CS228101B2 - Method of production of derivatives of 7-beta-aminocefam-3-on-4-carboxylic acid - Google Patents

Description

The present invention relates to a process for the preparation of Z / baminocefam-S-on-1-carboxylic acid derivatives of the general formula I

(/) in which

^And R represents hydrogen or an amino-protecting group R ^A of up to 18 carbon atoms, and

R ^1b represents hydrogen or an acyl group of Ac containing up to 18 carbon atoms, or

Ri ^and a R? together represent a divalent amino protecting group of up to 18 carbon atoms,

R 2i ^A is a residue forming, together with the carbonyl grouping -C (= O) -protected carboxy group having up to 19 carbon atoms as well as 1-oxides of compounds of formula I or their salts.

Cefam-3-one derivatives as well as the corresponding derivatives

The 1-oxides can exist in both ketoform and enolform of the cefem-3-ol derivatives of formula Ia

R ^a, R ^b and R ^a have the meanings given under formula I, which contain a double bond in position 2,3 or preferably 3,4-position or a mixture of both forms.

In the compounds of formula (Ia) with a double bond at the 2,3-position, the protected carboxyl group preferably occupies the α-configuration.

The amino protecting group R ^1A is a group replaceable by a hydrogen atom, in particular an acyl group Ac, a triarylmethyl group, in particular a trityl group, as well as an organic silyl group and a stannyl group. The group Ac, which may also be a radical R ^1b , is primarily an acyl radical of an organic carboxylic acid, preferably containing up to 18 carbon atoms, in particular an acyl radical, optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic aromatic, arylaliphatic, heterocyclic or heterocyclic- aliphatic carboxylic acids, including formic acid, as well as the acyl residue of the carbonic acid semi-derivative.

As zzbytek bivalent amino protective group formed together radicals R ^a and R ^b come into consideration especially divalent acyl radical of an organic dicarboxylic acid, preferably containing up to 18 carbon atoms, primarily the diacyl radical of an aliphatic or aromatic dicarboxylic acids, as the acyl residue "aminoacetic acid , preferably substituted in the α-position, for example by an aromatic or heterocyclic radical, wherein the amino group is bonded to the nitrogen atom through a methylene radical, preferably substituted, for example, by two lower alkyls such as methyl. Residues ^and R and R? they may also form together an organic, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or arylaliphatic ylidene residue, preferably containing up to 18 carbon atoms.

The protected carboxyl group of formula -C (= Oj-R a ⁾ is primarily an esterified carboxyl group, but may also be a mixed anhydride group or an optionally substituted carbamoyl or hydrazinocarbonyl group.

^Thus , R 2 ^A may be an organic moiety an etherified hydroxyl group, wherein the organic moiety preferably contains up to 18 carbon atoms, which together with the —C (= O) — form an esterified carboxyl group. Such organic radicals are, for example, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or arylaliphatic radicals, in particular optionally substituted hydrocarbon radicals of this type, as well as heterocyclic or heterocyclic-aliphatic radicals.

The group R 2 ^A may also be an organic silyloxy moiety as well as a lower organometallic moiety an etherified hydroxyl group such as the corresponding organic stannyloxy group, especially one to three optionally substituted hydrocarbon radicals, preferably containing up to 18 carbon atoms, such as aliphatic hydrocarbon radicals and optionally a halogen atom, such as chlorine, substituted silyloxy or stannyloxy groups.

The radical R 2 ^A formed by the group -C (= O) - primarily a mixed anhydride group, is in particular an acyloxy group, wherein acyl is the corresponding organic carboxylic acid residue, preferably containing up to 18 carbon atoms, such as aliphatic, cycloaliphatic, cycloaliphatic- aliphatic, aromatic or arylaliphatic carboxylic acids, or semi-derivatives of carbonic acid, such as a semi-ester of carbonic acid.

The radical R 2 ^A forming a - C (= O) - carbamoyl group is an optionally substituted amino group, wherein the substituents of the optionally substituted monovalent or divalent hydrocarbon radical preferably contain up to 18 carbon atoms, such as optionally substituted monovalent or divalent aliphatic, cycloaliphatic, cycloaliphatic-aliphatic , aromatic or arylaliphatic hydrocarbon radicals containing up to 18 carbon atoms, further corresponding heterocyclic or heterocyclic-aliphatic radicals containing up to 18 carbon atoms and / or functional groups such as, optionally, functionally modified, in particular free hydroxyls, further etherified or esterified hydroxyls, an ether or ester, for example, as defined above and preferably contains up to 18 carbon atoms, as well as acyl residues primarily derived from organic carboxylic acids and from semi-derivatives of carbon acid ITE, preferably containing up to 18 carbon atoms.

In a substituted hydrazinocarbonyl group of the formula —C (= Oj — R2) ⁴ , one or both of the nitrogen atoms may be substituted, in particular, optionally substituted mono- or divalent hydrocarbon radicals, preferably containing up to 18 carbon atoms, such as optionally substituted mono- or a divalent aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or arylaliphatic hydrocarbon radical containing up to 18 carbon atoms, further corresponding heterocyclic or heterocyclic-aliphatic radical containing up to 18 carbon atoms and / or a functional group such as an acyl radical, in particular derived from carboxylic acids or semi-derivatives of carbonic acid, preferably containing up to 18 carbon atoms.

For example, in the above and below description, the general terms have the following meanings:

The aliphatic radical including the aliphatic radical of the corresponding carboxylic acid as well as the corresponding ylidene radical is an optionally substituted monovalent or divalent aliphatic hydrocarbon radical, in particular lower alkyl as well as lower alkenyl or lower alkynyl, further lower alkylidene e.g. containing up to 7, preferably up to 4 carbon atoms . These radicals may optionally be mono-, di- or polysubstituted with functional groups, for example, free, etherified or esterified hydroxyl groups or mercapto groups, such as lower alkoxy groups, lower alkenyloxy groups, lower alkylenedioxy groups, optionally substituted phenyloxy groups or phenyl lower alkyl groups, or lower alkoxy groups, substituted phenylthio, phenyl lower alkylthio, heterocyclylthio or heterocyclyl lower alkylthio, optionally substituted lower alkoxycarbonyloxy, or lower alkanoyloxy or halogen, further oxo, nitro, optionally substituted with amino, e.g. as well as acylamino such as lower alkanoylamino, lower alkoxycarb onylamino, balogen-lower alkoxycarbonyl, optionally substituted phenyl-lower alkoxycarbonylamino, optionally substituted carbamoylamino, ureidocarbonylamino, or guanidinocarbonylamino, optionally in the form of a salt such as an alkali metal salt, an alkano group, an acido group, an acido group, an acido group, an acido group, benzoyl, optionally with a functionally modified carboxyl such as carboxyl in the form of a salt esterified with a carboxyl such as lower alkoxycarbonyl, optionally substituted carbamoyl such as N-lower alkylcarbamoyl or N, N-di-lower alkylcarbamoyl; substituted ureidocarbonyl or guanidinocarbonyl or cyano, optionally a functionally modified sulfo group such as sulfamoyl or in the form of a salt occurring sulfo group or O-mono- or O, O-disubstituted phosphono group, wherein the substituents are, for example, optionally substituted lower alkyl, phenyl or phenyl lower alkyl, O-unsubstituted or O-monosubstituted phosphone groups may also exist in the form of a salt, such as an alkali metal salt.

The divalent aliphatic residue, including the corresponding divalent aliphatic carboxylic acid residue, is, for example, lower alkylene or lower alkenylene, which may be mono-, di- or polysubstituted, for example by the aforementioned aliphatic residue and / or interrupted by a heteroatom such as oxygen, nitrogen or sulfur.

The cycloaliphatic or cycloaliphatic-aliphatic radical, including the cycloaliphatic or cycloaliphatic-aliphatic radical in the corresponding carboxylic acid or the corresponding cycloaliphatic or cycloaliphatic-aliphatic ylidene radical is an optionally substituted mono- or divalent cycloaliphatic or cycloaliphatic mono- or di-aliphatic, cycloalkyl or cycloalkenyl, further cycloalkylidene, optionally cycloalkyl- or cycloalkenyl-lower alkyl or lower alkenyl, further cycloalkyl-lower alkylidene or cycloalkenyl lower alkylidene, wherein the cycloalkyl and cycloalkylidene, for example, contain up to 12, such as 3 to 8, preferably 3 to 8 carbon ring atoms, while cycloalkenyl, for example, contains up to 12, such as 3 to 8, for example 5 to 8, preferably 5 or 6 carbon atoms, in the ring as well as 1 to 2 double bonds and an aliphatic moiety of the cycloaliphatic-aliphatic residue e.g. by 7, preferably up to 4, carbon atoms. The above-mentioned cycloaliphatic or cycloaliphatic-aliphatic radicals may optionally be mono-, di- or polysubstituted by functional groups, for example optionally substituted hydrocarbon radicals, such as the abovementioned optionally substituted lower alkyl groups or, for example, the aforementioned aliphatic hydrocarbon radicals.

The aromatic radical, including the aromatic radical of the corresponding carboxylic acid, is an optionally substituted aromatic hydrocarbon radical, for example a mono-, bi- or polycyclic aromatic hydrocarbon radical, in particular phenyl, as well as diphenylyl or naphthyl, which may optionally be mono-, or polysubstituted with e.g. and cycloaliphatic hydrocarbon residues.

The divalent aromatic radical, for example the aromatic carboxylic acid, is primarily 1,2-arylene, in particular 1,2-phenylene, which optionally can be mono-, di- or polysubstituted, for example by the aforementioned aliphatic and cycloallphatic hydrocarbon radical.

An arylaliphatic radical, including an arylaliphatic radical in the corresponding carboxylic acid, further in an arylaliphatic ylidene radical is, for example, an optionally substituted arylaliphatic hydrocarbon radical such as an optionally substituted, for example trisubstituted, optionally substituted mono-, di- or polycyclic aromatic hydrocarbon radical with an aliphatic such as phenyl-lower alkyl or phenyl-lower alkenyl as well as phenyl-lower alkynyl, phenyl-lower alkylidene, the hydrocarbon radicals containing, for example, 1-3 phenyl groups, and may be mono-, di- or polysubstituted in aromatic and / or aliphatic moieties, for example as well as the above-mentioned aliphatic and cycloaliphatic moieties.

Heterocyclic groups including heterocyclic-aliphatic residues and heterocyclic or heterocyclic-aliphatic residues in the corresponding carboxylic acids are primarily monocyclic as well as di- or polycyclic aza-, thia-, oxa-, thiaza-, thiadiaza-, oxaza-, diaza- , triaza- or tetraazacyclic aromatic radicals, further corresponding partially or fully saturated heterocyclic radicals of this type, these radicals being optionally mono-, di- or polysubstituted as well as the aforementioned cycloaliphatic radicals. The aliphatic moiety in the heterocyclic-aliphatic moieties has, for example, the meaning given for the corresponding cycloaliphatic228101 tico-aliphatic or arylaliphatic moieties.

The acyl radical of the semi-derivative of carbonic acid is preferably an acyl radical of the corresponding semi-ester, wherein the organic radical of the ester group is an optionally substituted aliphatic, cycloaliphatic, aromatic or arylaliphatic hydrocarbon radical or heterocyclic-aliphatic radical, primarily acyl, optionally in α- or β-position. substituted lower alkylpolester of carbonic acid, as well as in the organic moiety substituted lower alkenyl, cycloalkyl, phenyl or phenyl loweralkylpolester of carbonic acid. The acyl radicals of the semi-carbonic acid ester are furthermore the corresponding lower alkylpolesteres of carbonic acid, wherein the lower alkyl moiety contains a heterocyclic group, for example of the aforementioned aromatic heterocyclic group, wherein both the lower alkyl moiety and the heterocyclic group may optionally be substituted. The acyl residue of the carbonic acid semi-derivative may also be an optionally N-substituted carbamoyl group, such as an optionally halogenated N-lower alkylcarbamoyl group.

The etherified hydroxyl group is primarily an optionally substituted lower alkoxy group, wherein the substituents are primarily free or functionally modified, such as etherified or esterified hydroxyl groups, in particular a lower alkoxy or halogen atom, further lower alkenyloxy, cycloalkyloxy or optionally substituted phenyloxy as well as heterocyclyloxy or heterocyclyl-lower alkoxy, in particular also optionally substituted phenyl-lower alkoxy.

Optionally substituted amino is, for example, amino, lower alkylamino, lower alkylamino, lower alkyleneamino, oxanalkyleneamino, thianalkyleneamino, azanalkyleneamino, hydroxyamino, loweralkoxyamino, lower alkanoyloxyamino, lower alkanoyloxyamino, lower alkanoyloxyamino or lower alkanoyloxyamino.

Optionally substituted hydrazino is, for example, hydrazino, 2-lower alkylhydrazino, 2,2-lower alkylhydrazino, 2-lower alkoxycarbonylhydrazino, or 2-lower alkanoylhydrazino.

Lower alkyl is, for example, 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 is for example vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl, lower alkynyl such as propargyl or 2-butynyl and lower alkylidene such as isopropylidene or isobutylidene.

Lower alkylene is, for example, 1,2-ethylene,

1,2- or 1,3-propylene, 1,4-butylene, 1,5-pentylene or 1,6-hexylene, while lower alkenyl, for example 1,2-ethenylene or 2-butem-1,4-ylene. The heteroatom interrupted by lower alkylene is, for example, oxanalkylene alkylene, such as

3-oxa-1,5-pentylene, thianisalkylene, such as 3-thia-1,5-pentylene, or lazane-alkykylene, such as 3-lower-alkyl-3-aza-1,5-pentylene, for example 3- methyl-3-aza-1,5-pentylene.

Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl as well as 1 adamantyl, cycloalkenyl, for example cyclopropenyl, 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 3-cycloheptenyl or 1,4- cyclohexanedienyl and cycloalkylidene, for example cyclopentylidene or cyclohexylidene. Cycloalkyl-lower alkyl or lower alkenyl is, for example, cyclopropyl-, cyclopentyl-, cyclohexyl- or cycloheptylmethyl-, 1,1- or 1,2-ethyl, -1,1-, -1,2- or -1,3. -propyl, -vinyl or -allyl, while cycloalkenyl lower alkyl or -lower alkenyl, for example 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl- or 1-, 2 or 3-cycloheptenylmethyl, 1,1- or -1,2-ethyl-, 1,1-, -1,2- or -1,3-propyl, -vinyl or -allyl. Cycloalkyl loweralkylidene is, for example, cyclohexylmethylene, and cycloalkenyl-loweralkylidene, for example 3-cyclohexenylmethylene.

Naiftyl is 1- or 2-naphthyl, while biphenylyl is, for example, 4-biphenylyl.

Phenyl-lower alkyl or phenyl-lower alkenyl is, for example, benzyl, 1- or 2-phenylethyl,

1-, 2- or 3-phenylpropyl, diphenylmethyl, trityl, stylyl or cinamyl, naphthyl-lower alkyl such as 1- or 2-naphthylmethyl, and phenyl lower alkylidene such as benzylidene.

Heterocyclic radicals are primarily optionally substituted heterocyclic radicals of aromatic character, for example the corresponding monocyclic, monoala-, monothia- or monooxacyclic radicals such as pyrryl, for example 2-pyrryl or 3-pyrryl, pyridyl, for example 2-, 3- or 4- pyridyl, further pyridinium, thienyl, for example 2- or 3-thienyl, or furyl, for example 2-furyl, bicyclic monoaza-, mono-monobenzo monothiacyclic radicals, such as indolyl, for example 2- or 3-indolyl, chimolinyl, for example

2- or 4-quinollnyl, isoquinolinyl, for example 1-isoquinolinyl, benzoifuranyl, for example 2- or 3-benzofuranyl, or benzothienyl, for example 2- or 3-benzothienyl, monocyclic diaza, triaza, tetraaza-, oxaza-, thiaza- or thiadiazacyclic residues such as imidazolyl, for example 2-imidazolyl, pyrimidinyl, for example 2- or 4-pyrimidinyl, triazolyl, for example 1,2,4-triazol-3-yl, tetrazolyl, for example 1- or 5-tetrazolyl, oxazolyl, e.g. 2-oxazolyl, isoxazolyl, e.g. 3- or 4-isoxazolyl, thiazolyl, e.g.

2-thiazolyl, isothiazolyl, e.g.

4- ^: sothiazolyl or 1,2,4- or 1,3,4-thiadiazolyl, for example 1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl or bicyclic diaza-, oxaza- or thiazacyclic radicals such as benzimidazolyl, for example 2-benzimidazolyl, benzoxazolyl, for example. 2-benzoxazolyl, or benzthiazolyl, for example 2-benzthiazolyl. Corresponding partially or fully saturated residues are, for example, tetrahydrothienyl, such as 2-tetrahydrothienyl, tetrahydrofuryl, such as 2-tetrahydrofuryl, or piperidyl, for example 2- or 4-piperidyl. Heterocyclic-aliphatic radicals are heterocyclic groups, especially those mentioned above, containing lower alkyl or lower alkenyl. For example, the above-mentioned heterocyclic radicals may be optionally substituted by aliphatic or aromatic hydrocarbon radicals, such as, in particular, lower alkyl, for example methyl, or substituted by, for example, a halogen atom such as chlorine, substituted phenyl, for example phenyl or 4-chlorophenyl or leftovers.

Lower alkoxy is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy isobutyloxy, sec-butyloxy, t-butyloxy n-pentyloxy or t-pentyloxy. These groups may be substituted, such as, for example, halogen-lower alkoxy, especially 2-halo-lower alkoxy, for example 2,2,2-trichloro, 2-chloro, 2-bromo- or 2-iodoethoxy. Lower alkenyloxy is, for example, vinyloxy or allyloxy, lower alkylenedioxy, for example methylenedioxy, ethylenedioxy or isopropylenedioxy, cycloalkoxy, for example cyclopentyloxy, cyclohexyloxymethyloxy, phenyl or adamantyloxy, dimethoxydiphenylmethoxy or heterocyclyloxy or heterocyclyl lower alkoxy for example pyridyl lower alkoxy such as 2-pyridylmethoxy, furyl-lower alkoxy such as furfuryloxy or thienyl-lower alkoxy such as 2-thienyloxy.

Lower alkylthio is, for example, methylthio, ethylthio, or n-butylthio, lower alkenylthio, for example allylthio, and phenyl-loweralkylthio, for example benzylthio, while the beterocyclic or heterocyclic-aliphatic radical of an etherified mercapto group, in particular pyridylthio, imidazolylthio, thiazolylthio, for example 2-thiazolylthio,

1,2,4- or 1,3,4-thiadiazolylthio, for example 1,2,4-thiadiazol-2-ylthio or 1,3,4-thiadiazol-2-ylthio, or tetrazolylthio, for example 1-methyl- 5-Tetrazolylthio.

The esterified hydroxy groups are primarily halogen atoms, for example fluorine, chlorine, bromine or iodine, as well as lower alkanoyloxy, for example acetyloxy or propionyloxy, lower alkoxycarbonyl groups, for example methoxycarbonyloxy, ethoxycarbonyloxy or tert-butyloxycarbonyloxy, tert-butyloxycarbonyloxy, trichloroethoxycarbonyloxy, 2-bromoethoxycarbonyloxy or 2-iodoethoxycarbonyloxy or arylcarbonylmethoxycarbonyloxy, for example phenacyloxycarbonyloxy.

Lower alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl or t -pentyloxycarbonyl.

N-lower alkyl- or N, N-lower alkylcarbamoyl, for example N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl or Ν, Ν-diethylcarbamoyl, while N-loweralkylsulfamoyl is for example N-methylsulfamoyl or Ν, Ν-dimethylsulfam

The carboxyl or sulfo group in the salt form is, for example, the sodium or potassium salt of the carboxyl or sulfo group.

Lower alkylamino or di-lower alkylamino such as methylamino, ethylamino, dimeíhylaminoskupina or di-ethylamino, lower alkyleneamino, for example pyrrolidino or piperidino, oxanižší alkyleneamino, for example morpholino, thianižšíalkylenaminoskupina, for example, thiomorpholino, and czaolžsíalkylenríminoskupina such piporazínoskupina or 4 -methylplperazinoskupina, acylamino In particular carbamoylamino lower alkylkarbamoylamino- like methylkarbamoylaminoskupina, ureidokarbonylaminoskupina, guanidinokarbonylaminoskupina, lower alkoxycarbonylamino, e.g. methoxykarbonylaminoskupina, ethoxycarbonylamino terc.butyloxykarbonylaminoskupina, halogennižšíalkoxykarbonylaminoskupina such as 2,2,2-trichlorethoxykarbonylaminoskupina, fenylnižšíalkoxykarbonylaminoskupina such as 4-methoxybenzyl xykarbonylaminoskupina metB, loweralkanoyl a mini group such as acetylamino or propionylamino, phthalimido or sulfamino, optionally in the form of a salt, such as an alkali metal salt, for example sodium or in the form of an ammonium salt.

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

O-loweralkyl-phosphono is, for example, O-methyl- or O-ethyl-phosphono,

O, O'-lower alkyl-phosphono, for example O, O-dimethylphosphono or O, O'-diethylphosphono, O-phenyl-lower alkyl-phosphono, for example O-benzylphosphono and O-loweralkyl-O'-phenyl-lower-alkylphosphono, for example O-benzyl-O'-methyl-phosphonium.

Lower alkenyloxycarbonyl is, for example, vinyloxycarbonyl, while cycloalkoxycarbonyl and phenyl-loweralkoxycarbonyl are, for example, adamantyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or or-6-methyl-biphenylyl-α-biphenyl. Loweralkoxycarbonyl wherein the loweralkyl comprises, for example, a monocylic, monoaza-, monooxa- or monothiacyclic group, such as a furyl loweralkoxycarbonyl, such as furfuryloxycarbonyl, or a thienyl loweralkoxycarbonyl, such as 2-thieuyloxycarbonyl.

2-loweralkyl- and 2,2-loweralkylhydrazino is, for example, 2-methylhydrazino or 2,2-dimethylhydrazino, 2-loweralkoxycarbonylhydrazino, such as 2-methoxycarbonylhydrazino, 2-ethoxycarbonylhydrazino, or 2-tert-butyloxycarbonylhydrazino, and 2-tert-butyloxycarbonylhydrazino.

