Note: Descriptions are shown in the official language in which they were submitted.
~-13033/+
~minohydroxyphenyl compounds, processes Eor their manu-
facture, pharmaceutical preparations containing these
compounds, and the use of these compounds.
The present invention relates to novel 7~-1D-2-amino-
2-(aminohydroxyphenyl)-acetylamino]-ceph 3-em-~-carboxylic
acid compounds of the formula
tR)(Ro)~ O ~)n
OH ~ ~ R3 (I)
O
: R~
~k
-2- ~7~
in which
the index n represents O or 1,
R represents hydrogen or an acyl group,
Ro represents hydrogen or lower alkyl,
Rl represents hydrogen or a group of the
partial formula tR)~Ro)N~,
R2 represents carboxyl or protected carboxyl,
and
R3 represents hydrogen, halo~en having an
atomic number of up to 35 or lower alkoxy,
and hydrates and salts of compounds of the formula I,
processes for the manufacture of compounds of the formula I,
pharmaceutical preparations containing compounds of the
formula I, and the use of these compounds for the manu~act-
ure of pharmaceutical preparations or as pharmacologically
active compounds.
In the above formula, the index n represents
especially 0. If n has the value 1 the corresponding 1-
oxide compound is in the a- or ~-form.
In the present description, the term "lower" used in
connection with definitions of substituents or compounds
indicates that the corresponding substituents or compounds
contain up to 7, preferably up to 4, carbon atoms, unless
~ expressly defined otherwise.
; The general definitions used hereinbefore and herein-
after preferably have the following meanings within the
framework of the present description:
An acyl group R has up to 19 carbon atoms and is the
acyl group R of a carboxylic acid, a carbonic acid semi-
ester, carbamic acid, a substituted carbamic acid, thio-
carbamic acid, a substituted thiocarbamic acid, a sulphonic
acid, amidosulphonic acid or a substituted amidosulphonic
acid.
Such acyl groups R have, for example, the formulae:
R -CO-, Ra_O_co_, R~RaN_CO_, RaRaN-cs-~ Ra-S~2-orRaRaN-S~ ~'
in which Ra represents hydrogen or an optionally
~L~7B~ f3
--3--
substituted hydrocarbon radical and two radicals ~a in an
acyl group may, within the scope oE their meanings, be the
same or different.
~ n optionally substituted hydrocarbon radical Ra in
an acyl group R has up to 18 carbon atoms and is, for
example, a lower aliphatic, cycloaliphat:ic, cycloaliphatic-
aliphatic, aromatic or araliphatic radical which may be
substituted, for example, by lower alkyl, lower alkoxy,
halogen, nitro, oxo, hydroxy, optionally functionally modi-
fied carboxy, amino or lower alkylated amino, or a corres-
ponding protected functional group.
A lower aliphatic radical Ra is, for example, lower
alkyl, especially having from 1 to 6, preferably from 1 to
4, carbon atoms, for example methyl, ethyl, propyl or buty.l.,
or lower al~enyl, especially having from 2 to 5 carbon
atoms, for example vinyl, propenyl or butenyl.
A cycloaliphatic radical Ra is cycloalkyl h;lving
Erom 3 to 8, especially f:(.m 3 to 6, carbon atoms, for
example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
A cycloaliphatic-aliphatic radical Ra is one of the
mentioned aliphatic radicals that is substituted by one of
the mentioned cycloallphatic radicals, for example cyclo-
propylmethyl or ethyl or cyclohexylmethyl or -ethyl.
.~n aromatic radical Ra is especially phenyl or
napthyl.
An araliphatic radical Ra is one of the mentioned
aliphatic radicals that is substituted by from one to three
of the mentioned aromatic radicals, for example benzyl,
phenethyl, diphenylmethyl or trityl.
Preferred substituted hydrocarbon radicals Ra are,
for example, halo-lower alkyl, for example 2-fluoro-,
2-chloro-, 2-bromo- and 2-iodoethyl, oxo-lower alkyl, for
example acetonyl, optionally protected, for example
acylated, hydroxy-lower alkyl, for example 2-hydroxyethyl
and acetoxyethyl, optionally esterified carboxy-lower al'~yl,
for example 2-carboxymethyl and 2-ethoxycarbonylmethyl,
~.~L7~
--4--
amino- and mono- or di-lower alkylamino-lower alkyl, for
example 2-aminoethyl, 2-methylaminoethyl, 2-dimethylamino-
ethyl, and acylamino-lower alkyl, for example 2-acetami~o-
ethyl, lower alkylphenyl, for example tolyl and ~ylyl, lower
alkoxyphenyl, for example methoxyphenyl, halo-phenyl, for
example fluoro- or chlorophenyl, hydroxyphenyl, nitrophenyl,
carboxyph~nyl and aminophenyl, wherein in each case the sub-
stituents may be in the o-, m- or ~-position of the
phenyl nucleus, and phenacetyl.
Preferred acyl groups R are, for example, lower
alkanoyl, such as formyl, acetyl or propionyl; halo-lower
alkanoyl, such as 2-haloacetyl, especially 2-chloro-, 2-
bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloroacetyl;
benzoyl optionally subs~ituted, ~or example, by halog~n,
lower alkoxy or nitro, for example benzoyl, 4-chlorobenzoyl,
4-methoxybenzoyl or 4-nitrobenzoyl; lower alkoxycarbonyl
branched in the l-position of the lower al`~yl radical or
suitably substituted in the 1- or 2-position, especially
tert.-lower alkoxycarbonyl, for example tert.-butoxycar-
bonyl; arylmethoxycarbonyl having one or two aryl radicals
that are phenyl radicals optionally mono- or poly-substitu-
ted, for example, by lower alkyl, especially tert.-lower
alkyl, such as tert.-butyl, lower alkoxy, such as ~ethoxy,
hydroxy, halogen, for example chlorine, and/or nitro: such
as optionally substituted benzyloxycarbonyl, for example 4-
nitrobenzyloxycarbonyl, or optionally substitute~ diphenyl-
methoxycarbonyl, for example benzhydryloxycarbonyl or di-(4-
methoxyphenyl)-~ethoxycarbonyl; aroylmethoxycarbonyl, in
which the aroyl group is preferably benzoyl optionally sub-
stitute~, for example, by halo3en, such as bromine, for
example phenacyloxycarbonyl; 2-halo-lower alkoxycarbonyl,
for example 2,2,2-trichloroethoxycarbonyl, 2 chloroethoxycar-
bonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl;
carbamoyl; ~-lower alkylcarbamoyl, for example ~-methylcarb-
amoyl; N,N-di-lower alkylcarbamoyl, for example N,N-
dimethylcarbamoyl; thiocarbamoyl; N-lower alkyltnio-
IJ~ f ~
--5--
carbamoyl, foe example ~-methylthiocarbamoyl; N,N-di-lower
alkylthiocarbamoyl, for example N,N-dimethylthiocarbamoyl;
lower alkylsulphonyl, for exa~ple methylsulphonyl or
ethylsulphonyl, arylsulphonyl, for example phenylsul~honyl
or tolylsulphonyl; sulpha~oyl; N-lower alkylsulphamoyl, Eor
example N-methylsulphamoyl; or N,~-di-lower alkylsulphamoyl,
for example N,N-dimethylsulphamoyl.
Ro as lower alkyl is, for example, methyl, ethyl, n-
propyl, n-butyl, tert.-butyl, and n-pentyl, n-hexyl or n-
heptyl~
If Rl represents a partial formula (R~Ro)~~, the
two groups of the partial formula (R)~Ro)N- may, within
the scope of their meanings, be the sa~e or different. Pre-
ferably, one group takes up the 3-position (meta), the
other group the 5-position (meta) and the hydroxy group
takes up the 4-position (~ ) on the phenyl rin~.
R2 in the meaning of "protected carboxyl" is protec-
ted carboxyl that can be readily spli~ or carboxyl that can
be split under physiological conditions, and is esterified
by the groups described below.
R3 as halogen having an atomic number of up to 35
represents fluorine or bromine but especially chlorine.
R3 as lower alkoxy is, for example, ethoxy, n-
propoxy, isopropoxy, n-butoxy, tert.-butoxy, and n-pentyl-
oxy, n-hexyloxy, n-heptyloxy, or especially methoxy.
The functional groups in the compounds of the formula
I, especially the 4-carboxyl, the D-2-amino and the hydroxy
group on the phenyl ring, are optionally protected by pro-
tecting groups that are used in penicillin, cephalosporin
and peptide chemistry.
Such protecting groups can ~e split off readily, that
is to say without undesired side-reactions t~ing place, for
example by solvolysis, reduction, photolysis or alterna-
tively under physiological conditions.
Such protecting groups and the manner in which they
are split off are described, for example, in "Protective
Groups in Organic Chemistry", Plenum Press, Lon~on, New
YoLk, 1973, in "The Peptides", vol. I, Schr'oder and Lubke,
Academic Press, London, New York, 196~, and in "~lethoden ~er
organischen Cnemie", Houben-Weyl, 4th edition, vol. 15/1,
Georg Thieme Verlag, Stuttgart 1974.
Thus, carboxyl groups, for example the carboxyl group
R2, are usually protected in esterified form, such ester
groupings being readily split under mild conditions. Carb-
oxyl groups Qrotected in this manner contain as esterifying
groups especially lower alkyl groups branched in the 1-
pO5 i tion or suitably substituted in the 1- or 2-position.
Preferred carboxyl groups in esterified form are, inter
alia, tert.-lower alkoxycarbonyl, for example tert.-butoxy-
carbonyl; arylmethoxycarbonyl having one or two aryl
radicals that are phenyl radicals optionally mono- or poly-
substituted, for example, by lower alkyl, such ag tert.-
lowe~ alkyl, ~or example tert.-butyl, lower alkoxy, such as
methoxy, hydroxy, halogen, for example chlorine, and/or
nitro: such as benzyloxycarbonyl optionally substituted, for
example as indicated above, for example 4-nitrobenzyloxy-
carbonyl or 4-methoxybenzyloxycarbonyl, or diphenylmethoxy-
carbonyl optionally substituted, for example as indicated
above, for example diphenylmethoxycarbonyl or di-(4-methoxy-
phenyl)-methoxycarbonyl; l-lower alkoxy-lower alkoxy-
carbonyl, such as methoxymethoxycarbonyl, l-methoxyetlloxy-
carbonyl or l-ethoxymethoxycarbonyl; l-lower alkylthio-lower
alkoxycarbonyl, such as l-methylthiomethoxycarbonyl or 1-
ethylthioethoxycarbonyl; aroylmethoxycarbonyl, in which the
aroyl group is benzoyl optionally substituted, for example,
by halogen, such as bromine, for example phenacyloxycar-
bonyl; 2-halo-lower alkoxycarbonyl, for example 2,2,2-tri-
chloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxy-
carbonyl or 2-iodoethoxycarbonyl; or 2-(tri-substituted
silyl)-ethoxycarbonyl, in which each of the subs~ituents
represents, independently of one another, an aliphatic,
araliphatic, cycloaliphatic or aro.matic hydrocarbon r~dical
--7--
having, for example, up to 1~ carbon atoms and being option-
ally su~stituted, for example, by lower alkyl, lower alkoxy,
aryl, haloyen and/or nitro, such as corresponding option~lly
substituted lower alkyl, phenyl-lower alkyl, cycloalkyl or
phenyl: for example 2-tri-lower alkylsilylethoxycarbonyl,
such as 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-
methyl-silyl)-ethoxycarbonyl, or 2-triarylsilylethoxycar-
bonyl, such as 2-triphenylsilylethoxycarbonyl.
~ urther protected carboxyl groups in esterified form
are corresponding silyloxycarbonyl groups, especially
organic silyloxycarbonyl groups, or corresponding stannyl-
oxycarbonyl groups. In these, the silicon or tin atom
contains as substituent preferably lower alkyl, especially
methyl, but also lower alkoxy, for example metho~y, and/or
halogen, for example chlorine. Suitable 5ilyl or stannyl
protectin~ groups are especially tri-lower alkylsilyl, espe-
cially trimethylsilyl, also dimethyl-tert.-butyl-silyl,
lower alkoxy-lower alkyl-halo-silyl, for example methoxy-
methyl chloro-silyl, or di-lower alkyl-halo-silyl, for
example dimethyl-chloro-silyl, or correspo~dingly substitu-
ted stannyl compounds, for example tri-n-butylstannyl.
Preferred protected carboxyl groups are tert.-lower
alkoxycarbonyl, such as tert.-butoxycarbonyl, and especially
benzyloxycarbonyl optionally substituted, for example as
mentioned above, such as 4-nitrobenzyloxycarbonyl, and di-
~henyl~ethoxycarbonyl.
An esterified carboxyl group that can be split under
physiological conditions is especially an acyloxymethoxy-
carbonyl group wherein acyl represents, for example, the
radical of an organic carboxylic acid, especially of an
optionally substituted lower alkanecarboxylic acid, or
r~herein acyloxymethyl forms the radical of a lactone, or
alternatively l-lower alkoxycarbonyloxy-lower alkoxycar-
bonyl, wherein lower alkyl is methyl, propyl, butyl or
especially ethyl. Such groups are lower alkanoyloxy-
methoxycarbonyl, for example acetoxymethoxycarbonyl or
~L~7~'~7~3
--8--
pivaloyloxymethoxycarbonyl, amino-lower alkanoyloxy;nethoxy-
carbonyl, especially a-amino-lower alkanoyloxymethoxy-
carbonyl, for example glycyloxymethoxycarbonyl, L-valyloxy-
met~oxycarbonyl, L-leucyloxymethoxycarbonyl, phthalidyloxy-
carbonyl, for example 2-phthalidyloxycarbonyl, 4-crotono-
lactonyl or ~-butyrolacton-4-yl, indanyloxycarbonyl, for
exa~ple 5-indanyloxycarbonyl, or l-ethoxycarbonyloxyethoxy-
carbonyl.
A protected D-2-amino group may, for example, be in
the form of a readily splittable acylamino, arylmethylamino,
etherified mercaptoamino, 2-acyl-lower alk-l-enylamino,
silylamino or stannylamino group or in the form of an azido
group.
In a corresponding acylamino group, acyl is, for
example, the acyl radical of an organic carboxylic aci~
having, for example, up to 1~ carbon atoms, especially of an
alkanecarboxylic acid optionally substituted, for example,
by halogen or aryl, or o~ a benzoic acid optionally sub-
stituted, for example, by halogen, lower alkoxy or nitro, or
of a carbonic acid semi-ester. Such acyl groups are, for
example, lower alkanQyl, such as formyl, acetyl, or
propionyl; halo-lower alkanoyl, such as 2-haloacetyl, espe-
cially 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro or
2,2,2-trichloroacetyl benzoyl optionally substituted, for
example, by halogen, lower alkoxy or nitro, for example
benzoyl, 4-chloro-, 4-methQxy- or 4-nitrobenzoyl; lower
alkoxycarbonyl branched in the l-position of the lower alkyl
radical or suitably substituted in the 1- or 2-position,
especially tert.-lower alkoxycarbonyl, for example tert.-
butoxycarbonyl; arylmethoxycarbonyl having one or two aryl
radicals that are preferably phenyl optionally mono- or
poly-substituted, for example, by lower alkyl, especially
tert.-lower alkyl, such as tert.-butyl, lower alkoxy, such
as methoxy, hydroxy, halogen, for example chlorine, and/or
nitro: such as optionally substituted benzyloxycarbonyl, for
example 4-nitrobenzyloxycarbonyl, or optionally substitute~
g ~L71~
diphenylmethoxycarbonyl, for example benzhydryloxycar~onyl
or di-(4-m~thoxyphenyl)-methoxycarbonyl; aroylmethoxycar-
bonyl, in which the aroyl group is preferably benzoyl
optionally substituted, for example, by halogen, such as
bromine, for example phenacyloxycarbonyl; 2-halo-lower
alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl,
2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodo-
ethoxycarbonyl; or 2-~tri-substituted silyl)-e~hoxycarbonyl,
in which each of the substituents represents, independently
of one another, an aliphatic, araliphatic, cycloaliphatic or
aromatic hydrocarbon radical having, for exa~ple, up to 1~
carbon atoms and being optionally substituted, for example,
by lower alkyl, lower alkoxy, aryl, halogen or nitro, such
as corresponding optionally substituted lower alkyl, phenyl-
lower alkyl, cycloalkyl or phenyl: for example 2-tri-lower
alkylsilyleth~xycarbonyl, such as 2-trimethylsilylethoxy--
carbonyl or 2-(di-n-butyl-methyl-silyl~-ethoxycarbonyl, or
2-triarylsilylethoxycarbonyl, such as 2-triphenylsilyl-
ethoxycarbonyl.
Further acyl radicals coming into consideration as
amino-protecting groups are corresponding radicals of
organic phosphoric, phosphonic or phosphinic acids, such as
di-lower alkylphosphoryl, for example dimethylphosphoryl,
diethylphosphoryl, di-n-propylphosphoryl or diisopropylphos-
phoryl, dicycloalkylphosphonyl, for example dicyclohexyl-
phosphoryl, optionally substituted diphenylphosphory:L, for
example diphenylphosphoryl, diphenyl-lower alkylphosphoryl
optionally substituted, for example, by nitro, for example
dibenzylphosphoryl or di-4-nitrobenzylphosphoryl, optionally
substituted phenoxyphenylphosphonyl, for example phenoxy-
phenylphosphonyl, di-lower alkylphosphinyl, ~or example
diethylphosphinyl, or optionally substituted diphenylphos-
phinyl, for example diphenylphosphinyl.
In an arylmethylamino group that is a mono-, di-
or especially tri-arylmethylamino group, the aryl radicals
are especially optionally substituted phenyl eadicals. ~u_h
-10- ~ ~7~'~J~
groups are, ~or example, benzyl-, diphenylmethyl- and
especially tritylamino.
An etherified mercapto group in an amlno group pro-
tected by such a radical is especially arylthio or aryl-
lower alkylthio in which aryl is especially pher.yl option-
ally substituted, for example, by lower alkyl, such as
methyl or tert.-butyl, lower alkoxy, such as methoxy,
halogen, such as chlorine, and/or nitro. A corresponding
amino-protectin~ group is, for example, 4-nitrophenylthio.
In a l-acyl-lower alk-l-en-2-yl radical that may be
used as an amino-protecting group, acyl is, for example, the
corresponding radical of a lower alkanecarboxylic acid, of a
benzoic acid optionally substituted, for example, by lower
alkyl, such as methyl or tert.-butyl, lower alkoxy, such as
methoxy, halogen~ such as chlorine, and/or nitro, or
especially of a carbonic ac:id semiester, such as a carbonic
acid lower alkyl semiester~ Corresponding protecting groups
are especially l-lower alk~lnoylprop-l-en-2-yl~ or example
l-acetylprop-l-en-2-yl, or l-lower alkoxycarbonylprop-1-en-2-
yl, for example l-ethoxycarbonylprop-l-~n-2-yl.
A silyl- or stannylamino group is an organ~c silyl- or
stannylamino group in which the silicon or tin atom prefer-
ably contains as substituent lower alkyl, especially methyl,
but also lower alkoxy, for example methoxy, and/or halogen,
for example chlorine. Corresponding silyl or stannyl groups
are especially tri-lower alkylsilyl, especially trimethyl-
silyl, but also dimethyl-tert.-butyl-silyl, lower alkoxy-
lower alkyl-halo-silyl, for example methoxy-methyl-chloro-
silyl or di-lower alkyl-halo~silyl, for example dimethyl-
chloro-silyl, or correspondingly substituted stannylt for
example tri-n-butylstannyl.
An amino group may also be protec~ed in protonated
form; as anions there come into consideration especially
those of strong inorganic acids, such as hydrohalic acids,
for example the chlorine or bromine anion, or of organic
sulphonic acids, such as p-toluenesulphonic acid.
.,.~
,~J,'~3
Preferred amino-protecting groll~s are acyl ra~icals of
carbonic acid semiesters, especially tert.-butoxycarbonyl,
or benzyloxycarbonyl optionally substituted, for example as
indicated, for example 4-nitrobenæyloxycarbonyl, or di-
phenylmethoxycarbonyl, or 2-halo-lower alkoxycarbonyl, such
as 2,2,2-trichloroethoxycarbonyl, or trityl or formyl.
Hydroxy-protecting groups are, for example, acyl
radicals, such as lower alkanoyl optionally substituted, for
example, by halogen, such as 2,2-dichloroacetyl, or
especially the acyl radicals of carbonic acid semiesters
mentioned in connection with a protected amino group, espe-
cially 2,2,2-trichloroethoxycarbonyl, or organic silyl or
stannyl radicals, also etherifying groups that are readily
split off, such as tert.-lower alkyl, for example tert.-
butyl, 2-halo-lower alkyl, for example 2,2,2-trichloro-,
2-chloxo-, 2 bromo- or 2-iodoethyl, 2-oxa- or 2--thia-
aliphatic or -cycloaliphatic hydrocarbon radicals, espe-
cially l-lower alkoxy-lower alkyl or l-lower alkylthio-
lower alkyl, for example methoxymethyl, l~-methoxyethyl, 1-
ethoxyethyl, l-methylthiomethyl, l-methylthioethyl or 1-
ethylthioethyl, or 2-oxa- or 2-thiacycloalkyl having from 5
to 7 ring atoms, for example 2-tetrahydrofuryl or 2-tetra-
hydropyranyl or corresponding thia analogues, and also
optionally substituted l-phenyl-lower alkyl, such as option-
ally substituted benzyl or diphenylmethyl, there coming into
consideration as substituents of the phenyl radicals, for
example, halogen, such as chlorine, lower alkoxy, such as
methoxy, and/or nitro.
