CA1146947A - Cephem derivatives and processes for their preparation - Google Patents
Cephem derivatives and processes for their preparationInfo
- Publication number
- CA1146947A CA1146947A CA000337692A CA337692A CA1146947A CA 1146947 A CA1146947 A CA 1146947A CA 000337692 A CA000337692 A CA 000337692A CA 337692 A CA337692 A CA 337692A CA 1146947 A CA1146947 A CA 1146947A
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- CA
- Canada
- Prior art keywords
- acid
- cephem
- thiazol
- methyl
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
CEPHEM DERIVATIVES AND PROCESSES FOR THEIR PREPARATION
Abstract of the disclosure This application is directed to a process for the preparation of a 2-aminothiazol-4-yl-glyoxylic acid of the formula III
III
wherein R represents a protective group in which an acetylglyoxylic acid ester wherein Z represents the radical of an alcohol, is halogenated, the resulting compound is reacted with thiourea to give a 2-amino-thiazol-4-yl-glyoxylic acid ester
Abstract of the disclosure This application is directed to a process for the preparation of a 2-aminothiazol-4-yl-glyoxylic acid of the formula III
III
wherein R represents a protective group in which an acetylglyoxylic acid ester wherein Z represents the radical of an alcohol, is halogenated, the resulting compound is reacted with thiourea to give a 2-amino-thiazol-4-yl-glyoxylic acid ester
Description
. The invention relates to cephem derivatives of the general formula I
R
N ll C~CONH
N S~ ~ ~ ~N
COO~ i in which Rl denotes hydrogen or low-rr.o].ecular alkoxy, R2 denotes hydrogen, optionally substituted alkyl, phthalide or ~
cation1 X denotes sulfur, oxygen or CH2 and ~ denotes hydroge~, alkoxy, halogen or a group -CH2Y, in which Y represents hydro-gen3 acyloxy, alkoxy, optionally substi-tuted carbamoyloxy or a group -SR3, in which R3 can represent acyl t alkyl or an opt.ion-ally subs-titu-ted 5-membered or 6~membered heterocyc.lic struc-ture, The invention also relates to the process for the preparation of compounds of the ~eneral formula I, ~hich com-prises reacting lactams of the general formula II
~1 O
,' 1~ COO~
in which Rl~ R2, A and X have the.abovementioned meanings but ~ 2 R cannot represent hydrogen, with reactive derivatives of c.
carboxyli.c acid of the general formula III
.
~ ~ ~ C--COOH . III
- 1~ ' . . .
in~hich R ~ri~s a pr~ec-tive group, and converting the resulti.ng :
~ ~ 2 : .
, :
':..:: ' ' ~ ~ .
products of the general formula IV
R N - ~ CO~ ~ j IV
~H SJ . o~ f L~
CO oR2 in which the radicals R, Rl, R2, X and A have the meanings given ini-tially,i~ the compounds of -the general formula I.
The invention also rela-tes to the compounds of the general formula III and the process for the preparation of these compounds, which comprises halogenating acetoglyoxylic acid esters, subsequently reacting the resulting product with thio-urea to give a (2-amino-thiazol-4-yl~-glyoxylic acid ester of the general formula V, conver-ting the latter to derivat:ives of the general formula VI by introducing a pro-tective group R and ~hen saponi~yi.ng these derivatives to the carboxylic acids o~
the general formula III
.
Cll~ COQ7, Halogenating agent Hal~C~12-C-C-CC~
:~ -H ~ t Introduction ~ C-COOz n~ ~h~ I ~C-C007 V . VI
.
Saponification ~ . C-COOH
N ~
.. . . .
, ~4~
In these ~ormulae Z represents -the radical of an alco-hol, preferably of a low-molecular aliphatic alcohol an~ Hal represen-ts halogen, especially bromine and chlorine.
Rl can denote low-molecular alkoxy, such as methoxy, ethoxy, propoxy or butoxy, but especially hydrogen, Amongst the definitions given above for X, the prc--ferred meaning is that of a sulfur ato~.
I~ -the radical A in the general formula represents alkoxy, possible groups are, for example, low-molecular groups _ having 1 to 4 C atoms, such as, for example, methoxy, e~hoxy or butoxy, especially methoxy and ethoxy, bu-t preferably the methoxy group.
If A represents halogen, possible halogens are in part.icular chlorine and bromine.
~15 Preferably, the radical A represents the group -CH2Y, in which Y can have -the following meaningsJ
If Y represents acyloxy, possible radicals are, for example,-low-molecular aoyloxy radicals, such as, for example, ; acetoxy or propionyloxy. ~ The acetoxy radical is particula~l~
preferred.
If Y represents alkoxy, possible radicals are straight-chain or branched~alkoxy radicals having, for exampleS 1 - ~ C
atoms and pre~erably 1 - 4 C atoms, such as, for example, methoxy, ethoxy~, n-propoxy, iso-propoxy, n-butoxy or iso-buto~
~ If Y represents a carbamoyloxy group, thls group can be monosubstituted~or polysubstituted on -the nitrogen, for ex~.mple ; by low-molecular alkyl groups, such as, for example, methyl or ethyl~ and the two substituents can also be bonded with one 4 -~
- .
. .
ano-ther to form a ring, for exarnple to give a 5-membered or 6-membered ring, ~rhich can also be interrupted by a hetero-atom, such as, for example, oxygen, sulfur or nitrogen~ However, the unsubstituted carbamoyloxy group is preferred.
If Y represents a group SR3 and i:E R3 represents ~n acyl radical, possible radicals are, for example, low-molecular acyl radicals. The acetyl and propionyl radicals 9 especially the acetyl radical, are preferred.
If R3 denotes an alkyl radical, possible radicals are straight-chain or branched alkyl radicals having, for example, 1 - 8 C atoms and preferably 1 - 4 C atoms~ such as, for example, methyl, e-thyl, n-propyl, iso-propyl, n-bu-l;yl or iso-butyl, especially methyl and e-thyl, which can optional]y be substi-tuteA by am:ino, hydroxyl or low-molecular carbalkoxy~
especially carbomethoxy, or by phenyl which is op-tionally sub-stituted by low~molecular alkyl or alkoxy, ni~ro or halogen, especially chlorine or bromine, or by carboxyl groups.
If R3 is a heterocycliG structureg possible structures are optionally subs-tituted five-membered or six-membered, preferably five-membered, rings, which in the case of the 5-membered rings possess 1 to 4 hetero-atoms, such as oxygen, sulfur and/or nitrogen, especially nitrogen, optionally toge'her with sulfur, as ring atoms.
The heterocyclic ring system which forms the radical R~
can aiso be wholly or partially hydrogena-ted but is preferably not hydrogenated.
The following basic ring systems may be mentioned as examples of the radical R4: thie~yl, furanyl, pyrrol~l~
imidazolyl, pyrazolyl, -thiazolyl~ isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadlazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl~ pyridyl~ pyrimidyl, pyrazinyl, pyridazinyl, -thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxa-diazinyl~ dithiazinyll dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl and tetrahydropyrimidyl.
Amongst the ring sys-tems listed by way of example above, preferred systems are 5-membered ring systems with 1 to 2 nitrogen a-toms and optionally one oxygen atom, such as, for e~ample, oxazolyl, preferably oxazol-2-yl, oxadiazolyl and imidazollnyl, preferably imidazolin-2-yl, and 6-membered ring systems with 1 to 3, preferably 1 to 2 and especially one nitrogen atom and optionalLy one sulfur a-tom, such as, ~or example, pyridyl, such as pyrid-2-yl, pyrid~3-yl and pyrid-4-yl, pyrimidyl, preferably pyrimid-2-yl and pyrlmid-4-yl, tetra-hydropyrimidyl, preferably 1,4,5,6-tetrahydropyrimid-2-yl, ~; ~ thiadiazinyl, espeeially 4H-1,3,4-thiadiazin-2-yl, -triazinyl, preferably 1,354-triazin-2-yl and 1,3,5-triazin-4-yl, and pyridazinyl, especially pyridazin-3~yl The pyridyl radi-cals are preferred.
Particularly preferred ring systems are 5-membered ring systems with one sulfur atom and 1 to 2 nitrogen a-toms, such as thiazolyl, especially thlazol-2-yl, thiadlazolyl, espeGially 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, 5-membered ring systems with 3 to 4 nitrogen atoms, such as triazolyl, preferably 4H-1,2,4-triazol-3-yl and tetrazolyl, preferably 1'~-tetrazol-5-yL, and also the 1,3,4-oxadiazol-5-yl system~
.
.
~ - 6 -:
~ .
- ~ ~
~6~
Derivatives which can be used according to the invention are in particular the tetrazolyl derivatives.
When it denotes a heterocyclic structure, the radical R can be monosubstituted or polysubstituted, possible sub-stituents being, for example, those which follow: alkyl groups having, for examplel:l to 8 carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.-butyl, n-hexyl and octyl, preferably those having 1 to ~
carbon atoms, especially methyl, and low-molecular alkyl groups having 1 to 4 carbon atoms, preferably methyl, which are substituted, for example by low-molecular alkoxycarbonyl, such as, for example, methoxycarbonyl or ethoxycarbonyl, carboxyl, sulfo groups or low-molecular alkoxysulfonyl, such as, ~or example, methoxysulfonyl or ethoxysulfonyl, or by halogen, such as, for example, chlorine or bromine.
When it denotes a heterocyclic structure, R3 can also be substituted by cycloalkyl groups, such as, for example, cycl opentyl and cyclohexyl, or by low-molecular alkoxy groups, such as, for example, methoxy and ethoxy, low-molecular alkenyl groups, such as, for example, allyl, low-molecular alkylmercapto and alkenylmercapto groups, such as, for example methylmercapto and allylmercapto, low-molecular alkoxycar-bonyl, such as, for example, methoxycarbonyl, low-molecular alkoxycarbonylamino, such as, for example, ethoxycarbonyl- .i amino,low-molecular carboxy alkY1thio, such as, for example, carboxymethylthio, amino, low-molecular mono- and di-alkylamino, such as, for example, methylamino, dimethylamino, ethylamino and diethylamino, oxido, hydroxyl, nitro, cyano, halogen, ¦
preferably chlorine, mercapto, .
_ :""' . ~
~ ?
carboxyl, aryl radicals, such as, for exampleS phenyl, sub-stituted phenyl, such as, for example, low-molecular alkoxy-phenyl, such as methoxyphenyl and e-thoxyphenyl~ halogenophen~
such as, for example, chlorophenyl, hydroxyphenyl, aminophenyl, a'lkylphenyl, especially low-molecular allsylphenyl, such as tert.-butylphenyl, tolyl, cetylphenyl~ nitrophenyl and biphenyl, or pyridyl, methylpyridylS furyl, naphthyl, quinolyl, iso-~uinolyl, -thienyl, 2-thia olyl, 2-pyrrolyl, 4-imida~.olyl, 5-pyrazolyl and 4-isoxazolyl.
' When they denote a heterocyclic structure, preferred radicals R3 according to the invention are the unsubsti-tuted radicals and also the heterocyclic radicals R3 which axe sub-stituted by straight-chain or branched alkyl ha~ing 1 to 8 carbon atoms, especially low-molecul.ar alkyl, preferably methyl, and also by aryl, especially phenyl, which can op-tionally be substituted by low-molecular alkyl or alkoxy groupsy nitro groups or halogen, especially chlorine or brom'ne.
Particuiarly preferred possible radicals are the heterocyclic 5-membered rings substltuted by low-molecular alkyl.
Specific examples of the radical R3 which may b~ men-tioned are, in particular, those w'nich follow: lH-1,2,3-; triazo~-5-yl, 1,Z,4-triazol-3-yl, 5~methyl-1,2,4-triazol-3--yl, l-phenyl-3-methyl-lH-1,2,4-triazol-5-yl, 4,5-dimethyl-4H-1,2,4-triazol-3-yl, 5-methyl-4-amino-4H-1,2,4-triazol-3-yl, 4-phenyi-4~ ,4-triazol-3-yl, 5-ethyl-1,2,4-triazol-3-yl, 4-amino-~H-192,4-triazol-3-yl, 5-ethyl-4-amino-4H-1,2,4-triazol-3-yl, 5-phenyl-lj2,4-triazcl-3-yl, 5-~4-methoxyphenyl)-1,2,4-triazol-3-yl, 5-(4-chlorophenyl~-1,2,4-triazol-3-yl, 5-(4-pyridyl)-1,2,4-8 - .
