CA1087170A

CA1087170A - N-substituted aminomethyl-methoxy-heterocyclic compounds

Info

Publication number: CA1087170A
Application number: CA231,237A
Authority: CA
Inventors: Beat Muller; Peter Schneider; Heinrich Peter; Hans Bickel
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1974-07-12
Filing date: 1975-07-10
Publication date: 1980-10-07
Also published as: ATA537875A; ES439286A2; AU8293475A; FR2277580A2; IL47691A0; GB1512574A; DE2530339A1; FR2277580B2; AT339481B; JPS5119792A; AU499237B2; NL7508267A

Abstract

Abstract of the Disclosure 6.beta.-(Ra)(Rb)N-methylaryl-acetylamino-6.alpha.-methoxy-2,2-dimethyl-penam-3-carboxylic acid compounds and 7.beta.-(Ra)(Rb)N-methyl-aryl-acetylamino-7.alpha.-methoxy-3-cephem-4-carboxylic acid com-pounds, wherein one of the groups Ra and Rb represents optionally substituted lower alkyl and the other represents hydrogen or optionally substituted lower alkyl, or wherein Ra and Rb conjointly denote optionslly substituted lower alkylene, and wherein aryl represents thienyl .alpha.- furyl, and wherein the 3-position in 3-cephem compounds is unsubstituted or substituted by a modified hydroxyl group or an optionally substituted methyl group, exhibit antibiotic actions against Gram-negstive or Gram-positive microorganisms.

Description

. , .
i, The present invention relates to N-substituted amino-methyl-methoxy-heterocyclic co~pounds, especially 6~-acylam mo-6~-methoxy-penamr3-carboxylic : acid compounds and 7~-acylaminL-7-methoxy-3-cephemr4-carkoxylic acid compounds : of the formLla ,' :

:'~ Amr--CH2 ~ C ~ (~) ~ N A
, :
wherein Am represents an amino group of the formula ,,,~. Ra N

b ~' `~ in which one of the groups Ra and ~ represents optionally substituted lower :~ aIkyl and the other represents hydrogen or optionally substituted lower alkyl, or in which Ra and ~ conjointly denote optionally substituted lower alkylene, : and X represents sulphur or oxygen and wherein the grouping of the formula 1~ -S-A- denotes a radical of the formwla "~, .
.,~,, / S\

Ç-Rl ~` f O=C-R
(Ib)

2-.i., ' i ~ :

~087~70 in which Rl represents hydrogen, an etherified hydroxyl group or a radical of the ~ormula -CH2-R2, wherein R2 denotes hydro-gen, a free, etherified or esterified hydroxyl or mercapto group or a quaternary ammonium group, and R represents hydroxyl or an etherified hydroxyl group which, together with the carbonyl grouping -C(=O)-, forms an esterified carboxyl group which can be split under physiological conditions, as well as salts thereof and also processes for their manufacture as well as pharmaceutical preparations containing such com-pounds,and the use of such pharmaceutical preparations.
Lower alkyl Ra and/or Rb contains preferably up to 7, especially up to 4, carbon atoms and above all represents methyl, as well as ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec.-butyl, tert.-butyl, n-pentyl, n-hexyl, isohexyl or n-heptyl. Substituents are in particular optionally func-tionally modified, such as optionally etherified or esterified, hydroxyl, for example lower alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy or isobutoxy, or halogen, such as chlorine or bromine, (optionally functionally modified hydroxyl preferably being separated from the nitrogen atom of the amino group by at least two carbon atoms of a lower alkyl radical Ra and/or Rb), or optionally functionally modified carboxyl, such as esterified or amidised carboxyl, ~or example lower alkoxycarbonyl, such as methoxycarbonyl or ethoxy-carbonyl, or carbamoyl, as well as cyano.
A lower alkylene formed by Ra and Rb con~ointly is, for example, 1,2-ethylene, 1,3-propylene and, above all, 1,4-. . .

,; _ _ :.
~ . , . . ~ , .. .. -.. . .. : . . . ...
.. .. . . . , - . ~ , -- : ~ , : :
. . . . . , . -... . : . - . , .

1087~70 :

butylene or 1,5-pentylene, as well as 3-methyl-1,5-pentylene or 1,6-hexylene. Substituents of such lower alkylene radicals are, for example, the abovementioned optionally functionally modified hydroxyl and/or carboxyl groups.
The group X is above all sulphur but can also be oxygen.
The Am-methyl-substituted radical thus represents the correspond-ing Am-methyl-thienyl, for e~àmple 4- or 5-Am-methyl-2- or -3-thienyl, also 3-Am-methyl-2-thienyl or 2-Am-methyl-3-thienyl, or corresponding Am-methyl-furyl, for example 4- or 5-Am-methyl-2-furyl.
An etherified hydroxyl group Rl is a hydroxyl group etherified by a lower aliphatic hydrocarbon radical. Such a group is, in particular, lower alkoxy, preferably with up to 7, especially with up to 4, carbon atoms, above all methoxy, as well as ethoxy, n-propoxy or isopropoxy and also straight-chain or branched butoxy, pentoxy, hexyloxy or heptyloxy.
An etherified hydroxyl or mercapto group R2 is, for example, a hydroxyl or mercapto group etherified by a lower ali-phatic hydrocarbon radical. An etherified mercapto group R2 can also represent a mercapto group etherified by an optionally sub-stituted heterocyclic radical which is bonded to the sulphur via a ring carbon atom and which has 1 to 4 ring nitrogen atoms and optionally a further ring hetero-atom from the group oxygen and sulphur.
. ~, .
An esterified hydroxyl or mercapto group R2 is a . .~ .

, : .

~ ~ - 4 _ . .
.'' ~087~70 ; , hydroxyl or mercapto group esterified by a lower aliphatic carboxylic acid or by an optio~ally N-substituted carbamic acid. A mercapto group can al~o be esterified by benzoic acld or by a heterocyclic carboxylic acid, wherein the heterocyclic part repre4ents an optionally substituted hetero-cyclic radical which is bonded to the sulphur via a ring carbon atom and which has 1 to 4 ring nitrogen atoms and optionally a further ring hetero-atom from the group oxygen and ~ulphur.
Quaternary ammonium groups R2 are quaternary ammonium groups which are derived from tertiary organic bases, prefer-A,- ably from corresponding aliphatic amines or above all from ;il corresponding heterocyclic nitrogen bases, and which are bonded to the methyl carbon atom via the nitrogen atom.
`1 Hydroxyl and mercapto groups R2 etheri~ied with an aliphatic hydrocarbon radical are, in particular, lower alkoxy, preferably with up to 7, especially up to 4, carbon atoms, :
"~! above all methoxy as well as ethoxy, n-propoxy or isopropoxy J and also straight-chain or branched butoxy, pentoxy, hexyloxy ` or heptyloxy, or lower alkylthio, preferably with up to 7, -1 especially with up to 4, carbon atoms, above all methylthio cl as well as ethylthio, n-propylthio or isopropylthio and also straight-chain or branched butylthio, pentylthio, hexylthio or heptylthio.
In a mercapto group R2 etherified by the heterocyclic radical mentioned, this radical has aromatic properties or can be partially saturated. Substituents are, inter alia, lower ..
.~, " '.

.: . . ~ . . . - - . . .. .
,.. . . . . ... . ,,: . . . :

-: .
.
:

alkyl, especially methyl, as well as ethyl, n-propyl, iso-propyl or straight-chain or branched butyl, pentyl or hexyl, hydroxy-lower alkyl, for example hydroxymethyl, cycloalkyl, for example cyclopentyl or cyclohexyl, aryl, such as phenyl which is optionally æubstituted by halogen, for example chlorine, or by nitro, aryl-lower alkyl, for example benzyl, or heterocyclyl, such as furyl, for example 2-furyl, thienyl, ; for example 2-thienyl, or oxazolyl, for example 2-oxazolyl, or functional groups, such as halogen, for example fluorine, chlorine or bromine, optionally substituted amino, such as amino which is optionally monosubstituted or disubstituted by lower alkyl, for example amino, methylamino or dimethylamino, nitro, hydroxyl, lower alkoxy, for example methoxy, ethoxy, n-butoxy or 2-ethylhexyloxy, or optionally functionally modi-fied carboxyl, such as carboxyl, esterified carboxyl, such as lower alkoxycarbonyl, for example methoxycarbonyl or ethoxy-carbonyl, optionally substituted, such as N-mono-lower alkylated or N,N-di-lower alkylated, carbamoyl, for example N-methylcarbamoyl or N,N-dimethylcarbamoyl, or cyano as well as oxo or oxido, it being pos~ible for one or more such sub-stituents, which are bonded above all to ring carbon atoms but also, especially lower alkyl and oxido, to ring nitrogen atoms, to be present.
Such heterocyclic radicals are above all monocyclic, five-membered diaza-, triaza-, tetraza-, thiaza-, thiadiaza-, thiatriaza-, oxaza- or oxadiaza-cyclic radicals of aromatic character which are optionally substituted, for example which ' ,, .

. . .
' -' '' ' ' ~

~087170 contain the abovementioned substituents, especially lower alkyl, for example methyl, or corresponding radicals with a fused benzene ring, such as benzodiaza- or benzooxaza-cyclic radicals, which are optionally substituted, for example which contain the abovementioned substituents, monocyclic, six-membered monoaza- or diaza-cyclic radicals of aromatic character which are optionally substituted, for example which contain the abovementioned substituents, above all oxido, or ,~ ..
corresponding partially saturated radicals which are option-~ ally substituted, for example which contain the abovemen-: tioned substituents, above all oxo, or bicyclic triaza- or tetraza-cyclic radicals of aromatic character which are ~ optionally substituted, for example which contain the above-. mentioned substituents, or corresponding partially saturated radicals which are optionally substituted, for example which contain the abovementioned substituents, above all oxo.
Preferred mercapto groupsR2 which are etherified with ' a heterocyclic radical and wherein the heterocyclic radical . ~
~,.!; represents a corresponding monocyclic, five-membered radical ~; or a corresponding benzo-heterocyclic radical are, inter alia, ,, ~
. imidazolylthio, for example 2-imidazolylthio, triazolylthio . .
which is optionally substituted by lower alkyl and/or phenyl, for example 1-~ethyl-lH-1,2,3-triazol-4-ylthio, lH-1,2,4-triazol-3-ylthio, 5-methyl-lH-1,2,4-triazol-3-ylthio, 3-methyl-l-phenyl-lH-1,2,4-triazol-5-ylthio, 4,5-dimethyl-4H-1,2,4-triazol-3-ylthio or 4-phenyl-4H-1,2,4-triazol-3-ylthio, tetrazolylthio which is optionally substituted by lower alkyl, ., ~. . . . . .
:: .-, . -- : : . . .-- .... .. , :. -, : ',' " .,' . , ~ ' ~ -.
.,. ~ - .
" ::

1~87170 phenyl or halogenophenyl, for example lH-tetrazol-5-ylthio, l-methyl-lH-tetrazol-5-ylthio, 1-phenyl-lH-tetrazol-5-ylthio or 1-(4-chlorophenyl)-lH-tetrazol-5-ylthio, thiazolylthio or i~othiazolylthio which are optionally substituted by lower alkyl or thienyl, for example 2-thiazolylthio, 4-(2-thienyl)-2-thiazolylthio, 4,5-dimethyl-2-thiazolylthio, 3-isothiazolyl-thio, 4-isothiazolylthio or 5-isothiEzolylthio, thiadiazolyl-thio which is optionally substituted by lower alkyl, for example 1,2,3-thiadiazol-4-ylthio, 1,2,3-thiadiazol-5-ylthio, 1,3,4-thiadiazol-2-ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio, 1,2,4-thiadiazol-5-ylthio or 1,2,5-thiadiazol-3-ylthio, thia-triazolylthio, for example 1,2,3,4-thiatriazol-5-ylthio, oxazolylthio or isoxazolylthio which are optionally substituted by lower alkyl or phenyl, for example 5-oxazolylthio, 4-x-, ''.t methyl-5-oxazolylthio, 2-oxazolylthio, 4,5-diphenyl-2-oxazolyl-thio or 3-methyl-5-isoxazolylthio, oxadlazolylthio which is optionally substituted by lower alkyl, phenyl, nitrophenyl or thienyl, for example 1,2,4-oxadiazol-5-ylthio, 2-methyl-1,3,4-,. .
. oxadiazol-5-ylthio, 2-phenyl-1,~,4-oxadiazol-5-ylthio, 5-(4-nitrophenyl)-1,3,4-oxadiazol-2-ylthio or 2-(thienyl)-1,3,4-. oxadiazol-5-ylthio, benzimidazolylthio which is optionally substituted by halogen, for example 2-benzimidazolylthio or 5-chloro-2-benzimldazolylthio, or benzoxazolylthio which is !~ optionally substituted by halogen or nitro, for example 2-~- benzoxazolylthio,.5-nitro-2-benzoxazolylthio or 5-chloro-2-benzoxazolylthio.
Pre~erred mercapto groups R2 which are etherified with ~ ....
..:

.-, ~ - .
' :

1~87~7 a heterocyclic radical and wherein the heterocyclic radical represents a corresponding monocyclic, six-membered radical or a corresponding partially saturated radical are, inter alia, l-oxido-pyridylthio which is optionally Substituted by halogen, for example l-oxido-2-pyridylthio or 4-chloro-1-oxido-2-pyridylthio, pyridazinylthio which is optionally substituted by hydroxyl, for example 3-hydroxy-6-pyridazinylthio, N-oxido-pyridazinylthio which is optionally substituted by lower alkyl, lower alkoxy or halogen, for example 2-oxido-6-pyridazinylthio, 3-chloro-1-oxido_6-pyridazinylthio, 3-methyl-2-oxido-6-pyridazinylthio, 3-methoxy-1-oxido-6-pyridazinylthio, 3-ethoxy-1-oxido-6-pyridazinylthio, 3-n-butoxy-l-oxido-6-pyridazinylthio or 3-(2-ethylhexyloxy)-1-oxido-6-pyridazinylthio, or 2-oxo-1,2_dihydro-pyrimidinylthio which is optionally substituted by lower alkyl, amino, di-lower alkylamino or carboxyl, for example 2-oxo-1,2-dihydro-4-pyrimidinylthio, 6-methyl-2-oxo-1,2-dihydro-4-pyrimidinylthio, 5-methyl-2-oxo-1,2-dihydro-4-pyrimidinylthio, 6-amino-2-oxo-1,2-dihydro-4-pyrimidinylthio, 6-dimethylamino-2-oxo-1,2-dihydro-4-pyrimidinylthio, 5-carboxy-2-oxo-1,2-dihydro-4-pyrimidinylthio or 6-carboxy-2-oxo-1,2-dihydro-4-pyrimidinyl-thio.
Preferred mercapto groups R2 which are etherified with a heterocyclic radical and wherein the heterocyclic radical represents a corresponding bicyclic radical which is option-ally partially saturated are, inter alia, triazolopyridyl-thio, for example s-triazolo[4,3-a]pyrid-3-ylthio or 3H-v-_ g _ ,' ,: . -' , , ,::: , .

. , .~ .- . . ,, ~ .
., .- ', - :

~87~70 :
triazolo[4,5-b]pyrid-5-ylthio, or purinylthio which is option-ally substituted by halogen and/or lower alkyl, for example ,....
2-purinylthio, 6-purinylthio or 8-chloro-2-methyl-6-purinyl-, ~
thio, as well as 2-oxo-1,2-dihydro-purinylthio, for example 2-oxo-1,2_dihydro-6_purinylthio.
Hydroxyl groups R2 esterified with aliphatic carboxy-lic acids are, in particular, lower alkanoyloxy, especially acetoxy and also formyloxy, propionyloxy, valeryloxy, hexanoyl-oxy, heptanoyloxy or pivalyloxy.
An esterified hydroxyl group R2 is also a hydroxyl group esterified by an optionally N-substituted half-amide of carbonic acid. N-Substituents are lower alkyl which option-ally contains halogen, for example chlorine, for example methyl, ethyl or 2-chloroethyl, or lower alkanoyl, for example acetyl or propionyl. Hydroxyl groups R2 esterified in this way are, for example, carbamoyloxy, N-methylcarbamoyloxy, N-ethylcarbamoyloxy, N-(2-chloroethyl)-carbamoyloxy or N-acetylcarbamoyloxy.
A mercapto group esterified by a heterocyclic carboxy-lic acid contains, as the heterocyclic radical, for example one of the heterocyclic radicals mentioned above in connection with the etherified mercapto groups and also designated as preferred. Mercapto groups esteri~ied in this way are, in particular, triazolylcarbonylthio which is optionally sub-stituted by lower alkyl and/or phenyl, for example l-methyl-lH-1,2,3-triazol-4-ylcarbonylthio, thiazolylcarbonylthio or isothiazolylcarbonylthio which are optionally substituted by , ................ .
i .

~, - 10 -.,."
., ~,, .
.. - :
:
., ~
.; . .

,:

,:
...
,.,., ~087~qo lower alkyl or thienyl, for example 3-isothiazolylcarbonyl-thio, 4-isothiazolylcarbonylthio or 5-isothiazolylcarbonyl-thio, thiadi~azolylcarbonylthio which is optionally substituted by lower alkyl, for example 1,2,3-thiadiazol-4-ylcarbonylthio, 1,2,~-thiadiazol-5-ylcarbonylthio or 1,2,5-thiadiazol-3-yl-carbonylthio, or oxazolylcarbonylthio or isoxazolylcarbonyl-thio which are optionally substituted by lower alkyl or phenyl, for example 3-methyl-5-isoxazolylcarbonylthio.
In a quaternary ammonium group R2, which is derived from a tertiary organio base, the nitrogen atom is bonded to the methyl carbon atom and accordingly is present in the quaternised, positively charged form. Quaternary ammonium groups are, inter alia, tri-lower alkylammonium, for example trimethylammonium, triethylammonium, tripropylammonium or tributylammonium, but especially optionally substituted sulphonamido, for example sulphonamido substituted by lower alkyl, such as methyl, hydroxy-lower alkyl, such as hydroxy-methyl, or amino, such as 4-aminophenylsulphonamido, hydroxyl, halogen, such as fluorine, chlorine, bromine or iodine, halogeno-lower alkyl, such as trifluoromethyl, sulpho, option-ally functionally modified carboxyl, such as carboxyl, lower alkoxycarbonyl, for example methoxycarbonyl, cyano, carbamoyl which is optionally N-monosubstituted or N,N-disubstituted by lower alkyl, for example methyl or ethyl, or hydroxy-lower alkyl, for example hydroxy.methyl, for example carbamoyl, N-methylcarbamoyl or N,N-dimethylcarbamoyl, hydrazinocarbonyl which is optionally N-substituted by lower alkyl, for example ' . ' , . ' ' ' ~ ' . .'- .. ' .

r ~087~7 hydrazinocarbonyl, carboxy-lower alkyl, such as carboxymethyl, lower alkanoyl, such as acetyl, or l-lower alkyl-pyrrolidinyl, such as l-methyl-2-pyrrolidinyl, or monosubstituted or poly-subqtituted, monocyclic or bicyclic azacyclic ammonium groups ~` of aromatic character with 1 or 2 ring nitrogen atoms and , , ~ optionally one ring sulphur atom, such as pyrimidinium, b' pyridazinium, thiazolium, quinolinium and, above all, . ., pyridinium. ~
Heterocyclic ammonium groups R2 are, above all, sulphonamido which is optionally substituted by lower alkyl or . hydroxy-lower alkyl, or hydroxyl, halogen, trifluoromethyl, sulpho, carboxyl, lower alkoxycarbonyl, cyano, lower alkanoyl, lower alkyl-pyrrolidinyl or pyridinium which optionally con-; tains carbamoyl which is N-substituted by lower alkyl or hydroxy-lower alkyl, for example pyridinium, 2-, 3- or 4-,, methyl-pyridinium, 3,5-dimethyl-pyridinium, 2,4,6-trimethyl-: pyridinium, 2-, 3- or 4-ethyl-pyridinium, 2-, 3- or 4-propyl-pyridinium or especially 4-hydroxymethyl-pyridinium, also 2-amino-pyridinium or 2-amino-6-methyl-pyridinium, 2-(4-amino-phenylsulphonylamido)-pyridinium, 3-hydroxy-pyridinium, 3-fluoro-, 3-chloro-, 3-iodo- or eqpecially 3-bromo-pyridinium, 4-trifluoromethyl-pyridinium, 3-~ulpho-pyridinium, 2-, 3- or i 4-carboxy-pyridinium or 2,3-dicarboxy-pyridinium, 4-methoxy-~, carbonyl-pyridinium, 3- or 4-cyano-pyridinium, 3-carboxy-methyl-pyridinium, 3- or 4-acetyl-pyridinium, 3-(1-methyl-2-pyrrolidinyl)-pyridinium and especially 4-carbamoyl-. pyridinium as well as 3-carbamoyl-, 3- or 4-N-methylcarbamoyl-, - 12 _ . .