Salts of compoun~s of the formula I according to the
invention are especially pharmaceutically acceptable non-
toxic salts, such as those of compounds of the formula I
having acid groups, for example having a free carboxyl or
sulpho group. Such salts are especially metal or ammonium
salts, such as alkali metal and alkaline earth metal salts,
for example sodium, potassium, magnesium or calcium salts,
an~ also ammonium salt; lormed with ammoni~ or suitable
~'7~ 3
-12-
organic amines, wherein especially aliphatic,
cycloaliphatic, cycloaliphatic-aliphatic or araliphatic
primary, secondary or tertiary mono-, di- or polyamines and
also heterocyclic bases come into consideration for the salt
formation, for example lower alkylamines, for example
triethylamine, hydroxy-lower alkylamines, for example 2-
hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tris-(2-
hydroxyethyl)-amine, basic aliphatic esters of carboxylic
acids, for example 4-aminob~nzoic acid 2-diethylaminoethyl
ester, lower alkyleneamines, or example l-ethylpiperidine,
cycloal~ylamines, for example dicyclohexylamine, or
ben~ylamines, for example N,N'-dibenzylethylenediamine, also
bases of the pyridine type, for example pyridine, collidine
or quinoline. Compoun~s oE the formula I having a basic
group can form acid addition salts, for example with
inorganic acids, such ~s hydrochloric acid, sulphuric acid
or phosphoric acid, or with suitable organic carboxylic or
sulphonic acids, for example trifluoroacetic acid, and also
with amino acids, such as arginine and lysine. If several
acid or basic groups are present, mono- or poly-salts may be
formed. Compounds of the formula I having a free acid
group, for example the 4-carboxyl group, and a free basic
group, for example the D-2-amino group, may also be in the
form of internal salts, i.e. in zwitterion form, or one part
of the ~olecule may be in the form of an internal salt and
another may be in the form of a normal salt.
It is also possible to use pharmaceutically unaccept-
able salts for the isolation or purification of compounds of
the formula I. Only pharmaceutically aceptable non-toxic
salts are used therapeutically and these are therefore pre-
ferred.
~ he novel compounds of the formula I, in which the
functional groups are either in free form or the 4-carboxyl
group is optionally in an esterified form that can be split
under physiological conditions, and their pharmaceutically
acceptable non-toxic salts having valuable pharmacological
.
~L~7 !3Z~7a)
-13-
properties.
~ hus, compounds of the Eormula I in free form or in
the form of their salts are effective ln vitro against gram-
positive and gram-negative cocci, for example Staphylococcus
aureus, Stre3tococcus pyogenes or Neisseria spp., in con-
centrations of from approximately O.l to approximately
32 ~g/ml, against gram-negative bacteria, for example
enterobacteria, for example Escherichia coli, Klebsiella
pneumoniae or Proteus s~p., or against Haemophilus
_
influe_zae in concentrations of from 0.5 to approximately o4
~g/ml.
In vivo, when administered perorally or subcutaneously
to mice, compounds (I) are effective against systemic infec-
tions caused by gram-positive cocci, for example
S~aphylococcus aureus, in a dosage range of from approxi-
mately 1.5 to approximately 30 mg~kg and againqt systemic
infections caused by gram-negative bacteria, for example
Escher~chla coli, Proteus mlrabilis or Rlebsiella ~ in
dosage range of rom approximately 1.4 to approxlmately 100
mg/kg, and have a low level of toxicity.
~est evaluation
I. Tested_compounds
~ he antibiotic activity of the following compounds was
tested:
1. 7~-[D-2-amino-~-(3-methylsulphonylamino-4-hydroxy-
phenyl)-acetylamino~-3-methoxyceph-3-em-4-carboxylic acid
(Example la)).
2. 7~-[D-2-amino-2-~3-methylsulphonylamino-4-hydroxy-
phenyl)-acetylamino]-ceph-3-em-4-carboxylic acid (Example
2a)).
3. 7~-[D-2-amino-2-(3-methylsulphonylamino-4-hydroxy-
phenyl)-acetylamino]-3-chloroceph-3-em-4-carboxylic acid
(Example 3a)).
4. 7~-[D-2-amino-2-(3-ethylsulphonylamino-4-hydroxy-
~.7~2~13
--lg--
phenyl)-acetylamino] ceph-3-em-4-carboxylic acid (Example
9a))-
5. 7~-[D-2-amino~2-(3-et~ylsulphonylamino-4-hy~loxy-
phenyl)-acetylamino]-3-chloroce~h-3-em-4-carboxylic acid
~Example lOa)).
6. 7~-[D-2-amino-2-~3-ethylsulphonylamino-4-hydroxy-
phenyl) acetylamino~-3-methoxyceph-3-em-4-carboxylic acid
(Example lla)).
II. Methodol~
A. The antibiotic activity of the test compounds in
vitro was established by the agar dilution method according
to Ericsson, H.~., and Sherris, S.C., 1971, Acta Path.
Microb. Sc~nd. Section ~, Suppl. No. 217, vol. 1-90, in DST
agar. The minimum concentrations still inhibiting growth o~
the test organisms (MIC = minimum inhibiting concentra-
tions) are given in micrograms per millilitre (~g/ml) for
the tested compounds in Table 1.
B. The chemotherapeutic activity ln vivo against systemic
infections in female SPF, MF2 mice was established accord-
ing to the method of 2ak, 00, et al~, 1979, Drugs Exptl.
Clin. Res. 5, 45.59. The ED50 values found in milligrams
substance per kilogram mouse (mg/kg) against a number of
micro-organisms are indicated in Table 2 for the test com-
pounds administered orally (p.o.) or subcutaneously (s.c.).
~8J2
- 15 --
III. Results
Tabl _ ~antibiotic activity in vitro)
_ . _ . . _~
micro organisms MIC [~g/ml]
__ _ _ _
Tested compounds
_ . 1 2 ~ 4 _ S 6
Streptococcus pyro~enes
Aronson 0.1 4 O.S 1 0.5 O.S
~ei~9eria men_nqitidis 1 8 0.5 4 0.1 0.1
Escherichia coli DC20.5 4 0.5 4 2 2
Klebsiella Pneumoniae
. ~ _ _ _ _ 2 4 1 4 1 16
..~
.
- 16
78fX7~3
~ ~D I
. .~
U ~1 0 C ~
r ~ ,i
~ O ~ ~
-- . . I
O ~ ~ ~ O
~_ C
O
't N ~ ~
O ~ ~
U~
_~ O O Ul N
3 ~ N ~ N
O U U ~ ~ .
QU) ~ d c ~
-l O U- N
. I ,~ U~ 1~ N
51 u
.~ U~
_ .
m
:~ ~ ~
~ V~
c ou ~ k
,~ ,~ ,~ Q~ ~::
~1 u u~ ~ o l
E~
13 7B~
The novel compound~ of the formula I can therefore
be used accordingly, for example in the ~orm of anti-
biotically active preparations, for the treatment of
infections caused by gram-positive or gram-negakive
bacteria.
Compounds of the formula I in which the functional
groups are protected are used as intermediate~ for the
manufacture of compounds of the formula I in which the
functional groups are in fr~e form.
The invention relates preferably to those compounds
of the formula I in which functional group~ are in free
form or in which the 4-carbox~l group is protected in
a form that can be s~lit u~der physiological cond:itions
and to the pharmaceutically acceptable 5alt9 thereof,
since it i9 primarily these oompounds that have the
specified activity and can be used ~or the purpo~e indica~
ted.
Prominence should be ~iven to compounds of the
formula I in which
the index n represents 0,
R represents hydrogen or an acyl group,
for example lower alkanoyl, halo-lower
alkanoyl; benzoyl optionally ~ub~tituted
by halogen, lower alkoxy or nitro, tert.-
lower alkoxycarbonyl; arylmethoxycarbonyl
having one or two aryl radical~ that are
phenyl radicals optionally mono- or
polysubstituted by lower alkyl, lower
alkoxy, hydroxy, halogen and/or nitro;
aroylmethoxycarbonyl in which the
aroyl group is benzoyl optionally
substituted by halogen: 2-halo-lower
al~oxycar~onyl, carbamoyl, N-lower
alkylcarbamoyl, ~ di-lower alkyl-
carbamoyl; thiocarbamoyl; N-lower
alXylthiocarbamoyl ~,~-di-lower alkyl-
thiocarbamoyl, lower alkylsulphonyl;
- 18 -
aryl~ulphonyl, ~ulphamoyl, ~-lower
alkyl~ulphamoyl, or ~,~-di-lower
al~yl~ulpha~oyl,
~0 repre~nt~ hydrogen or low~r alkyl,
Rl repr~e~t~ hydro~en or a group o the
partial ~ormula (R)(Ro)~7-, in which R
and ~0 hav~ the m~aning~ yiven above,
R~ repre~entJ carboxyl or lower alka~oyl-
m~thoxycarbonyl, ~nd
R3 represent~ hydrog2n, fluorine, chlorine,
~romine, methoxy, ethoxy, i~opropoxy or
t~rt.-butoxy,
and hydrate~ and ~alt~ o~ ~ompound3 (I), e~pecially
pharmaceutically acceptable ~alts of compounds of the
formula I.
Special pro~inence ~hould b~ givon to compounds
of the fonnula I in which
the ind~x n repr~sent~ O,
R repre~ents hydrogen; lower alkanoyl ha~ing
up to 4 c~rbon atom~, ~or example ~oxmyl,
acetyl or propionyl, halo~lower alkanoyl
having up to 4 carbon ato~, ~or ~xample
2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-
tri~luoro- or 2,2,2-trichloroac~tyl,
benzoyl optionally ~ub~tituted by halog~n,
low~r alXoxy, for example methoxy, or
nitro, for example 4-chlorobenzoyl,
4-methoxybenzoyl or 4-nitro~enzoyl:
tert.-lowor alXoxycarbonyl, for example
tert.-butoxycarbonyl, ~enzyloxycarbonyl
optionally sub~tituted by nitro, for
example benzyloxycarbonyl or 4-nitro-
ben7.yloxycar~onyl, diphenyl~ethoxy-
carbonyl optionally ~ub3tituted by
lower alkoxy, for ~xample methoxy, for
example bsnzhydryloxycarbonyl or bi~-
..,
-- 19 -
(4-methoxyphenyl~-methoxycarbonyl;
phe~acyloxycarbonyl, 2-halo-lower alkoxy-
carbonyl having up to 4 carbon atoms,
for exa~ple 2,2,2-trichloro-, 2-chloro-,
2-bromo- or 2 iodoeth~xycarbonyl, carba-
moyl; N-lower alkyLcarbamoyl, ~or example
~-methylcarbamoyl, N,~-di-lower alkyl-
carbamoyl, for oxample ~,X-dimethyl-
carbamoyl: thiocarba~oyl, ~-lower alkyl-
thiocarbamoyl, ~or example ~-methylthio-
carbamoyl, ~ i-lower alkylthiocarbamoyl,
for exa~ple ~ dimethylthiocarba~loyl:
low~r alkyl~ulphonyl, for example m~hyl-
~ulphonyl or eth~l~ulpho~yl, aryI~ulphonyl,
~or example phenyl~ulphonyl or tolyl-
~ulphonyl, ~ulphamoyl, ~-lower alkyl-
aulphamoyl, ~or example ~-methyl3~1phamoyl,
or ~ lower alkyl~ulphamoyl, for
example N,~-dimethylsulphamoyl,
Ro repre~ent~ hydrogen or lower alkyl, for
example methyl or ethyl,
Rl represents hydrogen or a group o~ the
partial formula ~R)~Ro)~~, in which
R and Ro have th~ meanings yiven above,
R2 represent~ carboxyl, and
R3 represent~ hydrog~n, chlorine or methoxy,
and hydrate~ and salt of compound~ (I), especially pharma-
ceutically acceptable salts of compound~ of the formula
I.
The invention relate~ especially to compouncl3 of
the formula I in which
the index n represents 0,
R represent~ hydrogen, lower alkanoyl
having up to 4 carbon atoms, for exampl~
acetyl, lower alkylsulphonyl having up
to 4 carbon atom~, for example ~ethyl-
~ulphonyl or ethylsulphonyl,
~7~
- 20 -
Ro represent~ hydrogen,
Rl represents hydrogen or a group o~ the
partial formula (R)(Ro)~~ in which R
and Ro have the meanings given above,
R2 r~preJents carboxyl, an~
R3 represents hydrogen, chlorine or rnethoxy,
and salt~ o~ ~uch com~ounds, esp~cially pharmaceuti~ally
acceptable ~alts of co~pounds o~ the formula I.
The invention relates more especially to co~pound~
o the formula I in which
the index n represents 0,
repre~ent~ hydrog2n, lower alkanoyl having
up to 4 carbon atoms, for example ac~tyl,
lower alkyl~ulphonyl havi~g up to 4
carbon atoms, ~or example methyljulphonyl
or ethylsulphonyl,
Ro r~pre~ents hydrogen,
Rl repr~sent~ hydrogen or a group of the
partial ~ormula (R)~Ro~N- ~n w~ich R and
Ro have the maanings given above,
R2 repre~ent~ carboxyl, and
R3 represents hydrogen, chlorine or methoxy,
and in which the two group~ of the partial formula
~)(Ro)~~ take up the 3 and 5-position (meta) and the
hydroxy group taXes up the 4-position ~ ) on the phenyl
ring,
and hydrate~ and salts of such compounds, especially
pharmaceutically acceptable ~alt~ of compound~ of the
formula I.
Of all the compounds to which the invention relates,
special mention should be made of the compound~ of the
formula I described in the Examples and also of the
salts, especially the pharmaceutically acceptable salts,
of such compounds having salt-forming groups.
The compounds of the formula I of the present
invention are obtained according to processes Xnown
er _.
7~3
- 21 -
Compounds of the ormula I and hydrates and salts
of such compounds that have a salt-forming group are
manufactured, for example by
a) in a compound of the ~ormula
(~)n
H / S
i=N I_R3 ~II)
0~ \ ~
in which the index n represents O or 1 and the 7~-amino
group i~ optionally protected by a group allowing acylation,
and R~ and R3 have the meanings given under formula I,
acylating the 7~-amino group by reaction with an acylating
agent that introduces the acyl radical of a carboxylic
acid of the formula
(R)(Ro)N
CH~C-OH (III),
~ .=~ ~ ~ 2
in which R, Ro and R1 have the meanings given under
formula I and in which the hydroxy group on the phenyl
ring and/or the amino group(~) are optionally in
- 22 -
protected form and other functional group~ pre~ent are
optionally protected, or
b) i30merising a 2-cephem compound of the formula
(R)(~o)~
o S
~ C~ = < \~ (IV),
R2
in which R, Ro, Rl, R2 and R3
under ~ormula I and in which the hydroxy group on the
phenyl ring and/or the amino group~s) are optionaLly
in protected ~orm and other ~unctional group~ present
are optionally prot~cted, or
c) in a compound of the ormula
~2 ~)n
o S'
. ~ ~ . _ C~ N _ . / \.
OH Rl ~ 2 ~ R3 (V),
i
R2
,.
~i7B'~7~
- 23
in which the index n reprosent~ 0 or 1 and Rl represents
nitro or the radical Rl which has the meanings given
under ormula I, R~ and R3 have the meanings given
under formula I and in which the hyd:roxy group on the
phenyl ring and/or the amino group(s) are optionally
in protected form and other function,al yroups present
are sptiona}ly protected, reducing t'he nitro group(s)
on the phenyl ring by reaction with an agent that
converts nitro group~ into amino groups,
and, if de~ired, in a resulting rompound converting a
free amino group of the partial formula (R)(Ro)N- in
which ~ and Ro represent hydrogen into a substituted
amino group and/or, i de~ired, converting a resulting
compound in which n repre~enta 0 into a compound in
which n represents 1 and/or convertiny a re~ulting com-
pound ln which n represent~ 1 into a compound in which
n r~present~ 0 and/or convertin~ functional group~
pre3ent in protected form in a r~sulting co~pound into
the free functional group and/or co~verting a resulting
salt into the free compound or into a different salt
and/or converting a resulting compound having a salt-
forming group into a ~alt and/or separating a resulting
mixture of isomeri~ compounds into the individual isomers.
Proces~ a~ (Acylation):
In ~he ~tartinq'material of the formula II, the
4-carboxyl group may be protected prefera~ly in e~terified
form, for example as described above, especially in the
form of a ~ilyl e~ter, 3uch as a trimethylsilyl ester,
whi~h is generally formed immediately before the acylation
reaction by treatment with a correspon~ing silylating
agent, for example trimethylchlorosilane or N,o-bis-
(trimethylsilyl)-acetamide. The carboxylic acid starting
material of the-formula II may, however, al~o be used
in salt form, for example in ammonium salt form, such as
~7~13
- 24 -
in the form of a triethylammonium ~alt, or in protected
form, which can be obtained by rea~ting the carboxylic
acid starting material II with a suitabLe organic
phosphorus halide compound, ~uch a~ with a lower alXyl-
or lower alkoxypho~phoru~ dihalide, such as methyl-
phosphoru~ dichloride, ethylpho~phoru~ dibromide or
methoxxpho~phoru~ dichloride. Starting materials of the
formula II in which the ~-amino group i~ protected by
a group allowing the acylation reaction are protected,
for sxample, by a ~ilyl radical, such as one of the
~ilyl xadical~ mentioned a~ove.
Other group~ by which the 7~-amino group may
be protecte~ in reactive form are tha carbonyl group
- ~ C=O~- and optionally l-~ubstituted l-halo- or l-alXoxy-
mathylen~ group~. In such methylene group~, haloqen
i3 bromine or especially chlorine and al~oxy i8 especially
optionally ~ubstituted lowar alkoxy, ~uch as ethoxy,
propoxy, butoxy or pr~ferably m~thoxy. The optionally
pre3ent other ~ub~tituent in the l-po~ition o~ ~uch a
methylene group i9 any organic radical that i9 ~terically
hindered only slightly, ~or exampl~ optionally ~ub~tituted
lower alkyl, 3uch as methyl, 4-amino-4-carboxybutyl,
in which the amino group and the car~oxy group may be
protected, be~zyl, phenoxymethyl, thienylmethyl or
alternatively furylm~thyl, ~uch a~ 2-thienyl- or 2-
~urylmethyl.
In an acyl radical of an acid of the formula III,
the D-2-amino group is optionally protected by customary
amino-protecting groups or alternatively in ionic form,
i.e. the ~tarting material of the formula III having
the D- -amino group may alternatively be used in the form
of an acid addition 3alt, preferably with a strong
inorganic acid, such a~ a hydrohalic acid, far example
hydrochloric acid, or the D-2-amino group is optionally
protected in ma~ked form, for example in the form of an
azido group.
8~7~1~
- ~5 -
In a ~tarting material of the formula III, the
hydrogen Ro in ~ub~tituted amino groups of the partial
formula (R)(Ro)M~ in which R repre~ents an acyl group
and Ro represents hydrog~n is optionally replaced by a
further acyl group.
The hydroxy group on the phenyl ring i~ optionally
protected by one of the customary hydroxy-protecting
groups mentioned a~ove.
Free amino group~ Am present on the phenyl ring
are optionally protected ~y the customary amino-protecting
gr~up described above.
Acylating agents introducing the acyl radical of
~ carboxylic acid of the formula III are, for ex~nple,
the carboxylic acid itself or it~ reactlve functional
derivatives .
If there is u~ed ~or acylation a carboxylic acid
of the fonmula III, in w~ich functional group~ present,
apart ~rom the 4-carboxyl group participatin~ in the
reaction, may be protected, the reaction i~ normally
carried out in the pre~ence of ~uitable conden~ation
agent-~, s~ch as carbodiimides, for example ~ diethyl-,
N,N'-dipropyl-, N,~'-dicyclohexyl- or ~-ethyl-~' 3-
dimethylaminopropylcarbodiimide, suitable carbonyl
compound3, for example carbonyldiimidazole, or 1,2-
oxazolium compound~, such a~ 2-ethyl-5-phenyl-1,2-
oxazolium 3'-~ulphonate or 2-tert.-butyl-5-methyl-1,2-
oxazolium perchlorate, or a ~uitable acylamino compound,
for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-
quinoline~
The co~den~ation reaction is preferably carried
out in an anhydrou~ reaction medium, prefera~ly in the
pre~ence of a solvent or diluent, for example methylene
chloride, dimethylformamide, acetonitrile or tetrahydro-
furan, if desired or neces~ary w~ile cooling or heating,
for exa~ple in a temperature range of ~rom approximately
-40C to approximately +100C, preerably from approximatel~
. .
~ 3 7~'~J'7''~
-20C to approximately i50C and/or in an inert gas
atmosphere, for exampla a nitrogen atmosphere.