In particular, the acyl group Ac is an acyl radical of an organic carboxylic acid occurring in natural, biosynthetically, semi-synthetically or totally synthesized, preferably pharmacologically active, N-acyl derivatives of 6-aminopenam-3-carboxylic acid or 7-amino-3-cephem-4-carboxylic acid acids, preferably containing up to 18 carbon atoms, or an easily cleavable acyl radical, in particular a semi-derivative of carbonic acid.

The acyl residue of the ac pharmacologically active N-acyl derivative of 6-aminopenam-3-carboxylic acid or 7-amino-3-cephem-4-carboxylic acid is primarily a group of formula A

R ¹¹

I O

R ¹¹¹ (A) wherein n is 0 and R ¹ is a hydrogen atom or an optionally substituted cycloaliphatic or aromatic hydrocarbon radical or an optionally substituted heterocyclic radical, preferably of aromatic nature, functionally altered, for example esterified or etherified hydroxyl or mercapto or optionally substituted amino; wherein n is 1, R ¹ is a hydrogen atom or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or arylaliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclicaliphatic radical, wherein the heterocyclic radical is preferably aromatic in nature and / or has a quaternary nitrogen atom , optionally functionally modified, preferably etherified or esterified hydroxyl or mercapto, optionally functionally modified carboxyl, acyl, optionally substituted amino or azido and wherein each of R ¹¹ and R ¹¹¹ is hydrogen, or wherein n is 1, R ¹ is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or arylaliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, wherein the heterocyclic moiety is preferably aromatic, R is an optionally functionally modified, for example, an esterified or etherified hydroxy or mercapto group such as a halogen atom, an optionally substituted amino group, an optionally functionally modified carboxyl or sulfone group, optionally O-mono or O, O'-disubstituted phosphonic a group or O; and R ¹¹¹ is a hydrogen atom, or wherein n is 1, and each of the residues R ¹ and R "is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and R ¹¹¹ is a hydrogen atom, or wherein n is 1, R ¹ is hydrogen or optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and R ¹¹ and R ⁱⁿ together form optionally substituted double bond via a carbon atom attached aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or arylaliphatic hydrocarbon radicals or wherein n is 1 and R ¹ is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or arylaliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, wherein the heterocyclic radical preferably has

- aromatic character, R ¹¹ is optionally sub; The substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical, and R ⁱⁿ is hydrogen or optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical.

In the above-mentioned acyl groups of formula A, for example, n = 0 and R ¹ is a hydrogen atom or optionally, preferably at the 1-position, optionally protected amino, such as amino, acylamino, wherein acyl is primarily an acyl radical of a semiester carbonic acid such as lower; alkoxycarbonyl, 2-halo-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl or sulfoamino optionally in the form of a salt, for example an alkali metal salt, a substituted C 5 -C 7 cycloalkyl group, optionally with hydroxyl, a lower alkoxy such as methoxy or acyloxy, wherein acyl is primarily an acyl radical of a semi-carbonic acid ester such as a lower alkoxycarbonyl-, 2-halo-lower alkoxycarbonyl- or phenyl-lower alkoxycarbonyl, and / or a halogen such as chloro-substituted phenyl, naphthyl or tetrahydronaphthyl, optionally for example lower alkyl such as methyl220101 hem and / or bitches which may be further substituted by halogen, for example chlorine, a substituted heterocyclic group such as 4-isoxazolyl or preferably for example optionally by a halogen atom such as chlorine, a substituted N-substituted amino group containing lower alkyl, or n is 1, R ¹ is optionally preferably a halogen atom such as chlorine, hydroxyl or acyloxy, wherein acyl is as defined above and / or a phenyloxy group containing a halogen atom, for example chlorine, or optionally protected amino and / or carboxy substituted lower alkyl, for example 4-amino- 4-carboxybutyl with optionally protected amino and / or carboxy, such as silylated, such as tri-loweralkylsilylated, for example trimethylsilylated, amino- or acylamino, such as lower alkanoylamino-, halo-loweralkanoylamino- or phthaloylamino, and / or silylated, such as tri- lower alkylsilyl, for example trimethylsil alkylated or esterified, for example by lower alkyl, 2-halo-lower alkyl or phenyl-lower alkyl, such as diphenylmethyl, esterified carboxy, lower alkenyl, optionally substituted, such as, for example, by the above acylated hydroxyl and / or halogen atom, for example chlorine further optionally protected, for example by the above method, acylated, amino-lower alkyl such as aminomethyl, or optionally substituted as optionally for example by the above-acylated hydroxyl and / or halogen atom, for example chlorine, phenyl-containing phenyloxy, optionally for example lower alkyl, such as methyl or optionally protected, for example by the above-acylated amino or aminomethyl substituted pyridyl, for example 4-pyridyl, pyridinium, for example 4-pyridinium, thienyl, for example 2-thienyl, furyl, for example 2-furyl, imidazolyl, for example Ι-imidazolyl-, or tetrazolyl, for example 1-tetrazolyl, optionally substituted lower alkoxy, for example methoxy, optionally substituted as optionally protected, for example as above acylated hydroxy and / or halogen, such as chloro, containing phenyloxy, lower alkylthio, for example n-butylthio, or loweralkenylthio, for example allylthio, optionally for example lower alkyl such as methyl, substituted phenylthio, pyridylthio, for example 4-pyridylthio, 2-imidazolylthio, 1,2,4-triazol-3-ylthio, 3,4,4-triazol-2-ylthio, 1,2,4-thiadiazol-3-ylthio, such as 5-methyl-1,2,4-thiadiazol-3-ylthio, 1,3,4-thiadiazol-2- ylthio, such as 5-methyl-1,3,4-thiadiazol-2-ylthio, or 5-tetrazolylthio, such as 1-methyl-5-tetrazolylthio, halogen, especially chloro or bromo, optionally a functionally modified carboxyl group such as a lower alkoxycarbonyl, for example a methoxycarbonyl- or ethoxycarbonyl, a cyano group or an optionally lower alkyl such as methyl or phenyl, an N-substituted carbamoyl, an optionally substituted loweralkanoyl- such as acetyl- or propionyl- or benzoyl or an azido group; R ¹¹ and R ¹¹¹ are hydrogen atoms or n is 1, R ¹ is lower alkyl or optionally acylated hydroxyl and / or halogen, such as chloro-substituted phenyl, furyl, e.g. 2-furyl, thienyl, e.g.

2- or 3-thienyl or isothiazolyl, for example 4-isothiazolyl, further 1,4-cyclohexadienyl, R ¹¹ is an optionally protected or substituted amino, for example amino, acylamino, such as lower alkoxycarbonylamino, 2-halogen lower alkoxycarbonylamino or optionally substituted, such as aikoxylem lower, for example methoxy or nltroskupinu containing fenylnižšíalkoxykarbonylaminoskupina example terc.butyloxykarbonylaminoskupina, 2,2,2-trichlorethoxykarbonylaminoskupina 4-methoxybenzyloxykarbonylaminoskupina or difenylmethoxakorbonylaminoskupina, arylsulfonylamino, for example 4-methylfenvlsulfonylaminoskupina, trityl-amino, arylthioaminoskupina such nitrofenylthioaminoskupina, for example 2-nitrofenylthioaminoskupina or tritylthioaminoskupina or optionally substituted, such as lower alkoxycarbonyl, for example ethoxycarbonyl or lower alkanoyl, for example acetyl, 2-propylidenam an ino group such as 1-ethoxycarbonyl-2-propylideneamino or an optionally substituted carbamoylamino group such as guanidinocarbonylamino or sulfoamino, optionally in the form of a salt, for example an alkali salt, an azido or carboxyl, optionally in the form of a salt, eg in the form of an alkali salt or carboxyl group protected form, for example in the form of an ester such as lower alkoxycarbonyl-, for example methoxycarbonyl or ethoxycarbonyl- or phenyloxycarbonyl, for example diphenylinethoxycarbonyl, cyano, sulfo, optionally functionally modified hydroxy, wherein the functionally modified hydroxyl is especially acyloxy lower alkoxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy or optionally substituted, such as lower alkoxy, for example methoxy, or nitro containing phenyl-lower alkoxycarbonyloxy, e.g. for example tert-butyloxycarbonyloxy, 2,2,2-trichloroethoxycarbonyloxy, 4-methoxybenzyloxycarbonyloxy or diphenylmethoxycarbonyloxy or optionally substituted lower alkoxy, for example methoxy, or phenyloxy, O-lower alkyl or O, O'-lower alkyl or O, O'-lower alkyl or O, O'-lower alkyl or O, O'-lower alkyl or O, O'O'-dimethylphosphono or a halogen atom such as chlorine or bromine and R ^m is hydrogen, or n is 1, R ¹ and R ¹¹ are halogen atoms such as bromine, lower alkoxycarbonyl such as methoxycarbonyl and R ¹¹¹ is hydrogen or n is 1, R ¹ is optionally, for example, acylated by hydroxyl and / or a halogen atom such as chlorine, substituted phenyl, furyl such as 2-furyl or thienyl such as 2- or 3-thienyl or isothiazolyl such as 4-isothiazolyl R ⁴ is optionally aminomethyl protected as described above and R ¹¹¹ is a of thanks or n is 1 and each of R ¹ and R ¹¹ and ^{R! I} is lower alkyl such as methyl.

Such acyl radicals are, for example, formyl, cyclopentylcarbonyl, n -aminocyclopentylcarbonyl or α-aminocyclohexylcarbonyl (with optionally substituted amino, for example optionally in the form of a salt present with a sulfoamino or acyl radical, preferably readily cleavable, for example by reaction with an acidic reagent , reductively cleavable, for example zinc in the presence of aqueous acetic acid, or catalytically hydrogen, or hydrolytically cleavable, or acyl convertible to the above acyl radical, preferably a suitable acyl radical of a semi-carbonic acid such as lower alkoxycarbonyl, for example tert-butyloxycarbonyl, 2- halo-loweralkylcarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, arylcarbonylmethoxycarbonyl, for example phenacyloxycarbonyl, optionally substituted as lower alkoxy, for example methoxy or a phenyl-loweralkoxycarbonyl-containing nitro group, for example 4-methoxybenzyloxycarbonyl or diphenylmethoxycarbonyl, or a carbonic acid poloamide such as carbamoyl or N-substituted such as N-lower alkyl- e.g. N-methylcarbamoyl as well as tritylene, further arylthio such as e.g. 2-nitrophenylthio, an arylsulfonyl group, such as 4-methylphenylsulfonyl or 1-loweralkoxycarbonyl-2-propylidene, e.g. 1-ethoxycarbonyl-2-propylidene, 2,6-dimethoxybenzoyl, 5,6,7,8-tetrahydronaphtoyl, 2 -methoxy-1-naphthoyl, 2-ethoxy-1-naphthoyl, benzyloxycarbonyl, hexahydrobenzyloxycarbonyl, 5-methyl-3-phenyl-4-isoxazolylcarbonyl, 3- (2-chlorophenyl) -5-methyl-4-isoxazolylcarbonyl-, 3 - (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarbonyl, 2-chloroethylaminocarbonyl, acetyl, propionyl, butyryl, pivaloyl, hexanoyl, octanoyl, acrylyl, crotonoyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl, butylthioacetyl, allyl methylthioacetyl, chloroacetyl, bromo16

B acetyl, dibromoacetyl, 3-chloropropionyl, 3-bromopropionyl, aminoacetyl or 5-amino _; , no-5-carboxyvaleryl (optionally with the foregoing substituted amino group, for example monoacyl or diacyl, for example halogenated lower alkanoyl such as acetyl or dichloroacetyl, or phthaloyl, and / or a functionally modified carboxyl group, for example in the form of a salt such as is a sodium salt in the form of an ester such as lower alkyl (e.g. methyl, ethyl- or aryl-loweralkyl- e.g. diphenylmethyl ester), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bis-methoxycarbonylacetyl, N-phenylcarbamoylacetyl, cyanacetyl, α-cyanpropionyl -3,3-dimethyl-acrylyl, phenylacetyl, α-bromophenylacetyl, α-azidophenylacetyl, 3-chlorophenylacetyl, 2- or 4-aminomethylphenylacetyl, (optionally substituted with an amino group as described above), phenacylcarbonyl, phenyloxyacetyl, 4-trifluoromethylphenyloxyacetyl, benzyloxyacetyl , phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxyproplonyl, α-phenyloxyf enylacetyl, α-methoxyphenylacetyl, α-ethoxyphenylacetyl, α-methoxy-3,4-dichlorophenylacetyl, α-cyanophenylacetyl, especially phenylglycyl, 4-hydroxyphenylglycyl, 3-chloro-4-hydroxyphenylglycyl, 3,5-dichloro-4-hydroxyphenylglycyl, and -amino-ε- (1,4-cyclohexadienyl) -acetyl α-amino-α-phenylacetyl or α-hydroxyphenylacetyl (which may optionally contain an amino group, for example substituted and / or aliphatic and / or present as described above a phenolically bonded hydroxy group optionally analogous to an amino group protected with a suitable acyl, in particular the formyl or acyl residue of a carbonic acid semi-ester} or α-O-methylphosphonophenylacetyl or αO, O-dimethylphosphonophenylacetyl, benzylthioacetyl, benzylthiopropionyl 3-phenylpropionyl, 3- (3-cyanophenyl) propionyl, 4- (3-methoxyphenyl) butyryl, 2-pyridylacetyl,

4-aminopyridinium acetyl (optionally substituted with an amino group as described above), 2-thienylacetyl, 3-thienylacetyl 2-tetrahydrothienylacetyl, 2-furylacetyl, 1-imidazolylacetyl, 1-tetrazolylacetyl, α-carboxy-2-thienylacetyl or α-carboxy-3-thienylacetyl (optionally with a functionally modified, for example, the above-mentioned carboxy group), α-cyano-2-thienylacetyl, α-amino-α- (2-thienyl) -acetyl, α-amino- N - (2-furyl) -acetyl or n-amino-α- (4-isothiazolyl) -acetyl (optionally substituted with an amino group as described above), n -sulfophenylacetyl (optionally with the same method as carboxy, functionally modified sulfo group), 3-methyl-2-imidazolylthioacetyl; 2,4,4-triazol-3-ylthioacetyl, 1,3,4-triazol-2-yl 1228101 17

5-methyl-1,2,4-thiadiazol-3-yl-5-methyl-1,3,4-thladiazol-2-yl or 1-methyl-5-tetrazolylthiothioacetyl, thioacetyl, thioacetyl acetyl.

The readily cleavable acyl radical Ac is in particular a carbonic acid semi-ester residue, primarily by a reduction, for example by reaction with a chemical reducing agent or by an acidic method, for example trifluoroacetic acid, a cleavable acyl radical of a semi-carbonic acid such as a multiply branched and / or aromatically substituted lower alkoxycarbonyl or arylcarbonyl group, in particular a benzoyl substituted methoxycarbonyl group, or in the (3-position by a halogen atom substituted a lower alkoxycarbonyl group, for example tert-butyloxycarbonyl, trecpentyloxycarbonyl, tricycloxycarbonyl, tricyclohexyloxycarbonyl, 2-iodoethoxycarbonyl or a 2-iodoethoxycarbonyl group convertible such as 2-chloro- or 2-bromoethoxycarbonyl, further preferably a polycyclic cycloalkoxycarbonyl, for example adamantyloxycarbonyl, optionally substituted phenyl lower alkoxy carbonyl, primarily targeted where the «-position is multiple substituted, for example diphenylmethoxycarbonyl or α-4-biphenylyl-v-methylethoxycarbonyl or furyl loweralkoxycarbonyl, primarily, γ-furyl loweralkoxycarbonyl, for example furfuryloxycarbonyl.

An acyl group formed by the divalent radicals both R ^A and R ^B is ^an acyl radical for example a lower alkane or a lower alkene- acid such as succinyl or 0-arylendikarboxylové acids, such as phthaloyl.

The other divalent radical consisting of both R ^1A and R ^1b is particularly substituted in the 2-position, for example optionally substituted phenyl or thienyl, and in the 4-position optionally lower alkyl such as methyl, mono- or disubstituted 1-oxo-3-aza- 1,4-butylene, for example 4,4-dimethyl-2-phenyl-1-oxo-3-aza-1,4-butylene.

The etherified hydroxyl group R 2 ^A together with the carbonyl group preferably forms a readily cleavable or readily convertible to another functionally modified carboxyl group, such as a carbamoyl or hydrazinocarbonyl group, a convertible esterified carboxyl group. Such an R 2 ^A group is, for example, a lower alkoxy such as methoxy, ethoxy, n-propoxyl or isoprpoxyl, which together with the carbonyl group forms an esterified carboxyl group, which is readily converted to the free carboxyl group or other functionally modified carboxyl group.

The etherified hydroxyl group R 2 ^A , which together with the group --C (= Oj) - forms a particularly readily cleavable esterified carboxyl group, is, for example, 2-halo-lower alkoxy, where the halogen atom preferably has an atomic mass greater than 19. with —C (= Oj) - an esterified carboxyl group readily cleavable by a chemical reducing agent under neutral or slightly acidic conditions, for example zinc in the presence of aqueous acetic acid, or an esterified group readily convertible to such a group as 2,2,2-trichloroethoxy or

2-iodoethoxy and 2-chloroethoxy or 2-bromoethoxy, which are readily converted to the preceding group.

An etherified hydroxyl group R ^A, together with -C (= Oj- forms an esterified carboxyl group easily cleavable by treatment with chemical reducing agents under neutral or mildly acidic conditions such as by treatment with zinc in the presence of aqueous acetic acid, followed by treatment with suitable nucleophilic reagents such as is sodium thiophenolate, is arylcarbonylmethoxy, wherein aryl is especially optionally substituted phenyl and preferably phenylacyloxy.

The group R 2 ^A may also be an arylmethoxy group wherein aryl is in particular a monocyclic, preferably substituted aromatic hydrocarbon radical. Such a residue together with the group -C (= O) - forms an esterified carboxyl group readily cleavable by irradiation, preferably by ultraviolet light under neutral or acidic conditions. The aryl radical in such arylmethoxy is especially lower alkoxyphenyl, for example methoxyphenyl, (wherein the methoxy is primarily in the 3, 4 and / or 5-position) and / or particularly nitrophenyl (wherein the nitro group is preferably in the 2-position). Such residues are especially lower alkoxy, e.g. methoxy and / or nitrobenzyloxy, in particular 3 or 4-methoxybenzyloxy-, 3,5-dimethoxybenzyloxy-, 2-nitrobenzyloxy- or 4,5-dimethoxy-2-nitrobenzyloxy.

The etherified hydroxyl group R ^2A may also be a radical which together with the group C (= O 3) forms an esterified carboxyl group readily cleavable under acidic conditions, for example by treatment with trifluoroacetic acid or formic acid. optionally polysubstituted, optionally substituted with a hydrocarbon radical, in particular an aliphatic or aromatic hydrocarbon radical, such as lower alkyl, e.g. methyl and / or phenyl, or monosubstituted with electron-releasing substituents, a carbocyclic aryl group or a heteroeyl aromatic group with oxygen or ring sulfur, or wherein methyl is a chain link in a polycycloaliphatic hydrocarbon radical or in an oxa- or thiacycloaliphatic228101 radical in the α-position to an oxygen or sulfur atom.

Preferred polysubstituted methoxy groups of this type are tert-lower alkoxy, e.g. tert-butoxy or tert-pentyloxyl, optionally substituted diphenylmethoxy, for example diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, furthermore 2- (4-biphenylyl) -2-propyloxy while the above substituted with an aryl or methoxy-containing heterocyclic group is, for example, α-lower alkoxyphenyl-lower alkoxy, such as 4-methoxybenzyloxy or 3,4-dimethoxybenzyloxy, or furfuryloxy, such as 2-furfuryloxy, wherein the polycycloaliphatic hydrocarbon radical in which methyl methoxy is adamantyl, such as 1-adamantyl, and the aforementioned oxa- or thiacycloaliphatic moiety, wherein the methyl methoxy group is part of the ring at the α-position to the oxygen or sulfur atom, for example 2-oxa - or 2-thien lower alkylene or lower-alkenylene of 5 to 7 ring atoms, ja ko is 2-tetrahydrofuryl,

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

^A radical R2 can also be an etherified hydroxyl group which, together with the -C (= Oj- forms an esterified carboxyl group readily removable by hydrolysis, for example under mildly of basic or mildly acidic conditions. Such a radical is preferably etherified hydroxyl group forming a group - O (= O) - an activated ester group such as a nitrophenyloxy group such as a 4-nitrophenyloxy group or a 2,4-dinitrophenyloxy group, a nitrophenyl lower alkoxy group such as a 4-nitrobenzyloxy group, a hydroxy-lower alkylbenzyloxy group such as a 4-hydroxy-3,5-tert-butylbenzyl group a polyhalophenyloxy group, for example a 2,4,6-trichlorophenyloxy group, or a 2,3,4,5,6-pentachlorophenyloxy group, further a cyanomethoxy group, and an acylaminomethoxy group such as a phthaliminomethoxy group or a succinylliminomethoxy group.

The group Rz ^A may also be an etherified hydroxyl group which, with the carbonyl group of the formula —C (= O) - forms an esterified carboxyl group cleavable by hydrogenolysis, such as, for example, a loweralkoxy or nitrosubstituted α-phenyl lower alkoxy group such as benzyloxy, 4-methoxybenzyloxy or 4-nitrobenzyloxy.

The group R 2 ^A may also be an etherified hydroxyl group forming with a carbonyl group - C (= O) - an esterified carboxyl group cleavable under physiological conditions, in particular an acyloxymethoxy group, where acyl is, for example, an organic carboxyl group residue. or wherein the acyloxymethyl is a lactone residue. The etherified hydroxy groups are lower alkanoyloxymethoxy groups, for example acetyloxymethyloxy, or pivaloyloxymethoxy, amino-lower alkanoyloxymethoxy, especially α-amino lower alkanoyloxymethoxy, e.g. glycyloxymethoxy, L-valyloxymethyloxy.

