AU486993B2 - 7b-amino-cepham-3-on-4-carboxylic acid compounds and processes for their manufacture - Google Patents

Description

57,385/73 The present j.nventioI relates to oxo compounds,

a mirin m acid especially 7p o-cephar -3-one--carboxylic

compounds of tho formula a 11 N S

0= R

or an acyl group Ac of a wherein Ra represents hydrogen represents carboxylic acid, Rb represents hydrogen, and R2 carbonyl grouping a radical which together with the or ketal derivatives thereof forms a protected carboxyl group, a glycol, a thioglycol or a formed by the 3-oxo group with I, or dithioglycol, 1-oxides of compounds of the formula salt-forming groups, and salts of such compounds having

also processes for their manufacture. and the The present cepham-3-one compounds with the correspon- corresponding 1-oxides are in equilibrium 3 the formula ding cephem- -ol compounds of

a*

Rb/

0 N doi (Ia)

0=0- -R contain a double bond in hich the 3,4-position.

the 3,4-position. which contain a double bond in

2 486,993

57,385/73

An acyl group Ac of a carboxylic acid, not

ccunting any protecting groups contained therein, has up

to 18 carbon atoms, and is the acyl radical of an

optionally substituted aliphatic, cycloaliphatic, cyclo-

aliphatic-aliphatic, aromatic, araliphatic, heterocyclic

and heterocyclic-aliphatic carboxylic acid (including formic

acid) and the acyl radical of a carbonic acid half-derivative.

A protected carboxyl group of the formula A is an esterified carboxyl group, or an optionally

substituted carbamoyl or hydrazino carbonyl group, wherein A R 2 has up to 18 carbon atoms.

Such group RA is a hydroxyl group etherified by

a aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic

or araliphatic radical, which is optionally substituted, or

an heterocyclic or heterocyclic-aliphatic radical.

The group RA further represents an organic silyl-

oxy radical or a hydroxyl group etherified by a silyloxy or

stannyloxy group which is substituted by 1 to 3, optionally

substituted hydrocarbon radicals with up to 18 carbon atoms,

and optionally by halogen. A A radical R2 which forms a carbamoyl group with a

grouping is an optionally substituted amino group

wherein substituents represent optionally substituted

monovalent or

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7,38 5/73

cycloaliphatic-aliphatic, bivalent aliphatic, cycloaliphatic, with up to aromatic and araliphatic hydrocarbon radicals or heterocyclic- 18 carbon atoms, or represent heterocyclic

carbon atoms, and/or repre- aliphatic radicals with up to 18 hydroxyl, sent free hydroxyl, or etherified or esterified radicals have the wherein the etherifying or esterifying up to 18 carbon atoms, abovementioned meanings and contain

acyl radicals, of carboxylic acids and of carbonic or represent 18 carbon atoms. acid half-derivatives, with up to group of the In a substituted hydrazinocarbonyl

formula one or both nitrogen atoms are substituted

aliphatic, by optionally substituted monovalent or bivalent

cycloaliphatic, cycloaliphatic-aliphatic, aromatic or

18 carbon atoms araliphatic hydrocarbon radicals with up to radicals or by heterocyclic or heterocyclic-aliphatic of with up to 18 carbon atoms and/or by acyl radicals

organic carboxylic acids or of carbonic acid half-derivatives

with up to 18 carbon atoms.

The general concepts used in the preceding and

following description have the following

meanings:

An aliphatic radical, including the aliphatic

radical of a carboxylic acid,is an optionally substituted

monovalent or divalent aliphatic hydrocarbon radical,

or lower especially lower alkyl, as well as lower alkenyl

alkinyl, which contains up to 7, preferably up to 4, carbon

4 4 86,9 9 3

7,385 /73 atoms. Such radicals are unsubstituted, monosubstituted, disubstituted or polysubstituted by free, etherified or esterified hydroxyl or mercapto groups, including lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkyl- thio or optionally substituted phenylthio, phenyl-lower

alkylthio, heterocyclylthio or heterocyclyl-lower alkylthio, optionally substituted lower alkoxycarbonyloxy or lower alkanoyloxy, or halogen, or by oxo, nitro, optionally substi- tuted amino, including lower alkylamino, di-lower alkylamino, lower alkyleneamino, oxa-lower alkyleneamino, aza-lower

alkyleneamino, acylamino, including lower alkanoylamino, lower alkoxycarbonylamino, halogeno-lower alkoxycarbonyl- amino, optionally substituted phenyl-lower alkoxycarbonylamino,

optionally substituted carbamoylamino, ureidocarbonylamino

or guanidinocarbonylamino and sulphoamino which is optionally present in the form of a salt, including the form of an alkali metal salt, azido, acyl, including lower alkanoyl or benzoyl, carboxyl, carboxyl present in the form of a salt, esterified carboxyl, including lower alkoxycarbonyl, car-

bamoyl, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl and optionally substituted ureidocarbonyl or guanidinocar-

bonyl, or nitrile, sulpho, sulphamoyl or sulpho present in the form of a salt, or optionally O-monosubstituted or

O,0-disubstituted phosphono, wherein substituents represent optionally substituted lower alkyl, phenyl or phenyl-lower

alkyl, or 0-unsubstituted or 0-monosubstituted phosphono in the form of a salt, including the form of an alkali metal salt.

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57,385 /73

A cycloaliphatic or cycloaliphatic-aliphatic

radical, including the cycloaliphatic or cycloaliphatic-

aliphatic radical in an appropriate organic carboxylic acid

is an optionally substituted, monovalent or bivalent, cyclo-

aliphatic or cycloaliphatic-aliphatic hydrocarbon radical,

including monocyclic, bicyclic and polycyclic cycloalkyl,

or cycloalkenyl, or cycloalkyl- or cycloalkenyl-lower alkyl

or -lower alkenyl, wherein cycloalkyl contains up to 12,

preferably 3-6, ring carbon atoms, whilst cycloalkenyl con-

tains up to 12, preferably 5 or 6, ring carbon atoms and

1 to 2 double bonds, and the aliphatic part of a cycloalipha-

tic-aliphatic radical contains up to 7, preferably up to 4,

carbon atoms. The above cycloaliphatic or cycloaliphatic-

aliphatic radicals are unsubstituted, or mono-substituted,

disubstituted or polysubstituted by optionally substituted

aliphatic hydrocarbon'radicals, including the abovementioned

optionally substituted lower alkyl groups or, like the above-

mentioned aliphatic hydrocarbon radicals, by functional

groups.

An aromatic radical, including the aromatic

radical of a carboxylic acid, is an optionally substituted

aromatic hydrocarbon radical, including a monocyclic, bi-

cyclic or polycyclic aromatic hydrocarbon radical, especially

phenyl, further biphenylyl or naphthyl, which is optionally

monosubstituted, disubstituted or polysubstituted like the

abovementioned aliphatic and cycloaliphatic hydrocarbon

radicals.

4 8 6,993

57 385/73 An araliphatic radical, including the araliphatic

radical in carboxylic acid, is an optionally substituted

aliphatic hydrocarbon radical which is optionally substituted

and possesses up to three optionally substituted monocyclic,

bicyclic or polycyclic aromatic hydrocarbon radicals, and

includes phenyl-lower alkyl, phenyl-lower alkenyl, and

phenyl-lower alkinyl, it being possible for such radicals to

contain 1-3 phenyl groups and to be optionally monosubstituted,

disubstituted or polysubstituted in the aromatic and/or

aliphatic part like the abovementioned aliphatic and cyclo-

aliphatic radicals.

Heterocyclic groups, including heterocyclic or

heterocyclic-aliphatic groups in carboxylic acids, are

monocyclic, bicyclic or polycyclic, azacyclic, thiacyclic,

oxacyclic, thiazacyclic, thiadiazacyclic, oxazacyclic, diaza-

cyclic, triazacyclic or tetrazacyclic radicals of aromatic

character, and partially or wholly saturated heterocyclic

radicals of this nature, which radicals are unsubstituted,

monosubstituted, disubstituted or polysubstituted like the

abovementioned cycloaliphatic radicals. The aliphatic part

in heterocyclic-aliphatic radicals has the meaning indicated

for the corresponding cycloaliphatic-aliphatic or araliphatic

radicals.

The acyl radical of a carbonic acid half-deriva-

tive is the acyl radical of an half-ester, wherein the organic

radical of the ester group represents an optionally substi-

tuted aliphatic, cycloaliphatic, aromatic or araliphatic

7 4 86,9 93

57 385./73 hydrocarbon radical or a heterocyclic-aliphatic radical, and includes the acyl radical of a lower alkyl half-ester of carbonic acid which is optionally substituted in the a- or p-position, of a lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl half-ester of carbonic acid which is optionally substituted in the organic radical. Acyl radicals of a carbonic acid half-ester are furthermore radicals of

lower alkyl half-esters of carbonic acid, in which the lower alkyl part contains a heterocyclic group, including one of the abovementioned heterocyclic groups of aromatic character, wherein both the lower alkyl radical and the heterocyclic group are optionally substituted. The acyl radical of a carbonic acid half-derivative is furthermore an optionally N-substituted carbamoyl group, including an optionally halogenated N-lower alkylcarbamoyl group. An etherified hydroxyl group is optionally substituted lower alkoxy, wherein substituents represent free, etherified or esterified hydroxyl groups, including lower alkoxy or halogen, lower alkenyloxy, cycloalkyloxy or optionally substituted phenyloxy, heterocyclyloxy or hetero- cyclyl-lower alkoxy, and optionally substituted phenyl-lower alkoxy. An optionally substituted amino group is amino, lower alkylamino, di-lower alkylamino, lower alkylene- amino, oxa-lower alkyleneamino, thia-lower alkyleneamino, aza-lower alkyleneamino, hydroxyamino, lower alkoxyamino,

lower alkanoyloxyamino, lower alkoxycarbonylamino or lower alkanoylamino.

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57,.38.5/73

An optionally substituted hydrazino group is

hydrazino, 2-lower alkylhydrazino, 2,2-di-lower alkyihydrazi-

no, 2-lower alkoxycarbonylhydrazilo or 2-lower alkanoylhydrazi- no.

Lower alkyl includes methyl, ethyl, n-propyl,

isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl and n-heptyl; lower alkenyl includes vinyl, allyl, isopropenyl, 2- or 3-methallyl and 3-butenyl; lower alkinyl includes propargyl and 2-butinyl. Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl,

cyclohexyl or cycloheptyl or adamantyl; cycloalkenyl is cyclo- propenyl, 2- or 3-cyclopentenyl,' 1, 2- or 3-cyclohexenyl,

3-cycloheptenyl or 1 ,4-cyclohexadienyl. Gycloalkyl-lower alkyl or -lower alkenyl includes cyclopropyl-, cyclopentyl-, cyclohexyl- and cycloheptyl-methyl, or -1,2-ethyl,

and -1,3-propyl, -vinyl and -allyl; cycloalkenyl-

lower alkyl or -lower alkenyl includes 2- and 3-cyclo-

pentenyl-, 2- and 3-cyclohexenyl- and 2- and 3-cyclo-

heptenyl-methyl, and -1,2-ethyl, and

-1,3-propyl, -vinyl and -allyl. Naphthyl is 1- or 2-naphthyl; biphenylyl includes 4-b iphenylyl. Phenyl-lower alkyl or phenyl-lower alkenyl inclu-.

des benzyl, 1- and 2-phenylethyl, 2- and 3-phenyl-propyl,

diphenylmethyl, trityl, styryl and cinnamyl, and naphthyl- lower alkyl includes I- and 2-naphthylmethyl.

9 4 86,9 93

,57,385 /73 Hleterocyclic radicals are optionally substituted

heterocyclic radicals of aromatic character, including mono-

cyclic, monoazacyclic, monotbiacyclic or monooxacyclic radicals. Such radicals are pyrryl, including 2-pyrryl and 3-pyrryl, pyridyl, including 3- and 4-pyridyl and

pyridinium, thienyl, including 2- and 3-thienyl, furyl,

including 2-furyl, bicyclic monoazacyclic, monooxacyclic or monothiacyclic radicals, including indolyl,-for example 2- or 3- indolyl, quinolinyl, for example 2- or 4-quinolinyl, isoquinolinyl, for example 1-isoqu-inolinyl, benzfuranyl, for example 2- or 3-benzofuranyl, and benzothienyl, for example

2- or 3-benzothieny)., monocyclic diazacyclic, triazacyclic, tetrazacyclic, oxazacyclic, thiazacyclic or thiadiazacyclic radicals, including imidazolyl, for example 2-imidazolyl, pyrimidinyl, for example 2- or 4-pyrimidinyl, triazolyl, for example l-,2,4-triazol-. -yl, tetrazolyl, for example-1- or 3

tetrazolyl, oxazolyl, for example 2-oxazolyl, isoxazolyl, for example 3- or 4-isoxazolyl, thiazolyl, for example 2-thiazoltyl, isothiazolyl, for example 3- or 4-isothiazolyl, and 1,2,4- and 1,3,4-thiadiazolyl, for example 1,2,4-thia- diazol-3-yl or l,3,4-thiadiazol-2-yl, or bicyclic. diaza-

cyclic, oxazacyclic or thiazacyclic radicals, including

benzimidazolyl, for example 2-benzimidazolyl, benzoxazo-

lyl, for example 2-benzoxazolyl, and benzthiazolyl, for

example 2-benzthiazolyl. Partially or wholly saturated radicals include tetrahydrothienyl, such as 2-tetrahydro-

thienyl, tetrahydrofuryl, such as 2-tetrahydrofuryl, and

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57,385 /73

piperidyl, for example 2- or 4-piperidyl. Heterecyclic-

aliphatic radicals are lower alkyl or lower alkenyl

containing the heterocyclic groups mentioned above. The

abovementioned heterocyclyl radicals are unsubstituted or

substituted by optionally substituted aliphatic or aromatic

hydrocarbon radicals, including lower alkyl, such as methyl,

and phenyl which is optionally substituted by halogen such

as chlorine, including phenyl and 4-chlorophenyl, or which

is substituted like the aliphatic hydrocarbon radicals by

functional groups.

Lower alkoxy includes methoxy, ethoxy, n-propoxy,

isopropoxy, n-butoxy, isobutoxy, sec.-butoxy, tert.-butoxy,

n-pentoxy and tert.-pentoxy. These groups are optionally

substituted by halogen and include then 2,2,2-trichloro-

ethoxy, 2-chloroethoxy, 2-bromoethoxy and 2-iodoethoxy.

Lower alkenyloxy includes vinyloxy and allyloxy, lower alkylene-

dioxy includes methylenedioxy, ethylenedioxy and isopropyli-

denedioxy, cycloalkoxy includes cyclopentyloxy, cyclohexyl-

oxy and adamantyloxy, phenyl-lower alkoxy includes benzyloxy,

1- and 2-phenylethoxy, diphenylmethoxy and 4,4'-dimethoxy-

diphenylmethoxy and heterocyclyloxy or heterocyclyl-lower

alkoxy includes pyridyl-lower alkoxy, such as 2-pyridyl-

methoxy, furyl-lower alkoxy, such as furfuryloxy, or thienyl-

lower alkoxy, such as 2-thenyloxy.

Lower alkylthio includes methylthio, ethylthio

and n-butylthio, lower alkenylthio includes allylthio, and

phenyl-lower alkylthio includes benzylthio, whilst mercapto

11 48 6,9 9 3

57,385 /73 groups etherified by heterocyclyl radicals or heterocyclyl-

aliphatic radicals include pyridylthio, for example 4-pyridyl- thio, inidazolyltihio, f'or example 2-imidazolylthio, thiazolyl-

thio, for example 2-thiazolylthio, 1,2,4- or 1,.3,4-thiadiazolyl-

thio, for example 1,2,4-thi-adiazol-3-ylthio or 1,3,4-thia- diazol-2-ylthio, and tetrazolylthio, for example tetrazolylthio. Esterified hydroxyl groups are halogen, that is

fluorine, chlorine, bromine or iodine, lower alkanoyloxy, including acetoxy and propionyloxy; lower alkoxycarbonyloxy, including methoxycarbonyloxy, ethoxycarbonyloxy and tert.- butoxycarbonyloxy, 2-hal'ogeno-lower .alkoxycarbonyloxy, including 2,2 ,2-trichloroethoxycarbolyloxy, 2-bromoethoxy-

carbonyloxy and 2-iodoethoxycarbonyloxy, or arylcarbonyl- methoxycarbonyloxy, including phenacyloxycarbonyloxy. Lower alkoxycarbonyl includes methoxycarbonyl,

ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert. butoxycarbonyl and tert.-pentoxycarbonyl. N-Lower alkyl- or N,N-di-lower alkyl-carbamoyl

includes N-methylcarbamoyl, N-ethylcarbamoyl, N,N-.dimethyl- carbamoyl and N ,N-diethylcarbamoyl, whilst N-lower alkyl- suiphamoyl includes N-methylsulphamoyl and N,N-dimethyl- sulphamoyl. -A carboxyl or suipho present in the form of an

alkali metal salt includes a carboxyl or sulpho present in the form of a sodium or potassium salt. Lower alkylamino or'di-lower alkylamino includes methylamino, ethylamino, dimethylamino and diethylamino,

12 4 8 6,9 93

57385/7 lower alkyleneamino includes pyrrolidino or piperidino, oxa-lower alkyleneamino includes morpholino, thia-lower alkyleneamino includes thiomorpholino, and aza-lower

alkyleneamino includes piperazino or 4-methylpiperazino. Acylamino includes carbamoylamino, lower alkylcarbamoyl- amino, such as methylcarbamoylamino, ureidocarbonylamino,

guanidinocarbonylamino, lower alkoxycarbonylamino, for example methoxycarbonylamino, ethoxycarbonylamino or tert.- butoxycarbonylamino, halogeno-lower alkoxycarbonylanino,

such as 2,2 ,2-trichloroethoxycarboflylamino, phenyl-lower alkoxycarbonylamino, such as 4-methoxybenzyloxycar bonyl- amino, lower alkanoylamino, such as acetylamino or propionyl- amino, phthalimido, and sulphoamino optionally present in the form of a salt, including the form of an alkali metal

salt, for example the form of a sodium salt or ammonium salt. Lower alkanoyl includes formyl, acetyl, pr6pionyl and pivaloyl. 0-Lower alkyl-phosphono includes 0-methyl- and

0-ethyl-phosphono, 0,0 '-di-lower alkyl-phosphono includes 0,0'-dimethyl-phosphono and 0,0'-diethylphosphono, 0-phenyl- lower alkyl-phosphono includes 0-benzyl-phosphoflo, and 0-lower alkyl-0'-phenyl-lower alkyl-phosphono includes 0-benzyl-0' -methyl-phosphono.

Lower alkenyloxycarbonyl includes vinyloxycarbo- nyl, whilst cycloalkoxycarbonyl and phenyl-lower alkoxycar- bonyl include adamantyloxycarbonyl, benzyloxycarbonyl,

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57,385 /73

4-methoxy-bcnzyloxycarbonyi, dipherny iniethoxycarbonyl and

a-4-biphenylyl-a-methyl-ethoxycarbonyl. Lower alkoxycarbonyl,

wherein the lower alkyl moiety is substituted by a mono- cyclic, monoazacyclic, monooxacyclic or monothiacyclic group, includes furyl-lower alkoxycarbonyl, such as furfuryloxy- carbonyl, or thienyl-lower alkoxycarbonyl, such as 2-thenyl- oxycarbonyl. 2-Lower alkyihydrazino and 2,2-di-lower alkyl-

hydrazino include 2-methylhydrazino and 2,2-dimethylhydrazino, 2-lower alkoxycarbonylhydrazino includes 2-methoxycarbonyl-

hydrazino, 2-ethoxycarbonylhydrazino or 2-tert.-butoxycarbonyl- hydrazino and lower alkanoylhydrazino includes 2-acetyl- hydrazino.

An acyl group Ac in particular represents an acyl radical of an organic carboxylic acid. with up to 18 carbon atoms,contained'in a naturally occurring cr bicsynthetically, semi-synthetically or tota-l-synthetically, obtainable, preferably pharmacaokgically active, Nacyl derivative of a 6-amino-penam-3- carboxylic acid compound or 7-anino-3-cephem-4-carboxylic acid compound, or represents an easily removable acyl radical, including such of a carbonic acid half-derivative.

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

14 4 8.6,9 93

57.385 73

R 0 In R III. R I or an optionally wherein n represents O and R denotes hydrogen hydrocarbon radical or substituted cycloaliphatic or aromatic cha- heterocyclic radical of aromatic an optionally substituted or an hydroxyl or mercapto group racter, esterified or etherified 1, group, or wherein n represents optionally substituted amino an optionally substituted aliphatic, RI represents hydrogen or aromatic or araliphatic cycloaliphatic, cycloaliphatic-aliphatic., substituted heterocyclic hydrocarbon radical or an optionally wherein the heterocyclic or heterocyclic-aliphatic radical, and/or a quaternary nitro- radical possesses aromatic character or esterified hydroxyl or mercapto gen atom, a free, etherified an carboxyl group, an acyl group, group, a free or esterified each group or an azido group and optionally substituted amino I and RII represents hydrogen, or wherein of the radicals R aliphatic, an optionally substituted n represents 1, R denotes aromatic or aralipha- cycloaliphatic, cycloaliphatic-aliphatic, an optionally substituted hetero- tic hydrocarbon radical or radical, wherein the hetero- cyclic or heterocyclic-aliphatic I denotes free, character, R cyclic radical has aromatic or mercapto group, including esterified or etherified hydroxyl free. substituted amino group, a a halogen atom, an optionally O-mono- sulpho group, an optionally or esterified carboxyl or phosphono group or an azido substituted or O,0'-disubstituted 1, hydrogen, or wherein n represents group and RIII represents

4 86,9 93

57. 38 5 /73

each of the radicals R and RT denotes an etherified or

esterified, hydroxyl group or a free or esterified carboxyl III group, and R rcpresents hydrogen, or wherein n represents 1, R denotes hydrogen or an optionally substituted aliphatic,

cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphati 11 hydrocarbon radical and R and R togethelr represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic aliphatic or araliphatic hydrocarbon radical which is bonded to the carbon atom by a double bond, or wherein n represents 1. and

R denotes an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic--aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituited heterocyclic or heterocyclic-aliphatic radical, wherein heterocyclic radicals

possess aromatic character, R I denotes an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic--aliphatic, aromatic or araliphatic hydrocarbon radical and R 1 denotes hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical. In the abovementioned acyl groups of the formula A, for example, n represents 0 and R represents hydrogen or a cycloalkyl group with 5-7 ring carbon atoms which is optionally substituted in the 1-position by optionally protected amino, including amino, acylamino, wherein acyl represents the acyl radical of a carbonic acid half-ester, including a lower alkoxy- carbonyl, 2-halogeno-lower alkoxycarbonyl or phenyl-lower alkoxy- carbonyl. radical, or a sulphoamino group which is optionally

16 48 6,9 93

57,385 /73 present in the form of a salt, including the form of an

alkali metal salt', a phenyl, naphthyl or tetrahydronaphthyl

group which is optionally substituted by hydroxyl, lower

alkoxy, including methoxy, acyloxy, wherein acyl represents

the acyl radical of a carbonic acid half-ester,.including

a lower alkoxycarbonyl, 2-halogeno-lower alkoxycarbonyl or

phenyl-lower alkoxycarbonyl radical, and/or halogen, for

example chlorine, a heterocyclic group which is optionally

substituted by lower alkyl, including methyl and/or by

phenyl or phenyl substituted by halogen, including chlorine,

including a 4-isoxazolyl group, or an amino group which is

N-substituted by an optionally substituted lower alkyl radical,

including a lower alkyl radical containing halogen, for

example chlorine, or n represents 1, R represents a lower

alkyl group which is optionally substituted by halogen,

including chlorine, by'phenyloxy which is optionally substi-

tuted, including phenyloxy containing hydroxyl, acyloxy,

wherein acyl has the abovementioned meaning, and/or halogen,

including chlorine, or by optionally protected amino and/or

carboxyl, including a 4-amino-4-carboxyl-butyl radical which

has an optionally protected amino and/or carboxyl group,

including a silylated, such as tri-lower alkylsilylated,

including trimethylsilylated, amino or acylamino, including

a lower alkanoylamino, halogeno-lower alkanoylamino or

phthaloylamino group, and/or a silylated, including a tri-

lower alkylsilylated,for example trimethylsilylated, car-

boxyl group or a carboxyl group which is esterified

-17 4 86,9 93

57 385 /73 by lower alkyl, 2-halogeno-lower alkyl or phenyl-lower alkyl, including diphenylmethyl, or represents a lower alkenyl group, a phenyl group which is optionally substituted, including a phenyl group which optionally contains hydroxyl which is

acylated as indicated above, and/or halogen, including

chlorine, and optionally protected amino-lower alkyl, inclu- ding aminomethyl, which is optionally protected as indicated above, or phenyloxy which is optionally substituted, inclu- ding phenyloxy which possesses hydroxyl which is optionally acylated as indicated above, and/or halogen, including chlorine, or represents a pyridyl group, including 4-pyridyl

group, pyridinium group, including 4-pyridinium group, thienyl group, including 2-thienyl group, furyl group, inclu- ding 2-furyl group, imidazolyl group, including 1-imidazolyl

group, or tetrazolyl group, including 1-tetrazolyl group, which are optionally substituted by lower alkyl, such as methyl, or by amino or aminomethyl which are optionally protected as indicated above, or represents an optionally substituted lower alkoxy group, for example a methoxy group, a phenyloxy group which is optionally substituted, inclu- ding a phenyloxy group which contains optinally protected hydroxyl, including hydroxyl acylated as indicated above,

and/or halogen, including chlorine, or represents a lower alkylthio group, including n-butylthio group, or lower alkenylthio group, including allylthio group, a phenylthio,

pyridylthio, including 4-pyridylthio, 2-imidazolylthio, 1,2,4-triazol-3-ylthio, 1,3,4-triazol-2-ylthio, 1,2,4-thia-

18 48 6.9 93

57.38 5/73 diazol-3-ylthio, including 5-methyl-1l,2,4-thiadiazol-3-ylthio,

1,3,4-thiadiazol-2-ylthio, including 5-methyl-1,3,4-thiadia- zol-2-ylthio, or 5-tetrazolylthio, tetrazolylthio group, which are optionally substituted by lower alkyl, including methyl, or represents a halogen atom,

including chlorine or bromine atom, a carboxyl group, a lower alkoxycarbonyl group, including methoxycarbonyl or ethoxycarbonyl, nitrile or carbamoyl which is optionally N-substituted by lower alkyl, including methyl, or phenyl, or represents an optionally substituted lower alkanoyl group, including an acetyl or propionyl group, or a benzoyl group, II III or an azido group, and R and R represent hydrogen, or n

represents 1, R represents lower alkyl or a phenyl, furyl, including 2-furyl, thienyl, including 2- or 3-thienyl, or isothiazolyl, including a 4-isothiazolyl group which is

optionally substituted.by hydroxyl which is optionally acyla- ted as indicated above, and/or by halogen, including chlorine, or represents a 1,4-cyclohexadienyl group, R 1represents

optionally protected or substituted amino, including amino, acylamino, including lower alkoxycarbonylamino, 2-halogeno- lower alkoxycarbonylamino or optionally substituted phenyl- lower alkoxycarbonylamino including phenyl-lower alkoxycar-

bonylamino which contains lower alkoxy, including methoxy, or. nitro, including tert.-butoxycarbonylamino, 2,2,2-trichloro- ethoxycarbonylamino, 4-mrethoxybenzyloxycarbonylamino or

diphenylmethyloxycarbonylamino, arylsulphonylamino, including 4-methylphenylsulphonylamino, tritylamino, arylthioamino, in-

19 -4 86,9 93

57,38 5 73 cluding nitrophenylthioamino, including 2-nitrophenylthio-

amino, or tritylthioamino or 2-propylideneamino which is

optionally substituted, including 2-propylideneamino which

contains lower alkoxycarbonyl, including ethoxycarbonyl, or

lower alkanoyl, including acetyl, including 1-ethoxycarbonyl-

2-propylideneamino, or optionally substituted carbamoylamino,

including guanidinocarbonylamino, or a sulphoamino group

which is optionally present in the form of a salt, including

in the form of an alkali metal salt, an azido group, a car-

boxyl group which is optionally present in the form of a salt,

including in the form of an alkali metal salt, or in a pro-

tected form, including an esterified form, including a lower

alkoxycarbonyl group, for example a methoxycarbonyl group or

ethoxycarbonyl group, or as a phenyloxycarbonyl group, inclu-

ding a diphenylmethoxycarbonyl group, a nitrile group, a

sulpho group, a hydroxyl group, acyloxy, including formyloxy,

lower alkoxycarbonyloxy, 2-halogeno-lower alkoxycarbonyloxy,

phenyl-lower alkoxycarbonyloxy, phenyl-lower alkoxycarbonyl-

oxy which contains lower alkoxy, including methoxy, or nitro,

including tert.-butoxycarbonyloxy, 2,2,2-trichloroethoxycar-

bonyloxy, 4-methoxybenzyloxycarbonyloxy and diphenylmethoxy-

carbonyloxy, or optionally substituted lower alkoxy, inclu-

ding methoxy and phenyloxy, a 0-lower alkyl-phosphono group

or 0,0'-di-lower alkyl-phosphono group, including 0-methyl-

phosphono or O,0'-dimethylphosphono, or a halogen atom,

including chlorine and bromine, and R represents hydrogen,

or n represents 1, R and R I I each represent halogen, inclu-

20 4 86.9 93

57,385 /n ding bromine, or lower alkoxycarbonyl, including methoxy-

carbonyl, and R represents hydrogen, or n represents 1,

R I represents a phenyl, furyl, thienyl, or isothiazolyl,

or such group substituted by hydroxyl, acyloxy as indicated

above, and/or by halogen, including chlorine, or represents

a 1,4-cyclohexadienyl group, R represents aminomethyl

which is optionally protected as indicated above, and R

represents hydrogen, or n represents 1 and each of the groups

RI R and R represents lower alkyl, including methyl.

