned anhydrous reaction media, preferably in methylene chloride, dimethylformamii or acetonitrile.

An amide-forming functional acid derivative, preferably with any protected groups such as e.g. any amino groups are made up primarily of an anhydride of such an acid, including and preferably a mixed anhydride. Mixed an-hyarids are e.g. those with inorganic acids, in particular with hydrogen halide acids, i.e. the corresponding acid halides such as chlorides or bromides, further with nitrogen hydrogen acids, i.e. the corresponding acid azides with a phosphorus-containing acid such as phosphoric acid or phosphoric acid, with a sulfur-containing acid such as e.g. sulfuric acid or with hydrocyanic acid. Other mixed anhydrides are e.g. those with organic acids such as organic carboxylic acids, e.g. with halogen-like fluorine- or chlorine-substituted low alkane carboxylic acids, for example pivalic acid or trichloroacetic acid or with half-esters, especially lower alkyl half-esters of carbonic acid, such as ethyl or isobutyl half-esters of carbonic acid, or with organic and especially aliphatic or aromatic sulphonic acids of the type p-toluenesulphonic acid.

Furthermore, internal anhydrides such as ketenes can be used as acylating agent, e.g. diketene, isocyanates (ie internal anhydrides of carbamic acid compounds) or internal anhydrides of carboxylic acid compounds with carboxy-substituted hydroxy-

or amino groups such as manic acid-O-carboxylic anhydride or the anhydride of 1-K-carboxyamino-cyclohexanecarboxylic acid.

Other acid derivatives which are suitable for trading with

the free amino group is activated esters, usually with protected, functional groups such as esters with vinylogous alcohols (i.e. enols) such as vinylogous lower alkanols or aryl esters such as preferably nitro or halogen-, for example chlorine-substituted, phenyl-esters, examples are pentachlorophenyl-, 4 -aitrophenyl or 2,4-dinitrophenyl esters, heteroaromatic esters such as benztriazole esters or diacylimino esters such as succinylimino or phthalylimino esters.

Anare acylation derivatives are e.g. substituted formimino derivatives such as substituted W,K-dimethylchloroformimino derivatives of acids, or N-substituted W,H-diacylamines such as an H,N-diacylated aniline.

Acylation with an acid derivative such as an anhydride

and in particular an acid halide can be seen in the presence of an acid-attracting reagent, e.g. an organic base such as an organic amine, for example a tertiary amine such as trilower alkylamine of the triethylamine type, N,W-dilower alkyl-aniline such as W,N-dimethylaniline or a base of the pyridine type such as pyridine, an inorganic base such as an alkali metal or alkaline earth metal hydroxide, - carbonate or bicarbonate such as sodium, potassium or calcium hydroxide, carbonate or bicarbonate or an oxirane, e.g. a lower 1,2-alkylene oxide such as ethylene oxide or propylene oxide.

The above-mentioned acylation can be carried out in an aqueous or preferably non-aqueous solvent or solvent mixture, e.g. in a carboxylic acid amide such as N,H-dilavalkylamide, for example dimethylformamide, a halogenated hydrocarbon such as methylene chloride, carbon tetrachloride or chlorobenzene, a ketone such as acetone,

an ester such as ethyl acetate, or a nitrile such as acetonitrile,

or mixtures thereof, and if necessary at a lowered or elevated temperature and/or under an inert gas atmosphere such as nitrogen.

In the above-mentioned N-acylation reactions, one can proceed from compounds of formula IA or IB where denotes lower alkyl or an optionally substituted α-phenyl lower alkyl-, e.g. benzyl or diphenylmethyl group, and Rg has the previously stated meaning, where compounds with free carboxyl groups having the formula -C("0)-Rg, where Rg stands for hydroxyl, can also be used in the form of salts such as ammonium urea salts, e.g. with triethylamine, or in the form of a compound having a carboxyl group, protected by reaction with a suitable organic phosphorus or halogen compound, for example a lower alkyl or lower alkoxy phosphorus dihalide, such as methyl phosphorus dichloride, ethyl phosphorus dibromict or methoxyphosphorus chloride.

In the produced acylation products, the protected carboxyl group can be released in otherwise known mannerj, e.g. as previously described, including by hydrolysis or alcoholysis.

An acyl group can also be introduced as a compound

with formulas IA and IB, where R^ a and R-^ b together form a yliaene residue (which can optionally be introduced later, e.g. by treatment with a compound where R^<a> and R-^ denote hyarogen , with an aldehyde such as an aliphatic, aromatic or araliphatic aldehyde), is acylated according to the previously stated methods and the acylation product is preferably hydrolysed in a neutral or weakly acidic environment.

An acyl group can also be introduced stepwise. So can

one e.g. in a compound of formula IA or IB with a free amino group introduce a haloalkanoyl such as bromoacetyl group or introduce a halocarbonyl group such as a chlorocarbonyl group, e.g. with treatment with a carbonic acid dihalide such as phosgene, and reacting a H-halo-lavalkanoyl-penis and N-(halocarbonyl)-amino compound thus prepared with suitable exchange reagents such as e.g. basic compounds of the tetrazole type, thio compounds such as 2-mercaptol-1-methyl-imidazole or metal salts such as sodium acid, or alcohols such as lower alkanols, for example tert-butanepl, and in this way arrive at substituted ft-lower alkanoyl or N-hyroxycarbonylamino compounds .

In both reactants, free functional groups can be temporarily protected in a known manner during the acylation reaction and after the acylation released in a known manner, e.g. as

described above.

The acyl ring can also be carried out by replacing an already existing acyl group with another and preferably sterically hindered acyl group, e.g. as previously described, when preparing the imide halide compound, this is treated with an acid salt and in the product thus prepared, acyl groups, usually the least sterically hindered acyl group, are hydrolytically split off.

Furthermore, one can e.g. prepare a compound of formula IA or IB, where R-,a denotes a glycyl group which is preferably substituted in the a-position, such as phenylglycyl, and R^ denotes hydrogen, with an aldehyde such as formaldehyde or a ketone such as a lower alkane of the acetone type, and thus arrive at connections

A B

with formula IA or IB, where R^ or R^ together with the nitrogen atom forms a 5-oxo-1,3-diaza-cyclopentyl residue, which is preferably substituted in the 4-3-position and is optionally substituted in the 2-position.

In a compound of formula IA or IB, where R 3 and R 3 stand for hydrogen, the free amino group can also be protected by introducing a triarylmethyl group, which e.g. by treatment with a reactive ester of a triarylmethanol, for example trityl chloride, preferably in the presence of a basic agent such as pyridine.

An amino group can also be protected by introducing a silyl and stannyl group. Such groups are introduced in a generally known manner, e.g. by treatment with a suitable silylation agent, which can be a dihalo-di-lower alkyl silane, lower alkoxy-lower alkyl-dihalo silane or tri-lower alkyl silyl halide such as dichloro-dimethylsilane, methoxy-methyl-dichloro-silane, trimethylsilyl chloride or dimethyl-tert-butyl silyl chloride, where such silyl halide compounds are preferably used in the presence of a base such as pyridine, further with an optionally K-monolower alkylated, N,N-dilower alkylated, K-trilower alkylsilylated or N-lower alkyl-N-trilower alkylsilylated N-(tri-lower alkylsilyl)amine (see f .eg British Patent No. I.O73.53O); or with a silylated carboxylic acid amide such as a bis-tri-lower alkylsilyl-acetamide such as bis-trimethylsilyl-acetamide or trifluorosilylacetamide, further with a suitable stannylating agent such as bis-(tri-lower-alkyltin)-oxide, for example bis-(tri-n-butyl-tin) ) oxide, a tri-lower alkyl stannous hydroxide such as triethyltin hyaroxide, a tri-lower alkyl lower alkyltin, tetra lower alkyltin or tetralower alkyl tin compound, or a trilower alkyl tin halide such as fcri-n-butyl tin chloride (see f "e.g. Dutch interpretation document 67/11107).

In a compound of formula IA or IB prepared according to the invention and which contains a free carboxyl group of formula . -C(=»0)-Rg, such a group can be transferred in otherwise known manner to a protected carboxyl group. Thus, esters are obtained, e.g. by treatment with a suitable diazo compound, such as a diazole alkane, for example diazomethane or diazobutane, or a phenyl- diazolalkane, such as diphenyldiazomethane, if necessary in the presence of a Lewis acid such as boron trifluoride, or by reaction with an alcohol suitable for esterification, in the presence of an esterifying agent such as a carbodiimia, for example dicyclohexyldicarbodiimide, or carbonyldiimidazole, further with a MjJT-disubstituted 0- or S -substituted isourea or isothiourea, where an 0- and S-substituent is, for example, lower alkyl, especially tert-butyl, phenyl lower alkyl or cycloalkyl and the W- or N'-substituents form e.g. lower alkyl, especially isopropyl, cycloalkyl or phenyl, or by a completely different known and suitable esterification method such as e.g. reaction between an acid salt and a reactive ester of an alcohol and a strong inorganic acid, or a strong organic sulphonic acid. Furthermore, acid halide such as the -chloride (produced for example by treatment with oxalyl chloride), . activated esters (formed e.g. with N-hydroxy-nitrogen compounds, such as N-hydroxy-succinimide) or mixed anhydrides (prepared e.g. with haloformic acid lower alkyl esters such as chloroformate ethyl or chloroformate isobutyl ester, or with haloacetic acid halogens such as trichloroacetic acid chloride) are transferred to one esterified carboxyl group by reaction with alcohols, possibly together with a base such as pyridine.

In a manufactured compound with an esterified group of formula -Cf^OJ-Rg, this can be transferred to another esterified carboxy group of the same formula, e.g. 2-chloroethoxycarbonyl gels 2-bromomethoxycarbonyl by treatment with an iodine salt such as sodium iodide and in the presence of a suitable solvent such as acetone, to 2-iodoethoxycarbonyl.

Mixed anhydrides can be prepared by reacting a compound of formula IA or IB with a free carboxyl group of formula -C(=»O)-Rg, preferably a salt, and in particular an alkali metal salt such as sodium or ammonium, e.g. triethylammonium salt, is reacted with a reactive derivative such as a halide, especially a chloride, of an acid such as e.g. a haloformic acid lower alkyl ester or a lower alkane carbonic acid chloride.

In a compound with a free carboxyl group of the formula -C(=0)-Rg produced according to the invention*, such a group can also be transferred to an optionally substituted carbamoyl or hydrazinocarbonyl group, whereby reactive functionally converted derivatives such as the above-mentioned acid halides are preferably used, generally esters, or the previously mentioned activated esters, or mixed anhydrides or similar acids, by reaction with ammonia or amines, Including hydroxylamine or hydrazines.

Sn carboxyl group which is protected with an organic silyl group or stannyl group can be formed in a known manner, e.g. ware that compounds of formula IA or IB, where Rg stands for hydroxyl, or salts which are alkali metal, especially sodium salts, are treated with a suitable silylating agent or stannylating agent such as one of the previously mentioned. See e.g. British patent I.O73.530 or Dutch patent application 67/17107.

Furthermore, converted functional substituents in the groups R^ , R-^ and/or Rg, such as substituted amino groups, acylated hydroxyl groups, esterified carboxyl groups or 0,0'-disubstituted phosphono groups, can be released in otherwise known manner, e.g. as previously described, or free functional substituents

Ab<

in the groups R-^ , R^ and/or Rg, for example free amino, hydroxy, carboxy or phosphono groups, are functionally converted in an otherwise known manner, e.g. by acylation or esterification or substitution. Thus, one can e.g. converting an amino group into a sulfoamino group by treatment with sulfur trioxide, preferably in the form of a complex with an organic base such as a tri-lower alkylamine of

the type of triethylamine. Furthermore, the reaction mixture, which is prepared by reacting an acid addition salt of a 4-~guanylsemicarbacid with sodium nitrite, can be reacted with a compound of formula 1Å or IB, where e.g. the amino protecting group Ri A forms an optionally substituted glycyl group, and in this way the amino group can be transferred to a 3-guanylureido group. Furthermore, compounds with aliphatically bound halogen, e.g. with an optionally substituted

a-bromoacetyl group, is reacted with esters of phosphoric acid, such as trilavalkyl phosphite compounds, which give corresponding phosphono compounds.

Prepared cephem compounds of formula IA and IB can be transferred by oxidation with suitable oxidizing agents to be referred to as 1-oxides of the corresponding 3-cephem compounds of formula IA. Prepared 1-oxides of 3~cephem compounds of formula IA can be reduced to the corresponding 3**cephem compounds of formula IA by reduction with suitable reducing agents, e.g. as later described. With these reactions, care must be taken that free functional groups are protected if necessary and if the Desire is later released.

Prepared cephem compounds can be isomerized. Thus, prepared 2-cephem compounds of formula IB or prepared mixtures of 2- and 3-cephem compounds can be transferred to the corresponding 3-cephem compounds of formula IA by isomerizing a 2-cephem compound of formula IB or isomerizing a mixture consisting of a 2 - and 3~cefemfo4bond where the free functional groups can possibly be temporarily protected as previously stated. In this way, for example* 2-cephem compounds of formula IB can be used, where the group -G(=O)-R2 mixes a free or protected carboxyl group, but the protected carboxyl group can also be formed during the reaction.

Thus, a 2-cephem compound of formula IB can be isomerized by treating it with a basic reagent and isolating the corresponding 3-cephem compound of formula IA from possibly prepared equilibrium mixtures of the 2- and 3-cephem compound.

Suitable isomerizing agents are e.g. organic nitrogen-containing bases, such as tertiary heterocyclic bases of an aromatic character, and primarily tertiary, aliphatic, azacycloaliphatic or araliphatic bases, such as N,N,H-trilower alkylamine such as trimethylamine, N,K-dimethyl-W-ethylamine, N, K,K-triethylamine or K,W-diisopropyl-N-ethylamine, N-laalkyl-azacycloalkanes such as U-methylpiperidine or N-phenyl 1-laalkylI-N,U-dyl avalkylamines such as Bi-benzyl-N,i9-dimethylamine, as well mixtures of these, for example a mixture of a pyridine-type base such as pyridine itself and an N,N,N-trilower alkylamine such as pyridine or triethylamine. Furthermore, you can

also use inorganic or organic base salts, especially of miadel-strong bases with weak acids, such as alkali metal or ammonium salts of low alkane carboxylic acids, such as sodium acetate, triethylammonium acetate

or H-methyl-piperidine acetate or other analogous bases or mixtures of such basic agents.

The above-mentioned isomerization with basic agents can e.g. is carried out together with a carbonic acid derivative which is suitable for the formation of a mixed anhydride, for example a carbonic acid anhydride. or

-halide, e.g. with pyridine in the presence of acetic anhydria.

An anhydrous environment is preferably used, with or without a solvent, for example optionally halogenated, and especially chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbons, or a solvent mixture where bases that are used as a reaction agent and which are liquid under the reaction conditions can also serve as a solvent, and if necessary under cooling or heating, preferably within -30 to +100°C, and optionally under an inert gas atmosphere such as nitrogen or in a closed vessel.

The thus prepared 3-cephem compounds of formula IA can be separated from any 2-cephem compounds of formula IB in otherwise known manner, e.g. by adsorption and/or crystallization.

The isomerization of 2-cephem compounds of formula IB can also take place via this being oxidized in the l-position, a prepared isomer mixture of 1-oxides of 3-cephem compounds of formula IA is separated if desired and the prepared 1-oxides of the corresponding 3-cephem compounds with formula IA is reduced.

As suitable oxidizing agents for oxidation in the l-position of 2-cephem compounds, inorganic peracids which have a reduction potential of at least ^1.5 volts and consist of non-metallic elements, further organic peracids or mixtures of hydrogen peroxide and acids, especially organic carboxylic acids with a ctissociation constant of at least 1Q~-<*.>Suitable inorganic peracids are periodic and persulphuric acid. Organic peracids are corresponding percarboxylic and persulfonic acids which are added as such or can be formed in situ by using at least one equivalent of hydrogen peroxide and a carbonic acid. In this way, it is an advantage to use a large excess of carbonic acid when e.g. acetic acid is used as a solvent. Suitable peracids are e.g. permauric acid, peracetic acid, pertrifluoroacetic acid, permaleic acid, perbenzoic acid, monoperphthalic acid or p-toluene persulfonic acid.

The oxidation can optionally take place with nitrogen peroxide together with catalytic amounts of acid with a dissociation constant of at least 10"^, whereby one can use 1 to 2$ or less, but possibly also larger amounts of acid. The effect of the mixture depends primarily on the strength of the acid Suitable mixtures are, for example, mixtures of hydrogen peroxide and acetic acid, perchloric acid or trifluO/acetic acid.

The above oxidation can be carried out in the presence of suitable catalysts. Thus, e.g. the oxidation takes place with percarbonic acids by using an acid with a dissociation constant of at least

10-<5>3om acts as a catalyst, and the effect depends on the acid strength. Suitable catalyzing acids are e.g. acetic acid, perchloric acid or trifluoroacetic acid. Generally, at least equimolar amounts of oxidizing agent are used, preferably et. small profit of approx. 10 to 20$. The oxidation is carried out under mild conditions, e.g. at temperatures between approx. -50 and t-100°C and especially between approx. -10 and +4Q°C-.

The oxidation of 2-cephem compounds to 1-oxides of corresponding 3-cephem compounds can also be achieved by treatment with ozone, further with organic hypohalogen compounds such as lower alkyl hypochlorites of the tert-butyl hypochlorite type which are used in the presence of inert solvents, for example optionally halogenated hydrocarbons of the methylene chloride type and at temperatures of approx. -10 to +30°C, further with periodate compounds such as alkali metal periodates of the potassium periodate type, which are preferably used in an aqueous environment with a pH from approx. 6 and temperatures of approx. -10 to +30°C, with iodobenzene dichloride, which is used in an aqueous medium, preferably in the presence of an organic base such as pyridine and under cooling, e.g. at temperatures between approx. -20 and 0°C, or can be carried out with any other oxidizing agent suitable for converting a thio group into a sulfoxide group.

In the thus produced 1-oxides of 3-cephem compounds of formula IA, especially in compounds where R^, R^ and Rg have the previously indicated, preferred meanings, the groups R^<a>, and/or Rg can be transferred to each other within the specified frame, or split off or introduced. A mixture of isomers

a- and B-l-oxides can e.g. is resolved chromatographically.

The reduction of the 1-oxide of 3-cephem compounds of formula IA can be carried out in a known manner by treatment with a reducing agent, if necessary in the presence of an activating agent. The reducing agents can be catalytically activated hydrogen, together with noble metal catalysts containing palladium, platinum or rhodium, possibly together with a suitable carrier material such as coal or barium sulphate, reducing tin, iron, copper or manganese cations that exist in the form of corresponding compounds or complexes of inorganic or organic species, e.g. such as tin II chloride, fluoride, acetate or formate, iron II chloride, sulphate, oxalate or succinate, copper I chloride, benzoate or oxide, or manganese II chloride, -sulphate, -acetate or -oxide, or as complexes, e.g. with ethylene amine tetraacetic acid or nitrilotriacetic acid, reducing dithlonite, iodine or iron II cyanide anions which are used in the form of corresponding inorganic or organic salts such as alkali metal salts of the type sodium or potassium dithionite, sodium or potassium iodide or - iron II cyanide, or in the form of corresponding acids such as hydroiodic acid, reducing trivalent inorganic or organic phosphorus compounds such as phosphines*further esters, amides and halides of phosphinic acid, phosphonic acid or phosphoric acid, or phosphorus-sulfur compounds corresponding to these phosphorus-oxygen compounds, where the organic residues primarily aliphatic, aromatic or araliphatic residues or optionally substituted lower alkyl, phenyl or phenyl lower alkyl groups such as e.g. tri-phenylphosphine, tri-n-butylphosphine, diphenylphosphine methyl ester, diphenylchlorophosphine, phenyldichlorophosphine, benzenephosphonic acid dimethyl ester, butanephosphonic acid methyl ester, phosphoric acid triphenyl ester, phosphoric acid trimethyl ester, phosphorus trichloride, phosphorus tribromide etc: reducing silane compounds which have at least one hydrogen atom bonded to the silicon atom and which, apart from halogen, which chlorine, bromine or iodine, also have organic residues such as aliphatic or aromatic groups, e.g. optionally substituted lower alkyl or phenyl groups, examples are chlorosilane, bromosilane, di- or trichlorosilane, di- or tribromosilane, diphenylchlorosilane, dimethylchlorosilane, etc.: reducing quaternary chloromethyleneiminium salts, especially -chlorides or -bromides, where the iminium group is substituted with a divalent or two monovalent organic residues, for example substituted lower alkylene or lower alkyl groups together with N-chloromethylene-N,W-diethyliminium chloride or N-chloromethylene-pyrrolidinium chloride; and complex metal hyrias such as sodium boron hyoride in the presence of suitable activating agents such as cobalt II chloride or borane dichloride.

As activating agents used together with those of the usual reducing agents which themselves do not have Lewis acid properties, i.e. primarily the activating agents used together with dithionite, iodine or iron II cyanide and the non-halogenated trivalent phosphorus reducing agents, or which are used in the catalytic reduction, are organic carbon and sulphonic acid halides, further sulphur, phosphorus or silicon halides with the same or greater hydrolysis constant of a different order than benzoyl chloride, for example phosgene, oxalyl chloride, acetic acid chloride or bromide, chloroacetic acid chloride, pivalic acid chloride, 4-methoxybenzoic acid chloride, 4-cyanobenzoic acid chloride, p-toluenesulfonic acid chloride, methanesulfonic acid chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phenyldichlorophosphine, benzenephosphonic acid dichloride, dimethylchlorosilane or trichlorosilane, further suitable acid anhydrides such as triflupredlcic acid anhydride or cyclic sultones such as ethanesulton, 1,3 -propane sultone, 1,4-butane sultone or 1,3-he xansultone.

The reduction is advantageously carried out in the presence of solvents* or mixtures thereof, the selection being determined in particular by the solubility of the starting materials and the choice of reducing agent, thus one can use low-alkane carboxylic acids or their esters, such as acetic acid and acetic acid ethyl ester, for the catalytic reduction and e.g. optionally substituted, for example halogenated or nitrated, aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons such as benzene, methylene chloride, chloroform or nitromethane, suitable acid derivatives such as low alkane carboxylic acid esters or nitriles such as acetic acid ethyl ester or acetonitrile or amides of inorganic or organic acids such as dimethylformamide, dimethylacetamide or hexamethylphosphoramide, ethers such as diethyl ether, tetrahydrofuran or dioxane, ketones such as acetone or sulfones, especially aliphatic sulfones such as unmethyl sulfone or tetramethylene sulfone, together with the chemical reducing agents, whereby these solvents preferably do not contain water. Temperatures between approx. -20 and 100°C, and by using particularly reactive activators the reaction can go through at even lower temperatures.

In the thus produced 3-cephem compounds of formula IA, R^a, R^ and/or Rg, as previously described, can be converted to other groups R^a, R^ or Rg.

Salts of compounds of formula IA and IB can be prepared in a known manner. Salts of such compounds contain acidic groups such as are produced by treatment with metal compounds, such as alkali metal salts of suitable carboxylic acids, for example the sodium salt of α-ethyl-caproic acid, or with ammonia or a suitable organic amine, whereby one advantageously uses stoichiometric amounts or only small excesses of salt-forming reagent. Acid addition salts of compounds of formula IA and IB with basic groups take place in a known manner, e.g. - by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of formula IA and IB which have a salt-forming amino group and a free carboxyl group, can e.g. frens is added by neutralizing salts, e.g. acid addition salts, to the iso-electric point, with e.g. weak bases or when treated with liquid ion exchangers. Salts of 1-oxides of compounds of formula IA containing salt-forming groups can be prepared in an analogous manner.

Salts can be transferred in a known manner to the free compounds, metal and ammonium salts, e.g. by treatment with suitable acids, and acid addition salts, e.g. when treated with.

a suitable basic agent.

Predominantly isomeric mixtures can be separated in otherwise known manner into the individual isomers, mixtures of diastereomeric isomers can e.g. are separated by fractional crystallization, adsorption chromatography (column or thin-layer chromatography) or by means of suitable other separation methods. Formed race-feeds can be separated in a known manner, possibly after introduction of suitable salt-forming groups, e.g. by forming a mixture of diastereoisomeric salts with optically active salt-forming agents, separating the mixture into ae diastereomeric salts and transferring the salts to the free compounds, or by carrying out fractional crystallization from optically active solvents.

The present method also includes such embodiments where as starting materials compounds are used which appear as intermediates at one or another stage and the missing process steps are carried out with these substances, or whereby the process is interrupted at one or another stage, furthermore starting materials can be used in form of derivatives or form them in the reaction process.

As a rule, only one of the starting materials is used

to the particularly preferred compounds, the same applies to reaction conditions.

In starting substances of formula II, the leaving group Y is preferably a group -SOg-R^, where R^ has the stated meaning and especially the preferred meaning.

The process according to the invention differs from these known methods in that it starts from cheap and easily available starting materials, in particular 1-oxides of the fermantatively producible penicillins G or ? and 6-amino-penicillanic acid, whose reaction-active groups are protected in known ways and can be easily released after the reaction, and in that the production of intermediate products according to the invention takes place with high yields.

The starting substances with formula II according to the invention can e.g. is produced 1 according to the following reaction core:

Starting substances with formula III are known or can be prepared according to known methods.