The silyloxy or stannyloxy group R @ 2 ^A preferably contains, as substituents, optionally substituted aliphatic, cycloaliphatic, aromatic or arylaliphatic hydrocarbon radicals such as lower alkyl, halo-lower alkyl, cycloalkyl, phenyl or phenyl loweralkyl or optionally modified functional groups such as etherified hydroxyl, such as lower alkoxy or halogen, such as chlorine, and is primarily a tris-lower alkylsilyloxy group, e.g.

The acyloxy group R 2 ^A forming together with the group C (= O 3) preferably a hydrolytically cleavable mixed anhydride is, for example, the acyl of the abovementioned organic carboxylic acids or semi-derivatives of carbonic acid, such as optionally in the α-position with halogen, e.g. fluorine or chlorine. substituted lower alkanoyloxy, for example acetyloxy, pivalyloxy, or trichloroacetyloxy or lower alkoxycarbonyloxy, for example methoxycarbonyloxy or ethoxycarbonyloxy.

The radical R @ 2 ^and , together with the —C (= O) - group, an optionally substituted carbamoyl- or hydrazinocarbonyl group are, for example, amino, lower alkylamino, or di-loweralkylamino such as methylamino, ethylamino, dimethylamino or diethylamino, pyrido, lower alkyleneamino, alkyleneamino, for example morpholino, hydroxyamino, hydrazino, 2-lower alkylhydrazino or 2,2-lower alkylhydrazino, for example 2-methylhydrazino or 2,2-dimethylhydrazino.

Salts, especially salts of compounds of formula I with acidic groups such as carboxy, sulfo, or phosphono, are primarily metal salts or ammonium salts such as alkali metal and alkaline earth metal salts such as sodium, potassium, magnesium or calcium salt and also ammonium salts with ammonia or a suitable organic amine, in particular aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and arylaliphatic primary, secondary or ter228101 tertiary mono-, di- or polyamines, as well as heterocyclic bases such as lower alkylamines such as triethylamine, hydroxy lower alkylamines such as 2-hydroxyethylamine, bis- (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids such as 2-diethylaminoethyl ester of 4-aminobenzoic acid; 1-ethylpiperidine, cycloalkylamine such as bicyclohexylamine or benzylamines such as N , N‘-dibenzyl-ethylenediamine, and pyridine-type bases such as pyridine, collidine or quinoline. The compounds of formula I containing basic groups may also form together with acids, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic acids or sulfonic acids, for example trifluoroacetic acid or 4-methylphenylsulfonic acid. The compounds of formula I with an acidic and basic groups can also exist in the form of inner salts, i.e. in the form of a zwitterion. The 1-oxides of the compounds of formula I with salt-forming groups may also provide salts, e.g. as described above.

The novel compounds of the present invention are valuable intermediates which can be used to prepare compounds with pharmacological properties; they can be converted to these compounds, for example, as described below,

The present invention particularly relates to compounds cephem-3-one of formula I, wherein R ^is an acyl radical contained in fermentatively (i.e. natural), biosynthetically, semi or total synthesis preparable, in particular pharmacologically active, such as highly active N-acyl derivatives 6 / 3-aminopenam-3-carboxylic acid or 7 ₍₁ d-amino-3-cephem-4-carboxylic acid as above-named acyl residue of formula A, wherein the groups R ^1, R ^n, R ⁿ and n are especially preferred meaning, R ^b is hydrogen or wherein R ^a and R? together form a 1-oxo-3-aza-l, 4-butylene radical substituted, preferably in position 2, for example, aromatic or heterocyclic radical, such as phenyl and at position 4 is preferably, for example, two lower alkyls such as methyl, R 2 ^A is hydroxyl, optionally preferably in the--position, for example substituted aryloxy, such as lower alkoxyphenyloxy, for example 4-methoxyphenyloxy, lower alkanoyl oxy, such as acetyloxy or pivaioyloxy, α-amino lower alkanoyloxy, such as glycyloxy, L-valyloxy, or L-leucyloxy, arylcarbonyl such as benzoyl or optionally substituted with aryl such as phenyl, lower alkyl 4-methoxyphenyl, nitrophenyl such as 4-nitrophenyl or biphenylyl such as 4-biphenylyl or in the (3-position by halogen, e.g.

chloro, bromo or iodo, monosubstituted or polysubstituted lower alkoxy such as methoxy, ethoxy, n-propoxyl, isopropoxyl, n-butyloxy, tert-butyloxy or tert-pentyloxy, optionally lower alkoxy substituted bis-phenyloxymethoxy-4-yl, e.g. methoxyphenyloxymethoxy, lower alkanoyloxymethyl, e.g. acetyloxymethoxy, or pivaloyloxymethoxy, α-amino lower alkanoyloxymethoxy, e.g. glycyloxymethoxy, phenylacyloxy, optionally substituted phenyl lower alkoxy, especially

1-phenyl-lower alkoxy, such as phenylmethoxyl, which radicals may contain 1 to 3, optionally lower alkoxy, such as methoxy, nitro or phenyl substituted phenyl, for example benzyloxy,

4-methoxybenzyloxy, 2-biphenylyl-2-propyloxy, 4-nitrobenzyloxy, diphenylmethoxy, 4,4'-dimethoxydixenylmethoxy or trityloxy or 2-halogenoalkoxy, e.g. 2-iodoethoxy, 2-phthalidyloxy, and acyloxy such as lower alkoxycarbonyloxy, for example methoxycarbonyloxy or ethoxycarbonyloxy, or lower alkanoyloxy, for example acetyloxyalkyl or pivaloyloxy. hydroxy-substituted amino or hydrazino such as amino, lower alkyl or lower alkylamino such as methylamino or dimethylamino, hydrazino, 2-lower-alkyl- or

2,2-lower alkylhydrazino, e.g. 2-methylhydrazino or 2,2-dimethylbydrazino or hydroxyamino, as well as their 1-oxides or salts thereof with salt-forming groups.

Firstly it is a compound cephem-3-one of formula I, followed by 1-oxides of compounds eefam 3-one of formula I, or salts of these compounds with a salt-forming group, wherein R ^is hydrogen or an acyl radical contained in fermentatively ( this is in the natural) or biosynthetically obtainable N-acyl derivatives of 6S-aminopenam-3-carboxylic acids or N-amino-3-cephem-4-carboxylic acids, in particular of formula A, wherein R ¹ , R ⁿ , R ^m and ⁿ they have a preferred meaning, such as, for example, hydroxy-substituted phenylacetyl or phenyloxyacetyl, further optionally lower alkylthio or lower alkylethio, as well as optionally substituted such as acylated, amino and / or functionally modified such as esterified carboxy substituted lower alkanoyl or lower alkenoyl, e.g. 4-hydroxyphenylacetyl, hexanoyl, octanoyl or n-butylthioacetyl and in particular

5-amino-5-carboxyvaleryl, wherein the amino and / or carboxyl group is optionally protected and occurs as an acylamino group, optionally as an esterified carboxyl, phenylacetyl, or phenyloxyacetyl, or as an acyl residue in the highly active N-acyldervates 6i (3-aminopenam-3) carboxylic acid, or 7 ^and 1S-amino-3-cephem-4-carboxylic acid, particularly of formula A wherein ^{R1, R11, m} and n have primarily preferred meanings, such as formyl, 2-halogenethylkarbamoyl, e.g. 2-chloroethylcarbamoyl, cyanacetyl, phenylacetyl, thienylacetyl, e.g. 2-thienylacetyl, or tetrazolylacetyl, e.g.

1-tetrazolylacetyl, especially but in the «-cyclic position such as cycloaliphatic, aromatic or heterocyclic, primarily monocyclic or functional, primarily amino, carboxyl, sulfo or hydroxy substituted acetyl, especially phenylglycyl, where phenyl is optionally protected, for example, by hydroxy , such as acyloxy, e.g. optionally halogen-substituted lower alkoxycarbonyloxy or lower alkanoyloxy, and / or a halogen atom, e.g. chlorine, substituted phenyl, e.g. phenyl or 3- or 4-hydroxyl, 3-chloro-4-hydroxy- or 3 , 5-dichloro-4-hydroxyphenyl (optionally also protected, such as acylated hydroxy) and wherein the amino group may optionally also be substituted and, for example, may be present as a salt of a sulfoamino or amino group containing hydrolytically cleavable trityl groups as substituents; a series of acyl, j such as optionally substituted carbamoyl- such as optionally substituted ureidocarbonyl, for example ureidocarbonyl or N'-trichloromethylureidocarbonyl or optionally substituted guanidinocarbonyl such as guanidinecarbonyl or acyl, preferably readily cleavable by treatment with an acidic reagent such as a reducing agent or a trifluoroacetic agent is zinc in the presence of aqueous acetic acid or catalytic hydrogen or a hydrolytically cleavable or convertible acyl radical, preferably a suitable acyl radical of a semi-carbonic acid such as the aforementioned, e.g. optionally halogen or benzoyl substituted lower alkoxycarbonyl radical, e.g. butyloxycarbonyl, 2,2,2-trichlorethyloxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl or phenacyloxycarbonyl, optionally lower alkoxy or a nitro substituted phenyl loweralkoxycarbonyl, e.g. 4-methoxybenzyloxycarbonyl or diphenylmethoxycarbonyl, or a carbonic acid amide such as carbamoyl or N-methylcarbamoyl; for example 2-nitrophenylthio or tritylthio, by electrolytic reduction a cleavable arylsulfonyl radical, eg 4-methylphenylsulfonyl or with an acidic agent such as formic acid or an aqueous mineral acid, eg hydrochloric acid or phosphoric acid, cleavable

1-loweralkoxycarbonyl- or 1-loweralkanoyl-2-propylidene, e.g. 1-ethoxycarbonyl-2-propylidene, further α1,4-cyclohexadienylglycyl, α-thienylglycyl, such as α- 2- or α-3-thienylglycyl, α-furylglycyl such as N-2-furylglycyl, α-isothiazolylglycyl, such as α-4 isothiazolylglycyl, in which the amino group, e.g. in the phenylglycyl residue, is substituted or protected, further α-carboxyphenylacetyl or α-carbonylthienylacetyl, e.g. α-carboxy- 2-thienylacetyl (optionally a functionally modified carboxyl, e.g. in the form of a salt such as sodium salt or in the form of an ester such as lower alkyl- e.g. methyl- or ethyl- or phenyl-loweralkyl- e.g. diphenylmethyl ester), α-sulfophenylacetyl ( optionally also in the same manner as carboxyl, modified sulfo), .alpha.-phosphono, .alpha.-O-methylphosphonone or .alpha., O-dimethylphosphonophenylacetyl or .alpha.-hydroxyphenylacetyl (optionally and functionally modified hydroxy, in particular in the form of acy) alkoxy groups wherein the acyl is preferably readily cleavable, eg by treatment with an acidic agent such as trifluoroacetic acid or a chemical reducing agent such as zinc in the presence of aqueous acetic acid, or in a form readily convertible to the acyl residue, preferably suitable an acyl radical of a semi-carbonic acid ester such as the above-mentioned, optionally halogen or benzoyl substituted lower alkoxycarbonyl radical, e.g. 2,2,2-trichloroethoxycarbonyl,

2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert-butyloxycarbonyl or phenacyloxycarbonyl, furthermore formyl as well as 1-aminocyclohexylcarbonyl, aminomethylphenylacetyl, such as 2- or 4-aminomethylphenylacetyl, or aminopyridinium acetyl, optionally with aminopyridinium acetyl; for example as above, substituted with amino] or pyridylthioacetyl, e.g. 4-pyridyltbioacetyl, and R ^b is hydrogen or R ^a and R ^b together form an oxo-3-aza-l, 4-butylene substituted in position 2 with preferably an optionally protected hydroxyl group such as an acyloxy group, e.g. an optionally halogen-substituted lower alkoxycarbonyloxy or lower alkanoyloxy group and / or a halogen such as a chlorine-substituted phenyl such as phenyl or 3- or 4-hydroxy-, 3-chloro-4 -hydroxy or 3,5-dichloro-4-hydroxyphenyl (optionally also with a protected, eg acylated hydroxy group as described above), which in the 4-position, it optionally contains two lower alkyls such as methyl and R ^2A is lower alkoxy, in particular α-semi-branched lower alkoxy, e.g. tert-butyloxy, further methoxy, ethoxy, 2-halogen lower alkoxy, e.g. trichloroethoxy, 2-iodoethoxy or easily convertible to 2-chloroethoxy or 2-bromoethoxy, phenylacyloxy, 1-phenyl-lower alkoxy with 1-3, optionally lower alkoxy or nitro substituted phenyl radicals, such as 4-methoxybenzyloxy, 4-methoxybenzyloxy, 4-methoxybenzyloxy , difenylmethoxyskupina, 4,4'-dimethoxy?; ydifenylmethoxyskupina or trityloxy, lower alkanoyloxymethoxyskupina, e.g. acetyloxymethoxyskupina or pivaloyloxymethoxy, .alpha.-aminonížší alkanoyloxymethoxyskupina, e.g. glycyloxymethoxyskupina 2-ftalidyloxymethoxyskupina, lower alkoxycarbonyloxy, e.g. ethoxycarbonyloxy, or lower alkanoyloxy, e.g. acetyloxy; yloxy, e.g. trimethylsilyloxy.

The present invention firstly relates to the compounds 3-cephem-οηυ formula I wherein R ^is hydrogen or an acyl group of formula B

O

R _a - (X) m-CH-CR h (B) wherein R _a is phenyl or hydroxyphenyl, e.g. 3 or 4-hydroxyphenyl, and hydroxychlorophenyl, e.g. wherein in these radicals the hydroxy groups are protected by acyl radicals, such as optionally halogenated lower alkoxycarbonyl radicals, such as tert-butyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl, as well as thienyl, e.g. 2- or 3-thienyl, furthermore pyridyl, eg 4-pyridyl-, amlnopyridinium, eg 4-aminopyridinium, furyl, eg 2-furyl, isothiazolyl, eg 4-isothiazolyl or tetrazolyl, eg 1-tetrazolyl, or also 1,4-cyclohexadienyl, X is an atom oxygen or sulfur, m is 0 or 1 and R _b is hydrogen or, if m is 0, an amino group as well as a protected amino group such as an acylamino group, eg α-polybranched lower alkoxycarbonylamino group such as tert-butyloxycarbonylamino or such as 2,2,2-trichlorocarbones or a lower alkoxy or nitro substituted phenyl lower alkoxycarbonylamino group such as 4-methoxybenzyloxycarbonylamino or diphenylmethoxycarbonylamino, or 3-guanylureido, such as sulfoamino or trio; methyl 26 phenylsulfonylaminosupine or 1-loweralkoxycarbonyl-2-propylideneamino, e.g., 1-ethoxycarbonyl-2-propylideneamino, carboxyl or carboxyl in salt form, e.g. alkali metal salt such as sodium salt, as well as protected carboxyl, e.g. esterified carboxyl, such as phenyl-lower alkoxycarbonyl, e.g. diphnylmethoxycarbonyl, sulfo or sulfo in salt form, e.g. as sodium salt, as well as protected sulfo, hydroxyl as well as protected hydroxyl, such as acyloxy, e.g. lower alkoxycarbonyloxy, such as tert-butyloxycarbonyloxy, or 2-halogenoalkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy, or 2-bromoethoxycarbonyloxy or lower-alkoxycarbonyloxy; e.g., O-methylphosphono, or O, O'-dimethylphosphono or 5-amino-5-carboxyvaleryl, wherein the amino and / or carboxyl groups may also be protected and, for example, may exist as acylamino, e.g., lower alkanoylamino, such as acetylamino. , a halo-lower alkanoylamino group such as a dichloroacetylamino group, a benzoylamino group, or a phthaloylamino group, optionally as an esterified carboxyl such as a phenyl lower alkoxycarbonyl, e.g. diphenylmethoxycarbonyl, wherein preferably m is 1 when R _a is phenyl, hydroxyphenyl, hydroxychlorophenyl or pyridyl; and R _b is different from hydrogen when R _a is phenyl, hydroxyphenyl, hydroxychlorophenyl, thienyl, furyl, isothiazolyl or 1,4-cyclohexadienyl, R ^1b is hydrogen, R ^2A is lower alkoxy, especially α-polybranched loweralkoxy, e.g. tert-butyloxy, 2-halo-loweralkoxy, e.g. 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally lower alkoxy, e.g. methoxy, substituted diphenylmethoxy, e.g. trimethylsilyloxy and their 1-oxides of cefam-3-one compounds of the formula I or salts thereof with salt-forming groups such as salts with acids, e.g. mineral acids or strong carboxylic acids or sulfonic acids, such as preferably halogen substituted lower alkanecarboxylic or arylsulfonic acids, in particular trifluoroacetic acid or 4-methylphenylsulfonic acids Derived from the compounds of formula I wherein R ^a and R ^b is hydrogen.

These are primarily cefam-3-one compounds of formula (I) as well as salts thereof, with salt-forming groups as mentioned above for the salts where R ¹ is hydrogen, the acyl radical of formula B wherein R _a is phenyl, as well as hydroxyphenyl, e.g. 4-hydroxy228101 phenyl, thienyl, e.g. 2- or 3-thienyl, 4-isothiazolyl or 1,4-cyclohexadienyl, X is oxygen, m is 0 or 1, and R _b is hydrogen or if m is 0, an amino group as well as a protected amino group such as an acylamino group such as an α-polybranched lower alkoxycarbonylamino group such as a tert-butyloxycarbonylamino group or a 2-haloalkoxycarbonylamino group such as 2,2,2-trichloroethoxycarbonylamino, or optionally lower-alkoxy or nitro substituted phenyl-lower alkoxycarbonylamino, e.g. 4-methoxybenzyloxycarbonylamino or hydroxyl, as well as protected hydroxyl such as acyloxy, such as α-polybranched lower alkoxycarbonyloxy, such as tert-butyloxycarbonyl or 2-halo-loweralkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-iodoethoxycarbonyloxy or 2-iodoethoxycarbonyloxy or 2-iodoethoxycarbonyloxy or 2-haloalkoxy;

A 5-amino-5-carboxyvaleryl radical wherein the amino and carboxy group may also be protected, such as, for example, acylamino, such as lower alkanoylamino, such as acetylamino, haloalkanoylamino, such as dichloroacetylamino, benzoylamino, phenyl, , e.g. dlfenylmethoxykarbonyl, preferably wherein m is 1 _and when R is phenyl or hydroxyphenyl, R ^b is hydrogen and R 2 ^and optionally by halogen in position 2 substituted lower alkoxy, e.g. chloro-, bromo- or iodo-substituted nižšíalkoxyl, in particular α-polybranched lower alkoxy, e.g. tert-butyloxy or 2-halo-loweralkoxy, e.g. 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally lower alkoxy such as methoxy substituted diphenylmethoxy, or 4,4 1'-dimethoxydiphenylmethoxy, furthermore lower alkylsilyloxy, e.g. trimethylsilyloxy.

The present invention relates primarily to diphenylmethyl 7 / 3- (Da-amino-aR _and -acetylamino) -cepham-3-one-4e-carboxylic acid diphenylmethyl ester wherein R _a is phenyl, 4-hydroxyphenyl, 2-thlenyl or 1-carboxylic acid. The 4-cyclohexadienyl and amino group is preferably in protected form, e.g. as acylamino, e.g. α-polybranched lower alkoxycarbonylamino, such as tert-butyloxycarbonylamino or 2-halo-loweralkoxycarbonylamino, e.g. 2,2,2-trichloroethoxycarbonylamino iodoethoxycarbonylamino or 2-bromoethoxycarbonylamino or optionally lower alkoxy or optionally lower alkoxy or nitro substituted phenyl-lower alkoxycarbonylamino, e.g. 4-methoxybenzyloxycarbonylamino, and also the diphenyl ester of the .alpha. refers to diphenylmethyl 7H- (D-tert-butyloxycarbonylamino-α-phenylacetylamino) -cepham-3-one-4H-carboxylic acid.

The compounds of formula I are prepared by cepham compound II

in which

R ^a, R ^b and R 2 ^and are as defined under the name of I or the 1-oxide thereof or a salt of such a compound with salt-forming groups, oxidatively cleaving the methylene group in the 3 position, preferably with ozone, followed by reductive cleavage of the ozonide formed as an intermediate then recovering the compound of formula I or the obtained 1-oxide thereof in free or salt form.

In the starting material of formula II, the protected carboxyl group of formula -C (= O) -Ra ^A in the 4-position preferably has a " configuration.

In the starting material of formula II, the amino protecting group R ^{1A is} in particular an acyl group Ac, wherein the optionally present free functional groups such as amino, hydroxy, carboxy or phosphono are protected in a known manner, amino groups such as acylation, tritylation, silylation or stannylation and hydroxy , carboxy or phosphono groups, e.g., by etherification or esterification including silylation or stannylation, and R ^1b is a hydrogen atom, while R a ^A is preferably an etherified hydroxyl group together with the -C (= O) _ esterified carboxyl group especially cleavable under mild conditions, wherein optionally present functional groups in the carboxy protecting group ^{R2, and} may be a known manner, for example, the above protected. R2 ^and as especially optionally substituted, lower alkoxy, e.g. methoxy or nitro-containing 1 fenylnižšíalkoxyskupina such as the above manner difenylmethoxyskupina or substituted benzyloxy, e.g., benzyl, 4-methoxybenzyl, 4-nitrobenzyl or 4,4 difenylmethoxyl 1'-dimethoxydiphenylmethoxyl, as well as optionally α-polybranched lower alkoxy groups, e.g.

2 8 1 and 1

2,2,2-trichloroethoxy, 2-bromomethoxy or 2-iodoethoxy, furthermore an organic silyloxy or stannyloxy group such as a tris-lower alkylsilyloxy group, e.g. trimethylsilyloxy group.

The oxidative cleavage of the methylene group to form the oxo group at the 3-position of the cyclic backbone is performed in various ways.