Such acyl radicals Ac include formyl, cyclo-

pentylcarbonyl, a-aminocyclopentylcarbonyl or a-amino-cyclo-

hexylcarbonyl (with an optionally substituted amino group,

including a sulphoamino group optionally present in the form

of a salt, an amino group which is substituted by an acyl

radical which can be split off easily on treatment with an

acid agent or by reduction or hydrolytically, by an acyl

radical of a carbonic acid half-ester, including tert.-butoxy-

carbonyl, 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl,

2-iodoethoxycarbonyl, phenacyloxycarbonyl, phenyl-lower alkoxy-

carbonyl containing methoxy, or nitro, including 4-methoxy-

benzyloxycarbonyl and diphenylmethoxycarbonyl, an acyl

radical of a carbonic acid half-amide, including carbamoyl,

N-lower alkylcarbamoyl, N-methylcarbamoyl, and an amino group

substituted by trityl, 2-nitrophenylthio, 4-methylphenyl-

sulphonyl or l-ethoxycarbonyl-2-propylidene), 2,6-dimethoxy-

benzoyl, 5,6,7,8-tetrahydronaphthoyl, 2-methoxy-l-naphthoyl,

2-ethoxy-l-naphthoyl, benzyloxycarbonyl, hexahydrobenzyloxy-

21 48 6,9 93

57-385/7

carbonyl, 5-meth-yl-3-pheny1.-4-isoxazolylcarbonyl, 3- (2-

chiorphienyl) -5-mcthyl-4- isoxazolylcarbonyl, 3- chioro-

phenyl) -5-methiyl-4- isoxazolylcarbonyl, 3- (2 ,6-dichlorophenyl)

5-methyl-4- isoxazolylcarbonyl, 2-chloroethylamilocarbonyl,

acetyl, propionyl, buty7ryl, pivaloyl, hexanoyl, octanoyl, acrylyl, crotonyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl,

butyithioacetyl, allyithioacetyl, methylthioacetyl, chioro-

acetyl, bromoacetyl, dibromoacetyl, 3-chloropropiolyl, 3-broinopropi-onyl, aminoacetyl or

(with an amino group which is optionally substituted as indicated above), azidoacetyl, carboxyacetyl,

methoxycarbonylacetyl, ethoxycarbonylacetyl, bis-rnothoxy-

carbonylacetyl, N-phenylcarbamoylacetLyl, cyanoacetyl, a-cyano-

propionyl, 2-cyano-3, 3-dimothyl--acrylyl* phenylacetyl, aX-

bromophenylacetyl, a-azido--phenylacetyl, 3-chiorophenylacetyl, 2-.or 4-arinomethyiphenyl-acetyl (with an amino group which is

optionally substituted as indicated above), phenacyl- carbonyl,. phienoxyacetyl, 4-trifluorometlylplenoxyac etyl,

benzyloxyacectyl, phenylthioac etyl, brogiophenylthioacetyJ-, 2-

phenoxyprop ionyl, a-phenoxcyphcnylacetyl, a-rnetho'xypheny.-

acetyl, a-ethoxy-phenylacetyl, a-metloxy-3, 4-dichlorophenyl-

acetyl, a-cyano-phenylacetyl, 'especially phenylglycy., 4- hydroxyphienyiglycyl, 3-chloro-4--hydroxyphenylglyCyl,

dichloro-4-hydroxy-phenylglycyl, a-amino--a- 4-cyclohexa-

dionyl )-ac etyl, a-aminornethyi-a-phienylacet yl or a-hydroxy- phonylacotyl, (it being possible, in these, radicals, for an

22 4228-6.9 9 3

57,385 /73

amino group which is present to be optionally substituted as indicated above, and/or an aliphatic and/or phenolic-

ally bonded hydroxyl group which is present to be optionally protected analogously to the amino group, including by a suitable acyl radical, especially by formyl or by an acyl radical of a carbonic acid half-ester), or a-0-methyl-

phosphono-phenylacetyl or a-0,0-dimethyl-phosphono-phenyl- acetyl, benzylthioacetyl, benzylthiopropionyl, a-carboxy- phenylacetyl (with a carboxyl group which is optionally functionally modified as indicated above), 3-phenylpropionyl,

3-(3-cyanophenyl)-propionyl, 4-(3-methoxyphenyl)-butyryl, 2- pyridylacetyl, 4-amino-pyridiniumacetyl (optionally with an amino group which is substituted as indicated above), 2-thienylacetyl, 3-thienylacetyl, 2-tetrahydrothienylacetyl, 2-furylacetyl, 1-imidazolylacetyl, 1-tetrazolylacetyl, a-carboxy-2-thienylacetyl or a-carboxy-3-thienylacetyl

(optionally with a carboxyl group which is functionally modified as indicated above), a-cyano-2-thienylacetyl, a-amino-a-(2-thienyl)-acetyl, a-amino-a-(2-furyl)-acetyl or a-amino-a-(4-isothiazolyl)-acety (optionally with an amino group which is substituted as indicated above), a-sulphophenylacetyl (optionally with a sulpho group which is functionally modified like the carboxyl group), 3-methyl- 2-imidazolylthioacetyl, 1,2,4-triazol-3-yl-thioacetyl,

1,3,4-triazol-2-ylthioacetyl, 5-methyl-1,2,4-thiadiazol-3-

ylthioacetyl, 5-methyl-1,3,4-thiadiazol-2-yl-thioacetyl or

23 4 8 6,9 93

57..38 5 73

An easily removable acyl radical Ac includes

an acyl radical of a half-ester of carbonic acid which can

be split off by reduction, for example on treatment with a

chemical reducing agent, or by treatment with acid, for

example with trifluoroacetic acid, and includes a lower

alkoxycarbonyl group which preferably has multiple branching

and/or an aromatic substituent on the carbon atom in the

a-position to the oxy group, or a methoxycarbonyl group which

is substituted by benzoyl radicals, or a lower alkoxycarbonyl

radical which is substituted in the p-position by halogen

atoms. Such groups are tert.-butoxycarbonyl, tert.-pentoxy-

carbonyl, phenacyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl,

2-iodoethoxycarbonyl, or a radical which can be converted

into the latter, including 2-chloroethoxycarbonyl and 2-bromo-

ethoxycarbonyl, polycyclic cycloalkoxycarbonyl, including

adamantyloxycarbonyl, optionally substituted phenyl-iower

alkoxycarbonyl, including a-phenyl-lower alkoxycarbonyl,

wherein the a-position is polysubstituted, including diphenyl-

methoxycarbonyl and a-4-biphenylyl-a-methyl-ethoxycarbonyl,

furyl-lower alkoxycarbonyl, including a-furyl-lower alkoxy-

carbonyl, including furfuryloxycarbonyl.

An etherified hydroxyl group R 2 forms, together

with the carbonyl grouping, an esterified carboxyl group

which is splittable or convertible into another functionally

modified carboxyl group, including into a carbamoyl or A hydrazinocarbonyl group. Such a group R2 is, lower

"alkoxy, such as methoxy, ethoxy, n-propoxy

24 48 6,9 93

57.385 /73 or isopropoxy, which, together with the carbonyl grouping, forms an esterified carboxyl group, which can easily be con- verted, especially in 2-cephem compounds, into a free carboxyl group or into another functionally modified carboxyl group.

An etherified hydroxyl group R2A which together with a grouping forms an esterified carboxyl group which

can be split particularly easily represents 2- halogeno-lower alkoxy, wherein halogen has an atomic weight above 19. Such a radical forms, together

with the grouping, an esterified carboxyl group which can easily be split on treatment with chemical reducing agents under neutral or weakly acid conditions, for example with zinc in the presence of aqueous acetic acid, or an esterified

carboxyl group which can easily be converted into such a

group and includes 2,2,2-trichloroethoxy or. 2-iodo- ethoxy, also 2-chloroethcxy or 2-bromoethoxy, which can easily be converted into the latter.

An etherified hydroxyl group R2 which together with the grouping represents an esterified carboxyl group which can also be split easily on treatment with chemical reducing agents under neutral or weakly acid conditions, for example on treatment with zinc in the presence of aqueous acetic acid, and also on treatment with a suitable nucleophilic reagent,- for example sodium thiophenolate, is an arylcarbonylmnethoxy

group, wherein aryl in particular represents an optionally substituted phenyl group, and preferably phenacyloxy.

25 486.9 93

57,38 5/73 The group R2 further represents an arylmethoxy group wherein aryl denotes a monocyclic, substituted/ aromatic hydrocarbon radical. Such a radical forms, together with the grouping, an esterified carboxyl group which can easily be split on irradiation,

preferably with ultraviolet light, under neutral or acid conditions. An aryl radical in such an arylmethoxy group is in particular lower alkoxyphenyl, for example methoxyphenyl (wherein methoxy above all is in the 4- and/or and/or above all nitrophenyl (wherein nitro is preferably in the 2-position). Such radicals are, in particular, lower alkoxy-benzyloxy, for example methoxy-benzyloxy, and/or nitro- benzyloxy, above all 3- or 4-methoxy-benzyloxy, benzyloxy, 2-nitro-benzyloxy or 4,5-dimethoxy-2-nitro-benzyloxy. An etherified hydroxyl group R2 further represents a radical which, together with the grouping, forms an Sesterified carboxyl group which can easily be split under acid conditions, for example on treatment with trifluoroacetic acid Sor formic acid. Such a radical is a methoxy group in which methyl is polysubstituted by optionally substituted aliphatic or aromatic

hydrocarbon radicals, such as lower alkyl, for example methyl, and/or phenyl, or is monosubstituted by a carbocyclic aryl group possessing electron-donating substituents crbyaheterocydlic group of aromatic character possessing oxygen or slphur as aring

mnember, or in which methyl denotes a ring member in a poly- cycloaliphatic hydrocarbon radical or denotes the ring member which represents the a-position to the oxygen or sulphur atom in an oxacycloaliphatic or thiacycloaliphatic radical.

26 4 86,9 93

57.385/73 Preferred polysubstituted methoxy groups of

this nature are tert.-lower alkoxy, including tert.-butoxy

or tert.-pentoxy, optionally substituted diphenylmethoxy,

including diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy,

and 2-(4-biphenylyl)-2-propoxy, whilst a methoxy group which

contains the abovementioned substituted aryl group or the

heterocyclic group includes a-lower alkoxy-phenyl-lower

alkoxy, such as 4-methoxybenzyloxy or 3,4-dimethoxy-benzyl-

oxy, or furfuryloxy, such as 2-furfuryloxy. A polycyclo-

aliphatic hydrocarbon radical in which the methyl of the

methoxy group represents a triply branched ring member,

includes adamantyl, such as 1-adamantyl, and an abovementioned

oxacycloaliphatic or thiacycloaliphatic radical wherein the

methyl of the methoxy group is the ring member which repre-

sents the a-position to the oxygen atom or sulphur atom,

includes 2-oxa- or 2-thia-lower alkylene or -lower alkenylene

with 5-7 ring atoms, such as 2-tetrahydrofuryl, 2-tetrahydro-

propyranyl (sic) or 2,3-dihydro-2-pyranyl or corresponding

sulphur analogues.

The radical R further represents an etherified

hydroxyl group which, together with the grouping

forms an esterified carboxyl group which can be split

hydrolytically, for example under weakly basic or weakly

acid conditions. Such a radical includes an etherified hydroxyl

group which forms an activated ester group with the

grouping, such as nitrophenyloxy, for example 4-nitrophenyl-

oxy or 2,4-dinitrophenyloxy, nitrophenyl-lower alkoxy, for

27 486, 993

57,38 5 73 hydroxy-lower alkylbenzyloxy, for example 4-nitro-benzyloxy, 2 ,5-tert.-butyl-benzyloxy, polyhalogenophenyl- example 4-hydroxy- or 2,3,4,5,6-penta- oxy, for example 2,4,6-trichlorophenyloxy for chlorophenyloxy, and cyanomethoxy, acylaminomethoxy,

example phthaliminomethoxy or succinyliminomethoxy. an etherified The group RA further represents of hydroxyl group which, together with the carbonyl grouping

carboxyl group which the formula -C(=O)-,forms an esterified conditions and includes can be split under hydrogenolytic substituted, for a-phenyl-lower alkoxy, which is optionally such as benzyloxy, 4-methoxy- example by lower alkoxy or nitro,

benzyloxy or 4-nitrobenzyloxy. hydroxyl The group RA further is an etherified

grouping group which, together with the carbonyl which can be split under forms an esterified carboxyl group

an acyloxymethoxy group, physiological conditions, including an organic carboxylic wherein acyl denotes the radical of substituted lower alkane- acid, including such of an optionally forms the residue carboxylic acid, or wherein acyloxymethyl in this way are of a lactone. Hydroxyl groups etherified acetoxymethoxy and lower alkanoyloxymethoxy, including alkanoyloxymethoxy, inclu- pivaloyloxymethoxy, amino-lower for example glycyloxy- ding a-amino-lower alkanoyloxymethoxy, and phthalidyl- methoxy, L-valyloxymethoxy, L-leucyloxymethoxy

oxy. as A silyloxy or stannyloxy group R2 contains cyclo- substituents, optionally substituted aliphatic,

28 4 86.9 93

57.38 5 73 aliphatic, aromatic or araliphatic hydrocarbon radicals, including lower alkyl, halogeno-lower alkyl, cycloalkyl, phenyl, phenyl-lower alkyl, etherified hydroxyl groups, including lower alkoxy groups, or halogen atoms, for example chlorine atoms. Representative are tri-lower alkylsilyoxy, for example trimethylsilyloxy, halogeno-lower alkoxy-lower alkylsilyl, for example chloromethoxymethylsilyl, or tri- lower alkylstannyloxy, for example tri-n-butylstannyloxy.

A radical R2 which, together with a grouping, forms an optionally substituted carbamoyl or hydrazinocarbonyl group is amino, lower alkylamino or.di- lower alkylamino, such as methylamino, ethylamino, dimethyl- amino or diethylamino, lower alkyleneamino, including pyrroli- dino or piperidino, oxa-lower alkyleneamino, including morpholino, hydroxylamino, hydrazino, 2-lower alkylhydrazino or 2,2-di-lower alkylhydrazino, including 2-methylhydrazino or 2,2-dimethylhydrazino.

Salts are those of compounds of the formula I having an acid grouping, such as a carboxyl, sulpho or

phosphono group, and are metal salts, such as alkali metal salts and alkaline earth metal salts; for example sodium, potassium, magnesium or calcium salts, further ammonium salts with ammonia or suitable organic amines, amines for the salt formation being aliphatic, cycloaliphatic, cycloaliphatic- aliphatic and araliphatic primary, secondary or tertiary mono- amines, diamines or polyamines, heterocyclic bases, including lower alkylamines, for example triethylamine, hydroxy-

29 486,993

57,385 /73

lower alkylamines, for example 2-hydroxyethylamine, bis;-(2-

hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, basic

aliphatic esters of carboxylic acids, for example /i-amino- benzoic acid 2-diethylaminoethyl ester, lower alkyleneamines, for example 1-ethyl-piperidine, cycloalkylamines, for

example bicyclohexylamine, or benzylamines, for example N,N'-dibenzyl-ethylenediamine, and bases of the pyridine type, including pyridine, collidine and quinoline. Compounds of the formula I which possess a basic group form acid addition salts, with inorganic acids, such as hydrochloric acid, sulphuric acid or phosphoric acid, or with suitable organic

carboxylic acids or sulphonic acids, for example trifluoro-

acetic acid or 4-methylphenylsulphonic acid. Compounds of the formula I having an acid group and a basic group are present in the form of internal.salts, that is to say in the form of a zwitter-ion. 1-Oxides of compounds of the formula I having salt-forming groups form salts, as described above. The new compounds of formula I, the 1-oxides

thereof and the salts thereof are valuable intermediate products which are used for the manufacture of compounds having pharmacological properties; they can be converted into

these as described below. The invention in particular relates to the cepham-

3-one compounds of the formula I, wherein Ra denotes hydrogen or an acyl group of the formula (A)

30 486,9 93

7 .385I73 1 wherein n represents 0 and R denotes hydrogen or a cyclo-

alkyl group with 5-7 ring carbon atoms which is unsubstituted,

or substituted in the 1-position by amino or protected amino,

or R denotes a phenyl, naphthyl or tetrahydronaphthyl group

which is unsubstituted,or substituted by hydroxyl, lower

alkoxy, lower alkoxycarbonyl, 2-halogeno-lower alkoxycarbonyl and/or halogen, or R denotes or phenyl-lower alkoxycarbonyl, a heterocyclic group which is unsubstituted or substituted

by lower alkyl, and/or phenyl or phenyl substituted by

halogen, or R denotes an amino group which is substituted containing by a lower alkyl radical or.a lower alkyl radical alkyl group halogen, or n represents 1, R represents a lower which is unsubstituted or substituted by halogen, by phenyl- by acyloxy, and/or oxy, by phenyloxy containing hydroxyl, and/or carboxyl, halogen, or by amino or protected amino I denotes a phenyl or RI denotes a lower alkenyl grouplor R by hydroxyl, by group which is unsubstituted or substituted by unprotected or acylated hydroxyl, and/or by halogen, protected amino-lower alkyl, or by phenyloxy or by phenyloxy I

acyloxy, and/or by halogen, or R substituted by hydroxyl, group, a thienyl group, denotes a pyridyl group, a pyridinium group, .a furyl group, animidazolyl group, or a tetrazolyl alkyl, or by amino or or any such group substituted by lower unprotected or R- denotes aminomethyl which are protected or

31 48 6,993

57.385 73 a lower alkoxy group, a lphefyloxy group, a phenyloxy group which contains hydroxyl or protected hydroxyl, and/or halogen,

or Rdenotes a lower alkylthio group, or a lower alkenyithia group, a phenylthio, pyridylthio, 2-imidazolylthio, 1,2,4-

triazol-3-ylthio, l,3,4-triazol .2-ylthio, 1,2,4-thiadiazol- 3-ylthio, 1,3, 4-thiadiazol-2-ylthio, or group, or such group substituted by lower alkyl, or R denotes a halogen atom, lower alkoxycarbonyl, nitrile, or carbamoyl, or carbamoyl which is N-substituted by lower alkyl, or by

phenyl, or RIdenotes a low er alikanoyl group, a benzoyl group, or an azido group, and R TI and R represent hydrogen,

or n represents 1, Rrepresents lower alkyl1 or a phenyl, furyl, thienyl, or isothiazolyl group, *or such group substi-

tuted by hydroxyl or by acyloxy, and/or by halogen, orR

-denotes a 1, 4-cyclohexadienyl group, Rrepresents amino,

*acylamino, sulphoamino or sulphoamino present in the form of Ssalt, an azido group, a carboxyl group, a carboxyl group pres(

In the form of a salt, or in an esterified from, a nitrile grouf a sulpho group, a hydroxyl group, an acyloxy group, an 0-lower alkyl-phosphono group or 0.0'-di-lower alkyl-phosphono g .roup,

or a halogen atom, and R represents hydrogen, or n repre- sqnts 1, Rand R T each represent halogen, or lower alkoxy-

prbonyl, and R represents hydrogen, or n represents 1, ~I2 reresntsa peny, uryl, or thienyl, or isotiliazoiyl group, or su ch group substituted by. hydroxyl, acyloxy, and/or byhalogen, or RIdenotes a 1, 4 -cycloliexadienyl group,' 1

32 4 8 32 6.9 9 3

57,385/73

represents aminomethyl, or protected aminomethyl, andR

represents hydrogen, or n represents 1 and each of the groups 1 II TT R R and R represents lower alkyl, wherein lower alkoxy,

JcAwer alkyl, lower alkenyl and lower alkanoyl have up to 4 b A carbon atoms, Rl represents hydrogen, andR2 represents lower alkoxy, especially

1;-poly-brancheil lower alkoxy, for example tert.-butpoxy,

also methoxy or c Lhoxy, 2-halogeno-loiw.er alkoxy, for example

2,2,2-trichloroethoxy, 2-iodoethoxy or 2-chloroethoxy or

2.-broi-moethoxy which can easily be convecrted into 2-iodoethoxy, phenacyloxy, 1-phenyl-lower alkoxy with. 1-3 phenyl radicals whichi

are optionally substituted by lower alkoxy or nitro, for. example 4-me Lhoxybenzyloxy, Ii-nitro-benzyloxy, diphenylme Ihoxy,

1-dimethoxy-diphenylmetoxy or trityloxy, lower alkanoyloxy-

me-thoxy, for example acetoxymethoxy or pivaloyloxymethoxy,

a-ariino-lower alkanoyloxymetIhoxy, for example glycyloxymc-thoxy,

2-phthalidyloxymethoxy, and also tri-lower alkylsilyoxy, for example trimethylsilyloxy, to the 1-oxides thereof and salts of

such compounds having salt forming groups.Prefered compounds

of the invention are cepham-3-one compounds of the formula I, wherein Radenotes hydrogen or an acyl group of the formula

0

Rb.

33 4 86,9 93

57 385/73 wherein R- denotes phenyl, hydroxyphenyl, including 3- and a 4-hydroxyphenyl, or hydroxy-chlorophenyl, including 3-chloro- 4-hydroxyphenyl or 3,5-dichloro-4-hydroxy-phenyl, wherein a

hydroxy substituent in such a radical is free or protected

by an acyl radical, including an.optionally halogenated lower alkoxycarbonyl radical, for example tert.-butoxycarbonyl or

2,2,2-trichloroethoxycarbonyl, or Ra denotes thienyl, inclu- ding 2- and 3-thienyl, pyridyl, including 4-pyridyl, amino- pyridinium, including 4-aminopyridinium, furyl, including 2-furyl, isothiazolyl, including 4-isothiazolyl, or tetrzolyl, including 1-tetrazolyl, or 1,4-cyclohexadienyl, X represents

oxygen or sulphur, m represents 0 or 1 and Rb represents hydrogen, or, if m represents O, Rb represents free or protected amino, including acylamino, for example a-poly- branched lower alkoxycarbonylamino, such as tert.-butoxy- carbonylamino, or 2-halogeno-lower alkoxycarbonylamino, including 2,2 ,-trichloroethoxycarbonylamino, 2-iodoethoxy-

carbonylamino or 2-bromoethoxycarbonylamino, or optionally lower alkoxy-substituted or nitro-substituted phenyl-lower alkoxycarbonylamino, for example 4-methoxybenzyloxycarbonyl- amino or.diphenylmethoxycarbonylamino, or 3-guanylureido,

sulphoamino or tritylamino, arylthioamino, including 2-nitro- phenylthioamino, arylsulphonylamino, including 4-methylphenyl- sulphonylamino, or 1-lower alkoxycarbnpnyl-2-propylidene- amino, including l-ethoxycarbonyl-2-propylideneamino, car-

boxyl, or carboxyl present in the form of a salt, for example an alkali metal salt, such as a sodium salt, protected car-

34 4 8 6.9 93

57 385 /73 boxyl, including esterified carboxyl, such as phenyl-lower alkoxycarbonyl, for example diphenylmethoxycarbonyl, sulpho, or sulpho present in the form of a salt, for example an alkali metal salt, such as a sodium salt, protected sulpho,

hydroxyl, protected hydroxyl, including acyloxy, for example

a-polybranched lower alkoxycarbonyloxy, such as tert.- butoxycarbonyloxy or 2-halogeno-lower alkoxycarbonyloxy, such as 22,2-2trichloroethoxycarbonyloxy, 2-iodoethoxycar-

bonyloxy or 2-bromoethoxycarbonyloxy, or formyloxy, or O-lower alkylphosphono or O,0'-di-lower alkylphosphono, including O-methyl-phosphono or O,0'-dimethylphosphono, or Ra1 denotes a 5-amino-5-carboxy-valeryl radical, wherein the' amino and/or carboxyl groups are free or protected, inclu-

ding being present as acylamino, for example lower alkanoyl- amino, such as acetylamino, halogeno-lower alkanoylamino such as dichloroacetylamino, benzoylamino or phthaloylamino, or as esterified carboxyl, such as phenyl-lower alkoxycarbonyl, for example diphenylmethoxycarbonyl, whereby advantageously m is 1, when Ra represents phenyl, hydroxyphenyl, hydroxy-

chlorophenyl or pyridyl and m is O and Rb is different from

hydrogen, when Ra is phenyl, hydroxy-phenyl, hydroxy-chloro-

phenyl, thienyl, furyl, isothiazolyl or 1,4-cyclohexadienyl, Rb12denotes hydrogen and RA represents lower alkoxy, especially

a-poly-branched lower alkoxy, including tert.-butoxy, 2-halo- geno-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-iodo- ethoxy or 2-bromoethoxy, diphenylmethoxy, or diphenylmethoxy substituted by lower alkoxy, for example methoxy, including

4 8 6.9 93

57,385 /73 4,4'-dimethoxy-diphenylmethoxy, tri-lower alkylsilyloxy, for

example trimethylsilyloxy, the 1-oxides of such

cepham-3-one compounds of the formula I, or salts of such

compounds having. salt-forming groups, such as acid addition

salts, for example with mineral acids or strong carboxylic

acids or sulphonic acids such as preferably halogen-sub-

stituted lower alkanecarboxylic acids or arylsulphonic acids,

especially trifluoroacetic acid or 4-methylphenylsulphonic

acid, of compounds of the formula I wherein Ra and Rb

represent hydrogen.

