Note: Descriptions are shown in the official language in which they were submitted.
1V ~4
The preser.t in~ention relates to 7-amino-~ 3-cephem-4-
carboxylic acid esters and a process for their manufacture.
The esters of this invention have the advantage that tkey
are readlly soluble in organic solvents, in contradistinction to
the free acids, and thus are important as valuable intermediates
for further reactions in anhydrous medium. They can be used for
the acylation with mois+vure-sensi~ive carboxylic acid derivatives
to yield new 7-acylaminocephem-carboxylic acid esters which can
be split with the ester component suitably chosen without diffi-
culty into the 7-acylaminocephem-carboxylic acids which are
v~luable anti~iotics. Some of the acylated 7-amino-~3-cephem-
4-carboxylic acid esters are important therapeutic agents which
can be split after oral administration and resorption by un-
specific ester a~es.
Therefore, it was desirable to provide a process giving
good access to the esters of the 7-amino.D3-cephem-4-carboxylic
acids readily soluble in organic ~olvents.
It is known (according to Belgian Patent No. 717 741 and
719 712) that th corre~ponding amino acid esters having a free
amino group can be obtained by treating 7-acylamino-~3-cephem-
4-carboxylic acld e8ters with pho8phorou~ pentachloride, a base,
an alcohol and following hydrolysi~. However, thls known
reaction is not sati~factory, e~pecially with ~espec~ to the
yleld.
The Patent Specifications mentioned also do not describe
any examples of cephe~ compounds the CH2-group of which is
linked to cyclic compounds ~n 3-po~itlon oY4~ sulfur.
When these processes which are descrlbed as being op~imum
29 are used ~or those cephem compounds the end products desired are
_ 2 - ~
.
. , :
:
, .
1074~ HOE 73/F 363
obtained in hardly de~ectable amounts.
Now, it was found, that cephem compounds of the general
formula II bind one mol PC15 in complex form so that the amide
group is not attacked.
The present invention provides 7-amino- ~ 3-cephem-4-carb-
oxylic acid esters of the general formula I
O ~ CH2-S-Rl (I)
COOR2
and the salts of these esters,
wherein Rl represents a five-membered heterocyclic ring containing
one or two nitrogen atoms and one oxygen or sulfur atom, or is a
five-membered heterocyclic ring containing three or four nitrogen
atoms, or i8 a six-membered heterocyclic ring containing one to
three nitrogen atoms and one sulfur atom, or is one of the afore-
mentioned heterocyclic rings substituted by linear or branched
Cl-C8 alkyl, phenyl, Cl-C4 alkoxyphenyl, nitrophenyl, or chloro-
phenyl or wherein Rl is one of the aforementioned unsubstituted or
substituted heterocyclic rings annellated to a benzene ring, and
R2 stands for an optionally substituted linear or branched alkyl,
cycloalkyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, acyl-
oxyalkyl, aroylalkyl or a heterocyclic radical.
This invention also provides a process for the manufacture
of the esters of the general formula I by reacting 7-acylamino-
3-cephem-4-carboxylic acid esters of the general formula II
~ - 3 -
.
.
: .
:
.
1074295~ HOE 7 3/F 3 ~i 3
R3--CO-NH ~ , S
)--N~ CH2-S-R
COOR2
wherein R3 stands for optionally substituted alkyl, aryl,
aralkyl, aryloxyalkyl, alkoxyalkyl or a heterocyclic radical,
and Rl and R2 are defined as above, in an inert solvent with
a silylating agent in the presence of a base and converting it
with PC15 into a complex-like compound, converting the amido
group activated by the silylation into the iminohalide by
- 3a -
,
.
.
v ~ ~J~
adding a halogenating agent, reac-~ng it with an alcohol to
yield the iminoetner hydrohalide and hydrolizing the latter.
It is surpr~sing that the amido group could be silylated
in accordance with the invention, and that this would increase
the reactivity of this group to such ~n extent that the
following reaction rates could be increased to more than 90 %
at low temperatures, as low rates and low ~ were achieved
when an unactivated acyl group was split of~ in the known
reaction.
In the compounds used as starting materials R' may re-
present an optionally ~ubstituted alkyl radical, especially
an alkyl radic~l having from 1 to 8, preferably from 1 to 5
carbon atoms, a substituent advantageously being an amino or
carboxyl group. An optionally substituted aryl radical is
preferably a phenyl radical which may be substituted by a
halogen atom, preferably a chlorine or bromine atom, a low
molecular weight alkoxy group, preferably a methoxy ~roup or
a hydroxyl gro~p.
If Rl repre~ents an aralkyl radicai it is preferably a
benzyl radical which can be substituted in the aromatic ring,
for example, by a halogen atom, preferably a chlorine atom,
a low molecular weight alkoxy or a hydroxyl group and in the
alkyl portion, for example, by a low moleculaP weight alkyl
group, preferably a methyl, ethyl or propyl group, an amino
gl'OUp, a halogen atom, preferably a chlorine atom, an azide
group, a low molecular weight alkoxy group, preferably a methoxy
group, a low molecular weight acyloxy group, preferably an
acetoxy group. If R' represents an aryloxyalkyl group this
29 group is especially a phenyloxyalkyl radical the alkyl portion
,
.. ' ~ ~ - .
.. . .
: .. . .
. - :
.
.
.
, - . . . .
HOE 73/F 363
~ 10742~ !
of which may represen~ an optionally bra~ch~d low moiecular
weight alkyl group having fro~ 1 to 5 carbon atoms and the
branches which may be prese~t preIerably have 1 or 2 carbon
atoms. The aromatic portion may, for example, be substituted
by a halogen atom, preferably a chlorine atom, a low molecular
weight alkoxy group or a hydroxyl group. The alkylo~.yalkyl
radical preferred is a low molecular weight radical. When a
compound of the formula II with a heterocyclic radical R' this
I radical may be linked directly or by means of a low molecular
weight alkyl or oxyalkyl group, preferably a methyl or oxy-
methyl group, to the carbonyl group There may, for example,
be used a thienyloxymethyl grcup, a thienylmethyl group, a
pyridylmethyl group or an isoxalyl group.
