CA1074299A - 7-amino-.delta.-3-cephem-4-carboxylic acid esters and process for their manufacture - Google Patents
7-amino-.delta.-3-cephem-4-carboxylic acid esters and process for their manufactureInfo
- Publication number
- CA1074299A CA1074299A CA212,038A CA212038A CA1074299A CA 1074299 A CA1074299 A CA 1074299A CA 212038 A CA212038 A CA 212038A CA 1074299 A CA1074299 A CA 1074299A
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- Canada
- Prior art keywords
- cephem
- carboxylic acid
- converted
- amino
- delta
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
7-amino- .DELTA. 3-cephem-4-carboxylic acid esters of the general formula I
7-amino- .DELTA. 3-cephem-4-carboxylic acid esters of the general formula I
Description
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) 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
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 , .. ' ~ ~ - .
.. . .
: .. . .
. - :
.
.
.
, - . . . .
~ 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-` : ' .
, ,. ~ , , ,' ~ .
,, ~ , . - . . . . - . ~ ~
.
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-
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) 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
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 , .. ' ~ ~ - .
.. . .
: .. . .
. - :
.
.
.
, - . . . .
~ 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-` : ' .
, ,. ~ , , ,' ~ .
,, ~ , . - . . . . - . ~ ~
.
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-, .. .. . .. . . , . . -.
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 .
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 .
- . --~-.`- ' : - :
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, .
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 .
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 .
- . --~-.`- ' : - :
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, .... . . .
. :
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,
. :
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, . .. . . . . . . . ~ ~
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
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.
~ ~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-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:
~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 - __ -' ' ~
1~3742~ HOE 73/F 363 N N
C6Hg O
J~ - CH2-0-co- CH3 N N
~I J /C6H5 --N -CH
N~ - -C.H2- ~2 H
N N
J~N ~n-c4H9 -CH2-0-CH~
H
~S~
J~sJI t-C4Hg N~ CH ( C6H5 ) 2 .. . . . . . _ _ . .
" ' .
: . :
107425~ --N CH
~S~ -CH2-O-CO-C ( CH3 ) 3 i~ C6H5 - -CH2-O-CO-C(CH3)3 S
i~ C6H5 -CH2- ~>--OCH3 S
I~s~ -CH2-0-CO-C ( CH3 ) 3 ,~ n-C3H7 -CH2-CO- ~3--Br N--H \ C H
H2-o-co-c ( CH3 ) 3 Ck3 i--N -CH2-O-CO-CH3 _ 22 --., ......... ~" . ..
~074z99 HOE 73/~ 363 .
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 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 ~, ~ . _ 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).
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
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 .
HOE 73!F 363 lV74Z~
,, 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 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.
.. .: . :
~: . ' - :
. ' , .
-' - - ' ' -' :- :
- ~ ., .
- - - - ~ , :
..
~ ~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-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:
~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 - __ -' ' ~
1~3742~ HOE 73/F 363 N N
C6Hg O
J~ - CH2-0-co- CH3 N N
~I J /C6H5 --N -CH
N~ - -C.H2- ~2 H
N N
J~N ~n-c4H9 -CH2-0-CH~
H
~S~
J~sJI t-C4Hg N~ CH ( C6H5 ) 2 .. . . . . . _ _ . .
" ' .
: . :
107425~ --N CH
~S~ -CH2-O-CO-C ( CH3 ) 3 i~ C6H5 - -CH2-O-CO-C(CH3)3 S
i~ C6H5 -CH2- ~>--OCH3 S
I~s~ -CH2-0-CO-C ( CH3 ) 3 ,~ n-C3H7 -CH2-CO- ~3--Br N--H \ C H
H2-o-co-c ( CH3 ) 3 Ck3 i--N -CH2-O-CO-CH3 _ 22 --., ......... ~" . ..
~074z99 HOE 73/~ 363 .
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 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 ~, ~ . _ 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).
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
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 .
HOE 73!F 363 lV74Z~
,, 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 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.
.. .: . :
~: . ' - :
. ' , .
-' - - ' ' -' :- :
- ~ ., .
- - - - ~ , :
..