' :
triazol-~~yl, 5-~ 4- ( 2-methyl-pyridyl)] 1,~,4-triazol-~-yl, 5-phenoxymethyl-1,2,4-triazol-3-yl, 5-methoxymethyl-1,2,4-triazol-3-yl, 5-e-thoxymethyl-1,2,4-triazol-3-yl, 5-ethoxy-carbonylmethyl-1,2,4-triazol-~-yl, 5-(2-ethoxyethyl)-1,2,4-triazol-~-yl, 5-(2-aminoethyl)-1,2,4-triazol-3-yl, 4-me-thyl-5-phenyl-4H-1,2,4-triazol-3-yl, 4 (4-e-thoxyphenyl)-5-(4-pyridyl)-4H-1,2,4--triazol-3-yl, 4-(4-methoxyphenyl)-5-(4-pyridyl)-4~-1,2,4~triazol-3-yl, 4-(4-ethoxyphenyl)-5-(3-pyridyl)-4H-1,2,4-triazol-3-yl, 4-(4-ethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl, 4-(4-ethoxyphenyl)~5-(4-aminophenyl)-4H-1,2,4--triazol-3-yl, 4.,5-diphenyl-4H-1,2,4-triazol-3-yl~ 4,5-di-p-tolyl~4H-1,2l4-triazol-3-yl, 4-allyl-5-phenyl-4H-1,2,4--triazol-3-yl, 4-amino-5-methyl-4H-1,2,4-triazol--3-yl, 4-amino-5-e-thyl-4H--1,2,4-triazol-3-yl, 1-me-thyl-5-phenyl-1,2,4-triazol-3-yl, l~phe~yl-4-allyl-5-(m-nitrophenyl~-4H-1,2,4--trlazol~3-yl, 1--phenyl-4 allyl-5-t-butyl-4H-1,2,4-triazol-3-yl, lH-te-trazol-5-yl, 1-methyl-lH-tetrazol-5-yl, 1-ethyl-lH-tetrazol-5-yl, l-n-propyl-lH-tetrazol-5-yl, 1-i-propyl-lH-tetrazol-5-yl, l-n-butyl-lH-tetrazol-5-yl, 1-cyclopentyl-lH-tetrazol-5-yl, l-phenyl-lH-tetrazol-5-yl, 1-p-chlorophenyl-lH--tetrazol-5-yl, 1-cyclohex~rl-lH-tetrazol-5-yl, 1-benzyl-lH-tetrazol-5-yl, l-allyl-lH-tetrazol-5-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl;
~I,2,4-thiadia~ol-3-yl, 1,2,4-thiadiazol~5-yl, 1,2,5-thiadiazol-3-yl, 3-methyl-1,2,4~thiadiazol-5-yl, 3-phenyl-1,2,4-thiadiazol-5-yl, 2-methyl-1,3,4-thiadiazol-5-yl, 2-methylmercapto-1,3~4 thiadiazol-5-yl, 2-ethyl-1~3,4-thiadiazol-5-yl, 2~n-propyl-1,3~4-thiadiazol-5-yl, 2-i-propyl-1,3,4-thiadiazol-5-yl, 2-phenyl-1,3,4-thiadiazol-5-yl, 2-(4-methoxyphenyl)-1,3,4-thia~
.
'' .
. .
diazol-5-yl, 2 (4-chlorophenyl)-1,3,4-thiadiazol-5-yl, 2-n-heptyl-1,3,4-thiadiazol-5-yl, 2-(2-furyl)-1.,3,4-thiadiazol-5-yl 9 2-(3-pyridyl)-1,3,4-thiadiazol-5-yl, 2-n-butyl-1,3,4-thia-diazol-5-yl, 2-(2-pyridyl)~1~3,4-~thiadiazol-5-yl, 2-(4-pyridyl~--1,3,4-thiadiazol-5-yl, 2-(1-naphthyl)-1,3,4-thiadiazol-5-yl, 2-(2-quinolyl)-1,3,4--thiadiazol-5-yl, 2-(1-isoquinolyl)-1,3,4-thiadiazolyl-5-yl, 2~ethoxycarbonylme~thyl-1,3~4-thi.adiazol-5-yl, 2-phenyl.-3-methyl-1,3,4-thladiazol-5-yl, 2-e-thoxycar~onyl-amino-4-methyl-1S3,4-thiadiazol-5-yl, 3-methylmercapto-1,2,4-thiadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl, 2-ethyl-1,3,4-oxadiazol-5-yl, 2-phenyl-1,3,4-oxadiazol-5-y:l, 2-(4-nitrophenyl)-1,3,4-oxadiazol-5-yl, 2-(2-thienyl)-1,3,4-oxa-diazol-5-yl, 2-(3-thlenyl)-1,3,4-oxadiazol-~5-yl, 2-(4-chloro-phenyl)-1,3,4-oxadiazol-5 yl, 2-(2~-thiazolyl)-1,3,4-oxadiazol-5-yl, 2-(2-furyl)-1,3,4-oxadiazol-5-yl, 2-(4-pyridyl)-1,3,4-oxadiazol~5-yl, 2-(3-nitrophenyl)-1,3,4-oxadiazol-5-yl, 2-(2-me-thoxyphenyl)-193,4-oxadiazol-5-yl, 2-(2-tolyl)-1,3,4-oxa-diazol-5-yl, 2-(3-tolyl)-1,3,4-oxadiazol-5-yl; 2-(2-hydro~y-
R
N ll C~CONH
N S~ ~ ~ ~N
COO~ i in which Rl denotes hydrogen or low-rr.o].ecular alkoxy, R2 denotes hydrogen, optionally substituted alkyl, phthalide or ~
cation1 X denotes sulfur, oxygen or CH2 and ~ denotes hydroge~, alkoxy, halogen or a group -CH2Y, in which Y represents hydro-gen3 acyloxy, alkoxy, optionally substi-tuted carbamoyloxy or a group -SR3, in which R3 can represent acyl t alkyl or an opt.ion-ally subs-titu-ted 5-membered or 6~membered heterocyc.lic struc-ture, The invention also relates to the process for the preparation of compounds of the ~eneral formula I, ~hich com-prises reacting lactams of the general formula II
~1 O
,' 1~ COO~
in which Rl~ R2, A and X have the.abovementioned meanings but ~ 2 R cannot represent hydrogen, with reactive derivatives of c.
carboxyli.c acid of the general formula III
.
~ ~ ~ C--COOH . III
- 1~ ' . . .
in~hich R ~ri~s a pr~ec-tive group, and converting the resulti.ng :
~ ~ 2 : .
, :
':..:: ' ' ~ ~ .
products of the general formula IV
R N - ~ CO~ ~ j IV
~H SJ . o~ f L~
CO oR2 in which the radicals R, Rl, R2, X and A have the meanings given ini-tially,i~ the compounds of -the general formula I.
The invention also rela-tes to the compounds of the general formula III and the process for the preparation of these compounds, which comprises halogenating acetoglyoxylic acid esters, subsequently reacting the resulting product with thio-urea to give a (2-amino-thiazol-4-yl~-glyoxylic acid ester of the general formula V, conver-ting the latter to derivat:ives of the general formula VI by introducing a pro-tective group R and ~hen saponi~yi.ng these derivatives to the carboxylic acids o~
the general formula III
.
Cll~ COQ7, Halogenating agent Hal~C~12-C-C-CC~
:~ -H ~ t Introduction ~ C-COOz n~ ~h~ I ~C-C007 V . VI
.
Saponification ~ . C-COOH
N ~
.. . . .
, ~4~
In these ~ormulae Z represents -the radical of an alco-hol, preferably of a low-molecular aliphatic alcohol an~ Hal represen-ts halogen, especially bromine and chlorine.
Rl can denote low-molecular alkoxy, such as methoxy, ethoxy, propoxy or butoxy, but especially hydrogen, Amongst the definitions given above for X, the prc--ferred meaning is that of a sulfur ato~.
I~ -the radical A in the general formula represents alkoxy, possible groups are, for example, low-molecular groups _ having 1 to 4 C atoms, such as, for example, methoxy, e~hoxy or butoxy, especially methoxy and ethoxy, bu-t preferably the methoxy group.
If A represents halogen, possible halogens are in part.icular chlorine and bromine.
~15 Preferably, the radical A represents the group -CH2Y, in which Y can have -the following meaningsJ
If Y represents acyloxy, possible radicals are, for example,-low-molecular aoyloxy radicals, such as, for example, ; acetoxy or propionyloxy. ~ The acetoxy radical is particula~l~
preferred.
If Y represents alkoxy, possible radicals are straight-chain or branched~alkoxy radicals having, for exampleS 1 - ~ C
atoms and pre~erably 1 - 4 C atoms, such as, for example, methoxy, ethoxy~, n-propoxy, iso-propoxy, n-butoxy or iso-buto~
~ If Y represents a carbamoyloxy group, thls group can be monosubstituted~or polysubstituted on -the nitrogen, for ex~.mple ; by low-molecular alkyl groups, such as, for example, methyl or ethyl~ and the two substituents can also be bonded with one 4 -~
- .
. .
ano-ther to form a ring, for exarnple to give a 5-membered or 6-membered ring, ~rhich can also be interrupted by a hetero-atom, such as, for example, oxygen, sulfur or nitrogen~ However, the unsubstituted carbamoyloxy group is preferred.
If Y represents a group SR3 and i:E R3 represents ~n acyl radical, possible radicals are, for example, low-molecular acyl radicals. The acetyl and propionyl radicals 9 especially the acetyl radical, are preferred.
If R3 denotes an alkyl radical, possible radicals are straight-chain or branched alkyl radicals having, for example, 1 - 8 C atoms and preferably 1 - 4 C atoms~ such as, for example, methyl, e-thyl, n-propyl, iso-propyl, n-bu-l;yl or iso-butyl, especially methyl and e-thyl, which can optional]y be substi-tuteA by am:ino, hydroxyl or low-molecular carbalkoxy~
especially carbomethoxy, or by phenyl which is op-tionally sub-stituted by low~molecular alkyl or alkoxy, ni~ro or halogen, especially chlorine or bromine, or by carboxyl groups.
If R3 is a heterocycliG structureg possible structures are optionally subs-tituted five-membered or six-membered, preferably five-membered, rings, which in the case of the 5-membered rings possess 1 to 4 hetero-atoms, such as oxygen, sulfur and/or nitrogen, especially nitrogen, optionally toge'her with sulfur, as ring atoms.
The heterocyclic ring system which forms the radical R~
can aiso be wholly or partially hydrogena-ted but is preferably not hydrogenated.
The following basic ring systems may be mentioned as examples of the radical R4: thie~yl, furanyl, pyrrol~l~
imidazolyl, pyrazolyl, -thiazolyl~ isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadlazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl~ pyridyl~ pyrimidyl, pyrazinyl, pyridazinyl, -thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxa-diazinyl~ dithiazinyll dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl and tetrahydropyrimidyl.
Amongst the ring sys-tems listed by way of example above, preferred systems are 5-membered ring systems with 1 to 2 nitrogen a-toms and optionally one oxygen atom, such as, for e~ample, oxazolyl, preferably oxazol-2-yl, oxadiazolyl and imidazollnyl, preferably imidazolin-2-yl, and 6-membered ring systems with 1 to 3, preferably 1 to 2 and especially one nitrogen atom and optionalLy one sulfur a-tom, such as, ~or example, pyridyl, such as pyrid-2-yl, pyrid~3-yl and pyrid-4-yl, pyrimidyl, preferably pyrimid-2-yl and pyrlmid-4-yl, tetra-hydropyrimidyl, preferably 1,4,5,6-tetrahydropyrimid-2-yl, ~; ~ thiadiazinyl, espeeially 4H-1,3,4-thiadiazin-2-yl, -triazinyl, preferably 1,354-triazin-2-yl and 1,3,5-triazin-4-yl, and pyridazinyl, especially pyridazin-3~yl The pyridyl radi-cals are preferred.
Particularly preferred ring systems are 5-membered ring systems with one sulfur atom and 1 to 2 nitrogen a-toms, such as thiazolyl, especially thlazol-2-yl, thiadlazolyl, espeGially 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, 5-membered ring systems with 3 to 4 nitrogen atoms, such as triazolyl, preferably 4H-1,2,4-triazol-3-yl and tetrazolyl, preferably 1'~-tetrazol-5-yL, and also the 1,3,4-oxadiazol-5-yl system~
.
.
~ - 6 -:
~ .
- ~ ~
~6~
Derivatives which can be used according to the invention are in particular the tetrazolyl derivatives.
When it denotes a heterocyclic structure, the radical R can be monosubstituted or polysubstituted, possible sub-stituents being, for example, those which follow: alkyl groups having, for examplel:l to 8 carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.-butyl, n-hexyl and octyl, preferably those having 1 to ~
carbon atoms, especially methyl, and low-molecular alkyl groups having 1 to 4 carbon atoms, preferably methyl, which are substituted, for example by low-molecular alkoxycarbonyl, such as, for example, methoxycarbonyl or ethoxycarbonyl, carboxyl, sulfo groups or low-molecular alkoxysulfonyl, such as, ~or example, methoxysulfonyl or ethoxysulfonyl, or by halogen, such as, for example, chlorine or bromine.
When it denotes a heterocyclic structure, R3 can also be substituted by cycloalkyl groups, such as, for example, cycl opentyl and cyclohexyl, or by low-molecular alkoxy groups, such as, for example, methoxy and ethoxy, low-molecular alkenyl groups, such as, for example, allyl, low-molecular alkylmercapto and alkenylmercapto groups, such as, for example methylmercapto and allylmercapto, low-molecular alkoxycar-bonyl, such as, for example, methoxycarbonyl, low-molecular alkoxycarbonylamino, such as, for example, ethoxycarbonyl- .i amino,low-molecular carboxy alkY1thio, such as, for example, carboxymethylthio, amino, low-molecular mono- and di-alkylamino, such as, for example, methylamino, dimethylamino, ethylamino and diethylamino, oxido, hydroxyl, nitro, cyano, halogen, ¦
preferably chlorine, mercapto, .