Compounds of formula IVa are also known or can be prepared according to Dutch patent no. 72.08671•

The new compounds of the formulas IVb, IVc, Va, Vb, Vc, Via, VIb, VIc, Ila, Hb and lic, where Rx<a>, R^, Rg<A> and Y have meanings as indicated under formula II, as well as the method for their production, are also the subject of the present invention.

Compounds of formula IVb can be prepared from compounds of formula III by reaction with a sulfinic acid of formula HSOg-R^ or a sulfonyl cyanide of formula ft^S-SOg-R^. Compounds of formula IVc can be prepared from compounds of formula III by reaction with a thiosulfonic acid of formula H-S-SOg-R^. The reaction takes place in an inert solvent

or solution mii-elblaning, e.g. in an optionally halogenated, such as chlorinated, aliphatic. cycloaliphatic or aromatic hydrocarbon of the pentane, hexane type. cyclohexane, benzene toluene methylene chloride, chloroform or chlorobenzene, an aliphatic, cycloaliphatic or aromatic alcohol such as lower alkanol, of the methanol, ethanol, cyclohexanol or phenol type. a polyhydroxy compound such as a polyhydroxyalkane, of the hydroxyalkane type such as ethylene or propylene glycol, a lower ketone such as acetone or methyl ethyl ketone, an ethereal solvent such as diethyl ether, dioxane or tetrahydrofuran, a lower carboxylic acid ammonia such as methylformamide or dimethylacetamide, a lower dialkyl sulfoxide such as dimethyl sulfoxide and the like or also mixtures of these .

The reaction takes place at room temperature or preferably at an elevated temperature>e.g. at the boiling point of the solvent, and dried under an inert gas atmosphere such as nitrogen.

The reaction with sulfonyl cyanide of formula tMJ-SOg-R^ is accelerated by the addition of compounds which supply halogen anions. Suitable such halogen anion scavenging substances are e.g. quaternary ammonium halides, especially chlorides and bromides, e.g. lower alkyl-substituted, for example aryl-substituted, phenyl-mono- or poly-substituted tetra-lower alkylammonium halides, such as tetraethyl or benzyl triethylammonium chloride or bromide. The halogen-emitting compounds are added in amounts of approx. 1

to 50 mole percent, preferably 2 to approx. 5 mole percent.

Compounds of formula IVb and IVc can also be prepared by reacting a compound of formula IVa with a heavy metal sulfinate of formula M<n>~<*>(~SOg-R^)nrespectively with a heavy metal t i o sulf o nat with formula M^pS-SOg-R^ )n, where BI denotes a heavy metal cation and n denotes the value of these cations. Suitable heavy metal sulfinates or -thiosulfonates are particularly those which have a greater solubility product in the reaction medium used than the heavy metal compounds formed during the reaction, with the formula ^"^"S-R^^. Suitable heavy metal cations M<n+> are particularly those which form particularly sparingly soluble sulphides. The dtee includes e.g. monovalent or divalent cations of copper, mercury, silver and tin, whereby copper and silver cations are preferred.

Heavy metal sulfinates or -^thiosulfonates can either be used as such or formed in situ in the reaction mixture, e.g. starting from a sulfinic acid with the formula HSOg-R^ or a thiosulfonic acid with the formula H-S-SOg-R^ or a soluble salt of these, for example an alkali metal, such as a sodium salt, and a heavy metal salt, whose solubility product is greater than the product for the formed heavy metal sulfinate or -thiosulfonate, e.g. a heavy metal nitrate, acetate or sulphate, examples are silver nitrate, mercury II diacetate or copper II sulphate or a soluble chlorine such as stannous chloride dihyurate.

The reaction of a compound of formula IVa with heavy metal sulfinates of formula M<n>^(~"SOg-R^)n or -thio-sulfonates of formula Mn^(~S-SOg-R^)n can take place 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 of the type a w methanol, ethanol, cyclohecranol or phenol, polyhydroxy compounds such as polyhydroxyalkanes, for example dihydroxyalkanes such as ethylene or propylene glycol, carboxylic acid esters such as lower carbonic acid lower alkyl esters, such as ethyl acetate, lower ketones, such as acetone or methyl ethyl ketone, ether dissolving agents such as aioxane , tetrahydrofuran or polyethers such as dimethoxyethane, lower carboxylic acid amides such as dimethylformamide, lower alkyl nitriles such as aceto nitrile or lower sulfoxides such as aimethyl sulfoxide. In water, especially in mixtures of water and one of the best solvents, including in emulsions, the reaction usually proceeds much faster than in organic solvents alone.

The reaction temperature is usually at room temperature, but to dampen the reaction, it can be lowered or, to increase the reaction, increased to around the solvent's boiling point, as normal pressure or positive pressure can be used.

. In a prepared compound of formula IV, a group R^a, R^k or Rg^ can be transferred to another group R^<a>, R^ or

Rg A, as analogous reactions can be used as for the conversion

of these groups in compounds of formula IA or IB.

In step 2 or 3 or 2a, a compound of formula IV can be transferred to an oxo group in a compound of formula VI by oxy decomposing of the ethylene group.

The oxidative cleavage of the methylene group in compounds of formula IV during cleavage of an oxo group can occur without the formation of an ozonide compound of formula IV by treatment with ozone. Ozone is then normally used together with a solvent, e.g. an alcohol of the lower alkanol type such as methanol or ethanol, a ketone such as a lower alkanol of the acetone type, an optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. a haloalkane such as methylene chloride or carbon tetrachloride, or a solvent mixture, including aqueous mixtures, under cooling or gentle heating, e.g. at temperatures between approx. -90 and -»-40°C.

An ozonide of formula Va homo intermediate can, possibly without isolation, be transferred to a compound of formula Vb or Vc by reaction with a heavy metal sulfinate of formula Mn+(~S-SO2-R^)n or a -thiosulfonate of formula Mn^(~ S-SO2-R^)n, by analogy with the reaction of compounds of formula IVa to compounds of formula IVb or IVc.

An ozonide of formula V can be cleaved reductively in step 3 to a compound of formula VI, whereby catalytically activated hydrogen is used, as hyarogen together with a heavy metal hydrogenation catalyst such as nickel or palladium catalyst, preferably on a suitable carrier such as calcium carbonate or coal or chemical reducing agents such as reducing heavy metals including heavy metal alloys' or -amalgams, such as zinc in the presence of a halogen donor, such as an acid of the acetic acid type or an alcohol such as a lower alkanol, reausrenae inorganic salts such as

alkali metal iodides of the sodium iodide type in the presence of a hydrogen-donating compound such as e.g. an acid of the acetic acid type, or a reducing sulphide compound such as endyl alkyl sulphide, such as aimethyl sulphide, a reducing organic phosphorus compound such as a phosphine, which may optionally be substituted with aliphatic or aromatic hydrocarbon residues, for example tri-lower alkyl phosphines, such as tri-n-butyl phosphine , or triarylphosphines, such as triphenylphosphine,

further phosphites, which optionally contain substituted aliphatic hydrocarbon residues as substituents, for example tri-lower alkyl phosphites, usually in the form of additional alcohol adduct compounds, such as trimethyl soffite, or phosphoric acid triamides, which optionally contain aliphatic hydrocarbon residues as substituents, examples are hexa-lower alkyl phosphoric acid triamides, among others hexamethyl- phosphoric acid triamide, the latter preferably in the form of a methanol adduct, or tetracyanethylene. The splitting of the usually not isolated ozonide normally takes place under the same conditions as during the preparation, ie in the presence of a suitable solvent or solvent mixture, during cooling or slight heating.

Banol compounds of formula VI can also exist in the tautomeric keto form.

An enol compound of formula Via can, by reaction with a heavy metal sulfinate of formula Mnr(""SOg-R^)n, or -thiosulfonate of formula M<n>^(~S-SOg-R^)n, be transferred to a compound of formula VIb or Vie, in analogy with the conversion of compounds of formula IVa to compounds of formula IVb or IVc respectively.

In a prepared compound of formula VI can. a group Rj8, R^ or RgA is transferred to another group Rla ^ R^b or Rg^, for which one can use analogous reactions as for the transfer of these groups in compounds of formula IA or IB.

In step 4, a produced enol compound is transferred

of formula VI by etherification to a compound of formula II.

For the production of lower alkyl and optionally substituted α-phenyl lower alkyl enol ethers of formula II, the etherification reagent is used, e.g. a corresponding ciazo compound, in particular a diazolalkane, such as diazomethane, aiazoethane, diazo-n-butane or an optionally substituted o-phenyldiazolalkane, such as phenyl- or diphenyldiazomethane. These reagents are used together with a suitable inert solvent such as e.g. an aliphatic,. cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon such as methylene chloride,

a lower alkanol such as methanol, ethanol or tert-butanol, or an ether such as e.g. endyl dealkyl ether of the type diethyl ether, or a cyclic ether such as tetrahydrofuran or dioxane, or a solvent mixture, and, depending on the diazo reagent, under cooling, at room temperature or gentle heating, and further on

required in a closed container and/or under an inert gas atmosphere such as nitrogen.

Furthermore, lower alkyl and optionally substituted α-phenyl lower alkyl enol ethers of formula II can be obtained by treating an enol compound of formula VI with a reactive ester of a corresponding alcohol of formula R^°-OH. Suitable esters are primarily esters with strong inorganic or organic acids, such as mineral acids of the hydrohalic acid type, for example hydrochloric acid, hydrobromic acid or hydroiodic acid, further sulfuric acid or halo-sulfuric acid, such as fluorosulphuric acid or strong organic sulphonic acids such as optionally halogen-, such as fluorine-substituted low alkane sulphonic acids . These reagents and in particular lower alkyl sulfates such as dimethyl sulfate, further lower alkyl fluorosulfates such as methyl fluorosulfate, or optionally halogen-substituted methanesulfonic acid lower alkyl esters, such as trifluoromethanesulfonic acid methyl ester or corresponding α-phenylaalkyl, e.g. benzyl esters and olphenylmethyl esters, such as benzyl or diphenylmethyl halides such as chlorides or bromides, are advantageously used in the presence of a solvent such as e.g. an optionally halogenated, for example chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, such as methylene chloride, an ether such as dioxane or tetrahydrofuran or a lower alkanol such as methanol, or a solvent mixture. It is advantageous to use suitable co-entraining agents such as alkali metal carbonates or hydrogen carbonates, e.g. sodium or potassium carbonate or hydrogencarbonate (usually together with a sulfate), or organic bases which usually hinder tri-lower alkylamines, examples are N,N-diisopropyl-W-ethylamine (preferably together with lower alkyl halogen sulfates or optionally halogen-substituted methanesulfonic acid lower alkyl esters), and one uses cooling, room temperature or heating, e.g. at temperatures between approx. -20 and 50°C and, if necessary, in a closed container or inert gas such as nitrogen.

In the case of phase transfer catalysis (see E.V. Dehmlow, Angewandte Chemie 5/1974, page 187) the etherification reaction can be significantly accelerated. As phase transfer catalysts, quaternary phosphonium salts and especially quaternary ammonium salts can be used as optionally substituted tetraalkylammonium halides of the type tetrabutylammonium chloride, bromide or iodide, or benzyl triethylammonium chloride in catalytic or up to equimolar amounts. As an organic phase, one can use a solvent which is not miscible with water, e.g. one of the aforementioned halogenated, for example chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbons such as tri- or tetra-chloroethylene, di-, tri- or tetrachloroethane, chlorobenzene, especially tetrachlorocarbon or toluene or xylene. Alkali metal carbonates or hydrogen carbonates suitable as condensing agents, e.g. potassium or sodium carbonate or hydrogen carbonate, alcohol metal phosphates such as potassium phosphate and alkali metal hydroxides such as sodium hydroxide can be titrated into the reaction mixture when base-sensitive compounds are present, so that the pH during the etherification stays between approx. 7 and 8"5"

Lower alkyl enol ethers of formula II can likewise be prepared by treating an enol compound of formula VI with a compound which on a carbon atom of an aliphatic character has two or three lower alkyl etherified hydroxy groups of formula R^°-0, i.e. with a corresponding acetal or orthoester, in presence of an acidic reagent. Thus, one can e.g. as an etherifying agent use gem-lower carboxyl alkanes, such as 2,2-dimethoxy-propane, in the presence of a strong organic sulfonic acid, 3om p-toluenesulfonic acid and a suitable solvent such as a lower alkanol of the methanol type, or a lower alkyl or lower alkylene sulfoxy, such as dimethyl sulfoxide, or orthoformic acid tri-lower alkyl ester, such as orthoformic acid triethyl ester in the presence of a strong mineral acid such as 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 such as dioxane, and in the same way arrive at compounds of formula II where Rq° denotes lower alkyl such as methyl or ethyl.

Lower alkylenol ethers of formula II can also be prepared by treating enol compounds of formula VI with tri-lower alkyl oxonium salts of the formula (Ro°)qO®å® (so-called Meerwein salts), as well as with di-RoO carbenium salts of the formula (R^ JgHal Å or ai- Ho-halonium salts with formula (Ro<0>)5Hal^A<®>, where A<®> denotes

3©J

an acid anion and Hal denotes a halonium, especially a bromonium

ion and denotes lavallcyl. These are primarily tri-lower alkyloxonium urea salts as well as ailavaloxycarbenium

or lower alkylhalonium salts, in particular the corresponding salts with complex, fluorine-containing acids, for example the corresponding tetrafluoroborates, hexafluorophosphates, hexafluoroantimonates or hexachloroantimonates. Such reagents are e.g. trimethyloxonium or triethyloxonium hexafluoroantimonate, -hexachloroantimonate,

-hexafluorophosphate, or -tetrafluoroborate, dimethoxycarbenium hexafluorophosphate or dimethylbrominium hexafluoroantimonate. These etherification agents are preferably used in an inert solvent such as an ether or a halogenated hydrocarbon such as a diethyl ether, tetrahydrofuran or methylene chloride, or in a mixture of ice, if necessary in the presence of a base such as e.g. an organic base which can be a, preferably &erically hindered amine of the type N,N-diisopropyl-N-ethyl-amine and uncooling, at room temperature or under slight heating, e.g. at between approx. -20 and ^^ 0°C

and if necessary under inert gas atmospheres or in a closed container.

Compounds of formula II where the hydroxy protecting group Ro 0 denotes a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon residue are prepared by an acid-catalyzed addition, preferably catalyzed with a strong mineral acid, such as sulfuric acid or hydrochloric acid, of <x,{J -unsaturated aliphatic or cycloaliphatic ethers or thioethers such as 1-lower methoxy-lower alkenes of the type 1-methoxyethene or 1-methoxypropene, 1-lower alkylthio-lower alkenes such as 1-methylthio-ethene or 1-methylthio-propene, oxa- or thia-cyclovalkene-2 -enes or -2,4-dienes with 5~7 ring carbon atoms, e.g. 2,3-dihyarofuran, 2H-pyran, 3>4-dihydro-2H-pyran or corresponding analogous sulfur compounds, added on the 3-hydroxy group to a compound of formula VI. The addition can be carried out in an excess of unsaturated ether or thioether and optionally in an inert organic solvent, in particular an aliphatic, cycloaliphatic or aromatic hydrocarbon compound such as pentane, hexane, cyclohexane. benzene, toluene and the like, to the exclusion of water.

Silyl or stannyl ethers which are covered by formula II, i.e. compounds with formula II where R^° denotes a substituted silyl or stannyl group, are prepared using any suitable method for silylation or stannylation of enol groups, for example by treatment with a suitable silylating agent of the type dihalogenuyl-lower alkyl-silane, lower-alkyl-lower-alkyl-halo-silane or tri-lower-alkyl-silyl-halide, such as e.g. aichloro-dimethylsilane, methoxy-methyl-dichloro-silane, tri-ethylsilyl chloride or dimethyl-tert-butyl-silyl chloride, using such silyl halide compounds preferably in the presence of a base such as pyridine, with an optional N-mono-lower alkylated, N,N -di-lower alkylated, N-trilower alkylsilylated or N-lower alkyl-N-trilower alkylsilylated N-(tri-lower alkylsilyl)-amine (see e.g. British Patent No. 1,073,530)»e.g. with a hexalower alkyldisilazane such as hexamethyldisilazane or with a silylated carboxylic acid amide such as a bistriloweralkylsilylacetamide, such as bistrimethylsilylacetaride, or trifluorosilylacetamide, rather with a suitable stannylating agent such as e.g. a bis-(tri-lower alkyl tin) oxide such as bis-(tri-n-butyl tin) oxide, a tri-lower alkyl tin hydroxide, such as tri-ethyl tin hydroxide, a tri-lower alkyl lavalk xytrnn-, tetra-lavalkoxytin - or a tetra-lower alkyl tin compound, or with a tri-lower alkyl tin halogen, such as tri-n-butyl tin chloride (see e.g. Dutch explanatory document 67/IIIO7).

A compound of formula Ila, where R^<0> denotes lower alkyl or a hydroxy group protecting residue, can be transferred to a compound of formula Ilb, respectively lic by reaction with a heavy metal succinate of formula M (S0g-R^)n or -thiosulfonate of formula M<n>^(~S-S0g-R^)n, in analogy with the reaction of compounds with formula IVa to IVb or IVc.

In a prepared compound of formula II, a group a b R o Å or R Q can be transferred to another group ab

R^ , R-^ , Rg or R^ are transferred to another group R^ , R^ ,

Rg^ or R^ where analogous reactions are used for the conversion of other groups in compounds of formula Ia or IV.

The pharmacologically usable compounds according to the present invention can e.g. is used for the production of pharmaceutical preparations that contain an effective amount of active substance together with or in a mixture with inorganic or organic, solid or liquid, pharmaceutically usable carriers that are suitable for enteral or preferably parenteral administration. Thus, tablets or gelatin capsules containing the active substance are used together with diluents or thickeners such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and lubricants such as silica, talc, stearic acid or salts thereof such as magnesium or calcium stearate and/or polyethylene glycol. Tablets may contain a binder such as magnesiuraluminium silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and if desired disintegrants such as starch, agar, alginic acid or salts thereof which sodium alginate, and/or fizzy mixes or adsorbents, colourants, flavorings and sweeteners. Furthermore, the new pharmacologically active substances can be used in the form of injectable preparations, e.g. intravenous preparations such as infection solutions. Such solutions or preferably isotonic aqueous solutions or suspensions such as e.g. can be prepared before use from freeze-dried preparations containing the active substance alone or together with a carrier such as e.g. sardines. The pharmaceutical preparations can be sterilized and/or additives such as preservatives, stabilizers, wetting agents and/or emulsifiers, solubility mediators, salts for regulating the osmotic pressure and/or buffers can be added.

The present pharmaceutical preparations, which may, if desired, contain other pharmacologically active and valuable substances, are produced in otherwise known manner, e.g. by means of known mixing, granulating, dragging, dissolving and freeze-drying processes, and contents from approx. 0.1 to 100$, especially between 1 and approx. 50$, active substance, lyophilisates up to 100$ active substance.

In the context of the present description, organic residues associated with the designation "lower" will contain up to 7 and preferably up to 4 C atoms, if nothing else is expressly defined, acyl residues contain up to 20 and preferably up to 12 and especially up to 7 C atoms.

The following examples shall illustrate the invention, temperatures are in degrees Celsius. The cefem compounds mentioned in the examples have in the 6- and 7-position and the aforementioned azetidinone compounds have in the 3- and 4-sthioling R configuration.

Example 1.

To a solution of 133 mS (0»2 mmol) isomeric mixture consisting of 2/"~4/(p-toluenesulfonylthio)-3-£enoxy-acetamiano-2-oxbazetidine-1-yiyl-3-methylcrotaByre-p-nitrobenzyl ester and a corresponding isocrotonic acid ester in a ratio of about 4-.1 in 4 ml of dry tetrahydrofuran, is added during 5 min« a solution of 60 µl (2 equivalents) 1,5-aiazabicyclo/~<5>'4»Q7unclec -5"en in 1 ml of tetrahydrofuran. After resting at room temperature for 4° min. diluted with 20 ml of benzene, cooled in an ice bath and stirred for 10 min. with 10 ml of 10# citric acid solution. The organic layer is separated and washed in sequence sodium bicarbonate solution, 10# sodium bicarbonate solution and sodium bicarbonate solution. The solution is now dried over magnesium sulfate, concentrated in vacuo, and the resulting yellow oil purified by chromatography-filtration on 4 g of acid-washed silica gel (2 kg of silica gel stirred with 3X 2 liters of concentrated hydrochloric acid for 10 minutes, decanted, washed with distilled water to neutrality , washed afterwards with methanol and activated at 120°C for 60 hours) with benzene/ethyl ester 5-1 as elution medium. The fractions containing the mixture of isomers are combined and concentrated in vacuo. A semi-solid isomer mixture is obtained which consists of 7P-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid p-nitrobenzyl ester and 7P-f,enoxyacetamido-3-methoxy-cef-2-em-4-carboxylic acid p-nitrobenzyl ester in the ratio of approx. 1:3>which can be separated on Woelm silica gel (activity III) with benzene/ethyl acetate 5:1 into two isomers. The rapidly migrating 7P~£enoxyacetamido-3-methoxy-cef-2-em-4-carboxylic acid p-nitrobenzyl ester is recrystallized from methylene chloride-ether and has a melting point of 129-131»5°C. The slowly migrating 7P~phenoxyacetamido-3-methoxy-cef-3-3 m-4-carboxylic acid p-nitrobenzyl ester has a melting point of 140.5-142°C (methylene chloride/ether).

The products can be further processed as follows:

A solution prepared at 0°C containing 555 mg (1.11 mmol) of crude mixture consisting of 7B-phenoxyacetamido-3-methoxy-cef2-em-4a-carboxylic acid-1-nitrobenzylase and 7P-phenoxy-acetamido-3-methoxy -cef-3-em-4-carboxylic acid p-nitrobenzyl ester in the ratio of approx. 3.1 in 33 µl of tetrahydrofuran is added with stirring to 16 ml of 0.1N potassium hydroxide solution cooled to 0°C. The mixture is further stirred for 5 minutes at 0°C, 100 ml of ice water and 100 ml of pre-cooled methylene chloride are added and stirred briefly. Addition of 1 ml of saturated aqueous sodium chloride solution causes a separation of the two phases. The organic phase is separated, the aqueous phase is washed with 20 ml of methylene chloride, poured over with 50 ml of methylene chloride and acidified with 20 ml of 2N hydrochloric acid. After shaking, the organic phase is separated and the hydrochloric acid solution is extracted with 2 x 10 ml of methylene chloride. The combined methylene chloride extracts are dried over sodium sulphate and evaporated in vacuo. The residue is recrystallized from methylene chloride/ethyl ether/pentane and gives 8B-phenoxyacetamido-3-methoxy-cef-2-em-4a-carboxylic acid with m.p. 142-145°C»

The starting materials can be produced in the following way

a) A solution of 36>6 g (0.1 M) 6-phenoxyacetamidopenicillanic acid 1B-oxide, 11.1 ml (0.11 M) triethylamine and 23.8 g

(0.11 M) p-nitrobenzyl bromide and 200 ml of dimethylformamide are stirred for 4 hours at room temperature under nitrogen. The reaction solution is poured into 1.5 liters of ice water, the precipitate is filtered off, dried and recrystallized twice from ethyl acetate-methylene chloride. The colorless, crystalline 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester 18-oxide melts at 179-180°C.

b) A solution of 5.01 g (10 mmol) of 6-phenoxyacetamido-penicillanic acid p-nitrobenzyl ester 1B-oxide and 1.67 g (10 mmol)

2-mercaptobenzthiazole in 110 ml of dry toluene is boiled for 4 hours under reflux under a nitrogen atmosphere. The solution is concentrated by distillation to approx. 25 ml and dilute with approx. 100 ml of ether. The precipitated product is recrystallized from methylene chloride-ether and 2-/~4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxazetidin-1-yl^-3-methylene-butyric acid-p-nitrobenzyl ester is obtained with m.p. 138-141°C

c) To a solution of 3»25 g (5>0 mmol) 2-[~4-(benz-thiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methylene-butyric acid -p-nitrobenzyl ester in 200 ml of acetone/water 9*1 (v/v) is added to 1.06 g of finely powdered silver nitrate. Immediately afterwards, the solution 890 mg (5 mmol) of sodium p-toluene sulphinate in 100 ml of the same solvent mixture is added (within 10 minutes). A pale yellow precipitate immediately forms. After

After stirring for 1 hour at room temperature, filter by adding celite. The filtrate is diluted with water and extracted twice with ether. The combined ether extracts are dried over sodium sulfate and, after evaporation, give the pale yellow solid 2-/~<*>4*"(p-toluenesulfonyl-thio )-3_:pheno^syacetamido-2-oxazetidin-1-yl7-3-methylenebutyric acid- p- nitrobenzyl ester Thin-layer chromatogram on silica gel (toluene/ethyl acetate 2:1): Rf value = 0.24, IR spectrum (in CHgClg): characteristic bands at 3.90, 5.56, 5.70, 5.87 , 6.23, 6.53, 6.66, 7.40, 7.50, 810, 8.72, 9.25, 10.95/u The product can be used further without purification.

