NO159797B - ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTIC ACTIVE CEPHALOSPORINALS. - Google Patents

ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTIC ACTIVE CEPHALOSPORINALS. Download PDF

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NO159797B
NO159797B NO791776A NO791776A NO159797B NO 159797 B NO159797 B NO 159797B NO 791776 A NO791776 A NO 791776A NO 791776 A NO791776 A NO 791776A NO 159797 B NO159797 B NO 159797B
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methyl
oxo
salt
triazin
group
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NO791776L (en
NO159797C (en
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Marc Montavon
Roland Reiner
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Hoffmann La Roche
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Priority claimed from CH588278A external-priority patent/CH641468A5/en
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Publication of NO791776L publication Critical patent/NO791776L/en
Priority to NO823987A priority Critical patent/NO158346C/en
Priority to NO844103A priority patent/NO161221C/en
Priority to NO865360A priority patent/NO160301C/en
Publication of NO159797B publication Critical patent/NO159797B/en
Publication of NO159797C publication Critical patent/NO159797C/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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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  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
  • Public Health (AREA)
  • Oncology (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Compounds of the general formula <IMAGE> [wherein X represents the 1,2,5,6- tetrahydro-2-methyl-5,6-dioxo-as- triazin-3-yl group, the 2,5-dihydro-6- hydroxy-2-methyl-5-oxo-as-triazin-3- yl group of the 1,4,5,6-tetrahydro-4- methyl-5,6-dioxo-as-triazin-3-yl group] and readily hydrolysable esters, readily hydrolysable ethers and salts thereof and hydrates of these compounds have broad-spectrum anti-bacterial activity.

Description

Foreliggende oppfinnelse vedrører en analogifremgangsmåte The present invention relates to an analog method

ved fremstilling av terapeutisk aktive cefalosporinsalter med generell formel I in the preparation of therapeutically active cephalosporin salts of general formula I

Eksempler på salter med formel I er alkalimetallsalter, som natrium og kaliumsalter, ammoniumsalter, jordalkalimetall- Examples of salts with formula I are alkali metal salts, such as sodium and potassium salts, ammonium salts, alkaline earth metal

salter som kalsiumsalter, salter med organiske baser som salter med aminer, f.eks. salter med N-etyl-piperidin, salts such as calcium salts, salts with organic bases such as salts with amines, e.g. salts with N-ethyl-piperidine,

prokain, dibenzylamin, N,N'-dibenzyletyletylendiamin, alkyl-aminer eller dialkylaminer, samt salter med aminosyrer, som f.eks. salter med arginin eller lysin. Saltene er som det fremgår av formel I disalter, da den andre saltdannelsen opptrer i forbindelse med hydroksygruppen på 2,5-dihydro-6-hydroksy-2-metyl-5-okso-as-triazin-3-yl-gruppen. procaine, dibenzylamine, N,N'-dibenzylethylethylenediamine, alkylamines or dialkylamines, as well as salts with amino acids, such as e.g. salts with arginine or lysine. As can be seen from formula I, the salts are disalts, as the second salt formation occurs in connection with the hydroxy group on the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group.

Saltene med formel I er hydratisert, hvorved det dannes salthydrater. Hydratiseringen kan skje i løpet av fremstillingen eller med tiden som en følge av de hydroskopiske egenskapene til det opprinnelig vannfrie produkt. The salts of formula I are hydrated, whereby salt hydrates are formed. Hydration can occur during manufacture or with time as a result of the hydroscopic properties of the initially anhydrous product.

Som det fremgår av formel I foreligger cefalosporinsaltene As can be seen from formula I, the cephalosporin salts are present

som fremstilles i henhold til oppfinnelsen i den syn-isomere form: which is produced according to the invention in the syn-isomeric form:

Et foretrukket produkt er (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-(Z—metoksyimino)-acetamido]-3-/[2,5-dihydro-6-hydroksy-2-metyl-5-okso-as-triazin-3-yl)tio]-metyl/-8-okso-5-tia-l-azabicyklo-[4.2.0]okt-2-en-2-karboksylsyre-dinatriumsalt-trihydrat. Cefalosporlnsaltene fremstilles 1 henhold til oppfinnelsen ved at man ansetter en forbindelse med generell formel A preferred product is (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)-acetamido]-3-/[2,5-dihydro-6-hydroxy- 2-Methyl-5-oxo-as-triazin-3-yl)thio]-methyl/-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid disodium salt -trihydrate. The cephalosporin salts are produced according to the invention by employing a compound of general formula

hvori X er 1,2,5,6-tetrahy dro -2-metyl-5,6-diokso-as-triazin-3-ylgruppen, henholdsvis dens tilsvarende tautomere form, 2,5-dihydro-6-hyddroksy-2-metyl-5-okso-as-triazin-3-yl-gruppen wherein X is the 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group, respectively its corresponding tautomeric form, 2,5-dihydro-6-hydroxy-2- the methyl-5-oxo-as-triazin-3-yl group

i den syn-isomere form med minst to ekvivalenter av en base og isolerer det dannede salt i nærvær av vann eller atmos-færefuktighet som et salthydrat. in the syn-isomeric form with at least two equivalents of a base and isolates the formed salt in the presence of water or atmospheric moisture as a salt hydrate.

Utgangsforbindelsen med formel II kan igjen fremstilles ved at man i en forbindelse med generell formel III The starting compound with formula II can again be prepared by using a compound with general formula III

hvori X har den ovenfor oppførte betydning, wherein X has the above meaning,

R betyr en avspaltbar beskyttelsesgruppe og karboksylgruppen kan foreligge i beskyttet form, R means a cleavable protecting group and the carboxyl group can be present in protected form,

i den syn-isomere form spalter av beskyttelsesgruppen R, og eventuelt også en muligens foreliggende karboksy-beskyttelsesgruppe. Denne fremgangsmåten er gjenstand for den av-delte patentsøknad 86.5360. in the syn-isomeric form clefts of the protecting group R, and optionally also a possibly present carboxy protecting group. This method is the subject of the divided patent application 86.5360.

