NO812942L

NO812942L - CEPHALOSPORINDERIVATER.

Info

Publication number: NO812942L
Application number: NO812942A
Authority: NO
Inventors: Marc Montavon; Roland Reiner
Original assignee: Hoffmann La Roche
Priority date: 1981-07-17
Filing date: 1981-08-28
Publication date: 1983-01-18
Also published as: OA06901A; IN155426B; ES505718A0; PL233145A1; FI812838L; DK379681A; CS701481A2; MC1420A1; PL131752B1; GB2101581A; EP0070331A3; BR8106093A; AT375373B; PT73669B; IL63711A0; ZW22181A1; RO82723B; ATA371781A; CU35528A; CA1169853A

Description

Foreliggende oppfinnelse vedrører nye cephalosporinderivater og også lett hydrolyserbare estere av forbindelser med den generelle formel The present invention relates to new cephalosporin derivatives and also easily hydrolyzable esters of compounds with the general formula

hvor X er en av gruppene where X is one of the groups

hvori R<1>er laverealkyl, wherein R<1> is lower alkyl,

såvel som syreaddisjonssalter av disse estere og hydrater av disse estere henholdsvis syreaddisjonssalter. as well as acid addition salts of these esters and hydrates of these esters respectively acid addition salts.

Den lavere alkylgruppe R''"i gruppen (a) er fortrinnsvisThe lower alkyl group R"" in group (a) is preferred

en rettkjedet eller forgrenet alkylgruppe med 1-7 karbon-atomer, som etyl, n-propyl, isopropyl, n-butyl, isobutyl, sek.-butyl, t-butyl, n-pentyl eller spesielt metyl. a straight-chain or branched alkyl group with 1-7 carbon atoms, such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl or especially methyl.

Som lett hydrolyserbare estere av forbindelsene med formelAs easily hydrolyzable esters of the compounds of formula

I er å forstå forbindelser med formel I, hvori minst en I is to understand compounds of formula I, in which at least one

karboksygruppe foreligger i form av en lett hydrolyserbar estergruppe. Eksempler på slike estere er de lavere alka-, noyloksyalkylestere, eksempelvis acetoksymetyl-, pivaloyloksymetyl-, 1-acetoksyetyl- og 1-pivaloyloksyetylester, de lavere alkoksykarbonyloksyalkylestere, f.eks. metoksykar-nobyloksymetyl-, 1-etoksykarbonyloksyetyl- og 1-isopropoksy-karbonyloksyetylester; laktonylestrene, f.eks.ftalidy1- og tioftalidylester; de lavere alkoksymetylestere, f.eks. met-oksymetylesteren, og de lavere alkanoylaminometylestere, f. eks. acetamidometylesteren. Også andre estere, f.eks. ben- carboxy group exists in the form of an easily hydrolyzable ester group. Examples of such esters are the lower alka-, noyloxyalkyl esters, for example acetoxymethyl-, pivaloyloxymethyl-, 1-acetoxyethyl- and 1-pivaloyloxyethyl ester, the lower alkoxycarbonyloxyalkyl esters, e.g. methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl esters; the lactonyl esters, eg phthalidyl and thiophthalidyl esters; the lower alkoxymethyl esters, e.g. the methoxymethyl ester, and the lower alkanoylaminomethyl esters, e.g. the acetamidomethyl ester. Also other esters, e.g. leg-

I IN

zyl- og cyanmetylestrene kan være brukbare. Estrene kan i være monoestere eller også diestere. Den andre esterdannel-'1 se kan forekomme i forbindelse med karboksyre.sten av 3-karb-I Ioksy-l-metyl-lH-1,2,4-triazol-5-ylgruppen X (gruppe (b)) :. the zyl and cyanomethyl esters may be useful. The esters can be monoesters or diesters. The second ester formation can occur in connection with the carboxylic acid stone of 3-carb-1 Ioxy-1-methyl-1H-1,2,4-triazol-5-yl group X (group (b)):

i in

;De lett hydrolyserbare estere av forbindelsene med formel;The readily hydrolyzable esters of the compounds of formula

I danner addisjonssalter med organiske eller uorganiske syrer. Eksempler på slike salter er hydrohalogenider, eksempelvis hydroklorider, hydrobromider, hydrojodider>såvel I forms addition salts with organic or inorganic acids. Examples of such salts are hydrohalides, for example hydrochlorides, hydrobromides, hydroiodides>as well

som andre mineralsyresalter, som sulfater, nitrater, fosfa-ter og lignende, alkyl- og monoaryl-sulfonater, som etan-sulfonater, toluensulfonater, benzensulfonater og lignende, as other mineral acid salts, such as sulphates, nitrates, phosphates and the like, alkyl and monoaryl sulphonates, such as ethane sulphonates, toluene sulphonates, benzene sulphonates and the like,

og også andre organiske syresalter, som acetater, tartra-and also other organic acid salts, such as acetates, tartra-

<;>iter, maleater, citrater, benzoater, salicylater, askorbater og lignende. <;>iters, maleates, citrates, benzoates, salicylates, ascorbates and the like.

De lett hydrolyserbare estere av forbindelsene med formel I såvel som deres syreaddisjonssalter kan være hydratisert. Hydratiseringen kan skje i løpet av frernstillingsfremgangs-måten eller litt etter litt som følge av et nesten vann-'fritt produkts hygroskopiske egenskaper. The readily hydrolyzable esters of the compounds of formula I as well as their acid addition salts may be hydrated. The hydration can occur during the curing process or little by little as a result of the hygroscopic properties of an almost water-free product.

Produktene ifølge oppfinnelsen kan foreligge i den syn-iso-The products according to the invention can be present in the syn-iso-

mere form more form

eller i den anti-isomere form or in the anti-isomeric form

henh. som blandinger av begge diss former. Foretrukket, er den syn-isomere form henh. blandinger, i hvilke den syn-isomere form er overveiende. henh. as mixtures of both these forms. Preferred is the syn-isomeric form acc. mixtures, in which the syn-isomeric form predominates.

I IN

i Særlig foretrukne produkter er cephalosporinestrene med i ;den generelle formel In particularly preferred products are the cephalosporin esters included in the general formula

■2 ■2

hvor R er pivaloyloksymetyl- eller acetoksymetyl-gruppen, where R is the pivaloyloxymethyl or acetoxymethyl group,

såvel som syreaddisjonssalter av disse estere og hydrater av disse estere henh. syreaddisjonssalter. as well as acid addition salts of these esters and hydrates of these esters acc. acid addition salts.

Av disse forbindelser erOf these compounds are

- metylen(6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[(Z)-metoksy-imino] -acetamido] -3- [ [ [2-metyl-5- [ [ (pivaloyloksy). me tok sy ] - karbonyl] - 211-1, 2 , 4-triazol-3-yl] tio] -mety 1 ] -8-okso-5-tia-1-azabicyklo[4,2,0]okt-2-en-2-karboksylat-pivalat - methylene(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxy-imino]-acetamido] -3- [ [ [2-methyl-5- [ [ (pivaloyloxy). me tok sy ] - carbonyl] - 211-1, 2 , 4-triazol-3-yl] thio] -methyl 1 ] -8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2 -ene-2-carboxylate pivalate

såvel som dets syreaddisjonssalter og de tilsvarende hydrater spesielt foretrukne. as well as its acid addition salts and the corresponding hydrates particularly preferred.

Forannevnte cephalosporinderivater kan fremstilles ifølge foreliggende oppfinnelse ved at man unddrkaster en karboksylsyre med formel I eller et salt av denne forbindelse en tilsvarende forestring og hvis ønsket overfører det erholdte produkt i et syreaddisjonssalt eller hydrat henh. et hydrat av dette syreaddisjonssalt. The aforementioned cephalosporin derivatives can be prepared according to the present invention by subjecting a carboxylic acid of formula I or a salt of this compound to a corresponding esterification and, if desired, transferring the obtained product into an acid addition salt or hydrate according to a hydrate of this acid addition salt.

Den i forannevnte fremgangsmåte anvendte karboksylsyre med formel I kan fremstilles som følger ved å gå ut fra 7-aminocephalosporansyre: 7-aminocephalosporansyren omsettes i vandig løsning med et tiol med den generelle formel The carboxylic acid of formula I used in the aforementioned method can be prepared as follows starting from 7-aminocephalosporanic acid: 7-aminocephalosporanic acid is reacted in aqueous solution with a thiol of the general formula

hvor X har den foran-.angitte betydning, where X has the above meaning,

'f.eks. ved en temperatur mellom ca. 40 og 80°C, hensikts-I :messig ved ca. 60°C„ Løsningen pufres fortrinnsvis ved en 1pH på ca. 6-7, fortrinnsvis 6,5. 'e.g. at a temperature between approx. 40 and 80°C, appropriate at approx. 60°C„ The solution is preferably buffered at a 1pH of approx. 6-7, preferably 6.5.

i Den slik erholdte forbindelse med den generelle formel i The connection thus obtained with the general formula

hvor X har foran angitte betydning, where X has the above meaning,

omsettes deretter med en karboksylsyre med den generelle is then reacted with a carboxylic acid with the general

hvori R er en avspaltbar gruppe, wherein R is a leaving group,

eller med et reaksjonsdyktig funksjonelt derivat av denne karboksylsyre til en forbindelse med den generelle formel or with a reactive functional derivative of this carboxylic acid to a compound of the general formula

hvori R har foran angitte betydning. in which R has the above meaning.

Eventuelle R-beskyttelsesgrupper er eksempelvis syrehydro-lytisk avspaltbare beskyttelsesgrupper, som f.eks. t-but-oksykarbonyl eller trityl, eller også basisk-hydrolytisk Possible R-protecting groups are, for example, acid-hydrolytically cleavable protective groups, which e.g. t-but-oxycarbonyl or trityl, or also basic-hydrolytic

avspaltbare beskyttelsesgrupper, som f.eks. trifluoracetyl. ! i j Foretrukne R-beskyttelsesgrupper er klor-, brom- og jodacetyl, spesielt kloracetyl. Sistnevnte beskyttelsesgrup-; per kan avspaltes ved behandling med tiourea. cleavable protecting groups, such as trifluoroacetyl. ! i j Preferred R protecting groups are chloro-, bromo- and iodoacetyl, especially chloroacetyl. The latter protection group-; per can be cleaved by treatment with thiourea.

