NO744297L

NO744297L -

Info

Publication number: NO744297L
Application number: NO744297A
Authority: NO
Inventors: D Bormann; M Worm
Original assignee: Hoechst Ag
Priority date: 1973-11-29
Filing date: 1974-11-28
Publication date: 1975-06-23
Also published as: FI343674A; ATA953374A; AT333430B; SE7414995L; CA1074299A; DK616874A; NL7415274A; IT1051436B; FR2253023A1; BE822782A; IL46120A0; DE2359402A1; LU71380A1; JPS5088089A; CH615187A5; FR2253023B1

Description

7:'"amino-^3~ce:fem~4-karboksylsyreester og fremgangsmåte til deres fremstilling. 7:'"amino-^3~ce:fem~4-carboxylic acid ester and process for their preparation.

Oppfinnelsens gjenstand er " J- amino-^ Q- 0^em-4-karbok-sylsyreestere og en fremgangsmåte til deres fremstilling. Disse estere har den fordel at i motsetning til de frie syrer er lett oppløselige i organiske oppløsningsmidler og således har betydning som verdifulle mellomprodukter for ytterligere reaksjoner i vann-fritt miljø. De muliggjør på' den ene side en ny acylering med fuktighetsfølsomme karboksylderivater til nye 7-acylaminocefem-karboksylsyreestere som ved egnet valg av esterkomponentene lett spaltes i 7~acylaminocefemkarboksylsyrer, som har betydning som verdifulle antibiotika. På'den annen side er noen acylerte 7- amino-^-cef em-4-karboksylsyreestere viktige terapeutika som dessuten etter oral applikasjon og resorpsjon ved hjelp av uspesi-fikke esteraser igjen kan spaltes i de frie syrer. The object of the invention is "J-amino-^Q-O^em-4-carboxylic acid esters and a process for their production. These esters have the advantage that, unlike the free acids, they are easily soluble in organic solvents and thus have significance as valuable intermediates for further reactions in an anhydrous environment. They enable, on the one hand, a new acylation with moisture-sensitive carboxyl derivatives to new 7-acylaminocephem carboxylic acid esters which, by suitable selection of the ester components, are easily cleaved into 7-acylaminocephem carboxylic acids, which are important as valuable antibiotics On the other hand, some acylated 7-amino-4-cef em-4-carboxylic acid esters are important therapeutics which, moreover, after oral application and resorption with the help of non-specific esterases can again be split into the free acids.

Det var derfor, ønskelig å tilveiebringe en fremgangsmåte som gjør de i organiske oppløsningsmidler godt oppløselige estere av 7-amino-A3-cefem-4-karboksylsyrer godt tilgjengelige. It was therefore desirable to provide a method which makes the esters of 7-amino-A3-cephem-4-carboxylic acids, which are easily soluble in organic solvents, readily available.

Det er kjent (belgiske patenter nr.m 717 741 ogIt is known (Belgian patents no. m 717 741 and

719 712) at ved behandling av 7_acylamino-43-cefem-4-karboksyl-syreestere med fosforpentaklorid, kan det fåes en base, en alkohol og etterfølgende hydrolyse av den tilsvarende aminosyreester med frie aminogrupper. Denne kjente omsetning forløper imidlertid ikke tilfredsstillende spesielt med hensyn til utbyttene. 719 712) that by treating 7_acylamino-43-cephem-4-carboxylic acid esters with phosphorus pentachloride, a base, an alcohol and subsequent hydrolysis of the corresponding amino acid ester with free amino groups can be obtained. However, this known turnover does not progress satisfactorily, especially with regard to dividends.

I de nevnte patenter er det heller ikke omtalt noen eksempler på cefemforbindelser hvis GH^-gruppe i 3~stilling over svovel er forbundet med cykliske forbindelser. In the mentioned patents, there are also no examples of cephem compounds whose GH^ group in the 3~ position above sulfur is connected with cyclic compounds.

Anvender man nå de der som optimalt omtalte forbindelser for slike cefemforbindelser så får man de ønskede sluttproduk-ter bare i knapt påvisbare mengder. If one now uses the compounds mentioned there as optimal for such cephem compounds, the desired end products are obtained only in barely detectable quantities.

Overraskende er det nå funnet at cefemforbindelser med den generelle formel II binder komplekslignende 1 mol PCl^ således at amidgruppen ikke angripes. Surprisingly, it has now been found that cephem compounds of the general formula II bind complex-like 1 mol of PCl^ so that the amide group is not attacked.

Oppfinnelsens gjenstand er 7-amino-^3-cefem-4-karboksyl-syreestere med den generelle formel I The object of the invention is 7-amino-3-cephem-4-carboxylic acid esters of the general formula I

og salter av disse estere, hvori and salts of these esters, wherein

R-^betyr en eventuelt substituert 5- eller seksleddet ring som også kan være forbundet med et påkondensert ringsystem og R-^means an optionally substituted 5- or six-membered ring which can also be connected with a condensed ring system and

R2betyr eventuelt substituert rettlinjet eller forgrenet alkyl, cykbalkyl, aryl, aralkyl, aryloksyalkyl, alkoksyalkyl,acyloksyalkyl, aroylalkyl eller en heterocyklisk rest. R 2 means optionally substituted linear or branched alkyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, acyloxyalkyl, aroylalkyl or a heterocyclic residue.

Oppfinnelsens gjenstand er videre en fremgangsmåte til fremstilling av estere med den generelle formel I, hvor 7~acyl-amido-A 3-cemem-4-karboksylsyreestere med den generelle formel The object of the invention is further a process for the preparation of esters of the general formula I, where 7-acyl-amido-A 3-cemem-4-carboxylic acid esters of the general formula

II II

hvori in which

R^betyr eventuelt substituert alkyl, aryl, aralkyl, aryloksyalkyl, alkoksyalkyl eller en heterocyklisk rest, og R^ means optionally substituted alkyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl or a heterocyclic residue, and

R-^og Rg har ovennevnte betydning,R-^ and Rg have the above meaning,

omsettes i et inert oppløsningsmiddel med et silyleringsmiddelreacted in an inert solvent with a silylating agent

i nærvær av en base og overføres med PCl^i en kompleksaktig forbindelse, som ved hjelp av silyleringen aktiverte amidgruppe over-føres ved tilsetning av et halogeneringsmiddel i iminohalogenidet, denne omsettes med en alkohol til iminoeterhydrohalogenid og denne hydrolyseres ... •la acylspaltning av estere uten gjennomføring av silyleringstrinnet ifølge oppfinnelsen bare bragte utilfreds-.st Ulende utbytter, må-det anses overraskende at ved fremgangs-måten ifølge oppfinnelsen øker utbyttet vesentlig. Det kunne ikke ventes at. amidgruppens silylering ifølge oppfinnelsen dens reaksjonsevne øker så sterkt, at de dertil knyttede omsetninger ved lave temperaturer kunne økes til over ^' fo. Vet må videre anses overraskende at amidgruppen ifølge oppfinnelsen overhodet kunne silyleres. in the presence of a base and transferred with PCl^ into a complex compound, which by means of the silylation activated amide group is transferred by adding a halogenating agent to the iminohalide, this is reacted with an alcohol to iminoether hydrohalide and this is hydrolyzed ... • let acyl cleavage of esters without carrying out the silylation step according to the invention only brought unsatisfying yields, it must be considered surprising that with the method according to the invention the yield increases significantly. It could not be expected that. the silylation of the amide group according to the invention increases its reactivity so strongly that the associated reactions at low temperatures could be increased to over ^' fo. It must also be considered surprising that the amide group according to the invention could be silylated at all.

I de som utgangsmaterialet anvendte forbindelser kan R^bety én eventuelt substituert alkylrest, spesielt en slik med In the compounds used as the starting material, R^ can mean one optionally substituted alkyl residue, especially one with

1 til 8, fortrinnsvis 1 til 5 karbonatomer, idet det som substituenter fortrinnsvis kommer i betraktning en amino- eller karbok-sylgruppe. Som eventuelt substituerte arylrester skal det spesielt nevnes fenyl, som eksempelvis kan være substituert med halogen, fortrinnsvis klor eller brom, lavmolekylært alkoksy, for- 1 to 8, preferably 1 to 5 carbon atoms, the substituents preferably being an amino or carboxyl group. As optionally substituted aryl residues, special mention should be made of phenyl, which can for example be substituted with halogen, preferably chlorine or bromine, low molecular weight alkoxy, for-

trinnsvis metoksy eller hydroksy. Betyr R^en aralkylrest,stepwise methoxy or hydroxy. Means R^an aralkyl residue,

så skal det spesielt nevnes benzylresten,. som i aromater eksempelvis kan være substituert med halogen, fortrinnsvis klor, lavmolekylært alkoksy eller hydroksy og i alkyldelen eksempelvis med lavmolekylært alkyl, fortrinnsvis metyl, etyl, propyl, amino-gruppen, halogen, fortrinnsvis klor, en azidgruppe, lavmolekylært alkoksy, fortrinnsvis metoksy, lavmolekylært acyloksy, fortrinnsvis acetoksy. Har R^betydningen av en aryloksyalkylgruppe, så kommer det spesielt i betraktning en fenyloksyalkylrest, idet alkyldelen kan være en.eventuelt forgrenet lavmolekylær alkylgruppe og fortrinnsvis 1 til 5 karbonatomer og de eventuelt tilstede-værende forgreninger skal ha 1 til 2 karbonatomer. Den aromatiske del kan eksempelvis være substituert med halogen, fortrinns-, vis klor, lavmolekylært alkoksy eller hydroksy. Som alkoksy-alkylrest finner det fortrinnsvis anvendelse en lavmolekylær rest. Anvendes-.en forbindelse med formel II med en heterocyklisk rest R^, så kan denne enten være direkte bundet eller bundet til karbo-, nylgruppen gjennom en lavmolekylær alkyl- eller oksyalkyl-, fortrinnsvis en metyl- eller oksymetylgruppe. Det kommer altså eksempelvis i betraktning en tienyloksymetyl-, tienylmetyl-, pyridylmetyl- eller isoksazolylgruppe. then special mention must be made of the benzyl residue,. which in aromatics can for example be substituted with halogen, preferably chlorine, low molecular weight alkoxy or hydroxy and in the alkyl part for example with low molecular weight alkyl, preferably methyl, ethyl, propyl, the amino group, halogen, preferably chlorine, an azide group, low molecular weight alkoxy, preferably methoxy, low molecular weight acyloxy, preferably acetoxy. If R has the meaning of an aryloxyalkyl group, then a phenyloxyalkyl residue is particularly taken into account, the alkyl part can be an optionally branched low molecular weight alkyl group and preferably 1 to 5 carbon atoms and the possibly present branches must have 1 to 2 carbon atoms. The aromatic part can, for example, be substituted with halogen, preferably chlorine, low molecular weight alkoxy or hydroxy. A low molecular weight residue is preferably used as an alkoxy-alkyl residue. If a compound of formula II with a heterocyclic residue R 1 is used, this can either be directly bound or bound to the carbonyl, nyl group through a low molecular weight alkyl or oxyalkyl group, preferably a methyl or oxymethyl group. Thus, for example, a thienyloxymethyl, thienylmethyl, pyridylmethyl or isoxazolyl group comes into consideration.