Thus, an oxidizing agent that leads directly to the compound of formula I can be used. This is made possible by using, in particular, an oxidizing agent that contains a hexavalent chromium, such as dichromate, e.g. alkali metal dichromate, e.g. potassium dichromate, aqueous organic solvents such as suitable water-miscible solvents such as dioxane or ketones such as acetone and in the presence of a mineral acid such as sulfuric acid or chromium trioxide, commonly in the presence of acetic acid and, if necessary, in the presence or absence of water containing organic solvent. The oxidation is carried out with cooling, e.g. to about -90 ° C, at room temperature, or at most with moderate heating to about 40 ° C.

It is also possible, for example, to use an oxidizing agent which leads to the formation of a glycol as an intermediate which is converted to the compound of formula I in the next oxidation step. Such oxidizing agent preferably contains a seven-valent manganese or an eight-valent osmeum or ruthenium such as their corresponding salts or oxides first of all, for example, alkali metal permanganates such as potassium permanganate or heavy metal oxides, for example osmium tetroxide or ruthenium dioxide. These oxidizing agents are preferably used in the presence of solvents such as suitable ethers, e.g. dioxanes, ketones, e.g. acetone, optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbons, e.g. carbon tetrachloride or benzene, or in the presence of a solvent mixture, including aqueous mixtures, as well as with cooling or slight heating, e.g. at temperatures from about -90 ° to +40 ° C.

The methylene group in the starting material of formula II can also be converted to the O, O'-diester of the corresponding glycol moiety, e.g., by treatment with an organic carboxylic acid such as an aliphatic carboxylic acid, e.g. an optionally halogenated lower alkanecarboxylic acid such as trifluoroacetic acid; the diester group obtained is converted to a glycol which is converted to a keto group in the next oxidation step. A suitable oxidizing agent is iodo-trishalogen lower alkanoate, especially iodo-tris trifluoroacetate, and is conveniently worked in an inert solvent such as an optionally halogenated hydrocarbon, e.g. methylene chloride, optionally with cooling, but usually at room temperature. The glycol diester thus obtained, wherein the hydroxyl groups are esterified with a halogen-lower-alkanoyl radical, in particular a trifluoroacetate radical, can be hydrolytically cleaved to the corresponding glycol, preferably using a weakly basic medium, e.g. working in the presence of an alkali metal bicarbonate such as sodium bicarbonate or potassium, or a suitable phosphate buffer.

Further, in the starting material of formula II, the methylene group can be converted to the corresponding epoxide by oxidation with hydrogen peroxide, preferably in the presence of a suitable acid, such as formic acid, or in conjunction with other oxidizing agents such as heavy metal oxides, e.g. or an organic peracid, in particular a percarboxylic acid such as peracetic acid, trifluoroperacetic acid, perbenzoic acid, 3-chloroperbenzoic acid or monoperphthalic acid. The obtained oxide is then converted to a glycol by treatment with a weak base such as a metal alcoholate, such as an alkali metal lower alkanoate, e.g., sodium or potassium methanolate, tert-butanolate, in the presence of an alcohol such as a lower alkanol, e.g. tert.butanol.

The intermediate glycols obtained are not normally isolated and are directly subjected to further oxidation, preferably by treatment with periodate, such as an alkali metal periodate, e.g. sodium periodate or a oxidizing heavy metal acylate, such as lead acylate, e.g. lead acetate, or lead benzoate, acylate. thallium, such as thallium acetate or mercuric acylate, for example mercuric acetate, is preferably operated in the presence of a suitable solvent or solvent mixture, such as those mentioned above, with cooling or slight heating, e.g. at a temperature of about -70 ° C to about +40 ° C and the desired 3-oxocepham compounds of formula I are obtained as a product.

The oxidative cleavage of the methylene group in the starting material of formula (II) is preferably carried out to form ozonide by reaction with ozone. Ozone is preferably used in the presence of solvents such as an alcohol, for example a lower alkanol such as methanol or ethanol, a ketone such as a lower alkanone such as acetone or a halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon such as a halogen lower alkane such as methylene chloride or carbon tetrachloride, or in the presence of a mixture of solvents, including aqueous mixtures, and the reaction is carried out with a maximum gentle heating, preferably with cooling, that is at a temperature of about -90 ° C to +40 ^° C, preferably 70 ° C to 10 ° C.

the ozonide-forming intermediate is reductively cleaved using catalytically activated hydrogen, e.g. hydrogen in the presence of a heavy metal catalyst such as nickel catalysts, palladium, preferably on a suitable support such as calcium carbonate or coal, or the ozonide is cleaved by chemical reduction an agent such as reducing heavy metals including heavy metal alloys or heavy metal amalgams, for example zinc in the presence of a hydrogen donor such as an acid such as acetic acid or an alcohol such as a lower alkanol, reducing inorganic salts such as an alkali metal iodide e.g. sodium iodide, in the presence of a hydrogen donor such as an acid such as acetic acid or reducing organic compounds such as formic acid. Preference is given to using reducing agents which can readily be converted to oxides, whereby the formation of the oxide can take place on a carbon-carbon double bond or oxides can be formed at heteroatoms such as sulfur, phosphorus or nitrogen. Such compounds are suitably substituted ethylene compounds (which are converted into ethyleneoxy compounds in the reaction), such as tetracyanethylene, particularly suitable sulfides (which are converted to sulfoxides in the reaction), such as dinisalkylsulfides, primarily dimethylsulfide, suitable organic phosphorus compounds such as phosphine , which optionally may contain as a substituent aliphatic or aromatic hydrocarbon residues (and which are converted to a phosphine oxide in the reaction), such as tri-lower alkylphosphines, e.g. tri-n-butylphosphine or triacylphosphine, e.g. triphenylphosphine; substituted hydrocarbon radicals (and in the reaction are converted to phosphoric acid triesters), such as the threefold alkyl phosphites, commonly in the form of the corresponding alcohol adducts, such as trimethyl phosphite or phosphorous triamide, which may optionally contain as substituents include optionally substituted hydrocarbon radicals such as hexanalkylalkyl phosphorous triamide, e.g. hexamethylphosphoric triamide, preferably in the form of an adduct with methanol, suitable nitrogenous bases (which convert to N-oxides in the reaction), such as nitrogen-containing heterocyclic bases of aromatic character , for example pyridine type bases and especially pyridine itself. Cleavage of ozonides that are not normally isolated is carried out under the conditions commonly used in their preparation, i.e. in the presence of a suitable solvent or solvent mixture, as well as with cooling or slight heating, and temperatures of from about -10 ° C are preferably used. to about + 25 ° C and the reaction is conveniently carried out at room temperature.

Depending on the oxidation reaction, a compound of formula I or the corresponding 1-oxide or a mixture of both is obtained. Such a mixture may be separated into individual components, i.e. the compound of formula I and the corresponding 1-oxide, or it may be oxidized to a uniform 1-oxide of the compound of formula I.

A mixture of a compound of formula I with the corresponding

The 1-oxide can be separated into the individual components in a conventional manner, e.g., by functional crystallization or chromatography (e.g., on a column or thin layer).

Further, according to the present invention, the mixture of the compound of formula I and its 1-oxide obtained or the compound of formula I obtained can be converted to the corresponding 1-oxide. Suitable oxidizing agents are inorganic peracids having a reduction potential of at least +1.5 volts. They do not contain metal elements, organic peracids or mixtures of hydrogen peroxide and acids, in particular organic carboxylic acids with a dissociation constant of at least 10 A. Suitable inorganic peracids are iodine and open. Organic peracids are the corresponding percarboxylic and persulfonic acids which are added as such or which are formed in situ using at least one equivalent of hydrogen peroxide and carboxylic acid. A large excess of carboxylic acid is preferably used, for example acetic acid is used as the solvent. Suitable peracids are permenic acid, peracetic acid, pertrifluoroacetic acid, permaleic acid, perbenzoic acid, monoperphthalic acid or p-toluenesulfonic acid.

The oxidation can also be carried out using hydrogen peroxide and a catalytic amount of acid with a dissociation constant of at least 10 ⁵ , using a low concentration, eg 1-2%, but a larger amount of acid can also be used. The effectiveness of the mixture primarily depends on the strength of the acid. Suitable mixtures are, for example, hydrogen peroxide with acetic acid, perchloric acid or trifluoroacetic acid.

The above oxidation can be carried out in the presence of suitable catalysts. Thus, the oxidation can be carried out with organic peracids in the presence of an acid with a dissociation constant of at least 10 ⁵ , wherein the efficiency depends on its strength. Suitable acid catalysts are, for example, acetic acid, perchloric acid and trifluoroacetic acid. Normally, at least an equimolar amount of oxidizing agent is used, preferably a slight excess, about 10% to 20%, but a large excess of up to 10 times may also be used. The oxidation is carried out under mild conditions, e.g., at a temperature of from about -5 ° C to about +100 ° C, preferably from about -10 ° C to about +40 ° C.

Oxidation of the cefam-3-one compounds to the corresponding 1-oxides is also effected by ozone treatment, as well as by organic halogenates such as lower alkyl hypochlorite, e.g. tert-butyl hypochlorite, in the presence of inert solvents such as optionally halogenated hydrocarbons such as methylene chloride. about -10 ° C to about +30 ° C, periodates such as alkali periodates such as potassium periodate, which are preferably used in an aqueous environment at a pH of about 6 and at a temperature of from -10 ° C to +30 ° C, iodobenzene228101 dichloride, which is used in an aqueous medium, preferably in the presence of an organic base such as pyridine, the reaction being carried out with cooling at, for example, temperatures from about -20 ° C to about 0 ° C or other oxidizing agents may be used. for converting thio groups to a sulfoxide group.

Depending on the type of oxidizing agent used, the .alpha.-oxide or .beta.-oxide or mixtures thereof can be obtained.

In the compound obtained, for example, the amino protecting group R ^1A and R ^1b , in particular an easily cleavable acyl group, for example a ω-polybranched lower alkoxycarbonyl group such as tert-butyloxycarbonyl, can be cleaved by reaction with trifluoroacetic acid and 2-haloalkoxycarbonyl such as 2,2,2 the trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or phenacyloxycarbonyl group may be cleaved by treatment with a suitable reducing metal or a corresponding metal compound, for example a zinc or chromium compound such as chromium chloride or chromium acetate, preferably in the presence of a metal-releasing agent with hydrogen or metal from birth, preferably in the presence of acetic acid containing water.

In carrying out the process according to the invention, as well as in possible further work-ups, groups which are not involved in the reaction and present in free form in the starting materials or in the compounds obtained can, if necessary, be protected in a known manner. acylation, tritylation or silylation, the free hydroxy group of its mercapto group, for example by etherification or esterification, and the free carboxy group, for example by esterification including silylation, and after the desired reaction can be carried out individually or in a known manner. Thus, for example, preferably protecting the amino, hydroxy, carboxyl or phosphono group in the acyl residue R ^A respectively. R ^1b in the form of an acylamino group of the above type, e.g. as 2,2,2-trichloroethoxycarbonylamino, 2-bromoethoxycarbonylamino, 4-methoxybenzyloxycarbonylamino, diphenylmethoxycarbonylamino, or tert-butyloxycarbonylamino, or aryl- or aryl- or aryl-. 4-methylphenylsulfonylamino or 1-loweralkoxycarbonyl-2-propylideneamino, optionally as acyloxy of the above type, e.g. tert-butyloxycarbonyloxy, 2,2,2-trichloroethoxycarbonyloxy or 2-bromoethoxycarbonyloxy ester, e.g. optionally O, O'-disubstituted phosphono of the above type, e.g. OO'-lower alkylphosphono, e.g. O, O'-dimethylphosphono, and then optionally after transfer of the protecting groups, e.g. methoxycarbonyl to 2-iodoethoxycarbonyl, depending on the type of protecting group, for example, these are partially removed, if necessary, such as 2,2,2-trichloroethoxycarbonylamino or 2-iodoethoxycarbonylamino by reaction with a suitable reducing agent, such as zinc in the presence of aqueous methenylmethoxylamine or a tert-butyloxycarbonylamino group by reaction with formic acid or trifluoroacetic acid, an aryl- or aryl-lower alkylthioamino group by reaction with a nucleophilic reagent such as sulfuric acid, arylsulfonylamino group by electrolytic reduction, 1-loweralkoxycarbonyl-2-propylidino group by reaction with a tert-butyloxy group. with formic acid or trifluoroacetic acid, or 2,2,2-trichloroethoxycarbonyloxy by reaction with a chemical reducing agent such as zinc in the presence of aqueous acetic acid or diphenylmethox a carbonyl group by reaction with formic acid or trifluoroacetic acid or by hydrogenolysis, optionally an O, O-disubstituted phosphono group by reaction with an alkali metal halide.

Salts of the compounds of formula I can be prepared in a known manner. Thus, salts of compounds with acidic groups can be prepared, for example, by treatment with metal compounds, such as alkali metal salts with suitable carboxylic acids, such as sodium α-ethylcaproic acid or by reaction with ammonia or a suitable organic amine, preferably stoichiometric amounts or a slight excess of salt-forming agent. Salts of compounds of formula I with acids, i.e. compounds of formula I with basic groups, are prepared in a conventional manner, for example by reaction with an acid or a suitable anion exchange agent. Internal salts of the compounds of formula I which contain an amino group capable of forming a salt and a free carboxyl group can be prepared by neutralizing the salts to an isoelectric point, for example with a weak base, or treating with a liquid ion exchanger. The 1-oxide salts of the compounds of formula I with salt-forming groups can be prepared in an analogous manner.

Salts can be converted in conventional manner into free compounds, metal salts or ammonium salts, for example by reaction with a suitable acid and salts with acids, for example by reaction with a suitable basic agent.

The mixtures of isomers obtained can be separated into the individual isomers by known methods, mixtures of diastereomeric isomers, for example, fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other separation processes. The racemates obtained can be conventionally separated into individual antipodes, for example optionally after introduction of a suitable salt-forming group, converted into a mixture of diastereoisomeric salts with an optically active salt-forming agent, then the mixture is separated into diastereoisomeric salts and the separated salts converted to free compounds or functional crystallization from optically active solvents.

The process also relates to those embodiments in which the compounds obtained as intermediates are used as the starting compounds and the remaining steps of the process or to those in which the process is interrupted at a certain stage are carried out, and also to embodiments in which the starting compound is used in the form of derivative or when the starting compound is formed in the reaction.

Preferably, the starting compounds and reaction conditions are those compounds or conditions under which particularly preferred compounds are obtained.

For example, the starting compounds of formula II used in the process of the present invention can be prepared by preparing a cephem compound of formula IV

wherein R ^is preferably an amino protecting group R ^A, and wherein R2 is preferably hydroxyl, but R2 ^and converted acetyloxymethylskupina, for example by hydrolysis under mild basic conditions such as aqueous sodium hydroxide solution at pH 9-10, or by treatment with a suitable esterase , such as the corresponding enzyme from Rhizobium tritolli, Rhizoblum lupinii, Rhizobium japonicum or Bacillus subtilis, to a hydroxymethyl group, a free carboxyl group of the formula

-C (= O) -R ₂ is suitably functionalized, for example, esterified by reaction with a diazo compound such as diphenyldiazomethane and converted to a hydroxymethyl group such as chloromethyl or iodomethyl by reaction with a halogenating agent such as a chlorinating agent, for example thionyl chloride or an iodinating agent such as N-methyl-N, N'-dicyclohexylcarbodiimidium iodide. The chloromethyl group is either directly, for example by reaction with a suitable chromium compound, such as a corresponding inorganic or organic salt, for example chromium chloride or chromium acetate in a suitable solvent such as dimethyl sulfoxide or indirectly via an iodomethyl compound by reacting the chloromethyl compound with a metal iodide such as sodium iodide a solvent such as acetone is reacted with a suitable reducing agent such as zinc in the presence of acetic acid to give the methylene group of the starting material of formula II.

In the compound of formula II, which can also be prepared from the compound of formula IV also by electrochemical reduction or reduction with chromium salts or aluminum amalganes, the protected amino group at the 7-position can be released or converted to another protected amino group and / or the free amino group at the 7-position. can convert to a protected amino group; these reactions are carried out in a known manner, for example as described above.

The starting compounds of the formula III can be prepared by reacting in the aforementioned compound of the formula V \

h ^{N R} l '\ S

O ~ C -

O = CR _Z (V) wherein R 2 is preferably hydroxyl and the double bond is in the 2,3- or 3,4-position, oxidizes the hydroxymethyl group to formyl, and at a suitable stage the 3-cephem compound ismerized to the 2-cephem compound and optionally in the obtained compound, the hydroxy group R2 is replaced by a suitable etherified hydroxy group or an amino or hydrazino group. The oxidation can be carried out as described in U.S. Pat. No. 3,351,596, for example by treatment with metal oxidants such as oxides, for example chromium trioxide or manganese dioxide, 2-cephem compounds preferably oxidizing 2,3-dichloro-5,6- dicyano-1,4-benzoquinone and 3-cephem compounds preferably with aliphatic sulfoxides such as lower alkyl sulfoxides, e.g. dimethylsulfoxide, or lower alkylene sulfoxides, e.g. tetramethylsulfoxide in the presence of aliphatic carboxylic anhydrides, e.g. with an equimolar amount of anhydride based on the sulfoxide, wherein the reaction is carried out at temperatures from about -50 ° C to +70 ° C, optionally in the presence of an inert solvent such as benzene or toluene. The isomerization of the 3-cephem compound to the corresponding 2-cephem compounds is carried out by treatment of the optionally formed in situ ester or anhydride together with a base such as a tertiary amine, for example triethylamine and / or a heterocyclic base such as pyridine.

The starting 2-cephem compounds of formula III can also be prepared by total synthesis, for example, as described in Austrian Patent Nos. 263,768 and 264,537.

As mentioned above, the novel compounds of formula II can be used to prepare compounds with a cefam structure which either have advantageous pharmacological properties or can be used as intermediates.

Thus, for example, compounds of formula II may be converted to enolderivatives, for example by reaction with an optionally substituted aliphatic diazocarbon compound, such as diazonosalkane, for example diazomethane or phenyl-diazonosilane, such as phenyldiazomethane, converted to enolether or by reaction with an acid or a suitable acid derivative such as the halide, for example the chloride or anhydride, is converted to the enol ester, and in the enol derivatives thus obtained, the protected carboxyl group of formula —C (= O) —Ra ^A is converted into the free carboxyl group in known manner to give cephem compound VI about 0.001 to about 0.02 g / kg subcutaneously or per os] and gram-negative bacteria such as Escherlchia coli, Salmonella typhimurium, Shigella flexneri, Klebsiella pneumoniae, Enterobacter cloacae, Proteus vulgaris, Proteus rettgeri and Proteus mirabilis (e.g. at a dose of from about 0.001 to about 0.15 g / kg subunit These or per os), in particular against bacteria resistant to penicillin, and these compounds exhibit minimal toxicity. The novel compounds can therefore be used, for example, in the form of antibiotic active preparations, for example for the treatment of corresponding infections.

Further, the oxo group at the 3-position of the cefam compounds of formula I can be reduced to the hydroxy group by, for example, reaction with a suitable complex metal hydride such as sodium borohydride in the presence of a suitable solvent such as alcohol or ether. an esterified hydroxy group and / or a protected carboxyl group of the formula —C (= OO) - R @ 2 ^A is converted into the free carboxyl group.

which contains a double bond at the 3,4- and 2,3-a wherein R ^a and R ^b are as defined above, R is hydroxyl or the radical R forming a carbonyl group ^and a protected carboxyl group, and RA is an optionally substituted hydrocarbon radical of aliphatic character, or acyl group. Compounds of formula VI, particularly compounds in which R ^is an acyl radical contained in a pharmacologically active N-acyl derivatives 6/3-aminopenam-3-carboxylic acid ethyl ester and 7i / 3-amino-3-cephem-4-carboxylic acid R ^b is and R 2 is hydroxy or an etherified hydroxy group together with the carbonyl group forming a carboxyl group cleavable under physiological conditions and R a is as defined above, and wherein R 1 ^and optionally functional groups such as amino, carboxy, hydroxy and / or sulfo are present in free form or in the form of salts of these compounds with salt-forming groups, are effective against parenteral and / or oral administration against microorganisms such as gram-positive bacteria, for example Staphylococcus aureus, Staphylococcus pyogenes and Diplococcus pneumoniae (e.g. where R _b is hydrogen) or an acyl residue can be cleaved by elements of a compound of formula R _b OH (VIII) i.e., water or acid elements, the cleavage being carried out under acidic or basic conditions to give known 3-cephem compounds of formula IX

wherein R ^a, R ^b and R are as defined above, and wherein each of these residues can be converted in a known manner. Compounds of formula IX or salts thereof have valuable pharmacological either, especially antimicrobial properties, in particular those compounds, wherein R ^is an acyl radical contained in farmakolQ228101 cally active N-acyl derivatives aminopenam 6j3-3-carboxylic acid 7/3-amino-3- cefem-4-carboxylic acids, R ^1b is a hydrogen atom and R 2 is a hydroxyl or etherified hydroxyl group which together with the carbonyl group forms a carboxyl group cleavable under physiological conditions or can be used as intermediates for the preparation of said compounds with pharmacological properties.

When converting compounds of formula I of the present invention to compounds of formula IV, respectively. to the compounds of formulas V and VII, the compounds of formula I need not be isolated and can be converted directly to the compounds of formula VI and II, respectively, in the form of a crude mixture after the preparation of the compound of formula II. VII and IX.

In the present description, the organic moiety designated as "lower" contains up to 7, preferably up to 4 carbon atoms; an acyl radical of up to 20, preferably up to 12, carbon atoms.

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

Example 1

A solution of 0.50 g of 3-methylene-7β-phenylacetylaminocepham-4α-carboxylic acid diphenylmethyl ester in 100 mL of methanol at -70 ° C was treated with a stream of oxygen and ozone containing 0.175 mmol of ozone / min for 6.5 min. The reaction mixture was treated with 0.5 mL of dimethylsulfide and stirred at -70 ° C for one hour and then at room temperature for two hours and evaporated to dryness. The residue was dissolved in methylene chloride and chromatographed on 15 g of silica gel. 7-3-Phenylacetylaminocepham-3-one-4H-carboxylic acid amorphous diphenylmethyl ester, eluting with methylene chloride, thin layer chromatography (silica gel): Rf ~ 0.47 (system: toluene / acetone / methanol / acetic acid 80: 10: 5 : 5); infrared absorption spectrum (methylene chloride): characteristic bands at

2.95 μπι,

5,61 μπι,

5,77 μπι,

5,85 μϊη,

5.95 μπι,

6,21 μϊη,

6.87 μϊη;

the compound shows a positive reaction to ferric chloride, indicating the presence of enolform.