In preferred cepham-3-one compounds of the formula

I and in salts of such compounds which have salt-forming

groups, Ra represents hydrogen or the acyl radical of the

formula B, wherein R denotes phenyl, 4-hydroxy-phenyl,

2-thienyl or 3-thienyl, 4-isothiazolyl, or 1,4-cyclohexa-

dienyl, X denotes oxygen, m denotes 0 or 1 and Rb denotes

hydrogen, or, if m represents O, denotes amino or protected

amino, including acylamino, for example a-poly-branched lower

alkoxycarbonylamino, such as tert.-butoxycarbonylamino, or

2-halogeno-lower alkoxycarbonylamino, for example 2,2,2-tri-

chloroethoxycarbonylamino, 2-iodoethoxycarbonylamino or

2-bromoethoxycarbonylamino, or optionally lower alkoxy-sub-

stituted or nitro-substituted phenyl-lower alkoxycarbonyl-

amino, for example 4-methoxybenzyloxycarbonylamino, or Rb

denotes hydroxyl or protected hydroxyl, including acyloxy,

for example a-poly-branched lower alkoxycarbonyloxy, such as

tert.-butoxycarbonyloxy, or 2-halogeno-lower alkoxycarbonyl-

36. 48 6,993

57.38.5 /73 oxy, such as.2,2 ,2-trichloroethoxycarbonyloxy, 2-iodoethoxy- a carbonyloxy or 2-bromoethoxycarbonyloxy, or formyloxy, orR1 represents a 5-amino-5-carboxy-valeryl radical, wherein the amino and carboxyl group are free or protected, including in the form of acylamino, for example lower alkanoylamino,'such

as acetylamino, halogeno-lower alkanoylamino, such as dichlo- roacetylamino, benzoylamino or phthaloylamino, or in the form of esterified carboxyl, such as phenyl-lower alkoxycarbonyl, for example diphenylmethoxycarbonyl, Rb represents hydrogen and RAis lower alkoxy, especially a-poly--branched lower alkoxy, for example tert.-butoxy, or 2-halogeno-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-iodoethoAy or 2-bromo- ethoxy, or diphenylmethoxy, lower alkoxy-substituted, such as methoxy-substituted, diphenylmethoxy, including 4,4'- dimethoxy-diphenylmethoxy, or tni-lower alkylsilyloxy, inclu- ding trimethyls ilyloxy. A preferred group of compounds are 71-(D-a-amino- cz.R a-acetylamino) -ceplham-.3-one-4i-carboxylic acid .diphenyl- methyl esters, wherein Ra represents phenyl, 4-hydroxy- phenyl, 2-thienyl. or 1,4t-cyclohexadieniyl and amino is present in free or in protected form, for example as

acylamino, for example a-poly--branched lower alkoxycarbonyl- amino, such as ter-t.-bu-toxycarbonylamino, or 2-halogeno- lower alkoxycarbonylamino, for example 2,2,2 -trichloro- ethoxycarbonylamino,* 2-iodoethoxycarbonylamino or 2-bromo- ethoxycarbonylarnino, or optionally lower alkoxy-substituted or ni-tro-substituted phenyl-lower alkoxycarbonylanino,

37 786,9 -4 93

7 385 /73

for example 4-mothoxybenzyloxycarbonylamino, to 4 7p-amino-cepham-3-one- -carboxylic acid diphenylmethyl

ester and salts thereof and above allto 7p-(D-a-tert.-

butoxycarbonylamino-a-phenyl-aceylamino )-cepham-3-one-

4 -carboxylic acid diphenylmethyl ester.

A compound of the formula I is obtained if,

in a cepham compound of the formula

b N nA (II)

NO= 2

2

the methylene group in the 3- or in a 1-oxide thereof, a position is split off oxidatively and, when required, formula I and of the resulting mixture of a compound of the corresponding 1-oxide is separated or oxidised to the 1-oxide

of a compound of the formula I and/or, when required, a

resulting compound of the formula I is oxidised to the 1-

oxide of a compound of the formula I and/or, when required,

a resulting compound of theformula, I is converted into a

Sketal thereof formed with the 3-oxo group and the latter is

subsequently split, when required, and/or, when required, a

resulting compound of the formula I is converted into

another compound of the formula I and/or, when required, a

38 4 8 6,9 9 3

57.385/73 resulting compound having a salt-forming group is converted

into a salt or a resulting salt is converted into the free

compound or into another salt and/or, when required, a

resulting isomer mixture is separated into the individual

isomers. In a starting material of the formula II,-the

protected carboxyl group of the formula in the 4-position preferably has the a-configuration.

In a starting material of the formula II, a

group Ra in particular represents an acyl group Ac, wherein

functional groups, including amino, hydroxy, carboxyl,

or phosphono groups, are free or protected in a manner

which is described hereinbefore, amino

groups, for example, by acylation, tritylation, silylation

or stannylation and hydroxyl, carboxyl or phosphono groups,

for example,-by etherification or esterification, including

silylation or stannylation, and Rb represents hydrogen,.

whilst R2 preferably denotes an etherified hydroxyl group

R which forms, with the grouping, an esterified

carboxyl group which can be split, especially an esterified

carboxyl group which can be split under mild conditions,

.it being possible for optionally present functional groups

in a carboxyl protective group RA to be protected in a

manner which is in itself known, for example as indicated A above. A group R 2 is in particular an optionally substituted

1-phenyl-lower alkoxy group, including a 1-phenyl-lower alkoxy

group which contains lower alkoxy, for example methoxy, or

nitro, such as benzyloxy or diphenylmethoxy which is

39 4 86,9 9 3

57 385 /73 A optionally substituted as indicated. Such groups R 2 are

benzyloxy, 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenyl-

methoxy or 4,4'-dimethoxy-diphenylmethoxy, optionally halogen-

substituted lower alkoxy, including a-poly-branched lower

alkoxy, for example tert.-butoxy, or 2-halogeno-lower alkoxy,

wherein halogen represents chlorine, bromine or iodine, above

all 2,2,2-trichloroethoxy, 2-bromoethoxy or 2-iodoethoxy,

further organic silyloxy or stannyloxy including tri-lower

alkylsilyloxy, for example trimethylsilyloxy.

The oxidative degradation of the methylene

grcup in a starting material of the formula II is

carried out through the formation of an ozo.nide compound

by treatment with ozone. Ozone is used in the

presence of a solvent, such as an alcohol, for example a

lower alkanol, such as methanol or ethanol, a ketone, for

example a lower alkanone, such as acetone, an optionally

halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon,

for example a halogeno-lower alkane, such as methylene chloride or carbon tetrachloride, or a solvent mixture,

including an aqueous mixture, and with at most slight

warming, but preferably with cooling, that is to say at a

temperature of about -90°C to about +400C, preferably at

a temperature of about -70°0 "to about +100C, the reaction

advantageously being carried out in a temperature range of

about -100C to about +100C or in a substantially lower 0 temperature range of about -700C to about -40 C.

An ozonide formed as the intermediate product is

40 48 6.9 93

57.385/73

split by reduction, reducing agents used being catalytically

activated hydrogen, including hydrogen in the presence of a

heavy metal hydrogenation catalyst, for example a nickel

catalyst or a palladium catalyst on a suitable carrier, such

as calcium carbonate or charcoal, or a chemical reducing

agent, including a reducing heavy metal, including a heavy

metal alloy or a heavy metal amalgam, for example zinc, in

the presence of a hydrogen donor, such as an acid, for example

acetic acid, or an alcohol, for example a lower alkanol, a

reducing inorganic salt, including an alkali metal iodide,

for example sodium iodide, in the presence of a hydrogen

donor, such as an acid, for example acetic acid, or a re-

ducing organic compound, including formic acid. Advantage-

ously, a reducing agent which can easily be converted into

oxide compounds is employed, in which the oxide formation

takes place because of a carbon-carbon double bond which is

present or because of an oxide-forming hetero-atom, such as

sulphur, phosphorus or nitrogen atom, which is present. Such

compounds are a suitable substituted ethene compound (which

is converted into ethyleneoxy compound during the reaction),

including tetracyanoethylene, a suitable sulphide compound

(which is converted into sulphoxide compound in the

reaction) including a di-lower alkylsulphide, above all

dimethylsulphide, a suitable organic phosphorus compound,

including a phosphine which contains an optionally

41 48 6.9 993

57,385 /73 substituted aliphatic or aromatic hydrocarbon radical as

substituent (and which is converted, during the reaction,

into a phosphine oxide), such as a tri-lower alkylphosphine,

for example tri-n-butylphosphine, or a triarylphosphine, for

example triphenylphosphine or a phosphite which contains

optionally substituted aliphatic hydrocarbon radicals as

substituents (and which is converted into phosphoric acid

triesters during the reaction), including a tri-lower alkyl-

phosphite, usually in the form of the corresponding alcohol

adduct compound, such as trimethylphosphite, or a phosphorous

acid triamide, which contains optionally substituted

aliphatic hydrocarbon radicals as substituents, such as a

hexa-lower alkylphosphorous acid triamide, for example

hexamethylphosphorous acid triamide, the latter

in the form of a methanol adduct, and a suitable

nitrogen base (which is converted into the corresponding

N-oxide during the reaction), including a heterocyclic

nitrogen base of aromatic character, for example a base

of the pyridine type and especially pyridine itself. The

splitting of the ozonide which is usually not isolated, is

carried out under the conditions which are employed for

its manufacture, that is to say in the presence of a suit-

able solvent or solvent mixture, and with cooling or slight

warming, the reaction being carried out at a temperature of

about '-10 C to about +25' C and usually being concluded

at room temperature.

A compound of the formula I is further manufactu-

red by treating a cephem compound of the formula

42 4 86,9 93

57385 /73

a 1\

1 (III) N 1 CHO

0=C--R

which contains a double bond in the 2,3- or 3,4-position, or a 1-oxide of a 3-cephem compound of the formula III, with a per-acid, and in a resulting 3-formyloxy-4-R2- carbonyl-7-N-Ra-N-Rb-amino-cephem compound or a 1-oxide thereof splitting thn formyloxy group, and, if desired, carrying out the abovementioned additional steps. The above reaction is carried out according to the Baeyer-Villiger oxidation method. In this oxidation reaction there is used an inorganic per-acid which consists of non-metallic elements, an organic per-acid or a mixture of hydrogen peroxide and an acid, especially an organic carboxylic acid having a dissociation constant of at least 5 Suitable inorganic per-acids are periodic acid and per-sulphuric acid. Organic per-acids are a percarboxylic acid and a persulphonic acid which are added as such or are formed in situ by the use of at least one equivalent of hydrogen peroxide and of the corresponding acid.

43 4 86,9 93

57,385 /73

It is advisable to use a large excess of the carboxylic acid if, for example, acetic acid is used as the solvent. Examples of suitable per-acids are performic acid, peracetic acid, trifluoroperacetic acid, permaleic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid or p-toluenepersulphonic acid. The reaction is carried out in the presence of an inert solvent, including an optionally halogenated hydrocarbon, for example methylene chloride or chloroform, and with cooling at temperatures of about -100 C to about +200 C.

In a resulting 3-formyloxy-4-RA-carbonyl-7- N-RI-N-R -amino-cephem compound, the formyloxy group is split by solvolysis, especially hydrolysis, preferably in the presence of a basic agent, such-as an alkali metal bicarbonate, for example sodium bicarbonate or potassium bicarbonate.

Depending on the nature of the above-oxidation reactions, a compound of the formula I or the corresponding 1-oxide or a mixture of both compounds is obtained according to the invention. Such a mixture is separated into the compound of the formula I and the corresponding 1- oxide, or is 3xidised to give only the 1-oxide of a compound of the formula I.

A mixture of a compound of:the formula I with the corresponding 1-oxide is separated into the individual

-44 4 86,9 93

57 385/73 components,in the usual manner, including by fractional crystallisation'or by chromatography (for example column chromatography or thin layer chromatography). Furthermore, a mixture, obtainable according to the process, of a compound of the formula I and a 1-oxide thereof, or a resulting compound of the formula I, is oxidised to the corresponding 1-oxide. Suitable oxidising agents are inorganic per-acids which have a reduction potential of at least +1.5 volt and which consist of non- metallic elements, organic per-acids or mixtures of hydrogen peroxide and an acid, especially an organic carboxylic acid, having a dissociation constant of at least 10 5 Suitable inorganic per-acids are periodic acid and persulphuric acid. Organic per-acids are an appropriate percarboxylic acid and a persulphonic acid which is "added as such or is formed in situ by the use of at least one equivalent of hydrogen peroxide and of the corresponding acid. It is desirable to use a large excess of the carboxylic acid if, for example, acetic.acid is used as the solvent. Suitable per-acids include performic acid, peracetic acid, trifluoroperacetic acid, permaleic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid and p-toluene- persulphuric acid.

The oxidation is further carried out using hydrogen peroxide and a catalytic amount of an acid having a dissociation constant of at least 10-5 5 whereby a low

concentration, for example 1-2% or less, but also a larger amount, of the acid is employed. The activity of the mixture

45 4 86,9 93

57,38 5/73 above all depends on the strength of the acid. Examples of

suitable mixtures are those of hydrogen peroxide with acetic

acid, perchloric acid or trifluoroacetic acid.

The above oxidation is carried out in the

presence of a suitable catalyst. Thus, the oxidation

with a percarboxylic acid is catalysed by the presence of

an acid having a dissociation constant of at least 10

activity depending on its strength. Acids suitable as its

catalysts include acetic acid, perchloric acid and trifluoro-

acetic acid. Usually, at least equimolar amounts of the

oxidising agent or a small excess of about 10% to about

are used, it also being possible to use a larger excess, that

is to say up to the 10-fold amount of the oxidising agent,

or above. The oxidation is carried out under mild conditions

at temperatures of about -500 C to about +1000 C, preferably

of about -100 C to about +400 C:

The oxidation of a cepham-3-one compound to the

corresponding 1-oxide is further carried out by treatment

with ozone, or with an organic hypohalite compound, including

a lower alkyl hypochlorite, for example tert.-butylhypochlori-

inclu- te, which is used in the presence of an inert solvent,

ding an optionally halogenated hydrocarbon, for example

methylene chloride, and at a temperature of about -100 C to

about +300 C, with a periodate compound, including an alkali

metal periodate, for example potassium periodate, which is a used in an aqueous medium at a pH value of about 6 and at

temperature of about -100 C to about +300 C, with iodobenzene

-46- 4 86,9 9 3

57,385 73 dichloride,. which is used in an aqueous medium, in the

presence of an organic base, for example pyridine, and with 0 cooling at a temperature of about -200 C to about 0 ,or

with any other oxidising agent which is suitable for con-

version of a thio grouping into a sulphoxide grouping.

Depending on the oxidising agent used, the

la-oxide or the lp-oxide or a mixture of both is obtained.

A ketal derivative formed with the 3-oxo group

of a compound of the formula I is manufactured in a

manner which is in itself known, including by treat-

ment with a glycol, thioglycol or dithioglycol

in the presence of an acid catalyst, such as p-toluene- sulphonic acid, of a Lewis acid, such as zinc-II chloride, (especially when using thioglycol, where an agent which adsorbs water, such as sodium sulphate, is usually employed) or of an acid ion exchanger, usually in the presence of an inert solvent, such as an optionally halogenated, such as chlorinated, preferably aliphatic hydrocarbon, or of a suitable, optionally cyclic, ether, for example'dioxane, or by ketal exchange, for example by treatment with a ketal of a lower alkanone, for example 2,2-ethylenedioxybutane, in the

presence of a strong acid, such as p-toluenesulphonic acid, or with a ketal of a disubstituted formylamino compound, such as a N-formyl-N,N-di-lower alkylamine, for example (1,3- dioxolan-2-yl)-N,N-dimethylamino, in the presence of an acid, for example acetic acid.

47 4 86,9 93

57.38 5/73 Such a ketal compound of a compound of the

formula I is split subsequently in a manner which is in

itself known, a ketal and thioketal by means of acid hydroly-

sis, including with an aqueous inorganic or organic acid,

for example hydrochloric acid, formic acid or trifluoro-

acetic acid, in the presence of an inert solvent, such as

an optionally halogenated, such as chlorinated, aliphatic

hydrocarbon, or of a suitable, optionally cyclic, ether,

and a dithioketal, for example, by treatment with mercury-II

chloride (usually in the presence of an aqueous solvent, for

example acetone or dioxane) or with a N-halogenoamide or

N-halogenoimide, such as N-bromosuccinimide.

A compoui.d of the formula I obtainable according

to the invention is converted into another compound of the

formula I, it being necessary to ensure that reaction conditions are chosen under which the oxo group in the 3- position, and the protective carboxyl group of the formrula- remain intact, it being possible for the oxo group to be present in a protected form, for example in the form of a functionally modified enol group, such as a silylated or stannylated enol group, or of a ketal group. It is furthermore possible, where necessary, for.free functional groups which do not participate in the reaction to be protected in a manner which is in itself known, a free amino group, for example, by acylation, tritylation or silylation, a free hydroxyl or mercapto group, for example,

by etherification or esterification, and a free carboxyl

group, for example, by esterification, including silylation,

48 48 6,9 93

57.38 5 and, subsequently to be liberated, when required, in a manner

which is in itself known.

In a resulting compound an easily removable

acyl group is split off in a manner which is in itself

knovm, for example an a-poly-branched lower alkoxycarbonyl

group such as tert-butoxycarbonyl, by treatment with

trifluoroacetic acid, and a 2-halogeno-lower alkoxycarbonyl

group, such as 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxy- carbonyl or a phenacyloxycarbonyl group, by treatment with

a suitable reducing metal or corresponding metal compound,

for example zinc, or a chromium-II compound, such as

chromium-II chloride or chromium-II acetate, advantageously

in the presence of an agent which together with the metal

or the metal compound generates nascent hydrogen, preferably

in the presence of aqueous acetic acid.

Furthermore, in a resulting compound of the

formula I, an acyl group Ac, wherein optionally present

free functional groups are optionally protected, an amino

group, for example, in the form of acylamino group or

silylated amino group and/or a carboxyl group, for example,

in the form of an esterified or silylated carboxyl group,

is split off by treatment with an imide-halide-forming with an agent, reaction of the resulting imide-halide

alcohol and splitting of the iminoether formed.

An imide-halide-forming agent in which halogen

is bonded to an electrophilic central atom is an

49 48 6,9 93

57.385/73 acid halide, such as an acid bromide and especially an acid chloride. The acid halide is above all an acid halide of an inorganic aoid, above all of an acid containing phosphorus, such as a phosphorus oxyhalide, a phosphorus trihalide and especially a phosphorus p-entahalide, for example phosphorus _oxychloride, phosphorus trichloride and above all phosphorus pentachloride, and also pyrocatechyl- phosphorus trichloride, or an acid halide especially an acid chloride, of an acid containing sulphur or of a carboxylic acid, such as thienyl chloride, phosgene or oxalyl chloride. The reaction with one of the imide-halide-forming

agents mentioned is .carried out in the presence of a

suitable base, especially of an organic base, above all of a

tertiary amine, for example a tertiary aliphatic monoamaine or diamine, such as a tri-lower alkylamine, for example trimethyl- amie trehliioo -ethyl-N,N--diisopropylamine, a

Ni N, N' N'-tetra-lower alkyl-lower alkylenediamine, for example N, N, 1.1 -te rancthYl-l, 5-pentylenediamine or DI, DI, N'I N'I -tetr'a-

*mthyl-l, 6-hexyl enediamine, a monocyclic or bicyclic monoaminec or diamine, such as a N-substituted, for example N-loaer

alkylatod, alkyleneamine, a zaalkylencaminc or oxaa).kylcncarminc,

for example N-methyl-p iperidine or N-methyl-mrpholine, or 2,3,14,6,7, 8-hexabiydro-pyrrolo [1,2-a Ipyrimiidine (diazabicyclo

flene; DBN), or a tertiary aromiatic amino such as a di-lower

al)~ylaniline, for example DN,N-dimethylaniline, or above all a tertiary heterocyclic, monocyclic or bicyclic, base, such-as

50 0 86,9 -4 93

57 38 5/73 quinoline or isoquinoline, especially pyridine, preferably in

the presence of a solvent, such as an optionally halogenated,

for example chlorinated, aliphatic or aromatic hydrocarbon,

for example methylene chloride. Is is possible to use an approxi- mately equimolar amount' of the imide-halide-forming agent and

of the base; the latter can however also be present in more th-n

or less than equimolar amount, for example in about 0.2--fold

to about 1-fold amount or in, up to about 10-fold, in

particular about 3-fold to 5-fold, excess. The reaction with the imide-halide-forming agent is

preferably carried out with cooling, for example at a tempera-

ture of about -500 C to about +100 C, but it is also possible

to work at a higher temperature, that is to say up to about 750 C, if the stability of the starting substance and of the product permits a higher temperature. The imide-halide product which is further

processed without isolation, is reacted according to the process

with an alcohol, preferably in the presence of one of the above-- mentioned bases, to give the imino-ether. Examples of suitabld

alcohols are aliphatic as well as araliphatic alcohols, above all optionally substituted, such as halogenated, for example chlorinated, lower alkanols or lower alkanols possessing

additional hydroxyl groups, for example ethanol, propanol or

butanol but especially methanol, also 2-halogeno-lower alkanols,

for example 2,2,2-trichloroethanol or 2-bromoethanol, and

optionally substituted phenyl-lower alkanols, such as benzyl alcohol. Usually an excess, for example up to about 100-fold

excess, of the alcohol is employed and the reaction is

51 4 86,9 93

57 385/73

carried out with cooling at a temperature of about -500 C

to about 100 C.

The imino-ether product is advantageously

split without isolation. The splitting of the imino-ether

is achieved by treatment with a suitable hydroxy compound,

preferably by means of hydrolysis, and by alcoholysis, and

the latter can take place directly following the formation

of the imino-ether, if an excess of the alcohol is used.

Preferably, water or an alcohol, especially a lower alkanol,

for example methanol, or an aqueous mixture of an organic

solvent, such as an alcohol, is used. The reaction is

carried out in an acid medium at a pH value of about 1 to

about 5 which, if necessary, is obtained by adding a basic

agent, including an aqueous alkali metal hydroxide, for

example sodium hydroxide or potassium hydroxide, or an acid,

for example a mineral acid, or an organic acid, such as hydro- chloric acid, sulphuric acid, phosphoric acid, fluoboric acid, trifluoroacetic acid or p-toluenesulphonic acid. The three-stage process for splitting off an acyl group described above, is advantageously carried out without isolatio of the imide-halide and the imino-ether intermediate product, usually in the presence of an organic solvent which is inert towards the reactants, such as an optionally halogenated hydro- carbon, for example methylene chloride, and/or in an inert gas atmosphere, such as a nitrogen atmosphere.

52 48 6,9 9 3

57,38 573 If the imide-halide intermediate product obtainable

according to the above process, instead of being reacted w.ith

an alcohol, is reacted with a salt, such as an alkali metal salt, of a carboxylic acid, especially of a sterically hindered carboxylic acid, a compound of the formula I, wherein

both radicals R and R represent acyl groups, is obtained.

Certain acyl radicals Ac of an acylamino grouping in

compounds obtainable according to the invention such as, for

example, the 5-amino-5-carboxy-valeryl radical, wherein carboxyl is optionally protected, for example by esterification, especially by diphenylmethyl, and/or the amino group is optionally protected,

for example by acylation, especially by an acyl radical of an

organic carboxylic acid,. such as halogeno-lower alkanoyl, such

as dichloroacetyl, or phthaloyl, are split off by treatment with a nitrosilylating agent, such as nitrosyl chloride, with a carbocyclic arenediazonium salt,.such as benzenediazonium chloride, or with an agent which releases

positive halogen, .such as a N-halogeno-amide or -imide, for

example N-bromosuccinimide, in a suitable solvent or

Ssolvent mixture, such as formic acid, together with a nitro-

or cyano-lower alkane, and treatment of the reaction product with a hydroxylic agent, such as water or a lower alkanol,

for example methanol or, if in the

radical Ac the amino group is unsubstituted and the carboxyl

group is protected, for example by esterification, .by leaving the substance to stand in an inert solvent,

-53 4 86,9 93

57.385 /73

such as dioxane or a halogcnated aliphatic hydrocarbon, for example methylene chloride and, if necessary, working up the fr, or monoacylated amino compound according to methods which are in themselves known.

A formyl group Ac is split off by treatiment with an acid agent, for example.p-toluenesulphonic acid or hydrochloric acid, a weakly basic agent, for example dilute ammonia, or a decarbonylating agent, for example tris- (triphenylphosphine)-rhodium chloride.

In a .compound of the formula I, wherein Ra and Rb represent hydrogen, and the oxo group in the 3-position is protected, if necessary, for example as described, the free amino group is acylated by treatment with acids, such as carboxylic acids, or reactive acid derivatives thereof.

If a free acid wherein optionally present functional groups, such as an optionally present amino group, are prote.ted, is employed for the acylation, a suitable condensation agent is employed, such as a carbodiimide, for example N,N'-diethyl-, N,N'-dipropyl-, N,N'-diisopropyl-, N,N'-dicyclohexyl- or N-ethyl- N'-3-dimethylaminopropylcarbodiimide, a suitable carbonyl compounc

for example carbonyl diimidazole, or an isoxazolinium salt, for

example N-ethyl-5-phenyl-isoxazolinium-3'-sulphonate and N-tert.- butyl-5-methyl-isoxazolinium perchlorate, or a suitable acylamino

compound, for example 2 -ethoxy-l-ethoxycarbonyl-l,2-dihydro- quinoline.

54 48 6.9 93

57,385 /73

The condensation reaction is carried out in one of the anhydrous reaction media mentioned later, for example in methylene chloride, dimethylformamide or acetonitrile. An amide-forming functional derivative of an acid, wherein optionally present groups, such as an optionally present amino group, are protected,_is an

anhydride of such an acid, including, and preferably, a mixed anhydride. A mixed anhydride is the one with an inorganic acid, especially with a-hydrogen halide acid, that is to say the corresponding acid halide, for example acid chloride or acid bromide, and also with hydrazoic acid, that is to say the corresponding acid azide, with an acid containing phosphorus, for example phosphoric acid or phosphorous acid, with an acid containing sulphur, for example sulphuric acid, or with hydrocyanic acid. Further mixed anhydrides are those with a carboxylic acid, such as with a lower alkanecarboxylic acid which is optionally substituted,

for example by halogen, such as fluorine or chlorine, for example pivalic acid or trichloroacetic acid, or with a half-ester, especially a lower alkyl half-ester, of carbonic acid, such as the ethyl half-ester or isobutyl half-ester of carbonic acid, or with an aliphatic or aromatic sulphonic acid, for example. p-toluenesulphonic acid. Furthermore as an acylating agent,'there is used

an internal anhydride, such as a ketene, for example

55 4 86,9 93

57 385/73

diketene, an isocyanate, (that is to say an internal anhydride of a carbamic acid compound) or an internal anhydride of a carboxylic acid compound having a carboxyl-. substituted hydroxyl or amino groups, such as mandelic acid 0-carboxanhydride or the anhydride of l-N-carboxyamino- cyclohexanecarboxylic acid. Further acid derivatives suitable for reaction with the free amino group are activated esters, wherein the optionally present functional groups are usually protected, such as an ester with a vinylogous alcohol, (that is to say an enol), such as a vinylogous lower alkanol, or an aryl ester, such as a phenyl ester which is substituted, for example by nitro or halogen, such as chlorine, for example a pentachlorophenyl, a 4- nitrophenyl or a 2,4-dinitrophenyl ester, a hetero-aromatic ester, such as a benztriazole ester, or a diacylimino ester, such as a succinylimino ester or a phthalylimino ester. Further acylation derivatives are substituted formimino derivatives, such as a substituted N,N-dimethylchloroformimino derivative of an acid, or an N--substituted N,N-diacylamine, such as a N,N-diacylated aniline. The acylation with an acid derivative including an anhydride and an acid halide, is carried out in the presence of an acid-binding agent, for example of an organic base, such as an organic amine, for example a tertiary amine, such as tri-lower alkylamine, for example

56 4 86,9 93

57,385 /73

triethylamine, N,N-di-lower alkylaniline, for example N,N-

dimethylaniline, or a base of the pyridine type, for example pyridine, an inorganic base,. for example an alkali metal

hydroxide, carbonate or bicarbonate or an alkaline earth metal hydroxide, carbonate or bicarbonate, for example sodium hydroxide

carbonate or bicarbonate, potassium hydroxide, carbonate'-or

bicarbonate or calcium hydroxide, carbonate or bicarbonate, or an oxirane, for example a lower 1,2-alkylene oxide, such as

ethylene oxide or propylene oxide. The above acylation, is carried out in an aqueous or, preferably, anhydrous solvent or solvent mixture, for example in a carboxylic acid amide, such as a N,N-di-lower alkylamide, for example dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetra- chloride or chlorobenzene, a ketone, for example acetone, an ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or mixtures thereof, and, if necessary, at lowered or elevated temperature and/or in an inert gas atmosphere, for example a nitrogen atmosphere.. An acyl group is further introduced by acylating a a b compound of the formula I wherein Ra and Rb together represent an ylidene radical (which is introduced by treating a compound

wherein Ra and Rb represent hydrogen, with an aldehydre, such as an aliphatic, aromatic or araliphatic aldehyde) according to the methods indicated above, and hydrolysing the acylation product in a neutral or weakly acid medium.