The same compound can also be produced by the following method;

ci) To a solution of 3.25 g (5.0 mmol) 2-[4-(benz-thiazol-2-yldithio)-3-£enoxyacetamido-2-oxoazetidin-1-yl7-3-methylenebutyric acid-p -nitrobenzyl ester in 200 ml of aceto/water 9:1 (v/v) 1.58 g (1.2 equivalents) of silver p-toluenesulfinate are added in portions over the course of 10 min. Dispensations are stirred for 1 hour at room temperature, filtered and further processed as under lc). 2- /"~4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetiiin-1-yl7-3-methylene-butyric acid-p-nitrobenzyl ester7 is obtained in quantitative yield.

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

cii) 2-/~4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methylenebutyric acid p-nyl?robenzyl ester can also be prepared in analogy to example Ici) from 3>25£2 -/~4-(Benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetiiin-1-yl7-3- methylenebutyric acid p-nitrobenzyl ester and 1.87 g (2 equivalents) of copper II-di-p-toluenesulfinate in quantitative yield.

Copper II-di-p-toluenesulfinate is obtained by reacting copper sulfate and sodium p-toluenesulfinate (2 equivalents) in water. After filtration, the salt is dried in a vacuum for 12 hours at 60°C.

ciii) 2-/~"4-(p-toluenesulfonylthio)-3-phenoxyacetamido-3-oxoazetidin-1-yl7-3-methylenebutyric acid p-nitrobenzyl ester can also be prepared by analogy with example Ici) from 130 mg (2 -^f"4-(Benzthiazol-2-yldithio)-3-cephenoxyacetamido-2-oxoazetidin-1-yl/7~3-methylenebutyric acid p-nitrobenzyl ester and 85 mg (2 equivalents) of tin-II-di-p- toluenesulfinate.

Tin-II di-p-toluenesulfinate is prepared by reacting tin-II chloride (21^0) and sodium p-toluenesulfinate in water. After filtration and washing with water, the salt is dried in a vacuum for approx. 12 hours at 50-60°C.

cIV) 2-/~"4~ (p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl/-3-methylene isoacetic acid p-nitrobenzyl ester can also be prepared analogously to example Ici) from 130 mg 2 -/~<*>4-(benz-thiazol-2-yldlthio)-3-phenoxyacetamido-2-oxoazetidine/-1-yæ7-3-methylenetetramine-p-nitrobenzyl ester and 103 mg (2k equivalents) of mercury-II- di-p-toluenesulfinate.

Mercury-II-di-p-toluenesulfinate is produced by reacting mercury-II-di-acetate and sodium-p-toluenesulfinate in water. After filtering off and washing with water, the salt is dried under a vacuum for approx. 12 hours at 50-60°C.

cv) A solution of 517 mg (1.02 mmol) of 6-phenoxyacetaminopenicillanic acid p-nitrobrnyl ester -18-oxy and 187 mg (1.2 mmol) of p-toluenesulfinic acid in 10 ml of 1,2-dimethoxyethane (or dioxane) is heated for 4-5 hours in the presence of 3>5S molecular sieve 3A and under a nitrogen atmosphere at reflux, after which a further 308 mg (1.98 mmol) of p-toluenesulfinic acid dissolved in 2 ml of 1,2-dimethoxyethane is added in five portions of 45 minutes space. After 4 1/2 hours, the reaction mixture is poured into 100 ml of 5% 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 absorption residue is chromatographed on silica gel thick-layer plates with toluene/ethyl acetate 2:1 and gives 2-/~4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl-3-methyleneacetic acid p-nitrobenzyl ester.

evi) A mixture of 250 mg (0.5 mmol) 6-phenoxyacetamido-penicillanic acid p-nitrobenzyl ester-18-oxide, 110 mg (0.6l mmol) p-toluenesulfonyl cyanide and 5 mg (0.022 mmol) benzyl triethylarammonium chloride in 2 ml of dry, peroxide-free dioxane, stir under argon for 4 1/2 hours at 110°C. The solvent is evaporated in vacuo and the remaining yellow oil is chromatographed on acid-free silica gel. Elution with 3095 ethyl acetate in toluene gives 2-/~4-(p-toluenesulfonyl-thio)-3-phenoxyacetamido-2-oxoacetidin-1-yl7-3-methylene succinic acid p-nitrogenyl ester.

cvii) A mixture of 110 mg (0.61 mmol) of p-toluenesulfonyl cyanide and 4.5 mg (0.021 mmol) of tetraethylammonium bromide in 1 ml of pure

dioxane is stirred at 110°C under argon for 30 min." A suspension of 250 mg (0.5 mmol) of 6-phenoxyacetamido-penicillanic acid-p-nitrobenzyl ester-16-oxyci in 1 ml of dioxane is then added and the resulting solution is stirred for 4 hours vea 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. The organic phase is dried with magnesium sulfate and freed from the solvent in vacuo to give the crude product 2-[4-(P-toluenesulfonyl-thio)-3-phenoxyacetamido-2-oxoazetiain-1-yl7-3-methylene acetic acid p-nitrobenzyl ester .

d) In a solution of 1.92 g (3»0 mmol) 2-[4-(p-toluene-3n-sulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid-p -nitrobenzyl ester in 30 ml of dry methylene acetate is introduced

at -78°G within 33 min. 1.1 equivalents of ozone. Immediately afterwards, excess ozone is removed with a stream of nitrogen (15 min. at -78°C). 2.2 ml of dimethyl sulphide (10 equivalents) are added and the solution is warmed to room temperature. After a standstill of 5 hours, the solvent is distilled off in vacuo and the remaining colorless oil is taken up in 100 ml of benzene. The benzoic solution is washed with 3 x 50 ml portions of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. After recrystallization of the residue from toluene, 2-/~4"(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-.3-hydroxy-crotonic acid-p-nitrobenzyl ester with m.p. 159-160° C.

di) The crude product 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methylenebutyric acid p-nitrobenzyl ester prepared according to example lcvii) is dissolved in 20 ml of methyl acetate and ozonized at -70°C until, according to the thin-layer chromatogram, no starting material is present anymore. A stream of nitrogen is then passed through the solution which is heated to

0-5°C. A solution of 300 ml of sodium bisulphite is added

in 5 ml of water to the mixture and stir for approx. 5 min. until there is no longer any ozonide by detection on potassium iodide-starch paper. The mixture is diluted with ethyl acetate, the aqueous phase is separated, the organic phase is washed with water, dried over magnesium sulphate and evaporated in vacuo. The crude product is dissolved in 3 ml of methylene chloride and 15 ml of toluene is added. The precipitate is filtered off and the filtrate is evaporated in vacuo. The evaporation residue re-

is crystallized from methanol and gives 2-/~4-(p-toluenesulfon<y>ltio )-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-hydroxycrotonic acid-p^ nitrobenzyl ester with m.p. 159-160°C.

e) A solution of 1.93 S 2-[4-{p-toluenesulfonylthio)-3-phenoxyacetamido-28-oxoazetidin-1-yl7-3-oxobutyric acid"'P-nitro~

benzyl ester (350 mmol) in 15 ml of dry chloroform is cooled to 0°C

and is added within 10 min. 6 ml of ethereal diazomethane solution (0.75 molar, corresponding to 1.5 equivalents). The mixture is stirred for 2 hours at 0°C, excess ayazomethane is removed with a stream of nitrogen and the solvent is evaporated in vacuo. The crude product is purified by filtration through Woelm silica gel (activity III, 4° times the amount) with benzene/acetic ester 5:1. The colorless oil that remains after distilling off the solvent crystallizes on standing. After recrystallization from methylene chloride-ether, an isomer mixture is obtained consisting of 2-/~4-(p-toluenesulfonyl-thio)-3-phenoxyacetamiciO-2-oxoazetidin-1-yl7-3-methoxy-crotonic acid -p-nitrobenzyl ester and the corresponding isocrotonic acid ester in the ratio of approx. 4:1» Melting point of the mixture 155-156.5°C. Example 2.

A solution of 279 mg of (2-/~4-{p-toluenesulfonylthio)-3-phenoxyacetamiot-2-oxoazetidin-1-yl7-3~nycirolcsicrotonic acid diphenylmethyl ester (0.428 mmol) in 4 ml of chloroform and 1 ml of hexamethyl- disilazane is heated at reflux for 1 hour, concentrated in vacuo and the oily residue is dried in high vacuum for 1 hour. The silylated crude product consists of 2-£~ 4-~(p-toluenesulfon<y>ltio )-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-trimethylsilyloxy-crotonic acid diphenyl methyl ester and the corresponding isocrotonic acid diphenyl methyl ester.

The crude product formed is dissolved in 3 ml of dry chloroform, cooled to 0°C and, under nitrogen and stirring, 0.069 ml (0.47 mmol) of 1,5-diazabicyclo/~5.4.07undec-5-ene is added. After 1 hour of reaction time, 0.3 ml of acetic acid is added to the solution and diluted with chloroform. The chloroform solution is washed with dilute sulfuric acid, water and dilute sodium bicarbonate solution. The water phase is extracted with chloroform, the combined organic phases are dried over sodium sulphate and evaporated in vacuo. The crude product 76-phenoxyacetamido-3-hydroxy-cef-3-em-4-carboxylic acid di-phenylmethyl ester is obtained. RF value: 0.13 (silica gel, toluene/ethyl acetate 3:1).

The crude product is taken up in methanol and added to vea

0°C an overview of ethereal ayazomethane solution. After 5 min. reaction time, the solution is evaporated completely, and the oil residue is chromatographed on silica gel thick-layer plates (toluene/ethyl acetate 3:1). The silica gel layer in the zone weighing Rf = 0.19 is extracted with edaikester and gives 70-phenoxyacetamiio-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester, m.p. 120°C (ether), IR spectrum (CHCl 3<:>3310,<1>775, 1700, 1690;1600 cm"<1>.

The starting material is produced as follows.

a) From 100 g (27.3 mmol) 6-phenoxyacetamido-penicillanic acid-18-oxy, 500 ml dioxane and 58.4 g (30 mmol) diphenyl-1-methyldiazomethane, after approx. 2 hours 6-phenoxyacetamido-penicillanic acid-diphenylmethyl ester-1B-oxyate, m.p. I44-I460C (ethyl acetate/petroleum ether). b) Analogous to example lb) one obtained from 292 g (55 mmol) 6-phenoxyacetamido-penicillanic acid-phenylmethylester-1B-oxide and 99 g (59>5 mmol) 2-mercaptobenzthiazole the product 2-[f~4-(benz-thiazole -2-yldithio)-3-phenoxyacetamido-2-oxoazetiuin-1-yl7-3-methylene-butyric-ylphenylmethyl ester, m.p. 140-141°C (toluene/ether).

c) By analogy with e&example lc) it was obtained from 10 g

(14.7 mmol) 2-[4-(benzthiazol-2-yllathio)-3-phenoxyacetamiano-2-oxoazetidin-1-yl7-3-methylsramic acid diphenyl methyl ester in 50 ml ethyl acetate 4.92 g (24.98 mmol ) finely powdered silver p-toluene-sulfinate and after 7 hours of stirring at room temperature, the product 2-/~4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl7-3~methylbutyric acid diphenyl methyl ester. Rf value = 0.28 (silica gel, toluene/ethyl acetate 3:1), IR spectrum (CHCl 2 ): 1782, 1740, 1695, 134O, 150 cm"<1>.

2-/"~4-(p-toluenesulfonylthio)~3~phenoxyacetamido-2-oxo-azetidin-1-yl7-3~methylenebutyric acid diphenyl methyl ester can also be prepared in the following way: ci) A suspension of 106.5 g 6 -phenoxyacetamio-penicillanic acid-diphenylmethylester-1B-oxide and 33g of 2-mercaptobenzthiazole in °£>0 ml of toluene and 9 ml of iseaaic are boiled under nitrogen for 2 hours on a fitted water separator, and approx. 4>5 ml of water are collected. The solution is cooled to room temperature , a total of 85.5 g of silver p-toluenesulfinate is added in portions over the course of 1 hour and then stirred for 2 hours at 22°. The mixture is filtered through <tf>Hyflo" and the filtrate

washed twice with saturated ordinary sodium chloride solution.

The organic phase is dried over magnesium sulfate, evaporated in vacuum to approx. 1 litre, can be dyed approx. 3° S "Worit" and aamped in. The yellow foam formed is crystallized from methylene chloride/ethyl ether, m.p. 79/82°C. Rf value = 0.55 (silica gel: toluene/ethyl acetate 3:1). A little more substance could be extracted from the moaer liquors by crystallization from methylene chloride/ethyl ether,

u) Analogous example la) was obtained from 10.8 g (16.2 mmol) of 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamio-2-oxoazetidin-1-yl7-3-methylenebutyric acid diphenyl methyl ester in 1 liter of methylene chloride and 1.1 equivalents of ozone the product 2-/~4-(p-t°luensulfony1"thio )-3-phenoxyacetamido-2-oxoazetidin-1-y]7-3-nyaroxycicro'tonic acid diphenyl methyl ester, m.p. 142-143°C (ether/pentane).

Ozonation can also be carried out at 0°C:

In a solution of 9.23 g (13.8 mmol) of 2-/~4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methylene-butyric acid-diphenylmethyl ester at 9°0 ml of methylene chloride is stirred in at 0°C over the course of 19 minutes with 15.2 mmol of ozone. The clear reaction solution is added to 10 ml of dimethyl sulphi 1 and stirred for 20 min. at 5°C. After evaporation in a water jet vacuum and drying of the residue in a high vacuum, a pale yellow foam is obtained which crystallizes from methylene chloride/hexane. The melting point for the formed 2-[4-(P"toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3"hydroxycrotonic acid diphenylmethyl ester is at 134~13S°C. Thin layer chromatogram. Rf-veroi approx. 0.46 (silica gel: toluene/ ethyl acetate 3:1)»

The same compound can also be produced by the following methods: .

di) A solution of 684 ml (1 mmol) of 2-/~<*>4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-hydroxy-crotonic acid α-phenylmethyl ester in 20 ml acetone/water <$:1 (v/v) is added without stirring 341 mg (1.3 mmol) of silver p-toluenesulfinate at room temperature for 60 min. 50 ml of acetone is added to the yellow reaction mixture and filtered. The filtrate is evaporated in vacuo and the evaporation residue is chromatographed on 30 g of acid-washed silica gel with toluene/ethyl acetate 4-1» The resulting 2-/~4-(p-toluenesulfonyl-thio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3 -hydroxycrotonic acid-

Phenyl methyl ester is recrystallized from ether/pentane and melts at 142-143°C.

aii) A solution of 72»9mS (0.1 mmol) crude ozonide, prepared via ozonization of 68.1 mg (0.1 mmol) 2-/~4~(benz-thiazol-2-ylthio)-3- phenoxyacetamido-2-oxoazetidin-1-yl7-3~methylenebutyric acid-diphenylmethyl ester in ethyl ester and evaporation of the solvent, in 2 ml of acetone/water 9.1 (v/v), 35 mg (1.3 equivalents) of silver-p- toluenesulfinate and stirred for 1 hour at room temperature. The reaction mixture is diluted with 3 ml of acetone and filtered. 0.2 ml of aimethyl sulphide is added to the filtrate and stirred for 2 hours at room temperature (until a negative iodine-starch reaction). After the solvent has been evaporated in vacuo, the residue is chromatographed on 38 acid-washed silica gel with toluene/ethyl acetate 4:1. The formed 2-[4-(p-toluenesulfinylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-hydroxycrotonic acid phenylmethyl ester is recrystallized from ether/pentane and melts at 142-143°C

After once more recrystallization from methylene chloride/ethyl ether, a melting point of 144-145°0 (corrected) is obtained, (a)^0 5=8 -68° v 1° (c = 1, chloroform), thin-layer chromatogram: Rf value 0.8l (silica gel, methylene chloride/ethyl acetate 8:2), UV spectrum (ethyl alcohol): \ mav » 26l nm (£ = 14.4OO), IR spectrum (NUjol): characteristic bands at 3.00, 5.56, 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, 12.30, 1326, 14.30/hr.

Example 3.

A solution of 3°1 mg (0.462 mmol) 2-/~4-(p-t-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetiuin-1-yl7-3-hydroxy-crotonic acid diphenyl methyl ester in 3 ml of 1,2-dimethoxyethane 0.12 ml of bis-trimethylsilyl acetamide (0.508 mmol) is added under a nitrogen atmosphere and stirred for 1 hour at room temperature. The solution is evaporated completely and the oily residue is dried for 1 hour under high vacuum. The silylated crude product is taken up in 3 ml of dry 1,2-dimethoxyethane and, after cooling to 0°C, 0.075 ml (0.508 mmol) of 1,5-diazabicyclo/~5.4.o7undec-5-ene is added. After a reaction time of 6 hours at 0°C under a nitrogen atmosphere, 0.3 ml of acetic acid is added and 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 sulphate, evaporated under vacuum and dried under high vacuum. The crude 88-phenoxyacetaraido-3-hydroxy-cef-3-em-4-carboxylic acid diphenylmethyl ester is obtained. The solution of the crude product in chloroform is added at 0°C with an excess of an ethereal diazomethane solution and allowed to stand for 5 minutes at 0°C. Then, the fustine is evaporated and the residue is chromatographed on silica gel as in example 2. 78-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenyl methyl ester is obtained, Rf value = 0.19 (silica gel; toluene/acetic ester 3:1), m.p. 120°C (from ether) IR spectrum (in CHCl 2 ): 3310, 1775, 1710, 1690, 1600 cm"<1>.

Example 4.

A solution of 100 mg (0.15 mmol) isomer mixture consisting of 2-/~4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester 1 4 ml of dry 1,2-dimethyloxyethane is added with stirring under a nitrogen atmosphere to 0.045 ml (0.3 mmol) of 5-diazabicyclo/"~5.4.<0>7undec-5-ene. The solution is stirred under nitrogen at room temperature for 40 minutes, then cooled with ice and add 0.1 ml of acetic acid. The solution is diluted with methylene chloride and then 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, evaporated and freed from solvent in a high-vacuum fullsteinag. oily residues are chromatographed on a silica gel thick-layer plate (eluent toluene/acetate 3*1*, developed once). The two zones at Rf = 0.19 and 0.4 are extracted together with acetate and the resulting solution in amped up completely. An oily product is obtained which consists of 78-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenyl methyl ester and the isomeric 7P-f,enoxy-acetamido-3-methoxy-cef-2-em-4- carboxylic acid diphenyl methyl ester in a ratio of 1:4. Rf value = 0.14 resp. 0.32 (silica gel, toluene/ethyl acetate 3:D> IR spectrum

(in CHC13); 34OO, 33IO, I785, 1770, 1750, 1710, I69O, 1530, 1600 cm"<1>.

i) The ratio between produced cef-2-em and cef-3-em derivatives depends, among other things, on of the solvent used for

ring closure reaction, the concentration of the starting substances and the 1,5-diazabicyclo/~5*4«9j^unclec-5-ene concentration as well as of the reaction time. In the following table, some reactions are listed which have been carried out in analogy with the above-mentioned example from a lOOmg isomer mixture consisting of approx. 95$ 2-/~4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl7-3-methoxy-isocrotonic acid diphenyl methyl ester and approx. 5$ equivalent crotonic acid derivative. The reaction time was in all cases 20 minutes and the preparation took place in the same way as described in the example above. a) The isomer mixture as starting material can be prepared in analogy to example le) from 4 g (6.14 mmol) 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl7-3 ~Hydroxycrotonic acid-diphenyl methyl ester and an overview of ethereal diazomethane infusion. The prepared isomer mixture consisting of 2-/~4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidine-1-yi7-3-methoxycrotonic acid diphenyl methyl ester and the corresponding isocrotonic acid diphenyl methyl ester (approx. 3:1) is crystallized from ethyl acetate/pentane and has a melting point of 150-152°C.

The isomer mixture as starting material, respectively crotonic and isocrotonic acid derivative can also be prepared in the following way: ai) A solution of 698 mg (1 mmol) isomer mixture consisting of 2-/~4-(benzthiazol-2-yltlo)-3-phenoxy- acetamido-2-

oxoazetidin-1-yl7-3-methoxy-crotonic acid diphenyl methyl ester°S

the corresponding isocrotonic acid phenylmethyl ester in 20 ml of acetone/water 9:1 (v/v) is stirred with 341 mg (1.3 mmol) of silver p-toluenesulfinate for 1 hour at room temperature. The yellow reaction mixture is diluted with 50 ml of acetone and filtered. The filtrate is evaporated under vacuum and the residue is chromatographed on 30 g of acid-washed silica gel with toluene/ethyl acetate 2:1. An isomer mixture is obtained consisting of 2-/~4-(p-toluenesulfoylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxy-crotonic acid diphenylmethyl ester and 2-/~4-(p-tol7enesulfonyl-thio) )-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3"-methoxy-isocrotonic acid diphenyl methyl ester.

aii) The reaction described under ai) can also be carried out in tetrahydrofuran instead of acetone/water, whereby one must stir approx. 24 hours at room temperature.

aiii) A solution of 33 mg (0.5 mmol) of 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl7-3-hydroxycrotonic acid diphenylmethyl ester in 4 ml of ethyl chloride is added at 0°C, 0.21 ml (1.2 mmol) ethyl diisopropylamine and 0.12 ml (1.5 mmol) fluorosulfonic acid methyl ester and stirred for 30 minutes at 0°C

and for 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 then dried over sodium sulfate. The evaporation residue is chromatographed on silica gel. Toluene/ethyl acetate 4*-l first elutes some starting material.

With toluene/ethyl acetate 1:1, an isomer mixture consisting of 2-/~4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxy-crotonic acid diphenyl methyl ester and the corresponding isocrotonic acid diphenyl methyl ester is then eluted, and these boron bonds are isolated.

aiv) A solution of 300 mg (0.447 mmol) of 2-/~4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-hydroxycrotonic acid diphenylmethyl ester in 4 ml of acetone is added to 76 mg ( 0.55 mmol) potassium carbonate and 0.088 ml (0.92 mmol) dimethyl sulfate and the whole is stirred for 5 hours at room temperature. The solution is diluted with ethyl acetate, washed with water and dried over sodium sulphate. After removing the solvent, the residue is recrystallized from ethyl ester/pentane and gives an isomer mixture which

consists of 2-[~4-p-t-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonic acid diphenyl methyl ester and the corresponding isocrotonic acid aiphenyl methyl ester.

av) A solution of 6,73&2-/~4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidine-ipyl7-3-hydroxycrotonic acid diphenyl methyl ester (crystalline) in 67 ml of absolute tetrayrodurane is added at -20°C 1, 57 g of M₂-ainitroso-N.fT-dimethyloxamide and then, over the course of 15 minutes, a solution of 0.57 ml (0.51 g) of ethylenediamine in 5 ml of tetrahydrofuran. After the addition, dry for 1 hour at 0°C, add 0.53 ml (H mmol) glacial acetic acid and 6.7 g celite and filter. The residue is washed with 5 times 20 ml of tetrahydofuran. Filtrate and washing liquids are combined, evaporated to approx. 20 g and add 20 ml of hexane. The crystals are filtered off, washed with tetrahydrofuran/hexane 1:2 and dried in high vacuum.

The crystals consist mainly of 2-£4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoadetidin-1-yl7-3-methoxy-isocrotonic acid diphenylmethyl ester. A sample is recrystallized from ethyl acetate/diethyl ether and gives the following analytical values: m.p. 167-169°C, (a)^° = -30°+1° (c - 1, methylene chloride), thin layer chromatogram: Rf value 50 0.57 (silica gel, methylene chloride/ethyl acetate/glacial acetic acid 60:40:1), U¥ spectrum (ethyl alcohol), ~ Kmax<=>260nyu (£ = I6.6OO), IR spectrum (nujol): characteristic bands vea 2.97, 5.62, 5.90, 6.27, 6, 61, 6.66, 7.17, 7.53, 7.70, 7.9°, 8.02 , 8.20 , 8.80 , 9.20, 10.26, 12.24, 13.30 /U. JMMR spectrum

(100 megahertz in CDC1^):%2.32 (s/CHo), 2.34 (s/CH^l 3.73 (s/ OCH3), 4.30/4.44 (AB, J » 5/ azetidine-4-CH-), 6.8-7.5 (w/19 aromatic H,KH) ppm.

The mother liquor also contains a little isocrotonic acid derivative, mainly 2-/~4-(P-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxycrotonic acid diphenylmethyl ester, which after chromatography3k purification on silica gel has mp I46-I48<0>(corr., from ethyl acetate/hexane), NMR spectrum (100 megahertz+in CDCl„):S2.08 (s/vinyl-CH^), 2.26 (s/aromat.- CH3), 3.70 U/-OCH3), 4.47 (s/-0CH2C0-), 4.94 (dd/

J = 5 and 8/azetidine-3-CH-), 5.84 (d/J =» 5/azetidine-4-CH-),

6.8-7.5 (m/19 aromatic H, -NH-) ppm, (a)|° » +21° +1° (c = 1, methylene chloride).

avi) A suspension of 6.72 g (10 mmol) of 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetiline-1-yl]-3-hydroxycrotoic acid phenylmethyl ester (crystalline) and 0.36 g (1 mmol) of tetra-n-butylammonium iodide in 100 ml of toluene is added to 3.78 g (30 mmol) of dimethyl sulfate and 30 ml of a 20% aqueous potassium bicarbonate solution, and stirred vigorously for 4 hours at room temperature. During the first 15 minutes of ownership, the solid dissolves. The mixture is diluted with jtoluene and washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate and evaporation, crystallization from ethyl acetate/diethyl ether gives 2-/~4-(p-toluenesulfonyl-thio J^-phenoxyacetamido^-ofesoazetidin-1-yJjT^-methoxy-isocrotonic acid-diphenyl methyl ester).

avii) A suspension of 3.36 g (5 mmol) of 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-hydroxycrotonic acid diphenylmethyl ester (crystalline) in 15 ml of carbon tetrachloride and 10 ml of water, 1.08 g (3 mmol) of tetrabutylammonium iodide and 1.9 ml (2.52 g, 20 mmol) of dimethyl sulfate are added. The mixture is stirred vigorously at room temperature and added through an automatic ticrator which provides IN caustic soda, that the pH remains constant at 7>0»1 during 4-5 hours 1.5~2 equivalents of caustic soda are consumed. Vinegar is added to the mixture and diluted with water and some table salt is added. The organic phase is dried over sodium sulfate and concentrated. The residue is crystallized from a little ethyl ester/hexane 1:1 and gives 2-/~4-(p-toluenesulfonylthio)~3~phenoxyacetamiao-2-oxoazetidin-1-y37-3~metholccy-isocrotonic acid-aifenyl methyl ester.