If R represents a linear or branched alkyl group, an alkyl
group having from 1 to 10, preferably from 1 to 5 carbon atoms
ls preferably used, especially a methy~ or tertiary butyl group.
Suitable sub~tituents are, for example, halogen atoms, preferably
chlorine and lodine atoms, for example, 2, 2, 2-trichloroethyl
and 2-iodoethyl groups. Suitable cycloaikyl ra~icals are
especially those having from 5 to 10 carbon atoms, for example,
cyclohexyl, especially i~obornyl or adamantyl, radicals.
Suitsble aryl radicals are especially phenyl radicals, suitable
aralkyl radicals are those having a low molecular weight alkyl
moiety especially, benzyl or benzhydryl radical~ which may,
for example, be substitutcd by low molecular weight alkoxy or
nitro group~, examples of these being E-methoxybenzyl and p-nitro-
benzyl radicals. Suitable aryloxyalkyl and alkyloxyalkyl groups
are especially those ha~ing low molecular weight alkyl moieties,
29 preferably, ~or example, phenoxymethyl and methox~--methyl groups.
. . .
- 5 - .
.
.,
,
.,
:' . ,, ' ' - ~-
1074Z9~ !
Among the acyloxyalkyl groups those having low molec~lar weight
acyl and alkyl moieties, are preferred, for example, acetoxv-
methyl and pivaloyloxymethyl groups. Among the aroylalkyl
groups having low molecular weight alkyl moieties there may be
mentioned, for example, a benzoylmethyl group. A heterocyclic
radical is, for example, a thienyl radical.
Preferred esters are those wkich can be split again into
the free acids by a chemical or enzymatical process.
They can be split, for example by reduction, for example
by hydrogenolysis, such as in the case of the p-nitrobenzyl
ester, with zinc and acetic acid, as, for example in the case
of the trichloroethyl ester, and in acid medium, for example
as in the case of the tert. butyl ester, the p-methoxybenzyl
ester or the benzh~dryl ester. Especially suitable are the
p-methoxybenzyl- and benzhydryl e3ters w~ich can be converted
into the corresponding carboxylic acids in organic solvents
with trifluoroacetic acid in the presence of anisol.
As examples for e~ters which can be split enzymatically,
there may be mentioned the acetoxymethyl ester, the pi~aloyl-
oxymethyl ester and the phthalide ester.
R1 represents an optionally substituted 5- or 6-membered,
preferably 5- mem~ered, ring which may be substituted and which
may consist of carbon atoms, but which preferably contains 1
to 4 hetero-atoms such ~s o~ygen, ~ulfur and/or nitrogen as
ring atoms. The radical R1 may also be bound to ~n anellated
ring system, for example to a pyridine or triazole ring, pre-
~ ~ rac~,cc l
ferably to a benzene ring, the ~Y~t R1 which is not bound to
a ring system being preferred. The ring system forming the
29 rqdical R1 may be hydrogenated completely or partially, pre-
-- 6 --
` : '
.
,
,. ~ , , ,'
~ .
,, ~ , . - . . . . - . ~ ~
.
nv~--~ ~/ r~
~ 1074Z~ !
ferably however not hydrogenated.
For the radical R1 there may be mentioned, for example the
pfi~,a~
following ~a5iC~ -ring systems: -
cyclopentyl, cyclohexyl, thienyl, furanyl, pyrrolyl, imida-
zolyl, pyrazolyl, thiazolyl, isot~iazolyl, oxazolyl, isoxazolyl,
triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl,
oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl,
dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl,
oxatriazinyl, dithiadiazinyl, im~dazolinyl and tetrahydropyri-
mldyl.
Among the ring systems eited above by way of example,
there are preferably used 5-membered ring systems containing 1
to 2 nitrogen atoms and optionally 1 oxygen atom, for example
oxazolyl, preferably oxazole-2-yl, oxadiazolyl, preferably
1,3,4-oxadiazole-5-yl, imidazolinyl, preferably imidazoline-2-yl,
and 6-membered ring sy~tems containing 1 to 3 nitrogen atoms
and optionally 1 ~ulfur atom, for example pyridyl, such as
pyride-2-yl, pyride-3-yl, pyride-4-yl, pyrimidyl, preferably
pyrimide-2-yl and pyrlmide-4-yl, tetrahydropyrimidyl, preferably
1,4,5,6-tetrahydropyrlmlde-2-yl, thladiazlnyl, ln particular
4H-1,3,4-thiadiazine-2-yl, tria~inyl, preferably 1,3,4-triazine-
2-yl and 1,3,5-triazlne-4-yl and pyridazinyl, in particular
pyridazine-3-yl-
Particularly preferred ~re 5-membered ring systems contain-
ing 1 sulfur atom.and 1 to 2 nitrogen atoms, for example thiazo-
lyl, in particular thiazole-2-yl, thiadiazolyl, in particular
1,3,4-thiadiazole-5-yl a~d 1,2,4-thiazole-5-yl, 5-membered ring
29 ~ystems contalning 3 to 4 nitrogen atoms such as triazolyl, pre-
-- 7 --
,
.. .. . .. . . , . . -
.
nu~ /r ~o~
~ 07 ~ ~9 ~ !
ferably ~H-1,2,4-triazole-3-yl and tetrazolyl, preferably ~H-
tetrazole-5-yl.
The radical Z may be substituted once or several 'imes by,
for example:
alkyl groups containing, for example 1 to 15 carbon atoms
such as methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl,
n-hexyl, undecyl and pentadecyl, preferably those containing
1 to 4 carbon atoms, in particular methyl.