Som reaksjonsdyktige, funksjonelle derivater av karboksyl-, i As reactive, functional derivatives of carboxyl-, i

:syrer med formel IV kommer f.eks. i betraktning halogeni-:acids with formula IV come e.g. considering halogeni-

I i<!>I der, dvs. klorider, bromider og fluorider; azider; anhydrider, spesielt blandete anhydrider med sterkere syrer; reaksjonsdyktige estere, f.eks. N-hydroksysuccinimidester, I i<!>I there, i.e. chlorides, bromides and fluorides; azides; anhydrides, especially mixed anhydrides with stronger acids; reactive esters, e.g. N-hydroxysuccinimide ester,

og amider, f.eks. imidazolider.and amides, e.g. imidazolides.

Omsetningen av 7-aminoforbindelsen med formel III med kår-boksylsyren med formelen IV eller et reaksjonsdyktig funk- The reaction of the 7-amino compound of formula III with the carboxyl acid of formula IV or a reactive functional

; sjonelt derivat derav kan gjennomføres på i og for seg kjent måte. Således kan man f.eks. omsette et syrehaloge-nid, fortrinnsvis kloridet av en karboksylsyre med formel IV med aminet med formel IIIOmsetningen skjer fortrinnsvis i nærvær av et syrebindende middel, f.eks. i nærvær av vandig alkali, fortrinnsvis natronlut, eller også i nærvær av et alkalimetallkarbonat, som kaliumkarbonat, eller i nærvær av et lavere-alkylert amin, som trietylamin. ; technical derivative thereof can be carried out in a manner known per se. Thus, one can e.g. react an acid halide, preferably the chloride of a carboxylic acid of formula IV with the amine of formula III. 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.

Som løsningsmiddel•anvendes fortrinnsvis vann, eventuelt i blanding med et inert, organisk løsningsmiddel, som tetra-hydrofuran eller dioksan. Det kan også arbeides i et apro-tisk organisk løsningsmiddel, som f.eks. dimetylformamid, dimetylsulfoksyd eller heksametylfosforsyretriamid. Omsetningen kan hensiktsmessig skje ved temperaturer mellom ca. -40°C og romtemperatur, eksempelvis ved ca. 0-10°C. Water is preferably used as solvent, possibly in 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, dimethylsulfoxide or hexamethylphosphoric acid triamide. The conversion can conveniently take place at temperatures between approx. -40°C and room temperature, for example at approx. 0-10°C.

Deretter spaltes i den erholdte forbindelse med formel V aminobeskyttelsesgruppen R av, hvorved erholdes den ønskete utgangskarboksylsyre med formel I. Ved sur hydrolyse avspaltbare beskyttelsesgrupper kan fjernes fortrinnsvis ved hjelp av en lavere alkankarboksylsyre, som eventuelt kan halogeneres. Spesielt anvender man maursyre eller trifluoreddiksyre. Temperaturen er som regel romtemperatur, Then, in the obtained compound of formula V, the amino protecting group R is cleaved off, whereby the desired starting carboxylic acid of formula I is obtained. Protective groups that can be cleavable by acid hydrolysis can preferably be removed with the help of a lower alkane carboxylic acid, which can optionally be halogenated. In particular, formic acid or trifluoroacetic acid is used. The temperature is usually room temperature,

skjønt også svakt høyere henh. svakt lavere temperaturer kan anvendes, f.eks. i området 0° til + 40°C. Alkalisk although also slightly higher henh. slightly lower temperatures can be used, e.g. in the range 0° to + 40°C. Alkaline

avspaltbare beskyttelsesgrupper hydrolyseres vanligvis med fortynnet vandig lut ved 0°C til 30°C. Kloracetyl-, bromacetyl- og jodacetyl-beskyttelsesgruppene kan avspaltes ved hjelp av tiourea i surt, nøytralt eller alkalisk cleavable protecting groups are usually hydrolyzed with dilute aqueous lye at 0°C to 30°C. The chloroacetyl, bromoacetyl and iodoacetyl protecting groups can be removed using thiourea in acid, neutral or alkaline

miljø ved ca. 0-30°C. Hydrogenolytisk avspaltning (f.eks. avspaltning av benzyl) er ikke egnet her, da aminogruppens oksimfunksjon ville reduseres ved hydrogenolysen. environment at approx. 0-30°C. Hydrogenolytic cleavage (e.g. cleavage of benzyl) is not suitable here, as the oxime function of the amino group would be reduced by the hydrogenolysis.

Den erholdte karboksylsyre med formel I kan deretter over-føres i et salt, f.eks. i et syreaddisjonssalt som foran beskrevet, eller også i salter med baser, f.eks. alkali-metallsalter, som natrium- og kaliumsaltet, ammoniumsal-tet, jordalkalimetallsalter, som kalsiumsaltet, salter The obtained carboxylic acid of formula I can then be transferred into a salt, e.g. in an acid addition salt as described above, or also in salts with bases, e.g. alkali metal salts, such as the sodium and potassium salts, the ammonium salt, alkaline earth metal salts, such as the calcium salt, salts

med organiske baser, som salter med aminer, f.eks. salter med N-etyl-piperidin, prokain, dibenzylamin,. N,N'-diben-zyletylendiamin, alkylaminer eller dialkylaminer, såvel with organic bases, such as salts with amines, e.g. salts with N-ethyl-piperidine, procaine, dibenzylamine,. N,N'-dibenzylethylenediamine, alkylamines or dialkylamines, as well

som salter med aminosyrer, som f. eks. salter med arginin - i. eller lysin. Saltene kan være monosalter eller også di-salter. Saltene fremstilles på i og for seg kjent måte, f.eks. ved omsetning av karboksylsyren med formel I med en as salts with amino acids, such as salts with arginine - i. or lysine. The salts can be mono-salts or di-salts. The salts are prepared in a manner known per se, e.g. by reacting the carboxylic acid of formula I with a

ekvivalent mengde av den ønskete syre henh. base, hensiktsmessig i et løsningsmiddel, som vann eller i et organisk løsningsmiddel, som etanol, metanol, aceton og flere andre. Ved anvendelse av en andre ekvivalent av base skjer saltdannelse også ved karboksylfunksjonen av en eventuelt tilstedeværende gruppe (b), hvorved det oppstår et disalt. Temperaturen for saltdannelsen er ikke kritisk. Den ligger generelt ved romtemperatur, men kan også lett være over eller under denne, ca. i området 0°C equivalent amount of the desired acid acc. base, suitably in a solvent, such as water or in an organic solvent, such as ethanol, methanol, acetone and several others. When a second equivalent of base is used, salt formation also occurs at the carboxyl function of a possibly present group (b), whereby a disalt is formed. The temperature for salt formation is not critical. It is generally at room temperature, but can also easily be above or below this, approx. in the 0°C range

til +50°C.to +50°C.

Tiolene med formel II står i tautomer likevekt med de tilsvarende tioner med de etterfølgende formler The thiols of formula II are in tautomeric equilibrium with the corresponding thiones of the following formulas

' hvori R har foran angitte betydning, ' in which R has the above meaning,

;henh.;

Fremstillingen av disse forbindelser beskrives i de etter-følgende eksempler A og B. For fremstillingen av i 6-stil-ling foretrete tioler (tioner) tilsvarende gruppen (a) inn-føres vanligvis R^-gruppen, idet man omsetter et S-beskyt-tet tiol (f.eks. ved benzhydryl) med halogenidet som inneholder R^"-gruppen, fortrinnsvis jodidet, i et inert organisk løsningsmiddel i nærvær av et syrebindende middel, f. eks. kaliumkarbonat, fortrinnsvis ved ca. 10-50°C, og be-skyttelsesgruppen spaltes av (benzhydryl kan avspaltes med anisol og trifluoreddiksyre ved romtemperatur.) i- For fremstillingen ifølge oppfinnelsen av de lett hydrolyserbare estere av karboksylsyrene med formel I omsettes karboksylsyren fortrinnsvis med det tilsvarende halogenid som inneholder estergruppen, fortrinnsvis med jodidet. Reaksjonen kan fremskyndes ved hjelp av en base, f.eks. et alkalimetalllhydroksyd eller -karbonat, eller ét organisk amin, som trietylamin. Ved tilstedeværelsen av gruppen (b) forestres deres karboksyfunksjon likeledes, hvorved det erholdes en lett hydrolyserbar diester. Fortrinnsvis anvender man ved dette et overskudd av det tilsvarende halogenid. Forestringsreaksjonen gjennomføres fortrinnsvis i et inert, organisk løsningsmiddel, eventuelt i blanding med vann, som dimetylacetamid, heksametylfosforsyretriamid, dimetylsulfoksyd eller fortrinnsvis dimetylformamid. Temperaturen ligger fortrinnsvis i området ca. 0-40°C. The preparation of these compounds is described in the following examples A and B. For the preparation of 6-position etherified thiols (tions) corresponding to group (a), the R₂ group is usually introduced, by reacting an S-protect -tet thiol (e.g. by benzhydryl) with the halide containing the R^" group, preferably the iodide, in an inert organic solvent in the presence of an acid-binding agent, e.g. potassium carbonate, preferably at about 10-50° C, and the protecting group is cleaved off (benzhydryl can be cleaved off with anisole and trifluoroacetic acid at room temperature.) i- For the production according to the invention of the easily hydrolyzable esters of the carboxylic acids of formula I, react the carboxylic acid preferably with the corresponding halide containing the ester group, preferably with the iodide. The reaction can be accelerated using a base, e.g. an alkali metal hydroxide or carbonate, or an organic amine, such as triethylamine. In the presence of the group (b), their carboxy function is also esterified, whereby an easily hydrolysable diester is obtained. An excess of the corresponding halide is preferably used here. The esterification reaction is preferably carried out in an inert, organic solvent, possibly in a mixture with water, such as dimethylacetamide, hexamethylphosphoric acid triamide, dimethylsulfoxide or preferably dimethylformamide. The temperature is preferably in the range of approx. 0-40°C.

