NO871933L - 7-oxo-4-thia-1-azabicyclo (3.2.0) hept-2-ene derivative. - Google Patents

Description

Foreliggende oppfinnelse vedrører forbindelser av formelen The present invention relates to compounds of the formula

jSom er nyttige mellomprodukter for fremstilling av stoffer som har antibakteriell aktivitet og/eller p<->laktamase-inhiberende og/eller inaktiverende aktivitet. jWhich are useful intermediates for the production of substances having antibacterial activity and/or p<->lactamase-inhibiting and/or inactivating activity.

Penicillinene som en klasse har til felles p-laktam-strukturen Å kjent semi-systematisk som "penam"-kjernen. Inn-føringen av en dobbeltbinding mellom karbonatomene 2 og 3 i denne strukturen gir opphav til "penem"-kjernen B. The penicillins as a class have in common the β-lactam structure Å known semi-systematically as the "penam" core. The introduction of a double bond between carbon atoms 2 and 3 in this structure gives rise to the "penem" nucleus B.

Penemkjernen B er gitt det systematisk navnet "7-okso-4-tia-l-azabicyklo[3,2,]hept-2-en" , med nummerering spm angitt i formel C. En sidekjede ved posisjon 6 er nummerert som vist ved formel D. The penem core B is given the systematic name "7-oxo-4-thia-l-azabicyclo[3,2,]hept-2-ene", with numbering spm given in formula C. A side chain at position 6 is numbered as shown by formula D.

Det er velkjent at penicillin-antibiotika har vært anvendt i stor grad i mange år for å bekjempe bakterieinfeksjoner hos mennesker og andre dyr. Det første av disse penicillinanti-biotiske midlene som kom i generell terapeutisk anvendelse var benzylpenicillin, og denne forbindelsen finner fremdeles omfattende anvendelse i dag. It is well known that penicillin antibiotics have been used extensively for many years to combat bacterial infections in humans and other animals. The first of these penicillin antibiotics to come into general therapeutic use was benzylpenicillin, and this compound still finds widespread use today.

Det foreligger imidlertid et kontinuerlig behov for nye antibiotika, ikke bare for å bekjempe bakterielle patogener som ikke viser tilfredsstillende respons på behandling med konvensjonelle penici11iner, men også for å bekjempe de bakteriestammene som, selv om de en gang var mottagelige for penicillinbehandling, nå er resistente overfor slik behandling. Følgelig er det innenfor letingen etter nye typer antibiotika et viktig mål å finne forbindelser som har en bredspektret aktivitet sammen med en evne til å bekjempe infeksjoner forårsaker av penicillin-resistente organismer. However, there is a continuing need for new antibiotics, not only to combat bacterial pathogens that do not respond satisfactorily to treatment with conventional penicillins, but also to combat those bacterial strains which, although once susceptible to penicillin treatment, are now resistant against such treatment. Consequently, within the search for new types of antibiotics, an important goal is to find compounds that have a broad-spectrum activity together with an ability to fight infections caused by penicillin-resistant organisms.

Forskjellige patentpublikasjoner beskriver penemderivater som inneholder en fenyl- eller substituert fenylgruppe ved 2-posisjonen. EP 0 002 210A beskriver penemderivater som har et vidt utvalg av substituenter ved 2- og 6-posisjonene, det samme gjør GB 2 042 515A. EP 0 002 210A innbefatter i en tabell overfor forbindelser de som har en 1-hydroksyetylgruppe ved posisjon 6 og en fenyl-, aminometylfenyl-, aminofenyl- eller trifluormetylfenylgruppe ved posisjon 2. GB 2 042 515A innbefatter på tilsvarende måte i en tabell overfor forbindelser et 6-hydroksyetyl-penemderivat som har en fenylgruppe ved posisjon 2, denne fenylgruppen er usubstituert. EP 0 070 204A beskriver penemer med visse svært spesifikke substituerte fenylgrupper ved 2-posisjonen i kombinasjon med et hydrogenatom eller en eventuelt beskyttet hydroksyetylgruppe ved posisjon 6. De eksemplene som vedrører substituerte fenylgrupper ved posisjon 2 behandler dette i kombinasjon med et hydrogenatom ved posisjon 6. Various patent publications describe penem derivatives containing a phenyl or substituted phenyl group at the 2-position. EP 0 002 210A describes penem derivatives having a wide variety of substituents at the 2- and 6-positions, as does GB 2 042 515A. EP 0 002 210A includes in a table of compounds those having a 1-hydroxyethyl group at position 6 and a phenyl, aminomethylphenyl, aminophenyl or trifluoromethylphenyl group at position 2. GB 2 042 515A similarly includes in a table of compounds a 6-Hydroxyethylpenem derivative having a phenyl group at position 2, this phenyl group being unsubstituted. EP 0 070 204A describes penems with certain very specific substituted phenyl groups at the 2-position in combination with a hydrogen atom or an optionally protected hydroxyethyl group at position 6. The examples relating to substituted phenyl groups at position 2 treat this in combination with a hydrogen atom at position 6.

Det er i forbindelse med foreliggende oppfinnelse fremstilt og undersøkt visse 6-hydroksyetyl-2-substituerte fenyl-derivater som generelt er beskrevet innenfor tidligere kjent teknikk, og det er funnet at selv om de har aktivitet i en representativ antibakteriell undersøkelse, foreligger det et behov for forbindelser som har høyere aktiviteter. In connection with the present invention, certain 6-hydroxyethyl-2-substituted phenyl derivatives which are generally described within the prior art have been prepared and examined, and it has been found that although they have activity in a representative antibacterial examination, there is a need for compounds that have higher activities.

Ved foreliggende oppfinnelse tilveiebringes en forbindelse av formel I The present invention provides a compound of formula I

hvori in which

R står for et hydrogenatom eller en karboksylsyre-forestrende gruppe; R stands for a hydrogen atom or a carboxylic acid esterifying group;

Ri står for Ri stands for

(i) en av de følgende gruppene (i) one of the following groups

hvori Ra og Rb, som kan være like eller forskjellige, hver wherein Ra and Rb, which may be the same or different, each

står for en alkylgruppe som inneholder fra 1-4 karbonatomer, eller stands for an alkyl group containing from 1-4 carbon atoms, or

(ii) en -C0NH(CH2)mQ eller -NHCO(CH2 )mQ-gruppe, hvori m står for et helt tall fra 1 til 3, og Q står en av de følgende gruppene (ii) a -C0NH(CH2)mQ or -NHCO(CH2 )mQ group, wherein m represents an integer from 1 to 3, and Q represents one of the following groups

hvori Rc står for en metyl- eller etylgruppe, eller (iii) en -CC^Rd-gruppe, hvori Rd står for en metyl-eller etylgruppe som er usubstituert eller substituert med en eller flere substituenter, som kan være like eller forskjellige, valgt fra (a) halogenatomer og vinylgrupper, (b) fenylgrupper som er usubstituerte eller substituerte med en eller flere grupper valgt blant alkoksygrupper som inneholder fra 1-4 karbonatomer, nitrogrupper og halogenatomer, (c) silylgrupper SiReRfRg, hvor gruppene Re, Rf og Rg er like eller forskjellige, og hver står for en fenylgruppe eller en alkylgruppe som inneholder fra 1-4 karbonatomer, og (d) grupper Q som definert ovenfor; eller (iv) en -C02SiReRfRg-gruppe, hvori Re, Rf og Rg er definert som i (c) ovenfor, eller (v) en -COg-fenylgruppe, hvori fenyldelen er usubstituert eller substituert som definert i (b) ovenfor; wherein Rc represents a methyl or ethyl group, or (iii) a -CC^Rd group, wherein Rd represents a methyl or ethyl group which is unsubstituted or substituted by one or more substituents, which may be the same or different, selected from (a) halogen atoms and vinyl groups, (b) phenyl groups which are unsubstituted or substituted with one or more groups selected from alkoxy groups containing from 1-4 carbon atoms, nitro groups and halogen atoms, (c) silyl groups SiReRfRg, where the groups Re, Rf and Rg are the same or different, and each represents a phenyl group or an alkyl group containing from 1-4 carbon atoms, and (d) groups Q as defined above; or (iv) a -CO2SiReRfRg group, wherein Re, Rf and Rg are defined as in (c) above, or (v) a -COg-phenyl group, wherein the phenyl moiety is unsubstituted or substituted as defined in (b) above;

R<2>står for R<2> stands for

(i) et hydrogenatom, (i) a hydrogen atom,

(ii) en gruppe som definert ovenfor for R^ (R<*>og R<2>(ii) a group as defined above for R^ (R<*>and R<2>

er like eller forskjellige), eller are the same or different), or

(iii) et klor-, brom- eller jodatom, en alkylgruppe som inneholder fra 1-4 karbonatomer, en -NHg-, - (iii) a chlorine, bromine or iodine atom, an alkyl group containing from 1-4 carbon atoms, a -NHg-, -

NHRa- eller -NRaRb-gruppe, en -0H- eller -ORa-gruppe, eller en- OCOCH^-gruppe, hvor Ra og Rb er som definert ovenfor, og NHRa or -NRaRb group, an -OH or -ORa group, or an -OCOCH^ group, where Ra and Rb are as defined above, and

R<3>står for et hydrogenatom eller en hydroksy-beskyttende gruppe; og R<3> represents a hydrogen atom or a hydroxy protecting group; and

hvori R<1>og R<2>, uavhengig av hverandre, kan befinne seg i en hvilken som helst posisjon på fenylringen; og salter derav; og isomerer derav. wherein R<1> and R<2>, independently of each other, can be in any position on the phenyl ring; and salts thereof; and isomers thereof.

I en forbindelse av formel I er en beskyttet karboksygruppe-COOR, fortrinnsvis en forestret karboksygruppe som kan omvandles ved hydrolyse, ved fotolyse, ved oksydasjon, ved reduksjon eller, spesielt, ved esterase-enzymvlrkning, slik at man får den frie syren av formel I. Videre er i en forbindelse av formel I, en hydroksy-beskyttende gruppe R<3>fortrinnsvis en gruppe som kan omvandles ved hydrolyse, ved fotolyse, ved reduksjon eller, spesielt, ved esterase-enzymvirkning, slik at man får en forbindelse av formel I som har en fri 8-hydroksygruppe. Detaljer vedrørende slike karboksy- og hydroksy-beskyttende grupper er angitt nedenfor. In a compound of formula I, a protected carboxy group is COOR, preferably an esterified carboxy group which can be converted by hydrolysis, by photolysis, by oxidation, by reduction or, in particular, by esterase enzyme reaction, so that one obtains the free acid of formula I Furthermore, in a compound of formula I, a hydroxy-protecting group R<3> is preferably a group that can be converted by hydrolysis, by photolysis, by reduction or, in particular, by esterase enzyme action, so that a compound of formula I which has a free 8-hydroxy group. Details regarding such carboxy and hydroxy protecting groups are set forth below.

Grupper som kan fjernes ved esterase-virkning er grupper som kan spaltes in vivo. Forbindelser som inneholder slike grupper er kjent som "prodrugs". Foretrukne forbindelser av formel I er de hvori, uavhengig av hverandre, R står for et hydrogenatom, en fysiologisk tålbar saltdannende gruppe, eller en gruppe som kan spaltes in vivo, slik at man får den frie karboksygruppen eller en karboksylatgruppe, og R<3>står for et hydrogenatom eller en gruppe som kan spaltes in vivo, slik at man får den frie hydroksygruppen. Groups that can be removed by esterase action are groups that can be cleaved in vivo. Compounds containing such groups are known as "prodrugs". Preferred compounds of formula I are those in which, independently of each other, R stands for a hydrogen atom, a physiologically tolerable salt-forming group, or a group which can be cleaved in vivo to give the free carboxy group or a carboxylate group, and R<3> stands for a hydrogen atom or a group that can be split in vivo, so that the free hydroxy group is obtained.

Foreliggende oppfinnelse tilveiebringer salter av en forbindelse av formel I, spesielt fysiologisk tålbare salter derav. Et salt kan dannes ved 2-karboksylsyregruppen eller ved et hvilket som helst surt eller basisk senter som er tilstede. Når videre både et surt senter og et basisk senter er tilstede, kan en forbindelse av formel I eksistere i en dobbeltionisk form. Et karboksylsyresalt av en forbindelse av formel I er foretrukket fremfor den frie syren, dersom oppløselighet er viktig. The present invention provides salts of a compound of formula I, especially physiologically tolerable salts thereof. A salt can be formed at the 2-carboxylic acid group or at any acidic or basic center present. Furthermore, when both an acidic center and a basic center are present, a compound of formula I can exist in a doubly ionic form. A carboxylic acid salt of a compound of formula I is preferred over the free acid, if solubility is important.

I definisjonene av R<1>og R<2>, er en alkylgruppe Ra eller Rb fortrinnsvis en metyl- eller etylgruppe, spesielt en metylgruppe. Symbolet "m" betegner fortrinnsvis heltallet 1 eller 2. In the definitions of R<1> and R<2>, an alkyl group Ra or Rb is preferably a methyl or ethyl group, especially a methyl group. The symbol "m" preferably denotes the integer 1 or 2.

Av gruppene R<1>angitt ovenfor er de følgende foretrukne Of the groups R<1> indicated above, the following are preferred

Ra, Q og m er som definert ovenfor, og har spesielt de foretrukne betydningene angitt ovenfor. Spesielt foretrukket som R<1>er -C0NH2-, -CONHCH3-, -NHCHO- og -NHCOCH3-grupper. Ra, Q and m are as defined above, and in particular have the preferred meanings indicated above. Particularly preferred as R<1> are -C0NH2-, -CONHCH3-, -NHCHO- and -NHCOCH3 groups.

En forbindelse av formel I kan foreligge i forskjellige isomere former, hvorav alle er del av foreliggende oppfin- neise, f.eks. kan en substituent R-*- være tilstede ved en hvilken som helst posisjon på fenylringen når R<2>står for et hydrogenatom. Når R<2>står for noe annet enn et hydrogenatom, kan R<1>og R<2>besette hvilke to posisjoner som helst på ringen, underkastes kjente begrensninger vedrørende, f.eks., stereokjemiske betraktninger. Videre kan noen substituenter Ri og R<2>selv eksistere i forskjellige tautomere og/eller geometrisk isomere former, f.eks. kan et oksim være i syn-eller anti-form. Som nevnt ovenfor er alle isomerene del av foreliggende oppfinnelse. A compound of formula I can exist in different isomeric forms, all of which are part of the present invention, e.g. a substituent R-*- can be present at any position on the phenyl ring when R<2> represents a hydrogen atom. When R<2> stands for something other than a hydrogen atom, R<1> and R<2> can occupy any two positions on the ring, subject to known restrictions regarding, for example, stereochemical considerations. Furthermore, some substituents R1 and R<2> themselves may exist in different tautomeric and/or geometrically isomeric forms, e.g. an oxime can be in the syn or anti form. As mentioned above, all the isomers are part of the present invention.

Stereokjemien ved posisjonene 5, 6 og 8 av en forbindelse av formel I kan være R eller S, uavhengig av hverandre (R og S er definert ved Cahn-Ingold-Prelog-systemet for nomenklatur). Den foretrukne stereokjemien ved posisjon 5 er R, ved posisjon 6 S, og ved posisjon 8 R, 5R, 6S, 8R-stereokjemi er spesielt foretrukket. The stereochemistry at positions 5, 6 and 8 of a compound of formula I may be R or S, independently of each other (R and S are defined by the Cahn-Ingold-Prelog system of nomenclature). The preferred stereochemistry at position 5 is R, at position 6 S, and at position 8 R, 5R, 6S, 8R stereochemistry is particularly preferred.

Foreliggende oppfinnelse vedrører også en fremgangsmåte for fremstilling av en forbindelse av formel I, som innbefatter The present invention also relates to a method for producing a compound of formula I, which includes

(A) behandling av en forbindelse av formel II (A) treatment of a compound of formula II

hvori R<3>har betydningen angitt ovenfor, wherein R<3> has the meaning given above,

R<4>står for en karboksy-beskyttende gruppe, R<4> stands for a carboxy protecting group,

r<5>står en gruppe R^ som definert ovenfor eller en gruppe som kan omvandles til en gruppe R-'-, r<5>is a group R^ as defined above or a group which can be converted into a group R-'-,

R^ står for en gruppe R<2>som definert ovenfor eller en gruppe som kan omvandles til en gruppe R<2>, R^ represents a group R<2> as defined above or a group which can be converted into a group R<2>,

R<7>står en fenylgruppe eller en alkylgruppe som inneholder fra 1-4 karbonatomer, og R<7> is a phenyl group or an alkyl group containing from 1-4 carbon atoms, and

R<8>står for et brom- eller kloratom, spesielt et kloratom, med en base; eller R<8> represents a bromine or chlorine atom, especially a chlorine atom, with a base; or

(B) bevirkning av ringslutning av en forbindelse av formel (B) effecting cyclization of a compound of formula

III III

hvoriR<3>,R<4>, R<5>og R<6>er som definert ovenfor, X står for et oksygen- eller svovelatom, og gruppen P(Z)3står for en gruppe avledet fra en treverdig organofosforreagens, eller wherein R<3>, R<4>, R<5> and R<6> are as defined above, X represents an oxygen or sulfur atom, and the group P(Z)3 represents a group derived from a trivalent organophosphorus reagent, or

(C) behandling av en forbindelse av formel IV eller V (C) treating a compound of formula IV or V

hvori X, R<3>,R4,R5,R6 og R<8>er som definert ovenfor, med en treverdig organofosforforbindelse og gjennomføring av ringslutning, eller (D) omsetning av en forbindelse av formel VI hvori R<3>, R<4>og gruppen P(Z)3er som definert ovenfor, og R^<9>står for Cu(II), Pb(II) eller Hg(II), i hvilket tilfelle n står for 2, eller R<19>står for Ag(I), i hvilket tilfelle n står for 1, med en forbindelse av formel VII hvori rH står for en aktiverende gruppe, f.eks. en aktiverende estergruppe eller, fortrinnsvis, et halogenatom, og spesielt et kloratom, og X, R<5>og R^ er som definert ovenfor, og det bevirkes ringslutning, og (E) 1 en egnet forbindelse hvori R<5>og/eller R^ står for en gruppe som kan omvandles til en gruppe R<1>og/eller R<2>, wherein X, R<3>, R4, R5, R6 and R<8> are as defined above, with a trivalent organophosphorus compound and carrying out ring closure, or (D) reacting a compound of formula VI wherein R<3>, R <4>and the group P(Z)3 is as defined above, and R^<9>is Cu(II), Pb(II) or Hg(II), in which case n is 2, or R<19> stands for Ag(I), in which case n stands for 1, with a compound of formula VII in which rH stands for an activating group, e.g. an activating ester group or, preferably, a halogen atom, and especially a chlorine atom, and X, R<5> and R^ are as defined above, and cyclization is effected, and (E) 1 a suitable compound in which R<5>and/ or R^ represents a group which can be converted into a group R<1> and/or R<2>,

henholdsvis, omvandling av en slik gruppe eller grupper R^ og/eller R^ til en slik gruppe eller grupper R^ og/eller R<2>og, respectively, conversion of such a group or groups R^ and/or R^ to such a group or groups R^ and/or R<2> and,

(F) om ønsket eller påkrevet, i en egnet forbindelse omvandling av en gruppe R^ og/eller en gruppe R<2>til en annen (F) if desired or required, in a suitable connection conversion of a group R^ and/or a group R<2> into another

gruppe R-'- og/eller R<2>, henholdsvis; og group R-'- and/or R<2>, respectively; and

(G) om ønsket eller påkrevet, utførelse av et hvilket som helst eller flere av de følgende trinnene i en hvilken som (G) if desired or required, performing any one or more of the following steps in any which

helst ønsket rekkefølge: preferred order:

(a) hydrolysering av en 2-karboksylestergruppe I en egnet forbindelse slik at man får den tilsvarende frie syren, (b) behandling av en egnet fri syre eller et salt derav med et middel som er i stand til å danne en 2-karboksylsyreester, f.eks. med en alkohol, en fenol eller et reaktivt derivat derav, slik at man får 2-karboksylsyreesteren derav, (c) utførelse av en syre- eller base-katalysert ester-utveksling på en egnet 2-karboksylsyreester slik at man får en annen ester av forbindelsen, (d) behandling av en egnet fri syreforbindelse med en base slik at man får et salt ved karboksygruppen ved posisjon 2, (e) behandling av en egnet fri syre eller 2-karboksylsyreester som har en basisk gruppe tilstede med en syre slik at man får et syreaddisjonssalt derav, (f) behandling av et salt av en egnet forbindelse med en syre slik at man får en fri syre av forbindelsen, (g) fjernelse av en hydroksy-beskyttende gruppe fra en egnet forbindelse som har en beskyttet 8-hydroksygruppe, slik at man får den tilsvarende forbindelsen som har en fri 8-hydroksygruppe, (h) behandling av en egnet forbindelse som har en fri hydroksygruppe ved 8-posisjonen med et organisk syrederivat slik at det dannes en ester ved 8-posisjonen, og (i) behandling av en egnet forbindelse for å bevirke en endring i den stereokjemiske konfigurasjonen. (a) hydrolyzing a 2-carboxylic acid ester group in a suitable compound to give the corresponding free acid, (b) treating a suitable free acid or a salt thereof with an agent capable of forming a 2-carboxylic acid ester, e.g. with an alcohol, a phenol or a reactive derivative thereof to give the 2-carboxylic acid ester thereof, (c) performing an acid- or base-catalyzed ester exchange on a suitable 2-carboxylic acid ester to give another ester of the compound, (d) treating a suitable free acid compound with a base to give a salt at the carboxy group at position 2, (e) treating a suitable free acid or 2-carboxylic acid ester having a basic group present with an acid so that obtaining an acid addition salt thereof, (f) treating a salt of a suitable compound with an acid to obtain a free acid of the compound, (g) removing a hydroxy protecting group from a suitable compound having a protected 8- hydroxy group, so as to obtain the corresponding compound having a free 8-hydroxy group, (h) treating a suitable compound having a free hydroxy group at the 8-position with an organic acid derivative to form an ester at the 8-position, and (i) processing of a suitable compound to effect a change in the stereochemical configuration.

I formel I kan R<3>stå for et hydrogenatom eller en beskyttende gruppe. I visse av fremgangsmåtene innbefattet i fremstillingen av en forbindelse av formel I, kan det være foretrukket å beskytte 8-hydroksygruppen. Tilsvarende kan være å foretrekke eller av vesentlig betydning å beskytte 2-karboksygruppen under dannelsen av en forbindelse av formel I. Hydroksy- og karboksy-beskyttende grupper -og fremgangsmåter for innføring og fjernelse av disse er kjente (dvs., i vanlig bruk innenfor kjent teknikk eller beskrevet i littera-turen av teknikken) se f.eks. McOmie, "Protecting Groups in Organic Chemistry", Plenum Press, Londen, 1973 og T.W. Greene, "Protective Groups in Organic Synthesis", J. Wiley & Sons, Inc., 1981. Hydroksy- og karboksy-beskyttende grupper som fortrinnsvis anvendes ved foreliggende oppfinnelse og fremgangsmåter for innføring og fjernelse av disse er beskrevet i større detalj nedenfor. In formula I, R<3> can stand for a hydrogen atom or a protecting group. In certain of the processes involved in the preparation of a compound of formula I, it may be preferred to protect the 8-hydroxy group. Similarly, it may be preferable or of significant importance to protect the 2-carboxy group during the formation of a compound of formula I. Hydroxy and carboxy protecting groups - and methods for introducing and removing these are known (ie, in common use within known technique or described in the literature of the technique) see e.g. McOmie, "Protecting Groups in Organic Chemistry", Plenum Press, London, 1973 and T.W. Greene, "Protective Groups in Organic Synthesis", J. Wiley & Sons, Inc., 1981. Hydroxy and carboxy protective groups which are preferably used in the present invention and methods for their introduction and removal are described in greater detail below.

Hydroksy- og karboksybeskyttende grupper kan være tilstede uavhengig av hverandre i en forbindelse av formel I eller i et hvilket som helst mellomprodukt som er innbefattet i fremstillingen derav. Videre kan beskyttende grupper innføres og fjernes ved et hvilket som helst egnet punkt i en reak-sjonsrekke. Hydroxy and carboxy protecting groups may be present independently of each other in a compound of formula I or in any intermediate involved in its preparation. Furthermore, protecting groups can be introduced and removed at any suitable point in a reaction sequence.

En forbindelse av formel II behandles med en base slik at man får en forbindelse av formel I eller et forstadium derav. Karboksygruppen i forbindelsen av formel I er beskyttet, men hydroksygruppen kan være fri eller beskyttet. Basen kan være uorganisk eller organisk, f.eks. ammoniakk, eller et alkalimetall, spesielt et natrium- eller kaliumkarbonat, -bikarbonat, eller -hydroksyd; et primært amin, f.eks. metyl-amin, etylamin, anilin eller benzylamin; et alkalimetall-alkoksy, f.eks. natriummetoksyd; eller en heterocyklisk base, som f.eks. har en pKa innenfor området fra 5 til 9, f.eks. imidazol, pyridin eller substituert pyridin, f.eks. alkyl-, amino-, monoalkylamino- eller dialkylamino-substituert pyridin, f.eks. 4-metylpyridin eller 4-dimetylaminopyridin. Imidazol er spesielt foretrukket. A compound of formula II is treated with a base so that a compound of formula I or a precursor thereof is obtained. The carboxy group in the compound of formula I is protected, but the hydroxy group may be free or protected. The base can be inorganic or organic, e.g. ammonia, or an alkali metal, especially a sodium or potassium carbonate, bicarbonate, or hydroxide; a primary amine, e.g. methylamine, ethylamine, aniline or benzylamine; an alkali metal alkoxy, e.g. sodium methoxide; or a heterocyclic base, such as has a pKa within the range from 5 to 9, e.g. imidazole, pyridine or substituted pyridine, e.g. alkyl-, amino-, monoalkylamino- or dialkylamino-substituted pyridine, e.g. 4-methylpyridine or 4-dimethylaminopyridine. Imidazole is particularly preferred.

Reaksjonen gjennomføres generelt i et oppløsningsmiddel eller fortynningsmiddel, som kan velges innenfor vide grenser forutsatt at det er inert under reaksjonsbetingelsene. Eksempler på oppløsningsmidler og fortynningsmidler er oksygenerte hydrokarboner, f.eks. etere, som f.eks. inneholder opptil 4 karbonatomer, f.eks. dietyleter, videre tetrahydrofuran og dioksan; ketoner, som f.eks. inneholder opptil 4 karbonatomer, f.eks. aceton og metyletylketon; estere, f.eks. metylacetat og etylacetat; og amider, f.eks. dimetylformamid og dimetylacetamid; videre klorerte hydrokarboner, f.eks. kloroform, metylenklorid og karbontetraklorid; aromatiske hydrokarboner, f.eks. benzen og toluen; og andre oppløsningsmidler, f.eks. acetonitril og nitrometan. En blanding av to eller flere oppløsningsmidler kan benyttes, og oppløsningsmidler anvendes fortrinnsvis i blanding med vann; fortrinnsvis benyttes et vann-blandbart oppløsningsmiddel i blanding med 5 til 20$ (volum/volum) vann. The reaction is generally carried out in a solvent or diluent, which may be chosen within wide limits provided that it is inert under the reaction conditions. Examples of solvents and diluents are oxygenated hydrocarbons, e.g. ethers, such as contains up to 4 carbon atoms, e.g. diethyl ether, further tetrahydrofuran and dioxane; ketones, such as contains up to 4 carbon atoms, e.g. acetone and methyl ethyl ketone; esters, e.g. methyl acetate and ethyl acetate; and amides, e.g. dimethylformamide and dimethylacetamide; further chlorinated hydrocarbons, e.g. chloroform, methylene chloride and carbon tetrachloride; aromatic hydrocarbons, e.g. benzene and toluene; and other solvents, e.g. acetonitrile and nitromethane. A mixture of two or more solvents can be used, and solvents are preferably used in a mixture with water; preferably a water-miscible solvent is used in mixture with 5 to 20% (volume/volume) of water.

hvoriR<3>,R4,R5,R<6>,R<7>ogR<8>er som definert ovenfor, R<9>står for en alkylgruppe som inneholder fra 1-8, fortrinnsvis fra 1-4 karbonatomer, en alkenylgruppe som inneholder fra 2-4 karbonatomer, eller en fenylgruppe, og R^-0 står for en gruppe -SOg-Rh eller -CORh hvori Rh står for en alkylgruppe som inneholder fra 1-4 karbonatomer, en eventuelt substituert fenylgruppe, eller en polyfluoralkylgruppe, spesielt en trifluormetylgruppe. wherein R<3>, R4, R5, R<6>, R<7> and R<8> are as defined above, R<9> represents an alkyl group containing from 1-8, preferably from 1-4 carbon atoms, a alkenyl group containing from 2-4 carbon atoms, or a phenyl group, and R^-0 stands for a group -SOg-Rh or -CORh in which Rh stands for an alkyl group containing from 1-4 carbon atoms, an optionally substituted phenyl group, or a polyfluoroalkyl group, especially a trifluoromethyl group.

Noen forbindelser av formel VIII er kjente, se f.eks. GB 2.102.798A og belgisk patent 887.886. Andre forbindelser av formel VIII kan fremstilles analogt. Some compounds of formula VIII are known, see e.g. GB 2,102,798A and Belgian Patent 887,886. Other compounds of formula VIII can be prepared analogously.

For å oppnå forbindelse IX omsettes forbindelse VIII, i nærvær av en base, med et aktivert karboksylsyrederivat av formel Vila To obtain compound IX, compound VIII is reacted, in the presence of a base, with an activated carboxylic acid derivative of formula Vila

hvorir<5>, r6 og rH er som definert ovenfor. where r<5>, r6 and rH are as defined above.

Mange forbindelser av formel Vila er kjente, og de andre kan fremstilles ved fremgangsmåter analoge de som er beskrevet for fremstillingen av de kjente forbindelsene, se f.eks. "Organic Syntheses", samlevolum 4, s. 715, Wiley, New York, 1963, eller samlevolum 2, s. 528, 1943. Many compounds of formula VIIa are known, and the others can be prepared by methods analogous to those described for the preparation of the known compounds, see e.g. "Organic Syntheses", Collected Volume 4, p. 715, Wiley, New York, 1963, or Collected Volume 2, p. 528, 1943.

Reaksjonen mellom forbindelse VIII og forbindelse Vila utføres i nærvær av en base, som fortrinnsvis har en pKa 20, fortrinnsvis et metallholdig amin, og eksempler på foretrukne baser er litiumdiisopropylamid, litiumheksam-etyldisilazid, litium-2,2,6,6-tetrametylpiperidid, litium-cykloheksylisopropylamid og natriumamid. The reaction between compound VIII and compound Vila is carried out in the presence of a base, which preferably has a pKa of 20, preferably a metal-containing amine, and examples of preferred bases are lithium diisopropylamide, lithium hexamethyldisilazide, lithium 2,2,6,6-tetramethylpiperidide, lithium cyclohexylisopropylamide and sodium amide.

Reaksjonen utføres generelt ved en temperatur i området fra 0-4C<P>C, fortrinnsvis fra 0-20°C. The reaction is generally carried out at a temperature in the range from 0-4C<P>C, preferably from 0-20°C.

En forbindelse av formel Ia, dvs. en forbindelse som er analog med forbindelse I, men som inneholder gruppene R<5>og R<6>kan fremstilles som vist i det følgende reaksjonsskjema I: Reaksjonen utføres generelt i et aprotisk oppløsningsmiddel, f.eks. et oksygenert hydrokarbon, fortrinnsvis en eter, f.eks. dietyleter, tetrahydrofuran, dioksan, glym eller diglym. Reaksjonstemperaturen er f.eks. fra -120 til +30°C, fortrinnsvis fra -78 til -20°C. A compound of formula Ia, i.e. a compound which is analogous to compound I, but which contains the groups R<5> and R<6> can be prepared as shown in the following reaction scheme I: The reaction is generally carried out in an aprotic solvent, e.g. e.g. an oxygenated hydrocarbon, preferably an ether, e.g. diethyl ether, tetrahydrofuran, dioxane, glyme or diglyme. The reaction temperature is e.g. from -120 to +30°C, preferably from -78 to -20°C.

Mengden av base som benyttes er f.eks. fra 1-3 mol, beregnet pr. mol av forbindelse VIII, fortrinnsvis fra 1,5 - 2,5 mol base. Forbindelsen av formel Vila anvendes fortrinnsvis i en mengde på fra 1-1,5 mol pr. mol av forbindelse VIII, fortrinnsvis fra 1-1,1 mol av forbindelse Vila pr. mol av forbindelse VIII. The amount of base used is e.g. from 1-3 mol, calculated per moles of compound VIII, preferably from 1.5 - 2.5 moles of base. The compound of formula Vila is preferably used in an amount of from 1-1.5 mol per mol of compound VIII, preferably from 1-1.1 mol of compound Vila per moles of compound VIII.

Reaksjonen kan utføres som følger: Basen kan tilsettes til en omrørt oppløsning av forbindelsene VIII og Vila. Alternativt kan det, til en omrørt oppløsning av forbindelse VIII under en inert atmosfære, tilsettes basen og deretter en oppløsning av forbindelse Vila i det samme eller et annet oppløsnings-middel . The reaction can be carried out as follows: The base can be added to a stirred solution of the compounds VIII and Vila. Alternatively, to a stirred solution of compound VIII under an inert atmosphere, the base can be added and then a solution of compound Vila in the same or another solvent.

Forbindelse IX oppnås generelt i form av en blanding av isomerer som generelt innbefatter E-, Z- og dkso-Isomerene. Slike isomerer kan separeres, men dette er ikke generelt påkrevet. (Betegnelsene E og Z er definert på side 142 i Allinger et al., "Organic Chemistry", 1971, Worth, New York.) Compound IX is generally obtained in the form of a mixture of isomers which generally includes the E-, Z- and dkso-Isomers. Such isomers can be separated, but this is not generally required. (The terms E and Z are defined on page 142 of Allinger et al., "Organic Chemistry", 1971, Worth, New York.)

Forbindelse IX omsettes, i nærvær av en base, med en forbindelse av formel XII Compound IX is reacted, in the presence of a base, with a compound of formula XII

hvori R<10>er som definert ovenfor, og står f.eks. for en metylsulfonyl-, fenylsulfonyl- eller polyfluoralkylsulfonyl-gruppe , spesielt en tr if luormetylsulfonylgruppe, eller en trifluoracetylgruppe og R<11>står for en aktiverende gruppe som beskrevet ovenfor, til fremstilling av en forbindelse av formel X. in which R<10> is as defined above, and stands for e.g. for a methylsulfonyl, phenylsulfonyl or polyfluoroalkylsulfonyl group, in particular a trifluoromethylsulfonyl group, or a trifluoroacetyl group and R<11> represents an activating group as described above, for the preparation of a compound of formula X.

Basen som anvendes i reaksjonen mellom forbindelsene IX og XII kan være organisk eller uorganisk og er f.eks. et tertiært amin, f.eks. et trialkylamin, spesielt trietylamin eller etyldllsopropylamin, eller en heterocyklisk base, f.eks. pyridin eller alkyl-, dialkyl-, amino-, monoalkylamino- eller dialkylamino-substituert pyridin, f.eks. 4-dimetylaminopyridin. Reaksjonen utføres generelt i et oppløsningsmiddel eller fortynningsmiddel, f.eks. et klorert hydrokarbon, f.eks. diklormetan, en eter, f.eks. dietyleter eller tetrahydrofuran, eller en ester, f.eks. etylacetat. Temperaturen for reaksjonen ligger generelt innenfor området fra -80 til +20°C. Forbindelse X fremstilles generelt i form av en blanding av isomerer som generelt innbefatter E- og Z-isomerene. Slike isomerer kan separeres, men dette er generelt ikke påkrevet. The base used in the reaction between compounds IX and XII can be organic or inorganic and is e.g. a tertiary amine, e.g. a trialkylamine, especially triethylamine or ethylisopropylamine, or a heterocyclic base, e.g. pyridine or alkyl-, dialkyl-, amino-, monoalkylamino- or dialkylamino-substituted pyridine, e.g. 4-Dimethylaminopyridine. The reaction is generally carried out in a solvent or diluent, e.g. a chlorinated hydrocarbon, e.g. dichloromethane, an ether, e.g. diethyl ether or tetrahydrofuran, or an ester, e.g. ethyl acetate. The temperature for the reaction is generally within the range from -80 to +20°C. Compound X is generally prepared as a mixture of isomers which generally includes the E and Z isomers. Such isomers can be separated, but this is generally not required.

Forbindelse X omvandles til forbindelsen XI ved reaksjon med en forbindelse av formel XIII Compound X is converted to compound XI by reaction with a compound of formula XIII

hvori R<7>er som definert ovenfor og fortrinnsvis står for en metyl- eller, spesielt, t-butylgruppe. Forbindelsen XIII foreligger fortrinnsvis i form av et reaktivt derivat derav, f.eks. som et alkalimetall-, jordalkalimetall- eller organisk aminsalt. Forbindelse XIII kan omvandles til saltform in situ. wherein R<7> is as defined above and preferably represents a methyl or, in particular, t-butyl group. The compound XIII is preferably in the form of a reactive derivative thereof, e.g. as an alkali metal, alkaline earth metal or organic amine salt. Compound XIII can be converted to salt form in situ.

Reaksjonen mellom forbindelse X og forbindelse XIII utføres generelt i et polart oppløsningsmiddel, f.eks. acetonitril, dimetylformamid eller dimetylsulfoksyd. Reaksjonstemperaturen ligger generelt innenfor området fra 0-40°C, fortrinnsvis ved romtemperatur. The reaction between compound X and compound XIII is generally carried out in a polar solvent, e.g. acetonitrile, dimethylformamide or dimethylsulfoxide. The reaction temperature is generally within the range from 0-40°C, preferably at room temperature.

-SCOR2120-gruppen i denne resulterende forbindelsen av formel XI kan være E eller Z til -C00R<4>-gruppen. Isomerene kan The -SCOR2120 group in this resulting compound of formula XI can be E or Z to the -C00R<4> group. The isomers can

separeres for den etterfølgende reaksjonen, men dette er ikke generelt påkrevet, og isomerblandingen anvendes generelt idet begge isomerene gir en forbindelse av formel I. are separated for the subsequent reaction, but this is not generally required, and the mixture of isomers is generally used as both isomers give a compound of formula I.

Den resulterende forbindelsen XI halogeneres deretter slik at man får en forbindelse av formel II, ved å anvende et middel som er i stand til å spalte en karbo-svovelbinding og til å innføre et halogenatom. Slike midler er velkjente innen teknikken og innbefatter, f.eks., molekylært klor, sulfuryl-klorid, t-butylhypokloritt, cyanogenklorid og molekylært brom. The resulting compound XI is then halogenated to give a compound of formula II, using an agent capable of cleaving a carbo-sulfur bond and introducing a halogen atom. Such agents are well known in the art and include, for example, molecular chlorine, sulfuryl chloride, t-butyl hypochlorite, cyanogen chloride and molecular bromine.

Reaksjonen gjennomføres generelt ved en temperatur i området fra -60 til +20°C. Reaksjonen utføres generelt i et oppløs-ningsmiddel eller fortynningsmiddel som er ikke-protisk, og som er inert under reaksjonsbetingelsene, f.eks. en eter, en hydrokarbon eller en halogenert hydrokarbon, f.eks. dioksan, benzen, kloroform, eller diklormetan. En blanding av to eller flere oppløsningsmidler kan benyttes. Eksempler på halogenerende systemer er: klor i kloroform, klor i benzen og t-butylhypokloritt i benzen. I de to sistnevnte tilfellene er temperaturen fortrinnsvis fra 5-20°C, og normalt fra 5-10°C. Generelt anvendes 1-2 mol av det halogenerende midlet pr. mol av forbindelse Vila, se S. Kukolja, J. Amer. Chem. Soc. The reaction is generally carried out at a temperature in the range from -60 to +20°C. The reaction is generally carried out in a solvent or diluent which is non-protic and which is inert under the reaction conditions, e.g. an ether, a hydrocarbon or a halogenated hydrocarbon, e.g. dioxane, benzene, chloroform, or dichloromethane. A mixture of two or more solvents can be used. Examples of halogenating systems are: chlorine in chloroform, chlorine in benzene and t-butyl hypochlorite in benzene. In the two latter cases, the temperature is preferably from 5-20°C, and normally from 5-10°C. In general, 1-2 mol of the halogenating agent are used per moles of compound Vila, see S. Kukolja, J. Amer. Chem. Soc.

(1971), 93, 6267 og P.C. Cherry, CE. Newall og N.S. Watson, J.C.S. Chem. Comm. 1979 s. 663. (1971), 93, 6267 and P.C. Cherry, CE. Newall and N.S. Watson, J.C.S. Chem. Comm. 1979 p. 663.

Den resulterende forbindelsen av formel II kan omvandles til en forbindelse av formel I som beskrevet ovenfor. The resulting compound of formula II can be converted to a compound of formula I as described above.

I reaksjonsskjerna I beskrevet ovenfor, er det foretrukket at 8-hydroksygruppen i forbindelse VIII er beskyttet, for å forhindre at den reagerer med det aktiverte syrederivatet av formel Vila. Hydroksygruppen er også fortrinnsvis beskyttet under reaksjonen mellom forbindelse IX og forbindelse XII. En hydroksybeskyttende gruppe kan bevares i forbindelsene XI og II, men det er funnet at dersom en forbindelse av formel XI som har S-stereokj emi ved posisjon 3 og som inneholder en beskyttet hydroksygruppe ved posisjon 8, halogeneres, har den resulterende forbindelsen av formel I den mindre ønskelige 5S stereokjemien, og det er da påkrevet å endre stereokjemien ved posisjon 5, f.eks. ved oppvarming under tilbakestrømning, dersom 5R-stereokjemien er ønsket. In reaction core I described above, it is preferred that the 8-hydroxy group in compound VIII is protected, to prevent it from reacting with the activated acid derivative of formula Vila. The hydroxy group is also preferably protected during the reaction between compound IX and compound XII. A hydroxy protecting group may be preserved in compounds XI and II, but it has been found that if a compound of formula XI having S-stereochemistry at position 3 and containing a protected hydroxy group at position 8 is halogenated, the resulting compound of formula I has the less desirable 5S stereochemistry, and it is then required to change the stereochemistry at position 5, e.g. by heating under reflux, if the 5R stereochemistry is desired.

Følgelig er det generelt foretrukket å beskytte 8-hydroksygruppen inntil forbindelse X er dannet, og å fjerne den hydroksybeskyttende gruppen før halogenering av forbindelse XI til forbindelse II. En hydroksybeskyttende gruppe kan fjernes fra forbindelse X før den omvandles til forbindelse XI, eller den kan fjernes etter dannelsen av forbindelse XI. Accordingly, it is generally preferred to protect the 8-hydroxy group until compound X is formed, and to remove the hydroxy protecting group before halogenating compound XI to compound II. A hydroxy protecting group can be removed from compound X before it is converted to compound XI, or it can be removed after the formation of compound XI.

En type fortrukket beskyttet gruppe -OR<3>er en gruppe hvorfra den beskyttende gruppen R<3>kan fjernes under sure betingelser. Slike beskyttede grupper er velkjente innen teknikken og er f.eks. tetrahydropyranyloksy- og tetrahydrofuranyloksy-grupper; acetal- og ketalgrupper, f.eks. av formelen One type of preferred protected group -OR<3> is a group from which the protecting group R<3> can be removed under acidic conditions. Such protected groups are well known in the art and are e.g. tetrahydropyranyloxy and tetrahydrofuranyloxy groups; acetal and ketal groups, e.g. of the formula

hvoriR<i2>og R-^3, som kan være like eller forskjellige, begge står for et hydrogenatom eller en laverealkylgruppe, fortrinnsvis en metylgruppe, eller R-^-2 og R-^3 står sammen med det karbonatomet som de er bundet til for en cykloalkylring som inneholder fra 4-7 karbonatomer, og R^-4 står for en laverealkylgruppe, fortrinnsvis en metyl- eller etylgruppe, og R^-2 og R<i4>står sammen med det oksygenatomet som de er knyttet til for en tetrahydropyranylring; videre silyletere, som f.eks. inneholder 3 substituenter på si 1 isiumatomet, og fortrinnsvis opptil 24 karbonatomer samlet, de tre substituentene kan være like eller forskjellige, og valgt fra alkyl-, alkenyl- og cykloalkylgrupper, og fenyl- og fenylalkylgrupper wherein R<i2>and R-^3, which may be the same or different, both stand for a hydrogen atom or a lower alkyl group, preferably a methyl group, or R-^-2 and R-^3 stand together with the carbon atom to which they are attached for a cycloalkyl ring containing from 4-7 carbon atoms, and R^-4 represents a lower alkyl group, preferably a methyl or ethyl group, and R^-2 and R<i4> together with the oxygen atom to which they are attached for a tetrahydropyranyl ring; further silyl ethers, such as e.g. contains 3 substituents on said 1 isium atom, and preferably up to 24 carbon atoms in total, the three substituents may be the same or different, and selected from alkyl, alkenyl and cycloalkyl groups, and phenyl and phenylalkyl groups

som kan være usubstituerte eller substituerte som beskrevet ovenfor, f.eks. -OSiReRfRg-grupper, hvori Re, Rf og Rg er som definert ovenfor, dvs., de kan være like eller forskjellige, og hver står for en alkylgruppe som inneholder fra 1-4 karbonatomer eller en fenylgruppe, som f.eks. gir trimetyl-silyloksy, t r i e ty 1 s i ly 1 oksy , difenyl-t-butylsilyloksy , dimetylt-butylsilyloksy og metyldifenylsilyloksygrupper. which may be unsubstituted or substituted as described above, e.g. -OSiReRfRg groups, in which Re, Rf and Rg are as defined above, i.e., they may be the same or different, and each represents an alkyl group containing from 1-4 carbon atoms or a phenyl group, such as e.g. gives trimethyl-silyloxy, t r i e ty 1 s i ly 1 oxy , diphenyl-t-butylsilyloxy , dimethyl-t-butylsilyloxy and methyldiphenylsilyloxy groups.

Foretrukne hydroksybeskyttende grupper R<3>er tetrahydro-pyranyl, 2-metoksyprop-2-yl, trimetylsilyl og, spesielt, trietylsilyl og t-butyldimetylsilylgrupper. Preferred hydroxy protecting groups R<3> are tetrahydro-pyranyl, 2-methoxyprop-2-yl, trimethylsilyl and, in particular, triethylsilyl and t-butyldimethylsilyl groups.

Slike grupper kan fjernes ved syrehydrolyse, f.eks. ved å anvende 0,1 til 2M, fortrinnsvis 0,5M saltsyre, ved f.eks. å anvende den egnede mengden 6M HC1 i f.eks. tetrahydrofuran, se belgisk patent-beskrivelse nr. 881.012; n-Bu4~NF i et surt medium, f.eks. i eddiksyre, se belgisk patent-beskrivelse nr. 882.764; eller vandig hydrogenfluorid, f.eks. i nærvær av acetonitril, se J. Chem. Soc. Perkin 1, 1981, 2055. Such groups can be removed by acid hydrolysis, e.g. by using 0.1 to 2M, preferably 0.5M hydrochloric acid, by e.g. to use the appropriate amount of 6M HC1 in e.g. tetrahydrofuran, see Belgian Patent Specification No. 881,012; n-Bu4~NF in an acidic medium, e.g. in acetic acid, see Belgian Patent Specification No. 882,764; or aqueous hydrogen fluoride, e.g. in the presence of acetonitrile, see J. Chem. Soc. Perkins 1, 1981, 2055.

En forbindelse av formel Ia kan fremstilles fra en forbindelse av formel III, IV, V eller VI, som vist i det følgende reaksjonsskjerna II: En forbindelse av formel III vil ringsluttes slik at det oppstår en forbindelse av formel I ved romtemperatur dersom den får stå i tilstrekkelig tid, men generelt anvendes varme for å akselerere reaksjonen. Ringslutningen utføres fortrinnsvis i et oppløsningsmiddel, f.eks. en eter, f.eks. dietyleter, dioksan eller tetrahydrofuran, et aromatisk hydrokarbon, f.eks. benzen, toluen eller xylen, et halogenert hydrokarbon, f.eks. kloroform eller diklormetan, eller dimetylformamid eller dimetylsulfoksyd. Temperaturen som anvendes kan være fra romtemperatur til tilbakestrømnings-temperaturen for reaksjonsblandingen. A compound of formula Ia can be prepared from a compound of formula III, IV, V or VI, as shown in the following reaction core II: A compound of formula III will ring-close to form a compound of formula I at room temperature if it is allowed to stand for a sufficient time, but heat is generally used to accelerate the reaction. The cyclization is preferably carried out in a solvent, e.g. an ether, e.g. diethyl ether, dioxane or tetrahydrofuran, an aromatic hydrocarbon, e.g. benzene, toluene or xylene, a halogenated hydrocarbon, e.g. chloroform or dichloromethane, or dimethylformamide or dimethylsulfoxide. The temperature used can be from room temperature to the reflux temperature of the reaction mixture.

En forbindelse av formel III kan fremstilles fra en forbindelse av formel IV, V eller VI, som gjengitt i reaksjonsskjerna II, og kan isoleres dersom dette er ønsket. Hver av forbindelsene IV, V og VI kan, imidlertid, gi en forbindelse av formel Ia direkte, hvilket også er vist i reaksjonsskjerna II. Dersom generelt en forbindelse av formel IV, V eller VI omsettes ved lavere temperaturer, dannes en forbindelse av formel III, og denne kan isoleres og deretter fortrinnsvis oppvarmes som beskrevet ovenfor slik at man får en forbindelse av formel Ia. Dersom høyere reaksjonstemperaturer benyttes, er en forbindelse av formel Ia reaksjonsproduktet som oppnås. Den sistnevnte reaksjonen kan -.forløpe via en forbindelse av formel III eller via et annet mellomprodukt. Ytterligere detaljer vedrørende disse fremgangsmåtene er gjengitt nedenfor. I reaksjonsskjerna II erR<3>,R<4>,R<5>,R^,R8, X og Z som definert ovenfor, og L står for en avspaltbar gruppe, dvs. en gruppe som kan erstattes i en nukleofil utvekslingsreaksjon, f. eks. et halogenatom, spesielt et kloratom; en alkylkar-bonyloksygruppe hvori alkyldelen har fra 1-4 karbonatomer, har en rett eller forgrenet kjede, og kan være substituert med en elektron-tiltrekkende gruppe, f.eks. et halogenatom, spesielt et fluoratom, f.eks. en acetoksy- eller trifluorace-toksygruppe; en f enylkarbonyloksygruppe, f. eks. en benzoyl-oksygruppe; eller en -SC^Rj-gruppe hvori Rj står for en alkylgruppe som inneholder fra 1-4 karbonatomer eller en fenylgruppe. L står fortrinnsvis for en acetoksygruppe. A compound of formula III can be prepared from a compound of formula IV, V or VI, as shown in reaction core II, and can be isolated if this is desired. Each of the compounds IV, V and VI can, however, give a compound of formula Ia directly, which is also shown in reaction nucleus II. If, in general, a compound of formula IV, V or VI is reacted at lower temperatures, a compound of formula III is formed, and this can be isolated and then preferably heated as described above so that a compound of formula Ia is obtained. If higher reaction temperatures are used, a compound of formula Ia is the reaction product obtained. The latter reaction can proceed via a compound of formula III or via another intermediate product. Further details regarding these procedures are provided below. In reaction core II, R<3>, R<4>, R<5>, R^, R8, X and Z are as defined above, and L stands for a leaving group, i.e. a group that can be replaced in a nucleophilic exchange reaction, e.g. a halogen atom, especially a chlorine atom; an alkylcarbonyloxy group in which the alkyl part has from 1-4 carbon atoms, has a straight or branched chain, and may be substituted with an electron-withdrawing group, e.g. a halogen atom, especially a fluorine atom, e.g. an acetoxy or trifluoroacetoxy group; a f phenylcarbonyloxy group, e.g. a benzoyloxy group; or a -SC^Rj group in which Rj stands for an alkyl group containing from 1 to 4 carbon atoms or a phenyl group. L preferably stands for an acetoxy group.

Visse forbindelser av formel XIV er kjente, f.eks., når R<3>står for en dimetyl-t-butylsilyloksygruppe (belgisk patent-beskrivelse nr. 882.764) og når R<3>står for en p-nitrobenzyl-karbonylgruppe (EP 0.002.210A). Andre forbindelser av formel XIV kan fremstilles analogt.' Certain compounds of formula XIV are known, for example, when R<3> represents a dimethyl-t-butylsilyloxy group (Belgian Patent Description No. 882,764) and when R<3> represents a p-nitrobenzylcarbonyl group ( EP 0.002.210A). Other compounds of formula XIV can be prepared analogously.'

En forbindelse av formel XV kan fremstilles ved å omsette en forbindelse av formel XIV med en forbindelse av formel XVII A compound of formula XV can be prepared by reacting a compound of formula XIV with a compound of formula XVII

hvori X, R<5>og R^ er som definert ovenfor, og M står for et hydrogenatom eller et alkalimetall- eller jordalkalimetall-atom, eller en ammoniumgruppe som er usubstituert eller substituert med, f.eks., 1-4 grupper valgt blant alkylgrupper som inneholder fra 1-4 karbonatomer. (Når M står for hydrogen, utføres reaksjonen i nærvær av en base, nedenfor.) wherein X, R<5> and R^ are as defined above, and M represents a hydrogen atom or an alkali metal or alkaline earth metal atom, or an ammonium group which is unsubstituted or substituted with, e.g., 1-4 groups selected among alkyl groups containing from 1-4 carbon atoms. (When M stands for hydrogen, the reaction is carried out in the presence of a base, below.)

Forbindelse XVII fremstilles generelt in situ og isoleres generelt ikke før reaksjon med forbindelse XIV. Compound XVII is generally prepared in situ and is generally not isolated prior to reaction with compound XIV.

En forbindelse XVII kan fremstilles ved A compound XVII can be prepared by

(i) omsetning av en forbindelse av formel VII (i) turnover of a compound of formula VII

hvori. X,R<5>,R^ og rH er som definert ovenfor, med en forbindelse av formelen MSH eller M2S, hvori M er som definert ovenfor, (når M står for hydrogen, utføres reaksjonen i nærvær av en base, f.eks. pyridin eller et trialkylamin hvori hver alkyldel inneholder fra 1-4 karbonatomer); eller in which. X,R<5>,R^ and rH are as defined above, with a compound of the formula MSH or M2S, wherein M is as defined above, (when M stands for hydrogen, the reaction is carried out in the presence of a base, e.g. .pyridine or a trialkylamine in which each alkyl part contains from 1-4 carbon atoms); or

(il) omsetning av en forbindelse av formel XVIII (il) conversion of a compound of formula XVIII

hvori M<1>står for en alkalimetall- eller jordalkali-metallrist, sammen med et motion, dersom dette er påkrevet i tilfelle hvor M-*- står for et toverdig metallion, med karbondisulfid eller karbonoksysulfid, slik at man får en forbindelse av formel XVII, hvori M står for et alkalimetall- eller jordalkalimetall-atom. in which M<1> stands for an alkali metal or alkaline earth metal lattice, together with a counterion, if this is required in the case where M-*- stands for a divalent metal ion, with carbon disulfide or carbon oxysulfide, so that a compound of formula XVII, wherein M represents an alkali metal or alkaline earth metal atom.

I fremgangsmåte (ii) ovenfor, er forbindelsen av formel XVIII et organo-metal 1 isk derivat, f.eks. et fenyllitium- eller fenylmagnesiumhalogenidderivat, og kan fremstilles ved f.eks. å anvende det tilsvarende fenylhalogenidet, spesielt fenyl-bromidet eller -jodidet, med det egnede metallet, f,eks. litium eller magnesium, i et inert oppløsningsmiddel eller fortynningsmiddel, f.eks. en eter, f.eks. dietyleter, eller et aromatisk hydrokarbon, f.eks. toluen, eller ved å anvende en metall-alkylf orbindelse, f.eks. n-butyllitium eller t-butyllitium, i et inert oppløsningsmiddel, f. eks. en eter, f.eks. dietyleter eller tetrahydrofuran. In method (ii) above, the compound of formula XVIII is an organometallic derivative, e.g. a phenyllithium or phenylmagnesium halide derivative, and can be prepared by e.g. to use the corresponding phenyl halide, especially the phenyl bromide or iodide, with the appropriate metal, e.g. lithium or magnesium, in an inert solvent or diluent, e.g. an ether, e.g. diethyl ether, or an aromatic hydrocarbon, e.g. toluene, or by using a metal-alkyl compound, e.g. n-butyllithium or t-butyllithium, in an inert solvent, e.g. an ether, e.g. diethyl ether or tetrahydrofuran.

I hver av fremgangsmåtene (i) og (ii) ovenfor gjennomføres reaksjonen generelt i et oppløsningsmiddel som er inert under reaks j onsbetingelsene, f.eks. i en eter, såsom dietyleter, dioksan eller tetrahydrofuran, et aromatisk hydrokarbon, f.eks. bensen, toluen eller xylen, eller et halogenert hydrokarbon, f.eks. kloroform, karbontetraklorid eller diklormetan. In each of the methods (i) and (ii) above, the reaction is generally carried out in a solvent which is inert under the reaction conditions, e.g. in an ether such as diethyl ether, dioxane or tetrahydrofuran, an aromatic hydrocarbon, e.g. benzene, toluene or xylene, or a halogenated hydrocarbon, e.g. chloroform, carbon tetrachloride or dichloromethane.

En forbindelse av formel XV acyleres deretter ved å anvende en forbindelse av formel XIX A compound of formula XV is then acylated using a compound of formula XIX

hvori R<4>er som definert ovenfor og R<15>står for en gruppe som kan erstattes ved azetidinonnitrogenet i forbindelsen av formel XV slik at man får en forbindelse av formel IV. in which R<4> is as defined above and R<15> stands for a group that can be replaced at the azetidinone nitrogen in the compound of formula XV so that a compound of formula IV is obtained.

En gruppe R<15>er f.eks. et halogenatom, en imidazolidgruppe, eller en blandet anhydridgruppe, f.eks. en gruppe -OCORk eller -OC(0)ORk hvori Rk står for en rettkjedet eller forgrenet alkylgruppe som Inneholder fra 1-4 karbonatomer. R<15>står fortrinnsvis for et halogenatom, spesielt et kloratom. A group R<15> is e.g. a halogen atom, an imidazolide group, or a mixed anhydride group, e.g. a group -OCORk or -OC(0)ORk in which Rk stands for a straight-chain or branched alkyl group containing from 1-4 carbon atoms. R<15> preferably stands for a halogen atom, especially a chlorine atom.

Reaksjonen mellom forbindelse XV og acyleringsmidlet av formel XIX utføres i nærvær av en base, f.eks. et tertiært amin, fortrinnsvis et trialkylamin (hver alkyldel inneholder fra 1-4 karbonatomer og har en rett eller forgrenet kjede, de tre alkyldelene er like eller forskjellige), og spesielt trietylamin eller etyldiisopropylamin; eller pyridin eller en substituert pyridin, f.eks. 4-dimetylaminopyridin. Spesielt foretrukne baser er trietylamin og etyldiisopropylamin. En blanding av to eller flere baser kan benyttes, og en base kan være polymer-bundet. The reaction between compound XV and the acylating agent of formula XIX is carried out in the presence of a base, e.g. a tertiary amine, preferably a trialkylamine (each alkyl part contains from 1-4 carbon atoms and has a straight or branched chain, the three alkyl parts being the same or different), and especially triethylamine or ethyldiisopropylamine; or pyridine or a substituted pyridine, e.g. 4-Dimethylaminopyridine. Particularly preferred bases are triethylamine and ethyldiisopropylamine. A mixture of two or more bases can be used, and one base can be polymer-bound.

I tillegg til en organisk base som beskrevet ovenfor, er det foretrukket å innbefatte et syrebindende middel i reaksjonsblandingen. Eksempler på syrebindende midler er alkalimetall-og jordalkalimetallkarbonater og -bikarbonater, og organiske epoksyder, f.eks. propylenoksyd. Kalsiumkarbonat er et vanlig anvendt bindingsmiddel. In addition to an organic base as described above, it is preferred to include an acid-binding agent in the reaction mixture. Examples of acid binding agents are alkali metal and alkaline earth metal carbonates and bicarbonates, and organic epoxides, e.g. propylene oxide. Calcium carbonate is a commonly used binding agent.