The more polar compound eluting with methylene chloride containing 10% acetone is very likely identical to diphenylmethyl ester of 1-oxido-7/3-phenylacetylaminocepham-3-one-4 H -carboxylic acid, thin layer chromatography (silica gel): Rf = 0, 22 (system: toluene / acetone / methanol / acetic acid 80: 10: 5: 5); infrared absorption spectrum (methylene chloride): characteristic bands at

2.96 μπι,

5,58 μϊη,

5.76 μπι (inflex),

5,83 μϊη,

5,97 μΐη,

6,22 μϊη,

6,61 μπι;

the compound shows a positive reaction to ferric chloride, indicating the presence of enolform.

The starting material can be prepared as follows:

A solution of 11.82 g of crude 3-hydroxymethyl-7,3-phenylacetylamino-3-cephem-4-carboxylic acid sodium salt (prepared by enzymatic desacetylation of 3-acetoxymethyl-7 H -phenylacetylamino-3-cephem-4-carboxylic acid sodium salt by purified of an enzymatic extract of Bacillus subtilis, Stamm ATCC 6633 followed by freeze-drying of the reaction solution) in 200 ml of water is overlaid with 400 ml of ethyl acetate and acidified with concentrated aqueous phosphoric acid to pH 2. The aqueous phase is separated and extracted twice with 150 ml of ethyl acetate. The combined organic extracts are washed four times with 50 ml of water each time and dried over magnesium sulphate and then evaporated to about 400 ml. The solution was treated with an excess of diphenyldiazomethane, allowed to stand for three hours at room temperature, and the granular crystalline precipitate was then filtered off. The filtrate is evaporated to about 200 ml, treated warm with cyclohexane and allowed to stand at about 4 ° C for some time after cooling to room temperature. The precipitate is filtered off and recrystallized from a mixture of acetone and cyclohexane; the diphenylmethyl ester thus obtained

3-hydroxymethyl-7,3-phenylacetylamino-3-cephem-4-carboxylic acid has mp 176-176.5 ° C (uncorrected); bab ²⁰ = -6 ° ± 1 ° (c = 1.231% chloroform); thin layer chromatography (silica gel); proof by iodine vapor or ultraviolet light (x2S4 nm); Rf = 0.42 (system: chloroform / acetone 4: 1), Rf = 0.43 (system: toluene / acetone 2: 1) and Rf equals 0.41 (system: methylene chloride / acetone 6: 1).

1.03 g of 3-hydroxymethyl-7, 3-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester and 1.05 g of N-methyl-N, N'-dicyclohexylcarbodiimidium iodide are dissolved in 25 ml of absolute tetrahydrofuran under nitrogen. 1 hour at 35 ^DEG C. 1.05 g of N-methyl-N, N'-dicyclohexylcarbodiimidium iodide in 15 ml of absolute tetrahydrofuran is then added again and left to stand at room temperature in a nitrogen atmosphere for 17 hours. The solvent was removed from the reaction mixture in a rotary evaporator under reduced pressure. The residue is taken up in methylene chloride and filtered through a column of 50 g of silica gel (with the addition of 10% distilled water) and washed with 4 x 100 ml portions of methylene chloride. The eluate was evaporated to a small volume and chromatographed on a silica gel column (90 g; deactivated by addition of 10% distilled water). The non-polar impurities were eluted with a total of 900 ml of a 3: 7 mixture of toluene and methylene chloride. from benzene, freeze-dried fractions uniform according to thin-layer chromatography, infrared absorption spectrum (methylene chloride): characteristic bands at

3.00 ^ _m; ·; ·

5,62 μπι,

5.82 μΐη, / '

5,95 fim,

6.70 μπι, ^ř ' ^τ

7,32 μια,

8,16 μΐη.

The iodinating agent used above is prepared as follows:

Dissolve 42 g of freshly distilled N, N-dicyclohexylcarbodiimide in 90 ml methyl iodide under nitrogen atmosphere at room temperature in a 250 ml round-bottom flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet and stir the colorless reaction mixture at 70 ° C for 72 hours. Excess methyl iodide is then distilled off from the resulting red-brown solution under reduced pressure, and the viscous red-brown residue is dissolved at 150C in 150 ml of absolute toluene. Within a few hours, a crystalline mass crystallizes spontaneously, which is separated from the mother liquors under a nitrogen atmosphere on a glass frit, eliminating the ingress of air, rinsing the reaction vessel three times with 25 ml of ice-cold absolute toluene and washing the slightly yellowish crystalline mass from the frit also toluene. After 20 hours of drying at 13.3 Pa and room temperature, N-methyl-N, N‘-dicyclohexylcarbodiimidium iodide is obtained as colorless crystals, m.p. 111-113 ° C; infrared absorption spectrum (chloroform); characteristic belts at

4,72 μΐη,

6,00 μτη.

A solution of 0.400 g of 3-iodomethyl-7i (3-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester) in 15 ml of 90% aqueous acetic acid was cooled to 0 ° C in an ice bath and mixed portionwise with 2 After a reaction time of 30 minutes at 0 DEG C., unreacted zinc dust is filtered off over suction with a diatomaceous earth bed, the residue on the filter is suspended several times in fresh methylene chloride and filtered again, and the combined filtrates are concentrated under reduced pressure, mixed. The residue is taken up with stirring in 50 ml of methylene chloride and 30 ml of a 0.5 M aqueous solution of secondary potassium phosphate, the aqueous phase is separated, extracted with two portions of 30 ml of methylene chloride and discarded. The organic extracts were washed several times with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure. romatograph on a 22 g silica gel column (10% water addition) 3-methylene-7/3-phenylacetylaminocepham-4α-carboxylic acid diphenylmethyl ester eluted with methylene chloride and methylene chloride containing 2% methyl acetate and recrystallized from methylene chloride / hexane; mp 144-147 ° C;

[, J _{and D} 20 ₌ _ ₁₈ C + R _(C = 0.715, chloroform); ultraviolet absorption spectrum (95% aqueous ethanol): _λmax = 254 nm (ε = 1540) and 260 nm (ε = 1550); infrared absorption spectrum (methylene chloride): characteristic bands at

2.94 gm,

5,65 μπι,

5,74 μπι,

5.94 μπι,

6,26 μΐη,

6,67 μηι.

Example 2

A solution of 1.53 g of 3-formyl-7β-phenylacetylamino-2-cephem-4α-carboxylic acid diphenylmethyl ester in 40 mL of methylene chloride was cooled to 0 ° C and treated with 0.61 g of 3-chloroperbenzoic acid. Allow to warm to room temperature over one hour and then wash successively with 5% aqueous sodium bisulfite solution, 0.5 m aqueous potassium phosphate solution and water; the aqueous washings were extracted twice with methylene chloride and then discarded. The organic phase is dried over magnesium sulphate and evaporated under reduced pressure.

The yellow jelly-containing residue of 3-formyloxy-7/2-phenylacetylaminocephem-4-carboxylic acid diphenylmethyl ester, wherein the ring double bond is preferably in the 3-position, is stirred at 0 ° C for one hour with 30 ml of tetrahydrofuran and 30 ml. Concentrate to a volume of about 25 ml with 0.5 M sodium bicarbonate solution under reduced pressure. Dilute with 25 ml of water and then extract twice with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on 65 g of silica gel. 7 (3-Phenylacetylaminocepham-3-one) -a-carboxylic acid diphenylmethyl ester was eluted with methylene chloride containing 2-3% acetone and lyophilized from dioxane, the product not being pure by TLC and identical to the product prepared in Example 1 and used as starting material without further purification.

The starting material can be prepared as follows:

A suspension of 3.40 g of 3-acetoxymethyl-7 H -phenylacetylamino-2-cephem-4? -Carboxylic acid in 70 ml of distilled water is stirred with a 1 N aqueous sodium hydroxide solution until the pH is 7.3 with stirring by a vibrating stirrer. The solution is heated in a thermostated bath to 35 ° C and mixed with 0.4 grams of Bacillus subtilis cell lyophilisate, ATCC 6633 in 3 ml of water. The pH is kept constant at 7.4 by addition of 1 N aqueous sodium hydroxide solution; after about 2.5 hours, half the theoretical amount of sodium hydroxide was consumed. The reaction is allowed to complete until additional hydroxide is required and the pH of the reaction solution also does not change after standing at room temperature for several hours. The solution was overlaid with 300 mL of cooled ethyl acetate and acidified to pH 2 with 5 M aqueous phosphoric acid with good stirring. After separation of the layers, the aqueous phase is saturated with sodium chloride and extracted with two further portions of cold ethyl acetate each of 250 ml. The combined organic phases were washed five times with 50 ml of saturated aqueous sodium chloride solution each time, dried over sodium sulfate and evaporated. The residue consists of _{3-hydroxymethyl-7-one} 3-phenyl-acetylamino-2-cephem-4.alpha.-carboxylic acid, uniform chromatography according to a multiple recrystallization from ethyl acetate and cyclohexane forms white needle crystals mp 156 DEG-156.5 DEG.

A solution of 0.7 g of 3-hydroxymethyl-7, 3-phenylacetylamino-2-cephem-4α-carboxylic acid in 30 ml of 4: 1 dioxane / methanol is mixed with 0.507 g of diphenyldiazomethane in 5.07 ml of dioxane and left to leave. standing at room temperature; additional diphenyldiazomethane was added portionwise over 90 minutes until the mild color persisted. Evaporate to dryness and recrystallize from ethyl acetate-cyclohexane; the obtained 3-hydroxymethyl-7S-phenylacetylamino-2-cephem-4α-carboxylic acid diphenylmethyl ester forms fine colorless needles, mp 179-179.5 ° C; [.Alpha.] D @ ²⁰ = + 390 DEG. + -. 1 DEG (c = 1.174 chloroform; silica gel thin layer chromatography): Rf = 0.35 (system: benzene / acetone 4: 1); ultraviolet absorption spectrum (95% water ethanol): Λ _max = 250 nm (ε = 6500) and λ _min = 245 nm (ε = 6400); infrared absorption spectrum: characteristic bands at

2,74 μιη,

2.89 μιη,

5,58 μιη,

5,71 μιη,

5.90 μία,

6.61 μιη,

6,65 μιη (methylene chloride and at

3,00 μιη,

3,07 μιη,

5.62 μιη,

5,71 μιη,

6,04 μιη,

6.52 μΐη,

6,68 μΐη,

7,10 μΐη,

7,42 μΐη,

8,20 μΐη,

8.52 μΐη (mineral oil).

A mixture of 5.14 g of 3-Hydroxy-4-methyl-7'-phenylacetylamino-2-cephem-4a-carboxylic acid diphenylmethyl ester in 150 ml of acetone is added dropwise at -15 ° C to a chromic acid solution (prepared by dissolving 267 g of chromium trioxide in 230 ml of concentrated). sulfuric acid and 400 ml of water and dilution to 1000 ml with water) until permanent orange-brown color; after 20 minutes, 4.5 ml of reagent is consumed. The reaction mixture was stirred at -10 ° C for 20 minutes, then 0.5 mL of isopropanol was added and evaporated under reduced pressure. The concentrate was diluted with 50 mL of water and extracted with ethyl acetate. The organic extract was washed with water, dried (MgSO4) and evaporated. The residue was recrystallized from ethyl acetate-cyclohexane to give 3-formyl-7,3-phenylacetylamino-2-cephem-4'-carboxylic acid diphenylmethyl ester, mp 175.5-176 ° C (dec.; Thin layer chromatography (silica gel) Rf = 0.35 (system: toluene / acetone 4: 1) and Rf = 0.58 (system: toluene / acetone 65:35) ultraviolet absorption spectrum (95% ethanol): _λmax = 289 nm (ε = 20,200) Infrared absorption spectrum (mineral oil): characteristic bands at

3,00 μιη,

5,03 μιη,

5.76 μιη,

5,95 μΐη,

5,99 μιη,

6,07 μπι.

Example 1 and d 3

A solution of 0.553 g of 7/3-amino-3-methylencepham-4? -Carboxylic acid diphenylmethyl ester 4-methylphenylsulfonate in 50 ml of methanol cooled to -60 ° C was charged with a stream of oxygen and ozone (containing 0.35 mmol of ozone) for 4 min. / min). After 5 minutes, the light blue solution was treated with 0.3 mL of dimethylsulfide. The mixture was stirred for 15 minutes at -70 ° C, for one hour at -12 ° C and for one hour in an ice bath and then evaporated. The residue is taken up with a small amount of methylene chloride, then mixed with diethyl ether until turbid and allowed to stand. The microcrystalline red colored powdery precipitate was filtered off to give 7-amino-3-on-4-carboxylic acid diphenylmethyl ester, 4-methylphenylsulfonate, mainly in the enol form of 7-amino-3-ol-3-cephem-3-cephem-3-cephem-4-methylphenylsulfonate. carboxylic acids mp 143-145 ^° C (dec.; thin layer chromatography (silica gel) Rf ~ 0.28 (system: ethyl acetate / pyridine / water 85: 10: 5); ultraviolet absorption spectrum (ethanol): λ _max = = 262 nm (ε = 3050) and 282nm (ε = 3020); infrared absorption spectrum (methylene chloride): characteristic bands at

5,58 μπι,

6.77 μιη (inflex),

6,02 μιη,

6,22 μηι.

The starting material is prepared as follows:

A solution of 2.0 g of 3-methylene-7,3-phenylacetylaminocepham-4α-carboxylic acid diphenylmethyl ester in 80 ml of absolute methylene chloride cooled to -15 ° C was mixed with 3.2 ml of absolute pyridine and 32 ml of 8% phosphorus pentachloride in methylene chloride. and stirred for one hour under nitrogen at a temperature between -10 ° C and -5 ° C. The reaction mixture was then cooled to -25 ° C, 25 mL of absolute methanol was added and stirred for one hour at -10 ° C and then for 1.5 hours at room temperature. 80 ml of a 0.5 M aqueous potassium phosphate solution are added, the pH is adjusted to 2 with 20% aqueous phosphoric acid and the mixture is stirred at room temperature for 30 minutes.

The organic phase was separated; the aqueous phase is extracted twice with 150 ml of methylene chloride each time, the organic solutions are combined, dried over sodium sulphate and evaporated. The oily residue is taken up in 25 ml of ethyl acetate and a solution of 1.14 g of 4-methylphenylsulphonic acid monohydrate in 25 ml of methylene chloride is added at 0 ° C. A volumous precipitate precipitates, which is filtered off, washed with cold ethyl acetate and diethyl ether, dried and recrystallized from a mixture of methylene chloride and diethyl ether. 7-3-Amino-3-methylencepham-1-carboxylic acid 4-methylphenylsulfonate diphenylmethyl ester, mp 153-155 ° C, is obtained as colorless needles; [α] _D = -14 ^C ± 1 ° (c = 0.97 methanol); ultraviolet absorption spectrum (ethanblj: _λmax = 257 nm (ε = 1500); infrared absorption spectrum (methylene chloride): characteristic bands at

3.5 µm

5,60 um,

5,73 μτα,

8.50, um,

9,68 μΐη,

9.92 µm.

Example 4

One solution of 5.0 g of 3-methylene-7 / 3- (Da-tert-butyloxycarbonylamino-α-phenylacetylamino) -cepha-4-carboxylic acid diphenylmethyl ester in 500 ml of methylene chloride cooled to -70 ° C was charged with vigorous stirring. hour of oxygen and ozone flow containing 0.21 mmol ozone / min. After an additional 10 minutes, 3 mL of dimethylsulfide was added to the reaction mixture, stirred at -65 ° C for one hour and at room temperature for two hours, and then evaporated under reduced pressure. The crude product containing 7 / 3- (D-α-tert-butyloxycarbonylamino-phenylacetylamino) -cepham-3-one-4 H -carboxylic acid diphenylmethyl ester in 150 ml of methanol was treated with excess diazomethane solution at 0 ° C. in diethyl ether, stirred for 15 minutes and then evaporated. A yellowish foam is obtained which is chromatographed on 200 g of silica gel. Toluene / ethyl acetate 3: 1 was eluted with 3-methoxy-7 / 3- (D-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-cep-4-carboxylic acid amorphous diphenylmethyl ester, thin layer chromatography (silica gel): Rf = 0.22 (system: toluene / ethyl acetate 3: 1); infrared absorption spectrum (methylene chloride): characteristic bands at

2,94 μΐη,

5,60 μπι,

5,85 μΐη,

6,23 ftm,

6.70 m.

The starting material can be prepared as follows:

The chromatographic column (3 cm diameter) is filled with 350 g of zinc dust, amalgamated for 10 minutes with a 0.1 M solution of mercuric chloride in 0.1 N hydrochloric acid and washed well with water and finally with a small amount of 1 N hydrochloric acid. A solution of 55 g of green chromium trichloride hexahydrate in 55 ml of water, 11 ml of 2 N sulfuric acid is poured into the reduction tube and the effluent rate is adjusted by dropping a pure blue chromium chloride solution into the reaction vessel maintained under a nitrogen atmosphere. The blue chromium chloride solution is then mixed with a solution of 92 g of sodium acetate in 180 ml of air-free water, whereupon the solution turns red and a finely crystalline chromium acetate precipitates. After complete precipitation, the solution was removed and the chromium acetate was washed twice with 250 ml of air-free water each time. A solution of 10.0 g of 3-acetyloxymethyl-7 / 3- (D-tert-butyloxycarbonylamino-phenylacetylamino) -3-cephem-4-carboxylic acid in 200 ml of dimethylsulfoxide was added to the wet chromium acetate, and the reaction chamber was stirred for 15 hours. at room temperature under a nitrogen atmosphere. The reaction mixture was then aerated for 30 minutes and stirred for one hour after addition of 1000 g of polystyrenesulfonic acid-based ion exchange resin (Dowex 50 W) and 1000 ml of water. After removal of the ion exchanger, the pH of the solution was adjusted to 2 with 6 N hydrochloric acid and the aqueous phase was extracted three times with 2000 ml of ethyl acetate each time. The organic extracts were washed once with 1000 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated.

The crude product obtained is dissolved in 100 ml of methanol and stirred for one hour with a solution of 6 g of diphenyldiazomethane in 30 ml of benzene at room temperature. After evaporation, the crude product is chromatographed on 500 g of silica gel. 3-Methylene-7 / 3- (D-.alpha.-tert-butyloxycarbonylamino-phenylacetylamino) -cepha-4a-carboxylic acid diphenylmethyl ester was eluted with petroleum ether / diethyl ether 4: 1; up to 158 ° C; [Α] _D = -50 ° ± 1 '(c 228101 = 0.713, chloroform); ultraviolet absorption spectrum (95% aqueous ethanol); Λ _max = = 258 nm (ε = 990); infrared absorption spectrum (methylene chloride): characteristic bands at

2,94 μτα,

5,64 μΐη,

5,74 μτα,

5.88 μπι (inflex),

6.71 μτα.

Example 5

A solution of 1.0 g of 3-methylene-7 H -phenylacetylaminocepham-4α-carboxylic acid diphenylmethyl ester in 250 mL of methylene chloride was treated at -70 ° C with a mixture of oxygen and ozone (0.265 mmol ozone / min) for 8.5 minutes and reaction mixture. was mixed with 1 ml of dimethylsulfide was then stirred for 30 minutes at -70 ^{° C} Celsius for 1.5 hours at room temperature, then evaporated under reduced pressure to dryness. The residue containing a mixture of N, N-phenylacetylaminocepham-3-one-4-carboxylic acid diphenylmethyl ester and 1-Oxo-7, 3-phenylacetylaminocepham-3-one-4 H -carboxylic acid diphenylmethyl ester is taken up in 50 ml of methanol at 0 The mixture is treated with an excess of diazomethane (as a solution in diethyl ether). The reaction mixture was stirred at 0 ° C for one hour and then evaporated under reduced pressure. The residue is chromatographed on 50 g of silica gel. The toluene / ethyl acetate 4: 1 mixture was eluted with 3-methoxy-7H-phenylacetylamino-2-cephem-4a ^, -carboxylic acid diphenylmethyl ester, Rf = 0.57 (system: toluene / ethyl acetate 1: 1), mp 174-160. 177 ° C after crystallization from methylene chloride-pentane, ultraviolet absorption spectrum (95% aqueous ethanol): λ _max = 258 nm (ε = 4310); infrared absorption spectrum (methylene chloride): characteristic bands at

2,96 μΐη,

5.60, um,

5.71 μΐη,

6,15 μιη,

5,92 μία,

6.66 μιη;

further eluting 3-methoxy-7 H -phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester, R f 0,3 0.37 (system: toluene / ethyl acetate 1: 1); Ultraviolet Absorption Spectrum (95% aqueous ethanol): _.lambda.max = 258 nm (ε = 6,340), A _max = 264 nm (ε = 6350) and Ainfi _ex = 261 nm (ε = 5600); infrared absorption spectrum (methylene chloride): characteristic bands at

2,94 μτα,

3,02 μτα,

5,62 μτα,

5.67 μπι (inflex),

5,81 μΐη,

5,92 μΐη,

6,23 μαι,

6.67 μτα, and diphenylmethyl 48-tert-1-oxido-3-methoxy-7β-phenylacetylamino-3-cephem-4-carboxylic acid is eluted with ethyl acetate, R f = 0.31 (system: ethyl acetate); mp 152-155 ° C after crystallization from acetone / diethyl ether, ultraviolet absorption spectrum (95% aqueous ethanol): λ _max = 288 nm (ε = 3610) and linfiex = 247 nm; infrared absorption spectrum (methylene chloride): characteristic bands at

2.94 μτα,

5,59 μΐη,

5,81 μτα,

5.95 μπι,

6,22 μΐη,

6,61 μιη.