De karboksylgrupper som foreligger i forbindelsen med formel III kan eventuelt være beskyttet, f.eks. ved forestring med en lett avspaltbar ester, som silylesteren, f.eks. trimetyl-silylesteren. Også de ovenfor nevnte lett hydrolyserbare estere kommer i betraktning. Karboksygruppen kan også be-skyttes ved saltdannelse med en uorganisk eller tertiær organisk base, som trietylamin. Mulige R-beskyttelsesgrupper er f.eks. surt hydrolytisk avspaltbare beskyttelsesgrupper, som f.eks. t-butoksykarbonyl eller trityl, eller også basisk hydrolytisk avspaltbare beskyttelsesgrupper, som f.eks. trifluoracetyl. Foretrukne R-beskyttelsesgrupper er klor-, brom- og jodacetyl, særlig kloracetyl. De sistnevnte beskyttelsesgrupper kan avspaltes ved behandling med tiourea. The carboxyl groups present in the compound of formula III may optionally be protected, e.g. by esterification with an easily cleavable ester, such as the silyl ester, e.g. the trimethyl silyl ester. The above-mentioned easily hydrolyzable esters also come into consideration. The carboxy group can also be protected by salt formation with an inorganic or tertiary organic base, such as triethylamine. Possible R protecting groups are e.g. acidic hydrolytically cleavable protective groups, such as e.g. t-butoxycarbonyl or trityl, or also basic hydrolytically cleavable protecting groups, such as e.g. trifluoroacetyl. Preferred R protecting groups are chloro-, bromo- and iodoacetyl, especially chloroacetyl. The latter protective groups can be removed by treatment with thiourea.

Forbindelsene med formel III kan f.eks. fremstilles ved N-acylering av de tilsvarende 7-aminoforbindelser ved at man omsetter en forbindelse med generell formel IV The compounds of formula III can e.g. is produced by N-acylation of the corresponding 7-amino compounds by reacting a compound of general formula IV

hvori X har den ovenfor anførte betydning og karboksygruppen og/eller aminogruppen kan foreligge i beskyttet form, in which X has the meaning stated above and the carboxy group and/or the amino group can be present in protected form,

med en syre med generell formel with an acid of general formula

i hvilken R har den ovenfor oppførte betydning, in which R has the above meaning,

i den syn-isomere form eller med et reaktivt funksjonelt derivat av denne syre og avspalter en eventuelt foreliggende karboksybeskyttelsesgruppe. in the syn-isomeric form or with a reactive functional derivative of this acid and cleaves off a possibly present carboxy protecting group.

Karboksygruppen som foreligger i 7-aminoforbindelsen med formel IV kan eventuelt være beskyttet på samme måten som beskrevet ovenfor for den fremstillbare utgangsforbindelsen med formel III. Aminogruppen til forbindelsen med formel IV kan f.eks. være beskyttet med en silylbeskyttelsesgruppe som trimetylsilyl. The carboxy group present in the 7-amino compound of formula IV may optionally be protected in the same way as described above for the preparable starting compound of formula III. The amino group of the compound of formula IV can e.g. be protected with a silyl protecting group such as trimethylsilyl.

Som reaktive funksjonelle derivater av syrer med formel V kommer f.eks. halogenider, dvs. klorider, bromider og fluorider, azider, anhydrider, særlig blandede anhydrider med sterkere syrer, reaktive estere, f.eks. N-hydroksy-succinimidester, og amider, f.eks. imidazolider, i betraktning. As reactive functional derivatives of acids with formula V, e.g. halides, i.e. chlorides, bromides and fluorides, azides, anhydrides, especially mixed anhydrides with stronger acids, reactive esters, e.g. N-hydroxy-succinimide esters, and amides, e.g. imidazolides, in consideration.

Omsetningeen av 7-aminoforbindelsen med formel IV med syren med formel V eller med et reaktivt funksjonelt derivat derav kan gjennomføres på i og for seg kjent måte. Slik kan man f.eks. kondensere en fri syre med formel V med en av de nevnte estere som tilsvarer formel IV ved hjelp av et karbodiimid, såsom dicykloheksylkarbodiimid i et inert løsningsmiddel som eddikester, acetonitril, dioksan, kloroform, metylenklorid, benzen eller dimetylformamid, og deretter spalte av estergruppen. I stedet for kårbo-diimider kan det som kondensasjonsmidler også anvendes oksasoliumsalter, som f.eks. N-etyl-5-fenyl-isoksazolium-3'-sulfonat. The reaction of the 7-amino compound of formula IV with the acid of formula V or with a reactive functional derivative thereof can be carried out in a manner known per se. This is how you can e.g. condensing a free acid of formula V with one of the aforementioned esters corresponding to formula IV by means of a carbodiimide, such as dicyclohexylcarbodiimide in an inert solvent such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide, and then cleaving off the ester group. Instead of kårbo-diimides, oxazolium salts can also be used as condensation agents, such as e.g. N-ethyl-5-phenyl-isoxazolium-3'-sulfonate.

Ifølge en annen utførelsesform ansetter man et salt av en syre med formel IV, f.eks. et trialkylammoniumsalt som trietylammoniumsaltet, med et reaktivt funksjonelt derivat av en syre med formel V som nevnt ovenfor i et inert løsningsmiddel, f.eks. ett av de ovenfor nevnte. According to another embodiment, a salt of an acid with formula IV is employed, e.g. a trialkylammonium salt such as the triethylammonium salt, with a reactive functional derivative of an acid of formula V as mentioned above in an inert solvent, e.g. one of the above mentioned.

I henhold til en annen utførelsesform omsettes et syrehalo-genid, fortrinnsvis kloridet til en syre med formel V med aminet med formel IV. Omsetningen skjer fortrinnsvis i nærvær av et syrebindende middel, f.eks. i nærvær av vandig alkali, fortrinnsvis natronlut, eller også i nærvær av et alkalimetallkarbonat, såsom kaliumkarbonat, eller i nærvær av et lavere alkylert amin, som trietylamin. Som løsnings-middel anvendes fortrinnsvis vann, eventuelt i blanding med et inert organisk løsningsmiddel, som tetrahydrofuran eller dioksan. Det kan også arbeides i et aprotisk organisk løsningsmiddel som f.eks. dimetylformamid, dimetylsulfoksyd eller heksametylenfosforsyretriamid. Ved anvendelse av silylerte utgangsforbindelser med formel IV arbeides det i vanfritt medium. According to another embodiment, an acid halide, preferably the chloride of an acid of formula V is reacted with the amine of formula IV. The reaction preferably takes place in the presence of an acid-binding agent, e.g. in the presence of aqueous alkali, preferably caustic soda, or also in the presence of an alkali metal carbonate, such as potassium carbonate, or in the presence of a lower alkylated amine, such as triethylamine. The solvent used is preferably water, possibly in a mixture with an inert organic solvent, such as tetrahydrofuran or dioxane. It can also be worked in an aprotic organic solvent such as e.g. dimethylformamide, dimethyl sulfoxide or hexamethylene phosphoric acid triamide. When using silylated starting compounds of formula IV, work is carried out in an alcohol-free medium.