_ :""' . ~
~ ?
carboxyl, aryl radicals, such as, for exampleS phenyl, sub-stituted phenyl, such as, for example, low-molecular alkoxy-phenyl, such as methoxyphenyl and e-thoxyphenyl~ halogenophen~
such as, for example, chlorophenyl, hydroxyphenyl, aminophenyl, a'lkylphenyl, especially low-molecular allsylphenyl, such as tert.-butylphenyl, tolyl, cetylphenyl~ nitrophenyl and biphenyl, or pyridyl, methylpyridylS furyl, naphthyl, quinolyl, iso-~uinolyl, -thienyl, 2-thia olyl, 2-pyrrolyl, 4-imida~.olyl, 5-pyrazolyl and 4-isoxazolyl.
' When they denote a heterocyclic structure, preferred radicals R3 according to the invention are the unsubsti-tuted radicals and also the heterocyclic radicals R3 which axe sub-stituted by straight-chain or branched alkyl ha~ing 1 to 8 carbon atoms, especially low-molecul.ar alkyl, preferably methyl, and also by aryl, especially phenyl, which can op-tionally be substituted by low-molecular alkyl or alkoxy groupsy nitro groups or halogen, especially chlorine or brom'ne.
Particuiarly preferred possible radicals are the heterocyclic 5-membered rings substltuted by low-molecular alkyl.
Specific examples of the radical R3 which may b~ men-tioned are, in particular, those w'nich follow: lH-1,2,3-; triazo~-5-yl, 1,Z,4-triazol-3-yl, 5~methyl-1,2,4-triazol-3--yl, l-phenyl-3-methyl-lH-1,2,4-triazol-5-yl, 4,5-dimethyl-4H-1,2,4-triazol-3-yl, 5-methyl-4-amino-4H-1,2,4-triazol-3-yl, 4-phenyi-4~ ,4-triazol-3-yl, 5-ethyl-1,2,4-triazol-3-yl, 4-amino-~H-192,4-triazol-3-yl, 5-ethyl-4-amino-4H-1,2,4-triazol-3-yl, 5-phenyl-lj2,4-triazcl-3-yl, 5-~4-methoxyphenyl)-1,2,4-triazol-3-yl, 5-(4-chlorophenyl~-1,2,4-triazol-3-yl, 5-(4-pyridyl)-1,2,4-8 - .
' :
triazol-~~yl, 5-~ 4- ( 2-methyl-pyridyl)] 1,~,4-triazol-~-yl, 5-phenoxymethyl-1,2,4-triazol-3-yl, 5-methoxymethyl-1,2,4-triazol-3-yl, 5-e-thoxymethyl-1,2,4-triazol-3-yl, 5-ethoxy-carbonylmethyl-1,2,4-triazol-~-yl, 5-(2-ethoxyethyl)-1,2,4-triazol-~-yl, 5-(2-aminoethyl)-1,2,4-triazol-3-yl, 4-me-thyl-5-phenyl-4H-1,2,4-triazol-3-yl, 4 (4-e-thoxyphenyl)-5-(4-pyridyl)-4H-1,2,4--triazol-3-yl, 4-(4-methoxyphenyl)-5-(4-pyridyl)-4~-1,2,4~triazol-3-yl, 4-(4-ethoxyphenyl)-5-(3-pyridyl)-4H-1,2,4-triazol-3-yl, 4-(4-ethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl, 4-(4-ethoxyphenyl)~5-(4-aminophenyl)-4H-1,2,4--triazol-3-yl, 4.,5-diphenyl-4H-1,2,4-triazol-3-yl~ 4,5-di-p-tolyl~4H-1,2l4-triazol-3-yl, 4-allyl-5-phenyl-4H-1,2,4--triazol-3-yl, 4-amino-5-methyl-4H-1,2,4-triazol--3-yl, 4-amino-5-e-thyl-4H--1,2,4-triazol-3-yl, 1-me-thyl-5-phenyl-1,2,4-triazol-3-yl, l~phe~yl-4-allyl-5-(m-nitrophenyl~-4H-1,2,4--trlazol~3-yl, 1--phenyl-4 allyl-5-t-butyl-4H-1,2,4-triazol-3-yl, lH-te-trazol-5-yl, 1-methyl-lH-tetrazol-5-yl, 1-ethyl-lH-tetrazol-5-yl, l-n-propyl-lH-tetrazol-5-yl, 1-i-propyl-lH-tetrazol-5-yl, l-n-butyl-lH-tetrazol-5-yl, 1-cyclopentyl-lH-tetrazol-5-yl, l-phenyl-lH-tetrazol-5-yl, 1-p-chlorophenyl-lH--tetrazol-5-yl, 1-cyclohex~rl-lH-tetrazol-5-yl, 1-benzyl-lH-tetrazol-5-yl, l-allyl-lH-tetrazol-5-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl;
~I,2,4-thiadia~ol-3-yl, 1,2,4-thiadiazol~5-yl, 1,2,5-thiadiazol-3-yl, 3-methyl-1,2,4~thiadiazol-5-yl, 3-phenyl-1,2,4-thiadiazol-5-yl, 2-methyl-1,3,4-thiadiazol-5-yl, 2-methylmercapto-1,3~4 thiadiazol-5-yl, 2-ethyl-1~3,4-thiadiazol-5-yl, 2~n-propyl-1,3~4-thiadiazol-5-yl, 2-i-propyl-1,3,4-thiadiazol-5-yl, 2-phenyl-1,3,4-thiadiazol-5-yl, 2-(4-methoxyphenyl)-1,3,4-thia~
.
'' .
. .
diazol-5-yl, 2 (4-chlorophenyl)-1,3,4-thiadiazol-5-yl, 2-n-heptyl-1,3,4-thiadiazol-5-yl, 2-(2-furyl)-1.,3,4-thiadiazol-5-yl 9 2-(3-pyridyl)-1,3,4-thiadiazol-5-yl, 2-n-butyl-1,3,4-thia-diazol-5-yl, 2-(2-pyridyl)~1~3,4-~thiadiazol-5-yl, 2-(4-pyridyl~--1,3,4-thiadiazol-5-yl, 2-(1-naphthyl)-1,3,4-thiadiazol-5-yl, 2-(2-quinolyl)-1,3,4--thiadiazol-5-yl, 2-(1-isoquinolyl)-1,3,4-thiadiazolyl-5-yl, 2~ethoxycarbonylme~thyl-1,3~4-thi.adiazol-5-yl, 2-phenyl.-3-methyl-1,3,4-thladiazol-5-yl, 2-e-thoxycar~onyl-amino-4-methyl-1S3,4-thiadiazol-5-yl, 3-methylmercapto-1,2,4-thiadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl, 2-ethyl-1,3,4-oxadiazol-5-yl, 2-phenyl-1,3,4-oxadiazol-5-y:l, 2-(4-nitrophenyl)-1,3,4-oxadiazol-5-yl, 2-(2-thienyl)-1,3,4-oxa-diazol-5-yl, 2-(3-thlenyl)-1,3,4-oxadiazol-~5-yl, 2-(4-chloro-phenyl)-1,3,4-oxadiazol-5 yl, 2-(2~-thiazolyl)-1,3,4-oxadiazol-5-yl, 2-(2-furyl)-1,3,4-oxadiazol-5-yl, 2-(4-pyridyl)-1,3,4-oxadiazol~5-yl, 2-(3-nitrophenyl)-1,3,4-oxadiazol-5-yl, 2-(2-me-thoxyphenyl)-193,4-oxadiazol-5-yl, 2-(2-tolyl)-1,3,4-oxa-diazol-5-yl, 2-(3-tolyl)-1,3,4-oxadiazol-5-yl; 2-(2-hydro~y-
2~ phenyl)-193,4-oxadiazol-5-yl, 2-(4-hydroxyphenyl)-1,3,4--oxa-diazol-5-yl, 2-n-butyl-1,3,4-oxadiazol-5-yl, 2-n-propyl-1,3,4-^
oxadiazol-5-ylg 2-benzyl-1,3,4-oxadiazol-5-yl, 2-(1-naphthyl)--1,3,4-oxadia~ol-5-yl, 2-(2-pyrrolyl)-1,3,4~oxadiazol-5-yl, 2-(4-imidazolyl)-1,3,4-oxadiazol-5-yl, 2-(5-pyrazolyl)-1,3,4-oxadiazol-5-yl, 2-(3,5-dimethyi-4-isoxazolyl)-1,3,4-oxadiazol-5-yl, thiazol-2-yl, 4-methyl-thiazol-2-yl, 4-phen-yl-thiazol-2-yl, 4-pentyl-thiazol-2-yl, 4-hexyl~thiazol-2-yl, 4-1mdecyl-thiazol-2-yl; 4-tridecyl-thiazol-2-yl, 4-pentadecyl-thiazol-J-"' ' ' ' ' ' "
~: . - . . .
, , ~ ~ ; : , - ' ~' 6~
yl 9 4-p-~ert-butylphenyl-thia~ol~2-yl, 4-p~ce-tylphenyl-thiazol-2-yl, 4-p-phenylphenyl-thiazol-2-yl, 4-ethyl~thiazol-2-yl, 4,5-dimethyl-thiazol-2-yl, benzthiazol-2~yl, 4,5-dimethyl-o~.azol-2-yl, 4-phenyl-oxazol-2-yl, o~azolin-2-yl, imidazol-2-yl, imidazolin-2-yl, l-me-thyl-imidazolin-2--yl, 2-furyl, 2-thio-phenyl, 2-pyrrolyl, 2-thiazolinyl, ~-isoxazolyl, 3-pyrazolyl, thiatriazol-5-yl, purinyl, pyrid-2-yl, pyrid-3-yl, pyrid-4~yl, 5-nitro-pyrid-2-yl, 1 oxidopyrid-2-yl, p~rri.mid-2-yl, l,4,5,6-tetrahydropyrimid-2-yl, 4-hydroxy-pyrimid-2-yl, 4~hydroxy-6~
methyl-pyrimid-2-yl, 2-hydroxy-pyrimid-4-yl; 2-phenyl-5-etho~-carbonyl-6-methyl-pyrimid-4-yl, 2-phenyl-5-ethoxycarbonyl-6-ethoxy-pyrimid-4-yl, 2-phenyl-5-ethoxycarbonyl-6-amino-pyrimid-4-yl, 2-hydroxy-5-cyano-6-me-thyl-pyrimid-4~yl, 2,6--dimethy1-5-acetyl-pyrimid--4-yl, 2-undecyl-5-acetyl-6~methyl-pyrlmid-4~yl, 2,6-dimethyl-5-ethoxycarbonyl-pyrimid-4-yl, -tria~ollopyridyl, pyridazinyl, pyrazinyl, 2-rne-thylmercapto-6-phenyl~ ,5-triazin-4-yl, 5-methyl-6-hydroxy-l 5 3 9 4-triazin-2-yl, 5-phenyl-4H-l,3,4-thiadiazin-2-yl, 5-hydroxy-4H-l,3~4-thiadiazin-2-yl~
oxadiazol-5-ylg 2-benzyl-1,3,4-oxadiazol-5-yl, 2-(1-naphthyl)--1,3,4-oxadia~ol-5-yl, 2-(2-pyrrolyl)-1,3,4~oxadiazol-5-yl, 2-(4-imidazolyl)-1,3,4-oxadiazol-5-yl, 2-(5-pyrazolyl)-1,3,4-oxadiazol-5-yl, 2-(3,5-dimethyi-4-isoxazolyl)-1,3,4-oxadiazol-5-yl, thiazol-2-yl, 4-methyl-thiazol-2-yl, 4-phen-yl-thiazol-2-yl, 4-pentyl-thiazol-2-yl, 4-hexyl~thiazol-2-yl, 4-1mdecyl-thiazol-2-yl; 4-tridecyl-thiazol-2-yl, 4-pentadecyl-thiazol-J-"' ' ' ' ' ' "
~: . - . . .
, , ~ ~ ; : , - ' ~' 6~
yl 9 4-p-~ert-butylphenyl-thia~ol~2-yl, 4-p~ce-tylphenyl-thiazol-2-yl, 4-p-phenylphenyl-thiazol-2-yl, 4-ethyl~thiazol-2-yl, 4,5-dimethyl-thiazol-2-yl, benzthiazol-2~yl, 4,5-dimethyl-o~.azol-2-yl, 4-phenyl-oxazol-2-yl, o~azolin-2-yl, imidazol-2-yl, imidazolin-2-yl, l-me-thyl-imidazolin-2--yl, 2-furyl, 2-thio-phenyl, 2-pyrrolyl, 2-thiazolinyl, ~-isoxazolyl, 3-pyrazolyl, thiatriazol-5-yl, purinyl, pyrid-2-yl, pyrid-3-yl, pyrid-4~yl, 5-nitro-pyrid-2-yl, 1 oxidopyrid-2-yl, p~rri.mid-2-yl, l,4,5,6-tetrahydropyrimid-2-yl, 4-hydroxy-pyrimid-2-yl, 4~hydroxy-6~
methyl-pyrimid-2-yl, 2-hydroxy-pyrimid-4-yl; 2-phenyl-5-etho~-carbonyl-6-methyl-pyrimid-4-yl, 2-phenyl-5-ethoxycarbonyl-6-ethoxy-pyrimid-4-yl, 2-phenyl-5-ethoxycarbonyl-6-amino-pyrimid-4-yl, 2-hydroxy-5-cyano-6-me-thyl-pyrimid-4~yl, 2,6--dimethy1-5-acetyl-pyrimid--4-yl, 2-undecyl-5-acetyl-6~methyl-pyrlmid-4~yl, 2,6-dimethyl-5-ethoxycarbonyl-pyrimid-4-yl, -tria~ollopyridyl, pyridazinyl, pyrazinyl, 2-rne-thylmercapto-6-phenyl~ ,5-triazin-4-yl, 5-methyl-6-hydroxy-l 5 3 9 4-triazin-2-yl, 5-phenyl-4H-l,3,4-thiadiazin-2-yl, 5-hydroxy-4H-l,3~4-thiadiazin-2-yl~
3-hydroxy-pyridazin-6-yl and tetrazol-~4,5-b]-pyridazin-6-yl 2~ The cephem compounds of the general formula II
: ~ , ~ ' , ~R1 ' I ~ N
': l ' ~ .- Coo~
which are to be employed for the reacti.on according to the invention are known from the literature or can be prepared in accordance with the instructions in the literature, for ex~ple in accordance with the instructions in F.F. Fl~nn..Cephalo-:
. ' ' . , ~ ,, ' ': ' ~' ' ' ' ' '. ~ ' . ' :
sporins and Penicillins, Chemistry and siology, AcademicPress, New York and London, 1972, or - when X in formula II
represenLs oxygen or CH2 - in accordance with the instructions in J. Amer. Chem. Soc. 96, 7582 and 7584 (1974).