A reactive ~unctional derivative of a carboxylic
acid of th~ form~la III, in which functional group~
pre3ent, apart from the carboxyl group participating
in the reaction, may be protected, i~ especially an
anhydride of ~uch an acid, including and preferably
a mixed anbydride. Mixed anhydrides are, for example,
tho~e with inorganic acids, such as hydrohalic acids,
i.~. the corre~ponding acid halides, for example
chlorides or bromides, al~o with hydrazoic acid~ i.e4
the corresponding acid azide~, with a phosphoru~-
containing acid, for example pho3phoric acid, diethyl-
phosphoric acid or phosphorousacid, or with a sulphur-
containing acid, for example ~ulphuric acid, or with
hydrocyanic acid. Other mixed anhydrides are, ~or
example, ~ho~e with ~rganic carboxylic acids, ~uch a3
with lower al~anecarboxylic acids optionally su~titute~,
for example, by halogen, ~uch as fluorine or chlorine,
for example pivali~ acid or trichloroacetic acid, or with
~emiester~, e~pecially lower alkyl semiasters of carbonic
acid, such a~ the ethyl or isobutyl semiester of carbonic
acid, or with organic, especially aliphatic or aromatic,
~u~phonic acids, for example ~-toluenesulphonic acid.
Other derivatives, suitable for reaction with the
amino group, of an acid o~ the formula III, in which
functional groups present, apart from the carboxyl group
participating in the reaction, may be protected, are
activated esters, such as esters with vinylogous alcohols,
i.e. with enol~, such as vinylogous lower alkenols,
or intinomethyl ester halides, such a~ dimethyliminomethyl
ester chloride, manufactured from the carboxylic acid
of the form~la III and, for example, dimethyl~ chloro-
ethylidene)-iminium chloride of the formula
~CH3~2 ~=C(Cl)CH3Cl~ which can be obtained, for example,
- 27 -
from N,~-dimethylacetamide and phosgene, aryl esters,
for example phenyl e~ters substituted, for example, by
halogen, such a~ chlorine, and/or nit.ro, for example
4-nitrophenyl, 2,3-dinitrophenyl or pentachlorophe~yl
e~ter, N-heteroaromatic esters, such as ~-benztriazole
e~ter~, for example l-benztriazole ester, or M-diacylimino
esters, ~uch as N-succinylimino or ~-phthalylimino
e~ter~
The acylation wîth a reactive functional
derivative Q~ an acid of the ormula III, such as a
corre~ponding anhydride, especially an acid halide,
is pre~erably carried out in the presence o~ an acid-
binding agent, ~or example an organic ha~e, such a~
a~ organic amine, for exa~ple a tertiary amina, such
a~ tri-lower alkyl~mine, for example trimethylamine,
triethylamine or ethyldiisopropylamine, or N,N di-lower
alkylanillne, for exa~ple ~,N-dimethylaniline, or a
cyclic tertiary amine, such a~ an ~-lower alkylated
morpholine, such as ~-methylmorp~oline, or a base of
the pyridi~e type, ~or example pyridine, an inorganic
base, ~or example an alkali metal or alkaline earth
metal hydroxide, carbonate or bicarbonate, for example
~odium, potas~ium or calcium hydroxide, car~onate or
bicarbonate, or an oxirane, for example a 1,2-lower
al~ylene oxide, such as ethylene oxide or propylene
oxide.
The above acylations are prPferably carried out
in an inert, preferably anhydrou3, 301Yent or solvent
mixture, for example in a carboxylic acid amide, such
a~ a formamide, for example dimethylfonmamide, a
halogenated hydrocarbon, for example methylene chloride,
carbon tetrachloride or chlorobenzene, a ~cetone, for
example acetone, an ester, for example e~hyl acetate,
or a nitrile, for example acetonitrile, or a mixture
Y3
-- 2~ --
thereof, i nece~ary or de~irPd at reduced or elevated
temperature, for example in a temperature ran~e of from
approximately -40C to approximately ~100C, preferably
from approximately -10C to approximately +50C, and/or
in an inert ~as atmo~phere, for exampl~ a nitrogen
atmo3phere.
The acylation can al~o be carr:ied out by u~ing
a ~uitable derivative of the acid of the formula III
in the pre~ence of a suitable acylase. Such acylases
are know~ and can be formed by a num~er of micro-organism~,
for example by P~udomona~ E~L_ um ATCC 17 808 or
by numerou~ other acylating ~trains, ~uch a~ xanthomona~,
acetobacter, for example ~5~5~ E ~Y~
achromobacter, for example aS~5~2~ E ~ B~ æ ~hea
~, ~9~ urea, ~2a5~ 3~nati9,
ocardia g~s~ b~ or bacillus, for example B~acil:Lu~
~ oO. In an enzymatic acylation of thi~ type
thare are u~ed as corresponding derivatives especially
~mide~, e~ters or thioester~, such as lower alkyl e~ters,
for example methyl or ethyl ester, of the carboxylic acid
o~ the formula III. Acylation of thi~ type i5 generally
carried out in a nutrient medium containing the corres-
ponding micro-organism, in a filtrate of the culture
broth or, optionally after isolation of the acylase,
including after adsorption on a carrier, in an aqueous
medium optionally containing a buffer, for example in
a temperature ran~e of from approximately ~20C to
approxima ely ~0C, preferably at approximately 37C.
A reactive functional derivative of an acid of
the formula III used in the acylation reaction may, if
de3ired, be formed in itu. ~hus, for example, a mixed
anhydride can be manufactured by reacting an acid of
the formula III, optionally having appropriately protected
functional groups, or a ~uitable salt thereof, for
example an ammonium salt, which i9 formed, for example,
- 29 -
with an organic base, such as pyridine or 4-methyl-
morpholine, or a metal salt, for example an alkali
metal salt, with a suitable acid derivative, ~uch as
a corresponding acid halide of an optionally substituted
lower alkanecarboxylic acid, for example trichloroacetyl
chloride, with an e~ter of a carbonic acid semihalide,
for exampLe chloroformic acid ethyl ester or isobuty}
ester, or wi~h a halide of a di-lower alXylphosphoric
acid, for example diethyl phosphoro~romidate, which can
be formed by reacting triethyl phosphite with bromine,
and the mixed anhydride so obtained is used without
isolation in the acylation reaction.
If a racemic mixture of a ~taxting material of
the fonmula III i~ u~ed in the acylation, a racemi.c
mixture of a compound of the formula I i9 obtainecl.
This can be su~seqùently separated into the desir~d
D- and L- configuration antipodes by the cu~tomary
method3 de3cribed in the literature or the separation
o~ racemic mixtures. The D~configuration antipodes o~
a star~ing material of the formula III are, howe~er
preferably used in the acylation~
Process-b~ g~U~ ~E~ee):
In a 2-cephem starting material of the formula IV,
the optionally protected carboxyl group R2 in the 4-
position i~ preferably in the a-configuration.
2-cephem compounds of the formula IV can be iso-
merised ~y treatm0nt with a weakly basic agent and
i~olating the corresponding 3-cephem compound. Suitable
isomerising agents are, for example, organic nitrogen-
containing bases, especially tertiary heterocyclic bases
of aromatic character, especially bases of the pyridine
type, such as pyridine itself, and picolines, collidines
or lutidines, also quinoline, tertiary aromatic bases,
for example those of the aniline type, such as N,~-di-
lower alkylanilines, for example ~ dimethylaniline or
`7~
- 30 -
N,~-diethylaniline, or tertiary aliphatic, azacyclo-
aliphatic or araliphatic ba~es, such as ~,~,N-tri-lower
alXylamine~, for example ~,N,~-trimethylamine or ~
diisopropyl-N-ethylamine, ~-lowex alkylazacycloalkane~,
for example ~-methylpipexidine, or ~--phenyl-lower alXyl-
~,~-di-lower alkylamines, for e~ample N-benzyl-N,M-
dimethylamine, and mixtures of such basic agents,
such a~ the mixture of a base of the pyridine type
and an ~,N,~-tri-lower alkylamine, for example pyridine
and triet~ylamine. Furthermore, inorganic or organic
9alt8 of bases, especially of medium-~trength to strong
bases with weak acids, such a5 ~lkali metal salt~ or
ammonium salts of lower al~anecarboxylic acids, for
example sodium acetate, triethylammonium acetate or
~-methylpiperidine acetate, and other analogou3 b,asas
or mixtures o~ such basic agents can al~o be u~ed.
~ ha i~meri~atio~ of 2-cephem campound~ o the
formula IV with basic agents is preferably carried out
in an anhydro~-~ medium, in the presence or absence of
a 901vent, such a~ an optionally halogenated, for example
chlorinated, aliphatic, cycloaliphatic or aromatic
hydrocar~on, or a solvent mixture, it being possible
for the ba~es u~ed as reagents w~ich are liquid under
the reaction conditions to sexve, at the same time,
a~ ~olvents, optionally while cooling or while heating,
preferably in a temperature range of from approximately
-30C to approximately ~100C, in an inert gas atmosphere,
for example a nitrogen atmosphere, and/or in a closed
vessel .
The 3-cephem compound~ of the formula I obtainable
in this ~anner can be separated from the 2-cephem
compounds which may ~till be present in a manner known
se, for example by adsorption and/or crystallisation.
The isomerisation of 2-cephem compounds of the
formula IV to form the corresponding 3-cephem com~ounds
~ ~;lL 7~ r ~3
- 31 -
is preferably carried out by oxidising these ~n the
l-position, if desired, separating the isomeric mixture~
o~ the l-oxides formed, and reducing the l-oxides of the
correspondin~ 3-cephem compounds obtained in thi~ manner.
There come into consideration as suitable oxidi~ing
agents for the oxidation in the l-po~ition of 2-cephem
compounds of the formula IV, inorganic peracid~ that have
a reduction potential of at least +1.5 volts and comprise
non-metallic elements, organic peracids or mixtures
consi~ting o hydrogen peroxide and acids, especially
organic carboxylic acid~, having a dissociation constant
of at leas~ 1~ 5. Suitable inorganic peracid~ are
periodic acid and persulphuric acid. Organic peracids
are corre~ponding percarboxylic and per~ulphonic acids
which are added as ~uch or may be formed in itu~by
u~ing at least one equivalant of hydrog~n peroxide and
a carboxylic acid. In thi~ ca~e, it iA expedient to
u~e a large Qxce~s o~ the carboxylic acid i, for
ex~mple, acetic acid i3 used as solvent. Su~table
peracids are, for example, performic acid, peracetic
acid, trifluoroperacetic acid, permaleic acid, perbenzoic
acid, 3-~hloroperbenzoic acid, monoperpht~alic acid or
~-tolueneper~3ulphonic acid.
~ he oxidation can likewi~e be effected usin~
hydrogen peroxide with catalytic quantitie~ af an acid
having a dissociation conqtant of at l~ast lO 5, it
being pos3ible to use low concentration~, for example
1-2 % and below, or alternatively relatively large
amounts of the acid. In this case, the effectivenes~
of the mixture depends primarily on the strength of the
acid. Suitable mixture~ are, for example, those of
hydrogen peroxide with acetic acid, perchloric acid or
trifluoroacetic acid.
The foregoing oxidation may be carried out in
the pres~nce of ~uitable catalysts. ThU5, for example,
- 32 -
the oxidation with percar~oxylic a~ids can be catalysed
by the presence of an acid having a dissocation con-
stant of at least 10 5, the effectivenes~ of this acid
being dependent on its strength~ Acid~ ~uitable as
catalyst~ are, for example, acetic acid, perchloric
acid and trifluoroacetic acid. Usually, at 1east equi-
molar amounts of the oxidi~ing agent, and prefera~ly
a ~light excess of from approximately 10 % to approxi-
mately 20 %, are u~ed, it alternatively being possibl0
to u~e relatively large excesses, i.e. up to 10 times
the amount or more of the oxidising agent. The oxida-
tion is carried out under mild conditions, for example
at temperatures of from approximately -50C to approxi-
mately ~100C, pre~erably ~rom approximately -10C to
approximately +40C.
The reduction o~ the l-oxide~ o 3-cephem compounds
~an be carried out .in a manner Xnown ~ se ~y tre3tment
with a reducing agent, if nece~ary in tha presence of
an activating agent. There come into onsideration as
reducin~ agents, for exampleo catalytically activated
hydxoge~, thexe being used noble metal catalysts that
contain, for example, palladium, platinum or rhodium
and whic~ axe aptionally employed together with a
suitable carrier material, ~uch as carbon or barium
sulphate, reducing tin, iron, copper or manganese ca~ions,
which are used in the form of corresponding compo~mds
or complexes of an inorganic or organic kind, for example,
in the form of tin(II~ chloride, fluoride, acetate or
formate, iron(II) chloride, sulphate, oxalate or
succinate, copper(I~ chloride, benzoate or oxide, or
manganese~II) chloride, sulphate, acetate or oxide,
or in the form of complexe~, for example with ethylene-
diaminetetraacetic acid or nitrolotriacetic acid,
reducing dithionite, iodide or iron(II) cyanide ~nion~,
which are u~ed in the form of corresponding inorganic
0
or organic salt~, such a~ alkali metal dithionite,
iodide or iron(II) cyanide, for example ~odium or
potassium dithionite, sodium or pota~3iurn iodide or
30dium or pota~sium iron(II) cyanide, or in the form of
the corresponding acid~, such as hydriodic acid, reducing
trivalent inorganic or organic phosphoru~ compounds,
such as phosp~ines, also esters, amicles and halides of
phosphinou3, phosphorous or phosphonous acid, and also
phosphoru~-sulphur compounds corresponding to the~e
phosphorus-oxygen compounds, in which organic radicals
are especially aliphatic, aromatic or araliphatic radicals,
for example optionally sub~tituted lower alkyl, phenyl
or phenyl-lower alXyl group~, such as, for example, tri-
ph~nylphosphine, tri-n~butylphosphine, diphenylpho~phinous
acid methyl ester, diphenylchlorophosphine, phenyldichloFo-
pho3phine, benzenephosphonous acid dimethyl ester,
~utanepho~phonous aci~ methyl ester, phosphorous ~cid
triphenyl ester, phosphorou~ acid trimethyl e~ter,
phosphoru~ trichloride, pho~phorus tribromide, etc.,
reducing halosilane compounds that have at least one
hydrogen atom bonded to the ~ilicon atom and which may
contain, apart ~rom halogen, such as chlorine, bromine
or iodine, al~o organic radicals, such as aliphatic or
aromatic groups, for example optionally 3ubstituted lower
alkyl or phenyl groups, such as chlorosilane, bromo-
silane, di~; or trichlorosilane, di- or tribromosilane,
diphenylchlorosilane, or dimethylchlorosilane, or
alternatively halo~ilane compound~ in which a}l the
hydrogen atoms are replaced by organic radical~, such
as a tri-lower alkylhalo~ilane, for example trimethyl~
chloro~ilane or trimethyliodosilane, or cyclic sulphur-
containing silane~, such as 1,3-dithia-2,4-disilacyclo-
butanes or 1,3,5-trithia-2,4,6-trisilacyclohexanes,
of which the silicon atoms are substituted by hydrocarbon
radicals, such as especially lower al~yl radicals, for
example 2,2,4,4-tetramethyl-1,3-dithia-2,4-di~ilacyclo-
- 3~ -
butane or 2,2,4,4,6,6-hexamethyL-1,3,5-trithia-2,4,6-
trisilacyclohexane, etc., reducing quaternary chloro-
methyleneiminium salts, especially chlorides or bromides,
in which the iminium group is substituted by one bivalent
or two monovalent organic radicals, such as optionally
substituted lower alkylene or lower alkyl groups, such
as ~-chloromethylene-~,~-diethyliminium chloride or
~-chloromethylenepyrrolidinium chloride, and complex
metal hydrides, such as sodium ~orohydride, in the
presence of suitable activating agents, ~uch as cobalt(II)
chloride, and also borane dichloride.
As activating agents which are used togethe:r with
those of the above-mentioned reducing agant~ that do
not them~elves have the properties of Lewis acids, i.e.
especially together with the dithionite, iodide or
iron(II~ cyanide reducing agents and the triv~lent
phosphorus reducing agents that do not contain halogen,
or ar.e u~ed in the catalytic reduction, there may be
mentioned especially organic carboxylic and ~ulphonic
acid halide~, but alqo sulphur, pho~phorus or silicon
halide.~ having a second order hydrolysis con~tant which
is the same as or greater than that of benzoyl chloride,
fo~ example phosgene, oxalyl chloride, acetyl chloride
or ~romide, chloroacetic acid chloride, pivaloyl chloride,
4-methoxybenzoyl chloride, 4-cyanoben20yl chloride,
~-toluanesulphonyl chloride, methanesulphonyl chloride,
thionyl chloride, pho~phorus oxychloride, phosphorus
trichloride, phosphorus tribromide, phenyldichloro-
phosphine, benzenephosphonous acid dichloride, dimethyl-
chlorosilane or trichlorosilane, also ~uitable acid
anhydrides, such as trifluoroacetic acid anhydride, or
cyclic sultones, such as ethanesultone, propanesultone,
1,3-butanesultone or 1,3 hexanesultone.
The reduction is carried out preferably in the
presence of solvents or mixtures thereof, the choice
of which is determined primarily ~y the solu~ility of
2~
the starting material~ and by the chosen reducing agent,
thu~, for exa~ple, lower alkanecarboxylic acids or
esters thereof, such a~ acetic acid and ethyl acetate,
in the ca~e of catalytic reduction, and, for example,
aliphatic, cycloaliphatic, aromatic or araliphatic
hydrocarbons, optionally substituted by halogen or nitro,
for example benzene, methylene chloride, chloroform
or nitromethane, suitable acid derivative~, such as
lower alkanecar~oxylic acid esters or nitriles, for
example ethyl acetate or acetonitrile, or amide~ Gf
inorganic or organic acids, for exampla dimethylformamide
or hexamethylphosphoramide, ethers, for example diethyl
ether, tetrahydrofuran or dioxan, Xetone~, for example
acetone, or sulphones, especially aliphatic ~u~phones,
for example dimethyl~ulphone or tetramethylene~ulE~hone,
etc., together with the chemical reducing agent~, the~e
solvents preferably containing no ~ater. The reaction
is usually carried out at temperature~ of from approxi-
mately -20C to approximately 100C, it being possible,
when u~ing very reactive activating agents, to carry
out the reaction at lower temperatures.
If a racemic mixture of a starting material of
the formula IV is used in the isomerisation, a racemic
mixture of a compound of the formula I i5 obtainad.
This can be subsequently separated into the desired
D- and L-~on~iguration antipodes by the customary methods
de~cribed in the literature for the separation of racemic
mixtures.
The D-configuration antipodes of a starting
material of the formula IV are, however, preferably
used in the isomerisation.
Process c? (Red~ t tro qr~Q~l
In a compound of the formula V in which the D-2
amino group, tha hydroxy group on the phanyl ring and
the 4-carboxyl group are optionally in prote~ted form,
,
- 36 -
the aromatic nitro yroup(s) on the phenyl ring i~(are)
reduced by reaction with a suitable agent that converts
nitro groups into amino groups.
Suitable agents that convert ni.tro groups on the
phenyl ring into amino group~ are cu~tomary reducing
agents which are u~ed optionally in the presence of a
catalyst and/or a suitable carrier material.
As customary reducing agents there come into
consideration especially: catalytically activated hydxogen,
there being used as hydrogenation catalysts, for example,
noble metals, for example palladium, platinum or rhodium,
the~e being used optionally with a suitable carrier
material, ~uch a~ carbon, barium sulphate or carbonate
or calci~n carbonate, reducing tin~II) or iron~II)
cations which are used preferably in the form of their
chlorides, the latter al~o in the form of their sulphates,
reducing dithionite or sulphite anions which are used
as inorganic salts, for example with alkali metal
cations, in the form of alXali metal ~alt~, ~or example
~odium dithionite or sodium sulphite, or alkali metal
hydrogen calts, for example sodium bisulphite, non-
noble metals, for example iron, tin, zinc or aluminium
which are used optionally in the presence of their
corresponding metal salt~ or with other neutral salt~,
for example calcium, magnesium, potassium or sodil~n
chloride, al80 sulphides, for example hydrogen sulphide,
di- or polysulphides, for example sodium disulphide
or sodium polysulphide, alkali metal sulphide or
alXali metal bisulphide, for example sodium sulphide
or sodium bisulphide, ammonium sulphide or ammonium
polysulphide, hydro~en-yielding agent~, for example
sub~tituted or un~ubstituted hydrazine, for example
phenylhydrazine which iq used optionaLly in the form
of it~ acid addition ~alt, or molecular hydrogen which
i released by electrolytic reduction at the cathode.
The reduction with catalytically activated hydrogen
i5 carried out at normal pressure or moderately elevated
pressure up to approximately 5 atmospheres gauge.
The reduction with zinc, aluminium, tin or tin(II)
ions generally take~ place in acidic solution, for
example in a hydrochloric acid solution. If iron(II)
cations are used as the reducing agent, the operation
i~ generally carried out under slightly basic conditions.
In that cas , any soluble iron(II) salt, for example
iron(II) sulphate, i9 added to the reaction mixture
whereupon the reducing iron(II) hydroxide precipitates
out. The reduction with elementary iron, which may be
added, for example, in the form of iron powder, generally
takes place under slightly acidic conditions, for
example under hydrochloric acid condition~,or under
neutral conditions. In the latter case, salts, for
example iron(II) chloride, lron(II) sulphate, iron(III)
chloride, calcium ch}oride, magnesium chloride, potas~ium
chloride or sodium chloride, are also added for the
purpose o activation.