Omsetningen av 7-aminoforbindelsen med formel IV med syren med formel V eller et reaktivt funksjonelt derivat derav kan hensiktsmessig gjennomføres ved temperaturer mellom ca. The reaction of the 7-amino compound of formula IV with the acid of formula V or a reactive functional derivative thereof can conveniently be carried out at temperatures between approx.

-40°C og romtemperatur, eksempelvis ved ca. 0-10°C. -40°C and room temperature, for example at approx. 0-10°C.

For fremstilling av utgangsforbindelsen med formel II avspaltes som ovenfor nevnt aminobeskyttelsesgruppen R i en utgangsforbindelse med formel III. Beskyttelsesgrupper som kan avspaltes ved sur hydrolyse fjernes fortrinnsvis ved hjelp av en lavere alkankarboksylsyre, som eventuelt kan være halogenert. Særlig anvender man maursyre eller trifluoreddiksyre. Temperaturen er som regel romtemperatur, selv om det også kan anvendes lett forhøyede, henholdsvis lett senkede temperaturer, f.eks. i området fra ca. 0°C - +40°C. Alkalisk avspaltbare beskyttelsesgrupper hydrolyse-res generelt med fortynnet vandig lut ved 0°C - 30°C. Kloracetyl-, bromacetyl- og jodacetyl-beskyttelsesgrupper kan avspaltes ved hjelp av tlourea i surt, nøytralt eller alkalisk medium ved ca. 0-30°C. Hydrogenolytisk avspaltnlng (f.eks. avspalting av benzyl) er her uegnet, da oksimfunk-sjonen reduseres til en aminogruppe ved hydrogenolysen. For the preparation of the starting compound of formula II, as mentioned above, the amino protecting group R in a starting compound of formula III is cleaved off. Protective groups that can be split off by acid hydrolysis are preferably removed using a lower alkane carboxylic acid, which may optionally be halogenated. In particular, formic acid or trifluoroacetic acid is used. The temperature is usually room temperature, although slightly elevated or slightly lowered temperatures can also be used, e.g. in the area from approx. 0°C - +40°C. Alkaline-cleavable protective groups are generally hydrolysed with dilute aqueous lye at 0°C - 30°C. Chloroacetyl, bromoacetyl and iodoacetyl protecting groups can be removed with the help of tlourea in an acidic, neutral or alkaline medium at approx. 0-30°C. Hydrogenolytic cleavage (e.g. cleavage of benzyl) is unsuitable here, as the oxime function is reduced to an amino group by hydrogenolysis.

Etter avspaltnlng av aminobeskyttelsesgruppen R i en utgangsforbindelse med formel III kan, hvis ønsket, en eventuelt i reaksjonsproduktet foreliggende karboksybeskyttelsesgruppe avspaltes. Når beskyttelsesgruppen utgjør en silylgruppe (silylester), kan denne gruppen spesielt lett avspaltes ved behandling av omsetningsproduktet med vann. Lavere alkanoyloksyalkyl, alkoksykarbonyloksyalkyl-, laktonyl, alkoksymetyl- og alkanoylaminometylestere spaltes fortrinnsvis enzymatisk med hjelp av en egnet esterase (ved ca. 20-40°C). Når karboksylgruppen er blitt beskyttet ved saltdannelse (f.eks. med trietylamin, kan avspaltningen av den saltdannende beskyttelsesgruppe skje ved behandling med syre. Som syre kan det herved anvendes f.eks. saltsyre, svovelsyre, fosforsyre eller sitronsyre. After cleavage of the amino protecting group R in a starting compound of formula III, a carboxy protecting group possibly present in the reaction product can, if desired, be cleaved off. When the protecting group forms a silyl group (silyl ester), this group can be cleaved particularly easily by treating the reaction product with water. Lower alkanoyloxyalkyl, alkoxycarbonyloxyalkyl, lactonyl, alkoxymethyl and alkanoylaminomethyl esters are preferably cleaved enzymatically with the aid of a suitable esterase (at approx. 20-40°C). When the carboxyl group has been protected by salt formation (e.g. with triethylamine, the splitting off of the salt-forming protecting group can take place by treatment with acid. As an acid, e.g. hydrochloric acid, sulfuric acid, phosphoric acid or citric acid can be used.

Karboksybeskyttelsesgruppen kan avspaltes på samme måte som nettopp beskrevet før avspaltningen av beskyttelsesgruppen The carboxy protecting group can be removed in the same way as just described before the removal of the protecting group

R. R.

Fremstillingen i henhold til oppfinnelsen av cefalosporinsaltene med formel I skjer på i og for seg kjent måte ved omsetning av karboksylsyren med formel II med minst to ekvivalenter av den ønskede base, hensiktmessig i et løsningsmiddel som vann i et organisk løsningsmiddel som etanol, metanol, aceton eller andre. Ved anvendelse av to ekvivalenter med base skjer saltdannelsen også på den tautomere enolformen (2,5-dihydro-6-hydroksy-2-metyl-5-okso-as-treiazin-3-yl-gruppe X), hvorved det dannes et disalt. Temperaturen er ikke viktig, den ligger vanligvis ved romtemperatur, men kan også ligge noe over eller under, omtrent i området fra 0°C - +50°C. The preparation according to the invention of the cephalosporin salts of formula I takes place in a manner known per se by reacting the carboxylic acid of formula II with at least two equivalents of the desired base, suitably in a solvent such as water in an organic solvent such as ethanol, methanol, acetone or others. When two equivalents of base are used, salt formation also takes place on the tautomeric enol form (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-treiazin-3-yl-group X), whereby a disalt is formed . The temperature is not important, it is usually at room temperature, but can also be slightly above or below, approximately in the range from 0°C - +50°C.

Dannede salter med formel I kan naturligvis på vanlig måte overføres i andre salter med formel I med andre betydninger av M (se det følgende eksempel). Formed salts of formula I can of course be transferred in the usual way into other salts of formula I with other meanings of M (see the following example).

Fremstillingen av hydratene skjer vanligvis automatisk i løpet av fremstillingen eller som en følge av de hygro-skopiske egenskaper til et opprinnelig vannfritt produkt. For målrettet fremstilling av et hydrat kan et helt eller delvis vannfritt produkt (karboksylsyre med formel II, hhv. salt med formel I) utsettes for en fuktig atmosfære, f.eks. ved ca. +10°C - +40°C. The production of the hydrates usually occurs automatically during production or as a result of the hygroscopic properties of an initially anhydrous product. For the targeted production of a hydrate, a completely or partially anhydrous product (carboxylic acid with formula II, or salt with formula I) can be exposed to a moist atmosphere, e.g. at approx. +10°C - +40°C.