Har R2betydningen av -rettlinjet eller forgrenet alkyl, så kommer det spesielt i betraktning alkyl med 1 til 10 karbonatomer, fortrinnsvis fra 1 til 5 karbonatomer, spesielt metyl og tert. butyl. Som substituenter skal det eksempelvis nevnes halogenatomer, fortrinnsvis klor og jod. Tilsvarende substituenter skulle f.eks. være 2,2,2-trikloretyl eller 2-jod-et yl. Som cykloalkylrester kommer det spesielt i betfcaktring If R 2 has the meaning of straight or branched alkyl, alkyl with 1 to 10 carbon atoms, preferably from 1 to 5 carbon atoms, especially methyl and tert, comes into consideration in particular. butyl. Examples of substituents include halogen atoms, preferably chlorine and iodine. Corresponding substituents should e.g. be 2,2,2-trichloroethyl or 2-iodo-ethyl. As cycloalkyl residues, it comes particularly into betfcactring

slike med 5 til 10 karbonatomer, som f.eks. cykloheksyl, spesielt isobornyl eller adamantyl. Som arylrest skal det nevnes spesielt fenyl, som aralkylrest skal det nevnes slike med lavmolekylært alkyl, som spesielt benzyl eller benzhydryl, som eksempelvis kan være substituert med lavmolekylært alkyl, halogen, fortrinnsvis klor eller brom eller nitrogrupper. Som eksempler hertil skal det nevnes p-metoksybenzyl, p-klorbenzyl eller p-nitrobenzyl. Som aryloksyalkyl- alkyloksyalkyl-grupper kommer det spesielt i betraktning slike med lavmolekylære alkylgrupper som fortrinnsvis those with 5 to 10 carbon atoms, such as e.g. cyclohexyl, especially isobornyl or adamantyl. As an aryl residue, phenyl should be mentioned in particular, as an aralkyl residue, those with low molecular weight alkyl should be mentioned, such as especially benzyl or benzhydryl, which can for example be substituted with low molecular weight alkyl, halogen, preferably chlorine or bromine or nitro groups. Examples of this include p-methoxybenzyl, p-chlorobenzyl or p-nitrobenzyl. As aryloxyalkyl-alkyloxyalkyl groups, those with low molecular weight alkyl groups which preferably

feno.ksym.etyl eller metoksymetyl. Også av acyloksyalkylgruppene er de av interesse med lavmolekylært acyl og alkyl, som eksempelvis acetoksymetyl, pivaloyloksymetyl eller ftalyl. Av aroylalkyl-gruppene med lavmolekylært alkyl skal det eksempelvis nevnes benzoylmetyl, som eksempel for en heterocyklisk rest tienyl. pheno.xym.ethyl or methoxymethyl. Of the acyloxyalkyl groups, those with low molecular weight acyl and alkyl, such as acetoxymethyl, pivaloyloxymethyl or phthalyl, are also of interest. Of the aroylalkyl groups with low molecular weight alkyl, benzoylmethyl should be mentioned, as an example of a heterocyclic thienyl residue.

Foretrukket er slike estere som igjen kjemisk eller enzymatisk lar seg spalte i de frie syrer. Denne spaltning kan foregå bl.a. reduktivt f.eks. hydrogenolytisk som eksempelvis ved p-nitrobenzylester, med sink og eddiksyre, f.eks. ved tri-kloretylester, kan foregå i surt medium, som f.eks. ved tert.butyl-ester, p-metoksybenzylester eller benzhydrylesteren. Spesielt har det vist seg egnet p-metoksybenzyl og benzhydrylester som i organiske -oppløsningsmidler med trifluoreddiksyre i nærvær av anisol lar seg overføre i de--tilsvarende karboksylsyrer. Preferred are such esters which can again be chemically or enzymatically cleaved into the free acids. This splitting can take place i.a. reductive e.g. hydrogenolytically as for example with p-nitrobenzyl ester, with zinc and acetic acid, e.g. in the case of trichloroethyl ester, can take place in an acidic medium, such as e.g. by tert-butyl ester, p-methoxybenzyl ester or the benzhydryl ester. In particular, p-methoxybenzyl and benzhydryl esters have proved suitable which, in organic solvents with trifluoroacetic acid in the presence of anisole, can be transferred into the corresponding carboxylic acids.

Eksempler for enzymatisk spaltbare estere er acetoksy-metylester, pivaloyloksymetylester og ftalidester. Examples of enzymatically cleavable esters are acetoxy methyl ester, pivaloyloxy methyl ester and phthalide esters.

R-j_ betyr en eventuelt substituert 5- eller 6-leddet fortrinnsvis femleddet ring, som har karbonatomer og en til fire heteroatomer, som oksygen, svovel og/eller nitrogen som ringatomer. R-j_ means an optionally substituted 5- or 6-membered, preferably five-membered ring, which has carbon atoms and one to four heteroatoms, such as oxygen, sulfur and/or nitrogen as ring atoms.

Resten kan dessuten være forbundet med påkondensert ringsystem, eksempelvis en pyridin- eller triazolring, fortrinnsvis med en benzenring., idet imidlertid resten R-, som ikke er kon-densert med et ringsystem foretrekkes. Ringsystemet som danner resten kan også være hydrert helt eller delvis, fortrinnsvis imidlertid ikke. The residue can also be connected with a condensed ring system, for example a pyridine or triazole ring, preferably with a benzene ring. However, the residue R-, which is not condensed with a ring system, is preferred. The ring system forming the residue can also be fully or partially hydrated, but preferably not.

For resten R-^ skal det eksempelvis nevnes følgende grunnleggende ringsystemer: tienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, tiazolyl, isotioazolyl, oksazolyl, isoksazolyl, triazolyl, tiddiazolyl, oksadiazolyl, tetrazolyl, tiatriazolyl, oksa-triazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, tiazinyl, oksazinyl, triazinyl, tiadiazinyl, oksydiazinyl, ditiazinyl, dioksazinyl, oksatiazinyl, tetrazinyl, tiatriazinyl, okstriazinyl, ditiadiazinyl, imidazolinyl og tetrahydropyrimidyl. For the residue R-^, for example, the following basic ring systems should be mentioned: thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothioazolyl, oxazolyl, isoxazolyl, triazolyl, tiddiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl , pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxydiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxtriazinyl, dithiadiazinyl, imidazolinyl and tetrahydropyrimidyl.

Av ovennevnte eksempelvis oppførte ringsystemer kommer det fortrinnsvis i betraktning 5-leddede ringsystemer med 1 til 2 nitrogenatomer og eventuelt et oksygenatom, som f.eks. oksazolyl, fortrinnsvis oksazol-2-yl, oksadiazolyl, imidazolinyl resp. imida- zolin-2-yl og 6-leddede ringsystemer med 1 til 3 nitrogenatomer og eventuelt et svovelatom, som f.eks. pyridyl, som pyrid-2-yl, pyrid-3-yljpyrid-4-yl5pyrimidyl resp. pyrimid-2-yl og pyrimid-4-yl, tetrahydropyrimidyl resp. 1,4>5>6-tetrahydropyrimid-2-yl, tiadiazinyll, spesielt 4H-1, 3>4-'tia(iiazin-2-yl, triazinyl, Of the ring systems listed as examples above, 5-membered ring systems with 1 to 2 nitrogen atoms and possibly an oxygen atom, which e.g. oxazolyl, preferably oxazol-2-yl, oxadiazolyl, imidazolinyl or imidazolin-2-yl and 6-membered ring systems with 1 to 3 nitrogen atoms and optionally a sulfur atom, such as e.g. pyridyl, such as pyrid-2-yl, pyrid-3-ylpyrid-4-yl5pyrimidyl resp. pyrimid-2-yl and pyrimid-4-yl, tetrahydropyrimidyl resp. 1,4>5>6-tetrahydropyrimid-2-yl, thiadiazinyl, especially 4H-1, 3>4-thia(iiazin-2-yl, triazinyl,

resp. l,3J4_'triazin-2-yl og l,3>5-'triazin"4-yl°6pyridazinyl, spesielt pyridazin-3-yl. respectively 1,3J4_'triazin-2-yl and 1,3>5-'triazin"4-yl°6pyridazinyl, especially pyridazin-3-yl.

Spesielt foretrukket er 5-leddede ringsystemer med et svovelatom ogl til 2 nitrogenatomer som tiazolyl, spesielt tiazol-2-yl, tiadiazolyl, spesielt l^^-tiadiazol-^-yl og l,2,4-tiadiazol-5-yl55-leddede ringsystemer med 3 til 4 nitrogenatomer, som triazolyl, fortrinnsvis 4H-1>2,4-triazol-3_yl og tetrazolyl, fortrinnsvis lH-tetrazol-5-yl, såvel som l,3>4-oksa-diazol-5-yl- systemet. Particularly preferred are 5-membered ring systems with a sulfur atom and 1 to 2 nitrogen atoms such as thiazolyl, especially thiazol-2-yl, thiadiazolyl, especially 1^^-thiadiazol-^-yl and 1,2,4-thiadiazol-5-yl55-membered ring systems with 3 to 4 nitrogen atoms, such as triazolyl, preferably 4H-1>2,4-triazol-3_yl and tetrazolyl, preferably 1H-tetrazol-5-yl, as well as 1,3>4-oxa-diazol-5-yl- the system.

Resten R-^kan være substituert en eller flere ganger idet det eksempelvis kommer på tale følgende substituenter. The residue R- can be substituted one or more times, for example the following substituents are mentioned.

Alkylgrupper med eksempelvis 1 til 15 karbonatomer, som f.eks. metyl, etyl, n-propyl, i-propyl, n-butyl, t-butyl, n-heksyl, undecyl og pentadecyl, fortrinnsvis slike med 1 til 4 karbonatomer, spesielt metyl. Alkyl groups with, for example, 1 to 15 carbon atoms, which e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-hexyl, undecyl and pentadecyl, preferably those with 1 to 4 carbon atoms, especially methyl.