57 4 86,9 93

57 38 5/73 An acyl group, when required, is introduced stepwise

into a compound of the formula I having a free amino group, by treatment with a carbonic acid dihalide, such as phosgene,

and reacting a N-(halogeno-lower alkanoyl)-amino compound or N-(halogenocarbonyl)-amino compound thus obtainable with a suit-

able exchange reagent, such as a basic compound, for example

tetrazole, a thio compound, for example 2-mercapto-l-methyl-

imidazole, or a metal salt, for example sodium azide, or an

alcohol, such as a lower alkanol, for example tert.-butanol and thus obtain a substituted N-lower alkanoyl-amino or N-hydroxy- carbonylamino compound.

The acylation is further effected by replacement of an already existing acyl group by another, preferably sterically hindered, acyl group, for example according to the process described above, by manufacturing the imide-halide compound, treatihg this with a salt of an acid and splitting off hydro- lytically one of the acyl groups present in the product thus obtainable, usually the sterically less hindered acyl group. An amino group further is protected by introducing a silyl or stannyl group. Such groups are introduced in a manner which is in itself known, including by treatment with a suitable silylating agent, such as with a dihalogeno-di- lowcr alkylsilane, low/er alkoxy-lower alkyl-dihalogeno-silane or tri-lower alkyl-silyl halide, for example dichloro- dirnethylsilane, methoxy-methyl-dichloro-silane, trimethylsilyl chloride or dimethyl-tert.-butyl-silyl chloride, such silyl halide compounds being used in the presence of a

58 4 8 6,9 9 3 base, for example pyridine, or by treatment with an optionally N-mono-lower alkylated, N, N-di-lower al kylated, N-tni-low.er. alkyl silylated or 11-lower alkyl-N-tri-lower alkyl-silylated N-(tri-lowier alkylsilyl)-amine (see, for example, British Patent No. 1,073,530), or wifth a silylated carboxylic acid a-,iid-e, such as a bis-tri-loaer alkylsilyl-acetamide, for e xam;ple bis- trimethylsilyl-ac etaraide or trifluorosilylacetanlide, or by* treatment with a suitable, stannylating agent, such as a bis- (tni-lowaer alkyl-tin) oxide, for example- bis-(tri-n-butyl-tin) oxide, a tri-lower aikyl-tirf hydroxide, for example triethyl- tin hydroxide, a tni-lower alkyl-lower alkoxy-tin compoun~d, tetra-low..er alkoxy-tin compound or tetra-lo-aer alkyl-tin compound, or with a tni-lower alkyl-tin halide, for example tri-n-butyl-tin chloride (see, for example, Netherlands Published Specification 67/11,107). In a resulting compound having an esterified grouping fo ormla he grouping, when required, is con- verted into a different esterified carboxyl group of this formula, for example 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl is converted into 2-iodoethoxycarbonyl by treatment with an iodine salt, such as sodium iodide, in the presence of a suitable solvent, such as acetone. In the process according to the invention, and in additional measures which may require to be carried out it is possible, if necessary, transiently to protect free functional groups, which do not participate in the reaction, in the starting substance, or in the compoiund obtainable according to the process, for example free aino Groups; by

59 4 86,.9 93

57 385 /73

acylation, tritylation or silylation, free hydroxyl or

mercapto groups by etherification or esterification, and

free carboxyl groups by esterification, including silylation

and in each case to liberate them after the reaction has

taken place, when required, individually or conjointly, in a manner which.is in itself known. Thus it is possible to pro-

tect an amino, an hydroxyl, a carboxyl or a phosphono group

in an acyl radical Ac in the form of an acylamino group,

such as those mentioned above, for example as a

2,2,2-trichloroethoxycarbonylamino, 2-bromoethoxycarbonylamino, 4-methoxybenzyloxycarbonylamino,

diphenylmethoxycarbonylamino or tert-butoxycarbonylamino

group, or an arylthioamino or aryl-lower alkylthioamino group, for example a 2-nitrophenylthioamino group, or an

arylsulphonylamino group, for example a 4-methylphenyl- sulphonylamino group, or of a 1-lower alkoxycarbonyl-2-

propylideneamino group, or, respectively, of an acyloxy

group, such as those mentioned above, for example as a

tert.-butoxycarbonyloxy, 2,2, 2 -trichloroethoxycarbonyloxy 2 or -bromo-ethoxycarbonyloxy group, or, respectively, of

an esterified carboxyl group, such as .those mentioned above,

for example a diphenylmethoxycarbonyl group, or, respectively, an O,0'-disubstituted phosphono group, such

as those mentioned above, for example

60 4 8 6,9 9 3

57.385 173 an O,0'-di-lower alkylphosphono group, for example an

0,0'-dimethylphosphono group and subsequently, optionally after conversion of the protective group, for example of a- 2-bromoothoxycarbonyl group into a 2-iodoethoxycarbonyl group, to split the protected group in a-manner which is in itself known and depending on the nature of the protective group,

for example a 2,2,2-trichloroethoxycarbonylamino or 2-iodo- ethoxycarbonylamino group by treatment with suitable reducing

agents, such as zinc in the presence of aqueous acetic acid, a diphenylmethoxycarbonylamino or tert.-butoxycarbonylamino group by treatment with formic acid or trifluoroacetic acid, an arylthioamino or aryl-lower alkylthioamino group by treatment with a nucleophilic reagent, such as sulphurous acid, an aryl- sulphonylamino group by means of electrolytic reduction, a 1-lower alkoxycarbonyl-2-propylidenamino group by treatment with an aqueous mineral acid, or a tert.-butoxycarbonyloxy

group by treatment with formic acid or trifluoroacetic acid, or a 2 2 2 -trichloroethoxycarbonyloxy group by treatment with a chemical reducing agent, such as zinc in the presence of

aqueous acetic acid, or a diphenylmethoxycarbonyl group by treatment with formic acid or trifluoroacetic acid or by hydro- enolysis, or an O,0'-disubstistuted phosphono group by treatment. with an alkali metal halide, the splitting being carried out if desired partially. Salts of compounds of the formula I are manufactured in a manner which is in itself known. Thus, a salt of such a

compound which possesses an acid group is formed, by treat.-nt with a metal compound, such as an alkali

61 4 8 6,9 9 3

57,38 5 Ia metal salt, of a suitable carboxylic acid, for example the sodium salt of a-ethyl-caproic acid, or with ammonia or a suitable organic amine, preferably using a stoichiometric

amount or only a small excess of the salt-forming agent. An acid addition salt of a compound of the formulae I (sic) having a basic grouping is obtained in the customary manner, for example by treatment with an acid or with a suitable anion exchange reagent. An internal salt of a compound of the formulae I (sic) which contains a salt-forming amino group and a free carboxyl group is formed by neutralising a salt, such as an acid addition salt, to the isoelectric point, for example with a weak base, or by treatment with a liquid ion exchanger. A salt of a

1-oxide of a compound of the formula I having salt-forming group is manufactured analogously.

A salt is converted into the free compound in the customary manner, a metal salt and an ammonium salt, for example, by treatment with a suitable acid, and an acid addition salt, for example, by treatment with a suitable basic agent.

A resulting mixture of isomers is separated into the individual isomers according to methods which are in themselves known, a mixture of diastereomeric isomers,

by fractional crystallisation, adsorption chromatography (column chromatography or thin layer chromatography) or another suitable separation process. A resulting racemate is separated into the antipodes

in the usual manner, if appropriate after introducing a

62 486,9 9 3

57.38 5 /73

suitable salt-forming grouping, by forming a mixture of diastereomeric salts with an optionally active salt-forming agent, separating the mixture into the diastereomeric salts and converting the separated salts into the free compounds, or by fractional crystallisation from an optically active solvent.

Preferably, such a starting substance is used, and the reaction conditions are so chosen, that a compound initially mentioned as being particularly preferred is obtained. A starting compound of the formula II used according to the invention is manufactured by converting the acetoxymethyl group in a cephem compound of the formula

N 2 0 IV) Mz--O-O- CH3*

2 wherein Ra represents an acyl group Ac and wherein R 2

represents hydroxyl or a group R A 2 into the hydroxymethyl

group, for example by hydrolysis in a weakly basic medium,

such as with an aqueous

63 4 8 6,9 93

57,385 /73 sodium hydroxide solution at pH 9-10, or by treatment with a

suitable esterase, such as an appropriate enzyme .from

TRhizobium tritolii, Rhizobium lupinhi, Rhizobium japonicum or

Bacillus subtilis, functionally modifying a free carboxyl group

of the formula 2 in a suitable manner, for example

esterifying it by treatment with a diazo compound, such as

diphenyldiazomethane, and converting -the hydroxymethyl group ir

a halogenomethyl group, for example a chloromethyl or iodo-

methyl group. 'by treatment with a halogenating ager

such as a chlorinating agent, for example thionyl- chloride, or

an iodinating agent, for example N-methyl-N,N'-dicyclohexyl- carbodiimidium iodide. A chloromethyl group is converted into the methylene group of the starting material of the formula II either directly by treatment with a suitable

chromium-II compound, such as an inorganic or organic salt of

divalent chromium, for example chromium-II chloride or chromium

II acetate, in a suitable solvent, such'as dimethylsulphoxide, or indirectly via the iodomethyl group (which can be formed, .for example, by treating the chloromethyl compound with a metal

iodide, such as sodium iodide, in a suitable solvent, such as

acetone), by treatment of a resulting iodomethyl compound with a suitable reducing agent, such as zinc in the presence of

acetic acid. In a compound of the formula II which is further

obtained from compounds of the formula IV by electrochemical reduction or by reduction with chromium-II saltsor aluminium amalgam, a protected amino group in the 7-position .is

liberated or converted into another protected amino group

64 48 6,9 93

57.385 /73 and/or a free amino group in the 7-position is converted

into a protected amino group in a manner which is itself

known, for example as described above.

A starting substance of the formula III is

obtained, if in an abovementioned compound of the formula

R.\ 1R Ci CH I I (V) 0=C- N CH OH

0=0--R 2 2 a wherein R1 represent:, an acyl group Ac, R 2 preferably

represents hydroxyl and which contains a double bond in 3 4 the 2,3- or -position, the hydroxymethyl group is oxidi-

sed to the formyl group and, at a suitable stage, a 3-cephem

compound is isomerised to the desired 2-cephem compound and,

if desired or required, a hydroxyl group R 2 in a resulting

compound is replaced by a suitable etherified hydroxyl group

or by an amino or hydrazino group. The oxidation is carried

out according to the process described in U.S.A. Patent No.

3.351.596, that is to say by treatment with an oxidising metal

compound, such as a metal oxide, for example chromium trioxide

or manganese dioxide, or, in the case of a 2-cephem compound,

advantageously with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone

and, in the case of a 3-cephem compound, advantageously with

an aliphatic sulphoxide, such as a di-lower alkylsulphoxide,

for example dimethylsulphoxide, or a lower alkylenesulphoxide,

65 4 8 6,9 9 3

57,385 /73 for example tetramethylenesulphoxide, in the presence of an

aliphatic carboxylic acid anhydride, for example acetic

anhydride, preferably using an excess of the sulphoxide and

an equimolar amount of the anhydride as compared to the

sulphoxide, and at a temperature of about -50°C to about

+700 C, when required in the presence of an additional inert

solvent, such as benzene or toluene. The isomerisation of

a 3-cephem compound to the corresponding 2-cephem compound

is effected by treating an ester or anhydride, which has

optionally been formed in situ, with a base, such as a ter-

tiary amine, for example triethylamine, and/or a heterocyclic

base, for example pyrjdine.

A 2-cephem starting substance of the formula III

is further obtained by total synthesis, for example accor-

ding to the method described in Austrian Patents No. 263,768

and 264,537.

As mentioned above, the new compounds of the formula I are used as intermediate products for the manufacture

of compounds having the cepham structure, which either

possess valuable pharmacological properties or can again be

used as intermediate products.

Thus it is possible to convert a compound

of the formula I into an enol derivative thereof, for

example into an enol ether by treatment with an optional2ysubsti- tuted diazo-hydrocarbon compound of aliphatic character, such as a diazo-lower alkane, for example diazomethane, or

a phenyl-diazo-lower alkane, such as phcnyl-diazomethane,

66 486,9 93

57,385 /73 or into an enol ester by treatment with an acid or a suitable acid derivative, such as a halide, for example a

chloride, or an anhydride, and, if desired, to convert a A protected carboxyl group of the formula in an enol

derivative thus obtainable, into a free carboxyl group in

a manner which is in itself known, and thus to arrive at a

cephem compound of the formula

a

(VI) N -R

3,4-position and which contains a double bond in the 2,3- or b the abovementioned meanings, R 2 wherein Ra and R have theenR with represents hydroxyl or a radical RA which, together

the carbonyl grouping, forms a protected carboxyl group, radical and RA denotes an optionally substituted hydrocarbon

of aliphatic character or an acyl group. Compounds of the

an acyl formula VI, especially those in which Ra represents deri- radical contained in pharmacologically active N-acyl and vatives of 6p-amino-penam-3-carboxylic acid compounds Rb denotes 7p-amino-3-cephem-4-carboxylic acid compounds, hydroxyl hydrogen and R 2 represents hydroxyl or an etherified a group which together with the carbonyl grouping forms con- carboxyl group which can be split under physiological

*ditions, and RA has the abovementioned meaning, with func- 1' tional groups optionally present in an acyl radical

67 4 86,9 93

738 5/73 such as amino, carboxyl, hydroxyl and/or sulpho, usually being present in the free form, or salts of such compounds having salt-forming groups, on parenteral and/or oral administration are active against micro-organisms, such as Gram--positive bacteria, for example Staphylococcus aureus, Streptococcus pyogenes and Diplococcus oneumoniae, (for example in mice at doses of about 0.001 .to about 0.02 g/kg administered subcutaneously or orally), and Gram-negative bacteria, for example Escherichia coli, Salmonella ty:himuri.um, Shigella flexneri, Klebsiella pneumoniae, Enterobacter

cloacae, Proteus vulgaris, Proteus rett eri and Proteus

mirabilis, (for example in mice in doses of about 0.001 to

about 0.15 g/kg administered subcutaneously or orally), and

especially also against penicillin-resistant bacteria, whilst

being of low toxicity. These new compounds can therefore be

used,, for example in the form of antibiotically active prepar- ations, for the treatment of corresponding infections.

Furthermore, it is possible, in a cepham compound of the formula I, to reduce the oxo group in the, 3-position to the hydroxyl group, for example by treatment with a suitable complex metal hydride, such as sodium borohydride, in the presence of a suitable solvent, such as an alcohol or ether, and to convert the hydroxyl group, if desired, into an esterified hydroxyl group, especially into a hydroxyl group esterified by an organic carboxylic acid, and/or to convert a protected carboxyl group of the formula.-C(=o)-R into the free carboxyl group. In the cepham compound thus obtainable of the formula

68 4 86,9 93

57,385 /73

(VII) 0-0- 0= -R 2

wherein RB represents hydrogen or an acyl radical, the elements of a compound of the formula RB-OH VIII, that is to say of water of or an acid, are 'split off under acid or basic conditions, and a known 3-cephem compound of the formula

Ra

Rb/ S

Z (IX) 0=0-R 2 a b is thus obtained, wherein Ra, R1 and R2 have the above- mentioned meanings and in which these radicals are converted into one another in a manner which is in itself kno/n. The compounds of the formula IX or salts thereof however possess valuable pharmacological, especially antimicrobial properties, especially in those cases in which Ra represents an acyl radical contained in pharmacologically active N-acyl deriva- 6 tives of P-amino-penam-3-carboxylic acid compounds and 7p-amino-3-cephem-4-carboxylic. acid compounds,. Rb denotes hydrogen and R2 represents hydroxyl or an etherified hydroxyl group -which together with the carbonyl grouping forms a carboxyl group which can be split under physiological conditions,

69 4 86.9 93

57.385 /73

or salts thereof, or can be used as intermediatp products for the manufacture of the said compounds having pharmacological properties. In the above conversions of compounds according to the invention, of the formula I, to the compounds of the formula IV or to the compounds of the formulae V and VII, it is not necessary to isolate compounds of the formula I; it is possible to convert them directly, in the form of the crude reaction mixtures after the manufacture from the compounds of the formula II, into the compounds of the formula. VI or VII and IX. Throughout this specification, organic radicals described as "lower" contain up to 7, preferably up to 4, carbon atoms; acyl radicals contain up to. 1 8 preferably up to 12, carbon atoms. The terms "optionally substituted", "optionally present", "optionally protected", and the like, are used throughout this specification to mean unsubstituted or substituted, absent or present, free or protected, and the like, respectively. The Examples which follow illustrate the invention.

70 4 86,9 93

57385 /73 Example 1: A solution of 0.50 g of 3-methylene-7p-phenylacetyl- amino-cepham-4a-carboxylic acid diphenylmethyl ester in 100 ml of methanol is treated for 6.5 minutes at -70°C with a stream of oxygen and ozone, containing 0.175 mmol/min. of ozone.

The reaction mixture is treated with 0.5 ml of dimethyl- sulphide and is stirred for one hour at -70°C and then for 2 hours at room temperature and evaporated to dryness. The residue, in methylene chloride, is chromatographed on 15 g of silica gel. Amorphous 7p-phenylacetylamino-cepham-3-one- 4 -carboxylic acid diphenylmethyl ester is eluted with methylene chloride,thin layer chromatography (silica gel): Rf 0.47 (system: toluene/acetone/methanol/acetic acid, 80:10:5:5); infrared absorption spectrum (in methylene chlo- ride): characteristic bands at 2.95[, 5.61[, 5.77g, 5.854, 5.951, 6.21p and 6.874; the compound shows a positive iron-III chloride reaction, which indicates the presence of the enol form. Using methylene chloride, containing 10% of acetone, it is possible to elute a polar compound which is very pro- bably identical with 7p-phenylacetylamino-cepham-3-one-4 carboxylic acid diphenylmethyl ester-l-oxide, thin layer chromatogram (silica gel): Rf 0.22 (system: toluene/acetone/ methanol/acetic acid, 80:10:5:5); infrared absorption spec- trum (in methylene chloride): characteristic bands at 2.96[, 5.58, 5.761 (shoulder), 5.83[, 5.97p, 6.224 and 6.614; the compound shows a positive iron-III chloride'reaction which indicates the presence of the enol form.

4 8 6,9 93

57 38 5/73 The starting material can be manufactured as follows: A solution of 11.82 g of the crude sodium salt of 3-hydroxymethyl-7p-phenylacetylamino-3-cephem-4- carboxylic acid (manufactured by enzymatic desacetylation of the sodium salt of 3-acetoxymethyl-7f-phenylacetylamino- 3-cephem-4-carboxylic acid with the aid of a purified enzyme extract from Bacillus subtilis, strain ATCC 6,633, and subsequent lyophilisation of the reaction solution) in 200 ml of water is covered with 400 ml of ethyl acetate and acidified to a pH value of 2 with concentrated aqueous phosphoric acid. The aqueous phase is separated off and

twice re-extracted with 150 ml of ethyl acetate at a time. The combined organic extracts are washed four times with ml of water at a time, dried over magnesium sulphate and then-concentrated to about 400 ml. Excess diphenyl-

diazomethane is added to the solution, which is left to stand for 3 hours at room temperature, and the granular crystalline precipitate is then filtered off. The filtrate

is concentrated to about 200 ml, cyclohexane is added

whilst warm and after cooling to room temperature the 0 The mixture is left to stand for some time at about 4 C. precipitate is filtered off and recrystallised from a .mixture of acetone and cyclohexane; the 3-hydroxymethyl-

7 -phenylacetylamino-3-cephem-4-carboxylic acid diphenyl- methyl ester thus obtained melts at 176-176.5 C (uncorrected); [a]2 0 -6 1o (c 1.231% in chloroform);

thin layer chromatogram (silica gel; detection with iodine

486.9 93

57.385 /73 vapour or ultraviolet light, X 2 5 4 mp Rf 0.42 (system: chloroform/acetone, Rf 0.43 (system: toluene/ acetone, and Rf 0.41 (system: methylene chloride/

acetone, 6:1). 1.03 g of 3-hydroxymethyl-7p-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 tetrahydrofurane under

a-nitrogen atmosphere and warmed at 35 0 C for one hour.

Thereafter, a further 1.05 g of N-methyl-N,N'-dicyclo-

hexylcarbodiimidium iodide, in 15 ml of absolute tetra-

hydrofurane, is added and the mixture is left to stand for

17 hours at room temperature under a.nitrogen atmosphere.

The reaction mixture is freed of the solvent on 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 addition of 10% of distilled

water); the column is rinsed with 4 portions of methylene

chloride, each of 100 ml. The eluate is concentrated to

a small volume and chromatographed on a silica gel column

g; deactivated by adding 10% of distilled water).

Non-polar impurities are eluted with a total of 900 ml of

a 3:7 mixture of toluene and methylene chloride. Elution

.with 2 portions of methylene chloride, each of 200 ml,-

yields 3-iodomethyl-7P-phenylacetylamino-3-cephem-4-

carboxylic acid diphenylmethyl ester; the fractions which

according to a thin layer chromatogram are a single substance

are lyophilised from benzene. Infrared absorption spectrum

48 6,9 93

.57,385 /73

(in methylene chloride): characteristic bands at 3.00 j,

5.62 P, 5.82 4, 5.95 p, 6.70 p, 7.32 p and 8.16 p. The iodination reagent used. above can be manufactured as follows: 42 g of freshly distilled N,N'-dicyclohexyl-" carbodiimide are dissolved in 90 ml of methyl iodide in a 250 ml round flask equipped with a magnetic stirrer and reflux condenser and fitted nitrogen bulb, at room temperature under a nitrogen atmosphere, and the colourless reaction 0 mixture is stirred for 72 hours at a bath temperature of 70 C. At the end of the reaction time, the excess methyl iodide is distilled from the solution, which is now red-brown,

under reduced pressure and the viscous red-brown residue is dissolved in 150 ml of absolute toluene at 40°C. The

crystal mass, which crystallises out spontaneously within a few hours, is separated from the mother liquor with the aid of a glass suction filter with fitted nitrogen bulb, whilst excluding air, the reaction vessel is rinsed three times with 25 ml of absolute, ice-cold toluene at a time and the same toluene is used in order to wash the slightly yellowish crystal mass on the glass suction filter until it is colourless. After drying for 20 hours at 0.1 mm Hg and room temperature, the N-methyl-N,N-dicyclohexyl- carbodiimidium iodide is obtained in the form of colourless crystals, melting point 111-113 0 C; infrared absorption spectrum (in chloroform): characteristic bands at 4.72 p and 6.00 r. f

A solution of 0.400 g of 3-iodomethyl-7p-phenyl-

A 4 86,9 93

57 38 5 73 acetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester in 15 ml of 90% strength aqueous acetic acid is cooled to OOC in an ice bath and 2.0 g of zinc dust are added in portions whilst stirring well. After a reaction time

of 30 minutes at OC the unreacted zinc dust is filtered off by means of a suction filter covered with a layer of diatomaceous earth; the filter residue is repeatedly suspended in fresh methylene chloride and again filtered. The combined filtrates are concentrated under reduced pressure, mixed with absolute toluene and evaporated to dryness under reduced pressure. The residue is taken up in 50 ml of methylene chloride and 30 ml of an 0.5 molar aqueous

dipotassium hydrogen phosphate solution, whilst stirring; the aqueous phase is separated off, re-extracted with two portions of methylene chloride, each of 30 ml, and discarded. The organic extracts are repeatedly washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The

residue is chromatographed on a column of 22 g of silica gel (with addition of 10% of water). The 3-methylene-7p-

phenylacetylamino-cepham-4a-carboxylic acid diphenylmethyl ester is eluted with methylene chloride, and with methylene chloride containing 2% of methyl acetate, and is crystallised from a mixture of methylene chloride and hexane, melting 0 10 (c 0.715 in chloro- point 144-147C; -180

form); ultraviolet absorption spectrum (in 95% strength aqueous ethanol): max 254 mi (e 1,540) and 260 mp

(e 1,550); infrared absorption spectrum (in methylene

486,993

57,38 5 73

chloride): characteristic bands at 2.94 p, 5.65 R,

5.74 p, 5.94 p, 6.26 1i and 6.67 i. Example 2 A solution of 1.53 g of 3-formyl-7p-phenylacetyl- amino-2-cephem.-4-carboxylic acid diphenylmethyl ester in ml of methylene chloride is cooled to OoC and 0.61 g of 3-chloroperbenzoic acid is added. The mixture is left to stand for one hour whilst warming to room temperature and is thereafter successively washed with 5% strength aqueous sodium bisulphite solution, 0.5 molar aqueous dipotassium hydrogen phosphate solution and water; the aqueous wash solu- tions are twice extracted with methylene chloride and then discarded. The organic phase is dried over magnesium sul- phate and evaporated under reduced pressure. The yellow jelly-like residue, containing 3-formyl- oxy-7p-phenylacetylamino-cephem-4-carboxylic acid diphenyl- methyl ester, in which the ring double bond is preferably in the 3-position, is stirred for one hour at OOC with 30 ml of tetrahydrofurane and 30 ml of an 0.5 molar sodium bicarbonate solution and the mixture is concentrated under reduced pres- sure to a volume of about 25 ml. It is diluted with 25 ml of water and then extracted twice with ethyl acetate. The organic phase is washed with water, dried over magnesium sul- phate and evaporated under reduced pressure. The residue is chromatographed on 65 g of silica gel. 7p-Phenylacetylamino- cepham-3-one-4g-carboxylic acid diphenylmethyl ester is eluted with methylene chloride containing 2-3% of acetone and is lyophilised from dioxane; the product, which according

7C 486.9 93

57.385/73 to thin layer chromatography is not quite pure, is identical

with the product of the process described in Example 1 and is

used, without further purification, as a starting material.