. Cycloalkyl groups, for example cyclopentyl and cyclohexyl,
low molecular alkyl groups of 1 to 4 carbon atoms, preferably
methyl, which are substituted, for example by aryl such as
phenyl or thienyl, by aryloxy, for example phenoxy, by low
molecular alkoxy, for example methoxy, ethoxy, by low molecular
alkoxycarbonyl ~uch a~ methoxy- or ethoxycarbonyl, or by
halogen,
low molecular alkoxy groups such as methoxy and ethoxy,
low molecular alkenyl groups such as allyl, -.
low molecular alkyl- and alkenyl-mercapto groups, for
example methyl-mercapto and allyl-mercapto, low molecular alkoxy-
carbonyl, for example methoxycarbonyl, low molecular alkoxy-
carbonylamino, for example ethoxycarbonylamino, low molecular
carboxyalkylthio, for example carboxymethylthio, amino, low
molecular mono- and dialkylamino, for example methylamino, di-
methylamino, ethylamino,-diethylamino, oxido, hydroxy, nitro,
cyano, halogen, preferably chlorine, mercapto, carboxy,
aryl radicals, for example phenyl, substituted phenyl, for
example low molecular alkoxyphenyl such as methoxyphenyl,
ethoxy-phenyl, halogenophenyl such as chlorophenyl, hydroxy-
29 phenyl! aminophenyl, alkyl phenyl, in particular low molecular
-- 8 --
.
1074Z9~ OE 73/F 363 .!
`
al~ylphenyl suoh a~ t-butylphenyl, tolyl, cetylphenyl, nitro-
phenyl, biphenyl or pyridyl, methylpyridyl, furyl, napthyl,
quinolyl, isoquinolyl, thienyl, 2-thiazolyl, 2-pyrrolyl,
4-imidazolyl, 5-pyrazolyl ~nd ~-isoxazolyl.
A~ radicals R1, there are preferred according to the
invention those which are unsubstituted as well as those
radioals R1 which are substituted by linear or branched alkyl,
in particular low molecular alkyl, preferably methyl, and by
aryl, in particular phenyl, which may, optionally be substi-
tuted by low molecular alkoxy, nitro groups or halogen.
Special Examples of ~he radical R1are in particular the
following radicals:
1H-1,2,3-Triazole-3-yl,
1,2,4-trlazole-3-yl,
5-methyl-1,2,4-triazole-3-yl,
1-phenyi-3-met'ayl-1H-1,2,4-triazole-5-yl, ,,
4,5-dimethyl-4H-1,2,4-triazole-3-yl,
5-methyl-4-amino-4H-1,2,4-triazole-3-yl,
4-phenyl-4H-1,2,4-triazole-3-yl,
5-ethyl-1,2,4-triazole-3-yl,
4-amino-4H--1,2,4-triazole-3-yl,
5-ethyl-4-amino-4H-1,2,4-tr~azole-3-yl,
5-phenyl-1,2,4-triazole-3-yl,
5-(4-methoxyphenyl)-1,2,.4-triazole-3-yl,
~-(4-chlorophenyl)-1,2,4-tr~azole-3-yl,
5-(4-pyridyl)-1-2,4-triazole-3-yl,
5- ~-(2-methyl-pyridyl V-1,2,4-triazole-3-yl,
5-phenoxymethyl-1,2,4-triazole-3-yl,
29 5-methoxymethyl-1,2,4-triazole-3-yl,
g _
.
- 5-ethoxymethyl-1,2,4-triazole-3-yl,
5-ethoxycarbonyl methyl-1,2,4-triazole-3-yl,
5-(2-ethoxyethyl)1,2,4-triazoie-3-yl,
5-(2-aminoethyl)-1,2,4-triazole-3-yl,
4-methyl-5-phenyl-4H-1,2,4-triazole-3-yl,
4-(4-ethoxyphenyl)-5-(4-pyridyl)-4H-1,2,4-+riazole-3-yl,
r~ 4-(4-methoxyphenyl)-5-(4-pYri~l)-4H-1,2,4-triazole-3-yl,
4-(4-ethoxyphenyl)-5-(3-~1YrldYy~)-4H-1,2,4-triazole-3-yl,
I 4-(4-ethoxyphenyl)-5-phenyl-4H-1,2,4-triazole-3-yl,
j 4-(4-ethoxyphenyl)-5-(4-aminophenyl)-4H-1,2,4-triazole-3-yl,
4,5-diphenyl-4H-1.~2~4-triazole-3-yl,
4,5-di-p-tolyl-4H-1,2,4-triazole-3-yl,
4-allyl-5-phenyl-4H-1,2,4-triazole-3-yl,
4-amino-5-methyl-4H-1,2,4-triazole-3-yl,
4-amino-5-ethyl-4H-1,2,4-tri~zole-3-yl,
1-methyl-5-phenyl-1,2,4-triazole-3-yl,
1-phenyl-4-allyl-5-(m-nitrophenyl)-4H-1,2,4-tria70le-3-yl,
1-phenyl-4-allyl-5-t-butyl-4H-1,2,4-triazole-3-yl,
1H-tetrazole-5-yl,
1-methyl-1H-tetrazole-5-yl,
1-ethyl-1H-tetrazole-5-yl,
1-n-propyl-1H-tetrazole-5-yl,
1-i-propyl-1H-tetrazole-5-yl,
1-n-butyl-1H-tetrazole-5.-yl,
1-cyclopentyl-1H-tetrazole-5-yl,
1-phenyl-1H-tetrazole-5-yl,
1-p-chlorophenyl-1H-tetrazole-5-yl,
1-cyclohexyl-1H-tetrazole-5-yl,
2~ 1-benzyl-1H-tetrazole-5-yl,
_ 10
.
- . --~-
.`- ' : - :
HOE 73/F 363
iO7425~ !
,
1-allyl-1H-tetrazole-5-yl,
1,2,3-thiadiazole-5-yl,
1,3,4-thiadiazole-2-yl,
1,2,4-thiadiazole-3-yl,
1,2,4-thiadiazole-5-yl,
1,2,5-thiadiazole-3-yl, .