Cykloalkylgrupper som f.eks. cyklpentyl og cykloheksyl, lavmolekylære alkylgrupper med .1 til 4 karbonatomer, fortrinnsvis metyl, som er substituert, eksempelvis med aryl, som f.eks. fenyl eller tienyl, med aryloksy eksempelvis fenoksy, med lavmolekylært alkoksy, som f.eks. metoksy og etoksy, med lavmolekylært alkoksykarbonyl som f.eks. metoksy- eller etoksykarbonyl eller med halogen, lavmolekylære alkoksygrupper som f.eks. metoksy og etoksy, Cycloalkyl groups such as cyclopentyl and cyclohexyl, low molecular weight alkyl groups with .1 to 4 carbon atoms, preferably methyl, which are substituted, for example with aryl, which e.g. phenyl or thienyl, with aryloxy, for example phenoxy, with low molecular weight alkoxy, such as e.g. methoxy and ethoxy, with low molecular weight alkoxycarbonyl such as e.g. methoxy- or ethoxycarbonyl or with halogen, low molecular weight alkoxy groups such as e.g. methoxy and ethoxy,

lavmolekylære alkenylgrupper som f.eks. allyl, lavmolekylære alkyl- og alkenylmerkaptogrupper, som.f.eks. metylmerkapton og allylmerkapto, lavmolekylært alkoksykarbonyl, som f.eks. metoksy-karbonyl, lavmolekylært alkoksykarbonylamino, som f.eks. etoksy-karbonylamino, lavmolekylært karboksyalkyltio, som f.eks. karboksymetyltio, amino, lavmolekylært mono- og dialkylamino, som f.eks. metylamiao, dimetylamino, etylamino, dietylamino, oksido, hydroksy, nitro, cyano, halogen, fortrinnsvis klor, merkapto, karboksy, arylrester, som f ..eks. fenyl, substituert fenyl, som eksempelvis lavmolekylært alkoksyfenyl som metoksyfenyl low molecular weight alkenyl groups such as allyl, low molecular weight alkyl and alkenyl mercapto groups, such as methyl mercaptone and allyl mercapto, low molecular weight alkoxycarbonyl, such as e.g. methoxy-carbonyl, low molecular weight alkoxycarbonylamino, such as e.g. ethoxy-carbonylamino, low molecular weight carboxyalkylthio, such as e.g. carboxymethylthio, amino, low molecular weight mono- and dialkylamino, such as e.g. methylamino, dimethylamino, ethylamino, diethylamino, oxido, hydroxy, nitro, cyano, halogen, preferably chlorine, mercapto, carboxy, aryl residues, such as e.g. phenyl, substituted phenyl, such as, for example, low molecular weight alkoxyphenyl such as methoxyphenyl

etoksyfenyl, halogenfenyl, som f.eks. klorfenyl, hydroksyfenyl, aminofenyl, alkylfenyl, spesielt lavmolekylært alkylfenyl, som t-butylfenyl, tolyl, cetylfenyl, nitrogefenyl, bifenylyl eller pyridyl, metylpyridyl, furyl, naftyl, chinolyl, isochinolyl, tienyl, 2-tiazolyl, 2-pyrrolyl, 4-imidazolyl, 5-pyrazolyl°g 4- isoksazolyl. ethoxyphenyl, halophenyl, such as e.g. chlorophenyl, hydroxyphenyl, aminophenyl, alkylphenyl, especially low molecular weight alkylphenyl, such as t-butylphenyl, tolyl, cetylphenyl, nitrogephenyl, biphenylyl or pyridyl, methylpyridyl, furyl, naphthyl, quinolyl, isoquinolyl, thienyl, 2-thiazolyl, 2-pyrrolyl, 4-imidazolyl , 5-pyrazolyl and 4-isoxazolyl.

Som rester R-^ er ifølge oppfinnelsen foretrukket de usubstituerte samt restene R-|_ som er -substituert med rettlinjede eller forgrenede alkyl med 1 til -8 karbonatomer, spesielt lavmolekylært alkyl, fortrinnsvis metyl, samt med aryl, spesielt fenyl, som eventuelt- kan være substituert med lavmolekylære alkoksy-, nitrogrupper eller.halogen. According to the invention, preferred as residues R-^ are the unsubstituted and the residues R-|_ which are -substituted with linear or branched alkyl with 1 to -8 carbon atoms, especially low molecular weight alkyl, preferably methyl, as well as with aryl, especially phenyl, which optionally can be substituted with low molecular weight alkoxy, nitro groups or halogen.

Som spesielle eksempler for resten R]_ skal i det følgende spesielt nevnes: As special examples for the residue R]_, the following shall be specifically mentioned:

1H-1,2,3-triazol-5-yl,1H-1,2,3-triazol-5-yl,

l,2,4-triazol-3-yl,1,2,4-triazol-3-yl,

5- metyl-l,2,4-triazol~3-yl, -~ 5- methyl-1,2,4-triazol~3-yl, -~

1-fenyl-3-metyl-lH-l,2,4-triazol-5~yl, 1-phenyl-3-methyl-1H-1,2,4-triazol-5-yl,

4,5-dimetyl-4H-l,2,4-triazol~3-yl, 4,5-dimethyl-4H-1,2,4-triazol~3-yl,

5-metyl-4-amino-4H-l,2,4-triazol-3~yl>5-methyl-4-amino-4H-1,2,4-triazol-3-yl>

4- fenyl-4H-l,2,4-triazol~3-yl,4-phenyl-4H-1,2,4-triazol~3-yl,

5- etyl-l, 2,4-triazol-r3pyl,5-ethyl-1,2,4-triazol-yl,

4- amino-4H-l,2,4-triazol-3-yl, 4-amino-4H-1,2,4-triazol-3-yl,

5- etyl-4-amino^4H-l>2,4-triazol-3~yl, 5- ethyl-4-amino^4H-1>2,4-triazol-3~yl,

5-fenyl-1,2,4-triazol-3-yl, 5-phenyl-1,2,4-triazol-3-yl,

5-(4-metoksyfenyl)-l,2,4-triazol-3-yl5 5-(4-Methoxyphenyl)-1,2,4-triazol-3-yl5

5-(4-klorfenyl)-l,2,4-triazol-3-yl, 5-(4-chlorophenyl)-1,2,4-triazol-3-yl,

5-(4-pyridy1)-l,2,4-tria zol-3-yl, 5-(4-pyridyl)-1,2,4-triazol-3-yl,

5-/~4-(2-metyl-pyridylj7~l >2,4-triazol~3-yl, 5.-fenoksymetyl-l,2,4-triazol-3-yl, . 5-/~4-(2-methyl-pyridylj7~l >2,4-triazol~3-yl, 5.-phenoxymethyl-1,2,4-triazol-3-yl, .

5-metoksymetyl-l,2,4-triazol-3-yl, 5-methoxymethyl-1,2,4-triazol-3-yl,

5-etoksymetyl-l,2,4-triazol-3-yl, 5-ethoxymethyl-1,2,4-triazol-3-yl,

5-etoksykarbonylmetyl-l,2,4~triazol-3-yl, 5-ethoxycarbonylmethyl-1,2,4~triazol-3-yl,

5-(2-etoksyetyl)-l,2,4-triazol~3-yl, 5-(2-ethoxyethyl)-1,2,4-triazol~3-yl,

5-(2-aminoetyl)-l,2,4~triazol^3-yl, 5-(2-aminoethyl)-1,2,4-triazol-3-yl,

4-metyl-5-<f>enyl-4H-l,2,4-triazol-3~yl, 4-methyl-5-<f>enyl-4H-1,2,4-triazol-3-yl,

4-(4-etoksyfenyl)-5-(4-p<y>ridyl)-4H-l,2,4-triazol-3-yl, 4-(4-ethoxyphenyl)-5-(4-pyridyl)-4H-1,2,4-triazol-3-yl,

5-(4-metoksyfenyl)~5-(4-pyridyl)~4H-1,2,4-tria zol-3-yl, 4-(4-etoksyfenyl)-5- (3-pyridylJ-4H-1,2,4-triazol~3-yl, 4-(4-etoksyfenyl)-5-fenyl-4H-l,2,4-triazol-3~yl, 4- (4-etoksyf enyl )~5~ (4_aminof enyl )-4H-l, 2,4~t riazol-3-yl > 4,5-difenyl-4H-l,2,4-triazol~3-yl, 5-(4-methoxyphenyl)~5-(4-pyridyl)~4H-1,2,4-triazol-3-yl, 4-(4-ethoxyphenyl)-5-(3-pyridylJ-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-l,2,4-yriazol~3-yl, 4-allyl-5-fenyl-4H-l,2,4-triazol~3-yl, 4-amino-5-metyl-4H-l,2,4-triazol-3~yl, 4-amino-5-etyl-4H-l,2,4-triazol~3-yl, l-metyl-5-fenyl-1,2,4-triazol~3-yl>1-fenyl-4-allyl-5-(m-nitrofenyl)-4H-l,2,4-triazol-3-yl, 1-fenyl4-allyl-5-t-butyl-4H-l,2,4-triazol-3~yl, lH-tetrazol-5-yl, 4,5-di-p-tolyl-4H-1,2,4-yriazol~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-ethyl-4H-1,2,4-triazol-3-yl, 1-methyl-5-phenyl-1, 2,4-triazol~3-yl>1-phenyl-4-allyl-5-(m-nitrophenyl)-4H-1,2,4-triazol-3-yl, 1-phenyl4-allyl-5-t- butyl-4H-1,2,4-triazol-3-yl, 1H-tetrazol-5-yl,

l-metyl-lH-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl,

l-etyl-lH-tetrazol-5-yl, l-n-propyl-lH-tfetrazol-5-yl, l-i-propyl-lH-tetrazol-5-yl, l-n-butyl-lH-tetrazol-5-yl, l-cyklopentyl-lH-tetrazol-5-yl, 1-f enyl-lH-tet razol-5-yl, 1-p-clorfenyl-lH-tetrazol-5-yl, 1-cykloheksyl-lH-tetrazol-5-yl, l-benzyl-lH-tetrazol-5-yl, l-ethyl-lH-tetrazol-5-yl, l-n-propyl-lH-tetrazol-5-yl, l-i-propyl-lH-tetrazol-5-yl, l-n-butyl-lH-tetrazol-5-yl, l- cyclopentyl-1H-tetrazol-5-yl, 1-phenyl-1H-tetrazol-5-yl, 1-p-chlorophenyl-1H-tetrazol-5-yl, 1-cyclohexyl-1H-tetrazol-5-yl, 1-benzyl-1H-tetrazol-5-yl,