The starting material can be manufactured as follows:

A suspension of 3.40 g of 3-acetoxymethyl-70-phenylacetylamino-

2-cephem-4a-carboxylic acid in 70 ml of distilled water is

mixed with 1 N aqueous sodium hydroxide solution, whilst

stirring with a Vibro-mixer, until a pH value of 7.3 is

reached. The solution is warmed to 35 0 C in a thermostatic

bath and 0.4 g of the cell lyophilisate from Bacillus subtilis

ATCC 6633, in 3 ml of water is added. The pH value is kept

constant at 7.4 by adding 1 N aqueous sodium hydroxide solution;

after about 2 hours half the theoretical consumption of

sodium hydroxide is reached. The mixture is left to complete

reaction until no further sodium hydroxide is consumed and

the pH value of the reaction solution no longer changes even

after standing for several hours at room temperature. It is

covered with 300 ml of cooled ethyl acetate and acidified with

molar aqueous phosphoric acid to pH 2.0, whilst stirring

well. After separating the layers, the aqueous phase is

saturated with sodium chloride and extracted with two further

portions each of 250 ml of cold ethyl acetate. The combined

organic phases are washed five times with 50 ml portions of

a saturated aqueous sodium chloride solution, dried over sodium

sulphate and evaporated. The residue consists of chromato-

graphically pure 3-hydroxymethyl-7P-phenylacetylamino-2-cephem-

4a-carboxylic acid which after repeated crystallisation from a

mixture of ethyl acetate and cyclohexane is in the form of white

48 6,9 9 3

7 38 /73 0 needle-shaped crystals which melt at 156-156.5 C.

A solution of 0.7 g of 3-hydroxymethyl-73-phenylacetyl-

amino-2-cephem-4a-carboxylic acid in 30 ml of a 4:1 mixture of

dioxane and methanol is treated with 0.507 g of diphenyl-

diazomethane in 5.07 ml of dioxane and the mixture is left to

stand at room temperature; over the course of 90 minutes,

further quantities of diphenyldiazomethane are added in portions

until the slight discolouration persists. The mixture is

then evaporated to dryness and the residue is crystallised from

a mixture of ethyl acetate and cyclohexane; 3-hydroxymethyl-7P- phenylacetylamino-2-cephem-4a-carboxylic acid diphenylmethyl

ester, thus obtainable, is in the form of fine colourless

needles which melt at 17179-79.5 C; [a]20 +390° 1o

(c 1.174 in chloroform); thin layer chromatogram, silica gel:

Rf 0.35 (system: benzene/acetone ultraviolet

absorption. spectrum (95% strength aqueous ethanol): max 250 mp (e 6,500) and min 245 mp (e 6,400); infrared

absorption spectrum: Characteristic bands at 2.74 p, 2.89

5.58 p, 5.71 p, 5.90 p, 6.61 p and 6.65 p (in methylene chloride) and at 3.00 p, 3.07 p, 5.62 p, 5.71 p, 6.04 p, 6.52 p, 6.68 u, 7.10 p, 7.42 p, 8.20 p and 8.52 p (in mineral oil). A mixture of 5.14 g of 3-hydroxymethyl-7p-phenyl-acetyl-

amino-2-cephem-4a-carboxylic acid diphenylmethyl ester in 0 150 ml of acetone is treated dropwise, at -15 C, with a chromic acid solution (manufactured by dissolving 267 g of chromium-VI

oxide in 230 ml of concentrated sulphuric acid and 400 ml of

water and diluting with water to 1,000 ml) until -the orange-

brownish discolouration persists; after 20 minutes, 4.5 ml of

4 86,9 9 3

57,385 /3 the reagent have been consumed. The mixture is stirred for

minutes at -100 C, 0.5 ml of isopropanol is added and the whole is concentrated under reduced pressure. The concentrate

is diluted with 50 ml of water and extracted with ethyl acetate. The organic extract is washed with water, dried over magnesium sulphate and evaporated. The residue is recrystallised from a mixture of ethyl acetate and cyclohexane and yields 3-formyl- 7p-phenylacetylamino-2-cephem-4a-carboxylic acid diphenylmethyl ester, melting point 175.5-176°C (with decomposition); thin

layer chromatogram (silica gel): Rf 0.35 (system: toluene/

acetone, 4:1) and Rf 0.58 (system: toluene/acetone 65:35); ultraviolet absorption spectrum (in 95% strength ethanol): Xmax 289 mp (E 20,200); infrared absorption spectrum (in

mineral oil): Characteristic bands at 3.00 p, 5.63 p, -5.76 p, 5.95 p, 5.99 p and 6.07 p. Example 3: A stream of oxygen and ozone (containing 0.35 mmol of ozone per minute) is passed for 4 minutes through a solution, cooled to -60°C, of 0.553 g of the 4-methyl- phenylsulphonate of 7p-amino-3-methylene-cepham-4a- carboxylic acid diphenylmethyl ester in 50 ml of methanol. After a further 5 minutes, the pale blue-coloured solution is treated with 0.3 ml of dimethyl sulphide. The mixture is stirred for 15 minutes at -70°C, for one hour at -120 C and for one hour in an ice bath and is then evaporated. The residue is taken up in a small amount of methylene chloride, diethyl ether is then added until the mixture turns cloudy, and the mixture is left to stand. The micro-

486,993

57 385 /73 crystalline, reddish-coloured pulverulent precipitate is filtered off and yields the 4-methylphenylsulphonate of

7p-amino-cepham-3-one-4a-carboxylic acid diphenylmethyl.

ester which is mainly present in the enol form as the 4-methylphenylsulphonate of 7p-amino-3-cephem-3-ol-4- carboxylic acid diphenylmethyl ester, melting point 143-1450C (with decomposition); thin layer chromatogram" (silica gel) Rf-0.28 (system: ethyl acetate/pyridine/ water, 85:10:5); ultraviolet absorption spectrum (in ethanol): max 262 mg (s 3,050) and 282 mt (s 3,020);

infrared absorption spectrum (in methylene chloride): characteristic bands at 5.58 5.77 P (shoulder), 6.02 A

and 6.22 p. The starting material can be manufactured as follows: A solution, cooled to -15"C, of 2.0 g of 3-methylene-7p-phenylacetylamino-cepham-4a-carboxylic acid diphenylmethyl ester in 80 ml of absolute methylene chloride is mixed with 3.2 ml of absolute pyridine and 32 ml of an 8% strength solution of phosphorus pentachloride in methylene chloride and stirred for one hour under a nitrogen atmosphere at a temperature between -10 C and 0 0 C. The reaction mixture is then cooled to -25 C, mixed with 25 ml of absolute methanol and stirred for one hour at -100 C and then for 1.5 hours at room temperature. 80 ml

of an 0.5 molar aqueous solution of potassium dihydrogen phosphate are then added, the pH value is adjusted to 2 with 20% strength aqueous phosphoric acid and the mixture

48 69 93

57.385 /73 is stirred for 30 minutes at room temperature. The organic phase is separated off; the aqueous

phase is twice re-extracted with 150 ml of methylene chloride

at a time and 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

ethyl acetate is added at 00C. A voluminous precipitate

separates out, which is filtered off, rinsed with cold

ethyl acetate and diethyl ether, dried and recrystallised,

from a mixture of methylene chloride and diethyl ether.

The 4-methylphenylsulphonate of 73-amino-3-methylene-

cepham-4a-carboxylic acid diphenylmethyl ester is thus

obtained in the form of colourless needles, melting point 0 153-155 C; [a]D -140 10 (c 0.97 in methanol); ultra-

violet absorption spectrum (in ethanol): max 257/u

(6 1,500); infrared absorption spectrum (in methylene

chloride): characteristic bands at 3.5,u, 5.60.u, 5.75au,

8.50,u, 9.68,u and 9.92,u.

Examole 4

An oxygen-ozone stream, containing 0.21 mmol of

ozone/minute, is passed for one hour into a solution,

cooled to -70 0 C, of 5.0 g of 3-methylene-73-(D-a-tert.-

butoxycarbonylamino-a-phenylacetylamino)-cepham-4c-carboxylic

acid diphenylmethyl ester in 500 ml of methylene chloride,

whilst stirring vigorously. After a further 10 minutes, 3

ml of dimethyl sulphide are added to the reaction mixture, 0 which is stirred for one hour at -65 C and for 2 hours at

room temperature and then evaporated under reduced pressure.

The crude product, which contains the

8I1 486.993

57,385 /73 carbonyl-amino-a-phenylacetyl-amino)-cepham-3-one-4§ -carboxy-

lic acid diphenylmethyl ester, in 150 ml of methanol, is

treated at 00C with an excess amount of a solution of diazo-

methane in diethyl ether, stirred for 15 minutes and subse-

quently evaporated. A yellowish foam is obtained, which is

chromatographed on 200 g of silica gel. Amorphous 3-methoxy-

73-(D-a-tert.-but oxycarbonylamino-a-phenylacetylamino) -3- cephem-4-carboxylic acid diphenylmethyl ester is eluted with

.a 3:1 mixture of toluene and ethyl acetate. Thin layer

chromatogram (silica gel): Rf 0.22 (system: toluene/ethyl

acetate, infrared absorption spectrum (in methylene

chloride): characteristic bands at 2.94/u, 5.60,u, 5.85,u,

6.23,u and 6.70/u.

The starting material can be manufactured as

follows A chromatography column (diameter 3 cm) is

filled with 350 g of zinc grit, which is amalgamated for

minutes with an 0.1 molar solution of mercury-II chloride

in 0.1 N hydrochloric acid and is washed with a large

amount of water and subsequently with a small amount of

1 N hydrochloric acid. A solution of 55 g of green

chromium-Ill chloride hexahydrate in 55 ml of water and

12 ml of 2 N sulphuric acid is poured into the reduction

tube and the outlet speed is regulated so that a chromium-

II chloride solution of a pure blue colour drips into the

reaction vessel, which is kept under a nitrogen atmosphere.

The blue chromium-II chloride solution is subsequently

treated with a solution of 92 g of sodium acetate in 180 ml

of air-free water, whereupon the solution assumes a red

discolouration and finely crystalline chromium-II acetate

82 486,993

57,385 /73 precipitates. After completion of the precipitation,

the supernatant solution is removed and the chromium-II

acetate is twice washed with 250 ml of air-free water at

a time. A solution of 10.0 g of 3-acetoxymethyl-70-(D-

a-tert.-butoxycarbonyl-amino-a-phenylacetyl-amino)-3-

cephem-4-carboxylic acid in 200 ml of dimethylsulphbxide is

added to the moist chromium-II acetate and the reaction

mixture is stirred for 15 hours under a nitrogen atmosphere

at room temperature. For working up, the reaction mixture

is aerated for 30 minutes and after addition of 1,000 g

of a polystyrenesulphonic ion exchanger in the Na form

(Dowex 50 W) and 1,000 ml of water, the whole is stirred for

one hour. After removing the ion exchanger, the pH value

of the solution is adjusted to 2 with 6 N hydrochloric acid

and the aqueous phase is extracted three times with 2,000 ml

of ethyl acetate at a time. The organic extracts are

washed once with 1,000 ml of a saturated aqueous sodium

chloride solution, dried over magnesium sulphate and

evaporated.

The resulting crude product is dissolved in

100 ml of methanol and stirred with a solution of 6 g of

diphenyldiazomethane in 30 ml of benzene for 1 hour at

room temperature. The crude product obtained after the

evaporation is chromatographed on 500 g of silica gel;

48 6, 993

7 .385/73 3-methylene-7p-(D-a-tert.-butoxycarbonylamino-a-phenyl-

acetyl-amino)-cepham-4a-carboxylic acid diphenylmethyl ester

is eluted with a 4:1 mixture of petroleum ether and diethyl

ether; after crystallisation from a mixture of methylene 0 dichloride and hexane, the product melts at 156-158 C;

[a]D -50 t 10 (c 0.713, chloroform); ultraviolet

absorption spectrum in 95% strength aqueous ethanol):

iax 258 p E 990); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 p, 5.64u,

5.74 u, 5.88 p (shoulder) and 6.71 p. Example

A solution of 1.0 g of 3-methylene-7P-phenyl-

acetylamino-cepham-4a-carboxylic acid diphenylmethyl ester

in 250 ml of methylene chloride is treated for 8-1/2 minutes

at -700C with an oxygen-ozone mixture (0.265 mmol of ozone/

minute) and 1 ml of dimethyl sulphide is added to the react- 0 ion mixture. The mixture is stirred for 30 minutes at -70 C

and for 1-1/2 hours at room temperature and is then evapor-

ated to dryness under reduced pressure. The residue, con-

taining a mixture of 7p-phenylacetylamino-cepham-3-one-4

carboxylic acid diphenylmethyl ester and of 73-phenylacetyl-

amino-cepham-3-one-4a-carboxylic acid diphenylmethyl ester

1-oxide is taken up in 50 ml of methanol and treated with

an excess of diazomethane (in the form of a solution in

diethyl ether) at OOC. The whole is stirred for one hour

at 0°C and then evaporated under reduced pressure. The

residue is chromatographed on 50 g of silica gel. Elution

with a 4:1 mixture of toluene

4 8 6.9 93

57.385 /73 and ethyl acetate yields 3-methcxy-7p-phenylacetylamino- 2-cephem-4a-carboxylic acid diphenylmethyl ester of Rf

0.57 (system: toluene/ethyl acetate, melting point

174-177 0 C after recrystallisation from a mixture of methylene chloride and pentane; ultraviolet absorption spectrum (in 95% strength aqueous ethanol): Xmax= 258 m[i (e 4,000); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 p, 5.60.p, 5.71 P, 5.92 p, 6.15 p and 6.66 p; followed by 3-methoxy-7p- phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester of Rf-..37 (system: toluene/ethyl acetate 1:1): ultraviolet absorption spectrum (in 95% strength aqueous ethanol): max= 258 mi (e 6,340), Amax= 264 mi (e mp 5,600); infrared 6,350) and Xshoulder= 261 absorption spectrum (in methylene chloride): characteristic bands at 2.94 p, 3.02 p, 5.62 P, 5.67 p (shoulder), 5.81 p, 5.92 p, 6.23 p and 6.67 i; elution with ethyl acetate yields 3- methoxy-70-phenylacetylamino-3-cephem-4-carboxylic acid diphenyl- methyl ester 1-oxide of Rf 0.31 (system: .ethyl acetate); melting point 152-155°C after crystallisation from a mixture of acetone and diethyl ether; ultraviolet absorption spectrum (in 95% strength aqueous ethanol): e 3,610) and shoulder 247 mp; Amax% 288 m infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 p, 5.59 5.81 p, 5.95 (i, 6.22 p and 6.61 p. Example 6: A solution of 0.50 g of 3-methylene-7P-phenyl-

4 86,9 93

7,385 /73 acetylamino-cepham-4a-carboxylic acid diphenylmethyl ester in 50 ml of methanol is treated with an oxygen-ozone mixture at -700 C until a blue colouration starts to appear. The excess ozone is driven off with nitrogen; 0.5 ml of dimethyl sulphide is added and the mixture is stirred for 1- hours at room temperature. The reaction mixture, containing a mixture of 7p-phenylacetylamino-cepham-3-one- 4S-carboxylic acid diphenylmethyl ester and of 7P-phenyl- acetylamino-cepham-3-one-4S-carboxylic acid diphenylmethyl ester 1-oxide is then evaporated to dryness under reduced pressure. The residue is taken up in 10 ml of pyridine, ml of acetic anhydride are added and the mixture is left to stand 'for 16 hours at 00 C. It is evaporated to dryness under a high vacuum; the residue -is taken up in ethyl acetate and the organic solution is washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution,- dried over sodium sulphate and evaporated under reduced pressure. The residue is chromatographed on 30 g of silica gel, 3- acetoxy-7p-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester being eluted with a 4:1 mixture of toluene and ethyl acetate. The product is crystallised from a mixture of acetone and diethyl ether, melting point 158-160 0 C; ultraviolet absorption spectrum (in 95% strength aqueous ethanol): max 258 mg (e 6,580) and 264 mg (E 6,550); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95 p,

5.59 P, 5.69 p (shoulder), 5.78 9, 5.91 i, 6.06 p (shoulder)

4 86,9 93

57.385 /73 and 6.67

Example 7: A solution of 1.0 g of 3-methylene-7p-phenylacetyl- amino-cephat-4a-carboxylic acid diphenylmethyl ester in 100 ml of methanol is treated with an oxygen-ozone mixture at until a blue colouration begins to show, and the excess ozone is expelled with nitrogen. The reaction mixture is treated with 0.4 ml of dimethylsulphide and is stirred for 30 minutes at room temperature. It is then cooled to O0C and a solution of 0.10 g of sodium borohydride in 5 ml of water is added to the reaction mixture, which contains amino-cepham-3-one-4 -carboxylic acid diphenylmethyl ester and 7p-phenylacetylamino-c-,pham-3-one-4 -carboxylic acid diphenyl- methyl ester-l-oxide. The reaction is allowed to proceed for 30 minutes at 00 C, the pH value is adjusted to about 6 by adding acetic acid and the reaction mixture is evaporated under reduced pressure. The residue is taken up in ethyl acetate; the organic solution is washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The residue is chromato- graphed on 50 g of silica gel. 3-Hydroxy-7p-phenylacetyl- amino-cepham-4 -carboxylic acid diphenylmethyl ester is eluted with a 2:1 mixture of toluene and ethyl acetate and after crystallisation from a mixture of acetone and diethyl ether melts at 157-1600 C; [a]D +800 1 (c 0.492 in dioxane): 2 8t Xmax 5 850); infrared absorption spectrum (in methylene chloride): characteristic bands at 2 8 2, 2.94 p,

48 6.9 93

57.385 73 5.63P, 5.7 4 p, 5.92[, 6.25 and 6.63P. Example 8: A solution of 0.400 g of 7p-(D-a-tert.-butoxycarbonyl- amino-a-phenyl-acetylamino)-3-methylene-cepham-4ax-carboxylic acid

diphenylmethyl ester in 40 ml of methylene chloride is cooled to 00 C and 0.0835 g of tetracyanoethylene are added. The'yellow solu- tion is treated, at OOC, with an oxygen/ozone mixture until 0.773 mmol of ozone has been consumed and is then evaporated to dryness under a high vacuum at about 350 C. The residue, containing

7p-(D-a-tert.-butoxycarbonylamino-a-phenyl-acetylamino)-cepham- 3-one-4- -carboxylic acid diphenylmethyl ester is taken up in ml of methanol, treated with a solution of diazomethane in diethyl ether until the yellow colouration persists, and then 0 0.1 g of the evaporated under reduced pressure at about 35 C. residue is worked up by means of a layer chromatogram (silica gel; system: ethyl acetate/toluene, 3-methoxy-7P-(D-a- tert.-butoxycarbonylamino-a-phenyl-acetylamino)-3-cephem-4- carboxylic acid diphenylmethyl ester, which is identical with the product of Example 4, being obtained at Rff 0.5, and 7P-(D-a- tert.-butoxycarbonylamino-a-phenyl-acetylamino)-3-methylene- cepham-4a-carboxylic acid diphenylmethyl ester being obtained at Rf-o0.6. Example 9: A solution of 0.2 g of 7p-(D-a-tert.-butoxycarbonylamino- a-phenyl-acetylamino)-3-methylene-cepham-4a-carboxylic acid

diphenylmethyl ester in 3 ml of methylene chloride is cooled to 0 -22 C and treated, whilst cooling, first with 0.026 ml of pyridine and then with an ozone-oxygen mixture until 1.31 mmols

48 6,9 9 3

57,385 /73 of ozone have been passed through. The reaction mixture is evaporated to dryness in a high vacuum and the residue is purified by thin layer chromatography. 7P-(D-a-tert.-Butoxy- carbonylamino-a-phenyl-acetylamino)-cepham-3-one-45-carboxylic acid diphenylmethyl ester shows an Rf- value of-0.05 (silica gel; system: toluene/acetone/methanol/acetic acid,-'80:10:4:5); infrared absorption spectrum (in methylene chloride): Characteristic bands at 2.94 p, 3.40 p, 5.62 p, 5.77 p, 5.75- 5,95 p (broad band), 6.21 p and 6.88 p. Example The manufacture of phenyl-acetylamino)-cepham-3-one-4c-carboxylic acid diphenyl- methyl ester from 7p-(D-a-tert.-butoxycarbonylamino-a-phenyl- acetylamino)-3-methylene-cepham-4a-carboxylic acid diphenyl- methyl ester is advantageously carried out continuously: A 1% strength solution of 7P-(D-a-tert.-butoxycarbonylamino-a-phenyl- acetylamino)-3-methylene-cepham-4a-carboxylic acid diphenyl- methyl ester in methylene chloride, which has been precooled to O0 C, is allowed to flow through a reactor tube (about 3 cm diameter) which is filled with packings (for example Raschig rings) and is cooled to OOC, and an ozone-oxygen mixture which provides 0.245 mmol of ozone per minute is passed through the tube in counter-current. The gas stream is regulated so that 700 ml of the gas mixture flow hourly through the reactor tube. The dwell time of the solution of 7P-(D-a-tert.-butoxycarbonyl- amino-a-phenyl-acetylamino -3-methylene-cepham-4a-carboxylic acid diphenylmethyl ester in the reactor tube is 15 seconds. The reaction solution containing the ozonide is allowed to run

48 6,9 93

57.385/73 directly into a receiver containing a solution of dimethyl-

sulphide in methylene chloride until it contains an excess of

of dimethylsulphide; the receiver is then changed. The

solution of 7p-(D-a-tert.-butoxycarbonylamino-a-phenyl-

acetylamino)-cepham-3-one-4e-carboxylic acid diphenylmethyl

ester, thus obtainable, is evaporated under reduced pressure

at about 35 C and the residue is taken up in methanol and treated

with a solution of diazomethane in diethyl ether, for example as

described in Example 4. 3-Methoxy-7-(D-a-tert.-butoxycarbonyl-

amino- a-phenyl-acetylamino)-3-cephem-4-carboxylic acid diphenyl- methyl ester, which is identical with the product of Example 4,

is thus obtained.

Example 11: A mixture of 5 g of 3-methylene-7p-(D-a-tert.-

butoxycarbonylamino-a-phenylacetylamino)-cepham-4a-carboxylic

acid diphenylmethyl ester and 500 ml of methylene chloride is

treated, at -70 C, with 1.15 equivalents of ozone according

to the process described in the preceding examples, 2 ml of dimethylsulphide are subsequently added and the mixture is

stirred for one hour at -70C and 2 hours at room temperature

and is then evaporated under reduced pressure. The residue,

containing 7p-(D-a-tert.-butoxycarbonylamino-a-phenylacetyl-

amino)-cepham-3-one-4f-carboxylic acid diphenylmethyl ester, is dissolved in 150 ml of methanol and a solution of diazo-n- butane in diethyl ether is added at O00 until the yellow colouration persists. After 15 minutes, the solution is evaporated under reduced pressure and the residue is purified

by means of preparative layer chromatography (silica

4 86.9 3

57 385/73 gel; 1.5 mm thickness; plates of size 16 x 100 cm; system: toluene/ethyl acetate, 72:25). The zone which is visible under ultraviolet light, and has an Rf value of about 0.35, yields 3-n-butoxy-7p-(D-a-tert.-butoxycarbonylamino-a-phenyl- acetylamino)-3-cephem-4-carboxylic acid diphenylmethyl ester, which is again purified by renewed chromatography on silica gel and is lyophilised from dioxane, [a] 20 +110 1° 0.98 in chloroform); ultraviolet absorption spectrum (in strength aqueous ethanol): max 264 mpL (e 6,100); infra- red absorption spectrum (in methylene chloride): character- istic bands at 2.88 5.63 t, 5..8,4 (shoulder), 5.88 p, 6.26 p.and 6.71 I. Example 12: A solution of 0.258 g of 3-methylene-7p-phenylacetyl- amino-cepham-4a-carboxylic acid diphenylmethyl ester 1-oxide in 50 ml of methanol is treated with an oxygen/ozone mixture mmols of ozone per minute) at -650 C until the blue colouration persists. The reaction mixture is thereafter treated with 0.5 ml of dimethylsulphide, stirred for minutes at -65 C and 30 minutes at room temperature and evaporated under reduced pressure. The residue, containing 7P-phenylacetylamino-cepham-3-one-4 -carboxylic acid diphenyl- methyl ester 1-oxide is taken.up in 20 ml of methanol and treated, at 0oC, with an ethereal solution of diazomethane in diethyl ether until the yellow colouration persists. After standing for 15 minutes, the reaction mixture is evaporated under reduced pressure. The residue is purified by means of preparative thin layer chromatography; the zone

4 86.9 9.3

57.385 /73 which is visible under ultraviolet light (X 254 mL), of Rf-.0.20 (system: ethyl acetate; identification with iodine) is eluted with a 1:1 mixture of acetone and methanol and 3-methoxy-7p-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide is thus obtained, ultra- violet absorption spectrum (in 95% strength aqueous ethanol) max 276 mt (e 7,500); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 p, 5.56 I, 5.81 5.92 L, 6.22 R and 6.67 t.

The starting material used in the above example can be manufactured as follows: a solution, cooled to 0°C, of 0.50 g of 3-methylene-7-phenylacetylamino-cepham-4a- carboxylic acid diphenylmethyl ester in 50 ml of methylene chloride is mixed with a solution of 0.19 g of 3-chloro- perbenzoic acid in 10 ml of methylene chloride and the mix- ture is stirred for 30 minutes in an ice bath under a nitrogen. atmosphere. The reaction mixture is diluted with 100 ml of methylene chloride, washed twice with 50 ml of a saturated aqueous sodium bicarbonate solution and with 50 ml of a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The residue is chromatographed on 50 g of silica gel. 3- Methylene-7p-phenylacetylaminocepham-4a-carboxylic acid di- phenylmethyl ester 1-oxide is eluted with methylene chloride, containing 3-5% of acetone, and crystallised from a mixture of acetone, diethyl ether and hexane, melting point 172-1750 C; -680 (c 0.925 in chloroform); thin layer chromato- .gram (silica gel; identification with iodine): Rf-0.25

4 8 6,9 9 3

57.385 /73 (system: toluene/ethyl acetate, ultraviolet absorption spectrum (in 95% strength aqueous ethanol): no specific absorption; infrared absorption spectrum.(in methylene chloride): characteristic bands at 2.96 n, 5.60 P, 5.74 p, 5.92 p, 6.24 t, 6.63 p.and 9.60 p..