Fremstillingen av syreaddisjonssaltene og hydratene av forbindelsene med formel I henh. hydratene av disse syreaddi- The preparation of the acid addition salts and hydrates of the compounds of formula I according to the hydrates of these acid addi-

i sjonssalter kan skje på i og for seg kjent måte, syreaddi-in sion salts can occur in a manner known per se, acid addi-

I IN

sjonssaltene, f.eks. ved omsetning av karboksylsyren med : 'formel I med en ekvivalent mengde av den ønskete syre, hen-, .siktsmessig i et løsningsmiddel, som vann eller i et orga-. nisk løsningsmiddel, som etanol, metanol, aceton og flere.andre. Temperaturen for saltdannelsen er ikke kritisk. Den gigger vanligvis ved romtemperatur, men kan også lett være lover eller under denne, f.eks. i området 0°C til +50°C. the sion salts, e.g. by reacting the carboxylic acid with : 'formula I with an equivalent amount of the desired acid, suitably in a solvent, such as water or in an organic. nic solvent, such as ethanol, methanol, acetone and several others. The temperature for salt formation is not critical. It usually ferments at room temperature, but can also easily be cooler or below this, e.g. in the range 0°C to +50°C.

ii ii

Fremstillingen av hydrater skjer for det meste automatisk The production of hydrates is mostly automatic

i løpet av fremstillingsfrejngangsmåten eller som følge av et nesten vannfritt produkts hygroskopiske egenskaper. For during the manufacturing process or as a result of the hygroscopic properties of an almost anhydrous product. For

tilsiktet fremstilling av et hydrat kan et helt eller delvis vannfritt produkt (karboksylsyre med formel I henh. ester, eter eller salt derav) utsettes for en fuktig atmos-fære, f.eks. ved ca. +10°C til +40°C. intentional production of a hydrate, a completely or partially anhydrous product (carboxylic acid with formula I according to ester, ether or salt thereof) can be exposed to a moist atmosphere, e.g. at approx. +10°C to +40°C.

En mulig erholdt syn/anti-blanding kan oppdeles i de tilsvarende syn- og anti-former på vanlig måte, eksempelvis ved omkrystallisasjon eller ved kromatografiske metoder A possible syn/anti mixture obtained can be divided into the corresponding syn and anti forms in the usual way, for example by recrystallization or by chromatographic methods

under anvendelse av et egnet løsningsmiddel henh. løsnings-middelblanding. Fortrinnsvis får man imidlertid esteren i-følgé oppfinnelsen i syn-isomer-formen, idet man innfører using a suitable solvent acc. solvent mixture. Preferably, however, the ester according to the invention is obtained in the syn-isomer form, by introducing

en utgangsforbindelse .med formel IV i syn-form.a starting compound of formula IV in syn form.

Estrene ifølge oppfinnelsen såvel som de tilsvarende syre-addis jonssalter henh. hydratene av disse produkter er anti-^biotisk, spesielt bakterizid virksomme. De er i besiddelse av et bredt virkningsspektrum overfor gram-positive bak-terier, f.eks. streptokokker, og overfor gram-negative bak^.terier, som f.eks. Neisseria meningitidis, såvel som overfor forskjellige 3-laktamase-dannende gram-negative aktive-. ringsmiddel, som Escherichia coli og Serratia marcescens. The esters according to the invention as well as the corresponding acid addition salts acc. the hydrates of these products are anti-biotic, particularly bactericidal. They have a broad spectrum of action against Gram-positive bacteria, e.g. streptococci, and against gram-negative bacteria, such as e.g. Neisseria meningitidis, as well as against various 3-lactamase-forming Gram-negative active-. agent, such as Escherichia coli and Serratia marcescens.

Estrene ifølge forbindelsene med formel I ifølge oppfinnelsen såvel som de tilsvarende syreaddisjonssalter henh..hydratene for disse produkter kan anvendes for behandling og The esters according to the compounds of formula I according to the invention as well as the corresponding acid addition salts or the hydrates for these products can be used for treatment and

profylakse av infeksjonssykdommer. For voksne kommer en . daglig dose på ca. 0,1 g til ca. 4 g, spesielt ca. 0,25 g til ca. 2 g, i betraktning. Enteral. eller parenteral;;ad- prophylaxis of infectious diseases. For adults comes a . daily dose of approx. 0.1 g to approx. 4 g, especially approx. 0.25 g to approx. 2 g, in consideration. Enteral. or parenteral;;ad-

, ministråsjon er mulig. En spesiell fordel ligger"i anvend-, ministration is possible. A special advantage lies in the use of

<1>barheten av produktene ifølge oppfinnelsen for den enterale, jf. eks', den orale administrasjon. <1>ability of the products according to the invention for enteral, cf. for example, oral administration.

i i ■ i i ■

' '

i Den orale antimikrobielle virksomhet for produktene ifølge i i The oral antimicrobial activity for the products according to i

oppfinnelsen kan påvises ved in-vivo-forsøk på mus. I det , etterfølgende betyr den kurative dose (CD5Q, mg/kg) den dose ' ved hvilken 50% av de testete mus overlever. the invention can be demonstrated by in-vivo experiments on mice. In the following, the curative dose (CD5Q, mg/kg) means the dose at which 50% of the tested mice survive.

Prøveforbindelser:Test compounds:

Produkt A: Metylen (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2- [(Z)-metoksyimino]-acetamido]-3-[[[2-mety1-5-[t(pivaloyloksy)metoksy]karbonyl]-2H-1,2,4-triazol-3-yl]tio]metyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylat-pivalat Product A: Methylene (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2- [(Z)-methoxyimino]-acetamido]-3-[[[2-methyl-5-[t(pivaloyloxy)methoxy]carbonyl]-2H-1,2,4-triazol-3-yl]thio]methyl] -8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate pivalate

- Cephalexin; (tidligere kjent, anerkjent oralt virksomt cephalosporin) - Cephalexin; (formerly known, recognized orally active cephalosporin)

Resultat (CD5Q, mg/kg)Result (CD5Q, mg/kg)

Produkt A er betydelig mere virksomt enn Cephalexin både etter peroral som etter subkutan administrering. Product A is significantly more effective than Cephalexin both after oral and subcutaneous administration.

Den etter oral administrering erholdte b£>dspeilsverdi frem-kommer ved.følgende sammenligning med rotter.- The blood sample value obtained after oral administration is shown by the following comparison with rats.

Produkt A er minst likeså lite giftig som Cephalexin (LDj-q p.o. på mus etter 2 4 timer: >4000 mg/kg for produkt A, ' 1600-4500 mg/kg for Cephalexin). i Product A is at least as little toxic as Cephalexin (LDj-q p.o. on mice after 2 4 hours: >4000 mg/kg for product A, ' 1600-4500 mg/kg for Cephalexin). in

: ' ■ I: ' ■ I

i Produktene ifølge oppfinnelsen kan finne anvendelse som legemidler, f.eks. i form av farmasøytiske preparater,■ som inneholder dem eller deres salter i blanding med en for den enterale eller parenterale, fortrinnsvis enterale, administrering egnete farmasøytiske, organiske eller uorganiske j inerte bærer-materiale, som f.eks. vann. gelatiner, gummi-j arabikum, melkesukker, stivelse, magnesiumstearat, talkum,; vegetabilske oljer, polyalkylenglykoler, vaseliner, osv.. ' De farmasøytiske preparater kan foreligge i fast form,, f. eks. som tabletter, dragéer, suppositorier, kapsler, eller, i flytende form. f.eks. som løsninger, suspensjoner eller ' emulsjoner. Eventuelt er de sterilisert og henh. eller! inneholder hjelpestoffer, som konserverings-, stabilise-rings-, fukte eller emulgeringsmidler, salter til forandring av det osmotiske trykk, anestetika eller pufre. De kan også inneholde ytterligere andre terapeutisk verdifulle stoffer. i The products according to the invention can be used as pharmaceuticals, e.g. in the form of pharmaceutical preparations, ■ which contain them or their salts in admixture with a pharmaceutical, organic or inorganic carrier material suitable for enteral or parenteral, preferably enteral, administration, such as e.g. water. gelatins, gum arabic, milk sugar, starch, magnesium stearate, talc,; vegetable oils, polyalkylene glycols, petroleum jelly, etc.. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragees, suppositories, capsules, or, in liquid form. e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and appropriate. or! contains auxiliary substances, such as preservatives, stabilisers, wetting or emulsifying agents, salts to change the osmotic pressure, anesthetics or buffers. They may also contain further other therapeutically valuable substances.

Fremstilling av utgangsforbindelser:Making Output Connections:

EKSEMPEL A .1 EXAMPLE A .1

Fremstilling av natriumsaltet av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[(Z)-metoksyimino]acetamido]-3-[ ( 2 ,5-dihydro- i 6-metoksy-2-metyl-5-okso-as-triazin-3-yl) tio ] metyl ] -8-okso-''• 5- tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre: j ■ Preparation of the sodium salt of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-[(2,5-dihydro- i 6- methoxy-2-methyl-5-oxo-as-triazin-3-yl) thio ] methyl ] -8-oxo-''• 5- thia-1-azabicyclo[4,2,0]oct-2-en- 2-carboxylic acid: j ■

34,5 g natriumsalt av (6R,7R)-7-[2-( 2-(2-kloracetamido)-4-tiazolyl]-2-[(Z)-metoksyimino]acetamido]—3—[[(2,5-dihydro-j 6- metoksy-2-metyl-5-okso-as-triazin-3-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre oppløses i 700 ml vann sammen med 2Cg tiourea og røres over natten ved 25°C under nitrogen-gassing, hvorved pH-verdien for 1 reaksjonsløsningen under tilsetning av IN natronlut holdes 34.5 g sodium salt of (6R,7R)-7-[2-( 2-(2-chloroacetamido)-4-thiazolyl]-2-[(Z)-methoxyimino]acetamido]-3-[[(2, 5-dihydro-j 6- methoxy-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 dissolved in 700 ml of water together with 2 Cg of thiourea and stirred overnight at 25°C under nitrogen gassing, whereby the pH value of the 1 reaction solution is maintained while adding 1N caustic soda

i ved 7. Under kraftig røring tilbakestilles pH-verdien ved j i at 7. During vigorous stirring, the pH value is reset at j

I i tilsetning av IN saltsyre til 4. Det ved dette utfelte!materiale nutsjes av og kastes. Den gule moderlut innstilles, på pH 3 med IN saltsyre. Det utfelte produkt nutsjes av, vaskes med vann, etanol og lavtkokende petroleter og tør-kes i vakuum ved 40 o C. Man får beige-farget • (6R,7R)-7-[2- 'i (2-amino-4-tiazolyl)-2-[(Z)-metoksyimino]acetamido]-3-; I in the addition of IN hydrochloric acid to 4. The material precipitated by this is sieved off and discarded. The yellow mother liquor is adjusted to pH 3 with IN hydrochloric acid. The precipitated product is filtered off, washed with water, ethanol and low-boiling petroleum ether and dried in a vacuum at 40 o C. One obtains beige-coloured • (6R,7R)-7-[2-'i (2-amino-4 -thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-;