De ovenfor anvendte 7-aminoforbindelser med formel IV kan fremstilles utgående fra en forbindelse med formel VIII The 7-amino compounds of formula IV used above can be prepared starting from a compound of formula VIII

i hvilken Y utgjør en avgangsgruppe med et tiol med generell formel VII in which Y forms a leaving group with a thiol of general formula VII

i hvilken X har den ovenfor oppførte betydning. in which X has the above meaning.

Som avgangsgruppe Y i en forbindelse med formel VIII kommer eksempelvis halogenene, f.eks. klor, brom eller jod, acyloksygrupper, f.eks. lavere alkanoyloksygrupper som acetoksy, lavere alkyl- eller arylsulfonyloksygrupper, som mesyloksy eller tosyloksy eller azidogruppen i betraktning. As leaving group Y in a compound of formula VIII, for example, the halogens, e.g. chlorine, bromine or iodine, acyloxy groups, e.g. lower alkanoyloxy groups such as acetoxy, lower alkyl or arylsulfonyloxy groups such as mesyloxy or tosyloxy or the azido group in question.

Omsetningen av forbindelsen med formel VIII med tiolet med formel VII kan skje på I og for seg kjent måte, f.eks. ved en temperatur på mellom ca. 40 - 80°C, hensiktsmessig ved ca. 60°C, i vann eller 1 en pufferløsning med en pH på ca. 6-7, fortrinnsvis 6,5. The reaction of the compound of formula VIII with the thiol of formula VII can take place in a manner known per se, e.g. at a temperature of between approx. 40 - 80°C, suitable at approx. 60°C, in water or a buffer solution with a pH of approx. 6-7, preferably 6.5.

Cefalosporingsaltene som fremstilles I henhold til foreliggende opppfinnelse er antibiotisk, særljg bakterisid virksomme. De er i besittelse av et rikt virkningsspek-trum mot Gram-positive og Gram-negative mikroorganismer som omfatter e-lactamasedannende stafylokokker og forskjellige 3-lactamasedannende Gram-negative bakterier, som f.eks. pseudomonas aeruginosa, haemophilus influenzae, escherichia coli, serratia marcescens, proteus- og kleb-siella-arter. The cephalosporin salts produced according to the present invention are antibiotically, particularly bactericidally active. They possess a rich spectrum of activity against Gram-positive and Gram-negative microorganisms, which include ε-lactamase-producing staphylococci and various 3-lactamase-producing Gram-negative bacteria, such as e.g. pseudomonas aeruginosa, haemophilus influenzae, escherichia coli, serratia marcescens, proteus and klebsiella species.

Cefalosporinsaltene som fremstilles i henhold til foreliggende oppfinnelse kan anvendes til behandling og profy-lakse av infeksjonssykdommer. For en voksen person kommer en dagsdose på ca. 0,lg - 2g i betraktning. Den parenterale administrering av forbindelsene som fremstilles i henhold til oppfinnelsen er særlig foretrukket. The cephalosporin salts produced according to the present invention can be used for the treatment and prophylaxis of infectious diseases. For an adult, a daily dose of approx. 0.lg - 2g in consideration. The parenteral administration of the compounds produced according to the invention is particularly preferred.

For å vise den antimikrobielle aktivitet til de nevnte pro-dukter ble den følgende representative representant testet: Produkt A: (6R,7R)-7-[2-(2-amino-4-tiazolyla9-2-(Z- metoksyimino)acetamido]-3-/[2,5-dihydro-6-hydroksy-2-metyl-5-okso-as-triazin-3-yl)-tio]-metyl/-8-okso-5-tia-l-azabicyklo-[4.2.0]okt-2-en-2-karboksylsyre-dinatriumsalt . 3,5 H20. ("trihydrat") To demonstrate the antimicrobial activity of the aforementioned products, the following representative was tested: Product A: (6R,7R)-7-[2-(2-amino-4-thiazolyl9-2-(Z- methoxyimino)acetamido]-3-/[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]-methyl/-8-oxo-5-thia- 1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid disodium salt. 3.5 H 2 O. ("trihydrate")

Aktivitet in vivo Activity in vivo

Grupper på 5 mus infiseres med en vandig suspensjon av escherichia coli intraperitonealt. Tre ganger, dvs. 1 time, 2 1/2 timer og 4 timer eter infeksjonen appliseres forsøks-substansen i fysiologis koksaltoppløsning. Antall over-levende dyr bestemmes 4. dag. Det appliseres forskjellige doseringer og ved interpolasjon bestemmmes den dose ved hvilken 50$ av forsøksdyrene overlever (CD50, mg/kg). Groups of 5 mice are infected with an aqueous suspension of Escherichia coli intraperitoneally. Three times, i.e. 1 hour, 2 1/2 hours and 4 hours after the infection, the test substance is applied in physiological saline solution. The number of surviving animals is determined on the 4th day. Different dosages are applied and by interpolation the dose at which 50% of the test animals survive is determined (CD50, mg/kg).

Produktene som fremstilless i henhold til oppfinnelsen kan anvendes som medikamenter, f.eks. i form av farmasøytiske preparater, som inneholder dem eller deres salter i blanding i et for den enterale eller parenterale administrering egnet farmasøytisk, organisk eller uorganisk inert bære-middelmateriale, som f.eks. vann, gelatin, gummi arabicum, melkesukker, stivelse, magnesiumstearat, talkum, vege-tabilske oljer, polyalkylenglykoler, vaselin osv. De farma-søytiske preparater kan foreligge i fast form, f.eks. som tabletter, dragéer, suppositorier, kapsler eller i flyten-de form, f.eks. som oppløsninger, suspensjoner eller emul-sjoner. Eventuelt er de sterilisert og /eller inneholder hjelpestoffer som konserverings-, stabiliserings-, fornet-nings- eller emulgerlngsmidler, salter for endring av det osmotiske trykk, anestetika eller puffer. De kan også inneholde andre terapeutisk verdifulle stoffer. De kommer fortrinnsvis i betraktning for parenteral administrering og for dette formål tilberedes de fortrinnsvis som lyofilisater eller tørrpulvere til fortynnelse med vanlige midler som vann eller isotoniske koksaltoppløsninger. The products produced according to the invention can be used as medicines, e.g. in the form of pharmaceutical preparations, which contain them or their salts in admixture in a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as e.g. water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragées, suppositories, capsules or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and/or contain auxiliary substances such as preservatives, stabilisers, cross-linking or emulsifying agents, salts for changing the osmotic pressure, anesthetics or puffs. They may also contain other therapeutically valuable substances. They are preferably considered for parenteral administration and for this purpose they are preferably prepared as lyophilisates or dry powders for dilution with common agents such as water or isotonic saline solutions.