Example 13: A solution, cooled to -700 C, of 8.2 g of 7P-(D-a- tert.-butoxycarbonylamino-a-phenylacetylamino)-3-methylene- cepham-4a-carboxylic acid diphenylmethyl ester in 800 ml of methylene chloride is treated for 34 minutes with a stream of oxygen/oxone (0.49 mmol of ozone per minute), and is then treated with 3.5 ml of dimethylsulphide and stirred for one hour at -700C and for 2 hours at'room temperature. After evaporation under reduced pressure, the oily residue containing the 7p-(D-a-tert.-butoxycarbonylamino-a-phenylacetylamino)- cepham-3-one-4- -carboxylic acid diphenylmethyl ester is dissolved in 300 ml of benzene, 3.28 g of l-ethyl-3-(4- methylphenyl)-triazene are added and the whole is boiled for one hour under reflux in a nitrogen atmosphere and is then evaporated under reduced pressure. The residue is chromato- graphed on 360 g of silica gel. The amorphous 3-ethoxy-7p- (D-a-tert.-butoxycarbonylamino-a-phenylacetylamino)-3-cephem- .4-carboxylic acid diphenylmethyl ester is eluted with a 4:1 mixture of toluene and ethyl acetate, thin layer chromatography (silica gel): Rf^,0.28 (system: toluene/ethyl acetate, 3:1); ultraviolet absorption spectrum (in 95% strength aqueous ethanol): Xma x 258 mt (e 7,000) and Xmax 264 mp.(e 6,900); infrared absorption spectrum (in methylene chloride):

486,9 93

57,385/73 characteristic bands at 2.96 p, 5.64 5.90 p, 6.28 p and 6.73 P. Example 14:

A solution of 15 g of 3-methylene-7p-(D-a-tert.-

butoxycarbonylamino-a-phenylacetylamino)-cepham-4a-carboxylic.

acid diphenylmethyl ester in 1,500 ml of methylene, chloride is

treated for 62 minutes, at -65°C, with a mixture of oxygen

and ozone, containing 0.5 mmol of ozone per minute, -and 0 then mixed with 8.7 ml of dimethylsulphide at -70 C. The

mixture is stirred for 1 hour at -70°C and for 2 hours at

room temperature and is evaporated under reduced pressure. The residue, containing the crude 7p-(D-a-tert.-butoxy-

carbonylamino-a-phenylacetylamino)-cepham-3-one-4-carboxylic

acid diphenylmethyl ester, is dissolved in 350 ml of benzene,

11 g of l-benzyl-3-(4-methylphenyl)-triazene are added and the

whole is then boiled for 4 hours under reflux. After

cooling, it is washed with 100 ml of 2 N aqueous.hydrochloric

acid and with a saturated aqueous sodium chloride solution;

the organic phase is dried over sodium sulphate and evaporated

under reduced pressure. The residue is chromatographed on

650 g of silica gel; with toluene, containing 15% of ethyl

acetate, amorphous 3-benzyloxy-7p-(D-a-tert.-butoxycarbonyl-

amino-a-phenylacetylamino)-3-cephem-4-carboxylic acid di-

.phenylmethyl ester, which according to thin layer chromato- graphy is a single substance, is eluted; thin layer

chromatogram (silica gel; development with iodine):

Rf~0.34 (system: toluene/ethyl acetate [a]j =+7

10 (c 0.97 in chloroform); ultraviolet absorption

94 48 6,993

57 38 5 73 spectrum (in 95% strength aqueous ethanol): max 258 mt (e 6,800), and 264 m[ (F 6,800), and Xshoulder 280 m1 (e 6,300); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 j, 5.63 p, 5.88 t,

6.26 i and 6.72 t. Example A solution of 1.59 g of 7p-(5-benzoylamino-5-diphenyl- methoxycarbonyl-valeryl-amino)-3-methylene-cepham-4a-carboxylic acid diphenylmethyl ester in 150 ml of methylene chloride is cooled to -70.C and treated for 12 minutes and 43 seconds, whilst stirring vigorously, with a mixture of oxone and oxygen, containing 0.2 mmol of ozone per minute, and then with 1 ml of dimethylsulphide. The mixture is stirred for 5 minutes at -700C and for 30 minutes at room temperature and is evaporated under reduced pressure. The residue, containing

3-one-4+-carboxylic acid diphenylmethyl ester, is dissolved in ml of methanol, cooled in an ice bath, and treated with a solution of diazomethane in diethyl ether.until the yellow colouration persists. The reaction mixture is evaporated under reduced pressure and the residue is chromatographed.on 100 g of silica gel. 7p-(5-Benzoylamino-5-diphenylmethoxy- carbonyl-valeryl-amino)-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is eluted with a 1:1 mixture of toluene and ethyl acetate and obtained as an amorphous product, thin layer chromatogram (silica gel): Rf 0.45 (system: toluene/ ethyl acetate, ultraviolet absorption spectrum (in strength aqueous ethanol): Xshoulder 258 mp (E 7,450),

nc 48 6,993

57.385/73 264 my (e 7,050) and 268 mp (e 6,700); infrared characteristic absorption spectrum (in methylene chloride):

bands at 5.65 5.78 6.03 p and 6.64 r. follows: The starting material can be manufactured as

A solution of 50 g of the sodium salt of cephalo-

1,500 ml of 10% strength aqeous dipotassium tydrogen sporin C in and 21 g of phosphate is diluted with 1,200 ml of acetone

benzoyl chloride are added at 0 C. The mixture is stirred 0 at 20 C, whilst for 30 minutes at O0C and for 45 minutes of a 50% keeping the pH value constant at 8.5 by addition It is strength aqueous tripotassium phosphate solution.

concentrated to about half its volume under reduced pressure,

washed with ethyl acetate, acidified to pH 2.0 with ethyl strength aqueous phosphoric acid and extracted with

acetate. The organic phase is dried and evaporated under

reduced pressure; the residue, recrystallised from acetone, 117-119 C; yields N-benzoyl-cephalosporin C, melting point

thin layer chromatogram (silica gel): Rf 0.37 (system:

0.08 (system: n-butanol/acetic acid/water, 75:7.5:21) and Rf:

ethyl acetate/pyridine/acetic acid/water, 62:21:6:11). in A solution of 4.7 g of N-benzoyl-cephalosporin C phosphate ml of 0.5 M molar aqueous dipotassium hydrogen 4.7 g solution and 9 ml of dimethylformamide is stirred with 0 and 45 C, whilst of aluminium amalgam for 45 minutes at pH 6.0 20% strength keeping the pH value constant by addition of aqueous phosphoric acid. 100 ml of ice are added, and

the mixture is covered with cold ethyl acetate and adjusted The mixture to pH 2.0 with concentrated phosphoric acid.

96 486, 993

57 385 /7 is saturated with sodium chloride, the organic phase is separated off and the aqueous phase is twice rinsed with ethyl acetate. The combined organic extracts are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate and on evaporation under reduced pressure yield a residue which is caused to crystallise in ethyl acetate. It is slowly diluted with 15 ml of a 2:3 mixture of ethyl acetate-and hexane and filtered after standing for 2 hours at -50 and after crystallisation from a 1:4 mixture of ethyl acetate and di- ethyl ether, 7p{5-benzoylamino-5-carboxy-valerylamino)-3- methylene-cepham-4a-carboxylic acid is obtained, melting point 82-890C (with decomposition); thin layer chromatogram (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 aluminium amalgam used above can be manufactured as follows: a mixture of 3.3 g of aluminium grit and 100 ml of 50% strength aqueous sodium hydroxide solution is shaken for 30 seconds and after decanting the supernatant-liquid the aluminium is washed three times with 300 ml of water at a time. The residue is treated for 3 minutes with 130 ml of an 0.3% strength aqueous mercury-II chloride solution and is' washed three times with 300 ml of water at a time. The entire treatment is repeated once and the aluminium amalgam is finally washed three times with tetrahydrofurane. About ml of ethyl acetate are used to transfer the product into the reaction vessel.

4 86,9 93

57.385 /73

A solution of 2.3 g of 7p-(5-benzoylamino-5-carboxy- valeryl-amino)-3-methylene-cepham-4a-carboxylic acid in 25 ml of dioxane is treated dropwise, over the course of 10 minutes, with a solution of 2.5 g of diphenyldiazomethane in 10 ml of n-pentane. It is stirred for 30 minutes at room temperature, the excess diphenyldiazomethane is decomposed by adding a few drops of acetic.acid (glacial acetic acid) and the solution is evaporated under reduced pressure. The residue is chromato- graphed on 80 g of silica gel, 7P-(5-benzoylamino-5-diphenyl- methoxycarbonyl-valeryl-amino)-3-methylene-cepham-4a-carboxylic acid diphenylmethyl ester being eluted with a 3:1 mixture of toluene and ethyl acetate and then crystallised from a mixture of methyl acetate and cyclohexane, melting point 180-181 C; thin layer chromatogram (silica gel): Rf 0.24 (system: toluene/ethyl acetate, ultraviolet absorption spectrum (in 95% strength aqueous ethanol): no characteristic bands;. infrared absorption spectrum (in methylene chloride): characteristic bands at 5.66 5.76 p, 5.95 ji, 6.03' 6.64 i and 6.70 Example 16: A solution, cooled to O0C, of 0.400 g of 7p-(D-a- tert.-butoxycarbonylamino-a-phenylacetylamino)-3-methylene-. cepham-4a-carboxylic acid diphenylmethyl ester in 40 ml of" methylene chloride is treated for 3.6 minutes with an ozone- oxygen mixture containing 0-.21 mmol of ozone per minute, and is then mixed with 0.5 ml of dimethylsulphide and subsequently evaporated under reduced pressure. The residue, containing 7P-(D-a-tert.-butoxycarbonylamino-a-phenylacetylamino)-cepham-

98 486, 993

57385 /7 3-.one---4E-carboxylic acid diphenylmethyl ester, is dissolved in" ml of methanol and treated with a solution of diazomethane in diethyl ether until the yellow colouration persists. The mixture is evaporated under reduced pressure and-the residue is subjected to preparative layer chromatography (silica gel;' system: toluene/ethyl acetate, 1:,identification with ultraviolet light, X =254). A mixture of 7P-(D----tert.- butoxycarbonylamino-a~-phenylacetylamino )-3-methylene-cephan- 4a-carboxylic acid diphenylmethyl ester and of 7f3-(D-a-tert.- butoxycarbonylamino-cz-phenylacetylamino )-3-methoxcy-2-cepheni- 4a-carboxylic acid diphenylmethyl ester, both of Rf value 0.55, is thus obtained, followed by 7p-(D-a-tert.--butoxycarbonyl- amino-a-phenylacetylamiqo )-3-methoxy-3-cephem-4--carboxylic. acid diphenylmethyl ester of Rf value 0.45 and finally by a. mixture of 7P-(D--a-tert butoxycarbonylamino-a-phenylacetyl- amino )-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester lp-oxide of Rf value 0.17 and la-oxide of Rf value 0.97. Instead of 7p-(D-a-tert butoxycarbonylamino-a- p.henylacetylaiino)-3-methylene-cephaxn-4a-car~oxylic acid di- phenylmethyl ester it is possible to use, as starting substances in the above process, 7P-(D-a-tert.-butoxycarbonyl- amino-a-phenylac etylanino )-3-methylene-c epham-4a-carboxylic acid 4-nit~'obenzyl ester or 7f-(D-a-tert.-butoxycarbonylamiflo- a-phenylacetylamino -3-methylene-cepham-4a-carboxylic acid 2,2,2-trichloroethyl ester, which can be respectively obtained by treatment of the sodium salt of 7P-(D-a-tert.-butoxy- carbonylamino-a-phenylacetylamino )-3-methylene-cephem-4z- carboxylic acid with 4-nitrobenzyl bromide or of a reactive

99 4 86.9. 93

57,385 i7 mixed anhydride of 7p-(D-a-tert.-butoxycarbonylamino-a- acid with phenylacetylamino)-3-me thylene-cephan-4a-carboxylic to 2,2,2-trichloroethanol, and from these starting substances obtain, via 7p-(D-a-tert.-butoxycarbonylamino-a-phenylacetyl- amino)-cepham-3-one-4-carboxylic acid 4-nitrobenzyl ester and

7p-(D-a-tert -butoxycarbonylamino-a-phenylacetylamino-)-cepham- 3-one-4c-carboxylic acid 2,2,2-trichloroethyl ester respect- ively, 7p-(D-a-tert butoxycarbonylamino-a-phenylacetylamino) and 3-methoxy-3-cephem-4-carboxylic acid 4-nitrobenzyl ester 7p-(D-a-tert.-butoxycarbonylamino -a-phenylacetylamino)-3- methoxy-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester respectively. Example 17:

A solution of 0.250 g of the 4-methylphenylsulphonic acid salt of 7 0-amino-cepham-3-one-4-carboxylic acid diphenylmethyl ester, which is mainly present in the enol form of the 4-methyl- acid phenylsulphonate of 7 P-amino-3-cepham-3-ol-4-carboxylic is treated diphenylmethyl ester, in 10 ml of methylene chloride, pyridine with 0.063 ml of trimethylchlorosilane and 0.044 ml of cooled and stirred for 30 minutes at room temperature and then to OOC. 0.088 mi of pyridine and 0.092 ml of phenylacetic react for acid chloride are added, and the mixture is allowed to and one hour at 0 oC and for a further hour at room temperature 0

and is diluted with 5 ml of a 1:1 mixture of dioxane and water stirred for 10 minutes. The whole is diluted with 50 ml .of

methylene chloride, the phases are separated and the organic solution is washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution,

1 00 4 86.9 93

57,385 /73 dried over sodium sulphate and evaporated under reduced pressure. The residue is chromatographed on silica gel; 7P-phenylacetyl- anino-cepham-3-one-45,-carboxylic acid diphenylmethyl ester is eluted with methylene chloride; thin layer chromatogram. (silica gel): Rf -0.55 (system: ethyl acetate/pyridine/water, 85: 10:5); ultraviolet absorption spectrum (in 95%o strength aqueous ethanol): Xmax 283 mp (e 4,400); infrared absorption spectrum (in methylene chloride): Characteristic bands at 2.94 p, 5.12 p, 5.77 Pi, 5.93 Vi, 6.21 p and 6.63 P. Example 18: The following compounds can be obtained analogously if suitable starting substances are chosen: 7P-[D-cz-]tert.-butoxy- carbonylamino-a- (4--hydroxy-phenyl )-acetylamino ]-cepham-3-one-4- carboxylic acid diphenylmethyl ester; 7P-[D-a-tert.-butoxy- carbonylamino-c-(2-thienyl )-acetylamino-cepham-3-one-4... carboxylic acid diphenylmethyl ester; 7P-[D-a-tert butoxycar- bonylamino-a-(C3-thienyl )-acetylaniino ]-cepham-3-one-4g- carboxylic acid diphenylmethyl ester; 7P-[D-a-tert.-butoxycar- bonylamino-a- C2-furyl) aeyaiocehm3oe4 croyi acid diphenylmethyl ester; 7f3-D-ax-tert. -butoxycarbonyaiinoa- (4-i sothiazolyl) -acetyl-amino J-cepham-3-one-4S-carboxylic acid diphenylmethyl ester; 7P3-[D-a-tert butoxycarbonylamino.a 4 (1 -cyclohexadienyl)acetylaminocepham3one4Scarboxylic a cid diphenylmethyl ester; 70-( 2-thienyl )-acetylaxnino-cepham-3- one-4 carboxylic acid diphenylmethyl ester; 7P-(l-tetrazolyl)- acetylamino-cepham-3..one-4,g.carboxylic acid diphenylmethyl ester; 4 73- -pyridylthio)acetylaminoephaM3-one-4g.carboxylic acid diphenylmethyl ester; 71-(4-aminopyridinium-acetylamino)-

1 0 1,486,9 4 86.9 93,

57.385 73 and 7P-[D- cepham-3-one-4S-carboxylic acid diphenylmethyl ester a-(2,2, 2 -trichloroethoxycarbonyloxy)-a-phenyl-acetylamino]- ester. cepham-3-one-4 -carboxylic acid diphenylmethyl The compounds which can be manufactured according to as follows: the invention can be converted further, for example Example 19: 3 A solution of 0.050 g of 7 p-phenylacetylamino-cepham- g of one-4-carboxylic acid diphenylmethyl ester and 0.020 benzene is l-methyl-3-(4-methylphenyl)-triazene in 5 ml of boiled for 2 hours under reflux. After cooling, the mixture is purified is evaporated under reduced pressure and the residue 1 x 20 cm; system: by thin layer chromatography (silica gel; toluene/ethyl acetate, The zone (Rf-0.18) which is

visible under ultraviolet light (X=254 p) is eluted with acetone acid and 3-methoxy-7p-phenylacetylamino-3-cephem-4-carboxylic spec- diphenylmethyl ester is obtained, ultraviolet absorption trum (in ethanol): Xmax 264 p (c 6,300); infrared

absorption spectrum (in methylene chloride): Characteristic

bands at 2.94 p, 5.63 p, 5.83 5.94 p, 6.26 p and 6.68 p.

Example A solution of 0.50 g of the 4-methylphenyl-.

sulphonate of 7p-amino-cepham-3-one-4 -carboxylic acid in diphenylmethyl ester, which is predominantly present the enol form, that is to say as the 4-methylphenylsulphonate

of 7p-amino-3-cephem-3-ol-4-carboxylic acid diphenylmethyl a ester, in 25 ml of methanol, is treated, at 00C with yellow solution of diazomethane in diethyl ether until the colouration persists. The mixture is stirred for

102, 4 8 6,9 93

57.385 /73

minutes in an ice bath and is then evaporated. The residue

is chromatographed on silica gel. Oily 7p-amino-

3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is eluted with a 2:1 mixture of toluene and ethyl acetate, thin layer chromatogram (silica gel; development with iodine vapour): Rf ,0.39 (system: ethyl acetate);- ultraviolet absorption spectrum (in ethanol): max 265 P (s 6,100); infrared absorption spectrum (in methylene chloride): characteristic bands at 3.33 5.63 A,

5.81 p and 6.23 g.

Further elution with ethyl acetate yields oily dimethylamino-3-methoxy-3-cephem-4-carboxylic acid

diphenylmethyl ester, thin layer chromatogram (silica gel; development with iodine vapour): Rf-,0.20 (system: ethyl acetate); ultraviolet absorption spectrum (in ethanol): max 265 A (e 5,900); infrared absorption spectrum

(in methylene chlaide characteristic bands at 2.98 p,

3.33 5.62 p, 5.81 and 6.24 p.

A solution, cooled to OOC, of 0.253 g of D-a-tert.- butoxycarbonylamino-a-(1,4-cyclohexadienyl)-acetic acid in 75 ml of methylene chloride is stirred for 30 minutes with 0.097 ml of N-methyl-morpholine and 0.129 ml of chloroacetic acid isobutyl ester under a nitrogen atmosphere, the mixture is then cooled to -10°C and 0.30 g of 7p-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester and 0.085 g of N-methyl-morpholine are added successively. The reaction mixture is stirred for minutes at -10 0 C and for 30 minutes at 0 0 C, 30 ml of water are added and the pH value is adjusted to 7.9 by adding 40% strength

103 4 86,9 93

57.38 5/73 aqueous dipotassium hydrogen phosphate solution. The phases

are separated, the aqueous solution is extracted with methylene

chloride and the combined organic solutions are washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The residue

is purified by means of preparative layer chromatography (silica gel; system: diethyl ether; identification with

ultraviolet light, X 254 mp; RL-0.39). 7P-[D-a-tert.-

Butoxycarbonylamino-a-( ,4-cyclohexadienyl)-acetylamino]-3-meth-

oxy-3-cephem-4-carboxylic acid diphenylmethyl ester, which is pure according to thin layer chromatography, is obtained as an

amorphous product, thin layer chromatogram (silica gel; identification with diethyl ether): Rf/,0.39 (system: diethyl

ether); [a]20 10 1 o (c 0.745 in chloroform); ultra-

violet absorption spectrum (in 95% strength aqueous ethanol): Xmax 263 mp (E 6,700) and Xshoulder 280 mp (c=6,300);

infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96p5.64 p, 5.86 4, 5.90 4 (shoulder) 6.27 and 6.73 p. A mixture of 0.200 g of 7p-[D-a-tert.-butoxycarbonyl- amino-a-(1,4-cyclohexadienyl)-acetylamino]-3-methoxy-3- cephem-4-carboxylic acid diphenylmethyl ester, 0.5 ml of anisole and 10 ml of pre-cooled trifluoroacetic acid is stirred for 15 minutes at 0°C and subsequently mixed with ml of cold toluene and evaporated under reduced pressure. The residue is stirred with diethyl ether and the pulverulent precipitate is filtered off and dried. The salt, thus

obtained, of 7p-[D-a-amino-a-(l,4-cyclohexadienyl)-acetyl- amino]-3-methoxy-3-cephem-4-carboxylic acid with trifluoro-

4 4 86,9 93

57 28 5/73 acetic acid is dissolved in about 6 ml of water, the pH value of the solution is adjusted to 1.5 by adding Z N hydrochloric acid, the aqueous solution is washed with 20 ml of ethyl acetate and its pH value is adjusted to 5.0 by dropwise addition of a 20% strength solution of triethylamine in methanol. It is diluted with 20 ml of acetone and 10 ml of diethyl ether and the mixture is left to stand for 16 hours at 0OC. The resulting precipitate is filtered off, washed with acetone and diethyl ether and dried. a-(l,4-cyclohexadienyl)-acetylamino]-3-methoxy-3-cephem-4- carboxylic acid is thus obtained in the form of the internal salt, melting point 170 0 C (with decomposition); thin layer chromatogram (silica gel; identification with iodine): Rf~0.26 (system: n-butanol/acetic acid/water, 67:10:23) and Rf-'0.58 (system: isopropanol/formic acid/water, 77:4:19); ultraviolet absorption spectrum: Xmax 267 m. (e 6,100) in 0.1 N hydrochloric acid, and Xmax 268 mt (e 6,600) in 0.1 N aqueous sodium bicarbonate solution.

Example 21: A mixture of 250 ml of anisole in 1,200 ml of methylene chloride is added to 256.3 g of 3-methoxy-70-(D-a-tert.-butoxy- carbonylamino-a-phenyl-acetylamino)-3-cephem-4-carboxylic acid diphenylmethyl ester and the whole is treated, at 00 C, with 1,200 ml of trifluoroacetic acid which has been precooled to 00 C. The reaction mixture is left to stand for 30 minutes at O0C and is diluted, over the course of 15 minutes, with 12,000 ml of a 1:1 mixture of diethyl ether and petroleum ether which has been cooled to 000C. The trifluoroacetic acid salt of 3-methoxy-7P-

105. 4 8 6,9 9 3

57.385 /73 (D-a-phenyl-glycylamino)-3-cephem-4-carboxylic acid which has

precipitated is filtered off, washed with diethyl ether, dried

under reduced pressure and dissolved in 1,900 ml of water.

To remove the yellowish-coloured impurities, the solution is

washed with 900 ml of ethyl acetate; the organic wash liquid

is discarded and the aqueous solution (pH-1.5) is adjusted to

pH 4.5 with a 20% strength solution of triethylamine in methanol. The internal salt of 3-methoxy-7P-(D-a-phenyl-glycylamino)-

3-cephem-4-carboxylic acid crystallises out as the dihydrate,

in the form of colourless prisms, and is filtered off after

having been mixed with 1,800 ml of acetone and stirred for 2 0 hours at.OoC; melting point 175-177 C (with decomposition);

138 o 10 (c=l in 0.1 N hydrochloric acid); ultra-

violet absorption spectrum (in 0.1 N aqueous sodium bicarbonate

solution): max 265 mp (E 6,500); infrared absorption

spectrum (in mineral oil): Bands at 2.72 2.87 p, 3.14 p,

3.65 p, 5.68 p, 5.90 i, 6.18 p, 6.27 a, 6.37 p, 6.56 a, 6.92 p,

7.16 p, 7.58 I, 7.74 7.80 i, 8.12 p, 8.30 p, 8.43 8.52 p,

8.65 p, 8.95 P, 9.36 p, 9.55 9.70 I, 10.02 i, 10.38 p, 10.77 p,

11.70 i, 12.01 p, 12.15 p, 12.48 p, 12.60 p, 12.87 13.45 ti

and 14.30 p; microanalysis (C1 6 H 1 7 0 5 N 3 S 2H2 0; molecular

weight: 399.42): Calculated: C 48.11%, H 5.30%, N 10.52% and

S 8.03%; found: C 47.86%, H 5.27%, N 10.47% and S 8.00%.

Example 22: A mixture of 0.06 g of 3-methoxy-73-phenyl-

acetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester

and 0.05 ml of anisole and 1 ml of trifluoroacetic acid is

left to stand for 5 minutes at room temperature and is

1 0 6. 4 86.9 9.3

57.385 /73 then evaporated under reduced pressure. The residue is

twice evaporated to dryness together with a 1:1 mixture of chloroform and toluene and is chromatographed on 5 g of

silica gel (containing about 5% of water). The amorphous

3-methoxy-7p-phenylacetylamino-3-cephem-4-carboxylic acid

is eluted with methylene chloride containing 30-50% of

acetone and is lyophilised from dioxane. Ultraviolet absorption

spectrum (in 95% strength aqueous ethanol): Xmax= 259 ml

(e 4,970) and 265 m i (E 4,950); infrared absorption spectrum

(in methylene chloride): characteristic bands at 3.03 i,

5.60 p, 5 74 V5.9 2 p, 6.24 p and 6.67 p. Example 23: A mixture of 0.312 g of 35-hydroxy-7P-phenylacetyl-

amino-cepham-4+-carboxylic acid diphenylmethyl ester in

ml of pyridine and 7 ml of acetic anhydride is left to

stand for 16 hours at O°C and after addition of 50 ml of

toluene is evaporated under reduced pressure. The residue

is taken up in ethyl acetate; the organic solution is washed

with a saturated aqueous sodium bicarbonate solution and a

saturated aqueous sodium chloride solution, dried over

sodium sulphate and evaporated under reduced pressure. The

residue is purified by means of preparative thin layer

chromatography; a silica gel plate of 100 cm length is used

and development is carried out with a 1:1 mixture of toluene

and ethyl acetate. 3 -"Acetoxy-7p-phenylacetylamino-

cepham-4a-carboxylic acid diphenylmethyl ester of Rf 0.47 0 is obtained, melting at 162-164 °C after crystallisation from

a mixture of methylene chloride and pentane; [a]2 +550 1o

107 4 86.9 93

57,385 73 (c 0.492 in chloroform); ultraviolet absorption spectrum

(in 95% strength ethanol): Xmax 253 m[ (e 700), 258 my

(e 820) and 265 mL (E 660): infrared absorption spectrum 6 (in methylene chloride): characteristic bands at 2.9 1,

5.66i, 5.77t, 5.97[, 6.28[ and 6.71.

A mixture of 0.150 g of 35-acetoxy-7p-phenylacetyl-

amino-cepham-4 -carboxylic acid diphenylmethyl ester and 5 ml

of methylene chloride is treated with 0.1 ml of triethylamine

and left to stand for 16 hours at room temperature. The

reaction mixture is diluted with 100 ml of methylene chloride;

the organic phase is washed with 50 ml of 2 N hydrochloric

acid and 50 ml of a saturated aqueous sodium chloride solution,

dried over magnesium sulphate and evaporated under reduced

pressure. The residue is purified by means of preparative

thin layer chromatography (2 silica gel plates of 20 cm

length, system: toluene/ethyl acetate, At Rf

0.36, a pale yellowish oil is obtained, which crystallises

from a mixture of methylene chloride and hexane. The

product is 7p-phenylacetylamino-3-cephem-4-carboxylic acid

diphenylmethyl ester, melting point 161-163C, [I(0

+300 10 (c 0.968 in dioxane); thin layer chromatogram

(silica gel; identification in ultraviolet light and by

means of iodine vapour): Rf 0.55 (system: toluene/

acetone, Rf 0.35 (system: toluene/actone, 9:1) and

Rf 0.40 (system: toluene/ethyl acetate, ultra-

violet absorption spectrum: Xmax 258 mp (s 6,100) and

Amin 240 my (e 5,250) (in methylene chloride) and ma x

259 mu (s 6,050) and Amin 239 m[ (e 4,950) (in

108, 4 86.9 9 3

57.385 /73 strength aqueous ethanol); infrared absorption spectrum:

characteristic bands at 2.90t, 5.57L, 5.76., 5.91l, 6.09,

6.66[, 7.13, 8.12[, 8.63t, 9.07L, 10. 453[ and 12.22[1 (in

methylene chloride) and 3.01i, 5.60|, 5.82, 6.044, 6.081

(shoulder), 6.51[ and 7.13[L (in mineral oil). A solution of 1.94 g of 73-phenylacetylamino-3-cephem-

4-carboxylic acid diphenylmethyl ester in 100 ml of absolute methylene chloride is cooled to -15°C, 3.86 ml of absolute

pyridine and 31.6 ml of an 8% strength solution of phosphorus

pentachloride in methylene chloride are then added and the

reaction mixture is stirred for 30 minutes at -10°C and for

a further 30 minutes at The golden yellow solution

is cooled to -20°C and 26.8 ml of absolute methanol are added

at a speed such that the internal temperature does not rise

above -10 0 The reaction mixture is stirred for one hour

at -10 0°C and left to stand for a further hour at 25-30°C, and

is then mixed with 80 ml of an 0.5 molar aqueous potassium

dihydrogen phosphate solution, whilst stirring vigorously.