[[(2,5-dihydro-6-metoksy-2-métyl-5-okso-as-triazin-3-yl)- i tio]metyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre, som for overførsel i natriumsaltet, suspenderes i 350 ml metanol og tilsettes 20 ml av en 2N løsning, av 2-etylkapronsyre-natriumsalt i eddikester. Etter ca. 15 minutter er det oppstått en løsning som fortynnes med 300 ' ml etanol. Derved faller litt amorft materiale ut, som nutsjes fra og kastes. Filtratet konsentreres kraftig i vakuum ved 40°C. Det derved utfelte materiale nutsjes fra, vaskes med etanol og lavtkokende petroleter og tørkes over natten i høyvakuum ved 40°C. Man får rent natriumsalt av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[(Z)-metoksyimino]acet-amido] -3- [ [(2,5-dihydro6-metoksy-2-metyl-5-okso-as-triazin-3-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en 2-karboksylsyre som gullig pulver med [ct]D 2 5 = -140,9 o (c=[[(2,5-dihydro-6-methoxy-2-methyl-5-oxo-az-triazin-3-yl)- i thio]methyl]-8-oxo-5-thia-1-azabicyclo[4, 2,0]oct-2-ene-2-carboxylic acid, as for transfer into the sodium salt, is suspended in 350 ml of methanol and 20 ml of a 2N solution of 2-ethylcaproic acid sodium salt in acetic ester is added. After approx. After 15 minutes, a solution has formed which is diluted with 300 ml of ethanol. Thereby, some amorphous material falls out, which is scraped off and thrown away. The filtrate is vigorously concentrated in vacuo at 40°C. The thus precipitated material is sieved off, washed with ethanol and low-boiling petroleum ether and dried overnight in a high vacuum at 40°C. Pure sodium salt of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3- [ [(2,5-dihydro6 -methoxy-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 as a yellowish powder with [ct]D 2 5 = -140.9 o (c=

i vann).in water).

Den ved forannevnte fremgangsmåte som utgangsmateriale. an-, vendte forbindelse kan fremstilles som følger: j I å) Fremstilling av tetrahydro-2-metyl-5,6-diokso-3--i \ The by the aforementioned method as starting material. The compound used can be prepared as follows: Preparation of tetrahydro-2-methyl-5,6-dioxo-3

tiokso-as-triazin-1(2H)-karboksylsyre-benzylester: jThioxo-as-triazine-1(2H)-carboxylic acid benzyl ester: j

■ ■ ■ I ; ■ ■ ■ I ;

<!>I <!>I

•39,79 g 1,2,5,6-tetrahydro-5,6-diokso-3-merkapto-2-metyl- j as-triazin opptas i 500 ml dimetylformamid og tilsettes 35\ . ml trietylamin. I løpet av 15 minutter tilsettes 39 ml iben-zyloksykarbonylklorid dråpevis , hvorved :: temperaturen | f or reaksjonsblandingen stiger til 45°C, trietylamin-hydroklo-| rid feller ut og suspensjonen farges gul. Blandingen røres, i 2 1/2 time ved 2 5°C og konsentreres deretter i vakuum i ved 70°C. Den oljeaktige inndampningsrest røres med 500 ml vann i 1 time, hvorved denne blir fast. Faststoffet nut-. sjes av og vaskes med 50 ml vann. Det gule nutsjete produkt røres godt med 250 ml etanol, nutsjes av, vaskes med eta- j noi og tørkes i vakuum ved.40°C. Man får et fargeløst rå-krystallisat, som omkrystalliseres fra metanol og gir fargeløs te-trahydrb-2-metyl-5 , 6-diokso-3-tiokxo-as-triazin-l (2H) -: karboksylsyre-benzylester med smeltepunkt 150-153°C. b) Fremstilling av 3-[(difenylmetyl)tio]-5,6-dihydro-<!>2-metyl-5,6-diokso-as-triazin-l(2H)-karboksylsyre- i; benzylester: 13.2 g tetrahydro-2-metyl-5,6-diokso-3-tiokso-as-triazin-1(2H)-karboksylsyre-benzylester løses i 500 ml etylacetat og tilsettes en løsning av difenyldiazometan. i 90 ml lavtkokende petroleter. Den i begynnelsen fiolette reaksjons-løsning får henstå i 40 timer ved 25°C, hvorved fargen blir blekrød. Det tilsettes 3 ml iseddik, og blandingen inndampes etter 1 time i vakuum ved 40°C. Man får en gul olje • 39.79 g of 1,2,5,6-tetrahydro-5,6-dioxo-3-mercapto-2-methyl-jas-triazine are taken up in 500 ml of dimethylformamide and 35% are added. ml triethylamine. In the course of 15 minutes, 39 ml of benzene-xyloxycarbonyl chloride are added dropwise, whereby :: the temperature | for the reaction mixture rises to 45°C, triethylamine-hydrochloro-| rid precipitates out and the suspension turns yellow. The mixture is stirred, for 2 1/2 hours at 25°C and then concentrated in vacuo at 70°C. The oily evaporation residue is stirred with 500 ml of water for 1 hour, whereby it becomes solid. The solid nut-. drain and wash with 50 ml of water. The yellow nut-jet product is stirred well with 250 ml of ethanol, the nut-jet is washed off, washed with ethanol and dried in a vacuum at 40°C. A colorless crude crystallisate is obtained, which is recrystallized from methanol and gives colorless tetrahydrb-2-methyl-5,6-dioxo-3-thioxo-as-triazine-1 (2H)-: carboxylic acid benzyl ester with melting point 150- 153°C. b) Preparation of 3-[(diphenylmethyl)thio]-5,6-dihydro-<!>2-methyl-5,6-dioxo-as-triazine-1(2H)-carboxylic acid-i; benzyl ester: 13.2 g of tetrahydro-2-methyl-5,6-dioxo-3-thioxo-as-triazine-1(2H)-carboxylic acid benzyl ester are dissolved in 500 ml of ethyl acetate and a solution of diphenyldiazomethane is added. in 90 ml of low-boiling petroleum ether. The initially violet reaction solution is allowed to stand for 40 hours at 25°C, whereby the color becomes pale red. 3 ml of glacial acetic acid are added, and the mixture is evaporated after 1 hour in a vacuum at 40°C. You get a yellow oil

som inndampningsrest . Denne oppdeles ved hjelp av søyle-kromatografi på kiselgel med elueringsmidlene benzen, benzen/etylacetat 95:5 og benzen/etylacetat 90:10. Fraksjo-ner som inneholder det ønskete stoff samles og inndampes i vakuum ved 40°C. Man får etter omkrystallisasjon fra etanol fargeløse 3-[(difenylmetyl)tio]-5,6-dihydro-2-mety1-5,6-diokso-as-triazin-l(2H)-karboksylsyre-benzylester med smeltepunkt 90-92°C. ' as evaporation residue. This is separated using column chromatography on silica gel with the eluents benzene, benzene/ethyl acetate 95:5 and benzene/ethyl acetate 90:10. Fractions containing the desired substance are collected and evaporated in vacuum at 40°C. After recrystallization from ethanol, colorless 3-[(diphenylmethyl)thio]-5,6-dihydro-2-methyl-5,6-dioxo-as-triazine-1(2H)-carboxylic acid benzyl ester with melting point 90-92° is obtained C. '

i in

c) Fremstilling av 3- [. (dif eny lmetyl) tio]-1, 2-dihydro-2-metyl-as-triazin-5,6-dion: I c) Production of 3- [. (diphenylmethyl)thio]-1, 2-dihydro-2-methyl-as-triazine-5,6-dione: I