Eksempel Example

Fremstilling av dinatriumsalt-"trihydratet" til (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-(Z-metoksyimino)acetamido]-3-/ Preparation of the disodium salt "trihydrate" of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-/

[(2,5-dihydro^6-hydroksy-2-metyl-5-okso-as-triazin-3-yl)tio]-metyl-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre [(2,5-dihydro^6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct -2-ene-2-carboxylic acid

6,0 g (6R,7R)-7-[2-(2-mino-4-tiazolyl)-2-(-metoksyimino) acetamido]-3-/[(2,5-dihydro-6-hydroksy-2-metyl-5-okso-as-trIazin-3-yl)tio]-metyl-8-okso-5-tia-l-azabicyclo [4.2.0] okt-2-en-2-karboksylsyre suspenderes i en blanding av 40 ml av aceton og 40 ml vann og omsettes med 20 ml av en 2-n-oppløsning av 2-etylkapronsyre-natriumsalt i eddikester. Til den derved dannede orangefarvede oppløsning tilsettes 50 ml aceton, hvorved en brun harpiks felles ut, som ad-skilles ved hjelp av filtrering. Det gule filtrat røres i 30 minutter, hvorved dinatriumsaltet krystalliserer. Blandingen tilsettes porsjonsvis 50 ml aceton og oppbevares over natt i kjøleskap. Krystallisatet sugefUtreres og vaskes etter hverandre med en aceton-vann-blanding 85:15, ren aceton og lavtkokende petroleter og tørkes over natt i vakuum ved 40°C. Man erholder titelsubstansen som beige krystaller. [a]^<0> = -144° (c = 0,5 i vann). Kjerneresonans-spekteret og mikroanalysen tilsvarer den oppførte struktur. Det dannede dinatriumsalt inneholder 3,5 mol hydratvann pr. mol substans og nevnes deretter "trihydrat". 6.0 g (6R,7R)-7-[2-(2-mino-4-thiazolyl)-2-(-methoxyimino)acetamido]-3-/[(2,5-dihydro-6-hydroxy-2 -methyl-5-oxo-as-triazin-3-yl)thio]-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid is suspended in a mixture of 40 ml of acetone and 40 ml of water and reacted with 20 ml of a 2-n solution of 2-ethylcaproic acid sodium salt in acetic ester. 50 ml of acetone is added to the resulting orange-coloured solution, whereby a brown resin precipitates, which is separated by means of filtration. The yellow filtrate is stirred for 30 minutes, whereby the disodium salt crystallizes. Add 50 ml of acetone in portions to the mixture and store overnight in a refrigerator. The crystallisate is filtered off with suction and washed successively with an acetone-water mixture 85:15, pure acetone and low-boiling petroleum ether and dried overnight in a vacuum at 40°C. The title substance is obtained as beige crystals. [a]^<0> = -144° (c = 0.5 in water). The nuclear resonance spectrum and the microanalysis correspond to the listed structure. The formed disodium salt contains 3.5 mol of hydrated water per mole of substance and is then referred to as "trihydrate".

Det som utgangsprodukt anvendte (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-(Z-metoksyimino)acetamido]-3/[(2,5-dihydro-6-hydroksy-2-metyl-5-okso-as-triazin-3-yl)-tio)metyl/-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre kan fremstilles som følger: 22,24 g 2-(2-kloracetamido-tiazol-4-yl)-2-(Z-metoksyimino)-eddiksyre suspenderes i 240 ml metylenklorid. Denne suspensjon tilsettes 13,39 ml trietylamin hvorved det dannes en lysebrun oppløsnng. Denne oppløsning avkjøles til 0-5°C og tilsettes 16,72 g fosforpentaklorid, røres 5 minutter ved 0-5°C og 20 minutter uten avkjøling. Den gule oppløsning fordampes i vakuum ved 35°C. Resten som blir tilbake etter fordampning ristes to ganger med n-heptan og sistnevnte av-dekanteres. Den harplksaktige rest behandles med 240 ml tetrahydrofuran og det uoppløste trietylamin-hydroklorid frafUtreres. Det gule filtrat inneholder syrekloridet. 22 g (7R)-7-amino-3-desacetoksy-3-[(2,5-dihydro-6-hydroksy-2-metyl-5-okso-as-triazin-3-yl)-tio]-cefalosporansyre suspenderes i en blanding av 300 ml vann og 300 ml tetrahydrofuran. Til suspensjonen tilsettes dråpevis under kraftig nitrogentilføring ved hjelp av en autotitrator 2-n natronlut, til det dannes en brunrød oppløsning med pH 8. Denne avkjøles til 0-5°C og tilsetts dråpevis i løpet av 15 minutter den ovenfor fremstilte oppløsning av syrekloridet i tetrahydrofuran. Deretter røres det 1 2 1/2 time ved 25°C. pH til acyleringsblandingen holdes under tilsetning av 2-n natronlut konstant på 8. Den praktisk talt svarte oppløsning befris på vakuum ved 40°C fra tetrahydrofuran. Så tilsettees 100 ml 2-n svolvélsyre. Den derved utfelte substans sugef Utreres, vaskes med vann og sugef Utreres kraftig. Den fuktige, brune flltrerlngsmasse løses 1 1,5 1 aceton. Den mørke oppløsning frafiltreres over "Hyflo" fra noe mørkst uoppløst materiale, tilsettes karbon og røres i 30 minutter, og filtreres igjen over "Hyflo". Det orange-røde filtrat tørkes over natriumsulfat, fordampes i vakuum og fordampes med eddikester. Derved utfelles et svart harpiks, som filtreres fra og fjernes. 2-fasefiltratet som ennå inneholder vann, destilleres azeotropt tre ganger med benzen i vakuum ved 40°C. Den derved utfelte substans sugefUtreres og tørkes i vakuum ved 40°C. Sistnevnte røres to ganger med henholdsvis 1 1 acetoon, hvorved det blir tilbake et brunt harpiks, som kastes. De samlede orangefarvede acetonekstrakter fordampes i vakuum ved 40°C til ca. 150 ml, hvorved et brunt harpiks frafUtreres og kastes. Fil-tratet tilsettes 1 1 eddikester og fordampes i vakuum ved 40°C. Den derved utfelte substans sugefUtreres, vaskes med eddikester og deretter med eter. [(6R,7R)-7-/2-[2-(2-klor-acetamido)-4-tiazolyl]-2-(Z-metoksyimino)acetamido/-3-/ The starting product used (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3/[(2,5-dihydro-6-hydroxy-2 -methyl-5-oxo-as-triazin-3-yl)-thio)methyl/-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid can be prepared as follows : 22.24 g of 2-(2-chloroacetamido-thiazol-4-yl)-2-(Z-methoxyimino)-acetic acid are suspended in 240 ml of methylene chloride. 13.39 ml of triethylamine is added to this suspension, whereby a light brown solution is formed. This solution is cooled to 0-5°C and 16.72 g of phosphorus pentachloride is added, stirred for 5 minutes at 0-5°C and 20 minutes without cooling. The yellow solution is evaporated in vacuo at 35°C. The residue that remains after evaporation is shaken twice with n-heptane and the latter is decanted off. The resinous residue is treated with 240 ml of tetrahydrofuran and the undissolved triethylamine hydrochloride is filtered off. The yellow filtrate contains the acid chloride. 22 g of (7R)-7-amino-3-desacetoxy-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]-cephalosporanic acid are suspended in a mixture of 300 ml of water and 300 ml of tetrahydrofuran. 2-n caustic soda is added dropwise to the suspension under a vigorous nitrogen supply using an autotitrator, until a brownish-red solution with pH 8 is formed. This is cooled to 0-5°C and added dropwise over the course of 15 minutes to the above-prepared solution of the acid chloride in tetrahydrofuran. It is then stirred for 1 2 1/2 hours at 25°C. The pH of the acylation mixture is kept constant at 8 during the addition of 2-n caustic soda. The practically black solution is liberated under vacuum at 40° C. from tetrahydrofuran. Then 100 ml of 2-n sulfuric acid is added. The thereby precipitated substance is sucked out, washed with water and sucked out vigorously. The moist, brown filter mass is dissolved in 1 1.5 1 acetone. The dark solution is filtered over "Hyflo" from some darkest undissolved material, carbon is added and stirred for 30 minutes, and filtered again over "Hyflo". The orange-red filtrate is dried over sodium sulfate, evaporated in vacuo and evaporated with vinegar. This precipitates a black resin, which is filtered off and removed. The 2-phase filtrate, which still contains water, is azeotropically distilled three times with benzene in vacuum at 40°C. The thereby precipitated substance is filtered off with suction and dried in a vacuum at 40°C. The latter is stirred twice with respectively 1 1 acetone, whereby a brown resin remains, which is discarded. The combined orange colored acetone extracts are evaporated in vacuum at 40°C to approx. 150 ml, whereby a brown resin is filtered off and discarded. The filtrate is added to 1 1 of acetic acid and evaporated in vacuum at 40°C. The thereby precipitated substance is filtered off with suction, washed with vinegar and then with ether. [(6R,7R)-7-/2-[2-(2-chloro-acetamido)-4-thiazolyl]-2-(Z-methoxyimino)acetamido/-3-/