The pH value of the two-phase reaction mixture is adjusted to

2 by dropwise addition of 20% strength phosphoric acid, the

mixture is stirred for 20 minutes at room temperature and

the phases are separated. The aqueous solution is twice

washed with methylene chloride; the combined organic

solutions are washed with two portions of water, each of

ml, and are dried over anhydrous magnesium sulphate.

Thetsolvent is removed under reduced pressure; the

oily residue is applied to a column of 110 g of silica gel

water content). The elution with methylene chloride,

309 486.993

57.385 /73 phenylacetic acid methyl ester and methylene chloride con- taining 3% of methyl acetate yields 7p-amino-3-cephem-4- carboxylic acid diphenylmethyl ester, which is crystallised by dissolving in a small amount of methylene chloride and adding diethyl ether to the warm solution (giving needle- shaped crystals), and is washed with cold diethyl ether and dried melting point 153 1540C; thin layer chromatogram (silica gel): Rf 0.50 (system: toluene/acetone, 4:1), Rf 0.65 (system: toluene/acetone, Rf 0.40 (system:

toluene/ethyl acetate, 1:1) and Rf 0.33 (system: toluene/

diethyl ether, ultraviolet absorption spectrum: max 257 mu (e 8,150) and min 245 mi (e 7,730) (in methylene chloride) and Xmax 255 m (e 5,500) and Amin 236 mL (e 4,650) (in 95% ethanol); infrared absorption spectrum: characteristic bands at 2 .91, 2.971, 5.61. 5.78t, 6.114, 7.14, 8.15, 8.29, 9.14p and 9.83 (in methylene chloride) and at 2.99, 5.65., 5.77[. 6.08L, 7.14L, 7.74 1, 7.84L, 8.084, 8.53, 9.14 9.85L and 10.35 (in mineral oil).

0.380 g of 7p-amino-3-cephem-4-carboxylic acid di- phenylmethyl ester is covered with 2 ml of anisole and 8 ml of absolute trifluoroacetic acid, and the clear solution is left to stand for 10 minutes at room temperature and is then diluted with about 20 ml of absolute toluene. The mix-

ture is evaporated under reduced pressure; the residue is twice evaporated to dryness after addition of toluene and is then suspended in 5 ml of methanol, 5 ml of diethyl ether and ml of water. The pH value of the suspension is adjusted to 3.5 by dropwise addition of a 5% strength solution of

11 0. 4 86.9 93

57,385/73 triethylamine in methanol; the whole is left to stand for minutes in an ice bath and the fine precipitate is filtered off with the aid of a suitable glass suction filter. The pale beige-coloured filter residue is washed with a mixture of methanol and methylene chloride and then.with diethyl ether and is dried under reduced pressure at 35°C. The 7p-amino- 3-cephem-4-carboxylic acid thus obtainable as a fine micro- crystalline powder decomposes at 2150C; thin layer chromato- gram (silica gel; developing with iodine): Rf 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 (system: ethyl acetate/n-butanol/pyridine/acetic acid/ water, 42:21:21:6:10); infrared absorption spectrum (in mineral oil): characteristic bands at 3.12, 3.801. 4.12t (shoulder), 4.92i, 5.54i, 6 .051 (shoulder), 6.194, 6.55[, 7.05[1, 7.424, 8.234, 8.791, 9.55[, 12.081, 12.69,. and 13.04[. A suspension of 0.070 g of 7p-amino-3-cephem-4- carboxylic acid in 2 ml of absolute methylene chloride is treated with 0.031 g of triethylamine in 0.35 ml of methyleie chloride, the suspension is diluted with 5 ml of absolute tetrahydrofurane and the mixture is stirred for 30 minutes, periodically in an ultrasonics bath. 0.102 g of tert.-butoxycarbonyl-D-a-phenylglycine is dissolved in 5 ml of absolute methylene chloride, 0.040 g of 4-methylmorpholine is added and the mixture is diluted with ml of acetonitrile. It is cooled to -200 C and 0.060 g of chloroformic acid isobutyl ester is added whilst stirring, after which the reaction is allowed to proceed for 30 minutes

11 1, 4 86.9 9 3

57 38 5 /73 0 at -15°C. After again cooling to below -20 C, the milky

suspension of the triethylammonium salt of 7p-amino-3-cephem-

4-carboxylic acid is then added. The reaction mixture is 0 0 stirred for 30 minutes at -15 C, a further 30 minutes at 0 °C

and finally 2 hours at room temperature. It is filtered,

the residue is rinsed with acetonitrile, methylene chloride

and diethyl ether, and the filtrate is dried and evaporated

to dryness. The residue is taken up in ethyl acetate and

water and the mixture is acidified to pH 2 by adding 5 molar

aqueous phosphoric acid whilst stirring vigorously and cooling

with ice. The organic phase is separated off and washed

four times with a small amount of a saturated aqueous sodium

chloride solution. The aqueous extracts are re-extracted

with 2 portions of ethyl acetate and the combined organic

extracts are dried over anhydrous magnesium sulphate and

freed of the solvent under reduced pressure. The residue

is chromatographed on 10 g of silica gel (column; 5% water

added). First, unreacted tert.-butoxycarbonyl-D-a-

phenylglycine is eluted with methylene chloride and with

methylene chloride containing increasing proportions of

acetone, and subsequently 7P-(D--tert.-butoxycarbonylamino-

a-phenyl-acetylamino)-3-cephem-4-carboxylic. acid is eluted

and obtained in an amorphous form; ultraviolet absorption

spectrum (in 95% strength ethanol): Xmax 252 mi (c 5,100);

infrared absorption spectrum (in methylene chloride):

characteristic bands at 5.61p, 5.85P, 5.92p and 6.12g; thin

layer chromatogram (silica gel G; detection with iodine

vapour): Rf 0.6-0.7 (system: n-butanol/acetic acid/

11 2,. 4 86,9 9 3

57,385 /7 water, 44:12':44).

A solution of 0.02 g of 7P-(D-a-tert.-butoxycarbonylamino- .a-phenyl-acetylamino)-3-cephem-4-carboxylic acid in 3 ml of pure trifluoroacetic acid is left to stand for minutes at room temperature. The resulting solution is evaporated in a rotary evaporator and the residue is twice evaporated to dryness with addition of 20 ml of a 1:1 mixture of chloroform and toluene, in order to remove the trifluoro-. acetic acid completely, and is dried for 16 hours at 0.0001 mm Hg. -(D-a-Phenylglycyl)-amino]-3-cephem-4- carboxylic acid is obtained as a yellowish amorphous powder, by adding an equivalent amount of triethylamine to a solution of the resulting salt with trifluoroacetic acid, in water and methanol, evaporating and digesting the residue with methylene chloride. Thin layer chromatogram (silica gel; developing with iodine vapour): Rf 0.29 (system: n- butanol/pyridine/acetic acid/water, 40:24:6:30); ultra- violet absorption spectrum (in water): Xma x 250 mg (e 4,300). Example 24: A mixture of 0.5 g of 3-n-butoxy-7p-(D-a-tert.- butoxycarbonylamino-a-phenylacetylamino)-3-cephem-4-carboxylic acid diphenylmethyl ester, 1 ml of anisole and 15 ml of tri- fluoroacetic acid is left to stand for 15 minutes at 00 C and is then diluted with 200 ml of cold toluene and evaporated under reduced pressure. The residue is stirred with diethyl ether and the pulverulent colourless residue is filtered off, washed with diethyl ether and dried under a

113. 48 6,9 93

57,385 /73 high vacuum. The trifluoroacetate salt of 3-n-butoxy-7P-

(D-a-phenyl-glycylamino)-3-cephem-4-carboxylic acid is thus

obtained, and is dissolved.in 5 ml of water. The solution is twice washed with 10 ml of ethyl acetate at a time.and

the pH value of the aqueous phase is adjusted to 5.0 by

adding a solution of triethylamine in methanol. Thereafter

the solution is evaporated under reduced pressure; the

residue is taken up in a small amount of acetone and is

diluted with diethyl ether until the mixture is turbid.

The 3-n-butoxy-7p-(D-a-phenyl-glycylamino)-3-cephem-4-

carboxylic acid, which is present in the form of the internal

salt, is obtained as a crystalline precipitate and filtered

off, melting point 141-142 0 C; thin layer chromatogram (silica

gel): Rf -0.21 (system: ethyl acetate/pyridine/acetic acid/

water,. 62:21:6:11); ultraviolet absorption spectrum (in 0.1-

N aqueous sodium bicarbonate solution): max 267'mp (e

7,300).. Example

A mixture of 2 .70 g of 3-ethoxy-7p-(D-a-tert.-

butoxycarbonylamino-a-phenylacetylamino)-3-cephem-4-carboxylic

acid diphenylmethyl ester, 6.7 ml of anisole and 67 ml of

formic acid is stirred for one hour at room temperature,

diluted with 200 ml of toluene and then evaporated under

reduced pressure, and the residue is dried under a high vacuum,

digested with diethyl ether and filtered off. The formate

of 3-ethoxy-7p-(D-a-phenyl-glycylamino)-3-cephem-4-carboxylic

acid, which is obtained as a brownish powder, is dissolved

in 8 ml of water and the aqueous phase is acidified with 2 N

1 14. 48 6.9 9 3

57,385 /73 aqueous hydrochloric acid, washed with 10 ml of ethyl acetate,

adjusted to a pH value of about 5 with a 10% strength solution

of triethylamine in methanol and evaporated under.reduced

pressure The residue is taken up in a small amount of

methanol and the amorphous light yellowish 3-ethoxy-73-(D-a-

phenyl-glycylamino)-3-cephem-4-carboxylic acid is precipitated

as the internal salt by addition of methylene chloride and

diethyl ether; thin layer chromatogram (silica gel):

Rf~0.17 (system: ethyl acetate/pyridine/acetic acid/water,

62:21:6:11); ultraviolet absorption spectrum (in 0.1 molar.

aqueous sodium bicarbonate solution): X 263 mp (e ='5,500). Example 26: A mixture of 4.6 g of 3-benzyloxy-7P-(D-a-tert.-

butoxycarbonylamino-a-phenylacetylamino)-3-cephem-4-carboxylic

acid diphenylmethyl ester, 10 ml of anisole and 100 ml of

trifluoroacetic acid is stirred for 15 minutes at 0oC, then

diluted with 250 ml of pre-cooled toluene and evaporated under

reduced pressure, and the residue is dried in a high vacuum.

The product is stirred with diethyl ether and the pulverulent

trifluoroacetate of 3-benzyloxy-7p-(D-a-phenyl-glycylamino)-

3-cephem-4-carboxylic acid is thus obtained; this is filtered

off and dissolved in a 9:1 mixture of water and methanol. The

pH value is adjusted to.1.7 with 2 N aqueous hydrochloric acid;

the mixture is twice washed with 30 ml of ethyl acetate at a

time (the organic wash solutions are discarded) and the pH

value of the aqueous phase is adjusted to 5 by addition of a-

strength solution of triethylamine in methanol. The

aqueous phase is evaporated under reduced pressure, the

11 5, 4 86,9 9.3

57 385/73 residue is stirred with a mixture of acetone and diethyl ether, with and the pulverulent product is filtered off and rinsed

acetone and with diethyl ether. 3-Benzyloxy-7P-( Da-phenyl-

acid is thus obtained in glycylamino)-3-cephem-4-carboxylic (silica the form of a zwitter-ion, thin layer chromatogram

gel): Rf 0.17 (system:'ethyl acetate/pyridine/acetic acid/

ultraviolet absorption spectrum (in 0.1 N water, 62:21:'6:11);

aqueous sodium.,bicarbonate solution): max 266 my (e 6,500).

Example 27: A solution of 0.263 g of 7P-(5-benzoylamino-5- 4 diphenylmethoxycarbonyl-valeryl-amino) -3-methoxy-3-cepham-

carboxylic acid diphenylmethyl ester in 13 ml of methylene 0 chloride is cooled to -10 C and 0.132 ml of pyridine and 3.52 ml

of an 8% strength solution of phosphorus pentachloride in methylene chloride are added. The mixture is-stirred for

one hour at -10 C and is then cooled to -300C, 2.2 ml of 0 methanol cooled to -30 C are added rapidly and the'whole is 0 .stirred further for 30 minutes at -10 C and 30 minutes at Thereafter, 6.5 ml of an 0.5 molar aqueous solution

of potassium dihydrogen phosphate are added to the reaction

mixture, which is 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

the solution is treated with diethyl ether until it is slightly

turbid. 7p-Amino-3-methdxy-3-cephem-4-carboxylic acid di-

11 6. 48 6, 993

57,385 /73 phenylmethyl ester is thus obtained as an amorphous precipi- tate, thin layer chromatogram (silica gel): Rf 0.17

(system: ethyl acetate; development with iodine): ultra-

violet absorption spectrum (in 95% strength aqueous ethanol): m 258 mi (e 5,700); infrared absorption spectrum (in dioxane): characteristic bands at 2.87 5.62 p, 5.85 p and 6.26 t. Example 28: A solution, cooled to 0°C, of 0.63 g of 3-methoxy-7P- (D-a-tert.-butoxycarbonylamino-a-phenyl-acetylamino)-2-cephem- 4a-carboxylic acid diphenylmethyl ester in 25 ml of methylene chloride is treated with a solution of 0.20 g of 3-chloro- perbenzoic acid in 5 ml of methylene chloride. The mixture is stirred for 30 minutes at 00C, 50 ml of methylene chloride are added and the whole is washed successively with 25 ml of a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate and evaporated under reduced pressure. The residue is crystallised from a mixture of methylene chloride and diethyl ether; 3-methoxy-7p-(D-a-tert.-butoxycarbonylamino- a-phenyl-acetyl-amino)-3-cephem-4-carboxylic acid diphenylmethyl ester-l-oxide is thus obtained in the form of colourless needles, melting point 172-175oC; thin layer chromatogram (silica gel): Rf,0.44 (system: ethyl acetate; developing with iodine vapour); ultraviolet absorption spectrum (in ethanol): max 277 m (E 7,200); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 i, 5.56 p, 5.71 p,

5.83 P, 5.90 p, 6.27 p and 6.67 p.

11 7, 486.993

57.38 5/73 0 A solution, cooled to -10 C, of 1.30 g of 3-methoxy-7P-

(D-a-tert.-butoxycarbonylamino-a-phenyl-acetyl-amino)-3-cephem- 30 ml of 4-carboxylic acid diphenylmethyl ester-i-oxide in phosphorus dimethylformamide is treated with 2.80 g of trichloride whilst excluding air. After standing for onto a mixture of minutes, the reaction mixture is poured out solution; ice and an aqueous dipotassium hydrogen phosphate of ethyl the aqueous mixture is twice extracted with 100 ml acetate at a time. The organic extract is washed with a dried over sodium saturated aqueous sodium chloride solution, sulphate and evaporated. The residue is chromatographed on

silica gel; amorphous 3-methoxy-7P-(D-a-tert.-butoxycarbonyl- acid diphenyl- amino-a-phenyl-acetyl-amino)-3-cephem-4-carboxylic as a substance which methyl ester is eluted, with diethyl ether, Rf, 0.39 (system: is pure according to thin layer chromatography, 1 diethyl ether; developing with iodine vapour); spectrum (in (c=0.981 in chloroform);' ultraviolet absorption ethanol): Amax 264 p (s 6,300); infrared absorption bands at spectrum (in methylene chloride): characteristic 2.94 4, 5.62 P, 5.84 p, 5.88 p, 6.25 p amd 6.70 p.

11 8. 48 6,9 9 3

57385/73

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOW:-

1. A process for the manufacture of a 7/3-amino-cephem-

3-one-4-carboxylic acid compound of the formula

a/a

b wherein Ra represents A Ac, of a hydrogen or an acyl group 1 carboxylic acid, R I represents hydrogen, and R 2 represents

a radical which together with the carbonyl grouping

-C(=O)-forms a protected carboxyl group, or a ketal derivati-

ve thereof formed with-the 3-oxo group, or a 1-oxide of such

a compound or a salt of such a compound having a salt-

forming group, characterised in that in a cephem compound of

the formula

oe--tf g CH 2

RA

or in a 1-oxide thereof, the methylene group in the 3-position

119 4 86,9 93

57 38 5 /73

is split off oxidatively, or a cephem compound of the formula

R1 0

HO A o=C R2

which contains a double bond in the 2,3- or 3,4-position, or a

1-oxide of a 3-cephem compound of the formula III is treated A with a peracid, and in a resulting 3-formyloxy-4-R 2 -carbonyl-

7p-N-Ra-N-R -amino-cephem compound or a 1-oxide thereof the

formyloxy group is split off and, when required, a resulting

mixture of a compound of the formula I and of the corresponding

1-oxide is separated or oxidised to the 1-oxide of a compound

of the formula I and, when required, a resulting compound of

the formula I is oxidised to the 1-oxide of a compound of the

formula I and, when required, aresulting compound of the

formula I is converted into a ketal thereof formed with the

3-oxo group and the latter is subsequently split, and

when required, a resulting compound having a salt- forming

group is converted into a salt or a resulting salt is

converted into the free compound or into another salt and,

when required, a resulting isomer mixture is separated into

the individual isomers.

12 0. 4 86.9 93

57.385 73

2. Process for the manufacture of a 7p-amino-cepham-3-

one-4 -carboxylic acid compound of the formula I according to

Claim 1, wherein Ra Rb and R have the meanings given in

Claim 1, or a ketal derivative thereof formed with the 3-oxo-

group, or a 1-oxide of a compound of the formula I, or a salt

of such a compound having a salt-forming group, characterised

in that in a cepham compound of the formula II according to

Claim 1 or in a 1-oxide thereof, the methylene group in the 3 -position is split off oxidatively and, when required, a

resulting mixture of a compound of the formula I and of the

corresponding 1-oxide is separated or oxidised to the 1-oxide

of a compound of the formula I and, when required, a

resulting compound of the formula I is oxidised to the 1-oxide

of a compound of the formula I and, when required, a

resulting compound of the formula I is converted into a ketal

thereof formed with the 3-oxo group and, when required, the

latter is subsequently split, and, when required, a resulting

compound of the formula I having a salt-forming group is

converted into a salt or a resulting salt into the free compound

or into another salt and, when required, a resulting isomer

mixture is separated into the individual isomers.

3. A process according to Claim 1, characterised in

that a starting material of the formula II is used, wherein

R1 represents an acyl group Ac, wherein a functional group is

protected, Rb denotes hydrogen and R represents an etherified

12 1., 486,.993

57,38 5 /73 hydroxyl group which, together with the -C(=O)-grouping,

forms an esterified carboxyl group, and a functional group A in an esterified carboxyl group of the formula -C(=0)-R2

is. protected.

4. A process according to Claim 2, characterised in

that a starting material of the formula II is used,'wherein

Ra represents an acyl group Ac, wherein a functional group is

protected, Rb denotes hydrogen and R2 represents an etherified

hydroxyl group which, together with the -C(=O)-grouping,

forms an esterified carboxyl group, and a functional group

present in an esterified carboxyl group of the formula

is protected.

A process according to Claim 3, characterised in

that RA represents a 1-phenyl-lower alkoxy group, with 1-3

phenyl groups which is unsubstituted or substituted by lower

alkoxy or nitro, whereby lower alkoxy contains up to 4 car-

bon atoms.

6. A process according to Claim 4, characterised in

that R 2 represents a 1-phenyl-lower alkoxy group, with 1-3

phenyl groups which is unsubstituted or substituted by lower

alkoxy or nitro, whereby lower alkoxy contains up to 4 carbon

atoms.

7. A process according to Claim 3, characterised in that A R2 represents a diphenylmethcxy group.

8. A process according to Claim 4, characterised in that A R2 represents a diphenylne-thoxy group.

122 4 86,9 93

57 385/73 9. A process according to Claim 3, characterised in that A R 2 represents an unsubstituted or halogen-substituted lower

alkoxy group, with up to 7 carbon atoms.

A process according to Claim 4, characterised in that A R2 represents an unsbustituted or-halogen-substituted lower

alkoxy group, with up to 7 carbon atoms.

11. A process according to Claim 3, characterised in that A R2 represents tert.-butoxy, or 2,2,2-trichloroethoxy.

12. A process according to Claim 4, characterised in that A R2 represents tert.-butoxy, or 2,2,2-trichloroethoxy. 13. A process according to one of Claims 1, 3, 5, 7, 9 and 11, characterised in that ozone is used as the oxidising

agent. 14. A process according to one of Claims 2, 4, 6, 8, and 12, characterised in that ozone is used as the oxidising agent.

A process according to Claim 13, characterised in that an ozonide obtainable as an intermediate product is converted into a compound of the formula I by reduction with

catalytically activated hydrogen, with a reducing heavy metal,

heavy metal alloy or heavy metal amalgam in the presence of a

hydrogen donor, or with a reducing organic compound, with a

reducing sulphide compound or with a reducing organic phosphorus

compound. 16. A process according to Claim 14, characterised in

that an ozonide obtainable as an intermediate product is con-

verted into a compound of the formula I by reduction with

123 4 8 6,9 93

57, 385 /n S catalytically activated hydrogen,with a reducing heavy metal,

heavy metal alloy or heavy metal amalgam in the presence of

a hydrogen donor, with a reducing inorganic salt in the

presence of a hydrogen donor, or with a reducing organic

compound, with a reducing sulphide compound or with a reducing

organic phosphorus compound.

17. A process according to Claim 13, characterised in

that an ozonide obtainable as an intermediate product is

converted into a compound of the formula I by reduction with

catalytically activated hydrogen, with a reducing heavy metal,

heavy metal alloy or heavy metal amalgam in the presence of

a hydrogen donor, with a reducing inorganic salt in the

presence of a hydrogen donor, or with a reducing organic

compound,or with a reducing agent which can easily be conver-

ted into an oxide compound.

18. A process according to Claim 17, characterised in

that the reducing agents used which can easily be converted

into an oxide compound are tetracyanoethylene, a di-lower alkylsulphide, a phosphine, a phosphite or a phosphorous

acid triamide, or a nitrogen base of the pyridine type.

19. A process according to Claim 1, characterised in

that a compound of the formula III is treated with a

percarboxylic acid or a persulphonic acid. A process according to Claim 1 and 19, characterised a in that in a resulting 3-formyloxy-4-R A -carbonyl-7p-N-- -N-Rb- 2 1 amino-cephem compound or in a 1-oxide thereof the formyloxy

group is split by hydrolysis, in the presence of a basic

agent.

124 486,9 93

57.385/73

21. A process according to one of Claims 1, 3, 5, 7, 9,

11, 13, 15, 19 and 20, characterised in that a resulting

mixture of a compound of the formula I and of a corresponding

1-oxide thereof is oxidised to the 1-oxide of the compound of

the formula I by treatment with a peracid or hydrogen peroxide.

22. A process according to one of Claims 2, 4, 6, 8,

12, 14 and 16, characterised in that a resulting mixture of

a compound of the formula I and of a corresponding 1-oxide thereof

is oxidised to the 1-oxide of the compound of the formula I by treatment with a peracid or hydrogen peroxide.

23. A process according to Claim 17 or 18,

characetrised in that a resulting mixture of a compound of the

formula I and of a corresponding 1-oxide thereof is oxidised to

the 1-oxide of the compound of the formula I by treatment with a peracid or hydrogen peroxide. 24. A process according to one of Claims 1, 3, 5, 7, 9, 11,

13, 15 and 19-21, characterised in that a ketal derivative with

respect to the 3-oxo- group of a compound of the formula I is

manufactured by treatment a compound of formula I with a glycol,

thioglycol or dithioglycol in the presence of an acid catalyst,

or by ketal exchange. A process according to one of Claims 2, 4, 6, 8, 10, 12,

14, 16 and 22, characterised in that a ketal derivative with

respect to the 3-oxo group of a compound of the formula I is manu-

factured by treatment a compound of the formula I with a glycol, thioglycol or dithioglycol in the presence of an acid catalyst, or

by ketal exchange.

26. A process according to one of Claims 17, 18 and 23,

characterised in that a ketal derivative with respect to the

12 5. 486.9 93

57.385 /73

3-oxo group of a compound of the formula I is manufactured

by treatment a compound of the formula I with a glycol, thio

glycol or dithioglycol in the presence of an acid catalyst,

or by ketal exchange. 27. A process according to Claim 24, characterised in

that subsequently a ketal or a thioketal of a compound of the

formula Iis split by means of acid hydrolysis, or a dithio-

ketal of a compound of the formula I is split by treatment

with mercury-II chloride or a N-halogenoamide.

28. A process according to Claim 25, characterised in that subsequently a ketal or a thioketal of a compound of the

formula I is split by means of acid hydrolysis, or a dithio- S ketal of a compound of the formula I is split by treatment

with mercury-II chloride or a N-halogenoamide. 29. A process according to Claim 26, characterised in

that subsequently a ketal or a thioketal of a compound of

the formula I is split by means of acid hydrolysis, or a

dithibketal of a compound of the formula I is split by

treatment with mercury-II chloride or a N-halogenoamide.

A process according to one of Claims 1, 3, 5, 7, 9,

11, 13, 15, 19-21, 24 and 27, characterised in that in a a resulting compound wherein R1 represents a suitable

acyl group, the latter is split off and replaced by hydrogen

by treatment with an imide-halide forming agent, reaction

of the resulting imide-halide with an alcohol and splitting

of the imino-ether formed. 31. A process according to one of Claims 2, 4, 6, 8,

12, 14, 16, 22, 25 and 28, characterised in that in a

12 6. 486,.993

57 385 /7

resulting compound wherein Ra represents a suitable

acyl group, the letter is split off and replaced by hydrogen

by treatment with an imide-halide forming agent, reaction of

the resulting imide-halide with an alcohol and splitting of

the imino-ether formed.

32. Process according to one of Claims 17, 18, 23, 26

and 29, characterised in that in a resulting compound wherein

Ra represents a suitable acyl group, the latter is split

off and replaced by hydrogen by treatment with an imide-halide

forming agent, reaction of the resulting imide-halide with an

alcohol and splitting of the imino-ether formed.

33. Process according to one of Claims 1, 3, 5, 7, 9,

11, 13, 15, 19-21, 24, 27 and 30, characterised in that in a resulting compound a free amino group is acylated.

34. Process according to one of Claims 2, 4, 6, 8,

12, 14, 16, 22, 25, 28 and 31, characterised in that in a

resulting compound a free amino group is acylated. Process according to one of Claims 17, 18, 23, 26,

29 and 32, characterised in that in a resulting compound a free amino group is acylated.

36. A process according to one of Claims 1-16, 19-22,

24, 25, 27, 28, 30, 31, 33 and 34, characterised in that a cepham-3-one compound of the formula I according to Claim 1 or

a 1-oxide thereof, or a salt of such a compound having a

salt-forming group is manufactured,wherein Ra represents

hydrogen or an acyl radical of an organic carboxylic acid

12 7. 486.9 93

57.385 /73 b A with up to 18 carbon atoms, RI represents hydrogen, and R 2

is unsubstituted or halogen substituted lower alkoxy, phenyl- lower alkoxy, with 1-3 phenyl groups which are unsubstituted

or substituted by lower alkoxy or nitro, acyloxy, tri-lower

alkylsilyloxy, unsubstituted amino or hydrazino, or amino or

hydrazino substituted by lower alkyl or hydroxyl, wherein lower alkyl and lower alkoxy contain up to 4 carbon atoms. 37. A process according to one of Claims 2, 4, 6, 8, 12, 14, 16, 22, 25, 29, 31 and 34, characteri-

sed in that a cepham-3-one compound of the formula I according

to Claim 1 or a 1-oxide thereof, or a salt of such a compound

having a salt-forming group, is manufactured, wherein R I

represents hydrogen or an acyl radical of an organic carboxylic b acid with up to 18 carbon atoms, R 1 represents hydrogen and

RA has the meaning given in Claim 36.