1- allyl-lH-tetrazol-5-yl,1-allyl-1H-tetrazol-5-yl,

1.2.3- tiadiazol-5-yl,1.2.3-thiadiazol-5-yl,

1.3.4- tiadia zol-2-yl,1.3.4-thiadiazol-2-yl,

1,2,4-tiadiazol-3~yl,1,2,4-thiadiazol-3-yl,

1.2.4- tiadiazol-5~y1,1.2.4-thiadiazole-5~y1,

1.2.5- tiadiazol-3-yl, 1.2.5-thiadiazol-3-yl,

3-metyl-l,2,4-tiadiazol~5-yl, 3-methyl-1,2,4-thiadiazol~5-yl,

3-fenyl-1,2,4-tiadiazol-5-yl, 3-phenyl-1,2,4-thiadiazol-5-yl,

2- metyl-l,3,4_tiadiazol~5-yl, 2- methyl-1,3,4_thiadiazol~5-yl,

2-metylmerkapto-l,3 > 4-tiadiazol-5-yl, 2-etyl-l,3,4-tiadiazol-5-yl, 2-methylmercapto-1,3 > 4-thiadiazol-5-yl, 2-ethyl-1,3,4-thiadiazol-5-yl,

2-n-propyl-l,3 > 4-tiadiazol-5-yl, 2-i-propyl-l, 3 >4-'tiadiazol-5-yl, 2-fenyl-1,3,4-tiadia zol-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-iTiet oksyf enyl )-l, 3,4-tiadiazol-5-yl > 2-(4-klorfenyl )-l,3,4-tiadiazol-5-yl, 2-n-heptyl-l,3>4_tiadiazol-5-yl>2-(2-furyl)-l,3,4-tiadiazol~5-yl, 2-(3-pyridyl)-l,3,4-tiadiazol-5-yl, 2-n-butyl-l,3,4-tiadiazol-5-yl, 2-(2-pyridyl)-l,3,4-tiadiazol-5-yl, 2-(4-pyridyl^-1,3.4-tiadiazol-5-<y>l, 2- (1-naf tyl )-l, 3,4-tiadiazol-5-y'l, 2-(2-kinolyl)-l,3,4-tiadiazol-5-yl, 2-(1-isochinolyl)-l,3,4~tiadiazol~5-yl, 2-etoksykarbonylmetyl-l,3,4~tiadiazol-5-yl, 2-fenyl-3-metyl-l,3,4-tiadia zol-5-yl, 2- etoksykarbonylamino-4-metyl-l,3,4~tiadiazol-5-yl> 3- metylmerkapt(3-l ,2 ,4-tiadiazol~5-yl, l,2,4-oksadiazol-5-yl, 2-(4-Diethyloxyphenyl)-1,3,4-thiadiazol-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, 2-(3-pyridyl)-1,3,4-thiadiazol-5-yl, 2- n-butyl-1,3,4-thiadiazol-5-yl, 2-(2-pyridyl)-1,3,4-thiadiazol-5-yl, 2-(4-pyridyl^-1,3.4-thiadiazol- 5-<y>1, 2-(1-naphthyl)-1,3,4-thiadiazol-5-yl, 2-(2-quinolyl)-1,3,4-thiadiazol-5-yl, 2-(1-isoquinolyl)-1,3,4~thiadiazol~5-yl, 2-ethoxycarbonylmethyl-1,3,4~thiadiazol-5-yl, 2-phenyl-3-methyl-1,3,4- thiadiazol-5-yl, 2-ethoxycarbonylamino-4-methyl-1,3,4-thiadiazol-5-yl> 3-methylmercapt(3-1 ,2 ,4-thiadiazol-5-yl, 1,2,4 -oxadiazol-5-yl,

1,2,3-oksadiazol~5-yl, 1,2,3-oxadiazol~5-yl,

1,3 > 4~oksadiazol-5-yl, 1,3 > 4~oxadiazol-5-yl,

2-metyl-l,3>4-°ksadiazol-5-yl, 2-etyl-l,3>4-oksadiazol-5-yl, 2-fenyl-1,3,4-oksadiazol-5-yl, 2-(4-nitrofenyl)-l,3,4-°ksadiazol-5-yl 2-(2-tienyl)-l,3,4-oksadiazol-5-yl, 2-(3-tienyl )-l,3,4-oksadiazol-5-yl, 2-(4-klorfenyl)-l,3,4-oksadiazol~5-yl, 2-(2-tiazolyl)-l,3>4-oksadiazol-5-yl, 2-(2-furyl)-l,3,4-oksadiazol-5-yl, 2-(4-pyridyl)-l,3,4-oksadiazol-5-yl, 2-(3~nitrofenyl)-l,3,4-oksadiazol-5~yl, 2-(2-metoksyfenyl)-l,3>4-oksadiazol-5-yl, 2-(2-tolyl )-l,3,4-oksadiazol-5-yl, 2-(3-tolyl)-l,3,4-oksadiazol-5-yl, 2-(2-hydroksyfenyl)-l,3,4~oksadiazol-5-yl, 2-(4-hydroksyfenyl)-l,3>4-°ksadiazol-5-yl, 2-n-butyl-l,3,4-oksadiazol-5~yl, 2-n-propyl-l,3>4-oksadiazol-5-yl, 2-benzyl-l,3 >4~oksadiazol-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-yl, 2 -(4-nitrophenyl)-1,3,4-oxadiazol-5-yl 2-(2-thienyl)-1,3,4-oxadiazol-5-yl, 2-(3-thienyl)-1,3 ,4-oxadiazol-5-yl, 2-(4-chlorophenyl)-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-methoxyphenyl)-1,3>4-oxadiazol-5-yl, 2-(2-tolyl )-1,3,4-oxadiazol-5-yl, 2 -(3-tolyl)-1,3,4-oxadiazol-5-yl, 2-(2-hydroxyphenyl)-1,3,4~oxadiazol-5-yl, 2-(4-hydroxyphenyl)-1,3 >4-°xadiazol-5-yl, 2-n-butyl-1,3,4-oxadiazol-5-yl, 2-n-propyl-1,3>4-oxadiazol-5-yl, 2-benzyl- 1,3>4-oxadiazol-5-yl,

2~(l-naftyl)-l,3,4-oksadiazol-5-yl, 2-(1-naphthyl)-1,3,4-oxadiazol-5-yl,

2-(2-pyrrolyl1-1,3»4-oksadiazol-5-yl, 2-(4-imidazolyl)-l,3 5 4-°ksadiazol-5-yl, 2-(5~pyrazolyl)-l,3>4-°ksadiazol-5-yl, 2- (3 j 5-dime'tyl-4-isoksazolyl )-l, 3,4~oksadiazol-5-yl, tiazol-2-yl, 2-(2-pyrrolyl1-1,3'4-oxadiazol-5-yl, 2-(4-imidazolyl)-1,3 5 4-oxadiazol-5-yl, 2-(5-pyrazolyl)-1, 3>4-oxadiazol-5-yl, 2-(3j 5-dimethyl-4-isoxazolyl)-1, 3,4-oxadiazol-5-yl, thiazol-2-yl,

4-metyl-tiazol-2-yl, 4-methyl-thiazol-2-yl,

4-fenyl-tiazol-2-yl, 4-phenyl-thiazol-2-yl,

4-pentyl-tiazol-2-yl, 4-heksyl-tiazol-2-yl, 4-undecyl-tiazol-2-yl, 4-tridecyl-tiazol-2-yl, 4-pentadecyl-tiazol-2-yl, 4-p-t-butylfenyl-tiazol-2-yl, 4-p-cetylfenyl-tiazol-2-yl, 4-p-fenylfenyl-tiazol-2-yl, 4-etyl-tiazol-2-yl, 4-pentyl-thiazol-2-yl, 4-hexyl-thiazol-2-yl, 4-undecyl-thiazol-2-yl, 4-tridecyl-thiazol-2-yl, 4-pentadecyl-thiazol-2-yl, 4-p-t-butylphenyl-thiazol-2-yl, 4-p-cetylphenyl-thiazol-2-yl, 4-p-phenylphenyl-thiazol-2-yl, 4-ethyl-thiazol-2-yl,

4,5-dimetyl-tiazol-2-yl, benztiazol-2-yl, 4,5-dimethyl-thiazol-2-yl, benzthiazol-2-yl,

4,5-dimetyl-oksazol-2-yl, 4--f enyl-oksazol-2-yl, benzoksazol-2-yl, 4,5-dimethyl-oxazol-2-yl, 4-phenyl-oxazol-2-yl, benzoxazol-2-yl,

oksazolin-2-yl,oxazolin-2-yl,

imidazol-2-yl,imidazol-2-yl,

imidazolin-2-yl, imidazolin-2-yl,

benzimidazolin-2-yl, benzimidazolin-2-yl,

1- metyl-imidazolin-2-yl,1- methyl-imidazolin-2-yl,

2- furyl,2- furyl,

2-tiofenyl,2-thiophenyl,

2-pyrrolyl,2-pyrrolyl,

2- tiazolinyl,2-thiazolinyl,

3- isoksazolyl,3- isoxazolyl,

3-pyrazolyl,3-pyrazolyl,

tiatriazol-5-yl,thiatriazol-5-yl,

purinyl,purinyl,

pyrid-2-yl,pyrid-2-yl,

pyrid-3-yl,pyrid-3-yl,

pyrid-4-yl,pyrid-4-yl,

5-nitro-pyrid-2-yl,5-nitro-pyrid-2-yl,

1- oksidopyrid-2-yl,1- oxidopyrid-2-yl,

pyrimid-2-yl,pyrimid-2-yl,

1,4,5,6-tetrahydropyrimid-2-yl,1,4,5,6-tetrahydropyrimid-2-yl,

4-hydroksy-pyrimid-2-yl,4-hydroxy-pyrimid-2-yl,

4- hydroksy-6-metyl-pyrimid-2-yl,4-hydroxy-6-methyl-pyrimid-2-yl,

2- hydroksy-pyrimid-4-yl, 2-hydroxy-pyrimid-4-yl,

2-fenyl-5-etoksykarbonyl-6-metyl-pyrimid-4-yl, 2-phenyl-5-ethoxycarbonyl-6-methyl-pyrimid-4-yl,