3-methyl-1,2,4-thiadiazole-5-yl,
3-phenyl-1,2,4-thiadiazole-5-yl,
2-methyl-1,3,4-thiadiazole-5-yl,
2-methylmercapto-1,3,4-thiadiazole-5-yl,
2-ethyl-1,3,4-thiadiazole-5-yl,
2-n-propyl-1,3,4-thiadiazole-5-yl,
2-i-propyl-1,3,4-thiadiazole-5-yl,
2-phenyl-1,3,4-thiadiazole-5-yl,
2-(4-methoxyphenyl~-1,3,4-thiadiazole-5-yl,
2-(4-chlorophenyl)-1,3,4-thiadiazole-5-yl,
2-n-heptyl-1,3,4-thiadiazole-5-yl,
2-(2-furyl)-1,3,4-thiadlazole-5-yl,
2-(3-pyridyl)1,3,4-thiadiazole-5-yl,
2-n-butyl-1,3,4-thiadiazole~5-yl,
2-(2-pyr~dyl)1,3,4-thiadiazole-5-yl,
2-(4-pyridyl)-1,3,4-thiadiazole-5-yl,
2-(1-naphthyl)1,3,4-thiadiazole-5-yl,
2-(2-quinolyl)-1,3,4-thiadiazole-5-yl,
2-(1-isoquinolyl)-1,3,4-thiadiazole-5-yl,
2-et~oxycarbonylmethyl-1,3,4-thladiazole-5-yl,
2- ~ -3-methyl-1,3,4-thiadiazole-5-yl,
29 2--ethoxycarbonylamino-4-methyl-1,3,4-thiadiazole-5-yl,
- 11 -
.... . . .
. :
HOE 73~F 363
~07~29~ --
,--. ~
3-methylmeroapto-1~3,4-thiadiazole-5-yl,
1,2,4-oxadiazole-5-yl,
1,2,3-oxadi~zole-5-yl,
1,3,4-oxadiazole-5-yl,
2-methyl-1,3,4-oxadiazole-5-yl,
2-ethyl-1,3,4-oxadiazole-5-yl, ,
2-phenyl-1,3,4-oxadiazole-5-yl,
1 2-(4-nitrophenyl)-1,3,4-oxadiazole-5-yl,
2-(2-thienyl)-1,3,4-oxadiazole-5-yl,
2-(3-thienyl)-1,3,4-oxadiazole-5-yl,
2-(4-chlorophenyl)-1,3,4-oxadiazole-5-yl,
2-(2-thiazolyl)-1,3,4-oxadiazole-5-yl,
2-(2-furyl)-1,3,4-oxadiazole-5-yl,
2-(4-pyridyl)-1,3,4-oxadiazole-5-yl,
2-(3-nitrophenyl)-1,3,4-oxadiazole-5-yl,
2-(2-methoxyphenyl)-1,3,4-oxadiazole-5-yl,
2-(2-tolyl)-1,3,4-oxadiazole-5-yl,
2-(3-tolyl)-1,3,4-oxadiazole-5-yl,
2-(2-hydroxyphenyl)-1,3,4-oxadiazole-5-yl,
2-(4-hydroxyphenyl)-~,3,4-oxadiazoie-5-yl,
2-n-butyl-1,3,4-oxadiazole-5-yl,
2-n-propyl-1,3,4-oxadiazole-5-yl,
2-benzyl-1,3,4-oxadiazole-5-yl,
2-(1-naphthyl)-1,3,4-oxa~iazol¢-5-yl,
2-(2-pyrrolyl)-1,3,4-oxadiazole-5-yl,
2-(4-imidazolyl)-1,3,4-oxadiazole-5-yl,
2-(5-pyrazolyl)-1,3,4-oxadiazole-5-yl,
29 2-(3,5-dimethyl-4-isoxazolyl)-1,3,4-oxadiazole-5-yl,
_ 12 -
.. ..
. . . _. _
,` , ' - ,
- .
` ' . ' ` '~ - - : .
HOE 7~/F 363
~07429~ !
, .
thiazole~2-yl,
4-methyl-thiazole-2-yl,
4-phenyl-thiazole-2-yl,
4-pentyl-thiazole-2-yl,
4-hexyl-thiazole-2-yl,
4-undecyl-thiazole-2-yl,
4-tridecyl-thiazole-2-yl,
4-pentadecyl-thiazole-2-yl,
4-p-t-butylphenyl-thiazole-2-yl,
4-p-cetylphenyl-thiazole-2-yl,
4-p-phenylphenyl-thiazole-2-yl,
4-ethyl-thiazole-2-yl,
4,5-dimethyl-thiazole-2-yl,
benzthiazole-2-yl,
4,5-dimethyl-oxazole-2-yl,
4-phenyl-oxazole-2-yl,
'benzoxazole-2-yl,
oxazoline-2-yl,
imidazole-2-yl,
imidazoline-2-yl,
benzimidazoline-2-yl,
1-methyl-imidazoline-2-yl,
2-furyl,
2-thiophenyl,
2-pyr~olyl,
29 2-thiazolinyl,
- 13 -
. .. . . . . . . . ~ ~
iO7~2~ HOE 7~/F 3~3
.