Generelt anvendes det for hvert mol av forbindelse XV fra et 1-2 mol acyleringsmiddel XIX, fra 1-4 mol av en aminbase (eller totalt fra 1-4 mol av en blanding av aminbaser), og fra 0-10 mol av syrebindingsmidlet, dersom dette er tilstede. In general, for each mole of compound XV from 1-2 moles of an acylating agent XIX, from 1-4 moles of an amine base (or in total from 1-4 moles of a mixture of amine bases), and from 0-10 moles of the acid binding agent are used, if this is present.

Forbindelsen med formel XV og acyleringsmidlet av formel XIX omsettes generelt i et oppløsningsmiddel eller fortynningsmiddel som er inert ved reaksjonen, f.eks. i et halogenert hydrokarbon, f.eks. diklormetan eller kloroform, i et oksygenert hydrokarbon, f.eks. en eter, f.eks. tetrahydrofuran, dioksan eller dietylter, eller i et aromatisk hydrokarbon, f.eks. bensen eller toluen. Reaksjonen gjennomføres generelt ved en temperatur i området fra -20 til +60°C, fortrinnsvis fra 0-20°C. The compound of formula XV and the acylating agent of formula XIX are generally reacted in a solvent or diluent which is inert to the reaction, e.g. in a halogenated hydrocarbon, e.g. dichloromethane or chloroform, in an oxygenated hydrocarbon, e.g. an ether, e.g. tetrahydrofuran, dioxane or diethyl ether, or in an aromatic hydrocarbon, e.g. benzene or toluene. The reaction is generally carried out at a temperature in the range from -20 to +60°C, preferably from 0-20°C.

Forbindelse IV, produktet fra acyleringsreaks j onen, kan, om ønsket, isoleres, men omsettes generelt uten ytterligere rensing med en treverdig organofosforreagens slik at man får en forbindelse av formel III eller slik at man får en forbindelse av formel Ia direkte. Compound IV, the product of the acylation reaction, can, if desired, be isolated, but is generally reacted without further purification with a trivalent organophosphorus reagent to give a compound of formula III or to give a compound of formula Ia directly.

Forbindelse IV kan også oppnås ved oksydasjon av en forbindelse av formel XXVII Compound IV can also be obtained by oxidation of a compound of formula XXVII

hvoriR3,R4,R<5>,R<6>og X er som definert ovenfor. wherein R3, R4, R<5>, R<6> and X are as defined above.

Et egnet oksydasjonsmiddel er ozon eller et høyere oksyd av et metall, f.eks. et høyere oksyd av et metall valgt fra en av gruppene Ia, Vb, VIb, Vllb eller VIII i den periodiske tabell over elementene (se "CRC Handbook of Chemistry and Physics", 52. utgave, CRC Press, Cleveland, 1971), f.eks. osmiumtetroksyd, rutheniumtetroksyd, et alkalimetallperoksyd, f.eks. kaliumsuperoksyd; et periodat, f.eks. et alkalimetall-periodat, f.eks. natriumperiodat; eller et alkalimetallper-manganat, f.eks. kaliumpermanganat. En blanding av to eller flere oksydasjonsmidler, f.eks. valgt fra de som er spesielt beskrevet ovenfor, kan også benyttes. Reaksjonen utføres generelt ved en temperatur 1 området fra -80 til +50° C. Et inert oppløsningsmiddel eller fortynningsmiddel kan også benyttes, f.eks. vann; et halogenert hydrokarbon, f.eks. diklormetan; eller acetonitril. Spesielt foretrukne betingelser er ozon i diklormetan ved en temperatur fra -80 til 0°C, og kaliumpermanganat i vann ved en temperatur i området 0 til +40°C. A suitable oxidizing agent is ozone or a higher oxide of a metal, e.g. a higher oxide of a metal selected from one of groups Ia, Vb, VIb, Vllb or VIII of the periodic table of the elements (see "CRC Handbook of Chemistry and Physics", 52nd edition, CRC Press, Cleveland, 1971), f .ex. osmium tetroxide, ruthenium tetroxide, an alkali metal peroxide, e.g. potassium superoxide; a periodate, e.g. an alkali metal periodate, e.g. sodium periodate; or an alkali metal permanganate, e.g. potassium permanganate. A mixture of two or more oxidizing agents, e.g. selected from those specifically described above may also be used. The reaction is generally carried out at a temperature in the range from -80 to +50° C. An inert solvent or diluent can also be used, e.g. water; a halogenated hydrocarbon, e.g. dichloromethane; or acetonitrile. Particularly preferred conditions are ozone in dichloromethane at a temperature of -80 to 0°C, and potassium permanganate in water at a temperature in the range of 0 to +40°C.

En forbindelse av formel XXVII kan oppnås ved å omsette en forbindelse av formel XXVIII A compound of formula XXVII can be obtained by reacting a compound of formula XXVIII

hvori n,R3, R<4>ogR^<9>er som definert ovenfor, med en forbindelse av formel VII i et inert oppløsningsmiddel eller wherein n, R3, R<4> and R^<9> are as defined above, with a compound of formula VII in an inert solvent or

fortynningsmiddel, f.eks. en eter, såsom dietyleter, tetrahydrofuran eller dioksan; et halogenert hydrokarbon, f.eks. kloroform eller diklormetan; acetonitril; en ester, f.eks. etylacetat; eller et aromatisk hydrokarbon, f.eks. toluen. Reaksjonen utføres generelt ved en temperatur i området -80 til +60°C, fortrinnsvis fra -40 til 20'C. Eventuelt kan også en base benyttes: eksempler er trietylamin, pyridin og 4-dimetylaminopyridin. diluent, e.g. an ether such as diethyl ether, tetrahydrofuran or dioxane; a halogenated hydrocarbon, e.g. chloroform or dichloromethane; acetonitrile; an ester, e.g. ethyl acetate; or an aromatic hydrocarbon, e.g. toluene. The reaction is generally carried out at a temperature in the range -80 to +60°C, preferably from -40 to 20°C. Optionally, a base can also be used: examples are triethylamine, pyridine and 4-dimethylaminopyridine.

Noen forbindelser av formel XXVIII er kjente (M. Alpegiani et al., J. Amer. Chem. Soc, 107, 6398 (1985)), og andre kan fremstilles analogt. Some compounds of formula XXVIII are known (M. Alpegiani et al., J. Amer. Chem. Soc, 107, 6398 (1985)), and others can be prepared analogously.

Eksempler på treverdige organofosforreagenser som kan anvendes for å omvandle forbindelse IV til forbindelse III eller forbindelse Ia er fosfitter og fosforamider, f.eks. av de følgende formlene XX og XXI, og fosfiner av formelen XXII i kombinasjon med fosfitter av formel XX Examples of trivalent organophosphorus reagents that can be used to convert compound IV to compound III or compound Ia are phosphites and phosphoramides, e.g. of the following formulas XX and XXI, and phosphines of the formula XXII in combination with phosphites of the formula XX

i disse formlene R1^ , R17,R18 og R19, som kan være like eller forskjellige, alle får en rettkjedet eller forgrenet alkylgruppe som Inneholder fra 1-6 karbonatomer eller en fenylgruppe som kan være usubstituert eller substituert, f.eks. med en metylgruppe, spesielt en para-metylgruppe; videre cykliske tr ialky1 fosfi11er, hvor hver alkyldel Inneholder fra 1-4 karbonatomer, f.eks. av formel XXIII hvori hver gruppe A står for en alkylengruppe som inneholder fra 1-4 karbonatomer; og også katekolfosfitter og katekol-dimerfosfitter, f. eks. av henholdsvis de følgende formlene XXIV og XXV: in these formulas R 1^ , R 17 , R 18 and R 19 , which may be the same or different, all receive a straight-chain or branched alkyl group containing from 1-6 carbon atoms or a phenyl group which may be unsubstituted or substituted, e.g. with a methyl group, especially a para-methyl group; further cyclic trialkyl phosphites, where each alkyl part contains from 1-4 carbon atoms, e.g. of formula XXIII wherein each group A represents an alkylene group containing from 1-4 carbon atoms; and also catechol phosphites and catechol dimer phosphites, e.g. of the following formulas XXIV and XXV, respectively:

hvori R<1>^ og A har de ovenfor angitte betydninger. En treverdig organofosforforbindelse kan være bundet til en inert polymer. wherein R<1>^ and A have the meanings given above. A trivalent organophosphorus compound may be bound to an inert polymer.

En foretrukket treverdig organof osf orreagens er et fosfitt eller fosforamid av henholdsvis formelen XX eller XXi , eller en kombinasjon av en fosfin av formel XXII med en fosfitt av formel XX. Spesielt foretrukket er trialkylf osf ittene, og spesielt trimetylfosfitt og trietylfosfitt. A preferred trivalent organophosphorus reagent is a phosphite or phosphoramide of the formula XX or XXi, respectively, or a combination of a phosphine of the formula XXII with a phosphite of the formula XX. Particularly preferred are the trialkyl phosphites, and especially trimethyl phosphite and triethyl phosphite.

Når organofosforreagensen som benyttes er en fosfitt eller et fosforamid, anvendes generelt fra 2-3 mol derav pr. mol av forbindelse IV. Når et fosfin velges, anvendes generelt fra 1-3 mol pr. mol av forbindelse IV, i kombinasjon med et fosfitt, generelt 1 mol derav. Fosfitten tilsettes fortrinnsvis langsomt til en blanding av fosfinet og forbindelse IV. When the organophosphorus reagent used is a phosphite or a phosphoramide, generally from 2-3 mol thereof per moles of compound IV. When a phosphine is chosen, generally from 1-3 mol per moles of compound IV, in combination with a phosphite, generally 1 mole thereof. The phosphite is preferably added slowly to a mixture of the phosphine and compound IV.

Som beskrevet ovenfor kan en resulterende forbindelse av formel III isoleres og deretter ringsluttes til en forbindelse av formel Ia, eller en forbindelse av formel IV kan omsettes med organof osf orreagensen og ringsluttes in situ slik at man får en forbindelse Ia. I sistnevnte tilfelle kan reaksjonen forløpe via forbindelse III eller via et annet mellomprodukt. As described above, a resulting compound of formula III can be isolated and then cyclized to a compound of formula Ia, or a compound of formula IV can be reacted with the organophosphorus reagent and cyclized in situ to obtain a compound Ia. In the latter case, the reaction can proceed via compound III or via another intermediate product.

Ringslutningsreaksjonen gjennomføres generelt i et tilbake-strømmende oppløsningsmiddel. Når X i forbindelse IV eller forbindelse III står for et svovelatom, er foretrukne oppløs- ningsmidler aromatiske hydrokarboner, f.eks. benzen, toluen og xylen, og halogenerte hydrokarboner, f.eks. diklormetan, kloroform og 1,2-dikloretan. Når X i forbindelse III eller IV står for et oksygenatom, er foretrukne oppløsningsmidler benzen, toluen og xylen. The cyclization reaction is generally carried out in a refluxing solvent. When X in compound IV or compound III stands for a sulfur atom, preferred solvents are aromatic hydrocarbons, e.g. benzene, toluene and xylene, and halogenated hydrocarbons, e.g. dichloromethane, chloroform and 1,2-dichloroethane. When X in compound III or IV stands for an oxygen atom, preferred solvents are benzene, toluene and xylene.

C C

I en forbindelse av formel III fremgår det at gruppen -P(Z)3er avledet fra den treverdige organofosforreagensen eller blandingen av reagenser som er benyttet, denne reagensen eller blandingen av reagenser er fortrinnsvis valgt blant reagensene av formlene XX til XXVI beskrevet ovenfor. Som nevnt ovenfor kan organofosforreagensen være polymer-bundet, i dette tilfellet vil en resulterende forbindelse av formel III også være polymer-bundet. In a compound of formula III, it appears that the group -P(Z)3 is derived from the trivalent organophosphorus reagent or mixture of reagents used, this reagent or mixture of reagents being preferably selected from among the reagents of formulas XX to XXVI described above. As mentioned above, the organophosphorus reagent can be polymer-bound, in which case a resulting compound of formula III will also be polymer-bound.

Forbindelse Ia kan fremstilles fra forbindelse XV ved en alternativ fremgangsmåte via forbindelsene XVI, V og eventuelt III som vist i reaksjonsskjema II. Compound Ia can be prepared from compound XV by an alternative method via compounds XVI, V and optionally III as shown in reaction scheme II.

Ved denne fremgangsmåten omsettes en forbindelse av formel XV med en glyoksylsyreester av formel XXVI In this method, a compound of formula XV is reacted with a glyoxylic acid ester of formula XXVI

hvori R<4>er som definert ovenfor, eller med et reaktivt derivat derav, f.eks. et hydrat eller hemiacetal, en hemiacetal er fortrinnsvis dannet med en alkohol som Inneholder fra 1-4 karbonatomer, f.eks. etanol. wherein R<4> is as defined above, or with a reactive derivative thereof, e.g. a hydrate or hemiacetal, a hemiacetal is preferably formed with an alcohol containing from 1-4 carbon atoms, e.g. ethanol.

Når et hydrat av en forbindelse av formel XXVI benyttes, fjernes vannet som dannes ved reaksjonen fortrinnsvis, f.eks. azeotropisk eller ved å anvende et dehydrerIngsmiddel, f.eks. en molekylarsikt. When a hydrate of a compound of formula XXVI is used, the water formed by the reaction is preferably removed, e.g. azeotropically or by using a dehydrating agent, e.g. a molecular sieve.

Omsetningen utføres generelt i et oppløsningsmiddel eller fortynningsmiddel som er inert under reaksjonsbetingelsene, f.eks. en eter, såsom tetrahydrofuran, dioksan eller dietyleter, et aprotisk oppløsningsmiddel, såsom dimetylacetamid eller dimetylformamid, eller et aromatisk hydrokarbon, f.eks. benzen eller toluen. En blanding av to eller flere opp-løsningsmidler kan også benyttes. Omsetningen utføres generelt ved en temperatur i området fra 0 til 100°C. Fortrinnsvis benyttes 1-2 mol av glyoksylatderivatet pr. mol av forbindelsen XXII. The reaction is generally carried out in a solvent or diluent which is inert under the reaction conditions, e.g. an ether such as tetrahydrofuran, dioxane or diethyl ether, an aprotic solvent such as dimethylacetamide or dimethylformamide, or an aromatic hydrocarbon, e.g. benzene or toluene. A mixture of two or more solvents can also be used. The reaction is generally carried out at a temperature in the range from 0 to 100°C. Preferably, 1-2 mol of the glyoxylate derivative are used per moles of compound XXII.

Den resulterende forbindelsen av formel XVI oppnås som en blanding av R- og S-isomerene ved >CH-OH-gruppen. Disse isomerene kan separeres, om ønsket, men R, S-blandingen anvendes generelt i den neste reaksjonen. The resulting compound of formula XVI is obtained as a mixture of the R and S isomers at the >CH-OH group. These isomers can be separated, if desired, but the R, S mixture is generally used in the next reaction.

I det neste trinnet overføres alkoholen av formel XVI til et halogenid av formel V. Halogeneringen kan utføres på konvensjonell måte ved å anvende et egnet middel, f.eks. tionyl-klorid eller -bromid, fosforoksyklorid eller -oksybromid, eller f o s f o r hal ogen i d , f.eks. f osf orpentaklor id eller-pentabromid, eller en blanding av to eller flere derav. In the next step, the alcohol of formula XVI is transferred to a halide of formula V. The halogenation can be carried out in a conventional manner by using a suitable agent, e.g. thionyl chloride or -bromide, phosphorus oxychloride or -oxybromide, or phosphorus for halogen i d , e.g. phosphorus pentachloride or pentabromide, or a mixture of two or more thereof.

Omsetningen utføres fortrinnsvis i nærvær av en base, f.eks. en heterocyklisk base, såsom pyridin, 4-dimetylaminometyl-pyridin eller lutidin, eller et trlalkylamin, f.eks. trietylamin eller diisopropyletylamln. Basen kan være polymer-bundet . The reaction is preferably carried out in the presence of a base, e.g. a heterocyclic base, such as pyridine, 4-dimethylaminomethylpyridine or lutidine, or a trialkylamine, e.g. triethylamine or diisopropylethylamine. The base can be polymer-bound.

Omsetningen utføres generelt i et oppløsningsmiddel, f.eks. en eter, såsom dietyleter eller dioksan. Reaksjonstemperaturen er generelt i området fra -40 til +40°C, fortrinnsvis romtemperatur og, om ønsket, kan omsetningen utføres under en inert atmosfære. The reaction is generally carried out in a solvent, e.g. an ether, such as diethyl ether or dioxane. The reaction temperature is generally in the range from -40 to +40°C, preferably room temperature and, if desired, the reaction can be carried out under an inert atmosphere.

Den resulterende forbindelsen av formel V oppnås som en blanding av R- og S-isomerene ved >CH-C1- eller >CH-Br-gruppen. Som i tilfellet med forbindelse XVI, kan isomer blandingen separeres i de individuelle isomerene, men generelt benyttes R,S-blandingen. The resulting compound of formula V is obtained as a mixture of the R and S isomers at the >CH-C1 or >CH-Br group. As in the case of compound XVI, the isomeric mixture can be separated into the individual isomers, but generally the R,S mixture is used.

En forbindelse av formel V kan omvandles til en forbindelse av formel Ia. Denne reaksjonen kan forløpe via en forbindelse av formel III eller via et annet mellomprodukt. Om ønsket kan en forbindelse av formel V fosforyleres slik at man får en forbindelse av formel III, som deretter kan isoleres og ringsluttes slik at man får en forbindelse av formel Ia. A compound of formula V can be converted to a compound of formula Ia. This reaction can proceed via a compound of formula III or via another intermediate. If desired, a compound of formula V can be phosphorylated to obtain a compound of formula III, which can then be isolated and cyclized to obtain a compound of formula Ia.

En forbindelse av formel V kan omvandles til en forbindelse av formel Ia eller av formel III ved omsetning ved en egnet temperatur med en treverdig organof osf orreagens, f. eks. en forbindelse av formel XX, XXI, XXII, XXIII, XXIV eller XXV som beskrevet ovenfor. (I foreliggende tilfelle kan et fosfin av formel XX benyttes alene.) A compound of formula V can be converted into a compound of formula Ia or of formula III by reaction at a suitable temperature with a trivalent organophosphoric reagent, e.g. a compound of formula XX, XXI, XXII, XXIII, XXIV or XXV as described above. (In the present case, a phosphine of formula XX can be used alone.)

Reaksjonen utføres fortrinnsvis i nærvær av en base, f.eks. et organisk amin, såsom et tertiært amin, f.eks. pyridin eller et pyridinderivat, eller et trialkylamin , f.eks. trietylamin eller di isopropyletylamin. Reaksjonen utføres generelt i et oppløsningsmiddel som er inert*" under reaksjonsbetingelsene, f.eks. et aromatisk hydrokarbon, såsom benzen eller toluen, eller en eter, f.eks. dietyleter, tetrahydrofuran eller dioksan. The reaction is preferably carried out in the presence of a base, e.g. an organic amine, such as a tertiary amine, e.g. pyridine or a pyridine derivative, or a trialkylamine, e.g. triethylamine or diisopropylethylamine. The reaction is generally carried out in a solvent which is inert under the reaction conditions, eg an aromatic hydrocarbon such as benzene or toluene, or an ether eg diethyl ether, tetrahydrofuran or dioxane.

Reaksjonstemperaturen ligger generelt innenfor området fra-10 til 150" C. Som nevnt ovenfor muliggjør anvendelsen av lavere temperaturer, f.eks. romtemperatur eller lavere, isolering av en forbindelse III, mens høyere temperaturer, f.eks. over romtemperatur generelt fører til forbindelse Ia direkte. The reaction temperature is generally within the range of -10 to 150" C. As mentioned above, the use of lower temperatures, e.g., room temperature or lower, enables the isolation of a compound III, while higher temperatures, e.g., above room temperature generally leads to compound Directly.

En forbindelse av formel Ia kan fremstilles ved en tredje fremgangsmåte som også er vist i reaks j onsskj erna II. Denne fremgangsmåten innbefatter omsetning av et tungt merkaptid av formel VI hvori =P(Z)3,R<3>og R<4>er som definert ovenfor, og R<19>står for Cu(II), Pb(II) eller Hg(II) i hvilket tilfellet n står for det hele tallet 2, eller R<19>står for Ag(I), i hvilket tilfelle n står for det hele tallet 1, med en forbindelse av formel VII A compound of formula Ia can be prepared by a third method which is also shown in reaction core II. This process involves reacting a heavy mercaptide of formula VI wherein =P(Z)3,R<3>and R<4>are as defined above, and R<19>is Cu(II), Pb(II) or Hg(II) in which case n stands for the whole number 2, or R<19>stands for Ag(I), in which case n stands for the whole number 1, with a compound of formula VII

hvori R^, r6,R1<1>og X er som definert ovenfor. wherein R 1 , r 6 , R 1< 1> and X are as defined above.

En forbindelse av formel VI hvori Z står for en fenylgruppe er beskrevet i GB 2.042.515A, som også beskriver en fremgangsmåte for fremstilling derav. Andre forbindelser av formel VI kan fremstilles analogt, under anvendelse av egnet treverdig organofosforreagens. A compound of formula VI in which Z stands for a phenyl group is described in GB 2,042,515A, which also describes a method for its preparation. Other compounds of formula VI can be prepared analogously, using a suitable trivalent organophosphorus reagent.

Forbindelsene VI og VII omsettes generelt i et oppløsnings-middel, f.eks. en eter, såsom dietyleter eller dioksan, et aromatisk hydrokarbon, f.eks. benzen, toluen eller xylen, en ester, såsom etylacetat, et halogenert hydrokarbon, f.eks. diklormetan eller kloroform, eller et aprotisk oppløsnings-middel, f.eks. dimetylformamid eller dimetylacetamid. Reaksj onstemperaturen ligger generelt innenfor området fra -40 til 100°C, fortrinnsvis fra 0 til 40°C. The compounds VI and VII are generally reacted in a solvent, e.g. an ether, such as diethyl ether or dioxane, an aromatic hydrocarbon, e.g. benzene, toluene or xylene, an ester such as ethyl acetate, a halogenated hydrocarbon, e.g. dichloromethane or chloroform, or an aprotic solvent, e.g. dimethylformamide or dimethylacetamide. The reaction temperature is generally within the range from -40 to 100°C, preferably from 0 to 40°C.

Forbindelse VI kan omvandles til forbindelse Ia enten.via forbindelse III eller via et annet mellomprodukt, eller forbindelse VI kan omvandles til forbindelse III som så kan isoleres og omvandles til forbindelse Ia. Lavere temperaturer, f.eks. fra -40°C til romtemperatur, fører generelt til at forbindelse III isoleres, mens høyere temperaturer, f.eks. fra romtemperatur til 150°C, generelt fører til forbindelse Ia. Compound VI can be converted to compound Ia either via compound III or via another intermediate, or compound VI can be converted to compound III which can then be isolated and converted to compound Ia. Lower temperatures, e.g. from -40°C to room temperature, generally results in compound III being isolated, while higher temperatures, e.g. from room temperature to 150°C, generally leading to compound Ia.

I alle de forskjellige mellomproduktene som er innbefattet i fremstillingen av en forbindelse av formel Ia ved fremgangsmåtene beskrevet i reaksjonsskjerna II, er 8-hydroksygruppen og 2-kar b ok sygruppen, når de er tilstede, fortrinnsvis beskyttet, fjernelsen av beskyttel sesgruppene utsettes fortrinnsvis inntil etter at forbindelse Ia,er dannet, og, om aktuelt, inntil eventuelle omvandlinger av grupper R^ og/eller R^, og eventuelle gjensidige omvandlinger av grupper r! og/eller R<2>er utført. In all the various intermediates involved in the preparation of a compound of formula Ia by the methods described in reaction core II, the 8-hydroxy group and the 2-carboxyl group, when present, are preferably protected, the removal of the protecting groups being preferably delayed until after compound Ia is formed, and, if applicable, until any conversions of groups R^ and/or R^, and any mutual conversions of groups r! and/or R<2> is performed.

Som nevnt ovenfor kan et endelig produkt av formej I ha R-eller S-stereokjemien ved posisjon 5, 5R-stereokjemien er foretrukket. Stereokjemien ved posisjon 6 er"fortrinnsvis S. As mentioned above, a final product of form I may have the R or S stereochemistry at position 5, the 5R stereochemistry being preferred. The stereochemistry at position 6 is "preferably S.

I prosess (A) er stereokjemien i posisjon 5 i forbindelse I hovedsakelig den inverse av den ved posisjon 4 i forstadium azetidinonforbindelsen II. I de foregående reaksjonstrinnene vist i reaksjonsskjerna I, gir halogenering av forbindelse XI, når R<3>står for en annen rest enn et hydrogenatom, en forbindelse av formel II med en hovedsakelig trans-relasjon mellom R<8>og den beskyttede hydoksyetylgruppen ved 8-posisjonen. Den resulterende penemforbindelsen av formel I har da en hovedsakelig cis-relasjon mellom svovelatomet i ringen og den beskyttede hydroksyetylgruppen. Omvendt gir halogenering av en forbindelse av formel XI hvori R<3>står for hydrogen generelt en forbindelse av formel II med R<8>hovedsakelig cis til den frie hydroksyetylgruppen, den resulterende forbindelsen av formel I er da hovedsakelig trans. In process (A), the stereochemistry at position 5 in compound I is essentially the inverse of that at position 4 in the precursor azetidinone compound II. In the preceding reaction steps shown in reaction core I, halogenation of compound XI, when R<3> represents a residue other than a hydrogen atom, gives a compound of formula II with a predominantly trans relationship between R<8> and the protected hydroxyethyl group by the 8 position. The resulting penem compound of formula I then has a predominantly cis relationship between the sulfur atom in the ring and the protected hydroxyethyl group. Conversely, halogenation of a compound of formula XI in which R<3>is hydrogen generally gives a compound of formula II with R<8>mainly cis to the free hydroxyethyl group, the resulting compound of formula I being then mainly trans.

I prosessene (B), (C) og (D) er stereokjemien for forbindelse I ved posisjon 5 hovedsakelig bestemt av stereokjemien for tilknytningen av svovelatomet ved posisjon 4 på azetidinon-ringen i f or stadief orb indelsene III, IV, V og VI. I disse forbindelsene, og i forstadieforbindelsene vist i reaksjonsskjerna II, er dette svovelatomet generelt tilnærmet alltid trans til den eventuelt beskyttede hydroksyetylgruppen ved posisjon 3, hvilket også impliserer trans-relasjoner ved hydrogenatomene ved posisjonene 3 og 4. Følgelig vil i reaksjonsskjerna II forbindelse I med 6S-stereokjemi naturlig få 5R-stereokjemi, med hydrogenatomene ved posisjonene 5 og 6 som trans. In processes (B), (C) and (D), the stereochemistry of compound I at position 5 is mainly determined by the stereochemistry of the attachment of the sulfur atom at position 4 on the azetidinone ring in the first stages of steps III, IV, V and VI. In these compounds, and in the precursor compounds shown in reaction core II, this sulfur atom is generally almost always trans to the optionally protected hydroxyethyl group at position 3, which also implies trans relationships at the hydrogen atoms at positions 3 and 4. Consequently, in reaction core II, compound I with 6S stereochemistry naturally yields 5R stereochemistry, with the hydrogen atoms at positions 5 and 6 being trans.

Ved fremstillingen av en forbindelse av formel I, vil en viss grad av termisk likevektsinnstilling ved posisjon 5 finne sted, og denne effekten kan benyttes ved fremstillingen av forbindelser som har en annen relasjon mellom hydrogenatomene ved posisjonene 5 og 6. Spesielt understøttes 1ikevektsinn-sti 11ingsprosessen f.eks. ved oppvarming, f.eks. i et oppløsningsmiddel eller fortynningsmiddel ved en temperatur som generelt ligger innenfor området fra 60 til 150°C, spesielt ved tilbakestrømningstemperaturen for oppløsnings-middelsystemet som benyttes. In the preparation of a compound of formula I, a certain degree of thermal equilibrium setting at position 5 will take place, and this effect can be used in the preparation of compounds that have a different relationship between the hydrogen atoms at positions 5 and 6. In particular, the equilibrium setting process is supported e.g. by heating, e.g. in a solvent or diluent at a temperature generally within the range of 60 to 150°C, particularly at the reflux temperature of the solvent system used.

Som nevnt ovenfor kan R^ og/eller R^ stå for en gruppe som kan omvandles til henholdsvis en gruppe R<1>og/eller R<2>. En slik gruppe R<5>og/eller R^ kan omvandles til den egnede gruppen R<1>og/eller R<2>i en hvilken som helst forbindelse hvor det foreligger, en slik omvandling utgjør en del av foreliggende oppfinnelse. As mentioned above, R^ and/or R^ can stand for a group which can be converted into a group R<1> and/or R<2> respectively. Such a group R<5> and/or R^ can be converted to the suitable group R<1> and/or R<2> in any compound where it exists, such a conversion forms part of the present invention.

Videre kan en gruppe R^ og/eller R<2>omvandles til en annen gruppe R<1>og/eller R<2>. Som beskrevet ovenfor for R<5>og R^, kan en slik omvandling utføres i en hvilken som helst av forbindelsene som inneholder slike grupper, og en slik omvandling utgjør også en del av foreliggende oppfinnelse. Muligheten for å modifisere substituenter på fenylringen er spesielt nyttig for fremstillingen av forbindelser av formel I som inneholder en substituent R^ og/eller R<2>som er potensielt ustabil i en hvilken som helst av reaksjonene som er innbefattet i fremstillingen av forbindelse I, eller en kompatibel med en hvilken som helst av reagensene som benyttes. I et slikt tilfelle kan en gruppe R<5>og/eller R<6>, eller en annen gruppe R<1>og/eller R<2>, fungere som en beskyttet form av den ønskede gruppen, og det kan benyttes en annen, men stabil eller kompatibel gruppe som kan omvandles til den ønskede gruppen. Omvandlingstrinnet utføres følgelig etter reaksjonen eller reaksjonene hvori den ønskede substi-tuenten er potensielt ustabil eller inkompatibel. Furthermore, a group R^ and/or R<2> can be converted into another group R<1> and/or R<2>. As described above for R<5> and R^, such a conversion can be carried out in any of the compounds containing such groups, and such a conversion also forms part of the present invention. The possibility of modifying substituents on the phenyl ring is particularly useful for the preparation of compounds of formula I containing a substituent R^ and/or R<2> which is potentially unstable in any of the reactions involved in the preparation of compound I, or one compatible with any of the reagents used. In such a case, a group R<5>and/or R<6>, or another group R<1>and/or R<2>, may function as a protected form of the desired group, and a other but stable or compatible group that can be transformed into the desired group. Accordingly, the conversion step is carried out after the reaction or reactions in which the desired substituent is potentially unstable or incompatible.

Selv om en omvandling, om egnet, kan utføres på et forstadium av forbindelse av formel I, er det generelt å foretrekke og bevare omvandlebare grupper til etter dannelsen av en forbindelse av formel I eller formel Ia. (Som vist ovenfor er en forbindelse av formel Ia en forbindelse som er analog med en forbindelse I, men som inneholder grupper R^ og/eller R^ som kan omvandles til grupper henholdsvis R^" og/eller R<2>.) Although a transformation, if appropriate, can be carried out at a precursor stage of a compound of formula I, it is generally preferred to preserve convertible groups until after the formation of a compound of formula I or formula Ia. (As shown above, a compound of formula Ia is a compound analogous to a compound I, but containing groups R^ and/or R^ which can be converted into groups R^" and/or R<2> respectively.)

I en forbindelse av formel I eller Ia, kan en omvandling utføres før eller etter fjernelsen av en beskyttende gruppe fra 8-hydroksygruppen, og før eller etter fjernelsen av en 2-karboksy-beskyttende gruppe, dette er av betydning for den potensielle reaktiviteten av en fri hydroksygruppe eller av en fri karboksygruppe i den aktuelle reaksjonen. In a compound of formula I or Ia, a transformation can be carried out before or after the removal of a protecting group from the 8-hydroxy group, and before or after the removal of a 2-carboxy protecting group, this is of importance for the potential reactivity of a free hydroxy group or of a free carboxy group in the reaction in question.

Eksempler på slike omvandlinger (innbefattende omvandling av rester som utgjør en del av en større gruppe) er følgende: Examples of such transformations (including transformation of residues that form part of a larger group) are the following:

(-i) -COORd, -COOSiReRfRg eller -COO-fenyl til -COOH (-i) -COORd, -COOSiReRfRg or -COO-phenyl to -COOH

(ii) -COOH til -C0NH2, -CONHRa eller -C0NH(CH2)mQ (ii) -COOH to -C0NH2, -CONHRa or -C0NH(CH2)mQ

(lii) -COOH til -COOR<4>eller -C02CH2Q eller -C02CH2CH2Q eller (lii) -COOH to -COOR<4>or -CO2CH2Q or -CO2CH2CH2Q or

-C02CH(CH3)Q -CO 2 CH(CH 3 )Q

(iv) -COOH til -CORa (iv) -COOH to -CORa

(v) -NHRm eller -NRmRn hvori Rm og Rn er beskyttende grupper, til -NH2(v) -NHRm or -NRmRn wherein Rm and Rn are protecting groups, to -NH2

(vi) -NH2til (vi) -NH 2 to

(vii) -CONRaRm, hvor Rm er en beskyttende-gruppe, til -CONHRa (viii) -N3til -NH2 , som deretter eventuelt omvandles til en gruppe r! som beskrevet i (v) ovenfor, (vii) -CONRaRm, where Rm is a protecting group, to -CONHRa (viii) -N3 to -NH2, which is then optionally converted to a group r! as described in (v) above,

(ix) halogen til -CN eller -COOH (ix) halogen to -CN or -COOH

(x) -SRa til -SORa eller -S02Ra (x) -SRa to -SORa or -SO2Ra

(xi) -CN til -CH2NH2, som deretter eventuelt omvandles til en gruppe som definert i (v) ovenfor*" (xi) -CN to -CH2NH2, which is then optionally converted to a group as defined in (v) above*"

(xii) -SORa til -S02Ra (xii) -SO Ra to -SO 2 Ra

(xiii) -N02til -NH2, som deretter kan omvandles videre som (xiii) -NO2 to -NH2, which can then be further converted as

beskrevet i (vi) ovenfor. described in (vi) above.

Omvandlingene beskrevet ovenfor kan benyttes i en hvilken som helst egnet kombinasjon, f.eks. omvandling av et halogenatom til en nitrilgruppe som deretter kan omvandles til en amino-metylgruppe som kan omsettes videre. I noen tilfeller kan gruppen som omvandles ikke være en gruppe R^ eller R^ selv, men kan være en enhet som utgjør en del av en slik gruppe, f. eks. kan en -NH2-gruppe være en gruppe Q som definert ovenfor, eller terminaldelen av en gruppe Q. The transformations described above may be used in any suitable combination, e.g. conversion of a halogen atom into a nitrile group which can then be converted into an amino-methyl group which can be reacted further. In some cases, the group being converted may not be a group R^ or R^ itself, but may be an entity forming part of such a group, e.g. a -NH2 group can be a group Q as defined above, or the terminal portion of a group Q.

Mange av fremgangsmåtene for gjennomføring av slike reaksjoner er i og for seg kjente innen teknikkens stand, f.eks. Many of the methods for carrying out such reactions are in and of themselves known within the state of the art, e.g.

(i) en karboksy-beskyttende gruppe kan fjernes ved konvensjonelle fremgangsmåter, for nærmere detaljer, se nedenfor; (il) en karboksygruppe kan amideres ved å anvende et amin og et kondensas j onsmiddel, f.eks. et karbodiimid, eller ved å omsette et amin med et aktivert karboksyl syr eder i vat , f.eks. en aktiv ester eller et anhydrid (symmetrisk eller asymmetrisk), eller et syreklorid; (ili) en karboksylsyregruppe kan forestres ved å anvende en alkohol og et aktivert karboksylsyrederivat, f.eks. en aktiv ester, syreanhydrid eller syreklorid; (iv) en karboksygruppe kan omvandles til et keton ved reaksjon med en alkyllitiumforbindelse, f.eks. RaLi; (v) og (vi i) en beskyttet amingruppe kan avbeskyttes ved konvensjonelle fremgangsmåter, som f.eks. beskrevet i McOmie, loe. eit. og i Greene, loe. eit.; (vi) substitusjon av aminogruppen med en acylgruppe eller en alkyl eller substituert alkylgruppe som definert i (vi) kan utføres konvensjonelt, f.eks. kan en aminogruppe acyleres med f.eks. et syreklorid eller et syreanhydrid, f.eks. acetylklorid eller eddiksyreanhydrid, eller med det egnede syrederivatet; (viii) en azidgruppe kan omvandles til en aminogruppe ved katalytisk reduksjon; (i) a carboxy-protecting group can be removed by conventional methods, for further details, see below; (il) a carboxy group can be amidated by using an amine and a condensation agent, e.g. a carbodiimide, or by reacting an amine with an activated carboxyl acid in water, e.g. an active ester or an anhydride (symmetric or asymmetric), or an acid chloride; (iii) a carboxylic acid group can be esterified by using a alcohol and an activated carboxylic acid derivative, e.g. an active ester, acid anhydride or acid chloride; (iv) a carboxy group can be converted to a ketone by reaction with an alkyllithium compound, e.g. RaLi; (v) and (vi i) a protected amine group can be deprotected by conventional methods, such as e.g. described in McOmie, loe. one. and in Greene, loe. one.; (vi) substitution of the amino group with an acyl group or an alkyl or substituted alkyl group as defined in (vi) can be carried out conventionally, e.g. can an amino group be acylated with e.g. an acid chloride or an acid anhydride, e.g. acetyl chloride or acetic anhydride, or with the appropriate acid derivative; (viii) an azide group can be converted to an amino group by catalytic reduction;

(ix) et halogenid, spesielt et jodid, kan behandles med en organo metallisk forbindelse, f.eks. en organolitium-forbindelse, spesielt t-butyllltium, det resulterende komplekset behandles med cyanogen slik at -CN-gruppen dannes; (ix) a halide, especially an iodide, can be treated with an organometallic compound, e.g. an organolithium compound, especially t-butyllithium, the resulting complex being treated with cyanogen to form the -CN group;

(x) en alkyltiogruppe kan oksyderes, fortrinnsvis med en karboksylper syre , spesielt m-klorperbenzosyre , slik at man får den tilsvarende alkylsulfInyl- eller alkylsulfonylgruppen; (x) an alkylthio group can be oxidized, preferably with a carboxylic acid, especially m-chloroperbenzoic acid, so that the corresponding alkylsulfinyl or alkylsulfonyl group is obtained;

(xi) en cyanogruppe kan omvandles til en aminogruppe ved reduksjon, f.eks. ved anvendelse av et metallhydrid, (xi) a cyano group can be converted to an amino group by reduction, e.g. using a metal hydride,

denne aminogruppen omsettes deretter videre som beskrevet ovenfor; this amino group is then reacted further as described above;

(xii) en alkylsulfinylgruppe kan oksyderes til en alkylsul-fonylgruppe som beskrevet i (x) ovenfor; (xii) an alkylsulfinyl group can be oxidized to an alkylsulfonyl group as described in (x) above;

(xiii) en nitrogruppe kan reduseres til en aminogruppe ved hydrogenering katalysert med edelmetall, f.eks. ved å anvende platina eller 10% palladium på karbon, se M. Freifelder, "Catalytic Hydrogenation in Organic Synthesis", Wiley Interscience, 1978, s. 26, og P.N. Rylander, "Catalytic Hydrogenation over Platinum Metals", Academic Press, 1967, kap. 11, og aminogruppen omsettes deretter videre som beskrevet I (vi) ovenfor. (xiii) a nitro group can be reduced to an amino group by hydrogenation catalyzed by a noble metal, e.g. using platinum or 10% palladium on carbon, see M. Freifelder, "Catalytic Hydrogenation in Organic Synthesis", Wiley Interscience, 1978, p. 26, and P.N. Rylander, "Catalytic Hydrogenation over Platinum Metals", Academic Press, 1967, ch. 11, and the amino group is then reacted further as described in (vi) above.

I prosess (A), og i reaks j onsskj erna I, er det ikke generelt påkrevet å beskytte 8-hydroksygruppe, og de spesielle betraktningene vedrørende beskyttelse og fjernelse av beskyttelsen av 8-hydroksygruppen ved fremstillingen av en forbindelse av formel II er diskutert ovenfor. I prosessene In process (A), and in reaction cycle I, it is not generally required to protect the 8-hydroxy group, and the special considerations regarding protection and deprotection of the 8-hydroxy group in the preparation of a compound of formula II are discussed above . In the processes

(B), (C) og (D), og i reaks j onsskj erna II, er det imidlertid generelt foretrukket å beskytte 8-hydroksygruppen, og å (B), (C) and (D), and in reaction nucleus II, however, it is generally preferred to protect the 8-hydroxy group, and to

fjerne beskyttelsesgruppen som et av de siste trinnene i fremstillingen av forbindelse I. I forbindelsene av formlene III, IV, V, VI, XIV, XV og XVI står følgelig R<3>fortrinnsvis for en hydroksybeskyttende gruppe. remove the protecting group as one of the last steps in the preparation of compound I. Accordingly, in the compounds of formulas III, IV, V, VI, XIV, XV and XVI, R<3> preferably stands for a hydroxy protecting group.

Som nevnt ovenfor er hydroksy-beskyttende grupper og fremgangsmåter for innføring og fjernelse av disse velkjente, se f.eks. McOmie loe. eit. og Greene loe. eit. As mentioned above, hydroxy-protecting groups and methods for introducing and removing these are well known, see e.g. McOmie laughed. one. and Greene laughed. one.

Spesielt nyttige hydroksy-beskyttelsesgrupper R<3>og fremgangsmåter for deres fjernelse er beskrevet i detalj ovenfor. Particularly useful hydroxy protecting groups R<3> and methods for their removal are described in detail above.

I en forbindelse av formel I er 8-hydroksygruppen, dersom den er forestret, fortrinnsvis forestret med en gruppe som kan fjernes in vivo slik at den gir frie hydroksygruppen, dvs. en estergruppe som kan fjernes under fysiologiske betingelser. Eksempler på egnede forestrende grupper er karboksylsyre-acylgrupper av formelenR20C0-, hvoriR20 står for et hydrogenatom eller en rettkjedet eller forgrenet alkylgruppe som inneholder fra 1-6 karbonatomer, spesielt en metyl-, etyl- eller t-butylgruppe, eller står for en fenylgruppe eller en fenoksyalkylgruppe hvori alkyldelen er rettkjedet eller forgrenet og inneholder fra 1-4 karbonatomer, og er spesielt en metylengruppe. In a compound of formula I, the 8-hydroxy group, if it is esterified, is preferably esterified with a group that can be removed in vivo so that it gives the free hydroxy group, i.e. an ester group that can be removed under physiological conditions. Examples of suitable esterifying groups are carboxylic acid acyl groups of the formula R20C0-, in which R20 represents a hydrogen atom or a straight-chain or branched alkyl group containing from 1-6 carbon atoms, especially a methyl, ethyl or t-butyl group, or represents a phenyl group or a phenoxyalkyl group in which the alkyl part is straight-chain or branched and contains from 1-4 carbon atoms, and is especially a methylene group.

En ikke-fysiologisk fjernbar beskyttende gruppe R<3>fjernes generelt fra en resulterende forbindelse av formel I, og kan erstattes med en fysiologisk fjernbar gruppe dersom dette er ønsket. I noen tilfeller kan en karboksylsyre-acylgruppe R<3>spille en beskyttende rolle under syntesen av forbindelse I. En slik beskyttende gruppe med dobbelt funksjon kan, om ønsket, fjernes, bevares eller erstattes i formel I. A non-physiologically removable protecting group R<3> is generally removed from a resulting compound of formula I, and may be replaced with a physiologically removable group if desired. In some cases, a carboxylic acid acyl group R<3> may play a protecting role during the synthesis of compound I. Such a dual function protecting group may, if desired, be removed, preserved or substituted in formula I.

En estergruppe ved 8-posisjonen kan være den eneste estergruppen som er tilstede, eller den kan være tilstede i tillegg til en estergruppe ved 2-karboksylgruppen. Som nevnt ovenfor kan en fysiologisk fjernbar gruppe være tilstede som en beskyttende gruppe R<3>under fremstillingen av en forbindelse av formel I, eller den kan innføres ved den frie 8-hydroksygruppen av en forbindelse av formel I, etter fjernelse av en ikke-fysiologisk fjernbar hydroksy-beskyttende gruppe, dersom denne er tilstede. En forestrende gruppe kan innføres ved 8-hydroksygruppen ved en reaksjon med et organisk syrederivat på kjent måte. En spesielt hensikts-messig fremgangsmåte er å omsette en forbindelse av formel I med et aktivert syrederivat, f.eks. et syreanhydrid i nærvær av en organisk base, f.eks. 4-dimetylaminopyridin. An ester group at the 8-position may be the only ester group present, or it may be present in addition to an ester group at the 2-carboxyl group. As mentioned above, a physiologically removable group may be present as a protecting group R<3> during the preparation of a compound of formula I, or it may be introduced at the free 8-hydroxy group of a compound of formula I, after removal of a non- physiologically removable hydroxy-protecting group, if present. An esterifying group can be introduced at the 8-hydroxy group by a reaction with an organic acid derivative in a known manner. A particularly suitable method is to react a compound of formula I with an activated acid derivative, e.g. an acid anhydride in the presence of an organic base, e.g. 4-Dimethylaminopyridine.

Som angitt ovenfor kan en forbindelse av formel I foreligge i form av en ester ved karboksygruppen ved posisjon 2. En slik ester er spesielt en ester som kan omvandles til den frie syren ved hydrolyse, fotolyse, reduksjon, oksydasjon eller esterase-enzymvirkning. Eksempler på slike estere er de som dannes med usubstituerte eller substituerte alifatiske alkoholer eller fenoler som inneholder samlet opptil 20 karbonatomer. I en forestret karboksygruppe -C00R, kan gruppen R f.eks. være en rettkjedet eller forgrenet, substituert eller usubstituert alkyl-, alkenyl- eller alkynylgruppe som inneholder opptil 18 karbonatomer, fortrinnsvis opptil 8 karbonatomer, og spesielt opptil 6 karbonatomer, f.eks. en metyl-, etyl-, n-propyl-, iso-propyl-, n-butyl-, sek-butyl-, iso-butyl-, tert-butyl-, n-pentyl-, n-heksyl-, allyl- eller vinylgruppe. En alifatisk gruppe R, spesielt en metyl- eller etylgruppe, kan være substituert, f. eks. med en acyloksy-gruppe (ytterligere detaljer vedrørende slike grupper er gitt nedenfor); med en aminoalkanoyloksygruppe; med en eventuelt substituert aminogruppe; eller i tilfelle en metylgruppe, med en eller flere usubstituerte eller substituerte fenylgrupper. En fenylgruppe kan, enten som en fenol eller som en substituent av en metylgruppe, være substituert, f.eks. med en eller flere substituenter, valgt spesielt fra metoksy- og nitrogrupper og halogenatomer. Eksempler på fenyl-substituerte-alifatiske grupper er benzyl-, nitrobenzyl-, metoksy-benzyl-, dimetoksybenzyl-, benzhydryl- og tritylgrupper. As stated above, a compound of formula I can exist in the form of an ester at the carboxy group at position 2. Such an ester is in particular an ester that can be converted to the free acid by hydrolysis, photolysis, reduction, oxidation or esterase enzyme action. Examples of such esters are those formed with unsubstituted or substituted aliphatic alcohols or phenols containing a total of up to 20 carbon atoms. In an esterified carboxy group -C00R, the group R can e.g. be a straight-chain or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl group containing up to 18 carbon atoms, preferably up to 8 carbon atoms, and especially up to 6 carbon atoms, e.g. a methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, allyl or vinyl group. An aliphatic group R, especially a methyl or ethyl group, may be substituted, e.g. with an acyloxy group (further details regarding such groups are given below); with an aminoalkanoyloxy group; with an optionally substituted amino group; or in the case of a methyl group, with one or more unsubstituted or substituted phenyl groups. A phenyl group may, either as a phenol or as a substituent of a methyl group, be substituted, e.g. with one or more substituents, selected in particular from methoxy and nitro groups and halogen atoms. Examples of phenyl-substituted-aliphatic groups are benzyl, nitrobenzyl, methoxybenzyl, dimethoxybenzyl, benzhydryl and trityl groups.

Som angitt ovenfor er en estergruppe spesielt en gruppe som kan fjernes ved hydrolyse, fotolyse, oksydasjon, reduksjon eller enzymvirkning, eller to eller flere av disse fremgangsmåtene kan benyttes, f.eks. reduksjon etterfulgt av hydrolyse. En gruppe R som lett kan fjernes uten betydelig nedbrytning av resten av molekylet er spesielt nyttig som en karboksy-beskyttende gruppe R<4>. Eksempler på estere som lett avspaltes ved reduksjon er trikloretylestere, og fenyl-substi tuerte-metylestere, som kan være usubstituerte eller substituerte, f.eks. benzyl-p-nitrobenzyl, benzhydryl og tritylestere. As stated above, an ester group is in particular a group that can be removed by hydrolysis, photolysis, oxidation, reduction or enzyme action, or two or more of these methods can be used, e.g. reduction followed by hydrolysis. A group R which can be easily removed without significant degradation of the rest of the molecule is particularly useful as a carboxy-protecting group R<4>. Examples of esters which are easily split off by reduction are trichloroethyl esters and phenyl-substituted methyl esters, which can be unsubstituted or substituted, e.g. benzyl-p-nitrobenzyl, benzhydryl and trityl esters.

Reduksjon av en ester, f.eks. en fenyl-substituert-metyl-ester, såsom en p-nitrofenylester, kan utføres ved å anvende hydrogen og en metallkatalysator, f.eks. en edelmetallkata- lysator, såsom platina, palladium eller rhodium, denne katalysatoren kan være båret på f.eks. trekull eller kisel-gur. Slike reduksjoner kan utføres i nærvær av et saltdannende middel, f.eks. natrium- eller kaliumbikarbonat, dersom det er ønsket slik at det direkte dannes et salt ved 2-karboksylsyregruppen av formel I. Reduction of an ester, e.g. a phenyl-substituted-methyl ester, such as a p-nitrophenyl ester, can be made using hydrogen and a metal catalyst, e.g. a noble metal catalyst, such as platinum, palladium or rhodium, this catalyst can be supported on e.g. charcoal or diatomaceous earth. Such reductions can be carried out in the presence of a salt-forming agent, e.g. sodium or potassium bicarbonate, if desired so that a salt is directly formed at the 2-carboxylic acid group of formula I.

Alternativt kan en p-nitrobenzylester omvandles til den tilsvarende frie syren ved en to-trinnsfremgangsmåte, med en innledende reduksjon av nitrogruppen etterfulgt av hydrolyse. Nitrogruppen kan reduseres ved edelmetall-katalysert hydrogenering, ved f.eks. å anvende platina eller palladium på karbon, eller med et metallreduksjonsmiddel, f.eks. sink i eddiksyre. Andre metallreduksjonsmidler er f.eks. aluminium-amalgam, og jern- og ammoniumklorid, se f.eks. britisk patent nr. 1.582.960. Reduksjon av nitrogruppen etterfølges av hydrolyse som kan finne sted in situ under reduksjon av nitrogruppen eller som kan utføres deretter ved behandling med en syre eller en base. Alternatively, a p-nitrobenzyl ester can be converted to the corresponding free acid by a two-step process, with an initial reduction of the nitro group followed by hydrolysis. The nitro group can be reduced by noble metal-catalyzed hydrogenation, by e.g. to apply platinum or palladium to carbon, or with a metal reducing agent, e.g. zinc in acetic acid. Other metal reducing agents are e.g. aluminum amalgam, and iron and ammonium chloride, see e.g. British Patent No. 1,582,960. Reduction of the nitro group is followed by hydrolysis which can take place in situ during reduction of the nitro group or which can be carried out subsequently by treatment with an acid or a base.

En o-nitrobenzylester kan omvandles til den tilsvarende frie syren ved fotolyse. An o-nitrobenzyl ester can be converted to the corresponding free acid by photolysis.

Visse estergrupper kan avspaltes ved basehydrolyse, f.eks. acetylmetyl-, acetoksymetyl- og fenoksyetylestere. Certain ester groups can be split off by base hydrolysis, e.g. acetylmethyl, acetoxymethyl and phenoxyethyl esters.

Noen estergrupper kan avspaltes ved oksyderende hydrolyse, f.eks. dimetoksybenzylgruppen. Some ester groups can be split off by oxidative hydrolysis, e.g. the dimethoxybenzyl group.

Andre spaltbare estere innbefatter f.eks. silylestere, såsom trialkylsilyl og trialkylsilylalkylestere, hvori alkyldelene uavhengig av hverandre inneholder fra 1-4 karbonatomer, f.eks. trimetylsilyl og trimetylsilyletylestere. Other cleavable esters include e.g. silyl esters, such as trialkylsilyl and trialkylsilyl alkyl esters, in which the alkyl moieties independently contain from 1-4 carbon atoms, e.g. trimethylsilyl and trimethylsilyl ethyl esters.

I prosessen ovenfor kan fjernelse av forestrende grupper ved oksyderende eller reduserende prosesser oppnås elektro-kjemisk. In the above process, the removal of esterifying groups by oxidizing or reducing processes can be achieved electrochemically.

Det kan benyttes en forestrende gruppe som er fjernbar under fysiologiske betingelser, dvs. den forestrende gruppen avspaltes in vivo slik at man får den frie syren eller et karboksylat, f.eks. en acyloksymetyl- eller acyloksyetylester som inneholder fra 2-12 karbonatomer i acyldelen, f.eks. en actoksymetyl , 1' - ( acetoksy )ety 1 - eller pivaloyloksymetyl-ester, en 5-metyl-l,3-dioksalen-2-on-4-yl-metylester, en aminoalkanoyloksymetylester som inneholder fra 2-12 karbonatomer i alkanoyldelen, f.eks. en glycyloksymetyl-, L-valinyloksymetyl- eller L-leucyloksymetylester, eller en f tal idylester , eller en 1' - ( alkoksykarbonyloksy )etylester , f.eks. en 1'-(metoksykarbonyloksy)etyl- eller l'-(etoksy-karbonyloksy )etylester, eller en eventuelt substituert 2-aminoetylester, f.eks. en 2-dietylaminoetyl- eller 2-(l-morfolino)-etylester. An esterifying group can be used which is removable under physiological conditions, i.e. the esterifying group is split off in vivo so that the free acid or a carboxylate is obtained, e.g. an acyloxymethyl or acyloxyethyl ester containing from 2-12 carbon atoms in the acyl moiety, e.g. an actoxymethyl, 1'-(acetoxy)ethyl 1- or pivaloyloxymethyl ester, a 5-methyl-1,3-dioxalen-2-on-4-yl methyl ester, an aminoalkanoyloxymethyl ester containing from 2-12 carbon atoms in the alkanoyl part, e.g. a glycyloxymethyl-, L-valinyloxymethyl- or L-leucyloxymethyl ester, or a ftal idyl ester, or a 1'-( alkoxycarbonyloxy ) ethyl ester, e.g. a 1'-(methoxycarbonyloxy)ethyl or 1'-(ethoxycarbonyloxy)ethyl ester, or an optionally substituted 2-aminoethyl ester, e.g. a 2-diethylaminoethyl or 2-(1-morpholino)ethyl ester.

Foretrukne estere er p-nitrobenzyl, ftalidyl, pivaloyloksy-metyl , etoksykarbonyloksymetyl, 5-metyl-dioksalen-2-on-4-yl-metyl , acetylmetyl , acetoksymetyl, 1' - ( acetoksy )etyl, 1'-(acetyl)etyl og 1'-(etoksykarbonyloksy)etylestere. Preferred esters are p-nitrobenzyl, phthalidyl, pivaloyloxy-methyl, ethoxycarbonyloxymethyl, 5-methyl-dioxalen-2-on-4-yl-methyl, acetylmethyl, acetoxymethyl, 1'-(acetoxy)ethyl, 1'-(acetyl)ethyl and 1'-(ethoxycarbonyloxy)ethyl esters.

En ester ved en hvilken som helst posisjon i en forbindelse av formel I eller i en hvilken som helst annen fri syre-beskrevet ovenfor, kan fremstilles ved reaksjon mellom den egnede frie syren eller et aktivert derivat derav med en alkohol, en fenol eller et reaktivt derivat derav. Reaksjonen utføres fortrinnsvis under milde betingelser for å forhindre brudd i ringsystemet, f.eks. under nøytrale eller milde, sure eller basiske betingelser, og ved temperaturer i området fra An ester at any position in a compound of formula I or in any other free acid described above may be prepared by reaction of the appropriate free acid or an activated derivative thereof with an alcohol, a phenol or a reactive derivative thereof. The reaction is preferably carried out under mild conditions to prevent breakage of the ring system, e.g. under neutral or mild, acidic or basic conditions, and at temperatures ranging from

-70 til +35°C. -70 to +35°C.

En ester avledet fra en alkohol kan også fremstilles ved reaksjon mellom et reaktivt derivat av alkoholen, såsom et halogenid, f.eks. et klorid, bromid eller jodid, eller hy dr oksykarb ony 1 sul f ony 1 der i vat , såsom en mesyl-eller tosylester, med et salt av en syre av formel I eller av en annen fri syre beskrevet ovenfor, f.eks. et alkali- eller 3ordalkalimetallsalt, f.eks. et litium-, natrium-, kalium-, kalsium- eller bariumsalt, eller et aminsalt, f.eks. et trietylammoniumsalt. Reaksjonen utføres fortrinnsvis i et substituert sulfoksyd- eller amidoppløsningsmiddel, f.eks. i dimetylsulfoksyd, dimetylformamid, eller heksametylfosforamid eller alternativt kan en ester fremstilles ved omsetning av en alkohol eller fenol med syren, f.eks. i aktivert form, eventuelt i nærvær av et kondensasjonsmiddel, f.eks. dicyklo-heksylkarbodiimid. An ester derived from an alcohol can also be prepared by reaction between a reactive derivative of the alcohol, such as a halide, e.g. a chloride, bromide or iodide, or hy dr oxycarbony 1 sulf ony 1 der i vat , such as a mesyl or tosyl ester, with a salt of an acid of formula I or of another free acid described above, e.g. an alkali or alkaline earth metal salt, e.g. a lithium, sodium, potassium, calcium or barium salt, or an amine salt, e.g. a triethylammonium salt. The reaction is preferably carried out in a substituted sulphoxide or amide solvent, e.g. in dimethylsulfoxide, dimethylformamide, or hexamethylphosphoramide or alternatively an ester can be prepared by reacting an alcohol or phenol with the acid, e.g. in activated form, possibly in the presence of a condensation agent, e.g. dicyclohexylcarbodiimide.

Foreliggende oppfinnelse tilveiebringer også salter av de forbindelsene av formel I som har saltdannende grupper, spesielt saltene av en fri syre av formel I og syreaddisjonssalter av forbindelser av formel I som inneholder en basisk gruppe. Saltene er spesielt fysiologisk tålbare salter, f.eks. alkalimetall- og jordalkalimetallsalter, f.eks. natrium-, kalium-, litium-, kalsium- og magnesiumsalter, ammoniumsalter , og salter med organiske aminer; i tillegg fysiologisk tålbare syreaddisjonssalter. Disse kan dannes med en egnet uorganisk eller organisk syre, f.eks. saltsyre, svovelsyre, eller en organisk karboksylsyre eller organisk sulfonsyre, f.eks. p-toluensulfonsyre. The present invention also provides salts of those compounds of formula I which have salt-forming groups, especially the salts of a free acid of formula I and acid addition salts of compounds of formula I which contain a basic group. The salts are particularly physiologically tolerable salts, e.g. alkali metal and alkaline earth metal salts, e.g. sodium, potassium, lithium, calcium and magnesium salts, ammonium salts, and salts with organic amines; in addition, physiologically tolerable acid addition salts. These can be formed with a suitable inorganic or organic acid, e.g. hydrochloric acid, sulfuric acid, or an organic carboxylic acid or organic sulphonic acid, e.g. p-toluenesulfonic acid.

Et salt av en fri syre av formel I kan fremstilles ved å omsette den frie syren med den egnede basen i et oppløsnings-middel , fortrinnsvis under de betingelsene hvorved saltet utfelles. En foretrukket base er kalium-2-etylheksanoat. A salt of a free acid of formula I can be prepared by reacting the free acid with the suitable base in a solvent, preferably under the conditions under which the salt is precipitated. A preferred base is potassium 2-ethyl hexanoate.