Claims (26)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a 7-amino-.DELTA. 3-cephem-4-carboxylic acid ester of the formula I
(I) wherein R1 is 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 is 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 C1 - C8 alkyl, phenyl, C1 - C4 alkoxyphenyl, nitrophenyl, or chlorophenyl, or wherein R1 is one of the aforementioned un-substituted or substituted heterocyclic rings annellated to a benzene ring and R2 represents optionally substituted linear or branched alkyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, acyloxyalkyl, aroylalkyl or a heterocyclic radical;
and the salts thereof, in which a 7-acrylamino-.DELTA.3-cephem-4-carboxylic acid ester of the formula II
(II) wherein R1 and R2 are as defined above and R3 represents an optionally substituted alkyl, aryl, aralkyl, aryloxy-alkyl, alkoxyalkyl or heterocyclic radical, is reacted in an inert solvent with at least one silylating agent in the presence of a base and the product is converted with phosphorus pentachloride into a complex-like compound, the amido group activated by the silylation is then converted into the iminohalide by the addition of a halogenating agent, the imino-halide is reacted with an alcohol to produce the iminoether-hydrohalide, the hydrohalide is hydrolized and, if desired, the resultant product is converted into a salt.
(I) wherein R1 is 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 is 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 C1 - C8 alkyl, phenyl, C1 - C4 alkoxyphenyl, nitrophenyl, or chlorophenyl, or wherein R1 is one of the aforementioned un-substituted or substituted heterocyclic rings annellated to a benzene ring and R2 represents optionally substituted linear or branched alkyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, acyloxyalkyl, aroylalkyl or a heterocyclic radical;
and the salts thereof, in which a 7-acrylamino-.DELTA.3-cephem-4-carboxylic acid ester of the formula II
(II) wherein R1 and R2 are as defined above and R3 represents an optionally substituted alkyl, aryl, aralkyl, aryloxy-alkyl, alkoxyalkyl or heterocyclic radical, is reacted in an inert solvent with at least one silylating agent in the presence of a base and the product is converted with phosphorus pentachloride into a complex-like compound, the amido group activated by the silylation is then converted into the iminohalide by the addition of a halogenating agent, the imino-halide is reacted with an alcohol to produce the iminoether-hydrohalide, the hydrohalide is hydrolized and, if desired, the resultant product is converted into a salt.
2. A process as claimed in claim 1 in which the sily-lation reaction is carried out at a temperature ranging from 0 to 100°C.
3. A process as claimed in claim 1 in which the sily-lation reaction is carried out at a temperature ranging from +10 to +60°C.
4. A 7-amino-.DELTA.3-cephem-4-carboxylic acid ester of the formula I as defined in claim 1; and the salts thereof, whenever prepared according to a process as claimed in claim 1, claim 2 or claim 3 or by an obvious chemical equivalent thereof.
5. A process as claimed in claim 1 in which the silylation agent is selected from the group of trimethylchloro-silane, dimethyldichlorosilane, methyltrichlorosilane, triethyl-chlorosilane, trimethylbromosilane, N,O-bistrimethylsilylacetamide and trimethylsilyltrifluoroacetamide.
6. A process as claimed in claim 1 in which the complex is formed in an inert solvent at a temperature of from 0 to -80°C.
7. A process as claimed in claim 1 in which the complex is formed in an inert solvent at a temperature of from -10 to -15°C.
8. A 7-amino-.DELTA.3-cephem-4-carboxylic acid ester of the formula I
(I) wherein R1 is 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 is 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 C1 - C8 alkyl, phenyl, C1 - C4 alkoxyphenyl, nitrophenyl, or chlorophenyl, or wherein R1 is one of the aforementioned unsubsti-tuted or substituted heterocyclic rings annellated to a benzene ring and R2 represents optionally substituted linear or branched alkyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, acyloxyalkyl, aroylalkyl or a heterocyclic radical; and the salts thereof, whenever prepared according to a process as claimed in claim 5, claim 6 or claim 7 or by an obvious chemical equivalent thereof.
(I) wherein R1 is 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 is 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 C1 - C8 alkyl, phenyl, C1 - C4 alkoxyphenyl, nitrophenyl, or chlorophenyl, or wherein R1 is one of the aforementioned unsubsti-tuted or substituted heterocyclic rings annellated to a benzene ring and R2 represents optionally substituted linear or branched alkyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, acyloxyalkyl, aroylalkyl or a heterocyclic radical; and the salts thereof, whenever prepared according to a process as claimed in claim 5, claim 6 or claim 7 or by an obvious chemical equivalent thereof.
9. A process as claimed in claim 1 in which the reaction with the iminohalide forming agent and the reaction of the imino-halide with the alcohol are effected at a temperature in the range of from +30°C to -80°C.
10. A process as claimed in claim 9 in which this temperature is in the range of from -30 to?50°C.
11. A process as claimed in claim 9 in which the alcohol is present in an amount of 5 to 40 moles of alcohol per mole of iminohalide.