3-isoxazolyl,
3-pyrazolyl,
thiatriazole-5-yl,
purinyl,
pyride-2-yl,
pyride-3-yl,
pyride-4-yl~ . j
5-nitropyride-2-yl,
1-oxidopyride-2-yl
pyrimide-2-yl,
1,4,5,6,-tetrahydropyrimide-2-yl,
4-hydroxy-pyrimide-2-yl,
4-hydroxy-6-methyl-pyrimide-2-yl,
2-hydroxy-pyrimide-2-yl,
2-phenyl-5-ethoxycarbonyl-6-methyl-pyrimide-4-yl,
2-phenyl-5-ethoxycarbonyl-6-ethoxy-pyrimide-4-yl,
~2-phenyl-5-ethoxycarbonyl-6-amino-pyrimide-4-yl,
2-hydroxy-5-cyano-6-methyl-pyrimide-4-yl,
2,6-dimethyl-5-acetyl-pyrimide-4-yl,
2-undecyl-5-acet.yl-6-methyl-pyrimide-4-yl,
2,6-dimethyl-5-ethoxycarbonyl-pyrimide-4-yl,
triazolopyridyl,
pyridazinyl,
pyrazinyl,
2-methylmercapto-6-phenyl-1,3,5-triazine-4-yl,
5-methyl-6-hydroxy-1,3,4-triazine-2-yl,
5-phenyl-4H-1,3,4-thiadiazine-2-yl,
29 5-hydroxy-4H-1,3,4-thiadiazine-2-yl.
- 14 -
~ ~4Z9~ HO~ 731F 36-~
; -
The 7-acylamir.o-f~-cephem-4-carboxylic acids of the
I general formula II used as starting materials can easily be
- prepared from the corresponding acid~ disclosed in literature
(cf. Patent Specifications Nos. 3,516,997 and 3,530,123 and
the Netherland Specification No. 7,005,519) by esterification.
As esterification methods, there may be mentioned:
a) Reaction of the carboxylic acids with aliphatic diazo com-
pounds, for example diazomethane and diphenyl-diazomethane.
I b) Reaction of the carboxylic acids with alcohols R2-OH in the
presence of condensation agents, for example dicycl-ohexyl-
carbodiimide.
c) Activation of the carboxylic acids by formation o~ mixed
anhydrides and following reaction with alcohols ~2-OH.
d) Reaction of salts of the carboxylic ~cids with alkyl halides
for example methyl iodide, benzyl bromide, p-methoxybenzyl
chloride, pivalic acid chloromethyl ester, acetic acid chloro-
methyl ester, 3-bromophthalide and chloromethyl-methyl ether.
In the 7-acylamino-~ cephem-4-carboxylic acid ester~
of the general formula II used as starting materials functional
- 20 groups capable of disturbing the followlng reaction steps, must
be protected expediently.
Therefore, it is recommended to block hydroxy, amino and
carboxy groups according to generally known methods.
An ester of the general formula II is reacted, in accordance
with the invention, in an inert solvent with a silylating
reactant in the presence of a base.
Suitable inert solvents are, for example, halogenated
hydrocarbons, ethers, ketones and esters.
29 Suitable silylating agents are preferably strong silylating
-: 15
~' ~r
1~7429~ -
.
reactants, for example, trimethyl chlorosilane, dime~hyldi-
chlorosilane, methyltrichlorosilane, triethylchiorosilane,
trimethylbromosilane, phenyltrichlorosilane, methoxytrich'oro-
silane, N,0-bistrimethyl-silyl-acetamide and trimethylsi~yltri-
fluoro-acetamide. Trimethyl-chlorosilane and dimethyldichloro-
silane are preferably used.
Especially high yields may be obtained when molar amounts
of the reactants are used, especially with a molar excess of
-the silylating agent, for example, an excess of from 1.5 to
2 moles. However, less than molar amounts may also suffice to
increase the yield.
The bases used in accordance with the invention are pre-
ferably organic bases, especially tertiary amines which may
carry one or more than one substituent, these substituents
being the same or different, for example, triethylamir.e, N,N-
dimethyl aniline, N,N-diethyl aniline, N-methyl piperidine and
N-ethyl morpholine, and amines, whose nitrogen &tom is part of
~n aromatic ring, for example, pyridine and its substitution
products with inert substituents, for example, picolines, and
quinoline and derivatives thereof having inert substituents.
N,N--dimethyl aniline i8 especially suitable for the process of
the invention.
The base i5 used in at least an equimolar amoun~, cal-
culated on the silylating agent. The reaction may be carried
out at temperatures within the range of from about 0 to about
100C, preferably from 10 to 60C. When carrying out the reaction
at room temperature, which is the preferred temperature, it is
800n completed.
29 To these silylated products, one mol of PCl5 is added
_ 16 -
: : . .
- . -
. ~
^ - 1074zg~ ~
preferably in the same inert solvent whereupon a complex-like
compound is formed. Spectrographic data and model reactions show
that the complex is formed at the heterocyclic group in 3-position.
For example, the NMR-spectrum shows that the signal for the proton
in the thiadiazole is shifted from 538 Hz towards 565 Hz against
TMS (measured in CDC13). The stabillty of the complexes depends
above all on the reaction temperature. At low temperatures (-30
to -70C) and the complexes are stable, at room temperature
decomposition can be observed. Therefore, it is advantageous not
to isolate the complexes formed but to continue their reaction,
as that of the acylamino group activated by the silylation of the
invention with halogenating agents in the presence of bases to
form the iminohalide at low temperatures. For this purpose, acid
halides can be used, for example phosphorus oxychloride, phos-
phorus pentachloride, phosphorus trichloride, thionyl chloride,
phosgene or oxalkyl chloride. Especially suitable is phosphorus
pentachloride.
The halogenation reaction succeeds with at least equi-
molar amounts of halogenating agents, calculated on the cephem
compound. To obtain expecially high yields it is good to operate
_ with an excess amount, for example from 1.5 times to 3 times the
amount.
The conversion into the iminohalide group is also
carried out in an inert solvent. In order to simplify the experi-
mental conditions it is advantageous to use the same solvents as
those used for the silylation reaction and to introduce the agent
forming the iminohalide in substance or in solution.
For this reaction too, the presence of a base is re-
quired. Suitable bases are the organic bases already mentionedes-
- 17 -
1074~9 _ 73/F 363
-- . .
pecially tertiary amines. They are advàntageously the same
as those used for the silylation. The base can be added in
two portions, i. 2 . ~ when silylating the amido group and when
converting it into the iminohalide. It is, however, more
advantageous to add the total ameur,t of base required for both
steps before silylation.