The carboxylic acids of the formula III used for the acylation are novel compounds which can be prepared according to the inventiOn in good yields. The starting point for their preparation is the acetoglyoxylic acid ester, which is accessible from the acetoacetic acid ester in ac-cordance with the instructions in the literature. Preferably, the esters employed are the readily accessible low-molecular alkyl esters, especially the ethyl ester.
Several routes have been described in the literature for the formation of the aminothiazole ring, for example the reaction of chloroketo derivatives with thiourea in accordance with the following equation^ CH3 N¦H2 1 3 ~ ~
C C 2 1 ~ ~ f H
/ ~ H N
H2N S ' It has now been found, surprisingly, that an aceto-glyoxylic acid ester can be converted easily and in high yields to a halogeno-acetoglyoxylic acid ester. Halogenating agents which have proved suitable are especially sulfuryl chloride or elementary bromine. ~
The bromination is carried out in a solvent. Solvents which have proved suitable are in particular the halogenated hydrocarbons, such as, for example, methylene chloride, chloro-... , . ~ ... . ~ . , -': .
':
.
~6~
form or ethylene dichloride.
The reaction can be carried out ~ithin a wide tempera-ture range. In order to achieve high yields OI mOllOllalOgenO-acetoglyoxylic acid ester, a temperature range OI -20~ to ~20 is preferred.
If elementary bromine has been used for the halogenation, -the bromoacetoglyoxylic acid ester can be furt~ler reac-ted direct, as the ra~ material, with thiourea.
In order to achieve good yields it is advisabie to -~
employ the thiourea in equimolar amounts. It has Deen found, surprisingly, that (2-amino-thiazol-4-yl)~glyoxylic acid es~ers of the formula V form in high yields when the bromoaceto-glyoxylic acid ester is reacted wi-th thiourea.
The reaction can be carried out in vario~ls ways. A
preferred method comprises initial]y introducing the thiourea in solution and allowing the halogen compound to run into the ~eaction mixture SoIvents which have proved suitable for this rea~tion are mixtures of organic solvents with water. Mixtures of alcohols and wa-ter, especially mixtures of ethanol and ~ater~
are particularly suitable~
The reaction can be carried out within a wide tempera-ture range, for example at -5 to +80 The temperature range of 20 to 60 is particularly suitable.
The reaction products of the formula V can be isola~ed by routes kno~m from the laboratory, for example by evaporatin~
off the organic solvent and subsequently adjusting the pH value to 5-7. The adjustment of the pH value ls effected with ~ . ' ' - . ' ' ~ - 13 ~
~4~
. .
bases and organic or inorganic bases can be used. For example~ the inexpensive alkali metal hydroxides, alkali metal carbona-tes and alkali metal bicarbonates and the corresponding phosphates have proved suitable.
By means of the reaction which follows the reaction ~lith thiourea, the amino group in the compounds of the formula V is provided with a pro-tective group. Possible protective groups are groups known from the literature, such as, for example, tert.-butoxycarboIlyl, carbobenzyloxy, chloroacetyl, trichloroethyl, benzhydryl or formyl. The triphenylmethyl g~oup has proved particularly sultable as a protec-tive group and is introduced by reacting the compounds of the formula V
with triphenylchloromethane. The reaction is appropriately carried out in an organic solvent, such as, for example, halogenated hydrocarbons, in -the presence of bases.
Halogenated hydrocarbons which have proved particularly suitable are chloroform and methylene chloride. Bases which may be mentioned are, in particular, -the tertiary amines, such as, for example, triethylamine or N-methylmorpholineO
The esters of the formula VI, which are thus obtaine~, are saponified to the corresponding acids of the formula III~
Mixtures of dioxane and water have proved particularly suitable for the saponification~ Thus, it is advantageous to saponify the esters hot in dioxane with the addition of the calculated amount of base and then to isolate the resulting salts. Bases~which have proved suitable are, for example, alkali ~.etal hydroxides, especiall~ sodium hydroxide.
The sodium salts formed when sodium hy~roxide is used ir.
A ~ 14 ..... ... .
;~ ..
~: , .
. . ..
.
most cases crystallize out from the reaction mixture on cooling.
They can be conver-ted into the acids of the formula III, which are better suited for some activation reactions, by the addi~
tion of dilute mineral acids. Acids which may be mentione~
for this purpose are, in particular, hydrochloric acid or sulfuric acid.
Tn other cases, the sodium salts can also be employed direct for the activation.
The carboxylic acids of the general formula III can be converted by processes known from the literature into the activated carboxylic acid derivatives capable of forming an amide. A preferred process for activating the carboxyl group comprises converting it into a symmetrical or unsymmet-rical anhydride. The processes for the preparation of mixed or symmetrical anhydrides are known from the literature.
-For example, chloroformic acid esters or pivaloyl chloride can be used for the activation, in whlch case the acid of the formula III has to be converted into a corresponding salt.
It has been found that the reaction proceeds readily ~rhen the acid is suspended in halogenated hydrocarbons, such as, for example, methylene chloride, and converted, using organic bases, such as, for example, triethylamine, into the triethylammonium salt, Alternatively, in some cases ~it is also possible to employ, for example, a'kali metal salts of the acids of the formula III and in this case the addition of catalytic amo~nts of a tertiary base~ such as, for example, N,N-dimethylaniline, has proved advantageous, The inner a~hydrldes can also be formed from the - 15 - ?
.~,.~ ; , - .
, . : ' ~: .
carboxylic acids of the formula III using condensing agents, such as, ~or example, dicyclohexylcarbodiimide, and these inner anhydrides are then reacted with the aminocephem-carboxylic acid derivatives of the formula II.
A further variant comprises employing addition products of the carboxylic acids and condensing agents, such as, for example, dicyclohexylcarbodiimide, for acylatin~ the cephem acids or their esters of the formula IX
The preparation of the compounds of the general formula -I can be carried out under various experimental condi-tions Thus, for example, the aminocephem derivatives of the formula II can be acylated in very diverse solven-ts. Suitab]e sol-~ents are, for example, organic solvents, such as halogenated hydrocarbons, for example methylene chloride or chloroform, b~t also water or mixtures of wa~er and organic solven-ts which are miscible with water.
In order to achieve a good course of reaction, ~t i~
desirable to bring the aminolactam derivatives into solution In the case of the aminocephem esters o~ the genera]
formula II, the reaction is carried out in organic solvents in which rnost of the esters are readily solublec Examples of such solvents which may be mentioned are the halogenated hydro-carbons, such as methylene chloride or chloroform, but also the tertiary amides-, such as dimethylformamide or dimethylacet-amide;
Esters in the sense of the invention which can be used :
are, for example, those compounds of the formula II in ~hich R2 represents low-molecular alkyl~ preferably tertiary butyl or :, .
~ :: . : ~
6~
.. .
subs-titu-ted methyl, in which the methyl group is substltuted in particular by trichloromethyl, acyloxy, preferably acetoxy or pivaloyloxy, or by one or two phenyl radicals, which, in turn, can be substituted, for example, by low-moiecular alkoxy~
preferably methoxy, or the nitro group, or represents the phthalide ester. F~amples conforming to the above defini-tions which may be mentioned are, in particular, the tert -butyl esters, the trichloroethyl and p-methoxybenzyl estersS
the benzhydryl, acetoxymethyl and pivaloyloxymethyl esters or the phthalide es-ters.
When the aminocephemcarboxylic acids of the general formula II (R = hydrogen) are used, the cornpounds must be brought in-to solution wi-th the addition of bases.
Suitable bases which can be used for dissolvin~ 7-ACA
and also a large number of 7-amino~3-cephem-4-carboxylic acids are inorganic~or organic bases~ Thuss bases which have proved suitable for the preparation of solutions in organic solvents are in particular the tertiary amines, such as tri-ethylamine, N,N-dimethylaniline or N-methylmorpholine, and those which have proved suitable for preparing aqueous solutions are in particular the alkali metal bicarbonates, such as sodium bicarbonate or potassium bicarbonate, and also the tertiaIy amines. The bases are in general added in at least the stoichiometric amount, relative to the desired conversion.
2~ However, it is advisable to use an excess of base of, for example, about 20 to 80%~ -Especially in the case of compounds of the formula II
which are sensitive to bases, a constant pH of abou-t 4 to 8 17 ~;
: ':
.
and preferably 6 to 7, depending on the course of the reaction r can be maintained by continuous addition of the base.
The aminolactam derivatives of the formula II can be dissolved within a wide temperature range. In the case of derivatives sensitive to bases, however r it is advisable to choose a temperature range of about 0 to 15.
The activated glyoxylic acid derivatives of the formula III are added to the amino-cephem derivatives of the formula II, which are in solution or optionally in suspension. The reaction takes place in a manner which is in itself knownr at temperatures such as are cUstomary for the preparation of car-boxylic acid amides rom reactive carboxylic acid derivatives of the formula III.
When water or mixtures of water and organic solvents are used as the reaction medium, it is advisable to maintain a temperature range of about 5 to +10. When organic sol-vents are used, the acylation can also be carried out at room temperature.
In order to obtain a better course of reaction, the activated carboxylic acid derivatives of the formula III are taken up in a solvent which does not hinder the reaction and introduced in dilute form. If the acylation is carried out in an aqueous medium, solvents which can be used for the activated carboxylic acid derivatives, are, for example, anhydrous ketones, such as acetone or methyl ethyl ketone, or -with intensive stirring - ethers, such as, for example, diethyl ether or diisopropyl ether.
If the acylation is carried out in a non-aqueous medium, .~ . 1 it is advisable to use the same solven-t for the dilution of the acid derivatives as is used for the acylation.
In order to obtain high yields, the activated acid derivatives of the formula III are employed in at least the stoichiometric amount. An excess of about 5 - 25% can prove appropriate.
The acylation products can be isolated by methods which are in themselves known. Thus, for example J the resulting acid derivatives of the formula IV in which R represents hydrogen can be taken up, if necessary after evaporating off the organic solvent., in water and precipitated by adding mineral acids Sllitable mineral acids are, in particular1 dilute acids, such as dilute hydrochloric acid or sulfuric acid In most cases, the amidocephem acids of -the for~n~la IY
precipitate in the form of amorphous solids or in a crystalline form. They can also be separated off as the free acids b~r extracting at pH 2 to 1. Extraction agents which can be .
used~are diverse water-immiscible organic solvents, for example halogenated hydrocarbons, such as meth~lene chloride. or esters, ~; 20 ~ such as,~for example, ethyl ~cetate or n-butyl acetate, but also ketones, such as methyl isobutyl ketone.
The resulting amidocephem acids of the formula IV are obtained from the extracts, for example by e~raporating off the solvent and grinding the residue, for example with ether.
~ 25~ When the amidocephem compounds of the formula I are ; prepared from the compounds of the formula IV, t~e protective ~ group R must be removed. The reaction conditions to be ;~ employed depen~ on ihe nature of the proteclive group and are , ., .
'- ~ ' ' ' ~ ~ ' known from the li-terature.
If, for example, R is a triphenylmethyl group, this group is detached in an acid medium. Mixtures of formic acid and water, especially a mixture of water and formic ac~d in a ratio of 1 : 1, have proved sui-table. In the case of compounds of the formula IV in which R2 represents, ~or example, p-methoxybenzyl, benzhydryl or dime-thoxybenzyl and R represe-lts a -triphenylmethyl group, it is possible simultaneously to detach the ester group and to remove the trityl group by treat-ment with trifluoroacetic acid/anisole~
The isolation of -the amidocephem compounds o~ the formula I can be effected by l~own methods~ In many cases the resulting compound is dissolved in the reac-tion med:ium used, so -that an extraction is advisable and, in the case of triphenylmethyl being used as the protective group, the result-ing triphenylcarbinol can be filtered off or can be removed with extraction agents, such as, for example, ether, The amidocephem compo~mds of the formula I in which R2 represents hydrogen can also be converted to the physiologica1ly 20 acceptable esters of -the formula I by subsequent esterification by processes known from the literature. Thus, for example, the acetoxymethyl or pivaloyloxymethyl esters are obtained by reacting the alkali ~etal salts, preferably the sodium salts, or-the ammonium salts, preferably the triethylammonium salts, ~ith the corresponding halo~enomethy~.acyl compounds, such as~ for example, chloromethyl acetate, chloromethyl propionate or chloromethyl pivalate.