12. A 7-amino-.DELTA.3-cephem-4-carboxylic acid ester of the formula I
(I) wherein R1 is 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 is a six-membered heterocyclic ring containing one to three nitrogen atoms and one sulfur atom, or is one of the aforementioned heterocyclic rings substituted by linear or branched C1 - C8 alkyl, phenyl, C1 - C4 alkoxyphenyl, nitrophenyl, or chlorophenyl, or wherein R1 is one of the aforementioned unsubsti-tuted or substituted heterocyclic rings annellated to a benzene ring and R2 prepresents optionally substituted linear or branched alkyl, cycloalkyl, aryl, aralkyl, aryloxyalky, alkoxyalkyl, acyloxyalkyl, aroylalkyl or a heterocyclic radical; and the salts thereof, whenever prepared according to a process as claimed in claim 9, claim 10 or claim 11 or by an obvious chemical equivalent thereof.
(I) wherein R1 is 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 is a six-membered heterocyclic ring containing one to three nitrogen atoms and one sulfur atom, or is one of the aforementioned heterocyclic rings substituted by linear or branched C1 - C8 alkyl, phenyl, C1 - C4 alkoxyphenyl, nitrophenyl, or chlorophenyl, or wherein R1 is one of the aforementioned unsubsti-tuted or substituted heterocyclic rings annellated to a benzene ring and R2 prepresents optionally substituted linear or branched alkyl, cycloalkyl, aryl, aralkyl, aryloxyalky, alkoxyalkyl, acyloxyalkyl, aroylalkyl or a heterocyclic radical; and the salts thereof, whenever prepared according to a process as claimed in claim 9, claim 10 or claim 11 or by an obvious chemical equivalent thereof.
13. A process as claimed in claim 1 for the preparation of a 7-amino-.DELTA.3-cephem-4-carboxylic acid ester of the formula I
as defined in claim 1 wherein R1 represents the radical wherein R4 is hydrogen, linear or branched alkyl of 1 to 8 carbon atoms, or phenyl optionally substituted by low-molecular alkoxy, notro groups or halogen, and R2 is as defined in claim 1 in which a compound of the formula II as defined in claim 1 wherein R1 is as defined above and R2 and R3 are as defined in claim 1, is reacted in an inert solvent with at least one silylating agent in the presence of a base and the product is converted with phosphorus pentachloride into a complex-like compound, the amido group activated by the silylation is then converted into the iminohalide by the addition of a halogenating agent, the iminohalide is reacted with alcohol to produce the iminoether-hydrohalide, and the hydrohalide is hydrolized and, if desired, the resultant product is converted into a salt.
as defined in claim 1 wherein R1 represents the radical wherein R4 is hydrogen, linear or branched alkyl of 1 to 8 carbon atoms, or phenyl optionally substituted by low-molecular alkoxy, notro groups or halogen, and R2 is as defined in claim 1 in which a compound of the formula II as defined in claim 1 wherein R1 is as defined above and R2 and R3 are as defined in claim 1, is reacted in an inert solvent with at least one silylating agent in the presence of a base and the product is converted with phosphorus pentachloride into a complex-like compound, the amido group activated by the silylation is then converted into the iminohalide by the addition of a halogenating agent, the iminohalide is reacted with alcohol to produce the iminoether-hydrohalide, and the hydrohalide is hydrolized and, if desired, the resultant product is converted into a salt.
14. A 7-amino-.DELTA. 3-cephem-4-carboxylic acid ester as defined in claim 13, whenever prepared according to a process as claimed in claim 13 or by an obvious chemical equivalent thereof.
15. A process as claimed in claim 1 for the preparation of a 7-amino-.DELTA. 3-cephem-4-carboxylic acid ester of the formula I as defined in claim 1 wherein R1 represents the radical wherein R4 is hydrogen, linear or branched alkyl of 1 to 8 carbon atoms, or phenyl optionally substituted by low-molecular alkoxy, nitro groups or halogen, and R2 is as defined in claim 1 in which a compound of the formula II as defined in claim 1 wherein R1 is as defined above and R2 and R3 are as defined in claim 1 is re-acted in an inert solvent with at least one silylating agent in the presence of a base and the product is converted with phosphorus pentachloride into a complex-like compound, the amido group activated by the silylation is then converted into the imino-halide by the addition of a halogenating agent, the iminohalide is reacted with alcohol to produce the iminoether-hydrohalide, the hydrohalide is hydrolized and, if desired, the resultant product is converted into a salt.