Example 6

To a solution of 0.50 g of diphenylmethyl 3-methylene-7/3 ^L fenylacetylaminocefem 4Qř-carboxylic acid in 50 ml of methanol at - 70 ° C, a mixture of oxygen and ozone to commencing blue discoloration. Excess ozone was purged with nitrogen, 0.5 mL of dimethylsulfide was added and stirred at room temperature for 1.5 hours. The reaction mixture containing 7-3-phenylacetylaminocepham-3-one-4-carboxylic acid diphenylmethyl ester and 1-oxido-7H-phenylacetylaminocepham-3-one-4-carboxylic acid diphenylmethyl ester is then evaporated to dryness under reduced pressure. The residue is taken up in 10 ml of pyridine, treated with 5 ml of acetic anhydride and then allowed to stand at 0 ° C for 16 hours. It is then evaporated to dryness under high vacuum and the residue is taken up in ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on 30 g of silica gel, eluting with 3: 3-acetyloxy-7 H -phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester with toluene / ethyl acetate 4: 1. The product is recrystallized from acetone / diethyl ether, mp 158 ^{160, O} G, ultraviolet absorption spectrum (95% aqueous ethanol): z _max = 258 nm (ε = 6580) and 264 nm (ε - 6,550); Infrared absorption spectrum (methylene chloride): characteristic bands at

2.95, «m,

5.59 «m

5.69 fim (inflex),

5,78 μτα,

5,91 μΐη,

6.06 μπι (inflex),

6,67 μπι.

Example 7

A solution of 1.0 g of diphenylmethyl 3-methylene-7β-phenylacetylaminocepham-4α-carboxylic acid diphenyl ester in 100 ml of methanol is treated at -70 ^° C with a mixture of oxygen and ozone until the blue color begins and then

SO, the excess ozone is expelled by nitrogen. The reaction mixture was mixed with 0.4 mL of dimethylsulfide and stirred at room temperature for 30 minutes. It is then cooled to 0 ° C and to the reaction mixture containing 7/3-phenylacetylaminocepham-3-one-4-carboxylic acid diphenylmethyl ester and 1-oxido-7β-phenylacetylaminocepham-3-one-4-carboxylic acid diphenylmethyl ester solution of 0.10 g of sodium borohydride in 5 ml of water. It is allowed to react for 30 minutes at 0 ^° C, the pH is adjusted to about 6 by the addition of acetic acid, and the reaction mixture is evaporated under reduced pressure. The residue was taken up in ethyl acetate; the organic solution was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate, and evaporated under reduced pressure. The residue is chromatographed on 50 g of silica gel. The toluene / ethyl acetate mixture 2: 1 is eluted with 3-hydroxy-7/3-phenylacetylaminocepham-4 H -carboxylic acid diphenylmethyl ester, m.p. 157-160 ° C after crystallization from acetone / diethyl ether; [α] _D = + 80 ³ (c = 0.492, dioxane): = 258 nm (ε = 850);

infrared absorption spectrum (methylene chloride): characteristic bands at

2,82 μΐη,

2,94 μη,

5.63 μπι,

5.74, um,

5,92 μη,

6,25 μπι,

6.63 μπι.

Example 8

A solution of 0.400 g of 7β- (D-tert-butyloxycarbonylamino-phenyylacetylamino) -3-methylene-cep-4'-carboxylic acid diphenylmethyl ester in 40 ml of methylene chloride was cooled to 0 ° C and treated with 0.0835 g of tetracyanethylene. The yellow solution was introduced at 0 ° C with a mixture of oxygen and ozone until 0.773 mmol of ozone was consumed and then evaporated to dryness at 35 ° C under high vacuum, and the residue containing 7 / 3- (D-or-tert-butyloxycarbonylamino-af enylacetylamino) diphenylmethyl ester. 1 -cepham-3-one-4 H -carboxylic acid is taken up in 50 ml of methanol, a solution of diazomethane in diethyl ether is added until a permanent yellow color is obtained, and then evaporated under reduced pressure at about 35 ^° C. TLC (silica gel; system: ethyl acetate / toluene 1: 1) to give 3-methoxy-7 / 3- (D-tert-butyloxycarbonylamino-a-phenylacetylamino) -3-cephem-4-diphenylmethyl ester -carboxylic acids with Rf ~ 0.5 which is identical to the product of p EXAMPLE 4 and diphenylmethyl 7/3 (D - «- f t-butyloxycarbonylamino-acetylamino) -3-methylenecepham-4-carboxylic acid with an Rf ~ 0.6.

Example 9

A solution of 0.2 g of 7 / 3- (D-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-methylencepham-4α-carboxylic acid diphenylmethyl ester in 3 mL of methylene chloride was cooled to -22 ° C and 0.026 mL of pyridine was added with cooling and then introducing a mixture of ozone and oxygen until consumption of 1.31 mmol of ozone. The reaction mixture was evaporated to dryness under high vacuum and the residue was purified by thin layer chromatography. 7β- (D-tert-Butyloxycarbonylamino-α-phenylacetylamino] -cepham-3-one-4 H -carboxylic acid diphenylmethyl ester has an R f value of 0,50.5 (silica gel; system: toluene / acetone / methanol / acetic acid 80: 10: 4 Infrared absorption spectrum (methylene chloride: characteristic bands at

2,94 μιι,

3.40, um,

5,62 μΐη,

5,77 μΠΙ,

5.75 - 5.95 μΐη (wide band,

6.21 fim a

6,88 μη.

Example 10

Preparation of 7 / 3- (D-t-butyloxycarbonylamino-α-phenylacetylamino) -cepham-3-one-41 diphenylmethyl ester; The carboxylic acids from the 7 / 3- (D-α-tert-butyloxycarbonylamino-4-phenylacetylamino) -3-methylencepham-4α-carboxylic acid diphenylmethyl ester are preferably carried out continuously:

A 1% solution of 7 / 3- (D - tert-butyloxycarbonylamino-af enylacetylamino) -3-methylencepham-4'-carboxylic acid diphenylmethyl ester in methylene chloride cooled to 0 ° C is passed through a reaction tube (about 3 cm diameter) through solids. bodies (eg Raschig rings) filled, cooled to 0 ° C and ozone / oxygen mixture containing 0.245 mmol ozone / min are introduced in countercurrent. The gas flow is controlled by passing 700 ml of the gaseous mixture through the reaction tube in one hour. The 7β- (D-α-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-methylencepham-4α-carboxylic acid diphenylmethyl ester solution remains in the reaction tube for 15 seconds. The reaction solution with ozonide was allowed to flow directly into the receiver with a solution of dimethylsulfide in methylene chloride until a 5% excess of dimethylsulfide was formed. Then the original is replaced. The obtained 7 / 3- (D-tert-butyloxycarbonylamino-phenylacetylamino) -cepham-3-one-4'-carboxylic acid diphenylmethyl ester solution is evaporated under reduced pressure at about 35 ° C and the residue is taken up in methanol as in the procedure. according to Example 4 and a solution of diazomethane in diethyl ether is added. 3-Methoxy-7/32 2 Β 1 8 L diphenylmethyl ester is obtained

- (D-tert-Butyloxycarbonylamino-α-phenylacetylamino) -3-cephem-4-carboxylic acid, which is identical to the product of Example 4.

Example 11

A mixture of 5 g of 3-methylene-7β- (D-i-tert-butyloxycarbonylamino-N-phenylacetylamino) -cepham-4α-carboxylic acid diphenylmethyl ester and 500 ml of methylene chloride is treated at -70 ° C according to the procedure described above. of 1.15 equivalents of ozone, then mixed with 2 ml of dimethylsulfide, stirred for one hour at -70 ° C and for two hours at room temperature, and finally evaporated under reduced pressure. The residue containing 7 / 3- (D-tert-butyloxycarbonylamino-α-phenylacetylamino) -cepham-3-one-4'-carboxylic acid diphenylmethyl ester was dissolved in 150 mL of methanol and treated with a diazone solution at 0 ° C. butane in diethyl ether until a persistent yellow color is obtained. After 15 minutes the solution was evaporated under reduced pressure and the residue was purified by preparative layer chromatography (silica gel, 1.5 mm thickness, 16 x 100 cm plates; system: toluene / ethyl acetate 75:25). A zone visible under ultraviolet light with an Rf value of about 0.35 provides 3-n-butyloxy-7 / 3- (D-tert-butyloxycarbonylamino-of-phenylacetylamino) -3-cep-4-carboxylic acid diphenylmethyl ester it is purified several times by chromatography on silica gel and lyophilized from dioxane, [ _.alpha. ] _D @ ²⁰ = +11 ^DEG C. + - 1 DEG C. [c = 0.98, chloroform]; ultraviolet absorption spectrum (95% aqueous ethanol): λ _max = 264 nm (ε = 6100); infrared absorption spectrum (methylene chloride): characteristic bands at

2.88 μηι,

5,63 μΐη,

5.84 μη (inflex),

5.88 fim,

6,26 μΐη,

6,71 μη.

Example 12

To a solution of 0.258 g of 1-oxido-3-methylene-7/3-phenylacetylaminocepham-4α-carboxylic acid diphenylmethyl ester in 50 mL of methanol at -65 ° C was added a mixture of oxygen and ozone (20 mmol ozone / min) until permanent blue. color. 0.5 ml of dimethylsulfide was then added, stirred at -65 ° C for 20 minutes, at room temperature for 30 minutes and then evaporated under reduced pressure. The residue containing 1-oxido-7 (3-phenylacetylaminocepham-3-one-4 H -carboxylic acid diphenylmethyl ester) was taken up in 20 ml of methanol and stirred at 0 ° C with a solution of diazomethane in diethyl ether until a yellow color persisted. The residue was purified by preparative layer chromatography and the ultraviolet light zone (λ 52 = 254 nm with Rf 0 0.20 (system: ethyl acetate; iodine identification) was eluted with a 1: 1 mixture of acetone and methanol to give diphenylmethyl ester 1-oxido-3-methoxy-7β-phenylacetylamino-3-cephem-4-carboxylic acid, ultraviolet absorption spectrum (95% aqueous ethanol): λ _max = 276 nm (ε = 7500); infrared absorption spectrum (methylene chloride) : characteristic belts at

2,94 μη,

5.56 «m

5,81 fjm,

5.92 jum,

6,22 μηι a

6,67 μΐη.

The starting material can be prepared as follows:

A solution of 0.50 g of 3'-methylene-7/3-phenylacetylaminocepham-4H-carboxylic acid diphenylmethyl ester in 50 ml of methylene chloride, cooled to 0 ° C, is mixed with a solution of 0.19 g of 3-chloroperbenzoic acid in 10 ml of methylene chloride. Stir in an ice bath for 30 minutes under a nitrogen atmosphere. The reaction mixture was diluted with 100 ml of methylene chloride, washed twice with 50 ml of saturated aqueous sodium bicarbonate solution and 50 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on 50 g of silica gel. The methylene chloride containing 3-5% acetone was eluted with diphenylmethyl 1-oxido-3-methylene-7β-phenylacetylaminocepham-4α-carboxylic acid diphenyl ester which, after recrystallization from acetone / diethyl ether / hexane, had mp 172-175 ° C; [α] _D ²⁰ = -68 ° C (c = 0.925, chloroform); thin layer chromatography (silica gel; iodine identification): Rf ~ 0.25 (system: toluene / ethyl acetate 1: 1); ultraviolet absorption spectrum (95% aqueous ethanol): infrared absorption spectrum (methylene chloride): characteristic bands at

2.96, um,

5.60 μΐη,

5.74 f (m,

5,92 μΐη,

6,24 μηι,

6.63 μΐη a

9.60 μΐη.

Example 13

To a solution of 8.2 g of 7 / 3- (D-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-methylencepham-4α-carboxylic acid diphenylmethyl ester in 800 ml of methylene chloride cooled to -70 ° C was introduced for 34 minutes a stream of oxygen and ozone (0.49 mmol ozone / min), then 3.5 mL of dimethyl sulfide is added and stirred at -70 ^° C for one hour and at room temperature for two hours. After evaporation under reduced pressure, the oily residue containing diphenylmethyl ester 7 / 3- (D - # - tert -butyl-2-carboxylic acid-phenylacetylamino) -cepham-3-on-4-carboxylic acid is dissolved in 300 ml of benzene, mixed with 3, 28 g of 1-ethyl-3- (4-methylphenyl) -triazene and heated under reflux for one hour under a nitrogen atmosphere and then evaporated under reduced pressure. The residue is chromatographed on 360 g of silica gel, eluting with amorphous diphenylmethyl 3-ethoxy-7β- [Da-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-cephem-4-carboxylic acid amorphous diphenylmethyl ester, thin layer chromatography (silica gel): Rf ~ 0.28 (system: toluene / ethyl acetate 3: 1); ultraviolet absorption spectrum (95% aqueous ethanol): _λmax = 258 nm (ε = 7000) and _λmax = 264 nm (ε = - 6900); infrared absorption spectrum (methylene chloride): characteristic bands at

2,96 μΐη,

5,64 gm,

5.90 µm,

6.28 μΐη a

6.73)

Example 14

A solution of 15 g of 3-methylene-7 / 2- (D-tert-butyloxycarbonylamino-α-phenylacetylamino) -cepham-4α-carboxylic acid diphenylmethyl ester in 1500 ml of methylene chloride is treated with a mixture of oxygen at -65 ° C for 62 minutes. and ozone containing 0.5 mmol of ozone / min and then mixed with 8.7 ml of dimethylsulfide at -70 ° C. The residue containing crude 7β- (D-tert-butyloxycarbonylamino-1-phenylacetylamino) -cepham-3-one-4'-carbonylamino-1H-phenylacetylamino) -cepham-3-one-4H-carboxylic acid diphenylmethyl ester is dissolved in 350 ml of benzene and treated with 11 g of 1-benzyl-3- (4-methylphenyl) -triazene, then refluxed for 4 hours, washed with 100 ml of 2N aqueous hydrochloric acid and saturated aqueous sodium chloride solution after cooling; phase is dried over sodium sulphate and evaporated under reduced pressure is eluted on 650 g of silica gel with 3-benzyloxy-7 / 3- (D-os-tert-butyloxycarbonylamino) - N -phenylacetylamino) -3-cephem-4-carboxylic acid amorphous diphenylmethyl ester is uniform by thin layer chromatography. TLC (silica gel; iodine development): Rf ~ 0.34 (system: toluene / ethyl acetate 3: 1); | [Α] _D 20 = + 7 ° C ± 1 ° C (c = 0.97, chloroform); ultraviolet absorption spectrum (95% aqueous ethanol): λ _max = 258 nm (ε = 6800), and 264 nm (ε = 6800), and Amiex = 280 nm (ε = 6300); infrared absorption spectrum (methylene chloride): characteristic bands at

2,96 μΐίί,

5,63 μΐη,

5,88 μΐη,

6.26, um and

6,72 μΐη.

Example 15

A solution of 1.59 g of 7 / 2- (5-benzoylamino-5-diphenylmethoxycarbonylvalerylamino) -3-methylencepham-4α: -carboxylic acid diphenylmethyl ester in 150 ml of methylene chloride was cooled to -70 ° C and stirred vigorously for 12 minutes and 43 minutes. seconds introduces a mixture of ozone and oxygen containing 0.2 mmol ozone / min. and then 1 ml of dimethylsulfide is added. The reaction mixture was stirred at -70 ° C for 5 minutes and at room temperature for 30 minutes and then evaporated under reduced pressure. The residue, containing 7 / 2- (5-benzoylamino-5-diphenylmethoxycarbonylvalerylamino) -cepham-3-one-4-one carboxylic acid diphenylmethyl ester, is dissolved in 40 ml of methanol, cooled in an ice bath and mixed with a diazomethane solution in of diethyl ether until the yellow color persisted. The reaction mixture was evaporated under reduced pressure and the residue was chromatographed on 100 g of silica gel. Toluene / ethyl acetate 1: 1 was eluted with 7 / 2- (5-benzoylamino-5-diphenylmethoxycarbonylvaleroylamino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester as an amorphous product; thin layer chromatography (silica gel): Rf = 0.45 (system: toluene / ethyl acetate 1: 1); ultraviolet absorption spectrum (95% aqueous ethanol): λ, λ _{) ex} = 258 nm (ε = 7450), 264 nm (ε = 7050) and 268 nm (ε = 6700); infrared absorption spectrum (methylene chloride): characteristic bands at

5,65 fjm,

5,78 μπι,

6,03 μπι a

6,64 μΐη.

The starting material can be prepared as follows:

A solution of 50 g of cephalosporin C sodium in 1500 ml of a 10% aqueous solution of secondary potassium phosphate was diluted with 1200 ml of acetone and treated at 0 ^DEG C. with 21 g of benzoyl chloride. The reaction mixture was stirred at 0 ° C for 30 minutes and at 20 ° C for 45 minutes while maintaining the pH constant at 8.5 by adding 50% aqueous potassium tertiary phosphate solution. Evaporate to about half volume under reduced pressure, wash with ethyl acetate, acidify with 20% aqueous phosphoric acid to pH 2.0 and extract with ethyl acetate. The organic phase is dried and evaporated under reduced pressure; the residue was recrystallized from acetone to give N-benzoylcephalosporin C, mp 117-119 ° C; thin layer chromatography (silica gel): Rf = 0.37 (system: n-butanol / acetic acid / / water 75: 7.5: 21) and Rf = 0.08 (system: ethyl acetate / pyridine / acetic acid) water 62:

: 21: 6: 11.

223181

A solution of 4.7 g of N-benzoylcephalosporin C in 85 ml of a 0.5 M aqueous solution of secondary potassium phosphate and 9 ml of dimethylphosphoramide is stirred with 4.7 g of aluminum amalgam for 45 minutes at pH 6.0 and 45 ° C. The pH is kept constant by the addition of 20% aqueous phosphoric acid. 100 ml of ice are added, overlaid with cold ethyl acetate and concentrated phosphoric acid to pH 2.0. The mixture was saturated with sodium chloride, the organic layer was separated and the aqueous phase was washed twice with ethyl acetate. The combined organic extracts washed with saturated aqueous sodium chloride solution and dried over sodium sulfate are evaporated under reduced pressure and the residue is crystallized by addition of ethyl acetate. The reaction mixture was slowly diluted with 15 mL of ethyl acetate / hexane 2: 3, allowed to stand at -5 ° C for two hours, then filtered and recrystallized from a 1: 4 mixture of ethyl acetate and diethyl ether; There was obtained 7β- (5-benzoylamino-5-carboxyvalerylamino) -3-methylencepham-4α-carboxylic acid, m.p. 82-89 ° C (dec.). Thin layer chromatography (silica gel): Rf = 0.53 (system: n-butanol / acetic acid / water)

75: 7.5: 21) and Rf = 0.08 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11).

The aluminum amalgam used above is prepared as follows:

The mixture of 3.3 g of grit aluminum and 100 ml of 50% aqueous sodium hydroxide solution was shaken for 30 seconds and after decantation the remaining liquid was washed three times with 300 ml of water each time. The residue is treated with 130 ml of a 0.3% aqueous mercury chloride solution for 3 minutes and then washed three times with 300 ml of water each time. This entire treatment was repeated once more and the aluminum amalgam was finally washed three times with tetrahydrofuran. The product was transferred to a reaction vessel using about 15 mL of ethyl acetate.

A solution of 2.3 g of 7 / 3- (5-benzoylamino-5-carboxyvalerylamino) -3-methylencepham-4α-carboxylic acid in 25 ml of dioxane was added dropwise over 10 minutes to a solution of 2.5 g of diphenyldiazomethane in 10 ml of n-pentane. After stirring for 30 minutes at room temperature, the excess diphenyldiazomethane is quenched by the addition of a few drops of glacial acetic acid and the solution is evaporated under reduced pressure, the residue is chromatographed on 80 g of silica gel and eluted with diphenylmethyl 7 / 3- ( 5-benzoylamino-5-diphenylmethoxycarbonylvalerylamino) -3-methylencepham-4α-carboxylic acid, which is recrystallized from a mixture of methyl acetate and cyclohexane, mp 180-181 & C; (system: toluene / ethyl acetate 2: 1), ultraviolet absorption spectrum (95% aqueous ethanol): no characteristic bands, infrared absorption spectrum (methylene chloride): characteristic bands at

5,66 μΐη,

5,76 μΐη,

5,95 μτα,

6,03 μΐη,

6,64 μΠΙ,

6.70 Uin.

K i k 1 and d. 16

To a solution of 0.400 g of 7β- (D-tert-butyloxycarbonylamino-1-phenylacetylamino) -3-methylene-cefam-4α-carboxylic acid diphenylmethyl ester in 40 mL of cooled methylene chloride at 0 ° C was added a mixture of ozone and oxygen for 3.6 minutes. containing 0.21 mmol of ozone / min, then 0.5 mL of dimethyl sulfide is added and the solution is evaporated under reduced pressure. The residue, containing 7 / 3- (D-tert-butyloxycarbonylamino) - and phenylacetylamino) -cepham-3-one-4-carboxylic acid diphenylmethyl ester, was dissolved in 10 ml of methanol and treated with a solution of diazomethane in diethyl ether until a yellow solid persisted. color. The solution was evaporated under reduced pressure and the residue was subjected to preparative layer chromatography (silica gel; system: toluene / ethyl acetate 1: 1; ultraviolet identification λ = 254 nm) to give a mixture of diphenylmethyl ethyl 7β- (D-tert-butyloxycarbonylamino-af enylacetylamino) 3-Methylencepham-4α-carboxylic acid and diphenylmethyl 7 / 3- (D-tert-butyloxycarbonylamino-phenylacetylamino) -3-methoxy-2-cephem-4α-carboxylic acid, both having an Rf value of 0.55, then diphenylmethyl ester 7 (3- [D- tert -Butyloxycarbonylamino-phenylacetylamino) -3-methoxy-3-cephem-4-carboxylic acid having an Rf value of 0.45 and finally a 1/3-oxido-7 / 3- (D- .alpha.-tert-butyloxycarbonylamino-.alpha.-phenylacetylamino) -3-methoxy-3-cephem-4-carboxylic acid having an Rf value of 0.17 and diphenylmethyl ester of 1'-oxido-7 / 3- (Da-tert-butyloxycarbonylamino-.alpha.-phenylacetylamino) -3-Methoxy-3-cephem-4 carboxylic acid having an Rf value of 0.07.