2-fenyl-5-etoksykarbonyl-6-etoksy-pyrimid-4-yl, 2-phenyl-5-ethoxycarbonyl-6-ethoxy-pyrimid-4-yl,

2-fenyl-5-etoksykarbonyl-6-amino-pyrimid-4-yl, 2-phenyl-5-ethoxycarbonyl-6-amino-pyrimid-4-yl,

2-hydroksy-5-cyano-6-metyl-pyrimid-4-yl, 2-hydroxy-5-cyano-6-methyl-pyrimid-4-yl,

2,6-dimetyl-5-acetyl-pyrimid-4-yl, 2,6-dimethyl-5-acetyl-pyrimid-4-yl,

2-undecyl-5-acetyl-6-metyl-pyrimid-4-yl, 2-undecyl-5-acetyl-6-methyl-pyrimid-4-yl,

2,6-dimetyl-5-etoksykarbonyl-pyrimid-4-yl,2,6-dimethyl-5-ethoxycarbonyl-pyrimid-4-yl,

triazolopyridyl,triazolopyridyl,

pyridazinyl,pyridazinyl,

pyrazinyl, pyrazinyl,

2-metylmerkapto-6-fenyl-1,3, 5-triazin-4~yl, 2-methylmercapto-6-phenyl-1,3, 5-triazin-4-yl,

5- metyl-6-hydroksy-l,3,4~triazin-2-yl, 5-methyl-6-hydroxy-1,3,4~triazin-2-yl,

5-fenyl-4H-l,3,4-triadiazin-2-yl, 5-phenyl-4H-1,3,4-triadiazin-2-yl,

5-hydroksy-4H-l, 3,4-tiadiazin-2-yl..5-Hydroxy-4H-1,3,4-thiadiazin-2-yl..

De som utgangsmaterialer anvendte 7-acylamino-A 3-cefem-4-karboksylsyrer.med den generelle formel II lar seg lett fremstille av de tilsvarende litteraturkjente-syrer (fS-patent nr. 3.516.997 og 3.53O.I23 og hollandsk patent nr. 7:;:005.519) ved forestring. The 7-acylamino-A 3-cephem-4-carboxylic acids with the general formula II used as starting materials can be easily prepared from the corresponding acids known in the literature (fS patent no. 3.516.997 and 3.530.123 and Dutch patent no. .7:;:005.519) by esterification.

Som forsstringsmetoder skal det-eksempelvis revnes: a. Omsetning av karboksylsyrene med alifatiske diazoforbindelser, As reinforcement methods, for example: a. Reaction of the carboxylic acids with aliphatic diazo compounds,

som f.eks. diazometan og difenyldiazometan,like for example. diazomethane and diphenyldiazomethane,

b. Omsetning av karboksylsyrer med alkoholer Rg-OH i nærvær av b. Reaction of carboxylic acids with alcohols Rg-OH in the presence of

kondensasjonsmidler som f.eks. dicykloheksylkarbodiimid.condensation agents such as e.g. dicyclohexylcarbodiimide.

c. Aktivering av karboksylsyrer ved dannelse av blandede an-hydrider og etterfølgende reaksjon med alkoholer Rg-OH og d. Omsetning av salter av karboksylsyrer med alkylhalogenider, som f.eks. metyljodid, benzylbromid, p-metoksybenzylklorid, pivalinsyreklormetylester, eddiksyreklormetylester, 3~Drom~c. Activation of carboxylic acids by formation of mixed anhydrides and subsequent reaction with alcohols Rg-OH and d. Reaction of salts of carboxylic acids with alkyl halides, such as e.g. methyl iodide, benzyl bromide, p-methoxybenzyl chloride, pivalic acid chloromethyl ester, acetic acid chloromethyl ester, 3~Drom~

ftalid og klormetylmetyleter..phthalide and chloromethyl methyl ether..

I de som' utgangsprodukter anvendte 7-acylamino-A 3~cefem-4--karboksylsyreestere mdd den generelle formel II må på In the 7-acylamino-A 3-cephem-4-carboxylic acid esters used as starting products according to the general formula II must be

I egnet måte beskyttes for funksjonelle grupper som kan forstyrre de etterfølgende reaks jonstrinn.. In a suitable way, functional groups that can interfere with the subsequent reaction steps are protected.

Således lønner det seg eksempelvis å bbkkere hydroksy-amino og karboksygrupper etter generelt kjente metoder. Thus, for example, it pays to block hydroxy-amino and carboxy groups according to generally known methods.

Esterene med den generelle formel II omsettes ifølge oppfinnelsen i ethvert oppløsningsmiddel med silyleringsreagenser i nærvær av baser. According to the invention, the esters of the general formula II are reacted in any solvent with silylation reagents in the presence of bases.

Som inerte oppløsningsmidler kommer det eksempelvis As inert solvents it comes, for example

i betraktning halogenerte karbonatomer, etere, ketoner og estere. considering halogenated carbon atoms, ethers, ketones and esters.

Som silyleringsmidler skal det fortrinnsvis nevnes sterke silyleringsreagenser som f.eks. trimetylklorsilan, dimetyldiklorsilan, metyltriklorsilan,... trietylklorsilan, trimetylbromsilan, fenyltriklorsilan, metoksytriklorsilan, N,0-bistrimetyl-silylacetamid og trimetylsilyltrifluoracetamid.- Fortrinnsvis Strong silylation reagents such as e.g. trimethylchlorosilane, dimethyldichlorosilane, methyltrichlorosilane,... triethylchlorosilane, trimethylbromosilane, phenyltrichlorosilane, methoxytrichlorosilane, N,0-bistrimethylsilylacetamide and trimethylsilyltrifluoroacetamide.- Preferably

finner det anvendelse trimetylklorsilan og dimetyldiklorsilan. trimethylchlorosilane and dimethyldichlorosilane find use.

Spesielt gode utbytter får man når man arbeider med molare mengder spesielt med et overskudd som eksempelvis 1,5~til 2 ganger mengden av silyleringsmidler. - Imidlertid også med mindre molare mengder kan det oppnås et -økning av utbyttene. Particularly good yields are obtained when working with molar amounts, especially with an excess of, for example, 1.5~ to 2 times the amount of silylating agents. - However, even with smaller molar amounts, an increase in yields can be achieved.

Som ifølge oppfinnelsen anvendte.baser kommer det fortrinnsvis i betraktning organiske baser, spesielt tertiære aminer som kan være substituert likt eller forskjellige, som f.eks. trietylamin, N,N-dimetylanilin, N,N-dietylanilin, N-metyl-piperidin og etylmorfolin, men også aromatiske aminer som pyridin og dets substitusjonsprodukter med inerte substituenter, som f .eks. pikoliner eller også chinolin og dets inert.e substitus jons-produkter. Spesielt egnet ifølge oppfinnelsen er N,N-dimetyl-anilin. The bases used according to the invention are preferably organic bases, especially tertiary amines which may be substituted the same or differently, such as e.g. triethylamine, N,N-dimethylaniline, N,N-diethylaniline, N-methyl-piperidine and ethylmorpholine, but also aromatic amines such as pyridine and its substitution products with inert substituents, such as e.g. picolines or also quinoline and its inert substitution products. Particularly suitable according to the invention is N,N-dimethylaniline.

Basene anvendes i minst^ekvimolare-mengder referert til silyleringsmidlet. Reaksjonen gjennomføres ved jt emperaturer mellom ca. 0 og ca. 100°C, fortrinnsvis mellom 10 og 60°C. Gjennomføres reaksjonen på spesielt foretrukket måte ved værelsetemperatur, så er den allerede avsluttet etter kort tid. The bases are used in at least equimolar amounts with reference to the silylating agent. The reaction is carried out at jt temperatures between approx. 0 and approx. 100°C, preferably between 10 and 60°C. If the reaction is carried out in a particularly preferred manner at room temperature, it is already finished after a short time.

Disse silylerte produkter blandes fortrinnsvis i samme inerte oppløsningsmiddel med et mol PCl^, hvorved det danner seg en kompleksaktig forbindelse. Av spektroskopiske data og ved modellreaksjoner kan man-påvise at kompleksdannelsen finner sted ved den heterocykliske gruppe i 3-stilling. Således kan man eksempelvis i NMR-spektrum iaktta en forskyvning av signalet for protonet i tiadiazol fra 538 Hz mot 565 Hz overfor TMS (målt i CDCl^). Kompleksets stabilitet avhenger fremfor alt av reaksjons-temperaturen. Ved lave temperaturer (-30 til -70°C) er komplekset stabil, ved værelsetemperatur iakttas imidlertid en spaltning. Derfor er det fordelaktig ikke å isolere de dannede komplekser, men å omsette, -videre, nemlig bringes-den ved silyleringen ifølge oppfinnelsen aktiverte acylaminogrupper med halogeneringsmidler - i nærvær av baser til reaksjon til-iminøhalogenid ved lave temperaturer. -Hertil kan det finne anvendelse syrehalogenider som f.eks. fosforoksyklorid, fosforpentaklorid, fosfortriklorid, tionylklorid, fosgen eller oksalkylklorid. Spesielt kommer det ifølge oppfinnelsen i betraktning fosforpentaklorid. .Halogeneringsreaksjonen lykkes med minst ekvimolare mengder halogeneringsmiddel, referert til cefemforbindelser. For spesielt .å få høye utbytter, lønner det seg å benytte et overskudd som eksempelvis 1,5 - 3 ganger mengden. These silylated products are preferably mixed in the same inert solvent with one mole of PCl^, whereby a complex compound is formed. Spectroscopic data and model reactions show that the complex formation takes place at the heterocyclic group in the 3-position. Thus, for example, one can observe in the NMR spectrum a shift of the signal for the proton in thiadiazole from 538 Hz to 565 Hz compared to TMS (measured in CDCl^). The stability of the complex depends above all on the reaction temperature. At low temperatures (-30 to -70°C) the complex is stable, but at room temperature a cleavage is observed. Therefore, it is advantageous not to isolate the complexes formed, but to react, - further, namely bring the acylamino groups activated by the silylation according to the invention with halogenating agents - in the presence of bases to reaction to imine halide at low temperatures. - Acid halides such as e.g. phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, phosgene or oxalkyl chloride. In particular, according to the invention, phosphorus pentachloride comes into consideration. .The halogenation reaction succeeds with at least equimolar amounts of halogenating agent, referred to cephem compounds. In order to obtain particularly high yields, it pays to use a surplus of, for example, 1.5 - 3 times the amount.