i in

•6,9 g 3-[ (dif enylme1yl)tio]-5 , 6-dihydro:-2-metyi-5 , 6-diokso-l as-triazin-1(2H)-karboksylsyre-benzylester løses i 100 ml .etylacetat og gjennomrøres med 30 ml av en vandig, 7%'ig ! ammoniakkløsning ved 2 5°C i 15 minutter. Etylacetatfasen skilles fra og kastes. Den vandige fase tilsettes 7 mljjkon-sentrert saltsyre og røres 30 minutter i isbad. Det derved! utfelte stoff nutsjes av, vaskes med vann og omkrystalliseres straks fra etanol.. Man får fargeløst 3-[ (dif eny lmetyl)-tio]-1,2-dihydro-2-metyl-as-triazin-5,6-dion med smeltepunkt 180-182°C. d) Fremstilling av 3-[(difenylmetyl)tio]-6-metoksy-27; metyl-as-triazin-5(2H)-on:i' 3,9 g 3-[(difenylmetyl)tio]-1,2-dihydro-2-metyl-as-triazin-5,6-dion løses i 40 ml dimetylformamid og tilsettes 1,68 ' ml trietylamin samt 4 ml metyljodid. Etter 2 timers røring ved 25 o C tilsettes blandingen ytterligere 1,38 g kalium karbonat for å fremskynde reaksjonen. Etter ytterligere 2 timers røring ved 25°C er utgangsmaterialet fullstendig om-satt. Den resulterende, røde suspensjon helles på vann og ekstraheres tre ganger med etylacetat. De forenete eddik-esterekstrakter vaskes med vann, tørkes over natriumsulfat og inndampes i vakuum ved 40°C. Den røde inndampningsrest renses ved hjelp av søylekromatografi på kiselgel med etylacetat som elueringsmiddel. Omkrystallisasjon fra etylacetat/eter/petroleter gir. gullig 3-[(difenylmetyl)-tio]-6-metoksy-2-metyl-as-triazin-5(2H)-on med smeltepunkt 135-138°C. e) Fremstilling >av3,4-dihydro-6-metoksy-2-metyl-3-tiokso-as-triazin-5(2H)-on: 2,6 g 3-[(difenylemtyl)tio]-6-metoksy-2-metyl-as-triazin-5(2H)-on løses i 26 ml anisol og 50 ml trifluoreddiksyre\og røres i 3 timer ved 25°C. Reaksjonsløsningen inndampes ! 1 vakuum ved 40°C. Inndampningsresten røres med litt etylacetat og meget lavtkokende petroleter, nutsjes av og omkrystalliseres fra metanol. Man får 3,4-dihydro-6-metoksy- ! 2-metyl-3-tiokso-as-triazin-5(2H)-on som fargeløse, glin-sende krystaller med smeltepunkt 215-220°C.. ' ■ i f) Fremstilling av (6R> 7R)-7-amino-3- [ t (2 , 5-dihydro-6-r metoksy-2-metyl-5-okso-as-triazin-3-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksyl- j syre: j i 13,6 g 7-aminocephalosporansyre og 9,53 g 3,4-dihydro-6-metoksy-2-metyl-3-tiokso-as-triazin-5(2H)-on suspenderes i-^ 250 ml vann. pH-verdien for suspensjonen innstilles på j6,5j<y>ed 25°C med IN natronlut. Suspensjonen oppvarmes til 60°C|fog røres i 4 timer ved 60°C under nitrogengassing, hvorved pH-verdien holdes ved 6,5 med IN natronlut. Etter 1 time opptrer en løsning, etter 2 timer begynner noe materiale å felle ut, og intet natronlut forbrukes mer. Blandingen av-kjøles til 25°C og skilles fra fra litt uoppløst materiale ved filtrering. Det oransje filtrat innstilles på pH 3,5 med konsentert saltsyre ved 25°C. Det utfelte stoff nutsjes av, vaskes i rekkefølge med 100 ml vann, 300 ml aceton og 300 ml lavtkokende petroleter og tørkes over natten i va-kumm ved 40°C. Man får et beige-ifarget stoff som for rensning suspenderes i 150 ml vann/metanol 1:1 og tilsettes 3,6 ml trietylamin dråpevis i 1 time, hvorved det fremkonmer en mørk løsning ved pH 8,5, som inneholder ytterligere litt uoppløst materiale. Etter tilsetning av 3 g avfargningskull røres 15 minutter ved 25°C, filtreres fra over et hårdfilter av avfargningskull og ettervaskes med 50 ml vann/ metanol 1:1. Det oransje filtrat innstilles på pH 3 med ca. 2 ml konsentrert saltsyre. Det derved utfelte. stoff nutsjes av, vaskes i rekkefølge med 50 ml vann/metanol 1:1, 100 ral metanol, 50 ml eter og 50 ml lavtkokende petroleter og tør-kes over natten i vakuum ved 40°C. Man får ren, beige-farget (6R,7R)-7-amino-3-[[(2,5-dihydro-6-metoksy-2-mety1-5-okso-as-triazin-3-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo-[4,2,0]- i okt-2-en-2-karboksylsyre.'g) Fremstilling av natriumsaltet av (6R,7R)-7-[2-[2-<!>(2-kloracetamido)-4-tiazolyl]-2-[(Z)-metoksyimino]-acetamido]-3-[[(2,5-dihydro-6-metoksy-2-metyl-5-okso-as-triazin-3-yl)tio]metyl]-8-okso-5-tia-l-aza- i bicyklo[4,2,0]okt-2-en-2-karboksylsyre: ' 1 6.9 g of 3-[(diphenylmethyl)thio]-5,6-dihydro:-2-methyl-5,6-dioxo-l as-triazine-1(2H)-carboxylic acid benzyl ester are dissolved in 100 ml. ethyl acetate and stirred through with 30 ml of an aqueous, 7% ! ammonia solution at 25°C for 15 minutes. The ethyl acetate phase is separated and discarded. 7 ml of concentrated hydrochloric acid are added to the aqueous phase and stirred for 30 minutes in an ice bath. Thereby! The precipitated substance is filtered off, washed with water and immediately recrystallized from ethanol. Colorless 3-[(diphenylmethyl)-thio]-1,2-dihydro-2-methyl-as-triazine-5,6-dione is obtained with melting point 180-182°C. d) Preparation of 3-[(diphenylmethyl)thio]-6-methoxy-27; methyl-as-triazine-5(2H)-one: 3.9 g of 3-[(diphenylmethyl)thio]-1,2-dihydro-2-methyl-as-triazine-5,6-dione are dissolved in 40 ml of dimethylformamide and 1.68 ml of triethylamine and 4 ml of methyl iodide are added. After stirring for 2 hours at 25 o C, a further 1.38 g of potassium is added to the mixture carbonate to speed up the reaction. After a further 2 hours of stirring at 25°C, the starting material is completely converted. The resulting red suspension is poured onto water and extracted three times with ethyl acetate. The combined acetic ester extracts are washed with water, dried over sodium sulfate and evaporated in vacuo at 40°C. The red evaporation residue is purified by means of column chromatography on silica gel with ethyl acetate as eluent. Recrystallization from ethyl acetate/ether/petroleum ether gives yellowish 3-[(diphenylmethyl)-thio]-6-methoxy-2-methyl-as-triazin-5(2H)-one with melting point 135-138°C. e) Preparation of 3,4-dihydro-6-methoxy-2-methyl-3-thioxo-as-triazin-5(2H)-one: 2.6 g of 3-[(diphenylemthyl)thio]-6-methoxy- 2-methyl-as-triazin-5(2H)-one is dissolved in 26 ml of anisole and 50 ml of trifluoroacetic acid and stirred for 3 hours at 25°C. The reaction solution is evaporated! 1 vacuum at 40°C. The evaporation residue is stirred with a little ethyl acetate and very low-boiling petroleum ether, filtered off and recrystallized from methanol. 3,4-dihydro-6-methoxy- ! 2-methyl-3-thioxo-as-triazin-5(2H)-one as colourless, glistening crystals with a melting point of 215-220°C.. ' ■ i f) Preparation of (6R>7R)-7-amino-3-[t(2,5-dihydro-6-r methoxy-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: j i 13.6 g 7-aminocephalosporanic acid and 9.53 g 3,4 -dihydro-6-methoxy-2-methyl-3-thioxo-as-triazin-5(2H)-one is suspended in 250 ml of water. The pH value of the suspension is adjusted to j6.5j<y>ed 25°C with IN caustic soda. The suspension is heated to 60°C and stirred for 4 hours at 60°C under nitrogen gassing, whereby the pH value is maintained at 6.5 with 1N caustic soda. After 1 hour a solution appears, after 2 hours some material begins to precipitate, and no more caustic soda is consumed. The mixture is cooled to 25°C and separated from some undissolved material by filtration. The orange filtrate is adjusted to pH 3.5 with concentrated hydrochloric acid at 25°C. The precipitated substance is sieved off, washed in sequence with 100 ml of water, 300 ml of acetone and 300 ml of low-boiling petroleum ether and dried overnight in a vacuum at 40°C. A beige-coloured substance is obtained, which for purification is suspended in 150 ml water/methanol 1:1 and 3.6 ml triethylamine is added dropwise for 1 hour, whereby a dark solution at pH 8.5 is formed, which contains a little more undissolved material . After adding 3 g of decolorizing charcoal, stir for 15 minutes at 25°C, filter from over a hard filter of decolorizing charcoal and wash with 50 ml of water/methanol 1:1. The orange filtrate is adjusted to pH 3 with approx. 2 ml of concentrated hydrochloric acid. It thereby precipitated. substance is scraped off, washed in sequence with 50 ml water/methanol 1:1, 100 ral methanol, 50 ml ether and 50 ml low-boiling petroleum ether and dried overnight in vacuum at 40°C. Pure, beige-colored (6R,7R)-7-amino-3-[[(2,5-dihydro-6-methoxy-2-methyl-5-oxo-az-triazin-3-yl)thio] is obtained methyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]- in oct-2-ene-2-carboxylic acid.'g) Preparation of the sodium salt of (6R,7R)-7-[2-[2-<!>(2-chloroacetamido)-4-thiazolyl]-2-[( Z)-methoxyimino]-acetamido]-3-[[(2,5-dihydro-6-methoxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5 -thia-1-aza- i bicyclo[4,2,0]oct-2-ene-2-carboxylic acid: ' 1

• Til 200 ml over kalsiumklorid tørket metylenklorid tilset-'• To 200 ml of calcium chloride, dry methylene chloride is added-'

i tes 25 g fosforpentaklorid. Suspensjonen avkjøles til t10°C under røring, og i løpet av ca. 5 minutter tilsettes dråpevis 46 ml N,N-dimetylacetamid, hvorved temperaturen stiger! til -5°C. Suspensjonen kjøles til -15°C og røres i 15 minutter. Etter avkjølingen til -20°C tilsettes 33,3 g 27(2-. kloraceta- ido-4-tiazolyl)-2-(Z)-metoksyimino-eddiksyre!og røres i 45 minutter ved -15°C, hvorved det oppstår en gul-. oransjefarget løsning. Denne løsning avkjøles til -30 o C, tilsettes 50 g is og røres i 10 minutter ved -5°C. Metylen-kloridfasen som inneholder det dannete syreklorid skilles ' fra og oppbevares deretter ved ca. -15°C. Denne syreklorid-løsning tilsettes dråpevis i løpet av 30 minutter under kraftig omrøring en til 0-5°C kjølt løsning som ble frem- 1 stilt ved tilsetning av den under f) fremstilte (6R,7R)- i 7-amino-3-[[(2,5-dihydro-6-metoksy-2-metyl-5-okso-as-triazin-3-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre med 3N natronlut til pH 8,2 i 500 ml vann, hvorved pH-verdien for reaksjonblandingen holdes ved 8,0-8,2 med 3N natronlut ved hjelp av en autotitrator..Deretter tilsettes 300 ml metylenklorid og 2 liter n-butanol. Under kraftig omrøring tilbakestilles pH til 2 med 3N saltsyre. Den organiske fase skilles fra, vaskes tre ganger, in tea 25 g of phosphorus pentachloride. The suspension is cooled to t10°C while stirring, and during approx. After 5 minutes, 46 ml of N,N-dimethylacetamide is added drop by drop, causing the temperature to rise! to -5°C. The suspension is cooled to -15°C and stirred for 15 minutes. After cooling to -20°C, 33.3 g of 27(2-chloroacetido-4-thiazolyl)-2-(Z)-methoxyimino-acetic acid are added and stirred for 45 minutes at -15°C, whereby a yellow-. orange colored solution. This solution is cooled to -30 o C, 50 g of ice is added and stirred for 10 minutes at -5°C. The methylene chloride phase containing the acid chloride formed is separated and then stored at approx. -15°C. This acid chloride solution is added dropwise over the course of 30 minutes with vigorous stirring to a solution cooled to 0-5°C which was prepared by adding the (6R,7R)-in 7-amino-3- [[(2,5-dihydro-6-methoxy-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 with 3N caustic soda to pH 8.2 in 500 ml of water, whereby the pH of the reaction mixture is maintained at 8.0-8.2 with 3N caustic soda using an autotitrator..Then 300 ml of methylene chloride and 2 liters of n-butanol are added. With vigorous stirring, the pH is reset to 2 with 3N hydrochloric acid. The organic phase is separated, washed three times,

hver gang med 1 liter vann, røres i 15 minutter med 20 g avfargningskull og filtreres. Den lysegule filtrat kohsen-.treres kraftig i vakuum ved 60°C, hvorved reaksjonsproduk-tet faller ut. Sistnevnte nutsjes av og vaskes i rekkefølge med n-butanol, eter og lavtkokende petroleter og tørkes o-' ver natten i vakuum ved 40°C. Man får rå, beige (6R,7R)-7-[2-[2-(2-kloracetamido)-4-tiazolyl]-2-[(Z)-metoksyimino]-acetamido]-3-[[2,5-dihydro-6-metoksy-2-metyl-5-okso-as-triazin-3-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo[4,2,0]- i okt-2-en-2-karboksylsyre. For overføring i natriumsaltet i each time with 1 liter of water, stir for 15 minutes with 20 g of decolorizing charcoal and filter. The light-yellow filtrate is concentrated vigorously in a vacuum at 60°C, whereupon the reaction product precipitates out. The latter is skimmed off and washed in sequence with n-butanol, ether and low-boiling petroleum ether and dried overnight in vacuum at 40°C. One obtains crude, beige (6R,7R)-7-[2-[2-(2-chloroacetamido)-4-thiazolyl]-2-[(Z)-methoxyimino]-acetamido]-3-[[2,5 -dihydro-6-methoxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]- i oct- 2-ene-2-carboxylic acid. For transfer in the sodium salt i

og rensning oppløses sistnevnte i en blanding av 300 mland purification, the latter is dissolved in a mixture of 300 ml