.
If the esters, and especially tne physiologically .
' :
~
... ,. . . .. ' :
; ' ~ !
'' , . :
acceptable esters, have already been obtained from the acyla-tion 3 subsequent esterification of the carboxyl group is superfluous.
The esters which are obtained direct from the reactiGn according to the invention, such as, for example, p-methoxy-benzyl, p-nitroben~yl, tert.-butyl or benzhydryl esters, can also be converted to the free carboxylic acids of the ~ormula I
in a manner ~no~n from the litera-ture.
Compounds of the formula I which are in a form suitable for application in human medicine and veterinary medi-cine are, in particular, those in which R2 represents a physiologically acceptable cation, such as, for example, the alkali metal salts, especially the sodium and potassium saltsS
; or ammonium salts, especially tertiary amine salts, such as~ for example, procain salts. The sodium salts are particularly preferred If the salts are not isolated direct from the reaction :
solution, such as, for example, by precipltation with sui-table organlc solvents, such as, for example7 ether9 they can also be 20 ~ obtained by reacting the carboxylic acid of the for~ula I with the desired base, for example sodium hydroxide solution.
In additlon to the compounds of the formula I mentioned in the Examples, the following derivatives, for example, can also~be prepared by the process according~to the invention:
7[(2-aminothiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxyljc ac ~.
7[(2-aminothlazol-4-yl)-glyoxylamido]-3-chloro-3-cephem-4-carboxylic acid, 7~(2-aminothiazol-4-yl)-glyoxylamido]-3-methoxy-3-cephem-4-carboxylic acid, 7~(2-aminothiazol-4-yl)-:
.
. : .
~4~
glyoxylamido]-3-ethoxy-3-cephem-4-carboxyllc acid, 7[(2-amino--thiazol-4-yl)-glyoxylamido]-3-propoxy-3-cephem-4-carboxylic acid, 7[(2-aminothiazol-4-yl)-glyoxylamido~-3-butoxy-3-ce~he~-
: ~ , ~ ' , ~R1 ' I ~ N
': l ' ~ .- Coo~
which are to be employed for the reacti.on according to the invention are known from the literature or can be prepared in accordance with the instructions in the literature, for ex~ple in accordance with the instructions in F.F. Fl~nn..Cephalo-:
. ' ' . , ~ ,, ' ': ' ~' ' ' ' ' '. ~ ' . ' :
sporins and Penicillins, Chemistry and siology, AcademicPress, New York and London, 1972, or - when X in formula II
represenLs oxygen or CH2 - in accordance with the instructions in J. Amer. Chem. Soc. 96, 7582 and 7584 (1974).
The carboxylic acids of the formula III used for the acylation are novel compounds which can be prepared according to the inventiOn in good yields. The starting point for their preparation is the acetoglyoxylic acid ester, which is accessible from the acetoacetic acid ester in ac-cordance with the instructions in the literature. Preferably, the esters employed are the readily accessible low-molecular alkyl esters, especially the ethyl ester.
Several routes have been described in the literature for the formation of the aminothiazole ring, for example the reaction of chloroketo derivatives with thiourea in accordance with the following equation^ CH3 N¦H2 1 3 ~ ~
C C 2 1 ~ ~ f H
/ ~ H N
H2N S ' It has now been found, surprisingly, that an aceto-glyoxylic acid ester can be converted easily and in high yields to a halogeno-acetoglyoxylic acid ester. Halogenating agents which have proved suitable are especially sulfuryl chloride or elementary bromine. ~
The bromination is carried out in a solvent. Solvents which have proved suitable are in particular the halogenated hydrocarbons, such as, for example, methylene chloride, chloro-... , . ~ ... . ~ . , -': .
':
.
~6~
form or ethylene dichloride.
The reaction can be carried out ~ithin a wide tempera-ture range. In order to achieve high yields OI mOllOllalOgenO-acetoglyoxylic acid ester, a temperature range OI -20~ to ~20 is preferred.
If elementary bromine has been used for the halogenation, -the bromoacetoglyoxylic acid ester can be furt~ler reac-ted direct, as the ra~ material, with thiourea.
In order to achieve good yields it is advisabie to -~
employ the thiourea in equimolar amounts. It has Deen found, surprisingly, that (2-amino-thiazol-4-yl)~glyoxylic acid es~ers of the formula V form in high yields when the bromoaceto-glyoxylic acid ester is reacted wi-th thiourea.
The reaction can be carried out in vario~ls ways. A
preferred method comprises initial]y introducing the thiourea in solution and allowing the halogen compound to run into the ~eaction mixture SoIvents which have proved suitable for this rea~tion are mixtures of organic solvents with water. Mixtures of alcohols and wa-ter, especially mixtures of ethanol and ~ater~
are particularly suitable~
The reaction can be carried out within a wide tempera-ture range, for example at -5 to +80 The temperature range of 20 to 60 is particularly suitable.
The reaction products of the formula V can be isola~ed by routes kno~m from the laboratory, for example by evaporatin~
off the organic solvent and subsequently adjusting the pH value to 5-7. The adjustment of the pH value ls effected with ~ . ' ' - . ' ' ~ - 13 ~
~4~
. .
bases and organic or inorganic bases can be used. For example~ the inexpensive alkali metal hydroxides, alkali metal carbona-tes and alkali metal bicarbonates and the corresponding phosphates have proved suitable.
By means of the reaction which follows the reaction ~lith thiourea, the amino group in the compounds of the formula V is provided with a pro-tective group. Possible protective groups are groups known from the literature, such as, for example, tert.-butoxycarboIlyl, carbobenzyloxy, chloroacetyl, trichloroethyl, benzhydryl or formyl. The triphenylmethyl g~oup has proved particularly sultable as a protec-tive group and is introduced by reacting the compounds of the formula V
with triphenylchloromethane. The reaction is appropriately carried out in an organic solvent, such as, for example, halogenated hydrocarbons, in -the presence of bases.
Halogenated hydrocarbons which have proved particularly suitable are chloroform and methylene chloride. Bases which may be mentioned are, in particular, -the tertiary amines, such as, for example, triethylamine or N-methylmorpholineO
The esters of the formula VI, which are thus obtaine~, are saponified to the corresponding acids of the formula III~
Mixtures of dioxane and water have proved particularly suitable for the saponification~ Thus, it is advantageous to saponify the esters hot in dioxane with the addition of the calculated amount of base and then to isolate the resulting salts. Bases~which have proved suitable are, for example, alkali ~.etal hydroxides, especiall~ sodium hydroxide.
The sodium salts formed when sodium hy~roxide is used ir.
A ~ 14 ..... ... .
;~ ..
~: , .
. . ..
.
most cases crystallize out from the reaction mixture on cooling.
They can be conver-ted into the acids of the formula III, which are better suited for some activation reactions, by the addi~
tion of dilute mineral acids. Acids which may be mentione~
for this purpose are, in particular, hydrochloric acid or sulfuric acid.
Tn other cases, the sodium salts can also be employed direct for the activation.
The carboxylic acids of the general formula III can be converted by processes known from the literature into the activated carboxylic acid derivatives capable of forming an amide. A preferred process for activating the carboxyl group comprises converting it into a symmetrical or unsymmet-rical anhydride. The processes for the preparation of mixed or symmetrical anhydrides are known from the literature.
-For example, chloroformic acid esters or pivaloyl chloride can be used for the activation, in whlch case the acid of the formula III has to be converted into a corresponding salt.
It has been found that the reaction proceeds readily ~rhen the acid is suspended in halogenated hydrocarbons, such as, for example, methylene chloride, and converted, using organic bases, such as, for example, triethylamine, into the triethylammonium salt, Alternatively, in some cases ~it is also possible to employ, for example, a'kali metal salts of the acids of the formula III and in this case the addition of catalytic amo~nts of a tertiary base~ such as, for example, N,N-dimethylaniline, has proved advantageous, The inner a~hydrldes can also be formed from the - 15 - ?
.~,.~ ; , - .
, . : ' ~: .
carboxylic acids of the formula III using condensing agents, such as, ~or example, dicyclohexylcarbodiimide, and these inner anhydrides are then reacted with the aminocephem-carboxylic acid derivatives of the formula II.
A further variant comprises employing addition products of the carboxylic acids and condensing agents, such as, for example, dicyclohexylcarbodiimide, for acylatin~ the cephem acids or their esters of the formula IX
The preparation of the compounds of the general formula -I can be carried out under various experimental condi-tions Thus, for example, the aminocephem derivatives of the formula II can be acylated in very diverse solven-ts. Suitab]e sol-~ents are, for example, organic solvents, such as halogenated hydrocarbons, for example methylene chloride or chloroform, b~t also water or mixtures of wa~er and organic solven-ts which are miscible with water.
In order to achieve a good course of reaction, ~t i~
desirable to bring the aminolactam derivatives into solution In the case of the aminocephem esters o~ the genera]
formula II, the reaction is carried out in organic solvents in which rnost of the esters are readily solublec Examples of such solvents which may be mentioned are the halogenated hydro-carbons, such as methylene chloride or chloroform, but also the tertiary amides-, such as dimethylformamide or dimethylacet-amide;
Esters in the sense of the invention which can be used :
are, for example, those compounds of the formula II in ~hich R2 represents low-molecular alkyl~ preferably tertiary butyl or :, .
~ :: . : ~
6~
.. .
subs-titu-ted methyl, in which the methyl group is substltuted in particular by trichloromethyl, acyloxy, preferably acetoxy or pivaloyloxy, or by one or two phenyl radicals, which, in turn, can be substituted, for example, by low-moiecular alkoxy~
preferably methoxy, or the nitro group, or represents the phthalide ester. F~amples conforming to the above defini-tions which may be mentioned are, in particular, the tert -butyl esters, the trichloroethyl and p-methoxybenzyl estersS
the benzhydryl, acetoxymethyl and pivaloyloxymethyl esters or the phthalide es-ters.
When the aminocephemcarboxylic acids of the general formula II (R = hydrogen) are used, the cornpounds must be brought in-to solution wi-th the addition of bases.
Suitable bases which can be used for dissolvin~ 7-ACA
and also a large number of 7-amino~3-cephem-4-carboxylic acids are inorganic~or organic bases~ Thuss bases which have proved suitable for the preparation of solutions in organic solvents are in particular the tertiary amines, such as tri-ethylamine, N,N-dimethylaniline or N-methylmorpholine, and those which have proved suitable for preparing aqueous solutions are in particular the alkali metal bicarbonates, such as sodium bicarbonate or potassium bicarbonate, and also the tertiaIy amines. The bases are in general added in at least the stoichiometric amount, relative to the desired conversion.
2~ However, it is advisable to use an excess of base of, for example, about 20 to 80%~ -Especially in the case of compounds of the formula II
which are sensitive to bases, a constant pH of abou-t 4 to 8 17 ~;
: ':
.
and preferably 6 to 7, depending on the course of the reaction r can be maintained by continuous addition of the base.
The aminolactam derivatives of the formula II can be dissolved within a wide temperature range. In the case of derivatives sensitive to bases, however r it is advisable to choose a temperature range of about 0 to 15.
The activated glyoxylic acid derivatives of the formula III are added to the amino-cephem derivatives of the formula II, which are in solution or optionally in suspension. The reaction takes place in a manner which is in itself knownr at temperatures such as are cUstomary for the preparation of car-boxylic acid amides rom reactive carboxylic acid derivatives of the formula III.
When water or mixtures of water and organic solvents are used as the reaction medium, it is advisable to maintain a temperature range of about 5 to +10. When organic sol-vents are used, the acylation can also be carried out at room temperature.
In order to obtain a better course of reaction, the activated carboxylic acid derivatives of the formula III are taken up in a solvent which does not hinder the reaction and introduced in dilute form. If the acylation is carried out in an aqueous medium, solvents which can be used for the activated carboxylic acid derivatives, are, for example, anhydrous ketones, such as acetone or methyl ethyl ketone, or -with intensive stirring - ethers, such as, for example, diethyl ether or diisopropyl ether.
If the acylation is carried out in a non-aqueous medium, .~ . 1 it is advisable to use the same solven-t for the dilution of the acid derivatives as is used for the acylation.
In order to obtain high yields, the activated acid derivatives of the formula III are employed in at least the stoichiometric amount. An excess of about 5 - 25% can prove appropriate.
The acylation products can be isolated by methods which are in themselves known. Thus, for example J the resulting acid derivatives of the formula IV in which R represents hydrogen can be taken up, if necessary after evaporating off the organic solvent., in water and precipitated by adding mineral acids Sllitable mineral acids are, in particular1 dilute acids, such as dilute hydrochloric acid or sulfuric acid In most cases, the amidocephem acids of -the for~n~la IY
precipitate in the form of amorphous solids or in a crystalline form. They can also be separated off as the free acids b~r extracting at pH 2 to 1. Extraction agents which can be .
used~are diverse water-immiscible organic solvents, for example halogenated hydrocarbons, such as meth~lene chloride. or esters, ~; 20 ~ such as,~for example, ethyl ~cetate or n-butyl acetate, but also ketones, such as methyl isobutyl ketone.
The resulting amidocephem acids of the formula IV are obtained from the extracts, for example by e~raporating off the solvent and grinding the residue, for example with ether.