The reductions with dithionite anion are normally
carried out with dithionite anions in a neutral or
sligh~ly alkaline medium which i~ produced, for example,
by adding tertiary aromatic bases, for example pyridine.
The reduction3 with .sulphite anions take place in a
slightiy acidic medium, for example in an ace ic acid
medium, or in a neutral medium.
The reduction with 3ulphides may be carried out
in a slightly acidic medium, for axample in an acetic
acid medium, or in a neutral or slightly basic aqueous
medium which is produced during the reduction with
hydrogen sulphide in the presence of ammonia or or
tertiary aromatic bases, for example pyridine. Sodium
sulphide or sodium polysulphide are freshly manufactured
before the xeduction is carried out by introducing
the equivalent quantity of sulphur into a sodium sulphide
- 38 -
solution. Sodium bisulphide is produced by introducing
hydrogen sulphide into a ~odium sulphide solution.
A~monium sulphide or a~nonium pol~sulphide is advanta-
geously produced in situ by introducing hydrogen ~ulphide
i~to an ammoniacalaqueous reaction solution and optionally
adding elementary sulphur.
The reduction with hydrogen-yielding agentq, for
example hydrazi~es, is accelerated by the above~mentioned
hydrogenation catalysts, for example Raney nickel,
palladium-carbon or platinum. The electrolytic reduction
of ~he nitro groups to form the amine requires a high
eLectrode potential and is carried out using cathodes
made of metaLs with a high overvoltage, such as lead,
tin, nickel, copper or zinc. The electrolysis is
generally carried out in a sulphuric acid or hydrochloric
acid ~olution.
The above-mentioned reducing agent~ are u~d in
equimolar quantity or prefera~ly in excess. The addition
of an excess of reducing agent i9 intended to prevent
the formation of undesired intermediates, for example
nitro~o compounds or hydroxylamines.
The reduction is prsferably carried out in the
pre~ence of solvents or mixtures thereof, the c~oice
of which is determined primarily by the solubility of
the starting materials, the reducing agent chosen and the
ability to bind the reaction water formed during the
reduction, thus, for example, lower alkanols, for example
methanol or ethanol, lower alXyl ethers of ~lycol~,
for example ethylene glycol monomethyl ether or -ethyl
ether, }ower alkanecarboxylic acids or esters thereof,
such as acetic acid and ethyl acetate, i~ the case of
catalytic reduction, and, for example, aliphatic, cyclo-
aliphatic, aromatic or araliphatic hydrocarbons optional-
ly substituted by halogen or ~itro, for example benzene,
methylene chloride, chloroform or nitromethane, suitable
acid derivatives, such as lower alkanecarboxylic acid
- 39 -
esters or nitriles, for example ethyl acetate or
acetonitrile, or amides of inorganic or organic acids,
for example dimethylformamide or hexamethylphosphoric
acid triamide, ethars, for example diethyl ether,
tetrahydrofuran or dioxan, ketones, for example acetone,
or sulphones, especially aliphatic ~ulphone~, for example
dimethylsulphone or tetramethylene~u:Lphone etc.
In order to increase the solubility especially of
the salt-like reduciny agentsin the xeaction mixture,
water is added to that mixture as required. The operation
is usually carried out at temperatures of from approxi-
mately -20C to approximately 100C and when using
very reactive activating agents the reaction may also
be carried out at lower temperatures.
If ~ racemic mixture of a starting material of
the formula V i5 used in the reduction of the nitro
~roup(s), a racemlc mixture of a compound of the Eormula I
is obtained~ This can be ~ubsequently separated into the
D- and L-coniguration antipodes by the customary methods
described in the literature for the separation of racemic
mixtures. The D configuration antipodes of a starting
material of the formula V arepreferably used in the
reduction.
- ~o -
9~E~E~eratiens_
In a compound of the formula I, the sub~titue~t~
(R)(Ro)~ 1 and R2 ma~, withln the scope o~ their
mean.ings and in any ~eque~ce, be conNerted into dif~eren~
substituents (R)(Ro)N , R1 and R20 ~hus, a free ami~o
group of the partial formula (R)(Ro)N~ in which R and Ro
repre~ent hydrogen may be converted into an acylamino
group o~ the partial ~ormula (R)(Ro)~ in which R
represent~ an acyl group and Ro represents hydrogen or
lower alkyl. ~ free carbo~yl group may be est~rl~ied or
an esteri~ied carboxyl group R2 may be converted into a
~ree carbo~gl group. Protecti~ group~ optionally
pre~ent i~ a compou~d o~ tha ~ormula I, ~or exampl~ a
D~2-amino-protecting group or a hydroxy-protect~ng group,
ara ~plit off. ~hes~ ~3ub~eque~t operatlon~ are carried
out in a manner k~own ~E ~e, ~or example a~ foll~3:
II, in a resulting compouIld OI the ~ormula I~
R and Ro repre~ent h~drogen and/or the sub~tituent R
represents a group of the partial formula (~)(Ro)~~
in which R ar~d Ro likewi~e rspresen~ hydrogen, the iree
amlno group~s) on the phenyl ring may be sub~tituted
1~ a manner k~own E~ ~e b~ an ac~l group ~ or a lower
al~yl radical Ro~
This subst~tution ca~ ba carried out, for examplQ,
by acylat~ng ~ith a ~uitable acylati~g agen~ tha~ i~troduces
the oorre~po~di~g acyl radical R.
The amino group(s) on the phenyl ring is(are)
optionally i~ reactive ~orm i.e. in a form allowi~g
acylation and protected, ~or e~ample, by the customary
silyl radicals de~cribed above. ~he hydro~y group on the
phenyl r~ng is optionally protected by o~e of the customary
hydro~y-protecting groups de~cribed above and the D-2-
amino group is optionally protected by one of the cu~tomary
amino-protect~g groups described above.
B~
- 41 -
I~ the amino group(s) is~are) sub~tituted by a~
acyl radical Ra-aO-, there i9 used as acylating agen~,
for e~ample~ the correspondin~ carboxylic acid or a
reactive der~vative thereo-~, especially a~ anhydride,
including a mi3ed or internal anhyaride o~ ~uch a~ acid.
~ixed anhydrides o~ carboxyllc acids ar9 ~ ~or exampl~,
those with hydrohalic acids, i.e. the corresponding
carboxyl~c acld hal~de~, especially chloriae~, also with
hydroc~anic acid~ or those with s~itable carbonic acld
~emi-deri~ati~es, ~uch as corresponding ~emiesters,
for e ample the mi~ed anhydrides ~ormed with a halo~ormic
acid lower alkyl ester~ such as chloro~ormic ac d ethyl
ester or isobutyl ester, or with lower ~lkanecarbo~y:lic
acid~ optionall~ ~ubRtituted, ~or e~ample 9 by halogen,
such as chlorine, such as the mixed anhydrides formed with
piYaloyl chloride or trichloroacetyl chloride. Inte.rnal
anhydrides are, ~or example, tho~e o~ organio carboxrlia
acids, i.e. ~eten~ uch as ketene or diketene1 or thos~
of oarbamia or ~hiocarbamic ac~d, i.e. isocyanates or
isothlo~ganate~. ~urbhe~ reacti~e derivativs~ o~ or~an~c
oar~o~ylio acids tha~ oan be used a~ acylating agent~
are activated esters, such a~ suitably substitutea phe~l
esters, ~or esample pentachlorophenyl or 4-nitrophenyl
ester.
If the am~o group(~) on the phenyl r~ng in a
compou~d o~ the ~ormula I i~(are) substituted by an acyl
radical Ra-S02-, there i~ used as acylating agPn~, ~or
egample~ the corre~po~ding sulphonic acid or a reactive
derivativa thereof, especially an an~dride thereo~,
includ~ng and pr~erably a miged anhydride. ~ed anhydrides
of sulphonic acid~ are, for example, those ~ith inorganic
ac~ds, especially with hydrohalic ac~ds, i~e. the corres-
ponding sulphonic acid halides, ~or example the sulphonic
acid chlor~de or bromid0.
Other sulphonic acidderivatives suitable ~or
~ 78;~
-- 42 --
substitu~ing the amino group(~) on the phan~l rlng are
acti~ated esters o~ the lo~er alkylsulphonic acid~, such
as ester~ with vinylogous alcohols (i.e. e~ol~ uch aæ
vinglogous lower alkenol~, or aryl esters, ~uch as
phenyl e3ters pre~erably ~ub~titu~ed, ior ~xample, by
nitro or halogen, ~uch as chlorine, for e~ample penta-
chlorophenyl ester, 4 ~itrophengl e~ter or 2,4-dlnltro-
phenyl e~ter, heteroaromatic e ters, ~uch a~ benztriazole
e~ter~, or diacylimino e~ters~ such a~ ~uccinylimino or
phthalylimi~o ester,
II the ami~o group(s) on the phe~yl ring i~(are)
substituted by a~ ac~rl radioal R hav~ng the meaning Ra~
O-CO-, RaRa~ or ~aRa~-S02-, there i~ used as acylati
a~ent a reaoti~e deri~rat~e o:E the correspondlng ¢a~bonic
acid 3emiester, the corre~pondi~g carbamio acid, thio-
carbamic aeid or am~do~ulphonio acid. Su¢h reac~ive
derlvatives are, ~or exampl~ dr~de~, mixed anhydride~,
ior e:s~ample with irlorganic acids, such as hydro~a:li¢ aoid~
or, ~n the oa~e oY the ~arbamic ac~d or thiocarbamic
aoid, illte~al anhydride~, for e~ampla the cyanate9 or
thiocyanates .
~ he ac~lation reactions may, if necessary, be
carried ou~ in the presence of ~uitable conden~atio~ agents,
when u~ing ~ree carbo~ylic acids or sulphonic acids, ~or
e~ample in the presence o~ carbadi m~de~9 ~or e~ample
N,~'-diethyl~ diprop~ ,N'-diisopropyl ,
~,N'-dicyolohe~yl~ or N-eth~ 3-dimethylami~opropyl-
carbodiimide, ~uitable ¢arbonyl compound~9 ~or e~mple
carbonyldiimidazole, or isoxa~ollnium ~alts, ~or e~ampls
~-sth~1~5~phenyliso~azolin~um 31-sulphonate and ~-tert.-
butyl-5-methyliso~azolinium perchlorate, or a ~uitable
ac~lamino compound, ~or example 2-ethoxy-1-etho~ycarbonyl-
1,2-dihydroquinol~ne. Such conden~ation reactions are
pre~erably carried out in an anhydrous reaction medium~
~or e~ample in methylene chloride, dimethylformamide or
t'~
- ~3 -
acetonitrile.
~ he acylation reaction with a sulphonic acid
oorresponding to the radic~l R or with a reactive deriva-
tive thereof ~ay also be c~rried out in the presence o~
an acid-binding agent, for example an organic base9 ~uch
as an organic amine~ for example a tertiary amine t such
as tri-lower alkylamine, ~or example trie~h~lamine, N,~-
di-lower alkylaniline, for exa~ple ~,~-dimethylaniline,
or a base of the pyridine type; for example pyridi~e, an
inorganic base, for egample an alkali meta} or alkali~e
earth metal hydro~ide, carbonate or bicarbonate, for e~ample
sodium, potassium or cslcium h~dro~de, carbonate or bi-
carbonate, or an oxirane, ~or e~ample a lower 1,2-alkylene
o~ide, such ~ ~hylene o~ide or 1,2-propylene oxide.
~ he acylation reaction~ may be carr~ed out in
the absence or presence of a solvent or sol~e~t mixture,
~hile ~ooling, at room temperature or while heating, and9
if ~eces~ary, ~n a closed vessel and/or in an inert gas
atmosphere, for e~ample a nitrogen atmo~phere~ Suitable
solvents are those mentioned above or, for e~ample,
optionally substituted, especially optionall~ chlorinated,
aliphatic, cycloaliphatic or aromatic hydrocarbons, such
a~ benzene a~d toluene, it being possible to use
suitable esterifying reagents, such as acetic anhydride,
also as diluents.
~Ikylation of the amino group~s) o~ the phen~l ring:
Ifç 1~ a resulti~g compound of the formula I,
R and Ro represent hydrogen and/or the substituent R1
represents a group oD the partial formula (R)(Ro~N- in
which R and Ro likewise represent hydrogen9 the free amino
group(~) on the phenyl ring may be alkylated by a suitable
alk~lating agent that introduces the lower alkyl radical
Ro, ~or e~ample an alkyl halide, ~uch as methyl bromide,
to form the Ro ( lower alkyl)-substituted amino group(s).
J
-- 44 --
Such RO-~ub~tituted amino group(s) may be ~ub~equently
sub~tituted i~ the manner de cribed abo~e by an acylati~g
agent introducing the acyl radical Ro
In thi~ manner, compo~ds of the formula I are
obtained in which the group o~ the partial formula (R)(Ro)~-
is substituted by a lower alk~l radical a~d b~ acyl a~d
in which Rl 19 hydro~en or a group of the partial ~ormula
(R)(Ro)~~ ~ub~bituted by lower alkyl and acyl.
~ uch compounds can al90 be ma~ufactured preferably
b~ substit~ lng ~he ami~o group(s) on the pheny~ ring
by an acyl radical R corre~ponding to the mean~ng~ giYen
abo~e and then metallat~ng ~he 30 obtained ~econdary
amino group(~) on the phsnyl ring ~dith a suitable metallat-
ing reagent ~ollo~ed by a reactive compound correspondin~
to the radical Ro~
Suitable metallat~ng reagents are, ~or example,
lithiwm dii~opropylamiae or butyllithium. A reactiYe
compound corre~ponding to the radical Ro i9, fox e~ample,
a compound o~ the formula ~0-X in which X i~ a lluoleo-
~ugal l~avlng group, ~or e~ample a halogen atom, for e~ample
chlor~e, bromine or iodi~, or a ~ulp~onylo~y group,
for exam~le me~ylo~ or tosylo~.
~ compound of the formula I i~ which the index
n represents 0 can be conYerted by the oxidising agent~
describ0d under proces~ b) into the corre~pondlng 1~oxide
in whic~ the ~ndex n ha3 the value 1.
A 1-oxide of the formula I in which the inde2 n ha~
the value 1 can be converted by the reducing agents
desoribed under process b) into the corresponding 1-sulphide
in which the index _ ~as the value 0.
Esterification_f a ~35 ~ S~Y~L
~ he con~ersion of a free carboxyl group, especially
a corresponding group R2, in a compoun~ of the ~ormulaI
7~3~f'~
-- 45 ---
into an estsrified carbo2yl group, especially into an
esterifled carboxyl group that can be split under
phy~iological condltio~, is a~Pected according to
e~terification methods kr~own per se, for e:~:ample
by reacting a compound OI tl~e formula I ~ w}~ch oth~r,
optio~ re~ent ~unctional group~ ar~ optiox~lly
i~ protected for~n9 or a rea~titre Iu~ctio~al carbogg
der~vatlve9 irlclud:~g a ~alt, thereof, with a
correspond~ a}cohol or a reactive Lunctlorlal
dsri~ative thereo~.
The e~teriIica~ioll of the Iree carbo~l grouE
wi:th the des~red alcohol i~ carrled ou~ in tha prese~ce
of a su~table co:~densatio~ agent. Customary conden~ation
a~e~s are, ~r example, oarbodiimido~, ~or e~ample
~,N'-diethyl~ dipropg~ , ~,N'~dicyolohexyl-
or ~-ethyl-N' (3-dimebh~laminopropyl)-carbodiimide,
~ultablo carbonyl compounds, ~or example c~rbon~ldi
lm~dazol~5 or ~2-oxazolium ~ompou~d~, ~or ~xample 2-
ethyl-5-phenyl-1,2-o~azolium 3' sulphonate and 2~t~rt.--
but~l-5-methyliso~azol~um perchlorate, or a ~u~table
acylamino oompound, ior e~mpls 2-ethoxy-1-etho~y-
carbonyl-1,2-dlhydroqulnoline. ~he co~den~at~n reaction
i~ pre~erably carried ou~ ~n an anhydrou~ react~on medium,
preierabl~ ~n the pre~ence o~ a solvan~ or d~luent, ~or
e~ample methylerle chloride, dimethyl~o~mamlde, ~cetoni-
trile or tetrah~dro~uran, ~d, i~ necessary, whlle cooling
or heating and/or in an inert gas atmosphere.
Suitable react~ve functional derivatives o~
the carbo~yl compounds o~ the ~o~mula I to be esteri~ied
are, ~or e~ample, anhydrides, especially m~xed anhyclrldes,
and acti~ated esters.
Mixed anhydrides are~ ~or e~ample, ~ho~e with
inorganic acids7 ~uch a~ h~droh~lic acids, i~e. the
correspo~ding acid hal~des, ~or e~ample chloride~ or
bromide~, also hydrazoic ac~d, i.e. ~he corresponding
a~id azides, a~ well as phosphorus-coD~aining acld3,
J
-- ~6 --
for example pho~phoric acid, diethylphosphoric acid or
phosphorous acid, or sulphur-contai~ing acid~ îor
e~ample sulphuric acid, or hydrocya~ic acid. Further
migad anhydrides are, f or c~mple, those ~ith orga~ic
carboxylic acid~, such as with low~alkanecarbo,~lic
acids optio~ally subs~ituted, for e~:ample, by halogen,
such as fluor~ne or chlorlne, for e~ample pivalic
acid or trichloroacetic acid9 or with semie~ter~,
e~peciall~ lower aIkyl ~emie~ter~ of carbonic acid,
such as the ethyl or i~obutyl semiester o~ carbonic
acidg or ~ith organ~c, e~pecially aliphatic or aromatic,
~ulp~onic acid~, for example p-toluenesulphonic acid.
~ otivated e~ter~ ~uitable ~or reaction ~ith the
alcohol ~re, ~or e~ample9 ester~ with vinylo~ou~
alcohols (i.e. enols)~ such as vinglo~ou~ lo~er alkenol~,
or iminomethyl ester halides~ such as dimethyli~:Lnometh~l
s~ter chloride, manu~actured from the free carbo~lic
aoid and dimethyl-chloromethglidene-iminium chloride
o~ the ~ormula [(~3) ~ ~C~Cl~ ~ Cl ~ , or ~yl
e9ter9~ ~uch a~ pe~achlorophen~l, 4~nitrophenyl or
2,~-di~itrophenyl e~ter, heteroaromatic e~ters, ~uch as
be~2tria201e e~ter~, for e~ample 1-ben~triazole ester,
or diacylimi~o e3ter~, 3uch as 3ucc~nylimino or
phthalylimino e~ter.
~ he esteri~ication with such an acid derivative,
~uoh a~ an anhydride, especially with an aeid halide, is
preferably carried out in the pre3ence of an acid-
binding agent, for example an organic base, ~uch as an
organic amine~ for example a tertiary amine, 3uch a~
a tri-lower alkylamin~, for example trimethylamlne~
~rlethylamine or ethyldii30propylamine, or an ~ di-
lower alkylaniline, for example N,N-dimethylaniline,
or a cyclic tertiary amine, ~uch a~ an ~-lower alkylated
morpholine, ~uch as ~-methylmorpholine, or a ba~e of
~7;~
- ~7 -
the pyridine type, f or exampl~ pyridina, a~ inorganic
base, ~or e~ample an alkali metal or alkal.lne earth
metal hydra~ide, carbo~ate or bicarbonate, for example
~odium,pota~ium or calcium hydro~ide, carbonate or
b~carbonate, or an oxirane, for example a 1 72 -lower
alk~lene oxide, ~uch a~ eth~lene oæide or propylene
oxide .
A reacti~e, ~unc~io~al derivati~e of the
esterifyi~g alcohol is especially a corre~ponding
ester, pre~erably with a ~trong lnorganic or organic
acid, and i~ ~pecial~y a corr~sporLding halide 9 ~or
~Xampl8 chloride~ brom~de or iodida, or a corresponding
lower aIkylsulphonylo~y or aryl~ulphon~lo~y compound,
such a~ methyl~ulphonyloxy or 4-meth~lphcnyl~ulpho~1-
oxy ~
S~ch a reactive e~ter of an alcohol can bereacted with the ~ree oarbo~yl compound of the ~ormula
I or with a salt, euch a~ an alkali metal or ammonium
~alt thereo~, the reaction pre~erably being carried out
1~ ~he ~re~ence of an acid-bi~dlng age~t when usi~g tha
~ree acid~
~ h~ abo~e e3tert~$catio~ reac~ion~ are carried
ou~ in an inert, usually anhydrou~, ~olvent or 901vent
mi2ture, for e2ample ln a carbo2ylic acid amide, ~uch
as a ~or~amide, ~or e~ample dimethylformamide, a
halogenated hydrocarbon, ~or e~ample methylene chloride,
carbo~ tetrachloride or chlorobenzene, a ~etone, for
e~ample aceto~e, an ester, ~or example ethyl acetate,
or a nltrile, for example acetonitrile, or mi~tures
thereo~, if necessary while cooling or heating~ for
e~ample in a temperature range of ~rom appro~imately
-40C to appro~imately +100C, pre~erably at from
approxi~ately -10C to appro~imately +40C andJor in
an inert gas atmospherey ~or egample a nitrogen atmo~phere~
~ urthermor6, the acid derivati~e may, i~ desired,
48 -
b~ formed ln qitu. For example, a mi2ed anhydride i~
obtained by treating the carbo~ylic acld compound ha~i~g
appropriately protected ~ ctional groups, or a
~uitable ~alt thereof, such as an a~onium ~alt, ~or
e~mpl~ with an organic amine, such as piperidine
or 4-methylmorpholine, or a metal 3altp fo:r example
an a}~ali metal salt, with a suitable acid derivative,
such as the correspo~ding acid halide o~ an optio~ally
substituted lower alkanecarbo2ylic acid, for example
trichloroacetyl chloride9 with a ~emie~ter oP a carbo~ic
acid 3emiha1ide, for example chloro~o~2ic acid ethyl
~ter or i~obutyl ester, or with a hal$de of a di-
lower alkylphosphoric acid t ~or e~ample diethgl
pho3phorobromidate, a~d the mi~ced a~hydride 90 obtalned
i9 u~ed withou~ isolatio~.