.. . .

. ~

. .

~087170 4-N,N-dimethylcarbamoyl-, 4-N-ethylcarbamoyl-,3-N,N-diethyl-carbamoy~-~ 4-N-propylcarbamoyl-, 4-isopropylcarbamoyl- and 4-hydroxymethylcarbamoyl-pyridinium, and also optionally correspondingly substituted pyrimidinium, pyridazinium, thiazolium or quinolinium.
In an esterified carboxyl group of the ~ormula -C(=O)-R, which is splittable under physiological conditions, R is, above all, an acyloxymethoxy group, wherein acyl denotes, for example, the radical of an organic carboxylic acid, above all of an optionally substituted lower alkanecarboxylic acid, or wherein acyloxymethyl ~orms the radical of a lactone.
Such groups R2 are lower alkanoyloxymethoxy, for example acetoxymethoxy or pivaloyloxymethoxy, amino-lower-alkanoyloxy methoxy, especially ~amino-lower alkanoyloxymethoxy, for example glycyloxymethoxy, L-valyloxymethoxy or L-leucyloxy-methoxy, and also phthalidyloxy, for example 2-phthalidyloxy, or indanyloxy, for example 5-indanyloxy.
Salts are, in particular, those of compounds of the formula I having a free carboxyl group -C(=O)-R, above all metal salts or ammonium salts, such as alkali metal salts and alkaline earth metal salts, for example sodium salts, potassium salts, magnesium salts or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, it being possible to use, for formation of the salt, above all aliphatic, cycloaliphatic, cycloaliphatic-ali~hatic or arali-phatic primary, secondary or tertiary monoamines, diamines or polyamines, as well as heterocyclic bases, such as lower _ 13 -... . .

, , -. . .
~1 ., .

'` 1~87~qO

alkylamines, ~or example triethylamine, hydroxy-lower alkyl-amines, for example 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)-amine, basic aliphatic esters of carboxylic acids, for example 4-aminobenzoic acid 2-di-ethylaminoethyl ester, lower alkyleneamines, for example 1-ethyl-piperi~ine, cycloalkylamines, for example dicyclohexyl-amine, or benzylamines, for example N,N'-dibenzyl-ethylene-diamine, and also baæes of the pyridine type, for example pyridine, collidine or quinoline. Compounds of the formula I
can also form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulphuric acid or phosphoric acid, or with suitable organic carboxylic acids or sulphonic acids, for example trifluoroacetic acid, as well as with amino-acids, such as arginine and lysine. Compounds of the formula I having a free carboxyl group can also be present in the form of inner salts, that is to say in the zwitterionic form.
The compounds of the formula I and their pharmaceuti-cally usable, non-toxic salts are valuable substances which have an antibiotic action and which can be used especially as antibacterial antibiotics. For example, they are active against micro-organisms, such as Gram-positive bacteria, for example against Sta~hylococcus aureus (in vitro in minimum concentrations of about 0.0005 mg/ml), including penicillin-resistant Sta~hvlococcus aureus (in vitro in minimum concentratlons of about 0.001 mg/ml), and also against cillus subtili~ (in vitro in minimum concentrations o~ about 0.0002 mg/ml) and against Gram-negative bacteria, for ., ,. . ' .:
.

10~7170 .
~ example against Escherichia coli (in vitro in minimum concen-:. . ...... . _ _ ~
trations of about 0.001 mg/ml), including ampicillin- ~
!. ,~
resistant, carbenicillin-resistant and rifamycin-resistant Escherichia coli (in vitro in minimum concentrations of about , ., _ ~
0.002 mg/ml), and also against ebsiella pneumoniae and Salmonella tYPhimurium, including ampicillin-resistant, carbenicillin-resistant and rifamycin-resistant Salmonella tYDhimurium (in vitro in minimum concentrations of about .' ! _ o.ooo6 mg/ml), Proteus vul~aris, Proteus mirabilis, including carbenicillin-resistant Proteus mirabilis, and Proteus rett~eri (in vitro in minimum concentrations of about 0.005 mg/ml) as well as Proteus mor~anii (in vitro in minimum con-centrations of about 0.03 mg/ml). The new compounds are distinguished by an excellent stability against ~-lactamases, such as cephalosp~rinases, especially from Gram-negative bac-teria, which can be shown by means o~ the rates of hydrolysis in the presence of ~-lactamases isolated from various Gram-negative germs, such as Escherichia coli, Aerobacter cloacae, Proteus mor~anil and Pseudomonas aeru~inosa. The rates at which the new compounds are hydrolysed by ~-lactamases are, for example, more than a hundred times smaller than those of ,.,..~
cephalothln and cephaloridin. The new compounds can thus be ,;,t~. used accordingly, for example in tha form of antibiotically active preparation~, for the treatment of in~ections caused by Gram-positive or Gram-negative bacteria.
.`'!, The present invent~n relates above all to those com-~ pounds of the formula I, wherein Am represents lower alkyl-., ~ - 15 -'..;

:, ~ . . : -, . .
.
'',.. - . " ' . ,~ ' ' '-: , ' ': . . : , . . - - - . .

:: . .

,f ~

amino or di-lower alkylamino, wherein lower alkyl contains up to 4 carbon atoms, or represents lower alkyleneamino, wherein lower alkylene contains 4 to 6 chain carbon atoms, X represents oxygen or especially sulphur and the Am-methyl-substituted radical repre-. sents Am-methyl-2-thienyl, such as 4- or 5- and also 3-Am-methyl-., 2-thienyl, as well as Am-methyl-3-thienyl, or Am-methyl-2-furyl, such as 4- or 5- as well as 3-Am-methyl-2-furyl, and also Am-methyl-

3-furyl, and the grouping of the formula -S-A- represents a radical of the formula Ia but especially a radical of the formula Ib, where-in Rl denotes lower alkoxy, preferably with up to 4 carbon atoms, or the group of the formula -CH2-R2, and R2 represents hydrogen, lower alkanoyloxy, especially acetoxy, optionally substituted carbamoyloxy, etherlfied mercapto or quaternary ammonium, and wherein R represents hydroxyl, as well as salts, especially the non-toxic, pharmaceutically . usable salts, in particular the alkali metal or alkaline earth metal :~l salts, as well as the inner salts, of such compounds.
.i The present invention relates above all to compounds of ,, the formula I, wherein Am denotes lower alkylamino or di-lower alkyl-~: amino, wherein lower alkyl contains up to 4 carbon atoms, X repre-l 20 sents oxygen or especially sulphur, and the Am-methyl-substituted ' radical represents Am-methyl-2- or -3-thienyl, for example 4- or 5-and also 3-Am-methyl-2-thienyl, as well as Am-methyl-2-furyl, for .

" ~ .

~ ~ - 16 -, ~.

.

example 4- or 5-Am-methyl-2-furyl, and the grouping of the formula -S-A- represents a radical of the formula Ia or Ib, wherein Rl denotes lower alkoxy with up to 4 carbon atoms, such as methoxy, : or the group of the formula -C~2-R2, and R2 denotes hydrogen, lower alkanoyloxy, for example acetoxy, optionally N-lower alkylated, as ~:
well as N-halogeno-lower alkylated, carbamoyloxy, for example car-bamoyloxy, methylcarbamoyloxy, ethylcarbamoyloxy or 2-chloroethyl-carbamoyloxy, lower alkylthio, for example methylthio, optionally substituted heterocyclylthio, wherein heterocyclyl represents a monocyclic five-membered heterocyclic radical of aromatic character which is bonded to the thio sulphur atom via a ring carbon atom and which contains 2 or:3 ring nitrogen atoms and optionally additionally - -a ring oxygen atom, a ring sulphur atom or a ring nitrogen atom, it being possible for such a radical to be optionally substituted by . lower alkyl, especially methyll or wherein heterocyclyl represents an unsaturated monocyclic, six-membered heterocyclic radical, which is bonded to the thio sulphur atom via a ring carbon atom and which ~' contains 2 ring nitrogen atoms, and in which either a ring nitrogen atom carries an oxido group or a ring carbon atom carries an oxo group, it being possible for such a heterocyclyl radical to be optionally substituted by lower alkyl, for example methyl, lower alkoxy, for example methoxy, or halogen, for example chlorine, or R2 denotes a pyridinium radical, which can be optionally substituted by .. ~

,. .~
~ - 17 - .
, ~.

- ' . .

~o87~7 `,,.~
~i ., r` halogen, for example chlorine or bromine, lower alkyl, for `; example methyl or ethyl (preferably in the 4-position), -carboxyl, carbamoyl or hydrazinocarbonyl, and wherein R re-, .
presents hydroxyl, as well as salts, especially pharmaceuti-~ cally usable, non-toxic salts, in particular the alkali metal ,. . .
salts or alkaline earth metal salts, as well as the inner salts, of such compounds.
The invention relates especially to 3-cephem compounds ; of the formula I, wherein Am represents methylamino or di-methylamino, X above all represents sulphur and also oxygen, ... .
and the Am-methyl-substituted radical denotes Am-methyl-2-; thienyl or Am-methyl-2-furyl, for example 4- or preferably 5-~j and also ~-Am-methyl-2-thienyl or 4- or 5-Am-methyl-2-furyl, f~ and the grouping of the formula -S-A- denotes the radical of ~' the formula Ib, wherein ~ represents lower alkoxy with up to ;,'-1

4 carbon atoms, especially methoxy, or represents the radical of the formula -CH2-R2, in which R2 denotes hydrogen, acetoxy, carbamoyloxy, N-lower alkyl-carbamoyloxy, for example methyl-carbamoyloxy or ethylcarbamoyloxy, N-halogeno-lower alkyl-carbamoyloxy, for example 2-chloroethylcarbamoyloxy, lower alkylthio, for example methylthio, thiadiazolylthio which is .' optionally substituted by lower alkyl, ~or example methyl and ~ which is bonded to the thio sulphur atom via a ring carbon atom, for example 1,3,4-thiadiazol-2-ylthio, 5-methyl-1,3,4-~ thiadiazol-2-ylthio or 5-methyl-1,2,4-thiadiazol-2-ylthio, or : `
. tetrazolylthio, for example 1-methyl-5-tetrazolylthio, N-. oxido-pyridazinylthio which is optionally substituted by lower ' .
- 18 _ . . . .
. ~ :
,., . ~ . :

'' ' ' ~ . -,' ' ' ' , 1087~70 alkyl, for example methyl, lower alkoxy, for example methoxy, or halogen, for example chlorine, and which is bonded to the thio sulphur atom via a ring carbon atom, for example 3-methyl-2-oxido-6-pyridazinylthio, 3-methoxy-1-oxido-6-pyridazinyl-thio or 3-chloro-1-oxido-6-pyridazinylthio, or pyridinium which is optionally substituted by carbamoyl, for example pyridinium or 3-carbamoylpyridinium, and wherein the group R
represents hydroxyl, a~ well as salts, especially the non-toxic, pharmaceutically usable salts, in particular the alkali metal salts or alkaline earth metal salts, as well as the inner salts, of such compounds.
The invention relates above all to 3-cephem com-pounds of the formula I, wherein Am denotes methylamino or dimethylamino, X above all represents sulphur and also oxygen, and the Am-methyl-substituted radical denotes Am-methyl-2-thienyl or Am-methyl-2-furyl, for example 4- or preferably 5-as well as 3-Am-methyl-2-thienyl or -2-furyl, and the grouping . .
of the ~ormula -S-A- denotes the radical of the formula Ib, wherein Rl represents methoxy or the radical of the formula -CH2R2, in which R2 denotes hydrogen, acetoxy, carbamoyloxy, methylcarbamoyloxy, ethylcarbamoyloxy, 2-chloroethylcarbamoyl-oxy, methylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio or 1-methyl-5-tetrazolylthio, and wherein R represents hydroxyl, as well as salts, especially the non-toxic, pharmaceutically usable salts, in particular the alkali metal salts or alkaline earth metal salts, as well as the inner salts, of such compounds The invention relates especially to the compounds ., ".
_ 19 _ - ~ . . ... - - -:: , , -, , , . . . . ~ . -, . : , , . . . ~
:. ' : :
::
:: .

; 1087170 ;' .
described in the examples and to their salts, especially the non-toxic, pharmaceutically usable salts, such as the alkali metal salts or alkaline earth metal salts, and above all to their inner salts, which, in the indicated doses, exhibit outstanding antibiotic actions and which accordingly are used in the form of antibiotically active preparations.
, .. . .
~he proce~s for the manufacture of 7~-acylamino-7a-methoxy-~ 3-cephem-4-carboxylic acld compounds of the formula "~' . OCH H
3! ~
.. Am-CH2 ~ H2-C-HN ¦ ¦~ ~ H2 (I) ~ ~ ~J-R1 ' O= -R
,~ wherein Am represents an amino group of the formula .,~, Ra ~ R
:i. b ., ~' in which one of the groups Ra and Rb represents lower alkyl :~i and the other represents hydrogen or lower alkyl and X
' represents sulphur or oxygen and wherein Rl represents a .:, radical of the formula -CH2-R2, whereln R2 denotes acetoxy, ~, carbamoyloxy, optionally lower alkylated thiadiazolylthio .-1, or optionally lower alkylated tetrazolylthio and R represents represents hydroxyl, a~ well as salts thereof, i9 charac-terised in that the amino group ln a compound of the formu-la : O,CH~

H2N ~ ~ 2 (II) .; O ~-R
O= -Ro r.' ~ I
~ ~ - 20 -....

,........ .
. ,' ' ~ ,, .. - . . .

. ~ ..

~87170 wherein the amino group can be optionally substituted by anorganic silyl or stammyl group or by an ylidene group, : and wherein Ro has the meaning of R or reprèsents a carbo-; xyl protective radical which, with the carbonyl group of the formula -C(=0)-, forms a protected carboxyl group, or in a salt thereof, is acylated by treatment with an acid of the formula :, . Am-CH2 ~ CH2-C-OH (tII) . .

:` wherein an amino group Am, if necessary, is present in the ; protected form, or with a reactive functional acid deriva-1 tive thereof or with a salt of such a compoundJor the :~ methoxy group is introduced into the 7~-position of a 3-cephem compound of the formula . . :

Am-CH2 ~ H2-C-~N ~ ~ 2 , I X O ~o~~R

.~~
: wherein an amino group Am is preferably in the protected form and a carboxyl group of the formula -C(~0)-Ro is present in the protected form, or of a salt thereof, by treating an acylimino compound of the formula .
- 20a -.

. - .
.
:- ~ . : , -.' - : ' .~

., . .
'~: , . ' :

~087170 .

H -~--C13~CN -e~

o= -Ro jl wherein amlno of the aminomethyl group is ln a protected form, and Ro and Rl have the abovementioned meaning, and a carboxyl group of the formula -C(~OI-Ro is in a protected ` . form, with methanol or by treating a compound of the formula IV, wherein amino of the aminomethyl group and the carboxyl group of the formula -C(=O)-Ro, and addltional functional groups which may be present, are in a protected form, with an anion-forming agent followed by a N-haloge-nating agent and, lf required, reacting with a base which splits off hydrogen halide, and t~eating the resulting compound with methanol, or a compound of the formula C~2_e_~ ~ H2l (VI~

O~ \Ro wherein Ro and Rl have abovementioned meaning and a carbD-xyl group of the formula -C(=O)-Ro is present in the pro-tected form, is reacted with a compound of the formula Am-H
(VII), the additional hydrogen~atom in an amino group Am ~: which is monosubstituted by lower alkyl being replaced by an amino protective group, and with formaldehyde in the - presence of a strong, at most slightly nucleophilic, acid, or, in a compound of the formula ~ ~ 20b -' ' : '.

' ~
1087~70 .

: OCH 3~1 .' H2N-CH2 ~CH;~-~-HN ~3~fH2 (VIII) "" =L~
.'; ' ~ ~
, O Ro .
or ln a salt thereof, the free amlno group H2N- is con-~
.~ verted into a substi~uted amino group Am by treatment wlth .~- a reactive ester of an alcohol of the formula Ra-OH (IXa) :. . or Rb-OH (IXb) or of a diol of the formula HO-(RalRb)-OH
(IXc), or by reactlng a starting material of the formula ~III with a lower alkanal or a lower alkanone under .'. simultaneous or subsequent treatment wlth a reducing agent, and, in a resulting compound, a protected amino group in the Am-methyl radlcal is converted into the group Am and .;, .; a protected carboxyl group of the formula -C(=O)-Ro $s -, converted into a free carboxyl group and/or lf desired, a lower alkanoyloxy group R2 is converted into an optio-nally substituted heterocyclylthio group R2 and/or a re-sulting salt is converted into the free compound or into :.: another salt, or a resulting free compound is converted . , into a salt.
,; ,, , ~ Radlcals which substitute the amino group and permit :1 '!`,'`i acylation thereof and which are optlonally present in a starting material of the formula II are, for example, ; . organlc sllyl or stannyl group~ and also ylidene groups, .~ whlch, together with the amlno group, form a Schiff's base.
The organic qilyl or stannyl groups mentloned are, for example, the same as those which, with the carboxyl group .. ; .
: on the penam or cephem ring, are also able to form a pro-tected carboxyl : . ;

, . -~ ` .
.' :~. . . ' ,: . ' - ' : ~ ' ':
' ,' ~ : ' .
... . .
:
.. . .
' ' ' 10~7~70 group -C(=O)-Ro. On silylation or stannylation of a carboxyl group in a starting material of the formula II, the amino group can also be silylated or stannylated when an excess of the silylating or stannylating agent is used.
The ylidene groups mentioned are, above all, aryl-methylene groups, wherein aryl represents, in particular, a carbocyclic, above all monocyclic, aryl radical, for exa~ple phenyl which is optionally substituted, such as by nitro or hydroxyl; such arylmethylene groups are, for example, benzylidene, 2-hydroxybenzylidene or 4-nitrobenzylidene and also oxacycloalkylidene which is optionally substituted, for example by carboxyl, for example 3-carboxy-2-oxacyclohexyli-dene.
A protected carboxyl group of the formula -C(=O)-Ro in a starting material of the formula II is above all an esterified carboxyl group which preferably can be split easily, wherein Ro represents an etherified hydroxyl group, or a carboxyl group present in the form of an anhydride, wherein Ro denotes an esterified, and especially a phosphorylated, hydroxyl group.
An etherified hydroxyl group Ro which, in the starting material of the formula II, with the carbonyl group-ing of the formula -C(,O)-, forms an esterified carboxyl group which preferably can be split easily,~s, for èxample, a lower alkoxy group which preferably is substituted, above all in the a-position and also in the ~-position, and/or is branched in the a-position. Substituents of such a group are, for _ 22 -., .
. :
' ' '`:.;
':

.