~ 25~ When the amidocephem compounds of the formula I are ; prepared from the compounds of the formula IV, t~e protective ~ group R must be removed. The reaction conditions to be ;~ employed depen~ on ihe nature of the proteclive group and are , ., .
'- ~ ' ' ' ~ ~ ' known from the li-terature.
If, for example, R is a triphenylmethyl group, this group is detached in an acid medium. Mixtures of formic acid and water, especially a mixture of water and formic ac~d in a ratio of 1 : 1, have proved sui-table. In the case of compounds of the formula IV in which R2 represents, ~or example, p-methoxybenzyl, benzhydryl or dime-thoxybenzyl and R represe-lts a -triphenylmethyl group, it is possible simultaneously to detach the ester group and to remove the trityl group by treat-ment with trifluoroacetic acid/anisole~
The isolation of -the amidocephem compounds o~ the formula I can be effected by l~own methods~ In many cases the resulting compound is dissolved in the reac-tion med:ium used, so -that an extraction is advisable and, in the case of triphenylmethyl being used as the protective group, the result-ing triphenylcarbinol can be filtered off or can be removed with extraction agents, such as, for example, ether, The amidocephem compo~mds of the formula I in which R2 represents hydrogen can also be converted to the physiologica1ly 20 acceptable esters of -the formula I by subsequent esterification by processes known from the literature. Thus, for example, the acetoxymethyl or pivaloyloxymethyl esters are obtained by reacting the alkali ~etal salts, preferably the sodium salts, or-the ammonium salts, preferably the triethylammonium salts, ~ith the corresponding halo~enomethy~.acyl compounds, such as~ for example, chloromethyl acetate, chloromethyl propionate or chloromethyl pivalate.
.
If the esters, and especially tne physiologically .
' :
~
... ,. . . .. ' :
; ' ~ !
'' , . :
acceptable esters, have already been obtained from the acyla-tion 3 subsequent esterification of the carboxyl group is superfluous.
The esters which are obtained direct from the reactiGn according to the invention, such as, for example, p-methoxy-benzyl, p-nitroben~yl, tert.-butyl or benzhydryl esters, can also be converted to the free carboxylic acids of the ~ormula I
in a manner ~no~n from the litera-ture.
Compounds of the formula I which are in a form suitable for application in human medicine and veterinary medi-cine are, in particular, those in which R2 represents a physiologically acceptable cation, such as, for example, the alkali metal salts, especially the sodium and potassium saltsS
; or ammonium salts, especially tertiary amine salts, such as~ for example, procain salts. The sodium salts are particularly preferred If the salts are not isolated direct from the reaction :
solution, such as, for example, by precipltation with sui-table organlc solvents, such as, for example7 ether9 they can also be 20 ~ obtained by reacting the carboxylic acid of the for~ula I with the desired base, for example sodium hydroxide solution.
In additlon to the compounds of the formula I mentioned in the Examples, the following derivatives, for example, can also~be prepared by the process according~to the invention:
7[(2-aminothiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxyljc ac ~.
7[(2-aminothlazol-4-yl)-glyoxylamido]-3-chloro-3-cephem-4-carboxylic acid, 7~(2-aminothiazol-4-yl)-glyoxylamido]-3-methoxy-3-cephem-4-carboxylic acid, 7~(2-aminothiazol-4-yl)-:
.
. : .
~4~
glyoxylamido]-3-ethoxy-3-cephem-4-carboxyllc acid, 7[(2-amino--thiazol-4-yl)-glyoxylamido]-3-propoxy-3-cephem-4-carboxylic acid, 7[(2-aminothiazol-4-yl)-glyoxylamido~-3-butoxy-3-ce~he~-
4-carboxylic acid, 7[(2-aminothiazol-4-yl)-glyoxylamido]-3-methyl-thiomethyl-3-cephem-~-carboxylic acid, 7[(2-amino-thiazol-4-yl)-glyoxylamido3-3-propyl-thiomethyl-3-cephem-4-carboxylic acid, 7[(2-aminothiazol-4-yl)-glyoxylamido]-3-acet--thiomethyl-3-cephem-4-carboxylic acid, 7[(2-aminothiazol-4-yl)-glyoxylamido]-3[(1-propyl-tetrazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid, 7[(2-aminothiazol-4-yl)-glyoxylami.do]-3[(1-propenyl-tetrazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid, 7[(2~aminothiazol-4-yl)-glyoxylamido]-3[(oxazol-2-yl-thio-methyl)-3-cephem-4-carboxylic acid, 7[(2-aminothia~ol-4-yl)-glyoxylamido]-3C(5-amino-1,3,4-thiadiazol-2-yl~-thiomethyl~^-3-cephem-4-carbo}:~lic acid, 7[(2-aminothiazol-4-yl)-glyox~-amidoJ-~[(3-methyl-1,2,4-thiadiazol-5-yl)~thiomethyl]-~-cephem-4-carboxylic acid, 7[(2-aminothiazol-4-yl)-glyoxylamido]-3C(4-methyl-thiazol-2-yl)-thiomethyl]-3-cephem-4~carbGxylic acid, 7[(2-aminothiazol~4-yl)-glyoxylamido]-3[(1,3,4-thiadiazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid, 7~(2-aminothiazoL-~: 4-yl)-glyoxylamldo]-3[(1,2,4-triazol-5-yl)-thiome-thyl]-3-cephem-4-carboxylic acid, 7~(2-aminothiazol-4-yl)-glyoxyl-amido]-3[(1,2,3-thiadiazol-5-yl)--thiomethyl]-3-cephem-4- -;
carboxylic acld, 7C(2-aminothiazol-4-yl)-glyoxyiamido]-3 [(1,2,5-thiadiazo1-3-yl)-thiomethyl 3- 3-cephem-4-carboxylic acid, 7[(Z-aminothiazol-4-yl)-glyoxylamido]-3C(1,2,3-oxdiazol-5-yl)-~ thiomethyl~-3-c~ephem-4-carboxylic acid, 7[(2 aminothiazol-~-yl)-;~ ~glyoxy1amido]-~[~(5-methyl-1,3,4-oxdiazo1-2-yl)-thlomethy1]-3-' :
- ~2 - ~ -: ~ -~ , .
-.
:: - ~, . .
~6~3~
cephem-4-carb~xylic acid, 7[(2-aminothiazol-4-yl) glyoxyl-amido]-3[(5-butyi-1,~,4-oxdiazol--2-yl)-thiomethyl]-3-cephem-4-carboxylic acid, pivaloyloxymethyl 7~(2-amino-thiazol-4-yl)-glyoxylamido]-cephalosporanate, 7[(2-aminothia~ol-4-yl)-glyoxylamido]-cephalosporanic acid phthalide ester, ace-toxy-methyl 7[(2-aminothiazol-4-yl)-grlyoxylamido]-cephalosporanate, 7r(2-aminothiazol-4-yl)-glyoxylamido]-3[(pyrid-2-yl N-oxide)-thiomethyl]-3-cephem-4-carboxylic acid and 7[(2-aminothiazol-4-yl)-glyoxylamido~-3[(3-hydroxy-pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid.
The amidocephem derivatives of the formula I-;are valuable antibiotics which are surprisingly well suited for combating Gram-posi-tive and in par-ticular Gram-negative in.ec-tions and, moreover, also have an ~mexpec-tedly ~oocl action against penicillinase~forming staphylococcae~
The compounds according to the invention ca~l be employed~
as such or together with the auxiliaries and additives cus-tomarily employed therapeutically, such as, for example, tragacanth, laotose, talc, solvents and the like, in the form ~ of galenic formulations9 such as, for example, -tabletsl dr~Oees, :: :
capsules, suspensions, solutions and the li~e, perorally or preferably, however, parenterally, and as a rule an adminis-tration unlt contains the active compound ln an amount of abou~ -50 to 1,000 mgs preferably about 100 to 500 mg.
For parenteral use, the solvents known for therapeutlc ; ~ use, espec~ally 2 solution in wa-ter, can be used.
It is~also possible to combine the~compounds according to~the lnvent~on~/ith other active oompounds. Thus, lor 23 - ~ -.. . .
~ ~ .
.
. ~
example, other antibiotics can be administered, such as, for example, those from the series comprising the penicillins and cephalosporins, or compounds which influence the symptoms OI
bacterial infections, such as, for example, antipyre-tic agents, antiphlogistic agents or analgesics~ , The lllustrative examples which follow serve to further illustrate the invention but do not res-trict it thereto, Pre~aration of a startin~ com~ound a) Ethyl bromoacetoglyoxylate 120 g of ethyl acetoglyoxylate are dissolved in 700 ~1 .of methylene chloride and reacted in the course of 1 hour at
carboxylic acld, 7C(2-aminothiazol-4-yl)-glyoxyiamido]-3 [(1,2,5-thiadiazo1-3-yl)-thiomethyl 3- 3-cephem-4-carboxylic acid, 7[(Z-aminothiazol-4-yl)-glyoxylamido]-3C(1,2,3-oxdiazol-5-yl)-~ thiomethyl~-3-c~ephem-4-carboxylic acid, 7[(2 aminothiazol-~-yl)-;~ ~glyoxy1amido]-~[~(5-methyl-1,3,4-oxdiazo1-2-yl)-thlomethy1]-3-' :
- ~2 - ~ -: ~ -~ , .
-.
:: - ~, . .
~6~3~
cephem-4-carb~xylic acid, 7[(2-aminothiazol-4-yl) glyoxyl-amido]-3[(5-butyi-1,~,4-oxdiazol--2-yl)-thiomethyl]-3-cephem-4-carboxylic acid, pivaloyloxymethyl 7~(2-amino-thiazol-4-yl)-glyoxylamido]-cephalosporanate, 7[(2-aminothia~ol-4-yl)-glyoxylamido]-cephalosporanic acid phthalide ester, ace-toxy-methyl 7[(2-aminothiazol-4-yl)-grlyoxylamido]-cephalosporanate, 7r(2-aminothiazol-4-yl)-glyoxylamido]-3[(pyrid-2-yl N-oxide)-thiomethyl]-3-cephem-4-carboxylic acid and 7[(2-aminothiazol-4-yl)-glyoxylamido~-3[(3-hydroxy-pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid.
The amidocephem derivatives of the formula I-;are valuable antibiotics which are surprisingly well suited for combating Gram-posi-tive and in par-ticular Gram-negative in.ec-tions and, moreover, also have an ~mexpec-tedly ~oocl action against penicillinase~forming staphylococcae~
The compounds according to the invention ca~l be employed~
as such or together with the auxiliaries and additives cus-tomarily employed therapeutically, such as, for example, tragacanth, laotose, talc, solvents and the like, in the form ~ of galenic formulations9 such as, for example, -tabletsl dr~Oees, :: :
capsules, suspensions, solutions and the li~e, perorally or preferably, however, parenterally, and as a rule an adminis-tration unlt contains the active compound ln an amount of abou~ -50 to 1,000 mgs preferably about 100 to 500 mg.
For parenteral use, the solvents known for therapeutlc ; ~ use, espec~ally 2 solution in wa-ter, can be used.
It is~also possible to combine the~compounds according to~the lnvent~on~/ith other active oompounds. Thus, lor 23 - ~ -.. . .
~ ~ .
.
. ~
example, other antibiotics can be administered, such as, for example, those from the series comprising the penicillins and cephalosporins, or compounds which influence the symptoms OI
bacterial infections, such as, for example, antipyre-tic agents, antiphlogistic agents or analgesics~ , The lllustrative examples which follow serve to further illustrate the invention but do not res-trict it thereto, Pre~aration of a startin~ com~ound a) Ethyl bromoacetoglyoxylate 120 g of ethyl acetoglyoxylate are dissolved in 700 ~1 .of methylene chloride and reacted in the course of 1 hour at
5 with a solution of 146 g of bromine in 200 ml of methylene ~ chloride.
: After the solution has become decolori~ed, the sol~ent : 15 was stripped off and the residual oil was reac-ted wi~hout :
. further purification~ .
b) Ethyl 2-amlno-thiazol-4-ylglyoxylate 195 g of ethyl bromoacetoglyoxylate are added drop~ise t 5 to a solution of 66 g of thiourea in 450 ml of ~rater and :~ 20 450 ml o~ ethanol; after the addltlon is comple~e~ the mixture S stirred for 30 mlnutes at room temperature and for 30 minutes at.:50 and the resulting reaction mixture ls then fil-~: : tered after:adding actlve charcoal.~ The~pH o~ the filtrate ' is brought to 7 by adding sodium bica~bonate solution, ~here-upon ethyl 2-amino-thiazol-4-yl-glyoxylate crystallizes out as I
crystals having a~melting point o$ 147~
c) Ethyl 2-triphenylmethylamino-thiazol-4-yl-glyox~Tlate , ~27~g:of trlethylamlne are added to a solution of 90 g 24 ~ :~
69~7 of ethyl 2-aminothia701-4-yl-glyoxylate in 225 ml o~ dimethyl-formamide and 375 ml of CH2C12~ at -15, and 75 g of triphenyl_ chloromethane are then added at -~0. Af-ter 15 minutes at ~0, the mixture is stirred for 3 hours without a cooling bath, 500 ml of CH2C12 are added -to the resulting reaction mixture and the mix-ture is washed with ~00 ml of 1 N HCl and -then t~ice with 200 ml of water, the organic phase is dried over Na2S04 and the solvent is evaporated off. An oil remalns and this was used for the further reac-tions without prior purification.
d) 2-Triphenylmethylamino-thiazol-4-yl-glyoxylic acid A solution of 14.8 g of NaOH in 370 ml of methanol is added to a solution of 156 g of crude ethyl 2-triphenylmethyl-amino-thiazol-4~yl-glyoxylate in 150 ml of methanol and the mixture is boiled under reflux for 5 minutes, ~hereupon the 1~ sodium sal-t of~2-triphenylmethylamino-thlazol-4-yl-glyoxy1ic acid crystallizes out~
The sodium salt obtained is suspended in 380 ml of water ~nd 76 r~ of 2 N HCl are~added, whilst stirrlng vigorously.