Splitti~ of~ o~ ~rot~:
In a resulting compound of the formula I ~ whlch
one or more ~u~ctional ~roup3 are protected, these,
X~r example protected carboxyl, aml~o, hydro~y and/or
~ulpho groups, can be ~roed, ~n a ma~er ~now~ per se,
by means of solvolysi~, especially hydrolysis, alcoholy~i~
or acidoly~i~, or by means of reduct~on, especially
hydroge~oly~is or chemical reductlon, optionally ~tep-
wi~e or ~imultaneously.
~ hus, tert3-lo~er alkoxycarbon~l~ or lower alkogy-
carbonyl substituted in the 2-po3ition by an organic
~ilyl group or in the 1-position by lower alkoxy or
lower alkylthio, or optionally substituted diphenyl-
metho2ycarbonyl can be con~erted into frea carbo~yl, for
e~ample, by treatment with a ~uitable acid9 such as formic
acid or trifluoroaoetic acid, optionally with the addition
of a nucleophilic compound, such as phenol or anisole.
Optionally 3ubstituted benzylo~ycarbonyl can be freed,
~or e~ample, by means of hydrogenoly~i~, i.e. by treatment
~7i~
-- 49 --
~Aith hyarogen in the pre~ence of a metallic hydrogenation
cataly~t, such a~ a palladium catalyst. Furthermore,
~uitably ~ubstituted benzyloxycarbonyl, ~uch aY 4-nitro-
benzyloxycarbonyl, can be converted into free carboæyl
also bg chemical reduction, for e~ample b~ treatment with
an alkali metal dithionite, for example 90dium dithionite,
or with a reducing metal, for example zinc, or metal
salt~ such a~ a chromium(II) salt~ for example chromium(II)
chloride, usually i~ the presence of a hydrogen-yielding
agent which, together with the metal, is capable o~
produc~ng nascent hgdrogen, s~ch as an acid, especially
a 3uitable carboxylic acid, æuch as a lower alkane-
aarboxglic acld optio~ally ~ub~tituted, ~or eæample, by
hydroxy, ~or example acetic ~cid, I ormic acid, glyoolic
acid, diphenylglycolic acid, lactic acid, mandelic acid,
4-chloromandelic aoid or tartaric ac~d, or an alcohol or
thlol, water preforably bei~g added. ~y treatment
with a xeduc~n~ ~etal or metal ~alt a~ de~cribed above
it 13 also po3~1ble to co~vert 2-hala-low~r alkoxy-
carbo~yl t optionally a~ter con~erting a 2-brvmo-lower
alkoxycarbonyl group into a corresponding 2-iodo-lower
alko~ycarbonyl group, or aroylmetho~ycarbonyl in~o
~ree ~arbo~yl, it being possible to split aroylm~thogy-
oarbonyl li~ewi~e by treatment with a nucleophilic,
pre~erably salt-formi~g, reage~t, ~uch as SQdiUm thio-
phenolate or sodium iodide~ ~ubstltut~d 2-silyletho~y-
carbonyl can also be oo~erted into ~ree carboxyl by
treatme~t with a salt o~ hydro~luoric acld which yields
the ~luoride anion, such as an alkali metal fluoride,
~or e~ample ~odium or potassium Yluoride, in the presence
o~ a macrocycl~c polyether ("Crown ether"), or with a
~luoride of an organic quaternary base, such as tetra-
lower alkylammonium fluorida or tri-lower alkyl-aryl-
ammonium ~luoride, ~or sxample tetraethylammonium ~luorlde
or tetrabutylammonium ~luoride, in the presenoe o~ an
- 50 -
aprotic ~olvent, ~uch as dimethyl sulphoxid~ or ~
dimethylacetamide. ~ carbo~yl group esteri~ied by an
organic silyl or stannyl groupt ~uch as tri-lower alkyl-
~ilyl or tri-lower alkyl~tannyl, for example trimethyl-
silyl, can be ~reed i~ the u~ua~ manner by sol~oly~
~or exampl~ by treatment with water, an alcohol or an
acid.
~ protected amino group ls ~reed in a manner
known ~ e and, depending on the type o~ protecting
group, in di~ferent ~ay~, pre~erably b~ means o~ solvolys~s
or reduction. 2-halo-lower alko~ycarbonylamino, optionally
a~ter conve~lng a 2-bromo-lower alkoæycarbonglamino
group ~nto a 2-iodo-lower alko~ycarbonylamino group,
aroylmotho~ycarbonylami~o or 4-nitrobe~zyloxycarbonyl-
amino can be ~pli-t, ~or e~ample, by treatment with a
~uitable chemical reducing age~t, ~uch a~ c, in the
pre~encc o~ a ~uitable carbox~lic acid, ~uch ag aq~leou~
acetic acid. Aroylmethoxyaarbonylamino can also be split
by -treatment with a nucleophilic, pre~erabl~ salt-forming,
reagent, such a~ ~odium thiophenolate, and 4-nitrobenzyl-
o~ycarbonylami~o al~o by treatment with a~ alkall metal
dithio~ite, for e~ample ~odium dithionite~ Optionally
~ub~titutad diphenylmetho~ycarbonylamino, tert.-lower
alko~ycarbo~ylamino or 2-tri-~ubstituted silyletho~y-
carbonylamino can be freed by treatment with a ~uitable
acid, for e~ample formic or tri~luoroacetic acid,
optionQlly sub~tituted benzyloxycarbonylamino, for
exampls b~ means o~ hydrogenolysi~, i.e. by treatment
with hydrogen in the presence of a suitablo hydroge~ation
catalyst, such as a palladium catalyst, optionally sub-
~tituted triarylmethylamino, formylamino or 2-acyl-lower
alk-1-anylamino, for example by treatment with an acid,
~uch as a mineral acid, for e~ample hydrochloric acid,
or an organic acid, for egample formic, acetic or tri-
fluoroacetic acid, optionally in the presence of water,
~17~3~ i 11
_ 51 -
and an amino group protected by an organic silyl or
qtannyl group, for example by means of hydrolysis or
alcoholysis. An amino group protected by 2-haloacetyl,
~or e~ample 2-chloroacetyl, can ~e ~reed ~y treatment
with thiourea in the presence o~ a base, or with a thio-
late salt, such as an alkali metal thiolate, of thio~ea,
and by subsequent solvoly~ij, such as alcoholysis or
hydrolysis, of the resulting condensation product. ~n
amino group protected by 2-substituted silyletho3ycar-
bonyl can also be converted into tke free amino group
by treatment with a salt o~ hydro~luoric acid which yields
fluoride anions, as stated above in connection with -the
free~ng of a corre~pondingly protected carboxyl group.
pho~phoramido, phosphonamido or pho~phinamido group
can be converted into the ~ree amino group, ~or example
by treatment with a phosphorus-co~tainin~ acid, such as
a pho~phoric, phosphonic or pho~phin~ a¢id, ~or example
orthophosphoric acid or polyphosphoric ~cid, a~ acid
ester thereof~ for e2ample monomethyl, monoethyl, dimethyl
or diethyl phosphate, or monom~thylphosphonic acld, or
an anhydride thereof, ~uch a~ phosphoru~ pento~ide.
~ n amino gro~p masked in the ~orm o~ an azido
group is converted into the free amino group, ~or example
by reduction, ~or e~ample by cata}~tic hydrogenation
with hydrogen in the presence o~ a hydrogenatio~
catalyst, such as platinum o~ide, palladium or Raney nickel,
or alterna~ively by treatment with zinc in the presence
o~ an acid, such as acetic acid~ Catalytic hydrogenation
i~ pre~erably carried out in an inert solvent, such as
a ~alogenated hydrocarbon, ~or example methylene chloride,
or alternatively in water or a mi~ture of water and an
organic solvent, such as an alcohol or dioxan, at from
approximately 20C to 25C, c alternatively while
cooling or heatingO
~7~
- 52 -
~ hydro~y group protected by a suitable acyl grOUp9
an organic ~ilyl or 3ta~nyl group or by optionally sub
stituted 1~pheny1-lower alkyl i~ ~reed in the same manner
a~ a correspondingly protected ami~o g:roup~ ~ hydroxy
group protected by 2,2-dichloroacetyl i9 freed, for exampl~,
by ba~ic hydrolysis, whil~t a hydroxy ~roup etheri-~ied
tert.-lower al~yl or by a 2-o~a- or 2-thla-aliphatic
or a 2-oæa- or 2-thiacycloaliphatic hydrocarbo~ radical
is freed by acidolysis, ~or e~ampie by treatment with a
mineral acid or a strong carboxylic acid, ~or example
tri~luoroacetic acid. A 2-halo-lo~ler alkyl group i~
split off by reduction,.
A protected, especially e~teri~ied, sulpho group
i~ ~reed analogou~ly to a protected carbo~yl group9
~ he de~cribed ~pl~tting reaction~ are aarr~ ~3d out
under condltions known ~ e, if nece~ary while cooling
or heating, in a clo~3ed ve~sel and/or i~ an inert ga9
atmo~phere, for example a nitrogen atmosphere.
~ he reductive splltting methods ~nown ~ se
~or 2-halo-lower alko~ycarbonyl and 2-halo-lower alkoxy
groups may advantageou~ly be carri~d out under especially
mild condition~ in the presence of a catalytic quantity
o~ a transition metal oomplex of a corrin or porph~n
compound, it bei~g pos~ible to ~plit even groups that are
normally di~ficult to split, for example 2-chloroetho~y-
carbonyl a~d 2-c~loroetho:~ groups.
~ i!ransition metal complege~ of corrin and porph~n
compounds which are u~ed as catalyst3 for reductivs
splitting are derived from transition metal3 tha~ appear
i~ more than one ~alency stage, ~uch a~ copper, palladium~
rhodium and especially cobalt. Pre~erred catalysts are
model compounds for the ~ynthe~is of vitamin B12, for
e~ample derivative~ that are dsrived from the 2,2,393,
7,7,8,8,12,12,13,13,17,17,18,18-hexadecamethyl-10j20-
diazahe~ahydroporphin cobalt(III) cation and especially
-- 53 --
vitami~ of the ~t2 group including, e~pecially, cyano-
cobalamin, aquocobalamin and hydroxycobalamin, and their
derivati~e~ and decompo~ition product3, such a~ cobyrinic
aoid and the e~ters thereof, corphyrinic acid, corph~nic
acid, cobamic acid and cobamide. The ~uantlty o~ the
catalyst i~ generally from appro~imately 0.1 to
appro~imately 0~001, pre~erably ~rom appro.~imately
0.03 to appro~imately 0.003, molar equivalent, ba~ed
o~ th~ component to be reduced, but in a favourable
experimental arrangement, ~or e~ample in an optimi~ed
electro-reductio~, the qua~tity may be ~ar belcw the
lowe~t limit~
~ he reduction i3 carried out in a manner known
e by conventional method~i~ the pre~encs of a proton
~ource. Any inorganic and crganic acld~ a~d ousto~lry
protic ~olvents may be used a~ the proton ~ol~ce; acid~
are advantageou~ly u~ed in a bu~fered form or a~ sa.lts,
the pE ~alue belng preIerably between approximately
4.0 and 9.5, e~pecially betwe~ approximatel~ 5.5 a~d
7.5 and above all in the region o~ the neutral point.
A reduction method th~t recommends itsel~ as one
of the most gentle methods i~ cathodic electroreduction
under con~entional condltions, such a~ u~ing a mercury
cathode or some other cathode that may generally be used
in electroreductio~, ~uch as a carbon cathode~ in the
pre~ence of customary au~iliary electrolytes, such as
ammonium and/or alkali metal ~alts, especlally lithium
salt~, o~ ~trong inorganic acids, such as, especially,
halides and perchloratss, pre~arably those that are
di~tingui~hed by a good solubilit~ in the aqueous-organic
medium used. ~he sol~ents used9 apart ~rom water, are
conventional water-mi~cible organic ~olvents, for e~ample
low~r alkanols, such a3 methanol, ethanol and i30prop~1
alcohol, or di~ethylformamide 7 and similar l~rer aliphat$c
amides, also nitriles, such as acetonitrile, ether~, such
~L1,7~; t`,,~3
- 54 -
as diethyl ether, 1,2-dimethoxy- and 1,2-diethoxyethan~
and cyclic ethers of the tetrahydro~uran type, ketones,
such as acetone, carbonate~, such a~ dimethyl and dieth~l
carbonate, a~d ~ulpho~ldes, ~uch a~, especially, dimethyl
sulphoxide. ~he tern~ rature of the electroreduction may
be varied with~n a wide ran~e, i.e. from approximately
-20C up to the boiling temperature of the reaction
mixture; it i~ pref~rably at room temperature or belo~
~ ~urther suitable ~ariant o~ the reductive spl~tting
i9 reductio~ with a metal, especially with ~in¢ or
alternatively with magne~ium. If neces~ary, the customary
~igorou~ cond~tions may be applied, for e~ample ~ro~ima-
tel~ 90~O aqueou3 acetic acid as the medium and/or ele~ated
temperature up to the boiling poi~t o~ the mi.~ture with
a corre~pondingly 3hortened reaction timeO ~he operation
i9 7 ho~ever, pre~erably carried out under as mild condition~
a~ po~ible, ~or e~ample i~ the abo~e-mentioned pre~erred
pH range i~ the re~ion o~ the neutral point and at
temperature~ o~ from appro~imately 0 to approximately
40a, pre~erably at appro2imately from 10 ~o 25C; the
operation is generally carried out with a~ approximately
10-~old molar exces3 of the metal, pre~rably zi~c in
the ~orm o~ zinc du~t which i9 ad~a~tageously activated
immediately be~ore ~he reaction i~ a co~ventional manner,
~or example by stirring with dilute hydrochloric acid
and carefully washing until nau~ral. In order to obtain
the de~ired buf~er e~fect, ammonium salts of hydrohalic
acids may advantageously be used, especially tho~e to
be found in the p~rticular group of the formula I to be
split of~. The reduction is carried out in the above-
men~ioned organ~c solvents or mi~ture~ thereof; protic
solvent~ are pre~erred. It is also possible to use
other conventional variants o~ the reduction process; an
e~ample i~ reduction ~ith metal cations in low valency
stages, for example with chromium(II~ salts, uch as
c:hromium(II) chloride or acetate, al~o reduction with
- 55 -
comple~ metal h~drides, for e~ample with ~odium boro-
hydride and related lower alko~y sodium borohydride~
and lower alko~ylithium borohydride~, and also catalytic
hydrogenation, for example using a palladium catalyst.
When ~everal protected functional groups are
prese~t, the protecting gIoups ar~ pre.~erabl~ ~o chosen
thst more than one ~uch group can be 9plit off ~imul-
taneously, ~or example by acidelysis, ~uch a~ b~ treat-
ment with tri~luoroacetic acid or formic acid, or by
re~uct~on; æuch a~ by treatment with zinc and acetic
acid, or with hydrogsn a~d a hydrogenation cataly~t,
~uch a~ a palladium-carbon catalyst.
~a~
Salt~ o~ compound~ of the formula I haYin~ ~c~lt-
~orml~g group~ ca~ be manu~actured in a manner ~nowu
E~ se. ~hu~, ~alt~ o~ compounds of the formu~ I ha~ing
acid group~ can be formed, ~or e~ample, by treatment
with metal compounds, ~uch a~ all~sli metal salt~ of ~uitable
orga~ic carbo~ylia acids, ~or example the sodium salt of
a-ethylcaproic acid, or with inorganlc alkali metal or
alkaline eart~ metal salts, for ~xample sodium bicarbonate9
or with am~onia or a suitable organic ~ine, preferably
stoichiometric quantities or only a small e~ae~s of the
salt-~orming agent being used. ~cid addition ~alts o~
compound~ o~ the formula I are obtained in the u~ual
manner, ~or e~ample bg trea~ment with an acid or a .quit-
able anion e~change reagent. Internal ~alts of compound~
of the formula I that contain, for example, a free carb-
o~yl group can be formsd, ~or e~ample, by ~eutralising
salt~, such as acid addition salt~, to the isoelectric
point, for e~ample ~ith weak bases, or by treatment with
liquid ion exchangers.
Salts can be con~erted in the usual manner into
the free compounds; metal and ammonium salts can be
~17~
- 56 -
converted, for e~a~ple, by treatment with sui~able aclds
and acid additio.n salts, for e~ample, by treatment with
a suitable basic agent.
~ he l-o~ide o~ -the formula I in which the index
n ha~ the value 1 may b~ u~ed in the ~-- or ~-~orm or
in the ~orm o~ a mi~:ture OI the two isomers i~ the
sub~equent reactions de~cribed aboveO
~ he methods de~cribed in the literature, for
e~mple ~ractio~al cry~talli~ation, c~romatography,
etc., are suitable for separating racemie migtures
The process also includes th~ e embodimer.ts
according to which compounds ~ormed a~ lntermediate~
are u~ed aq starting material~ and the remaining proces3
steps are carrled out with the~e, or the process i~
discontinued at an~ stage; in addition., starting mat;erials
~ay be u~ed in the ~orm o~ derivative~ or may be formed
during the reaction.
Pre~erabl~, the ~tartin~ materials and the
reactio~ co~ditions are 50 chosen that the compound~
mentioned above as being especially pre~erred are o~tainedO
~ e ~tarting materials used in the process ~or
th~ manu~acture o~ the compound~ of the pre~ent invention
are k~own or, i~ novel, can be manu~actured in a manner
known ~er se.
The ~tarting compounds of the type of ~he formula
II a~d al~o oorresponding compounds hav~ng protected
~unctional group3 are k~own.
~ hs following compounds of the formula III a~d
proce~se~ ~or the manufacture thereof are known ~rom
Germa~l Offenlegungs3chrift 2,4~2,190 or can be ma~ufactured
in a l~anner kno~m Per se: R, Ro and Rl repre~ent hydrogen,
R repre~e~ts an acyl radic~l o~ the ~ormula Ra-S02- ,
in which Ra represents lower alkyl, Ro represents hydrogen
y~'v
- 57 -
or lower alkyl and R1 represe~ts hgdro~en; R represent~
an acyl radical ~ the formula RaRaN-CO-, R~R~N-C~- or
R ~aN-~02- , In which in each ca~e one radical ~a represents
lower alkyl and the other radical Ra represents hydrogen,
and R1 represent h~drogen.
Compounds of the formula III in which R repre~ent~
an acyl radical of the formula Ra-O-CO- in which ~a has
the meanings g~ven abo~e or comp~und~ of the ~ormula III
in which R repre~ents a~ acyl radical of the formula
~ CO~, RaRaN-C~ or R~Ra~-S02- in which ~n each case
both radicals Ra represen~ optionally ~ub~tituted h~dro-
carbon radicals or both radicals Ra repre~ent hydroge~,
can be mant~aotured analogously ~ prooess a~, for e~cample~
by acyla~ing a compound of the formula III in which R,
R~ and R1 represe~t h~droge~ w~th the acyl radical R of
a correspondingly substitut~d carbonio ac~d semie~ter,
o~ a correspondin~l~ sub~tituted carbami~ acid, ~hio-
carbamio acid or amidosulpho~ic acid, or a reaative
derivati~e o~ ~uch aoids, ~or e~ample an acid anhydride,
such a~ an acid chloride.
aompounds o~ the formula III in which R represe~t~
an acyl group having the meanings glven above and R~ repre-
~ents hydroga~ and Rl represents a group of -the partial
formula (R)(Ro)N~ in which R rapre~ent~ a~ acyl gro~lp
and Ro represents hydrogen, can be manufactured analogously
to proces~ a) by acylating ~ree amino groups of a corres-
ponding compou~d of the formula III with the acyl radical
of a correspondingly substituted carbo~ylic acid or
sulphonic acid, of a carbonic acid semiester, a carbamic
acid, ~hiocarbamic acid or amidosulphonic acid, or a
reactive derivative of such acids, ~or e~ample an acid
anhydride, such as an acid chloride.
Compound~ oi the formula III in which R and Ro
represent hydrogen and R1 represents a group o~ the partial
iormula (R)~Ro)N~ in which R and Ro likewise represent
~ ~7~
- 58 -
hydrogan9 can be manufactured by reducing the correspond-
i~g dinitrohydroxyphenyl-D-2-aminoacet$c acid~, for
e~ample 3,5-dinitro-4-hydroxyphe~yl-~-2-aminoaaetic acid,
with Raney nickel or one o~ the abo~e-mentioncd reducing
agents that co~vert nitro groups into amino groups,
~or example with palladium-carbon.