<:>aceton og 50 ml metanol og tilsettes 35 ml av en 2N løsning av 2-etylkapronsyre-natriumsalt i eddikester. Det utfelte j natriumsalt nutsjes av, vaskes i rekkefølge med acetonjog j 1 lavtkokende petroleter og tørkes i vakuum ved 25°C. Man får 1beige-farget v natriumsalt av (6R,7R)-7-[2-[2-(2-kloracetami-do)-4-tiazolyl]-2-[(Z)-metoksyimino]acetamido]-3-[[(2,5-dihydro-6-metoksy-2-metyl-5-okso-as-triazin-3-yl)tio]metyL] - <:>acetone and 50 ml of methanol and add 35 ml of a 2N solution of 2-ethylcaproic acid sodium salt in ethyl acetate. The precipitated sodium salt is filtered off, washed successively with acetone and 1 low-boiling petroleum ether and dried in a vacuum at 25°C. One obtains 1 beige-colored v sodium salt of (6R,7R)-7-[2-[2-(2-chloroacetami-do)-4-thiazolyl]-2-[(Z)-methoxyimino]acetamido]-3-[ [(2,5-dihydro-6-methoxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl] -

i i 8-okso-5-tia-l-azabicyklo [4 , 2 ,0]okt-2-en-i2-karboksylsyre j 2 5 O I med [a]D = -131,5 (c = 1 i vann)... | • i i 8-oxo-5-thia-l-azabicyclo [4 , 2 ,0]oct-2-ene-i2-carboxylic acid j 2 5 O I with [a]D = -131.5 (c = 1 in water). .. | •

i in

EKSEMPEL B i EXAMPLE B i

Fremstilling av dinatriumsaltet av (6R, 7R)-7-[2-(2-amino-4-tiazolyl)-2-[(Z)-metoksyimino]acetamido]-3-[[(3-karboksy-1-metyl-lH-L 2,4-triazol-5-yl)tio]metyl]-8-okso-5-tia-lr azabicyklo[4,2,0]okt-2-en-2-karboksylsyre; . ! I;! Preparation of the disodium salt of (6R, 7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-[[(3-carboxy-1-methyl- 1H-L 2,4-triazol-5-yl)thio]methyl]-8-oxo-5-thia-l azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid; . ! IN;!

53 g (6R,7R)-3- [ [ (3-karboksy-l-metyl-lH-l, 2 , 4-triazol-5-yl) r i tio]metyl]-7-[2-[2-(2-kloracetamido)-4-tiazolyl]-2-[(Z)- metoksyimino]acetamido]-8-okso-5-tia-l-azabicyklo[4,2,0]- \ okt-2-en-2-karboksylsyre suspenderes il liter vann sammen| med 34 g tiourea. pH innstilles på 7 ved tildrypning av IN natronlut, hvorved det oppstår en mørkebrun løsning. Denne røres ved pH 7 over natten under nitrogengassing, idet pH ! holdes konstant med IN natronlut ved hjelp av en autotitrator. pH for reaksjonsløsningen innstilles under røring på , 3,5 med IN saltsyre. Det utfelte stoff (fraksjon I) nutsjes av, vaskes med 250 ml vann og tørkes ved 40°C i vakuum. Fraksjonen I er brunfarget og sterkt forurenset. Den kastes. Den oransje moderlut tilbakestilles på pH 2,65 under røring med IN saltsyre. Det utfelte materiale nutsjes av<p>g vaskes med 250 ml vann. Det beige-fargete nutsjete materiale azeo-troperes med etanol under redusert trykk, nutsjes av, vaskes med etanol og lavtkokende petroleter og tørkes ved 40°C i vakuum. Man får således en beige-brun fraksjon II, som for rensning og overføring i dinatriumsaltet suspenderes i 2 liter metanol, tilsettes 50 ml av en 2N løsning av na-: triumsaltet av 2-etylkapronsyre i etylacetat og røres deretter med 200 ml vann i 30 minutter. Litt uoppløst, brunt 53 g (6R,7R)-3-[[(3-carboxy-1-methyl-1H-1,2,4-triazol-5-yl)r i thio]methyl]-7-[2-[2-(2-chloroacetamido)-4-thiazolyl]-2-[(Z)- Methoxyimino]acetamido]-8-oxo-5-thia-1-azabicyclo[4,2,0]- \ oct-2-ene-2-carboxylic acid is suspended in 1 liter of water together. with 34 g of thiourea. The pH is adjusted to 7 by adding 1N caustic soda drop by drop, which results in a dark brown solution. This stirred at pH 7 overnight under nitrogen gassing, as pH ! kept constant with IN caustic soda using an autotitrator. The pH of the reaction solution is set, while stirring, to 3.5 with IN hydrochloric acid. The precipitated substance (fraction I) is filtered off, washed with 250 ml of water and dried at 40°C in a vacuum. Fraction I is brown and heavily contaminated. It is thrown. The orange mother liquor is reset to pH 2.65 while stirring with IN hydrochloric acid. The precipitated material is sieved and washed with 250 ml of water. The beige-coloured nut-jet material is azeotroped with ethanol under reduced pressure, nut-jetted off, washed with ethanol and low-boiling petroleum ether and dried at 40°C in vacuum. A beige-brown fraction II is thus obtained, which for purification and transfer into the disodium salt is suspended in 2 liters of methanol, 50 ml of a 2N solution of the sodium salt of 2-ethylcaproic acid in ethyl acetate is added and then stirred with 200 ml of water for 30 minutes. Slightly undissolved, brown

materiale filtreres fra og kastes. Fra det oransjefargete filtrat dampes ca. 1 liter av i vakuum ved 40°C, deretter j tilsettes 1 liter etanol og det konsentreres i vakuum til ! et volum på ca. 500 ml. Man avdekanterer fra den ved dettejutfelte, klebrige brune harpiks, som foreligger som enj j. sterk blanding. Den avdekanterte guloransje løsning til-<1>settes 1 liter etanol og konsentreres sterkt i vakuum ved 40°C, hvorved materiale delvis feller ut. Etter tilsetningj av 2,5 liter metanol oppstår en gul løsning som konsentre-i res kraftig i vakuum ved 40°C. Det derved utfelte dinatriumsalt nutsjes av, vaskes med metanol og lavtkokende petrol-' eter og tørkes i høyvakuum ved 35°C . Man får rent, beige-, farge dinatriumsalt a<y>(6R,7R)-7-[2-(2-amino-4-tiazolyl)-<1>2-[(Z)-metoksyimino]acetamido]-3-[[(3-karboksy-l-metylr1H-, 1, 2 , 4-triazol-5-yl) tio]metyl]-8-okso-5-tia-l-azabicyklo-[4,2,0]okt-2-en-2-karboksylsyre med [ a]^ 5 = -38,7° (c = 1 i vann). \ ■ material is filtered off and discarded. From the orange-coloured filtrate, evaporate approx. 1 liter of in vacuum at 40°C, then 1 liter of ethanol is added and it is concentrated in vacuum to ! a volume of approx. 500 ml. It is decanted from the sticky brown resin precipitated by this, which is present as enj j. strong mixture. The decanted yellow-orange solution is added to 1 liter of ethanol and strongly concentrated in a vacuum at 40°C, whereby material partially precipitates out. After the addition of 2.5 liters of methanol, a yellow solution is formed which is strongly concentrated in a vacuum at 40°C. The thus precipitated disodium salt is filtered off, washed with methanol and low-boiling petroleum ether and dried in a high vacuum at 35°C. Pure, beige-colored disodium salt α<y>(6R,7R)-7-[2-(2-amino-4-thiazolyl)-<1>2-[(Z)-methoxyimino]acetamido]-3 is obtained -[[(3-carboxy-1-methylr1H-,1,2,4-triazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct -2-ene-2-carboxylic acid with [ a]^ 5 = -38.7° (c = 1 in water). \ ■

Den i ovenfor nevnte fremgangsmåte som utgangsmateriale anvendte forbindelse kan fremstilles som følger: i i a) Fremstilling av 4,5-dihydro-l-metyl-5-tiokso-lH- | 1,2,4-triazol-3-karboksylsyre-metylester: 12,9 g l-metoksyoksalyl-2-metyl-tiosemikarbazid tilsettes en løsning av 1,6 g natrium i 200 ml metanol. Blandingen ko-kes i 4 timer under tilbakeløpskjøling. Det etter 1/2 time utfelte materiale skilles fra. Moderluten inndampes ved 40°C i vakuum. Inndampningsresten løses i 100 ml vann og ansyres med konsentrert, saltsyre. Det derved utskilte kry-stallisat gir etter omkrystalliseringen fra vann ren, farge-løs 4,5-dihydro-l-metyl-5-tiokso-lH-l,2,4-tiazol-3-karboksylsyre-metylester med. smeltepunkt 188-190°C (spaltning). b) Fremstilling av 4,5-dihydro-l-metyl-5-tiokso-lH-1,2,4-triazol-3-karboksylsyre: 3,46 g 4,5-dihydro-l-metyl-5-tiokso-lH-l,2,4-triazol-3- ■ karb<p>ksylsyre-metylester løses i 50 ml IN natronlut. Etter, The compound used as starting material in the above-mentioned process can be prepared as follows: i i a) Preparation of 4,5-dihydro-1-methyl-5-thioxo-1H- | 1,2,4-triazole-3-carboxylic acid methyl ester: 12.9 g of 1-methoxyoxalyl-2-methylthiosemicarbazide is added to a solution of 1.6 g of sodium in 200 ml of methanol. The mixture is boiled for 4 hours under reflux cooling. The material precipitated after 1/2 hour is separated. The mother liquor is evaporated at 40°C in a vacuum. The evaporation residue is dissolved in 100 ml of water and acidified with concentrated hydrochloric acid. The resulting crystallisate gives, after recrystallization from water, pure, colorless 4,5-dihydro-1-methyl-5-thioxo-1H-1,2,4-thiazole-3-carboxylic acid methyl ester with. melting point 188-190°C (decomposition). b) Preparation of 4,5-dihydro-1-methyl-5-thioxo-1H-1,2,4-triazole-3-carboxylic acid: 3.46 g of 4,5-dihydro-1-methyl-5-thioxo- 1H-1,2,4-triazole-3- ■ carboxylic acid methyl ester is dissolved in 50 ml 1N caustic soda. After,