10871qO

example, carbocyclic aryl, such as phenyl which is optionally substituted, for example by lower alkyl, such as tert.-butyl, phenyl, hydroxyl, lower alkoxy, such as methoxy, and/or nitro, furyl, such as 2-furyl, aryloxy, such as phenyloxy which is optionally substituted, for example by lower alkoxy, such as methoxy, arylcarbonyl, such as benzoyl which is optionally substituted, for example by halogen, such as bromine, cyano or acylamino, such as diacylamino, ~or example phthalimino or succinylimino; such substituents are preferably in the a-position of the lower alkoxy group Ro, it being possible for the latter, depending on the nature of the substituents, to i contain one, two or more such radicals. Further substituents which are preferably in the ~-position of the lower alkoxy . radical Ro are halogen, for example chlorine, bromine or iodine, an individual chlorine or bromine in such radicals being readily convertible into iodine before a carboxyl group protected in this way is liberated. Examples o~ the above-mentioned, optionally 3ubstituted lower alkoxy gro~ps Ro are tert.-lower alkoxy, for example tert.-butoxy or tert.-pentoxy, a-phenyl-lower alkoxy which is optionally substituted in the phenyl radical, for example as indicated, such as benzyloxy, ; 4-hydroxy-3,5-di-tert.-butyl-benzyloxy, 2-biphenylyl-2-propyloxy, 4-methoxy-benzyloxy, 4,5-dimethoxy-2-nitro-benzyl-oxy or 4-nitro-benzyloxy, diphenylmethoxy which is optionally substituted in the phenyl radicals, for example as indicated, ! especially by lower alkoxy, for example methoxy, such as benz-hydryloxy or 4,4'-dime~hoxy-diphenylmethoxy, as well as _ 23 _ .~ ;1, . , - .
... . .
.
- ~ .
- .
'',' . ' , ,. ,~
,, -~087~qo .
trityloxy, bis-phenyloxy-methoxy which is optionally substitu-,, ted in the phenyl radicals, for example as indicated, especially by lower alkoxy, such as bis-4-methoxyphenyloxy-methoxy, phenacyloxy ~hich is optionally substituted, especi-; ally by halogen, such as phenacyloxy or 4-bromo-phenacyloxy, ~ cyanomethoxy, diacyliminomethoxy, such as phthalylimino-.~
methoxy or succinyliminomethoxy, or 2-halogeno-lower alkoxy, ~i `1 such as 2,2,2-trichloroethoxy, 2-bromoethoxy or 2-iodoethoxy.
., Furthermore, an etherified hydroxyl group Ro which, with the carbonyl grouping of the formula -C(=O)-, forms an esterified carboxyl group which preferably can be split easily, can also denote a cycloalkoxy group, the a-position of which , preferably represents a bridge head carbon atom. A cyclo-alkoxy group Ro of this type is, for example, l-adamantyloxy.
Further etherified hydroxyl groups which represent ~:, the radical Ro are organic silyloxy or stannyloxy groups, wherein organic radicals, 1 to 3 of which can be present, are especially optionally substituted aliphatic hydrocarbon radi-cals, such as lower alkyl, for example methyl, ethyl, n-propyl or tert.-butyl, or halogeno-lower alkyl, for example chloromethyl or 2-chloroethyl, as well as optionally sub-stituted cycloaliphàtic, aromatic or araliphatic hydrocarbon radicals, such as cycloalkyl, phenyl or phenyl-lower alkyl and also functional groups with organic substituents, such as etherified hydroxyl groups, for example lower alkoxy, such as methoxy or ethoxy, these silyloxy or stannyloxy groups being able optionally to contain, as ~urther substituents, for .....
:..
_ 24 -,... ..
.~ .

-:
, , . , . ~ . .
.
- , ", . ,. . . ~ . .: ..

~087170 example halogen, such as chlorine. Such radicals Ro are, inter alia, tri-lower alkylsilyloxy, for example trimethyl-silyloxy or tert.-butyldimethylsilyloxy, lower alkoxy-lower alkyl-halogeno-silyloxy, for example chloromethoxymethyl-silyloxy, or tri-lower alkylstannyloxy, for example tri-n-butylstannyloxy.
The group Ro can also represent a phosphoryloxy group which contains a substituted trivalent or pentavalent phos-phorus atom and which, together with the carboxyl grouping of the formula -C(=O)-, forms a protected carboxyl group.
Substituents of trivalent phosphorus, which can be identical or different, are, inter alia, optionally substituted hydro-carbon radicals, such as corresponding aliphatic or araliphatic hydrocarbon radicals, for example lower alkyl or halogeno-lower alkyl, such as methyl, ethyl or chloromethyl, or phenyl-lower alkyl, such as benzyl, etherified hydroxyl or mercapto groups, such as hydroxyl or mercapto groups etherified by optionally su~stituted aliphatic, aromatic or araliphatic hydrocarbon radicals, for example lower alkoxy or lower alkyl-thio, such as methoxy, ethoxy, methylthio or n-butylthio, phenyloxy or phenylthio which are optionally substituted, for example by lower alkyl, lower alkoxy or halogen, or phenyl-lower alkoxy or phenyl-lower alkylthio which are optionally substituted, for example by lower alkyl, lower alkoxy or halo-gen, for example benzyloxy or benzylthio, halogen, for example fluorine, chlorine or bromine, and/or a divalent hydrocarbon radical which is optionally substituted and/or interrupted by ~ ' - 25 _ ~'',' ' ' ~''~ ' ' ' ' 'i: ' : . ' '' ~ , ' .' , ' ' ' , .
",, ''" ' ' ' ' ' ' ' ' ' ' :, 10~7170 hetero-atoms, such as oxygen or sulphur, such as a corres-ponding aliphatic or araliphatic radical, for example lower alkylene, such as 1,4-butylene or 1,5-pentylene, l-oxa-lower alkylene, wherein the second methylene group which is bonded to the phosphorus atom can also optionally be replaced by an oxygen atom or sulphur atom, for example l-oxa-1,4-pentylene, l_oxa-1,5-pentylene or 1,5-dioxa-1,5-pentylene, or two hydroxyl groups which are etherified by a divalent, optionally sub-stituted hydrocarbon radical, such as a corresponding ali-phatic, aromatic or araliphatic radical, such as lower alky-lene or 1,2-phenylene. Substituents of pentavalent phos-phorus are those of trivalent phosphorus and additionally an :
. oxo group.
In a starting material of the formula II any further free functional groups which may be present in addition to the carboxyl group o~ the formula -C(=O)-Ro, such as a free . hydroxyl group R2~ are, if desired or necessary, customarily .~ present, during the acylation reaction, in a protected, : preferably easily splittable, form; a free hydroxyl group can ,1 be present, for example, in an easily splittable etherified or esterified form, for example in the form of a lower alkoxy group, for example a methoxy group, or a 2-oxacycloalkoxy . group, for example a 2-tetrahydropyranyloxy group, or, res-.- pectively, in the form of an acyloxy group, such as a lower alkanoyloxy group, for example an acetyloxy group, or a suit-~ able etherified hydroxycarbonyloxy group.
:. In a starting material of the formula III, a secondary .

_ 26 -. ~ - . . . . .
. : :: : : : . . -, : . . . . .
, , . .

~87170 amino group Am, in particular, is advantageously protected by any one of the amino protective groups, preferably the easily removab~e amino protective groups, which are known in peptide chemistry or in penicillin and cephalosporin chemistry.
Such protective groups can be, for example, acyl, arylmethyl, 2-carbonyl-1-vinyl~ arylthio or aryl-lower alkylthio groups and also arylsulphonyl groups as well as organic silyl or stannyl groups. The starting material of the formula III can also be used in the form of an acid addition salt, in which the amino group Am is protected in the ionic ~orm.
An easily removable acyl group is, for example, the formyl group or the acyl radical of a half-ester o~ carbonic acid, such as a lower alkoxycarbonyl group which preferably has multiple aliphatic substituents or branching and/or aro-., matic or hetero-aromatic substituents on the carbon atom in the ~-position to the oxy group, or a methoxycarbonyl group which is substituted by an arylcarbonyl radical, especially a benzoyl radical, or a lower alkoxycarbonyl group which is sub-stituted in the ~-position by halogen, such as tert.-lower alkoxycarbonyl, for example tert.-butoxycarbonyl or tert.-pentyloxycarbonyl, arylcarbonylmethoxycarbonyl, for example phenacyloxycarbonyl, 2-halogenoethoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, or a ;
~ group which can be converted into the latter, such as 2-., chloroethoxycarbonyl or 2-bromoethoxycarbonyl, and also ~ preferably polycyclic cycloalkoxycarbonyl, for example ,~ adamantyloxycarbonyl, phenyl-lower alkoxycarbonyl, especially ,~
~ - 27 -j,:
.
:~ .. . - . .. . . - - .. ..

.- . .' ' '' ` "

` 10~37170 a-phenyl-lower alkoxycarbonyl, which is optionally substitu-ted, for example by lower alkyl, such as tert.-butyl, hydroxyl, lower alkoxy, such as methoxy and/or nitro, for example 4-methoxy-benzyloxycarbonyl, 4-hydroxy-3,5-bis-tert.-butyl-benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or ~-4-biphenylyl-~-methyl-ethoxycarbonyl, and also diphenylmethoxycarbonyl which is optionally substituted, for example by lower alkoxy, such as methoxy, for example diphenylmethoxycarbonyl, or furyl-lower alkoxycarbonyl, above all a-furyl-lower alkoxycarbonyl, for example furfuryloxycarbonyl. An acyl group for the pro-tection of an amino group Am can also be the corresponding radical of a suitable carboxylic acid, such as an aryldicar-boxylic acid, for example the phthaloyl radical, or of a - halogeno-lower alkanecarboxylic acid, for example the tri-fluoroacetyl radical.
Examples of easily removable arylmethyl groups which may be mentioned are optionally substituted polyarylmethyl groups, such as diarylmethyl or triarylmethyl groups, for example trityl which is optionally substituted, such as by lower alkyl, for example methyl, and/or lower alkoxy, such as methoxy, in particular optionally o- and/or p-methoxy-sub-stituted trityl.
Easily removable 2-carbonyl-1-vinyl groups, which together with the amino group form an enamine, are, for . example, 2-lower alkoxycarbonyl-l-lower alkylvinyl groups, especially the 2-methoxycarbonyl-1-methyl-1-vinyl group.
Easily removable arylthio or aryl-lower alkylthio .~
r _ 2 8 ~

!. .
;

':; : ~ - . : - : ' :
, ' ,. ' : ' ' ' . ' : . ' . ~ ' ' ' , :' . ', ' ' ~ ' ' ' ' . . . -' .

~ 1087170 groups are, for example, substituted phenylthio groups, for example phenylthio groups substituted by nitro or halogen, for example chlorine, such as the 2-nitrophenylthio group, the 2,4-dinitrophenylthio group or the pentachlorophenylthio group, and also triarylmethylthio groups, for example the tri-phenylmethylthio group.
An easily removable organic silyl or stannyl group can preferably carry as substituents optionally substituted hydrocarbon radicals, especially aliphatic hydrocarbon radi-cals, such as lower alkyl, for example methyl, ethyl or tert.-butyl, or halogeno-lower alkyl, for example 2-chloroethyl, and also functional groups, for example etherified or esterified hydroxyl groups, such as lower alkoxy, for example methoxy or ethoxy, or halogen, for example chlorine. Such silyl or stannyl radicals are, inter alia, tri-lower alkylsilyl, for example trimethylsilyl or tert.-butyldimethylsilyl, lower .',r, alkoxy-lower alkyl-halogeno-silyl, for example chloromethoxy-fi methylsilyl, or tri-lower alkylstannyl, for example tri-n-butylstannyl.
The acylation of the free amino group or of an amino group substituted by a radical which permits acylation, can be arried out in a known manner by treatment with an acid of the formula III or a reactive functional derivative thereof.
If a free acid of the formula III, preferably having a protected amino group Am, is employed for the acylation, suit-able condensing agents are customarily used, such as carbodi-imides, for example N,N'-diethyl-, N,N'-dipropyl-, N,N'-diiso-i" , ,.
r - . :
.. ~ , . .

S ~

, .

~)87170 propyl-, N,N'-dicyclohexyl- or N-ethyl-N'-3-dimethylamino-propyl-carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or isoxazolinium salts, for example N-ethyl-5-phenyl-isoxazolinium-3'-sulphonate and N tert.-butyl-

5-methyl-isoxazolinium perchlorate, or an acylamino compound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.
The condensation reaction is preferably carried out in an anhydrous reaction medium, preferably in the presence of a solvent or diluent, for example methylene chloride, dimethyl-formamide or acetonitrile, and, if desired or necessary, with cooling or heating and/or in an inert gas atmosphere.
An amide-forming functional derivative of an acid of the formula III, preferably having a protected amino group Am, is above all an anhydride of such an acid, including and preferably a mixed anhydride, but also anlinner anhydride, that is to say the corresponding ketene. Mixed anhydrides are, for example, those with inorganic acids, such as with hydrogen halide acids, that is to say the corresponding acid halides, for example acid chlorides or acid bromides, and also with hydrozoic acid, that is to say the corresponding acid azides, with an acid containing phosphorus, for example phos-phoric acid or phosphorous acid, or with an acid containing sulphur, for example sulphuric acid, or with hydrocyanic acid.
Further mixed anhydrides are, for example, those with organic carboxylic acids, such as with lower alkanecarboxylic acids which are optionally substituted, for example by halogen, such as fluorine or chlorine, for example pivalic acid or tri-., . ,. ,: ' . . :

,. . : ' ~ : ' 10~37170 chloroacetic acid, or with half-esters, especially lower alkyl half-esters, of carbonic acid, such as the ethyl half-ester or the isobutyl half-ester of carbonic acid, or with organic, especially aliphatic or aromatic, sulphonic acids, for example p-toluenesulphonic acid. ~:
Further acid derivatives of an acid of the formula III
which are suitable for reaction with the amino group are activated esters, customarily with a protected amino group Am in the Am-methyl grouping, such as esters with vinylogous alcohols (that is to say enols), such as vinylogous lower alkenols, or aryl esters, such as 4-nitrophenyl esters or 2,4-dinitrophenyl esters, heteroaromatic esters, such as benz-triazole esters, for example 2-benztriazole esters, or diacyl-imino esters, such as succinylimino esters or phthalylimino esters.
The acylation with an acid derivative, such as an anhydride, and especially with an acid halide, can be carried out in the presence of an acid-binding agent, for example of an organic base, such as an organic amine, for example a tertiary amine, such æ atri-lower alkylamine, for example tri-methylamine, triethylamine or ethyl-diisopropylamine, or a N,N-di-lower alkyl-aniline, for example N,N-dimethylaniline, or a base of the pyridine type, for example pyridine, or of an inorganic base, for example an alkali metal hydroxide, car-bonate or bicarbonate or an alkaline earth metal hydroxide, carbonate or bicarbonate, for example sodium hydroxide, car-bonate or bicarbonate, potassium hydroxide, carbonate or bi-- ~ , ., : , . . . . . . . . . .
'. , ' ' ~
.
' . ' , ~ ' .
, ~87'170 carbonate, or calcium hydroxide, carbonate or bicarbonate, or of an oxirane, for example a lower 1,2-alkylene oxide, such as ethylene oxide or propylene oxide.
The above acylation can be carried out in an inert, preferably anhydrous sol~ent or solvent mixture, for example in a carboxylic acid amide, such as a formamide, for example dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride 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.
In an acid of the formula III, or in an acid deriva-tive thereof, the amino group Am is~customarily in the pro-tected form, it alæo being possible for a protected amino group Am in a starting material of the formula III to be in the ionic form, that i8 ~ay the starting material of the formula III is used in the form of an acid addition salt, preferably with a strong inorganic acid, such as a hydrogen halidé acid, for example hydrochloric acid, or sulphuric acid.
Furthermore, if desired, an acid derivative can be formed in situ. Thus, for example, a mixed anhydride is obtained by treating an acid of the formula III, or a suitable .
salt thereof, such as an ammonium salt, with, for example, an organic amine, such as 4-methylmorpholine, or a metal salt, - for example an alkali metal salt, with a suitable acid deriva-~ , .. .. . .. . : ,. .
. : . . . .. , : . ~ . . ~ :

, . . . . . .
, . . . .

`` 1~)87170 tive, such as a corresponding acid halide of an optionally ~ -substituted lower alkanecarboxylic acid, for example tri-chloroacetyl chloride, or with a half-ester of a carbonic acid half-halide, for example the ethyl ester or isobutyl ester of chloroformic acid, and the mixed anhydride thus obtainable is used without isolation.
In a resulting compound, functional, optionally pro-tected groups can be converted, i~ desired or necessary, in a manner which is in itself known into other functional groups, for example free functional groups. Above all, in a compound obtainable according to the invention, a protected amino group in the Am-methyl substituent of the acylamino grouping must be liberated and/or a protected carboxyl group of the formula -C~=0)-Ro, which is different from a carboxyl grouping of the formula -C~0)-R, must be converted into a group of the formula -C(sO)-R; also, if desired, in a manner which is in itself known, a free carboxyl group of the formula -C(=0)-R can be converted into a physiologically splittable carboxyl group of the formula -C(=0)-R and/or a group Rl in a grouping of the formula Ib can be converted into another group Rl. These conversions are carried out in a manner which is in itself known and multiple conversions can be carried out in any desired sequence, the latter usually depending on the nature of the radicals to be converted or to be split off and on the reactions used for this purpose. It is also possible simul-taneously to convert more than one protected functional group into the corresponding free functional groups. Thus, for .

.

,.. : . .. , . . . . ~
.

example, by treatment with a suitable acid, such as trifluoro-acetic acid, optionally in the presence o~ anisole, it is possible, in a resulting compound, simultaneously to convert a tert.-butoxycarbonylamino group or a diphenylmethoxycar-bonylamino group in the Am-methyl substituent of the acylamino radical in the 6- or 7-position and a diphenylmethoxycarbonyl group, which represents the radical of the formula -C(=O)-Ro, in the 3- or 4-position of a resulting penam compound or 3-cephem compound into the amino group and the carboxyl group respectively.
A protected amino group Am can be converted into an amino group Am in a manner which is in itself known, usually by solvolysis or reduction.
A formyl group, as an amino protective group, can be split off, for example by treatmentjwith an acid agent, for example p-toluenesulphonic acid or hydrochloric acid, with a weakly basic agent, for example dilute ammonia, or with a decarbonylating agent, for example tris-(triphenylphosphine)-rhodium chloride.
In a resulting compound, an easily removable acyl group, such as an ~-poly-branched lower alkoxycarbonyl group, for example tert.-butoxycarbonyl, also a polycyclic cyclo-alkoxycarbonyl group, for example l-adamantyloxycarbonyl, an optionally substituted diphenylmethoxycarbonyl group, for example diphenylmethoxycarbonyl, or an a-furyl-lower alkoxy-Garbonyl group can be split off from an acylamino group, for example, by acidolysis, such as treatment with a suitable acid, !
. . . . ' ' . . . .