38. A process according to one of Claims 1-35, characteri-

sed in that the compounds described in Claim 36 are manufactu- red. 39. A process according to one of Claims 1-16, 19-22,

24, 25, 27, 28, 30, 31, 33 and 34, characterised in that a

cepham-3-one compound of the formula I according to Claim 1 or a 1-oxide thereof, or a salt of such a compound having a salt- forming group is manufactured, wherein Ra denotes hydrogen or an acyl radical of an organic carboxylic acid with up to 18 carbon A atoms, Rb represents hydrogen, and R denotes lower alkoxy,

2-halogeno-lower alkoxy, phenacyloxy, 1-phenyl-lower alkoxy

128 486,993

57,385 /73 with 1-3 phenyl radicals which are unsubstituted or substi-

tuted by lower alkoxy or nitro, lower alkanoyloxymethoxy,

lower alkoxycarbonyloxy or lower alkanoyloxy, wherein lower

alkyl, lower alkoxy and lower alkanoyl have up to 4 carbon

atoms.

A process according to one of Claims 2, 4, 6, 8,

10,.12, 14, 16, 22, 25,.28, 31 and 34, characterised in

that a cepham-3-one compound of the formula I according to

Claim 1 or a 1-oxide thereof, or a salt of such a compound a having a salt-forming group, is manufactured, wherein R I

denotes hydrogen or an acyl radical of an organic carboxylic b acid having up to 18 carbon atoms, R I represents hydrogen

and R 2 has the meaning given in Claim 39.

41. A process according to one of Claims 1-35,

characterised in that a cepham-3-one compound of the formula

I according to Claim I or a l-oxide thereof, or a salt of

such a compound having a salt-forming group, is manufactured, a b wherein R and Rb have the meanings given in Claim and

R2 denotes lower alkoxy, 2-halogeno-lower alkoxy, phenacyl-

oxy, 1-phenyl-lower alkoxy with 1-3 phenyl radicals which

are unsubstituted or substituted by lower alkoxy or nitro,

lower alkanoyloxymethoxy, a-amino-lower alkanoyloxymethoxy,

lower alkoxycarbonyloxy or lower alkanoyloxy, wherein lower

alkyl, lower alkoxy and lo-wer alkanoyl have up to 4 carbon

atoms.

129- 486,993

57385 /73

42. A process according to one of Claims 1-16, 19-22,

24, 25, 27, 28, 30, 31, 33 and 34, characterised in that a

cepham-3-one compound of the formula I according to Claim 1

or a 1-oxide thereof, or a salt of such a compound having

a salt-forming group is manufactured, wherein Rb and R

have the meanings given in Claim 39 and Ra is hydrogen or a

group of the formula

II R 0

R CY I II C- (A) (A) RII

1 wherein n represents 0 and R denotes hydrogen or a cyclo-

alkyl group with 5-7 ring carbon atoms which is unsubstituted,

or substituted in the 1-position by amino or protected amino, or RI denotes a phenyl, naphthyl or tetrahydronaphthyl group

which is unsubstituted, or substituted by hydroxyl, lower

alkoxy, lower alkoxycarbonyl, 2-halogeno-lower alkoxycarbonyl

or phenyl-lower alkoxycarbonyl, and/or halogen, or R denotes

a heterocyclic group which is unsubstituted or substituted

by lower alkyl, and/or phenyl or phenyl substituted by I halogen, or R denotes an amino group which is substituted

by a lower alkyl radical or a lower alkyl radical containing halogen, or n represents 1, R represents a lower alkyl group

which is unsubstituted or substituted by halogen, by phenyl-

13 0, 4 8 6,9 93

5738 5/73

oxy, by phenyloxy containing hydroxyl, by acyloxy, and/or

halogen, or by amino or protected amino and/or carboxyl,

or R denotes a lower alkenyl group, or R I denotes a phenyl

group which is unsubstituted or substituted by hydroxyl, by

acylated hydroxyl, and/or by halogen, by unprotected or protected amino-lower alkyl, or by phenyloxy or by phenyloxy substituted

by hydroxyl, acyloxy, and/or by halogen, or R I denotes a pyridyl group,a pyridinium group, a thienyl group, a furyl group, animidazolyl group, or a tetrazolyl group,

or any such group substituted by lower alkyl, or by amino

or aminoemthyl which are protected or unprotected, or R denotes a lower alkoxy group, a phenyloxy group, aphenyloxy group

which contains hydroxyl or protected hydroxyl, and/or halogen,

or R denotes a lower alkylthio group, or a lower alkenylthio

group, a phenylthio, pyridylthio, 2-imidazolylthio, 1,2,4- triazol-3-ylthio, 1,3,4-triazol-2-ylthio,l,2,4-thiadiazol- 3-ylthio, 1,3,4-thiadiazol-2-ylthio, or

group, or such group substituted by lower alkyl, or R denotes a halogen atom, lower alkoxycarbonyl, nitrile, or carbamoyl,

or carbamoyl which is N-substituted by lower alkyl, or by

phenyl, or R denotes a lower alkanoyl group, a benzoyl group, or an azido group, and R and R IIIrepresent hydrogen,

or n represents 1, R represents lower alkyl, or a phenyl, furyl, thienyl, or isothiazolyl group, or such group substi-

tuted by hydroxyl or by acyloxy, and/or by halogen, or RI

denotes a 1,4-cyclohexadienyl group, R I I represents amino,

acylamino, sulphoamino or sulphoamino present in the form

of asalt, an azido group, a carboxyl group, a carboxyl group

present in the form of a salt, or in an esterified from,

13 4 86,9 9 3

57 38 5 73

a nitrile group, a sulpho group, a hydroxyl group, an acyloxy

group, an O-lower alkyl-phosphono group or O,0'-di-lower alkyl-

phosphono group, or a halogen atom, and R represents I hydrogen, or n represents 1, R and R each represent halogen,

or lower alkoxy-carbonyl, and R represents hydrogen, or n I represents 1, R represents a phenyl, furyl, or thienyl, or isothiazolyl group, or such group substituted by hydroxyl,

acryloxy, and/or by halogen, or R denotes a 1,4-cyclohexadienyl

group, R I I represents aminomethyl, or protected aminomethyl, and

R represents hydrogen, or n represents 1 and each of the groups

R, R and RI represents lower alkyl, wherein lower alkoxy,

lower alkyl, lower alkenyl and lower alkanoyl have up to 4 carbon atoms.

43. A process according to one of Claims 2, 4, 6, 8,

12, 14, 16, 22,.25, 28, 31 and 34, characterised in that

a cepham-3-one compound of the formula I according to

Claim 1 or a 1-oxide thereof, or a salt of such a compound

having a salt-forming group is manufactured, wherein Ra and given in Claim 42 and Rb represents 2 have the meanings RA

hydrogen.

44. A process according to one of Claims 1-35,

characterised in that a cepham-3-one compound of the formula

I or a 1-oxide thereof, or a salt of such a compound having

a salt-forming group is manufactured, wherein R 2 has the a meanings given in Claim 41 and R 1 the meanings given in Claim

42 and R represents hydrogen. 1

13 2, 486,993

57385 /73

A process according to one of Claims 1-16,

19-22, 24, 25, 27, 28, 30, 31, 33 and 34,

characterised in that a cepham-3-one compound of the formula

I according to Claim 1, or a 1-oxide thereof, or a salt of

such a compound having a salt-forming group is manufactured,

wherein Rb denotes hydrogen, R a denotes hydrogen or an acyl

group of the formula

0

Ra (B) in

wherein Ra represents phenyl, hydroxyphenyl or hydroxy-

chlorophenyl, wherein a hydroxy substituent in such a radical is free or protected by an acyl radical, thienyl,

pyridyl, amino-pyridinium, furyl, isothiazolyl or tetrazolyl, X represents oxygen or sulphur, m represents 0 or 1 and Rb

represents hydrogen or, if m denotes O, R represents free or

protected amino, carboxyl, sulpho or hydroxyl, or 0-lower

alkylphosphono or O,0'-di-lower alkylphosphono, or denotes a 5-amino-5-carboxyvaleryl radical, wherein the amino and

carboxyl group are free or protected, and RA denotes lower

alkoxy, 2-halogeno-lower alkoxy, unsubstituted diphenylmethoxy

or diphenylmethoxy substituted by lower alkoxy, wherein lower

alkyl and lower alkoxy have up to 4 carbon atoms.

46. A process accoridng to one of Claims 2, 4, 6,

8, 10, 12, 14, 16, 22, 25, 28, 31 and 34, characterised

in that a cepham-3-one compound of the formula I according

13 3 4 86.9 93

57,285/73 or a salt of such a com- to Claim 1, or a 1-oxide thereof, group is manufactured) wherein pound having a salt- forming hydrogen or anaclgopf RIdenotes hydrogen, R, denotes Claim 45, wherein Ra represents the formula B accor ding to .a hy droxy-chlorophenyl, wherein phenyl, hydroxyphenyl or a radical is free or protected hydroxy substituent in such 5 radical, or 2-thienyl, or Ra denotes a 5-amino- by an acyl the amino and carboxyl group carboxyvaleryl radical wherein the wherein X, m, Rb and RA have are free or protected, and meanings given in Claim of Claims 1-35, 47. A process .according to one compound of the formula characterised in that a cepham-3-one salt of a 1-oxide thereof, or a according to Claim 1, or salt-forming group is manufactured, such a compound having a acyl R~ denoces hydrogen or an wherein Rb denotes hydrogen,

to Claim 45, wherein Ra group of the formula B according or hydroxy-chloroplhenyl, represents phenyl-, hydroxypheflyl in such a radical is free or wherein a hydroxy substituent thienyl, pyridyl, amino- protected by an acyl radical, tetrazolyl 'or 1, 4-cyclohexa- pyridinium, furyl isothiazolyl, radical, dienyl, or Ra denotes a 5-mn--abx-acy group are free or protected, 'Wherein the airino and carboxyl given in Claim 54,* and herein X, mn and Rb have the meanings A alkoxy, unsub- and R~ denoces lower alkoxy, 2-halogeno-lCwer substituted by lower stituted dipheny).mcthoxY, d iphenyl-methoxy wherein lower alkyl and alkroxy, or tri-lower alkylsilyloxy, atomns. low*er alkoxy have up to 4 carbon

-134- 4 86,9 93

57.385 /73

48. A process according to one of Claims 1-16, 19-22,

24, 25, 27, 29, 30, 31, 33 and 34,

characterised in that a cepham-3-one compound of the formula

I according to Claim 1 or a 1-oxide thereof, or a salt of

such a compound having a salt-forming group, is manufactured,

wherein Ra represents hydrogen or the acyl radical of the

formula B according to Claim 45,wherein R denotes phenyl,

X denotes oxygen, m denotes 0 or 1 and Rb denotes hydrogen or,

if m represents O, Rb denotes free or protected amino or free

or protected hydroxyl, or Ra represents a

valeryl radical wherein the amino and carboxyl group are free b A or protected, Rb represents hydrogen and R denotes lower

alkoxy,2-halogeno-lower alkoxy,diphenylmethoxy or diphenylmethoxy

substituted by lower alkoxy, wherein lower alkoxy has up to

,4 carbon atoms.

'49. A process according to one of Claims 2, 4, 6, 8,

12, 14, 16, 22, 25, 28, 31 and 34, characterised in

that the compounds described in Claim 48 are manufactured.

A process according to one of Claims 1-35, characteri-

sed in that a cepham-3-one compound of the formula I according

to Claim 1 or a 1-oxide thereof or a salt of such a compound

haying a salt-forming group is manufactured, wherein Ra re-

presents hydrogen or the acyl radical of the formula B accor-

ding to Claim 45, wherein R a denotes phenyl, hydroxyphenyl,

thienyl, 4-isothiazolyl, or 1,4-cyclohexedienyl, and X, m and

-135- 4 86,9 93

57.38 5 /73 a a Rb have the meanings given in Claim 49, or Ra represents

radical wherein the amino and

carboxyl group are free or protected, Rb dnotes hydrogen

A 2-halogeno-lo--.er alkoxy,diphenyl- and denotes lower alkoxy, 2 methoxy, diphenylmethoxy substituted by lower alkoxy, or

tri-lower alkylsilyloxy, wherein lower alkoxy and lower alkyl

have up to 4 carbon atoms.

51. A process according to one of Claims 1-.35,characteri-

4 sed in that a 7p-(D-4-amino-a-R a -acetylamino)-cepham-3-one-

carboxylic acid diphenylmethyl ester, wherein Ra represents

phenyl, 4-hydroxyphenyl, 2-thienyl, or 1,4-cyclohexadienyl,

and amino is present in free or in protected form or a salt

a compound having salt-forming groups, is manufactured. of such

52. A process according to one of Claims 1-16, 19-22,

24, 25, 27, 28, 30, 31, 33 and 34, characterised in that

7J-phenylacetylamino-cepham-3-one-4 -carboxylic acid diphenyl-

methyl ester is manufactured.

53. A process according to one of Claims 2, 4, 6, 8,

12, 14, 16, 22, 25, 29, 31 and 34, characterised in that the

compound described in Claim 52 is manufactured.

54. A process according to one of Claims 1-35, characteri-

sed in that the compound described in Claim 52 is manufactured.

A process according to one of Claims 1-16, 19-22,

24, 25, 27, 28, 30, 31, 33 and 34, characterised in that

7p-(D-a-tert.-butoxycarbonylamino-a-phenylacetylamino)-cepham-3-

one-46-carboxylic acid diphenylmethyl ester is manufactured.

136 4 86,9 93

57 385 73 56. A process according to one of Claims 2, 4, 6, 8,

12, 14, 16, 22, 25, 29, 31 and 34, characterised in

that the compound described in Claim 55 is manufactured.

57. A process according to one of Claims 1-35, cha-

racterised in that the compound described in Claim 55 is manu-

factured.

58. A process according to one of Claims 1-16, 19-22,

24, 25, 27, 28, 30 and 31, characterised in that 7p-amino-

cepham-3-one-4§-carboxylic acid diphenylmethyl ester or a

salt thereof is manufactured.

59. A process according to one of Claims 1-32,

characterised in that the compounds described in Claim 58

are manufactured.

A process according to one of Claims 1-35, cha-

racterised in that 7p-(5-benzoylamino-5-diphenylmethoxycar-

bonyl-valerylamino)-cepham-3-one-4(-carboxylic acid diphenyl-

methyl ester is manufactured.

61. A compound of formula I, a 1-oxide thereof, or a

salt thereof, obtainable according to the process of anyone

of Claims 1-16, 19-22, 24, 25, 27, 28, 30, 31, 33, 34, 36,

37, 39, 40, 42, 43, 45, 46, 48, 49, 52, 53, 55, 56 and 58.

62. A compound of formula I, a 1-oxide thereof, or a

salt thereof, obtainable according to the process of anyone

of Claims 2, 4, 6, 8, 10, 12, 14, 16, 22, 25, 28, 31, 34, 37,

43, 46, 49, 53 and 56.

63. A compound of formula I, a 1-oxide thereof, or a

salt thereof, obtainable according to the process of anyone

of Claims 1-60.

64. A 7p-amino-cepham-3-one-4-carboxylic acid compound

of the formula -137- 4 86.,9 933

57,385 173

O=--R2

wherein Ra represents hydrogen or an acyl group Ac of a car-

b and RA represents boxylic acid and R represents hydrogen,

a radical which together with the carbonyl grouping

forms a protected carboxyl group, and a salt of such a

compound having a salt-forming group.

A ketal derivative of the compound described in

Claim 64 formed with the 3-oxo group.

66. A 1-oxide of the compound described in Claim 64

or Claim

67. A cepham-3-one compound of the formula I according

to Claim 64, wherein Ra represents hydrogen or an acyl radical

of an organic carboxylic acid with up to 18 carbon atoms, Rb

represents hydrogen, and R is substituted

lower alkoxy, phenyl-lower alkoxy with 1-3 phenyl groups which

or substituted by lower alkoxy or nitro, are unsubstituted

acyloxy, tri-lower alkylsilyloxy, unsubstituted amino or

or amino or hydrazino substituted by lower alkyl hydrazino,

wherein lower alkyl and lower alkoxy contain up or hydroxyl,

a salt of such a compound having a salt- to 4 carbon atoms,and

forming group.

-138- 4 86,9 93

57.38 5/73

68. A 1-oxide of the compound described in Claim 67.

69. A cepham-3-one compound of the formula I according

to Claim 64, wherein Ra represents hydrogen or an acyl radical

of an organic carboxylic acid with up to 18 carbon atoms,

Rb represents hydrogen and RA has the meaning given in Claim

67, and a salt of such a compound having a salt-forming group. A 1-oxide of the compound describedin claim 69.

71. A cepham-3-one compound of the formula I according a to Claim 64, wherein R denotes hydrogen or an acyl radical of b an organic carboxylic acid with up to 18 carbon atoms, R1 re-

presents hydrogen and RA2 denotes lower alkoxy, 2-halogeno-

lower alkoxy, phenacyloxy, 1-phenyl-lower alkoxy with 1-3

phenyl radicals which are unsubstituted or substituted by lower alkoxy or nitro, lower alkanoyloxymethoxy, lower alkoxycar-

bonyloxy, or lower alkanoyloxy, wherein lower alkyl, lower alkoxy and lower alkanoyl have up to 4 carbon atoms, and a

salt of such a compound having a salt-forming group.

72. A 1-oxide of the compound described in Claim 71.

73. A cepham-3-one compound of the formula I according

to Claim 64, wherein Ra and Rb have the meanings given in

Claims 71, and R denotes lower alkoxy, 2-halogeno-lower

alkoxy,phenacyloxy, 1-phenyl-lower alkoxy with 1-3 phenyl

radicals which are unsubstituted or substituted by lower

alkoxy or nitro, lower alkanoyloxymethoxy, LE-amino-lower

alkanoyloxymethoxy, lower alkoxycarbonyloxy or lower alkanoyl-

oxy, wherein lower alkyl, lower alkoxy and lower alkanoyl have up to 4 carbon atoms, and a salt of such a compound

having a salt-forming group.

13.9. 4 86, 993

57.38 5 73

74. A 1-oxide of the compound described in Claim 73.

A cepham-3-one compound of the formula I according

to claim 64, wherein Rb and RA have the meanings given in 1 2 Claim 71 and Ra represents hydrogen or a group of the

formula

R O

c R C) (A)

R

1 wherein n represents O and R denotes hydrogen or a cyclo-

alkyl group with 5-7 ring carbon atoms which is unsubstituted,

or substituted in the 1-position by amino or protected amino,

or R denotes a phenyl, naphthyl or tetrahydronaphthyl group

which is unsubstituted, or substituted by hydroxyl, lower

alkoxy, lower alkoxycarbonyl, 2-halogeno-lower alkoxycarbonyl

or phenyl-lower alkoxycarbonyl, and/or halogen, or R denotes

a heterocyclic group which is unsubstituted or substituted by lower alkyl, and/or phenyl or phenyl substututed by halogen,

or R denotes an amino group which is substituted by a lower

alkyl radical or a lower alkyl radical containing halogen, or

n represents 1, R represents a lower alkyl group which is

unsubstituted or substituted by halogen, by phenyloxy, by

phenyloxy containing hydroxyl, by acyloxy, and/or halogen, or I by amino or protectej amino and/or carboxyl, or R denotes a lower alkenyl group, or R denotes a Phenyl group wnich is unsubstituted or substituted by hydroxyl, by acylated hydroxyl, and/or by halogen, by unprotected or

140. 4 86,9 93

57.385 /73

protected amino-lower alkyl, or by phenyloxy or by phenyloxy

substituted by hydroxyl, acyloxy, and/or by halogen, or R

denotes a pyridyl group, a pyridinium group, a thienyl group,

a furyl group, animidazolyl group, or a tetrazolyl group,

or any such group substituted by lower alkyl, or by amino or

aminomethyl which are protected or unprotected, or R denotes a lower alkoxy group, a phenyloxy group, a phenyloxy group

which contains hydroxyl or protected hydroxyl, and/or halogen,

or R denotes a lower alkylthio group, or a lower alkenylthio-

group, a phenylthio, pyridylthio, 2-imidazolylthio, 1,2,4- triazol-3-ylthio, 1,3,4-triazol-2-ylthio, 1,2,4-thiadiazol- 3-ylthio,1,3,4,-thiadiazol-2-ylthio, or

group, or such group substituted by lower alkyl, or R denotes

a halogen atom, lower alkoxycarbonyl, nitrile, or carbamoyl,

or carbamoyl which is N-substituted by lower alkyl, or by

phenyl, or R denotes a lower alkanoyl group, a benzoyl group,

or an azido group, and R and R represent hydrogen,

or n represents 1, R represents lower alkyl, or a phenyl,

furyl, thienyl, or isothiazolyl group, or such group substi-

tuted by hydroxyl or by acyloxy, and/or by halogen, or R I denotes a 1,4-cyclohexadienyl group, R represents amino,

acylamino, sulphoamino or sulphoamino present in the form of

a salt, in azido group, a carboxyl group, a carboxyl group present

in the form of a salt, or in an esterified from, nitrile group, a sulpho group, a hydroxyl group, an acyloxy group, an O-lower

alkyl-phosphono group or O,0'-di-lower alkyl-phosphono group, or a halogen atom, and R represents hydrogen, or n repre- II sents 1, R and R each represent halogen, or lower alkoxy-

141, 486,.993

57.385 /73

carbonyl, and RI represents hydrogen, or n represents 1,

R I represents a phenyl, furyl, or thienyl, or isothiazolyl

group, or such group substituted by hydroxyl, acyloxy, and/or I by halogen, or R denotes a 1,4-cyclohexadienyl group, R

represents aminomethyl, or protected aminomethyl, and R

represents hydrogen, or n represents 1 and each of the groups

R R and RI represents lower alkyl, wherein lower alkoxy,

lower alkyl, lower alkenyl and lower alkanoyl have up to 4

carbon atoms, and a salt of such a compound having a salt- forming group.

76. A 1-oxide of the compound described in Claim

77. A cepham-3-one compound of the formula I according

to Claim 64, wherein Rb denotes hydrogen, Ra denotes hydrogen

or an acyl group of the formula

R (B)

m b

wherein R a represents phenyl, hydroxyphenyl or hydroxy-

chlorophenyl, wherein a hydroxy substituent in such a

radical is free or protected by .an acyl radical, thienyl,

pyridyl, amino-pyridinium, furyl, isothiazolyl, or tetrazolyl, X represents oxygen or sulphur, m represents O or 1, and Rb

represents hydrogen or, if m denotes O, Rb represents free or

protected amino, carboxyl, sulpho or hydroxyl, or O-lower

alkylphosphono or O,0'-di-lower alkylphosphono, or Ra denotes

a 5-amino-5-carboxyvaleryl radical, wherein the amino and

142 486.993

Claims (1)

1. 57 385 /73

   lower carboxyl group are free or protected, and RA denotes alkoxy, 2-halogeno-lower alkoxy, unsubstituted diphenylmethoxy

   or diphenylmethoxy substituted by lower alkoxy, wherein lower and a alkyl and lower alkoxy have up to 4 carbon atoms, salt of such a compound having a salt-forming group.

   78. A 1-oxide of the compound described in Claim 77.

   79. A cepham-3-one compound of the formula I according

   to Claim 73, wherein Rb denotes hydrogen, Ra denotes hydrogen wherein or an acyl .group of the formula B according to Claim 77, R denotes phenyl, hydroxyphenyl, or hydroxy-chlorophenyl, or wherein a hydroxy substituent in such a radical is free a denotes a protected by an acyl radical, or 2-thienyl, or R 1 radical, wherein the amino and car- Rb and boxyl group are free or protected, and wherein X, m, such a RA have the meanings given in Claim 77, and a salt of

   compound having a salt-forming group. A 1-oxide of the compound described in claim 79.

   81. A cepham-3-one compound of the formula I according

   to Claim 64 wherein Rb denotes hydrogen, Ra denotes hydrogen 77 wherein or an acyl group of the formula B according to Claim where- R represents phenyl, hydroxyphenyl, or hydroxy-chlorophenyl, or protected in a hydroxy substituent in such a radical is free

   by an acyl radical, thienyl, pyridyl, amino- or 1,4-cyclohexa- pyridinium, furyl, isothiazolyl, tetrazolyl, dienyl, or Ra denotes a 5-amino-5-carboxy-valeryl radical,

   wherein the amino and carboxyl group are free or protected, in Claim 77 and wherein X, m and Rb have the meanings given alkoxy, unsub- and RA denotes lower alkoxy, 2-halogeno-lower 2

   14 3, 48 6,9 93

   5738 5 173

   stituted diphenylmethoxy, diphenylmethoxy substituted by lower

   alkoxy, or tri-lower alkylsilyloxy, wherein lower alkyl and

   lower alkoxy have up to 4 carbon atoms, and a salt of such

   a compound having salt-forming group.

   82. A 1-oxide of the compound described in Claim 77,

   83. A cepham-3-one compound of the formula I according

   to Claim 64, wherein Ra denotes hydrogen, or the acyl radical of the formula B according to Claim 77, wherein R a denotes phenyl,

   X denotes oxygen, m denotes 0 or 1, and R denotes hydrogen or,

   if m represents O, R denotes free or protected amino, or free

   or protected hydroxyl, or Ra represents a

   valeryl radical wherein the amino and carboxyl group are free

   or protected, Rb represents hydrogen and R denotes lower alkoxy,

   2-halogeno-lower alkoxy, diphenylmethoxy, or diphenylmethoxy

   substituted by lower alkoxy, wherein lower alkoxy and lower

   alkyl have up to 4 carbon atoms, and a salt of such a

   compound having a salt-forming group.

   84. A 1-oxide of the compound described in Claim 83.

   A cepham-3-one compound of the formula I according a, to Claim 64, wherein R 1 represents hydrogen or the acyl

   radical of the formula B according to Claim 77,

   wherein Ra denotes phenyl, 4-hydroxyphenyl, 2-thienyl,

   4-isothiazolyl, or 1,4-cyclohexadienyl, and X, m and

   R have the meanings given in Claim 83, or R 1 represents a

   radical wherein the amino and

   carboxyl group are free or protected, R, denotes hydrogen,

   and RA denoted lower alkoxy, 2-halogeno-lower alkoxy, diphenyl-

   methoxy, diphenylmethoxy substituted by lower alkoxy, or

   14 4. 4 86,993

   7.2 5 13

   tri-lower alkylsilyloxy, wherein lower alkoxy and lower alkyl

   have up to 4 carbon atoms, and a slat of such a compound

   having a salt-forming group.

   86. A 1-oxide of the compound described in Claim

   87. A 7 DC aio0- ctyaio-ehm3oe4

   carboxylic acid dihnlehlester, wherein Rarpeet phenyl, 4-hydroxyphenyl, 2-thienyl, or 1,4-cvclohexadienyl,

   and amino is in free or in protected form, or a salt of

   such a compound having a salt-forming group.

   88. p-Phenylacetylailo-cepham-3one-4 carboxcylic acid 7

   diphenylmethyl ester.

   89. 7fC--et-uoyabnyaio-.pey-ctl

   amino)-cepham-3-one-4 -carboxylic acid diphenylmethyl ester.

   7P-Amnino-cepham-3-one-4 -carboxylic acid diphenyl- methyl ester or a salt thereof.

   91. 7p-

   valerylaminoY -cepham-3-one-4&4-carboxylic acid diphenylmethyl

   ester.

   DATED THIS 8th day of SEPTEMBER, 1977.

   CIBA-GEIGY AG

   EDWD. WATERS trneet, PatQuen Attrneys, MELBOURNE. VIC. 3000. SONS, I AUSTRALIA.

   14 5. 14 45.8 6.9 93