1/2 times røring ved 25 C innstilles reaksjonsløsningen surt med 25 ml 2N saltsyre og konsentreres ved 40°C i va- I kuum, idet den ønskete syre krystalliserer. Denne nutsjes av, vaskes med isvann og tørkes ved 4 5 o C i høyvakuum. Man får fargeløs 4,5-dihydro-l-metyl-5-tiokso-lH-1,2,4-triazol-3-karboksylsyre med smeltepunkt 177-178°C (spaltning).I | c) Fremstilling av (6R, 7R)-7-amino-3- [ [ (3-karboksy-l-: metyl-1,2,4-triazol-5-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo [4 , 2 ,0] okt-2-en-2-karboksylsyre : i j 34 g 7-aminocephalosporansyre suspenderes i 500 ml vann I sammen med 25,5 g 4,5-dihydro-l-metyl-5-tiokso-lH-l,2,4-triazol-3-karboksylsyre. pH innstilles på 6,5 med 3N na- j tronlut. Blandingen røres i 4 timer ved 55°C undernitrogen-gassing, hvorved pH holdes konstant ved 6,5 med 3N natronlut med hjelp av en autotitrator. Den mørke løsning kjøles<!>til! 25°C og innstilles på pH 3,5 med konsentrert saltsyre.Etter 15 minutter nutsjes det utfelte materiale fra, suspen-, deres i 500 ml vann og bringes ved pH 7 i løs ning med 3N natronlut. Den oransjerøde løsning innstilles på pH 3 med konsentrert saltsyre. Den utfelte substans nutsjes fra og ,vaskes i rekkefølge med 250 ml vann, 500 ml aceton, 500 ml. lavtkokende petroleter og tørkes over natten i vakuum ved 40-45°C. Man får (6R,7R)-7-amino-3-[[(3-karboksy-l-metyl-1,2,4-triazol-5-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo-[4,2,0]okt-2-en-2-karboksylsyre med beige-farget pulver. d) Fremstilling av (6R, 7R)-[ [ (3-karboksy-l-metyl-lH-l, 2 , 4-triazol-5-yl)tio]metyl]-7-[2-[2-(2-kloracetamido)-4-tiazolyl]-2-[(Z)-metoksyimino]acetamido]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre: Denne forbindelse fremstilles ifølge avsnitt g) i eksempel 1 ved å gå ut fra 100 g 2-(2-kloracetamido-4-tiazolyl)-2-(Z)-metoksyimino-eddiksyre og 111,5 g (6R,7R)-7-amino-3-[[(3-karboksy-l-metyl-l,2,4-triazol-5-yl)tio]metyl]-8-' okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre. j Man får beige-farget (6R,7R)-3-[[(3-karboksy-l-metyl-lH- After stirring for 1/2 hour at 25°C, the reaction solution is made acidic with 25 ml of 2N hydrochloric acid and concentrated at 40°C in a vacuum, the desired acid crystallising. This nut is washed off, washed with ice water and dried at 4 5 o C in a high vacuum. Colorless 4,5-dihydro-1-methyl-5-thioxo-1H-1,2,4-triazole-3-carboxylic acid with melting point 177-178°C (decomposition) is obtained. c) Preparation of (6R,7R)-7-amino-3-[[(3-carboxy-1-:methyl-1,2,4-triazol-5-yl)thio]methyl]-8-oxo-5 -thia-l-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid: i j 34 g of 7-aminocephalosporanic acid are suspended in 500 ml of water I together with 25.5 g of 4,5-dihydro-1-methyl-5-thioxo-1H-1,2,4-triazole-3-carboxylic acid. The pH is adjusted to 6.5 with 3N sodium hydroxide solution. The mixture is stirred for 4 hours at 55°C under nitrogen gassing, whereby the pH is kept constant at 6.5 with 3N caustic soda with the help of an autotitrator. The dark solution is cooled<!>to! 25°C and adjusted to pH 3.5 with concentrated hydrochloric acid. After 15 minutes, the precipitated material is sieved from, suspended in 500 ml of water and brought to pH 7 in solution with 3N caustic soda. The orange-red solution is adjusted to pH 3 with concentrated hydrochloric acid. The precipitated substance is filtered off and washed in sequence with 250 ml water, 500 ml acetone, 500 ml. low-boiling petroleum ether and dried overnight in vacuum at 40-45°C. (6R,7R)-7-amino-3-[[(3-carboxy-1-methyl-1,2,4-triazol-5-yl)thio]methyl]-8-oxo-5-thia- 1-azabicyclo-[4,2,0]oct-2-ene-2-carboxylic acid with beige-colored powder. d) Preparation of (6R,7R)-[[(3-carboxy-1-methyl-1H-1,2,4-triazol-5-yl)thio]methyl]-7-[2-[2-(2 -chloroacetamido)-4-thiazolyl]-2-[(Z)-methoxyimino]acetamido]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid: This compound is prepared according to section g) in example 1 by starting from 100 g of 2-(2-chloroacetamido-4-thiazolyl)-2-(Z)-methoxyimino-acetic acid and 111.5 g of (6R,7R)-7- amino-3-[[(3-carboxy-1-methyl-1,2,4-triazol-5-yl)thio]methyl]-8-'oxo-5-thia-1-azabicyclo[4,2,0 ]oct-2-ene-2-carboxylic acid. j One obtains beige-colored (6R,7R)-3-[[(3-carboxy-1-methyl-1H-

1,2,4-triazol-5-yl)tio]metyl]-7-[2-(2-kloracetamido)-4-tiazolyl]-2-[(Z)-metoksyimino]acetamido]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre. J 1,2,4-triazol-5-yl)thio]methyl]-7-[2-(2-chloroacetamido)-4-thiazolyl]-2-[(Z)-methoxyimino]acetamido]-8-oxo-5 -thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid. J

j Fremstilling av sluttprodukter: , j Manufacture of end products: ,

i t in t

I IN

EKSEMPEL 1 i' i Fremstilling av metylen-(6R,7R)-7-[2-(2-amino-4-tiazolyl)-, 2-[(Z)-metoksyimino]-acetamido]-3-[[[2-metyl-5-[[(pivaloyl-okso)metoksy]karbonyl]-2H-1,2,4-triazol-3-yl]-tio]metyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylat-pivalat: . I EXAMPLE 1 i' i Preparation of methylene-(6R,7R)-7-[2-(2-amino-4-thiazolyl)-, 2-[(Z)-methoxyimino]-acetamido]-3-[[[2 -methyl-5-[[(pivaloyl-oxo)methoxy]carbonyl]-2H-1,2,4-triazol-3-yl]-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4 ,2,0]oct-2-ene-2-carboxylate pivalate: . IN

, i 3,9 g av dinatriumsaltet av (6R,7R)-7-[2-(2-amino-4-tiazo-lyl)-2-[(Z)-metoksyimino]acetamido]-3-[[3-karboksy-l-metyl-1H-1,2,4-triazol-5-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo-[4,2,0]okt-2-en-2-karboksylsyre oppløses i en blanding av j 100 ml dimetylformamid og 2 5 ml vann. Denne oppløsning tilsettes ved 0-5°C under nitrogengassing 3,13 g jodmetyl-! pivalat. Reaksjonsblandingen røres i 30 minutter ved 0-5°C, helles derpå på 500 ml vann og ekstraheres tre ganger,,hver gang med 200 ml etylacetat. Den vandige fase kastes. De i forenete etylacetatfaser vaskes etter hverandre med vann, , in 3.9 g of the disodium salt of (6R,7R)-7-[2-(2-amino-4-thiazol-lyl)-2-[(Z)-methoxyimino]acetamido]-3-[[3- carboxyl-1-methyl-1H-1,2,4-triazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]oct-2-ene- 2-Carboxylic acid is dissolved in a mixture of j 100 ml of dimethylformamide and 2 5 ml of water. This solution is added at 0-5°C under nitrogen gassing to 3.13 g of iodomethyl-! pivalate. The reaction mixture is stirred for 30 minutes at 0-5°C, then poured into 500 ml of water and extracted three times, each time with 200 ml of ethyl acetate. The aqueous phase is discarded. The combined ethyl acetate phases are washed successively with water,

1 fortynnet vandig natriumhydrogenkarbonatløsning ennå en-gang med vann, tørkes over natriumsulfat og konsentreres kraftig ved 40°C i vakuum. Etter tilsetning av lavtkokende petroleter nutsjes det utfelte råprodukt av, vaskes med lavtkokende petroleter og tørkes ved 40°C i høyvakuum. Man får beigé-farget, amorft råprodukt. For rensning kromato-grafere.s dette produkt på en søyle med 100 g kiselgel (0,2 -0,5 mm) og etylacetat som elueringsmiddel. Man får ren, beige-farget, amorf tittelsubstans med Rf = 0,31 i tynn-sjiktskromatografi på kiselgel-60F-254-ferdigplater med etylacetat som eiueringsmiddel. Den spesifikke dreining er, [a]D 25 = -121,6 o (c = 0,4924 i aceton); kjerneresonansspektret og mikroanalysen tilsvarer den angitte struktur. 1 diluted aqueous sodium bicarbonate solution once more with water, dried over sodium sulphate and concentrated vigorously at 40°C in vacuum. After adding low-boiling petroleum ether, the precipitated crude product is filtered off, washed with low-boiling petroleum ether and dried at 40°C in a high vacuum. A beige-coloured, amorphous raw product is obtained. For purification, chromatograph this product on a column with 100 g of silica gel (0.2-0.5 mm) and ethyl acetate as eluent. Pure, beige-coloured, amorphous title substance with Rf = 0.31 is obtained in thin-layer chromatography on silica gel 60F-254 finished plates with ethyl acetate as eluent. The specific rotation is, [α]D 25 = -121.6 o (c = 0.4924 in acetone); the nuclear resonance spectrum and the microanalysis correspond to the indicated structure.