In compound~ o~ the formula III in which R and Ro
repre~ent hydrogen and R1 represents hydroger, or a group
of the partial formula (R~(Ro)~~ having the meanings given
abo~e for R a~d Ro~ tke amino group(s) on the phenyl
ring can be al~ylated in a manner known E~E se by ~ ~uit-
able alkylating agent that introduce~, for example, a
lower alkyl radical Ro~ ~or e~ample an aI~yl halide,
~uch as methyl bromide.
Such alk~lated amino group(8) on the phenyl ring
may be ~ub~equently ~ub~tituted in the manner de~crihed
above by a~ acylating agent that introduces the acyl
rad~oal R.
Oompound~ of the formula III are thus obtained in
which R repre ents an acyl group, Ro represents a lower
alkyl radical and R1 represents hydrogen or a group of
the partial ~ormula (R)(Ro~N~ in which ~ likewise repre-
sen~s an acyl group a~d Ro represent3 a lower alkyl
radical.
~ hch compounds can be manufactured pre~erably by
substituting the amino group(s) on the phenyl ring b~
an acyl radial R corresponding to the meaning~ give~ abo~e
and then metallating the resulting secondar~ amino group(s)
on the phenyl ring with a ~uitable metallatinb~ reagent
followed by a reacti~e compound corresponding to the radical
Ro~
Suitable metallating reagents are, for e~ample,
lithium diisopropylamide or but~llithium. ~ reactive
compound corresponding to the radical Ro is, for e~ample,
-- 5~ --
a compound of the formula Ro~'~ in ~rhich ~ i~ a nueleo-
fugal leaving group, ~or e~ample a halogen atom, ~or
examplQ chlorine, brominQ or iodine, or a sulphonyloxy
group, for e~ample mesylo~y or tosylo~y.
I~ the ca~e o~ the acylation and alkyla~ion
reaction~ of the amino group(~) on the phenyl ri~g, tha
hydroxy group on t~e phenyl ring is opt~onally protected
by the eu~toma~y hydroæy-~roteeting group9 deseribed
above and the D-2-amino group is optionally proteeted by
the eu~tomary amino-proteeting groups de~eribed abova~
Compounds of the formula III ha~e a chiralitg
ee~tre on the earbon atom in the 2 or a-position of the
aeetyl radical.
For ths above acylation proee~s according to a)
for the manu~aeture of compound~ o~ the ~ormula I, compound~
of the formula III are pre~erably us~d in which the amino
group that i~ in the 2- or a-position o~ the acyl radical,
ha~ the D-eo~iguxatio~. Sueh compound~ ean be obtainod,
~or example, by ~eparatin~ raeemle mixtures o~ eompound~
cf the ~ormula III into the des.ired D-eonflguration
antipodes. ~ ~umber of conventional methods described
in li~erature, especially those u~ed ~or splitting racemic
a-amino acid~q, m~y be used.
Starting materials of the formula IV may be ~ormed,
~nter alia, a~ a by-product in the manu~acture of compounds
o~ the type of the formula I, ~or example when tb~se are
~ormed under basic conditions. ~he~ need not be in pure
form but may be u~ed, ~or sxample, in admixtuxe ~ith
corresponding compounds of the formula I.
~ he invention relate3 also to compounds of the
formula ~ 1~ which Rl represents hydrogen, nitro or a
group of t~e partial ~ormula (R)(Ro)N~, i~ which
represents hydrogen ox an acyl group and Ro represents
h~drogen or lower alkyl, R2 represents carbo~yl or protectad
~7~ 3
- 60 -
carboxyl and R~ represents hydrogen, halogen having
an atomic number of up to ~5 or lower alko~y, and
hydrates and salts of compou~ds of the formula V and
processes for the manu~acture thereo~. Compounds o~
the formula V are manu~actured, for example, by, in a
compound o~ the formula
()n
H H ~
~2N_ _ ~,S~. (II)
O
~2
in which the index ~ repre~ent~ 0 or 1 and the 7~-
amino group i~ optionally protected by a group allowi~g
acylation~ a~d R2 a~d R~ ha~e the mea~ings gi~en under
formula ~, acylating the 7~-amlno group by reaction
with an acylating agent that introduces the acyl radical
of a carbo~ylic acid of the formula
N2 0
C~--C~ 0~ ~YI)
~ '~- R' ~ 2
in which the hydro~y group on the phenyl ring and/or
the D-2-amino group are optionally in protected form a~d
in which other fu~ctional groups present are optionally
protected, and5 if desired, converting a resulting
compound in which the index n represent~ 1 into a
compound in which the inde~ n repre~ents O and/or, if
7~
~ 61 -
desired, oonverting ~unctional groups pre~ent in protected
form in a re~ulting compound into free functional group~
and/or conNerting a re~ulting salt into the free compound
or into a ~ifferent ~alt and/or ~onverting a resulti~g ~ree
compound that ~3~ a ~alt-~orming group into a salt
and/or separating a resulting miæture o~ isomeric compounds
into the individual isomers.
~ he novel compounds of the ~or~ula 7 in which
the ~unctional groups are either in free form or the 4-
carboxyl ~roup is optionally in an esterified ~orm that
can be ~plit under physiological conditions, a~d their
pharmaceutically acceptable non-toxic ~alt~ have valuable
pharma¢ological pr~perties~
~ hu~, oompound~ of the ~ormula V in ~ree ~orm or
in the form of their sal~s are effective ~n v~tro aga~n.
~ram-po~iti~e and gram-negative cocci, ~or example
~taPhyloQoccus aureu~, Streptococcus E~s~ or _isseria
., ln conoentration~ o~ from approxlmately 0.1 to
a~p~o~imatel~ 32 ~g/ml and against gram-negat~ve bacteria,
for example en~erobacteria, ~or example ~3cherichia col~,
Eleb~iel~a E~ 9~ Salmonella t~phimurium, Proteu~
., in concentration~ o~ from approgimateiy 2 to
appro2imately 64 ~g/ml, and a~ainst anaerobes~ for example
Chlostridium E~ e~, in a concentration of approxi~
mately ~ g/ml.
In ~i~o, in the case of peroral administration
to mice, compounds of the formula Y are e~fecti~e again3t
sy~temic infection3 caused by gram-positive cocci J ~or
example StaPhylococ_us aureus, and against gram negati~e
bacteria, for e~ample E3cherichia coli or Elebsiella
pneumoniae, in a do3age range o~ ~rom appro~imately
7 to ap~proximately 18 mg/kg, and ha~e a low toxicity.
In compounds of the ~ormula Y, R, Ro~ ~ and R~
have the pre~erred meanings given above under formula I.
78
_ 62 -
~ he functional groups present in compounds of
the formula V, e~pecially the 4-carbo~yl, the D-2 amino
and the h~droxy group on the phenyl ringJ are optionally
protected by the protecting groups given above under
formula I.
Salts o~ compound~ o~ the formula V are the
~alt~ given abo~e under formula I~
Compounds of the fonmula V have a chirality centre
at the carbon atom in the 2- or -position of the acetyl
radical. ~or the manu~acture of compoc~ds o~ the ~ormula
there are u~ed ~n ~he acylation pr~ferably compounds
of the ~ormula III in which the ~mino group in the 2-
po~ition of the acetyl radical ha~ ~he D-configuration.
~he~a compound~ can ~e obtalned, for e~a~ple, by ~eparating
racemic mixture~ o~ compound~ o~ the formula VI by means
of the con~entional method~
~ he acylation proce3s i~ carried out analogou~ly
to the processe~ described above l~der a).
Carbo~yl~c acids o~ the formula ~I in which ~1
repre3ents nitro or hydrogen are known from German
Of~enlegungs~chrift 2,444,762.
Compound~ of the formula VI in which R1 represents
a group of the partial formula (R)(Ro)~~ in which ~
r~presents an ac~l group havi~g the meanlngs given abovs
and ~0 repre~ent~ hydrogen, can be obtained, ~or e~a~ple,
by acylating a carboxylic acid of the ~ormula VI in which
R1 repre~ents a group o~ the partial ~ormula (R)(Ro)~~ in
which R and Ro represent hydrogen~ with the acyl radical
of a cQrrespondingly ~ub~tituted carboxylic acid or
sulphonic acid, o~ a carbonic acid semiester, carbamic
acid, thiocar~amic acid or amido~ulphonic acid, or a
reactive derivative of such acid~, for examp1e an acid
anh~dride, ~uch as an acid chloride. Compound~ o~ the
formula VI in which R1 represents a group of the partial
~ormula (R~(Ro)~- i~ which R represents an acyl group
~ 7~
_ 63 -
ha~ing the meanings given above and Ro represents lower
alkyl, can be obtained, ~or example, by alkylating a
free amino group on the phenyl ring b~ a suitable alkylatlng
agent that introduce~ the radical ~0, ~or e~ample an alkyl
halide, optionally i~ the presence of ba3e~, such a8 pyri-
dine, to ~orm the seco~dary amlno group and then acylating.
~ he present invention rela-tes al~o to no~el
s-tarting compounds, and i~termediates and processes for
the manu~actura thereof,
The no~el compounds of the formulae I and V
of the pre3snt invention can be used, for e~ample, for
the manufacture of pharmaceutical pre~arations that
contain an ef~ective quantity of the active ~ubstance
together or i~ admixture with inorganic or organic, ~olid
or liquid, pharmaceutically acceptable carriers that
are suitable for enteral or parenteral administration.
~hus~ tabl~t~ or gelat~n capsules are u~ed that contain
the active ~ubstance to~ether with dilue~ts, ~or example
lactose, de~trose~ sucrose, man~itol, sorbltol, cellulose
and~or gl~cine, and lubricants; ~or e~ample silica, talc,
stearic acid or salts thereo~ t such as magne~ium or calcium
~tearate, and/or polyethylene ~lycol; tablets also contain
binders~ for example magnesium aluminium silicate, ~tarches,
~uch as ma~æe~ wheat, rice or arrowroot starch~ gelatin~
tragacanth, methylcellulose, sodium carbo~ymethylcellulose
and/or polyv1nylpyrrolidone and, if desired~ disinte-
grating agents, ~or egample starches, agar, alginic acid
or a salt ther~of, such a~ sodium alginate,and/or ef~erves-
cing m~turss, or adsorbents,dyestuffs, ~1avouring sub~tances
and ~weeteners. It i9 also possible to use the novel
pharmacologically active compounds in the ~orm of injectable,
for example intravenously administrable) preparations
or in the ~orm of in~usion solutions. Such solu~ions
are pre~erably isotonic aqueous solutions or suspensions ,
~ 3
- 64 -
it being po_sible to manu~acture these before use, ~or
example ~rcm lyophili~qed preparations that contain the
active substance alone or together ~ith a carriar, for
example mannitol. The pharmaceutlcal preparations may be
sterilised and/or co~tain adjunct~, for e~ample pre~erva
tives, stabili~ers, wettin~ agent~ and/or emulsifiers,
solubiliser~, salt~ for regula~ing the osmotic pres~ure
and/or buffers. The pre~ent ~harmaceutical prepQration~,
which may, l~ de~ired, contain other pharmacologically
valuable ~qubstances, are manufactured in a manner known
e, for e~ample by means of conventional mi~ing,
granulati~g, dragée-making, dissolYing or lyophilising
proccsse~, and contai~ ~rom appro~imately 001% bo lO~o~
e~peciall~ ~rom appro~imately 1~o to apuroximately 5~/0,
a~d in the ca~e of lyophilisates up to 100%~ o~ the active
substance.
aompound~ o~ the formulae I and IV, e~pecially
tho3e in which R2 repre~ent~ an e~terified carboxyl
~roup that oan be split under phy~iological condib~ons,
for example pi~aloylox~metho~ycarbonyl, can also be ad-
mini3tered orally, ~or example in the form of capsule~.
~he~e contain the active ~ub~tance, optionally together
with suitable carriers, in the form of a granulate and
i~ doses of from approximate~y 0.2 g to approximately
0.5 g per do~age un~t.
Dependi~g on the type ¢ in~eation and the condi
tion of the ln~ected organism, daily do~es of from
0.5 g to 5 g 3.c~ or p~o. are used for the trsatment o~
warm-blooded animals weighing appro~imately 70 kg.
~L:a'7~Z'.`i~
- 6S -
The following Examples serve to illustrate the
invention. Temperatures are given in degrees Centigrade.
Example 1
a) 18 ml of cold trifluoroacetic acid are added to
a solution cooled to 0 of 3.5 g (4.7 n~ole) of 7~-
[D~2-tert.-butoxycarbonylamino-2~(3-methylsulphonylamino-
4-hydroxyphenyl)-acetylamino 3 -3-methoxyceph-3-em-4-
carboxylic acid diphenylmethyl ester and 3.5 ml of ani~ole
in 18 ml of absolute methylene chloride, the mixture is
stirred at 0 for 45 minutes under a nitrogen atmos~hers
and then, at 0, 100 ml of diethyl ether are added. The
b~ige precipitate i~ filtered o, wa~hed with a smalll
quantity o~ diethyl ether and dried und~r reduced pressura.
The requlting t~ifluoroace~ia acid ~alt o~ 7~-CD-2-amino-
2-(3-methylsulphonylaml~o-4-hydro~y~hanyl) -acetylamino] -
3-methoxyceph-3-em-4-carboxylic acid i~ dissolved in 20 ml
of ice water and extracted with ethyl acetate (5 x 10 ml ).
The acidic aqueou~ phase (pH 2) i~ adjusted to pH 4.5
by the dropwi~e addition of 2~ qodium hydroxide solution
and, at 0, ethanol ~100 ml) i9 added. The precipitate
~ormed i~ filtered off, washed with ~0 ml of water/ethanol
1-4, taken up in approximately 10 ml of water in order to
remove the organic solvent and concentrated in a rotary
evaporator. After drying, ~16 hours, room temperature,
0.05 torr), 7~-[D-2-amino-2-(3-methylsulphonylamino~-
hydroxyphenyl)-acetylamino]-3-methoxyceph-3-em-~-carboxylic
acid is ob~ained in the form of a monohydrate.
Melting point: from 150 (with decomposition~;
~LC (silica gel, developing with ninhydrin): R~ 0.46
(system: secO-butanol/acetic acid/water 67:10:23),
W spectrum (in 0.1N aqueous hydrochloric acid~: 278 nm
( F = 7700),
~7~
- 66 -
~]D = ~144 + 1 (in 0.1~ aqueou~ hydrochloric acid,
c - 1.34~ ~0).
The ~tarting material may be obtained as ollows:
b) To a solution cooled to -15 of S.26 g t14.6
mmole) of D~2-tert.-butoxycarbonylamino-2-(3-methyl-
sulphonylamino-4-hydrox~phenyl)-acetic acid and 1.6 ml
of ~-methylmorpholine in 100 ml of absolute tetrahydro-
furan there are added, under a nitrogen atmo~phere,
1.9 ml of chloroformic acid isobutyl ester and, after one
~our, 6.3 g (14.6 mmole) of 7~-amino-3-methoxyceph-3-em-4-
carboxylic acid diphenylmethyl ester hydrochloride and
1.6 ml of N-methylmorphQline. After stirring at room
temperature for 3 hour~, the reaction mixture is diluted
with ethyl acetate, wa~hed twice with ice water and twice
with saturated sodium chloride solution, dried over ~odium
sulphate and ~reed of solvent in a rotary e~aporator.
The residue i~ purified on ~ilica gel using diethyl
ether~ethyl acetate 1:1 as eluant, yielding 7~-tD-2-tert.-
butoxycarbanylamino-2-~3-methyl2~ulphonylamino-4-hydroxy
phenyl)-acetylamino~-3-methoxyceph~3~em-4-carboxylic
acid diphenylmethyl ester in the form of a colourless
amorphous powder.
TLC (silica gel, identification with iodine) R ~ .26
tdiethyl ether/ethyl acetate 1
Exam~e 2
a) In a manner analogous to Example la), 7~-[D~2-
a~ino-2-(3-methylsulphonylamino 4-hydroxyphenyl~-
acetylamino~-ceph-3-em-4-carboxylic acid is obtained in
the form of a 1.5 hydrate by treating 2.13 g ~3 mmole)
of 7~D-2-tert.-butoxycarbonylamino-2-(3-methylsul-
phonylamino-4-hydroxyphenyl)-acetylamino~-ceph-3-em-4-
carboxylic acid diphenylmethyl e~ter with 10 ml of tri-
fluoroacetic acid and 2 ml of anisole in 10 ml of absolute
methylene chloride.
- 67 -
Melting point: from 20Q with decomposition,
TLC (~ilica ~el, developing with ninhydrin): R ~ .1g
(system: sec.-butanol/acetic ac.id/water 67:10:23),
W spectrum (in o~lN a~ueous hydrochloric acid: 232 nm
( F = 11600), ~70 nm (~houlder):
Ca~D = + 122 ~ 1 to.lN a~ueou3 hydrochloric acid,
c = l.353 %).
The starting material may be obtained as follow~:
b) In a manner analogous to Example 1b)l 7~-
[D-2-tert.-butoxycar~onylamino-2-~3-methylsulphonylamino-
4-hydroxyphenyl)-acetylamino]-ceph-3-em~4-carboxylic acid
diphenylmethyl ester i~ obtained by treating a mixed
anhydride, obtained from 3.6 g (lo.o mmole) of D-2-tertO-
butoxycarbonylamino-2-~3-methylsulphonylamino-4-hydroxy-
phenyl)-acetic acid and 1.3 ml of chloroformic acid
isobutyl ester in the presence of 1.1 ml of N-methyl-
morpholine and 100 ml of absolute tetrahydrofuran at
-15, with 3.66 g (10 mmole) of 7~-aminoceph -3-em-4-
carboxylic acid diphenylmethyl ester according to the
proces~ described in Example 1b).
~LC (~ilica gel, identification with iodine): Rf~0.48
(ethyl acetate).
~) In a manner analogous to Example 1a), 7~-[D-2-
amino-2-(3-methylsulphonylamino-4-hydroxyphenyl)--
acetylamino~-3-chloroceph-3-em-4-carboxylic acid is
obtained in the form of a monohydrate by treating 2.3 g
(3.1 mmole) of 7~-[D-2-tert~-buto~carbonylamino-2-
(~-methylsulphonylamino-4-hydroxyphenyl)-acety1amino]-
3-chloroceph-3-em 4-carboxylic.acid diphenylmethyl
ester with 11 ml of trifluoroacetic acid and 2.3 ml
of anisole in 11 ml of absolute methylene chloride
according to the process described.
Z Lr O
_ 68 -
Melting point: from 172 with decomposition
TLC (3ilica gel, developing with ninhydrin~: R~-0.16
(system: sec.-butanol/acetic acidJwater 67:10:23)
W spectrum (in 0.1N aqueous hydrochloric acid):
235 nm (~houlder), 270 n~ (~ a 8600 );
C~]D = ~9~ ~ 1 ~0.1~ aqueous hydr~chloric acid,
c = ~.313 %~.
The starting material may be obtained as follows:
b) In a manner analogous to Example 1b), 7~ 2-
tert.-butoxycarbonylamino-2-(3-methylsulphonylamlno-4-
hydroxyphenyl)-methylamino]-3 chloroceph-3-em-4-carboxylic
acid diphenylmethyl ester is obtained by treating a
mixed anhydride, obtainPd from 3.0 g ~8.3 mmole) of D-2-
~ert.-butoxycarbonylamino-2-~3-m2thylsulphonylamino-4-
hydroxyphenyl3 -acetic acid and 1.'l ml of chlo~of~rmic
acid isobutyl ester in the presence o~ 0.32 ml of N-
methylmorpholine and 100 ml of absolute tetrahydrofuran
at -15, with 3.33 g ~8.3 mmole~ of 7~-amino-3-chloro-
ceph-3 em-4-carboxylic acid diphenylmethyl ester according
to the proces~ de~cribed in Example 1b).
TLC (silica gel, identification with iodine): R~0~38
(toluene/ethyl acetate 1:1).
a) 20 ml of cold trifluoroacetic acid are added to
a ~o}ution c~oled to 0 of 3.8 g (5.75 mmole) of 7~
~D-2-tert.-butoxycarbonylamino -2-(3-amino-4-hydroxyphenyl)-
acetylamino-3-methoxyceph-3-em-4-carkoxylic acid diphenyl-
methyl ester and 3.8 ml of ani30le in 20 ml of absolute
methylene chloride, the mixture is stirred at 0 for 45
minutes under a nitrogen atmosphere and then 200 ml of
petroleum ether/diethyl ether 1-1 are added. The beige
precipitate i~ filtered off, wa~hed with a $mall quantity
of diethyl ether, then dissol~ed in 40 ml of ice water
and extracted with ethyl acetate (4 x 20 ml). The a~ueous
~:~7~J~7~
_ 69 -
phase (pH~2) is adjusted to pH 5 wnth ~N sodium hydroxide
qolution, concentrated to approximately half it~ volume
under reduced pre~ure and, at 0, ethanol (80 ml) i5
added dropwi~e. The re~ulting crude product, 7~-[D-2-
amino-2-(3-amino-4-hydroxyphenyl)-acetylamino]-3-
methoxyceph-3 em-4-carboxylic acid,i~ purified on
Amberlite XAD- ~u~ing water/i~oprop~no.l ~8:12 as eluant.