The isomer blank that is used as starting material can also be prepared via the corresponding 2-benzoxazole derivatives as follows: aviii) A solution of 10 g of 6-phenoxyacetamio-penicillanic acid-diphenylmethylester-18-oxide and 3 g of 2-mercapto-benzoxazole in 25 ml of dry tetrahydrofuran is completely evaporated in vacuo. The remaining foam is heated in a water jet vacuum for 70 minutes at 120°C (oil bath temperature). The melt residue is chromatographed after cooling on 500 g of acid-washed silica gel with toluene/ethyl acetate 6:1 and then 3:1. 2-[4-(benzoxazol-2-ylthidio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]f-3-methylene-butyric acid-diphenyl methyl ester is obtained in the form of a white foam, IR spectrum (methylene chloride): characteristic bands at 5.6, 5.75, 5>SP>6»7/u»

aix) Wet a solution of 3.35 g of 2-[4-(benzoxazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methylene-butyric-diphenylmethyl ether cooled to ~70°C and dissolved in 125 ml of ethyl acetate, an equivalent amount of ozone (in the form of a Og/O^ mixture) is introduced, until the starting material can no longer be detected by thin-layer chromatography (silica gall, toluene/ethyl acetate 3:1). The solution is evaporated in vacuum to approx. 50 ml, add 5 ml of dimethyl sulphide and stir until no reaction is obtained with the potassium iodide-starch test. The mixture is evaporated in vacuo, the residue is dissolved in 150 ml of benzene and washed with water. The organic phase is dried over sodium sulfate and evaporated. The evaporation residue is chromatographed on 150 g of acid-washed silica gel with token/ethyl acetate 4:1, 2-/~4-(benzoxazol-2-yldithio)-3-phenoxy^-acetamido-2-oxoazetidin-1-yl7-3-nyar9oxy- crotonic acid diphenyl methyl ester in the form of a white foam, IR spectrum (methylene chloride): characteristic bands at 5>60> 5>90»6.0µU.

ax) To a solution of 1.7 g of 2-[benzoxazol-2-yl-dithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-hydroxy-crotonic acid diphenyl methyl ester in 12.5 ml methylene chloride is added dropwise by 0°C with stirring an ether-diazomethane solution, until starting material can no longer be detected by thin-layer chromatography (silica gel: toluene/ethyl acetate 3:1). 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. An isomer mixture is obtained which consists of 2-/~"4-(benzoxazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1/yl7-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxycrotonic acid- dif eny Imet yl ester in the ratio of about 5-.I, IR spectrum (methylene chloride): characteristic bands at 5.60, 5.85 sh, 5.90, 6.40, 6.65 ju .

axi) A solution of 682 mg (1 mmol) isomer mixture consisting of 2-/~4-(benzoxazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid aiphenylmethyl ester in 20 ml of acetone/water 9:1 (v/v) is stirred with 350 mg (1.3 mmol) of silver p-toluenesulfinate

for 90 min. at room temperature. The mixture is filtered through "Celite", the filtrate is evaporated in vacuo to 5 ml and extracted with 30 ml of methylene chloride. The methylene chloride phase is dried over sodium sulphate and evaporated in vacuo. The evaporation 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-toluenesulfonyIl)-3-phenoxyacetamido-2-oxoazethioin-1-yl7-3-methoxy-crotonic acid -diphenyl methyl ester and the corresponding isocrotonic acid diphenyl methyl ester.

Example 5.

A solution of 300 mg (0.45 mmol) of the crystallized mixture of isomers prepared in example 4 a) and consisting of 2-/~4-(p-t toluenesulfonyl io-3-phenoxy y c etamido-2-oxoazetidin-l-ylJ- 3-Methoxy-crotGns<y>re-diphenyl methyl ester and the corresponding isocrotonic acid ester in 4 ml of dry 1,2-dimethoxyethane are stirred at room temperature under a nitrogen atmosphere with 0.134 ml (0.9 mmol) of 1,5-diazabicyclo/~5.4.07unaec-5 -en. After a reaction time of 4° minutes, the solution is cooled to 0°C and 0.4 ml of acetic acid is added and then 180 mg (1.36 mmol) of m-chloroperbenzoic acid (85 µg). The solution is stirred for 10 minutes at 0°C under nitrogen, dilute with chloroform and wash 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, evaporated in vacuo and the solvent is evaporated in high vacuum. The crude product formed is separated on silica gel -thick layer plates (developing agent vinegar, one time development).Sil The ikagel mass in the zone at Rf = 0.51 is extracted with acetic acid, the resulting solution is evaporated and the residue is dried in high vacuum. One obtains as an oily residue " J-phiphenoxy-acetamido-3-methoxy-cef-3-em-4-carboxylic acid aiphenylmethylester-16-oxide which crystallizes from methylene chloride/pentane, m.p. 115-120°C.

By extracting the silica gel in the zone at Rf =» 0.22 with acetic acid, evaporating the solution in a rotary evaporator and drying the oil residue, 7$- £enoxyacetami ;.o-3-methoxy-cef-4-em-4- can be obtained carbonic acid dif eny Imet yl ester loc oxide, m.p. 175-180°C (chloroform).

The same compounds can also be prepared according to example i) or ii): i) A solution of 24.7 mg (3& mmol) of crystallized isomer mixture prepared as in example 4 a)>consisting of 2-/J~4-(p -toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3"methoxycrotonic acid aiphenyl methyl ester and the corresponding isocrotonic acid ester in 247 ml of dry 1,2-dimethoxyethane are stirred at room temperature under nitrogen with 8.22 ml (54 mmol) 1,5-diaza-bicyclo/~5.4«07dnoec-5-ene After a reaction time of 40 minutes the solution is cooled to 0°C and cet is added 3.73 ml of formic acid and then 37.3 ml (108 mmol) of performatic acid (prepared from 33 ml of perhyarol (30$-ig) and 100 ml of formic acid). The solution is stirred for 10 minutes at 0°C under nitrogen, diluted with chloroform and washed with dilute sulfuric acid/sodium thiosulphate, water and dilute sodium bicarbonate solution. The aqueous phase is extracted with chloroform, containing organic phases are dried over sodium sulfate, concentrated in a vacuum and freed from solvent in a high vacuum. The crude product formed is crystallized from methylene chloride/pentane and gives 7P~phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid-Giphenyl-methylester-18-oxy mea m.p. 115-120°C.

ii) A solution of 1.5 g (2.19 mmol) of crystallized isomer mixture prepared according to example 4a)°6 consisting of 2- /~"4-( p-toluenesulfonylthio )-3-phenoxyacetamido-2-oxoazetian-1-yl7- 3""Methoxy-crotonic acid iiphenyl methyl ester and the corresponding isocrotonic acid ester in 7»5 ml of dry 1,2-dimethoxyethane are stirred at room temperature under nitrogen with 0.43 ml (2.84 mmol) of 1,5-^iaza-bicyclo/~5.4» 9_/dnaec-5-ene. After 40 minutes of reaction time, the solution is cooled to 0°C and 0.375 ml (6.55 mmol) of acetic acid is added, followed by 0.667 ml (4.8 mmol) of 7>2N peracetic acid. The solution is stirred for 20 minutes . at 0°C under nitrogen, 0.24 ml of sodium bisulfite solution (20 µg) is then added. With vigorous stirring, 22.5 ml of water is added to the reaction mixture. Thereby the mixture of 76-phenoxyacetamido-3-methoxy-cef crystallizes -3-em-4-carboxylic acid phenylmethyl ester-IB- and -la-oxy out. The precipitate is filtered, washed with water and dried under high vacuum.

iii) To a suspension of 98.8 g (144 mmol) of 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxy-isocrotonic acid diphenyl methyl ester in 988 ml of 1, The 2-dimethoxyethane is placed at room temperature under a nitrogen atmosphere during 2 min. and while stirring 32»9ml (216 mmol) 1,5-diazabicyclo/~5.4.0/-

the undec-5. The solution now becomes clear and is stirred further for 25 min. at room temperature, cooled to 0°C, 14*9ml (395 mmol) of formic acid are added at the same time and after cooling to -20°C, 149 ml of a mixture of 66 ml of perhyirol (approx. 30$-ig) and 134 ml of formic acid ( 432 mmol HgOg). The reaction solution is stirred for 15 min. at 0°C and add 37 g of sodium thiosulphate dissolved in 500 ml of water. Over the course of an hour, at 5°0, approx. 300 ml of water.

After a further 2 to 3 hours of stirring at 5°G, the crystalline substance consisting mainly of 7P-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethylester-1B-oxide is filtered off, washed with cold water (3° C) and diethyl ether and dried in high vacuum over calcium chloride.

The filtrate is added with vigorous stirring at fj°C

7 liters of water. The precipitate is initially oily and on standing overnight becomes solid and consists predominantly of "Jphi-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid-aphenyImethylester-ip-oxide,

washed off with ice-cold water and dried in high vacuum over calcium chloride.

iv) 34.35 g (50 mmol) of 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxy-isocrotonic acid diphenyl methyl ester is suspended at 20°C under a nitrogen atmosphere in 340 ml of tetrahydrofuran (the majority dissolves). After rapid addition of 11.4 ml (75 mmol) 1,5-diazabicyclo/~5.4.07-unaec-5-ene, the solution is stirred for 15 min. at 20°C, 1.9 ml (30.2 mmol) of glacial acetic acid are then added and evaporated in vacuo at 30°C to dryness. The brown frothy residue is dissolved in 130 ml of methylene chloride and washed successively with 60 ml of water, 30 ml of 0.5N hydrochloric acid, 30 ml of water, 30 ml of 1M NaHCO 3 solution and 30 ml of water. The aqueous phases are extracted twice with 10 ml of methylene chloride.

The combined and not dried methylene chloride phases are cooled to -10°C and 7.0 ml of peracetic acid/acetic acid (containing approx. 5 mmol of peracetic acid) are slowly added (temperature rise up to

-KL0°C). After 15 minutes of stirring at 0 to 5°C, the excess of peracid is destroyed with aqueous sodium thiosulphate. The water phase is separated and washed with a little methylene chloride. After the solution has been dried over magnesium sulphate, it is evaporated in a vacuum. The pale yellow residue consisting of a mixture of 7P-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester-1-oxide and 7B-

Phenoxyacetamido-3-methoxyacetate-1-oxide in a ratio of approx. 2:1 is dissolved in 120 ml of monoglyme at room temperature, 3° ml of water is added, whereby first 7P-phenylacetamido-3-methoxy-cef-3-em-4-carboxylic acid-diphenylmethylester-1B-oxy crystallizes out. The thick crystal porridge is first stirred for 1/2 hour, then added during approx. 5 hours at room temperature and while stirring 150 ml of water, whereby the corresponding 1B-oxygen also crystallizes out. After a total of 17 hours of stirring, the ice bath is cooled for 1 hour, filtered and the residue is washed with slightly cooled monoglyme/water 1:1.5. The crystals are dried in a high vacuum for 16 hours over P205'Man £^ r 7P~phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid-diphenylmethylester-18-oxy which still contains part of the corresponding lcc-oxy.

The produced 1-oxides can be processed further in the following way: a) A solution of 150 mg (0.275 mmol) of 7p-phenoxy-acetamiao-3-methoxy-cef-3-em-4-carboxylic acid-diphenylmethylester-18-oxide in 3 ml of methylene chloride and 0.1 ml of methylformamii are added after cooling to 0°C 188 mg (1.37 mmol) of phosphorus trichloride. Up- . the solution is stirred at 0°C for 30 minutes, diluted with methylene chloride and washed with aqueous sodium bicarbonate solution. The water phase is extracted with methylene chloride, the combined organic phases are dried over sodium sulphate and evaporated in vacuo. The resulting crude 78-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenyl methyl ester is recrystallized from ether, m.p. 120°C.

ai) A suspension of 5.0 g (9»16 mmol) of 7p-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid phenylmethyl ester-1a-oxide in 25 ml of methylene chloride and 1.25 ml of dimethylacetamia is added after cooling to 0°C 1.69 ml (19.3 mmol) phosphorus trichloride. The solution is stirred at 0°C for 3° min., diluted with acetic acid and washed with aqueous sodium bicarbonate solution. The water phase is extracted with acetic acid, the combined organic phases are dried over sodium sulphate and evaporated in a vacuum. The crude 7β-phenoxyacetamido-3-methoxy-3cef-3-em-4-carboxylic acid diphenylmethyl ester formed is recrystallized from ether, m.p. 120°C.

b) A solution of 2.0 g (3.78 mmol) of 7p-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester in

5 ml of methylene chloride is added to 0.87 ml of anisole, cooled to 0°C

and set aside after adding 1.2 ml of trifluoroacetic acid i

1 hour. The reaction mixture is then concentrated in vacuo and the residue is crystallized from acetone/ether. 7B-phenoxyacetamido-3"methoxy-cef-3-em-4-carboxylic acid is obtained with m.p. 170 C (decomp).

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

bi) . A suspension of 3.0 g (5.5 mmol) of a mixture of 7B-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid aiphenylmethyl ester-18- and -1a-oxide in 15 ml of methylene chloride and 0 .75 ml of dimethylacetamide is added after cooling to 0°C 0.966 ml (1.11 mmol) of phosphorus trichloride. The solution is stirred at 0°C for 40 minutes, then 4.65 ml (ÉI mmol) of trifluoroacetic acid is added and stirred at 0°C for a further 30 minutes. The reaction ion solution is adjusted to neutrality with saturated sodium bicarbonate solution and the organic phase is washed with dilute bicarbonate solution.

The combined water phases are washed twice with vinegar and adjusted to pH 2.6 with phosphoric acid. The precipitated 78-phenoxyacetaoido-3-methoxy-cef-3-em-4-carboxylic acid is filtered off, washed with water and dried in high vacuum, m.p. 170°C (decomp.).

bii) A suspension of 54>4 g (97.7 mmol) of 70-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenyl methyl ester-18-oxide (from example 5iii) in 320 ml of methylene chloride and 16 ml of di- methylacetamide is cooled to 0°C and 17.3 ml (19.8 mmol) of phosphorus triclide is added slowly. After 20 minutes of stirring at 0 - 5°C, 80 ml (1.05 mol) of trifluoroacetic acid are added dropwise. The clear solution is further stirred for 20 minutes at 0-5°C, then diluted with 1300 ml of ethyl acetate and washed successively with 240 ml of 2M dipotassium phosphate solution, 100 ml of water and 250 ml of half-saturated, aqueous sodium chloride solution. 7s*-fe*1oxyacetamido-3-methoxy-cef-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 extracted twice with a total of 250 ml of a solution of 50 ml of saturated aqueous sodium bicarbonate solution, 100 ml of water and 100 ml of saturated aqueous atrium chloride solution. The combined bicarbonate solutions are poured with 1,500 ml of ethyl acetate and the pH value of the solution is adjusted with vigorous stirring to approx. 2.5 with 20% phosphoric acid. The water phase is then extracted twice with 500 ml of ethyl acetate. The combined organic phases are dried over

magnesium sulfate, filtered and evaporated in vacuo. The crystallising residue is suspended in 130 ml of ethyl acetate and left overnight at -10°C. The pale yellow crystals of the produced 78-phenoxyacetamido-3-nEthoxy-cef-3-em-4-carboxylic acid are filtered off, washed with cooled ethyl acetate and dried in high vacuum to constant weight.

biii) A solution of 23.9 g of 78-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid aiphenylmethylester-lo£-oxide (From Example 5iii) in 140 ml of methylene chloride and 7»2 ml of dimethylacetamide is cooled to 0°C and stirred further after slow addition of 7>°* ml of phosphorus trichloride, for 20 minutes at 0-5°C. Add 36 ml of trifluoroacetic acid dropwise to the reaction solution, stir further for 20 min. at 0~5°C and then worked up as described under example 5°ii) »You get 78-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid in the form of a pale yellow crystal.

c) To a suspension of 2.55 g (7 mmol) 78-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid and 2.9 ml (22.4 mmol)

N,K-dimethylaniline in 11 ml of absolute methylene chloride is added

under nitrogen at 20°C 0.7 ml (5.7 mmol) dimethyl-dichloro-silane and the mixture is stirred for 30 minutes at the same temperature. The clear solution formed is cooled to -20°C, 1.6 g (7.7 mmol) of solid phosphorus pentachloride is added and stirred for 30 minutes. At the same temperature, add over 2 to 3 minutes. a pre-cooled (-20°C) mixture of 0.9 ml (7 mmol) N,N-dimethylaniline and 0.9 ml n-butanol, then rapidly 10 ml pre-cooled (-20°C) n-butanol and then stirred for 20 minutes at -20°C and 10 min. without cooling. At approx. -10°C, add 0.4 ml of water, stir for 10 min. in an ice bath (0°C), add 11 ml of dioxane and, after a further 10 minutes of stirring, add at approx. 0°C approx. 4»5ml tri-n-butylamine in portions, until samples diluted with water have a constant pH value equal to 3.5. After stirring for 1 hour at 0°C, the precipitate is filtered off, washed with dioxane and recrystallized from water/dioxane. The 7P-amino-3-methoxy-cef-3-em-4-carboxylic acid hydrochloride dioxanate formed has a melting point of over 300°C. Thin-layer chromatogram: Rf value 0.17 (silica gel, system n-butanol/tetrachlorocarbon/methanol/formic acid/water 30:40:20.5:5)•

ci) .A suspension of 11.75 g 93#-ig (equivalent to 10.93 g 100$-ig) Jp-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid and

13.4 ml (12.73 g) of H,M-dimethylaniline in 47 ml of absolute methylene chloride (distilled over PgO^) are added at +20°C under nitrogen 3.6 ml (3.87 g) of dimethyldichlorosilane and stirred for 3^ my. at the same temperature. The now clear solution is cooled to -18/-19PC and 7.8 g of solid phosphorus pentachloride are added, whereby the mixture temperature rises to -10°C. After stirring for 30 minutes in a bath maintained at -20°, the clear solution is stirred for approx. 7 min. a pre-cooled (20°C) mixture of 47 ml n-butanol (water-free, dried over "Sikkan") and 4.4 ml (4.18 g) aimethylaniline. Thereby the mixture temperature rises to -8°C. Stir for 30 minutes. - initially in a bath that holds -20°C, later in an ice bath (0°C) - so that a final dissolution temperature of -10°C is reached. At this temperature, a mixture of 47 ml of dioxane and 1.6 ml of water is added dropwise (within approx. 5 minutes). Thereby, the product slowly crystallizes out. After a further 10 minutes of stirring, the mixture is added to the ice bath in portions

9.5 ml of tri-n-butylamine during approx. 1 hour (the first 5 ml are added during the first 5 min.) so that the pH value is kept between 2.2 and 2.4. Then filtered off, washed in portions with approx. 30 ml of dioxane, then 15 ml of methylene chloride, whereby the crystalline 7P-amino-3-methoxy-cef-3-em-4-carboxylic acid hydrochloride dioxanate is obtained, m.p. above JDQ°C, UV spectrum (0.1M sodium bicarbonate), 7<w>max<=>270nyu (£ = 76OO), IR spectrum (Kujol), characteristic bands at 5.62, 5.80, 5, 88, 6.26, 6.55, 7.03, 7.45, 7.72, 796, 8.14, 8.26, 8.45, 8.64, 8.97, 9.29, 10, 40, 11.47nyu, (a)^°»+134° 1° (c = 1, 0.5N sodium bicarbonate solution).

From the hydrochloride-dioxanate formed, wood can be used

adding a 20% aqueous solution of the former with 2W caustic soda to a pH value of 4.1 (isoelectric point) produces the zwitterions of 7P_amino-3-methoxy-c ef-3~em-4-carboxylic acid, which

in the filtered and dried state has a m.p. of above 300°C UV spectrum (0.1H sodium bicarbonate solution) XraQV- 270 nm { £= 76OO). Thin layer chromatogram; Rf value identical to the value for the hydrochloride (silica gel, same system), (a)^° = ■t_232°2. 1°

(c = 1, 0.5K sodium bicarbonate solution).

d) A suspension of 1 g (2.82 mmol) of 7B-amino-3-methoxy-cef-3-em-4-carboxylic acid hydrochloride aioxanate in 20 ml

dry methylene chloride is added at room temperature under a nitrogen atmosphere to 1.65 ml of bis(trimethylsilyl)acetamide. After 40 min. a clear solution is cooled to 0°C and 900 mg (4.37 mmol) of solid D-oc-phenyl-glycylic acid chloride hydrochloride is added. 5 months later, 0.7 ml (10 mmol) of propylene oxide is added. The suspension is then stirred for 1 hour at 0°C under nitrogen, then 0.5 ml of methanol is added, whereby 7B-(D-a-phenylglycylamino)-3-methoxy-cef-3-em-4-carboxylic acid hyurochloride precipitates out in crystalline form . The hydrochloride is filtered off, dissolved in 9 ml of water and the solution adjusted with IN caustic soda at 4>6. The precipitated dihydrate of the inner salt of 7β-(D-α-phenyl-glycylaminoj-3-methoxy-cef-3-em-4-carboxylic acid) is filtered off, washed with acetone and diethyl ether and dried, m.p. 174-176<0>( decomp.), (a)^° - +132° (c = 0.714, in 0.1N hydrochloric acid), thin-layer chromatogram (silica gel): Rf value about 0.18 (system: n-butanol/acetic acid/water 67: 10:23)* UV spectrum (i

0.1N aqueous sodium bicarbonate solution) " K^^ = 269^u

(£ = 7OOO), IR spectrum (in mineral oil), characteristic bands

at 5.72, 5.94, 6.23 and 6.60 yu.

di) A suspension of 993 mg (4»32 mmol) 7P-amino-3-methoxy-cef-3_em-4-carboxylic acid (inner salt) in 10 ml methylene chloride is added to 1.37 ml (5.6 mmol) N,N -bis(trimethylsilyl)-acetamide and stirred for 45 min. at room temperature and under a nitrogen atmosphere. The clear solution is cooled to 0°C and 1.11 g (5.4 mmol) of D-α-phenylglycylic acid chloride hydrochloride is added. After 5 min. 0.4 ml (5.6 mmol) of propylene oxide is added. The suspension is stirred for 1 hour at 0°C under nitrogen and then 0.6 ml of methanol is added. The surface crystallising 7P-(D-a-phenyl-glycylamido)-3-methoxy-cef-3-em-4-carboxylic acid hydrochloride and dissolves at 0°C

in 15 ml of water, after which the solution is set to approx. pH 4 with 5 ml IN caustic soda. The solution is warmed to room temperature and adjusted with triethylamine at approx. pH 4.8, whereupon 76_(D-a-phenyl-glycylamido)-3-methoxy-cef-3-em-4-carboxylic acid crystallizes out in the form of the dihyarate.

Example 6.

To a solution of 0.697 g (1.0 mmol) isomeric mixture consisting of 2-/~4-(benzthiazol-2-yldithio)~3-phenoxy acetamido-2-oxoazetidin-1-yl^-3-methoxy-crotonic acid diphenyl methyl ester and the corresponding isocrotonic acid diphenylmethyl ester in 4 ml of dry tetrahydrofuran, a solution of 0.228 g (1.5 mmol) of 1,5-diazabicyclo/~5.4.07undec-5-ene in 10 ml of tetrahydrofuran is added. The mixture is stirred for 40 min. at room temperature, dilute with 200 ml of benzene and wash 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 formed is chromatographed on 30 g of hydrochloric acid-washed silica gel. Toluene/acetic ester 7:1 first elutes 2-mercaptobenzthiazole and then 7P-phenoxyacetamido-3-methoxy-cef-2-em-4-carboxylic acid-di-phenyl Imethyl ester. IR spectrum (CH 2 Cl 2 ): 5.60 , 5.74 , 5.90 , 8.28/u.

The ester produced can be transferred to the free acid as follows: i) A mixture of 53 mg (0.1 mmol) 7$-£enoxyacetamido-3-methoxy-cef-2-em-4<x-carboxylic acid oiphenyl methyl ester, 0 .07 ml of trifluoroacetic acid, 0.06 ml of anisole and 0.5 ml of methylene chloride are stirred for 15 hours at 0°C. The mixture is diluted with 5 ml of pentane/ethyl ether 3:1 and shaken vigorously. The precipitated white, amorphous 7P~phenoxyacetamiuo-3-methoxy-cef-2-em-4e-carboxylic acid is filtered off and washed but pentane/diethyl ether 3;1» IR spectrum (CHgCl^: 5.60, 5.SO, 8 ,27/U.