Overføringen i iminohalogenidgruppen foregår likeledes i et inert oppløsningsmiddel. Med henblikk på en forenkling av de eksperimentelle betingelser lønner det seg å anvende samme oppløsningsmiddel som ved silyleringsreaksjonen og å innføre kompleksdannelse og det iminohalogeniddannende middel i stoff eller i oppløsning. The transfer in the iminohalide group likewise takes place in an inert solvent. With a view to simplifying the experimental conditions, it pays to use the same solvent as in the silylation reaction and to introduce complexation and the iminohalide-forming agent in substance or in solution.

Også for denne omsetning er det nødvendig med nærvær av baser. Som baser kommer det i betraktning de allerede nevnte organiske baser-, spesielt tertiære aminer. Man vil også her hensiktsmessig anvende de samme som ble anvendt ved silyleringen. Basen kan-tilsettes i toporsjoner, dvs. ved silyleringen av amidgruppen og overføringen i iminohalogenidet. Det er imidlertid hensiktsmessig allerede ved forangående silylering å tilsette den samlede for begge trinn nødvendige basemengde. The presence of bases is also necessary for this turnover. As bases, the already mentioned organic bases, especially tertiary amines, come into consideration. The same ones that were used in the silylation will also be suitably used here. The base can be added in two portions, i.e. during the silylation of the amide group and the transfer into the iminohalide. However, it is expedient to add the total amount of base required for both steps already during preceding silylation.

Iminohalogeniddannelsen lar seg gjennomføre i et vidt temperaturområde fra -100 til +100°C. For oppnåelse av høye utbytter lønner det seg imidlertid, å arbeide i området fra 0 til -80°C, fortrinnsvis mellom -30 til -50°C. The iminohalide formation can be carried out in a wide temperature range from -100 to +100°C. To achieve high yields, however, it pays to work in the range from 0 to -80°C, preferably between -30 to -50°C.

Overføringen av iminohalogenid i en iminoeter foregår på i og for seg kjent måte ved tilsetning av-alkoholer til reak-sjonsblandingen. Derved anvendes hensiktsmessig et overskudd på ca. 5 til 4-0-m°l alkohol pr. mol iminohalogenid. Som alkoholer kommer det her spesielt i betraktning de prisgunstige lavere alifatiske alkoholer, som etanol, metanol, isopropanol og n-butanol. For unngåelse av uønskede bireaksjoner må det arbeides med mest mulige vannfrie alkoholer og ved lave temperaturer fra ca. +30 til -80°C, spesielt ved ca. -30 til -50°C. Iminoeterens etter-følgende hydrolyse foregår på i og for seg kjent måte, spesielt således at man heller den lavtkjølte reaksjonsblaniing i 2- til 3- ganger vannmengden, omrører noen tid og deretter isolerer den dannede ester-med den generelle formel I. The transfer of iminohalide into an iminoether takes place in a manner known per se by adding alcohols to the reaction mixture. Thereby, a surplus of approx. 5 to 4-0-m°l of alcohol per moles of iminohalide. As alcohols, the inexpensive lower aliphatic alcohols, such as ethanol, methanol, isopropanol and n-butanol, are particularly taken into account here. To avoid unwanted side reactions, work must be done with as many anhydrous alcohols as possible and at low temperatures from approx. +30 to -80°C, especially at approx. -30 to -50°C. The subsequent hydrolysis of the iminoether takes place in a manner known per se, in particular by pouring the low-cooled reaction mixture into 2 to 3 times the amount of water, stirring for some time and then isolating the formed ester with the general formula I.

Isoleringen-kan.foregå på forskjellig måte, idet man frafiltrerer den.eksempelvis i form av et ved omsetningen dannet tungtoppløs elig salt som f.eks. hydrokloridet eller idet man The isolation can take place in different ways, as it is filtered out, for example in the form of a poorly soluble salt formed during the reaction, such as e.g. the hydrochloride or as one

frigjør esteren ved tilsetning av uorgands ke baser fra et slikt salt, idet den adskilles med den organiske fase og kan isoleres direkte eller også i form av salter. Som salter kommer det hertil eksempelvis i betraktning sulfonatene som p-toluensulfonater eller (3-naftalinsulfonater eller salter av organiske syrer, som f.eks. acetater. releases the ester by the addition of inorganic bases from such a salt, as it separates with the organic phase and can be isolated directly or also in the form of salts. As salts, for example, sulphonates such as p-toluenesulphonates or (3-naphthalene sulphonates or salts of organic acids, such as acetates.

Saltene av 7-amino-A -3-cefem-4-karboksylsyreestere med den generelle formel I er spesielt egnet til rensing av produkter ifølge oppfinnelsen, spesielt ved omkrystallisering. Dessuten er en mer stabil lagringsform av forbindelsen ifølge opp-' finnelsen hensiktsmessig. Det kommer eksempelvis i betraktning salter med uorganiske syrer som f.eks. med saltsyre, bromhydrogen-syre, svovelsyre og fosforsyre eller med organiske syrer, som f.eks. med eddiksyre og arylsulfonsyrer, som f.eksk. p-toluen-sulf onsyre, p-naftalinsulfonsyre og alkylsulfonsyre som f.eks. metansulfonsyre. The salts of 7-amino-A-3-cephem-4-carboxylic acid esters of the general formula I are particularly suitable for the purification of products according to the invention, especially by recrystallization. Moreover, a more stable storage form of the compound according to the invention is appropriate. For example, salts with inorganic acids such as with hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid or with organic acids, such as e.g. with acetic acid and arylsulfonic acids, such as e.g. p-toluenesulfonic acid, p-naphthalenesulfonic acid and alkylsulfonic acid such as e.g. methanesulfonic acid.

Fremstillingen kan foregå på vanlig måte ved sammen- føring av ekvimolare mengder av base og syrekomponenter i et egnet oppløsningsmiddel. The preparation can take place in the usual way by combining equimolar amounts of base and acid components in a suitable solvent.

Ifølge oppfinnelsen kan det foruten de i utførelses-eksemplene omtalte 7-amino-^-3-cef em-4--karboksylsyreestere eksempelvis også fåes .de i følgende tabell oppstilte forbindelser med According to the invention, in addition to the 7-amino-3-cef em-4-carboxylic acid esters mentioned in the embodiment examples, for example, the compounds listed in the following table can also be obtained with

.den generelle formel I .the general formula I

Oppfinnelsen-skal forklares nærmere ved følgende, ^Lkke—heg-r-ens;end'e| eksempler. The invention-shall be explained in more detail by the following, ^Lkke—heg-r-ens;end'e| examples.

Eksempler.Examples.

De nye forbindelser blekarakterisert vedspektroskopiske data -Og ved tynnsjiktskromatografi. I infrarødspektrum (KBr-presslegemer) viste de p-laktamabsorpsjon ved 1760-1775 cm og esterabsorpsjon ved 1710-1740 cm~"K The new compounds were characterized by spectroscopic data - and by thin-layer chromatography. In the infrared spectrum (KBr-press bodies) they showed β-lactam absorption at 1760-1775 cm and ester absorption at 1710-1740 cm~"K

I NMR-spektrum (60 MHz, CDCl^) fremtrer proton av C-7 ved 8 = 4>7°S NH^-protoner ved S = 1,8 ppm. In the NMR spectrum (60 MHz, CDCl^) proton of C-7 appears at 8 = 4>7°S NH^ protons at S = 1.8 ppm.

Ved tynnsjiktskromatografi ble det som sjikt anvendt kiselgel (Merck) og som flytemiddel eddiksyreetylester. Utvik-lingen av platene foregikk ved innvirkning av joddamp. De rensede produkter ga korrekt elementæranalyse og godt inter-preterbare målespektra. In thin-layer chromatography, silica gel (Merck) was used as the layer and acetic acid ethyl ester as the eluent. The plates were developed by exposure to iodine vapour. The purified products gave correct elemental analysis and well-interpretable measurement spectra.

Eksempel 1. -v -Example 1. -v -

Til 1,86 g 3å-(l,3,4-tiadiazol-2-yl)-tiometyl-7-( tien-2-yl-acetamido)-A ^-cefem-4-karboksylsyre-benzhydrylester i 20 ml absolutt metylenklorid har man 1,56. ml N,N-dimetylanilin og 0,6l ml trimetylklorsilan og lar det omrøre 1 time ved værelsetemperatur. To 1.86 g of 3α-(1,3,4-thiadiazol-2-yl)-thiomethyl-7-(thien-2-yl-acetamido)- N -cephem-4-carboxylic acid benzhydryl ester in 20 ml of absolute methylene chloride you have 1.56. ml of N,N-dimethylaniline and 0.6l ml of trimethylchlorosilane and let it stir for 1 hour at room temperature.

Etter avkjøling til -70°C tilsetter man i første rekke 0,63 g fosforpentaklorid og omrører 30 min. ved -50°C. Etter denne tid har det dannet seg en kompleksaktig forbindelse. Nå avkjøler man igjen til~70°C og tilsetter ytterligere 0,68 g f osf orpentaklorid, omrører to timer ved r-40°C, avkjøler igjen til -70°C, tilsetter 20 ml metanol og omrører igjen, to timer ved -40°C. Deretter helles oppløsningen.i 100 ml vann, omrøres l/2 time, nøytraliseres med natriumbikarbonat, den organiske fase adskilles, den vandige fase ekstraheres ennå to ganger med metylenklorid og de forenede organiske faser tørkes over natriumsulfat. Etter filtrering inndampes oppløsningen i vakuum og ved tilsetning av petroleter utfelles 1,40 g (94$ av det teoretiske ) 3~(1»3>4-'tiadiazol-2-yl)-tiometyl-7-amino-A^-cefem-4-karboksylsyre-benzhydrylester. For rensing oppløses dette produkt varmt i metylenklorid og 'en oppløsning av p-toluensul-fonsyrehydrat i eddiksyreetylester tilsettes. Etter tilsetning av litt metanol og dietyleter krystalliserer 1,48 g (74$ av det teoretiske) 3-(1»3 >4-tiadiazol-2-yl)-tiometyl-7-amino-^-cefem-4-karboksylsyre-benzhydrylesterrp-toluensulfonatj, fargeløse krystaller av smeltepunkt 151-152°C (under spaltning). After cooling to -70°C, 0.63 g of phosphorus pentachloride is added first and stirred for 30 min. at -50°C. After this time, a complex connection has formed. Now cool again to ~70°C and add another 0.68 g of phosphorus pentachloride, stir for two hours at r-40°C, cool again to -70°C, add 20 ml of methanol and stir again, two hours at -40 °C. The solution is then poured into 100 ml of water, stirred for 1/2 hour, neutralized with sodium bicarbonate, the organic phase is separated, the aqueous phase is extracted twice more with methylene chloride and the combined organic phases are dried over sodium sulphate. After filtration, the solution is evaporated in vacuo and by adding petroleum ether, 1.40 g (94% of the theoretical) 3~(1»3>4-'thiadiazol-2-yl)-thiomethyl-7-amino-α-cephem is precipitated -4-carboxylic acid benzhydryl ester. For purification, this product is dissolved hot in methylene chloride and a solution of p-toluenesulfonic acid hydrate in ethyl acetate is added. After the addition of a little methanol and diethyl ether, 1.48 g (74$ of the theoretical) 3-(1»3 >4-thiadiazol-2-yl)-thiomethyl-7-amino-^-cephem-4-carboxylic acid benzhydryl ester crystallizes -toluenesulfonatej, colorless crystals of melting point 151-152°C (under decomposition).