[(2,5-dihydro-6-hydroksy-2-metyl-5-okso-as-trlazin-3-yl)tlo]-metyl-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre, fraksjon I: Denne fraksjon I kan deretter anvendes direkte for fremstilling av det ønskede slutt-produkt . [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-az-trlazin-3-yl)tlo]-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct -2-ene-2-carboxylic acid, fraction I: This fraction I can then be used directly for the production of the desired end product.

Eddikestermoderluten inndampes sterkt i vakuum ved 40°C, fortynnes med eter og den utfelte substans sugefUtreres [(6R,7R)-7-/2-[2-(2-kloracetamido)-4-tiazolyl]-2-(Z-metoksyimino)acetamido/-3-/[(2,5-dihydro-6-hydroksy-2-metyl-5-okso-as-triazin-3-yl-)tio]metyl-8-okso-5-tia-l-azablcyklo [4.2.0]okt-2-en-2-karboksylsyre, fraksjon II: en lyse beige, amorf syre], tynnsjiktkromatografisk noe renere enn fraksjon The acetic ester mother liquor is strongly evaporated in vacuo at 40°C, diluted with ether and the precipitated substance filtered off with suction [(6R,7R)-7-(2-[2-(2-chloroacetamido)-4-thiazolyl]-2-(Z-methoxyimino) )acetamido/-3-/[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl-)thio]methyl-8-oxo-5-thia-1- azablcyklo [4.2.0]oct-2-ene-2-carboxylic acid, fraction II: a light beige, amorphous acid], thin-layer chromatographically somewhat purer than fraction

I]. IN].

For fremstilling av dinatriumsaltet oppløses 3,5 g syre (fraksjon II). 1 en blanding av 20 ml aceton og 11 ml vann. Oppløsningen tilsettes 7 ml av en 2-n oppløsning av 2-etylkapronsyre-natrlumsalt i eddikester, hvorved dinatriumsaltet krystalliserer. Nå tilsettes porsjonsvis 25 ml aceton og blandingen oppbevares 2 timer i dypfryser. Deretter sugefUtreres krystallisatet, vaskes etter hverandre med 25 ml av en Iskald aceton-vannblanding (80:20), rent aceton og lavtkokende petroleter og tørkes over natt i høyvakuum ved 40 °C. Man erholder dinatriumsaltet til (6R,7R)-7-/2-[2-(2-kloracetamido)—4-tiazolyl]-2-(Z-metoksyimino)-acetamido/-3-/[(2,5-dihydro-6-hydroksy-2-metyl-5-okso-as-triazin-3-yl)tio]-metyl/-8-okso-5-tla-l-azabicyklo[4.2.0]-okt-2-en-2-karboksylsyre som lysegule krystaller. Ccx]<2>^0 = -142,7° (c = 1 i vann). Kjerneresonans-spekteret og mikroanalysen tilsvarer den oppførte struktur. To prepare the disodium salt, dissolve 3.5 g of acid (fraction II). 1 a mixture of 20 ml of acetone and 11 ml of water. To the solution is added 7 ml of a 2-n solution of 2-ethylcaproic acid sodium salt in acetic ester, whereby the disodium salt crystallizes. Now add 25 ml of acetone in portions and store the mixture for 2 hours in a deep freezer. The crystallisate is then filtered off with suction, washed successively with 25 ml of an ice-cold acetone-water mixture (80:20), pure acetone and low-boiling petroleum ether and dried overnight in a high vacuum at 40 °C. The disodium salt of (6R,7R)-7-/2-[2-(2-chloroacetamido)-4-thiazolyl]-2-(Z-methoxyimino)-acetamido/-3-/[(2,5-dihydro -6-hydroxy-2-methyl-5-oxo-az-triazin-3-yl)thio]-methyl/-8-oxo-5-tla-1-azabicyclo[4.2.0]-oct-2-ene- 2-carboxylic acid as pale yellow crystals. Ccx]<2>^0 = -142.7° (c = 1 in water). The nuclear resonance spectrum and the microanalysis correspond to the listed structure.