. . - ' . :
.
' such as a strong, preferably aliphatic, carboxylic acid, for example an optionally halogenated, especially fluorinated, lower alkanecarboxylic acid, above all formic acid or tri-fluoroacetic acid, optionally in the presence of a nucleo-philic reagent, such as anisole, and a formyl group can be split off by treatment with a strong acid, such as a mineral acid, for example hydrochloric acid, or a strong organic sulphonic acid, for example 4-methylphenylsulphonic acid, and also by treatment with a decarbonylating agent, for example tris-triphenylphosphine-rhodium chloride, whilst, for example, a suitably substituted benzyloxycarbonyl group, such as 4-hydroxy-3,5-bis-tert.-butyl-benzyloxycarbonyl, can be removed, for example by treatment with an optionally anhydrous, weak base, such as an alkali metal salt of an organic carboxylic acid, for example the sodium salt or potassium salt of 2-ethyl-pentanecarboxylic acid, with an alkali metal salt of a thiophenol, for example the sodium salt of thiophenol, or with a suitable organic amine, for example ethylamine or cyclo-hexylamine, or a suitably substituted lower alkanoyl group, for example trifluoroacetyl, can be removed by hydrolysis under weakly basic conditions. A 2-halogeno-lower alkoxycarbonyl group, such as 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxy-carbonyl, or a phenacyloxycarbonyl group can be split off, for example by treatment with a chemical reducing agent, such as a suitable reducing metal or a corresponding metal compound, for example zinc, or a chromium-II compound, such as chromium-II
chloride or chromium-II acetate, usually in the presence of an :
. .

agent which, together with the metal or the metal compound, generates nascent hydrogen, and preferably in the presence of aqueous acetic acid. A phenacyloxycarbonyl group can also be replaced by hydrogen by treatment with a suitable nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate.
Furthermore, in a resulting compound, an amino group which is protected by a suitably substituted benzyloxycar-bonyl group, such as 4-methoxy- or 4-nitro-benzyloxycarbonyl-amino, can be split reductively, such as hydrogenolytically, for example by treatment with hydrogen in the presence of a -hydrogenation catalyst, for example palladium, and, in parti-cular, 4-nitrobenzyloxycarbonylamino can be split by treatment with a chemical reducing agent, for example sodium dithionite.
A polyarylmethyl group, such as the trityl group, can be split off, for example, by treatment with an acid agent, such as a mineral acid, for example hydrochloric acid.
An amino group protected in the form o~ an enamine, and also an amino group protected by arylthio, aryl-lower alkylthio or arylsulphonyl, can be split, for example, by treatment with an acid agent, above all an aqueous acid, such as an organic carboxylic acid, for example formic acid, acetic acid or propionic acid, or a mineral acid, for example hydro-chloric acid or sulphuric acid, optionally in the presence of a water-miscible solvent, such as a lower alkanol, for example methanol, a ketone, for example acetone, an ether, for example tetrahydrofurane, or a nitrile, for example acetonitrile.
The thio protected groups mentioned can be split off parti-, - , : : -,~ .. , cularly rapidly in the presence of additional reagents, suchas sodium thiosulphate, sulphurous acid, thioacetamide, thio-urea and potassium iodide.
An amino group protected with an organic silyl or stannyl group, in a re~ulting compound, can be liberated by treatment with an aqueous or alcoholic agent, for example with . a lower alkanol, such as methanol, or a mixture thereof;
usually, the splitting of an amino group protected in this way already takes place during working up of the acylation product.
The reaction products which are formed by the acyla- -.
. tion, according to the invention, of compounds of the formula II, wherein the amino group is substituted by a silyl or stannyl group, and in which the organic silyl or stannyl group is still on the amide nitrogen, are customarily con-verted during working up, especially under hydrolytic.and/or alcoholytic eonditions, for example such as are customary for 1 the removal of organic silyl or stannyl groups from amino groups, into compounds of the formula I.
The reaction products which are formed by the acyla-tion, according to the invention, of compounds of the formula II, wherein the amino group is substituted by an ylidene group, are also customarily converted during working up, especially by hydrolysis, for example by treatment with water, into compounds of the formula I.
In a compound of the formula I obtainable according to the invention and poss~ssing a protected, especially esteri-fied, carboxyl groups of the formula -C(=O)-Ro, the latter - ~7 -:; - . . ~ :
, . .
. . ~

1~)87170 can be converted into the free carboxyl group in a manner which is in itself known, for example by solvolysis, treatment with a nucleophilic reagent, irradiation or reduction, that is to say depending on the nature of the group Ro. A carboxyl group esterified by a suitable 2-halogeno-lower alkyl group, such as 2,2,2-trichloroethyl or 2-iodoethyl, or by an aryl-carbonylmethyl group, such as phenacyl, can be split, for example by treatment with a chemical reducing agent, such as a metal, for example zinc, or a reducing metal salt, such as a chromium-II salt, for example chromium-II acetate, usually in the presence of a hydrogen donor which, together with the metal, is capable of producing nascent hydrogen, such as an acid, above all acetic acid and also formic acid, water preferably being added; a carboxyl group esterified by an arylcarbonyl group, for example a phenacyl group, can also be converted into the free carboxyl group by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate or sodium iodide. A carboxyl group esterified by a suitably substituted arylmethyl group can be converted into the free carboxyl group, for example by irradiation, preferably with ultraviolet light, for example below 290 m~, if the arylmethyl group repreæents, for example, a benzyl radical which is optionally substituted in the 3-, 4- and/or 5-position, for example by lower alkoxy and/or nitro groups, or with ultraviolet light of longer wavelengths, for example above 290 m~, if the arylmethyl group denotes, for example, a benzyl radical which is substituted in the 2-position by a .
- 38 _ , .

,' ~ '' , ~ ', ' . ... .
. .

nitro group. The carboxyl group can be liberated from a carboxyl group esterified with a suitakly branched lower aIkyl group, for example tert.-butyl, with a suitable cycloalkyl group, such as l-adamantyl, or with a diphenylmethyl group, for example benzhydryl, for example by treatment with a suit-able acid agent, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic reagent, such as phenol or anisole. An esterified carboxyl group which can be split hydr~lytically, such as a carboxyl group esterified by a suitably substituted phenyl radical or a diacylimLno-mRthyl radical, and also a carb~xyl group esterified with the 4-hydrDxy-3,5-di-tert.-butyl-benzyl radical, can be split, depending on the nature of the ester grouping, for exa~ple by treatment with an acid or weakly basic aqueous agent, such as hydrochloric acid or aqueous sodium bicarbonate or an aqueous potassium phosphate buffer of pH akout 7 to akout 9, an~ an esterified carboxyl group which can be split hydrogenolyti-cally, such as an ~-aryl-lower alkyl group which is optionally substituted in the aryl radical, for exa~ple benzyl, 4-methoxy-benzyl or 4-nitrobenzyl, can be split ky hydrogenolysis, for example by treatment with hydrogen in the presence of a noble metal catalyst, for example a palladium catalyst.
A carboxyl group protected, for example, by silylation or stannylation, as well as by phosphorylation, can be libe-rated in the custcmary manner, for e~ample by hydrolysis or alcoholysis.

~.. ~

~01~7~70 In the starting material of the formula rva, free functional groups, especially a secondary amino group ~m and a carboxyl group - C(=O)-R in a radical -S-AO-/ and also free functional grcups which may be pres nt in a radical ~, are present in the protected form, for example as indicated above, an amino group Am is present, for example, in the form of a corresponding acylamuno group, which preferably can be split easily, and also of a corresponding arylmethylamin~ group, a 2-carbonyl-1-vinyl-amino group, an arylthioamino group or an aryl-lower aIkylthioamino group, a carboxyl group is present, for example, as an esterified carboxyl group, which preferably can be split easily, and a functional group in the radical R2, such as, for example, a hydroxyl group, is present as indicated above in the protected form, for example in the form of an acyloxy group.
The above reaction is carried out in a manner which is in itself kncwn, usually in the presence of a solvent or diluent or of a mixture thereof, it being possible for methanol .

~ ~ -40-~ .

~:: -', ,' ' ' ': .' ' ' ~ ' ' ' .

~0~7170 at the same time also to serve as the solvent or diluent, preferably with cooling, for example down to about -80, as well as at room temperature or with slight warming and, if necessary, in a closed vessel and/or under an inert gas atmosphere, for example a nitrogen atmosphere.
The starting material of the formula IVa is usually reacted in the crude form, that is to say without being iso-lated after its preparation, with the methanol or is formed in the presence of this reagent. In this reaction, for example, a compound of the formula rv, wherein an amino group Am, if necessary, and the carboxyl group of the formula -C(=0)-Ro as well as any additional functional groups which may be present are in the protected form, is used as the starting material and is treated with an anion-forming agent, followed by a N-halogenating agent, and, if necessary, the resulting product is reacted with a base which splits off hydrogen halide, or a compound of the formula Am-CU2--~ r ~2-e~ ~ S (IVb) wherein R represents an organic radical and wherein an amino group Am, i~ necessary, and the carboxyl group of the formula -C(=0)-Ro as well as any additional functional groups which may be present are in the protected form, is reacted with halogen, followed by a base. In this way it is possible to ~1' 41 `; . :
.

: - .

1~71~70 obtain, as a product which is usually not isolated, the corresponding 6-acylimino-penam compound of the formula IVa, or 7-acylimino-3-cephem compound of the formula IVa, which is converted, in the presence of methanol, into the desired 6~-acylamino-6a-methoxy-penam compound or 7~-acylamino-7a-methoxy-3-cephem compound, on which the abovementioned additional steps are carried out, if necessary or desired.
A suitable anion-forming agent, with which a starting material of the formula IV is reacted, is above all an organo-metallic base, especially an organo-alkali metal base, above all an organo-lithium base. Such compounds are, in particular, corresponding alcoholates, such as suitable lithium lower alkanolates, above all lithium methylate, or corresponding metal-hydrocarbon bases, especially lithium-lower alkanes and preferably lithiumphenyl. The reaction with the anion-forming organometallic base is usually carried out with cooling, for example at about 0C down to about -80C, and in the presence of a suitable solvent or diluent, for example an ether, such as tetrahydrofurane, also in the presence of methanol when lithium methylate is used, and, if desired, in a closed vessel and/or in an inert gas atmosphere, ~or example a nitrogen atmosphere.
A sterically hindered, organic hypohalite, especially hydrochlorite, and above all a corresponding aliphatic hypo-halite, for example hypochlorite, such as a tert.-lower alkyl hypohalite, ~or example hypochlorite, is customarily used as the N-halogenating agent. Above all, tert.-butyl hypo-~ 4 2 . .

... . . . .. . . .

.. . : - ., . . :: .
., . . ~. . .

chlorite is used, which is reacted with the non-isolated product from the anionisation reaction.
The N-halogenated intermediate is converted, in the presence of an excess of the anion-forming base, especially of lithium methylate, under the reaction conditions and without being isolated, into the acylimino compound of the formula IVa and this is converted, in the presence of metha-nol, directly into the 6a-methoxy-penam compound or 7~-methoxy-3-cephem compound. If necessary, the elements of the hydrogen halide acid, especially of hydrochloric acid, must be split off from the N-halogenated intermediate; this is effected by the addition of a base which splits off hydro-gen halide, such as a suitable alkali metal lower alkanolate, for example lithium tert.-butylate, and this reaction usually takes place under the conditions of the anion-forming and N-halogen compound-forming reaction, it being possible to work in the presence of methanol and to obtain direct the 6_ methoxy-penam compound or 7~-methoxy-3-cephem compound in place of the acylimino compound. That is to say,a compound of the formula IV, wherein functional groups are customarily present in the protected form, is used as the starting material and this is reacted with an excess of the anion-forming agent, for example lithium methylate or phenyl lithium, in the presence of methanol, the reaction product is then treated with the N-halogenating agent, for example tert.-butyl hypochlorite and in this way the desired compound of the formula I is obtained direct, it being possible, if necessary , ~
- - , -, - ~ ..
, lOB7170 or desired, to liberate protected functional groups in this compound of the formula I. However, it is also possible to add the methanol subsequently, in which case the -~e~ydrp~alogenation and the addition of methanol can be car-ried out at somewhat higher temperatures than the anion-forming and N-halogen compound-forming reactions, for example at about 0C down to about -20C, if necessary in a closed vessel and/or in an inert gas atmosphere, for example a nitro-gen atmosphere.
In a starting material of the formula IVb, an organic radical R above all denotes a hydrocarbon radical of ali-phatic character, such as lower alkyl and especially methyl.
The reaction with halogen, above all with chlorine, and with a base is customarily carried out in the presence of a suitable solvent or diluent, such as a halogenated hydrocarbon, for example methylene chloride, and with cooling, for example down to about -80C, and, if necessary, is carried out in a closed vessel and/or in an inert gas atmosphere, for example a nitro-gen atmosphere. A suitable organic base, such as a tertiary amine, for example a tri-lower alkylamine, such as triethyl-amine, is preferably used as the base and is usually added to the above halogenation mixture together with methanol and under the conditions of the halogenation process. In this way the

6-acylimino-penam starting material of the formula IV, or the

7-acylimin~-3-cephem starting material of the formula IV, is converted direct into a 6~-acylamino-6a-methoxy-penam compound of the formula I, or a 7~-acylamino-7a-methoxy-3-cephem com-~3 4 L

.- - : . . : - :

. . . . . .. .
~
.. . ~ ~ ..
....
.. . . . : - .` . ::: :: . :- :
. . . ~ . .
, . . .
. . . . . .

pound o~ the formula I, which compoundscan be converted, if necessary or desired, into the desired compound o~ the formula I.
The methoxy group can also be introduced into the 6~-position of 6~-acylamino-penam compound~ or into the 7~-position of 7~-acylamino-3-cephem compounds, by exchanging an exchangeable group which is present in this position. Thus, a compound of the formula IVb, wherein R has the indicated meaning and above all represents an aliphatic hydrocarbon radical, such as lower alkyl and especially methyl, and wherein an amino group Am, if necessary, and the carboxyl group of the formula -C(=0)-Ro, as well as any additional functional groups which may be present, are in the protected form, can be reacted with methanol in the presence of a desulphurising agent.
Desulphurising in the presence of methanol is cus-tomarily carried out using a suitable silver or mercury com-pound, such as silver oxide or mercury oxide, or especially a corresponding salt, such as a silver-I salt or mercury-II
salt with an organic carboxylic acid, for example a silver-I
lower alkanoate or a mercury-II lower alkanoate, especially mercury-II acetate. The reaction is carried out in the pre-sence of a solvent or diluent, ~or example an ether, such as dimeth~xyethane, or of a solvent mixture, it also being pos-sible to use an excess of methanol as the solvent or diluent, with cooling, ~or example down to about -~0C, at room tem-perature or with slight warming, for example up to about +70C, ~1 ~5 L~

, . . . .

-.

if necessary in a closed vessel and/or in an inert gas atmos-phere, for example a nitrogen atmosphere.
In the compounds obtainable according to the variants of the above methoxylation process, which preferably are carried out by the methods described by Koppel and Kocher, J. Am.Chem. Soc., Volume 95, page 2403 (1973), Spitzer and Goodson, Tetrahedron Letters, page 273 (1973), and Slusarchyk et al, J.Org.Chem., Volume 38, page 943 (1973), a pro-tected amino group Am is liberated by the abovementioned pro-cesses and, if necessary, a protected carboxyl group of the formula -C(=O)-Ro is converted, by the indicated process, into a carboxyl group of the formula -C(=O)-R; if desired, it is possible, as indicated, in a resulting compound, to convert the carboxyl group of the formula -C(=O)-R into another car-boxyl group of the formula -C(=O)-R and!or to convert a group Rl into another group Rl.
The compounds of the present invention can also be obtained when, in a compound of the formula OCH H

- AmrCH2 ~ 2-~- N - ~ i X I ~ o O-C (V) (C112)3 ~ R1 ~m--CH2-----C--O
wherein AmO represents a protected amino group and Rlo denotes a radical which, together with the carbonyl grouping of the formula -C(=O)-, forms a preferably protected carboxyl group ~ ii 46 , - :

and wherein an amino group Am, if necessary, is present in a protected form, which differs in the way it is converted into the corresponding free amino group Am from that of the pro-tected amino group AmO, the group AmO is converted into the free amino group, the 5-amino-5-carboxy-valeryl radical being split off under the reaction conditions, and, in a resulting compound, a protected amino group Am is converted into the corresponding free amino group Am and, i~ necessary or desired, a carboxyl group of the formula -C(=O)-Ro is converted into a carboxyl group of the formula -C(=O)-R and/or, if desired, a group Rl is converted into another group Rl and/or, if desired, a resulting salt is converted into the free compound or into another salt, or a resulting free compound is converted into a salt.
In the abovementioned starting material, the carboxyl groups of the formula -C(=O)-Ro in the radical of the formula -S-Ao~, and the carboxyl groups of the formula -C(=O)-Rlo, usually represent protected carboxyl groups, such as, for example, the abovementioned protected carboxyl groups, it also being possible for a group of the formula -C(=O)-Rlo to be an esterified carboxyl group which cannot be split, such as, for example, methoxycarbonyl. An amino group Am, above all a secondary amlno group Am, is present, as already mentioned, in the protected form; usually functional groups which are present in a radical Rl are also protected, for example as indicated.
Groups protected in this way are usually not liberated under the reaction conditions.

,. .. . . .

. . ~, . .

'~ ' ' . :

A protected amino group AmO is usually a corres-ponding amino group which can be converted into the free amino group, preferably under mild conditions. Protective groups are, for example, acyl, arylmethyl, 2-carbonyl-1-vinyl, arylthio, aryl-lower alkylthio or arylsulphonyl groups, which can be split off in different ways.
An easily removable acyl group is, for example, the formyl group or the acyl radical of a half-ester of carbonic acid, such as a lower alkoxycarbonyl group which preferably has multiple aliphatic substituents or branching and/or aro-matic or heteroaromatic substituents on the carbon atom in the a-position to the oxy group, or a methoxycarbonyl group which is substituted by an arylcarbonyl radical, especially a benzoyl radical, or a lower alkoxycarbonyl group which is sub-stituted in the ~-position by halogen, such as tert.-lower alkoxycarbonyl, for example tert.-butoxycarbonyl or tert.-pentyloxycarbonyl, arylcarbonylmethoxycarbonyl, for example phenacyloxycarbonyl, 2-halogenoethoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, or a group which can be converted into the latter, such as 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl, and also preferably polycyclic cycloalkoxycarbonyl, for example adamantyloxycarbonyl, phenyl-lower alkoxycarbonyl, especially a-phenyl-lower alkoxycarbonyl, which is optionally substituted, for example by lower alkyl, such as tert.-butyl, hydroxyl, lower alkoxy, such as methoxy, and/or nitro, for example 4-methoxy-benzyloxycarbonyl, 4-hydroxy-3,5-bis-tert.-butyl-~ .
~1 ~B
~.... .~

: - - - .; - . . , . . - , . . ` .
- -. . ~ ....
. . . . . ... . . .
- ~ ~ . . - -.. . . .. . .

~ ~ .
.