Et salt kan fremstilles direkte fra en ester ved å avspalte estergruppen under egnede reaksj onsbetingelser, f.eks. gir katalytisk reduksjon av en ester, såsom en p-nitrobenzylester, i et vandig/organisk oppløsningsmiddel som f.eks. innbefatter vann og etylacetat, dioksan eller tetrahydrofuran, i nærvær av et metallsalt, spesielt et metallbi-karbonat, f.eks. i en ekvivalent mengde eller i et lite overskudd, saltet direkte. A salt can be prepared directly from an ester by cleaving the ester group under suitable reaction conditions, e.g. provides catalytic reduction of an ester, such as a p-nitrobenzyl ester, in an aqueous/organic solvent such as e.g. includes water and ethyl acetate, dioxane or tetrahydrofuran, in the presence of a metal salt, especially a metal bicarbonate, e.g. in an equivalent amount or in a small excess, the salt directly.

Når et surt sentrum og et basisk sentrum begge er tilstede i en forbindelse av formel I, kan forbindelsen foreligge på dobbeltionisk form. When an acidic center and a basic center are both present in a compound of formula I, the compound may be in doubly ionic form.

Beskyttende grupper kan innføres eller fjernes ved et hvilket som helst egnet punkt i omsetningene som innbefattes i fremstillingen av en forbindelse av formel I. Protecting groups may be introduced or removed at any suitable point in the reactions involved in the preparation of a compound of formula I.

Ved et hvilket som helst trinn i fremstillingen av en forbindelse av formel I, kan en fremstilt forbindelse isoleres fra reaksjonsblandingen hvori den ble fremstilt, og, om ønsket, renses ved de egnede, teknikkene som benyttes for rensing av "organiske forbindelser, f.eks. kromatografi og krystallisasj on. At any step in the preparation of a compound of formula I, a compound prepared may be isolated from the reaction mixture in which it was prepared and, if desired, purified by the appropriate techniques used for the purification of "organic compounds, e.g. .chromatography and crystallization.

Som angitt ovenfor, kan forskjellige mellomprodukter fremstilles i form av blandinger av isomerer av forskjellige typer. Slike blandinger kan separeres eller oppløses på et hvilket som helst trinn, eller en isomerblanding kan benyttes per se for etterfølgende reaksjoner. As indicated above, various intermediates can be prepared in the form of mixtures of isomers of different types. Such mixtures may be separated or resolved at any step, or a mixture of isomers may be used per se for subsequent reactions.

En forbindelse av formel I kan uavhengig ha R- eller S-stereokjemi ved posisjonene 5, 6 og 8. En hvilken som helst blanding av to eller flere isomere former kan oppløses, om ønsket, eller en forbindelse av formel I kan benyttes i form av en isomer blanding. Den foretrukne stereokjemien ved posisjon 5 I forbindelse I er generelt R, svarende til den i naturlig forekommende penicilliner og cef alosporiner, ved posisjon 6 S og ved posisjon 8 R. A compound of formula I may independently have R or S stereochemistry at positions 5, 6, and 8. Any mixture of two or more isomeric forms may be dissolved, if desired, or a compound of formula I may be used in the form of an isomeric mixture. The preferred stereochemistry at position 5 in compound I is generally R, corresponding to that in naturally occurring penicillins and cephalosporins, at position 6 S and at position 8 R.

Forbindelser av formel I har utmerket aktivitet mot gram-positive bakterier og gram-negative bakterier. Videre viser forbindelsene av formel I og salter derav aktivitet mot disse organismene i nærvær av p-laktamase-enzymer som produseres av både gram-positive organismer, f.eks. Staphylococcus aureus og gram-negat i ve organismer, f. eks. Enterobacter cloacae, hvilket indikerer resistens overfor disse enzymene. Compounds of formula I have excellent activity against gram-positive bacteria and gram-negative bacteria. Furthermore, the compounds of formula I and salts thereof show activity against these organisms in the presence of β-lactamase enzymes produced by both gram-positive organisms, e.g. Staphylococcus aureus and gram-negative organisms, e.g. Enterobacter cloacae, indicating resistance to these enzymes.

Forbindelser av formel I er også inhibitorer for p<->laktamase-enzymer. Compounds of formula I are also inhibitors of β-lactamase enzymes.

Forbindelsene av formel I og fysiologisk tålbare salter derav kan benyttes i mennesker og andre dyr for å behandle f.eks. bakterieinfeksjoner forårsaket av både gram-positive og gram-negative bakterier, f.eks. Staphylococcus aureus, Strepto-coccus pyogenes, Escherichia coli, Bacillus subtilis og Proteus morganii, noen stammer av disse er resistente for konvensjonell penicillinbehandling. The compounds of formula I and physiologically tolerable salts thereof can be used in humans and other animals to treat e.g. bacterial infections caused by both gram-positive and gram-negative bacteria, e.g. Staphylococcus aureus, Strepto-coccus pyogenes, Escherichia coli, Bacillus subtilis and Proteus morganii, some strains of which are resistant to conventional penicillin therapy.

Det er funnet at forbindelser av formel I (og estere derav ved 2-karboksylsyregruppen) som inneholder en forestret hydroksygruppe ved 8-posisjonen også har antibakterielle og/eller3-laktamase-inhiberende egenskaper, spesielt siden 8-estergruppen kan spaltes in vivo ved esteraser. I tillegg kan forestringen ved 8-hydroksygruppen øke absorpsjonsgraden ved oral administrering. It has been found that compounds of formula I (and esters thereof at the 2-carboxylic acid group) containing an esterified hydroxy group at the 8-position also have antibacterial and/or 3-lactamase inhibitory properties, especially since the 8-ester group can be cleaved in vivo by esterases. In addition, the esterification at the 8-hydroxy group can increase the degree of absorption when administered orally.

Forbindelser av foreliggende formel I har visse fordeler med hensyn til antimikrobiell aktivitet sammenlignet med de tilsvarende usubstituerte fenyl- og også 4-klor-, 4-fluor-, 4-metoksy-, 4-metyltio- og 3-metyltiofenylforbindelsene , f.eks. har 5R,3-(3-aminokarbonylfenyl)-6S-(lR-hydroksyetyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat og de tilsvarende (4-aminokarbonylfenyl)-, (3-formylaminofenyl)- og (4-f ormylaminofenyl)forbindelsene større antibakteriel1 aktivitet mot en rekke mikroorganismer, spesielt3-laktamase-produserende organismer enn sammenligningsforbindelsene ovenfor, som vist i tabellen nedenfor. Compounds of the present formula I have certain advantages with regard to antimicrobial activity compared to the corresponding unsubstituted phenyl and also 4-chloro-, 4-fluoro-, 4-methoxy-, 4-methylthio- and 3-methylthiophenyl compounds, e.g. has 5R,3-(3-aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate and the corresponding ( 4-aminocarbonylphenyl)-, (3-formylaminophenyl)- and (4-formylaminophenyl)-compounds greater antibacterial1 activity against a variety of microorganisms, especially 3-lactamase-producing organisms than the above comparison compounds, as shown in the table below.

Den antimikrobielle aktiviteten ble bestemt ved å måle den minimale inhiberingskonsentrasjonen (MIC). MIC for forbindelsene ble bestemt ved et standardforsøk, "agarfortynnings- forsøket" ifølge Lorian ("Ant ib i ot ics in Laboratory Medicine", Williams and Wilkins, Baltimore/London 1980) som følger: Serier med avtagende fortynninger, med en faktor 2, av hver forbindelse ble fremstilt i Petri-skåler inneholdende 15 ml "Mueller Hinton-agar" (Difco). En Petri-skål inneholdende bare "Mueller Hinton-agar" tjente som kontroll for bakteriell vekst. Hver Petri-skål ble inokulert med en flerpunkts inokulator (Denley) som overførte 0,6 jjI av en 1:100 fortynnet 18 timers kultur av det egnede forsøksbakterium. Etter 16-18 timers inkubering ved 37° C ble Petri-skålene undersøkt med henblikk på bakterievekst. Den laveste konsentrasjonen av forbindelsen som forårsaker fullstendig inhibering av vekst, angis som MIC, bortsett fra at veksten av en enkelt koloni eller en uklar oppløsning ikke tas som bevis for vekst. The antimicrobial activity was determined by measuring the minimal inhibitory concentration (MIC). The MIC of the compounds was determined by a standard test, the "agar dilution test" according to Lorian ("Ant ib iot ics in Laboratory Medicine", Williams and Wilkins, Baltimore/London 1980) as follows: Series of decreasing dilutions, by a factor of 2, of each compound was prepared in Petri dishes containing 15 ml "Mueller Hinton Agar" (Difco). A Petri dish containing only "Mueller Hinton agar" served as a control for bacterial growth. Each Petri dish was inoculated with a multipoint inoculator (Denley) transferring 0.6 µl of a 1:100 diluted 18 hour culture of the appropriate test bacterium. After 16-18 hours of incubation at 37° C, the Petri dishes were examined for bacterial growth. The lowest concentration of the compound which causes complete inhibition of growth is given as the MIC, except that the growth of a single colony or a cloudy solution is not taken as evidence of growth.

Foreliggende oppfinnelse tilveiebringer følgelig et farmasøy-tisk preparat som innbefatter en forbindelse av formel I, eller et fysiologisk tålbart salt derav, eller en blanding av to eller flere slike stoffer som aktiv bestanddel, i blanding med en farmasøytisk egnet bærer. Preparatet kan også innbefatte et eller flere andre farmasøytisk aktive stoffer, f.eks. et annet antibakterielt stoff, spesielt et stoff som har en p<->laktamring. Preparatene kan foreligge i en form som er egnet for enteral eller parenteral administrering, f.eks. for oral, intravenøs eller intramuskulær administrering, f.eks. som tabletter, kapsler, siruper eller sterile inj eks j onsoppløsninger eller infusjonsoppløsninger. Preparatene foreligger fortrinnsvis i enhetsdoseform og innbefatter fortrinnsvis fra 10-2000 mg av den aktive bestanddelen pr. enhetsdose. Den daglige dosen av den aktive bestanddelen er generelt fra 20-8000 mg, i oppdelte doser, generelt opptil 4 doser. The present invention consequently provides a pharmaceutical preparation which includes a compound of formula I, or a physiologically tolerable salt thereof, or a mixture of two or more such substances as active ingredient, in mixture with a pharmaceutically suitable carrier. The preparation may also include one or more other pharmaceutically active substances, e.g. another antibacterial substance, especially a substance having a p<->lactam ring. The preparations may be in a form suitable for enteral or parenteral administration, e.g. for oral, intravenous or intramuscular administration, e.g. as tablets, capsules, syrups or sterile injection solutions or infusion solutions. The preparations are preferably available in unit dose form and preferably contain from 10-2000 mg of the active ingredient per unit dose. The daily dose of the active ingredient is generally from 20-8000 mg, in divided doses, generally up to 4 doses.

Oppfinnelsen vedrører videre anvendelsen av en forbindelse med formel I eller en fysiologisk tålbar ester eller et salt derav for fremstilling av et medikament for behandling av bakterieinfeksjoner. The invention further relates to the use of a compound of formula I or a physiologically tolerable ester or a salt thereof for the production of a medicament for the treatment of bacterial infections.

Oppfinnelsen vedrører videre en fremgangsmåte for behandling av pattedyr, spesielt mennesker, for å bekjempe en bakterie-infeksjon, som innbefatter at det til pattedyret admini-streres en forbindelse av formel I eller en fysiologisk tålbar ester eller et salt derav. The invention further relates to a method for treating mammals, especially humans, to combat a bacterial infection, which includes administering to the mammal a compound of formula I or a physiologically tolerable ester or a salt thereof.

Oppfinnelsen innbefatter videre et farmasøytisk preparat som Innbefatter en aktiv bestanddel som definert ovenfor i enhetsdoseform. The invention further includes a pharmaceutical preparation which includes an active ingredient as defined above in unit dose form.

Oppfinnelsen tilveiebringer også et farmasøytisk preparat som innbefatter en aktiv bestanddel som definert ovenfor, eller et fysiologisk tålbart salt derav eller en blanding av to eller flere slike stoffer, og et eller flere andre farmasøy-tisk aktive stoffer, i enhetsdoseform. Enhetsdoser er fortrinnsvis som beskrevet ovenfor. The invention also provides a pharmaceutical preparation which includes an active ingredient as defined above, or a physiologically tolerable salt thereof or a mixture of two or more such substances, and one or more other pharmaceutically active substances, in unit dose form. Unit doses are preferably as described above.

Forbindelser av formel I er også nyttige ved fremstillingen av de antibakterielt aktive forbindelsene. Compounds of formula I are also useful in the preparation of the antibacterially active compounds.

Spesielt interessante forbindelser av formel I er Particularly interesting compounds of formula I are

(i) 3-(3-aminokarbonylfenyl)-6-(1-hydroksyetyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylsyre; (ii) 3-(4-aminokarbonylfenyl)-6-(1-hydroksyetyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylsyre; (iii) 3-(3-f or my lami no f enyl ) - 6-( 1-hydroksyetyl )-7-okso-4-tia-l-aza bicyklo[3,2,0]hept-2-en-2-karboksylsyre; (iv) 3-(4-f or my lami no f enyl ) - 6-( 1-hydroksyetyl )-7-okso-4-tia-l-aza bicyklo[3,2,0]hept-2-en-2-karboksylsyre. (i) 3-(3-aminocarbonylphenyl)-6-(1-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid; (ii) 3-(4-aminocarbonylphenyl)-6-(1-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid; (iii) 3-(3-formylaminophenyl)-6-(1-hydroxyethyl)-7-oxo-4-thia-1-aza bicyclo[3,2,0]hept-2-en- 2-carboxylic acid; (iv) 3-(4-formylaminophenyl)-6-(1-hydroxyethyl)-7-oxo-4-thia-1-aza bicyclo[3,2,0]hept-2-ene- 2-carboxylic acid.

Av disse forbindelsene er 3-aminokarbonylfenylforbindelsen (i) og 4-formylaminofenylforbindelsen (iv) spesielt foretrukne. Of these compounds, the 3-aminocarbonylphenyl compound (i) and the 4-formylaminophenyl compound (iv) are particularly preferred.

I hver av forbindelsene (i) til (iv) ovenfor, er 5R,6S,8R-stereokjemien foretrukket. Forbindelsene kan foreligge i form av estere eller salter som beskrevet ovenfor. In each of the compounds (i) to (iv) above, the 5R,6S,8R stereochemistry is preferred. The compounds can be in the form of esters or salts as described above.

Foreliggende oppfinnelse tilveiebringer også forbindelser av formlene II, III, IV, V, IX, X, XI, XV og XVI. The present invention also provides compounds of formulas II, III, IV, V, IX, X, XI, XV and XVI.

De følgende eksemplene illustrerer oppfinnelsen, men er ikke begrensende. The following examples illustrate the invention, but are not limiting.

I eksemplene er forholdene mellom oppløsningsmidler beregnet som volumdeler. In the examples, the ratios between solvents are calculated as parts by volume.

Eksempel 1 Example 1

4- ni trobenzyl- 3-( 4- cyanof enyl )- 2 -{ 3S- f IR- ( d ime tyl ( 2- metyl-pr op- 2- yl ) silyloksy) etyl] - 4R- etyl t ioazetidin- 2- on- l- yl )- 3-hydroksypropenoat 4-nitrobenzyl-3-(4-cyanophenyl)-2-{3S-fIR-(dimethyl (2-methyl-prop-2-yl)silyloxy)ethyl]-4R-ethylthioazetidin-2 -on-l-yl)-3-hydroxypropenoate

En blanding av 4-nitrobenzyl-2-{3S-[lR-(dimetyl(2-metylprop-2-yl)silyloksy)etyl]-4R-etyltioazetidin-2-on-l-yl)acetat (9,65 g) og 4-cyanobenzoylklorid 3,97 g) i tetrahydrofuran (100 ml) ble avkjølt til -40"C og behandlet med en oppløsning av 1 itiumheksametyldisilazid [fremstilt fra n-butyllitium i tetrahydrofuran (1,6 M, 28,10 ml) og heksametyldisilazan (10,46 ml)]. Blandingen ble omrørt i en time, deretter ble iseddiksyre (4,80 g) tilsatt. Inndamping ga en rest som ble fordelt mellom etylacetat og vann. Det organiske laget ble fraseparert, vasket med mettet vandig natriumbikarbonat og s al t vann s opp 1 ø sn ing og inndampet. Kromatografi av den resulterende oljen med etylacetat-heksan-blandinger over silikagel ga forbindelsen i overskriften som en brun gummi (10,18 g) hvis ^H N. M. R.-spektrum viste at det var en kompleks blanding av E- og Z-isomerer og den tilsvarende keto-tautomeren. A mixture of 4-nitrobenzyl-2-{3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-4R-ethylthioazetidin-2-on-1-yl)acetate (9.65 g) and 4-cyanobenzoyl chloride 3.97 g) in tetrahydrofuran (100 mL) was cooled to -40°C and treated with a solution of 1 lithium hexamethyldisilazide [prepared from n-butyllithium in tetrahydrofuran (1.6 M, 28.10 mL) and hexamethyldisilazane (10.46 mL)]. The mixture was stirred for one hour, then glacial acetic acid (4.80 g) was added. Evaporation gave a residue which was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and brine and evaporated. Chromatography of the resulting oil with ethyl acetate-hexane mixtures over silica gel gave the title compound as a brown gum (10.18 g) whose ^H N. M. R. spectrum showed that it was a complex mixture of E and Z isomers and the corresponding keto tautomer.

S (CDC13) bl.a. 3,02 (1H, m), 4,26 (1H, nr) , 5,62 (1H, d, J=l,5Hz) S (CDC13) i.a. 3.02 (1H, m), 4.26 (1H, nr) , 5.62 (1H, d, J=1.5Hz)

Eksempel 2 Example 2

4- ni tr obenzyl - 3- ( 4- cyanof enyl )- 2-( 3S- f IR-( dimetvl ( 2- metylprop- 2- yI ) silyloksy) etyll - 4R- ety 11 ioazetidin- 2- on- l- yl )- 3-( metylsulf onyloksy) propenoat 4-nitrobenzyl - 3-( 4- cyanophenyl )- 2-( 3S- f IR-( dimethyl ( 2- methylprop- 2- yl ) silyloxy) ethyl - 4R- eth y 11 ioazetidin- 2- one- l- yl)-3-(methylsulfonyloxy)propenoate

En oppløsning av 4-ni trobenzyl-3-( 4-cyanof enyl )-2-( 3S-[ 1R-(dimetyl(2-metylprop-2-yl)silyloksy)etyl]-4R-etyltioazetidin-2-on-l-yl)-3-hydroksypropenoat (4,04 g) i diklormetan (100 ml) ble avkjølt til -60°C, behandlet med trietylamin (1,00 g) etterfulgt av metansulfonylklorid (1,13 g) og omrørt i en time. Oppløsningen ble vasket trinnvis med 0,5M vandig saltsyre, mettet vandig bikarbonat og saltvannsoppløsning, og inndampet. Den resulterende gummien ble kromatografert med etylacetat-heksanblandinger over silikagel slik at man fikk produktet som et svakt gult skum (2,29 g) som en blanding av E- og Z-isomerene. A solution of 4-nitrobenzyl-3-(4-cyanophenyl)-2-(3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-4R-ethylthioazetidin-2-one-1 -yl)-3-hydroxypropenoate (4.04 g) in dichloromethane (100 mL) was cooled to -60°C, treated with triethylamine (1.00 g) followed by methanesulfonyl chloride (1.13 g) and stirred for one hour . The solution was washed stepwise with 0.5M aqueous hydrochloric acid, saturated aqueous bicarbonate and brine, and evaporated. The resulting gum was chromatographed with ethyl acetate-hexane mixtures over silica gel to give the product as a pale yellow foam (2.29 g) as a mixture of the E and Z isomers.

S (CDCI3) 0,00-0,01 (6H, m), 0,96-1,06 (9H, 2xs), 2,16-2,46 (6H, m), S (CDCl 3 ) 0.00-0.01 (6H, m), 0.96-1.06 (9H, 2xs), 2.16-2.46 (6H, m),

2,50 og 2,77 (2H, 2q, J=8,4Hz), 3,08 (3H, 2xs), 3,10 og 3,40 (1H, 2xdd, J=2,6 og 3,0Hz), 2.50 and 2.77 (2H, 2q, J=8.4Hz), 3.08 (3H, 2xs), 3.10 and 3.40 (1H, 2xdd, J=2.6 and 3.0Hz) ,

4,26 og 4,43 (1H, m), 5,07 og 5,40 (2H, 2xAB, Jgem=12,9Hz), 7,23-7,27 (1H, m); 7,56-8,14 (5H, m) , 4.26 and 4.43 (1H, m), 5.07 and 5.40 (2H, 2xAB, Jgem=12.9Hz), 7.23-7.27 (1H, m); 7.56-8.14 (5H, m) ,

8.21- 8,27 (2H, 2xd, J=8,9Hz). 8.21- 8.27 (2H, 2xd, J=8.9Hz).

Eksempel 3 Example 3

4- nitrobenzyl- 3-( 4- cyanofenyl)- 2- r4R- etyltio- 3S-( lR- hydroksyetyl) azetidin- 2- on- l- yll- 3-( metylsulfonyloksy)- propenoat 4- nitrobenzyl- 3-( 4- cyanophenyl)- 2- r4R- ethylthio- 3S-( 1R- hydroxyethyl) azetidin- 2- on- 1- yl- 3-( methylsulfonyloxy)- propenoate

En oppløsning av 4-nitrobenzyl-3-(4-cyanofenyl )-2-(3S-[lR-(dimetyl(2-metylprop-2-yl)silyloksy)etyl]-4R-etyltioazetidin-2-on-l-yl>-3-(metylsulfonyloksy)propenoat (4,36 g) i tetrahydrofuran (60 ml) ble behandlet med vann (2,0 ml) og konsentrert (35%) saltsyre (1,94 g) og omrørt ved romtemperatur i 22 timer. Tetrahydrofuranen ble fjernet i vakuum og den vandige resten ble nøytralisert med mettet vandig natriumbikarbonat. Etter ekstraksjon med etylacetat, ble det organiske ekstraktet tørket over vannfritt magnesiumsulfat og inndampet, og resten ble kromatografert med etylacetat-heksan-blandlnger over silikagel slik at man fikk forbindelsen i overskriften (2,26 g) som en blanding av E- og Z-isomerene. A solution of 4-nitrobenzyl-3-(4-cyanophenyl)-2-(3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-4R-ethylthioazetidin-2-on-1-yl >-3-(methylsulfonyloxy)propenoate (4.36 g) in tetrahydrofuran (60 mL) was treated with water (2.0 mL) and concentrated (35%) hydrochloric acid (1.94 g) and stirred at room temperature for 22 h . The tetrahydrofuran was removed in vacuo and the aqueous residue was neutralized with saturated aqueous sodium bicarbonate. After extraction with ethyl acetate, the organic extract was dried over anhydrous magnesium sulfate and evaporated, and the residue was chromatographed with ethyl acetate-hexane mixtures over silica gel to give the compound in the title (2.26 g) as a mixture of the E and Z isomers.

S (CDCI3) 0,96-1,30 (6H, m), 2,30 og 2,60 (2H, 2xm), 2,10 S (CDCl3) 0.96-1.30 (6H, m), 2.30 and 2.60 (2H, 2xm), 2.10

(3H, s), (3H, s),

2,98 og 3,28 (1H, 2xdd, J=2,6 og 4,3Hz), 2.98 and 3.28 (1H, 2xdd, J=2.6 and 4.3Hz),

4,15 og 4,30 (1H, 2xm), 5,05 og 5,31 (2H, 2xAB, J=13,2Hz), 4,74 og 5,33 (1H, 2xd, J=2,6Hz), 8.22- 8,80 (6H, m), 4.15 and 4.30 (1H, 2xm), 5.05 and 5.31 (2H, 2xAB, J=13.2Hz), 4.74 and 5.33 (1H, 2xd, J=2.6Hz) , 8.22- 8.80 (6H, m),

8,10-8,15 (2H, 2xd, J=8,7Hz). 8.10-8.15 (2H, 2xd, J=8.7Hz).

Eksempel 4 Example 4

4- nitrobenzyl- 3-( 4- cyanofenyl)- 3-( 2, 2- dimetylpropanovltio)- 2-r4R- etyltlo- 3S-( lR- hydroksyetyl) azetidin- 2- on- l- yllpropenoat 4- nitrobenzyl- 3-( 4- cyanophenyl)- 3-( 2, 2- dimethylpropanovlthio)- 2-r4R- ethylthlo- 3S-( 1R- hydroxyethyl) azetidin- 2- on- 1- ylylpropenoate

En omrørt oppløsning av 4-nitrobenzyl-3-(4-cyanofenyl)-2-[4R-etyltio-3S-(lR-hydroksyetyl)azetidin-2-on-l-yl]-3-(metylsulf onyloksy )propenoat (1,32 g) i acetonitril (100 ml) ble behandlet med kalium-2,2-(dimetyl)tiopropanoat (0,54 g). Etter 4,5 timer ble oppløsningsmidlet fjernet i vakuum og resten ble fordelt mellom etylacetat og vann. Det organiske laget ble fraseparert, vasket med mettet vandig natriumbikarbonat og saltvannsoppløsning, tørket over vannfritt magnesiumsulfat og inndampet. Den resulterende gummien ble kromatografert med etylacetat-heksan-blandinger over silikagel slik at man fikk forbindelsen i overskriften som gul gummi (0,57 g) som var en blanding av E- og Z-isomerene. A stirred solution of 4-nitrobenzyl-3-(4-cyanophenyl)-2-[4R-ethylthio-3S-(1R-hydroxyethyl)azetidin-2-on-1-yl]-3-(methylsulfonyloxy)propenoate (1 .32 g) in acetonitrile (100 ml) was treated with potassium 2,2-(dimethyl)thiopropanoate (0.54 g). After 4.5 hours, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated. The resulting gum was chromatographed with ethyl acetate-hexane mixtures over silica gel to give the title compound as a yellow gum (0.57 g) which was a mixture of the E and Z isomers.

§ (CDC13) 1,00-1,40 (15H, m), 2,45 og 2,68 (2H, 2xm), § (CDC13) 1.00-1.40 (15H, m), 2.45 and 2.68 (2H, 2xm),

3,15 og 3,37 (1H, 2xdd, J=2,9 og 4,3Hz), 3.15 and 3.37 (1H, 2xdd, J=2.9 and 4.3Hz),

4,23 og 4,31 (1H, 2xm), 4.23 and 4.31 (1H, 2xm),

4,93, 5,13 og 5,27, 5,44 (2H, 2xAB, Jgem=13,0Hz); 4.93, 5.13 and 5.27, 5.44 (2H, 2xAB, Jgem=13.0Hz);

4,43 og 5,45 (1H, 2xd, J=2,7Hz), - 4.43 and 5.45 (1H, 2xd, J=2.7Hz), -

7,18-7,30 (1H, m), 7,40-7,68 (5H, m), 7.18-7.30 (1H, m), 7.40-7.68 (5H, m),

8,10-8,26 (2H, m). 8.10-8.26 (2H, m).

Eksempel 5 Example 5

4- nitrobenzyl- 2- r4S- klor- 3S-( lR- hydroksyetyl)- azetidin- 2- on-l- yll- 3-( 4- cyanofenyl)- 3-( 2. 2- dimetylpropanoyltio) propenoat. 4- nitrobenzyl- 2- r4S- chloro- 3S-( 1R- hydroxyethyl)- azetidin- 2- one-1- yl- 3-( 4- cyanophenyl)- 3-( 2. 2- dimethylpropanoylthio) propenoate.

En oppløsning av 4-nitrobenzyl-3-(4-cyanofenyl)-3-(2,2-dimetylpropanoyltio)-2-[4R-etyltio-3S-(lR-hydroksyetyl)azetidin-2-on-l-yl]propenoat (0,57 g) i CDCI3(15 ml) ble avkjølt til -60°C, behandlet med en oppløsning av klor i karbontetraklorid (30 mg/ml, 2,5 ml) og omrørt i 1 time. Blandingen ble inndampet og den resulterende gummien ble kromatografert med etylacetat-heksan-blandinger over silikagel slik at man fikk forbindelsen i overskriften som et gult skum (0,34 g) som en blanding av E- og Z-isomerer. A solution of 4-nitrobenzyl-3-(4-cyanophenyl)-3-(2,2-dimethylpropanoylthio)-2-[4R-ethylthio-3S-(1R-hydroxyethyl)azetidin-2-on-1-yl]propenoate (0.57 g) in CDCl 3 (15 mL) was cooled to -60°C, treated with a solution of chlorine in carbon tetrachloride (30 mg/mL, 2.5 mL) and stirred for 1 hour. The mixture was evaporated and the resulting gum was chromatographed with ethyl acetate-hexane mixtures over silica gel to give the title compound as a yellow foam (0.34 g) as a mixture of E and Z isomers.

S (CDCI3) 1,10-1,50 (12H, m), 3,47 og 3,58 (1H, 2xdd, S (CDCl3) 1.10-1.50 (12H, m), 3.47 and 3.58 (1H, 2xdd,

J=4,0Hzog 9,5Hz), 4,25 og 4,49 (1H, 2xm), 5,04 og 5,44 (2H, 2xAB, Jgem=12 , 7Hz), 5,28 og 6,31 (1H, 2xd, J=4,0Hz), J=4.0Hz and 9.5Hz), 4.25 and 4.49 (1H, 2xm), 5.04 and 5.44 (2H, 2xAB, Jgem=12 , 7Hz), 5.28 and 6.31 ( 1H, 2xd, J=4.0Hz),

7,18-7,80 (6H, m), 8,16-8,27 (2H, m). 7.18-7.80 (6H, m), 8.16-8.27 (2H, m).

Eksempel 6 Example 6

4- nitrobenzyl- 5R, 3-( 4- cyanofenyl) - 6S-( IR- hydroksyetyl )- 7-okso- 4- tia- l- aza' blcyklor3 , 2 , Olhept- 2- en- karboksylat Til en oppløsning av 4-nitrobenzyl-2-[4S-klor-3S-( lR-hydroksyetyl )azetidin-2-on-l-yl]-3-(4-cyanofenyl)-3-(2,2-dimetyl-propanoyltio)propenoat (0,04 g) i dioksan (5 ml) ble det tilsatt en oppløsning av imidazol (7 mg) i vann (0,5 ml) og blandingen ble oppvarmet ved romtemperatur i 3 timer. Reaksjonsblandingen ble kromatografert direkte med etylacetat-heksan-blandinger over silikagel slik at man fikk forbindelsen i overskriften som en gul gummi (0,03 g). 4-nitrobenzyl-5R,3-(4-cyanophenyl)-6S-(IR-hydroxyethyl)-7-oxo-4-thia-l-aza'blcyclo3,2,Olhept-2-ene-carboxylate To a solution of 4 -nitrobenzyl-2-[4S-chloro-3S-(1R-hydroxyethyl)azetidin-2-on-1-yl]-3-(4-cyanophenyl)-3-(2,2-dimethyl-propanoylthio)propenoate (0 .04 g) in dioxane (5 ml) was added a solution of imidazole (7 mg) in water (0.5 ml) and the mixture was warmed at room temperature for 3 hours. The reaction mixture was chromatographed directly with ethyl acetate-hexane mixtures over silica gel to give the title compound as a yellow gum (0.03 g).

^maks (CDCI3) 3400 br, 1790 og 1720 crn-<1>^max (CDCI3) 3400 br, 1790 and 1720 crn-<1>

S (CDCI3) 1,41 (3H, d, J=6,3Hz); 3,89 (1H, dd, J=l,6 og 6,3Hz), S (CDCl 3 ) 1.41 (3H, d, J=6.3Hz); 3.89 (1H, dd, J=1.6 and 6.3Hz),

4,32 (1H, m), 5,12, 5,33 (2H, AB, Jgem=13,6Hz), 5,80 (1H, d, J=l,6Hz), 7,55, 7,66 (4H, AA'BB', J=8,5Hz), 4.32 (1H, m), 5.12, 5.33 (2H, AB, Jgem=13.6Hz), 5.80 (1H, d, J=1.6Hz), 7.55, 7.66 (4H, AA'BB', J=8.5Hz),

7,50, 8,20 (4H, AA'BB', J=8,5Hz) 7.50, 8.20 (4H, AA'BB', J=8.5Hz)

Eksempel 7 Example 7

Kalium- 5R. 3-( 4- cyanofenyl)- 6S-( lR- hydroksyetyl)- 7- okso- 4- tia-l- azabicyklor3 , 2 , 0~ lhept- 2- en- 2- karboksylat Potassium- 5R. 3-(4-Cyanophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo3,2,0~lhept-2-ene-2-carboxylate

4-nitrobenzyl-5R-3-(4-cyanofenyl)-6S-(lR-hydroksyetyl )-7-okso-4-t ia-l-azabicyklo[3 ,2 ,0]hept-2-en-2-karboksylat (0,11 g) ble oppløsat i dioksan (10 ml) og blandet med en oppløsn-ing av kaliumhydrogenkarbonat (24 mg) i vann (10 ml). 4-nitrobenzyl-5R-3-(4-cyanophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (0.11 g) was dissolved in dioxane (10 ml) and mixed with a solution of potassium bicarbonate (24 mg) in water (10 ml).

Blandingen ble hydrogenert ved 375 kPa (4 atm.) over 10% palladium-på-trekull (0,11 g) i 1 time og deretter filtrert gjennom "Hyflo". Filtratet ble frysetørket. Resten ble oppløst i vann, vasket med etylacetat og frysetørket, slik at man fikk forbindelsen i overskriften som et svakt gult pulver (0,08 g). The mixture was hydrogenated at 375 kPa (4 atm.) over 10% palladium-on-charcoal (0.11 g) for 1 hour and then filtered through "Hyflo". The filtrate was freeze-dried. The residue was dissolved in water, washed with ethyl acetate and freeze-dried, so that the title compound was obtained as a pale yellow powder (0.08 g).

(D20) 1,31 (3H, d, J=6,5Hz), 4,02 (1H, m), 4,25 (1H, m), (D20) 1.31 (3H, d, J=6.5Hz), 4.02 (1H, m), 4.25 (1H, m),

5,82 (1H, d, J=l,4Hz), 7,55, 7,75 (4H, AA'BB', J=8,lHz) 5.82 (1H, d, J=1.4Hz), 7.55, 7.75 (4H, AA'BB', J=8.1Hz)

Eksempel 8 Example 8

4- nitrobenzvl- 3-( 3- cvanofenyl)- 2-( 3S- fIR-( dimetvl( 2- metvlprop- 2- yl) silyloksy) etyll- 4R- etyltioazetidin- 2- on- l- yl)- 3-hydroksypropenoat 4- nitrobenzvl- 3-( 3- cyanophenyl)- 2-( 3S- fIR-( dimethyl( 2- methylpropyl- 2- yl) silyloxy) ethyl- 4R- ethylthioazetidin- 2- on- 1- yl)- 3- hydroxypropenoate

Ved en fremgangsmåte analog den som er beskrevet i eksempel 1, og ved anvendelse av 4-nitrobenzyl-2-(3S-[lR-(dimetyl(2-metyl-prop-2-yl )silyloksy)etyl] -4R-etyltioazetidin-2-on-l-yl)acetat (14,48 g), 3-cyanobenzoylklorid (5,96 g), n-butyllitium i tetrahydrofuran (1,6M, 42,2 ml), heksametyldisilazan (15,70 ml), iseddiksyre (7,20 g) og tetrahydrofuran (200 ml), ble forbindelsen i overskriften oppnådd som et brunt skum (19,47 g) hvis -'-H N.M.R.-spektrum viste at det var en kompleks blanding av E- og Z-isomerene og den tilsvarende keto-tautomeren. In a method analogous to that described in example 1, and using 4-nitrobenzyl-2-(3S-[1R-(dimethyl(2-methyl-prop-2-yl)silyloxy)ethyl]-4R-ethylthioazetidine- 2-on-1-yl)acetate (14.48g), 3-cyanobenzoyl chloride (5.96g), n-butyllithium in tetrahydrofuran (1.6M, 42.2ml), hexamethyldisilazane (15.70ml), glacial acetic acid (7.20 g) and tetrahydrofuran (200 ml), the title compound was obtained as a brown foam (19.47 g) whose -'-H N.M.R. spectrum showed it to be a complex mixture of E- and Z- the isomers and the corresponding keto tautomer.

<v>maks (CDCI3) 1800, 1750 og 1700 cm"<1><v>max (CDCI3) 1800, 1750 and 1700 cm"<1>

S (CDCI3) bl.a. 3,04 (1H, m), 4,25 (1H, m), 5,60 (1H, d, S (CDCI3) i.a. 3.04 (1H, m), 4.25 (1H, m), 5.60 (1H, d,

J=5,6Hz) J=5.6Hz)

Eksempel 9 Example 9

4- ni trobenzyl- 3-( 3- cvanofenyl)- 2-{ 3S- l" lR-( dimetyl( 2- metvlprop- 2- yl ) silyloksy) etyll- 4R- etyltioazetidin- 2- on- l- yl)- 3-( metylsulfonyloksy) propenoat 4-nitrobenzyl-3-(3-cyanophenyl)-2-{3S-1"1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl-4R-ethylthioazetidin-2-on-1-yl)- 3-(methylsulfonyloxy)propenoate

Ved fremgangsmåten ifølge eksempel 2 og ved å anvende 4-ni trobenzyl-3-(3-cyanofenyl)-2-(3S-[IR-(dimetyl(2-metylprop-2-yl )silyloksy )etyl] -4R-etyltioazetidin-2-on-l-yl )-3-hydroksypropenoat (19,47 g), trietylamin (4,85 g), metansulfonylk-lorld (5,50 g) og diklormetan (150 ml) ble forbindelsen i overskriften oppnådd som en oransje gummi (20,47 g) innbefattende en blanding av E- og Z-isomerene. By the method according to example 2 and by using 4-nitrobenzyl-3-(3-cyanophenyl)-2-(3S-[IR-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-4R-ethylthioazetidine- 2-on-1-yl)-3-hydroxypropenoate (19.47 g), triethylamine (4.85 g), methanesulfonyl chloride (5.50 g) and dichloromethane (150 ml), the title compound was obtained as an orange gum (20.47 g) comprising a mixture of the E and Z isomers.

S (CDCI3) 0,00-0,10 (6H, m), 0,81-0,91 (9H, 2xs), 1,09-1,31 (6H, m), 2,41 og 2,66 (2H, 2xq, J=7,5Hz); S (CDCl3) 0.00-0.10 (6H, m), 0.81-0.91 (9H, 2xs), 1.09-1.31 (6H, m), 2.41 and 2.66 (2H, 2xq, J=7.5Hz);

3.06 og 3,08 (3H, 2xs), 2,94 og 3,28 (1H, 2xdd, J=2,7 og 4,3Hz), 4,13 og 4,31 (1H, 2xm), 5,08 og 5,41 (2H, 2xs), 5,01 og 5,43 (1H, 2xd, J=2,7Hz), 7,24-7,28 (1H, m), 7,43-7,74 (4H, m); 7,94-8,28 (3H, m). 3.06 and 3.08 (3H, 2xs), 2.94 and 3.28 (1H, 2xdd, J=2.7 and 4.3Hz), 4.13 and 4.31 (1H, 2xm), 5.08 and 5.41 (2H, 2xs), 5.01 and 5.43 (1H, 2xd, J=2.7Hz), 7.24-7.28 (1H, m), 7.43-7.74 ( 4H, m); 7.94-8.28 (3H, m).

Eksempel 10 Example 10

4- nitrobenzvl- 3-( 3- cvanofenyl)- 2-[ 4R- etvltio- 3S-( lR- hydroksyetyl) azetidin- 2- on- l- yll- 3-( metylsulfonyloksy) propenoat 4- nitrobenzvl- 3-(3- cyanophenyl)- 2-[ 4R- ethylthio- 3S-( 1R- hydroxyethyl) azetidin- 2- on- 1- yl- 3-( methylsulfonyloxy) propenoate

Ved fremgangsmåten ifølge eksempel 3 og ved anvendelse av 4-nitrobenzyl-3-(3-cyanofenyl)-2-{3S-[IR-(dimetyl(2-metylprop2-2yl )silyloksy )etyl] -4R-etyltioazetidin-2-on-l-yl }-3-(me tyl-sulfonyloksy)propenoat (20,47 g), vann (18,2 ml), konsentrert ( 35%) saltsyre (18,15 g) og tetrahydrofuran (174 ml) ble forbindelsen i overskriften oppnådd som en blanding av E- og Z-isomerene i form av et oransje skum. In the method according to example 3 and using 4-nitrobenzyl-3-(3-cyanophenyl)-2-{3S-[IR-(dimethyl(2-methylprop2-2yl)silyloxy)ethyl]-4R-ethylthioazetidin-2-one -1-yl }-3-(methyl-sulfonyloxy)propenoate (20.47 g), water (18.2 ml), concentrated (35%) hydrochloric acid (18.15 g) and tetrahydrofuran (174 ml) gave the compound in the title obtained as a mixture of the E and Z isomers in the form of an orange foam.

S (CDCI3) 1,03-1,38 (6H, m), 2,40 og 2,70 (2H, 2xm), 3,19 S (CDCl3) 1.03-1.38 (6H, m), 2.40 and 2.70 (2H, 2xm), 3.19

(3H, s), (3H, s),

3.07 og 3,33 (2H, 2xdd, J=2,7og 4,3Hz"), 4,24 og 4,38 (2H, 2xm), 4,13 og 5,39 (2H, 2xs) , 4,75 og 5,40 (1H, 2xd, J=2,7Hz), 7,56-8,25 (8H, m). 3.07 and 3.33 (2H, 2xdd, J=2.7and 4.3Hz"), 4.24 and 4.38 (2H, 2xm), 4.13 and 5.39 (2H, 2xs), 4.75 and 5.40 (1H, 2xd, J=2.7Hz), 7.56-8.25 (8H, m).

Eksempel 11 Example 11

4- nltrobenzyl- 3-( 3- cyanofenyl)- 3-( 2, 2- dlmetylpropanoyltlo)- 2-f4R- etyltio- 3S-( lR- hydroksyetyl)- azetidin- 2- on- l- yllpropenoat Ved fremgangsmåten ifølge eksempel 4 og ved anvendelse av 4-ni trobenzyl-3 - ( 3-cyanofenyl )-2- [4R-etyltio-3S-( lR-hydroksyetyl)-azetidin-2-on-l-yl]-3-(metyl sulf onyloksy )-propenoat (5,76 g), kalum-2 , 2-( dimetyl ) t i opropanoat (2,34 g) og acetonitril (250 ml) ble forbindelsen 1 overskriften oppnådd 4-nitrobenzyl-3-(3-cyanophenyl)-3-(2,2-dlmethylpropanoyltlo)-2-f4R-ethylthio-3S-(1R-hydroxyethyl)-azetidin-2-one-1-ylylpropenoate By the method according to example 4 and using 4-nitrobenzyl-3-(3-cyanophenyl)-2-[4R-ethylthio-3S-(1R-hydroxyethyl)-azetidin-2-on-1-yl]-3-(methyl sulfonyloxy) -propenoate (5.76 g), calum-2,2-(dimethyl)thiopropanoate (2.34 g) and acetonitrile (250 ml), the title compound 1 was obtained

som en oransje gummi (2,65 g) innbefattende en blanding av E-og Z-isosmerene. as an orange gum (2.65 g) comprising a mixture of the E and Z isomers.

§ (CDCI3) 1,40 (15H, m), 2,50 og 2,75 (2H, 2xq, J=7,5Hz), § (CDCI3) 1.40 (15H, m), 2.50 and 2.75 (2H, 2xq, J=7.5Hz),

3,13 og 3,42 (1H, 2xdd, J=2,7 og 4,3Hz), 4,25 og 4,35 (1H, 2xm), 5,04, 5,16 og 5,27, 5,40 (2H, 2xAB, Jgem=13,0Hz ) , 5,43 og 5,44 (1H, 2xd, J=2,7Hz), 7,26-7,40 (3H,m), 7,45-7,84 (3H, m), 8,14-8,20 (2H, 2xd, J=8,7 Hz). 3.13 and 3.42 (1H, 2xdd, J=2.7 and 4.3Hz), 4.25 and 4.35 (1H, 2xm), 5.04, 5.16 and 5.27, 5, 40 (2H, 2xAB, Jgem=13.0Hz ), 5.43 and 5.44 (1H, 2xd, J=2.7Hz), 7.26-7.40 (3H,m), 7.45-7 .84 (3H, m), 8.14-8.20 (2H, 2xd, J=8.7 Hz).

Eksempel 12 Example 12

4- ni trobenzyl- 2- r4S- klor- 3S-( lR- hydroksyetyl)- azetidin- 2- on-l- yll- 3-( 3- cyanofenyl)- 3-( 2, 2- dimetylpropanoyltio) propenoat 4- nitrobenzyl- 2- r4S- chloro- 3S-( 1R- hydroxyethyl)- azetidin- 2- one-l- yl- 3-( 3- cyanophenyl)- 3-( 2, 2- dimethylpropanoylthio) propenoate

Ved fremgangsmåten ifølge eksempel 5 og ved anvendelse av 4-ni trobenzyl-3 - ( 3-cyanofenyl )-3-( 2 ,2-dimetylpropanoyltio)-2-[4R-etyl tio-3S-(lR-hydroksyetyl)azetidin-2-on-l-yl]propenoat (1,39 g), klor i karbontetraklorid (33 mg/ml, 5,76 ml) og CDCI3(30 ml), ble forbindelsen i overskriften oppnådd som en gul gummi (0,53 g) innbefattende en blanding av E- og Z-isomerene. In the method according to example 5 and using 4-nitrobenzyl-3-(3-cyanophenyl)-3-(2,2-dimethylpropanoylthio)-2-[4R-ethyl thio-3S-(1R-hydroxyethyl)azetidine-2 -on-l-yl]propenoate (1.39 g), chlorine in carbon tetrachloride (33 mg/ml, 5.76 ml) and CDCl 3 (30 ml), the title compound was obtained as a yellow gum (0.53 g ) including a mixture of the E and Z isomers.

<v>maks (CDCI3) 1780 og 1700 crn-1 <v>max (CDCI3) 1780 and 1700 crn-1

§ (CDCI3) 1,10-1,50 (12H, m), 3,36 og 3,58 (1H, 2xdd, J=4,3§ (CDCI3) 1.10-1.50 (12H, m), 3.36 and 3.58 (1H, 2xdd, J=4.3

og 9,3Hz), 4,20 og 4,5 0 (1H, 2xm), 5,07 og 5,37 (2H, 2xAB, Jgem=13,6Hz), 5,42 og 6,32 (1H, 2xd, J=4,3Hz), 7,16-7,36 (2H,m), 7,47-7,79 (4H, m), 8,14-8,28 (2H, 2xd, J=8,7Hz). and 9.3Hz), 4.20 and 4.5 0 (1H, 2xm), 5.07 and 5.37 (2H, 2xAB, Jgem=13.6Hz), 5.42 and 6.32 (1H, 2xd , J=4.3Hz), 7.16-7.36 (2H,m), 7.47-7.79 (4H,m), 8.14-8.28 (2H, 2xd, J=8, 7Hz).

Eksempel 13 4- nitrobenzyl- 5R, 3-( 3- cyanof enyl)- 6S-( IR- hydroksyetyl )- 7-okso- 4- tia- l- azabicyklor3. 2, Olhept- 2- en- 2- karboksylat Example 13 4-nitrobenzyl-5R,3-(3-cyanophenyl)-6S-(IR-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo3. 2, Olhept-2-ene-2-carboxylate

Ved fremgangsmåten ifølge eksempel 6 og ved å anvende 4-nitrobenzyl- 2-[4S-klor-3S-(lR-hydroksyetyl )azetidin-2-on-l-yl]-3-(4-cyanofenyl)-3-(2,2-dimetylpropanoyltio ) propenoat (0,53 g), dioksan (10 ml), imidazol (95 mg) og vann (1 ml) ble forbindelsen i overskriften oppnådd som en gul gummi (0,16 g). By the method according to example 6 and by using 4-nitrobenzyl-2-[4S-chloro-3S-(1R-hydroxyethyl)azetidin-2-on-1-yl]-3-(4-cyanophenyl)-3-(2 ,2-dimethylpropanoylthio) propenoate (0.53 g), dioxane (10 ml), imidazole (95 mg) and water (1 ml) the title compound was obtained as a yellow gum (0.16 g).

<v>maks ("Nujol"-mold) 3440, 2220, 1770 og 1700 crn-1 <v>max ("Nujol" mold) 3440, 2220, 1770 and 1700 crn-1

§ (CDC13) 1,40 (3H, d, J = 6,3Hz), 3,90 (1H, dd, J=l,6 og 6,3Hz), 4,31 (1H, m); 5,13, 5,32 (2H, AB, Jgem=13,6Hz), 5,80 (1H, d, J=l,6Hz), 7,43-7,52 (3H, m), 7,66-7,74 (3H, m), 8,18 (2H, d, J=8,8Hz). § (CDCl 3 ) 1.40 (3H, d, J = 6.3Hz), 3.90 (1H, dd, J = 1.6 and 6.3Hz), 4.31 (1H, m); 5.13, 5.32 (2H, AB, Jgem=13.6Hz), 5.80 (1H, d, J=1.6Hz), 7.43-7.52 (3H, m), 7.66 -7.74 (3H, m), 8.18 (2H, d, J=8.8Hz).

Eksempel 14 Example 14

Kallum- 5R, 3-( 3- cyanofenyl)- 6S-( lR- hydroksyetyl)- 7- okso- 4- tla-l- azablcyklofS, 2, 0lhept- 2- en- 2- karboksylat Kallum- 5R, 3-( 3- cyanophenyl)- 6S-( 1R- hydroxyethyl)- 7- oxo- 4- tla-1- azablcyclofS, 2, 0lhept- 2- ene- 2- carboxylate

Ved fremgangsmåten ifølge eksempel 7 og ved å anvende 5R,3-( 3-cyanof enyl ) - 6S- (lR-hydroksyetyl )-7-okso-4 - t ia-l-azabicyklo[3,2,0lhept-2-en-2-karboksylat (0,16 g), dioksan (10 ml), kaliumbikarbonat (35 mg) vann (10 ml) og palladium-på-trekull (0,16 g) ble forbindelsen i overskriften oppnådd som et svakt gult pulver (0,09 g). By the method according to example 7 and by using 5R,3-(3-cyanophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0lhept-2-ene -2-carboxylate (0.16 g), dioxane (10 ml), potassium bicarbonate (35 mg), water (10 ml) and palladium-on-charcoal (0.16 g), the title compound was obtained as a pale yellow powder ( 0.09g).

S (D20) 1,27 (3H, d, J=5,8Hz), 3,97 (1H, dd, J=l,4 og 4,2Hz), S (D20) 1.27 (3H, d, J=5.8Hz), 3.97 (1H, dd, J=1.4 and 4.2Hz),

4,26 (1H, m); 5,76 (1H, d, J=l,4Hz), 7,43-7,97 4.26 (1H, m); 5.76 (1H, d, J=1.4Hz), 7.43-7.97

(4H, m). (4H, m).

Eksempel 15 Example 15

4- metyltio- tiobenzosyre 4- methylthio- thiobenzoic acid

Til en omrørt oppløsning av 4-metyltiobenzoylklorid (9,82 g) i diklormetan (150 ml) ved 0°C ble det dråpevis tislatt pyridin (8,5 ml); etter at blandingen var omrørt i ytterligere 10 minutter ble hydrogensulfid (overskudd) boblet gjennom. Etter omrøring i ytterligere 60 minutter ble blandingen ekstrahert med mettet vandig natriumbikarbonat. Det vandige ekstraktet ble vasket med diklormetan, deretter surgjort til pH 2 med fortynnet saltsyre, og ekstrahert med etylacetat. Dette organiske ekstraktet ble vasket med vann, og saltvannsoppløsning, tørket over vannfritt natriumsulfat og inndampet i vakuum, slik at man fikk forbindelsen i overskriften som et gult faststoff (5,72 g). To a stirred solution of 4-methylthiobenzoyl chloride (9.82 g) in dichloromethane (150 ml) at 0°C was added dropwise pyridine (8.5 ml); after the mixture was stirred for an additional 10 minutes, hydrogen sulfide (excess) was bubbled through. After stirring for an additional 60 minutes, the mixture was extracted with saturated aqueous sodium bicarbonate. The aqueous extract was washed with dichloromethane, then acidified to pH 2 with dilute hydrochloric acid, and extracted with ethyl acetate. This organic extract was washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound as a yellow solid (5.72 g).

S (CDCI3) 2,53 (3H, s), 5,40 (1H, bs), 7,28, 7,83 (4H, S (CDCl 3 ) 2.53 (3H, s), 5.40 (1H, bs), 7.28, 7.83 (4H,

AA'BB', J=8,0Hz). AA'BB', J=8.0Hz).

Eksempel 16 Example 16

3S-( lR- fdimetyl- f 2- metylprop- 2- yl) si 1yloksvietyl>- 4R-( 4-metyltiobenzoyltio) azetidin- 2- on 3S-(1R-fdimethyl-f 2-methylprop-2-yl)si1yloxyethyl>- 4R-(4-methylthiobenzoylthio)azetidin-2-one

Til en omrørt oppløsning av 4-metyltio-tiobenzosyre (5,7 g) i 100 ml aceton ble det tilsatt IM natriumhydroksyd inntil pH var 8,5 etterfulgt av en oppløsning av 4-acetoksy-3R-(1R-[dimetyl-(2-metylprop-2-yl)silyloksy[etyl>azetidin-2-on (7,41 To a stirred solution of 4-methylthio-thiobenzoic acid (5.7 g) in 100 ml of acetone was added 1M sodium hydroxide until the pH was 8.5 followed by a solution of 4-acetoxy-3R-(1R-[dimethyl-(2 -methylprop-2-yl)silyloxy[ethyl>azetidin-2-one (7.41

g) i aceton (100 ml). Etter omrøring i ytterligere en time ble blandingen fordelt mellom etylacetat og vann; den g) in acetone (100 ml). After stirring for an additional hour, the mixture was partitioned between ethyl acetate and water; it

organiske fasen ble vasket med vann, med mettet vandig natriumbikarbonat, med vann, og med saltvannsoppløsning, ble tørket over vannfritt magnesiumsulfat, og inndampet i vakuum, slik at man fikk et gulaktig faststoff (11 g), kromatografi over silikagel, og eluering med etylacetat-heksan-blandinger ga forbindelsen i overskriften (9,9 g). the organic phase was washed with water, with saturated aqueous sodium bicarbonate, with water, and with brine, was dried over anhydrous magnesium sulfate, and evaporated in vacuo to give a yellowish solid (11 g), chromatographed over silica gel, and eluted with ethyl acetate -hexane mixtures gave the title compound (9.9 g).

vmaks (CDCI3) 1770 cm"<1>vmax (CDCI3) 1770 cm"<1>

S (CDCI3) 1,23 (3H, dm J=6,4Hz), 2,523 (3H, s), 3,27 (1H, S (CDCl3) 1.23 (3H, dm J=6.4Hz), 2.523 (3H, s), 3.27 (1H,

dd, J=2,5og 3,6Hz), 4,30 (1H, m), 5,46 (1H, d, J=2,5Hz), 6,50 (1H, bs), 7,25 (2H, d, J=8,7Hz), 7,81 (2H, d, J=8,7Hz). dd, J=2.5and 3.6Hz), 4.30 (1H, m), 5.46 (1H, d, J=2.5Hz), 6.50 (1H, bs), 7.25 (2H , d, J=8.7Hz), 7.81 (2H, d, J=8.7Hz).

Eksempel 17 Example 17

4- ni trobenzyl-{ 3S- fIR-( dimetyl( 2- metylprop- 2- yl)- silyloksy)-etyll- 4R-( 4- metyltiobenzoyltio) azetidin- 2- on- l- yl) oksoacetat Til en omrørt blanding av 3S-{lR-[dimetyl(2-metylprop-2-yl)-si ly lok sy]etyl}-4R-(4-metyltiobenzoyltio)azetidin-2-on ( 9 ,89 4- nitrobenzyl-{ 3S- fIR-( dimethyl( 2- methylpropyl- 2- yl)- silyloxy)-ethyl- 4R-( 4- methylthiobenzoylthio) azetidin- 2- on- 1- yl) oxoacetate To a stirred mixture of 3S-{1R-[dimethyl(2-methylprop-2-yl)-silyloxy]ethyl}-4R-(4-methylthiobenzoylthio)azetidin-2-one ( 9.89

g), kalsiumkarbonat (10,g) og diisopropyletylamin (6,27 ml) ved 0"C ble det tilsatt en oppløsning av 4-nitrobenzyl-kloroksoacetat (6,99 g) i diklormetan (150 ml). Etter at blandingen var omrørt i ytterligere 30 minutter ble den fordelt mellom vann og diklormetan; det organiske laget ble vasket trinnvis med fortynnet saltsyre, med vann og med saltvannsoppløsning, og ble tørket over vannfritt natriumsulfat. Avdampning av oppløsningsmidlet ga forbindelsen 1 overskriften (15,6 g) som en oransje olje. g), calcium carbonate (10.g) and diisopropylethylamine (6.27 ml) at 0°C was added a solution of 4-nitrobenzyl chloroxoacetate (6.99 g) in dichloromethane (150 ml). After the mixture was stirred for a further 30 minutes it was partitioned between water and dichloromethane; the organic layer was washed stepwise with dilute hydrochloric acid, with water and with brine, and was dried over anhydrous sodium sulfate. Evaporation of the solvent gave the title compound 1 (15.6 g) as a orange oil.

S (CDCI3) 0,09 (6H, s), 0,82 (9H, s), 1,26 (3H, d J=6,3H-z), 2,53 (3H, s), 3,63 (1H, t, J=3,0Hz), 4,40 (1H, m), 5,39 (2H, AB, Jgem=13, 0Hz), 6,20 (1H, d, J=3,0Hz), 7,25 og 7,63 (4H, AA'BB', J=8,6Hz), 7,56 og 8,21 (4H, AA'BB', J=8,8Hz). S (CDCl 3 ) 0.09 (6H, s), 0.82 (9H, s), 1.26 (3H, d J=6.3H-z), 2.53 (3H, s), 3.63 (1H, t, J=3.0Hz), 4.40 (1H, m), 5.39 (2H, AB, Jgem=13, 0Hz), 6.20 (1H, d, J=3.0Hz) , 7.25 and 7.63 (4H, AA'BB', J=8.6Hz), 7.56 and 8.21 (4H, AA'BB', J=8.8Hz).

Eksempel 18 Example 18

4- nitrobenzyl- 5R, 6S-{ lR- fdimetyl( 2- metylprop- 2- yl) silyloksy]-etyl >- 3- ( 4- metyl ti of enyl )- 7- okso- 4- tia- l- azabicyklor3 , 2 , Ol - hept- 2- en- 2- Rarboksylat En blanding av 4-nitrobenzyl-{3S-[lR-(dimetyl(2-metylprop-2-yl )siyloksy)etyl]-4R-(4-metyltiobenzoyltio)-azetidin-2-on-l-yl}oksoacetat (15,6 g), trietylfosfitt (8,23 ml) og o-xylen (100 ml) ble oppvarmet under tilbakestrømning (badtemperatur 130°C) i 12 timer, og deretter inndampet i vakuum. Kromatografi av resten over silikagel, og eluering med dietyleter-heksan-blandinger ga forbindelsen i overskriften (6,87 g). 4-nitrobenzyl-5R,6S-{1R-fdimethyl(2-methylpropyl-2-yl)silyloxy]-ethyl >- 3-(4-methylthiofenyl)-7-oxo-4-thi-1-azabicyclo3, 2 , Ol - hept- 2- en- 2- Rarcarboxylate A mixture of 4-nitrobenzyl-{3S-[1R-(dimethyl(2-methylprop-2-yl)siyloxy)ethyl]-4R-(4-methylthiobenzoylthio)- Azetidin-2-on-l-yl}oxoacetate (15.6 g), triethyl phosphite (8.23 mL) and o-xylene (100 mL) were heated under reflux (bath temperature 130°C) for 12 h, then evaporated in vacuum. Chromatography of the residue over silica gel, and elution with diethyl ether-hexane mixtures gave the title compound (6.87 g).

vmaks(CDCI3 ) 1783 cm"1 vmax(CDCI3 ) 1783 cm"1

S (CDCI3) 0,06 (3H, s), 0,08 (3H, s), 0,85 (9H, s), 1,27 S (CDCl 3 ) 0.06 (3H, s), 0.08 (3H, s), 0.85 (9H, s), 1.27

(3H, d, J=6,3Hz), 2,48 (3H, s), 3,80 (1H, dd, J-1,6 og 4,2Hz), 4,30 (1H, m), 5,21 (2H, AB, Jgem=13,8Hz), 5,68 (1H, d, J=l,6Hz), 7,18 (2H, d, J=8,5Hz), 7,41 (4H, m), 8,16 (2H, d, J=8,8Hz). (3H, d, J=6.3Hz), 2.48 (3H, s), 3.80 (1H, dd, J-1.6 and 4.2Hz), 4.30 (1H, m), 5 .21 (2H, AB, Jgem=13.8Hz), 5.68 (1H, d, J=1.6Hz), 7.18 (2H, d, J=8.5Hz), 7.41 (4H, m), 8.16 (2H, d, J=8.8Hz).