The formation of iminohalide may be carried out in a wide
témperature range, for example, from -100 to + 100C.
High yields, however, are obtained when a temperature within
the range of from 0 to -80C, preferably from -30 to -50C,
i~ uQed.
The iminohalide is con~.~erted into an imino ether in
known manner by adding an alcohol to the reaction mixture.
For thi~ purpose, an exce~s of from 5 to 40 moles of alcohol
per mole of imino halide i~ ad~antageou~ly used. Suitable
alcohols are especially the inexpensive low molecular weight
aliphatic alcohols, for example, methanol, ethanol, isopro-
panol or n-butanol. To avoid undesired ~ide reactionsthe
alcohol used should be as anhydrous as possible and the
temperature as low as from ~30 to -80C, especially from
-30 to -50C.
The hydrolysis of the imino ether may be carried out in
known manner, especially by pouring the deep frozen reaction
mixture into 2 to 3 t1me~ the amount of water, ~tirring for
some time and isolatin6 the resulting ester of the general
formula I.
The isolation may be carried out according to various
methods. The ester may, for example, be separated by filtration
29 in the form of a scarcely soluble ~alt formed during the
-
. ~,
--
.-
. . .
' ' . ~ : -:
.
lCr7429~ - ~OE 73/F 303
,~
reaction, for example, the hydrochloride, cr the ester may be
freed from such a s lt by adding an inorganic base, in which
case it may be separated with the organic phase and isolated
directly or in the form of salts. Suitable salts for this
purpose are, for example, the sulphonates, for example ~-toluene
sulphonates or B-~Qp~hth ~ ino sulphonates or salts of organic
acids, for example, acetates.
The salts of the 7-amino-~-cephem-4-carboxylic acid
esters of the general formula I are especially suitable for
purifying the products of the invention, for example by re-
crystallisation. Moreover, their storage capacity is better in
this form than that of the compounds of the invention. There
may be used, for example salts with inorganic acids, for
example hydrochloric acid, hydrobromic acid, sulfuric acid and
phosphoric acid or with organic acids, for example acetic acid
and arylsulfonic acids, for example p--toluene-sulfonic acid,
~-naphthalenesulfonic acid and alkylsulfonic acid, for example
methanesulfonic acid.
The preparation can be effected in usual maImer, by
associating equimolar amounts of base and acid component in a
suitable solvent.
In addition to the 7-amino-~ 3-cephem-4-carboxylic acid
esters described in the following experimental examples there
may also be obtained, in accordance with the invention, the
compounds of the general formula I
, H2N ~6
F ~ CH2-S-R1 (I)
o CbOR2
29 summarized in the following Table:
- 19 -
HGE 73/F 353
~O'~,Z~
R1 ~2
1~ -CH( C6H5 )2
~3 -CH2-0-CO-C(CH3)3
- ~J CH3 -CH2-0-CO-CH3
~l.o~--CH3 ~C ¢~
N--~1' ~ 3
-n-C3 7
N N -CH2-0-CO-c ( CH3 ) 3
~s~l--n-C3H7
-~s3 ~n-C3H7 -CH2-C0- ~ Br
N--N
~SJl--C6H~ -CH2-0-CO- CH3
-- 20 --
- __
-
' ' ~
1~3742~ HOE 73/F 363
N N
C6Hg O
J~ - CH2-0-co- CH3
N N
~I J /C6H5
--N -CH
H C6H5
N~ - -C.H2- ~2
H
N N
J~N ~n-c4H9 -CH2-0-CH~
H
~S~
N--1
J~sJI t-C4Hg
N~ CH ( C6H5 ) 2
- 21 -
.. . . . . . _ _
. .
" ' .
: . :
HOE 73/F 363
107425~ --
N CH
CH2 0 CO CH3
N - CH3
~S~ -CH2-O-CO-C ( CH3 ) 3
i~ C6H5 - -CH2-O-CO-C(CH3)3
S
i~ C6H5 -CH2- ~>--OCH3
S
N C3H7
I~s~ -CH2-0-CO-C ( CH3 ) 3
,~ n-C3H7 -CH2-CO- ~3--Br
C6H5
N--
H \ C H
H2-o-co-c ( CH3 ) 3
Ck3
i--N -CH2-O-CO-CH3
CH3
_ 22 --
., ......... ~" . ..
~074z99 HOE 73/~ 363
R1 R2
.
N--N
J~N~ -CH2--~--OCH3
H-
N O~
CH3 o
N q
-~N.~ -CH2-O-CH3
b2H5
N--1~
N -C~I2-0-CO-C ( CH3 ) 3
n-C4Hg
CH3
C2H5
-- 23 --
1~742~ HOE 73/Y 363
The following examples illustrate the invention:
E X A M P L ~ S: -
~yeC+t~C~ SCop ~~ C
rAl The new compounds were characterized b~ ~p^otrosoopic~l
data and by thin-layer chromatog~aphy. In the infrared spectrum
(KBr block) the B-lactam absorption was shown at 1760-1775 cm~
and the ester absorption at 1710-1740 cm 1.
In the ~R-spectrum (60 MHz in CDC13) the proton of C-7
appeared at ~ - 4.7 ppm. and the NH2 protons at d = 1.8 ppm.
e~ t
The layer used was silica gel tMerck) and the eluont was
acetic acid ethyl ester. The plates were developed by the
action of iodine vapour. ~ne purified products yielded correct
elementary analyse~ and weli interpretable mass spectra.
E X A M P L E 1:
To 1.86 g of 3-(1,3,4-thiadiazol-2-yl)-thiomethyl-7-
(thier-2-yl acetamido)-~-cephem-4-carboxylic acid benzhydryl
ester ln 200 ~l of absolute methylene chloride 1.56 ml of
N,N-dimethyl-aniline and 0.61 ml of trlmethyl-chlorosilane
were added and the mixture was allowed to dwell for 1 hour at
room temperatur~.