16. A 7-amino-.DELTA. 3-cephem-4-carboxylic acid ester as defined in claim 15, whenever prepared according to a process as claimed in claim 15 or by an obvious chemical equivalent thereof.
17. A process as claimed in claim 1 for the preparation of a 7-amino-.DELTA. 3-cephem-4-carboxylic acid ester of the formula 1 as defined in claim 1 wherein R1 represents a radical wherein R4 is hydrogen, linear or branched alkyl of 1 to 8 carbon atoms, or phenyl optionally substituted by low-molecular alkoxy, nitro groups or halogen, and R2 is as defined in claim 1 in which a compound of the formula II as defined in claim 1 wherein R1 is as defined above and R2 and R3 are as defined in claim 1 is reacted in an inert solvent with at least one silylating agent in the presence of a base and the product is converted with phosphorus pentachloride into a complex-like compound, the amido group activated by the silylation is then converted into the imino-halide by the addition of a halogenating agent, the iminohalide is reacted with an alcohol to produce the iminoether-hydrohalide, the hydohalide is hydrolized and, if desired, the resultant product is converted into a salt.
18. A 7-amino-.DELTA. 3-cephem-4-carboxylic acid ester as defined in claim 17, whenever prepared according to a process as claimed in claim 17 or by an obvious chemical equivalent thereof.
19. A process as claimed in claim 1 for the preparation of a 7-amino-.DELTA. 3-cephem-4-carboxylic acid ester of the formula I as defined in claim 1 wherein R1 represents the radical wherein R4 is hydrogen, linear or branched alkyl of 1 to 8 carbon atoms, or phenyl optionally substituted by low-molecular alkoxy, nitro groups or halogen, and R2 is as defined in claim 1, in which a compound of the formula II as defined in claim 1 wherein R1 is as defined above and R2 and R3 are as defined in claim 1 is reacted in an inert solvent with at least one silylating agent in the presence of a base and the product is converted with phosphorus pentachloride into a complex-like compound, the amido group activated by the silylation is then converted into the iminohalide by the addition of a halogenating agent, the imino-halide is reacted with an alcohol to produce the iminoether-hydrohalide, the hydrohalide is hydrolized and, if desired, the resultant product is converted into a salt.
20. A 7-amino-.DELTA. 3-cephem-4-carboxylic acid ester as defined in claim 19, whenever prepared according to a process as claimed in claim 19 or by an obvious chemical equivalent thereof.
21. A process as claimed in claim 1 for the preparation of a 7-amino-.DELTA. 3-cephem-4-carboxylic acid ester of the formula I as defined in claim 1 wherein R1 represents the radical wherein R4 is hydrogen, linear or branched alkyl of 1 to 8 carbon atoms, or phenyl optionally substituted by low-molecular alkoxy, nitro groups or halogen, and R2 is as defined in claim 1, in which a compound of the formula II as defined in claim 1 wherein R1 is as defined above and R2 and R3 are as defined in claim 1 is reacted in an inert solvent with at least one silylating agent in the presence of a base and the product is converted with phosphorus pentachloride into a complex-like compound, the amido group activated by the silylation is then converted into the iminohalide by the addition of a halogenating agent, the iminohalide is reacted with an alcohol to produce the iminoether-hydrohalide, the hydrohalide is hydrolized and, if desired, the resultant product is converted into a salt.
22. A 7-amino-.DELTA. 3-cephem-4-carboxylic acid ester as defined in claim 21, whenever prepared according to a process as claimed in claim 21 or by an obvious chemical equivalent thereof.
23. A process as claimed in claim 1 for the preparation of a 7-amino-.DELTA. 3-cephem-4-carboxylic acid ester of the formula I as defined in claim 1 wherein R1 represents the radical wherein R4 is hydrogen, linear or branched alkyl of 1 to 8 carbon atoms, or phenyl optionally substituted by low-molecular alkoxy, nitro groups or halogen, and R2 is as defined in claim 1, in which a compound of the formula II as defined in claim 1 wherein R1 is as defined above and R2 and R3 are as defined in claim 1 is reacted in an inert solvent with at least one silylating agent in the presence of a base and the product is converted with phosphorus pentachloride into a complex-like compound, the amido group activated by the silylation is then converted into the iminohalide by the addition of a halogenating agent, the imino-halide is reacted with an alcohol to produce the iminoether-hydro-halide, the hydrohalide is hydrolized and, if desired, the resultant product is converted into a salt.