Eksempel 19 Example 19

4- ni trobenzyl- 5R, 6S-( lR- hvdroksvetyl)- 3-( 4- metyltiofenyl)- 7-okso- 4- tia- l- azabicyklor3, 2, 0lhept- 2- ene- 2- karboksylat 4- nitrobenzyl- 5R, 6S-( 1R- hydroxymethyl)- 3-( 4- methylthiophenyl)- 7-oxo- 4- thia- 1- azabicyclo3, 2, 0lhept- 2- ene- 2- carboxylate

Til en omrørt oppløsning av 4-nitrobenzyl-5R,6S-(IR-[dimetyl-(2-metylprop-2-yl)silyloksy]etyl)-3-(4-metyltiofenyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-ene-2-karboksylat (6,87 g) i tørr tetrahydrofuran (100 ml) ble det tilsatt iseddlksyre To a stirred solution of 4-nitrobenzyl-5R,6S-(1R-[dimethyl-(2-methylprop-2-yl)silyloxy]ethyl)-3-(4-methylthiophenyl)-7-oxo-4-thia-1 -azabicyclo[3,2,0]hept-2-ene-2-carboxylate (6.87 g) in dry tetrahydrofuran (100 ml) was added glacial acetic acid

(9,37 ml) og en IM oppløsning av tetra-n-butylammoniumfluorid i tetrahydrofuran (35 ml). Etter at blandingen var omrørt i 16 timer, ble den fordelt mellom etylacetat og vann; det organiske laget ble trinnvis vasket med mettet vandig natriumbikarbonat, med vann, med saltvannsoppløsning, ble tørket over vannfritt magnesiumsulfat og inndampet i vakuum. Kromatografi av råresten over silikagel, og eluering med etylacetat-heksan-blandinger ga forbindelsen i overskriften som et gult faststoff (3,3 g). (9.37 mL) and an IM solution of tetra-n-butylammonium fluoride in tetrahydrofuran (35 mL). After the mixture was stirred for 16 hours, it was partitioned between ethyl acetate and water; the organic layer was washed stepwise with saturated aqueous sodium bicarbonate, with water, with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. Chromatography of the crude residue over silica gel, and elution with ethyl acetate-hexane mixtures gave the title compound as a yellow solid (3.3 g).

S (CDC13) 1,19 (3H, d, J=6,3Hz), 2,38 (3H, s), 3,78 (1H, S (CDCl 3 ) 1.19 (3H, d, J=6.3Hz), 2.38 (3H, s), 3.78 (1H,

dd, J=l,5og 6,3Hz), 4,08 (1H, m), 5,14 (2H, AB, Jgem=14,0Hz), 5,71 (1H, d, J=l, 5Hz), 7,11, 7,31 ("4H, AA'BB ' , J=8,5Hz) , dd, J=l.5and 6.3Hz), 4.08 (1H, m), 5.14 (2H, AB, Jgem=14.0Hz), 5.71 (1H, d, J=l, 5Hz) , 7.11, 7.31 ("4H, AA'BB ' , J=8.5Hz) ,

7,39, 8,06 (2H, AA'BB', J=9,0Hz). 7.39, 8.06 (2H, AA'BB', J=9.0Hz).

Eksempel 20 Example 20

4- nitrobenzyl- 5R. 6S-( lR- hydroksyet. yl ) - 3-( 4- metyl sulf inyl-fenyl)- 7- okso- 4- tia- l- azabicyklor3, 2. 0~] hept- 2- en- 2- karboksylat 4- nitrobenzyl- 5R. 6S-(1R-hydroxyet.yl)-3-(4-methylsulfinyl-phenyl)-7-oxo-4-thia-1-azabicyclo3,2.0~]hept-2-ene-2-carboxylate

Til en blanding av 4-nitrobenzyl-5R,6S-(lR-hydroksyetyl)-3-(4-metyl ti of enyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (306 mg), etylacetat (10 ml) og aceton (10 ml) ved -40° C ble det tilsatt en oppløsning av 80% 3-klorperbenzosyre (154 mg) i etylacetat (10 ml). Etter at blandingen var oppvarmet i to timer til 0°C, og denne omrørt i ytterligere en time ved romtemperatur, ble den fordelt mellom etylacetat og 5% vandig kaliummetabisulf itt. Det organiske laget ble vasket med mettet vandig natriumbikarbonat, med vann og med saltvannsoppløsning, og deretter inndampet til tørrhet. Kromatografi over silikagel og eluering med etylacetat-heksanblandinger ga forbindelsen i overskriften (173 mg). To a mixture of 4-nitrobenzyl-5R,6S-(1R-hydroxyethyl)-3-(4-methylthiofenyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2 -ene-2-carboxylate (306 mg), ethyl acetate (10 ml) and acetone (10 ml) at -40° C. was added a solution of 80% 3-chloroperbenzoic acid (154 mg) in ethyl acetate (10 ml). After the mixture had been heated for two hours to 0°C, and this stirred for a further hour at room temperature, it was partitioned between ethyl acetate and 5% aqueous potassium metabisulphite. The organic layer was washed with saturated aqueous sodium bicarbonate, with water and with brine, and then evaporated to dryness. Chromatography over silica gel and eluting with ethyl acetate-hexane mixtures gave the title compound (173 mg).

vmaks(CDCI3 ) 1780 cm"1 vmax(CDCI3 ) 1780 cm"1

S (aceton-d6) 1,19 (3H, d, J = 6,3), 2,59 (3H, s), 3,84 S (acetone-d6) 1.19 (3H, d, J = 6.3), 2.59 (3H, s), 3.84

(1H, dd, J=l,5og 6,1Hz), 4,09 (1H, m), (1H, dd, J=1.5and 6.1Hz), 4.09 (1H, m),

5,07, 5,22 (2H, AB, Jgem=13,8Hz), 5,79 (1H, d, J=l,5Hz), 7,41, 8,06 (4H, AA'BB', J=8,4Hz), 7,56 (4H, s). 5.07, 5.22 (2H, AB, Jgem=13.8Hz), 5.79 (1H, d, J=1.5Hz), 7.41, 8.06 (4H, AA'BB', J =8.4Hz), 7.56 (4H, s).

Eksempel 21 Example 21

Kallum- 5R, 6S-( lR- hydroksvetyl )- 3-( 4- metvlsulf Invlfenvl )- 7-okso- 4- tia- l- azablcyklor3, 2, Olhept- 2- en- 2- karboksylat Kallum- 5R, 6S-( 1R- hydroxymethyl )- 3-( 4- methylsulfinylphenyl )- 7-oxo- 4- thia- 1-azablcyclo3, 2, Olhept- 2-ene- 2- carboxylate

Forbindelsen 1 overskriften (140 mg) ble oppnådd ved en fremgangsmåte analog den beskrevet i eksempel 7 og ved anvendelse av 4-nitrobenzyl-5R,6S-(lR-hydroksyetyl )-3-( 4-metyl sul f inylf enyl )-7-okso-4-tia-l-azabicyklo[3 ,2 , 0]hept-2-en-2-karboksylat (170 mg), kaliumbikarbonat (35,3 mg), 10% palladium-på-trekull (170 mg), dioksan (5 ml) og vann (5 ml). The title compound 1 (140 mg) was obtained by a method analogous to that described in example 7 and by using 4-nitrobenzyl-5R,6S-(1R-hydroxyethyl)-3-(4-methylsulfinylphenyl)-7- oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (170 mg), potassium bicarbonate (35.3 mg), 10% palladium-on-charcoal (170 mg), dioxane (5 mL) and water (5 mL).

S (D20) 1,26 (3H, d, J=6,3Hz), 2,83 (3H, s), 3,96 (1H, dd, S (D20) 1.26 (3H, d, J=6.3Hz), 2.83 (3H, s), 3.96 (1H, dd,

J=l,5 og 5,8Hz), 4,22 (1H, m), 5,76 (1H, d, J=l,5Hz), 7,56, 7,64 (4H, AA'BB', J=8,2Hz). J=1.5 and 5.8Hz), 4.22 (1H, m), 5.76 (1H, d, J=1.5Hz), 7.56, 7.64 (4H, AA'BB', J=8.2Hz).

Eksempel 22 Example 22

4- nitrobenzyl- 5R, 6S-( 1R- hydroksyetyl )- 3-( 4- metylsulfonyl-fenyl)- 7- okso- 4- tia- l- azabicyklor3. 2. 0lhept- 2- en- 2- karboksylat 4- nitrobenzyl- 5R, 6S-( 1R- hydroxyethyl )- 3-( 4- methylsulfonyl-phenyl)- 7- oxo- 4- thia- l-azabicyclo3. 2. 0lhept-2-ene-2-carboxylate

Tittelforbindelsen (148 mg) ble oppnådd ved en fremgangsmåte analog den beskrevet i eksempel 20 ved å anvende 4-nitrobenzyl-5R, 6S-(lR-hydroksyetyl)-3-(4-metyltiofenyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (1,00 g), 80% 3-klorperbenzosyre (1,00 g), etylacetat (35 ml) og aceton (15 ml). The title compound (148 mg) was obtained by a method analogous to that described in Example 20 by using 4-nitrobenzyl-5R,6S-(1R-hydroxyethyl)-3-(4-methylthiophenyl)-7-oxo-4-thia-1 -azabicyclo[3,2,0]hept-2-ene-2-carboxylate (1.00 g), 80% 3-chloroperbenzoic acid (1.00 g), ethyl acetate (35 ml) and acetone (15 ml).

vmaks (CDCI3 ) 1780 cm"<1>vmax (CDCI3 ) 1780 cm"<1>

S (aceton-d6) 1,31 (3H, d, J=6,3Hz), 3,13 (3H, s), 3,98 S (acetone-d6) 1.31 (3H, d, J=6.3Hz), 3.13 (3H, s), 3.98

(1H, dd, J = l,6 og 6,0Hz), 4,22 (1H, m), 5,26 (2H, AB, Jgem=l3,8Hz), 5,94 (1H, d, J=l,6Hz), 7,52, 7,93 (4H, AA'BB', J=8,4Hz), 7,73, 8,18 (4H, AA'BB', J=8,7Hz). (1H, dd, J = l.6 and 6.0Hz), 4.22 (1H, m), 5.26 (2H, AB, Jgem=l3.8Hz), 5.94 (1H, d, J= 1.6Hz), 7.52, 7.93 (4H, AA'BB', J=8.4Hz), 7.73, 8.18 (4H, AA'BB', J=8.7Hz).

Eksempel 23 Example 23

Kalium- 5R . 6S-( lR- hydroksyetyl )- 3-( 4- metylsulfonvlfenyl )- 7-okso- 4- tia- l- azabicyklor3. 2, 0~ lhept- 2- en- 2- karboksylat Potassium- 5R . 6S-(1R-hydroxyethyl)-3-(4-methylsulfonylphenyl)-7-oxo-4-thia-1-azabicyclo3. 2, 0~ lhept- 2- en- 2- carboxylate

Forbindelsen i overskriften (91 mg) ble oppnådd ved en fremgangsmåte analog den beskrevet i eksempel 7 ved å anvende 4-nitrobenzyl-5R,6S-(IR-hydroksyetyl)-3-(4-metylsulf onyl-fenyl )-7-okso-4-tia-l-azabicyklo [3,2,0]hept-2-en-2-karboksylat (148 mg), kaliumbikarbonat (29,7 mg), 10% palladium-på-trekull (70 mg), vann (5 ml) og dioksan (5 ml). The compound in the title (91 mg) was obtained by a method analogous to that described in example 7 by using 4-nitrobenzyl-5R,6S-(1R-hydroxyethyl)-3-(4-methylsulfonyl-phenyl)-7-oxo- 4-thia-l-azabicyclo [3,2,0]hept-2-ene-2-carboxylate (148 mg), potassium bicarbonate (29.7 mg), 10% palladium-on-charcoal (70 mg), water ( 5 ml) and dioxane (5 ml).

S (D20) 1,29 (3H, d, J=6,3Hz), 3,25 (3H, s), 4,02 (1H, dd, S (D20) 1.29 (3H, d, J=6.3Hz), 3.25 (3H, s), 4.02 (1H, dd,

J-1,5 og 5,9Hz), 4,25 (1H, m), 5,82 ( 1H, d, J=l,5Hz), 7,64, 7,91 (4H, AA'BB', J=8,5Hz). J-1.5 and 5.9Hz), 4.25 (1H, m), 5.82 ( 1H, d, J=1.5Hz), 7.64, 7.91 (4H, AA'BB', J=8.5Hz).

Eksempel 24 Example 24

4- cyanotiobenzosyre 4- cyanothiobenzoic acid

En oppløsning av 4-cyanobenzoylklorid (1,66 g) i diklormetan (50 ml) ble behandlet med pyridin (0,81 ml) og mettet med hydrogensulfid i 30 minutter. Blandingen ble spylt med nitrogen, deretter inndampet og resten ble fordelt mellom etylacetat og 2M vandig saltsyre. Det organiske laget ble separert og ekstrahert med mettet vandig natriumbikarbonat. Det basiske vandige ekstraktet ble surgjort med 2M vandig saltsyre og ekstrahert med etylacetat. Etter tørking over vannfritt magnesiumsulfat ble det organiske ekstraktet inndampet slik at man fikk 4-cyanotiobenzosyre som et gult faststoff (1,25 g). A solution of 4-cyanobenzoyl chloride (1.66 g) in dichloromethane (50 mL) was treated with pyridine (0.81 mL) and saturated with hydrogen sulfide for 30 minutes. The mixture was flushed with nitrogen, then evaporated and the residue was partitioned between ethyl acetate and 2M aqueous hydrochloric acid. The organic layer was separated and extracted with saturated aqueous sodium bicarbonate. The basic aqueous extract was acidified with 2M aqueous hydrochloric acid and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the organic extract was evaporated to give 4-cyanothiobenzoic acid as a yellow solid (1.25 g).

<v>maks ("Nujol"-mold) 2500, 2230 og 1700 cm"<1><v>max ("Nujol" mold) 2500, 2230 and 1700 cm"<1>

S (aeton-d6) 7,90, 8,20 (4H, AA'BB', J=8,0Hz) S (aeton-d6) 7.90, 8.20 (4H, AA'BB', J=8.0Hz)

Eksempel 25 Example 25

4R-( 4- cyanobenzoyltio)- 3S-( lR- rdimetyl( 2- metylprop- 2- yl )-silyloksyletyl) azetidin- 2- on 4R-(4-cyanobenzoylthio)-3S-(1R-rdimethyl(2-methylprop-2-yl)-silyloxyethyl)azetidin-2-one

En oppløsning av 4-cyanotiobenzosyre (0,34 g) i aceton (5 ml) ble behandlet med IM vandig natriumhydroksyd (2,1 ml) og blandingen ble tilsatt dråpevis til en avkjølt (0°C) oppløs-ning av 4R-acetoksy-3R-[lR-[dimetyl(2-metylprop-2-yl )silyloksy] etyl }azetidin-2-on (0,58 g) i aceton-vann (70:30) (10 ml). Blandingen ble omrørt i 45 minutter, deretter fordelt mellom etylacetat og saltvannsoppløsning. Den organiske fasen ble fraseparert, tørket over vannfritt magnesiumsulfat og inndampet. Kromatografi av den resulterende oljen med etylacetat-heksanblandinger over silikagel ga forbindelsen i overskriften som en fargeløs olje (0,56 g). A solution of 4-cyanothiobenzoic acid (0.34g) in acetone (5ml) was treated with 1M aqueous sodium hydroxide (2.1ml) and the mixture was added dropwise to a cooled (0°C) solution of 4R-acetoxy -3R-[1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl}azetidin-2-one (0.58 g) in acetone-water (70:30) (10 ml). The mixture was stirred for 45 minutes, then partitioned between ethyl acetate and brine. The organic phase was separated, dried over anhydrous magnesium sulfate and evaporated. Chromatography of the resulting oil with ethyl acetate-hexane mixtures over silica gel gave the title compound as a colorless oil (0.56 g).

S (CDC13) 0,07 (6H, s), 0,89 (9H, s), 1,25 (3H, d, S (CDCl 3 ) 0.07 (6H, s), 0.89 (9H, s), 1.25 (3H, d,

J=6,2Hz), 3,32 (1H, m), 4,32 (1H, m), 5,50 (1H, d, J=2,3Hz), 6,46 (1H, bs), 7,80, 8,00 (4H, ÅA'BB', J=8,5Hz). J=6.2Hz), 3.32 (1H, m), 4.32 (1H, m), 5.50 (1H, d, J=2.3Hz), 6.46 (1H, bs), 7 .80, 8.00 (4H, ÅA'BB', J=8.5Hz).

Eksempel 26 Example 26

4- nitrobenzyl- 4R-( 4- cyanobenzoyltio)- 3S-{ IR- fdimetyl( 2- metylprop- 2- yl) silyloksyletyl)- azetidin- 2- on- l- yl- oksoacetat En oppløsning av 4R-( 4-cyanobenzoylt io )-3S-[lR-dimetyl ( 2-metylprop-2-y1)si ly1oksyéty1]azetidin-2-on (0,76 g) i diklormetan (15 ml) ble avkjølt (0°C) og omrørt. Fast kalsiumkarbonat (0,49 g) ble tilsatt etterfulgt av diisopropyletylamin (0,51 ml). En oppløsning av 4-nitrobenzyl-kloroksoacetat (0,57 g) i diklormetan (6 ml) ble innført dråpevis og omrøringen ble fortsatt i 30 minutter. Blandingen ble filtrert og filtratet ble vasket med 0,IM vandig saltsyre, tørket over vannfritt magnesiumsulfat og inndampet slik at man fikk forbindelsen i overskriften som et gult skum (1,16 g). 4- nitrobenzyl- 4R-( 4- cyanobenzoylthio)- 3S-{ IR- fdimethyl( 2- methylprop- 2- yl) silyloxyethyl)- azetidin- 2- on- 1- yl- oxoacetate A solution of 4R-( 4- cyanobenzoyl io )-3S-[1R-dimethyl (2-methylprop-2-yl)syloxyethyl]azetidin-2-one (0.76 g) in dichloromethane (15 ml) was cooled (0°C) and stirred. Solid calcium carbonate (0.49 g) was added followed by diisopropylethylamine (0.51 mL). A solution of 4-nitrobenzyl-chloroxoacetate (0.57 g) in dichloromethane (6 ml) was added dropwise and stirring was continued for 30 minutes. The mixture was filtered and the filtrate was washed with 0.1 M aqueous hydrochloric acid, dried over anhydrous magnesium sulfate and evaporated to give the title compound as a yellow foam (1.16 g).

S (CDCI3) 0,03 (3H, s), 0,09 (3H, s), 0,87 (9H, s), 1,26 S (CDCl 3 ) 0.03 (3H, s), 0.09 (3H, s), 0.87 (9H, s), 1.26

(3H, d, J=6,4Hz), 3,63 (1H, m), 4,41 (1H, m), 5,43 (2H, s), 6,17 (1H, d, J=3,5Hz), 7,57, 8,04 (4H, AA'BB', J=8,8Hz), (3H, d, J=6.4Hz), 3.63 (1H, m), 4.41 (1H, m), 5.43 (2H, s), 6.17 (1H, d, J=3 .5Hz), 7.57, 8.04 (4H, AA'BB', J=8.8Hz),

7,80, 8,23 (4H, AA'BB', J=8,8Hz). 7.80, 8.23 (4H, AA'BB', J=8.8Hz).

Eksempel 27 Example 27

4- ni trobenzvl- 5R . 3-( 4- cyanof enyl )- 6S-( IR- Taimetvi( 2- metvi-prop- 2- yl) sllyloksyletyl )- 7- okso- 4- tia- l- azabicykloT3 , 2. 01-hept- 2- en- 2- karboksylat 4- nine trobezvl- 5R . 3-( 4- cyanophenyl )- 6S-( IR- Taimetvi( 2- metvi-prop- 2- yl) slyloxylethyl )- 7- oxo- 4- thia- l- azabicycloT3, 2. 01-hept- 2- one - 2- carboxylate

En oppløsning av 4-nitrobenzyl-4R-(4-cyanobenzoyltio)-3S-[lR-[dimetyl(2-metylprop-2-yl)silyloksy]etyl}-azetidin-2-on-l-yl-oksoacetat (1,16 g) i xylen (25 ml) ble oppvarmet til 70°C og behandlet med trietylfosfitt (0,67 ml). Blandingen ble oppvarmet til tilbakestrømning i en time og deretter Inndampet, og resten ble kromatografert i eter-heksan over sl 11 siumoksyd slik at man fikk produktet som en gul olje (0,61 g). A solution of 4-nitrobenzyl-4R-(4-cyanobenzoylthio)-3S-[1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl}-azetidin-2-on-1-yl-oxoacetate (1, 16 g) in xylene (25 ml) was heated to 70°C and treated with triethyl phosphite (0.67 ml). The mixture was heated to reflux for one hour and then evaporated, and the residue was chromatographed in ether-hexane over silica gel to give the product as a yellow oil (0.61 g).

S (CDC13) 0~05 (3H, s), 0,09 (3H, s), 0,89 (9H, s), 1,27 S (CDC13) 0~05 (3H, s), 0.09 (3H, s), 0.89 (9H, s), 1.27

(3H, d, J=6,2Hz), 3,86 (1H, dd, J=l,6 og 3,8Hz), 4,33 (1H, m), 5,12, 5,31 (2H, AB, Jgem=13, 6Hz), 5,79 (1H, d, J=l,6Hz), 7,50, 7,66 (4H, AA' , BB' , J=8,5Hz), 7,56, 8,18 (4H, AA'BB', J=8,5Hz). (3H, d, J=6.2Hz), 3.86 (1H, dd, J=1.6 and 3.8Hz), 4.33 (1H, m), 5.12, 5.31 (2H, AB, Jgem=13, 6Hz), 5.79 (1H, d, J=1.6Hz), 7.50, 7.66 (4H, AA' , BB' , J=8.5Hz), 7.56 , 8.18 (4H, AA'BB', J=8.5Hz).

Eksempel 28 Example 28

4- nitrobenzyl- 5R. 3-( 4- cyanofenyl) 6S-( lR- hydroksyetyl)- 7- okso-4- tla- l- azabicyklor3 . 2 . 0lhept- 2- en- 2- karboksylat ... 4- nitrobenzyl- 5R. 3-(4-Cyanophenyl)6S-(1R-hydroxyethyl)-7-oxo-4-tla-1-azabicyclo3. 2. 0lhept- 2- en- 2- carboxylate ...

Til en omrørt oppløsning av 4-nitrobenzyl-5R,3-(4-cyanofenyl )6S-( IR- [ dimetyl ( 2-metylprop-2-yl )-silyloksy] etyl )-7-okso-4-t ia-l-azabicyklo[3 ,2 , 0]hept-2-en-2-karboksylat (0,29 g) i tetrahydrofuran (10 ml), avkjølt til 0°C, ble det tilsatt iseddiksyre (0,30 g). En oppløsning av tetra-n-butylammoniumfluorid i tetrahydrofuran (IM, 1,47 ml) ble innført dråpevis og omrøringen ble fortsatt i 65 timer. Fordamping ga en rest som ble oppløst i etylacetat, vasket med mettet vandig bikarbonat, vann og saltvannsoppløsnlng. Det organiske ekstraktet ble tørket over vannfritt magnesium-sulf at, fordampet, og den resulterende gummien ble kromatografert med etylacetat-heksanblandinger over silikagel, slik at man fikk forbindelsen i overskriften som en gul gummi (0,11 g). Denne forbindelsen hadde IR- og<1>H NMR-spektra identiske med de for forbindelsen fremstilt i eksempel 6. To a stirred solution of 4-nitrobenzyl-5R,3-(4-cyanophenyl)6S-(IR-[dimethyl (2-methylprop-2-yl)-silyloxy]ethyl)-7-oxo-4-thia-l -azabicyclo[3,2,0]hept-2-ene-2-carboxylate (0.29 g) in tetrahydrofuran (10 ml), cooled to 0°C, was added glacial acetic acid (0.30 g). A solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1M, 1.47 mL) was introduced dropwise and stirring was continued for 65 hours. Evaporation gave a residue which was dissolved in ethyl acetate, washed with saturated aqueous bicarbonate, water and brine. The organic extract was dried over anhydrous magnesium sulfate, evaporated, and the resulting gum was chromatographed with ethyl acetate-hexane mixtures over silica gel to give the title compound as a yellow gum (0.11 g). This compound had IR and <1>H NMR spectra identical to those of the compound prepared in Example 6.

Eksempel 29 Example 29

4- f 2 . 4- dimetoksybenzyloksykarbonyl ) tiobenzosyre 4- f 2 . 4- dimethoxybenzyloxycarbonyl ) thiobenzoic acid

En oppløsning av tereftaloylklorid (20,30 g) i dioksan (250 ml) ble behandlet dråpevis med en oppløsning av 2,4-di-metoksybenzylalkohol (20,18 g) i dioksan (40 ml). Trietylamin (16,70 ml) ble tilsatt og blandingen ble omrørt i en time før den ble filtrert. Filtratet ble fordampet og den resulterende gummien ble oppløst i diklormetan (200 ml), behandlet med pyridin (9,71 ml) og mettet med hydrogensulfid i 40 minutter. Blandingen ble spylt med nitrogen, deretter inndampet og resten ble fordelt mellom etylacetat og 2M vandig saltsyre. Det organiske laget ble fraseparert og ekstrahert med mettet vandig natriumbikarbonat. Det basiske vandige ekstraktet ble surgjort med 2M vandig saltsyre og ekstrahert med etylacetat. Etter tørking over vannfritt magnesiumsulfat ble det organiske ekstraktet inndampet slik at man fikk forbindelsen i overskriften som et gult faststoff (18,00 g). A solution of terephthaloyl chloride (20.30 g) in dioxane (250 ml) was treated dropwise with a solution of 2,4-dimethoxybenzyl alcohol (20.18 g) in dioxane (40 ml). Triethylamine (16.70 mL) was added and the mixture was stirred for one hour before being filtered. The filtrate was evaporated and the resulting gum was dissolved in dichloromethane (200 mL), treated with pyridine (9.71 mL) and saturated with hydrogen sulfide for 40 minutes. The mixture was flushed with nitrogen, then evaporated and the residue was partitioned between ethyl acetate and 2M aqueous hydrochloric acid. The organic layer was separated and extracted with saturated aqueous sodium bicarbonate. The basic aqueous extract was acidified with 2M aqueous hydrochloric acid and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the organic extract was evaporated to give the title compound as a yellow solid (18.00 g).

<v>maks (CDCI3) 2580, 1720 og 1700 crn-<1><v>max (CDCI3) 2580, 1720 and 1700 crn-<1>

S (CDCI3) 3,85 (6H, s), 5,39 (2H, s), 6,53 (3H, m), 7,40 S (CDCl 3 ) 3.85 (6H, s), 5.39 (2H, s), 6.53 (3H, m), 7.40

(1H, d, J=9,0Hz), 8,10 C4H, m) (1H, d, J=9.0Hz), 8.10 C4H, m)

Eksempel 30 Example 30

4R- f 4 - ( 2 . 4- dimetoksybenzyloksykarbonvl ) benzoyltiol - 3S-( 1R-rdimetyl( 2- metylprop- 2- yl) silyloksyl- etyl)- azetidin- 2- on 4R- f 4 - ( 2 . 4- dimethoxybenzyloxycarbonyl ) benzoylthiol - 3S-( 1R-rdimethyl( 2- methylprop- 2- yl) silyloxy- ethyl)- azetidin- 2- one

En oppløsning av 4-(2,4-dimetoksybenzyloksykarbonyl)tiobenzosyre (16,2 g) i aceton (150 ml) ble behandlet med IM vandig natriumhydroksyd (62 ml) og blandingen ble tilsatt dråpevis til en avkjølt (0°C) oppløsning av 4R-acetoksy-3R-(1R-[ dimetyl(2-metylprop-2-yl)silyloksy]-etyl)-azetidin-2-on (11,5 g) i aceton/vann (70:30) (100 ml). Blandingen ble omrørt i 45 minutter, deretter fordelt mellom etylacetat og saltvannsoppløsning. Den organiske fasen ble fraseparert, tørket over vannfritt magnesiumsulfat og inndampet. Kromatografi av den resulterende oljen med etylacetat-heksanblandin ger over silikagel ga forbindelsen i overskriften som et fargeløst skum (17,40 g). A solution of 4-(2,4-dimethoxybenzyloxycarbonyl)thiobenzoic acid (16.2 g) in acetone (150 mL) was treated with 1M aqueous sodium hydroxide (62 mL) and the mixture was added dropwise to a cooled (0°C) solution of 4R-acetoxy-3R-(1R-[dimethyl(2-methylprop-2-yl)silyloxy]-ethyl)-azetidin-2-one (11.5 g) in acetone/water (70:30) (100 mL) . The mixture was stirred for 45 minutes, then partitioned between ethyl acetate and brine. The organic phase was separated, dried over anhydrous magnesium sulfate and evaporated. Chromatography of the resulting oil with ethyl acetate-hexane mixtures over silica gel gave the title compound as a colorless foam (17.40 g).

<v>maks (CDCI3) 3420, 1775 og 1720 cm"<1><v>max (CDCI3) 3420, 1775 and 1720 cm"<1>

S (CDCI3) 0,07 (6H, s), 0,87 (9H, s), 1,24 (3H, d, S (CDCl 3 ) 0.07 (6H, s), 0.87 (9H, s), 1.24 (3H, d,

J=6,3Hz), 3,82 (6H, s), 4,30 (1H, m), 5,34 (2H, s), 5,49 (1H, d, J=2,4Hz), 6,49 (2H, m), 6,61 (1H, bs), 7,32 (1H, d, J=8,9Hz), 7,93, 8,13 (4H, AA'BB' , J=8,5Hz). J=6.3Hz), 3.82 (6H, s), 4.30 (1H, m), 5.34 (2H, s), 5.49 (1H, d, J=2.4Hz), 6 .49 (2H, m), 6.61 (1H, bs), 7.32 (1H, d, J=8.9Hz), 7.93, 8.13 (4H, AA'BB' , J=8 .5Hz).

Eksempel 31 Example 31

4- nitrobenzyl-- 4R-[ 4-( 2, 4- dimetoksybenzyloksykarbonyl)-benzoyltiol- 3S-( IR- fdimetyl( 2- metylprop- 2- yl) silyloksy1- etyl-azetidin- 2- 6n- l- yl- oksoacetat 4- nitrobenzyl-- 4R-[ 4-( 2, 4- dimethoxybenzyloxycarbonyl)-benzoylthiol- 3S-( IR- fdimethyl( 2- methylprop- 2- yl) silyloxy1- ethyl-azetidin- 2- 6n- l- yl- oxoacetate

Til en avkjølt (0"C), omrørt oppløsning av 4R-[4-(2,4-dimetoksybenzyloksykarbonyl )benzoyltio]-3S-(1R-[dimetyl(2-metylprop-2-yl )silyloksy]-etyl>-azetidin-2-on (5,60 g) i diklormetan (50 ml) ble det tilsatt kalsiumkarbonat (2,50 g) etterfulgt av diisopropyletylamin (2,61 ml). En oppløsning av 4-nitrobenzyl-kloroksoacetat (2,92 g) i diklormetan (10 ml) ble tilsatt dråpevis, og etter 30 minutter ble blandingen filtrert, vasket med 0,IM vandig saltsyre, tørket over vannfritt magnesiumsulfat og inndampet slik at man fikk forbindelsen i overskriften som et svakt gult skum (7,67 g). To a cooled (0"C), stirred solution of 4R-[4-(2,4-dimethoxybenzyloxycarbonyl)benzoylthio]-3S-(1R-[dimethyl(2-methylprop-2-yl)silyloxy]-ethyl>-azetidine -2-one (5.60 g) in dichloromethane (50 ml) was added calcium carbonate (2.50 g) followed by diisopropylethylamine (2.61 ml).A solution of 4-nitrobenzyl-chloroxoacetate (2.92 g) in dichloromethane (10 ml) was added dropwise, and after 30 minutes the mixture was filtered, washed with 0.1 M aqueous hydrochloric acid, dried over anhydrous magnesium sulfate and evaporated to give the title compound as a faint yellow foam (7.67 g) .

S (CDCI3) 0,01 (3H, s), 0,08 (3H, s), 0,82 (9H, s), 1,27 S (CDCl 3 ) 0.01 (3H, s), 0.08 (3H, s), 0.82 (9H, s), 1.27

(3H, d, J=6,3Hz), 3,64 (1H, dd, J=2,7 og 3,5Hz), 3,82 (6H, s), 4,39 (1H, dq, J=2,7og 6,3Hz), 5,35 (2H, s), 5,40 (2H, s), 6,18 (1H, . d, J=3,5Hz), 6,49 (2H, m), 7,32 (1H, d, J=8, 9Hz) , 7,96, 8,12 (4H, AA'BB', J=8,6Hz), 7,57, 8,22 (4H, AA'BB', J=8,7Hz). (3H, d, J=6.3Hz), 3.64 (1H, dd, J=2.7 and 3.5Hz), 3.82 (6H, s), 4.39 (1H, dq, J= 2.7 and 6.3Hz), 5.35 (2H, s), 5.40 (2H, s), 6.18 (1H, . d, J=3.5Hz), 6.49 (2H, m) , 7.32 (1H, d, J=8, 9Hz) , 7.96, 8.12 (4H, AA'BB', J=8.6Hz), 7.57, 8.22 (4H, AA' BB', J=8.7Hz).

Eksempel 32 Example 32

4- ni t robenzyl- 5R- 3- f4-( 2. 4- dimetoksybenzyloksykarbonyl)-fenyll - 6S-( lR- fdimetvK 2- metvlprop- 2- vl ) silvloksyl- etyl )- 7-okso- 4- tia- l- azabicyklor3, 2, Olhept- 2- en- 2- karboksylat 4-nitrobenzyl-5R-3-f4-(2.4-dimethoxybenzyloxycarbonyl)-phenyl-6S-(1R-fdimetvK 2-methylprop-2-vl)silvoxyl-ethyl)-7-oxo-4-thia-l - azabicyclo 3, 2, Olhept- 2- en- 2- carboxylate

En oppløsning av 4-nitrobenzyl--4R-[4-(2,4-dimetoksybenzyloksykarbonyl )benzoyltio]-3S-{IR-[dimetyl(2-metylprop-2-yl )silyloksy]-etyl>-azetidin-2-on-l-yl-oksoacetat (7,67 g) i xylen (100 ml) ble oppvarmet til 70°C og behandlet med trietylfosfitt (3,43 ml). Blandingen ble oppvarmet til tilbakestrømning i 4 timer, deretter inndampet og resten ble kromatografert med eter-heksanblandinger over silikagel, slik at man fikk produktet som et gult skum (4,38 g). A solution of 4-nitrobenzyl--4R-[4-(2,4-dimethoxybenzyloxycarbonyl)benzoylthio]-3S-{1R-[dimethyl(2-methylprop-2-yl)silyloxy]-ethyl>-azetidin-2-one -1-yl-oxoacetate (7.67 g) in xylene (100 mL) was heated to 70°C and treated with triethyl phosphite (3.43 mL). The mixture was heated to reflux for 4 hours, then evaporated and the residue chromatographed with ether-hexane mixtures over silica gel to give the product as a yellow foam (4.38 g).

S (CDC13) 0,07 (3H, s), 0,08 (3H, s), 0,85 (9H, s), 1,27 S (CDCl 3 ) 0.07 (3H, s), 0.08 (3H, s), 0.85 (9H, s), 1.27

(3H, d, J=6,2Hz), 3,82 (7H, m), 4,30 (1H, m), 5,09, 5,27 (2H, AB, Jgem=13, 6Hz), 5,34 (2H, s), 5,75 (1H, d, J=l,6Hz), 6,48 (2H, m), 7,32 (1H, d~, J=8,4Hz), 7,40, 8,03 (4H, AA'BB' , J=8,6Hz), 7,48, 8,13 (4H, AA'BB', J=8,7Hz). (3H, d, J=6.2Hz), 3.82 (7H, m), 4.30 (1H, m), 5.09, 5.27 (2H, AB, Jgem=13, 6Hz), 5 .34 (2H, s), 5.75 (1H, d, J=1.6Hz), 6.48 (2H, m), 7.32 (1H, d~, J=8.4Hz), 7, 40, 8.03 (4H, AA'BB' , J=8.6Hz), 7.48, 8.13 (4H, AA'BB', J=8.7Hz).

Eksempel 33 Example 33

4- nitrobenzvl- 5R. 3-( 4- karboksvfenvl)- 6S-( IR- f dimetyl-( 2-me tyl pr op- 2- yl ) s i 1, yl ok sy] - etyl )- 7- okso- 4- tia- l- azabicyklor-3, 2. 0] hept- 2- en- 2- karboksylat 4- nitrobenzvl- 5R. 3-(4-Carboxyphenyl)-6S-(IR-fdimethyl-(2-methylprop-2-yl)si1,yloxy]-ethyl)-7-oxo-4-thia-l-azabicyclo -3, 2.0] hept-2-ene-2-carboxylate

En oppløsning av 4-nitrobenzyl-5R,3-(2,4-dimetoksybenzyloksykarbonyl )fenyl]-6S-(IR-[dimetyl(2-metylprop-2-yl)silyloksy]-etyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (2,02 g) i diklormetan (100 ml) inneholdende vann (1 ml) ble behandlet med 2,3-diklor-5,6-dicyano-l , 4-benzokinin (DDQ) A solution of 4-nitrobenzyl-5R,3-(2,4-dimethoxybenzyloxycarbonyl)phenyl]-6S-(1R-[dimethyl(2-methylprop-2-yl)silyloxy]-ethyl)-7-oxo-4-thia -1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (2.02 g) in dichloromethane (100 mL) containing water (1 mL) was treated with 2,3-dichloro-5,6 -dicyano-l,4-benzoquinine (DDQ)

(1,63 g). Blandingen ble omrørt ved romtemperatur i 30 timer, deretter inndampet og resten ble kromatografert på etylacetat-heksanblandinger over silikagel slik at man fikk forbindelsen i overskriften som et brunt skum (1,11 g). (1.63g). The mixture was stirred at room temperature for 30 hours, then evaporated and the residue was chromatographed on ethyl acetate-hexane mixtures over silica gel to give the title compound as a brown foam (1.11 g).

vmaks (CDCI3) 3660br, 1790, 1720 og 1700 cm"<1>vmax (CDCI3) 3660br, 1790, 1720 and 1700 cm"<1>

S (aceton-d6) 0,07 (3H, s), 0,10 (3H, s), 0,86 (9H, s), S (acetone-d6) 0.07 (3H, s), 0.10 (3H, s), 0.86 (9H, s),

1,29 (3H, d, J=6,3Hz), 4,04 (1H, dd, J=l,6 og 3,5Hz), 4,36 (1H, dq, J=3,5og 6,3Hz), 5,15, 5,31 (2H, AB, Jgem=13,7Hz), 5,91 (1H, d,J=l,6Hz), 7,59, 7,98 (4H, AA'BB', J=8,6Hz), 7,52, 8,14 (4H, AA'BB', J=8,9Hz). 1.29 (3H, d, J=6.3Hz), 4.04 (1H, dd, J=l.6 and 3.5Hz), 4.36 (1H, dq, J=3.5and 6.3Hz ), 5.15, 5.31 (2H, AB, Jgem=13.7Hz), 5.91 (1H, d,J=1.6Hz), 7.59, 7.98 (4H, AA'BB' , J=8.6Hz), 7.52, 8.14 (4H, AA'BB', J=8.9Hz).

Eksempel 34 Example 34

4- nitrobenzyl— 5R, 3-( 4- aminokarbonylfenyl)- 6S-( IR- fdimetyl( 2-metylprop- 2- yl ) silyloksyl - etyl )- 7- okso- 4- tia- l- azabicyklor-3. 2. 0lhept- 2- en- 2- karboksylat 4- nitrobenzyl— 5R, 3-( 4- aminocarbonylphenyl)- 6S-( IR- fdimethyl( 2-methylpropyl- 2- yl ) silyloxyl - ethyl )- 7- oxo- 4- thia- l-azabicyclo-3. 2. 0lhept-2-ene-2-carboxylate

Til en omrørt oppløsning av 4-nitrobenzyl—5R,3-(4-karboksyfenyl )-6S-{ IR-[dimetyl ( 2-metylprop-2-yl )silyloksy] -etyl }-7-okso-4-t ia-l-azabicyklo[3 , 2 , 0]hept-2-en-2-karboksylat (0,41 To a stirred solution of 4-nitrobenzyl-5R,3-(4-carboxyphenyl)-6S-{IR-[dimethyl (2-methylprop-2-yl)silyloxy]-ethyl}-7-oxo-4-thia- l-azabicyclo[3 , 2 , 0]hept-2-ene-2-carboxylate (0.41

g) 1 acetonitril (10 ml) ble det tilsatt en oppløsning av 1-hydroksybenzotriazolhydrat (HOBT) (0,19 g) i tetrahydrofuran g) 1 acetonitrile (10 ml) was added to a solution of 1-hydroxybenzotriazole hydrate (HOBT) (0.19 g) in tetrahydrofuran

(2 ml) etterfulgt av l-(3-dimetylaminopropyl)-3-etylkarbodiimidhydroklorid (0,20 g). Etter 20 minutter ble en oppløsning av ammoniakk i etanol (39 mg/ml, 1 ml) innført og blandingen ble omrørt f* ytterligere 10 minutter. Inndamping og kromatografi av den resulterende resten over silikagel og eluering med etylacetat-heksanblandinger ga produktet i form av en gul olje (0,25 g). (2 ml) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.20 g). After 20 minutes, a solution of ammonia in ethanol (39 mg/ml, 1 ml) was introduced and the mixture was stirred for a further 10 minutes. Evaporation and chromatography of the resulting residue over silica gel eluting with ethyl acetate-hexane mixtures gave the product as a yellow oil (0.25 g).

S (CDC13) 0,04 (3H, s), 0,07 (3H, s), 0,85 (9H, s), 1,26 S (CDCl 3 ) 0.04 (3H, s), 0.07 (3H, s), 0.85 (9H, s), 1.26

(3H, d, J=6,3Hz), 3,83 (1H, dd, J=l,6 og 4,0Hz), 4,2 9 (1H, dq, J=4,0og 6,3Hz), 5,08, 5,26 (2H, AB, Jgem=13,7Hz), 5,75 (1H, d, J=l,6Hz), 6,32 (2H, bs), 7,49, 7,78 (4H, AA'BB' , J = 8,3Hz), 7,42, 8,13 (4H, AA'BB', J=8,7Hz). (3H, d, J=6.3Hz), 3.83 (1H, dd, J=1.6 and 4.0Hz), 4.2 9 (1H, dq, J=4.0and 6.3Hz), 5.08, 5.26 (2H, AB, Jgem=13.7Hz), 5.75 (1H, d, J=1.6Hz), 6.32 (2H, bs), 7.49, 7.78 (4H, AA'BB' , J = 8.3Hz), 7.42, 8.13 (4H, AA'BB', J=8.7Hz).

Eksempel 35 Example 35

4- nitrobenzyl- 5R, 3-( 4- am in okar b ony 1 f enyl )- 6S-( lR- hydr oksyetyl )- 7- okso- 4- tia- l- azabicyklor3, 2, 0lhept- 2- en- 2- karboksyIat En oppløsning av 4-nitrobenzyl—5R,3-(4-aminokarbonylfenyl)-6S-{ IR- [dimetyl ( 2-me tyl pr op-2-yl ) silyloksy] etyl )-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (0,41 g) i tetrahydrofuran (20 ml) ble avkjølt (CC) og behandlet med iseddiksyre (0,42 g) etterfulgt av en oppløsning av tetra-n-butylammoniumfluorid i tetrahydrofuran (IM, 2,1 ml). Blandingen ble omrørt i 45 timer, deretter inndampet og den resulterende gummien ble kromatografert med etylacetat over 4- nitrobenzyl- 5R, 3-( 4- aminocarbony 1 phenyl )- 6S-( 1R- hydroxyethyl )- 7- oxo- 4- thia- l- azabicyclo3, 2, 0lhept- 2- en- 2-carboxylate A solution of 4-nitrobenzyl—5R,3-(4-aminocarbonylphenyl)-6S-{ IR- [dimethyl ( 2-methyl prop-2-yl ) silyloxy] ethyl )-7-oxo-4- Thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (0.41 g) in tetrahydrofuran (20 mL) was cooled (CC) and treated with glacial acetic acid (0.42 g) followed by a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1M, 2.1 mL). The mixture was stirred for 45 hours, then evaporated and the resulting gum chromatographed with ethyl acetate over

silikagel slik at man fikk forbindelsen i overskriften som et svakt gult pulver (0,13 g). silica gel so that the title compound was obtained as a pale yellow powder (0.13 g).

<v>maks("Nujol"-mold) 3460-3260br, 1775, 1705 og 1650 crn-1 <v>max("Nujol" mold) 3460-3260br, 1775, 1705 and 1650 crn-1

S (aceton-d6) 1,31 (3H, d, J=6,3Hz), 3,94 (1H, dd, J=l,6 S (acetone-d6) 1.31 (3H, d, J=6.3Hz), 3.94 (1H, dd, J=1.6

og 6,2Hz), 4,21 (1H, m), 5,18, 5,31 (2H, AB, Jgem=13,9Hz), 5,89 (1H, d, J=l,6Hz), 6,73 (1H, bs), 7,54, 7,90 (4H, AA'BB', J=9,4Hz), 7,46, 8,14 (4H, AA'BB', J=8,9Hz) and 6.2Hz), 4.21 (1H, m), 5.18, 5.31 (2H, AB, Jgem=13.9Hz), 5.89 (1H, d, J=1.6Hz), 6 .73 (1H, bs), 7.54, 7.90 (4H, AA'BB', J=9.4Hz), 7.46, 8.14 (4H, AA'BB', J=8.9Hz )

Eksempel 36 Example 36

Kalium- 5R . 3-( 4- aminokarbonylf enyl )- 6S-( lR- hydroksyetyl )- 7-okso- 4- tia- l- azabicyklor3. 2, Olhept- 2- en- 2- karboksylat Potassium- 5R . 3-(4-aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo3. 2, Olhept-2-ene-2-carboxylate

4-ni trobenzyl-5R , 3 - ( 4-aminokarbonylf enyl )-6S-( lR-hydr oksyetyl )-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (0,12 g) ble oppløst i dioksan (10 ml), kaliumhydrogenkarbonat (25 mg) ble oppløst i vann (10 ml) og de to oppløs-ningene ble blandet og hydrogenert ved 375 kPa (4 atm.) over 10% palladium-på-trekull (0,12 g) i en time. Blandingen ble filtrert gjennom "Hyflo" og filtratet ble frysetørket. Resten ble oppløst i vann, vasket med etylacetat og frysetørket, slik at man fikk forbindelsen i overskriften som et svakt gult pulver (0,09 g). 5 (D20) 1,30 (3H, d, J=6,3Hz), 3,99 (1H, dd, J=l,l og 5,9Hz), 4,26 (lH,m), 5,79 (1H, d, J=l,1Hz), 7,50, 7,80 (4H, AA'BB', J=8,3Hz). 4-nitrobenzyl-5R,3-(4-aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-en-2 -carboxylate (0.12 g) was dissolved in dioxane (10 ml), potassium bicarbonate (25 mg) was dissolved in water (10 ml) and the two solutions were mixed and hydrogenated at 375 kPa (4 atm.) over 10 % palladium-on-charcoal (0.12 g) for one hour. The mixture was filtered through "Hyflo" and the filtrate was freeze-dried. The residue was dissolved in water, washed with ethyl acetate and freeze-dried, so that the title compound was obtained as a pale yellow powder (0.09 g). 5 (D20) 1.30 (3H, d, J=6.3Hz), 3.99 (1H, dd, J=l,l and 5.9Hz), 4.26 (lH,m), 5.79 (1H, d, J=1.1Hz), 7.50, 7.80 (4H, AA'BB', J=8.3Hz).

Eksempel 37 Example 37

4- ni trobenzyl- 5R, 3-( 4- karboksyfenyl)- 6S-( lR- hydroksyetyl)- 7-okso- 4- tia- l- azabicyklor3, 2, 0] hept- 2- en- 2- karboksylat 4- nitrobenzyl- 5R, 3-( 4- carboxyphenyl)- 6S-( 1R- hydroxyethyl)- 7-oxo- 4- thia- 1- azabicyclo3, 2, 0] hept- 2- ene- 2- carboxylate

En oppløsning av 4-nltrobenzyl-5R,3-(4-karboksyfenyl)-6S-(1R-[ dimetyl ( 2-me tyl pr op-2-yl ) silyloksy] -etyl}-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (0,20 g) i tetrahydrofuran (10 ml) ble avkjølt (0°C) og behandlet med iseddiksyre (0,20 g) etterfulgt av en oppløsning av tetra-n-butylammoniumfluorid i tetrahydrofuran (IM, 1,02 ml). Blandingen ble omrørt i 24 timer, deretter inndampet og resten ble fordelt mellom etylacetat og mettet, vandig natriumbikarbonat. Det basiske vandige laget ble fraseparert, for-siktig surgjort til pH 6 med 2M vandig saltsyre og ekstrahert med etylacetat. Inndamping av ekstraktet ga forbindelsen i overskriften som en brun olje (0,08 g). A solution of 4-nitrobenzyl-5R,3-(4-carboxyphenyl)-6S-(1R-[dimethyl (2-methyl prop-2-yl)silyloxy]-ethyl}-7-oxo-4-thia- 1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (0.20 g) in tetrahydrofuran (10 mL) was cooled (0°C) and treated with glacial acetic acid (0.20 g) followed by a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1M, 1.02 mL). The mixture was stirred for 24 h, then evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The basic aqueous layer was separated, carefully acidified to pH 6 with 2M aqueous hydrochloric acid and extracted with ethyl acetate.Evaporation of the extract gave the title compound as a brown oil (0.08 g).

<v>maks ("Nujol"-mold) 1770 og 1700 cm-<1><v>max ("Nujol" mold) 1770 and 1700 cm-<1>

S (aceton-d6) 1,31 (3H, d, J=6,3Hz), 3,95 (1H, dd, J=l,6 S (acetone-d6) 1.31 (3H, d, J=6.3Hz), 3.95 (1H, dd, J=1.6

og 6,4Hz), 4,21 (1H, m), 5,16, 5,30 (2H, AB, Jgem=13,8Hz), 5,94 (1H, d, J=l,6Hz), 7,55, 7,98 (4H, AA'BB', J=8,4Hz), 7,47, 8,13 (4H, AA'BB', J=8,8Hz). and 6.4Hz), 4.21 (1H, m), 5.16, 5.30 (2H, AB, Jgem=13.8Hz), 5.94 (1H, d, J=1.6Hz), 7 .55, 7.98 (4H, AA'BB', J=8.4Hz), 7.47, 8.13 (4H, AA'BB', J=8.8Hz).

Eksempel 38 Example 38

4- nitrobenzyl- 5R, 3-( 4- aminokarbonylf enyl )- 6S-( lR- hydr oksyetyl )- 7- okso- 4- tia- l- azabicyklor3, 2, 0] hept- 2- en- 2- karboksylat En oppløsning av 4-nitrobenzyl-5R,3-(4-karboksyfenyl)-6S-(1R-hydroksyetyl )-7-okso-4 -t ia-1 - azabi cyklo[3,2 ,0]hept-2-en-2-karboksylat (0,08 g) i acetonitril (10 ml) ble omrørt og behandlet med en oppløsning av 1-hydroksybenzotriazol (HOBT) 4- nitrobenzyl- 5R, 3-( 4- aminocarbonylphenyl )- 6S-( 1R- hydroxyethyl)- 7- oxo- 4- thia- l- azabicyclo3, 2, 0] hept- 2-ene- 2- carboxylate En solution of 4-nitrobenzyl-5R,3-(4-carboxyphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene- 2-carboxylate (0.08 g) in acetonitrile (10 mL) was stirred and treated with a solution of 1-hydroxybenzotriazole (HOBT)

(0,04 g) i tetrahydrofuran (2 ml) etterfulgt av l-(3-dimetylaminopropyl)-3-etyl-karbodiimidhydroklorid (0,05 g). Etter en time ble det tilsatt en oppløsning av ammoniakk i etanol (50 mg/ml, 0,5 ml) og omrøringen ble fortsatt i ytterligere 10 minutter. Blandingen ble inndampet og resten oppløst i diklormetan, vasket med IM vandig sitronsyre, mettet vandig natriumbikarbonat og saltvannsoppløsning. Inndamping av det organiske ekstraktet ga forbindelsen i overskriften (0,07 g) med egenskaper identiske med de for forbindelsen fremstilt i eksempel 35. (0.04 g) in tetrahydrofuran (2 ml) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.05 g). After one hour, a solution of ammonia in ethanol (50 mg/ml, 0.5 ml) was added and stirring was continued for another 10 minutes. The mixture was evaporated and the residue dissolved in dichloromethane, washed with 1M aqueous citric acid, saturated aqueous sodium bicarbonate and brine. Evaporation of the organic extract gave the title compound (0.07 g) with properties identical to those of the compound prepared in Example 35.

Eksempel 39 Example 39

4- nitrobenzyl- 5R. 3- f4-( 2. 4- dimetoksybenzyloksykarbonyl)-fenyl1- 6S-( lR- hydroksyetyl)- 7- okso- 4- tia- l- azabicvklor3. 2. 01 - hept- 2- en- 2- karboksylat 4- nitrobenzyl- 5R. 3- f4-(2. 4- dimethoxybenzyloxycarbonyl)-phenyl1- 6S-(1R- hydroxyethyl)- 7- oxo-4- thia-1- azabicvchloro3. 2. 01 - hept- 2- en- 2- carboxylate

En oppløsning av 4-nitrobenzyl—5R,3-[4-(2,4-dimetoksybenzyloksykarbonyl )fenyl]-6S-{lar-[dimetyl(2-metylprop-2-yl)silyloksy]-etyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (1,00 g) i tetrahydrofuran (40 ml) ble avkjølt (0°C) og behandlet med iseddiksyre (0,82 g) etterfulgt av en oppløsning av tetra-n-butylammoniumfluorid i tetrahydrofuran (IM, 4,1 ml). Blandingen ble omrørt i 24 timer, deretter inndampet og resten ble kromatografert over silikagel og eluert med etylacetat-heksanblandinger slik at man fikk forbindelsen 1 overskriften som en gul olje (0,27 g). A solution of 4-nitrobenzyl-5R,3-[4-(2,4-dimethoxybenzyloxycarbonyl)phenyl]-6S-{lar-[dimethyl(2-methylprop-2-yl)silyloxy]-ethyl)-7-oxo- 4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (1.00 g) in tetrahydrofuran (40 mL) was cooled (0°C) and treated with glacial acetic acid (0.82 g) followed by a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1M, 4.1 mL). The mixture was stirred for 24 hours, then evaporated and the residue was chromatographed over silica gel eluting with ethyl acetate-hexane mixtures to give the title compound 1 as a yellow oil (0.27 g).

§ (CDC13) 1,38 (3H, d, J=6,3Hz), 3,82 (6H, s), 3,87 (1H, § (CDCl 3 ) 1.38 (3H, d, J=6.3Hz), 3.82 (6H, s), 3.87 (1H,

dd, J=l,6 og 6,3Hz), 4,30 (1H, m), 5,08, 5,25 (2H, AB, Jgem=13,6Hz), 5,33 (2H, s), 5,77 (1H, d, J=l,6Hz), 6,48 (2H, m), 7,31 (3H, m), 7,45, 7,99 (4H, AA'BB', J=8,5Hz), 8,11 (2H, d, J=8,7H-z). dd, J=1.6 and 6.3Hz), 4.30 (1H, m), 5.08, 5.25 (2H, AB, Jgem=13.6Hz), 5.33 (2H, s), 5.77 (1H, d, J=1,6Hz), 6.48 (2H, m), 7.31 (3H, m), 7.45, 7.99 (4H, AA'BB', J= 8.5Hz), 8.11 (2H, d, J=8.7H-z).

Eksempel 40 Example 40

4- nitrobenzyl- 5R, 3-( 4- karboksyfenyl)- 6S-( lR- hydroksyetyl)- 7-okso- 4- tia- l- azabicyklor3, 2, 0] hept- 2- en- 2- karboksylat 4- nitrobenzyl- 5R, 3-( 4- carboxyphenyl)- 6S-( 1R- hydroxyethyl)- 7-oxo- 4- thia- l- azabicyclo3, 2, 0] hept- 2- ene- 2- carboxylate

En oppløsning av 4-nitrobenzyl—5R,3-[4-(2,4-dimetoksybenzyloksykarbonyl )fenyl]-6S-(lR-hydroksyetyl)-7-okso-4-tia-l-azabicyklo[3 ,2 ,0]hept-2-en-2-karboksylat (0,27 g) i diklormetan (20 ml) inneholdende vann (1 ml) ble omrørt og behandlet med 2,3-diklor-5,6-dicyano-l,4-benzokinon (DDQ) (0,20 A solution of 4-nitrobenzyl—5R,3-[4-(2,4-dimethoxybenzyloxycarbonyl)phenyl]-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0] Hept-2-ene-2-carboxylate (0.27 g) in dichloromethane (20 mL) containing water (1 mL) was stirred and treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone ( DDQ) (0.20

g). Etter 24 timer ble blandingen inndampet og resten ble fordelt mellom etylacetat og vann. Det organiske laget ble g). After 24 hours, the mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer became

fraseparert, tørket over vannfritt magnesiumsulfat, inndampet og den resulterende gummien ble kromatografert over silikagel med etylacetat-heksanblandinger slik at man fikk forbindelsen i overskriften (0,13 g) med egenskaper identiske med egenskapene for forbindelsen fremstilt i eksempel 37. separated, dried over anhydrous magnesium sulfate, evaporated and the resulting gum was chromatographed over silica gel with ethyl acetate-hexane mixtures to give the title compound (0.13 g) with properties identical to those of the compound prepared in Example 37.

Eksempel 41 Example 41

4- nitrobenzyl- 5R. 3-( 4- f4-( cyanometyl) amlnokarbonyl] fenyl)- 6S- 4- nitrobenzyl- 5R. 3-( 4- f4-( cyanomethyl) aminocarbonyl] phenyl)- 6S-

{ lR- fdimetyH 2- metylprop- 2- yl) silyloksy]- etyl)- 7- okso- 4- tia-1- azabicyklor3, 2, 0lhept- 2- en- 2- karboksylat { 1R- fdimethylH 2- methylpropyl- 2- yl) silyloxy]- ethyl)- 7- oxo- 4- thia-1- azabicyclo3, 2, 0lhept- 2- en- 2- carboxylate

Til en omrørt oppløsning av 4-nitrobenzyl-5R,3-(4-karboksyfenyl )-6S-{ IR-[dimetyl ( 2-metylprop-2-yl)silyloksy] -etyl }7-okso-4-t ia-l-azabicyklo[3 ,2 , 0]hept-2-en-2-karboksylat ( 0 ,36 To a stirred solution of 4-nitrobenzyl-5R,3-(4-carboxyphenyl)-6S-{IR-[dimethyl (2-methylprop-2-yl)silyloxy]-ethyl}7-oxo-4-thia-1 -azabicyclo[3 ,2 ,0]hept-2-ene-2-carboxylate ( 0 ,36

g) i acetonitril (10 ml) ble det tilsatt en oppløsning av 1-hydroksybenzotriazol (HOBT) (0,17 g) i tetrahydrofuran (2 ml) g) in acetonitrile (10 ml) was added a solution of 1-hydroxybenzotriazole (HOBT) (0.17 g) in tetrahydrofuran (2 ml)

etterfulgt av 1-( 3-dimetylaminopropyl )-3-etylkarbodiimidhydroklorid (0,18 g). Etter 30 minutter ble aminoacetonitril-hydroklorid (0,17 g) tilsatt, straks etterfulgt av trietylamin (0,26 ml), og omrøring ble fortsatt i ytterligere 30 minutter. Blandingen ble inndampet, resten ble oppløst i etylacetat og vasket med 2M vandig saltsyre, mettet vandig natriumbikarbonat og saltvannsoppløsning, og inndamping av den organiske fasen ga en brun gummi som ble kromatografert med etylacetat-heksanblandinger over silikagel slik at man fikk produktet i form av et gult skum (0,24 g). followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.18 g). After 30 minutes, aminoacetonitrile hydrochloride (0.17 g) was added, immediately followed by triethylamine (0.26 ml), and stirring was continued for another 30 minutes. The mixture was evaporated, the residue was dissolved in ethyl acetate and washed with 2M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine, and evaporation of the organic phase gave a brown gum which was chromatographed with ethyl acetate-hexane mixtures over silica gel to give the product in the form of a yellow foam (0.24 g).