På analog måte fremstiller man fra det ifølge eksempel i l1iIn an analogous way, one produces from it according to example in l1i

i fremstilte natriumsalt av (6R, 7R)-7- [2-(2-amino-4-tiazolyl) - 2-[(Z)-metoksyimino]acetamido]-3-[f(2,5-dihydro-6-metoksy-| 2-metyl-5-okso-as-triazin-3-yl)tio]metyl]-8-okso-5-tia-1- j azabicyklo [4,2,0]okt-2-en-2-karboksylsyre det tilsvarende metylen (6R,7R)-[2-(2-amino-4-tiazolyl)-2-[(Z)-metoksyimi^no]-acetamido]-3-[[(2,5-dihydro-6-metoksy-2-metyl-5-okso- in prepared sodium salt of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-[f(2,5-dihydro-6- methoxy-|2-methyl-5-oxo-az-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1- azabicyclo [4,2,0]oct-2-en-2 -carboxylic acid the corresponding methylene (6R,7R)-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]-acetamido]-3-[[(2,5-dihydro- 6-methoxy-2-methyl-5-oxo-

l i as-triazin-3-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo[4,2,;0]okt-2-en-2-karboksylat-pivalat. i!| 1 in as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4,2,;0]oct-2-ene-2-carboxylate pivalate. in!|

EKSEMPEL 2 \ EXAMPLE 2 \

Fremstilling av metylen (6R, 7R)-7- [2-(2-amino-4-tiazolyl) - 2- [ (Z) -metoksyimino] -acetamido] -3- [ [ [2-metyl-5- [ [ (acetoksy/)>-metoksy]karbonyl]-2H-1,2,4-triazol-3-yl]tio]metyl]-8-okso-, Preparation of methylene (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]-acetamido]-3-[[[2-methyl-5-[[ (acetoxy)>-methoxy]carbonyl]-2H-1,2,4-triazol-3-yl]thio]methyl]-8-oxo-,

! i 5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylat-acetat: J ! i 5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate-acetate: J

I i 5,98 g (6R,7R)-7-amino-3-[[(3-karboksy-l-metyl-l,2,4-tria-zol-5-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre-dinatriumsalt oppløses i en blanding av 70 ml dimetylformamid og 25 ml vann. Løsningen tilsettes , under nitrogengassing ved 0-5°C 6,12 g eddiksyre-brommetyl-.'ester og røres 3 timer ved 0-5°C. Reaksjonsblandingen helles på 500 ml vann og ekstraheres to ganger med etylacetat under j tilsetning av litt aceton. De forenete organiske faser vaskes i rekkefølge med fortynnet vandig natriumhydrogen-karbonatløsning og vann, tørkes over natriumsulfat og konsentreres kraftig i vakuum ved 40°C. Etter tilsetning av lavtkokende petroleter nutsjes den amorfe, utfelte substans fra, vaskes med lavtkokende petroleter og tørkes over natten i høyvakuum ved '25°C. Man får et beige råprodukt ! som for rensning kromatograféres på en søyle med 80 g kiselgel (0,2-0,5 mm diameter) og etylacetat som eluerings- , middel. Man får ren, beige, amorf tittelsubstans (fra etylr acetat/lavtkokende petroleter) med [d]D 2 5 = -107,16° (c = 1,0358 i aceton). Kjerneresonansspektret og mikroanalysen i tilsvarer den angitte struktur. I in 5.98 g of (6R,7R)-7-amino-3-[[(3-carboxy-1-methyl-1,2,4-triazol-5-yl)thio]methyl]-8- oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid disodium salt is dissolved in a mixture of 70 ml of dimethylformamide and 25 ml of water. The solution is added, under nitrogen gassing at 0-5°C, to 6.12 g of acetic acid bromomethyl ester and stirred for 3 hours at 0-5°C. The reaction mixture is poured into 500 ml of water and extracted twice with ethyl acetate while adding a little acetone. The combined organic phases are washed successively with dilute aqueous sodium hydrogen carbonate solution and water, dried over sodium sulfate and concentrated vigorously in vacuo at 40°C. After addition of low-boiling petroleum ether, the amorphous, precipitated substance is filtered off, washed with low-boiling petroleum ether and dried overnight in a high vacuum at 25°C. You get a beige raw product! which for purification is chromatographed on a column with 80 g silica gel (0.2-0.5 mm diameter) and ethyl acetate as eluent. Pure, beige, amorphous title substance is obtained (from ethyl acetate/low-boiling petroleum ether) with [d]D 2 5 = -107.16° (c = 1.0358 in acetone). The nuclear resonance spectrum and the microanalysis in correspond to the indicated structure.

På analog måte får man fra det i eksempel 1 fremstilte natriumsalt av (6R, 7R)-7-[2-(2-amino-4-tiazolyl)-2-[ (Z)-met-' oksyimino]acetamido]-3-[[(2,5-dihydro-6-metoksy-2-metyl-5-okso-as-triazin-3-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo-' In an analogous way, from the sodium salt of (6R, 7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-meth-'oxyimino]acetamido]-3 prepared in example 1 is obtained -[[(2,5-dihydro-6-methoxy-2-methyl-5-oxo-az-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-'

l [4,2,0]okt-2-en-2-karboksylsyre det tilsvarende metylen ' l [4,2,0]oct-2-ene-2-carboxylic acid the corresponding methylene '

(6R,7R)-[2-(2-amino-4-tiazolyl)-2-[(Z)-metoksyimino]-acet-amido]-3-[[(2,5-dihydro-6-metoksy-2-metyl-5-okso-as-triazin-3-yl)tio]metyl]-8-okso5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylat-acetat. ' j (6R,7R)-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]-acetamido]-3-[[(2,5-dihydro-6-methoxy-2 -methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate acetate. 'j

EKSEMPEL 3 EXAMPLE 3

På vanlig måte fremstilles en gelatin-stikk-kapsel med;føl-gende sammensetning:<!>•<!>In the usual way, a gelatin suppository capsule is produced with the following composition:<!>•<!>

EKSEMPEL 4 'i På vanlig måte fremstilles en tablett med følgende sammensetning: EXAMPLE 4 In the usual way, a tablet is prepared with the following composition:

. Et granulat fremstilles på vanlig måte med det virksomme stoff, laktosen, polyvinylpyrrolidonet og 40 vektdeler maisstivelse. Dette blandes med de gjenværende 25 vektdeler maisstivelse og 5 vektdeler magnesiumstearat og kom-primeres til tabletter. j . A granule is produced in the usual way with the active substance, lactose, polyvinylpyrrolidone and 40 parts by weight of corn starch. This is mixed with the remaining 25 parts by weight of corn starch and 5 parts by weight of magnesium stearate and compressed into tablets. j

i in

J I J. I

Claims

1. Process for the production of easily hydrolyzable esters of cephalosporin derivatives with the general formula in flour I in

where X means one of the groups I

and R lower alkyl, i as well as acid addition salts of these esters and of hydrates of these esters acc. acid addition salts, characterized in that a carboxylic acid of formula I or a salt of this compound is subjected to a corresponding esterification, and if desired, the resulting product is transferred into an acid addition salt or hydrate acc. a hydrate of this acid addition salt.

2. Process according to claim 1 for the production of esters in the syn-isomeric form acc. of mixtures in which the syn-isomeric form is the predominant one, characterized by using a starting compound with a corresponding configuration or cleaving an obtained syn/anti mixture. i i I 3. Method according to claim 1 or 2 for the production of cephalosporin derivatives with the general formula } I

i i where R <2> is pivaloyloxymethyl- or acetoxymethyl- the group, • as well as acid addition salts of these compounds and low hydrates of the compounds of formula IA acc. of their acid addition salts, characterized by | that one uses correspondingly substituted output compounds | parts.

4. Process according to claim 3 for the production of cephalosporin derivatives in the syn-isomeric form acc. mixture gives in which the syn-isomeric form is the predominant one, | in characterized by using an *out gang junction with corresponding configuration or cleaves an obtained syn/anti mixture.;

5. Method according to claim 4 in the preparation of methylene (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxy-imino]-acetamido]-3-[[ [2-methyl-6-[[(pivaloyloxy)methoxy]carbonyl]-2H-1,2,4-triazol-3-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4 ,2,0]oct-2-ene-2-carboxylate pivalate as well as acid addition salts of this compound and hydrates thereof for obligation acc. acid addition salts, characterized by using correspondingly substituted starting compounds.;

6. Method according to claim 4 in the preparation of methylene(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxy-imino]-acetamido]-3- [[[2-methyl-5-[[(acetoxy)methoxy]carbonyl]-2H-1,2,4-triazol-3-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo- [4 , 2 ,0.] oct-2-ene-2-carboxylate-acetate as well as acid addition salts of this compound and hydrates of this compound acc. acid addition salts, graded by using a correspondingly substituted acid!! output connections. in I in

7. Method according to one of the claims 1-6, k a r a k-J In the sense that the corresponding halide, especially the iodide, is used as an esterification agent.;

8. Procedure for the production of pharmaceutical pre-I preparations, characterized in that one blany ! in which an easily hydrolyzable ester of the compound of jdenj general formula ;i where X means one of the groups; in which R"*" is lower alkyl, or an acid addition salt of this ester acc. a hydrate of such an ester acc. such an acid addition salt as active ingredient with suitable for therapeutic administration, <]> non-toxic, inert, in and of itself in such preparations, usual solid and liquid carriers and/or excipients. in .

9. Process according to claim 7, characterized in that methylene(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxy-.j iimino] is used as the active ingredient. -acetamido]-3-[[[2-methyl-5-[[(pivaloyloxy)methoxy]-1 carbonyl]-2H-1,2,4-triazol-3-yl]thio]methyl]-8-oxo- 5-thia-1-azabicyclo [4,2,0]-oct-2-ene-2-carboxylate pivalate or in an acid addition salt of this compound acc. a hydrate I of such a compound acc. such an acid addition salt. <....> • <!>