Melting point: from 150 with decompo~ition.
TLC (~ilica gel, developing with ninhydrin)0 R ~ .13
(sec.-butanol/acetic acid/water 67:10:23).
The starting material may be prepared a~ follow~:
b) A solution of 8 g (11.6 mmole) of 7~-~D-2-tert.-
butQxycarbonylamino -2-(3-nitro-4-hydroxyphenyl~-
ac~tylaminoJ-3-m~thoxyceph-3-em-4-carboxylic acid d.iphenyl-
m~thyl aster in ethyl acetate (150 ml) i~ hydrogenaited in
the pre~ence of 2 g of palladium c æ bon (10 ~) a5 c,~taly9t~
After the theoretical quantity (778 ml) of hydrogen ha~
been absorbed, the reaction m~cture i~ filtered over
Celite~)and ~reed of solvent under reduced pres~sure. Ihe
reqidue i9 then purified on silica gel u~ing ethyl
acetate a-~ eluant, yielding 7~-[D-2-tert.-butoxycarbonyl-
amino-2-(3-amino-4-hydroxyphenyl)-ace~ylamino]-3-methoxy~
ceph-3-em 4-carboxylic acid diphenylmethyl ester in the
form of an amorphou~ heige powder.
TLC ~silica gel, d~veloping with iodine): R~-o.35 ~ethyl
acetate).
C) To a ~olution cooled to -15 of 10.9 g (35 r~mole)
of D-2-tert.-butoxycarbonylamino-2-(3-nitro-4-hydroxy-
phenyl~-acetic acid and 3.9 ml of ~-methylmorpholine in
350 ml of absolute methylene chloride ~here are added,
under a nitro~en atmosphere, 4.6 ml o~ chloroformic acid
i~obutyl ester and later 15.15 g (35 mmole) of 7~-amino-
3-methoxyceph-3-em-4-carboxylic acid diphenylmethyl ester
hydrochloride and 3.9 ml of N-methylmorpholine. After
stirring at room ~emperature for 3 hours, the reaction
h ~``
_ 70 -
mixture is diluted with ethyl acetate, washed twice wi th
ice water and ~wice with saturated sodium chloride
solution, dried over sodium sulphate and freed of solvent
in a rotary e~aporator. The residue i~ purified on
~ilica gel using diethyl ether/ethyl acetate 3:1 as
eluant, yielding 7Q-[D-2-tert~-bu~oxycarbonylamino~2-
(3-nitro-4-hydroxyphenyl)-acetylamino~3-methoxyceph-3-
em-4-carbcxylic acid diphenylmethyl ester in the form o
a colourless amorphous powder.
T~C ~ilica gel, identification with iodine): R~Oo 65
(diethyl ether~ethyl acetate 1:1).
d) ~hile stirring, a su~pension cooled to 0 of 30 g
(0.14 mole~ o~ D-2-amino-2-(3-nitro-4-hydroxyphenyl)-
acetic acid in 140 ml of water is adju~ted to pH 7 with
2N sodium hydroxide solution, then diluted with 280 ml
o~ dioxan, and 15 g (0.14 mole) of sodium carb~nate and
33.8 g (0.15 mole) o dl-ter~.-butyldicarbona~e are added.
~fter a reaction period of 3 hour~ at room temperaturQ,
the reaction mixture, cooled again to 0, i9 adjusted to
pH 7 wnth 4N hydrochloric a~id and freed of the 901vent S
in a rotary e~apvrator. The oily residue i~ taken up in
1~ sodium bicarbonate solution (200 ml3 and extracted
with diethyl ether (4 x 100 ml)~ The aqueous pha~e i9
then adiusted to pH 2 with 4~ hydrochloric acid a~d
extracted with ethyl acetate (4x 1 50 ml ) . The combined
organic pha~es are dried over sodium sulphate and freed
of ~olvent under xeduced pressure, yielding D-2-tert.-
butoxycarbonylamino-2-(3-nitro-4-hydroxyphenyl)-acetic
acid.
TLC: (~ilica gel, indentification with ninhydrin3:
Rf-0.73 (sec.-butanol/acetic acid/water 67:10;23).
e) While stirring, 33.4 g (0.2 mo~e) of D-2-amino-
2-(4-hydroxyphenyl)-acetic acid are added, in portions,
to 40 % nitric acid (86 ml) cooled to 0. After 3 hours
~7~
_ 71 -
at room temperature, the reaction mixture, cooled again
to 0, is diluted with 40 ml of ice water and adjusted
to pH 3.5 with 2~ sodium hydroxide solution (250 ml).
The resulting precipi~ate is then fil~ered off, washed
with a small quantity of ice water and dried in a high
~acuum to constant weight. D-2-amino-2-~3-nitro-4-
hydroxyphenyl~-acetic acid is obtained in the ~nm of a
yellow powder which can ke used in the next reaction
step without further purification.
TLC (~ilica yel, identification with ninhydrin): Rf~0.38
(sec.-~utanol/acetic acid/water 67:10:23).
In a manner analogous to Example 4a), 7~-[D-2-
~mino-2-(3-nitro-4-hydroxyphenyl)-acetylamino]-3-
metboxyceph~3~em-4-carboxylic acid is obtained by treating
3.4S g t5.0 mmole) o~ 7~-[~-2-tert. butoxycarbonylamino-
2-t3-nitro-4-hydroxyphenyl)-acetylamino]-3-methoxyceph-
3-em-4-carboxylic acid diphenylmethyl e~ter with 17 ml
of tri~luoroacetic acid and 3.5 ml o~ anisole in 17 ml
of absolute methylene chloride.
Melting point: fro~ 160 with decomposition:
TLC (silica gel, developing with ninhydrin): R ~ ~31
(n-butanol/acetic acid/water 45:45:10~:
W (0.1N ~aHC03 solution~: 216 nm ( = 17100), 268 nm
(~ = 7200), 343 nm (~ = 2280).
~mBa~
a~ 5 ml of cold trifluoroacetic acid are added to
a solution cooled to 0 of 0~95 g (1.4 mmole) of 7~-
ED-2-tert.-butoxycarbonylamino-2-(3,5-diamino-4-
hydroxyphenyl)~acetylamino 3 3-methoxyceph-3-em-4-car~oxylic
acid diphenylmethyl ester and 1.0 ml of anisole in 5 ml
of absolute methylene chloride, and the mLXtUre i3 stirred
at 0 under a nitrogen atmosphere for 45 minutas, and then
- 72 -
100 ml of diethyl ether are added. The beige precipitate
is filterecl off, washed with a small q~lantity o~ diethyl
ether, then poured into 10 ml of ice water and extracted
with ethyl acetate (4 x 10 ml). The aqueous phase
(pH~~) is adjusted to pH 5 with 1~ sodium hydroxide
solution and then, at 0, 50 ml of isopropanol are addea
dropwi~e. The resulting crude product, 7~-[D-2-amino-2-
(3,5-diamino-4-hydroxyphenyl)-acetylamino]-3-mRthoxyceph-
3-em 4-carhoxylic acid~is puriied on Amkerlite XAD-2
using water/isopropanol 88:12 as eluant.
TLC (silica gell developi~g with ninhydrin): Rf~0.05
(sec.-butanol/acetic acid/water 67:10:~3),
W spectrum (in o.1N aqueous hydrochloric acid):
250 nm (~houlder), 270 nm ~7800).
The starting material may be prepared as ~ollow~:
b) A solution of 2.S g t3~ mmole) o 7~-[~-2-tert.-
bu~oxycarbonylamino-2-(3,5-dinitro-4-hydroxyphenyl)-
acetylamino]-3-methoxyceph-3-em-4-carboxylic acid di-
phenylmethyl ester in ethyl acetate (50 ml) i~ hydrogenated
in the presence of 2 g of palladium-carbon ~10 %) as
catalyst. After the theoretical quantity of hydrogen has
been absorbed, the reaction mixture is filtered over
Celite and freed of solvent under reduced pressure. The
residue is then purified on ~ilica gel using ethyl acetate
as elua~t, yielding 7~-[D-2-tert.-butoxycarbonylamino-2-
(3,5~diamino~4 hydroxyphenyl~-acetylamino]-3-methoxyceph-
3~em-4-carboxylic acid diphenylmethyl ester in the form of
an amorphous brown powder.
TLC (silica gel, developing with iodine): Rf~o.1o
(ethyl acetate~.
c) To a solution cooled to -15 of 7.14 g (20 mmole)
of D-2-tert~-butoxycarbonylamino-2-~3,5-dinitro-4-
hydroxyphenyl)-acetic acid and 2.2 ml of ~-methylmorpholine
in 200 ~1 o~ absolute methylene chloride there are added,
_ 73 -
under a nitrogen atmosphere, 2.6 ml of chloro~ormic
acid isobutyl ester and, after one hour, 8.66 ~ (20
mmole) of 7~-~mino-3-methoxyceph-3-em-4-carboxylic
acid diphenylmethyl ester hydrochloride and 2.2 ml of
~-methyLmor~holine. Ater 3 hours at room temperature,
the reaction mixture is diluted with ethyl acetate,
washed twice with ice water and twice with ~aturated
sodium chloride solution, dried over ~odium sulphate
and freed of solvent in a rotary evaporator. The
residue i~ purified on 3ilica gel using ethyl acetate
a~ eluant, yielding 7~-~D-2-tertO-butoxycarbonylamino-
2-(3,5-dinitro-4-hydroxyphenyl)-acetylamino]-3-methoxy-
ceph-3-em-4-carboxylic acid diphenylmethyl ester in the
form ofan amorphous yellow powder.
TLC (silica gel, identification with i~dine): R~Oa25
(ethyl acetate).
d) ~t 0~5~ ~6 ml O~ nitric acid are added dropwise,
while 3tirring, to a 3u~pension o~ 33.44 g ~0.2 mole) of
D-2-amino-2-(4-hydroxyphenyl)-acatic acid in 56 ml of
concentrated sulphuric acid. After a reaction period of
2 hour~ at 20-25, the reaction mixture is diluted with
160 ml of ice water, adjusted to pH 7 with 2N sodium
hydroxide solution and concentrated to approximately
200 ml under reduced pressure. After the addition of
400 ml o~ dioxan and 21.2 g of sodium carbonate, 48 g of
di-tert.-butyl dicarbonate are added. After 3 hour~,
the reaction mixture iY concentrated in order to remove
~he organic solvent, diluted again with water ~200 ml)
and extracted with diethyl ether (2 x 200 ml). The
aqueous phase is then adjustad to pH 2 with 4N hydro-
chloric acid and extracted with ethyl acetate (4 x 200 ml).
Ater dryin~ the combined organic phases over sodium
sulphate, the solvent is removed in a rotary evaporator.
- 74 -
The resulting D-2-tert.-butoxycarbonylamino-2-(3,5-
dinitro-4-hydroxyphenyl)-acetic acid is a pale yellow
crystallisate.
Melting point: 96-98:
TLC (silica gel, identification with iodine):
Rf-0.68 (~ec.-butanol/acetic acid/water 67~10:23).
Example 7
15 ml of cold trifluoroacetic acid are added to
a solution cooled to 0 of 2.94 g ~4 mmole) of 7~-
~D-2-tert.-butoxycarbonylamino-2~(3,5-dinitro-4-hydroxy-
phenyl)-acetylamino]-3-methoxyceph-3~em-4-carboxylic- acid
diphenylmethyl ester (Example 6c)) and 3 ml of anisole
in 15 ml of absolute methylene chloride, stirred at 0
under a nitrogen atmosphere ~or 4S minutes and then 150 ml
of diethyl ether are added. The resulting yellow
precipitate is ~iltered off, washed with a small quant~ty
o~ diethyl ether, then taken up in 20 ml of ice water.
The aqueous phase i~ adjusted to pH 4.5 with 2N sodium
hydroxide solution, isopropanol (80 ml) is added drop-
wise thereto and the mixture is stirred for approximately
30 minutes. After filtration, in order to remove the
organic solvent, the 7~-[D-2-amino-2-~3,4-dinitro-4-
hydroxyphenyl~-acetylamino]-3-metho~yceph-3 em-4-carboxylic
acid. i3 suspended twice in a ~mall quantity of water and
concentrated to dryness under reduced pressure.
TLC (silica gel, identification with ninhydrin):
R ~ .15 (sec.-butanol/acetic acid/water 67:10:23)
[a3D = +1~5 f 1 (in 0.1~ aqueous hydrochloric acid,
c = 0.17g %).
~7~
_ 75 -
~m~2~
In a manner analogous to Example 6a~, 7~-~D 2-
amino-2-(3,4-diamino-~-hydroxyphenyl)-acetyl~mino]
ceph-3-em-4-carboxylic acid i~ obtained b~ treating
1.7 g (2.6 mmole) of 7~-~D-2-tert.-butoxycarbonyl-
~mino-2-(3,5-diamino 1-hydroxyphenyl)-acetylamino]-
ceph-3-em-4-carb~xylic acid diphenylmethyl ester with
107 ml of an~ole and 8~5 ml o~ tri~luoroacetic acid
in 8.5 ml of absolute methylene chloride according to
the process described.
Melting p~int- ~rom 190 (decomposition),
TLC (silica gel, identifica~ion with ninhydrin):
Rf~0.05 (sec.-butanol/acetic acid/water 67:10:23):
~a~D - ~14~ ~ ~ (in o~1~ aqueou~ hydrochloric acid,
c = 0.181 %).
~,2a~
a) In a mannar analogous to Example 1a), 7~-
~D-2 amino-2-(3-ethylsulphonylamlno-4-hydroxyphenyl)-
acetylamino]-ceph-3-em-4-carboxylic acid is obtained in
the form of a dihydrate ~y treating 2 g (2.77 mmole) o~
7~-[D-2-tert.-butoxycarbonylamino-2-(3-e~hylsulphonyl-
amino-4-hydroxyphenyl)-acetylamino]-ceph-3-em-4-carboxylic
acid diphenylmRthyl ester with 10 ml of trifluoroacetic
acid and 2 ml of anisole in 10 ml of absolute methylene
chloride.
Melting point: from 181 with decomposition.
The ~tarting material may be prepared as follows:
b) 3.664 g (10 mmole) of 7~-aminoceph -3-em-4-
carboxyli~ acid diphenylmethyl ester and 3.743 g (10 mmole)
of D-2-tert.-butoxycarkonylamino-2-(3-ethylsulphonylamino-
4-hydroxyphenyl)-acetic acid are added to 80 ml of
~7~
- 76 -
tetrahydrofuran and the mixture is cooled to 0 5~
2.063 g ~10 mmole) of N,N'-dicyclohexylcarbodiimide
dissolved in 20 ml of tetrahydrofuran are added drop-
wise to the yellow solution~ The mixture is stirred
for 1 hour at 0-5 and for 3 hours at room temperatureO
The yellow suspension i9 iltered with suction and
washed with THF. The solvent i9 removed at 30 in
vacuo, yielding a yellow foamy residue to which 500 ml
of ethyl acetate are added~ The organic phase is then
washe~ 4 times using 60 ml of ice water each time and
shaken once with 50 ml of saturated sodium chloride
~olution. The ethyl acetate pha~e is dried over sodium
sulpha~e and filtered. The solver~t is removed at
30 in vacuo, yielding 7~-~D-2-tert.-butoxycar~onylamino-
2-(3rethyl~ulphonylamino-4-hydroxyphenyl)-acetylamino]-
ceph~3-em-4-carboxylic acid diphenylme~hyl ester in ~he
orm of a yellow foam~ residue.
c) 2.823 g t10 mmole) of D-2-tert.-butoxycarbonyl-
a~ino-2-(3-amino-4-hydroxyphenyl)-acetic acid are added
to 56 ml of mRthylane chloride. 5064 ml to.o2 mole) of
87 % strength ~,0 bis-~trimethylsilyl~-acetamide are
added dropwi~e thereto over a period of 10 minutes and
the mixture is qtirred at room temperature for ~ hour.
1~61 ml (0.02 mole) of pyridine are then addedand the
mixture is cooled to 0-5~. 1.89 ml (0~02 mole) of
ethane sulphochloride are added and the mixture is
maintained at 0~ for ~ hour and then, after heating,
at room temperature for 2 hour ~ The solvent is eva~orated
off, ethyl acetate i~ added to the reAidue and the mixture
is then washed twice with dilute hydrochloric acid
solution. The ethyl acetate pha~e is extracted several
times with dilute 5 ~ strength s~dium bicarbonate solution.
The aqueous phases are combined and adjusted to pH~ with
approximately-25 ml of 2~ hydrochloric acid~ The product
~3L7~
- 77 -
that is thus precipitated out i5 extracted several
times with ethyl acetate. The organic phases are
combined, washed with saturated sodium chloride
solution, dried over sodium sulphate, filtered and
concentrated. D-2-tert.-butoxycarbonylamino-2-(3-
ethylsulphonylamino-4-hydroxyphenyl)-acetic acid is
obtained in the form of a pinkish-beige foam.
TLC (silica gel, identification with iodine):
Rf 0078 (sec.-butanol/acetic acid/water 67:10:23).
Example 10
a) ~n a manner analogous to Ex~mple la), 7~-~D-2-
amino-2-(3-ethylsulphonylamino-4-hydroxyphenyl)-
ac~tylamino]-3-chloroceph-3-em-4-carboxylic acid is
obtained in the form o~ a 1.5 hydrate by treating
3.4 g (4.5 mmole) of 7~-CD-2-tert.-butoxycarbonylamino-
2-(3-ethylsulphonyl2mino-4-hydroxyphenyl)-acetylamino]-3-
chloroceph-3-em-4-carboxylic acid diphenylmethyl ester
with 17 ml of trifluoroacetic acid and 3~4 ml of anisole
in 17 ml of absolute methylene chloride according to the
proces~ described.
Melting point: from 165 with decompo~ition.
TLC (silica gel, developing with ninhydrin):
R~0.34 ~ystem : sec.-butanol/acetic acid/
water 67:10:23),
~]D = +95 ~ 1 (O,lN aqueous hydrochloric acid,
c = 1.163 %).
b) In a manner analogous to Example ~b), 7~-~D-
2-tert.-butoxycarbonylamino-2-~3-ethylsulphonyl~mino-
4-hydroxyphenyl)-acetylamino~-3-chloroceph-3-em-4-
carboxylic acid diphenylmethyl ester is obtained from
3.74 g (10 mmole) of D-2-tert.-butoxycarbonylamino-2~
~3-ethylsulphonylamino-4-hydroxyphenyl~-acetic acid and
- 78 -
4.0 g (10 mmole) of 7~-amino-3-chloroceph-3-em-4-
carbo~ylic acid diphenylmethyl ester in the presence
of 2.06 g (10 mmole) of ~,~'-dicyclohe:~ylcarbodiimide
in tetrahydrofuran according to the process described.
~,2a~
a) In a manner analogous to Example ~a), 7~-~D-
2-amino-2-(3-ethylsulphonylamino-~-hydroxyphenyl)-
acetylamino~-3-methoxyceph-3-em-4-car~oxylic acid is
obkained in the form of a monohydrate by treating 2074 g
(3.6 mmole) of 7~D-2-~er~-butoxycarhonylamino-2-
(3-ethylsulphonylamino-4-hydroxyphenyl~-acetylamino]-3-
methoxyceph-3-em-4-carboxylic acid diphenylmethyl ester
with 14 ml of trifluoroacetic acid and 2.7 ml o~ anisole
in 14 ml o absolute methylene ch~oride according ~o
the process described.
MRlting point: from 190~ with decompo~ition,
TLC ~silica gel, developing with ninhydrin: R~Vo.32
(system: ec.-butanol/acetic acid/water 67:10:23);
W ~pactrum (in 0.1N aqueou~ hydrochloric acid):
279 1~111 ( = 825Q ),
~]D = +138 + 1 (0.1N aqueous hydrochloric acid,
c = 0.967 %).
b) In a manner analoyous to Example 9b), 7~-~D-
2-tert.-butoxycarbonylamino-2.-(3-ethylsulphonylamino-
4-hydroxyphenyl) acetylamino}3-methoxyceph-3-em-4-
carboxylic acid diphenylme~hyl ester is obtained from
2~28 g (6.1 mmole) of D-2-tert.-butoxycarbonylamino-2-
(3-ethylsulphonylamino-4-hydroxyphenyl)acetic acid and
2.12 g (6.1 mmole) of 7~-amino-3-methoxyceph-3-em-4-
carboxylic acid diphenylmethyl ester in the presence of
1.26 g (6.1 mmole~ of N,N'-dicyclohexylcarkcdiimide in
tetrahydr~furan according to the pr~cess decribed.
-- 79 --
TLC ( ~;ilica gel, identification with iodi.ne):
R~O. 34 ~ diethyl ether/ethyl acetate 1:1 ) .