After 15 minutes the precipitate is filtered off, washed with water~ and dried.
2-Triphenylmethylamino-thiazol-4-yl-glyoxylic acid is obtained;ln the form of yellow crystals ha~ing a melting point of 16~ - 165 (decomposition). ~ -The Rf values indicated in the Examples which followr were~determined by thin layer chromatography on silica gel ready-to-use plates 60 F 254 from Messrs. Merck, Darmstadt.
. . .
' : ' , :
~ .
~6~
Example 1:
7[(2-Triphenylmethylamino-thiazol-4-yl)-glyoxylamido]-cephalo-sporanic acid a~ 2.4 g of triethylamine are added to a suspension of 9.1 g of (2-triphenylmethylamino-thiazol~4-yl)~glyoxylic acid in 50 ml of methylene chloride, the resulting solution is cooled to -50 under nitrogen and with the exclusion of moisture and a solution of 2.66 g of pivaloyl chloride in 200 ml of methylene chloride is added.
After the addition is complete, the mixture is stirred for a further 2 hours at 0, the solution of the mixed anhydride is then again cooled to -50 and a solution of 5.44 g of 7-aminocephalosporanic acid in a mixture of 50 ml of methylene chloride and 4.04 g of triethylamine is added.
After the addition is complete, the mixture is stirred for a further 3 hours without a cooling bath, the solvent is then stripped off in vacuo, the residue is taken up in S00 ml of water and the solution is acidified to pH 1 with 2 N HCl and immediately taken up several times in methylene chloride. After drying, the organic phase is removed and the residue is ground with ether. 7[(2 Triphenyl-methylamino-thiazol-4-yl)-glyoxylamido]-cephalosporanic acid is isolated as a solid product.
Rf (butanol, H2O, ethyl alcohol, acetic acid, 5 : 2 : 1.5 :
1.5) 0.53 IR in KBr : lactam CO : 1,780 cm 1 b) 7[(2-Aminothiazol-4-yl)-glyoxylamido]-cephalosporanic acid . . .
If the 7-((2-trlphenylmethylamino-thiazol-4-yl)-
: After the solution has become decolori~ed, the sol~ent : 15 was stripped off and the residual oil was reac-ted wi~hout :
. further purification~ .
b) Ethyl 2-amlno-thiazol-4-ylglyoxylate 195 g of ethyl bromoacetoglyoxylate are added drop~ise t 5 to a solution of 66 g of thiourea in 450 ml of ~rater and :~ 20 450 ml o~ ethanol; after the addltlon is comple~e~ the mixture S stirred for 30 mlnutes at room temperature and for 30 minutes at.:50 and the resulting reaction mixture ls then fil-~: : tered after:adding actlve charcoal.~ The~pH o~ the filtrate ' is brought to 7 by adding sodium bica~bonate solution, ~here-upon ethyl 2-amino-thiazol-4-yl-glyoxylate crystallizes out as I
crystals having a~melting point o$ 147~
c) Ethyl 2-triphenylmethylamino-thiazol-4-yl-glyox~Tlate , ~27~g:of trlethylamlne are added to a solution of 90 g 24 ~ :~
69~7 of ethyl 2-aminothia701-4-yl-glyoxylate in 225 ml o~ dimethyl-formamide and 375 ml of CH2C12~ at -15, and 75 g of triphenyl_ chloromethane are then added at -~0. Af-ter 15 minutes at ~0, the mixture is stirred for 3 hours without a cooling bath, 500 ml of CH2C12 are added -to the resulting reaction mixture and the mix-ture is washed with ~00 ml of 1 N HCl and -then t~ice with 200 ml of water, the organic phase is dried over Na2S04 and the solvent is evaporated off. An oil remalns and this was used for the further reac-tions without prior purification.
d) 2-Triphenylmethylamino-thiazol-4-yl-glyoxylic acid A solution of 14.8 g of NaOH in 370 ml of methanol is added to a solution of 156 g of crude ethyl 2-triphenylmethyl-amino-thiazol-4~yl-glyoxylate in 150 ml of methanol and the mixture is boiled under reflux for 5 minutes, ~hereupon the 1~ sodium sal-t of~2-triphenylmethylamino-thlazol-4-yl-glyoxy1ic acid crystallizes out~
The sodium salt obtained is suspended in 380 ml of water ~nd 76 r~ of 2 N HCl are~added, whilst stirrlng vigorously.
After 15 minutes the precipitate is filtered off, washed with water~ and dried.
2-Triphenylmethylamino-thiazol-4-yl-glyoxylic acid is obtained;ln the form of yellow crystals ha~ing a melting point of 16~ - 165 (decomposition). ~ -The Rf values indicated in the Examples which followr were~determined by thin layer chromatography on silica gel ready-to-use plates 60 F 254 from Messrs. Merck, Darmstadt.
. . .
' : ' , :
~ .
~6~
Example 1:
7[(2-Triphenylmethylamino-thiazol-4-yl)-glyoxylamido]-cephalo-sporanic acid a~ 2.4 g of triethylamine are added to a suspension of 9.1 g of (2-triphenylmethylamino-thiazol~4-yl)~glyoxylic acid in 50 ml of methylene chloride, the resulting solution is cooled to -50 under nitrogen and with the exclusion of moisture and a solution of 2.66 g of pivaloyl chloride in 200 ml of methylene chloride is added.
After the addition is complete, the mixture is stirred for a further 2 hours at 0, the solution of the mixed anhydride is then again cooled to -50 and a solution of 5.44 g of 7-aminocephalosporanic acid in a mixture of 50 ml of methylene chloride and 4.04 g of triethylamine is added.
After the addition is complete, the mixture is stirred for a further 3 hours without a cooling bath, the solvent is then stripped off in vacuo, the residue is taken up in S00 ml of water and the solution is acidified to pH 1 with 2 N HCl and immediately taken up several times in methylene chloride. After drying, the organic phase is removed and the residue is ground with ether. 7[(2 Triphenyl-methylamino-thiazol-4-yl)-glyoxylamido]-cephalosporanic acid is isolated as a solid product.
Rf (butanol, H2O, ethyl alcohol, acetic acid, 5 : 2 : 1.5 :
1.5) 0.53 IR in KBr : lactam CO : 1,780 cm 1 b) 7[(2-Aminothiazol-4-yl)-glyoxylamido]-cephalosporanic acid . . .
If the 7-((2-trlphenylmethylamino-thiazol-4-yl)-
6 -. ~
glyoxylamido)-cephalosporanic acid obtained according to a) is reacted ~nder the conditions indicated in Example 3 b), this gives 7[(2-aminothiazol-L~-yl)-glyoxylamido]-cephalosporanic acid in the form of yellow crystals.
Rf (conditions as in Example 1) : 0.38 IR in XBr: lactam C0 : 1,776 cm 1 E~ e 2-.
a) 7~2-Tri~llenylmethvlamino-thiazol~4-yl~-glvoXvlamido carboxvlic acid In the manner indicated in E~ample 1 a), 7((2-tri-phenylmethyl-amino-thiazol-4-yl)-glyoxylamido)-3[(5-methyl-1~,4-thiadiazol-2-yl)-thiomethyl]-~-cephem-4-carboxylic acid is obtalned as a solid using 7-amino-3-((5-methyl-1,3J4-thia-diazol-2-yl)-thiomethyl)-3 cephem-4-carboxylic acid.
.
Rf (conditions as in Example 1~ : 0.~8 IR in KBr : lactam C0 : 1,780 cm 1 b) 7r (2-Amino-thiazol-4-yl~-~lyoxylamidol-3r(5-m~y~ 4-vlic acid 20~ Analogously t~o Example 3 b)~ 7~(2-amino-thiazoi-4-yl)-glyoxylamido]-3[(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl3-3-cephem-4-~carboxyli~o aci~d ls;obtained from -the 7[(2-triphenyl-methylaminothiazol-4-yl)-glyoxylamido]~3~(5-methyl-1,3,4-thia-diazol-2-yl)-thiomethyl]-3-cephem-4-oarboxylic acid prepared according to a).
Rf (conditions as in Example 1~ : 0.39 IR : in ~Br : lactam C0 : 1~770 cm 1 : : : ~ :
~ ~ - 27 - -. ~ ~
. ::: :
1~4G~147 Example 3:
a) 7[(2-Triphenylmethylamino-thiazol-4-yl ? -glyoxylamido]-3 [(l-methyl-tetrazol-2-yl~-thiomethyl]-3-cephem-4-carboxylic acid In the manner indicated in Example 1 a), 7[(2-tri-phenylmethylamino-thiazol-4-yl)-glyoxylamido~-3~ methyl-tetrazol-2-yl)-thiomethyl~-3-cephem-4-carboxylic acid is obtained as a solid using 7-amino-3((1-methyl~tetrazol-2-yl)-thiomethyl)-3-cephem-4-carboxylic acidO
Rf (conditions as in Example 1) : 0.56 IR in KBr : lactam CO : 1,772 cm b) 7[(2-Aminothiazol-4-yl)-glyoxylamido~-3~(1-methyltetrazol-.
2-yl)-thiomethyl]-3-cephem-4-carboxylic acid 14 g of the 7[(2-triphenylmethylamino-thiazol-4-yl)-glyoxylamido)-3-((l methyl-tetrazol-2-yl)-thiomethyl)-3-cephem-4-carboxylic acid prepared according to a~ are introduced into a mixture of 30 ml af formic acid and 30 ml of water, the reaction mixture is warmed to 50 - 60 for 30 minutes and cooled, 100 ml of water are added and the triphenylcarbinol which has been spl1t off is filtered off.
The filtrate was e~aporated to dryness and the residue was ground with ether. This gives 7~2-aminothiazol-4-yl)-glyoxylamido]-3[(1-methyl-tetrazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid in the form of a pale yellow solid.
IR in KBr : lactam CO : 1,775 cm 1 Example 4:
a) p-Methoxybenzyl 7[(2-triphenylmethylamino-thiazol-4-yl)-glyoxylamido]-3-methyl-3-cephem-4-carboxylate ' : .
-. .
100 ml of methylene chloride were added -to a suspension of 2.8 g of the sodium salt of 2-triphenylmethylamino-thiazol-4-yl-glyoxylic acid in 20 ml of water 7 the aqueous solution r~s acidified to pH 1 with 2 N HCl and the acid ~hich precipitated out was extracted.
After repeated extraction, the combined extracts were dried and the solvent was removed in vacuo, 40 ml of methylene chloride and 0.63 g of trie-thylamine were added to the oily residue, -the resulting solution was cooled to -25 and reacted with a solution of 0.75 g of pivaloyl chloride in ~0 ml of methylene chloride to give,the mixed Qnhydride and the reac-.
~ -tion mix-ture was stirred for a further 2 hours a-t +5, .
The solution was then cooled to -30 and reacted with a solu-tion which~had been prepared from 3.14 g of the'p-toluene-' ~ 15 sulfonate of p-methoxybenzyl 7-ami~o-3-methyl--3-cephem-L~-carboxylate by extraction with 5Q ml of methyle~e c~loride at pH 8. ~ ~ ~
, : :
After 1 hour~the cooling bath was removed ? the mixture was stirred for a~urther hour at room temperature and the 2~ organic solvent was then removed~in vacuo.
~ The residual~oil was ground with~ether. p-Metho~y-,~ ~ benzyl 7((2-triphenylmethylamlno--thiazol-4-yl)-g]yoxylamido)-3-~ethyl-3-cephem-4-carboxylate is isolated as a beige-colored solid.
Rf (in CHCl3/ethyl acetate, 3~ 0.635 IR in KBr : lactam C0 : 1,775 cm 1 b) ~ nothiazol-4-y~ lvoxylamidol-3-met~ ce~hem-4-- ~. . .
- ~ . .
-~ 6~
.
2,5 g of -the p-methoxyben~yl 7[(2-triphenylmethylamino_ thiazol-4-yl)-gIyoxylamido]-3-methyl-3-cephem-4-carboxylate prepared according to a) are dissolved in 7.5 ml of anisole, 2~5 ml of CF~COOH are added to the solution and the reaction mixture is stirred for 5 hours at 25 - 30, The reaction mi~ture is -then concen-trated to dr~ness., the residue is ground ~i-th ether and the solid product is iso-lated.
The solid is stirred with 10 ml o methylene chloride for 30 minutes at room temperature and free 7[(2-aminothiazol-4-yl)-glyoxylamido~3-methyl-3-cephem-4-carboxylic acid is ~ :
: obtained, IR in KBr : lactam CO : 1,763 cm 1 ~ .