The starting material can be produced in the following way:

a) In a solution of 68l mg (1.0 mmol) 2-/~4-(benz-thiazol-2-yldithio)-3-phenoxyacetamiao-2-oxo-azethiain-1-yl7-3-methylene-butyric acid- diphenyl methyl ester in 30 ml of acetic acid cooled to -70°C, 1 equivalent of ozone (diluted with oxygen) is introduced.

The reaction solution is allowed to warm up, it is evaporated in vacuo to 10 ml, 1.0 ml of dimethyl sulphide is added and stirred for 15 hours at room temperature. Solvent and excess reagent are removed in vacuo and the evaporation residue is chromatographed on 30 g of acid-washed silica gel with toluene/acetic ester 4:1 (15 ml fractions). 2-/~4-(Benzthiazol-2-ylaithio)-3~phenoxyacetamido-2-oxo-azetidin-1-yl7-3-hyroxycrotonic acid diphenyl methyl ester is obtained as a solid amorphous compound, (a)^= I30<0> <+>1°

(CHCl 2 , c = 0.8) IR spectrum (CH 2 Cl 2 ): 2.95, 5.60, 5.92, 6.04, 8.10/u.

b) A solution of crude 2-[4-(benzthiazol-2-yl-athio)-3-phenoxyacetamido-2-oxo-azethiain-1-yl7-3-hydroxycrotonic acid aphenylmethyl ester, prepared via ozonization of 681 mg (1 .0 mmol) 2- /~4-(benzthiazol-2-yldithio)-3-phenoxy-acetamido-2-oxo-azetidin-1-yl/-3-methylene-butyric acid diphenyl methyl ester in 5 ml of methylene chloride is added at 0° C an ethereal, freshly astilled diazomethane solution (containing 1.3 mmol of diazomethane). The mixture is stirred for 1 hour at 0°C, washed with water and the organic layer is dried over sodium sulphate. The solvent is removed in vacuo and the residue is chromatographed on 35 S acid-washed silica gel with toluene/acetic ester 2:1. An isomer mixture is obtained which consists of 2-/ 4~

(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetiyl-in-1-yl7-3-methoxy-crotonic acid diphenyl Imethyl ester and the resulting isocrotonic acid diphenyl Imethyl ester. IR spectrum (CH 2 Cl 2 ): 5>60, 5"88j 6.67, 9*15, 9.92/u.

Example 7.

Analogously to example 4, one obtains from 200 mg (0.307 mmol) the isomer mixture consisting of 2-/-4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxy-crotonic acid-2,2 ,2-trichloroethyl ester and the corresponding isocrotonic acid 2,2,2-trichloroethyl ester and 0.09 ml (0.6 mmol) of 1s5-diazabicyclo/~5'4'Q7unciec-5-ene after 30 minutes of stirring at room temperature for 3 ml 1,2-dimethoxyethane an isomeric mixture consisting of 7P-phenoxyacetamido-3-methoxy-cef-2-em-4-carboxylic acid 2,2,2-trichloroethyl ester and 7P-phenoxy-acetamiao-3-methoxy-cef-3- em-4-carboxylic acid-2,2,2-trichloroethyl ester (in a ratio of approximately 1:1). Rf value = 0.36 and 0.18 respectively (silica gel: toluene/ethyl acetate 3:D»

The starting material can be produced as follows:

a) Analogous to example 1 b) one obtains from 49°" mg (1 mmol) 6-phenoxy-acetamido-penicillanic acid-2,2,2-trichloroethyl ester and 200.7 mg (1.2 mmol) 2-mercaptobenzthiazole, the compound 2-/~4-(Benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methylene-butyric acid-2,2,2-trichloroethyl ester, m.p. 144-149°C (from methylene chloride/pentane), Rf value = 0.5 (silica gel: ether). b) Analogous to example 6a) is prepared from 647 mg (1 mmol) 2- /~4-(benzthiazol-2-yldithio)-3~phenoxyacetamido- 2-oxo-azetidin-1-yl7-3-methylenebutyric acid-2,2,2-trichloroethyl ester and 1.2 equivalents of ozone, with subsequent cleavage of the ozone with dimethyl sulfide, for the bond 2-/~4-(benzthiazol-2-ylaithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl7-3",nyciroxycrotonic acid 2,2,2-trichloroethyl ester, m.p. 129-130°C (ether/petroleum ether). c) In analogy with example 6 b) one obtains from 5 6 (7>71 mmol) 2-/~4-(benzthiazol-2-yldithio)-3-phenoxyacetamiao-2-oxoaze-tidin-1-yl7-3 -ny<iroxycrotonic acid-2,2,2-trichloroethyl ester and an excess of aliazomethane an isomeric mixture consisting of 2-/~4~{benzthiazol-2-yldithio)-3-phenoxyacetamiio-2-oxoazetiin-1-yl7-3- methoxy -crotonic acid 2,2,2-trichloroethyl ester and the corresponding isocrotonic acid 2,2,2-trichloroethyl ester, m.p. 170-174°C (from methylene chloride/ether).d) Analogous to example lc) one obtains from 1.9 S (2.87 mmol) of an isomer mixture consisting of 2-/~4-(benzthiazol-2-yl- dithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxy-crotonic acid-2,2,2-trichloroethyl ester and the corresponding isocrotonic acid-2,2,2-trichloroethyl ester, by stirring for five hours at room temperature with 0, 8 g (4.05 mmol) silver p-toluenesulfinate in 35 ml acetonitrile/ethylacela t 3:4” an isomer mixture consisting of 2-/~<*>4-(p-toluenesulf onylthio )-3-phenoxyacetamido-2 -oxoazetiiin-1-y^-3-methoxy-crotonic acid-2,2,2-trichloroethyl ester and the corresponding isocrotonic acid-2,2,2-trichloroethyl ester. Temp. 155-158°C (from ethyl acetate/ether). Example 8.

A solution of 100 mg (0.146 mmol) 2-[<*>4-(benz-thiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetiaiin-1-yl7-3-hyroxycrotonic acid aphenylmethyl ester in 2 ml of dry methylene chloride 0.02 ml (0.16 mmol) of trimethylchlorosilane is added at 0° C. To the solution, nitrogen is added and with stirring 0.0477 ml (0.32 mmol) 1,5-diazabicyclo/~5.4.07undec-5-ene and stir for 1 hour at 0° C. After adding 0.2 ml of acetic acid, dilute with methylene chloride. The organic phase is washed successively with dilute sulfuric acid, water and standard sodium bicarbonate solution, dried over sodium sulfate and evaporated to dryness in vacuo.

The crude 7P-phenoxyacetamido-3-hydroxy-cef-3-em-4-carboxylic acid diphenylmethyl ester is dissolved in methanol and added at 0°C to an ethereal diazomethane solution. After 10 min. the solution is carefully evaporated and the residue is dried in a high vacuum. The residue is purified by thick-layer chromatography (toluene/acetic ester 3:1, silica gel). After elution of the silica gel in the zone around Rf = 0.17 with ethyl acetate and evaporation of the solution in a rotary evaporator, 76-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester is obtained, m.p. 120°C (from ether).

Example Q.

A solution of 266 mg (0.5 mmol) of a crude mixture consisting of 2-[4-(benzthiazol-2-yldithio)-3-phenox<y>acetamido-2-oxoazetidin-1-yl7-3-methoxy -crotonic acid chloride°S 2-Z~4-(benz-thiazol-2-yldithio)-3-phenoxy-acetamiuo-2-oxoazetidin-1-yl7-3-methoxy-isocrotonic acid chloride in 5 ml of dry methylene chloride, added dropwise at 0 °C without stirring and during 15 minutes ter to a solution of 0.10 ml of triethylamine in 0.5 ml of dry tert-butanol and 3 ml of methylene chloride. After 15 min. stirring, the reaction mixture is diluted with methylene chloride, washed with water, dilute hydrochloric acid and again with water, dried over sodium sulfate and evaporated in vacuo. The inoculum residue is crotographed on 10 g of acid-washed silica gel with toluene/ethyl acetate (4:1) as development medium. 7P-phenoxyacetamido-3-methoxy-cef-2-em-4-carboxylic acid tert-butyl ester is obtained. IR spectrum (CH 2 Cl 2 ): characteristic bands at 5.60, 5.77, 5.90, 8.29/U.

The starting material can be produced as follows:

a) To a solution of 698 mg (1 mmol) of a mixture consisting of 2-[f~4-(benzthiazol-2-yllathio)-3~phenoxy-acetamido-2-oxoazetidin-1-yl7-3-methoxy -crotonic acid diphenyl methyl ester and 2- /~4-(benzthiazol-2-yllaithio)-3-phenoxy-acetamido-2-oxozetidin-1-yl7-3-methoxy-isocrotonic acid diphenyl methyl ester in 1.5 ml of methylene chloride, are added at 0°C while stirring slowly a mixture of 0.7 ml of trifluoroacetic acid, 0.6 ml of anisole and 2.5 ml of methylene chloride. The reaction mixture is stirred for 3 hours at 0°C, shaken with 100 ml ether/pentane 1:3 and the precipitate is filtered off. The precipitate consisting of a mixture of 2-/~4-(benzthiazol-2-ylaithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl/-3""methoxy-crotonic acid and 2-/~4-(benzthiazol- 2-yldithio)-3-phenoxyacetamido-2-oxoazethioin-1-yl7-3-methoxy-isocrotonic acid is washed with 25 ml of ether/pentane 1:3 and dried in vacuum. Ir spectrum (CHgClg): characteristic bands at 5.60, 5.80, 5.94, 8.55, 19.95/u. b) A solution of 532 mg (1.0 mmol) of a mixture of 2- /~4-(benzthiazol-2-yldithio)-3-phenoxy-acetamido-2-oxoazetidine-1-<y>l7-3- methoxy-crotonic acid and 2-/~4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxy-isocrotonic acid in 5 ml of dry dioxane containing 10% oxalyl chloride, stirred for 15 hours at room temperature and then evaporated in vacuo. The solid and non-crystalline residue consisting of a mixture of 2-/~4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxy-crotonic acid chloride and 2-/~4 -{benzthiazol-2-yldithio-3-phenoxyacetamido-2-oxoazetiain-1-yl7-3-methoxy-isocrotonic acid chloride can be processed further without purification. IR spectrum (CHgClg):

characteristic bands at 5.58, 59O, 9.95/u.

Example 10.

A solution of 367 mg (0.5 mmol) of a mixture of 2- /~4-(p-nitrobenzenesulfonylthio)-3-phenoxy-acetaraio-2-oxo-azetidin-1-yl7-3-methoxy-crotonic acid diphenyl methyl ester °S the corresponding isocrotonic acid diphenyl methyl ester and 152 mg (1.0 mmol) of 1,5-aiazabicyclo/~5.4.07undec-5-ene in 10 ml of dry tetrahydrofuran, are stirred for 40 min. vea room temperature. The reaction mixture is diluted with benzene, then subsequently washed with dilute hydrochloric acid, water and dilute aqueous sodium bicarbonate solution, dried over sodium sulfate and freed of solvent in vacuum. The residue is chromatographed on acid-washed silica gel with toluene/ethyl acetate f:1 as eluent, and pure 7P-phenoxyacetamiGO-3-methoxy-cef-2-em-4-carboxylic acid diphenylmethyl ester is obtained. By elution with toluene/ethyl acetate 2:1, a mixture is then obtained which, in addition to 7P-phenoxyacetamido-3-methoxy-cef-2-em-4-carboxylic acid aiphenyl-methylase, also contains 7p-phenoxyacetamido-3-methoxy-cef- 3-em-4-carboxylic acid diphenyl methyl ester.

The starting materials can be prepared in the following way.

a) In analogy with example 4 ai), 348.5 mg (0.5 mmol) of an isomer mixture of 2-[4-(benzthiazol-2-ylthio)-3-phenoxyacetamido-2-oxoazatiuin-1 is obtained -yl7-3-methoxycrotonic acid diphenyl methyl ester and the corresponding isocrotonic acid diphenyl methyl ester as well as 200 mg (0.68 mmol) silver p-nitrobenzene sulfoxide, after 1 hour stirring at 60°C in 10 ml acetone/water 9;1>en mixture which

consists of 2-[7*4-(p-nitrobenzenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester.

Silver-p-nitrobenzenesulfinate is first prepared by combining usual solutions of equimolar amounts of silver nitrate and sodium p-nitrobenzenesulfinate^ The precipitate is filtered and dried in a vacuum for 24 hours at 5O-6O C.

Example 11.

Analogous example 10 is prepared from 351»5mg

(0.5 mmol) of an isomeric mixture of 2-[4-(p-methoxybenzenesulfonyl-thio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxycrotonic acid phenylmethyl ester and the corresponding isocrotonic acid phenylmethyl ester , as well as 152 mg (1 mmol) 1,5-iiaza-bic<y>chlo/~<5>.4.07unaec-5-ene, a mixture consisting of 78-phenoxyacetamido-3-methoxy-cef-2-em -4-carboxylic acid diphenyl methyl ester and 78-phenoxyacetaarido-3-methoxy-cef-3-em-4-carboxylic acid iiphenyl methyl ester, together by chromatography can be separated into the two isomers.

The starting materials can be prepared as follows:

a) In analogy with example 4ai) is prepared from 697 mg (1 mmol) of an isomer mixture of 2-[~4-(benzthiazol-2-ylthio)-3-phenoxyacetamide dp-2-oxoazetiiin-1-yl7-3- Methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester as well as 361 mg (1.3 mmol) silver p-methoxybenzenesulfinate by stirring for 1 hour at room temperature in 20 ml acetone/water 9;1>a mixture consisting of 2-/" ~4_(P"*Methoxybenzenesulfonylthio)-3~ phenoxyacetamiao-2-oxoazetiiin-1-yl7-3-methoxycrotonic acid phenylmethyl ester and the corresponding isocrotonic acid phenylmethyl ester. Ir spectrum (CHgClg): characteristic bands at 5>°0, 5.88, 6.18, 8.76yu.

Silver p-methoxybenzenesulfinate is produced from aqueous solutions of equimolar amounts of silver nitrate and sodium p-methoxybenzenesulfinate. The precipitate is filtered off and dried in a vacuum for 24 hours at 5O-6O C

Example 12.

Analogously to example 10, 336.3 ^ ^.5 mmol) of

an isomeric mixture of 2-/4*"Denzensulfonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethylase as well as 152 mg

(1 mmol) 1,5-diazabicyclo/<*>"5«4»Q7dnctec-5-ene, a mixture consisting of J$-£enoxy-acetamido-3-methoxy-cef-2-em-4-carboxylic acid -aiphenyl methyl ester and 7P-£enoxyacetamido-3-methoxy-cef-3-em-4-

carboxylic acid aiphenyl methyl ester which can be separated into two isomers by chromatography.

The starting materials can be prepared as follows:

a ) In analogy with example 4ai) is prepared from 697 mg (1 mmol) of an isomer mixture of 2-/"~4-(benzthiazol-2-ylthio)"3~phenoxyacetamido-2-oxoazetidin-1-yl7-3- Methoxycrotonic acid iphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester and 324 mg (1.3 mmol) silver benzenesulfinate, after 90 min stirring at room temperature in 20 ml acetone/water 9:^» a mixture consisting of 2-( 4-benzenesulfonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-ethoxy-crotonic acid aiphenyl methyl ester and the corresponding isocrotonic acid diphenyl methyl ester, and the corresponding isocrotonic acid diphenyl methyl ester. IR spectrum (CHgClgh characteristic band at 5.60 , 5.88, 8.74/U.

Silver benzenesulfinate is prepared by combining aqueous solutions of equimolar amounts of silver nitrate and sodium benzenesulfinate. The precipitate is filtered off and dried for 24 hours in a vacuum at 50-60°C.

Example 13.

Analogously to example 1, one can start from an isomer mixture consisting of 2-/"~4-(p-toluenesulfonylthio)-3-phenoxyacetamia.o-2-oxoazetidin-1-yl7-3-methoxycrotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester after 12 to 14 hours of stirring at room temperature with tetramethylguanidine in tetrahydrofuran produces an isomeric mixture consisting of 7P-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid p-nitrobenzyl ester and 78-phenoxyacetamido-3-methoxy-cef -2-em-4-carboxylic acid-p-nitrobenzyl ester. Example 14.

A mixture of 104.5 mg (0.15 mmol) of an isomeric mixture of 2-/~"4-(benathiazol-2~ylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxy-crotonic acid- diphenyl methyl ester and the corresponding isocrotonic acid aiphenyl methyl ester, 35 mg (0.225 mmol) of p-toluenesulfinic acid and 80 mg (0.525 mg) of 1,5-diazabicyclo[5*4»07unciec-5-ene in 3 ml of dry tetrahydrofuran are stirred in 40 min.

at room temperature. The mixture is diluted with benzene and washed successively with dilute hydrochloric acid, dilute aqueous sodium chloride solution, 0.5N sodium hydroxide solution and again with

diluted aqueous atrial chloral solution. The organic phase is dried over sodium sulfate and evaporated in vacuo. Chromatography of the distillation residue on 3"5S acid-washed silica gel, with toluene/ethyl acetate 7:1, first gives pure 7B-phenoxyacetamido-3-methoxy-cef-2-em-4a-carboxylic acid diphenylmethyl ester. Toluene/ethyl acetate 2.1 then elutes 7B-phenoxy-6acetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester.

Example 15.

A mixture of 141 mg (0.2 mmol) of 2-/~4-(o-methoxy-benzenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl/-3-raethoxy-crotonic acid diphenyl methyl ester and 6l mg (0 .4 mmol) of 1,4-diazabicyclo/~5.4.07unctec-5-ene in 4 ml of dry tetrahydrofuran is stirred for 70 min. at room temperature. Processing which in example 10 gives a crude mixture consisting of 7B-phenoxyacetamido-3-methoxy-cef-2-em-4<x-carboxylic acid diphenyl methyl ester and 70-phenoxyacetamido-3-methoxyc-cef-3-em-4-carboxylic acid -diphenyl methyl ester in a ratio of approx. 4,4'• 1»and these compounds can be separated into individual isomers by chromatograph! on silica gel as described in example 10.

The two compounds decompose* in approximately the same ratio when 141 mg (0.2 mmol) of 2-[4-(p-methoxybenzenesulfonylthio)-3-phenoxyacetamido-2-oxoazetiain-1-yl7-3-methoxy-isocrotonic acid aiphenylmethyl ester is treated analogously .

The two isomeric starting substances can be prepared as follows:

a) 3>49g (5 mmol) isomer mixture of 2-/~4-(benzthiazol-2-ylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl7-3-Oethoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid -dif eny Imet yles ter in relation approx. 4^1 is stirred with 1.82 g (6.5 mmol) of silver o-methoxybenzenesulfinate in 100 ml of acetone/water for 1130 min. at room temperature. The mixture is filtered and the filtrate is evaporated in vacuo. The evaporation 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-methoxy-benzenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxy-isocrotonic acid diphenyl methyl ester, IR spectrum (CHgClg): 5.60, 5.90, 8.72, 9.15/U and fraction 25 and the following fractions contain pure 2-/~4-(o-methoxybenzenesulfonylthio)-3~phenoxyacetamido-2-oxoazetidine- 1-yl7-3-methoxy-crotonic acid-diphenyl-

methyl ester, IR spectrum (CH2C12)<:>5.60, 5.90, 8.20, 8.30,

8.72, 8.90^u. Fractions 14 to 24 contain mixtures of ie two isomers. Example 16.

A mixture of 57 mg (0.1 mol) of crude 2-[<*>4-(o-methoxy-benzenesulfonylthio)-3-phenoxyacetamido-2-oxoazetiain-1-yl7-3-methoxy-isocrotonic acid chloride and 43 mg ( 0.3 mmol) 1,5-diazabicyclo/~5»4»Q7unaec"5-ene in 2 ml of dry methylene chloride is stirred for 80 min. at room temperature. Blanctin one is diluted with methylene chloride, washed with dilute hydrochloric acid and water, dried over sodium sulfate and is freed from 9PPlösnirg smiadel in vacuum. The evaporation residue is dissolved in 0.5 ml of methylene chloride, 5 ml of pentane/diethyl ether y.l is added and shaken out. The precipitate is filtered and washed with pentane/diethyl ether y.l. It consists of fairly pure 78*-phenoxyacetamido-3 -methoxy-cef-2-em-4oc-carboxylic acid.

The starting material can be produced as follows:

a) A mixture of 7^3 mg (1 mmol) of pure 2-/~4-(o-methoxybenzenesulfonylthio)-3~phenoxyacetamido-2-oxoazetidin-1-yl7-3"'

Methoxy-isocrotonic acid aiphenyl methyl ester, 0.7 ml of trifluoroaic acid and 0.66 ml of anisole in 4 ml of methylene chloride are stirred for 3 hours at 0°G. The mixture is then added to 50 ml of pentane/diethyl ether. l and shake vigorously. The hot precipitate of pure 2-[<*>4-(o-methoxy-benzenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxy-isocrotonic acid is filtered off and washed with pentane/ethyl ether 3: 1. IR spectrum (CH 2 Cl 2 ): 5.60, 5.93, 6.25, 8.72/u.

b) To a solution of 54 mg (0.1 mmol) 2-/~~^_^0_

methoxybenzenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidine-1-yi7-3-methoxy-isocrotonic acid in 0.5 ml of a 10^-ig oxalyl chloride solution in dioxane is added one drop of dimethylformamide, after which gas evolution immediately occurs. The mixture is stirred for 2 hours at room temperature and the solvent and excess oxalyl chloride are evaporated in vacuo. The residue is dried under high vacuum and gives

2- /~"4- (o-Methoxybenzenesulfonylta.0 )-3-phenoxyacetamido-2-oxo-azetiiin-1-yl7-3-methoxy-isocrotonic acid chloride in the form of a faint orange colored foam, IR spectrum (CHgClg) : 5.60, 5.90, 8.70^u Example 17.

A solution of 200 mg. Methoxy-crotonic acid diphenylmethyl ester in 2 ml of dimethylformamide is stirred with 5 µl (0.38 mmol) of 1,5-diazabicyclo/~5.4.07undec-5-ene for 30 min at room temperature, then ethyl acetate is added and washed with water and 2W hydrochloric acid for an acidic reaction and with saturated aqueous sodium chloride solution for a neutral reaction. The organic phase is dried over sodium sulfate and evaporated in vacuo. The evaporation residue is chromatographed on silica gel thick-layer plates with toluene/ethyl acetate 1:1 as developing agent. You get 7B-(D-a- tert-butylcarbonylamino-a-phenylacetyl-amino)-3-methoxy-cef-2-em-4a-carboxylic acid diphenyl raethyl ester with m.p. 166-168°C (methylene chloride/pentane), thin-layer chromatography (silica gel, diethyl ether): Rf value approx. 0.51, UV spectrum Oethanol), ^■maoc *° 257<m>/<y>^ £ = 35°°i» IR spectrum (in methylene chloride): characteristic bands at 2.96, 5.63, 5.74, 5.85 (shoulders), 5.92, 6.16, 6.64 and 6.72/u and 7B-(D-α-tert-butylcarbonylamino-α-phenyl-acetaylamino)-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester with m.p..162-163°C (diethyl ether), thin-layer chromatogram: Rf value approx. 0.33 (silica gel, diethyl ether), UV spectrum (ethanol), = 265 nyu (£ = 6600), 280 nyu (£ = 6200), IR spectrum (methylene chloride), 2.92, 5.58, 5, 64 (shoulder), 5.82, 6.22 and 6.67/U.

The compounds produced can be processed further as follows: a) A mixture of 8.8 g of 7P-(D-a-tert-butyloxycarbonylamino-a-phenyl-acetylamino)-3-methoxy-3-ref em-4-carboxylic acid α-phenylmethyl ester, 8.6 ml of anisole and 145 ml of trifluoroacetic acid are stirred for 15 min. at 0°C, 400 ml of pre-cooled toluene are then added and evaporated under reduced pressure. The residue is dried in high vacuum, triturated with diethyl ether and filtered off. The trifluoroacetate of 7P-(D-a-phenyl-glycyl-amino)-3-methoxy-3-cephem-4-carboxylic acid is thus obtained in powder form, which is dissolved in 20 ml of water. It is washed twice with 25 ml of acetic acid ethyl ester each time

The pH is adjusted with a 20% triethylamine solution in methanol of approx. 5>°S a colorless precipitate forms. You stir for 1 hour in an ice bath, add 20 ml of acetone and let the whole thing stand for 16 hours at approx. 4°C. The colorless precipitate is filtered off, washed with acetone and diethyl ether and dried under reduced pressure.