~e~
a) In a m~nner analogous to Examp~.e la ), 7~-~D-2
amino- 2- ~ 3-acetylamino-4-hydrox~henyL )-acetylamino]-
3-methoxyceph-3-em-4-~ar~oxylic acid is o~tained in
the form of a monohydrate by treating 1. 32 g ( 1. 88 mmole)
of 7~-~D-2-tert.-butoxycarbonylamino-2-(3-acetylamino-
4-hydroxyphenyl)-acetylamino]-3-methoxyceph -3~em-4-
carboxylic acid diphenylmethyl ester with 6.60 ml of
trifluoroacetic acid and 1.32 ml of ani~ole in 6.60 ml
of a~solute methylene chloride.
~elting point: from 149 with decomposition:
TLC (sili~a gel, identification with ninhydrin):
0~22 (~ec.-butan~l/acatia acid~water 67:10:23~,
~]D w ~156 + 1 (O~lN aqueous hydrochloric acid,
c = O.90C~ %).
The ~tarting material may ~e prepared as follows:
b) 2.38 g (5.5 mmole) of the hydrochloride of 7~
amino 3-methoxyceph-3-em-4-carboxylic acid diphenyl-
methyl e~ter, la78 g (5.5 mmole) of D~2-tert.-butoxy-
carbonylamino-2-(3-acetylamino-4-hydroxyphenyl)-acetic
acid and 0.64 ml (5.5 mmole) of 2,6-lutidine are ad~ed
to 80 ml of tetrahydrofuran and the mixture is cooled
to 0. 1.13 g (5.5 mmole) of ~,~'-dicyclohexylcarbodiimide
di~solved in 10 ml of tetrahydrofuran are added dropwise
to the white suspen~ion. The mixture is stirred at room
temperature for 1 hour. The beige suspension is filter2d
with ~uction and washed with THF. The solvent is removed
at 30 in vacuo, yielding a yellow foamy residue to which
250 ml of ethyl acetate are added. The mixture is then
shaken ~everal times with 25 ml of 5 % ~trength sodium
bicarbonate solution and ~uffer so}ution ~pH = 2.06).
'Z~
- ~o -
The ethyl acetate pha e is washed several times with
saturated sodium chloride solution, dried over sodium
sulphate and filtered off. The solvent is removed at
30~ ~n vacuo, yielding 7~-~D-2-tert.-butoxycarbonylamino-
2-(3-acetylamino-4-hydroxyphenyl)-acetylamino~-3-
methoxyceph-3-em-4-carboxylic acid d:iphenylmethyl ester.
TLC (silica gel, identiication with iodine):
Rf 0.39 (ethyl acetate).
c~ 4.23 g ~15 mmole) of D-2-tert.-butoxycarbonyl-
amino-2~(3-amino-4-hydroxyphenyl)-acetic acid are added
to 85 ml of methylene chloride. 7.35 ml (30 mmole) of
87 % strength N,O-bis-(trimethylsilyl)-acetamide are
added dropwice thereto and the mixture i~ stirred at
room temperature for ~ hour. 2.42 ml ~30 mmol~) of
pyridine are then added and the dark yellow solution is
cooled to 0-5. 2.13 ml (30 mmo~e) of acetyl chloride
are added thereto and the mixture i~ maintained at 0
for ~ hour and then, a~ter heatin~, at room temperature
for 2 hours. The solvent i~ evaporated off, ethyl
ac~tatc i9 added to the residue and the mixture is wa~hed
twice with dilute hydrochloric acid solution. The organic
phase is extracted several times with 5 % strength sodium
bicarbonate ~olution. The aqueous phases are combined
and adjusted to p~2 with approximately 30 ml of 2~
hydrochloric acid~ Ethyl acetate is added to the aqueous
phase. The organic pha~e is then washed with saturated
sodium chloride solution, dried with sodium sulphate and
concentrated. D-2-tert.--butoxycarbonylamino 2-~3-acetyl-
amino-4-hydroxyphenyl)-acetic acid is obtained in the
form of a yellow powder.
TLC (silica gel, identification with iodine):
R~o~ 75 (sec.-butanol/acetic acidJwater-67:10:23).
~ ~ 7
- 81
Examole .13
a) 20 ml of cold txi~luoroacetic acid are added to
a solution cooled to 0 of 4.1 g (4.9 mmole) of 7~-[D-
2-tert.-butoxycar~onylamino- 2- ~ 3, 5-bis- (methylsulphonyl-
amino)-4-hydroxyphenyl)-acetylamino~-ceph-3-em-4-
carboxylic acid diphenylmethyl ester and 4.1 ml of anisole
in 20 ml of absolute methylene chloride, the mixture is
stirred at 0 under a nitrogen atmo~phere for 1 hour
and then,at 0~, 300 ml of diethyl ether are added thereto.
The beige-coloured precipita~e is filtered off, washed
with a small quantity of diethyl ether and dried under
reduced pre~sure. The re~ulting acetic acid ~alt o
7~- rD- 2-tert.-butoxycarbonylamino-2-(3,5-bi~-(methyl-
~ulphonylamino)-4-hydroxyphenyl)-acetylamino~-ceph-3-
em-4-carboxylic acid is di~solved in 30 ml of acet:ic acid
and extracted with 4 x 15 ml of ethyl acetate. ~le
acidic aqueous phase (approximat~ly pH 2) i~ adju~ted
to p~ 4.8 by the dropwise addition of 2~ sodium hy~roxide
~olution, concentrated to approximately 20 ml i~ a
rotary evaporator a~d, at 0, 60 ml o~ iqopropanol
are added. The precipitate formed i9 filtered of
and wa~hed with 20 ml of isopropanol/water (1:4) and
20 ml of isopropanol. The crude product i~ then purified
by column chromatography (silica gel: Opti-UPC12 by
Antec) using water/acetonitrile (19:1) as eluant, and,
after the removal of the solvent and drying, (16 hours
at room temperature and 0.05 torr), 7~-~D-2-amino-2-
~3,5-bis-(methyl~ulphonylamino)-4-hydroxyph2nyl)-
acetylamino]-3-metho~yceph-3-em-4-carboxylic acid is
obtained in the form of a dihydrate.
Melting point: from 150 (with decomposition):
$LC (~ilica gel, developing with ninhydrin) R~: approximately
0.18 (system: sec.-butanol/acetic acid~water 67:10:23),
~7~2~
- 82 -
W ~pectrum (in O.lN aqueous hydrochloric acid):
281 nm (E = 8120),
~a]D ~ +107 - 1 - ( in 0. lN aqueou~ hydrochloric acid,
c = 1~054 %).
The 3tarting material may be obtained a~ follow~:
b) A solution of 2.476 g ~12 mmole) of ~
dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran is
added dropwise to a suspension cooled to 0-5 of 4. 76 g
(12 mmole~ of 7~-amino-3-methoxyceph-3-em-4-car~oxylic
acid diphenylmethyl ester and 5.44 ~ (12 mMole) of D-2-
tert~-butoxycarbonylamino-2-~3,5~bis-lmethylsulphonyl-
amino)-4-hydroxyphenyl}-acetic acid in 50 ml of tetra-
hydrofuran. After a reaction period of l hour at 0-5
and 3 hours at room temperature, the precipitate formed
is filtered off from the ~,N'-dicyclohexylurea and
waqhed with a small ~uantity of tetrahydro~uran. After
removing th~ ~olvent, the yellow residue is dis~olved
in 500 ~l of ethyl acetate, and washed 4 times with
50 ml of 5 % strength sodium bicarbonate solution (pH = 2)
and 4 times with ~aturated sodium ~hloride solution.
After drying the organic phase over ~odium sulphate and
removing the solvent in a rotary evaporator, the crude
product i8 purified by column chromatography (silica
gel) using diethyl ether/ethyl acetate (2:1) as eluant,
yielding 7~-[D-2-tert.-butoxycarbonylamino-2-(3,5-bis-
(methylsulphonylamino)-4-hydroxyphenyl)-acetylamino~-
3-methoxyceph-3-em-4-carboxylic acid diphenylmethyl
eqter .
TLC (silica gel, identification with iodine):
Rf-0.28 (ethyl acetate).
c) 6.7 ml (27.3 mmole)-of ~,0-bis-(trimethylsilyl)-
acetamide are added, with the exclusion of moisture and
while stirring, to a solution of 5.4 g (18.2 mmole) of
D-2-tert.-butoxycarbonylamino-2-(3,5-diamino-4-hydroxy-
phenyl)-acetic acid in lO0 ml of abso}ute methylene
- 83 -
chloride and the mixture i9 allowed to react for 1 hour~
After the addition of 4.4 ml of pyridine and 4.24 ml
(54.6 mmole) of methane ~ulphochloricle to the solution
cooled to 0, the reaction mixture i~ stirred for 30
minutes at 0 and for 3 hours at room temperature. The
reaction mixture is then diluted with 2~0 ml of ethyl
acetate and washed 3 time~ with 30 ml of ice water
and 3 times wit~ saturated sodium chloride solution.
~he organic phase i~ dried over sodil~m ~ulphate and
freed of solvent in a rotary ~vaporator. The crude
product is purified by col~mn chromato~raphy ~ silica
gel) using diethyl eth~r/ethyl acetate 9 :1 a~ eluant,
yielding D-2-tert.-butoxycarbonylamino-2-~3,5-bi 9-
~(methylsulphonylamino-4-hydroxyphenyl)~acetic acid in
the form of an amorphous yellow powder.
TLC (silica gel, identification with ninhydrin),
R~ 0.~8 (~ec.-butanol/acetic acid/water 67:10:23~,
~a]D ~ 83 ~ 1 ~ab301ute ethanol, c - 0.60 %).
d) A solution of 11.5 g (32.2 ~mole~ of D-2-tert~
butoxycarbonylamino-2-(3,$-dinitro-4-hydroxyphenyl)-
acetic acid in 200 ml of methanol i3 hydrogenated in the
pre3ence o~ 1.5 g of palladium-carbon (10 %) as catalyst.
After the theoretical quantity of hydrogen has been
ab~or~ed, the reaction mixture is filtered over Celite and
freed of solvent in a rotary evaporator, yielding D 2-
tart .-butoxycarbonylamino-2 (3,5-diami~o-4-hydroxyphenyl~-
acetic acid which i~ used in reaction tep C) without
further purification.
TLC (silica gel, identification with ninhydrin):
Rf 0.50 (sec.-butanol/acetic acid/water 67:10:23).
Exam~le 14
a) In a manner analogous to Example 13a), 7~-[D-2-
amino-2-~3,5-bis-methylsulphonylamino-4-hydroxyphenyl)-
-- 84 ~
acetylamino]-ceph-3-em-4-carboxylic acid is obtained
in the form o~ a dihydrate by treating 2.3 g (2.~7
mmole) of 7~-[D 2-tert.-butoxycarbonylamino-2-(3,5-
bis-(methylsulphonylamino-4~hydroxyphe~1yl)~acetylamino]-
ceph-3-em-4-carboxylic acid diphenylmethyl ester with
11.5 ml of trifluoroacetic acid and 2.3 ml of anisole in
11.5 ml of absolute methylene chloride.
Melting point: from 150 (with decomposition).
~LC ~silica gel, identification with ninhydrin)
Rf 0~13 (sec.-butanol/acetic acid~water 67:10:23),
~]D = +91 + 1 (001N aqueous hydrochloric acid,
c = 0.89 %).
The starting matexial may ~e obtained as follows:
b) In a manner analogous to Example 13b), 7~-~D-
2-tert.-butoxycarbonylamino-2-(3,5-bis-(methyl~ulphonyl-
amino)-4-hydroxyphenyl)-acetylamino]-ceph-3-em-4-
carboxylic acid diphenylmethyl ester i~ obtained from
4.532g~10 mmolo) o D-2-~ert.-b~toxycarbonylamino-2-(3,5
bi3-(methylsulphonylamino)~4-hydroxyphenyl 3 -acetic acid
and 3.654 g (10 mmole) of 7~-aminoceph-3-em-4-carboxylic
acid dip~enylmethyl ester in the presence of 30063 g
(10 mmole) of ~ dicyclohexylcarbodiimide in tetra-
hydrofuran according to the process described.
a) In a manner analogous to Example 13a), 7~- CD 2
amino-2-(3,5-bis-(methylsulphonylamino)-4-hydroxyphenyl)-
acetylamino]-3-chloroceph-3-em-4-carboxylic acid is
obtained in the form of a dihydrate by treating 4.47 g
(5.35 mmole) of 7~-[D-2-tert.-butoxycarbonylamino-2-
(3,5-bis-(methylsulphonylamino)-4-hydroxyphenyl)-
acetylamino]-3-chloroceph~3-em-4-carboxylic acid diphenyl-
methyl ester with 20 ml of trifluoroacetic acid ard 4 ml
.
7~
- 8S -
of anisole in 20 ml of absolute methylene chloride
according to the process described.
Melting point: from 150 with decomposition;
TLC (silica gel, developing with ninhydrin)
R~0.23 (system: sec.-butanol/acetic acid/water
67:~0:23),
W spectrum (in 0.1~ aqueous hydrochloric acid):
270 nm ~ - 7600),
L~D = +62 ~ ~ (0.1N aqueous hydrochloric acid,
c = O.g80 %).
b~ In a manner analogous to Example 13b), 7~-[D-
2~tert.-butoxycarbonylamino-2-(3,5-bis-~methylsulphonyl-
amino-4-hydroxyphenyl)-acetylamino~-3-chloroceph-3-~m-
4-carboxylic acid diphenylmethyl ester is o~tained from
4.53 g (10 mmole) o~ D-2-tert.-butoxycarbonylamino-2`~
C3,5-bis-(methyl~lphonylamino)-4-hydroxyphenyl]-ac~tic
acid and 4.0 g (10 mmole~ of 7~-amino-3-chloroceph-3iem-
4-carboxylic acid diphenylmethyl ester in the presence
of 2.06 g (10 mmole) of N,N'-dicyclohexylcarbodiimide in
tetrahydrofuran a~cording to the process described.
TLC (silica gel, identi~ica ion with iodine):
Rf 0.43 (diethyl ether/~thyl acetate
Example 16
While ~tirring and checking the pH value, a
suspension of 4.75 g of 7~-[D-2-amino-2-(3-methyl-
sulphonylamino-4-hydroxyphenyl)-acetylamino]-3-
methoxyceph -3-em 4-carkoxylic acid in 50 ml of water and
2 ml of alcohol i~ slowly made into a solution at a pH
value o~ 1PSS than 7.6 with a total of approximately
5 ml of 2N sodium hydroxide solutionO The solution is
freed of the small quantity of residual sub~tances by
- 86 -
filtxation and, after lyophilising, yields 4.9 g of
the sodium ~alt o 7~-[D-2-amino-2-(3-methylsulphonyl-
amino-4-hydroxyphenyl)-acetylamino]-3-methoxyceph-3-
em-4-carboxylic acid.
W ~pectrum in OolN HCl: 278 nm ( = 7600);
TLC: Rf 0.46.
~a~
In a manner analogous to Example 16 it i~ possiblP
to prepare:
the sodium ~alt of 7~-~D-2-amino-2-~3-methylsulphonyl-
amino-4-hydroxyphenyl) acetylamino]-3-chloroceph-3-em-
4-carboxylic acid,
W spectrum in O.lN HCl: 235 nm ~shoulder3, 270 ~n
(c = 85~0),
TLC: R ~ 0.16:
the sodium salt of 7~-~D-2-amino-2-(3-methylsulphonyl-
amino-4-hydroxyphenyl)-acetylamin~]-ceph-3-em-4-carbaxylic
acid,
W ~pectr~m in 0.1~ HCl: 235 nm ~ = 11400),
TLC: Rf 0.19:
the sodium salt o~ 7~-~D-2-amino-2-(3-amino 4-hydroxy-
phenyl)-acetylamino]-3-methoxycep~-3-em-4-carboxylic
acid:
the ~odium salt of 7~-~D-2-amino-2-(3,5-diami~o-
4-hydroxyphenyl)-acetylamino]-3-methoxyceph-3-em-4-
carboxylic acid,
W ~pectrum in O.lN HCl: 270 nm S = 7600),
T~C: Rf 0.05;
TLC: silica gel, developing with ninhydrin, system:
sec.-butanol/acetic acid/water 67:10:23.
- 87 -
Exam~le 18
The ollowing compounds may be p:repared
analogously to Examples 1 to 16:
7~-CD-2-amino-2-(3,5-bis-(ethylsulphonylamino) 1-
hydroxyphenyl)-acetylamino]-ceph-3-em-4-carboxylic
acid,
W spectrum in O.lN HC1: 209 nm (~ = 3900),
272 nm (shoulder),
TLC: Rf-0.13
7~-[D-2-amino-2-(3,5-bi~-(ethylsulphonylamino)~4-
hydroxyphenyl)~acPtylamino]-3-methoxyceph-3-em-4~
carbo~ylic acid,
W ~pectrum in 0.1~ HC1:281 nm (~ = 8100),
TLC: Rf~0.18
7~-~D-2-amino-2-(3,5-bis-(athyl~ulphonylamino)-4-hydroxy-
~henyl)-acetylamins]-3-chloroceph-3-em-4-carb~ylic acid,
W spectrum in O~N ~C~: 21~ nm ~ = 37000), 270 Nm ~ =
7500) :
7~-[D-2-amino-2-(3-acetylamino 4-hydroxyphenyl)-acetyl-
amino~-ceph-3-em-4-carboxylic acid,
W spectrum in 0.1N HC~: 275 nm (~ = 6900),
7~-[D2-amino-2-[3-formylamino-4-hydroxyphenyl~
acetylamin~]-3-methoxyceph-3-em-4-carboxylic acid,
W ~pectrum in o.1N HC1: 279 nm ~ = 7600):
7~-[D-2-amino-2-(3-formylamino-4-hydroxyphenyl)~acetyl-
amino]-3-chloroceph-3 em-4-carboxylic acid,
W spectrum in 0.1~ HC1: 270 nm (~ = 8100),
7~-~D-2-amino-2-t3-formylamino-4-hydroxyphenyl~-acetyl-
amino]-ceph-3-em 4-carboxylic acid,
W spectr~m in 0.1N HC1: 232 nm (~ = 11500),
270 nm (shou~der),
r
~ 88 --
7~-~D-2-amino-2-~3-(3-methylureido)-4-hydroxyphenyl]-
acetylamino~-3-methoxyceph-3-em-4-carboxylic acid,
W spectrum in O.lN HCl: 244 nm (~ - 8500~ 275 nm
(shoulder);
7~D-2-amino-2-~3-(3-methylureido)-4-hydroxyphenyl~-
acetylamino]-3-chloroceph-3-em-4-carboxylic acid;
7~D-2-amino-2-~3-(3-methylthioureido)-4-hydroxyphenyl3-
acetylamino}-ceph-3-em-4-carboxylic acid,
7~-~D-2-amino-2-~3-(3-methylthioureido)-4-hydroxyphenyl]-
acetylamino]-3-methoxyceph-3-em-4-car~oxylic acid,
7~-~D-2-amino-2-~3-(3-methylthioureido)-4-hydroxyphenyl]-
acetylamino]-3-chloroceph-3-em-4-carboxylic acid and
salts thereof, for example the sodium salt~,
TLC: thin-layer chromatography on silica gel prepared
plates, sy~tem: sec.-butanol/acetic acid/water 67:10:23.
Ex~me~
~ ry ampoule~ or phials containing 0.5 g of the
internal salt of 7~-~D~2-amino-2-~3-methyl~ulphonyl~mino-
4-hydroxyphenyl)-acetylamino]-3 methoxyceph-3-em-4-
carboxylic acid are prepared as follows:
Com~osition (for 1 ampoule or phial~
internal salt of 7~-~D-2-amino-2-
(3-methylsulphonylamino-4-
hydroxyphenyl)-acetylamino~-3-methoxy_
ceph-3-em-4-carboxylic acid 0.5 g
mannitol ~.05 g
A sterile aqueous solution of the internal salt
of 7~-~D-2-amino-2-(3-methylsulphonylamino-4-hydroxy-
phenyl)-acetylamino]-3-methoxyceph-3-em-4-carboxylic
acid and the mannitol in 5 ml ampoules or 5 ml phials
i5 freeze dried under aseptic conditions and the ampoules
or phials are sealed and tested.
89 _ ~L'7~
Example 20
Cap~ules containing 0.~5 g of the internal ~alt
of 7~-~D-2-amino-2-~3-methylsulphonylamino-4-hydroxy-
phenyl)-acetylamino]-3-methoxyceph-3 em-4-carboxylic
acid are prepared as follows:
om~osition (for 1000 cap~ules)
internal salt of 7~-[D-2-~mino~
2-(3-methylsulphonylamino-4-
hydroxyphenyl)-acetylamino]-3-
methoxyceph-3-em-4-carboxylic acid 250.000 g
maize starch 50.000 g
polyvinylpyrrolidona 15.000 g
magnesium stearate 5.000 g
ethanol ~. 8 .
The internal salt of 7~-[D-2-amino-2-(3-methyl-
sulphonylamino-4-hydroxyphenyl)-acetylamino]-3~
methoxyceph-3-em-4-car~oxylic acid and the maize ~tarch
are mixed together and moi~tened with a aolution of
the polyvinylpyrrolidone in 50 g o ethanol. The
moist ma~s is pressed through a sieve having a mesh
width of 3 mm and dried at 45. The dry granulate is
~orced through a sieve having a mesh width of 1 mm
and mixed with 5 g of magne~ium stearate. The mixture
i~ introduced in 0.320 ~ portions into size 0 dry-
filled capsule~.