15,3 g (6R,7R)-7-/2-[2-(2-kloracetamldo)'-4-tiazolyl]-2-(Z-metoksyimino)acetamido/-3-/[(2,5-dlhydro-6-hydroksy-2-metyl-5-okso-as-triazin-3-yl)-tio]metyl/-8-okso-5-tia-l-azabi-cyklo[4.2.0]okt-2-en-2-karboksylsyre (fraksjon I, se det føgende) suspenderes sammen med 5 g tiourea i 150 ml vann. Under kraftig nitrogentilsetnlng og omrøring innstilles pH med mettet natriumhydrogenkabonatoppløsning på 6,8-7,0, hvorved det oppstår en orangefarget oppløsning. Ved hjelp av autotltrator under tilsetning av natriumhydrogenkar-bonatoppløsning holdes pH til reaksjonsoppløsningen konstant ved 6,8 i løpet av 6 timer. Deretter tilsettes ytterligere 2,5 g tiourea og oppløsningen røres videre 1 3 timer, hvorved pH holdes på 6,8 ved tilsetning av mettet natrium-hydrogenkarbonatoppløsning. Deretter oppbevares den røde oppløsning over natt 1 kjøleskap, hvorved den blir mørkere. pH til denne oppløsning innstilles ved tilsetning av 100^-ig maursyre på 2,0-2,5, hvorved substansen felles ut. Denne sugef Utreres, vaskes med 100 ml 10#-ig maursyre. Moder-luten kastes. Den brune filtreringsmasse suspenderes i 200 ml vann og pH innstilles med trietylamln, hvorved det dannes en brun oppløsning. Denne oppløsning røres i 30 minutter med 2 g aktivt kull, filtreres fra kullet, og det fremdeles brune filtrat innstilles på pH 3,5 med 100#-ig mmaursyre under kraftig omrøring. Den derved utfelte substans sugefUtreres, vaskes med 50 ml 10%-lg maursyre og kastes. Det mørkegule filtrat Innstilles på pH 2-2,5 med 100#-Ig maursyre, hvorved substansen felles ut. Denne blir sugef11-trert, vasket mmed isvann og tørket. Man erholder (6R,7R)-7-[2-(2-amino-4-tiazolyl )-2-(Z-meife^syimino )-acetamido]-3-/[(2,5-dihydro-6-hydroksy-2-metyl-5-okso-as-triazln-3-yl)tio]-metyl-8-okso-5-tia-l-azablocyklo-[4.2.0] 15.3 g (6R,7R)-7-(2-[2-(2-chloroacetamido)'-4-thiazolyl]-2-(Z-methoxyimino)acetamido/-3-/[(2,5-dlhydro -6-hydroxy-2-methyl-5-oxo-az-triazin-3-yl)-thio]methyl/-8-oxo-5-thia-1-azabi-cyclo[4.2.0]oct-2-ene -2-carboxylic acid (fraction I, see below) is suspended together with 5 g of thiourea in 150 ml of water. During vigorous nitrogen addition and stirring, the pH is adjusted with saturated sodium hydrogen carbonate solution to 6.8-7.0, whereby an orange colored solution is produced. By means of an autofilter while adding sodium hydrogen carbonate solution, the pH of the reaction solution is kept constant at 6.8 during 6 hours. A further 2.5 g of thiourea is then added and the solution is stirred for a further 13 hours, whereby the pH is kept at 6.8 by the addition of saturated sodium bicarbonate solution. The red solution is then stored overnight in a refrigerator, whereby it darkens. The pH of this solution is adjusted by adding 100 µg of formic acid to 2.0-2.5, whereby the substance precipitates out. This suction is drained, washed with 100 ml of 10# formic acid. The mother liquor is discarded. The brown filter mass is suspended in 200 ml of water and the pH is adjusted with triethylamine, whereby a brown solution is formed. This solution is stirred for 30 minutes with 2 g of activated charcoal, filtered from the charcoal, and the still brown filtrate is adjusted to pH 3.5 with 100 µg mmauric acid with vigorous stirring. The thus precipitated substance is filtered off with suction, washed with 50 ml of 10% formic acid and discarded. The dark yellow filtrate is adjusted to pH 2-2.5 with 100#-Ig of formic acid, whereby the substance precipitates out. This is suctioned, washed with ice water and dried. One obtains (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-meifesymino)-acetamido]-3-/[(2,5-dihydro-6-hydroxy -2-methyl-5-oxo-as-triazln-3-yl)thio]-methyl-8-oxo-5-thia-1-azablocyclo[4.2.0]

okt-2-en-2-karboksylsyre, som omsettes videre uten ytterligere rensing. oct-2-ene-2-carboxylic acid, which is reacted further without further purification.

Claims (2)

1. Analogifremgangsmåte for fremstilling av et terapeutisk aktivt cephalosporinsalt med den generelle formel I hvori M betyr kationet fra en farmasøytisk akseptabel base i hydratisert form, samt i syn-formen, karakterisert ved at man omsetter en forbindelse med den generelle formel II hvori X betyr gruppen 1,2,5,6-tetrahydro-2-metyl-5,6-diokso-as-triazin-3-yl, henholdsvis gruppen 2,5-dihydro-6-hydroksy-2-metyl-5-okso-as-triazin-3- yl, i den synisomere form, med minst to ekvivalenter av en base, og isolerer det dannede salt i nærvær av vann eller av atmosfærisk fuktighet som et salt-hydrat.1. Analogous process for the preparation of a therapeutically active cephalosporin salt of the general formula I wherein M means the cation from a pharmaceutically acceptable base in hydrated form, as well as in the syn form, characterized by reacting a compound of the general formula II in which X means the group 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl, respectively the group 2,5-dihydro-6-hydroxy-2-methyl-5- oxo-as-triazin-3-yl, in the synisomeric form, with at least two equivalents of a base, and isolates the formed salt in the presence of water or of atmospheric moisture as a salt hydrate. 2. Fremgangsmåte i henhold til krav 1 til fremstilling av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-(Z-metoksyimino^acet-amido]- 3- J_[(2,5-dihydro-6-hydroksy-2-metyl-5-okso-as-triazin-3-yl)tio]-metyl/-8-okso-5-tia-l-azabicyklo[4.2.0]-okt-2-en-2-karboksylsyre-dinatriumsalt-trihydrat, karakterisert ved at man anvender en base som avgir natriumioner og isolerer det dannede saltet som et omtrentlig trihydrat.2. Process according to claim 1 for the preparation of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino^acetamido]-3- J_[(2 ,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]-methyl/-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct- 2-ene-2-carboxylic acid disodium salt trihydrate, characterized in that a base is used which emits sodium ions and the salt formed is isolated as an approximate trihydrate.
NO791776A 1978-05-30 1979-05-29 ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTIC ACTIVE CEPHALOSPORINALS. NO159797C (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
NO823987A NO158346C (en) 1978-05-30 1982-11-26 Cephalosporin.
NO844103A NO161221C (en) 1978-05-30 1984-10-12 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE CEPHALOSPORINE SALTS.
NO865360A NO160301C (en) 1978-05-30 1986-12-30 ANALOGY PROCEDURE FOR THE PREPARATION OF A THERAPEUTIC ACTIVE CEPHALOSPORIN SALT.