Dette p-toluensulfonat suspenderes i vandig natrium-bikarbonatoppløsning, blandes med metylenklorid og omrøres ved værelsetemperatur. Etter, adskillelse av metylenkloridfasen og avdestillering av oppløsningsmidlet i vakuum får man igjen 3- (1,3 > 4-tiadiazol-2-yl)-tiometyl-7-amino-A^-cefem-4-karboksylsyre-benzhydrylester som svakt gulaktige krystaller av smp. l86-l87°C (under spaltning). This p-toluenesulfonate is suspended in aqueous sodium bicarbonate solution, mixed with methylene chloride and stirred at room temperature. After separation of the methylene chloride phase and distillation of the solvent in vacuo, 3-(1,3 > 4-thiadiazol-2-yl)-thiomethyl-7-amino-A^-cephem-4-carboxylic acid benzhydryl ester is obtained as slightly yellowish crystals of m.p. l86-l87°C (during cleavage).

DC: Rj 0,59DC: Rj 0.59

IR-spektrum: (3-kaktam-ved I76O og ester ved 1715 cm<->^.IR spectrum: (3-cactam-at 176O and ester at 1715 cm<->^.

Eksempel 2.Example 2.

Analogt eksempel 1 vil man av 1,90 g 3- i^- metjl-1,3,4-tiadiazol-2-yl )-tiometyl-7-(tien-2-yl-acetamido )-/ S'- cef em-4- karboksylsyre-benzhydrylester få 1,11 g (73$ av det teoretiske) 3-(5-metyl-l,3 , 4-tiadiazol-2-yl)-tiometyl-7-amino-Z?-cefem-4-karboksylsyre-benzhydrylester som svakt gulaktig krystaller av smp. 145_147°C (under spaltning). Analogous to example 1, from 1.90 g of 3-[[methyl-1,3,4-thiadiazol-2-yl]-thiomethyl-7-(thien-2-yl-acetamido)-/S'-cef -4- carboxylic acid benzhydryl ester yield 1.11 g (73$ of the theoretical) 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-amino-Z?-cephem-4 -carboxylic acid benzhydryl ester as slightly yellowish crystals of m.p. 145_147°C (during decomposition).

DC: Rf 0,43. IR-spektrum: p-laktam ved' I76O og ester ved 1715 cm-''". DC: Rf 0.43. IR spectrum: β-lactam at' 176O and ester at 1715 cm-''".

Eksempel 3»Example 3»

Anvender man den i eksempel 1 angitte måte 1,9363-(5-metyl-l,3,4-tiadiazol-2-yl)-tiometyl-7~fenoksyacetamido-A cefem-4-karboksylsyrebenzhydrylester, så får man 1,19 g (7$$ If the method specified in example 1 is used 1,9363-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-phenoxyacetamido-A cephem-4-carboxylic acid benzhydryl ester, then 1.19 g (7$$

av det teoretiske) 3-(5-metyl-l,3,4-tiadiazol-2-yl)-tiometyl-7-amino-A^-cefem-4-karboksylsyrebenzhydrylester av smp. 144- of the theoretical) 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-amino-N,-cephem-4-carboxylic acid benzhydryl ester of m.p. 144-

146°C (under spaltning).146°C (during decomposition).

Eksempel 4.Example 4.

Den i eksempel 1 anførte reaksjon gjentas med 2,85 g dibenzhydrylester av 3-(5_metyl-l,3,4-"kiadiazol-2-yl)-tiometyl-7-(D-a-ftaloylamino-adipoylamido)-A^-cefem-4-karboksylsyre. The reaction stated in example 1 is repeated with 2.85 g of the dibenzhydryl ester of 3-(5_methyl-1,3,4-"chiadiazol-2-yl)-thiomethyl-7-(D-a-phthaloylamino-adipoylamido)-A^-cephem- 4-carboxylic acid.

Det oppstår 1,10 g (72% av det teoretiske) 3-(5-metyl-l,3,4-t iadia zol-2-yl )-tiometyl-7-amino-A^-c'ef em-4-karboksylsyre-benzhydrylester av smeltepunkt 144a145°C (under spaltning). 1.10 g (72% of theoretical) of 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-amino-N,-c'ephem-4 -carboxylic acid benzhydryl ester of melting point 144 to 145°C (under decomposition).

Eksempel 5»Example 5»

Setter man 1,85 g 3-(l,3,4-tiadiazol-2-yl)-!tiometyl-7-fenylacetamido-Z!?-cefem-4-karboksylsyrebenzhydrylester på den i eksempel 1 angitte måte får man 1,22 g (82% av det teoretiske) 3- (1,3 > 4-"t iadia zol-2-yl )-tiometyl-7-amino-A^-cef em-4-karboksylsyrebenzhydrylester av smp. l85-l86°C (under spaltning). Eksempel 6. If you add 1.85 g of 3-(1,3,4-thiadiazol-2-yl)-1thiomethyl-7-phenylacetamido-Z1?-cephem-4-carboxylic acid benzhydryl ester in the manner indicated in example 1, you get 1.22 g (82% of theoretical) 3-(1,3 > 4-thiadiazol-2-yl)-thiomethyl-7-amino-N,-cef-4-carboxylic acid benzhydryl ester of m.p. 185-186°C (under cleavage) Example 6.

Den i eksempel 2 angitte reaksjonsrekkefølge gjentas med den forskjell at i stedet for det anvendte 0,6l ml trimetylklorsilan anvendes 0,62 g dimetyldiklorsilan som silylerlngs-middel. The reaction order specified in example 2 is repeated with the difference that instead of the 0.61 ml of trimethylchlorosilane used, 0.62 g of dimethyldichlorosilane is used as silylation agent.

Man vil av 1,90 g 3-(5-metyl-l,3,4-tiadiazol-2-yl)-tiometyl-7-(tien-2-yl-acetamido)-Æ<?->cefem-4-karboksylsyre-benzhydrylester lå 1,24 g (8l% av det teoretiske) 3-(5-metyl-l,3,4-tiadiazol-2-yl)-tiometyl-7-amino-A ^-cefem-4-karboksylsyrebenz-hydrylester av.smp. 145-146°C (under spaltning). One wants from 1.90 g of 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-(thien-2-yl-acetamido)-Æ<?->cephem-4- carboxylic acid benzhydryl ester was 1.24 g (81% of the theoretical) 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-amino-A^-cephem-4-carboxylic acid benz- hydryl ester of m.p. 145-146°C (under decomposition).

Eksempel 71.Example 71.

Den i eksempel 1 angitte reaksjonsrekkefølge gjentas med den forandring at i stedet for 1,56 ml N,N-dimetylanilin anvendes 1,63 ml N,N-dietylanilin som base. Man vil av 1,86 g 3-(l,3,4-tiadiazol-2-yl)-tiometyl-7-(tien-2-yl-acetamido)- A<3->cefem-4-karboksylsyrebenzhydrylester få 1,18 g (79,5$ av det teoretiske ) 3-(1,3,4-tiadiazol-2-yl)-tiometyl-7-amino-Z?-cefem-4-karboksylsyrebenzhydrylester av smp. l85-l86°C (nder spaltning). Eksempel 8. The reaction sequence given in example 1 is repeated with the change that instead of 1.56 ml of N,N-dimethylaniline, 1.63 ml of N,N-diethylaniline is used as base. From 1.86 g of 3-(1,3,4-thiadiazol-2-yl)-thiomethyl-7-(thien-2-yl-acetamido)-A<3->cephem-4-carboxylic acid benzhydryl ester you will get 1, 18 g (79.5% of the theoretical) 3-(1,3,4-thiadiazol-2-yl)-thiomethyl-7-amino-Z?-cephem-4-carboxylic acid benzhydryl ester of m.p. l85-l86°C (under cleavage). Example 8.

ANALOGT eksempel 1 vil man av 1,88 g 3-(5-metyl-l,3,4-tiadiazol-2-yl)-tiometyl-7-(tien-2-yl-acetamido)pA^-cefem-4-karboksylsyre-3-ftalidester få 0,89 g f62% av det teoretiske) 3-(5-metyl-l,3,4~tiadiazol-2-yl)-tiometyl~7-amino-Z?-cefem-4-karboksylsyre-3-ftalidester som amorft fast stoff som spalter seg ved 175°C. Analogous to example 1, from 1.88 g of 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-(thien-2-yl-acetamido)β-cephem-4- carboxylic acid 3-phthalide ester yield 0.89 g (62% of the theoretical) 3-(5-methyl-1,3,4~thiadiazol-2-yl)-thiomethyl~7-amino-Z?-cephem-4-carboxylic acid -3-phthalide esters as an amorphous solid which decomposes at 175°C.

DC: Rf 0,38.DC: Rf 0.38.

IR-spektrum: p-laktam ved I77O og ester ved I75O cm .IR spectrum: β-lactam at 1770 and ester at 1750 cm .

Eksempel Q.Example Q.

Analogt eksempel 1 vil man av 1,90 g 3-(4~metyl-tiazol-2-yl)-tiometyl--7-(tien-2-yl-acetamido)-A^-cefem-4-karboksylsyre-benzhydrylester få 1,04 g (68% av det teoretiske) 3-(4-metyl-tiazol-2-yl)-tiometyl-7-amino-Z?-cefem-4-karboksylsyre-benzhydrylester som amorft fast stoff, som spalter seg ved 145°C Analogous to example 1, 1.90 g of 3-(4-methyl-thiazol-2-yl)-thiomethyl-7-(thien-2-yl-acetamido)-N-cephem-4-carboxylic acid benzhydryl ester will be obtained 1.04 g (68% of theory) 3-(4-methyl-thiazol-2-yl)-thiomethyl-7-amino-Z?-cephem-4-carboxylic acid benzhydryl ester as an amorphous solid, which decomposes at 145°C

DC: Rf 0,69. DC: Rf 0.69.