<v>maks ("Nujol"-mold) 3400,3300br, 1790, 1720 og 1665 cm-<1><v>max ("Nujol" mold) 3400,3300br, 1790, 1720 and 1665 cm-<1>

S (CDC13) 0,04 (3H, s), 0,06 (3H, s), 0,84 (9H,_s), 1,25 S (CDCl 3 ) 0.04 (3H, s), 0.06 (3H, s), 0.84 (9H,_s), 1.25

(3H, d, J=6,3Hz), 3,82 (1H, dd, J-1,6 og 3,9Hz), 4,28 (1H, dq, J = 3 ,9 og 6,3HzK 4,35 (2H, d, J=5,9Hz), 5,08, 5,26 (2H, AB, Jgem=13,6Hz), 5,75 (1H, d, J=l,6Hz), 6,67 (1H, bt, J=5,9Hz), 7,51, 7,72 (4H, AA'BB' , J=8,5Hz), 7,43, 8,12 (4H, AA'BB' J=8,7Hz). (3H, d, J=6.3Hz), 3.82 (1H, dd, J-1.6 and 3.9Hz), 4.28 (1H, dq, J = 3.9 and 6.3HzK 4, 35 (2H, d, J=5.9Hz), 5.08, 5.26 (2H, AB, Jgem=13.6Hz), 5.75 (1H, d, J=1.6Hz), 6.67 (1H, bt, J=5.9Hz), 7.51, 7.72 (4H, AA'BB' , J=8.5Hz), 7.43, 8.12 (4H, AA'BB' J= 8.7Hz).

Eksempel 42 Example 42

4- ni trobenzyl- 5R . 3-{ 4- fN-( cyanometyl ) aminokarbonyll - fenyl)-6S-( IR- hydroksyetyl)- 7- okso- 4- tia- l- azabicyklor3. 2, Olhept- 2-en- 2- karboksylat 4- nitrobenzyl- 5R . 3-{4-fN-(cyanomethyl)aminocarbonyl-phenyl)-6S-(IR-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo3. 2, Olhept-2-ene-2-carboxylate

Til en avkjølt (CC) oppløsning av 4-nitrobenzyl—5R,3-(4-[N-(cyanometyl)aminokarbonyl]fenyl)-6S-(IR-[dimetyl(2-metylprop-2- yl )silyloksy]etyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (0,23 g) i tetrahydrofuran (50 ml) ble det tilsatt iseddiksyre (0,22 g) og en oppløsning av tetra-n-butylammoniumfluorid i tetrahydrofuran (IM, 1,1 ml). Bland ingen ble omrørt i 40 timer, deretter inndampet og resten.ble kromatografert med etanol-etylacetatblandinger over silikagel, slik at man fikk forbindelsen i overskriften i form av et svakt gult faststoff (0,10 g). To a cooled (CC) solution of 4-nitrobenzyl—5R,3-(4-[N-(cyanomethyl)aminocarbonyl]phenyl)-6S-(1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl) -7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (0.23 g) in tetrahydrofuran (50 ml) was added glacial acetic acid (0.22 g) and a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1M, 1.1 mL). The mixture was stirred for 40 hours, then evaporated and the residue was chromatographed with ethanol-ethyl acetate mixtures over silica gel to give the title compound as a pale yellow solid (0.10 g).

S (aceton-d6) 1,31 (3H, d, J=6,3Hz), 3,95 (1H, dd, J-1,7 S (acetone-d6) 1.31 (3H, d, J=6.3Hz), 3.95 (1H, dd, J-1.7

og 6,2Hz), 4,21 (1H, m), 4,41 (2H, d, J=3,3Hz), 5,17, 5,31 (2H, AB, Jgem=13,8Hz) , 5,90 (1H, d, J=l,7Hz), 7,57, 7,68 (4H, AA'BB ' , J = 8,5Hz), 7,49, 8,15 (4H, AA'BB' , J=8,8Hz), 8,51 (1H, bt, J=3,3Hz). and 6.2Hz), 4.21 (1H, m), 4.41 (2H, d, J=3.3Hz), 5.17, 5.31 (2H, AB, Jgem=13.8Hz) , 5 .90 (1H, d, J=1.7Hz), 7.57, 7.68 (4H, AA'BB ' , J = 8.5Hz), 7.49, 8.15 (4H, AA'BB' , J=8.8Hz), 8.51 (1H, bt, J=3.3Hz).

Eksempel 43 Example 43

Kalium- 5R. 3-{ 4- rN-( cyanometyl ) aminokarbonyllfenyl)- 6S-( 1R-hydr oksyetyl ) - 7- okso- 4- t ia- l- azabi cyklofS , 2 . 0] hept- 2- en- 2-karboksylat Potassium- 5R. 3-{4-rN-(cyanomethyl)aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-l-azabi cyclophS, 2. 0] hept-2-ene-2-carboxylate

4-nitrobenzyl--5R,3-(4-[N-(cyanometyl)aminokarbonyl]fenyl-6S-(lR-hydroksyetyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (0,10 g) ble oppløst i dioksan (10 ml), kaliumhydrogenkarbonat (19 mg) ble oppløst i vann (10 ml) og de to oppløsningene ble blandet og hydrogenert ved ca. 375 kPa (4 atm.) over 10 % palladium-på-trekull (0,10 g) i en time. Blandingen ble filtrert gjennom "Hyflo" og filtratet ble frysetørket. Resten ble oppløst i vann, vasket med etylacetat og frysetørket slik at man fikk forbindelsen i overskriften i form av et svakt gult pulver (0,07 g). 4-nitrobenzyl--5R,3-(4-[N-(cyanomethyl)aminocarbonyl]phenyl-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept- 2-ene-2-carboxylate (0.10 g) was dissolved in dioxane (10 mL), potassium bicarbonate (19 mg) was dissolved in water (10 mL) and the two solutions were mixed and hydrogenated at about 375 kPa (4 atm) over 10% palladium-on-charcoal (0.10 g) for one hour. The mixture was filtered through "Hyflo" and the filtrate was freeze-dried. The residue was dissolved in water, washed with ethyl acetate and freeze-dried to give the compound in the title in the form of a pale yellow powder (0.07 g).

S (D20) 1,30 (3H, d, J=6,4Hz), 4,00 (1H, dd, J=l,4og 5,9Hz), 4,25 (1H, m), 4,36 (2H, s), 5,79 (1H, d, J=l,4Hz), 7,51 og 7,75 (4H, AA'BB', J=8,5Hz). S (D20) 1.30 (3H, d, J=6.4Hz), 4.00 (1H, dd, J=1.4and 5.9Hz), 4.25 (1H, m), 4.36 ( 2H, s), 5.79 (1H, d, J=1.4Hz), 7.51 and 7.75 (4H, AA'BB', J=8.5Hz).

Eksempel 44 Example 44

4-( metoksyamlnokarbonyl) t i obenzo syre 4-(Methoxyaminocarbonyl) t i obenzo acid

Til en oppløsning av tereftalylklorid (7,0 g) i diklormetan (250 ml) ble det tilsatt en 25% vandig oppløsning av metoksy-aminhydroklorid (15 ml) etterfulgt av en oppløsning av trietylamin (12,5 ml) i diklormetan (250 ml). Etter at blandingen var omrørt i en time, ble pyridin (4,2 ml) tilsatt, og deretter ble gassformig hydrogensulfid (overskudd) boblet gjennom i 30 minutter. Etter omrøring i ytterligere 30 minutter ble blandingen spylt med nitrogen, og fordelt mellom etylacetat og vandig sitronsyre. Det organiske laget ble vasket med vann, og deretter ekstrahert med mettet vandig natriumbikarbonat. Dette vandige ekstraktet ble vasket med etylacetat, og deretter igjen surgjort til pH 2 med 11M saltsyre. Ekstraksjon med etylacetat ga et organisk ekstrakt som deretter ble vasket med vann og med saltvannsoppløsning, og inndampet i vakuum, slik at det oppsto en rest som ble kromatografert over silikagel. Eluering med etylacetat-heksanblandinger ga forbindelsen i overskriften (2,0 g). To a solution of terephthalyl chloride (7.0 g) in dichloromethane (250 ml) was added a 25% aqueous solution of methoxyamine hydrochloride (15 ml) followed by a solution of triethylamine (12.5 ml) in dichloromethane (250 ml) ). After the mixture was stirred for one hour, pyridine (4.2 mL) was added and then gaseous hydrogen sulfide (excess) was bubbled through for 30 minutes. After stirring for a further 30 minutes, the mixture was flushed with nitrogen and partitioned between ethyl acetate and aqueous citric acid. The organic layer was washed with water, and then extracted with saturated aqueous sodium bicarbonate. This aqueous extract was washed with ethyl acetate, and then again acidified to pH 2 with 11M hydrochloric acid. Extraction with ethyl acetate gave an organic extract which was then washed with water and brine, and evaporated in vacuo to give a residue which was chromatographed over silica gel. Elution with ethyl acetate-hexane mixtures gave the title compound (2.0 g).

S (aceton-d6) 3,80 (3H, s), 7,79-8,30 (4H, m). S (acetone-d6) 3.80 (3H, s), 7.79-8.30 (4H, m).

Eksempel 45 Example 45

3S-( lR- rdimetvl( 2- metylprop- 2- yl) silyloksvi etyl)- 4R-( 4-metoksyaminokarbonylbenzoyltio)- azetidin- 2- on 3S-(1R-dimethyl(2-methylpropyl-2-yl)silyloxyethyl)- 4R-(4-methoxyaminocarbonylbenzoylthio)-azetidin-2-one

Forbindelsen i overskriften (1,85 g) ble fremstilt ved en fremgangsmåte analog fremgangsmåten beskrevet i eksempel 16 ved å anvende 4-acetoksy-(lR-[dimetyl(2-metylprop-2-yl )silyloksy] etyl )azetidinon (21,9 g), 4-(metoksyaminokarbonyl )tiobenzosyre (1,9 g), IM natriumhydroksyd (8,7 ml) og aceton (10 ml). The compound in the title (1.85 g) was prepared by a method analogous to the method described in example 16 by using 4-acetoxy-(1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl)azetidinone (21.9 g), 4-(methoxyaminocarbonyl)thiobenzoic acid (1.9 g), 1M sodium hydroxide (8.7 ml) and acetone (10 ml).

vmaks (film) 1758, 1665 cm_<l>vmax (film) 1758, 1665 cm_<l>

S (CDC13) 0,10 (6H, s), 0,90 (9H, s), 1,25 (3H, d, S (CDCl 3 ) 0.10 (6H, s), 0.90 (9H, s), 1.25 (3H, d,

J = 6,3Hz), 3,30 (1H, dd, J=2,4 og 3,7Hz), 3,93 (3H, s), 4,30-4,35 (1H, m), 5,49 (1H, d, J=2,4Hz), 6,52 (1H, bs), 7,85, 7,98 (4H, AA'BB', J=8,4Hz), 9,13 (1H, bs). J = 6.3Hz), 3.30 (1H, dd, J=2.4 and 3.7Hz), 3.93 (3H, s), 4.30-4.35 (1H, m), 5, 49 (1H, d, J=2.4Hz), 6.52 (1H, bs), 7.85, 7.98 (4H, AA'BB', J=8.4Hz), 9.13 (1H, bs).

Eksempel 46 Example 46

4- nitrobenzyl-( 3S-[" lR-( dimetyl ( 2- metylprop- 2- yl) silyloksy )-etyll - 4R- r4-( metoksy-( 4- nitrobenzyloksykarbonyl- karbonyl )-aminokarbonyl) benzoyltiol- azetidin- 2- on- l- yl) oksoacetat 4- nitrobenzyl-( 3S-[" 1R-( dimethyl ( 2- methylpropyl- 2- yl) silyloxy )-ethyl- 4R- r4-( methoxy-( 4- nitrobenzyloxycarbonyl- carbonyl)-aminocarbonyl) benzoylthiol- azetidine- 2- on-l-yl)oxoacetate

Forbindelsen i overskriften (4,1 mmol) ble fremstilt ved en fremgangsmåte analog fremgangsmåten beskrevet i eksempel 17 ved anvendelse av 3S-{ IR-[dimetyl ( 2-metylprop-2-yl )silyloksy] -etyl}-4R-(4-metoksyaminokarbonylbenzoyltio)azetidin-2-on (1,8 g), 4-nitrobenzylkloroksoacetat (2,5 g), kalsiumkarbonat (1,8 g), diisopropyletylamin (2,2 ml) og diklormetan (20 ml). The compound in the title (4.1 mmol) was prepared by a method analogous to the method described in example 17 using 3S-{IR-[dimethyl (2-methylprop-2-yl)silyloxy]-ethyl}-4R-(4- methoxyaminocarbonylbenzoylthio)azetidin-2-one (1.8 g), 4-nitrobenzylchloroxoacetate (2.5 g), calcium carbonate (1.8 g), diisopropylethylamine (2.2 ml) and dichloromethane (20 ml).

vmaks(CDCI3) 1815 cm"1 vmax(CDCI3) 1815 cm"1

S (CDCI3) 0,10 (6H, s), 0,84 (9H, s), 1,27 (3H, d, S (CDCl 3 ) 0.10 (6H, s), 0.84 (9H, s), 1.27 (3H, d,

J = 6,3Hz), 3,64-3,68 (1H, m), 3,90 (3H, s), 4,40-4,43 (1H, m), 5,39-5,44 (4H, m), 6,19 (1H, d, J=3,4Hz), 7,55-8,26 (12H, m). J = 6.3Hz), 3.64-3.68 (1H, m), 3.90 (3H, s), 4.40-4.43 (1H, m), 5.39-5.44 ( 4H, m), 6.19 (1H, d, J=3.4Hz), 7.55-8.26 (12H, m).

Eksempel 47 Example 47

4- nitrobenzyl- 5R, 6S-( IR-[ dimetyl( 2- prop- 2- yl) silyloksyletyl)-3-{ 4-[ metoksy-( 4- nitrobenzyloksykarbonylkarbonyl)- aminokarbonyll f enyl )- 7- okso- 4- tia- l- azabicyklo [ 3. 2, 0~ lhept- 2- en- 2-karboksylat 4- nitrobenzyl- 5R, 6S-( IR-[ dimethyl( 2- prop- 2- yl) silyloxyethyl)-3-{ 4-[ methoxy-( 4- nitrobenzyloxycarbonylcarbonyl)- aminocarbonyl phenyl )- 7- oxo- 4- thia-l-azabicyclo [3.2,0~lhept-2-ene-2-carboxylate

Forbindelsen i overskriften (113 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten beskrevet i eksempel 18 ved anvendelse av 4-nitrobensyl-{3S-[lR-(dimetyl(2-metylprop-2-yl )silyloksy )etyl] -4R- [4-(metoksy-4-nitrobenzyloksykarbo-nylkarbonyl) -aminokarbonyl )benzoyltio] -azetidin-2-on-l-yl )-oksoacetat (1,25 mmol), trietylfosfitt (428 pl) og xylen (5 ml). The compound in the title (113 mg) was obtained by a method analogous to the method described in example 18 using 4-nitrobenzyl-{3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-4R- [ 4-(Methoxy-4-nitrobenzyloxycarbonylcarbonyl)-aminocarbonyl)benzoylthio]-azetidin-2-on-1-yl)-oxoacetate (1.25 mmol), triethyl phosphite (428 µl) and xylene (5 mL).

vmaks (film) 1775, 1748 og 1725 crn-<1>vmax (film) 1775, 1748 and 1725 crn-<1>

5 (CDCI3) 0,07 (6H, s), 0,83 ( 9H, s), 1,25 (3H, d, J = 6,3Hz), 3,80-3,83 (1H, m), 3,89 (3H, s), 4,30-4,38 (1H, m), 5,07, 5,20 (2H, AB, J=13,6Hz), 5,37 (2H, s), 5,75 (1H, d, J=l,5Hz), 7,39, 7,98 (4H, AA'BB ' , J=8,6Hz), 7,45, 8,09 (4H, AA'BB', J=8,3Hz), 7,50, 8,22 (4H, AA'BB', J=8,7Hz). 5 (CDCl3) 0.07 (6H, s), 0.83 (9H, s), 1.25 (3H, d, J = 6.3Hz), 3.80-3.83 (1H, m), 3.89 (3H, s), 4.30-4.38 (1H, m), 5.07, 5.20 (2H, AB, J=13.6Hz), 5.37 (2H, s), 5.75 (1H, d, J=1.5Hz), 7.39, 7.98 (4H, AA'BB ' , J=8.6Hz), 7.45, 8.09 (4H, AA'BB ', J=8.3Hz), 7.50, 8.22 (4H, AA'BB', J=8.7Hz).

Eksempel 48 Example 48

4- nitrobenzyl- 5R, 6S-( IR- hydroksvetyl)- 3-( 4- metoksyamlno-karbonvl fenyl) - 7- okso- 4- tia- l- azabicyklor3 . 2 . 0~| hept- 2- en- 2-karboksylat 4- nitrobenzyl- 5R, 6S-( IR- hydroxymethyl)- 3-( 4- methoxyamino-carbonyl phenyl)- 7- oxo- 4- thia-1-azabicyclo3 . 2. 0~| hept-2-ene-2-carboxylate

Forbindelsen i overskriften (250 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten beskrevet i eksempel 19 ved anvendelse av 4-nitrobenzyl-5R,6S-{lR-[dimetyl(2-prop-2-yl)-si lyloksy]etyl)-3-{4-[metoksy-4-nitrobenzyloksykarbonyl-karbonyl )-aminokarbonyl] f enyl } - 7-okso-4-tia-l-azabicyklo[-3 , 2 , 0]hept-2-en-2-karboksylat (670 mg), eddiksyre (570 >il), IM tetra-n-butylammoniumfluorid i tetrahydrofuran (2,88 ml) og tetrahydrofuran (10 ml). The compound in the title (250 mg) was obtained by a method analogous to the method described in example 19 using 4-nitrobenzyl-5R,6S-{1R-[dimethyl(2-prop-2-yl)-silyloxy]ethyl)- 3-{4-[Methoxy-4-nitrobenzyloxycarbonyl-carbonyl)-aminocarbonyl]phenyl}-7-oxo-4-thia-1-azabicyclo[-3,2,0]hept-2-ene-2-carboxylate ( 670 mg), acetic acid (570 µl), 1M tetra-n-butylammonium fluoride in tetrahydrofuran (2.88 ml) and tetrahydrofuran (10 ml).

v[<m>aks (film) 1788, 1722 cm-<1>v[<m>aks (film) 1788, 1722 cm-<1>

(CDC13) 1,41 (3H, d, J = 6,3Hz), 3,88 (1H, dd, J=l,6 og 6,4Hz), 3,94 (3H, s), 4,28-4,35 (1H, m), 5,10, 5,26 (2H, AB, Jgem=13,5Hz), 5,79 (1H, d, J=1,6H-z), 7,32, 7,98 (4H, AA'BB', J=8,5Hz), 7,47, 8,13 (4H, AA'BB', J=8,7Hz). (CDCl 3 ) 1.41 (3H, d, J = 6.3Hz), 3.88 (1H, dd, J = 1.6 and 6.4Hz), 3.94 (3H, s), 4.28- 4.35 (1H, m), 5.10, 5.26 (2H, AB, Jgem=13.5Hz), 5.79 (1H, d, J=1.6H-z), 7.32, 7 .98 (4H, AA'BB', J=8.5Hz), 7.47, 8.13 (4H, AA'BB', J=8.7Hz).

Eksempel 49 Kal ium- 5R , 6S- ( IR- hyd r oksyetyl ) - - 3 - ( 4 - metoksyaminokarbonyl-fenyl)- 7- okso- 4- tia- l- azabicyklor3, 2, 0lhept- 2- en- 2- karboksylat Example 49 Potassium- 5R, 6S- ( IR- hydroxyethyl ) - - 3 - ( 4 - methoxyaminocarbonyl-phenyl)- 7- oxo-4- thia-1-azabicyclo3, 2, 0lhept-2-en-2- carboxylate

Forbindelsen i overskriften (28 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten beskrevet i eksempel 7 ved anvendelse av 4-nitrobenzyl-5R,6S-(lR-hydroksyetyl)-3-(4-metok syaminokarbonylfenyl)-7-okso-4-tia-l-azabicyklo[3,2,0]-hept-2-en-2-karboksylat (60 mg), 10% palladium-på-trekull (60 mg), kaliumbikarbonat (12 mg), dioksan (5 ml) og vann (5 ml). The compound in the title (28 mg) was obtained by a method analogous to the method described in example 7 using 4-nitrobenzyl-5R,6S-(1R-hydroxyethyl)-3-(4-methoxyaminocarbonylphenyl)-7-oxo-4- thia-l-azabicyclo[3,2,0]-hept-2-ene-2-carboxylate (60 mg), 10% palladium-on-charcoal (60 mg), potassium bicarbonate (12 mg), dioxane (5 ml) and water (5 mL).

S (D20) 1,29 (3H, d, J=6,4Hz), 3,90 (3H, s), 4,00 (1H, dd, S (D20) 1.29 (3H, d, J=6.4Hz), 3.90 (3H, s), 4.00 (1H, dd,

J=l,5og 5,9Hz), 4,21-4,28 (1H, m), 5,79 (1H, d, J=l,5Hz), 7,49, 7,97 (4H, AA'BB', J=8,5Hz). J=1.5 and 5.9Hz), 4.21-4.28 (1H, m), 5.79 (1H, d, J=1.5Hz), 7.49, 7.97 (4H, AA' BB', J=8.5Hz).

Eksempel 50 Example 50

4-( metvlaminokarbonyl) tiobenzosyre 4-(methylaminocarbonyl)thiobenzoic acid

Forbindelsen i overskriften (3,1 g) ble oppnådd ved en fremgangsmåte analog fremgangsmåten beskrevet i eksempel 4 ved å anvende tereftaloylklorid (10,0 g), diklormetan (300 ml), metylaminhydroklorid (4,2 g), trietylamin (17,4 ml), pyridin (7,76 ml) og overskudd hydrogensulfid. The compound in the title (3.1 g) was obtained by a method analogous to the method described in example 4 by using terephthaloyl chloride (10.0 g), dichloromethane (300 ml), methylamine hydrochloride (4.2 g), triethylamine (17.4 ml), pyridine (7.76 ml) and excess hydrogen sulphide.

S (aceton-d6) 2,90 ( 3H, s), 7,96, 8,10 (4H, AA' BB' , S (acetone-d6) 2.90 ( 3H, s), 7.96, 8.10 (4H, AA' BB' ,

J=8,4Hz). J=8.4Hz).

Eksempel 51 Example 51

3S-( lR- rdlmetvl( 2- metylprop- 2- yl) silyloksvletyl)- 4R-( 4- metyl-aminokarbonylbenzoyltio)- azetidin- 2- on 3S-( 1R- rdlmethyl( 2- methylpropyl- 2- yl) silyloxyvletyl)- 4R-( 4- methyl-aminocarbonylbenzoylthio)- azetidin- 2- one

Forbindelsen i overskriften (1,7 g) ble oppnådd ved en fremgangsmåte analog fremgangsmåten beskrevet i eksempel 16 ved anvendelse av 4-acetoksy-3R-(IR-[dimetyl(2-metylprop-2-yl )silyloksy]etyl)-azetidin-2-on (3,0 g), 4-(metylamino-karbonyl )tiobenzosyre (3,0 g, IM natriumhydroksyd _ (15 ,6 ml) og aceton (50 ml). The compound in the title (1.7 g) was obtained by a method analogous to the method described in example 16 using 4-acetoxy-3R-(IR-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl)-azetidin- 2-one (3.0 g), 4-(methylaminocarbonyl)thiobenzoic acid (3.0 g, 1M sodium hydroxide (15.6 ml) and acetone (50 ml).

<v>maks (film) 1765, 1660 cm_<l><v>max (film) 1765, 1660 cm_<l>

S (CDC13) 0,08 (6H, s), 0,88 ( 9H, s), 1,23 (3H, d, S (CDCl 3 ) 0.08 (6H, s), 0.88 ( 9H, s), 1.23 (3H, d,

J=6,3Hz), 3,03 (3H, d, J=4,8Hz), 3,28 (1H, dd, J=2,4Hz og 3,8Hz), 4,28-4,32 (1H, m), 5,47 (1H, d, J=2,4Hz), 6,37 (1H, bd, J=4,8Hz), 6,54 (1H, bs), 7,83, 7,94 (4H, AA'BB', J=8,5Hz). J=6.3Hz), 3.03 (3H, d, J=4.8Hz), 3.28 (1H, dd, J=2.4Hz and 3.8Hz), 4.28-4.32 (1H , m), 5.47 (1H, d, J=2.4Hz), 6.37 (1H, bd, J=4.8Hz), 6.54 (1H, bs), 7.83, 7.94 (4H, AA'BB', J=8.5Hz).

Eksempel 52 Example 52

4- ni trobenzyl-{ 3S- [ IR- ( dimetyl ( 2- metylprop- 2- yl) silyloksy )-etyll - 4R- [ 4-( metvlaninokarbonyl) benzoyltiol- azetidin- 2- on- l-yl) oksoacetat 4-nitrobenzyl-{3S-[IR-(dimethyl(2-methylpropyl-2-yl)silyloxy)-ethyl-4R-[4-(methylaminocarbonyl)benzoylthiol-azetidin-2-on-1-yl)oxoacetate

Forbindelsen i overskriften (2,5 g) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet! eksempel 17 ved anvendelse av 4-nitrobenzylkloroksoacetat (1,17 g), 3S-(1R-(dimetyl-( 2-metylprop-2-yl)silyloksy)etyl)-4R-(4-metylamino- karbonylbenzoyltio )-azetidin-2-on (1,7 g), kalsiumkarbonat (1,7 g), diisopropyletylamin (1,05 ml) og diklormetan (15 ml). The compound in the title (2.5 g) was obtained by a method analogous to the method used! Example 17 using 4-nitrobenzylchloroxoacetate (1.17 g), 3S-(1R-(dimethyl-(2-methylprop-2-yl)silyloxy)ethyl)-4R-(4-methylaminocarbonylbenzoylthio)-azetidine-2 -one (1.7 g), calcium carbonate (1.7 g), diisopropylethylamine (1.05 ml) and dichloromethane (15 ml).

S (CDC13) 0,09 (6H, s), 0,86 ( 9H, s), 1,27 (3H, d, S (CDCl 3 ) 0.09 (6H, s), 0.86 ( 9H, s), 1.27 (3H, d,

J=6,3Hz), 3,04 (3H, d, J=4, 9Hz), 3,63 (1H, dd, J=3,4 og 2,7Hz), 4,39-4,43 (1H, m), 5,35, 5,43 (2H, AB, Jgem=13,7Hz), 6,19 (1H, d, J=3,4Hz), 7,57, 7,97 (4H, AA'BB', J=8,1Hz). 7,86, 8,22 (4H, AA'BB', J=8,7Hz). J=6.3Hz), 3.04 (3H, d, J=4, 9Hz), 3.63 (1H, dd, J=3.4 and 2.7Hz), 4.39-4.43 (1H , m), 5.35, 5.43 (2H, AB, Jgem=13.7Hz), 6.19 (1H, d, J=3.4Hz), 7.57, 7.97 (4H, AA' BB', J=8.1Hz). 7.86, 8.22 (4H, AA'BB', J=8.7Hz).

Eksempel 53 Example 53

4- nitrobenzyl- 5R, 6S-( lR- fdimetyl( 2- metylprop- 2- yl) silyloksy] - etyl)- 3-( 4- metylaminokarbony1fenyl)- 7- okso- 4- tia- l- azabicyklo[ 3 , 2 , 0~ lhept- 2- en- 2- karboksylat 4- nitrobenzyl- 5R, 6S-( 1R- fdimethyl( 2- methylpropyl- 2- yl) silyloxy] - ethyl)- 3-( 4- methylaminocarbonylphenyl)- 7- oxo- 4- thia- l- azabicyclo[ 3 , 2 , 0~ lhept- 2- en- 2- carboxylate

Forbindelsen i overskriften (0,66 g) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 18 ved anvendelse av 4-nitrobenzyl-(3-[lR-(dimetyl(2-metylprop-2-yl )silyloksy )etyl] -4R- [4-(metylaminokarbonyl )benzoyltio] - azet idin-2-on-2-yl }oksoacetat (2,5 g), tr ietylf osf i tt (1,37 ml), hydrokinon (5 mg), o-xylen (15 ml). The compound in the title (0.66 g) was obtained by a method analogous to the method used in example 18 using 4-nitrobenzyl-(3-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-4R - [4-(methylaminocarbonyl)benzoylthio]-azetidin-2-on-2-yl}oxoacetate (2.5 g), triethyl phosphate (1.37 ml), hydroquinone (5 mg), o-xylene (15ml).

vmaks (fllm) 1778, 1715 cm"<1>vmax (fllm) 1778, 1715 cm"<1>

S (CDCI3) 0,082 (6H, s), 0,90 (9H, s), 1,22 (3H, d, S (CDCl 3 ) 0.082 (6H, s), 0.90 (9H, s), 1.22 (3H, d,

J=6,3Hz), 3,01 (3H, d, J=4, 6Hz) , 3,83 (1H, dd, J=l,5og 4,2Hz), 4,12-4,19 (1H, m), 5,10, 5,27 (2H, AB, Jgem=13,6Hz), 5,76 (1H, d, J=l, 5Hz ), 6,15 (1H, bd, J=4,6Hz), 7,43, 7,71 (4H, AA 'BB' , J=8,4Hz), 7,46, 8,14 (4H, AA'BB', J=8,7Hz). J=6.3Hz), 3.01 (3H, d, J=4, 6Hz), 3.83 (1H, dd, J=1.5and 4.2Hz), 4.12-4.19 (1H, m), 5.10, 5.27 (2H, AB, Jgem=13.6Hz), 5.76 (1H, d, J=l, 5Hz ), 6.15 (1H, bd, J=4.6Hz ), 7.43, 7.71 (4H, AA'BB' , J=8.4Hz), 7.46, 8.14 (4H, AA'BB', J=8.7Hz).

Eksempel 54 Example 54

4- nitrobenzyl- 5R, 6S-( lR- hydroksyetyl)- 3-( 4- me ty lami no-karbonyl f enyl ) - 7- okso- 4- tia- l- azabicyklo[ 3. 2 . 0~ lhept- 2- en- 2-karboksylat 4-nitrobenzyl-5R,6S-(1R-hydroxyethyl)-3-(4-methylamino-carbonylphenyl)-7-oxo-4-thia-1-azabicyclo[3.2. 0~ lhept- 2- en- 2-carboxylate

Forbindelsen i overskriften (175 mg) ble oppnådd ved en fremgangsmåte analoge fremgangsmåten benyttet i eksempel 19 ved anvendelse av 4-nitrobenzyl-5R,6S-(IR-[dimetyl(2-metyl- pr op-2-yl )silyloksy] etyl } -3 - ( 4-metylaminokarbonylf enyl )-7-okso-4-tia-l-azabicyklo[3 , 2 , 0]hept-2-en-2-karboksylat (660 mg), iseddiksyre (660 pl), IM tetra-n-butylammoniumfluorid 1 tetrahydrofuran (3,3 ml) og tetrahydrofuran (5 ml). The compound in the title (175 mg) was obtained by a method analogous to the method used in example 19 using 4-nitrobenzyl-5R,6S-(IR-[dimethyl(2-methyl-prop-2-yl)silyloxy]ethyl} -3-(4-methylaminocarbonylphenyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (660 mg), glacial acetic acid (660 µl), IM tetra -n-butylammonium fluoride 1 tetrahydrofuran (3.3 mL) and tetrahydrofuran (5 mL).

<v>maks (KBr) 1770 cm_<1><v>max (KBr) 1770 cm_<1>

8 (DMS0-d6) 1,17 (3H, d, J=6, 1Hz ), 2,78 (3H, d, J=4 , 5Hz), 3,96-4,02 (2H, m), 5,20 (2H, m), 5,82 (1H, d, J = l,5Hz), 7,32, 7,76 (4H, AA'BB ' , J=7,2Hz), 7,46, 8,10 (4H, AA'BB', J=8,6Hz), 8,49 (1H, bd, J=4,0Hz). 8 (DMS0-d6) 1.17 (3H, d, J=6, 1Hz ), 2.78 (3H, d, J=4 , 5Hz), 3.96-4.02 (2H, m), 5 .20 (2H, m), 5.82 (1H, d, J = 1.5Hz), 7.32, 7.76 (4H, AA'BB ' , J=7.2Hz), 7.46, 8 .10 (4H, AA'BB', J=8.6Hz), 8.49 (1H, bd, J=4.0Hz).

Eksempel 55 Example 55

Kalium- 5R. 6S-( lR- hydroksyetyl)- 3-( 4- metylaminokarbonylfenyl)-7- okso- 4- tla- l- azabicyklor3 . 2 . 0lhept- 2- en- 2^- karboksylat Potassium- 5R. 6S-(1R-hydroxyethyl)-3-(4-methylaminocarbonylphenyl)-7-oxo-4-tla-1-azabicyclo3. 2. 0lhept- 2- en- 2^- carboxylate

Forbindelsen i overskriften (117 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 7 ved å anvende 4-ni trobenzyl-5R , 6S-( lR-hydroksyetyl )-3-( 4-metyl-aminokarbonylf enyl )-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (175 mg), 10% palladium-på-trekull_(175 mg), kaliumbikarbonat (36,2 mg), dioksan (5 ml) og vann (5 ml). The compound in the title (117 mg) was obtained by a method analogous to the method used in example 7 by using 4-nitrobenzyl-5R,6S-(1R-hydroxyethyl)-3-(4-methyl-aminocarbonylphenyl)-7-oxo -4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (175 mg), 10% palladium-on-charcoal_(175 mg), potassium bicarbonate (36.2 mg), dioxane (5 ml) and water (5 ml).

S (D20) 1,26 (3H, d, J=6,4Hz), 2,86 (3H, s), 3,96 (1H, dd, S (D20) 1.26 (3H, d, J=6.4Hz), 2.86 (3H, s), 3.96 (1H, dd,

J=l,3 og 6,0Hz), 4,19-4,26 (1H, m), 5,75 (1H, d, J=l,3Hz), 7,44, 7,64 (4H, AA'BB', J=8,3Hz). J=1.3 and 6.0Hz), 4.19-4.26 (1H, m), 5.75 (1H, d, J=1.3Hz), 7.44, 7.64 (4H, AA 'BB', J=8.3Hz).

Eksempel 56 Example 56

4-( propylaminokarbonyl)- tiobenzosyre 4-(propylaminocarbonyl)-thiobenzoic acid

Forbindelsen i overskriften (3,4 g) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 44 ved å anvende tereftaloylklorid (10,0 g), propylamin (4,84 ml), trietylamin (10,2 ml), pyridin (8,36 ml), overskudd hydrogensulfid og diklormetan (300 ml). The compound in the title (3.4 g) was obtained by a method analogous to the method used in Example 44 by using terephthaloyl chloride (10.0 g), propylamine (4.84 ml), triethylamine (10.2 ml), pyridine (8 .36 ml), excess hydrogen sulphide and dichloromethane (300 ml).

§ (aceton-d6) 0,93 (3H, t, J=7,4Hz), 1,60 (2H, m), 3,30-3,40 (2H, m), 7,96-8,13 (4H, m). § (acetone-d6) 0.93 (3H, t, J=7.4Hz), 1.60 (2H, m), 3.30-3.40 (2H, m), 7.96-8.13 (4H, m).

Eksempel 57 Example 57

3S-( lR- rdimetyl( 2- metvlprop- 2- yl) silyloksvletyl)- 4R-( 4-propylaminokarbonylbenzoyltio) azetldin- 2- on 3S-(1R-dimethyl(2-methylprop-2-yl)silyloxyethyl)-4R-(4-propylaminocarbonylbenzoylthio)azetldin-2-one

Forbindelsen i overskriften (250 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 16 ved anvendelse av 4-(propylaminokarbonyl )-tiobenzosyre (330 mg) , 4-acetoksy-3R-{lR-[dimetyl(2-metylprop-2-yl)silyloksy]-etyl >azetidin-2-on (280 mg), IM natriumhydroksydoppløsning (1,46 ml), vann (1,5 ml og aceton (7 ml). The compound in the title (250 mg) was obtained by a method analogous to the method used in example 16 using 4-(propylaminocarbonyl)-thiobenzoic acid (330 mg), 4-acetoxy-3R-{1R-[dimethyl(2-methylprop-2 -yl)silyloxy]ethyl >azetidin-2-one (280 mg), 1M sodium hydroxide solution (1.46 ml), water (1.5 ml and acetone (7 ml).

vmaks (film) 1758, 1660 cm_<l>vmax (film) 1758, 1660 cm_<l>

(CDC13) 0,10 (6H, s), 0,90 (9H, s), 0,93 (3H, t, (CDCl 3 ) 0.10 (6H, s), 0.90 (9H, s), 0.93 (3H, t,

J=7,3Hz), 1,19 (3H, d, J=6,2Hz), 1,43-1,63 (2H, m), 3,23 (1H, dd, J=2,4og 3,8Hz), 3,34 (2H, m), 4,23-4,27 (1H, m), 5,42 (1H, d, J=2,4Hz), 6,18 (1H, bs), 6,41 (1H, bs), 7,78, 7,91 (4H, AA'BB', J=8,6Hz). J=7.3Hz), 1.19 (3H, d, J=6.2Hz), 1.43-1.63 (2H, m), 3.23 (1H, dd, J=2.4and 3, 8Hz), 3.34 (2H, m), 4.23-4.27 (1H, m), 5.42 (1H, d, J=2.4Hz), 6.18 (1H, bs), 6 .41 (1H, bs), 7.78, 7.91 (4H, AA'BB', J=8.6Hz).

Eksempel 58 Example 58

4- ni trobenzyl-( 3S- f IR- ( dimetyl ( 2- metylprop- 2- vl ) silyloksy )-etyll - 4R- r4-( propylaminokarbonyl) benzoyltio) azetidin- 2- on- l-yl) oksoacetat 4-nitrobenzyl-(3S-fIR-(dimethyl (2-methylprop-2-vl)silyloxy)-ethyl-4R-r4-(propylaminocarbonyl)benzoylthio)azetidin-2-on-l-yl)oxoacetate

Forbindelsen i overskriften (361 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 17 ved anvendelse av 3S-( IR-[dimetyl-(2-metylprop-2-yl )silyloksy]-etyl)-4R-(4-propylaminokarbonylbenzoyltio)azetidin-2-on (250 mg), 4-nitrobenzylkloroksoacetat (162 mg), diisopropyletylamin (0,145 ml), kalsiumkarbonat (250 mg) og diklormetan (5 ml). The compound in the title (361 mg) was obtained by a method analogous to the method used in example 17 using 3S-(IR-[dimethyl-(2-methylprop-2-yl)silyloxy]-ethyl)-4R-(4-propylaminocarbonylbenzoylthio )azetidin-2-one (250 mg), 4-nitrobenzylchloroxoacetate (162 mg), diisopropylethylamine (0.145 ml), calcium carbonate (250 mg) and dichloromethane (5 ml).

S (CDCI3) 0,11 (6H, s), 0,92 (9H, s), 1,01 (3H, t, S (CDCl 3 ) 0.11 (6H, s), 0.92 (9H, s), 1.01 (3H, t,

J=7,3Hz), 1,27 (3H, d, J=6,3Hz), 1,53-1,65 (2H, m), 3,46-3,51 (2H, m), 3,66 (1H, dd, J=2,8og 3,5Hz), 4,32-4,39 (1H, m), 5,43 (2H, s), 6,22 (1H, d, J=3,5Hz), 7,57-8,30 (8H, m). J=7.3Hz), 1.27 (3H, d, J=6.3Hz), 1.53-1.65 (2H, m), 3.46-3.51 (2H, m), 3, 66 (1H, dd, J=2.8and 3.5Hz), 4.32-4.39 (1H, m), 5.43 (2H, s), 6.22 (1H, d, J=3, 5Hz), 7.57-8.30 (8H, m).

Eksempel 59 Example 59

4- nitrobenzyl- 5R. 6S-( lR- fdimetyl( 2- metylprop- 2- yl ) silyloksy]-etyl ) - 7- okso- 3- r4-( propylaminokarbonyI) fenyll- 4- tia- l- azabicyklof3, 2, Olhept- 2- en- karboksylat 4- nitrobenzyl- 5R. 6S-(1R-fdimethyl(2-methylpropyl-2-yl)silyloxy]-ethyl)-7-oxo-3-r4-(propylaminocarbonyl)phenyl-4-thi-1-azabicyclof3,2,Olhept-2-en- carboxylate

Forbindelsen i overskriften (45 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 18 ved anvendelse av 4-nitrobenzyl-{3S-[lR-(dimetyl-(2-metylprop-2-yl ) si lyloksy )etyl ] -4R-( 4-propylaminokarbonylbenzoyl-tio )azet idin-2-on-l-yl )oksoacetat (361 mg), trietylfosfitt (0,185 ml) og o-xylen (5 ml). The compound in the title (45 mg) was obtained by a method analogous to the method used in example 18 using 4-nitrobenzyl-{3S-[1R-(dimethyl-(2-methylprop-2-yl)silyloxy)ethyl]-4R -( 4-propylaminocarbonylbenzoyl-thio )azetidin-2-on-1-yl )oxoacetate (361 mg), triethyl phosphite (0.185 ml) and o-xylene (5 ml).

vmaks (film) 1789 cm"<1>vmax (film) 1789 cm"<1>

S (CDC13) 0,90 (6H, s), 0,94 ( 9H, s), 1,04 (3H, t, S (CDCl 3 ) 0.90 (6H, s), 0.94 ( 9H, s), 1.04 (3H, t,

J=7,4Hz), 1,23 (3H, d, J=6,3Hz), 1,27-1,34 (2H, m), 3,44-3,52 (2H, m), 3,89 (1H, dd, J=l,6 og 4,2Hz), 4,19-4,30 (1H, m), 5,15 og 5,34 (2H, AB, Jgem=13,6Hz) , 5,81 (1H, d, J=l,6Hz), 6,10 (1H, bs), 7,40, 7,80 (4H, AA'BB', J=9Hz), 7,56, 8,22 (4H, AA'BB', J=8,7Hz). J=7.4Hz), 1.23 (3H, d, J=6.3Hz), 1.27-1.34 (2H, m), 3.44-3.52 (2H, m), 3, 89 (1H, dd, J=l.6 and 4.2Hz), 4.19-4.30 (1H, m), 5.15 and 5.34 (2H, AB, Jgem=13.6Hz) , 5 .81 (1H, d, J=1.6Hz), 6.10 (1H, bs), 7.40, 7.80 (4H, AA'BB', J=9Hz), 7.56, 8.22 (4H, AA'BB', J=8.7Hz).

Eksempel 60 Example 60

4- ni trobenzyl- 5R, 6S-( lR- hydroksyetyl)- 7- okso- 3- r4-( propylam-1 nok arb ony 1 ) f enyll - 4- tia- l- azabicyklor3. 2. 0~ lhept- 2- en- 2-karboksylat 4- nitrobenzyl- 5R, 6S-( 1R- hydroxyethyl)- 7- oxo- 3- r 4-( propylam-1 noc arbony 1 ) phenyl - 4- thia- 1- azabicyclo3. 2. 0~lhept-2-ene-2-carboxylate

Forbindelsen i overskriften (50 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 19 ved anvendelse av 4-nitrobenzyl-5R,6S-( lR-[dimetyl(2-metylprop-2-yl )silyloksy]etyl)-7-okso-3-[4-(propylaminokarbonyl)-fenyl] - 4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (670 mg), iseddiksyre (0,64 ml), tetrahydrofuran (5 ml) og IM tetra-n-butylammoniumfluorid i tetrahydrofuran (3,2 ml). The compound in the title (50 mg) was obtained by a method analogous to the method used in example 19 using 4-nitrobenzyl-5R,6S-(1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl)-7- oxo-3-[4-(propylaminocarbonyl)-phenyl]-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (670 mg), glacial acetic acid (0.64 ml), tetrahydrofuran (5 ml) and 1M tetra-n-butylammonium fluoride in tetrahydrofuran (3.2 ml).

vmaks (CDCI3) 1778, 1728 cm"<!>vmax (CDCI3) 1778, 1728 cm"<!>

S (CDCI3) 0,99 (3H, t, J=7,4Hz), 1,29 (2H, m), 1,39 (3H, S (CDCl3) 0.99 (3H, t, J=7.4Hz), 1.29 (2H, m), 1.39 (3H,

d, J=6,3Hz), 3,38-3,47 (2H, m), 3,87 (1H, dd, J=l,6 og 6,6Hz), 4,2-4,3 (1H, m), 5,11, 5,30 (2H, AB, Jgem=13,7Hz), 5,70 (1H, d, J=l,6Hz), d, J=6.3Hz), 3.38-3.47 (2H, m), 3.87 (1H, dd, J=1.6 and 6.6Hz), 4.2-4.3 (1H , m), 5.11, 5.30 (2H, AB, Jgem=13.7Hz), 5.70 (1H, d, J=1.6Hz),

6,10 (1H, bt), 7,41, 7,72 (4H, AA'BB', J=8,5Hz), 7,50, 8,15 (4H, AA'BB', J=8,9Hz). 6.10 (1H, bt), 7.41, 7.72 (4H, AA'BB', J=8.5Hz), 7.50, 8.15 (4H, AA'BB', J=8, 9Hz).

Eksempel 61 Example 61

Kalium- 5R, 6S-( lR- hydroksyetyl)- 7- okso- 3- f 4-( propylamino-karbonyl) fenyll- 4- tia- l- azabicyklor3, 2, Olhept- 2- en- 2- karboksylat Forbindelsen i overskriften (30 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 7 ved anvendelse av 4-nitrobenzyl-5R,6S-(lR-hydroksyetyl)-7-okso-3-[4-(propylaminokarbonyl)fenyl]-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (50 mg), 10% palladium-på-trekull (50 mg), kaliumbikarbonat (9,8 mg), dioksan (5 ml) og vann (5 ml). Potassium- 5R, 6S-( 1R- hydroxyethyl)- 7- oxo- 3- f 4-( propylamino-carbonyl) phenyl- 4- thia- l- azabicyclo3, 2, Olhept- 2-ene- 2- carboxylate The compound in the title (30 mg) was obtained by a method analogous to the method used in example 7 using 4-nitrobenzyl-5R,6S-(1R-hydroxyethyl)-7-oxo-3-[4-(propylaminocarbonyl)phenyl]-4-thia -l-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (50 mg), 10% palladium-on-charcoal (50 mg), potassium bicarbonate (9.8 mg), dioxane (5 ml) and water (5 mL).

S (D20) 0,91 (3H, t, J=7,3Hz), 1,28 (3H, d, J=6,4Hz), 1,50-1,59 (2H, m), 3,27-3,37 (2H, m), 3,96 (1H, dd, J-1,5 og 5,9Hz), 4,20-4,26 (1H, m), 5,76 (1H, d, J=l,5Hz), 7,46 og 7,65 (4H, AA'BB', J=8,3Hz). S (D20) 0.91 (3H, t, J=7.3Hz), 1.28 (3H, d, J=6.4Hz), 1.50-1.59 (2H, m), 3.27 -3.37 (2H, m), 3.96 (1H, dd, J-1.5 and 5.9Hz), 4.20-4.26 (1H, m), 5.76 (1H, d, J=1.5Hz), 7.46 and 7.65 (4H, AA'BB', J=8.3Hz).

Eksempel 62 Example 62

4-( acetylamino) tiobenzosyre 4-(Acetylamino)thiobenzoic acid

Til en omrørt suspensjon av 4-acetylaminobenzosyre (10,0 g) i tørr diklormetan (50 ml) ved -15°C ble det tilsatt trietylamin (6 ml) etterfulgt av kloroformat (6 ml). Etter 3 timer ble hydrogensulfid (overskudd) boblet gjennom; blandingen ble oppvarmet til romtemperatur, behandlet med 2M saltsyre og filtrert. Filtratet ble fordelt og det vandige laget ble ekstrahert med etylacetat. De samlede organiske lagene ble vasket med vann, med saltvannsoppløsning, ble tørket og inndampet i vakuum. Kromatografi av resten over silikagel og eluering med etylacetat-heksanblandinger ga forbindelsen i overskriften (2,2 g). To a stirred suspension of 4-acetylaminobenzoic acid (10.0 g) in dry dichloromethane (50 ml) at -15°C was added triethylamine (6 ml) followed by chloroformate (6 ml). After 3 hours, hydrogen sulfide (excess) was bubbled through; the mixture was warmed to room temperature, treated with 2M hydrochloric acid and filtered. The filtrate was partitioned and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, with brine, dried and evaporated in vacuo. Chromatography of the residue over silica gel and eluting with ethyl acetate-hexane mixtures gave the title compound (2.2 g).

S (aceton-d6) 2,17 (3H, s), 3,42 (1H, bs), 7,90, 8,01 S (acetone-d6) 2.17 (3H, s), 3.42 (1H, bs), 7.90, 8.01

(4H, AA'BB', J=8,8Hz). (4H, AA'BB', J=8.8Hz).

Eksempel 63 Example 63

4R- ( 4- acetylaminobenzoyl tio )- 3S-{ IR- f dimetyl ( 2- metylprop- 2-yl) silyloksyl- etyl)- azetidin- 2- on 4R-(4-Acetylaminobenzoylthio)-3S-{IR-fdimethyl(2-methylprop-2-yl)silyloxyl-ethyl)-azetidin-2-one

Forbindelsen i overskriften (0,85 g) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 16 ved å anvende 4-(acetylamino )-tiobenzosyre (2,0 g), 4-acetoksy-3R-( IR- [dimetyl (2-metylprop-2-yl) si lyloksy] -etyl )-azetidin-2-on (2,2 g), natriumhydroksyd (0,44 g), vann (2 ml), diklormetan (5 ml) og tetrahydrofuran (2 ml). The compound in the title (0.85 g) was obtained by a method analogous to the method used in example 16 by using 4-(acetylamino)-thiobenzoic acid (2.0 g), 4-acetoxy-3R-(IR-[dimethyl (2 -methylprop-2-yl)silyloxy]-ethyl)-azetidin-2-one (2.2 g), sodium hydroxide (0.44 g), water (2 ml), dichloromethane (5 ml) and tetrahydrofuran (2 ml ).

<v>maks (CDC13) 1769, 17000, 1655 crn-<1><v>max (CDC13) 1769, 17000, 1655 crn-<1>

S (CDCI3) 0,09 (6H, s), 0,89 ( 9H, s), 1,24 (3H, d, S (CDCl 3 ) 0.09 (6H, s), 0.89 ( 9H, s), 1.24 (3H, d,

J=6,3Hz), 2,23 (3H, s), 3,28 (1H, dd, J=2,4 og 4~0Hz), 4,24-4,36 (1H, m), 5,47 (1H, d, J=2,4H-z), 6,41 (1H, bs), 7,41 (1H, bs), 7,62, 7,88 (4H, AA'BB', J=8,8Hz). J=6.3Hz), 2.23 (3H, s), 3.28 (1H, dd, J=2.4 and 4~0Hz), 4.24-4.36 (1H, m), 5, 47 (1H, d, J=2.4H-z), 6.41 (1H, bs), 7.41 (1H, bs), 7.62, 7.88 (4H, AA'BB', J= 8.8Hz).

Eksempel 64 Example 64

4- nitrobenzyl-( 4R-[ 4-( acetylamino) benzoyltio]- 3S-[ lR-( dimetyl( 2- metylprop- 2- yl) silyloksy) etyll- azetidln- 2- on- l-yl) oksoacetat 4- nitrobenzyl-( 4R-[ 4-( acetylamino) benzoylthio]- 3S-[ 1R-( dimethyl( 2- methylprop- 2- yl) silyloxy) ethyl- azetidln- 2- on- 1-yl) oxoacetate

Forbindelsen i overskriften (151 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 17 ved anvendelse av 4R-( 4-acetylaminobenzoyltio )-3S-( 1R-{dimetyl-(2-metylprop-2-yl)-silyloksy)etyl )-azetidin-2-on (100 mg), 4-nitrobenzyl-klorooksoacetat (69 mg), kalsiumkarbonat (100 mg), diisopropyletylamin (49 pl) og diklormetan (4 ml). The compound in the title (151 mg) was obtained by a method analogous to the method used in example 17 using 4R-(4-acetylaminobenzoylthio)-3S-(1R-{dimethyl-(2-methylprop-2-yl)-silyloxy)ethyl )-azetidin-2-one (100 mg), 4-nitrobenzyl-chlorooxoacetate (69 mg), calcium carbonate (100 mg), diisopropylethylamine (49 µl) and dichloromethane (4 ml).

<v>maks (CDCI3) 1813, 1760 cm-<1><v>max (CDCI3) 1813, 1760 cm-<1>

S (CDCI3) 0,09 (6H, s), 0,83 ( 9H, s), 1,26 (3H, d, S (CDCl 3 ) 0.09 (6H, s), 0.83 ( 9H, s), 1.26 (3H, d,

J=6,3Hz), 2,22 (3H, s), 3,60 (1H, dd, J=3,0 og 3,4Hz), 4,35 (1H, m), 5,41 (2H, s), 6,15 (1H, d, J=3,4Hz), 7,4-8,3 (8H, m). J=6.3Hz), 2.22 (3H, s), 3.60 (1H, dd, J=3.0 and 3.4Hz), 4.35 (1H, m), 5.41 (2H, s), 6.15 (1H, d, J=3.4Hz), 7.4-8.3 (8H, m).

Eksempel 65 Example 65

4- ni trobenzyl - 5R , 3-( 4- acetylaminof enyl )- 6S-{ IR- f dimetyl ( 2-metylprop- 2- yl ) s ilyloksvletyl) - 7- okso- 4- tla- l- azabicyklor-3, 2, 0lhept- 2- en- 2- karboksylat 4-nitrobenzyl-5R, 3-(4-acetylaminophenyl)-6S-{IR-fdimethyl (2-methylpropyl-2-yl)silyloxvletyl)-7-oxo-4-tla-l-azabicyclo-3, 2,0lhept-2-ene-2-carboxylate

Forbindelsen i overskriften (430 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 18 ved anvendelse av 4-nitrobenzyl-(4R-[4-(acetylamino)benzoyltio]-3S-[lR-(dimetyl( 2-me ty lpr op-2-yl ) si lyloksy ) etyl] - azetidin-2-on-l-yl>oksoacetat (1,0 g), trietylfosfitt (0,566 ml) og o-xylen (8 ml). The compound in the title (430 mg) was obtained by a method analogous to the method used in example 18 using 4-nitrobenzyl-(4R-[4-(acetylamino)benzoylthio]-3S-[1R-(dimethyl(2-methyl) op-2-yl)silyloxy)ethyl]-azetidin-2-on-1-yl>oxoacetate (1.0 g), triethyl phosphite (0.566 ml) and o-xylene (8 ml).

vmaks(CDCI3) 1785, 1705 cm"<1>vmax(CDCI3) 1785, 1705 cm"<1>

S (CDCI3) 0,08 (6H, s), 0,85 ( 9H, s), 1,27 (3H, d, S (CDCl 3 ) 0.08 (6H, s), 0.85 ( 9H, s), 1.27 (3H, d,

J=6,3Hz), 2,19 (3H, s), 3,78 (1H, dd, J=l,6 og 4,2Hz), 4,30 (1H, m), 5,10, 5,30 (2H, AB, Jgem=13,7Hz), 5,65 (1H, d, J=l,6Hz), 7,29-8,19 (8H, m). J=6.3Hz), 2.19 (3H, s), 3.78 (1H, dd, J=1.6 and 4.2Hz), 4.30 (1H, m), 5.10, 5, 30 (2H, AB, Jgem=13.7Hz), 5.65 (1H, d, J=1.6Hz), 7.29-8.19 (8H, m).

Eksempel 66 Example 66

4- nitrobenzyl- 5R. 3-( 4- acetylaminofenyl)- 6S-( lR- hydroksyetyl)-7- okso- 4- tia- l- azabicyklor3, 2, 0] hept- 2- en- 2- karboksylat 4- nitrobenzyl- 5R. 3-( 4- Acetylaminophenyl)- 6S-( 1R- hydroxyethyl)-7- oxo- 4- thia- 1- azabicyclo3, 2, 0] hept- 2-ene- 2- carboxylate

Forbindelsen i overskriften (131 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 19 ved anvendelse av 4-nitrobenzyl-5R,3-(4-acetylaminofenyl)-6S-{lR-[dimetyl(2-metylprop-2-yl)silyloksy]etyl)-7-okso-4-tia-l-azabicyklo [3 , 2 , 0]hept-2-en-2-karboksylat (430 mg), iseddiksyre (0,534 ml), tetrahydrofuran (10 ml) og IM tetra-n-butylammoniumfluorid i tetrahydrofuran (2,7 ml). The compound in the title (131 mg) was obtained by a method analogous to the method used in example 19 using 4-nitrobenzyl-5R,3-(4-acetylaminophenyl)-6S-{1R-[dimethyl(2-methylprop-2-yl) )silyloxy]ethyl)-7-oxo-4-thia-1-azabicyclo [3 , 2 , 0 ]hept-2-ene-2-carboxylate (430 mg), glacial acetic acid (0.534 ml), tetrahydrofuran (10 ml) and 1M tetra-n-butylammonium fluoride in tetrahydrofuran (2.7 mL).

vmaks(CDCI3) 1786 cm"1 vmax(CDCI3) 1786 cm"1

S (CDCI3) 1,40 (3H, d, J=6,3Hz), 1,63 (1H, bs), 2,20 (3H, S (CDCl3) 1.40 (3H, d, J=6.3Hz), 1.63 (1H, bs), 2.20 (3H,

s), 3,60 (1H, dd, J=l,6 og 6,6Hz), 4,2 (1H, m), 5,10, 5,29 (2H, AB, Jgem=13, 7Hz), 5,70 (1H, d, J=l,6Hz), 7,23-8,16 (8H, m). s), 3.60 (1H, dd, J=1.6 and 6.6Hz), 4.2 (1H, m), 5.10, 5.29 (2H, AB, Jgem=13, 7Hz), 5.70 (1H, d, J=1.6Hz), 7.23-8.16 (8H, m).

Eksempel 67 Example 67

Kalium- 5R. 3-( 4- acetvlaminofenyl)- 6S-( lR- hydroksyetyl)- 7- okso-4- tia- l- azabicyklo[ 3, 2 . 0lhept- 2- en- 2- karboksylat Forbindelsen i overskriften (65 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 7 ved anvendelse av 4-nitrobenzyl-5R,3-(4-acetylaminofenyl)-6S-(lR-hydroksyetyl )-7-okso-4-t ia-l-azabicyklo[3,2 , 0]hept-2-en-2-karboksylat (123 mg), 10% palladium-på-trekull (123 mg), kaliumbikarbonat (33,3 mg), dioksan (5 ml) og vann (5 ml). Potassium- 5R. 3-(4-acetylaminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2. 0lhept-2-ene-2-carboxylate The compound in the title (65 mg) was obtained by a method analogous to the method used in example 7 using 4-nitrobenzyl-5R,3-(4-acetylaminophenyl)-6S-(1R-hydroxyethyl) )-7-oxo-4-thia-l-azabicyclo[3,2 , 0]hept-2-ene-2-carboxylate (123 mg), 10% palladium-on-charcoal (123 mg), potassium bicarbonate (33 .3 mg), dioxane (5 ml) and water (5 ml).

S (D20) 1,34 (3H, d, J=6,4Hz), 2,19 (3H, s), 4,00 (1H, dd, S (D20) 1.34 (3H, d, J=6.4Hz), 2.19 (3H, s), 4.00 (1H, dd,

J-1,6 og 6,1Hz), 4,17-4,28 (1H, m), 5,79 (1H, d, J=l,6Hz), 7,46 (4H, s). J-1.6 and 6.1Hz), 4.17-4.28 (1H, m), 5.79 (1H, d, J=1.6Hz), 7.46 (4H, s).