`" ~0~7170 benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or ~-4-biphenylyl-a-methylethoxycarbonyl, as well as diphenylmethoxycarbonyl which is optionally substituted, for example by lower alkoxy, such as methoxy, for example diphenylmethoxycarbonyl, or furyl-lower alkoxycarbonyl, above all a-furyl-lower alkoxy-carbonyl, for example furfuryloxycarbonyl. An acyl group can also be the corresponding radical of a suitable carboxylic acid, such as of an aryldicarboxylic acid, for example the phthaloyl radical, or of a halogeno-lower alkanecarboxylic acid, for example the trifluoroacetyl radical.
Examples of easily removable arylmethyl groups which may be mentioned are optionally substituted polyarylmethyl groups, such as diarylmethyl groups or triarylmethyl groups, for example trityl which is optionally substituted, such as by lower alkoxy, such as methoxy, in particular optionally o-and/or p-methoxy-substituted trityl.
Easily removable 2-carbonyl-1-vinyl groups, which, together with an amino group, form either an enamine or the ketimine tautomeric thereto, are, for example, 2-lower alkoxy-carbonyl-l-lower alkylvinyl groups, especially the 2-methoxy-carbonyl-l-methyl-l-vinyl group.
Easily removable arylthio or aryl-lower alkylthio groups are, for example, substituted phenylthio groups, for example phenylthio groups substituted by nitro or halogen, for example chlorine, such as the 2-nitrophenylthio group, the 2,4-dinitrophenylthio group or the pentachlorophenylthio group, and also triarylmethylthio groups, for example the tri-~1 49 1~)87170 phenylmethylthio group.
An amino group AmO protected in this way can be con-verted into the free amino group in a manner which is in it- -self known; the liberated amino group effects the intra-molecular aminolysis, which takes place under the reaction conditions, of the 5-amino-5-carboxy-valeroyl radical, which is split off and is then customarily present in the form of the protected 2-oxo-piperidine-6-carboxylic acid.
A protected amino group AmO can be split into a free amino group in a manner which is in itself known but which differs depending on the nature of the protective group, especially by sol~olysis, treatment with a nucleophilic reagent or reduction.
A formylamino group AmO can be split, for example, by treatment with an acid agent, for example p-toluenesulphonic acid or hydrochloric acid, with a weakly basic agent, for example dilute ammonia, or with a decarbonylating agent, for example tris-(triphenylphosphine)-rhodium chloride.
An a-polybranched lower alkoxycarbonylamino group, for example tert.-butoxycarbonylamino, and also a polycyclic cycloalkoxycarbonylamino group, for example l-adamantyloxy-carbonylamino, an optionally substituted diphenylmethoxycar-bonylamino group, for example diphenylmethoxycarbonylamino, or an a-furyl-lower alkoxycarbonylamino group AmO can be split, for example, by treatment with a suitable acid, such as a strong, preferably aliphatic, carboxylic acid, such as an optionally halogenated, especially fluorinated, lower alkane-, ~

t7170 carboxylic acid, above all formic acid or trifluoroaceticacid, optionally in the presence of a nucleophilic reagent, for example anisole, whilst a suitably substituted benzyloxy-carbonylamino group, for example 4-hydroxy-3,5-di-tert.-butyl-benzyloxycarbonylamino, can be split preferably by treatment with an optionally anhydrous, weak base, such as an alkali metal salt of an organic carboxylic acid, for example the sodium salt or potassium salt of 2-ethylpentanecarboxylic acid, with an alkali metal salt of a thiophenol, for example the sodium salt of thiophenol, or with a suitable organic amine, for example ethylamine or cyclohexylamine, or a suit-ably substituted lower alkanoylamino group, for example tri-fluoroacetylamino, can be split hydrolytically under weakly basic conditions. A 2-halogeno-lower alkoxycarbonylamino group, such as 2,2,2-trichloroethoxycarbonylamino or 2-iodo-ethoxycarbonylamino (a group which can be converted into 2-iodoethoxycarbonylamino, such as the corresponding 2-chloro-ethoxycarbonylamlno or 2-bromoethoxycarbonylamino, being con-verted, before removal, into 2-iodoethoxycarbonylamino in a manner which is in itself known, for example by treatment with a suitable iodine salt, such as an alkali metal iodide, such as sodium iodide, in the presence of a solvent, such as ace-tone), or a phenacyloxycarbonylamino group, such as phenacyl-oxycarbonylamino, can be split by treatment with a chemical reducing agent, such as a suitable reducing metal or a corres-ponding metal compound, for example zinc, or a chromium-II
compound, such as chromium-II chloride or chromium-II acetate, ..... ~ .

' ~87~70 usually in the presence of an agent which, together with the metal or the metal compound, produces nascent hydrogen, preferably in the presence of aqueous acetic acid.
Furthermore, an amino group AmO protected by a pre-ferably suitably substituted benzyloxycarbonyl group, such as 4-methoxy- or 4-nitro-benzyloxycarbonylamino, can be split hydrogenolytically, for example by treatment with hydrogen in the presence of a hydrogenation catalyst, for example palla-dium, or, in particular, 4-nitrobenzyloxycarbonylamino, can be split by treatment with a chemical reducing agent, for example sodium dithionite.
A polyarylmethylamino group AmO, such as tritylamino, can be split, for example, by treatment with an acid agent, such as a mineral acid, for example hydrochloric acid.
An amino group protected in the form of an enamine or of a ketimine tautomeric thereto, as well as the amino groupsAmO protected by arylthio, aryl-lower alkylthio and arylsulphonyl, which have been mentioned, can be split, for example, by treatment with an acid agent, above all an aqueous acid, such as an organic carboxylic acid, for example formic acid, acetic acid or propionic acid, or a mineral acid, for example hydrochloric acid or sulphuric acid, optionally in the presence of a water-miscible solvent, such as a lower alkanol, for example methanol, a ketone, for example acetone, an ether, for example tetrahydrofurane, or a nitrile, for example acetonitrile. The thio-protective groups mentioned can be split off particularly rapidly in the presence of ~ ~ 5~
... .

. ' ' . :~ .
"~-., .~ ^ ~

10~7170 additional reagents, such as sodium thiosulphate, sulphurous acid, thioacetamide, thiourea and potassium iodide.
The splitting reactions described above are carried out under conditions which are in themselves known, if necessary with cooling or warming, in a closed vessel and/or in an inert gas atmosphere, for example a nitrogen atmosphere.
As mentioned above, simultaneous liberation of other protected functional groups present in the starting material should not take place under the reaction conditions. Thus, for example, the protected amino group AmO can be an amino group which can be split on treatment with a chemical reducing agent, for example with zinc in the presence of aqueous acetic acid, for example a 2-halogeno-lower alkoxycarbonylamino group which can be split under these conditions, such as 2,2,2-trichloroethoxycarbonylamino, whilst an amino group Am can be protected by a lower alkoxycarbonyl group which can be split ~cntreatment with a suitable acid, such as trifluoro-acetic acid, for example by an ~-poly-branched lower alkoxy-carbonyl group, such as tert.-butoxycarbonyl, and a carboxyl group of the formula -C(=O)-Ro, and also a free carboxyl group which may be present in a group R2 in the radical of the for-mula -S-Ao~, can be protected by a diphenylmethyl group which can also be split off on treatment with a suitable acid, such as trifluoroacetic acid, for example by an optionally sub-stituted diphenylmethyl group, for example benzhydryl; in the protected form the latter groups withstand the above-mentioned reductive splitting conditions and, if necessary or 5~
. ~

- . ,' ~
., .
.
.
- . - . ,. - , , , - :. , , ' . . ~', .: ' . : ' ~

~0~37170 desired, are liberated only after intramolecular aminolysis of a 5-amlno-5-carhoxy-valeryl radical has taken place.
The above process can be carried out, for example, according to the methcd described by sletzinger et al.
J.Am.Chem.Soc., Volume 94, page 1410 (1972).
A monosubstituted amino group present in the pr~tec-ted form in the starting material of the formula VII contains, ; as the amino protective group, one of the abovementioned amino protective groups, for example the amino protective groups which were mentioned in connection with an amino group Am and which cannot be split off under the reaction con~itions, that is to say in the presence of the strong, at most slightly nucleophilic, acid. Such an amino protective grcup is, ahove all, a corresponding acyl group, such as formyl or suitable, option~lly substituted, lower alkanoyl, especially trifluoro-acetyl, and above all suitably etherified hydroxycarbonyl, which can be split off, for example, under reductive condit-~9~S, on treab~ent with a nucleophilic reagent or on irradia-tion, above all 2-halogeno-lcwer alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoe thoxycarbonyl or 2-iodoethoxy OE bonyl, arylcarbonyl-methoxycarbonyl, for example phenacyloxycarbonyl, or ~-aryl-lower alkoxycarbonyl, such as ~-phenyl-lower alkoxycarbonyl which is optionally substituted, for example by lower alkoxy, such as methoxy, and~or nitr~, for example ben2yloxycarbonyl, 4imethoxy-benzyloxycar~onyl, 4-nitrohenzyloxycarbonyl or 4,5-dimethoxy-2-nitrobenzyloxycarbonyl.

~ -54-~ , , -" ~. . -. , . , , . - .

..

.

~0~37~70 Form~ldehyde can be used as such or in the form ~f a reaction derivative thereof, above all in the fonm of a poly-mer, such as paraformaldehyde.
Strong, at most slightly nucleophilic, acids are, above ... . . .: . .:

.. : . : .. ,: . . . ~ . , ~ .

. : . :

~7~70 all, strong organic carboxylic acids, such as preferably halogen-substituted lower alkanecarboxylic acids, for example formic acid (optionally in the presence of a strong organic sulphonic acid, such as a strong arylsulphonic acid, for example 4-methylbenzenesulphonic acid) and above all tri-fluoroacetic acid.
The above reaction is customarily carried out by treating a reaction mixture of a compound of the formula VII
with the formaldehyde or a derivative thereof (which is pre-pared, for example, in the presence of an inert solvent and a weakly basic agent, such as an alkali metal carbonate, for example potassium carbonate, and, if necessary, with removal of water and with formation of a compound of the formula RX-NH-CH2-OH (VIIa), which is obtainable as an intermediate), with the starting material of the formula VI and with the strong, at most slightly nucleophilic, acid and working in the presence of an inert solvent or solvent mixture, with stirring or warming and/or in an inert gas atmosphere.
In a compound of the formula I, obtainable by this process, an amino group Am is optionally present in the pro-tected form, amino protective groups being, above all, the abovementioned acyl radicals. They are split off in a manner which is in itself known, for example as described above, a formyl group being split off, for example, by treat-ment with a strong acid, for example hydrochloric acid or 4-methylphenylsulphonic acid, a trifluoroacetyl group being split off, for example, hydrolytically under weakly basic L~ 56 :, - . . . . . .
..... . ..... . ~ .. . .

.

conditions, a suitable 2-halogeno-lower alkoxycarbonyl group or arylcarbonylmethoxycarbonyl group being split off, for example, by treatment with a chemical reducing agent, such as a suitable reducing metal or a corresponding metal compound, for example zinc, or a chromium-II compound, such as chromium-II chloride or chromium-II acetate, usually in the presence of an agent which, together with the metal or the metal compound, produces nascent hydrogen, preferably in the presence of aqueous acetic acid, an arylcarbonylmethoxycarbonyl group also being split off by treatment with a suitable nucleophilic, preferably salt-forming, reagent, such as sodium thiopheno-late, and an ~-aryl-lower alkoxycarbonyl group being split off hydr.ogenolytically, for example by treatment with hydrogen in the presence of a hydrogenation catalyst, for example palla-dium, or, such as 4-nitrobenzyloxycarbonyl, by treatment with a chemical reducing agent, for example sodium dithionite.
The compounds of the present invention can also be manufactured when, in a compound of the formula H2N CH2 - ~ 2 c-H~ ~ T S (VIII) ~ X . N Ao or in a salt thereof, the free amino group H2N- is converted into a substituted amino group Am and, if desired or necessary, the additional process steps are carried out.
The substitution of the free amino group in a starting L~ 57 .. . ~, , . .. . , ...... : . . . . ~

.- . . .
. . . .. .

~0~7~70 material of the formula VIII is carried out in a manner which is in itself known, for example by treatment with a reactive ester of an alcohol of the formula Ra-OH (IXa) or Rb-OH (IXb) or of a diol of the formula HO-(Ra+Rb)-OH (IXc). Such reactive esters are, in particular, esters with strong inorganic acids, especially mineral acids, or with strong organic acids, especially corresponding organic sulphonic acids. Esters of this type are corresponding halides, for example chloridesor bromide~ as well as sulphatesor bisul-phateS or corresponding lower alkylsulphonyloxy compounds, for example methylsulphonyloxy compounds or arylsulphonyloxy com-pounds, for example 4-methylphenylsulphonyloxy compounds.
The reaction with such reagents is carried out, if necessary, in the presence of a condensing agent, such as an alkali metal bicarbonate or a suitable organic base, such basic condensing agents preferably being used in at most slight excess. The substitution of the free amino group in a starting material of the formula ~III can also be effected by reaction with an optionally substituted lower alkanal or lower alkanone, with simultaneous or subsequent treatment with a reducing agent.
A suitable reducing agent is, above all, catalytically activated hydrogen, a noble metal catalyst, such as a palladium or platinum catalyst preferably being used as the catalyst.
When formaldehyde is used as the lower alkanal, the reducing agent is, above all, formic acid.
The above substitution reactions are usually carried out in the presence of a solvent or diluent, it also being ~ ~ 8 , ~ . .. .. .. .
-. . - .

.
- :

~IIY37170 possible to employ reactants as the solvent or diluent, and, if necessary, with cooling or warming, in a closed vessel and/
or in an inert gas atmosphere.
, The 3-cephem compounds of the present invention can also be obtained when a 2-cephem compound of the formula ', , O
Il OCH H
Am - CH2 ~ O ~ ~ - Rl (X) O=C - Ro wherein an amino group Am and/or a carboxyl group of the formula -C(=O)-Ro, if necessary or desired, is present in the protected form, is isomerised to give a 3-cephem compound and, if desired or necessary, the additional process steps are carried out.
The isomerisation of a 2-cephem compound into the corresponding 3-cephem compound can be carried out in a manner which is in itself known.
Thus, a 2-cephem compound of the formula X can be isomerised by treating it with a weakly basic agent and iso-lating the corresponding 3-cephem compound from an equilibrium mixture which may be obtained.
Examples of suitable isomerising agents are organic nitrogen-containing bases, such as tertiary heterocyclic bases of aromatic character, and above all tertiary aliphatic, aza-cycloaliphatic or araliphatic bases, such as N,N,N-tri-lower , R

: . - .. . ... ., . , . . . . : . ...
i.: . . . ` ... . . . . . ~ . .
: `.: `. :. .... .. .. . . . . .

.

10871qO

alkylamines, for example N,N,N-trimethylamine, N,N-dimethyl-N-ethylamine, N,N,N-triethylamine or N,N-diisopropyl-N-ethyl-amine, N-lower alkyl-azacycloalkanes, for example N-methyl-piperidine, ~r N-phenyl-lower alkyl-N,N-di-lower alkylamines, for example N-benzyl-N,N-dimethylamine, as well as mixtures thereof, such as the mixture of a base of the pyridine type, for example pyridine, and a N,N,N-tri-lower alkylamine, for example pyridine and triethylamine. Furthermore, it is also possible to use inorganic or organic salts of bases, especially of medium strength to strong bases, with weak acids, such as alkali metal salts or ammonium salts of lower alkanecarboxylic acids, for example sodium acetate, triethyl-ammonium acetate or N-methyl-piperidine acetate, as well as other analogous bases or mixtures of such basic agents.
The above isomerisation with basic agents can be carried out, for example, in the presence of a derivative of a carboxylic acid which is suitable for forming a mixed anhydride, such as a carboxylic acid anhydride or carboxylic acid halide, for example with pyridine in the presence of acetic anhydride. This reaction is preferably carried out in an anhydrous medium, in the presence or absence of a solvent, such as an optionally halogenated, for example chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, or of a solvent mixture, it being possible for bases which are used as reactants and are liquid under the reaction conditions at the same time also to serve as solvents, if necessary with cooling or heating, preferably in a temperature range from about -30C

,,~ 1 6 0 - . . . . . .
.. . . . . . .
. . . - . ~ . - . -.

: ~ :
.

to about +100C, in an inert gas atmosphere, for example a nitrogen atmosphere, and/or in a closed vessel.
3-Cephem compounds which are thus obtainable can be separated from any 2-cephem compounds of the formula X which may still be present, in a manner which is in itself known, for example by adsorption and/or crystallisation.
The isomerisation o~ 2-cephem compounds of the for-mula X can also be carried out by oxidising these in the 1-position, if desired separating an isomer mixture of the 1-oxides of corresponding 3-cephem compounds, which is obtain-able, and reducing the l-oxides of the corresponding 3-cephem compounds, which are thus obtainable.
Suitable oxidising agents which can be used for the oxidation of 2-cephem compounds in the l-position 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 acids, especially organic carboxylic acids, having a dissociation constant of at least 10 5. Suitable inorganic per-acids are periodic acid and persulphuric acid. Organic per-acids are appropriate percarboxylic acids and persulphonic acids, which can be added as such or can be formed in situ by the use of at least one equivalent of hydrogen peroxide and of a carboxylic acid.
It is appropriate to use a large excess of the carboxylic acid when, for example, acetic acid is used as the solvent. Suit-able per-acids are, for example, performic acid, peracetic acid, pertrifluoroacetic acid, permaleic acid, perbenzoic J~l ~1.

... ... , . . .. . ~ , ..

. : : ;.
- . ~ . : , .
i , ', .,. : ' . ' r ~

acid, monoperphthalic acid or p-toluenepersulphonic acid.
The oxidation can also be carried out using hydrogen peroxide with catalytic amounts of an acid having a dissocia-tion constant of at least 10 5, it being possible to employ low concentrations, for example 1-2% and less, but also larger amounts, of the acid. The activity of the mixture depends above all 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 can be carried out in the presence of suitable catalysts. Thus, for example, the oxidation with percarboxylic acids can be catalysed by the presence of an acid having a dissociation constant of at least 10 5, its activity depending on its strength. Acids suitable as cata-lysts are, for example, acetic acid, perchloric acid and tri-fluoroacetic acid. Usually, at least equimolar amounts of the oxidising agent, and preferably a small excess of about 10%
to about 20% are used. The oxidation is carried out under mild conditions, for example at temperatures from about -50C to about +100C, preferably from about -10C to about +40C.
The oxidation of 2-cephem compounds to the l-oxides of the corresponding 3-cephem compounds can also be carried out by treatment with ozone, as well as with or~anic hypohalite compounds, such as lower alkyl hypochlorites, for example tert.-butyl hypochlorite, which are used in the presence of inert solvents, such as optionally halogenated hydrocarbons, for example methylene chloride, and at temperatures from about , 62 ' ;
~: :

1[)87~70 -10C to about +30C, with periodate compounds, such as alkali metal periodates, for example potassium periodate, which are preferably used in an aqueous medium at a pH value of about 6 and at temperatures from about -10C to about +30C, with iodobenzene dichloride, which is used in an aqueous medium, preferably in the presence of an organic base, for example pyridine, and with cooling, for example at tem-peratures from about -20C to about 0, or with any other oxidising agent which is suitable for conversion of a thio grouping into a sulphoxide grouping.
In the l-oxides of 3-cephem compounds, thus obtainable, the additional process steps mentioned in connection with the isomerisation process can be carried out, if desired.
Furthermore, a mixture of isomeric a- and ~ oxides can be separated, for example chromatographically.
The reduction of the l-oxides of 3-cephem compounds can be carried out in a manner which is in itself known, by treatment with a reducing agent, if necessary in the presence of an activating agent. Possible reducing agents are:
catalytically activated hydrogen, using noble metal catalysts which contain palladium, platinum or rhodium and which are optionally employed together with a suitable support, such as charcoal or barium sulphate; reducing tin, iron, copper or manganese cations, which are used in the form of appropriate compounds or complexes of inorganic or organic nature, for example as tin-II chloride, fluoride, acetate or formate, iron-II chloride, sulphate, oxalate or succinate, copper-I

~;~ S3 :.. . - . ` , .
~' ' : ` :' ` . ` : .,'' . ' `

1087~70 chloride, benzoate or oxide, or manganese-II chloride, sul-phate, acetate or oxide, or as complexes, for example with ethylenediaminetetraacetic acid or nitrilotriacetic acid;
reducing dithionite, iodide or ferrocyanide anions, which are used in the form o~ appropriate inorganic or organic salts, such as alkali metal dithionite, iodide or ferrocyanide, for example sodium dithionite or potassium dithionite, sodium iodide or potassium iodide or sodium ferrocyanide or potassium ferrocyanide, or in the form of the corresponding acids, such as hydriodic acid; reducing trivalent inorganic or organic phosphorus compounds, such as phosphines, and also esters, amides and halides of phosphinous, phosphonous or phosphorous acid as well as phosphorus-sulphur compounds corresponding to these phosphorus-oxygen compounds, in which compounds organic radicals above all represent aliphatic, aromatic or arali-phatic radicals, for example optionally substituted lower alkyl, phenyl or phenyl-lower alkyl groups, such as, for example, triphenylphosphine, tri-n-butylphosphine, diphenyl-phosphinous acid methyl ester, diphenylchlorophosphine, phenyldichlorophosphine, benzenephosphonous acid dimethyl ester, butanephosphonous acid methyl ester, phosphorous acid triphenyl ester, phosphorous acid trimethyl ester, phosphorus trichloride, phosphorus tribromide and the like; reducing halogenosilane compounds which possess at least one hydrogen atom bonded to the silicon atom and which, in addition to halogen, such as chlorine, bromine or iodine, can also possess organic ~adicals, such as aliphatic or aromatic groups, ~or ., ~
~ ~4 ~, . .. . . .
' :

1087~70 example optionally substituted lower alkyl or phenyl groups, such as chlorosilane, bromosilane, di- or tri-chlorosilane, di- or tri-bromosilane, diphenylchlorosilane, dimethylchloro-silane and the like; reducing quaternary chloromethylene-iminium salts, especially the chlorides or bromides, wherein the iminium group is substituted by one divalent or by two monovalent organic radicals, such as optionally substituted lower alkylene or lower alkyl groups, such as N-chloromethylene-N,N-diethyliminium chloride or N-chloromethylene-pyrrolidinium chloride; and complex metal hydrides, such as sodium boro-hydride, in the presence o~ suitable activating agents, such as cobalt-II chloride, as well as borane dichloride.
As activating agents which are used together with those of the abovementioned reducing agents which do not them-selves possess Lewis acid properties, that is to say which are above all employed together with the dithionite, iodide or ferrocyanide reducing agents and the trivalent phosphorus reducing agents which do not contain halogen, or in the cata-lytic reduction, there should be mentioned in particular organic carboxylic acid halides and sulphonic acid halides, as well as sulphur halides, phosphorus halides or silicon halides having a second order hydrolysis constant equal to or greater than that of benzoyl chloride, ~or example phosgene, oxalyl chloride, acetic acid chloride or acetic acid bromide, chloroacetic acid chloride, pivalic ac~d chloride, 4-methoxy-benzoic acid chloride, 4-cyanobenzoic acid chloride, p-toluenesulphonic acid chloride, methanesulphonic acid chloride, . ~. . . .............. . ..