Eksempel 10.Example 10.

Analogt eksempel 1 vil man av 1,80 g 3-(4-metyl-tiazol-2-yl)-tiometyl-7-(tien-2-yl-acetamido)-A^-cefem-4-karboksylsyre-2-ftalidester få 0,90 g (63% av det teoretiske) 3-(4_metyltiazol-2-yl)-tiometyl-7-amino- A^-cefem-4-karboksylsyre-3- ftalidester som lysegult pulver som spalter seg ved l65-170°C. Analogously to example 1, from 1.80 g of 3-(4-methyl-thiazol-2-yl)-thiomethyl-7-(thien-2-yl-acetamido)-N-cephem-4-carboxylic acid-2-phthalide ester obtain 0.90 g (63% of theoretical) 3-(4_methylthiazol-2-yl)-thiomethyl-7-amino- ?-cephem-4-carboxylic acid-3-phthalide ester as a pale yellow powder which decomposes at l65-170 °C.

DC: Rf 0,55. DC: Rf 0.55.

IR-spektruåm: p-laktam ved 1775°S ester ved 1750 cmIR spectrum: β-lactam at 1775°S ester at 1750 cm

Eksempel 11.Example 11.

Analogt eksempel 1 vil man av 1,45 S 3-(5-me'ty1~1,3,4-tiadiazol-2-yl)-tiometyl-7-(tien-2-yl-acetamido)-A^-cefem-4- karboksyøsyre-metylester få 0,90 g (83% av det teoretiske) 3-(5-metyl-l ,3,4-'tiadiazol-2-yl )-tiometyl-7-amino-^-cef em-4-karboksylyre-metylester som kremfarget faststoff, som spalter seg ved 140°C. Analogously to example 1, from 1.45 S 3-(5-methyl~1,3,4-thiadiazol-2-yl)-thiomethyl-7-(thien-2-yl-acetamido)-α-cephem -4-carboxylic acid methyl ester obtain 0.90 g (83% of the theoretical) 3-(5-methyl-1,3,4-'thiadiazol-2-yl)-thiomethyl-7-amino-^-cef em- 4-Carboxylyl methyl ester as a cream-colored solid, which decomposes at 140°C.

DC: R. 0,26 IR-spektrum: p-laktam ved 1770°S ester ved 1715 cm DC: R. 0.26 IR spectrum: β-lactam at 1770°S ester at 1715 cm

Eksempel 12.Example 12.

Analogt eksempel 1 vil man av 1,68 g 3-(5~£enyl~1,3 j 4-oksadia zol-2-yl)-tiometyl-7-(tien-2-yl-acetamido)-A~^-cefem-4-karboksylsyre-metoksymetylester få 1,01 g (78$ av det teoretiske) J-(^- fenyl-1,3,4-oksadiazol-2-yl)-tiometyl~7-amino-A-^-cefem-4-karboksylsyre-metoksymetylester som amorft pulver, som spalter ved 190°C. Analogous to example 1, from 1.68 g of 3-(5~£enyl~1,3j 4-oxadiazol-2-yl)-thiomethyl-7-(thien-2-yl-acetamido)-A~^- cephem-4-carboxylic acid methoxymethyl ester obtain 1.01 g (78$ of the theoretical) J-(^-phenyl-1,3,4-oxadiazol-2-yl)-thiomethyl~7-amino-A-^-cephem -4-carboxylic acid methoxymethyl ester as amorphous powder, which decomposes at 190°C.

DC: RF 0,52 IR-spektrum:. p-laktam ved 1770 og ester ved 1720 cm DC: RF 0.52 IR spectrum:. β-lactam at 1770 and ester at 1720 cm

Eksempel 13»Example 13»

Analogt eksempel 1 vil'man av 1,41 g 3~(1>3>4-tiadiazol-2-yl)-tiometyl-7-(tien-2-yl-acetamido)-A^-cefem-4-karboksyl-syremetylester få 0,91 g (88% av det teoretiske) 3-(l,3,4-tiadiazol-2-yl)-tiometyl-7-amino-A^-cefem-4-karboksylsyre-metyl-ester som seig olje. Analogous to example 1, 1.41 g of 3-(1>3>4-thiadiazol-2-yl)-thiomethyl-7-(thien-2-yl-acetamido)-N-cephem-4-carboxyl- acid methyl ester yield 0.91 g (88% of theory) 3-(1,3,4-thiadiazol-2-yl)-thiomethyl-7-amino-N,-cephem-4-carboxylic acid methyl ester as a viscous oil .

DC: Rf 0,34DC: Rf 0.34

IR-spektrum: p-laktam ved 177° °S ester ved 1715 cm-1.IR spectrum: β-lactam at 177° °S ester at 1715 cm-1.

Eksempel 14.Example 14.

Analogt eksempel 1 vil man..av 1,50 g 3-(l>3>4-tiadiazol-2-yl)-tiometyl-7-(tien-2-yl-acetamido)- fc?- cefem-4-karboksylsyre-metoksymetylester få 0,84 g (75$ av det teoretiske) 3- (1,3,4-tiadiazol-2-yl)-tiometyl-7-amino-A^-cefem-4-karboksylsyre-metoksymetylester som amorft faststoff. Analogously to example 1, one will.. of 1.50 g of 3-(1>3>4-thiadiazol-2-yl)-thiomethyl-7-(thien-2-yl-acetamido)-fc?-cephem-4-carboxylic acid -methoxymethyl ester obtain 0.84 g (75$ of the theoretical) 3-(1,3,4-thiadiazol-2-yl)-thiomethyl-7-amino-N,-cephem-4-carboxylic acid methoxymethyl ester as an amorphous solid.

DC: Rf 0,58.DC: Rf 0.58.

IR-spektrum: p-laktam ved 177° °S ester ved 1720 cm-"1".IR spectrum: β-lactam at 177° °S ester at 1720 cm-"1".

Eksempel 15»Example 15»

Analogt eksempel 1 vil man av 1,71 g 3-(l>3>4-tiadiazol-2-yl)-tiometyl-7-(t'ien-2-yl-acetamido )-A^-cefem-4-karboksylsyre-pivaloyloksymetylester få 0,93 S (70$ av det "teoretiske ) 3-(1,3,4-tiadiazol-2-yl)-tiometyl-7-amind-^-cefem-4- karboksylsyre-pivaloyloksymetylester som amorft faststoff. Analogously to example 1, from 1.71 g of 3-(1>3>4-thiadiazol-2-yl)-thiomethyl-7-(thien-2-yl-acetamido)-N,-cephem-4-carboxylic acid -pivaloyloxymethyl ester obtain 0.93 S (70$ of the "theoretical ) 3-(1,3,4-thiadiazol-2-yl)-thiomethyl-7-amine-^-cephem-4-carboxylic acid pivaloyloxymethyl ester as an amorphous solid.

DC: R. 0,50.DC: R. 0.50.

IR-spektrum: p-laktam ved 1775°S ester ved 1740 cm IR spectrum: β-lactam at 1775°S ester at 1740 cm

Claims

1.. 7-Amino-^_cephem-4-carboxylic acid ester of the general formula I

in which R^ means an optionally substituted 5~ or 6-membered ring which can also be connected to a condensed ring system, and Rg means optionally substituted straight-line or branched alkyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, acyloxyalkyl, aroylalkyl or a heterocyclic residue, and salts of these esters.

2. 7~ amino-A^-cephem-4-carboxylic acid ester according to claim 1, in which R-^ denotes the residue

in which R^ means hydrogen, straight or branched alkyl with 1 to 8 carbon atoms, or optionally with low molecular weight alkoxy, nitro groups or halogen substituted phenyl..

3* 7-amino-A^-cephem-4-carboxylic acid ester according to claim 1, wherein R-^ means the residue

wherein R^ has the above meaning.

4. 7~ amine° -^~ cephem-4-carboxylic acid ester according to claim 1, wherein R-^ means the residue

wherein R^ has the above meaning.

5. 7-amino-N-cephem-4-carboxylic acid ester according to claim 1, wherein R-^ means the residue

. wherein R^ has the above meaning.

6. 7-amino-A^-cephem-4-carboxylic acid ester according to claim 1, wherein R-^ denotes the residue

wherein R^ has the above meaning.

7« 7~ amino~ A^-cephem-4-carboxylic acid ester according to claim 1, wherein R-^ means the residue

in which R^ has the above meaning..

8. 7-Amino-N-cephem-4-carboxylic acid ester according to claim 1. where Rp means the remainder

wherein A means straight or branched alkyl of 1 to 8 carbon atoms.

9' Process for the production of 7-amino-A?-cephem- 4-carboxylic acid ester of the general formula I

characterized in that 7-acylamino-N,-cephem-4-carboxylic acid ester of the general formula II

in which R-j_ means an optionally substituted 5- or 6-membered ring which can also be connected with a condensed ring system, and means optionally substituted, straight-line or branched alkyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, acyloxyalkyl, aroylalkyl or a heterocyclic residue, and Ro means optionally substituted alkyl, aryl, aralkyl, aryloxy-, alkyl, alkoxyalkyl or a heterocyclic residue, reacted in an inert solvent with a silylating agent in the presence of a base and transferred with phosphorus pentachloride in a complex compound which transfers the silylation-activated amide group by adding a halogenating agent to iminohalide, reacts this with an alcohol to imine hydrohalide and hydrolyzes and optionally transfers into salt .

10. Method according to claim 9, characterized in that the silylation reaction is carried out at a temperature between 0 and 100°C, preferably between 10 and 60°C.

11. Process according to claims 9 to 10, characterized in that trimethylchlorosilane, dimethyldichlorosilane, methyltrichlorosilane, triethylchlorosilane, trimethylbromosilane, N,0-bistrimethylsilylacetamide and trimethylsilyltrifluoroacetamide are used as silylating agents.

12. Method according to claim 9> characterized in that the complex formation is carried out with phosphorus penta- chloride.

13» Method according to claim 9° S 12, characterized in that the complex formation is carried out in inert . solvents-at 0 to -80°C, -preferably at -10 to -50°C.

14. Method according to claim 9, characterized in that the reaction with iminohalide-forming agents and the reaction of iminohalide with alcohol is carried out at temperatures from 30 to -80°C, preferably at -30 to -50°C.