Eksempel 68 Example 68

3-( metylaminokarbonyl)- tiobenzosyre 3-(methylaminocarbonyl)-thiobenzoic acid

Forbindelsen i overskriften (4,5 g) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 44 ved anvendelse av isoftaloylklorid (10,0 g), trietylamin (17,8 ml), metylaminhydroklorid (5 g), diklormetan (200 ml), pyridin (7,5 ml) og hydrogensulfid (overskudd). The compound in the title (4.5 g) was obtained by a method analogous to the method used in example 44 using isophthaloyl chloride (10.0 g), triethylamine (17.8 ml), methylamine hydrochloride (5 g), dichloromethane (200 ml) , pyridine (7.5 mL) and hydrogen sulfide (excess).

S (aceton-d6) 2,91 (3H, d, J=l,2Hz), 7,5-8,3 (4H, m). S (acetone-d6) 2.91 (3H, d, J=1.2Hz), 7.5-8.3 (4H, m).

Eksempel 69 Example 69

3S-( lR- rdimetvl( 2- me ty lpr op- 2- vi ) s i lyl ok svi e tyl )- 4R- f 3-( metylaminokarbonyl) benzoyltiolazetidin- 2- on 3S-( 1R- dimethyl( 2- methyl lpr op- 2- vi ) silyl oc svi e tyl )- 4R- f 3-( methylaminocarbonyl) benzoylthioazetidin- 2- one

Forbindelsen i overskriften (1,0 g) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 16 ved anvendelse av 4-acetoksy-3R-(IR-[dimetyl(2-metylprop-2-yl )silyloksy]etyl)azetidin-2-on (2,04 g), 3-(metylamino-karbonyl )-tiobenzosyre (4,5 g), IM natriumhydroksyd (21 ml) og aceton (50 ml). The compound in the title (1.0 g) was obtained by a method analogous to the method used in example 16 using 4-acetoxy-3R-(IR-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl)azetidine-2 -one (2.04 g), 3-(methylaminocarbonyl)-thiobenzoic acid (4.5 g), 1M sodium hydroxide (21 ml) and acetone (50 ml).

vmaks (film) 1768, 1655 cm_<l>vmax (film) 1768, 1655 cm_<l>

§ (CDC13) 0,10 (6H, s), 0,89 (9H, s), 1,24 (3H, d, § (CDCl 3 ) 0.10 (6H, s), 0.89 (9H, s), 1.24 (3H, d,

J=6,3Hz), 3,03 (3H, d, J=4,8Hz), 3,29 (1H, d,, J=6.3Hz), 3.03 (3H, d, J=4.8Hz), 3.29 (1H, d,,

J=2,4 og 3,8Hz), 4,30-4,36 (1H, m), 5,49 (1H, d, J=2,4Hz), 6,96 (1H, bs, J=4,8Hz), 7,14 (1H, bs), 7,53-8,30 (4H, m). J=2.4 and 3.8Hz), 4.30-4.36 (1H, m), 5.49 (1H, d, J=2.4Hz), 6.96 (1H, bs, J=4 .8Hz), 7.14 (1H, bs), 7.53-8.30 (4H, m).

Eksempel 70 Example 70

4- ni trobenzyl-! 3S - f IR- ( dimetyl ( 2- metylprop- 2- vl) silyloksy)-etyl 1 - 4R- f 3 - ( metylaminokarbonyl ) benzoyltiol azetidin- 2- on- l-yl) oksoacetat 4- ni trobenzyl-! 3S - f IR-( dimethyl ( 2- methylprop- 2- vl) silyloxy)-ethyl 1 - 4R- f 3 - ( methylaminocarbonyl ) benzoylthiol azetidin- 2- on- l-yl) oxoacetate

Forbindelsen i overskriften (1,43 g) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 17 ved anvendelse av 3S-( lR-[dimetyl-(2-metylprop-2-yl )silyloksy] etyl } -4R- ( 3-metyl aminokarbonylbenzoyltio )azetidin-2-on (1,0 g), 4-nitrobenzyl-klor-oksoacetat (720 mg), diklormetan (10 ml), kalsiumkarbonat (1,0 g) og diisopropyletylamin (0,60 ml). The compound in the title (1.43 g) was obtained by a method analogous to the method used in example 17 using 3S-(1R-[dimethyl-(2-methylprop-2-yl)silyloxy]ethyl}-4R-(3- methyl aminocarbonylbenzoylthio)azetidin-2-one (1.0 g), 4-nitrobenzyl-chloro-oxoacetate (720 mg), dichloromethane (10 ml), calcium carbonate (1.0 g) and diisopropylethylamine (0.60 ml).

S (CDC13) 0,09 ((6H, s), 0,83 (9H, s), 1,25 (3H, d, S (CDCl 3 ) 0.09 ((6H, s), 0.83 (9H, s), 1.25 (3H, d,

J=6,3Hz), 3,04 (3H, d, J=4,9Hz), 3,60-3,66 (1H, m), 4,30-4,40 (1H, m), 5,38, 5,42 (2H, AB, J=13,0Hz), 6,19 (1H, d, J=3,4Hz), 7,53-8,26 (8H, m). J=6.3Hz), 3.04 (3H, d, J=4.9Hz), 3.60-3.66 (1H, m), 4.30-4.40 (1H, m), 5, 38, 5.42 (2H, AB, J=13.0Hz), 6.19 (1H, d, J=3.4Hz), 7.53-8.26 (8H, m).

Eksempel 71 Example 71

4- nitrobenzyl- 5R. 6S-{ lR- fdimetyl( 2- metylprop- 2- yl) silyloksyletyl)- 3- f3-( me tyl aminokarbonyl) f enyll - 7- okso- 4- tia- l- azabl-cyklof3, 2, 0lhept- 2- en- 2- karboksylat 4- nitrobenzyl- 5R. 6S-{1R-fdimethyl(2-methylpropyl-2-yl)silyloxyethyl)-3-f3-(methylaminocarbonyl)phenyl-7-oxo-4-thia-1-azabl-cyclof3,2,0lhept-2- en- 2- carboxylate

Forbindelsen i overskriften (0,48 g) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 18 ved anvendelse av 4-nitrobenzyl-(3S-[lR-(dimetyl(2-metylprop-2-yl )silyloksy)etyl]-4R - [3-(metylaminokarbonyl )benzoyltio] - azetidin-2-on-l-yl)oksoacetat (1,43 g), trietylfosfitt (0,78 ml), hydrokinon (5 mg) og o-xylen (10 ml). The compound in the title (0.48 g) was obtained by a method analogous to the method used in example 18 using 4-nitrobenzyl-(3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-4R - [3-(methylaminocarbonyl)benzoylthio]-azetidin-2-on-l-yl)oxoacetate (1.43 g), triethyl phosphite (0.78 ml), hydroquinone (5 mg) and o-xylene (10 ml).

vmaks (film) 1779 cm"<!>vmax (film) 1779 cm"<!>

§ (CDCI3) 0,08 (6H, s), 0,86 ( 9H, s), 1,25 (3H, d, § (CDCl 3 ) 0.08 (6H, s), 0.86 ( 9H, s), 1.25 (3H, d,

J=6,4Hz), 3,01 (3H, d, J=4, 9Hz), 3,81 (1H, dd, J=l,6 og 4,2Hz), 4,10-4,25 (1H, m), 5,20, 5,28 J=6.4Hz), 3.01 (3H, d, J=4, 9Hz), 3.81 (1H, dd, J=1.6 and 4.2Hz), 4.10-4.25 (1H , m), 5.20, 5.28

(2H, AB, J=13,6Hz), 5,74 (1H, d, J=l,6Hz), 6,11 (1H, bd, J=4,9Hz), 7,39-8,29 (8H, m). (2H, AB, J=13.6Hz), 5.74 (1H, d, J=1.6Hz), 6.11 (1H, bd, J=4.9Hz), 7.39-8.29 ( 8H, m).

Eksempel 72 Example 72

4- nitrobenzyl- 5R, 6S-( lR- hydroksyetyl)- 3- f3 - ( metylamino-karbonyl ) fenyll- 7- okso- 4- tia- l- azabicyklor3, 2. Olhept- 2- en- 2-karboksylat 4- nitrobenzyl- 5R, 6S-( 1R- hydroxyethyl)- 3- f3 - ( methylamino-carbonyl ) phenyl- 7- oxo- 4- thia- l- azabicyclo3, 2. Olhept- 2- en- 2-carboxylate

Forbindelsen i overskriften (160 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 19 ved anvendelse av 4-nitrobenzyl-5R,6S-{lR-[dimetyl(2-metylprop-2-yl )silyloksy] etyl >-3[3-(metylaminokarbonyl )fenyl]-7-okso-4-tia-l-azabicyklo[3 , 2 , 0] hept-2-en-2-karboksylat (480 mg), iseddiksyre (0,48 ml), tetrahydrofuran (10 ml) og IM tetra-n-butylammoniumfluorid i tetrahydrofuran (2,4 ml). The compound in the title (160 mg) was obtained by a method analogous to the method used in example 19 using 4-nitrobenzyl-5R,6S-{1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl>-3[ 3-(Methylaminocarbonyl)phenyl]-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (480 mg), glacial acetic acid (0.48 mL), tetrahydrofuran ( 10 ml) and 1M tetra-n-butylammonium fluoride in tetrahydrofuran (2.4 ml).

<v>maks (Kbr) 1785 cm_<1><v>max (Kbr) 1785 cm_<1>

S (CDC13) 1,41 (3H, d, J=6,3Hz), 1,68 (1H, bs), 3,01 (3H, S (CDCl 3 ) 1.41 (3H, d, J=6.3Hz), 1.68 (1H, bs), 3.01 (3H,

d, J = 4,9Hz), 3,87 (1H, dd, J = l,6 og 6 , 5Hz) , 4,28-4,35 (1H, m), 5,13, 5,30 (2H, AB, J=13,6Hz), 5,77 (1H, d, J=l,6Hz), 6,08 (1H, bs), 7,37-8,17 (8H, m). d, J = 4.9Hz), 3.87 (1H, dd, J = 1.6 and 6 , 5Hz) , 4.28-4.35 (1H, m), 5.13, 5.30 (2H , AB, J=13.6Hz), 5.77 (1H, d, J=1.6Hz), 6.08 (1H, bs), 7.37-8.17 (8H, m).

Eksempel 73 Example 73

Kalium- 5R, 6S-( IR- hyd r oksyetyl ) - 3- f 3 - ( metyl aminokarbonyl )-fenyll- 7- okso- 4- tia- l- azabicyklor3, 2, 0lhept- 2- en- 2- karboksylat Potassium- 5R, 6S-( IR- hydroxyethyl ) - 3- f 3 - ( methyl aminocarbonyl )-phenyl- 7- oxo- 4- thia- l- azabicyclo3, 2, 0lhept- 2-ene- 2- carboxylate

Forbindelsen i overskriften (80 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 7 ved anvendelse av 4-nitrobenzyl-5R,6S-(lR-hydroksyetyl )-3-[3-(metyl aminokarbonyl)fenyl]-7-okso-4-tia-l-azabicyklo[3,2,0]-hept-2-en-2-karboksylat (160 mg), 10% palladium-på-trekull (160 mg), kaliumbikarbonat (33,1 mg), vann (5 ml) og dioksan (5 ml). The compound in the title (80 mg) was obtained by a method analogous to the method used in example 7 using 4-nitrobenzyl-5R,6S-(1R-hydroxyethyl)-3-[3-(methyl aminocarbonyl)phenyl]-7-oxo -4-thia-1-azabicyclo[3,2,0]-hept-2-ene-2-carboxylate (160 mg), 10% palladium-on-charcoal (160 mg), potassium bicarbonate (33.1 mg), water (5 ml) and dioxane (5 ml).

S (D20) 1,30 (3H, d, J=6,4Hz), 2,89 (3H, s), 3,99 (1H, dd, S (D20) 1.30 (3H, d, J=6.4Hz), 2.89 (3H, s), 3.99 (1H, dd,

J=l,2 og 5,8Hz), 4,21-4,29 (1H, m), 5,78 (1H, d, J=l,2Hz), 7,44-7,79 (4H, m). J=1.2 and 5.8Hz), 4.21-4.29 (1H, m), 5.78 (1H, d, J=1.2Hz), 7.44-7.79 (4H, m ).

Eksempel 74 Example 74

4-( nitro)- tiobenzosyre 4-(nitro)-thiobenzoic acid

Forbindelsen i overskriften (9,8 g) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 24 ved anvendelse av 4-nitrobenzoylklorid (10,0 g), diklormetan (200 ml), pyridin (8,6 ml) og hydrogensulfid (overskudd). The compound in the title (9.8 g) was obtained by a method analogous to the method used in example 24 using 4-nitrobenzoyl chloride (10.0 g), dichloromethane (200 ml), pyridine (8.6 ml) and hydrogen sulphide (excess ).

S (aceton-d6) 4,30 (1H, bs), 8,30, 8,37 (4H, AA' BB' , S (acetone-d6) 4.30 (1H, bs), 8.30, 8.37 (4H, AA' BB' ,

J=9,9Hz). J=9.9Hz).

Eksempel 75 Example 75

3S-( IR- fdimetyl( 2- metvlprop- 2- vl) silvloksv1etyl)- 4R-( 4- nitro-benzoyltio) åzetidin- 2- on 3S-(1R-dimethyl(2-methylprop-2-yl)silyloxyethyl)-4R-(4-nitro-benzoylthio)azetidin-2-one

Forbindelsen i overskriften (2,6 g) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 16 ved anvendelse av 4-acetoksy-3R-{IR-[dimetyl(2-metylprop-2-yl )silyloksy]etyl)azetidin-2-on (2,0 g), 4-(nitro)-tiobenzosyre (1,7 g), diklormetan (50 ml), vann (50 ml) og natriumhydroksyd (0,36 g). The compound in the title (2.6 g) was obtained by a method analogous to the method used in example 16 using 4-acetoxy-3R-{IR-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl)azetidine-2 -one (2.0 g), 4-(nitro)-thiobenzoic acid (1.7 g), dichloromethane (50 ml), water (50 ml) and sodium hydroxide (0.36 g).

vmaks (CDCI3 ) 1775cm"1 vmax (CDCI3 ) 1775cm"1

S (CDCI3) 0,10 (6H, s), 0,89 (9H, s), 1,27 (3H, d, S (CDCl 3 ) 0.10 (6H, s), 0.89 (9H, s), 1.27 (3H, d,

J=6,3Hz), 3,32 (1H, dd, J=2,3og 3,8Hz), 4,30 (1H, m), 5,51 (1H, d, J=2,3Hz), 6,50 (1H, bs), 8,07, 8,32 (4H, AA'BB', J=9,0Hz). J=6.3Hz), 3.32 (1H, dd, J=2.3and 3.8Hz), 4.30 (1H, m), 5.51 (1H, d, J=2.3Hz), 6 .50 (1H, bs), 8.07, 8.32 (4H, AA'BB', J=9.0Hz).

Eksempel 76 Example 76

4- nitrobenzyl-( 3S-[ lR - ( dimetyl ( 2- metylprop- 2- yl) si lyloksy )-etvll- 4R-( 4- nitrobenzoyltio) azetidin- 2- on- l- yl) oksoacetat 4-nitrobenzyl-(3S-[1R-(dimethyl (2-methylpropyl-2- yl)silyloxy)-ethyl-4R-(4-nitrobenzoylthio)azetidin-2-on-1-yl)oxoacetate

Forbindelsen i overskriften (754 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 17 ved anvendelse av 3S-{ IR-[dimetyl ( 2-metylprop-2-yl )silyloksy] etyl)-4R-(4-nitrobenzoyltio)azetidin-2-on (0,5 g), kalsiumkarbonat (0,5 g), 4-nitrobenzyl-kloroksoacetat (0,36 g), diklormetan (10 ml) og diisopropyletylamin (0,255 ml). The compound in the title (754 mg) was obtained by a method analogous to the method used in example 17 using 3S-{IR-[dimethyl (2-methylprop-2-yl)silyloxy]ethyl)-4R-(4-nitrobenzoylthio)azetidine -2-one (0.5 g), calcium carbonate (0.5 g), 4-nitrobenzyl-chloroxoacetate (0.36 g), dichloromethane (10 ml) and diisopropylethylamine (0.255 ml).

<v>maks (film) 1817, 1712 cm-<1><v>max (film) 1817, 1712 cm-<1>

S (CDCI3) 0,10 (6H, s), 0,84 (9H, s), 1,28 (3H, d, S (CDCl 3 ) 0.10 (6H, s), 0.84 (9H, s), 1.28 (3H, d,

J=6,3Hz), 3,64 (1H, dd, J=3,0 og 3, 4Hz ) , 4,38-4,47 (1H, m), 5,41 (2H, s), 6,18 (1H, d, J = 3,4Hz), 7,57, 8,22 (4H, AA'BB' , J = 8,8Hz), 8,08, 8,33 (4H, AA'BB', J=8,9Hz). J=6.3Hz), 3.64 (1H, dd, J=3.0 and 3.4Hz ), 4.38-4.47 (1H, m), 5.41 (2H, s), 6, 18 (1H, d, J = 3.4Hz), 7.57, 8.22 (4H, AA'BB' , J = 8.8Hz), 8.08, 8.33 (4H, AA'BB', J=8.9Hz).

Eksempel 77 Example 77

4- nitrobenzyl- 5R. 6S-{ IR- fdimetyl( 2- metylprop- 2- yl) silyloksyletyl ) - 3- ( 4- nitrofenyl)- 7- okso- 4- tia- l- azabicyklo[ 3, 2. Olhept-2- en- 2- karboksylat 4- nitrobenzyl- 5R. 6S-{ IR- fdimethyl( 2- methylpropyl- 2- yl) silyloxylethyl ) - 3- ( 4- nitrophenyl)- 7- oxo- 4- thia- l- azabicyclo[ 3, 2. Olhept-2- en- 2- carboxylate

Forbindelsen i overskriften (215 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet I eksempel 18 ved anvendelse av 4-nitrobenzyK3S-[lR-(dimetyl(2-metylprop-2-yl )silyloksy)etyl]-4R-( 4-ni trobenzoyl tio )azetidin-2-on-l-yl)-oksoacetat (754 mg), trietylfosfitt (0,418 ml) og o-xylen (5 ml). The compound in the title (215 mg) was obtained by a method analogous to the method used in example 18 using 4-nitrobenzyK3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-4R-(4-ni trobenzoyl thio)azetidin-2-on-1-yl)-oxoacetate (754 mg), triethyl phosphite (0.418 ml) and o-xylene (5 ml).

vmaks(CDCI3) 1778 cm"<1>vmax(CDCI3) 1778 cm"<1>

S (CDCI3) 0,09 (6H, s), 0,86 ( 9H, s), 1,27 (3H, d, S (CDCl 3 ) 0.09 (6H, s), 0.86 ( 9H, s), 1.27 (3H, d,

J=6,3Hz), 3,87 (1H, dd, J=l,5 og 4,0Hz), 4,29 (1H, m), 5,12, 5,30 (2H, AB, Jgem=13,6Hz), 5,81 (1H, d, J=l,5Hz), 7,51, 8,16 (4H, AA'BB', J=8,6Hz), 7,62, 8,20 (4H, AA'BB', J=8,8Hz). J=6.3Hz), 3.87 (1H, dd, J=1.5 and 4.0Hz), 4.29 (1H, m), 5.12, 5.30 (2H, AB, Jgem=13 ,6Hz), 5.81 (1H, d, J=1.5Hz), 7.51, 8.16 (4H, AA'BB', J=8.6Hz), 7.62, 8.20 (4H , AA'BB', J=8.8Hz).

Eksempel 78 Example 78

4- nitrobenzyl- 5R. 6S-( lR- hydroksyetyl)- 3-( 4- nitrofenyl )- 7-okso- 4- tla- l- azabicyklor3, 2. Olhept- 2- en- 2- karboksylat 4- nitrobenzyl- 5R. 6S-(1R-hydroxyethyl)-3-(4-nitrophenyl)-7-oxo-4-tla-1-azabicyclo3, 2.Olhept-2-ene-2-carboxylate

Forbindelsen i overskriften (106 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 19 ved anvendelse av 4-n i t r obenzyl--5R , 6S-( IR-[dimetyl ( 2-metylprop-2-yl)silyloksy]etyl)-3-(4-nitrofenyl)7-okso-4-tia-1-azabicyklo[3 , 2,0]hept-2-en-2-karboksylat ( 200 mg), iseddiksyre (0,204 ml), tetrahydrofuran (5 ml) og IM tetra-n-butylammoniumfluorid i tetrahydrofuran (1,02 ml). The compound in the title (106 mg) was obtained by a method analogous to the method used in example 19 using 4-nitrobenzyl--5R, 6S-(IR-[dimethyl (2-methylprop-2-yl)silyloxy]ethyl)- 3-(4-nitrophenyl)7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (200 mg), glacial acetic acid (0.204 ml), tetrahydrofuran (5 ml) and 1M tetra-n-butylammonium fluoride in tetrahydrofuran (1.02 mL).

vmaks (film)1790, 1712 cm-<1>vmax (film)1790, 1712 cm-<1>

S (CDCI3) 1,41 (3H, d, J=6,3Hz), 1,61 (1H, bs), 3,91 (1H, S (CDCl3) 1.41 (3H, d, J=6.3Hz), 1.61 (1H, bs), 3.91 (1H,

dd, J=l,6, 6,4Hz), 4,20-4,39 (1H, m), 5,12, 5,31 (2H, AB, Jgem=13,5Hz), 5,82 ( 1H, d, J=l,6Hz), 7,47, 8,17 (4H, AA'BB', J=8,7Hz), 7,58, 8,21 (4H, AA'BB', J=8,9Hz). dd, J=1.6, 6.4Hz), 4.20-4.39 (1H, m), 5.12, 5.31 (2H, AB, Jgem=13.5Hz), 5.82 ( 1H , d, J=1.6Hz), 7.47, 8.17 (4H, AA'BB', J=8.7Hz), 7.58, 8.21 (4H, AA'BB', J=8 .9Hz).

Eksempel 79 Example 79

Kallum- 5R. 3-( 4- aminofenyl)- 6S-( lR- hydroksyetyl )- 7- okso- 4- tla-l- azabicyklofS, 2, Olhept- 2- en- 2- karboksylat Kallum- 5R. 3-(4-Aminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-tla-1-azabicyclofS, 2,Olhept-2-ene-2-carboxylate

Forbindelsen i overskriften (44 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 7 ved anvendelse av 4-nitrobenzyl-5R,6S-(lR-hydroksyetyl )-3-(4-ni t rofenyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (100 mg), 10% pal1adium-på-trekul1 (100 mg), kaliumbikarbonat (21,2 mg), vann (5 ml) og dioksan (5 ml). The compound in the title (44 mg) was obtained by a method analogous to the method used in example 7 using 4-nitrobenzyl-5R,6S-(1R-hydroxyethyl)-3-(4-nitrophenyl)-7-oxo-4 -thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (100 mg), 10% palladium-on-carbon (100 mg), potassium bicarbonate (21.2 mg), water (5 ml) and dioxane (5 ml).

(D20) 1,33 (3H, d, J=6,3Hz), 3,93 (1H, dd, J=l,4og 5,3Hz), 4,23 (1H, m), 5,70 (1H, d, J=l,4Hz), 6,80, 7,30 (4H, AA'BB', J=8,4Hz). (D20) 1.33 (3H, d, J=6.3Hz), 3.93 (1H, dd, J=1.4and 5.3Hz), 4.23 (1H, m), 5.70 (1H , d, J=1.4Hz), 6.80, 7.30 (4H, AA'BB', J=8.4Hz).

Eksempel 80 Kalium- 5R- 3( 4- acetylaminofenyl)- 6S-( lR- hydroksyetyl)- 7- okso-4- tia- l- azabicyklor3, 2, Olhept- 2- en- 2- karboksylat Example 80 Potassium-5R-3(4-acetylaminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo3,2,Olhept-2-ene-2-carboxylate

En oppløsning av 4-ni trobenzyl-5R , 3-( 4-aminof enyl )-6S-( 1R-hydroksyetyl ) - 7-okso-4-t ia-1 - azabicyklo[3 ,2 , 0]hept-2-en-2-karboksylat (33 mg) i vann (0,5 ml) og dioksan (0,5 ml) ble behandlet ved 0°C med eddiksyreanhydrid (0,05 ml). Blandingen ble oppvarmet i 30 minutter til romtemperatur og omrørt i ytterligere en time. Lyof i 1 i sering ble etterfulgt av for-deling av det faste stoffet mellom etylacetat og vann, og lyof 11 iser ing av den vandige fasen ga forbindelsen i overskriften (29 mg) med egenskaper analoge egenskapene angitt i eksempel 67. A solution of 4-nitrobenzyl-5R,3-(4-aminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2- ene-2-carboxylate (33 mg) in water (0.5 mL) and dioxane (0.5 mL) was treated at 0°C with acetic anhydride (0.05 mL). The mixture was warmed for 30 minutes to room temperature and stirred for an additional hour. Lyophilization of the aqueous phase was followed by partitioning the solid between ethyl acetate and water, and lyophilization of the aqueous phase gave the title compound (29 mg) with properties analogous to those given in Example 67.

Eksempel 81 Example 81

2-( trimetylsilyl) etyl- kloroksoacetat 2-(trimethylsilyl)ethyl-chloroxoacetate

Til en omrørt oppløsning av oksalylklorid (12,7 g) i tørr dietyleter (25 ml) ved 00 c ble det dråpevis tilsatt 2-(trimetylsilyl)etanol (11,8 g). Blandingen ble omrørt i ytterligere 16 timer, og deretter destillert slik at man fikk forbindelsen i overskriften (19,9 g), kokepunkt 80°C/8 mm. To a stirred solution of oxalyl chloride (12.7 g) in dry diethyl ether (25 ml) at 00 C was added dropwise 2-(trimethylsilyl)ethanol (11.8 g). The mixture was stirred for a further 16 hours, and then distilled to give the title compound (19.9 g), bp 80°C/8 mm.

S (CDC13) 0,83 (9H, s), 1,16 (2H, m), 4,46 (2H, m). S (CDCl 3 ) 0.83 (9H, s), 1.16 (2H, m), 4.46 (2H, m).

Eksempel 82 Example 82

2-( trimetylsilyl ) etyl-( 3S- f IR-( dimetyl ( 2- metylprop- 2- yl )-silyloksy) etyl" l- 4R-( 4- nitrobenzoyltio) azetidin- 2- on- l-yl ) oksoacetat 2-(trimethylsilyl)ethyl-(3S-fIR-(dimethyl (2-methylprop-2-yl)-silyloxy)ethyl"l- 4R-(4-nitrobenzoylthio)azetidin-2-on-l-yl)oxoacetate

Forbindelsen i overskriften (8,0 g) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 17 ved anvendelse av 4-acetoksy-3S-{IR-[dimetyl(2-metylprop-2-yl )silyloksy] etyl)-azetidin-2-on (5,0 g), kalsiumkarbonat (5,0 g), 2-(trimetylsilyl)etylkloroksoacetat (3,35 ml), diklormetan (100 ml) og diisopropyletylamin (4,2 ml). The compound in the title (8.0 g) was obtained by a method analogous to the method used in example 17 using 4-acetoxy-3S-{IR-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl)-azetidine- 2-one (5.0 g), calcium carbonate (5.0 g), 2-(trimethylsilyl)ethylchloroxoacetate (3.35 ml), dichloromethane (100 ml) and diisopropylethylamine (4.2 ml).

S (CDCI3) 0,07 (9H, s), 0,12 (6H, s), 0,88 (9H, s), 1,11 S (CDCl 3 ) 0.07 (9H, s), 0.12 (6H, s), 0.88 (9H, s), 1.11

(2H, t, J=8,4Hz), 1,29 (3H, d, J=6,3Hz), 3,62 (1H, t, J=3,3Hz), 4,40 (3H, m), 6,18 (1H, d, J=3,3Hz), 8,11, 8,34 (4H, AA'BB', J=8,8Hz). (2H, t, J=8.4Hz), 1.29 (3H, d, J=6.3Hz), 3.62 (1H, t, J=3.3Hz), 4.40 (3H, m) , 6.18 (1H, d, J=3.3Hz), 8.11, 8.34 (4H, AA'BB', J=8.8Hz).

Eksempel 83 Example 83

2-( tr i me tyl silvl) etyl- 5R. 6S-( IR- fdimetyl( 2- metvlprop- 2-yl) silyloksy1etyl)- 3-( 4- nitrofenyl )- 7- okso- 4- tia- l- azabicyklo[ 3, 2, 0] hept- 2- en- 2- karboksylat 2-(trimethylsilyl)ethyl- 5R. 6S-(IR-fdimethyl(2-methylprop-2-yl)silyloxy1ethyl)-3-(4-nitrophenyl)-7-oxo-4- thia-1-azabicyclo[3,2,0]hept-2-ene- 2- carboxylate

Forbindelsen i overskriften (2,86 g) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 18 ved anvendelse av 2-(trimetylsilyl )etyl-(3S-[lR-(dimetyl(2-metylprop-2-yl )silyloksy)etyl] - 4R-( 4-ni trobenzoyl tio ) - azet idin-2-on-l-yl )oksoacetat (8,0 g), trietylf osf i tt (4,2 ml, o-xylen (100 ml) og hydrokinon (10 mg). The compound in the title (2.86 g) was obtained by a method analogous to the method used in example 18 using 2-(trimethylsilyl)ethyl-(3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl ] - 4R-(4-nitrobenzoylthio)-azetidin-2-on-l-yl)oxoacetate (8.0 g), triethyl phosphate (4.2 ml, o-xylene (100 ml) and hydroquinone (10mg).

vmaks (film) 1796, 1711 cm-<1>vmax (film) 1796, 1711 cm-<1>

S (CDCI3) 0,01 (9H, s), 0,11 (3H, s), 0,12 (3H, s), 0,91 S (CDCl 3 ) 0.01 (9H, s), 0.11 (3H, s), 0.12 (3H, s), 0.91

(11H, m), 1,28 (3H, d, J=6,3Hz), 3,82 (1H, dd, J-1,6 og 4,6Hz), 4,18 (2H, m), 4,29 (1H, m), 5,76 (1H, d, J = l,6Hz), 7,64, 8,23 (4H, AA 'BB' , J=8,9Hz). (11H, m), 1.28 (3H, d, J=6.3Hz), 3.82 (1H, dd, J-1.6 and 4.6Hz), 4.18 (2H, m), 4 .29 (1H, m), 5.76 (1H, d, J = 1.6Hz), 7.64, 8.23 (4H, AA 'BB' , J=8.9Hz).

Eksempel 84 Example 84

2-( trimetylsilyl) etvl- 5R. 6S-( lR- hydroksyetyl)- 3-( 4- nitrofenyl)- 7- okso- 4- tia- l- azabicyklor3, 2, 0lhept- 2- en- 2- karboksylat 2-(trimethylsilyl)ethyl-5R. 6S-(1R-hydroxyethyl)-3-(4-nitrophenyl)-7-oxo-4-thia-1-azabicyclo3,2,0lhept-2-ene-2-carboxylate

Forbindelsen i overskriften (142 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 19 ved anvendelse av 2-(trimetylsilyl)etyl-5R,6S-(lR-[dimetyl(2-metylprop-2-yl)silyloksy]etyl)-3-(4-nitrofenyl)-7-okso-4-tia-1- azabicyklo[3,2,0]hept-2-en-2-karboksylat (360 mg), iseddiksyre (0,4 ml, tetrahydrofuran (10 ml) og IM tetra-n-butylammoniumfluorid i tetrahydrofuran (2 ml). The compound in the title (142 mg) was obtained by a method analogous to the method used in example 19 using 2-(trimethylsilyl)ethyl-5R,6S-(1R-[dimethyl(2-methylprop-2-yl)silyloxy]ethyl) -3-(4-nitrophenyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (360 mg), glacial acetic acid (0.4 ml, tetrahydrofuran ( 10 ml) and 1M tetra-n-butylammonium fluoride in tetrahydrofuran (2 ml).

vmaks(CDCI3) 1789, 1710 cm-<1>vmax(CDCI3) 1789, 1710 cm-<1>

§ (CDCI3) 0,01 (9H, s), 0,92 (2H, m), 1,40 (3H, d, § (CDCl3) 0.01 (9H, s), 0.92 (2H, m), 1.40 (3H, d,

J = 6,3Hz), 3,86 (1H, dd, J-1,6 og 6 ,.6Hz) , 4,20 (2H, m), 4,30 (1H, m), 5,79 (1H, d, J=l,6Hz), 7,63, 8,24 (4H, AA'BB', J=8,9Hz). J = 6.3Hz), 3.86 (1H, dd, J-1.6 and 6.6Hz), 4.20 (2H, m), 4.30 (1H, m), 5.79 (1H , d, J=1.6Hz), 7.63, 8.24 (4H, AA'BB', J=8.9Hz).

Eksempel 85 Example 85

2- ( trimetylsilyl) etyl- 5R. 6S-( lR- hvdroksvetvl)- 3-( 4- hydroksy-aminof enyl )- 7- okso- 4- tia- l- azabicyklor3. 2. 0] hept- 2- en- 2- karboksylat 2-(trimethylsilyl)ethyl- 5R. 6S-(1R-hydroxymethyl)-3-(4-hydroxyaminophenyl)-7-oxo-4-thia-1-azabicyclo3. 2. 0] hept-2-ene-2-carboxylate

En blanding av 2-(trimetylsilyl)etyl-5R,6S-(lR-hydroksyetyl)-3- (4-nitrofenyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (2,1 g) ,. 10$ pal ladium-på-trekull (2,1 g) og dioksan (50 ml) ble hydrogenert ved 375 kPa (4 atm.) i 2 timer, ble filtrert gjennom diatomejord og inndampet i vakuum. Kromatografi av resten over silikagel og eluering med etylacetat-heksanblandinger ga forbindelsen i overskriften (1,5 g). A mixture of 2-(trimethylsilyl)ethyl-5R,6S-(1R-hydroxyethyl)-3-(4-nitrophenyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2- ene-2-carboxylate (2.1 g) ,. 10$ palladium-on-charcoal (2.1 g) and dioxane (50 mL) were hydrogenated at 375 kPa (4 atm.) for 2 hours, filtered through diatomaceous earth and evaporated in vacuo. Chromatography of the residue over silica gel and eluting with ethyl acetate-hexane mixtures gave the title compound (1.5 g).

S (aceton-d6) 0,02 (9H, s), 0,95 (2H, m), 1,31 (3H, d, S (acetone-d6) 0.02 (9H, s), 0.95 (2H, m), 1.31 (3H, d,

J = 6,3Hz), 3,76 (1H, dd, J = l , 5 og 7, 0Hz), 4,17 (3H, m), 4,42 (1H, d, J=4, 9Hz) , 5,69 (1H, d, J=l,5Hz), 6,95 og 7,43 (4H, AA'BB', J=8,6Hz), 7,90 (1H, bred), 8,15 (1H, bred). J = 6.3Hz), 3.76 (1H, dd, J = l , 5 and 7, 0Hz), 4.17 (3H, m), 4.42 (1H, d, J=4, 9Hz) , 5.69 (1H, d, J=1.5Hz), 6.95 and 7.43 (4H, AA'BB', J=8.6Hz), 7.90 (1H, wide), 8.15 ( 1H, wide).

Eksempel 86 Example 86

2-( trimetylsilyl ) etyl- 5R . 3-( 4- aminof enyl )- 6S-( lR- hvdroksvetyl)- 7- okso- 4- tia- l- azabicyklor3. 2, Olhept- 2- en- 2- karboksylat En blanding av 2-(trimetylsilyl)etyl-5R,6S-(lR-hydroksyetyl)-3 - ( 4 -hydroksyaminof enyl ) -7-okso-4-t ia-l-azabicyklo[3 , 2,0]-hept-2-en-2-karboksylat (1,4 g), platinadioksyd (500 mg) og tørr etylacetat (30 ml) ble hydrogenert ved 375 kPa (4 atm.) ved 20°C og deretter filtrert og inndampet i vakuum. Kromatografi av resten over silikagel og eluering med etylacetat-heksanblandinger ga forbindelsen i overskriften (1,06 g). 2-(trimethylsilyl)ethyl-5R. 3-(4-aminophenyl)-6S-(1R-hydroxymethyl)-7-oxo-4-thia-1-azabicyclo3. 2, Olhept-2-ene-2-carboxylate A mixture of 2-(trimethylsilyl)ethyl-5R,6S-(1R-hydroxyethyl)-3-(4-hydroxyaminophenyl)-7-oxo-4-thia-1 -azabicyclo[3,2,0]-hept-2-ene-2-carboxylate (1.4 g), platinum dioxide (500 mg) and dry ethyl acetate (30 mL) were hydrogenated at 375 kPa (4 atm.) at 20 °C and then filtered and evaporated in vacuo. Chromatography of the residue over silica gel and eluting with ethyl acetate-hexane mixtures gave the title compound (1.06 g).

<v>maks (Kbr) 1780, 1706 cm-<1><v>max (Kbr) 1780, 1706 cm-<1>

S (aceton-d6) 0,01 (9H, s), 0,96 (2H, m), 1,29 (3H, d, S (acetone-d6) 0.01 (9H, s), 0.96 (2H, m), 1.29 (3H, d,

J = 6,3Hz), 3,70 (1H, dd, J = l,5 og 7, 1Hz), 4,15 (3H, m), 5,20 (1H, bred), 5,60 (1H, d, J=l,5Hz), 6,63 og 7,33 (4H, AA'BB', J=8,8H-z). J = 6.3Hz), 3.70 (1H, dd, J = 1.5 and 7, 1Hz), 4.15 (3H, m), 5.20 (1H, wide), 5.60 (1H, d, J=1.5Hz), 6.63 and 7.33 (4H, AA'BB', J=8.8H-z).

Eksempel 87 Example 87

2-( trimetylsilyl) etyl- 5R. 3-( 4- formylaminofenyl)- 6S-( lR-hydroksyetyl )- 7- okso- 4- t ia- l- azabicyklofS , 2 . 0] hept- 2- en- 2-karboksylat 2-(trimethylsilyl)ethyl- 5R. 3-(4-formylaminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclofS, 2. 0] hept-2-ene-2-carboxylate

Til en omrørt oppløsning av 2-( trimetylsilyl )etyl-5R,3-(4-aminof enyl)-6S-(lR-hydroksyetyl)-7-okso-4-tia-l-azabicyklo[-3,2,0]hept-2-en-2-karboksylat (200 mg) i deuterokloroform (5 ml) ved 0°C ble det tilsatt maursyre (22,3 pl) etterfulgt av 1-( 3-dimetylaminopropyl )-3-etylkarbodiimidhydroklorid (113 mg). Blandingen ble omrørt i ytterligere 15 minutter, og ble deretter fordelt mellom vann og kloroform. Det organiske laget ble vasket med IM sitronsyre, med vann, med mettet vandig natriumbikarbonat, med saltvannsoppløsning, ble tørket over vannfritt natriumsulfat og ble inndampet i vakuum. Kromatografi av resten over silikagel og eluering med etylacetat-heksanblandinger ga forbindelsen i overskriften (162 mg). To a stirred solution of 2-(trimethylsilyl)ethyl-5R,3-(4-aminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[-3,2,0] hept-2-ene-2-carboxylate (200 mg) in deuterochloroform (5 ml) at 0°C was added formic acid (22.3 µl) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113 mg) . The mixture was stirred for an additional 15 minutes, then partitioned between water and chloroform. The organic layer was washed with 1M citric acid, with water, with saturated aqueous sodium bicarbonate, with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. Chromatography of the residue over silica gel and eluting with ethyl acetate-hexane mixtures gave the title compound (162 mg).

<v>maks (KBr) 1774, 1702 og 1623 cm-<1><v>max (KBr) 1774, 1702 and 1623 cm-<1>

S (DMS0-d6) 0,01 (9H, s), 0,84 (2H, m), 1,18 (3H, d, S (DMS0-d6) 0.01 (9H, s), 0.84 (2H, m), 1.18 (3H, d,

J=6,3Hz), 3,85 (1H, dd, J=l,5 og 6,3Hz), 4,00 (1H, m), 4,10 (2H, m), 5,23 (1H, d, J=4,8Hz), 5,71 (1H, d, J = l,5Hz), 7,42 og 7,61 (4H, AA'BB', J=8,5Hz), 8,31 (1H, s), 10,31 (1H, bred). J=6.3Hz), 3.85 (1H, dd, J=1.5 and 6.3Hz), 4.00 (1H, m), 4.10 (2H, m), 5.23 (1H, d, J=4.8Hz), 5.71 (1H, d, J = 1.5Hz), 7.42 and 7.61 (4H, AA'BB', J=8.5Hz), 8.31 ( 1H, s), 10.31 (1H, wide).

Eksempel 88 Example 88

Kalium- 5R. 3-( 4- formylaminofenyl)- 6S-( lR- hydroksyetyl)- 7- okso-4- tia- l- azabicyklor3. 2, 0] hept- 2- en- 2- karboksylat Potassium- 5R. 3-(4-formylaminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo3. 2.0] hept-2-ene-2-carboxylate

Til en omrørt oppløsning av 2-( trimetylsilyl )etyl-5R,3-(4-f ormylaminof enyl)-6S-(lR-hydroksyetyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (80 mg) i tetrahydrofuran (3 ml) ved 0°C ble det tilsatt en oppløsning av IM tetra-n-butylammoniumfluorid i tetrahydrofuran (0,184 ml) som var tørket over 4Å molekylarsikter. Etter 16 timer ble blandingen behandlet med en vandig oppløsning av kaliumbikarbonat (18,4 mg). Den vandige oppløsningen ble vasket med etylacetat, og deretter lyofilisert slik at man fikk et råprodukt (110 mg). Rensing enten ved kromatografi over "HP20A"-harpiks eller ved surgjøring/nøytralisering eller preparativ høytrykksreversert fasekromatografi (C^g-silikagel) og eluering med vann-acetonitril-maursyreblandinger ga, etter lyofilisering og fornyet nøytral i sas j on med kal iumbikarbonat, forbindelsen i overskriften (50 mg). To a stirred solution of 2-(trimethylsilyl)ethyl-5R,3-(4-formylaminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0] hept-2-ene-2-carboxylate (80 mg) in tetrahydrofuran (3 ml) at 0°C was added a solution of 1M tetra-n-butylammonium fluoride in tetrahydrofuran (0.184 ml) which had been dried over 4Å molecular sieves. After 16 hours, the mixture was treated with an aqueous solution of potassium bicarbonate (18.4 mg). The aqueous solution was washed with ethyl acetate, and then lyophilized to give a crude product (110 mg). Purification either by chromatography over "HP20A" resin or by acidification/neutralization or preparative high pressure reversed phase chromatography (C^g silica gel) and elution with water-acetonitrile-formic acid mixtures gave, after lyophilization and renewed neutralization with potassium bicarbonate, the compound in the title (50 mg).

S (D20) 1,35 ( 3H, d, J = 6,3Hz), 3,95 (1H, dd, J = l , 5 og 5,5Hz), 4,25 (1H, m), 5,75 (1H, d, J=l,5Hz), 7,43 og 7,49 (4H, AA'BB', J=8,9Hz), 8,25 (1H, bs). S (D20) 1.35 (3H, d, J = 6.3Hz), 3.95 (1H, dd, J = l , 5 and 5.5Hz), 4.25 (1H, m), 5.75 (1H, d, J=1.5Hz), 7.43 and 7.49 (4H, AA'BB', J=8.9Hz), 8.25 (1H, bs).

Eksempel 89 Example 89

2-( trimetylsilyl ) etvl - 5R . 6S-( lR- hydroksyetyl )- 3-( 4- l"( metvl-amino ) karbonylaminoi f enyl ) 7- okso- 4- tia- l- azabicyklor3 . 2. Ol - hept- 2- en- 2- karboksylat 2-(trimethylsilyl)ethyl-5R. 6S-(1R-hydroxyethyl)-3-(4-1"(methylamino)carbonylaminoiphenyl)7-oxo-4-thia-1-azabicyclo3. 2. Ol-hept-2-ene-2-carboxylate

En blanding av 2-(trimetylsilyl)etyl-5R,3-(4-aminofenyl)-6S-(IR-hydroksyetyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat ( 200 mg), tørr tetrahydrofuran (5 ml) og metyl i socyanat (0,3 ml) ble omrørt ved romtemperatur i 16 timer, og deretter fordelt mellom etylacetat og vann. Det organiske laget ble vasket med vann og med saltvannsopp-løsning, ble tørket over vannfritt natriumsulfat og inndampet i vakuum. Kromatografi av resten over silikagel og eluering med etylacetat-heksanblandinger ga forbindelsen i overskriften (86~mg). A mixture of 2-(trimethylsilyl)ethyl-5R,3-(4-aminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2- ene-2-carboxylate (200 mg), dry tetrahydrofuran (5 ml) and methyl in cyanate (0.3 ml) were stirred at room temperature for 16 hours, and then partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. Chromatography of the residue over silica gel and eluting with ethyl acetate-hexane mixtures gave the title compound (86~mg).

vmaks (film) 1785 cm-<1>vmax (film) 1785 cm-<1>

S (aceton-d6) 0,01 (6H, s), 0,93 (2H, m), 1,29 (3H, d, S (acetone-d6) 0.01 (6H, s), 0.93 (2H, m), 1.29 (3H, d,

J=6,3Hz), 2,73 (3H, d, J=4,6Hz), 3,77 (1H, dd, J-1,6 og 6,9Hz), 4,15 (3H, m), 4,37 (1H, d, J=5,0Hz), 5,70 (1H, d, J=l,6Hz), 5,78 (1H, bred), 7,41 og 7,52 (4H, AA'BB' , J=8,8Hz), 8,21 (1H, bred). J=6.3Hz), 2.73 (3H, d, J=4.6Hz), 3.77 (1H, dd, J-1.6 and 6.9Hz), 4.15 (3H, m), 4.37 (1H, d, J=5.0Hz), 5.70 (1H, d, J=1.6Hz), 5.78 (1H, wide), 7.41 and 7.52 (4H, AA 'BB' , J=8.8Hz), 8.21 (1H, wide).

Eksempel 90 Example 90

Kal ium- 5R . 6S-( IR- hyd r oksyetyl )- 3-{ 4- f ( metyl amino ) karbonyl-aminol f enyl )- 7- okso- 4- tia- l- azabicyklor3. 2, 01 hept- 2- en- 2-karboksylat Kal ium- 5R . 6S-(IR-hydroxyethyl)-3-{4-f (methylamino)carbonyl-aminolphenyl)-7-oxo-4-thia-l-azabicyclo3. 2.01 hept-2-ene-2-carboxylate

Forbindelsen i overskriften (55 mg) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 88 ved anvendelse av 2-( trimetylsilyl )etyl-5R ,.6S-( lR-hydroksyetyl )-3-( 4-[(metylamino)karbonylamino]fenyl)-7-okso-4-tia-1-azabicyklo[3 ,2 , 0]hept-2-en-2-karboksylat (80 mg), en tørket oppløsning av IM tetra-n-butylammoniumfluorid i tetrahydrofuran (0,17 ml), tetrahydrofuran (5 ml) og kaliumbikarbonat (17,3 mg). The compound in the title (55 mg) was obtained by a method analogous to the method used in example 88 using 2-(trimethylsilyl)ethyl-5R,6S-(1R-hydroxyethyl)-3-(4-[(methylamino)carbonylamino] phenyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (80 mg), a dried solution of 1M tetra-n-butylammonium fluoride in tetrahydrofuran (0, 17 ml), tetrahydrofuran (5 ml) and potassium bicarbonate (17.3 mg).

S (D20) 1,3 (3H, d, J=6,3Hz), 2,71 (3H, s), 3,91 (1H, dd, S (D20) 1.3 (3H, d, J=6.3Hz), 2.71 (3H, s), 3.91 (1H, dd,

J-1,5 og 5,8Hz), 4,23 (1H, m), 5,70 (1H, d, J=l,5Hz), 7,26 og 7,36 (4H, AA'BB', J=8,7Hz). J-1.5 and 5.8Hz), 4.23 (1H, m), 5.70 (1H, d, J=1.5Hz), 7.26 and 7.36 (4H, AA'BB', J=8.7Hz).

Eksempel 91 Example 91

4- nitrobenzyl- 5R , 3- ( 3- karboksyfenyl )- 6S- < lR- fdimetyl ( 2- metylprop- 2- yl ) silyloksyletyl ) 7- okso- 4- t ia- l- azabicyklof3 , 2, Ol - hept- 2- en- 2- karboksylat 4- nitrobenzyl- 5R , 3- ( 3- carboxyphenyl )- 6S- < 1R- fdimethyl ( 2- methylprop- 2- yl ) silyloxyethyl ) 7- oxo- 4- thia- l- azabicyclof 3 , 2, Ol - hept- 2- en- 2- carboxylate

Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 29, men med utgangspunkt i en oppløsning av isoftaloylklorid (10,15 g) i dioksan (150 ml), en oppløsning av 2,4-dimetoksybenzylalkohol (10,09 g) i dioksan (20 ml), trietylamin (8,35 ml), diklormetan (100 ml), pyridin (4,85 ml) og hydrogensulfid (overskudd) fikk man In a method analogous to the method used in example 29, but starting from a solution of isophthaloyl chloride (10.15 g) in dioxane (150 ml), a solution of 2,4-dimethoxybenzyl alcohol (10.09 g) in dioxane (20 ml) ), triethylamine (8.35 ml), dichloromethane (100 ml), pyridine (4.85 ml) and hydrogen sulphide (excess) gave

3-( 2, 4- dimetoksybenzyloksykarbonyl) tiobenzosyre (11,6 g):<v>maks 2550, 1721, 1675 og 1615 cm"<1>3-(2,4-dimethoxybenzyloxycarbonyl)thiobenzoic acid (11.6 g):<v>max 2550, 1721, 1675 and 1615 cm"<1>

§ (aceton-d6) 3,72 (3H, s), 3,77 (3H, s), 5,26 (2H, s), § (acetone-d6) 3.72 (3H, s), 3.77 (3H, s), 5.26 (2H, s),

6,44 (1H, dd, J=2,4 og 8,3Hz), 6,50 (1H, d, J=2,3Hz), 7,28 (1H, d, J=8,3Hz), 7,60 (1H, m), 8,16 (2H, m), 8,53 (1H, m). 6.44 (1H, dd, J=2.4 and 8.3Hz), 6.50 (1H, d, J=2.3Hz), 7.28 (1H, d, J=8.3Hz), 7 .60 (1H, m), 8.16 (2H, m), 8.53 (1H, m).

En oppløsning av denne tiobenzosyren (10,9 g) i aceton (70 ml) ble behandlet ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 30 med IM natriumhydroksyd (43 ml) og en oppløsning av 4-acetoksy-3R-(IR-[dimetyl(2-mety1-prop-2-yl)silyloksy]etyl>-azetidin-2-on (7,85 g) i aceton-vann (3:1) A solution of this thiobenzoic acid (10.9 g) in acetone (70 ml) was treated by a method analogous to the method used in Example 30 with 1M sodium hydroxide (43 ml) and a solution of 4-acetoxy-3R-(IR-[dimethyl (2-methyl-prop-2-yl)silyloxy]ethyl>-azetidin-2-one (7.85 g) in acetone-water (3:1)

(100 ml) slik at man fikk (100 ml) so that one got

4R- f 3 - ( 2 , 4- dimetoksybenzyloksykarbonyl ) benzoyltiol - 3S-( 1R-rdimetyl( 2- metylprop- 2- yl) silyloksyletyl) azetidin- 2- on (7,66 4R- f 3 - ( 2 , 4- dimethoxybenzyloxycarbonyl ) benzoylthiol - 3S-( 1R-rdimethyl( 2- methylprop- 2- yl) silyloxyethyl) azetidin- 2- one (7.66

g)<:>g)<:>

<v>maks (CDC13) 3418, 1772, 1719 cm"<1><v>max (CDC13) 3418, 1772, 1719 cm"<1>

S (CDCI3) 0,07 (6H, s), 0,86 ( 9H, s), 1,22 (3H, d, S (CDCl 3 ) 0.07 (6H, s), 0.86 ( 9H, s), 1.22 (3H, d,

J=6,3Hz), 3,27 (1H, dd, J=2,5og 4Hz), 3,80 (3H, s), 3,81 (3H, s), 4,29 (3H, m), 5,34 (2H, s), 5,46 (1H, d, J=2,5Hz), 6,47 (2H, m), 6,54 (1H, s), 7,30 (1H, d, J=8,9Hz), 7,51 (1H, t, J=7,8H-z), 8,05 (1H, ddd, J=l,4og 7,8Hz), 8,25 (1H, dd, J=l,4 og 7,8Hz), 8,54 (1H, t, J=l,4Hz). J=6.3Hz), 3.27 (1H, dd, J=2.5and 4Hz), 3.80 (3H, s), 3.81 (3H, s), 4.29 (3H, m), 5.34 (2H, s), 5.46 (1H, d, J=2.5Hz), 6.47 (2H, m), 6.54 (1H, s), 7.30 (1H, d, J=8.9Hz), 7.51 (1H, t, J=7.8H-z), 8.05 (1H, ddd, J=1.4and 7.8Hz), 8.25 (1H, dd, J=1.4 and 7.8Hz), 8.54 (1H, t, J=1.4Hz).

En oppløsning av dette azetidinonet (2,8 g) i diklormetan (20 ml) ble behandlet ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 31 med kalsiumkarbonat (1,25 g), diisopropyletylamin (0,97 g) og en oppløsning av 4-nitrobenzyl-kloroksalat (1,46 g) i diklormetan (5 ml) slik at man, i form av et gult skum, fikk A solution of this azetidinone (2.8 g) in dichloromethane (20 ml) was treated by a method analogous to the method used in example 31 with calcium carbonate (1.25 g), diisopropylethylamine (0.97 g) and a solution of 4- nitrobenzyl chlorooxalate (1.46 g) in dichloromethane (5 ml) to give, in the form of a yellow foam,

4- nitrobenzyl- 4R- r3-( 2, 4- dimetoksybenzyloksykarbonyl) benzoyltio~|- 3S-{ IR- f dimetyl ( 2- metylprop- 2- yl ) silyloksyl etyl ) azetidin- 2- on- l- ylloksoacetat (3,8 g). 4- nitrobenzyl- 4R- r3-( 2, 4- dimethoxybenzyloxycarbonyl) benzoylthio~|- 3S-{ IR- f dimethyl ( 2- methylprop- 2- yl ) silyloxyl ethyl ) azetidin- 2- on- l-ylloxoacetate (3, 8g).

vmaks (film) 1818, 1761 og 1720 cm-<1>vmax (film) 1818, 1761 and 1720 cm-<1>

S (CDC13) 0,01 (3H, s), 0,09 (3H, s), 0,83 (9H, s), 1,26 S (CDCl 3 ) 0.01 (3H, s), 0.09 (3H, s), 0.83 (9H, s), 1.26

(3H, d, J=6,3Hz), 3,64 (1H, t, J=3Hz), 3,82 (3H, s), 3,83 (3H, s), 4,40 (1H, m), 5,36 (2H, s), 5,40 (2H, s), 6,19 (1H, d, J=3,4Hz), 6,50 (1H, m), 7,32 (1H, d, J=8,9Hz), 7,55 (3H, m), 8,09 (1H, d, J=7,9Hz), 8,21 (2H, d, J=8,8Hz), 8,29 (1H, d, J=7,9Hz), 8,57 (1H, d, J=l,7Hz). (3H, d, J=6.3Hz), 3.64 (1H, t, J=3Hz), 3.82 (3H, s), 3.83 (3H, s), 4.40 (1H, m ), 5.36 (2H, s), 5.40 (2H, s), 6.19 (1H, d, J=3.4Hz), 6.50 (1H, m), 7.32 (1H, d, J=8.9Hz), 7.55 (3H, m), 8.09 (1H, d, J=7.9Hz), 8.21 (2H, d, J=8.8Hz), 8, 29 (1H, d, J=7.9Hz), 8.57 (1H, d, J=1.7Hz).

En oppløsning av dette skummet (3,8 g) i xylen (100 ml) ble behandlet ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 32 med en oppløsning av trietylfosfitt (1,66 g) i xylen (10 ml) slik at man fikk A solution of this foam (3.8 g) in xylene (100 ml) was treated by a method analogous to the method used in example 32 with a solution of triethyl phosphite (1.66 g) in xylene (10 ml) so that one obtained

4- ni t robenzyl- 5R. 3- f3-( 2, 4- dimetoksybenzyloksykarbonyl)-fenyll- 6S-( IR- fdimetyl( 2- metylprop- 2- yl) silyloksyletyl) 7-okso- 4- tia- l- azabicyklor3. 2. Ol hept- 2- en- 2- karboksyl at (1,84 4- nitrobenzyl- 5R. 3- f3-(2, 4-dimethoxybenzyloxycarbonyl)-phenyl-6S-(IR-fdimethyl(2-methylprop-2-yl)silyloxyethyl)7-oxo-4-thi-1-azabicyclo3. 2. Ol hept-2-ene-2-carboxyl at (1.84

g)<:>g)<:>

<v>maks (CDCI3) 1790 og 1721 cm"<1><v>max (CDCI3) 1790 and 1721 cm"<1>

5 (CDCI3) 0,07 (3H, s), 0,08 (3H, s), 0,85 (9H, s), 3,82 (3H, s+m), 4,30 (1H, m), 5,08, 5,25 (2H, AB, Jgem=13'7Hz)>5, 32 (2H, s), 5,74 (1H, d, δ (CDCl 3 ) 0.07 (3H, s), 0.08 (3H, s), 0.85 (9H, s), 3.82 (3H, s+m), 4.30 (1H, m), 5.08, 5.25 (2H, AB, Jgem=13'7Hz)>5.32 (2H, s), 5.74 (1H , d,

J=l,5Hz), 6,48 (2H, m), 7,31 (1H, d, J=8,9Hz), 7,40 (3H, m), 7,59 (1H, m), 8,08 (4H, m). J=1.5Hz), 6.48 (2H, m), 7.31 (1H, d, J=8.9Hz), 7.40 (3H, m), 7.59 (1H, m), 8 .08 (4H, m).

En oppløsning av dette 4-nitrobenzylkarboksylatet (1,84 g) i diklormetan (100 ml) ble behandlet ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 33 med vann (1 ml) og 2,3-diklor-5,6-dicyano-l,4-benzokinon (DDQ) (1,14 g) slik at man fikk 3-karboksyfenyl-forbindelsen i overskriften (0,98 A solution of this 4-nitrobenzylcarboxylate (1.84 g) in dichloromethane (100 ml) was treated by a method analogous to the method used in Example 33 with water (1 ml) and 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone (DDQ) (1.14 g) to give the 3-carboxyphenyl compound in the title (0.98

g)<:>g)<:>

S (CDC13) 0,07 (3H, s), 0,09 (3H, s), 0,86 (9H, s), 1,28 S (CDCl 3 ) 0.07 (3H, s), 0.09 (3H, s), 0.86 (9H, s), 1.28

og 1,29 (3H, 2xd, J=6,3Hz), 3,83 (1H, dd, J-1,6 og 4Hz), 4,31 (1H, m), 5,12, 5,28 ( 2H, AB, Jgem=13,6Hz), 5,77 (1H, d, J-l, 5Hz) , 7,46 (3H, m), 7,70 (lH, m), 8,15 (4H, m). and 1.29 (3H, 2xd, J=6.3Hz), 3.83 (1H, dd, J-1.6 and 4Hz), 4.31 (1H, m), 5.12, 5.28 ( 2H, AB, Jgem=13.6Hz), 5.77 (1H, d, J-l, 5Hz) , 7.46 (3H, m), 7.70 (lH, m), 8.15 (4H, m) .

Eksempel 92 Example 92

4- ni t robenzyl- 5R. 3- f3-( 2. 4- dimetoksybenzyloksykarbonyl)-fenyl1- 6S-( lR- hydroksvetvl)- 7- okso- 4- tia- l- azabicvklor3. 2. Ol - hept- 2- en- 2- karboksylat 4- nitrobenzyl- 5R. 3- f3-(2.4- dimethoxybenzyloxycarbonyl)-phenyl1- 6S-(1R- hydroxymethyl)-7- oxo-4- thia-1- azabicchloro3. 2. Ol - hept-2-ene-2-carboxylate

Forbindelsen i overskriften (6,6 g) ble fremstilt ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 37 ved anvendelse av 4-nitrobenzyl-5R,3-[3-(2,4-dimetoksybenzyloksykarbonyl )f enyl] -6S-( IR-[dimetyl ( 2-metylprop-2-yl )silyloksy]etyl)7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (8,0 g), iseddiksyre (6,5 g) og en IM oppløsning av tetra-n-butylammoniumfluorid i tetrahydrofuran (32,6 ml). The compound in the title (6.6 g) was prepared by a method analogous to the method used in example 37 using 4-nitrobenzyl-5R,3-[3-(2,4-dimethoxybenzyloxycarbonyl)phenyl]-6S-(IR- [dimethyl ( 2-methylprop-2-yl )silyloxy]ethyl)7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (8.0 g), glacial acetic acid (6.5 g) and an IM solution of tetra-n-butylammonium fluoride in tetrahydrofuran (32.6 ml).