The compound 78-(D-α-phenyl-glycylamino)-3-methoxy-3-cephem-4-carboxylic acid is thus obtained in the form of a microcrystalline powder as an internal salt, which is also in the form of a hydrate. Temp. 174-176°C (decomp.), (a)<2>° » i-1490 (c = 1.03 1 0.1 n hydrochloric acid), thin-layer chromatogram (silica gel, development with iodine),

Rf approx. 0.36 (system: n-butanol/pyridine/acetic acid/water 40:24:6:30), UV absorption spectrum (in 0.1 n aqueous sodium bicarbonate solution), X max<=>267/u ( £= 6200), IR absorption spectrum (mineral oil), characteristic bands i.a. at 5.72, 5.94, 6.23

and 6.60yU.

b) A mixture of 0.063 g of 7B-(D-α-tert.butyloxy-carbonylamirio-α-phenylacetylamino)-3-methoxy-2-cephem-4α-carboxylic acid diphenylmethyl ester, 0.1 ml of anisole and 1.5 ml of trifluoroacetic acid is placed in 15 min. at 0°C and then evaporated under reduced pressure. The residue is triturated with diethyl ether, filtered off and dried. The colorless and powdery trifluoroacetate of 70-(D-α-phenyl-glycylamino)-3-methoxy-2-cephem-4α-carboxylic acid is dissolved in 0.5 ml of water and the pH value of the solution is adjusted by dropwise addition of a 10% solution of triethylamine in methanol on

about. 5. One continues to stir for 1 hour in an ice bath, filter off the colorless precipitate and dry in a bending vacuum. One thus obtains 7P"*(E,-α-phenyl-glycylamino)-3-methoxy-2-cephem-4"-carboxylic acid as an inner salt, thin-layer chromatogram (silica gel, development with iodine): Rf approx. 0.44 ( system: n-butanol/pyrain/acetic acid/water 40:24:6:30), UV spectrum (0.1 n sodium hyurogen carbonate solution),

Unshoulder =<260>/u-

c) A solution of 0.63 g of 7e"(D-a-tert-butyloxycarbonylamino-a-phenyl-acetylamino)-3-methoxy-2-cephem-4a-carboxylic acid diphenyl methyl ester in 25 ml of methylene chloride cooled to 0°C is added a solution of 0.20 g of 3-chloro-perbenzoic acid in 5 ml of methylene chloride. The mixture is stirred for 30 min at 0°C, 50 ml of methylene chloride is added and washed with 25 ml of saturated ordinary sodium bicarbonate solution and the same amount of 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, thus obtaining 78-(D-a-tert-butyloxycarbonylamino-ot-phenyl-acetyl amino)-3-methoxy-3 -cephem-4-carboxylic acid aiphenylmethylester-1-oxide in the form of colorless needles, m.p. 172-175°C, thin-layer chromato-

grams (silica gel): Rf approx. 0.44 (system: acetic acid ethyl ester, development with iodine vapor), UV-3 spectrum (ethanol): J\ max<=>277m/u (£7200), IR spectrum (methylene chloride): characteristic bands vea 2,S6, 5, 56, 5.71, 5.83, 5.90»6.27 and 6.67/u.

d) A solution of 1.30 g of 78-(D-α-tert-butyloxycarbonylamino-α-phenyl-acetyl-amino)-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1-oxide cooled to -10°C 2.80 g of phosphorus trichloride are added to the exclusion of air. After 15 min. allowed to stand, the reaction mixture is poured onto a mixture of ice and aqueous potassium hydrogen phosphate solution. The aqueous mixture is extracted twice with 100 ml ethyl acetate. The organic extract is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The evaporation residue is chromatographed on silica gel, the amorphous 7P-(D-a-tert-butyloxycarbonylamino-a-phenyl-acetylamino)-3-methoxy-3-cephem-4-carboxylic acid aiphenylmethyl ester is eluted with diethyl ether as a thin-layer chromatographically pure compound, Rf approx. 0.39 (system: diethyl ether, development with iodine vapor), (a)D = 1° + 10 (c = 0.981 in chloroform), UV spectrum (ethanol): X mav = 264/U (£ = 63OO), IR - absorption spectrum (methylene chloride): characteristic bands

vea 2.94, 5.62, 5.84, 5.88, 6.25 and 6.70/U.

The starting material can be produced in the following way:

e) A solution of 31.2 g (0.12 mmol) of D-N-tert-butyloxycarbonyl-phenylglycine and 16.7 ml (0.12 mmol) of triethylamine in

300 ml of tetrahydrofuran, 16.5 ml (0.12 mmol) of chloroformic acid isobutyl ester are added, and stirred for 3° min. at -10°C. A solution of 21.6 g (0.10 mmol) 6-amino-penicillanic acid and 15.4 ml (0.11 mmol) triethylamine in 300 ml tetrahydrofuran/water 2:1 is then added. The reaction mixture is stirred for 1 hour at 0°C and 2 hours at room temperature, during which the pH value is kept constant at approx.

6.9 vea addition of triethylamine. The reaction mixture is adjusted at 5°C to pH 2.0 with phosphoric acid. sodium chloride is added to saturation and extracted three times with 500 ml of ethyl acetate, the organic phase is washed with saturated ordinary sodium chloride solution, dried over sodium sulfate and evaporated. You get the product as

a pale yellow foam of W-tert-butyloxy-ampicillin which in the thin-layer chromatographic frame has an Rf value of approx. 0.65 (silica gel: ethyl acetate/n-butanol/pyridine/acetic acid/water 42:21:21:6:10).

f) A solution of 57.22 g of raw N-tert-butyloxycarbonyl-ampicillin in 100 ml of glacial acetic acid is added over 10 minutes

21.6 ml of 30% hydrogen peroxide (0.25 mol) and stirred for 2 1/2 hours at room temperature. The reaction mixture is then poured into 2 liters of ice water, N-tert-butyloxycarbonyl-ampicillin-1-oxide is obtained in the form of a voluminous precipitate which is filtered off, washed well with water and dried in a vacuum. By extracting the filtrate with ethyl acetate, some additional crude K-tert-butylcarbonyl-ampicillin-1-oxide could be obtained. Thin layer chromatogram (silica gel, ethyl acetate/n-butanol/pyriain/edaic acid/water 42:21:21:6:10), Rf value approx. 0.30.

g) A mixture of 67.76 ra fJ-tert-butyloxycarbonyl-ampicillin-1-oxide in 3^0 ml of apoxane is added to a solution of

42 g (0.23 mol) diphenyldiazomethane in 130 ml dioxane and stir in

2 1/2 hours at room temperature. After adding 5 ml of glacial acetic acid, infuse in vacuo. The evaporation residue is rubbed out with petroleum ether, the petroleum ether extract is discarded and the remainder of methylene chloride/ether/hexane is crystallized. One obtains W-tert.butyloxycarbonyl-ampicillin-1-oxy-diphenylmethyl ester with m.p. 164-166°C, (a)<2>)<0>=<+>117°11° (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/u, thin layer chromatogram: Rf value approx. 0.23 (silica gel: toluene/acetic ester y.l).

h) A mixture of 11.2 g (17.7 mmol) of N-tert-butyloxycarbonyl-ampicillin-1-oxyphenylmethyl ester and 3.26 g (19.5

mmol) of mercaptobenzthiazole in 170 ml of toluene is boiled for 3 hours in a reflux apparatus with a water separator, and is then evaporated. The absorption residue is chromatographed on silica gel with toluene/ethyl acetate 3:1 as eluent and the amorphous 2/"~4-(benz-thiazol-2-yldithio)-3-(a-tert.butyloxycarbonylamino-a-phenylacetyl-amino)- 2-oxoazetidin-1-yl7-3-methylene-butyric acid-diphenyl methyl ester, thin-layer chromatogram: Rf value approx. 0.37 (silica gel, toluene/acetic ester 3:1)<*>IR spectrum (methylene chloride): characteristic bands at 2 .94, 5.64, 5.76, 5.86 (shoulder), 5.91 and 6.71/U.

i) A solution of 2.34 g (3.0 mmol) of 2-[4-(benzthiazol-2-yldithio)-3-(a-tert.butyloxycarbonylamino-a-phenyl-acetylamino)-2-oxoazetidin-1 -yi/-3-methylene-butyric acid-diphenyl methyl ester in 30 ml of acetone/water 9:1 is added at 0°C to 0.868 g (3.46 mmol) of silver toluenesulfinate, and stirred for 1 hour in an ice bath. The precipitate is filtered off. The filtrate is taken up in toluene and shaken out with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and, after evaporation, yields the amorphous 2-[~~4-(p-toluenesulfonylthio)-3-(a-tert.butyloxy-carbonylamino-a-phenylacetylamino)-2-oxoazetidine-1-y3j* -3-methylene-butyric acid-diphenyl methyl ester, thin-layer chromatogram: Rf value approx. °»33 (silica gel, toluene/ethyl acetate 3:1), IR spectrum (methylene chloride): characteristic bands vea 2.93, 5.57, 5.70, 5.82, 6.21

and 6.65/h.

j) In a solution cooled to -70°C containing 2.30 g (3.0 mmol) of 2-[4-(p-toluenesulfonylthio)-3-(a-tert.b8tyloxy-carbonylamino-a-phenylac ethylamino )-2-oxoazet idin-1-yl l/-3-methylene-butyric acid-diphenyl methyl ester in 230 ml of methylene chloride, an ozone/oxygen stream (0.5 mmol ozone per min.) is introduced over the course of 7 ml*1». After adding 1 ml of dimethylsulfoxide, the solution is stirred for 1 hour without cooling, then evaporated in vacuo. The residue is recrystallized from methylene chloride/ether/hexane and gives 2-/~4-(p-toluenesulfonylthio)-3-(a-tert.butyloxycarbonylamino-a-phenyl-acetylamino)-2-oxoazetidin-1-yl7-3-nyarolcsycrotonic acid- aiphenyl methyl ester with m.p. 182-184°C, UV spectrum (ethanol): 7vrnax"259nyu (£ ** 13«400), Ir spectrum (methylene chloride): characteristic bands at 2.92, 5.59, 5.83, 5.9 <2,>6.03 (shoulders), 6.18, 6.68/u, thin-layer chromatogram: Rf value about 0.55 (silica gel, toluene/ethyl acetate 1:1).

k) A solution of 0.54 g (0.7 mmol) of 2-[4-(p-toluenesulfonylthio)-3-(a-tert.butyloxycarbonylamino-a-phenylacetylamino)-2-oxo-azetidine-1- yl7-3-hydroxycrotonic acid diphenylmethyl ester in 20 ml of methylene chloride/methanol 1:1 is stirred at 0°G with an excess of ethereal diazomethane solution and then evaporated in vacuo. Preparative layer chromatography of the residue on silica gel with toluene/ethyl acetate 1:1 as propellant and stirring in the UV-visible zone gives 2-/~4-(p-toluenesulfonylthio)-3-(a-tert.butyloxycarbonylamino-a-phenyl-acetylamino)- 2-oxoazetidin-1-yl7-3-methoxy-crotonic acid-

diphenyl methyl ester which is recrystallized from ethylene chloride/diethyl ether/hexane. Temp. 204-206°C, UV spectrum (ethanol),

7vmaxB 259n<y>u (£= 16,000), IR spectrum (Nujol): characteristic bands at 2.93, 5.58, 5.80, 5.84, 5»93, 6.25, 6.57/u, thin-layer chromatography: Rf value approximately 0.33 (silica gel, toluene/ethyl acetate 1:1).

Example 18.

A mixture of 670 mg (1 mmol) 2-/~4-(p-toluenesulfonylthio)-3-phenylacetamido-2-oxoazetidin-1-yJ^-3-methoxycrotonic acid diphenylmethyl ester, 6.7 ml 1,2 -dimethoxyethane q* 0.22 ml of 1,5-diazabicyclo/~5.4.07undec-5-ene is stirred for 25 min. at room temperature in a nitrogen atmosphere. The reaction mixture is diluted with toluene and successively added 2W hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue yields a preparative thick-layer chromatography on silica gel with toluene/ethyl acetate 1:1 phenylacetamido-3-methoxy-cef-2-em-4a-carboxylic acid diphenylmethyl ester of m.p. 166-169°C (from methylene chloride/hexane) UV spectrum (ethanol): rf. a„ 258 nyu { £ æ 4500), IR spectrum (methylene chloride): characteristic bands at 2.93, 5.62, 5.73, 5.93, 6.66/u, Rf value approx. 0.54 (silica gel: system toluene/ethyl acetate 1:1) and the amorphous 7P-phenylacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenyomethyl ester, UV spectrum (ethanol): X max - 258 nyu (£ = 635O), 264 n<y>u (€=6350), 282 nyu (£ - 56OO) (shoulder), IR spectrum (methylene chloride): characteristic bands at 2.94, 5.63, 5, 83, 5.94, 6.26, 6.66yU, Rf value approx. 0.37 (silica gel: system toluene/ethyl acetate 1:1), in the ratio 8:1.

The further processing can take place in the following way: 7B-phenylacetamido-3-methoxy-cef-2-em-4ot-carboxylic acid diphenylmethyl ester can be transferred in analogy with example 17 c) to 78-phenylacetamido-3-methoxy-cef-3- m-4-carboxylic acid diphenylmethyl ester 1-oxide with m.p. 152-155° C (acetone/diethyl ether)' Rf value 0.31 (silica gel, system: ethyl acetate)<1>UV spectrum (96^-ig ethanol): X max - 288 nyu (£ » 36IO) and shoulder at X = 247 m^u, IR spectrum (methylene chloride): characteristic bands at 2.94, 5>59>5.81, 5.95, 6.22 and 6.6l/u.

A purer product, consisting mainly of 7P-phenyl-acetamido-3-methoxy-3cef-3-em-4-carboxylic acid diphenylmethylester-1p-oxide, can be prepared as follows: A solution of 6.7 g (10 mmol) of 2- /~4~(p-toluenesulfonylthio)~3-phenylacetamiao-2-oxoazetidin-1-yl7-3-methoxy-isocrotonic acid diphenylmethyl ester in 67 ml of abs. tetrahydrofuran is stirred with 2.28 ml (15 mmol) of 1,5-Jiazabicyclo[5.4]J^undee-5-ene for 15 min. at 20°C, add 0.7 ml of glacial acetic acid and then evaporate in vacuo. The oily, dark residue is dissolved in 30 ml of methylene chloride and shaken out successively with 15 ml of water, 10 ml of 0.5N hydrochloric acid, 10 ml of saturated water, 1 ig of sodium bicarbonate solution and 10 ml of water. The water phase is then extracted with 10 ml of methylene chloride, the organic extracts are combined and stirred at 0°C together with 2.24 ml of 40% peracetic acid for 15 min. in an ice bath. A solution of 1.50 g (6 mmol) of sodium thiosulphate pentahydrate in 20 ml of water is then added to the reaction mixture, stirred for 10 min. and the habitual phase separated from. The organic phase is washed again with 10 ml of water, dried over sodium sulphate and evaporated in vacuo. Crystallization of a solid residue from methylene chloride/petroleum ether gives the product 7P"phenylacetamido-3-methoxy-cef-3-em-4-carboxylic acid-diphenylmethylester-1B-oxide m.p. 175-176°C, thin layer chromatogram (silica gel) : Rf value approximately 0.1 (toluene/ethyl acetate 1:1), UV spectrum (ethanol): \ max<->279 m/U(£ « 7300), IR spectrum (methylene chloride). characteristic bands at 2 .94"

5.56, 5.78, 5.91, 6.20 and 6.67/h.

From the 1-oxides, in analogy with example 17 e), 7P-phenylacetamiao-3-methoxy-cef-3-em-4-carboxylic acid can be prepared.

From the latter, one can via saponification as described in example 17 a) produce a crude 76" phenylacetamiu.o-3-methoxy-cef-3-em-4-carboxylic acid, which by chromatography on silica gel (with 5% water) with methylene chloride containing 30 -50$ acetone and subsequent freeze-drying from dioxane can be purified, UV spectrum (96$-ig ethanol): \ max=265nyu { £.- 58OO), IR spectrum (methylene chloride): characteristic bands vea 3.03, 5, 60, 5.74, 5»92, 6.24 and 6.67/u.

The starting material and the intermediate products can be prepared as follows: a) A mixture of 37.24 g (0.1 mol) penicillin G potassium salt in 90 ml water, 7.3 ml acetone and 150 ml chloroform is added

cease stirring at 0°C and in the course of 40 minutes 19.4 ml of 40% peracetic acid. After a further 15 minutes, 28 g (0.15 mol) of benzophenone hyarazone are added in portions at the same temperature, then 6.3 ml of l$-1g of ordinary potassium iodide solution and finally, over the course of 1.5 hours, a mixture of 32.5 ml of 10 $-ig sulfuric acid and 28 ml 40^-ig gerealic acid. After the addition has been completed, stirring is continued at 0 C for 30 min., heated to 15 and diluted with 400 ml of chloroform. The aqueous phase is separated and the organic phase is washed successively with 3°0 ml of 5% aqueous sodium bisulfite solution, 300 ml of saturated aqueous sodium bicarbonate solution, 300 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The distillation residue is recrystallized from ethyl acetate/petroleum ether and gives 6-phenylacetamidopenicillanic acid phenyl methyl ester-18-oxide, m.p. 139°C, thin layer chromatogram (silica gel): Rf value approximately 0.40 (system toluene/ethyl acetate 1:L): IR spectrum (methylene chloride): characteristic bands vea 2.94, 5.5^,

5.7<0.>5.9<2>and<6.>57/h.

b) A mixture of 5.165 g (10 mmol) of 6-phenylacetamido-penicillanic acid-diphenylmethyl ester-10-oxide in 50 ml of toluene and 0.5 ml

1.83 g (11 mmol) of 2-mercaptobenzthiazole is added to ice water and boiled for 2 hours in a reflux cooker with a water separator. On cooling, 2-[4-(benzthiazol-2-yldithio)-3-phenylacetamino-2-oxoazetidin-1-yl7-3-methylene-butyric acid-diphenylmethyl ester spontaneously crystallizes out. After a single recrystallization from methylene chloride/.iiethyl-

one is you get crystals with m.p. 134-136°C, thin layer chromatogram (silica gel): Rf value approximately 0.52 (system toluene/ethyl acetate 1:1), UV spectrum (ethanol): \ mav<«>■ 269 mm (£ = 12,700), IR -spectrum (methylene chloride): characteristic bands at 2.90, 5.60, 5.72, 5.92

and 6.6l^u.

c) The product produced in b) does not need to be isolated for further reaction. After cooling, the reaction mixture can

is diluted directly with 30 ml of toluene, 3.95 g (^5 mmol) of silver p-toluenesulfinate is added and stirred for 2 hours at room temperature. The precipitated yellow precipitate is filtered through "Hyflo" and then washed with toluene. The filtrate is quenched with saturated aqueous sodium*, chloride

solution, dried over sodium sulfate and evaporated in vacuo. The distillation residue is taken up in toluene and petroleum ether is added. The precipitate is filtered off and recrystallized from ethyl acetate/petroleum ether. The resulting 2-[4-(p-toluenesulfonylthio)-3-phenyl-acetamino-2-oxoazetidin-1-yl7-3-niethylene-butyric acid-alpha-phenylmethyl ester has m.p. 75°C, thin layer chromatogram (silica gel): Rf value approximately 0.47 (system toluene/ethyl acetate 1:1)' UV spectrum (ethanol): Xmax= 259 m/u (£ = 4300), IR spectrum (methylene chloride ): characteristic bands at 2.92, 5.62, 5.74, 5.94 and 6.63/U.

a) A solution of 655 mg (1 mmol) 2-/"~4-(p<->toluenesulfonylthio)-3-iphenylacetamido-3-oxoazetidin-1-yl7-3-methylene-butyric acid-diphenylmethyl ester in 65 ml methylene chloride is treated at -65°C with an ozone/oxygen mixture until a faint blue color is obtained. After the addition of 0.5 ml of dimethyl sulphide, the mixture is allowed to warm to room temperature and inniamp in vacuum. Detdanneae raw 2-/~4-(p -toluenesulfonylthio)-3-phenylacetamino-2-oxoazetidin-1-yl7-3-hyroxycrotonic acid diphenylmethyl ester, Rf value approximately 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/u, can be processed further without purification,

e) The crude product prepared under d) is dissolved in 20 ml of methanol and added via 0°C ethereal diazomethane solution to

permanent yellowing has occurred. After evaporating the solvent in vacuum, the lamp residue is purified by means of preparative thick-layer chromatography on silica gel with toluene/ethyl acetate 1:1 as the driving medium. 2-[4-(p-toluenesulfonylthio)-3-phenyl-acetamino-2-oxoazetidin-1-yl7-3-methoxycrotonic acid diphenylmethyl ester is obtained, Rf value approximately 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/u, next to some 2-/~4-(p- toluenesulfonylthio)-3-phenylacetamido-2-Bxoazetidin-1-yl7-3-methoxy-isocrotonic acid diphenyl methyl ester.

Example 19.

To a solution of 6.06 g (10 mmol) 3:1-oiling of ae isomers 2-/~4-(p-toluenesulfonylthio)-3-phenoxy-acetamido^-oxoazetidin-1-yl/^-methoxy- croton-°g -isocrotonic acid benzyl ester and 2.33 g (3-5 mmol) p-toluenesulfinic acid in 200 ml of absolute tetrahydrofuran, one puts at room temperature and with stirring 5.20 (35 mmol) 1,5-diazabicyclo/~5.4 .0j"undec-5-ene. The mixture is stirred further for 4° min. at room temperature, 500 ml of methylene chloride is added and subsequently washed with 200 ml of 0.5 W hydrochloric acid,

200 ml water, 200 ml 0.5N sodium bicarbonate and 200 ml water. The methylene chloride phase is dried over sodium sulphate and evaporated in vacuo. The absorption residue is chromatographed on 200 g of acid-washed silica gel with toluene/ethyl acetate 3:1, and by adding diethyl ether to the fractions amn 78-phenoxyacetamiao-3-methoxy-cef-2-em-4a-carboxylic acid benzyl ester with m.p. 148-151°C. IR spectrum (methylene chloride): characteristic bands at 5.60, 5.75, 5.SO, 8.25/U,

(a)<2>,<0>- +284<0>in 1° (c - 1, chloroform).

Toluene/ethyl acetate 2:1 elutes 7£-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid benzyl ester with m.p. 89-91°C, which is also precipitated with diethyl ether IR spectrum (methylene chloride): characteristic bands at 5.60, 5.85, 5.90, (a)<2>° - -r47° ± 1°

(c = 1, chloroform).

The ratio between the cef-2-em and cef-3-em compounds is approx. 3:1.

The connections can be translated further as follows:

A solution at 0°G of 454 mg (1 mmol) 3*.l mixture of 7$-£enoxyacetamido-3-methoxy-cef-2-em-4a-carboxylic acid benzyl ester and 70-phenoxyacetamiao-3-methoxy- Cef-3-em-4-carboxylic acid benzyl ester in 30 ml of tetrahydrofuran is added with minimal stirring to 15 ml of pre-cooled 0.1N potassium hydroxide solution. The mixture is stirred for 5 min. at 0°C, 100 ml of ice water and 100 ml of pre-cooled methylene chloride are then added and stirred vigorously. Addition of some saturated aqueous sodium chloride solution causes it to separate into two phases. The methylene chloride phase is separated and the water phase is washed with a further 30 ml of methylene chloride. The water phase is poured over with 50 ml of methylene chloride, 10 ml of 2N hydrochloric acid is added and shaken. After separation of the organic phase, extract twice with 30 ml of methylene chloride. The combined methylene chloride extracts are dried over sodium sulphate and evaporated in vacuo. The white foam formed crystallizes on addition of chloroform and diethyl ether and gives 78-phenoxyacetamido-3-methoxy-cef-2-em-4a-carboxylic acid with m.p. 142°C (decomp.). IR spectrum.(KBr): characteristic bands at 5.65, 5.75, 5>95/u.

The starting material can be produced as follows:

a) To a solution of 3616 g (0.1 mol) 6-phenoxy-acet-amido-penicillanic acid-18-oxyci in 150 ml of dry dimethylformamide

while cooling with tap water, 20 ml (14.6 g, 0.145 mol) of triethylamine and 17 ml (24.5 g, 0.143 mol) of benzyl bromide are added. The mixture is stirred for 20 hours at room temperature, poured onto ice. The precipitate is filtered off, washed with approx. 1000 ml water, dried

2 aag in vacuum at 40<0>, taken up in 200 ml of methylene chloride and dried again with sodium sulphate. The white foam that remains after evaporation of the solvent is dissolved in 150 ml of ethyl acetate and set aside first at room temperature and then at -20°C for crystallization of pure 6-phenoxyacetamido-penicillanic acid benzyl ester-18-oxide. Temp. 139-140°C, IR spectrum (methylene chloride): characteristic bands vea 5.55, 5.75, 5.90/U, (a)<2>° - +174°+1°

(c = 1, chloroform).