24. A 7-amino-.DELTA. 3-cephem-4-carboxylic acid ester as defined in claim 23, whenever prepared according to a process as claimed in claim 23 or by an obvious chemical equivalent thereof.
25. A process as claimed in claim 1 for the preparation of a 7-amino-.DELTA. 3-cephem-4-carboxylic acid ester of the formula I as defined in claim 1 wherein R1 is as defined in claim 1 and R2 represents the radical wherein A is linear or branched alkyl of 1 to 8 carbon atoms, in which a compound of the formula II as defined in claim 1 wherein R1 and R3 are as defined in claim 1 and R2 is as defined above, is reacted in an inert solvent with at least one silylating agent in the presence of a base and the product is converted with phosphorus pentachloride into a complex-like compound, the amido group activated by the silylation is then converted into the iminohalide by the addition of a halogenating agent, the imino-halide is reacted with an alcohol to produce the iminoether-hydro-halide, the hydrohalide is hydrolized and, if desired, the resultant product is converted into a salt.
26. A 7-amino-.DELTA. 3-cephem-4-carboxylic acid ester as defined in claim 25, whenever prepared according to a process as claimed in claim 25 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2359402A DE2359402A1 (en) | 1973-11-29 | 1973-11-29 | 7-AMINO-DELTA 3-CEPHEM-4-CARBONIC ACID ESTER AND THE PROCESS FOR THEIR PRODUCTION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1074299A true CA1074299A (en) | 1980-03-25 |
Family
ID=5899369
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA212,038A Expired CA1074299A (en) | 1973-11-29 | 1974-10-22 | 7-amino-.delta.-3-cephem-4-carboxylic acid esters and process for their manufacture |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS5088089A (en) |
| AT (1) | AT333430B (en) |
| BE (1) | BE822782A (en) |
| CA (1) | CA1074299A (en) |
| CH (1) | CH615187A5 (en) |
| DE (1) | DE2359402A1 (en) |
| DK (1) | DK616874A (en) |
| FI (1) | FI343674A (en) |
| FR (1) | FR2253023B1 (en) |
| IL (1) | IL46120A0 (en) |
| IT (1) | IT1051436B (en) |
| LU (1) | LU71380A1 (en) |
| NL (1) | NL7415274A (en) |
| NO (1) | NO744297L (en) |
| SE (1) | SE7414995L (en) |
-
1973
- 1973-11-29 DE DE2359402A patent/DE2359402A1/en not_active Withdrawn
-
1974
- 1974-10-22 CA CA212,038A patent/CA1074299A/en not_active Expired
- 1974-11-22 NL NL7415274A patent/NL7415274A/en not_active Application Discontinuation
- 1974-11-25 IL IL46120A patent/IL46120A0/en unknown
- 1974-11-26 CH CH1569274A patent/CH615187A5/en not_active IP Right Cessation
- 1974-11-27 FI FI3436/74A patent/FI343674A/fi unknown
- 1974-11-27 LU LU71380A patent/LU71380A1/xx unknown
- 1974-11-27 DK DK616874A patent/DK616874A/da unknown
- 1974-11-27 IT IT29921/74A patent/IT1051436B/en active
- 1974-11-28 NO NO744297A patent/NO744297L/no unknown
- 1974-11-28 FR FR7439017A patent/FR2253023B1/fr not_active Expired
- 1974-11-28 AT AT953374A patent/AT333430B/en not_active IP Right Cessation
- 1974-11-29 SE SE7414995A patent/SE7414995L/xx unknown
- 1974-11-29 JP JP49136374A patent/JPS5088089A/ja active Pending
- 1974-11-29 BE BE151012A patent/BE822782A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CH615187A5 (en) | 1980-01-15 |
| DE2359402A1 (en) | 1975-06-05 |
| AT333430B (en) | 1976-11-25 |
| NO744297L (en) | 1975-06-23 |
| JPS5088089A (en) | 1975-07-15 |
| LU71380A1 (en) | 1976-09-06 |
| NL7415274A (en) | 1975-06-02 |
| DK616874A (en) | 1975-07-28 |
| FR2253023B1 (en) | 1979-10-12 |
| BE822782A (en) | 1975-05-29 |
| SE7414995L (en) | 1975-05-30 |
| ATA953374A (en) | 1976-03-15 |
| IT1051436B (en) | 1981-04-21 |
| FR2253023A1 (en) | 1975-06-27 |
| IL46120A0 (en) | 1975-02-10 |
| FI343674A (en) | 1975-05-30 |
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