- . - .

:

thionyl chloride, phosphorus oxychloride, phosphorus tri-chloride, phosphorus tribromide, phenyldichlorophosphine, benzenephosphonous acid dichloride, dimethylchlorosilane or trichlorosilane, and also suitable acid anhydrides, such as trifluoroacetic a~hydride, or cyclic sultones, such as ethanesultone, 1,3-propanesultone, 1,4-butanesultone or 1,3-hexanesultone.
The reduction is preferably carried out in the pre-sence of solvents or mixtures thereof, the choice of which is above all determined by the solubility of the starting materials and the choice of the reducing agent, thus, for example, lower alkanecarboxylic acids or esters thereo~, such as acetic acid and ethyl acetate, are used in the case of the catalytic reduction and, for example, optionally substituted, such as halogenated or nitrated, aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, for example benzene, methylene chloride, chloroform or nitromethane, suitable acid derivatives, such as lower alkanecarboxylic acid esters or nitriles, for example ethyl acetate or acetonitrile, or amides o~ inorganic or organic acids, for example dimethyl~ormamide or hexamethylphosphoramide, ethers, for example diethyl ether, tetrahydro~urane or dioxane, ketones, for example acetone, or sul~hones, especially aliphatic sulphones, for example dimethyl-s~phon~ or tetramethylene sulphone, and the like are used together with the chemical reducing agents, these solvents preferably not contalning any water. The reaction is usually carried out at temperatures from about _20C to about 100C, ~ 66 .. - , .

:
: . - - -~.0~7'170 it being possible to carry out the reaction at lower tempera-tures if very reactive activating agents are used.
In a compound of the formula I, obtainable according to the invention, which contains a free carboxyl group of the formula -C(=O)-R and in which an amino group Am is optionally present in the protected form, the free carboxyl group can be converted in a manner which is in itself known into an esterified carboxyl group which can be split under physio-logical conditions. Thus, for example, in a compound of the formula I having a free carboxyl group, or in a salt thereof, for example in an alkali metal salt, such as the sodium salt or potassium salt, or in an alkaline earth metal salt, such as the calcium salt or magnesium salt, or in an optionally sub- -stituted ammonium salt, such as the triethylammonium salt, thereof, the carboxyl group can be converted, by reaction with a suitable halide, for example chloride or bromide, into the corresponding esterified carboxyl group -C~=O)-R.
In a compound of the formula I, obtainable according to the invention, wherein Am represents a monosubstituted amino group, such a group can be converted into a corresponding disubstituted tertiary amino group in a manner which is in it-self known, for example as described above, by treatment with a reactive ester of an optionally substituted lower alkanol or with an optionally substituted lower alkanal or lower alkanone in the presence of a reducing agent. Furthermore, a substituent, above all a methyl group, can be ~plit off from a disubstltuted amino group Am, especially from a corresponding . - ~ .
.
`

.. . .
,. ` ,: . . ~.: .. `

1~37170 disubstituted amino group Am which contains a methyl group, in a manner which is in itself known, for example by treat-ment with a halogenoformic acid lower alkyl ester, for example ethyl chloroformate, or with a cyanogen halide, for example cyanogen bromide, and removal of a lower alkoxy car-bonyl or cyano group, introduced in this way, under acid con-ditions, for example by treatment with hydrobromic acid in the presence of formic acid, or with hydrochloric acid.
Furthermore, in a compound of the formula I, obtain-able according to the invention, wherein an amino group Am is protected if necessary and wherein the grouping of the formula -S-A- corresponds to a radical of the formula Ib, it is pos-sible, in a manner which ls in itself known, to replace a group Rl by another radical Rl or to convert a group Rl into another radical Rl.
Thus, for example, it is possible, in a compound of the formula I having a radical of the formula Ib as the grouping of the formula -S-A-, wherein Rl denotes a group of the formula -CH2-R2, and R2 represents, for example, a radi-cal which can be replaced by nucleophilic substituents, or in a salt thereof, to replace such a radical R2 by an etherified or esterified mercapto group R2 by treatment with a mercaptan compound or with a thiol-carboxylic acid com-pound. A suitable radical which can be replaced by an etherified mercapto group is, for example, an esteri~ied hydroxyl group, for example a hydroxyl group esterified by a hydrogen halide acid, such as hydrochloric acid or hydrobromic ~ .

lOB7170 acid, or preferably by an organic carboxylic acid, such as an aliphatic (including formic acid), cycloaliphatic, cyclo-aliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid, and also by a car-bonic acid half-derivative, such as a carbonic acid half-ester. Such esterified hydroxyl groups are, for example, j lower alkanoyloxy which is optionally substituted, for example by halogen, such as fluorine or chlorine, especially acetoxy as well as halogeno-lower alkanoyloxy, such as halogeno-acetoxy, for example trifluoroacetoxy, as well as dichloro-acetoxy, and also formyloxy, or optionally substituted benzoyloxy, such as 4-chlorobenzoyloxy.
The reaction of such a compound with a suitable mercaptan compound can be carried out under neutral or weakly basic conditions in the presence of water and optionally of a water-miscible organic solvent. The basic conditions can be set up, for example, by adding an inorganic base, such as 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. Organic solvents which can be used are, for example, water-miscible alcohols, for example lower alkanols, such as methanol or ethanol, ketones, for example lower alkanones, such as acetone, amides, such as lower alkanecarboxrlic acid amides, such as dimethylformamide, and the like.

~ ~9 ... . . . .

. . . . . . .

. . : -. - : . . . .
.

11~)87170 Esterified hydroxyl groups R2 in a compound of the formula I, wherein the group -S-A- represents the partial formula Ib and R1 denotes the group -CH2-R2, in which R2 :represents a hydroxyl group esterified by the acyl radical of an optionally substituted half-amide of carbonic acid, can be introduced, for example, by reacting a corresponding compound of the formula I, wherein R2 represents free hydroxyl (which can be liberated, for example, by splitting off the acetyl radical from an acetoxy group R2, for example by hydroly-sis in a weakly ba~ic medium, such as with an aqueous sodium hydroxide solution at pH 9-10, or by treatment with a suitable esterase, such as an appropriate enzyme from Rhizobium tri-tolii, Rhizobium lu~inii, Rhizobium ~a~onicum or Bacillus subtilis, or a suitable citrus esterase, for example from orange peel), with a suitable carbonic acid derivative, especially with an isocyanate compound or a carbamic acid com-pound, such as a silyl isocyanate, for example silyl tetraiso-cyanate, a sulphonyl isocyanate, for example chlorosulphonyl isocyanate, or a carbamic acid halide, for example carbamic acid chloride (which lead to N-unsubstituted 3-aminocarbonyl-oxymethyl compounds), or with a N-~ubstituted isocyanate com-pound or wlth a N-monosubstituted or N,N-disubstituted car-bamic acid compound, such as a corresponding carbamic acid halide, for example carbamic acid chloride, the reaction usually being carried out in the presence of a solvent or diluent and, if necessary, with cooling or warming, in a closed vessel and/or in an inert gas atmosphere, for example ~ ?0 a nitrogen atmosphere.
Furthermore, a compound of the formula I, wherein the grouping -S-A- corresponds to a radical of the formula Ib, in which R2 represents, for example, the radical defined above, which can be replaced by nucleophilic substitution, can be reacted with a tertiary organic base, especially an optionally substituted pyridine, under neutral or weakly acid conditions, preferably at a pH value of about 6.5, in the presence of water and optionally in a water-miscible organic sol~ent and compounds of the formula I, wherein the grouping of the formula -S-A_ denotes a radical of the formula Ib, wherein Rl represents the radical of the formula -CH2-R2 and R2 represents a quaternary ammonium group, can thus be obtained. The weakly acid conditions can be set up by adding -a suitable organic or inorganic acid, for example acetic acid, hydrochloric acid, phosphoric acid or sulphuric acid.
Organic solvents which can be used are, for example, the abovementioned water-miscible solvents. In order to increase the yield, certain salts can be added to the reaction mixture, for example alkali metal salts, such as sodium salts and especially potassium salts, of inorganic acids, such as hydrogen halide acids, for example hydrochloric acid and especially hydriodic acid, as well as of thiocyanic acid, or of organic acids, such as lower alkanecarboxylic acids, for example acetic acid. Representatives of such salts are, for example, potassium iodide and potassium thiocyanate. Salts of suitable anion exchangers, for example liquid ion . ~.
- . : . . ~ , ~
,: ~.~: : : . . . .
.
.. .

1~)87170 exchangers in the form of a salt, such as, for example, Amberlite LA-l (liquid secondary amines with a molecular weight of 351-39~; soluble in oil and insoluble in water;
meq/g = 2.5-2.7, for example in the form of the acetate), with acids, for example acetic acid, can also be used for this purpose.
Quaternary ammonium groups R2 can be introduced advantageously using an intermediate product of the formula I, in which R2 of the radical Rl in a partial formula Ib represents a substituted carbonylthio group, especially a carbonylthio group with an aromatic substituent, and above all represents the benzoylthio group. An intermediate product of this type, which can be obtained, for example, by reacting a compound of the formula I, wherein -S-A- represents the partial formula Ib, wherein R2 in the radical Rl denotes an esterified hydroxyl group and above all an asyloxy group, especially a lower alkanoyloxy group, for example an acetoxy group, with a suitable salt, such as an alkali metal salt, for example the sodium salt, of a thiocarboxylic acid, such as an aromatic thiocarboxylic acid, for example thiobenzoic acid, is reacted with the tertiary amine, especially a tertiary heterocyclic base, such as an optionally substituted pyridine, whereupon the quaternary ammonium compound is obtained. The reaction is usually carried out in the presence of a suitable desulphurising agent, especlally a mercury salt, for example mercury-II perchlorate, and of a sultable solvent or dlluent, or of a mixture, if necessary wlth cooling or warming, in a -. ~: .. , .`

1~87170 closed vessel and/or in an inert gas atmosphere, for example a nitrogen atmosphere.
Salts of compounds of the formula I can be manufac-tured in a manner which is in itself known. Thus, salts of compounds of the formula I having acid groups can be formed, for example, by treatment with metal compounds, such as alkali metal salts of suitable carboxylic acids, for example the sodium salt of ~-ethyl-caproic acid, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent.
Acid addition salts of compounds of the formula I are obtained in the customary manner, for example by treatment with an acid or with a suitable anion exchange reagent. Inner salts of compounds of the formula I, which contain a free carboxyl group, can be formed, for example, by neutralising salts, such as acid addition salts, to the isoelectric point, for example using weak bases, or by treatment with liquid ion exchangers.
Salts can be converted into the free compounds in the customary manner, metal salts and ammonium salts, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.
The process also encompasses those embodiments accordlng to which compounds arising as intermediate products are used as starting materials and the remaining process steps are carried out with these, or the process is discontinued at any stage; ~urthermore, starting materials can be used in the ~ 73 ~.

form of derivatives or can be formed during the reaction.
Preferably, the starting materials used and the reaction conditions chosen are such that the compounds men-tioned above as being particularly preferred are obtained.
Starting materials of the formula II, wherein the amino group is optionally substituted by a group which permits acylation, are known or can be manufactured according to known methods.
Thus, compounds of the formula II can be obtained when, i in corresponding compounds of the formula ; H
I
H2 ~ I (VIII) O - A
.

the amino group is converted into the diazo group, ~or example by treatment with a suitable diazotising agent, especially with nitrous acid or with nitrogen tetroxide, the diazo com-pound is treated with a halogen azide~ for example bromine azide, and the 6-azido-6-halogeno-penam compound or 7-azido-7-halogeno-3-cephem compound, thus obtainable, wherein halo-gen above all represents bromine and which may be present in the form of the 6- or 7-epimer mixture, is reacted with a suitable silver salt, such as silver-I tetrafluoborate, in the presence of methanol. The 6~-azido-6a-methoxy-penam com-pound or 7~-azido-7a-methoxy-3-cephem compound is thus obtained, in which the azido group is converted into the amino ~j 74 . .

10t~7170 group by reduction, for example by catalytic hydrogenation in the presence of a noble metal catalyst, such as platinum oxide or palladium-on-charcoal, and, if necessary, of an activating agent, such as a cobalt salt, for example cobalt-II acetate. This reaction sequence is described, inter alia, for example by Cama e~ al~ J. Am. Chem. SOC., Volume 94, page 1408 (1972).
In a resulting starting material of the formula II, the free amino group can be converted into a substituted amino group which permits acylation, for example by silylation or stannylation, such as by treatment with a suitably substitu-ted silyl halide, for example trimethylsilyl chloride, or by treatment with an aldehyde, especially with ~n arylcarbox-aldehyde, for example an optionally substituted benzaldehyde.
' Starting materials of the formula III are known or can be manufactured according to methods which are in themselves known. Thus, ~or example, the 5-Am-methyl-2-thienyl-acetic acid compounds or 5-Am-methyl-2-furyl-acetic acid compounds can be obtained when a corresponding Am-methylthiophene or Am-methylfurane, wherein an amino group Am is protected, if necessary, for example by one of the protective groups mentioned, or an acid addition salt thereof, such as the hydrochlorlde, is acetylated by treatment with a suitable acetylating agent, for example with an acetic anhydride, including an acetyl halide, such as acetyl chloride, or pre-ferably with acetic anhydride, in the presence of a suitable catalyst, such as a Lewis acid, for example aluminium chloride L ~ 75 ..
, , ` .
, , ~ '', ~
, .

l~B7170 or aluminium bromide, or an acid, such as polyphosphoric acid, or preferably trifluoroacetic acid, as well as the anhydride thereof. The reaction can be carried out in an anhydrous solvent, such as an aromatic hydrocarbon, for example benzene, or an excess of the liquid reagents employed, for example an excess of trifluoroacetic acid or acetic acid and/or the anhydrides thereof. When trifluoroacetic acid or trifluoro-acetic anhydride is used, a free amino group can be acylated at the same time by the trifluoroacetyl radical.
--- An acetylated Am-methylthiophene or Am-methylfurane com-pound, wherein an amino group Am is protected if necessary, for example by the trifluoroacetyl radical, can be converted into a compound of the formula (III), for example according to the method of Willgerodt or Willgerodt-Kindler, for example by heating with ammonium polysulphide or with a primary or secondary amine, such as morpholine, and subsequently hydro-lysing the thioamide formed as an intermediate.
On the other hand, an acetylated Am-methyl-thiophene compound or Am-methyl-furane compound, especially such a com-pound wherein an amino group Am i8 protected, if necessary, in the indicated manner, for example by the trifluoroacetyl radical, can be converted, by warming with thallium-(III) nitrate in the presence of a lower alkanol, especially methanol, and an acid, for example perchloric acid, into a lower alkyl ester, for example the methyl ester, of an acid of the formula III, from which the free acid can be prepared by hydrolysis.
~ 76 . :

When a thioamide obtained according to Willgerodt or Willgerodt-Kindler or an ester obtained by the thallium-(III) nitrate method is hydrolysed, an amino protective group which may be present can, depending on the hydrolysis conditions and on the nature of the protective group, also be split off or, if desired, converted. The complete hydrolysis to give a compound of the formula III and an optional subsequent introduction of an amino protective group can also be carried out in one step. For example, a resulting methyl ester of a compound of the formula III, wherein an amino group Am is acylated if necessary, for example with the trifluoroacetyl group, can first be hydrolysed by treatment with a base, for example an alkali metal hydroxide, such as sodium hydroxide, in water or water together with a water-miscible organic sol-vent, such as dioxane, and, if desired or necessary, can then be treated in the same reaction mixture, for example with tert.-butoxycarbonyl azide, after which, after acidification and customary working up, the desired thiophene-acetic acid or furane-acetic acid having anAm-methyl group protected by tert.-butoxycarbonyl can be obtained.
Furthermore, for example, 4-Am-methyl-2-thienyl-acetic acid compounds or 4-Am-methyl-2-furyl-acetic acid compounds can be obtained when 2-acetyl-thiophene or 2-acetyl-furane is halogeno-methylated, especially chloromethylated, for example by treatment with formaldehyde or a derivative thereof, such as paraformaldehyde, in the presence of a hydrogen halide acid, such a~ hydrochloric acid, and, in the 2-acetyl-4-~,~

- -. '. ~ . ~. , ' ' ' i'. .