Additional crystalline benzyl ester-18-oxide can be eluted from the mother route by chromatography on 250 g of acid-washed silica gel with toluene/ethyl acetate (1:1).

b) 4.56 g (10 mmol) 6-phenoxyacetamido-penicillanic acid benzyl ester-18-oxide and 1.84 g (11 mmol) 2-mercaptobenzthiazole

is heated in 100 ml of toluene for 5 hours at reflux (bath temperature 135°0). The mixture is allowed to stand and 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid benzyl ester crystallizes. The crystals are filtered off, washed with 50 ml of toluene and dried under high vacuum. By chromatography of the mother liquor on 70 g of acid-washed silica gel with toluene-ethyl acetate (3:1), further crystalline product can be recovered. Melting point of the pure product 150-153°C, IR spectrum (methylene chloride): characteristic bands vea 5.60, 5.75, 5.90/u, (a)<2>° » -112 -5-1° (c = 1, chloroform).

c) Through a solution of 6.06 g (10 mmol) 2-/~4-(benz-thiazol-2-yldithio)-3-phenoxy-acetamido-2-oxoazetidin-1-yl7-3-methylene-butyric acid- benzyl ester in 300 ml of methylene chloride, a mixture of oxygen and ozone is introduced at -20°C until the starting material is completely ozonized (check by means of thin-layer chromatography, silica gel, toluene/ethyl acetate 1:1). To the mixture, add 50 ml of a standard 10% sodium bicarbonate solution and stir for approx. 5 min. until potassium iodide starch can no longer be detected

ozonide. About 30 ml of water is added to the mixture and the product is distributed between o.e two f a.; is formed. The organic base is dried over sodium sulfate and freed from solvent. The distillation residue is triturated in 100 ml of ether-pentane (1.1) at 0°C, after which 2-/~4-(benzthiazol-2-ylthio)-3~phenox<y>acetamioo-2-oxoazetidin-1-yl7_3-hy- roxycrotonic acid benzyl ester, m.p. 58-62°C>IR spectrum (methylene chloride): characteristic bands veu 5.60, 5.90, 6.00/u3(a)20 - -92° l 1° (c = 1?chloroform). d) 6.08 g (0.01 mol) 2-[4-(benzthiazol-2-yllathio)-3-phenoxyacetamiao-2-oxoazetidin-1-y37-3-nyurloxy-^rotonic acid Denzyl ester and 3 .50 g (0.013 mo1) of silver p-toluenesulfinate is stirred in 200 ml of acetone-water (9^1) for 60 min. at room temperature. The yellow precipitate formed is filtered through "Cellit", the residue is washed with acetone and the filtrate is evaporated in vacuum to a volume of approx. 20 ml. The product is distributed between methylene chloride and dilute aqueous sodium sulfate solution. The organic phase is dried over sodium sulphate and the solvent is evaporated in vacuo. The evaporation residue is dissolved in 70 ml of ethyl acetate, if necessary while heating, some insoluble material is filtered off and evaporated again. On addition of 100 ml of ether-pentane ver 0 C, 2-/~4-(p-toluenesulfonylthio)~ 3~ £enoxyacetamiuo-2-oxoazetian-1-yl/- 3~hydroxy-crotonic acid benzyl ester crystallizes with m.p. 151-152°C, IR spectrum (methylene chloride): characteristic bands at 5.60»5>90»6S00, 8.75^, (a)<20>= -16° z 1° (c - 1, chloroform ). e) To a solution of 5.976 (0.01 mol) of pure 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-6xazetidin-1-yl7-3-hydroxy-crotonic acid benzyl ester in 50 ml of methylene chloride drop at 0°C without stirring an ethereal azomethane solution until the starting material is completely merylated (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 of glacial acetic acid), after which the mixture is concentrated in a vacuum. The yellow, foamy residue is crystallized from diethyl ether/pentane (1:1) and an isomer mixture is obtained which consists of 2-/~4-(P~toluenesulfonylthio)-3-phenoxyacetamiao-2-oxoazeticin-1-yl7-3 -methoxy-crotc5Byre benzyl ester and 2-/~4-(p-t-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxy-isocrotoic acid benzyl ester in the forehole of approx. 3- 1. By repeated Chrosa tography on silica gel with toluene/acetic acid ethyl ester 1.1, two isomers can be separated. The prepared 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetamiuo-2-oxoazethio.in-1-yl7-3-methoxy-crotonic acid benzyl ester when m.p. 166-168°C, (a)p° = -36<0>2. 1° (c = 1, chloroform), IR spectrum (methylene chloride). characteristic bands at 5.60, 5.B0, 5V90„ 8.72/U.1MMR spectrum (chloroform), characteristic oån ve. 2, 12 (s), 5.00 (dd), 5.9O (a) ppm, thin layer chromatogram. Rf value approximately 0.10 (silica gel., toluene/ethyl acetate 1.1). The prepared 2-[4-(p-toluenesulfonylthio)-3-phenoxyacetami.LO-2-oxoazeti^in-1-yl7-3-methoxy-isocrotonic acid benzyl ester has m.p. 59-b3°C, (a)<2>)<0>= -111° (c = 1, chloroform), IR spectrum (methylene chloride); characteristic båno ve_ 5.60, 5.87

pp. 5.90, 8.72 µU, MfR spectrum (chloroform), characteristic bands vec-, 2.32 (s), 5.45 ('« )»5.72(0 ppm, thin layer chromatogram. Rf value approx. 0.13 (silica gel. toluene/ethyl acetate 1.1).Example 20.

A solution of 534 mg (1 mmol) of a mixture of 2-/~4-(p-toluenesulfonylthio enoxyacetamino-2-oxoazeti.*in-1-yl7-3-methoxy-isocrotonic acid methyl ester and 2- j_ 4~( p-toluene-sulfonylthio)-3-phenoxyacetamico-2-oxoazeti'in-1-yl7-3-methoxy-crotonic acid methyl ester in a ratio of approx. 4.1 in 20 ml of tetrahydrofuran is stirred with 302 mg (2 mmol) of 1,5- iazaoicyklo/<->5v4.0_7unaec-5-ene for 40 min. The mixture is diluted with 70 ml of methylene chloride and washed successively with dilute acid, water, dilute aqueous sodium bicarbonate solution and again with water. The organic the phase is dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on 15 g of acid-washed silica gel with toluene/ethyl acetate 2.1 and ether 1:1, where a pure rJP~^ eil0^ Lsy~ acetaraiao-3-methoxy- cef-2-em-4a-cardonic acid methyl ester, IR spectrum (in methylene chloride), characteristic bands 5.°°, 5.70, 5>SQ»8.25^u and ..then the pure 7P -^endicsyacetamiu.o-3-methoxy-cef-3-em-4-carboxylic acid methyl ester, IR spectrum (methylene chloride). characteristic orbits,'. ve:- 5>kU, 5»85, 5.90, 7.10/U, in the form of colorless foam.

The precursors produced can be reacted as follows: To an ice-cooled solution of 3°*2 mg of 7P-phenoxyacetamido-3-methoxy-cef-2-em-4a-carboxylic acid methyl ester in 30 ml of tetrahydrofuran, add 15 ml of cooled 0.1 µM ordinary potassium hydroxide solution. After 5 min. 100 ml of water and 70 ml of methylene chloride are added and the mixture is acidified by adding 10 ml of normal hydrochloric acid. The methylene chloride phase is separated and the water phase is extracted with 30 ml of methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated in a vacuum. The evaporation residue is crystallized from chloroform/ethyl ether and

gives 78-i,enoxyacetamiao-3-methoxy-cef-2-em-4a-carboxylic acid with m.p. 142°C (ae comp.).

The same compound with m.p. 142°C (decomp.) obtains

when 70-phenoxyacetamiio-3-methoxy-cef-3-em-4-carboxylic acid methyl ester is reached, saponify with. 0J3JJ nalium hyur9cyto solution, as previously described.

The starting materials can be produced in the following way:

a) A solution of 19.25g (5° mmol) 6-phenoxyacetamido-penicillanic acid-methylesterl-Ø-oxy and 9.4 g (55 mmol) 2-mercapto-Denzthiazole in 500ml dry toluene is boiled for 8 hours under reflux and then amplified in a vacuum. The evaporation residue is dissolved under heating (approx. 80°C) in 400 ml of ethyl acetate, treated with 0.2 g of activated carbon and filtered through an electrically heated glass filter. len cooling separates 2-/"<*>4-(benzthiazol-2-ylthio-thio)-3-phenoxyacetamido-2-oxoazetiin-1-yl7-3-methylene-butyric acid methyl ester with m.p. 132-134° C. Some of this compound can still be recovered from the mother route (m.p. 135-137°C). b) Through a solution of 20.6 g (40 mmol) 2-/~4-(benz-thiazol-2-yldithio )-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methylene-butyric acid methyl ester in 400 ml of acetone, an ozone/oxygen mixture is conducted at -20°C until thin-layer chromatography (silica gel, toluene/ethyl acetate 1:1 ) can no longer detect the starting material. The mixture is then added to 40 ml of dimethylsulfide and stirred for 3 days at room temperature until ozone can no longer be detected with potassium iodide starch. The mixture is absorbed in a vacuum, and a liquid residue is poured into 400 ml of ice water. The precipitate is filtered off, washed with 200 ml of ice water, dried in vacuo and crystallized from diethyl ether/pentane at 0° C. The prepared 2-/~4-(benzthiazol-2-yldithio)-3-phenoxyacetamiao-2-oxoazetidin-1-yl7-3-hydroxy -crotonic acid methyl ester h ar a melting point of 127-130°C, IR spectrum (methylene chloride). characteristic band weight 5.60, 5.90, 6.00, 8.10/u. By chromatography, the moaer liquor can deliver additional amounts of product on silica gel with toluene/ethyl acetate 3;1» c) To a solution of 4.85 g (0.01 mol) 2-/~4~(benz-thiazol-2-yldithiob)-3 -phenoxyacetamiao-2-oxoazetidin-1-yl7-3-hyroxy-crotonic acid methyl ester in 50 ml of methylene chloride is added at 0°C and with stirring so much ethereal ayazomethane solution that after 15 minutes of stirring thin-layer chromatography (silica gel, toluene/ethyl acetate 1: 1) can no longer detect starting material. Excess dlazomethane is neutralized with the smallest possible amount of acetic acid and the mixture is pumped into a vacuum. The evaporation residue consists of a mixture of 2-/~4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetiGin-1-yl7-3-methoxy-isocrotonic acid methyl ester and 2-/~4-(benzthiazol- 2-yldithio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl7-3-methoxy-crotinic acid methyl ester in the ratio of approx.

4:1. IR spectrum (methylene chloride): characteristic bands at 5.60, 5.85, 5.90, 9.05, 10.00/U.

a) A mixture of 5.03 S (0.01 mol) consisting of 2-/~4-(benzthiazol-2-yldithio)«3-phenoxy-acetamido-2-oxoazetidin-1-yl7-3-methoxy-isocrotonic acid -methyl ester and the corresponding crotonic acid methyl ester in a ratio of approx. 4:1, 3.5° g (0.013 mol) silver p-toluenesulfinate qg 200 ml acetone/water 9:1 is stirred for 40 minutes at room temperature and filtered through °Cellit<n>. The filter residue is washed with acetone and the combined filtrates are evaporated to a volume of

about. 20 ml. After adding approx. 100 ml of methylene chloride and 100 ml of diluted aqueous sodium sulphate solution are shaken out, the water phase is separated and the methylene chloride phase is dried over sodium sulphate and evaporated under vacuum. The residue is triturated at 0°C with diethyl ether/pentane for purification and filtered. A mixture of 2-/~"4-( p-toluenesulfonyl lt lo )-3-phenoxyacetamiao-2-oxoazetidin-1-yl7-3-methoxy-isocrotonic acid methyl ester and 2-/~4-(p-toluenesulfonyl -phenylthio )-3-phenoxyacetamiao-2-oxoazetidin-1-yl7-3-methoxy-crotonic acid methyl ester in a ratio of about 4:1> in the form of a white powder IR spectrum (methylene chloride): characteristic bands at 5.60, 5.85, 5.90, 8.75/U.

Example 21.

A solution of 73^ mg (1 mmol) 1:1 mixture of 2- /~4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-benzyloxy-crotone- and the corresponding - isocrotonic acid p-nitrobenzyl ester is stirred in a mixture of 0.185 ml (1.2 mmol) of 1,5-iazabicyclo/""5»4-Q7unaec-5-ene in 20 ml of dry tetrahydrofuran for exactly 35 minutes at room temperature. 50 ml of methylene chloride is added to the mixture and washed successively with dilute hydrochloric acid, water and dilute aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulfate and concentrated in vacuo. The evaporation residue is chromatographed on .25 g of acid-washed silica gel with toluene/ethyl acetate (3:1)" A mixture of cef-2-em and cef-3-em compounds is obtained in the ratio approx. 2:1, which by repeated chromatography can be washed into the pure isomers, in which 7P-£enoxy-acetamido-3-benzyloxy-cef-2-em-4a-carboxylic acid p-nitrobenzyl ester has a m.p. at 160-162°G (diethyl ether/pentane), IR spectrum (methylene chloride): characteristic bands at 5,6, 5,7, 5,9, 7,4/U, and 7B-phenoxyacetamido-3-benzyloxy-cef -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 µU.

The produced mixture of isomers can be converted via

such:

The isomer mixture consists of 7P-phenoxyacetamido-3-benzyloxy-cef-2-em-4a-carboxylic acid-p-nitrobenzyl ester and 7P-phenoxyacetamido-3-benzyloxy-cef-3-em-4-carboxylic acid-p-nitrobenzyl ester in a ratio of approx. 3:1 is dissolved in 8 ml of trifluoroacetic acid and stirred for approx. 9^ min. at room temperature. The reaction mixture is evaporated in vacuo and residues of trifluoroacetic acid are washed off several times with toluene. The residue is chromatographed on 20 g of acid-washed silica gel with toluene/ethyl acetate (3«1*), and 7P-phenoxyacetamido-3~hyroxy-3-em-4-carboxylic acid p-nitrobenzyl ester is obtained in the form of a colorless foam. IR spectrum (methylene chloride). characteristic trajectories at 2.95, 3.3, 5,<6,>5.75 sh, 5.9, 5.95 sh, 6.55, 7.45, 8.15, 8.3/u, WMR -spectrum (deuterochloroform): characteristic bands at 3.4 (2H, AB q, J = 17 Hz), 4.57 (2H, s), 5.06 (1H, d, J = 5 Hz), 5.35 (2H, AB q, J = 14 Hz), 5.7 <1H, dd, J « 5, 10 Hz), 6.8-8.4 (10H, c), 11.4 (1H, 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-3-oxoazetidin-1-yl7-3-hydroxycrotonic acid p-nitrobenzyl ester in 4 ml of distilled dioxane is added 30 ml of an in situ-freely prepared solution of 1.2 g (ca. 10 mmol) of phenyldiazomethane in ether (prepared from N-benzyl-M-nitro-toluenesulfonamide) at room temperature. The mixture is boiled

for 6 hours at 45°C bath temperature at reflux, dilute with 100 ml of methylene chloride and then wash with 100 ml of water. The organic phase is dried over sodium sulfate, evaporated under vacuum and dried under high vacuum. The yellow oil formed is chromatographed on 100 g of acid-washed silica gel with toluene/ethyl acetate. l and 2:1 as eluent. A mixture of isomers consisting of 2-/~4-(p-toluenesulfonylthio)-3-phenoxyacetamiao-2-oxoazetidin-1-yl7"* 3-benzyloxy-crotonic acid p-nitrobenzyl ester and 2-/~*4-( p -toluenesulfonyl)-3-phenoxyacetamido-2-oxoazetidin-1-yl/-3-benzyloxy-isocrotonic acid p-nitrobenzyl ester in a ratio of approximately 1:1, which can be separated into the individual isomers by repeated chromatography as previously described. IR spectrum of the faster migrating crotonic acid derivative (methylene chloride): characteristic bands at 5>6, 5.80, 5.90, 8.75/u>WMR spectrum (deterochloroform): characteristic bands at 2.2 (s ), 5.05 (dd), 5.93 (d) ppm, thin layer chromatogram: Rf value approximately 0.3 (silica gel, toluene/ethyl acetate 2:1), IR spectrum for the slower migrating isocrotonic acid derivative (methylene chloride) : characteristic bands at 5.6, 5>&5 sn>5«9°»» 8.75/u>WMR spectrum (deuterochloroform): characteristic bands at 2.5 (s), 5»41(dd)»5 »77(d) ppm, thin layer chromatogram: Rf value about 0.25 (silica gel: toluene/ethyl acetate 2:1).

Example 22.

405 mg (0.5 mmol) of isomeric mixture consisting of 2-/~4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoacetidine/1-yl7-3-diphenylmethoxycrotonic acid p-nitrobenzyl ester and the corresponding isomeric isocrotonic acid ester in 8 ml of dry tetrahydrofuran, containing 0.9 ml (0.6 mmol) of 1,5-diazabicyclo/ /~5»4»Q7kundec-l-ene and stir for exactly 45 min. at room temperature. The yellow reaction mixture is diluted with 25 ml of methylene chloride

and washed with 0.5% hydrochloric acid, water and dilute aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulphate and evaporated.

An isomer mixture is obtained which consists of 7P~£enoxy-acetamdio-3-diphenylmethoxy-cef-2-em-4a-carboxylic acid p-nitrobenzyl ester and 7P-phenoxyacetamido-3-phenylmethoxy-cef-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/u.

It formed an isomeric mixture of the two compounds

can be further processed in the following way:

A solution of 340 mg of prepared isomeric mixture of 78-phenoxyacetamido-3-aif eny lmethoxy-cef-2-em-4ot-carboxylic acid p-nitrobenzyl ester and 7P-phenoxyacetamido-3-diphenylImethoxy-3cef-3-em-4-carboxylic acid -p-nitrobenzyl ester in a mixture of 0.5 ml of trifluoroacetic acid and 9.5 ml of methylene chloride is stirred for 40 min. at room temperature. The mixture is pumped into a vacuum, the evaporation residue is added to toluene and evaporated again. The residue formed (still contains trifluoroacetic acid) is chromatographed on 15 g of acid-washed silica gel with toluene/ethyl acetate (3:1)>, whereby 7P-phenoxyacetamido-3-hydroxy-cef-3-em-4carboxylic acid p-nitrobenzyl ester is obtained, 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, røa__spectrum (deuterochloroform): characteristic bands at 3.4 (2H, AB q, J = 17 Hz), 4.57 (2H, s), 5.06 (1H, d,

J - 5 Hz), 5.35 (2H, AB q, J = 14 Hz), 5.7 (1H, dd, J => 5, 10 Hz), 6.8-8.4 (10 H, c ), 11.4 UH» br.z.) ppm.

The starting material can be produced in the following way:

To a solution of 641 mg (L mmol) 2-/~4-{p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-hydroxy-crotonic acid p-nitrobenzyl ester in 0.5 ml distilled dioxane, a solution of 350 mg (1.75 mmol) of diphenylaizomethane in 0.3 ml of dioxane is added, and the reaction mixture is heated for JS hours without stirring at 50°C. The mixture is evaporated in vacuo, the remaining aioxane is driven off with toluene by repeated evaporation and the evaporation residue is chromatographed on 20 g of acid-washed silica gel with toluene/ethyl acetate (7-1) and (3-1)-

An isomer mixture is obtained which consists of 2-/"~4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl/-3-diphenylmethoxy-crotonic acid p-nitrobenzyl ester and 2-/~4-( p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-diphenyl-methoxy-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/hr.

Example 23.

A solution of 933 mg (1.5 mmol) isomeric mixture consisting of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-benzyloxy-crotonic acid methyl ester and the corresponding isocrotonic acid methyl ester in the ratio approx. 1:1, and 350 mg (2.25 mmol) of p-toluenesulfinic acid in 30 ml of dry tetrahydrofuran are added to 800 mg (5.25 mmol) of 1,5-diazabicyclo/"5,4-0_7-unoec-5-ene and stirred in exactly 40 min. at room temperature. The reaction mixture is diluted with 100 ml of benzene and with dilute aqueous hydrochloric acid, water, dilute aqueous sodium hydroxide solution and again with water. The benzene phase is dried over sodium sulfate and concentrated in vacuo. By chromatography with toluene/ethyl acetate (5:1)P& silica gel, an isomer mixture is obtained consisting of fp-phenoxyacetamido-3-benzyloxy-cef-3-em-4-carboxylic acid methyl ester and 7P~phenoxyacetamido-3-benzyloxy-cef-2-em-4-carboxylic acid methyl ester, IR -spectrum (methylene chloride): characteristic bands at 5>°0, 5»72, 5.85 sh, 5.90/U.

The starting material can be produced as follows:

A solution of 483 mg (1 mmol) of 2-[~4-(benzthiazol-2-yldithio)-3-phenoxyacetamiano-2-oxoazetidin-1-yl7-3-hydroxy-crotonic acid methyl ester in 1.5 ml of methylene chloride/ diethyl ether is added to 960 mg (approx. 8 mmol) of freshly distilled phenylalazomethane and stirred for 20 hours at 0°C. 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 high vacuum. The evaporation 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-ylaithio)-3~phenoxyacetamido-2-oxoazetidin-1-yl7 -3-benz<y>l-ox<y->croton<y>re-arethyl ester and the corresponding isocrotonic acid methyl ester in a ratio of about 1:1, IR spectrum (methylene chloride): characteristic bands at 5,6, 5 .85sh, 5.9, 9.9/U.

Example 24.

In analogy to example 4d, one can by converting 1.16 g (3 mmol) of 7P-amino-3-methoxy-cef-3-em-4-carbonic acid hydrochloride dioxanate, which is produced according to the invention,

with 1.5 ml (6.2 mmol) of bis-(trimethylsilyl)-acetamide and then

a) with 7&5 mg (3.6 mmol) D-α-amino-(2-thienyl)-acetic acid chloride-hydrochloride prepare 7P-Z~^-α-amino°-α-(2-thienyl)-acetylaminoy-3- methoxy-3-cephem-4-carboxylic acid in the form of its inner salt, m.p. 140°C (decomp.), thin-layer chromatogram (silica gel: identification with iodine): Rf approx. 0.22 (system: n-butanol/acetic acid/water 67:10:23) and Rf approx. 0.53 (system: isopropanol/formic acid/water 77:4:19), UV absorption spectrum: Xmax- 235 ayu (£ = II.4OO) and 7, shoulder 272 a<y>u (£ = 6100) in 0 ,ln hydrochloric acid, and ABax<->238 nyu (£ = 11,800) and X shoulder<=>26? m/u 6500^ in Oil» aqueous ntrium hydrogen carbonate solution,

b) with 940 mg (4.5 mmol) of D-α-amino-(1,4-cyclohexadienyl)-acetic acid chloride hydrochloride, prepare 7P-Z"D""α-amino°-α-U,4-cyclohexadienyl)-α c ethylamino/ -3-Me£oxy-§-cephem-4-carboxylic acid in the form of its inary salt, m.p. 170 C (decomp.), thin-layer chromatogram (silica gel, identification with iodine): Rf approx. 0.19 (system: n -butanol/acetic acid/water 67:10:23) and Rf approximately 0.58 (system: isopropanol/formic acid/water 77:4;19)» UV absorption spectrum: Xmax = 267ayu (£ = 63OO) in 0.ln hydrochloric acid, and

7^ max = 2^® m/u 6600) in 0.ln aqueous sodium hydrogencarbom t solution (a)g° «• +88 + 1° (c - 1.06, 0.1M hydrochloric acid), and

c) with 800 mg (3.6 mmol) of D-cc-amino-4-hydroxyphenyl-acetic acid-chlorine hydrochloride prepare 7B-/<*>~D-a-amino-a-(4-hydroxyphenyl)-acetylamino7-3- iBetoxy-3-cephem-4-carboxylic acid in the form of its inner salt, m.p. 243-244.5°C (initial sintering from 23I<0>) (decomp), thin-layer chromatogram (silica gel: detection with iodine): Rf approx. 0.24 (system: n-butanol/acetic acid/water 67%.10:23 ) and Rf approximately 0.57 (system: isopropanol/formic acid/

water 77<:>4<:>19), U?-absorption spectrum: \ max 228nyu (£= 12000) and 271nyu (£ 69OO) in 0.1 N hydrochloric acid, and Xmax = 227nyu ( £ 10,500) and 7V scular " 2^2m/u 8000) in 0.1 N aqueous sodium hyalurogen carbonate solution, (a)<2>° - +165+ 1° (c = 1.3, 0.1W hydrochloric acid).

Example 25.

In an analogous way, one can start from intermediate products such as

can be produced according to the invention, produce the following compounds: 78-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester or salts thereof,

3-n-butyloxy-7B-phenylacetylamino-3-cephem-4-carboxylic acid diphenyl methyl ester,

3-n-butyloxy-76-(D-a-tert.butyloxycarbonylamino-a-phenyl-acetyl-amino)-3-cephem-4-carboxylic acid diphenylmethyl ester, 3-n-butyloxy-76-(D-a-phenyl-glycylamino)- 3^cephem—4-carboxylic acid or its salts,

3-Methoxy-7B-phenylacetylamino-3-cephem-4-carboxylic acid methyl ester,

3-ethoxy-7B-(D-a-tert.butyloxycarbonylamino-a-phenyl-acetylamino)-3-cephem-4-carboxylic acid diphenylmethyl ester,

3-ethoxy-78-(D-a-phen<y>1-<g>l<y>c<y>lamino)—3-cephem-4-carboxylic acid or salts thereof,

3-benzyloxy-78-(D-α-tert.-butyloxycarbonylamino-α-phenylacetylamino)-3-cephem-4-carboxylic acid diphenylmethyl ester,

3-benzyloxy-78-(D-α-phenyl-glycylamino)-3-cephem-4-carboxylic acid or salts thereof,

78-(5-benzoylamino-5-diphenylmethoxycarbonylvaleryl-amino)-3-methoxy-3-cephem-4-carboxylic acid aiphenylmethyl? ter,

78-(D-α-tert-butyloxycarbonylamino-α-phenylacetyl-amino)-3-methoxy-3-cephem-4-carboxylic acid or salts thereof,

78-/~b-a-tert.butyloxycarbonylamino-a-(2-thienyl)-acetylamino7-3-methoxy-3-cephem-4-carboxylic acid diphenyl methyl ester, 7 B-/"~D-a-t tert.butyloxycarbonylamino-a-(1, 4-cyclohexadienyl)-acetylamino7-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester,

7P-Z~0-α-amino-α-(1-cyclohexen-1-yl)-acetylamino7-3-methoxy-3-cephem-4-carboxylic acid or salts thereof, 78-/~D-α-tert.butyloxycarbonylamino- α-(4-hyroxyphenyl)-acetylamino7-3-phletoxy-3-cephem-4-carboxylic acid diphenylmethyl ester,

7B-/~D-α-tert.butyloxycarbonylamino-α-(4-isothiazolyl)-acetylamino7-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester,

78-(D-α-tert.butyloxycarbonylamino-α-phenylacetyl-amino)-3-methoxycarbonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester,

as well as corresponding cef-2-em compounds and isomeric mixtures consisting of cef-3-em and cef-2-em compounds, as well as 1-oxys of corresponding cef-3-em compounds.