S (CDCI3) 1,31 (3H, d, J=6Hz), 3,75 (6H, s), 3,80 (1H dd, S (CDCl3) 1.31 (3H, d, J=6Hz), 3.75 (6H, s), 3.80 (1H dd,

J-l,2 og 6,5Hz), 4,03 (1H, m), 5,00, 5,17 (2H, AB, Jgem=13,6Hz), 5,25 (2H, s), 5,69 (1H, d, J=l,2Hz), 6,42 (2H, m), 7,2-7,5 (5H, m), 7,9-8,2 (4H, m). J-l.2 and 6.5Hz), 4.03 (1H, m), 5.00, 5.17 (2H, AB, Jgem=13.6Hz), 5.25 (2H, s), 5.69 ( 1H, d, J=1.2Hz), 6.42 (2H, m), 7.2-7.5 (5H, m), 7.9-8.2 (4H, m).

Eksempel 93 Example 93

4- nit r obenzyl- 5R, 3-( 3- karboksyfenyl)- 6S-( lR- hvdroksyetyl)- 7-okso- 4- tia- l- azabicyklo[ 3. 2. Olhept- 2- en- 2- karboksylat 4- nitrobenzyl- 5R, 3-( 3- carboxyphenyl)- 6S-( 1R- hydroxyethyl)- 7-oxo- 4- thia- l- azabicyclo[ 3. 2. Olhept- 2- en- 2- carboxylate

Forbindelsen i overskriften (1,39 g) ble oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 40 ved anvendelse av 4-nitrobenzyl-5R,3-[3-(2,4-dimetoksybenzyloksykarbonyl )fenyl]-6S-(IR-hydroksyetyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (6,2 g), diklormetan (200 ml), vann (10 ml) og DDQ (4,54 g): S (aceton-d6) 1,20 (3H, d, J=6,3Hz), 3,84 (1H, dd, J-l ,7 og 6,4 Hz), 4,10 (1H, m), 5,06, 5,19 (2H, AB, Jgem=13,8Hz), 5,79 (1H, d, J=l,7Hz), 7,35-7,45 (3H, m), 7,61 (1H, dd, J=7,8 og~l,4Hz), 7,90-8,06 (4H, m). The compound in the title (1.39 g) was obtained by a method analogous to the method used in example 40 using 4-nitrobenzyl-5R,3-[3-(2,4-dimethoxybenzyloxycarbonyl)phenyl]-6S-(1R-hydroxyethyl) )-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (6.2 g), dichloromethane (200 mL), water (10 mL) and DDQ ( 4.54 g): S (acetone-d6) 1.20 (3H, d, J=6.3Hz), 3.84 (1H, dd, J-l .7 and 6.4 Hz), 4.10 (1H, m), 5.06, 5.19 (2H, AB, Jgem=13.8Hz), 5.79 (1H, d, J=1.7Hz), 7.35-7.45 (3H, m), 7.61 (1H, dd, J=7.8 and~1.4Hz), 7.90-8.06 (4H, m).

Eksempel 94 Example 94

4- nitrobenzyl- 5R, 3-( 3- aminokarbonylfenyl)- 6S-( IR-[ dimetyl-( 2-me tyl pr op- 2- yl ) s i lyll oksyetyl - 7- okso- 4 - t ia- 1 - azabicyklo ["-3. 2. 0] hept- 2- en- 2- karboksylat 4- nitrobenzyl- 5R, 3-( 3- aminocarbonylphenyl)- 6S-( IR-[ dimethyl-( 2-methyl prop- 2- yl) silyl oxyethyl- 7- oxo- 4- thia- 1- azabicyclo ["-3. 2. 0] hept- 2- en- 2- carboxylate

Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 34, men ved anvendelse av 4-nitrobenzyl-5R, 3-( 2-karboksyf enyl)-6S-(IR-[dimetyl-(2-metylprop-2-yl)silyloksy]-etyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (786 mg), HOBT (365 mg), acetonitril (840 .ml), tetrahydrofuran (4 ml), 1-( 3-dimetylaminopropyl )-3-etylkarbodiimidhydroklorid (389 mg) og en oppløsning av ammoniakk i etanol (36 g/l, 2ml) ble forbindelsen i overskriften oppnådd: § (aceton-d6) 0,08 (3H, s), 0,10 (3H, s), 0,93 (9H, s), In a method analogous to the method used in example 34, but using 4-nitrobenzyl-5R, 3-(2-carboxyphenyl)-6S-(IR-[dimethyl-(2-methylprop-2-yl)silyloxy]-ethyl )-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (786 mg), HOBT (365 mg), acetonitrile (840 ml), tetrahydrofuran (4 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (389 mg) and a solution of ammonia in ethanol (36 g/l, 2 ml) the title compound was obtained: § (acetone-d6) 0.08 (3H , s), 0.10 (3H, s), 0.93 (9H, s),

1,28 (3H, d, J=6,3), 4,02 (1H, dd, J-l,7 og 3,6 Hz), 4,35 (1H, dq, J = 3,6 og 6 , 3Hz), 5,30, 5,15 (2H, AB, Jgem=13,9Hz), 5,87 (1H, d, J=l,7Hz), 6,92 (1H, bs), 7,47 (1H, t, J=7,8Hz), 7,54, 8,13 (4H, AA'BB', JAB=8,6H-z), 7,64 (1H, dt, J-l,4 og 7,8Hz), 8,00 (1H, dt, J-l,4 og 7,8Hz), 8,07 (1H, t, J=l,4Hz). 1.28 (3H, d, J=6.3), 4.02 (1H, dd, J-1.7 and 3.6 Hz), 4.35 (1H, dq, J = 3.6 and 6 , 3Hz ), 5.30, 5.15 (2H, AB, Jgem=13.9Hz), 5.87 (1H, d, J=1.7Hz), 6.92 (1H, bs), 7.47 (1H , t, J=7.8Hz), 7.54, 8.13 (4H, AA'BB', JAB=8.6H-z), 7.64 (1H, dt, J-1,4 and 7.8Hz) , 8.00 (1H, dt, J-1.4 and 7.8Hz), 8.07 (1H, t, J=1.4Hz).

Eksempel 95 Example 95

4- nitrobenzyl- 5R, 3-( 3- aminokarbonyl f enyl )- 6S-( lR- hydr oksyetyl )- 7- okso- 4- tia- l- azabicyklor3, 2, Olhept- 2- en- 2- karboksylat Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 38, men ved anvendelse av 4-nitrobenzyl-5R,3-(3-karboksyfenyl)-6S-(lR-hydroksyetyl )-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (492 mg), 1-hydrksybenzo-triazol (HOBT) (283 mg), l-( 3-dimetylaminopropyl )-3-etyl-karbodiimid-hydroklorid (301 mg) og en oppløsning av ammoniakk i etanol (29,8 g/l, 1,78 ml), acetonitril (50 ml) og tetrahydrofuran (82 ml) fikk man forbindelsen i overskriften (392 mg). 4- nitrobenzyl- 5R, 3-( 3- aminocarbonyl phenyl )- 6S-( 1R- hydroxyethyl )- 7- oxo- 4- thia- l- azabicyclo3, 2, Olhept- 2- ene- 2- carboxylate By a method analogous to the method used in example 38, but using 4-nitrobenzyl-5R,3-(3-carboxyphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2, 0]hept-2-ene-2-carboxylate (492 mg), 1-hydroxybenzotriazole (HOBT) (283 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (301 mg) and a solution of ammonia in ethanol (29.8 g/l, 1.78 ml), acetonitrile (50 ml) and tetrahydrofuran (82 ml) gave the title compound (392 mg).

S (aceton-d6) 1,30 (3H, d, J=6,3Hz), 3,93 (1H, dd, J-1,6 S (acetone-d6) 1.30 (3H, d, J=6.3Hz), 3.93 (1H, dd, J-1.6

og 6,3Hz), 4,18 (1H, m),- 5,16, 5,29 (2H, AB, Jgem=14,0Hz) , 5,88 (1H, d, J = l,6Hz), 6,79 (1H, bs), 7,48 (3H, m), 7,62 (1H, dt, J = l,3Hz og 7,8Hz), 7,97 (1H, dt, J-l, 3 og 7,8Hz), 8,03 (1H, t, J=l,3Hz), 8,13 (2H, d, J=8,8Hz). and 6.3Hz), 4.18 (1H, m), - 5.16, 5.29 (2H, AB, Jgem=14.0Hz), 5.88 (1H, d, J = 1.6Hz), 6.79 (1H, bs), 7.48 (3H, m), 7.62 (1H, dt, J = 1.3Hz and 7.8Hz), 7.97 (1H, dt, J-l, 3 and 7 .8Hz), 8.03 (1H, t, J=1.3Hz), 8.13 (2H, d, J=8.8Hz).

Alternativt ble forbindelsen i overskr if ten-'-(314 mg) oppnådd fra den tilsvarende dimetyl-(2-metylprop-2-yl)silyloksyetyl-forbindelsen (744 mg) fremstilt i eksempel 94 ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 35 ved anvendelse av iseddiksyre (766 mg) og en oppløsning av tetra-n-butylammoniumfluorid i tetrahydrofuran (IM, 3,84 ml). Alternatively, the compound in the title -'-(314 mg) was obtained from the corresponding dimethyl-(2-methylprop-2-yl)silyloxyethyl compound (744 mg) prepared in example 94 by a method analogous to the method used in example 35 by using glacial acetic acid (766 mg) and a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1M, 3.84 mL).

Eksempel 96 Example 96

Kalium- 5R . 3- ( 3- aminokarbonyl fenyl )- 6S-( lR- hydroksyetyl )- 7-okso- 4- tia- l- azabicyklor3, 2. Olhept- 2- en- 2- karboksylat Potassium- 5R . 3-(3-aminocarbonyl phenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo3, 2.Olhept-2-ene-2-carboxylate

Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 36, og under anvendelse av 4-nitrobenzyl-5R,3-( 3-aminokarbonylfenyl)-6S-(lR-hydroksyetyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (250 mg), dioksan (1 ml), kaliumbikarbonat (51 mg), vann (10 ml) og 10% palladium- på-trekull ( 250 mg), fikk man forbindelsen i overskriften (125 mg). In a method analogous to the method used in example 36, and using 4-nitrobenzyl-5R,3-(3-aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3, 2,0]hept-2-ene-2-carboxylate (250 mg), dioxane (1 ml), potassium bicarbonate (51 mg), water (10 ml) and 10% palladium-on-charcoal (250 mg), gave the compound in the title (125 mg).

S (D20) 1,30 (3H, d, J=6,3Hz), 3,98 (1H, dd, J=l,5og 5,9Hz), 4,25 (1H, m), 5,78 (1H, d, J-l,5Hz), 7,48 (1H, t, J = 8,0Hz), 7,6 0 (1H, dt, J-l, 4 og 7, 9Hz), 7,75-7,79 (2H, m). S (D20) 1.30 (3H, d, J=6.3Hz), 3.98 (1H, dd, J=1.5and 5.9Hz), 4.25 (1H, m), 5.78 ( 1H, d, J-l,5Hz), 7.48 (1H, t, J = 8.0Hz), 7.6 0 (1H, dt, J-l, 4 and 7, 9Hz), 7.75-7.79 ( 2H, m).

Eksempel 97 Example 97

4- ni trobenzyl- 5R, 3-( 3- aminokarbonylmetylaminokarbonylfenyl)-6S-( lR- hydroksyetyl)- 7- okso- 4- tia- l- azabicyklor3, 2. Olhept- 2-en- 2- karboksylat 4- nitrobenzyl- 5R, 3-( 3- aminocarbonylmethylaminocarbonylphenyl)-6S-( 1R- hydroxyethyl)- 7- oxo- 4- thia- 1- azabicyclo3, 2. Olhept- 2-ene- 2- carboxylate

Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 38, men ved anvendelse av 4-nitrobenzyl-5R,3-(3-karboksyfenyl)-6S-(lR-hydroksyetyl )-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (243 mg), HOBT (140 mg), 1- ( 3-dimetylaminopropyl) - 3-etylkarbodiimidhydroklorid (148 mg), acetonitril (20 ml), tetrahydrofuran (2 ml), glycinamid-hydroklorid ( 285 mg) og trietylamin (261 mg) fikk man forbindelsen i overskriften i form av et gult faststoff (132 mg). In a method analogous to the method used in example 38, but using 4-nitrobenzyl-5R,3-(3-carboxyphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3, 2,0]hept-2-ene-2-carboxylate (243 mg), HOBT (140 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (148 mg), acetonitrile (20 ml), tetrahydrofuran (2 ml ), glycinamide hydrochloride (285 mg) and triethylamine (261 mg), the title compound was obtained as a yellow solid (132 mg).

S (aceton-d6) 1,32 (3H, d, J=6,3Hz), 3,96 (1H, dd, J-l,7 S (acetone-d6) 1.32 (3H, d, J=6.3Hz), 3.96 (1H, dd, J-1.7

og 6,3Hz), 4,03 (2H, d, J-5,6), 4,22 (1H, m), 4,47 (1H, d, J=4,8z), 5,18 og 5,31 (2H, AB, Jgem=13,8Hz), 5,91 (1H, d, J=l,6Hz), 6,44 (1H, bs), 7,05 (1H, bs), 7,49 og 8,16 (4H, AA'BB', J=8,8Hz), 7,52 (1H, m), 7,64 (1H, dt, J-l, 3 og 7,8Hz), 7,97 (1H, dt, J-l,4 og 7,8Hz), 8,04 (1H, m). and 6.3Hz), 4.03 (2H, d, J-5.6), 4.22 (1H, m), 4.47 (1H, d, J=4.8z), 5.18 and 5 .31 (2H, AB, Jgem=13.8Hz), 5.91 (1H, d, J=1.6Hz), 6.44 (1H, bs), 7.05 (1H, bs), 7.49 and 8.16 (4H, AA'BB', J=8.8Hz), 7.52 (1H, m), 7.64 (1H, dt, J-1, 3 and 7.8Hz), 7.97 (1H , dt, J-1.4 and 7.8Hz), 8.04 (1H, m).

Eksempel 98 Example 98

Kalium- 5R . 3-( 3- aminokarbonyImetylaminokarbonylfenyl)- 6S-( lR-hyd r oksyetyl ) - 7- ok so- 4 - t ia- 1 - azabi cyklofS . 2 . 0] hept- 2- en- 2-karboksylat Potassium- 5R . 3-(3-Aminocarbonylmethylaminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabi cyclophosph. 2. 0] hept-2-ene-2-carboxylate

Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 36 og ved anvendelse av 4-nitrobenzyl-5R,3-(3- aminokarbonylmetylaminokarbonylfenyl)-6S-(lR-hydroksyetyl)-7-okso-4-t ia-l-azabi cyklo [ 3,2,0] hept-2-en-2-karboksylat (130 mg), dioksan (10 ml), kal iumbikarbonat (24,7 mg), vann (10 ml) og 10% palladium-på-trekull (130 mg), fikk man forbindelsen i overskriften (102 mg). In a method analogous to the method used in example 36 and using 4-nitrobenzyl-5R,3-(3-aminocarbonylmethylaminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabi cyclo [ 3 ,2,0] hept-2-ene-2-carboxylate (130 mg), dioxane (10 mL), potassium bicarbonate (24.7 mg), water (10 mL), and 10% palladium-on-charcoal (130 mg ), the title compound was obtained (102 mg).

§ (D20) 1,30 (3H, d, J=6,4Hz), 4,00 (1H, dd, J-l,4 og 5,9Hz), 4,08 (2H, s), 4,24 (1H, m), 5,80 (1H, d, J=l,4Hz), 7,48-7,82 (4H, m). § (D20) 1.30 (3H, d, J=6.4Hz), 4.00 (1H, dd, J-1.4 and 5.9Hz), 4.08 (2H, s), 4.24 (1H , m), 5.80 (1H, d, J=1.4Hz), 7.48-7.82 (4H, m).

Eksempel 99 Example 99

5R. 3-( 3- cyanometylaminokarbonylfenyl)- 6S-( lR- hydroksyetyl)- 7-okso- 4- tia- l- azabicyklor3, 2, 0] hept- 2- en- 2- karboksylsyre 5R. 3-( 3- cyanomethylaminocarbonylphenyl)- 6S-( 1R- hydroxyethyl)- 7-oxo- 4- thia- 1- azabicyclo3, 2, 0] hept- 2-ene- 2- carboxylic acid

Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 34, men ved anvendelse av 4-nitrobenzyl-5R,3-(3-karboksyf enyl )-6S-{lR - [dimetyl (2-metylprop-2-yl) silyloksy] - etyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (400 mg), HOBT (186 mg), acetonitril (10 ml), tetrahydrofuran (2 ml) og 1-( 3-dimetylaminopropyl)-3-etylkarbodiimid-hydro-klorid (198 mg), trietylamin (209 mg) og aminoacetonitril-hydroklorid (192 mg) fikk man 4- nitrobenzyl- 5R, 3-( 3- cyano-mety1aminokarbonylf enyl)- 6S-( IR-[ dimetyl-( 2- metylprop- 2-yl) silyloksy] etyl)- 7- okso- 4- tia- l- azabicyklof3. 2. 0] hept- 2- en-2- karboksylat (165 mg). In a method analogous to the method used in example 34, but using 4-nitrobenzyl-5R,3-(3-carboxyphenyl)-6S-{1R - [dimethyl (2-methylprop-2-yl) silyloxy] - ethyl) -7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (400 mg), HOBT (186 mg), acetonitrile (10 mL), tetrahydrofuran (2 mL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (198 mg), triethylamine (209 mg) and aminoacetonitrile hydrochloride (192 mg) gave 4-nitrobenzyl-5R,3-(3-cyano-methylaminocarbonyl) enyl)- 6S-( IR-[ dimethyl-( 2- methylprop- 2-yl) silyloxy] ethyl)- 7- oxo- 4- thi- 1- azabicyclof3. 2.0] hept-2-ene-2-carboxylate (165 mg).

S (CDCI3) 0,05 (3H, s), 0,08 (3H, s), 0,84 (9H, s), 1,26 S (CDCl 3 ) 0.05 (3H, s), 0.08 (3H, s), 0.84 (9H, s), 1.26

(3H, d, J=6Hz), 3,83 (1H, m), 4,27 (1H, m), 4,33 (2H, d, J = 5,7Hz), 5,08 og 5,25 (2H, AB, Jgem=13,7Hz) , 5,75 (1H, d, J=l,5Hz), 7,11 (1H, t, J=5,7Hz), 7,41 og 8,12 (4H, AA 'BB', J=8,9Hz), 7,45 (1H, m), 7,61 (1H, dt, J = 7,9 og 1 , 4Hz), 7,80 (1H, dt, J = l,4 og 7,9Hz), 7,94 ( 1H, t, J=l,4Hz). (3H, d, J=6Hz), 3.83 (1H, m), 4.27 (1H, m), 4.33 (2H, d, J = 5.7Hz), 5.08 and 5.25 (2H, AB, Jgem=13.7Hz) , 5.75 (1H, d, J=l.5Hz), 7.11 (1H, t, J=5.7Hz), 7.41 and 8.12 ( 4H, AA 'BB', J=8.9Hz), 7.45 (1H, m), 7.61 (1H, dt, J = 7.9 and 1 , 4Hz), 7.80 (1H, dt, J = 1.4 and 7.9Hz), 7.94 ( 1H, t, J=1.4Hz).

Dette produktet (159 mg) ble behandlet ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 35, men ved anvendelse av iseddiksyre (187 mg) og en oppløsning av tetra- n-butylammoniumfluorid i tetrahydrofuran (IM, 0,93 ml), og tetrahydrofuran (5 ml) slik at man fikk 4- nitrobenzyl- 5R,3-( 3- cyanometylaminokarbonylfenyl)- 6S-( lR- hydroksyetyl)- 7- okso-4 - t i a - 1 - az ab i cyklo f 3, 2, Ol hept- 2- en- 2- karboksyl at som en viskøs gul olje (89 mg). This product (159 mg) was treated by a method analogous to the method used in Example 35, but using glacial acetic acid (187 mg) and a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1M, 0.93 ml), and tetrahydrofuran ( 5 ml) so that one got 4-nitrobenzyl-5R,3-(3-cyanomethylaminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-t i a - 1 - aza ab i cyclo f 3, 2, Ol hept - 2- en- 2- carboxyl that as a viscous yellow oil (89 mg).

5 (aceton-d6) 1,22 (3H, d, J=6, 3Hz), 3,86 (1H, dd, J-1,6 og 6,3Hz), 4,13 (1H, m), 4,31 (2H, d, J=5,7Hz), 4,50 (1H, bred), 5,08 og 5,21 5 (acetone-d6) 1.22 (3H, d, J=6, 3Hz), 3.86 (1H, dd, J-1.6 and 6.3Hz), 4.13 (1H, m), 4 .31 (2H, d, J=5.7Hz), 4.50 (1H, wide), 5.08 and 5.21

(2H, AB, Jgem=13,8Hz), 5,81 (1H, d, J-1.6H-z), 7,39 og 8,05 (4H, AA'BB', J08,5Hz), 7,44 (1H, m), 7,59 (1H, dt, J-l,5 og 7,6Hz), 7,86 (1H, dt, J-l,5 og 7,6Hz), 7,92 (1H, t, J-l,5Hz). (2H, AB, Jgem=13.8Hz), 5.81 (1H, d, J-1.6H-z), 7.39 and 8.05 (4H, AA'BB', J08.5Hz), 7.44 ( 1H, m), 7.59 (1H, dt, J-l.5 and 7.6Hz), 7.86 (1H, dt, J-l.5 and 7.6Hz), 7.92 (1H, t, J-l.5Hz ).

Denne 4-nitrobenzylesteren (89 mg) ble behandlet ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 36 med vann (10 ml), dioksan (10 ml), kaliumbikarbonat (17,5 mg) og 10% palladium-på-trekul 1 (90 mg) slik at man fikk det tilsvarende kaliumsaltet (66 mg). Dette råproduktet ble kromatografert over en silylert silikagel, og eluering med acetonitril-vann-maursyreblandinger ga karboksyl syren i overskriften (20 mg). This 4-nitrobenzyl ester (89 mg) was treated by a procedure analogous to the procedure used in Example 36 with water (10 ml), dioxane (10 ml), potassium bicarbonate (17.5 mg) and 10% palladium-on-charcoal 1 (90 mg) so that the corresponding potassium salt (66 mg) was obtained. This crude product was chromatographed over a silylated silica gel, and elution with acetonitrile-water-formic acid mixtures gave the title carboxylic acid (20 mg).

S (D20 inneholdende KHC03) 1,30 (3H, d, J=6,4Hz), 3,99 (1H, S (D 2 O containing KHCO 3 ) 1.30 (3H, d, J=6.4Hz), 3.99 (1H,

dd, J-l,5 g 4,8Hz), 4,25 (1H, m), 4,36 (2H, s), 5,78 (1H, d, J=l,5Hz), 7,50 (1H, t, J=8Hz) , 7,63 (1H, d, J=8Hz), 7,77 (2H, m). dd, J-1.5 g 4.8Hz), 4.25 (1H, m), 4.36 (2H, s), 5.78 (1H, d, J=1.5Hz), 7.50 (1H, t, J=8Hz) , 7.63 (1H, d, J=8Hz), 7.77 (2H, m).

Eksempel 100 Example 100

Kalium- 5R , 6S-( lR- hydroksyetyl)- 3-[ 4-( lR- hvdroksvetyl^ aminokarbonyl f enyll - 7- okso- 4- tia- l- azabicyklor3 . 2 . 0lhept- 2- en- 2-karboksylat Potassium- 5R , 6S-( 1R- hydroxyethyl)- 3-[ 4-( 1R- hydroxyethyl^ aminocarbonyl phenyl - 7- oxo- 4- thia- 1- azabicyclo3 . 2 . 0lhept- 2-ene- 2-carboxylate

Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 34 og ved anvendelse av 4-nitrobenzyl-5R,3-(4-karboksyf enyl) - 6S-( IR - [dimetyl (2-metylprop-2-yl) si lyloksy] - etyl )7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat In a method analogous to the method used in example 34 and using 4-nitrobenzyl-5R,3-(4-carboxyphenyl)-6S-(IR-[dimethyl (2-methylprop-2-yl)silyloxy]-ethyl) 7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate

(117 mg), acetonitril (10 ml), HOBT (54 mg), tetrahydrofuran (2 ml) og 1-(3-dimetylaminopropyl)-3-etylkarbodiimid-hydro-klorid (58 mg) og etanolamin (13,4 mg) fikk man i form av et gult skum (117 mg), acetonitrile (10 ml), HOBT (54 mg), tetrahydrofuran (2 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg) and ethanolamine (13.4 mg) was obtained in the form of a yellow foam

4- nitrobenzvl- 5R . 6S-( IR- f dimetyl - ( 2- me ty lpr op- 2- yl ) si lyl-oksyl etyl)- 3- f4-( 2- hydroksyetyl) aminokarbonylfenyll- 7- okso- 4-tia- l- azabicyklor3, 2. 0lhept- 2- en- 2- karboksylat (94 mg). 4- nitrobenzvl- 5R . 6S-(IR-fdimethyl-(2-methylpropyl-2-yl)silyl-oxylethyl)-3-f4-(2-hydroxyethyl)aminocarbonylphenyll-7-oxo-4-thia-l-azabicyclo3, 2. 0lhept-2-ene-2-carboxylate (94 mg).

S (CDC13) 0,06 (3H, s), 0,08 (3H, s), 0,85 (9H, s), 1,27 S (CDCl 3 ) 0.06 (3H, s), 0.08 (3H, s), 0.85 (9H, s), 1.27

(3H, d, J=6,3Hz), 3,58 (2H, m), 3,78 (2H, m), 3,84 (1H, dd, J-1,6 og 4Hz), 4,29 (1H, m), 5,08 og 5,26 (2H, AB, Jgem=13,7Hz), 5,76 (1H, d, J=l,6Hz), 7,06 (1H, bred m), 7,41 (2H, d, J=8,7Hz), 7,46 (2H, d, J-8,4Hz), 7,73 (2H, d, J=8,4Hz), 8,13 (2H, d, J-8,7Hz). (3H, d, J=6.3Hz), 3.58 (2H, m), 3.78 (2H, m), 3.84 (1H, dd, J-1.6 and 4Hz), 4.29 (1H, m), 5.08 and 5.26 (2H, AB, Jgem=13.7Hz), 5.76 (1H, d, J=1.6Hz), 7.06 (1H, wide m), 7.41 (2H, d, J=8.7Hz), 7.46 (2H, d, J-8.4Hz), 7.73 (2H, d, J=8.4Hz), 8.13 (2H , d, J-8.7Hz).

Dette produktet (94 mg) ble behandlet ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 35 ved anvendelse av iseddiksyre (90 mg), en oppløsning av tetra-n-butylammoniumfluorid i tetrahydrofuran (IM, 0,45 ml) og tetrahydrofuran (10 ml) slik at man fikk This product (94 mg) was treated by a method analogous to the method used in Example 35 using glacial acetic acid (90 mg), a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1M, 0.45 ml) and tetrahydrofuran (10 ml) so that one got

4- nitrobenzyl- 5R, 6S-( lR- hydroksyetyl )- 3- r4-(- 2- hydroksyetyl )-aminokarbonyl f enyl 1 - 7- okso- 4- tia- l- azabicyklor3 , 2 , Ol hept- 2-en- 2- karboksylat (30 mg). 4-nitrobenzyl-5R,6S-(1R-hydroxyethyl)-3-r4-(-2-hydroxyethyl)-aminocarbonyl phenyl 1-7-oxo-4-thia-1-azabicyclo3,2,Ol hept-2-ene - 2- carboxylate (30 mg).

S. (aceton-d6) 1,31 (3H, d, J = 6Hz ) , 3,53 (2H, m), 3,70 S. (acetone-d6) 1.31 (3H, d, J = 6Hz ) , 3.53 (2H, m), 3.70

(2H, m), 3,95 (1H, dd, J-l,3 og 6,3Hz), 4,22 (1H, m), 5,18 og 5,31 (2H, AB, JgenT14-Hz), 5,90 (1H, d, J=l,3Hz), 7,46 (2H, d, J=8,7Hz), 7,53 (2H, d, J=8,3Hz), 7,89 (2H, d, J=8,3Hz), 8,15 (2H, d, J=8,7Hz). (2H, m), 3.95 (1H, dd, J-1,3 and 6.3Hz), 4.22 (1H, m), 5.18 and 5.31 (2H, AB, JgenT14-Hz), 5 .90 (1H, d, J=1.3Hz), 7.46 (2H, d, J=8.7Hz), 7.53 (2H, d, J=8.3Hz), 7.89 (2H, d, J=8.3Hz), 8.15 (2H, d, J=8.7Hz).

Dette produktet (30 mg) ble behandlet ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 36, men under anvendelse av dioksan (5 ml), vann (5 ml), kaliumbikarbonat (5,9 mg) og 10% palladium-på-trekull (30 mg) slik at man fikk kaliumsaltet i overskriften (24 mg). This product (30 mg) was treated by a procedure analogous to the procedure used in Example 36, but using dioxane (5 ml), water (5 ml), potassium bicarbonate (5.9 mg) and 10% palladium-on-charcoal ( 30 mg) so that the potassium salt in the title (24 mg) was obtained.

S (D20) 1,30 (3H, d, J=6,4Hz), 3,53 (2H, m), 3,76 (2H, m), S (D20) 1.30 (3H, d, J=6.4Hz), 3.53 (2H, m), 3.76 (2H, m),

2,94 (lH,m), 4,28 (1H, m), 5,81 (1H, d, J=l,5Hz), 7,51 og 7,73 (4H, AA'BB', J=8,3Hz). 2.94 (1H,m), 4.28 (1H, m), 5.81 (1H, d, J=1.5Hz), 7.51 and 7.73 (4H, AA'BB', J= 8.3Hz).

Eksempel 101 Example 101

2 -( trimetylsilyl ) etvl- 5R . 3-( 3- aminofenyl )- 6S-( lR- hydroksyetyl)- 7- okso- 4- tia- l- azabicyklor3, 2, Olhept- 2- en- 2- karboksylat Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 24 og under anvendelse av 3-nitrobenzoylklorid (10 2-(trimethylsilyl)ethyl-5R. 3-(3-aminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-l-azabicyclo3,2,Olhept-2-ene-2-carboxylate In a method analogous to the method used in example 24 and below use of 3-nitrobenzoyl chloride (10

g), diklormetan (200 ml), pyridin (8,7 ml) og hydrogensulfid (overskudd) fikk man g), dichloromethane (200 ml), pyridine (8.7 ml) and hydrogen sulphide (excess) gave

3-( nitro)- tiobenzosyre som et svakt gult faststoff (9,3 g). 3-(nitro)-thiobenzoic acid as a pale yellow solid (9.3 g).

S (CDC13) 4,8 (1H, bred), 7,72 (1H, t, J=8,0Hz), 8,23 (1H, S (CDC13) 4.8 (1H, broad), 7.72 (1H, t, J=8.0Hz), 8.23 (1H,

dt, J-l,4 og 7,8Hz), 8,47 (1H, dt, J-l,2 og 8,2Hz), 8,74 (1H, t, J=l,8Hz). dt, J-1.4 and 7.8Hz), 8.47 (1H, dt, J-1.2 and 8.2Hz), 8.74 (1H, t, J=1.8Hz).

Denne 3-( ni t r o )-t iobenzosyr en (9,3 g) ble omsatt ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 16 med en blanding av 4-acetoksy-3R-(IR-[dimetyl(2-metylprop-2-yl )silyloksy]etyl)-azetidin-2-on (10 g) og ■"natriumhydroksyd (2,08 g) i aceton (250 ml) og vann (52 ml) slik at man fikk This 3-(nitro)-thiobenzoic acid (9.3 g) was reacted by a method analogous to the method used in example 16 with a mixture of 4-acetoxy-3R-(IR-[dimethyl(2-methylprop-2- yl)silyloxy]ethyl)-azetidin-2-one (10 g) and sodium hydroxide (2.08 g) in acetone (250 ml) and water (52 ml) to give

3S-( lR-[ dimetyl( 2- metvlprop- 2- vl) silvloksvletyl)- 4R-( 3- nitro-benzoyltio) azetidin- 2- on (13 g) 3S-(1R-[dimethyl(2-methylprop-2-yl)silvloxvletyl)-4R-(3-nitro-benzoylthio)azetidin-2-one (13 g)

vmaks (film) 1770 cm"<1>vmax (film) 1770 cm"<1>

S (CDCI3) 0,10 (6H, s), 0,90 (9H, s), 1,26 (3H, d, S (CDCl 3 ) 0.10 (6H, s), 0.90 (9H, s), 1.26 (3H, d,

J=6,3Hz), 3,34 (1H,~t, J~3Hz), 4,33 (1H, m), 5,53 (1H, d, J=2,4Hz), 6,54 (1H, s), 7,72 (1H, t, J=8Hz), 8,25 (1H, ddd, J-l, 2 og 8Hz), 8,49 (1H, ddd, J-l, 2 og 8Hz), 8,76 (1H, t, J=2Hz). J=6.3Hz), 3.34 (1H,~t, J~3Hz), 4.33 (1H, m), 5.53 (1H, d, J=2.4Hz), 6.54 (1H , s), 7.72 (1H, t, J=8Hz), 8.25 (1H, ddd, J-l, 2 and 8Hz), 8.49 (1H, ddd, J-l, 2 and 8Hz), 8.76 (1H, t, J=2Hz).

Behandling av dette azetidinonet (13 g) ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 17 ved anvendelse av diklormetan (300 ml), kalsiumkarbonat (13 g), diisopropyl etylamin (11 ml) og 2-(trimetylsilyl)etylkloroksoacetat (8,9 ml) ga Treatment of this azetidinone (13 g) by a method analogous to the method used in example 17 using dichloromethane (300 ml), calcium carbonate (13 g), diisopropyl ethylamine (11 ml) and 2-(trimethylsilyl)ethylchloroxoacetate (8.9 ml ) gave

2-( trimetylsilyl ) etvl-( 3S- flR-( dimetyl ( 2- metylprop- 2- yl )-silyloksy) et, yll - 4R- ( 3- ni trobenzoyl tio ) azetidin- 2- on- l- yl )-oksoacetat 2-(trimethylsilyl)ethyl-(3S-flR-(dimethyl (2-methylpropyl-2-yl)-silyloxy)eth,yl - 4R-(3-nitrobenzoylthio)azetidin-2-on-1-yl)- oxoacetate

§ (CDC13) 0,08 (6H, s), 0,09 (9H, s), 0,91 (11H, s ogm), § (CDC13) 0.08 (6H, s), 0.09 (9H, s), 0.91 (11H, s andgm),

1,27 (3H, d, J=6,7Hz), 3,65 (1H, t, J=3Hz), 4,42 (3H, m), 6,23 ( 1H, d, J = 3Hz ) , 7,72 (1H, t, J=8Hz), 8,28 (1H, ddd, J=l,2og 8Hz), 8,49 (1H, ddd, J-l, 2 og 8Hz), 8,80 (1H, t, J=2Hz). 1.27 (3H, d, J=6.7Hz), 3.65 (1H, t, J=3Hz), 4.42 (3H, m), 6.23 ( 1H, d, J = 3Hz ), 7.72 (1H, t, J=8Hz), 8.28 (1H, ddd, J=1,2and 8Hz), 8.49 (1H, ddd, J-1, 2 and 8Hz), 8.80 (1H, t, J=2Hz).

Dette oksoacetatet ble straks behandlet ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 18 med trietylfosfitt (10,8 ml), hydrokinon (10 mg) og. o-xylen (300 ml) slik at man fikk This oxoacetate was immediately treated by a method analogous to the method used in example 18 with triethyl phosphite (10.8 ml), hydroquinone (10 mg) and. o-xylene (300 ml) so that one got

2-( trimetylsilyl) etyl- 5R, 6S-{ IR- fdimetyl( 2- metvlprop- 2-yl) silyloksvletyl)- 3-( 3- nitrofenyl )- 7- okso- 4- tia- l- azabicyklof3. 2. 0lhept- 2- en- 2- karboksvlat (10,5 g). 2-(trimethylsilyl)ethyl-5R,6S-{IR-fdimethyl(2-methylpropyl-2-yl)silyloxyvletyl)-3-(3-nitrophenyl)-7-oxo-4-thia-1-azabicyclof3. 2. 0lhept-2-ene-2-carboxylate (10.5 g).

<v>maks (CDCI3) 1792, 1710, 1535 crn-<1><v>max (CDCI3) 1792, 1710, 1535 crn-<1>

§ (CDCI3) 0,01 (9H, s), 0,10 (3H, s), 0,T2 (3H, s), 0,94 § (CDCl3) 0.01 (9H, s), 0.10 (3H, s), 0.T2 (3H, s), 0.94

(11H, s og m), 1,28 (3H, d, J=6,3Hz), 3,82 (1H, dd, J-1,6 og 4,6Hz), 4,15-4,42 (3H, m), 5,75 (1H, d, J=l,6Hz), 7,57 (1H, t, J=8Hz), 7,80 (1H, dt, J=l og 8Hz), 8,25 (1H, ddd, J=l, 2 og 8Hz), 8,36 (1H, t, J=2Hz). (11H, s and m), 1.28 (3H, d, J=6.3Hz), 3.82 (1H, dd, J-1.6 and 4.6Hz), 4.15-4.42 ( 3H, m), 5.75 (1H, d, J=l,6Hz), 7.57 (1H, t, J=8Hz), 7.80 (1H, dt, J=l and 8Hz), 8, 25 (1H, ddd, J=l, 2 and 8Hz), 8.36 (1H, t, J=2Hz).

Behandling av dette silylerte penemet (1 g) ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 19 med iseddiksyre (1 ml), tetrahydrofuran (20 ml) og en oppløsning av tetra-n-butylammoniumfluorid i tetrahydrofuran (IM, 5,6 ml ) ga 2-( trimetylsilyl ) etyl- 5R . 6S-( lR- hydr oksyetyl )- 3-( 3-ni tr of enyl )- 7- okso- 4- t ia- l- azabi cyklo f 3 . 2 , 0~ lhept- 2- en- 2- karboksylat (300 mg). Treatment of this silylated penem (1 g) by a method analogous to the method used in example 19 with glacial acetic acid (1 ml), tetrahydrofuran (20 ml) and a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1M, 5.6 ml) gave 2-(trimethylsilyl)ethyl-5R. 6S-(1R-hydroxyethyl)-3-(3-nitrofenyl)-7-oxo-4-thia-l-azabicyclo f 3 . 2,0~ lhept-2-ene-2-carboxylate (300 mg).

<v>maks (CDCI3) 1785, 1710, 1532 cm-<1><v>max (CDCI3) 1785, 1710, 1532 cm-<1>

S (CDCI3) 0,01 (9H, s), 0,91 (2H, m) , 1,39 (3H, d, S (CDCl 3 ) 0.01 (9H, s), 0.91 (2H, m), 1.39 (3H, d,

J=6,3Hz), 3,86 (1H, dd, J=l,6 og 6,6 Hz) , 4,1-4,3 (3H, m), 5,78 (1H, d, J=l,6Hz), 7,57 (1H, t, J = 8Hz), 7,79 (1H, dt, J=log 8Hz) , 8,26 (1H, ddd, J-l, 2 og 8Hz), 8,35 (1H, t, J=2Hz). J=6.3Hz), 3.86 (1H, dd, J=1.6 and 6.6 Hz) , 4.1-4.3 (3H, m), 5.78 (1H, d, J= l.6Hz), 7.57 (1H, t, J = 8Hz), 7.79 (1H, dt, J=log 8Hz) , 8.26 (1H, ddd, J-l, 2 and 8Hz), 8.35 (1H, t, J=2Hz).

En oppløsning av dette 3-nitrofenyl-penem-karboksylatet (4,5 A solution of this 3-nitrophenyl-penem-carboxylate (4.5

g) i tørr etylacetat (100 ml) ble hydrogenert ved 375 kPa (4 atm.) ved 20°C i nærvær av platinadioksyd (1,1 g), ble g) in dry ethyl acetate (100 ml) was hydrogenated at 375 kPa (4 atm.) at 20°C in the presence of platinum dioxide (1.1 g), was

filtrert og inndampet i vakuum. Kromatografi av resten over silikagel, og eluering med etylacetat-heksanblandinger ga 3-aminofenyl-forbindelsen i overskriften. filtered and evaporated in vacuo. Chromatography of the residue over silica gel, and elution with ethyl acetate-hexane mixtures gave the 3-aminophenyl compound in the title.

<v>maks (CDCI3) 3600 (bred), 3400 (bred), 3178, 1710, 1621 cm-1. <v>max (CDCI3) 3600 (broad), 3400 (broad), 3178, 1710, 1621 cm-1.

S (CDCI3) 0,01 (9H, s), 0,93 (2H, m), 1,36 (3H, d, S (CDCl 3 ) 0.01 (9H, s), 0.93 (2H, m), 1.36 (3H, d,

J=6,3Hz), 2,84 (2H, bred), 3,78 (1H, dd, J=l,5 og 6,6Hz), 4,18 (3H, m), 5,67 (1H, d, J-l,5Hz), 6,70 (1H, dd, J=2,2og 7,3Hz), 6,77 (1H, m), 6,83 (1H, dd, J=7,7og 1Hz), 7,14 (1H, t, J=7,7Hz). J=6.3Hz), 2.84 (2H, wide), 3.78 (1H, dd, J=1.5 and 6.6Hz), 4.18 (3H, m), 5.67 (1H, d, J-1.5Hz), 6.70 (1H, dd, J=2.2and 7.3Hz), 6.77 (1H, m), 6.83 (1H, dd, J=7.7and 1Hz), 7.14 (1H, t, J=7.7Hz).

Eksempel 102 Example 102

Kalium- 5R. 3-( 3- formylaminofenyl)- 6S-( lR- hydroksyetyl)- 7- okso-4- tia- l- azabicyklor3. 2. 01hept- 2- en- 2- karboksylat Potassium- 5R. 3-(3-formylaminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo3. 2. 01hept- 2- en- 2- carboxylate

Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 87 og ved anvendelse av 2-(trimetylsilyl)etyl-5R,3-( 3-aminof enyl )-6S-( lR-hy dr oksyetyl )-7-okso-4-t ia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (200 mg) i tørr diklormetan (5 ml), maursyre (0,022 ml) og 1-(3-dimetylaminopropyl)-3-etylkarbodiimidhydroklorid (113 mg) fikk man In a method analogous to the method used in example 87 and using 2-(trimethylsilyl)ethyl-5R,3-(3-aminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia- l-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (200 mg) in dry dichloromethane (5 mL), formic acid (0.022 mL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113 mg) was obtained

2-( trimetylsilyl) etvl- 5R, 3-( 3- formylaminofenyl)- 6S-( lR-hydroksyetyl )- 7- ok so- 4- t ia- 1 - azabi cyklo f 3 . 2 . 0] hept- 2- en- 2-karboksylat (171 mg): 2-(trimethylsilyl)ethyl-5R,3-(3-formylaminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo f 3 . 2. 0] hept-2-ene-2-carboxylate (171 mg):

<v>maks (CDCI3) 3500 (sh) , 3320 (bred), 1787, 1596 cm-<1>. S (CDCI3) [observert som en blanding av begge formamid-formene] (a) 0,01 (6H, s), 0,91 (2H, m), 1,36 (3H, d, J=6,3Hz), 2,73 (1H, bred), 3,80 (2H, m), 4,17 (3H, m), 5,70 (1H, d, J-l, 4Hz), 7,1-7,6 (4H, m), 7,81 (1H, d, J=l,6Hz), 8,33 (1H, d, J-l,6Hz), og (b) 0,01 (6H, s), 0,91 (2H, m), 1,37 (3H, d, J=6,3Hz), <v>max (CDCI3) 3500 (sh) , 3320 (wide), 1787, 1596 cm-<1>. S (CDCl3) [observed as a mixture of both formamide forms] (a) 0.01 (6H, s), 0.91 (2H, m), 1.36 (3H, d, J=6.3Hz) , 2.73 (1H, wide), 3.80 (2H, m), 4.17 (3H, m), 5.70 (1H, d, J-l, 4Hz), 7.1-7.6 (4H , m), 7.81 (1H, d, J=1.6Hz), 8.33 (1H, d, J-1.6Hz), and (b) 0.01 (6H, s), 0.91 (2H , m), 1.37 (3H, d, J=6.3Hz),

2,68 (1H, bred), 3,80 (2H, m), 4,17 (3H, m), 5,72 (1H, d, J = l,4Hz), 7,1-7,6 (4H, m), 8,19 (1H, d, J=ll,3Hz), 8,67 (1H, d, J=ll,3Hz). 2.68 (1H, wide), 3.80 (2H, m), 4.17 (3H, m), 5.72 (1H, d, J = 1.4Hz), 7.1-7.6 ( 4H, m), 8.19 (1H, d, J=11.3Hz), 8.67 (1H, d, J=11.3Hz).

En oppløsning av dette produket (168 mg) i tetrahydrofuran (5 ml) ble deretter behandlet ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 88 med en tørr oppløsning av tetra-n-butylammoniumfluorid i tetrahydrofuran (IM, 0,387 ml) og endelig med kaliumhydrogenkarbonat (38,7 mg) slik at man fikk råproduktet (218 mg). Rensing som i eksempel 88 ga deretter forbindelsen i overskriften (37 mg). A solution of this product (168 mg) in tetrahydrofuran (5 ml) was then treated by a procedure analogous to that used in Example 88 with a dry solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1M, 0.387 ml) and finally with potassium hydrogen carbonate ( 38.7 mg) so that the crude product (218 mg) was obtained. Purification as in Example 88 then gave the title compound (37 mg).

S (D20) 1,31 (3H, d, J=6,5Hz), 3,98 (1H, dd,_J-l,3 og 5,8Hz), 4,24 (1H, m), 5,77 (1H, d, J=l,3Hz), 7,22-7,27 (2H, m), 7,39 (1H, t, J=7,4Hz f, 7,48 (1H, m), 8,24 (1H, s). S (D20) 1.31 (3H, d, J=6.5Hz), 3.98 (1H, dd,_J-1,3 and 5.8Hz), 4.24 (1H, m), 5.77 (1H, d, J=l,3Hz), 7.22-7.27 (2H, m), 7.39 (1H, t, J=7.4Hz f, 7.48 (1H, m), 8 .24 (1H, p).

Eksempel 103 Example 103

Kalium- 5R. 3-( 3- acetylaminofenyl)- 6S-( lR- hydroksyetyl)- 7- okso-4- tia- l- azabicyklo[ 3, 2, 0] hept- 2- en- 2- karboksylat Potassium- 5R. 3-( 3- acetylaminophenyl)- 6S-( 1R- hydroxyethyl)- 7- oxo-4- thia- 1- azabicyclo[ 3, 2, 0] hept- 2-ene- 2- carboxylate

En blanding av 2-(trimetylsilyl)etyl-5R,3-(3-aminofenyl)-6S-(lR-hydroksyetyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (200 mg), tetrahydrofuran (3 ml), eddiksyreanhydrid (0,051 ml) og N-metylmorfolin (0,06 ml) ble omrørt ved 20 ° C i en time, ble deretter fordelt mellom etylacetat og vann. Det organiske laget ble vasket med vann, med IM sitronsyre, med mettet natr iumbikarbonatoppløsning, og tørket. Inndamping i vakuum og kromatografi av resten over silikagel, og eluering med etylacetat-heksanblandinger ga 2-( trimetylsilyl) etyl- 5R. 3-( 3acetylaminofenyl)- 6S-( lR- hydroksv etyl)- 7- okso- 4- tia- l- azabicyklof3. 2. Olhept- 2- en- 2- karboksylat (210 mg); A mixture of 2-(trimethylsilyl)ethyl-5R,3-(3-aminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2- ene-2-carboxylate (200 mg), tetrahydrofuran (3 mL), acetic anhydride (0.051 mL), and N-methylmorpholine (0.06 mL) were stirred at 20 °C for one hour, then partitioned between ethyl acetate and water. The organic layer was washed with water, with 1M citric acid, with saturated sodium bicarbonate solution, and dried. Evaporation in vacuo and chromatography of the residue over silica gel, and elution with ethyl acetate-hexane mixtures gave 2-(trimethylsilyl)ethyl-5R. 3-(3acetylaminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclof3. 2. Olhept-2-ene-2-carboxylate (210 mg);

<v>maks (CDC13) 3350 (bred), 1782, 1680 cn<T1><v>max (CDC13) 3350 (wide), 1782, 1680 cn<T1>

S (CDCI3) 0,01 (9H, s,), 0,95 (2H, m), 1,39 (3H, d, S (CDCl 3 ) 0.01 (9H, s, ), 0.95 (2H, m), 1.39 (3H, d,

J=6,3Hz), 2,18 (3H, s), 3,81 (1H, dd, J=l, 5 og 6,8Hz), 4,1-4,3 (3H, m), 5,70 (1H, d, J=l,5Hz), 7,1-7,7 (5H, m). J=6.3Hz), 2.18 (3H, s), 3.81 (1H, dd, J=1, 5 and 6.8Hz), 4.1-4.3 (3H, m), 5, 70 (1H, d, J=1.5Hz), 7.1-7.7 (5H, m).

Dette materialet (194 mg) ble behandlet ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 88 med tørr tetrahydrofuran (5 ml), en oppløsning av tetra-n-butylammoniumfluorid i tetrahydrofuran (IM, 0,433 ml) og kaliumhydrogenkarbonat (43,3 mg), slik at man fikk forbindelsen i overskriften (260 mg). Rensing som i eksempel 88 ga den rene forbindelsen i overskriften (47 mg). This material (194 mg) was treated by a method analogous to the method used in Example 88 with dry tetrahydrofuran (5 ml), a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1M, 0.433 ml) and potassium bicarbonate (43.3 mg), so that the compound in the title was obtained (260 mg). Purification as in Example 88 gave the pure title compound (47 mg).

S (D20) 1,30 (3H, d, J=6,4Hz), 2,14 (3H, s), 3,98 (1H, dd, S (D20) 1.30 (3H, d, J=6.4Hz), 2.14 (3H, s), 3.98 (1H, dd,

J=5,9 og 1,4Hz), 4,25 (1H, m), 5,77 (1H, d, J = l,4Hz), 723 (1H, dt, J=7,2og 1, 4Hz)7,3-7,5 (3H, m). J=5.9 and 1.4Hz), 4.25 (1H, m), 5.77 (1H, d, J = 1.4Hz), 723 (1H, dt, J=7.2and 1.4Hz) 7.3-7.5 (3H, m).

Eksempel 104 Example 104

5R, 3- ( 4- f cyanoacetamidolfenyl- 6S-( lR- hydroksyetyl)- 7- okso- 4-tia- l- azabicyklor3, 2. 0lhept- 2- en- 2- karboksylsyre 5R, 3- ( 4- f cyanoacetamidolphenyl- 6S-( 1R- hydroxyethyl)- 7- oxo- 4-thia- l- azabicyclo3, 2. 0lhept- 2- en- 2- carboxylic acid

Til en omrørt oppløsning av 2-( trimetylsilyl )etyl-5R, 3-( 4-aminof enyl )-6S-(lR-hydroksyetyl)-7-okso-4-tia-l-azabicyklo[-3,2,0]hept-2-en-2-karboksylat (400 mg) i tetrahydrofuran (20 ml) ble det tilsatt cyanoeddiksyre (126 mg) og dicykloheksyl-karbodiimid (304 mg). Etter 30 minutter ble blandingen filtrert; filtratet ble fordelt mellom etylacetat og vann. Det organiske laget ble vasket med IM sitronsyre, med mettet vandig natriumbikarbonat og saltvannsoppløsning, ble tørket og inndampet i vakuum. Kromatografi av resten over silikagel og eluering med heksan-etylacetatblandinger ga To a stirred solution of 2-(trimethylsilyl)ethyl-5R,3-(4-aminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[-3,2,0] to hept-2-ene-2-carboxylate (400 mg) in tetrahydrofuran (20 ml) was added cyanoacetic acid (126 mg) and dicyclohexylcarbodiimide (304 mg). After 30 minutes, the mixture was filtered; the filtrate was partitioned between ethyl acetate and water. The organic layer was washed with 1M citric acid, with saturated aqueous sodium bicarbonate and brine, dried and evaporated in vacuo. Chromatography of the residue over silica gel and eluting with hexane-ethyl acetate mixtures gave

2-( trimetylsilyl) etyl- 5R. 3-( 4- rcyanoacetamidolfenyl)- 6S-( lR- 2-(trimethylsilyl)ethyl- 5R. 3-( 4- rcyanoacetamidolphenyl)- 6S-( 1R-

hydr oksyetyl ) - 7- okso- 4- t ia- l- azabi cyklo f 3 , 2 , 0] hept- 2- en- 2-karboksylat (177 mg): hydroxyethyl)-7-oxo-4-thia-l-azabicyclof 3,2,0]hept-2-ene-2-carboxylate (177 mg):

v maks (CDC13) 1788 og 1710 cm"<1>v max (CDC13) 1788 and 1710 cm"<1>

S (CDCI3) 0,01 (9H, s), 0,98 (2H, m), 1,38 (3H, d, S (CDCl 3 ) 0.01 (9H, s), 0.98 (2H, m), 1.38 (3H, d,

J=6,3Hz), 3,59 (2H, s), 3,80 (1H, dd, J=l,6 og 7,1Hz), 4,2 0 (3H, m), 5,68 (1H, d, J=l,6Hz), 7,53 (4H, m), 8,14 (1H, s). J=6.3Hz), 3.59 (2H, s), 3.80 (1H, dd, J=1.6 and 7.1Hz), 4.2 0 (3H, m), 5.68 (1H , d, J=1.6Hz), 7.53 (4H, m), 8.14 (1H, s).

Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 88, ble en oppløsning av denne estren (177 mg) i tørr tetrahydrofuran (5 ml) behandlet med en IM oppløsning av tørr tetrabutylammoniumfluorid (0,374 ml), med tilsats av kaliumhydrogenkarbonat (37 mg) slik at man fikk et råprodukt (145 mg) som ble renset ved reversert-fase HPLC slik at man fikk forbindelsen i overskriften (9 mg): S (D20, inneholdende spor av KHCO3) 1,3 0 (3H, d, J = 6,4Hz), 3,96 (1H, In a method analogous to the method used in example 88, a solution of this ester (177 mg) in dry tetrahydrofuran (5 ml) was treated with an IM solution of dry tetrabutylammonium fluoride (0.374 ml), with the addition of potassium bicarbonate (37 mg) so that a crude product (145 mg) was obtained which was purified by reversed-phase HPLC to give the title compound (9 mg): S (D 2 O, containing traces of KHCO 3 ) 1.3 0 (3H, d, J = 6, 4Hz), 3.96 (1H,

dd, J-l,4 og 6,0Hz), 4,25 (1H, m),^5,75 (1H, d, J=l,4Hz), 7,44 (4H, s). dd, J-1.4 and 6.0Hz), 4.25 (1H, m), ^5.75 (1H, d, J=1.4Hz), 7.44 (4H, s).

Eksempel 105 Example 105

5 R , 6S - ( IR- hydr oksyetyl ) - 3- ( 4 - [" metyl am i not i of ormylaminol - fenyl)- 7- okso- 4- tia- l- azabicyklof3, 2. Olhept- 2- en- 2- karboksylsyre 5 R , 6S - ( IR- hydroxyethyl ) - 3- ( 4 - [" methyl amino in ormylaminol - phenyl)- 7- oxo- 4- thia- l- azabicyclof3, 2. Olhept- 2- en- 2- carboxylic acid

En blanding av 2-(trimetylsilyl)etyl-5R,3-(4-aminofenyl)-6S-(lR-hydroksyetyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (200 mg), tetrahydrofuran (5 ml) og metyliso-tiocyanat (72 mg) ble omrørt i 16 timer, og deretter fordelt mellom etylacetat og vann. Det organiske laget ble vasket med vann, med kald IM saltsyre, med vann, med mettet vandig natriumbikarbonat, med saltvannsoppløsning og ble inndampet i vakuum. Kromatografi av resten over silikagel og eluering med etylacetat-heksanblandinger ga 2-( trimetylsilyl ) etyl- 5R. 6S-( IR- hydr oksyetyl ) - 3 - ( 4 - f metyl aminotl of ormylaminol - f enyl )- 7- okso- 4- tia- l- azabicyklor3, 2, Olhept- 2- en- 2- karboksylat (80 mg): vm@aks(CDCI3) 3600, 3410, 1788, 1708 cm-<1>; A mixture of 2-(trimethylsilyl)ethyl-5R,3-(4-aminophenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2- ene-2-carboxylate (200 mg), tetrahydrofuran (5 ml) and methyl isothiocyanate (72 mg) were stirred for 16 hours, then partitioned between ethyl acetate and water. The organic layer was washed with water, with cold 1M hydrochloric acid, with water, with saturated aqueous sodium bicarbonate, with brine and evaporated in vacuo. Chromatography of the residue over silica gel and elution with ethyl acetate-hexane mixtures gave 2-(trimethylsilyl)ethyl-5R. 6S-( IR - hydroxyethyl ) - 3 - ( 4 - f methyl aminotl of ormylaminol - phenyl ) - 7 - oxo - 4 - thia - l - azabicyclo3, 2, Olhept - 2 - en - 2 - carboxylate (80 mg ): vm@aks(CDCI3) 3600, 3410, 1788, 1708 cm-<1>;

S (CDCI3) 0,001 (9H, s), 0,99 (2H, m), 1,39 (3H, d, S (CDCl 3 ) 0.001 (9H, s), 0.99 (2H, m), 1.39 (3H, d,

J=6,3Hz), 1,96 (1H, bred), 3,16 (3H, d, J=4,5H-z), 3,81 (1H, dd, J=l,6 og 6,6Hz), 4,23 (3H, m), 5,71 (1H, d, J=l,6Hz), 6,24 (1H, bred), 7,20og 7,55 (4H, AA'BB', J=8,5Hz), 7,74 (1H, s). J=6.3Hz), 1.96 (1H, broad), 3.16 (3H, d, J=4.5H-z), 3.81 (1H, dd, J=1.6 and 6.6Hz ), 4.23 (3H, m), 5.71 (1H, d, J=1,6Hz), 6.24 (1H, broad), 7.20 and 7.55 (4H, AA'BB', J =8.5Hz), 7.74 (1H, s).

Denne esteren (200 mg) ble behandlet ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 88 med tetrahydrofuran (10 ml) og en oppløsning av tørr tetrabutylammoniumfluorid i tetrahydrofuran (IM, 0,417 ml), med tilsats av kal iumbikarbonat (42 mg). Etter ioneveksling og reversert fasekromatografi fikk man forbindelsen i overskriften (16 mg). This ester (200 mg) was treated by a method analogous to the method used in Example 88 with tetrahydrofuran (10 ml) and a solution of dry tetrabutylammonium fluoride in tetrahydrofuran (1M, 0.417 ml), with the addition of potassium bicarbonate (42 mg). After ion exchange and reversed phase chromatography, the title compound was obtained (16 mg).

S (D20, inneholdende KHCO3) 1,29 (3H, d, J=6,4Hz), 2,96 (3H, S (D2O, containing KHCO3) 1.29 (3H, d, J=6.4Hz), 2.96 (3H,

s), 3,96 (1H, dd, J-l ,3 og 5, 9Hz) , 4,24. (1H, m), 5,75 (1H, d, J-l, 3Hz), 7,23 og 7,43 (4H, AA' BB' , J=8,6Hz). s), 3.96 (1H, dd, J-1 ,3 and 5, 9Hz) , 4.24. (1H, m), 5.75 (1H, d, J-1, 3Hz), 7.23 and 7.43 (4H, AA' BB' , J=8.6Hz).