~o _11 5 g of Na acetate are added to a suspension of 10 g of the 7[~2-amino-thiazol-4-yl)~glyoxylamido~-cephalosporanic ac~d obtained according to Example 1 in 50 ml of CH30H an~ the acid :20 briefly goes into solution, After a short time the pale yellow sodium salt of 7~(2-aminothiazol-4-yl)-g1yoxylamldo~-: cephalosporanic acid crystalIizes out, ~Rf (oonditions as in Example 1) : 0,38 IR in I~B~ : lactam CO : 1,745 cm 1 ~ Example 6:
The sodium salt_ol 7 U 2-aminothiazol-4-~rl)-~lyoxylamldol-3r(l-. ~ methvl-tetrazol-2~yl ~th-omethyl~-3-ce~hem-~-carboxylic ac~d In the m~nner indica-ted in Example 5, 1he sodium sa1t : 3Q - -, .
.
: ~ . . .:
-. . , :
o 7[(2-aminothiazol-4-yl)-glyoxylamido]-3[(1-methyl-tetrazol-2-yl)-thiomethyl]-~-cephem-4-carboxylic acid is obtained in tt1e ~orm of yello~ crys-tals from the cephem acid prepared ln Example 3, Rf (conditions as in Example 1) : 0.40 IR in KBr : lactam C0 : 1~755 cm 1 Example 7-~ .
Benzh~T~ l ~ othiazol-4-y~ oxyl-amidol-?-methoxY-ce~halos~oranate 2~2 g of -triethylamine are added to a suspension of 4,1 g of (2-triphenylmethylamino~thiazol-4-yl)-glyoxy]ic acid in 30 ml o~ methylene chloride, ~hereupon the acid goes into solution. The resulting solution is cooled to --30 with ~he exclusion of moisture and a solution o~ 2,66 ~ of pivaloyl chloride in 20 ml of methylene chloride is added.
After the addition is complete, the reaction mixtu~e ~s stirred for a further 60 minutes and -then again cooled to -50 ~nd a solution of 4,0 g of benzhydryl 7-amino-7-metho~y-cephalosporanate in 30 ml of methylene chloride is added, After the addition is complete, the caoling ba-th is removed, the mixture is stirred for 4 hours at room telnpercature and then for 1 hour under reflux, the organic s~lvent is then removed and ether is added to the residue. Benzhydryl r~[ (2 t~1phenylmethylamino-thiazol-4-yl)-glyoxylami~o]-'7-methoxy-cephalosporanate separates out as a yellow-bro~ solid.
I~ in KBr : lactam C0 : 1,780 cm 1 Rf (conditions as in Example 4) : 0.68 .
~ ~ .
.' .
~1~L4~ 7 The elimination of the protecti~e group and simultaneous saponification are effected as indicated in Example 4.
This application is a division of Canadian Appliaation Serial Number 298,713, filed March 10, 1978.
, .
- :
glyoxylamido)-cephalosporanic acid obtained according to a) is reacted ~nder the conditions indicated in Example 3 b), this gives 7[(2-aminothiazol-L~-yl)-glyoxylamido]-cephalosporanic acid in the form of yellow crystals.
Rf (conditions as in Example 1) : 0.38 IR in XBr: lactam C0 : 1,776 cm 1 E~ e 2-.
a) 7~2-Tri~llenylmethvlamino-thiazol~4-yl~-glvoXvlamido carboxvlic acid In the manner indicated in E~ample 1 a), 7((2-tri-phenylmethyl-amino-thiazol-4-yl)-glyoxylamido)-3[(5-methyl-1~,4-thiadiazol-2-yl)-thiomethyl]-~-cephem-4-carboxylic acid is obtalned as a solid using 7-amino-3-((5-methyl-1,3J4-thia-diazol-2-yl)-thiomethyl)-3 cephem-4-carboxylic acid.
.
Rf (conditions as in Example 1~ : 0.~8 IR in KBr : lactam C0 : 1,780 cm 1 b) 7r (2-Amino-thiazol-4-yl~-~lyoxylamidol-3r(5-m~y~ 4-vlic acid 20~ Analogously t~o Example 3 b)~ 7~(2-amino-thiazoi-4-yl)-glyoxylamido]-3[(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl3-3-cephem-4-~carboxyli~o aci~d ls;obtained from -the 7[(2-triphenyl-methylaminothiazol-4-yl)-glyoxylamido]~3~(5-methyl-1,3,4-thia-diazol-2-yl)-thiomethyl]-3-cephem-4-oarboxylic acid prepared according to a).
Rf (conditions as in Example 1~ : 0.39 IR : in ~Br : lactam C0 : 1~770 cm 1 : : : ~ :
~ ~ - 27 - -. ~ ~
. ::: :
1~4G~147 Example 3:
a) 7[(2-Triphenylmethylamino-thiazol-4-yl ? -glyoxylamido]-3 [(l-methyl-tetrazol-2-yl~-thiomethyl]-3-cephem-4-carboxylic acid In the manner indicated in Example 1 a), 7[(2-tri-phenylmethylamino-thiazol-4-yl)-glyoxylamido~-3~ methyl-tetrazol-2-yl)-thiomethyl~-3-cephem-4-carboxylic acid is obtained as a solid using 7-amino-3((1-methyl~tetrazol-2-yl)-thiomethyl)-3-cephem-4-carboxylic acidO
Rf (conditions as in Example 1) : 0.56 IR in KBr : lactam CO : 1,772 cm b) 7[(2-Aminothiazol-4-yl)-glyoxylamido~-3~(1-methyltetrazol-.
2-yl)-thiomethyl]-3-cephem-4-carboxylic acid 14 g of the 7[(2-triphenylmethylamino-thiazol-4-yl)-glyoxylamido)-3-((l methyl-tetrazol-2-yl)-thiomethyl)-3-cephem-4-carboxylic acid prepared according to a~ are introduced into a mixture of 30 ml af formic acid and 30 ml of water, the reaction mixture is warmed to 50 - 60 for 30 minutes and cooled, 100 ml of water are added and the triphenylcarbinol which has been spl1t off is filtered off.
The filtrate was e~aporated to dryness and the residue was ground with ether. This gives 7~2-aminothiazol-4-yl)-glyoxylamido]-3[(1-methyl-tetrazol-2-yl)-thiomethyl]-3-cephem-4-carboxylic acid in the form of a pale yellow solid.
IR in KBr : lactam CO : 1,775 cm 1 Example 4:
a) p-Methoxybenzyl 7[(2-triphenylmethylamino-thiazol-4-yl)-glyoxylamido]-3-methyl-3-cephem-4-carboxylate ' : .
-. .
100 ml of methylene chloride were added -to a suspension of 2.8 g of the sodium salt of 2-triphenylmethylamino-thiazol-4-yl-glyoxylic acid in 20 ml of water 7 the aqueous solution r~s acidified to pH 1 with 2 N HCl and the acid ~hich precipitated out was extracted.
After repeated extraction, the combined extracts were dried and the solvent was removed in vacuo, 40 ml of methylene chloride and 0.63 g of trie-thylamine were added to the oily residue, -the resulting solution was cooled to -25 and reacted with a solution of 0.75 g of pivaloyl chloride in ~0 ml of methylene chloride to give,the mixed Qnhydride and the reac-.
~ -tion mix-ture was stirred for a further 2 hours a-t +5, .
The solution was then cooled to -30 and reacted with a solu-tion which~had been prepared from 3.14 g of the'p-toluene-' ~ 15 sulfonate of p-methoxybenzyl 7-ami~o-3-methyl--3-cephem-L~-carboxylate by extraction with 5Q ml of methyle~e c~loride at pH 8. ~ ~ ~
, : :
After 1 hour~the cooling bath was removed ? the mixture was stirred for a~urther hour at room temperature and the 2~ organic solvent was then removed~in vacuo.
~ The residual~oil was ground with~ether. p-Metho~y-,~ ~ benzyl 7((2-triphenylmethylamlno--thiazol-4-yl)-g]yoxylamido)-3-~ethyl-3-cephem-4-carboxylate is isolated as a beige-colored solid.
Rf (in CHCl3/ethyl acetate, 3~ 0.635 IR in KBr : lactam C0 : 1,775 cm 1 b) ~ nothiazol-4-y~ lvoxylamidol-3-met~ ce~hem-4-- ~. . .
- ~ . .
-~ 6~
.
2,5 g of -the p-methoxyben~yl 7[(2-triphenylmethylamino_ thiazol-4-yl)-gIyoxylamido]-3-methyl-3-cephem-4-carboxylate prepared according to a) are dissolved in 7.5 ml of anisole, 2~5 ml of CF~COOH are added to the solution and the reaction mixture is stirred for 5 hours at 25 - 30, The reaction mi~ture is -then concen-trated to dr~ness., the residue is ground ~i-th ether and the solid product is iso-lated.
The solid is stirred with 10 ml o methylene chloride for 30 minutes at room temperature and free 7[(2-aminothiazol-4-yl)-glyoxylamido~3-methyl-3-cephem-4-carboxylic acid is ~ :
: obtained, IR in KBr : lactam CO : 1,763 cm 1 ~ .
~o _11 5 g of Na acetate are added to a suspension of 10 g of the 7[~2-amino-thiazol-4-yl)~glyoxylamido~-cephalosporanic ac~d obtained according to Example 1 in 50 ml of CH30H an~ the acid :20 briefly goes into solution, After a short time the pale yellow sodium salt of 7~(2-aminothiazol-4-yl)-g1yoxylamldo~-: cephalosporanic acid crystalIizes out, ~Rf (oonditions as in Example 1) : 0,38 IR in I~B~ : lactam CO : 1,745 cm 1 ~ Example 6:
The sodium salt_ol 7 U 2-aminothiazol-4-~rl)-~lyoxylamldol-3r(l-. ~ methvl-tetrazol-2~yl ~th-omethyl~-3-ce~hem-~-carboxylic ac~d In the m~nner indica-ted in Example 5, 1he sodium sa1t : 3Q - -, .
.
: ~ . . .:
-. . , :
o 7[(2-aminothiazol-4-yl)-glyoxylamido]-3[(1-methyl-tetrazol-2-yl)-thiomethyl]-~-cephem-4-carboxylic acid is obtained in tt1e ~orm of yello~ crys-tals from the cephem acid prepared ln Example 3, Rf (conditions as in Example 1) : 0.40 IR in KBr : lactam C0 : 1~755 cm 1 Example 7-~ .
Benzh~T~ l ~ othiazol-4-y~ oxyl-amidol-?-methoxY-ce~halos~oranate 2~2 g of -triethylamine are added to a suspension of 4,1 g of (2-triphenylmethylamino~thiazol-4-yl)-glyoxy]ic acid in 30 ml o~ methylene chloride, ~hereupon the acid goes into solution. The resulting solution is cooled to --30 with ~he exclusion of moisture and a solution o~ 2,66 ~ of pivaloyl chloride in 20 ml of methylene chloride is added.
After the addition is complete, the reaction mixtu~e ~s stirred for a further 60 minutes and -then again cooled to -50 ~nd a solution of 4,0 g of benzhydryl 7-amino-7-metho~y-cephalosporanate in 30 ml of methylene chloride is added, After the addition is complete, the caoling ba-th is removed, the mixture is stirred for 4 hours at room telnpercature and then for 1 hour under reflux, the organic s~lvent is then removed and ether is added to the residue. Benzhydryl r~[ (2 t~1phenylmethylamino-thiazol-4-yl)-glyoxylami~o]-'7-methoxy-cephalosporanate separates out as a yellow-bro~ solid.
I~ in KBr : lactam C0 : 1,780 cm 1 Rf (conditions as in Example 4) : 0.68 .
~ ~ .
.' .
~1~L4~ 7 The elimination of the protecti~e group and simultaneous saponification are effected as indicated in Example 4.
This application is a division of Canadian Appliaation Serial Number 298,713, filed March 10, 1978.
, .
- :
Claims (2)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a 2-aminothiozol-4-yl-glyoxylic acid of the formula III
III
wherein R represents a protective group in which an acetylglyoxylic acid ester wherein Z represents the radical of an alcohol, is halogenated, the resulting compound is reacted with thiourea to give a 2-amino-thiazol-4-yl-glyoxylic acid ester an amino protective group R is introduced into the compound and the product is saponified to a carboxylic acid of the general formula III.
III
wherein R represents a protective group in which an acetylglyoxylic acid ester wherein Z represents the radical of an alcohol, is halogenated, the resulting compound is reacted with thiourea to give a 2-amino-thiazol-4-yl-glyoxylic acid ester an amino protective group R is introduced into the compound and the product is saponified to a carboxylic acid of the general formula III.
2. A 2-aminothiazol-4-yl-glyxylic acid of the formula III
as defined in claim 1, whenever obtained according to a process as claimed in claim 1 or by an obvious chemical equivalent thereof.
as defined in claim 1, whenever obtained according to a process as claimed in claim 1 or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000337692A CA1146947A (en) | 1977-03-12 | 1979-10-16 | Cephem derivatives and processes for their preparation |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP2710902.0 | 1977-03-12 | ||
| DE19772710902 DE2710902A1 (en) | 1977-03-12 | 1977-03-12 | CEPHEM DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
| CA298713 | 1978-03-10 | ||
| CA000337692A CA1146947A (en) | 1977-03-12 | 1979-10-16 | Cephem derivatives and processes for their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1146947A true CA1146947A (en) | 1983-05-24 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000337692A Expired CA1146947A (en) | 1977-03-12 | 1979-10-16 | Cephem derivatives and processes for their preparation |
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| Country | Link |
|---|---|
| CA (1) | CA1146947A (en) |
-
1979
- 1979-10-16 CA CA000337692A patent/CA1146947A/en not_active Expired
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