Claims (71)

1. Process for the production of 7P-amino-3-cef®m-3-ol-4-carboxylic acid compounds with formula: where Ra-, denotes hydrogen or an amino protecting group R,\ and E^ denotes hydrogen or an acyl group Ac, or R^ and R^ together form a divalent amino protecting group, R2 denotes hydroxyl or a residue Rg^ which together with the carbonyl group -C(=0) forms a protected carboxyl group, and R^ denotes hydrogen, lower alkyl, or a hydroxy protecting group, as well as 1-oxys of 3-cephem-3 compounds of formula IA and the corresponding 2-cephem compounds of formula where R p R 1} Rg and have the meanings indicated above, or salts of such compounds containing salt-forming groups, characterized by treating a compound with a formula where R <a>^ , R <*> ^, and"R2* where meaning as indicated under formula was, R^ ° denotes lower alkyl or a hyaroxy protecting group and Y denotes an elongated group, with a base, and if desired, the protected carboxyl group of formula -01=0 )-Rg A transfers to a free or other protected carboxyl group, in a prepared compound of formula IA or IB and/or, if desired, transfers a protected hydroxy group -OåR^ ° to a free hydroxy group, and/or transfers a produced free hydroxy group or the protected hydroxyl group -O-R-^ to a lower hydroxy group -O-R^» and /or if desired, within the definition of the final products, transfers a prepared compound to another compound, and/or, if desired, converts a prepared compound containing a salt-forming group into a salt, or converts a prepared salt into the free compound or another salt, and/or, if desired, separates a prepared isomer mixture into the individual isomers. 2. Method as stated in claim 1, characterized in that starting substances of formula II are used a A o where R ^ denotes an amino protecting group R-^ , which stands for an acyl group Ac, in which any free functional groups b A may be protected, R^ b denotes hyarogen, Rg denotes halogen or an etherified hydroxyl group which together with the -C(=0) group forms an esterified carboxyl group, where any functional groups in an esterified carboxyl group of the formula -Cf^ Oj-Rg ^" may be protected, R^ ° denotes lower alkyl or a hydroxy protecting group, and Y denotes a group -S-R^ , a group -SOg-R^ which is bonded with the sulfur atom to the thio group -S-, or a group -S-SO <g-R> ^ <.> 3« Process as set forth in claim 2, characterized in that Rg A denotes an optionally substituted 1-phenyllower alkoxy group, such as benzyloxy, p-nitrobenzyloxy or diphenylmethoxy group, or an optionally halogen-substituted lower alkoxy group such as methoxy, α-multi-branched lower alkoxy, like for example. tert-butyloxy or 2-halo-lower alkoxy, such as 2,2,2-trichloroethoxy, or halogen such as chlorine. 4» Method as stated in claim 1 or 2, characterized in that Ro ° denotes lower alkyl such as methyl, or a substituted silyl group such as trimethylsilyl. 5. Method as stated in claim 1 or 2, characterized in that ¥ denotes a group -S-R^ where R^ forms an optionally substituted, aromatic, heterocyclic residue with up to 15, and preferably up to 9 C atoms, and contains at least one ring -nitrogen atom and optionally a further hetero-ring atom such as oxygen or sulphur, which residue is bound to the thio group -S- with one of the ring carbon atoms which in turn is connected to a ring nitrogen atom through a double bond. 6. Method as stated in one or more of claims 1, 2 or 5, characterized in that R» denotes 1-methyl-imidazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazole 2-yl, 1,3,34,5-thiatriazol-2-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,3»4>5-°Xatriazole -2-yl, 2-quinolyl, 1-methyl-benziraidazol-2-yl, benzoxazol-2-yl and especially benzthiazol-2-yl. 7« Method as set forth in claim 1 or 2, characterized in that R^ denotes an optionally substituted aliphatic, cycloaliphatic, araliphatic or aromatic acyl or thioacyl group, with up to 18, and preferably up to 10 C atoms, such as lower alkanoyl, of the type acetyl or propionyl, lower thioalkanoyl such as thioacetyl or thiopropionyl, cycloalkanecarbonyl such as cyclohexanecarbonyl, cycloalkanethiocarbonyl such as cyclohexanethiocarbonyl, benzoyl, thiobenzoyl, naphthylcarbonyl-, naphthylthiocarbonyl, 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 correspondingly substituted, mono- or polysubstituted acyl or thioacyl group, for example substituted with lavalyl such as methyl, halogen as fluorine or chlorine, lower alkyloxy as methoxy, aryl as phenyl, aryloxy as phenyloxide. 8. Process as stated in claim 1, 2, 5 or 6, characterized in that R 1 denotes benthiazol-2-yl. 9" Method as stated in claim 1, 2, 5 or 6, characterized in that R" denotes benzoxazol-2-yl. 10. Method as specified in claim 1 or 2, characterized in that Y denotes a group -SOg-R^ , where R^ forms an optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbon residue with up to 18 and preferably up to 10 C atoms. 11. Method as stated in claim 1 or 2, characterized in that Y denotes a group -S-SOg-R^ where R^ denotes an optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbon residue with up to 18, and preferably up to 10, C atoms. 12. Method as specified in one or more of claims 1, 2, 10 or 11, characterized in that R denotes an alkyl, in particular lower alkyl group such as methyl, ethyl or butyl group, alkenyl group such as allyl or butenyl group, cycloalkyl group such as cyclopentyl or cyclohexyl group which groups are optionally mono- or polysubstituted with lower alkyloxy such as methoxy, halogen, such as fluorine, chlorine or bromine, aryl such as phenyl, aryloxy such as phenyloxy, or denotes naphthyl or especially a phenyl group which is optionally mono- or polysubstituted with lower alkyl such as methyl, lower alkyl such as methoxy, halogen such as fluorine, chlorine or bromine, aryl as phenyl, aryloxy as phenyloxy or with nitro, e.g. phenyl, o-, m- or preferably p-tolyl, o-, m- or preferably p-raethoxyphenyl, o-, m- or p-chlorophenyl, p-biphenylyl, p-phenoxyphenyl, p-nitrophenyl or 1- or 2 -naphthyl. 13* Method as stated in one or more of claims 1, 2, 10, 11 or 12, characterized in that Y denotes a group -SOg-R^ where R^ denotes phenyl, p-toly}, p-methoxyphenyl or p-nitrophenyl . 14- Method as stated in one or more of claims 1 to 13, characterized in that a bicyclic amidine is used as a base. 15. Method as stated in one or more of claims 1 to 14, characterized in that one uses as a base etd iazabicycloalkene, such as 1,5-iazabicyclo/"~4.3.9_7- non-5-ene or 1^-diazabicyclo/^ ^-^non-^"6 *1, 16. Method as stated in one or more of claims 1 to 13" characterized in that substituted guanidines are used as a base, e.g. polysubstituted with lower alkyl, for example tetramethylguanidine, or tri-lower alkylamines such as triethylamine. 17. Method as stated in one or more of claims 1-16, characterized in that in a prepared compound the hydroxy protecting group R« is split off and replaced with hydrogen. 18. Process as stated in claim 17, characterized by cleaving off a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon residue R^ by acid hydrolysis, or cleaving off a silyl or stannyl group R^ by hydrolysis, alcoholysis or acidolysis. 19. Method as set forth in one or more of claims 1-18, characterized in that one transfers a prepared compound where R^ denotes hydrogen, to a compound where R^ denotes lower alkyl, by etherification. 20. Method so r, indicated in one or more of claims 1-19, characterized in that T>an transfers a prepared compound where R^ denotes hydrogen to a compound where R^ denotes methyl, by etherification. 21. A method as set forth in one or more of claims 19 or 20, characterized in that the addition is carried out with a diazole alkane of formula R^Wg, for example diazomethane. 22. Method as stated in one or more of claims 19 or 20, characterized in that the etherification is carried out by treatment with a reactive ester of a lower alkanol of formula R 1 -OH. 23. Method as stated in one or more of claims 1-22, characterized in that in a prepared compound where R a ^ or R h ^ denotes an acyl group, a suitable acyl group is cleaved off, e.g. by treatment with an imide halide forming agent, reaction of the formed imi halide with an alcohol and cleavage of the formed iminoether, and replaces the group with hydrogen. 24. Method as stated in one or more of claims 1-23, characterized in that in a prepared compound a free amino group is protected, e.g. by acylation. 25. Method as specified in one or more of claims 1-24, characterized in that free functional groups in the starting materials or in compounds produced 1 according to the invention, and which do not participate in the reaction, is temporarily protected during methods according to the invention or during any additional reactions, and if desired is released after the reaction has ended. 26. Method as stated in one or more of claims 1-25, characterized in that in a primary oxygen compound with a protected carboxyl group of formula -Ct^OJ-Rg this is converted into a free carboxyl group by irradiation or by means of alkaline or acid hydrolysis, alcoholysis, acidolysis or by treatment with a reducing agent. 27. Method as stated in one or more of claims 1-26, characterized in that a prepared compound of formula IB or a prepared mixture consisting of compounds of formula IB and a compound of formula IA is converted into a 1-oxide of a compound of formula IA. 28. Method as stated in one or more of claims 1-27, characterized in that a prepared 1-oxide of a compound of formula IA is reduced to a compound of formula IA. 29. Method as specified in one or more of claims 1-28, characterized in that as starting materials compounds are used which can be obtained as intermediates according to the method of the invention and the remaining method steps are carried out with these, or the process is interrupted at one or another step. 30. Method as specified in one or more of claims I-29, characterized in that starting materials are used in the form of derivatives, or form it in the reaction mixture. 31" Method as specified in one or more of claims I-30, characterized in that one prepares 3-cephem compounds of formula IA according to claim 1 or their 1-oxides, via the corresponding 2-cephem compounds of formula IB according to claim 1, as well as salts of such compounds containing salt-forming groups, where R^<a> constitutes hydrogen or an acyl residue occurring in a fermentative or biosynthetic, semi-synthetic or fully synthetically producible N-acyl derivative of a 6B-amino-penam- 3-carboxylic acid or 7B-anulno-3,-cef em-4-carboxylic acid compound, R^ denotes hydrogen, Rg denotes hydroxy, optionally substituted lower alkyloxy, acyloxy, trilower alkylsilyloxy or optionally substituted amino or hydrazino, and R^ denotes hydrogen, lower alkyl or a hydroxy protecting group. 32. Method as stated in one or more of claims 1-31, characterized in that 3-cephem compounds of formula IA according to claim 1 or their 1-oxides, as well as corresponding 2-cephem compounds of formula IB are prepared in according to claim 1, further salts of such compounds with salt-forming groups, where R<a>^ denotes hydrogen, an acyl residue occurring in fermentatively or biosynthetically producible W-acyl derivatives of 66-amino-penam-3-carboxylic acid- or 78-amino -3-cephem-4-carboxylic acid compounds, or an acyl residue occurring in highly active N-acyl derivatives of 68-amino-penam-3-carboxylic acid or 7P-amino-3-cephem-4-carboxylic acid compounds, R-^ denotes hydrogen, Rg denotes hydroxyl, lower alkyloxy, 2-halolower alkyloxy, phenacyloxy, 1-phenyllower alkyloxy with 1-3, optionally lower methoxy- or nitro-substituted phenyl radicals, lower alkanoyloxymethoxy, lower alkyloxycarbonyloxy or lower alkanoyloxy, and R^ denotes hydrogen, lower alkyl or a hydroxy protecting group, or where Rg and R^ has the above meanings and R^<a> and R^ together form a l-oxo-3-aza-1,4-butylene residue which is substituted in the 2-position with optionally substituted phenyl, and which in the 4-position optionally contains 2- lower alkyl groups. 33" Method according to one of claims 1-32, characterized in that 3-cephem compounds of formula IA according to claim 1 or their 1-oxides, or their corresponding 2-cephem compounds of formula IB according to claim 1 are prepared 1, further salts of such compounds containing salt-forming groups, where R^ a and R-^ b have meanings as stated in claim 32, Rg denotes hydroxy, lower alkyloxy, 2-halolower alkyloxy, phenacyloxy, 1-phenyllower alkyloxy with 1-3, possibly lower alkyloxy or nitro-substituted phenyl radicals, lower alkanoyloxymethoxy, α-aminolower alkanoyloxy-methoxy, lower alkyloxycarbonyloxy or lower alkanoyloxy and R^ denotes lower alkyl, or denotes a hydroxy protecting group such as trilower alkylsilyl, or where Rg and R^ have the above meaning, and R a ^ and R b ^ together denote a 18oxo-2-aza-1,4-butylene residue which is substituted in the 2-position with optionally substituted phenyl and which optionally contains two lower alkyl groups in the 4-position. 34" Method as stated in one or four of claims 1-33*characterized by preparing 3-cephem compounds of formula IA according to claim 1 or their 1-oxys, or the equivalent 2-cephem compounds of formula IB according to claims 1, further salts of such compounds containing saltd other groups, where R^^ , Rg and R^ have meanings as stated in claim 33° S Ri a stands for hydrogen or a group mea formula where n = 0 and R T denotes hydrogen or an optionally substituted cycloaliphatic or aromatic hydrocarbon residue, or an optionally substituted heterocyclic residue of preferably aromatic character, a functionally converted, e.g. esterified or etherified, hydroxy- or mercapto group, or an optionally substituted amino group- T or where n = 1. R denotes hydrogen or an optionally substituted aliphatic, cycloaliphatic. cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residue, or an optionally substituted heterocyclic or heterocyclic-aliphatic residue, where the heterocyclic residue preferably has an aromatic character and/or contains a quaternary nitrogen atom, an optionally functionally converted, preferably etherified or esterified hydroxyl or mercapto group, an optionally functionally converted carboxyl group, an acyl group, an optionally substituted amino group. or an aziao group, and each of the radicals R <**> and R**1 denotes hydrogen, or where n «= 1 R <*> denotes an optionally substituted, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residue or a optionally substituted heterocyclic or heterocyclic-aliphatic residue, where the heterocyclic residue preferably has an aromatic character, R denotes a functionally converted, e.g. esterified or etherified, hydroxy or mercapto group, as a halogen atom, an optionally substituted amino group, an optionally functionally converted carboxyl group or sulfo group, an optionally O-mono- or 0,Of <->d isubstituted phosphono group or an azido group, III and R denotes hydrogen, or where n = 1, each of the residues R <*> and R <**> denotes a functionally converted, preferably etherified or esterified, hydroxyl group, or an optionally functionally converted carboxyl group, and R <***> denotes hydrogen, or where T n *= lj R denotes hydrogen or an optionally substituted aliphatic, cycloaliphatic-aliphatic, cycloaliphatic, aromatic or II III araliphatic hydrocarbon residue, and R and R together form an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon residue, connected to the carbon atom through a double bond, or where na 1, and R denotes a substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residue, or an optionally substituted heterocyclic or heterocyclic-aliphatic residue, where the heterocyclic residues preferably have an aromatic character, R <**> denotes an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic III hydrocarbon residue, and R is hydrogen, or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residue, where Rg and R^ have the above meanings, and R^<a> and R^ together form a l~ oxo-3-aza-1,4-butylene residue which is substituted in the 2-position with optionally substituted phenyl, and which is optionally substituted in the 4-position with two lower alkyl groups. 35. Method as specified in one or more of claims I-34, characterized in that 3-cephem or 2-cephem compounds of formula IA or IB according to claim 1 are prepared, or salts of such compounds containing salt-forming groups, where R-^ b denotes hydrogen, R^ a denotes hydrogen, an acyl group of formula where R_ forms phenyl, hydroxyphenyl, hydroxychlorophenyl, thienyl, pyridyl, aminopyridinium, faryl, isothiazyl, tetrazolyl or 1,4-cyclohexadienyl, where hydroxy substituents in such residues may be protected with acyl residues, X denotes oxygen or sulphur, m = 0 or 1, and R^ denotes hydrogen, or when m =» 0, optionally protected amino, carboxy, sulfo or hyaroxy, or 0-lower-alkylphosphono or 0,0'-di-loweralkyl-phosphono, or the denominator 5- amino-5-carboxyl-valeryl residue, where the amino and carboxyl groups are optionally protected, and Rg and R^ have meanings as stated in claim 33. 36. Method as stated in one or more of claims 1-35 > characterized in that 3-cephem compounds of formula IA are produced according to claim 1, as well as their 1-oxides, or further the corresponding 2-cephem compounds, with formula IB according to claim 1, or salts of such compounds, with salt-forming groups, where R^<a> denotes hydrogen, or an acyl residue with formula B, where Roa l forms phenyl, hydroxy-phenyl, as 4~ bydroxyphenyl, thienyl as 2- or 3-thienyl, 4-isothiazolyl or 1,4-cyclohexadienyl, X represents oxygen, ra = 0 or 1, and R^ represents hydrogen or, when m = 0, amino, protected amino as acylamino, e.g. α-multibranched lower alkoxycarbonylamino as well as tert-butyloxycarbonylamino, or 2-halolower alkoxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, 2-iodoethoxycarbonylamino or 2-bromomethoxycarbonylamino or optionally lower alkoxy- or nitro-substituted phenyllower alkoxycarbonylamino such as 4-methoxy-benzyloxycarbonylamino or hydroxy, further protected hydroxy as acyloxy, for example α-multi-branched lower alkoxycarbonyloxy such as tert-butyloxycarbonyloxy, or 2-halogen-lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromomethoxycarbonyloxy, further formyloxy, or denotes a 5-amino-5 -carboxy-valeryl residue, where the amino and carboxy groups can also be protected and e.g. exists as acylamino of the lower alkanoyl amino type, for example acetylamino, haloalkanoylamino such as cycloacetylamino, benzoylamino, or phthaloylamino, for example esterified carboxy, as phenyllower carboxycarbonyl of the diphenyl-methoxycarbonyl type, h1 preferably m = 1 when R_ = phenyl or hydroxyphenyl, R^ denotes hydrogen, Rg denotes hydroxyl, lower alkoxy which is optionally substituted in the 2-position with halogen, such as chloro-, bromo- or iodo, in particular α-multi-branched lower alkoxy such as tert-butyloxy or 2-halo-lower alkyloxy, such as 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromomethoxy, or optionally lower carboxy- or methoxy-substituted diphenylmethyloxy, for example diphenylmethoxy or 4>4<*->dimethoxy-diphenylmethoxy, p-nitro-benzyloxy, further tri-lower alkylsilyloxy, such as trimethylsilyloxy and R^ denotes hydrogen, lower alkyl, especially methyl or tri-lower alkylsilyl. 37" Method as specified in one or more of claims I-36, characterized in that 76-(D-a-amino-a-Rapac <y>l et <y>l amino)-3-laval coke <y-> 3-cephem-4-carboxylic acid, where R c„ l denotes phenyl, 4-hydroxyphenyl, 2-thienyl or 1,4-cyclohexadienyl, and the lower alkoxy groups contain up to 4 C atoms, or their internal salts. 38. Method as stated in one or more of claims I-36, characterized in that 78-phenoxyacetamiao-3-methoxy-cef-3-em-4-carboxylic acid p-nitrobenzyl ester is produced. 39» Process as stated in one or more of claims I-36, characterized in that 78-phenoxyacetamido-3-methoxy-cef-2-em-4-carboxylic acid p-nitrobenzyl ester is produced. 40» Method as stated in one or more of claims I-36, characterized in that 7p-phenoxyacetamiao-3-hydroxy-cef-3-em-4-carboxylic acid diphenylmethyl ether is produced. 41. Method as stated in one or more of claims I-36, characterized in that 7P-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester is produced. 42. Process as set forth in one or more of claims I-36, characterized in that 7P-phenoxyacetamido-3-methoxy-cef-2-em-4-*carboxylic acid cif enyl methyl ester is produced. 43» Method as stated in one or more of claims I-36, characterized in that 7B-phenoxyacetamicto-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethylester-1-oxide is produced. 44• Process as stated in one or more of claims I-36, characterized in that 78-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid-2,2,2-trichloroethyl ester is produced. 45» Process as stated in one or more of claims I-36, characterized in that 78-phenoxyacetamido-3-methoxy-cef-2-em-4-carboxylic acid-2,2,2-trichloroethyl ester is produced. 46. Method as stated in one or more of claims I-36, characterized in that 76-phenoxyacetamido-3-methoxy-cef-2-em-4-carboxylic acid tert-butyl ester is produced. 47' Process as stated in one or more of claims I-36, characterized in that 3-methoxy-7B-phenylacetylamino-3-carboxylic acid or alt thereof is produced. 48« Method as specified in one or more of claims 1-37, characterized in that 3-methoxy-7B-(D-a-tert.butyloxy-carbonylamino-a-phenylacetyl-amino)-3-cephem-4-carboxylic acid is produced -ciif enyl methyl ester. 49" Method as stated in one or more of claims 1-37, characterized in that 3-methoxy-78-(D-a-phenylglycylamino)-3-cephem-4-carboxylic acid or salts thereof are produced. 50. Method as stated in one or more of claims 1-37, characterized in that the inner salt of 3-methoxy-78-(D-a-phenylglycylamino)-3-cephem-4-carboxylic acid is prepared. 51. Process as stated in one or more of claims 1-37, characterized by the preparation of 3-n-butyloxy-7B-(D-a-phenylglycylamino)-3-cephem-4-carboxylic acid or salts thereof. 52. Method as stated in one or more of claims 1-37, characterized in that 78-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester or salts thereof are produced. 53» Procedure as specified in one or more of claims 1-37. characterized in that 78-/~D-α-amino-α-(2-thienyl)-acylamino7-3-methoxy-3-cephem-4-carboxylic acid or salts thereof are produced. 54* Process as stated in one or more of claims 1-37, characterized in that 7PP-/"~D-α-amino-α-(4-hydroxyphenyl)-acetylamino)-3-methoxy-3-cef is produced -4-carbonic acid or a salt thereof. 55" Method as stated in one or more of claims 1-37, characterized in that 3-ethoxy-70-(D-a-phenyl-glycylamino)-3-cephem-4-carboxylic acid or salts thereof are produced. 56. Process as set forth in one or more of claims 1-37, characterized in that 3-benzyloxy-7B-(D-a-phenylglycylamino)-3-cephem-4-carboxylic acid or salts thereof are produced. 57» Process as stated in one or more of claims 1-37, characterized in that one prepares 78-/~D-a-amino-a-(1,4-cyclohexadienyl)-acetylamio7-3-methoxy-3-cephem-4- carbonic acid or salts thereof. 58. Method as set forth in one or more of claims 1-37> characterized in that 7P-amino-3-methoxy-3-cephem-4-carboxylic acid or salts thereof are produced. 59» Process as stated in one or more of claims 1-37, characterized in that 7P-(5-benzoylamino-5-diphenylmethoxycarbonyl-valerylamino)-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is produced. 60. Method as described in examples 1-13 for the production of compounds according to claim 1. 61. Method as specified in one or more of claims 1-9 and 14-59"characterized by treating a compound of formula II, where Y forms a group -S-R^ and R^a, R1b and RgA have meanings as indicated under formula IA, and denotes lower alkyl or a hydroxy protecting group, and where R^ has the meaning as stated in claims 5-9" with a base in the presence of a sulfinic acid of formula HSOg-R^ . 62. Process as stated in claim 6l, characterized in that R* denotes benzthiazol-2-yl. 63. Method as stated in one or more of claims 61 or 62, characterized in that R 1 denotes phenyl, p-tolyl, o- or p-methoxyphenyl or p-nitrophenyl. 64. Procedure as stated in one or more of the claims 61-63, character! by using a bicyclic amidine as a base. 65. Method as specified in one or more of claims 61-64, characterized in that a diazabicycloalkene is used as a base, such as 1,5-diazabicyclo/~4«3-07non-5-ene or 1,5-d iazabicyclo/ ~5»4»27non-5-ene. 66. Method as described in examples 6, $ 1, 5^» 5ai, 5bi, 5c 5d and 14 to 18, for the production of compounds according to claim 1. 67. Method as set forth in one or more of claims 1-34 and 61-66, characterized in that 3~ cephem compound ices of formula IA are produced, where R a denotes an acyl group of formula (B), where R fi forms a cyclohexenyl. 68. Process as described in examples 1, 4i> 5iii, 5biii, 5ci, 19 and 20, for the preparation of compounds according to claim 1. 69. Method as specified in one or more of claims 1-16, 21, 23-35, 61, 67 and 68, characterized in that compounds of formula IA and their 1-oxides, compounds of formula IB, or salts are prepared of such compounds containing salt-forming groups, where R 2 forms an easily cleavable, optionally substituted α-phenylia alkyl group. 70. Method according to claim 69, characterized in that R 1 denotes an optionally substituted benzyl or diphenylmethyl group. 71. Method as described in examples 5*v, 21, 22 and 23, for the production of compounds as specified in claim 1.