halogenomethyl-thiophene compound or 2-acetyl-4-halogeno-methyl-furane compound, thus obtainable, wherein halogen above all denotes chlorine, halogen is converted into an amino group Am in a manner which is in itself known, for example by treatment with an amine of the formula Am-H (XI), and the acetyl substituent is then converted into the desired carboxy-methyl radical, for example by the process described above.
In a compound of the formula III having an unprotec-ted amino group Am, the latter can, if necessary, be conver-ted by any known method into one of the protected amino groups Am which have been mentioned. Thus, it is possible to intro-duce an acyl radical as an amino protective group into a secondary amino group Am, for example by the acylation pro-cess described above, and also by treatment with a carbonic acid halide compound or carbonic acid azide compound, such as tert.-butoxycarbonyl azide. Furthermore, a secondary amino group Am can be substituted by a di- or tri-arylmethyl group, for example by treatment with a reactive ester of a di- or tri-arylmethanol, such as trityl chloride, preferably in the presence of a basic agent, such as pyridine.
An amino group Am can also be protected by introducing a silyl group and stannyl group. Such groups are introduced in a manner which is in itself known, for example by treat-ment with a suitable silylating agent, such as a di-halogeno-di-lower alkylsilane or tri-lower alkylsilyl halide, for example dichlorodimethylsilane or trimethylsilyl chloride, or an optionally N-mono-lower alkylated, N,N-di-lower alkylated, j 7 8 ~ 7170 N-tri-lower alkylsilylated or N-lower alkyl-N-tri-lower - alkylsilylated N-(tri-lower alkyl-silyl)-amine (see, for example, British Patent No. 1,073,530), or with a suitable stannylating agent, such as a bis-(tri-lower alkyl-tin) oxide, for example bis-(tri-n-butyl-tin) oxide, a tri-lower alkyl-tin hydroxide, for example triethyl-tin hydroxide, a tri-lower alkyl-lower alkoxy-tin compound, a tetra-lower alkoxy-tin compound or a tetra-lower alkyl-tin compound as well as a tri-lower alkyl-tin halide, for example tri-n-butyl-tin chloride (see, for example, Netherlands Published Speci~ication 67/
11,107).
An amino group Am can also be protected by introducing a 2-carbonyl-1-vinyl group, enamine compounds being formed.
Such groups can be obtained, for example, by treating the amine with a 1,3-dicarbonyl compound, for example with aceto-acetic acid methyl ester or acetoacetic acid N,N-dimethylamide, in an anhydrous medium, for example a lower alkanol, such as methanol.
Arylthio or aryl-lower alkylthio and also arylsul-phonyl protective groups can be introduced into suitable amino groups Am by treatment with a corresponding arylthio, aryl-lower alkylthio or arylsulphonyl halide, for example an aryl-thio, aryl-lower alkylthio or arylsulphonyl chloride.
The reactive functional acid derivatives of an acid of the formula III can be manufactured in a manner which is in itself known. Acid halides are obtained, for example, by reacting a compound o~ the formula III, if necessary having a !~1 79 ,, .
: -.
-~.

protected amino group, or a salt thereof, with a halogenatingagent, for example with an acid halide, such as an acid fluoride or acid chloride, of an inorganic acid containing phosphorus or sulphur, for example phosphorus pentachloride, thionyl chloride or oxalyl chloride. The reaction is preferably carried out in a non-aqueous solvent or solvent mixture, such as a carboxylic acid amide, ~or example dimethyl-formamide. The resulting acid halide does not need to be further purified but can be reacted direct with the starting material of the formula II, it being possible to use, for example, the same solvents or solvent mixtures as are employed in the manufacture of the acid halide.
Symmetrical anhydrides, or mixed anhydrides which differ from halides, of compounds of the formula III, if necessary having a protected amino group, can be prepared, for example, by reacting a corresponding compound having a free carboxyl group,cr ~f~ably a salt, especially an alkali metal salt, for example a sodium salt or ammonium salt, for example the triethylammonium salt, thereof, with a reactive derivative, such as a halide, for example the chloride, of a suitable acid, for example a halogenoformic acid lower alkyl ester, for example chloroformic acid isobutyl ester, or a lower alkanecarboxylic acid halide, for example trichloro-acetic acid chloride.
Activated esters of compounds of the formula III, if necessary having a protected amino group, can be prepared, for example, by reacting a corresponding compound having a ~ j a o .:

~ .

; free carboxyl group, in the presence of a carbodiimide, for -.
example N,N'-dicyclohexylcarbodiimide, with a phenol which is optionally substituted, for example by nitro or halogen, such as chlorine, such as a nitrophenol, for example 4-nitrophenol .
. or 2,4-dinitrophenol, or a polyhalogenophenol, for example 2,3,4,5,6-pentachlorophenol.
The starting materials of the formula IV, which are : also active against Gram-positive and Gram-negative micro-: organisms, such as those mentioned in connection with the com-pounds of the formula I, and which thus also constitute a subject of the present invention, can be manufactured by introducing the group of the formula . . .

~ Am CH ~ CH2- ~ (IIIa) .~ wherein an amino group Am is present, if necessary, in the protected form, into the amino group of a compound of the formula VIII, wherein the amino group can optionally be sub-stituted by a group permitting acylation and wherein the grouping of the formula -S-Ao~ has the abovementioned meaning, above all by acylation, for example by the acylation process described above for starting materials of the formula II.
The starting materials of the formula IVb can be obtained, for example, when a 6~-amino-penam compound of the formula VIII, or a 7~-amino-3-cephem compound of the formula ~J a1 ~ ... .

~, .
... . . .

~87170 VIII, wherein functional groups which are present, such as, for example, a carboxyl group of the formula -C(=O)-R, are preferably present in the protected form, is used as the starting material and this is converted, by reaction with an aldehyde, especially an aromatic aldehyde, such as benzalde-hyde, into the Schiff's base and this is reacted with an anion-forming agent, such as a preferably sterically hindered alkali metal lower alkanolate, such as potassium tert.-buty-late, an alkali metal hydride, for example sodium hydride, an alkali metal-hydrocarbon compound, for example n-butyllithium or phenyllithium, or a suitable alkali metal compound of a secondary organic base, such as, for example, the lithium com-pound of a di-lower alkylamine or lower alkyleneamine, such as lithium diethylamide, preferably with cooling, for example at temperatures from about -30C to about 0C, and in the presence of a solvent or diluent, such as glycol dimethyl ether. The etherified mercapto group of the formula R-S- can be intro-duced into the anion, thus obtainable, direct, for example by treatment with a suitable thiol-sulphonic acid ester, such as a lower alkylthiol-sulphonic acid lower alkyl ester, for example methanethiolsulphonic acid methyl ester, or with a sulphenyl halide, such as a lower alkylsulphenyl halide, for example methylsulphenyl chloride, or indirectly via the corresponding 6a-fluoro-penam Schiff's base or 7~-fluoro-3-cephem Schiff's base; the latter is obtained, for example, by treatment with fluorine perchlorate and it can be converted into the desired 6a-R-thio-penam Schiff's base or 7a-R-~ ~2 , . . - .
.

.. . , . ,. . . . ~ . .
~: . , -~ -`
10~7170 thio-3-cephem Schif~'s base by reaction with a mercaptan, - such as a lower alkylmercaptan, for example methylmercaptan, in the presence of a strong acid, such as an optionally halogenated lower alkanecarboxylic acid, for example tri-fluoroacetic acid. In an intermediate product of this type, the nitrogen atom of the methyleneamino grouping is acylated by introducing the group of the formula IIIa, wherein an amino group Am is present in the protected form if necessary, for example by the process described above and the starting material of the formula IVb is thus obtained. This reaction sequence is carried out, for example, according to the methods described by Slusarchyk et al. J. Org. Chem, Volume 38, page 943 (1973), and Spitzer and Goodson, Tetrahedron Letters, page 273 (1973).
The starting material of the formula V can be obtained, for example, when, in a compound of the formula OC~
tl~- ~ i S
O =C O Ao - 1 '; (IX) (CH2)3 Il H ~ - C~l ~ C - Ro wherein the carboxyl group in a radical of the formula -S-Ao-is usually present in the protected form, the amino group in the 5-amino-5-carboxy-valeryl radical is converted into a protected amino group AmO and the acyl radical of the formula ` IIIa, wherein an amino group Am is present, if necessary, in , . :

.
.. . .. .. .. . . .. .
' ' ' . ' ~ : ".' ' . -- ~
- - . .: . .
,. . , . .. .. :
.
.
.

10~37170 a protected form, which differs, in the way it is removed, from that of the protected amino group AmO, is introduced on the nitrogen atom of the amide grouping of a compound which is thus obtainable, for example by acylation according to the process described above, for example by treatment with an acid halide, for example acid chloride, of a compound of the for-mula III and a suitable silylating agent, such as a mono-silylated or di-silylated acid amide, such as an optionally halogenated N-mono-tri-lower alkylsilyl-lower alkanecarboxylic acid amide or N,N-bis-tri-lower alkylsilyl-lower alkanecar-boxylic acid amide, it being possible for the latter also to be present in the N,0-bis-tri-lower alkylsilylated enol form of the amide, for example bis-trimethylsilyl-acetic acid amide or N-trimethylsilyl-trifluoroacetic acid amide, in a suitable solvent or diluent, for example in a halogenated hydrocarbon, such as methylene chloride, and, if necessary, with warming, in a closed vessel and/or in an inert gas atmosphere, such as a nitrogen atmosphere. The manufacture of the starting material of the formula V by the above process can be carried out, for example, according to the method described by Sletzinger et al J.Am. Chem. Soc., Volume 94, page 1,410 (1972).
The starting material of the formula VI is known or can be prepared in a manner which is in itself known, for example by acylating the amino group in a compound of the formula II by treatment with an acid of the formula ~4 L~;~

- . . . . .. . . .

. .
.. : : , . . . . .
, .

~ ~ C~12-C-OH (XII) X

or a suitable derivative, such as a mixed anhydride, especially a halide, for example the chloride, thereof, for example according to the acylation process described above.
Starting materials of the formula VIII can be obtained according to one of the processes described above for the manufacture of compounds of the formula I, for example by acylating the primary amino group in a compound of the formula II by treatment with an acid of the formula ~ -H2N - CH~ ~ ~ U2- C - OH (XIII) wherein the.amino group is preferably in the protected form, for example as indicated, or with a reactive functional acid derivative thereof or with a salt of such a compound, or by introducing the methoxy group into the 6a-position or 7a-position of a penam compound or 3-cephem compound of the formula H2~1--CH2~3--CH- PC--H~ S

,. ~ . . . . .
:: :
.

10~7~70 wherein amino of the aminomethyl group is preferably present in the protected form and the radical of the formula -S-Ao~
has the abovementioned meaning and a carboxyl group of the formula -C(=O)-Ro is preferably present in the protected form, or of a salt thereof, and, if necessary, liberating the amino group in the aminomethyl substituent. The above reactions are carried out analogously to the processes described above.
2-Cephem starting materials of the formula X can also be prepared analogou~ly to the processes described above in connection with the pr~ration of the corresponding 3-cephem compounds, for example by acylating the primary amino group in a compound of the formula O = C-Ro .
by treatment with an acid of the formula III, wherein an amino group Am is present, if necessary, in the protected form, or with a reactive functional acid derivative thereof or with a salt of such a compound. The above acylation reac-tion can be carried out, for example, analogously to the methods described above.
In the process according to the invention, and in additional measures which may need to be carried out, as well as in the ~eparation of the starting materials, it is ~ ~6 . , .
. . : - :
.. . .
.
. .. . .. .
: :
~ ' . ~ ' : .

10~7170 possible, if necessary, temporarily to protect, in a manner which is in itself known, free functional groups, which do not participate in the reaction, in the starting materials or in the compounds obtainable according to the process, as des-cribed above, for example free amino groups by acylation, tritylation or silylation, free hydroxyl or mercapto groups by, for example, etherification or esterification, and free carboxyl groups by, for example, esterification, including silylation, and in each case to liberate them after the reac-tion has taken place, if desired, in a manner which is in it-self known, by solvolysis or reduction.
The pharmacologically usable compounds of the present invention can be used, for example, to manufacture pharma-ceutical preparations which contain an effective amount of the active substance together or in a mixture with inorganic or organic, solid or liquid, pharmaceutically usable excipients, which preferably are suitable for parenteral administration.
Preferably, the pharmacologically active compounds of the present invention are used in the form of injectable preparations, for example preparations which can be adminis-tered intravenously, or of infusion solutions. Such solu-tions are preferably isotonic aqueous solutions or suspensions, it being possible to prepare these before use, for example from lyophilised preparations, which contain the active sub-stance alone or together with an excipient, for example mannitol. The pharmaceutical preparations can be sterilised and/or contain auxiliaries, for example preservatives, ,.,~. .~..V

- ' . -., . . - : : .
.
, . ~ - ., . - - . :.

.

1~7170 stabilisers, wetting agents and/or emulsifiers, solubilising agents, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations, which, if desired, can contain further pharmacologically valuable sub-stances, are manufactured in a manner which is in itself known, for example by means of conventional solution or lyophilisation processes and contain from about 0.1~ to 100~, especially from about 1% to about 50%, of lyophilisates and up to lOOyo of the active substance. Depending on the nature of the infection and the condition of the infected organism, daily doses of about 0.5 g to about 5 g are used subcutaneous-ly for the treatment of warm-blooded animals with a weight of about 70 kg.
Unless otherwise defined, the expression "lower" used in connection with the definition of organic radicals or compounds, for example in lower alkyl, lower alkanol and the like, denotes that the particular radicals or compounds con-tain up to 7, preferably up to 4, carbon atoms.
The examples which follow serve to illustrate the invention.
Example 1: -5.00 g of 3-acetoxymethyl-7~-[2-(5-N-tert.-butoxy-carbonyl-N-methyl-aminomethyl-2-thienyl)-acetylamino]-3-cephem-4-carboxylic acid tert.-butyl ester are dissolved in 350 ml of tetrahydrofurane, the solution is cooled to -70 to _75C under a nitrogen atmosphere and a solution of lithium methoxide in methanol, which is obtained by dissolving 0.150 g

8~

, . .. . . . . .

- . - -. .. . . - .
, . . . . : . . ~ .. . . -. . . - ~ . . :

1~7170 .
of lithium in 50 ml of methanol, is added in the course of 1 minute, while stirring. After 3 minutes, 0.955 g of tert.-butyl hypochlorite are added and the mixture is stirred for a further 20 minutes at -70 to -75C, neutralised with ~ ml of acetic acid and concentrated in a water pump vacuum to about 70 ml. 200 ml of water are added an~ the mixture is extrac-ted with twice 300 ml of ethyl acetate. The organic extracts are washed with water and with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The crude product is chromato-graphed on 250 g of silica gel, 3-acetoxymethyl-7a-methoxy-7~-5~ [ 2-(5-N-tert.-butoxy-carbonyl-N-methyl-aminomethyl-2-thienyl)-acetylamino]-3-cephem-4-carboxylic acid tert.-butyl ester ., .
belng eluted with a 3:2 mixture of toluene and ethyl acetate;
thin layer chromatogram (silica gel): Rf = 0.40 (system:
toluene/ethyl acetate, ~:2).
The starting material can be prepared as follows:
2.~ g of an approximately 55% strength dispersion of sodium hydride in mineral oil are added in portions, under a nitrogen atmosphere at 20-25C, to a solution of 5.0 g of 2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetic acid and 20.9 g of methyl iodide in 100 ml of tetrahydrofurane and 10 ml of di-methylformamide. The mixture is stirred for 7 hours at 20-25C, 5 ml of ethanol are added to the reaction solution and the latter is concentrated under reduced pressure. 100 ml of water are added to the residue; the mixture is extracted with ethyl acetate, the pH of the aqueous phase is adjusted to 2 .
, .
- .- . - - .
.
. :.. . .
~'. ' ' . '. . . .

~871qO

using 20% strength phosphoric acid and the aqueous phase is extracted with twice 100 ml of ethyl acetate.
The two organic extracts are washed with a concen-trated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The resi-due is crystallised from diethyl ether and gives 2-(5-N-tert.-butoxycarbonyl-N~hyl-aminomethyl-2-thienyl)-acetic acid of melting point 100 - 101C; thin layer chromatogram (silica gel): Rf = 0.24 (system: chloroform/ethyl acetate/
acetic acid, 80:19:1); ultraviolet absorption spectrum (ethanol): AmaX = 242 m~ ( = 9~00); infrared absorption spectrum (mineral oil): characteristic bands at 5.77 ~ and 6.03 ~.
1.70 g of 4-methyl-morpholine are added to a solution of 4.80 g of 2-(5-N-tert.-butoxycarbonyl-N-methyl-aminomethyl-2_thienyl)-acetic acid in 250 ml of methylene chloride (distilled over phosphorus pentoxide), the mixturè is cooled to -20C and 2.30 g o~ chloroformic acid isobutyl ester are added dropwise. After 30 minutes, a solution of 5.25 g of 3-acetoxy-methyl-7~-amino-3-cephem-4-carboxylic acid tert.-butyl ester in 25 ml of methylene chloride is added, the temperature being maintained at -15C to -20C. The coolant is then removed and the reaction solution is left to stand for 18 hours at room temperature. 100 ml of water are then added, the pH is adjusted to 8.0 with di-potassium hydrogen phosphate and the methylene chloride solution is separated off. The aqueous phase is again extracted with methylene chloride and ~ 90 ....~

- . . .: - . . -- . .~ ~ - .
. .

.. . . , . . .. - .. ;.
. . . .. . . .
' ~ ' ~37170 the two organic phases are washed with a concentrated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. This gives 3-acetoxymethyl-7~-[2-(5-N-tert.-butoxycarbonyl-N-methyl-aminomethyl-2-thienyl)-acetylamino]-3-cephem-4-carboxylic acid tert.-butyl ester; thin layer chromatogram (silica gel): Rf = 0.45 (system: toluene/ethyl acetate, 2:1); ultraviolet absorption spectrum (in 96%
strength aqueous ethanol): AmaX = 245 m~ ( = 14,600); infra-red absorption spectrum (in methylene chloride): characteris-tic bands at 2.93 ~, 5.73 ~, 5.78 ~, 5.90 ~ and 6.63 ~.
Example 2: -20 ml of trifluoroacetic acid are added to the 3-acetoxymethyl-7~-[2-(5-N-tert.-butoxycarbonyl-N-methyl-amino-methyl-2-thienyl)-acetylamino]-7a-methoxy-3-cephem-4-car-boxylic acid tert.-butyl ester, obtained according to the process of Example 1, and the mixture is left to stand for 30 minutes.
The reaction mixture containing the trifluoroacetic acid salt of 3-acetoxymethyl-7a-methoxy-7~-[2-(5-methylamino-methyl-2-thienyl)-acetylamino~-3-cephem-4-carboxylic acid is evaporated under reduced pressure and the residue is taken up in water and rendered neutral by adding triethylamine. This gives the inner salt of 3-acetoxymethyl-7a-methoxy-7~-[2-(5-methylaminomethyl-2-thienyl)-acetylamino]-3-cephem-4-car-boxylic acid; thin layer chromatogram (silica gel): Rf =
0.28 (system: tert.-butanol/isopropanol/water, 35:35:30);
ultraviolet absorption spectrum (in water): AmaX = 242 m~ -.. . ~ .. . . . ~ , . .

,, 1~871qO

( = 14,800); in~rared absorption spectrum (in mineral oil):
characteristic bands at 5.67 ~, 5.75 ~, 6.01 ~ and 6.55 ~.
Example 3:
A solution of 0.670 g of 7~-[2-(5-N-tert.-butoxycar-bonyl-N-methyl-aminomethyl-2-thienyl)-acetylamino]-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid tert.-butyl ester in 50 ml of tetrahydrofurane is treated at -70C
with a solution of 0.025 g of lithium in 20 ml of methanol and immediately thereafter with 0.130 ml of tert.-butyl hypo-chlorite. After a reaction time of 15 minutes at -70C, 1 ml of acetic acid is added and the reaction mixture is evaporated in a water pump vacuum. The residue is taken up in 50 ml of ethyl acetate; the organic solution is washed with dilute aqueous sodium thiosulphate solution and with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated in a water pump vacuum to a volume of about 5 ml. The concentrated solution is diluted slowly with 40 ml of petroleum ether; the precipitate is filtered off and dried in a high vacuum at room temperature. This gives 7~-[2-(5-N-tert.-butoxycarbonyl-N-methyl-aminomethyl-2-thienyl)-acetyl-amino~-7a-methoxy-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid tert.-butyl ester; thin layer chromatogram (silica gel): Rf = 0.21 (system: toluene/ethyl acetate, 3:2).
The starting material can be prepared as follows:
1.54 g of 2-(5-N_tert._butoxycarbonyl_N_methyl-amino-methyl-2-thienyl)-acetic acid are dissolved in 60 ml of methy-~1 92 . - ` . . .