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CH588278A CH641468A5 (en) 1978-05-30 1978-05-30 CEPHEM DERIVATIVES.
CH224879 1979-03-08

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FI67385C (en) * 1979-11-21 1985-03-11 Hoffmann La Roche PROCEDURE FOR FRAMSTATION OF AV (6R 7R) -7- (2- (2-AMINO-4-THIAZOLYL) -2- (Z-METHOXYIMINO) ACETAMIDO) -3-CEFEM-4-CARBOXYL SYRATER DERIVATIVES
US4349672A (en) * 1979-11-29 1982-09-14 Hoffmann-La Roche Inc. Cephalosporin derivatives
CA1154009A (en) * 1980-03-25 1983-09-20 Roland Reiner Cephalosporin derivatives
CA1177823A (en) * 1980-03-25 1984-11-13 Andre Furlenmeier Cephalosporin derivatives
GR75706B (en) * 1980-06-30 1984-08-02 Sanofi Sa
US4308267A (en) 1980-07-03 1981-12-29 Smithkline Corporation 7-[2-Alkoxyimino-2-(amino-thiazole)acetamido]-3-[1-(sulfaminoalkly)tetrazolthiomethyl]cephalosporins
DK379581A (en) * 1980-10-06 1982-04-07 Hoffmann La Roche PROCEDURE FOR THE PREPARATION OF ACYL DERIVATIVES
FR2494278A1 (en) * 1980-11-20 1982-05-21 Rhone Poulenc Ind NEW DERIVATIVES OF CEPHALOSPORIN, THEIR PREPARATIONS AND THE MEDICINAL PRODUCTS CONTAINING THEM
EP0058250A3 (en) * 1981-02-17 1983-08-17 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Cephalosporin derivatives, their preparation and pharmaceutical compositions containing them
EP0185220A3 (en) * 1984-12-19 1987-09-02 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Intermediates for the preparation of cephalosporins
EP0238060B1 (en) 1986-03-19 1992-01-08 Banyu Pharmaceutical Co., Ltd. Cephalosporin derivatives, processes for their preparation and antibacterial agents
RU2021274C1 (en) 1991-05-17 1994-10-15 Польска Акадэмия Наук Институт Хэмии Органичнэй Process for preparing aminothiazolyl cephalosporin derivatives
KR950014571B1 (en) * 1991-11-18 1995-12-08 제일제당주식회사 Process for the preparation of cephem derivatives
AT398764B (en) * 1992-01-28 1995-01-25 Lek Tovarna Farmacevtskih METHOD FOR PRODUCING CEFTRIAXONDINATRIUM SALZHEMIHEPTAHYDRATE
AT399877B (en) * 1992-02-20 1995-08-25 Biochemie Gmbh NEW METHOD FOR PRODUCING CEFTRIAXONE
KR100197788B1 (en) * 1995-06-30 1999-06-15 김충환 Processes for manufacturing cephem derivatives
DE102011117421A1 (en) 2011-11-02 2013-05-02 Hans-Peter Gabel Pharmaceutical composition useful for treating Lyme disease, comprises mixture of active substances including ceftriaxone and cefotaxime
RU2504548C1 (en) * 2012-09-28 2014-01-20 Федеральное Государственное Автономное Образовательное Учреждение Высшего Профессионального Образования "Сибирский Федеральный Университет" (Сфу) DERIVATIVE OF β-LACTAM CEFTRIAXONE ANTIBIOTIC

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CH609989A5 (en) * 1974-06-21 1979-03-30 Hoffmann La Roche Process for the preparation of acyl derivatives
CA1100129A (en) * 1974-08-02 1981-04-28 William H.W. Lunn Cephalosporin compounds
FR2345153A1 (en) * 1976-03-25 1977-10-21 Roussel Uclaf NEW ALCOYLOXIMES DERIVED FROM 7-AMINO THIAZOLYL ACETAMIDO CEPHALOSPORANIC ACID, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICINAL PRODUCTS
DK162391C (en) * 1976-04-12 1992-03-09 Fujisawa Pharmaceutical Co ANALOGY PROCEDURE FOR PREPARING SYN-ISOMERS OF 3,7-DISUBSTITUTED 3-CEPHEM-4-CARBOXYLIC ACID COMPOUNDS
GR63088B (en) 1976-04-14 1979-08-09 Takeda Chemical Industries Ltd Preparation process of novel cephalosporins
JPS5329936A (en) * 1976-08-31 1978-03-20 Takeda Chem Ind Ltd Antibiotic composition
GB1599232A (en) * 1977-06-03 1981-09-30 Hoffmann La Roche 7-(2-oximinoacetamido)-cephalosporin derivatives
US4200745A (en) * 1977-12-20 1980-04-29 Eli Lilly And Company 7[2-(2-Aminothiazol-4-yl)-2-alkoxyimino]acetamido 3[4-alkyl-5-oxo-6-hydroxy-3,4 dihydro 1,2,4-triazin 3-yl]thio methyl cephalosporins

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FI65434C (en) 1984-05-10
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SE437522B (en) 1985-03-04
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GB2022090B (en) 1982-12-15
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ES488687A0 (en) 1980-12-16
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NO791776L (en) 1979-12-03
EP0045525A3 (en) 1982-02-17
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CS219254B2 (en) 1983-03-25
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