Instead of 7 / 3- (D-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-methylencepham-4α-carboxylic acid diphenylmethyl ester, 7 / 3- (D-tert-butyloxycarbonylamino-a) 4-nitrobenzyl ester can be used as starting material in the above process. -phenylacetylamino) -3-methylencepham-4a-carboxylic acid or 7,3- (D-tert-butyloxycarbonylamino-xphenylacetylamino) -3-methylencepham-4a-carboxylic acid 2,2,2-trichloroethyl ester, obtained by sodium reaction salts of 7 / 3- (Da-tert-butyloxycarbonylumino-af enylacetylamino-3-methylencepham-4α-carboxylic acid with 4-nitrobenzyl bromide, or reactive mixed anhydrides 7β- (Da-tert-butyloxycarbonylamino-af enylacetylamino) -3-methylencepham -4a-carboxylic acids with 2,2,2-trichloroethanol, and 7 / 3- (Da-tert-butyloxycarbonylamino-a223101) via 4-nitrobenzyl ester

7-3- (D-tert-butyloxycarbonylamino-phenylacetylamino) -cepham-3-one-4 H -carboxylic acid, 2-phenylacetylamino) -cepham-3-one-4 H -carboxylic acid, optionally 2,2,2-trichloroethyl ester to give 4-nitrobenzyl 7β- (D-tert-butyloxycarbonylamino-4-phenylacetylamino) -3-methoxy-3-cephem-4-carboxylic acid, optionally

7β- (D-α-tert-Butyloxycarbonylamino-α-phenylacetylamino) -3-methoxy-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester.

Example 17

A solution of 0.250 g of 7/3-aminocepham-3-one-4-carboxylic acid 4-methylphenylsulphonate 4-methylphenylsulphonate which is found predominantly in the enolform of 7/3-amino-3-cephem-3-ol-4-carboxylic acid 4-methylphenylsulphonate 4-methylphenylsulphonate of the acid, in 10 ml of methylene chloride, was mixed with 0.063 ml of trimethylchlorosilane and 0.044 ml of pyridine and stirred at room temperature for 30 minutes and then cooled to 0 ° C. 0.088 ml of pyridine and 0.092 ml of phenylacetic acid chloride are added, left at 0 ° C for one hour and at room temperature for another hour, and then diluted with 5 ml of dioxane: water 1: 1 and stirred for 10 minutes. The reaction mixture is diluted with 50 ml of methylene chloride, the phases are separated, the organic phase is washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel. 7/3-Phenylacetylaminocephani-3-one-4H-carbonyl acid diphenylmethyl ester is eluted with methylene chloride; thin layer chromatography (silica gel): Rf ~ 0.55 (system: ethyl acetate / pyridine / water 85: 10: 5); ultraviolet absorption spectrum (95% aqueous ethanol): _λmax = 283 nm (ε = 4400); infrared absorption spectrum (methylene chloride): characteristic bands at

2.94 fim,

5,12 μΐη,

5,77 μΐη,

5.93 / tm,

6.21 / tm,

6.63 / tm.

Example 18

The following compounds can be prepared in an analogous manner from suitable starting materials:

7β- [D-tert-Butyloxycarbonylamino-α- (4-hydroxyphenyl) -acetylamino] -cepham-3-one-4'-carboxylic acid diphenylmethyl ester;

7β- [D-α-tert-Butyloxycarbonylamino-α- (2-thienyl) -acetylamino) -cepham-3-one-4 H -carboxylic acid diphenylmethyl ester;

7S- [D-α-tert-Butyloxycarbonylamino- N - (3-thienyl) -acetylamino] -cepham-3-one-4 H -carboxylic acid diphenylmethyl ester;

7β- [D-α-tert-Butyloxycarbonylamino-α- (2-furyl) -acetylamino] -cepham-3-one-4 H -carboxylic acid diphenylmethyl ester;

7β- [D-α-tert-Butyloxycarbonylamino-α- (4-isothiazolyl) -acetylamino] -cepham-3-one-4 H -carboxylic acid diphenylmethyl ester;

7β- [D-α-tert-Butyloxycarbonylamino-N- (1,4-cyclohexadienyl) -acetylamino [-cepham-3-one-4-carboxylic acid diphenylmethyl ester;

7β- (2-Thienyl) -acetylaminocepham-3-one-4 H -carboxylic acid diphenylmethyl ester;

7 / 3- (1-Tetrazolyl) -acetylaminocepham-3-one-4H-carboxylic acid diphenylmethyl ester;

7 / 3- (4-Pyridylthio) -acetylaminocepham-3-one-4S-carboxylic acid diphenylmethyl ester;

7β- (4-Amino-pyridinium-acetylamino) -cepham-3-one-4-carboxylic acid diphenylmethyl ester and 7β- [D-α- (2,2,2-trichloroethoxycarbonyloxy) -α-phenylacetylamino] -cepham-3-one diphenylmethyl ester -4-carboxylic acids.

The compounds prepared according to the present invention can be further processed as follows:

Example 19

A solution of 0.050 g of 7/3-phenylacetylaminocepham-3-one-4-carboxylic acid diphenylmethyl ester and 0.020 g of 1-methyl-3- (4-methylphenyl) triazene in 5 ml of benzene was refluxed for two hours. Purify under reduced pressure and purify the residue by thin layer chromatography (silica gel; 1 x 20 cm; System: toluene / ethyl acetate 3: 1). to give 3-methoxy-7/3-phenylacetylamino 3-cephem-4-carboxylic acid dilenylmethyl ester, ultraviolet absorption spectrum (ethanol): λ _max = 264 nm (ε = 6300); infrared absorption spectrum (methylene chloride): characteristic bands at

2.94 μπί,

5,83 μΐπ,

5.83 / im,

5.94 / rev,

6.26

6.68 / im,

Example 20

A solution of 0.50 g of 7/3-aminocepham-3-one-4-carboxylic acid diphenylmethyl ester 4-methylphenylsulphonate, found predominantly in enolform, i.e. as 7/3-amino-3-cephem-3- diphenylmethylsulphonate 4-methylphenylsulphonate of 4-carboxylic acid, in 25 ml of methanol, was treated at 0 ° with a solution of diazomethane in diethyl ether until a yellow color persisted. The reaction mixture was stirred in an ice bath for 10 minutes and then evaporated. The residue is chromatographed on silica gel. Toluene / ethyl acetate 2: 1 was eluted with oily diphenylmethyl 7 (3-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester); ethyl acetate]; ultraviolet absorption spectrum (ethanol): λ _max = 265 nm (ε = 6100); infrared absorption spectrum (methylene chloride): characteristic bands at

3,33 μπι,

5,63 μΐη,

5.81, um,

6.23. «M.

Further elution with ethyl acetate afforded oily diphenylmethyl 7 (3-dimethylamino-3-methoxy-3-cephem-4-carboxylic acid), thin layer chromatography (silica gel, iodine vapor evolution): Rf ~ 0.20 (system: ethyl acetate); absorption spectrum (ethanol): λ _max = 265 nm (ε = 5900); infrared absorption spectrum (methylene chloride): characteristic bands at

2,98 μπι,

3,33 μΐη,

5,62 μπι,

5.81, um,

6.24 μπι.

A solution of 0.253 g of D-α-tert-butyloxycarbonylamino-α- (1,4-cyclohexadienyl) -acetic acid in 75 ml of methylene chloride, cooled to 0 ° C, is stirred for 30 minutes under N 2 with 0.097 ml of N-methylmorpholine and 0.129 ml of isobutyl ester. chloroacetic acid, then cooled to -10 ° C and treated sequentially with 0.30 g of diphenylmethyl ester of 7 (3-amino-3-methoxy-3-cephem-4-carboxylic acid and 0.085 ml of N-methylmorpholine). 30 minutes at -10 ° C and 30 minutes at 0 ° C, 30 ml of water are added and the pH is adjusted to 7.9 with 40% aqueous potassium phosphate solution. The phases are separated, the aqueous solution is extracted with methylene chloride and the combined organic solutions are separated. The residue was purified by preparative layer chromatography (silica gel, system: diethyl ether, ultraviolet light identification λ = 254 nm, Rf ~ 0.39). thin layer chromatography 7β- [D - N-tert-butyloxycarbonylamino-α- (1,4-cyclohexadienyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester as an amorphous product, thin-layer chromatography layer (silica gel; diethyl ether identification): Rf ~ 0.39 (system: diethyl ether); [Α] ²⁰ D = + 1 ° ± 1 ° (c = 0.745, chloroform); Ultraviolet Absorption Spectrum (95% aqueous ethanol): _.lambda.max = 263 nm (ε = 6700), and i and _{F ex} = 280 nm (ε = 6300); infrared absorption spectrum (methylene chloride): characteristic bands at

2,96 μΐη,

5.64 / rev,

5.86 fim,

5.90 μη (inflex),

6.27 um,

6,73 μιη.

A mixture of 0.200 g of diphenylmethyl 7 (3- [Da-tert-butyloxycarbonylamino-α- (1,4-cyclohexadienyl) -acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, 0.5 ml of anisole and 10 ml of precooled of trifluoroacetic acid is stirred for 15 minutes at 0 ° C, then treated with 50 ml of cold toluene and evaporated under reduced pressure. The residue was stirred with diethyl ether, the powdered precipitate was filtered off and dried. The trifluoroacetic acid salt of 7- (3- [N-amino-N- (1,4-cyclohexadienyl) -acetylamino) -3-methoxy-3-cephem-4-carboxylic acid is dissolved in about 6 ml of water, pH solution is adjusted to 1.5 by addition of 2N hydrochloric acid and the aqueous solution is washed with 20 ml of ethyl acetate and adjusted to pH 5.0 by dropwise addition of a 20% solution of triethylamine in methanol. The resulting precipitate was filtered off, washed with acetone and diethyl ether and dried to give 7 / 3- [Da-amino-α- (1,4-cyclohexadienyl) acetylamino) -3-methoxy-3-cephem. -4-carboxylic acid as its inner salt, mp 170 ° C (dec.; Thin layer chromatography (silica gel, iodine identification)): Rf ~ 0.26 (system: n-butanol / acetic acid / water 67: 10) : 12), Rf ~ 0.58 (system: isopropanol / / formic acid / water 77: 4: 19); ultraviolet absorption spectrum: _.lambda.max = 267 nm (ε = 6100), 0.1 N hydrochloric acid _lllax and A = 268 nm (ε = 6600), 0.1 N aqueous sodium bicarbonate solution.

Example 21

256.3 g of 3-methoxy-7 (3- (D-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-tert-4-carboxylic acid diphenylmethyl ester) were mixed with a mixture of 250 ml of anisole in 1200 ml of methylene chloride and added at 0 ° C. 1200 ml of trifluoroacetic acid cooled to 0 DEG C. It is allowed to stand for 30 minutes at 0 DEG C. and the reaction mixture is diluted over 15 minutes with 1200 ml of a 1: 1 mixture of diethyl ether and petroleum ether cooled to 0 DEG C. Precipitated 3-methoxy-7-trifluoroacetate. - (D-Phenylglycylamino) -3-cep-4-carboxylic acid is filtered off, washed with diethyl ether, dried under reduced pressure and dissolved in 1900 ml of water. The yellowish-colored impurities are washed with 900 ml of ethyl acetate, the organic wash liquid is discarded and aqueous solution (pH ~ 1.5) was adjusted to pH 4.5 with 20% triethylamine in methanol

3-methoxy-7 (S- (diphenylglycylamino) -3-cephem-4-carboxylic acid crystallizes as a dihydrate as colorless needles and is filtered off after mixing with 1800 ml acetone and stirring at 0 ° C for 2 hours; mp 175-177 ° C (decomposition; 1 _D ²⁰ = + 138 ° ± 1 ° (c = 1; 0.1 N hydrochloric acid); ultraviolet absorption spectrum (0.1 N aqueous sodium hydrogen sulphite): λ _max = 265 nm (ε = 6500), infrared absorption spectrum (mineral oil): bands at

2,72 μϊΏ.,

2,87 / tm,

3,14 μπι,

3.65 μΐη,

5,68 μΐη,

5,90 μΐη,

6.18 jum,

6,27 μΓΠ,

6.37 um,

6.56 µm.

6.92 «m

7.16 / tm,

7,58 μπι,

7.74 / tm,

7,80 / tm,

8,12 μΐη,

8,30 / tm,

8,43 μΐη,

8.52 / tm,

8.65 μπι,

8,95 / tm,

9.36 / tm,

9.55 / tm,

9,70 μπι,

10.02 / tm,

10.38 / tm,

10.77 / tm,

11,70 / tm,

12.01 / tm,

12.15 / tm,

12.48 / tm,

12.60 / tm,

12.87 / tm,

13.45 / tm,

14.30 / tm;

microanalysis (C16H17O5N3S. 2 H2O; molecular weight 399.42): calculated:

C, 48.11; H, 5.30; N, 10.52; S, 8.03; found:

H, 5.27; N, 10.47; S. 8.00.

Example 22

A mixture of 0.06 g of 3-methoxy-7 (3-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester), 0.05 ml of anisole and 1 ml of trifluoroacetic acid is allowed to stand for one minute at room temperature and then evaporated under reduced pressure. The residue is taken up twice in a 1: 1 mixture of chloroform and toluene and chromatographed on 5 g of silica gel (about 5% water content), with methylene chloride containing 30 to 50% acetone eluting with amorphous 3-methoxy-7,3-phenylacetylamino-3- ultraviolet absorption spectrum (95% aqueous ethanol): λ _max = 259 nm (ε = 4970) and 265 nm (ε =

4950); infrared absorption spectrum (methylene chloride): characteristic bands at

3.03 / tm,

5,60 / tm,

5.74, ttm,

5.92 / tm,

6.24 / tm,

6.67 / tm.

Example 23

A mixture of 0.312 g of 3? -Hydroxy-7/3-phenylacetylamino-cefam-4? -Carboxylic acid diphenylmethyl ester in 15 ml of pyridine and 7 ml of acetic anhydride is allowed to stand at 0 DEG C. for 16 hours and after adding 50 ml of toluene under reduced pressure. evaporate. The residue was taken up in ethyl acetate, the organic solution was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography; A 100 cm silica gel plate is used and developed with a 1: 1 mixture of toluene and ethyl acetate. This gives 3β-acetyloxy-7/3-phenylacetylamino-cefam-4β-carboxylic acid diphenylmethyl ester with Rf = 0.47 which, after crystallization from a mixture of methylene chloride and pentane, mp 162-164 ° C; kV ° = + 55 ° ± 1 ° (c = 0.492, chloroform); ultraviolet absorption spectrum (95% ethanol); Λ _max = 253 nm (ε = 700), 258 nm (ε = 820) and 265 nm (ε = 660); infrared absorption spectrum (methylene chloride): characteristic bands at

2.96 um,

5.66 / tm,

5.77 / tm,

5.97 / tm

6.28 / tm,

6.71, «m.

A mixture of 0.150 g of diphenylmethyl _and 3-acetoxy-7 / S-fenylacetylaminocefam-4R-carboxylic acid and 5 ml of methylene chloride was treated with 0.1 ml of triethylamine and the reaction mixture was allowed to stand for 16 hours at room temperature. The reaction mixture is then diluted with 100 ml of methylene chloride, the organic phase is washed with 50 ml of 2 N hydrochloric acid and 50 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (2 cm 20 cm silica gel plates, system: toluene / ethyl acetate 3: 1). A slightly yellowish oil is obtained with Rf = 0.36 which is recrystallized from methylene chloride / hexane. 7-3-Phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester, mp 161-163 ° C, [α] D ²⁰ = + 30 ° ± 1 ° (c = 0.968, dioxane); thin layer chromatography (silica gel, identification in ultraviolet light and iodine vapors): Rf = 0.55 (system: toluene / acetone 4: 1), Rf = 0.35 (system: toluene / acetone 9: 1) and Rf = 0.40 (system: toluene / ethyl acetate 4: 1); ultraviolet absorption spectrum: λ _max = 258 nm (ε = 6100) and λ _min - 240 nm (ε = 5250) (methylene chloride) and λ _max = 259 nm (ε = 6050) and λ _min = = 239 nm (ε = 4950) (95% aqueous ethanol); infrared absorption spectrum; characteristic belts at

2.90 μΐη,

5.57 Rome,

5.76 µm,

5.91 μϊϊΐ,

6,09 μπί,

6,66 μΐη,

7,13 μπί,

8.12 μτη,

8,63 μΐη,

9,07 μΐη,

10,43 μτη,

12,22 μπί (methylene chloride),

3,01 μπί,

5,60 μΐη,

5,82 μπί,

6,04 μΐη,

6,08 μΐη (inflex),

6,51 μΐη,

7.13 μΐη (mineral oil).

A solution of 1.94 g of 7/3-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester in 100 ml of absolute methylene chloride is cooled to -15 ° C, mixed with 3.86 ml of absolute pyridine and 31.6 ml of 8% solution. of phosphorus pentachloride in methylene chloride, and the reaction mixture was stirred at -10 ° C for 30 minutes and at -5 ° C for a further 30 minutes. The gold-yellow solution is cooled to -20 ° C and 26.8 ml of absolute methanol is added so that the internal temperature does not exceed -10 ° C. The reaction mixture was stirred at -10 ° C for one hour and allowed to stand at 25-30 ° C for another hour. It is then treated with vigorous stirring with 80 ml of a 0.5 M aqueous solution of secondary potassium phosphate and the pH of the biphasic reaction mixture is adjusted to 2 by dropwise addition of 20% phosphoric acid. Stir for 20 minutes at room temperature and separate the phases. The aqueous solution was washed twice with methylene chloride, the combined organic solutions were washed twice with 20 ml portions of water each time and dried over anhydrous magnesium sulfate.

The solvent was removed under reduced pressure; The oily residue is applied to a column of 110 g of silica gel (5% water content). Phenylacetic acid methyl ester is eluted with methylene chloride and diphenylmethyl ester 7/384

The amino-3-cephem-4-carboxylic acid was eluted with methylene chloride containing 3% methyl acetate. The compound was dissolved in a small amount of methylene chloride, and the solution was treated with diethyl ether while warming, thereby crystallizing needle-like crystals which were washed with cold diethyl ether and dried. Mp 153-154 ° C; TLC (silica gel): Rf = 0.50 (system: toluene / acetone 4: 1), Rf = 0.65 (system: toluene / acetone 2: 1), Rf = 0.40 (system: toluene) [ethyl acetate 1: 1] and Rf = 0.33 (system: toluene / diethyl ether 1: 1); ultraviolet absorption spectrum: λ _max = 257 nm (ε = 8150) and λ _min equals 245 nm (ε = 7730) (methylene chloride) and λ _max - 255 nm (ε = 5500) and λ _min = 236 nm (ε = 4650 (95% ethanol); Infrared absorption spectrum: characteristic bands at

2,91 μπί,

2,97 «m

5,61 μΐη,

5,78 μΐη,

6.11 (tm,

7.14 μπί,

8.15 μΐη,

8,29 μη,

9.83 μη (methylene chloride) and at

2,99 μη,

5,65 μΐη,

5,77 μη,

6,08 μη,

7.14 μπί,

7,74 μπί,

7.84 μΐη,

8,08 μη,

8,53 μπί,

9.14 μπί,

9.85 μπί,

10.35 μπί (mineral oil).

0.380 g of 7/3-amino-3-cephem-4-carboxylic acid diphenylmethyl ester was covered with 2 ml of anisole and 8 ml of absolute trifluoroacetic acid, the clear solution was allowed to stand at room temperature for 10 minutes and then diluted with about 20 ml of absolute toluene. The mixture was evaporated under reduced pressure; the residue is co-evaporated twice with toluene to dryness and then suspended in 5 ml of methanol, 5 ml of diethyl ether and 0.5 ml of water. The pH of the suspension was adjusted to 3.5 by dropwise addition of a 5% solution of triethylamine in methanol; then stand in an ice bath for 30 minutes and filter the fine precipitate through a suitable glass frit. The light beige residue was washed on the filter with a mixture of methanol and methylene chloride, then diethyl ether and dried at 35 ° C under reduced pressure. The 7β-amino-3-cephem-4-carboxylic acid thus obtained forms a finely microcrystalline powder which decomposes at 215 ° C, thin layer chromatography (silica gel; iodine evolution): R f = 0.12 (system: n- butanol / acetic acid / water 67: 10: 23), Rf = 0.28 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6: 30) and Rf = 0.21

Pi (system: ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10); infrared absorption spectrum (mineral oil): characteristic bands at

3.12 / tm

3,80 / tm,

4.12 / tm (inflex)

4.92 / tm,

5.54 / tm

6.05 / tm (inflex),

6.19 / tm,

6.55 / tm

7.05 / tm,

7.42 / tm,

8.23 / tm,

8.79 / tm,

9.55 / tm

12.08 / tm,

12.69 / tm,

13.04 / tm.

A suspension of 0.070 g of 7 ₁ d-amino-3-cephem-4-carboxylic acid in 2 ml of absolute methylene chloride is treated with 0.031 triethylamine in 0.35 ml of methylene chloride, diluted with 5 ml of absolute tetrahydrofuran and stirred for 30 minutes, partially ultrasonically. bath.

Dissolve 0.102 g of tert-butyloxycarbonyl-D-phenylglycine in 5 ml of absolute methylene chloride, mix with 0.040 g of 4-methylmorpholine and dilute with 10 ml of acetone. The reaction mixture was cooled to -20 ° C and 0.060 g of isobutyl chloroformate was added with stirring and then allowed to react at -15 ° C for 30 minutes. After further cooling to -20 ° C, a milky suspension of triethylammonium salt of 7 (3-amino-3-cephem-4-carboxylic acid) is added and the reaction mixture is stirred at -15 ° C for 30 minutes, at 0 ° C for a further 30 minutes. It was then filtered, washed with acetonitrile, methylene chloride and diethyl ether, and the filtrate was evaporated to dryness, the residue was taken up in ethyl acetate and water and acidified with 5 M aqueous phosphoric acid to pH 2 with vigorous stirring and ice cooling. The organic phase is separated and washed four times with a small amount of saturated aqueous sodium chloride solution, the aqueous extracts are extracted with two portions of ethyl acetate and the combined organic extracts are dried over anhydrous magnesium sulphate and the solvent is removed under reduced pressure. First, unreacted tert-butyloxycarbonyl-D-c-phenylglycine methyl is eluted. lench chloride and methylene chloride containing increasing amounts of acetone and finally eluting with N - (D-tert-butyloxycarbonylamino-phenyylacetylamino) -3-cep-4-carboxylic acid, which is obtained in amorphous form; ultraviolet absorption spectrum (95% ethanol): λ _max = 252 nm (ε = 5100); infrared absorption spectrum (methylene chloride): characteristic bands at

5.61 / tm,

5.85 / tm,

5.92 / im,

6.12 / tm;

tlc (silica gel G; iodine vapor proof): Rf = 0.6 to 0.7 (system: n-butanol / acetic acid / water 44: 12: 44).