Eksempel 106 Example 106

Kalium- 5R . 6S-( lR- hvdroksvetyl )- 3-( 3- metvlsulf inylf enyl )- 7-okso- 4- tia- l- azabicyklor3. 2, 0lhept- 2- en- 2- karboksylat Ved fremgangsmåter analoge de som er benyttet i eksemplene 15, 16, 17, 18 og 19, og med utgangspunkt i 3-(metyltio )-benzosyre fikk man Potassium- 5R . 6S-(1R-hydroxymethyl)-3-(3-methylsulfinylphenyl)-7-oxo-4-thia-1-azabicyclo3. 2,0lhept-2-ene-2-carboxylate By methods analogous to those used in examples 15, 16, 17, 18 and 19, and starting from 3-(methylthio)-benzoic acid, one obtained

4- nitrobenzyl- 5R. 6S-( lR- hydroksyetyl)- 3-( 3- metyItiofenyl)- 7-okso- 4- tia- l- azabicyklof3. 2, Olhept- 2- en- 2- karboksylat som et gult skum. 4- nitrobenzyl- 5R. 6S-(1R-hydroxyethyl)-3-(3-methylthiophenyl)-7-oxo-4-thia-1-azabicyclof3. 2, Olhept- 2- en- 2- carboxylate as a yellow foam.

§ (CDCI3) 1,40 (3H, d, J = 6,4Hz), 2,10 (1H, d, J=4,3Hz), § (CDCl3) 1.40 (3H, d, J = 6.4Hz), 2.10 (1H, d, J=4.3Hz),

2,44 (3H, s), 3,86 (1H, dd, J-l,5 og 6,4Hz), 4,31 (1H, m), 5,12 og 5,28 (2H, AB, Jgem=13,8Hz), 2.44 (3H, s), 3.86 (1H, dd, J-1.5 and 6.4Hz), 4.31 (1H, m), 5.12 and 5.28 (2H, AB, Jgem=13 ,8Hz),

5,75 (1H, d, J=l,5Hz), 7,17 (1H, m), 7,28 (3H, m), 8,13 (2H, d, J=8,8Hz). 5.75 (1H, d, J=1.5Hz), 7.17 (1H, m), 7.28 (3H, m), 8.13 (2H, d, J=8.8Hz).

Dette sulfidet (183 mg) ble behandlet ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 20 med 80% 3-klorpenbenzosyre (92 mg) slik at man fikk 4- nitrobenzyl-5R. 6S-( lR- hvdroksvetvl)- 3-( 3- metylsulfinvlfenyl) 7- okso- 4- tia-l- azabicyklor3. 2, 0lhept- 2- en- 2- karboksylat This sulfide (183 mg) was treated by a method analogous to the method used in example 20 with 80% 3-chloropenbenzoic acid (92 mg) so that 4-nitrobenzyl-5R was obtained. 6S-(1R-hydroxymethyl)-3-(3-methylsulfinylphenyl)7-oxo-4-thia-1-azabicyclo3. 2,0lhept-2-ene-2-carboxylate

(107 mg). (107 mg).

S (aceton-d6) 1,33 (3H, d, J=6,3Hz), 2,67 (3H, s), 3,98 S (acetone-d6) 1.33 (3H, d, J=6.3Hz), 2.67 (3H, s), 3.98

(1H, dd, J-l,7 og 6,2Hz), 4,23 (1H, m), 4,48 (1H, d, J=4,9Hz), 5,21 og 5,35 (2H, AB, Jgem=14,2Hz), 5,93 (1H, d, J=l,7Hz), 7,51 og 8,16 (4H, AA'BB', J=8,5Hz), 7,6-7,8 (4H, m). (1H, dd, J-1,7 and 6.2Hz), 4.23 (1H, m), 4.48 (1H, d, J=4.9Hz), 5.21 and 5.35 (2H, AB, Jgem=14.2Hz), 5.93 (1H, d, J=1.7Hz), 7.51 and 8.16 (4H, AA'BB', J=8.5Hz), 7.6-7, 8 (4H, m).

Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 7 ble dette sulfoksydet (107 mg) hydrogenert i nærvær av 10% palladium-på-trekull (100 mg), kaliumhydrogenkarbonat, dioksan (6 ml) og vann (6 ml) slik at man fikk forbindelsen i overskriften (65 mg). By a method analogous to the method used in example 7, this sulfoxide (107 mg) was hydrogenated in the presence of 10% palladium-on-charcoal (100 mg), potassium bicarbonate, dioxane (6 ml) and water (6 ml) so that the compound was obtained in the title (65 mg).

S (D20) 1,29 (3H, d, J=6,5Hz), 2,85 (3H, s), 3,99 (1H, dd, S (D20) 1.29 (3H, d, J=6.5Hz), 2.85 (3H, s), 3.99 (1H, dd,

J-l,5 og 6Hz), 4,25 (1H, m), 5,79 (1H, d, J=l,5Hz), 7,58-7,80 (4H, m). J-1.5 and 6Hz), 4.25 (1H, m), 5.79 (1H, d, J=1.5Hz), 7.58-7.80 (4H, m).

Eksempel 107 Example 107

Kalium- 5R . 6S-( lR- hvdroksyetyl )- 3-( 3- metvlsulfonvlfenyl )- 7-okso- 4- tia- l- azabicyklor3 . 2 , 0~ lhept- 2- en- 2- karboksylat Potassium- 5R . 6S-(1R-hydroxyethyl)-3-(3-methylsulfonylphenyl)-7-oxo-4-thia-1-azabicyclo3. 2 , 0~ lhept- 2- en- 2- carboxylate

Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 22 og ved anvendelse av 4-nitrobenzyl-5R,6S-( 1R-hy dr oksyetyl )-3-( 3-me ty 1 sul f i ny If enyl )-7-okso-4-tia-l-azabicyklo[3 ,2 , 0]hept-2-en-2-karboksylat (414 mg), 80% 3-klorperbenzosyre (165 mg) og etylacetat (40 ml) fikk man 4-nitrobenzyl- 5R, 6S-( lR- hydroksyetyl)- 3-( 3- metylsulfonvlfenyl)- 7- ok so- 4- t ia- l- azabi cyklo f 3 . 2 , 0" lhept- 2- en- 2- karboksylat (76 mg). In a method analogous to the method used in example 22 and using 4-nitrobenzyl-5R,6S-(1R-hydroxyethyl)-3-(3-methylsulfinyl)-7-oxo-4- thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (414 mg), 80% 3-chloroperbenzoic acid (165 mg) and ethyl acetate (40 ml) gave 4-nitrobenzyl-5R,6S -(1R-hydroxyethyl)-3-(3-methylsulfonylphenyl)-7-oxo-4-thia-l-azabi cyclo f 3 . 2.0" lhept-2-ene-2-carboxylate (76 mg).

(aceton-d6) 1,33 (3H, d, J=6,3Hz), 2,84 (3H, s), 4,00 (acetone-d6) 1.33 (3H, d, J=6.3Hz), 2.84 (3H, s), 4.00

(1H, dd, J = l,7 og 6,1Hz), 4,23 (1H, m), 4,47 (1H, d, J=4,9Hz), 5,20 og 5,35 (2H, AB, Jgem=14Hz), 5,95 (1H, d, J=l,7Hz), 7,52 og 8,18 (4H, AA'BB', J=8,9Hz), 7,70 (1H, t, J=7,6Hz), 7,85 (1H,~d, J=7,4Hz), 8,00 (1H, dd, J-l,2 og 7,3Hz), 8,06 (1H, m). (1H, dd, J = 1.7 and 6.1Hz), 4.23 (1H, m), 4.47 (1H, d, J=4.9Hz), 5.20 and 5.35 (2H, AB, Jgem=14Hz), 5.95 (1H, d, J=1.7Hz), 7.52 and 8.18 (4H, AA'BB', J=8.9Hz), 7.70 (1H, t, J=7.6Hz), 7.85 (1H,~d, J=7.4Hz), 8.00 (1H, dd, J-l,2 and 7.3Hz), 8.06 (1H, m) .

Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 7 ble dette sulfonet (76 mg) hydrogenert i nærvær av 10% palladium-på-trekull (75 mg), kaliumhydrogenkarbonat (15,3 mg), dioksan (4 ml) og vann (4 ml) .slik at man fikk kaliumsaltet i overskriften (39 mg). By a method analogous to the method used in Example 7, this sulfone (76 mg) was hydrogenated in the presence of 10% palladium-on-charcoal (75 mg), potassium bicarbonate (15.3 mg), dioxane (4 ml) and water (4 ml ) .so that the potassium salt in the title was obtained (39 mg).

S (D20) 1,31 (3H, d, J=6,4Hz), 3,25 (3H, s), 4,00 (1H, dd, S (D20) 1.31 (3H, d, J=6.4Hz), 3.25 (3H, s), 4.00 (1H, dd,

J-l,4 og 5 , 9Hz) , 4,26 (1H, m), 5,80 ( 1H, d, J=l,4Hz), 7,63 (1H, t, J=7,8Hz), 7,77_(1H, m), 7,91 (1H, dm, J~7,8Hz), 7,98 (1H, t, J~l,6Hz). J-l,4 and 5 , 9Hz) , 4.26 (1H, m), 5.80 ( 1H, d, J=l,4Hz), 7.63 (1H, t, J=7.8Hz), 7, 77_(1H, m), 7.91 (1H, dm, J~7.8Hz), 7.98 (1H, t, J~1.6Hz).

Eksempel 108 Example 108

2-( trimetylsilyl ) etvl- 5R . 6S-( lR- hydroksyetyl )- 3-( 4- formyl-am inofenyl)- 7- okso- 4- tia- l- azabicyklor3, 2, 0lhept- 2- en- 2-karboksylat 2-(trimethylsilyl)ethyl-5R. 6S-(1R-hydroxyethyl)-3-(4-formyl-aminophenyl)-7-oxo-4-thi-1-azabicyclo3,2,0lhept-2-ene-2-carboxylate

En blanding av 2 - (tr Imetyl si ly 1 )etyl-5R , 3-( 4-f ormylamino )-fenyl-6S-( lR-hydroksyetyl)-7-okso-4-tia-l-azabicyklo[3,2,0]-hept-2-en-2-karboksylat (500 mg), tetrahydrofuran (10 ml), 4-dimetylaminopyridin (15 mg) og eddiksyreanhydrid (1,09 ml) ble omrørt ved romtemperatur i 30 minutter, og deretter fordelt mellom etylacetat og vann. Det organiske laget ble vasket med mettet vandig natriumbikarbonat, med saltvannsopp-løsning, ble tørket over vannfritt natriumsulfat, og inndampet i vakuum. Kromatografi på silikagel og eluering med etylacetat-heksanblandinger ga forbindelsen i overskriften (211 mg). A mixture of 2-(trimethylsilyl)ethyl-5R,3-(4-formylamino)-phenyl-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2 ,0]-hept-2-ene-2-carboxylate (500 mg), tetrahydrofuran (10 ml), 4-dimethylaminopyridine (15 mg) and acetic anhydride (1.09 ml) were stirred at room temperature for 30 minutes, and then distributed between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium bicarbonate, with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. Chromatography on silica gel and eluting with ethyl acetate-hexane mixtures gave the title compound (211 mg).

S (CDCI3) 0,00 (9H, s), 0,97 (2H, m) , 1,42 (3H, d, S (CDCl 3 ) 0.00 (9H, s), 0.97 (2H, m), 1.42 (3H, d,

J=6,4Hz), 2,08 (3H, s), 3,90 (1H, dd, J=l, 5 og 7,6Hz), 4,20 (2H, m), 5,29 (1H, m), 5,64 og 5,62 (1H, 2d, J=l,5Hz), 7,06 (-0.8H, d, J=8,6Hz), 7,4-7,6 (~3,8H, m), 7,88 (~0,4H, d, J=ll,4Hz), 8,37 (~0,6H, d, J=l,6Hz) og 8,75 (~0,4H, d, J=6.4Hz), 2.08 (3H, s), 3.90 (1H, dd, J=l, 5 and 7.6Hz), 4.20 (2H, m), 5.29 (1H, m), 5.64 and 5.62 (1H, 2d, J=1.5Hz), 7.06 (-0.8H, d, J=8.6Hz), 7.4-7.6 (~3, 8H, m), 7.88 (~0.4H, d, J=11.4Hz), 8.37 (~0.6H, d, J=1.6Hz) and 8.75 (~0.4H, d,

J=ll,4Hz). J=11.4Hz).

S (DMS0-d6) 0,00 (9H, s), 0,84 (2H, t, J=7,5Hz), 1,30 (3H, S (DMS0-d6) 0.00 (9H, s), 0.84 (2H, t, J=7.5Hz), 1.30 (3H,

d, J=6,3Hz), 2,03 (3H, s), 4,12 (2H, m), 4,21 (1H, dd, J-l,5 og 5,5Hz), 5,17 (1H, m), 5,78 (1H, d, J = l,5Hz), 7,43 og 7,62 (4H, AÅ'BB' , JAB=8,8Hz), 8,31 (~0,8H, d, J-l,5Hz), 8,89 d, J=6.3Hz), 2.03 (3H, s), 4.12 (2H, m), 4.21 (1H, dd, J-1,5 and 5.5Hz), 5.17 (1H, m), 5.78 (1H, d, J = 1.5Hz), 7.43 and 7.62 (4H, AÅ'BB' , JAB=8.8Hz), 8.31 (~0.8H, d , J-1.5Hz), 8.89

~(~0,2H, d, J = ll,5Hz), 9,36 (~0,'2H, d, J=ll,5Hz), og 10,44 (~0,8H, d, J=l,5Hz). ~(~0.2H, d, J = ll.5Hz), 9.36 (~0.'2H, d, J=ll.5Hz), and 10.44 (~0.8H, d, J=l .5Hz).

Eksempel 109 Example 109

5R, 6S- ( 1 R- acetoksyetyl)- 3-( 4- formylaminofenyl)- 7- okso- 4- tia-l- azabi cyklo f 3 , 2 , 0lhept- 2- en- 2- karboksylsyre 5R, 6S-(1R-acetoxyethyl)-3-(4-formylaminophenyl)-7-oxo-4-thia-1-azabicyclof 3,2,0lhept-2-ene-2-carboxylic acid

Råproduktet oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 88, men ved anvendelse av 2-(trimetylsilyl)etyl-5R,6S-(lR-acetoksyetyl)-3-(4-formylamino-fenyl )- 7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (200 mg), tetrahydrofuran (10 ml) og en oppløsning av tørr tetrabutylammoniumfluorid i tetrahydrofuran (IM, 0,41 ml), med tilsats av kal iumbikarbonat (41 mg) ble renset ved ioneveksling og reversert-fasekromatografi slik at man fikk den rene forbindelsen i overskriften (49 mg). The crude product obtained by a method analogous to the method used in example 88, but using 2-(trimethylsilyl)ethyl-5R,6S-(1R-acetoxyethyl)-3-(4-formylamino-phenyl)-7-oxo-4-thia -1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (200 mg), tetrahydrofuran (10 ml) and a solution of dry tetrabutylammonium fluoride in tetrahydrofuran (1M, 0.41 ml), with the addition of potassium bicarbonate (41 mg) was purified by ion exchange and reversed-phase chromatography to give the pure title compound (49 mg).

S (D20) 1,41 (3H, d, J=6,3Hz), 2,15 (3H, s), 4,21 (1H, dd, S (D20) 1.41 (3H, d, J=6.3Hz), 2.15 (3H, s), 4.21 (1H, dd,

J-l,5 og 5,5Hz), 5,30 (1H, m), 5,82 (1H, d, J=l,5Hz), 7,4 5 og 7,5 0 (4H, AA'BB', JAB=8,8Hz), 8,25 (1H, bs). J-1.5 and 5.5Hz), 5.30 (1H, m), 5.82 (1H, d, J=1.5Hz), 7.4 5 and 7.5 0 (4H, AA'BB', JAB=8.8Hz), 8.25 (1H, bs).

Eksempel 110 Example 110

4- nitrobenzyl- 5S, 3-( 3- aminokarbonyl f enyl )- 6S-( lR- hydr oksyetyl )- 7- okso- 4- tia- l- azabicyklof3, 2. Olhept- 2- en- 2- karboksylat 4- nitrobenzyl- 5S, 3-( 3- aminocarbonyl phenyl )- 6S-( 1R- hydroxyethyl )- 7- oxo- 4- thia- l- azabicyclof3, 2. Olhept- 2- ene- 2- carboxylate

En blanding av 4-nitrobenzyl-5R,3-(3-aminokarbonylfenyl)-6S-(IR-hydr ok syetyl)-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2- karboksylat (120 mg) og acetonitril (7,5 ml) ble oppvarmet i en forseglet flaske ved 85±3°C i 20 timer, og ble deretter inndampet i vakuum. Kromatografi av resten ga noe utgangs-trans-penem og forbindelsen i overskriften (20 mg). A mixture of 4-nitrobenzyl-5R,3-(3-aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene -2-carboxylate (120 mg) and acetonitrile (7.5 mL) were heated in a sealed flask at 85±3°C for 20 hours, then evaporated in vacuo. Chromatography of the residue gave some starting trans-penem and the title compound (20 mg).

S (DMS0-d6) 1,48 (3H, d, J=6,3Hz), 4,02 (1H, dd, J=3,8og 5,5Hz), 4,30 (1H, m), 5,15 og 5,30 (2H, AB, Jgem=13,8Hz) , 5,95 (1H, d, J=3,8Hz), 7,2-8,1 (10H, m). S (DMS0-d6) 1.48 (3H, d, J=6.3Hz), 4.02 (1H, dd, J=3.8and 5.5Hz), 4.30 (1H, m), 5, 15 and 5.30 (2H, AB, Jgem=13.8Hz), 5.95 (1H, d, J=3.8Hz), 7.2-8.1 (10H, m).

Eksempel 111 Example 111

Kalium- 5S , 3-( 3- aminokarbonylf enyl )- 6S-( lR- hydroksyetyl )- 7-okso- 4- tia- l- azabicyklor3. 2, 0lhept- 2- en- 2- karboksylat Potassium- 5S, 3-( 3- aminocarbonylphenyl )- 6S-( 1R- hydroxyethyl)- 7-oxo- 4- thia- 1-azabicyclo3. 2,0lhept-2-ene-2-carboxylate

Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 36, og ved anvendelse av 4-nitrobenzyl-5S,3-(3-aminokarbonylfenyl)- 6S-(lR-hydroksyetyl )-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (50 mg), dioksan (5 ml), vann (5 ml), kaliumbikarbonat (10 mg) og 10% palladium-på-trekull (50 mg), fikk man forbindelsen i overskriften In a method analogous to the method used in example 36, and using 4-nitrobenzyl-5S,3-(3-aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3, 2,0]hept-2-ene-2-carboxylate (50 mg), dioxane (5 ml), water (5 ml), potassium bicarbonate (10 mg) and 10% palladium-on-charcoal (50 mg), gave the connection in the header

(27 mg). (27 mg).

S (D20) 1,42 (3H, d, J=6,3Hz), 4,05 (1H, dd, J=4og 6Hz), S (D20) 1.42 (3H, d, J=6.3Hz), 4.05 (1H, dd, J=4and 6Hz),

4,26 (1H, m), 5,90 (1H, d, J=4Hz), 7,4-7,8 (4H, m). 4.26 (1H, m), 5.90 (1H, d, J=4Hz), 7.4-7.8 (4H, m).

Eksempel 112 Example 112

4- nitrobenzyl- 5R. 3- r3-( allyloksykarbonyl ) fenyl1- 6S-( 1R-hydroksyetyl )- 7- okso- 4- tia- l- azabicyklor3. 2, 0~ lhept- 2- en- 2-karboksylat 4- nitrobenzyl- 5R. 3-r3-(allyloxycarbonyl)phenyl1-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo3. 2,0~lhept-2-ene-2-carboxylate

Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 39, men med utgangspunkt i en oppløsning av isoftaloylklorid (60,9 g) i dioksan (400 ml), allylalkohol (20,9 g), trietylamin (36,4 g), diklormetan (600 ml), pyridin (28,5 g) og hydrogensulfid (overskudd) fikk man In a method analogous to the method used in example 39, but starting from a solution of isophthaloyl chloride (60.9 g) in dioxane (400 ml), allyl alcohol (20.9 g), triethylamine (36.4 g), dichloromethane (600 ml), pyridine (28.5 g) and hydrogen sulphide (excess) were obtained

3- ( allyloksykarbonyl) tiobenzosyre. 3-(allyloxycarbonyl)thiobenzoic acid.

vmaks 2550, 1725 cm-<1>vmax 2550, 1725 cm-<1>

S (CDCI3) 5,0 (2H, m), 5,5 (3H, bred m), 6,0 (1H, m), S (CDCl3) 5.0 (2H, m), 5.5 (3H, broad m), 6.0 (1H, m),

7,5-9,1 (4H, m) 7.5-9.1 (4H, m)

En oppløsning av denne tiobenzosyren (5 g) i aceton (35 ml) ble behandlet ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 30 med en blanding av IM natriumhydroksy-doppløsning (22 ml) og en oppløsning av 4-acetoksy-3R-(1R-[dimetyl(2-metylprop-2-yl)silyloksy]etyl)-azetidin-2-on (4,3 g) i acetonrvann (3:1) (50 ml) slik at man fikk 4R- f3-( allvloksvkarbonyllbenzoyltiol- 3S-( IR- fdimetyl( 2- metylprop- 2-yl) silvloksyletyl) azetidin- 2- on (4,3 g). A solution of this thiobenzoic acid (5 g) in acetone (35 ml) was treated by a method analogous to the method used in Example 30 with a mixture of 1M sodium hydroxide solution (22 ml) and a solution of 4-acetoxy-3R-(1R -[dimethyl(2-methylprop-2-yl)silyloxy]ethyl)-azetidin-2-one (4.3 g) in acetone/water (3:1) (50 ml) to give 4R-f3-(alloxycarbonylbenzoylthiol- 3S-(IR-fdimethyl(2-methylprop-2-yl)silvoxylethyl)azetidin-2-one (4.3 g).

S (CDCI3) 0,00 (6H, s), 0,80 (9H, s), 1,15 (3H, d, S (CDCl 3 ) 0.00 (6H, s), 0.80 (9H, s), 1.15 (3H, d,

J=6,3Hz), 3,22 (1H, d,, J=2,5 og 3,6Hz), 4,22 (1H, m), 4,76 (1H, dd, J-1,1 og 6,8Hz), 5,2-5,4 (2H, m), 5,41 (1H, d, J=2,5Hz) , 5,92 (1H, m), 6,64 (1H, s), 7,5-8,6 (4H, m). J=6.3Hz), 3.22 (1H, d,, J=2.5 and 3.6Hz), 4.22 (1H, m), 4.76 (1H, dd, J-1.1 and 6.8Hz), 5.2-5.4 (2H, m), 5.41 (1H, d, J=2.5Hz) , 5.92 (1H, m), 6.64 (1H, s) , 7.5-8.6 (4H, m).

En oppløsning av dette azetidinonet (22,1 g) i diklormetan (250 ml) ble behandlet ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 31 med kalsiumkarbonat (12,3 g) og diisopropyletylamin (9,5 g) og en oppløsning av 4-nitroben-zylkloroksalat (14,4 g) i diklormetan A solution of this azetidinone (22.1 g) in dichloromethane (250 ml) was treated by a method analogous to the method used in example 31 with calcium carbonate (12.3 g) and diisopropylethylamine (9.5 g) and a solution of 4- nitrobenzyl chlorooxalate (14.4 g) in dichloromethane

(25 ml) slik at man i form av en gul olje fikk 4- nitrobenyl-( 4R . 3- f3-( allvloksvkarbonvl ) benzovlt iol - 3S- f IR- rdimetvl ( 2-metylprop- 2- yl) silyloksyletyl) azetidin- 2- on- l- vl) oksoacetat (25 ml) so that, in the form of a yellow oil, 4-nitrobenyl-(4R.3-f3-(allvloxvcarbonvl)benzovlt iol-3S-fIR- dimethvl (2-methylprop-2-yl)silyloxyethyl)azetidin- 2-on-l-vl) oxoacetate

S (CDCI3) 0,00 (3H, s), 0,09 (3H, s), 0,83 (9H, s), 1,26 S (CDCl 3 ) 0.00 (3H, s), 0.09 (3H, s), 0.83 (9H, s), 1.26

(3H, d, J=6,3Hz), 3,65 (1H,~t, J=3, 5Hz), 4,41 (1H, m), 4,85 (2H,~d, J=5,8Hz), 5,30-5,45 (4H, m), 6,02 (1H, m), 6,20 (1H, d, J=3,5Hz), 7,5-7,6 (3H, m), 8,09-8,3 (4H, m), 8,60 (1H,~t, J=l,6Hz). (3H, d, J=6.3Hz), 3.65 (1H,~t, J=3, 5Hz), 4.41 (1H, m), 4.85 (2H,~d, J=5, 8Hz), 5.30-5.45 (4H, m), 6.02 (1H, m), 6.20 (1H, d, J=3.5Hz), 7.5-7.6 (3H, m), 8.09-8.3 (4H, m), 8.60 (1H,~t, J=1.6Hz).

En oppløsning av denne oljen i xylen (500 ml) ble behandlet ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 32 med en oppløsning av trietylfosfitt (16,3 g) i xylen (100 ml) slik at man fikk A solution of this oil in xylene (500 ml) was treated by a method analogous to the method used in example 32 with a solution of triethyl phosphite (16.3 g) in xylene (100 ml) so that one obtained

4- nitrobenbenzyl- 5R, 3- f 3-( allyloksykarbonylfenyll- 6S-( 1R-fdimetyl( 2- metylprop- 2- yl) silyloksy] etyl) 7- okso- 4- tia- l-azabicyklor3, 2, 0lhept- 2- en- 2- karboksylat 25,3 g). 4- nitrobenbenzyl- 5R, 3- f 3-( allyloxycarbonylphenyll- 6S-( 1R-fdimethyl( 2- methylpropyl- 2- yl) silyloxy] ethyl) 7- oxo- 4- thia- l-azabicyclo3, 2, 0lhept- 2 - one-2-carboxylate 25.3 g).

S (CDC13) 0,06 (3H, s), 0,08 (3H, s), 0,85 (9H, s), 1,27 S (CDCl 3 ) 0.06 (3H, s), 0.08 (3H, s), 0.85 (9H, s), 1.27

(3H, d, J=6,3Hz), 3,83 (1H, dd, J-l,3 og 3,9Hz), 4,28 (1H, m), 4,81 (2H, d, J=5,5Hz), 5,09 (1H, d, J=13,7Hz), 5,2-5,4 (3H, m), 5,75 (1H, d, J-l,3Hz), 6,00 (1H, m), 7,3-7,6 (4H, m), 8,1-8,3 (4H, m). (3H, d, J=6.3Hz), 3.83 (1H, dd, J-1,3 and 3.9Hz), 4.28 (1H, m), 4.81 (2H, d, J=5, 5Hz), 5.09 (1H, d, J=13.7Hz), 5.2-5.4 (3H, m), 5.75 (1H, d, J-l,3Hz), 6.00 (1H, m), 7.3-7.6 (4H, m), 8.1-8.3 (4H, m).

En oppløsning av dette 4-nitrobenzylkarboksylatet (34,2 g) i tetrahydrofuran (70 ml) ble behandlet ved. en fremgangsmåte analog fremgangsmåten benyttet i eksempel 37 med iseddiksyre (32,8 g) og en IM oppløsning av tetrabutylammoniumfluorid i tetrahydrofuran (163 ml) slik at man fikk hydroksyetylfor-bindelsen i overskriften (20,4 g). A solution of this 4-nitrobenzylcarboxylate (34.2 g) in tetrahydrofuran (70 ml) was treated with a method analogous to the method used in example 37 with glacial acetic acid (32.8 g) and an IM solution of tetrabutylammonium fluoride in tetrahydrofuran (163 ml) so that the hydroxyethyl compound in the title was obtained (20.4 g).

S (CDCI3) 1,40 (3H, d, J = 6,3Hz), 3,88 (1H, dd, J-1,6 og 6,5Hz), 4,31 (1H, m), 4,80 (2H"; m), 5,10 (1H, d, J=13,7Hz), 5,2-5,5 (3H, m), 5,79 (1H, d, J=l,6Hz), 6,00 (1H, m), 7,33 (2H, d, J=8,8Hz), 7,44 (1H, t, J=7,8Hz), 7,61 (1H, m), 8,05-8,23 (4H, m). S (CDCl3) 1.40 (3H, d, J = 6.3Hz), 3.88 (1H, dd, J-1.6 and 6.5Hz), 4.31 (1H, m), 4.80 (2H"; m), 5.10 (1H, d, J=13.7Hz), 5.2-5.5 (3H, m), 5.79 (1H, d, J=1.6Hz), 6.00 (1H, m), 7.33 (2H, d, J=8.8Hz), 7.44 (1H, t, J=7.8Hz), 7.61 (1H, m), 8, 05-8.23 (4H, m).

Eksempel 113 Example 113

4- nitrobenzyl- 5R. 6S-( lR- acetoksyetyl)- 3- r3-( allyloksykarbonyl ) f enyl]- 7- okso- 4- tia- l- azabicyklof3. 2. 0] hept- 2- en- 2-karboksylat 4- nitrobenzyl- 5R. 6S-(1R-acetoxyethyl)-3-r3-(allyloxycarbonyl)phenyl]-7-oxo-4-thia-1-azabicyclof3. 2. 0] hept-2-ene-2-carboxylate

En blanding av 4-nitrobenzyl-5R,3[3-(allyloksykarbonyl)-fenyl] -6S-( lR-hydroksyetyl )-7-okso-4-tia-l-azabicyklo[3 ,2,0.]-hept-2-en-2-karboksylat (1,0 g), tørr tetrahydrofuran (15 ml), eddiksyreanhydrid (1,0 g) og 4-dimetylaminopyridin (23 mg) ble omrørt under en nitrogenatmosfære i 30 minutter, og deretter fordelt mellom etylacetat og vann. Det organiske laget ble vasket med vann, med mettet vandig natriumbikarbo-natoppløsning og ble deretter tørket og inndampet i vakuum. Kromatografi av resten over silikagel og eluering med etylacetat-heksanblandinger ga forbindelsen i overskriften (0,9 g). A mixture of 4-nitrobenzyl-5R,3[3-(allyloxycarbonyl)-phenyl]-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3,2,0.]-hept- 2-ene-2-carboxylate (1.0 g), dry tetrahydrofuran (15 ml), acetic anhydride (1.0 g) and 4-dimethylaminopyridine (23 mg) were stirred under a nitrogen atmosphere for 30 minutes, then partitioned between ethyl acetate and water. The organic layer was washed with water, with saturated aqueous sodium bicarbonate solution and was then dried and evaporated in vacuo. Chromatography of the residue over silica gel and eluting with ethyl acetate-hexane mixtures gave the title compound (0.9 g).

S (CDCI3) 1,45 (3H, d, J=6,3Hz), 2,09 (3H, s), 3,99 (1H, S (CDCl3) 1.45 (3H, d, J=6.3Hz), 2.09 (3H, s), 3.99 (1H,

dd, J=l,8og 5,8Hz), 4,81 (2H,~d, J=5,8Hz), 5,13 (1H, d, J=13,7Hz), 5,2-5,4 (4H, m), 5,73 (1H, d, J=l,8Hz), 6,01 (1H, m), 7,35 (2H, d, J=8,7Hz), 7,45 (1H,~t, J=7,9Hz), 7,62 (1H, m), 8,08-8,16 (4H, m). dd, J=1.8and 5.8Hz), 4.81 (2H,~d, J=5.8Hz), 5.13 (1H, d, J=13.7Hz), 5.2-5.4 (4H, m), 5.73 (1H, d, J=1.8Hz), 6.01 (1H, m), 7.35 (2H, d, J=8.7Hz), 7.45 (1H ,~t, J=7.9Hz), 7.62 (1H, m), 8.08-8.16 (4H, m).

Eksempel 114 Example 114

4- nitrobenzyl- 5R, 6S-( lR- acetoksyetyl )- 3-( 3-^ karboksyf enyl )- 4-tia- l- azablcyklor3, 2, 0lhept- 2- en- 2- karboksylat 4-nitrobenzyl-5R,6S-(1R-acetoxyethyl)-3-(3-^carboxyphenyl)-4-thia-1-azablcyclo3,2,0lhept-2-ene-2-carboxylate

En blanding av 4-ni trobenzyl-5R, 6S-(lR-acetoksyetyl )-3-[3-( allyloksykarbonyl ) f enyl ] -7-okso-4-t ia-l-azabi cyklo [3 , 2,0]-hept-2-en-2-karboksylat (0,9 g), diklormetan (10 ml), kallum-2-etylheksanoat (0,46 g), trif enylf osf in (17 mg) _og tetra-kis(trifenylfosfin)palladium (38 mg) ble omrørt ved romtemperatur i en time, og pH ble deretter regulert til 4,4 ved tilsats av kaliumdihydrogenfosfatoppløsning. Den resulterende blandingen ble ekstrahert med etylacetat, som deretter ble tørket og inndampet i vakuum. Kromatografi av resten og eluering med heksan-etylacetat-maursyreblandinger ga forbindelsen i overskriften. A mixture of 4-nitrobenzyl-5R,6S-(1R-acetoxyethyl)-3-[3-(allyloxycarbonyl)phenyl]-7-oxo-4-thia-l-azabicyclo[3,2,0] -hept-2-ene-2-carboxylate (0.9 g), dichloromethane (10 ml), callum-2-ethyl hexanoate (0.46 g), triphenyl phosphine (17 mg) _and tetrakis(triphenylphosphine) palladium (38 mg) was stirred at room temperature for one hour, and the pH was then adjusted to 4.4 by the addition of potassium dihydrogen phosphate solution. The resulting mixture was extracted with ethyl acetate, which was then dried and evaporated in vacuo. Chromatography of the residue and eluting with hexane-ethyl acetate-formic acid mixtures gave the title compound.

S (CDCI3) 1,45 (3H, d, J=6,4Hz), 2,09 (3H, s), 3,99 (1H, S (CDCl3) 1.45 (3H, d, J=6.4Hz), 2.09 (3H, s), 3.99 (1H,

dd, J-l,5 og 7,5 Hz), 5,13 og 5,26 (2H, AB, Jgem=13,1Hz), 5,31 (1H, m), 5,73 (1H, d, J=l,5Hz), 7,36 (2H, d, J=8,8Hz), 7,45-7,72 (2H, m), 7,9-8,2 (4H, m). dd, J-l.5 and 7.5 Hz), 5.13 and 5.26 (2H, AB, Jgem=13.1Hz), 5.31 (1H, m), 5.73 (1H, d, J= 1.5Hz), 7.36 (2H, d, J=8.8Hz), 7.45-7.72 (2H, m), 7.9-8.2 (4H, m).

Eksempel 115 Example 115

4- nitrobenzyl- 5R. 6S-( lR- acetoksyetyl)- 3 - ( 3- aminokarbonylfenyl)- 7- okso- 4- tia- l- azabicyklor3, 2, 0lhept- 2- en- 2- karboksylat 4- nitrobenzyl- 5R. 6S-(1R-acetoxyethyl)-3-(3-aminocarbonylphenyl)-7-oxo-4-thi-1-azabicyclo3,2,0lhept-2-ene-2-carboxylate

Til en omrørt suspensjon av 4-nitrobenzyl-5R,6S-(lR-acetoksyetyl )-3 - ( 3-karboksyf enyl )-7-okso-4-t ia-l-azabi cyklo [3 ,2 ,0] - hept-2-en-2-karboksylat (200 mg) i tørr diklormetan (10 ml) ved 0°C ble det tilsatt trietylamin (0,11 ml) og etylkloro-format (47 mg), etterfulgt etter en time av en oppløsning av ammoniakk (20 mg) i etanol (1 ml). Blandingen ble omrørt i ytterligere en time og ble deretter inndampet i vakuum. Resten ble kromatografert på silikagel. Eluering med etylacetat-heksanblandinger ga forbindelsen i overskriften (98 mg). 5 (DMS0-d6) 1,42 (3H, d, J=6,3Hz), 2,13 (3H, s), 4,22 (1H, dd, J-l,5 og 6Hz), 5,15 og 5,30 (2H, AB, Jgem=13'8Hz).5-14 (1H>d>J=6Hz), 5,92 (1H, d, J=l,5Hz), 6,85 (1H, bs), 7,47-7,8 (4H, m), 7,99 (1H, dt, J-l og 8Hz), 8,03 (1H, t, J-lHz), 8,13 (2H, d, J=8,8Hz). To a stirred suspension of 4-nitrobenzyl-5R,6S-(1R-acetoxyethyl)-3-(3-carboxyphenyl)-7-oxo-4-thia-1-azabicyclo[3,2,0]-hept -2-ene-2-carboxylate (200 mg) in dry dichloromethane (10 ml) at 0°C was added triethylamine (0.11 ml) and ethyl chloroformate (47 mg), followed after one hour by a solution of ammonia (20 mg) in ethanol (1 ml). The mixture was stirred for an additional hour and then evaporated in vacuo. The residue was chromatographed on silica gel. Elution with ethyl acetate-hexane mixtures gave the title compound (98 mg). 5 (DMS0-d6) 1.42 (3H, d, J=6.3Hz), 2.13 (3H, s), 4.22 (1H, dd, J-l.5 and 6Hz), 5.15 and 5 .30 (2H, AB, Jgem=13'8Hz).5-14 (1H>d>J=6Hz), 5.92 (1H, d, J=1.5Hz), 6.85 (1H, bs) , 7.47-7.8 (4H, m), 7.99 (1H, dt, J-l and 8Hz), 8.03 (1H, t, J-lHz), 8.13 (2H, d, J= 8.8Hz).

Alternativt ble forbindelsen i overskriften (83 mg) oppnådd ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 113 ved anvendelse av 4-nitrobenzyl-5R,3-(3-aminokarbonylfenyl )-6S-( (lR-hydroksyetyl )-7-okso-4-tia-l-azabicyklo[3 , 2 , 0] hept-2-en-2-karboksylat (200 mg), tørr tetrahydrofuran (3 ml), eddiksyreanhydrid (0,2 ml) og 4-dimetylaminopyridin (10 mg). Alternatively, the compound in the title (83 mg) was obtained by a method analogous to the method used in example 113 using 4-nitrobenzyl-5R,3-(3-aminocarbonylphenyl)-6S-((1R-hydroxyethyl)-7-oxo-4 -thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (200 mg), dry tetrahydrofuran (3 ml), acetic anhydride (0.2 ml) and 4-dimethylaminopyridine (10 mg).

Eksempel 116 Example 116

Kalium- 5R . 6S-( lR- acetoksyety 1 )- 3-( 3- aminokarbonylfenyl )- 7-okso- 4- tia- l- azabicyklor3. 2 . 0~ lhept- 2- en- 2- karboksylat Potassium- 5R . 6S-(1R-acetoxyethyl 1)-3-(3-aminocarbonylphenyl)-7-oxo-4-thia-1-azabicyclo3. 2. 0~ lhept- 2- en- 2- carboxylate

Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 36 og ved anvendelse av 4-nitrobenzyl-5R, 6S-( 1R-acetoksyetyl )-3-( 3-aminokarbonylf enyl )-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (100 mg), dioksan (1 ml), kaliumbikarbonat (19 mg), vann (1 ml) og 10% palladium-på-trekull (100 mg), fikk man forbindelsen i overskriften (57 mg). In a method analogous to the method used in example 36 and using 4-nitrobenzyl-5R, 6S-(1R-acetoxyethyl)-3-(3-aminocarbonylphenyl)-7-oxo-4-thia-1-azabicyclo[3, 2,0]hept-2-ene-2-carboxylate (100 mg), dioxane (1 ml), potassium bicarbonate (19 mg), water (1 ml) and 10% palladium-on-charcoal (100 mg), gave the title compound (57 mg).

§ (D20) 1,38 (3H, d, J=6,3Hz), 2,13 (3H, s), 4,20 (1H, dd, § (D20) 1.38 (3H, d, J=6.3Hz), 2.13 (3H, s), 4.20 (1H, dd,

J-l, 4 'og 5 , 9Hz ) , 5,31 ( 1H , m), 5,88 (1H, d, J-l,4Hz), 7,48 (1H, t, J=8Hz), 7,60 (1H, dt, J-l,4 og 8Hz), 7,7-7,8 (2H, m). J-l, 4 'and 5 , 9Hz ), 5.31 ( 1H , m), 5.88 (1H, d, J-l,4Hz), 7.48 (1H, t, J=8Hz), 7.60 (1H , dt, J-1.4 and 8Hz), 7.7-7.8 (2H, m).

Eksempel 117 Example 117

2-( trimetvlsilvl) etyl- 2-( 3S- f IR-( dimetyl( 2- metvlprop- 2-yl) si lyloksy) etyl"! - 4R- r4- nltrobenzoyltio"| azetidin- 2- on- l- yl )-3. 3. 3- trietoksy- 3- fosfa- propenoat 2-(trimethylsilyl)ethyl-2-(3S-fIR-(dimethyl(2-methylpropyl-2-yl)silyloxy)ethyl"!-4R-r4-nitrobenzoylthio"|azetidin-2-on-l-yl) -3. 3. 3- triethoxy- 3- phospha-propenoate

Til en oppløsning av 2-(trimetylsilyl)etyl-{3S-[IR-(dimetyl-( 2-me tyl pr op-2-yl) si lyloksy) etyl] - 4R - [4-ni trobenzoyltio] - azetidin-2-on-l-yl-oksoacetat (330 mg) i toluen (5 ml) ved 100° C ble det i løpet av 30 minutter dråpevis tilsatt en oppløsning av trietylfosfitt (0,24 ml) i toluen (1 ml). Etter at blandingen var oppvarmet til 100°C i ytterligere en time, ble den inndampet i vakuum, slik at man fikk en rest som ble kromatografert over silikagel. Eluering med heksan-etylacetatblandinger ga forbindelsen i overskriften-~~ (150 mg) som en gul gummi. To a solution of 2-(trimethylsilyl)ethyl-{3S-[IR-(dimethyl-(2-methyl prop-2-yl)silyloxy)ethyl]-4R-[4-nitrobenzoylthio]-azetidine-2 -on-1-yl-oxoacetate (330 mg) in toluene (5 ml) at 100° C., a solution of triethyl phosphite (0.24 ml) in toluene (1 ml) was added dropwise over the course of 30 minutes. After the mixture was heated to 100°C for a further hour, it was evaporated in vacuo to give a residue which was chromatographed over silica gel. Elution with hexane-ethyl acetate mixtures gave the title compound-~~ (150 mg) as a yellow gum.

v (CDC13) 1752, 1670 og 1620 cm-<1>5.(CDC13) 0,10 (6H, s), 0,84 (11H, m), 1,22 (3H, d, J=6,3Hz), 1,33 (9H, t, J=7Hz), 3,27 (1H, m), 4,21 (9H, m), 5,81 (1H, bred), 8,10 og 8,33 (4H, AA'BB »,<J>AB<=>8,8Hz). v (CDC13) 1752, 1670 and 1620 cm-<1>5.(CDC13) 0.10 (6H, s), 0.84 (11H, m), 1.22 (3H, d, J=6.3Hz ), 1.33 (9H, t, J=7Hz), 3.27 (1H, m), 4.21 (9H, m), 5.81 (1H, wide), 8.10 and 8.33 ( 4H, AA'BB »,<J>AB<=>8.8Hz).

En blanding av denne fosforanen (15 0 mg) og o-xylen (3 ml) ble oppvarmet til 140°C i en time, og deretter inndampet i vakuum. Kromatografi av resten over silikagel og eluering med heksan-etylacetatblandinger ga 2-( trimetylsilyl )-5R , 6S-( 1R-[dimetyl ( 2-metylprop-2-yl)silyloksy]-etyl)-3-(4-nitrofenyl)-7-okso-4-t ia-l-azabi cyklo[3 ,2 , 0]hept-2-en-2-karboksylat ( 97 mg) med egenskaper identiske med egenskapene beskrevet i eksempel 83. A mixture of this phosphorane (150 mg) and o-xylene (3 ml) was heated to 140°C for one hour and then evaporated in vacuo. Chromatography of the residue over silica gel and eluting with hexane-ethyl acetate mixtures gave 2-(trimethylsilyl)-5R,6S-(1R-[dimethyl (2-methylprop-2-yl)silyloxy]-ethyl)-3-(4-nitrophenyl)- 7-oxo-4-thia-l-azabi cyclo[3,2,0]hept-2-ene-2-carboxylate (97 mg) with properties identical to the properties described in example 83.

Eksempel 118 Example 118

4- nitrobenzyl- 2{ 4R- f 3- aminokarbonylbenzoyltiol -3S- f 1R-( dimetyl ( 2- metylprop- 2- yl) si lyloksy ) etyl] - azetidln- 2- on- l-yl)- 3- metylpropenoat 4- nitrobenzyl- 2{ 4R- f 3- aminocarbonylbenzoylthiol -3S- f 1R-( dimethyl ( 2- methylprop- 2- yl) silyloxy ) ethyl] - azetidln- 2- on- l-yl)- 3- methylpropenoate

En oppløsning av sølv-3S-{lR-[dimetyl(2-metylprop-2-yl)silyloksy]-etyl-l-[2-metyl-l-(4-nitrobenzyloksykarbonyl)propenyl]-azetidin-2-on-4R-tiolat (400 mg) i acetonitril (10 ml) ble tilsatt dråpevis til en omrørt oppløsning av isftaloylklorid (612 mg) i acetonitril (29 ml) ved 0°C. Etter 30 minutter ble det tilsatt en oppløsning av ammoniakk (90 mg) i kloroform (5 ml); blandingen ble filtrert og filtratet inndampet i vakuum. Kromatografi av resten på silikagel, og eluering med heksan-etylacetatblandinger ga forbindelsen i overskriften (206 mg). A solution of silver 3S-{1R-[dimethyl(2-methylprop-2-yl)silyloxy]-ethyl-1-[2-methyl-1-(4-nitrobenzyloxycarbonyl)propenyl]-azetidin-2-one-4R -thiolate (400 mg) in acetonitrile (10 mL) was added dropwise to a stirred solution of isophthaloyl chloride (612 mg) in acetonitrile (29 mL) at 0°C. After 30 minutes, a solution of ammonia (90 mg) in chloroform (5 ml) was added; the mixture was filtered and the filtrate evaporated in vacuo. Chromatography of the residue on silica gel, and elution with hexane-ethyl acetate mixtures gave the title compound (206 mg).

§ (CDC13) 0,03 (3H, s), 0,06 (3H, s), 0,82 (9H, s), 1,26 § (CDCl 3 ) 0.03 (3H, s), 0.06 (3H, s), 0.82 (9H, s), 1.26

(3H, d, J=6,3Hz), 2,03 (3H, s), 2, 21 (3H, s), 3,36 (1H, dd, J = 2,6 og 5 , 6Hz ) , 4,25_(1H, m), 5,34 (2H, s), 5,90 (1H, d, J=2,6Hz), 6,2 (2H, bred), 7,50-7,61 (3H, m), 8,17-8,36 (5H, m). (3H, d, J=6.3Hz), 2.03 (3H, s), 2.21 (3H, s), 3.36 (1H, dd, J = 2.6 and 5 , 6Hz ) , 4 .25_(1H, m), 5.34 (2H, s), 5.90 (1H, d, J=2.6Hz), 6.2 (2H, wide), 7.50-7.61 (3H , m), 8.17-8.36 (5H, m).

Eksempel 119 Example 119

4- ni trobenzyl- 2-( 4 R- r3- aminokarbonylbenzoyltio1 - 3S-[" 1R-( dimetyl ( 2- metyl pr op- 2- yl ) si lyloksy ) ety 11 - azetidin- 2- on- l-yl) oksoacetat 4-nitrobenzyl-2-(4R-r3-aminocarbonylbenzoylthio1-3S-["1R-(dimethyl (2- methyl propyl-2-yl)silyloxy)ethyl 11-azetidin-2-on-l-yl) oxoacetate

En oppløsning av 4-nitrobenzyl-2-(4R-[3-aminokarbonylbenzo-yl tio]-3S-[lR-(dimetyl(2-metylprop-2-yl)silyloksy)etyl]-azetidin-2-on-l-yl)-3-metylpropenoat (182 mg) i tørr diklormetan (30 ml) ble behandlet ved -78° C med ozon (overskudd); oksygen ble deretter boblet gjennom blandingen i 5 minutter, og dimetylsulfid (overskudd) ble tilsatt. Blandingen ble oppvarmet til romtemperatur, og inndampet i vakuum. Den resulterende oljen ble fordelt mellom etylacetat og vann; det organiske laget ble fraseparert, vasket med vann, med saltvannsoppløsning, ble tørket og inndampet i vakuum, slik at man fikk forbindelsen i overskriften (140 mg). A solution of 4-nitrobenzyl-2-(4R-[3-aminocarbonylbenzo-ylthio]-3S-[1R-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-azetidin-2-one-1- yl)-3-methylpropenoate (182 mg) in dry dichloromethane (30 mL) was treated at -78°C with ozone (excess); oxygen was then bubbled through the mixture for 5 minutes, and dimethyl sulfide (excess) was added. The mixture was warmed to room temperature and evaporated in vacuo. The resulting oil was partitioned between ethyl acetate and water; the organic layer was separated, washed with water, with brine, dried and evaporated in vacuo to give the title compound (140 mg).

S (CDCI3) 0,03 (3H, s), 0,06 (3H, s), 0,82 (9H, s), 1,27 S (CDCl 3 ) 0.03 (3H, s), 0.06 (3H, s), 0.82 (9H, s), 1.27

(3H, d, J=6Hz), 3,64 (1H,~t, J=3Hz), 4,40 (1H, m), 5,36 og 5,43 (2H, AB, J=12,9Hz), 6,20 (1H, d, J=3,5Hz), 6,2 (2H, bred), 7,5-7,7 (3H, m), 8,1-8,4 (5H, m). (3H, d, J=6Hz), 3.64 (1H,~t, J=3Hz), 4.40 (1H, m), 5.36 and 5.43 (2H, AB, J=12.9Hz ), 6.20 (1H, d, J=3.5Hz), 6.2 (2H, wide), 7.5-7.7 (3H, m), 8.1-8.4 (5H, m ).

Eksempel 120 Example 120

4- nit r obenzyl- 5R, 3-( 3- aminokarbonylf enyl)- 6S-( IR- fdimetyl( 2-metylprop- 2- yl) silyloksyl- etyl)- 7- okso- 4- tia- l- azabicyklor3.-2, 0] hept- 2- en- 2- karboksylat 4- nitrobenzyl- 5R, 3-( 3-aminocarbonylphenyl)- 6S-( IR- fdimethyl( 2-methylprop- 2- yl) silyloxyl- ethyl)- 7- oxo- 4- thia- l- azabicyclo3.- 2.0] hept-2-ene-2-carboxylate

Til en blanding av 4-nitrobenzyl-2-{4R-[3-aminokarbonylbenzoyltio]-3S-[IR-(dimetyl(2-metylprop-2-yl)silyloksy)etyl]-azet idin-2-on-l-yl )oksoacetat (140 mg) i xylen (15 ml) ved 130°C ble det tilsatt en blanding av trietylfosfitt (0,073 ml) i xylen (5 ml). Blandingen ble oppvarmet i ytterligere en time ved 130°C, og deretter avkjølt og inndampet i vakuum. Kromatografi av resten på silikagel, og eluering med heksan-etylacetatblandinger ga forbindelsen i overskriften (100 mg) med egenskaper identisk med egenskapene beskrevet i eksempel 94. To a mixture of 4-nitrobenzyl-2-{4R-[3-aminocarbonylbenzoylthio]-3S-[IR-(dimethyl(2-methylprop-2-yl)silyloxy)ethyl]-azetidin-2-on-l-yl )oxoacetate (140 mg) in xylene (15 ml) at 130°C was added a mixture of triethyl phosphite (0.073 ml) in xylene (5 ml). The mixture was heated for a further hour at 130°C, then cooled and evaporated in vacuo. Chromatography of the residue on silica gel, and elution with hexane-ethyl acetate mixtures gave the title compound (100 mg) with properties identical to those described in Example 94.

Eksempel 121 Example 121

l-( acetoksyetyl)- 5R, 3-( 3- aminokarbonylfenyl)- 6S-( lR- hydroksyetyl)- 7- okso- 4- tia- l- azabicyklor3. 2, Olhept- 2- en- 2- karboksylat Under en nitrogenatmosfære ble en omrørt blanding av kalium-5R , 3 - ( 3-aminokarbonylf enyl ) -6S- (IR-hydr oksyetyl )-7-okso-4-tia-l-azabicyklo[3,2,0]hept-2-en-2-karboksylat (100 mg), natriumjodid (80 mg) og tørr dimetylformamid (2,5 ml) behandlet ved romtemperatur med en oppløsning av 1-kloretyl-acetat (164 mg) i kloroform (0,26 ml). Etter 18 timer ble blandingen fordelt mellom etylacetat og vann; det organiske laget ble inndampet til tørrhet og kromatografert på silikagel. Eluering med etylacetat-etanolblandinger ga forbindelsen i overskriften (16 mg) som en gul gummi i form av en blanding av diastereoisomerer. 1-(acetoxyethyl)- 5R, 3-( 3- aminocarbonylphenyl)- 6S-( 1R- hydroxyethyl)- 7- oxo- 4- thia- 1- azabicycloro3. 2, Olhept-2-ene-2-carboxylate Under a nitrogen atmosphere, a stirred mixture of potassium-5R,3-(3-aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1 -azabicyclo[3,2,0]hept-2-ene-2-carboxylate (100 mg), sodium iodide (80 mg) and dry dimethylformamide (2.5 ml) treated at room temperature with a solution of 1-chloroethyl acetate ( 164 mg) in chloroform (0.26 mL). After 18 hours, the mixture was partitioned between ethyl acetate and water; the organic layer was evaporated to dryness and chromatographed on silica gel. Elution with ethyl acetate-ethanol mixtures gave the title compound (16 mg) as a yellow gum in the form of a mixture of diastereoisomers.

§ (CDCI3) 1,37 (6H, d, J=6,5Hz), 2,01 (3H, s), 3,82 (1H, § (CDCl3) 1.37 (6H, d, J=6.5Hz), 2.01 (3H, s), 3.82 (1H,

dd, J-l,5 og 6,7Hz), 4,27 (1H, m), 5,73 (1H, d, J=l,5Hz), 5,95 (1H, bred), 6,57 (1H, bred), 6,79 (1H, m), 7,48 (1H,~t, J=7,8Hz), 7,60 (1H, m), 7,91 (1H, m). dd, J-1.5 and 6.7Hz), 4.27 (1H, m), 5.73 (1H, d, J=1.5Hz), 5.95 (1H, wide), 6.57 (1H, wide), 6.79 (1H, m), 7.48 (1H,~t, J=7.8Hz), 7.60 (1H, m), 7.91 (1H, m).

Eksempel 122 Example 122

Acetoksymetyl- 5R . 3-( 3- aminokarbonyl f enyl )- 6S-( lR- hydroksyetyl )- 7- okso- 4- tia- l- azabicyklor3 . 2 , 0~ lhept- 2- en- 2- karboksylat Ved en fremgangsmåte analog fremgangsmåten benyttet i eksempel 121, men ved anvendelse av kalium-5R,3-(3-aminokarbonyl f enyl )-6S-(lR-hydroksyetyl )-7-okso-4-tia-l-azabicyklo[3 , 2 , 0]hept-2-en-2-karboksylat (100 mg), natriumjodid (80 mg), tørr dimetylformamid (2 ml) og klormetylacetat (150 mg), ble forbindelsen i overskriften (25 mg) oppnådd som en gul gummi. Acetoxymethyl- 5R . 3-(3-aminocarbonylphenyl)-6S-(1R-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo3. 2,0~ lhept-2-ene-2-carboxylate In a method analogous to the method used in example 121, but using potassium 5R,3-(3-aminocarbonyl phenyl)-6S-(1R-hydroxyethyl)-7 -oxo-4-thia-1-azabicyclo[3 , 2 , 0]hept-2-ene-2-carboxylate (100 mg), sodium iodide (80 mg), dry dimethylformamide (2 ml) and chloromethyl acetate (150 mg), the title compound (25 mg) was obtained as a yellow gum.

(CD3CN) 1,22 (3H, d, J=6,3Hz), 2,01 (3H, s), 3,85 (1H, (CD3CN) 1.22 (3H, d, J=6.3Hz), 2.01 (3H, s), 3.85 (1H,

dd, J-l,5 og 6Hz), 4,2 (1H, ml, 5,75 (1H, d, J=l,5Hz), 5,72 og 5,80 (2H, AB, J=6Hz), 6,0 og 6,9 (2H, bred s), 7,50 (1H,~t, J=8Hz), 7,60 (1H, m) og 7,92 (1H, m). dd, J-1.5 and 6Hz), 4.2 (1H, ml, 5.75 (1H, d, J=1.5Hz), 5.72 and 5.80 (2H, AB, J=6Hz), 6 ,0 and 6.9 (2H, wide s), 7.50 (1H,~t, J=8Hz), 7.60 (1H, m) and 7.92 (1H, m).

Claims (1)

1. Forbindelse,karakterisert vedformel (II) 1. Compound characterized by formula (II) som er et verdifullt mellomprodukt for fremstiling av penem-antibiotika, hvori substituentene har følende betydninger: R<3>står for hydrogen eller en hydroksybeskyttende gruppe, R<4>står for en karboksybeskyttende gruppe,R^ står for (i) en av de følgende gruppene hvori Ra og Rh, som kan være like eller forskjellige, hver står for en alkylgruppe som inneholder fra 1-4 karbonatomer, eller (ii) en -C0NH(CH2)mQ eller -NHCO(CH2)mQ-gruppe, hvori m står for et helt tall fra 1 til 3, og Q står en av de følgende gruppene which is a valuable intermediate for the preparation of penem antibiotics, in which the substituents have sensitive meanings: R<3>represents hydrogen or a hydroxy protecting group, R<4>represents a carboxy protecting group, R^ represents (i) one of the the following groups in which Ra and Rh, which may be the same or different, each represent an alkyl group containing from 1-4 carbon atoms, or (ii) a -C0NH(CH2)mQ or -NHCO(CH2)mQ group, in which m stands for an integer from 1 to 3, and Q stands for one of the following groups hvori Rc står for en metyl- eller etylgruppe, eller (ili) en -C02Rd-gruppe, hvori Rd står for en metyl- eller etylgruppe som er usubstituert eller substituert med en eller flere substituenter, som kan være like eller forskjellige, valgt fra (a) halogenatomer og vinylgrupper, (b) fenylgrupper som er usubstituerte eller substituerte med en eller flere grupper valgt blant alkoksygrupper som inneholder fra 1-4 karbonatomer, nitrogrupper og halogenatomer, (c) silylgrupper SiReRfRg, hvor gruppene Re, Rf og Rg er like eller forskjellige, og hver står for en fenylgruppe eller en alkylgruppe som inneholder fra 1-4 karbonatomer, og (d) grupper Q som definert ovenfor; eller (iv) en -C02SiReRf Rg-gruppe, hvori Re, Rf og Rg er som definert i (c) ovenfor, eller (v) en -COg-fenylgruppe, hvori fenyldelen er usubsti- tuert eller substituert som definert i (b) ovenfor;R<6>står for (i) et hydrogen, (ii) en gruppe som definert for R<5>(R<5>og R<6>er like eller forskjellige), (iii) et klor-, brom- eller jodatom, en alkylgruppe inneholdende fra 1 til 4 karbonatomer, en -NH2-,-NHRa- eller -NRaRb-gruppe, en -0H- eller -ORa-gruppe, eller en -OCOCH^-gruppe, hvor Ra<p>g Rb er som er like eller forskjellige står hver for (C1-C4)-alkyl; R<7>står for en fenylgruppe eller en ( C^- C^ )-^alkyl, og R<8>står for brom eller klor.wherein Rc represents a methyl or ethyl group, or (iii) a -CO 2 Rd group, wherein Rd represents a methyl or ethyl group which is unsubstituted or substituted with one or more substituents, which may be the same or different, selected from (a) halogen atoms and vinyl groups, (b) phenyl groups which are unsubstituted or substituted with one or more groups selected from alkoxy groups containing from 1- 4 carbon atoms, nitro groups and halogen atoms, (c) silyl groups SiReRfRg, where the groups Re, Rf and Rg are the same or different, and each represents a phenyl group or an alkyl group containing from 1-4 carbon atoms, and (d) groups Q as defined above; or (iv) a -CO2SiReRf Rg group, wherein Re, Rf and Rg are as defined in (c) above, or (v) a -COg-phenyl group, wherein the phenyl moiety is unsubstituted tuated or substituted as defined in (b) above; R<6> represents (i) a hydrogen, (ii) a group as defined for R<5> (R<5> and R<6> are the same or different) , (iii) a chlorine, bromine or iodine atom, an alkyl group containing from 1 to 4 carbon atoms, a -NH2-, -NHRa- or -NRaRb group, an -OH- or -ORa group, or an -OCOCH ^-group, where Ra<p>g Rb are which are the same or different each represents (C1-C4)-alkyl; R<7> stands for a phenyl group or a (C^-C^)-^alkyl, and R<8> stands for bromine or chlorine.