. .

.. , . ... .
:

lene chloride containing 0.60 ml of N-methyl-morpholine, the solution is cooled to -20C, moisture being excluded, and 0.785 ml o~ chloroformic acid isobutyl ester are added drop-wise. After 30 minutes, a solution prepared from 1.97 g of 7~-amino-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid and 2.82 ml of N,0-bis-(trimethylsilyl)-acet-amide in 60 ml of methylene chloride is added dropwise, after which the reaction mixture is further stirred for one hour at _20C and for 4 hours whilst slowly warming to room tempera-ture and then concentrated under reduced pressure. The resi-due is dissolved in water, sodium bicarbonate being added until a pH value of 8 is obtained. The solution is washed with ethyl acetate and the aqueous solution, which is separated off, is acidified to pH 2 with 20% strength aqueous phosphoric acid and extracted with ethyl acetate. The organic extract is washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. This gives 7~-[2-(5_N-tert.-butoxycarbonyl-N-methyl-aminomethyl-2-thienyl)-acetylamino]-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid; thin layer chromatogram (silica gel): Rf = 0.34 (system: n-butanol/acetic acid/water, 75:
7.5:21), in~rared absorption spectrum (in methylene chloride):
characteristic bands at 2.95 ~, 5.58 ~, 5.84 ~ and 6.55 ~.
A mixture of 2.0 g of dicyclohexylcarbodiimide, 0.86 g of tert.-butyl alcohol and 0.02 g of copper-(I) chloride is stirred for 5 days at room temperature. The suspension of 0-tert.-butyl-N,N~-dicyclohexyl-isourea, thus obtainable, is . .

7~70 diluted with 10 ml of methylene chloride and added to a solu-tion of 2.5 g of 7~-[2-(5-N-tert.-butoxycarbonyl-N-methyl-aminomethyl-2-thienyl)-acetylamino]-3-(1-methyl-5-tetrazolyl-thiomethyl)-3-cephem-4-carboxylic acid in 20~ml of methylene chloride, this solution being kept at room temperature.
After 5 hours, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is chromato-graphed on 30 g of silica gel, 7~-[2-(5-N-tert.-butoxycar-bonyl-N-methyl-aminomethyl-2-thienyl)-acetylamino]-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid tert.-butyl ester being eluted with ethyl acetate; thin layer chromatogram (silica gel): Rf = 0.24 (system: toluene/ethyl acetate, 3:2).
, Exam~le 4:
i A solution of 0.44 g of 7~-[2-(5-N-tert.-butoxycar-bonyl-N-me~hyl-aminomethyl-2-thienyl)-acetylamino]-7a-methoxy-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic ~ acid tert.-butyl ester in 10 ml of formic acid and 2 ml of ; trifluoroacetic acid is left to stand for 15 minutes at room temperature, moisture being excluded, and is then evaporated in a water pump vacuum, toluene being added. The residue is triturated with diethyl ether and the trifluoroacetic acid salt of 7~-~2-(5-methylaminomethyl-2-thienyl)-acetylamino]-7a-methoxy-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid, thus obtainable, is dried in a high vacuum at room temperature and then dissolved in 20 ml of water. The aqueous solution is washed with ethyl acetate, the pH value ~ 94 `

. . . :: . . , . , : - - . : .
- . . . . . . .. ... .. .

.
- : ' ~,:
. . .. .
.. . . . ..
:, , ~ . . .

~37170 is adjusted to 6 with triethylamine and the solution is con-centrated under a water pump vacuum to a volume of about 2 ml.
'rhis concentrate is diluted by adding 10 ml o~ acetone drop-wise and le~t to stand for 2 hours at 4C and the precipitate is filtered off. The latter is washed with acetone and dried under a high vacuum at room temperature; this gives the inner salt of 7~-[2-(5-methylaminomethyl-2-thienyl)-acetyl-amino]-7a-methoxy-3-(l_methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid; thin layer chromatogram (silica gel): Rf = 0.12 (system: n-butanol/acetic acid/water, 45:
45:10).
By a suitable selection of the starting materials, the ~ollowing compounds can be obtained in an analogous manner:
3-acetoxymethyl-7~-[2-(5-dimethylaminomethyl-2-thienyl)-acetylamino]-7a-methoxy-3-cephem-4-carboxylic acid; 7a-methoxy-7~-[2-(5-methylaminomethyl-2-thienyl)-acetylamino]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-car-boxylic acid; 7~-[2-(5-dimethylaminomethyl-2-thienyl)-acetyl-amino~-7a-methoxy-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid; 7~-[2-(5-dimethylaminomethyl-2-thienyl)-acetylamino]-7a-methoxy-3-(1-methyl-5-tetrazolylthio-methyl)-3-cephem-4-carboxylic acid and 3-carbamoyloxymethyl-7a-methoxy-7~-[2-(5-methylaminomethyl-2-thienyl)-acetylamino]-3-cephem-4-carboxylic acid which are usually obtained in the form o~ their inner salts.
Example 5:
Dry a~poules or phials, containing 0.5 g o~ the inner ~; 35 : . ,, ? - ~ -,, ,, ", " ," ,~, .. . . .. .

, .~
' .

~ 37170 salt of 3-acetoxymethyl-7a-methoxy-7~-[2-(5-methylamino-methyl-2-thienyl)-acetylamino]-3-cephem-4-carboxylic acid, are manufactured as follows:
Composition (for 1 ampoule or phial) inner salt of 3-acetoxymethyl-7a-methoxy-7~-[2-(5-methylaminomethyl-2-thienyl)-acetylamino]-3-cephem-4-carboxylic acid 0.5 g mannitol 0. 5 g A sterile aqueous solution of the inner salt of 3- :
acetoxymethyl-7a-methoxy-7~-[2-(5-methylaminomethyl-2-thienyl)-acetylamino]-3-cephem-4-carboxylic acid and mannitol is sealed, under aseptic conditions, in 5 ml ampoules or 5 ml phials and checked. :; ---. .
.

. :. . . .. . . :: - ` . -.. , . .- -. ~ .

:

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Process for the manufacture of 7.beta.-acylamino-7.alpha.-methoxy-3-cephem-4-carboxylic acid compounds of the formula (I) wherein Am represents an amino group of the formula in which one of the groups Ra and Rb represents lower alkyl and the other represents hydrogen or lower alkyl and X represents sulphur or oxygen and wherein R1 repre-sents a radical of the formula -CH2-R2, wherein R2 denotes acetoxy, carbamoyloxy, optionally lower alkylated thiadia-zolylthio or optionally lower alkylated tetrazolylthio and R represents hydroxyl, as well as salts thereof, charac-terised in that the amino group in a compound of the for-mula (II) wherein the amino group can be optionally substituted by an organic silyl orstammyl group or by an ylidene group, and wherein R0 has the meaning of R or represents a carbo-xyl protective radical which, with the carbonyl group of the formula -C(=O)-, forms a protected carboxyl group, or in a salt thereof, is acylated by treatment with an acid of the formula (III) wherein an amino group Am, if necessary, is present in the protected form, or with a reactive functional acit deriva-tive thereof or with a salt of such a compound, or the methoxy group is introduced into the 7.alpha.-position of a 3-cephem compound of the formula (IV) wherein an amino group Am is preferably in the protected form and a carboxyl group of the formula -C(=O)-R0 is present in the protected form, or of a salt thereof, by treating an acylimino compound of the formula (IVa) wherein amino of the aminomethyl group is in a protected form, and Ro and R1 have the abovementioned meaning, and a carboxyl group of the formula -C(=O)-Ro is in a protected form, with methanol or by treating a compound of the formula IV, wherein amino of the aminomethyl group and the carboxyl group of the formula -C(=O)-Ro, and additional functional groups which may be present, are in a protected form, with an anion-forming agent followed by a N-halogenating agent and, if required, reacting with a base which splits off hydrogen halide, and treating the resulting compound with methanol or a compound of the formula (VI) wherein Ro and R1 have abovementioned meaning and a carbo-xyl group of the formula -C(=O)-Ro is present in the protected form, is reacted with a compound of the formula Am-H (VII), the additional hydrogen atom in an amino group Am which is monosubstituted by lower alkyl being replaced by an amino protective group, and with formaldehyde in the presence of a strong, at most slightly nucleophilic, acid, or, in a compound of the formula (VIII) or in a salt thereof, the free amino group H2N- is converted into a substituted amino group Am by treatment with a reactive ester of an alcohol of the formula Ra-OH (IXa) or Rb-OH (IXb) or of a diol of the formula HO-(Ra+Rb)-OH (IXc), or by reacting a starting materlal of the formula VIII with a lower alkanal or a lower alkanone under simultaneous or subsequent treatment with a reducing agent, and, in a resulting compound, a protected amino group in the Am-methyl radical is converted into the group Am and a protected carboxyl group of the formula -C(=O)-R0 is converted into a free carboxyl group and/or if desired, an acetoxy group R2 is converted into an optio-nally substituted heterocyclylthio group R2 and/or a resulting salt is converted into the free compound or into another salt, or a resulting free compound is converted into a salt.

2. Process according to claim 1, characterised in that a protected carboxyl group of the formula -C(=O)-R0 in a starting material represents an esterified carboxyl group, which can be split easily, wherein R0 represents an etherified hydroxyl group.

3. Process according to claim 1, characterised in that free functional groups which may be present, in addition to a carboxyl group of the formula -C(=O)-R0, in a starting material are present in a protected, easily splittable form.

4. Process according to claim 3, characterised in that, in a starting material, an amino group Am is protected by an amino protective group, which can be split off easily.

5. Process according to one of claims 1-3, charac-terised in that the acylation of a starting material of the formula II is carried out by treatment with an acid of the formula III in the presence of a condensation agent.

6. Process according to claim 1, charac-terised in that the acylation of a starting material of the formula II is carried out by treatment with an anhyd-ride, including a mixed or inner anhydride, of an acid of the formula III.

7. Process according to claim 6, characterised in that the anhydride used is the anhydride of an acid of formula III with a hydrogen halide acid or with a half-ester of carbonic acid.

8. Process according to claim 1, characterised in that a methoxy group is introduced into the 7.alpha.-position of a 3-cephem compound of the formula IV by treating an acylimino compound of the formula (IVa) wherein an amino group Am is present in the protected form, and the radical R1 has the abovementioned meaning and a carboxyl group of the formula -C(=O)-R0 is present in the protected form, with methanol.

9. Process according to claim 8, characterised in that a starting material of the formula IVa according to claim 8 is prepared in the presence of methanol by treating a compound of the formula IV, wherein amino of the aminomethyl group and the carboxyl group of the formula -C(=O)-R0 as well as any additional functional groups which may be present are in the protected form, with an anion-forming agent, followed by a N-halogenating agent, and, if necessary, reacting the resulting product with a base which splits off hydrogen halide, or by treating a compound of the formula (IVb) wherein Ro represents an organic radical and wherein an amino group Am, if necessary, and the carboxyl group of the formula -C(=O)-R0 as well as any additional functional groups which may be present are in the protected form, with halogen, followed by a base and these reactions are carried out in the presence of methanol and in a 7.alpha.-methoxy-3-cephem compound thus obtained, a protected amino group in the Am-methyl radical is converted into the group Am and a protected carboxyl group of the formula -C(=O)-R0 is converted into a free carboxyl group and/or if de-sired, an acetoxy group R2 is converted into an option-ally substituted heterocyclylthio group R2 and/or a resulting salt is converted into the free compound or into another salt, or a resulting free compound is converted into a salt.

10. Process according to claim 9, characterised in that an organo-metallic base is used as the anion-forming agent, it being possible for a base of this type at the same time to serve as an agent which splits off hydrogen halide, and a sterically hindered organic hypohalite is used as the N-halogenating agent.

11. Process according to claim 10, characterised in that an alkali metal alcoholate is used as the anion-forming agent a tert.-lower alkyl hypohalite is used as the N-halogenating agent.

12. Process according to claim 11, characterised in that lithium methylate is used as the anion-forming agent and tert-butyl hypochlorite is used as the N-halogenating agent.

13. Process according to claim 9, characterised in that Ro in a starting material of the formula IVb according to claim 9 represents lower alkyl.

14. Process according to claim 9 or 13 characterised in that Ro in a starting material of the formula IVb according to claim 9 represents methyl.

15. Process according to claim 9, characterised in that a starting material of the formula IVb according to claim 9 is reacted with chlorine, followed by a tertiary aliphatic amine.

16. Process according to claim 15, characterised in that a starting material of the formula IVb according to claim 9 is reacted with chlorine, followed by a tri-lower alkylamine.

17. Process according to claim 9, characterised in that a methoxy group is introduced into the 7.alpha.-position of a 3-cephem compound of the formula IVb by reacting a compound of the formula IVb according to claim 9, wherein Ro has the meaning indicated in claim 9, and wherein an amino group Am and the carboxyl group of the formula -C(=O)-R0 as well as any addition-al functional groups which may be present are in the protected form, with methanol in the presence of a desulphurising agent.

18. Process according to claim 9, characterised in that a methoxy group is introduced into the 7.alpha.-position of a 3-cephem compound of the formula IVb by reacting a compound of the formula IVb according to claim 9, wherein Ro has the meaning indicated in claim 9 or 13, and wherein an amino group Am and the carboxyl group of the formula -C(=O)-R0 as well as any additional functional groups which may be present are in the protected form, with methanol in the presence of a desulphur-ising agent selected from silver compounds and mercury compounds.

19. Process according to claim 9, characterised in that a methoxy group is introduced into the 7.alpha.-position of a 3-cephem compound of the formula IVb by reacting a compound of the formula IVb according to claim 9, wherein Ro has the mean-ing indicated in claim 9 or 13, and wherein an amino group Am and the carboxyl group of the formula -C(=O)-R0 as well as any additional functional groups which may be present are in the protected form, with methanol in the presence of a desulphur-ising agent which is a silver oxide or mercury oxide or a silver-I salt or mercury-II salt.

20. Process according to claim 1, characterised in that, in a starting material of the formula VII, the amino protective group of a monosubstituted amino group Am is an acyl group which cannot be split off under the reaction conditions in the presence of the strong, at most slightly nucleophilic acid.

21. Process according to claim 1, characterised in that formaldehyde is used in the form of a reactive derivative there-of or in its polymeric form.

22. Process according to claim 1 or 20, characterised in that the strong, at most slightly nucleophilic acid used is trifluoroacetic acid.

23. Process according to claim 1, characterised in that, in a compound of the formula I, wherein R1 denotes a group of the formula -CH2-R2 and R2 represents an acetoxy-radical or in a salt thereof, such an acetoxy radical R2 is replaced by one of the heterocyclic etherified mercapto groups R2 of claim 1, by treatment with the corresponding heterocyclic mercaptan compound.

24. Process according to claim 1, characterised in that 3-cephem compounds of the formula I according to claim 1, or salts thereof, wherein Am represents methyl-amino or dimethylamino, X represents sulphur or oxygen and the Am-methyl-2-thienyl or Am-methyl-2-furyl, R1 represents the radical of the formula -CH2-R2, in which R2 denotes acetoxy, or thiadiazolylthio or tetrazolylthio which are optionally substituted by lower alkyl and which are bonded to the thio sulphur atom via a ring carbon atom, and wherein R represents hydroxyl, are manufactured by react-ing a 3-cephem compound of the formula IV according to claim 1, wherein X and R1 have the meaning mentioned above, and wherein Am is dimethylamino or protected methylamino and R0 is a protected Carboxyl group, with an anion forming agent followed by a N-halogenating agent in the presence of methanol, then splitting off the protecting groups and isolating the resulting compound as the free acid or a salt thereof.

25. Process according to claim 1, characterised in that 3-cephem compounds of the formula I according to claim 1, or salts thereof, wherein Am represents methylamino or dimethylamino, X represents sulphur or oxygen and the Am-methyl-substituted radical denotes Am-methyl-2-thienyl or Am-methyl-2-furyl, R1 represents the radical of the formula -CH2-R2, in which R2 denotes acetoxy, 5-methyl-1,3,4-thia-tiazol-2-ylthio or 1-methyl-5-tetrazolylthio, and wherein R represents hydroxyl, are manufactured by reacting a 3-cephem compound of the formula IV according to claim 1, wherein X and R1 have the meaning mentioned above, and wherein Am is dimethylamino or protected methylamino and Ro is a protected Carboxyl group, with an anion forming agent followed by a N-halogenating agent in the presence of methanol, then splitting off the protecting groups and isolating the resulting compound as the free acid or a salt thereof.

26. Process according to claim 1, characterised in th8t 3-acetoxymethyl-7.alpha.-methoxy-7.beta.-[2-(5-methylaminomethyl-2-thienyl)-acetylamino-3-cephem-4-carboxylic acid or salts thereof are manufaceured by reacting 3-acetoxymethyl-7.alpha.-[2-(5-N-tert-butyloxycarbonyl-N-methylaminomethyl-2-thienyl)-acetylamino]-3-cephem-4-carboxylic acid tert.-butyl ester with lithium methoxite and tert-butylhypochlorite in the presence of methanol, then splitting off the protecting groups and isolating the resulting compound as the free acid or a salt thereof.

27. Process according to claim 1, characterised in that 7.alpha.-methoxy-7.beta.-[2-(5-methylaminomethyl-2-thienyl)-acetylamino]-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem 4-carboxylic acid or salts thereof are manufactured by re-acting 3-(1-methyl-5-tetrazolylthiomethyl-7.alpha.-[2-(5-N-tert-butyloxycarbonyl-N-methyl-aminomethyl-2-thienyl)-acetylamino]-3-cephem-4-carboxylic acid tert.-butyl ester with lithium methoxide and tert-butylhypochlorite in the presence of methanol, then splitting off the protecting groups and isolating the resulting compound as the free acid or a salt thereof.

28. 7.beta.-acylamino-7.alpha.-methoxy-3-cephem-4-carboxylic acid compounds of the formula (I) wherein Am represents an amino group of the formula in which one of the groups Ra and Rb represents lower alkyl and the other represents hydrogen or lower alkyl and X
represents sulphur or oxygen and wherein R1 represents a radical of the formula -CH2-R2, wherein R2 tenotes acetoxy, carbamoyloxy,optionally lower alkylated thiadia-zolylthio or optionally lower alkylated tetrazolylthio and R represents hydroxyl, as well as salts thereof,when-ever prepared according to the process of claim 1 or an obvious chemical equivalent thereof.

29. 3-acetoxymethyl-7.alpha.-methoxy-7.beta.-[2-(5-methylamino-methyl-2-thienyl)-acetylamino-3-cephem-4-carboxylic acid or salts thereof,whenever prepared according to the process of claim 26 or an obvious chemical equivalent thereof.

30. 3-(1-methyl-5-tetrazolylthiomethyl)-7.alpha.-methoxy-7.beta.-[2-(5-methylaminomethyl-2-thienyl)-acetylamino-3-cephem-4-carboxylic acid or salts thereof, whenever prepared accord-ing to the process of claim 27 or an obvious chemical equivalent thereof.