After cooling to -70C 0.63 g of phosphorous penta-
chloride were added and stirring followed at -50C for
30 minutes. After this period of time the complex-like com-
pound was ~ormed. It wa~ cooled anew to -7~C and-further
0.68 g of phosphorous pentachloride were added, the mixture
was stirred at -40C for 2 hours, again cooled to -70C,
20 ml o~ methanol were added and the mixture was ~tirred at
-40C for 2 hours. The ~olution was then poured into 100 ml
of water, stirred for half an hour, neutralized with sodium
2g bicarbonate, the organic phase ~as separated, the aqueous phase
- 24 -
~, ~ . _
1 0 74 2~ ~ F 363
was extracted two times with methylene chloride and the combined
organic phases were dried over sodium sulfate. After filtra~ion,
the solution was condensed in Jaouo, and by adding petrol ether,
1.40 g (94 % of the theoretical amount) of 3-(1,3,4-thiadiazol-
2-yl)-thiomethyl-7-amino- ~ ~-cephem-4-carboxylic acid-benz-
hydryl ester were precipitated. This product was purified by
pouring it into warm methylene chloride and a solution of p-
toluenesulfonic acid hydrate in acetic acid ethyl ester was
I added. After adding a small amount of methanol and diethyl
ether 1.48 g (= 74 % of the theoretical amount) of 3-51,3j4~
thiadiazol-2-yl)-thiomethyl-7-amino- ~ 3-cephem-4-carboxylic
acid-benzhydryl ester-p-toluene-sulfonate were obtained as
colorless crystal~, having an m.p. of 151 - 152C (under de-
composition).
s~spend~J
15 r~ This p-toluene-sulfonate was ~ ~e~ in aqueous ~odium
bicarbonate solution, methylene chloride was added, and the
mlxture was ~tirred at room temperature. After separating the
~chloride phase and distilling the solvent in vacuo. the
3-(1,3,4-thiadiazol-2-yl)-thiomethyl-7-amino~3-cephem-4-carb-
oxylic-acid-benzhydryl ester was again obtained as slightly
yellow crystals having a melting point of 186 - 187C (under
decompositlon).
Thin-layer chromatography: Rr = . 59
IR-sPectrum: ~-lactam at 1760 snd ester at 1715 cm 1
.
E X A M P L E 2:
The procedure carried out as de~cribed in example 1
yielded from 1.90 g of 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thio-
methyl-7-(thien-2-yl-acetamide)-~3-cephem-4-carboxylic acid-
29 benzhydryl ester 1.11 g (= 73 % of the theoretical amo~nt) of
. - 25 _
.. , . , . ~ .~,
10~429~ ~L~3
,. ..
3-(5-methyi-1,3,4-~hiadiazol-2-yi)-thiomethyl-7-amino-~3----
cephem-4-carboxylic asid benzhydryl ester as slightly yellow
crystals having a melt-ng poin' of 145 - 147C (under decom-
position).
Thin-layer chromatography: Rf = 0.43
IR-sPectrum: B-lactam at 1760 cm~1 and ester at 1715 cm~1.
E X A M P L E 3:
When proceeding according to the method described in
Example 1 and using 1.93 g of 3-(5-methyl-1,3,4-thiadiazol-
2-yl)-thiomethyl-7-phenoxyacetamido-~ 3-cephem-4-carboxylic
acid-benzhydryl e~ter, 1.19 g (= 78 % of the theoretical) of
3-(5-methyl-1,3,4-thladiazol-2_yl)_thiomethyl_7_amillo_A 3_
cephem-4-carboxylic acid-benzhydryl ester were obtained having
a melting point of 144 - 146C (under decomposition).
E X A M P L E 4:
The reaction described in Examplt 1 was repeated with
2.85 g of dibenz-hydryl e~ter of the 3-(5-methyl-1,3,4-thia-
diazol-2-yl)-thio-methyl-7(D~ -phthaloylamino-adipoylamido)-
~3-cephem-4-carboxylic acid. 1.10 g (= 72 % of the theoretical)
of 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-amino-~ 3-
cephem-4-carboxylic acid benzhydryl ester were obtained having
a melting point of 144 - 145C (under decomposition).
E X A M P L E 5- -
When 1.85 g of 3-(1,3,4-thiadiazol-2-yl)-thiomethyl-7-
phenyl-acet-amidoy~ 3-cephem-4-carboxylic acid-benzhydryl
e~ter were reacted in the manner de~cribed in Example 1,
~.22 g (= 82 % of the theoretical) of 3-(1,3,4-thiadiazol-2-yl)-
thiomethyl 7-amino-~3-cephem-4-carboxyli_ acid-benæhydryl
29 ester were obtained having a melting point of 185 - 186C
- 26 -
1~3742~ HOE 731F 363
(under de~omposition).
E X A M P L E 6:
The procedure of Example 2 was repeated USill~ O . 52 g 0
dimethyl-dichloro5ilane~ instead of 0.61 ml of trimethyl-chloro-
silane as silylating agent.
From 1.90 g of 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thio-
methyl-7-(thien-2-yl-acetamido)-~3-cephem-4-carbcxylic acid-
benzhydryl ester 1.24 g (= 81 % of the theoretical) of 3-(5-
methyl-1,3,4-th,a-diazol-2-yl)-thiomethyl-7-amino-~3-cephem-
carboxylic acid-benzhydryl ester were obtained having a melting
point of 145 - 146C (under decomposition).
E X A M P L E 7:
The procedure of Example 1 was repeated using 1.63 ml of
N,N-diethyl-aniline instead of 1.56 ml of N,N-dimethylaniline
as base.
From 1.86 g of 3-(1,3,4-thiadiazol-2-yl)-thiomethyl-7-
(thien-2-yl-acetamido)~3-cephem-4-carboxylic acid-benzhydryl
ester, 1.18 g (= 79.5 % of the theoretical) were obtained
having a melting point of 185 - 186C (under decomposition).