A solution of 0.02 g of 70- (Da-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-cephem-4-carboxylic acid in 3 ml of pure trifluoroacetic acid was allowed to stand at room temperature for 15 minutes. The solution obtained is evaporated on a rotary evaporator, 20 ml of a 1: 1 mixture of chloroform and toluene are added twice to the residue and evaporated to dryness to remove trifluoroacetic acid completely and then dried at 0.0133 Pa for 16 hours. To a solution of the obtained trifluoroacetic acid salt in water and methanol was added an equivalent amount of triethylamine, evaporated and the residue digested in methylene chloride. There was thus obtained 7 [beta] - (Daphenylglycylamino) -3-cephem-4-carboxylic acid as a yellowish amorphous powder. pyridine / acetic acid / water 40: 24: 6: 30) ultraviolet absorption spectrum (water): λ _max = 250 nm (ε = 4300).

Example 24

A mixture of 0.5 g of 3-n-butyloxy-7H-D-tert-butyloxycarbonylamino-α-phenylacetylamino-3-carboxylic acid 4-carboxylic acid, diphenylmethyl ester, 1 ml of anisole and 15 ml of trifluoroacetic acid is left to leave. After standing for 15 minutes at 0 ° C, it is diluted with 200 ml of cold toluene and evaporated under reduced pressure. The residue is stirred in diethyl ether and the powdered colorless residue is filtered off, washed with diethyl ether and dried under high vacuum. There was thus obtained 3-n-butyloxy-7H- (diphenylglycylamino) -3-cephem-4-carboxylic acid trifluoroacetate salt which was dissolved in 5 ml of water and washed twice with 10 ml of ethyl acetate each time and the pH of the aqueous phase. The solution was evaporated to dryness under reduced pressure, the residue was taken up in acetone and diluted with diethyl ether to the base to give 3-n-butyloxy-76- (Da-phenylglycylamino) as a crystalline precipitate. -3-cephem-4-carboxylic acid in the form of the inner salt and filtered, mp 141-142 ° C, thin layer chromatography: (silica gel): R f = 0.21 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11) ultraviolet absorption spectrum (0.1 N aqueous sodium bicarbonate): λ _max = 267 nm (ε = 7300).

Example 25

A mixture of 2.70 g of diphenylmethyl _{3-ethoxy-7-one} 6- (Da-terc.butyloxykarbonylamino- « '

Phenylacetylamino-3-cephem-4-carboxylic acid, 6.7 ml of anisole and 67 ml of formic acid are stirred for one hour at room temperature, then diluted with 200 ml of toluene, evaporated under reduced pressure and dried under high vacuum. , digest with diethyl ether and filter. 3-Ethoxy-7 / 3- (D-N-phenylglycylamino) -3-cephem-4-carboxylic acid formate is obtained as a brownish powder, which is dissolved in 8 ml of water, the aqueous phase is acidified with 2-N aqueous hydrochloric acid, It is washed with 10 ml of ethyl acetate, the pH is adjusted to about 5 with 10% triethylamine in methanol and the solution is evaporated under reduced pressure. The residue is taken up in a small amount of methanol and amorphous pale yellow 3-ethoxy-7, (3- (diphenylglycylamino) -3-cephem-4-carboxylic acid as an internal salt) is precipitated by addition of methylene chloride and diethyl ether: thin layer chromatography (silica gel): Rf ~ 0.17 (system: ethyl acetate / / pyridine / acetic acid / water 62: 21: 6: 11) ultraviolet absorption spectrum (0.1 M aqueous sodium bicarbonate): λ = 263 nm (ε = 5500j).

Example 26

A mixture of 4.6 g of 3-benzyloxy-7H / 3- (D-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-tert-4-carboxylic acid diphenylmethyl ester, 10 ml of anisole and 100 ml of trifluoroacetic acid is stirred at 0 for 15 minutes. ° C and then diluted with 250 ml of cooled toluene, evaporated under reduced pressure and dried under high vacuum. The product was triturated with diethyl ether to give 3-benzyloxy-7 (3- (diphenylglycylamino) -3-cephem-4-carboxylic acid 3-benzyloxy-trifluoroacetate) which was filtered off and dissolved in a 9: 1 mixture of water and methanol. is adjusted to 1.7 with 2 N aqueous hydrochloric acid and the solution is washed twice with 30 ml of ethyl acetate each time (the organic washes are discarded) and the pH of the aqueous phase is adjusted to 5 by addition of a 10% solution of triethylamine in methanol. The residue is stirred with a mixture of acetone and diethyl ether, the powdered product is filtered off and washed with acetone and diethyl ether to give 3-benzyloxy-7 / 3- (D-i-phenylglycylamino) -3-cephem-4-carboxylic acid as zwitteriont, thin layer chromatography (silica gel: Rf = 0.17 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 1; ultraviolet absorption spectrum (0.1 N aqueous sodium bicarbonate)): A _max = 266 nm (ε = 6500).

Example 27

A solution of 0.263 g of diphenylmethyl 7 (3- (5-benzoylamino-5-diphenylmethoxycarbonylvalerylamino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester) in 13 ml of methylene chloride was cooled to -10 ° C and treated with 0.132 ml of pyridine. and 3.52 ml of an 8% solution of phosphorus pentachloride in methylene chloride The reaction mixture was stirred at -10 ^° C for one hour, then cooled to -30 ° C, 2.2 ml of methanol cooled to -30 ° C were quickly added and stirred The reaction mixture is treated with 6.5 ml of a 0.5 M aqueous solution of primary potassium phosphate, stirred for 5 minutes at room temperature and the phases are separated. The aqueous phase is washed with methylene chloride, the combined methylene chloride phases are washed with concentrated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure, the residue is dissolved in methanol and mixed with diethyl ether until slightly turbid. 7 (3-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester), thin layer chromatography (silica gel: Rf = 0.17 (system: ethyl acetate, iodine evolution)): ultraviolet absorption spectrum (95% aqueous ethanol) _Λmax = 258 nm (ε = 5700); infrared absorption spectrum (dioxanj: characteristic bands at

2,87 μΐη,

5,62 μτη,

5.85 ^ m,

6.26 μτη.

P, k k 1 and d 28

A solution of 0.63 g of 3-methoxy-7j (3- (D-tert-butyloxycarbonylamino-α-phenylacetylamino) -2-tert-4-carboxylic acid diphenylmethyl ester) in 25 methylene chloride cooled to 0 ° C is mixed with solution 0, 20 g

Of 3-chloroperbenzoic acid in 5 ml of methylene chloride. The mixture was stirred at 0 ° C for 30 minutes, 50 mL of methylene chloride was added and washed successively with 25 mL of saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution respectively. Organic phase. It is dried over sodium sulphate and evaporated under reduced pressure. The residue was recrystallized from methylene chloride / diethyl ether. There was thus obtained 1-oxido-3-methoxy-7β- (D-α-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester as colorless needles, mp 172-175 ° C; thin layer (silica gel): Rf = 0.44 (system: ethyl acetate, iodine vapor evolution; ultraviolet abrasion spectrum (ethanol: λ _max = 277 nm (ε = 7200); infrared absorption spectrum (methylene chloride j: characteristic bands at

2,96 μτη,

5,56 μτη,

5.71> μΐη,

5,83 μτη,

5,90 μϊη,

6.27 μϊη,

6,67 μϊη.

A solution of 1.30 g of 1-oxido-3-methoxy-7, (3- (D-, α-tert-butyloxycarbonyl) -228101 nylamino-α-phenylacetylamino) -3-cep-4-carboxylic acid diphenylmethyl ester in 30 ml of dimethylformamide cooled to 2.80 g of phosphorus trichloride were added to -10 ° C in the absence of air, after standing for 1 minute, the reaction mixture was poured onto a mixture of ice and an aqueous solution of secondary potassium phosphate, and the aqueous mixture was extracted twice with 100 ml of ethyl acetate. The residue is chromatographed on silica gel, eluting with diethyl ether, amorphous diphenylmethyl 3-methoxy-7 / 3- (D-or-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-cep-4-amine. carboxylic acid, which according to TLC pure substance, Rf - 0.39 (system: diethyl ether; development vapor iodinated f «i = _D L ^C ± 1 ° (c = 0.981, chloroform); ultraviolet absorption spectrum ( ethanol): _.lambda.max = 264 nm ( = 6300) IR absorption spectrum (methylene chloride): characteristic bands at

2,94 μϊη,

5,62 μϊη,

5,84 μτη,

5,88 μϊη,

6.25 / tm,

6.70 / <m.

Claims (24)

A process for the preparation of 7S-aminocepham-3-one-4-carboxylic acid derivatives of the general formula I wherein: ^And R represents hydrogen or an amino-protecting group R ^A of up to 18 carbon atoms, 'and R ^1b represents hydrogen or an acyl group of Ac containing up to 18 carbon atoms, or R ^a and R ^b together represent a divalent amino-protecting group having up to 18 carbon atoms, R ^A is a residue forming, together with the carbonyl grouping -C (= Oj- protected carboxyl group having up to 19 carbon atoms as well as 1-oxides of compounds of formula I, or salts of such compounds having salt-forming groups, characterized in. That the derivative of general cefamu of formula II wherein R ^a, R ^b and R 2 ^A have the meanings given below In the ΪΝ1L EZU of formula I, or in 1 oxide of the compound, or in a salt of such a salt-forming compound, oxidatively cleaves the methylene group at the 3-position, preferably by ozone followed by reductive ozonide cleavage formed as an intermediate. . id of this compound is isolated in free form or in salt form. 2. A process according to claim 1, wherein the starting material is a compound of formula (II) in which R &lt; a &gt; is an amino protecting group R &lt; ^1A &gt; free functional groups optionally protected, R ^1b represents hydrogen and R ^2A represents an etherified hydroxyl group of up to 19 carbon atoms that forms with the group -C (= O) an esterified carboxyl group, with any functional groups present in the esterified carboxyl group of formula -C (= O) —R 2 ^A are optionally protected. 3. Method according to claim 2, characterized in that as the starting material used is a compound of formula II wherein R2 represents ^A or lower alkoxy having 1 to 4 carbon atoms or nitro-substituted, phenyl (lower jalkoxyskupinu such with up difenylmethoxyskupinu And R 1 ^and R ^1b have the meanings given in point 2. 4. A process according to claim 2, wherein R @ 2 ^A is an optionally halogenated lower alkoxy group having from 1 to 7 carbon atoms, such as an alpha-polybranched lower alkoxy group having from 1 to 7 atoms. alkyl, for example tert-butyloxy or a 2-halo (lower jalkoxyskupinu having 1-7 carbon atoms such as 2,2,2-trichloroethoxy, and R ^a and R ^b are as defined in throwing the second 5. A process according to claim 1, wherein the intermediate intermediate ozonide is converted to a compound of formula I, for example, by treatment with catalytically activated hydrogen, a heavy metal reducing agent, a heavy metal alloy or a heavy metal amalgam in the presence of a hydrogen donor. salts in the presence of a hydrogen donor or by treatment with a reducing active organic compound such as formic acid, a reducing active sulfide derivative or a reducing active organic phosphorus derivative. 6. The process of claim 1, wherein the intermediate intermediate ozonide is converted to a compound of formula I by reduction, for example, by treatment with catalytically activated hydrogen, a heavy metal reducing agent, a heavy metal alloy or a heavy metal amalgam in the presence of a hydrogen donor. inorganic salts in the presence of a hydrogen donor or by treatment with a reducing active organic compound, such as formic acid, or with a reducing agent, which can readily be converted to an oxide derivative. 7. A process according to claim 6, characterized in that suitably substituted ethylene derivatives such as tetracyanethylene, sulfide derivatives such as dialkyl sulfides, for example dimethylsulfide, suitable phosphorus compounds such as phosphines are used as reducing agents which can be easily converted to oxide. phosphites or phosphites of phosphorous acid or suitable nitrogenous bases such as heterocyclic nitrogen bases of aromatic character, for example of the pyridine type, such as pyridine. 8. Method according to one of claims 1 to 5, characterized in that the starting materials used cefamu derivatives of formula II according to claim 1 or their 1-oxides and the salts of such compounds having salt-forming groups, in which R represents hydrogen ^and or acyl radical having up to 18 carbon atoms, R ^b is hydrogen or R ^a and R ^b together represent an oxo-3-aza-l, 4-butylene radical having up to 18 carbon atoms, which is preferably in the 2 position and optionally in the position 4 is substituted, and R 2 ^A is optionally halogen-substituted lower alkoxy of 1 to 7 carbon atoms, optionally lower alkoxy of 1 to 4 carbon atoms or nitro substituted phenyl (lower) alkoxy of 1 to 7 carbon atoms in the lower alkoxy moiety, acyloxy C 1 -C 19, tri (lower C 1 -C 7 lower alkylsilyloxy) or optionally C 1 -C 7 lower alkyl , lower alkylene of 1 to 7 carbon atoms, oxa (lower) alkylene of 1 to 7 carbon atoms, hydroxy, amino, (lower jalkylamino of 1 to 7 carbon atoms, mono- or di (lower jalkylamino) of C1-C7 lower alkyl radicals substituted amino or hydrazino. Process according to one of Claims 1 to 7, characterized in that cefam derivatives of the general formula are used as starting materials II according to claim 1 or their 1-oxides and the salts of such compounds having salt-forming groups, ^and wherein R represents hydrogen or an acyl radical having up to 18 carbon atoms, R ^b represents hydrogen and R2 ^and is defined as in point 8. 10. Method according to one of claims 1 to 5, characterized in that the starting materials used cefamu derivatives of formula II according to claim 1 or their 1-oxides, salts of such compounds having salt-forming groups, ^and wherein R represents hydrogen or an acyl radical having up to 18 carbon atoms, R ^b is hydrogen or R ^a and R ^b together represent the 2-position or lower alkoxy having 1 to 4 carbon atoms or hydroxy substituted phenyl substituted oxo-3-aza-l, 4-butylene having up to 18 carbon atoms, which comprises in position 4 or two lower alkyl radicals having 1 to 4 carbon atoms, and R2 ^and is lower alkoxy having 1-7 carbon atoms, 2-halo (lower) alkoxy having 1-7 carbon atoms , phenacyloxy, 1-phenyl (lower) C 1 -C 4 alkoxy in the C 1 -C 3 alkoxy group, optionally lower C 1 -C 4 alkoxy, or phenyl substituted with nitro lower radicals, lower alkanoyloxymethoxy with C 1 -C 7 lower alkanoyl, lower C 1 -C 7 lower alkoxycarbonyloxy or C 1 -C 7 lower alkanoyloxy. Process according to one of Claims 1 to 7, characterized in that cefam derivatives of the general formula are used as starting materials II according to claim 1 or their 1-oxides and the salts of such compounds súlitvornými groups ^and in which R denotes hydrogen or an acyl radical having up to 18 carbon atoms, R ^b represents hydrogen and R2 ^and has the meaning as defined in the tenth 12. Method according to one of claims 1 to 5, characterized in that the starting materials used cefamu derivatives of formula II according to claim 1, or 1-oxides of these compounds, and salts of such compounds having salt-forming groups, wherein R ^b is hydrogen, ^and R is hydrogen, acyl having up to 18 carbon atoms of formula B O R _and - (X) _m -CH = CR _b (B) wherein R _a represents a phenyl group, a hydroxyphenyl group or a hydroxychlorophenyl group, in which the hydroxyl groups are optionally protected by acyl radicals having 1 to 8 carbon atoms, furthermore a thienyl group, a pyridyl group, an aminopyridinium group, furyl group, isothiazolyl group or tetrazolyl group , X is oxygen or sulfur, m is 0 or 1 a, R _b is hydrogen or, when m is 0, optionally represents an protected amino, carboxy, sulfo or hydroxy group, or an O- (lower) C 1 -C 7 alkylphosphono group in a lower alkyl radical or O, O'-di (lower-alkylphosphono having 1 to 7 carbon atoms in the lower alkyl radicals or a 5-amino-5-carboxyvaleryl radical in which the amino and carboxy groups are optionally protected, and ^And RZ is lower alkoxy having 1-7 carbon atoms, 2-halo (lower) alkoxy having 1-7 carbon atoms or lower alkoxy optionally having 1 to 4 carbon atoms or nitro substituted difenylmethoxyskupinu. 13. Method according to one of claims 1 to 5, characterized in that the starting materials used are derivatives of 3-cefamu formula II according to claim 1 or their 1-oxides, salts of such compounds having salt-forming groups, wherein R ^b is hydrogen, R ^a is hydrogen, acyl having up to 18 carbon atoms of formula B according to claim 12, wherein R _a is phenyl, hydroxyphenyl or hydroxychlorfenylovou, where in these radicals may be hydroxyl substituents also protected by acyl radicals having 1 to 8 carbon atoms or is 2-thienyl, or 5-amino-5-karboxyvalerylovou group wherein the amino and carboxy is optionally protected, and wherein X, m, and R _b ^and R 2 have the meanings given in point 12. Process according to one of Claims 1 to 7, characterized in that cefam derivatives of the general formula II according to item 1 or their 1-oxides are used as starting materials, furthermore salts of such compounds with salt-forming groups, wherein R ^1b represents hydrogen, R 1 ^a is hydrogen, an acyl group of up to 18 carbon atoms of formula B according to item 12, wherein R _a is a phenyl group, a hydroxyphenyl group or a hydroxychlorophenyl group, wherein in such residues the hydroxyl substituents are optionally protected with acyl residues of 1 to 8 carbon atoms; is thienyl, pyridyl, aminopyridinium, furyl, isothiazolyl, tetrazolyl or 1,4-cyclohexadienyl, or is 5-amino-5-carboxyvaleryl in which the amino and carboxy groups are optionally protected and in which X, m and R _b are as defined in paragraph 12 above, and R 'is lower alkoxy 1 to 7 carbon atoms, 2-halo (lower) C 1 -C 7 alkoxy, optionally lower C 1 -C 4 alkoxy, or nitro substituted diphenylmethoxy or tri (lower C 1 -C 4 alkylsilyloxy) lower alkyl radicals. 15. Method according to one of claims 1 to 5, characterized in that the starting materials used cefamu derivatives of formula II according to claim 1 or 1-oxides of these compounds, salts of such compounds having salt-forming groups, in which R ^a is hydrogen, an acyl group of up to 18 carbon atoms of formula B according to item 12, wherein R _a represents a phenyl group, X represents oxygen, m represents 0 or 1, and R _b represents hydrogen or, if m represents 0, represents an optionally protected amino or hydroxy group; A 5-amino-5-carboxyvaleryl group in which the amino and carboxy group is optionally protected, R ^1b is hydrogen and R ^2A is optionally in the 2-position halogen-substituted lower alkoxy of 1 to 7 carbon atoms or optionally lower alkoxy of 1 to 4 carbon atoms substituted diphenylmethoxy. 16. Method according to one of claims 1 to 7, characterized in that the starting materials used cefamu derivatives of formula II according to claim 1 or 1-oxides of these compounds, salts of such compounds having salt-forming groups, in which R ^a is hydrogen, an acyl radical having up to 18 carbon atoms of formula b according to claim 12, wherein Ra _represents phenyl, 4-hydroxyphenyl, 2-thienyl, 4-isothiazolyl, or 1,4-cyclohexadienyl, X, m and R _b have the meanings or a 5-amino-5-carboxyvaleryl radical in which the amino and carboxy group is optionally protected, R ^1b is hydrogen, R ^2A is optionally substituted at the 2-position by halogen substituted lower alkoxy of 1 to 7 carbon atoms, optionally lower a (C 1 -C 4) alkoxy substituted diphenylmethoxy group or a tri (lower C 1 -C 4 alkylsilyloxy) lower alkyl radical. Process according to one of Claims 1 to 3 and 5 to 7, characterized in that 7 / 3- (D-α-amino-αR _and -acetylamino) -3-methylencepham-4 H -carboxylic acid diphenylmethyl ester is used as starting material. an acid wherein R _a is phenyl, 4-hydroxyphenyl, 2-thienyl or The 1,4-cyclohexadienyl and amino groups are preferably present in protected form, or salts of such compounds with salt-forming groups. Process according to one of Claims 1 to 3 and 5, characterized in that diphenylmethyl 7,3-phenylacetylamino-3-methylencepham-4'-carboxylic acid diphenylmethyl ester is used as starting material. 19. A process according to any one of Claims 1 to 3 and 5 to 7, characterized in that the compound mentioned in point 18 is used as the starting material. Process according to one of Claims 1 to 3 and 5, characterized in that the N-diphenylmethyl ester of N - (D-α-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-methylencepham-4? -Carboxylic acid is used as starting material. Process according to one of Claims 1 to 3 and 5 to 7, characterized in that the compound mentioned in point 20 is used as the starting material. Process according to one of Claims 1 to 3 and 5, characterized in that 7 (2-amino-3-methylencepham-4H-carboxylic acid diphenylmethyl ester) is used as the starting material. Process according to one of Claims 1 to 3 and 5 to 7, characterized in that the compound described in point 22 or a salt thereof is used as the starting material. Process according to one of Claims 1 to 3 and 5 to 7, characterized in that diphenylmethyl ester of 7β- (5-benzoylamino-5-diphenylmethoxycarbonylvalerylamino) -3-methylencepham-4 H -carboxylic acid is used as starting material.