E X A M P L E 8:
The procedure carried out as in Example 1 yielded from
1.88 g of 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-
(thien-2-yl-acet-amido)-~3-cephem-4-carboxylic acid-3-phthalide
ester 0.89 g (= 62 % of the theoretical) of 3-(5-methyl-1,3,4-
thiadiazol-2-yl)-tniomethyl-7-amino-~3-cephem-4-carboxylic
acid-3-phthalide ester as amorphous solid having a decom-
position point of 175C.
Thin-layer-chromatography: Rf = 0.38
29 IR-spectrum: ~-lactam at 1770 ar.d ester at 1750 cm 1
- 27 -
.
HOE 73!F 363
lV74Z~
,,
E X A M P L E 9
The procedure carried out as in Example 1 yielded from
1.90 g of 3-(4-methyl-thiazol-2-yl)-thiomethyl-7-(thien-2-yl-
acetamido)~3-cepnem-4-carboxylic acid-benzhydryl ester, 1.04g 1 :
(= 68 % of the theoretical) of 3-(4-methyl-thiazol-2-yl)-thio-
methyl-7-amino- A3-cephem-4-carboxylic acid-benzhydryl ester
as amorphous solid body havin~ a decomposition point of 145C.
Thin-layer~chromatography: Rf = 0.69
IR-spectrum: B-lactam at 1775 cm 1 and ester at 1715 cm 1
E X A M P L E 10:
.. . . . _
In a manner analogous to that described in Example 1 there
were obtained from 1.80 g of 3-~4-methyl-thiazol-2-yl)-thio-
methyl-7-(thien-2-yl-acetamido)-~.3-cephem~4-carboxylic acid-
3-phthalide ester, 0.90 g (= 63 % of the theoretical) of 3-
(4-methyl-thiazol-2-yl)-thiomethyl-7-amino~3-cephem-4-carb-
oxylic acid-3-~hthalide ester as falrly yeilow pol~der having
a decomposition point of 165 - 170C,
Thin-layer-chromatography: Rf = 0.55
IR-5Pectrum: ~-lactam at 1775 cm 1 and ester at 1750 cm 1.
E X A M P L E 11:
In a manner analogous to that described in Example 1 there
were obtained from 1~45 g of.3-(5-methyl-1,3,4-thiadiazol-2-yl)-
thio-methyl-7-(thien-2-yl-acetamido~-3-cephem-4-carboxylic
acid-methyl ester, 0.90 ~ (= 83 % of the theoretical) of 3-
(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-amino-~3-cephem-
c~eam-co/o~d
r ~ 4-carboxylic acid-methyl ester as orcmc--colored solid body
having a decomposition point of 140C.
Thin-layer-chromatography: Rf = 0.26
29 IR-spectrum: ~-lactam at 1770 cm 1 and ester at 1715 cm~1.
.- 28 - ~
~ . , ,. . . . . . " ,,, ,",,~ .
.
... .
'
- HOE 73!F 363
- - 1079LZ
E X A M P L E 12:
In a ma~ner analogous to t~at described in Example 1 there
were obtained from 1.68 g of ~-(5-pheny'-1,3,4-oxadiazol-~-yl)-
thiomethyl-7-(thien-2-yl-acetamido)-~3-cephem-4-carbo~rlic acid-
methoxymethyl ester, 1.01 g (?8 ~ of the theoretical) of ~
phenyl-1,3,4-oxadiazol-2-yl)-thiomethyl-7-amino-~ 3-cephem-4-
carboxylic acid-methoxymethyl ester as amorphous powder having
a decomposition point of 190C.
I Thin-layer-chromatography: Rf = 0.52
IR-spectrum: B-lactam at 1770 cm~1 and ester at 1720 cm~1.
E X A M P L E 13:
In a manner analogous to that described in Example 1 there
were obtained from 1.41 g of ~ ,4-thiadiazol-2-yl?-thio-
methy}-7-(thien-2-yl-acetamido)-~3-cephem-4-carboxylic acid-
methyl ester 0.91 g (= 88 % of the theoretical) of 3-(1,3,4-
thiadiazol-2-yl)-thiomethyl-7-amino-~ 3-cephem-4-carboxylic
acid-methyl e~ter as ~ oil.
Thin-layer-chromatography: Rf = 0.58
IR-~ectrum: ~-lactam at 1770 cm 1 and est~r at 1715 cm 1.
E X A M P L E 14:
In a manner analogou~ to that described in Example 1 there
were obtained from 1.50 g of 3-(1,~,4-thiadiazol-2-yl)-thio-
methyl-7-)thien-2-yl-acetamido)-~ ~-cephem-4-carboxylic acid-
methoxymethyl-ester 0.84 g (= 75 % of the theoretical) of
3-(1,3,4-thiadiazol-2-yl)-thiomethyl_?-amino-~ 3-cephem-4-carb-
oxylic acid-methoxymethyl ester as amorphous solid body.
Thin-layer chromatography: Rf = 0.58
IR-s~e trum~ ctam at 1770 and ester at 1720 cm 1.
E X A M P L E 15:
In a manner analogous to that described in Example 1 there
_ ,~y _
1074Z9~ HOE 73/F 363
:
were obtained from 1.71 g of 3-(1,3,4-thiadiazol-2~yl)-thi~-
methyl-7-~thien-2-yl-acetamido)-~ 3-cephem-4-carboxylic acid-
pivaloyloxy-methyl ester 0.93 g (= 70 % of the theoretical) of
3-(1,3,4-thiadiazol-2-yl)-thiomethyl-7-amino-~ 3-cephem-4-
carboxylic acid-pivaloyl-oxymethyl ester as amorphous solid
body.
I'hin-layer-chromatography: Rf = 0.50 ~:
IR-sPéctrum: ~-lactam at 1775 cm 1 and ester at 1740 cm 1.
- 30 -
.. .: . :
~: . ' - :
. ' ,
.
-' - - ' ' -' :- :
- ~ ., .
- - - - ~ , :
..
